Buprenorphine's Usefulness May Be Broader Than First Proposed

A depot-injectable formulation of the partial μ-opioid agonist, buprenorphine, appears to extend opioid blockade significantly and minimizes the risk of the medication itself being abused by patients who are addicted to opiates. In addition, the medication may be just as effective in patients who are addicted to both opiates and cocaine.

The novel depot formulation of buprenorphine, developed by Biotek Inc. in collaborat\ion with the National Institute on Drug Abuse (NIDA), is investigational, with Phase II clinical studies having been recently completed. The proposed brand name is Norvex.

The active medication is suspended in polymer microcapsules that release buprenorphine for approximately 40 days after subcutaneous injection. Studies in animals have indicated the formulation suppresses opioid withdrawal for as long as 60 days in morphine-dependent animals.

A report by George Bigelow, Ph.D., a professor of psychiatry and behavioral sciences at Johns Hopkins University School of Medicine, and his colleagues detailed results of the first open-label clinical trial of the new formulation in humans. That report appeared in the January Drug and Alcohol Dependence.

Five opioid-dependent volunteers received a single subcutaneous injection containing 58 mg of buprenorphine, and they were assessed during at least four weeks of residential treatment followed by two weeks of outpatient observation. The depot formulation appeared to provide effective relief from symptoms of opioid withdrawal, with none of the five participants requiring additional medication for withdrawal relief after receiving their depot injection.

In addition, the depot formulation appeared to be well tolerated, with no significant side effects, signs of intoxication, or respiratory suppression. Two of the five patients developed transient pain and/or tenderness at the site of injection, which resolved within seven days.

Subjectively, all five patients reported relief and felt "normal" and "comfortable" through the end of the study at six weeks. Observer assessments were similar. Illicit drug use was checked through both urine and blood analyses.

All five patients achieved opioid detoxification by week 4 and were discharged to the outpatient phase of the study, having required no additional medications for withdrawal and having no significant observable symptoms of withdrawal. Urine samples were negative, with one exception: one patient's urine screen was positive in week 6, due to prescription pain medication used for significant dental problems.

A second recently published report indicates that buprenorphine may be effective at reducing cocaine and heroin use in patients addicted to both.

The report, conducted by Ivan Montoya, M.D., M.P.H., a research scientist in NIDA's Division of Treatment Research and Development in Baltimore, appeared in the January Clinical Pharmacology and Therapeutics.

Two hundred outpatients dependent on both drugs were randomly assigned to receive buprenorphine (2 mg, 8mg, or 16 mg a day or 16 mg every other day) for 10 weeks, following by a three-week taper. All patients also received weekly individual drug-abuse counseling for that same period.

The researchers sought to answer two questions: How many subjects taking buprenorphine stopped using heroin and cocaine? And of those subjects who didn't stop using, did any decrease their usage?

The researchers found that the highest dose of buprenorphine (16 mg daily) was the most effective at stopping both heroin and cocaine use, as well as decreasing use in those who continued to test positive. In the group receiving 16 mg a day, the percentage of all urine samples testing positive for heroin fell by 43 percent, and the number testing positive for cocaine fell by nearly 53 percent. Urine concentrations in those samples continuing to test positive for heroin use fell by 92 percent, and in those continuing to test positive for cocaine use, by 95 percent. The group taking 8 mg a day of buprenorphine also had statistically significant reductions in both the number of sample continuing to test positive for heroin and cocaine and the amount of drug used. However, the effect was much smaller.

No statistically significant effects were seen at 2 mg. In addition, those taking 16 mg every other day improved slightly, but generally less than those receiving 8 mg every day; however, this effect was also not statistically significant.

Together, these two studies support the growing evidence base for the effectiveness of buprenorphine in the treatment of addiction, specifically to opiates and possibly to cocaine. Montoya and his colleagues noted that in their analysis the therapeutic effect of the drug on cocaine use appears to be independent of that on opiate use.

Abstracts of "Open-Label Trial of an Injection Depot Formulation of Buprenorphine in Opioid Detoxification" and "Randomized Trial of Buprenorphine for Treatment of Concurrent Opiate and Cocaine Dependence" are posted online at www.sciencedirect.com.▪