Is There Evidence for Effectiveness of Acamprosate in Maintaining Abstinence in Alcohol Dependent Patients?

Introduction

Ninety percent of all United States (US) residents have had an alcoholic drink at least once in their lifetime.¹ About 51 percent of US adult population are current users of alcohol. Alcohol-related disorders constitute the third largest health problem in US. It is estimated that around 200,000 deaths each year could be attributed to alcohol-related disorders.¹ Around 30 to 45 percent of adults in US have had an alcohol-related health problem during their lifetime. Around 20 percent of men and 10 percent of the women have met the diagnostic criteria of alcohol abuse in their lifetime and 3 to 5 percent of the women and 10 precent of the men have met the diagnostic criteria for alcohol dependence. Alcohol has been estimated to cost US economy $185 million in lost productivity, healthcare costs, and damages due to alcohol-related accidents.²

The treatment of alcohol can be divided into multiple stages: intervention, withdrawal, detoxification, rehabilitation, and interventions to maintain long-term abstinence.² The interventions to maintain abstinence can be further subdivided into psychosocial and pharmacological methods. Multiple medications have been used in the past to help patients maintain abstinence like disulfiram, naltrexone, and serotonin reuptake inhibitors. Acamprosate had been available in Europe for many years but has only recently been approved by the Food and Drug Administration (FDA) for use in US (Campral^®, Merck).

Mechanism of Action of Acamprosate

Acamprosate is a drug that promotes abstinence, but the mechanism of action of acamprosate still remains obscure. Various hypotheses have been proposed. Acamprosate has a chemical structure similar to endogenous amino acid homotaurine, which is the structural analogue of γ-amino butyric acid and the amino acid neuromodulator taurine. Chronic alcohol use has been hypothesized to lead to alterations in the normal balance between neuronal excitation and inhibition. Acamprosate is thought to interact with glutamate and GABA neurotransmitter systems in the central nervous system and restore this balance.⁴ Following chronic exposure to alcohol, there is an up regulation of the glutamatergic system in the central nervous system (CNS). This leads to excess glutamatergic activity on sudden withdrawal of alcohol. These changes persist for months after stopping intake of alcohol. Acamprosate attenuates this surge in glutamic acid release.⁵ Glutamatergic neurotransmission has been postulated to be involved in the acquisition of cue-related drinking behaviors and hence can be modulated by acamprosate.

Evidence for Effectiveness

Paille, et al.,⁶ in a 12-month, prospective, placebo-controlled, randomized, double-blind trial, studied the efficacy of acamprosate at two dose levels in maintaining abstinence in alcohol-dependent patients. Five-hundred and thirty-eight patients took part in this study. After detoxification, the patients included were randomly assigned to one of three groups: 177 patients received placebo, 188 received acamprosate at 1.3g/day (low dose group), and 173 received 2.0g/day (high-dose group) for 12 months. Craving was not substantially reduced by acamprosate. The study showed a dose-dependent relationship, with the higher dosage of acamprosate showing a better response than the lower dosage. The patients showed good tolerance to acamprosate with only diarrhea being reported more frequently.

Sass, et al.,⁷ studied the effectiveness of acamprosate in a randomized, double-blind, placebo-controlled study. After detoxification, 272 patients received routine counseling and either acamprosate or placebo for 48 weeks. They were followed for another 48 weeks without medications. It was shown that patients who were receiving acamprosate showed a significantly higher abstinence rate and also had significantly higher mean abstinence duration of 224 days vs. 163 days for placebo-treated patients. Acamprosate was shown to be a very safe medication with minimal side effects.

Pelc, et al.,⁸ compared the efficacy of acamprosate in maintaining abstinence in recently detoxified alcoholic patients in a double-blind study. The double-blind trial was conducted using two dosages of acamprosate (1,332mg/day and 1,998mg/day). Acamprosate was shown to be significantly superior to placebo. Better effect was seen with higher dosage. Acamprosate was shown to be safe in recently detoxified alcoholic patients.

Palmer, et al.,⁹ performed a computer-aided study looking at the long-term cost effectiveness of improving abstinence from alcohol using adjuvant acamprosate. Despite the high acquisition costs, the authors concluded that adjuvant acamprosate therapy was both clinically and economically attractive.

Rychlik, et al.,¹⁰ performed an open, prospective, cohort study to evaluate the costs of treating alcohol dependence under real-world conditions. Eight-hundred and fourteen recently detoxified alcohol-dependent patients were provided with psychosocial rehabilitation support. In addition, 540 alcohol-dependent patients treated with adjuvant acamprosate therapy were compared with 274 patients without pharmacotherapy. Real costs were assessed over a period of one year. Of the patients who were treated with acamprosate, 33.6 percent remained abstinent compared to 21.1 percent in the standard cohort. The mean total costs per patient treated with acamprosate were EUR 1,631.49 per year, whereas that in the standard cohort, total costs were EUR 2,068.83, and the difference was shown to be highly significant (p=0.012).

Mann, et al.,¹¹ did a comprehensive meta-analysis of randomized, placebo-controlled studies assessing the efficacy of acamprosate in the maintenance of abstinence in alcohol-dependent subjects. They studied the evidence from 17 trials including 4087 patients from 13 countries. The primary endpoint was continuous abstinence rate at six months. Thirty-six percent of the patients receiving acamprosate and 23.4 percent of patients receiving placebo were abstinent at six months (p<0.001). Statistically significant differences in rates were noted at three months and 12 months also.

Pelc, et al.,¹² in a 26-week study, evaluated the benefits of a follow-up by a community nurse when treating alcohol dependence with acamprosate. The cumulative abstinence duration was significantly longer in subjects, who received community nurse support.

Basu, et al.,¹³ in a 2005 study compared the efficacy of Acamprosate and naltrexone to that of placebo in maintaining abstinence from alcohol. Seventy-seven of the patients taking Acamprosate remained abstinent compared to that of 36 percent of patients taking naltrexone and 50 percent of the patients taking placebo. Follow-up studies showed that patients on acamprosate had better functioning in several areas.

De Sousa, et al.,¹⁴ in an open-label, eight-month study conducted in western India, compared the efficacy of acamprosate and disulfiram in maintaining abstinence from alcohol. Eight-eight percent of the patients on disulfiram remained abstinent compared to 46 percent of patients on acamprosate. This study concluded that disulfiram is superior to acamprosate for preventing relapse in alcohol-dependent men with good family support.

Poldrugo, et al.,¹⁵ did a critical review of pharmacoeconomics studies of acamprosate and concluded that acamprosate enhances abstinence rate, reduces the costs of treatment, and was found to be better than other rehabilitation strategies not involving pharmacotherapy.

Conclusion

Acamprosate has only recently been introduced in US, but it has been in use in Europe and other parts of the world for many years. Acamprosate has proved to be a safe and cost-effective treatment modality in the treatment of alcohol dependence. Studies in Europe and Asia have shown that it is more effective in alcohol-dependent patients with good family support and in those patients who are followed in the community by health professionals.