Acamprosate did not appear to provide any benefit over placebo in reducing dropout or otherwise improving detoxification outcomes in alcohol dependent patients participating in outpatient detoxification. In this trial, dropout during detoxification was relatively rare (15%), and dropouts were evenly distributed between acamprosate and placebo treated patients (16% for acamprosate and 14% for placebo). Acamprosate treatment did not reduce: the duration of detoxification, the amount of benzodiazepines taken during detoxification, alcohol withdrawal symptom severity experienced during detoxification, measured by the CIWA-Ar, or the amount of drinking during detoxification.
Starting acamprosate during detoxification, instead of starting it after patients had successfully completed detoxification and were abstinent for at least 3 days, did not provide any benefit in a subsequent 10-week outpatient alcohol treatment trial. In fact, patients who started acamprosate during detoxification appeared to have worse drinking outcomes compared to those treated with placebo during detoxification. Patients given acamprosate during detoxification reported a significantly higher percent days of heavy drinking and drank significantly more drinks per drinking day during a 10-week outpatient trial that included open-label acamprosate and weekly medication management sessions. Patients who received acamprosate during detoxification took fewer of their prescribed open-label acamprosate pills during the Rehabilitation Phase of treatment compared to patients who had received placebo during detoxification.
The fact that acamprosate did not improve detoxification outcomes, and that patients treated with acamprosate during detoxification appeared to drink more alcohol in the subsequent 10-week outpatient trial were both unexpected results. That is, we had predicted, based on acamprosate’s proposed mechanism of action, that acamprosate could be beneficial during detoxification. Also, in several animal models acamprosate reduced alcohol withdrawal symptom severity. In human laboratory trials, acamprosate ameliorated sleep disturbances associated with alcohol withdrawal and reduced brain hyperexcitability associated with alcohol withdrawal (Boeijinga et al., 2004
; Staner et al., 2006
). At least one previous outpatient trial has shown that acamprosate was more effective than placebo when started from the day of intake (Gual & Lehert, 2001
). However, no previous study has compared the efficacy of acamprosate initiated at the start of detoxification to the efficacy of acamprosate started after patients have successfully completed detoxification and achieved at least five days of abstinence from alcohol.
Evidence from most clinical trials suggests that acamprosate may be more efficacious in patients who have attained abstinence from alcohol prior to initiating treatment. In the three European trials used to obtain US FDA approval of acamprosate, 95% of the subjects were abstinent from alcohol at the start of acamprosate treatment. In contrast, in two large negative trials, one conducted in the United Kingdom and one conducted in the United States, 30% and 51% of the subjects, respectively, had resumed drinking prior to randomization (Kranzler & Gage, 2008
). A large meta-analysis of acamprosate clinical trials, including 4457 subjects, showed that detoxification prior to starting acamprosate was associated with better outcomes (Lipha Pharmaceuticals, 2002
). Why acamprosate appears to be more efficacious after a longer duration of abstinence has not been determined. However, in a rodent model, the activity of acamprosate at the NMDA receptor in vitro has been shown to be dependent on prior exposure of the brain to alcohol (al Qatari, Bouchenafa, & Littleton, 1998
). It may be that the activity of acamprosate at NMDA receptors is different in the presence of very recent alcohol use compared to after patients have been detoxified and free from alcohol for several days.
Why exposure to acamprosate during detoxification phase affected subsequent medication adherence in the rehabilitation phase is not known. It is possible that starting acamprosate during detoxification alters the adverse effect profile of acamprosate leading to poor adherence. If this occurred during the trial, it was not detected by a comparison of the rates of adverse events, which did not differ between the two groups. It is also possible that starting acamprosate during detoxification reduced its beneficial effects and patients simply stopped taking acamprosate because they could detect no benefit from the medication.
This trial has several weaknesses. The number of patients was relatively small and thus the results should be considered preliminary. In addition, patients admitted into this trial had to be suitable for outpatient detoxification and may not have been reflective of the population of alcohol dependent patients in general. The reported alcohol withdrawal symptom severity as measured by the CIWA was relatively low and, based on our results, it is impossible to say if acamprosate would have been more useful in the detoxification of alcohol dependent patients who presented with more severe alcohol withdrawal symptoms. However, a meta-analysis of acamprosate clinical trials involving 1485 patients did not shown that withdrawal symptom severity or alcohol dependence severity at baseline were predictors of acamprosate efficacy (Verheul, Lehert, Geerlings, Koeter & van den Brink, 2005
). In addition, acamprosate detoxified patients in this trial consumed alcohol on average, 80% of the days in the month prior to entry. They consumed an average of 15 standard drinks per drinking day during this time (slightly more than the average of 12.4 drinks per day over the entire 90 day pretrial period). This rate of drinking is comparable to the rate of drinking noted in the three pivotal trials of acamprosate. In those trials, 73% of patients drank more than 10 standard drinks per day. Thus, patients in the current trial were drinking at rates that were comparable to patients included in previous trials in which acamprosate was found to be efficacious.
Although only powered to detect large effects, it is unlikely that this trial failed to detect a significant advantage to starting acamprosate at the beginning of detoxification because of its relatively small sample size. The differences between acamprosate and placebo treated patients noted in the main Detoxification Phase outcome measures were extremely small and, in fact, most (5/7) numerically favored placebo over acamprosate. In the Rehabilitation Phase, drinking outcomes, including percent days heavy drinking and drinks per drinking day were statistically significantly greater among patients who received acamprosate during detoxification.
Despite its weaknesses, the results of this trial suggest that initiating acamprosate at the start of an outpatient detoxification does not improve treatment retention or otherwise improve detoxification treatment outcomes. In addition, initiating acamprosate during outpatient detoxification did not improve outcomes in subsequent rehabilitation treatment and appeared to worsen drinking outcomes, compared to patients who started acamprosate after detoxification was completed, and who had attained, at least, 3 days of abstinence. The data do not support the initiation of treatment with acamprosate during outpatient detoxification.