Extended-Release Injection vs Sublingual Buprenorphine for Opioid Use Disorder With Fentanyl Use: A Post Hoc Analysis of a Randomized Clinical Trial

Edward V Nunes; Sandra D Comer; Michelle R Lofwall; Sharon L Walsh; Stefan Peterson; Fredrik Tiberg; Peter Hjelmstrom; Natalie R Budilovsky-Kelley

doi:10.1001/jamanetworkopen.2024.17377

. 2024 Jun 25;7(6):e2417377. doi: 10.1001/jamanetworkopen.2024.17377

Extended-Release Injection vs Sublingual Buprenorphine for Opioid Use Disorder With Fentanyl Use

A Post Hoc Analysis of a Randomized Clinical Trial

Edward V Nunes ^1,², Sandra D Comer ^1,², Michelle R Lofwall ³, Sharon L Walsh ³, Stefan Peterson ⁴, Fredrik Tiberg ⁴, Peter Hjelmstrom ⁵, Natalie R Budilovsky-Kelley ^6,^✉

¹Division on Substance Use Disorders, New York State Psychiatric Institute, New York

²Columbia University Irving Medical Center Department of Psychiatry, New York, New York

³Department of Behavioral Science and Center on Drug and Alcohol Research, University of Kentucky, Lexington

⁴Camurus AB, Lund, Sweden

⁵Uppsala Monitoring Centre, Uppsala, Sweden

⁶Medical Affairs, Braeburn Inc, Plymouth Meeting, Pennsylvania

Accepted for Publication: April 17, 2024.

Published: June 25, 2024. doi:10.1001/jamanetworkopen.2024.17377

^✉

Corresponding Author: Natalie R. Budilovsky-Kelley, PharmD, Medical Affairs, Braeburn Inc, 450 Plymouth Rd, Ste 400, Plymouth Meeting, PA 19462 (nbudilovsky@braeburnrx.com).

Author Contributions: Drs Nunes and Budilovsky-Kelley had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Nunes, Walsh, Peterson, Tiberg, Hjelmstrom, Budilovsky-Kelley.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Nunes, Walsh, Tiberg, Hjelmstrom, Budilovsky-Kelley.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Nunes, Peterson, Tiberg.

Administrative, technical, or material support: Comer, Lofwall, Walsh, Tiberg, Hjelmstrom.

Supervision: Walsh, Tiberg, Budilovsky-Kelley.

Conflict of Interest Disclosures: Dr Nunes reported serving as an uncompensated consultant for Camurus AB, Indivior, Alkermes, and Pear Therapeutics; receiving in-kind medication for a National Institutes of Health (NIH)-funded study from Camurus AB and Braeburn Inc; received in-kind digital therapeutics for NIH-funded studies from Pear Therapeutics and CHESS Health outside the submitted work; and received in-kind medication donations to NIH funded studies from Alkermes and Indivior. Dr Comer reported receiving personal fees from Alkermes, Opiant, and Syneos Health; and grants for NIH-funded studies from Lyndra Therapeutics, Intra-Cellular Therapies, BioXcel Therapeutics, and Coridea outside the submitted work. Dr Lofwall reported receiving personal fees from Braeburn Inc, Berkshire Biomedical, Journey Colab, and Titan Pharmaceuticals outside the submitted work. Dr Walsh reported receiving personal fees from Cerevel Therapeutics, AstraZeneca, Opiant, Pocket Naloxone, Lundbeck, Braeburn Inc, and Titan Pharmaceuticals outside the submitted work; in addition, Dr Walsh had a patent for Tradipitant 62,682,831 issued to the University of Kentucky and Vanda Pharmaceuticals. Dr Peterson reported receiving personal fees from Camurus AB during the conduct of the study. Dr Tiberg is an employee and shareholder of Camurus and also reported having a US patent for 8,236,292 issued and a US patent for 9,937,164 issued. Dr Hjelmstrom reported being an employee of Camurus AB during the conduct of the study. Dr Budilovsky-Kelley reported being an employee of Braeburn. No other disclosures were reported.

Funding/Support: The primary study on which this secondary analysis is based was supported by Braeburn Inc and by grant UL1TR001998 from the University of Kentucky Center for Clinical and Translational Science for research services and facilities for the study at this site.

Role of the Funder/Sponsor: The sponsors participated in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. They had no role in the collection of the data.

Data Sharing Statement: See Supplement 3.

Additional Contributions: Technical editorial assistance was provided, under the direction of the authors, by Pratibha Hebbar, PhD, and Sophie Bolick, PhD, Synchrony Medical Communications LLC; funding for this assistance was provided by Braeburn Inc.

^✉

Corresponding author.

PMCID: PMC11200143 PMID: 38916892

Key Points

Question

What is the effectiveness of sublingual buprenorphine-naloxone or injections of extended-release subcutaneous buprenorphine for opioid use disorder (OUD) with fentanyl use?

Findings

In this post hoc analysis of a randomized 24-week clinical trial with 428 participants, the percentage of urine samples negative for opioids among participants with fentanyl use was 28.5% for subcutaneous buprenorphine and 18.8% for buprenorphine-naloxone and 36.7% for subcutaneous buprenorphine and 30.6% for buprenorphine-naloxone among those without fentanyl use; among participants with fentanyl use, the percentage of urine samples negative for fentanyl was 74.6% for subcutaneous buprenorphine vs 61.9% for buprenorphine-naloxone. Opioid withdrawal and craving diminished rapidly across groups.

Meaning

This study suggests that buprenorphine appears effective for treating OUD with fentanyl use; the extended-release injected formulation may provide an advantage in reducing fentanyl use.

Abstract

Importance

Fentanyl has exacerbated the opioid use disorder (OUD) and opioid overdose epidemic. Data on the effectiveness of medications for OUD among patients using fentanyl are limited.

Objective

To assess the effectiveness of sublingual or extended-release injection formulations of buprenorphine for the treatment of OUD among patients with and without fentanyl use.

Design, Setting, and Participants

Post hoc analysis of a 24-week, randomized, double-blind clinical trial conducted at 35 outpatient sites in the US from December 2015 to November 2016 of sublingual buprenorphine-naloxone vs extended-release subcutaneous injection buprenorphine (CAM2038) for patients with OUD subgrouped by presence vs absence of fentanyl or norfentanyl in urine at baseline. Study visits with urine testing occurred weekly for 12 weeks, then 6 times between weeks 13 and 24. Data were analyzed on an intention-to-treat basis from March 2022 to August 2023.

Intervention

Weekly and monthly subcutaneous buprenorphine vs daily sublingual buprenorphine-naloxone.

Main Outcomes and Measures

Retention in treatment, percentage of urine samples negative for any opioids (missing values imputed as positive), percentage of urine samples negative for fentanyl or norfentanyl (missing values not imputed), and scores on opiate withdrawal scales and visual analog craving scales.

Results

Of 428 participants, 123 (subcutaneous buprenorphine, n = 64; sublingual buprenorphine-naloxone, n = 59; mean [SD] age, 39.1 [10.8] years; 75 men [61.0%]) had evidence of baseline fentanyl use and 305 (subcutaneous buprenorphine, n = 149; buprenorphine-naloxone, n = 156; mean [SD] age, 38.1 [11.1] years; 188 men [61.6%]) did not have evidence of baseline fentanyl use. Study completion was similar between the fentanyl-positive (60.2% [74 of 123]) and fentanyl-negative (56.7% [173 of 305]) subgroups. The mean percentage of urine samples negative for any opioid were 28.5% among those receiving subcutaneous buprenorphine and 18.8% among those receiving buprenorphine-naloxone in the fentanyl-positive subgroup (difference, 9.6%; 95% CI, −3.0% to 22.3%) and 36.7% among those receiving subcutaneous buprenorphine and 30.6% among those receiving buprenorphine-naloxone in the fentanyl-negative subgroup (difference, 6.1%; 95% CI, −1.9% to 14.1%), with significant main associations of baseline fentanyl status and treatment group. In the fentanyl-positive subgroup, the mean percentage of urine samples negative for fentanyl during the study was 74.6% among those receiving subcutaneous buprenorphine vs 61.9% among those receiving sublingual buprenorphine-naloxone (difference, 12.7%; 95% CI, 9.6%-15.9%). Opioid withdrawal and craving scores decreased rapidly after treatment initiation across all groups.

Conclusions and Relevance

In this post hoc analysis of a randomized clinical trial of sublingual vs extended-release injection buprenorphine for OUD, buprenorphine appeared to be effective among patients with baseline fentanyl use. Patients with fentanyl use had fewer opioid-negative urine samples during the trial compared with the fentanyl-negative subgroup. These findings suggest that the subcutaneous buprenorphine formulation may be more effective at reducing fentanyl use.

Trial Registration

ClinicalTrials.gov Identifier: NCT02651584

This post hoc analysis of a randomized clinical trial assesses the effectiveness of sublingual or extended-release injection formulations of buprenorphine for the treatment of opioid use disorder (OUD) among patients with and without fentanyl use.

Introduction

The rise in availability of fentanyl and fentanyl analogues has been implicated in the rapid increase in overdose fatalities over the past decade.^{1,2,3,4,5,6,7} Because of its potency (30-50 times more potent than heroin),^7,8,9,10 rapid distribution, lipophilicity, and propensity to induce muscle rigidity, fentanyl is more likely to cause an overdose than other opioids, including heroin.^3,11 People who use illicit drugs often lack awareness that fentanyl is present in the drugs they buy, which further increases overdose risk.⁵ Fentanyl is not detected by immunoassay urine drug testing typically used as first-line point-of-care screening.¹²

Buprenorphine, a partial μ-opioid receptor agonist with high binding affinity and slow dissociation from the μ-opioid receptor, is well established as an effective treatment for opioid use disorder (OUD).¹³ However, data are limited on the effectiveness of buprenorphine or other medications (eg, methadone and extended-release injection naltrexone) for treatment of OUD when the patient is using fentanyl.^14,15 A retrospective cohort study of patients initiating office-based buprenorphine treatment showed that patients with baseline fentanyl use demonstrated 6-month abstinence and treatment retention rates comparable with patients with baseline heroin use.¹⁴

We report findings on buprenorphine treatment of fentanyl use from a previously reported phase 3 trial in which patients with OUD (N = 428), including a substantial subgroup (123 [28.7%]) with fentanyl or norfentanyl detected in urine at baseline, were randomly assigned to treatment with sublingual buprenorphine-naloxone or a formulation of weekly and monthly injections of extended-release subcutaneous buprenorphine, previously known as CAM2038 and granted US Food and Drug Administration approval in 2023.¹⁶ Levels of fentanyl and its metabolite norfentanyl were measured in urine throughout the study.

Methods

Study Design and Patients

The patient population and study design have been described previously.¹⁶ The study was conducted between December 2015 and November 2016. Adults aged 18 to 65 years with a diagnosis of moderate-to-severe OUD, according to the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition), who voluntarily sought treatment were eligible for study inclusion. Patients were excluded if they had received pharmacotherapy for OUD within 60 days prior to randomization; had a diagnosis of moderate-to-severe substance use disorder for psychoactive substances other than opioids, caffeine, or nicotine, with the nonopioid substance use disorders considered primary or coprimary and causing significant impairment in the past 30 days; or had chronic pain requiring opioids. Participants’ demographic characteristics, including race and ethnicity (Black, White, and other [American Indian or Alaska Native, Asian, and Native Hawaiian or Other Pacific Islander]), were self-reported. Participants provided written informed consent and received attendance stipends. The study protocol was approved by central and local institutional review boards (trial protocol and statistical analysis plan in Supplement 1). The Consolidated Standards of Reporting Trials (CONSORT) reporting guideline was followed for reporting of the original study¹⁶ and this post hoc analysis.

This 24-week, randomized, double-blind, double-dummy, active-controlled, multicenter, phase 3 study was conducted at 35 US outpatient clinical centers. The study involved a 3-week screening period, a 12-week phase 1 (weekly visits), a 12-week phase 2 (monthly visits at weeks 16, 20, and 24, with 3 additional visits randomly assigned for urine sample collection and self-reporting of illicit drug use), and a 4-week follow-up period.

On day 1 (start of phase 1), eligible participants presented in opioid withdrawal and received a test dose of open-label sublingual buprenorphine-naloxone, 4 mg/1 mg. Participants who tolerated the test dose were randomly assigned 1:1 to treatment with daily sublingual buprenorphine-naloxone tablets (up to 24 mg/d) and weekly subcutaneous placebo injections (group 1) or daily sublingual placebo tablets and weekly subcutaneous buprenorphine injections (≤32 mg/week; group 2) for 12 weeks (phase 1). During phase 2 (weeks 13-24), participants continued to receive the same medications in a double-blind fashion, except that the subcutaneous injections transitioned from weekly to monthly administration (subcutaneous buprenorphine ≤160 mg/mo or matching placebo). After completing phase 2, patients transitioned to standard treatment (eg, sublingual buprenorphine) during the 4-week follow-up period.

Assessments

Assessments conducted at scheduled study visits included urine drug testing, self-report of illicit drug use (Timeline Followback interview), Clinical Opiate Withdrawal Scale (range, 0-48, where 0 indicates no withdrawal and 48 indicates severe withdrawal), Subjective Opiate Withdrawal Scale (range, 0-64, where 0 indicates no withdrawal and 64 indicates severe withdrawal), and visual analog scale for craving (range, 0-100, where 0 indicates no need or desire to use and 100 indicates maximum need or desire to use) since the last visit, as well as adverse events (AEs).

Urine samples were collected at baseline (screening and day 1) and at each of the scheduled weekly visits during phase 1, each of the scheduled monthly visits during phase 2, and 3 randomly scheduled visits during phase 2. Gas chromatography–mass spectrometry was used to detect codeine, dihydrocodeine bitartrate, hydrocodone, morphine sulfate, oxycodone hydrochloride, and oxymorphone hydrochloride, while liquid chromatography–tandem mass spectrometry was conducted to detect fentanyl (lower limit of quantification, 0.1 ng/mL), norfentanyl (lower limit of quantification, 0.2 ng/mL), and methadone and its metabolite 2-ethylidene-1,5 dimethyl-3,3-diphenylpyrrolidine in urine.

Statistical Analysis

Post hoc analysis of data presented herein was conducted from March 2022 to August 2023. This is a comparative effectiveness analysis, comparing urine-based opioid outcomes of participants receiving subcutaneous buprenorphine vs sublingual buprenorphine-naloxone, stratified into subgroups, who (1) exhibited evidence of fentanyl use at baseline (screening or day 1), based on positive urine toxicology results for fentanyl or norfentanyl (ie, fentanyl positive), or (2) showed no fentanyl or norfentanyl in urine samples at baseline (ie, fentanyl negative). The analyses included all participants randomly assigned to treatment (intention-to-treat population). For each patient, the percentage of urine samples negative for any opioids ([number of urine samples collected from a given patient with negative results for all opioids/18 total expected urine samples] × 100, yielding a continuous score ranging from 0 to 100 for each patient) was calculated, with missing urine samples imputed as positive. This percentage score was a primary outcome in the parent trial.¹⁶ The percentage scores were evaluated using an analysis of variance, as in the parent trial, including fentanyl use at baseline as well as treatment as fixed factors and a term for the interaction between treatment and baseline fentanyl use. For the outcome of percentages negative for fentanyl and norfentanyl, the difference between treatments and its confidence limits were estimated within the baseline fentanyl-positive subgroup only, because the baseline fentanyl-negative subgroup had predominantly negative scores across outcome points with little variance. For the fentanyl analyses, missing urine samples were not imputed as positive because a missing sample could be negative for fentanyl but positive for other opioids, complicating data interpretation. For repeated-measures analysis of the binary outcome of urine test results at each time point over time in the study, separate mixed models for repeated measurements (MMRMs) were estimated in each stratum (ie, separate models for baseline fentanyl-positive results and for baseline fentanyl-negative results), with fixed factors for treatment, visit, and treatment by visit interaction. Separate models were run for each stratum because the main interest was the treatment effect within stratum. The Kenward Roger method was used to calculate the df. An unstructured covariance structure was used to account for intervisit correlations. The MMRM will generally adjust for missing values that were dependent on previous observed values (data missing at random principle¹⁷). A 2-sided P < .05 was considered statistically significant. Adjustment for multiplicity was not used due to the exploratory nature of the analyses.

Summary statistics of demographic and baseline characteristics, as well as safety data, are presented as mean (SD) values, counts, and percentages. The calculations and analyses were conducted using SAS software, version 9.2 or higher (SAS Institute Inc) and R software, version 4.2.3 (R Project for Statistical Computing). Safety analyses were conducted among the safety population (ie, all patients in the intention-to-treat population who received any dose of study drug).

Results

Participant Characteristics

Of 428 participants randomly assigned to treatment, 123 (subcutaneous buprenorphine, n = 64; sublingual buprenorphine-naloxone, n = 59; mean [SD] age, 39.1 [10.8] years) demonstrated evidence of fentanyl use at baseline and 305 (subcutaneous buprenorphine, n = 149; buprenorphine-naloxone, n = 156; mean [SD] age, 38.1 [11.1] years) did not have evidence of baseline fentanyl use (Table 1). Overall, at the time of the trial, Florida and Ohio had the greatest percentage of fentanyl-positive participants of the 17 states included in this study. Of those in the fentanyl-positive subgroup, 75 (61.0%) were male, and 48 (39.0%) were women; 30 (24.4%) were Black, 90 (73.2%) were White, and 3 (2.4%) were other race or ethnicity, which was comparable with the fentanyl-negative subgroup (188 men [61.6%] and 117 women [38.4%]; 65 [21.3%] Black, 233 [76.4%] White; and 7 [2.3%] other race or ethnicity). Most participants in the fentanyl-positive subgroup (104 [84.6%]) identified heroin as their primary opioid of use, compared with 199 participants (65.2%) in the fentanyl-negative subgroup. The percentage of participants with intravenous route of use was similar for the fentanyl-positive (68 [55.3%]) and fentanyl-negative subgroups (156 [51.1%]). A greater percentage of participants in the fentanyl-positive subgroup than the fentanyl-negative subgroup had urine toxicology results positive for cocaine (47 [38.2%] vs 59 [19.3%]) or benzodiazepines (26 [21.1%] vs 39 [12.8%]). Baseline withdrawal and craving scores were similar between groups.

Table 1. Demographic and Baseline Characteristics by Baseline Fentanyl Use and Treatment (Intention-to-Treat Population).

Parameter	Fentanyl-positive group, No. (%)			Fentanyl-negative group, No. (%)
Parameter	Subcutaneous buprenorphine (n = 64)	Buprenorphine-naloxone (n = 59)	Overall (n = 123)	Subcutaneous buprenorphine (n = 149)	Buprenorphine-naloxone (n = 156)	Overall (n = 305)
Age, mean (SD), y	39.8 (11.1)	38.2 (10.5)	39.1 (10.8)	38.3 (11.2)	37.9 (11.1)	38.1 (11.1)
Sex
Female	30 (46.9)	18 (30.5)	48 (39.0)	62 (41.6)	55 (35.3)	117 (38.4)
Male	34 (53.1)	41 (69.5)	75 (61.0)	87 (58.4)	101 (64.7)	188 (61.6)
Race and ethnicity
Black	14 (21.9)	16 (27.1)	30 (24.4)	33 (22.1)	32 (20.5)	65 (21.3)
White	48 (75.0)	42 (71.2)	90 (73.2)	111 (74.5)	122 (78.2)	233 (76.4)
Other^a	2 (3.1)	1 (1.7)	3 (2.4)	5 (3.4)	2 (1.3)	7 (2.3)
Geographic region^b
Alabama	2 (3.1)	4 (6.8)	6 (4.9)	10 (6.7)	5 (3.2)	15 (4.9)
California	2 (3.1)	1 (1.7)	3 (2.4)	19 (12.8)	27 (17.3)	46 (15.1)
Florida	21 (32.8)	14 (23.7)	35 (28.5)	18 (12.1)	20 (12.8)	38 (12.5)
Missouri	7 (10.9)	10 (16.9)	17 (13.8)	13 (8.7)	15 (9.6)	28 (9.2)
New Jersey	8 (12.5)	6 (10.2)	14 (11.4)	16 (10.7)	20 (12.8)	36 (11.8)
Ohio	18 (28.1)	15 (25.4)	33 (26.8)	10 (6.7)	8 (5.1)	18 (5.9)
Pennsylvania	2 (3.1)	1 (1.7)	3 (2.4)	13 (8.7)	8 (5.1)	21 (6.9)
Texas	0	1 (1.7)	1 (0.8)	19 (12.8)	17 (10.9)	36 (11.8)
Employed full time or part time	19 (29.7)	16 (27.1)	35 (28.5)	57 (38.3)	56 (35.9)	113 (37.0)
History of any arrest	38 (59.4)	32 (54.2)	70 (56.9)	92 (61.7)	112 (71.8)	204 (66.9)
Duration since OUD diagnosis, mean (SD), y	10.6 (14.6)	4.0 (6.0)	7.3 (11.3)	2.9 (4.8)	4.8 (6.2)	3.6 (5.4)
Injection route of illicit opioid use	38 (59.4)	30 (50.8)	68 (55.3)	76 (51.0)	80 (51.3)	156 (51.1)
Heroin primary opioid of use (self-report)	56 (87.5)	48 (81.4)	104 (84.6)	96 (64.4)	103 (66.0)	199 (65.2)
Nonopioid drug use at screening	39 (60.9)	38 (64.4)	77 (62.6)	95 (63.8)	91 (58.3)	186 (61.0)
Methamphetamines	8 (12.5)	4 (6.8)	12 (9.8)	30 (20.1)	28 (17.9)	58 (19.0)
Benzodiazepines	13 (20.3)	13 (22.0)	26 (21.1)	17 (11.4)	22 (14.1)	39 (12.8)
Marijuana	13 (20.3)	17 (28.8)	30 (24.4)	44 (29.5)	47 (30.1)	91 (29.8)
Cocaine	23 (35.9)	24 (40.7)	47 (38.2)	30 (20.1)	29 (18.6)	59 (19.3)
Hepatitis C antibody–positive at screening	35 (54.7)	23 (39.0)	58 (47.2)	51 (34.2)	58 (37.2)	109 (35.7)
COWS score, mean (SD)	11.5 (5.1)	11.6 (5.4)	11.6 (5.2)	12.5 (5.5)	12.5 (6.2)	12.5 (5.9)
SOWS score, mean (SD)	33.8 (14.4)	34.0 (16.0)	33.9 (15.1)	30.5 (15.8)	29.3 (16.0)	29.9 (15.8)
Opioid craving: desire-to-use VAS score, mean (SD)	78.5 (21.9)	75.0 (25.0)	76.8 (23.4)	76.7 (27.9)	77.3 (25.6)	77.0 (26.7)
Opioid craving: need-to-use VAS score, mean (SD)	76.4 (26.2)	76.8 (25.7)	76.6 (25.9)	76.6 (25.1)	75.1 (24.7)	75.9 (24.9)

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Abbreviations: COWS, Clinical Opioid Withdrawal Scale; OUD, opioid use disorder; SOWS, Subjective Opioid Withdrawal Scale; VAS, visual analog scale.

^{^a}

Includes American Indian or Alaska Native, Asian, and Native Hawaiian or Other Pacific Islander.

^{^b}

Includes states with 20 or more participants overall.

Buprenorphine Dosing

Mean buprenorphine dosing at week 1 was comparable across treatment groups for both the fentanyl-positive and fentanyl-negative subgroups (eTable in Supplement 2). Most patients’ sublingual buprenorphine doses were titrated to 16 mg to 24 mg per day or the subcutaneous buprenorphine equivalent.

Treatment Outcomes

Retention in Treatment

The percentage of patients completing the study was similar for the fentanyl-positive (60.2% [74 of 123]) and fentanyl-negative (56.7% [173 of 305]) subgroups. It did not differ between fentanyl-positive patients receiving subcutaneous buprenorphine (40 of 64 [62.5%]) or sublingual buprenorphine-naloxone (34 of 59 [57.6%]) (Figure 1).

Figure 1. — BPN-NX indicates sublingual buprenorphine-naloxone; SC-BPN, weekly and monthly subcutaneous injection buprenorphine.

^aBased on urine toxicology evidence of fentanyl use at baseline.

Any Opioid Use

Figure 2A displays the percentage of urine samples with negative results for any opioids across the 24-week trial. Analysis of variance on the summary score of percentage of samples negative for any illicit opioids across the trial yielded significant main results of the fentanyl-positive subgroup (F_1,424 = 6.878; P = .009) in the direction of lower scores (lower percentage of opioid-negative urine samples) in the fentanyl-positive subgroup (point estimates, 24.7% in the fentanyl-positive subgroup and 34.6% in the fentanyl-negative subgroup), and of the treatment group (F_1,424 = 4.265; P = .04) in the direction of lower scores for buprenorphine-naloxone than for subcutaneous buprenorphine. The interaction of fentanyl-positive subgroup by treatment was not significant (F_1,424 = 0.216; P = .64). The percentages of negative scores in the fentanyl-positive subgroup were 28.5% among those receiving subcutaneous buprenorphine vs 18.8% among those receiving buprenorphine-naloxone (difference between treatments, 9.6%; 95% CI, −3.0% to 22.3%; P = .14), and in the fentanyl-negative subgroup were 36.7% among those receiving subcutaneous buprenorphine vs 30.6% among those receiving buprenorphine-naloxone (difference between treatments, 6.1%; 95% CI, −1.9% to 14.1%; P = .14). The MMRM of the percentage of negative urine samples over time in the fentanyl-negative subgroup yielded a significant result of treatment (F_1,288 = 5.49; P = .02) in the direction of greater negative urine samples for subcutaneous buprenorphine compared with buprenorphine-naloxone, with no associations of time or treatment by time. In the fentanyl-positive subgroup, the mixed model yielded significant results of time (F_17,63 = 2.21; P = .01) and treatment by time (F_17,63 = 1.99; P = .03). This finding was consistent with the observations of the raw data (Figure 2A) in the fentanyl-positive subgroup that percentage of negative urine samples started low and gradually increased over the early weeks of the trial, whereas after week 5, the treatment groups separated, with greater fentanyl-negative percentages in the subcutaneous buprenorphine group.

Fentanyl Use

Figure 2B and C displays the raw percentages of urine samples negative for fentanyl and norfentanyl, respectively, over time. For the subgroup negative for fentanyl at baseline, fentanyl-positive and norfentanyl-positive urine samples were infrequent, with negative rates in the 82% to 97% range across the trial and little apparent difference between treatments. In the baseline fentanyl-positive subgroup, subcutaneous buprenorphine appeared to produce higher rates of urine samples negative for fentanyl or norfentanyl compared with buprenorphine-naloxone, mainly in the later weeks of the trial. In the baseline fentanyl-positive subgroup, the summary score of percentage urine samples negative for fentanyl across the trial was significantly greater for subcutaneous buprenorphine compared with buprenorphine-naloxone (74.6% vs 61.9%; difference between treatments, 12.7%; 95% CI, 9.6%-15.9%; P < .001), as was the percentage negative for norfentanyl (61.3% vs 43.3%; difference between treatments, 18.0%; 95% CI, 14.4%-21.7%; P < .001).

Opioid Withdrawal and Craving

Opioid withdrawal, as evaluated by the Clinical Opiate Withdrawal Scale and Subjective Opiate Withdrawal Scale (Figure 3A and B) and measures of opioid craving (Figure 3C and D), decreased rapidly over the early weeks of the trial, with no discernable differences between fentanyl-positive and fentanyl-negative subgroups or those receiving subcutaneous buprenorphine or sublingual buprenorphine-naloxone.

Safety Outcomes

There were no clinically meaningful differences in AE rates between the fentanyl-positive and fentanyl-negative subgroups, or between treatment groups (Table 2). With the exception of injection-site AEs (ie, swelling, inflammation, and induration), the AEs observed were consistent with the known safety profile of buprenorphine.¹⁶ Three nonfatal overdoses involving heroin were reported overall, 1 in the fentanyl-negative subgroup and 2 in the fentanyl-positive subgroup, all receiving sublingual buprenorphine-naloxone.

Table 2. Summary of Adverse Events (Safety Population).

Adverse event	Fentanyl-positive group, No. (%)			Fentanyl-negative group, No. (%)
Adverse event	Subcutaneous buprenorphine (n = 64)	Buprenorphine-naloxone (n = 59)	Overall (n = 123)	Subcutaneous buprenorphine (n = 149)	Buprenorphine-naloxone (n = 156)	Overall (n = 305)
Participants with any AEs	37 (57.8)	31 (52.5)	68 (55.3)	98 (65.8)	94 (60.3)	192 (63.0)
AEs, No.	173	222	395	349	388	737
Participants with serious AEs	0	6 (10.2)	6 (4.9)	7 (4.7)	7 (4.5)	14 (4.6)
Participants with serious AEs in infections and infestations SOC	0	4 (6.8)	4 (3.3)	1 (0.7)	4 (2.6)	5 (1.6)
Participants with AEs that led to drug discontinuation	0	0	0	7 (4.7)	3 (1.9)	10 (3.3)
Participants with AEs suspected to be drug-related	21 (32.8)	19 (32.2)	40 (32.5)	49 (32.9)	45 (28.8)	94 (30.8)
Deaths	0	0	0	1 (0.7)^a	0	1 (0.3)^a
Most common AEs^b
Nausea	7 (10.9)	7 (11.9)	14 (11.4)	9 (6.0)	11 (7.1)	20 (6.6)
Constipation	5 (7.8)	8 (13.6)	13 (10.6)	13 (8.7)	9 (5.8)	22 (7.2)
Increased alanine aminotransferase level	5 (7.8)	5 (8.5)	10 (8.1)	1 (0.7)	0	1 (0.3)
Injection-site erythema	4 (6.2)	5 (8.5)	9 (7.3)	10 (6.7)	7 (4.5)	17 (5.6)
Upper respiratory tract infection	6 (9.4)	3 (5.1)	9 (7.3)	4 (2.7)	7 (4.5)	11 (3.6)
Injection-site pain	4 (6.2)	4 (6.8)	8 (6.5)	17 (11.4)	13 (8.3)	30 (9.8)
Injection-site pruritus	3 (4.7)	5 (8.5)	8 (6.5)	10 (6.7)	8 (5.1)	18 (5.9)
Injection-site inflammation	2 (3.1)	6 (10.2)	8 (6.5)	0	3 (1.9)	3 (1.0)
Increased aspartate aminotransferase level	4 (6.2)	4 (6.8)	8 (6.5)	0	1 (0.6)	1 (0.3)
Headache	4 (6.2)	2 (3.4)	6 (4.9)	12 (8.1)	16 (10.3)	28 (9.2)
Vomiting	3 (4.7)	3 (5.1)	6 (4.9)	6 (4.0)	7 (4.5)	13 (4.3)
Injection-site swelling	3 (4.7)	3 (5.1)	6 (4.9)	7 (4.7)	4 (2.6)	11 (3.6)
Back pain	2 (3.1)	4 (6.8)	6 (4.9)	1 (0.7)	2 (1.3)	3 (1.0)
Injection-site induration	1 (1.6)	4 (6.8)	5 (4.1)	3 (2.0)	2 (1.3)	5 (1.6)
Urinary tract infection	2 (3.1)	2 (3.4)	4 (3.3)	12 (8.1)	11 (7.1)	23 (7.5)
Insomnia	3 (4.7)	1 (1.7)	4 (3.3)	11 (7.4)	5 (3.2)	16 (5.2)
Increased blood glucose	0	3 (5.1)	3 (2.4)	1 (0.7)	0	1 (0.3)

Open in a new tab

Abbreviations: AE, adverse event; SOC, system organ class.

^{^a}

Participant was hit by a car and died. The death was considered unlikely to be related to the study drug.

^{^b}

In 5.0% or more of any treatment group.

Discussion

To our knowledge, this is one of the first reports of a randomized clinical trial to examine medication treatment of OUD among patients using fentanyl that has compared subgroups with vs without fentanyl use at baseline. The findings support previous observational studies,^14,18 suggesting that buprenorphine is effective among people who use fentanyl. Participant retention in this 24-week trial was similar between the fentanyl-positive (60.2%) and fentanyl-negative (56.7%) subgroups, comparing favorably with other large trials that have shown 24-week retention rates for buprenorphine treatment in the 40% to 50% range.^19,20 Withdrawal and craving scores improved rapidly across the fentanyl-positive and fentanyl-negative subgroups. Adverse events were comparable across groups and consistent with the known safety profile of buprenorphine. The main association of the fentanyl-positive subgroup with the summary score of percentage of urine samples negative for any opioids across the 24-week trial (point estimates, 24.7% in the fentanyl-positive subgroup and 34.6% in the fentanyl-negative subgroup) and the slow increase in opioid-negative rates over the early weeks of the trial in the fentanyl-positive subgroup (Figure 2) suggest that abstinence may be more difficult to achieve among people who use fentanyl. Nonetheless, studies of OUD in which participants were treated with placebo or counseling without medication have shown much lower opioid-negative rates.^21,22 Participants in the fentanyl-positive subgroup had baseline characteristics suggestive of greater disease severity compared with the fentanyl-negative subgroup, such as more heroin use and more co-occurring cocaine and benzodiazepine use. Thus, lower percentages of urine samples negative for opioids and slower response in the fentanyl-positive subgroup could be associated with greater overall disease severity.

Consistent with the primary outcome analysis,¹⁶ the main association of medication with the summary score of percentage of urine samples negative for any opioids suggests that subcutaneous buprenorphine is modestly more effective than buprenorphine-naloxone in reducing overall opioid use. The difference between treatment groups in the fentanyl-positive subgroup, although numerically favoring subcutaneous buprenorphine, was not significant. However, the treatment by time interaction in the repeated-measures analysis suggests that after the slow start for opioid-negative urine samples in the fentanyl-positive subgroup mentioned above, those treated with subcutaneous buprenorphine had more negative urine samples than those treated with buprenorphine-naloxone in the later weeks of the trial (Figure 2). Furthermore, within the fentanyl-positive subgroup, the summary scores of percentage of urine samples negative for fentanyl or norfentanyl were significantly greater among those treated with subcutaneous buprenorphine compared with buprenorphine-naloxone. An extended-release injectable formulation of buprenorphine may be advantageous, particularly for more severely ill patients using fentanyl, perhaps due to blood levels of the medication being more sustained than with sublingual buprenorphine-naloxone (for which patients may miss daily doses). The extended-release injectable formulation of naltrexone has been found to be advantageous for patients with alcohol use disorder or OUD and indicators of greater severity or adverse social determinants.^23,24

In the present study, there was no evidence of greater early dropout or withdrawal symptoms suggestive of precipitated withdrawal among the fentanyl-positive subgroup, consistent with recent studies.^25,26 However, precipitated withdrawal continues to be described when buprenorphine is initiated in the setting of fentanyl or other high-potency opioids, which have increased in prevalence and in likely levels of exposure since the present study.^27,28,29 As this study was not specifically designed to evaluate withdrawal during buprenorphine initiation, more research is needed to clarify the factors and conditions that may complicate buprenorphine initiation among individuals using high-potency opioids.

Strengths and Limitations

This study has some strengths, including its double-blind, double-dummy design, with injections administered by unblinded personnel not involved in study assessments. Opioid use outcomes were based on an objective measure, urine toxicology, measured with assays that have high sensitivity for fentanyl and other opioids.¹⁶

This study also has some limitations. In 2016, the year the study was completed, fentanyl use and fentanyl-related fatal overdoses were surging, and illicitly manufactured synthetic opioids, including fentanyl and its analogues, surpassed prescription opioids as the most common drugs involved in overdose-related deaths in the US.^30,31 Most patients in the fentanyl-positive subgroup reported primarily using heroin, consistent with the heroin supply being mixed with fentanyl, often unbeknownst to those who used the drug,⁶ and exposure to fentanyl may have been intermittent. The presence of fentanyl and other highly potent fentanyl analogues in the illicit drug supply has increased since 2016. Thus, it is not clear how well the findings would generalize to contemporary patients presenting for treatment, who may be using higher and more consistent doses of fentanyl and other high-potency synthetic analogues.

Other limitations include this secondary analysis of fentanyl use not being prespecified, and the parent trial not being designed to assess differences in treatment response between the subgroups. Differences in outcomes between the fentanyl-positive and fentanyl-negative subgroups could be related to overall disease severity rather than fentanyl per se, given baseline characteristics suggestive of greater severity in the fentanyl-positive subgroup. Furthermore, findings regarding fentanyl use are limited to the geographic locations included as study sites, which may not be representative of the entire US or state-specific trends.

Conclusions

In this post hoc analysis of a large, multisite US-based trial comparing sublingual buprenorphine-naloxone vs an extended-release injection of buprenorphine for treatment of OUD, completed in 2016, more than one-fourth of patients had evidence of fentanyl use at study entry, reflecting the emergence of fentanyl in the illicit drug supply. The findings suggest that buprenorphine is similarly effective in regard to opioid withdrawal, craving, and treatment retention, although abstinence may be somewhat more difficult to achieve for patients with evidence of fentanyl use. The findings provide tentative evidence that extended-release, subcutaneously injected formulations of buprenorphine may be advantageous for reducing opioid use among people who use fentanyl. Further research is warranted to assess the efficacy of buprenorphine and other medications for OUD among contemporary persons using fentanyl, and to further assess the relative efficacy of standard vs extended-release formulations.

Supplement 1.

Trial Protocol and Statistical Analysis Plan

jamanetwopen-e2417377-s001.pdf^{(1,021.5KB, pdf)}

Supplement 2.

eTable. Buprenorphine Dosing in SC-BPN Dose Equivalents at the End of Week 1

jamanetwopen-e2417377-s002.pdf^{(240.8KB, pdf)}

Supplement 3.

Data Sharing Statement

jamanetwopen-e2417377-s003.pdf^{(16.6KB, pdf)}

References

1.Trends & statistics: drug overdose death rates. National Institute on Drug Abuse . Accessed June 23, 2023. https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates
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5.Mars SG, Rosenblum D, Ciccarone D. Illicit fentanyls in the opioid street market: desired or imposed? Addiction. 2019;114(5):774-780. doi: 10.1111/add.14474 [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Frank RG, Pollack HA. Addressing the fentanyl threat to public health. N Engl J Med. 2017;376(7):605-607. doi: 10.1056/NEJMp1615145 [DOI] [PubMed] [Google Scholar]
7.Comer SD, Cahill CM. Fentanyl: receptor pharmacology, abuse potential, and implications for treatment. Neurosci Biobehav Rev. 2019;106:49-57. doi: 10.1016/j.neubiorev.2018.12.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
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15.Volkow ND. The epidemic of fentanyl misuse and overdoses: challenges and strategies. World Psychiatry. 2021;20(2):195-196. doi: 10.1002/wps.20846 [DOI] [PMC free article] [PubMed] [Google Scholar]
16.Lofwall MR, Walsh SL, Nunes EV, et al. Weekly and monthly subcutaneous buprenorphine depot formulations vs daily sublingual buprenorphine with naloxone for treatment of opioid use disorder: a randomized clinical trial. JAMA Intern Med. 2018;178(6):764-773. doi: 10.1001/jamainternmed.2018.1052 [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Siddiqui O, Hung HMJ, O’Neill R. MMRM vs. LOCF: a comprehensive comparison based on simulation study and 25 NDA datasets. J Biopharm Stat. 2009;19(2):227-246. doi: 10.1080/10543400802609797 [DOI] [PubMed] [Google Scholar]
18.Carroll JJ, Marshall BDL, Rich JD, Green TC. Exposure to fentanyl-contaminated heroin and overdose risk among illicit opioid users in Rhode Island: a mixed methods study. Int J Drug Policy. 2017;46:136-145. doi: 10.1016/j.drugpo.2017.05.023 [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Hser YI, Saxon AJ, Huang D, et al. Treatment retention among patients randomized to buprenorphine/naloxone compared to methadone in a multi-site trial. Addiction. 2014;109(1):79-87. doi: 10.1111/add.12333 [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Lee JD, Nunes EV Jr, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018;391(10118):309-318. doi: 10.1016/S0140-6736(17)32812-X [DOI] [PMC free article] [PubMed] [Google Scholar]
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23.Smith-Bernardin S, Rowe C, Behar E, et al. Low-threshold extended-release naltrexone for high utilizers of public services with severe alcohol use disorder: a pilot study. J Subst Abuse Treat. 2018;85:109-115. doi: 10.1016/j.jsat.2017.11.005 [DOI] [PubMed] [Google Scholar]
24.Nunes EV Jr, Scodes JM, Pavlicova M, et al. Sublingual buprenorphine-naloxone compared with injection naltrexone for opioid use disorder: potential utility of patient characteristics in guiding choice of treatment. Am J Psychiatry. 2021;178(7):660-671. doi: 10.1176/appi.ajp.2020.20060816 [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Mariani JJ, Mahony AL, Podell SC, et al. Open-label trial of a single-day induction onto buprenorphine extended-release injection for users of heroin and fentanyl. Am J Addict. 2021;30(5):470-476. doi: 10.1111/ajad.13193 [DOI] [PMC free article] [PubMed] [Google Scholar]
26.D’Onofrio G, Hawk KF, Perrone J, et al. Incidence of precipitated withdrawal during a multisite emergency department–initiated buprenorphine clinical trial in the era of fentanyl. JAMA Netw Open. 2023;6(3):e236108. doi: 10.1001/jamanetworkopen.2023.6108 [DOI] [PMC free article] [PubMed] [Google Scholar]
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28.Silverstein SM, Daniulaityte R, Martins SS, Miller SC, Carlson RG. “Everything is not right anymore”: buprenorphine experiences in an era of illicit fentanyl. Int J Drug Policy. 2019;74:76-83. doi: 10.1016/j.drugpo.2019.09.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Spadaro A, Faude S, Perrone J, et al. Precipitated opioid withdrawal after buprenorphine administration in patients presenting to the emergency department: a case series. J Am Coll Emerg Physicians Open. 2023;4(1):e12880. doi: 10.1002/emp2.12880 [DOI] [PMC free article] [PubMed] [Google Scholar]
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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

Trial Protocol and Statistical Analysis Plan

jamanetwopen-e2417377-s001.pdf^{(1,021.5KB, pdf)}

Supplement 2.

eTable. Buprenorphine Dosing in SC-BPN Dose Equivalents at the End of Week 1

jamanetwopen-e2417377-s002.pdf^{(240.8KB, pdf)}

Supplement 3.

Data Sharing Statement

jamanetwopen-e2417377-s003.pdf^{(16.6KB, pdf)}

[zoi240572r1] 1.Trends & statistics: drug overdose death rates. National Institute on Drug Abuse . Accessed June 23, 2023. https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates

[zoi240572r2] 2.Kuehn BM. Fentanyl drives startling increases in adolescent overdose deaths. JAMA. 2023;329(4):280-281. doi: 10.1001/jama.2022.23563 [DOI] [PubMed] [Google Scholar]

[zoi240572r3] 3.O’Donnell JK, Halpin J, Mattson CL, Goldberger BA, Gladden RM. Deaths involving fentanyl, fentanyl analogs, and U-47700—0 states, July–December 2016. MMWR Morb Mortal Wkly Rep. 2017;66(43):1197-1202. doi: 10.15585/mmwr.mm6643e1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240572r4] 4.DEA Intelligence Brief. Counterfeit prescription pills containing fentanyls: a global threat: DEA-DCT-DIB-021-16. July 2016. Drug Enforcement Administration Strategic Intelligence Section . Accessed April 24, 2024. https://www.dea.gov/sites/default/files/docs/Counterfeit%2520Prescription%2520Pills.pdf

[zoi240572r5] 5.Mars SG, Rosenblum D, Ciccarone D. Illicit fentanyls in the opioid street market: desired or imposed? Addiction. 2019;114(5):774-780. doi: 10.1111/add.14474 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240572r6] 6.Frank RG, Pollack HA. Addressing the fentanyl threat to public health. N Engl J Med. 2017;376(7):605-607. doi: 10.1056/NEJMp1615145 [DOI] [PubMed] [Google Scholar]

[zoi240572r7] 7.Comer SD, Cahill CM. Fentanyl: receptor pharmacology, abuse potential, and implications for treatment. Neurosci Biobehav Rev. 2019;106:49-57. doi: 10.1016/j.neubiorev.2018.12.005 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240572r8] 8.Han Y, Cao L, Yuan K, Shi J, Yan W, Lu L. Unique pharmacology, brain dysfunction, and therapeutic advancements for fentanyl misuse and abuse. Neurosci Bull. 2022;38(11):1365-1382. doi: 10.1007/s12264-022-00872-3 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240572r9] 9.Kelly E, Sutcliffe K, Cavallo D, Ramos-Gonzalez N, Alhosan N, Henderson G. The anomalous pharmacology of fentanyl. Br J Pharmacol. 2023;180(7):797-812. doi: 10.1111/bph.15573 [DOI] [PubMed] [Google Scholar]

[zoi240572r10] 10.Drug Enforcement Administration (DEA), U.S. Department of Justice . Control of a chemical precursor used in the illicit manufacture of fentanyl as a List I chemical: interim rule with request for comments. Fed Regist. 2007;72(77):20039-20047. [PubMed] [Google Scholar]

[zoi240572r11] 11.Gill H, Kelly E, Henderson G. How the complex pharmacology of the fentanyls contributes to their lethality. Addiction. 2019;114(9):1524-1525. doi: 10.1111/add.14614 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240572r12] 12.Keary CJ, Wang Y, Moran JR, Zayas LV, Stern TA. Toxicologic testing for opiates: understanding false-positive and false-negative test results. Prim Care Companion CNS Disord. 2012;14(4):PCC.12f01371. doi: 10.4088/PCC.12f01371 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240572r13] 13.Connery HS. Medication-assisted treatment of opioid use disorder: review of the evidence and future directions. Harv Rev Psychiatry. 2015;23(2):63-75. doi: 10.1097/HRP.0000000000000075 [DOI] [PubMed] [Google Scholar]

[zoi240572r14] 14.Wakeman SE, Chang Y, Regan S, et al. Impact of fentanyl use on buprenorphine treatment retention and opioid abstinence. J Addict Med. 2019;13(4):253-257. doi: 10.1097/ADM.0000000000000486 [DOI] [PubMed] [Google Scholar]

[zoi240572r15] 15.Volkow ND. The epidemic of fentanyl misuse and overdoses: challenges and strategies. World Psychiatry. 2021;20(2):195-196. doi: 10.1002/wps.20846 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240572r16] 16.Lofwall MR, Walsh SL, Nunes EV, et al. Weekly and monthly subcutaneous buprenorphine depot formulations vs daily sublingual buprenorphine with naloxone for treatment of opioid use disorder: a randomized clinical trial. JAMA Intern Med. 2018;178(6):764-773. doi: 10.1001/jamainternmed.2018.1052 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240572r17] 17.Siddiqui O, Hung HMJ, O’Neill R. MMRM vs. LOCF: a comprehensive comparison based on simulation study and 25 NDA datasets. J Biopharm Stat. 2009;19(2):227-246. doi: 10.1080/10543400802609797 [DOI] [PubMed] [Google Scholar]

[zoi240572r18] 18.Carroll JJ, Marshall BDL, Rich JD, Green TC. Exposure to fentanyl-contaminated heroin and overdose risk among illicit opioid users in Rhode Island: a mixed methods study. Int J Drug Policy. 2017;46:136-145. doi: 10.1016/j.drugpo.2017.05.023 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240572r19] 19.Hser YI, Saxon AJ, Huang D, et al. Treatment retention among patients randomized to buprenorphine/naloxone compared to methadone in a multi-site trial. Addiction. 2014;109(1):79-87. doi: 10.1111/add.12333 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240572r20] 20.Lee JD, Nunes EV Jr, Novo P, et al. Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial. Lancet. 2018;391(10118):309-318. doi: 10.1016/S0140-6736(17)32812-X [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240572r21] 21.Haight BR, Learned SM, Laffont CM, et al. ; RB-US-13-0001 Study Investigators . Efficacy and safety of a monthly buprenorphine depot injection for opioid use disorder: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2019;393(10173):778-790. doi: 10.1016/S0140-6736(18)32259-1 [DOI] [PubMed] [Google Scholar]

[zoi240572r22] 22.Cochran G, Stitzer M, Campbell ANC, Hu MC, Vandrey R, Nunes EV. Web-based treatment for substance use disorders: differential effects by primary substance. Addict Behav. 2015;45:191-194. doi: 10.1016/j.addbeh.2015.02.002 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240572r23] 23.Smith-Bernardin S, Rowe C, Behar E, et al. Low-threshold extended-release naltrexone for high utilizers of public services with severe alcohol use disorder: a pilot study. J Subst Abuse Treat. 2018;85:109-115. doi: 10.1016/j.jsat.2017.11.005 [DOI] [PubMed] [Google Scholar]

[zoi240572r24] 24.Nunes EV Jr, Scodes JM, Pavlicova M, et al. Sublingual buprenorphine-naloxone compared with injection naltrexone for opioid use disorder: potential utility of patient characteristics in guiding choice of treatment. Am J Psychiatry. 2021;178(7):660-671. doi: 10.1176/appi.ajp.2020.20060816 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240572r25] 25.Mariani JJ, Mahony AL, Podell SC, et al. Open-label trial of a single-day induction onto buprenorphine extended-release injection for users of heroin and fentanyl. Am J Addict. 2021;30(5):470-476. doi: 10.1111/ajad.13193 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240572r26] 26.D’Onofrio G, Hawk KF, Perrone J, et al. Incidence of precipitated withdrawal during a multisite emergency department–initiated buprenorphine clinical trial in the era of fentanyl. JAMA Netw Open. 2023;6(3):e236108. doi: 10.1001/jamanetworkopen.2023.6108 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240572r27] 27.Bisaga A. What should clinicians do as fentanyl replaces heroin? Addiction. 2019;114(5):782-783. doi: 10.1111/add.14522 [DOI] [PubMed] [Google Scholar]

[zoi240572r28] 28.Silverstein SM, Daniulaityte R, Martins SS, Miller SC, Carlson RG. “Everything is not right anymore”: buprenorphine experiences in an era of illicit fentanyl. Int J Drug Policy. 2019;74:76-83. doi: 10.1016/j.drugpo.2019.09.003 [DOI] [PMC free article] [PubMed] [Google Scholar]

[zoi240572r29] 29.Spadaro A, Faude S, Perrone J, et al. Precipitated opioid withdrawal after buprenorphine administration in patients presenting to the emergency department: a case series. J Am Coll Emerg Physicians Open. 2023;4(1):e12880. doi: 10.1002/emp2.12880 [DOI] [PMC free article] [PubMed] [Google Scholar]

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PERMALINK

Extended-Release Injection vs Sublingual Buprenorphine for Opioid Use Disorder With Fentanyl Use

Edward V Nunes, MD

Sandra D Comer, PhD

Michelle R Lofwall, MD

Sharon L Walsh, PhD

Stefan Peterson, PhD

Fredrik Tiberg, PhD

Peter Hjelmstrom, MD, PhD

Natalie R Budilovsky-Kelley, PharmD

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Intervention

Main Outcomes and Measures

Results

Conclusions and Relevance

Trial Registration

Introduction

Methods

Study Design and Patients

Assessments

Statistical Analysis

Results

Participant Characteristics

Table 1. Demographic and Baseline Characteristics by Baseline Fentanyl Use and Treatment (Intention-to-Treat Population).

Buprenorphine Dosing

Treatment Outcomes

Retention in Treatment

Figure 1. Study Flowchart Through Follow-Up.

Any Opioid Use

Figure 2. Urine Toxicology Results During Study by Baseline Fentanyl Use and Treatment.

Fentanyl Use

Opioid Withdrawal and Craving

Figure 3. Opioid Withdrawal and Craving by Baseline Fentanyl Use.

Safety Outcomes

Table 2. Summary of Adverse Events (Safety Population).

Discussion

Strengths and Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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