Acamprosate

Acamprosate (calcium acetyl homotaurinate) is a drug used in conjunction with psychosocial treatment to facilitate abstinence in alcohol-dependent individuals who have recently stopped drinking. Acamprosate has been prescribed in Europe for nearly 20 years. In 2004, it was approved by the U.S. Food and Drug Administration (FDA), becoming the third drug (along with disulfiram and naltrexone) to receive FDA approval for the treatment of alcohol dependence. [Page 3]Developed by Merck, acamprosate is marketed under the brand name Campral (delayed-release tablets) and distributed in the United States by Forest Laboratories, Inc.

Acamprosate is structurally similar to the naturally occurring brain amino acid taurine and the neurotransmitter gamma-aminobutyric acid (GABA). Although its precise mechanism of action is unknown, acamprosate is thought to facilitate abstinence by normalizing alcohol-induced neurotransmitter imbalances in the central nervous system. Specifically, chronic alcohol consumption can lead to compensatory upregulation (overactivity) of the excitatory glutamate system and downregulation (underactivity) of the inhibitory GABA system. If the glutamate system becomes overactive to compensate for the presence of alcohol, the removal of alcohol may result in a surge in glutamate activity. This neurotransmitter imbalance has been proposed to contribute to some of the aversive aspects of withdrawal and may therefore heighten the risk of relapse. Acamprosate, a weak inhibitor of glutamate activity and possible instigator of GABA activity, is thought to limit glutamate hyperactivity during and after withdrawal (specifically, by targeting N-methyl-D-aspartate receptors), thereby helping to normalize the balance between glutamate and GABA systems. This proposed mechanism of action is distinct from that of other drugs used for treating alcohol dependence: Acamprosate does not alter the rewarding effects of alcohol (as does naltrexone), nor does it alter acute pharmacological effects of alcohol (as does disulfiram).

A number of double-blind, placebo-controlled trials support the efficacy of acamprosate for reducing the incidence of relapse in patients with alcohol dependence. Most studies were conducted in Europe and included adults (18–65 years old) meeting criteria listed in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition or Third Edition, Text Revision (DSM-III or DSM-III-TR) for alcohol dependence. Nearly all participants had attained at least several days abstinence prior to study onset. Typically, participants in acamprosate (2 grams per day (g/day) or 1.3 g/day) and placebo conditions also received psychosocial support, with treatment duration ranging from 3 to 12 months. Results from these studies, summarized in several reviews and meta-analyses, suggest a consistent and significant (although modest) effect of acamprosate for increasing continuous abstinence rates (number of days from treatment initiation until the first drinking day) and cumulative abstinence duration (percentage of nondrinking days during the trial period). Despite some variability in findings across studies, acamprosate generally appeared to increase abstinence rates by a factor of 1.5 to 2. The drug proved effective across a range of patient characteristics, and its benefits were often sustained after treatment ended.

In contrast to findings from European studies, initial findings from large-scale trials in the United States have not been supportive. The COMBINE Study, a randomized, multisite trial that included 1,383 individuals diagnosed with alcohol dependence based on criteria listed in the DSM-IV-TR was designed to test the individual and combined effectiveness of acamprosate (3 g/day), naltrexone, and a combined behavioral intervention (CBI). Interventions were delivered during a 16-week outpatient program and participants were assessed for up to 1 year following treatment. Whereas naltrexone and CBI each reduced drinking independently, acamprosate had no effect on primary drinking outcomes and did not enhance the efficacy of naltrexone or CBI. Findings from the COMBINE Study contradicted previous evidence that acamprosate and naltrexone are more effective in combination than alone. However, it has been noted that because these drugs have differing mechanisms of action and are well tolerated together, their combination deserves further consideration. Another randomized, multisite U.S. trial examined acamprosate (2 g/day vs. 3 g/day) versus placebo among 601 participants with DSM-IV-TR criteria-based alcohol dependence. Participants also received psychosocial treatment. No significant benefits of acamprosate were found in primary analyses. However, additional analyses showed that acamprosate increased abstinence for a subset of individuals with high initial motivation for abstinence. Although the reasons for discrepancies between European and U.S. studies are not clear, it was noted that most participants in the European studies had undergone recent inpatient detoxification, whereas this practice is relatively uncommon in the United States. Another difference was that the psychosocial treatments were more highly controlled in U.S. trials compared to European studies.

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