WO2011109743A2

WO2011109743A2 - Synergistic effects of combinations of buprenorphine and opioids for the treatment of pain

Info

Publication number: WO2011109743A2
Application number: PCT/US2011/027253
Authority: WO
Inventors: Jerry N. Rand
Original assignee: Rand Jerry N
Priority date: 2010-03-04
Filing date: 2011-03-04
Publication date: 2011-09-09
Also published as: WO2011109743A3

Abstract

Disclosed herein are compositions and methods for treating pain, and addiction, said methods comprising administering: at least one Opioid or a pharmaceutically acceptable salt thereof; and at least one of a μ- receptor partial agonist or a κ-receptor antagonist, or pharmaceutically acceptable salts thereof; in amounts effective to cause or enhance a supra-additive synergistic analgesic response to pain and for a duration effective to inhibit pain in the individual in need thereof. The co-administration of an Opioid with the μ-receptor partial agonist and the κ-receptor antagonist results in decreased tolerance, decreased dependence potential, and diminishing side effects, compared to conventional opioid therapy alone.

Description

SYNERGISTIC EFFECTS OF COMBINATIONS OF BUPRENORPHINE AND OPIOIDS FOR

THE TREATMENT OF PAIN

CROSS-REFERENCE

[0001] This application related to U.S. Provisional Application No. 61/310,624, filed on March 04, 2010, now abandoned and US. Provisional Application No. 61/311,108 filed March 05, 2010, now abandoned, both applications incorporated in their entirety by reference herein.

FIELD OF INVENTION

[0002] This invention relates to pharmaceutical compositions for the treatment of pain wherein said pharmaceutical composition does not cause an Opioid euphoria or a result in abuse. This invention also relates to pharmaceutical compositions for the treatment of Opioid addiction wherein said pharmaceutical composition does not cause an Opioid euphoria or a result in abuse. Specifically, the instant invention relates to supra-additive pharmaceutical compositions comprising an Opioid; and a μ receptor partial agonist or a κ receptor antagonist and method of use thereof. BACKGROUND OF THE INVENTION

[0003] Opioids, also are a group of drugs that exhibit opium or Morphine-like properties. The Opioids are employed primarily as moderate to strong analgesics, but have many other pharmacological effects as well, including drowsiness, respiratory depression, changes in mood and mental clouding without a resulting loss of consciousness. Opioids act as agonists, antagonists, reverse agonists, and partial agonists against both exogenous and endogenous Opioid ligands interacting with stereo-specific and saturable binding sites in the brain and other tissues.

SUMMARY OF THE INVENTION

[0004] Disclosed herein are combinations of Opioids with different receptor selectivity and different effects on endogenous Opioid receptors. These combinations utilize the synergistic effects of the combined Opioids to create an array of synergistic effects inclusive of analgesia, and addiction control.

[0005] Encompassed herein are compositions useful for the treatment of pain in an individual. In embodiments, the compositions comprise at least one Opioid or a pharmaceutically acceptable salt thereof; and at least one of a μ receptor partial agonist or a κ receptor antagonist or a pharmaceutically acceptable salt thereof. In an embodiment, the μ receptor partial agonist is also a κ receptor antagonist. In a certain embodiment, the μ receptor partial agonist and κ receptor antagonist is Buprenorphine.

[0006] Encompassed herein are methods of treating pain in an individual in need thereof, said method comprising administering to said individual: at least one Opioid or a pharmaceutically acceptable salt thereof; and at least one of a μ-receptor partial agonist or a κ-receptor antagonist, or pharmaceutically acceptable salts thereof; in amounts effective to cause or enhance a supra-additive synergistic analgesic response to pain for a duration effective to inhibit pain in the individual in need thereof. In an embodiment, the μ receptor partial agonist is also a κ receptor antagonist. In a certain embodiment, the μ receptor partial agonist and κ receptor antagonist is Buprenorphine. In certain embodiments, the pain treated is nociceptive pain, neuropathic pain or acute pain.

[0007] Disclosed herein are methods of treating opioid addiction in an individual in need thereof, said method comprising administering to said individual: at least one Opioid or a pharmaceutically acceptable salt thereof; and at least one of a μ-receptor partial agonist or a κ-receptor antagonist, or pharmaceutically acceptable salts thereof. In a certain embodiment, the μ receptor partial agonist and κ receptor antagonist is Buprenorphine. In certain embodiments, the methods and compositions further comprise a μ receptor competitive antagonist such as Naloxone.

[0008] Disclosed herein are methods of reducing Opioid tolerance in an Opioid tolerant individual comprising administering to said individual: at least one Opioid or a pharmaceutically acceptable salt thereof; and at least one of a μ-receptor partial agonist or a κ-receptor antagonist, or pharmaceutically acceptable salts thereof; in amounts effective to reduce Opioid tolerance in the individual.

[0009] In an embodiment of the instant invention is provided a method of reducing pain in an Opioid tolerant patient, said method comprising administering: Buprenorphine or a pharmaceutical salt thereof; and an Opioid or a pharmaceutical salt thereof; in an amount effective to reduce pain in the individual.

[0010] In certain embodiments, the Opioid is chosen from Oxycodone, Hydromorphone or pharmaceutical salt thereof. In certain embodiments, the Opioid is not an Opioid receptor competitive antagonist. In some embodiments, the Opioid is not a μ receptor competitive antagonist.

[0011] In an embodiment of the instant invention, is a method of reducing the onset of Opioid tolerance in a patient receiving pain therapy, said method comprising administering: Buprenorphine or a pharmaceutical salt thereof; and an Opioid or a pharmaceutical salt thereof; in an amount effective to reduce pain in the individual.

[0012] In an embodiment is provided a method for administration of an Opioid described herein, at dosages lower than current US dosage formulations intended for use as a therapeutically effective dosage amount. The mixed receptor activity in titrating doses effectively augments efficacy and decreases development of, or offsets, existing untoward Opioids properties.

[0013] Also provided herein is a method for treating pain in a patient, with an opioid analgesic having addictive liability while decreasing the patient's likelihood of addiction to said opioid analgesic comprising: administering to said patient an effective amount of at least one of a μ-receptor partial agonist or a κ-receptor antagonist, or pharmaceutically acceptable salts thereof; and administering to said patient an effective amount of the Opioid analgesic or a pharmaceutical salt thereof; wherein said least one of a μ-receptor partial agonist or a κ-receptor antagonist is administered before or simultaneously with said analgesic. In an embodiment, the μ receptor partial agonist is also a κ receptor antagonist. In a certain embodiment, the μ receptor partial agonist and κ receptor antagonist is Buprenorphine. In embodiments, the Opioid analgesic is selected from the group consisting of Morphine, Fentanyl, Dihydroetorphine, Sufentanyl, Butorphanol, Alfentanyl, Pentazocine, Morphine, Phenazocine,

Hydromorphone, Codeine, Oxymorphone, Meperidine, Methadone, Propoxyphene, Oxycodone,

Tramadol, Hydrocodone, Remifentanil, Levorphanol, Dihydrocodeine, L-acetylmethadol, Ethylmorphine, Diacetylmorphine, Nalbuphine, Etorphine, Buprenorphine, Normethadone, Dihydromorphine,

Noroxycodone, Normorphine, Tapentadol, and Norlevorphanol. In certain embodiments, the Opioid is not an Opioid receptor competitive antagonist. In some embodiments, the Opioid is not a μ receptor competitive antagonist.

[0014] In certain embodiments are methods and compositions for the prevention of relapse into opioid abuse in individuals with a history of abuse. These methods comprise administering to the individual in need thereof, a stabilizing amount of at least one Opioid or a salt thereof, and a stabilizing amount of at least one of a μ-receptor partial agonist or a κ-receptor antagonist, or pharmaceutically acceptable salts thereof. In certain embodiments, the Opioid and μ-receptor partial agonist and/or κ-receptor antagonist is administered to the individual on a daily basis for a time period of up to one year. In certain other embodiments, the composition is administered over a period of up to five years. In certain embodiments, the individual is administered the composition comprising at least one Opioid, and a μ-receptor partial agonist and κ-receptor antagonist on a daily basis for life.

[0015] Other aspects and features of the present invention will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the invention.

INCORPORATION BY REFERENCE

[0016] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0017] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

DETAILED DESCRIPTION OF THE INVENTION

[0018] Prescription drug abuse is the intentional use of a medication such as an opioid, without a prescription; in a way other than as prescribed; or for the experience or feeling it causes. It is not a new problem, but one that deserves renewed attention. For although prescription drugs can be powerful allies, they also pose serious health risks related to their abuse. [0019] Prescription drug abuse is a significant emerging problem in the United States. In 2009, approximately 7.0 million (M) persons reported past month non-medical use of psychotherapeutic drugs (2.8 percent of the U.S. population). This class of drugs is broadly described as those targeting the central nervous system, including drugs used to treat psychiatric disorders (NSDUH, 2009). The medications most commonly abused are opioids with 5.3 M abusers reported in 2009 in the US alone.

[0020] In 2009, nearly 1 in 12 high school seniors in the US reported nonmedical use of Vicodin that comprises the opioid: hydrocodone. Additionally 1 in 20 high school students reported abuse of the opioid: Oxycodone. Among those who abuse opioids, high rates of other risky behaviors, including abuse of other drugs and alcohol, have also been reported. Abuse of opioids, alone or in combination with alcohol or other drugs, can depress respiration. Overdose is a major concern: the number of fatal poisonings involving prescription pain relievers has more than tripled since 1999. Additionally, injecting opioids increases the risk of HIV and other infectious diseases through use of unsterile or shared equipment. Opioid abusers frequently alter the route of administration (e.g., snorting or injecting vs. taking orally) to intensify the effect; some even report moving from prescription opioids to heroin. It is also common for individuals to orally consume transdermal formulations of opioids such as

buprenorphine.

Opioids

[0021] Opioids are any endogenous or exogenous compounds that bind to an opioid receptor. Opioid receptors are localized primarily in the brain, spinal cord, and gastrointestinal tract. There are four broad groups of Opioids: endogenous Opioid peptides produced in the body; naturally occurring Opioid alkaloids such as Morphine and Codeine; semi-synthetic Opioids such as Hydrocodone and Oxycodone, and synthetic Opioids such as Fentanyl and Methadone. Endogenous Opioid-like peptides are present particularly in areas of the central nervous system that are presumed to be related to the perception of pain; to movement, mood and behavior, and to the regulation of neuroendocrinological functions. When Opioids bind to their receptors in the brain and spinal cord they block pain transmission signals from the periphery of the body. Although opioids are very effective for moderate to severe pain, there are many well known problems associated with opioid therapy. Those problems include serious side effects such as cognitive dysfunction, respiratory depression, nausea/vomiting, urinary retention, and constipation. Further, chronic opioid therapy often results in the development of tolerance to the analgesic effect (resulting in dose escalation) as well as physical and psychological dependence. Neuroendocrine and immune functions, as well as the sleep center (SCN), are affected.

[0022] The limbic system, the main regulator of emotion, surrounds the brain stem just below the cerebral cortex. Opioid receptors are more dense in the limbic system than anywhere else in the body, consistent with the strong effects Opioids have on emotional behavior. A notable emotional effect of Opioids is euphoria. Because Opioids are not rapidly broken down after acting, they continue to activate receptors for extended periods and produce a level of euphoria that is considerably more intense than that initiated by endorphins. This is a contributing factor to Opioid abuse. Additional issues of tolerance, loss of control, impulse control, and emotional deregulation can occur. Salience to Opioids effects, can lead to changes of the dopaminergic system, and addiction.

[0023] The potential for the development of tolerance and physical dependence with repeated Opioid use is a characteristic feature of all Opioids, and the possibility of developing psychological dependence (i.e., addiction) is one of the major concerns in the use of the treatment of pain with Opioids. Tolerance refers to the need to increase the dose of Opioid over a period of time in order to achieve the same level of analgesia or euphoria, or the observation that repeated administration of the same dose results in decreased analgesia, euphoria, or other Opioid effects. It has been found that a remarkable degree of tolerance develops to the respiratory depressant, analgesic, sedative, emetic and euphorigenic effects of Opioids. However, the rate at which this tolerance may develop depends on the pattern of use. If the Opioid is used frequently, it may be necessary to increase the dose.

[0024] Physical dependence may develop upon repeated administrations or extended use of Opioids. Physical dependence is gradually manifested after stopping Opioid use or is precipitously manifested (e.g., within a few minutes) after administration of a narcotic antagonist (referred to "precipitated withdrawal"). Depending upon the drug to which dependence has been established and the duration of use and dose, symptoms of withdrawal vary in number and kind, duration and severity. The most common symptoms of the withdrawal syndrome include anorexia, weight loss, pupillary dilation, chills alternating with excessive sweating, abdominal cramps, nausea, diarrhea, vomiting, muscle spasms, hyperirritability, lacrimation, rhinorrhea, goose flesh and increased heart rate. Natural abstinence syndromes typically begin to occur as the Opioids dissociate from the receptors after the last dose. The syndromes reach maximum intensity depending on the speed of dissociation, G-protein adaptations, generalized physiological functions, and may persist for extended periods of time. Precipitated abstinence syndromes produced by administration of an Opioid antagonist used for treatment, vary in intensity and duration with the dose and the specific antagonist, but generally vary from a few minutes to several hours in length, the intensity and length of symptoms are related by the neuroplastic changes that have occurred.

[0025] Psychological addiction on Opioids is characterized by drug-seeking addiction behavior directed toward achieving euphoria and escape from conditions such as emotional stress, psycho-socioeconomic pressures etc. An addict will continue to administer Opioids for non-medicinal purposes and in the face of self-harm. Pain symptoms can intensify for extended periods of time, depending on the physiological abstinence syndrome.

[0026] The overall abuse potential of an Opioid is established by a composite of factors, including, the capacity of the drug to produce the kind of physical dependence in which drug withdrawal causes sufficient distress to bring about drug-seeking behavior; the ability to suppress withdrawal symptoms caused by withdrawal from other agents; the degree to which the Opioid induces euphoria similar to that produced by morphine and other Opioids and the patterns of toxicity that occur when the Opioid is dosed above its recommended therapeutic range. The abuse potential also depends on the physical

characteristics of the Opioids such as water solubility, receptor binding. Additionally, any dissociation effects are significantly impacted by receptor specificity and regulation, and a modulation of the endogenous Opioid receptors.

Buprenorphine

[0027] Buprenorphine is a weak partial agonist at μ-Opioid receptors and κ-Opioid receptor antagonist. It is a thebaine derivative used as an analgesic and as an alternative to methadone. Buprenorphine is 50 to 100 times more potent than morphine, but has a safer therapeutic index than morphine (see Wallenstein S L, et al., Crossover Trials in Clinical Analgesic Assays: Studies of Buprenorphine and Morphine, Pharmacotherapy, G(5): 225-235, 1986). Buprenorphine also has a low oral bioavailability and has been considered to be habit-forming (see, e.g., U.S. Pat. No. 5,240,711 to Hille, et al.) and induce tolerance (see, e.g., U.S. Pat. No. 5,613,958 to Kochinke, et al.). As reported in Hille, et al., the form of administration of a medicinal drug contributes to the risk of addiction, and higher blood levels created immediately after administration of a drug such as Buprenorphine, followed by a drastic decrease (causing euphoria and then ineffective pain treatment in succession), cause the patient to start to long for the next dosage (referred to as an "iatrogenic" addiction). In the case of Buprenorphine, Hille et al. reported that continuous infusion would be considered the most suitable mode to avoid such an iatrogenic addition by providing constant blood levels; however, continuous infusion requires physician control and insertion of a cannula which may cause inflammation at the site.

[0028] Hille, et al. circumvent this by use of a transdermal delivery system which includes

Buprenorphine or one of its pharmaceutically compatible salts and which releases the drug over a period of at least 24 hours in a controlled manner, and ensures that the Buprenorphine does not notably decompose when the transdermal delivery system is stored. Kochinke et al. and Reder et al. (US 6,231,866) also describe transdermal systems for the modulated administration of tolerance-inducing drugs including Buprenorphine. These systems and methods strictly teach trans-dermal delivery of the tolerance-inducing drug. As described herein, addicts and habitual opioid users are known to frequently alter the route of administration (e.g., snorting or injecting vs. oral or transdermal consumption) to intensify the effect. It is also common for individuals to consume orally or via other modes of administration, transdermal formulations of opioids such as buprenorphine

Opioid Combinations:

[0029] Combinations of Opioids have significant effects on the immune system, resulting in immune destabilization affecting both co-occurring immune responses and autoimmune disorders. In addition, secondary pain pathways are affected differently by combining receptor modulation. Combining Opioids is typically frowned upon due to the legitimate risk of overdose, and high tendency for abuse.

[0030] Specifically, it is known in the art that the use of Buprenorphine with a second Opioid is counterintuitive to many who use Buprenorphine, as used in Suboxone/Subutex. It is well known in the art that Buprenorphine in forms such as Suboxone/Subutex is for Opioid dependence and/or addiction, and will displace other Opioids and precipitate withdrawal. As a result, there are countless numbers of pain patients, and high grade dependency/addicted individuals who suffer protracted withdrawal or uncontrolled pain in changing Opioids or in ongoing Opioid prescriptions, or by the use of

Buprenorphine as a sole agent.

[0031] Currently, Physicians and Pharmacists who have been taught to utilize Buprenorphine for treatment of opioid addiction, are of the belief that one cannot combine Buprenorphine with other Opioids. Indeed, the danger of combining Opioids is quickly seen, when one changes to and from Buprenorphine to other μ agonists which results in very bad side effects such as the ones desceibed supra for opioid dependency. As such, it acts as a deterrent. Combining Opioids is risky as it can drastically affect precipitated withdrawal and pain escalation by changing the effects and properties of Opioids in combination. This can be seen if an individual is prescribed two Opioids together, but alters the use of one or starts and stops either, individually. The result of starting or stopping one or the other Opioid, can result in Opioid's selectivity either precipitating withdrawal or creating adverse effects. [0032] Provided herein are methods and compositions drawn to the co-administration of an Opioid with μ-Opioid receptor partial agonist or a κ-Opioid receptor antagonist such as Buprenorphine. These methods and compositions result in decreased tolerance, decreased dependence potential and diminishing side effects, compared to therapy using either component individually. As such, the methods and compositions described herein can be selected for best pain control for a select population, as well as a deterrent and preventative agent against opioid addiction or dependency.

[0033] In general, the following words or phrases have the indicated definitions when used in the description, examples, and claims.

[0034] "Analgesic effect" or "analgesia" means the relief from pain resulting from the action of a drug.

[0035] "Analgesic" is any agent, or composition described herein that provides an "analgesic effect" when administered to a patient or an individual.

[0036] "Drug delivery profile" means the concentration of the drug, over time, at the site of drug effect, as determined by the amount and rate of drug administered to the patient and the pharmacokinetics relating dose inhaled to concentration in the lungs, plasma and at the site of drug effect.

[0037] "Hypoxia" is a toxic effect of Opioid administration, and is defined in this application as a decrease in blood 0₂ concentration to less than 90% saturation. [0038] "Ventillatory depression" means a decrease in the rate, tidal volume, and/or flow rate of air into the lungs. Ventillatory depression may manifest as dizziness, shortness of breath, or a slowing in rate of breathing. "Opioid induced ventillatory depression" refers to ventillatory depression caused by the action of an Opioid at a site of drug effect.

[0039] "Sedation" means a decrease in attention, mental awareness, focus, and state of consciousness caused by Opioids, and manifests in a lack of physical strength (muscle fatigue), lack of voluntary activity, lethargy, drowsiness, and sleep. "Opioid-induced sedation" refers to sedation caused by the action of an Opioid at a site of drug effect.

[0040] "Rapid onset", when used to describe a drug formulation, means a formulation which has an analgesic effect that rapidly follows the rise in plasma Opioid concentration. A "rapid onset Opioid" is an Opioid that has an analgesic effect within 5 minutes of administration.

[0041] "Sustained effect" means a formulation which has an analgesic effect that is sustained over several hours. A "sustained effect Opioid" means an Opioid that has analgesic effect that lasts over 2 hours.

[0042] "Side effect" means an effect of an Opioid that is not analgesic or toxic. For example, severe ventillatory depression is an example of Opioid toxicity, while mild ventillatory depression and sedation are not considered signs of Opioid toxicity, but are side effects of the Opioid.

[0043] "Site of effect" refers to a physical or hypothetical site of drug action within the patient. "Site of effect" may be a compartment of the body, such as the brain, the liver, or the spleen, or it may be a theoretical and unknown location based on correlation and pharmacokinetic modelling. For example, it is known that Opioids exert their analgesic actions, in part, in the substantial gelatinous of the spinal cord, so this is a site of Opioid analgesic effect. The concentration of Opioid at the effect site may be determined by direct measurement, or through the use of pharmacokinetic and pharmacodynamic modelling.

[0044] "Effective amount" means the amount of drug needed to reach an analgesic effect.

[0045] "Titration to effect" means administering an Opioid until a satisfactory analgesic effect is felt by the patient, then ceasing administration of the Opioid.

[0046] "Titration to side effect" means administering an Opioid until a side effect is felt, then ceasing administration. The ceasing of administration may be voluntary (for example, by instructing patients to cease administration of the Opioid when they start to feel drowsy, dizzy or short of breath) or involuntary (for example, when patients are no longer able to breathe effective dosages of Opioid due to ventillatory depression or sedation).

[0047] The terms "toxic", "toxicity", "toxic effect" and "Opioid toxicity" refer to effects of Opioids that place a patient at risk of death.

[0048] The term "Opioid receptor" refers to a "classical" type of Opioid receptor: μ, δ, and κ. A "heterodimeric Opioid receptor" or "Opioid receptor heterodimeric" refers to a G-protein coupled receptor of the invention, comprising an Opioid receptor subunit and another GAPER receptor subunit, which maybe another Opioid receptor subunit or a non-Opioid receptor subunit.

[0049] By "administered in combination", or "administering a composition comprising component (i) and component (ii)" or the like, when referring to component (i), and component (ii), it is meant that the components are administered concurrently to an individual being treated. By concurrently, it is meant that each component is administered at the same time or sequentially in any order at different points in time, however if not administered at the same time, they are administered sufficiently closely in time so as to provide the desired treatment effect. Suitable dosing intervals and dosing order with such compounds are readily apparent to those skilled in the art, once armed with the present disclosure.

[0050] As used herein, "addict" or "addiction" or "addiction disorder" is meant to include a habitual or recurrent use of a substance, such as stimulants, nicotine (e.g., which is meant to include all forms of nicotine administration, such as smoking, chewing tobacco, or other forms of nicotine administration), opioid (e.g., morphine, heroin, oxycodone, and other opioids described herein), amphetamines, cocaine, and alcohol. It is meant to include, but is not meant to be limited to, a dependency on the substance. Dependency is characterized by a patient's persistence in substance use or abuse or the recurrence of such use or abuse in the face of negative social or medical consequences of this use or abuse or in face of the patient's declared or undeclared intent to abandon or reduce his or her use of the substance. A patient's dependency can be manifested in objective criteria or other indices of drug seeking behavior, such as repeated attempts to abandon use or abuse of the substance, as evidenced by, for example, past participation in encounter groups designed to reduce the participants' use of cocaine or amphetamine, commitment to a drug or alcohol rehabilitation program, arrest or conviction of drug possession or trafficking, hospitalization for complications arising from drug or alcohol use, including overdose, and the like.

[0051] "Stabilizing dose" or "Stabilizing amount" as used herein refers to a dosage level of the compositions described herein. On being administered a stabilizing dose at predetermined intervals, the individual does not feel the need to abuse escalating amount of Opioids. Additionally, the proper administration of the stabilizing dose allows the individual to maintain regular day-to-day functionality, and alleviates craving and addiction. The stabilizing dose is different for different individuals depending on the extent of addiction, the nature and intensity of pain (if any), and the physiology of the individual.

[0052] "Patient" or "Individual", as used herein, is meant to be a human in certain embodiments.

However, in certain embodiments, the compositions and methods of the present invention can be used to treat pain and addiction disorders in mammals other than humans, such as primates other than humans, rats, mice, cats dogs, and the like. Using the methods of the present invention, mammals addicted to opioids can be humanely weaned from the substance, and the physiological and psychological damage or changes which result from past opioid use can be assessed. In addition, these mammals can be used to study the progression of or recovery from such physiological and psychological damage or changes subsequent to the patient's abandoning or reducing his, her, or its drug use.

[0053] The term "prodrug" as used herein refers to compounds that are rapidly transformed in vivo to a compound having structural formula (I), for example, by hydrolysis. Prodrug design is discussed generally in Hardma et al. (Eds.), Goodman and Gilman's The Pharmacological Basis of Therapeutics, 9th ed., pp. 11-16 (1996). A thorough discussion is provided in Higuchi et al., Prodrugs as Novel Delivery Systems, Vol. 14, ASCD Symposium Series, and in Roche (ed.), Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). Typically, administration of a drug is followed by elimination from the body or some biotransformation whereby the biological activity of the drug is reduced or eliminated. Alternatively, a biotransformation process can lead to a metabolic by-product, which is itself more or equally active compared to the drug initially administered. Increased understanding of these biotransformation processes permits the design of so-called "prodrugs," which, following a biotransformation, become more physiologically active in their altered state. Prodrugs, therefore, encompass compounds that are converted to pharmacologically active metabolites.

[0054] Embodiments disclosed herein are combinations of Opioids with different receptor selectivity and different effects on endogenous Opioid receptors. These combinations utilize the synergistic effects of the combined Opioids to create an array of synergistic effects. Also provided are methods for the treatment of pain and opioid addiction, wherein said methods comprise administering to a patient in need thereof an Opioid; and μ receptor partial agonist or a κ receptor antagonist.

[0055] Encompassed herein are compositions useful for the treatment of pain in an individual. In embodiments, the compositions comprise at least one Opioid; and at least one of a μ receptor partial agonist or a κ receptor antagonist. In certain embodiments, the methods and compositions further comprise administration of a μ receptor competitive antagonist such as Naloxone.

[0056] In an embodiment, the μ receptor partial agonist is also a κ receptor antagonist. In a certain embodiment, the μ receptor partial agonist and κ receptor antagonist is Buprenorphine. In embodiments, the Opioid is selected from the group consisting of Morphine, Fentanyl, Dihydroetorphine, Sufentanyl, Butorphanol, Alfentanyl, Pentazocine, Morphine, Phenazocine, Hydromorphone, Codeine,

Oxymorphone, Meperidine, Methadone, Propoxyphene, Oxycodone, Tramadol, Hydrocodone,

Remifentanil, Levorphanol, Dihydrocodeine, L-acetylmethadol, Ethylmorphine, Diacetylmorphine, Nalbuphine, Etorphine, Buprenorphine, Normethadone, Dihydromorphine, Noroxycodone, Normorphine, Tapentadol, and Norlevorphanol.

[0057] Encompassed herein are methods of treating pain in an individual in need thereof, said method comprising administering to said individual: at least one Opioid or a pharmaceutically acceptable salt thereof; and at least one of a μ-receptor partial agonist or a κ-receptor antagonist, or pharmaceutically acceptable salts thereof; in amounts effective to cause or enhance a supra-additive synergistic analgesic response to pain for a duration effective to inhibit pain in the individual in need thereof. In an embodiment, the μ receptor partial agonist is also a κ receptor antagonist. In a certain embodiment, the μ receptor partial agonist and κ receptor antagonist is Buprenorphine. In certain embodiments, are methods of treating nociceptive pain, neuropathic pain and acute pain. In some embodiments, the nociceptive pain is one or more of post-operative pain, cluster headaches, dental pain, surgical pain, pain resulting from severe burns, pain from third degree burns, post partum pain, angina pain, genitourinary tract related pain, and pain from cystitis. In certain embodiments, the neuropathic pain is one or more of lower back pain, pain associated with arthritis, cancer-associated pain, herpes neuralgia, phantom limb pain, central pain, Opioid resistant neuropathic pain, bone injury pain, and pain during labor and delivery. In certain other embodiments, the acute pain is one or more of lower back pain, pain associated with arthritis, cancer- associated pain, herpes neuralgia, phantom limb pain, central pain, Opioid resistant neuropathic pain, bone injury pain, and pain during labor and delivery.

[0058] Encompassed are methods of treating pain caused by, for example, but not limited thereto, trauma, surgery, herniation of an intervertebral disk, spinal cord injury, shingles, HIV/AIDS, cancer related pain, amputation, neurodegenerative disorders, carpal tunnel syndrome, diabetic neuropathy, post- herpetic neuralgia, fibromyalgia, musculoskeletal disorder, irritable bowel syndrome (IBS), various noxious stimuli (mechanical, chemical and thermal) that cause acute and chronic inflammatory pain, as well as from lesions in the nervous system that cause neuropathic pain, and pain and/or inflammation in those pathologies involving visceral pain, neuropathic pain, inflammatory pain, visceral pain, including abdominal pain, pain of the digestive system, pain of the respiratory system, pain of the urogenital system, pain of the endocrine system, heart pain, pancreatic pain, intestinal pain, stomach pain, spleen pain, blood vessel pain, tensional headache pain, headache associated with sinusitis, migraine, eye pain, dry eye syndrome, post-operative pain, including post-operative pain due to surgical incisions, the insertion of implants in bone, bone replacement and/or infection, pain due to cancer, including pain due to bone cancer, pain associated with benign bone tumors, including osteoid osteoma, osteoblastomas, pain due to cancer treatment, nerve pain, neck pain associated with cervical dystonia, back pain, including lumbago and/or sciatica, neurogenic inflammation, skin irritation, sensitive skin, atopic dermatitis, contact dermatitis, diaper dermatitis, eczema, arthritis, rheumatoid arthritis, osteoarthritis, peripheral neuropathies, phantom pain, allodynia, burning pain, paresthesias, facial pain, trigeminal neuralgia, pain associated with tattooing or tattoo removal, pain due to bunions, testicular pain, myofascial pain, spastic muscle pain, pain of the urinary bladder, pain of the urinary tract, vulvar pain, vaginal pain, scrotal pain, perineal pain, pelvic pain, and pain or skin irritation after surgery, after treatment with pulsed light therapy (IPL, Intense Pulse Light), after treatment with pulsed monochromatic light therapy (laser), after treatment with chemical exfoliating agents or after overexposure to aggressive external agents such as overexposure to sunlight or extreme cold or heat

[0059] The compositions described herein are administered to provide effective, safe pain control when Opioids management is needed. These effects not only relieve pain, but have therapeutic effects on certain illnesses caused by Opioids, alcohol, tranquilizers, hypnotics, and stimulants, as well as reduce adverse effects caused by medical illnesses, syndromes, functional disorders and infectious disorders as a consequence of immune system modulation. The compositions are useful to elderly patients and cancer patients in treating pain and illness, where Opioids are frequently prescribed, is of particular interest. Therapeutic use in cancer patients receiving chemotherapy helps the patients avoid the use of high dose Opioids, which have a high risk of negative and/or adverse Opioid effects on physiology and healing.

[0060] Disclosed herein are methods of reducing Opioid tolerance in an Opioid tolerant individual comprising administering to said individual: at least one Opioid or a pharmaceutically acceptable salt thereof; and at least one of a μ-receptor partial agonist or a κ-receptor antagonist, or pharmaceutically acceptable salts thereof; in amounts effective to reduce Opioid tolerance in the individual.

[0061] Encompassed herein are methods of treating opioid addiction in an individual, said method comprising administering to said individual: an effective amount of at least one Opioid or a

pharmaceutically acceptable salt thereof; and an effective amount of at least one of a μ-receptor partial agonist or a κ-receptor antagonist, or pharmaceutically acceptable salts thereof.

[0062] In an embodiment of the instant invention is provided a method of reducing pain in an Opioid tolerant patient, said method comprising administering: Buprenorphine or a pharmaceutical salt thereof; and an Opioid or a pharmaceutical salt thereof; in an amount effective to reduce pain in the individual.

[0063] In certain embodiments, the Opioid is chosen from Oxycodone, Hydromorphone or

pharmaceutical salt thereof.

[0064] In an embodiment of the instant invention, is a method of reducing the onset of Opioid tolerance in a patient receiving pain therapy, said method comprising administering: Buprenorphine or a pharmaceutical salt thereof; and an Opioid or a pharmaceutical salt thereof; in an amount effective to reduce pain in the individual.

[0065] In an embodiment is provided a method for administration of an Opioid described herein, at dosages lower than current US dosage formulations intended for use as a therapeutically effective dosage amount. The mixed receptor activity in titrating doses effectively augments efficacy and decreases development of, or offsets, existing untoward Opioids properties.

[0066] Provided herein is a method for administration of an Opioid described herein, at dosages lower than current US dosage formulations intended for use as a therapeutically effective dosage amount. The mixed receptor activity in titrating doses effectively augments efficacy and decreases development of, or offsets, existing untoward Opioids properties. In an embodiment is provided a method for limiting progressive Opioid tolerance in an Opioid tolerant patient, said method comprising administering to a patient in need thereof an Opioid; and μ receptor partial agonist, and κ receptor antagonist.

[0067] Also provided herein is a method for treating pain in a patient, with an opioid analgesic having addictive liability while decreasing the patient's likelihood of addiction to said opioid analgesic comprising: administering to said patient an effective amount of at least one of a μ-receptor partial agonist or a κ-receptor antagonist, or pharmaceutically acceptable salts thereof or a pharmaceutical salt thereof; and administering to said patient an effective amount of the Opioid analgesic or a pharmaceutical salt thereof; wherein said least one of a μ-receptor partial agonist or a κ-receptor antagonist is administered before or simultaneously with said analgesic. In an embodiment, the μ receptor partial agonist is also a κ receptor antagonist. In a certain embodiment, the μ receptor partial agonist and κ receptor antagonist is Buprenorphine. In embodiments, the Opioid analgesic is selected from the group consisting of Morphine, Fentanyl, Dihydroetorphine, Sufentanyl, Butorphanol, Alfentanyl, Pentazocine, Morphine, Phenazocine, Hydromorphone, Codeine, Oxymorphone, Meperidine, Methadone,

Propoxyphene, Oxycodone, Tramadol, Hydrocodone, Remifentanil, Levorphanol, Dihydrocodeine, L- acetylmethadol, Ethylmorphine, Diacetylmorphine, Nalbuphine, Etorphine, Buprenorphine,

Normethadone, Dihydromorphine, Noroxycodone, Normorphine, Tapentadol, and Norlevorphanol. In certain embodiments, the Opioid analgesic is not an Opioid receptor competitive antagonist. In some embodiments, the Opioid analgesic is not a μ receptor competitive antagonist.

[0068] In an embodiment of the instant invention is provided methods for reducing pain in an Opioid tolerant patient comprising administering to said patient Buprenorphine and an Opioid, wherein said

Opioid is Hydromorphone. In another embodiment is provided a method for reducing the onset of Opioid tolerance in a patient receiving pain therapy comprising administering to said patient Buprenorphine and an Opioid, wherein said Opioid is Hydromorphone.

[0069] In certain embodiments, are provided methods of reducing the craving sensations in an individual suffering from pain and being treated with Opioids. In certain embodiments, are provided methods of reducing the Opioid side effects.

[0070] In many cases, an individual with a history of Opioid use or abuse is seen to go back to abuse or addiction to Opioids repeatedly, even after multiple treatment regimen that seem successful over the short term for overcoming Opioid addiction. It is believed that the body of the individual becomes sensitized to the Opioid, thus returning to Opioid abuse eventually. The methods and compositions of the instant invention overcome this abuse tendency and put an end to this recurring action when administered to the individual as a stabilizing, non-addiction dosage of the combination of Buprenorphine and an Opioid. In certain embodiments, are methods of treating an individual with a history of recurring addiction to Opioids, said methods comprising administering to the individual in need thereof, a stabilizing amount of at least one Opioid or a salt thereof, and a stabilizing amount of at least one of a μ-receptor partial agonist or a K-receptor antagonist, or pharmaceutically acceptable salts thereof.

[0071] In certain embodiments are methods and compositions for the prevention of relapse into opioid abuse in individuals with a history of abuse. In a certain embodiment is a method comprising

administering to an individual who has relapsed into Opioid abuse, a stabilizing amount of at least one Opioid or a salt thereof, and a stabilizing amount of at least one of a μ-receptor partial agonist or a κ- receptor antagonist, or pharmaceutically acceptable salts thereof. In certain embodiments, the Opioid and μ-receptor partial agonist and/or κ-receptor antagonist is administered to the individual on a daily basis for a time period of up to one year. In certain other embodiments, the composition is administered over a period of up to five years. In certain embodiments, the individual is administered the composition comprising at least one Opioid, and a μ-receptor partial agonist and κ-receptor antagonist on a daily basis for life.

Synergistic action of Buprenorphine and Opioids

[0072] Buprenorphine has high receptor affinity, and slowly dissociates from receptors. Surprisingly, and unexpectedly Buprenorphine, when used with other Opioids (or Opioid combinations) that effect Opioid receptor attachment, produces a synergistic effect via physiologic activation of receptor function. Opioid receptors are G-protein substances of a finite number. As described herein, the dosage of Buprenorphine is adjusted to occupy a percentage of the total receptor sites. The remaining receptor site also leaves a finite number of unbound (vacant, partially altered) receptors, open to be occupied by the second Opioid ligand. The end result is that both Opioids are working at the same time, since the combination usually involves an Opioid with, at times, a shorter half life. The regularity of dosing is adjusted to provide ongoing pain relief in a specific manner in a more long term physiological basis over time.

[0073] A combination of Opioids, dependent blockers, partial agonists, and central and peripheral blockers, with the use of μ-receptor partial agonist or a κ-receptor antagonist such as Buprenorphine has one or more of several effects. It creates a stabilization (modulation with unique efficacy) effect by its blockade, or it alters the endogenous Opioids including dimorphisms, encephalin, and endorphins. This alters the function of the receptors, including the μ, κ, and δ receptors, resulting in alteration of the Opioids' G-protein receptor function, via both receptor attachment and endogenous dependent effects on the G-proteins, This alteration limits perceived and biochemical alterations, thereby reducing dysfunction and negative effects of Opioids.

[0074] The resultant combined effects limit certain undesirable neuroplastic changes, resulting in combination effects that alter the individual drug effects and are useful in minimizing further evolution of tolerance from Opioids, neuroplastic and/or all static changes (tolerance to Opioids), effects relating to psychological and emotional stability, dependent craving, and hyperalgesia. These effects and combinations minimize perception of pain and aid in the reduction of physiological fluctuations and rapid evolution of receptor and endogenous dependent related function. This combination of Opioids has beneficial effects, including decrease in allodynia and limitation and/or prevention of the evolution of hyperalgesia that can occur from pure dependent agonists alone.

[0075] Combining Buprenorphine with other Opioids that are not μ receptor antagonists limits exposure to certain unwanted effects including differing effects on mode euphoria, dysphoria, and alteration of the evolution of neuroplastic changes that occur, particularly with higher doses of prolonged pure Opioid agonists.

[0076] This synergy - drugs working together - also relates to the synergy resulting from antagonistic properties that are multi-factorial and neutralize selective properties (not total) of either compound, thereby creating a previously unknown effect that is very different than either drug's individual properties. This provides a new foundation for total generalized effects forming a new receptor activator medication. As such, Buprenorphme work as a partial agonist on the μ receptors and an antagonist with a K and δ receptors, which affect the receptors as a whole. Combinations of multi-modal Opioids create receptor modulation that result in a more uniform and stable state of system function and allow for a different allostasis and sub-point of the Opioid systems in which the secondary Opioids now act on (in addition to and in conjunction with). The combination has a high rate of stabilization and minimizes adverse Opioid effects, while allowing for finer pain modulating and improved control. This receptor attachment allows for a new spectrum of receptor modulation to provide different Opioid effects that improve treatment in some patients with varying physiologies who may be experiencing addiction, pseudo-addiction, hyperalgesia, self medicating, aberrant behaviors, and difficult to manage pain or behavior, as well as provide a new treatment option for pain conditions with unstable levels of acute, chronic, and/or fluctuating pain conditions.

[0077] By combining Buprenorphme with other Opioids, there is improvement in evolving and negative effects from long term Opioid use, such as anxiety, stress, and potential cognitive impairment. Positive emotional effects are present in therapeutic dosages based on underlying disorders. The importance of patients individual physiologies are being increasingly recognized to identify individual physiological factors that predispose some patients to addiction and other physiological variations of neuroplastic responses, as well as known potential adverse effects.

[0078] One or more Opioids and Buprenorphme combinations have the benefit of providing this higher level (larger) effect by binding to a higher percentage of receptors, and at the same time other Opioids can bind to a small number of receptors with different dissociation affinities, creating positive effects of both Opioids. The result is having pure Opioid agonist effects on varying levels of receptor activation, with co-existing binding from the partial receptor agonist and antagonist Buprenorphine.

[0079] The effects of adding Opioids and Buprenorphine with different receptor modulation affects the co-occurring effects of Opioids on the interaction between the μ, κ, δ, and ORL receptors, as well as the effects of the endogenous Opioids (beta endorphins, encephalins, and dynorphins). It is in the combined effects of combining one or more Opioids and Buprenorphine with different affinities, receptor activities, and effects on the endorphin binding that creates a unique effect on both pain dependency and addiction. The total effect creates feedback in the associated areas of the brain related systems, such as

Norepinephrine, Dopamine, and Glutamate, as well as affecting a cascade of pain modulating substances. Dosage of Combinations of Buprenorphine and an Opioid

[0080] Dose ratios of Buprenorphine with other Opioids vary for two reasons. First, higher potency Opioid agonists can be used in higher doses without escalating the total daily dose of Buprenorphine. Second, smaller doses of Buprenorphine are used in individuals for prophylactic and therapeutic reasons, but higher doses can be used in individuals that are more prone to and/or have existing or evolving adverse effects. The ratio can be adjusted depending on the length of time the patient has been taking Opioids, symptoms of intolerable pain, hyperalgesia, decreased activity (tolerance), and aberrant drug related behaviors. Combinations can be used initially, or utilized when Opioid rotation is used to treat individuals with fluctuating, unstable or escalating pain thought to be associated with medication effects. The use of combinations may help eliminate or reduce the physiological presence of co-occurring Opioid side effects, as well as avoid acquired prescription drug behaviors (aberrant drug behaviors) that can occur from ongoing Opioid use.

[0081] Long term effects of treatment of pain, including pseudo-addiction and addiction, are easier to gauge and minimize due to the low incidence of tolerance and craving. This is due to the slow receptor dissociation that occurs with Buprenorphine and Norbuprenorphine. These combinations can potentially minimize adverse physiological effects such as intermittent withdrawal symptoms and fluctuating Opioid blood levels, which create a more secure foundation with very stable long term receptor attachments. Fluctuations in serum Opioid levels and the resultant physiological effects of fluctuating partial abstinence syndromes are positively affected by the slow dissociation from Opioids receptors. As a result, there is improved fluid receptor stabilization and consistency of pain control.

[0082] Combinations disclosed herein have regular and controlled release formulations. Controlled release tablets would have minimal effect on the blood levels of Buprenorphine, but alter the release of the other Opioid, thus having slower and more uniform effect on serum levels. The primary purpose of the controlled release tablet is to delay and spread out the release of Opioids of abuse, such as

Oxycodone. The dosage of Buprenorphine varies so that if the preparation is abused, a higher amount of Buprenorphine prevents abuse of the second Opioid as a result of Buprenorphine receptor affinity. This creates a serum blood level of Buprenorphine that hastens displacement of the secondary Opioids. The minimization of abuse that results when taking higher than prescribed dosages of the short acting preparation also creates rapid release of the timed release preparations when chewed, ground, smoked or injected. The combination therefore prevents and or minimizes the potential of abuse and addictive use, as well as limits the street value that the Opioids have.

[0083] Absorption of Buprenorphine is known to vary. Buprenorphine has the following receptor binding profile: 16 mg per day has roughly 90-92% total receptor binding; 32mg per day has roughly 97%) receptor binding. Absorption and excretion may be affected by related to first pass cytochrome P450 transporters, slow and fast metabolizers, genetic variables, issues related to hepatitis B, C, alcohol use, polypharmacy, age and illness. Clarity of these variables is known, and clinical judgment and knowledge of physiology are ever evolving. Absorption may vary from patient to patient, but dosages of Opioid pain medications are predictable, and awareness of side effects and individual dosing remains the key to prescribing. Variability of absorption and receptor response of Opioids varies. For example,

approximately 7% of US citizens have various enzymes affecting absorption and physiological effects needed for the absorption and pain relief response of codeine. From a pain standpoint we have provided various preparations and Buprenorphine ratios designed to treat the variables safely and effectively. Receptor activity has a stabilizing effect on the regulatory system of neurophysiology and the endogenous Opioid system. This leads to a co-mingling of effects with secondary Opioids and the reduction of potential negative effects, allowing for effective pain control and modulation.

[0084] The ratio of Buprenorphine to the other Opioid is adjusted to keep the effect of mild

Buprenorphine low during acute pain. If the Opioids are abused, a higher level of Buprenorphine is released, creating a better safety profile and limiting abuse. Formulation of combined Opioids disclosed herein may further comprise Naloxone to deter intravenous use.

[0085] Treatment of acute pain using a combination of Buprenorphine and another Opioid can limit ongoing problems of continued use that can occur from tolerance, dependency, and cravings. These commonly occurring unwanted side effects can result in continued use, hyperalgesia, and a continued focus on refilling and continuing pain management after the acute phase of pain has diminished. This combination can limit the ongoing use pattern caused by these Opioids, with titration of the

Buprenorphine as the key to the minimization of these effects.

[0086] The higher potency Opioids have a history of continued use and abuse, as well as increasing street use and value. The preparations and compositions described herein are therefore designed to prevent the continued use effects, and to minimize the potential for exposure to pure μ-Opioid receptor agonists in the highly vulnerable age group under 25 years of age who have frequent exposure to pain medications at home and on the street. The combinations described herein can be used to prevent the epidemic of Opioid abuse that is becoming one of the gateway drugs of abuse in our society.

[0087] Ratios of μ-receptor partial agonist, κ-receptor antagonist such as Buprenorphine and other Opioids have been developed herein based on use in individuals that are predisposed towards tolerance and physiological dependency. These individuals are evaluated based on their genetic predisposition, environmental psychosocial traumas, as well as known history of Opioid sensitization based on prior drug and alcohol use. Other factors, such as the age of onset, particularly in the child adolescent range, are evaluated regarding safety and minimization of long-term changes.

[0088] When deciding the ratio of a combination of drugs, evolving adverse Opioid effects are considered such as tolerance, dysphoria, anxiety, and sleep disorders in each patient, as well as in those whose daily consumption of Opioids escalates on an ongoing basis, or on a basis determined to cause concern. Ongoing use of combinations continue providing needed analgesia, and minimize potential adverse effects. [0089] A combination of Opioids assists in treating pain safely, and limit long term Opioid sensitization and neuroplastic changes that evolve. Also, the effects minimize progression of tolerance, immune dysfunction, and limit the effects of Opioid agonists on the neuroendocrine system, sleep, pituitary hypothalamic axis, and cognitive effects that can occur.

[0090] Also of note is the relative receptor binding to both the exogenous and endogenous Opioid systems. The combined effects on G-protein receptors and viable ability of the mu, kappa, and delta receptors, as well as the physiological effects of receptor activation, are impacted both by the effects of blocking the endogenous Opioids on receptors, as well as the altering effects of exogenous Opioids. These receptor synergistic effects are created by a combination combining Opioids of partial agonists, antagonists, and pure agonists. This comprehensive blending has an effect on the whole Opioid system. The use of Buprenorphine in relative doses has some known effect on the body's Opioid receptors. It has a stable profile of total body receptor binding that is different than many of the other Opioids. Opioids are known to have effect on receptors, and alteration of G-proteins. Effects on cell surfaces, endocytosis, and exocytosis, are thought to vary based on exogenous and endogenous Opioids, effecting the neuroplastic events and receptor functions. The use of Buprenorphine limits the total body wide receptor activities in a unique manner. This allows for combined action on occupied and unoccupied Opioid receptors with Opioid agonists, to allow effects of partial agonists, agonists and antagonists, working on receptors in a synergistic manner. Formulations

[0091] In certain embodiments, the methods and compositions described herein are formulated such that the formulations are designed for dependence term temporary use. In certain embodiments, the formulations provide more stable physiological combination for safety in long term treatment of chronic persistent pain. It is a goal of the formulations provided herein to provide a safe combination to treat chronic episodic pain after development of a pain syndrome associated with physiological Opioid side effects and dependence. The compositions described herein are also formulated to provide relief and treatment to disease states of addiction and pain caused by opioid addiction. In certain embodiments, the opioid and buprenorphine combination compositions are formulated to assist the countless numbers that have developed the sequelae physiological neuroplastic changes consistent with dependence and/or addiction, and the ongoing effects of chronic persistent and episodic pain in an uncontrolled state; E. The formulations of the instant invention are useful as an alternative treatment regimen for individuals who are on Methadone maintenance in controlled environments.

[0092] The formulations described herein are usedful to taper individuals off pain medication after treatments such as spinal surgeries, disc replacements, joint replacements, and neurosurgical procedures with protracted need for medication prior to and during the stabilization process. Many injuries result in acute, subacute, protracted pain, requiring pain stabilization over protracted time, sufficient to result in dependence. Many instances of long term dependency can, therefore, occur resulting in untoward Opioid effects. Resultant chronic Opioid use with adverse on anticipated sequelae can occur. Many individuals are faced with issues of under treatment of pain, as a result of fear of Opioid side-effects, or fear of Physician's prescribing, as a result of aberrant drug related behaviors, acquired prescription drug behaviors, dependence and/or addiction. Facing the challenge of a growing population of chronic Opioid users, the formulations, methods and compositions described herein provide long term stabilization, and avoid long term use and Abuse of Opioids.

[0093] In the methods of the present invention, the compositions comprising the Opioid and the μ receptor partial agonist and/or κ receptor antagonist form the active ingredient (also referred to as active drug components or drug components), and are typically administered in a mixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

[0094] In certain embodiments, for oral administration in the form of a tablet or capsule, the active drug components are combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components are combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents are incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

[0095] In certain embodiments, the Opioid and the μ receptor partial agonist and/or κ receptor antagonist such as Buprenorphine, are provided as a combined single dosage form. This single dosage is formulated for suitable oral, parenteral, or transdermal administration according to the methods described herein. In certain other embodiments, the Opioid and the μ receptor partial agonist and/or κ receptor antagonist such as Buprenorphine are administered in separate dosage forms, formulated as described herein. In certain embodiments, the Opioid and the buprenorphine are formulated for immediate release. In certain other embodiments, the Opioid and buprenorphine are formulated for controlled or delayed release. In certain embodiments, one of the Opioid and buprenorphine are formulated for controlled or delayed release. In certain embodiments, the Opioid is formulated for controlled release, while buprenorphine is formulated for immediate release. In another embodiment, the buprenorphine is formulated for controlled release while the Opioid is formulated for immediate release. [0096] In certain embodiments, the compositions described herein are administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. In some embodiments, liposomes are formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

[0097] In certain embodiments, the compositions described herein are coupled with soluble polymers as targetable drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer,

polyhydroxypropylmethacrylamide -phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide- polylysine substituted with palmitoyl residues. Furthermore, the compounds of in certain embodiments, the compositions described herein are coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and cross linked or amphipathic block copolymers of hydrogels.

[0098] Dosage forms (compositions) suitable for administration contain about 1 milligram to 500 milligrams of active ingredient per unit. In these pharmaceutical compositions, the active ingredient are present in an amount of about 0.5-95% by weight based on the total weight of the composition.

[0099] In certain embodiments, the compositions described herein are administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.

[00100] Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. In certain embodiments, similar diluents are used to make compressed tablets. In certain other embodiments, tablets and capsules are manufactured as sustained release products to provide for continuous release of medication over a period of hours. In some embodiments, compressed tablets are sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

[00101] In certain embodiments, the compositions described herein are formulated in liquid dosage forms for oral administration, wherein said liquid dosage forms further comprise coloring and flavoring to increase patient acceptance.

[00102] In certain embodiments, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. In certain embodiments, solutions for parenteral administration contain a water soluble salt of the active ingredient, suitable stabilizing agents, and buffer substances. Antioxidizing agents such as sodium bisulfate, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In certain embodiments, parenteral solutions contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. [00103] Suitable pharmaceutical carriers and methods of preparing pharmaceutical dosage forms are described in Remington's Pharmaceutical Sciences, Mack Publishing Company.

[00104] Certain useful pharmaceutical compositions (dosage forms) for administration of the compounds of this invention are illustrated as follows:

Capsules

[00105] A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

[00106] A mixture of active ingredients in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 100 milligrams of the active ingredient. The capsules are washed and dried.

Tablets

[00107] A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. In certain embodiments, appropriate coatings are applied to increase palatability or delay absorption.

Suspension

[00108] An aqueous suspension is prepared for oral administration so that each 5 ml contains 25 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S. P., and 0.025 mg of vanillin.

Injectable

[00109] A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10%> by volume propylene glycol and water. The solution is sterilized by commonly used techniques.

[00110] Each therapeutic agent component of this invention is independently formulated in any dosage form, such as those described above, and is administered in various ways, as described above. The component Opioids and μ receptor partial agonist and/or κ receptor antagonist of the invention are formulated together, in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.) as a composition (combination product). When components not formulated together in a single dosage unit, the Opioid component (I) is administered at the same time as the μ receptor partial agonist and/or κ receptor antagonist component (ii) or in any order. For example, in certain embodiments, component (i) is administered first, followed by administration of component (ii), or they are

administered in the reverse order. When not administered at the same time, in certain embodiments, the administration of component (i) and component (ii) occurs less than about one hour apart. In certain embodiments, the route of administration of component (i) and component (ii), of the invention is oral. The terms oral agent, oral release enhancer, oral compound, or the like, as used herein, denote compounds which are orally administered. In certain embodiments, the component (i), and (ii), are both administered by the same route (that is, for example, both orally) or in the same dosage form (that is, for example, as a tablet). In certain other embodiments, they are each be administered by different routes (that is, for example, one component of the combination product is administered orally, and another component is administered intravenously) or in different dosage forms (that is, for example, one component as a tablet and another as a liquid).

[00111] Dosage of the compositions described herein varies depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above.

[00112] The proper dosage of Opioid (component (i)), and μ receptor partial agonist and/or κ receptor antagonist (component (ii)) are ascertainable by a medical practitioner skilled in the art, based upon the present disclosure. In certain embodiments, the compositions described herein are formulated such that, although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized. In order to minimize contact, for example, where the product is orally administered, one or more of the active ingredients are enteric coated in certain embodiments. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. Another embodiment of this invention where oral administration is desired provides for a combination product wherein one or more of the active ingredients is coated with a sustained-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. In certain embodiments the sustained-released component is enteric coated such that the release of this component occurs only in the intestine. In another embodiment, the formulation of a combination product in which the one or more components is coated with a sustained and/or enteric release polymer, and the other(s) component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

Prodrugs

[00113] In certain embodiments, the compositions, and combinations of Opioids and Buprenorphine described herein are formulated as prodrugs. To illustrate, prodrug forms of the Opioids and

Buprenorphine can be converted into a pharmacologically active form through hydrolysis of, for example, an ester or amide linkage, thereby introducing or exposing a functional group on the resultant product. The prodrugs can be designed to react with an endogenous compound to form a water-soluble conjugate that further enhances the pharmacological properties of the compound, for example, increased circulatory half-life. Alternatively, prodrugs can be designed to undergo covalent modification on a functional group with, for example, glucuronic acid, sulfate, glutathione, an amino acid, or acetate. The resulting conjugate can be inactivated and excreted in the urine, or rendered more potent than the parent compound. High molecular weight conjugates also can be excreted into the bile, subjected to enzymatic cleavage, and released back into the circulation, thereby effectively increasing the biological half-life of the originally administered compound. Additionally, prodrugs can be designed to minimize or prevent abuse of the Opioid and/or Buprenorphine by designing the combination or the individual opioid to degrade in the intestine, thereby discouraging improper administration such as snorting.

[00114] In certain embodiments, are dosage forms of the compositions described herein wherein one active ingredient is enteric coated in the form of tablets such that the enteric coated component and the other active ingredients are blended together and then compressed into a tablet or such that the enteric coated component is compressed into one tablet layer and the other active ingredient is compressed into an additional layer. In certain embodiments, in order to further separate the two layers, one or more placebo layers are present such that the placebo layer is between the layers of active ingredients. In certain embodiments dosage forms of the compositions described herein are in the form of capsules wherein one active ingredient is compressed into a tablet or in the form of a plurality of micro tablets, particles, granules or non-perils, which are then enteric coated. These enteric coated micro tablets, particles, granules or non-perils are placed into a capsule or compressed into a capsule along with a granulation of the other active ingredient.

[00115] In certain embodiments are provided pharmaceutical kits useful for the treatment of pain, which comprise a therapeutically effective amount of Opioids and μ receptor partial agonist and/or κ receptor antagonist formulated in one or more containers. In certain embodiments, ssterilization of the container is carried out using conventional sterilization methodology well known to those skilled in the art. In certain embodiments, the Opioid and the μ receptor partial agonist and/or κ receptor antagonist are placed in the same container or in separate containers. The containers of materials may comprise separate containers, or one or more multi-part containers, as desired. The Opioid and μ receptor partial agonist and/or κ receptor antagonist are separate, or physically combined into a single dosage form or unit as described above. In certain embodiments, smuch kits further include, one or more of various conventional pharmaceutical kit components, such as for example, one or more pharmaceutically acceptable carriers, additional vials for mixing the components, etc. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, are included in the kit in certain embodiments.

[00116] Significant beneficial effects derived from using Buprenorphine in combination with Opioids are described herein. Clinical data described herein shows an improved profile in regards to cognitive involvement, limiting the dynamics and other evolutionary effects seen with certain individuals on pure Opioids. These combinations have a positive effect on co-occurring illnesses, the minimization of any impact on information processing, as well as other social issues. Buprenorphine, due to its effect on stabilization of the endogenous Opioid system, is useful to avoid the problems seen with using Opioids for emotional coping, and therefore, these combinations are effective in limiting chemical coping.

Combinations disclosed herein minimize the potential use of Opioids, not only for pain, but the secondary use of chemical coping. They are useful in avoiding the effect of self-medicating for emotional reasons. Combinations, therefore, have the ability to assist in coping with certain emotional and psychological events. This is true not only in individuals who have pre-existing psychological issues, but also includes issues that occur while people are on Opioids. This combination has a better foundation when faced with psychosocial issues when taken correctly.

EXAMPLES [00117] The examples described below demonstrate the supra-additive synergistic analgesic effect of an Opioid, administered in combination with a μ receptor partial agonist and/or κ receptor antagonist such as Buprenorphine. The examples described below demonstrate that a representative Opioid acts

synergistically with a representative μ receptor partial agonist and/or κ receptor antagonist,

Buprenorphine, resulting in reduction of pain, treatment of addiction and reduced side-effects inclusive of abuse. The examples also show that the Opioid acts synergistically with Buprenorphine for reducing pain in an Opioid tolerant patient. The Examples demonstrate that by combining Opioids in the fashion described herein, the desire and availability to abuse an opioid that is a pure μ agonist is avoided.

Additionally, the examples demonstrate that the onset of Opioid tolerance in a patient receiving pain therapy can be reduced by administering an Opioid in synergy with a μ receptor partial agonist and/or κ receptor antagonist such as Buprenorphine.

Example 1 : Risk Minimization, Assessment and Outcomes in Patients With Chronic Pain

[00118] Context: Individuals having two conditions: 1) a well-documented pain disorder and 2) clear evidence of a substance use disorder with opiate dependency. Prior to this study, it was not known how to manage these patients. Herein, for the treatment of chronic pain, combination administration of

Buprenorphine and an Opioid is given.

[00119] Objective: The objective of this study is to demonstrate that the administration of Buprenorphine to Opioid administration improves clinical outcome relative to usual administration of Opioid alone.

[00120] Design: Randomized control trial.

[00121] Setting: The study is conducted with in-patients in a hospital. [00122] Participants: The participants are those who have: 1) a well-documented pain disorder and 2) clear evidence of a substance use disorder with opiate dependency.

[00123] Baseline data collected: Data collected at baseline includes (with examples): demographics (age, gender, race), substance use history (type of substances used, duration of use, routes of abuse), type of pain disorder (previous traumatic injury, musculoskeletal, neuropathic), co-existing medical problems (seizures, hepatitis C), prior injuries (accidents, interpersonal violence), prior mental health problems (prior treatment, diagnoses), prior substance abuse treatment (outpatient, inpatient), socioeconomic variables (educational level, occupation, employment history), criminal history (number of arrests and convictions, total amount of time spent in jail or prison), family history (first degree relatives with substance use disorders) and scores on psychometric testing (ASI).

[00124] Outcome data: Three main outcome variables are examined: relapse to substance use (as documented by toxicology), quality of life, and successful participation in the pain management program for six months, which included the completion of the study Buprenorphine treatment protocols. The treatment based on administering the compositions described herein, which is the combination an Opioid and Buprenorphine results in excellent pain management, and negligible relapse to substance abuse, along with an appreciable improvement in quality of life. This is further illustrated by the individual examples described in detail herein.

Examples 2: Administration of Buprenorphine and an Opioid in an Adult with severe traumatic pain

[00125] Subject: 53-year-old Caucasian male.

[00126] Background: Recurrent history of trauma as a result of war, incurred from parachuting, and ongoing hostilities. History of migraines since childhood, multiple fractures and lumbar disc surgeries. Cervical disc surgery. History of multiple years on Opioids.

[00127] Condition: Bedridden and in intractable pain for many years. Opioid dependent for multiple years.

[00128] Treatment: Treatment of pain and Opioid addiction by means of a combination of Opioid Oxymorphone HCWOmg ER, and Buprenorphine 4mg, QID.

[00129] Prognosis: Over the course of treatment, patient has overcome Opioid dependency, and has a pronounced relief from pain. The individual has resumed work and his normal life prior to trauma.

Examples 3: Administration of Buprenorphine and an Opioid in an Adult Opioid Addict

[00130] Subject: Adult female.

[00131] Background: For many years this patient had been on Oxycontin, and abused Oxymorphone HC1. Ongoing abuse of Oxycontin was well documented over several years. [00132] Condition: Rheumatoid arthritis with significant degeneration of her joints, primarily the knees, shoulders, ankles, and hips.

[00133] Treatment: Initially treated by using a combination of Buprenorphine and Hydrocodone Bitartrate and Acetaminophen. During treatment, she had both knees replaced, and a shoulder replaced. She persistently was treated with combinations of Buprenorphine and Hydromorphone, Hydrocodone, and Morphine. Currently suffering from acute arthritic pain in the ankles. Treated with Buprenorphine 4mg, qid, and Morphine 30mg, qid.

[00134] Prognosis: Opioid addiction and abuse has been overcome. Pain is treated successfully, as the patient undergoes surgical procedures to alleviate cause of pain.

Examples 4: Administration of Buprenorphine and an Opioid in an Adult with chronic pain due to several factors, and severe Opioid dependency cause by escalating doses

[00135] Subject: 39-year-old Caucasian female.

[00136] Background: History of migraines, fibromyalgia, Lupus erythematosus, chronic fatigue syndrome, lumbar disc disease, Opioid dependence, sleep disorder, history of high dose Opioid dependence and abuse, and Benzodiazapine dependence. She has been in and out of Psychiatric and medical hospitals, and was on multiple treatments for all of her disorders. Subject had been in intractable pain going back several years, resulting in a chronic bedridden state.

[00137] Condition: The Lupus had been unstable, and she had used steroids, Cortisone,

Methotrexate, etc. She had nerve palsies, joint, and muscle pain, confusion, flash-backs, and non- restorative sleep. This condition had been going on 8 years. She had previously been taking Aptiq, Oxycodone, Fentanyl, and Norco, in progressive dosages. She had an unstable work and social history for 8 years.

[00138] Treatment: Successfully stabilized on Oxymorphone HC1 lOmg, qid, and Buprenorphine 4mg, qid.

[00139] Prognosis: She has had no further flare-ups of the Lupus, and her pain disorder has been stable. She is actively in a recovery program. She is currently stable, successfully overcoming her Opioid dependency and is raising her children. Examples 5: Administration of Buprenorphine and an Opioid in Adult with acute pain and Opioid Dependency

[00140] Subject: 30-year-old Female.

[00141] Background and Condition: She had a long term issue of lumbosacral disease, and spinal fusion. At the age of 20, she underwent back surgery and ended up taking multiple Opioids over the following 9 years lying in bed 90% of the time. [00142] Treatment: Stabilized on Buprenorphme 4mg, qid, Oxymorphone 20mg, qid, and Oxymorphone Immediate Release formulation 1 Omg, qid. During this time, active rehabilitation took over 18 months to restore function, and activity, and restore her to a quality of life.

[00143] Prognosis: Currently on the same medications, and has been stable for the last 2-1/2 years, leading an active functional life.

Examples 6: Administration of Buprenorphine and an Opioid in Adult with acute pain and Opioid Dependency

[00144] Subject: 52-year-old Caucasian male.

[00145] Background: Underwent back surgery in 2001, with rods and plates, following a fall off a ladder. He underwent neck surgery when he was younger, and had ongoing issues with Opioid dependence. He was abusing Morphine, and had taken 500-600mg, daily. He has a prior history of using Duragesic Patches, and Oxycodone.

[00146] Treatment: stabilized on Buprenorphine 4mg, qid, and Hydrocodone lOmg, qid in the form of Hydrocodone lOmg and 325mg of Acetaminophen.

[00147] Prognosis: One and one -half years later, he remained stable on a fixed dose of Buprenorphine 4mg, and Hydrocodone 1 Omg, qid. He has been restored to normalized activities of daily living. He retired in a stabilized state. No more pain, or need for escalating Opioid doses. Example 7: Dosage Range

[00148] For Opioid naive patients with high risk for abuse of Opioids, dosage ranges start as low as 0.02 mg Buprenorphine, with mug Hydrocodone, or 5mg Oxycodone. Dose ranges go up sequentially, and include 0.02 mg, 0.05 mg, 0.2 mg, 0.5 mg, 1.0 mg, and 2.0 mg doses of Buprenorphine combined with doses of Oxycodone. The combination of Oxycodone to Buprenorphine is as follows: (Oxycodone: Buprenorphine) 5:0.02, 10:0.05, 20:0.05 ER, 40: 1.0 ER, and 80:2.0 ER. The 5 mg and 10 mg doses of Oxycodone are immediate release forms, while the 20 mg, 40 mg, and 80 mg doses of Oxycodone are extended release formulations.

[00149] Chronic pain is ongoing pain for 6 or more months. These clients often receive Opioid treatment for pain. When considering placing a client on ongoing Opioid medication, one should consider that high risk clients that need preparations with low amounts of Buprenorphine, such as 5 mg Oxycodone: 0.02 mg Buprenorphine as a starting point for safety. Those patients that are known to have a longer history and are Opioid dependent and problematic require the addition of higher doses of Buprenorphine relative to the Opioids. It is noted that as total Buprenorphine daily dose rises, it takes over a rapidly increasing percent of receptors and begins to have a higher blocking effect on the second Opioids. The doses of Buprenorphine range from as low as 0.02 mg, 5 times daily, up to preparations with maximums of a total of 16 mg of Buprenorphine, in combination during the total daily dosing. This variation ranges from the Opioid naive patient to the Opioid dependent patients, with different guidelines for both.

Combination with behavioral therapy

[00150] As in other treatment paradigms for addiction, the effects of treatment are noted when combining the medication used for addiction with a behavioral treatment for addiction to see the effects of medication. The combination of Opioids and receptor/endorphin effects with behavioral treatment combined to stabilize individuals that are poorly controlled on a pure Opioid agonist, or partial agonist by itself, particularly if pain is not well controlled.

Claims

A composition useful for the treatment of pain in an individual, comprising:

at least one Opioid or a pharmaceutically acceptable salt thereof; and

at least one of a μ receptor partial agonist or a κ receptor antagonist or pharmaceutically acceptable salts thereof.

The composition of claim 1 , wherein the μ receptor partial agonist is a κ receptor antagonist

The composition of claim 2 wherein the μ receptor partial agonist and κ receptor antagonist is

Buprenorphine.

The composition of claim 1 , wherein the at least one Opioid is morphine, Fentanyl,

Dihydroetorphine, Sufentanil, Butorphanol, Alfentanil, Pentazocine, Morphine, Phenazocine, Hydromorphone, Codeine, Oxymorphone, Meperidine, Methadone, Propoxyphene, Oxycodone, Tramadol, Hydrocodone, Remifentanil, Levorphanol, Dihydrocodeine, L-acetylmethadol, Ethylmorphine, Diacetylmorphine, Nalbuphine, Etorphine, Buprenorphine, Normethadone, Dihydromorphine, Noroxycodone, Normorphine, Norlevorphanol or a combination thereof. The composition of claim 1 , wherein at least one Opioid is not an Opioid receptor competitive antagonist.

The composition of claim 5, wherein at least one Opioid is not a μ receptor competitive antagonist.

The composition of claim 1 , further comprising a μ receptor competitive antagonist.

The composition of claim 6, wherein the μ receptor competitive antagonist is Naloxone.

The composition of claim 1 , wherein administration of the composition results in a higher degree of pain relief as compared to the administration of the individual components.

The composition of claim 1 , wherein administration of said composition to an individual does not cause euphoria.

The composition of claim 1 , wherein said composition is formulated for oral dosage.

The composition of claim 1 , wherein administration of the composition to an individual results in a longer analgesic duration as compared to administration of said at least one Opioid in the absence of a μ receptor partial agonist or a κ receptor antagonist.

The composition of claim 1 , wherein administration of the composition to an individual causes reduced side effects as compared to administration of said at least one Opioid in the absence of the μ receptor partial agonist or the κ receptor antagonist.

The composition of claim 1 , wherein administration of the composition to an individual results in a reduction in craving sensations as compared to administration of said at least one Opioid in the absence of the μ receptor partial agonist or the κ receptor antagonist.

15. A method of treating withdrawal symptoms of opioid abuse, dependency or addiction, in a patient in need thereof, said method comprising administering to said patient a pharmaceutically effective amount of a composition according to claim 1.

16. A method for treating opioid addiction in a patient, said method comprising: administering to the patient a composition according to claim 1.

17. A method of treating opioid addiction or pain in an individual in need thereof, said method

comprising administering to said individual:

at least one Opioid or a pharmaceutically acceptable salt thereof; and

at least one of a μ-receptor partial agonist or a κ-receptor antagonist, or pharmaceutically acceptable salts thereof;

in amounts effective to cause a supra-additive synergistic analgesic response to pain and for a duration effective to inhibit pain in the individual in need thereof.

18. The method of claim 17, wherein the μ receptor partial agonist is also a κ receptor antagonist.

19. The method of claim 17 wherein the μ receptor partial agonist and κ receptor antagonist is

Buprenorphine.

20. The method of claim 17, wherein the at least one Opioid is Morphine, Fentanyl,

Dihydroetorphine, Sufentanil, Butorphanol, Alfentanil, Pentazocine, Morphine, Phenazocine, Hydromorphone, Codeine, Oxymorphone, Meperidine, Methadone, Propoxyphene, Oxycodone, Tramadol, Hydrocodone, Remifentanil, Levorphanol, Dihydrocodeine, L-acetylmethadol, Ethylmorphine, Diacetylmorphine, Nalbuphine, Etorphine, Buprenorphine, Normethadone,

Dihydromorphine, Noroxycodone, Normorphine, Norlevorphanol or a combination thereof.

21. The method according to claim 17, wherein at least one Opioid is not an Opioid receptor

competitive antagonist.

22. The method according to claim 17, wherein at least one Opioid is not a μ receptor competitive antagonist.

23. The method according to claim 17, further comprising a μ receptor competitive antagonist.

24. The method of claim 23, wherein the μ receptor competitive antagonist is Naloxone.

25. The method of claim 17, wherein said administration does not result in euphoria.

26. The method according to claim 17, wherein at least one of said Opioid, or said μ-receptor partial agonist or κ-receptor antagonist is in a solid oral dosage form.

27. The method according to claim 17, wherein at least one of said drugs is suitable for dosing once or twice a day.

28. The method according to claim 17, wherein said μ-receptor partial agonist and κ-receptor

antagonist is not formulated for trans-dermal delivery.

29. The method according to claim 17, wherein pain is neuropathic pain. The method of claim 29 wherein the neuropathic pain is selected from the group consisting of lower back pain, pain associated with arthritis, cancer-associated pain, herpes neuralgia, phantom limb pain, central pain, Opioid resistant neuropathic pain, bone injury pain, and pain during labor and delivery.

The method of claim 17 wherein pain is nociceptive pain.

The method of claim 31 wherein the nociceptive pain is selected from the group consisting of post-operative pain, cluster headaches, dental pain, surgical pain, pain resulting from severe burns, pain from third degree burns, post partum pain, angina pain, genitourinary tract related pain, and pain from cystitis.

The method of claim 17 wherein the pain is acute pain.

The method of claim 33 wherein the acute pain is selected from the group consisting of headache, arthritis, simple muscle strain, and dysmenorrhea.

The method of claim 17, wherein the pain is one or more of abdominal pain, pain of the digestive system, pain of the respiratory system, pain of the urogenital system, pain of the endocrine system, heart pain, pancreatic pain, intestinal pain, stomach pain, spleen pain, blood vessel pain, tensional headache pain, headache associated with sinusitis, migraine, eye pain, dry eye syndrome, post-operative pain due to surgical incisions, post-operative pain due to the insertion of implants in bone, post-operative pain due to bone replacement, pain due to cancer, pain due to bone cancer, pain associated with benign bone tumors, pain due to osteoid osteoma, pain due to osteoblastomas, pain due to cancer treatment, nerve pain, neck pain associated with cervical dystonia, back pain, lumbago, sciatica, neurogenic inflammation, skin irritation, sensitive skin, atopic dermatitis, contact dermatitis, diaper dermatitis, eczema, arthritis, rheumatoid arthritis, osteoarthritis, peripheral neuropathies, phantom pain, allodynia, burning pain, paresthesias, facial pain, trigeminal neuralgia, pain associated with tattooing or tattoo removal, pain due to bunions, testicular pain, myofascial pain, spastic muscle pain, pain of the urinary bladder, pain of the urinary tract, vulvar pain, vaginal pain, scrotal pain, perineal pain, pelvic pain, and pain or skin irritation after surgery, after treatment with pulsed light therapy (IPL, Intense Pulse Light), after treatment with pulsed monochromatic light therapy, pain after treatment with chemical exfoliating agents, pain after overexposure to aggressive external agents, pain after overexposure to sunlight, pain due to extreme cold and pain due to extreme heat.

A method of reducing opioid tolerance in an opioid tolerant individual comprising administering to said individual:

at least one opioid or a pharmaceutically acceptable salt thereof; and

in amounts effective to reduce Opioid tolerance in the individual. The method of claim 36, wherein the μ receptor partial agonist is also a κ receptor antagonist. The method of claim 37 wherein the μ receptor partial agonist and κ receptor antagonist is Buprenorphine.

The method of claim 36, wherein the at least one Opioid is Fentanyl, Dihydroetorphine, Sufentanil, Butorphanol, Alfentanil, Pentazocine, Morphine, Phenazocine, Hydromorphone, Codeine, Oxymorphone, Meperidine, Methadone, Propoxyphene, Oxycodone, Tramadol, Hydrocodone, Remifentanil, Levorphanol, Dihydrocodeine, L-acetylmethadol, Ethylmorphine, Diacetylmorphine, Nalbuphine, Etorphine, Buprenorphine, Normethadone, Dihydromorphine, Noroxycodone, Normorphine, Norlevorphanol or a combination thereof.

The method of claim 36, wherein at least one Opioid is not an Opioid receptor competitive antagonist.

The method of claim 36, wherein at least one Opioid is not a μ receptor competitive antagonist.

The method of claim 36, further comprising a μ receptor competitive antagonist.

The method of claim 42, wherein the μ receptor competitive antagonist is Naloxone.

A method of reducing pain in an Opioid tolerant patient, said method comprising administering:

Buprenorphine or a pharmaceutical salt thereof; and

an Opioid or a pharmaceutical salt thereof;

in an amount effective to reduce pain in the individual.

The method as recited in claim 44 wherein said opioid is chosen from Oxycodone,

Hydromorphone or pharmaceutical salt thereof.

The method of claim 44, wherein said administration is by an oral route.

A method of reducing the onset of Opioid tolerance in a patient receiving pain therapy, said method comprising administering:

Buprenorphine or a pharmaceutical salt thereof; and

an Opioid or a pharmaceutical salt thereof;

in an amount effective to reduce pain in the individual.

The method as recited in claim 47 wherein said Opioid is chosen from Oxycodone,

Hydromorphone or pharmaceutical salt thereof.

The method of claim 47, wherein said administration is by an oral route.

A method for treating pain in a patient, with an opioid analgesic having addictive liability while decreasing the patient's likelihood of addiction to said opioid analgesic comprising:

administering to said patient an effective amount of at least one of a μ-receptor partial agonist or a κ-receptor antagonist, or pharmaceutically acceptable salts thereof or a

pharmaceutical salt thereof; and

administering to said patient an effective amount of the Opioid analgesic or a pharmaceutical salt thereof; wherein said least one of a μ-receptor partial agonist or a κ-receptor antagonist is administered before or simultaneously with said analgesic.

51. The method as recited in claim 50 wherein said opioid analgesic is one or more of Fentanyl, Dihydroetorphine, Sufentanil, Butorphanol, Alfentanil, Pentazocine, Morphine, Phenazocine, Hydromorphone, Codeine, Oxymorphone, Meperidine, Methadone, Propoxyphene, Oxycodone,

Tramadol, Hydrocodone, Remifentanil, Levorphanol, Dihydrocodeine, L-acetylmethadol, Ethylmorphine, Diacetylmorphine, Nalbuphine, Etorphine, Buprenorphine, Normethadone, Dihydromorphine, Noroxycodone, Normorphine, Norlevorphanol or a salt thereof.

52. The method of claim 50, wherein the μ receptor partial agonist is also a κ receptor antagonist. 53. The method of claim 52 wherein the μ receptor partial agonist and κ receptor antagonist is

Buprenorphine

54. A method for treating Opioid abuse in an individual who has relapsed into Opioid abuse, said method comprising administering:

a stabilizing amount of at least one Opioid or a pharmaceutically acceptable salt thereof; and a stabilizing amount of at least one of a μ-receptor partial agonist or a κ-receptor antagonist, or pharmaceutically acceptable salts thereof.

55. The method of claim 54, wherein the μ receptor partial agonist is also a κ receptor antagonist.

56. The method of claim 55 wherein the μ receptor partial agonist and κ receptor antagonist is

Buprenorphine.

57. The method as recited in claim 54 wherein said at least one Opioid is Fentanyl,

Dihydroetorphine, Sufentanil, Butorphanol, Alfentanil, Pentazocine, Morphine, Phenazocine, Hydromorphone, Codeine, Oxymorphone, Meperidine, Methadone, Propoxyphene, Oxycodone, Tramadol, Hydrocodone, Remifentanil, Levorphanol, Dihydrocodeine, L-acetylmethadol, Ethylmorphine, Diacetylmorphine, Nalbuphine, Etorphine, Buprenorphine, Normethadone, Dihydromorphine, Noroxycodone, Normorphine, Norlevorphanol or combinations thereof.

58. The method of claim 54, wherein at least one Opioid is not an Opioid receptor competitive

antagonist.

59. The method of claim 54, wherein at least one Opioid is not a μ receptor competitive antagonist.

60. The method of claim 54, further comprising a μ receptor competitive antagonist.

61. The method of claim 60, wherein the μ receptor competitive antagonist is Naloxone.

62. The method of claim 54, wherein the stabilizing amount of at least one Opioid or a

pharmaceutically acceptable salt thereof; and the stabilizing amount of at least one of a μ- receptor partial agonist or a κ-receptor antagonist, or pharmaceutically acceptable salts thereof, are administered to the individual on a regular basis.

63. The method of claim 54, wherein the administration is daily, weekly, biweekly, or monthly.

64. The method of claim 63, wherein the administration is continued for a period of about five years.

65. The method of claim 63, wherein the administration is continued for life

66. A composition useful for overcoming a tendency to recurring opioid abuse in an individual, said composition comprising:

at least one Opioid or a pharmaceutically acceptable salt thereof; and

67. The composition of claim 66, wherein the μ receptor partial agonist is a κ receptor antagonist

68. The composition of claim 67 wherein the μ receptor partial agonist and κ receptor antagonist is Buprenorphine.

69. The composition of claim 66, wherein the at least one Opioid is morphine, Fentanyl,

Dihydroetorphine, Sufentanil, Butorphanol, Alfentanil, Pentazocine, Morphine, Phenazocine, Hydromorphone, Codeine, Oxymorphone, Meperidine, Methadone, Propoxyphene, Oxycodone, Tramadol, Hydrocodone, Remifentanil, Levorphanol, Dihydrocodeine, L-acetylmethadol, Ethylmorphine, Diacetylmorphine, Nalbuphine, Etorphine, Buprenorphine, Normethadone, Dihydromorphine, Noroxycodone, Normorphine, Norlevorphanol or a combination thereof.

70. The composition of claim 66, wherein the at least one Opioid is in the form of a prodrug

71. The composition of claim 70, wherein the Buprenorphine is in the form of a prodrug.

72. The composition of claim 66, wherein at least one Opioid is not an Opioid receptor competitive antagonist.

73. The composition of claim 66, wherein at least one Opioid is not a μ receptor competitive

antagonist.

74. The composition of claim 66, further comprising a μ receptor competitive antagonist.

75. The composition of claim 74, wherein the μ receptor competitive antagonist is Naloxone.