CHARLOTTESVILLE, Va. -- Topiramate (Topamax), a migraine agent, appeared to help alcoholic patients curtail their heavy-drinking behavior, according to investigators here.
CHARLOTTESVILLE, Va., Oct. 10 -- Topiramate (Topamax), a migraine agent, appeared to help alcoholic patients curtail their heavy-drinking behavior, according to investigators here.
When used off-label in a randomized trial sponsored by the drug-maker, Ortho-McNeil Janssen, topiramate led to a reduction in the percentage of heavy drinking days, compared with placebo, Bankole A. Johnson D. Sc., M.D., Ph.D., of the University of Virginia, and colleagues at 16 other sites, reported in the Oct. 10 issue of the Journal of the American Medical Association.
These findings showed that individuals while drinking heavily can still be treated safely and reliably with topiramate, the researchers wrote. Unlike other drugs, establishing abstinence before starting treatment was not required.
The JAMA report, particularly an associated press package issued by the university, triggered an impassioned protest by Sidney Wolfe, M.D., of Public Citizen, the drug-safety advocacy group. He complained to the FDA that a question-and-answer sheet for journalists amounted to illegal off-label promotion for topiramate.
"It is not the research or the publication of the study that is illegal but the promotional material that goes beyond the research to solicit new sales for the drug," said Dr. Wolfe.
Dr. Wolfe objected to a comment in a question-and-answer sheet that "since topiramate is currently FDA-approved for seizures and migraines, it is available to your doctor to prescribe it off label."
According to Dr. Wolfe, "Not only is this off-label promotion illegal, but it is also potentially dangerous."
The university press office denied that there was any intent to promote off-label use. "We are not suggesting a go-ahead for doctors, but we are stating a fact," said a spokesperson. "Doctors who are interested are allowed to prescribe it. No off-label use is being proposed, advocated, or promoted."
It had been hypothesized that topiramate might act by reducing alcohol's reinforcing effects through facilitation of ?-aminobutyric acid function and inhibition of glutaminergic pathways in the corticomesolimbic system, the researchers wrote.
In the 14-week double-blind trial of 371 men and women, ages 18 to 65, the participants were diagnosed with alcohol dependence and were not required to be abstinent during the study. The trial was conducted from Jan. 27, 2004, through Aug. 4, 2006, at 17 U.S. sites.
Men consumed 35 or more standard drinks a week, and women consumed 28 or more drinks a week. A standard drink was 0.5 oz of absolute alcohol, equivalent to 4 oz of wine, 10 oz of beer, or one oz of 100-proof liquor.
Of the participants, 183 received 300 mg/d of topiramate, and 188 got a placebo, along with a brief weekly psychosocial visit by a health professional to promote adherence to the medication and the treatment regimen.
Secondary outcomes included other self-reported drinking measures (percentage of days abstinent and drinks per drinking day) including a laboratory measure of alcohol consumption (plasma ?-glutamyltransferase).
Treating all dropouts as relapse to baseline, topiramate was more efficacious than placebo at reducing the self-reported percentage of heavy drinking days from baseline to week 14 from an average of 81.9% to 43.8% for topiramate versus 82.0% to 51.8% for placebo.
This amounted to a mean difference of 8.44% (95% confidence interval, 3.07% to 13.80%; P=0.002).
A prespecified mixed-model analysis also showed that topiramate compared with placebo decreased the percentage of heavy drinking days (mean difference, 16.19%; 95% confidence interval, 10.79% to 21.60%; PThe authors suggested that titrating topiramate over eight weeks instead of six weeks would have improved the retention rate.
The study had certain limitations they said. As in most clinical trials in this field, participants have to meet criteria to make a safe study possible. Thus because this cohort was generally healthier and perhaps more homogeneous than the general population seeking treatment, the ability to generalize without restriction to clinical practice is limited.
Also, they said, the study lacked a follow-up period so it was not possible to determine relapse after medication withdrawal.
In an accompanying editorial, Mark L. Willenbring, M.D., of the National Institute on Alcohol Abuse and Alcoholism, wrote that topiramate produced significant and meaningful improvements in a wide variety of drinking outcomes.
Judging from the study, Dr. Willenbring said, it is possible that even more improvement may occur with longer use, and in contrast to other medications, patients were not required to stop drinking prior to entering the study.
Dr. Johnson, the study author reported being a consultant for Ortho-McNeil Janssen Scientific Affairs, Organon, and TransOral Pharmaceuticals.
Normal Rosenthal, M.D., Frank Wiegand, M.D., Lian Mao, Ph.D., Amy McKay, Pharm.D., Julie Capece, B.A., and Karen Beyers, M.S., reported being employees of Ortho-McNeil Janssen Scientific Affairs.
Other co-authors reported various financial relationships with Ortho-McNeil Janssen, Scientific Affairs LLC, 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, DrugAbuse Sciences, Lipha, UCB Pharma, Catalyst Pharmaceutical Partners, Elbion, GlaxoSmithKline, Johnson & Johnson, Mallinckrod, US World Meds and Bristol-Myers Squibb.
Ortho-McNeil Janssen Scientific Affairs provided the medication and funding for this study. The sponsor was involved in all stages from study design through interpretation of the results including critical review of the manuscript. Data were managed initially and analyzed by Ortho-McNeil Janssen Scientific Affairs and PharmaNet Inc, a contract research organization, and were interpreted by the study authors with input from Ortho-McNeil Janssen Scientific Affairs LLC clinical and statistical staff.
An independent statistical analysis, paid for by Ortho-McNeil Janssen, was done by Daniel O. Scharfstein, Sc.D., of the Johns Hopkins University Bloomberg School of Public Health.
Dr. Willenbring, the editorialist, reported no financial conflicts of interest. The views expressed in this article are his, he wrote, and not necessarily those of the National Institute on Alcohol Abuse or Alcoholism, or any other federal agency.