Disulfiram Efficacy in the Treatment of Alcohol Dependence: A Meta-Analysis

<div><p>Background</p><p>Despite its success with compliant or supervised patients, disulfiram has been a controversial medication in the treatment of alcoholism. Often, study designs did not recognize a pivotal factor in disulfiram research, the importance of an open-label design. Our objectives are: (1) to analyze the efficacy and safety of disulfiram in RCTs in supporting abstinence and (2) to compare blind versus open-label studies, hypothesizing that blinded studies would show no difference between disulfiram and control groups because the threat would be evenly spread across all groups.</p><p>Methods and Findings</p><p>We searched PubMed, EMBASE and the Cochrane Central Register for RCTs on disulfiram use with alcoholics in comparison to any alcoholic control group. The primary outcome was defined by the authors of each trial. Additional analyses included: blind vs. open-label, with or without supervision, cocaine study or not, and type of control. </p><p>Overall, the 22 included studies showed a higher success rate of disulfiram compared to controls Hedges'g = .58 (95%CI = .35–.82). When comparing blind and open-label RCTs, only open-label trials showed a significant superiority over controls g = .70 (95%CI = .46–.93). RCTs with blind designs showed no efficacy of disulfiram compared to controls. Disulfiram was also more effective than the control condition when compared to naltrexone g = .77, 95%CI = .52–1.02, to acamprosate g = .76, 95%CI = .04–1.48, and to the no disulfiram groups g = .43, 95%CI = .17–.69. </p><p>Limits include: (1) a population of 89% male subjects and (2) a high but unavoidable heterogeneity of the studies with a substantial I-square in most subgroups of studies.</p><p>Conclusions</p><p>Blinded studies were incapable of distinguishing a difference between treatment groups and thus are incompatible with disulfiram research. Based on results with open-label studies, disulfiram is a safe and efficacious treatment compared to other abstinence supportive pharmacological treatments or to no disulfiram in supervised studies for problems of alcohol abuse or dependence.</p></div

Meta-analysis of adverse events rate ratio comparisons in controls and disulfiram treated patients.

<p>Meta-analysis of adverse events rate ratio comparisons in controls and disulfiram treated patients.</p

Flowchart of selection of studies for inclusion in the meta-analysis.

<p>Flowchart of selection of studies for inclusion in the meta-analysis.</p

Meta-analysis for blinded versus open-label RCTs.

<p>Meta-analysis of Hedges' g effect-size comparing the efficacy of disulfiram and controls in blinded versus open-label RCTs.</p

Methodological Quality of Included Studies.

<p>Methodological Quality of Included Studies.</p

Subgroup analysis of Hedges' g effect-size comparing the efficacy of disulfiram and controls by control types.

<p>Subgroup analysis of Hedges' g effect-size comparing the efficacy of disulfiram and controls by control types.</p

Study Description.

<p>ACA Acamprosate, DIS disulfiram, NTX Naltrexone, TPM Topimirate, GHB <i>g</i>-hydroxybutyrate* SADQ Severity of Alcohol Dependence Questionnaire <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0087366#pone.0087366-Stockwell1" target="_blank">[66]</a>** SDS- Severity of Dependence Scale questionnaire for cocaine and alcohol dependence.</p

Meta-analysis of Hedges' g effect-size of all RCTs comparing the efficacy of disulfiram and controls.

<p>Meta-analysis of Hedges' g effect-size of all RCTs comparing the efficacy of disulfiram and controls.</p

Differences within ordered-category answer patterns for question M (“What is your personal opinion on baclofen’s efficacy, by comparison with approved treatments?”).

<p>Comparisons between the 5 ordered-category answers were made using Fisher exact tests for categorical variables and Kruskall-Wallis tests for quantitative variables. Differences in the response patterns to question A (ordered-categories defining the number of patients treated) within the 5 possible answers to question M were analysed by considering ordered-category answers to question A as a discrete continuous variable (from 1 to 4), and then using a Kruskall-Wallis test. By considering response patterns to both questions A and M as discrete continuous variables, we also calculated a Spearman’s correlation coefficient between these two variables (ρ = −0.41, p<10E-4), indicating that the more the prescribers treated patients with baclofen, the more they deemed that this drug was more efficacious than approved medications.</p

Survey questions and answers.

<p>After defining their age and gender, participants had to precise whether or not they prescribe baclofen for AUDs in their daily practice.</p><p>Physicians who indicated that they do not prescribe baclofen had to complete only two additional questions, whereas physicians who declared prescribing baclofen for AUDs were asked to complete 17 additional questions. Response patterns to each question are noted in brackets.</p><p>AUDs = Alcohol Use Disorders.</p><p>TRU = ‘Temporary Recommendations for Use’. TRU is a new official measure for regulating the off-label prescribing practices in France. Baclofen will be the first drug to which TRU will be applied.</p><p>ADRs = Adverse Drug Reactions.</p><p>Hors-AMM = ‘Hors Autorisation de Mise sur le Marché’, i.e., ‘Out of Approval’. This mention is theoretically compulsory on any off-label prescription, but it involves that the treatment cannot be reimbursed to the patient.</p><p>NR = ‘Non remboursable, i.e., ‘Non-reimbursable’. This was the former compulsory mention to add on the prescription. It has no legal value anymore, since the last law that redefined in 2011 the conditions for prescribing off-label in France.</p