WO2008008380A1 - Combination therapy for addiction disorders - Google Patents

Abstract

The present invention provides a therapeutic method comprising administering at least one opioid receptor antagonist and at least one glutathione-increasing agent to an individual afflicted with an addiction disorder, in amounts that are effective to eliminate or reduce at least one symptom of said addiction disorder.

Description

COMBINATION THERAPY FOR ADDICTION DISORDERS

Related Application

This application claims priority from U.S. Provisional Application Serial No. 60/830,416, filed July 12, 2006, the content of the provisional application is incorporated herein by reference in its entirety.

Background of the Invention Addiction Disorders

Addiction Disorders are complex patterns of human activity. These patterns are characterized by extreme behavior that can be difficult to define and categorize (Shaffer, H. J., Substance Use & Misuse, 32, 1573 (1997)). Addictive behaviors have historically been associated with substance dependence.

An individual can be diagnosed with substance dependence if he or she persists in the use of alcohol or other drugs despite impairment or distress related to the use of the substance. This impairment or distress is manifested by various indications. Compulsive and repetitive use of the substance may result in tolerance to the effect of the drug, increasing.use and withdrawal symptoms when use is reduced or stopped.

Substance dependence can be broken down into the following categories: alcohol dependence; amphetamine or amphetamine-like dependence; cannabis dependence; cocaine dependence; hallucinogen dependence; inhalant dependence; nicotine dependence; opioid dependence; phencyclidine (PCP) or phencyclidine-like dependence; sedative, hypnotic, or anxiolytic related dependence; and polysubstance related disorder. More recently, the concept of addiction has been broadened to include behavior patterns that do not necessarily include ingestion of substances such as alcohol or drugs. Impulse-control disorders including intermittent explosive disorder, kleptomania, pyromania, pathological gambling, and trichotillomania can be grouped as addiction disorders, as can addictions to the internet, television, work, skin picking, video games, exercise, shopping, binge eating, sexual activities, self-injury and religion. Addictions may thus be divided into two broad categories: substance addictions and process or behavioral addictions. Poly-behavioral addiction is the synergistically integrated dependence on multiple addictive substances and behaviors. For example, an individual might abuse substances such as nicotine, alcohol, or drugs, while simultaneously acting impulsively regarding gambling, binge eating, sex, or religion. Addiction disorders have been considered refractory to known pharmacological or psychotherapeutic treatments over time. In addition, treating various neurological and psychiatric disorders with naltrexone alone shows heterogenous results. Furthermore, naltrexone may exhibit hepatotoxicity at doses greater than 50 mg/day. Therefore, a continuing need exists for treatments that are effective in eliminating or reducing the symptoms associated with addiction disorders while maintaining low hepatotoxicity at effective doses.

It is therefore an object of the present invention to provide methods to treat addiction disorders.

Summary of the Invention

The present invention provides a therapeutic method comprising administering at least one opioid receptor antagonist and at least one glutathione- increasing agent to an individual afflicted with an addiction disorder, in amounts that are effective to eliminate or reduce at least one symptom of said addiction disorder.

When the opioid receptor antagonist is naltrexone and the glutathione- increasing agent is N-acetylcysteine (NAC), multiple benefits are provided, due to NACs activities of brain glutamate neurotransmission modulation and protection against liver toxicity, in addition to naltrexone's opioid antagonism. As used herein, the term "addiction disorder" includes all substance dependence and impulse-control disorders as defined in the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders), as well as other behavioral or process addictions characterized by the failure to resist urges and repeated behavior or behaviors that cause harm to the individual, others, or property. As used herein, the term "addictive behavior" means any behavior that is associated with or considered a symptom of an addiction disorder.

As used herein, a "glutathi one-increasing agent" is any agent, precursor or analog that increases glutathione levels in any part or parts of a subject. An increase in glutathione includes both the new presence of glutathione where there was previously an absence of glutathione, and an increase in levels of glutathione where glutathione was already present in the subject. Glutathi one- increasing agents include, but are not limited to, glutathione, glutathione precursors or other glutathione analogs; enzymes which catalyze GSH synthesis, including γ-glutamylcysteine synthetase and GSH synthetase; and other precursors for glutathione biosynthesis including iV-acetylcysteine (NAC), L-2- oxothiazolidine-4-carboxylate (also known as OTC and Procysteine®), L- glutamine, glutamate/glutamic acid, 2(R,S)-n~propyl-thiazolidine-4R- carboxylate, 2(R,S)-n-pentyl-thiazolidine-4R-carboxylate, 2(R,S)-methyl- thiazolidine-4R-carboxylate, 2(R,S)-D-ribo-(l '^'.S'^'-tetrahydroxybutyl) thiazolidine-4(R)-carboxylic acid (also known as Ribose-Cysteine and RibCys), γ-glutamylcysteine, cysteinylglycine, lipoic acid, S-allyl cysteine, methionine, S- adenosylmethionine, S-adenosylhomocysteine, and cystathionine.

As used herein, the term "impulse-control disorder" (ICD) includes intermittent explosive disorder, trichotillomania, kleptomania, pyromania, pathological gambling and compulsive shopping. These disorders are well- characterized and diagnosable by the art, as discussed herein below.

As used herein, the term "opioid receptor antagonist" includes both pure and mixed opioid receptor antagonists, as defined in Goodman and Gilman's The Pharmacological Basis of Therapeutics, Pergamon Press, NY at pages 487-489. Antagonists that bind with high specificity to μ, δ or K receptors are included within the term, such as NTI, as are relatively nonspecific antagonists, such as naltrexone and naloxone.

The term "at least one" as used herein with respect to opioid receptor antagonists and glutathione-increasing agents means that the antagonists and agents can be used simultaneously, sequentially or separately, to achieve the desired effect, i.e., 1-3 or more antagonists or glutathione-increasing agents may be delivered in one or a plurality of unit dosage forms.

Thus, the invention provides a therapeutic method of treating an addiction disorder, comprising administering to an individual afflicted with an addiction disorder at least one opioid receptor antagonist and at least one glutathione-increasing agent in an amount effective to reduce or eliminate at least one symptom of the addiction disorder. The at least one opioid receptor antagonist can be any antagonist, including an antagonist that is mu, delta, or kappa receptor-specific, for example. In one embodiment, at least one antagonist can be, for example, naltrexone, nalmefene, levallorphan, naloxone, or the like.

At least one glutathi one-increasing agent can be, for example, glutathione (GSH), a glutathione precursor, a glutathione analog, a precursor for glutathione biosynthesis or an enzyme which catalyzes GSH. In one embodiment, at least one glutathione-increasing agent can be, for example, 7-glutamylcysteine synthetase, GSH synthetase, N-acetylcysteine (NAC), L-2-oxothiazolidine-4- carboxylate (also known as OTC and Procysteine®), L-glutamine, glutamate/glutamic acid, 2(R,S)-n-propyl-thiazolidine-4R-carboxylate, 2(R,S)-n- pentyl-thiazolidine-4R-carboxylate, 2(R,S)-methyl-thiazolidine-4R-carboxylate, 2(R,S)-D-ribo-(l '^'.S'Λ'-tetrahydroxybutyl) thiazolidine-4(R)-carboxylic acid (also known as Ribose-Cysteine and RibCys), 7-glutamylcysteine, cysteinylglycine, lipoic acid, S-allyl cysteine, methionine, S- adenosylmethionine, S-adenosylhomocysteine, and cystathionine. In some embodiments at least one glutathione-increasing agent can be, for example, N- acetylcysteine and the opioid antagonist can be nalmefene.

In some embodiments, at least one agent can be administered by any suitable route or method. In one embodiment, at least one agent can be administered orally, for example. Also, at least one agent can be administered parenterally, including for example, by injection, infusion, or by a controlled release dosage form. The controlled release dosage form can be for example, a transdermal patch. Furthermore, in some aspects, at least one agent can be administered by inhalation. The glutathione-increasing agent(s) and opioid antagonist(s) can be administered at any suitable or effective dose. For example, N-acetylcysteine can administered at doses of about 1200-2400 mg/day. As another example, naltrexone is administered at doses of about 100-200 mg/day. Further, at least one agent can be administered for about four to six weeks, for example. The addiction disorder can be, for example, substance dependence or a behavioral addiction/disorder. The substance dependence can be, for example, amphetamine dependence, amphetamine-like dependence, cannabis dependence, cocaine dependence, hallucinogen dependence, inhalant dependence, nicotine dependence, alcohol dependence, opioid dependence, phencyclidine (PCP), phencyclidine-like dependence, sedative, hypnotic, or anxiolytic related dependence, or a polysubstance related disorder. As one non-limiting example, the amphetamine-like dependence can be methamphetamine dependence. In some aspects, the methods can specifically exclude one or more of the above- listed dependences. For example, in some aspects the substance dependence is not cocaine dependence. The behavioral addiction can be, for example, an impulse control disorder (ICD). For example, the ICD can be pathological gambling, intermittent explosive disorder, kleptomania, pyromania, or trichotillomania. Furthermore, the disorder/addiction can be associated with the internet, television, work, skin picking, video game, exercise, shopping, binge eating, an eating disorder, sexual activity, self-injury (for example, cutting), or religion. In some aspects, the methods can specifically exclude one or more of the above-listed addictions/disorders. Also, in some aspects, the methods can specifically include or exclude treating an obsessive compulsive disorder (OCD). Furthermore, some embodiments relate to methods of treating an addiction disorder comprising administering nalmefene and N-acetylcysteine. In one embodiment, the nalmefene is administered orally. In another embodiment the addiction disorder is a behavioral addiction, such as an ICD. For example, the behavioral addiction/disorder can be pathological gambling, intermittent explosive disorder, kleptomania, pyromania, trichotillomania, the internet, television, work, skin picking, video game, exercise, shopping, binge eating, an eating disorder, sexual activity, self-injury, or religion. In some aspects, one or more of the above-listed disorders/addictions can be specifically excluded from the methods. One embodiment relates to therapeutic methods of treating an addiction disorder, comprising administering to an individual afflicted with an addiction disorder an amount of a glutathione-increasing agent and an amount of an opioid receptor antagonist agent of formula (I):

wherein R¹ is (C₃-C₄)cycloalkylmethyl or allyl, R² is H or OH, R³ is H or (Ci- C₄)alkyl, R is O, CH₂ or (H)₂, or a pharmaceutically acceptable salt or ester thereof, effective to reduce or eliminate at least one symptom of the addiction disorder. The compound of formula (I) can be, for example, naltrexone, naloxone, or nalmefene. The glutathione-increasing agent can be any such agent, including those listed elsewhere herein. In one embodiment, the agent can be N-acetylcysteine.

Brief Description of the Figures

Figure 1 depicts decreased urge intensity in Impulse-Control Disorders upon treatment with naltrexone and NAC. A sample often clinic patients having a range of Impulse-Control Disorders including gambling, stealing, hair pulling and shopping, were asked to assess the intensity of their urges based on a 1-10 scale prior to treatment with naltrexone ("pre-treatment), after four to six weeks of treatment with naltrexone ("post-treatment"), and after an additional four to six weeks of treatment with combination naltrexone and NAC ("+ NAC"). An urge intensity value of 1 was equivalent to mild or no urges and a value of 10 was equivalent to intense, uncontrollable urges. The urge values were averaged for the ten patients and the (mean) values are represented on the y-axis. Naltrexone was administered at the FDA-approved dose of 50 mg/day and NAC was administered at doses between 1200 mg/day and 2400 mg/day NAC.

Figure 2 shows a decrease in serum levels of liver enzymes upon addition of NAC to naltrexone treatment. Serum levels of the liver enzymes aspartate transaminase (AST) and alanine transaminase (ALT) were measured in two patients who were treated for Impulse-Control Disorders (Figure 2). The y-axis represents the serum level for these proteins measured in U/L. Normal serum levels range from 0 to 65 U/L for ALT and from 0 to 55 U/L for AST (depending somewhat on age, gender, and the laboratory used). The AST and ALT levels were measured before naltrexone treatment was initiated, after naltrexone treatment for approximately one to two months at doses greater than the FDA-approved dose (150 mg/day), and after the further addition of 1800 mg/day NAC to the naltrexone treatment for approximately six to eight weeks.

Detailed Description of the Invention The Diagnostic and Statistical Manual of Mental Disorders, (4^th ed.,

1994; also known as the DSM-IV) was prepared by the Task Force on Nomenclature and Statistics of the American Psychiatric Association. The DSM-IV provides descriptions of diagnostic categories of Substance Dependence and Impulse-Control Disorders, which are excerpted below. The skilled artisan will recognize that there are alternative nomenclatures, nosologies, and classification systems for pathologic psychological conditions and that these systems can evolve. Substance Dependence

Substance dependence is classified as a substance use disorder. When an individual persists in the use of alcohol or other drugs despite problems related to the use of the substance, the individual can be diagnosed with substance dependence. Compulsive and repetitive use of the substance can result in tolerance to the effect of the drug, and withdrawal symptoms when use is reduced or stopped. The essential feature of substance dependence is a maladaptive pattern of substance use, leading to clinically significant impairment or distress. This impairment or distress is manifested by various indications, and Substance Dependence is diagnosed if three or more of the following seven indications occur during a 12-month period. The first indication of substance dependence is tolerance, defined as either a need for markedly increased amounts of the substance to achieve intoxication or some other desired effect; or the achievement of a markedly diminished effect with continued use of the same amount of the substance. The second indication of substance dependence is withdrawal, as manifested by either the characteristic withdrawal syndrome for the substance; or the taking by the individual of the same or a closely related substance to relieve or avoid withdrawal symptoms.

The third and fourth indications of substance dependence occur when the individual takes the substance in larger amounts or over a longer period than was intended; and when the individual has a persistent desire, or has made efforts, to cut down or control the substance use, but has failed. The fifth indication of substance dependence is when an individual spends a great deal of time engaging in activities necessary to obtain the substance (e.g., visiting multiple doctors or driving long distances), to use the substance (e.g., chain-smoking), or to recover from its effects.

The sixth indication of substance dependence is a decrease in attendance at important social, occupational, or recreational activities due to the substance use. The seventh indication of substance dependence occurs when the substance use is continued despite the individual's knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance (e.g., current cocaine use despite recognition of cocaine-induced depression, or continued drinking despite recognition that an ulcer was made worse by alcohol consumption). If tolerance or withdrawal symptoms are present (as in the first or second indications above), the dependence is classified as physiological dependence. If there is no evidence of tolerance or withdrawal, then the dependence is not classified as physiological.

Substance dependence can be broken down into the following categories: alcohol dependence; amphetamine or amphetamine-like dependence; cannabis dependence; cocaine dependence; hallucinogen dependence; inhalant dependence; nicotine dependence; opioid dependence; phencyclidine (PCP) or phencyclidine-like dependence; sedative, hypnotic, or anxiolytic related dependence; and polysubstance related disorder. A more detailed discussion excerpted from the DSM-IV follows.

Alcohol is a sedative. It is available as a regulated retail substance and is usually consumed orally in beverages or intravenously.

Amphetamines belong to the group of medicines called central nervous system (CNS) stimulants. They increase attention and decrease restlessness in individuals who are overactive, unable to concentrate for very long or are easily distracted, and have unstable emotions. Amphetamine drugs include Adderall®, Adderall XR™, Benzadrine, Biphetamine® (combination with dextroamphetamine, Fisons Corporation), Delcobese, and Dexedrine. Amphetamine-like drugs (also known as sympathomimetic amines) include Adderall®, Adipex-P®, amphetamine, amphetamine/dextroamphetamine, Banobese, Benzadrine, benzphetamine, Biphetamine®, chlorphentermine, cocaine, Cylert, Delcobese, Desoxyn®, Dexedrine, dexmethylphenidate, dextroamphetamine, DextroStat, Didrex, diethylpropion, Fastin®, fenfluramine, Focalin™, Ionamin, mazindol, Mediatric, Methadrine, methamphetamine, Methylin™, methylphenidate, Obenix, Oby-Cap, Oby-Trim, paramethoxyamphetamine, pemoline, phendimetrazine, phenmetrazine, phentermine, PMA, Pondimin®, Ritalin, Tenuate, Tepanil, and Zantryl. Uppers, diet pills, and analeptics are also included in the class of Amphetamine- like drugs. ^

The active ingredient in cannabis is delta-9-tetrahydrocannabinol (THC). Naturally-occurring cannabis is cultivated in Cannabis saliva, Cannabis indica, and Cannabis ruderalis. Cannabis is taken orally or smoked. Cannabis is also known as dronabinol, tetrahydrocannabinol, and Marino 1®. Cocaine is used as a local anesthetic and psychostimulant. Cocaine usually makes the user feel euphoric and energetic. It comes from coca leaves and is administered nasally, orally, by mucous membrane, by injection, or smoked.

Hallucinogens are named for their ability to cause hallucinations in normal subjects. This class of drug includes 2,5-Dimethoxy-4- methylamphetamine (DOM or STP), diethyltryptamine (DET), dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), mescaline (Peyote), methylene dioxyamphetamine (MDA), methylene dioxymethamphetarnine (MDMA), morning glory seed, nutmeg, paramethoxyamphetamine, PMA, psylocybin, and psylocin.

Inhalants are a group of ubiquitous substances so varied that they have little in common other than their volatility and route of administration. Only a few are primarily produced as drugs, while the majority have a variety of industrial and household uses. Few, if any, are controlled substances. They are found in glue, hair spray, paints, nail polish and other products. Many are flammable and contain aerosols or propellants. Inhalants include cleaning fluids containing carbon tetrachloride, tetrachloro ethylene, trichloroethane, and trichloroethylene. Fuels containing butane, gasoline, isopropane, propane, and tetraethyl lead, are used as inhalants. Gases containing freon, brornochlorodifluoromethane, other fluorocarbons, and nitrous oxide, are also used as inhalants. Nitrites such as amyl nitrite, butyl nitrite, and isobutyl nitrite, and solvents such as acetates, acetone, benzene, butylacetate, chloroform, ether, hexane, methanol, naphtha, methyl chloride, methyl ethyl ketone, methylene chloride, and toluene, are used as inhalants.

Nicotine Dependence is characterized by dependence on tobacco products that are smoked, chewed, or cheeked.

Opioids are a class of analgesic drugs, often referred to as narcotics. Opioids include both natural derivatives of opium and synthetic drugs with similar properties. Some are used to control diarrhea or cough (anti-tussive). Natural opioid agonists include codeine, morphine, MS Contin, opium, and paregoric. Semi-synthetic opioids include DHCplus, diacetylmorphine, dihydrocodeine, Dilaudid, Endocet®, Endodan®, heroin, Hycodan®, Hycomine, Hycotuss®, hydrocodone, hydromorphone, Lortabs, Numorphan®, oxycodone, Oxycontin, oxymorphone, Palfium®, Percocet®, Percodan®, Percolone,

Roxicet, Roxicodone, Tussionex, Vicodin, Zantryl, and Zydone®. Synthetic opioids include alfenta, alfentanil, anileridine, carfentanil, Darvon®, dextromoramide, Demerol®, Dolophine, Duragesic, fentanyl, LAAM, Leritine, Levo-Dromoran, levorphanol, Mepergan®, meperidine, methadone, methadose, Pathadol, Pethadol, propoxyphene, Rapifen, sufentanil, Sufenta, and Wildnil®. Partial opioid agonists include buprenex, buprenorphine, butorphanol, Dalgan, dezocine, nalbuphine, Nubain®, pentazocine, Stadol, Suboxone®, Subutex®, Talwin®, and Temgesic.

Phencyclidine (PCP) is a manufactured substance that is formulated as tablets, capsules, or colored powder. It can be snorted, smoked, injected, or taken orally. Developed in the 1950s as an anesthetic, PCP was never approved for human use because of problems during clinical studies, including intensely negative psychological effects. Sedatives, sedative-hypnotics, and anxiolytics are similar to one another in effect and are often used interchangeably. Sedatives and hypnotics are central nervous system depressant drugs. These drugs have a calming effect and can facilitate, induce or maintain sleep. Drugs from the chemical classes benzodiazepines and barbiturates can be included in this class. Some of these drugs may also be used to induce or enhance general anesthesia and narcosynthesis. This class of drugs includes Ambien, amobarbital, Amytal, chloral hydrate, Dalmane, Doral, eszopiclone, flurazepam, Halcion, Lunesta, midazolam, Noctec, pentothal, quazepam, ramelteon, Restoril, Rozerem, Somnos, Sopor, temazepam, Valium (diazepam), Versed, and Zolpidem.

The term anxiolytic (or anti-anxiety) describes the category of drug whose original or most common use and intended therapeutic effect is to control or prevent the psychiatric symptom of anxiety or mental disorders whose primary feature is anxiety. This term may also be used to describe the anti- anxiety effect of a treatment. Impulse-Control Disorders

Intermittent explosive disorder, kleptomania, pyromania, pathological gambling, and trichotillomania can be grouped as impulse-control disorders. Individuals with these mental disorders suffer from recurrent failure to resist impulsive behaviors that may be harmful to themselves or others.

The essential feature of intermittent explosive disorder is the occurrence of discrete episodes of failure to resist aggressive impulses that result in serious assaultive acts or destruction of property. The degree of aggressiveness expressed during an episode is grossly out of proportion to any provocation or precipitating psychosocial stressor. A diagnosis of intermittent explosive disorder is made only after other mental disorders that might account for episodes of aggressive behavior have been ruled out (e.g., antisocial personality disorder, borderline personality disorder, a psychotic disorder, a manic episode, conduct disorder, or attention deficit/hyp eractivity disorder). The aggressive episodes are not due to the direct physiological effects of a substance (e.g., an abused drug, a medication) or a general medical condition (e.g., head trauma, Alzheimer's disease). The individual may describe the aggressive episodes as "spells" or "attacks" in which the explosive behavior is preceded by a sense of tension or arousal and is followed immediately by a sense of relief. Later the individual may feel upset, remorseful, regretful, or embarrassed about the aggressive behavior.

The essential feature of kleptomania is the recurrent failure to resist impulses to steal items even though the items are not needed for personal use or for their monetary value. The individual experiences a rising subjective sense of tension before the theft and feels pleasure, gratification, or relief when committing the theft. The stealing is not committed to express anger or vengeance, is not done in response to a delusion or hallucination, and is not better accounted for by conduct disorder, a manic episode, or antisocial personality disorder.

The objects are stolen despite the fact that they are typically of little value to the individual, who could have afforded to pay for them and often gives them away or discards them. Occasionally the individual may hoard the stolen objects or surreptitiously return them. Although individuals with this disorder will generally avoid stealing when immediate arrest is probable (e.g., in fill view of a police officer), they usually do not preplan the thefts or fully take into account the chances of apprehension. The stealing is done without assistance from, or collaboration with, others.

The essential feature of pyromania is the presence of multiple episodes of deliberate and purposeful fire setting. Individuals with this disorder experience tension or affective arousal before setting a fire. There is a fascination with, interest in, curiosity about, or attraction to fire and its situational contexts (e.g., paraphernalia, uses, consequences).

Individuals with this disorder are often regular "watchers" at fires in their neighborhoods, may set off false alarms, and derive pleasure from institutions, equipment, and personnel associated with fire. They may spend time at the local fire department, set fires to be affiliated with the fire department, or even become firefighters. Individuals with this disorder experience pleasure, gratification, or a release of tension when setting the fire, witnessing its effects, or participating in its aftermath. The fire setting is not done for monetary gain, as an expression of sociopolitical ideology, to conceal criminal activity, to express anger or vengeance, to improve one's living circumstances, or in response to a 'delusion or a hallucination. The fire setting does not result from impaired judgment (e.g., in dementia, mental retardation, or substance intoxication).

The essential feature of pathological gambling is persistent and recurrent maladaptive gambling behavior that disrupts personal, family, or vocational pursuits. The diagnosis is not made if the gambling behavior is better accounted for by a manic episode. The individual may be preoccupied with gambling (e.g., reliving past gambling experiences, planning the next gambling venture, or thinking of ways to get money with which to gamble).

Most individuals with pathological gambling say that they are seeking "action" (an aroused, euphoric state) even more than money. Increasingly larger bets, or greater risks, may be needed to continue to produce the desired level of excitement. Individuals with pathological gambling often continue to gamble despite repeated efforts to control, cut back, or stop the behavior. There may be restlessness or irritability when attempting to cut down or stop gambling. The individual may gamble as a way of escaping from problems or to relieve a dysphoric mood (e.g., feelings of helplessness, guilt, anxiety, depression). A pattern of "chasing" one's losses may develop, with an urgent need to keep gambling (often with larger bets or the taking of greater risks) to undo a loss or series of losses. The individual may abandon his or her gambling strategy and try to win back losses all at once. Although all gamblers may chase for short periods, it is the long-term chase that is more characteristic of individuals with pathological gambling.

The individual may lie to family members, therapists, or others to conceal the extent of involvement with gambling. When the individual's borrowing resources are strained, the person may resort to antisocial behavior (e.g., forgery, fraud, theft, or embezzlement) to obtain money. The individual may have jeopardized or lost a significant relationship, job, or educational or career opportunity because of gambling. The individual may also engage in "bailout" behavior, turning to family or others for help with a desperate financial situation that was caused by gambling.

The essential feature of trichotillomania is recurrent pulling out of one's hair resulting in noticeable hair loss. Individuals with this disorder experience an increasing sense of tension immediately before pulling out the hair or when attempting to resist the behavior. When the hair is pulled out, the individual experiences pleasure, gratification, or relief. The behavior is not better accounted for by another mental disorder and is not due to a general medical condition such as a dermatological condition. The behavior can cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. Trichotillomania may also be classified as an obsessive- compulsive disorder (OCD), because it has significant comorbidity and overlapping phenomenology with severe OCD (S.E. Stewart et al., J. CHn. Psychiatry, 66, 864 (2005)). However, in contrast to compulsions in OCD, hair- pulling in trichotillomania is not in response to obsessive thoughts but rather due to an irresistible urge and subsequent gratification when pulling out hair (C. Lochner, et al., BMC Psychiatry, 5:2, doi:10.1186/1471-244X-5-2 (2005)).

Other behavioral addictions not specifically identified in the DSM-IV include addictions to the internet, television, work, skin picking, video games, exercise, shopping, binge eating, sexual activities, self-injury, and religion. The present methods include administration of at least two different agents for treating one or more addiction disorders, including poly-behavioral addictions. The first agent is an opioid antagonist; the second agent is a glutathione-increasing agent. Therapeutic treatment with Opioid Antagonists . Endogenous opioid peptides are involved in the mediation or modulation of a variety of physiological processes, many of which are mimicked by opiates or other non-endogenous opioid ligands. Some of the effects that have been investigated are analgesia, tolerance and dependence, appetite, renal function, gastrointestinal motility, gastric secretion, learning and memory, mental illness, epileptic seizures and other neurobiological disorders, cardiovascular responses and respiratory depression.

Opioid antagonists involve opioidergic modulation of mesolimbic dopamine circuitry. Behaviorally, opioid antagonist administration leads to diminished urges to engage in addictive behaviors and longer periods of abstinence, consistent with a mechanism of action involving ventral striatal dopamine systems.

The fact that the effects of endogenous and exogenous opioids are mediated by at least three different types, mu (μ), delta (δ), kappa (K), of opioid receptors indicates that highly selective exogenous opioid agonist or antagonist ligands might have therapeutic applications. See W. R. Martin, Pharmacol. Rev., 35, 283 (1983). Thus, if a ligand acts at a single opioid receptor type or subtype, the potential side effects mediated through other opioid receptor types can be minimized or eliminated. The prototypical opioid antagonists, naloxone and naltrexone, are used primarily as pharmacologic research tools and for the reversal of toxic effects of opioids in case of overdose. Also, the efficacy of naltrexone has been tested in bulimia nervosa (J. M. Jonas et al., Psych. Res., 24, 195 (1987)), alcoholism (J. R. Volpicelli et al., Arch. Gen. Psych., 49 876 (1992)), opioid dependence (S. Minozzi et al., Cochrane Database Syst Rev., (l):CD001333 (2006)), borderline personality disorder with self-injurious behavior (A. S. Roth et al., J. Clin. Psychiatry, 57, 233 (1996)), drug abuse (T. R. Kosen et al., Life Sciences, 44, 887 (1989)), obsessive-compulsive disorder (OCD) (R. Sandyk, Int. J. Neurosci. 35, 93 (1987)), mental retardation with self-injurious behavior (S. H. Willemsen- Swinkels, Arch. Gen. Psychiatry, 52, 766 (1995)), and other psychiatric disorders (M. Campbell et al., J. Amer. Acad. Child Adolescent Psych., 32, 1283 (1993)). Both positive and negative efficacy data for naltrexone have been reported except in alcohol dependence, in which the efficacy has been established (J. R. Volpicelli et al., J. Clin. Psychiatry, 7 (suppl.), 39 (1995); C. Bouza et al., Addiction, 99, 811 (2004); DJ. Rohsenow, CNS Drugs, 18, 547 (2004)).

The FDA issued a black box warning for doses of naltrexone exceeding 50 mg/day due to dose-related hepatotoxicity. The drug is also contraindicated in patients with hepatitis or liver failure (P. L. Doering, in: J.T. DiPiro, et al., eds. Pharmacotherapy: a Pathophysiologic Approach. 4th ed. Stamford, Conn.:

Appleton & Lange, 1999). Thus, health care practitioners may avoid prescribing naltrexone because of the possible negative effects on the liver of patients.

Nalmefene is another opioid antagonist and also can be used to treat any of the disorders contemplated or described herein. Nalmefene can be used in combination with a glutathione-increasing agent, such as N-acetylecysteine, to treat one or more disorders. Nalmefene is commercially marketed under the name Revex^® for use in the medical treatment of alcoholism because it has been found to reduce craving for some alcohol dependent patients. In one embodiment, opioid antagonists for use in the present methods include those of formula (I):

wherein R¹ is (C₃-C₄)cycloalkylmethyl, or allyl, R² is H or OH₅ R³ is H or (C]- C₄)alkyl, R is O₅ CH₂ or (EQ₂, or a pharmaceutically acceptable salt thereof. This group of morphinan derivatives includes those depicted in Table I below:

TABLE I

R¹ R² R³ R Common Merck No. Name

CH₂CH(CH₂)₂ OH H O naltrexone 6278 CH₂CH=CH₂ OH H O naloxone 6277 CH₂CH(CH₂)₂ OH H CH₂ nalmefene 6274 'The Merck Index, Merck & Co., Rahway, NH (11th ed., 1989).

Another group of delta-specific antagonists includes the compounds of formula (II):

wherein R¹ is (Ci-C₅)EIlCyI, C₃-C₆(cycloalkyl)alkyl, C₅-C₇-(cycloalkenyl)alkyl, aryl, aralkyl, trans(C₄-Cs)alkenyl, allyl or furan-2-ylalkyl, R² is H, OH or O₂C(C, -C₅)alkyl; R³ is H, (C_rC₅)alkyl or (Ci -C₅)alkylCO; X is O, S or NY, wherein Y is H, phenyl, benzyl or (Ci-C₅)alkyl; and R⁴ and R^s are individually H, F, Cl, Br, NO₂, NH₂, (Ci-C₅)alkyl, (Ci-C₅)alkoxy or together are benzo; and pharmaceutically acceptable salts thereof. The synthesis of these compounds is set forth in U.S. Pat. No. 4,816,586. NTI is the compound of formula (II) wherein R¹ is cyclopropylmethyl, R² is OH, R³-R⁵ are H and X is NH.

Delta-, mu- or mixed delta-, mu- antagonists for use in the present invention are disclosed in U.S. Pat. No. 5,298,622. Kappa opioid receptor- specific NTI derivatives are disclosed in U.S. Pat. No. 5,457,208.

Other opioid receptor antagonists, including mixed agonist-antagonists, useful in the practice of the present invention include (followed by their Merck Index No.), cyclazocine (2710), nadide (6259), amphenazole, butorphenol, diprenorphine, etazocine, levallorphan (5342), nalbuphine, nalorphine (6275), pentazocine, cyprenorphine (2777), 7-benzylidenenaltrexone and buprenorphine. Pentapeptides structurally related to the enkephalins have been reported to be highly delta-selective opioid antagonists. Such compounds (e.g., ICI

174864) currently are employed as pharmacologic tools, but they can possess the disadvantage of transient activity and poor penetration into the central nervous system (CNS). See J. W. Shaw et al., Life ScL, 31, 1259 (1982) and R. Cotton et al., Eur. J. Pharmacol., 97, 331 (1984). However, suppression of ethanol ingestion may be mediated by the delta opioid receptor subtype. For example, the established δ antagonist, N,N-diallyl-Tyr-Aib-Aib<Phe-Leu-OH (ICI 174864), strongly inhibits ethanol drinking, but has a very short duration of action. See J. C. Froehlich et al., Psychopharmacol., 103, 467 (1991). Glutathione and N-acetylcysteine Glutathione (GSH) is the most abundant thiol present in mammalian cells

(R.Dringen et al., Eur. J. Biochem. 267, 4912 (2000)). Its antioxidant properties protect cells against exogeneous and endogenous stressors that generate harmful free radicals. Conjugation is the primary mechanism of GSH in eliminating electrophilic xenobiotics from the liver, and GSH contributes to hepatoprotection by maintaining a normal redox state of the liver (A. Meister, J. Biol. Chem., 269, 9397 (1994); R.K. Murray, In: RK Murray et al., eds., Harper's Biochemistry. 24^th ed. Stamford, CT, Appleton and Lange (1996); M.H. Tang et al., Biofactors 19, 33 (2003)). GSH is important in maintaining the structural integrity of cell and organelle membranes and in the synthesis of microtubules and macromolecules (CD. Klassen et al., Fundamental Appl. Toxic, 5, 806 (1985)).

GSH also modulates the toxicity of chemicals that gain access to the brain and plays additional roles in brain function and neurodegenerative diseases including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia and amyotrophic lateral sclerosis (J.B. Schulz et al., Eur. J. Biochem. 267, 4904 (2000)).

GSH exists in two forms: thiol-reduced GSH and disulfide-oxidized GSSG (S.C. Lu, FASEB J. 13, 1169 (1999)). Biosynthesis of GSH involves two sequential reactions that are catalyzed by the enzymes γ-glutamylcysteine synthetase and glutathione synthetase. The three precursor amino acids L- glutamic acid, L-cysteine, and glycine, are the building blocks of GSH. The first reaction, in which L-cysteine is required, is the rate-limiting step of glutathione biosynthesis; thus, the availability of intracellular L-cysteine is a critical factor in the overall biosynthesis of GSH (Lu, FASEB J. 13:1169 (1999)).

While not being bound by any particular theory, it is believed that increases in GSH levels by the methods of the current invention can ameliorate the hepatotoxicity associated with naltrexone treatment, while providing additional neurological benefits in individuals with addiction disorders.

Glutathione-increasing agents include, but are not limited to, glutathione, glutathione precursors or other glutathione analogs; enzymes which catalyze GSH synthesis, including γ-glutamylcysteine synthetase and GSH synthetase; and other precursors for glutathione biosynthesis including N-acetylcysteine (NAC), L-2-oxothiazolidine-4-carboxylate (also known as OTC and Procysteine®), L-glutamine, glutamate/glutamic acid, 2(R,S)-n-propyl- thiazolidine-4R-carboxylate, 2(R,S)-n-pentyl-thiazolidine-4R-carboxylate, 2(R,S)-methyl4hiazolidine-4R-carboxylate, 2(R,S)-D-ribo-(l¹,2\_>3',4¹- tetrahydroxybutyl) thiazolidine-4(R)-carboxylic acid (also known as Ribose- Cysteine and RibCys), 7-glutamylcysteine, cysteinylglycme, lipoic acid, S-allyl cysteine, methionine, S-adenosylmethionine, S-adenosylhomocysteine, and cystathionine.

In one embodiment, the glutathione-increasing agent is TV-acetylcysteine, which is the compound of formula (III):

//-acetylcysteine (NAC) is a thiol (sulfhydryl-containing) compound having the chemical formula C5H₉NO3S and a molecular weight of 163.2.1. NAC has been in clinical use for more than 30 years, primarily as a mucolytic. In addition to its mucolytic action, NAC is being studied and utilized in numerous clinical conditions with decreased glutathione (GSH) or oxidative stress such as HIV infection, cancer, liver injury or failure, and heart disease. Intravenous and oral administration of NAC have been used extensively to treat acute acetaminophen overdose (G.S. Kelley, Ahem. Med. Rev. 3, 114 (1998)). NAC can both act as a scavenger of free radicals and by augmenting intracellular levels of glutathione. NAC is an effective hepatoprotectant, mainly due to its ability to regenerate liver stores of glutathione to maintain a normal redox state of the liver. When hepatic glutathione stores are depleted, an enormous oxidative stress is placed on the liver, which can lead to hepatic failure and be life- threatening. As a source of sulfhydryl (SH) groups, NAC can stimulate GSH synthesis, enhance glutathione-S-transferase activity, promote detoxification, and act directly on reactive oxidant radicals (N. De Vries et al., J. Cell. Biochem., 17F:S270-S277 (1993)). In cell culture experiments, NAC promotes the uptake of cystine from culture medium for cellular GSH biosynthesis (R.D. Issels et al., Biochem. Pharmacol., 37, 881(1988)). In vivo, NAC can increase intracellular GSH levels in liver and lung cells (S. De Flora et al.,

Carcinogenesis, 6, 1735 (1985)), and replenish GSH stores following experimental depletion (K. Nakata et al., Mech. Ageing. Dev., 90, 195 (1996)). In a rat model of hepatic injury, NAC protected against RMP-induced oxidative injury to the liver (S.V. Rana et al., World J Gastroenterol., 12, 287 (2006)). NAC also acts to modulate brain glutamate neurotransmission. It is thought that the key pathophysiologies of many neurological and psychiatric disorders are mediated through excessive glutamate activity and dysfunctional transport of cystine into glial cells (T. Murphy et al., Neuron, 2, 1547 (1989). In the nucleus accumbens, basal levels of extracellular glutamate are maintained primarily by the action of cystine/glutamate antiporters. Once administered to the body, NAC is converted to cystine, which is taken up by glial cells. This causes the reverse transport of glutamate into the extracellular space, where it can stimulate inhibitory glutamate receptors on glutamatergic nerve terminals, thereby reducing the synaptic release of glutamate and restoring extracellular glutamate concentrations in the nucleus accumbens (M. Moran, et al., J. Neurosci., 25, 6389 (2005)).

Systemic administration of NAC has been shown to block the reinstitution of compulsive cocaine-seeking behavior in a rodent model (D. A. Baker et al., Nat. Neurosci., 6, 743 (2003) and Ann. NY. Acαd. ScL, 1003, 349 (2003)), and a recent Phase I clinical trial showed a reduction in withdrawal symptoms and cravings in cocaine-dependent individuals by treatment with NAC (S.D. LaRowe et al., Am. J. Addict., 15, 105 (2006)). Augmentation of fluvoxamine treatment with NAC in a patient with serotonin reuptake inhibitor (SRI)-refractory OCD resulted in a clinically significant improvement in symptoms and Yale-Brown Obsessive Compulsive Scale score (D.L. Lafleur et al., Psychophαrmαcology, 184, 254 (2006)).

While not being bound by any particular theory, it is believed that NAC plays multiple roles in the methods of the current invention. It can function to ameliorate naltrexone hepatotoxicity and improve brain function via generation of GSH, and can additionally provide its own neurological benefits by modulation of brain glutamate neurotransmission.

Although the free-base forms of the antagonists and glutathione- increasing agents can be used in the methods of the present invention, it is preferred to prepare and use pharmaceutically acceptable salts thereof. Thus, the compounds used in the methods of this invention form pharmaceutically acceptable acid and base addition salts with a wide variety of inorganic and organic acids and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts? thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, β- hydroxybutyrate, butyne- 1 ,4-dioate, hexyne-l,4-dioate, caprate, caprylate, chloride, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, terephthalate, phosphate, monohydrogenphosphate, propriolate, propionate, phenyl-propionate, salicylate, sebacate, succinate, suberate, sulfate, bisulfate, pyrosulate, sulfite, bisulfite, sulfonate, benzenesulfonate, p-bromophenylsulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfon ate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like. The pharmaceutically acceptable acid addition salts are typically formed by reacting the free base with an equimolar or excess amount of acid. The reactants are generally combined in a mutual solvent such as diethyl ether or benzene. The salt normally precipitates out of solution within about one hour to 10 days and can be isolated by filtration or the solvent can be removed by conventional means.

The organic acids can also be used to form nontoxic esters of the free hydroxyl groups present on the antagonists and GSH-increasing agents. For example, the mono- or dinicotinates or the 3-beta-D-glucuronide esters of nalmefene, nalorphine, naltrexone and naloxone can be prepared by methods known to the art. Ester can be formed by reacting the OH group or groups with an activated form of the acid, such as the acid chloride or anhydride.

The pharmaceutically acceptable salts generally have enhanced solubility characteristics compared to the compound from which they are derived, and thus are often more amenable to formulation as liquids or emulsions.

The compounds useful in the present method can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds can be formulated prior to administration, the selection of which will be decided by the attending physician. Typically, one or more of the compounds, or pharmaceutically acceptable salts or esters thereof, is combined with a pharmaceutically acceptable carrier, diluent or excipient to form a pharmaceutical formulation, or unit dosage form.

The total active ingredients in such formulations comprise from 0.1% to 99.9% by weight of the formulation. By "pharmaceutically acceptable" it is meant that the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.

Pharmaceutical formulations containing the compounds useful in the present method can be prepared by procedures available to the art using well- known and readily available ingredients. For example, the compounds can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, suspensions, powders, and the like. Examples of excipients, diluents, and carriers that are suitable for such formulations include the following fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and other cellulose derivatives, alginate, gelatin, and polyvinyl-pyrrolidone; moisturizing agents such as glycerol; disintegrating agents such as calcium carbonate and sodium bicarbonate; agents for retarding dissolution such as paraffin; resorption accelerators such as quaternary ammonium compounds; surface active agents such as cetyl alcohol, glycerol monostearate; adsorptive carriers such as kaolin and bentonite; and lubricants such as talc, calcium and magnesium stearate and solid polyethylene glycols. The compounds also can be formulated as tablets or in capsules or as elixirs or solutions for convenient oral administration or as solutions appropriate for parenteral administration, for example, by intramuscular, subcutaneous or intravenous routes.

Additionally, the compounds are well suited to formulation as sustained or controlled release dosage forms. The formulations can be so constituted that they release the active ingredient only or in a particular physiological location, optionally over a period of time. The coatings, envelopes, and protective matrices may be made, for example, from polymeric substances such as collagen or silicone, or from waxes. The compounds can also be delivered via patches for transdermal delivery, s.c. implants, infusion pumps or release from implanted depot sustained release dosage forms.

The compounds useful in the present method can be administered simultaneously, sequentially or separately. They can be administered for the same or for different durations of time, and can be formulated in the same or in different dosages and dosage forms.

As used herein, the term "effective amount" means an amount of compound which is capable of inhibiting at least one of the symptoms of the addiction disorders herein described. The specific dose of a compound administered according to this invention will, of course, be determined by the particular circumstances surrounding the case including, for example, the compound administered, the route of administration, the condition of the patient, and the severity of the symptoms being treated. A typical daily dose will contain a nontoxic dosage level of from about 0.25 mg to about 500 mg/day of an opioid receptor antagonist, combined with a nontoxic dosage level of from about 800 mg to about 3000 mg/day of a glutathione-increasing agent. Preferred daily doses generally will be from about 1 mg to about 300 mg/day of an opioid receptor antagonist, combined with a dose from about 1000 mg to about 3000 mg/day of a glutathione-increasing agent. Since naltrexone and nalmefene have been evaluated clinically to assess their ability to inhibit ethanol consumption by alcoholic patients, effective dosages of the compounds of the present invention can be extrapolated from doses found to be effective in those studies, as well as from the dosages of NTI found to be effective to decrease cocaine use in the rat model. See, for example, Volpicelli et al., cited above, and U.S. Pat. No. 5,086,058. In addition, since NAC has been in clinical use for several decades and has recently been evaluated clinically to assess its ability to reduce withdrawal symptoms and cravings in cocaine-dependent individuals and improve symptoms of OCD in combination with fluvoxamine, effective dosages of NAC of the present invention can be extrapolated from effective doses in the study and in clinical practice, as well as the effective doses in the rodent model study. See, for example, LaRowe et al., Lafleur et al., and Baker et al., cited above.

The amount of the compounds, or active salts or derivatives thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.

In general, however, a suitable dose will be in the range of from about 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.

The compounds are conveniently administered in unit dosage form; for example, containing 5 mg to as much as 1-3 g, conveniently 10 to 1000 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form.

Ideally, the active ingredients should be administered to achieve peak plasma concentrations of the active compounds of from about 0.5 to about 75 μM, preferably, about 1 to 50 μM, most preferably, about 2 to about 30 μM. This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredients, optionally in saline. For example, as much as about 0.5-3 g of the compounds can be dissolved in about 125-500 ml of an intravenous solution comprising, e.g., 0.9% NaCl, and about 5-10% glucose. Such solutions can be infused over an extended period of up to several hours, optionally in conjunction with other anti-viral agents, antibiotics, etc. The active ingredients can also be orally administered as a bolus containing about 1-100 mg of the active ingredients. Desirable blood levels may be maintained by continuous infusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusions containing about 0.4-15 mg/kg of the active ingredients.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.

Of course, the clinically effective dosages in the human subjects as disclosed in the examples herein below may readily be extrapolated to human patients of other ages and in other conditions. For example, results may be achieved with naltrexone HCl at 1.5-5 mg/kg/day and 15-60 mg/kg/day NAC. It is preferable that the dose of antagonist and NAC be up-titrated until the effect emerges or when the symptoms recur. In most cases the effect emerges in adults at 100-200 mg/day of naltrexone and 1200-3000 mg/day, e.g. at 2000-2750 mg/day of NAC. Because of a wide margin of dose-response pattern, a flexible- instead of fixed-dose program should be employed until a minimum effective dose is established for each disorder.

The method of the present invention may also be administered in connection with and/or subsequent to an educational and/or behavioral modification program to enhance continued abstinence from the addictive behavior.

The invention will be further described by reference to the following detailed, non-limiting examples.

Example 1

Treatment of Impulse-Control Disorders A sample often clinic patients having a range of impulse-control disorders including gambling, stealing, hair pulling and shopping, were asked to assess the intensity of their urges based on a 1-10 scale prior to treatment with naltrexone ("pre-treatment), after four to six weeks of treatment with naltrexone ("post-treatment"), and after an additional four to six weeks of treatment with combination naltrexone and NAC ("+ NAC"). An urge intensity value of 1 was equivalent to little or no urges and a value of 10 was equivalent to intense, uncontrollable urges. The urge values were averaged for the ten patients and the (mean) values are represented on the y-axis of the graph in Figure 1. Naltrexone was administered at the FDA-approved dose of 50 mg/day and NAC was ■ administered at doses between 1200 mg/day and 2400 mg/day.

Example 2 Serum Levels of Transaminases Decrease after Combination Treatment Serum levels of the liver enzymes aspartate transaminase (AST) and alanine transaminase (ALT) were measured in two patients who were treated for impulse-control disorders (Figure 2). The y-axis in Figure 2 represents the serum level for these proteins measured in U/L. Normal serum levels range from 0 to 65 U/L for ALT and from 0 to 55 U/L for AST (depending somewhat on age, gender, and the laboratory used). The AST and ALT levels were measured before naltrexone treatment was initiated, after naltrexone treatment for approximately one to two months at doses greater than the FDA-approved dose (150 mg/day), and after the further addition of 1800 mg/day NAC to the naltrexone treatment for approximately six to eight weeks. Although the AST and ALT levels are only slightly above the upper end of the normal range with naltrexone treatment, those levels decrease significantly when NAC is added to the naltrexone treatment, to nearly pre-treatment levels.

All of the publications cited hereinabove are incorporated by reference herein. The invention has been described with reference to various specific embodiments and techniques. However, it should be understood that many variations and modifications maybe made while remaining within the spirit and scope of the invention.

Claims

WHAT IS CLAIMED IS:

1. A method of treating an addiction disorder, comprising administering to an individual afflicted with an addiction disorder at least one opioid receptor antagonist agent and at least one glutathione-increasing agent in an amount effective to reduce or eliminate at least one symptom of the addiction disorder.

2. The method of claim 1, wherein at least one glutathione-increasing agent is N-acetylcysteine.

3. The method of claim 1, wherein at least one opioid receptor antagonist agent is naltrexone, nalmefene, levallorphan or naloxone.

4. The method of claim 1, wherein at least one glutathione-increasing agent is glutathione (GSH), a glutathione precursor, a glutathione analog, a precursor for glutathione biosynthesis or an enzyme which catalyzes GSH synthesis.

5. The method of claim 4, wherein at least one opioid receptor antagonist is nalmefene or naltrexone.

6. The method of claim 4, wherein at least one glutathione-increasing agent is γ-glutamylcysteine synthetase, GSH synthetase, ΛΛ-acetylcysteine (ΝAC), L-2- oxothiazolidine-4-carboxylate, L-glutamine, glutamate/glutamic acid, 2(R,S)-n- propyl-thiazolidine-4R-carboxylate, 2(R,S)-n-pentyl-thiazolidine-4R- carboxylate, 2(R,S)-methyl-thiazolidine-4R-carboxylate, 2(R,S)-D-ribo- (r,2',3',4'-tetrahydroxybutyl) thiazolidine-4(R)-carboxylic acid, γ- glutamylcysteine, cysteinylglycine, lipoic acid, S-allyl cysteine, methionine, S- adenosylmethionine, S-adenosylhomocysteine, or cystathionine.

7. The method of claim 6, wherein at least one opioid receptor antagonist is nalmefene or naltrexone.

8. The method of claim 1, wherein the at least one opioid receptor antagonist is nalmefene or naltrexone, and the at least one glutathione-increasing agent is //-acetylcysteine.

9. The method of claim 1, wherein at least one agent is administered orally.

10. The method of claim 1, wherein at least one agent is administered parenterally.

11. The method of claim 10, wherein at least one agent is administered by injection or infusion.

12. The therapeutic method of claim 10, wherein at least one agent is administered by means of a controlled release dosage form.

13. The method of claim 12, wherein at least one agent is administered by means of a transdermal patch.

14. The method of claim 1, wherein at least one agent is administered by inhalation.

15. The method of claim 2, wherein the ^-acetylcysteine is administered at doses of about 1200-2400 mg/day.

16 The method of claim 3, wherein naltrexone is administered at doses of about 100-200 mg/day.

17. The method of claim 2 or 3, wherein at least one agent is administered for four to six weeks.

18. The method of claim 1, wherein the addiction disorder is substance dependence.

19. The method of claim 18, wherein the substance dependence is amphetamine dependence, amphetamine-like dependence, cannabis dependence, cocaine dependence, hallucinogen dependence, inhalant dependence, nicotine dependence, alcohol dependence, opioid dependence, phencyclidine (PCP), phencyclidine-like dependence, sedative, hypnotic, or anxiolytic related dependence, or polysubstance related disorder.

20. The method of claim 19, wherein the substance dependence is amphetamine-like dependence.

21. The method of claim 20, wherein the amphetamine-like dependence is methamphetamine dependence.

22. The method of claim 1, wherein the substance dependence is not cocaine dependence.

23. The method of claim 1 , wherein the addiction disorder is a behavioral addiction.

24. The method of claim 23, wherein the addiction disorder is addiction to the internet, television, work, skin picking, video games, exercise, shopping, binge eating, an eating disorder, sexual activity, self-injury, or religion.

25. The method of claim 24, wherein the opioid receptor antagonist is nalmefene or naltrexone.

26. The method of claim 25, wherein the glutathione-increasing agent is N- acetylcysteine.

27. The method of claim 23, wherein the addiction disorder is not an obsessive compulsive disorder (OCD).

28. The method of claim 23, wherein the addiction disorder is an obsessive compulsive disorder (OCD).

29. The method of claim 1 , wherein the addiction disorder is an impulse- control disorder.

30. The method of claim 29, wherein the impulse-control disorder is pathological gambling, compulsive shopping, intermittent explosive disorder, kleptomania, pyromama, or trichotillomania.

31. The method of claim 30, wherein the impulse-control disorder is pathological gambling.

32. The method of claim 30, wherein the impulse-control disorder is compulsive shopping.

33. The method of claim 30, wherein the impulse-control disorder is pyromania.

34. The method of claim 30, wherein the impulse-control disorder is trichotillomania or intermittent explosive disorder.

35. The method of claim 30, wherein the impulse-control disorder is kleptomania.

36. The method of claim 30, wherein the opioid receptor antagonist is nalmefene or naltrexone.

37. The method of claim 36, wherein the glutathione-increasing agent is N- acetylcysteine.

38. The method of claim 1, wherein the antagonist is mu receptor-specific.

39. The method of claim 1, wherein the antagonist is delta receptor-specific.

40. The method of claim I₃ wherein the antagonist is kappa receptor-specific.

41. A method of treating an addiction disorder, comprising administering to an individual afflicted with an addiction disorder an amount of a glutathione- increasing agent and an amount of an opioid receptor antagonist agent of formula (I):

wherein R¹ is (C₃-C₄)cycloalkylmethyl or allyl, R² is H or OH, R³ is H or (Ci-C^alkyl, R is O₅ CH₂ or (H)₂, or a pharmaceutically acceptable salt or ester thereof, effective to reduce or eliminate at least one symptom of the addiction disorder.

42. The method of claim 41, wherein the compound of formula (I) is naltrexone.

43. The method of claim 41 , wherein the compound of formula (I) is naloxone.

44. The method of claim 41, wherein the compound of formula (I) is nalmefene.

45. The method of claim 41 , wherein the glutathione-increasing agent is N- acetylcysteine.

46. The method of claim 44, wherein the glutathione-increasing agent is N- acetylcysteine.

47. The method of claim 41, wherein the addiction disorder is an impulse- control disorder.

48. The method of claim 47, wherein the impulse-control disorder is pathological gambling.

49. The method of claim 47, wherein the impulse-control disorder is intermittent explosive disorder.

50. The method of claim 47, wherein the impulse-control disorder is compulsive shopping.

51. The method of claim 47, wherein the impulse-control disorder is pyromania.

52. The method of claim 47, wherein the impulse-control disorder is kleptomania.

53. The method of claim 41, wherein the addiction disorder is substance dependence.

54. The method of claim 53, wherein the substance dependence is amphetamine-like dependence.

55. The method of claim 54, wherein the amphetamine-like dependence is methamphetamine dependence.

56. The method of claim 41 , wherein the addiction disorder is a behavioral addiction.

57. The method of claim 41, wherein at least one agent is administered orally.

58. The method of claim 41, wherein at least one agent is administered parenterally.

59. The method of claim 58, wherein at least one agent is administered by injection or infusion.

60. The method of claim 58, wherein at least one agent is administered by means of a controlled release dosage.

61. The method of claim 60, wherein at least one agent is administered by means of a transdermal patch.

62. The method of claim 41, wherein at least one agent is administered by inhalation.

63. A method of treating an addiction disorder comprising administering nalmefene and a glutathione-inducing agent in an amount effective to reduce or eliminate at least one symptom of the addiction disorder.

64. The method of claim 63, wherein the glutathione inducing agent is N- acetylcysteine.

65. The method of claim 63, wherein the nalmefene is administered orally.

66. The method of claim 63, wherein the addiction disorder is a behavioral addiction.

67. The method of claim 63, wherein the addiction disorder is an impulse control disorder.

68. The method of claim 66, wherein the behavioral addiction is pathological gambling, intermittent explosive disorder, kleptomania, pyromania, trichotillomania, addiction to the internet, addiction to television, addiction to work, addiction to skin picking, addiction to video games, addiction to exercise, addiction to shopping, an eating disorder, addiction to sexual activity, addiction to self-injury, or addiction to religion.