Background: Topiramate (Topamax) decreases cravings for alcohol by reducing corticomesolimbic dopamine release. A preliminary trial showed that topiramate improved drinking patterns in patients with alcohol dependence. Johnson and colleagues conducted a more definitive randomized, double-blind, placebo-controlled study designed to evaluate the effectiveness and safety of topiramate in the treatment of alcoholism.
The Study: The study included patients 18 to 65 years of age with alcohol dependence. Male participants drank at least 35 drinks per week, and female participants drank more than 28 drinks per week. Participants also had negative urine toxicology findings, with limited exceptions, and a score of 8 or more on the Alcohol Use Disorders Identification Test. Exclusion criteria were extensive and mostly related to severe alcoholism, other psychiatric or health conditions (e.g., Diagnostic and Statistical Manual of Mental Disorders, 4th ed., axis I disorders), substance abuse over the previous six months, serious symptoms of alcohol withdrawal, four or more unsuccessful attempts at inpatient treatment programs, and neurodegenerative disorders.
Patients were initially assessed for drinking characteristics, alcohol level, medication use, and mood. In addition, patients recorded their drinking patterns on a diary card. The initial assessment was followed by a physical examination. Patients were followed weekly for 14 weeks. At the follow-up visits, patients were assessed for alcohol withdrawal symptoms, weekly drinking, vital signs, medication adherence, and alcohol level (participants with a breath alcohol concentration greater than 0.04 percent were not allowed to complete the assessment). Participants were also evaluated for γ-glutamyltransferase (GGT) levels and depression.
After a one-week initial-assessment period, participants were randomly assigned to receive topiramate or placebo. The topiramate dose was titrated upward through week 5 and then maintained for the rest of the trial. All patients received Brief Behavioral Compliance Enhancement Treatment, which emphasized medication adherence. The primary outcome measure was the percentage of days on which the participant drank four or more standard drinks for women and five or more for men. Secondary outcomes were self-reported drinking, drinks per drinking day, and plasma GGT level.
Results: Of the 371 persons enrolled in the study, 183 received topiramate and 188 received placebo. The topiramate group had a greater decrease in heavy drinking days than the placebo group; the mean difference between the groups was 8.44 percent (95% confidence interval [CI], 3.07 to 13.80; P = .002). There was also a significant difference in self-reported drinking and GGT levels between the two groups. Patients taking topiramate did significantly better in achieving 28 or more days of non-heavy drinking (hazard ratio [HR] = 2.28; 95% CI, 1.44 to 3.59; P < .001) or complete abstinence (HR = 5.03; 95% CI, 2.07 to 12.20; P < .001).
When dropout data were not included, the mean difference in heavy drinking days between the two groups was even higher at 16.19 percent (95% CI, 10.79 to 21.60). This method of analysis also showed a higher rate of achieving 28 or more days of non-heavy drinking and abstinence in the topiramate group. Depending on the method of analysis, benefits were apparent at week 2 or 4. Patients in the topiramate group had reduced liver enzyme levels and decreased body mass indices. There was no difference in mood or depression between the two groups, and medication adherence was similar. The serum topiramate level did not correlate with the percentage of heavy drinking days. More than 10 percent of patients had paresthesia; taste perversion; fatigue; anorexia; difficulty with concentration, attention, and memory; nervousness; somnolence; diarrhea; dizziness; and pruritus. All of these adverse effects were more common in the topiramate group.
Conclusion: Regardless of analysis method, topiramate was consistently more effective in reducing the percentage of drinking days, reducing heavy drinking, and increasing abstinence compared with placebo. Adverse effects were common and appeared to be dose-related. Slow titration of the medication was associated with greater adherence. The authors acknowledge that further trials are necessary to determine if the findings are transferable to a community setting.