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Original Investigation
June 2018

Weekly and Monthly Subcutaneous Buprenorphine Depot Formulations vs Daily Sublingual Buprenorphine With Naloxone for Treatment of Opioid Use DisorderA Randomized Clinical Trial

Author Affiliations
  • 1Center on Drug and Alcohol Research, University of Kentucky, Lexington
  • 2Division on Substance Use Disorders, New York State Psychiatric Institute and Columbia University Department of Psychiatry, New York
  • 3Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, Rhode Island
  • 4Department of Psychiatry, University of Vermont, Burlington
  • 5Department of Psychiatry, Hospital of the University of Pennsylvania, Philadelphia
  • 6The Frost Medical Group, LLC, Conshocken, Pennsylvania
  • 7Camurus AB, Lund, Sweden
  • 8Braeburn Pharmaceuticals, Inc, Princeton, New Jersey
  • 9Now affiliated with FORCE Alliance, Princeton, New Jersey
  • 10StatMind AB, Lund, Sweden
  • 11TDM Group, Inc, Berkeley Heights, New Jersey
JAMA Intern Med. 2018;178(6):764-773. doi:10.1001/jamainternmed.2018.1052
Key Points

Question  Are weekly and monthly subcutaneous buprenorphine depot formulations noninferior to a daily sublingual combination of buprenorphine and naloxone when comparing the proportion of urine samples negative for illicit opioids for 24 weeks and the response rate among treatment-seeking adults with moderate-to-severe opioid use disorder?

Findings  In this randomized clinical trial of 428 participants, the proportion of opioid-negative urine samples was 1347 of 3834 (35.1%) and response rate was 37 of 213 participants (17.4%) for the subcutaneous depot buprenorphine group compared with 1099 of 3870 (28.4%) and 31 of 215 participants (14.4%), respectively, for the sublingual buprenorphine-naloxone group. Both primary outcomes demonstrated noninferiority.

Meaning  Long-acting buprenorphine depot formulations appear to be efficacious for treatment of opioid use disorder.

Abstract

Importance  Buprenorphine treatment for opioid use disorder may be improved by sustained-release formulations.

Objective  To determine whether treatment involving novel weekly and monthly subcutaneous (SC) buprenorphine depot formulations is noninferior to a daily sublingual (SL) combination of buprenorphine hydrochloride and naloxone hydrochloride in the treatment of opioid use disorder.

Design, Setting, and Participants  This outpatient, double-blind, double-dummy randomized clinical trial was conducted at 35 sites in the United States from December 29, 2015, through October 19, 2016. Participants were treatment-seeking adults with moderate-to-severe opioid use disorder.

Interventions  Randomization to daily SL placebo and weekly (first 12 weeks; phase 1) and monthly (last 12 weeks; phase 2) SC buprenorphine (SC-BPN group) or to daily SL buprenorphine with naloxone (24 weeks) with matched weekly and monthly SC placebo injections (SL-BPN/NX group).

Main Outcomes and Measures  Primary end points tested for noninferiority were response rate (10% margin) and the mean proportion of opioid-negative urine samples for 24 weeks (11% margin). Responder status was defined as having no evidence of illicit opioid use for at least 8 of 10 prespecified points during weeks 9 to 24, with 2 of these at week 12 and during month 6 (weeks 21-24). The mean proportion of samples with no evidence of illicit opioid use (weeks 4-24) evaluated by a cumulative distribution function (CDF) was an a priori secondary outcome with planned superiority testing if the response rate demonstrated noninferiority.

Results  A total of 428 participants (263 men [61.4%] and 165 women [38.6%]; mean [SD] age, 38.4 [11.0] years) were randomized to the SL-BPN/NX group (n = 215) or the SC-BPN group (n = 213). The response rates were 31 of 215 (14.4%) for the SL-BPN/NX group and 37 of 213 (17.4%) for the SC-BPN group, a 3.0% difference (95% CI, −4.0% to 9.9%; P < .001). The proportion of opioid-negative urine samples was 1099 of 3870 (28.4%) for the SL-BPN/NX group and 1347 of 3834 (35.1%) for the SC-BPN group, a 6.7% difference (95% CI, −0.1% to 13.6%; P < .001). The CDF for the SC-BPN group (26.7%) was statistically superior to the CDF for the SL-BPN/NX group (0; P = .004). Injection site adverse events (none severe) occurred in 48 participants (22.3%) in the SL-BPN/NX group and 40 (18.8%) in the SC-BPN group.

Conclusions and Relevance  Compared with SL buprenorphine, depot buprenorphine did not result in an inferior likelihood of being a responder or having urine test results negative for opioids and produced superior results on the CDF of no illicit opioid use. These data suggest that depot buprenorphine is efficacious and may have advantages.

Trial Registration  ClinicalTrials.gov Identifier: NCT02651584

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