Pharmacological treatment of alcoholism

Maristela G . Monteiro

Associate Professor of Psychopharmacology, Department of Psychobiology, Escola Paulista de Medicina, S i o Paulo, Brazil

Abstract: This paper presents an overview on pharmacologic treatment of alcoholism. A wide range of drugs have been tested over the years, some showing a reduction of alcohol drinking in alcoholics. However, at present, there is little evidence that phnrmacotherapy is effective in the rehabilitation of alcoholics. Although research in this area still has several methodological problems and much needs to be done, a greater understanding of the neuropharmacoiogy and neurobiology of alcohol use and abuse will certainly open new avenues for investigation and drug development. Patient-treatment matching and the combination of two or more modalities of intervention may also help increase overall effectiveness of alcohol treatment. (Aust NZ J Med 1992; 22: 220-223.) Key words: Alcoholism, disulfram, serotonin.

INTRODUCTION ne of the most important goals of alcohol research is to develop new and better treatments for alcoholism. The components of treatment include management of alcohol withdrawal, long-term management of alcohol dependence, and prevention of relapse.' A number of treatment approaches are under study, and pharmacotherapy is only one of the alternatives being tested.z In clinical practice, two or more treatment modalities are combined in one design, although relatively little research has been carried out for testing pharmacotherapy as adjunctive to other appro ache^.'.^ This is especially important because at present no drug has proven to be effective in the rehabilitation of alcoholic patient^.^ At the same time, as research into the mechanisms of action of ethanol and drinking behaviour offers a better understanding on how and why one becomes an alcoholic, new agents will probably be developed which might prove to be effective in producing long-lasting reduction in drinking behaviour. The present paper is a brief overview of pharmacologic treatment of alcoholism, with emphasis on drugs aimed at decreasing alcohol drinking direct or indirectly, rather than on those used for treatment of alcohol withdrawal syndrome. 220 Aust NZ J Med

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ALCOHOL SENSITISING DRUGS Disulfiram (Antabuse) has been widely used over 40 years as an aversive therapy to treat alcoholics.' It is an irreversible inhibitor of aldehyde dehydrogenase (ALDH), an enzyme responsible for degrading acetaldehyde, the breakdown product of the action of alcohol dehydrogenase on alcohol. Acetaldehyde is a noxious intermediary that produces an unpleasant syndrome of vasodilation, facial flushing, nausea, vomiting, lightheadedness, throbbing headache, sweating, thirst, chest pain, increased pulse rate, weakness, orthostatic hypotension, and palpitations. Severe reactions may occur in susceptible subjects, including myocardial infarction, congestive heart failure, respiratory depression, and cardiac arrhythmia.2 It is used in daily doses ranging from 125-500 mg. Inhibition of the enzyme activity may last up to two weeks, thus helping the patient maintain abstinence over a longer period of time. Nevertheless, some alcoholics may overcome the acetaldehyde reaction and drink even with an aversive experience. Disulfiram also blocks dopamine-beta hydroxylase, thus having several side effects, and is reported to be hepatotoxic. Until now, the experimental rationale for its use has not been established.' More recent studies have shown that its mechanism of action may involve effects other than accumulation of acetaldehyde,6 1992; 22

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such as an increase of biogenic amines (serotonin and dopamine) and their active condensation products- tetrahydroisoquinolines and betacarbolines, which in turn may affect drinking behaviour and motivation.' Calcium carbamide (Temposil, Abstem) has been used in Europe and Canada, though it is not available in the United States. It binds reversibly to ALDH for approximately 24 hours, producing a more rapid onset, duration of action and recovery from blockade as compared to disulfiram. As a result, it has been tested with relapse prevention therapies, where high risk situations could be anticipated by the patient.' It has less side effects because it does not block dopamine beta hydroxylase. However, it appears to be hepatotoxic after long term therapys and studies have not shown evidence of an effect of calcium carbamide on drinking behavio~r.~ Nitrefazole, an imidazole derivative now being tested in Europe, has a shorter onset of action, irreversibly inhibiting ALDH after one hour of administration but, like disulfiram, has a long lasting effect. It does not block dopamine beta hydro~ylase.~~'~

LITHIUM Lithium was first reported to suppress voluntary alcohol drinking of rats in 1974,1'~'2without conditioned taste aversion, while the first clinical trial was described by Kline in the same year." Although some studies have reported a beneficial effect of lithium among both depressed and non-depressed alcoholics, research on effectiveness of lithium salts has not shown significant reductions in alcohol consumption, abstinen~e,'~ or significant effects on mood or social adjustment of patients.15In addition, there are additive effects between alcohol and lithium, with increased lithium toxicity after acute and chronic alcohol use.4 However, the value of lithium with other medications or with other psychiatric problems is yet to be determined.' BENZODIAZEPINES In recent years, much attention has been given to the GABA-benzodiazepine systems and their relationship with alcohol use and abuse.l.I6 Ro 15-4513 has been shown to reduce alcohol intoxication and anxiolytic effects of alcohol in experimental animal^.'^ Uncontrolled studies have suggested that benzodiazepines (e.g. chlordiazepoxide) reduced consumption in animals, reduced treatment dropout and increased recovery rate among alcoholics. There are also interactions between these drugs and alcohol which limit their use. However, studies distinguishing primary alcoholics with secondary ALCOHOLISM - PHARMACOLOGICAL TREATMENT

anxiety from primary anxiety patients with secondary alcoholism's are needed in order to study the potential usefulness of these drugs in selected population^.^

NON-BENZODIAZEPINE ANXIOLYTICS Buspirone, a putative partial agonist of 5HT1A receptors is another promising agent being tested for the treatment of alcoholism. It has been shown to reduce alcohol consumption in rodents and ~rirnates.'~ Preliminary clinical studies suggest that it may act by modifying the urge, craving or desire to drink, while having no interaction with alcohol, few side effects, and low abuse and dependence l i a b i l i t ~ Its . ~ mechanism of action is not yet fully understood. CALCIUM CHANNEL ANTAGONISTS Recent research has shown the importance of calcium channels in ethanol's mechanism of action. Acute doses of alcohol produce a decrease in calcium uptake, while chronic treatment results in an increase in uptake,20 with a parallel increase in calcium channels binding sites.z' At the same time, these channels are related to the NMDA receptor, which in turn is very sensitive to ethanol." Research in this area has grown substantially in the last years and may lead to the development of new drugs in the future. SEROTONIN UPTAKE INHIBITORS At present, the most promising group of drugs under study for reducing alcohol consumption is the serotonin uptake inhibitors.' Several of these agents, such as zimelidine, norzimelidine, citalopram, fluoxetine, fluvoxamine, viqualine, have been shown to decrease alcohol drinking in animal models.22 The first clinical trials have indicated these drugs increase abstinent days and decrease alcohol consumption in low dependent problem drinker^.*^-*^ Studies are needed to investigate the interaction between these drugs and nonpharmacologic treatments, their efficacy in selected populations, their usefulness in relapse prevention and so on. Since serotonin is involved in a number of behaviours and processes, such as memory, consummatory behaviour and cognition, specific basic and clinical studies on the mechanism of action of serotonin uptake inhibitors after both acute and chronic ethanol use may give new insights to our understanding of drinking behaviour and alcohol dependence.26 OPIOIDS It has been demonstrated that the opioid antagonists naloxone and naltrexone reduce alcohol consumption Aust NZ J Med 1992; 22 22 1

and/or self-administration in rodents and monkey~.~ Several ' studies show that moderate to large doses of opiate agonists (morphine, levorphanol, met-enkephalin) suppress alcohol drinking in animals, regardless of temporary disruption of food and water intakes. No controlled clinical trials have been conducted yet." OTHER DRUGS Several other centrally acting drugs have been studied, such as dopaminergic agents (bromocriptine),28-29 monoamine oxidase inhibitors, cholecystokinin and angioten~in,~ thus indicating that more than one neurotransmitter or system might play a role in alcohol drinking and dependence. The relative importance of each one has to be determined.

CONCLUSIONS Ultimately, effective pharmacotherapy for alcoholism relies upon the elucidation of the neurobiology of alcohol intoxication, reinforcement and dependence. Basic and clinical research are much needed, while some current shortcomings in both basic and clinical studies must be overcome. These include a more suitable animal model of alcoholism; wellcontrolled, randomised and blinded clinical designs; detailed characterisation of the population studied with respect to drinking patterns, severity of dependence and comorbid psychiatric problems; more accurate outcome evaluation methods, treatment efficacy measures and more specific goals for treatment; specification of other approaches being used at the same time; pharmacokinetic data of the drug being tested, among many others. In addition, regardless of the therapeutic approach being tested, it must be kept in mind that alcoholism treatment has a high drop-out rate of patients early in treatment and many patients present medical contraindications for entering a drug testing study. Finally, an emerging picture in alcoholism treatment is the combination of different techniques as well as patient-treatment mat~hing,'.~'based on individual patient characteristics. Researchers and clinicians must have an open mind to future challenges, when neuropsychology and pharmacology will be combined under the same rationale for a treatment approach, which in turn might give us a better answer to a difficult question we have been facing for years - can alcoholism be treated? References 1. Seven Special Report to the U.S. Congress on alcohol and health, 1990, Chap. XI, 271-80. 2. Kissin B. The use of psychoactive drugs in the long-term treatment of chronic alcoholics. Ann Acad Sci 1975; 252: 385-95.

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Pharmacological treatment of alcoholism.

This paper presents an overview on pharmacologic treatment of alcoholism. A wide range of drugs have been tested over the years, some showing a reduct...
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