Drugs for Relapse Prevention of Alcoholism (Milestones in Drug Therapy)

Editors: Spanagel, Rainer; Mann, Karl F.

Title: Drugs for Relapse Prevention of Alcoholism, 1st Edition

Copyright 2005 Springer

> Table of Contents > Acamprosate: clinical data

Acamprosate: clinical data

Karl F. Mann

Department of Addictive Behavior and Addiction Medicine, University of Heidelberg, Central Institute of Mental Health, J 5, 68159 Mannheim, Germany

Development and first testing

Around 1982 French pharmaceutical companies started to synthesize amino acid neuromediators. In a close collaboration with several universities a number of taurine and homotaurine compounds were investigated. The regular screening procedures provided evidence that one molecule in particular, calcium acetylhomotaurinate, provided some interesting pharmacological properties. Acamprosate was consequently tested in an animal model of alcohol relapse at the University of Rouen. Administration of acamprosate to alcohol-preferring rats reduced their alcohol consumption significantly compared to a group of control rats. The results of this study were presented at the second International Society for Biomedical Research on Alcoholism (ISBRA) Conference in Santa Fe [1]. Acamprosate was further tested in another animal model of alcoholism where it again revealed a significant dose-dependent reduction of voluntary alcohol consumption (Le Magnen et al. [2]).

The first clinical studies in patients with alcohol problems were also carried out in the early 1980s in France. The positive results in men were published in the Lancet [3]. A larger multi-center double-blind placebo-controlled study in 569 detoxified alcohol-dependent patients over a three month treatment period also showed a significant benefit of acamprosate over placebo [4]. Upon these results the French health authorities registered acamprosate in 1989. Marketing in France started under the brand name Aotal . At the same time the health authorities asked for additional assessments especially on the long-term efficacy of the molecule. At this stage the developing company was joined by Groupe LIPHA (today an affiliate of Merck KgA) for the further development of the compound. A clinical program was launched in different research centers throughout Europe. More than 4000 alcohol-dependent patients have been treated meanwhile in studies of 3, 6 or 12 months duration [5, 6]. Today the compound is registered in about fourty different countries worldwide and more than 50 million patients have been treated. In August 2004 the FDA approved acamprosate for use in the USA, twenty years after the first report in Santa Fe.

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Pharmacology of acamprosate

Acamprosate (calcium acetylhomotaurinate; Campral , Merck-Sant , Lyon, France) has a molecular structure similar to that of several endogenous amino acids. Its mechanism of action as an anti-dipsotropic agent is not entirely clear, although its main interactions appear to be with the glutamatergic system [7, 8, 9 and 10]. It modulates the NMDA receptor function [11, 12]. There is further evidence of an additional binding site on the metabotropic mGluR5 receptor [13]; this receptor has been implicated in addictive processes, modulates glutamatergic neurotransmission and interacts with the NMDA receptor. It is likely that these effects of acamprosate on the polyamine binding sites and mGluR5 receptors attenuate glutamatergic hyperexcitability [14, 15]. For details of the preclinical studies see the adjacent chapter by Spanagel in this book.

Randomized controlled studies in patients

The effects of a therapy on total abstinence from or a reduction in alcohol consumption are the major determinants of efficacy in alcohol-dependent individuals (Fig. 1). There are a number of ways in which this can be measured (see Kranzler, this book), and several have been used in the published acamprosate trials [6]. Continuous abstinence, defined as abstinence from randomization to

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In most of the acamprosate clinical trials, Cumulative Abstinence Duration (CAD), which provides an estimate of the proportion of abstinent days over the total length of the trial, has been used as the main efficacy endpoint (Fig. 2). This measure encompasses all patients at all time points during study participation and allows for minor lapses in abstinence without categorical assessment as a treatment failure. However, CAD is a difficult measure to compare between trials, because of lack of standardization in the methods used to collect information on daily alcohol consumption and the methods used to calculate the CAD proportion.

This drug has been evaluated in over 3000 patients in eighteen placebo-controlled clinical trials in Europe and one in South Korea. A further study has been performed in the United States of America, whose results have not yet

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These studies have produced consistent results showing acamprosate treatment to be superior to placebo in maintaining abstinence. In all but three published controlled clinical studies, the proportion of treated patients abstaining at the end of the study was roughly twice as high as for patients receiving placebo. Treatment periods of up to a year were studied. In addition, two studies [16, 17] evaluated long-term abstinence one year after the end of the treatment period and shown the treatment effects to be maintained. Two of the negative studies [18, 19] were small, and could have been underpowered; one also used a two-month treatment period, [19] which was lower than that of all the other studies. The absence of effect in the other negative study by Chick et al. [20], which was the largest of all published trials with acamprosate, may be attributable to the latency in initiating treatment. The study drug was introduced

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An evidence-based medicine approach has also been brought to bear on the efficacy data for acamprosate. In the systematic review of Garbutt, which analysed all data available up to 1997 [23], it was concluded that the proof of efficacy for acamprosate was strong, with the most consistent finding being a decrease in drinking frequency, with several studies reporting abstinence rates to be doubled. A literature-based meta-analysis, comparing eleven randomised clinical trials has also concluded that acamprosate is efficacious in reducing alcohol consumption [24]. In a more recent meta-analysis, in which the original clinical trial data from seventeen trials were re-analysed, Mann et al. [6] also concluded that acamprosate was effective, and suggested that the treatment effect could increase with time (see also below).

Five (four earlier and one recent) meta-analyses on the efficacy of acamprosate in the treatment of alcohol dependence have been undertaken, all of which have concluded that acamprosate is effective in maintaining abstinence in detoxified alcohol-dependent individuals [24, 25, 26, 27 and 28]. However, the first four meta-analyses were limited in their conclusions, as they were based almost exclusively on literature reports.

The aim of the most recent meta-analysis [6] was to undertake a more extensive analysis of the relative benefit of acamprosate in alcohol-dependent individuals using the studies published to date, supplemented, where possible, by data obtained from the manufacturer's in-house reports.

The relative benefit (relative risk) was 1.47% with continuous abstinence rates at 6 months of 36.1% acamprosate and 23.4% placebo. The numbers needed to treat (NNT) for one successful outcome calculated for all 17 studies at 6 months were 7.78 and at 12 months 7.5 (see Fig. 4).

Cost-effectiveness

Data on the cost-effectiveness on different treatment approaches in the alcohol research field are still extremely scarce. First attempts for an economic evaluation of acamprosate treatment compared with placebo showed favourable results for acamprosate [29]. The authors based their analyses primarily on the Austrian double-blind RCT [17]. They came up with net cost saving of 528 /patient in the 24-month treatment and aftercare period. This would mean a global anticipated net saving of 1.74 million over two years for the Belgian health insurance system. With reference to the total costs of alcoholism these estimations may represent a significant potential for cost savings [30].

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Combining acamprosate and other medications

The effects of acamprosate and naltrexone appear to relate to different aspects of drinking behaviour, with the former stabilising abstinence and the latter decreasing alcohol consumption [5]. There are little direct comparative data on the relative benefits of the two treatments. A recent head-to-head study performed in Spain by Rubio et al. [31] suggested that naltrexone was more efficacious in preventing relapse to heavy drinking. However, the conclusions from this trial should be treated with caution, since the study was not blinded and there was imbalance in the drop-out rate. In another study performed in Germany, which did not have these methodological limitations, a combination of naltrexone and acamprosate was compared to each drug alone and to placebo [32]. Both naltrexone and acamprosate alone increased the time to first drink and the time to first relapse into heavy drinking compared to placebo, and there was no significant difference observed between the effects of the two drugs. The combination of both drugs was about 4 more effective than placebo. A larger comparative study addressing this issue involving more than 1300 patients, The COMBINE Research Group [33], is currently underway in the United States of America. A small (28 patients) short-duration (one month) study in Italy [34] compared acamprosate with fluoxetine and found both agents to reduce alcohol consumption, although the small number of

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Acamprosate and psychotherapy

Although the concomitant use of psychotherapy was not standardised in the early studies of acamprosate, the fact that efficacy was indeed demonstrated suggests that efficacy is manifest irrespective of the psychotherapy regime used. This idea is also supported by a recent open-label study of acamprosate which found that abstinence duration was essentially similar across five different forms of psycho-social support [36], although it should be pointed out that allocation to psychotherapy groups was not randomised. However, a similar result was obtained in another randomized study comparing cognitive behavioural therapy versus minimal motivational support [37]. The authors found no additional effect of behavioural therapy over minimal support. So the question remains open of how much and what kind of additional psychotherapy should be offered. The issue is also being addressed in the ongoing COMBINE study [33].

Feeney et al. [38] conducted an interesting study where an established treatment program with Cognitive Behavioural Treatment (CBT) for alcoholics in Australia was compared with the same program and additional administration of acamprosate. Whereas program attendance in both groups was similar, relapse rates occurred significantly sooner and more frequently in the CBT group alone. Alcohol abstinence after 12 weeks was 38% (CBT + acamprosate) compared with 14% (CBT alone)

Conclusions and perspectives

Acamprosate is the most widely validated treatment medication for alcohol-dependent patients. Nevertheless, several questions remain unanswered. (i) The combination issue with naltrexone and other psychotropic medications deserves further attention and study. (ii) Despite the significant benefit, the effect sizes are only in the modest to moderate range. This means that there is certainly room for improvement. One attempt could be to identify potential acamprosate responders a priori. Such a study is currently being undertaken in PROJECT PREDICT [39]. Based on the assessment of biological variables, including neuroimaging and neuro-physiological measures as well as questionnaires, the prediction of acamprosate or a naltrexone responder is made. Consequently all 432 patients are randomized to acamprosate, naltrexone or placebo. This study is closely linked to preclinical research, where predictors for treatment response to several drugs are tested [40].

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