Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial
Open accessAbstract
Background Extended-release naltrexone (XR-NTX), an opioid antagonist, and sublingual buprenorphine-naloxone (BUP-NX), a partial opioid agonist, are pharmacologically and conceptually distinct interventions to prevent opioid relapse. We aimed to estimate the difference in opioid relapse-free survival between XR-NTX and BUP-NX.Methods We initiated this 24 week, open-label, randomised controlled, comparative effectiveness trial at eight US community-based inpatient services and followed up participants as outpatients. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 opioid use disorder, and had used non-prescribed opioids in the past 30 days. We stratified participants by treatment site and opioid use severity and used a web-based permuted block design with random equally weighted block sizes of four and six for randomisation (1:1) to receive XR-NTX or BUP-NX. XR-NTX was monthly intramuscular injections (Vivitrol; Alkermes) and BUP-NX was daily self-administered buprenorphine-naloxone sublingual film (Suboxone; Indivior). The primary outcome was opioid relapse-free survival during 24 weeks of outpatient treatment. Relapse was 4 consecutive weeks of any non-study opioid use by urine toxicology or self-report, or 7 consecutive days of self-reported use. This trial is registered with ClinicalTrials.gov, NCT02032433.Findings Between Jan 30, 2014, and May 25, 2016, we randomly assigned 570 participants to receive XR-NTX (n=283) or BUP-NX (n=287). The last follow-up visit was Jan 31, 2017. As expected, XR-NTX had a substantial induction hurdle: fewer participants successfully initiated XR-NTX (204 [72%] of 283) than BUP-NX (270 [94%] of 287; p<0·0001). Among all participants who were randomly assigned (intention-to-treat population, n=570) 24 week relapse events were greater for XR-NTX (185 [65%] of 283) than for BUP-NX (163 [57%] of 287; hazard ratio [HR] 1·36, 95% CI 1·10-1·68), most or all of this difference accounted for by early relapse in nearly all (70 [89%] of 79) XR-NTX induction failures. Among participants successfully inducted (per-protocol population, n=474), 24 week relapse events were similar across study groups (p=0·44). Opioid-negative urine samples (p<0·0001) and opioid-abstinent days (p<0·0001) favoured BUP-NX compared with XR-NTX among the intention-to-treat population, but were similar across study groups among the per-protocol population. Self-reported opioid craving was initially less with XR-NTX than with BUP-NX (p=0·0012), then converged by week 24 (p=0·20). With the exception of mild-to-moderate XR-NTX injection site reactions, treatment-emergent adverse events including overdose did not differ between treatment groups. Five fatal overdoses occurred (two in the XR-NTX group and three in the BUP-NX group).Interpretation In this population it is more difficult to initiate patients to XR-NTX than BUP-NX, and this negatively affected overall relapse. However, once initiated, both medications were equally safe and effective. Future work should focus on facilitating induction to XR-NTX and on improving treatment retention for both medications.Funding NIDA Clinical Trials Network.
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Buprenorphine is prescribed to prevent relapse in opioid use disorder.
“is used for relapse prevention in opioid use disorder (278).”
From A brain-centric model of suicidal behavior (2020) · cites this paper as [278]
Extended-release naltrexone and buprenorphine have high relapse rates, 65% and 57% respectively.
“extended release naltrexone and buprenorphine have unacceptably high relapse rates (65% vs. 57% respectively) [9].”
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- Authors
- Lee, J. D., Nunes, E. V., Novo, P., Bachrach, K., Bailey, G. L., Bhatt, S., Farkas, S., Fishman, M., Gauthier, P., Hodgkins, C. C., King, J., Lindblad, R., Liu, D., Matthews, A. G., May, J., Peavy, K. M., Ross, S., Salazar, D., Schkolnik, P., Shmueli-Blumberg, D., Stablein, D., Subramaniam, G., & Rotrosen, J.
- Affiliations
- New York University (US)
- Columbia University Irving Medical Center (US)
- NYU Langone Health (US)
- Tarzana Treatment Centers (US)
- Brown University (US)
- University of New Mexico (US)
- Johns Hopkins University (US)
- Gateway Community Services (United States) (US)
- Emmes (United States) (US)
- National Institutes of Health (US)
- Corresponding author
- Lee, Joshua D
- ORCID
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 391
- Issue
- 10118
- Pages
- 309-318
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC5806119
- OpenAlex
- W2768214444
- Cited by
- 700
- References
- 24
- Citations by year
- 2026: 45 · 2025: 66 · 2024: 67 · 2023: 77 · 2022: 78 · 2021: 98 · 2020: 99 · 2019: 96 · 2018: 69 · 2017: 4
- FWCI
- 68.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIDA National Drug Abuse Treatment Clinical Trials Network (U10DA013046, UG1/U10DA013035, UG1/U10DA013034, U10DA013045, UG1/U10DA013720, UG1/U10DA013732, UG1/U10DA013714, UG1/U10DA015831, U10DA015833, HHSN271201200017C, and HHSN271201500065C) and K24DA022412 (EVN Jr))
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Opioid Use Disorder Treatment
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
- Keywords
- extended-release naltrexone, buprenorphine/naloxone, opioid use disorder, relapse-free survival, opioid antagonists, partial opioid agonists, treatment initiation, treatment retention, medication adherence, outpatient care, comparative effectiveness, harm reduction
- MeSH terms
- Buprenorphine, Naloxone Drug Combination, Administration, Oral, Adult, Delayed-Action Preparations, Female, Humans, Injections, Intramuscular, Male, Naltrexone, Narcotic Antagonists, Opioid-Related Disorders, Research Design
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