Buprenorphine Implants May Be Effective for Opioid Dependence, Phase 3 Study Suggests

Caroline Cassels

October 13, 2010

October 13, 2010 — Subdermal buprenorphine (Probuphine, Titan Pharmaceuticals) implants are effective in the treatment of opioid dependence and may help address common problems of adherence and medication diversion in this patient population, new research suggests.

A large, randomized, controlled, multicenter phase 3 trial shows buprenorphine implants that provide a low, steady level over 6 months in opioid-dependent patients significantly reduced opioid use compared with placebo.

"Those who received buprenorphine implants also had fewer clinician-rated and patient-rated withdrawal symptoms, had lower patient ratings of craving, and experienced a greater change on clinician global ratings of improvement than those who received placebo implants," write Walter Ling, MD, and colleagues from the University of California, Los Angeles.

The study was published in the October 13 issue of the Journal of the American Medical Association.

Poor Treatment Adherence

According to investigators, sublingual buprenorphine is an increasingly common treatment for opioid dependence, with numerous studies supporting its efficacy.

However, they note a major concern is poor treatment adherence, which results in craving and withdrawal symptoms and increases the likelihood of relapse.

To address problems of adherence, diversion, and nonmedical use, an implantable formulation of buprenorphine was developed. A preliminary phase 2 study reported favorable results with the implant in opioid-dependent patients.

The current phase 3 study looked at its efficacy in a larger trial conducted at 18 centers in the United States between April 2007 and June 2008 and included 163 opioid-dependent adults.

A total of 108 participants were randomized to receive buprenorphine implants and 55 to receive placebo implants.

The study's primary outcome measure was the percentage of the 48 urine samples that tested negative for illicit opioids for weeks 1 through 16 of the trial.

The secondary outcome measure included percentages of the 24 urine samples that were negative for illicit opioids from weeks 17 through 24.

According to the article, "treatment failure was defined as receiving a fifth implant and subsequently requiring 3 or more days per week of supplemental sublingual buprenorphine-naloxone treatment for 2 consecutive weeks or 8 or more days of supplemental sublingual buprenorphine-naloxone treatment over 4 consecutive weeks at any time after the implant dosage increase. Patients who met this definition of treatment were withdrawn from the study."

After induction with sublingual buprenorphine-naloxone tablets, participants received either 4 implants, each of which gradually released 80 mg of buprenorphine, or 4 placebo implants placed below the skin in the inner side of the nondominant arms of study participants. The implants were removed after 6 months. Standardized individual drug counseling was provided to all patients.

Less Opioid Use

The implants were placed and removed by physicians from various medical specialties, including psychiatry, dermatology, obstetrics and gynecology, and family medicine, who had been trained in the procedure but were not site investigators.

After implant placement, patients experiencing significant withdrawal or craving symptoms could receive supplemental sublingual buprenorphine-naloxone tablets starting at 4 mg and increasing to 2-mg increments up to 13 mg.

During weeks 1 through 16, patients with buprenorphine implants had an average percentage of urine samples that tested negative for illicit opioids of 40.4% vs 28.3% for the control group.

In addition, 65.7% (n = 71) of patients in the buprenorphine implant group remained in the study for the full 24-week duration compared with 30.9% (n = 17) of those in the placebo group.

The investigators report that urine samples taken from week 17 to 24 that tested negative for opioid use also showed a statistically significant difference (P < .001).

During the full 24-week treatment period, which included 72 urine samples from each patient, the buprenorphine group had a mean of 36.6% of opioid-negative urine samples vs 22.5% for the placebo group.

Furthermore, none of the patients in the active treatment group met the definition of treatment failure. In comparison, 30.9% of placebo patients were classified as treatment failures.

"In summary, this study found that the use of buprenorphine implants compared with placebo resulted in less opioid use over 16 weeks and also across the full 24 weeks," the investigators write.

Experts Weigh In

In an accompanying editorial, Patrick G. O'Connor, MD, MPH, Yale University School of Medicine, New Haven, Connecticut, describes the findings as a potential important step forward in the effort to improve and expand the treatment options for opioid dependence.

He notes that before such implants are integrated into clinical practice there needs to be a head-to-head comparison of implants and current opioid maintenance treatment.

"If further research suggests that this buprenorphine implant is as good as or better than current treatment approaches, then the study by Ling et al would represent a major advance in the substantial and continued progress that has occurred in the treatment of opioid dependence since methadone maintenance began in the 1960s," Dr. O'Connor writes.

Nora Volkow, MD, director of the National Institute on Drug Abuse (NIDA), agrees the findings are promising. She notes that if successful the implant could improve on the efficacy of daily administered buprenorphine. She noted that NIDA is supporting research on the "clinical efficacy of Probuphine, in the hopes that it too will become part of the arsenal of weapons against crippling effects of opioid addiction."

The study was funded by Titan Pharmaceuticals. Dr. Ling reports receiving research support from Reckitt Benckiser, Titan, and Hythiam and speaker fees from Reckitt Benckiser and is a member of the Advisory Board of US World Med. The disclosures of the other investigators can be found in the original study. Dr. O'Connor and Dr. Volkow have disclosed no relevant financial relationships.

JAMA. 2010;304:1576-1583.

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