Antiepileptic Drug Curbs Cocaine Use
November 17, 2009 — Vigabatrin, an antiepileptic drug that is approved in some countries to treat severe pediatric epilepsy, has been shown to reduce cocaine use at a rate that is almost 4 times greater than placebo, new research suggests.
A study of cocaine-addicted parolees taking vigabatrin had a total abstinence rate almost 4 times that of addicts taking placebo (28% vs 7.5%) and a similar improved rate for partial abstinence after 9 weeks of treatment (34.0% vs 9.4%).
The study results suggest that vigabatrin, approved in some countries to treat severe pediatric epilepsy, might be able to break the vicious cycle of cocaine addiction, criminal behavior, incarceration, and recidivism that plagues much of society, said lead author Jonathan D. Brodie, MD, PhD, Marvin Stern professor of psychiatry, New York University School of Medicine, in New York.
"If you can get these people clean, you have a start," Dr. Brodie told Medscape Psychiatry .
Cocaine addiction is a "scourge that's eating away at the fabric of life," said Dr. Brodie. "Yet there hasn't been a single drug that has ever been approved in the US for the treatment of cocaine dependence."
The study, the first randomized, double-blind, placebo-controlled trial of vigabatrin in cocaine dependence, is published in the November issue of the American Journal of Psychiatry .
The study group consisted of mostly male parolees from a Mexico City prison who were aged 18 to 55 years (mean age, almost 30 years), had a Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) diagnosis of cocaine dependence, and were urine positive for cocaine and negative for heroin and methamphetamine.
Cocaine Use Endemic in Prisons
Cocaine use is endemic in Mexican prisons and is considered a principal cause of recidivism among ex-convicts. The individuals in the study reported using a mean of almost 2 g of cocaine per day during the previous 9 years. "Many of the people were using 4 to 7 g of crack a day," said Dr. Brodie. "That's a huge amount of heavy duty daily usage."
Although these addicted parolees were poor, unemployed or underemployed, and "desperate," they were motivated and many had tight-knit families and social support, said Dr. Brodie.
The study participants were randomized to either vigabatrin (n = 50) or placebo (n = 53). The treatment drug was dissolved in 250 mL of orange juice. The placebo consisted of identical bottles of orange juice.
Vigabatrin blocks regions of the brain tied to addiction by inhibiting γ-aminobutyric acid (GABA) transaminase, the primary enzyme involved in GABA metabolism.
"This drug does not work by blocking a receptor; it works by blocking the enzyme that's responsible for removing high amounts of GABA from the presynaptic terminal," explained Dr. Brodie. The presynaptic terminal acts like a reservoir for GABA and when it receives a signal from the cocaine-stimulated dopamine neuron, it dumps the GABA and "quenches" the dopamine firing, he said.
Stimulates Dopamine
Dopamine has been shown to modulate pleasure and reward. Cocaine seems to stimulate a flood of dopamine in the brain regions that govern reinforcing and rewarding behavior in humans and animals.
The drug works differently than other GABAergic agents in treating addiction, said Dr. Brodie. "You don't get tolerance; it has no street value; it does not get people high; it has no stimulating effect at all. What it does is merely cause a "dump" or quench when the brain begins to respond to a drug like cocaine."
Animal studies have shown that vigabatrin prevents behavioral manifestations of cocaine dependence. "It seems to block the high or reward so animals stop seeking cocaine; they stop pressing a bar for cocaine," said Dr. Brodie.
During the 9-week trial, participants visited the clinic twice a week. During a 4-week follow-up phase, participants visited the clinic weekly. All participants received weekly group therapy sessions.
Full abstinence was defined as no positive urine toxicology screening result during the final 3 weeks of the 9-week trial. Partial abstinence was only 1 positive urine toxicology screening result during this period.
At the end of the trial, 28% of the parolees taking vigabatrin were abstinent and 34% had partial abstinence compared with 7.5% who were fully abstinent and 9.4% who had partial abstinence among those taking placebo.
Thrilling Results
Dr. Brodie said he was "thrilled" by these results. "These are hard-core addicts who were paid next to nothing to participate in this study," he said. "These were people who wanted to get clean."
He pointed out that it was "twice as onerous" to participate in the study as it was to just be out on parole. "They not only had to take the medicine, but they also had to show up at the clinic and spend 2 days a week there as opposed to spending 30 minutes in the parole office." Getting to and from the clinic wasn't easy and took quite a bit of time out of their day, he said.
Vigabatrin appeared to also cut alcohol use, which commonly occurs along with cocaine use. Those taking vigabatrin were 7 times more likely than those taking placebo to report full alcohol abstinence at the end of the trial (43.5% vs 6.3%).
There were no differences in cocaine craving or depression scores between the 2 groups.
Subject retention was 62.0% in the vigabatrin arm vs 41.5% in the placebo arm.
Vigabatrin was well tolerated with no serious adverse events. The adverse events that occurred did not differ from those in the placebo group. Early somnolence was the most common concern among all study participants.
Humbling Experience
During a previous study in the area, Dr. Brodie said he was humbled to be surrounded by families of the study participants who were eager to thank him for helping their loved one. "It was one of the most moving experiences of my life," he said. "This is what being a doctor is all about."
One limitation of this current study was that due to travel restrictions researchers could only test urine twice a week, so the study may not have captured some cocaine use. As well, because the study participants did not have telephones, the researchers could not ascertain why the participants dropped out.
It is important to continue to find a treatment that works for cocaine dependence because this and other drug addictions ruin lives, cause increased morbidity, and are costly in terms of healthcare, said Dr. Brodie.
Visual Effects
In an accompanying editorial, Kathleen T. Brady, MD, PhD, from the Department of Psychiatry, Medical University of South Carolina, Charleston, raised the question of whether the benefits of treating cocaine and alcohol dependence can ever outweigh the risk for severe visual field defects, an adverse effect of the drug that has been reported with long-term use defined as more than 12 months.
"It must be remembered that these are diseases that threaten and ruin the lives of those affected and their loved ones," Dr. Brady said. "While every precaution must be taken to minimize the risks and further investigation of visual field defects is warranted, serious diseases warrant aggressive treatment."
Dr. Brodie added that there appears to be a "threshold" of a cumulative amount of 1500 g of vigabatrin under which constriction of the visual field may not be an issue. "We carefully stayed well below that" threshold — the dose never exceeded 3 g a day in the study," he said.
He also pointed out that the visual adverse effects tend to be mild and easily compensated for. "The drug was on the market for 10 years before there was the very first report of a visual field constriction. Until it's incredibly severe, you don't even know there's a problem."
In her editorial, Dr. Brady commended Dr. Brodie and his colleagues for conducting a well-designed, ethically sound clinical trial in "a very treatment-resistant real-world population."
She said that although the results are "not tremendously robust," the study is "an important exploration of an agent with a novel mechanism of action in cocaine dependence, a disorder that is a substantial public health problem without good pharmacotherapeutic treatments available."
Dr. Brodie, Dr. Dewey, and Dr. Laska are paid members of the Scientific Advisory Board of Catalyst Pharmaceutical Partners Inc, which has licensed vigabatrin for the indication of cocaine dependence from Brookhaven National Laboratory. Dr. Brodie and Dr. Dewey are the inventors but not patent holders of the property; they receive no royalties and were fully compliant with the requirements of the Con¬flict of Interest Board of the New York University School of Medicine following institutional review. Dr. Brodie, Dr. Dewey, and Dr. Laska are also shareholders with Catalyst Pharmaceutical Partners Inc. A coauthor, Brady G. Case, MD, has received financial support from the American Academy of Child and Adolescent Psychiatry (AACAP) through the AACAP Eli Lilly Pilot Research Award and from the American Psychological Association (APA) through the APA Janssen Psychiatric Research Scholarship, APA Shire Child and Adolescent Psychiatry Fellowship, and APA AstraZeneca Young Minds in Psychiatry Award; he is also supported by the Leon Levy Foundation. Of the other coauthors, Joseph A. Wanderling, MA, has served as a paid consultant to Catalyst Pharmaceutical Partners Inc, and Emilia Figueroa, MD, and James A. Robinson, Med, report no competing interests.
Am J Psychiatry . 2009;166:1269–1277. Abstract
Authors and Disclosures
Journalist
Pauline Anderson
Pauline Anderson is a freelance writer for Medscape.
-From: http://www.medscape.com/viewarticle/712561 Medscape Psychiatry News, retrieved 11/23/09.
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