Journal Article Annotations
2023, 4th Quarter

Addiction

Annotations by Julian J. Raffoul, MD, PhD
January, 2024

Examining the benefit of a higher maintenance dose of extended-release buprenorphine in opioid-injecting participants treated for opioid use disorder

PUBLICATION #1 — Addiction

Examining the benefit of a higher maintenance dose of extended-release buprenorphine in opioid-injecting participants treated for opioid use disorder

Mark K Greenwald, Katharina L Wiest, Barbara R Haight, Celine M Laffont, Yue Zhao

Abstract: Randomized Controlled Trial Harm Reduct J actions. 2023 Dec 2;20(1):173.

Background:
BUP-XR (Sublocade®) is the first buprenorphine extended-release subcutaneous injection approved in the USA for monthly treatment of moderate-to-severe opioid use disorder (OUD). Among patients with OUD, those who inject or use high doses of opioids likely require higher doses of buprenorphine to maximize treatment efficacy. The objective of this analysis was to compare the efficacy and safety of 100-mg versus 300-mg maintenance doses of BUP-XR in OUD patients who inject opioids.

Methods:
This was a secondary analysis of a randomized, double-blind, placebo-controlled study in which adults with moderate or severe OUD received monthly injections of BUP-XR (2 × 300-mg doses, then 4 × 100-mg or 300-mg maintenance doses) or placebo for 24 weeks. Abstinence was defined as opioid-negative urine drug screens combined with negative self-reports collected weekly. Each participant’s percentage abstinence was calculated after the first, second, and third maintenance doses in opioid-injecting and non-injecting participants. The proportion of participants achieving opioid abstinence in each group was also calculated weekly. Treatment retention rate following the first maintenance dose was estimated for opioid-injecting participants with Kaplan-Meier method. Risk-adjusted comparisons were made via inverse propensity weighting using propensity scores. Buprenorphine plasma concentration-time profiles were compared between injecting and non-injecting participants. The percentages of participants reporting treatment-emergent adverse events were compared between maintenance dose groups within injecting and non-injecting participants separately.

Results:
BUP-XR 100-mg and 300-mg maintenance doses were equally effective in non-injecting participants. However, in opioid-injecting participants, the 300-mg maintenance dose delivered clinically meaningful improvements over the 100-mg maintenance dose for treatment retention and opioid abstinence. Exposure-response analyses confirmed that injecting participants would require higher buprenorphine plasma concentrations compared to non-injecting opioid participants to achieve similar efficacy in terms of opioid abstinence. Importantly, both 100- and 300-mg maintenance doses had comparable safety profiles, including hepatic safety events.

Conclusions:
These analyses show clear benefits of the 300-mg maintenance dose in injecting participants, while no additional benefit was observed in non-injecting participants relative to the 100-mg maintenance dose. This is an important finding as opioid-injecting participants represent a high-risk and difficult-to-treat population. Optimal buprenorphine dosing in this population might facilitate harm reduction by improving abstinence and treatment retention.

Trial registration:
ClinicalTrials.gov, NCT02357901.

Annotation

The finding:
The current recommended dose of buprenorphine extended-release (BUP-XR) for opioid use disorder (OUD) following open-label induction and dose stabilization with sublingual buprenorphine/naloxone is 300-mg monthly for the first two months followed by a maintenance dose of 100-mg monthly. In this secondary analysis of a randomized, double-blind, placebo-controlled study that enrolled treatment-seeking adults who met the DSM-5 criteria for moderate or severe OUD at screening, the utilization of a higher 300-mg maintenance dose of BUP-XR for the treatment of OUD in patients who inject opioids resulted in improved treatment retention and abstinence from opioids over the standard 100-mg maintenance dose. Furthermore, exposure-response analyses confirmed that patients who inject opioids likely require higher buprenorphine plasma concentrations compared to opioid non-injecting patients to achieve and maintain abstinence. Interestingly, the standard 100-mg maintenance dose and experimental 300-mg maintenance doses were equally effective in patients who do not inject opioids and both maintenance doses had comparable safety profiles.

Strength and weaknesses:
This study demonstrated a clear benefit for utilizing the 300-mg maintenance dose for patients who inject opioids. This is an important finding as opioid-injecting patients are a high-risk and difficult-to-treat patient population and optimal dosing for this group would facilitate harm-reduction by improving treatment retention and abstinence promotion. A limitation of this study was that it did not compare the BUP-XR 300-mg versus 100-mg during the maintenance dose period in the randomized intent-to-treat population. As a result, the treatment comparison could have been subject to the bias introduced by participants discontinuation prior to receiving the maintenance dose. Unmeasured confounders may have also influenced the efficacy of comparison results.

Relevance:
Despite the availability of effective treatments for OUD such as buprenorphine, methadone, and naltrexone, opioid use remains at epidemic levels in the US. Factors such as opioid use duration, frequency of use, use via injection, and inadequate therapeutic doses of treatments, particularly buprenorphine treatments, are all associated with increased likelihood of return to use. C-L psychiatrists need to be familiar with strategies to improve OUD treatment and retention in these highly vulnerable patient populations. Patients who inject opioids and prescribed a maintenance dose of 300-mg of BUP-XR maintained abstinence and remained in treatment longer than those prescribed the 100-mg maintenance dose. Recommending higher doses of buprenorphine for patients with OUD, particularly patients who inject opioids and/or use synthetic opioids such as fentanyl, may need higher doses of buprenorphine for effective treatment.