The Lancet 2018;391(10118):309-318. [doi: 10.1016/S0140-6736(17)32812-X]
Joshua D. Lee, MD, MSc (NYU School of Medicine, GNY Node), Edward V. Nunes, MD (Columbia University, GNY Node), Patricia Novo, MPA, MPH (NYU School of Medicine, GNY Node), Ken Bachrach, PhD (Tarzana Treatment Centers, WS Node), Genie L. Bailey, MD (Stanley Street Treatment and Resources, NEC Node), Snehal Bhatt, MD (University of New Mexico School of Medicine, SW Node), Sarah Farkas, MA (NYU School of Medicine, GNY Node), Marc J. Fishman, MD (Maryland Treatment Centers, MA Node), Phoebe Gauthier, MA (NYU School of Medicine, GNY Node), Candace C. Hodgkins, PhD (Gateway Community Services, FNA Node), Jacquie King, MS (Emmes Corporation, CTN Data & Statistics Center), David S. Liu, MD (NIDA Center for the Clinical Trials Network), Abigail G. Matthews, PhD (Emmes Corporation, CTN Data & Statistics Center), Jeanine May, PhD (Emmes Corporation, CTN Data & Statistics Center), K. Michelle Peavy, PhD (Evergreen Treatment Services, PN Node), Stephen Ross, MD (NYU School of Medicine, GNY Node), Dagmar Salazar, MS (Emmes Corporation, CTN Clinical Coordinating Center), Paul Schkolnik, PhD (Maryhaven, OV Node), Dikla Shmueli-Blumberg, PhD (Emmes Corporation, CTN Clinical Coordinating Center), Don Stablein, PhD (Emmes Corporation), Geetha A. Subramaniam, MD (NIDA Center for the Clinical Trials Network), John Rotrosen, MD (NYU School of Medicine, GNY Node).
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. (Article (Peer-Reviewed), PDF, English, 2018)
Lott DC. Extended-release naltrexone: Good but not a panacea. The Lancet 2017 (in press). (Comment)
Volkow N. Medications for opioid use disorder: bridging the gap in care. The Lancet 2017 (in press). (Comment)
Keywords: Buprenorphine/Naloxone | CTN primary outcomes | Heroin | Naltrexone | Opioid dependence | Pharmacological therapy | Prescription-type opiates | Relapse prevention | Treatment induction | The Lancet (journal)
Document No: 1292., PMID: 29150198, PMCID: PMC5806119.
Submitted by Patricia Novo, MPA, MPH, GNY Node, 11/15/2017.