Current Progress in Pharmacologic Treatment Strategies for Alcohol Dependence

Peter Clapp

Disclosures

Expert Rev Clin Pharmacol. 2012;5(4):427-435. 

In This Article

Acamprosate

Pharmacology

Approved by the FDA in 2004 for the use in alcohol-dependent individuals, the effectiveness of acamprosate was first demonstrated in Europe. Acamprosate is available for oral administration in a delayed-release oral formula under the brand Campral. Acamprosate is the calcium salt of N-acetyl homotaurine, which bears many structural similarities to the amino acids glutamate, GABA, glycine and taurine, all of which have activity in the CNS as neurotransmitters or neuromodulators.[40]

There is no consensus on the primary mechanism of action of acamprosate, but alternative models suggest that acamprosate may antagonize the NMDA glutamate receptor,[41] modulate neurotransmission through Type 5 metabotropic glutamate receptors (mGluR5)[42] and reduce accumulation of glutamate during repeated episodes of alcohol withdrawal.[43] Acamprosate has been proposed to normalize the balance between excitatory and inhibitory pathways that become adapted to chronic alcohol use and alleviate psychological and physiological discomfort that follows withdrawal.[44] During chronic alcohol consumption, neuroadaptation occurs via increased synaptic expression or trafficking of excitatory NMDA receptors.[1] Abrupt removal of alcohol leaves the NMDA-receptor system unopposed in a state of hyperactivity. Acamprosate appears to act at the regulatory sites on both ionotropic and metabotropic glutamate receptors and normalize this hyperexcitability to re-establish homeostasis. Although recent in vitro findings suggest that within the therapeutic dose range acamprosate has no effects on metabotropic glutamate receptors, earlier studies had demonstrated an effect of chronic acamprosate on the abundance of NMDA receptors.[45]

Acamprosate has a favorable safety and tolerability profile, with patients in all clinical trials reporting minimal side effects after prolonged use of the drug. It has no abuse potential, and the only acute side effect noted is diarrhea.[46] Studies have also shown acamprosate to be a cost-effective treatment.[47]

Evidence-based Findings

The efficacy of acamprosate in reducing alcohol use in alcohol-dependent patients was first established through multiple randomized, controlled trials in Europe. Three trials conducted in the mid-1990s concluded that acamprosate shows efficacy in preventing relapse and maintaining abstinence in recently detoxified patients with alcohol dependence. Initial findings from US multisite studies, such as the COMBINE trial, differed significantly from the European trials, showing no benefit for acamprosate when compared with placebo in reducing alcohol use in treatment-seeking alcoholic patients.[29] It is possible that the high percentage of abstinent days across all groups in the COMBINE trial masked any benefit of acamprosate to promote abstinence above the combined behavioral intervention and/or medical management provided to all patients. In contrast, another large US trial did suggest therapeutic benefit for acamprosate in a subgroup of individuals with a goal of abstinence.[48] Meta-analyses and reviews examining data from former clinical trials have since found significant improvements in abstinence rates, percentage days abstinent and time to first drink with acamprosate treatment.[49,50] The reason for the discrepancies between the COMBINE and the European trials may be related to differences in the percentage of heavy drinkers in the studies (i.e., phenotypic subtype differences), higher levels of psychosocial intervention provided in the US trials and the period of abstinence achieved on initiating acamprosate therapy. Acamprosate is suggested to provide the most therapeutic benefit in individuals who remain abstinent from alcohol ingestion during initiation of the drug. However, the drug was recently associated with poorer response compared with placebo for consistent daily drinkers who had longer durations of pretreatment abstinence, based on a secondary analysis of COMBINE trial data.[51]

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