Weekly and Monthly Subcutaneous Buprenorphine Depot Formulations vs Daily Sublingual Buprenorphine With Naloxone 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

Optimal dose of buprenorphine in opioid use disorder treatment: a review of pharmacodynamic and efficacy data

“…However, despite high mean doses in some studies, which result in BUP plasma exposures at steadystate well over 3 ng/ml conferring a high level of opioid receptor blockade, there was still considerable use of illicit opioids in a large proportion of the patients. The continued use of illicit opioids despite high doses of BUP is also shown in the recently published studies with extended-release formulations using flexible [10] or high fixed doses of BUP [7]. Reduction in opioid cravings conferred by opioid receptor blockade might not be sufficient to stop illicit drug use in all patients and this is further supported by a recent finding of low correlation between opioid cravings and opioid use in patients treated with BUP [55].…”

“…The randomized clinical trials were limited to those with a duration of at least 24 weeks in order to capture all the treatment phases induction, stabilization and maintenance in this chronic relapsing remitting disease generally requiring long-term therapy. Furthermore, a clinical efficacy trial duration of 24 weeks is required by regulatory agencies for approval of new medications for treatment of OUD [7,10]. The clinical trials selected were also limited to those conducted in Europe and North America.…”

Medications for Treatment of Opioid Use Disorder among Persons Living with HIV

“…Buprenorphine is the only medication that falls into this category. It is available as a monoproduct and in combination with naloxone in tablet and film forms for sublingual administration, and more recently in a long-acting monthly injection [25] and a 6-month implant [26], with additional promising formulations in development [27]. The addition of naloxone to the sublingual products is intended as an abuse-deterrent because the naloxone is only bioavailable if the pill or film is injected, and then would cause precipitated withdrawal in the opioid-dependent individual.…”

Perceptions of extended‐release buprenorphine injections for opioid use disorder among people who regularly use opioids in Australia

“…In the United States, 6‐monthly subdermal buprenorphine implants have been approved for the treatment of opioid use disorder since 2016 . More recently, once‐monthly XR‐buprenorphine subcutaneous injections have been approved in the United States and once‐weekly and once‐monthly subcutaneous injections have been approved in Australia and Europe .…”