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Naltrexone: Critical review of studies in animals for their relevance to alcoholism treatment
163
5-50 Uses ofNarcotic Antagonists in the Treatment ofAddiction
I8-50-21
Naltrexone: Critical Review of Studies in Animals for Their Relevance to Alcoholism Treatment
J.H. Woods 2, K. Williams 2, J. Vivian J, D. Jewett 3, E. Pakarinen I. I Department of Pharmacology, 2 Department of Psychology, Univ. of Michigan, USA; 3 Department of Psychology, Wayne State Univ., USA A sizeable number of studies have shown that alcohol consumption by various animals is reduced following naltrexone administration. The factors that control alcohol consumption in animals appear to be numerous, and mayor may not be related to the human conditions that control alcohol consumption. Parallels between these circumstances will be sought that could enlighten or focus research on this very interesting treatment indication for naltrexone. For example, naltrexone reduces food and water consumption in animals. It also reduces the consumption of sweet substances and liquids and other preferred substances in a variety of animals. The relevance of some of these effects to the indication will be evaluated. As a narcotic antagonist, naltrexone shares a pharmacological profile with other antagonists in animals that allows certain hypotheses to be evaluated. Two of these are that naltrexone reduces opioid effects that are brought about by alcohol administration and that its actions on alcohol effects are due to its selective, mu-opioid receptor affinity. These hypotheses will also be discussed for their relevance to the indication. Research supported by USPHS Grants DA-00254, DA-07268, and DA-08568.
I8-50-31
Narcotic Antagonists in the Treatment of Alcoholism
C. O'Brien, J. Volpicelli. Department of Psychiatry, University of PennsylvanialVA Medical Center, Philadelphia, PA, USA Studies beginning in the 1970s in rodents and non-human primates suggested that the endogenous opioid system was involved in alcohol reinforcement. We, therefore, embarked on a double-blind, placebocontrolled study of the opioid receptor antagonist, naltrexone, as an adjunct in a comprehensive alcoholism rehabilitation program. This rehabilitation program began after detoxification and consisted of intensive outpatient treatment for three months. Those patients randomly assigned to naltrexone had significantly less craving for alcohol, lower relapse rates and those who "slipped" by ingesting alcohol reported less pleasure than expected from the drink. Subsequently, these findings were essentially replicated by O'Malley and associates. We have recently completed a new double-blind trial of naltrexone in alcoholics showing positive results on relapse rates in comparison to placebo. We also conducted a laboratory study of non-alcoholic drinkers ingesting alcohol while receiving either naltrexone or placebo. Stimulant effects of alcohol were reduced by naltrexone in subjects with a positive family history of alcoholism. Our data are compatible with the studies of Schuckit showing hereditary influence on the subjective effects of alcohol and the data of Gianoulakis showing that subjects with a strong family history of alcoholism have a larger endogenous opioid response to a test dose of alcohol in the laboratory.
I8-50-41
Use of Narcotic Antagonist in Treating Opioid Addiction
recent increase in heroin addiction among the middle and upper middle class has led to a renewed interest in narcotic antagonists. Clinical issues and potential side-effects that may limit use will be discussed as well as approaches that might enhance retention and effectiveness.
18-50-51 European Experience with Narcotic Antagonists in the Treatment of Opioids and Alcohol Dependence E. Tempesta, P. Mannelli I. I Depts. of Pharmacology and Psychiatry, Univ. Cattolica S. Cuore, Roma, Italy Naltrexone was introduced in Europe for the opiate addiction treatment in the second half of the 80's, while the same experience had already showed not completely satisfying results in U.S.A. The differences in philosophy and policy of treatment among the European countries accounts for the non homogeneous diffusion of the drug. Up to now only Spain and Italy are carrying on naltrexone maintenance programmes on large basis. Other countries, such as Austria and u.K., have a more limited use of the drug. We intend to discuss these differences, particularly in relation to the position of naltrexone in the framework of the harm reduction policy in Europe. Clinical trials in Italy and Spain show a higher retention rate in naltrexone maintenance programmes (6-12 months), with respect to the U.S. trials. Possible explanations of these results will also be discussed. Recently naltrexone has been proposed as a tool for an Ultra-rapid detoxification from opiates, to facilitate the introduction of naltrexone maintenance. Since this method implies the use of a general anesthetic procedure, there is a large debate on the ethical, cost-effectiveness and safety issues involved with it. Not scientifically fully valuable results are provided by now, even if there is evidence for an increasing number of Centers applying this methodology. The use of naltrexone in the treatment of alcohol dependence is under investigation in different European countries. Preliminary results on its efficacy in preventing relapse in alcoholics were presented at recent conferences and need further evaluation
I8-50-61 Endogenous Opioids and Experimental Addiction J.M. Van Ree, M.A.F.M. Gerrits. Rudolf Magnus Institute for Neurosciences, Utrecht University, Utrecht, The Netherlands The discovery of endogenous opioids has led to the postulate that these peptides are involved in addiction to opiates and also to other drugs. The main characteristics of drug addiction are the rewarding properties of drugs and the drug-induced craving. Both aspects can be studied in animals by using the self-administration procedure among others. Blockade of endogenous opioid activity by opiate antagonists made rats less sensitive to the rewarding action of cocaine and decreased alcohol consumption in monkeys. After imposed abstinence the monkeys appeared to be more sensitive to naltrexone. Application of local infusion of naltrexone in brain regions, measurement of I'l-endorphin-immunoactivity, in vivo opioid receptor occupancy using brain autoradiography and the place preference procedure resulted in the postulate that endogenous opioids in different brain areas are involved in modulation of the drug reward (ventral tegmental area) and in the drug-induced craving (limbic areas). These aspects may be of importance for the individual sensitivity to addictive behavior and for pharmacotherapeutic intervention of drug addiction.
M.W. Fischman. Department of Psychiatry, Division on Substance Abuse Columbia University, New York, New York I
Use of narcotic antagonists to treat opioid addiction on a maintenance basis began in the 1960's with oral naloxone and cyclazocine and was succeeded by naltrexone, a longer acting antagonist with minimal sideeffects. Antagonists have the advantage over agonists such as methadone of producing no physical dependence or reinforcing psychological effects, no withdrawal, and no heightened effects in combination with drugs of abuse from different pharmacologic classes. Research from 1973 to 1984 established naltrexone's safety, dosage parameters, lack of tolerance, and efficacy. Use during the decade 1984-1994 has been limited primarily to health care professionals and more middle-class addicts, although some studies have shown promise in individuals on probation or parole. The
8-50-7 1 Usesof Narcotic Antagonists in the Treatment of Addiction
H.D. Kleber, J.M. van Ree. Department of Psychiatry, Division on Substance Abuse, Columbia University, New York, NY This symposium will provide up-to-date research and clinical data from animal and human studies on both current and new uses for narcotic antagonists. Dr. James Woods University of Michigan, will discuss animal research on the mechanism of action of narcotic antagonists both with opioids and alcohol. Animal data is much more recent on the putative mechanism whereby antagonists diminish alcohol's hedonic effects. Dr. van Ree of Utrecht University, Netherlands, examines from the animal
5-50 Uses ofNarcotic Antagonists in the Treatment ofAddiction
I8-50-21
Naltrexone: Critical Review of Studies in Animals for Their Relevance to Alcoholism Treatment
J.H. Woods 2, K. Williams 2, J. Vivian J, D. Jewett 3, E. Pakarinen I. I Department of Pharmacology, 2 Department of Psychology, Univ. of Michigan, USA; 3 Department of Psychology, Wayne State Univ., USA A sizeable number of studies have shown that alcohol consumption by various animals is reduced following naltrexone administration. The factors that control alcohol consumption in animals appear to be numerous, and mayor may not be related to the human conditions that control alcohol consumption. Parallels between these circumstances will be sought that could enlighten or focus research on this very interesting treatment indication for naltrexone. For example, naltrexone reduces food and water consumption in animals. It also reduces the consumption of sweet substances and liquids and other preferred substances in a variety of animals. The relevance of some of these effects to the indication will be evaluated. As a narcotic antagonist, naltrexone shares a pharmacological profile with other antagonists in animals that allows certain hypotheses to be evaluated. Two of these are that naltrexone reduces opioid effects that are brought about by alcohol administration and that its actions on alcohol effects are due to its selective, mu-opioid receptor affinity. These hypotheses will also be discussed for their relevance to the indication. Research supported by USPHS Grants DA-00254, DA-07268, and DA-08568.
I8-50-31
Narcotic Antagonists in the Treatment of Alcoholism
C. O'Brien, J. Volpicelli. Department of Psychiatry, University of PennsylvanialVA Medical Center, Philadelphia, PA, USA Studies beginning in the 1970s in rodents and non-human primates suggested that the endogenous opioid system was involved in alcohol reinforcement. We, therefore, embarked on a double-blind, placebocontrolled study of the opioid receptor antagonist, naltrexone, as an adjunct in a comprehensive alcoholism rehabilitation program. This rehabilitation program began after detoxification and consisted of intensive outpatient treatment for three months. Those patients randomly assigned to naltrexone had significantly less craving for alcohol, lower relapse rates and those who "slipped" by ingesting alcohol reported less pleasure than expected from the drink. Subsequently, these findings were essentially replicated by O'Malley and associates. We have recently completed a new double-blind trial of naltrexone in alcoholics showing positive results on relapse rates in comparison to placebo. We also conducted a laboratory study of non-alcoholic drinkers ingesting alcohol while receiving either naltrexone or placebo. Stimulant effects of alcohol were reduced by naltrexone in subjects with a positive family history of alcoholism. Our data are compatible with the studies of Schuckit showing hereditary influence on the subjective effects of alcohol and the data of Gianoulakis showing that subjects with a strong family history of alcoholism have a larger endogenous opioid response to a test dose of alcohol in the laboratory.
I8-50-41
Use of Narcotic Antagonist in Treating Opioid Addiction
recent increase in heroin addiction among the middle and upper middle class has led to a renewed interest in narcotic antagonists. Clinical issues and potential side-effects that may limit use will be discussed as well as approaches that might enhance retention and effectiveness.
18-50-51 European Experience with Narcotic Antagonists in the Treatment of Opioids and Alcohol Dependence E. Tempesta, P. Mannelli I. I Depts. of Pharmacology and Psychiatry, Univ. Cattolica S. Cuore, Roma, Italy Naltrexone was introduced in Europe for the opiate addiction treatment in the second half of the 80's, while the same experience had already showed not completely satisfying results in U.S.A. The differences in philosophy and policy of treatment among the European countries accounts for the non homogeneous diffusion of the drug. Up to now only Spain and Italy are carrying on naltrexone maintenance programmes on large basis. Other countries, such as Austria and u.K., have a more limited use of the drug. We intend to discuss these differences, particularly in relation to the position of naltrexone in the framework of the harm reduction policy in Europe. Clinical trials in Italy and Spain show a higher retention rate in naltrexone maintenance programmes (6-12 months), with respect to the U.S. trials. Possible explanations of these results will also be discussed. Recently naltrexone has been proposed as a tool for an Ultra-rapid detoxification from opiates, to facilitate the introduction of naltrexone maintenance. Since this method implies the use of a general anesthetic procedure, there is a large debate on the ethical, cost-effectiveness and safety issues involved with it. Not scientifically fully valuable results are provided by now, even if there is evidence for an increasing number of Centers applying this methodology. The use of naltrexone in the treatment of alcohol dependence is under investigation in different European countries. Preliminary results on its efficacy in preventing relapse in alcoholics were presented at recent conferences and need further evaluation
I8-50-61 Endogenous Opioids and Experimental Addiction J.M. Van Ree, M.A.F.M. Gerrits. Rudolf Magnus Institute for Neurosciences, Utrecht University, Utrecht, The Netherlands The discovery of endogenous opioids has led to the postulate that these peptides are involved in addiction to opiates and also to other drugs. The main characteristics of drug addiction are the rewarding properties of drugs and the drug-induced craving. Both aspects can be studied in animals by using the self-administration procedure among others. Blockade of endogenous opioid activity by opiate antagonists made rats less sensitive to the rewarding action of cocaine and decreased alcohol consumption in monkeys. After imposed abstinence the monkeys appeared to be more sensitive to naltrexone. Application of local infusion of naltrexone in brain regions, measurement of I'l-endorphin-immunoactivity, in vivo opioid receptor occupancy using brain autoradiography and the place preference procedure resulted in the postulate that endogenous opioids in different brain areas are involved in modulation of the drug reward (ventral tegmental area) and in the drug-induced craving (limbic areas). These aspects may be of importance for the individual sensitivity to addictive behavior and for pharmacotherapeutic intervention of drug addiction.
M.W. Fischman. Department of Psychiatry, Division on Substance Abuse Columbia University, New York, New York I
Use of narcotic antagonists to treat opioid addiction on a maintenance basis began in the 1960's with oral naloxone and cyclazocine and was succeeded by naltrexone, a longer acting antagonist with minimal sideeffects. Antagonists have the advantage over agonists such as methadone of producing no physical dependence or reinforcing psychological effects, no withdrawal, and no heightened effects in combination with drugs of abuse from different pharmacologic classes. Research from 1973 to 1984 established naltrexone's safety, dosage parameters, lack of tolerance, and efficacy. Use during the decade 1984-1994 has been limited primarily to health care professionals and more middle-class addicts, although some studies have shown promise in individuals on probation or parole. The
8-50-7 1 Usesof Narcotic Antagonists in the Treatment of Addiction
H.D. Kleber, J.M. van Ree. Department of Psychiatry, Division on Substance Abuse, Columbia University, New York, NY This symposium will provide up-to-date research and clinical data from animal and human studies on both current and new uses for narcotic antagonists. Dr. James Woods University of Michigan, will discuss animal research on the mechanism of action of narcotic antagonists both with opioids and alcohol. Animal data is much more recent on the putative mechanism whereby antagonists diminish alcohol's hedonic effects. Dr. van Ree of Utrecht University, Netherlands, examines from the animal