Here is the latest in a long series of studies that have failed to demonstrate a single medication with efficacy in treating cocaine dependence. In some ways this is surprising because cocaine is a single receptor focused drug, so it simplifies the search for medications that have activity at that receptor. Alcohol, on the other hand, is highly complex and affects many areas of the brain at once. It is not receptor focused. Yet, there are proven effective treatments for alcohol dependence.
Vigabatrin Fails to Achieve Efficacy for Cocaine Dependence in Phase 2 US Trial
April 23, 2010 (San Francisco, California) — A double-blind, placebo-controlled phase 2 clinical trial of the anticonvulsant agent vigabatrin for cocaine dependence in the United States failed to show that the drug was effective for achieving abstinence, according to research presented here at the American Society of Addiction Medicine 41st Annual Medical-Scientific Conference.
The trial's results contradict those of a similar phase 2 Mexican trial, published in the American Journal of Psychiatry in 2009, which showed a significant difference between subjects given vigabatrin vs placebo for cocaine addiction.
Yet researchers who conducted the US trial said the negative results may have been the result of problems with study design, rather than failure of vigabatrin to achieve efficacy in treating cocaine dependence.
"The take-home message from our trial is that it didn't work," said Eugene Somoza, MD, PhD, from the University of Cincinnati College of Medicine and the Veteran's Administration Medical Center in Cincinnati, Ohio. "But it's not that vigabatrin doesn't work — the study didn't work."
High Drop-Out Rate
In the US trial, 186 participants from 11 medical centers were randomly assigned either to 3 g/day vigabatrin daily by mouth in 2 divided doses or to placebo for 12 weeks. All patients received computerized behavioral therapy and counseling once a week, and urine specimens were collected 3 times a week to test for cocaine use.
There was a high drop-out rate — 61 patients dropped out of the study and only 125 completed at least 12 weeks of treatment. Abstinence was defined as not having used cocaine for the last 2 weeks of the study treatment period, validated by self-report and levels of benzoylecgonine in urine samples. Treatment adherence was evaluated through pill counts and self-reports.
The study failed to meet its primary endpoint — a significantly greater rate of drug abstinence in the vigabatrin group. However, the researchers found that patients receiving vigabatrin used consistently less cocaine than placebo during the 12-week treatment phase (P = .006), as measured by benzoylecgonine levels.
In a secondary analysis, the researchers also examined patient compliance with their medication regimens by reviewing urine vigabatrin concentrations in the treatment group. They found that 47.6% of the 61 patients who had completed the study in the vigabatrin group were not compliant with their medication regimens. Compliers were considered to be those with vigabatrin concentration of 630 μg/mL or more, and partial compliers were defined as those with levels of 158 μg/mL or more in urine samples. Secondary analysis indicated that those in the complier vigabatrin group used cocaine for fewer days than those in the noncomplier group (P = .084).
Although concerns have been raised about visual field defects with long-term use of vigabatrin, the researchers did not observe this adverse effect in either the treatment or placebo group. Adverse events included headache, nasopharyngitis, diarrhea, nausea, and back pain.
Lack of Adherence
So why did the US study fail while the Mexican trial showed that vigabatrin was effective for achieving abstinence? "The 2 main reasons are that patients didn't take their medications in the American study, and those in the Mexican study may have been a lot more motivated to abstain from cocaine," Dr. Somoza said in an interview with Medscape Psychiatry.
He noted that in the Mexican study, patients were observed taking their medication for 2 of 7 days. The subjects in the Mexican study were also parolees from prison, and showing up at least once per week at the vigabatrin study treatment center satisfied requirements for parole. In contrast, the American study consisted of patients who had been recruited by academic medical centers through radio and TV ads and who were paid for their participation. Dr. Somoza said.
The 9-week phase 2 Mexican trial of 103 patients randomly assigned to either vigabatrin or placebo used a treatment dosage similar to that administered in the US trial, and cocaine use was also determined with twice-weekly urine toxicology tests. In that trial, 28% of vigabatrin-treated patients vs 7.5% of participants in the placebo group achieved abstinence, defined as 3 weeks without using cocaine.
In an accompanying editorial to the publication of the Mexican trial in the American Journal of Psychiatry in November 2009, Kathleen Brady, MD, PhD, from the Medical University of South Carolina, Charleston, noted that the results were "not tremendously robust." She also cautioned that vigabatrin can cause visual field defects in 30% to 50% of patients who take it for more than 12 months. The question of whether this adverse effect could affect those with cocaine dependence who use the drug for a shorter time remains open, she said.
"We've been looking for a medication for cocaine addiction for 35 years, and to date we have no [US Food and Drug Administration]-approved medications. We haven't found anything that works," commented Timothy Fong, MD, assistant professor of psychiatry and codirector of the addiction medicine clinic at the University of California–Los Angeles.
Whether or not the differences in the Mexican and US trial results could be the result of dissimilarity in the 2 studies' population characteristics is difficult to assess, Dr. Fong noted. "But when we have used advertisements to recruit people for cocaine trials in Los Angeles, we find that their motivations are pretty high to quit — even though it's sometimes difficult to get them to stay and finish the experiment," he said.
New Trial Planned
One problem with studies on cocaine dependence is that cocaine addiction is a complicated disease, and cocaine addicts are not all the same, Dr. Fong said. "The differences between those who use crack vs powder and those who inject vs snorting need to be teased out a little more," he added. "There may be people with cocaine addiction who may respond to vigabatrin, but I don't think we've figured out who that would be yet," he said.
Although Dr. Fong noted that, in his clinical experience, vigabatrin is not that effective for treating cocaine addiction, the investigators working on the US trial plan to continue studying the drug.
A new trial funded by the National Institute on Drug Abuse is planned, Dr. Somoza said. The investigators hope to address some of the problems in the US trial by using more observed doses, by adding a marker substance to vigabatrin and placebo formulations to better assess adherence, and by enrolling patients who might be more motivated to quit cocaine, such as those in substance abuse treatment centers, Dr. Somoza added.
The study was supported by Catalyst Pharmaceutical Partners. Dr. Fong disclosed being on speakers' bureaus for Reckitt-Benckiser, Pfizer Pharmaceuticals, and Lilly Pharmaceuticals. Dr. Somoza has disclosed no relevant financial relationships.
American Society of Addiction Medicine 41st Annual Medical-Scientific Conference: Abstract 4. Presented April 16, 2010.