CA2408098A1

CA2408098A1 - Opioid antagonist containing composition for enhancing the potency or reducing adverse side effects of opioid agonists

Info

Publication number: CA2408098A1
Application number: CA002408098A
Authority: CA
Inventors: Barry Sherman; Mary Remien; Remi Barbier; Kathleen Dumas; Grant Schoenhard
Original assignee: Individual
Current assignee: Albert Einstein College of Medicine; Pain Therapeutics Inc
Priority date: 2000-05-05
Filing date: 2001-05-04
Publication date: 2001-11-15
Also published as: EP1280529A2; AU2001259560B2; JP2004501094A; AU2001259458B2; AU5956001A; WO2001085150A3; WO2001085150A2

Abstract

0he invention generally relates to novel compositions and methods with an opioid agonist and an opioid antagonist to differentially dose a human subje ct so as to either enhance analgesic potency without attenuating an adverse sid e effect of the agonist, or alternatively maintain the analgesic potency of th e agonist while attenuating an adverse side effect of the agonist. The inventi on additionally relates to novel opioid compositions and methods for the gender - based dosing of men and women.

Description

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

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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. 601202,227 filed May 5, 2000 (provisional); 601202,268 filed May 5, 2000 (provisional); 09/756,331 filed January 8, 2001, which is a continuation of 09/566,071 filed May 5, 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 PCTlIJS00112493 [WO 00!67739] filed May S, 2000. The applications cited above are hereby incorporated herein by reference in their entirety to provide continuity of disclosure.
FIELD OF THE INVENTION
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 rnen andlor 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 axe 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 in the brain, spinal cord, and other tissues. The principal therapeutic actions are analgesia and sedation.

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, i.e., 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-hydroxydihydroxydihydronor-morphine) 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 (e.g., leading to constipation), respiratory depression (especially at high-doses), peripheral vasodilation (e.g., 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 (e.g., 50 mg naltrexone). For these uses, doses must be relatively high in order to be therapeutically effective (i.e., 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 (e.g., 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 axe directed to methods fox selectively enhancing the analgesic potency of a bimodally-acting opioid agonist and simultaneously attenuating anti-analgesia, hyperalgesia, hyperexcitability, physical dependence andlor 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 andlor tolerance effects of the bimodally-acting opioid agonist.
Also included in these patents are methods for treating pain in a subject comprising administering to the 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 simultaneously attenuate anti-analgesia, hyperalgesia, hyperexcitability, physical dependence andlor 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 anti-analgesia, 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 PCAlIV 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 gender-based 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. 3. Clin. Phaxmacol. Ther. 37 (11): 529-(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 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 5 another recent review, Miaskowski and Levine [Pain Forum 8(1): 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:

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, e.g., butorphanol [Gear et al., Nature, 2: 124.8-1250 (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 gender-related effects. Studies in rats and mice evaluating the role of mu 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., Anesthesiolo~y, 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 (1) enhancement of analgesic potency of the agonist without attenuation (e.g., reduction) or increase of one or more of the adverse side effects associated with that dose of agonist in humans, or (2) maintenance of analgesic potency of the agonist with attenuation (e.g., reduction) of one or more of the adverse side effects associated 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 effects) 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 (e.g., reduced) adverse side effect(s). The maintained potency with attenuated side effects) 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 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 hypo s analgesia. This is based in part on surprising results from human clinical trials that the responses to naltrexone, an opioid antagonist, axe 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 non-kappa 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 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, (e.g., 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 gender-specific interactions of such agonists in women and men. Compositions and methods axe provided for administering a non-kappa opioid receptor agonist, preferably a mu opioid receptor agonist, at a gender-specific compensatory dose based on different pharmacodynamic effects in women and men, wherein such a gender-specific compensatory dose provides enhancement of analgesia and/or attentuation of an adverse side effect of the agonist.
The present invention provides compositions and methods that include a non-kappa opioid receptor agonist, preferably a mu opioid receptor agonist, and an opioid antagonist in amounts that are useful for men only, or for women only, or for both men and women, based on the differences described herein.
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 l: placebo; morphine; morphine and low dose (O.Olmg) 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 (SPm) results at 4 hours (see also Table 5) in the five study groups in Example l: placebo; morphine;
morphine and low dose (O.Olmg) 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 (O.Olmg) 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 (O.Olmg) naltrexone (NTX); morphine and mid dose (0.1 mg) NTX; and morphine and high dose (1.0 mg) NTX.
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 (o); morphine represented as squares (~); morphine and low dose (0.01 mg) NTX represented as large circles (O); morphine and mid dose (0.1 mg) NTX represented as triangles (~);
and morphine and high dose (1.0 mg) NTX represented as larger diamonds (0).
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 low dose (O.Olmg) 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 5 Example 1: placebo; morphine; morphine and low dose (O.Olmg) 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 10 (60 mg); morphine and low-dose (0.01 mg) naltrexone (NTX); morphine and mid-dose (0.1 mg) NTX; morphine and high-dose (1.0 mg) NTX.
Figures 10A and lOB 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 20A 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 mid-dose (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 (Pm) 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.

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 low-dose (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 high-dose (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 (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 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 high-dose (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);
naltrexane (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 21 shows the pain intensity differences (P)D) results (see also Table 36) 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 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 (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.
Figures 23A, 23B and 23C show the summary of pain intensity difference (SP>D) 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) naltrexone (NTX); morphine and mid-dose (0.01 mg) NTX; and morphine and high-dose (0.1 mg) NTX, for women and rnen, respectively.
Figures 28A for women and 28B for men show the pain intensity difference (P)D) 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 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 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 law-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 (A);
HC/APAP
(B); HCIAPAP and 1.0 mg naltrexone (NTX) (C); HC/APAP and 0.1 mg NTX (D);
HC/APAP and 0.01 mg NTX (E); HC/APAP and 0.001 mg NTX (F).
Figure 31 shows the summary of pain intensity difference (SPm) results at 4 hours (SPm-4), at 6 hours (SPm-6), and at 8 hours (SPID-8) (see also Table 57) for subjects in the six study groups as described in Example S: placebo (A);
HC/APAP
(B); HC/APAP and 1.0 mg naltrexone (NTX) (C); HC/APAP and 0.1 mg NTX (D);
HC/APAP and 0.01 mg NTX (E); HC/APAP and 0.001 mg NTX (F).
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 (A); HC/APAP (B); HC/APAP and 1.0 mg naltrexone (NTX) (C); HC/APAP and 0.1 mg NTX (D); HC/APAP and 0.01 mg NTX (E); HCIAPAP and 0.001 mg NTX (F).
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 (A);
HC/APAP
(B); HC/APAP and 1.0 mg naltrexone (NTX) (C); HC/APAP and 0.1 mg NTX (D);
HCIAPAP and 0.01 mg NTX (E); HC/APAP and 0.001 mg NTX (F).
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 5:

placebo (A); HC/APAP (B); HC/APAP and 1:0 mg naltrexone (NTX) (C); HC/APAP
and 0.1 mg NTX (D); HC/APAP and 0.01 mg NTX (E); HC/APAP and 0.001 mg NTX (F).
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 (A); HC/APAP (B);
HC/APAP and 1.0 mg naltrexone (NTX) (C); HC/APAP and 0.1 mg NTX (D);
HC/APAP and 0.01 mg NTX (E); HC/APAP and 0.001 mg NTX (F) Figure 36 shows the pain intensity differences (Pm) results (see also Table 62) for subjects in the six study groups as described in Example 5: placebo (A);
HC/APAP (B); HC/APAP and 1.0 mg naltrexone (NTX) (C); HC/APAP and 0.1 mg NTX (D); HC/APAP and 0.01 mg NTX (E); HC/APAP and 0.001 mg NTX (F) 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 (A); HC/APAP (B); HC/APAP and 1.0 mg naltrexone (NTX) (C); HC/APAP and 0.1 mg NTX (D); HC/APAP and 0.01 mg NTX (E); 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.

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 (30 mg); morphine (30 mg) and NTX (0.I mg); morphine (60 mg); morphine (60 mg) and NTX (0.1 mg); morphine (90 mg); morphine (90 mg) and NTX (0.1 mg).
5 Figure 42 shows the summary of pain intensity difference (SPm) 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).
10 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 (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 44 shows the probability to remedication (rescue medication) over time 15 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 (P)D) 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 (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 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 (Pm) 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 (Pm) 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 (Pm) 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 (Pm) results for women and men, respectively, in the five study groups as described in Example 9: placebo (A); tramadol and placebo (B); tramadol and 1.0 mg naltrexone (NTX) (C); tramadol and 0.1 mg NTX (D); tramadol and 0.01 mg NTX (E).
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 (e.g., reducing, blocking, inhibiting or preventing) the side effects of the agonist in humans, or maintaining the analgesic potency of the agonist while attenuating (e.g., 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 (1) enhance (e.g., increase) analgesic potency of the opioid agonists without substantially reducing or increasing (e.g., maintain) the adverse side effects in humans associated with that dose of agonist; or (2) maintain the analgesic potency (e.g., neither substantially increase or decrease potency) of the opioid agonists while attenuating (e.g., 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 (e.g., increased) potency. For compositions and methods of the invention that attenuate (e.g., 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 1 S and women. Such novel combinations of such agonists and antagonists are unexpectedly efficacious in enhancing (e.g., 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 (e.g., 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 (i) 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 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 anti-analgesic 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 (2) analgesia in women using an analgesic dose of a non kappa 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 (e.g., in number andlor 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 (e.g., increase) pain relief or attenuate (e.g., 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 (e.g., 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 (e.g., 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.

It will be appreciated that compositions and methods of the invention useful for human subjects (e.g., 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-6 glucuronide 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, ethylinorphine, etonitazene, fentanyl, heroin, hydrocodone, hydroxymethylinorphinan, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, methylmorphine, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, 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, 5 tramadol, tilidine, salts thereof, mixtures of any of the foregoing, mixed mu-agonists/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 10 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.
15 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, bimodally-20 acting opioid agonists are compounds which elicit prolongation of the APD
of DRG
neurons at pM-nM concentrations (i. e., excitatory effects), and shortening of the APD
of DRG neurons at ~,M concentrations (i.e., 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 (e.g., 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, 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 (e.g., 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 (e.g., 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 (e.g., analgesic activity), but excluding agonists that primarily bind to and interact with kappa opioid receptors, and from such interactions produce their therapeutic effects (e.g., 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 [e.g., a cyclic enkephalin analog [D-Pent, D-Pens]-(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 (e.g., analgesic activity), but excluding agonists that primarily bind to and interact with kappa opioid receptors, and from such interactions produce their therapeutic effects (e.g., 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 [e.g., 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 [e.g., diarylinethylpiperazines and piperdines such as 3-((a R) - a - ((2S, SR) - 4 -allyl -2, 5, - dimethyl - 1 - piperazinyl) -3-hydroxybenzyl) - N, N-diethylbenzamine]; and the synthetic pentapeptide known as DADLE (see, e.g., 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 (e.g., 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 [e.g., morpholine derivatives]; U.S. Patent No. 6,110,947 hereby incorporated by reference in its entirety [e.g., pyrrolidinyl hydroxamic acid compounds]; U.S. Patent No.
5,965,701 hereby incorporated by reference in its entirety [e.g., 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 andlor interacts with sigma opioid receptors and from such interactions produces its therapeutic effects (e.g., analgesic activity), but excluding agonists that primarily bind to and interact with kappa opioid receptors, and from such interactions produce their therapeutic effects (e.g., 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 (e.g., 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 (e.g., 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 (e.g., 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, LYl 17413, MR2266, or an opioid antagonist having the same pentacyclic nucleus as nalrnefene, 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 (i.e., excitatory effects) but not the shortening of the APD of DRG neurons (l. e., 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.

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, malefic, 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(methylcarbamate), bi(pentaflouropropionate), mesylate, bi(pyridine-3-caxboxylate), bi(triflouroacetate), bitaxtrate, 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 ration, or a metal .ration. Lists of suitable salts are found in texts such as Remingto~z's Pharmaceutical Sciences, 18th Ed. (Alfonso R. Gennaro, ed.; Mack Publishing Company, Easton, PA, 1990); Remington: the Science and Practice of Pharmacy l9tn Ed. (Lippincott, Williams & Wilkins, 1995); Handbook of Pharmaceutical Excipients, 3rd Ed. (Arthur H. Kibbe, ed.; Amer. Pharmaceutical Assoc., 1999); the Pharmaceutical Codex: Principles and Practice of Pharmaceutics 12th 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 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, S 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 (e.g., dysphoria, euphoria), or lightheadedness. An "adverse side effect" also includes a serious adverse side effect such as respiratory 10 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 15 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 subj ects include nausea, vomiting, dizziness, headache, somnolence (sedation), and pruritus. Some additional adverse side effects are listed in the Physician Desk Reference (PDR) for selected 20 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 25 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.

"Co-administer," "co-administration," "concurrent administration" or "co-treatment" 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 axe given in a manner to allow both agents to achieve effective concentrations to yield their desirable therapeutic effects (e.g., 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 (NSA.IDS) such as ibuprofen, COX-1 and/or COX-2 inhibitors such as aspirin, rofecoxib (marketed as VIOXX~), and celcoxib (marketed as CELEBREX~).
"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 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 earners 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 well-known 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, e.g., buffers, flavoring agents, surface active agents, or the like.
The choice of earner 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 (e.g., non-kappa opioid receptor agonist and/or opioid antagonist andJor other active pharmaceutical ingredient) calculated to produce the desired therapeutic effect (e.g., analgesia), in association with a suitable pharmaceutical earner. Thus, the active ingredients according to the invention (e.g., 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, e.g., 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 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 (e.g., SYNALGOS-DC~ from Wyeth-Ayerst Pharmaceuticals), fentanyl (e.g., ACTIQ~ from Abbott Laboratories)., hydrocodone (e.g., 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 (e.g., DILAUDID~ from Knoll), levorphanol (e.g., LEVO-DROMORAN~ from ICN
Pharmaceuticals), meperidine (e.g., DEMEROL~ from Sanofi Pharmaceuticals), methadone (e.g., METHADOSE~ from Mallinckrodt; and DOLOPHINE~ HCl from Roxane Laboratories), morphine (e.g., KADIAN~ from Faulding Laboratories; MS
CONTIN~ from Purdue Frederick; ORAMORPH~ SR from Roxane), oxycodone (e.g., PERCOCET~ and PERCODAN~ from Endo; OXYCET~ from Mallinckrodt;
OXYCONTIN~ from Purdue Frederick; TYLOX~ from Ortho-McNeil Pharmaceutical; ROXICODONE~, ROXILOX~ and ROXICET~ from Roxane), pentazocine (e.g., TALACEN~ and TALWIN~ from Sanofi Pharmaceuticals), propoxyphene (e.g., DARVOCET-N~ and DARVON~ from Eli Lilly ~ Co.;
DOLENE~ from Lederle; WYGESIC~ from Wyeth-Ayerst), and tramadol (e.g., 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 (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Liquid dose forms for human administration include: hydrocodone (e.g., HYDROPHANE~ from Halsey), hydromorphone (e.g., DILAUDID~ from Knoll), meperidine (e.g., DEMEROL~
from Sanofi), methadone (e.g., DOLOPHINE~ from Roxane), oxycodone (e.g., HYCOMINE~ from Knoll; ROXILOX~ from Roxane), and propoxyphene (e.g., DARVON-N~ from Eli Lilly).
S 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, andlor rendering said solution sterile. The formulations may be present in unit dose forms or mufti-dose forms, including in containers such as sealed ampoules or vials. Parenteral dose forms for human administration include:
alfentanil (e.g., ALFENTA~ from Akorn), buprenorphine (e.g., BUPRENEX~ from Reckitt & Colinan Pharmaceuticals), butorphanol (e.g., STADOL~ from Apothecon), dezocine (e.g., DALGAN~ from Astrazeneca), fentanyl, hydromorphone (e.g., DILAUD117-HP~ from Knoll), levallorphan (e.g., LORFAN~ from Roche), levorphanol (e.g., LEVO-DROMORAN~ from ICN), meperidine (e.g., DEMEROL~
from Sanofi), methadone (e.g., DOLOPHINE~ HCI from Roxane), mozphine (e.g, ASTRAMORPH~ from Astrazeneca; DURAMORPH~ and INFLTMORPH~ from Ellcins-Sinn), oxymorphone (e.g., NUMORPHAN~ from Endo), nalburphine (e.g., 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 compoundlenhancer 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 material to provide a patch. Transdermal dose forms for human administration include fentanyl (e.g., DURAGESIC~ from Janssen).
Additional dose forms available as suppositories for human administration include oxymorphone (e.g., NUMORPHAN~ from Endo).
5 "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 10 analgesia (e.g., 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 SP)D from such pain relief scores or pain intensity 15 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 20 provide or enhance the analgesic potency (e.g., as measured by pain relief or pain intensity difference) of the opioid agonist, without substantially increasing (e.g., 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 (e.g., maintain analgesia as measured by pain relief 25 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 30 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.

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 (e.g., 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 (e.g., 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 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 (Pm). A PID score of 0 means no change in.
the level of pain, whereas a negative P)D score means that pain increased, and a positive PJD score indicates analgesia. Within 15 minutes, the Pm 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 -0.3) 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 P117 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 60 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 30 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 PJD score remaining at or above about 0.6 for this time period. Thereafter, the PID
score slowly fell, and by about 6 hours, the PID score was at about 0.5. The PID remained at about 0.5 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 45 minutes, with the Pll~ score being about -0.2. 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 4), 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 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 occurnng 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 subj ects 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 andlor males.

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 5 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.
10 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 15 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/LTS00/12493 [W000/67739], 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 20 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 compendia) in the USP/NF, when there was an existing monograph.
In the following examples, encapsulated dose forms of naltrexone HCl (NTX) 25 and various opioid agonists were prepared for clinical studies as follows.
Encapsulated dose forms of naltrexone HCl were produced in the following doses and weight concentrations.

Naltrexone HC1 Naltrexone HC1 Active Capsule Capsule Dose Blend Concentration (%
w/w) 1.0 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 HCl and other inactive components (e.g., magnesium stearate and microcrystalline cellulose) into a planetary mixer. The inactive components were added in portion-wise steps with mixing between each addition to achieve uniformity of the NTX.
The S intermediate active blend was transferred from the planetary mixer to a double-cone blender.
An amount of preblended inactive components was used to rinse the planetary mixer. The rinsings were added to the double-cone blender to achieve quantitative recovery of naltrexone HCI. 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 HCl (e.g., 0.03% w/w/, 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 (e.g., 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 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 (e.g., 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 (Carnrick Laboratories), which contained hydrocodone bitartrate (5 mg) with acetaminophen (500 mg) and various inactive components.

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.

A clinical study was designed as follows: (1) 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 (2) 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: (1) to compare the analgesic efficacy of MS 60 mg to placebo to establish the assay sensitivity of the study; (2) 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 (3) 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.

Inclusion criteria were as follows:
(1) 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;
(2) subjects willing and able to complete the pain evaluations;
(3) 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.
(4) female subjects were postmenopausal, or physically incapable of child bearing, or practicing an acceptable method of birth control (ICTD, 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;
1 S (5) subjects in generally good health;
(6) subjects able to speak and understand English and provide meaningful written informed consent;
(7) subjects able to remain at the study site for the entire eight-hour study period;
(8) 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 (9) 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:
(1) pregnant or breast feeding;
(2) have known allergy or significant reaction to opioids or opioid antagonists;
(3) history of chronic opioid use or opioid abuse within six months prior to study.
(4) have participated in a study of an investigational drug or device within 30 days prior to this study;

(5) 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 5 (Versed), lidocaine (with or without epinephrine), mepivacaine, nitrous oxide, and propofol (Diprivan) given during surgery;
(6) have taken a long-acting analgesic (e.g., long-acting NSAIDS) within 12 hours prior to this study;
(7) have taken monoamine oxidase inhibitors or tricyclic antidepressant 10 drugs within four weeks prior to study medication;
(8) 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 1 gm/day;
15 (9) have a medical or psychiatric condition that compromises the subject's ability to give informed consent or appropriately complete the pain assessments; and (10) 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 10 years.
20 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 25 randomized to treatment. In order to achieve balance among treatment groups with respect to starting pain, the study stratif ed 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.
30 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 concealed drug identification. The tear-off label was taped unopened onto the case report form.
NUMBER OF CAPSULES PER BOTTLE FOR EACH
TREATMENT GROUP
Ca sules TreatmentContents MS NTX NTX NTX Placebo Group 60 mg 1mg 0.1 0.01 mg mg Treatment Group Placebo ' 0 0 0 0 2 A

Group MS 60 mg 1 0 0 0 1 B

Group MS 60 mg with 1 0 0 1 0 C NTX 0.01 mg Group MS 60 mg with 1 0 1 0 0 D NTX 0.1 mg Group MS 60 mg with 1 1 0 0 0 E 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 subj ects, 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 mere accomplished within 14 days prior to surgery: (a) review of inclusion and exclusion criteria; (b) informed consent; (c) urine pregnancy test for women of child-bearing potential (at screening and immediately prior to surgery); (d) medical history and demographics; (e) brief physical examination; and (f) vital signs.
Baseline measurements and procedures included: (a) vital signs (prior to dosing); (b) review of medications received within 12 hours prior to dosing;
and (c) 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:
(a) Following dosing, the subject remained at the study facility for eight hours;
(b) 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.";
(c) For treated subjects, vital signs, were takn one hour after dosing and at the end of the eight-hour observation period;
(d) 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 ~ 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=1, some=2, a lot=3, and complete=4;
(e) Subjects not completing at least 90 minutes after dosing were considered not evaluable and were replaced;

(f) Adverse events were assessed by non-directed questioning and recorded for the eight hours following dosing;
(g) All concomitant medications (including rescue medications) were recorded for the eight-hour observation period;
(h) 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-=1, good=2, very good=3 and excellent=4; and (i) 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 subj ects 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: (a) brief physical examination; (b) 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:

(1) 8-hour Total Pain Relief Scores (TOTPAR-8) described below;
(2) 8-Hour Sum of Pain Intensity Difference Scores (SPID-8) described below;
(3) Time to Rescue;
(4) Percent of Subjects Remedicating with Rescue Medication; and (5) Time to Onset of Meaningful Pain Relief.
The secondary efficacy parameters included:
(1) Hourly Pain Relief Scores;
(2) Hourly Pain Intensity Difference Scores;
(3) Maximum Pain Relief Scores;
(4) Peak Pain Intensity Difference Scores;
(5) Global Evaluations; and (6) Time to Onset of First Perceptible Pain Relief.
Safety evaluations included (1) vital signs; and (2) 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
treatment-emergent 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 occurnng 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 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 O~one, 1=mild, 2=moderate, 3=severe).
The extent to which pain changes over the entire test period was measured by 5 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, 1=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 8-hour observation period, weighted by the time difference between adjacent points 10 (i.e., 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 I S 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 20 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 25 analysis could be done on the evaluable analysis set.
Demographic and baseline characteristics were summarized with descriptive statistics (fox 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 30 (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 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 I~aplan-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/0.1 NTX groups was not evaluable because the subject took rescue medication less than 90 minutes after dosing.

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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 2). Demographic characteristics included age, racelethnicity, 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 5 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).

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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, i.e., 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 1.0-mg NTX combination treatment mean was comparable to ar 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.

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The patterns of the 6-hour and 8-hour SPm 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.

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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 5 placebo (Figure 4). 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 10 groups, and were also different for the morphine, low-dose, and mid-dose groups compared to the placebo group (Figure S). 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.

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The hourly pain intensity difference (Pm) data presented in Table 10 and Figure 7. The hourly Pm scores for the placebo treatment were generally flat while the hourly Pm 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 Pm 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 Pm scores was observed (see, e.g., 2-3 hours) in the MS alone group and the high-dose (1.0 mg NTX) combination group (Figure 7). Highest pain relief as measured by PB7 scores was observed for the low-dose (0.01 mg NTX) combination group.

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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 low-dose and mid-dose groups.

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W .wr 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.

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 axe shown in the following Tables and Figures.
A total of 204 subj ects were randomized; among them 201 subj ects 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.

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O r, H~ z v ~w a 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 S 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 5 treatment groups. Female subjects (51%) 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 for males.

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The TOTPAR results (4 hour, 6 hour, 8 hour) are summanzea m 1 awes i iH
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 1.0 mg and 0.01 mg NTX combinations were higher than morphine alone for the 8 hour TOTPAR scores.

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Tables 18A for females and 18B for males, summarize the results of the 4, 6, and 8 hour SPm results and the 4 hour SPm 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 SPm scores. All 4 of the active treatment groups exhibited improved profiles in mean SPm relative to placebo. The mean SPm 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 SPm scores. For the 4 hour SPm score, the placebo treatment was similar to the MS
alone treatment. The mean SPm 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.

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Figures lOA for females and lOB 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.

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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 morplune, 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.

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~aaUAw 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, IO highest pain relief scores were observed for the Iow-dose (0.0I mg NTX) and mid-dose (0.1 mg NTX) combination groups (Figure 13A). For males, highest pain relief scores were observed for the Iow-dose (0.01 mg NTX) and high-dose (1.0 mg NTX) combination groups.

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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.

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~o pa~~1 ~~~~~~w w~~o ~z ~~~e ~~°z 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 PEAI~Pm 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 PEAKPm 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 low-dose (0.01 mg NTX) combination groups had the highest mean PEAKPIl7 scores.

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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 .
(1.0 mg NTX) combination group was most often rated as "excellent." The profiles of the global evaluations scores are based on subjects' evaluations.

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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 26I~ 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.

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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: (1) 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); (3) subjects had three or four full or partial bony impacted third molars (not 2 or more impacted third molars); (4) meaningful pain relief only (not meaningful and perceptible pain relief with two stopwatches) was measured using one stopwatch; (5) the primary efficacy variables included TOTPAR-4 and SPID-4 measured through 4 hours (not TOTPAR-8 and SP1D-8 measured through 8 hours); (6) 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-b 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; (7) additional exclusion criteria were patients with known history of severe hepatic or renal impairment, and midazolam (Versed) was not permissible medication during surgery; and (8) 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).

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w ~ia~w ~' a 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.

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scores that were numerically higher than NTX alone or placebo. The combination treatments had a dose-response relation in the mean TOTPAR scores, i.e.,.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.

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Table 31 summarizes the results of the 4, 6, and 8 hour SPm results. The 4 hour SPm results are also represented in Figure 23A. The 0.01 mg NTX alone and placebo treatment groups had the lowest mean 4 hour SPm scores. All 4 of the active treatment groups with MS alone or in combination with NTX exhibited improved S profiles in mean SPm relative to NTX alone or placebo. The mean 4 hour SPm 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 SPm scores were similar to those at 4 hours.

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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 32,B. The median time to onset of analgesia was shortest in the 0.1 mg NTX combination treatment group.

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, E-~ d G4 U f~ W w 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.

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E-i W ~ ~4 U ~l W w 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 high-dose NTX (0.1 mg) combination group and more than 30% of subjects in the mid-dose 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.

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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 20).

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a ~ z Tables 37A and 37B present the mean MAXI'AR and PEAKPm 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 PEAI~Pm 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 PEAKPm scores were highest for the 0.1 mg NTX combination treatment group.

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Table 38 presents the summary and analysis of global evaluations. The NTX
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The maj ority of adverse events reported were categorized as digestive (nausea or vomiting) or nervous system (dizziness or somnolence) as fiuther 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.

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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.

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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.

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H E-I ~ P~ U ~1 W fuel a Tables 44A for females and 44B for males summarize the results of the 4, 6, and 8 hour SPID results and the 4 hour SPm results are shown in Figures 23B
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In males, the MS alone group had the lowest mean SPm scores. All of the combination groups had highex 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.

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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.

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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 O.lmg NTX combination group and was similar for all other groups. This was true at both 8 and 24 hours.

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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.

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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.

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Tables S1A for females and S1B 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 rnid-dose (0.01 mg NTX ) and high-dose (0.1 mg NTX) combination groups were most often rated as "excellent."

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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 somnolence (sedation), the placebo group and the NTX
alone group have the lowest incidence.

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DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

~~ TTENANT LES PAGES 1 A 447 NOTE : Pour les tomes additionels, veuillez contacter 1e Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME
NOTE POUR LE TOME / VOLUME NOTE:

Claims

WHAT IS CLAIMED IS:

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.

5. 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.

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.

15. 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.

20. 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.

24. A method according to claim 23 wherein the opioid antagonist is morphine.

25. A method according to claim 23 wherein the opioid antagonist is naltrexone, naloxone, or nalmefene.

26. A method according to claim 23 wherein the opioid antagonist is naltrexone.

27. A method according to claim 23 wherein the opioid antagonist is nalmefene.

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.

30. 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.

35. A method according to claim 32 wherein the opioid antagonist is naltrexone, naloxone, or nalmefene.

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.

40. 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 composition comprising 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.

44. A composition according to claim 43 wherein the opioid agonist is morphine, hydrocodone, oxycodone, or tramadol.

45. A composition according to claim 43 wherein the opioid agonist if morphine.

46. A composition according to claim 43 wherein the opioid antagonist is naltrexone, naloxone, or nalmefene.

47. A composition according to claim 43 wherein the opioid antagonist is naltrexone.

48. A composition according to claim 43 wherein the opioid antagonist of nalmefene.

49. A composition according to claim 43 wherein the administration is oral, sublingual, intramuscular, subcutaneous, intravenous, transmucosal or transdermal.

50. A composition according to claim 43 wherein the administration is oral.

51. A composition comprising 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.

52. A composition according to claim 51 wherein the opioid agonist is morphine, hydrocodone, oxycodone, or tramadol.

53. A composition according to claim 51 wherein the opioid agonist is morphine.

54. A composition according to claim 51 wherein the opioid antagonist is naltrexone, naloxone, or nalmefene.

55. A composition according to claim 51 wherein the opioid antagonist is naltrexone.

56. A composition according to claim 51 wherein the opioid antagonist is nalmefene.

57. A composition according to claim 51 wherein the administration is oral, sublingual, intramuscular, subcutaneous, intravenous, transmucosal or transdermal.

58. A composition according to claim 51 wherein the administration is oral.

59. A composition according to claim 51 wherein the analgesic potency of the agonist is maintained without increasing or decreasing the cumulative daily dose of the agonist relative to the antagonist.

60. 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.

61. A method according to claim 60 wherein the non-kappa opioid receptor agonist is a mu opioid receptor agonist.

62. A method according to claim 60 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.

63. A method according to claim 60 wherein the dose of the antagonist prolongs the time to remedication.

64. A method according to claim 60 wherein the dose of the antagonist enhances the global evaluation of pain relief.

65. A method according to claim 60 wherein the agonist is morphine.

66. A method according to claim 60 wherein the antagonist is naltrexone.

67. A method according to claim 60 wherein the pain relief is measured by the men using a categorical scale or a visual analog scale.

68. A composition for providing or enhancing pain relief in men comprising a hypo-analgesic amount of a non-kappa opioid receptor agonist and an amount of an opioid antagonist that in combination provides or enhances pain relief.

69. A composition according to claim 68 wherein the non-kappa opioid receptor agonist is a mu opioid receptor agonist.

70. A composition according to claim 68 wherein the hypo-analgesic amount of the agonist is a non-analgesic dose or an anti-analgesic amount in men and an analgesic dose in women.

71. A composition according to claim 68 wherein the dose of the antagonist prolongs the time to remedication.

72. A composition according to claim 68 wherein the dose of the antagonist enhances the global evaluation of pain relief.

73. A composition according to claim 68 wherein the agonist is morphine.

74. A composition according to claim 68 wherein the antagonist is naltrexone.

75. A composition according to claim 68 wherein the pain relief produced by the composition is measured by the men using a categorical scale or a visual analog scale.

76. A method of enhancing pain relief in women comprising administering to a woman 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.

77. A method according to claim 76 wherein the non-kappa opioid receptor agonist is a mu opioid receptor agonist.

78. A method according to claim 76 wherein the dose of the agonist is an analgesic dose in women and a hypo-analgesic dose in men.

79. A method according to claim 76 wherein the dose of the antagonist prolongs the time to remedication.

80. A method according to claim 76 wherein the dose of the antagonist enhances the global evaluation of pain relief.

81. A method according to claim 76 wherein the agonist is morphine.

82. A method according to claim 76 wherein the antagonist is naltrexone.

83. A method according to claim 76 wherein the pain relief is measured by the women using a categorical scale or a visual analog scale.

84. A composition for enhancing pain relief in women comprising an analgesic amount of a non-kappa opioid receptor agonist and an amount of an 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.

85. A composition according to claim 84 wherein the non-kappa opioid receptor agonist is a mu opioid receptor agonist.

86. A composition according to claim 84 wherein the amount of the agonist is an analgesic amount in women and a hypo-analgesic amount in men.

87. A composition according to claim 84 wherein the amount of the antagonist prolongs the time to remedication.

88. A composition according to claim 84 wherein the dose of the antagonist enhances the global evaluation of pain relief.

89. A composition according to claim 84 wherein the agonist is morphine.

90. A composition according to claim 84 wherein the antagonist is naltrexone.

91. A composition according to claim 84 wherein the pain relief produced by the composition is measured by the women using a categorical scale or a visual analog scale.

92. A composition for treating pain in women, comprising:
(a) morphine in a dose range of about 0.1 mg to about 300 mg;
and;
(b) naltrexone in a dose range of about 0.0001 mg to about 1.0 mg.

93. A composition according to claim 92 wherein:
(a) morphine is about 15 mg, 30 mg, 60 mg or 90 mg; and (b) naltrexone is about 0.001 mg, 0.01 mg, 0.1 mg or 1.0 mg.

94. A composition for treating pain in men, comprising:
(a) morphine in a dose range of about 0.1 mg to about 300 mg; and (b) naltrexone in a dose range of about 0.0001 mg to about 1 mg.

95. A composition according to claim 94 wherein:
(a) morphine is about 15 mg, 30 mg, 60 mg or 90 mg; and (b) naltrexone is about 0.001 mg, 0.01 mg, 0.1 mg or 1.0 mg.

96. A composition for treating pain in men, comprising:
(a) hydrocodone;
(b) acetaminophen; and (c) an amount of naltrexone sufficient to enhance analgesia associated with (a) or (b) above.

97. A composition according to claim 96, wherein the amount of the hydrocodone is about 5 mg.

98. A composition according to claim 96, wherein the amount of the acetominophen is about 500 mg.

99. A composition according to claim 96, wherein the amount of the naltrexone is about 0.001 mg.

100. A composition for treating pain in women, comprising:
(a) hydrocodone;
(b) acetaminophen; and (c) an amount of naltrexone sufficient to attenuate an adverse side effect associated with (a) or (b) above.

101. A composition according to claim 100, wherein the amount of the hydrocodone is about 5 mg.

102. A composition according to claim 100, wherein the amount of the acetominophen is about 500 mg.

103. A method for providing analgesia in a human subject administered a non-analgesic amount of an opioid agonist comprising concurrently administering with the agonist, an amount of opioid antagonist effective to provide analgesia.

104. A method according to claim 103 wherein the human subject is a man.

105. A method according to claim 104 wherein the opioid agonist is morphine.

106. A method according to claim 103 wherein the human subject is a woman.

107. A method according to claim 106 wherein the opioid agonist is tramadol.

108. 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.

109. A method according to claim 108 wherein the opioid agonist is morphine, hydrocodone, oxycodone, or tramadol.

110. A method according to claim 108 wherein the opioid agonist is morphine.

111. A method according to claim 108 wherein the opioid antagonist is naltrexone, naloxone, or nalmefene.

112. A method according to claim 108 wherein the opioid antagonist is naltrexone.

113. A method according to claim 108 wherein the opioid antagonist is nalmefene.

114. A method according to claim 108 wherein the administration is oral, sublingual, intramuscular, subcutaneous, intravenous, transmucosal or transdermal.

115. A method according to claim 108 wherein the administration is oral.

116. A method according to claim 108 wherein the human subject is male.

117. A method according to claim 108 wherein the human subject is female.

118. A method according to claim 108 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.

119. A method according to claim 108 wherein the dose of the antagonist prolongs the time to remedication.

120. A method according to claim 108 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.