Comparative effectiveness of extended release naltrexone versus buprenorphine naloxone for opioid relapse prevention (X:BOT) a multicentre, open label, randomised controlled trial
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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