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

Joshua Lee, Edward V. Nunes, Patricia Novo, Ken Bachrach, Genie L. Bailey, Snehal Bhatt, Sarah Farkas, Marc Fishman, Phoebe Gauthier, Candace C. Hodgkins, Jacquie King, Robert Lindblad, David Liu, Abigail G. Matthews, Jeanine May, K. Michelle Peavy, Stephen Ross, Dagmar Salazar, Paul Schkolnik, Dikla Shmueli-BlumbergDon Stablein, Geetha Subramaniam, John Rotrosen

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalThe Lancet
DOIs
StateAccepted/In press - Jan 1 2017

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Naltrexone
Secondary Prevention
Opioid Analgesics
Randomized Controlled Trials
Recurrence
Population
Naloxone Drug Combination Buprenorphine
Outpatients
Urine
Therapeutics
Narcotic Antagonists
Intramuscular Injections
Random Allocation
Diagnostic and Statistical Manual of Mental Disorders
Toxicology
Self Report
Inpatients

ASJC Scopus subject areas

  • Medicine(all)

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Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X : BOT): A multicentre, open-label, randomised controlled trial. / Lee, Joshua; Nunes, Edward V.; Novo, Patricia; Bachrach, Ken; Bailey, Genie L.; Bhatt, Snehal; Farkas, Sarah; Fishman, Marc; Gauthier, Phoebe; Hodgkins, Candace C.; King, Jacquie; Lindblad, Robert; Liu, David; Matthews, Abigail G.; May, Jeanine; Peavy, K. Michelle; Ross, Stephen; Salazar, Dagmar; Schkolnik, Paul; Shmueli-Blumberg, Dikla; Stablein, Don; Subramaniam, Geetha; Rotrosen, John.

In: The Lancet, 01.01.2017.

Research output: Contribution to journalArticle

Lee, J, Nunes, EV, Novo, P, Bachrach, K, Bailey, GL, Bhatt, S, Farkas, S, Fishman, M, Gauthier, P, Hodgkins, CC, King, J, Lindblad, R, Liu, D, Matthews, AG, May, J, Peavy, KM, Ross, S, Salazar, D, Schkolnik, P, Shmueli-Blumberg, D, Stablein, D, Subramaniam, G & Rotrosen, J 2017, 'Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X: BOT): A multicentre, open-label, randomised controlled trial', The Lancet. https://doi.org/10.1016/S0140-6736(17)32812-X
Lee, Joshua ; Nunes, Edward V. ; Novo, Patricia ; Bachrach, Ken ; Bailey, Genie L. ; Bhatt, Snehal ; Farkas, Sarah ; Fishman, Marc ; Gauthier, Phoebe ; Hodgkins, Candace C. ; King, Jacquie ; Lindblad, Robert ; Liu, David ; Matthews, Abigail G. ; May, Jeanine ; Peavy, K. Michelle ; Ross, Stephen ; Salazar, Dagmar ; Schkolnik, Paul ; Shmueli-Blumberg, Dikla ; Stablein, Don ; Subramaniam, Geetha ; Rotrosen, John. / Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X : BOT): A multicentre, open-label, randomised controlled trial. In: The Lancet. 2017.
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title = "Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X: BOT): A multicentre, open-label, randomised controlled trial",
abstract = "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.",
author = "Joshua Lee and Nunes, {Edward V.} and Patricia Novo and Ken Bachrach and Bailey, {Genie L.} and Snehal Bhatt and Sarah Farkas and Marc Fishman and Phoebe Gauthier and Hodgkins, {Candace C.} and Jacquie King and Robert Lindblad and David Liu and Matthews, {Abigail G.} and Jeanine May and Peavy, {K. Michelle} and Stephen Ross and Dagmar Salazar and Paul Schkolnik and Dikla Shmueli-Blumberg and Don Stablein and Geetha Subramaniam and John Rotrosen",
year = "2017",
month = "1",
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language = "English (US)",
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TY - JOUR

T1 - Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X

T2 - BOT): A multicentre, open-label, randomised controlled trial

AU - Lee, Joshua

AU - Nunes, Edward V.

AU - Novo, Patricia

AU - Bachrach, Ken

AU - Bailey, Genie L.

AU - Bhatt, Snehal

AU - Farkas, Sarah

AU - Fishman, Marc

AU - Gauthier, Phoebe

AU - Hodgkins, Candace C.

AU - King, Jacquie

AU - Lindblad, Robert

AU - Liu, David

AU - Matthews, Abigail G.

AU - May, Jeanine

AU - Peavy, K. Michelle

AU - Ross, Stephen

AU - Salazar, Dagmar

AU - Schkolnik, Paul

AU - Shmueli-Blumberg, Dikla

AU - Stablein, Don

AU - Subramaniam, Geetha

AU - Rotrosen, John

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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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