Seizure Drug May Help Some Heavy Drinkers Cut Alcohol Use

Deborah Brauser

February 20, 2014

Treatment with the anticonvulsant topiramate may help alcohol-dependent individuals who do not want to stop drinking completely reduce their alcohol consumption, new research shows.

A randomized controlled trial of 138 adult heavy drinkers in the United States showed that those who received topiramate at a maximum daily dose of 200 mg for 12 weeks were 5 times less likely to experience a heavy drinking day compared with those who received matching placebo. In addition, participants in the topiramate group experienced significantly more abstinent days.

In further analysis, the investigators found that the effect on heavy drinking days after topiramate treatment was only shown in the participants who carried the rs2832407 genotype. They note that, if validated, this finding could help identify patients most likely to respond to this treatment.

"We had 2 main results. First, topiramate is useful to help people reduce drinking at a lower dosage, and it was well tolerated," lead author Henry R. Kranzler, MD, professor of psychiatry at the University of Pennsylvania Perelman School of Medicine in Philadelphia and director of the school's Center for Studies of Addiction, told Medscape Medical News.

"We have very complete data, which gives us confidence that the findings are real," he added.

Secondly, "it is possible with an SNP [single-nucleotide polymorphism] genotype, which is easy to get done these days, to predict who will respond better to topiramate than to placebo."

Dr. Kranzler noted that the findings also implicate the importance of the kainate receptor, and specifically its GluK1 subunit, in controlling alcohol drinking behavior.

"This means it might be possible to design a new drug to specifically block that subunit and avoid many of the side effects that topiramate has," he said.

The study was published online February 14 in the American Journal of Psychiatry.

Few Seek Treatment

Data released in 2010 showed that 23% of all US residents older than 11 years consumed 5 or more drinks in 1 setting during the previous month ― and 7% reported doing so at least 5 days per month.

Dr. Henry Kranzler

"Despite this, few heavy drinkers seek out treatment ― especially those who do not meet the clinical criteria for an alcohol use disorder but whose drinking causes substantial damage to individuals, their families, and the community," note the researchers in a release.

Previous research has shown that topiramate can reduce drinking in those who want to abstain from alcohol. But for this trial, the investigators sought to determine whether it could also help those who wanted to limit their alcohol consumption to safe levels, rather than to stop drinking altogether.

Topiramate increases γ-aminobutyric acid (GABA) while also inhibiting glutamate activity by blocking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors.

As reported by Medscape Medical News, a recent randomized controlled trial showed that adults who were dependent on both cocaine and alcohol were significantly more likely to be abstinent from cocaine after 13 weeks of treatment with 300 mg/day of topiramate plus cognitive-behavioral therapy (CBT) than those who received placebo plus CBT.

"By increasing GABAergic activity in the nucleus accumbens, topiramate may reduce the dopamine release associated with cocaine or alcohol use and reduce the reinforcing effects," the researchers wrote at the time.

In the current study, 138 heavy drinkers (62.3% men) between the ages of 18 and 65 years were enrolled and underwent a 1-week pretreatment assessment. All of the men consumed on average more than 23 standard drinks per week, and all the women consumed on average more than 18 standard drinks per week.

They were randomly assigned to receive for 12 weeks 25 mg/day of topiramate titrated as needed to a maximum dose of 200 mg/day (n = 67; mean age, 49.3 years) or matching placebo (n = 71; mean age, 52.8 years). Both groups also received 9 weekly sessions of brief counseling.

A 9-day medication taper period then followed.

During the first half of the treatment period, patients were seen once weekly. This was followed by 3 biweekly visits. At these assessments, breath alcohol concentration, weight, and vital signs were measured. In addition, questions were asked about drinking and medication use since the last visit.

Potential Treatment Target

Results showed that the patients receiving topiramate reduced their heavy drinking significantly more than those receiving placebo (P < .001), and they decreased their drinking more rapidly (P < .0001).

During the last week of treatment, the odds of the placebo group having a heavy drinking day was 5.33 times that of the topiramate group (95% confidence interval [CI], 1.68 - 7.28).

In addition, during the last 4 weeks of treatment, 35.8% of the topiramate group had no heavy drinking days vs 16.9% of the placebo group (odds ratio, 2.75; 95% CI, 1.24 - 6.10).

Although that was not necessarily their goal, the group receiving topiramate also had significantly more days of alcohol abstinence (P = .03). And their odds of abstaining by the last week of treatment was 2.57 times that of the group receiving placebo (95% CI, 1.13 - 5.84).

The topiramate group also showed significantly lower concentrations of the liver enzyme γ-glutamyl transpeptidase after the treatment period ended than did the placebo group (mean, 36.3 IU/L vs 47.9 IU/L, respectively; P = .01) and lower scores on the 15-item Short Index of Problems (P = .001), which measured alcohol-related difficulties.

In further analysis, the investigators assessed a subsample of 122 European-Americans to see whether having the SNP rs2832407 in GRIK1 would moderate the therapeutic effects.

"This SNP is associated with alcohol dependence. So we decided we wanted to look at it. Allele frequencies differ by population; but for now, we could really only assess the European- Americans," explained Dr. Kranzler.

The findings showed that topiramate was efficacious only in rs2832407 C-allele carriers and not in A-allele carriers. In fact, those with the C-allele genotype had significantly fewer heavy drinking days after being treated with topiramate than with placebo (P < .001), but there was no difference between treatments in the A-allele group.

"This study indicates that this [kainate] receptor plays a key role in topiramate's effects on drinking," said the investigators in the release.

"Because topiramate interacts with multiple neurotransmitter and enzyme systems, this provides a specific target for the development of medications to reduce heavy drinking," they add.

Dr. Kranzler added that this could also lead to new medications that have fewer of topiramate's common treatment-related adverse events, including fatigue and memory problems.

Overall, "our hope is that the study will result in additional research on how best to help patients who have struggled with heavy drinking…but who are unable or unwilling to abstain from alcohol altogether," said Dr. Kranzler, adding that further research is also needed into effects on other populations.

As for treating with topiramate, "these findings may allow us to predict, in advance, who may benefit, thereby avoiding the unnecessary use of the medication."

"Exciting Results"

"I think this is a great study and a real advance," Mark Willenbring, MD, founder and CEO of Alltyr, an addiction treatment practice in St. Paul, Minnesota, told Medscape Medical News.

Dr. Willenbring, who was not involved with this trial, is a former director of the Division of Treatment and Recovery Research at the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

He noted that it was interesting that the patient population's goal was not abstinence.

"And this was a group with a good prognosis. They were employed, mostly married, mostly educated individuals who did not have any other drug use disorders or any psychiatric disorders, other than around one third to one fourth had a past history of major depression," said Dr. Willenbring.

"Also, the genetic component was only composed of the European-American subsample. But with all that said, what was really remarkable was that the effects, which were really quite profound, were only in the C-allele homozygotes. And this is potentially a very important finding," he added.

Dr. Willenbring said that there are currently only 3 antirelapse medications for alcohol use disorder that have significant moderating effects by genotype. These include naltrexone, which is moderated by polymorphisms in the μ-opioid receptor gene; topiramate, which appears to be moderated by polymorphisms associated with the kainate receptor; and ondansetron.

"In contrast to most psychiatric disorders, or even medical disorders such as hypertension or diabetes, I think we're getting pretty close to where genetic analysis could potentially guide pharmacotherapy for alcohol use disorder. I just think it's very exciting."

Still, study limitations that he pointed out include the fact that the findings might not be generalizable to other ethnic groups and that the investigators did not say whether this treatment was effective for people with severe withdrawal symptoms. But a strength was finding that the "C homozygotes" had fewer treatment-related adverse events.

"This suggests that if you give someone a low dose of topiramate and they have a lot of side effects, they're probably not a C homozygote. So before we start sending out samples for genetic analysis, that might be one clue that could help clinicians," said Dr. Willenbring.

Dr. Kranzler has served as a consultant to or advisory board member for Alkermes, Lilly, Lundbeck, Pfizer, and Roche and is a member of the Abbott-, Lilly-, Lundbeck-, and Pfizer-supported American Society of Clinical Psychopharmacology's Alcohol Clinical Trials Initiative. One other study author reports having received study supplies from Pfizer from a smoking cessation trial. The other 8 study authors have reported no relevant financial relationships.

Am J Psychiatry. Published online February 14, 2014. Abstract

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