Friday, October 12, 2007
Topamax for Alcoholism: A Closer Look
Epilepsy drug gains ground, draws fire as newest anti-craving pill
A drug for seizure disorders and migraines continues to show promise as an anti-craving drug for alcoholism, the third leading cause of death in America, the Journal of the American Medical Association (JAMA) reported in its current issue.
371 male and female alcoholics between the ages of 18 and 65 took part in the study. The subjects received either topiramate or a placebo. Over 14 weeks, patients taking topiramate showed a significantly higher rate of abstinence for 28 consecutive days or more. (Rates of abstinence increased slightly in the placebo group as well. Both groups received some psychological counseling.)
Topamax is currently only approved by the Food and Drug Administration (FDA) for use against seizures and migraine. The controversial practice of “off-label” prescribing—using a drug for indications that are not formally approved by the FDA—has become so common that Johnson & Johnson (JNJ) said it had no plans to seek formal approval for the use of Topamax as a medicine for addiction.
In an editorial accompanying the study, published in the October 10 issue of JAMA, Mark Willenbring of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) wrote: “We now have very high-quality evidence that shows efficacy. The medical world doesn’t wait for the indication. Topamax is a drug that many physicians have used and many patients have had an experience with because of its use in migraines.”
In addition, Topamax is already prescribed off-label in some cases for depression and Post Traumatic Stress Disorder, according to reports.
At present, there four medications legally available by prescription for alcoholism: disulfiram (Antabuse), SSRIs (off-label), naltrexone (Revia and Vivitrol), and acamprosate, the latest FDA-approved entry. Acamprosate binds to both GABA and glutamate receptors. Acamprosate, marketed in the U.S. as Campral, has been widely used in Europe on problem drinkers.
Dr. Bankole Johnson, chairman of Psychiatry and Neurobehavioral Sciences at the University of Virginia, told Bloomberg News that Topamax does everything researchers want to see in a pharmaceutical treatment for alcoholism: “First, it reduces your craving for alcohol; second, it reduces the amount of withdrawal symptoms you get when you start reducing alcohol; and third, it reduces the potential for you to relapse after you go down to a low level of drinking or zero drinking.”
According to Forbes.com, “The drug isn’t cheap—it costs about $1,000 for three months, according to Johnson. “And, patients, don’t see benefits for two to four weeks.”
Moreover, Topiramate is not without serious side effects for some users, including vision problems, difficulty remembering words, and a tingling in the arms and legs known as parasthesia.
The study was funded by Ortho-McNeil-Janssen, the subsidiary of Johnson & Johnson that produces and markets Topamax. Citing this and other alleged irregularities, Public Citizen’s Sidney Wolfe, Director of the Health Research Group, sent a stinging letter to the FDA demanding that the agency “stop the illegal and dangerous promotional campaign by Ortho-McNeil-Janssen-funded researchers for the unapproved use of Topamax (topiramate) for treating alcoholics.”
And to make things even more interesting, drug developer Mylan (MYL) received FDA approval last month for a generic form of Topamax, seeking a share of the estimated $50 million in annual sales the drug currently enjoys.
Like Campral, Topamax causes changes in the GABA and glutamate systems, which in turn affect dopamine and serotonin function. Acamprosate, like topiramate, harkens back to earlier work on GABA transmission in alcoholism. Both drugs attack the craving and relapse dilemma by stimulating GABA, the inhibitory transmitter that is the target of benzodiazepines like Valium, Xanax and Klonopin. However, Campral is not sedating. There is no buzz, no psychoactive effect, and no evidence of abuse potential whatsoever. Major side effects of acamprosate include gastrointestinal cramps and diarrhea. In addition, Campral may also “restore receptor tone” in the hyperactivated glutamate system of the alcoholic, specifically in the nucleus accumbens.
In a dozen clinical trials conducted in Europe, involving thousands of alcohol abusers, 50 per cent of acamprosate users maintained sobriety for three months without relapse, compared to 39 per cent of the placebo group. (The distressingly low numbers are testimony to the fierce mechanism of relapse.)
Topamax shows a similar mechanism of action. Earlier, researchers from the University of Texas conducted topiramate studies at the South Texas Addiction Research and Technology Center, later published in Lancet. Alcoholic patients achieved a rate of continuous abstinence six times higher than those in a placebo group did. They also reported fewer cravings, compared to a placebo group.
The downside to Topiramate may prove to be side effects. The NIAAA’s Raye Z. Litten, chief of treatment research, believes that the drug may ultimately be a strong player. “On the other hand,” he cautions, “Topiramate appears to have more severe side-effects than naltrexone and acamprosate.” Litten argues that greater efforts at testing are needed.
The National Institutes of Health (NIH) estimated that it would be sponsoring more than 30 new clinical trials of drugs for alcoholism in the next few years. The JAMA editorial, “Medications to Treat Alcohol Dependence,” concludes that the pace of development for alcoholism drugs in increasing. “A solid understanding of the neurobiology of alcohol addiction is providing the framework for multiple avenues of further medication development.”