It has been well known for a number of years that abrupt withdrawal from alcohol following chronic use is associated with adverse consequences, ranging from mild tremors to withdrawal seizures. The overall purposes of treating alcohol withdrawal (AW) are to relieve patient discomfort, to prevent the development of more serious withdrawal symptoms, and to initiate long-term alcohol rehabilitation. Several areas of controversy exist in the clinical management of AW, including the optimal treatment setting, the need for pharmacologic management, and the most appropriate agent to prescribe when medication is deemed necessary. This article reviews the clinical features, general management, and treatment of AW.

The majority of studies that have examined the usefulness of pharmacotherapies selective for serotonin (5-hydroxytryptamine; 5-HT) as a treatment for alcohol dependence have been standard, double-blind clinical trials that include patients with a variety of clinical presentations. Almost all of the early studies evaluated heavy social drinkers and found only a modest advantage for 5-HT pharmacotherapies in reducing the number of drinks per day. Also, the advantage of these pharmacotherapies was observed primarily when these agents were given at higher daily dosages than suggested prescribing practices for use as an antidepressant. The few studies that evaluated treatment-seeking patients found that 5-HT pharmacotherapies were not instrumental in reducing drinking rates compared with placebo. These results led to a dampening of enthusiasm for use of these agents in treating alcohol dependence. However, more recent investigations have begun to target subgroups with potential abnormalities in 5-HT neurotransmission. The thinking is that these medications should be most useful in alcohol-dependent individuals who have more clearly delineated suggestive signs of 5-HT dysfunction, such as concomitant depression or anxiety. Although few results are available to date, there is growing evidence to suggest that alcohol-dependent subgroups are differentially responsive to 5-HT pharmacotherapies with respect to drinking-related outcomes. This may explain the modest and variable 5-HT pharmacotherapeutic effects that were reported in the earlier studies, which included large heterogeneous patient groups. Further investigations are needed to confirm these initial optimistic results.

The increasing evidence for a neurobiologic basis for alcoholism has spurred the search for pharmacologic agents to treat alcohol abuse. The complex set of symptoms and behaviors that characterizes alcoholism has been linked to dopaminergic and opioid neurotransmitter systems, suggesting that opioid antagonists, such as naltrexone, may alter the positive reinforcement effects and craving involved in alcoholism. Laboratory and clinical investigations of naltrexone have demonstrated the potential for this agent to reduce craving, increase the aversive effects of alcohol, decrease drinking days, and increase abstinence. While naltrexone and other opioid antagonists, such as nalmefene, may be effective components of an alcohol-treatment program, they should only be used in combination with psychosocial interventions, such as support groups and psychotherapy.

Acamprosate (calcium acetyl-homotaurine) is a synthetic compound that crosses the blood-brain barrier and has a chemical structure similar to that of the naturally occurring amino acid neuromediators, homotaurine and γ-aminobu-tyric acid (GABA). Acamprosate appears to act primarily by restoring normal N-methyl-D-aspartate (NMDA) receptor tone in the glutamate system, and has been shown to have a specific dose-dependent effect on decreasing voluntary alcohol intake in animals with no effects on food and water consumption. The safety and efficacy of acamprosate in alcohol-dependent outpatients is currently under evaluation in the United States. Acamprosate has been available by prescription since 1989 in France and more recently in most European and Latin American coutries as well as Australia, South Africa, and Hong Kong. More than 4 million people have been treated with acamprosate since it became commercially available.

The purpose of this article is to review all available double-blind, placebo-controlled clinical trials evaluating the safety and efficacy of acamprosate treatment of alcohol dependence. This work encompasses 16 controlled clinical trials conducted across 11 European countries and involves more than 4,500 outpatients with alcohol dependence. Fourteen of 16 studies found alcohol-dependent patients treated with acamprosate had a significantly greater rate of treatment completion, time to first drink, abstinence rate, and/or cumulative abstinence duration than patients treated with placebo. Additionally, a multinational open-label study of acamprosate in 1,281 patients with alcohol dependence found acamprosate to be equally effective across four major psychosocial concomitant treatment programs in maintaining abstinence and reducing consumption during any periods of relapse. An absence of known strong predictors of response to acamprosate, in conjunction with a modest but consistent effect on prolonging abstinence, and an excellent safety profile, lend support to the use of acamprosate across a broad range of patients with alcohol dependence.

Combination pharmacotherapy has proven effective in a number of psychiatric disorders, including depression and schizophrenia. However, compared with other affective disorders, few studies have explored the use of combination therapy in alcoholism, and the majority have been limited to animal models. There is evidence to support a role for combination therapy in alcoholism. For example, several neurochemical systems, including the dopaminergic, serotonergic, and opioidergic, appear to affect alcohol intake. Studies in several different types of alcohol-preferring rats have suggested that coadministration of agents to target more than one of these systems simultaneously may produce beneficial effects on alcohol intake, while avoiding problematic effects, such as alterations in food or water intake. Data from preliminary clinical studies have shown trends toward combination therapy reducing alcohol intake in humans. While such findings are encouraging, they must be explored further in larger, randomized, double-blind trials.