AU2001259560B2 - Opioid antagonist containing composition for enhancing the potency or reducing adverse side effects of opioid agonists - Google Patents

Opioid antagonist containing composition for enhancing the potency or reducing adverse side effects of opioid agonists Download PDF

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AU2001259560B2
AU2001259560B2 AU2001259560A AU2001259560A AU2001259560B2 AU 2001259560 B2 AU2001259560 B2 AU 2001259560B2 AU 2001259560 A AU2001259560 A AU 2001259560A AU 2001259560 A AU2001259560 A AU 2001259560A AU 2001259560 B2 AU2001259560 B2 AU 2001259560B2
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ntx
ms
treatment
placebo
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Remi Barbier
Kathleen Dumas
Mary Remien
Grant Schoenhard
Barry Sherman
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Albert Einstein College of Medicine
Pain Therapeutics Inc
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Albert Einstein College of Medicine
Pain Therapeutics Inc
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Priority to US20222700P priority
Priority to US60/202,227 priority
Priority to PCT/US2000/012493 priority patent/WO2000067739A2/en
Priority to US09/566,071 priority
Priority to US24448200P priority
Priority to US60/244,482 priority
Priority to US60/245,110 priority
Priority to US24511000P priority
Priority to US60/246,235 priority
Priority to US24623500P priority
Priority to US09/756,331 priority
Priority to US75633101A priority
Priority to PCT/US2001/014644 priority patent/WO2001085150A2/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • AHUMAN NECESSITIES
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    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445Non condensed piperidines, e.g. piperocaine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/485Morphinan derivatives, e.g. morphine, codeine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
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    • A61K9/2013Organic compounds, e.g. phospholipids, fats
    • A61K9/2018Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4858Organic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4866Organic macromolecular compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5036Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs

Description

NOVEL COMPOSITIONS AND METHODS FOR ENHANCING POTENCY OR REDUCING ADVERSE SIDE EFFECTS OF OPIOID AGONISTS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the priority of the following U.S. Patent Application Nos.

60/202, 227 filed May 5, 2000 (provisional); 60/202,268 filed May 5, 2000 (provisional); 09/756,331 filed January 8, 2001, which is a continuation of 09/566,071 filed May 2000; 60/244,482 filed October 30, 2000 (provisional); 60/245,110 filed November 1, 2000 (provisional); and 60/246,235 filed November 2, 2000 (provisional); and PCT/US00/12493 [WO 00/67739] filed May 5, 2000. The applications cited above are hereby incorporated herein by reference in their entirety to provide continuity of disclosure.

FIELD OF THE INVENTION Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

The present invention relates to novel compositions and methods, including gender-based compositions and methods, for enhancing potency or reducing adverse side effects of opioid agonists in humans. The present invention also relates to novel compositions and methods with an opioid agonist and an opioid antagonist to differentially dose a human subject, including men and/or women, so as to either enhance analgesic potency without attenuating an adverse side effect of the agonist, or alternatively maintain the analgesic potency of the agonist while attenuating an adverse side effect of the agonist.

BACKGROUND OF THE INVENTION Opioid agonists, including morphine sulfate (hereafter called morphine or MS), have been marketed for many years and are widely used for the relief of moderate to severe acute and chronic pain. The potency of oral morphine is less than that of parenteral morphine, however, the use of the oral product for chronic pain control has increased dramatically in the past decade. An opioid agonist, such as morphine, exerts its primary effects on the central nervous system and organs containing smooth muscle, and acts as an agonist interacting with steriospecific and saturable binding sites or receptors ID -la- Ci in the brain, spinal cord, and other tissues. The principal therapeutic actions are aanalgesia and sedation.

WO 01/85150 PCT/US01/14644 2 Opioid antagonists are generally accepted for use in the treatment of human conditions or ailments for reversing opioid toxicity and overdoses, and in preventing abuse of opioid agonists, such as heroin or morphine. For these uses, the antagonist such as naloxone or naltrexone is used in relatively high concentrations in order to effectively block the activity and/or effects of the opioid agonist by antagonizing the opioid agonist at opioid receptors on nociceptive neurons.

Naloxone (4,5-epoxy-3,14-dihydroxy-17-(2-prophenyl)morphinan-6-one) was the first of these compounds to be synthesized in 1960 and is considered a "pure" antagonist, exhibiting virtually no agonist activity. Naloxone became the preferred regime for the treatment of acute opioid toxicity. Since naloxone exhibits a relatively short duration in the body, it became clear that a longer acting agent having similarly pure antagonist character would be even more advantageous. Naltrexone (17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxy-morphinan-6-one) was developed in 1965 and has greater potency and longer action than its N-allyl cogener, naloxone, and is active when given orally. For example, 50 mg dosage forms of naltrexone, are marketed as ReVia® in the United States or Trexan in other countries. Nalmefene (6-methylene-6-desoxy-N-cyclopropyl-methyl- 14-hydroxydihydroxydihydronormorphine) was also developed as a long acting, orally available, potent opioid antagonist, and has also been characterized as a pure antagonist. These drugs are presently commercially available in certain dosage forms, and are so far as is known, the only opioid antagonists characterized as pure antagonists which have received governmental approval for administration to humans.

Opioid agonists, such as morphine, are commonly used by clinicians in the treatment of moderate to severe acute and chronic pain. The analgesic activity of these agents contributes to their pharmacological effects on a large number of inhibitory opioid receptors on sensory nerve cells that receive and transmit pain signals in the nervous system; the role of these receptors is to inhibit the transmission of pain signals into the brain. The precise mechanisms of opioid agonists such as morphine are not known, although morphine, for example, is believed to act preferentially at mu-opiate receptors on neurons in the central and peripheral nervous system. In addition to pain relief, other actions of opioid agonists such as morphine, in human subjects, include adverse side effects such as inhibition of gastrointestinal motility WO 01/85150 PCT/US01/14644 3 leading to constipation), respiratory depression (especially at high-doses), peripheral vasodilation leading to orthostatic hypotension), dizziness, sedation/drowsiness, nausea, vomiting, headache, pruritus, dry mouth, difficulty in urination, dependence, mood swings, and clouded sensorium.

Opioid antagonists have been widely used in high-doses for the treatment of overdoses of opioid agonists and to prevent abuse of opioid agonists such as heroin or morphine 50 mg naltrexone). For these uses, doses must be relatively high in order to be therapeutically effective block) the analgesic potency and the side effects of the opioid agonist, by antagonizing the agonist at opioid receptors on nociceptive neurons.

Crain and Shen (Brain Research 757: 176-190 (1997)) reported that opioid agonists not only activate inhibitory opioid receptors leading to analgesia but also simultaneously activate a smaller group of excitatory opioid receptors on sensory nerve cells. These effects on the excitatory opioid receptors were proposed to weaken opioid induced analgesia and under certain conditions actually enhance pain.

Surprisingly, Crain and Shen U.S. Patent No. 5,512,578 reissued as RE 36,457) showed that co-administration of remarkably low-doses of an opioid antagonist, such as naloxone or naltrexone on the order of ng/kg, when administered to mice with morphine or similar opioid agonists selectively blocked their effects on excitatory, but not inhibitory, opioid receptors, thus markedly enhancing the analgesic potency of opioid agonists. These surprising results of Crain and Shen have been described in U.S. Patent Nos. 5,472,943; 5,512,578 reissued as RE 36,457; 5,580,876 and 5,767,125, which are directed to methods for selectively enhancing the analgesic potency of a bimodally-acting opioid agonist and simultaneously attenuating antianalgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects associated with the administration of the bimodally-acting opioid agonist.

These methods comprise administering to a subject an analgesic or sub-analgesic amount of a bimodally-acting opioid agonist and an amount of an excitatory opioid receptor antagonist effective to enhance the analgesic potency of the bimodally-acting opioid agonist and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the bimodally-acting opioid agonist.

Also included in these patents are methods for treating pain in a subject comprising WO 01/85150 PCT/US01/14644 4 administering to the subject an analgesic or sub-analgesic amount of a bimodallyacting opioid agonist and an amount of an excitatory opioid receptor antagonist effective to enhance the analgesic potency of the bimodally-acting opioid agonist and simultaneously attenuate anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the bimodally-acting opioid agonist. Also included are methods for treating an opiate addict comprising administering to the opiate addict an amount of an excitatory opioid receptor antagonist either alone or in combination with a bimodally-acting opioid agonist effective to attenuate physical dependence caused by a bimodally-acting opioid agonist and enhance the analgesic potency of a bimodally-acting opioid agonist. Also included are compositions comprising an analgesic or sub-analgesic amount of a bimodally-acting opioid agonist and an amount of an excitatory opioid receptor antagonist effective to enhance the analgesic potency of the bimodally-acting opioid agonist and attenuate the antianalgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the bimodally-acting opioid agonist in a subject administered the composition. In all of these studies, the antagonist simultaneously enhanced potency while attenuating such adverse effects. Two clinical studies on postsurgical hysterectomy patients [Joshi, et al., Anesthesiol. 90: 1007-1011 (1999); Gan et al., Anesthesiol. 87: 1075-1081 (1997)] demonstrated that cotreatment of women with PCA/IV morphine together with a low-dose of the opioid antagonist naloxone (IV) or nalmefene (IV) enhanced potency of morphine in varying cumulative doses of morphine over a 24 hour period. Adverse side effects were attenuated in these studies. Nothing in these studies with women suggested or related to any genderbased effect on either opioid-induced analgesia and/or the adverse effects associated with opioids.

In a recent review of gender differences in pharmacokinetics and pharmacodynamics [Beierle et al., Intl. J. Clin. Pharmacol. Ther. 37 529-547 (1999)], it was pointed out that until 1993, women were excluded from clinical phase I and early phase II trials. Therefore, for most drugs, including analgesics, there is a real paucity of information on sex differences in the pharmacokinetics as well as in the dose-response relationship or adverse effects of these drugs. The U.S. Food and Drug Administration (FDA) recognized this situation and developed new guidelines WO 01/85150 PCT/USD1/14644 for drug research in 1993. Sex-related analgesic responses, including a summary and critique of animal and human studies and discrepancies between such studies were recently reviewed by Levine and his colleagues [Miaskowski et al., Chapter 11, pages 209-230, Editor: Fillingim, IASP Press, Seattle, Sex Gender and Pain (2000)]. In another recent review, Miaskowski and Levine [Pain Forum 34-44 (1999)], summarize data from human studies on sex-related differences in responses to opioid analgesics, particularly kappa opioids.

Certain gender-based pain responses have been reported in both animal and human clinical studies [for reviews, see Fillingham and Maixner, Pain Forum 4: 209- 221 (1995); Unruh, Pain 65: 123-167 (1996) Miaskowski et al. (2000), supra.] Gender-based differences in analgesia and anti-analgesia have recently been shown by Levine and his colleagues in patients with postoperative pain with several kappa opioid agonists, butorphanol [Gear et al., Nature, 2: 1248-1250 (1996)]; pentazocine [Gear et al., Neuroscience Let., 205: 207-209 (1996)]; nalbuphine [Gear et al., Pain 83: 339-345 (1999)]; and nalbuphine in combination with naloxone, an opioid antagonist [Gear et al., J. Pain, 1: 122-127 (2000)], but not with the mu opioid agonist morphine [Gordon et al., Neuroscience 69(2): 345-349 (1995)]. According to Levine and his colleagues, kappa opioid receptor agonists are unique in their genderrelated effects. Studies in rats and mice evaluating the role ofmu opioid agonists and antagonists show gender-based effects, although the results of these studies are contradictory and appear to be dependent upon both species and gender (for reviews, see Kest et al., J. Pharmacol. Exper. Therapeutics, 289: 1370-1375 (1999); and Kest et al., Anesthesiology, 93: 539-547 (2000)).

SUMMARY OF THE INVENTION The present invention relates to novel compositions and methods for enhancing potency or reducing adverse side effects of opioid agonists in humans. The present invention is directed to compositions and methods for the differential dosing of human subjects with opioid agonists and low doses of opioid antagonists to yield either enhancement of analgesic potency of the agonist without attenuation reduction) or increase of one or more of the adverse side effects associated with that dose of agonist in humans, or maintenance of analgesic potency of the agonist with attenuation reduction) of one or more of the adverse side effects associated WO 01/85150 PCT/US01/14644 6 with that dose of agonist in humans. The present invention is based on surprising results from human clinical trials that demonstrate that the analgesic potency of opioid agonists can be dissociated from the opioid-related adverse side effects in humans.

One novel composition and dosing method of the invention utilizes a dose of agonist with a low dose of antagonist that gives more pain relief in men and/or women but with essentially the same adverse side effect(s) of agonist alone. A second novel composition and dosing method of the invention utilizes a dose of agonist with a low dose of antagonist that gives essentially the same pain relief in men and/or women as agonist alone, but with attenuated reduced) adverse side effect(s). The maintained potency with attenuated side effect(s) is accomplished without increasing or decreasing the cumulative daily dose of agonist. Thus, at appropriate differential dosing of humans according to the invention, a low dose of antagonist surprisingly can enhance analgesia with no increase in side effects or suppress side effects with no loss in analgesia.

The present invention is also directed to novel compositions and.methods for gender-based dosing of non-kappa opioid receptor agonists, preferably mu opioid receptor agonists such as morphine sulfate, and/or opioid antagonists such as naltrexone. Such compositions and methods are designed to achieve appropriate and even optimal analgesia, and are useful for treating moderate or severe pain, wherein the pain is either acute or chronic. Appropriate and even optimal analgesia is only possible when pain relief is enhanced, without enhancing and preferably attenuating, adverse side effects of such agonists or antagonists.

The present invention is based in part on additional surprising results from human clinical trials that demonstrate that the analgesic potency and/or the adverse side effects of morphine sulfate, a mu opioid receptor agonist, is gender-specific.

Additionally surprising are gender-specific responses to such agonists, including the discovery of the problem that current methods of treatment with such agonists result in hypo-analgesia in men, including anti-analgesia, while similar treatment of women results in analgesia but with significant adverse side effects. Compositions and methods described herein provide for the first time a solution to problems related to previously undiscovered differences in drug effects, including pain intensity WO 01/85150 PCT/US01/14644 7 differences, pain relief or adverse side effects, using such agonists in women and men, including those effects associated with the management of pain.

The present invention is also directed to novel compositions and methods for gender-based dosing of opioid antagonists, such as naltrexone, to avoid hypoanalgesia. This is based in part on surprising results from human clinical trials that the responses to naltrexone, an opioid antagonist, are also gender-specific.

Additionally surprising are results that indicate that such an antagonist can act as a partial opioid agonist on opioid receptors differentially in women and men.

The present invention is also directed to novel compositions and methods for gender-based dosing of combinations of non-kappa opioid receptor agonists, preferably mu opioid receptor agonists, with opioid antagonists to achieve optimal analgesia. This is based in part on surprising results from human clinical trials that there are gender-based differences in the interactions between such agonists and antagonists.

The present invention provides compositions and methods for administering to a woman, for example, a dose of a non-kappa opioid receptor agonist, preferably a mu opioid receptor agonist, that alone is analgesic in women but hypo-analgesic in men, while attenuating one or more adverse side effects of such agonists in women. The present invention also provides compositions and methods for administering to a man, for example, a dose of a non-kappa opioid receptor agonist, preferably a mu opioid receptor agonist, that alone is hypo-analgesic in men but analgesic in women, without substantially enhancing one or more adverse side effects of such agonists in men.

The present invention is also directed to novel compositions and methods for ethnic-based dosing of combinations of opioid receptor agonists, including non-kappa opioid receptor agonists, and preferably mu opioid receptor agonists, with opioid antagonists to achieve optimal analgesia. This is based in part on surprising results from human clinical trials that there are ethnic-based differences in the interactions between such agonists and antagonists.

The present invention provides compositions and methods for administering to a Hispanic man, for example, a dose of opioid receptor agonist, preferably a nonkappa opioid receptor agonist, most preferably a mu opioid receptor agonist, that alone is analgesic in Hispanic men but hypo-analgesic in non-Hispanic men, while WO 01/85150 PCT/US01/14644 8 attenuating one or more adverse side effects of such agonists in Hispanic men. The present invention also provides compositions and methods for administering to a Black man, for example, a dose of a opioid receptor agonist, preferably a non-kappa opioid receptor agonist, most preferably a mu opioid receptor agonist, that alone is hypo-analgesic in Black men but analgesic in women and/or Hispanic men, without substantially enhancing one or more adverse side effects of such agonists in Black men.

The present invention thus provides compositions and methods for the differential dosing in women and men, for example, with non-kappa opioid receptor agonists, preferably mu opioid receptor agonists, based on co-treatment of such agonists with low doses of opioid receptor antagonists. Specifically provided are compositions and methods of enhancing pain relief or attenuating pain intensity in men comprising administering, for example, to a man a hypo-analgesic dose (including a non-analgesic or anti-analgesic dose) of a mu opioid receptor agonist and a dose of an opioid antagonist that in combination enhances pain relief or attenuates pain intensity. Such compositions and methods convert non-responder human subjects, men) into responders. Also specifically provided are compositions and methods of enhancing pain relief or attenuating pain intensity, for example, in women comprising administering to a woman an analgesic dose of a mu opioid receptor agonist and a dose of opioid antagonist that in combination enhances pain relief or attenuates pain intensity comparable to that of the analgesic dose of agonist alone but with attenuation of one or more adverse side effects of the agonist. Thus, compositions and methods for providing, enhancing or maintaining pain relief, as well as for attenuating pain intensity, are specifically provided as gender-specific compositions and methods for women or men.

The present invention provides compositions and methods for the differential dosing in women and men of non-kappa opioid receptor agonists, preferably mu opioid receptor agonists, based on gender-based differences in their pharmacodynamic effects, including pain relief or adverse side effects, from genderspecific interactions of such agonists in women and men. Compositions and methods are provided for administering a non-kappa opioid receptor agonist, preferably a mu opioid receptor agonist, at a gender-specific compensatory dose based on different IND -9c pharmacodynamic effects in women and men, wherein such a gender-specific Scompensatory dose provides enhancement of analgesia and/or attentuation of an adverse side effect of the agonist.

SThe present invention provides compositions and methods that include a nonkappa opioid receptor agonist, preferably a mu opioid receptor agonist, and an opioid C ntagonist in amounts that are useful for men only, or for women only, or for both men and women, based on the differences described herein.

C1 In a first aspect, the present invention provides a method for enhancing the Spotency of an opioid agonist in a human subject comprising administering to the human subject an analgesic or subanalgesic amount of the agonist and an amount of an opioid antagonist effective to enhance the analgesic potency of the agonist without attenuating an adverse side effect of the agonist.

In a second aspect, the present invention provides a method for attenuating an adverse side effect associated with administration of an opioid agonist to a human subject comprising administering to the human subject an analgesic or subanalgesic amount of the agonist and an amount of an opioid antagonist effective to attenuate the adverse side effect while maintaining analgesic potency of the agonist.

In a third aspect, the present invention provides a method for treating pain in a human subject comprising administering to the human subject an analgesic or subanalgesic amount of the agonist and an amount of an opioid antagonist effective to enhance the analgesic potency of the agonist without attenuating an adverse side effect of the agonist.

In a fourth aspect, the present invention provides a method for treating pain with an opioid agonist and attenuating an adverse side effect of the agonist in a human subject comprising administering to the human subject an analgesic amount of the agonist and an amount of an opioid antagonist effective to attenuate the adverse side effect while maintaining analgesic potent of the agonist.

In a fifth aspect, the present invention provides a method providing or enhancing pain relief in men comprising administering to a man a hypo-analgesic dose of a nonkappa opioid receptor agonist and a dose of an opioid antagonist that in combination provides or enhances pain relief.

In a sixth aspect, the present invention provides a method of enhancing pain relief in women comprising administering to a women an analgesic dose of a non-kappa I- 9a-

O

CI opioid receptor agonist and a dose of opioid antagonist that in combination provides pain relief comparable to that of the agonist alone but with attenuation of one or more adverse side effects of the agonist.

O In a seventh aspect, the present invention provides a method for providing analgesia in a human subject administered a non-analgesic amount of an opioid agonist 0 comprising concurrently administering with the agonist, an amount of opioid antagonist O effective to provide analgesia.

NC In an eighth aspect, the present invention provides a method of converting a 0 hypo-analgesic dose of an opioid agonist into an analgesic dose of the agonist ri 10 comprising administering to a human subject a combination of the hypo-analgesic dose of the agonist and an amount of an opioid antagonist sufficient to provide analgesia.

Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the total pain relief (TOTPAR) results at 4 hours (see also Table 4) in the five study groups in Example 1: placebo; morphine; morphine and low dose (0.01 mg) naltrexone (NTX); morphine and mid dose (0.1 mg) NTX; and morphine and high dose (1.0 mg) NTX.

Figure 2 shows the sum of pain intensity differences (SPID) results at 4 hours (see also Table 5) in the five study groups in Example 1: placebo; morphine; morphine and low dose (0.01 mg) naltrexone (NTX); morphine and mid dose (0.1 mg) NTX; and morphine and high dose (1.0 mg) NTX.

Figure 3 shows the time to onset of meaningful pain relief results (see also Table 6) in the five study groups in Example 1: placebo; morphine; morphine and low dose (0.01 mg) naltrexone (NTX); morphine and mid dose (0.1 mg) NTX; and morphine and high dose (1.0 mg) NTX.

Figures 4 and 5 show the time to remedication (rescue medication) up to 8 and 24 hours, respectively (see also Table 7) in the five study groups in Example 1: placebo; morphine; morphine and low dose (0.01 mg) naltrexone (NTX); morphine and mid dose (0.1 mg) NTX and morphine and high dose (1.0 mg) NTX.

9b Figure 6 shows the pain relief results (see also Table 9) for 4 hours in the five study groups in Example 1: placebo represented as small diamonds morphine represented as squares morphine and low dose (0.01 mg) NTX represented as large circles morphine and mid dose (0.1 mg) NTX represented as triangles and morphine and high dose (1.0 mg) NTX represented as larger diamonds Figure 7 shows the pain intensity difference (PID) results (see also Table 10) for 4 hours in the five study groups in Example 1: placebo; morphine; morphine and WO 01/85150 PCT/US01/14644 low dose (0.01mg) naltrexone (NTX); morphine and mid dose (0.1 mg) NTX; and morphine and high dose (1.0 mg) NTX.

Figure 8 shows a summary of adverse side effects of nausea, vomiting, dizziness, headache, somnolence (sedation) or pruritus in the five study groups in Example 1: placebo; morphine; morphine and low dose (0.01mg) naltrexone (NTX); morphine and mid dose (0.1 mg) NTX; and morphine and high dose (1.0 mg) NTX.

Figures 9B and 9C show the summary of pain intensity difference (SPID) results at 4 hours (SPID-4) (see also Tables 18A and 18B) for women and men, respectively, in the five study groups as described in Example 2: placebo; morphine (60 mg); morphine and low-dose (0.01 mg) naltrexone (NTX); morphine and middose (0.1 mg) NTX; morphine and high-dose (1.0 mg) NTX.

Figures 10A and 10B show the time to onset of meaningful pain relief results (see also Tables 19A and 19B) in the five study groups as described in Example 2: placebo; morphine; morphine and low-dose (0.01 mg) naltrexone (NTX); morphine and mid-dose (0.1 mg) NTX; and morphine and high-dose (1.0 mg) NTX, for women and men, respectively.

Figures 11A and 12A for women, and 11B and 12B for men, show the time to remedication (rescue medication) up to 8 and 24 hours, respectively (see also Tables and 20B) in the five study groups as described in Example 2: placebo; morphine; morphine and low-dose (0.01 mg) naltrexone (NTX); morphine and middose (0.1 mg) NTX; and morphine and high-dose (1.0 mg) NTX, for women and men, respectively.

Figures 13A for women, and 13B for men, show the pain relief results (see also Tables 22A and 22B) in the five study groups as described in Example 2: placebo; morphine; morphine and low-dose (0.01 mg) naltrexone (NTX); morphine and mid-dose (0.1 mg) NTX; and morphine and high-dose (1.0 mg) NTX, for women and men, respectively.

Figures 14A for women and 14B for men show the pain intensity difference (PID) results (see also Tables 23A and 23B) in the five study groups as described in Example 2: placebo; morphine; morphine and low-dose (0.01 mg) naltrexone (NTX); morphine and mid-dose (0.1 mg) NTX; and morphine and high-dose (1.0 mg) NTX, for women and men, respectively.

WO 01/85150 PCT/US01/14644 11 Figures 15A for women (see also Tables 26A and 26B) and 15B for men (see also Tables 26C and 26D) show a summary of adverse side effects of nausea, vomiting, dizziness, headache, somnolence (sedation) or pruritus in the five study groups as described in Example 2: placebo; morphine (60 mg); morphine and lowdose (0.01 mg) naltrexone (NTX); morphine and mid-dose (0.1 mg) NTX; morphine and high-dose (1.0 mg) NTX.

Figure 16 shows the time to onset of meaningful pain relief results (see also Table 32A) for subjects in the six study groups as described in Example 3: placebo; morphine (60 mg); naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) naltrexone; morphine and highdose (0.1 mg) NTX.

Figure 17 shows the time to onset of analgesia results (see also Table 32B) for subjects in the six study groups as described in Example 3: placebo; morphine mg); naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) naltrexone; morphine and high-dose (0.1 mg)

NTX.

Figure 18 shows the time to remedication (rescue medication) up to 8 hours (see also Table 33) for subjects in the six study groups as described in Example 3: placebo; morphine (60 mg); naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) naltrexone; morphine and highdose (0.1 mg) NTX.

Figure 19 shows the time to remedication (rescue medication) up to 8 and 24 hours, (see also Table 33) for subjects in the six study groups as described in Example 3: placebo; morphine (60 mg); naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) naltrexone; morphine and high-dose (0.1 mg) NTX.

Figure 20 shows the pain relief (PR) results (see also Table 35) for subjects in the six study groups as described in Example 3: placebo; morphine (60 mg); naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) naltrexone; morphine and high-dose (0.1 mg)

NTX.

WO 01/85150 PCT/US01/14644 12 Figure 21 shows the pain intensity differences (PID) results (see also Table 36) for subjects in the six study groups as described in Example 3: placebo; morphine mg); naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) naltrexone; morphine and high-dose (0.1 mg)

NTX.

Figure 22 shows the summary of adverse side effects (see also Tables 39A and 39B) of nausea, vomiting, dizziness, headache, somnolence (sedation) or pruritus for subjects in the six study groups as described in Example 3: placebo; morphine mg); naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) naltrexone; morphine and high-dose (0.1 mg)

NTX.

Figures 23A, 23B and 23C show the summary of pain intensity difference (SPID) results at 4 hours (SPID-4) (see also Tables 44A and 44B) for the total study population, followed by women and men, respectively, in the six study groups as described in Example 4: placebo; morphine (60 mg); naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) NTX; morphine and high-dose (0.1 mg) NTX.

Figures 24A and 24B show the time to onset of meaningful pain relief results (see also Tables 45A and 45B) in the six study groups as described in Example 4: placebo; morphine (60 mg); naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) NTX; morphine and high-dose (0.1 mg) NTX for men and women respectively.

Figures 25A and 26A for women, and 25B and 26B for men, show the time to remedication (rescue medication) up to 8 and 24 hours, respectively (see also Tables 46A and 46B) in the six study groups as described in Example 4: placebo; morphine; naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) NTX; and morphine and high-dose (0.1 mg) NTX, for women and men, respectively.

Figures 27A for women, and 27B for men, show the pain relief results (see also Tables 48A and 48B) in the six study groups as described in Example 4: placebo; morphine; naltrexone (0.01 mg); morphine and low-dose (0.001 mg) WO 01/85150 PCT/US01/14644 13 naltrexone (NTX); morphine and mid-dose (0.01 mg) NTX; and morphine and highdose (0.1 mg) NTX, for women and men, respectively.

Figures 28A for women and 28B for men show the pain intensity difference (PID) results (see also Tables 49A and 49B) in the six study groups as described in Example 4: placebo; morphine (60 mg); naltrexone (0.01 mg); morphine and lowdose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) NTX; and morphine and high-dose (0.1 mg) NTX, for women and men, respectively.

Figures 29A for women (see also Tables 52A and 52B) and 29B for men (see also Tables 52C and 52D) show a summary of adverse side effects of nausea, vomiting, dizziness, headache, somnolence (sedation) or pruritus in the six study groups described in Example 4: placebo; morphine (60 mg); naltrexone (0.01 mg); morphine and low-dose (0.001 mg) naltrexone (NTX); morphine and mid-dose (0.01 mg) NTX; morphine and high-dose (0.1 mg) NTX.

Figure 30 shows the total pain relief (TOTPAR) results (see also Table 56) for subjects in the six study groups as described in Example 5: placebo HC/APAP HC/APAP and 1.0 mg naltrexone (NTX) HC/APAP and 0.1 mg NTX HC/APAP and 0.01 mg NTX HC/APAP and 0.001 mg NTX Figure 31 shows the summary of pain intensity difference (SPID) results at 4 hours (SPID-4), at 6 hours (SPID-6), and at 8 hours (SPID-8) (see also Table 57) for subjects in the six study groups as described in Example 5: placebo HCIAPAP HC/APAP and 1.0 mg naltrexone (NTX) HC/APAP and 0.1 mg NTX HC/APAP and 0.01 mg NTX HC/APAP and 0.001 mg NTX Figure 32 shows the time to onset of meaningful pain relief results (see also Table 58A) for subjects in the six study groups as described in Example 5: placebo HC/APAP HC/APAP and 1.0 mg naltrexone (NTX) HC/APAP and 0.1 mg NTX HC/APAP and 0.01 mg NTX HC/APAP and 0.001 mg NTX Figure 33 shows the time to onset to analgesia results (see also Table 58B) for subjects in the six study groups as described in Example 5: placebo HC/APAP HC/APAP and 1.0 mg naltrexone (NTX) HC/APAP and 0.1 mg NTX HC/APAP and 0.01 mg NTX HC/APAP and 0.001 mg NTX Figure 34 shows the time to remedication (rescue medication) up to 8 hours (see also Table 59) for subjects in the six study groups as described in Example WO 01/85150 PCT/US01/14644 14 placebo HC/APAP HC/APAP and 1.0 mg naltrexone (NTX) HC/APAP and 0.1 mg NTX HC/APAP and 0.01 mg NTX HC/APAP and 0.001 mg NTX Figure 35 shows the pain relief (PR) results (see also Table 61) for subjects in the six study groups as described in Example 5: placebo HC/APAP HC/APAP and 1.0 mg naltrexone (NTX) HC/APAP and 0.1 mg NTX HC/APAP and 0.01 mg NTX HC/APAP and 0.001 mg NTX Figure 36 shows the pain intensity differences (PID) results (see also Table 62) for subjects in the six study groups as described in Example 5: placebo HC/APAP HC/APAP and 1.0 mg naltrexone (NTX) HC/APAP and 0.1 mg NTX HC/APAP and 0.01 mg NTX HC/APAP and 0.001 mg NTX Figure 37 shows the summary of adverse side effects (see also Table 65) of nausea, vomiting, dizziness, headache, somnolence (sedation) or pruritus for subjects in the six study groups as described in Example 5: placebo; HC/APAP; HC/APAP and 1.0 mg naltrexone (NTX); HC/APAP and 0.1 mg NTX; HC/APAP and 0.01 mg NTX; HC/APAP and 0.001 mg NTX.

Figures 38B and 38C show the summary of pain intensity difference (SPID) results at 4 hours (SPID-4) (see also Tables 69A and 69B) for women and men, respectively, in the six study groups as described in Example 6: placebo; HC (5 mg)/ APAP (500 mg); HC/APAP and 0.001 mg naltrexone (NTX); HC/APAP and 0.01 mg NTX; HC/APAP and 0.1 mg NTX; HC/APAP and 1.0 mg NTX.

Figures 39A and 39B show the time to remedication (rescue medication) up to 8 hours, for women and men, respectively (see also Tables 72A and 72B) in the six study groups as described in Example 6: placebo HC/APAP HC/APAP and 1.0 mg naltrexone (NTX) HC/APAP and 0.1 mg NTX HC/APAP and 0.01 mg NTX HC/APAP and 0.001 mg NTX (F) Figures 40A for women and 40B for men show a summary of adverse side effects (see also Tables 77A and 77B) of nausea, vomiting, dizziness, headache, somnolence (sedation) or pruritus in the six study groups described in Example 6: placebo; HC (5 mg)/ APAP (500 mg); HC/APAP and 0.001 mg naltrexone (NTX); HC/APAP and 0.01 mg NTX; HC/APAP and 0.1 mg NTX; HC/APAP and 1.0 mg

NTX.

WO 01/85150 PCT/US01/14644 Figure 41 shows the total pain relief (TOTPAR) results (see also Table 81) for subjects in the seven study groups as described in Example 7: placebo; morphine mg); morphine (30 mg) and NTX (0.1 mg); morphine (60 mg); morphine (60 mg) and NTX (0.1 mg); morphine (90 mg); morphine (90 mg) and NTX (0.1 mg).

Figure 42 shows the summary of pain intensity difference (SPID) results at 4 hours (SPID-4) (see also Table 82) for subjects in the seven study groups as described in Example 7: placebo; morphine (30 mg); morphine (30 mg) and NTX (0.1 mg); morphine (60 mg); morphine (60 mg) and NTX (0.1 mg); morphine (90 mg); morphine (90 mg) and NTX (0.1 mg).

Figure 43 shows the probability to onset of analgesia (see also Table 43) for subjects in the seven study groups as described in Example 7: placebo; morphine mg); morphine (30 mg) and NTX (0.1 mg); morphine (60 mg); morphine (60 mg) and NTX (0.1 mg); morphine (90 mg); morphine (90 mg) and NTX (0.1 mg).

Figure 44 shows the probability to remedication (rescue medication) over time up to 24 hours (see also Table 84) for subjects in the seven study groups as described in Example 7: placebo; morphine (30 mg); morphine (30 mg) and NTX (0.1 mg); morphine (60 mg); morphine (60 mg) and NTX (0.1 mg); morphine (90 mg); morphine (90 mg) and NTX (0.1 mg).

Figure 45 shows the pain relief (PR) results (see also Table 86) for subjects in the seven study groups as described in Example 7: placebo; morphine (30 mg); morphine (30 mg) and NTX (0.1 mg); morphine (60 mg); morphine (60 mg) and NTX (0.1 mg); morphine (90 mg); morphine (90 mg) and NTX (0.1 mg).

Figure 46 shows the pain intensity differences (PID) results (see also Table 87) for subjects in the seven study groups as described in Example 7: placebo; morphine (30 mg); morphine (30 mg) and NTX (0.1 mg); morphine (60 mg); morphine (60 mg) and NTX (0.1 mg); morphine (90 mg); morphine (90 mg) and NTX (0.1 mg).

Figure 47 shows the global evaluations of pain relief (see also Table 89) for subjects in the seven study groups as described in Example 7: placebo; morphine mg); morphine (30 mg) and NTX (0.1 mg); morphine (60 mg); morphine (60 mg) and NTX (0.1 mg); morphine (90 mg); morphine (90 mg) and NTX (0.1 mg).

WO 01/85150 PCT/US01/14644 16 Figure 48 shows the summary of adverse side effects (see also Table 90) of nausea, vomiting, dizziness, headache, somnolence (sedation) or pruritus for subjects in the seven study groups as described in Example 7: placebo; morphine (30 mg); morphine (30 mg) and NTX (0.1 mg); morphine (60 mg); morphine (60 mg) and NTX (0.1 mg); morphine (90 mg); morphine (90 mg) and NTX (0.1 mg).

Figure 49 shows the day-one mean pain intensity difference (PID) results (see also Table 91) for the three intrathecal morphine study groups as described in Example 8: placebo, NTX (0.001 mg), and NTX (0.01 mg).

Figure 50 shows the mean pain intensity difference (PID) results (see also Table 92) for days two through seven results for the three intrathecal morphine study groups as described in Example 8: placebo, NTX (0.001 mg), and NTX (0.01 mg).

Figure 51 shows the day-one pain intensity difference (PID) results morphine study groups as described in Example 8: Tables 93A and 93B for days two through eight results for the three intrathecal placebo, NTX (0.001 mg), and NTX (0.01 mg).

Figures 52A and 52B show the mean hourly pain intensity difference (PID) results for women and men, respectively, in the five study groups as described in Example 9: placebo tramadol and placebo tramadol and 1.0 mg naltrexone (NTX) tramadol and 0.1 mg NTX tramadol and 0.01 mg NTX DETAILED DESCRIPTION The present invention is directed to novel compositions and methods with opioid agonists and opioid antagonists. Novel combinations of such agonists and antagonists were unexpectedly efficacious in enhancing the analgesic potency of the agonist without attenuating reducing, blocking, inhibiting or preventing) the side effects of the agonist in humans, or maintaining the analgesic potency of the agonist while attenuating reducing, blocking, inhibiting or preventing) side effects of the agonist in humans.

The present invention is based on surprising results from clinical trials that the analgesic potency effects of opioid agonists can be dissociated from their adverse effects in humans. Thus, for the first time, the present invention provides compositions and methods to differentially dose or treat humans with opioid agonists and opioid antagonists to specifically either enhance increase) analgesic WO 01/85150 PCT/US01/14644 17 potency of the opioid agonists without substantially reducing or increasing maintain) the adverse side effects in humans associated with that dose of agonist; or maintain the analgesic potency neither substantially increase or decrease potency) of the opioid agonists while attenuating reducing, blocking, inhibiting or preventing) the adverse side effects in humans associated with that dose of agonist.

For compositions and methods of the invention that enhance analgesic potency of the opioid agonist, it is advantageous that adverse side effects are maintained or not increased with that enhanced increased) potency. For compositions and methods of the invention that attenuate reduce, block or prevent) the adverse side effects of the opioid agonist, it is advantageous that the analgesic potency is maintained without increasing or decreasing the cumulative daily dose of agonist.

The present invention is also directed to novel compositions of and methods using non-kappa opioid receptor agonists, preferably mu opioid receptor agonists, and opioid antagonists for gender-based dosing of the agonist and/or the antagonist in men and women. Such novel combinations of such agonists and antagonists are unexpectedly efficacious in enhancing increasing) the analgesic potency of the agonists without enhancing the side effects of the agonists in men, and in maintaining the analgesic potency of the agonist while attenuating reducing, blocking, inhibiting or preventing) the adverse side effects of the agonist in women.

The present invention is based on several surprising results from human clinical trials, including that the analgesic potency and/or the adverse side effects of morphine sulfate, a non-kappa (mu) opioid receptor agonist is gender-specific; (ii) the effects of naltrexone, an opioid antagonist, are gender-specific, and it appears to act as a partial opioid agonist on opioid receptors in women and men, but its partial agonist effects are gender-specific; and (iii) interactions between such a non-kappa (mu) opioid receptor agonist and an opioid antagonist are gender-specific.

Additionally surprising from these clinical trials is that the analgesic activity, including analgesic potency, of such non-kappa (mu) opioid receptor agonists can be dissociated from their adverse effects in humans based upon gender. Thus, for the first time, the present invention provides compositions and methods for the differential dosing of non-kappa opioid receptor agonists, perferably mu opioid receptor agonists, and/or opioid antagonists in men and women. Compositions and WO 01/85150 PCT/US01/14644 18 methods according to the invention include those that yield, for example, either (1) analgesia in men using a hypo-analgesic dose (including a non-analgesic or antianalgesic dose) of a non-kappa opioid receptor agonist, preferably a mu opioid receptor agonist, and a dose of opioid receptor antagonist that in combination provides or enhances analgesia, thus converting non-responder human subjects (e.g.

men) into responder, or analgesia in women using an analgesic dose of a nonkappa opioid receptor agonist, preferably a mu opioid receptor agonist, and a dose of opioid receptor antagonist that in combination maintains the analgesia comparable to that of the against alone, but with attenuation in number and/or severity) of one or more of the adverse side effects associated with such an agonist.

For compositions and methods of the invention that provide or enhance increase) pain relief or attenuate decrease) pain intensity with a non-kappa opioid receptor agonist, preferably a mu opioid receptor agonist, for example, in men, it is advantageous that the adverse side effects associated with the agonist are not enhanced with the provided or enhanced pain relief or attenuated pain intensity. For compositions and methods of the invention that enhance pain relief or attenuate pain intensity of a non-kappa opioid receptor agonist, preferably a mu opioid receptor agonist, for example, in women, it is advantageous that the adverse side effects are attenuated. For compositions and methods of the invention that attenuate the adverse side effects in number and/or severity) of such agonists, it is advantageous that the analgesic potency be maintained while decreasing the cumulative 24 hour dose of such agonists, thus maintaining responder human subjects women) as responders but with attenuation of one or more adverse side effects.

Compositions and methods according to the invention include those with a non-kappa opioid receptor agonist, preferably a mu opioid receptor agonist, and opioid antagonist in amounts that are useful for men only, useful for women only, or useful for both men and women, taking into account the gender-based differences described and claimed herein. Such compositions and methods are useful to provide or enhance pain relief, attenuate pain intensity, or attenuate one or more of the adverse side effects of the agonist.

WO 01/85150 PCT/US01/14644 19 It will be appreciated that compositions and methods of the invention useful for human subjects patients) will be primarily of use in the alleviation or attenuation of established symptoms but prophylaxis is not excluded.

The term "opioid" refers to compounds or compositions including metabolites of such compounds or compositions which bind to specific opioid receptors and have agonist (activation) or antagonist (inactivation) effects at these receptors, such as opioid alkaloids, including the agonist morphine and its metabolite morphine-6glucuronide and the antagonist naltrexone and its metabolite and opioid peptides, including enkephalins, dynorphins and endorphins. The opioid can be present as a member selected from an opioid base and an opioid pharmaceutically acceptable salt.

The pharmaceutically acceptable salt embraces an inorganic or an organic salt.

Representative salts include hydrobromide, hydrochloride, mucate, succinate, n-oxide, sulfate, malonate, acetate, phosphate dibasic, phosphate monobasic, acetate trihydrate, bi(heplafluorobutyrate), maleate, bi(methylcarbamate), bi(pentafluoropropionate), mesylate, bi(pyridine-3-carboxylate), bi(trifluoroacetate), bitartrate, chlorhydrate, fumarate and sulfate pentahydrate. The term "opiate" refers to drugs derived from opium or related analogs.

An "opioid receptor agonist" or "opioid agonist" is an opioid compound or composition including any active metabolite of such compound or composition that binds to and activates opioid receptors, for example, on nociceptive neurons which mediate pain. Such agonists have analgesic activity (with measurable onset, peak, duration and/or total effect) and can produce analgesia. Opioid agonists include: alfentanil, allylprodine, alphaprodine, anileridine, apomorphine, apocodeine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, cyclorphen, cyprenorphine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxyaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydroxymethylmorphinan, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, methylmorphine, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, WO 01/85150 PCT/US01/14644 normethadone, nalorphine, normorphine, norpipanone, ohmefentanyl, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, pholcodine, piminodine, piritramide, propheptazine, promedol, profadol, properidine, propiram, propoxyphene, remifentanil, sufentanil, tramadol, tilidine, salts thereof, mixtures of any of the foregoing, mixed muagonists/antagonists, mu-antagonist combinations, or the like. Preferred opioid agonists for human use are morphine, hydrocodone, oxycodone, codeine, fentanyl (and its relatives), hydromorphone, meperidine, methadone, oxymorphone, propoxyphene or tramadol, or mixtures thereof. Particularly preferred opioid agonists include morphine, hydrocodone, oxycodone or tramadol. Opioid agonists include exogenous or endogenous opioids.

"Bimodally-acting opioid agonists" are opioid agonists that bind to and activate both inhibitory and excitatory opioid receptors on nociceptive neurons which mediate pain. Activation of inhibitory receptors by said agonists causes analgesia.

Activation of excitatory receptors by said agonists results in anti-analgesia, hyperexcitability, hyperalgesia, as well as development of physical dependence, tolerance and other undesirable side effects. Bimodally-acting opioid agonists may be identified by measuring the opioid's effect on the action potential duration (APD) of dorsal root ganglion (DRG) neurons in tissue cultures. In this regard, bimodallyacting opioid agonists are compounds which elicit prolongation of the APD of DRG neurons at pM-nM concentrations excitatory effects), and shortening of the APD of DRG neurons at gM concentrations inhibitory effects).

A "non-kappa opioid receptor agonist" or "morphine-like opioid receptor agonist" is an opioid agonist that primarily binds to and/or interacts with opioid receptors that are not kappa receptors and does not produce its therapeutic effects primarily via kappa opioid receptors. Such agonists include mu, delta and sigma opioid receptor agonists and specifically exclude kappa opioid receptor agonists.

Such agonists exclude, for example, agonists that primarily bind to and interact with kappa opioid receptors, and from such interactions produce their therapeutic effects analgesic activity), such as pentazocine, nalbuphine and butorphanol. Such agonists include, for example, morphine, hydrocodone, oxycodone, codeine, hydromorphone, levorphanol, meperidine, fentanyl, (and its relatives), oxymorphone, WO 01/85150 PCT/US01/14644 21 propoxyphene, methadone or tramadol. A preferred non-kappa opioid agonist is a mu opioid receptor agonist. According to the invention, such agonists include an agonist that exhibits non-kappa gender-based effects in men and women as described and claimed herein.

A "mu opioid receptor agonist" is an opioid agonist that primarily binds to and/or interacts with mu opioid receptors and from such interactions produces its therapeutic effects analgesic activity), such as morphine, hydrocodone, and oxycodone, but excluding agonists that primarily bind to and interact with kappa opioid receptors, and from such interactions produce their therapeutic effects analgesic activity), such as pentazocine, nalbuphine and butorphanol.

A "delta opioid receptor agonist" is an opioid agonist that primarily binds to and/or interacts with delta opioid receptors and from such interactions produces its therapeutic effects analgesic activity), but excluding agonists that primarily bind to and interact with kappa opioid receptors, and from such interactions produce their therapeutic effects analgesic activity), such as pentazocine, nalbuphine and butorphanol. Selective delta opioid receptor agonists include those described by U.S.

Patent Nos. 5,389,645 and 5,985,880 hereby incorporated by reference in its entirety a cyclic enkephalin analog [D-Pen 2 D-Pen 5 ]-(enkephalin) and, heptapeptides of frog skin origin [deltorphin I and II] (see also U.S. Patent No. 4,518,711 hereby incorporated by reference in its entirety)].

A "mu-delta opioid receptor agonist" is an opioid agonist that primarily binds to and/or interacts with mu and delta opioid receptors and from such interactions produces its therapeutic effects analgesic activity), but excluding agonists that primarily bind to and interact with kappa opioid receptors, and from such interactions produce their therapeutic effects analgesic activity), such as pentazocine, nalbuphine and butorphenal. Selective mu-delta opioid receptor agonists include those described by U.S. Patent No. 5,389,645 hereby incorporated by reference in its entirety tyrosyldiamine amide opioid agonists such as U.S. Patent No. 6,054,557 hereby incorporated by reference in its entirety; U.S. Patent No. 5,872,097 hereby incorporated by reference in its entirety; U.S. Patent Nos. 6,568,908, 5,681,830, 5,658,908 and 5,854,249, each and all incorporated by reference in their entirety diarylmethylpiperazines and piperdines such as R) a 5R) 4 allyl WO 01/85150 PCT/US01/14644 22 2, 5, dimethyl 1 piperazinyl) -3-hydroxybenzyl) N, N-diethylbenzamine]; and the synthetic pentapeptide known as DADLE (see, U.S. Patent No. 5,985,600 hereby incorporated by reference in its entirety).

A "kappa opioid receptor agonist" is an opioid agonist that primarily binds to and/or interacts with kappa opioid receptors and from such interactions produces its therapeutic effects analgesic activity), including, for example, pentazocine, nalbuphine and butorphenol. Selective kappa opioid agonists include those described by: U.S. Patent No. 4,923,863 hereby incorporated by reference in its entirety morpholine derivatives]; U.S. Patent No. 6,110,947 hereby incorporated by reference in its entirety pyrrolidinyl hydroxamic acid compounds]; U.S. Patent No.

5,965,701 hereby incorporated by reference in its entirety kappa receptor opioid peptides with affinity for the kappa opioid receptor at least 1,000 times greater than its affinity for the mu opioid receptor].

A "sigma opioid receptor agonist" is an opioid agonist that primarily binds to and/or interacts with sigma opioid receptors and from such interactions produces its therapeutic effects analgesic activity), but excluding agonists that primarily bind to and interact with kappa opioid receptors, and from such interactions produce their therapeutic effects analgesic activity), such as pentazocine, nalbuphine and butorphanol. Selective sigma opioid agonists include those described by: U.S. Patent Nos. 5,656,633 and 5,556,857, both incorporated by reference carbostyril derivatives).

An "opioid antagonist" is an opioid compound or composition including any active metabolite of such compound or composition that in a sufficient amount attenuates blocks, inhibits, or competes with) the action of an opioid agonist.

An "effective antagonistic" amount is one which effectively attenuates the analgesic activity of an opioid agonist. An opioid antagonist binds to and blocks inhibits) opioid receptors, for example, on nociceptive neurons which mediate pain. Opioid antagonists according to the present invention include: naltrexone, naloxone nalmefene, naloxone methiodide, nalorphine, naloxonazine, nalide, nalmexone, nalbuphine, nalorphine dinicotinate, naltrindole (NTI), naltrindole isothiocyanate, (NTII), naltriben (NTB), nor-binaltorphimine (nor-BNI), b-funaltrexamine (b-FNA), BNTX, cyprodime, ICI-174,864, LY117413, MVR2266, or an opioid antagonist having WO 01/85150 PCT/US01/14644 23 the same pentacyclic nucleus as nalmefene, naltrexone, nalorphine, nalbuphine, thebaine, levallorphan, oxymorphone, butorphanol, buprenorphine, levorphanol, meptazinol, pentazocine, dezocine, or their pharmacologically effective esters or salts.

An opioid antagonist with partial agonist activity is cholera toxin B. Preferred opioid antagonists include naltrexone, nalmefene, naloxone, or mixtures thereof. Particularly preferred antagonists include naltrexone and nalmefene. Naltrexone as a most preferred opioid antagonist.

"Excitatory opioid receptor antagonists" are opioids which bind to and act as antagonists to excitatory but not inhibitory opioid receptors on nociceptive neurons which mediate pain. That is, excitatory opioid receptor antagonists are compounds which bind to excitatory opioid receptors and selectively block excitatory opioid receptor functions of nociceptive types of DRG neurons at 1,000 to 10,000-fold lower concentrations than are required to block inhibitory opioid receptor functions in these neurons. Excitatory opioid receptor antagonists may also be identified by measuring their effect on the action potential duration (APD) of dorsal root ganglion (DRG) neurons in tissue cultures. In this regard, excitatory opioid receptor antagonists are compounds which selectively block prolongation of the APD of DRG neurons excitatory effects) but not the shortening of the APD of DRG neurons inhibitory effects) elicited by a bimodally-acting opioid receptor agonist. Preferred excitatory opioid receptor antagonists are naltrexone and nalmefene because of their longer duration of action as compared to naloxone and their greater bioavailability after oral administration.

Other compounds and compositions of opioid agonists, including non-kappa opioid receptor agonists, preferably mu opioid receptor agonists, and opioid antagonists are known and will be readily apparent to those skilled in the art, once armed with the present disclosure.

The opioid agonists or opioid antagonists may be provided in the form of free bases or pharmaceutically acceptable acid addition salts. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the therapeutic compound is modified by making acid or base salts thereof.

The pharmaceutically acceptable salt embraces an inorganic or an organic salt.

WO 01/85150 PCT/US01/14644 24 Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the opioid antagonist or opioid agonist. The pharmaceutically acceptable salts include the conventional non-toxic salts made, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfonic, sulfamic, phosphoric, nitric and others known to those skilled in the art; and the salts prepared from organic acids such as amino acids, acetic, propionic, succinic, glycolic, stearic, lactic, malic, malonic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, glucuronic, and other acids. Other pharmaceutically acceptable salts and variants include mucates, phosphate (dibasic), phosphate (monobasic), acetate trihydrate, bi(heptaflourobutyrate), bi(methylcarbaniate), bi(pentaflouropropionate), mesylate, bi(pyridine-3-carboxylate), bi(triflouroacetate), bitartrate, chlorhydrate, and sulfate pentahydrate. An oxide, though not usually referred to by chemists as a salt, is also a "pharmaceutically acceptable salt" for the present purpose. For acidic compounds, the salt may include an amine-based (primary, secondary, tertiary or quaternary amine) counter ion, an alkali metal cation, or a metal cation. Lists of suitable salts are found in texts such as Remington's Pharmaceutical Sciences, 18 t h Ed. (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, PA, 1990); Remington: the Science and Practice ofPharmacy 19 th Ed. (Lippincott, Williams Wilkins, 1995); Handbook ofPharmaceutical Excipients, 3 rd Ed. (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc., 1999); the Pharmaceutical Codex: Principles and Practice of Pharmaceutics 12 th Ed. (Walter Lund ed.; Pharmaceutical Press, London, 1994); The United States Pharmacopeia: The National Formulary (United States Pharmacopeial Convention); and Goodman and Gilman's: the Pharmacological Basis of Therapeutics (Louis S. Goodman and Lee E. Limbird, eds.; McGraw Hill, 1992), the disclosures of which are hereby incorporated by reference.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human WO 01/85150 PCT/US01/14644 beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ration.

An "adverse side effect" of an opioid agonist is a side effect in humans, typically associated with opioid analgesics such as morphine, including nausea, vomiting, dizziness, somnolence/sedation, pruritus, reduced gastrointestinal mortality including constipation, difficulty in urination, peripheral vasodilation including leading to orthostatic hypotension, headache, dry mouth, sweating, asthenia, dependence, mood changes dysphoria, euphoria), or lightheadedness. An "adverse side effect" also includes a serious adverse side effect such as respiratory depression or also apnea, respiratory arrest, circulatory depression, hypotension or shock.

As demonstrated herein, opioid agonists may produce certain adverse side effects. Among the side effects that have been recognized for products containing morphine or other opioid agonists are: respiratory depression; depression of the cough reflex; miosis; reduced gastrointestinal motility including constipation; peripheral vasodilation which may result in orthostatic hypotension; and release of histamine.

Adverse side effects that are of particular interest in human subjects include nausea, vomiting, dizziness, headache, somnolence (sedation), and pruritus. Some additional adverse side effects are listed in the Physician Desk Reference (PDR) for selected opioid agonists as follows: morphine: respiratory depression; apnea; circulatory depression; shock respiratory arrest, and cardiac arrest; oxycodone: light-headedness, euphoria, dysphoria, constipation, skin rash; hydrocodone: mental clouding, lethargy, impairment of mental and physical performance, anxiety, fear, dysphoria, dependence, mood changes; constipation; ureteral spasm; spasm of vesical sphincter and urinary retention; and tramadol: seizures; anaphylactoid reactions (lessened resistance to toxins); asthenia; sweating; dyspepsia; dry mouth; diarrhea; CNS stimulation ("CNS stimulation" is a composite that can include nervousness, anxiety, agitation, tremor, spasticity, euphoria, emotional liability and hallucinations); malaise; vasodilation; anxiety, confusion, coordination disturbance, euphoria, nervousness, sleep disorder; abdominal pain, anorexia, flatulence, hypertonia, rash, visual disturbance, menopausal symptoms, urinary frequency, urinary retention.

WO 01/85150 PCT/US01/14644 26 "Co-administer," "co-administration," "concurrent administration" or "cotreatment" refers to administration of an opioid agonist and an opioid antagonist, in conjunction or combination, together, or before or after each other. The opioid agonist and the opioid antagonist may be administered by different routes. For example, the agonist may be administered orally and the antagonist intravenously, or vice versa. The opioid agonist and opioid antagonist are preferably both administered orally, as immediate or sustained release formulations. The opioid agonist and opioid antagonist may be administered simultaneously or sequentially, as long as they are given in a manner to allow both agents to achieve effective concentrations to yield their desirable therapeutic effects analgesia). Optionally, an additional active pharmaceutical ingredient may be co-administered with the opioid agonist and opioid antagonist. For example, other active pharmaceutical ingredients include acetaminophen as shown herein, steroidal drugs or non-steroidal anti-inflammatory drugs (NSAIDS) such as ibuprofen, COX-1 and/or COX-2 inhibitors such as aspirin, rofecoxib (marketed as VIOXX®), and celcoxib (marketed as CELEBREXM).

"Combination" refers to more than one active compound or active pharmaceutical ingredient (API), including for example, a combination of opioid agonist and opioid antagonist.

"Therapeutic effect" or "therapeutically effective" refers to an effect or effectiveness that is desirable and that is an intended effect associated with the administration of an opioid agonist including the opioid agonist in combination with an opioid antagonist according to the invention, including, for example, analgesia, pain relief, decrease in pain intensity, euphoria or feeling good or calming so as to reduce heart rate, blood pressure or breathing rate.

The opioid agonists preferably and the opioid antagonists for use in the present invention may be in the form of free bases or pharmaceutically acceptable acid addition salts thereof.

The opioid antagonist alone, or in combination with the opioid agonist, may be administered to the human subject by known procedures including but not limited to oral, sublingual, transmucosal (including buccal), intramuscular, subcutaneous, intravenous, intratracheal, or transdermal modes of administration. When a combination of these compounds are administered, they may be administered together WO 01/85150 PCT/US01/14644 27 in the same composition, or may be administered in separate compositions. If the opioid agonist and the opioid antagonist are administered in separate compositions, they may be administered by similar or different modes of administration, or may be administered simultaneously with one another, or shortly before or after the other.

The opioid agonists and the opioid antagonists may be formulated in compositions with a pharmaceutically acceptable carrier. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Examples of suitable pharmaceutical carriers include lactose, sucrose, starch, talc, magnesium stearate, crystalline cellulose, methyl cellulose, carboxymethyl cellulose, glycerin, sodium alginate, gum arabic, powders, saline, water, among others. The formulations may conveniently be presented in unit dosage and may be prepared by methods wellknown in the pharmaceutical art, by bringing the active compound into association with a carrier or diluent, as a suspension or solution, or optionally with one or more accessory ingredients, buffers, flavoring agents, surface active agents, or the like.

The choice of carrier will depend upon the route of administration. "Unit dose form" or "unit dosage form" refers to physically discreet units suitable as unitary doses for human subjects, each unit containing a predetermined quantity of active material non-kappa opioid receptor agonist and/or opioid antagonist and/or other active pharmaceutical ingredient) calculated to produce the desired therapeutic effect analgesia), in association with a suitable pharmaceutical carrier. Thus, the active ingredients according to the invention agonist, antagonist, or other active pharmaceutical ingredient) either each alone or in combination may conveniently be presented to the subject for administration in unit dose form.

For oral or sublingual administration, including transmucosal, the formulation may be presented as capsules, tablets, caplets, pills, powders, granules or a suspension, prepared by conventional means with pharmaceutically acceptable excipients, with conventional additives or fillers such as lactose, mannitol, corn starch or potato starch; with binders or binding agents such as crystalline cellulose, cellulose derivatives, acacia, corn starch (including pregelatinized) or gelatins; with disintegrators or disintegrants such as corn starch, potato starch or sodium carboxymethyl-cellulose; or with lubricants or wetting agents such as talc or WO 01/85150 PCT/US01/14644 28 magnesium stearate. Tablets may be coated, including by methods well known in the art. The formulation may be presented as an immediate-release or as a slow-release, sustained-release or controlled-release form. The formulation may also be presented as a solid drug matrix, for example, on a handle. Oral dose forms for human administration include: codeine, dihydrocodeine SYNALGOS-DC® from Wyeth-Ayerst Pharmaceuticals), fentanyl ACTIQ® from Abbott Laboratories)., hydrocodone VICODIN® and VICOPROFEN® from Knoll Laboratories; NORCO® from Watson Laboratories; HYCODAN® from Endo Pharmaceuticals; NORCET® from Abara; ANEXSIA®, HYDROCET®, and LORCET-HD® from Mallinckrodt; LORTAB® from UCB Pharma; HY-PHEN® from Ascher; CO- GESIC® from Schwarz Pharma; ALLAY® from Zenith Goldline), hydromorphone DILAUDID® from Knoll), levorphanol LEVO-DROMORAN® from ICN Pharmaceuticals), meperidine DEMEROL® from Sanofi Pharmaceuticals), methadone METHADOSE® from Mallinckrodt; and DOLOPHINE® HC1 from Roxane Laboratories), morphine KADIAN® from Faulding Laboratories; MS CONTIN® from Purdue Frederick; ORAMORPH® SR from Roxane), oxycodone PERCOCET® and PERCODAN® from Endo; OXYCET® from Mallinckrodt; OXYCONTIN® from Purdue Frederick; TYLOX® from Ortho-McNeil Pharmaceutical; ROXICODONE®, ROXILOX® and ROXICET® from Roxane), pentazocine TALACEN® and TALWIN® from Sanofi Pharmaceuticals), propoxyphene DARVOCET-N® and DARVON® from Eli Lilly Co.; DOLENE® from Lederle; WYGESIC® from Wyeth-Ayerst), and tramadol ULTRAM® from Ortho-McNeil Pharmaceutical).

Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents lecithin or acacia); non-aqueous vehicles methyl or propyl-p-hydroxybenzoates or sorbic acid). Liquid dose forms for human administration include: hydrocodone HYDROPIIANE® from Halsey), WO 01/85150 PCT/US01/14644 29 hydromorphone DILAUDID® from Knoll), meperidine DEMEROL® from Sanofi), methadone DOLOPHINE® from Roxane), oxycodone HYCOMINE® from Knoll; ROXILOX® from Roxane), and propoxyphene DARVON-N® from Eli Lilly).

For parenteral administration, including intravenous, intramuscular, or subcutaneous administration, the compounds may be combined with a sterile aqueous solution which is preferably isotonic with the blood of the recipient. Such formulations may be prepared by dissolving solid active ingredient in water containing physiologically compatible substances such as sodium chloride, glycine, or the like, and/or having a buffered pH compatible with physiological conditions to produce an aqueous solution, and/or rendering said solution sterile. The formulations may be present in unit dose forms or multi-dose forms, including in containers such as sealed ampoules or vials. Parenteral dose forms for human administration include: alfentanil ALFENTA® from Akorn), buprenorphine BUPRENEX® from Reckitt Colman Pharmaceuticals), butorphanol STADOL® from Apothecon), dezocine DALGAN® from Astrazeneca), fentanyl, hydromorphone DILAUDID-HP® from Knoll), levallorphan LORFAN® from Roche), levorphanol LEVO-DROMORAN® from ICN), meperidine DEMEROL® from Sanofi), methadone DOLOPHINE® HCI from Roxane), morphine (e.g, ASTRAMORPH® from Astrazeneca; DURAMORPH® and INFUMORPH® from Elkins-Sinn), oxymorphone NUMORPHAN® from Endo), nalburphine NUBAIN® from Endo Pharmaceutical), and pentazocine (TALWIN® from Abbott).

For transdermal administration, the compounds may be combined with skin penetration enhancers such as propylene glycol, polyethylene glycol, isopropanol, ethanol, oleic acid, N-methylpyrrolidone, or the like, which increase the permeability of the skin to the compounds, and permit the compounds to penetrate through the skin and into the bloodstream. The compound/enhancer compositions also may be combined additionally with a polymeric substance such as ethylcellulose, hydroxypropyl cellulose, ethylene/vinylacetate, polyvinyl pyrrolidone, or the like, to provide the composition in gel form, which can be dissolved in solvent such as methylene chloride, evaporated to the desired viscosity, and then applied to backing WO 01/85150 PCT/US01/14644 material to provide a patch. Transdermal dose forms for human administration include fentanyl DURAGESIC® from Janssen).

Additional dose forms available as suppositories for human administration include oxymorphone NUMORPHAN® from Endo).

"Analgesia" refers to the attenuation, reduction or absence of sensibility to pain, including the provision of pain relief, the enhancement of pain relief, or the attenuation of pain intensity. An "analgesic" amount refers to an amount of the opioid agonist which causes analgesia in a subject administered the opioid agonist alone, and includes standard doses of the agonist which are typically administered to cause analgesia mg doses). An "analgesic" amount also refers to an amount that results in analgesic efficacy, for example, as measured by a female or male subject with a pain relief score or a pain intensity difference score, at a given time point, or over time, or as compared to a baseline, and includes calculations based on area under the curve such as TOTPAR or SPID from such pain relief scores or pain intensity difference scores. A "hypo-analgesic" amount is a less-than-analgesic amount, including an amount which is not analgesic or is weakly analgesic in a subject administered the opioid agonist alone, and further includes an "anti-analgesic" or "algesic" amount which is an amount which increases pain. For example, men or women in the opioid antagonist may be administered in an amount effective to provide or enhance the analgesic potency as measured by pain relief or pain intensity difference) of the opioid agonist, without substantially increasing maintaining) the adverse side effects as compared to the agonist alone. For example, in women or men, the opioid antagonist may be administered in an amount effective to maintain the analgesic potency maintain analgesia as measured by pain relief or pain intensity differences) of the opioid against, while attenuating one or more adverse side effects of the agonist. The opioid antagonist may be administered in an amount effective to produce or enhance analgesic potency in combination with, for example, a mu opioid receptor agonist. The optimum amounts, for example, of the opioid agonist and the opioid antagonist administered, will of course depend upon the particular agonist and antagonist used, the carrier chosen, the route of administration, and/or the pharmacokinetic properties of the subject being treated, as well as the desired gender-related effects according to the teachings of the present invention.

WO 01/85150 PCT/US01/14644 31 When the opioid antagonist is administered alone, the amount of the opioid antagonist administered is an amount effective to enhance or maintain the analgesic potency of the opioid agonist and/or attenuate or maintain the adverse side effects of the opioid agonist, according to the teachings of the present invention.

Examples 1-9 that follow, describe in detail, results from human clinical trials, including those with a retrospective or prospective gender analysis, that unexpectedly demonstrate that the responses to opioid agonists such as morphine, hydrocodone, or tramadol and the responses to naltrexone, an opioid antagonist, as well as the responses to the interactions between such an agonist and antagonist, show surprising effects in humans, including surprising clinical benefits from the combination of such agonists and antagonists. Such clinical benefits include enhancing the potency increasing pain relief or decreasing pain intensity in humans) of a dose of the opioid agonist, while maintaining the adverse side effects of the agonist at that dose or maintaining the potency of a dose of the opioid agonist while attenuating reducing, blocking, inhibiting or preventing) one or more adverse side effects in humans associated with that dose of agonist. The responses to non-kappa opioid receptor agonists, such as morphine, hydrocodone or tramadol are strikingly different in women and men. By way of example, Examples 1-4 and 7 describe data that have been collected from observations in populations of human patients, wherein males and/or females were subjected to painful stimulation during the course of dental extractions and then treated with naltrexone and/or morphine. In Examples 1 and 2, subjects had two or more impacted third molars requiring extraction, wherein at least one extracted tooth was a partial or full bony mandibular impaction. In Examples 3-4 and 7, subjects had three or four full or partial bony impacted third molars requiring extraction. The levels of pain experienced by the subjects, for example, those in Examples 3-4, are not explicable by the known activity of naltrexone as a pure antagonist of morphine on nociceptive pathways. Data presented herein relate to novel gender-based differences and the data are consistent with a mechanism whereby an opioid antagonist such as naltrexone can act as a partial agonist on opioid receptors that are responsive to an opioid agonist such as morphine.

The studies demonstrate a number of gender-related differences, first with respect to the responses of the female and male subjects to the antagonist alone. For WO 01/85150 PCT/US01/14644 32 example, in females, naltrexone, by itself, acts as a hypo-analgesic agent in that it can cause increased pain in subjects experiencing pain associated with the dental extractions studied. Data from a study are described in Examples 3 and 4 in which female subjects were given an oral dose of 0.01 mg naltrexone. Pain scores were determined as pain intensity differences (PID). A PID score of 0 means no change in.

the level of pain, whereas a negative PID score means that pain increased, and a positive PID score indicates analgesia. Within 15 minutes, the PID score in the female subjects decreased below 0, indicating that the subjects experienced increased pain. The response to naltrexone was characterized by three features. First, there was a rapid increase in pain (anti-analgesia), with a peak in pain score of less than -0.3 observed at about 45 minutes after administration of the naloxone. Thereafter, there was a slight attenuation of the pain score (rebound), which lasted about 2 hours, and thereafter, the pain score increased (late phase anti-analgesia) and remained approximately steady (PID score of about for the duration of the study (8 hours).

In contrast to the results observed for females, naltrexone given to males in the same study had no anti-analgesic or analgesic effects. Data from this study are also shown in Examples 3 and 4 in which males undergoing dental extractions were given an oral dose of 0.01 mg naltrexone. Naltrexone did not change the PID score, which remained at about 0 for the duration of the 8 hours of the study. Thus, there was no rapid anti-analgesia, rebound, or late phase anti-analgesia as observed for the female patients.

Gender-related differences were also observed in the female and male subjects with respect to the agonist alone. As with the responses to the opioid antagonist naltrexone, the responses to the opioid agonist morphine differed unexpectedly between female and male patients. For example, the results from this study as described in Examples 3 and 4 of the responses of females given an oral dose of mg morphine, show that the time course of the response to morphine was slower than the time course of the response to naltrexone, with little or no effect observed at minutes after administration. However, by 60 minutes, substantial analgesia was observed, as indicated by a PID score of greater than about 0.4. A broad peak in analgesia was observed between about 1.5 and about 5 hours, with the PID score remaining at or above about 0.6 for this time period. Thereafter, the PID score slowly WO 01/85150 PCT/US01/14644 33 fell, and by about 6 hours, the PID score was at about 0.5. The PID remained at about for the duration of the study. In another study of female patients as described in Examples I and 2, a 60 mg oral dose of morphine was associated with progressive analgesia. In striking contrast to the results observed for females, in the males the same dose of morphine did not cause any analgesia. In fact, quite unexpectedly, morphine increased the pain that the men experienced (anti-analgesia). Within the first 15 minutes, the PID score began to fall below 0, indicating that pain was increased compared to the baseline. PID decreased to a minimum at about minutes, with the PID score being about Thereafter, the PID score slowly rose, so that by about 4 hours, the PID score had returned to about 0, where it remained for the duration of the study. In this study of male patients as described in Examples 1 and 2, morphine did cause some analgesia, but the analgesia observed was preceded by a period of anti-analgesia.

Gender-related differences were observed in the female and male subjects with respect to combinations of agonist and antagonist, in addition to the differences described above between males and females in the response to naltrexone and morphine individually. For example, in female patients (Examples 3 and the combination of naltrexone and morphine at certain times and at certain concentrations caused a decrease in analgesia as compared with morphine alone. At two hours, the lowest dose of naltrexone (0.001 mg) administered in combination with morphine decreased the PID score produced in the presence of morphine from a peak of about 0.7, to about 0.4. However, by 5 hours and thereafter, naltrexone did not decrease the PID score compared to those for morphine over the same time period. Increasing the dose of naltrexone to 0.01 mg with the morphine produced somewhat more reduction in PID than did the lowest combination dose (0.001 mg). However, further increasing the dose of naltrexone to 0.1 mg produced no further decrease in PID score. Thus, the dose of naltrexone having maximal effect in females when administered with 60 mg morphine is about 0.01 mg. In another study in female patients (Examples 1 and 2), naltrexone at doses of 0.01 mg and 0.1 mg each potentiated the analgesia associated with morphine (60 mg). Further increasing the dose of naltrexone to 1.0 mg however, decreased the analgesia associated with morphine. In male patients, in the study as described in Examples 3 and 4, the lowest dose of naltrexone (0.001 mg) increased WO 01/85150 PCT/US01/14644 34 analgesia in the presence of 60 mg morphine. The increase in analgesia was moderate, with an initial analgesic effect observed by about 2 hours after administration. Increasing the dose of naltrexone to 0.01 mg increased the analgesic effect compared to the lowest dose, and further increasing the dose of naltrexone (0.1 mg) increased the analgesia further, with a substantial effect occurring at about 1 hour, and reaching a broad plateau at about 2 hours, and lasting for the duration of the study. The PID score during this time was greater than about 0.8, with several points above about 0.9. In another study in male patients as described in Examples 1 and 2, naltrexone in combination with morphine produced more analgesia than did morphine alone. The effect of naltrexone was dose-dependent with the highest doses (1.0 mg) having the greatest effect.

As shown herein, gender-related differences were observed in the female and male subjects with respect to combinations of agonist and antagonist, for example, as shown by pain relief (PR) scores, pain intensity difference scores, or adverse side effects for female and male patients, respectively, as described herein in Examples.

Gender-based opioid compositions according to the invention may have therapeutic advantages. For example, females can exhibit significant analgesic responses to an opioid agonist such as morphine, and at certain doses, an opioid antagonist such as naltrexone can potentiate the analgesia induced by morphine.

However, effective doses of an opioid agonist such as morphine may have undesirable adverse side effects, including nausea, vomiting, other gastrointestinal symptoms, and other serious side effects such as respiratory depression. Additionally, an opioid antagonist such as naltrexone by itself may increase pain in females experiencing pain.

In certain embodiments of the invention, compositions are provided for use in females comprising low concentrations of opioid agonists including, by way of example only, morphine or oxycodone, that by themselves may not produce a desired degree of analgesia, along with doses of naltrexone that are sufficiently low to avoid producing undesirable adverse side effects themselves. By selecting doses of opioid agonist and antagonist, it is now possible to maintain a desirable therapeutic effect such as pain relief, while attenuating undesirable adverse side effects, for example, in females and/or males.

WO 01/85150 PCT/US01/14644 In certain other embodiments of this invention, compositions are provided for use in males comprising concentrations of morphine or other opioid agonists that alone are ineffective, along with naltrexone or other opioid antagonists in doses sufficient to potentiate or enhance the analgesic effects of the opioid agonist such as morphine. Additionally, because an opioid antagonist such as naltrexone can substantially potentiate or enhance the effects of an opioid agonist such as morphine, it is now possible to reduce the dose of an opioid agonist such as morphine to well below those doses that cause undesirable side effects, while at the same time, providing substantial pain relief, for example, in females and/or males.

Novel pharmaceutical compositions and dosage forms of opioid antagonists are described in U.S. Provisional Application No. 60/202,227, incorporated by reference herein. Novel compositions and gender-based methods for enhancing potency or reducing adverse side effects of opioid agonists are described in U.S.

Provisional Application Nos. 60/244,482, 60/245,110, and 60/246,235, incorporated by reference herein. Additional human clinical study results with tramadol are described in U.S. Application Nos. 09/566,071 and 09/756,331 as well as PCT/US00/12493 [WO00/67739], that are all incorporated by reference herein.

The present invention is described in the following examples which are set forth to aid in the understanding of the invention, and should not be construed to limit in any way the invention as defined in the claims which follow thereafter.

Pharmaceutical active and inactive ingredients used in the preparation of the example formulations were compendial in the USP/NF, when there was an existing monograph.

In the following examples, encapsulated dose forms of naltrexone HC1 (NTX) and various opioid agonists were prepared for clinical studies as follows.

Encapsulated dose forms of naltrexone HC1 were produced in the following doses and weight concentrations.

WO 01/85150 PCT/US01/14644 Naltrexone HCI Naltrexone HCI Active Capsule Capsule Dose Blend Concentration w/w) mg 0.3% 0.1 mg 0.03% 0.01 mg 0.003% 0.001 mg 0.0003% A batch of NTX, 0.3% w/w blend was made by first adding naltrexone HC1 and other inactive components magnesium stearate and microcrystalline cellulose) into a planetary mixer. The inactive components were added in portionwise steps with mixing between each addition to achieve uniformity of the NTX. The intermediate active blend was transferred from the planetary mixer to a double-cone blender.

An amount ofpreblended inactive components was used to rinse the planetary mixer. The rinsings were added to the double-cone blender to achieve quantitative recovery of naltrexone HC1. The remaining balance of preblended inactive components were added in portion-wise steps to the double cone blender containing the in-process material. The resulting intermediate and final mixtures were blended for an appropriate time to achieve uniformity.

Less potent formulated blends of naltrexone HCI 0.03% 0.003 w/w, and 0.0003% w/w) were prepared from the 0.3% w/w blend by serial dilution with the inactive components. A premeasured portion of the more concentrated active blend were added to the double cone blender. A measured amount of the preblended inactive components was added to achieve the desired dilution. The inactive blend was added in portion-wise steps to the double cone blender, with interim mixing to achieve uniformity. The NTX blends were filled into hard gelatin capsules at a controlled weight to achieve the desired unit dose of NTX.

Encapsulated dose forms of opioid agonists were prepared for clinical studies employing the same inactive components and hard gelatin capsule. Encapsulated dose forms of morphine were prepared from commercially obtained tablets (Roxane), which contained 15 mg morphine sulfate pentahydrate and various inactive components. A 60 mg morphine sulfate strength capsule was made by mixing microcrystalline cellulose and magnesium stearate) to form a blend, and this blend and four morphine sulfate tablets were loaded into a hard gelatin capsule shell to WO 01/85150 PCT/US01/14644 37 obtain a capsule for clinical studies. Encapsulated dose forms of tramadol were prepared from commercially obtained ULTRAM® tablets (Ortho-McNeil), which contained 50 mg tramadol hydrochloride and various inactive components. A 50 mg tramadol hydrochloride strength capsule was made by mixing inactive components microcrystalline cellulose and magnesium stearate) to form a blend, and this blend and one ULTRAM®, immediate release tablet were loaded into a hard gelatin capsule shell to obtain a capsule for clinical studies. Encapsulated dose forms of hydrocodone were prepared from commercially obtained tablets immediate release HYDROCET® capsules (Carrick Laboratories), which contained hydrocodone bitartrate (5 mg) with acetaminophen (500 mg) and various inactive components. A mg hydrocodone bitartrate/500 mg acetaminophen strength clinical capsule was made from the commercially obtained HYDROCET® capsules in the following manner.

The average weight of 20 HYDROCET® capsules was determined, and the hydrocodone/acetaminophen blend contained in a predetermined number of HYDROCET® capsules was emptied into a clean bowl. The total weight of hydrocodone/acetaminophen blend needed to fill the clinical capsules with the same average weight (including 1% overage) was transferred to a capsule machine. The capsule machine filled clinical capsule shells with the hydrocodone/acetaminophen blend.

WO 01/85150 PCT/US01/14644 38 EXAMPLE 1 A clinical study was designed as follows: to compare the analgesic activity (onset, peak, duration, and total effect) of three different doses of NTX in combination with MS 60 mg versus MS 60 mg alone in subjects with moderate to severe pain in a postsurgical dental pain model to determine whether NTX enhances the analgesic effect of MS 60 mg; and to evaluate the safety of three different doses of NTX in combination with MS 60 mg versus MS 60 mg alone in subjects with moderate to severe pain in a postsurgical dental pain model to determine whether the addition of NTX reduces the frequency or severity of morphine-related side effects.

Additional objectives of the study included: to compare the analgesic efficacy of MS 60 mg to placebo to establish the assay sensitivity of the study; to compare the analgesic activity (onset, peak, duration, and total effect) of three different doses of NTX in combination with MS 60 mg versus placebo in subjects with moderate to severe pain in a postsurgical dental pain model; and to evaluate the safety of three different doses of NTX in combination with MS 60 mg versus placebo in subjects with moderate to severe pain in a postsurgical dental pain model.

A randomized, double-blind, placebo- and active-controlled, single-dose study was thus designed. There were five treatment groups: three test products, a positive control (MS 60 mg), and a negative control (placebo). Separation of placebo and MS 60 mg were used to determine the assay sensitivity of the study. The active control (MS 60mg) was used to determine the sensitivity of the clinical endpoints. Placebo was used to control for factors not related to drug treatment. The test products were MS 60 mg with naltrexone (NTX) 1 mg, MS 60 mg with NTX 0.1 mg, and MS 60 mg with NTX 0.01 mg. A single oral dose of one of the treatments was administered when the subject was suffering moderate to severe postoperative pain. The observation period for efficacy was eight hours post treatment. The observation period for safety was 24 hours post treatment.

The Study Population was two hundred male and female outpatients with moderate to severe pain and a pain intensity score of at least 50 mm on the 100 mm Visual Analog Scale (VAS) following extraction of two or more impacted third molars. All subjects remained in the study facility for the eight-hour duration of the single-dose evaluation and then were permitted to leave the study site.

WO 01/85150 PCT/US01/14644 39 Inclusion criteria were as follows: subjects with two or more impacted third molars requiring extraction and considered to have had surgery significant enough to warrant an opioid analgesic, where at least one extracted tooth was a partial or full bony mandibular impaction; subjects willing and able to complete the pain evaluations; subjects at least 16 years of age, and if the subject was less than age 18, the subject was emancipated, or the parent or guardian gave written consent.

female subjects were postmenopausal, or physically incapable of child bearing, or practicing an acceptable method of birth control (IUD, hormones, diaphragm with spermicide, condoms with spermicide, or abstinence), and if practicing an acceptable method of birth control, must also have maintained her normal menstrual pattern for the three months prior to study entry and have had a negative urine pregnancy test performed at screening and immediately prior to surgery; subjects in generally good health; subjects able to speak and understand English and provide meaningful written informed consent; subjects able to remain at the study site for the entire eight-hour study period; subjects had an initial pain intensity score of at least 50 mm on a 100 mm visual analog scale and must also describe the initial pain as moderate or severe on a four-point categorical scale; and subjects willing and able to return to the study site for the post treatment visit five to nine days after surgery.

Exclusion criteria for subjects were as follows: pregnant or breast feeding; have known allergy or significant reaction to opioids or opioid antagonists; history of chronic opioid use or opioid abuse within six months prior to study.

have participated in a study of an investigational drug or device within days prior to this study; WO 01/85150 PCT/US01/14644 have taken any of the following drugs within four hours prior to dosing: analgesics, including aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS), opioids, and opioid combinations, minor tranquilizers, muscle relaxants and antihistamines, where exempted from this prohibition were midazolam (Versed), lidocaine (with or without epinephrine), mepivacaine, nitrous oxide, and propofol (Diprivan) given during surgery; have taken a long-acting analgesic long-acting NSAIDS) within 12 hours prior to this study; have taken monoamine oxidase inhibitors or tricyclic antidepressant drugs within four weeks prior to study medication; have taken serotonin reuptake inhibitors (SSRI) or St. John's wort within four weeks prior to the study unless the subject has been on a stable dose for at least six weeks and the stable dose for St. John's wort must have been no more than 1gm/day; have a medical or psychiatric condition that compromises the subject's ability to give informed consent or appropriately complete the pain assessments; and have a history of seizure, however, subjects with a history of juvenile febrile seizures could be included if there was no seizure history within the past years.

Subjects were assigned to treatment groups based on a randomization schedule prepared prior to the study. The randomization was balanced by using equally balanced blocks. Based on the randomization code, the assigned study drug was packaged and labelled for each subject. Subject numbers were preprinted onto the study drug labels and assigned as subjects qualified for the study and were randomized to treatment. In order to achieve balance among treatment groups with respect to starting pain, the study stratified randomization according to initial pain intensity. Subjects with moderate starting pain were assigned medication with the lowest available number. Subjects with severe starting pain were assigned medication with the highest available number.

Each subject was assigned one bottle containing two capsules. The label on the bottle consisted of two parts. One part was attached firmly to the bottle and did not contain drug identification. The other part was a tear-off label containing the WO 01/85150 PCT/US01/14644 41 concealed drug identification. The tear-off label was taped unopened onto the case report form.

NUMBER OF CAPSULES PER BOTTLE FOR EACH TREATMENT GROUP Capsules Treatment Contents MS NTX NTX NTX Placebo Group 60 mg 1mg 0.1 mg 0.01 mg Treatment Group A Placebo 0 0 0 0 2 Group B MS 60 mg 1 0 0 0 1 Group C MS 60 mg with 1 0 0 1 0 NTX 0.01 mg Group D MS 60 mg with 1 0 1 0 0 NTX 0.1 mg Group E MS 60 mg with 1 1 0 0 0 NTX 1 mg___ Included on the open portion of the label was the protocol identification, subject number, number of capsules, directions for use, storage instructions, and cautionary statement about investigational status.

The randomization code was not revealed to study subjects, investigators, clinical staff or study monitors until all subjects completed therapy and the data base has been finalized and closed.

Following washout from previous analgesia as stated in the exclusion criteria, and following a suitable recovery from anesthesia after surgery, all subjects who had moderate to severe pain and a score of at least 50 mm on the 100 mm VAS received one dose of study medication, consisting of two capsules. There was one bottle per subject, labeled by subject number, as described above.

The following screening procedures were accomplished within 14 days prior to surgery: review of inclusion and exclusion criteria; informed consent; (c) urine pregnancy test for women of child-bearing potential (at screening and immediately prior to surgery); medical history and demographics; brief physical examination; and vital signs.

Baseline measurements and procedures included: vital signs (prior to dosing); review of medications received within 12 hours prior to dosing; and (c) WO 01/85150 PCT/US01/14644 42 after a suitable washout period from the anesthesia, the subject's pain level was assessed by a trained observer, and when the pain level was moderate or severe, and the score on the 100 mm VAS was at least 50 mm, the subject was randomized to a treatment group.

Provided the subject met the above-referenced criteria, the subject was assigned the next sequential 'treatment number in ascending or descending order depending upon the starting pain. The subject then took one dose of study medication consisting of two capsules.

Treatment period procedures and measurements included: Following dosing, the subject remained at the study facility for eight hours; Two stopwatches were started at the time the study medication was taken at baseline and each subject was first instructed, "Stop the first stopwatch when you first feel any paid relief whatsoever. This does not mean you feel completely better, although you might, but when you first feel any difference in the pain you have now." and then the subject was instructed, "Stop the second stopwatch when the pain relief is meaningful to you."; For treated subjects, vital signs were takn one hour after dosing and at the end of the eight-hour observation period; For treated subjects, pain intensity and pain relief were measured by a trained observer at the following times: 30 minutes, 60 minutes and hourly thereafter through Hour 8 after dosing, and all efficacy assessments were recorded by the subject in a diary in response to questioning by a trained observer, wherein the trained observer questioned the subject for all observations and provided instruction as needed; pain intensity was measured in response to the question, "What is your pain level at this time?" with subject response choices of none=0, mile 1, moderate=2 and severe=3 on a categorical scale and the pain relief relative to baseline was assessed in response to the question, "How much relief have you had from your starting pain?" with subject response choices of none=0, a little=l, some=2, a lot=3, and complete-4; Subjects not completing at least 90 minutes after dosing were considered not evaluable and were replaced; WO 01/85150 PCT/US01/14644 43 Adverse events were assessed by non-directed questioning and recorded for the eight hours following dosing; All concomitant medications (including rescue medications) were recorded for the eight-hour observation period; At the end of eight hours, or at the termination of hourly observations if sooner than eight hours, a global evaluation was made by observer and subject in response to the question, "How do you rate the pain relief?" with response choices of poor=0, fair-=l, good=2, very good=3 and excellent=4; and Upon discharge from the study facility, the subject was given a diary to take home for recording medications taken and adverse events experienced from the time of discharge until 24 hours after the time of dosing with study medication; a member of the study staff telephoned the patient 24 hours after the time of dosing to query the subject about medications taken, adverse events experienced, and to remind the subject to complete the diary.

The study was considered completed after eight hours of evaluation or upon receipt of rescue medication. Subjects could discontinue the study at any time.

Subjects who did not get adequate pain relief provided a final set of pain assessments and a global evaluation before taking rescue medication. Subjects were then given a rescue medication and pain assessments were discontinued. Subjects were encouraged to wait at least 90 minutes after administration of the study medication before using rescue medication. Subjects remedicating earlier than 90 minutes were not included in the analysis for efficacy.

For subjects who completed eight hours of evaluation without using rescue medication, the time of the first dose of analgesic within 24 hours after dosing with study medication was recorded on the take-home diary.

All subjects who received a dose of study medication returned to the study facility 5 to 9 days after surgery for a post treatment visit. The following was accomplished: brief physical examination; collection and review of subject's diary for 24-hour post-dosing adverse events, and medications (including rescue medications).

Efficacy evaluations were performed using primary and secondary efficacy (outcome) parameters. The primary efficacy paramaters included: WO 01/85150 PCT/US01/14644 44 8-hour Total Pain Relief Scores (TOTPAR-8) described below; 8-Hour Sum of Pain Intensity Difference Scores (SPID-8) described below; Time to Rescue; Percent of Subjects Remedicating with Rescue Medication; and Time to Onset of Meaningful Pain Relief.

The secondary efficacy parameters included: Hourly Pain Relief Scores; Hourly Pain Intensity Difference Scores; Maximum Pain Relief Scores; Peak Pain Intensity Difference Scores; Global Evaluations; and Time to Onset of First Perceptible Pain Relief.

Safety evaluations included vital signs; and adverse events. All adverse events were recorded on the case report forms (CRF) provided. Serious adverse events were reported promptly to the Institutional Review Board (IRB) and to the sponsor. The investigator transmitted a written report of the circumstances and outcome. All serious adverse events were reported to the FDA in compliance with Federal Regulations. An adverse event (AE) was defined as any untoward, noxious, or unintended event experienced by a subject in a clinical trial of an investigational agent, whether considered related to that investigational agent or not. A treatmentemergent adverse event was defined as an AE that was new in onset or aggravated in severity or frequency following administration of the investigational agent. A serious adverse event was defined as any AE occurring at any dose that resulted in any of the following outcomes: death, a life-threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity, or congenital anomaly or birth defect.

A subject who completed Hour 8 or who completed at least 90 minutes and remedicated before Hour 8 was evaluable for efficacy. In any case, the reason for discontinuation was documented.

For the data analysis, parameters were computed as follows. The extent to which pain changes at each time point was measured by pain relief scores (PR, with WO 01/85150 PCT/US01/14644 0-none, 1=a little, 2=some, 3=a lot, 4=complete), and pain intensity difference scores (PID, the difference between baseline and the current time, with the pain intensity scale consisting of 0=none, 1=mild, 2-moderate, 3=severe).

The extent to which pain changes over the entire test period was measured by the total pain relief score (TOTPAR-8), sum of pain intensity differences (SPID-8), maximum pain relief score (MAXPAR), peak pain intensity difference (PEAKPID), and global evaluation (0=poor, l=fair, 2=good, 3=very good, 4=excellent). TOTPAR- 8 and SPID-8 are defined as the sum of PR and PID, respectively, for the entire 8hour observation period, weighted by the time difference between adjacent points area under the curve using the trapezoidal rule). MAXPAR and PEAKPID are defined as the maximum of PR and PID, respectively.

Where required, the following imputation schemes were employed.

Intermediate missing values were replaced by linear interpolation, whereas missing values after administration of rescue medication or other premature discontinuation were replaced by the last observation carried forward procedure (LOCF).

Further efficacy variables were time to rescue, percent of patients remedicating with rescue medication, time to onset of meaningful pain relief, and time to onset of first perceptible pain relief.

Safety was assessed through vital signs and adverse events (including body systems and preferred terms from the COSTART dictionary).

All testing of statistical significance were two-sided, and a difference resulting in a p-value of less than or equal to 0.05 was considered statistically significant.

Efficacy analyses was conducted on the intent-to-treat (ITT) analysis set, consisting of all randomized patients who received study medication. A second analysis could be done on the evaluable analysis set.

Demographic and baseline characteristics were summarized with descriptive statistics (for continuous variables) or frequencies (for categorical variables).

One-way analysis of variance (ANOVA) by treatment group was performed on PR, PID, TOTPAR-8, SPID-8, MAXPAR, PEAKPID, and the global evaluation (with PR and PID analyzed separately for each time point). Baseline pain intensity was investigated as a possible blocking factor, and baseline pain intensity VAS was investigated as a possible covariate. If the ANOVA treatment effect is significant at WO 01/85150 PCT/US01/14644 46 the p 0.05 level, one-sided Fisher's protected least significant difference test (LSD) was performed to investigate pairwise differences. For all pairwise comparisons, the error mean square from the overall analysis of variance with all treatments was used as the estimate of error variance.

Time to rescue (remedication) was analyzed using the Kaplan-Meier estimate to compute the survival distribution function. The distributions were compared among treatment groups using the log rank and Wilcoxon tests. A patient was considered censored at 24 hours if remedication had not occurred. Patients who dropped out because of reasons other than rescue medication were censored at the dropout time. The proportion of patients remedicating were compared among treatment groups using Fisher's exact test or a chi-squared test. Time to onset of meaningful pain relief and time to onset of first perceptible pain relief was analyzed in a similar fashion to time to rescue. Patients who did not achieve meaningful pain relief or perceptible pain relief were considered treatment failures and were assigned a time of 8 hours.

All patients who received study medication were assessed for clinical safety.

Vital signs, including changes from baseline, were summarized with descriptive statistics. Adverse event frequencies were tabulated by body system and preferred term, and Fisher's exact test or a chi-squared test was used to test for differences in adverse event frequencies among the treatment groups by body system.

The sample size was estimated from historical data and from practical considerations rather than from calculation of expected measured differences.

A total of 204 subjects were randomized; among them 201 subjects were deemed evaluable. One subject in each of the placebo, MS and MS/O.1 NTX groups was not evaluable because the subject took rescue medication less than 90 minutes after dosing.

Table 1 Subject Disposition Treatments Placebo MS (60 mg) MS (60 mg) MS (60 mg) MS (60 mg) with with with with NTX with NTX NTX (1.0 mg) Total Placebo Placebo (0.01 mg) (0.1 mg) Number of Subjects Screened 40 41 41 41 41 204 Analyzed for Efficacy: Intent-To-Treat 40 41 41 41 41 204 Evaluable Subjects 39 40 41 40 41 201 Analyzed for Safety: Intent-To-Treat 40 41 41 41 41 204 WO 01/85150 PCT/US01/14644 48 The demographic and baseline characteristics were summarized by treatment groups for the ITT population (all randomized patients) and the evaluable population (all randomized patients with at least one efficacy evaluation at 90 minutes or more after dosing) (Table Demographic characteristics included age, race/ethnicity, sex, weight, height, medical history, teeth extracted (impacted and non-impacted), baseline pain intensity, and baseline visual analog scale.

The demographics for the ITT population were comparable across all treatment groups. Subjects ranged in age from 18 to 39 years; 67% were Caucasian and 51% were female. There was comparability among treatment groups regarding the degree of surgical trauma rating. For the evaluable population, but not for the ITT population, there was a difference among treatment groups in the maximum degree of impaction of third molar extracted. Patients in the placebo group had a lesser degree of bony impaction compared to patients in the low-dose group, and patients in both the low-dose and mid-dose groups had a greater degree of impaction compared to patients in the high-dose group. No adjustments in the analyses were made to take into account these differences among treatment groups. These differences had no influence on pain assessments at baseline. Generally, no differences among treatment groups were noted in the number of patients with either a significant medical history or disease of any body system. The baseline pain intensity scores and visual analog scale scores also were comparable across treatment groups (Table 3).

Table 2 Baseline Demographic Characteristics Intent-To-Treat Subjects Treatments Placebo MS (60 ing) with MS (60 mg) with MS (60Wmg) with MS (60 mng) -with P-Value with Placebo NTX (0.0 1 mog) NTX 1 mg) NTX 1.0 mg) Placebo Number of Subjects 204 Sex Male 18 18 21 21 21 0.918 [2] Female 22 23 20 20 20 (48.8%) Total 40 41 41 41 41 Age (yrs) N 40 41 41 41 41 0.715 [1] Mean 22.1 22.9 22.0 23.1 22.5 SD 2.92 3.87 3.55 5.10 4.28 Median 21.5 22.0 21.0 22.0 22.0 18-28 19-32 18-35 16-39 18-39 Height (cm) N 40 41 41 41 41 0,596 [1] Mean 170.3 170.7 173.8 171.4 171.4 SD 9.70 12.22 9.38 10.87 10.05 Median 170.2 167.6 172.7 172.7 171.5 Range 152.4 188.0 149.9 -198.1 157.5 193.0 139.7 194.3 154.9 188.0 Weight (kg) N 40 41 41 41 41 0.384 [1] Mean 68.8 75.5 72.1 70.8 72.6 SD 13.94 17.39 12.99 14.49 17.34 Median 67.3 75.0 73.2 70.9 69.8 Range 47.3 -106.4 42.7- 117.3 50.9 -105.5 46.4 -104.5 47.3 -122.3 Ethnic Origin Caucasian 26 25 31 28 26 0.666 [2] Black 4 4 1 1 3 Hispanic 7 11 7 9 6 (14.6%) Asian 3 1 1 2 5 (12.2%) Other 0 0 1 1 1 40 41 41 41 41 ONE-WAY ANALYSIS OF VARIANCE WITH TREATMENT AS THE FACTOR FISHER'S EXACT TEST.

BLACK, ASIAN, HISPANIC, AND OTHER ARE COMBINED INTO ONE CATEGORY TO DERIVE P-VALUE.

Table 3A Summary of Baseline Pain Intensity Scores Intent-To-Treat Population PAIN INTENSITY P-VALUE FOR PAIRWISE COMPARISONS P-VALUE FOR MS 60 mg MS 60 mg MS 60 mg OVERALL TREATMENT MODERATE SEVERE MS 60mg NTX 0.01 mg NTX 0.1mg NTX 1 mg TREATMENT Placebo 16 24 0.822 1.000 0.822 1.000 0.997 MS 60 mg 18 23 1.000 1.000 1.000 MS 60 mg /NTX 0.01 mg 17 24 1.000 1.000 MS 60 mg /NTX 0.1 mg 18 23 1.000 MS 60 mg /NTX 1 mg 17 24 (58.5%) NOTE: P-VALUES ARE FROM FISHER'S EXACT TEST.

Table 3B Summary of Baseline Visual Analog Scale (VAS) Scores Intent-To-Treat Population BASELINE VAS SCORE P-VALUE FOR PAIRWISE COMPARISONS TREATMENT Moderate Severe Total MS 60 mg MS 60 mg MS 60 mg MS 60 P-Value NTX 0.01 NTX 0.1 mg for mg mg NTX 1 Overall mg Treatment N Mean (SD) N Mean (SD) N Mean (SD) Placebo 16 65.5 (7.91) 24 79.4 (9.91) 40 73.9 (11.39) 0.250 0.890 0.296 0.966 0.512 MS 60mg 18 68.1 (6.58) 23 84.1 (8.23) 41 77.1 (11.00) 0.195 0.922 0.231 MS 60 mg/NTX 0.01 mg 17 60.7 (9.29) 24 82.5 (10.77) 41 73.5 (14.81) 0.234 0.923 MS 60 mg/NTX 0.1 mg 17 65.5 (10.62) 23 85.2 (9.18) 40 76.8 (13.83) 0.274 MS 60 mg/NTX 1 mg 17 67.6 (10.53) 24 78.1 (10.23) 41 73.7 (11.48) NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS.

BASELINE PAIN INTENSITY ON THE CATEGORICAL SCALE.

WO 01/85150 PCT/US01/14644 51 The TOTPAR results (4-hour, 6-hour, 8-hour) are summarized in Table 4 and the 4-hour TOTPAR scores are shown in Figure 1. The placebo treatment group had the lowest mean TOTPAR scores. All 4 of the active treatment groups exhibited mean TOTPAR scores that were numerically higher than placebo. The combination treatments had a reverse dose-response relation in the mean TOTPAR scores, the highest dose of NTX had the lowest mean TOTPAR scores and the lowest dose of NTX had the highest mean TOTPAR scores. This pattern (low-dose (0.01 mg NTX) mid-dose (1.0 mg NTX) was observed for all pain relief variables throughout the study. The mean TOTPAR scores for the 0.01-mg NTX and 0.1-mg NTX combination treatments were higher than that for the MS alone treatment, whereas the NTX combination treatment mean was comparable to or lower than that for the MS alone treatment (Figure 1).

Analyses of TOTPAR for the evaluable subgroup yielded results similar to those for the ITT population.

Table 4 Total Pain Relief Scores Intent-To-Treat Population TOTAL PAIN RELIEF SCORE P-VALUE P-VALUE TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE [2] TOTAL PAIN RELIEF SCORE (0-4 HOURS) A) Placebo 40 2.20 2.836 0.0 0.25 9.5 TRT 0.003** 0.004** B) MS 60 mg 41 4.38 4.035 0.0 3.75 13.2 BASEPI N/A 0.312 C) MS 60 mg /NTX 0.01 mg 41 5.50 4.106 0.0 5.73 14.0 BASEPI*TRT N/A 0.081 D) MS 60 mg/NTX 0.1 mg 41 5.09 4.278 0.0 3.25 12.3 B-A 0.014* 0.013* E) MS 60 mg/NTX 1 mg 41 4.18 4.439 0.0 2.75 14.0 C-A <0.001*** D-A 0.001** 0.001** E-A 0.026* 0.024* C-B 0.203 0.198 D-B 0.416 0.411 E-B 0.828 0.826 TOTAL PAIN RELIEF SCORE (0-6 HOURS) A) Placebo 40 3.62 4.851 0.0 0.25 14.5 TRT 0.004** 0.006** B) MS 60 mg 41 7.52 6.962 0.0 8.25 21.2 BASEPI N/A 0.419 C) MS 60 mg/NTX 0.01 mg 41 8.85 6.470 0.0 9.23 20.5 BASEPI*TRT N/A 0.044* D) MS 60 mg/NTX 0.1 mg 41 8.25 7.089 0.0 6.75 20.3 B-A 0.008** 0.007** E) MS 60 mg /NTX 1 mg 41 6.60 7.277 0.0 2.75 22.0 C-A <0.001*** D-A 0.001** 0.001** E-A 0.043* 0.041* C-B 0.359 0.353 D-B 0.613 0.608 E-B 0.530 0.524 FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/A: NOT APPLICABLE Table 4 (Continued) Total Pain Relief Scores Intent-To-Treat Population TOTAL PAIN RELIEF SCORE P-VALUE P-VALUE TREATMENT N MEAN SD MIN MEDIA MAX SOURCE [2] N TOTAL PAIN RELIEF SCORE (0-8 HOURS) A) Placebo 40 5.12 7.026 0.0 0.25 20.5 TRT 0.007** 0.009** B) MS 60 mg 41 10.73 9.988 0.0 13.50 29.2 BASEPI N/A 0.470 C) MS 60 mg/NTX 0.01 mg 41 12.15 9.139 0.0 11.75 27.5 BASEPI*TRT N/A 0.037* D) MS 60 mg/NTX 0.1 mg 41 11.52 10.130 0.0 10.75 28.3 B-A 0.007** 0.007** E) MS 60 mg /NTX 1 mg 41 9.14 10.337 0.0 2.75 30.0 C-A <0.001*** D-A 0.002** 0.002** E-A 0.056 0.053 C-B 0.496 0.489 D-B 0.705 0.701 E-B 0.442 0.436 FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/A: NOT APPLICABLE WO 01/85150 PCT/US01/14644 54 Table 5 summarizes the results of the 4, 6, and 8-hour SPID results. The 4hour results are also represented in Figure 2. The placebo treatment had the lowest mean 4-hour SPID scores (0.68 2.165). All 4 of the active treatment groups exhibited improved profiles in mean SPID relative to placebo. The mean SPID scores for the 0.01-mg NTX and 0.1-mg NTX combination treatments were higher than that for the MS alone treatment, whereas the 1.0-mg NTX combination treatment was comparable to that for the MS alone treatment (Figure 2).

The patterns of the 6-hour and 8-hour SPID scores were similar to those at 4 hours. Analyses of SPID for the evaluable subgroup also yielded profiles that were similar to those found in the ITT population.

Table Summary of Pain Intensity Differences Intent-To-Treat Population SUM OF PAIN INTENSITY DIFFERENCES P-VALUE P-VALUE TREATMENT iN MEAN SD MIN MEDIAN MAX ISOUCRE [3] SUMMARY OF PAIN INTENSITY DIFFERENCES (0-4 HOURS) A) Placebo 40 0.68 2.165 -3.8 0.00 5.0 TRT 0.009** 0.003** B) MS 60 mg 41 1.91 3.296 -3.8 2.50 8.0 BASEPI N/A <0.001*** C) MS 60 mg /NTX 0.01 mg 41 3.08 3.309 -3.8 3.24 10.3 BASEPI*TRT N/A 0.040* D) MS 60 mg/NTX 0.1 mg 41 2.62 2.790 -3.8 2.48 8.5 B-A 0.077 0.048* E) MS 60 mg/NTX 1 mg 41 2.01 3.763 -3.8 1.25 8.5 C-A <0.001*** D-A 0.005** 0.001** E-A 0.054* 0.031* C-B 0.090 0.058 D-B 0.302 0.248 E-B 0.875 0.860 PAIN INTENSITY DIFFERENCE PAIN INTENSITY AT BASELINE -PAIN INTENSITY AT CURRENT TIME.

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/A: NOT APPLICABLE Table 5 (Continued) Summary of Pain Intensity Differences Intent-To-Treat Population P-VATUF. P-VATUE? I I TREATMENT N MEAN SD MIN MEDIAN MAX SOUCRE [31 SUMMARY OF PAIN INTENSITY DIFFERENCES (0-6 HOURS) A) Placebo 40 1.15 3.435 -5.8 0.00 8.3 TRT 0.013* 0.004** B) MS 60 mg 41 3.33 5.510 -5.8 4.50 12.0 BASEPI N/A <0.001*** C) MS 60 mg/NTX 0.01 mg 41 4.86 5.069 -5.8 5.25 15.3 BASEPI*TRT N/A 0.021* D) MS 60 mg/NTX 0.1 mg 41 4.36 4.606 -5.8 4.48 14.5 B-A 0.053 0.031* E) MS 60 mg/NTX 1 mg 41 3.20 6.136 -5.8 1.25 14.5 C-A 0.001** <0.001*** D-A 0.004** 0.001** E-A 0.068 0.042* C-B 0.170 0.127 D-B 0.355 0.303 E-B 0.911 0.901 PAIN INTENSITY DIFFERENCE PAIN INTENSITY AT BASELINE PAIN INTENSITY AT CURRENT TIME.

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/A: NOT APPLICABLE Table 5 (Continued) Summary of Pain Intensity Differences Intent-To-Treat Population SUM OF PAIN INTENSITY DIFFERENCES P-VALUE P-VALUE TREATMENT N I MEAN SD I MIN MEDIAN MAX SOURCE [3] SUMMARY OF PAIN INTENSITY DIFFERENCES (0-8 HOURS) A) Placebo 40 1.65 4.781 -7.8 0.00 12.8 TRT 0.019* 0.007** B) MS 60 mg 41 4.80 7.821 -7.8 6.50 17.3 BASEPI N/A <0.001*** C) MS 60 mg/NTX 0.01 mg 41 6.62 7.090 -7.8 7.25 19.8 BASEPI*TRT N/A 0.016* D) MS 60 mg/NTX 0.1 mg 41 6.18 6.581 -7.8 6.49 20.5 B-A 0.048* 0.028* E) MS 60 mg/NTX 1 mg 41 4.54 8.716 -7.8 1.25 20.0 C-A 0.001** <0.001*** D-A 0.004** 0.001"** E-A 0.069 0.043* C-B 0.248 0.199 D-B 0.380 0.329 E-B 0.870 0.855 PAIN INTENSITY DIFFERENCE PAIN INTENSITY AT BASELINE PAIN INTENSITY AT CURRENT TIME.

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/A: NOT APPLICABLE WO 01/85150 PCT/US01/14644 58 Figure 3 is a visual presentation of the summary and analysis of time to onset of meaningful pain relief scores presented in Table 6. The median time to onset of meaningful pain relief was shortest in the 0.01-mg NTX (low-dose) combination treatment group. The placebo treatment had the lower number of subjects who reached meaningful pain relief.

Analyses of times to onset of meaningful pain relief for the evaluable subgroup yielded similar result.

Table 6 Time To Onset of Meaningful Pain Relief Intent-To-Treat Population OF SURVIVAL CURVES1 MEDIAN 95% CONFIDENCE ITIME INTERVAL TREATMENT 4N (hh:mm) (hh:mm) SOURCE LOG-RANK WILCOXON Placebo MS 60 mg MS 60 mg/NTX 0.01 mg MS 60 mg/NTX 0. 1 mg MS 60 mg/NTX I mg 8:00 2:37 2:23 3:10 8:00 8:00, >8:00) (1:07, >8:00) 1 :12, >8:00) (1:33, >8:00) (2:00, >8:00)

TREATMENT

B-A

C-A

D-A

E-A

C-B3

D-B

E-B

0.029* 0.006** 0.001** 0.007** 0.030* 0.725 0.830 0.592 0.062

N/D

N/D

N/D

N/D

N/D

N/D

I P-VALUE 0105, 0.01, or 0.00 1 RESPECTIVELY.

N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

I/

WO 01/85150 PCT/US01/14644 Figures 4 and 5 are a visual presentation of the summary and analysis of time to remedication (rescue medication) up to 8 and 24 hours presented in Table 7. The survival distributions (0-8 hours) were different across treatment groups. The survival distributions were different for the low-dose and mid-dose groups compared to placebo (Figure The median times to administration of rescue medication were longer for the morphine 8 hours), low-dose 8 hours), and mid-dose 8 hours) groups compared to the high-dose (3 hours, 4 minutes) and placebo (2 hours, 18 minutes) groups.

The survival distributions (0-24 hours) were also different across treatment groups, and were also different for the morphine, low-dose, and mid-dose groups compared to the placebo group (Figure Again, the median times to administration of rescue medication were longer for the morphine, low-dose, and mid-dose groups.

Analyses of time to remedication up to 24 hours yielded similar results, however, the data should be viewed with caution because subjects were not under close supervision after 8 hours. Analyses for the evaluable subjects yielded results similar to those for the ITT population.

Table 7 Time To Rescue Medication Intent-To-Treat Population TEST OF SURVIVAL CURVES MEDIAN 95% CONFIDENCE TIME INTERVAL TREATMENT N (hh:mm) (hh:mm) SOURCE LOG-RANK WILCOXON EFFICACY OBSERVATION PERIOD (0-8 HOURS) A) Placebo 40 2:18 (2:02, 4:05) TREATMENT 0.047* 0.014* B) MS 60 mg 41 8:00 (2:33, >8:00) B-A 0.092 0.114 C) MS 60.mg /NTX 0.01 mg 41 8:00 (6:03, >8:00) C-A 0.011* 0.002** D) MS 60 mg /NTX 0.1 mg 41 8:00 (3:06, >8:00) D-A 0.020* 0.010* E) MS 60 mg /NTX 1 mg 41 3:04 (2:00, >8:00) E-A 0.506 0.471 C-B 0.506 0.234 D-B 0.605 0.422 E-B 0.285 0.347 SAFETY OBSERVATION PERIOD (0-24 HOURS) A) Placebo 40 2:18 (2:02, 4:05) TREATMENT 0.015* 0.003** B) MS 60 mg 41 8:37 13:28) B-A 0.029* 0.043* C) MS 60 mg /NTX 0.01 mg 41 9:14 (6:03, 20:59) C-A 0.001** <0.001*** D) MS 60 mg /NTX 0.1 mg 41 8:26 (3:06, 18:17) D-A 0.005** 0.003** E) MS 60 mg/NTX 1 mg 41 3:04 (2:00, 9:09) E-A 0.169 0.266 C-B 0.388 0.167 D-B 0.539 0.424 E-B 0.562 0.427 P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

WO 01/85150 PCT/US01/14644 62 Table 8 presents the summary and analysis of percent of subjects who took remedication up to 8 and 24 hours. Analyses of the percentage of subjects who remedicated within 24 hours indicated that all 5 treatment groups were comparable, however, the data should be interpreted with caution because subjects were not under close supervision after 8 hours. Analyses for the evaluable subjects led to conclusions similar to those for the ITT population.

Table 8 Percent of Subjects Rescued Intent-To-Treat Population RESCUED S U C -A TM 1 TREATMENT -YE-S TNOSO CEPATJ[1 EFFICACY OBSERVATION PERIOD (0-8 HOURS) A) Placebo 27 13, TREATMENT 0.193 B) MS 60mg 20 21 B3-A N/D C) MS 60 mg /NTX 0.0 1 mg 19 22 C-A N/D D) MS 60Omg /NTX 0. 1mg 19 22 D-A N/D E) MS 60 mg /NTX 1mng 25 16 E-A N/D C-B N/D D-B N/D E-B N/D SAIFETY OBSERVATION PERIOD (0-24 HOURS) A) Placebo 37 3 TREATMENT 0.536 B) MS 60 mg 35 6 B-A N/D C) MS 60 mg /NTX 0.01 mg 33 8 C-A N/D D) MS 60mg /NTXO0.l1mg 33 8 D-A N/D E) MS 60 mg INTX 1 mg 35 6 E-A N/D C-B N/D D-13 N/D E-B N/D N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

WO 01/85150 PCT/US01/14644 64 Figures 6 is a visual presentation of the hourly pain relief scores presented in Table 9. The hourly pain relief scores were summarized and analyzed in 2 ways: first as a categorical variable and second as a numerical variable. Because results of these two methods were similar, only the results from the numerical version are presented here. Whereas the hourly pain relief scores for the placebo treatment were less than those for the active treatment groups which improved over time. There was separation between the placebo and the active treatment groups that continued throughout the 8-hour study period. Comparable pain relief was observed (see, e.g., 1-3 hours) in the MS alone group and the high-dose (1.0 mg NTX) combination group (Figure Highest pain relief scores were observed for the low-dose (0.01 mg NTX) combination group (Figure 6).

Table 9 Pain Relief (PR) Scores [1] Intent-To-Treat Population PAIN RELIEF SCORE (PR) P-VALUE P-VALUE TREATMENT N MEAN SD MIN MEDIAN I MAX SOURCE [3]

MINUTES

A) Placebo 40 0.38 0.628 0 0.00 2 TRT 0.522 0.552 B) MS 60 mg 41 0.56 0.923 0 0.00 4 BASEPI N/A 0.535 C) MS 60 mg/NTX 0.01 mg 41 0.63 0.888 0 0.00 3 BASEPI*TRT N/A 0.959 D) MS 60 mg /NTX 0.1 mg 41 0.61 0.997 0 0.00 3 B-A N/D N/D E) MS 60 mg/NTX 1 mg 41 0.71 0.929 0 0.00 3 C-A N/D N/D D-A N/D N/D E-A N/D N/D C-B N/D N/D D-B N/D N/D E-B N/D N/D PAIN RELIEF (PR) SCORES: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, 4 COMPLETE.

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCD TEST.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/A: NOT APPLICABLE, N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 9 (Continued) Pain Relief (PR) Scores [1] Intent-To-Treat Population PAIN RELIEF SCORE (PR) P-VALUE P-VALUE TREATMENT I N IMEAN SD I MIN MEDIAN MAX SOURCE [3] 1 HOUR A) Placebo 40 0.50 0.934 0 0.00 4 TRT 0.004** 0.009** B) MS 60 mg 41 1.02 0.908 0 1.00 3 BASEPI N/A 0.337 C) MS 60 mg /NTX 0.01 mg 41 1.37 1.280 0 1.00 4 BASEPI*TRT N/A 0.627 D) MS 60 mg/NTX 0.1 mg 41 1.29 1.167 0 1.00 4 B-A 0.032* 0.033* E) MS 60 mg /NTX 1 mg 41 1.10 1.114 0 1.00 4 C-A <0.001*** D-A 0.001** 0.001** E-A 0.014* 0.014* C-B 0.153 0.154 D-B 0.260 0.261 E-B 0.749 0.750 PAIN RELIEF (PR) SCORES: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, 4 COMPLETE.

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/A: NOT APPLICABLE, N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 9 (Continued) Pain Relief (PR) Scores [1] Intent-To-Treat Population PAIN RELIEF SCORE (PR) P-VALUE P-VALUE TREATMENT IN MEAN SD |MIN MEDIAN MAX SOURCE [3] 2 HOURS A) Placebo 40 0.58 0.813 0 0.00 3 TRT <0.001*** B) MS 60 mg 41 1.22 1.235 0 1.00 4 BASEPI N/A 0.169 C) MS 60 mg /NTX 0.01 mg 41 1.66 1.237 0 2.00 4 BASEPI*TRT N/A 0.054 D) MS 60 mg/NTX 0.1 mg 41 1.54 1.267 0 1.00 4 B-A 0.015* 0.013* E) MS 60 mg/NTX 1 mg 41 1.20 1.289 0 1.00 4 C-A <0.001*** D-A <0.001*** E-A 0.019* 0.017* C-B 0.094 0.089 D-B 0.226 0.219 E-B 0.925 0.924 PAIN RELIEF (PR) SCORES: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, 4 COMPLETE.

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/A: NOT APPLICABLE, N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 9 (Continued) Pain Relief (PR) Scores [1] Intent-To-Treat Population PAIN RELIEF SCORE (PR) P-VALUE P-VALUE TREATMENT IN I MEAN I SD I MIN MEDIAN I MAX I SOURCE [3] 3 HOURS A) Placebo 40 0.68 0.997 0 0.00 3 TRT 0.010* 0.013* B) MS 60 mg 41 1.34 1.334 0 1.00 4 BASEPI N/A 0.515 C) MS 60 mg/NTX 0.01 mg 41 1.68 1.404 0 1.00 4 BASEPI*TRT N/A 0.032* D) MS 60 mg/NTX 0.1 mg 41 1.49 1.362 0 1.00 4 B-A 0.023* 0.021* E) MS 60 mg/NTX 1 mg 41 1.22 1.423 0 0.00 4 C-A <0.001*** D-A 0.005** 0.005** E-A 0.063 0.060 C-B 0.241 0.234 D-B 0.614 0.609 E-B 0.675 0.670 PAIN RELIEF (PR) SCORES: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, 4 COMPLETE.

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/A: NOT APPLICABLE, N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 9 (Continued) Pain Relief (PR) Scores [1] Intent-To-Treat Population PAIN RELIEF SCORE (PR) PVLE -AU P-VALUE P -VALUE [3] TREATMENT IN MEAN SD I MIN MEDIAN MAX I SOURCE 4 HOURS A) Placebo 40 0.78 1.187 0 0.00 4 TRT 0.027* 0.030* B) MS 60 mg 41 1.56 1.501 0 2.00 4 BASEPI N/A 0.460 C) MS 60 mg/NTX 0.01 mg 41 1.66 1.353 0 2.00 4 BASEPI*TRT N/A 0.018* D) MS 60 mg/NTX 0.1 mg 41 1.61 1.498 0 1.00 4 B-A 0.013* 0.011* E) MS 60 mg/NTX 1 mg 41 1.22 1.492 0 0.00 4 C-A 0.005** 0.004** D-A 0.008** 0.007** E-A 0.158 0.150 C-B 0.754 0.750 D-B 0.875 0.873 E-B 0.275 0.266 PAIN RELIEF (PR) SCORES: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, 4 COMPLETE.

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/A: NOT APPLICABLE, N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 9 (Continued) x~ain Relief (PR) Scores [1] Intent-To-Treat Population PAIN RELIEF SCORE (PR) P-VALUE P-VALUE TREATMENT IN IMEAN74 SD IMIN MEDIAN MAX SOURCE [3]

HOURS

A) Placebo 40 0.68 0.997 0 0.00 3 TRT 0.008** 0.009** B) MS 60mg 41 1.56 1.534 0 2.00 4 BASEPI N/A 0.818 C) MS 60 mg /NTX 0.01 mg 41 1.71 1.453 0 2.00 4 BASEPI*TRT N/A 0.045* D) MS 60 mg /NTX 0. 1 mg 41 1.56 1.534 0 1.00 4 B-A 0.005** 0.004* E) MS 60mg /NTXlImg 41 1.20 1.487 0 0.00 4 C-A 0.00l** 0.00l** D-A 0.005'*' 0.004** B-A 0.100 0.096 C-B 0.640 0.636 D-B 1.000 1.000 -B 0.243 0.238 PAIN RELIEF (PR) SCORES: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, 4 COMPLETE.

FROM ONE-WAY ANALYSIS OF VARIANCE ANT) FISHIER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR ANDI FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, =0.01, or 0.00 1 RESPECTIVELY.

N/A: NOT APPLICABLE, NI): NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 9 (Continued) Pain Relief (PR) Scores [1] Intent-To-Treat Population PAIN RELIEF SCORE (PR) P-VALUE P-VALUE TREATMENT IN I MEAN I SD MIN I MEDIAN IMAX SOURCE [3] 6 HOURS A) Placebo 40 0.73 1.086 0 0.00 3 TRT 0.024* 0.029* B) MS 60 mg 41 1.61 1.547 0 2.00 4 BASEPI N/A 0.534 C) MS 60 mg /NTX 0.01 mg 41 1.63 1.479 0 1.00 4 BASEPI*TRT N/A 0.026* D) MS 60 mg/NTX 0.1 mg 41 1.61 1.611 0 1.00 4 B-A 0.007** 0.006** E) MS 60 mg /NTX 1 mg 41 1.24 1.562 0 0.00 4 C-A 0.005** 0.005** D-A 0.007** 0.006** E-A 0.114 0.108 C-B 0.940 0.939 D-B 1.000 1.000 E-B 0.261 0.253 PAIN RELIEF (PR) SCORES: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, 4 COMPLETE.

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/A: NOT APPLICABLE, N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 9 (Continued) Pain Relief (PR) Scores [1] Intent-To-Treat Population PAIN RELIEF SCORE (PR) P-VALUE P-VALUE TREATMENT -FN 1 MEAN SD I MIN I MEDIAN MAX I SOURCE [3] 7 HOURS A) Placebo 40 0.75 1.127 0 0.00 3 TRT 0.026* 0.029* B) MS 60 mg 41 1.61 1.595 0 1.00 4 BASEPI N/A 0.616 C) MS 60 mg/NTX 0.01 mg 41 1.71 1.569 0 1.00 4 BASEPI*TRT N/A 0.036* D) MS 60 mg/NTX 0.1 mg 41 1.66 1.622 0 1.00 4 B-A 0.011* 0.010* E) MS 60 mg/NTX 1 mg 41 1.27 1.613 0 0.00 4- C-A 0.005** 0.004** D-A 0.007** 0.006** E-A 0.126 0.120 C-B 0.771 0.768 D-B 0.884 0.882 E-B 0.309 0.303 PAIN RELIEF (PR) SCORES: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, 4 COMPLETE.

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/A: NOT APPLICABLE, N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 9 (Continued) Pain Relief (PR) Scores [1] Intent-To-Treat Population PAIN RELIEF SCORE (PR) P-VALUE P-VALUE [3]

TREATMENT

N MEAN SD I MIN MEDIAN MAX SOURCE 8 HOURS A) Placebo 40 0.78 1.187 0 0.00 4 TRT 0.056 0.067 B) MS 60 mg 41 1.61 1.595 0 1.00 4 BASEPI N/A 0.709 C) MS 60 mg /NTX 0.01 mg 41 1.63 1.577 0 1.00 4 BASEPI*TRT N/A 0.088 D) MS 60 mg/NTX 0.1 mg 41 1.61 1.611 0 1.00 4 B-A N/D N/D E) MS 60 mg /NTX 1 mg 41 1.29 1.632 0 0.00 4 C-A N/D N/D D-A N/D N/D E-A N/D N/D C-B N/D N/D D-B N/D N/D E-B N/D N/D PAIN RELIEF (PR) SCORES: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, 4 COMPLETE.

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/A: NOT APPLICABLE, N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

WO 01/85150 PCT/US01/14644 74 The hourly pain intensity difference (PID) data presented in Table 10 and Figure 7. The hourly PID scores for the placebo treatment were generally flat while the hourly PID scores generally improved over time for the active treatment groups.

The mean scores for the morphine and morphine/naltrexone groups were higher than the mean PID scores for the placebo group at each assessment time. The means for the low-dose and mid-dose groups were greater than the means for high-dose and placebo groups. Comparable pain relief as measured by PID scores was observed (see, 2-3 hours) in the MS alone group and the high-dose (1.0 mg NTX) combination group (Figure Highest pain relief as measured by PID scores was observed for the low-dose (0.01 mg NTX) combination group.

Table Pain Intensity Difference (PID) Scores [1] Intent-To-Treat Population PAIN RELIEF SCORE (PR) P-VALUE P-VALUE TREATMENT IN MEAN SD MIN MEDIAN MAX SOURCE [3]

MINUTES

A) Placebo 40 0.08 0.572 -1 0.00 1 TRT 0.367 0.317 B) MS 60 mg 41 0.17 0.667 -1 0.00 2 BASEPI N/A <0.001*** C) MS 60 mg /NTX 0.01 mg 41 0.34 0.762 -1 0.00 2 BASEPI*TRT N/A 0.854 D) MS 60 mg/NTX 0.1 mg 41 0.32 0.650 -1 0.00 2 B-A N/D N/D E) MS 60 mg/NTX 1 mg 41 0.29 0.782 -1 0.00 2 C-A N/D N/D D-A N/D N/D E-A N/D N/D C-B N/D N/D D-B N/D N/D E-B N/D N/D 1 HOUR A) Placebo 40 0.10 0.744 -1 0.00 2 TRT 0.11* 0.007** B) MS 60 mg 41 0.38 0.886 -1 0.00 2 BASEPI N/A <0.001*** C) MS 60 mg /NTX 0.01 mg 41 0.78 1.013 -1 1.00 3 BASEPI*TRT N/A 0.361 D) MS 60 mg/NTX 0.1 mg 41 0.59 0.836 -1 0.00 2 B-A 0.164 0.131 E) MS 60 mg /NTX 1 mg 41 0.56 0.950 -1 0.00 2 C-A <0.001*** D-A 0.015* 0.008** E-A 0.020* 0.012* C-B 0.041* 0.026* D-B 0.289 0.250 E-B 0.348 0.309 PAIN INTENSITY SCORES: 0 =NONE, 1 MILD, 2 MODERATE, 3 SEVERE.

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or< 0.001 RESPECTIVELY.

N/A: NOT APPLICABLE, N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 10 (Continued) Pain Intensity Difference (PID) Scores [1] Intent-To-Treat Population PAIN RELIEF SCORE (PR) P-VALUE P-VALUE TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE [3] 2 HOURS A) Placebo 40 0.20 0.648 -1 0.00 2 TRT 0.001** <0.001*** B) MS 60 mg 41 0.56 1.001 -1 1.00 3 BASEPI N/A <0.001*** C) MS 60 mg/NTX 0.01 mg 41 1.00 1.000 -1 1.00 3 BASEPI*TRT N/A 0.042* D) MS 60 mg/NTX 0.1 mg 41 0.83 0.834 -1 1.00 2 B-A 0.080 0.052 E) MS 60 mg/NTX 1 mg 41 0.54 1.075 -1 0.00 2 C-A <0.001*** D-A 0.002** <0.001*** E-A 0.103 0.069 C-B 0.032* 0.017* D-B 0.190 0.145 E-B 0.905 0.894 3 HOURS A) Placebo 40 0.23 0.660 -1 0.00 2 TRT 0.031* 0.021* B) MS 60 mg 41 0.63 1.067 -1 1.00 3 BASEPI N/A <0.001*** C) MS 60 mg/NTX 0.01 mg 41 0.93 1.081 -1 1.00 3 BASEPI*TRT N/A 0.025* D) MS 60 mg/NTX 0.1 mg 41 0.76 0.888 -1 1.00 3 B-A 0.066 0.043* E) MS 60 mg/NTX 1 mg 41 0.63 1.199 -1 0.00 3 C-A 0.001** <0.001*** D-A 0.017* 0.009** E-A 0.066 0.043* C-B 0.185 0.145 D-B 0.580 0.543 E-B 1.000 1.000 PAIN INTENSITY SCORES: 0= NONE, 1= MILD, 2 MODERATE, 3 SEVERE.

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/A: NOT APPLICABLE, N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 10 (Continued) Pain Intensity Difference (PID) Scores [1] Intent-To-Treat Population PAIN RELIEF SCORE (PR) P-VALUE P-VALUE TREATMENT N MEAN SD M1IN MEDIAN IMAX ISOURCE [3] 4 HOURS A) Placebo 40 0.28 0.751 -1 0.00 2 TRT 0.078 0.035* B) MS 60 mg 41 0.71 1.146 -1 1.00 3 BASEPI N/A <0.001*** C) MIS 60 mg /NTX 0.01 mg 41 0.80 0.954 -1 1.00 3 BASEPI*TRT N/A 0.010* D) MS 60 mg /NTX 0. 1 mg 41 0.88 0.980 -1 1.00 3 B-A N/D 0.039* B) MS 60mg /NTX 1mg 41 0.59 1.245 -1 0.00 3 C-A N/D 0.011* D-A N/D 0.004** E-A N/D 0.38 C-B NfD 0.638 D-B N/D 0.411 -B N/D 0.556

HOURS

A) Placebo 40 0.23 0.660 -1 0.00 2 TRT 0.24* 0.011* B3) NIS60Omg 41 0.71 1.167 -1 1.00 3 BASEPI N/A <0.001*** C) MS 60Omg /NIX 0.0 mg 41 0.93 1.058 -1 1.00 3 BASEPI*TRT N/A 0.024* D) MS 60 mg INTX 0. 1 mg 41 0.85 0.989 -1 1.00 3 B-A 0.038* 0.025* B) MS 60 mg INTX 1 mg 41 0.59 1.224 -1 0.00 3 C-A 0.002** 0.001""" D-A 0.007** 0.003** B-A 0.120 0.093 C-B 0.340 0.302 D-B3 0.524 0.491 -B 0.596 0.566 [11 PAIN INTENSITY SCORES: 0= NONE, 1= MILD, 2 MODERATE, 3 SEVERE.

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER' S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUJE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/A: NOT APPLICABLE, N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 10 (Continued) Pain Intensity Difference (PID) Scores [1] Initent-To-Treat Population PAIN RELIEF SCORE (PR) P-VALUEAU TREATMENT IN IMEAN ISD IMIN IMEDIAN IMAX ISOURCE -21U [1 6 HOURS A) Placebo 40 0.23 0.660 -1 0.00 2 TRT 0.032* 0.016* B) NIS 60mg 41 0.73 1.162 -1 1.00 2 BASEPI N/A <0.00l*** C) NIS60mg /NTX0.01 mg 41 0.90 1.114 -1 1.00 3 BASEPI*TRT N/A 0.013* D) MS 60Omg /NTXO0.1 mg 41 0.90 1.044 -1 1.00 3 B-A 0.035* 0.021* E) MS 60 mg /NTX 1 mg 41 0.63 1.299 -1 0.00 3 C-A 0.005** 0.002** D-A 0.005** 0.002** E-A 0.089 0.063 C-B3 0.474 0.433 D-B 0.474 0.433 -B 0.682 0.654 7 HOURS A) Placebo 40 0.25 0.707 -1 0.00 2 TRT 0.052 0.027* B) MIS 60 mg 41 0.76 1.220 -1 1.00 3 BASEPI N/A <0.001*** C) MIS 60Omg /NTXO0.01 mg 41 0.90 1.136 -1 1.00 3 BASEPI*TRT N/A 0.017* D) MIS 60mig /NTX 0.1 mg 41 0.93 1.058 -1 1.00 3 B-A N/D 0.027* E) MS 60 mg /NTX 1 mg 41 0.68 1.368 -1 0.00 3 C-A N/D 0.004** D-A N/D 0.003** E-A N/D 0.059 C-B3 N/D 0.519 D-B N/D 0.452 _E-B3 N/D 0.747 PAIN INTENSITY SCORES: 0 NONE, 1 -MILD, 2 MODERATE, 3 =SEVERE.

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANICE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or =0.001 RESPECTIVELY.

N/A: NOT APPLICABLE, NJD: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 10 (Continued) Pain Intensity Difference (PID) Scores [1] Intent-To-Treat Population PAIN RELIEF SCORE (PR) P-VALUE P-VALUE TREATMENT N MEAN SD MN I MEDIAN I MAX SOURCE [3] 8 HOURS A) Placebo 40 0.28 0.784 -1 0.00 3 TRT 0.095 0.056 B) MS 60 mg 41 0.71 1.230 -1 1.00 3 BASEPI N/A <0.001*** C) MS 60 mg /NTX 0.01 mg 41 0.88 1.144 -1 1.00 3 BASEPI*TRT N/A 0.029* D) MS 60 mg /NTX 0.1 mg 41 0.90 1.044 -1 1.00 3 B-A N/D N/D E) MS 60 mg /NTX 1 mg 41 0.68 1.350 -1 0.00 3 C-A N/D N/D D-A N/D N/D E-A N/D N/D C-B N/D N/D D-B N/D N/D E-B N/D N/D PAIN INTENSITY SCORES: 0 NONE, 1= MILD, 2 MODERATE, 3 SEVERE.

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/A: NOT APPLICABLE, N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

WO 01/85150 PCT/US01/14644 The mean MAXPAR scores presented in Table 11A were different among treatment groups. The mean MAXPAR scores were highest for the low-dose and mid-dose groups compared to all other groups. The mean scores for the low-dose and mid-dose groups were greater than the mean score for the morphine group, which in turn, was greater than the mean score for the placebo group. The mean PEAKPID scores presented in Table 11B were different among treatment groups, and were greater for the morphine/naltrexone groups compared to the placebo group.

Compared to all other groups, the mean PEAKPID scores were higher for the lowdose and mid-dose groups.

Table 11lA Maximum Pain Relief Scores (MAXPAR) Intent-To-Treat Population MAXIMUM PAIN RELIEF SCORE P-VALUEI P-VALUE TREATMENT IN IMEAN ISD IMIN I MEDIAN IMAX I SOUCRE [11 [21 A) Placebo 40 1.10 1.355 0.0 0.5 4.0 TRT 0.002** 0.004** B) MS 6 0 mg 41 1.95 1.532 0.0 3.0 4.0 BASEPI N/A 0.569 C) MS 60 mg /NTXO.0 1 mg 41 2.39 1.531 0.0 3.0 4.0 BASEPI*TRT N/A 0.100 D) MS 60 mg /NTX 0. 1mg 41 2.10 1.463 0.0 2.0 4.0 B-A 0.011* 0.011* E) MS 60 mg /NTX 1 mg 41 1.71 1.632 0.0 1.0 4.0 C-A <0.001*** D-A 0.003"' 0.003" E-A 0.071 0.068 C-B 0.188 0.184 D-B3 0.660 0.657 0.464 0.460 FROM ONE-WAY ANALYSIS OF VARIANCE AND) FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

[21 FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR ANT) FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE =0.05, =0.01, or =0.001 RESPECTIVELY.

N/A: NOT APPLICAB3LE Table 11B Peak Pain Intensity Difference (PEAKPID) Intent-To-Treat Population PEAK PAIN INTENSITY DIFFERENCE TREATMENT N MEAN -SD MIN MEDIAN MAX SOURCE P-VALUE P-VALUE [2] A) Placebo 40 0.53 0.877 -1 0.0 3 TRT 0.007** 0.004** B) MS 60 mg 41 1.10 1.068 -1 1.0 3 BASEPI N/A <0.001*** C) MS 60 mg/NTX 0.01 mg 41 1.41 1.140 -1 2.0 3 BASEPI*TRT N/A 0.073 D) MS 60 mg/NTX 0.1 mg 41 1.17 1.022 -1 1.0 3 B-A 0.019* 0.011* E) MS 60 mg/NTX 1 mg 41 1.00 1.304 -1 1.0 3 C-A <0.001*** D-A 0.008** 0.004** E-A 0.051 0.034* C-B 0.190 0.154 D-B 0.761 0.742 E-B 0.686 0.660 FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/A: NOT APPLICABLE WO 01/85150 PCT/US01/14644 83 Table 12 presents the summary and analysis of global evaluations. The placebo treatment had the highest number of subjects who had poor global evaluation scores based on subject evaluation. The profiles of the global evaluations scores are based on subjects' evaluations. Analyses of global evaluations for the evaluable subgroup also yielded similar results.

Table 12 Global Evaluation of Study Medication Intent-To-Treat Population TREATMENT N EXCELLENT VERY GOOD FAIR POOR MEAN (SE) SOURCE P-VALUE P-VALUE GOOD [2] A) Placebo 40 0 6 4 2 28 0.7 (1.16) TRT 0.004** 0.010* B) MS 60mg 41 3 10 8 3 17 1.5 (1.43) BASEPI N/A 0.958 C) MS 60mg/NTX0.01 mg 41 3 14 9 3 11 1.9 (1.36) BASEPI*TRT N/A 0.029* MS60mg/NTX 0.1mg 41 3 9 7(17.1%) 8(19.5%) 14 1.5 (1.36) B-A 0.008** 0.008** E) MS60mg/NTXl 1mg 41 4 5 10 2 20 1.3 (1.44) C-A D-A 0.007** 0.008 E-A 0.045 0.047 C-B 0.214 0.190 D-B 1.000 1.000 0.536 0.509 FROM ONE-WAY ANALYSIS OF VARIANCE AND ITS FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

FROM TWO-WAY ANALYSIS OF VARIANCE WITH BASELINE PAIN INTENSITY AS A BLOCKING FACTOR AND ITS FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, OR <=0.001 RESPECTIVELY N/A: NOT APPLICABLE WO 01/85150 PCT/US01/14644 The majority of adverse events reported were categorized as digestive (nausea or vomiting) or nervous system (dizziness or somnolence) as further shown in Tables 13A or 13B. Figure 8 represents a summary of exemplary adverse side effects attenuated according to methods and compositions of the invention.

Table 13A Adverse Events By Body System And Severity Safety Population Total No. Of Total Severity [2] Body System No. Of Subjects Source P-Value No. Of Mild Moderate Severe Adverse Events Treatment Subjects W/Event Events (Costart English) Total Number Of Events Adverse Events (All Body Systems) A) PLACEBO 40 11 TRT 17 7 5 5 (29.4%) B) MS60MG 41 35 A-B 82 28 32 22 (26.8%) C) MS 60 MG/NTX 0.01 MG 41 36 A-C 93 22 40 31 (33.3%) D) MS 60 MG/NTX 0.1 MG 41 37 A-D 102 28 40 34 (33.3%) E) MS 60 MG/NTX 1MG 41 31 A-E 64 31 22 11 (17.2%) Body As A Whole All Events A) PLACEBO 40 4 TRT 0.675 4 1 3 0 B) MS 60MG 41 6 7 4 3 0 C) MS 60 MG/NTX 0.01 MG 41 8 19.5%) 8 2 25.0%) 4 50.0%) 2 25.0%) D) MS 60 MG/NTX 0.1MG 41 7 10 3 5 2 (20.0%) E) MS 60 MG/NTX 1 MG 41 4( 4 2 2 0 Abdominal Pain A) PLACEBO 40 0 TRT 0.512 0 0 0 0 MG 41 0 0 0 0 0 C) MS 60 MG/NTX 0.01 MG 41 2 2 0 0 2 (100.0%) D) MS 60 MG/NTX 0.1MG 41 1 1 0 0 1 (100.0%) E) MS 60 MG/NTX I MG 41 0 0 0 0 0 P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR 0.001 RESPECTIVELY.

Table 13A (Continued) Adverse Events By Body System And Severity Safety Population Total No. Of Total Severity [2] Body System No. Of Subjects Source P-Value No. Of -Mild Mode Adverse Events Treatment Subjects W/Event Events (Costart English) Asthenia Fever A) PLACEBO B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MG/NTX 1 MG A) PLACEBO B) MS 60MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MG/NTX 1 MG A) PLACEBO B) MS 60MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MG/NTX 1 MG A) PLACEBO B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MG/NTX 1 MG 2.4%) 2.4%) 2.4%) 2.4%) TRT 1.000 0 1 (100.0%) 0 0 1 (100.0%) Headache Injection Site Hemorrhage 1 2.5%) 0 0 0 0 3 7.5%) 5 (12.2%) 3 7.3%) 4 9.8%) 3 7.3%) 0 1 2.4%) 0 0 0 TRT 0.196 0 0 1 (100.0%) 1 (100.0%) 0 1 (100.0%) 0 0 0 0 2 66.7%) 3 60.0%) 1 33.3%) 3 50.0%) 2 66.7%) 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (16.7%) 0 TRT 0.960 1 33.3%) 2 40.0%) 2 66.7%) 2 (33.3%) 1 (33.3%) 0 1 (100.0%) 0 0 0 TRT 1.000 P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL I SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR 0.001 RESPECTIVELY.

FREATMENT EFFECT AND Table 13A (Continued) Adverse Events By Body System And Severity Safety Population Total No. Of Total Severity [2] Body System No. Of Subjects Source P-Value No. Of Mild Moderate Severe Adverse Events Treatment Subjects W/Event Events (Costart English) Overdose A) PLACEBO 40 0 TRT 1.000 0 0 0 0 Pain Cardiovascular All Events Hemorrhage B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60MG/NTX 0.1 MG E) MS 60 MG/NTX 1 MG A) PLACEBO B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MG/NTX 1 MG A) PLACEBO B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MG 60 MG/NTX 1 MG A) PLACEBO B) MS 60MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MG 60 MG/NTX 1 MG 0 1 2.4%) 0 0 0 0 1 2.4%) 2 4.9%) 0 0 0 TRT 0.512 TRT 0.124 0 0 0 1 (50.0%) 0 0 2 (66.7%) 2 (50.0%) 2 (40.0%) 1 (100.0%) 0 1 (100.0%) 0 0 0 0 1 (100.0%) 1 50.0%) 0 0 1 (33.3%) 1 25.0%) 3 (60.0%) 0 0 0 0 1 (100.0%) 0 7.3%) 9.8%) 12.2%) 2.4%) 0 0 0 0 0 0 0 1 (25.0%) 0 0 0 0 0 0 0 TRT 1.000 2.4%) P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR 0.001 RESPECTIVELY.

Table 13A (Continued) Adverse Events By Body System And Severity Safety Population Total No. Of Total Severity [2] Body System No. Of Subjects Source P-Value No. Of Mild Moderate Severe Adverse Events Treatment Subjects WfEvent [11 Events (Costart English) Hypertension A) PLACEBO 40 0 TRT 1.000 0 0 00 Vasodilatation Digestive All Events Diarrhea 13) MS 60 MG C) MS 60 MGINTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MG 60MGINTX IMG A) PLACEBO B) MS 60 MG C) MS 60 MGINTX 0.01 MG D) MS 60 MG/NTX 0. 1 MG E) MS 60 MG/NTh 1 MG A) PLACEBO B) MIS 60MG C) MS 60 MGINTX 0.01 MG D) MS 60 MG!NTX 0. 1 MG E) MS 60 MG/NTX 1 MG A) PLACEBO B) MS 60 MG C) MS 60 MG/NTh 0.01 MG D) MS 60OMG/NTX 0. 1 MG E) MG 60MG/NTX IMG 0 0 1 0 0 3 4 3 1 5 (12.5%) 23 (56.1%) 25 (61.0%) 29 (70.7%) 16 (39.0%) 0 0 0 2 0 TRT 0.257 <0.00 1** <0.001 <0.001*** <0.001*** <0.010* <0.007** 0 0 1 (100.0%) 0.

0 2 (66.7%) 2 (50.0%1) 1 33.3%) 1 (100.0%) 1 (12.5%) 6 (15.0%) 7 (15.2%) 8 (17.0%) 6 (24.0%) 0 0 0 1 (50.0%) 0 1 (33.3%) 1 25.0%) 2 (66.7%) 0 2 (25.0%) 4 (35.0%) .5 (32.6%) 2 (25.5%) 8 (32.0%) 0 0 0 1 (50.0%) 0 0 0 0 5 62.5%) 20 (50.0%1) 24 (52.2%) 27 (57.4%) 11 (44.0%) 0 0 0 TRT 0.196 P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

[21 THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR 0.001 RESPECTIVELY.

Table 1 3A (Continued) Adverse Events By Body System And Severity Safety Population Total No. Of Total Severity [2] Body System No. Of Subjects Source P-Value No. Of MAild Moderate Severe Adverse Events Treatment Subjects W/Event El] Events (Costart English) Dyspepsia A) PLACEBO 40 1 TRT 0.512 1 1 (10u%) 0 0 Nausea Vom-iting Musculoskeletal All Events B) MS 60 MG C) MS 60OMG/NTIX 0.0 1 MG D) MS 60 MG/NTX 0. 1 MG E) MS 60 MGINTX 1 MG A) PLACEBO B) MS 60 MG C) MS 60 MG/NTX 0.0 1 MG D) MS 60OMG/NTX0. 1 MG E) MS 60 MGINTIX 1 MG A) PLACEBO B) MS 60 MG C) MS 60OMGINTX 0.0 1 MG D) MS 60 MG[NTX 0. 1 MG E) MS 60 MG/NTX 1 MG A) PLACEBO B) MS 60 MG C) MS 60 MGNTXO0.0 1MG D) MS 60 MG/NTh 0. 1 MG E) MS 60 MG/NTX 1 MG 0 0 0 1 2.4%) 4 (10.0%) 21 (51.2%) 23 (56.1%) 25 (61.0%) 14 (34.1%) <0.001*** <0.001*** <0.001*** <0.00 <0.014* <0.026* <0.001*** <0.001*** <0.001 <0.001*** <0.020* <0.035* 27.3%) 26.9%) 26.9%) 33.3%) (50.0%) (63.6%) 57.7%) 42.3%) 53.3%) 50.0%) 9.1%) 15.4%) 30.8%) 13.3%) 0 0 0 1 (100.0%) 7.5%) C43.9%) (48.8%) (46.3%) (22.0%) 3 (100.0%) 18 (100.0%) 20 (100.0%) 19 (100.0%) 9 (100.0%) 0 0 0 0 0 0 1 2.4%) 0 0 0 TRT 1.000 0 1 (100.0%) 0 0 0 P-VALUES ARE FROM FISHER'S EXACT TEST AND) ARE PROVIDED SIGNIFICANT PAIRWISE COMPARISONS ONLY.

FOR OVERALL TREATMENT EFFECT AN) THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE =0.05, 0.01, OR <K 0.001 RESPECTIVELY.

Table 1 3A (Continued) Adverse Events By Body System And Severity Safety Population Total No. Of Total Severity [2] Body System No. Of Subj ects Source P-Value No. Of Mild Moderate Severe Adverse Events Treatment Subjects W/Event Events (Costart English) Myalgia Nervous System All Events A) PLACEBO B) MS 60 MG C) MS 60 MG/NTX 0.0 1 MG D) MS 60 MG/NTX 0. 1 MG E) MS 60MGINTX 1MG A) PLACEBO B) MS 60 MG C) MS 60 MG/NTfX 0.01 MG D) MS 60 MG/NTh 0. 1 MG E) MS 60OMG/NTX I MU A) PLACEBO B) MS 60 MG C) MS 60MG/N'IX 0.0 1 MG D) MS 60 MG/NTh 0. 1 MG E) MS 60 MG/NTfX I MG A) PLACEBO B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NIX 0. 1 MG E) MS 60 MGINTX 1 MG 0 1 2.4%) 0 0 0 2 18 (43.9%) 22 (53.7%) 22 (53.7%) 20 (48.8%) 0 0 1 2.4%) 1 2.4%) 0 2 15 (36.6%) 16 (39.0%) 17 C41.5%/,) 13 (31.7%) TRT 1.000 <0.001 <0.001 <0.001*** <0.001*5* <0.001 *5* Anxiety TRT 1.000 2 (100.0%) 11 (45.8%) 6 (24.0%) 9 (31.0%) 16 (61.5%) 0 0 0 1 (100.0%) 0 2 (100.0%) 9 S 2.9%) 5 (31.3%) G 30.0%) 8 61.5%) 0 1 (100.0%) 0 0 0 0 11 45.8%) 15 60.0%) 15 51.7%/) 10 38.5%) 0 0 1 (100.0%) 0 0 0 6 35.3%/) 9 56.3%) 10 (50.0%) 5 (38.5%) 0 2 4 (16.0%) 5 (17.2%) 0 Dizziness <0.001 <0.001 <0.001 <0.001*5 <0.003 0 2 (118%) 2 (12.5%) 4 (20.0%) 0 P-VALUES ARE FROM FISHER'S EXACT TEST AND1T ARE PRO VIDED FOR OVERALL I SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VA-LUE 0.05, 0.01, OR 0.001 RESPECTIVELY.

'REATMENT EFFECT AND Table 13A (Continued) Adverse Events By Body System And Severity Safety Population Total No. Of Total Severity [2] Body System No. Of Subjects Source P-Value No. Of Mild Moderate Severe Adverse Events Treatment Subjects W/Event Events (Costart English) Dry Mouth Euphoria Hallucinations Hypertonia A) PLACEBO B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MG/NTX 1MG A) PLACEBO B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MG/NTX IMG A) PLACEBO B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MG/NTX 1 MG A) PLACEBO B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MG/NTX 1 MG 0 0 0 0 2 4.9%) 0 0 5 (12.2%) 2 4.9%) 0 0 1 2.4%) 0 0 0 TRT 0.196 TRT 0.005** TRT 1.000 TRT 1.000 0 0 0 0 1 (50.0%) 0 0 0 1 50.0%) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (50.0%) 0 0 4 (80.0%) 1 (50.0%) 0 0 1 (100.0%) 0 0 0 0 1 (100.0%) 0 1 (100.0%) 0 0 0 0 0 0 0 0 1 (20.0%) 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 2.4%) 2.4%) 2.4%) P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR 0.001 RESPECTIVELY.

Table 13A (Continued) Adverse Events By Body System And Severity Safety Population Total No. Of Total Severity [2] Body System No. Of Subjects Source P-Value No. Of Mild Moderate Severe Adverse Events Treatment Subjects W/Event Events (Costart English) Paresthesia A) PLACEBO 40 0 TRT 0.802 0 0 0 0 Somnolence Tremor B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MG/NTX 1 MG A) PLACEBO B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MG/NTX 1 MG A) PLACEBO B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MGINTX 1 MG A) PLACEBO B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MG/NTX 1 MG 2.4%) 2.4%) 4.9%) 9.8%) 2.4%) 7.3%) 19.5%) 2.4%) 2.4%) 2.4%) 5.0%) 2.4%) 2.4%) TRT 0.009** A-E 0.005** C-E 0.029* TRT 1.000 TRT 0.335 0 1 (100.0%) 0 1 (50.0%) 0 2 50.0%) 0 0 5 (62.5%) 0 0 0 1 (100.0%) 1 (100.0%) 2 (100.0%) 0 0 0 1 (100.0%) 0 0 1 (100.0%) 1 50.0%) 0 2 50.0%) 1 (100.0%) 2 (66.7%) 3 (37.5%) 0 1 (100.0%) 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 1 (33.3%) 0 0 0 0 0 0 0 0 0 0 0 Respiratory All Events P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR 0.001 RESPECTIVELY.

Table 13A (Continued) Adverse Events By Body System And Severity Safety Population Total No. Of Total Severity [2] Body System No. Of Subjects Source P-Value No. Of Mild Moderate Severe Adverse Events Treatment Subjects W/Event Events (Costart English) Dyspnea A) PLACEBO 40 0 TRT 1.000 0 .0 0 0 B) MS 60 MG 41 0 0 0 0 0 C) MS 60 MG/NTX 0.01 MG 41 0 0 0 0 0 D) MS 60MG/NTX 0.1 MG 41 0 0 0 0 0 E) MS 60 MG/NTX 1 MG 41 1 1 1 0 0 Epistaxis A) PLACEBO 40 1 TRT 0.512 1 1 (100.0%) 0 0 B) MS 60MG 41 0 0 0 0 0 C) MS 60 MG/NTX 0.01 MG 41 1 1 0 1 (100.0%) 0 D) MS 60 MG/NTX 0.1 MG 41 0 0 0 0 0 E) MS 60 MG/NTX 1 MG 41 0 0 0 0 0 Rhinitis A) PLACEBO 40 1 TRT 0.196 1 1 (100.0%) 0 0 B) MS 60MG 41 0 0 0 0 0 C) MS 60 MG/NTX 0.01 MG 41 0 0 0 0 0 D) MS 60 MG/NTX 0.1 MG 41 0 0 0 0 0 E) MS 60 MG/NTX 1 MG 41 0 0 0 0 0 Skin/Appendages All Events A) PLACEBO 40 0 TRT 0.244 0 0 0 0 B) MS 60MG 41 4 4 2 50.0%) 2 50.0%) 0 C) MS 60 MG/NTX 0.01 MG 41 4 5 2 3 60.0%) 0 D) MS 60 MG/NTX 0.1 MG 41 4 4 0 4 (100.0%) 0 E) MS 60 MG/NTX 1 MG 41 4 5 3 2 0 P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR 0.001 RESPECTIVELY.

Table 13A (Continued) Adverse Events By Body System And Severity Safety Population Total No. Of Total Severity [2] Body System No. Of Subjects Source P-Value No. Of Mild Moderate Severe Adverse Events Treatment Subjects W/Event Events (Costart English) Puritus A) PLACEBO 40 0 TRT 0.264 0 0 0 0 Sweating B) MS 60MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MG/NTX 1 MG A) PLACEBO B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MG/NTX 1 MG A) PLACEBO B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MG/NTX 1 MG A) PLACEBO B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MG/NTX 1 MG 4.9%) 9.8%) 9.8%) 4.9%) 2.4%) 2.4%) 1 (50.0%) 2 (50.0%) 0 2 (100.0%) TRT 1.000 0 2 0 0 2 4.9%) (50.0%) (50.0%) (100.0%) TRT 0.223 Special Senses All Events 0 1 (50.0%) 0 0 1 50.0%) 1 (100.0%) 2 (100.0%) 3 (100.0%) 3 75.0%) 2 (100.0%) 0 0 1 (100.0%) 0 1 (100.0%) 0 1 50.0%) 0 0 1 (50.0%) 0 0 0 1 (25.0%) 0 2.5%) 4.9%) 7.3%) 9.8%) 4.9%) TRT 0.798 P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR 0.001 RESPECTIVELY.

Table 13A (Continued) Adverse Events By Body System And Severity Safety Population Total No. Of Total Severity [2] Body System No. Of Subjects Source P-Value No. Of Mild Moderate Severe Adverse Events Treatment Subjects W/Event Events (Costart English) Conjunctivitis A) PLACEBO 40 1 TRT 0.798 1 1 (100.0%) 0 0 Urogenital All Events Dysuria Metrorrhagia B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MG/NTX 1 MG A) PLACEBO B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MG/NTX 1 MG A) PLACEBO B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MG/NTX 1 MG A) PLACEBO B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MG/NTX 1 MG 4.9%) 7.3%) 9.8%) 4.9%) 2.4%) 2.4%) 7.3%) 2 (100.0%) 3 (100.0%) 3 75.0%) 2 (100.0%) 0 0 1 25.0%) 0 0 0 1 (100.0%) 0 0 TRT 0.278 TRT 1.000 0 0 1 1 (100.0%) 1 0 3 3 (100.0%) 0 0 0 0 0 0 0 0 1 1 (100.0%) 0 0 0 0 1 1 (100.0%) 0 0 0 0 0 0 2.4%) 2.4%) TRT 1.000 P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR 0.001 RESPECTIVELY.

Table 13A (Continued) Adverse Events By Body System And Severity Safety Population Total No. Of Total Severity [2] Body System No. Of Subjects Source P-Value No. Of Mild Moderate Severe Adverse Events Treatment Subjects W/Event Events (Costart English) Urinary Retention A) PLACEBO 40 0 TRT 0.512 0 0 0 0 B) MS 60 MG C) MS 60 MG/NTX 0.01 MG D) MS 60 MG/NTX 0.1 MG E) MS 60 MGINTX 1 MG 0 1 2.4%) 2 4.9%) 0 0 0 2 (100.0%) 0 0 1 (100.0%) 0 0 P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR 0.001 RESPECTIVELY.

Table 13B SELECTED ADVERSE EVENTS SAFETY POPULATION FISHER'S EXACT P-VALUE [1] NO. OF SUBJECTS WITH AEs FOR AEs RELATED

RELATED

ADVERSE TOTAL TO WITH TO FOR EVENT NO. OF WITH STUDY SERIOUS STUDY SERIOUS (ENGLISH) TREATMENT SUBJECTS AEs DRUG AEs SOURCE FOR AEs DRUG AEs DIZZINESS A) PLACEBO 40 2 2 0 TREATMENT N/A B) MS 60 MG 41 15(36.6%) 15(36.6%) 0 A-B N/A C) MS 60 MG/NTX 0.01 MG 41 16 16(39.0%) 0 A-C N/A D) MS 60 MG/NTX 0.1MG 41 17(41.5%) 17(41.5%) 0 A-D N/A E) MS 60 MG/NTX 1 MG 41 13 13 0 A-E 0.003** 0.003** N/A B-C 1.000 1.000 N/A B-D 0.821 0.821 N/A B-E 0.816 0.816 N/A C-D 1.000 1.000 N/A C-E 0.644 0.644 N/A D-E 0.491 0.491 N/A P-VALUE COMPARES THE PROPORTION OF SUBJECTS WITH EVENTS.

RELATIONSHIP TO STUDY DRUG= 'SUSPECTED' OR 'PROBABLE'.

N/A: NOT APPLICABLE.

P-VALUE 0.01, OR 0.001 RESPECTIVELY.

Table 13B SELECTED ADVERSE EVENTS SAFETY POPULATION FISHER'S EXACT P-VALUE [1] NO. OF SUBJECTS WITH AEs FOR AEs RELATED

RELATED

ADVERSE TOTAL TO WITH TO FOR EVENT NO. OF WITH STUDY SERIOUS STUDY SERIOUS (ENGLISH) TREATMENT SUBJECTS AEs DRUG AEs SOURCE FOR AEs DRUG AEs NAUSEA A) PLACEBO 40 4 3 0 TREATMENT N/A B) MS 60MG 41 21(51.2%) 21(51.2%) 0 A-B N/A C) MS 60 MG/NTX 0.01 MG 41 23 23 0 A-C N/A D) MS 60 MG/NTX 0.1 MG 41 25 25 0 A-D N/A E) MS 60 MG/NTX 1 MG 41 14(34.1%) 12(29.3%) 0 A-E 0.014* 0.020* N/A B-C 0.824 0.824 N/A B-D 0.504 0.504 N/A B-E 0.180 0.070 N/A C-D 0.822 0.822 N/A C-E 0.075 0.024* N/A D-E 0.026* 0.007** N/A P-VALUE COMPARES THE PROPORTION OF SUBJECTS WITH EVENTS.

RELATIONSHIP TO STUDY DRUG 'SUSPECTED' OR 'PROBABLE'.

N/A: NOT APPLICABLE.

P-VALUE 0.01, OR 0.001 RESPECTIVELY.

Table 13B SELECTED ADVERSE EVENTS SAFETY POPULATION FISHER'S EXACT P-VALUE [1] NO. OF SUBJECTS WITH AEs FOR AEs RELATED

RELATED

ADVERSE TOTAL TO WITH TO FOR EVENT NO. OF WITH STUDY SERIOUS STUDY SERIOUS (ENGLISH) TREATMENT SUBJECTS AEs DRUG AEs SOURCE FOR AEs DRUG AEs SOMNOLENCE A) PLACEBO 40 0 0 0 TREATMENT 0.009** 0.009** N/A B) MS 60MG 41 4( 4( 0 A-B 0.115 0.115 N/A C) MS 60 MG/NTX 0.01 MG 41 1( 0( 0 A-C 1.000 1.000 N/A D) MS 60 MG/NTX 0.1 MG 41 3 3( 0 A-D 0.240 0.240 N/A E) MS 60 MG/NTX 1 MG 41 8 8 0 A-E 0.005** 0.005** N/A B-C 0.359 0.359 N/A B-D 1.000 1.000 N/A B-E 0.349 0.349 N/A C-D 0.615 0.615 N/A C-E 0.029* 0.029* N/A D-E 0.193 0.193 N/A P-VALUE COMPARES THE PROPORTION OF SUBJECTS WITH EVENTS.

RELATIONSHIP TO STUDY DRUG= 'SUSPECTED' OR 'PROBABLE'.

N/A: NOT APPLICABLE.

P-VALUE 0.01, OR 0.001 RESPECTIVELY.

Table 13B SELECTED ADVERSE EVENTS SAFETY POPULATION FisHER'S EXACT P-VALUE [11 NO. OF SUBJECTS WITH AEs FOR AEs RELATED

RELATED

ADVERSE TOTAL TO WITH TO FOR EVENT NO. OF WITH STUDY SERIOUS STUDY SERIOUS (ENGLISH) TREATMENT SUBJECTS AEs DRUG AEs SOURCE FOR AEs DRUG AEs VOMITING A) PLACEBO 40 3 3 0 TREATMENT N/A B) MS 60 MG 41 18 18 0 A-B N/A C) MS 60 MG/NTXO0.0 1 MG 41 20 20 0 A-C <0.001** N/A D) MS 60 MGINTX 0.1 MG 41 19(46.3%) 19 0 A-D <0.001* <0.001** N/A E) MS 60MG/NTX 1 MG 41 9(22.0%) 9(22.0%) 0 A-E 0.115 0.115 N/A B-C 0.824 0.824 N/A B-D 1.000 1.000 N/A B-E 0.059 0.059 N/A C-D 1.000 1.000 N/A C-E 0.020* 0.020* N/A 0.035* 0.035* N/A P-VALUE COMPARES THE PROPORTION OF SU13JECTS WITH EVENTS.

RELATIONSHIP TO STUDY DRUG 'SUSPECTED' OR 'PROBABLE'.

N/A: NOT APPLICABLE.

P-VALUE 0.01, OR 0.001 RESPECTIVELY.

WO 01/85150 PCT/US01/14644 102 Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of various aspects of the invention. Thus, it is to be understood that numerous modifications may be made in the illustrative embodiments and other arrangements may be devised without departing from the spirit and scope of the invention.

WO 01/85150 PCT/US01/14644 103 EXAMPLE 2 The results from the clinical study as described in Example 1 were analyzed by gender.

The results for females and males from the Example 1 clinical study are shown in the following Tables and Figures.

A total of 204 subjects were randomized; among them 201 subjects were deemed evaluable. One subject in each of the placebo, MS and MS/0.1 NTX groups was not evaluable because the subject took rescue medication less than 90 minutes after dosing. Tables 14A and 14B show the number of female and male subjects separately.

Table 14A Analysis Populations, Female Patients Treatments Placebo with MS (60 mg) MS (60 mg) MS (60 mg) MS (60 mg) Placebo with Placebo with NTX with NTX with NTX Total (0.01 mg) (0.1 mg) (1.0 mg) Patients Enrolled 22 23 20 20 20 105 Safety 22 (100.0%) 23 (100.0%) 20 (100.0%) 20 (100.0%) 20(100.0%) 105 (100.0%) Intent-To-Treat 22 (100.0%) 23 (100.0%) 20 (100.0%) 20 (100.0%) 20(100.0%) 105 (100.0%) Evaluable 22 (100.0%) 23 (100.0%) 20 (100.0%) 19 20(100.0%) 104 (99.0%) PATIENTS WITH DEMOGRAPHIC INFORMATION.

Table 14B Analysis Populations, Male Patients Treatments Placebo with MS (60 mg) MS (60 mg) MS (60 mg) MS (60 mg) Placebo with Placebo with NTX with NTX with NTX Total (0.01 mg) (0.1 mg) (1.0 mg) Patients Enrolled 18 18 21 21 21 99 Safety 18 (100.0%) 18 (100.0%) 21 (100.0%) 21 (100.0%) 21(100.0%) 99 (100.0%) Intent-To-Treat 18 (100.0%) 18 (100.0%) 21. (100.0%) 21 (100.0%) 21(100.0%) 99 (100.0%) Evaluable 17 17 21 (100.0%) 21 (100.0%) 21(100.0%) 97 (98.0%) PATIENTS WITH DEMOGRAPHIC INFORMATION.

WO 01/85150 PCT/US01/14644 106 The demographic and baseline characteristics were summarized by treatment groups for the ITT population (all randomized patients) and the evaluable population (all randomized patients with at least one efficacy evaluation at 90 minutes or more after dosing) (Table 15A for females and Table 15B for males). Demographic characteristics included age, race/ethnicity, sex, weight, height, medical history, teeth extracted (impacted and non-impacted), baseline pain intensity, and baseline visual analog scale.

The demographics for the total ITT population were comparable across all treatment groups. Female subjects ranged in age from 16 to 35 years; male subjects ranged in age from 16 to 39 years. There were some differences among treatment groups in the maximum degree of impaction of third molar extracted. No adjustments in the analyses were made to take into account these differences among treatment groups. Generally, no differences among overall treatment groups were noted in the number of patients with either a significant medical history or disease of any body system. The baseline pain intensity scores and visual analog scale scores, respectively, are shown in Tables 16A and 16B for females and Tables 16C and 16D for males.

Table Baseline Characteristics Intent-To-Treat Population, Female Patients Placebo MS (60 mg) MS (60 mg) MS (60 mg) with MS (60 mg) with P-Value with NTX NTX (0.1 mg) NTX 1.0 mg) (0.01 mg) Age (yrs) N 22 23 20 20 20 0.294 [1] Mean 21.6 22.6 21.4 23.5 22.9 SD 2.63 3.92 2.56 5.03 3.18 Median 21.0 22.0 21.0 22.0 23.0 Range 19-27 19-32 18-28 16-35 19-29 Race/Ethnic Caucasian 13 12 15 12 14 0.566 [2] Origin Black 4 2 1 1 1 Asian 2 1 0 2 1 Hispanic 3 8 4 5 4 (20.0%) Total 22 23 20 20 Height (cm) N 22 23 20 20 20 0.323 [1] Mean 165.0 163.1 167.2 163.5 163.6 SD 7.48 6.96 5.42 8.52 6.48 Median 165.1 162.6 167.6 163.2 162.6 Range 152.4 179.1 149.9 177.8 157.5 176.5 139.7- 177.8 154.9- 180.3 One-Way Analysis of Variance with Treatment as the Factor.

Fisher's Exact Test.

Black, Asian, Hispanic, and Other are Combined into One Category to Derive P-Value.

3 or More Third Molars Extracted as One Category to Derive P-Value.

Table 15A (Continued) Baseline Characteristics Intent-To-Treat Population, Female Patients Placebo MS (60 mg) MS (60 mg) MS (60 mg) with MS (60 mg) with P-Value with NTX NTX (0.1 mg) NTX 1.0 mg) (0.01 mg) Weight (kg) N 22 23 20 20 20 0.535 [1] Mean 64.5 68.1 67.5 61.4 67.3 SD 14.00 15.87 13.55 9.37 17.98 Median 60.5 65.0 66.2 61.8 62.1 Range 47.3 106.4 42.7 117.3 50.9 105.5 46.4- 79.1 47.3 105.9 Number of 2 22 (100.0%) 23 (100.0%) 20 (100.0%) 19 19 0.324 [2] Third Molars 3 0 0 0 0 1 Extracted 4 0 0 0 1 0 TOTAL 22 23 20 20 Time N 22 23 20 20 20 0.741 [2] Between End Mean 137.8 144.9 145.6 156.3 141.5 of Surgery SD 36.86 47.22 54.74 47.28 33.94 and Study Median 130.0 138.0 134.5 156.5 146.0 Medication Range 79.0 222.0 71.0 259.0 88.0 299.0 78.0-255.0 88.0 224.0 (Minutes) One-Way Analysis of Variance with Treatment as the Factor.

Fisher's Exact Test.

Black, Asian, Hispanic, and Other are Combined into One Category to Derive P-Value.

3 or More Third Molars Extracted as One Category to Derive P-Value.

Table Baseline Characteristics Intent-To-Treat Population, Male Patients Placebo MS (60 mg) MS (60 mg) MS (60 mg) with MS (60 mg) with P-Value with NTX NTX (0.1 mg) NTX 1.0 mg) (0.01 mg) Age (yrs) N 18 18 21 21 21 0.980 [1] Mean 22.6 23.1 22.7 22.7 22.1 SD 3.24 3.90 4.24 5.25 5.17 Median 22.0 22.5 21.0 21.0 20.0 Range 18-28 19-31 18-35 16-39 18-39 Race Caucasian 13 13 16 16 12 0.688[2] Black 0 2 0 0 2 Asian 1 0 1 0 4 (19.0%) Hispanic 4 3 3 4 2 Other 0 0 1 1 1 Total 18 18 21 21 21 Height (cm) N 18 18 21 21 21 0.666 [1] Mean 176.8 180.4 180.2 179.0 178.8 SD 8.13 10.47 7.87 6.62 6.68 Median 177.8 180.3 182.9 180.3 177.8 Range 160.0- 152.9- 198.1 162.6 193.0 167.6 194.3 165.1 188.0 188.0 One-Way Analysis of Variance with Treatment as the Factor.

Fisher's Exact Test.

Black, Asian, Hispanic, and Other are Combined into One Category to Derive P-Value.

3 or More Third Molars Extracted as One Category to Derive P-Value.

Table 15B (Continued) Baseline Characteristics Intent-To-Treat Population, Male Patients Placebo MS (60 mg) MS (60 mg) MS (60 mg) with MS (60 mg) with P-Value with NTX NTX (0.1 mg) NTX 1.0 mg) (0.01 mg) Weight (kg) N 18 18 21 21 21 0.145 [1] Mean 74.1 85.0 76.5 79.8 77.6 SD 12.24 14.70 11.03 12.72 15.47 Median 72.5 81.8 77.7 75.5 73.6 Range 56.8 103.6 64.1 114.5 55.9 95.5 56.8 104.5 56.8 122.3 Number of 2 18 (100.0%) 17 21 (100.0%) 18 21 (100.0%) 0.275 [2] Third Molars 3 0 1 0 2 0 Extracted 4 0 0 0 1 0 TOTAL 18 18 21 21 21 Time N 18 18 21 21 21 0.797 [2] Between End Mean 169.8 150.4 156.4 156.6 152.1 of Surgery SD 55.51 34.90 40.98 64.90 50.28 and Study Median 159.0 151.0 155.0 152.0 149.0 Medication Range 92.0 307.0 88.0 216.0 82.0 226.0 62.0 303.0 76.0 277.0 (Minutes) One-Way Analysis of Variance with Treatment as the Factor.

Fisher's Exact Test.

Black, Asian, Hispanic, and Other are Combined into One Category to Derive P-Value.

3 or More Third Molars Extracted as One Category to Derive P-Value.

Table 16A Baseline Pain Intensity Scores SIntent-To-Trea Population, Female Patients PAIN INTENSITY P-VALUE FOR PAIRWISE COMPARISONS P-VALU-E FOR MS MS 60 mg MS 60 mg MS 60 mg OVERALL TREATMENT MODERATE SEVERE 60 mg NTX NTX NTX TREATMENT 0.01 mg 0.1 mg I1mg Placebo 6 16 0.749 0.515 0.335 0.335 0.722 MS 60 mg 8 15 0.761 0.545 0.545 MS 60 mg /NTX 0.01 mg 8 12 1.000 1.000 MS 60Omg /NTX 0. 1mg 9 11 1.000 IMS 60 mg /NTX 1 mg 9 111 (5 NOTF: P-VALUES, ARE FROM FISHEI{'S EXACT TE~ST.

Table 16B Baseline Visual Analog Scale (VAS) Scores Intent-To-Treat Population, Female Patients BASELINE VAS SCORE P-VALUE FOR PAIRWISE COMPARISONS TREATMENT Moderate[l] Severe Total MS MS 60 mg MS 60 mg MS 60mg P-Value for NTX 0.01 NTX 0.1 NTX 1 Overall mg mg mg mg Treatment N Mean (SD) N Mean (SD) N Mean (SD) g mm g nretn Placebo 6 65.0 (8.02) 16 80.0 (11.33) 22 75.9 (12.40) 0.256 0.300 0.452 0.776 0.257 MS 60mg 8 68.4 (7.67) 15 87.0 (6.80) 23 80.5 (11.42) 0.032 0.736 0.410 MS 60 mg/NTX0.01m ng 8 59.0 (8.50) 12 79.9 (13.15) 20 71.6 (15.40) 0.084 0.198 MS 60 mg/NTX0.1 mg 8 67.9 (14.61) 11 87.3 (9.22) 19 79.1 (15.07) 0.644 MS 60 mg/NTX 1 mg 9 69.9 (12.19) 11 83.0 (11.93) 20 77.1 (13.50) NOTE:P-VALUEbS AIKiRUMUNE-WAY ANAL YWIN UP VAIILIN.JAIMI i3i a..UiNflt->1L) BASELINE PAIN INTENSITY ON THE CATEGORICAL SCALE.

Table 16C B~aseline Pain Intensity Scores Intent-To-Treat Population, Male Patients PAIN INTENSITY P-VALUE FOR PAIRWISE COMPARISONS MS 60 mg MS 60 mg P-VALUE FOR MS 60 NTX NTX MS 60 mg OVERALL TREATMENT MODERATE SEVERE mg 0.01 mg 0.1 mg NTX 1 mg TREATMENT Placebo 10 8 1.000 0.527 0.527 0.343 0.749 MS 60 mg 10 8 0.527 0.527 0.343 MS 60 mg /NTX 0.01 mg 9 12 1.000 1.000 MS 60mg /NTX 0.1mg 9 12 1.000 IMS 60 mg /NTX 1 mg 18 113 NOTE: P-VALUES ARE FROM FISHER'S EXACT TEST.

Table 16D Baseline Visual Analog Scale (VAS) Scores Intent-To-Treat Population, Male Patients BASELINE VAS SCORE P-VALUE FOR PAIRWISE COMPARISONS MS P-Value TREATMENT Moderate[l] Severe Total MS 60 MS 60 mg MS 60 mg 60 mg for Overall mg NTX NTX NTX Treatment 0.01 mg 0.1 mg 1 mg N Mean (SD) N Mean (SD) N Mean (SD) Placebo 10 65.8 (8.26) 8 78.3 (6.76) 18 71.3 (9.77) 0.719 0.271 0.346 0.821 0.586 MS 60mg 10 67.8 (6.00) 8 78.8 (8.35) 18 72.7 (8.89) 0.465 0.568 0.550 MS 60 mg/NTX 0.01 mag 9 62.2 (10.20) 12 85.1 (7.40) 21 75.3 (14.36) 0.868 0.168 MS 60mg/NTX0.1mg 9 63.3 (5.29) 12 83.3 (9.11) 21 74.7 (12.60) 0.225 MS 60 mg/NTX 1 mg 8 65.0 (8.32) 13 73.9 (6.40) 21 70.5 NOTE: P-VALUES ARE FROM UNE-WAY ANALYSIS U VAKIANt.J AN) 11 CUIN t1 AiS1 BASELINE PAIN INTENSITY ON THE CATEGORICAL SCALE.

WO 01/85150 PCT/US01/14644 115 The TOTPAR results (4 hour, 6 hour, 8 hour) are summanzeci m iaoDes /A for females and 17B for males. The placebo treatment group had the lowest mean TOTPAR scores. All 4 of the active treatment groups exhibited mean TOTPAR scores that were numerically higher than placebo. In females, the mean TOTPAR scores for the 0.01 mg NTX and 0.1 mg NTX combination treatments were higher than that for the MS alone treatment, whereas the 1.0 mg NTX combination treatment mean was comparable to or lower than that for the MS alone. In males, the scores for the 1.0 mg NTX, 0.1 mg NTX, and 0.01 mg combination treatments were higher than that for the MS alone treatment for 4 hour and 6 hour TOTPAR scores, and the mg and 0.01 mg NTX combinations were higher than morphine alone for the 8 hour TOTPAR scores.

Table 17A Total Pain Relief Scores Intent-To-Treat Population, Female Patients TOTAL PAIN RELIEF SCORE P-VALUE TREATMENT N MEAN SD MIN I MEDIAN MAX SOURCE [1] TOTAL PAIN RELIEF SCORE (0-4 HOURS) A) Placebo 22 1.86 2.677 0.0 0.00 8.0 TRT <0.001** B) MS 60 mg 23 5.07 4.478 0.0 5.75 13.2 B-A 0.006** C) MS 60mg/NTX 0.01 mg 20 6.18 3.948 0.0 5.99 14.0 C-A <0.001*** D) MS 60 mg/NTX 0.1 mg 20 6.00 4.208 0.0 6.74 12.0 D-A <0.001*** E) MS 60 mg/NTX 1 mg 20 3.14 3.928 0.0 1.00 11.3 E-A 0.290 C-B 0.352 D-B 0.432 E-B 0.109 TOTAL PAIN RELIEF SCORE (0-6 HOURS) A) Placebo 22 3.16 4.635 0.0 0.00 14.0 TRT <0.001** B) MS 60 mg 23 8.38 7.548 0.0 11.25 21.2 B-A 0.007** C) MS 60 mg /NTX 0.01 mg 20 9.63 6.172 0.0 9.60 20.5 C-A <0.001 D) MS 60 mg/NTX 0.1 mg 20 9.76 7.172 0.0 10.75 20.0 D-A <0.001** E) MS 60 mg/NTX 1 mg 20 4.59 6.202 0.0 1.00 16.5 E-A 0.473 C-B 0.527 D-B 0.484 E-B 0.056 FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or <0.001 RESPECTIVELY.

Table 1 7A (Continued) Total Pain Relief Scores Intent-To-Treat Population, Female Patients TOTAL PAIN RELIEF SCORE

P-VALUE

TREATMENT IN IMEAN ISD MIN I MEDIANIMWAX ISOURCE 1 [1] TOTAL PAIN RELIEF SCORE HOURS) A) Placebo 22 4.45 6.666 0.0 0.00 20.5 TRT 0.002** B) MS 60 mg 23 11.68 10.691 0.0 16.48 29.2 B-A 0.009** C) MS 60 ng /NTX 0.01 mg 20 12.97 8.787 0.0 11.25 27.0 C-A 0.003** D) MS 60mg /NTXO0.l1mg 20 13.66 10.500 0.0 15.75 28.0 D-A <0.001,*' E) MS 60 mgI/NTX 1 mg 20 6.19 8.905 0.0 1.00 24.5 E-A 0.544 C-B3 0.650 D-B 0.485 0.054 1] FROM ONE-WAY ANALYSIS OF VARIANCE AM) FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or =<0.001 RESPECTIVELY.

Table 17B Total Pain Relief Scores Intent-To-Treat Population, Male Patients TOTAL PAIN RELIEF SCORE P-VALUE TREATMENT IN IMEAN I SD I MIN IMEDIAN MAX SOURCE [1] TOTAL PAIN RELIEF SCORE (0-4 HOURS) A) Placebo 18 2.61 3.044 0.0 1.50 9.5 TRT 0.281 B) MS 60 mg 18 3.49 3.301 0.0 3.50 10.1 B-A N/D C) MS 60 mg /NTX 0.01 mg 21 4.85 4.243 0.0 5.73 14.0 C-A N/D D) MS 60 mg/NTX 0.1 mg 21 4.22 4.261 0.0 3.00 12.3 D-A N/D E) MS 60 mg/NTX 1 mg 21 5.18 4.757 0.0 5.25 14.0 E-A N/D C-B N/D D-B N/D E-B N/D TOTAL PAIN RELIEF SCORE (0-6 HOURS) A) Placebo 18 4.19 5.179 0.0 1.50 14.5 TRT 0.299 B) MS 60mg 18 6.41 6.165 0.0 6.75 18.1 B-A N/D C) MS 60 mg/NTX 0.01 mg 21 8.11 6.810 0.0 9.23 20.0 C-A N/D D) MS 60 mg/NTX 0.1 mg 21 6.82 6.872 0.0 5.25 20.3 D-A N/D E) MS 60 mg/NTX 1 mg 21 8.51 7.841 0.0 8.75 22.0 E-A N/D C-B N/D D-B N/D E-B N/D FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or <0.001 RESPECTIVELY.

Table 17B (Continued) Total Pain Relief Scores Intent-To-Treat Population, Male Patients TOTAL PAIN RELIEF SCORE P-VALUE TREATMENT IN IMEAN S D MT )JEDAN I MAX I SOURCE [1] TOTAL PAIN RELIEF SCORE (0-8 HOURS) A) Placebo 18 5.94 7.553 0.0 1.50 20.0 TRT 0.334 B) MS 60 mg 18 9.52 9.168 0.0 10.38 26.1 B-A N/D C) MS 60mg /NTX 0.0O1mg 21 11.38 9.611 0.0 13.73 27.5 C-A N/D D) MS 60Omg /NTX 0. 1mg 21 9.48 9.569 0.0 7.25 28.3 D-A N/D E) MS 60mgI/NTX 1mg 21 11.94 11.02 0.0 11.26 30.0 E-A N/D C-B N/D D-B N/D E-B N/D 1] FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGN[FICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or <0.001 RESPECTIVELY.

WO 01/85150 PCT/US01/14644 120 Tables 18A for females and 18B for males, summarize the results of the 4, 6, and 8 hour SPID results and the 4 hour SPID results are shown in Figures 9B for females and 9C for males. In females, the placebo treatment had the lowest mean 4, 6 and 8 hour SPID scores. All 4 of the active treatment groups exhibited improved profiles in mean SPID relative to placebo. The mean SPID scores for the 0.01 mg NTX and 0.1 mg NTX combination treatments were higher than that for the MS alone treatment. In males, the placebo treatment had the lowest mean 6 and 8 hour SPID scores. For the 4 hour SPID score, the placebo treatment was similar to the MS alone treatment. The mean SPID scores for the 0.01 mg NTX, 0.1 mg NTX and 1.0 mg combination treatments were higher than that for the MS alone treatment.

Table 18A Sum of Pain Intensity Differences Intent-To-Treat Population, Female Patients SUM OF PAIN INTENSITY DIFFERENCES

P-VALUE

TREATMENT IN MEAN I SD I MIN I MEDIAN MAX ISOURCE [2] SUM OF PAIN INTENSITY DIFFERENCES (0-4 HOURS) A) Placebo 22 0.58 2.047 -3.8 0.00 4.5 TRT 0.002** B) MS 60 mg 23 2.78 3.429 -3.3 2.50 8.0 B-A 0.012* C) MS 60 mg/NTX 0.01 mg 20 3.77 2.727 0.0 3.12 10.3 C-A <0.001*** D) MS 60 mg /NTX 0.1 mg 20 3.08 2.663 0.0 2.36 7.5 D-A 0.006** E) MS 60 mg /NTX 1 mg 20 1.29 3.434 -3.8 0.00 7.5 E-A 0.433 C-B 0.268 D-B 0.743 E-B 0.095 SUM OF PAIN INTENSITY DIFFERENCES (0-6 HOURS) A) Placebo 22 1.10 3.350 -5.8 0.00 8.3 TRT 0.002** B) MS 60 mg 23 4.56 5.676 -5.3 4.50 12.0 B-A 0.015* C) MS 60 mg/NTX 0.01 mg 20 5.90 4.227 0.0 6.23 15.3 C-A <0.001** D) MS 60 mg/NTX 0.1 mg 20 5.22 4.382 0.0 5.12 11.5 D-A 0.005** E) MS 60mg/NTX 1 mg 20 1.82 5.388 -5.8 0.00 12.0 E-A 0.619 C-B 0.351 D-B 0.645 E-B 0.059 [1] [2] PAIN INTENSITY DIFFERENCE PAIN INTENSITY AT BASELINE PAIN INTENSITY AT CURRENT TIME.

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or <0.001 RESPECTIVELY.

Table 18A (Continued) Sum of Pain Intensity Differences Intent-To-Treat Population, Female Patients SUM OF PAIN INTENSITY DIFFERENCES

P-VALUE

TREATMENT IN MEAN SD MIN |MEDIAN MAX SOURCE [2] SUM OF PAIN INTENSITY DIFFERENCES (0-8 HOURS) A) Placebo 22 1.58 4.741 -7.8 0.00 12.8 TRT 0.004** B) MS 60 mg 23 6.34 8.005 -7.3 6.50 17.3 B-A 0.018* C) MS 60 mg /NTX 0.01 mg 20 7.86 6.023 0.0 8.37 19.8 C-A 0.003** D) MS 60 mg/NTX 0.1 mg 20 7.52 6.389 0.0 7.63 16.8 D-A 0.004** E) MS 60mg/NTX 1 mg 20 2.52 7.710 -7.8 0.00 18.0 E-A 0.648 C-B 0.458 D-B 0.565 E-B 0.065 [1] [2] PAIN INTENSITY DIFFERENCE PAIN INTENSITY AT BASELINE PAIN INTENSITY AT CURRENT TIME.

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or <0.001 RESPECTIVELY.

Table 18B Sum of Pain Intensity Differences Intent-To-Treat Population, Male Patients SUM OF PAIN INTENSITY DIFFERENCES

P-VALUE

TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE [2] SUM OF PAIN INTENSITY DIFFERENCES (0-4 HOURS) A) Placebo 18 0.79 2.356 -3.8 0.25 5.0 TRT 0.200 B) MS 60mg 18 0.78 2.823 -3.8 1.88 4.0 B-A N/D C) MS60 mg/NTX 0.01 mg 21 2.41 3.726 -3.8 3.25 10.3 C-A N/D D) MS60 mg/NTX 0.1 mg 21 2.18 2.901 -3.8 2.49 8.5 D-A N/D E) MS 60mg/NTX 1 mg 21 2.70 4.011 -3.8 3.74 8.5 E-A N/D C-B N/D D-B N/D

N/D

SUM OF PAIN INTENSITY DIFFERENCES (0-6 HOURS) A) Placebo 18 1.21 3.633 -5.8 0.25 7.5 TRT 0.245 B) MS 60mg 18 1.75 5.008 -5.8 4.13 8.0 B-A N/D C) MS60 mg/NTX 0.01 mg 21 3.86 5.683 -5.8 5.00 14.3 C-A N/D D) MS60 mg/NTX 0.1 mg 21 3.54 4.769 -5.8 3.00 14.5 D-A N/D E) MS60mg/NTX 1 mg 21 4.51 6.634 -5.8 5.74 14.5 E-A N/D C-B N/D D-B N/D

N/D

PAIN INTENSITY DIFFERENCE PAIN INTENSITY AT BASELINE PAIN INTENSITY AT CURRENT TIME.

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or <0.001 RESPECTIVELY.

Table 1 8B (Continued) Sum of Pain Intensity Differences Intent-To-Treat Population, Male Patients SUM OF PAIN INTENSITY DIFFERENCES P-VALUE TREATMENT N IMEAN ISD IMIN MEDIAN MAX ISOURCE [2] SUM OF PAIN INTENSITY DIFFERENCES (0-8 HOURS) Placebo MS 60 mg MS 60 mg /NTX 0.01 mg MS 60 mg /NTX 0. 1mg MS 60 mg /NTX I mg 1.74 2.84 5.45 4.92 6.47 4.966 7.329 7.943 6.661 9.353 0.50 6.13 6.00 3.00 7.74 10.0 12.0 19.8 20.5 20.0

TRT

B-A

C-A

D-A

E-A

C-B3

D-B

E-B

0.2 74

NID

N/D

N/D

N/D

N/D

N/D

N/D

P1] [2] PAIN INTENSITY DIFFERENCE PAIN INTENSITY AT BASELINE PAIN INTENSITY AT CURRENT TIME.

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 05, =0.0 1, or 00 1 RESPECTIVELY.

WO 01/85150 PCT/US01/14644 125 Figures 10A for females and 10B for males are visual presentations of the summary and analysis of time to onset of meaningful pain relief scores presented in Tables 19A for females and 19B for males. In females, the median time to onset of meaningful pain relief was shortest in the 0.01 mg NTX (low-dose) combination treatment group. In males, the median time to onset of meaningful pain relief was shortest for the MS alone treatment, followed by the 1.0 mg NTX combination and then the 0.01 mg NTX combination.

Table 19A Time To Onset of Meaningful Pain Relief Intent-To-Treat Population, Female Patients TEST OF SURVIVAL CURVES MEDIAN 95% CONFIDENCE TIME INTERVAL TREATMENT N (hh:mm) (hh:mm) SOURCE LOG-RANK WILCOXON A) Placebo 22 >8:00 8:00, 8:00) TREATMENT 0.004** 0.013* B) MS 60 mg 23 1:50 (0:57, 8:00) B-A 0.005** 0.009** C) MS 60 mg/NTX 0.01 mg 20 1:18 (0:37, 8:00) C-A <0.001** D) MS 60 mg/NTX 0.1 mg 20 1:41 (0:56, 8:00) D-A <0.001** 0.003** E) MS 60 mgfNTX 1 mg 20 >8:00 (0:56, 8:00) E-A 0.064 0.077 C-B 0.254 0.212 D-B 0.591 0.642 E-B 0.385 0.538 P-VALUE 0.05, 0.01, or <0.001 RESPECTIVELY.

N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 19B Time To Onset of Meaningful Pain Relief Intent-To-Treat Population, Male Patients OF SURVIVAL CURVES MEDIAN 95% CONFIDENCE TEff INTERVAL TREATMENT N (lih:mm) (bh:mm) SOURCE LOG-RANK WILCOXON A) Placebo 18 >8:00 (3:17, 8:00) TREATMENT 0.732 0.648 B) MS 60mg 18 2:47 (1:00, >8:0O) B-A. N/D N/D C) MS 60 mg/NTX 0.01 mg: 21 4:05 (1:58, 8:00) C-A. N/D NID D) MS 60 mg/NTX 0. 1 mg 21 >8:00 (3:00, 8:00) D-A. N/D N/D E) MS 60mgINTXl1mg 21 3:47 (1:27, >8:00) E-A N/D N/Dl C-B KID K/D D-B KID N/D KID KID **:P-VALUE 0.05, 0.01, or <0.001 RESPECTIVELY.

N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNTFICANT).

WO 01/85150 PCT/US01/14644 128 Figures 11 A and 12A for females and 11B and 12B for males are visual presentations of the summary and analysis of time to remedication (rescue medication) up to 8 and 24 hours, respectively, presented in Tables 20A for females and 20B for males. The survival distributions (0-8 hours) were different across treatment groups (Figures 11A and 11B). In females, the survival distributions were different for the low-dose and mid-dose groups compared to placebo. The median times to administration of rescue medication were longer for the morphine 8 hours), low-dose 8 hours), and mid-dose 8 hours) groups compared to the highdose (2 hours, 30 minutes) and placebo (2 hours, 2 minutes) groups. In males, the median times to administration of rescue medication were longer for the placebo (>8 hours), MS alone hours), low-dose hours) and high-dose hours) compared to the mid-dose (3 hours, 6 minutes) group.

The survival distributions (0-24 hours) were also different across treatment groups (Figures 12A and 12B). In females, the median times to administration of rescue medication were longer for the morphine, low-dose, and mid-dose groups. In males, the median times to administration of rescue medication were longest for the low-dose and high-dose groups.

Analyses of time to remedication up to 24 hours yielded similar results, however, the data should be viewed with caution because subjects were not under close supervision after 8 hours.

Table Time To Rescue Medication Intent-To-Treat Population, Female Patients TEST OF SURVIVAL CURVES MEDIAN 95% CONFIDENCE TIME INTERVAL TREATMENT N (hh:mm) (hh:mm) SOURCE LOG-RANK WILCOXON EFFICACY OBSERVATION PERIOD (0-8 HOURS) A) Placebo 22 2:02 (1:38, 2:32) Treatment <0.001*** B) MS 60 mg 23 >8:00 (4:01, 8:00) B-A 0.004** 0.010* C) MS 60 mg /NTX 0.01 mg 20 >8:00 (4:02, 8:00) C-A <0.001*** D) MS 60 mg /NTX 0.1 mg 20 >8:00 (5:03, 8:00) D-A <0.001*** E) MS 60 mg /NTX 1 mg 20 2:30 (1:44, 7:54) E-A 0.205 0.172 C-B 0.659 0.493 D-B 0.341 0.303 E-B 0.081 0.128 SAFETY OBSERVATION PERIOD (0-24 HOURS) A) Placebo 22 2:02 (1:38, 2:32) Treatment <0.001*** B) MS 60 mg 23 8:37 (4:01, 17:45) B-A 0.003** C) MS 60 mg /NTX 0.01 mg 20 9:37 (4:02, 21:50) C-A <0.001*** D) MS 60 mg /NTX 0.1 mg 20 10:27 (5:03, 21:24) D-A <0.001*** E) MS 60 mg /NTX 1 mg 20 2:30 (1:44, 7:54) E-A 0.049* 0.120 C-B 0.465 0.382 D-B 0.502 0.409 E-B 0.203 0.153 P-VALUE 0.05, 0.01, or <0.001 RESPECTIVELY.

Table Time To Rescue Medication _______Intent-To-Treat Population, Male Patients OF SURVIVAL CURVES MEDIAN 95% CONFIDENCE TIM4E INTERVAL TREATMENT N (hh:nim) (h:mm) SOURCE LOG-RANK WILCOXON EFFICACY OB3SERVATION PERIOD (0-8 HOURS) A) Placebo 18 >8:00 (2:21, 8:00) Treatment 0.961 0.876 B) MS 60 mg 18 >8:00 (2:01, 8:00) B-A N/D N/D C) MS 60Omg /NTX .01 mg 21 >8:00 (2:36, 8:00) C-A N/D N/ID D) MS 60mg /NTX 0.l1mg 21 3:06 (2:03, 8:00) ID-A N/ID N/D E) MS 60 mg /NTX Img 21 >8:00 (1:43, 8:00) B-A N/ID NID C-B N/ID N/ID D-B N/DN/D

N/ID

SAFETY OBSERVATION PERIOD (0-24 HOURS) A) Placebo 18 8:57 (2:21, 9:51) Treatment 0.988 0.869 B) MS 60mg 18 5:41 (2:01, 17:28) B-A NID N/ID C) MS 60mg /NTX0.01 mg 21 9:14 (2:36, 21:44) C-A NID N/D ID) MS 60mg /NTXO0.l1mg 21 3:06 (2:03, 18:17) ID-A N/ID N/ID E) MS 60mg /N'TX 1mg 21 9:01 (1:43 17:47) B-A NID N/D C-B ID N/ID D-B NIDN/D

N/ID

**:P-VALUE 0.05, 0.01, or =<0.001 RESPECTIVELY.

WO 01/85150 PCT/US01/14644 131 Tables 21A for females and 21B for males present the summary and analysis of percent of subjects who took remedication up to 8 and 24 hours. For females, analysis of the percentage of subjects who remedicated within 8 hours showed the lowest percentage for the low-dose (0.01 mg NTX) and mid-dose (0.1mg NTX) combination groups. In males, the percentage of subjects remedicating (0-8 hours) was comparable across all treatment groups. Analyses of the percentage of subjects who remedicated within 24 hours indicated that all 5 treatment groups were comparable, however, the data should be interpreted with caution because subjects were not under close supervision after 8 hours.

Table 21A Percent of Subjects Rescued Itent-To-Treat Population, Female Patients TREATMENT jYES NOSOURCE P-VALUE [lI EFFICACY OBSERVATION PERIOD (0-8 HOURS) A) Placebo 19 3 TREATMENT <0.001** B) MS 60 mg 11 12 B-A N/D C) MS 60mg /NTX0.01lmg 9 11 C-A NfD D) MS 60 mgLNTX 0, 1mg 7 13 D-A N/D E) MS 60 mg /NTX 1 mg 15 5 E-A NID C-B N/D D-B3 N/D E-B NID SAFETY OBSERVATION PERIOD (0-24 HOURS) A) Placebo 22 (100.0%) 0 TREATMENT 0.182 B) MS 60 mg 20 3 B-A N/D C) MS 60 mg /NTX 0.01 mg 16 4 C-A N/D D) MS 60 mg /NTX 0. 1 mg 16 4 D-A N/D E) MS 60Omg /NTX I1mg 18 2 E-A N/D C-B N/D D-13 N/D E-B N/D N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICAN4T).

Table 2113 Percent of Subjects Rescued Intent-To-Treat Population, Male Patients TREATMENT YSN UC -AU 1 EFFICACY OBSERVATION PERIOD (0-8 HIOURS) A) Placebo 8 10 TREATMENT0.6 B) MS 60 mg 9 (50.0%1) 9 (5 B-A C) MS 60 mg /NTX 0.01 mg 10 11 C-A D) MS 60mgI/NTXO0.l1mg 12 9 D-A E) MS 60OmgI/NTX 1 mg 10 11 B-A N/D C-B N/D D-B N/D E-B N/D SAFETY OBSERVATION P -ERIOD (0-24 HOURS) A) Placebo 15 3 TREATMENT 1.000 B) MS 60 mg 15 3 B-A N/D C) MS 60 mg /NTX 0.01 mg 17 4 C-A N/D iD) MS 60mg /NTXO0.l1mg 17 4 D-A N/D B) MS 60mgI/NTXl1mg 17 4 B-A N/D C-B N/D D-B3 N/D -B N/D NID: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

WO 01/85150 PCT/US01/14644 134 Figures 13A for females and 13B for males are visual presentations of the hourly pain relief scores presented in Table 22A for females and 22B for males. The hourly pain relief scores were summarized and analyzed in 2 ways: first as a categorical variable and second as a numerical variable. Because results of these two methods were similar, only the results from the numerical version are presented here.

In females, the hourly pain relief scores for the placebo treatment were less than those for the active treatment groups. This was true for males from hour 1 through hour 8.

For females and males, there was separation between the placebo and the active treatment groups that continued throughout the 8-hour study period. For females, highest pain relief scores were observed for the low-dose (0.01 mg NTX) and middose (0.1 mg NTX) combination groups (Figure 13A). For males, highest pain relief scores were observed for the low-dose (0.01 mg NTX) and high-dose (1.0 mg NTX) combination groups.

Table 22A Pain Relief (PR) Scores [1] Intent-To-Treat Population, Female Patients PAIN RELIEF SCORE (PR) TP-VALUE TREATMENT N IMEAN ISD -SOURCE[1

MINUTES_____

A) Placebo 22 0.32 0.646 TRT 0.482 B) MS 60 mg 23 0.74 1.096 B-A N[D C) MS 60 mg /NTX 0.01 mg 20 0.75 0.967 C-A N/D D) MS 60mg /NTXO0.l1mg 20 0.80 1.105 D-A NfD E) MS 60 mg /NTX 1 mg 20 0.70 0.979 E-A N/D C-B N/D D-B N/D -B N/D 1 HOUR A) Placebo 22 0.36 0.790 TRT 0.002** B) MS 60 mg 23 1.09 1.041 B-A 0.029* C) MS 60mg /NTX0.01lmg 20 1.70 1.380 C-A <0.00l*** D) MS 60mg /NTXO0. 1mg 20 1.40 1.188 D-A 0.002** E) MS 60 mg /NTX 1 mg 20 1.00 1.026 B-A 0.062 C-B 0.070 D-B 0.352 -B 0.795 FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or =<0.001 RESPECTIVELY.

N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 22A (Continued) Pain Relief (PR) Scores [1] Intent-To-Treat Population, Female Patients PAIN RELIEF SCORE (PR) P-VALUE [1] TREATMENT N MEAN SD SOURCE 2 HOURS A) Placebo 22 0.50 0.802 TRT <0.001*** B) MS 60 mg 23 1.52 1.377 B-A 0.004** C) MS 60 mg /NTX 0.01 mg 20 1.90 1.252 C-A <0.001*** D) MS 60 mg /NTX 0.1 mg 20 1.80 1.281 D-A <0.001*** E) MS 60 mg /NTX 1 mg 20 0.90 1.165 E-A 0.279 C-B 0.301 D-B 0.446 E-B 0.091 3 HOURS A) Placebo 22 0.59 0.908 TRT 0.004** B) MS 60 mg 23 1.52 1.442 B-A 0.015* C) MS 60 mg /NTX 0.01 mg 20 1.75 1.333 C-A 0.003** D) MS 60 mg /NTX 0.1 mg 20 1.80 1.361 D-A 0.002** E) MS 60 mg /NTX 1 mg 20 0.80 1.240 E-A 0.595 C-B13 0.557 D-B 0.475 E-B 0.065 FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or <0.001 RESPECTIVELY.

N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 22A (Continued) Pain Relief (PR) Scores [1] Intent-To-Treat Population, Female Patients PAIN RELIEF SCORE (PR) P-VALUE TREATMENT N MEAN ISD ISOURCE 4 HOURS A) Placebo 22 0.68 1.086 TRT 0.006** B) MS 60mg 23 1.70 1.579 B-A 0.016* C) MS 60mg /NTX0.01lmg 20 1.75 1.410 C-A 0.014* D) MS 60mgI/NTXO0.l1mg 20 1.90 1.553 D-A 0.005** E) MS 60mg /NTX Img 20 0.75 1.251 E-A 0.874 C-B 0.898 D-B 0.631* -B 0.028* HOURS____ Placebo MS 60 mg MS 60 mg /NTX 0.01 mg MS 60 mg /NTX 0. 1mg MS 60 mg /NTX 1 mg 0.64 1.65 1.75 1.85 0.70 1.002 1.613 1.482 1.663 1.2 18

TRT

B-A

C-A

D-A

E-A

C-B

D-B

B-B

0.007** 0.018* 0.012* 0.006** 0.884 0.821 0.648 0.030* FROM ONE-WAY ANALYSIS OF VARIANCE ANT) FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or <=<0.001 RESPECTIVELY.

NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 22A (Continued) Pain Relief (PR) Scores [1] Intent-To-Treat Population, Female Patients PAIN RELIEF SCORE (PR) P-VALUE TREATMENT N IMEAN ISD ISOURCE 6 HOURS A) Placebo 22 0.64 1.002 TRT 0.015* B) MS 60 mg 23 1.65 1.584 lB-A 0.023* C) MS 60mg /NTX0.01lmg 20 1.65 1.531 C-A 0.028* D) MS 60Omg /NTX 0. 1mg 20 1.95 1.761 D-A 0.004** E) MS 60Omg /NTX 1 mg 20 0.80 1.436 B-A 0.721 C-B 0.996 D-B 0.511 E-B 0.062 7 HOURS A) Placebo 22 0.64 1.002 TRT 0.014* B) MS 60 mg 23 1.65 1.668 B-A 0.026* C) MS60OmgI/NTX0.01lmg 20 1.75 1.585 C-A 0.018* D) MS 60mgf/NTX 0.l1mg 20 1.95 1.761 D-A 0.005** E) MS 60OmgI/NTX 1 mg 20 0.80 1.436 E-A 0.726 C-B 0.832 D-B 0.520 E-B 0.067 FROM ONE-WAY ANALYSIS OF VARIANCE AM) FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or =<0.001 RESPECTIVELY.

N/fl: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 22A (Continued) Pain Relief (PR) Scores [11 Intent-To-Treat Population, Female Patients PAIN RELIEF SCORE (PR) P-VALUE TREATMENT N IMEAN ISD FSOURCE 8 HOURS____ A) Placebo 22 0.68 1.129 TRT 0.027* B) MS 60 mg 23 1.65 1.668 B-A 0.036* C) MS 60 mg /NTX 0.01 mg 20 1.65 1.631 C-A 0.044* D) MS 60Omg /NTX 0. 1 mg 20 1.95 1.761 D-A 0.008** E) MS 60mg /NTX 1mg 20 0.80 1.436 E-A 0.804 C-B 0.996 D-IB 0.528 0.073 FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or =<0.001 RESPECTIVELY.

NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 22B Pain Relief (PR) Scores [1] Intent-To-Treat Population, Male Patients PAIN RELIEF SCORE (PR) P-VALUE R1] TREATMENT N IMEAN ISD ISOURCE MIINUTES A) Placebo 18 0.44 0.616 TRT 0.612 B) MS 60 mg 18 0.33 0.594 B-A N/D C) MS 60mg /NTXO0.0O1mg 21 0.52 0.814 C-A N/D D) MS 60 mg /NTX 0. 1 mg 21 0.43 0.870 D-A N/D E) MS 60mg /NTX 1mg 21 0.71 0.902 B-A N/D C-B N/D D-B N/D E-B3 N/D 1 HOUR___ A) Placebo 18 0.67 .1.085 TRT 0.548 B) MS 60 mg 18 0.94 0.726 lB-A N/D C) MS 6Omg /NTX 0.0O1mg 21 1.05 1.117 C-A NfD D) MS 60mg /NTXO0.l1mg 21 1.19 1.167 D-A N/D E) MS 60mgf/NTXl1mg 21 1.19 1.209 B-A N/D C-B N/D D-B N/D -B N/D FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TBST.

P-VALUE =0.05, 0.01, or =<0.001 RESPECTIVELY.

N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 22B (Continued) Pain Relief (PR) Scores [1] Intent-To-Treat Population, Male Patients PAIN RELIEF SCORE (PR) P-VALUE TREATMENT N IMEAN ISD ISOURCE 2 HOURS A) Placebo 18 0.67 0.840 TRT 0.107 B) MS 60 mg 18 0.83 0.924 B-A KID C) MS 60mg /NTXO0.0O1mg 21 1.43 1.207 C-A KID D) MS 60mgI/NTX 0.l1mg 21 1.29 1.231 D-A N/D E) MS 60mg /NTXlImg 21 1.48 1.365 E-A NID C-13 K/D D-13 KID

K/D

3 HOURS__ Placebo MS 60 mg MS 60 mg /NTX 0.01 mg MS 60Omg /NTX 0. 1mg MS 60 mg /NTX 1 mg 0.78 1.11 1.62 1.19 1.62 1.114 1.183 1.499 1.327 1.499

TRT

B-A

C-A

D-A

E-A

C-B

D-B

E-B

0.243

KID

NID

KID

K/D

KID

K/D

KID

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALU =0.01, or =<0.001 RESPECTIVELY.

KID: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 22B (Continued) Pain Relief (PR) Scores [1] Intent-To-Treat Population, Male Patients PAIN RELIEF SCORE (PR) P-VALUE TREATMENT N IMEAN ISD ISOURCE 4 HOURS A) Placebo 18 0.89 1.323 TRT 0.497 B) MS 60 mg 18 1.39 1.420 B-A N/D C) MS 60mg /NTXO0.0O1mg 21 1.57 1.326 C-A N/D D) MS 60mg /NTX0.1mg 21 1.33 1.426 D-A N/D E) MS 60mg /NTX 1mg 21 1.67 1.592 E-A N/D C-B N/D D-B N/D

N/D

HOURS

A) Placebo 18 0.72 1.018 TRT 0.222 B) MS 60 mg 18 1.44 1.464 B-A N/D C) MS 60mg /NTXO0.0O1mg 21 1.67 1.461 C-A N/D D) MS 60mg/INTXO0.l1mg 21 1.29 1.384 D-A N/D E) MS 60mg /NTX 1mg 21 1.67 1.592 E-A N/D C-B N/D D-B N/D E-B N/D FROM ONE-WAY ANALYSIS OF VARIANCE ANDIT FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or <0.001 RESPECTIVELY.

N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 22B (Continued) Pain Relief (PR) Scores [11 Intent-To-Treat Population, Male Patients PAIN RELIEF SCORE (PR) P-VALUE TREATMENT N IMEAN ISD ISOURCE 6 HOURS A) Placebo 18 0.83 1.200 TRT 0.379 B) MS 60 mg 18 1.56 1.542 B-A N/D C) MS 60mg /NTXO0.0Olmg 21 1.62 1.465 C-A N/D D) MS 60mg /NTXO0.l1mg 21 1.29 1.419 D-A N/D E) MS 60mg /NTX 1mg 21 1.67 1.592 E-A N/D C-B3 N/D D-B N/D

N/D

7 HOURS____ A) Placebo 18 0.89 1.278 TRT 0.463 B) MS 60 mg 18 1.56 1.542 B-A N/D C) MS 60mgI/NTX0.01lmg 21 1.67 1.592 C-A N/D D) ,MS 60mgI/NTX 0.1mg 21 1.38 1.465 D-A N/D E) MS 60mgI/NTX Img 21 1.71 1.678 E-A N/D C-B N/D D-B N/D E-B N/D FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHIER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or <0.00 1 RESPECTIVELY.

N/D: NOT DONE (BECAUSE OVERALL P-VALUTE NOT SIGNIFICANT).

Table 22B (Continued) Pain Relief (PR) Scores [1] Intent-To-Treat Population, Male Patients PAIN RELIEF SCORE (PR) P-VALUE [1] TREATMENT N MEAN SD SOURCE 8 HOURS A) Placebo 18 0.89 1.278 TRT 0.417 B) MS 60 mg 18 1.56 1.542 B-A N/D C) MS 60 mg/NTX 0.01 mg 21 1.62 1.564 C-A N/D D) MS 60 mg/NTX 0.1 mg 21 1.29 1.419 D-A N/D E) MS 60 mg/NTX 1 mg 21 1.76 1.700 E-A N/D C-B N/D D-B N/D E-B N/D [1]

N/D:

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or <0.001 RESPECTIVELY.

NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

WO 01/85150 PCT/US01/14644 145 The hourly pain intensity difference (PID) data are presented in Table 23A and Figure 14A for females and in Table 23B and Figure 14B for males. For females, the mean scores for the morphine and morphine/naltrexone combination groups were higher than the mean PID scores for the placebo group at each assessment time. The means for the low-dose (0.01 mg NTX) and mid-dose (0.1 mg NTX) combination groups were greater than the means for high-dose (1.0 mg NTX combination) and placebo groups. Highest pain relief as measured by PID scores was observed for the low-dose (0.01 mg NTX) and mid-dose (0.1 mg NTX) combination groups. In males, the highest PID scores were most often observed for the high dose (1.0 mg NTX) combination group.

Table 23A Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Female Patients PAIN RELIEF SCORE (PR) P-VALUE TREATMENT N MIA SD ISOURCE I

MINUTES

A) Placebo 22 0.00 0.535 TRT 0.144 B) MS 60 mg 23 0.39 0.722 B-A N/fl C) MS 60 mg INTX 0.01 mg 20 0.55 0.759 C-A N/D D) MS 60 mng /NTX 0. 1 mg 20 0.45 0.759 D-A N/D E) MS 60mgI/NTX 1mg 20 0.30 0.865 E-A N/D C-B N/fl D-B N/D N/fl 1 HOUR A) Placebo 22 0.05 0.722 TRT 0.013* B) MS 60 mg 23 0.57 0.945 B-A 0.050 C) MS 6Omg/INTX 0.01lmg 20 1.00 0.973 C-A <0.001*** D) MS 60mg /NTXO0.l1mg 20 0.70 0.865 D-A 0.018* E) MS 60 mg /NTX 1 mg 20 0.45 0.887 E-A 0.140 C-B 0.109 fl-B 0.618 E-B 0.670 FROM ONE-WAY ANALYSIS OF VARIANCE ANT) FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE =0.05, =0.01, or <0.001 RESPECTIVELY.

N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 23A (Continued) Pai Intensity Difference (PID) Scores Intent-To-Treat Population, Female Patients PAIN RELIEF SCORE (PR) P-VALUE TREATMENT N IMEAN I SD FSOURCE 2 HOURS A) Placebo 22 0.18 0.664 TRT <0.00l** B) MS 60mg 23 0.83 1.072 B-A 0.016* C) MS 60 mg /NTX 0.01 mg 20 1.20 0.834 C-A <0.00** D) MS 60 mg /NTX 0. 1 mg 20 0.90 0.788 D-A 0.009** E) MS 60 mg /NTX 1 mg 20 0.35 0.988 E-A 0.53 9 C-B 0.169 D-B 0.785 0.081 3 HOURS A) Placebo 22 0.23 0.612 TRT 0.012* B) MS 60mg 23 0.87 1.100 B-A 0.020* C) MS 60Omg/NTXO0.01 mg 20 1.05 0.887 C-A 0.004** D) MS 60Omg /NTX0.l 1 ng 20 0.90 0.852 D-A 0.019* E) MS 60 mg /NTX 1 mg 20 0.35 1.040 E-A 0.665 C-B3 0.520 D-B 0.913 0.066 FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or <0.001 RESPECTIVELY.

N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 23A (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Female Patients PAIN RELIEF SCORE (PR) P-VALUE TREATMENT N MEAN I SD ISOURCE 4 HOURS A) Placebo 22 0.27 0.703 TRT 0.007** B) MS 60 mg 23 0.96 1.186 B-A 0.019* C) MS 60mg /NTXO0.01lmg 20 1.00 0.918 C-A 0.016* D) MS 60mg /NTXO0.l1mg 20 1.05 0.945 D-A 0.010* E) MS 60 mg /NTX 1 mg 20 0.25 1.020 E-A 0.93 9 C-B 0.883 D-B 0.753 0.019*

HOURS

A) Placebo 22 0.27 0.703 TRT 0.008** B) MS 60 mg 23 0.87 1.180 B-A 0.047* C) MS 60mg /NTXO0.01lmg 20 1.10 1.021 C-A 0.008** D) MS 60mg /NTXO0.l1mg 20 1.05 0.999 D-A 0.013* E) MS 60 mg /NTX 1 mng 20 0.25 1.020 E-A 0.94 1 C-B 0.451 D-B 0.555 E-B 0.044* FROM ONE-WAY ANALYSIS OF VARIANCE AND) FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE =0.05, =0.01, or <0.001 RESPECTIVELY.

N/D: NOT DONE (BECAUSE OVERALL P-VA-LUE NOT SIGNIFICANT).

Table 23A (Continued) Pain Intensity Difference (PIP) Scores Intent-To-Treat Population, Female Patients PAIN RELIEF SCORE (PR) P-VALUE 1 [1] TREATMENT N IrAN SD ISOURCE 6 HOURS A) Placebo 22 0.23 0.685 TRT 0.015* B) MS 60 mg 23 0.87 1.140 B-A 0.044* C) MS 60mg /NTX 0.01lmg 20 1.05 1.099 C-A 0.013* D) MS 60mg /NTX0.1mg 20 1.15 1.089 D-A 0.005** E) MS 60 mg /NTX 1 mg 20 0.35 1.226 E-A 0.708 C-B 0.579 D-B 0.389 E-B 0.112 7 HOURS Placebo MS 60 mg MS 60 mng /NTX 0.01 mg MS 60 ng /NTX 0.1mig MS 60 mg /NTX I mng 0.23 0.91 1.00 1.15 0.35 0.685 1.240 1-026 1.089 1-226

TRT

B3-A

C-A

D-A

F-A

C-B

D-B

E-B

0.019* 0.034* 0.021 0.006** 0.711 0.791 0.471 0.088 FROM ONE-WAY ANALYSIS OF VARIANCE AND) FISHIER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or =<0.001 RESPECTIVELY.

NfD: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 23A (Continued) Pain Intensity Difference (PIP) Scores Intent-To-Treat Population, Female Patients PAIN RELIEF SCORE (PR) P-VALUE [1] TREATMENT N MEAN SD SOURCE 8 HOURS A) Placebo 22 0.27 0.827 TRT 0.042* B) MS 60 mg 23 0.87 1.254 B-A 0.071 C) MS 60 mg /NTX 0.01 mg 20 0.95 1.050 C-A 0.049* D) MS 60mg /NTXO0.l1mg 20 1.15 1.089 D-A 0.011* E) MS 60 mg /NTX 1 mg 20 0.35 1.226 F-A 0.820 C-B 0.811 D-B 0.406 0.125 FROM ONE-WAY ANALYSIS OF VARhIANCE AND) FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or <0.001 RESPECTIVELY.

N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 23B Pain Intensity Difference (PIP) Scores Intent-To-Treat Population, Male Patients PAIN RELIEF SCORE (PR) P-VALUE [1] TREATMENT N MEAN SD

MINUTES

A) Placebo 18 0.17 0.618 TRT 0.378 B) MS 60 mg 18 -0.11 0.471 B-A N/D C) MS 60mgI/NTX 0.01mg 21 0.14 0.727 C-A N/D D) MS 60mg /NTXO0.l1mg 21 0.19 0.512 D-A N/D E) MS 60mg /NTX Imig 21 0.29 0.717 E-A N/D C-B N/D D-13 N/D f-B N/D_ 1 HOUR A) Placebo 18 0.17 0.786 TRT 0.244 B) MS 60 mg 18 0.13 0.761 B-A N/D C) MS 6OmgI/NTX0.01lmg 21 0.57 1.028 C-A N/D D) MS 60mg /NTX0.lm ig 21 0.48 0.814 D-A N/D E) MS 60mg /NTX Img 21 0.67 1.107 E-A N/D C-B N/D D-13 N/D f-B N/D FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHIER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE =0.05, 0.01, or <0.001 RESPECTIVELY.

NfD: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 23B (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Male Patients PAIN RELfIF SCORE (PR) P-VALUE TREATMENT N MEANI4 SD ISOURCE 2 A) Placebo 18 0.22 0.647 TRT 0.124 B) MS60Omg 18 0.22 0.808 B-A N/D C) MS 60mg /NTX0.01lmg 21 0.81 1.123 C-A N/D D) MS 60mg /NTXO0.l1mg 21 0.76 0.889 D-A N/D E) MS 60mg /NTX Img 21 0.71 1.146 E-A N/D C-B N/D D-B N/D _E-B NfD 3 HOURS Placebo MS 60 mg MS 60 mg /NTX 0.01 mg MS 60 mg [NTX 0. 1 mg MS 60 mg /NTX 1 mg 0.22 0.33 0.81 0.62 0.90 0.732 0.970 1.250 0.921 1.300

TRT

B-A

C-A

D-A

E-A

C-B

D-B

E-B

0.215

N/D

N/B

N/D

N/D

N/D

N/D

N/D

FROM ONE-WAY ANALYSIS OF VARIANCE AN]) FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE =0.05, 0.01, or <0.001 RESPECTIVELY.

N/D: NOT DONE (BECAUSE OVERALL P-VALUJE NOT SIGNIFICANT).

Table 23B (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Male PAIN RELIEF SCORE (PR) }P-VALUE 1 [1] TREATMENT N MAN SD FSOURCE 4 HOURS A) Placebo 18 0.28 0.826 TRT 0,372 B) MS 60mg 18 0.39 1.037 B-A NfD C) MS 60 mg /NTX 0.01 mg 21 0.62 0.973 C-A N/D D) MS 60mgI/NTXO0.l1mg 21 0.71 1.007 D-A N/D E) MS 60mg/INTX 1mg 21 0.90 1.375 E-A N/D C-B N/D D-B NfD

N/D

HIOUIRS Placebo MS 60 mng MS 60 mg INTX 0.01 mng MS 60 mg /NTX 0. 1 mg MS 60 mg INTX 1 mg 0.17 0.50 0.76 0.67 0.90 0.618 1.150 1.091 0.966 1.338

TRT

B-A

C-A

D-A

E-A

C-B

D-B

E-B

0.260

N/D

N/D

N/D

N/D

N!D

N/D

N/D

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or <0.001 RESPECTIVELY.

N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 23B (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Male PAIN RELIEF SCORE (PR) fP-VALUE TREATMENT N MEAN ISD 6 HOURS A) Placebo 18 0.22 0.647 TRT 0.378 B) MS 60mg 18 0.56 1.199 B-A NfD C) MS 60mg /NTXO0.01 mg 21 0.76 1.136 C-A N/D D) MS 60mgI/NTXO0.l1mg 21 0.67 0.966 D-A N/D E) MS 60mg /NTX 1mg 21 0.90 1.338 E-A NfD C-B N/D D-B N/D

N/D

7 HOURS Placebo MS 60 mg MS 60 mg /NTX 0. 01 mg MS 60 mg /NTX 0. 1 mg MS 60 mg [NTX 1 mg 0.28 0.56 0.81 0.71 1.00 0.752 1.199 1.250 1.007 1.449

TRT

B-A

C-A

D-A

E-A

C-B

D-B

E-B

0.384

N/D

N/D

N/D

N/D

N/D

N/D

N/D

FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or <0.001 RESPECTIVELY.

N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 23B (Continued) Pain Intensity Difference (PIh) Scores Intent-To-Treat Population, Male Patients PAIN RELIEF SCORE (PR) P-VALUTE TREATMENT N MAN ISD ISOURCE 8 HOURS A) Placebo 18 0.28 0.752 TRT 0.345 B) MS 60 mg 1s 0.50 1.200 B-A N/D C) MS 60 mg /NTX 0.01 mg 21 0.81 1.250 C-A N/D D) MS 60nmg /NTX 0.lmg 21 0.67 0.966 D-A N/D E) MS 60mg /NTX 1mg 21 1.00 1.414 E-A N/D C-B N/D D-B N/D -B N/D FROM ONE-WAY ANALYSIS OF VARlUNCE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE =0.05, =0.01, or <0.00 1 RESPECTIVELY.

N/D: NOT DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

WO 01/85150 PCT/US01/14644 156 The mean MAXPAR scores are presented in Table 24A for females and 24C for males. In females, the mean MAXPAR scores were highest for the low-dose (0.01 mg NTX) and mid-dose (0.1 mg NTX) combination groups compared to all other groups. The mean scores for the low-dose and mid-dose groups were greater than the mean score for the morphine group, which in turn, was greater than the mean score for the placebo group. In males, the mean MAXPAR scores were highest for the high-dose (1.0 mg NTX) and low-dose (0.01 mg NTX) combination groups.

The mean PEAKPID scores presented in Table 24B for females and 24D for males were different among treatment groups, and were greater for the morphine/naltrexone groups compared to the placebo group. In females, the mean PEAKPID scores for the low-dose (0.01 mg NTX) and mid-dose (0.1 mg NTX) combination groups were highest. In males, the high-dose (1.0 mg NTX) and lowdose (0.01 mg NTX) combination groups had the highest mean PEAKPID scores.

Table 24A Maximum Pain Relief Scores (MAXPAR) Intent-To-Treat Population, Female Patients MNAXIN1UM PAIN RELIEF SCORE P-VALUE TREATMENT IN IMEAN ISD IMIN IMEDIAN -1MAX SOURCE [1] A) Placebo 22 0.91 .1.342 0.0 0.0 4.0 TRT 00** B) MS 60 mng 23 2.04 1.637 0.0 3.0 4.0 B-A 0.009** C) MS 60mgI/NTX0.01 mg 20 2.80 1.281 0.0 3.0 4.0 C-A <0.00l*** D) MS 60 mgfNTXO0.l1mg 20 2.40 1.501 0.0 3.0 4.0 D-A <0.001** E) MS 60 mg /NTX 1 mg 20 1.40 1.429 0.0 1.0 4.0 E-A 0.275 C-B 0.090 D-B 0.422 0.149 1] FROM ONE-WAY ANALYSIS OF VARIANCE AND FISHER' PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, =0.01, or =<0.001 RESPECTIVELY.

Table 24B Peak Pain Intensity Differences (PEAKPID) Intent-To-Treat Population, Female Patients PEAK PAIN INTENSITY DIFFERENCES P-VALUE TREATMENT N MEAN SD MN MEDIAN MAX SOURCE [1] A) Placebo 22 0.50 0.913 -1 0.0 3 TRT <0.001"" B) MS 60 mg 23 1.35 1.071 0 1.0 3 B-A 0.005** C) MS 60 mg /NTX 0.01 mg 20 1.70 0.923 0 2.0 3 C-A <0.001*** D) MS 60 mg /NTX 0.1 mg 20 1.40 0.940 0 1.5 3 D-A 0.004** E) MS 60 mg /NTX 1mg 20 0.70 1.174 -1 0.0 3 E-A 0.522 C-B 0.256 D-B 0.866 F-B 0.038* ni n TmCnha Cfl\n Tr 1A A hTAnT VTC~ C~O~TA/DT AN~Tr A MTTV1ZrntCU'V t CRT\TrT1Th TPV' T TTCi ATT ThTPTRTr RO, T rDIVI VJN2- VY .1 PLNYL 1 kJ V* *I LLj1N.. LJY .IAbjlJ 3 I 'J 0.0 5, =0.01, or .=<0001REPE CTVEY P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 24C Maximum Pain Relief Scores (MAXPAR) Intent-To-Treat Population, Male Patients MAXIMUM PAIN RELIEF SCORE I N I MEAN ISD IMIN IMEDIAN MAX

P-VALUE

Illi TREATMENT

SOURCE

A) Placebo 18 1.33 1.372 0.0 1.0 4.0 TRT 0.674 B) MS 60 mg 18 1.83 1.425 0.0 2.5 4.0 B-A N/D C) MS 60 mg /NTX 0.01 mng 21 2.00 1.673 0.0 3.0 4.0 C-A N/D D) MS 60mgI/NTX0.1lmg 21 1.81 1.401 0.0 2.0 4.0 D-A N/D E) MS 60mgI/NTX Img 21 2.00 1.789 0.0 2.0 4.0 E-A N/D C-B N/D D-B N/D -B N/D [1] FROM ONE-WAY ANALYSIS OF VAINE AND FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE TEST.

P-VALUE 0.05, 0.01, or <0.001 RESPECTIVELY.

Table 24D Peak Pain Intensity Differences (PEALKPIiD) Intent-To-Treat Population, Male Patients PEAK PAIN INTENSITY P-VALUE TREATMENT N MEAN ISD IMIN MEDIANj MAX SOURCE E1l A) Placebo 18 0.56 0.856 -1 1.0 2 TRT 0.302 B) MS 60Omg 18 0.78 1.003 -1 1.0 2 B-A N/D C) MS 60mg/iNTX 0.01mg 21 1.14 1.276 -1 1.0 3 C-A N/ID D) MS 6Omg /NTX 0.1lmg 21 0.95 1.071 -1 1.0 3 D-A N/D E) MS 6Omg INTX Img 21 1.29 1.384 -1 2.0 3 E-A IN/D C-B N/D D-B N/D

N/D

[1] FROM ONE-WAY ALYIS OF VRNCE AN) FISHER'S PROTECTED LEAST SIGNIFICANT DIFFERENCE, TEST.

P-VALUE 0.05, 0.01, or <0.001 RESPECTIVELY.

WO 01/85150 PCT/US01/14644 161 Tables 25A for females and 25B for males present the summary and analysis of global evaluations. For both females and males, the placebo treatment had the highest number of subjects who had poor global evaluation scores based on subject evaluation. For females, the low-dose (0.01 mg NTX) and mid-dose (0.1 mg NTX) combination groups were most often rated as "excellent." For males, the high-dose mg NTX) combination group was most often rated as "excellent." The profiles of the global evaluations scores are based on subjects' evaluations.

Table Global Evaluation of Study Medication Population, Female Patients TREATMENT N POOR FAIR~ GOOD VERY EXCELLENT MEAN (SD) SOURCE P-VALUE GOOD [t] A) Placebo 22 17 1 2 2 0 0.5 (1.01) TRT <0.001** B) MS 60 mg 23 9 1 4 7 2 1.7 (1.50) B-A 0.005** C) MS 60 mgI/NTX 0.0 1 mg 20 4 1 6 6 3 2.2 (1.35) C-A <0.001*** D) MS 60Omg /NTX 0. 1mg 20 6 3 2 6 3 1.9 (1.53) D-A 0.002** E) MS 60 mgI/NTX 1 mg 20 12 0 4 4 0 1.0 (1.30) E-A 0.166 C-B 0.256 D-B 0.665 FROM COCH7RAN-MAITEL-ANEL TEST FOR RAW MEAN'SCORES DIFFERENCE. 0.3 P-VALUE 0.05, 0.01, OR <0.001 RESPECTIVELY.

Table Global Evaluation of Study Medication Population, Male Patients TREATMENT N POOR FAIR GOOD VERY EXCELLENT MEAN (SD) SOURCE P-VALUE GOOD (4)[1 A) Placebo 18 11 1 2 4 0 0.9 (1.30) TRT 0.488 B) MS 60 mg 18 8 2 4 3 1 1.3 (1.36) B-A f/D C) MS 60mg INTXO0.0O1mg 21 7 2 3 8 0 1.6 (1.35) C-A N/D D) MS 60 mg /NTX 0. 1mg 21 8 5 5 3 0 1.1 11) D-A NID E) MS 60mg /NTXlImg 21 8 2 6 1 4 1.6 (1.54) E-A N/D C-B NID D-B I/D E-B3 /D FROM COCHIRAN-MANT-HAEZEL TEST FOR RAW MEAN SCORES DIFFERENCE.

P-VA-LUE 0.05, 0.01, OR <=<0.001 RESPECTIVELY.

WO 01/85150 PCT/US01/14644 164 The majority of adverse events reported were categorized as digestive (nausea or vomiting) or nervous system (dizziness or somnolence) as further shown in Tables 26A or 26B for females and 26C or 26D for males. Figures 15A for females and for males represent a summary of exemplary adverse side effects according to methods and compositions of the invention.

In females, the placebo group had the lowest incidence of nausea, vomiting, dizziness and somnolence (sedation). For nausea, vomiting and dizziness, the 1.0 mg NTX combination group had the lowest incidence of adverse events compared to the other active treatment groups. For somnolence, the 0.01 mg NTX combination group had the lowest incidence among the active treatment groups.

In males, the placebo group showed the lowest incidence of adverse events.

Among the active treatment groups, the 1.0 mg NTX combination group had the lowest incidence of adverse events. Except for somnolence which was lowest in the 0.1 mg NTX combination group.

Table 26A ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, FEMALE PATIENTS Severity r21 BODY SYSTEM ADVERSE EVENTS (COSTART ENGLISH)

TOTAL

NO. OF

SUBJECTS

NO. OF

SUBJECTS

W/EVENT TREATMENT SOURCE P-Value Number Of Events MILD Moderate SEVERE TOTAL NUMBER OF EVENTS ADVERSE EVENTS (ALL BODY SYSTEMS) BODY AS A WHOLE ALL EVENTS A) PLACEBO B) MS 60 mg C) MS 60 mg/NTX 0.01 mg D) MS 60 mg/NTX 0.1 mg E) MS 60 mg/NTX 1 mg A) PLACEBO B) MS 60 mg C) MS 60 mg/NTX 0.01 mg D) MS 60 mg/NTX 0.1 mg E) MS 60 mg/NTX 1 mg 7 (31.8%) 22 (95.7%) 19 (95.0%) 20(100.0%) 17 (85.0%) Treatment

A-B

A-C

A-D

A-E

<0.001*** <0.001*** <0.001*** <0.001*** <0.001*** 4 (33.3%) 18 (32.7%) 13 (22.4%) 17 (25.0%) 16 (47.1%) 3 (25.0%) 20 (36.4%) 24 (41.4%) 25 (36.8%) 10 (29.4%) 2 (66.7%) 3 (60.05) 1 (33.3%) 4 (57.1%) 0 5 (41.7%) 17 (30.9%) 21 26 (38.2%) 8 (23.5%) (13.6%) (17.4%) (15.0%) (20.0%) Treatment 0.284 3 1 (33.3%) 5 2 (40.05) 3 1 (33.3%) 7 1 (14.3%) 0 0 0 0 1 (33.3%) 2 (28.6%) 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE" P-VALUES ARE FROM FISCHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.01, OR <0.001 RESPECTIVELY.

Table 26A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, FEMALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events ABDOMINAL PAIN A) PLACEBO 22 0 Treatment 0.412 0 0 0 0 B) MS 60 mg 23 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 20 1 1 0 0 1(100.0%) D) MS 60 mg/NTX 0.1 mg 20 1 1 0 0 1(100.0%) E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0 ASTHENIA A) PLACEBO 22 0 Treatment 0.571 0 0 0 0 B) MS 60 mg 23 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 20 0 0 0 0 0 D) MS 60 mg/NTX 0.1 mg 20 1 1 0 1(100.0%) 0 E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0 HEADACHE A) PLACEBO 22 3 Treatment 0.279 3 1 2 0 B) MS60mg 23 4 4 1 3(75.0%a0 0 C) MS 60 mg/NTX 0.01 mg 20 1 1 1 (100.0%) 0 0 D) MS 60 mg/NTX 0.1 mg 20 3 5 1 3 1 (20.0%) E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE" P-VALUES ARE FROM FISCHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.01, OR <0.001 RESPECTIVELY.

Table 26A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, FEMALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events INJECTION SITE A) PLACEBO 22 0 Treatment 1.000 0 0 0 0 HEMORRHAGE B) MS 60 mg 23 1 1 1(100.0%) 0 0 C) MS60 mg/NTX 0.01 mg 20 0 0 0 0 0 D) MS60 mgINTX 0.1 mg 20 0 0 0 0 0 E) MS 60 mg/NTX I mg 20 0 0 0 0 0 PAIN A) PLACEBO 22 0 Treatment 0.571 0 0 0 0 B) MS 60 mg 23 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 20 1 1 0 1(100.0%) 0 D) MS60 mg/NTX 0.1 mg 20 0 0 0 0 0 E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE" P-VALUES ARE FROM FISCHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.01, OR <0.001 RESPECTIVELY.

Table 26A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, FEMALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events

CARDIOVASCULAR

ALL EVENTS A) PLACEBO 22 0 Treatment 0.201 0 0 0 0 B) MS 60 mg 23 2 2 1 1 0 C) MS 60 mgiNTX 0.01mg 20 3 3 1 1 1 (33.3%) D) MS 60 mg/NTX 0.1mg 20 2 2 1 1 (50.0%)a 0 E) mg 60 mg/NTX 1 mg 20 0 0 0 0 0 VASODILATATION A) PLACEBO 22 0 Treatment 0.201 0 0 0 0 B) MS 60 mg 23 2 2 1 1 0 C) MS 60 mg/NTX 0.01 mg 20 3 3 1 1 1 (33.3 D) MS 60 mg/NTX 0.1 mg 20 2 2 1 1 (50.0%)a 0 E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE" P-VALUES ARE FROM FISCHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.01, OR <0.001 RESPECTIVELY.

Table 26A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, FEMALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W!EVENT SOURCE Of MILD Moderate SEVERE Events

DIGESTIVE

ALL EVENTS A) PLACEBO 22 4 Treatment 7 1 1 5 (71.4%) B) MS 60mg 23 16 A-B 30 4 10 16 (53.3%) C) MS 60 mg/NTX 0,01mg 20 17 A-C 31 4 11 16 (51.6%) D) MS 60 mg/NTX 0.1mg 20 18 A-D 33 6 7 20 (60.6" E) MS60mg/NTXl 1mg 20 11 A-E 0.023* 18 5 5 8 (44.4 D-E 0.030* DIARRHEA A) PLACEBO 22 0 Treatment 0.104 0 0 0 0 B) MS60 mg 23 0 0 0 0 0 C) MS60 mg/NTX 0.01 mg 20 0 0 0 0 0 D) MS 60 mg/NTX 0.1mg 20 2 2 1 1 0 E) MS60 mg/NTX I mg 20 0 0 0 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE" P-VALUES ARE FROM FISCHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.01, OR <0.001 RESPECTIVELY.

Table 26A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, FEMALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events DYSPEPSIA A) PLACEBO 22 1 Treatment 0.654 1 1 (100.0%) 0 0 B) MS 60 mg 23 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 20 0 0 0 0 0 D) MS 60 mg/NTX 0.1 mg 20 0 0 0 0 0 E) MS 60 mg/NTX 1 mg 20 1 1 1(100.0%) 0 0 NAUSEA A) PLACEBO 22 3 Treatment 3 0 1 2 (66.; B) MS 60 mg 23 15 A-B 16 4 10 2 (12.' C) MS 60 mg/NTX 0.01 mg 20 15 A-C 16 4 11 1 (6.

D) MS 60 mg/NTX 0.1 mg 20 16 A-D 17 5 6 6 E) MS 60 mg/NTX 1 mg 20 10 A-E 0.018* 11 4 5 2 (18.; VOMITING A) PLACEBO 22 3 Treatment 3 0 0 3 (100.( B) MS 60mg 23 14 A-B <0.001** 14 0 0 14(100.07o) C) MS 60 mg/NTX 0.01 mg 20 15 A-C 15 0 0 15(100.0%) D) MS 60 mg/NTX 0.1 mg 20 14 A-D 14 0 0 14(100.0%) E) MS 60 mg/NTX 1 mg 20 6 C-E 0.010* 6 0 0 6 (100.0%) D-E 0.025* NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE" P-VALUES ARE FROM FISCHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.01, OR <0.001 RESPECTIVELY.

Table 26A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, FEMALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events NERVOUS SYSTEM ALL EVENTS A) PLACEBO 22 1 Treatment 1 1(100.0%) 0 0 B) MS 60mg 23 10 A-B 0.004** 14 7 6 1 C) MS 60 mg/NTX 0.01 mg 20 12 A-C 14 4 7 3 (21.4%) D) MS 60 mg/NTX 0.1 mg 20 12 A-D 19 6 9 4 E) MS 60 mg/NTX 1 mg 20 10 A-E <0.001** 12 8 4 0 DIZZINESS A) PLACEBO 22 1 Treatment 0.022* 1 1(100.0%) 0 0 B) MS 60mg 23 7 A-B 0.046* 9 5 3 1 (11.: C) MS 60 mg/NTX 0.01 mg 20 8 A-C 0.007** 8 3 4 1 (12.' D) MS 60 mg/NTX 0.1 mg 20 9 A-D 0.003** 12 5 4 3 E) MS 60 mg/NTX Img 20 6 A-E 0.040* 6 4 2 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE" P-VALUES ARE FROM FISCHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.01, OR <0.001 RESPECTIVELY.

Table 26A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, FEMALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events EUPHORIA A) PLACEBO 22 0 Treatment 0.007** 0 0 0 0 B) MS 60 mg 23 0 A-C 0.043* 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 20 4 B-C 0.039* 4 0 3 1 (25.0%) D) MS 60 mg/NTX 0.1 mg 20 1 1 0 1(100.0%) 0 E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0 HALLUCINATIONS A) PLACEBO 22 0 Treatment 1.000 0 0 0 0 B) MS 60 mg 23 1 1 0 1 (100.0%) 0 C) MS 60 mg/NTX 0.01 mg 20 0 0 0 0 0 D) MS 60 mg/NTX 0.1 mg 20 0 0 0 0 0 E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0 HYPERTONIA A) PLACEBO 22 0 Treatment 0.838 0 0 0 0 B) MS 60 mg 23 1 1 0 1 (100.0%) 0 C) MS 60 mg/NTX 0.01 mg 20 1 1 0 0 1(100.0%) D) MS 60 mg/NTX 0.1 mg 20 1 1 0 1(100.0%) 0 E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE" P-VALUES ARE FROM FISCHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.01, OR <0.001 RESPECTIVELY.

Table 26A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, FEMALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events PARESTHESIA A) PLACEBO 22 0 Treatment 0.549 0 0 0 0 B) MS 60 mg 23 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 20 1 1 1(100.0%) 0 0 D) MS 60 mg/NTX 0.1 mg 20 1 1 0 1(100.0%) 0 E) MS 60 mg/NTX I mg 20 1 1 0 1 (100.0%) 0 SOMNOLENCE A) PLACEBO 22 0 Treatment 0.021" 0 0 0 0 B) MS 60mrag 23 3 A-E 0.018* 3 2 1 0 C) MS60 mg/NTX0.01 mg 20 0 C-E 0.047* 0 0 0 0 D) MS 60 mg/NTX 0.1 mg 20 3 3 0 2 1 (33.- E) MS 60 mg/NTX 1 mng 20 5 5 4 1 0 TREMOR A) PLACEBO 22 0 Treatment 0.571 0 0 0 0 B) MS 60mg 23 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 20 0 0 0 0 0 D) MS60 mg/NTX 0.1 mg 20 1 1 1(100.0%) 0 0 E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE" P-VALUES ARE FROM FISCHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.01, OR <0.001 RESPECTIVELY.

Table 26A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, FEMALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events

RESPIRATORY

ALL EVENTS A) PLACEBO 22 1 Treatment 0.654 1 1(100.0%) 0 0 B) MS 60 mg 23 0 0 0 0 0 C) MS 60 mg/NTX 0.01mg 20 1 1 0 1(100.0%) 0 D) MS60 mg/NTX 0.1 mg 20 0 0 0 0 0 E) MS60 mg/NTX 1 mg 20 0 0 0 0 0 EPISTAXIS A) PLACEBO 22 0 Treatment 0.571 0 0 0 0 B) MS 60 mg 23 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 20 1 1 0 1(100.0%) 0 D) MS60mg/NTX0.1 mg 20 0 0 0 0 0 E) MS 60 mg/NTX I mg 20 0 0 0 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE" P-VALUES ARE FROM FISCHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.01, OR <0.001 RESPECTIVELY.

Table 26A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, FEMALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events RHINITIS A) PLACEBO 22 1 Treatment 0.780 1 1 (100.0%) 0 0 B) MS 60 mg 23 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 20 0 0 0 0 0 D) MS 60 mg/NTX 0.1 mg 20 0 0 0 0 0 E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0

SKIN/APPENDAGES

ALL EVENTS A) PLACEBO 22 0 Treatment 0.211 0 0 0 0 B) MS 60 mg 23 1 1 1 (100.0%) 0 0 C) MS 60 mg/NTX 0.01 mg 20 3 4 1 3 0 D) MS 60 mg/NTX 0.1mg 20 3 3 0 3(100.0%) 0 E) MS 60 mg/NTX 1 mg 20 3 4 3 1 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE" P-VALUES ARE FROM FISCHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.01, OR <0.001 RESPECTIVELY.

Table 26A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, FEMALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events PURITUS A) PLACEBO 22 0 Treatment 0.081 0 0 0 0 B) MS60 mg 23 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 20 3 3 1 2 0 D) MS 60 mg/NTX 0.1 mg 20 3 3 0 3(100.0%) 0 E) MS 60 mg/NTX 1 mg 20 2 2 2 (100.0%) 0 0 RASH A) PLACEBO 22 0 Treatment 0.412 0 0 0 0 B) MS 60 mg 23 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 20 1 1 0 1(100.0%) 0 D) MS 60 mg/NTX 0.1 mg 20 0 0 0 0 0 E) MS 60 mg/NTX 1 mg 20 1 1 0 1(100.0%) 0 SWEATING A) PLACEBO 22 0 Treatment 0.907 0 0 0 0 B) MS 60 mg 23 1 1 1(100.0%) 0 0 C) MS 60 mg/NTX 0.01 mg 20 0 0 0 0 0 D) MS 60 mg/NTX 0.1 mg 20 0 0 0 0 0 E) MS 60 mg/NTX 1 mg 20 1 1 1(100.0%) 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE" P-VALUES ARE FROM FISCHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.01, OR <0.001 RESPECTIVELY.

Table 26A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, FEMALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events SPECIAL SENSES ALL EVENTS A) PLACEBO 22 0 Treatment 0.201 0 0 0 0 B) MS 60 mg 23 2 2 2 (100.0%) 0 0 C) MS 60 mg/NTX 0.01 mg 20 2 2 2(100.0%) 0 0 D) MS 60 mg/NTX 0.1 mg 20 3 3 2 1 0 E) MS 60 mg/NTX I mg 20 0 0 0 0 0 CONJUNCTIVITIS A) PLACEBO 22 0 Treatment 0.201 0 0 0 B) MS 60 mg 23 2 2 2 (100.0%) 0 0 C) MS 60 mg/NTX 0.01 mg 20 2 2 2 (100.0%) 0 0 D) MS 60 mg/NTX 0.1 mg 20 3 3 2 0 0 E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE" P-VALUES ARE FROM FISCHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.01, OR <0.001 RESPECTIVELY.

Table 26A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, FEMALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events

UROGENITAL

ALL EVENTS A) PLACEBO 22 0 Treatment 0.907 0 0 0 0 B) MS 60mg 23 1 1 1(100.0%) 0 0 C) MS 60 mg/NTX 0.01 mg 20 0 0 0 0 0 D) MS 60 mg/NTX 0.1 mg 20 1 1 1(100.0%) 0 0 E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0 METRORRHAGIA A) PLACEBO 22 0 Treatment 1.000 0 0 0 0 B) MS 60 mg 23 1 1 1(100.0%) 0 0 C) MS 60 mg/NTX 0.01 mg 20 0 0 0 0 0 D) MS 60 mg/NTX 0.1 mg 20 0 0 0 0 0 E) MS 60 mg/NTX 1 mg 20 0 0 0 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE" P-VALUES ARE FROM FISCHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.01, OR <0.001 RESPECTIVELY.

Table 26A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, FEMALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events URINARY RETENTION A) PLACEBO 22 0 Treatment 0.571 0 0 0 0 B) MS 60 mg 23 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 20 0 0 0 0 0 D) MS 60 mg/NTX 0.1 mg 20 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX I mg 20 0 0 0 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE" P-VALUES ARE FROM FISCHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.01, OR <0.001 RESPECTIVELY.

Table 26B SELECTED ADVERSE EVENTS SAFETY POPULATION, FEMALE PATIENTS Adverse Event Total No. Of P-Value Number Severity [2] (English) No. Of Subjects Of Mild Moderate Severe Treatment Subjects W/Event Source Events Mild Mode DIZZINESS A) PLACEBO 22 1 Treatment 0.022* 1 1(100.0%) 0 0

NAUSEA

B) MS 60 mg C) MS 60 mg/NTX 0.01 mg D) MS 60 mg/NTX 0.1 mg E) MS 60 mg/NTX 1 mg A) PLACEBO B) MS 60 mg C) MS 60 mg/NTX 0.01 mg D) MS 60 mg/NTX 0.1 mg E) MS 60 mg/NTX 1 mg A) PLACEBO B) MS 60 mg C) MS 60 mg/NTX 0.01 mg D) MS 60 mg/NTX 0.1 mg E) MS 60 mg/NTX 1 mg (13.6%) (65.2%) (75.0%) (80.0%) (50.0%) 7 (30.4%) 8 (40.0%) 9 (45.0%) 6 (30.0%)

A-B

A-C

A-D

A-E

Treatment

A-B

A-C

A-D

A-E

Treatment

A-E

C-E

0.046* 0.007** 0.003** 0.040* <0.001*** <0.001*** <0.001*** <0.001*** 0.018* 5 3 3 4 5 4 4 2 (33.3%) (50.0%) (33.3%) (33.3%) (33.3%) (62.5%) (68.8%) (35.3%) (45.5%) (11.1%) (12.5%) (25.0%) (66.7%) (12.' (6.

(35.3 (18., (25.0%) (25.0%) (29.4%) (36.4%) SOMNOLENCE 0 3 (13.0%) 0 3 (15.0%) 5 (25.0%) 0.021* 0.018* 0.047* 0 0 2 1 (33.3%) 0 0 0 2 (66.7%) 4 1 (20.0%) 0 0 0 1 (33.3%) 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE" P-VALUES ARE FROM FISCHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.01, OR <0.001 RESPECTIVELY.

Adverse Event (English) Treatment VOMITING A) PLACEBO B) MS 60 mg C) MS 60 mg/NTX 0.01 mg D) MS 60 mg/NTX 0.1 mg E) MS 60 mg/NTX 1 mg Table 26B (Continued) SELECTED ADVERSE EVENTS SAFETY POPULATION, FEMALE PATIENTS Total No. Of P-Value No. Of Subjects [1] Subjects W/Event Source 22 3 Treatment <0.001*** 23 14 A-B <0.001** 20 15 A-C <0.001*** 20 14 A-D <0.001*** 20 6 C-E 0.010* Number Of Events 3 14 15 14 6 Severity [2] Moderate Mild Severe 3 (100.0%) 14(100.0%) 15(100.0%) 14(100.0%) 6(100.0%) D-E 0.025* NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE" P-VALUES ARE FROM FISCHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.01, OR <0.001 RESPECTIVELY.

Table 26C ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, MALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events TOTAL NUMBER OF EVENTS ADVERSE EVENTS (ALL BODY SYSTEMS) ALLEVENTS A) PLACEBO 18 4 22.2%) Treatment <0.001** 5 3 60.0%) 2 0 B) MS 60mg 18 13 A-B 0.006 27 10( 37.0%) 12(44.4%) 5( C) MS 60 mg/NTX 0.01mg 21 17( 81.0%) A-C 35 9 16(45.7%) 10(28 D) MS 60 mg/NTX 0. 1mg 21 17(81.0%) A-D 34 11(32.4%) 15(44.1%) 8(23.

MS 60 mg/NTX 1 mg 21 14 A-E 0.009** 30 15( 50.0%) 12(40.0%) 3(10.

BODY AS A WHOLE ALL EVENTS A) PLACEBO 18 1 Treatment 0.624 1 0 1(100.0%) 0 B) MS60mg 18 2 2 2(100.0%) 0 0 C) MS 60 mg/NTX 0.01 mg 21 5 5 1( 20.0%) 3( 60.0%) 1(20.,,,j D) MS 60 mg/NTX 0.I mg 21 3 3 2 1 0 E) MS 60 mg/NTX 1 mg 21 4 4 2 50.0%) 2 50.0%) 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE." P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR <0.001 RESPECTIVELY.

Table 26C (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, MALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events ABDOMINAL PAIN A) PLACEBO 18 0 Treatment 1.000 0 0 0 0 B) MS 60mg 18 0 0 0 0 0 C) MS60 mg/NTX 0.01 mg 21 1 1 0 0 1 (100.0%) D) MS60 mg/NTX 0.1 mg 21 0 0 0 0 0 E) MS 60 mg/NTX 1 mg 21 0 0 0 0 0 ASTHENIA A) PLACEBO 18 0 Treatment 0.940 0 0 0 0 B) MS60mg 18 1 1 1(100.0%) 0 0 C) MS 60 mg/NTX 0.01 mg 21 1 1 0 1(100.0%) 0 D) MS 60 mg/NTX 0.1 mg 21 0 0 0 0 0 E) MS 60 mg/NTX 1 mg 21 1 1 1(100.0%) 0 0 FEVER A) PLACEBO 18 1 Treatment 0.363 1 0 1 0 18 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.1 mg 21 0 0 0 0 0 E) MS 60 mg/NTX 1 mg 21 0 0 0 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE." P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR <0.001 RESPECTIVELY.

Table 26C (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, MALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events HEADACHE A) PLACEBO 18 0 Treatment 0.637 0 0 0 0 B) MS60mg 18 1 1 1(100.0%) 0 0 C) MS 60 mg/NTX 0.01 mg 21 2 2 1 1 0 D) MS60 mg/NTX 0.1mg 21 1 1 1(100.0%) 0 0 E) MS 60 mg/NTX 1 mg 21 3 3 1 2 0 OVERDOSE A) PLACEBO 18 0 Treatment 1.000 0 0 0 0 B) MS 60mg 18 0 0 0 0 0 C) MS60 mg/NTX 0.01mg 21 1 0 0 1(100.0%) 0 D) MS60 mg/NTX 0.1 mg 21 0 0 0 0 0 E) MS 60 mg/NTX 1 mg 21 0 0 0 0 0 PAIN A) PLACEBO 18 0 Treatment 0.192 0 0 0 0 mg 18 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 21 0 0 0 0 0 D) MS60 mg/NTX 0.1mg 21 2 2 1 1 0 E) MS 60 mg/NTX 1 mg 21 0 0 0 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE." P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR<= <0.001 RESPECTIVELY.

Table 26C (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, MALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events

CARDIOVASCULAR

ALL EVENTS A) PLACEBO 18 0 Treatment 0.540 0 0 0 0 B) MS 60mg 18 1 1 1(100.0%) 0 0 C) MS 60 mg/NTX 0.01 mg 21 1 "1 1(100.0%) 0 0 D) MS 60 mg/NTX 0.1 mg 21 3 3 1 2 0 E) MS 60 mg/NTX 1 mg 21 1 1 1(100.0%) 0 0 HEMORRHAGE A) PLACEBO 18 0 Treatment 1.000 0 0 0 0 B) MS 60 mg 18 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.1 mrag 21 1 1 0 1(100.0%) 0 E) MS 60 mg/NTX I mg 21 0 0 0 0 0 HYPERTENSION A) PLACEBO 18 0 Treatment 1.000 0 0 0 0 mg 18 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.1mg 21 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 1 mg 21 0 0 0 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE." P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR <0.001 RESPECTIVELY.

Table 26C (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, MALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events VASODILATATION A) PLACEBO 18 0 Treatment 1.000 0 0 0 0 B) MS 60mg 18 1 1 1 (100.0%) 0 0 C) MS 60 mg/NTX 0.01 mg 21 1 1 1 (100.0%) 0 0 D) MS 60 mg/NTX 0.1 mg 21 1 1 0 1(100.0%) 0 E) MS 60 mg/NTX 1 mg 21 1 1 1(100.0%) 0 0

DIGESTIVE

ALL EVENTS A) PLACEBO 18 1 Treatment 0.017* 1 0 1(100.0%) 0 B) MS 60 mg 18 7 A-B 0.040* 10 2 4 4( C) MS 60 mg/NTX 0.01 mg 21 8 A-C 0.023* 15 3 4 9 26.7%) 8(53.2 D) MS 60 mg/NTX 0.1 mg 21 11 A-D <0.001** 14 2 5 7( E) MS 60 mg/NTX 1 mg 21 5 7 1 3 3 42.9%0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE." P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR<= <0.001 RESPECTIVELY.

Table 26C (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, MALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events NAUSEA A) PLACEBO 18 1 Treatment 0.048* 1 0 1(100.0%) 0 B) MS 60mg 18 6 0.023* 6 2 4 0 C) MS 60 mg/NTX 0.01 mg 21 8 0.010* 10 3 4 3(30.0%) D) MS 60 mg/NTX 0.1mg 21 9 9 2 5 2(20.2%) E) MS60 mg/NTX 1 mg 21 4 4 1 3 0 VOMITING A) PLACEBO 18 0 Treatment 0.166 0 0 0 0 B) MS60 mg 18 4 A-C 4 0 0 4 (100.0' C) MS 60 mg/NTX 0.01 mg 21 5 A-D 5 0 0 (100.0' D) MS60 mg/NTX 0.1mg 21 5 5 0 0 (100.0' E) MS 60 mg/NTX I1mg 21 3 3 0 0 3 (100.0%) NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE." P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR <0.001 RESPECTIVELY.

Table 26C (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, MALE PATIENTS BODY SYSTEM ADVERSE EVENTS (COSTART ENGLISH)

TOTAL

NO. OF

SUBJECTS

NO. OF

SUBJECTS

W/EVENT

Severity [2] MILD Moderate SEVERE TREATMENT SOURCE P-Value Number Of Events

MUSCULOSKELETAL

ALL EVENTS

MYALGIA

A) PLACEBO B) MS 60 mg C) MS 60 mg/NTX 0.01 mg D) MS 60 mg/NTX 0.1 mg E) MS 60 mg/NTX 1 mg A) PLACEBO B) MS 60 mg C) MS 60 mg/NTX 0.01 mg D) MS 60 mg/NTX 0.1 mg E) MS 60 mg/NTX 1 mg 0 1 0 0 0 0 1 0 0 0 Treatment 0.363 Treatment 0.363 0 1(100.0%) 0 0 0 0 1 (100.0%) 0 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE." P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR <0.001 RESPECTIVELY.

Table 26C (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, MALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events NERVOUS SYSTEM ALL EVENTS A) PLACEBO 18 1 Treatment 0.016* 1 1 (100.0%) 0 0 B) MS 60 mg 18 8 A-B 0.017* 10 4 5 1(10.0%) C) MS 60 mg/NTX 0.01 mg 21 10 A-C 0.004** 11 2 8 72.7%) 1 9.1%) D) MS 60 mg/NTX 0.1 mg 21 10 A-D 0.004** 10 3 6 1(10.0%) E) MS 60 mg/NTX 1 mg 21 10 A-E 0.004** 14 8 6 0 ANXIETY A) PLACEBO 18 0 Treatment 1.000 0 0 0 0 B) MS 60 mg 18 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 21 1 1 0 1 (100.0%) 0 D) MS 60 mg/NTX 0.1 mg 21 1 1 0 1(100.0%) 0 E) MS 60 mg/NTX Img 21 0 0 0 0 0 DIZZINESS A) PLACEBO 18 1 Treatment 0.065 1 1 (100.0%) 0 0 B) MS 60 mg 18 8 A-B 0.017 8 4 50.0%) 3 1(12.5%) C) MS 60 mg/NTX 0.01 mg 21 8 A-C 0.023 8 2 5 1(12.5%) D) MS 60 mg/NTX 0.1 mg 21 8 A-D 0.023 8 1 6 1(12.5%) E) MS 60 mg/NTX 1 mg 21 7 A-E 0.048 7 4 3 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG "SUSPECTED" OR "PROBABLE." DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR <0.001 RESPECTIVELY.

Table 26C (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, MALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events DRY MOUTH A) PLACEBO 18 0 Treatment 0.192 0 0 0 0 B) MS 60 mg 18 0 0 0 0 0 C) MS60 mg/NTX0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.1 mg 21 0 0 0 0 0 E) MS 60 mg/NTX 1 mg 21 2 2 1 1 0 EUPHORIA A) PLACEBO 18 0 Treatment 1.000 0 0 0 0 B) MS 60 mg 18 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 21 1 1 0 1(100.0%) 0 D) MS 60 mg/NTX 0.1 mg 21 1 1 1(100.0%) 0 0 E) ms 60 mg/NTX 1 mg 21 0 0 0 0 0 PARESTHESIA A) PLACEBO 18 0 Treatment 1.000 0 0 0 0 B) MS 60mg 18 0 0 0 0 0 C) MS60 mg/NTX0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.1 mg 21 0 0 0 0 0 E) MS 60 mg/NTX 1 mg 21 1 1 1 (100.0%) 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP T( DRUG "SUSPECTED" OR "PROBABLE." P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR <0.001 RESPECTIVELY.

SSTUDY

Table 26C (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, MALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events SOMNOLENCE A) PLACEBO 18 0 Treatment 0.265 0 0 0 0 B) MS 60mg 18 1 1 0 1(100.0%) 0 C) MS 60 mg/NTX 0.01 mg 21 1 1 0 1(100.0%) 0 D) MS60 mg/NTX 0.1 mg 21 0 0 0 0 0 E) MS 60 mgINTX 1 mg 21 3 3 1 2 0 TREMOR A) PLACEBO 18 0 Treatment 0.727 0 0 0 0 B) MS 60mg 18 1 1 0 1(100.0%) 0 C) MS 60 mg/NTX 0.01 mg 21 0 0 0 0 0 D) MS60 mg/NTX 0.1 mg 21 0 0 0 0 0 E) MS 60 mg/NTX 1 mg 21 1 1 1 (100.0%) 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE." P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR <0.001 RESPECTIVELY.

Table 26C (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, MALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events

RESPIRATORY

ALL EVENTS A) PLACEBO 18 1 Treatment 0.727 1 1 (100.0) 0 0 18 0 0 0 0 0 C)MS60mg/NTX0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.1mg 21 0 0 0 0 0 E) MS 60 mg/NTX lImg 21 1 1 1 (100.0) 0 0 DYSPNEA A) PLACEBO 18 0 Treatment 1.000 0 0 0 0 B) MS60 mg 18 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 21 0 0 0 0 0 D) MS60 mg/NTX 0.1 mg 21 0 0 0 0 0 E) MS 60 mg/NTX 1 mg 21 1 1 1 (100.0%) 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE." P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR <0.001 RESPECTIVELY.

Table 26C (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, MALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events EPISTAXIS A) PLACEBO 18 1 Treatment 0.363 1 1 (100.0%) 0 0

SKIN/APPENDAGES

B) MS 60 mg C) MS 60 mg/NTX 0.01 mg D) MS 60 mg/NTX 0.1 mg E) MS 60 mg/NTX 1 mg A) PLACEBO B) MS 60 mg C) MS 60 mg/NTX 0.01 mg D) MS 60 mg/NTX 0.1 mg E) MS 60 mg/NTX 1 mg 0 0 0 0 0 0 0 0 1 (33.3%) 1 (100.0%) 0 0 ALL EVENTS 0 3 (16.7%) 1 1 1 Treatment 0.399 0 3 1 1 1 0 2 (66.7%) 0 1 (100.0%) 1 (100.0%) NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE." P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR <0.001 RESPECTIVELY.

Table 26C (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, MALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events PURITUS A) PLACEBO 18 0 Treatment 0.416 0 0 0 0 B) MS 60mg 18 2 2 1 1(50.0%) 0 C) MS 60 mg/NTX 0.01 mg 21 1 1 1 (100.0%) 0 0 D) MS 60 mg/NTX 0.1 mg 21 1 1 0 1(100.0%) 0 E) MS 60 mg/NTX 1 mg 21 0 0 0 0 0 SWEATING A) PLACEBO 18 0 Treatment 0.727 0 0 0 0 B) MS 60mg 18 1 1 0 1(100.0%) 0 C) MS 60 mg/NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 omg/NTX 0.1 mg 21 0 0 0 0 0 E) MS 60 mg/NTX 1 mg 21 1 1 0 1(100.0%) 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE." P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR <0.001 RESPECTIVELY.

Table 26C (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, MALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events SPECIAL

SENSES

ALL EVENTS A) PLACEBO 18 1 Treatment 0.958 1 1 (100.0%) 0 0 B) MS 60mg 18 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 21 1 1 1(100.0%) 0 0 D) MS 60 mg/NTX 0.1 mg 21 1 1 1(100.0%) 0 0 E) MS 60 mg/NTX 1 mg 21 2 2 2 (100.0%) 0 0 CONJUNCTIVITIS A) PLACEBO 18 1 Treatment 0.958 1 1 (100.0%) 0 0 B) MS60 mg 18 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 21 1 1 1(100.0%) 0 0 D) MS 60 mg/NTX 0.1 mg 21 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 1 mg 21 2 2 2 (100.0%) 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE." P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR <0.001 RESPECTIVELY.

Table 26C (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, MALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events

UROGENITAL

ALL EVENTS A) PLACEBO 18 0 Treatment 0.507 0 0 0 0 B) MS 60 mg 18 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 21 1 1 0 1(100.0%) 0 D) MS 60 mg/NTX 0.1 mg 21 2 2 2 (100.0%) 0 0 E) MS 60 mg/NTX 1 mg 21 0 0 0 0 0 DYSURIA A) PLACEBO 18 0 Treatment 1.000 0 0 0 0 B) MS 60mg 18 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.1 mg 21 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 1 mg 21 0 0 0 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE." P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR <0.001 RESPECTIVELY.

Table 26C (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY SAFETY POPULATION, MALE PATIENTS Severity BODY SYSTEM TOTAL NO. OF [2] ADVERSE EVENTS NO. OF SUBJECTS P-Value Number (COSTART ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE Of MILD Moderate SEVERE Events URINARY RETENTION A) PLACEBO 18 0 Treatment 1.000 0 0 0 0 B) MS 60 mg 18 0 0 0 0 0 C) MS 60 mg/NTX 0.01 mg 21 1 1 0 1(100.0%) 0 D) MS 60 mg/NTX 0.1 mg 21 1 1 1(100.0%) 0 0 E) MS 60 mg/NTX 1 mg 21 0 0 0 0 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE." P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR <0.001 RESPECTIVELY.

Table 26D SELECTED ADVERSE EVENTS SAFETY POPULATION, MALE PATIENTS ADVERSE TOTAL NO. OF P-VALUE NUMBER SEVERITY [2] EVENT NO. OF SUBJECTS OF ML M (ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE EVENTS MILD MODERATE SEVERE DIZZINESS A) PLACEBO 18 1 Treatment 0.065 1 1(100.0%) 0 0 B) MS60mg 18 8 A-B 0.017* 8 4 3 1 (12.5%) C) MS60 mg/NTX 0.01mg 21 8 A-C 0.023* 8 2 5 1 (12.5%) D) MS 60 mg/NTX0.1mg 21 8 A-D 0.023* 8 1 6 1 (12.5%) E) MS 60mg/NTX 1mg 21 7 A-E 0.048* 7 4 3 0 NAUSEA A) PLACEBO 18 1 Treatment 0.048* 1 0 1 (100.0%) 0 B) MS60mg 18 6 0.023* 6 2 4 0 C) MS 60 mg/NTX 0.01mg 21 8 0.010* 10 3 4 3 (3( D) MS 60 mg/NTX 0.1 mg 21 9 9 2 5 2 (2( E) MS 60 mg/NTX I mg 21 4 4 1 3 0 SOMNOLENCE A) PLACEBO 18 0 Treatment 0.265 0 0 0 0 B) MS 60mg 18 1 1 0 1(100.0%) 0 C) MS60 mg/NTX 0.01 mg 21 1 1 0 1(100.0%) 0 D) MS60 mg/NTX 0.1 mg 21 0 0 0 0 0 E) MS 60 mg/NTX 1 mg 21 3 3 1 2 0 NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE." P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR <0.001 RESPECTIVELY.

Table 26D (Continued) SELECTED ADVERSE EVENTS SAFETY POPULATION, MALE PATIENTS ADVERSE TOTAL NO. OF P-VALUE NUMBER SEVERITY [2] EVENT NO. OF SUBJECTS OF (ENGLISH) TREATMENT SUBJECTS W/EVENT SOURCE EVENTS MILD MODERATE SEVERE VOMITING A) PLACEBO 18 0 Treatment 0.166 0 0 0 0 B) MS 60 mg C) MS 60 mg/NTX 0.01 mg D) MS 60 mg/NTX 0.1 mg E) MS 60 mg/NTX 1 mg 4 (22.2%) 5 (23.8%) 5 (23.8%) 3 (14.3%)

A-C

A-D

4 (100.0%) 5 (100.0%) 5(100.0%) 3(100.0%) NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG ARE DEFINED AS THOSE EVENTS WITH RELATIONSHIP TO STUDY DRUG "SUSPECTED" OR "PROBABLE." P-VALUES ARE FROM FISHER'S EXACT TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, OR <0.001 RESPECTIVELY.

WO 01/85150 PCT/US01/14644 200 EXAMPLE 3 An additional clinical study using morphine alone and in combination with low doses of naltrexone was designed substantially the same as that described in Example 1, with the following differences: six treatment groups (not 5) with three different doses of NTX (0.1 mg, 0.01 mg and 0.001 mg) in combination with MS mg versus MS 60 mg alone, versus NTX 0.01 mg alone, and versus placebo alone, in subjects with moderate to severe pain in a postsurgical dental pain clinical study; (2) each group was 50 patients (not 40) for a total of 300 (not 200); subjects had three or four full or partial bony impacted third molars (not 2 or more impacted third molars); meaningful pain relief only (not meaningful and perceptible pain relief with two stopwatches) was measured using one stopwatch; the primary efficacy variables included TOTPAR-4 and SPID-4 measured through 4 hours (not TOTPAR- 8 and SPID-8 measured through 8 hours); the secondary efficacy variables included 6 and 8 hour Total Pain Relief Scores (TOTPAR-6 AND TOTPAR-8), 6 and 8 hour Sum of Pain Intensity Difference Scores (SPID-6 and SPID-8), and Time to Onset of Analgesia, time to an hourly PID Score of 1, instead of Time to Onset of First Perceptible Pain Relief; additional exclusion criteria were patients with known history of severe hepatic or renal impairment, and midazolam (Versed) was not permissible medication during surgery; and for adverse events, body systems and preferred terms were from the MedDRA (not the COSTART) dictionary.

A total of 304 subjects were randomized; among them 302 subjects were deemed evaluable (Table 27).

Table 27 Analysis Populations, All Patients Treatments Placebo MS -(60 mg) NTX MS (60 mg) MS (60 mg) MS (60 mg) 0.01 MG NTX NTX NTX Total mg) (0.01 mg) 1mg) Patients Enrolled 51 53 51 50 51 48 304 Safety 51 (100.0%) 53 (100.0%) 51 (100.0%) 50 (100.0%) 51 (100.0%) 48 (100.0%) 304(100.0%) Intent-To-Treat 51 (100.0%) 53 (100.0%) 51 (100.0%) 50 (100.0%) 51 (100.0%) 48 (100.0%) 304(100.0%) Evaluable 51 (100.0%) 53 (100.0%) 51 (100.0%) 49 51 (100.0%) 47 302 (99.3%4) PATIENTS WITH DEMOGRAPHIlC INIFORMATION.

WO 01/85150 PCT/US01/14644 202 The demographic and baseline characteristics were summarized by treatment groups for the ITT population (all randomized patients) and the evaluable population (all randomized patients with at least one efficacy evaluation at 90 minutes or more after dosing) (Table 28). Demographic characteristics included age, race/ethnicity, sex, weight, height, medical history, teeth extracted (impacted and non-impacted), baseline pain intensity, and baseline visual analog scale.

The demographics for the total ITT population were generally comparable across all 5 treatment groups. Subjects ranged in age from 16 to 49 years; 66.8% were Caucasian and 53.3% were female. There were some differences among treatment groups in the number of third molars extracted and the degree of impaction of third molar extracted. No adjustments in the analyses were made to take into account differences among treatment groups. These differences had little or no influence on pain assessments at baseline. The baseline pain intensity scores (Table 29A) and visual analog scale scores (Table 29B) were generally comparable across treatment groups.

Table 28 Baseline Characteristics Intent-To-Treat Population, All Patients MS (60 mg) MS (60 mg) MS (60 mg) TOTAL P-Value Placebo MS NTX 0.01 mg NTX NTX NTX (0.1 [1] (0.001 mg) (0.01 mg) mg) Age (yrs) 0.434 N 51 53 51 50 51 48 304 Mean 22.5 23.4 24.0 22.5 24.1 24.0 23.4 SD 3.84 5.85 5.41 4.37 5.97 6.17 5.34 Median 22.0 22.0 23.0 22.0 22.0 21.5 22.0 Range 16-31 16-49 16-41 16-38 16-41 17-40 16-49 Gender 0.126 Male 19 25 21 32 23 22 142 (46.7%) Female 32 28 30 18 28 26 162 (53.3%) Total 51 53 51 50 51 48 304 Race/Ethnic 0.694 Origin Caucasian 31 35 34 31 37 35 203 (66.8%) Black 8 8 7 7 8 5 43 (14.1%) Asian 2 2 0 0 0 2 6 Hispanic 9 8 9 11 5 5 47 (15.5%) Other 1 0 1 1 1 1 5 Total 51 53 51 50 51 48 304 FOR AGE, HEIGHT, WEIGHT, AND TIME BETWEEN END OF SURGERY AND STUDY MEDICATION, P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS; FOR GENDER, RACE/ETHNIC ORIGIN, AND NUMBER OF THIRD MOLARS EXTRACTED, P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTING FOR SITE.

BLACK, ASIAN, HISPANIC, AND OTHER ARE COMBINED INTO ONE CATEGORY TO DERIVE P-VALUE.

4 OR MORE THIRD MOLARS EXTRACTED AS ONE CATEGORY TO DERIVE P-VALUE.

Table 2 (Continued) Baseline Characteristics Intent-To-Treat Population, All Patients MS (60 mg) MS (60 mg) MS (60 mg) TOTAL P-Value Placebo MS. NTX 0.01 mg NTX NTX NTX (0.1 [1] rag) 0.001 mng) (0.01 mg) mg) Height (cm) 0.888 N 51 53 51 50 51 48 304 Mean 170.0 171.7 169.6 170.2 170.0 170.9 170.4 SD 8.99 9.91 8.84 9.90 8.99 9.11 9.25 Median 170.2 170.2 167.6 170.2 170.2 170.6 170.2 Range 152.4-190.5 152.0-195.6 154.9-190.5 149.9-198.1 151.0-191.0 157.5-190.5 149.9-198.1 Weight (kg) 0.528 N 51 53 51 50 51 48 304 Mean 73.3 75.3 79.4 73.4 77.3 76.7 75.9 SD 19.71 14.32 19.72 21.59 15.21 19.94 18.53 Median 67.7 74.5 80.0 66.5 76.2 72.5 74.0 Range 44.5-129.1 45.4-112.7 45.9-120.7 44.9-147.7 52.7-111.6 48.6-157.8 44.5-157.8 Number of 0.297 Third Molars 3 13 18 9 10 13 16 79 (26.0%) Extracted 4 36 35 39 39 38 31 218 (71.7%) 5 1 0 3 1 0 0 5 6 1 0 0 0 0 0 1 7 0 0 0 0 0 1 1 TOTAL 51 53 51 50 51 48 304 FOR AGE, HEIGH, WEIGHT, AND TIME BETWEEN END OF SURGERY AND STUDY MEDICATION, P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS; FOR GENDER, RACE/ETHNIC ORIGIN, AND NUMBER OF THIRD MOLARS EXTRACTED, P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTING FOR SITE.

BLACK, ASIAN, HISPANIC, AND OTHER ARE COMBINED INTO ONE CATEGORY TO DERIVE P-VALUE.

4 OR MORE THIRD MOLARS EXTRACTED AS ONE CATEGORY TO DERIVE P-VALUE.

Table zs (uonutinued) Baseline Characteristics Intent-To-Treat Population, All Patients MS (60 mg) MS (60 mg) MS (60 mg) TOTAL P-Value Placebo MS NTX 0.01 mg NTX NTX NTX (0.1 [1] mg) (0.001 mg) (0.01 mg) mg) Time 0.224 Between End N 51 53 51 50 51 48 304 of Surgery Mean 152.9 141.1 154.8 161.3 152.9 159.9 153.7 and Study SD 39.71 38.31 44.15 46.10 33.65 58.37 44.01 Medication Median 150.0 137.0 154.0 160.5 149.0 149.5 150.0 (Minutes) Range 58.0-263.0 74.0-277.0 80.0-294.0 89.0-275.0 85.0-244.0 81.0-348.0 58.0-348.0 FOR AGE, HEIGH, WEIGHT, AND TIME BETWEEN END OF SURGERY AND STUDY MEDICATION, P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS; FOR GENDER, RACE/ETHNIC ORIGIN, AND NUMBER OF THIRD MOLARS EXTRACTED, P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTING FOR SITE.

BLACK, ASIAN, HISPANIC, AND OTHER ARE COMBINED INTO ONE CATEGORY TO DERIVE P-VALUE.

4 OR MORE THIRD MOLARS EXTRACTED AS ONE CATEGORY TO DERIVE P-VALUE.

Table 29A Baseline Pain Intensity Scores Intent-To-Treat Population, All Patients PAIN INTENSITY P-VALUE FOR PAIRWISE COMPARISONS P-Value for NTX MS 60 mg MS 60 mg MS 60 mg Overall TREATMENT MODERATE SEVERE MS 60 0.01 mg NTX NTX NTX Treatment 0.001 mg 0.01 mg 0.1 Mg Placebo 25 26 0.989 0.994 0.935 1.000 0.916 0.949 MS 60 mg 26 27 0.998 0.923 0.989 0.925 NTX 0.01 MG 25 26 (5 0.923 0.994 0.923 MS 60 mg /NTX 0.001 mg 24 26 0.935 0.851 MS 60 mg /NTX 0.01 mg 25 26 (5 0.9 16 MS 60 mg /NTX 0. 1 mg 24 ,24 (50.0%) NOTE: P-VALUES ARE FROM COCEHRAN-MANTEL-HAENZl, TEST ADJUJST hG FOR SITE.

Table 29B Baseline Visual Analog Scale (VAS) Scores Intent-To-Treat Population, All Patients BASELINE VAS SCORE _____P-VALUE FOR PAIRWISE COMPARISONS P-Value MS for TREATMENT Moderate[l] Severe Total MS 60 NTX 60 mg MS 60 MS Overall mg 0.01 NTX mg 60 mg Treatment mg 0.001 mg NTX NTX 0.01 mg 0.1 mg N Mean (SD) N Mean (SD) N Mean Placebo 25 69.0 (12.72) 26 82.5 (9.04) 51 75.9 (12.86) 0.464 0.922 0.378 0.127 0.173 0.552 MS 60mg 26 69.9 (8.26) 27 78.5 (8.46) 53 74.3 (9.35) 0.527 0.871 0.418 0.511 NTX 0.01 mg 25 69.8 (10.08) 26 81.3 (7.29) 51 75.7 (10.45) 0.433 0.153 0.205 MS 60 mg/ NTX 0.001 mg 24 65.3 (7.55) 26 81.9 (9.02) 50 73.9 (11.79) 0.524 0.624 MS 60 mg/ NTX 0.01 mg 25 63.2 (8.74) 26 81.3 (8.77) 51 72.4 (12.57) 0.889 MS 60 mg/ NTX 0.1 mg 24 64.8 (7.85) 24 80.7 (7.64) 48 72.8 NOTE: P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS.

BASELINE PAIN INTENSITY ON THE CATEGORICAL SCALE.

WO 01/85150 PCT/US01/14644 208 The TOTPAR results 4 hour, 6 hour, 8 hour) are summarized in Table The 0.01 mg NTX only group and the placebo treatment group had the lowest mean TOTPAR scores. All 4 of the active treatment groups exhibited mean TOTPAR scores that were numerically higher than NTX alone or placebo. The combination treatments had a dose-response relation in the mean TOTPAR scores, the highest dose of NTX (0.1 mg) had the highest mean TOTPAR scores and the lowest dose of NTX (0.001 mg) had the lowest mean TOTPAR scores. This pattern (high-dose (0.1 mg NTX) mid-dose (0.01 mg NTX) low dose (0.001 mg NTX) was generally observed for pain relief variables throughout the study. The mean TOTPAR score for the 0.01 mg NTX combination treatment was higher than that for the MS alone treatment, whereas the 0.001 mg NTX combination treatment mean was comparable to or lower than that for the MS alone treatment.

Table Total Pain Relief Scores Intent-to-Treat Population, All Patients TOTAL PAIN RELIEF SCORE P-VALUT E -TREATMENT IN MEA SD MIN IMEDIAN IMAX ISOURCE [1] TOTAL PAIN RELIEF SCORE (0-4 A) Placebo B) MS 60 mg C) NTX 0.01 mg D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60 mg/NTX 0.1 mg 1.55 3.88 1.40 3.46 4.22 4.71 2.469 3.557 2.461 3.912 4.023 3.858 0.00 2.88 0.00 2.56 3.88 3.56 11.3 11.0 10.4 12.5 14.5 14.5

TREATMENT

SITE

TREATMENT BY SITE

A-B

A-C

A-D

A-E

A-F

B-C

B-D

B-E

B-F

C-D

C-E

C-F

D-E

D-F

E-F

0.924 0.518 0.001 0.786 0.009** 0.563 0.601 0.352 0.004** <.001* 0.277 0.140 0.678 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIAN( TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUJE 0.05, 0.01, or 0.00 1 RESPECTIVELY.

E AND ITS CONTRASTS WITH TREATMENT, SITE, ANT) Table 30 (Continued) Total Pain Relief Scores Intent-to-Treat Population, All Patients TOTAL PAIN RELIEF SCORE P-VALUE TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE [1] TOTAL PAIN RELIEF SCORE (0-6 HOURS) A) Placebo 51 2.78 4.608 0.0 0.00 19.3 TREATMENT B) MS 60 mg 53 6.32 5.895 0.0 4.75 18.4 SITE 0.797 C) NTX 0.01 mg 51 2.14 3.897 0.0 0.00 16.4 TREATMENT BY SITE 0.370 D) MS 60 mg/NTX 0.001 mg 50 5.86 6.647 0.0 3.81 20.5 A-B 0.003** E) MS 60 mg/NTX 0.01 mg 51 6.92 6.468 0.0 5.88 22.5 A-C 0.560 F) MS 60 mg/NTX 0.1 mg 48 7.92 6.565 0.0 5.63 22.5 A-D 0.012* A-E <001*** A-F <.001** B-C <001*** B-D 0.698 B-E 0.585 B-F 0.294 C-D 0.002** C-E C-F <001** D-E 0.357 D-F 0.159 E-F 0.609 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 30 (Continued) Total Pain Relief Scores Intent-to-Treat Population, All Patients TOTAL PATN RELEEF SCORE P-VALUE TREATMENT IN MEAN ISD MIN IMEDIAN IMAX ISOURCE[1 -TOTAL PAIN RELIEF SCORE (0-8 HOURS) A) Placebo B) MS 60 mg C) NTX 0.01 mng D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60 mg/NTX 0. 1 mg 4.00 8.56 2.86 8.19 9.58 11.19 6.759 U.15 5.339 9.450 9.049 9.407 0.00 6.75 0.00 4.38 7.88 8.06 26.3 26.4 22.4 28.5 30.5 30.5

TREATMENT

SITE

TREATMENT BY SITE

A-B

A-C

A-D

A-E

A-F

B3-C

B-D

B-E

B-F

C-D

C-E

C-F

D-E

D-F

E-F

<.001 0.656 0.3 12 0.007** 0.485 0.016* 0.796 0.514 0.215 0. 002* 0.370 0.142 0.550 []P-VA-LUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE =0.05, =0.01, or =0.001 RESPECTIVELY.

WO 01/85150 PCT/US01/14644 212 Table 31 summarizes the results of the 4, 6, and 8 hour SPID results. The 4 hour SPID results are also represented in Figure 23A. The 0.01 mg NTX alone and placebo treatment groups had the lowest mean 4 hour SPID scores. All 4 of the active treatment groups with MS alone or in combination with NTX exhibited improved profiles in mean SPID relative to NTX alone or placebo. The mean 4 hour SPID scores for the 0.01 mg NTX and 0.1 mg NTX combination treatments were higher than that for the MS alone treatment, whereas the 0.001 mg NTX combination treatment was comparable to that for the MS alone treatment (Figure 23A).

The patterns of the 6 hour and 8 hour SPID scores were similar to those at 4 hours.

Table 31 Sum of Pain Intensity Differences Intent-To-Treat Population, All Patients SUM OF PAIN INTENSITY DIFFERENCES P-VALUE N MEAN SD IMIN MEDIAN MAX SOURCE [2] SUM OF PAIN INTENSITY DIFFERENCES (0-4 HOURS) A) Placebo 51 -0.25 2.293 -4 0.00 6 TREATMENT 0.001** B) MS 60 mg 53 0.83 2.659 -4 0.00 6 SITE 0.285 C) NTX 0.01 mg 51 -0.59 2.370 -4 0.00 7 TREATMENT BY SITE 0.559 D) MS 60 mg/NTX 0.001 mg 50 0.91 3.261 -4 0.00 10 A-B 0.076 E) MS 60 mg/NTX 0.01 mg 51 1.18 3.157 -4 0.00 11 A-C 0.522 F) MS 60 mg/NTX 0.1 mg 48 1.78 3.077 -4 1.63 11 A-D 0.065 A-E 0.021* A-F 0.001** B-C 0.016* B-D 0.919 B-E 0.585 B-F 0.158 C-D 0.013* C-E 0.003** C-F D-E 0.663 D-F 0.197 E-F 0.382 PAIN INTENSITY DIFFERENCE PAIN INTENSITY AT BASELINE PAIN INTENSITY AT CURRENT TIME.

P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 31 (Continued) Sum of Pain Intensity Differences Intent-To-Treat Population, All Patients SUM OF PAIN INTENSITY DIFFERENCES P-VALUE N I MEAN I SD I MIN MEDIAN I MAX I SOURCE [2] SUM OF PAIN INTENSITY DIFFERENCES (0-6 HOURS) A) Placebo 51 -0.21 3.973 -6 0.00 10 TREATMENT 0.001** B) MS 60 mg 53 1.44 4.385 -6 0.00 11 SITE 0.153 C) NTX 0.01 mg 51 -0.91 3.705 -6 0.00 11 TREATMENT BY SITE 0.405 D) MS 60 mg/NTX 0.001 mg 50 1.77 5.375 -6 0.00 16 A-B 0.096 E) MS 60 mg/NTX 0.01 mg 51 2.03 5.056 -6 0.00 17 A-C 0.433 F) MS 60 mg/NTX 0.1 mg 48 3.06 5.146 -6 1.81 17 A-D 0.050 A-E 0.026* A-F 0.002** B-C 0.014* B-D 0.742 B-E 0.567 B-F 0.157 C-D 0.006** C-E 0.002** C-F D-E 0.814 D-F 0.285 E-F 0.397 PAIN INTENSITY DIFFERENCE PAIN INTENSITY AT BASELINE PAIN INTENSITY AT CURRENT TIME.

P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 31 (Continued) Sum of Pain Intensity Differences Intent-To-Treat Population, All Patients SUM OF PAIN INTENSITY DIFFERENCES P-VALUE IN MEAN SD I MIN MEDIAN MAX SOURCE [2] SUM OF PAIN INTENSITY DIFFERENCES (0-8 HOURS) A) Placebo 51 -0.20 5.641 -8 0.00 13 TREATMENT 0.001** B) MS 60 mg 53 1.87 6.021 -8 0.00 15 SITE 0.092 C) NTX 0.01 mg 51 -1.23 5.046 -8 0.00 15 TREATMENT BY SITE 0.368 D)MS 60 mg/NTX 0.001 mg 50 2.50 7.411 -8 0.00 22 A-B 0.132 E)MS 60mg/NTX 0.01 mg 51 2.92 7.111 -8 0.00 23 A-C 0.421 F) MS 60 mg/NTX 0.1 mg 48 4.32 7.247 -8 3.00 23 A-D 0.054 A-E 0.025* A-F 0.002** B-C 0.021* B-D 0.654 B-E 0.455 B-F 0.123 C-D 0.007** C-E 0.002** C-F D-E 0.773 D-F 0.281 E-F 0.421 PAIN INTENSITY DIFFERENCE PAIN INTENSITY AT BASELINE PAIN INTENSITY AT CURRENT TIME.

P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

WO 01/85150 PCT/US01/14644 216 Figure 16 is a visual presentation of the summary and analysis of time to onset of meaningful pain relief presented in Table 32A. The median time to onset of meaningful pain relief was shortest in the 0.1 mg NTX combination treatment group.

Figure 17 is a visual presentation of the summary and analysis of time to onset of analgesia presented in Table 32B. The median time to onset of analgesia was shortest in the 0.1 mg NTX combination treatment group.

Table 32A Time To Onset of Meaningful Pain Relief Intent-To-Treat Population, All Patients TEST OF SURVIVAL CURVES MEDIAN 95% CONFIDENCE TIME INTERVAL TREATMENT N (hh:mm) (hh:mm) SOURCE LOG-RANK WILCOXON A) Placebo 51 >8:00 >8:00) TREATMENT B) MS 60 mg 53 >8:00 (5:00, >8:00) A-B 0.024* 0.016* C) NTX 0.01 mg 51 >8:00 >8:00) A-C 0.965 0.899 D) MS 60 mg/NTX 0.001 mg 50 >8:00 >8:00) A-D 0.054 0.031* E) MS 60 mg/NTX 0.01 mg 51 >8:00 (3:00, >8:00) A-E 0.008** 0.004** F) MS 60 mg/NTX 0.1 mg 48 3:58 (1:31, >8:00) A-F <001*** B-C 0.028* 0.025* B-D 0.783 0.859 B-E 0.664 0.574 B-F 0.046* 0.094 C-D 0.062 0.046* C-E 0.010* 0.006** C-F <001*** D-E 0.488 0.474 D-F 0.026* 0.073 E-F 0.127 0.286 P-VALUE 0.05, 0.001, OR 0.001 RESPECTIVELY.

Table 32B Time to Onset of Analgesia Intent-To-Treat Population, All Patients OF SURVIVAL CURVES MEDIAN 9S% CONFIDENCE TIME INTERVAL TREATMENT N (hh:mm) (hh:mm) SOURCE LOG-RANK WILCOXON A) Placebo 51 >8:00 >8:00) TREATMENT 0.001** <.001** B) MS 60 mg 53 >8:00 (1:30, >8:00) A-B 0.099 0.094 C) NTX 0.01 mg 51 >8:00 >8:00) A-C 0.373 0.325 D) MS 60 mg/NTX 0.001 mg 50 >8:00 (1:30, >8:00) A-D 0.077 0.060 E) MS 60OmgiNTX 0.01 mg 51 >8:00 (1:27, >8:00) A-E 0.054 0.027* F) MS 60 mg/NTX 0. 1mg 48 1:47 (1:00, >8:00) A-F 0.002** 0.003** B-C 0.011* 0.008** B-D 0.866 0.787 B-E 0.744 0.54 1 B-F 0.143 0.179 C-D 0.008** 0,004** C-E 0.005** 0.001'*' C-F D-E 0.878 0.740 D-F 0.207 0.302 E-F 0.265 0.486

U

0.001, OR 0.001 RESPECTIVELY.

WO 01/85150 PCT/US01/14644 219 Figures 18 and 19 are a visual presentation of the summary and analysis of time to remedication (rescue medication) up to 8 and 24 hours presented in Table 33.

The survival distributions (0-8 hours) were different across treatment groups. The cumulative percent distributions were different for the MS alone or in combination with NTX compared to 0.01 mg NTX alone or placebo (Figure 18). The median times to administration of rescue medication were longer for the MS alone or in combination with NTX treatment groups compared to the 0.01 mg NTX alone and placebo groups. The longest duration of action was observed in the 0.1 mg NTX combination treatment group, followed by the 0.001 mg NTX combination treatment group.

The cumulative percent distributions (0-24 hours) were also different across treatment groups, and were also different for the MS alone or in combination with NTX groups compared to the 0.01 mg NTX alone or placebo group (Figure 19).

Again, the median times to administration of rescue medication were longer for the morphine and combination treatment groups.

Analyses of time to remedication up to 24 hours yielded generally similar results, however, the data should be viewed with caution because subjects were not under close supervision after 8 hours.

Table 33 Time To Rescue Medication Intent-To-Treat Population, All Patients OF SURVIVAL CURVES MEDIAN 95% CONI'4DENCE TIME INTERVAL TREATMENT N (hh:mm) (hh:mm) SOURCE LOG-RANK WILCOXON EFFICACY OBSERVATION PERIOD (0-8 HOURS) A) Placebo 51 1:34 (1:32, 1:48) TREATMENT <01* B) MS 60 mg 53 2:19 (2:01, 4:21) A-B 0.O01** <01* C) NTX 0.01 mg 51 1:34 (1:32, 1:36) A-C 0.140 0.872 D) MS 60mg/NTX 0.001mg 50 2:29 (1:47, 5:01) A-D 0.001**<.01* E) MS 60Omg /NTX 0.01 mg 51 2:03 (1:35, 5:00) A-E 0.002** 0.003** F) MS 60mg /NTX 0. 1mg 48 4:12 (2:09, >8:00) A-F <01* B-C B-D 0.871 0.907 B-F 0.960 0.412 B-F 0.309 0.303 C-F 0.001** C-F D-E 0.838 0.495 D-F 0.407 0.270 -F 0.305 0.079 P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 33 (Continued) Time To Rescue Medication Population, All Patients 1 OF SURVIVAL CURVES MEDIAN 95% CONFIDENCE TIME INTERVAL TREATMENT JN (hh:inm) (hh:mm) SOURCE LOG-RANK WILCOXON EFFICACY OBSERVATION PERIOD (0-24 HOURS) A) Placebo 51 1:34 (1:32, 1:48) TREATMENT B) MS 60mrg 53 2:19 (2:01, 4:21) A-B 0.002** <01* C) NTX 0.01 mg 51 1:34 (1:32, 1:36) A-C 0.056 0.866 D) MS 60 mg/NTX 0.001 mg 50 2:29 (1:47, 5:01) A-D <01* E) MS 60Omg /NTX 0.01 mg 51 2:03 (1:35, 5:00) A-E 0.002** 0.002** F) MS 60OmgI/NTX0. 1 mg 48 4:12 (2:09, 8:48) A-F K.001*** <01* B-C 0** B-D 0.660 0.973 B-E 0.913 0.459 B-F 0.154 0.219 C-E 0.00l** C-F <01* D-E 0.748 0.458 D-F 0.332 0.25 1 0.199 0.062 P-VALUE 0.05, 0.01, or 0.00 1 RESPECTIVELY.

WO 01/85150 PCT/US01/14644 222 Table 34 presents the summary and analysis of percent of subjects who took rescue medication up to 8 and 24 hours. Approximately 40% of subjects in the highdose NTX (0.1 mg) combination group and more than 30% of subjects in the middose NTX (0.01 mg) and low-dose NTX (0.001 mg) combination groups did not require rescue medication during 8 hours. Thus, the longest duration of action was observed in the 0.1 mg NTX combination treatment group. Analyses of the percentage of subjects who remedicated within 24 hours indicated that the NTX (0.001 mg, 0.01 mg, 0.1 mg) combination treatment groups were comparable and different from the placebo, 0.01 mg NTX and MS alone treatment groups, however, the data should be interpreted with caution because subjects were not under close supervision after 8 hours.

Table 34 Percent of Patients Rescued Intent-To-Treat Population, All Patients

RESCUED

TREATMENT IYES NO ISOURCE P-VALUE [1] EFFICACY OBSERVATION PERIOD (0-8 HOURS) A) Placebo 45 6 TREATMENT <01* B) MS 60 mg 40 13 A-B 0.092 C) NTX 0.01 mg 48 3 A-C 0.302 D) MS 60Omg /NTX 0.001 mg 34 16 A-D 0.015* E) MS 60Omg /NTX 0.0 1mg 34 17 (33.39/) A-E 0.008** F) MS 60Omg /NTX 0. 1mg 29 19 A-F 0.001** B-C 0.008** B-D 0.400 B-E 0.322 B-F 0.103 C-D <01* C-E <.01* C-F <01* D-E 0.840 D-F 0.391 E-F 0.532 P-VALUES ARE FROM COCHRAN-MANTEL-HABNZEL TEST ADJUJSTING FOR SITE.

Table 34 (Continued) Percent of Patients Rescued Intent-To-Treat Population, All Patients

RESCUED

TREATMENT IYES NO ISOURCE, P-VALUE [1] EFFICACY OBSERVATION PERIOD (0-24 HOURS) A) Placebo 49 2 TREATMENT 0.005** B) MS 60 mg 49 4 A-B 0.427 C) NTX0.01lmg 50 1 A-C 0.558 D) MS 60 mg /NTX 0. 00 1 mg 42 8 A-D 0.045* E) MS 60 mg INTX 0.01 mg 43 8 A-E 0.042* F) MS 60Omg /NTX 0. 1mg 37 11 A-F 0.004** B-C 0.182 B-D 0.179 B-E 0.194 B-F 0.03 0* C-D 0.013* C-B 0.013* C-F 0.001** D-E 0.999 D-F 0.367 E-F 0.369 P-VALUES ARE FROM COCI{RAN-MANTEL-HAENZEL TEST ADJUSTING FOR SITE.

WO 01/85150 PCT/US01/14644 225 Figure 20 is a visual presentation of the hourly pain relief scores presented in Table 35. The hourly pain relief scores for the 0.01 mg NTX alone or placebo treatment were less than those for the active treatment groups (MS alone or in combination with NTX) which improved over time. There was separation between the 0.01 mg NTX alone or placebo and the active treatment groups that continued throughout the 8 hour study period. Highest pain relief scores were observed for the 0.1 mg NTX combination group followed by the 0.01 mg NTX combination group (Figure Table Pain Relief (PR) Scores hItent-To-Treat Population, All Patients SPAIN RELIEF SCORE (PR) MI A ORE P-VALUE TREATMENT N MEN SD MNAXSUC[1

MINUTES

A) Placebo 51 0.12 0.382 0 2 Treatment 0.716 B) MS 60 mg 53 0.11 0.375 0 2 Site 0.031* C) NTX 0.01 mg 51 0.20 0.530 0 2 Treatment by Site 0.886 D) MS 60 mg /NTX 0.001 mg 50 0.24 0.517 0 2 A-B N/D E) MS 60mg /NTXO0.0O1mg 51 0.24 0.619 0 3 A-C N/D F) MS 60mg /NTX 0.l1mg 48 0.19 0.532 0 2 A-D N/D A-E N/D A-F N/D B-C N/D B-D N/D B-F N/D B-F N/D C-D N/D C-E N/D C-F N/D D-E N/D D-F N/D E-F N/D P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE ANT) ITS CONTRASTS WITH TREATMENT, SITE, ANT) TREATMENT BY SITE INTERACTION AS FACTORS.

P-VA-LUE 0.05, 0.01, or 0.00 1 RESPECTIVELY.

N/D: NOTE DONE (BECAUSE OVERALL P-VA-LUE NOT SIGNIFICANT).

Table 35 (Continued) Pain Relief (PR) Scores Inten-T-Teat ll fli nn All t;Pfti f oJLJJt opu Lw .ty&UJJI, ensXI a~II.

PAIN RELIEF SCORE (PR) P-VALUE M1N MAX SOURCE TREATMENT N MEAN SD [1]

MINUTES

A) Placebo 51 0.29 0.540 0 2 Treatment 0.459 B) MS 60 mg 53 0.32 0.581 0 2 Site 0.107 C) NTX 0.01 mg 51 0.29 0.610 0 3 Treatment by Site 0.378 D) MS 60 mg /NTX 0.001 mg 50 0.26 0.487 0 2 A-B N/D E) MS 60 mg /NTX 0.01 mg 51 0.47 0.857 0 4 A-C N/D F) MS 60 mg /NTX 0.1 mg 48 0.44 0.741 0 3 A-D N/D A-E N/D A-F N/D B-C N/D B-D N/D B-E N/D B-F N/D C-D N/D C-E N/D C-F N/D D-E N/D .D-F N/D E-F N/D P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 35 (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, All PAIN RELIEF SCORE (PR)

P-VALUESURC

TREATMENT N MEAN SID MN-V MXSUC[1]

MINUJTES

A) Placebo 51 0.29 0.540 0 2 Treatment 0.017* B) MS 60 mg 53 0.64 0.762 0 3 Site 0.464 C) NTX 0.01 mg 51 0.35 0.658 0 3 Treatment by Site 0.481 D) MS 60mg/NTXO.00 1mg 50 0.58 0.835 0 3 A-B 0.054 E) MS 60mgI/NTX0.01lmg 51 0.84 1.065 0 4 A-C 0.875 F) MS 60mg /NTXO0.l1mg 48 0.65 0.863 0 4 A-D 0.137 A-E 0.001** A-F 0.080 B-C 0.079 B-D 0.685 B-E 0.216 B-F 0.900 C-D 0.185 C-E 0.003** C-F 0.111 D-E 0.106 D-F 0.785 0.183 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE ANT) ITS CONTRASTS WITH TREATMENT, SITE, AM) TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or =0.001 RESPECTIVELY.

N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 35 (Continued) Pain Relief (PR) Scores Population, All Patients PAIN RELIEF SCORE (PR) 1 I MA1OUC P-VALUE TREATMENT N MEAN SD IMN MXSUC 1 iHOUR A) Placebo B) MS 60 mg C) NTX0.01lmg D) MS 60 mg INTX 0.001 mg E) MS 60 mg INTX 0.01 mg F) MS 60mg /NTXO0. 1mg 0.31 0.87 0.47 0.76 0.96 0.96 0.616 0.962 0.809 1.041 1.038 1.010 Treatment Site Treatment by Site

A-B

A-C

A-D

A-B

A-F

B-C

B-D

B3-B3

B-F

C-D

C-B

C-F

D-E

D-F

0.002** 0.478 0.687 0.004** 0.5 0.033* 0.001** 0.002** 0.029* 0.499 0.650 0.767 0.141 0.009** 0.016* 0.264 0.343 0.881 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AM) ITS CONTRASTS WITH TREATMENT, SITE, ANT) TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, =0.01, or 0.001 RESPECTIVELY.

NfD: NOTE DONE (BECAUSE OVERALL P-VA-LUE NOT SIGNIFICANT).

Table 35 (Continued) Pain Relief (PR) Scores Population, All Patients- PEW SCR P) M ORPVALUE TREATMENT N RELEAN SDOR (PR MI [1]SORC HOURS 1,rr A) Placebo 13) MS 60 mg C) NTX0.01lmg D) MS 60Omg /NTX 0.001 mg E) MS 60 mg /NTX 0.01 mg F) MS 60 mg/NTX 0. 1 mg 0.35 1.13 0.39 0.98 1.22 1.31 0.658 1.038 0.723 1.169 1.154 1.095 Treatment Site Treatment by Site

A-B

A-C

A-D

A-E

A-F

B-C

B-D

B-E

B-F

C-D

C-E

C-F

D-E

D-F

B-F

<.001 0.863 0.479 0.905 0.002** 0.462 0.699 0.565 0.003** <.001*I** <001 0.267 0.200 0.846 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, ANT) TREATMENT BY SITE INTER-ACTION AS FACTORS.

P-VALUTE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 35 (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, All Patients PAIN RELIEF SCORE (PR) MIJA SUC P-VALUE TREATMENT N MEAN rSD MN MXSUC 1 2 HTOURS A) Placebo 51 0.35 0.658 0 3 Treatment <01* B) MS 60 mg 53 1.21 1.150 0 3 Site 0.926 C) NTX 0.01 mg 51 0.37 0.692 0 3 Treatment by Site 0.519 D) MS 60mg /NTXO.001mg 50 1.02 1.237 0 4 A-B <01* E) MS 60mg INTX0.01mg 51 1.16 1.173 0 4 A-C 0.944 F) MS 60Omg /NTX0. 1 mg 48 1.40 1.250 0 4 A-D 0.002** A-E A-F <01* B-C <01* B-D 0.405 B-E 0.866 B-F 0.540 C-D O.003** C-E <01* C-F <01* D-E 0.508 D-F 0.158 0.440 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE =0.05, 0.01, or =0.001 RESPECTIVELY.

N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 35 (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, All Patients PAIN RELIEF SCORE (PR) MIN MAX SOURCE P-VALUE TREATMENT N MEAN SD [1] 3 HOURS A) Placebo 51 0.51 0.925 0 4 Treatment B) MS 60 mg 53 1.18 1.180 0 3 Site 0.830 C) NTX 0.01 mg 51 0.35 0.716 0 3 Treatment by Site 0.641 D) MS 60 mg/NTX 0.001 mg 50 1.06 1.331 0 4 A-B 0.005** E) MS 60 mg/NTX 0.01 mg 51 1.31 1.288 0 4 A-C 0.503 F) MS 60 mg /NTX 0.1 mg 48 1.50 1.321 0 4 A-D 0.021* A-E A-F B-C <001*** B-D 0.657 B-E 0.531 B-F 0.253 C-D 0.003** C-E C-F D-E 0.291 D-F 0.120 E-F 0.599 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 35 (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, All Patients PAIN RELIEF SCORE (PR) N MX S P-VALUE TREATMENT N MEAN SD [1] 4 HOURS A) Placebo 51 0.61 1.078 0 4 Treatment B) MS 60 mg 53 1.26 1.273 0 3 Site 0.558 C) NTX 0.01 mg 51 0.37 0.747 0 3 Treatment by Site 0.460 D) MS 60 mg/NTX 0.001 mg 50 1.18 1.410 0 4 A-B 0.010* E) MS 60 mg/NTX 0.01 mg 51 1.37 1.326 0 4 A-C 0.360 F) MS 60 mg/NTX 0.1 mg 48 1.67 1.449 0 4 A-D 0.029* A-E 0.003** A-F B-C B-D 0.737 B-E 0.665 B-F 0.193 C-D 0.002** C-E C-F D-E 0.448 D-F 0.109 E-F 0.383 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 35 (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, All Patients PAIN RELIEF SCORE (PR) SOUR P-VALUE TREATMENT N MEAN SD [1]

HOURS

A) Placebo 51 0.61 1.097 0 4 Treatment B) MS 60 mg 53 1.25 1.285 0 4 Site 0.467 C) NTX 0.01 mg 51 0:37 0.747 0 3 Treatment by Site 0.161 D) MS 60 mg /NTX 0.001 mg 50 1.22 1.461 0 4 A-B 0.014* E) MS 60 mg/NTX 0.01 mg 51 1.37 1.341 0 4 A-C 0.364 F) MS 60 mg /NTX 0.1 mg 48 1.56 1.443 0 4 A-D 0.019* A-E 0.002** A-F 0.001** B-C B-D 0.944 B-E 0.560 B-F 0.385 C-D 0.001** C-E C-F D-E 0.521 D-F 0.357 E-F 0.767 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

CONTRASTS WITH TREATMENT, SITE, AND Table 35 (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, All Patients PAIN RELIEF SCORE (PR) [INf MAX SOURCE P-VALUE TREATMENT N MEfAN S D [1 6 HOURS____ A) Placebo 51 0.65 1.180 0 4 Treatment B) MS 60 mg 53 1.13 1.194 0 4 Site 0.385 C) NTX 0.01 mg 51 0.35 0.716 0 3 Treatment by Site 0.236 D) MS 60mg /NTXO.001mg 50 1.18 1.466 0 4 A-B 0.060 E) MS 60mg /NTXO0.0Olmg 51 1.27 1.313 0 4 A-C 0.243 F) MS 60mg /NTXO0.l1mg 48 1.63 1.482 0 4 A-D 0.053 A-F 0.015* A-F <01* B-C 0.002** B-D 0.932 B-F 0.567 B-F 0.122 C-D 0.002** C-F C-F <01* D-E 0.633 D-F 0.151 E-F 0.327 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

NfD: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 35 (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, All Patients PAIN RELIEF SCORE (PR) N MX P-VALUE TREATMENT N MEAN SD [1] 7 HOURS A) Placebo 51 0.59 1.080 0 4 Treatment <.001** B) MS 60 mg 53 1.11 1.204 0 4 Site 0.362 C) NTX 0.01 mg 51 0.37 0.747 0 3 Treatment by Site 0.194 D) MS 60 mg/NTX 0.001 mg 50 1.16 1.448 0 4 A-B 0.035* E) MS 60 mg/NTX 0.01 mg 51 1.35 1.397 0 4 A-C 0.433 F) MS 60 mg/NTX 0.1 mg 48 1.65 1.495 0 4 A-D 0.035* A-E 0.002** A-F B-C 0.004** B-D 0.966 B-E 0.324 B-F 0.095 C-D 0.004** C-E C-F <001*** D-E 0.355 D-F 0.110 E-F 0.483 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 35 (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, All Patients PAIN RELIEF SCORE (PR) MIN MX P-VALUE TREATMENT N MEAN SD [1] 8 HOURS A) Placebo 51 0.61 1.115 0 4 Treatment B) MS 60 mg 53 1.11 1.204 0 4 Site 0.458 C) NTX 0.01 mg 51 0.35 0.716 0 3 Treatment by Site 0.202 D) MS 60 mg/NTX 0.001 mg 50 1.16 1.476 0 4 A-B 0.049* E) MS 60 mg/NTX 0.01 mg 51 1.33 1.409 0 4 A-C 0.317 F) MS 60 mg/NTX 0.1 mg 48 1.63 1.468 0 4 A-D 0.048* A-E 0.004** A-F B-C 0.003** B-D 0.966 B-E 0.360 B-F 0.110 C-D 0.003** C-E C-F D-E 0.392 D-F 0.127 E-F 0.487 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

WO 01/85150 PCT/US01/14644 238 The hourly pain intensity difference (PID) scores are presented in Table 36 and Figure 21. The hourly PID scores for the 0.01 mg NTX alone and placebo treatment groups were generally flat while the hourly PID scores generally improved over time for the active treatment groups (MS alone or in combination with NTX).

The mean scores for the morphine and morphine/naltrexone groups were higher than the mean PID scores for the 0.01 mg NTX alone or placebo group at each assessment time from 1-8 hours. Highest pain relief as measured by mean PID scores was observed for the high-dose (0.1 mg NTX) combination group.

Table 36 Pain Intensity Difference (PID) Scores Intent-To-Treat Population, All Patients Pain Intensity Difference Score (PID) P-Value Min Max Source Treatment N Mean SD [1]

MINUTES

A) Placebo 51 -0.04 0.344 -1 1 Treatment 0.650 B) MS 60mg 53 0.13 0.342 -1 0 Site 0.710 C) NTX 0.01mg 51 -0.06 0.420 -1 1 Treatment by Site 0.676 D) MS 60 mg /NTX 0.001 mg 50 -0.04 0.402 -1 1 A-B N/D E) MS 60 mg /NTX 0.01 mg 51 -0.06 0.544 -1 2 A-C N/D F) MS 60mg/NTX0.1 mg 48 0.02 0.483 -1 2 A-D N/D A-E N/D A-F N/D B-C N/D B-D N/D B-E N/D B-F N/D C-D N/D C-E N/D C-F N/D D-E N/D D-F N/D E-F N/D P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 36 (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, All Patients Pain Intensity Difference Score (PID) Min Max Soce P-Value Min Max Source Treatment N Mean SD [1]

MINUTES

A) Placebo 51 -0.02 0.424 -1 1 Treatment 0.350 B) MS 60 mg 53 -0.08 0.474 -1 1 Site 0.710 C) NTX 0.01mg 51 -0.18 0.590 -1 1 Treatment by Site 0.566 D) MS 60 mg/NTX 0.001 mg 50 -0.10 0.544 -1 1 A-B N/D E) MS 60 mg/NTX 0.01 mg 51 -0.08 0.744 -1 3 A-C N/D F) MS 60 mg/NTX0.1 mg 48 0.06 0.522 -1 2 A-D N/D A-E N/D A-F N/D B-C N/D B-D N/D B-E N/D B-F N/D C-D N/D C-E N/D C-F N/D D-E N/D D-F N/D E-F N/D P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 36 (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, All Patients Pain Intensity Difference Score (PID) Max Soce P-Value I- Min Max Source Treatment N Mean SD [1]

MINUTES

A) Placebo 51 -0.08 0.523 -1 1 Treatment 0.067 B) MS 60 mg 53 0.00 0.650 -1 2 Site 0.632 C) NTX O.Olmg 51 -0.22 0.610 -1 2 Treatment by Site 0.896 D) MS 60 mg /NTX 0.001 mg 50 0.06 0.793 -1 2 A-B N/D E) MS 60 mg NTX 0.01 mg 51 0.22 0.945 -1 3 A-C N/D F) MS 60 mg/NTX 0.1 mg 48 0.17 0.724 -1 3 A-D N/D A-E N/D A-F N/D B-C N/D B-D N/D B-E N/D B-F N/D C-D N/D C-E N/D C-F N/D D-E N/D D-F N/D E-F N/D P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 36 (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, All Patients Pain Intensity Difference Score (PID) Min Max Soce P-Value Treatment N Mean SD [1] 1 HOUR A) Placebo 51 -0.10 0.539 -1 1 Treatment 0.023* B) MS 60 mg 53 0.17 0.727 -1 2 Site 0.560 C) NTX 0.01 mg 51 -0.12 0.739 -1 2 Treatment by Site 0.798 D) MS 60 mg/NTX 0.001 mg 50 0.16 0.866 -1 3 A-B 0.098 E) MS 60 mg /NTX 0.01 mg 51 0.27 0.896 -1 3 A-C 0.842 F) MS 60mg/NTX0.1 mg 48 0.35 0.812 -1 3 A-D 0.159 A-E 0.031* A-F 0.008** B-C 0.065 B-D 0.827 B-E 0.599 B-F 0.296 C-D 0.110 C-E 0.019* C-F 0.004** D-E 0.464 D-F 0.216 E-F 0.598 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 36 (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, All Patients Pain Intensity Difference Score (PID) Ma Sou P-Value Min Max Source Treatment N Mean SD [1]

HOURS

A) Placebo 51 -0.08 0.627 -1 2 Treatment 0.010* B) MS 60 mg 53 0.28 0.744 -1 2 Site 0.497 C) NTX 0.01mg 51 -0.10 0.700 -1 2 Treatment by Site 0.617 D) MS 60 mg/NTX 0.001 mg 50 0.20 0.948 -1 3 A-B 0.038* E) MS 60 mg /NTX 0.01 mg 51 0.35 0.890 -1 3 A-C 0.853 F) MS 60mg/NTX 0.1mg 48 0.42 0.871 -1 3 A-D 0.126 A-E 0.015* A-F 0.008** B-C 0.024* B-D 0.609 B-E 0.707 B-F 0.519 C-D 0.088 C-E 0.009** C-F 0.004** D-E 0.381 D-F 0.258 E-F 0.783 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 36 (Continued) Pain Intensity Difference (IPIiD) Scores Intent-To-Treat Population, All Patients Pain Intensity Difference Score (PID) MmMxSource jP-Value Treatment N Mean SD_ Mi MaxI 2 HOURS A) Placebo 51 -0.12 0.683 -1 2 Treatment B) MS 60 mg 53 0.30 0.868 -1 2 Site 0.290 C) NTX 0.01 mg 51 -0.16 0.674 -1 2 Treatment by Site 0.489 D) MS 60 mg /NTX 0.001 mg 50 0.26 0.965 -1 3 A-B 0.019* B) MS 60mgI/NTXO0.0O1mg 51 0.31 0.883 -1 3 A-C 0.817 F) MS 60 mg INTX 0.1 mg 48 0.58 0.964 -1 3 A-D 0.039* A-B 0.016* A-F <01* B-C 0.010* B-D 0.813 B-B 0.946 B-F 0.170 C-D 0.022* C-B 0.009** C-F <01* D-B 0.763 D-F 0.114 -F 0.194 P-VALULES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

**:P-VALU-E 0.05, 0.01, or 0.001 RESPECTIVELY.

NJD: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 36 (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, All Patients Pain Intensity Difference Score (PID) Max Soce P-Value Min Max Source Treatment N Mean SD [1] 3 HOURS A) Placebo 51 -0.06 0.785 -1 2 Treatment <001** B) MS 60mg 53 0.27 0.858 -1 2 Site 0.168 C) NTX 0.01 mg 51 -0.18 0.684 -1 2 Treatment by Site 0.526 D) MS 60 mg /NTX 0.001 mg 50 0.36 1.064 -1 3 A-B 0.087 E) MS 60 mg /NTX 0.01 mg 51 0.43 0.964 -1 3 A-C 0.504 F) MS 60 mgINTX0.1 mg 48 0.60 1.005 -1 3 A-D 0.029* A-E 0.011* A-F 0.001** B-C 0.017* B-D 0.610 B-E 0.402 B-F 0.119 C-D 0.004** C-E 0.001** C-F D-E 0.751 D-F 0.300 E-F 0.462 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 36 (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, All Patients Pain Intensity Difference Score (PID) Min Max Soce P-Value Min Max Source Treatment N Mean SD [1] 4 HOURS A) Placebo 51 0.02 0.883 -1 2 Treatment 0.001** B) MS 60mg 53 0.36 0.963 -1 3 Site 0.163 C) NTX 0.01 mg 51 -0.18 0.684 -1 2 Treatment by Site 0.414 D) MS 60mg/NTX 0.001mg 50 0.42 1.108 -1 3 A-B 0.103 E) MS 60 mg /NTX 0.01 mg 51 0.43 0.964 -1 3 A-C 0.298 F) MS 60 mg/NTX 0.1 mg 48 0.67 1.136 -1 3 A-D 0.054 A-E 0.051 A-F 0.004** B-C 0.007** B-D 0.743 B-E 0.741 B-F 0.202 C-D 0.003** C-E 0.003** C-F <001*** D-E 0,997 D-F 0.350 E-F 0.343 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 36 (Continued) Pain Intensity Difference (PTD) Scores Intent-To-Treat Population, All Patients Pain Intensit Difference Score (PD) min MaxSuc P-Value Treatment N Mean SD[1

HOURS

A) Placebo 51 0.02 0.883 -1 2 Treatment 0.001** B) MS 60 mg 53 0.32 0.936 -1 2 Site 0.058 C) NTX 0.01 mg 51 -0.16 0.674 -1 2 Treatinent by Site 0.174 D) MS 60mg /NTXO.001mg 50 0.46 1.129 -1 3 A-B 0.141 E) MS 60mgI/NTX0.01 ng 51 0.43 1.005 -1 3 A-C 0.355 F) MS 60mgI/NTX 0.l1mg 48 0.65 1.120 -1 3 A-D 0.029* A-E 0.046* A-F 0.007** B-C 0.017* B-D 0.452 B-E 0.591 B-F 0.209 C-D 0.002** C-E 0.003** C-F <01* D-E 0.826 D-F 0.615 0.467 P-VALUJES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT B3Y SITE INTERACTION AS FACTORS.

P-VA-LUE 0.05, 0.01, or 0.001 RESPECTIVELY.

NfD: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 36 (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, All Patients Pain Intensity Difference Score (PID) Mi Max S P-Value I- Min Max Source Treatment N Mean SD [1] 6 HOURS A) Placebo 51 0.02 0.905 -1 3 Treatment 0.005** B) MS 60mg 53 0.23 0.869 -1 2 Site 0.019* C) NTX 0.01mg 51 -0.16 0.674 -1 2 Treatment by Site 0.191 D) MS 60 mg/NTX 0.001 mg 50 0.38 1.086 -1 3 A-B 0.302 E) MS 60 mg/NTX 0.01 mg 51 0.41 1.062 -1 3 A-C 0.367 F) MS 60 mg/NTX 0.1 mg 48 0.60 1.086 -1 3 A-D 0.077 A-E 0.053 A-F 0.011* B-C 0.053 B-D 0.448 B-E 0.359 B-F 0.124 C-D 0.008** C-E 0.004** C-F D-E 0.883 D-F 0.439 E_-F 0.525 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Table 36 (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, All Patients Pain Intensity Difference Score (PID) Max So P-Value Min Max Source Treatment N Mean SD [1] 7 HOURS A) Placebo 51 0.00 0.872 -1 3 Treatment 0.002*** B) MS 60mg 53 0.21 0.885 -1 2 Site 0.025* C) NTX 0.01mg 51 -0.16 0.674 -1 2 Treatment by Site 0.361 D) MS 60 mg /NTX 0.001 mg 50 0.36 1.064 -1 3 A-B 0.287 E) MS 60mg/NTX 0.01 mg 51 0.45 1.101 -1 3 A-C 0.442 F) MS 60mg/NTX0.1 mg 48 0.65 1.120 -1 3 A-D 0.083 A-E 0.025* A-F 0.004** B-C 0.067 B-D 0.487 B-E 0.230 B-F 0.061 C-D 0.013* C-E 0.002** C-F D-E 0.625 D-F 0.245 E-F 0.490 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/D: NOTE DONE (BECAUSE OVERALL P-VALUE NOT SIGNIFICANT).

Pai Table 36 (Continued) PanIntensity Difference (PID) Scores Intent-To-Treat Population, All Patients Pain Intensity Difference Score (FID) Min Max Source P-Value Treatment N Mean SD [1] 8 HOURS A) Placebo 51 0.00 0.872 -1 3 Treatment 0.002** B) MS 60 mg 53 0.21 0.906 -1 2 Site 0.039* C) NTX 0.01 mg 51 -0.16- 0.674 -1 2 Treatment by Site 0.365 D) MS 60 mgI/NTXO0.001 mg 50 0.36 1.064 -1 3 A-B3 0.304 E) MS 60mg /NTX0.01lmg 51 0.45 1.101 -1 3 A-C 0.420 F) MS 60mg /NTXO0.l1mg 48 0.63 1.084 -1 3 A-D 0.089 A-E 0.027* A-F 0.005** B-C 0.067 B-D 0.486 B-E 0.229 B-F 0.074 C-D 0.013* CGE 0.002** C-F <01* D-E 0.625 D-F .0.282 0.546 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE ANT) ITS CONTRASTS WITH TREATMENT, SITE, ANT) TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

N/D: NOTE DONE (BECAUSE OVERALL P-VALUEB NOT SIGNIFICANT).

WO 01/85150 PCT/US01/14644 251 Tables 37A and 37B present the mean MAXPAR and PEAKPID scores. The mean MAXPAR scores presented in Table 37A varied among treatment groups. The mean MAXPAR score was highest for the 0.1 mg NTX combination treatment group compared to all other groups. The mean scores for the 0.01 mg NTX and 0.001 mg NTX combination treatment groups were comparable to the mean score for the MS alone treatment group, which in turn, was greater than the mean score for the placebo and the 0.01 mg NTX alone treatment groups. The mean PEAKPID scores presented in Table 37B varied among treatment groups, and were greater for the MS alone or NTX combination treatment groups compared to the placebo and the 0.01 mg NTX alone treatment groups. Compared to all other groups, the mean PEAKPID scores were highest for the 0.1 mg NTX combination treatment group.

Table 37A Maximum Pain Relief Scores (MAXPAR) Intent-To-Treat Population, All Patients MAXIMUM PAIN RELIEF SCORE P-VALUE TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE [2] A) Placebo 51 0.86 1.167 0 0.00 4 TREATMENT B) MS 60 mg 53 1.64 1.257 0 1.00 4 SITE 0.663 C) NTX 0.01 mg 51 0.63 0.894 0 0.00 3 TREATMENT BY SITE 0.321 D) MS 60 mg/NTX 0.001 mg 50 1.54 1.460 0 1.00 4 A-B 0.004** E) MS 60 mg/NTX 0.01 mg 51 1.61 1.471 0 2.00 4 A-C 0.337 F) MS 60 mg/NTX 0.1 mg 48 2.06 1.405 0 2.00 4 A-D 0.010* A-E 0.007** A-F B-C B-D 0.789 B-E 0.847 B-F 0.194 C-D C-E C-F D-E 0.938 D-F 0.125 E-F 0.140 PAIN RELIEF (PR) SCORES: 0 =NONE, 1 A LITTLE, 2 SOME, 3 A LOT, 4 COMPLETE.

P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, OR 0.001 RESPECTIVELY.

[1] [2] Table 37B Peak Pain Intensity Differences (PEAKPID) Intent-To-Treat Population, All Patients PEAK PAIN INTENSITY DIFFERENCES (PEAKPID) P-VALUE TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE [1] A) Placebo 51 0.35 0.820 -1 0.00 3 TREATMENT 0.001** B) MS 60 mg 53 0.64 0.901 -1 0.00 3 SITE 0.187 C) NTX 0.01 mg 51 0.16 0.612 -1 0.00 2 TREATMENT BY SITE 0.307 D) MS 60 mg/NTX 0.001 mg 50 0.72 0.927 -1 0.00 3 A-B 0.137 E) MS 60 mg/NTX 0.01 mg 51 0.71 1.064 -1 0.00 3 A-C 0.252 F) MS 60 mg/NTX 0.1 mg 48 0.96 0.988 -1 1.00 3 A-D 0.069 A-E 0.096 A-F 0.004** B-C 0.008** B-D 0.718 B-E 0.850 B-F 0.147 C-D 0.003** C-E 0.005** C-F D-E 0.862 D-F 0.283 E-F 0.209 [1] r- VALU AIFRKUIVI IWU-WAY AINAELY SISP VIKIW N-i INAi I bUP Ii I Wl Ii -I IVMIN 1, AIRII, UDN) TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, OR 0.001 RESPECTIVELY.

WO 01/85150 PCT/US01/14644 254 Table 38 presents the summary and analysis of global evaluations. The NTX alone and placebo treatment groups had the highest number of subjects who had "poor" global evaluation scores. The profiles of the global evaluations scores are based on subjects' evaluations.

Table 38 Global Evaluation of Study Medication Intent-To-Treat Population, All Patients L~ T T r r FAIR GOOD VERY MEAN SOURCE P-VALUE [1]

GOOD

I KbATMENT POOR (0)

FAIR

(1)

GOOD

(2) (3)

EXCELLENT

(4) MEAN SOURCE P-VALUE [1] I t I I I k) Placebo 3) MS 60 mg NTX0.01 mg D) MS 60 mgI/NTX 0.001 mg B) MS 60 mg /NTX 0.01 mg F) MS 60mg /NTX 0.l1mg (78.4%, (48.1%' (9 0. 0%; (55.3%: (42.0%' (35A%, (13.5%; (12.8%: (18.0%; (20.8%] 5 11 (21.2%) 0 5 (10.6%) 4 5 (10.4%) (13.5%) (14.9%) (22.0%) (20.8%) 3. 8%) (10.0%) (12.5%) rreatment o-

N-C

A -D

A-E

B-C

B-D

B-E

B-F

D-E

D-F

B-F

<.00 1 0.001* 0.222 0.006** <.00 1** 0.770 0.287 0.114 <.001*I** 0.195 0.072 0.661 .2 .2 .2 1 1 1 J

I

FROM COCHRAN-MANTEL-HAENZEL TEST FOR RAW MEAN' SCORES DIFFERENCE, ADJUSTING FOR SITE. 4 ~,~**:P-VALLUE 0.05, 0.01, OR 0.001 RESPECTIVELY. 1i WO 01/85150 PCT/US01/14644 256 The majority of adverse events reported were categorized as digestive (nausea or vomiting) or nervous system (dizziness or somnolence) as further shown in Table 39A and 39B. Figure 22 represents a summary of exemplary adverse side effects that may be attenuated according to methods and compositions of the invention.

Table 39A ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe ALL BODY SYSTEMS All EVENTS A) PLACEBO 51 29 Treatment 53 18 19 16 (30.2%) B) MS 60mg 53 46 A-B 175 62 77 36 (20.6%) C) NTX 0.01 mg 51 28 A-D 61 17 27 17 (27.9%) D) MS 60 mg/NTX 0.001 mg 50 46 A-E 141 47 58 36 (25.5%) E) MS 60 mg/NTX 0.01 mg 51 48 A-F 161 53 58 50 (31.1 0 F) MS 60 mg/NTX 0.1 mg 48 44 B-C 143 43 61 39 (27.39 C-D C-E C-F <001*** CARDIAC DISORDERS ALL EVENTS A) PLACEBO 51 1 Treatment 0.785 1 1(100.0%) 0 0 B) MS 60 mg 53 2 2 2(100.0%) 0 0 C) NTX 0.01 mg 51 2 2 1 1 0 D) MS 60 mg/NTX 0.001 mg 50 2 2 1 1 0 E) MS 60 mg/NTX 0.01 mg 51 1 1. 1(100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe BRADYCA.RDIA NOS A) PLACEBO 51 1 Treatment 0.418 1 1 (100.0%) 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 PALPITATIONS A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 1(100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 TACHYCARDIA NOS A) PLACEBO 51 0 Treatment 0.309 0 0 0 0 B) MS 60 mg 53 2 2 2 (100.0%) 0 0 C) NTX 0.01 mg 51 2 2 1 1 0 D) MS 60 mg/NTX 0.001 mg 50 2 2 1 1 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe EAR AND LABYRINTH DISORDERS ALL EVENTS A) PLACEBO 51 3 Treatment 0.305 4 2 2 0 B) MS 60mg 53 1 E-F 0.047* 1 1(100.0%) 0 0 C) NTX 0.01 mg 51 2 2 0 2(100.0%) 0 D) MS 60 mg/NTX 0.001 mg 50 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 51 4 4 0 4(100.0%) 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 EARACHE A) PLACEBO 51 3 Treatment 0.265 4 2 2 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 2 2 0 2 (100.0%) 0 D) MS 60 mg/NTX 0.001 mg 50 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 51 3 3 0 3 (100.0%) 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe HEARING IMPAIRED A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 0 1 (100.0%) 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 HYPERACUSIS A) PLACEBO 51 0 Treatment 0.446 0 0 0 0 B) MS 60 mg 53 1 1 1 (100.0%) 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe EYE DISORDERS ALL EVENTS A) PLACEBO 51 1 Treatment 0.017* 1 0 1 (100.0%) 0 B) MS 60 mg 53 10 A-B 0.005** 10 7 2 1 (10.0%) C) NTX 0.01 mg 51 1 A-D 0.047* 1 0 1(100.0%) 0 D) MS 60 mg/NTX 0.001 mg 50 6 B-C 0.005** 6 5 0 1 (16.7%) E) MS 60 mg/NTX 0.01 mg 51 4 C-D 0.047 4 3 0 1 (25.0%) F) MS 60 mg/NTX 0.1 mg 48 4 4 4(100.0%) 0 0 AMBLYOPIA NOS A) PLACEBO 51 0 Treatment 0.374 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 1 1 1(100.0%) 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe CONJUNCTIVITIS NEC A) PLACEBO 51 0 Treatment 0.068 0 0 0 0 B) MS 60 mg 53 7 A-B 0.007** 7 6 1 0 C) NTX 0.01 mg 51 1 A-D 0.020* 1 0 1(100.0%) 0 D) MS 60 mg/NTX 0.001 mg 50 5 A-E 0.041* 5 5(100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 51 4 B-C 0.031* 4 3 0 1 (25.0%) F) MS 60 mg/NTX 0.1 mg 48 3 3 3 (100.0%) 0 0 PHOTOPHOBIA A) PLACEBO 51 1 Treatment 0.418 1 0 1 (100.0%) 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 RED EYE A) PLACEBO 51 0 Treatment 0.446 0 0 0 0 B) MS 60 mg 53 1 1 0 0 1(100.0%) C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 3 9A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

r21 Body System Adverse Events Total No. of patients No. of Patients w/Event No. of Events Treatment Source P-Value [1] Mild TII?,ED EYES A) PLACEBO B) MS 60 mg C) NTXO0.0O1mg D) MS 60 mgINTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60mgINTXO0.l1mg A) PLACEBO 13) MS 60 mg C) NTX 0.0 1 mng D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60mg/NTX 0. 1mg Treatment 0.404 0 0 Moderate Severe 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 VISION BLURRED Treatment 0.089 0 1 (50.0%) 0 0 0 1 (50.0%) 0 0 0 0 P-VALUES ARE FROM CHISQ TEST ANT) ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND) SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, -0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe GASTROINTESTINAL DISORDERS ALL EVENTS A) PLACEBO 51 12 Treatment 16 4 4 8 (50.0%) B) MS 60mg 53 33 A-B 61 17 23 21 (34.4%) C) NTX0.01 mg 51 13 A-D 19 6 6 7 (36.8%) D) MS 60 mg/NTX 0.001 mg 50 35 A-E 66 14 26 26 (39.4%) E) MS 60 mg/NTX 0.01 mg 51 34 A-F 62 13 18 31 (50.0%) F) MS 60 mg/NTX 0.1 mg 48 33 B-C 63 10 26 27 (42.9' C-D C-E C-F ABDOMINAL PAIN A) PLACEBO 51 1 Treatment 0.439 1 0 0 1 (100.0

NOS

B) MS 60 mg 53 2 2 1 1 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe ABDOMINAL PAIN A) PLACEBO 51 0 Treatment 0.540 0 0 0 0 UPPER B) MS 60 mg 53 1 1 0 0 1 (100.0%) C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 1 1 0 1(100.0%) 0 DYSPEPSIA A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 1 1 1(100.0%) 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 DYSPHAGIA A) PLACEBO 51 1 Treatment 0.208 1 0 0 1(100.0%) B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 2 2 0 1 1 (50.0%) E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe HICCUPS A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 0 1(100.0%) 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 MELAENA A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 1 1 1(100.0%) 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe NAUSEA A) PLACEBO 51 7 Treatment 8 3 2 3 (37.5%) B) MS 60 mg 53 27 A-B 31 12 15 4 (12.9%) C) NTX 0.01 mg 51 9 A-D 10 3 5 2 (20.0%) D) MS 60 mgfNTX 0.001 mg 50 30 A-E 31 9 16 6 (19.4%) E) MS 60 mg/NTX 0.01 mg 51 27 A-F 31 9 12 10 (32.3%) F) MS 60 mg/NTX 0.1 mg 48 26 B-C 28 7 19 2 C-D C-E <001*** C-F ORAL PAIN A) PLACEBO 51 0 Treatment 0.214 0 0 0 0 B) MS 60 mg 53 1 1 0 0 1(100.0%) C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 2 2 0 0 2 (100.0%) E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe SORE THROAT NOS A) PLACEBO 51 2 Treatment 0.217 2 0 2(100.0%) 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 1 1 1(100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 STOMATITIS A) PLACEBO 51 0 Treatment 0.524 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 0 0 1 (100.0%, F) MS 60 mg/NTX 0.1 mg 48 1 1 0 0 1(100.0%) P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe VOMITINGNOS A) PLACEBO 51 4 Treatment 4 1 0 3 (75.0%) B) MS 60mg 53 25 A-B 26 4 7 15 (57.7%) C) NTX 0.01 mg 51 7 A-D 7 1 1 5 (71.4%) D) MS 60 mg/NTX 0.001 mg 50 27 A-E 29 3 9 17 (58.6%) E) MS 60 mg/NTX 0.01 mg 51 25 A-F 29 4 5 20 (69.0%) F) MS 60 mg/NTX 0.1 mg 48 27 B-C 33 3 6 24 (72.7%) C-D C-E <.001** C-F GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS ALL EVENTS A) PLACEBO 51 5 Treatment 0.139 5 2 2 1 (20.0%) B) MS 60mg 53 13 A-B 0.047* 13 5 7 1 C) NTX 0.01 mg 51 4 B-C 0.021* 5 1 2 2 (40.0%) D) MS 60 mg/NTX 0.001 mg 50 7 B-E 0.047* 7 4 3 0 E) MS 60 mg/NTX 0.01 mg 51 5 8 4 2 2 (25.0%) F) MS 60 mg/NTX 0.1 mg 48 6 6 4 2 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe ASTHENIA A) PLACEBO 51 0 Treatment 0.001** 0 0 0 0 B) MS 60mg 53 6 A-B 0.013* 6 3 3 0 C) NTX 0.01 mg 51 0 B-C 0.013* 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 1 B-F 0.016* 1 0 1 (100.0%) 0 E) MS 60 mg/NTX 0.01 mg 51 1 2 1 0 1 (50.0%) F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 FATIGUE A) PLACEBO 51 0 Treatment 0.446 0 0 0 0 B) MS 60 mg 53 1 1 0 1 (100.0%) 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 FEELING ABNORMAL A) PLACEBO 51 0 Treatment 0.446 0 0 0 0 B) MS 60 mg 53 1 1 0 0 1(100.0%) C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe FEELING HOT A) PLACEBO 51 0 Treatment 0.542 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 1 1 0 0 1 (100.0%) D) MS 60 mg/NTX 0.001 mg 50 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 FEELING JITTERY A) PLACEBO 51 0 Treatment 0.548 0 0 0 0 B) MS 60 mg 53 2 2 1 1 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 2 2 1 1 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 1 (100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 48 1 1 0 1(100.0%) 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe PAIN IN FACE A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 0 0 1(100.0%) F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 PAIN NOS A) PLACEBO 51 1 Treatment 0.960 1 0 0 1(100.0, B) MS 60 mg 53 1 1 0 1(100.0%) 0 C) NTX 0.01 mg 51 1 1 0 0 1(100.09 D) MS 60 mg/NTX 0.001 mg 50 1 1 1(100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 1 1 0 1(100.0%) 0 PYREXIA A) PLACEBO 51 2 Treatment 0.975 2 2(100.0%) 0 0 B) MS 60mg 53 2 2 1 1 0 C) NTX 0.01 mg 51 1 1 1(100.0%) 0 0 D) MS 60 mg/NTX 0.001 mg 50 1 1 1(100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 51 2 2 1 1 0 F) MS 60 mg/NTX 0.1 mg 48 2 2 2(100.0%) 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe RIGORS A) PLACEBO 51 2 Treatment 0.623 2 0 2 (100.0%) 0 B) MS 60 mg C) NTX 0.01 mg D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60 mg/NTX 0.1 mg A) PLACEBO B) MS 60 mg C) NTX 0.01 mg D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60 mg/NTX 0.1 mg 0 0 0 0 1(100.0%) 0 1(100.0%) 1(100.0%) 0 0

SHIVERING

Treatment 0.418 0 0 1 (100.0%) 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe WEAKNESS A) PLACEBO 51 0 Treatment 0.211 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 2 2 1 1 0 F) MS 60 mg/NTX 0.1 mg 48 1 1 1(100.0%) 0 0 HEPATO-BILIARY DISORDERS ALL EVENTS A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 0 0 1 (100.0%) F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe CHOLELITHIASIS A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 0 0 1(100.0%) F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 INFECTIONS AND INFESTATIONS ALL EVENTS A) PLACEBO 51 8 Treatment 0.606 10 4 1 5 (50.00/ B) MS60mg 53 6 7 1 3 3 (42.90/ C) NTX0.01mg 51 9 10 1 5 4 (40.00/, D) MS 60 mg/NTX 0.001 mng 50 6 6 0 1 5 (83.3%) E) MS 60 mg/NTX 0.01mg 51 4 5 0 0 5(100.0%) F) MS 60 mg/NTX 0.1 mg 48 4 5 0 2 3 (60.0%) P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe CELLULITIS A) PLACEBO 51 0 Treatment 0.211 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 2 2 0 0 2 (100.0%) D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 1 1 0 0 1(100.0%) DRY SOCKET NOS A) PLACEBO 51 3 Treatment 0.848 3 0 1 2 (66.75 B) MS 60 mg 53 3 3 0 1 2 (66.7° C) NTX 0.01mg 51 4 4 0 3 1 (25.09 D) MS 60 mg/NTX 0.001 mg 50 4 4 0 0 4 (100.09 E) MS 60 mg/NTX 0.01 mg 51 3 3 0 0 3 (100.0%) F) MS 60 mg/NTX 0.1 mg 48 1 2 0 0 2(100.0%) NASOPHARYNGITIS A) PLACEBO 51 0 Treatment 0.446 0 0 0 0.

B) MS 60 mg 53 1 1 0 0 1(100.0%) C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients wlEvent Source Mild Moderate Severe ORAL INFECTION NEC A) PLACEBO 51 0 Treatment 0.542 0 0 0 0 PHAR.YNGITIS NOS TOOTH INIFECTION B) MS 60 mg C) NTX0.01 mg D) MS 60 mgINTX 0.001 mg E) MS 60mg/NTX0.01mg F) MS 60mg/NTXO0. 1mg A) PLACEBO B) MS 60 mg C) NTX0.01lmg D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60 mg/NTX 0. 1 mg A) PLACEBO B) MS 60 mg C) NTX0.01lmg D) MS 60 mgINTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60 mg/NTX 0. 1 mg Treatment 0.546 (50.0%) (33.3%) (25.0%) 0 0 1(100.0%) 0 0 0 2 (66.7%) 2 (50.0%) 0 0 1(100.0%) 0 0 0 0 0 1 (100.0%) 0 0 0 1(100.0%) 0 3 (50.0-1 0 1 (25.0' 1 (100.0-, 1 (100.0%) 0 Treatment 0.3 74 P-VALUES ARE FROM CITISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THlE TOTAL NUM~BER OF EVENTS.

P-VALUE 0.05, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe UPPER RESPIRATORY A) PLACEBO 51 1 Treatment 0.418 1 1 (100.0%) 0 0 TRACT INFECTION B) MS 60 mg 53 0 0 0 0 0 NOS C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 INJURY AND POISONING ALL EVENTS A) PLACEBO 51 1 Treatment 0.418 1 0 1(100.0%) 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe HYPOTHERMIA A) PLACEBO 51 1 Treatment 0.418 1 0 1 (100.0%) 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0

INVESTIGATIONS

ALL EVENTS A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 1(100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events -No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe HAEMATURIA A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 .PRESENT B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 1(100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 MUSCULOSKELETAL, CONNECTIVE TISSUE AND BONE DISORDERS ALL EVENTS A) PLACEBO 51 0 Treatment 0.068 0 0 0 0 B) MS 60 mg 53 3 5 0 4 1 (20.09 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 2 (3.9%0 2 1 1 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe JOINT DISORDER NOS A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 0 1(100.0%) 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 MUSCLE TWITCHING A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 1(100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 MYALGIA A) PLACEBO 51 0 Treatment 0.446 0 0 0 0 B) MS 60 mg 53 1 1 0 1(100.0%) 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe NECK STIFFNESS A) PLACEBO 51 0 Treatment 0.446 0 0 0 0 B) MS 60 mg 53 1 1 0 1(100.0%) 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 SENSATION OF A) PLACEBO 51 0 Treatment 0.089 0 0 0 0 HEAVINESS B) MS 60mg 53 2 3 0 2 1 (33.35 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe NEOPLASMS BENIGN AND MALIGNANT (INCLUDING CYSTS AND POLYPS) ALL EVENTS A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 1 1 0 0 1(100.0%) D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 ADENOMABENIGN A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 NOS B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 1 1 0 0 1 (100.0 0

A

D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe NERVOUS SYSTEM DISORDERS ALL EVENTS A) PLACEBO 51 13 Treatment 13 5 6 2 (15.4%) B) MS 60mg 53 33 A-B 52 12 34 6 (11.5%) C) NTX 0.01 mg 51 14 A-D 15 5 8 2 (13.3%) D) MS 60 mg/NTX 0.001 mg 50 31 A-E 40 16 21 3 E) MS 60 mg/NTX 0.01 mg 51 33 A-F 50 21 23 6 (12.0%) F) MS 60 mg/NTX 0.1 mg 48 30 B-C 45 19 20 6 (13.30 C-D <.001** C-E C-F <001** DIZZINESS (EXC A) PLACEBO 51 2 Treatment 2 0 2(100.0%) 0 VERTIGO) B) MS 60 mg 53 19 A-B 21 4 14 3 (14.3%) C) NTX 0.01 mg 51 2 A-D 2 2(100.0%) 0 0 D) MS 60 mg/NTX 0.001 mg 50 18 A-E 19 7 11 1 E) MS 60 mg/NTX 0.01 mg 51 20 A-F 23 10 12 1 F) MS 60 mg/NTX 0.1 mg 48 16 B-C 19 7 9 3 (15.8%) C-D <001*** C-E C-F P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe HEADACHE NOS A) PLACEBO 51 9 Treatment 0.905 9 4 3 2 (22.2%) B) MS 60mg 53 11 12 3 9 0 C) NTX 0.01 mg 51 8 8 2 4 2 (25.0%) D) MS 60 mg/NTX 0.001 mg 50 8 9 1 6 2 (22.2%) E) MS 60 mg/NTX 0.01mg 51 8 8 2 4 2 (25.0%) F) MS 60 mg/NTX 0.1 mg 48 11 11 5 5 1 HYPERTONIA A) PLACEBO 51 0 Treatment 0.551 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 1 1 0 1(100.0%) 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 1(100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 HYPOAESTHESIA A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS'60mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 1(100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe HYPOTONIA A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS 60mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 0 1(100.0%) 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 MIGRAINE NOS A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 MG 51 1 1 0 0 1(100.0%, F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 MUSCLE SPASTICITY A) PLACEBO 51 0 Treatment 0.446 0 0 0 0 B) MS 60 mg 53 1 1 1(100.0%) 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) *ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe PARAESTHESIA A) PLACEBO 51 0 Treatment 0.404 0 0 0 0 CIRCUMORAL B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 1 1 1(100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 PARAESTHESIA NEC A) PLACEBO 51 2 Treatment 0.993 2 1 1 0 B) MS 60 mg 53 3 5 2 2 1 (20.0'/ C) NTX 0.01 mg 51 3 3 1 2 0 D) MS 60 mg/NTX 0.001 mg 50 3 3 3 (100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 51 3 3 2 1 0 F) MS 60 mg/NTX 0.1 mg 48 2 2 1 1 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe SOMNOLENCE A) PLACEBO 51 0 Treatment 0 0 0 0 B) MS60mg 53 11 A-B 13 2 9 2 (15.4%) C) NTX 0.01 mg 51 0 A-D 0.005** 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 7 A-E 0.003** 8 4 4 0 E) MS 60 mg/NTX 0.01 mg 51 8 A-F 8 4 4 0 F) MS 60 mg/NTX 0.1 mg 48 12 B-C 12 6 5 1 C-D 0.005** C-E 0.003** C-F <001*** SYNCOPE A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 0 0 1(100.0%) F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe TASTE LOSS A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 TENSION HEADACHES TREMOR NEC B) MS 60 mg C) NTX 0.01 mg D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60 mg/NTX 0.1 mg A) PLACEBO B) MS 60 mg C) NTX 0.01 mg D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60 mg/NTX 0.1 mg A) PLACEBO B) MS 60 mg C) NTX 0.01 mg D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60 mg/NTX 0.1 mg 0 0 1 (100.0%) 0 0 0 0 0 0 0 Treatment 0.374 0 1 0 0 0 0 1 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 1 (33.3%) 0 Treatment 0.010* 0 0 0 0 1 (33.3%) 0 0 0 0 0 1 (33.3%) 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe PREGNANCY, PUERPERIUM AND PERINATAL CONDITIONS ALL EVENTS A) PLACEBO 51 0 Treatment 0.446 0 0 0 0 B) MS 60mg 53 1 1 1(100.0%) 0 0 C) NTX 0.01 Olmg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 PREGNANCY NOS A) PLACEBO 51 0 Treatment 0.446 0 0 0 0 B) MS 60mg 53 1 1 1(100.0%) 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe PSYCHIATRIC DISORDERS ALL EVENTS A) PLACEBO 51 1 Treatment 0.179 1 0 1(100.0%) 0 B) MS 60mg 53 6 7 2 2 3 (42.9%) C) NTX 0.01 mg 51 1 1 0 1(100.0%) 0 D) MS 60 mg/NTX 0.001 mg 50 2 2 0 2 (100.0%) 0 E) MS 60 mg/NTX 0.01 mg 51 4 4 4(100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 48 5 7 2 4 1 (14.3 0 9 ANXIETY NEC A) PLACEBO 51 0 Treatment 0.446 0 0 0 0 B) MS 60 mg 53 1 1 0 0 1(100.0/ C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe CONFUSION A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 1(100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 DEPERSONALISATION A) PLACEBO 51 0 Treatment 0.540 0 0 0 0 B) MS 60 mg 53 1 1 0 0 1(100.0/ C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 1 1 1(100.0%) 0 0 DISORIENTATION A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS 60 mg -53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 1(100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe DISSOCIATION A) PLACEBO 51 0 Treatment 0.056 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 2 2 0 1 1 (50.0%) EUPHORIC MOOD A) PLACEBO 51 0 Treatment 0.130 0 0 0 0 B) MS 60mg 53 2 2 1 0 1 (50.0' C) NTXO.01mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 1 1 0 1(100.0%) 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 3 3 1 2 0 NERVOUSNESS A) PLACEBO 51 1 Treatment 0.827 1 0 1(100.0%) 0 B) MS 60 mg 53 3 3 1 2 0 C) NTX 0.01 mg 51 1 1 0 1(100.0%) 0 D) MS 60 mg/NTX 0.001 mg 50 1 1 0 1(100.0%) 0 E) MS 60 mg/NTX 0.01 mg 51 2 2 2(100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 48 1 1 0 1(100.0%) 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe RENAL AND URINARY DISORDERS ALL EVENTS A) PLACEBO 51 0 Treatment 0.226 0 0 0 0 B) MS 60 mg 53 1 1 1(100.0%) 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 2 2 0 2 (100.0%) 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 URINARY RETENTION A) PLACEBO 51 0 Treatment 0.226 0 0 0 0 B) MS 60 mg 53 1 1 1(100.0%) 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 2 2 0 2 (100.0%) 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe REPRODUCTIVE SYSTEM AND BREAST DISORDERS ALL EVENTS A) PLACEBO B) MS 60 mg C) NTX 0.01 mg D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60 mg/NTX 0.1 mg Treatment 0.542 0 0 0 0 1 (50.0%) 0 0 0 0 1 (100.0%) 1 (50.0%) 0 0 0 0 1 (100.0%) 0 DYSMENORRHOEA A) PLACEBO B) MS 60mg C) NTX 0.01 mg D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60 mg/NTX 0.1 mg Treatment 0.404 0 1 0 0 0 0 0 0 0 1 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe PROSTATIC A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 DISORDERNOS B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 0 1(100.0%) 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 TESTICULAR A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 DISORDERNOS B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 0 0 1 (100.0", F) MS 60 mg/NTX O.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS ALL EVENTS A) PLACEBO 51 0 Treatment 0.796 0 0 0 0 B) MS 60 mg 53 2 2 2 (100.0%) 0 0 C) NTX 0.01 mg 51 2 2 1 0 1 (50.0%) D) MS 60 mg/NTX 0.001 mg 50 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 2 0 0 2(100.0%) F) MS 60 mg/NTX 0.1 mg 48 1 1 1 (100.0%) 0 0 COUGH A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 1 1 0 0 1 (100.0° D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe EPISTAXIS A) PLACEBO 51 0 Treatment 0.542 0 0 0 0 NECK TIGHTNESS B) MS 60 mg C) NTX 0.01 mg.

D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60 mg/NTX 0.1 mg A) PLACEBO B) MS 60 mg C) NTX 0.01 mg D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60 mg/NTX 0.1 mg A) PLACEBO B) MS 60 mg C) NTX 0.01 mg D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60 mg/NTX 0.1 mg 48 0 0 0 1 1 (100.0%) 1 1 (100.0%) 0 0 0 0 Treatment 0.374 RHINITIS NOS 0 0 1(100.0%) 0 Treatment 0.243 0 2 (100.0%) 0 0 1(100.0%) 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe SINUS CONGESTION A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 0 0 1 (100.0%) F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 SKIN SUBCUTANEOUS TISSUE DISORDERS ALL EVENTS A) PLACEBO 51 0 Treatment 0.062 0 0 0 0 B) MS 60 mg 53 4 A-B 0.045* 6 5 1 0 C) NTX 0.01 mg 51 1 A-E 0.006** 1 0 1(100.0%) 0 D) MS 60 mg/NTX 0.001 mg 50 3 C-E 0.027* 5 2 3 0 E) MS 60 mg/NTX 0.01 mg 51 7 8 4 3 1 (12.5%) F) MS 60 mg(NTX 0.1 mg 48 3 4 0 2 2 (50.0%) P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe DERMATITIS NOS A) PLACEBO 51 0 Treatment 0.567 0 0 0 0 B) MS 60 mg 53 1 1 1(100.0%) 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 1(100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 ECCHYMOSIS A) PLACEBO 51 0 Treatment 0.404 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 1 1 1(100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 ERYTHEMA NEC A) PLACEBO 51 0 Treatment 0.446 0 0 0 0 B) MS 60 mg 53 1 1 1 (100.0%) 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients wlEvent Source Mild Moderate Severe PHOTOSENSITIVITY A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 REACTIONNOS B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 1(100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 PRURITUS NOS A) PLACEBO 51 0 Treatment 0.056 0 0 0 0 B) MS 60 mg 53 1 A-E 0.021* 1 0 1(100.0%) 0 C) NTX 0.01 mg 51 0 C-E 0.021* 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 3 4 1 3 0 E) MS 60 mg/NTX 0.01 mg 51 5 5 1 3 1 (20.0%) F) MS 60 mg/NTX 0.1 mg 48 2 2 0 0 2 (100.0%) SWEATING A) PLACEBO 51 0 Treatment 0.845 0 0 0 0 INCREASED B) MS 60 mg 53 1 1 1(100.0%) 0 0 C) NTX 0.01 mg 51 1 1 0 1(100.0%) 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 1(100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 48 1 1 0 1(100.0%) 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe URTICARIA NOS A) PLACEBO 51 0 Treatment 0.540 0 0 0 0 B) MS 60 mg 53 1 2 2(100.0%) 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mgINTX 0.1 mg 48 1 1 0 1(100.0%) 0 VASCULAR DISORDERS ALL EVENTS A) PLACEBO 51 1 Treatment 0.153 1 0 1(100.0%) 0 B) MS 60mg 53 7 A-B 0.031* 7 6 1 0 C) NTX0.01 mg 51 2 A-F 0.021* 2 2(100.0%) 0 0 D) MS 60 mg/NTX 0.001 mg 50 4 4 3 1 0 E) MS 60 mg/NTX 0.01 mg 51 5 5 1 4 0 F) MS 60 mg/NTX 0.1 mg 48 7 8 3 5 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe FLUSHING A) PLACEBO 51 0 Treatment 0.418 0 0 0 0 B) MS 60 mg 53 0 0 0 0 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 1(100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 48 0 0 0 0 0 HOT FLUSHES NOS A) PLACEBO 51 0 Treatment 0.540 0 0 0 0 B) MS 60 mg 53 1 1 0 1(100.0%) 0 C) NTX 0.01 mg 51 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 51 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 48 1 1 0 1(100.0%) 0 HYPERTENSION NOS A) PLACEBO 51 0 Treatment 0.500 0 0 0 0 B) MS 60 mg 53 1 1 1(100.0%) 0 0 C) NTX 0.01 mg 51 1 1 1(100.0%) 0 0 D) MS 60 mg/NTX 0.001 mg 50 3 3 2 1 0 E) MS 60 mg/NTX 0.01 mg 51 1 1 0 1(100.0%) 0 F) MS 60 mg/NTX 0.1 mg 48 1 1 1(100.0%) 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39A (Continued) ADVERSE EVENTS BY BODY SYSTEM AND SEVERITY INTENT-TO-TREAT POPULATION, ALL PATIENTS

SEVERITY

Body System Total No. of No. of [2] Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe VASODILATATION A) PLACEBO 51 1 Treatment 0.087 1 0 1(100.0%) 0 B) MS 60mg 53 5 A-F 0.040* 5 5(100.0%) 0 0 C) NTX 0.01 mg 51 1 C-F 0.040* 1 1(100.0%) 0 0 D) MS 60 mg/NTX 0.001 mg 50 1 D-F 0.043* 1 1(100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 51 3 3 0 3(100.0%) 0 F) MS 60 mg/NTX 0.1 mg 48 6 6 2 4 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39B SELECTED ADVERSE EVENTS INTENT-TO-TREAT POPULATION, ALL PATIENTS Body System Total No. of No. of Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe DIZZINESS A) PLACEBO 51 2 Treatment 2 0 2(100.0%) 0 (EXC B) MS 60mg 53 19 A-B 21 4 14 3 (14.3%) VERTIGO) C) NTX 0.01 mg 51 2 A-D 2 2(100.0%) 0 0 D) MS 60 mg/NTX 0.001 mg 50 18 A-E 19 7 11 1 E) MS 60 mg/NTX 0.01 mg 51 20 A-F 23 10 12 1 F) MS 60 mg/NTX 0.1 mg 48 16 B-C 19 7 9 3 (15.8%) C-D C-E C-F NAUSEA A) PLACEBO 51 7 Treatment 8 3 2 3 (37.5%) B) MS 60mg 53 27 A-B 31 12 15 4 (12.9%) C) NTX 0.01mg 51 9 A-D 10 3 5 2 (20.0%) D) MS 60 mg/NTX 0.001 mg 50 30 A-E 31 9 16 6 (19.4%) E) MS 60 mg/NTX 0.01 mg 51 27 A-F 31 9 12 10 (32.3%) F) MS 60 mg/NTX 0.1 mg 48 26 B-C 28 7 19 2 C-D C-E C-F P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 39B (Continued) SELECTED ADVERSE EVENTS INTENT-TO-TREAT POPULATION, ALL PATIENTS Body System Total No. of No. of Adverse Events No. of Patients P-Value Events Treatment Patients w/Event Source Mild Moderate Severe SOMNOLENCE A) PLACEBO 51 0 Treatment 0 0 0 0 B) MS 60mg 53 11 A-B 13 2 9 2 (15.4%) C) NTX 0.01 mg 51 0 A-D 0.005** 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 50 7 A-E 0.003** 8 4 4 0 E) MS 60 mg/NTX 0.01 mg 51 8 A-F 8 4 4 0 F) MS 60 mg/NTX 0.1mg 48 12 B-C 12 6 5 1 C-D 0.005** C-E 0.003** C-F VOMITING NOS A) PLACEBO 51 4 Treatment 4 1 0 3 (75.0%) B) MS 60mg 53 25 A-B 26 4 7 15 (57.7%) C) NTX 0.01 mg 51 7 A-D 7 1 1 5 (71.4%) D) MS 60 mgNTX 0.001mg 50 27 A-E 29 3 9 17 (58.6%) E) MS 60 mg/NTX 0.01 mg 51 25 A-F 29 4 5 20 (69.0%) F) MS 60 mg/NTX 0.1 mg 48 27 B-C 33 3 6 24 (72.7%) C-D C-E C-F <001*** P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

WO 01/85150 PCT/US01/14644 307 EXAMPLE 4 The results from the clinical study using morphine alone and in combination with low doses ofnaltrexone as described in Example 3 were analyzed by gender.

The results for females and males from the Example 3 clinical study are shown in the following Tables and Figures.

A total of 304 subjects were randomized; among them 302 subjects were deemed evaluable. Tables 40A and 40B show the number of female and male subjects separately.

Table Analysis Populations, Female Patients Treatments Placebo MS (60 mg) NTX MS (60 mg) MS (60 mg) MS (60 mg) 0.01 MG NTX NTX NTX Total (0.001 mg) (0.01 mg) (0.1 mg) Patients Enrolled 32 28 30 18 28 26 162 Safety 32 (100.0%) 28 (100.0%) 30 (100.0%) 18 (100.0%) 28 (100.0%) 26 (100.0%) 162 (100.0%) Intent-To-Treat 32 (100.0%) 28 (100.0%) 30 (100.0%) 18 (100.0%) 28 (100.0%) 26 (100.0%) 162 (100.0%) Evaluable 32 (100.0%) 28 (100.0%) 30 (100.0%) 17 94.4%) 28 (100.0%) 26 (100.0%) 161 99.4%) PATIENTS WITH DEMOGRAPHIC INFORMATION.

Table Analysis Populations, Male Patients Treatments Placebo MS (60 mg) NTX MS (60 mg) MS (60 mg) MS (60 mg) 0.01 MG NTX NTX NTX Total (0.001 mg) (0.01 mg) (0.1 mg) Patients Enrolled 19 25 21 32 23 22 142 Safety 19 (100.0%) 25 (100.0%) 21 (100.0%) 32 (100.0%) 23 (100.0%) 22 (100.0%) 142 (100.0%) Intent-To-Treat 19 (100.0%) 25 (100.0%) 21 (100.0%) 32 (100.0%) 23 (100.0%) 22 (100.0%) 142 (100.0%) Evaluable 19 (100.0%) 25 (100.0%) 21 (100.0%) 32 (100.0%) 23 (100.0%) 21 95.5%) 141 99.3%) PATIENTS WITH DEMOGRAPHIC INFORMATION.

WO 01/85150 PCT/US01/14644 310 The demographic and baseline characteristics were summarized by treatment groups as shown in Table 41A for females and Table 41B for males.

The baseline pain intensity scores and visual analog scores are shown in Tables 42A and 42C for females and Tables 42B and 42D for males.

Table 41A Baseline Characteristics Intent-To-Treat Population, Female Patients MS (60 mg) MS (60 mg) MS (60 mg) TOTAL P-Value Placebo MS NTX 0.01 mg withNTX withNTX with NTX [1] mg) (0.001 mg) (0.01 mg) Age (yrs) 0.315 N 32 28 30 18 28 26 162 Mean 23.2 23.8 22.1 21.4 22.2 24.2 22.9 SD 3.82 6.46 3.99 3.26 3.27 6.51 4.80 Median 23.0 23.0 21.0 21.0 22.0 22.0 22.0 Range 16-31 17-49 16-34 16-28 16-28 17-40 16-49 Race/Ethnic 0.518 Origin Caucasian 17 18 20 11 21 19 106 (65.4%) Black 6 4 5 3 3 3 24 (14.8%) Asian 2 1 0 0 0 2 5 Hispanic 7 5 5 4 4 2 27 (16.7%) Total 32 28 30 18 28 26 162 FOR AGE, HEIGHT, WEIGHT, AND TIME BETWEEN END OF SURGERY AND STUDY MEDICATION, P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS; FOR RACE/ETHNIC ORIGIN, AND NUMBER OF THIRD MOLARS EXTRACTED, P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTING FOR SITE.

BLACK, ASIAN, HISPANIC, AND OTHER ARE COMBINED INTO ONE CATEGORY TO DERIVE P-VALUE.

4 OR MORE THIRD MOLARS EXTRACTED AS ONE CATEGORY TO DERIVE P-VALUE.

Table 41A (Continued) Baseline Characteristics Intent-To-Treat Population, Female Patients MS (60 mg) MS (60 mg) MS (60 mg) TOTAL P-Value Placebo MS NTX 0.01 mg withNTX withNTX withNTX [1] mg) (0.001 mg) (0.01 mg) (0.1mg) Height (cm) 0.148 N 32 28 30 18 28 26 162 Mean 164.7 165.7 164.3 161.0 164.7 165.8 164.6 SD 5.81 7.40 5.22 5.44 6.98 6.55 6.36 Median 164.0 165.1 163.5 162.6 165.6 165.1 165.1 Range 152.4-175.3 152.0-190.5 154.9-176.0 149.9-170.2 151.0-177.8 157.5-184.0 149.9-190.5 Weight (kg) 0.115 N 32 28 30 18 28 26 162 Mean 66.7 70.4 72.2 60.3 72.7 70.9 69.4 SD 17.92 15.06 19.47 11.98 13.58 16.16 16.42 Median 61.2 67.3 62.9 58.0 73.4 71.4 65.6 Range 44.5-115.7 45.4-112.7 45.9-115.5 44.9-97.1 52.7-98.4 48.6-117.0 44.5-117.0 FOR AGE, HEIGHT, WEIGHT, AND TIME BETWEEN END OF SURGERY AND STUDY MEDICATION, P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS; FOR RACE/ETHNIC ORIGIN, AND NUMBER OF THIRD MOLARS EXTRACTED, P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTING FOR SITE.

BLACK, ASIAN, HISPANIC, AND OTHER ARE COMBINED INTO ONE CATEGORY TO DERIVE P-VALUE.

4 OR MORE THIRD MOLARS EXTRACTED AS ONE CATEGORY TO DERIVE P-VALUE.

Table 41A (Continued) Baseline Characteristics Intent-To-Treat Population, Female Patients MS (60 mg) MS (60 mg) MS (60 mg) TOTAL P-Value Placebo MS NTX 0.01 mg withNTX with NTX with NTX [1] mg) (0.001 mg) (0.01 mg) (0.1mg) Number of 0.738 Third Molars 3 9 11 6 5 8 8 47 (29.0%) Extracted 4 22 17 23 13 20 17 112 (69.1%) 5 0 0 1 0 0 0 1 6 1 0 0 0 0 0 1 7 0 0 0 0 0 1 1 TOTAL 32 28 30 18 28 26 162 Time 0.680 Between End N 32 28 30 18 28 26 162 of Surgery Mean 154.7 139.5 146.5 143.9 152.7 142.3 147.0 and Study SD 36.57 37.97 35.85 41.45 35.59 52.82 39.87 Medication Median 149.0 136.5 148.0 129.5 146.5 136.0 145.0 (Minutes) Range 92.0-241.0 81.0-221.0 80.0-210.0 89.0-230.0 98.0-244.0 81.0-333.0 80.0-333.0 FOR AGE, HEIGHT, WEIGHT, AND TIME BETWEEN END OF SURGERY AND STUDY MEDICATION, P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS; FOR RACE/ETHNIC ORIGIN, AND NUMBER OF THIRD MOLARS EXTRACTED, P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTING FOR SITE.

BLACK, ASIAN, HISPANIC, AND OTHER ARE COMBINED INTO ONE CATEGORY TO DERIVE P-VALUE.

4 OR MORE THIRD MOLARS EXTRACTED AS ONE CATEGORY TO DERIVE P-VALUE.

Table 41B Baseline Characteristics Intent-To-Treat Population, Male Patients MS (60 mg) MS (60 mg) MS (60 mg) TOTAL P-Value Placebo MS NTX 0.01 mg with NTX withNTX with NTX [1] mg) (0.001 mg) (0.01 mg) (O.lmg) Age (yrs) 0.019* N 19 25 21 32 23 22 142 Mean 21.4 23.1 26.6 23.1 26.5 23.9 24.1 SD 3.72 5.20 6.15 4.82 7.57 5.89 5.85 Median 21.0 22.0 26.0 22.0 23.0 21.5 22.0 Range 16-31 16-36 18-41 16-38 18-41 18-39 16-41 Race/Ethnic 0.961 Origin Caucasian 14 17 14 20 16 16 97 (68.3%) Black 2 4 2 4 5 2 19 (13.4%) Asian 0 1 0 0 0 0 1 Hispanic 2 3 4 7 1 3 20 (14.1%) Other 1 0 1 1 1 1 5 Total 19 25 21 32 23 22 142 FOR AGE, HEIGHT, WEIGHT, AND TIME BETWEEN END OF SURGERY AND STUDY MEDICATION, P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS; FOR RACE/ETHNIC ORIGIN, AND NUMBER OF THIRD MOLARS EXTRACTED, P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTING FOR SITE.

BLACK, ASIAN, HISPANIC, AND OTHER ARE COMBINED INTO ONE CATEGORY TO DERIVE P-VALUE.

4 OR MORE THIRD MOLARS EXTRACTED AS ONE CATEGORY TO DERIVE P-VALUE.

Table 41B (Continued) Baseline Characteristics Intent-To-Treat Population, Male Patients MS (60 mg) with MS (60 mg) MS (60 mg) TOTAL P-Value Placebo MS NTX 0.01 mg NTX (0.001 mg) withNTX with NTX [1] mg) (0.01 mg) (O.lmg) Height 0.486 (cm) N 19 25 21 32 23 22 142 Mean 178.9 178.4 177.2 175.3 176.4 176.8 177.0 SD 5.68 7.88 7.23 7.92 6.74 8.17 7.38 Median 177.8 177.8 177.8 175.2 177.0 176.5 177.0 Range 170.2-190.5 162.6-195.6 160.0-190.5 162.6-198.1 162.6-191.0 160.0-190.5 160.0-198.1 Weight 0.581 (kg) N 19 25 21 32 23 22 142 Mean 84.4 80.8 89.6 80.7 82.8 83.6 83.3 SD 17.84 11.42 15.39 22.42 15.52 22.09 18.05 Median 81.2 -77.6 86.4 77.0 78.2 82.1 78.5 Range 57.1-129.1 61.4-111.8 69.4-120.7 56.7-147.7 61.7-111.6 56.2-157.8 56.2-157.8 !1Jt !Jt ~Jm FORAGE, HEIGHT, WEIGHT, AND TIME BETWEEN END OF SURGERY AND STUDY MEDICATION, P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS; FOR RACE/ETHNIC ORIGIN, AND NUMBER OF THIRD MOLARS EXTRACTED, P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTING FOR SITE.

BLACK, ASIAN, HISPANIC, AND OTHER ARE COMBINED INTO ONE CATEGORY TO DERIVE P-VALUE.

4 OR MORE THIRD MOLARS EXTRACTED AS ONE CATEGORY TO DERIVE P-VALUE.

r .rI Table 41B (Continued) Baseline Characteristics Intent-To-Treat Population, Male Patients MS (60 mg) with MS (60 mg) MS (60 mg) TOTAL P-Value Placebo MS NTX 0.01 mg NTX (0.001 mg) with NTX with NTX [1] mg) (0.01 mg) (0.1mg) Number of 3 4 7 3 5 5 8 32 0.415 Third 4 14 18 16 26 18 14 106(74.6%) Molars 5 1 0 2 1 0 0 4 Extracted TOTAL 19 25 21 32 23 22 142 [31 Time 0.045* Between N 19 25 21 32 23 22 142 End of Mean 149.8 142.9 166.8 171.2 153.1 180.7 161.2 Surgery SD 45.40 39.40 52.50 46.26 31.93 58.88 47.31 and Study Median 152.0 137.0 160.0 169.5 149.0 186.0 155.5 Medicatio Range 58.0-263.0 74.0-277.0 93.0-294.0 92.0-275.0 85.0-218.0 93.0-348.0 58.0-348.0 (Minutes) FOR AGE, HEIGHT, WEIGHT, AND TIME BETWEEN END OF SURGERY AND STUDY MEDICATION, P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS; FOR RACE/ETHNIC ORIGIN, AND NUMBER OF THIRD MOLARS EXTRACTED, P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTING FOR SITE.

[23 BLACK, ASIAN, HISPANIC, AND OTHER ARE COMBINED INTO ONE CATEGORY TO DERIVE P-VALUE.

4 OR MORE THIRD MOLARS EXTRACTED AS ONE CATEGORY TO DERIVE P-VALUE.

Table 42A Baseline Pain Intensity Scores Intent-To-Treat Population, Female Patients PAIN INTENSITY P-VALUE FOR PAIRWISE COMPARISONS P-Value for MS 60 NTX MS 60 mg MS 60 mg MS 60 mg Overall TREATMENT MODERATE SEVERE mg 0.01 mg NTYIX NTX NTX Treatment mg 0.01 mg 0.1 mg Placebo 15 17 0.834 0.311 0.846 0.811 0.816 0.950 MS 60 mg 14 14 0.459 0.697 0.968 0.987 NTX 0.01 MG 18 12 0.304 0.454 0.461 MS 60 mg /NTX 0.001 mg 8 10 0.691 0.706 MS 60 mg /NTX 0.01 mng 14 14 1.000 MS 60 mg /NTX 0. 1 mg 13 13 (50.0%) NOTE: P-VALUES ARE FROM COCI{RAN-MANTEL-HAENZEL TEST ADJUSTING FOR SITE.

Table 42B Baseline Pain Intensity Scores Intent-To-Trea Population, Male Patients PAIN INTENSITY P-VALUE FOR PAIRWISE COMPARISONS P-Value for NTX MS 60 mg MS 60 mg MS 60 mg Overall TREATMENT MODERATE SEVERE MS 60 0.01 mg NTX NTX NTX Treatment mg .0.001 mg 0.01 mg 0.1 mg Placebo 10 9 0.737 0.206 0.871 0.781 0.876 0.891 MS 60 mg 12 13 0.290 0-933 0.953 0.859 NTX 0.01 MG 7 14 0.204 0.3 03 0.257 MS 60 mg /NTX 0.001 mg 16 16 0.888 0.997 MS 60 mng /NTX 0.01 mg 11 12 0.896 MS 60'mg /NTX 0. 1mg 11 11 (50.0%) NOTE: P-VALUES ARE FROM COCHIIAN-MANTEL-HAENZEL TEST ADJUSTING FOR SITE.

Table 42C Baseline Visual Analog Scale (VAS) Scores Intent-To-Treat Population, Female Patients BASELINE VAS SCORE P-VALUE FOR PAIRWISE COMPARISONS

MS

TREATMENT Moderate Severe Total MS 60 NTX 60 mg MS 60 MS 60 P-Value mg 0.01 mg NTX mg mg for 0.001 NTX NTX Overall mg 0.01 mg 0.1 mg Treatment N Mean (SD) N Mean (SD) N Mean (SD) Placebo 15 66.8 (13.33) 17 82.1 (10.40) 32 74.9 (13.99) 0.847 0.744 0.948 0.170 0.332 0.471 MS 60mg 14 73.1 7.03) 14 77.7 (10.26) 28 75.4 8.95) 0.899 0.919 0.131 0.262 NTX 0.01mg 18 70.8 (10.71) 12 83.1 7.46) 30 75.7 (11.21) 0.830 0.097 0.206 MS 60 mg/ 8 67.8 8.65) 10 80.8 7.50) 18 75.0 (10.25) 0.216 0.369 NTX 0.001 mg MS 60 mg/ 14 63.6 8.74) 14 78.1 7.07) 28 70.9 (10.77) 0.715 NTX 0.01 mg 13 63.6 8.48) 13 80.2 9.37) 26 71.9 (12.18) NTX 0.1 mg NOTE: P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS.

BASELINE PAIN INTENSITY ON THE CATEGORICAL SCALE.

Table 42D Baseline Visual Analog Scale (VAS) Scores Intent-To-Treat Population, Male Patients BASELINE VAS SCORE P-VALUE FOR PAIRWISE COMPARISONS

MS

TREATMENT Moderate Severe Total MS 60 NTX 60 mg MS 60 MS 60 P-Value mg 0.01 NTX mg mg for mg 0.001 NTX NTX Overall mg 0.01 mg 0.1 mg Treatment N Mean (SD) N Mean (SD) N Mean (SD) Placebo 10 72.2 (11.64) 9 83.4 6.17) 19 77.5 (10.86) 0.198 0.642 0.192 0.345 0.283 0.765 MS 60 mg 12 66.2 8.28) 13 79.3 6.29) 25 73.0 9.80) 0.407 0.957 0.729 0.847 NTX 0.01 mg 7 67.1 8.38) 14 79.9 7.06) 21 75.6 9.55) 0.410 0.629 0.534 MS 60 mg/ 16 64.0 6.90) 16 82.6 (10.03) 32 73.3 (12.70) 0.754 0.880 NTX 0.001 mg MS 60mg/ 11 62.8 9.14) 12 84.9 9.41) 23 74.3 (14.48) 0.883 NTX 0.01 mg MS 60mg/ 11 66.3 7.16) 11 81.3 5.29) 22 73.8 9.83) NTX 0.1 mg NOTE: P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS.

BASELINE PAIN INTENSITY ON THE CATEGORICAL SCALE.

WO 01/85150 PCT/US01/14644 321 The TOTPAR results (4 hour, 6 hour, 8 hour) are summarized in Tables 43A for females and 43B for males. In females, all of the active treatment groups exhibited mean TOTPAR scores that were higher than the placebo group score, except for the 8 hour TOTPAR for NTX 0.01 mg alone which was comparable to placebo. The morphine alone group had the highest mean TOTPAR scores, followed by the 0.1 mg NTX and the 0.01 mg NTX combination groups. In males, the mean TOTPAR scores for the 0.001 mg NTX, 0.01 mg NTX, and 0.1 mg NTX combination groups were higher than the mean TOTPAR score for MS alone.

Table 43A Total Pain Relief Scores Intent-to-Treat Population, Female Patients TOTAL PAIN RELIEF SCORE P-VALUE TREATMENT N IMEAN SD MIN MEDIAN IMAX I SOURCE [1] TOTAL PAIN RELIEF SCORE (0-4 HOURS) A) Placebo 32 1.10 2.069 0.0 0.00 7.4 TREATMENT <0.001 B) MS 60mg 28 5.40 3.696 0.0 6.38 11.0 SITE 0.061 C) NTX 0.01 mg 30 1.43 2.439 0.0 0.00 10.4 TREATMENT BY SITE 0.390 D) MS 60 mg/NTX 0.001 mg 18 4.07 4.370 0.0 2.88 12.3 A-B <0.001 E) MS 60 mg/NTX 0.01 mg 28 4.28 3.642 0.0 4.06 12.1 A-C 0.581 F) MS 60 mg/NTX 0.1 mg 26 4.12 2.901 0.0 3.38 9.5 A-D <0.001 A-E <0.001 A-F <0.001 B-C <0.001 B-D 0.454 B-E 0.167 B-F 0.120 C-D 0.002 C-E 0.002 C-F 0.005 D-E 0.652 D-F 0.530 E-F 0.830 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY Table 43A (Continued) Total Pain Relief Scores Intent-to-Treat Population, Female Patients TOTAL PAIN RELIEF SCORE P-VALUE TREATMENT N IMEAN SD MIN MEDIAN MAX SOURCE [1] TOTAL PAIN RELIEF SCORE (0-6 HOURS) A) Placebo 32 2.04 4.118 0.0 0.00 13.4 TREATMENT <0.001 B) MS 60 mg 28 8.64 6.015 0.0 10.06 18.4 SITE 0.147 C) NTX 0.01 mg 30 2.17 3.836 0.0 0.00 16.4 TREATMENT BY SITE 0.407 D) MS 60 mg/NTX 0.001 mg 18 6.57 7.369 0.0 3.88 20.3 A-B <0.001 E) MS 60 mg/NTX 0.01 mg 28 6.94 5.805 0.0 6.06 17.1 A-C 0.793 F) MS 60 mg/NTX 0.1 mg 26 6.79 5.144 0.0 5.38 15.9 A-D 0.001 A-E <0.001 A-F 0.001 B-C <0.001 B-D 0.513 B-E 0.247 B-F 0.175 C-D 0.002 D-E 0.727 D-F 0.586 E-F 0.813 [1J f-VALUIE AK J FKUIVI WU-WAY ANALYSIS UP VARIANUCE AND IlS AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY CUNITKASIS Wil- ITH AIIMIIN, SIltE, Table 43A (Continued) Total Pain Relief Scores Intent-to-Treat Population, Female Patients TOTAL PAIN RELIEF SCORE P-VALUE TREATMENT IN MEAN SD MIN MEDIAN MAX SOURCE [1] TOTAL PAIN RELIEF SCORE (0-8 HOURS) A) Placebo 32 2.94 6.136 0.0 0.00 19.4 TREATMENT <0.001 B) MS 60 mg 28 11.46 8.279 0.0 12.56 26.4 SITE 0.215 C) NTX 0.01 mg 30 2.90 5.255 0.0 0.00 22.4 TREATMENT BY SITE 0.427 D) MS 60 mg/NTX 0.001 mg 18 8.93 10.292 0.0 4.88 28.3 A-B <0.001 E) MS 60 mg/NTX 0.01 mg 28 9.57 8.088 0.0 8.06 22.9 A-C 0.873 F) MS 60 mg/NTX 0.1 mg 26 9.41 7.295 0.0 7.38 23.9 A-D 0.002 A-E <0.001 A-F 0.002 B-C <0.001 B-D 0.585 B-E 0.371 B-F 0.257 C-D 0.004 C-E 0.002 C-F 0.006 D-E 0.819 D-F 0.649 E-F 0.788 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY Table 43B Total Pain Relief Scores Intent-to-Treat Population, Male Patients TOTAL PAIN RELIEF SCORE P-VALUE TREATMENT IN I MEAN SD MIN MEDIAN I MAX SOURCE [1] TOTAL PAIN RELIEF SCORE (0-4 HOURS) A) Placebo 19 2.31 2.931 0.0 1.38 11.3 TREATMENT 0.009 B) MS 60 mg 25 2.17 2.505 0.0 0.88 7.5 SITE 0.408 C) NTX 0.01 mg 21 1.36 2.551 0.0 0.00 7.8 TREATMENT BY SITE 0.226 D) MS 60 mg/NTX 0.001 mg 32 3.12 3.658 0.0 2.56 12.5 A-B 0.800 E) MS 60 mg/NTX 0.01 mg 23 4.15 4.528 0.0 3.63 14.5 A-C 0.337 F) MS 60 mg/NTX 0.1 mg 22 5.41 4.727 0.0 5.88 14.5 A-D 0.631 A-E 0.123 A-F 0.021 B-C 0.442 B-D 0.418 B-E 0.055 B-F 0.006 C-D 0.115 C-E 0.010 C-F <0.001 D-E 0.214 D-F 0.035 E-F 0.413 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY CONTRASTS WITH TREATMENT, SITE, Table 43B (Continued) Total Pain Relief Scores Intent-to-Treat Population, Male Patients TOTAL PAIN RELIEF SCORE P-VALUE TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE [1] TOTAL PAIN RELIEF SCORE (0-6 HOURS) A) Placebo 19 4.05 5.205 0.0 1.38 19.3 TREATMENT 0.008 B) MS 60 mg 25 3.73 4.616 0.0 0.88 13.5 SITE 0.319 C) NTX 0.01 mg 21 2.10 4.078 0.0 0.00 11.8 TREATMENT BY SITE 0.223 D) MS 60 mg/NTX 0.001 mg 32 5.46 6.292 0.0 3.81 20.5 A-B 0.786 E) MS 60 mg/NTX 0.01 mg 23 6.89 7.329 0.0 5.88 22.5 A-C 0.261 F) MS 60 mg/NTX 0.1 mg 22 9.26 7.843 0.0 10.69 22.5 A-D 0.601 A-E 0.168 A-F 0.022 B-C 0.354 B-D 0.381 B-E 0.078 B-F 0.006 C-D 0.072 C-E 0.010 C-F <0.001 D-E 0.312 D-F 0.041 E-F 0.328 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY Table 43B (Continued) Total Pain Relief Scores Intent-to-Treat Population, Male Patients TOTAL PAIN RELIEF SCORE P-VALUE TREATMENT IN MEAN ISD IMIN I MEDIAN I MAX ISO-URCE [I] TOTAL PAIN RELIEF SCORE (0-8 HOURS)___ A) Placebo B) MS 60 mg C) NTX 0.01 mg D) MS 60Omg/NTX0.00 1lmg E) MS 60 mglNTX 0.01 mng F) MS 60 mgfNTX 0. 1 mg 5.78 5.31 2.81 7.77 9.59 13.30 7.531 6.793 5.587 9.088 10.287 11.230 1.38 0.88 0.00 4.38 7.88 14.69 26.3 19.5 15.8 28.5 30.5 30.5

TREATMENT

SITE

TREATMENT BY SITE

A-B

A-C

A-D

0.007 0.275 0.229 0.795 0.240 0.607 A-EU.I!yJy A-F 0.020~ B-C 0.319 B-D 0.393 B-E 0.099 B-F 0.005 C-D 0.064 C-E 0.011* C-F <0.001 D-E 0.362 D-F 0.036* _E-F 0.264 CONTRASTS WITH TREATMENT, SITE, P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

WO 01/85150 PCT/US01/14644 328 Tables 44A for females and 44B for males summarize the results of the 4, 6, and 8 hour SPID results and the 4 hour SPID results are shown in Figures 23B for females and 23C for males. In females, the NTX 0.01 mg alone and the placebo groups had the lowest mean SPID scores for 4, 6, and 8 hours. The MS alone and the 0.001 mg NTX combination groups had the highest mean SPID scores.

In males, the MS alone group had the lowest mean SPID scores. All of the combination groups had higher mean SPID scores than the MS alone, placebo, or NTX alone groups, and the 0.1 mg NTX combination group had the highest mean scores.

Table 44A Sum of Pain Intensity Differences Intent-To-Treat Population, Female Patients SUM OF PAIN INTENSITY DIFFERENCES P-VALUE IN -TMEAN I SD I MIN MEDIAN MAX I SOURCE [2] SUM OF PAIN INTENSITY DIFFERENCES (0-4 HOURS) A) Placebo 32 -0.52 2.030 -4 0.00 6 TREATMENT <0.001 B) MS 60mg 28 1.90 2.639 -4 2.19 6 SITE 0.107 C) NTX 0.01 mg 30 -1.02 2.275 -4 0.00 4 TREATMENT BY SITE 0.308 D) MS 60 mg/NTX 0.001 mg 18 1.69 3.354 -3 0.44 10 A-B <0.001 mg/NTX0.01 mg 28 1.17 3.057 -4 0.31 7 A-C 0.532 F) MS 60 mg/NTX 0.1 mg 26 1.16 2.331 -3 0.13 6 A-D <0.001 A-E 0.020 A-F 0.020* B-C <0.001 B-D 0.820 B-E 0.203 B-F 0.238 C-D 0.001 C-E 0.004 C-F 0.004 D-E 0.181 D-F 0.208 0.952 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY Table 44A (Continued) Sum of Pain Intensity Differences Intent-To-Treat Population, Female Patients SUM OF PAIN INTENSITY DIFFERENCES P-VALUE N MEAN SD MIN MEDIAN MAX SOURCE [2] SUM OF PAIN INTENSITY DIFFERENCES (0-6 HOURS) A) Placebo 32 -0.74 3.517 -6 0.00 10 TREATMENT <0.001 B) MS 60 mg 28 3.08 4.471 -6 3.56 11 SITE 0.286 C) NTX 0.01 mg 30 -1.57 3.534 -6 0.00 6 TREATMENT BY SITE 0.355 D) MS 60 mg/NTX 0.001 mg 18 2.85 5.629 -5 0.44 16 A-B <0.001 E) MS 60 mg/NTX 0.01 mg 28 1.95 4.804 -6 0.56 11 A-C 0.520 F) MS 60 mg/NTX 0.1 26 2.02 3.882 -5 0.31 9 A-D 0.001 A-E 0.023 A-F 0.024 B-C <0.001 B-D 0.751 B-E 0.260 B-F 0.290 C-D <0.001 C-E 0.005 C-F 0.005 D-E 0.192 D-F 0.214 E-F 0.968 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY Table 44A (Continued) Sum of Pain Intensity Differences Intent-To-Treat Population, Female Patients

-AU

SUM OF PAIN INTENSITY DIFFERENCES P-VALUE IN I MEAN I SD I MIN I MEDIAN I MAX I SOURCE [2] SUM OF PAIN INTENSITY DIFFERENCES (0-8 HOURS) A) Placebo 32 -1.01 4.916 -8 0.00 12 TREATMENT <0.001 mg 28 3.92 6.218 -8 3.94 15 SITE 0.489 C)NTX 0.01mg 30 -2.10 4.803 -8 0.00 8 TREATMENT BY SITE 0.410 D) MS 60 mg/NTX 0.001 mg 18 3.85 7.787 -7 0.44 22 A-B 0.001** E) MS 60 mg/NTX 0.01 mg 28 2.81 6.743 -8 0.56 15 A-C 0.544 mg/NTX 0.1 mg 26 2.81 5.399 -7 0.38 11 A-D 0.001** A-E 0.020 A-F 0.027 B-C <0.001 B-D 0.689 B-E 0.408 B-F 0.391 C-D <0.001 C-E 0.004 C-F 0.007** D-E 0.260 D-F 0.251 0.957 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS..

P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY Table 44B Sum of Pain Intensity Differences Intent-To-Treat Population, Male Patients SUM OF PAIN INTENSITY DIFFERENCES P-VALUE N MEAN SD MIN MEDIAN MAX SOURCE [2] SUM OF PAIN INTENSITY DIFFERENCES (0-4 HOURS) A) Placebo 19 0.22 2.672 -4 0.00 5 TREATMENT 0.045 B) MS 60 mg 25 -0.37 2.153 -4 0.00 4 SITE 0.020 C) NTX 0.01 mg 21 0.02 2.423 -4 0.00 7 TREATMENT BY SITE 0.378 D) MS 60 mg/NTX 0.001 mg 32 0.46 3.176 -4 0.00 9 A-B 0.443 E) MS 60 mg/NTX 0.01 mg 23 1.20 3.343 -4 0.00 11 A-C 0.781 F) MS 60 mg/NTX 0.1 mg 22 2.51 3.700 -4 2.56 11 A-D 0.986 A-E 0.353 A-F 0.037* B-C 0.619 B-D 0.373 B-E 0.073 B-F 0.002 C-D 0.741 C-E 0.212 C-F 0.015 D-E 0.302 D-F 0.019 E-F 0.220 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY Table 44B (Continued) Sum of Pain Intensity Differences Intent-To-Treat Population, Male Patients SUM OF PAIN INTENSITY DIFFERENCES P-VALUE N MEAN SD MIN MEDIAN MAX SOURCE [2] SUM OF PAIN INTENSITY DIFFERENCES (0-6 HOURS) A) Placebo 19 0.69 4.602 -6 0.00 9 TREATMENT 0.056 B) MS 60 mg 25 -0.39 3.540 -6 0.00 7 SITE 0.018* C) NTX 0.01 mg 21 0.02 3.827 -6 0.00 11 TREATMENT BY SITE 0.329 D) MS 60 mg/NTX 0.001 mg 32 1.15 5.216 -6 0.00 15 A-B N/D E) MS 60 mg/NTX 0.01 mg 23 2.14 5.455 -6 0.00 17 A-C N/D F) MS 60 mg/NTX 0.1 mg 22 4.28 6.198 -6 4.56 17 A-D N/D A-E N/D A-F N/D B-C N/D B-D N/D B-E N/D B-F N/D C-D N/D C-E N/D C-F N/D D-E N/D D-F N/D E-F N/D P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY Table 44B (Continued) Sum of Pain Intensity Differences Intent-To-Treat Population, Male Patients SUM OF PAIN INTENSITY DIFFERENCES P-VALUE IN MEAN SD MIN MEDIAN MAX |SOURCE [2] SUM OF PAIN INTENSITY DIFFERENCES (0-8 HOURS) A) Placebo 19 1.16 6.607 -8 0.00 13 TREATMENT 0.056 B) MS 60 mg 25 -0.43 4.963 -8 0.00 11 SITE 0.016 C) NTX 0.01 mg 21 0.02 5.237 -8 0.00 15 TREATMENT BY SITE 0.341 D) MS 60 mg/NTX 0.001 mg 32 1.73 7.203 -8 0.00 21 A-B N/D E) MS 60 mg/NTX 0.01 mg 23 3.05 7.687 -8 0.00 23 A-C N/D F) MS 60 mg/NTX 0.1 mg 22 6.10 8.757 -8 6.56 23 A-D N/D A-E N/D A-F N/D B-C N/D B-D N/D B-E N/D B-F N/D C-D N/D C-E N/D C-F N/D D-E N/D D-F N/D E-F N/D P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY WO 01/85150 PCT/US01/14644 335 Figures 24A for females and 24B for males are visual presentations of the summary and analysis of time to onset of meaningful pain relief scores presented in Tables 45A for females and 45B for males. In females, the median time to onset of meaningful pain relief was shortest for the MS alone group and comparable for all other groups. In males, the 0.1 mg NTX combination group had the shortest median time to onset of meaningful pain relief while all other groups were comparable.

Table Time To Onset of Meaningful Pain Relief Intent-To-Treat Population, Female Patients OF SURVIVAL CURVES MEDIAN 95% CONFIDENCE TIME INTERVAL TREATMENT N (lih:mm) (bli:mm) SOURCE LOG-RANK WILCOXON A) Placebo 32 8:00 8:00, 8:00) TREATMENT <0.001 <0.001 B) MS 60 mg 28 2.57 1.28, 8:00) A-B <0.001 <0.001 C) NTX 0.01 mg 30 8:00 8:00, 8:00) A-C 0.883 0.901 D) MS 60 mg/NTX 0.001 mg 18 8:00 1:24, 8:00) A-D 0.057 0.031* E) MS 60OmgINTX0.01lmg 28 8:00 1:42, 8:00) A-E 0.009* 0.003* F) MS 60mg/NTX0.1lmg 26 8:00 1:31, 8:00) A-F 0.012* 0.008* B-C <0.001 <0.001 B-D 0.276 0.369 B-E 0.412 0.590 B-F 0.345 0.356 C-D 0.046* 0.027* C-E 0.007 **0.003 C-F 0.009 **0.007 D-E 0.725 0.68 1 D-F 0.800 0.920 E-F 0.909 0.719 0.05, 0.01, or 0.001 RESPECTIVELY.

Table Time To Onset of Meaningful Pain Relief Intent-To-Treat Population, Male Patients TEST OF SURVIVAL CURVES MBDIAN 95% CONI\IDENCE TIMP INTERVAL TREATMENT N (hh:rnm) (hh:mm) SOURCE LOG-RANK WRLCOXON A) Placebo 19 8:00 8:00, 8:00) TREATMENT 0.007 **0.026* B) MS 60 mg 25 8:00 8:00, 8:00) A-B 0.918 0.868 C) NTX 0.01mg 21 8:00 8:00, 8:00) A-C 0.826 0.776 D) MS 60mg/NTX 0.001lmg 32 8:00 8:00, 8:00) A-D 0.469 0.454 B) MS 60mgINTX 0.01mg 23 8:00 3:00, 8:00) A-B 0.343 0.313 F) MS 60 mg/NTX 0.1 mg 22 1:33 0:57, 8:00) A-F 0.001 **0.005 B-C 0.733 0.633 B-D 0.363 0.309 B-E 0.260 0.204 B-F <0.001 0.001** C-D 0.623 0.662 C-B 0.463 0.473 C-F 0.001 **0.012 D-E 0.757 0.724 D-F 0.003 0.018 -F 0.014 *0.064 ***:P-VALUE <Z 0.05, 0.01, or 0.001 RESPECTiVELY.

WO 01/85150 PCT/US01/14644 338 Figures 25A and 26A for females and 25B and 26B for males are visual presentations of the summary and analysis of time to remedication (rescue medication) up to 8 and 24 hours presented in Tables 46A for females and 46B for males. In females, the median time to remedication was longer for the NTX combination groups and the morphine alone group than the placebo and NTX alone groups. This was true at both 8 and 24 hours. In males, the median time to rescue medication was longest in the 0.lmg NTX combination group and was similar for all other groups. This was true at both 8 and 24 hours.

Table 46A Time To Rescue Medication _____Intent-To-Treat Population, Female Patients OF SURVIVAL CURVES MIDJAN TIME CONFIDENCE TREATMENT N (hh:mm) INTERVAL SOURCE LOG-RANK WILCOXON I_ (hh:mm) EFFICACY OBSERVATION PERIOD (0-8 HOURS) A) Placebo 32 1:34 (1:31, 1:48) TREATMENT <0.001** <0J.00J** B) MS 60 mg 28 5:11 (3:01, 7:47) A-B <0.001 <0.001~'" C) NTXO0.1 mg 30 1:33 (1:32, 1:36) A-C 0.071 0.714 D) MS 60 mg/NTX 0.001 mg 18 3:03 (2:03, 5:12) A-fl 0.005 **0.002 E) MS 60 mg INTX 0.01 mg 28 2:03 (1:40, 7:33 A-E 0.002 0.001 F) MS 60 mg /NTX 0. 1 mg 26 2:29 (2:03, 5:04) A-F 0.002 <0.001 B-C <0.001 <0.001 B-D 0.566 0.339 B-E 0.459 0.136 B-F 0.495 0.309 C-fl <0.001 <0.001 C-E <0.001 <0.001 C-F <0.001 <0.001 D-E 0.943 0.728 D-F 0.984 0.938 ****P-VALUE 0.05, 0.01, OR 0.001 RESPECTIVELY -0.5062 Table 46A (Continued) Time To Rescue Medication Intent-To-Treat Population, Female Patients OF SURVIVAL CURVES MEDIAN 95%1 TIME CONFIDENCEI TREATMENT N (hh:mm) INTERVAL SOURCE jLOG-RAN'K WILCOXON ~(hh:mm) _I EFFICACY OBSERVATION PERIOD (0-24HOURS) A) Placebo 32 1:34 (1:31, 1:48) TREATMENT <0.001 <0.001 B) MS 60mg 28 5:11 (3:01, 7:47 A-B <0.001~' <0.001~* C) NTX 0.01 mg 30 1:33 (1:32, 1:36) A-C 0.054 0.705 D) MS 60mg/NTX0.001lmg 18 3:03 (2:03, 5:12) A-D <0.001~' 0.001~" E) MS 60Omg /NTX 0.01 mg 28 2:03 (1:40, 7:33 A-E 0.002 0.001 F) MS 60Omg/INTX0. 1 mg 26 2:29 (2:03, 5:04) A-F 0.002 <0.001** B-C <0.001 <0.001** B-D 0.785 0.502 B-B 0.611 0.163 B-F 0.665 0.348 C-D <0.001 <0.001 C-E <0.001 <0.001 C-F <0.001 <0*.001~ D-E 0.488 0.602 D-F 0.531 0.903 0.944 0.634 *PVALE< 0.05001, OR <=0.001 RESPECTIVELY Table 46B Time To Rescue Medication ____Intent-To-Trea Population, Male Patients OF SURVIVAL CURVES MEDIAN TIME CONFIDENCE TREATMENT N (hh:nnn) INTERVAL SOURCE LOG-RAM( WILCOXON (hh:mm)_ EFFICACY OBSERVATION PERIOD (0-8 HOURS) A) Placebo 19 1:34 (1:32, 2:13) TREATMENT 0.027* 0.029* B) MS 60mg 25 1:53 (1:36, 2:08 A-B 0.552 0.288 C) NTX0.01lmg 21 1:34 (1:32, 1:48) A-C 0.612 0.982 D) MS 60 mgfNTX 0.001 mg 32 1:59 (1:35, 6:06 A-D 0.120 0.074 E) MS 60mg /NTX0.01lmg 23 1:42 (1:31, >8:00) A-E 0.256 0.514 F) MS 60Omg /NTX 0. 1mg 22 >8:00 (1:45, >8:00) A-F 0.012 *0.005 B-C 0.246 0.26 1 B-D 0.288 0.415 B-E 0.528 0.729 B-F 0.032 0.039* C-D 0.03 0 0.05 C-E 0.091 0.500 C-F 0.002 0.003 D-E 0.739 0.285 D-F 0.207 0.156 -F 0.154 0.028 0.05, 0.01, or =0.001 RESPECTIVELY.

Table 461B (Continued) Time To Rescue Medication Population, Male Patients OF SURVIVAL CURVES MEIAN TIME CONFIDENCE TREATMENT N (hh:mm) INTERVAL SOURCE LOG-RANK WIILCOXON (hh:ni EFFICACY OBSERVATION PERIOD (0-24HOURS) A) Placebo '19 1:34 (1:32, 2:13) TREATMENT 0.007 **0.014 B) MS 60mg 25 1:53 (1:36, 2:08 A-B 0.517 0.272 C) NTX 0.01 mg 21 1:34 (1:32, 1:48) A-C 0.298 0.984 D) MS 60 mg/NTX 0.001 mg 32 1:59 (1:35, 6:06) A-D 0.253 0.086 E) MS 60 mg /NTX 0.0 1 mg 23 1:42 (1:31, 9:35 A-E 0.255 0.491 F) MS 60 mg /NTX 0. 1mg 22 8:48 (1:45, >24:00) A-F 0.008 0.002 B-C 0.078 0.223 B-D 0.603 0.502 B-B 0.575 0.727 B-F 0.027 0.02 1 C-D 0.021 0.056 C-B 0.027 0.448 C-F <0.001 <0.001** D-B 0.919 0.338 D-F 0.055 0.067 -F 0.106 0.014* **:P-VALUE 0.05, or 0.001 RESPECTIVELY.

WO 01/85150 PCT/US01/14644 343 Tables 47A for females and 47B for males present the summary and analysis of percent of subjects who took remedication (rescued) up to 8 and 24 hours. In females, the 0.001 mg NTX combination group had the lowest percentage of patients remedicating both at 8 and 24 hours. In males, at 8 hours, all three NTX combination groups had lower percentages of patients remedicating than the MS alone, NTX alone, or placebo groups. The 0.1 mg NTX combination group had the lowest percentage remedicating. At 24 hours, all groups were comparable except the MS and NTX 0.01 mg NTX and 0.1 mg NTX combination groups which had fewer patients remedicating.

Table 47A Percent of Patients Rescued Intent-To-Treat Population, Female Patients

RESCUED

TREATMENT YES INO ISOURCE P-VALUE [I1 EFFICACY OBSERVATION PERIOD (0-8 HOURS) A) Placebo 29 3 TREATMENT 0.0 13* B) MS 60 mg 19 9 A-B 0.029* C) NTX 0.01 mg 29 1 A-C 0.359 D) MS 60 mg /NTX 0.001 mg 12 6 A-D 0.039* E) MIS 60 mg /NTX 0.01 mg 19 9 A-B 0.025* F) MS 60mg /NTX0.1mg 19 7 A-F 0.079 B-C 0.004 B-D 0.924 B-B 0.963 B-F 0.700 C-D 0.005 C-E 0.003 C-F 0.008 D-E 0.975 D-F 0.713 0.565 P-VALUES ARE FROM COCITRAN-MANTEL-HAENZEL TEST ADJUSTING FOR SITE.

Table 47A (Continued) Percent of Patients Rescued Intent-To-Treat Population, Female Patients

RESCUED

TREATMENT IYES INO ISOURCE IP-VALUE [1] EFFICACY OBSERVATION PERIOD (0-24 HOURS) A) Placebo 31 1 TREATMENT 0.015 B) MS 60 mg 26 2 A-B3 0.447 C) NTX 0.01 mg 29 1 A-C 0.940 D) MS 60 mg /NTX 0.001 mg 12 6 A-D 0.004 E) MS 60 mg /NTX 0.01 mg 24 4 A-fl 0.101 F) MS 60mg /NTXO0.l1mg 23 3 A-F 0.218 B-C 0.541 B-D 0.022* B-fl 0.381 B-F 0.587 C-D 0.005 C-fl 0.118 C-F 0.230 D-fl 0.163 D-F 0.090 -F 0.673 P-VALUES ARE FROM COCHkAN-MANTEL-HAENZEL TEST ADJUSTING FOR SITE.

Table 47B Percent of Patients Rescued Intent-To-Treat Population, Male Patients

RESCUED

-TREATMENT IYES INO ISOURCE P-VALUE [1] EFFICACY OBSERVATION PERIOD (0-8 HOURS) A) Placebo 16 3 TREATMENT 0.010* B) MS 60 mg 21 4 A-B 0.997 C) NTX 0.01 mg 19 2 A-C 0.567 D) MS 60Omg /NTX 0.001 mg 22 10 A-D 0.230 E) MS 60 mgI/NTX 0.01 mg 15 8 A-E 0.177 F) MS 60 mg /NTX 0. 1 mg 10 12 A-F 0.008 13-C 0.494 B-D 0.191 B-E 0.141 B-F 0.006 C-D 0.075 C-E 0.057 C-F 0.001 D-E 0.798 D-F 0.076 0.147 P-VALUES ARE FROM COCIIRAN-MANTEL-HAENZEL TEST ADJTUSTING FOR SITE.

Table 47B (Continued) Percent of Patients Rescued Intent-To-Treat Population, Male Patients

RELSCUED

TREATMENT IYES NO ISOURCE P-VALUE [1] EFFICACY OBSERVATION PERIOD (0-24 A) Placebo 18 1 TREATMENT 0.003 B) MS 60 mg 23 2 A-B 0.722 C) NTX 0.01 mg 21(100.0%) 0 A-C 0.317 D) MS 60 mg /NTX 0.001 mg 30 2 A-D 0.890 B) MS 60 mg INTX 0.01 mg 19 4 A-B 0.243 F) MS 60 mg /NTX 0. 1 mg 14 (8 A-F 0.0 14 B-C 0.193 B-D 0.809 B-E 0.345 B-F 0.019* C-D 0.246 C-B 0.055 C-F 0.002* D-E 0.200 D-F 0.004 -F 0.131 P-VALUES ARE FROM COCHRA N-MANTEL-HANEL TEST ADJUSTING FOR SITE.

WO 01/85150 PCT/US01/14644 348 Figures 27A for females and 27B for males are visual presentations of the mean pain relief scores presented in Tables 48A for females and 48B for males. In females, from 45 minutes to 8 hours all three NTX combination groups, as well as the MS alone group, have higher mean pain relief scores than the placebo group. In males, the pain relief score of the MS alone group is not statistically different from the placebo group. All three NTX combination groups have higher mean pain relief scores than the placebo or morphine groups from 15 minutes to 8 hours. The 0.01 mg NTX and the 0.1 mg NTX combination groups have the highest pain relief scores.

Table 48A Pain Relief (PR) Scores Intent-To-Treat Population, Female Patients

P-VALUE

PAIN RELIEF SCORE (PR) P-V TREATMENT N MEAN SD SOURCE

MINUTES

A) Placebo 32 0.09 0.390 Treatment 0.778 B) MS 60 mg 28 0.14 0.448 Site 0.127 C) NTX 0.01 mg 30 0.13 0.434 Treatment by Site 0.275 D) MS 60 mg/NTX 0.001 mg 18 0.28 0.575 A-B N/D E) MS 60 mg /NTX 0.01 mg 28 0.29 0.713 A-C N/D F) MS 60 mg /NTX 0.1 mg 26 0.19 0.567 A-D N/D A-E N/D A-F. N/D B-C N/D B-D N/D B-E N/D B-F N/D C-D N/D C-E N/D C-F N/D D-E N/D D-F N/D E-F N/D P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall P-Value not significant).

Table 48A (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, Female PAWN RELIEF SCORE (PR) [1]LU TREATMENT N MEAN SD SOURCE MvINUJTES A) Placebo 32 0.28 0.581 Treatment 0.883 B) MS 60 mg 28 0.46 0.693 Site 0.205 C) NTX 0.01mig 30 0.33 0.661 Treatment by Site 0.621 D) MS 60mngNTXO.001lmg 18 0.28 0.461 A-B N/D E) MS 60 mg /NTX 0.01 mg 28 0.43 0.879 A-C N/D F) MS 6Omg /NTXO0.l1mg 26 0.46 0.811 A-D N/D A-E NfD A-F NfD B-C N/D B-D N/D B-E N/D B-F N/D C-D N/D C-E N/D C-F N/D D-E N/D D-F NfD -F N[D 1]P-Values are from two-way-analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value =0.05, 0.01, or =0.001 respectively.

NOD: Not done (because overall P-Value not significant).

Table 48A (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, Female Patients

P-VALUE

PAIN RELIEF SCORE (PR) [1P TREATMENT N MEAN SD SOURCE

MINUTES

A) Placebo 32 0.22 0.491 Treatment 0.015 B) MS 60 mg 28 0.86 0.848 Site 0.087 C) NTX 0.01 mg 30 0.37 0.669 Treatment by Site 0.390 D) MS 60 mg INTX 0.001 mg 18 0.78 0.878 A-B 0.004 E) MS 60 mg NTX 0.01 mg 28 0.82 1.020 A-C 0.521 F) MS 60mg/NTX0.1 mg 26 0.58 0.703 A-D 0.011* A-E 0.009 A-F 0.113 B-C 0.029 B-D 0.972 B-E 0.760 B-F 0.220 C-D 0.052 C-E 0.056 C-F 0.353 D-E 0.763 D-F 0.267 E-F 0.345 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall P-Value not significant).

Table 48A (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, Female Patients PAIN RELIEF SCORE (PR) [1]LU TREATMENT N FMEAN SD ISOURCE 1 HOUR A) Placebo 32 0.22 0.608 Treatment <0.001 B) MS 60 mg 28 1.18 1.056 Site 0.019* C) NTX 0.01 mg 30 0.47 0.776 Treatment by Site 0.675 D) MS 60mgNTXO.001mg 18 1.11 1.132 A-B <0.001** E) MS 60 mg /NTX 0.01 mg 28 0.96 0.962 A-C 0.285 F) MS 60mg /NTXO0.l1mg 26 0.81 0.634 A-D <0.001~' A-E 0.002 A-F 0.012* B-C 0.002* B-D 0.935 B-E 0.253 B-F 0.113 C-D 0.006 C-E 0.050 C-F 0.153 D-E 0.280 D-F 0.141 -F 0.630 [11 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall P-Value not significant).

Table 48A (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, Female Patients

P-VALUE

PAIN RELIEF SCORE (PR) [1 TREATMENT N MEAN SD SOURCE

HOURS

A) Placebo 32 0.22 0.491 Treatment <0.001 B) MS 60 mg 28 1.54 1.036 Site 0.134 C) NTX 0.01 mg 30 0.40 0.724 Treatment by Site 0.217 D) MS 60 mg/NTX 0.001 mg 18 1.28 1.274 A-B <0.001 E) MS 60 mg/NTX 0.01 mg 28 1.25 1.041 A-C 0.355 F) MS 60 mg/NTX 0.1 mg 26 1.19 0.801 A-D <0.001 A-E <0.001 A-F <0.001 B-C <0.001 B-D 0.687 B-E 0.173 B-F 0.098 C-D <0.001 C-E 0.001 C-F 0.004 D-E 0.434 D-F 0.290 E-F 0.735 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall P-Value not significant).

Table 48A (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, Female Patients

P-VALUE

PAIN RELIEF SCORE (PR) P-V TREATMENT N MEAN SD SOURCE 2 HOURS A) Placebo 32 0.22 0.491 Treatment <0.001 B) MS 60 mg 28 1.75 1.175 Site 0.042* C) NTX 0.01 mg 30 0.40 0.724 Treatment by Site 0.136 D) MS 60 mg/NTX 0.001 mg 18 1.17 1.425 A-B <0.001 E) MS 60 mg /NTX 0.01 mg 28 1.21 1.067 A-C 0.368 F) MS 60 mg /NTX 0.1 mg 26 1.19 0.981 A-D <0.001 A-E <0.001 A-F <0.001 B-C <0.001*** B-D 0.233 B-E 0.034 B-F 0.026 C-D 0.001 C-E 0.003 C-F 0.007 D-E 0.514 D-F 0.435 E-F 0.870 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall P-Value not significant).

Table 48A (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, Female 'n'D NP-VALUJE PAIN RELIEF SCORE (PR) [1] TREATMENT N IMEAN ISD ISOURCE 3 HOURS A) Placebo 32 0.38 0.833 Treatment <0.001 B) MS 60mg 28 1.66 1.261 Site 0.125 C) NTX 0.01 mg 30 0.37 0.718 Treatment by Site 0.432 D) MS 60mg /NTXO.001mg 18 1.17 1.425 A-B <0.001 E) MS 60mgIJNTX0.01lmg 28 1.32 1.188 A-C 0.866 F) MS 60mgI/NTXO0.l1mg 26 1.31 1.158 A-D 0.003* A-E 0.001 A-F 0.002* B-C <0.001 B-D 0.399 B-B 0.264 B-F 0.217 C-D 0.006* C-B 0.002 C-F 0.005 D-E 0.903 D-F 0.802 0.879 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or =0.001 respectively.

N/D: Not done (because overall P-Value not significant).

Table 48A (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, Female TREATMENT N MEAN SD SOURCE 4 HOURS A) Placebo 32 0.44 0.982 Treatment <0.001 B) MS 60 mg 28 1.71 1.301 Site 0.306 C) NTX 0.01 mng 30 0.37 0.718 Treatment by Site 0.529 D) MS 60mgI/NTXO.00 1mg 18 1.28 1.565 A-B <0.001** E) MS 60 mgIJNTX 0.01 mg 28 1.36 124A-C 0.957 F) MS 60mgLINTXO0. 1mg 26 1.42 1.238 A-D 0.005* A-E 0.003 A-F 0.003 B-C <0.001 B-D 0.497 B-B 0.281 B-F 0.318 C-D 0.005 C-B 0.003 C-F 0.003 D-E 0.798 D-F 0.837 -F 0.959 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, =0.01, or =0.001 respectively.

N/D: Not done (because overall P-Value not significant).

Table 48A (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, Female Patients

P-VALUE

PAIN RELIEF SCORE (PR) P- TREATMENT N MEAN SD SOURCE

HOURS

A) Placebo 32 0.47 1.047 Treatment <0.001 B) MS 60 mg 28 1.64 1.311 Site 0.463 C) NTX 0.01 mg 30 0.37 0.718 Treatment by Site 0.254 D) MS 60 mg/NTX 0.001 mg 18 1.28 1.565 A-B <0.001 E) MS 60mg/NTX 0.01mg 28 1.32 1.188 A-C 0.889 F) MS 60mg/NTX0.1 mg 26 1.31 1.192 A-D 0.006** A-E 0.004 A-F 0.015 B-C <0.001 B-D 0.679 B-E 0.401 B-F 0.246 C-D 0.005 C-E 0.004 C-F 0.013 D-E 0.753 D-F 0.542 E-F 0.727 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall P-Value not significant).

Table 48A (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, Female PAIN RELIIEF SCORE (PR)

P-AU

-TREATMENT N IMEAN ISD ISOURCE_______ 6 HOURS A) Placebo 32 0.50 1.107 Treatment 0.001 B) MS 60 mg 28 1.46 1.232 Site 0.535 C) NTX 0.01 mg 30 0.37 0.718 Treatment by Site 0.456 D) MS 60mg/NTXO.001mg 18 1.17 1.505 A-B 0.002* E) MS 60mg /NTX0.01lmg 28 1.32 1.219 A-C 0.790 F) MS 60mg /NTXO0.l1mg 26 1.31 1.158 A-D 0.028* A-E 0.006* A-F 0.021* B-C 0.001 B-D 0.666 B-E 0.737 B-F 0.502 C-D 0.018* C-E 0.003 C-F 0.013* D-E 0.886 D-F 0.870 0.725 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

NID: Not done (because overall P-Value not significant).

Table 48A (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, Female PAIN RELIEF SCORE (PR) [1]LU -TREATMENT N MEAN ISD ISOURCE 7 HOURS A) Placebo 32 0.44 1.014 Treatment <0.001 B) MS 60 mg 28 1.39 1.227 Site 0.551 C) NTX 0.01 nag 30 0.37 0.7 18 Treatment by Site 0.427 D) MS 60mg/NTXO.001mg 18 1.17 1.505 A-B 0.001* E) MS 60mg /NTX0.01mg 28 1.32 1.219 A-C 0.988 F) MS 60mg /NTXO0.l1mg 26 1.31 1.123 A-D 0.014* A-E 0.002* A-F 0.009 B-C 0.002 11-D 0.775 B-E 0.870 13-F 0.608 C-D 0.016* C-E 0.003 C-F 0.011* D-E 0.883 D-F 0.867 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall P-Value not significant).

Table 48A (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, Female PAIN RELIEF SCORE (PR) I P-VALUE TREATMENT N IMEAN ISD ISOURCE 8 HOURS____ A) Placebo 32 0.44 0.982 Treatment <0.001 B) MS 60 mg 28 1.39 1.227 Site 0.364 C) NTX 0.01 mg 30 0.37 0.718 Treatment by Site 0.353 D) MS 60mgL/NTX 0.001lmg 18 1.22 1.592 A-B 0.002* E) MS 60Omg/JNTX 0.0 1mg 28 1.29 1.243 A-C 0.956 F) MS 60mg /NTX 0.l1mg 26 1.31 1.123 A-D 0.008* A-E 0.004* A-F 0.011 B-C 0.002 B-D 0.957 B-B 0.793 B-F 0.611 C-D 0.009 C-B 0.004 C-F 0.012* D-E 0.861 D-F 0.694 -F 0.797 P-Values are from two-way analysis of variance and its'contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall P-Value not significant).

Table 48B Pain Relief (PR) Scores Intent-To-Treat Population, Male PAIN RELIEF SCORE (PR)

P-VALUE

M[1 TREATMENT N MEN SD M MEDIAN MAX SOURCE MINUTES__ A) Placebo 19 0.16 0.375 Treatment 0.742 B) MS 60mig 25 0.08 0.277 Site 0.144 C) NTX 0.01 mng 21 0.29 0.644 Treatment by Site 0.116 D) MS 60 mng /NTX 0.00 1 mg 32 0.22 0.49 1 A-13 N/D E) MS 60 mng /NTX 0.01 mng 23 0.17 0.491 A-C N/D F) MS 6Omg /NTX0.1lmg 22 0.18 0.501 A-D N/D A-E N/D A-F N/D B-C N/D B-E N/D 13-F N/D C-D N/D C-E NI) C-F NI) D-E NID D-F NI) E-F N/D P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N[D: Not done (because overall P-Value not significant).

Table 48B (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, Male Patients

P-VALUE

PAIN RELIEF SCORE (PR) P- [1] TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE

MINUTES

A) Placebo 19 0.32 0.478 Treatment 0.165 B) MS 60 mg 25 0.16 0.374 Site 0.182 C) NTX 0.01 mg 21 0.24 0.539 Treatment by Site 0.038 D) MS 60 mg /NTX 0.001 mg 32 0.25 0.508 A-B N/D E) MS 60 mg /NTX 0.01 mg 23 0.52 0.846 A-C N/D F) MS 60mg /NTX0.1 mg 22 0.41 0.666 A-D N/D A-E N/D A-F N/D B-C N/D B-D N/D B-E N/D B-F N/D C-D N/D C-E N/D C-F N/D D-E N/D D-F N/D E-F N/D P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall P-Value not significant).

Table 48B (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, Male Patients PAIN RELIEF SCORE (PR)

P-VALUE

TREATMENT N MEAN SD MIN MEDIA MAX SOURCE

MINTUTES

A) Placebo 19 0.42 0.607 Treatment 0.195 B) MS 60 mg 25 0.40 0.577 site 0.857 C) NTX 0.01 mg 21 0.33 0.658 Treatment by Site 0.281 D) MS 60 mg INTX 0.001 mg 32 0.47 0.803 A-B N/D E) MS 60 mg /NTX 0.01 mg 23 0.87 1.140 A-C N/D F) MS 60 mg /NTX 0. 1 mg 22 0.73 1.032 A-D N/D A-E N/D A-F N/D B-C N/D B-D N/D B3-E N/D B-F N/D C-D N/D C-E N/D C-F NID D-E N/D D-F NJD

N/D

P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value <c 0.05, 0.01, or =0.001 respectively.

N/D: Not done (because overall P-Value not significant).

Table 48B (Continued) Pain Relief (PR) Scores Intent-To-TreatPopulation,_Male Patients_________ PAINRELIF

SCREPR)P-VALUE,

PAI R~iF COE [1 -TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE 1 HOUR A) Placebo 19 0.47 0.612 Treatment 0.137 B) MS 60 mg 25 0.52 0.714 Site 0.553 C) NTX 0.01 mg 21 0.48 0.873 Treatment by Site 0.297 D) MS 60 mg /NTX 0.001 mg 32 0.56 0.948 A-B N/D E) MS 60mg/INTX0.01lmg 23 0.96 1.147 A-C N/D F) MS 60mgI/NTXO0.l1rng 22 1.14 1.320 A-D N/D A-E N/D A-F N/D B3-C N/D B-D N/D B-B N/D 13-F N/D C-D N/D C-E N/D C-F N/D D-E N/D ID-F N/D -F N/D P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall P-Value not significant).

Table 481B (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, Male Patients PAIN RELIEF SCORE (PR)

P-VALUE

TREATMENT N MEAN SD MIN MIEDIAN MAX SOURCE

HIOURS

A) Placebo 19 0.58 0.838 Treatment 0.024* B) MS 60 mng 25 0.68 0.852 Site 0.7 19 C) NTX 0.01 mng 21 0-38 0-740 Treatment by Site 0.448 D) MS 6Omg /NTXO0.001lmg 32 0.81 1.091- A-B 0.841 E) MS 60mg /NTXO0.01lmg 23 1.17 1.302 A-C 0.479 F) MS 60ing /NTX0.lm ig 22 1.45 1.371 A-D 0.607 A-E 0.086 A-F 0.026* B-C 0.334 B-D 0.739 13-E 0.102 B-F 0.028 C-D 0.184 C-E 0.012* C-F 0.002* D-E 0.161 D-F 0.047* 0.576 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.00 1 respectively.

NID: Not done (because overall P-Value not significant).

Table 48B (Continued) Pain Relief (IPR) Scores Intent-To-Treat Population, Male Patients PAIN RELIEF SCORE (PR)

P-VA-LUE

TREATMENT N MEANISD IN IMEDIAN[MAX SOURCE 2 HOURS A) Placebo 19 0.58 0.838 Treatment 0.005 B) MS 60 mg 25 0.60 0.764 Site .0.289 C) NTX 0.01 mg 21 0.33 0.658 Treatment by Site 0.160 D) MS 60 mg INTX 0.001 mg 32 0.94 1.134 A-B 0.939 E) MS 60mg INTXO0.01 mg 23 1.09 1.311 A-C 0.401 F) MS 60mg INTX0.1lmg 22 1.64 1.497 A-D 0.418 A-E 0.147 A-F 0.007 1B-C 0.410 13-D 0.333 B-E 0.102 B-F 0.003 C-D 0.075 C-E 0.018* C-F <0.001** D-E 0.430 D-F 0.029* -F 0.191 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall P-Value not significant).

Table 48B (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, Male Patients_________ PAIN RELIEF SCORE TREATMENT N IMEAN ISD IMN MDA MAX SOURCE 3 HOURS A) Placebo 19 0.74 1.046 Treatment 0.006 B) MS 60 mg 25 0.64 0.810 Site 0.283 C) NTX 0.01 mg 21 0.33 0.730 Treatment by Site 0.431 D) MS 60 mg /NTXO.001 mg 32 1.00 1.295 A-B 0.713 E) MS 60 mg/INTX- 0.0 1 mg 23 1.30 1.428 A-C 0.242 F) MS 60mg /NTXO0.l1mg 22 1.73 1.486 A-D 0.606 A-E 0.166 A-F 0.023* B-C 0.380 B-D 0.328 B-E 0.062 B-F 0.005 C-D 0.065 C-E 0.008 C-F <0.001 D-E 0.305 D-F 0.042* F-F 0.340 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, =0.01, or =0.001 respectively.

NID: Not done (because overall P-Value not significant).

Table 48B (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, Male Patients PAN RELIEF SCORE (PR)

P-VALUE

TREATMENT N ME~fAN SID IMIN IMEDIAN MAX SOURCE 4 HOURS A) Placebo 19 0.89 1.197 Treatment 0.007 B) MS 60 mg 25 0.76 1.052 Site -0.235 C) NTX 0.01 mg 21 0.38 1.805 Treatment by Site 0.349 D) MS 60mg /NTXO.001mg 32 1.13 1.338 A-B 0.685 E) MS 60mgI/NTXO0.0O1mg 23 1.39 1.469 A-C 0.184 F) MS 60mgI/NTXO0 1mg 22 1.95 1.647 A-D 0.705 A-E 0.283 A-F 0.026* B-C 0.314 iB-D 0.383 B-E 0.115 B3-F 0.005 C-D 0.060 C-E 0.013* C-F <0.001 D-E 0.415 D-F 0.033* E-F 0.219 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

NID: Not.dorie (because overall P-Value not significant).

Table 48B (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, Male Patients PAIN RELIEF SCORE (PR)

P-VALUEF-

TREATMENT N MEAN SD MIN MEDILAN MAX SOURCE

HOURS

A) Placebo 19 0.84 1.167 Treatment 0.019* B) MS 60Omg 25 0.80 1.118 Site 0.277 C) NTX 0.01 mg 21 0.38 0.805 Treatment by Site 0.200 D) MS 60mg /NTXO.001mg 32 1.19 1.424 A-B 0.864 Ei) MS 60 mg /NTX 0.01 mng 23 1.43 1.532 A-C 0.236 F) MS 60 mgINTXO0.l1mg 22 1.86 1.670 A-D 0.514 A-E 0.199 A-F 0.044* B-C 0.273 B-D 0.366 B-E 0.119 B-F 0.019* C-D 0.045* C-E 0.011* C-F 0.001 D-E 0.442 D-F 0.109 -F 0.434 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall P-Value not significant).

Table 48B (Continued) Pain Relief (PR) Scores Intent-To-Treat Population, Male Patients PAIN RELIEF SCORE (PR) P-VA dJUE TREATMENT N IMEAN ISD IMIN IMEDIAN MAX SOURCE 6HfOURS A) Placebo 19 0.89 1.286 Treatment 0.009 B) MS 60 mg 25 0.76 1.052 Site 0.197 C) NTXO0.01lmg 21 0.33 0.730 Treatment by Site 0.276 D) MS 60mg/NTXO.O001lmg 32 1.19 1.469 A-B 0.713 E) MS 60Omg /NTXO0.01 mng 23 1.22 1.445 A-C 0.162 F) MS 60mg /NTXO0.l1mg 22 2.00 1.746 A-D 0.617 A-E 0.547 A-F 0.025* B-C 0.262 B-D 0.336 B-E 0.303 B-F 0.005 C-D 0.037* C-E 0.038* C-F <0.001 D-E 0.877 D-F 0.044* 0.084 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value =0.05, =0.0 1, or 0.00 1 respectively.

N/D: Not done (because overall P-Value not significant).

Table 48B (Continued) Pain Relief (PR) Scores Tntent-To-Treat Papulation, Male Patients PAIN RELIEF SCORE (PR)

P-VALUE

[1] -TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE 7 HOURS___ A) Placebo 19 0.84 1.167 Treatment 0.008 B) MS 60mg 25 0.80 1.118 Site 0.211 C) NTX0.01lmg 21 0.38 0.805 Treatment by Site 0.270 D) MS 60mgNTX.001lmg 32 1.16 1.439 A-B 0.901 E) MS 60 mgJ/NTX 0.01 mg 23 1.39 1.616 A-C 0.268 F) MS 60Omg /NTX 0. 1mg 22 2.05 1.786 A-D 0.584 A-E 0.230 A-F 0.015* B-C 0.289 B-D 0.461 B-E 0.156 B-F 0.006 C-D 0.070 C-E 0.017* C-F '<0.001 D-E 0.434 D-F 0.030* 0.196 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, =0.01, or 0.001 respectively.

N/Dl: Not done (because overall P-Value not significant).

Table 48B (Continued) Pain Relief CPR) Scores Intent-To-Treat Population, Male Patients PAIN RELIEF SCORE (PR)

P-VALUE

TREATMENT N MEAN SD T M]IN MDA MA SOURCE 8 HOURS A) Placebo 19 0.89 1.286 Treatment 0.009 B) MS 60mg 25 0.80 1.118 Site 0.217 C) NTX 0.01 mg 21 0.33 0.730 Treatment by Site 0.259 D) MS 60mg /NTXO.001mg 32 1.13 1.431 A-B 0.784 E) MS 60mg /NTX0.01lmg 23 1.39 1.616 A-C 0.172 F) MS 60 mg /NTX 0.1 mg 22 2.00 1.746 A-D 0.767 A-E 0.290 A-F 0.028* B-C 0.23 6 B-D 0.526 B-E 0.155 B-F 0.008 C-D 0.065 C-E 0.012* C-F <0.001 D-E 0.376 D-F 0.030* E-F 0.228 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, =0.01, or =0.001 respectively.

N/D: Not done (because overall P-Value not significant).

WO 01/85150 PCT/US01/14644 373 The hourly pain intensity difference (PID) data presented in Table 49A and Figure 28A for females and Table 49B and Figure 28B for males. In females, the mean PID scores for 45 minutes to 8 hours are higher for all three NTX combination groups and the MS group than for the placebo group. In males, all three NTX combination groups have higher mean PID scores than the placebo and MS alone groups for 45 minutes to 8 hours. The 0.1 mg NTX combination group has the highest mean PID scores.

Table 49A Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Female Patients TIME PAIN INTENSITY DIFFERENCE SCORE (PID)

P-VALU-E

TREATMENT N ImEAN FSD IM1N TMEDLAN MAX SOURCE

MINUTES

A) Placebo 32 -0.03 0.309 Treatment 0.444 B) MS60Omg 28 -0.14 0.356 Site 0.158 C) NTX 0.01 mg 30 -0.13 0.434 Treatment By Site 0.088 D) MS 60mg /NTX .001mg 18 0.11 0.323 A-B N/D B) MS 60 mng /NTX 0.0 1 mng 28 -0.07 0.663 A-C N/D F) MS 60 mg /NTX 0. 1 mng 26 -0.04 0.445 A-D N/D A-B N/D A-F N/D B-C N/D B-D N/D B-E N/D B-F N/D C-D N/D C-F N/D C-F N/D D-B N/D D-F N/D B-F N/D [11 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49A (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Female Patients TIME PAIN INTENSITY DIFFERENCE SCORE

P-VALUTE

TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE

MINUTES

A) Placebo 32 -0.03 0.400 Treatment 0.388 B) MS 60 mg 28 0.00 0.544 Site 0.116 C) NTX 0.01 mg 30 -0.23 0.626 Treatment By Site 0.333 D) MS 60Omg /NTXO.00 1 mg 18 0.06 0.236 A-IB N/D E) MS 60 mg INTX 0.01 mg 28 -0.07 0.858 A-C N/D F) MS 60 mg /NTX 0. 1 mg 26 0.08 0.560 A-D N/D A-E N/D A-F N/U B-C N/U B-U N/U B-B N/U B-F NfD C-D N/D C-B N/U C-F N/U U-E N/U U-F N/D E-F N/D P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value =0.05, =0.01, or =0.001 respectively.

N/U: Not done (because overall p-value not significant).

Table 49A (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Female Patients r TIME PAIN INTENSITY DIFFERENCE SCORE (PID) -4VALUE TREATNMNT N MEAN SD MIN MEDIAN MAX I SOURCE MINUTES Tramn0.4* A) Placebo 32 -0.09 0.390Tramn0.4* B) MIS 60 mg 28 0.18 0.670 site 0.061 C) NTX0.01lmg 30 -0.33 0.606 Treatment By Site 0.289 ID) MS 60 mg /NTX 0.001 mg 1 8 0.39 0.778 A-B 0.115 E) MS 60mg /NTX 0.0O1mg 28 0.18 0.945 A-C 0.215 F) MS 60 mg INTX 0. 1 mg 26 0.08 0.628 A-D 0.005** A-E 0.184 A-F 0.278 B-C 0.007** B-D 0.170 B-E 0.789 B-F 0.647 C-E 0.013* C-F 0.027* D-E 0.106 D-F 0.079 E-F 0.841 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, =0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49A (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Female Patients

P-VALUE

TIME PAIN INTENSITY DIFFERENCE SCORE (PID) [1] TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE 1 HOUR A) Placebo 32 -0.13 0.421 Treatment <0.001*** B) MS 60 mg 28 0.46 0.744 Site 0.045* C) NTX 0.01 mg 30 -0.27 0.691 Treatment By Site 0.422 D) MS 60 mg /NTX 0.001 mg 18 0.50 0.786 A-B <0.001*** E) MS 60 mg /NTX 0.01 mg 28 0.25 0.844 A-C 0.508 F) MS 60mg/NTX 0.1 mg 26 0.19 0.634 A-D 0.001** A-E 0.064 A-F 0.070 B-C <0.001*** B-D 0.760 B-E 0.127 B-F 0.141 C-D <0.001*** C-E 0.015* C-F 0.018* D-E 0.101 D-F 0.111 E-F 0.991 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49A (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Female Patients

P-VALUE

TIME PAIN INTENSITY DIFFERENCE SCORE (PID) [1] TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE

HOURS

A) Placebo 32 -0.16 0.574 Treatment <0.001*** B) MS 60 mg 28 0.57 0.690 Site 0.172 C) NTX 0.01 mg 30 -0.23 0.679 Treatment By Site 0.300 D) MS 60 mg /NTX 0.001 mg 18 0.44 0.922 A-B <0.001*** E) MS 60 mg /NTX 0.01 mg 28 0.36 0.870 A-C 0.772 F) MS 60 mg /NTX 0.1 mg 26 0.31 0.736 A-D 0.001** A-E 0.012* A-F 0.031* B-C <0.001** B-D 0.943 B-E 0.205 B-F 0.133 C-D <0.001*** C-E 0.007** C-F 0.018* D-E 0.301 D-F 0.211 E-F 0.783 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49A (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Female Patients

P-VALUE

TIME PAIN INTENSITY DIFFERENCE SCORE (PID) [1] TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE 2 HOURS A) Placebo 32 -0.19 0.644 Treatment <0.001** B) MS 60 mg 28 0.68 0.905 Site 0.121 C) NTX 0.01 mg 30 -0.23 0.679 Treatment By Site 0.232 D) MS 60 mg /NTX 0.001 mg 18 0.44 1.097 A-B <0.001*** E) MS 60 mg /NTX 0.01 mg 28 0.32 0.863 A-C 0.934 F) MS 60 mg /NTX 0.1 mg 26 0.38 0.804 A-D 0.001** A-E 0.022* A-F 0.013* B-C <0.001*** B-D 0.756 B-E 0.080 B-F 0.144 C-D 0.001** C-E 0.022* C-F 0.013* D-E 0.224 D-F 0.329 E-F 0.803 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49A (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Female Patients

P-VALUE

TIME PAIN INTENSITY DIFFERENCE SCORE (PID) [1 TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE 3 HOURS A) Placebo 32 -0.16 0.723 Treatment <0.001*** B) MS 60 mg 28 0.59 0.872 Site 0.165 C) NTX 0.01 mg 30 -0.30 0.651 Treatment By Site 0.321 D) MS 60mg /NTX 0.001mg 18 0.50 1.098 A-B <0.001*** E) MS 60 mg /NTX 0.01 mg 28 0.43 0.920 A-C 0.551 F) MS 60mg/NTX0.1 mg 26 0.38 0.804 A-D 0.001** A-E 0.011* A-F 0.024* B-C <0.001*** B-D 0.838 B-E 0.392 B-F 0.300 C-D <0.001*** C-E 0.002** C-F 0.006** D-E 0.340 D-F 0.266 E-F 0.835 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49A (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Female Patients

P-VALUE

TIME PAIN INTENSITY DIFFERENCE SCORE (PID) I [1] TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE 4 HOURS A) Placebo 32 -0.13 0.751 Treatment <0.001** B) MS 60 mg 28 0.68 1.020 Site 0.458 C) NTX 0.01 mg 30 -0.30 0.651 Treatment By Site 0.517 D) MS 60mg/NTX0.001 mg 18 0.61 1.195 A-B 0.001** E) MS 60 mg /NTX 0.01 mg 28 0.43 0.920 A-C 0.509 F) MS 60 mg /NTX 0.1 mg 26 0.46 0.905 A-D 0.002** A-E 0.025* A-F 0.025* B-C <0.001*** B-D 0.816 B-E 0.282 B-F 0.322 C-D <0.001*** C-E 0.005** C-F 0.005** D-E 0.241 D-F 0.272 E-F 0.953 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49A (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Female Patients

P-VALUE

TIME PAIN INTENSITY DIFFERENCE SCORE (PID) P-V TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE

HOURS

A) Placebo 32 -0.09 0.818 Treatment <0.001*** B) MS 60 mg 28 0.61 0.994 Site 0.789 C) NTX 0.01 mg 30 -0.27 0.640 Treatment By Site 0.311 D) MS 60 mg NTX 0.001 mg 18 0.61 1.195 A-B 0.004** E) MS 60 mg /NTX 0.01 mg 28 0.36 0.911 A-C 0.501 F) MS 60 mg/NTX 0.1 mg 26 0.42 0.857 A-D 0.002** A-E 0.065 A-F 0.061 B-C <0.001*** B-D 0.612 B-E 0.287 B-F 0.335 C-D <0.001*** C-E 0.015" C-F 0.015* D-E 0.150 D-F 0.178 E-F 0.939 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49A (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Female Patients

P-VALUE

TIME PAIN INTENSITY DIFFERENCE SCORE (PID) [1] TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE 6 HOURS A) Placebo 32 -0.13 0.751 Treatment 0.004** B) MS 60 mg 28 0.46 0.962 Site 0.666 C) NTX 0.01 mg 30 -0.27 0.640 Treatment By Site 0.562 D) MS 60 mg/NTX 0.001 mg 18 0.50 1.150 A-B 0.016* E) MS 60 mg /NTX 0.01 mg 28 0.43 1.034 A-C 0.612 F) MS 60 mg /NTX 0.1 mg 26 0.42 0.857 A-D 0.010* A-E 0.024* A-F 0.043* B-C 0.005** B-D 0.641 B-E 0.859 B-F 0.729 C-D 0.003** C-E 0.007** C-F 0.015* D-E 0.530 D-F 0.444 E-F 0.860 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49A (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Female Patients

P-VALUE

TIME PAIN INTENSITY DIFFERENCE SCORE (PID) [1 TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE 7 HOURS A) Placebo 32 -0.13 0.751 Treatment 0.005** B) MS 60 mg 28 0.39 0.956 Site 0.810 C) NTX 0.01 mg 30 -0.27 0.640 Treatment By Site 0.600 D) MS 60 mg/NTX 0.001 mg 18 0.50 1.150 A-B 0.028* E) MS 60 mg/NTX 0.01 mg 28 0.43 1.034 A-C 0.608 F) MS 60 mg/NTX 0.1 mg 26 0.38 0.804 A-D 0.010* A-E 0.022* A-F 0.056 B-C 0.009** B-D 0.505 B-E 0.961 B-F 0.801 C-D 0.003** C-E 0.007** C-F 0.020* D-E 0.527 D-F 0.378 E-F 0.761 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49A (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Female Patients PAIN INTENSITY DIFFERENCE SCORE (PID)

P-VALLTE

TIWvE A 'T"A A~TNTm I XT I mfpAx I v.n Ium Ik~__FMTAN IMAX ISOUJRCE I rlntlk I MrIK4 I 8 HOURS A) Placebo B) MS 60 mg C) NTXO0.01lmg D) MS 60 mg /NTX 0.001 mg E) MS 60mig /NTX 0.01 mg F) MS 60mg /NTX 0.lmig 32 28 30 18 28 26 0.43 -0.27 0.50 0.43 0.38 0.677 0.997 0.640 1.150 1.034 0.804 Treatment Site Treatment By Site

A-B

A-C

A-D

A-E

A-F

B-C

B-D

B-E

B-F

C-D

C-E

C-F

D-E

D-F

0. 002** 0.945 0.5 62 0.012* 0.687 0.007** 0.016* 0.043* 0.005** 0.622 0.875 0.65 0 0.003** 0.007** 0.020* 0.525 0.376 0.760 I _I P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-au =0.05, =0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49B Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Male Patients

P-VALUE

TIME PAIN INTENSITY DIFFERENCE SCORE (PR) [1] TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE

MINUTES

A) Placebo 19 -0.05 0.405 Treatment 0.460 B) MS 60 mg 25 -0.12 0.332 Site 0.314 C) NTX 0.01 mg 21 0.05 0.384 Treatment By Site 0.584 D) MS 60 mg INTX 0.001 mg 32 -0.13 0.421 A-B N/D E) MS 60 mg /NTX 0.01 mg 23 -0.04 0.367 A-C N/D F) MS 60 mg /NTX 0.1 mg 22 0.09 0.526 A-D N/D A-E N/D A-F N/D B-C N/D B-D N/D B-E N/D B-F N/D C-D N/D C-E N/D C-F N/D D-E N/D D-F N/D E-F N/D P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49B (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Male Patients

P-VALUE

TIME PAIN INTENSITY DIFFERENCE SCORE (PR) [1] TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE

MINUTES

A) Placebo 19 0.00 0.471 Treatment 0.564 B) MS 60 mg 25 -0.16 0.374 Site 0.389 C) NTX 0.01 mg 21 -0.10 0.539 Treatment By Site 0.422 D) MS 60 mg/NTX 0.001 mg 32 -0.19 0.644 A-B N/D E) MS 60 mg /NTX 0.01 mg 23 -0.09 0.596 A-C N/D F) MS 60 mg /NTX 0.1 mg 22 0.05 0.486 A-D N/D A-E N/D A-F N/D B-C N/D B-D N/D B-E N/D B-F N/D C-D N/D C-E N/D C-F N/D D-E N/D D-F N/D E-F N/D P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49B (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Male Patients TIME PAIN INTENSITY DIFFERENCE SCORE

TREATMENT

MINUTES

A) Placebo B) MS 60mig C) NTX 0.01mg D) MS 60 mng /NTX 0.001 mg B) MS 60 mng /NTX 0.01 mg F) MS 60mg /NTX0.1 mg -0.05 -0.20 -0.05 -0.13 0.26 0.27 0.705 0.577 0.590 0.751 0.964 0.827 Treatment Site Treatment By Site

A-B

A-C

A-D

A-B

A-F

B-C

B-D

B-E

B-F

C-D

C-E

C-F

D-E

D-F

E-F

I

0.170 0.056 0.622

N/D

N/D

N/D

N/D

N/D

N/D

N/D

N/D

N/D

N/D

N/D

N/D

N/D

N/D

N/D

1] P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

**P.Value =0.05, =0.01, or =0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49B (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Male Patients

P-VALUE

TIME PAIN INTENSITY DIFFERENCE SCORE (PR) 1]P TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE 1 HOUR A) Placebo 19 -0.05 0.705 Treatment 0.068 B) MS 60 mg 25 -0.16 0.554 Site 0.032* C) NTX 0.01 mg 21 0.10 0.768 Treatment By Site 0.660 D) MS 60 mg /NTX 0.001 mg 32 -0.03 0.861 A-B N/D E) MS 60 mg /NTX 0.01 mg 23 0.30 0.974 A-C N/D F) MS 60 mg/NTX 0.1 mg 22 0.55 0.963 A-D N/D A-E N/D A-F N/D B-C N/D B-D N/D B-E N/D B-F N/D C-D N/D C-E N/D C-F N/D D-E N/D- D-F N/D E-F N/D P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49B (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Male Patients TIME PAIN INTENSITY DIFFERENCE SCORE (PR) [1 TREATMENT N MEAN SD MW MEDIA A X SORE__

HOURS

A) Placebo B) MS 60 mg C) NTXO0.01lmg D) MS 60 mg /NTX 0.00 1 mg E) MS 60 mng /NTX 0.01 mg F) MS 60mgI/NTX0.1mg 0.05 -0.04 0.10 0.06 0.35 0.55 0.705 0.676 0.700 0.948 0.935 1.011 Treatment Site Treatment By Site

A-B

A-C

A-D

A-E

A-F

B-C

B-D

B-E

B-F

C-D

C-E

C-F

D-E

D-F

B-F

0.234 0.128 0.611

N/D

N/D

N/D

N/D

N/D

N/D

N/D

N/D

N/D

N/D

N/D

N/D

N/D

N/D

N/D

I I I I I I P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49B (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Male Patients

P-VALUE

TIME PAIN INTENSITY DIFFERENCE SCORE (PR) P-VAUE TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE 2 HOURS _T4 A) Placebo 19 0.00 0.745 Treatment 0.008** B) MS 60 mg 25 -0.12 0.600 Site 0.022* C) NTX 0.01 mg 21 -0.05 0.669 Treatment By Site 0.182 D) MS 60 mg/NTX 0.001 mg 32 0.16 0.884 A-B 0.541 E) MS 60 mg /NTX 0.01 mg 23 0.30 0.926 A-C 0.796 F) MS 60 mg/NTX0.1 mg 22 0.82 1.097 A-D 0.745 A-E 0.291 A-F 0.007** B-C 0.722 B-D 0.295 B-E 0.077 B-F <0.001"** C-D 0.530 C-E 0.175 C-F 0.002** D-E 0.394 D-F 0.006** E-F 0.080 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49B (Continued) Pain Intensity Difference (PID) Scores itent-To-Treat Population, Male Patients TIME PAIN IN.TENSITY DIFFERENCE SCORE (PR)TP-A

E

TREATMENT N MEAN SD 7MN MEDIA A SOURCEI___ 3 HOURS A) Placebo 19 o.ii 0.875 Treatment 0.032* B) MS 60 mng 25 -0.08 0.702 site O.009** C) NTXO0.01lmg 21 0.00 0.707 Treatment By Site 0.479 D) MS 60 mg/NTXO0.00 1mig 32 0.28 1.054 A-B 0.465 E) MS 60 mg /NTX 0.01 mg 23 0.43 1.037 A-C 0.704 F) MS 60mg /NTX0.lnmg 22 0.86 1.167 A-D 0.668 A-E 0.325 A-F 0.027* B-C 0.727 B-D 0.196 B-E 0.069 B-F 0.001** C-D 0.383 C-E 0.158 C-F 0.007** D-E 0.507 D-F 0.040* E-F 0.194 P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or =0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49B (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Male Patients

P-VALUE

TIME PAIN INTENSITY DIFFERENCE SCORE (PR) [1] TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE 4 HOURS A) Placebo 19 0.26 1.046 Treatment 0.084 B) MS 60 mg 25 0.00 0.764 Site 0.035* C) NTX 0.01 mg 21 0.00 0.707 Treatment By Site 0.369 D) MS 60 mg/NTX 0.001 mg 32 0.31 1.061 A-B N/D E) MS 60 mg/NTX 0.01 mg 23 0.43 1.037 A-C N/D F) MS 60 mg/NTX 0.1 mg 22 0.91 1.342 A-D N/D A-E N/D A-F N/D B-C N/D B-D N/D B-E N/D B-F N/D C-D N/D C-E N/D C-F N/D D-E N/D D-F N/D E-F N/D P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49B (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Male Patients

SP-VALUE

TIME PAIN INTENSITY DIFFERENCE SCORE (PR) [1] TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE

HOURS

A) Placebo 19 0.21 0.976 Treatment 0.078 B) MS 60 mg 25 0.00 0.764 Site 0.020* C) NTX 0.01 mg 21 0.00 0.707 Treatment By Site 0.274 D) MS 60 mg/NTX 0.001 mg 32 0.38 1.100 A-B N/D E) MS 60 mg /NTX 0.01 mg 23 0.52 1.123 A-C N/D F) MS 60 mg/NTX 0.1 mg 22 0.91 1.342 A-D N/D A-E N/D A-F N/D B-C N/D B-D N/D B-E N/D B-F N/D C-D N/D C-E N/D C-F N/D D-E N/D D-F N/D E-F N/D P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49B (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Male Patients

P-VALUE

TIME PAIN INTENSITY DIFFERENCE SCORE (PR) [1] TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE 6 HOURS A) Placebo 19 0.26 1.098 Treatment 0.158 B) MS 60 mg 25 -0.04 0.676 Site 0.016* C) NTX 0.01 mg 21 0.00 0.707 Treatment By Site 0.231 D) MS 60 mg/NTX 0.001 mg 32 0.31 1.061 A-B N/D E) MS 60mg/NTX0.01 mg 23 0.39 1.118 A-C N/D F) MS 60 mg /NTX 0.1 mg 22 0.82 1.296 A-D N/D A-E N/D A-F N/D B-C N/D B-D N/D B-E N/D B-F N/D C-D N/D C-E N/D C-F N/D D-E N/D D-F N/D E-F N/D P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49B (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Male Patients

P-VALUE

TIME PAIN INTENSITY DIFFERENCE SCORE (PR) [1] TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE 7 HOURS A) Placebo 19 0.21 1.032 Treatment 0.058 B) MS 60 mg 25 0.00 0.764 Site 0.015* C) NTX 0.01 mg 21 0.00 0.707 Treatment By Site 0.438 D) MS 60 mg/NTX 0.001 mg 32 0.28 1.023 A-B

N/D

E) MS 60 mg /NTX 0.01 mg 23 0.48 1.201 A-C N/D F) MS 60 mg/NTX 0.1 mg 22 0.95 1.362 A-D N/D A-E N/D A-F N/D B-C N/D B-D N/D B-E N/D B-F N/D C-D N/D C-E N/D C-F N/D D-E N/D D-F N/D E-F N/D P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

Table 49B (Continued) Pain Intensity Difference (PID) Scores Intent-To-Treat Population, Male Patients

P-VALUE

TIME PAIN INTENSITY DIFFERENCE SCORE (PR) [1] TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE 8 HOURS A) Placebo 19 0.26 1.098 Treatment 0.064 B) MS 60 mg 25 -0.04 0.735 Site 0.020* C) NTX 0.01 mg 21 0.00 0.707 Treatment By Site 0.494 D) MS 60 mg/NTX 0.001 mg 32 0.28 1.023 A-B N/D E) MS 60 mg/NTX 0.01 mg 23 0.48 1.201 A-C N/D F) MS 60 mg /NTX 0.1 mg 22 0.91 1.306 A-D N/D A-E N/D A-F N/D B-C N/D B-D N/D B-E N/D B-F N/D C-D N/D C-E N/D C-F N/D D-E N/D D-F N/D E-F N/D P-Values are from two-way analysis of variance and its contrasts with treatment, site, and treatment by site interaction as factors.

P-Value 0.05, 0.01, or 0.001 respectively.

N/D: Not done (because overall p-value not significant).

WO 01/85150 PCT/US01/14644 398 Tables 50A and 50B for females and Tables 50C and 50D for males present the mean MAXPAR and PEAKPID scores. In females, the mean MAXPAR and PEAKPID scores were higher for the MS alone and the NTX combination groups than for the placebo group. In males, the three NTX combination groups had higher mean MAXPAR and PEAKPID scores than the placebo or MS alone groups. The 0.1 mg NTX combination group had the highest mean score for MAXPAR and

PEAKPID.

Tables 51A for females and 51B for males present the summary and analysis of global evaluations. For both females and males, the placebo treatment had the highest number of subjects who had poor global evaluation scores based on subject evaluation. For females, the morphine and high-dose (0.1 mg NTX) combination groups were most often rated as "excellent." For males, the mid-dose (0.01 mg NTX) and high-dose (0.1 mg NTX) combination groups were most often rated as "excellent." Table Maximum Pain Relief Scores (MAXPAR) Intent-To-Treat Population, Female Patients MAXIMUM PAIN RELIEF SCORE

P-VALUE

TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE [2] A) Placebo 32 0.75 1.107 0 0.00 3 TREATMENT <0.001 B) MS 60 mg 28 2.14 1.177 0 2.50 4 SITE 0.484 C) NTX 0.01 mg 30 0.63 0.850 0 0.00 3 TREATMENT BY SITE 0.271 D) MS 60 mg/NTX 0.001 mg 18 1.67 1.572 0 2.00 4 A-B <0.001 E) MS 60 mg/NTX 0.01 mg 28 1.61 1.370 0 1.50 4 A-C 0.684 F) MS 60 mg/NTX 0.1 mg 26 1.85 1.084 0 2.00 4 A-D 0.003 A-E 0.009** A-F 0.001 B-C <0.001 B-D 0.493 B-E 0.098 B-F 0.292 C-D 0.001 C-E 0.003 C-F <0.001 D-E 0.450 D-F 0.805 E-F 0.568 Pain Relief (PR) Scores: 0 None, 1 A Little, 2 Some, 3 A Lot, 4 .ompiete.

P-Values are from Two-Way Analysis of Variance and its Contrasts with Treatment, Site, and Treatment by Site Interaction as Factors.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table Peak Pain Intensity Differences (PEAKPID) Intent-To-Treat Population, Female Patients PEAK PAIN INTENSITY DIFFERENCES (PEAKPID)

P-VALUE

TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE [1] A) Placebo 32 0.25 0.672 -1 0.00 2 TREATMENT <0.001 B) MS 60 ing 28 1.04 0.881 -1 1.00 3 SITE 0.707 C) NTX 0.01 mg 30 0.10 0.548 -1 0.00 1 TREATMENT BY SITE 0.384 D) MS 60 mg/NTX 0.001 mg 18 0.89 0.963 0 1.00 3 A-B <0.001 E) MS 60 mg/NTX 0.01 mg 28 0.68 1.090 -1 0.50 3 A-C 0.579 F) MS 60 mg/NTX 0.1 mg 26 0.77 0.765 0 1.00 2 A-D 0.007 A-E 0.086 A-F 0.038 B-C <0.001 B-D 0.728 B-E 0.076 B-F 0.182 C-D 0.002 C-E 0.028 C-F 0.012 D-E 0.231 D-F 0.406 S L E-F 0.690 P-Values are from Two-Way Analysis of Variance and its Contrasts with Treatment, Site, and Treatment by te Intmerac on as r suur.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table Maximum Pain Relief Scores (MAXPAR) Intent-To-Treat Population, Male Patients MAXIMUM PAIN RELIEF SCORE [11 P-VALUE TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE [2] A) Placebo 19 1.05 1.268 0 1.00 4 TREATMENT 0.007** mg 25 1.08 1.115 0 1.00 3 SITE 0.501 C) NTX 0.01 mg 21 0.62 0.973 0 0.00 3 TREATMENT BY SITE 0.581 D) MS 60 mg/NTX 0.001 mg 32 1.47 1.414 0 1.00 4 A-B 0.978 E) MS 60 mg/NTX 0.01 mg 23 1.61 1.616 0 2.00 4 A-C 0.303 F) MS 60 mg/NTX 0.1 mg 22 2.32 1.701 0 3.00 4 A-D 0.373 A-E 0.255 A-F 0.010 B-C 0.257 B-D 0.348 B-E 0.232 B-F 0.006 C-D 0.038 C-E 0.025* C-F <0.001 D-E 0.725 D-F 0.049 0.132 [1J [2] Pain Relief (PR) Scores: 0 None, 1 A Little, 2 Some, 3 A Lot, 4 Complete.

P-Values are from Two-Way Analysis of Variance and its Contrasts with Treatment, Site, and Treatment by Site Interaction as Factors.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table Peak Pain Intensity Differences (PEAKPID) Intent-To-Treat Population, Male Patients PEAK PAIN INTENSITY DIFFERENCES (PEAKPID) P-VALUE TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE [1] A) Placebo 19 0.53 1.020 -1 0.00 3 TREATMENT 0.019 B) MS 60 mg 25 0.20 0.707 -1 0.00 2 SITE 0.080 C) NTX 0.01 mg 21 0.24 0.700 -1 0.00 2 TREATMENT BY SITE 0.583 D) MS 60 mg/NTX 0.001 mg 32 0.63 0.907 -1 0.00 3 A-B 0.236 E) MS 60 mg/NTX 0.01 mg 23 0.74 1.054 -1 0.00 3 A-C 0.303 F) MS 60 mg/NTX 0.1 mg 22 1.18 1.181 -1 1.00 3 A-D 0.863 A-E 0.573 A-F 0.060 B-C 0.903 B-D 0.125 B-E 0.066 B-F 0.001 C-D 0.181 C-E 0.098 C-F 0.002 D-E 0.648 D-F 0.052 E-F 0.165 P-Values are from Two-Way Analysis of Variance and its Contrasts with Treatment, Site, and Treatment by Site Interaction as Factors.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 51A Global Evaluation of Study Medication Intent-To-Treat Population, Female Patients TREATMENT N Poor Fair Good Very Good Excellent Mean (SD) Source P-Value [1] A) Placebo 32 26 2 3 1 0 0.3 0.79 Treatment <0.001 B) MS 60 mg 27 7 4 7 7 2 1.7 1.32 A-B <0.001 C) NTX 0.01 mg 29 26 2 0 1 0 0.2 0.60 A-C 0.403 D) MS 60mg /NTX 0.001 mg 16 8 2 3 2 1 1.1 1.36 A-D 0.015 E) MS 60mg/NTX0.01 mg 27 9 8 2 7 1 1.4 1.31 A-E <0.001 F) MS 60mg/NTX 0.1mg 26 9 7 3 5 2 1.4 1.36 A-F 0.001** B-C <0.001 B-D 0.155 B-E 0.319 B-F 0.345 C-D 0.003 C-E <0.001 C-F <0.001 D-E 0.564 D-F 0.546 E-F 0.997 FROM COCHRAN-MANTEL-HAENZEL TEST FOR RAW MEAN SCORES DIFFERENCE, ADJUSTING FOR SITE..

P-VALUE 0.05, 0.01, OR <=0.001 RESPECTIVELY.

Table 51B Global Evaluation of Study Medication Intent-To-Treat Population, Male Patients TREATMENT N Poor Fair Good Very Good Excellent Mean (SD) Source P-Value [1] A) Placebo 19 14 2 2 1 0 0.5 0.90 Treatment <0.001 B) MS 60 mg 25 18 3 4 0 0 0.4 0.77 A-B 0.891 C) NTX 0.01 mg 21 19 1 0 0 1 0.2 0.89 A-C 0.432 D) MS 60mg/NTX0.001 mg 31 18 4 2 5 2 1.0 1.39 A-D 0.154 E) MS 60mg/NTX0.01 mg 23 12 1 2 4 4 1.4 1.67 A-E 0.035* F) MS 60mg /NTX 0.1 mg 22 8 3 2 5 4 1.7 1.61 A-F 0.004** B-C 0.413 B-D 0.085 B-E 0.012 B-F 0.001 C-D 0.040 C-E 0.008 C-F <0.001 D-E 0.292 D-F 0.060 E-F 0.510 [11 FROM COCHRAN-MANlTL-HAENZ L EbT HJKKAW MEAN SCbtS DIfIKJtNUih, AIJU6flN JPUK P-VALUE 0.05, 0.01, OR <=0.001 RESPECTIVELY.

SITE.

WO 01/85150 PCT/US01/14644 405 The majority of adverse events reported were categorized as digestive (nausea or vomiting) or nervous system (dizziness or somnolence) as further shown in Tables 52A and 52B for females and Tables 52C and 52D for males. Figures 29A for females and 29B for males represent a summary of exemplary adverse side effects according to methods and compositions of the invention. In females, the placebo group has the lowest incidence of adverse events for nausea, vomiting, and dizziness.

For somnolence (sedation), both the placebo group and the NTX alone group have the lowest incidence. In males, the NTX alone group has the lowest incidence of nausea, vomiting and dizziness. For sonmolence (sedation), the placebo group and the NTX alone group have the lowest incidence.

Table 52A Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events TOTAL NUMBER OF EVENTS ADVERSE EVENTS (ALL BODY SYSTEMS) All EVENTS A) PLACEBO 32 16 Treatment 27 8 7 12 (44-4%) B) MS60mg 28 26 A-B 116 32 55 29 (25.0%) C) NTX0.01 mg 30 21 A-D 48 12 21 15 (31.3%) D) MS 60 mg/NTX 0.001 mg 18 18 (100.0%) A-E 66 15 29 22 (33.3%) E) MS 60 mg/NTX 0.01 mg 28 28 (100.0%) A-F 103 33 38 32 (31.1%) F) MS 60 mg/NTX 0.1 mg 26 24 B-C 0.026* 86 22 40 24 (27.9%) C-D 0.009** C-E 0.001** C-F 0.036* CARDIAC DISORDERS ALL EVENTS A) PLACEBO 32 0 Treatment 0.328 0 0 0 0 B) MS 60mg 28 1 1 1 (100.0%) 0 0 C) NTX 0.01 mg 30 1 1 0 1 (100.0%) 0 D) MS 60 mg/NTX 0.001 mg 18 2 2 1 1 0 E) MS 60 mg/NTX 0.01 mg 28 1 1 1 (100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND PAIRWISE COMPARISONS ONLY.

ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events PALPITATIONS A) PLACEBO 32 0 Treatment 0.438 0 0 0 0 B) MS60mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mgNTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 1 1 1 (100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 TACHYCARDIA NOS A) PLACEBO 32 0 Treatment 0.156 0 0 0 0 B) MS 60mg 28 1 1 1 (100.0%) 0 0 C) NTX 0.01 mg 30 1 1 0 1 (100.0%) 0 D) MS 60 mg/NTX 0.001 mg 18 2 2 1 1 0 E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 EAR AND LABYRINTH DISORDERS ALL EVENTS A) PLACEBO 32 2 Treatment 0.454 3 2 1 0 B) MS 60 mg 28 1 1 1 (100.0%) 0 0 C) NTX 0.01 mg 30 2 2 0 2 (100.0%) 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 3 3 0 3 (100.0%) 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events EARACHE A) PLACEBO 32 2 Treatment 0.413 3 2 1 0 B) MS 60 mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 2 2 0 2 (100.0%) 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 2 2 0 2 (100.0%) 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 HEARING IMPAIRED A) PLACEBO 32 0 Treatment 0.438 0 0 0 0 B) MS 60 mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 1 1 0 1 (100.0%) 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 HYPERACUSIS A) PLACEBO 32 0 Treatment 0.438 0 0 0 0 B) MS 60mg 28 1 1 1 (100.0%) 0 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0 F) MS 60 mg/NTX 0.1mg 26 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events EYE DISORDERS ALL EVENTS A) PLACEBO 32 0 Treatment 0.008** 0 0 0 0 B) MS 60mg 28 6 A-B 0.005** 6 3 2 1 (16.7%) C) NTX 0.01 mg 30 0 A-F 0.048* 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 1 B-C 0.007** 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 28 1 B-E 0.043* 1 1 (100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 26 3 3 3 (100.0%) 0 0 AMBLYOPIA NOS A) PLACEBO 32 0 Treatment 0.384 0 0 0 0 B) MS 60mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 26 1 1 1 (100.0%) 0 0 CONJUNCTIVITIS A) PLACEBO 32 0 Treatment 0.109 0 0 0 0 NEC B) MS 60 mg 28 4 A-B 0.026* 4 3 1 0 C) NTX 0.01 mg 30 0 B-C 0.031* 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 28 1 1 1 (100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 26 2 2 2 (100.0%) 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATME1 PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

IT EFFECT AND SIGNIFICANT Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events RED EYE A) PLACEBO 32 0 Treatment 0.438 0 0 0 0 B) MS 60mg 28 1 1 0 0 1 (100.0%) C) NIX 0.01mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60mgNTX 0.01mg 28 0 0 0 0 0 F) MS 60Omg/NTX 0. 1mg 26 0 0 0 0 0 VISION BLURRED A) PLACEBO 32 0 Treatment 0.438 0 0 0 0 B) MS 60 mg 28 1 1 0 1 (100.0%) 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60mgINTXO0.001lmg 18 0 0 0 0 0 E) MS 60OmgINTX 0.0O1mg 28 0 0 0 0 0 F) MS 60 mg/NTX 0. 1mg 26 0 0 0 0 0 GASTROINTESTINAL DISORDERS ALL EVENTS A) PLACEBO 32 9 Treatment 11 3 3 5 (45.5%) B) MS 60 mg 28 22 A-B 40 6 17 17 (42.5%) C) NTX 0-01 mg 30 13 A-D 19 6 6 7 (36.8%A) D) MS 60 mg/NTXO0.001 mg 18 17 A-E 35 5 13 17 (48.6%) E) MS 60 mgfNTX 0.01 mg 28 24 A-F <0.001 44 10 13 21 (47.7%) F) MS 60 mg/NTX 0. 1 mg 26 20 B-C 0.006** 40 3 20 (50.0%1) 17 (42.5%) C-E <0.00] C-F 0.010* P-VALUES ARE FROM CHISQ TEST AN]) ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR TEE PERCENTAGES IS THE TOTAL NUMBffER OF EVENTS.

**:P-VALUE 0.05, K= 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events ABDOMINAL PAIN A) PLACEBO 32 0 Treatment 0.438 0 0 0 0 UPPER B) MS 60mg 28 1 1 0 0 1 (100.0%) C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 DYSPEPSIA A) PLACEBO 32 0 Treatment 0.489 0 0 0 0 B) MS 60 mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 1 1 1 (100.0%) 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mgfNTX 0.01 mg 28 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 DYSPHAGIA A) PLACEBO 32 0 Treatment 0.153 0 0 0 0 B) MS 60 mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 1 1 0 1 (100.0%) 0 E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events MELAENA A) PLACEBO 32 0 Treatment 0.489 0 0 0 0 B) MS 60mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 1 1 1 (100.0%) 0 0 D) MS 60 mg/NTXO0.001 mg 18 0 0 0 0 0 E) MS 60mgINTXO0.0O1mg 28 0 0 0 0 0 F) MS 60mg/NTXO0.I1mg 26 0 0 0 0 0 NAUSEA A) PLACEBO 32 5 Treatment 6 2 1 3 (50.0%) B) MS 60 mg 28 17 A-B 21 5 12 4 (19.0%) C) ND( 0.01 mg 30 9 A-D 10 3 5 2 (20.0%) D) MS 60 mg/NIX 0.001 mg; 18 16 A-E 16 4 9 3 (18.8%) E) MS 60 mg/NIX 0.01 mg 28 21 A-F 25 7 10 8 (32.0%) F) MS 60 ng/NTX 0. 1mg 26 16 (61J5%) B-C 0.018* 18 1 15 2 (11.1%) B-D 0.038* C-D 00** C-E 00** C-F 0.017* D-F 0.045* P-VALUES ARE FROM CI{ISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND11 SIGNIFICANT PAIRWISE COMPARISONS ONLY.

[21 THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Body System Adverse Events (Costart English) Total No. Of Patients No. Of Patients W/Event P-Value No. Of Events Moderate Severe Treatment Source ORAL PAIN SORE THROAT

NOS

A) PLACEBO B) MS 60 mg C) NTX 0.01mg D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60 mg/NTX 0. 1 mg A) PLACEBO B) MS 60 mg C) NIX 0.01mg D) MS 60 mg/NTX 0.001 mg E) MS 60 mgINTX 0.0 1 mg F) MS 60mg/NTX 0.l1mg A) PLACEBO B) MIS 60 mg C) NTX0.01lmg D) MS 60 mg/NTX 0.001 mg F) MS 60 mg/NTX 0.01 mug F) MS 60 mg/NTX 0. 1 mg (3.601) (11.1%) Treatment 0.048* Treatment 0 0 0 1 (100.0%) 0 0 0 2 (100.0%) 0 0 0 0 0.144 2 (100.0%) 0 0 0 0 0 STOMATJTIS Treatment 0.541 0 0 0 0 1 (100.0%) 1 (100.0%) (3.81%) P-VALUES ARE FROM CHISQ TEST AM) ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THlE TOTAL NUJMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events VOMITING NOS A) PLACEBO 32 3 Treatment 3 1 0 2 (66.7%) B) MS 60 mg 28 16 A-B 17 1 5 11 (64.7%) C) NTX 0.01 mg 30 7 A-D 7 1 1 5 (71.4%) D) MS 60 mg/NTX 0.001 mg 18 15 A-E 16 1 3 12 (75.0%) E) MS 60 mg/NTX 0.01 mg 28 17 A-F 18 3 3 12 (66.7%) F) MS 60 mg/NTX 0.1 mg 26 16 B-C 0.008** 21 2 5 14 (66.7%) C-D <0.001*** C-E 0.003** C-F 0.003** GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS ALL EVENTS A) PLACEBO 32 2 Treatment 0.214 2 1 0 1 (50.0%) B) MS 60 mg 28 8 A-B 0.020* 8 3 5 0 C) NTX 0.01 mg 30 3 3 1 1 1 (33.3%) D) MS 60 mg/NTX 0.001 mg 18 3 3 1 2 0 E) MS 60 mg/NTX 0.01 mg 28 5 8 4 2 2 (25.0%) F) MS 60 mg/NTX 0.1 mg 26 3 3 2 1 0 ASTHENIA A) PLACEBO 32 0 Treatment 0.124 0 0 0 0 B) MS 60 mg 28 3 3 2 1 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 1 1 0 1 (100.0%) 0 E) MS 60 mg/NTX 0.01 mg 28 1 2 1 0 1 (50.0%) F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity hitent-To-Treat Population, Female Patients Severity [2] Body System Adverse Events (Costart English) Total No. Of Patients No. Of Patients W/Event P-Value No. Of Events Moderate Severe Treatment Source

FATIGUE

FEELING JITTERY PAIN IN FACE A) PLACEBO B) MS 60 mg C) NTX0.01lmg D) MS 60 mgINTX 0.001 mng E) MS 60 mg/ND( 0.01 mg F) MS 60 mgINTX 0. 1 mg A) PLACEBO B) MS 60 mg C) NTX0.01lmg D) MS 60 rngINTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60 mgINTX 0. 1 mg A) PLACEBO B) MS 60 mg C) NTX 0.01 mg D) MS 60 mgJNTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60mgINTX 0.l1mg Treatment 0.43 8 Treatment 0.298 0 1 (100.0%) 0 0 0 0 (7.10K) (11. (50.0%) (50.0%) (100.0%) (50.0%) (50.0%) (100.0%) Treatment 0.43 8 0 0 0 0 1 (100.0%) 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMEI\ PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

FEFFECT AN.D SIGNIFICANT Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients' Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events PAIN NOS A) PLACEBO 32 1 Treatment 0.782 1 0 0 1 (100.0%) B) MS 60mg 28 1 1 0 1 (100.0%) 0 C) NTX 0.01 mg 30 1 1 0 0 1 (100.0%) D) MS 60mg/NTXO.001mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0 F) MS 60mg/NTXO0. 1mg 26 0 0 0 0, 0 PYREXIA A) PLACEBO 32 1 Treatment 0.893 1 1 (100.0%) 0 0 B3) MS 60 mg 28 1 1 0 1 (100.0%) 0 C) NIX 0.01 mg 30 1 1 1 (100.0%) 0 0 D) MS 60mgINTXO0.00 1mg 18 0 0 0 0 0 E) MS 60 mgfNTX 0.0 1 iug 28 2 2 1 1 0 F) MS 60Omg/NTX 0. 1 mg 26 1 1 1 (100) 0 0 RIGORS A) PLACEBO 32 0 Treatment 0.384 0 0 0 0 B) MS 60mg 28 0 0 0 0 0 C) NTX 0.01mg 30 0 0 0 0 0 D) MS 60mgINTX0.001lmg 18 0 0 0 0 0 E) MS 60OmgINTX 0.0 1mg 28 0 0 0 0 0 F) MS 60 mg[NTX 0. 1 mg 26 1 1 1 (100.0%) 0 0 P-VALUES ARE FROM CHISQ TEST ANT) PATRWISE COMPARISONS ONLY.

ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events SHIVERING A) PLACEBO 32 0 Treatment 0.489 0 0 0 0 B) MS 60 mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 1 1 0 1 (100.0%) 0 D) MS 60 mg/NTX0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 WEAKNESS A) PLACEBO 32 0 Treatment 0.084 0 0 0 0 B) MS 60 mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 2 2 1 1 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 HEPATO-BILIARY DISORDERS ALL EVENTS A) PLACEBO 32 0 Treatment 0.438 0 0 0 0 28 0 0 0 0 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 1 1 0 0 1 (100.0) F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events CHOLELITHIASIS A) PLACEBO 32 0 Treatment 0.438 0 0 0 0 B) MS 60mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 1 1 0 0 1 (100.0%) F) MS60 mg/NTX0.1 mg 26 0 0 0 0 0 INFECTIONS AND INFESTATIONS ALL EVENTS A) PLACEBO 32 4 Treatment 0.400 4 0 0 4 (100.0%) B) MS 60mg 28 4 5 1 3 1 (20.0%) C) NTX 0.01 mg 30 7 8 1 3 4 (50.0%) D) MS 60 mg/NTX 0.001 mg 18 4 4 0 1 3 (75.0%) E) MS 60 mg/NTX 0.01 mg 28 2 2 0 0 2 (100.0%) F) MS 60 mg/NTX 0.1 mg 26 2 3 0 1 2 (66.7%) CELLULITIS A) PLACEBO 32 0 Treatment 0.112 0 0 0 0 B) MS60 mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 2 2 0 0 2 (100.0%) D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events Bly Body System And Severity Intent-To-Treat Population, Female Patients Sevenity [2J Body System Adverse Events (Costar English) Total No. Of Patients No. Of Patients W/Event P-Value Ill NO. Of Events Moderate Severe Treatment Source DRY SOCKET

NOS

ORAL INFECTION

NEC

PHARYNGITIS

NOS

A) PLACEBO B) MS 60 mg C) NTX 0.01 mg D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NDC 0.01 mg F) MS 60 mg/NTX 0. 1 mg A) PLACEBO B) MS 60 mg C) NTX 0.0 1 mg D) MS 60 mg/NrIX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60mg/NTXO0. 1mg A) PLACEBO, B) MS 60 mg C) NT?(0.0O1mg; D) MS 60 mgINTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60mg/NfXO0. 1mg (7.10%) Treatment (50.0%) (66.7%) 0.868 Treatment 0.153 (5.60A) (3.601) 2 (100.0%) 1 (50-0%) 1 (33.3%) 2 (100.0%) 1 (100.0%) 2 (100.0%) 0 0 0 1 (100.0%) 0 0 0 2 (66.7%) 1 (33-3%) 0 0 1 (100.0%) Treatment 0.988 (33.3%) (3 3.3%) 2 (100.0%) 1 (33.3%) 1 (100.0%) 1 (100.0%) 0 [11 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWTSE COMPARISONS ONLY.

THE DENOMINATOR FOR THlE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or K= 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events MUSCULOSKELETAL, CONNECTIVE TISSUE AND BONE DISORDERS ALL EVENTS A) PLACEBO 32 0 Treatment 0.238 0 0 0 0 B) MS 60 mg 28 1 3 0 2 1 (33.3%) C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 2 2 1 1 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 JOINT DISORDER NOS A) PLACEBO 32 0 Treatment 0.438 0 0 0 0 B) MS 60 mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 0 0 0 -0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 1 1 0 1 (100.0%) 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 MUSCLE A) PLACEBO 32 0 Treatment 0.438 0 0 0 0 TWITCHING B) MS 60 mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/N'lX 0.01 mg 28 1 1 1 (100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events MYALGIA A) PLACEBO 32 0 Treatment 0.438 0 0 0 0 B) MS 60mg 28 1 1 0 1 (100.0%) 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS60 mg/NTX0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 SENSATION OF A) PLACEBO 32 0 Treatment 0.438 0 0 0 0 HEAVINESS B) MS 60 mg 28 1 2 0 1 1 (50.0%) C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 NEOPLASMS BENIGN AND MALIGNANT (INCLUDING CYSTS AND POLYPS) ALL EVENTS A) PLACEBO 32 0 Treatment 0.489 0 0 0 0 B) MS 60 mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 1 1 0 0 1 (100.0%) D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Body System Adverse Events (Costart English) Total No. Of Patients No. Of Patients W/Event P-Value No. Of Events Moderate Severe Treatment Source ADENOMA BENIGN

NOS

A) PLACEBO B) MS 60 mg C) NTXO0.0O1mg D) MS 60 mgNTX 0.00 1mg E) MS 60 mg/NIX 0.01 mg F) MS 60 mg/NIX 0. 1 mg Treatment 0.489 0 0 1 (100.0%) 0 NERVOUS SYSTEM DISORDERS ALL EVENTS A) PLACEBO B) MS 60 mg C) NTXO0.0O1mg D) MS 60 mng/NIX 0.001 mg E) MS 60 mg/NIfX 0.01 mg F) MS 60 mg/NIX 0. 1mg (21.9%) (71.4%) (33.3%) (61.1%) (67.9%) (57.7%) Treatment

A-B

A-D

A-E

A-F

B-C

C-E

<0.001*** <0.001*** 0.005** <0.001 0.005** 0.003** 0.008** (28.6%) (18.9%) (27.3%) (28.6%) (34.5%) (41.7%) (42.9%) (64.9%) (63.6%) (64.3%) (55.2%) (4 1.7%) (28.6%) (16.2%) (10.3%) (16.7%) P-VALUES ARE FROM CIIISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AM) SIGNIFICANT PAIRWISE COMPARISONS ONLY.

TBE DENOMINATOR FOR TH4E PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Total No. Of Svrt 2 Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients WfEvent Source Events DIZZINESS A) PLACEBO 32 1 Treatment 1 0 1 (100.0%) 0 (EXC VERTIGO) B) MS 60mg 28 16 A-B 18 3 12 3 (16.7%) C) NTX 0.01 mg 30 2 A-D <0.001 2 2 (100.0%4) 0 0 D) MS 60 mgJNTX 0.001 mg 18 9 A-E 9 3 6 0 E) MS 60 mg/NTX 0.01 mg 28 12 A-F 0.001** 14 5 (35.70%) 8 1 F) MS 60 mg/NTX 0.1 mg 26 9 B-C 10 3 5 2 (20.0%) C-D <0.001*** C-E 0.001*' C-F 0.008** HEADACHE NOS A) PLACEBO 32 6 Treatment 0.966 6 2 2 2 (33.3%) 13) MS 60 mg 28 5 (17.9%K) 5 1 4 0 C) NTX 0.01 mg 30 5 5 1 (20.0% 3 1 (20.0%) D) MS 60 mgINTX 0.001 mg 18 2 2 0 1 1 (50.0%) E) MS 60mg/NTX0.01lmg 28 6 6 1 4 1 (16.7%) F) MS 60Omg/NTX 0. 1mg 26 4 4 1 2 1 (25.0%) HYPERTONIA A) PLACEBO 32 0 Treatment 0.489 0 0 0 0 B) MS 60mg 28 0 C 0 0 0 C) NTX 0.01 mg 30 1 1 0 1 (100.0%) 0 D) MS 60mg/NTX0.001lmg 18 0 0 0 0 0 E) MS 60mgINTX0.01lmg 28 0 C 0 0 0 F) MS 60mg/NTXO0. 1mg 26 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST ANT) ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events HYPOTONIA A) PLACEBO 32 0 Treatment 0.438 0 0 0 0 B) MS60 mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mrng/NTX 0.01 mg 28 1 1 0 1 (100.0%) 0 F) MS60 mg/NTX 0.1 mg 26 0 0 0 0 0 PARAESTHESIA A) PLACEBO 32 0 Treatment 0.657 0 0 0 0 NEC B) MS 60mg 28 3 5 2 2 1 (20.0%) C) NTX 0.01 mg 30 2 2 0 2 (100.0%) 0 D) MS 60 mg/NTX 0.001 mg 18 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 28 2 2 1 1 0 F) MS 60 mg/NTX 0.1 mg 26 2 2 1 1 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Total No. Of Svrt 2 Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events SOMNOLENCE A) PLACEBO 32 0 Treatment 0 0 0 0 13) MS 60mg 28 8 A-B 0.001** 9 1 6 2 (22.2%) C) NTX0.01 mg 30 0 A-E 0.012* 0 0 0 0 D) MS 60 mg/NIX 0.001 mg 18 2 A-F 2 0 2 (100.0%) 0 E) MS 60 mg/NIX 0.01 mg 28 5 B-C 0.00l** 5 3 2 0 F) MS 60 mg/NIX 0. 1 mg 26 8 C-E 0.015* 8 5 2 1 (12.5%) C-F 0.001** TASTE LOSS A) PLACEBO 32 0 Treatment 0.489 0 0 0 0 3) MS 60mg 28 0 0 0 0 0 C) NIX 0.01 mg 30 1 1 0 1 (100.0%) 0 D) MS 60mgfNIXO.00 1mg 18 0 0 0 0 0 E) MS 60mgINIX0.01lmg 28 0 0 0 0 0 F) MS 60mgINIX0.lnmg 26 0 0 0 0 0 TREMOR NEC A) PLACEBO 32 0 Treatment 0.43 8 0 0 0 0 D) MS 60mg 28 0 0 0 0 0 C) NTX0.01lmg 30 0 0 0 0 0 D) MS 6Omng/NTX0.001lmg 18 0 0 0 0 0 E) MS 60 mg/NIX 0.01 mg 28 1 1 0 0 1 (100.0%) F) MS 60mg/NIXO0.l1mg 26 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST ANDJT ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIR WISE COMPARISONS ONLY.

THE DENOMINATOR FOR TILE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity itent-To-Treat Population, Female Patients ~everny

L.~J

Seventy L2j Body System Adverse Events (Costart English) Total No. Of Patients No. Of Patients W/Event P-Value No. Of Events Moderate Severe Treatment Source PREGNANCY, PUERPERIUM AND PERINATAL CONDITIONS ALL EVENTS A) PLACEBO B) MS 60 mg Q)NTX 0.01mg D) MS 60 mgINIX0.00 1mg E) MS 60 mg/NTX 0.01mg F) MS 60 mg/NTX 0. 1 mg Treatment 0.438 0 1 (100.0%) 0 0 0 0 PREGNANCY NOS A) PLACEBO B) MS 60 mg C) NTX 0.0 1 g D) MS 60 mgJNTX 0.00 1 mg E) MS 60 mg/NTX 0.01 mg F) MS 60mgINfX 0. 1mg Treatment 0.438 0 0 1 1 (100.0%) 0 0 0 0 0 0 0 0 PSYCHIATRIC DISORDERS ALL EVENTS A) PLACEBO B) MS 60 mg C) NTX0.01lmg D) MS 60 mg/NTX 0.001 mig E) MS 60 mgINTX 0.01 mg F) MS 60 mg/NTfX 0-.1 mg Treatment 0.156 A-B 0.026* (14.3%) (10.7%) 0 1(20.0%) 0 0 3 (100.0%) 1 (25.0%) 0 1 (20.0%) 1 (100.0%) 0 0 3 (75.0%) (60.0%) P-VALUES ARE FROM CHISQ TEST AND~T ARE PROVIDED FOR OVERALL TREATMVENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUTE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events ANXIETY NEC A) PLACEBO 32 0 Treatment 0.438 0 0 0 0 B) MS60 mg 28 1 1 0 0 1 (100.0%) C) NTX 0.01 mg 30 0 0 0. 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 CONFUSION A) PLACEBO 32 0 Treatment 0.438 0 0 0 0 B) MS 60 mg 28 0 0 0 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 1 1 1 (100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 DEPERSONALISATION A) PLACEBO 32 0 Treatment 0.541 0 0 0 0 B) MS 60 mg 28 1 1 0 0 1 (100.0%) C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 26 1 1 1 (100.0%) 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events DISSOCIATION A) PLACEBO 32 0 Treatment 0.384 0 0 0 0 B) MS60 mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS60 mg/NTX 0.01 mg 28 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 26 1 1 0 1 (100.0%) 0 EUPHORIC MOOD A) PLACEBO 32 0 Treatment 0.541 0 0 0 0 B) MS60mg 28 1 1 0 0 1 (100.0%) C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 26 1 1 0 1 (100.0%) 0 NERVOUSNESS A) PLACEBO 32 0 Treatment 0.579 0 0 0 0 B) MS 60mg 28 2 2 1 1 0 C) NTX 0.01 mg 30 1 1 0 1 (100.0%) 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS60 mg/NTX 0.01 mg 28 2 2 2 (100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 26 1 1 0 1 (100.0%) 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events RENAL AND URINARY DISORDERS ALL EVENTS A) PLACEBO 32 0 Treatment 0.438 0 0 0 0 B) MS60mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 1 1 0 1 (100.0%) 0 F) MS 60 mg/NTX .1 mg 26 0 0 0 0 0 URINARY A) PLACEBO 32 0 Treatment 0.438 0 0 0 0

RETENTION

B) MS60 mg 28 0 0 0 0 0 C) NTX 0.01 nmg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 1 1 0 1 (100.0%) 0 F) MS 60 mg/NTX O.l mg 26 0 0 0 0 0 REPRODUCTIVE SYSTEM AND BREAST DISORDERS ALL EVENTS A) PLACEBO 32 0 Treatment 0.153 0 0 0 0 B) MS60 mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 1 1 0 0 1 (100.0%) E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0 F) MS 60 mg/NTX O.1 mg 26 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Total No. Of Svrt 2 Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W[Event Source Events DYSMENORRHOEA A) PLACEBO 32 0 Treatment 0.153 0 0 0 0 B) MS 60 mg 28 0 0 0 0 0 C) NTX0.01lmg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.00 1mrg 18 1 1 0 0 1 (100.0%) E) MS 60mgNTX 0.0 1mg 28 0 0 0 0 0 F) MS 60mgJNTXO0. 1mg 26 0 0 0 0 0 RESPIRATORY, THORACIC AN D MEDIASTINAL DISORDERS ALL EVENTS A) PLACEBO 32 0 Treatment 0.768 0 0 0 0 B) MS 60mg 28 1 1 1 (100.0%) 0 0 C) NTh 0.01 mg 30 1 1 0 0 1 (100.0%) D) MS 60 nmg/NTX 0.00 1 mg 18 1 1 1 (100.0%) 0 0 E) MS 60OmgINTX 0.0 1mg 28 1 2 0 0 2 (100.0%) F) MS 60mgfNTX0.1lmg 26 0 0 0 0 0 COUGH A) PLACEBO 32 0 Treatment 0.489 0 0 0 0 B) MS 60mg 28 0 0 0 0 0 C) NTh 0.01 mig 30 1 1 0 0 1 (100.0%) D) MS 60 g/NTXO.00 1mg 18 0 0 0 0 0 E) MS 60 mg/NfXO.01 mg 28 0 0 0 0 0 F) MS 60mgJNTXO0. 1mg 26 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT ANT) SIGNIFICANT PAIRWISE COMPARISONS ONLY.

TBlE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

:P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [21 Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events EPISTAXIS A) PLACEBO 32 0 Treatment 0.153 0 0 0 0 B) MS 60mg 28 0 0 0 0 0 C) NTh 0.01 mg 30 0 0 0 0 0 D) MS 60Omg/NTX 0.00 1mg 18 1 1 1 (100.0%) 0 0 E) MS 60 mg[NTfX 0.01 mg 28 0 0 0 0 0 F) MS 60mgINTX0.1lmg 26 0 0 0 0 0 RHINITIS NOS A) PLACEBO 32 0 Treatment 0.573 0 0 0 0 B) MS 60 mg 28 1 1 1 (100.0%) 0 0 C) NTX0.01lmg 30 0 0 0 0 0 D) MS 60mgINTX0.00 1rmg 18 0 0 0 0 0 E) MS 60 mg[NTX 0.01 mg 28 1 1 0 0 1 (100.0%) F) MS 60mg/NTX0.1mg 26 0 0 0 0 0 SINUS CONGESTION A) PLACEBO 32 0 Treatment 0.438 0 0 0 0 B) MS6Omg 28 0 0 0 0 0 C) NTX0.01lmg 30 0 0 0 0 0 D) MS 60mg/NIXO0.00 1mg 18 0 0 0 0 0 E) MS 60OmgfNTfX 0.0 1mg 28 1 1 0 0 1 (100.0%) F) MS 60mgNTXO0. 1mg 26 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

TBE DENOMINATOR IFOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events SKIN SUBCUTANEOUS TISSUE DISORDERS ALL EVENTS A) PLACEBO 32 0 Treatment 0.087 0 0 0 0 B) MS 60 mg 28 2 A-D 0.017* 4 3 1 0 C) NTX 0.01 mg 30 0 C-D 0.020* 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 3 5 2 3 0 E) MS 60 mg/NTX 0.01 mg 28 3 3 2 0 1 (33.3%) F) MS 60 mg/NTX 0.1 mg 26 1 2 0 1 1 (50.0%) DERMATITIS NOS A) PLACEBO 32 0 Treatment 0.573 0 0 0 0 B) MS60mg 28 1 1 1 (100.0%) 0 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mng 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 1 1 1 (100.0%) 0 0 F) MS 60 mg/NTX 0. mg 26 0 0 0 0 0 ECCHYMOSIS A) PLACEBO 32 0 Treatment 0.153 0 0 0 0 B) MS 60 mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events PRURITUS NOS A) PLACEBO 32 0 Treatment 0.074 0 0 0 0 B) MS 60 mg 28 1 A-D 0.017* 1 0 1 (100.0%) 0 C) NTX 0.01 mg 30 0 C-D 0.020* 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 3 4 1 3 0 E) MS 60 mg/NTX 0.01 mg 28 2 2 1 0 1 (50.0%) F) MS 60 mg/NTX 0.1 mg 26 1 1 0 0 1 (100.0%) URTICARIANOS A) PLACEBO 32 0 Treatment 0.541 0 0 0 0 B) MS 60mg 28 1 2 2 (100.0%) 0 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 26 1 1 0 1 (100.0%) 0 VASCULAR DISORDERS ALL EVENTS A) PLACEBO 32 0 Treatment 0.015* 0 0 0 0 B) MS 60mg 28 4 A-B 0.026* 4 4 (100.0%) 0 0 C) NTX 0.01 mg 30 1 A-F 0.004** 1 1 (100.0%) 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 C-F 0.025* 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 3 D-F 0.028* 3 1 2 0 F) MS 60 mg/NTX 0:1 mg 26 6 7 3 4 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events FLUSHING A) PLACEBO 32 0 Treatment 0.438 0 0 0 0 B) MS 60 mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 1 1 1 (100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 26 0 0 0 0 0 HOT FLUSHES NOS A) PLACEBO 32 0 Treatment 0.384 0 0 0 0 B) MS 60 mg 28 0 0 0 0 0 C) NTX 0.01 mg 30 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 26 1 1 0 1 (100.0%) 0 HYPERTENSION NOS A) PLACEBO 32 0 Treatment 0.721 0 0 0 0 B) MS60mg 28 1 1 1 (100.0%) 0 0 C) NTX 0.01 mg 30 1 1 1 (100.0%) 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 26 1 1 1 (100.0%) 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52A (Continued) Adverse Events By Body System And Severity Intent-To-Treat Population, Female Patients Severity [2] Total No. Of Body System No. Of Patients P-Value No. Of Mild Moderate Severe Adverse Events (Costart English) Treatment Patients W/Event Source Events VASODILATATION A) PLACEBO 32 0 Treatment 0.015* 0 0 0 0 B) MS 60 mg 28 3 A-F 0.009** 3 3 (100.0%) 0 0 C) NTX 0.01 mg 30 0 C-F 0.011* 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 18 0 D-F 0.048* 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 28 2 2 0 2 (100.0%) 0 F) MS 60 mg/NTX 0.1 mg 26 5 5 2 3 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52B Selected Adverse Events Intent-To-Treat Population, Female Patients TOTAL NO. OF NO. SEVERITY [2] BODY SYSTEM NO. OF SUBJECTS P-VALUE OF ADVERSE EVENTS TREATMENT SUIBJECTS WEVENT SOURCE EVENTS Mild Moderate Severe DIZZINESS A) PLACEBO 32 1 Treatment 1 0 1 (100.0%) 0 (EXC VERTIGO) B) MS 60 mg 28 16 (57.1%1) A-B <0.001 18 3 12 3 (16.7%) C) NTX 0.01 mg 30 2 A-D <0.001 2 2(100.0%) 0 0 D) MS 60 mg/NTh 0.00 1mg 18 9 A-E 9 3 6 0 E) MS 60 mg/NTX 0.01 mg 28 12 A-F 0.001** 14 5 8 1 F) MS 60 mgINTX 0.1 mg 26 9 B-C <0.001 10 3 5 2 (20.0%) C-E 0.001*1 C-F 0.008** NAUSEA A) PLACEBO 32 5 Treatment <0.001 6 2 1 (16.7%4) 3 (50.0%) B) MS 60 mg 28 17 A-B <0.001 21 5 12 4 (19.0%) C) NTX 0.01 mg 30 9 A-D 10 3 5 2 (20.0%) D) MS 60 mg/NTX 0.00 1 mg 18 16 A-E <0.001 16 4 9 3 (18.8%) E) MS 60 mgINTX 0.01 mg 28 21 A-F <0.001 25 7 10 8 (32.0%) F) MS 60 mg/NTX 0.1 mg 26 16 B-C 0.018* 18 1 15 2 (11.1%) B-D 0.038* C-F <0.001*** C-F 0.017* D-F 0.045* P-VALUES ARE FROM CITISQ TEST ANT) ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG ='SUSPECT' OR 'PROBA-BLE'.

P-VALUE, 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52B (Continued) Selected Adverse Events Intent-To-Treat Population, Female Patients TOTAL NO. OF NO. SEVERITY [2] BODY SYSTEM NO. OF SUBJECTS P-VALUE OF ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT SOURCE EVENTS Mild Moderate Severe SOMNOLENCE A) PLACEBO 32 0 Treatment 0 0 0 0 B) MS60 mg 28 8 A-B 0.001** 9 1 6 2 (22.2%) C) NTX 0.01 mg 30 0 A-E 0.012* 0 0 0 0 D) MS 60 mg/NTX 0.001mg 18 2 A-F 2 0 2 (100.0%) 0 E) MS 60 mg/NTX 0.01 mg 28 5 B-C 0.001** 5 3 2 0 F) MS 60 mg/NTX 0.1 mg 26 8 C-E 0.015* 8 5 2 1 (12.5%) C-F 0.001** VOMITING A) PLACEBO 32 3 Treatment 3 1 0 2 (66.7%) NOS B) MS 60 mg 28 16 A-B 17 1 5 11 (64.7%) C) NTX 0.01 mg 30 7 A-D <0.001** 7 1 1 5 (71.4%) D) MS 60 mg/NTX 0.001 mg 18 15 A-E 16 1 3 12 (75.0%) E) MS 60 mg/NTX 0.01 mg 28 17 A-F 18 3 3 12 (66.7%) F) MS 60 mg/NTX 0.1 mg 26 16 B-C 0.008** 21 2 5 14 (66.7%) C-D <0.001*** C-E 0.003** C-F 0.003** P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe TOTAL NUMBER OF EVENTS ADVERSE EVENTS (ALL BODY SYSTEMS) All EVENTS A) PLACEBO 19 13 Treatment <0.001 26 10 12 4 (15.4%) B) MS 60mg 25 20 (80.0% A-C 0.026* 59 30 22 7 (11.9%) C) NTX 0.01 mg 21 7 B-C 0.001** 13 5 6 2 (15.4%) D) MS 60 mg/NTX 0.001 mg 32 28 C-D <0.001 75 32 29 14 (18.7%) E) MS 60 mg/NTX 0.001 mg 23 20 C-E <0.001** 58 20 20 18 (31.0%) F) MS 60 mg/NTX 0.1mg 22 20 C-F <0.001 57 21 21 15 (26.3%) CARDIAC DISORDERS ALL EVENTS A) PLACEBO 19 1 Treatment 0.590 1 1 (100.0%) 0 0 B) MS60mg 25 1 1 1 (100.0%) 0 0 C) NTX 0.01 mg 21 1 1 1 (100.0%) 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe BRADYCARDIANOS A) PLACEBO 19 1 Treatment 0.258 1 1 (100.0%) 0 0 B) MS60mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 TACHYCARDIA NOS A) PLACEBO 19 0 Treatment 0.509 0 0 0 0 B) MS 60 mg 25 1 1 1 (100.0%) 0 0 C) NTX 0.01 mg 21 1 1 1 (100.0%) 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 EAR AND LABYRINTH DISORDERS ALL EVENTS A) PLACEBO 19 1 Treatment 0.685 1 0 1 (100.0%) 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 23 1 1 0 1 (100.0%) 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG= 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe EARACHE A) PLACEBO 19 1 Treatment 0.685 1 0 1 (100.0%) 0 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 0.01mg 23 1 1 0 1 (100.0%) 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 EYE DISORDERS ALL EVENTS A) PLACEBO 19 1 Treatment 0.555 1 0 1 (100.0%) 0 B) MS 60mg 25 4 4 4 (100.0%) 0 0 C) NTX 0.01 mg 21 1 1 0 1 (100.0%) 0 D) MS 60 mg/NTX 0.001 mg 32 5 5 4 0 1 (20.0%) E) MS 60 mg/NTX 0.01 mg 23 3 3 2 0 1 (33.3%) F) MS 60 mg/NTX 0.1 mg 22 1 1 1 (100.0%) 0 0 CONJUNCTIVITIS A) PLACEBO 19 0 Treatment 0.511 0 0 0 0 NEC B) MS 60 mg 25 3 3 3 (100.0%) 0 0 C) NTX 0.01 mg 21 1 1 0 1 (100.0%) 0 D) MS 60 mg/NTX 0.001 mg 32 4 4 4 (100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 23 3 3 2 0 1 (33.3%) F) MS 60mg/NTX 0.1 mg 22 1 1 1 (100.0%) 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe PHOTOPHOBIA A) PLACEBO 19 1 Treatment 0.258 1 0 1 (100.0%) 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 TIRED EYES A) PLACEBO 19 0 Treatment 0.629 0 0 0 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 1 1 0 0 1 (100.0%) E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 VISION BLURRED A) PLACEBO 19 0 Treatment 0.451 0 0 0 0 B) MS 60 mg 25 1 1 1 (100.0%) 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG= 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe GASTROINTESTINAL DISORDERS ALL EVENTS A) PLACEBO 19 3 Treatment 5 1 1 3 (60.0%) B) MS 60mg 25 11 A-B 0.046* 21 11 6 4 (19.0%) C) NTX 0.01 mg 21 0 A-D 0.004** 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 18 A-F 0.004** 31 9 29.0%) 13 9 (29.0%) E) MS 60 mg/NTX 0.01 mg 23 10 B-C 18 3 5 10 (55.6%) F) MS 60 mg/NTX 0.1 mg 22 13 C-D 23 7 6 10 (43.5%) C-E <0.001*** C-F <0.001*** ABDOMINAL PAIN A) PLACEBO 19 1 Treatment 0.441 1 0 0 1 (100.0%) NOS B) MS 60 mg 25 2 2 1 1 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 ABDOMINAL PAIN A) PLACEBO 19 0 Treatment 0.358 0 0 0 0 UPPER B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 1 1 0 1 (100.0%) 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG= 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe DYSPHAGIA A) PLACEBO 19 1 Treatment 0.547 1 0 0 1 (100.0%) B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 1 1 0 0 1 (100.0%) E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 HICCUPS A) PLACEBO 19 0 Treatment 0.390 0 0 0 0 B) MS60mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 1 1 0 1 (100.0%) 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 NAUSEA A) PLACEBO 19 2 Treatment 0.001** 2 1 1 0 B) MS 60 mg 25 10 A-B 0.029* 10 7 3 0 C) NTX 0.01 mg 21 0 A-D 0.013* 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 14 A-F 0.014* 15 5 7 3 (20.0%) E) MS 60 mg/NTX 0.01 mg 23 6 B-C 0.001** 6 2 2 2 (33.3%) F) MS 60 mg/NTX 0.1 mg 22 10 C-D 10 6 4 40.0%) 0 C-E 0.011* C-F <0.001*** P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe SORE THROATNOS A) PLACEBO 19 0 Treatment 0.629 0 0 0 0 B) MS 60mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001mg 32 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 VOMITING NOS A) PLACEBO 19 1 Treatment 1 0 0 1 (100.0%) B) MS 60 mg 25 9 A-B 0.015* 9 3 2 4 (44.4%) C) NTX 0.01 mg 21 0 A-D 0.010* 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 12 A-E 0.020* 13 2 6 5 (38.5%) E) MS 60 mg/NTX 0.01 mg 23 8 A-F 0.001** 11 1 2 8 (72.7%) F) MS 60 mg/NTX 0.1 mg 22 11 B-C 0.002** 12 1 1 10 (83.3%) C-D 0.001** C-E 0.002** C-F <0.001*** P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG ='SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS ALL EVENTS A) PLACEBO 19 3 Treatment 0.280 3 1 2 0 B) MS 60 mg 25 5 A-E 0.047* 5 2 2 1 (20.0%) C) NTX 0.01 mg 21 1 B-E 0.023* 2 0 1 1 (50.0%) D) MS 60 mg/NTX 0.001 mg 32 4 4 3 1 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 3 3 2 1 0 ASTHENIA A) PLACEBO 19 0 Treatment 0.013* 0 0 0 0 B) MS 60 mg 25 3 B-D 0.044* 3 1 2 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 FEELING ABNORMAL A) PLACEBO 19 0 Treatment 0.451 0 0 0 0 B) MS60mg 25 1 1 0 0 1 (100.0%) C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG= 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe FEELING HOT A) PLACEBO 19 0 Treatment 0.600 0 0 0 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 1 1 0 0 1 (100.0%) D) MS 60 mg/NTX 0.001 ing 32 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 PAINNOS A) PLACEBO 19 0 Treatment 0.624 0 0 0 0 B) MS60mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 1 1 0 1 (100.0%) 0 PYREXIA A) PLACEBO 19 1 Treatment 0.839 1 1 (100.0%) 0 0 B) MS 60 mg 25 1 1 1 (100.0%) 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 1 1 1 (100.0%) 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients B3ODY SYSTEM ADVERSE EVENTS (COSTART ENGLISH)

TOTAL

NO. OF

PATIENTS

NO. OF

PATIENTS

WIEVENT

No.

P-Value of [:11 Events

SEVERITY

[2] Moderate

SOURCE

TREATMENT Severe

RIGORS

TREATMENT

A) PLACEBO B) MS 60 mg C) NTX 0.0O1mg D) MS 60 mg/NTX 0.001 mg E) MS 630 mngJNTX 0.01 mg F) MS 60 mgfNTX 0. 1 mg A) PLACEBO B) MS, 60 mg C) NTX 0.0 1 mg D) MS 6Omg/NTX 0.00 1mg E) MS 60 mg/NTX 0.01 mg F) MS 60 mg/NTX 0.1 mg 2 (10.5%) 0 1 (4.58%) 1 0 0 0 0 0 0 0 1 (4.5%1) Treatment 0.264 2 0 0 0 2 (100.0%) 0 1 (100.0%) 1 (100.0%) 0 0 WEAKNESS Treatment 0.358 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 4 (66.7%) 0 0 0 0 0 INFECTIONS AND INFESTATIONS ALL EVENTS A) PLACEBO B) MS 60 mg C) NThO.0O1mg D) MS 60 mgNTXO.00 1mg E) MS 60 mgINTX 0.01mg F) MS 60 ing/NNX 0. 1 mg (21.1%) Treatment 0.654 6 2 2 2 3 2 1 (16.7%) 0 2 (100.0%) 0 0 1 (50.0%1) 1 (16.7%) 2 (100.0%) 0 2 (100.0%) 3 (100.0%) 1 (50.0%) P-VALUES ARE FROM CHISQ TEST ANT) PAIRWISE COMPARISONS ONLY.

ARE PRO VIDED FOR OVERALL TREATMENT EFFECT ANT) SIGN]IFICANT THE DENOMINATOR FOR THE PERCENTAGES IS THlE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe CELLULITIS A) PLACEBO 19 0 Treatment 0.358 0 0 0 0 DRY SOCKET NOS B) MS 60 mg C) NTX 0.01 mg D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60 mg/NTX 0.1 mg A) PLACEBO B) MS 60 mg C) NTX 0.01 mg D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60 mg/NTX 0.1 mg A) PLACEBO B) MS 60 mg C) NTX 0.01 mg D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NTX 0.01 mg F) MS 60 mg/NTX 0.1 mg 25 21 32 23 22 0 0 0 0 1 0 0 0 0 0 1 (100.0%) 0 1 (100.0%) 0 0 0 o 0 Treatment 0.848 0 0 0 0 1 (100.0%) 0 1 (100.0%) 0 2 (100.0%) 2 (100.0%) 0 0 1 (100.0%) 0 0 0 0 NASOPHARYNGITIS 0 1 0 0 0 0 Treatment 0.451 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe ORAL INFECTION NEC A) PLACEBO 19 0 Treatment 0.390 0 0 0 0 B) MS60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 1 1 0 0 1 (100.0%) F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 PHARYNGITIS NOS A) PLACEBO 19 2 Treatment 0.093 4 3 0 1 (25.0%) B) MS60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 1 1 0 1 (100.0%) 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0-.1 mg 22 0 0 0 0 0 TOOTH INFECTION A) PLACEBO 19 0 Treatment 0.358 0 0 0 0 B) MS60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 1 1 0 1 (100.0%) 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG ='SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe UPPER RESPIRATORY TRACT INFECTION NOS A) PLACEBO 19 1 Treatment 0.258 1 1 (100.0%) 0 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 INJURY AND

POISONING

ALL EVENTS A) PLACEBO 19 1 Treatment 0.258 1 0 1 (100.0%) 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 HYPOTHERMIA A) PLACEBO 19 1 Treatment 0.258 1 0 1 (100.0%) 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

INVESTIGATIONS

ALL EVENTS A) PLACEBO 19 0 Treatment 0.390 0 0 0 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 1 1 1 (100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0

HAEMATIJRIA

PRESENT A) PLACEBO 19 0 Treatment 0.390 0 0 0 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 1 1 1 (100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 MUSCULOSKELETAL, CONNECTIVE TISSUE AND BONE DISORDERS ALL EVENTS A) PLACEBO 19 0 Treatment 0.090 0 0 0 0 B) MS 60 mg 25 2 2 0 2 (100.0%) 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG= 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE 1] Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe NECK STIFFNESS A) PLACEBO 19 0 Treatment 0.451 0 0 0 0 B) MS 60 mg 25 1 1 0 1 (100.0%) 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS60 mg/NTX 0.1 mg 22 0 0 0 0 0 SENSATION OF HEAVINESS A) PLACEBO 19 0 Treatment 0.451 0 0 0 0 B) MS60mg 25 1 1 0 1 (100.0%) 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No.

SEVERITY

BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe NERVOUS SYSTEM

DISORDERS

ALL EVENTS A) PLACEBO 19 6 Treatment 0.005** 6 3 3 0 B) MS 60 mg 25 13 A-D 0.032* 15 5 10 0 C) NTX 0.01 mg 21 4 A-F 0.019* 4 2 1 1 (25.0%) D) MS 60 mg/NTX 0.001 mg 32 20 B-C 0.021* 26 12 12 2 E) MS 60 mg/NTX 0.01 mg 23 14 C-D 0.001** 21 11 7 3 (14.3%) F) MS 60 mg/NTX 0.1 mg 22 15 C-E 0.004** 21 9 10 2 C-F 0.001** DIZZINESS A) PLACEBO 19 1 Treatment 0.008** 1 0 1 (100.0%) 0 (EXC VERTIGO) B) MS 60mg 25 3 A-D 0.046* 3 1 2 0 C) NTX 0.01 mg 21 0 A-E 0.020* 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 9 A-F 0.032* 10 4 5 1 (10.0%) E) MS 60 mg/NTX 0.01 mg 23 8 C-D 0.007** 9 5 4 0 F) MS 60 mg/NTX 0.1 mg 22 7 C-E 0.002** 9 4 4 1 (11.1%) C-F 0.004** HEADACHE NOS A) PLACEBO 19 3 Treatment 0.444 3 2 1 0 B) MS 60mg 25 -6 7 2 5 0 C) NTX 0.01 mg 21 3 3 1 1 1 (33.3%) D) MS 60 mg/NTX 0.001 mg 32 6 7 1 5 1 (14.3%) E) MS 60 mg/NTX 0.01 mg 23 2 2 1 0 1 (50.0%) F) MS 60 mg/NTX 0.1 mg 22 7 7 4 3 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe HYPERTONIA A) PLACEBO 19 0 Treatment 0.390 0 0 0 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.

0 01 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 1 1 1 (100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 HYPOAESTHESIA A) PLACEBO 19 0 Treatment 0.390 0 0 0 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 1 1 1 (100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 MIGRAINE NOS A) PLACEBO 19 0 Treatment 0.390 0 0 0 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 1 1 0 0 1 (100.0%) F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe MUSCLE SPASTICITY A) PLACEBO 19 0 Treatment 0.451 0 0 0 0 B) MS 60 mg 25 1 1 1 (100.0%) 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0

PARAESTHESIA

CIRCUMORAL A) PLACEBO 19 0 Treatment 0.629 0 0 0 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 PARAESTHESIA NEC A) PLACEBO 19 2 Treatment 0.510 2 1 1 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 1 1 1 (100.0%) 0 0 D) MS 60 mg/NTX 0.001 mg 32 2 2 2 (100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 23 1 1 1 (100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe SOMMOLENCE A) PLACEBO 19 0 Treatment 0.209 0 0 0 0 B) MS 60 mg 25 3 C-F 0.040* 4 1 3 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 5 6 4 2 0 E) MS 60 mg/NTX 0.01 mg 23 3 3 1 2 0 F) MS 60 mg/NTX 0.1 mg 22 4 4 1 3 0 SYNCOPE A) PLACEBO 19 0 Treatment 0.390 0 0 0 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 1 1 0 0 1 (100.0%) F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 TENSION HEADACHES A) PLACEBO 19 0 Treatment 0.358 0 0 0 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 1 1 0 0 1 (100.0%) P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe TREMOR NEC A) PLACEBO 19 0 Treatment 0.062 0 0 0 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 2 2 1 1 0 F) MS 60 mg/NTX0.1 mg 22 0 0 0 0 0

PSYCHIATRIC

DISORDERS

ALL EVENTS A) PLACEBO 19 1 Treatment 0.593 1 0 1 (100.0%) 0 B) MS 60 mg 25 2 2 1 1 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 2 2 0 2 (100.0%) 0 E) MS 60 mg/NTX 0.01 mg 23 1 1 1 (100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 22 3 3 1 1 1 (33.3%) DISORIENTATION A) PLACEBO 19 0 Treatment 0.390 0 0 0 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 1 1 1 (100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe DISSOCIATION A) PLACEBO 19 0 Treatment 0.358 0 0 0 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 1 1 0 0 1 (100.0%) EUPHORIC MOOD A) PLACEBO 19 0 Treatment 0.400 0 0 0 0 B) MS 60 mg 25 1 1 1 (100.0%) 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 1 1 0 1 (100.0%) 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 2 2 1 1 0 NERVOUSNESS A) PLACEBO 19 1 Treatment 0.711 1 0 1 (100.0%) 0 B) MS60mg 25 1 1 0 1 (100.0%) 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 1 1 0 1 (100.0%) 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND PAIRWISE COMPARISONS ONLY.

ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe RENAL AND URINARY DISORDERS ALL EVENTS A) PLACEBO 19 0 Treatment 0.551 0 0 0 0 B) MS 60mg 25 1 1 1 (100.0%) 0 0 C)NTX 0.01 mrng 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 1 1 0 1 (100.0%) 0 F) MS 60 mg/NTX .lmg 22 0 0 0 0 0 URINARY RETENTION A) PLACEBO 19 0 Treatment 0.551 0 0 0 0 B) MS60mg 25 1 1 1 (100.0%) 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mng 23 1 1 0 1 (100.0%) 0 F) MS 60 mg/NTX O.1 mg 22 0 0 0 0 0 REPRODUCTIVE SYSTEM AND BREAST DISORDERS ALL EVENTS A) PLACEBO 19 0 Treatment 0.390 0 0 0 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 1 2 0 1 1 (50.0%) F) MS 60 mg/NTX O.1 mg 22 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND PAIRWISE COMPARISONS ONLY.

ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe

PROSTATIC

DISORDER NOS A) PLACEBO 19 0 Treatment 0.390 0 0 0 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 1 1 0 1 (100.0%) 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0

TESTICULAR

DISORDERNOS A) PLACEBO 19 0 Treatment 0.390 0 0 0 0 B) MS 60mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 1 1 0 0 1 (100.0%) F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS ALL EVENTS A) PLACEBO 19 0 Treatment 0.643 0 0 0 0 B) MS 60 mg 25 1 1 1 (100.0%) 0 0 C) NTX 0.01 mg 21 1 1 1 (100.0%) 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 1 1 1 (100.0%) 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe EPISTAXIS A) PLACEBO 19 0 Treatment 0.325 0 0 0 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 1 1 1 (100.0%) 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0" 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 NECK TIGHTNESS A) PLACEBO 19 0 Treatment 0.358 0 0 0 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 1 1 1 (100.0%) 0 0 RHINITIS NOS A) PLACEBO 19 0 Treatment 0.451 0 0 0 0 B) MS 60 mg 25 1 1 1 (100.0%) 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG= 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe SKIN SUBCUTANEOUS TISSUE DISORDERS ALL EVENTS A) PLACEBO 19 0 Treatment 0.122 0 0 0 0 B) MS 60 mg 25 2 D-E 0.014* 2 2 (100.0%) 0 0 C) NTX 0.01 mg 21 1 1 0 1 (100.0%) 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 4 5 2 3 0 F) MS 60 mg/NTX 0.1 mg 22 2 2 0 1 1 (50.0%) ERYTHEMA NEC A) PLACEBO 19 0 Treatment 0.451 0 0 0 0 B) MS 60 mg 25 1 1 1 (100.0%) 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 PHOTOSENSITIVITY A) PLACEBO 19 0 Treatment 0.390 0 0 0 0 REACTION NOS B) MS60mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 1 1 1 (100.0%) 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 P-VALUES ARE FROM CHISQ TEST AND PAIRWISE COMPARISONS ONLY.

ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe PRURITUS NOS A) PLACEBO 19 0 Treatment 0.037* 0 0 0 0 B) MS60 mg 25 0 D-E 0.035* 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 3 3 0 3 (100.0%) 0 F) MS 60 mg/NTX 0.1mg 22 1 1 0 0 1 (100.0%) SWEATING A) PLACEBO 19 0 Treatment 0.801 0 0 0 0 INCREASED B) MS 60mg 25 1 1 1 (100.0%) 0 0 C) NTX 0.01 mg 21 1 1 0 1 (100.0%) 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 1 1 1 (100.0%) 0 0 F) MS 60 mg/NTX 0.1mg 22 1 1 0 1 (100.0%) 0 VASCULAR DISORDERS ALL EVENTS A) PLACEBO 19 1 Treatment 0.829 1 0 1 (100.0%) 0 B) MS 60mg 25 3 3 2 1 0 C) NTX 0.01 mg 21 1 1 1 (100.0%) 0 0 D) MS 60 mg/NTX 0.001 mg 32 4 4 3 1 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG ='SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52C (Continued) Adverse Events By Body System And Intent-To-Treat Population, Male Patients No. SEVERITY BODY SYSTEM TOTAL NO. OF P-Value of [2] ADVERSE EVENTS NO. OF PATIENTS SOURCE Events (COSTART ENGLISH) TREATMENT PATIENTS W/EVENT Mild Moderate Severe HOT FLUSHES NOS A) PLACEBO 19 0 Treatment 0.451 0 0 0 0 B) MS 60 mg 25 1 1 0 1 (100.0%) 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 0 0 0 0 0 E) MS 60 mg/NTX 0.01 mg 23 0 0 0 0 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 HYPERTENSION NOS A) PLACEBO 19 0 Treatment 0.170 0 0 0 0 B) MS 60 mg 25 0 0 0 0 0 C) NTX 0.01 mg 21 0 0 0 0 0 D) MS 60 mg/NTX 0.001 mg 32 3 3 2 1 0 E) MS 60 mg/NTX 0.01 mg 23 1 1 0 1 (100.0%) 0 F) MS 60 mg/NTX 0.1 mg 22 0 0 0 0 0 VASODILATATION A) PLACEBO 19 1 Treatment 0.979 1 0 1 (100.0%) 0 B) MS 60 mg 25 2 2 2 (100.0%) 0 0 C) NTX 0.01 mg 21 1 1 1 (100.0%) 0 0 D) MS 60 mg/NTX 0.001 mg 32 1 1 1 (100.0%) 0 0 E) MS 60 mg/NTX 0.01 mg 23 1 1 0 1 (100.0%) 0 F) MS 60 mg/NTX 0.1 mg 22 1 0 1 (100.0%) 0 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG= 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52D SELECTED ADVERSE EVENTS SAFETY POPULATION, MALE PATIENTS ADVERSE TOTAL NO. OF P-VALUE NUJMBER SEVERITY [2] EVENT NO. OF SUBJECTS OF Ml oeae Svr (ENGLISH) TREATMENT SUBJECTS WEVENT SOURCE EVENTS Ml oeae Svr

DIZZINESS

(Exc. Vertigo)

NAUSEA

A) PLACEBO B) MS 60 mg C) NTX 0.01mg D) MS 60mg/NTX0.001lmg E) MS 60 mg/NTX 0.0 1 mg F) MS 60 mgJNTX 0. 1 mg A) PLACEBO B) MS 60mrg C) NTXO0.0 1mg D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NTX 0.01 mng F) MS 60mg/NTXO0. 1mg 1 3 (12.0%) 0 9 (28.1%) 8 (34.8%) 7 (31.8%) 2 (10.5%) 10 (40.0%) 0 14 (43.8%) 6 (26.1%) 10 (45.5%) Treatment A-fl

A-E

A-F

C-fl

C-E

C-F

Treatment

A-B

A-fl

A-F

B-C

C-fl

C-E

0.008** 0.046* 0.020* 0.032* 0.007** 0.002** 0.004** 0.001* 0.029* 0.013* 0.0 14* 0.001** <0.001 0.0 11* (33.3%) (40.0%) (55.6%) (44.4%) (50.0%) (70.0%) (33.3%) (33.3%) (60.0%) 1 (100.0%) 2 (66.7%) 0 5 (50.0%) 4 (44.4%) 4 (44.4%) (10.0%) (1 1. 1- L- (50.0%) (30.0%) (46.7% (33.3%) (40.0%) 0 0 0 3 (20.0 2 (33.3', 0 P-VALUES ARE FROM CHISQ TEST ANT) ARE PRO VIIDED FOR OVERALL TREATMENT EFFECT AND SIGN IFICANT PAIRWISE COMPARISONS ONLY.

THlE DENOMINATOR FOR THlE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUTDY DRUG: RELATIONSHIP~ TO STUJDY DRUG 'SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 52D (Continued) SELECTED ADVERSE EVENTS SAFETY POPULATION, MALE PATIENTS ADVERSE TOTAL NO. OF P-VALUE NUMBER SEVERITY [2] EVENT NO. OF SUB3JECTS [Ii] OF (ENGLISH) TREATMENT SUBJECTS W/E VENT SOURCE EVE NTS Mild Moderate severe SOMNOLENCE A) PLACEBO B) MS 60 mg C) NTX 0.01 mg D) MS 60 mgINTX 0.001 mg E) MS 60mg/NTXO0.0 1mg F) MS 60mgfNTX 0. 1mg Treatment 0.209 C-F 0.040*(2.% (12.0%) (15.6%) (13.0%) (18.2%) (66.7%) (33.3%) (25.0%) (75.0%) (33.3%) (66.7%) (75.0%) VOMITING A) PLACEBO NOS B) MS 60 mg C) NTX0.01lmg D) MS 60 mg/NTX 0.001 mg E) MS 60 mg/NTX 0.0 1 mg F) MS 60 mg/NTX 0.1 mg 1 9 (36.0%) 0 12 (37.5%) 8 (34.8%) 11 (50.0%) Treatment

A-B

A-D

A-E

A-F

B-C

<0.001*** 0.015* 0.010* 0.020* 0.001** 0,002** 3 (33.3%) 0 2 (15.4%) 1 1 0 2 (22.2%) 0 6 (46.2%) 2 (18.2%) 1 1 (100.0 4 (44.4 0 5 (38.5 8 (72.7 10 (83.3 P-VALUES ARE FROM CHISQ TEST AND ARE PROVIDED FOR OVERALL TREATMENT EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ONLY.

THE DENOMINATOR FOR THE PERCENTAGES IS THE TOTAL NUMBER OF EVENTS.

NOTE: ADVERSE EVENTS RELATED TO STUDY DRUG: RELATIONSHIP TO STUDY DRUG ='SUSPECT' OR 'PROBABLE'.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

WO 01/85150 PCT/US01/14644 467 EXAMPLE An additional clinical study, this one using hydrocodone with acetaminophen (instead of morphine) alone and in combination with naltrexone, was designed substantially the same as that described in Example 3, with the following differences: six treatment groups with four different doses of NTX (1.0 mg, 0.1 mg, 0.01 mg and 0.001 mg) in combination with hydrocodone 5 mg/acetaminophen 500 mg versus hydrocodone 5 mg/acetaminophen 500 mg (HC/APAP) alone, and versus placebo alone in subjects with moderate to severe pain in a postsurgical dental pain clinical study; the primary efficacy variable was the categorical sum of pain intensity difference scores through 4 hours (SPID-4); and the secondary efficacy variables were: 4, 6 and 8 hour total pain relief scores (TOTPAR-4, TOTPAR-6 and TOTPARcategorical 6 and 8 hour sum of pain intensity difference scores (SPID-6 and SPID-8); categorical pain intensity difference (PID) scores through 8 hours; pain relief (PR) scores through 8 hours; peak categorical PID scores through 8 hours (PEAKPID); peak pain relief score through 8 hours (TOTPAR); time to onset of analgesia at least a one category improvement in the pain intensity score); time to onset of meaningful pain relief; time to taking backup medication; percent of patients taking backup medication; and patient overall evaluation of study drug.

A total of 300 subjects were randomized; all 300 subjects were deemed evaluable (Table 53).

Table 53 Patients Enrollment and Evaluability

TREATMENTS____

Placebo HC/APAP W/NTX 1 mg W/NTX W/NTX W/NTX TOTAL 0.1 mg 0.01 mg 0.001 mg Number of Patients 50 50 50 50 50 50 300 PaietsInlde i te 50 (100%) 50 (100%) 50 50 (100%) 50 (100%) 50(100%) 300 (100%) Safety Analyses Patients Excluded from the Safety Analyses (100%) 50 (100%) 50 (100%) 50 (100%) 50 (100%) 50 (100%) 300 (100%) Patients Included in the Efficacy Analyses Patients Excluded from the Efficacy []P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE ANDT ITS CONTRASTS WITH TREATMENT, SITE, AN\D TREATMENT BY SITE INTERACTION AS FACTORS.

****P-VALUE 0.05, 0.01, or =0.001 RESPECTIVELY.

WO 01/85150 PCT/US01/14644 469 The demographic and baseline characteristics were summarized by treatment groups for all 300 randomized patients which were all evaluable (Table 54).

Demographic characteristics included age, race/ethnicity, sex, weight, height, medical history, teeth extracted (impacted and non-impacted), baseline pain intensity, and baseline visual analog scale.

Subjects ranged in age from 16 to 53 years; 79.0% were Caucasian and 63.0% were female. No adjustments in the analyses were made to take into account differences among treatment groups. These differences had little or no influence on pain assessments at baseline. The baseline pain intensity scores and visual analog scale scores were generally comparable across treatment groups (Tables 55A and Table 54 Baseline Characteristics Safety Patients Placebo HC/APAP WINTX W/NTX W/NTX 0.01 W/NTX TOTAL P 1 nig 0.1 mg Ig 0.001 mg Value Number of Patients 50 50 50 50 50 50 300 Gender Female 28 34 31 35 31 30 189 .716B Male 22 16 19 (38% 15 19 20 111 (37%) Age N 50 50 50 50 50 50 300 0.199a (yrs) Mean 23.9 21.6 22.5 23.1 21.1 21.5 22.3 SD 7.8 4.5 6.0 7.2 4.4 6.8 6.3 Median 22.0 20.0 20.5 21.5 20.0 19.0 20.0 Range 16to46 16to35 16to41 16to 53 16to35 16to48 16 to 53 Height N 50 50 50 50 50 50 300 0.823a (in) Mean 67.2 66.9 67.0 66.4 66.9 67.6 67.0 SD 4.4 3.7 3.9 4.2 4.3 4.2 4.1 Median 66.5 66.0 66.0 66.0 66.3 67.0 66.0 Range 60 to 76 61 to 75 61 to 78 61 to 79 61 to 77 61 to 79 60 to 79 Weight N 50 50 50 50 50 50 300 0.955a (lbs) Mean 159.4 152.5 156.4 154.9 155.3 156.3 155.8 SD 40.5 32.9 29.5 36.4 24.9 37.3 33.8 Median 155.5 149.5 154.5 144.5 155.5 150.0 150.5 Range 61 to 256 104 to 271 101 to 239 105 to 284 98 to 218 105 to 244 61 to 284 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTIONS AS FACTORS.

P-VALUE 0.05, 0.01, OR 0.001 RESPECTIVELY Table 54 (Continued) Baseline Characteristics Safety Patients Placebo HCAA W/NTX W/NTX W/NTX 0.01 W/NTX TOTAL- Placebo HC/APAP

TOTAL

1 mg 0.1 mg mg 0.001 mg Value Ethnic Caucasian 34 40 42 42 38 41 237(79%) 0.362 b Origin Hispanic 14 4 5 7 10 5 45 Black 1 3 2 0 0 3 9 3%) Asian 0 2 1 0 0 0 3 Caucasian/Hispanic 0 0 0 1 0 0 1 German/Arabic 0 0 0 0 1 0 1 Lebanese 0 1 0 0 0 0 1 Mexican/Korean 0 0 0 0 1 0 1 Moroccan 1 0 0 0 0 0 1 Mullato 0 0 0 0 0 1 1 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTIONS AS FACTORS.

P-VALUE 0.05, 0.01, OR 0.001 RESPECTIVELY Table Summary of Baseline Pain Intensity Scores (Safety Patients) PAIN INTENSITY P-Value TREATMENT MODERATE SEVERE A) Placebo 34 16 1.000 b HC/APAP 34 16 (32%) C) W/NTX 1 mg 34 16 (32%) D) W/NTX 0.1 mg 35 15 E) W/NTX 0.01 mg 34 16 (32%) F) W/NTX 0.001 mg 34 16 (32%) TOTAL 205 95 (32%) P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table Summary of Baseline Visual Analog Scale (VAS) Scores (Safety Patients) BASELINE VAS SCORE (0-100 mm Scale) TREATMENT N MEAN SD MEDIAN RANGE P-Value A) Placebo 50 61.0 9.9 59.0 47 to 94 0.866 a B) HC/APAP 50 62.2 11.6 60.0 47 to 92 C) W/NTX 1 mg 50 61.0 8.5 60.0 47 to 83 D) W/NTX 0.1 mg 50 62.3 11.6 60.0 47 to 100 E) W/NTX 0.01 mg 50 63.3 9.4 60.0 48 to 89 F) W/NTX 0.001 mg 50 62.6 10.4 60.0 47 to 87 TOTAL 300 62.1 10.2 60.0 47 to 100 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

WO 01/85150 PCT/US01/14644 474 The TOTPAR results (4 hour, 6 hour, 8 hour) are summarized in Table 56 and the 4 hour TOTPAR scores are shown in Figure 30. The placebo treatment group had the lowest mean TOTPAR scores. All 5 of the active treatment groups with HC/APAP alone or in combination with NTX exhibited mean TOTPAR scores that were numerically higher than placebo. The mean TOTPAR score for the 0.001 mg NTX combination treatment was higher than that for the HC/APAP alone treatment, whereas the other NTX combination treatment means were comparable to or lower than that for the HC/APAP alone treatment (Figure Table 56 Efficacy Results Means and Standard Deviations for TOTPARs (Trapezoidal Method) (Safety Patients) TOTAL PAIN RELIEF SCORES P-Value TREATMENT N I MEAN SD SOURCE [1] TOTAL PAIN RELIEF SCORES (4 HOURS) A) Placebo 50 1.83 2.54 TRT <0.001 B) HC/APAP 50 4.29 3.99 A-B <0.001 C) W/NTX 1 mg 49 4.04 3.82 A-C 0.003 D) W/NTX 0.1 mg 50 4.29 3.47 A-D <0.001 E) W/NTX 0.01 mg 50 3.47 3.64 A-E 0.025 F) W/NTX 0.001 mg 50 5.25 4.15 A-F <0.001 B-C 0.736 B-D 0.994 B-E 0.259 B-F 0.188 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 56 (Continued) Efficacy Results Means and Standard Deviations for TOTPARs (Trapezoidal Method) (Safety Patients) TOTAL PAIN RELIEF SCORES P-Value TREATMENT N MEAN SD SOURCE [1] TOTAL PAIN RELIEF SCORES (6 HOURS) A) Placebo 50 2.02 3.32 TRT 0.001 B) HC/APAP 50 5.21 5.70 A-B 0.001 C) W/NTX 1 mg 49 4.51 4.79 A-C 0.012 D) W/NTX 0.1 mg 50 4.77 4.47 A-D 0.005 E) W/NTX 0.01 mg 50 3.96 4.76 A-E 0.050 F) W/NTX 0.001 mg 50 6.19 6.01 A-F <0.001 B-C 0.480 B-D 0.659 B-E 0.204 B-F 0.320 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

Table 56 (Continued) Efficacy Results Means and Standard Deviations for TOTPARs (Trapezoidal Method) (Safety Patients) TOTAL PAIN RELIEF SCORES P-Value TREATMENT I N I MEAN SD SOURCE [1] TOTAL PAIN RELIEF SCORES (8 HOURS) A) Placebo 50 2.17 4.14 TRT 0.002 B) HC/APAP 50 5.48 6.25 A-B 0.004 C) W/NTX 1 mg 49 4.68 5.38 A-C 0.027 D) W/NTX 0.1 mg 50 5.01 5.20 A-D 0.012 E) W/NTX 0.01 mg 49 3.74 4.58 A-E 0.164 F) W/NTX 0.001 mg 50 6.77 7.53 A-F <0.001 B-C 0.482 B-D 0.680 B-E 0.126 B-F 0.253 P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE AND ITS CONTRASTS WITH TREATMENT, SITE, AND TREATMENT BY SITE INTERACTION AS FACTORS.

P-VALUE 0.05, 0.01, or 0.001 RESPECTIVELY.

WO 01/85150 PCT/US01/14644 478 Table 57 summarizes the results of the 4, 6, and 8 hour SPID results (Figure 31). The 4 hour results are also represented in Figure 38A. The placebo treatment group had the lowest mean 4 hour SPID scores. All 5 of the active treatment groups with HC/APAP alone or in combination with NTX exhibited improved profiles in mean SPID relative to placebo. The mean 4 hour SPID score for the 0.001 mg NTX combination treatment was higher than that for the HC/APAP alone treatment, whereas the other NTX combination treatments were comparable to or lower than that for the HC/APAP alone treatment (Figure 31 or 38A).

The patterns of the 6 hour and 8 hour SPID scores were similar to those at 4 hours.

Table 57 Efficacy Results Means and Standard Deviations for the SPIDS (Safety Patients) Summary of Pin Intensity Differences (SPIDS) CATEGORICAL SPID SCORES P-Value TREATMENT N MEAN SD SOURCE [1] CATEGORICAL SPID SCORES (4 HOURS) A) Placebo 50 -0.22 2.51 TRT 0.001 B) HC/APAP 50 1.55 2.42 A-B <0.001 C) W/NTX 1 mg 49 1.13 2.69 A-C 0.008 D) W/NTX 0.1 mg 50 1.46 2.07 A-D <0.001 E) W/NTX 0.01 mg 50 1.15 2.33 A-E 0.007 F) W/NTX 0.001 mg 50 1.87 2.89 A-F <0.001 B-C 0.406 B-D 0.852 B-E 0.422 B-F 0.529 MEANS GIVEN ARE LEAST SQUARE MEANS.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 57 (Continued) Efficacy Results Means and Standard Deviations for the SPIDS (Safety Patients) Summary of Pin Intensity Differences (SPIDS) CATEGORICAL SPID SCORES P-Value TREATMENT N IMEAN SD SOURCE [1] CATEGORICAL SPID SCORES (6 HOURS) A) Placebo 50 -0.79 3.68 TRT 0.001 B) HC/APAP 50 1.80 3.43 A-B <0.001 C) W/NTX 1 mg 49 0.81 3.53 A-C 0.025 D) W/NTX 0.1 mg 50 1.47 2.84 A-D 0.001 E) W/NTX 0.01 mg 50 1.19 3.34 A-E 0.005 F) W/NTX 0.001 mg 50 1.98 4.17 A-F <0.001 B-C 0.164 B-D 0.643 B-E 0.386 B-F 0.804 MEANS GIVEN ARE LEAST SQUARE MEANS.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 57 (Continued) Efficacy Results Means and Standard Deviations for the SPIDS (Safety Patients) Summary of Pin Intensity Differences (SPIDS) CATEGORICAL SPID SCORES P-Value TREATMENT N MEAN SD SOURCE [1] CATEGORICAL SPID SCORES (8 HOURS) A) Placebo 50 -1.36 4.92 TRT 0.002 B) HC/APAP 50 1.73 3.92 A-B <0.001 C) W/NTX 1 mg 49 0.38 4.34 A-C 0.045 D) W/NTX 0.1 mg 50 1.38 3.55 A-D 0.002 E) W/NTX 0.01 mg 49 0.74 3.40 A-E 0.016 F) W/NTX 0.001 mg 50 1.91 5.27 A-F <0.001 B-C 0.119 B-D 0.683 B-E 0.250 B-F 0.839 MEANS GIVEN ARE LEAST SQUARE MEANS.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

WO 01/85150 PCT/US01/14644 482 Figure 32 is a visual presentation of the summary and analysis of time to onset of meaningful pain relief presented in Table 58A. The median time to onset of meaningful pain relief was shortest in the 0.001 mg NTX (lowest-dose) combination treatment group. The placebo and the 0.01 mg NTX combination treatment groups had the lowest number of subjects who reached meaningful pain relief.

Figure 33 is a visual presentation of the summary and analysis of time to onset of analgesia presented in Table 58B. The median time to onset of analgesia was shortest in the 0.001 mg NTX and 0.1 mg NTX combination treatment groups. The placebo treatment group had the lower number of subjects who reached analgesia.

Table 58A Efficacy Results Results of Time to Onset of Relief (Safety Patients) TIME TO ONSET OF RELIEF (hours) TREATMENT NUMBER OF MEDIAN 95% INTERVAL PATIENTS TIME P-Value P-Value (hh:mm) (hmm(h P-Value vs. vs.

LOWER UPPER Placebo HC/APAP LIMIT LIMIT A) Placebo 50 >8.0 2.1 >8.0 0.008 B) HC/APAP 50 2.0 0.8 >8.0 0.230 C) W/NTX 1 mg 50 >8.0 0.8 >8.0 0.347 0.891 D) W/NTX 0.1 mg 50 0.8 0.6 >8.0 .0.019 0.199 E) W/NTX 0.01 mg 50 >8.0 8.0 >8.0 0.619 0.087 F) W/NTX 0.001 mg 50 0.8 0.5 1.9 0.010 0.122 TOTAL 300 >8.0 1.1 P-VALUES FOR TIME TO EVENT ARE FROM THE LOG RANK TEST.

P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM THE LIKELIHOOD -RATIO CHI-SQUARE TEST.

Table 58B Efficacy Results Results of Analgesia (Safety Patients) TIME TO ONSET OF ANALGESIA (hours) TREATMENT NUMBER OF MEDIAN 95% INTERVAL PATIENTS TIME P-Value P-Value (lh:mm) (bh:mm) -P-Value vs. vs.

(hh:m) LOWER UPPER Placebo HC/APAP LIMIT LIMIT A) Placebo 50 0.8 0.5 >8.0 0.058 B) HC/APAP 50 0.8 0.5 1.0 0.178 C) W/NTX 1 mg 50 0.8 0.5 0.8 0.311 0.830 D) WINTX 0.1 mg 50 0.5 0.5 0.8 0.088 0.618 E) W/NTX 0.01 mg 50 1.0 0.8 >8.0 0.818 0.216 F) W/NTX 0.001 mg 50 0.5 0.5 0.8 0.012 0.145 TOTAL 300 0.8 0.5 0.8 P-VALUES FOR TIME TO EVENT ARE FROM THE LOG RANK TEST.

P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM THE LIKELIHOOD RATIO CHI-SQUARE TEST.

WO 01/85150 PCT/US01/14644 485 Table 59 summarizes the results of the time to remedication (see also Figure 34). The placebo and the 1.0 mg NTX combination treatment groups had the shortest median time to remedication and the 0.1 mg NTX and the 0.001 NTX combination treatment groups had the longest median time to remedication.

Table 60 summarizes the results of the percent of patients remedicating. The percentage of patients remedicating was comparable across all treatment groups, except that the 0.001 mg NTX combination group had a lower percentage of patients remedicating.

Table 59 Efficacy Results Time to Rescue Medication (Safety Patients) TIME TO REMEDICATION (hours) TREATMENT NUMBER MEDIAN 95% INTERVAL P-Value P-Value P-Value OF TIME (hh:mm) vs. vs.

PATIENTS (hh:mm) LOWER UPPER Placebo HC/APAP LIMIT LIMIT A) Placebo 50 1.6 1.6 1.6 <0.001 B) HC/APAP 50 1.9 1.6 2.7 <0.001 C) W/NTX 1 mg 50 1.6 1.6 2.4 0.008 0.346 D) W/NTX 0.1 mg 50 2.2 1.9 2.9 <0.001 0.749 E) W/NTX 0.01 mg 50 1.7 1.6 2.1 0.017 0.208 F) W/NTX 0.001 mg 50 2.2 2.0 3.1 <0.001 0.587 TOTAL 300 1.8 1.6 2.1 NOTE: MEDIAN TIME AND ITS CONFIDENCE INTERVAL ARE ESTIMATED USING KAPLAN-MEIER METHOD. LOG-RANK AND WILCOXON TESTS ARE USED TO TEST THE EQUALITY OF KAPLAN-MEIER SURVIVAL FUNCTIONS OVER DIFFERENT TREATMENT GROUPS.

Table Efficacy Results Percent of Patients Remedicating (Safety Patients) PATIENTS REMEDICATING TREATMENT YES NO P-Value P-Value P-VALUE vs. vs.

Placebo HC/APAP A) Placebo 49 1 0.699 B) HC/APAP 49 1 1.000 C) W/NTX 1 mg 48 2 1.000 1.000 D) W/NTX 0.1 mg 48 2 1.000 1.000 E) W/NTX 0.01 mg 49 1 1.000 1.000 F) W/NTX 0.001 mg 46 4 0.362 0.362 TOTAL 289 11 P-VALUES FOR TIME TO EVENT ARE FROM THE LOG RANK TEST.

P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM THE LIKELIHOOD RATIO CHI-SQUARE TEST.

WO 01/85150 PCT/US01/14644 488 Figure 35 is a visual presentation of the mean pain relief scores presented in Table 61. The mean pain relief score for the placebo treatment group was less than those for the active treatment groups (HC/APAP alone or in combination with NTX).

There was separation between placebo and the active treatment groups from 1 hour to 5 hours of the 8 hour study period. Highest pain relief scores were observed for the 0.001 mg NTX combination group (Figure Table 61 Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) PAIN RELIEF SCORE (PR) TREATMENT N MEAN SD SOURCE P-VALUE

MINUTES

A) Placebo 50 0.64 0.88 TRT 0.214 B) HC/APAP 50 0.42 0.64 A-B 0.174 C) W/NTX 1 50 0.58 0.88 A-C 0.711 D) W/NTX0.1 50 0.70 1.04 A-D 0.711 E) W/NTX 0.01 50 0.34 0.59 A-E 0.064 F) W/NTX 0.001 50 0.58 0.73 A-F 0.711 B-C 0.323 B-D 0.084 B-E 0.621 B-F 0.323 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0=NONE, 1=A LITTLE, 2-SOME, 3=A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 61 (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) PAIN RELIEF SCORE (PR) TREATMENT N MEAN SD SOURCE P-VALUE

MINUTES

A) Placebo 50 0.84 1.04 TRT 0.001 B) HC/APAP 50 1.05 1.07 A-B 0.337 C) W/NTX 1 50 1.38 1.19 A-C 0.016 D) W/NTX 0.1 50 1.34 1.12 A-D 0.024 E) W/NTX 0.01 50 0.88 1.10 A-E 0.857 F) W/NTX 0.001 50 1.66 1.14 A-F <0.001 B-C 0.143 B-D 0.194 B-E 0.435 B-F 0.007 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0=NONE, 1=A LITTLE, 2=SOME, 3=A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 61 (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) PAIN RELIEF SCORE (PR) TREATMENT N MEAN SD SOURCE P-VALUE

MINUTES

A) Placebo 50 0.92 1.01 TRT <0.001 B) HC/APAP 50 1.52 1.11 A-B 0.007 C) W/NTX 1 50 1.71 1.14 A-C <0.001 D) W/NTX 0.1 50 1.84 1.18 A-D <0.001 E) W/NTX 0.01 50 1.32 1.00 A-E 0.069 F) W/NTX 0.001 50 1.95 1.13 A-F <0.001 B-C 0.381 B-D 0.148 B-E 0.363 B-F 0.053 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0=NONE, 1=A LITTLE, 2=SOME, 3=A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 61 (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) PAIN RELIEF SCORE (PR) TREATMENT N MEAN SD SOURCE P-VALUE 1 HOUR A) 'Placebo 50 0.92 1.14 TRT <0.001 B) HC/APAP 50 1.69 1.06 A-B 0.002 C) W/NTX 1 50 1.72 1.29 A-C 0.001 D) W/NTX 0.1 50 1.96 1.27 A-D <0.001 E) W/NTX 0.01 50 1.59 1.29 A-E 0.006 F) W/NTX 0.001 50 2.18 1.22 A-F <0.001 B-C 0.913 B-D 0.276 B-E 0.671 B-F 0.046 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0=NONE, 1=A LITTLE, 2=SOME, 3=A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 61 (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) PAIN RELIEF SCORE (PR) TREATMENT N MEAN SD SOURCE P-VALUE

HOURS

A) Placebo 50 0.70 0.95 TRT <0.001 B) HC/APAP 50 1.62 1.29 A-B <0.001 C) W/NTX 1 50 1.52 1.40 A-C 0.001 D) W/NTX 0.1 50 1.64 1.27 A-D <0.001 E) W/NTX 0.01 50 1.58 1.31 A-E <0.001 F) W/NTX 0.001 50 2.08 1.29 A-F <0.001 B-C 0.692 B-D 0.937 B-E 0.874 B-F 0.069 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0=NONE, 1=A LITTLE, 2=SOME, 3=A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 61 (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) PAIN RELIEF SCORE (PR) TREATMENT N MEAN SD SOURCE P-VALUE 2 HOURS A) Placebo 50 0.32 0.91 TRT <0.001 B) HC/APAP 50 1.30 1.50 A-B <0.001 C) W/NTX 1 50 1.19 1.52 A-C 0.002 D) W/NTX 0.1 50 1.28 1.37 A-D <0.001 E) W/NTX 0.01 50 0.94 1.35 A-E 0.024 F) W/NTX 0.001 50 1.50 1.45 A-F <0.001 B-C 0.699 B-D 0.942 B-E 0.188 B-F 0.464 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0=NONE, 1=A LITTLE, 2=SOME, 3=A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 61 (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) PAIN RELIEF SCORE (PR) TREATMENT N MEAN SD SOURCE P-VALUE 3 HOURS A) Placebo 50 0.22 0.79 TRT 0.076 B) HC/APAP 50 0.80 1.28 A-B 0.013 C) W/NTX 1 50 0.70 1.23 A-C 0.039 D) W/NTX 0.1 50 0.65 1.08 A-D 0.066 E) W/NTX 0.01 50 0.54 1.13 A-E 0.170 F) W/NTX 0.001 50 0.88 1.38 A-F 0.005 B-C 0.678 B-D 0.517 B-E 0.265 B-F 0.731 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0=NONE, 1=A LITTLE, 2=SOME, 3=A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 61 (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) PAIN RELIEF SCORE (PR) TREATMENT N MEAN SD SOURCE P-VALUE 4 HOURS A) Placebo 50 0.14 0.70 TRT 0.098 B) HC/APAP 50 0.64 1.24 A-B 0.018 C) W/NTX 1 49 0.36 0.97 A-C 0.291 D) W/NTX 0.1 50 0.32 0.91 A-D 0.393 E) W/NTX 0.01 50 0.40 0.99 A-E 0.217 F) W/NTX 0.001 50 0.68 1.36 A-F 0.011 B-C 0.193 B-D 0.129 B-E 0.255 B-F 0.849 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0=NONE, 1=A LITTLE, 2=SOME, 3=A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 61 (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) PAIN RELIEF SCORE (PR) TREATMENT N MEAN SD SOURCE P-VALUE

HOURS

A) Placebo 50 0.08 0.44 TRT 0.253 B) HC/APAP 50 0.44 1.07 A-B 0.040 C) W/NTX 1 49 0.20 0.76 A-C 0.479.

D) W/NTX 0.1 50 0.26 0.80 A-D 0.303 E) W/NTX 0.01 50 0.22 0.82 A-E 0.422 F) W/NTX 0.001 50 0.44 1.15 A-F 0.040 B-C 0.179 B-D 0.303 B-E 0.208 B-F 1.000 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0=NONE, 1=A LITTLE, 2=SOME, 3=A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 61 (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) PAIN RELIEF SCORE (PR) TREATMENT N MEAN SD SOURCE P-VALUE 6 HOURS A) Placebo 50 0.08 0.57 TRT 0.445 B) HC/APAP 50 0.32 0.89 A-B 0.111 C) W/NTX 1 49 0.16 0.72 A-C 0.582 D) W/NTX 0.1 50 0.12 0.59 A-D 0.790 E) W/NTX 0.01 50 0.14 0.64 A-E 0.690 F) W/NTX 0.001 50 0.32 1.00 A-F 0.111 B-C 0.300 B-D 0.184 B-E 0.232 B-F 1.000 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0=NONE, l=A LITTLE, 2=SOME, 3=A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 61 (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) PAIN RELIEF SCORE (PR) TREATMENT N MEAN SD SOURCE P-VALUE 7 HOURS A) Placebo 50 0.08 0.57 TRT 0.492 B) HC/APAP 50 0.08 0.40 A-B 1.000 C) W/NTX 1 49 0.06 0.43 A-C 0.878 D) W/NTX 0.1 50 0.12 0.59 A-D 0.742 E) W/NTX 0.01 50 0.10 0.51 A-E 0.869 F) W/NTX 0.001 50 0.28 0.97 A-F 0.101 B-C 0.878 B-D 0.742 B-E 0.869 B-F 0.101 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0=NONE, 1=A LITTLE, 2=SOME, 3=A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 61 (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) PAIN RELIEF SCORE (PR) TREATMENT N MEAN SD SOURCE P-VALUE 8 HOURS A) Placebo 50 0.06 0.42 TRT 0.179 B) HC/APAP 50 0.06 0.42 A-B 1.000 C) W/NTX 1 49 0.06 0.43 A-C 0.991 D) W/NTX 0.1 50 0.12 0.59 A-D 0.589 E) W/NTX 0.01 49 0.00 0.00 A-E 0.591 F) W/NTX 0.001 50 0.28 0.97 A-F 0.048 B-C 0.991 B-D 0.589 B-E 0.591 B-F 0.048 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0=NONE, I=A LITTLE, 2=SOME, 3=A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

WO 01/85150 PCT/US01/14644 501 The mean categorical pain intensity difference (PID) scores are presented in Table 62 and Figure 36. The mean PID scores for placebo treatment groups decreased over the first 2 hours and then were generally flat, while the mean PID scores first increase, then decreased over time for the active treatment groups (HC/APAP alone or in combination with NTX). The hourly mean scores for the HC/APAP alone and the HC/APAP NTX combination treatment groups were higher than the mean PID scores for the placebo group at each hourly assessment time from 1-8 hours. Highest pain relief as measured by mean PID scores was observed for the 0.001 NTX combination treatment group.

Table 62 .Efficacy Results Means and Standard Deviations for the (Safety Patients) Categorical PID Scores CATEGORICAL PID SCORES P-Value TREATMENT N [MEAN SD SOURCE

MINUTES

A) Placebo 50 0.21 0.61 TRT 0.542 B) HC/APAP 50 0.06 0.55 A-B 0.187 C) W/NTX 1 mg 50 0.06 0.51 A-C 0.187 D) W/NTX 0.1 mg 50 0.20 0.57 A-D 0.930 E) W/NTX 0.01 mg 50 0.06 0.51 A-E 0.187 F) W/NTX 0.001 mg 50 0.15 0.64 A-F 0.597 B-C 1.000 B-D 0.218 B-E 1.000 B-F 0.428 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Efficacy Results Table 62 (Continued) Means and Standard Deviations for the Categorical PID Scores (Safety Patients) CATEGORICAL PID SCORES P-Value TREATMENT N MEAN SD SOURCE

MINUTES

A) Placebo 50 0.32 0.74 TRT 0.208 B) HC/APAP 50 0.44 0.79 A-B 0.420 C) W/NTX 1 mg 50 0.48 0.81 A-C 0.283 D) W/NTX 0.1 mg 50 0.57 0.64 A-D 0.089 W/NTX 0.01 mg 50 0.34 0.63 A-E 0.893 F) W/NTX 0.001 mg 50 0.64 0.83 A-F 0.032 B-C 0.788 B-D 0.370 B-E 0.502 B-F 0.180 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 62 (Continued) Efficacy Results Means and Standard Deviations for the (Safety Patients) Categorical PID Scores CATEGORICAL PID SCORES P-Value TREATMENT N MEAN SD SOURCE

MINUTES

A) Placebo 50 0.22 0.86 TRT 0.003 B) HC/APAP 50 0.58 0.76 A-B 0.023 C) W/NTX 1 mg 50 0.72 0.81 A-C 0.002 D) W/NTX 0.1 mg 50 0.76 0.77 A-D <0.001 E) W/NTX 0.01 mg 50 0.50 0.68 A-E 0.077 F) W/NTX 0.001 mg 50 0.78 0.84 A-F <0.001 B-C 0.376 B-D 0.255 B-E 0.613 B-F 0.206 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 62 (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) CATEGORICAL PID SCORES P-Value TREATMENT N MEAN SD SOURCE 1 HOUR A) Placebo 50 0.17 0.99 TRT <0.001 B) HC/APAP 50 0.69 0.76 A-B 0.003 C) W/NTX 1 mg 50 0.69 0.90 A-C 0.003 D) W/NTX 0.1 mg 50 0.80 0.78 A-D <0.001 E) W/NTX 0.01 mg 50 0.65 0.80 A-E 0.006 F) W/NTX 0.001 mg 50 0.98 0.94 A-F <0.001 B-C 0.966 B-D 0.538 B-E 0.803 B-F 0.099 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 62 (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) CATEGORICAL PID SCORES P-Value TREATMENT N IMEAN SD SOURCE

HOURS

A) Placebo 50 0.04 0.81 TRT <0.001 B) HC/APAP 50 0.62 0.83 A-B <0.001 C) W/NTX 1 mg 50 0.56 0.97 A-C 0.003 D) W/NTX 0.1 mg 50 0.64 0.78 A-D <0.001 E) W/NTX 0.01 mg 50 0,52 0.81 A-E 0.005 F) W/NTX 0.001 mg 50 0.86 0.93 A-F <0.001 B-C 0.727 B-D 0.907 B-E 0.560 B-F 0.163 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 62 (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) CATEGORICAL PID SCORES P-Value TREATMENT N MEAN SD SOURCE 2 HOURS A) Placebo 50 -0.18 0.77 TRT <0.001 B) HC/APAP 50 0.48 0.86 A-B <0.001 C) W/NTX 1 mg 50 0.35 1.01 A-C 0.002 D) W/NTX 0.1 mg 50 0.43 0.79 A-D <0.001 E) W/NTX 0.01 mg 50 0.32 0.77 A-E 0.004 F) W/NTX 0.001 mg 50 0.50 0.95 A-F <0.001 B-C 0.468 B-D 0.787 B-E 0.356 B-F 0.908 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 62 (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) CATEGORICAL PID SCORES P-Value TREATMENT N MEAN SD SOURCE 3 HOURS A) Placebo 50 -0.22 0.74 TRT 0.035 B) HC/APAP 50 0.24 0.72 A-B 0.003 C) W/NTX 1 mg 50 0.06 0.86 A-C 0.062 D) W/NTX 0.1 mg 50 0.10 0.59 A-D 0.034 E) W/NTX 0.01 mg 50 0.14 0.73 A-E 0.018 F) W/NTX 0.001 mg 50 0.22 0.86 A-F 0.004 B-C 0.242 B-D 0.363 B-E 0.508 B-F 0.895 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 62 (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) CATEGORICAL PID SCORES P-Value TREATMENT N MEAN SD SOURCE 4 HOURS A) Placebo 50 -0.26 0.69 TRT 0.008 B) HC/APAP 50 0.22 0.71 A-B <0.001 C) W/NTX 1 mg 49 -0.09 0.68 A-C 0.227 D) W/NTX 0.1 mg 50 0.05 0.55 A-D 0.025 E) W/NTX 0.01 mg 50 0.08 0.67 A-E 0.015 F) W/NTX 0.001 mg 50 0.16 0.84 A-F 0.003 B-C 0.027 B-D 0.231 B-E 0.315 B-F 0.666 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 62 (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) CATEGORICAL PID SCORES P-Value TREATMENT N MEAN SD SOURCE

HOURS

A) Placebo 50 -0.30 0.58 TRT 0.006 B) HC/APAP 50 0.12 0.63 A-B <0.001 C) W/NTX 1 mg 49 -0.18 0.57 A-C 0.344 D) W/NTX 0.1 mg 50 0.01 0.48 A-D 0.011 E) W/NTX 0.01 mg 50 0.02 0.65 A-E 0.009 F) W/NTX 0.001 mg 50 0.04 0.73 A-F 0.006 B-C 0.014 B-D 0.382 B-E 0.413 B-F 0.513 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 62 (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) CATEGORICAL PID SCORES P-Value TREATMENT N MEAN SD SOURCE 6 HOURS A) Placebo 50 -0.28 0.67 TRT 0.064 B) HC/APAP 50 0.04 0.49 A-B 0.006 C) W/NTX 1 mg 49 -0.18 0.57 A-C 0.409 D) W/NTX 0.1 mg 50 -0.05 0.45 A-D 0.045 E) W/NTX 0.01 mg 50 -0.04 0.57 A-E 0.039 F) W/NTX 0.001 mg 50 -0.02 0.68 A-F 0.026 B-C 0.056 B-D 0.454 B-E 0.490 B-F 0.605 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 62 (Continued) Efficacy Results -Means and Standard Deviations for the Categorical PID Scores (Safety Patients) CATEGORICAL PID SCORES P-Value TREATMENT N IMEAN SD SOURCE 7 HOURS A) Placebo 50 -0.28 0.67 TRT 0.063 B) HC/APAP 50 -0.06 0.31 A-B 0.032 C) W/NTX 1 mg 49 -0.22 0.47 A-C 0.589 D) W/NTX 0.1 mg 50 -0.05 0.45 A-D 0.023 E) W/NTX 0.01 mg 50 -0.06 0.47 A-E 0.032 F) W/NTX 0.001 mg 50 -0.04 0.60 A-F 0.019 B-C 0.110 B-D 0.898 B-E 1.000 0.845 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 62 (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) CATEGORICAL PID SCORES P-Value TREATMENT N MEAN SD SOURCE 8 HOURS A) Placebo 50 -0.30 0.58 TRT 0.026 B) HC/APAP 50 -0.06 0.31 A-B 0.012 C) W/NTX 1 mg 49 -0.22 0.47 A-C 0.427 D) W/NTX 0.1 mg 50 -0.05 0.45 A-D 0.008 E) 'W/NTX 0.01 mg 49 -0.12 0.33 A-E 0.062 F) W/NTX 0.001 mg 50 -0.04 0.60 A-F 0.006 B-C 0.084 B-D 0.890 B-E 0.511 B-F 0.832 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

WO 01/85150 PCT/US01/14644 514 Tables 63A and 63B present the mean peak (maximum) pain relief (MAXPAR) and mean peak pain intensity difference (PEAKPID) scores, respectively. The mean MAXPAR scores presented in Table 63A varied among treatment groups. The mean MAXPAR score was highest for the 0.001 mg NTX combination treatment group compared to all other groups. The mean scores for the other NTX combination treatment groups were generally comparable to the mean score for the HC/APAP alone treatment. group, which in turn, was greater than the mean score for the placebo group. The mean PEAKPID scores presented in Table 63B varied among treatment groups, and were greater for the HC/APAP alone or HC/APAP NTX combination treatment groups compared to the placebo group.

Compared to all other groups, the mean PEAKPID scores were highest for the 0.001 mg NTX combination treatment group.

Table 63A Efficacy Results Means and Standard Deviations for the MAXPAR (Safety Patients) MAXIMUM PAIN RELIEF (MAXPAR) P-Value TREATMENT N MEAN SD SOURCE A) Placebo 50 1.46 1.30 TRT <0.001 B) HC/APAP 50 2.12 1.14 A-B 0.007 C) W/NTX 1 mg 50 2.21 1.18 A-C 0.002 D) W/NTX 0.1 mg 50 2.19 1.21 A-D 0.003 E) W/NTX 0.01 mg 50 1.90 1.27 A-E 0.069 F) W/NTX 0.001 mg 50 2.52 1.13 A-F <0.001 B-C 0.706 B-D 0.787 B-E 0.362 B-F 0.098 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 63B Efficacy Results Means and Standard Deviation for the Categorical PEAKPID (Safety Patients) CATEGORICAL PEAK PAIN INTENSITY DIFFERENCE P-Value TREATMENT N MEAN SD SOURCE A) Placebo 50 0.70 0.93 TRT 0.058 B) HC/APAP 50 0.92 0.75 A-B 0.170 C) W/NTX 1 mg 50 0.96 0.80 A-C 0.107 D) W/NTX 0.1 mg 50 0.94 0.68 A-D 0.135 E) W/NTX 0.01 mg 50 0.82 0.83 A-E 0.454 F) W/NTX 0.001 mg 50 1.20 0.78 A-F 0.002 B-C 0.810 B-D 0.901 B-E 0.532 B-F 0.081 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

WO 01/85150 PCT/US01/14644 517 Table 64 presents the summary and analysis of global evaluations. The placebo treatment group had the highest number of subjects who had "poor" global evaluation scores. The 0.001 mg NTX combination treatment group had the highest number of subjects with a total of "excellent", "very good" and "good" global evaluation scores. The profiles of the global evaluation scores are based on subjects' evaluations.

Table 64 Efficacy Results Patient Global Assessments (Safety Patients) TREATMENT N POOR FAIR GOOD VERY EXCELLENT P-Value P-Value P-Value GOOD vs. vs.

Placebo HC/APAP 0.017 Placebo 50 26 11 8 5 0 B) HC/APAP 50 13 15 12 6 4 0.045 C) W/NTX 1 mg 50 12 12 15 7 4 0.021 0.942 W/NTX 0.1mg 50 15 8 15 9 3 0.048 0.506 W/NTX 0.01mg 50 13 19 8 10 0 0.045 0.184 W/NTX0.001 mg 50 9 11 14 13 3 0.003 0.383 OTAL 300 88 76 72 50 (17%)14 OVERALL P-VALUE (AND ANY PAIRWISE RESULTS) FROM THE COCHRAN-MANTEL-HAENSZEL TEST FOR ROW MEAN

SCORES.

WO 01/85150 PCT/US01/14644 519 The majority of adverse events reported were categorized as digestive (nausea or vomiting) or nervous system (dizziness or sedation) as further shown in Tables and 65B. Figure 37 represents a summary of exemplary adverse side effects that may be attenuated according to methods and compositions of the invention.

Table Summary of Adverse Events by Body System and Preferred Term (Safety Patients) Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of Treatment Subjects W/Event Events Mild Moderate Severe ALL BODY SYSTEMS EAR AND LABRYRINTH

DISORDERS

A) PLACEBO B) HCAPAP C) W/NTX 1mg D) WJNTX 0.l1img E) WINTX 0.01 rmg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HCINPAP C) WINTX 1 mng D) WINTX 0.I1mg E) W/NTX 0.01mg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HC1APAP C) W/NTX Img D) WINTX 0.l1mg E) W/NTX 0.01 mg F) W/NTX0.001 mg

TOTAL

14(28%) 15(30%) 23(46%) 21(42%) 2 1(42%) 20(40%) 114(38%/,) 0(0%) 1(2%) 0(0%) 0(0%) 1 0(0%) 0(0%) 0(0%) 1 (28%) (30%) (46%) (42%) (42%) (40%) (38%) (8%N (10%) (12%) (14%) (16%) (24%) (26%) (26%) (24%) (32%) 1 0 1 0

TINNITUS

1 0 1 0 NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65A (Continued) Summary of Adverse Events by Body System and Preferred Term (Safety Patients) Body System Total NO. Of Total Severity Adverse Events No. Of Subjects No. Of Treatment Subjects W/Event Events Mild Moderate Severe EYE DISORDERS VISION BLURRED A) PLACEBO B) HC/AIPAP C) W/NTX Img D) W/NTX 0.1 mg E) W/NTX 0.0O1mg F) W/NTX 0.00 1 mg

TOTAL

A) PLACEBO B) HC/AT'AP C) W/NTX 1 mg D) WINTXO0.l1mg W/NTX 0.0 1 mg F) WINTX 0.001 mg

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) WINTXO0.l1mg E) WJNTX0.01lmg F) WINTX 0.001 mg

TOTAL

0(0%) 0(0%) 1(2%) 0(0%) 0(0%) 0(0%) 1 0(0%) 1(2%) 0(0%) 0(0%) 0(0%) 10(20%) 14(28%/) 17(34%) 16(32%) 17(34%/) 18(36%/) 92(31%) 1 0 0 1 1 0 0 1

GASTROINTESTINAL

DISORDERS

(20%) (28%) (34%) (32%) (34%) (36%) (60%) (12%) (10%) (14%) (22%) (20%) (22%) (18%) (24%) (4%A) NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIZENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65A (Continued) Summary of Adverse Events by Body System and Preferred Term (Safety Patients) Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of Treatment Subjects W/Event Events Mild Moderate Severe

ABDOMINAL

DISTENSION

ABDOMINAL PAIN NOS A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX O.lmg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

0(0%) 1(2%) 0(0%) 0(0%) 0(0%) 0(0%) 0(0%) 0(0%) 0(0%) 1(2%) 0(0%) 0(0%) 0(0%) 0(0%) 1(2%) 0(0%) 1(2%) 0(0%) 2(1%) 1 0 1 0 1 0 1 0 ABDOMINAL PAIN

UPPER

1 0 1 0 1 0 0 1 NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65A (Continued) Summary of Adverse Events by Body System and Preferred Term (Safety Patients) Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of Treatment Subjects W/Event Events Mild Moderate Severe

CONSTIPATION

DIARRHEA NOS

DYSPEPSIA

A) PLACEBO B) HC/APAP C) W/NTX 1mg D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX O.lmg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

0(0%) 0(0%) 0(0%) 1(2%) 0(0%) 1(2%) 2(1%) 0(0%) 0(0%) 1(2%) 0(0%) 0(0%) 1(2%) 2(1%) 1(2%) 0(0%) 0(0%) 0(0%) 0(0%) 0(0%) 1 0 1 0 1 1 0 0 1 1 0 0 1 0 0 1 1 0 1 0 NOTE:AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65A (Continued) Summary of Adverse Events by Body System and Preferred Term (Safety Patients) Body System Total NO. Of Total Severity Adverse Events No. Of Subj ects No. Of Treatment Subjects WlEvrint Events Mild Moderate severe

FLATULENCE

NAUSEA

A) PLACEBO B) HC/APAP C) WINTX 1 mg D) W/NTX 0. 1 mg E) W/NTX 0.0Olmg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) IIC/APAP C) WINTX 1 mg D) W/NTX 0. 1 rag E) WINTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) 1{CIAPAP C) W/NTX 1 mg D) W/NTX 0. 1 mg E) W/NTX0.01lmg F) W/NTX0.001lmg

TOTAL

0(0%) 0(0%) 1(2%) 0(0%) 1(2%) 0(0%) 2(1%) 1 0 1 0 (0%)0 1 0 1 0 9(18%Y) 14(28%/) 17(34%) 15(30%/) 12(24%) 17(34%) 84(28%/) 0(0%) 0(0%) 1(2%) I 9 (18%) 14 (28%) 17 (34%) 15 (30%) 12 (24%) 17 (34%) (10%) (12%) (10%) (12%) (22%) (18%) (18%) (12%) (26%) (0%)0 (00/) SORE THROAT NOS 1 0 1 0 NOTE: AT EACH LEVEL OF SUMhMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65A (Continued) Summary of Adverse Events by Body System and Preferred Term (Safety Patients) Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of Treatment Subjects W/Event Events Mild Moderate Severe VOMITING NOS A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0.l1mg E) W/NTX 0.0 1mg F) W/NTX 0.001 mg

TOTAL

GENERAL DISORDERS AND ADMIN. SITE CONDITIONS A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0. 1mg E) WINTX 0.01mg F) W/NTX 0.001 mg

TOTAL

3(6%) 6(12%) 4(8%) 7(14%) 8(16%) 4(8%) 32(11%) 0(0%) 1(2%) 1(2%) 0(0%) 1(2%) 1(2%) 4(1%) 0(0%) 0(0%) 1(2%) 0(0%) 0(0%) 0(0%) 1 (12%) (14%) (16%) (20%) (00%) (00%) (10%) (10%) 1 0 0 0 0 1 0 0 1 1 0 0 (00/0 APPLICATION SITE

BLEEDING

A) PLACEBO B) EC/APAP C) W/NTX 1mg D) W/NTXO0.l1mg E) WINTX 0.01 mg F) W/NTX 0.00 1 mg

TOTAL

1 0 0 1 NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65A (Continued) Summary of Adverse Events by Body System and Preferred Term (Safety Patients) Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of Treatment Subjects W/Event Events Mild Moderate Severe

FATIGUE

PYREXIA

RIGORS

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX O.lmg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

0(0%) 0(0%) 0(0%) 0(0%) 0(0%) 1(2%) 0(0%) 0(0%) 0(0%) 0(0%) 1(2%) 0(0%) 0(0%) 1(2%) 0(0%) 0(0%) 0(0%) 0(0%) 1 1 1 0 1 0 0 1 0 1 0 0 NOTE:AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65A (Continued) Summary of Adverse Events by Body System and Preferred Term (Safety Patients) Body System Total NO. Of Total Severity Adverse Events No. Of Subjects No. Of Treatment Subjects \VlEvent Events Mild Moderate Severe INJUY AND POISONING ABRASION NOS

INVESTIGATIONS

A) PLACEBO B) HC/APAP C) W/NTX I mg D) W/NTX0.1mg E) W/NTX 0.01 mg F) W/NTX 0.00 1 rug

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX I mg D) W/NTX 0.1mg E) W/NTX 0.01 mg F) WINTX 0.001 mg

TOTAL

A) PLACEBO B) TCIAiPAP C) W/NTX 1mg D) W/NTX 0.l1mg E) W/NTX0.O1mg F) WINTXO0.001 rg

TOTAL

0(0%) 1(2%) 0(0%) 0(0%) 1 0 0(0%) 1(2%) 0(0%) 0(0%) 0(0%) 0(0%) 0(0%) 1(2%) 0(0%) 0(0%) 0(0%) I 1 1 0 0 1 1 0 0 1 1 0 0 NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AN) PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GWVEN.

Table 65A (Continued) Summary of Adverse Events by Body System and Preferred Term (Safety Patients) Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of Treatment Subjects W/Event Events Mild Moderate Severe BLOOD PRESSURE

INCREASED

MUSCULOSKELETAL,

CONNECT. TISSUE AND BONE DISORDERS A) PLACEBO B) HC/APAP C) W/NTX I mg D) W/NTX 0.1 mg E) W/NTX O.Olmg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0.1mg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

0(0%) 0(0%) 1(2%) 0(0%) 0(0%) 0(0%) 0(0%) 0(0%) 0(0%) 1(2%) 0(0%) 0(0%) 0(0%) 0(0%) 0(0%) 1(2%) 0(0%) 0(0%) 1 1 1 0 0 1 0 0 NECK PAIN 1 1 0 0 NOTE:AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65A (Continued) Summary of Adverse Events by Body System and Preferred Term (Safety Patients) Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of Treatment Subjects W/Event Events Mild Moderate Severe NERVOUS SYSTEM

DISORDERS

DIZZINESS EXC.

VERTIGO

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0.1 mg E) V/NTX 0.Olmg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX O.lmg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

50 6(12%) 50 6(12%) 50 8(16%) 50 11(22%) 50 4(8%) 50 10(20%) 300 45(15%) 50 2(4%) 50 2(4%) 50 7(14%) 50 6(12%) 50 0(0%) 50 5(10%) 300 22(7%) 50 2(4%) 50 1(2%) 50 1(2%) 50 1(2%) 50 2(4%) 50 1(2%) 300 8(3%) 6 2 6 2 8 2 11 6 4 1 10 2 2 1 2 1 7 3 6 4 5 2 2 4 5 5 2 8 1 1 3 2 (10%) (10%) (16%) 3 0 HEADACHE NOS 0 1 0 1 1 0 1 0 1 0 1 1 NOTE:AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65A (Continued) Summary of Adverse Events by Body System and Preferred Term (Safety Patients) Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of Treatmnent Subjects W/Event Events Mild Moderate Severe IMRAINE NOS

SEDATION

SYNCOPE

A) PLACEBO B) HC/APAP C) W/NTX 1 Ig D) W/NTX0.1mg E) WINTX0.01lmg F) WINTX 0.001mg

TOTAL

A) PLACEBO B3) HC/APAP C) WINTX I mg D) W/NTXO0.l1mg E) W/NTX0.01lmg F) W/NTX 0.00 1 mg

TOTAL

A) PLACEBO B) HC/APAP C) WINTX Img D) WINTX 0.l1mg E) WINTX 0.01mg F) W/NTX 0.001 mg

TOTAL

0(00/) 0(0%) 0(0%) 1(2%) 0(00/) 2(4%) 2(4%) 0(0%) 3(6%) 8(3%) 1(2%) 1(2%) 2(40%) 2(4%) 1(2%) 1(2%) 8(3%) 1 0 0 1 1 1 0 0 2 1 1 0 2 3 0 2 0 0 3 0 NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AN) PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65A (Continued) Summary of Adverse Events by Body System and Preferred Term (Safety Patients) Body System Total NO. Of Total Severity Adverse Events No. Of Subjects No. Of Treatment Subjects WlEvent Events Mild Moderate Severe

TREMORNI.EC

PHYCHIATRIC

DISORDERS

A) PLACEBO B) HC/APAP C) WINTX 1 mg D) WINTX 0.l1mg E) W/NTX 0. 01 mg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HC/APAP C) WINTX 1 mg D) WINTX 0.l1mg E) W/NTX 0.01 mg F) WINTX 0.001 mg

TOTAL

A) PLACEBO B) U1C/APAP C) WINTX I mg D) W/NTX 0. 1mg E) WINTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

0(0%) 1(2%) 0(0%) 1(2%) 0(0%) 0(0%) 2(1%) 0(0%) 1(2%) 2(4%) 0(0%) 0(0%) 3(1%) 0(0%) 1(2%) 0(0%) 0(0%) 0(0%) 0(0%) 1 1 0 1 0 (00/0 1 0 0 1 2 1 2 0 0 (00/0 AN)CElTY N~EC 1 0 1 0 (0%)0 NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM ANT) PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65A (Continued) Summary of Adverse Events by Body System and Preferred Term (Safety Patients) Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of Treatment Subjects W/Event Events Mild Moderate Severe

CRYING

NERVOUSNESS

RENAL AND URINARY

DISORDERS

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX O.l mg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HC/APAP C) WINTX 1 mg D) W/NTX 0.lmg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) WINTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

0(0%) 1(2%) 0(0%) 0(0%) 0(0%) 0(0%) 0(0%) 0(0%) 2(4%) 0(0%) 0(0%) 0(0%) 2(1%) 0(0%) 0(0%) 0(0%) 0(0%) 1(2%) 0(0%) 1 0 1 0 2 0 2 0 1 1 0 0 NOTE:AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65A (Continued) Summary of Adverse Events by Body System and Preferred Term (Safety Patients) Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of Treatment Subjects W/Event Events Mild Moderate Severe DIFFICULTY IN

MICTURITION

RESPIRATORY,

THORACIC

AND MEDIASTINAL

DISORDERS

RESPIRATORY

DISORDER NOS A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX O.lmg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

0(0%) 0(0%) 0(0%) 0(0%) 1(2%) 0(0%) 0(0%) 1(2%) 0(0%) 0(0%) 0(0%) 0(0%) 0(0%) 1(2%) 0(0%) 0(0%) 0(0%) 0(0%) 1 1 1 1 0 0 0 1 0 0 1 0 NOTE:AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65A (Continued) Summary of Adverse Events by Body System and Preferred Term (Safety Patients) Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of Treatment Subjects W/Event Events Mild Moderate Severe SKIN AND SUBCUTANEOUS TISSUE

DISORDERS

FACE OEDMA PRURITUS NOS A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) WINTX 0.001 mg

TOTAL

2(4%) 1(2%) 4(8%) 4(8%) 4(8%) 2(4%) 17(6%) 0(0%) 0(0%) 0(0%) 0(0%) 1(2%) 0(0%) 2(4%) 0(0%) 0(0%) 2(4%) 2(4%) 0(0%) 6(2%) 1 0 1 0 2 2 2 1 1 0 1 1 0 0 NOTE:AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65A (Continued) Summary of Adverse Events by Body System and Preferred Term (Safety Patients) Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of Treatment Subj ects W/Event Events Mild Moderate Severe

SWEATING

INCREASED

URTICARIA NOS A) PLACEBO B) HC/APAP W/NTX 1 mg D) W/NTX0.1mg E) W/NTX 0.01 mg F) W/NTX 0.00 1 mg

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0.1 mg E) W/NTX0.01lmg F) W/NTX 0.00 1 mg

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0. 1 mg E) WINTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

1(2%) 1(2%) 2 9(3%) 0(0%) 0(0%) 1(2%) 0(0%) 0(0%) 1 1(2%) 0(0%) 4(8%) 0(0%) 1(2%) 1(2%) 7(2%) (0%)0 (2%A)

VASCULAR

DISORDERS

1 1 4 1 1 0 1 0 1 0 0 0 3 1 0 1 0 1 0 D0 NOTE:AT EACH LEVEL OF SUMMVATION (BODY SYSTEM AN~D PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65A (Continued) Summary of Adverse Events by Body System and Preferred Term (Safety Patients) Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of Treatment Subjects W/Event Events Mild Moderate Severe

FLUSHING

HOT FLUSHES NOS HYPERTENSION NOS A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0.1 mg E) W/NTX O.Olmg F) W/NTX 0.001 mg

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 mg D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

1(2%) 0(0%) 0(0%) 0(0%) 0(0%) 0(0%) 0(0%) 0(0%) 2(4%) 0(0%) 0(0%) 0(0%) 2(1%) 0(0%) 0(0%) 1(2%) 0(0%) 1(2%) 0(0%) 2(1%) 1 1 0 0 2 0 1 1 1 0 1 0 1 0 1 0 NOTE:AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65A (Continued) Summary of Adverse Events by Body System and Preferred Term (Safety Patients) Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of Treatment Subjects W/Event Events Mild Moderate Severe PALLOR A) PLACEBO 50 0(0%) B) HC/APAP 50 0(0%) C) W/NTX 1 mg 50 2 0 2 0 D) W/NTX 0 .1 mg 50 0(0%) E) W/NTX 0.01 mg 50 0(0%) F) WINTX 0.001 mg 50 1 0 1 0 TOTAL 300 3(1%) NOTE:AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table Summary of Adverse Events by Body System and Preferred Term (Safety Patients) Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of Treatment Subjects W/Event Events Mild Moderate Severe NAUSEA A) PLACEBO 50 9(18%) 9 3 6 0 B) HC/APAP 50 14(28%) 14 3 11 0 C) W/NTX 1 mg 50 17(34%) 17 5 9 3 D) W/NTX 0.1 mg 50 15(30%) 15 6 9 0 E) W/NTX 0.01 mg 50 12(24%) 12 5 6 1 F) W/NTX 0.001 mg 50 17(34%) 17 4 13 0 TOTAL 300 84(28%) VOMITING NOS A) PLACEBO 50 3 1 2 0 B) HC/APAP 50 6(12%) 6 1 5 0 C) W/NTX 1 mg 50 4 0 4 0 D) W/NTX 0.1 mg 50 7(14%) 7 2 3 2 E) W/NTX 0.01 mg 50 8(16%) 8 2 5 1 F) W/NTX 0.001 mg 50 4 0 4 0 TOTAL 300 32(11/%) DIZZINESS EXC. A) PLACEBO 50 2 1 1 0 VERTIGO B) HC/APAP 50 2 1 1 0 C) W/NTX 1 mg 50 7(14%) 7 3 3 1 D) W/NTX 0.1 mg 50 6(12%) 6 4 2 0 E) W/NTX 0.01 mg 50 0(0%) F) W/NTX 0.001 mg 50 5(10%) 5 2 3 0 TOTAL 300 22(7%) NOTE:AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 65B (Continued) Continued: Summary of Adverse Events by Body System and Preferred Term (Safety Patients) Body System Total No. Of Total Severity Adverse Events No. Of Subjects No. Of Treatment Subjects W/Event Events Mild Moderate Severe SEDATION A) PLACEBO B) HC/APAP C) W/NTX mg D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001 mg

TOTAL

1(2%) 2(4%) 0(0%) 2(4%) 0(0%) 3(6%) 8(3%) 1 1 0 1 0 0 2 0 2 0 3 0 3 0 NOTE:AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

WO 01/85150 PCT/US01/14644 540 EXAMPLE 6 An additional clinical study, this one using hydrocodone with acetaminophen (instead of morphine) alone and in combination with naltrexone, was designed substantially the same as that described in Example 2, with the following differences: six treatment groups with four different doses of NTX (1.0 mg, 0.1 mg, 0.01 mg and 0.001 mg) in combination with hydrocodone 5 mg/acetaminophen 500 mg versus hydrocodone 5 mg/acetaminophen 500 mg (HC/APAP) alone, and versus placebo alone in subjects with moderate to severe pain in a postsurgical dental pain clinical study; the primary efficacy variable was the categorical sum of pain intensity difference scores through 4 hours (SPID-4); and the secondary efficacy variables were: 4, 6 and 8 hour total pain relief scores (TOTPAR-4, TOTPAR-6 and TOTPARcategorical 6 and 8 hour sum of pain intensity difference scores (SPID-6 and SPID-8); categorical pain intensity difference (PID) scores through 8 hours; pain relief (PR) scores through 8 hours; peak categorical PID scores through 8 hours (PEAKPID); peak pain relief score through 8 hours (TOTPAR); time to onset of analgesia at least a one category improvement in the pain intensity score); time to onset of meaningful pain relief; time to taking backup medication; percent of patients taking backup medication; and patient overall evaluation of study drug.

The results for females and males separately are shown in the following tables and figures.

A total of 300 subjects were randomized; all 300 subjects were deemed evaluable as shown in Table 66. Table 67 shows the number of female and male subjects separately for each treatment group.

Table 66 Patient Enrollment and Evaluability

TREATMENTS

Placebo HC/APAP W/NTX 1 W/NTX 0.1 W/NTX W/NTX TOTAL 0.01 0.001 Number of Patients 50 50 50 50 50 50 300 (100%) 50 (100%) 50 (100%) 50 (100%) 50 (100%) 50 (100%) 300 (100%) Patients Included in the Safety Analyses 0 0 0 0 0 0 0 Patients Excluded in the Safety Analyses (100%) 50 (100%) 50 (100%) 50 (100%) 50 (100%) 50 (100%) 300 (100%) Patients Included in the Efficacy Analyses 0 0 0 0 0 0 0 Patients Excluded in the Efficacy Analyses Table 67 Patient Characteristics (Safety Patients) Placebo NC/APAP W/NTX 1 W/NTX 0. 1 WINTX 0.01 WINTX 0.001 TOTAL P-Value Sex_ Female 28 j34 131 (62%)l 35 1 31 (62%)l 30 (60%)1189 0.u16 Male 122 (44%) 16 (32%) 19 (38%) 15 (30%) 19 (38%) 20 (40%) 111 (37%) b- P-VALUE FROM A LIKELIHOOD RATIO CHI-SQUARE TEST. FOR RACE, NON-CAUCASiANS WERE COMBINED AS ONE CATEGORY FOR THE ANALYSIS.

WO 01/85150 PCT/US01/14644 543 The total pain relief scores (TOTPAR) results for 4, 6 and 8 hours are summarized in Tables 68A for females and 68B for males.

In females, all of the active treatment groups exhibited mean TOTPAR scores that were higher than the placebo group score. The HC/APAP alone treatment group had mean TOTPAR scores that were higher than the scores for the four NTX combination groups.

In males, all of the active treatment groups exhibited mean TOTPAR scores that were higher than the placebo group score. Both the 0.1 mg NTX and 0.001 mg NTX combination treatment groups had higher mean TOTPAR scores than the HC/APAP alone group. The 0.001 mg NTX combination group had the highest mean TOTPAR scores for the 4, 6 and 8 hours.

Table 68A Efficacy Results Means and Standard Deviations for TOTPARs (Trapezoidal Method) Female Safety Patients TOTAL PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT IN MEAN SD TOTAL PAIN RELIEF SCORES (4 HOURS) A) Placebo 28 1.56 2.23 TRT 0.012 B) HC/APAP 34 4.55 4.15 B-A 0.001 C) With NTX 1 30 4.42 3.88 C-A 0.002 D) W/NTX 0.1 35 4.35 3.26 D-A 0.002 E) W/NTX 0.01 31 3.76 4.07 E-A 0.018 F) W/NTX 0.001 30 4.28 3.00 F-A 0.004 C-B 0.882 D-B 0.810 E-B 0.367 F-B 0.760 MEANS GIVEN ARE LEAST SQUARE MEANS.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 68A (Continued) Efficacy Results Means and Standard Deviations for TOTPARs (Trapezoidal Method) Female Safety Patients TOTAL PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD TOTAL PAIN RELIEF SCORES (6 HOURS) A) Placebo 28 1.65 2.59 TRT 0.034 B) HC/APAP 34 5.56 6.04 B-A 0.001 C) With NTX 1 30 4.96 5.01 C-A 0.008 D) W/NTX 0.1 35 4.69 3.98 D-A 0.012 E) W/NTX 0.01 31 4.53 5.57 E-A 0.020 W/NTX 0.001 30 4.71 3.97 F-A 0.014 C-B 0.612 D-B 0.441 E-B 0.379 F-B 0.471 MEANS GIVEN ARE LEAST SQUARE MEANS.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 68A (Continued) Efficacy Results Means and Standard Deviations for TOTPARs (Trapezoidal Method) J Female Safety Patients TOTAL PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD TOTAL PAIN RELIEF SCORES (8 HOURS) A) Placebo 28 1.65 2.59 TRT 0.036 B) HC/APAP 34 5.81 6.56 B-A 0.001 C) With NTX 1 30 5.23 5.87 C-A 0.008 D) W/NTX 0.1 35 4.69 3.98 D-A 0.019 E) W/NTX 0.01 30 4.20 5.37 E-A 0.056 F) W/NTX 0.001 30 4.96 4.77 F-A 0.014 C-B 0.647 D-B 0.357 E-B 0.206 0.503 MEANS GIVEN ARE LEAST SQUARE MEANS.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

ri r_ Table 68B Efficacy Results Means and Standard Deviations for TOTPARs (Trapezoidal Method) Male Safety Patients TOTAL PAIN RELIEF SCORES TREATMENT N MEAN SD SOURCE P-VALUE TOTAL PAIN RELIEF SCORES (4 HOURS) A) Placebo 22 2.16 2.90 TRT 0.007 B) HC/APAP 16 3.73 3.66 B-A 0.212 C) With NTX 1 19 3.45 3.75 C-A 0.284 D) W/NTX 0.1 15 4.17 4.05 D-A 0.117 E) W/NTX 0.01 19 2.99 2.83 E-A 0.490 F) W/NTX 0.001 20 6.70 5.19 F-A <0.001 C-B 0.824 D-B 0.748 E-B 0.565 F-B 0.022 MEANS GIVEN ARE LEAST SQUARE MEANS.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 68B (Continued) Efficacy Results Means and Standard Deviations for TOTPARs (Trapezoidal Method) Male Safety Patients TOTAL PAIN RELIEF SCORES TREATMENT N MEAN SD SOURCE P-VALUE TOTAL PAIN RELIEF SCORES (6 HOURS) A) Placebo 22 2.48 4.08 TRT 0.008 B) HC/APAP 16 4.45 5.01 B-A 0.251 C) With NTX 1 19 3.79 4.46 C-A 0.423 D) W/NTX 0.1 15 4.97 5.61 D-A 0.155 E) W/NTX 0.01 19 3.02 2.89 E-A 0.743 F) W/NTX 0.001 20 8.40 7.79 F-A <0.001 C-B 0.707 D-B 0.780 E-B 0.417 F-B 0.025 MEANS GIVEN ARE LEAST SQUARE MEANS.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 68B (Continued) Efficacy Results -Means and Standard Deviations for TOTPARs (Trapezoidal Method) Male Safety Patients TOTAL PAIN RELIEF SCORES TREATMENT N MEAN SD SOURCE P-VALUE TOTAL PAIN RELIEF SCORES (8 HOURS) A) Placebo 22 2.82 5.52 TRT 0.014 B) HC/APAP 16 4.77 5.64 B-A 0.357 C) With NTX 1 19 3.82 4.53 C-A 0.621 D) W/NTX 0.1 15 5.77 7.45 D-A 0.171 E) W/NTX 0.01 19 3.02 2.89 E-A 0.924 F) W/NTX 0.001 20 9.48 9.94 F-A 0.001 C-B 0.662 D-B 0.661 E-B 0.422 F-B 0.030 MEANS GIVEN ARE LEAST SQUARE MEANS.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

WO 01/85150 PCT/US01/14644 550 The sum of pain intensity difference scores (SPID) results at 4, 6 and 8 hours are summarized in Tables 69A for females and 69B for males and the 4 hour SPID results are shown in Figures 38B for females and 38C for males. In females, all of the active treatment groups exhibited mean SPID scores that were higher than the placebo group score. The HC/APAP along group had the highest mean SPID scores throughout the 4, 6 and 8 hours. In males, all of the active treatment groups exhibited mean SPID scores that were higher than the placebo group score. Both the 0.1 mg NTX and the 0.001 mg NTX combination groups had higher mean SPID scores than the HC/APAP alone group. The 0.001 mg NTX combination group had the highest mean SPID scores for the 4, 6 and 8 hours.

Table 69A Efficacy Results Means and Standard Deviations for the SPIDS (Trapezoidal Method) Female Safety Patients CATEGORICAL SPID SCORES TREATMENT N MEAN SD SOURCE P-VALUE CATEGORICAL SPID SCORES (4 HOURS) A) Placebo 28 -0.41 2.21 TRT 0.027 B) HC/APAP 34 1.66 2.69 B-A 0.001 C) With NTX 1 30 1.34 2.74 C-A 0.008 D) WiNTX 0.1 35 1.43 1.75 D-A 0.004 E) W/NTX 0.01 31 1.27 2.79 E-A 0.011 F) W/NTX 0.001 30 1.22 2.69 F-A 0.014 C-B 0.617 D-B 0.708 E-B 0.537 F-B 0.486 MEANS GIVEN ARE LEAST SQUARE MEANS.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 69A (Continued) Efficacy Results Means and Standard Deviations for the SPIDS (Trapezoidal Method) Female Safety Patients CATEGORICAL SPID SCORES TREATMENT N MEAN SD SOURCE P-VALUE CATEGORICAL SPID SCORES (6 HOURS) A) Placebo 28 -1.03 3.11 TRT 0.028 B) HC/APAP 34 1.97 3.85 B-A <0.001 C) With NTX 1 30 1.05 3.74 C-A 0.024 D) W/NTX 0.1 35 1.40 2.28 D-A 0.007 E) W/NTX 0.01 31 1.40 4.05 E-A 0.008 F) W/NTX 0.001 30 1.00 3.72 F-A 0.028 C-B 0.299 D-B 0.501 E-B 0.517 F-B 0.273 MEANS GIVEN ARE LEAST SQUARE MEANS.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 69A (Continued) Efficacy Results Means and Standard Deviations for the SPIDS (Trapezoidal Method) Female Safety Patients CATEGORICAL SPID SCORES TREATMENT N MEAN SD SOURCE P-VALUE CATEGORICAL SPID SCORES (8 HOURS) A) Placebo 28 -1.67 4.01 TRT 0.031 B) HC/APAP 34 1.86 4.35 B-A <0.001 C) With NTX 1 30 0.62 4.64 C-A 0.035 D) W/NTX 0.1 35 1.21 2.58 D-A 0.006 E) W/NTX 0.01 30 0.74 4.06 E-A 0.027 F) W/NTX 0.001 30 0.75 4.80 F-A 0.026 C-B 0.229 D-B 0.508 E-B 0.275 F-B 0.282 MEANS GIVEN ARE LEAST SQUARE MEANS.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 69B Efficacy Results Means and Standard Deviations for the SPIDS (Trapezoidal Method) Male Safety Patients CATEGORICAL SPID SCORES TREATMENT N MEAN SD SOURCE P-VALUE CATEGORICAL SPID SCORES (4 HOURS) A) Placebo 22 0.03 2.89 TRT 0.018 B) HC/APAP 16 1.32 1.75 B-A 0.118 C) With NTX 1 19 0.80 2.63 C-A 0.328 D) W/NTX 0.1 15 1.51 2.75 D-A 0.078 E) W/NTX 0.01 19 0.94 1.32 E-A 0.243 F) W/NTX 0.001 20 2.83 2.99 F-A <0.001 C-B 0.537 D-B 0.829 E-B 0.657 F-B 0.074 MEANS GIVEN ARE LEAST SQUARE MEANS.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 69B (Continued) Efficacy Results Means and Standard Deviations for the SPIDS (Trapezoidal Method) Male Safety Patients CATEGORICAL SPID SCORES TREATMENT N MEAN SD SOURCE P-VALUE CATEGORICAL SPID SCORES (6 HOURS) A) Placebo 22 -0.47 4.36 TRT 0.019 B) HC/APAP 16 1.45 2.36 B-A 0.103 C) With NTX 1 19 0.43 3.24 C-A 0.420 D) W/NTX 0.1 15 1.65 3.95 D-A 0.077 E) W/NTX 0.01 19 0.84 1.66 E-A 0.241 F) W/NTX 0.001 20 3.43 4.48 F-A <0.001 C-B 0.400 D-B 0.874 E-B 0.615 F-B 0.098 MEANS GIVEN ARE LEAST SQUARE MEANS.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 69B (Continued) Efficacy Results Means and Standard Deviations for the SPIDS (Trapezoidal Method) Male Safety Patients CATEGORICAL SPID SCORES TREATMENT N MEAN SD SOURCE P-VALUE CATEGORICAL SPID SCORES (8 HOURS) A) Placebo 22 -0.95 5.96 TRT 0.040 B) HC/APAP 16 1.45 2.91 B-A 0.115 C) With NTX 1 19 0.01 3.90 C-A 0.507 D) W/NTX 0.1 15 1.78 5.26 D-A 0.078 E) W/NTX 0.01 19 0.73 2.05 E-A 0.243 F) W/NTX 0.001 20 3.63 5.59 F-A 0.002 C-B 0.357 D-B 0.839 E-B 0.648 F-B 0.158 MEANS GIVEN ARE LEAST SQUARE MEANS.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

WO 01/85150 PCT/US01/14644 557 Tables 70A for females and 70B for males summarize the results of the time to onset of analgesia. In females, the 0.1 mg NTX and the 0.001 mg NTX combination groups had the shortest median times to onset of analgesia. In males, the placebo, HC/APAP alone, and 0.001 mg NTX combination groups had the shortest median times to onset of analgesia. In females, the 0.1 mg NTX and the 0.001 mg NTX combination groups had the highest percentage of patients with analgesia. All active treatment groups had a higher percentage of patients with analgesia than the placebo group. In males, the 0.001 mg NTX combination group had the highest percentage of patients with analgesia.

Table Efficacy Results -Results of Time to Analyses and Percent of Patients with Events (Safety Patients) Female Patients TIME TO ONSET OF ANALGESIA (hours) TREATMENT NUMBER OF MEDIAN 95% INTERVAL PATIENTS TIME LOWER UPPER SOURCE P-VALUE LIMIT LIMIT A) Placebo 28 >0.8 0.5 >8.0 TRT 0.061 B) HC/APAP 34 0.8 0.5 1.5 B-A 0.143 C) W/NTX 1 31 0.8 0.5 0.8 C-A 0.116 D) W/NTX 0.1 35 0.5 0.5 0.8 D-A 0.016 E) W/NTX 0.01 31 1.3 0.8 >8.0 E-A 0.744 F) W/NTX 0.001 30 0.5 0.5 1.0 F-A 0.048 TOTAL 189 0.8 0.5 1.0 C-B 0.707 D-B 0.211 E-B 0.232 F-B 0.470 P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM THE LIKELIHQOD-RATIO CHI-SQUARE TEST.

P-VALUES FOR TIME TO EVENT ARE FROM THE LONG RANK TEST.

Table 70A (Continued) Efficacy Results Results of Time to Analyses and Percent of Patients with Events (Safety Patients) Female Patients TIME TO ONSET OF ANALGESIA (hours) PATIENTS WITH ANALGESIA NO YES SOURCE P-VALUE A) Placebo 15 (54 13 (46 TRT 0.015 B) HC/APAP 10 (29 24 (71 B-A 0.053 C) W/NTX 1 7 (23 24 (77 C-A 0.013 D) W/NTX 0.1 6 (17 29 (83 D-A 0.002 E) W/NTX 0.01 13 18 E-A 0.371 F) W/NTX 0.001 6 (20 24 (80 F-A 0.007 TOTAL 57(30%) 132(70%) C-B 0.530 D-B 0.226 E-B 0.291 F-B 0.383 P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM THE LIKELIHOOD-RATIO CHI-SQUARE TEST.

P-VALUES FOR TIME TO EVENT ARE FROM THE LONG RANK TEST.

iable /uIB Efficacy Results Results of Time to Analyses and Percent of Patients with Events (Safety Patients) Male Patients TIME TO ONSET OF ANALGESIA (hours) TREATMENT NUMBER OF MEDIAN 95% INTERVAL PATIENTS TIME LOWER UPPER SOURCE P-VALUE LIMIT LIMIT A) Placebo 22 0.5 0.5 >8.0 TRT 0.237 B) HC/APAP 16 0.5 0.5 1.0 B-A 0.624 C) W/NTX 1 19 0.8 0.5 >8.0 C-A 0.832 D) W/NTX 0.1 15 0.8 0.5 >8.0 D-A 0.735 E) W/NTX 0.01 19 0.8 0.5 1.5 E-A 0.934 F) W/NTX 0.001 20 0.5 0.3 0.8 F-A 0.119 TOTAL 111 0.5 0.5 0.8 C-B 0.427 D-B 0.383 E-B 0.526 F-B 0.210 P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM THE LIKELIHOOD-RATIO CHI-SQUARE TEST.

P-VALUES FOR TIME TO EVENT ARE FROM THE LONG RANK TEST.

Table 70B (Continued) Efficacy Results Results of Time to Analyses and Percent of Patients with Events (Safety Patients) Male Patients TIME TO ONSET OF ANALGESIA (hours) PATIENTS WITH ANALGESIA NO YES SOURCE P-VALUE A) Placebo 8(36 14(64 TRT 0.087 B) HC/APAP 3 (19 13 (81 B-A 0.296 C) W/NTX 1 7(37%) 12(63%) C-A 1.000 D) W/NTX 0.1 6(40 9(60%) D-A 1.000 E) W/NTX 0.01 5 (26 14 (74 E-A 0.524 F) W/NTX 0.001 1(5 19(95 F-A 0.022 TOTAL 30 (27 81(73 C-B 0.285 D-B 0.252 E-B 0.700 F-B 0.303 P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM THE LIKELIHOOD-RATIO CHI-SQUARE TEST.

P-VALUES FOR TIME TO EVENT ARE FROM THE LONG RANK TEST.

WO 01/85150 PCT/US01/14644 562 Tables 71A for females and 71B for males summarize the results of the time to onset of meaningful pain relief. In females, the time to onset of relief was shortest in the 0.1 mg NTX and the 0.001 mg NTX combination groups. In males, the time to onset of relief was shortest in the HC/APAP alone, 0.1 mg NTX and the 0.001 mg NTX combination groups. In females, the 0.001 mg NTX combination group had the highest percentage of patients reporting relief. In males, the placebo group had the lowest percentage of patients reporting relief and the 0.001 mg NTX combination group had the highest percentage reporting relief.

Table 71A Efficacy Results Results of Time Onset of Meaningful Pain Relief (Safety Patients) Female Patients TIME TO ONSET OF RELIEF (hours) TREATMENT NUMBER OF MEDIAN 95% INTERVAL PATIENTS TIME LOWER UPPER SOURCE P-VALUE LIMIT LIMIT A) Placebo 28 >8.0 0.8 >8.0 TRT 0.302 B) HC/APAP 34 >8.0 1.0 >8.0 B-A 0.806 C) W/NTX 1 31 >8.0 0.8 >8.0 C-A 0.988 D) W/NTX 0.1 35 0.9 0.5 >8.0 D-A 0.391 E) W/NTX 0.01 31 >8.0 1.3 >8.0 E-A 0.336 F) W/NTX 0.001 30 1.0 0.5 >8.0 F-A 0.341 TOTAL 189 2.0 1.1 >8.0 C-B 0.730 D-B 0.185.

E-B 0.473 F-B 0.133 P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM THE LIKELIHOOD-RATIO CHI-SQUARE TEST.

P-VALUES FOR TIME TO EVENT ARE FROM THE LOG RANK TEST.

Table 71A (Continued) Efficacy Results Results of Time Onset of Meaningful Pain Relief (Safety Patients) Female Patients TIME TO ONSET OF RELIEF (hours) PATIENTS WITH RELIEF NO YES SOURCE P-VALUE A) Placebo 15(54%) 13(46%) TRT 0.378 B) HC/APAP 18(53%) 16(47%) B-A 0.961 C) W/NTX 1 15(48%) 16(52%) C-A 0.691 D) W/NTX 0.1 14 (40 21(60 D-A 0.282 E) W/NTX 0.01 19 12 (39 E-A 0.549 F) W/NTX 0.001 11(37%) 19(63%) F-A 0.195 TOTAL 92(49%) 97(51%) C-B 0.714 D-B 0.281 E-B 0.497 F-B 0.190 P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM THE LIKELIHOOD-RATIO CHI-SQUARE TEST.

P-VALUES FOR TIME TO EVENT ARE FROM THE LOG RANK TEST.

Table 71B Efficacy Results -Results of Time Onset of Meaningful Pain Relief (Safety Patients) Male Patients TIME TO ONSET OF RELIEF (hours) TREATMENT NUMBER MEDIAN 95% INTERVAL OF TIME PATIENTS LOWER UPPER SOURCE P-VALUE LIMIT LIMIT A) Placebo 22 >8.0 0.8 >8.0 TRT 0.018 B) HC/APAP 16 0.7 0.5 >8.0 B-A 0.023 C) W/NTX 1 19 >8.0 0.4 >8.0 C-A 0.153 D) W/NTX 0.1 15 0.7 0.3 >8.0 D-A 0.008 E) W/NTX 0.01 19 >8.0 1.1 >8.0 E-A 0.781 F) W/NTX 0.001 20 0.7 0.5 >8.0 F-A 0.005 TOTAL 111 >8.0 0.8 >8.0 C-B 0.488 D-B 0.756 E-B 0.041 F-B 0.744 P-VALUES FOR TIME TO EVENT ARE FROM THE LOG RANK TEST.

I

r .r Table 71B (Continued) Efficacy Results -Results of Time Onset of Meaningful Pain Relief (Safety Patients) Male Patients TIME TO ONSET OF RELIEF (hours) PATIENTS WITH RELIEF NO YES SOURCE P-VALUE A) Placebo 16 (73 6 (27 TRT 0.020 B) HC/APAP 6 (38 10 (63 B-A 0.029 C) W/NTX 1 10 (53 9 (47 C-A 0.182 D) W/NTX 0.1 5 (33 10 (67 D-A 0.017 E) W/NTX 0.01 13 (68 6 (32 E-A 0.763 F) W/NTX 0.001 6 (30 14 (70 F-A 0.005 TOTAL 56 (50 55 (50 C-B 0.369 D-B 0.808 E-B 0.065 F-B 0.636 P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM THE LIKELIHOOD-RATIO CHI-SQUARE TEST.

P-VALUES FOR TIME TO EVENT ARE FROM THE LOG RANK TEST.

WO 01/85150 PCT/US01/14644 567 Tables 72A for females and 72B for males summarize the results of the time to remedication (see also Figures 39A for females and 39B for males). In females, the placebo group had the shortest median time to remedication and the 0.1 mg NTX treatment group had the longest median time to remedication. In males, the placebo and 1.0 mg NTX combination groups had the shortest median times to remedication and the 0.001 mg NTX combination group had the longest median time to remedication.

Tables 73A for females and 73B for males summarize the results of the percent of patients remedicating. In females, the percentage of patients remedicating was comparable across all treatment groups. In males, the 0.1 mg NTX and the 0.001 mg NTX combination groups had the lowest percentages of patients remedicating.

Table 72A Efficacy Results Time to Rescue Medication (Safety Patients) Female Patients TIME TO REMEDICATION (hours) TREATMENT NUMBER MEDIAN 95% INTERVAL OF TIME PATIENTS LOWER UPPER SOURCE P-VALUE LIMIT LIMIT A) Placebo 28 1.6 1.6 1.6 TRT 0.002 B) HC/APAP 34 1.9 1.6 3.1 B-A <0.001 C) W/NTX 1 31 2.0 1.6 3.0 C-A 0.011 D) W/NTX 0.1 35 2.3 1.9 3.1 D-A <0.001 E) W/NTX 0.01 31 1.7 1.6 2.1 E-A 0.011 F) W/NTX 0.001 30 2.1 1.6 3.1 F-A 0.002 TOTAL 189 1.9 1.6 2.1 C-B 0.664 D-B 0.218 E-B 0.525 F-B 0.523 P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM FISHER'S EXACT TEST.

Table 72B Efficacy Results Time to Rescue Medication (Safety IPatients) Male Patients TIME TO REMEDICATION (hours) TREATMENT NUMBER MEDIAN 95% INTERVAL OF TIE PATIENTS LOWER UPPER SOURCE P-VALUE LIMIT A) Placebo 22 1.6 1.6 1.7 TRT 0.040 B) HC/APAP 16 1.9 1.6 3.1 B-A 0.121 Q) W/NTX 1 19 1.6 1.6 2.4 C-A 0.338 D) W/NTX 0. 1 15 1.8 1.6 3.7 D-A 0.066 E) W/NTX 0.01 19 1.7 1.6 2.2 E-A 0.385 F) W/NTX 0.00 1 20 2.7 1.7 4.8 F-A 0.007- TOTAL 111 1.7 1.6 2.1 C-B 0.508 D-B 0.659 E-13 0.288 __F-B3 0.283 P-VALUES FOR TIME TO EVENT ARE FROM THE LOG RANK TEST.

Table 73A Efficacy Results Percent of Patients Remedicating Intent-To-Treat Population, Female Patients PATIENTS REMEDICATING TREATMENT NO YES SOURCE P-VALUE A) Placebo 0 28 (100%) TRT 0.314 B) HC/APAP 0 34 (100%) B-A 0.314 C) W/NTX1 2 29 C-A 0.493 D) W/NTX 0.1 0 35 (100%) D-A 0.493 E) W/NTX 0.01 1 30 E-A 1.000 F) W/NTX 0.001 1 29 F-A 1.000 TOTAL 4 185 C-B 0.224 D-B 0.224 E-B 0.477 F-B 0.469 P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM FISHER'S EXACT TEST.

Table 73B Efficacy Results Percent of Patients Remedicating Intent-To-Treat Population, Male Patients PATIENTS REMEDICATING TREATMENT NO YES SOURCE P-VALUE A) Placebo 1 21 TRT 0.222 B) HC/APAP 1 15 B-A 1.000 C) W/NTX 1 0 19 (100%) C-A 1.000 D) W/NTX 0.1 2 13 D-A 0.554 E) W/NTX 0.01 0 19 (100%) E-A 1.000 F) W/NTX 0.001 3 17 F-A 0.333 TOTAL 7 104 C-B 0.457 D-B 0.600 E-B 0.457 F-B 0.613 P-VALUES FOR PERCENT OF PATIENTS WITH EVENT ARE FROM FISHER'S EXACT TEST.

WO 01/85150 PCT/US01/14644 572 Tables 74A for females and 74B for males summarize the results of the pain relief (PR) scores, and Tables 74C for females and 74D for males summarize the MAXPAR scores. In females, the placebo group had the lowest mean pain relief scores from 30 minutes to 5 hours. In males, the 0.001 mg NTX combination group had the highest mean pain relief scores from 15 minutes to 8 hours. In females, the mg NTX and the 0.001 mg NTX combination groups had the highest mean peak relief scores. In males, the 0.001 mg NTX combination group had the highest mean peak relief scores.

Table 74A Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Female Patients PAIN RELIEF SCORES N MEAN SOURCE PR-VALUE TREATMENT SD

MINUTES_____

A) Placebo 28 0.61 0.96 TRT 0.440 B) HC/APAP 34 0.44 0.66 B-A 0.447 C) W/NTX1 31 0.65 0.91 C-A 0.864 D) W/NTX 0.1 35 0.77 1.14 D-A 0.448 E) W/NTX 0.01 31 0.39 0.62 E-A 0.324 F) W/NTX 0.001 30 0.47 0.68 F-A 0.532 C-B 0.337 D-B 0.110 E-B 0.799 0.905 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74A (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Female Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD

MINUTES

A) Placebo 28 0.79 1.03 TRT 0.054 B) HC/APAP 34 1.02 1.08 B-A 0.423 C) W/NTX 1 31 1.42 1.18 C-A 0.035 D) W/NTX 0.1 35 1.50 1.22 D-A 0.015 E) W/NTX 0.01 31 1.03 1.20 E-A 0.410 F) W/NTX 0.001 30 1.53 1.14 F-A 0.014 C-B 0.162 D-B 0.086 E-B 0.966 F-B 0.075 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74A (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Female Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD

MINUTES

A) Placebo 28 0.89 0.99 TRT 0.008 B) HC/APAP 34 1.56 1.19 B-A 0.021 C) W/NTX 1 31 1.76 1.12 C-A 0.003 D) W/NTX 0.1 35 1.91 1.20 D-A <0.001 E) W/NTX 0.01 31 1.35 1.02 E-A 0.116 F) W/NTX 0.001 30 1.73 1.17 F-A 0.005 C-B 0.466 D-B 0.190 a E-B 0.465 F-B 0.535 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2= SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

r_ Table 74A (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Female Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N IMEAN SD 1 HOUR A) Placebo 28 0.82 1.12 TRT <0.001 B) HC/APAP 34 1.73 1.17 B-A 0.004 C) W/NTX 1 31 1.94 1.34 C-A <0.001 D) W/NTX 0.1 35 2.00 1.21 D-A <0.001 E) W/NTX 0.01 31 1.48 1.31 E-A 0.040 F) W/NTX 0.001 30 2.10 1.18 F-A <0.001 C-B 0.492 D-B 0.354 E-B 0.429 F-B 0.225 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74A (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Female Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD

HOURS

A) Placebo 28 0.57 0.96 TRT 0.001 B) HC/APAP 34 1.65 1.35 B-A 0.001 C) W/NTX 1 31 1.81 1.47 C-A <0.001 D) W/NTX 0.1 35 1.69 1.21 D-A <0.001 E) W/NTX 0.01 31 1.55 1.34 E-A 0.003 F) W/NTX 0.001 30 1.93 1.17 F-A <0.001 C-B 0.612 D-B 0.899 E-B 0.754 F-B 0.367 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74A (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Female Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD 2 HOURS A) Placebo 28 0.21 0.79 TRT 0.009 B) HC/APAP 34 1.41 1.50 B-A <0.001 C) W/NTX 1 31 1.35 1.59 C-A 0.002 D) W/NTX 0.1 35 1.29 1.36 D-A 0.002 E) W/NTX 0.01 31 1.00 1.41 E-A 0.027 F) W/NTX 0.001 30 1.23 1.25 F-A 0.005 C-B 0.844 D-B 0.699 E-B 0.222 F-B 0.599 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

4 .a.

Table 74A (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Female Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD 3 HOURS A) Placebo 28 0.18 0.67 TRT 0.211 B) HC/APAP 34 0.91 1.33 B-A 0.012 C) W/NTX 1 31 0.71 1.25 C-A 0.069 D) W/NTX 0.1 35 0.60 1.03 D-A 0.142 E) W/NTX 0.01 31 0.68 1.30 E-A 0.091 F) W/NTX 0.001 30 0.50 0.97 F-A 0.279 C-B 0.482 D-B 0.252 E-B 0.403 F-B 0.146 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74A (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Female Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD 4 HOURS A) Placebo 28 0.11 0.57 TRT 0.199 B) HC/APAP 34 0.71 1.31 B-A 0.021 C) W/NTX 1 30 0.39 0.99 C-A 0.281 D) W/NTX 0.1 35 0.29 0.86 D-A 0.486 E) W/NTX 0.01 31 0.61 1.20 E-A 0.056 F) W/NTX 0.001 30 0.33 0.88 F-A 0.395 C-B 0.220 D-B 0.086 E-B 0.711 F-B 0.143 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74A (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Female Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD

HOURS

A) Placebo 28 0.04 0.19 TRT 0.406 B) HC/APAP 34 0.47 1.16 B-A 0.043 C) W/NTX 1 30 0.23 0.90 C-A 0.370 D) W/NTX 0.1 35 0.20 0.68 D-A 0.440 E) W/NTX 0.01 31 0.35 1.02 E-A 0.146 F) W/NTX 0.001 30 0.17 0.65 F-A 0.553 C-B 0.260 D-B 0.181 E-B 0.579 F-B 0.149 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74A (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Female Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD 6 HOURS A) Placebo 28 0.00 0.00 TRT 0.239 B) HC/APAP 34 0.38 1.02 B-A 0.040 C) W/NTX 1 30 0.23 0.90 C-A 0.222 D) W/NTX 0.1 35 0.00 0.00 D-A 1.000 E) W/NTX 0.01 31 0.23 0.80 E-A 0.234 F) W/NTX 0.001 30 0.20 0.81 F-A 0.295 C-B 0.413 D-B 0.030 E-B 0.386 F-B 0.317 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74A (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Female Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD 7 HOURS A) Placebo 28 0.00 0.00 TRT 0.639 B) HC/APAP 34 0.06 0.34 B-A 0.592 C) W/NTX 1 30 0.10 0.55 C-A 0.376 D) W/NTX 0.1 35 0.00 0.00 D-A 1.000 E) W/NTX 0.01 31 0.16 0.64 E-A 0.151 F) W/NTX 0.001 30 0.10 0.55 F-A 0.376 C-B 0.702 D-B 0.570 E-B 0.337 F-B 0.702 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 =NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74A (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Female Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD 8 HOURS A) Placebo 28 0.00 0.00 TRT 0.518 B) HC/APAP 34 0.00 0.00 B-A 1.000 C) W/NTX 1 30 0.10 0.55 C-A 0.221 D) W/NTX 0.1 35 0.00 0.00 D-A 1.000 E) W/NTX 0.01 30 0.00 0.00 E-A 1.000 F) WINTX 0.001 30 0.10 0.55 F-A 0.221 C-B 0.200 D-B 1.000 E-B 1.000 F-B 0.200 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME,.3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

4 .4.

Table 74B Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Male Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD

MINUTES

A) Placebo 22 0.68 0.78 TRT 0.307 B) HC/APAP 16 0.38 0.62 B-A 0.206 C) W/NTX 1 19 0.47 0.84 C-A 0.367 D) W/NTX 0.1 15 0.53 0.74 D-A 0.547 E) W/NTX 0.01 19 0.26 0.56 E-A 0.071 F) W/NTX 0.001 20 0.75 0.79 F-A 0.764 C-B 0.692 D-B 0.549 E-B 0.654 F-B 0.130 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74B (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Male Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD

MINUTES

A) Placebo 22 0.91 1.06 TRT 0.013 B) HC/APAP 16 1.13 1.09 B-A 0.535 C) W/NTX 1 19 1.32 1.25 C-A 0.222 D) W/NTX 0.1 15 0.99 0.78 D-A 0.825 E) W/NTX 0.01 19 0.63 0.90 E-A 0.403 F) W/NTX 0.001 20 1.85 1.14 F-A 0.005 C-B 0.596 D-B 0.718 E-B 0.171 F-B 0.043 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74B (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Male Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD

MINUTES

A) Placebo 22 0.95 1.05 TRT 0.005 B) HC/APAP 16 1.44 0.96 B-A 0.171 C) W/NTX 1 19 1.63 1.21 C-A 0.045 D) W/NTX 0.1 15 1.66 1.15 D-A 0.051 E) W/NTX 0.01 19 1.26 0.99 E-A 0.357 F) W/NTX 0.001 20 2.27 1.02 F-A <0.001 C-B 0.593 D-B 0.562 E-B 0.631 F-B 0.022 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74B (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Male Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD 1 HOUR A) Placebo 22 1.05 1.17 TRT 0.030 B) HC/APAP 16 1.63 0.81 B-A 0.148 C) W/NTX 1 19 1.37 1.16 C-A 0.396 D) W/NTX 0.1 15 1.86 1.45 D-A 0.046 E) W/NTX 0.01 19 1.76 1.27 E-A 0.061 F) W/NTX 0.001 20 2.30 1.30 F-A 0.001 C-B 0.533 D-B 0.585 E-B 0.737 F-B 0.099 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74B (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Male Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD

HOURS

A) Placebo 22 0.86 0.94 TRT 0.009 B) HC/APAP 16 1.56 1.21 B-A 0.094 C) W/NTX1 19 1.05 1.18 C-A 0.632 D) W/NTX 0.1 15 1.53 1.46 D-A 0.115 E) W/NTX 0.01 19 1.63 1.30 E-A 0.054 F) W/NTX 0.001 20 2.30 1.45 F-A <0.001 C-B 0.235 D-B 0.949 E-B 0.872 F-B 0.083 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74B (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Male Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD 2 HOURS A) Placebo 22 0.45 1.06 TRT 0.036 B) HC/APAP 16 1.06 1.53 B-A 0.186 C) W/NTX 1 19 0.95 1.39 C-A 0.260 D) W/NTX 0.1 15 1.27 1.44 D-A 0.084 E) W/NTX 0.01 19 0.84 1.26 E-A 0.375 F) W/NTX 0.001 20 1.90 1.65 F-A 0.001 C-B 0.807 D-B 0.683 E-B 0.641 F-B 0.075 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74B (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Male Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N IMEAN SD 3 HOURS A) Placebo 22 0.27 0.94 TRT 0.033 B) HC/APAP 16 0.56 1.15 B-A 0.465 C) W/NTX 1 19 0.68 1.25 C-A 0.277 D) W/NTX 0.1 15 0.76 1.20 D-A 0.225 E) W/NTX 0.01 19 0.32 0.75 E-A 0.909 F) W/NTX 0.001 20 1.45 1.70 F-A 0.002 C-B 0.766 D-B 0.642 E-B 0.547 0.030 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74B (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Male Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD 4 HOURS A) Placebo 22 0.18 0.85 TRT 0.023 B) HC/APAP 16 0.50 1.10 B-A 0.377 C) W/NTX 1 19 0.32 0.95 C-A 0.696 D) W/NTX 0.1 15 0.40 1.06 D-A 0.552 E) W/NTX 0.01 19 0.05 0.23 E-A 0.706 F) W/NTX 0.001 20 1.20 1.77 F-A 0.003 C-B 0.620 D-B 0.799 E-B 0.230 F-B 0.059 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74B (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Male Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N I MEAN SD

HOURS

A) Placebo 22 0.14 0.64 TRT 0.064 B) HC/APAP 16 0.38 0.89 B-A 0.427 C) W/NTX 1 19 0.16 0.50 C-A 0.940 D) W/NTX 0.1 15 0.40 1.06 D-A 0.389 E) W/NTX 0.01 19 0.00 0.00 E-A 0.633 F) W/NTX 0.001 20 0.85 1.57 F-A 0.013 C-B 0.484 D-B 0.939 E-B 0.227 0.123 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74B (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Male Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD 6 HOURS A) Placebo 22 0.18 0.85 TRT 0.342 B) HC/APAP 16 0.19 0.54 B-A 0.983 C) W/NTX 1 19 0.05 0.23 C-A 0.602 D) W/NTX 0.1 15 0.40 1.06 D-A 0.410 E) W/NTX 0.01 19 0.00 0.00 E-A 0.463 F) W/NTX 0.001 20 0.50 1.24 F-A 0.194 C-B 0.615 D-B 0.455 E-B 0.485 F-B 0.240 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74B (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Male Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD 7 HOURS A) Placebo 22 0.18 0.85 TRT 0.228 B) HC/APAP 16 0.13 0.50 B-A 0.832 C) W/NTX 1 19 0.00 0.00 C-A 0.477 D) W/NTX 0.1 15 0.40 1.06 D-A 0.425 E) W/NTX 0.01 19 0.00 0.00 E-A 0.477 F) W/NTX 0.001 20 0.55 1.36 F-A 0.146 C-B 0.652 D-B 0.349 E-B 0.652 F-B 0.123 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74B (Continued) Efficacy Results Means and Standard Deviations for the Pain Relief Scores (Safety Patients) Male Patients PAIN RELIEF SCORES SOURCE P-VALUE TREATMENT N MEAN SD 8 HOURS A) Placebo 22 0.14 0.64 TRT 0.214 B) HC/APAP 16 0.19 0.75 B-A 0.847 C) W/NTX 1 19 0.00 0.00 C-A 0.588 D) W/NTX 0.1 15 0.40 1.06 D-A 0.329 E) W/NTX 0.01 19 0.00 0.00 E-A 0.588 F) W/NTX 0.001 20 0.55 1.36 F-A 0.098 C-B 0.492 D-B 0.463 E-B 0.492 F-B 0.181 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 74C Efficacy Results Means and Standard Deviations for MAXPAR (Safety Patients) Female Patients MAXPAR SCORES SOURCE P-VALUE TREATMENT N MEAN SD PEAK RELIEF A) Placebo 28 1.36 1.31 TRT 0.010 B) HC/APAP 34 2.12 1.23 B-A 0.015 C) W/NTX 1 31 2.40 1.18 C-A 0.001 D) W/NTX 0.1 35 2.29 1.15 D-A 0.003 E) W/NTX 0.01 31 1.90 1.30 E-A 0.085 F) W/NTX 0.001 30 2.37 1.10 F-A 0.002 C-B 0.341 D-B 0.565 E-B 0.477 F-B 0.413 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS: 0 NONE, 1 A LITTLE, 2 SOME, 3 A LOT, AND 4 COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table74D Efficacy Results Means and Standard Deviations for MAXPAR (Safety Patients) Male Patients MAXPAR SCORES SOURCE P-VALUE TREATMENT N MEAN SD PEAK RELIEF A) Placebo 22 1.59 1.30 TRT 0.065 B) HC/APAP 16 2.13 0.96 B-A 0.179 C) W/NTX1 19 1.89 1.15 C-A 0.422 D) W/NTX 0.1 15 1.95 1.35 D-A 0.374 E) W/NTX 0.01 19 1.89 1.24 E-A 0.422 F) W/NTX 0.001 20 2.75 1.16 F-A 0.002 C-B 0.574 D-B 0.687 E-B 0.574 F-B 0.124 MEANS GIVEN ARE BEST SQUARE MEANS.

THE PAIN RELIEF SCALE WAS 0=NONE, 1=A LITTLE, 2=SOME, 3=A LOT, AND 4= COMPLETE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

WO 01/85150 PCT/US01/14644 599 Tables 75A for females and 75B for males summarize the results of the pain intensity difference (PID) scores. In females, the placebo group had the lowest mean PID scores from 45 minutes to 8 hours. All active treatment groups had higher mean PID scores than the placebo group. In males, the placebo group had the lowest mean PID scores from 30 minutes to 8 hours. The 0.001 mg NTX combination group had the highest mean PID scores from 15 minutes to 8 hours.

Tables 75C for females and 75D for males summarize the PEAKPID scores.

In females, the placebo group had the lowest PEAKPID score and the 1.0 mg NTX and the 0.001 mg NTX combination groups had the highest PEAKPID scores. In males, the 0.001 mg NTX combination group had the highest PEAKPID score.

Table Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Female Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD

MINUTES

A) Placebo 28 0.20 0.55 TRT 0.561 B) HC/APAP 34 0.06 0.60 B-A 0.360 C) W/NTX 1 31 0.03 0.48 C-A 0.285 D) W/NTX 0.1 35 0.23 0.60 D-A 0.829 E) W/NTX 0.01 31 0.00 0.58 E-A 0.202 F) W/NTX 0.001 30 0.08 0.70 F-A 0.465 C-B 0.856 D-B 0.232 E-B 0.687 F-B 0.868 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75A (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Female Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD

MINUTES

A) Placebo 28 0.32 0.72 TRT 0.522 B) HC/APAP 34 0.41 0.89 B-A 0.652 C) W/NTX 1 31 0.52 0.77 C-A 0.341 D) W/NTX 0.1 35 0.65 0.68 D-A 0.102 E) W/NTX 0.01 31 0.32 0.70 E-A 0.996 F) W/NTX 0.001 30 0.50 0.90 F-A 0.386 C-B 0.592 D-B 0.212 E-B 0.647 0.653 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75A (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Female Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD

MINUTES

A) Placebo 28 0.18 0.90 TRT 0.042 B) HC/APAP 34 0.56 0.86 B-A 0.074 C) W/NTX 1 31 0.81 0.79 C-A 0.004 D) W/NTX 0.1 35 0.80 0.72 D-A 0.004 E) W/NTX 0.01 31 0.48 0.77 E-A 0.160 F) W/NTX 0.001 30 0.57 0.94 F-A 0.077 C-B 0.231 D-B 0.229 E-B 0.717 F-B 0.970 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75A (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Female Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD 1 HOUR A) Placebo 28 0.05 0.91 TRT 0.003 B) HC/APAP 34 0.70 0.87 B-A 0.004 C) W/NTX 1 31 0.88 0.86 C-A <0.001 D) W/NTX 0.1 35 0.80 0.72 D-A <0.001 E) W/NTX 0.01 31 0.58 0.85 E-A 0.019 F) W/NTX 0.001 30 0.87 1.01 F-A <0.001 C-B 0.394 D-B 0.620 E-B 0.593 F-B 0.434 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75A (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Female Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD

HOURS

A) Placebo 28 -0.04 0.74 TRT 0.012 B) HC/APAP 34 0.65 0.92 B-A 0.003 C) W/NTX 1 31 0.68 1.01 C-A 0.002 D) W/NTX 0.1 35 0.60 0.69 D-A 0.005 E) W/NTX 0.01 31 0.52 0.89 E-A 0.016 F) W/NTX 0.001 30 0.73 0.94 F-A <0.001 C-B 0.889 D-B 0.823 E-B 0.547 F-B 0.694 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75A (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Female Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD 2 HOURS A) Placebo 28 -0.25 0.65 TRT 0.010 B) HC/APAP 34 0.56 0.93 B-A <0.001 C) W/NTX 1 31 0.41 1.07 C-A 0.004 D) W/NTX 0.1 35 0.42 0.71 D-A 0.003 E) W/NTX 0.01 31 0.39 0.88 E-A 0.006 F) W/NTX 0.001 30 0.37 0.93 F-A 0.008 C-B 0.493 D-B 0.505 E-B 0.429 F-B 0.380 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75A (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Female Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD 3 HOURS A) Placebo 28 -0.25 0.59 TRT 0.104 B) HC/APAP 34 0.26 0.75 B-A 0.007 C) W/NTX 1 31 0.07 0.92 C-A 0.098 D) W/NTX 0.1 35 0.08 0.51 D-A 0.083 E) W/NTX 0.01 31 0.23 0.88 E-A 0.014 F) W/NTX 0.001 30 0.00 0.69 F-A 0.199 C-B 0.289 D-B 0.289 E-B 0.832 F-B 0.154 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75A (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Female Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD 4 HOURS A) Placebo 28 -0.29 0.53 TRT 0.032 B) HC/APAP 34 0.26 0.79 B-A 0.002 C) W/NTX 1 30 -0.08 0.75 C-A 0.257 D) W/NTX 0.1 35 0.05 0.49 D-A 0.056.

E) W/NTX 0.01 31 0.16 0.82 E-A 0.013 F) W/NTX 0.001 30 -0.07 0.64 F-A 0.223 C-B 0.044 D-B 0.187 E-B 0.542 F-B 0.054 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75A (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Female Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD

HOURS

A) Placebo 28 -0.32 0.48 TRT 0.040 B) HC/APAP 34 0.15 0.70 B-A 0.003 C) W/NTX 1 30 -0.17 0.65 C-A 0.337 D) W/NTX 0.1 35 -0.01 0.35 D-A 0.046 E) W/NTX 0.01 31 0.06 0.81 E-A 0.016 F) W/NTX 0.001 30 -0.13 0.57 F-A 0.243 C-B 0.042 D-B 0.288 E-B 0.587 F-B 0.069 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75A (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Female Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD 6 HOURS A) Placebo 28 -0.32 0.48 TRT 0.191 B) HC/APAP 34 0.06 0.55 B-A 0.011 C) W/NTX 1 30 -0.17 0.65 C-A 0.309 D) W/NTX 0.1 35 -0.10 0.29 D-A 0.124 E) W/NTX 0.01 31 -0.03 0.71 E-A 0.056 F) W/NTX 0.001 30 -0.10 0.71 F-A 0.146 C-B 0.121 D-B 0.268 E-B 0.526 F-B 0.273 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75A (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Female Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD 7 HOURS A) Placebo 28 -0.32 0.48 TRT 0.218 B) HC/APAP 34 -0.09 0.29 B-A 0.048 C) W/NTX 1 30 -0.23 0.50 C-A 0.466 D) W/NTX 0.1 35 -0.10 0.29 D-A 0.054 E) W/NTX 0.01 31 -0.06 0.57 E-A 0.033 F) W/NTX 0.001 30 -0.13 0.57 F-A 0.121 C-B 0.209 D-B 0.947 E-B 0.835 F-B 0.695 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75A (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Female Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD 8 HOURS A) Placebo 28 -0.32 0.48 TRT 0.243 B) HC/APAP 34 -0.09 0.29 B-A 0.033 C) W/NTX 1 30 -0.23 0.50 C-A 0.431 D) W/NTX 0.1 35 -0.10 0.29 D-A 0.037 E) W/NTX 0.01 30 -0.17 0.38 E-A 0.167 F) W/NTX 0.001 30 -0.13 0.57 F-A 0.094 C-B 0.174 D-B 0.943 E-B 0.462 F-B 0.672 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Male Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD

MINUTES

A) Placebo 22 0.23 0.69 TRT 0.894 B) HC/APAP 16 0.06 0.44 B-A 0.355 C) W/NTX 1 19 0.11 0.57 C-A 0.472 D) W/NTX 0.1 15 0.13 0.52 D-A 0.604 E) W/NTX 0.01 19 0.16 0.37 E-A 0.682 F) W/NTX 0.001 20 0.25 0.55 F-A 0.892 C-B 0.816 D-B 0.716 E-B 0.604 F-B 0.303 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75B (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Male Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD

MINUTES

A) Placebo 22 0.32 0.78 TRT 0.159 B) HC/APAP 16 0.50 0.52 B-A 0.415 C) W/NTX 1 19 0.42 0.90 C-A 0.628 D) W/NTX 0.1 15 0.40 0.51 D-A 0.718 E) W/NTX 0.01 19 0.37 0.50 E-A 0.813 F) W/NTX 0.001 20 0.85 0.67 F-A 0.012 C-B 0.731 D-B 0.681 E-B 0.567 _F-B 0.126 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75B (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Male Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD

MINUTES

A) Placebo 22 0.27 0.83 TRT 0.015 B) HC/APAP 16 0.63 0.50 B-A 0.133 C) W/NTX 1 19 0.58 0.84 C-A 0.170 D) W/NTX 0.1 15 0.67 0.90 D-A 0.100 E) W/NTX 0.01 19 0.53 0.51 E-A 0.255 F) W/NTX 0.001 20 1.10 0.55 F-A <0.001 C-B 0.848 D-B 0.870 E-B 0.682 F-B 0.048 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75B (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Male Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD 1 HOUR A) Placebo 22 0.32 1.09 TRT 0.030 B) HC/APAP 16 0.69 0.48 B-A 0.192 C) W/NTX 1 19 0.37 0.90 C-A 0.852 D) W/NTX 0.1 15 0.80 0.94 D-A 0.095 E) W/NTX 0.01 19 0.76 0.71 E-A 0.100 F) W/NTX 0.001 20 1.15 0.81 F-A 0.002 C-B 0.274 D-B 0.715 E-B 0.795 F-B 0.110 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75B (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Male Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD

HOURS

A) Placebo 22 0.14 0.89 TRT 0.019 B) HC/APAP 16 0.56 0.63 B-A 0.124 C) W/NTX 1 19 0.37 0.90 C-A 0.378 D) W/NTX 0.1 15 0.73 0.96 D-A 0.036 E) W/NTX 0.01 19 0.53 0.70 E-A 0.140 F) W/NTX 0.001 20 1.05 0.89 F-A <0.001 C-B 0.496 D-B 0.571 E-B 0.899 F-B 0.085 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75B (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Male Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD 2 HOURS A) Placebo 22 -0.09 0.92 TRT 0.096 B) HC/APAP 16 0.31 0.70 B-A 0.157 C) W/NTX 1 19 0.26 0.93 C-A 0.193 D) W/NTX 0.1 15 0.47 0.99 D-A 0.056 E) W/NTX 0.01 19 0.21 0.54 E-A 0.267 F) W/NTX 0.001 20 0.70 0.98 F-A 0.004 C-B 0.866 D-B 0.620 E-B 0.728 F-B 0.183 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75B (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Male Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N IMEAN SD 3 HOURS A) Placebo 22 -0.18 0.91 TRT 0.079 B) HC/APAP 16 0.19 0.66 B-A 0.151 C) W/NTX 1 19 0.05 0.78 C-A 0.338 D) W/NTX 0.1 15 0.16 0.75 D-A 0.187 E) W/NTX 0.01 19 0.00 0.33 E-A 0.457 F) W/NTX 0.001 20 0.55 1.00 F-A 0.003 C-B 0.610 D-B 0.933 E-B 0.479 F-B 0.167 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75B (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Male Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD 4 HOURS A) Placebo 22 -0.23 0.87 TRT 0.029 B) HC/APAP 16 0.13 0.50 B-A 0.132 C) W/NTX 1 19 -0.11 0.57 C-A 0.582 D) W/NTX 0.1 15 0.07 0.70 D-A 0.216 E) W/NTX 0.01 19 -0.05 0.23 E-A 0.431 F) W/NTX 0.001 20 0.50 1.00 F-A 0.001 C-B 0.338 D-B 0.819 E-B 0.460 F-B 0.116 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75B (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Male Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD

HOURS

A) Placebo 22 -0.27 0.70 TRT 0.043 B) HC/APAP 16 0.06 0.44 B-A 0.095 C) W/NTX 1 19 -0.21 0.42 C-A 0.744 D) W/NTX 0.1 15 0.07 0.70 D-A 0.097 E) W/NTX 0.01 19 -0.05 0.23 E-A 0.249 F) W/NTX 0.001 20 0.30 0.86 F-A 0.003 C-B 0.187 D-B 0.985 E-B 0.577 F-B 0.245 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75B (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Male Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD 6 HOURS A) Placebo 22 -0.23 0.87 TRT 0.386 B) HC/APAP 16 0.00 0.37 B-A 0.245 C) W/NTX 1 19 -0.21 0.42 C-A 0.928 D) W/NTX 0.1 15 0.07 0.70 D-A 0.141 E) W/NTX 0.01 19 -0.05 0.23 E-A 0.348 F) W/NTX 0.001 20 0.10 0.64 F-A 0.076 C-B 0.296 D-B 0.754 E-B 0.794 F-B 0.615 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, I MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75B (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) M ale PatientsSO R Er V L CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD 7 HOURS A) Placebo 22 -0.23 0.87 TRT 0.386 B) HC/APAP 16 0.00 0.37 B-A 0.245 C) W/NTX1 19 -0.21 0.42 C-A 0.928 D) W/NTX 0.1 15 0.07 0.70 D-A 0.141 E) W/NTX 0.01 19 -0.05 0.23 E-A 0.348 F) W/NTX 0.001 20 0.10 0.64 F-A 0.076 C-B 0.296 D-B 0.754 E-B 0.794 F-B 0.615 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table 75B (Continued) Efficacy Results Means and Standard Deviations for the Categorical PID Scores (Safety Patients) Male Patients CATEGORICAL PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD 8 HOURS A) Placebo 22 -0.27 0.70 TRT 0.198 B) HC/APAP 16 0.00 0.37 B-A 0.131 C) W/NTX 1 19 -0.21 0.42 C-A 0.716 D) W/NTX 0.1 15 0.07 0.70 D-A 0.066 E) W/NTX 0.01 19 -0.05 0.23 E-A 0.200 F) W/NTX 0.001 20 0.10 0.64 F-A 0.029 C-B 0.258 D-B 0.734 E-B 0.777 F-B 0.586 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table Efficacy Results Means and Standard Deviations for PEAK PID (Safety Patients) Female Patients PEAK PID SCORES SOURCE P-VALUE TREATMENT N MEAN SD PEAK PID A) Placebo 28 0.57 0.79 TRT 0.130 B) HC/APAP 34 0.94 0.85 B-A 0.077 C) W/NTX 1 31 1.09 0.83 C-A 0.015 D) W/NTX 0.1 35 0.97 0.62 D-A 0.054 E) W/NTX 0.01 31 0.77 0.92 E-A 0.341 F) W/NTX 0.001 30 1.07 0.87 F-A 0.022 C-B 0.450 D-B 0.878 E-B 0.410 F-B 0.539 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FOR PAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

Table Efficacy Results Means and Standard Deviations for PEAK PID (Safety Patients) Male Patients PEAK PTD SCORES SOURCE P-VALUE TREATMENT N MEAN SD PEAK PID A) Placebo 22 0.86 1.08 TRT 0.120 B) HC/APAP 16 0.88 0.50 B-A 0.964 C) W/NTX 1 19 0.74 0.73 C-A 0.600 D) W/NTX 0.1 15 0.87 0.83 D-A 0.991 E) W/NTX 0.01 19 0.89 0.66 E-A 0.898 F) W/NTX 0.001 20 1.40 0.60 F-A 0.026 C-B 0.598 D-B 0.976 E-B 0.940 F-B 0.045 MEANS GIVEN ARE LEAST SQUARE MEANS.

THE CATEGORICAL SCALE FORPAIN INTENSITY WAS: 0 NONE, 1 MILD, 2 MODERATE, AND 3 SEVERE.

OVERALL TREATMENT P-VALUE FROM A ONE-WAY ANOVA, WHILE PAIRWISE RESULTS ARE FROM FISHER'S PROTECTED LSD TEST (MEANING, PAIRWISE P-VALUES ARE ONLY OBSERVED IF THE OVERALL TREATMENT EFFECT IS SIGNIFICANT).

WO 01/85150 PCT/US01/14644 626 Tables 76A for females and 76B for males present the summary and analysis of global assessments. In females, the placebo group had the highest percentage of "poor" assessments. The 0.1 mg NTX and the 0.001 mg NTX combination groups had the highest percentage of "good" to "excellent" ratings. In males, the placebo group had the highest percentage of "poor" assessments. The 0.001 mg NTX combination group had the highest percentage of "good" to "excellent" ratings.

Table 76A Efficacy Results Patient Global Assessments (Safety Patients) Female Patients TREATMENT NUMBER POOR FAIR GOOD VERY EXCELLENT SOURCE P-VALUE OF GOOD

PATIENTS

A) Placebo 28 15 7 5 1 0 TRT 0.035 B) HC/APAP 34 10 7 9 4 4 B-A 0.120 C) W/NTX1 31 7 7 8 5 4 C-A 0.041 D) W/NTX0.1 35 9 6 12 6 2 D-A 0.056 W/NTX0.01 31 7 12 5 7 0 E-A 0.038 F) W/NTX 0.001 30 7 6 8 8 1 F-A 0.042 TOTAL 189 55 45 47 31 11 C-B 0.968 D-B 0.811 E-B 0.109 F-B 0.477 OVERALL P-VALUE (AND ANY PAIRWISE RESULTS) FROM THE COCHRAN-MANTEL-HAENSZEL TEST FOR ROW MEAN

SCORES.

Table 76B Efficacy Results Patient Global Assessments (Safety Patients) Male Patients TREATMENT NUMBER POOR FAIR GOOD VERY EXCELLENT SOURCE P-VALUE OF GOOD

PATIENTS

A) Placebo 22 11 4 3 4 0 TRT 0.147 B) HC/APAP 16 3 8 3 2 0 B-A 0.132 C) W/NTX 1 19 5 5 7 2 0 C-A 0.229 D) W/NTX 0.1 15 6 2 3 3 1 D-A 0.741 E) W/NTX 0.01 19 6 7 3 3 0 E-A 0.538 W/NTX 0.001 20 2 5 6 5 2 F-A 0.057 TOTAL 111 33 31 25 19 3 C-B 0.479 D-B 0.232 E-B 0.804 F-B 0.324 OVERALL P-VALUE (AND ANY PAIRWISE RESULTS) FROM THE COCHRAN-MANTEL-HAENSZEL TEST FOR ROW MEAN

SCORES.

WO 01/85150 PCT/US01/14644 629 The majority of adverse side effects (adverse events) reported were categorized as digestive (nausea or vomiting) or nervous system (dizziness or somnolence) as further shown above in Tables 77A for females and 77B for males.

In females, the placebo group had the lowest incidence of nausea and vomiting. The 0.01 mg NTX combination group had the lowest incidence of dizziness. The placebo, 1.0 mg NTX and the 0.01 mg NTX combination groups had the lowest incidence of sedation.

In males, the HC/APAP alone group had the lowest incidence of nausea. The HC/APAP alone and the 1.0 mg NTX combination groups had the lowest incidence of vomiting. The placebo, HC/APAP alone, and 0.01 mg NTX combination groups had the lowest incidence of dizziness. The 1.0 mg NTX, 0.1 mg NTX and 0.01 mg NTX combination groups had the lowest incidence of sedation.

Figures 40A for females and 40B for males represent a summary of exemplary adverse side effects according to methods and compositions of the invention.

Table 77A Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Female Patients BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT (COSTART ENGLISH) ALL BODY SYSTEMS A) PLACEBO 28 11 (39%)

GASTROINTESTINAL

DISORDERS

Abdominal Distension B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

(38%) (58%) (48%) (46%) (29%) (38%) (48%) (34%) (42%) NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 77A (Continued) Summnary Of Adverse Events By Body System And Preferred Term .Safety Patients, Female Patients BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS ADVERSE EVENTS TREATMENT SUBJECTS WEVENT (COSTART ENGLISH) Abdonal Pain Nos A) PLACEBO 28 0 Abdominal Pain Upper Constipation B) HC/APAP C) W/NTX I DJ)W/NTX 0. 1 mg E) W/NTX0.01 mg F) W/NTXO0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0. 1 mg E) W/NTX 0.01mg F) W/NTXO0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D)W/NTXO-1 mg E) WINTX 0.01 mg F) W/NTXO.001

TOTAL

(10/0 (0%/0 NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATTENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GWVEN.

Table 77A (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Female Patients BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT (COSTART ENGLISH) Diarrhea Nos A) PLACEBO 28 0 Dyspepsia Flatulence B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 77A (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Female Patients BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT (COSTART ENGLISH) Nausea A) PLACEBO 28 7 Vomiting Nos GENERAL DISORDERS AND ADMIN. SITE CONDITIONS B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

(38%) (48%) (34%) (32%) (47%) (38%) (18%) (13%) (14%) (23%) (14%) NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 77A (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Female Patients BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS ADVERSE EVENTS TREATMENT SUBJECTS W/E VENT (COSTART ENGLISH) Application Site Bleeding A) PLACEBO 28 0 Pyrexia Rigors B) HC/APAP C) WINTX I D) WINTX 0. 1mg E) W/NTDC 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0. 1mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/AiPAP C) W/NTX 1 D) WNTXO0.l1mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

0%) (00/0 NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM ANDh PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 77A (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Femnale Patients ~EM TOTAL NO. OF 11 ENTS TREATMENT SUBJECTS BODY SYS J ADVERSE EV (COSTART EN( NERVOUS SYSTE

DISORDERS

0O. OF SUBJECTS W/E VENT

GLLSH)

Af A) PLACEBO 28 4 B) HC/APAP 34 5 C) W/NTX 1 31 4 D) WINTXO0.l1mg 35 7 E) W/NTX 0.01mg 31 4 F) W/NTX 0.001 30 6 TOTAL 189 30 Dizziness exc. Vertigo Headache Nos A) PLACEBO B) HC/APAP C) W/NTh 1 D) WINTX 0. 1 mg E) W/NTX 0.01 mg F) W/NTXO0.001

TOTAL

A) PLACEBO B) HC/APAP C) WINTX 1 D) W/NTX 0-I mg E) W/NTX 0.01 mg F) W/NTXO0.001

TOTAL

(14%) (13%) (13%) (16%) (13%) (14%) (13%) NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND) PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 77A (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Female Patients BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT (COSTART ENGLISH) Migraine Nos A) PLACEBO 28 0 Sedation Syncope B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) IIC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

NOTE: AT EACH LEVEL OF. SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 77A (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Female Patients 'EM TOTAL NO. OF NTS TREATMENT SUBJECTS BODY SYST ADVERSE EV (COSTART EN( Tremor Nee 40. OF SUBJECTS

WEVENT

IiLISH)

PSYCHIATRIC

DISORDERS

Anxiety Nee A) PLACEBO B) HC/AIPAP C) W/NTX 1 D) W/NTX 0. 1mg E) W,'NTX 0.01 mg F) W/NTXO0.01

TOTAL

A) PLACEBO0 B) IIC/APAP C) W/NTX 1 D) W[NTX 0. 1 mg E) W/NTX 0.01 mg F) W/NTXO0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0. 1mg E) W/NTX 0.01 mg F) W,'NTXO0.001

TOTAL

(00/0 NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 77A (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Female Patients BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT (COSTART ENGLISH) Crying A) PLACEBO 28 0 Nervousness B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

RESPIRATORY, THORACIC AND MEDIASTINAL

DISORDERS

JTS REPORTING MORE THAN ENT GROUP ARE ALSO GIVEN.

NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIEN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATM Table 77A (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Female Patients BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT (COSTART ENGLISH) Respiratory Disorder Nos A) PLACEBO 28 0 SKIN AND SUBCUTANEOUS TISSUE

DISORDERS

Face Oedma B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 77A (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Female Patients BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT (COSTART ENGLISH) Pruritus Nos A) PLACEBO 28 1 Sweating Increased Urticaria Nos B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) IIC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) WINTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 77A (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Female Patients BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT (COSTART ENGLISH) Vascular Disorders A) PLACEBO 28 1 Flushing B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

Hot Flushes Nos NTS REPORTING MORE THAN ENT GROUP ARE ALSO GIVEN.

NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIE ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATM Table 77A (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Female Patients 'EM TOTAL NO. OF I ENTS TREATMENT SUBJECTS BODY SYST ADVERSE EV (COSTART EN( Hypertension Nos O. OF SUBJECTS

W/EVENT

GLISH)

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

Pallor NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 77B Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Male Patients BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT (COSTART ENGLISH) ALL BODY SYSTEMS A) PLACEBO 22 3 (14%) EAR AND LABRYRINTH

DISORDERS

Tinnitus B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

(13%) (26%) (47%) (32%) NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 77B (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Male Patients BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT (COSTART ENGLISH) EYE DISORDERS A) PLACEBO 22 0 Vision Blurred

GASTROINTESTINAL

DISORDERS

B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

(11%) (27%) (21%) (14%) NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 77B (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Male Patients BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT (COSTART ENGLISH) Abdominal Pain Upper A) PLACEBO 22 0 Nausea B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) WINTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

(11%) (11%) (12%) Sore Throat Nos.

ENTS REPORTING MORE THAN MENT GROUP ARE ALSO GIVEN.

NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATI ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREAT Table 77B (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Male Patients BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS ADVERSE EVENTS TREATMENT SUBJECTS WEVENT (COSTART ENGLISH) Vomiting Nos A) PLACEBO 22 1 GENERAL DISORDERS AND ADMIN. SITE CONDITIONS Fatigue B) HC/APAP C) W/NTX I D) W/NTX 0.1 mg E) W/NX 0.01 mg F) W/NTX 0.00 1

TOTAL

A) PLACEBO B) HC/APAP C) WINTX 1 D) W/NTXO0.l1mg E) W/NTXO0.0O1mg F) W/NTX 0.00 1

TOTAL

A) PLACEBO B) HC/APAP C) WINTX 1 D) W/NTX 0. 1mg E) W/NTX0.01 mg F) W/NTXO0.001

TOTAL

(13%) NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM ANTD PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATME~NT GROUP ARE ALSO GIVEN.

Table 77B (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Male Patients BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT (COSTART ENGLISH) INJURY AND POISONING A) PLACEBO 22 0 Abrasion Nos

INVESTIGATIONS

B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 77B (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Male Patients BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT (COSTART ENGLISH) Blood Pressure Increased A) PLACEBO 22 0

MUSCULOSKELETAL

CONNECT TISSUE AND BONE DISORDERS Neck Pain B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 77B (Continued) Sumimary Of Adverse Events By Body System And Preferred Term Safety Patients, Male Patients EM TOTAL NO. OF N ENTS TREATMENT SUBJECTS BODY SYS1 ADVERSE EV (COSTART EN' NERVOUS SYSTE

DISORDERS

0. OF SUBJECTS W/E VENT ZiLISH) Dizziness exc. Vertigo Headache Nos A) PLACEBO B) HCIAPAP C) W/NTX 1 D) W/NTX 0. 1mg E) W/NTX 0.01 mg F) W/NTX 0.00 1

TOTAL

A) PLACEBO B) IHC/APAP C) WINTX 1 D) W/NTX 0. 1mg E) W/NTX 0.01 mg F) WINTXO0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTXO0.A mg E) W/NTX 0.01 mg F) W/NTXO0.001

TOTAL

(21%) (27%) (14%) (16%) NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MOR-E THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP~ ARE ALSO GIVEN.

Table 77B (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Male Patients BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS ADVERSE EVENTS TREATMENT SUBJECTS WEVENT (COSTARf ENGLISH) Sedation A) PLACEBO 22 1 Syncope Tremor Nee B) HC/APAP C) WINTX 1 D) W/NTX0. 1 mg E) WINTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B3) IIC/APAP C) WINTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01mg F) WINTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) WINTX 1 D) WNTX 0. 1 mg E) W/NTX 0.01 mg F) WINTX0,O01

TOTAL

NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AM) PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 77B (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Male Patients 'EM TOTAL NO. OF N ENTS TREATMENT SUBJECTS BODY SYS] ADVERSE EV (COSTART EN

PSYCHIATRIC

DISORDERS

0. OF SUBJECTS

W/EVENT

GLhISH) Nervousness A) PLACEBO B) UC/APAP C) W/NTX 1 D) WINTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.00 1

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTXO.00l

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0. mg E) W/NTX 0.01 mg F) W/NTX 0.00 1

TOTAL

RENAL AND URINARY

DISORDERS

ENTS REPORTING MORE THAN MENT GROUP ARE ALSO GIVEN.

NOTE: AT EACH LEVEL OF SUMM\ATION (BODY SYSTEM ANT) PREFERRED TERMS), PATE ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREA Table 77B (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Male Patients BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT (COSTART ENGLISH) Difficulty in Micturition A) PLACEBO 22 0 SKIN AND SUBCUTANEOUS TISSUE

DISORDERS

Pruritus Nos B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

16 19 15 19 20 111 (13%) NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 77B (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Male Patients BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT (COSTART ENGLISH) Sweating Increased A) PLACEBO 22 0 VASCULAR DISORDERS Hot Flushes Nos B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

(11%) NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

Table 77B (Continued) Summary Of Adverse Events By Body System And Preferred Term Safety Patients, Male Patients BODY SYSTEM TOTAL NO. OF NO. OF SUBJECTS ADVERSE EVENTS TREATMENT SUBJECTS W/EVENT (COSTART ENGLISH) Hypertension Nos A) PLACEBO 22 0 B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

A) PLACEBO B) HC/APAP C) W/NTX 1 D) W/NTX 0.1 mg E) W/NTX 0.01 mg F) W/NTX 0.001

TOTAL

Pallor NOTE: AT EACH LEVEL OF SUMMATION (BODY SYSTEM AND PREFERRED TERMS), PATIENTS REPORTING MORE THAN ONE EVENT ARE COUNTED ONLY ONCE. PERCENTAGES OF PATIENTS FOR EACH TREATMENT GROUP ARE ALSO GIVEN.

WO 01/85150 PCT/US01/14644 655 EXAMPLE 7 An additional dose ranging clinical study with morphine sulfate (MS or morphine) alone or in combination with low doses of naltrexone hydrochloride (NTX or naltrexone) was designed substantially the same as that described in Example 1, with the following differences: seven treatment groups (not 5) with three different doses of MS (30 mg, 60 mg and 90 mg) alone or in combination with 0.1 mg NTX versus placebo alone, in subjects with moderate to severe pain in a postsurgical dental pain clinical study; each group was 30 patients (not 40) for a total of 210 males only (not 200 females and males); subjects had three or four third molars, including at least one mandibular partial or complete bony impaction (not 2 or more impacted third molars); time to onset of analgesia (not time to onset of meaningful and perceptible pain relief or time to onset of meaningful pain relief) was measured; the primary efficacy variable was SPID measured through 4 hours (not TOTPAR and SPID measured through 8 hours); the secondary efficacy variables included: 4, 6 and 8 hour Total Pain Relief Scores (TOTPAR-4, TOTPAR-6, and TOTPAR-8); MAXPAR scores; pain relief (PR) scores; 6 and 8 hour Sum of Pain Intensity Difference Scores (SPID-6 and SPID-8); categorical PID scores (pain intensity differences on the categorical scale); PEAKPID scores; VAS-PID scores (pain intensity differences on the visual analog scale); PEAK-VAS-SPID scores; VAS- SPID-4, -6 and -8 scores; additional exclusion criteria were patients with known history of severe hepatic or renal impairment; and for adverse events, body systems and preferred terms were from the MedDRA (not the COSTART) dictionary.

A total of 210 male subjects were randomized; among them all 210 subjects were deemed evaluable (Table 78).

Table 78 Analysis Populations Treatments A B C D E F G MS (30 mg) MS (60 mg) MS (90 mg) Population Placebo M with NTX with NTX with NTX Total (60 mg) (90 mg) (0.1 mg) (0.1 mg) (0.1 mg) Safety 31 30 30 30 Primary Efficacy 31 30 30 30 Per Protocol 31 30 30 30 210 210 210 WO 01/85150 PCT/US01/14644 657 The demographic and baseline characteristics were summarized by treatment groups for all 210 randomized patients which were all evaluable (Table 79).

Demographic characteristics included age, race/ethnicity, sex, weight, height, medical history, teeth extracted (impacted and non-impacted), baseline pain intensity, and baseline visual analog scale.

Subjects ranged in age from 16 to 49 years; 62.9% were Caucasian and all were male. No adjustments in the analyses were made to take into account differences among treatment groups. These differences had little or no influence on pain assessments at baseline. The baseline pain intensity scores and visual analog scale scores were generally comparable across treatment groups (Tables 80A and iaoie tiy Baseline Demographic Characteristics Primary Efficacy Population Treatments A B C D E F G MS (30 mg) MS (60 ing) MS (90 mg) Placebo MS (30 mg) MS (60 mg) MS (90 mg) with NTX with NTX with NTX Total P-Value 1mrg) 1mg) (0.1mIg) Age (yrs) N 31 30 30 30 31 30 28 210 0.363 Mean 23.3 25.0 22.5 24.6 22.3 24.6 23.3 23.6 SD 5.49 5.48 5.14 6.06 4.56 6.69 5.52 5.60 Median 21.0 24.0 21.0 23.0 22.0 24.0 22.0 22.0 Range 17-43 16-34 16-37 16-40 16-36 17-49 16-38 16-49 Height (cm) N 31 30 30 30 31 30 28 210 0.399 Mean 177.8 176.8 177.0 175.3 176.1 175.5 176.3 176.4 SD 7.63 10.18 7.02 8.07 9.26 6.82 6.49 7.97 Median 177.8 175.3 177.8 176.0 176.5 174.2 175.3 176.2 Range 162.6-190.5 152.4-208.3 162.6-195.6 150.7-191.8 154.9-195.6 165.1-185.4 167.6-193.0 150.7-208.3 Weight (kg) N 31 30 30 30 31 30 28 210 0.352 Mean 80.3 81.9 83.3 81.7 82.3 82.5 77.6 81.4 SD 15.38 15.05 21.75 13.62 12.44 15.09 12.57 15.30 Median 77.3 80.0 75.8 78.8 78.0 81.4 76.4 78.D ,Range 56.7-123.6 55.3-113.6 52.6-140.5 65.0-124.5 57.3-109.3 61.4-116.8 61.4-105.0 52.6-140.5 Race! Asian 2 1 1 0 1 0 6 0.946 Ethnic Origin Black 1 1 1 2 0 0 7 Caucasian 18 17(56.7%) 21 20 17 20 19 132 (62.9%) Hispanic 10 9(30.0%) 7 7 12 8 9 62 (29.5%) Other 0 0 1 0 1 0 3 31 130 30 30 31 30 28 J210 NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE FOR AGE, HEIGHT, AND WEIGHT AN) FROM CHI-SQUARE TEST FOR RACE/ETHMIC ORIGIN.

Table Baseline Pain Intensity Scores (Categorical) Primary Efficacy INTENSITY _______IP-VALUE TREATMENT N MODERATE SEVERE SOURCE P-VALUE A) Placebo B) MS30 mg C) MS 60 mg D) MS 90 mg E) MS 30mg/NTX0.1 mug F) MS 60Omg /NTX0.1 mg G) MS 90 mg INTX 0.1 mg (58.1%) (60.0%) (60.0%) (60.0%) (58.1%) (53.3%) (57.1%) 13 12 12 12 13 14 12 1 (40.0%) 1 (40.0%) 1 (40.0%) 1 (41.9%) 1 (46.7%) 1 (42.9%) TREATMENT 0.999 NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE FOR AGE, HEIGHT, ANT) WEIGHT AND FROM CHI-SQUARE TEST FOR RACE/ETHNIC ORIGIN.

Table SOB Baseline Pain Intensity Scores (VAS) Primary Efficacy Population BASELINE VAS SCORE P-VALUE TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE P-VALUE A) Placebo 31 74.5 12.20 53 74.0 99 TREATMENT 0.407 mg 30 71.3 14.17 51 68.0 97 MS90- 0.031* MS60/NTX.1 mg 30 72.6 12.13 55 72.0 99 D) MS 90 mg 30 69.6 12.85 50 68.0 97 mg/NTX 0.1 mg 31 71.5 9.88 55 70.0 93 mg/NTX 0.1 mg 30 76.4 12.31 55 76.5 100 mg/NTX 0.1 mg 28 72.0 11.08 52 71.5 FORAGE, HEIGHT, WEIGHT, AND TIME BETWEEN END OF SURGERY AND STUDY MEDICATION, P-VALUES ARE FROM TWO-WAY ANALYSIS OF VARIANCE WITH TREATMENT AND SITE AS FACTORS; FOR GENDER, RACE/ETHNIC ORIGIN, AND NUMBER OF THIRD MOLARS EXTRACTED, P-VALUES ARE FROM COCHRAN-MANTEL-HAENZEL TEST ADJUSTING FOR SITE.

BLACK, ASIAN, HISPANIC, AND OTHER ARE COMBINED INTO ONE CATEGORY TO DERIVE P-VALUE.

4 OR MORE THIRD MOLARS EXTRACTED AS ONE CATEGORY TO DERIVE P-VALUE.

WO 01/85150 PCT/US01/14644 661 The sum of pain relief (total pain relief or TOTPAR) scores (4 hour, 6 hour, 8 hour) are summarized in Table 81 and the mean 4 hour scores are shown in Figure 41.

The placebo treatment group had the lowest mean TOTPAR scores. All 6 of the active treatment groups with 30 mg, 60 mg or 90 mg MS alone or in combination with 0.1 mg NTX exhibited mean TOTPAR scores that were numerically higher than placebo. The mean TOTPAR score for the 90 mg MS/0.1 mg NTX combination treatment was the highest among all treatment groups.

The mean TOTPAR scores for the 30 mg, 60 mg and 90 mg MS alone treatment groups were comparable. In contrast, the mean TOTPAR scores for the mg MS/0.1 mg NTX, 60 mg MS/0.1 mg NTX and 90 mg/MS 0.1 mg NTX combination treatment groups demonstrated a dose response as shown in Table 81 and Figure 41.

Table 81 Sum of Pain Relief Scores (TOTPAR) Primary Efficacy Population TOTAL PAIN RELIEF SCORE TREATMENT N MEAN SD MIN MEDIA MAX SOURCE P-VALUE TOTAL PAIN RELIEF SCORE (0-4 HOURS) A. Placebo 31 2.4 3.47 0.0 0.4 11.7 TRT <0.001** B. MS 30 mg 30 4.1 3.20 0.0 4.5 11.2 A-B 0.050 C. MS 60mg 30 4.7 3.59 0.0 4.9 11.9 A-C 0.011* D. MS 90 mg 30 4.5 3.71 0.0 4.2 12.6 A-D 0.020* E. MS 30mg /NTX0.1mg 31 3.8 3.54 0.0 3.8 9.9 A-E 0.106 F. MS 60 mg /NTX 0. 1 mg 30 4.4 3.73 0.0 4.3 13.3 A-F 0.025* G. MS 90mgI/NTX0.1mg 28 6.8 3.10 0.0 7.4 11.6 A-G <0.001*** B-C 0.555 B-D 0.705 B-E 0.720 B-F 0.775 B-G 0.004* C-D 0.833 C-E 0.341 C-F 0.761 C-G 0.02 1* D-E 0.459 D-F 0.926 D-G 0.012* E-F 0.518 E-G 0.001** 0.009** NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 81 (Continued) Sum of Pain Relief Scores (TOTPAR) Primary Efficacy Population TOTAL PAIN RELIEF SCORE TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE P-VALUE TOTAL PAIN RELIEF SCORE (0-6 HOURS) A. Placebo 31 4.1 5.95 0.0 0.4 19.7 TRT <0.001 B. MS 30 mg 30 7.4 5.79 0.0 8.9 17.7 A-B 0.027* C. MS 60 mg 30 7.8 5.88 0.0 8.4 17.9 A-C 0.016* D. MS 90 mg 30 7.6 6.17 0.0 8.1 20.1 A-D 0.021* E. MS 30 mg /NTX 0.1 mg 31 6.7 6.33 0.0 6.5 17.9 A-E 0.084 F. MS 60 mg /NTX 0.1 mg 30 7.6 6.09 0.0 6.9 21.3 A-F 0.020* G. MS 90 mg /NTX 0.1 mg 28 11.5 5.32 0.0 12.9 19.6 A-G <0.001*** B-C 0.830 B-D 0.918 B-E 0.618 B-F 0.901 B-G 0.010* C-D 0.910 C-E 0.474 C-F 0.927 C-G 0.019* D-E 0.547 D-F 0.983 D-G 0.014* E-F 0.532r E-G 0.002** F-G 0.015* NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 81 (Continued) Sum of Pain Relief Scores (TOTPAR) Primary Efficacy Population TOTAL PAIN RELIEF SCORE TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE P-VALUE TOTAL PAIN RELIEF SCORE (0-8 HOURS) A. Placebo 31 5.8 8.56 0.0 0.4 27.7 TRT 0.001 B. MS 30 mg 30 10.8 8.46 0.0 13.4 25.7 A-B 0.024* C. MS 60 mg 30 11.1 8.47 0.0 11.4 24.4 A-C 0.016* D. MS 90 mg 30 11.1 8.84 0.0 13.4 26.1 A-D 0.017* E. MS 30 mg /NTX 0.1 mg 31 9.6 9.21 0.0 8.8 25.9 A-E 0.083 F. MS 60 mg/NTX 0.1 mg 30 11.0 8.71 0.0 11.4 29.3 A-F 0.018* G. MS 90 mg /NTX 0.1 mg 28 16.4 7.73 0.0 18.4 27.6 A-G <0.001*** B-C 0.887 B-D 0.890 B-E 0.586 B-F 0.919 B-G 0.013* C-D 0.997 C-E 0.491 C-F 0.967 C-G 0.019* D-E 0.494 D-F 0.970 D-G 0.019 E-F 0.518 E-G 0.003** F-G 0.018* NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

WO 01/85150 PCT/US01/14644 665 Table 82 summarizes the 4, 6, and 8 hour sum of pain intensity difference (SPID) scores. The mean 4 hour results are also represented in Figure 42. The placebo treatment group had the lowest mean 4 hour SPID scores. All 6 of the active treatment groups with 30 mg, 60 mg or 90 mg MS alone or in combination with 0.1 mg NTX exhibited improved profiles in mean SPID relative to placebo. The mean 4 hour SPID score for the 90 mg MS/0.1 mg NTX combination treatment was the highest among all treatment groups.

The mean SPID scores for the 30 mg, 60 mg and 90 mg MS alone treatment groups were comparable. In contrast the mean SPID scores for the 30 mg MS/0.1 mg NTX, 60 mg MS/0.1 mg NTX and 90 mg MS/0.1 mg NTX combination treatment groups demonstrated a dose response as shown in Table 82 and Figure 42.

Table 82 Sum of Pain Intensity Difference Scores (SPIh) Primary Efficacy Population SUM OF PAIN INTENSITY DIFFERENCE

FP-AU

TREATMENT I N I MEAN I SD MIN IMEDIAN IMAX SOURCE P-AU SUM OF PAIN INTENSITY DIFFERENCE (0-4 HOURS) A. Placebo B. MS 30 mg C. MS 60 mg D. MS 90mg E. MS 30 mg /NTX 0. 1mg F. MS 60 mg/INTX 0. 1mg G. MS 90 mg INTX 0.1 mg -0.1 1.3 1.5 1.8 1.3 1.8 2.9 3.01 2.62 3.09 3.04 2.38 2.62 2.08

TRT

A-B

A-C

A-D

A-E

A-F

A-G

B-C

B-D

B-E.

B-F

B-G

C-D

C-E

C-F

C-G

D-E

D-F

D-G

E-F

E-G

F-G

0.004** 0.040* 0.024* 0.007**- 0.042* 0.006"* <0.001 0.834 0.508 0.969 0.475 0.026* 0.65 1 0.803 0.613 0.042* 0.480 0.958 0.111 0.448 0.022* 0.123 NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 82 (Continued) Sum of Pain Intensity Difference Scores (SPID) Primary Efficacy Population SUM OF PAIN INTENSITY DIFFERENCE TREATMENT IN MEAN ISD I MIN I MEDIAN IMAX ISOURCE TP-VALUE SUM OF PAIN INTENSITY DIFFERENCE (0-6 HOURS) A. Placebo B. MS 30 mg C. MS 60 mg D. MS 90mg E. MS 30 mg /NTX0. 1 mg F. MS 60Omg /NTXO0.1 mg G. MS 90mg /NTX 0.1mg -0.0 2.6 2.6 3.1 2.4 3.2 5.1 5.03 4.50 4.92 4.93 4.39 4.35 3.48 14.1 10.1 12.4 14.6 12.7 12.8 11.0

TRT

A-B

A-C

A-D

A-E

A-F

A-G

B-C

B-D

B-F

B-F

B-G

C-D

C-F

C-F

C-G

D-E

D-F

D-G

E-F

E-G

F-G

0.004** 0.024* 0.024*.

0.008** 0.033* 0.007** <0.0o1*** 0.997 0.682 0.876 0.64 8 0.039* 0.679 0.879 0,645 0.038* 0.569 0.962 0.095 0,537 0,026* 0.105 NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 82 (Continued) Sum of Pain Intensity Difference Scores (SPID) Primary Efficacy Population SUM OF PAIN INTENSITY DIFFERENCE TREATMENT -7N -1MEAN ISD MIN MEDIAN IMAX SOURCE P-VALUE SUM OF PAI INTENSITY DIFFERENCE (8 HOURS) A. Placebo B. MS 30 mg C. MS 60 mg D. MS 90mg E. MS 30Omg /NTX 0.1 mg F. MS 60 mg /NTX 0.1 mg G. MS 90 mg /NTX 0.1 mg 31 30 30 30 31 30 28 7.16 6.40 6.79 6.91 6.46 6.33 5.01 -7.8 -7.8 -7.8 -7.8 -7.8 -7.5 -0.3 20.1 13.6 16.9 18.6 18.7 18.8 15.0

TRI

A-B

A-C

A-D

A-E

A-F

A-G

B-C

B-D

B-H.

B-F

B-G

C-D

C-H

C-F

C-G

D-E

D-F

D-G

B-F

E-G

F-G

0.0 04* 0.020* 0.021 0.007** 0.033* 0.006** <0.00 0.990 0.684 0.839 0.682 0.040* 0.675 0.849 0.673 0.039* 0.540 0.997 0.097 0.538 0. 023 0.097 NOTE: P-VALUES ARE FROM ON-E-WAY ANALYSIS OF VARIANCE.

WO 01/85150 PCT/US01/14644 669 Figure 43 is a visual presentation of the summary and analysis of time to onset of analgesia presented in Table 83. The median time to onset of analgesia was shortest in the 90 mg MS/O.1 mg NTX combination treatment group.

Table 83 Time to Onset of Analgesia Primary Efficacy Potiulation MEDIAN 95% CONFIDENCE TREATMENT N TIME INTERVAL SOURCE LOG-RANK WILCOXON (hh:rnm) (lih1:11Un) A) Placebo 31 8:00 8:00, 8:00 TRT K0.001* B) MS 30 mg 30 3:00 2:00, 8:00 A-B 0.009** 0.023* C) MS 60 mg 30 2:00 1:00, 8:00 A-C 0.003** 0.008** D) MS 90 mg 30 2:00 1:00, 7:00 A-D .001** 0.004** E) MS 3 0 mg/NTX 0. 1 mg 31 4:00 1:30, 8:00 A-B 0.029* 0.048* F) MS 60 mg/NTX 0.1 mg 30 3:00 1:30, 8:00 A-F 0.006** 0.014* G) MS 90mg/NTXO0.lmg 28 1:00 1:00, 1:30 A-G <0.001** <0.001*** B-C 0.537 0.341 B-D 0.407 0.289 B-E 0.826 0.869 B-F 0.817 0.659 B-G 0.002** <0.001*** C-D 0.780 0.815 C-E 0.468 0.550 C-F 0.778 0.767 C-G 0.017* 0.013* D-E 0.306 0.401 D-F 0.60 1 0.635 D-G 0.043* 0.036* F-F 0.62 1 0.720 E-G 0.005** 0.006** 0.01 1* 0.013* !1Jt ,Jt 0 0 Note: median time and its confidence interval are estimated using kaplan-meler method. Log-rank and wilcoxon tests are used to test the equality of Kaplan-Meier survival functions over different treatment groups.

WO 01/85150 PCT/US01/14644 671 Table 84 summarizes the results of the time to remedication (see also Figure 44). The placebo group had the shortest median time to remedication and the 90 mg MS/0.1 mg NTX combination treatment group had the longest median time to remedication.

Table 84 Time to Re-Medication Primary Efficacy Population MEDIAN 95% CONFIDENCE TREATMENT N ME D IA N 9 IDE SOURCE LOG-RANK WILCOXON TIME (hh:mm) INTERVAL (hh:mn) A) Placebo 31 1:38 (1:35, 2:07 TRT <0.001*** B) MS 30 mg 30 8:33 2:31, 9:55 A-B 0.003** <0.001*** C) MS 60 mg 30 7:17 2:08, 10:13 A-C 0.012* 0.002** D) MS 90 mg 30 9:09 2:09, >24:00 A-D <0.001*** E) MS 30 mg/NTX 0.1 mg 31 2:23 1:40, 9:53 A-E 0.073 0.043* F) MS 60 mg/NTX 0.1 mg 30 5:23 (2:09, 10:17 A-F 0.003** <0.001*** G) MS 90 mg/NTX 0.1 mg 28 9:50 6:06, 12:26 A-G <0.001*** B-C 0.699 0.723 B-D 0.265 0.607 B-E 0.349 0.159 B-F 0.828 0.830 B-G 0.162 0.250 C-D 0.109 0.353 C-E 0.598 0.334 C-F 0.477 0.807 C-G 0.060 0.120 D-E 0.037* 0.067 D-F 0.444 0.586 D-G 0.802 0.602 E-F 0.202 0.209 E-G 0.023* 0.021* F-G 0.275 0.221 NOTE: MEDIAN TIME AND ITS CONFIDENCE INTERVAL ARE ESTIMATED USING KAPLAN-MEIER METHOD. LOG-RANK AND WILCOXON TESTS ARE USED TO TEST THE EQUALITY OF KAPLAN-MEIER SURVIVAL FUNCTIONS OVER DIFFERENT TREATMENT GROUPS.

WO 01/85150 PCT/US01/14644 673 The summary and analysis of percent of subjects who took rescue medication up to 4, 8 and 24 hours are presented in Table 85. More than 70% of subjects at 4 hours in the 90 mg MS/0.1 mg NTX combination group and more than 60% of subjects in the same combination group at 8 hours did not require rescue medication.

Table Time to Re-Medicated Efficacy Population I RE-MEDICATED TREATMENT N YES NO SOURCE_ P-VALUE EFFICACY OBSERVATION PERIOD (0-4 HOURS) A) Placebo 31 .24 (77.42%) 7 (22.58%) TRT 0.007** B) MS 30 mg. 30 13 (43 17 (56.67%) A-B 0.006** C) MS 60 mg 30 12 (40.00%) 18 A-C 0.003** D) MS 90 mg 30 13 (43.33%) 17 (56.67%) A-D 0.006** E) MS 30Omg /NTX 0. 1mg 31 17 (54.84%) 14 (45.16%) A-E 0.060 F) MS 60Omg /NTX 0. 1mg 30 12 (40.00%) 18 (60.00%) A-F 0.003** G) MS 90mgI/NTXO0.l1mg 28 8 (28.57%) 20 (71.43%) A-G <0.001*** B-C 0.793 B-D 1.000 B-E 0.369 B-F 0.793 B-G 0.242 C-D 0.793 C-B 0.246 C-F 1.000 C-G 0.360 D-E 0.369 D-F 0.793 D-G 0.242 E-F 0.246 r E-G 0.041*q 0.360 NOTE: P-VALUES ARE FROM CHI-SQUARE TEST.

Table 85 (Continued) Time to Re-Medicated Efficacy Population TREATMENT N YES F NO SOURCE P-VALUE EFFICACY OBSERVATION PERIOD (0-8 HOURS)___ A) Placebo 31 25 B) MS 30 mg. 30 14 C) MS 60mg 30 15 D) MS 90 mg 30 14 E) MS 30mg /NTXO0.l1mg 31 19 F) MS 60mg /NTXO0. 1mg .30 17 G) MS 90mg /NTXO0.l1mg 28 10 (80.65%/) (46.67%) (50.00%) (46.67%) (61.29%) (56.67%) (35.71%) (19.35%) (53.33%) (50.00%) (53.33%) (38.71%) (43.33%) (64.29%)

TRT

A-B

A-C

A-D

A-E

A-F

A-G

B-C

B-D

B-E

B-F

B-G

C-D

C-E

C-F

C-G

D-E

D-F

D-G

E-F

E-G

F-G

0.021* 0.006** 0.012* 0.006** 0.093 0. 043 <0.00l*** 0.796 1.000 0.252 0.438 0.397 0.796 0.375 0.605 0.272 0.252 0.438 0.397 0.714 0.050* 0.110 NOTE: P-VALUES ARE FROM CHI-SQUARE TEST.

Table 85 (Continued) Time to Re-Medicated Efficacy Population SI RE-MEDICATED TREATMENT N YES NO SOURCE P-VALUI2 EFFICACY OBSERVATION PERIOD (0-24 HOURS) A) Placebo 31 29 (93.55%) 2 TRT 0.026* B) MS 30 mg. 30 25 (83.33%) 5 (16.67%) A-B 0.211 C) MS 60 mg 30 27 (90.00%) 3 (10.00%) A-C 0.614 D) MS 90 mg 30 20 (66.67%) 10 (33 A-D 0.008** E) MS 30 mg /NTX 0. 1 mg 31 28 (90.32%) 3 A-F 0.641 F) MS 60 mg /NTX 0. 1 mg 30 23 (76.67%) 7 (23.33%) A-F 0.063 G) MS 90mg /NTXO0.l1mg 28 19 (67.86%) 9 (32.14%) A-G 0.011* B-C 0.448 B-D 0.136 B-E 0.419 B-F 0.519 B-G 0.169 C-D 0.028* C-F 0.966 C-F 0.166 C-G 0.038* D-E 0.024* D-F 0.390 D-G 0.923 E-F 0.150 E-G 0.032*q F-G 0.453 NOTE: P-VALUES ARE FROM CHI-SQUARE TEST.

WO 01/85150 PCT/US01/14644 677 Figure 45 is a visual presentation of the mean pain relief scores presented in Table 86. The mean pain relief score for the placebo treatment was less than those for the active treatment groups (30 mg, 60 mg, 90 mg MS alone or in combination with 0.1 mg NTX) which improved over time. There was separation between the placebo and the active treatment groups that continued throughout the 8 hour study period.

Highest pain relief scores were observed for the 90 mg MS/0.1 mg NTX combination group (Figure Table 86 Pain Relief (PR) Score Primary Efficacy Population PAIN RELIEF SCORE (P-R) TREATMENT N MEAN SD MIN MEDAN MAX SOURCE P-VALU1E

MINUTES

A) Placebo 31 0.26 0.58 0.00 TRT 0.881 B) MS 30 mg 30 0.27 0.52 0.00 A-B 0.951 C) MS 60 mg 30 0.30 0.47 0.00 A-C 0.765 D) MS 90 mg 30 0.37 0.61 0.00 A-D 0.440 B) MS 30 mg /NTX 0.1 mg 31 0.19 0.48 0.00 A-E 0.644 F) MS 60OmgA/NTX0. 1 mg 30 0.37 0.61 0.00 A-F 0.440 G) MS 90 mg /NTX 0. 1 mg 28 0.32 0.55 0.00 A-G 0.658 B-C 0.814 B-D 0.481 B-E 0.603 B-F 0.481 B-G 0.704 C-D 0.638 C-B 0.449 C-F 0.638 C-G 0.882 D-E 0.219 D-F 1.000 D-G 0.754 B-F 0.219 E-G 0.372 F-G 0.754 NOTE: P-VALUTES ARE FROM ONE-WAY ANALYSIS OF VARIANCE Table 86 (Continued) Pain Relief (PR) Score Primary Efficacy Population PAIN RELIEF SCORE (PR) TREATMENT N MEAN ISD MIN MEDIAN MAX SOURCE P-VALUE

MINUJTES

A) Placebo 31 0.45 0.81 0.00 TRT 0.222 B) MS 30mg 30 0.60 0.67 1.00 A-B 0.463 C) MS 60 mg 30 0.67 0.66 1.00 A-C 0.288 D) MS 90 mg 30 0.83 0.91 1.00 A-D 0.060 E) MS 30 mg /NIX 0. 1mg 31 0.58 0.67 0.00 A-E 0.520 F) MS 60mg /NTXO0.l1mg 30 0.73 0.83 1.00 A-F 0.164 G) MS 90mg /NTXO0.l1mg 28 0.96 0.92 1.00 A-cl 0.013* B-C 0.744 B-D 0.253 B-E 0.924 B-F 0.513 B-Cl 0.080 C-D 0.414 C-E 0.670 C-F 0.744 C-G 0.152 D-E 0.212 D-F 0.624 D-cl 0.528 E-F 0.450 E-cl 0.063 0.266 NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARTANCE Table 86 (Continued) Pain Relief (PR) Score Primary Efficacy Population PAIN4 RELIE SCORE (PR) TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE P-VALUE MINUTES A) Placebo 31 0.55 0.89 0.00 TRT 0.001** B) MS 30 mg 30 0.90 0.80 1.00 A-B 0.143 C) MS 60 mg 30 0.97 0.96 1.00 A-C 0.082 D) MS 90 mg 30 1.17 1.09 1.00 A-D 0.010* E) MS 30Omg /NTX0. 1 mg 31 0.74 0.89 0.00 A-E 0.416 F) MS 60 mg/NTX0.1mg 30 1.03 1.10 1.00 A-F 0.044* G) MS 90mg JNTXO0.l1mg 28 1.61 0.74 2.00 A-G <0.001*** B-C 0.782 B-D 0.270 B-E 0.509 B-F 0.581 B-G 0.004** C-D 0.408 C-E 0.349 C-F 0.782 C-G 0.010** D-E 0.077 D-F 0.581 D-G 0.074 E-F 0.225 E-G 00** 0.020* NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE Table 86 (Continued) Pain Relief (PR) Score Primary Efficacy Population TREATMENTPAIN RELIEF SCORE (PR)J TREAMNT N MEAN FSD MIN MEDIAN MAX SOURCE IP-VALUE_ A) Placebo 31 0.61 0.92 0.00 TRT 0.001** B) MS 30mg 30 0.97 0.81 1.00 A-B 0.169 C) MS 60 mg 30 1.17 0.99 1.00 A-C 0.032* D) MS 90 mg 30 1.17 1.05 1.00 A-D 0.032* E) MS 30mg /NTX 0.1lmg 31 1.03 1.05 1.00 A-E 0.100 F) MS 60mg /NTX0.lmig 30 1.13 1.22 1.00 A-F 0.044* G) MS 90Omg /NTX 0. 1mg 28 1.82 0.90 2.00 A-G <0.001*** B-C 0.440 lB-D 0.440 B-E 0.798 B-F 0.520 B-CG 0.001** C-U 1.000 C-E 0.600 C-F 0.897 C-G 0.014* U-E 0.600 U-F 0.897 D-G 0.014* F-F 0.694 E-G 0.003** 0.010** NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE Table 86 (Continued) Pain Relief (PR) Score Primary Efficacy Population PAIN RELIEF SCORE (PR) TREATMENT N MEAN SID MTN MEDIAN MAX SOURCE P-VALUE 2 HOURS A) Placebo 31 0.65 0.98 0.00 TRT B) MS 30 mg 30 1.17 0.95 1.00 A-B 0.059 C) MS 60 mg 30 1.37 1.19 1.00 A-C 0.009** D) MS 90 mg 30 1.30 1.18 1.00 A-D 0.018* E) MS 30mg /NTXO0.l1mg 31 1.13 1.06 1.00 A-B 0.078 F) MS 60mg /NTX 0.l1mg 30 1.17 1.12 1.00 A-F 0.059 G) MS 90mg /NTXO0.l1mg 28 2.00 1.02 2.00 A-G <0.00l*** B-C 0.472 B-D 0.63 1 B-B 0.891 B-F 1.000 B-G 0.004** C-D 0.810 C-B 0.389 C-F 0.472 C-G 0.026* D-E 0.535 D-F 0.631 D-G 0.014* B-F 0.891 B-G 0.002** 0.004** NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE Table 86 (Continued) Pain Relief (PR) Score Primary Efficacy Population PAIN RELIEF SCORE (PR) TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE P-VALUE 3 HOURS A) Placebo 31 0.74 1.12 0.00 TRT 0.001** B) MS 30 mg 30 1.40 1.13 2.00 A-B 0.031* C) MS 60 mg 30 1.57 1.30 2.00 A-C 0.007** D) MS 90 mg 30 1.30 1.15 1.00 A-D 0.068 B) MS 30mg /NTX 0.l1mg 31 1.23 1.23 1.00 A-B 0.110 F) MS 60mg /NTXO0.l1mg 30 1.40 1.22 1.00 A-F 0.03 1* G) MS 90mg /NTX 0.l1mg 28 2.18 1.12 3.00 A-G <0.001** B-C 0.587 B-D 0.744 B-B 0.567 B-F 1.000 B-G 0.013* C-D 0.385 C-B 0.263 C-F 0.587 C-G 0.051 D-E 0.807 D-F 0.744 D-G 0.005** B-F 0.567 E-G 0.002** F-G 0.013* NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE Table 86 (Continued) Pain Relief (PR) Score Primary Efficacy Population PAIN RELIEF SCORE (PR) TREATMENT N MEANTSD MIN I MEDIAN I MAX ISOURCE P-VALUE 4 HOURS A) Placebo 31 0.81 1.22 0.00 TRT 0.005** B) MS 30mg 30 1.47 1.31 1.50 A-B 0.046* C) MS 60 mg 30 1.57 1.30 1.50 A-C 0.022* D) MS 90 mg 30 1.50 1.28 2.00 A-D 0.036* E) MS 30mg /NTX 0.l1mg 31 1.35 1.40 1.00 A-E 0.094 F) MS 60 mg /NTXO0.l1mg 30 1.53 1.28 1.50 A-F 0.028* G) MS 90mg /NTXO0.l1mg 28 2.25 1.17 3.00 A-G <0.001*** B-C 0.763 B-D 0.920 B-B 0.734 B-F 0.841 B-G 0.021* C-D 0.841 C-B 0.520 C-F 0.920 C-G 0.044* D-E 0.660 D-F 0.920 D-G 0.027* B-F 0.588 E-G 0.008** 0.035* NOTE: P-VALUES ARE FROM NOT: PVALES RE ROMONE-WAY ANALYSIS OF VARIANCE Table 86 (Continued) Pain Relief (PR) Score Primary Efficacy Population PAIN RELIIEF SCORE (PR) TREATMENT N MEAN SD -MIN MEDLAN MX SOURCE P-VALUE

HOURS

A) Placebo 31 0.84 1.29 0.00 TRT 0.004** B) MS 30 mg 30 1.70 1.39 2.00 A-B 0.013* C) MS 60 mg 30 1.50 1.31 1.00 A-C 0.055 D) MS 90 mg 30 1.53 1.33 1.50 A-D 0.044* E) MS 30mg /NTXO0.l1mg 31 1.45 1.46 1.00 A-E 0.073 F) MS 60Omg /NTX 0. 1mg 30 1.63 1.35 2.00 A-F 0.022* G) MS 90mg /NTXO0.l1mg 28 2.36 1.22 3.00 A-G <0.00t** B-C 0.564 B-D 0.631 B-E 0.470 B-F 0.847 B-G 0.063 C-D 0.923 C-E 0.888 C-F 0.700 C-G 0.01 6* D-E 0.812 D-F 0.773 D-G 0.020* E-F 0.597 E-G 0.010* 0.041 NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE Table 86 (Continued) Pain Relief (PR) Score Primary Efficacy Population PAIN RELIEF SCORE (PR)

C

TREATMENT N MEAN ISD IMIN IMEDIAN 11MAX FSO0_URCE P-VALUE 6 HOURS Placebo MS 30mg MS 60 mg MS 90 mg MS 30 mg /NTX 0.1 mg MS 60 mg /NTX 0.1 mg MS 90 mg /NTX 0.1 mg 0.87 1.73 1.63 1.67 1.45 1.67 2.39 1.36 1.44 1.35 1.42 1.50 1.40 1.23 0.00 2.00 2.00 2.00 1.00 2.00 3.00

TRT

A-B

A-C

A-D

A-E

A-F

A-G

B-C

B-D

B-E

B-F

B-G

C-D

C-E

C-F

C-G

D-E

D-F

D-G

E-F

E-G

F-G

0.007** 0.016* 0.033* 0.026* 0.102 0.026* <0.00** 0.78 1 0.853 0.430 0.853 0.072 0.926 0.610 0.92 6 0.039* 0.546 1.000 0. 048* 0.546 0.010* 0.048* 1. L J I I NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE Table 86 (Continued) Pain Relief (PR) Score Primary Efficacy Population PAIN RELIEF SCORE (PR) TREATMENT N MEAN S MN MEDIAN MAX ISOURCE P-VALUE 7 HOURS A) Placebo 31 0.84 1.32 0.00 TRT 0.003** B) MS 30mg 30 1.67 1.42 2.00 A-B 0.022* C) MS 60 mg 30 1.63 1.38 1.50 A-C 0.028* D) MS 90 mg 30 1.77 1.45 2.00 A-D 0.011* E) MS 30mg /NTX 0.1Img 31 1.45 1.52 1.00 A-E 0,087 F) MS 60Omg /NTXO0.l1 mg 30 1.70 1.42 2.00 A-F 0.018* G) MS 90mg /NTXO0.l1mg 28 2.46 1.29 3.00 A-G <0.001*** B-C 0.927 B-D 0.783 B-E 0.550 B-F 0.927 B-G 0.032* C-D 0.713 C-E 0.614 C-F 0.854 C-G 0.025* D-E 0.382 D-F 0.854 D-G 0.060 E-F 0.490 E-G 0.006** 0.040* NOTE: P-VALUES ARE FROM ON-WAY ANALYSIS OF VARIANCE Table 86 (Continued) Pain Relief (PR) Score Primary Efficacy Population PAIN RELIEF SCORE (PR) TREATMENT N MEAN SD MIN MEDIAN MX] SOURCE P-VALUE 8 HOURS A) Placebo 31 0.84 1.32 0.00 TRT 0.002** B) MS 30 mg 30 1.57 1.38 1.50 A-B 0.042* C) MS 60 mg 30 1.70 1.42 2.00 A-C 0.017* D) MS 90 mg 30 1.73 1.41 2.00 A-D 0.013* E) MS 30mg /NTX0.l mg 31 1.39 1.45 1.00 A-E 0.122 F) MS 60 mg /NTX 0.1 mg 30 1.63 1.40 1.50 A-F 0.027* G) MS 90 mg /NTX 0.1 mg 28 2.50 1.35 3.00 A-G <0.00** B-C 0.711 B-D 0.643 B-fl 0.615 B-F 0.853 B-G 0.011* C-D 0.926 C-fl 0.381 C-F 0.853 C-G 0.030* D-E 0.332 D-F 0.781 D-G 0.037* E-F 0.490 fl-G 0.002"* F-G 0.019* NOTE: P-VALUES ARE FROM ON-WAY ANALYSIS OF VARIANCE WO 01/85150 PCT/US01/14644 689 The mean categorical pain intensity difference (PID) scores are presented in Table 87 and Figure 46. The mean PID scores for the placebo treatment group was generally flat while the mean PID scores generally improved over time for the active treatment groups (30 mg MS, 60 mg MS and 90 mg MS alone or in combination with 0.1 mg NTX). The mean scores for the morphine alone and morphine/naltrexone combination treatment groups were higher than the mean PID scores for the placebo group at each hourly assessment time from 1-8 hours. Highest pain relief as measured by PID scores was observed for the 90 mg MS/0.1 mg NTX combination treatment group.

Table 87 Pain itensity Difference Score (Categorical) Primary Efficacy Population PAIN INTENSITY DIFFERENCE SCORE (Categorical) P-VALUE TREATMENT N MEAN SD MM MEDIAN IMAX ISOURCE MINUTES-060.2 A) Placebo 31 6 0.51 0.00 TRT052 B) MS 30 mg 30 -0.07 0.45 0.00 A-B 0.985 C) MS 60 mg 30 -0.07 0.58 0.00 A-C 0.985 D) MS 90 mg 30 0.07 0.52 0.00 A-D 0.266 E) MS 30Omg /NTX0.l 1rmg 31 -0.03 0.31 0.00 A-E 0.783 F) MS 60Omg /NTX0. 1 mg 30 0.13 0.43 0.00 A-F 0.094 G) MS 90Omg /NTX0. 1 mg 28 0.04 0.33 0.00 A-G 0.404 B-C 1.000 B-D 0.262 B-E 0.770 B-F 0.093 B-G 0.398 C-D 0.262 C-E 0.770 C-F 0.093 C-G 0.398 D-E 0.402 D-F 0.575 D-G 0.798 EXF 0.161 E-G 0.571 0.420 NOTE: P-VALUMS ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 87 (Continued) Pain Intensity Difference Score (Categorical) Primary Efficacy Population PAIN INTENSITY DIFFERENCE SCORE (Categorical) :P-VALUE TREATMENT N MEAN SD MIN MEDIAN IMAX ISOURCE 1 MINUTES A) Placebo 31 0.00 0.63 0.00 TRT 0.396 B) MS 30mg 30 0.17 0.70 0.00 A-B 0.332 C) MS 60 mg 30 0.13 0.68 0.00 A-C 0.437 D) MS 90 mg 30 0.27 0.78 0.00 A-D 0.121 E) MS 30 mg /NTX 0.1 mg 31 0.16 0.45 0.00 A-E 0.343 F) MS 60 mg /NTX 0.1 mg 30 0.33 0.76 0.00 A-F 0.053 G) MS 90 mg /NTX 0. 1 mg 28 0.36 0.62 0.00 A-G 0.042* B-C 0.847 B-D 0.563 B-F 0.975 B-F 0.336 B-G 0.280 C-D 0.441 C-F 0.871 C-F 0.248 C-G 0.204 D-E 0.539 D-F 0.700 D-G 0.607 E-F 0.316 E-G 0.263 0.892 NOTE: P-VALUTES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 87 (Continued) Pain Intensity Difference Score (Categorical) Primary Efficacy Population PAIN INTENSITY DIFFERENCE SCORE (Categorical) P-VALUE TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE

MINUTES

A) Placebo 31 -0.10 0.75 0.00 TRT 0.012* B) MS 30 mg 30 0.30 0.70 0.00 A-B 0.040* C) MS 60 mg 30 0.27 0.83 0.00 A-C 0.060 D) MS 90 mg 30 0.50 0.90 0.50 A-D 0.002** E) MS 30 mg /NTX 0.1 mg 31 0.23 0.62 0.00 A-E 0.091 F) MS 60 mg /NTX 0.1 mg 30 0.43 0.82 0.00 A-F 0.006** G) MS 90 mg/NTX 0.1 mg 28 0.61 0.57 1.00 A-G <0.001*** B-C 0.863 B-D 0.302 B-E 0.699 B-F 0.491 B-G 0.120 C-D 0.229 C-E 0.832 C-F 0.390 C-G 0.085 D-E 0.154 D-F 0.731 D-G 0.587 E-F 0.281 E-G 0.052 F-G 0.378 NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 87 (Continued) Pain Intensity Difference Score (Categorical) Primary Efficacy Population PAIN IN~TENSITY DIFFERENCE SCORE (Categorical) P-VALUE TREATMENT N MEAN SD MIN IMEDIAN IMAX ISOURCE

MINUTES

A) Placebo 31 -0.06 0.85 0.00 TRT 0.012* B) MS 30 mg 30 0.27 0.69 0.00 A-B 0.091 C) MS 60 mg 30 0.30 0.84 0.00 A-C 0.063 D) MS 90 mg 30 0.43 0.86 0.50 A-D 0.0111* B) MS 30Omg /NTX0.1 mg .31 0.39 0.67 0.00 A-B 0.021* F) MS 60 mgI/NTX0.1 mg 30 0.43 0.77 0.00 A-F 0.011* G) MS 90mg /NTXO0.l1mg 28 0.71 0.60 1.00 A-C <0.00l*** B-C 0.866 B-D 0.398 B-E 0.538 B-F 0.398 B-G 0.026* C-D 0.499 C-B 0.656 C-F 0.499 C-G 0.040* D-B 0.813 D-F 1.000 D-G 0.162 B-F 0.813 E-G 0.101 F-G 0.162 NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 87 (Continued) Pain Intensity Difference Score (Categorical) Primary Efficacy Population PAIN INTENSITY DIFFERENCE SCORE (Categorical) P-VALUE TREATMENT N EN S N MDAN IMAX SOURCE 2 HOURS__ A) Placebo -31 -0.10 0.87 0.00 TRT 0.003** B) MS 30 mg 30 0.33 0.76 0.00 A-B 0.042* C) MS 60 mg 30 0.47 0.97 0.50 A-C 0.008** D) MS 90 mg 30 0.50 0.94 0.50 A-D 0.005** E) MS 30 mg /NTX 0.1 mg 31 0.39 0.72 0.00 A-E 0.02 1* F) MS 60 mg /NTX 0. 1 mg 30 0.43 0.73 0.00 A-F 0.0 12* G) MS 90 mg INTX 0. 1 mg 28 0.86 0.71 1.00 A-G <0.001*** B-C 0.530 B-D 0.432 13-E 0.798 B-F 0.637 B-G 0.016* C-D 0.875 C-F 0.705 C-F 0.875 C-G 0.071 D-E 0.591 D-F 0.753 D-G 0.099 E-F 0.826 E-G 0.029* F-G 0.051 NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 87 (Continued) Pain Intensity Difference Score (Categorical) Primary Efficacy Population PAIN INTENSITY DIFFERENCE SCORE (Categorical) P-VALUE TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE 3 HOURS A) Placebo 31 0.00 0.97 0.00 TRT 0.003** B) MS 30 mg 30 0.43 0.86 0.00 A-B 0.056 C) MS 60 mg 30 0.53 0.97 1.00 A-C 0.019* D) MS 90 mg 30 0.57 0.90 1.00 A-D 0.013* E) MS 30 mg/NTX 0.1 mg 31 0.39 0.80 0.00 A-E 0.084 F) MS 60 mg /NTX 0.1 mg 30 0.60 0.86 0.50 A-F 0.008** G) MS 90 mg NTX 0.1 mg 28 1.00 0.77 1.00 A-G <0.001*** B-C 0.660 B-D 0.557 B-E 0.837 B-F 0.463 B-G 0.015* C-D 0.883 C-E 0.517 C-F 0.769 C-G 0.045* D-E 0.426 D-F 0.883 D-G 0.062 E-F 0.345 E-G 0.008** F-G 0.085 NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 87 (Continued) Pain Intensity Difference Score (Categorical) Primary Efficacy Population PAIN INTENSITY DIFFERENCE SCORE (Categorical) I P-VALUE TREATMENT N MEAN SD MIN IMEDIAN IMAX ISOURCE I 4 HOURS A) Placebo 31 0.06 1.03 0.00 TRT 0.012* B) MS 30 mg 30 0.67 0.99 1.00 A-B 0.015* C) MS 60 mg 30 0.60 1.04 1.00 A-C 0.031* D) MS 90 mg 30 0.60 0.97 1.00 A-D 0.031* E) MS 30 mg /NTX 0.1 mg 31 0.55 0.99 0.00 A-E 0.049* F) MS 60mg /NTXO0.l1mg 30 0.67 0.88 1.00 A-F 0.015* G) MS 90 mg/NTXO0.l1mg 28 1.07 0.77 1.00 A-G <0.001*** B-C 0.788 B-D 0.788 B-E 0.631 B-F 1.000 B-G 0.110 C-D 1.000 C-E 0.834 C-F 0.788 C-G 0.063 D-E 0.834 D-F 0.788 D-G 0.063 E-F 0.631 E-G 0.038* F-G 0.110 NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 87 (Continued) Pain Intensity Difference Score (Categorical) Primary Efficacy Population PAIN INTENSITY DIFFERENCE SCORE (Categorical) P-VALUE TREATMENT N MEAN SD MIN IMEDIAN IMAX ISOURCE

HOURS

A) Placebo 31 0.03 1.02 0.00 IRT 0.007** B) MS 30 mg 30 0.63 0.96 1.00 A-B 0.018* C) MS 60 mg 30 0.57 1.01 1.00 A-C 0.034* D) MS 90 mg 30 0.67 1.03 1.00 A-D 0.012* E) MS 30Omg /NTX0.1 m ig 31 0.58 1.03 0.00 A-E 0.029* F) MS 60Omg /NTX0.1f mg 30 0.67 0.99 0.00 A-F 0.012* G) MS 90mg /NTXO0.ltmg 28 1.11 0.79 1.00 A-G <0.00l*** B-C 0.792 B-D 0.895 B-E 0.834 B-F 0.895 B-G 0.067 C-D 0.693 C-E 0.956 C-F 0.693 C-G 0.037* D-E 0.732 D-F 1.000 D-G 0.089 EXF 0.732 E-G 0.041* 0.089 NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 87 (Continued) Pain Intensity Difference Score (Categorical) Primary Efficacy Population PAIN INTENSITY DIFFERENCE SCORE (Categorical) :P-VALUE TREATMENT N MEAN SD MIN MEDIAN MAX ISOURCE 6 HOURS A) Placebo 31 0.06 1.09 0.00 TRT 0.014* B) MS 30 mg 30 0.70 1.02 1.00 A-B 0.016* C) MS 60 mg 30 0.60 1.00 1.00 A-C 0.042* D) MS 90 mg 30 0.73 1.05 1.00 A-D 0.011* E) MS 30Omg /NTX0. 1 mg 31 0.61 1.09 0.00 A-E 0.035* F) MS 60Omg /NTX 0. 1mg 30 0.73 1.05 0.50 A-F 0.011* G) MS 90mg/NTX 0.l1mg 28 1.11 0.79 1.00 K-G <0.001*** B-C 0.705 B-D 0.899 B-E 0.739 B-F 0.899 B-G 0.130 C-D 0.613 C-E 0.961 C-F 0.613 C-G 0.060 D-E 0.645 D-F 1.000 D-G 0.165 E-F 0.645 E-G 0.065 0.165 NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 87 (Continued) Pain Intensity Difference Score (Categorical) Primary Efficacy Population PAIN INTENSITY DIFFERENCE SCORE (Categorical) P-VALUE TREATMENT N MEAN SD MI MEAN AX SUC 7 HOURS A) Placebo 31 0.03 1.08 0.00 TRT 0.005** B) MS 30 mg 30 0.67 0.99 1.00 A-B 0.017* C) MS 60 mg 30 0.63 1.00 1.00 A-C 0.023* D) MS 90 mg 30 0.77 1.07 1.00 A-D 0.006** E) MS 30 mg/NTX 0. 1mg 31 0.58 1.09 0.00 A-E 0.036* F) MS 60Omg /NTX0.l m rg 30 0.73 1.05 0.50 A-F 0.008** G) MS 90mg/NTX0.1mg 28 1.18 0.86 1.00 A-G <0.001*** B-C 0.900 ]3-D 0.706 B-E 0.744 B-F 0.801 B-G 0.059 C-D 0.615 C-F 0.841 C-F 0.706 C-G 0.044* D-E 0.480 D-F 0.900 D-G 0.128 E-F 0.562 E-G 0.026* F-G 0.100 NOTE: P-VALUES ARE FROM ON'E-WAY ANALYSIS OF VARIANCE.

Table 87 (Continued) Pain Intensity Difference Score (Categorical) Primary Efficacy Population PAIN INTENSITY DIFFERENCE SCORE (Categorical) P-VALUE TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE 8 HOURS A) Placebo 31 0.03 1.08 0.00 TRT 0.002** B) MS 30 mg 30 0.57 0.94 1.00 A-B 0.041* C) MS 60 mg 30 0.70 1.09 1.00 A-C 0.011* D) MS 90 mg 30 0.73 1.05 1.00 A-D 0.008** E) MS 30 mg/NTX 0.1 mg 31 0.52 1.00 0.00 A-E 0.062 F) MS 60 mg/NTX 0.1 mg 30 0.70 1.06 0.00 A-F 0.011* G) MS 90 mg/NTX 0.1 mg 28 1.21 0.88 1.00 A-G <0.001*** B-C 0.612 B-D 0.526 B-E 0.846 B-F 0.612 B-G 0.016* C-D 0.899 C-E 0.480 C-F 1.000 C-G 0.055 D-E 0.405 D-F 0.899 D-G 0.073 E-F 0.480 E-G 0.009** F-G 0.055 NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

WO 01/85150 PCT/US01/14644 701 Tables 88A and 88B present the mean maximum pain relief (MAXPAR) and mean peak pain intensity difference (PEAKPID) scores. The mean MAXPAR scores presented in Table 88A varied among treatment groups. The mean MAXPAR score was highest for the 90 mg MS/0.1 mg NTX combination treatment group compared to all other groups. The mean scores for all 6 active treatment groups were greater than the mean score for the placebo group. The mean PEAKPID scores presented in Table 88B varied among treatment groups, and were greater for all 6 active treatment groups compared to the placebo group. Compared to all other groups, the mean PEAKPID scores were highest for the 90 mg MS/0.1 mg NTX combination treatment group.

Table 88A Maximum Pain Relief Score (MAXPAR) Primary Efficacy Population MAXIMUM PAIN RELIEF SCORE (MAXPAR) P-VALUE TREATMENT N MEAN SD MIN MEDIAN MAX SOURCE A) Placebo 31 1.03 1.33 1.00 TRT 0 0 0 1 B) MS 30 mg 30 2.00 1.29 2.00 A-B 0.005** C) MS 60 mg 30 2.13 1.31 2.00 A-C 0.002** D) MS 90 mg 30 2.10 1.45 3.00 A-D 0.002* E) MS 30 mg /NTX 0. 1 mg 31 1.77 1.45 2.00 A-E 0.030" F) MS 60Omg/NTX0. 1 mg 30 1.97 1.43 2.50 A-F 0.007** G) MS 90 mg /NTX 0.1 mg 28 2.79 1.07 3.00 A-G <0.001*** B-C 0.700 B-D 0.773 B-E 0.511 B-F 0.923 B-G 0.027* C-D 0.923 C-E 0.296 C-F 0.630 C-G 0.065 D-E 0.343 D-F 0.700 D-G 0.053 E-F 0.575 E-G 0.004** F-G 0.021* NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

Table 88B Pain Intensity Difference Score (Categorical) Primary Efficacy Population PAIN INTENSITY DIFFERENCE SCORE (ategorical) P-VALUE TREATMENT N MEAN SD MIN MEDIAN MAX ISOURCE A) Placebo 31 0.35 0.98 0.00 TRT 0.006** B) MS 30 mg 30 0.87 0.90 1.00 A-B3 0.039* C) MS 60 mg 30 0.97 1.03 1.00 A-C 0.014* D) MS 90mg 30 1.00 1.0S 1.00 A-D 0.0l0** E) MS 30mg /NTX 0.1lmg 31 0.74 1.00 0.00 A-E 0.115 F) MS 60mg /NTX0.1lmg 30 1.00 0.87 1.00 A-F 0.0l0** G) MS 90Omg /NTX0.1 mg 28 1.39 0.83 2.00 A-G K.00l*** B-C 0.688 B-D 0.592 B-E 0.613 B-F 0.592 B-G 0.039* C-D 0.893 C-E 0.363 C-F 0.893 C-G 0.094 D-E 0.296 D-F 1.000 D-G 0.122 E-F 0.296 E-G 0.010* 0.122 NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE.

WO 01/85150 PCT/US01/14644 704 Table 89 presents the summary and analysis of global evaluations (see also Figure 47). The placebo treatment group had the highest number of subjects who had "poor" global evaluation scores. The 90 mg MS/0.1 mg NTX combination treatment group had the highest number of subjects with a total of "excellent", "very good" and "good" global evaluation scores. The profiles of the global evaluation scores are based on subjects' evaluations.

Table 89 Global Evaluation of Study Medication Primary Efficacy Population Poor Fair Good Very Excellent TREATMENT N (0) oor F ai G o od Good E x cell e t Mean (SD) Median Source P-Value A) Placebo 31 20 7 2 1 1 0.58 0.99 0.00 TRT <0.001*** B) MS30mg 29 10 9 5 3 2 (6.9%)1.24 1.24 1.00 A-B 0.049* C) MS60mg 30 11 3 5 8 3 (10.0%)1.63 1.47 2.00 A-C 0.002** D) MS 90 mg 30 9 2 11 7 1 1.63 1.25 2.00 A-D 0.002** E) MS 30 mg/NTX0.1 mg 31 14 5 2 7 3 (9.7%)1.35 1.50 1.00 A-E 0.019* F) MS 60 mg/NTX 0.1 mg 30 10 7 4 7 2 (6.7%)1.47 1.36 1.00 A-F 0.008** G) MS 90mg/NTX0.1 mg 28 3 3 7 12 3 2.32 1.16 3.00 A-G <0.001*** B-C 0.246 B-D 0.246 B-E 0,.734 B-F 0.504 B-G 0.002** C-D 1,000 C-E 0.401 C-F 0.618 C-G 0.044* D-E 0.401 D-F 0.618 D-G 0.044* E-F 0.736 E-G 0.005** F-G 0.013* NOTE: P-VALUES ARE FROM ONE-WAY ANALYSIS OF VARIANCE WO 01/85150 PCT/US01/14644 706 The majority of adverse events reported were categorized as digestive (nausea or vomiting) or nervous system (dizziness or somnolence) as further shown in Table Figure 48 represents a summary of exemplary adverse side effects that may be attenuated according to methods and compositions of the invention.

Table Adverse Events Primary Efficacy Population Body System Adverse Events Total NO. Of Treatment Patients No. Of Patients WlEvent Source P-Value Total No. Of Events Severity Mild Moderate Severe ALL BODY SYSTEMS ALL EVENTS

PLACEBO

MS30 M530/NTX. I

I

MS90INTX.1 (29.0%) (66.7%) (90.0%) (93.3%) (80.0%) (85.7%)

TRT

A-B

A-C

A-D

A-E

A-F

A-G

B-C

B-D

C-E

D-E

E-F

E-G

TRT

<0.001 0.003** <0.001* <0.001*** 0.039* <0.00l*** <0.001*** 0.028* 0.0l0** 0.002** K0.001*** 0.036* 0-010* (42.9%) (36.8%) (53.0%) (43.5%) (38.8%) (49.4%) (33.3%) (43.9%) (32.5%) (36.1%) (50.0%) (43.8%) (32.9%) (23.8%) (19.3%) (14.5%) (20.4%) (17.5%) (17.7%) CARDIAC DISORDERS ALL EVENTS

PLACEBO

MS30 MS3O/NTX. I MS6O/NTX. I

I

0.420 0 0 0 0 0 1 0 0 0 0 0 0 1 0 0 0 0 0 0 (100.0%) 0 0 NOTE:P-VALIJE ARE FROM CHI-SQUJARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT (P<=0.05) PAlIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total No. Of P-Value Total Severity Body System No. Of Patients Source No. Of Mild Moderate Severe Adverse Events Treatment Patients W/Event Events CHEST PRESSURE

SENSATION

EAR AND LABYRINTH

DISORDERS

ALL EVENTS SENSATION OF PRESSURE IN EAR PLACEBO 31 MS30 30 30 30 MS30/NTX.1 31 MS60/NTX.1 30 MS90/NTX.1 28 PLACEBO 31 MS30 30 MS60 30 30 MS30/NTX.1 31 MS60/NTX.1 30 MS90/NTX.1 28 PLACEBO 31 MS30 30 30 30 MS30/NTX.1 31 MS60/NTX.1 30 MS90/NTX.1 28 0 TRT 0 0 0 0 1 0 0 TRT 0 0 0 1 1 0 0 TRT 0 0 0 0 1 0 0.420 0 0 0 0 0 1 0 0.552 0 0 0 0 1 1 0 0.420 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 NOTE:P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT (P<=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total No. Of P-Value Total Severity Body System No. Of Patients Source No. Of Mild Moderate Severe Adverse Events Treatment Patients W/Event Events

TINNITUS

EYE DISORDERS ALL EVENTS BLOODSHOT EYE

PLACEBO

1 1 MS90/NTX.1

PLACEBO

MS30 1 1 1

PLACEBO

MS30/NTX.1 1 1

TRT

0.446 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 2 TRT 6 A-C 8 A-D 9 A-G 3 D-E 7 (23.3%) 7 (25.0%) 2 TRT 6 A-C 8 A-D 9 A-G 3 D-E 7 (23.3%) 7 (25.0%) 0.175 0.033* 0.017* 0.048* 0.046* 0.175 0.033* 0.017* 0.048* 0.046* 1 1 0 3 3 0 5 1 2 (25.0%) 8 2 1 2 1 0 2 5 0 6 3 0 1 1 0 3 3 0 5 1 2 (25.0%) 7 1 1 (11.1%) 2 1 0 2 5 0 5 2 0 NOTE:P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT (P<=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Body Systemn Adverse Events EYE IRRITATION Tota NO. C Treatment Patien Table 90 (Continued) Adverse Events Primary Efficacy Population I No. Of P-Value Total f Patients Source No. Of ts WlEvent Events Severity Moderate Severe Mild EYE PAW

MIOSIS

PLACEBO

1 MS9O!NTX.1

PLACEBO

I

MS6O1NTX.1 MS9ONTX. I

PLACEBO

MS3O/NTX.1 MS6OINTX.I MS9OINTX. I o TRT o 0 1 0 o 0 0 TRT 0 0 0 0 0 1 0 TRT 0 0 1 0 0 0 0.420 0 0 0 1 0 0 0 0.366 0 0 0 0 0 0 1 0.420 0 0 0 1 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 0 NOTE:P-VALIE ARE FROM CIHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT ANT) SIGNIFICANT (P<=0.05) PAIRWISE CONPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total No. Of P-Value Total No. Of Patients Source No. Of Treatment Patients W/Event Events Severity Body System Adverse Events Mild Moderate Severe PHOTOPHOBIA PLACEBO MS3OINTX. 1 MS6O/NTX. 1 MS9O/NTX. I (33.3%) (50.00%) (63.3%) (22.6%) (53.3%1) (64.3%) TRT 0.366 0 0 0 0 0 0 1 0 0 0 0 0 0 1 0 0 0 0 0 0 (100.0%) 0 GASTROINTESTINAL DISORDERS ALL EVENTS PLACEBO MS3O/NTX. I MS6O/NTX. 1 MS9O/NTX. 1

TRT

A-B

A-C

A-D

A-F

A-G

B-D

B-G

C-E

D-E

E-F

E-G

<0.001*-* 0.008"* <0.001*11 <0.001*-* <0.001*** <0.00** 0.020* 0.018* 0.026* 0.001** 0.013* 0.00l** (66.7%) (2 8.6%) (4t1.4%) (26.2%) (37.5%) (21.21%) (28.1%) (35.7%) (27.6%) (42.9%) (50.0%) (45.5%) (34.4%) (33.3%) (35.7%) (3 (31.0%) (12.5%) (33.3%) NOTE:P-VAL.E ARE~ FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT ANT) SIGNIFICANT (P<=0.05) PAII{WISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total No. Of P-Value Total No. Of Patients Source No. Of Treatment Patients W/Event Events Body System Adverse Events ABDOMINAL PAIN NOS PLACEBO MS30/NTX.1 MS60/NTX.1 MS90/NTX.1 ABDOMINAL PAIN

LOWER

ABDOMINAL PAIN

UPPER

PLACEBO

MS30 MS30/NTX.1 MS60/NTX.1 MS90/NTX.1

PLACEBO

MS30 1 MS60/NTX.1 MS90/NTX.1 o TRT 0 0 o 0 2 0 0 TRT 1 0 0 0 0 0 0 TRT 0 0 0 0 0 1 0.059 0 0 0 0 0 2 0 0.420 0 1 0 0 0 0 0 0.366 0 0 0 0 0 0 1 Severity Mild Moderate Severe 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 (50.0%) 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 NOTE:P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT (P<=0.05) PAIR WISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total No. Of P-Value Total Severity Body System No. Of Patients Source No. Of Mild Moderate Severe Adverse Events Treatment Patients W/Event Events DRY MOUTH DRY THROAT

PLACEBO

MS3O/NTX.1 MS60/NTX.1 MS9O/NTX. 1

PLACEBO

MS3O/NTX. 1 MS6O/NTX. I MS9O/NTX. 1

PLACEBO

1 1 MS9OINTX. 1 o TRT 0 0 0 0 (0.00%) 1 0 o TRT 0 0 1 0 0 0 0 TRT o 2 0 0 0 1 0.420 0 0 0 0 0 1 0 0.420 0 0 0 1 0 0 0 0.176 0 0 2 0 0 0 1 0 0 0 00 0 00 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 o 0 0 o 0 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 ~FECT AND SIGNIFICANT (P<c

DYSPEPSIA

NOTE:P-VALUE ARE FROM CI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN ET PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total No. Of P-Value Total Severity Body System No. Of Patients Source -No. Of Mild Moderate Severe Adverse Events Treatment Patients W/Event Events

DYSPHAGIA

HICCUPS

MOUTH

HEMORRHAGE

PLACEBO

MS3O/NTX. 1

I

MS9O/NTX. 1

PLACEBO

M590 MS3O/NTX.1 MS60/NTX.1 MS9ONTX. 1

PLACEBO

MS30 MS3O/NTX. 1 1 1 o TRT 1 0 1 0 1 0 0 IRT 0 0 0 0 1 1 0 TRT 0 0 0 0 0 1 0.669 0 0 1 0 1 0 0.506 0 0 0 0 0 0.366 0 0 0 0 0 0 1 0 0 0 0 1 (100.0%) 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 10 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 1(100.0%) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (10D.0%) 0 0 NOTE:P-VALIJE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAN EFFECT AND) SIGNIFICANT (P<=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Body Systemn Adverse Events Total No. Of Treatmnent Patients NO. Of Patients W/Event Source F-Value Total No. Of Events Severity Mild Moderate Severe

NAUSEA

PARAESTHESIA LIP~S

PLACEBO

MS3OINTX. 1 MS6O/NTX. 1 1

PLACEBO

MS3OINTX. 1 1 MS9O!NTX. 1

PLACEBO

MS3OINTX. 1 MS6OINTX. 1 MS9O/NTX. 1 (40.0%) (56.7%) (19A4%) (43.3%) (53.6%)

TRT

A-C

A-D

A-F

A-G

B-D

B-G

D-E

E-F

E-G

TRT

0.002** <0.001** <0.001* 001* 0.008** 0.018* 0.003** 0 .043 0.0061* (50.0%) (57.1%) (57.1%) (28.6%) (33.3%) (33-3%) (26.7%) (14.3%) (28.6%) (57.1%) (5 0.0%) (53.3%) (60.0%) (50.0%1) (28.6%) (14.3%) (14.3%) (16.7%) (13.3%) (13.3%) 0.420 0 0 0 0 0 0 1 1 0 0 0 0 0 0 (100.0%) 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 RETCHING TRT 0.420 0 0 0 1 0 0 0 0

D

0 0 0 NOTE:P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT 0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Body Systemn Adverse Events Total NO. Of Treatment Patients No. Of Patients W/Event Source P-Value Total No. Of Events Severity Moderate Severe Mild SORE THROAT NOS PLACEBO MS3OINTX. 1 MS60INTX.1 MS9OINTX. 1

PLACEBO

MS3O!NTX. 1 1 1 (13.3%) (40.0%) (50.0%) (43.3%) (46.4%) TRT 0.809 0 0 0 (100.0%) (100.0%) (100.0%/) (16.7%) (12.5%) (15.4%) (15.4%) (100.0%) (50.0%1) (25.0%) (31.3%) (100.0%) (23.1%) (15.4%) 0 1(100.0%) 0 0 0 0 0 VOMITING NOS

TRT

A-C

A-fl

A-F

A-G

B-C

B-D

B-F

B-G

C-E

D-E

E-F

E-G

<0.001*** <0.00** 0.020* 0.002** 0.010** 0.006** <0.001* <0.001 <0.0o1*** <0.00** (50.0%1) (58.3%) (56.3%) (61.5%) (69.2%) NOTE:P-VALUTE ARE FROM CI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AM) SIGNIFICANT 0.05) PAIR WISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total No. Of P-Value Total Severity Body System NO. Of Patients Source No. Of Mild Moderate Severe Adverse Events Treatment Patients WlEvent Events GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS ALL EVENTS

ENERGY

INCREASED

PLACEBO

1 1 1

PLACEBO

MS30 MS3OI'NTX.1 1

I

PLACEBO

M530/NTX.1 1 1 TRT 5 (16.7%) 4 (13.3%) 4 (13.3%) 4 (12.9%) 5 (16,7%) 3 (10.7%)

TRT

0.739 1 6 4 9 4 6 3 0.420 0 0 1 0 0 0.312 0 0.035* 1 1 5 2 0 0 1 0 0 0 0 1 0 0 1 4 1 (16.7%) 1 3 0 2 5 2 (22.2%) 2 (50.0%1) 2 0 3 (50.0% 3 0 1 2 0 0 0 0 0 0 0 0 FATIGUE 0 TRT 1 A-D 1 4 (13.39%) 2 1 1 0 0 0 0 1 (100.0%) 0 0 1 (100.0%) 0 0 4 1 (20.0%) o 2 (100.0%) 0 0 1 (100.0%) 0 0 1 (100.0%) 0 NOTE:P-VALUE ARE FROM CHI-SQU[ARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT 0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total No. Of P-Value Total No. Of Patients Source No. Of Treatment Patients WlEvent Events Severity Mild Moderate Severe Body System Adverse Events FEELING HOT FEELING JITTERY

PLACEBO

M530/NTX.1 1 MS9O/NTX. 1

PLACEBO

MS3O/NTXl MS6OINTX. 1

PLACEBO

1

TRT

TRT

TRT

0.835 1 2 0 2 1 2 1 0.538 0 0 1 0 0 1 0 0.366 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 1 (100.0%) 0 0 0 1 (100.0%) 0 0 1 0 1 (50.0%) 0 0 0 2 (100.0%) 0 0 1 (100.0%) 0 0 1 1 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 NECK SWELLING 0 0 0 0 1 (100.0%) 0 NOTE:P-VAL'UE ARE FROM CI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND) SIGNIFICANT (P<=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total No. Of P-Value Total Severity Body System No. Of Patients Source No. Of Mild Moderate Severe Adverse Events Treatmaent Patients WlEvent Events

PYREXIA

SHIVERING

WEAKNESS

PLACEBO

MS30JNTX.1 MS60INTX.1 MS9OINTX.l

PLACEBO

MS3O/NTX.l MS6OINTX.1 MS9O/NTX.l

PLACEBO

MS30/NTX.1 MS6O/NTX.l

TRT

TRT

TRT

0.538 0 1 0 1 0 0 0.679 0 0 10 0 0.802 0 1 1 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 1(100.0%) 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 1 (100.0%) 0 0 1 (100.0%) 0 0 0 o 0 0 0 0 0 1 (100.0%) 0 0 1 (100.0%) 0 0 1 (100.0%) 0 0 0 0 0 1 (100.0%) 0 0 0 0 NOTE:P-VALIJE ARE FROM CIL-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total NO. Of P-Value Total No. Of Patients Source No. Of Treatment Patients WlEvent Events Severity Moderate Severe Body System Adverse Events Mild 1NVESTIGATIONS ALL EVENTS BLOOD PRESSURE

INCREASED

PLACEBO

MS30 MS30INTX.1 MS6OINTX.1 MS90INTX.1

PLACEBO

MS30 M530/NTX.1 MS6OINTX.1 MS90/NTX.1

PLACEBO

MS30 MS60 MS30/NTX.1 MS60JNTX.1 MS90/NTX.1 o TRT 2 :1 o 1 0 o (0u%) 0 TRT 0 1 0 0 0 0 0 TRT 2 0 0 0 0 0 0.363 0 2 1 0 1 0 0 0.420 0 0 1 0 0 0 0 .059 0 2 0 0 0 0 0 2 (100.0%) 0 0 1 (100.0%) 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 (100.0%) 0 0 0 0 0 0 0 0

BODY

TEMPERATURE

INCREASED

0 0 NOTE:P-VALUE ARE FROM CHII-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT ANDff SIGNIFICANT 0.05) PAIR WISE COMP~ARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total No. Of P-Value Total No. Of Patients Source No. Of Treatment Patients W/Event Events Severity Moderate Severe Body System Adverse Events Mild HEART RATE

INCREASED

PLACEBO

MS30 MS30/NTX.1 MS60/NTX.1 MS90/NTX.1 0 TRT 0 0 0 1 0 0 MUSCULOSKELETAL CONNECTIVE TISSUE AND BONE DISORDERS ALL EVENTS PLACEBO 31 1 TRT 30 0 30 1 30 1 MS30/NTX.1 31 0 MS60/NTX.1 30 0 MS90/NTX.1 28 0 0.446 0 0 0 0 1 0 0 0.679 1 0 2 1 0 0 0 0.446 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 2 (100.0%) 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 JOINT RANGE OF

MOTION

DECREASED

PLACEBO

MS30 MS60 MS30/NTX.1 MS90/NTX.1 1 TRT 0 0 0 0 0 0 NOTE:P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT (P<=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total No. Of P-Value Total No. Of Patients Source No. Of Treatment Patients W/Event Events Severity Moderate Severe Body System Adverse Events Mild MUSCLE SPASMS PLACEBO MS30/NTX.1 MS60/NTX.1 MS90/NTX.1

PLACEBO

MS30/NTX.1 MS60/NTX.1 MS90/NTX.1 o TRT 0 0 1 0 0 0 0 TRT 0 1 0 0 0 0 0.420 0 0 0 1 0 0 0 0.420 0 0 2 0 0 0 0

MYALGIA

0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 (100.0%) 0 0 0 0 0 0 0 0 0 0 0 0 0 5 5 4 (28.6%) 8 11 4 (17.4%) 16 12 1 17 9 5 (16.1%) 7 6 2 (13.3%) 13 9 3 (12.0%) 18 8 2 NERVOUS SYSTEM DISORDERS ALLEVENTS PLACEBO MS30/NTX.1 MS60/NTX.1 MS90/NTX.1 7 TRT 14 15 A-B 0.026* 23 21 A-C 29 19 A-D 31 11 A-F 0.048* 15 14 A-G 25 19 C-E 0.007** 28 D-E 0.030* E-G 0.013* NOTE:P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT (P<=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total No. Of P-Value Total Severity Body System NO. Of Patients Source NO. Of Mild Moderate Severe Adverse Events Treatment Patients W/Event Events DIZZINESS (EXC

VERTIGO)

HEADACHE NOS

PLACEBO

MS30

I

1 1

PLACEBO

MS3O/NTX. I 1 MS9OINTX-l

PLACEBO

MS3OINTX. 1 MS6O!NTX. 1 1

TRT

A-B

A-C

A-D

A-E

A-F

A-G

IRT

(26.7%) (26.7%) (20.0%) (12.9%) (16.7%) (25.0%)

TRT

0.007** 0.005** 0.001** <0.o01*** 0.023* <0.001*** <0.001*** 0 5 (50.0%) 7 (58.3%) 9 (64.3%) 3 (37.5%) 7 (58.3%) 8 (57.1%) 4 (44.4%) 1 (12.5%) 6 (60.0%) 5 (83.3%) 3 2 (40.0%) 6 (85.7%) 0.810 9 8 10 6 4 5 7 0.446 1 0 0 0 0 0 0 0 1(100.0%) 3 2 (20.0%) 5 (4 0 4 1 4 1 (12.5%) 4 1 4 2 (14.3%) 2 3 (33.3%) 5 2 (25.0%) 4 0 1 0 1 0 2 1 (20.0%) 1 0

HYPERAESTHESIA

(00) 1 (100.0%) 0 0 0 0 0 0 0 0 0 0 0 0. 0 AND SIGNIFICANT (P<c=0.05) NOTE: P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT PAIR WISE COMPARISONS ARE PRESENTED.

Body System Adverse Events Tota] NO.C0 Treatment Patien Table 90 (Continued) Adverse Events Primary Efficacy Population No. Of P-Value Total if Patients Source No. Of ts WlEvent Events Mild Severity Moderate Severe

HYPOAESTHESIA

PARAESTHESIA

NEC

PLACEBO

MS3O/NTX. 1 1 MS9o/NTX. 1

PLACEBO

MS30 MS3O/NTX. 1 1 1

PLACEBO

MS3O/NTX. 1 M560/NTX.l M590/NTX. 1 (13.3%) (23.3%) (23.3%) (13.3%) (17,9%) TRT 0.420 0 0 0 0 0 0-506 0 0.506 0 0 2 (100.0%) TRT 0 0 0 0 0 0 0 0 0 0 0 0 0 0

SOMNOLENCE

TRT

A-C

A-D

0.174 0.020* 0.020* (100.0%) (100.0%) (40.0%) (42.9%) (28.6%) (0-0A) (20.0%) (40.0%) (100.0%) (60.0%) (42.9%) (57.1%) (50.0%) (60.0%) (60.0%) (14.3%) (14.3%) (50.0%) (20.0%) NOTE:P-VAJUIE ARE FROM CI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNI]FICANT (P<=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total NO. Of P-Value Total Severity Body System No. Of Patients Source NO. Of Mild Moderate Severe Adverse Events Treatment Patients WlEvent Events

SYNCOPE

TENSION

HEADACHES

TREMOR NEC

PLACEBO

t MS6ONTX. 1 MS9O/NTX. 1

PLACEBO

MS30 MS3OINTX. 1 MS60INTX.1I MS9OINTX.I

PLACEBO

MS30INTX.1

I

MS90INTX.1 1 TRT o o 2 1 0 0 1 TRT 0 0 0 0 0 0 0 TRT 0 0 0 2 0 1 0 0.368 1 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 2 0 0 2(100.0%) 1 1 (100.0%) 0 0 0 *0 0 0 0 0 0 0 0.446 1 0 0 0 0 0 0 0.186 0 0 0 2 0 1 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1 (50.0%) 0 0 0 1 (100.0%) 0 0 0 0 0 NOTE:P-VALIJE ARE FROM CHIl-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT (P<=0.05) PAIR WISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total No. Of P-Value Total Severity Body System No. Of Patients Source NO. Of Mild Moderate Severe Adverse Events Treatment Patients W/Event Events PSYCHITATRIC DISORDERS ALL EVENTS ANXIETY NEC

PLACEBO

MS30/NTX.1 MS6OINTX. 1 MS9OINTX.1

PLACEBO

MS3OINTX.1 MS6OINTX.1 MS9OJNTX.1

PLACEBO

MS3O/NTX.1 MS60/NTX.1 MS9O/NTX.1

TRT

TRT

TRT

0.554 0 2 0 1 0 0.538 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 1 (100.0%) 0 0) 2 (100.0%) 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 2 (100.0%) 0 0 0 0 0 0 0 0 0 0 0 EUPHORIC MOOD NOTE:P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AM) SIGNIFICANT (P<r=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total No. Of P-Value Total Severity Body System No. Of Patients Source No. Of Mild Moderate Severe Adverse Events Treatment Patients W/Event Events NERVOUSNESS PLACEBO MS3 0/NIX. 1 MS6O/NTX. 1 MS9O/NTX. I RENAL AND URINARY DISORDERS ALL EVENTS PLACEBO MS3O/NTX.1 MS6O/NTX. 1 1

PLACEBO

MS30 M530/NTX.1 MS 60/NIX. 1 0 TRT 0 0 0 0 1 0 0 TRT 0 0 1 0 0 1 0 TRT 0 0 1 0 0 1 0.420 0 0 0 0 0 1 0 0-506 0 0 0 1 0 0 1 0.506 0 0 0 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 0 00 0 00 0 0 1 (100.0%) 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 1 (100.0%) 0 0 DIFFICULTY IN

MICTURITION

NOTE: P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AN) SIGNIFICANT (P<=0.05) PAIRWISE, COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total NO. Of P-Value Total Severity Body System No. Of Patients Source No. Of Mild Moderate Severe Adverse Events Treatment Patients W/Event Events RESPIRATORY, THO0RACIC AND MEDIAST~INAL DISORDERS ALL EVENTS PLACEBO 3 1 0 30 1 30 1 30 1 31 0 MS6O/NTX.1 30 1 MS90INTX.1 28 0 CHEST TIGHTNESS PLACEBO MS3O/NTX.1 MS60/NTX.1 MS9OINTX.1

PLACEBO

MS3O/NTX.1 MS60!NTX.1 MS90/NTX.1

TRT

TRT

0.802 0 1 1 0 0 0.420 1 0 0 0 0 058 0 0 0.538 0 0 0 0 (100.0%) 0 (100.0%) 0 1 0 1 0 (100.0%) (100.0%) (100.0%) 0 0 0 0 0 0 0 0 0 0 (100.0%) 0 0 0 0 DYSPNOEA NOS (100.0%) NOTE:P-VALUB ARE FROM CIHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT (P<=0.05) PA[RWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total No. Of P-Value Total Severity Body System No. Of Patients Source No. Of Mild Moderate Severe Adverse Events Treatment Patients W/Event Events

THROAT

TIGHTNESS

PLACEBO

MS30 MS30INTX.1 MS6OINTX. 1

I

SKIN SUBCUTANEOUS TISSUE DISORDERS ALL EVENTS PLACEBO0 MS3ONTX.1 MS9O/NTX.1 o TRT 0 0 0 0 1 0 0 TRT 3 A-C 5 A-D 6 A-G 2 3 (10.0%) 4 (14.3%) 0 TRT 0 0 (0a0%) 1 0 1 0 0.420 0 0 0 0 0 1 0 0.213 0.018* 0.009* 0.029* 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 2 0 1 (33.3%) 6 1 0 5 1 1 (14.3%) 0 2 (100.0%) 0 5 (100.0%) 0 0 2 2 0 0 0 0 0 0 0 0 0 0 0 0 1(100.0%) 0 0 0 1 (100.0%) 0 0 0 0 0 CLAMMIENESS PLACEBO MS3OINTX.l 1 MS9OJNTX.1 0.538 0 0 0 1 0 1 0 NOTE: P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total No. Of P-Value Total Severity Body System No. Of Patients Source No. Of Mild Moderate Severe Adverse Events Treatment Patients WlEvent Events DERMATITIS NOS

ECCHYMOSIS

PLACEBO

MS30/NTX.1 MS90INTX.1

PLACEBO

MS30/NTX.1 MS60/NTX.1 o TRT 1 2 1 0 0 0 0 TRT 1 0 o 0 0 0 0 TRT 0 (00%) 0 1 0 0 0 0.357 0 1 2 1 0 0 0 0.420 0 1 0 0 0 0 0 0.420 0 0 0 1 0 0 0 0 0 0 0 0 1(100.0%) 2 (100.0%) 0 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 0 0 PHOTOSENSITIVITY PLACEBO REACTION NOS MS30 MS3OINTX.1 MS60/NTX.1 MS90/NTX.1 NOTE: P-VALUE ARE FROM CHI-SQUJARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT ANDI SIGNIFICANT PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total No. Of P-Value Total Severity Body System No. Of Patients Source No. Of Mild Moderate Severe Adverse Events Treatment Patients W/Event Events PRURITUS NOS RASH MACULAR

SWEATING

INCREASED

PLACEBO

MS30/NTX.1 MS60/NTX.1 MS90/NTX.1

PLACEBO

MS30/NTX.1 MS60/NTX.1 MS90/NTX.1

PLACEBO

MS30 MS30/NTX.1 MS60/NTX.1 MS90/NTX.1 0 TRT 0 1 1 0 1 1 0 TRT 0 0 0 0 1 0 0 TRT 1 3 (10.0%) 3 (10.0%) 2 0 3 (10.7%) 0.785 0 0 2 1 0 2 1 0.420 0 0 0 0 0 2 0 0.286 0 1 3 3 2 0 3 0 0 0 0 0 0 2 (100.0%) 0 0 1 (100.0%) 0 0 0 0 0 2 (100.0%) 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 (100.0%) 0 0 0 0 0 0 0 0 1 (100.0%) 0 0 2 1 0 2 1 0 0 2 (100.0%) 0 0 0 0 2 1 0 NOTE:P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT (P<=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total No. Of P-Value Total Severity Body System No. Of Patients Source No. Of Mild Moderate Severe Adverse Events Treatment Patients WlEvent Events ALL EVENTS

FLUSHING

PLACEBO

MS6OJNTX.1 MS90INTX.1

PLACEBO

MS3O MS30/NTX.1 1

PLACEBO

MS30INTX.1 MS6OI'NTX. 1 MS9OINTX. 1

TRT

(10.0%)

TRT

TRT

0.199 0 1 1 3 0 0 2 0.785 0 1 1 1 0 0 1 0.506 0 0 0 1 0 0 1 0 0 0 0 1 (100.0%) 0 1 (100.0%) 0 0 1 2 0 0 0 0 0 0 0 2 (100.0%) 0 0 (0.00) 0 0 0 0 1 (100.0%) 0 1 (100.0%) 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 1 (100.0%) 0 0 HOT FLUSHES NOS 0 0 0 0 0 0 1 (1 00.0%) 0 0 0 0 0 1 (100.0%) 0 0 0 0 0 0 0 0 NOTE: P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AN) SIGNIFCANf(P<=0.05) PAIRWISE COMPARISONS ARE PRESENTED.

Table 90 (Continued) Adverse Events Primary Efficacy Population Total No. Of P-Value Total Severity Body System No. Of Patients Source No. Of Mild Moderate Severe Adverse Events Treatment Patients W/Event Events H{YPOTENSION NOS PLACEBO MS230/NTX. 1 MS60/NTX.1 1 0.420 0 0 0 1 0 0 0 0 000% 0 (00% 0 0 0 0 0 (100.0%) 0 0 0 0 NOTE:P-VALUE ARE FROM CHI-SQUARE TEST. P-VALUES FOR TREATMENT MAIN EFFECT AND SIGNIFICANT (P<=0.05) PAIIRWISE COMPARISONS ARE PRESENTED.

WO 01/85150 PCT/US01/14644 734 EXAMPLE 8 In addition to the clinical studies described in Examples 1-7, several small pilot clinical studies were done with varying results.

One pilot study involved the co-administration of oral naltrexone and intrathecal morphine in patients with refractory chronic pain. This pilot study was performed to preliminarily evaluate and compare the analgesic effectiveness of intrathecal morphine and alone and in combination with two different doses of oral naltrexone in patients with chronic refractory pain. The 15 subject study had three treatment groups: a) morphine placebo (5 patients); b) morphine naltrexone 0.1 mg (3 patients); c) morphine naltrexone 0.01 mg (7 patients). In this pilot study, all patients had an indwelling intrathecal catheter and were currently receiving intrathecal morphine for refractory chronic pain. Each subject took one capsule of oral study medication every 12 hours for seven days. Subjects completed pain and side effect assessments before dosing and at 30 minutes, 1, 2, 3, 4, 5, 6, 7 and 8 hour after receiving the first dose of oral study medication. Subjects then completed assessments three times each day for the remaining six days of treatment, with a follow-up visit on the eighth day.

The efficacy and safety evaluations included: pain evaluation questionnaires (VAS), side effect scoring sheets, global efficacy evaluations (VAS), and adverse event assessments.

The mean pain intensity difference (PID) scores are shown by day and time in Tables 91 and 92, and Figures 49 and 50. Generally, the 0.1 mg NTX combination treatment group showed the highest mean PID scores.

The mean daily global assessment of pain scores are shown for days 2-8 in Table 93 and Figure 51. Particularly, for days 2-4, the 0.1 mg NTX combination treatment group showed the best (lowest mean) global assessment scores.

WO 01/85150 PCT/US01/14644 Table 91 Day 1 Mean Pain Intensity Difference (PID) Scores Placebo NTX 0.01 mg NTX 0.1 mg 0.44 -0.04 1.87 1 0.76 0.03 2.27 2 0.64 0.34 2.17 3 0.22 0.56 2.47 4 0.76 0.71 2.23 0.74 0.49 3.47 6 0.86 0.24 3.37 7 0.70 0.10 4.30 8 0.64 0.39 5.03 Table 92 Day 1 Mean Pain Intensity Difference (PID) Scores Placebo NTX 0.01 NTX 0.1 mg mg Day 2 Morning 0.10 0.27 2.37 Afternoon 0.50 -0.06 2.90 Night 0.56 0.47 3.00 Day 3 Morning 0.86 0.27 1.93 Afternoon 0.96 1.06 3.13 Night 0.10 -0.44 2.83 Day 4 Morning 0.96 1.33 2.53 Afternoon 0.22 0.80 2.83 Night 0.38 0.27 3.73 Day 5 Morning 0.84 0.21 2.90 Afternoon 0.88 -0.33 2.03 Night 1.08 -0.50 2.47 Day 6 Morning 0.56 0.66 2.60 Afternoon 1.04 0.73 1.07 Night 0.04 0.34 0.70 Day 7 Morning 0.76 0.43 1.40 Afternoon -0.14 0.47 2.30 Night 0.12 0.10 1.43 WO 01/85150 PCT/US01/14644 736 Table 92 Mean Daily Global Assessment Scores Placebo NTX 0.01 mg NTX 0.1 mg Day 2 6.32 6.27 4.70 Day 3 6.58 6.93 4.13 Day 4 6.26 6.81 4.17 Day 5 5.24 7.23 5.67 Day 6 6.48 6.30 6.63 Day 7 6.06 6.56 6.23 Day 8 6.62 6.06 4.73 In another pilot study, very low doses 1 mg, 5 mg) of morphine-in combination with naltrexone (0.01 mg or 0.001 mg) were administered for moderate to severe pain in patients following dental surgery. This pilot study was performed to investigate the analgesic efficacy (onset, peak, duration, and total effect) of 60 mg morphine alone, two different doses (0.01 mg or 0.001 mg) of naltrexone in combination with two different low doses (1 mg, 5 mg) of morphine, and placebo.

The 50 subject study was designed with six treatment groups: a) placebo patients); b) morphine 60 mg (5 patients); c) morphine 1.0 mg and naltrexone 0.01 mg 1t (10 patients); d) morphine 1.0 mg and naltrexone 0.001 mg (10 patients); e) morphine mg and naltrexone 0.01 mg (10 patients); and f) morphine 5.0 mg and naltrexone 0.001 mg (10 patients). In this pilot study in the treatment of moderate to severe pain following extraction of 3 or 4 full or partial bony impacted third molars, a single oral dose of one of the treatments was administered when the patient was suffering moderate to severe postoperative pain. The observation period for efficacy was 8 hours post treatment and for safety was 24 hours post treatment.

The efficacy and safety evaluations included pain intensity, pain relief, global pain evaluation, evaluation of time to meaningful pain relief (stopwatch), visual analog scale (VAS), and adverse event assessment. This pilot study did not reveal any efficacy differences in the active treatment groups as compared with placebo.

In another pilot study of 25 subjects, the analgesic effects of morphine (5 mg, in the presence of varying doses of an opioid antagonist naloxone; 5 mg, mg, 0.05 mg) as compared with morphine alone and placebo in healthy volunteers using the cold pain test.

WO 01/85150 PCT/US01/14644 737 Treatments were administered by 15 min i.v. infusion: Treatment A 5 mg morphine sulphate 4 x 0.9% saline solution (placebo Treatment B 5 mg morphine sulphate 4 x 5pg naloxone HCI Treatment C 5 mg morphine sulphate 4 x 0. 5 [g naloxone HCI Treatment D 5 mg morphine sulphate 4 x 0.05pg naloxone HCI Treatment E 0.9% saline solution (placebo) 4 x 0.9% saline solution The cold pain test was performed pre-dose and at 20 minutes, 1 hr 20 in, 2 hr in, 4 hr 20 min, and 6 hr 20 min post-dose on each of the five dosing occasions. In the test, a subject's hand is immersed in cold water usually over the range of 1 to 3 0

C.

The initial sensation of cold is replace by a deep burning discomfort in the hand. It is thought that this is mediated by nociceptors in veins. The discomfort gradually builds to a plateau over 90 seconds or so and then either stays the same or decreases slightly.

The test statistic for each cold pain test was the cumulative area under the curve of the visual analogue scale-time profile from 0-120 seconds (AUCcpr) calculated automatically by the cold pain test software. AUCcpr values from the cold pain test were listed and plotted for each subject and treatment.

Minimum AUCcpt and the time to achieve minimum AUCopt was determined for each subject and treatment/dose level. This pilot study did not reveal any efficacy differences in the active treatment groups as compared with placebo.

WO 01/85150 PCT/US01/14644 738 EXAMPLE 9 A study oftramadol alone and in combination with naltrexone is described in Example 10 of U.S. Application Serial No. 09/566,071, filed May 5, 2000 and 09/756,331, filed January 8, 2001, as well as ofPCT/USOO/12493 [WO/00 67739] filed May 5, 2000, the entire disclosures of which are hereby incorporated by reference. A summary of exemplary study results follows.

In this study in human subjects with pain, tramadol hydrochloride (tramadol) was administered alone or in combination with various amounts (doses) of an opioid antagonist, naltrexone. In this study, one objective was to determine whether an opioid antagonist such as naltrexone hydrochloride (hereafter referred to in this example as naltrexone or NTX) enhanced the analgesic properties oftramadol hydrochloride (hereafter referred to in this example as tramadol or T) in human subjects/patients with pain following dental surgery. An additional objective was to evaluate whether an opioid antagonist such as NTX attenuated reduced, blocked or prevented) tramadol's adverse side effects in humans.

Human subjects were randomized into one of the following five treatment groups: Group 1: T (50 mg) with NTX (1 mg) Group 2: T (50 mg) with NTX (0.1 mg) Group 3: T (50 mg) with NTX (0.01 mg) Group 4: T (50 mg) with Placebo Group 5: Placebo with Placebo All subjects with moderate to severe pain received one dose of study medication. Subjects received two capsules to take by mouth, one tramadol or placebo, the other naltrexone or placebo.

A pain assessment was performed pre-treatment. Following the dental surgery, the subject's pain level was assessed by a trained observer. The subject reported the initial pain intensity by both verbalizing one pain category (0 none, 1 mild, 2 moderate or 3 severe), and using a Visual Analog Scale (VAS) of 0 -100 mm where 0 no pain and 100 worst pain imaginable, by placing a single slash on the scale. A pain assessment was also performed post-treatment.

WO 01/85150 PCT/US01/14644 739 The efficacy and safety evaluations included pain intensity, pain relief, global pain evaluation, evaluation of time to meaningful pain relief (stop watch), visual scale analog (VAS), and adverse event assessments. For the data analysis, certain pain parameters were computed as generally described above.

The placebo treatment group had the lowest mean 4-hour Total Pain Relief scores. All 4 of the active treatment groups exhibited mean 4-hour Total Pain Relief scores that were numerically higher than placebo. The combination treatments had a reverse dose-response relation in the mean 4-hour Total Pain Relief scores, the highest dose of NTX had the lowest mean 4-hour Total Pain Relief scores and the lowest dose of NTX had the highest mean 4-hour Total Pain Relief scores. The mean 4-hour Total Pain Relief scores for the 0.01 -mg NTX and 0.1 -mg NTX combination treatments were higher than that for the T alone treatment, whereas the 1.0-mg NTX combination treatment mean was lower than that for the T alone treatment.

The placebo treatment had the lowest mean 4-hour Sum of Pain Intensity Differences scores. All 4 of the active treatment groups exhibited improved profiles in mean 4-hour Sum of Pain Intensity Differences relative to placebo. The mean 4hour Sum of Pain Intensity Differences scores for the 0.01-mg NTX and 0.1-mg NTX combination treatments were higher than that for the T alone treatment, whereas the NTX combination treatment was lower than that for the T alone treatment.

The patterns of the 6-hour and 8-hour Sum of Pain Intensity Differences scores were similar to those at 4 hours.

The 4, 6, and 8 hour Visual Analog Scale Sum of Pain Intensity Differences results were as follows. The placebo treatment had the lowest mean 4-hour VAS-Sum of Pain Intensity Differences. The 4 active treatment groups exhibited mean VAS- Sum of Pain Intensity Differences scores that were higher than that for the placebo.

The mean 4-hour VAS-Sum of Pain Intensity Differences for the 3 NTX combination treatments was higher than that for T alone. The profiles of 6-hour and 8-hour VAS- Sum of Pain Intensity Differences scores were similar to those at 4 hours.

The placebo treatment had the lowest number of subjects who reached meaningful pain relief. In addition, all the combination treatment groups had higher numbers of subjects reaching meaningful pain relief than did the group that received T alone.

WO 01/85150 PCT/US01/14644 740 Whereas the hourly pain relief scores for the placebo treatment were generally flat, those for the active treatment groups were generally improving over time. There was separation between the placebo and the active treatment groups that continued throughout the 8-hour study period.

The majority of adverse events reported were categorized as gastrointestinal disorders (nausea or vomiting) or nervous system disorders (dizziness, headache or sedation).

The results from this clinical study using tramadol alone and in combination with naltrexone were analyzed by gender. The results for females and males with respect to pain intensity difference (PID) scores are shown in Tables 93A and 93B and in Figures 52A and 52B.

Table 93A Pain Intensity Difference (PID) Scores Intent-to-Treat Population, Female Patients SUM OF PAIN INTENSITY DIFFERENCES Overall P-Value P-Value N Mean SD Median Range Source P-Value vs. vs.

Placebo Tramadol SUM OF PAIN INTENSITY DIFFERENCES (0.5 HOURS) A) Placebo 24 -0.21 0.59 0.00 -1 1 TRT 0.3257 B) T (50 mg) with Placebo 34 -0.21 0.54- 0.00 -1 1 A-B 0.9849 C) T (50 mg)/NTX 1.0 mg 32 -0.16 0.45 0.00 -1 1 B-C 0.6920 0.6789 D) T (50 mg)/NTX 0.1 mg 26 0.04 0.45 0.00 -1 1 B-D 0.0748 0.0555 E) T (50 mg)/NTX 0.01 mg 34 -0.12 0.41 0.00 -1 1 B-E 0.4850 0.4552 SUM OF PAIN INTENSITY DIFFERENCES (1 HOUR) A) Placebo 24 -0.17 0.64 0.00 -1 1 TRT 0.0372* B) T (50 mg) with Placebo 34 -0.35 0.65 0.00 -1 1 A-B 0.2760 C) T (50 mg)/NTX 1.0 mg 32 -0.28 0.58 0.00 -1 1 B-C 0.5077 0.6494 D) T (50mg)/NTX 0.1 mg 26 0.12 0.59 0.00 -1 1 B-D 0.1211 0.0056* E) T (50 mg)/NTX 0.01 mg 34 -0.03 0.72 0.00 -1 2 B-E 0.4217 0.0386* PAIN INTENSITY SCORE: 0=NONE, 1-MILD, 2=MODERATE, 3=SEVERE. THE PAIN INTENSITY DIFFERENCE (PID) AT EACH TIME POINT IS CALCULATED AS THE DIFFERENCE BETWEEN THE PAIN INTENSITY SCORE AT HOUR 0 AND THE SCORE AT OBSERVATION TIME.

P-VALUES COMPARING ALL 5 TREATMENT GROUPS AND PAIRWISE COMPARISONS ARE DETERMINED USING ANOVA.

*SIGNIFICANCE IS AT 0.05 NOMINAL LEVEL.

LAST OBSERVATION CARRIED FORWARD METHOD IS USED TO IMPUTE MISSING VALUES.

Table 93A (Continued) Pain Intensity Difference (PID) Scores Intent-to-Treat Population, Female Patients SUM OF PAIN INTENSITY DIFFERENCES Overall P-Value P-Value N Mean SD Median Range Source P-Value vs. vs.

Placebo Tramadol SUM OF PAIN INTENSITY DIFFERENCES (2 HOURS) A) Placebo 24 -0.21 0.72 0.00 -1 1 TRT 0.2525 B) T (50 mg) with Placebo 34 -0.21 0.77 0.00 -1 1 A-B 0.9907 C) T (50 mg)/NTX 1.0 mg 32 -0.13 0.91 0.00 -1 3 B-C 0.6944 0.6759 D) T (50 mg)/NTX 0.1 mg 26 0.08 0.74 0.00 -1 2 B-D 0.2007 0.1683 E) T (50 mg)/NTX 0.01 mg 34 0.15 0.74 0.00 -1 -2 B-E 0.0912 0.0655 SUM OF PAIN INTENSITY DIFFERENCES (3 HOURS) 1 Tr Placebo T (50 mg) with Placebo T (50 mg)/NTX 1.0 mg T (50 mg)/NTX 0.1 mg T (50 mg)/NTX 0.01 mg -0.13 -0.15 0.00 0.08 0.21 0.95 0.82 1.02 0.84 0.84 0.00 0.00 0.00 0.00 0.00 -1-2 -1-2 -1 3 -1-2 -1-2

TRT

A-B

B-C

B-D

B-E

0.5012 0.9265 0.6060 0.4270 0.1679 0.5060 0.3387 0.1064 PAIN INTENSITY SCORE: 0=NONE, 1-MILD, 2=MODERATE, 3=SEVERE. THE PAIN INTENSITY DIFFERENCE (PID) AT EACH TIME POINT IS CALCULATED AS THE DIFFERENCE BETWEEN THE PAIN INTENSITY SCORE AT HOUR 0 AND THE SCORE AT OBSERVATION TIME.

P-VALUES COMPARING ALL 5 TREATMENT GROUPS AND PAIRWISE COMPARISONS ARE DETERMINED USING ANOVA.

*SIGNIFICANCE IS AT 0.05 NOMINAL LEVEL.

LAST OBSERVATION CARRIED FORWARD METHOD IS USED TO IMPUTE MISSING VALUES.

Table 93A (Continued) Pain Intensity Difference (PID) Scores Intent-to-Treat Population, Female Patients SUM OF PAIN INTENSITY DIFFERENCES Overall P-Value P-Value N Mean SD Median Range Source P-Value vs. vs.

Placebo Tramadol SUM OF PAIN INTENSITY DIFFERENCES (4 HOURS) A) Placebo 24 -0.08 0.97 0.00 -1 2 TRT 0.6085 B) T (50 mg) with Placebo 34 -0.03 0.90 0.00 -1 2 A-B 0.8292 C) T (50 mg)/NTX 1.0 mg 32 0.00 1.02 0.00 -1 3 B-C 0.7420 0.8986 D) T (50 mg)/NTX 0.1 mg 26 0.19 0.90 0.00 -1-2 B-D 0.2998 0.3646 E) T (50 mg)/NTX 0.01 mg 34 0.24 0.89 0.00 -1 2 B-E 0.2036 0.2454 SUM OF PAIN INTENSITY DIFFERENCES (5 HOURS) Placebo T (50 mg) with Placebo T (50 mg)/NTX 1.0 mg T (50 mg)/NTX 0.1 mg T (50 mg)/NTX 0.01 mg 24 34 32 26 34 -0.13 -0.09 0.00 0.19 0.24 0.95 0.87 1.05 0.90 0.92 0.00 0.00 0.00 0.00 0.00 -1-2 -1 2 -1 3 -1-2 -1 3

TRT

A-B

B-C

B-D

B-E

0.4673 0.8833 0.6223 0.2339 0.1517 0.7030 0.2527 0.1570 PAIN INTENSITY SCORE: 0=NONE, 1-MILD, 2=MODERATE, 3=SEVERE. THE PAIN INTENSITY DIFFERENCE (PID) AT EACH TIME POINT IS CALCULATED AS THE DIFFERENCE BETWEEN THE PAIN INTENSITY SCORE AT HOUR 0 AND THE SCORE AT OBSERVATION TIME.

P-VALUES COMPARING ALL 5 TREATMENT GROUPS AND PAIRWISE COMPARISONS ARE DETERMINED USING ANOVA.

*SIGNIFICANCE IS AT 0.05 NOMINAL LEVEL.

LAST OBSERVATION CARRIED FORWARD METHOD IS USED TO IMPUTE MISSING VALUES.

Table 93A (Continued) Pain Intensity Difference (PID) Scores Intent-to-Treat Population, Female Patients SUM OF PAIN INTENSITY DIFFERENCES Overall P-Value P-Value N Mean SD Median Range Source P-Value vs. vs.

Placebo Tramadol SUM OF PAIN INTENSITY DIFFERENCES (6 A) Placebo 24 -0.13 0.95 0.00 -1 2 TRT 0.7751 B) T (50 mg) with Placebo 34 -0.06 0.95 0.00 -1 2 A-B 0.7899 C) T(50 mg)/NTX 1.0mg 32 -0.03 1.09 0.00 -1-3 B-C 0.5348 0.6947 D) T (50 mg)/NTX 0.1 mg 26 0.19 0.85 0.00 -1 2 B-D 0.2300 0.3017 E) T (50 mg)/NTX 0.01 mg 34 0.06 0.78 0.00 -1 2 B-E 0.4596 0.6027 SUM OF PAIN INTENSITY DIFFERENCES (7 HOURS)____ A) Placebo 24 -0.08 1.06 0.00 -1 3 TRT 0.7077 B) T (50 mg) with Placebo 34 -0.12 0.84 0.00 -1-2 A-B 0.8909 C) T (50 mg)/NTX 1.0 mg 32 -0.03 1.09 0.00 -1 3 B-C 0.8371 0.7085 D) T(50 mg)/NTX 0.1mg 26 0.19 0.85 0.00 -1-2 B-D 0.3000 0.2059 E) T (50 mg)/NTX 0.01 mg 34 0.09 0.83 0.00 -1 2 B-E 0.4930 0.3661 PAIN INTENSITY SCORE: 0=NONE, 1-MILD, 2=MODERATE, 3=SEVERE. THE PAIN INTENSITY DIFFERENCE (PID) AT EACH TIME POINT IS CALCULATED AS THE DIFFERENCE BETWEEN THE PAIN INTENSITY SCORE AT HOUR 0 AND THE SCORE AT OBSERVATION TIME.

P-VALUES COMPARING ALL 5 TREATMENT GROUPS AND PAIRWISE COMPARISONS ARE DETERMINED USING ANOVA.

*SIGNIFICANCE IS AT 0.05 NOMINAL LEVEL.

LAST OBSERVATION CARRIED FORWARD METHOD IS USED TO IMPUTE MISSING VALUES.

Table 93A (Continued) Pain Intensity Difference (PID) Scores Intent-to-Treat Population, Female Patients SUM OF PAIN INTENSITY DIFFERENCES Mean SD Median Range Source Overall P-Value [1] P-Value vs.

Plane hn P-Value vs.

Trmadnl SUM OF PAIN INTENSITY DIFFERENCES (8 HOURS) A) Placebo 24 -0.08 1.06 0.00 -1 3 TRT 0.8312 B) T (50 mg) with Placebo 34 -0.09 0.93 0.00 -1 -2 A-B 0.9846 C) T (50 mg)/NTX 1.0 mg 32 -0.03 1.09 0.00 -1-3 B-C 0.8399 0.8085 D) T (50 mg)/NTX 0.1 mg 26 0.15 0.83 0.00 -1-2 B-D 0.3807 0.3311 E) T (50 mg)/NTX 0.01 mg 34 0.09 0.83 0.00 -1 2 B-E 0.5005 0.4464 PAIN INTENSITY SCORE: 0=NONE, 1-MILD, 2=MODERATE, 3=SEVERE. THE PAIN INTENSITY DIFFERENCE (PID) AT EACH TIME POINT IS CALCULATED AS THE DIFFERENCE BETWEEN THE PAIN INTENSITY SCORE AT HOUR 0 AND THE SCORE AT OBSERVATION TIME.

P-VALUES COMPARING ALL 5 TREATMENT GROUPS AND PAIRWISE COMPARISONS ARE DETERMINED USING ANOVA.

*SIGNIFICANCE IS AT 0.05 NOMINAL LEVEL.

LAST OBSERVATION CARRIED FORWARD METHOD IS USED TO IMPUTE MISSING VALUES.

Pain Intensity Difference (PTD) Scores Intent-to-Treat Population, Male Patients SUM OF PAIN INTENSITY DIFFERENCES Overall P-Value P-Value N Mean SD Median Range Source P-Value vs. vs.

Placebo Tramadol SUM OF PAIN INTENSITY DIFFERENCES (0.5 HOURS) A) Placebo 27 -0.11 0.42 0.00 -1 1 TRT 0.5082 B) T (50 mg) with Placebo 16 -0.25 0.45 0.00 -1 0 A-B 0.3464 C) T (50 mg)/NTX 1.0 mg 18 -0.17 0.38 0.00 -1 0 B-C 0.6956 0.6034 D) T (50 mg)/NTX 0.1 mg 26 -0.15 0.46 0.00 -1 1 B-D 0.7389 0.5170 E) T (50 mg)/NTX 0.01 mg 17 -0.35 0.61 0.00 -1 1 B-E 0.0964 0.5268 SUM OF PAIN INTENSITY DIFFERENCES (1 HOUR) A) Placebo 27 -0.30 0.61 0.00 -1 1 TRT 0.6315 B) T (50 mg) with Placebo 16 -0.19 0.66 0.00 -1 1 A-B 0.5901 C) T (50 mg)/NTX 1.0 mg 18 -0.17 0.51 0.00 -1 1 B-C 0.5059 0.9245 D) T (50 mg)/NTX 0.1 mg 26 -0.08 0.74 0.00 -1 1 B-D 0.2137 0.5867 E) T (50 mg)/NTX 0.01 mg 17 -0.35 0.61 0.00 -1 1 B-E 0.7749 0.4583 PAIN INTENSITY SCORE: 0=NONE, 1-MILD, 2=MODERATE, 3=SEVERE. THE PAIN INTENSITY DIFFERENCE (PID) AT EACH TIME POINT IS CALCULATED AS THE DIFFERENCE BETWEEN THE PAIN INTENSITY SCORE AT HOUR 0 AND THE SCORE AT OBSERVATION TIME.

P-VALUES COMPARING ALL 5 TREATMENT GROUPS AND PAIRWISE COMPARISONS ARE DETERMINED USING ANOVA.

*SIGNIFICANCE IS AT 0.05 NOMINAL LEVEL.

LAST OBSERVATION CARRIED FORWARD METHOD IS USED TO IMPUTE MISSING VALUES.

Table 93B (Continued) Pain Intensity Difference (PID) Scores Intent-to-Treat Population, Male Patients SUM OF PAIN INTENSITY DIFFERENCES Overall P-Value P-Value N Mean SD Median Range Source P-Value vs. vs.

Plcrohr Tramaol SUM OF PAIN INTENSITY DIFFERENCES (2 HOURS)__ A) Placebo 27 -0.41 0.64 0.00 -1 1 TRT 0.1038 B) T (50 mg) with Placebo 16 0.25 0.86 0.00 -1 2 A-B 0.0068* C) T (50 mg)/NTX 1.0 mg 18 -0.17 0.71 0.00 -1 1 B-C 0.2968 0.1111 D) T (50 mg)/NTX 0.1 mg 26 -0.08 0.84 0.00 -1 1 B-D 0.1140 0.1757 E) T (50 mg)/NTX 0.01 mg 17 -0.18 0.73 0.00 -1 1 B-E 0.3252 0.1077 SUM OF PAIN INTENSITY DIFFERENCES (3 HOURS) A) Placebo 27 -0.41 0.64 0.00 -1 1 TRT 0.1795 B) T (50 mg) with Placebo 16 0.13 0.89 0.00 -1-2 A-B 0.0379* C) T (50 mg)/NTX 1.0 mg 18 -0.17 0.79 0.00 -1 1 B-C 0.3264 0.2925 D) T (50 mg)/NTX 0.1 mg 26 0.00 0.85 0.00 -1 1 B-D 0.0675 0.6249 E) T (50 mg)/NTX 0.01 mg 17 0.06 0.90 0.00 -1 -2 B-E 0.0634 0.8133 PAIN INTENSITY SCORE: 0=NONE, 1-MILD, 2=MODERATE, 3=SEVERE. THE PAIN INTENSITY DIFFERENCE (PID) AT EACH TIME POINT IS CALCULATED AS THE DIFFERENCE BETWEEN THE PAIN INTENSITY SCORE AT HOUR 0 AND THE SCORE AT OBSERVATION TIME.

P-VALUES COMPARING ALL 5 TREATMENT GROUPS AND PAIRWISE COMPARISONS ARE DETERMINED USING ANOVA.

*SIGNIFICANCE IS AT 0.05 NOMINAL LEVEL.

LAST OBSERVATION CARRIED FORWARD METHOD IS USED TO IMPUTE MISSING VALUES.

.Ic .Ia Table 93B (Continued) Pain Intensity Difference (PID) Scores Intent-to-Treat Population, Male Patients SUM OF PAIN INTENSITY DIFFERENCES Overall P-Value P-Value N Mean SD Median Range Source P-Value vs. vs.

___Placebo Tramadol SUM OF PAIN INTENSITY DIFFERENCES (4 HOURS) A) Placebo 27 -0.41 0.64 0.00 -1 1 TRT 0.1325 B) T (50 mg) with Placebo 16 0.25 0.93 0.00 -1 -2 A-B 0.0194* C) T (50 mg)/NTX 1.0 mg 18 -0.11 0.90 0.00 -1-2 B-C 0.2694 0.2334 D) T (50 mg)/NTX 0.1 mg 26 0.08 0.98 0.00 -1-2 B-D 0.0471* 0.5358 E) T (50 mg)/NTX 0.01 mg 17 0.06 0.97 0.00 -1 2 B-E 0.0890 0.5327 SUM OF PAIN INTENSITY DIFFERENCES (5 HOURS) A) Placebo 27 -0.41 0.64 0.00 -1 1 TRT 0.1417 B) T (50 mg) with Placebo 16 0.19 0.91 0.00 -1 -2 A-B 0.0465* C) T (50 mg)/NTX 1.0 mg 18 -0.17 0.86 0.00 -1-2 B-C 0.3996 0.2730 D) T (50 mg)/NTX 0.1 mg 26 0.12 1.03 0.00 -1 -2 B-D 0.0446* 0.8087 E) T (50 mg)/NTX 0.01 mg 17 0.18 1.24 0.00 -1 -3 B-E 0.0465* 0.9731 PAIN INTENSITY SCORE: 0=NONE, 1-MILD, 2=MODERATE, 3=SEVERE. THE PAIN INTENSITY DIFFERENCE (PID) AT EACH TIME POINT IS CALCULATED AS THE DIFFERENCE BETWEEN THE PAIN INTENSITY SCORE AT HOUR 0 AND THE SCORE AT OBSERVATION TIME.

P-VALUES COMPARING ALL 5 TREATMENT GROUPS AND PAIRWISE COMPARISONS ARE DETERMINED USING ANOVA.

*SIGNIFICANCE IS AT 0.05 NOMINAL LEVEL.

LAST OBSERVATION CARRIED FORWARD METHOD IS USED TO IMPUTE MISSING VALUES.

Table 93B (Continued) Pain Intensity Difference (PID) Scores Intent-to-Treat Population, Male Patients SUM OF PAIN INTENSITY DIFFERENCES Overall P-Value P-Value N Mean SD Median Range Source P-Value vs. vs.

Placebo Tramadol SUM OF PAIN INTENSITY DIFFERENCES (6 HOURS) A) Placebo 27 -0.37 0.69 0.00 -1 1 TRT 0.1871 B) T (50 mg) with Placebo 16 0.25 0.93 0.00 -1 -2 A-B 0.0420* C) T (50 mg)/NTX 1.0 mg 18 -0.11 1.02 0.00 -1 3 B-C 0.3743 0.2736 D) T (50 mg)/NTX 0.1 mg 26 0.15 1.08 0.00 -1 2 B-D 0.0484* 0.7519 E) T (50 mg)/NTX 0.01 mg 17 0.12 1.05 0.00 -1-2 B-E 0.1019 0.6915 SUM OF PAIN INTENSITY DIFFERENCES (7 HOURS) A) Placebo 27 -0.37 0.69 0.00 -1 -1 TRT 0.1844 B) T (50 mg) with Placebo 16 0.19 0.91 0.00 -1 -2 A-B 0.0697 C) T (50 mg)/NTX 1.0 mg 18 -0.11 1.02 0.00 -1 3 B-C 0.3791 0.3697 D) T (50 mg)/NTX 0.1 mg 26 0.23 1.14 0.00 -1 -2 B-D 0.0255* 0.8880 E) T (50 mg)/NTX 0.01 mg 17 0.06 1.03 0.00 -1 2 B-E 0.1537 0.7025 PAIN INTENSITY SCORE: 0=NONE, 1-MILD, 2=MODERATE, 3=SEVERE. THE PAIN INTENSITY DIFFERENCE (PID) AT EACH TIME POINT IS CALCULATED AS THE DIFFERENCE BETWEEN THE PAIN INTENSITY SCORE AT HOUR 0 AND THE SCORE AT OBSERVATION TIME.

P-VALUES COMPARING ALL 5 TREATMENT GROUPS AND PAIRWISE COMPARISONS ARE DETERMINED USING ANOVA.

*SIGNIFICANCE IS AT 0.05 NOMINAL LEVEL.

LAST OBSERVATION CARRIED FORWARD METHOD IS USED TO IMPUTE MISSING VALUES.

Table 93B (Continued) Pain Intensity Difference (PID) Scores Intent-to-Treat Population, Male Patients SUM OF PAIN INTENSITY DIFFERENCES Overall P-Value P-Value N Mean SD Median Range Source P-Value vs. vs.

Placebo Tramadol SUM OF PAIN INTENSITY DIFFERENCES (8 HOURS) A) Placebo 27 -0.37 0.69 0.00 -1 1 TRT 0.1562 B) T (50 mg) with Placebo 16 0.25 0.93 0.00 -1 -2 A-B 0.0447* C) T (50 mg)/NTX 1.0 mg 18 -0.11 1.02 0.00 -1 -3 B-C 0.3805 0.2799 D) T (50 mg)/NTX 0.1 mg 26 0.23 1.14 0.00 -1 -2 B-D 0.0259* 0.9502 E) T (50 mg)/NTX 0.01 mg 17 0.06 1.03 0.00 -1 -2 B-E 0.1550 0.5717 PAIN INTENSITY SCORE: 0=NONE, 1-MILD, 2=MODERATE, 3=SEVERE. THE PAIN INTENSITY DIFFERENCE (PID) AT EACH TIME POINT IS CALCULATED AS THE DIFFERENCE BETWEEN THE PAIN INTENSITY SCORE AT HOUR 0 AND THE SCORE AT OBSERVATION TIME.

P-VALUES COMPARING ALL 5 TREATMENT GROUPS AND PAIRWISE COMPARISONS ARE DETERMINED USING ANOVA.

*SIGNIFICANCE IS AT 0.05 NOMINAL LEVEL.

LAST OBSERVATION CARRIED FORWARD METHOD IS USED TO IMPUTE MISSING VALUES.

Claims (65)

1. A method for enhancing the potency of an opioid agonist in a human subject comprising administering to the human subject an analgesic or subanalgesic amount of the agonist and an amount of an opioid antagonist effective to enhance the analgesic potency of the agonist without attenuating an adverse side effect of the agonist.
2. A method according to claim 1 wherein the opioid agonist is morphine, hydrocodone, oxycodone, or tramadol.
3. A method according to claim 1 wherein the opioid agonist is morphine.
4. A method according to claim 1 wherein the opioid antagonist is naltrexone, naloxone, or nalmefene. A method according to claim 1 wherein the opioid antagonist is naltrexone.
6. A method according to claim 1 wherein the opioid antagonist is nalmefene.
7. A method according to claim 1 wherein the administration is oral, sublingual, intramuscular, subcutaneous, intravenous, transmucosal or transdermal.
8. A method according to claim 1 wherein the administration is oral.
9. A method according to claim 1 wherein the human subject is male.
10. A method according to claim 1 wherein the human subject is female.
11. A method for attenuating an adverse side effect associated with administration of an opioid agonist to a human subject comprising administering to the human subject an analgesic or subanalgesic amount of the agonist and an amount of an opioid antagonist effective to attenuate the adverse side effect while maintaining analgesic potency of the agonist. WO 01/85150 PCT/US01/14644 752
12. A method according to claim 11 wherein the adverse side effect is nausea, vomiting, dizziness, headache, sedation or pruritus.
13. A method according to claim 11 wherein the opioid agonist is morphine, hydrocodone, oxycodone or tramadol.
14. A method according to claim 11 wherein the opioid agonist is morphine. A method according to claim 11 wherein the opioid antagonist naltrexone, naloxone, or nalmefene.
16. A method according to claim 11 wherein the opioid antagonist is naltrexone.
17. A method according to claim 11 wherein the opioid antagonist is nalmefene.
18. A method according to claim 11 wherein the administration is oral, sublingual, intramuscular, subcutaneous, intravenous, transmucosal or transdermal.
19. A method according to claim 11 wherein the administration is oral. A method according to claim 11 wherein the analgesic potency of the agonist is maintained without increasing or decreasing the cumulative daily dose of the agonist relative to the antagonist.
21. A method according to claim 11 wherein the human subject is female.
22. A method according to claim 11 wherein the human subject is male.
23. A method for treating pain in a human subject comprising administering to the human subject an analgesic or subanalgesic amount of the agonist and an amount of an opioid antagonist effective to enhance the analgesic potency of the agonist without attenuating an adverse side effect of the agonist. WO 01/85150 PCT/US01/14644 753
24. A method according to claim 23 wherein the opioid antagonist is morphine. A method according to claim 23 wherein naltrexone, naloxone, or nalmefene. the opioid antagonist is
26. A method according to claim 23 wherein the opioid antagonist is naltrexone.
27. nalmefene. A method according to claim 23 wherein the opioid antagonist is
28. A method according to claim 23 wherein the administration is oral, sublingual, intramuscular, subcutaneous, intravenous, transmucosal or transdermal.
29. A method according to claim 23 wherein the administration is oral. A method according to claim 23 wherein the human subject is male.
31. A method according to claim 23 wherein the human subject is female.
32. A method for treating pain with an opioid agonist and attenuating an adverse side effect of the agonist in a human subject comprising administering to the human subject an analgesic amount of the agonist and an amount of an opioid antagonist effective to attenuate the adverse side effect while maintaining analgesic potency of the agonist.
33. A method according to claim 32 wherein the opioid agonist is morphine, hydrocodone, oxycodone or tramadol.
34. The method according to claim 32 wherein the opioid agonist is morphine. A method according to claim 32 wherein the opioid antagonist is naltrexone, naloxone, or nalmefene. -754-
36. A method according to claim 32, wherein the opioid antagonist is naltrexone.
37. A method according to claim 32, wherein the opioid antagonist is nalmefene.
38. A method according to claim 32, wherein the administration is oral, sublingual, intramuscular, subcutaneous, intravenous, transmucosal or transdermal.
39. A method according to claim 32, wherein the administration is oral. A method according to claim 32, wherein the analgesic potency of the agonist is maintained without increasing or decreasing the cumulative daily dose of the agonist relative to the antagonist.
41. A method according to claim 32, wherein the human subject is female.
42. A method according to claim 32, wherein the human subject is male.
43. A method providing or enhancing pain relief in men comprising administering to a man a hypo-analgesic dose of a non-kappa opioid receptor agonist and a dose of an opioid antagonist that in combination provides or enhances pain relief.
44. A method according to claim 43, wherein the non-kappa opioid receptor agonist is a mu opioid receptor agonist. A method according to claim 43, wherein the hypo-analgesic dose of the agonist is a non-analgesic dose or an anti-analgesic dose in men and an analgesic dose in women.
46. A method according to claim 43, wherein the dose of the antagonist prolongs the time to remedication.
47. A method according to claim 43, wherein the dose of the antagonist enhances the global evaluation of pain relief.
48. A method according to claim 43, wherein the agonist is morphine.
49. A method according to claim 43, wherein the antagonist is naltrexone. A method according to claim 43, wherein the pain relief is measured by the men using a categorical scale or a visual analog scale.
51. A method of enhancing pain relief in women comprising administering to a women an analgesic dose of a non-kappa opioid receptor agonist and a dose of opioid antagonist that in combination provides pain relief comparable to that of the agonist alone but with attenuation of one or more adverse side effects of the agonist.
52. A method according to claim 51, wherein the non-kappa opioid receptor agonist is a mu opioid receptor agonist.
53. A method according to claim 51, wherein the dose of the agonist is an analgesic dose in women and a hypo-analgesic dose in men. ,O -755- O CI 54. A method according to claim 51, wherein the dose of the antagonist prolongs the time to remedication. A method according to claim 51, wherein the dose of the antagonist enhances the 0 global evaluation of pain relief.
56. A method according to claim 51, wherein the agonist is morphine. \0 57. A method according to claim 51, wherein the agonist is naltrexone.
058. A method according to claim 51, wherein the pain relief is measured by the CI women using a categorical scale or a visual analog scale. O 59. A method for providing analgesia in a human subject administered a non-analgesic CI 10 amount of an opioid agonist comprising concurrently administering with the agonist, an amount of opioid antagonist effective to provide analgesia. A method according to claim 59, wherein the human subject is a man.
61. A method according to claim 60, wherein the opioid agonist is morphine.
62. A method according to claim 59, wherein the human subject is a women.
63. A method according to claim 62, wherein the opioid agonist is tramadol.
64. A method of converting a hypo-analgesic dose of an opioid agonist into an analgesic dose of the agonist comprising administering to a human subject a combination of the hypo-analgesic dose of the agonist and an amount of an opioid antagonist sufficient to provide analgesia.
65. A method according to claim 64, wherein the opioid agonist is morphine, hydrocodone, oxycodone, or tramadol.
66. A method according to claim 64, wherein the opioid agonist is morphine.
67. A method according to claim 64, wherein the opioid antagonist is naltrexone, naloxone, or nalmefene.
68. A method according to claim 64, wherein the opioid antagonist is naltrexone.
69. A method according to claim 64, wherein the opioid antagonist is nalmefene. A method according to claim 64, wherein the administration is oral, sublingual, intramuscular, subcutaneous, intravenous, transmucosal or transdermal.
71. A method according to claim 64, wherein the administration is oral.
72. A method according to claim 64, wherein the human subject is male.
73. A method according to claim 64, wherein the human subject is female.
74. A method according to claim 64, wherein the hypo-analgesic dose of the agonist is a non-analgesic dose or an anti-analgesic dose in men and an analgesic dose in women. -756- A method according to claim 64, wherein the dose of the antagonist prolongs the time to remedication.
76. A method according to claim 64, wherein the analgesia is measured by a pain relief score or a pain intensity difference score using a categorical scale or a visual analog scale.
77. A method for enhancing the potency of an opioid agonist in a human subject, s;ubstantially as herein described with reference to any one of the examples but excluding comparative examples. '78. A method for attenuating an adverse side effect associated with administration of an opioid agonist to a human subject, substantially as herein described with reference to any one of the examples but excluding comparative examples. '79. A method of treating pain in a human subject, substantially as herein described with reference to any one of the examples but excluding comparative examples. A method of treating pain with an opioid agonist and attenuating an adverse side effect of the agonist to a human subject, substantially as herein described with reference to any one of the examples but excluding comparative examples.
81. A method for providing or enhancing pain relief in men, substantially as herein described with reference to any one of the examples but excluding comparative examples.
82. A method for providing or enhancing pain relief in women, substantially as herein described with reference to any one of the examples but excluding comparative examples.
83. A method for providing analgesia in a human subject, substantially as herein described with reference to any one of the examples but excluding comparative examples.
84. A method of converting a hypo-analgesic dose of an opioid agonist into an analgesic dose of the agonist, substantially as herein described with reference to any one of the examples but excluding comparative examples. DATED this 7 1h day of September 2006 Shelston IP Attorneys for: Albert Einstein College of Medicine of Yeshiva University and Pain Therapeutics, Inc.
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DK2266564T3 (en) 1997-12-22 2013-06-03 Euro Celtique Sa A pharmaceutical oral dosage form comprising a combination of an opioid agonist and an opioid antagonist
US6375957B1 (en) 1997-12-22 2002-04-23 Euro-Celtique, S.A. Opioid agonist/opioid antagonist/acetaminophen combinations
AR031682A1 (en) * 1999-11-19 2003-10-01 Reckitt Benckiser Helthcare Uk pharmaceutical compositions
EP1392265A2 (en) * 2000-10-30 2004-03-03 Pain Therapeutics, Inc. Inhibitors of abc drug transporters at the blood-brain barrier
CA2446550C (en) 2001-05-11 2012-03-06 Endo Pharmaceuticals, Inc. Abuse-resistant controlled-release opioid dosage form
TWI334779B (en) 2002-04-05 2010-12-21 Euro Celtique Sa Pharmaceutical preparation containing oxycodone and naloxone
MY135852A (en) 2003-04-21 2008-07-31 Euro Celtique Sa Pharmaceutical products
EP1680143A2 (en) * 2003-10-15 2006-07-19 Pain Therapeutics, Inc. Treatment of arthritic conditions, chronic inflammation or pain
US20050245557A1 (en) * 2003-10-15 2005-11-03 Pain Therapeutics, Inc. Methods and materials useful for the treatment of arthritic conditions, inflammation associated with a chronic condition or chronic pain
EP1702558A1 (en) 2005-02-28 2006-09-20 Euro-Celtique S.A. Method and device for the assessment of bowel function
CA2609733C (en) * 2005-05-25 2011-07-19 Shionogi & Co., Ltd. 6,7-unsaturated-7-carbamoyl-substituted morphinan derivative
WO2006126529A1 (en) 2005-05-25 2006-11-30 Shionogi & Co., Ltd. 6,7-unsaturated-7-carbamoyl substituted morphinan derivative
JP2011511782A (en) * 2008-02-12 2011-04-14 アボット・ラボラトリーズAbbott Laboratories Extended release hydrocodone acetaminophen and its related methods and applications
WO2010103039A1 (en) 2009-03-10 2010-09-16 Euro-Celtique S.A. Immediate release pharmaceutical compositions comprising oxycodone and naloxone
ES2703623T3 (en) * 2013-06-28 2019-03-11 Purdue Pharma Lp Opioid antagonists for use in the treatment of arrhythmia induced by opioid analgesics
JP2016525138A (en) 2013-07-23 2016-08-22 ユーロ−セルティーク エス.エイ. The combination of oxycodone and naloxone for use in the treatment of pain in patients suffering from diseases increase the risk for diseases and / or Enterobacteriaceae migration results in pain and intestinal Disconnect bio cis
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
CA2955229A1 (en) 2014-07-17 2016-01-21 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996002251A1 (en) * 1994-07-19 1996-02-01 Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists
US5580876A (en) * 1992-09-21 1996-12-03 Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists
WO2000001377A2 (en) * 1998-07-07 2000-01-13 David Lew Simon Nalmefene in combination with opioid analgesics

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK2266564T3 (en) * 1997-12-22 2013-06-03 Euro Celtique Sa A pharmaceutical oral dosage form comprising a combination of an opioid agonist and an opioid antagonist
CA2314896C (en) * 1997-12-22 2005-09-13 Euro-Celtique, S.A. A method of preventing abuse of opioid dosage forms

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5580876A (en) * 1992-09-21 1996-12-03 Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists
US5767125A (en) * 1992-09-21 1998-06-16 Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists
WO1996002251A1 (en) * 1994-07-19 1996-02-01 Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists
WO2000001377A2 (en) * 1998-07-07 2000-01-13 David Lew Simon Nalmefene in combination with opioid analgesics

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