Buprenorphine implants helped approximately 40% of patients addicted to opioids markedly reduce their drug use for 6 months in a phase III study of this new method of delivery, according to a report in the Oct. 13 issue of JAMA.

In addition, two-thirds of the study subjects who received the implants completed 24 weeks of treatment without experiencing cravings or withdrawal symptoms compelling them to drop out, said Dr. Walter Ling of the UCLA Integrated Substance Abuse Programs, Los Angeles, and his associates.

In comparison, studies of sublingual buprenorphine found a median adherence of only 40 days in clinical settings, and 6-month clinical trials report subject retention rates of 35%-38%, the investigators noted.

The implantable formulation of buprenorphine was developed to address dependent patients’ problems with adherence and “diversion,” or using the drug for some purpose other than treatment, such as selling it. The implants deliver an initial pulse of buprenorphine followed by the release of a constant, low level for 6 months. This avoids the peaks and troughs in plasma levels that occur with other methods of delivery.

Dr. Ling and his colleagues performed their industry-sponsored phase III study at 18 community addiction treatment centers across the United States. In all, 108 subjects were randomly assigned to receive four buprenorphine implants and 55 to receive four placebo implants in the subdermal space in the inner side of the nondominant arm.

The study subjects were allowed to receive supplemental sublingual buprenorphine-plus-naloxone tablets if they experienced significant withdrawal symptoms or cravings. They also were allowed to get one additional implant if necessary. All also received individual drug counseling twice a week for 3 months and weekly thereafter.

The patients’ use of illicit drugs was monitored throughout the study by urinalyses done 3 times per week.

The primary outcome measure was early treatment response, assessed as the percentage of the 48 urine samples obtained during the first 16 weeks of the trial that were negative for illicit opioids. This rate was 40% with the buprenorphine implants, compared with 28% with the placebo implants, the investigators said (JAMA 2010;304:1576-83).

For the full 6-month treatment period, in which 72 urine samples were analyzed for each subject, 37% were negative for illicit opioids in the buprenorphine group, compared with 22% in the placebo group.

Treatment adherence was significantly better with the active treatment at 16 weeks (82% with buprenorphine vs. 51% with placebo) and at the conclusion of the study (66% vs. 31%). Throughout the study, the implant group also had significantly lower scores on measures of opiate withdrawal and opioid craving.

No patients who received buprenorphine implants were classified as treatment failures, while 31% who received placebo implants were.

Adverse reactions at the treatment site were common and expected in both groups, and resolved without incident in all but three patients. One serious adverse event may have been related to treatment: A pulmonary embolism and exacerbation of chronic obstructive pulmonary disease occurred in a patient with a history of pulmonary embolism and COPD, whose respiratory function might have been impaired by the buprenorphine. One patient in the placebo group also had a serious adverse event, cellulitis at the implant site.

“There were no clinically meaningful changes” in vital signs, physical exam findings, electrocardiograms, hematology values, or coagulation values.

In addition, no evidence was found of attempted removal of the implants, so “diversion” appears unlikely with this method of delivery, Dr. Ling and his associates said.

The investigators cited several limitations. For example, all of the patients received psychosocial counseling in addition to the implants. Also, they pointed out that their trial is not “statistically powered to examine efficacy within subgroups of patients.”

The findings in this study suggest that a promising new approach to opioid addiction may be close at hand. If further study shows that buprenorphine implants are as good as or better than current treatments, the current study would represent a major advance, said Dr. Patrick G. O’Connor in an editorial accompanying this report (JAMA 2010;304:1612-4).

However, further improvement in the implant delivery system appears to be warranted, given the low plasma levels of buprenorphine that the study subjects attained and the degree to which they required supplemental sublingual drug.

In addition, the treatment is complex and resource intense, requiring implantation and removal procedures as well as specialized counseling. This study tested its use in special treatment centers with close medical supervision, but provided “relatively little information about how implants might be used in office practice,” said Dr. O’Connor, an internist at Yale University, New Haven, Connecticut.

This study was funded by Titan Pharmaceuticals, maker of the buprenorphine implants, which was involved in the design and management of the study, data collection and analysis, and preparation and approval of the manuscript. Dr. Ling and his associates reported numerous ties to drug and device manufacturers. Dr. O’Connor reported no financial disclosures.

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