Alcohol dependence is a major public health problem that is characterised by recidivism and a host of medical and psychosocial complications. Besides psychosocial interventions, different pharmacological interventions have been or currently are under investigation through Cochrane systematic reviews.
The primary aim of the review is to assess the benefits/risks of anticonvulsants for the treatment of alcohol dependence.
We searched the Cochrane Drugs and Alcohol Group Trials Register (October 2013), PubMed (1966 to October 2013), EMBASE (1974 to October 2013) and CINAHL (1982 to October 2013).
Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing anticonvulsants alone or in association with other drugs and/or psychosocial interventions versus placebo, no treatment and other pharmacological or psychosocial interventions.
Data collection and analysis
We used standard methodological procedures as expected by The Cochrane Collaboration.
A total of 25 studies were included in the review (2641 participants). Most participants were male, with an average age of 44 years. Anticonvulsants were compared with placebo (17 studies), other medications (seven studies) and no medication (two studies). The mean duration of the trials was 17 weeks (range four to 52 weeks). The studies took place in the USA, Europe, South America, India and Thailand. Variation was reported in the characteristics of the studies, including their design and the rating instruments used. For many key outcomes, the risk of bias associated with unclear or unconcealed allocation and lack of blinding affected the quality of the evidence.
Anticonvulsants versus placebo: For dropouts (16 studies, 1675 participants, risk ratio (RR) 0.94, 95% confidence interval (Cl) 0.74 to 1.19, moderate-quality evidence) and continuous abstinence (eight studies, 634 participants, RR 1.21, 95% Cl 95% 0.97 to 1.52, moderate-quality evidence), results showed no evidence of differences. Moderate-quality evidence suggested that anticonvulsants reduced drinks/drinking days (11 studies, 1126 participants, mean difference (MD) -1.49, 95% Cl -2.32 to -0.65) and heavy drinking (12 studies, 1129 participants, standardised mean difference (SMD) -0.35, 95% Cl -0.51 to -0.19). Moreover, withdrawal for medical reasons (12 studies, 1410 participants, RR 1.22, 95% Cl 0.58 to 2.56, moderate-quality evidence) showed no evidence of difference, but for specific adverse effects (nine studies, 1164 participants), two of 18 adverse event outcomes favoured placebo. The direction of results was confirmed by subgroup analyses for topiramate and partially for gabapentin and valproate.
Anticonvulsants versus naltrexone: No evidence of difference was shown in dropout rates (five studies, 528 participants, RR 0.74, 95% CI 0.52 to 1.06), severe relapse rates (four studies, 427 participants, RR 0.69, 95% Cl 0.44 to 1.07) and continuous abstinence rates (five studies, 528 participants, RR 1.21, 95% Cl 0.99 to 1.49); anticonvulsants were associated with fewer heavy drinking days (three studies, 308 participants, MD -5.21, 95% Cl -8.58 to -1.83), more days to severe relapse (three studies, 244 participants, MD 11.88, 95% Cl 3.29 to 20.46) and lower withdrawal for medical reasons (three studies, 245 participants, RR 0.13, 95% Cl 0.03 to 0.58).
At the current stage of research, randomised evidence supporting the clinical use of anticonvulsants to treat alcohol dependence is insufficient. Results are conditioned by heterogeneity and by the low number and quality of studies comparing anticonvulsants with other medications. The uncertainty associated with these results leaves to clinicians the need to balance possible benefits/risks of treatment with anticonvulsants versus other medications as supported by evidence of efficacy.
Plain language summary
Anticonvulsants for alcohol dependence
This review looked at evidence on the efficacy and acceptability of anticonvulsants alone or in combination with another medication or a psychosocial intervention for the treatment of alcohol dependence.
Alcohol dependence is a major public health problem characterised by recidivism and a host of medical and psychosocial complications. Together with psychosocial interventions, different pharmacological interventions have been tested in trials and systematic reviews. In this review, we wanted to discover whether anticonvulsants are better than placebo or are better than other medications, psychosocial interventions or no intervention.
In October 2013, we used electronic medical databases to find all published and unpublished medical trials that compared anticonvulsants with placebo or other interventions. We also used other sources, such as conference proceedings, likely to contain trials relevant to the review. To be included in the review, medical trials had to have a randomised design and had to include adult participants (older than 18 years of age) with a diagnosis of alcohol dependence.
We identified 25 medical trials involving a total of 2641 participants. 80% of participants in these trials were male; mean age was 44 years. Most studies compared anticonvulsants versus placebo (17 studies), but some researchers compared anticonvulsants versus other medications (seven studies) or no medication (two studies). The mean duration of the trials was 17 weeks (range four to 52 weeks). Half of the trials took place in the USA, the other half in Spain, Brasil, Germany, Greece, Italy, India and Thailand. The anticonvulsant included in most of the trials was topiramate; other medications were gabapentin, valproate, levetiracetam, oxcarbazepine, zonisamide, carbamazepine, pregabalin and tiagabine. Included studies used 73 different rating instruments and differed in design, quality, characteristics of patients, tested medications, services provided and treatments delivered.
In 17 studies versus placebo, anticonvulsants were shown to be more effective than placebo in terms of number of drinks per drinking day and average heavy drinking. However, we found no clear evidence that anticonvulsants led to more participants abstaining from alcohol, fewer participants drinking heavily or fewer participants leaving treatment (dropouts). In terms of safety issues, the rate of withdrawal from treatment due to adverse effects was not lower or higher in participants treated with anticonvulsants than in those treated with placebo. Moreover, for two of 18 specific side effects (dizziness and paraesthesia), anticonvulsants were worse than placebo. Other major known side effects, such as those affecting cognitive functioning (attention, confusion, speech problems), were insufficiently explored by primary studies. For single medications, results were globally confirmed for topiramate and partially for gabapentin and valproate.
In the five studies in which anticonvulsants were compared with naltrexone, a medication considered efficacious for the treatment of alcohol dependence, anticonvulsants were associated with a lower number of heavy drinking days, with a higher number of days before a severe relapse occurred and with a lower rate of patient withdrawal for medical reasons. However, anticonvulsants were not more or less effective than naltrexone in affecting the rate of participants who showed severe relapse, who were not drinking during the trial or who left treatment (dropouts).
Quality of evidence
In looking at primary outcomes (dropouts, abstinence from alcohol during the trial, number of drinks per drinking day, heavy drinking, rate of patient withdrawal for medical reasons), the quality of the included studies was considered moderate. However, moving to subgroup analysis, as in the case of single types of medications, as well as to comparisons versus other medications, the finding of the review is limited by the small number of available studies.
At the current stage of research, evidence supporting the clinical use of anticonvulsants to treat alcohol dependence is insufficient. Results are conditioned by heterogeneity and by the low number and quality of studies comparing anticonvulsants versus other medications. The uncertainty associated with these results leaves to clinicians the need to balance the possible benefits/risks of treatment with anticonvulsants versus other medications as supported by evidence of efficacy.