Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): A multicentre, open-label, randomised controlled trial.
This is the primary outcomes article for CTN-0051.
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. This study in the NIDA Clinical Trials Network (CTN-0051) aimed to estimate the difference in opioid relapse-free survival between XR-NTX and BUP-NX.
This 24-week, open-label, randomized controlled, comparative effectiveness trial was initiated at eight U.S. community-based inpatient services and followed up participants as outpatients. Participants were 18 years or older, had opioid use disorder as defined by the DSM-5, and had used non-prescribed opioids in the past 30 days. Participants were stratified by treatment site and opioid use severity and a web-based permuted block design was used with random equally weighted block sizes of 4 and 6 for randomization (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 outcomes 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.
Between January 30, 2014 and May 25, 2016, 570 participants were randomly assigned to receive XR-NTX (n=283) or BUP-NX (n=287). The last follow-up visit was January 31, 2017. As expected, XR-NTX had a substantial induction hurdle: fewer participants successfully initiated XR-NTX (204 [72%] of 283; p<0.0001) than BUP-NX (270 [94%] of 287). 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) favored 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 (2 in the XR-NTX group and 3 in the BUP-NX group).
Conclusions: In this population, it is more difficult to initiate patients to XR-NTX than to 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.
Related protocols: CTN-0051