October 9, 2007 — Topiramate was effective for treatment of alcohol dependence, according to the results of a double-blind, randomized controlled trial reported in the October 10 issue of the Journal of the American Medical Association.

"Hypothetically, topiramate can improve drinking outcomes among alcohol-dependent individuals by reducing alcohol's reinforcing effects through facilitation of gamma-aminobutyric acid function and inhibition of glutaminergic pathways in the corticomesolimbic system," write Bankole A. Johnson, DSc, MD, PhD, from the University of Virginia in Charlottesville, and colleagues from the Topiramate for Alcoholism Advisory Board and the Topiramate for Alcoholism Study Group. "Initial evidence that topiramate can improve the drinking outcomes of alcohol-dependent individuals comes from an earlier, single-site, double blind, randomized controlled trial with a different design and a shorter duration. Now, in a multisite, 14-week, randomized controlled trial, we sought to determine the efficacy of topiramate (up to 300 mg/d) compared with placebo as a treatment for alcohol-dependent individuals receiving weekly manual-guided Brief Behavioral Compliance Enhancement Treatment (BBCET) to promote adherence with the study medication and the treatment regimen."

Between January 27, 2004, and August 4, 2006, 371 men and women aged 18 to 65 years and diagnosed with alcohol dependence were enrolled at 17 US sites and were randomized to receive up to 300 mg/day of topiramate (n = 183) or placebo (n = 188), along with a weekly compliance enhancement intervention.

The main efficacy outcome variable was self-reported percentage of heavy drinking days, and secondary outcomes included other self-reported drinking measures (percentage of days abstinent and drinks per drinking day) as well as plasma gamma-glutamyltransferase (GGT) as the laboratory measure of alcohol consumption. All dropouts from the study were considered to have relapsed to baseline.

Compared with placebo, topiramate was more effective at decreasing the percentage of heavy drinking days from baseline to week 14 (mean difference, 8.44%; 95% confidence interval [CI], 3.07% - 13.80%; P = .002). Topiramate vs placebo also reduced the percentage of heavy drinking days (mean difference, 16.19%; 95% CI, 10.79% - 21.60%; P < .001) and all other drinking outcomes (P < .001 for all comparisons), based on prespecified mixed-model analysis.

Adverse events that were more frequently observed with topiramate vs placebo included paresthesia (50.8% vs 10.6%), taste perversion (23.0% vs 4.8%), anorexia (19.7% vs 6.9%), and difficulty with concentration (14.8% vs 3.2%).

"Topiramate is a promising treatment for alcohol dependence," the study authors write. "We propose that topiramate's therapeutic effect that improves drinking outcomes is probably due to its diversity of pharmacological action."

Limitations of the study include decreased study adherence with more rapid titration; clinical sites that were least familiar with topiramate experienced more difficulties with retention; participants had to meet criteria enabling the conduct of a safe study, limiting generalizability to clinical practice; and lack of follow-up.

"Because topiramate pharmacotherapy can be paired with a brief intervention deliverable by nonspecialist health practitioners, a next step would be to examine its efficacy in community practice settings," the study authors conclude.

Ortho-McNeil Janssen Scientific Affairs LLC provided the medication and funding for this study. Some of the authors have disclosed various financial relationships with Ortho-McNeil Janssen Scientific Affairs LLC, Organon, TransOral Pharmaceuticals Inc, AstraZeneca, Axis Shield, Cephalon, DrugAbuse Sciences, Sanofi-Aventis, Eli Lilly, Solvay Pharmaceuticals, Forest Laboratories, Alkermes Inc, Bristol-Myers Squibb, Hythiam, Pfizer, Contral Pharma/Biotie Pharmaceuticals, Lipha Pharmaceuticals, UCB Pharma, Catalyst Pharmaceutical Partners, Elbion, Mallinckrodt, and US World Meds.

In an accompanying editorial, Mark L. Willenbring, MD, from the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health in Bethesda, Maryland, describes the role of pharmacotherapy in the treatment of alcohol dependence.

"For patients with severe, relapsing or chronic disorders, specialty addiction treatment, especially the medical component, is needed," Dr. Willenbring writes. "These patients often have serious coexisting physical and mental disorders that require disease management that integrates multiple approaches.... The first step in this process, however, will be for all physicians to begin to see alcohol dependence as a disorder they can and should treat, and treat effectively."

Dr. Willenbring has disclosed no relevant financial relationships.

JAMA. 2007;298:1641-1651, 1691-1692.