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

Abstract

Summary 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 wo...

Antagonists in the medical management of opioid use disorders: Historical and existing treatment strategies

“…In a 24‐week trial of XR‐NTX for alcohol dependence ( N  = 624), depressive symptoms were reported by 10% of patients treated with XR‐NTX, compared with 5% of patients treated with placebo 99. However, depressed mood or suicidal thinking was not reported by patients treated with either XR‐NTX or placebo in the pivotal XR‐NTX trial ( N  = 250),64 and psychiatric adverse effects occurred at comparable rates in recent reports of patients treated with buprenorphine and XR‐NTX 73, 74. Studies have demonstrated that depressive symptoms, often present at treatment entry, improve with opioid abstinence whether in the setting of receipt of oral naltrexone, XR‐NTX, or placebo 70, 100, 101.…”

“…Patients treated with oral naltrexone had a higher risk of overdose than those treated with methadone94 or naltrexone implants95; the risk was comparable in patients maintained on methadone or naltrexone implants 96. In two recent large comparative effectiveness trials of XR‐NTX versus buprenorphine‐naloxone, risk of overdose was similar in the XR‐NTX ( n  = 2/283 and n  = 0/71, respectively) and buprenorphine ( n  = 3/287 and n  = 1/72, respectively) groups 73, 74. Notably, patients dropping out of treatment with methadone or buprenorphine were also at elevated risk of overdose 97, 98…”

“…A study using historical controls found that patients treated with XR‐NTX had higher retention rates and less relapse than patients treated with oral naltrexone 72. Recent studies directly comparing the efficacy of XR‐NTX and buprenorphine/naloxone show that among patients who successfully initiated treatment with medications, treatment outcomes were comparable 73, 74…”

“…Up to one third of patients who receive XR‐NTX use illicit opioids at some point during treatment, commonly as single episodes to “test” the blocking effect of the medication 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 62. A recent study of patients using opioids during XR‐NTX blockade found that most did not feel euphoria and used lower doses than before receiving XR‐NTX.…”

Commentary: Providing technical assistance for the state targeted response for opioid use disorders: Time is of the essence

“…9,10 More recently, several studies have found that extended-release naltrexone (vivitrol) is equally effective as agonist treatments in reducing the risk of relapse once an individual is successfully inducted onto extended-release naltrexone. 11,12 Several research groups have carried out work on how to facilitate induction onto this life-saving product; however, work in this area is still desperately needed. 13,14 …”