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Randomized Controlled Trial
. 2024 May 1;7(5):e249744.
doi: 10.1001/jamanetworkopen.2024.9744.

Rapid Initiation of Injection Naltrexone for Opioid Use Disorder: A Stepped-Wedge Cluster Randomized Clinical Trial

Matisyahu Shulman  1 , Miranda G Greiner  1 , Hiwot M Tafessu  2 , Onumara Opara  1 , Kaitlyn Ohrtman  1 , Kenzie Potter  1 , Kathryn Hefner  2 , Eve Jelstrom  2 , Richard N Rosenthal  3 , Kevin Wenzel  4 , Marc Fishman  4 , John Rotrosen  5 , Udi E Ghitza  6 , Edward V Nunes  1 , Adam Bisaga  1
Affiliations
Randomized Controlled Trial

Rapid Initiation of Injection Naltrexone for Opioid Use Disorder: A Stepped-Wedge Cluster Randomized Clinical Trial

Matisyahu Shulman et al. JAMA Netw Open. .

Abstract

Importance: Injectable extended-release (XR)-naltrexone is an effective treatment option for opioid use disorder (OUD), but the need to withdraw patients from opioid treatment prior to initiation is a barrier to implementation.

Objective: To compare the effectiveness of the standard procedure (SP) with the rapid procedure (RP) for XR-naltrexone initiation.

Design, setting, and participants: The Surmounting Withdrawal to Initiate Fast Treatment with Naltrexone study was an optimized stepped-wedge cluster randomized trial conducted at 6 community-based inpatient addiction treatment units. Units using the SP were randomly assigned at 14-week intervals to implement the RP. Participants admitted with OUD received the procedure the unit was delivering at the time of their admission. Participant recruitment took place between March 16, 2021, and July 18, 2022. The last visit was September 21, 2022.

Interventions: Standard procedure, based on the XR-naltrexone package insert (approximately 5-day buprenorphine taper followed by a 7- to 10-day opioid-free period and RP, defined as 1 day of buprenorphine at minimum necessary dose, 1 opioid-free day, and ascending low doses of oral naltrexone and adjunctive medications (eg, clonidine, clonazepam, antiemetics) for opioid withdrawal.

Main outcomes and measures: Receipt of XR-naltrexone injection prior to inpatient discharge (primary outcome). Secondary outcomes included opioid withdrawal scores and targeted safety events and serious adverse events. All analyses were intention-to-treat.

Results: A total of 415 participants with OUD were enrolled (mean [SD] age, 33.6 [8.48] years; 205 [49.4%] identified sex as male); 54 [13.0%] individuals identified as Black, 91 [21.9%] as Hispanic, 290 [69.9%] as White, and 22 [5.3%] as multiracial. Rates of successful initiation of XR-naltrexone among the RP group (141 of 225 [62.7%]) were noninferior to those of the SP group (68 of 190 [35.8%]) (odds ratio [OR], 3.60; 95% CI, 2.12-6.10). Withdrawal did not differ significantly between conditions (proportion of days with a moderate or greater maximum Clinical Opiate Withdrawal Scale score (>12) for RP vs SP: OR, 1.25; 95% CI, 0.62-2.50). Targeted safety events (RP: 12 [5.3%]; SP: 4 [2.1%]) and serious adverse events (RP: 15 [6.7%]; SP: 3 [1.6%]) were infrequent but occurred more often with RP than SP.

Conclusions and relevance: In this trial, the RP of XR-naltrexone initiation was noninferior to the standard approach and saved time, although it required more intensive medical management and safety monitoring. The results of this trial suggest that rapid initiation could make XR-naltrexone a more viable treatment for patients with OUD.

Trial registration: ClinicalTrials.gov Identifier: NCT04762537.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Hefner reported having a contract with the National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) during the conduct of the study. Dr Jelstrom reported contract work from the NIDA Clinical Coordinating Center during the conduct of the study. Dr Wenzel reported receiving grants from the National Institutes of Health (NIH) during the conduct of the study and grants from Alkermes Inc outside the submitted work. Dr Fishman reported receiving grants from the NIDA and study medication from Alkermes during the conduct of the study; consultant fees and study medication from Alkermes, consultant fees from Indivior for staff training, study medication from Braeburn, consultant fees from Nirsum Laboratories, and Drug Delivery LLC; and grants from Alkermes to the institution outside the submitted work. Dr Rotrosen reported receiving grants from the NIDA/NIH, study medication from Alkermes, which provided Vivitrol and, in some cases, funds for studies conducted at NYU and, in some cases, sponsored and/or funded by the NIDA, and nonfinancial support from Indivior, which provided buprenorphine and, in some cases, funds for studies conducted at NYU and sponsored and/or funded by the NIDA during the conduct of the study; grants from the NIDA/NIH, nonfinancial support from Alkermes, which provided Vivitrol and, in some cases, funds for studies conducted at NYU and sponsored and/or funded by NIDA, and nonfinancial support from Indivior, which provided buprenorphine and in, some cases, funds for studies conducted at NYU and sponsored and/or funded by NIDA outside the submitted work; and is currently involved in studies using injectable buprenorphine in some cases supplied by Indivior or Braeburn. Buprenorphine and injectable buprenorphine could be considered a Vivitrol competitor. In all cases, funds were provided only to either NYU or NIDA. Dr Nunes reported receiving nonfinancial support from Alkermes and has been an investigator on NIH-funded studies that receive in-kind medication from Alkermes outside the submitted work. Dr Bisaga reported receiving grants and medication samples from Alkermes during the conduct of the study; and medication samples from Sophrosyne and Go Medical outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Stepped-Wedge Design in Which Treatment Sites Switched From Standard Procedure for Initiation of Extended-Release (XR)-Naltrexone to the Rapid Procedure Over Successive 14-Week Steps
Figure 2.
Figure 2.. Patient Flowchart
AMA indicates against medical advice; OUD, opioid use disorder; XR, extended-release.
Figure 3.
Figure 3.. Mean (SD) Daily Maximum Clinical Opiate Withdrawal Scale (COWS) Score During the First 15 Days of the Standard and Rapid Procedures
See this image and copyright information in PMC

References

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