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Aims: The prevalence of insomnia ranges from 36% to 91% in alcohol-dependent patients and may persist after alcohol withdrawal. Acamprosate has been shown to decrease insomnia in abstinent patients. Based on a large clinical trial database, the aim of the present study is to assess the efficacy of acamprosate in reducing insomnia, and if indeed it does reduce insomnia, to better understand its action mechanism., Short Summary: The aim of the study is to confirm the efficacy of acamprosate to reduce insomnia using an individual patient data meta-analysis. Twelve studies were found including 3508 patients. After a 6-month follow-up, the mean insomnia decrease over baseline was -26% and -45% for the placebo and acamprosate groups, respectively (P < 0.001)., Methods: An individual patient data meta-analysis selected all the randomized trials of acamprosate in which insomnia was documented. Our main endpoint was insomnia change after a 6-month follow-up, measured by the validated Short Sleep Index (SSI) derived from the Hamilton Depression and Anxiety Scale. The meta-analysis was conducted using a two-level multilevel (patient/trial) mixed model with random treatment effect, random study effect and adjusting for baseline severity covariates., Results: Twelve studies were found including 3508 patients, 59.8% of whom were suffering from insomnia (95% CI 58.1-61.4). Psychiatric history, severe addiction, living alone and abnormal gamma-GT levels were found to be the risk factors of insomnia. After 6 months, the mean SSI decrease over baseline was -26% and -45% for placebo and acamprosate, respectively (treatment effect = 19%, 12.5-25.5; P < 0.001). By using a univariate mediation model, we found that the mediating effect of abstinence on insomnia accounted for 55.7% of the overall effect of acamprosate on insomnia reduction., Conclusions: Insomnia is prevalent among alcohol-dependent patients. It decreases spontaneously with abstinence but more frequently with acamprosate treatment.

Background: It is unknown whether women derive comparable benefits and have a similar safety and tolerability profile as men from acamprosate, a widely prescribed drug for the maintenance of abstinence in alcohol dependence. The objective of this study was to assess sex-specific differences in the efficacy, safety, and tolerability of acamprosate in the treatment of women and men with alcohol dependence., Methods: A sex-specific meta-analysis was conducted based on individual patient data (IPD). Data were obtained from double-blind, randomized controlled trials with quantitative drinking measures in patients with alcohol dependence receiving oral acamprosate or placebo. Sources included PubMed, PsychInfo, and Cochrane electronic databases; reference lists from retrieved articles and presentations at professional meetings; and direct access to authors and companies who provided IPD., Results: Individual records were obtained from 1,317 women and 4,794 men who participated in 22 eligible studies conducted in 18 countries. IPD meta-analyses found a significant beneficial effect of acamprosate relative to placebo across all 4 efficacy end points: an incremental gain of 10.4% (95% CI 7.1 to 13.7, p < 0.001) in percentage of abstinent days, an incremental gain of 11.0% (7.4 to 14.6, p < 0.001) in percentage of no heavy drinking days, an odds ratio of 1.9 (1.6 to 2.2, p < 0.001) for rate of complete abstinence, and an odds ratio of 1.9 (1.6 to 2.3, p < 0.001) for rate of no heavy drinking, over the study duration. Acamprosate was also associated with significantly higher rates of treatment completion (p = 0.004) and medication compliance (p < 0.001) than placebo. Men and women did not differ on any measure of acamprosate efficacy, safety, or tolerability., Conclusions: This sex-specific IPD meta-analysis provides evidence that acamprosate has a significant effect compared with placebo in improving rates of abstinence and no heavy drinking in both women and men with alcohol dependence. Further, acamprosate was associated with significantly higher rates of treatment completion and medication compliance than placebo among both women and men and had a comparable safety and tolerability profile., (Copyright © 2011 by the Research Society on Alcoholism.)

Aims: Sleep disturbance symptom (SDS) is commonly reported in alcoholic patients. Polysomnography studies suggested that acamprosate decreased SDS. We assessed this hypothesis by using data of a randomized controlled trial. As a secondary objective, we suggested and tested the validity of a simple measurement of SDS based on the Hamilton depression and anxiety inventory subset., Methods: We re-analysed a multi-center study evaluating the efficacy of acamprosate compared with placebos on alcohol-dependent patients in concentrating on SDS change in time. The Sleep sum score index (SAEI) was built from check-lists on adverse effects reported at each visit and constituted our main endpoint. We also tested the validity of the short sleep index (SSI) defined by the four sleep items of the Hamilton depression and anxiety scales. Statistical analyses were conducted on an intention to treat basis., Results: A total of 592 patients were included, and 292 completed the 6-month trial. Compared with SAEI considered as our reference, the observed specificity and sensitivity of SSI were 91.6 and 87.6%. From 40.2% of patients experiencing SDS at baseline, this proportion decreased until 26.1% at M6 in the placebo group and 19.5% in the acamprosate group (relative risk placebo/acamprosate = 1.49, 95% confidence interval 1.10, 1.98, P = 0.04)., Conclusion: Treating alcoholic patients to enhance abstinence has a beneficial effect in reducing SDS, and the duration of abstinence during the treatment constitutes the main positive factor. An additional effect of acamprosate is conjectured from its effect on the glutamatergic tone. The SSI constitutes a simple, reasonably sensitive and specific instrument tool to measure SDS.

Aims: To examine the predictors and correlates of depression in alcoholic patients following detoxification and during outpatient treatment, and the role of acamprosate., Method: The international research program of acamprosate has involved 6500 patients in randomized, placebo-controlled trials. Extensive baseline and follow-up data were documented for each patient. An individual patient data meta-analysis was conducted on a partial database., Results: From 3354 patients in 11 studies (10 countries), we found 1120 (33.4% confidence intervals: 31.8-35.0) depressed patients (DPs). Among alcohol patients, the profile of DPs can be defined by five predictors: being female, younger, unemployed and living alone and being an episodic drinker. Compared with non-depressed patients (NDPs), their motivation to start a treatment and the compliance to treatment were lower. DPs performed less than NDPs in achieving abstinence. The acamprosate effect in increasing abstinence was similar for both DPs and NDPs patients. Abstinence during the trial was the key factor of depression remission: DPs were 7.58 times more likely to become NDPs if they were continuously abstinent., Conclusion: Our results justify the need to systematically identify depression among alcohol-dependent patients, but to treat the alcohol dependence as a first step, because enhancing abstinence will often involve remission of the depressive disorder.

Background: The aim of this study is to assess the influence of early and late compliance of acamprosate on attendance and abstinence duration in the treatment of alcohol dependence., Methods: Individual patient data of 2,305 patients from 11 randomized controlled trials comparing acamprosate (n = 1,128) with placebo (n = 1,177) were used to predict early and late compliance and to study the effect of early and late compliance on attendance and abstinence duration using regression analysis and structural equation modeling., Results: Early compliance was predicted by baseline motivation to become fully abstinent and baseline abstinence (R(2) = .26); late compliance was predicted by early compliance (R(2) = .13); treatment discontinuation was predicted by young age, marital status, compliance, and treatment condition (R(2) = .26); and abstinence duration was predicted by motivation to become fully abstinent early compliance and the interaction of early compliance and treatment condition (R(2) = .27). Structural equation modeling showed that abstinence duration was significantly associated with motivation at baseline, late compliance, and treatment condition (Goodness of Fit Index [GFI] chi(2)/df = 1.56; Parsimonious Goodness of Fit Index [PGFI] = 0.69)., Conclusions: Motivation to become fully abstinent and abstinence at the start of treatment are important for early compliance. Early compliance in turn predicts late compliance. Late compliance, in combination with motivation to become fully abstinent, and treatment condition (acamprosate vs. placebo) predict duration of abstinence. This suggests that motivational interventions directed toward full abstinence motivation and abstinence at the start of treatment are crucial for both compliance with acamprosate and successful treatment outcome., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Background: Alcohol dependence is among the main leading health risk factors in most developed and developing countries. Therapeutic success of psychosocial programs for relapse prevention is moderate, but could potentially be increased by an adjuvant treatment with the glutamate antagonist acamprosate., Objectives: To determine the effectiveness and tolerability of acamprosate in comparison to placebo and other pharmacological agents., Search Strategy: We searched the Cochrane Drugs and Alcohol Group (CDAG) Specialized Register, PubMed, EMBASE and CINAHL in January 2009 and inquired manufacturers and researchers for unpublished trials., Selection Criteria: All double-blind randomised controlled trials (RCTs) which compare the effects of acamprosate with placebo or active control on drinking-related outcomes., Data Collection and Analysis: Two authors independently extracted data. Trial quality was assessed by one author and cross-checked by a second author. Individual patient data (IPD) meta-analyses were used to verify the primary effectiveness outcomes., Main Results: 24 RCTs with 6915 participants fulfilled the criteria of inclusion and were included in the review. Compared to placebo, acamprosate was shown to significantly reduce the risk of any drinking RR 0.86 (95% CI 0.81 to 0.91); NNT 9.09 (95% CI 6.66 to 14.28) and to significantly increase the cumulative abstinence duration MD 10.94 (95% CI 5.08 to 16.81), while secondary outcomes (gamma-glutamyltransferase, heavy drinking) did not reach statistical significance. Diarrhea was the only side effect that was more frequently reported under acamprosate than placebo RD 0.11 (95% 0.09 to 0.13); NNTB 9.09 (95% CI 7.69 to 11.11). Effects of industry-sponsored trials RR 0.88 (95% 0.80 to 0.97) did not significantly differ from those of non-profit funded trials RR 0.88 (95% CI 0.81 to 0.96). In addition, the linear regression test did not indicate a significant risk of publication bias (p = 0.861)., Authors' Conclusions: Acamprosate appears to be an effective and safe treatment strategy for supporting continuous abstinence after detoxification in alcohol dependent patients. Even though the sizes of treatment effects appear to be rather moderate in their magnitude, they should be valued against the background of the relapsing nature of alcoholism and the limited therapeutic options currently available for its treatment.

This secondary analysis of the first U.S. acamprosate trial (N = 601) for alcohol dependence examines the effects of subsyndromal psychiatric symptoms or history of severe psychopathology on alcoholism treatment outcomes and any mitigating effects of acamprosate. Psychiatric antecedents were documented using a protocol-specific interview. Current psychiatric symptoms were assessed using Hamilton Anxiety and Depression (HAM-A, HAM-D) rating scales. Predictors of good response, defined as abstinence for > or =90% of trial duration, were identified using logistic regression. Subsyndromal anxiety (as determined by HAM-A "Anxious Mood" item) and the presence of > or =1 psychiatric antecedent were significant negative predictors of good response. Lower pretreatment drinking intensity, baseline motivation to have abstinence as a goal, and treatment with acamprosate were significant positive predictors of good response. No significant interactions among predictors were detected, indicating that they are independent, additive factors. Thus, the beneficial effects of acamprosate treatment in combination with motivational therapy may offset the liabilities for alcoholism recovery that are associated with current anxiety symptoms and/or a significant past psychiatric history. (Am J Addict 2010;00:1-8).

Two pharmacological agents have repeatedly been shown to be efficacious for relapse prevention in alcohol dependence: The putative glutamate-antagonist acamprosate and the opioid-antagonist naltrexone. Clinical evidence for both drugs is based on various outcome criteria. Whereas for acamprosate primarily abstinence maintenance has been demonstrated, studies with naltrexone have mostly emphasised the prevention of heavy drinking. The remaining effects of both drugs are not always reported; accordingly the corresponding database is fragmentary. Thus, the primary objective of the present meta-analysis was to complete the efficacy profiles for acamprosate and naltrexone and to compare them with each other. Unreported results, requested from the study investigators and the drug manufacturers, were integrated in the computation of effect sizes. For the meta-analysis, emphasis was placed on the conceptual distinction between having a first drink and returning to heavy drinking. Naltrexone was found to have a significant effect on the maintenance of abstinence as well as the prevention of heavy drinking. Acamprosate was shown only to support abstinence; it did not influence alcohol consumption after the first drink. When the efficacy profiles of the two drugs were compared, acamprosate was found to be more effective in preventing a lapse, whereas naltrexone was better in preventing a lapse from becoming a relapse. The superiority of either one drug or over the other one cannot be determined as a general rule, it rather depends on the therapeutic target. Benefits in the treatment of alcohol dependence might be optimized by matching the efficacy profiles of specific antidipsotropics with the motivational status of alcohol-dependent patients.

This is the first US study to evaluate the clinical efficacy of acamprosate (Campral), a newly FDA-approved medication for maintaining abstinence in patients with alcohol dependence following alcohol withdrawal. We compared effects of the standard 2 g dose (n=258) and an exploratory 3 g dose of acamprosate (n=83) versus placebo (n=260), and evaluated drug safety in a double-blind, placebo-controlled 6-month trial conducted in 21 outpatient clinics across the US. Participants were 601 volunteers with current alcohol dependence recruited primarily by advertisement. All patients concomitantly received eight sessions of brief manual-guided counseling (www.alcoholfree.info). The main outcome measure was the percentage of alcohol-free days over the 6-month study. Self-report was validated by breath alcohol concentration, gamma-glutamyltransferase (GGT) and collateral informant interviews. The percentage of abstinent days did not differ significantly across groups in a priori analysis (54.3% for placebo, 56.1% for 2 g, 60.7% for 3 g). Post-hoc analysis controlling for baseline variables and treatment exposure found acamprosate was associated with a significantly higher percentage of abstinent days than placebo (52.3% for placebo, 58.2% for 2 g, 62.7% for 3 g; P=0.01), with an even greater effect in the subgroup of 241 patients having a baseline goal of abstinence (58.1% for placebo, 70.0% for 2 g, 72.5% for 3 g; P=0.02). There were no deaths or serious drug-related adverse events. The US study findings suggest that acamprosate is safe and well tolerated in a broadly inclusive sample of alcoholics and appears effective in populations of patients motivated to have a treatment goal of abstinence.

Rationale: Acamprosate is a proven effective intervention in the treatment of alcohol dependence. However, acamprosate prevents lapses or relapses only in a minority of patients. An important question, therefore, is whether there is a specific subgroup of patients who respond particularly well to acamprosate., Objectives: To identify predictors of acamprosate efficacy. Based upon the available evidence and hypotheses about the mechanisms underlying acamprosate's effects on drinking behavior, the following variables were considered to be potential positive predictors: high physiological dependence at baseline, negative family history of alcoholism, late age-of-onset, serious anxiety symptomatology at baseline, severe craving at baseline, and female gender., Method: Potential predictors of acamprosate's efficacy were analyzed in a pooled analysis of data from seven randomized placebo-controlled trials involving a total of 1485 patients with alcohol dependence. Outcome is measured in terms of cumulative abstinence duration (CAD), continuous abstinence (ABST), and time to first relapse (TFR)., Results: CAD and ABST were predicted by baseline measures of craving and anxiety, as well as by study and treatment condition. Acamprosate efficacy was not differentially associated with any of the predictor variables. Importantly, the hypotheses were rejected despite the large sample size and sufficient statistical power., Comment: The most straight-forward clinical implication of this study is that acamprosate can be considered as a potentially effective pharmacotherapy for all patients with alcohol dependence. The effect size of acamprosate alone is, however, moderate. Some evidence indicates that the combination of acamprosate with naltrexone or disulfiram leads to substantially better outcomes.

Aims: To assess the effectiveness of pharmacotherapy with acamprosate in alcohol-dependent patients treated in a naturalistic setting in primary care in France., Methods: The ARES (Acamprosate et Repercussions Economiques et Sociales; Acamprosate and Economic and Social Repercussions) study was performed by 149 general practitioners interested in treating alcohol use disorders in France who included patients fulfilling DSM-IV criteria for alcohol dependence. The only exclusion criteria concerned contra-indications to acamprosate, co-medication with naltrexone and multiple substance abuse. Eligible patients were randomized to one of two treatment arms, either standard care alone or standard care with acamprosate, using an open-label design and followed up quarterly for a period of 1 year. The primary outcome variable was the change from baseline on the Alcohol-Related Problems Questionnaire. Secondary efficacy variables were abstinence, Clinical Global Impression, quality of life measured with the SF-36 and incidence of adverse events. An intent-to-treat population was used for outcome analysis., Results: 422 patients were included, of whom 348 (82%) completed the protocol as planned. At the end of the study, patients randomized to the acamprosate group had significantly better outcomes in terms of total ARPQ score, change from baseline (-2.61 vs -3.44) and number of subjects with no alcohol-related problem. On average, patients treated with acamprosate had one less alcohol-related problem than did the controls. The number needed to treat in order to save one additional patient from alcohol-related problems compared to standard care was 7.14. Statistically significant differences in favour of the acamprosate group were observed for all secondary efficacy outcome measures including quality of life., Conclusions: Adjunctive therapy with acamprosate in primary care is associated with significantly better functional outcome. Pragmatic trials in alcohol dependence are both feasible and informative.

The study aimed to discover whether acamprosate reduces the severity of relapse for those patients undergoing abstinence-orientated treatment who are unable to abstain completely. Data on patients' alcohol consumption from 15 placebo-controlled treatment studies (n = 3309) were examined to test whether, at a given time point, patients who have taken one or more drinks since the last assessment ('relapsers', n = 1010) take alcohol on fewer days, report lower average number of drinks per day, and consume less alcohol in total with acamprosate compared to placebo. These studies had varying duration (90 days, 180 days and 360 days). There were four dates that were common to some studies (days 30, 90, 180 and 360). Among relapsers, acamprosate was significantly associated with less quantity (Q) and frequency (F) of drinking compared to placebo in each of the four follow-up periods (p < 0.001). The differences were most marked for the product Q x F (overall weekly consumption). For each period, there were fewer who were drinking an average of five or more drinks per day in the acamprosate compared to the placebo groups. Acamprosate helps reduce the severity of relapse in patients undergoing abstinence-orientated treatment.