Combination Drug Therapy Promising in Cocaine Dependence

Deborah Brauser

December 05, 2012

Combining a psychostimulant and an anticonvulsant might help decrease cocaine use in dependent individuals, new research suggests.

In a randomized study of 81 adults with cocaine dependence, almost twice as many of the participants who received mixed amphetamine salts and topiramate for 3 months achieved 3 consecutive weeks of abstinence as those who received matching placebo.

Dr. Frances Levin

"We were pleased with these results but not overly surprised," principal investigator Frances R. Levin, MD, professor of clinical psychiatry at Columbia University in New York City and director of the addiction psychiatry residency program at New York Presbyterian Hospital, told Medscape Medical News.

"I've done a number of clinical trials over the years looking at treating this disorder that have been negative. So this is good news. But it really does need to be replicated in a large, multisite trial, and I would be cautious in overstating the results. I'd say 'cautious optimism' is the correct term," said Dr. Levin, who is also president of the American Academy of Addiction Psychiatry.

Currently, there are no medications approved by the US Food and Drug Administration (FDA) for treating cocaine dependence.

"The challenge of developing pharmacotherapies for cocaine is daunting. Yet, this combination therapy approach is a promising new strategy," said John Krystal, MD, editor of Biological Psychiatry, in a release.

The study is published in the December 1 issue of Dr. Krystal's journal.

Treatments Sorely Needed

According to the researchers, there are currently about 1.6 million people in the United States who use cocaine.

Psychostimulants, such as amphetamine and methylphenidate, have been shown to "reduce reward dysfunction and deficits in executive cognitive control mechanisms associated with addiction," they explain in a release.

The anticonvulsant topiramate has been shown to be an effective add-on treatment for alcohol and nicotine dependence. It has also been found to enhance activity in γ-aminobutyric acid (GABA), which modulates the dopaminergic system; to inhibit glutamate transmission; and to reduce stimulant-induced dopamine activation.

"Coming up with a strategy that might include pharmacotherapy with other psychotherapeutic approaches is still highly needed. Laboratory research has found that agonist treatment, and specifically amphetamine interventions, show some promise in treating cocaine dependence. But there hasn't been any definitive work," said Dr. Levin.

"We felt that these 2 medications that had different mechanisms of action might work together in modulating the dopaminergic system, and that they might work better when combined than alone."

Setting the Bar High

For this study, 81 cocaine-dependent adults from the New York City area who were between the ages of 18 and 60 years were enrolled.

All were randomly assigned to receive for 12 weeks either a combination of extended-release mixed amphetamine salts (MAS-ER) and topiramate (n = 39; 84.6% men; mean age, 41.5 years) or placebo (n = 42; 88.1% men; mean age, 42.4 years).

"MAS-ER doses were titrated over 2 weeks to a maximum dose of 60 mg daily, and topiramate doses were titrated over 6 weeks to a maximum dose of 150 mg twice daily," write the investigators. Participants in both groups also underwent a behavioral intervention.

Any 3 consecutive weeks of abstinence was the primary outcome measure, as shown by urine toxicology. Secondary outcomes included treatment retention and medication safety, tolerability, and adherence.

"We felt that a high bar would be continuous abstinence, rather than just reduction in use. And that that would certainly get the attention of clinicians," said Dr. Levin.

Patient exclusions included a clinical diagnosis of any psychotic disorder other than related to substance use, having a prescription for any psychotropic medication other than for insomnia, or pregnancy.

Two Better Than One?

Results showed that significantly more of the patients in the combination group achieved the primary outcome than did those in the placebo group (33.3% vs 16.7%).

In addition, "there was a significant moderating effect of baseline total number of cocaine use days...on outcome [P = .05], suggesting that the combination treatment was most effective for participants with a high baseline frequency of cocaine use," report the researchers.

Retention and medication adherence rates did not differ significantly between the 2 treatment groups.

Two participants, 1 in each group, had a serious adverse event. The most common moderate to severe adverse events that were reported included increased/decreased appetite (44% of the combination group vs 10% of the placebo group), insomnia (41% vs 17%, respectively), fatigue (28% vs 14%), gastrointestinal upset (28% vs 12%), and headache (28% vs 12%).

Overall, the findings "provide evidence that the combination of MAS-ER and topiramate is efficacious in promoting abstinence in cocaine-dependent individuals," write the investigators.

Although they note that the study's positive results need to be replicated in larger trials, the findings "provide encouragement for the strategy of testing medication combinations, rather than single agents, for cocaine dependence."

Promising Approach

Dr. Nora Volkow

In an accompanying editorial, Phil Skolnick, PhD, and Nora Volkow, MD, both from the National Institute on Drug Abuse (NIDA) in Bethesda, Maryland, write that although research over the past 20 years has provided insights that could "potentially revolutionize the treatment" of substance use disorders (SUDs), developing highly effective medications has mostly remained an unmet goal.

"The dearth of innovative medications to treat SUDs has been attributed to a low level of interest by the pharmaceutical and biotechnology sections, a problem exacerbated by the retrenchment in psychiatry research and development," write the editorialists.

"However, both the number of potential targets and the molecules that have either failed in other psychiatric indications or are now parked for strategic reasons make SUDs an attractive rescue indication."

They note that recent developments, including the current study, now offer several "exciting" new therapeutic opportunities. They add that lorcaserin and a combination of phentermine and topiramate (Qsymia, Vivus) were recently approved for the treatment of obesity and have the potential for treating SUDs.

Dr. Skolnick and Dr. Volkow note that, in view of Dr. Levin's study, topiramate could be used to further explore the hypothesis that it plus an amphetaminelike molecule could modify cocaine intake.

"As a combined medication, compliance is likely to be higher and the risk of diversion lower. Moreover, if a signal is obtained with Qsymia, the sponsor may have an incentive to support the clinical program necessary for FDA approval as well as support its distribution and promotion," they write.

"Despite the formidable obstacles..., there are now unprecedented opportunities on both the short- and mid-term horizons for translating the many promising approaches identified by basic research into therapies for SUDs," they conclude.

The study was supported by grants from NIDA. Dr. Levin reports being a past consultant for and receiving support from Eli Lily and Company, Shire Pharmaceuticals Group, AstraZeneca, and OrthoMcNeil Pharmaceutical Inc. She has also received research support from UCB Pharma Inc and is currently receiving medication from US WorldMed for an ongoing study. The other study authors and the editorialists have disclosed no relevant financial relationships.

Biol Psychiatry. 2012;72:890-891,950-956. Abstract, Editorial

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