Psychostimulant Promising for Long-term Cocaine Dependence

Megan Brooks

March 31, 2016

Sustained-release (SR) dexamfetamine is safe and effective in reducing cocaine use in patients with long-term cocaine dependence who are receiving heroin-assisted treatment, new research shows.

"We found SR dexamfetamine to be superior to placebo on all cocaine use–related outcomes, with effect sizes that were at least comparable to those found in studies on other chronic disorders, including alcohol dependence and many other psychiatric and general medical conditions," study investigator Mascha Nuijten, a doctoral candidate with the Parnassia Addiction Research Centre (Brijder Addiction Treatment), the Hague, told Medscape Medical News.

The study was published online March 22 in the Lancet.

Mechanism Unclear

The placebo-controlled trial included 111 patients from four heroin-assisted treatment centers in the Netherlands who regularly (≥8 days/month) used crack-cocaine and for whom at least two treatments intended to cause reduction of or abstention from cocaine use had failed. By random assignment, 73 pateitns received 12 weeks of supervised therapy with oral SR dexamfetamine (60 mg/day), and 38 received placebo in addition to coprescribed methadone and diacetylmorphine.

SR dexamfetamine led to significantly fewer days of cocaine use than placebo (mean, 44.9 days vs 60.6 days; 95% confidence interval [CI] of difference, 3.1 - 28.4; P = .031; Cohen's d = 0.58), the researchers report.

All secondary cocaine use–related outcomes also favored SR dexamfetamine. For example, the longest consecutive period of self-reported abstinence from cocaine was significantly higher in the dexamfetamine group than in the placebo group (17.9 vs 6.7 days; P < .0001). Similarly, patients in the dexamfetamine group were more often abstinent from cocaine for at least 3 consecutive weeks (11 patients [29%] vs 2 patients [6%]; P = .019) and had more days of cocaine abstinence in the final 4 weeks of the study (15.2 vs 7.5 days; P = .004).

SR dexamfetamine was acceptable and well tolerated, the researchers say. One or more adverse events were reported by 28 (74%) patients in the dexamfetamine group and by 16 (46%) patients in the placebo group (odds ratio, 3.3). In the dexamfetamine group, the most common adverse events were sleeping problems (34%), agitation/irritability (16%), changes in appetite (16%), physical arousal (13%), and gastrointestinal problems (13%). Most adverse events were transient.

Nuijten noted that future studies are needed to replicate these findings in patients with long-term cocaine dependence, with and without concurrent opiate dependence, in "more routine treatment settings." He and his colleagues are currently seeking funding for such a study.

She also noted that "the exact working mechanisms underlying our positive findings are not yet clear: neither craving reduction nor experienced reward seem to explain the substantial reductions in cocaine use found in the study."

Holy Grail?

In an accompanying editorial, Kenneth M. Dürsteler and Marc Vogel, of the Psychiatric University Clinics Basel, in Switzerland, note that cocaine dependence is prevalent throughout the world and is a cause of major illness and death, and that there is currently no effective pharmacotherapy for it.

Although agonist replacement therapy has been used successfully in opioid and tobacco dependence, prior studies testing this approach in cocaine dependence either failed to find statistically significant benefits in terms of reduced cocaine use or showed inconclusive results. "This could be due to limitations in the methods, such as small sample sizes, inadequate dosing schemes, or large attrition rates. The study by Nuijten and colleagues overcomes most of these shortcomings," the editorialists write.

The trial was "adequately powered," and it used an adequate dose of SR dexamfetamine, which has been shown to be an important factor in the effectiveness of agonist replacement therapies, they add.

They note, however, that although SR dexamfetamine led to a significant reduction in cocaine use and an increase in the proportion of participants able to abstain from cocaine use for longer than 21 days, participants who received SR dexamfetamine continued to use cocaine for more than half of the days on average.

"The results of this study are promising," Dr Dursteler and Dr Vogel conclude, "and have important implications for the treatment of cocaine-dependent patients. Although this might not be the 'holy grail' of cocaine-dependence treatment, it could be an important step in the quest for an effective pharmacotherapy of this severe disorder."

Commenting on the study for Medscape Medical News, Victor M. Karpyak, MD, PhD, psychiatrist and medical director, Intensive Addiction Treatment Program, Mayo Clinic, Rochester, Minnesota, said, "At the present time, there is no approved medication options for controlling craving for cocaine. In these circumstances, reported research findings are of interest.

"However, given the highly addictive nature of psychostimulants (including dexamphetamine) and lack of evidence about potential outcomes of the long-term use of this approach, results of this study should be considered with caution and not ready for wide implementation," said Dr Karpyak, who was not involved in the study.

The study was funded by the Netherlands Organization for Health Research and Development. The study investigators and the editorialists have disclosed relationships with several pharmaceutical companies, all of which are listed in the original articles. Dr Karpyak reports no relevant financial relationships.

Lancet. Published online March 22, 2016. Abstract, Editorial

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