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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 D; Nunes, Edward V Jr; 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
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, 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.
PMID: 29150198
ISSN: 1474-547x
CID: 2785132

Extended-Release Naltrexone to Prevent Opioid Relapse in Criminal Justice Offenders

Lee, Joshua D; Friedmann, Peter D; Kinlock, Timothy W; Nunes, Edward V; Boney, Tamara Y; Hoskinson, Randall A Jr; Wilson, Donna; McDonald, Ryan; Rotrosen, John; Gourevitch, Marc N; Gordon, Michael; Fishman, Marc; Chen, Donna T; Bonnie, Richard J; Cornish, James W; Murphy, Sean M; O'Brien, Charles P
BACKGROUND: Extended-release naltrexone, a sustained-release monthly injectable formulation of the full mu-opioid receptor antagonist, is effective for the prevention of relapse to opioid dependence. Data supporting its effectiveness in U.S. criminal justice populations are limited. METHODS: In this five-site, open-label, randomized trial, we compared a 24-week course of extended-release naltrexone (Vivitrol) with usual treatment, consisting of brief counseling and referrals for community treatment programs, for the prevention of opioid relapse among adult criminal justice offenders (i.e., persons involved in the U.S. criminal justice system) who had a history of opioid dependence and a preference for opioid-free rather than opioid maintenance treatments and who were abstinent from opioids at the time of randomization. The primary outcome was the time to an opioid-relapse event, which was defined as 10 or more days of opioid use in a 28-day period as assessed by self-report or by testing of urine samples obtained every 2 weeks; a positive or missing sample was computed as 5 days of opioid use. Post-treatment follow-up occurred at weeks 27, 52, and 78. RESULTS: A total of 153 participants were assigned to extended-release naltrexone and 155 to usual treatment. During the 24-week treatment phase, participants assigned to extended-release naltrexone had a longer median time to relapse than did those assigned to usual treatment (10.5 vs. 5.0 weeks, P<0.001; hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.68), a lower rate of relapse (43% vs. 64% of participants, P<0.001; odds ratio, 0.43; 95% CI, 0.28 to 0.65), and a higher rate of opioid-negative urine samples (74% vs. 56%, P<0.001; odds ratio, 2.30; 95% CI, 1.48 to 3.54). At week 78 (approximately 1 year after the end of the treatment phase), rates of opioid-negative urine samples were equal (46% in each group, P=0.91). The rates of other prespecified secondary outcome measures--self-reported cocaine, alcohol, and intravenous drug use, unsafe sex, and reincarceration--were not significantly lower with extended-release naltrexone than with usual treatment. Over the total 78 weeks observed, there were no overdose events in the extended-release naltrexone group and seven in the usual-treatment group (P=0.02). CONCLUSIONS: In this trial involving criminal justice offenders, extended-release naltrexone was associated with a rate of opioid relapse that was lower than that with usual treatment. Opioid-use prevention effects waned after treatment discontinuation. (Funded by the National Institute on Drug Abuse; number, NCT00781898.).
PMID: 27028913
ISSN: 1533-4406
CID: 2079662

Public sector low threshold office-based buprenorphine treatment: outcomes at year 7

Bhatraju, Elenore Patterson; Grossman, Ellie; Tofighi, Babak; McNeely, Jennifer; DiRocco, Danae; Flannery, Mara; Garment, Ann; Goldfeld, Keith; Gourevitch, Marc N; Lee, Joshua D
BACKGROUND: Buprenorphine maintenance for opioid dependence remains of limited availability among underserved populations, despite increases in US opioid misuse and overdose deaths. Low threshold primary care treatment models including the use of unobserved, "home," buprenorphine induction may simplify initiation of care and improve access. Unobserved induction and long-term treatment outcomes have not been reported recently among large, naturalistic cohorts treated in low threshold safety net primary care settings. METHODS: This prospective clinical registry cohort design estimated rates of induction-related adverse events, treatment retention, and urine opioid results for opioid dependent adults offered buprenorphine maintenance in a New York City public hospital primary care office-based practice from 2006 to 2013. This clinic relied on typical ambulatory care individual provider-patient visits, prescribed unobserved induction exclusively, saw patients no more than weekly, and did not require additional psychosocial treatment. Unobserved induction consisted of an in-person screening and diagnostic visit followed by a 1-week buprenorphine written prescription, with pamphlet, and telephone support. Primary outcomes analyzed were rates of induction-related adverse events (AE), week 1 drop-out, and long-term treatment retention. Factors associated with treatment retention were examined using a Cox proportional hazard model among inductions and all patients. Secondary outcomes included overall clinic retention, buprenorphine dosages, and urine sample results. RESULTS: Of the 485 total patients in our registry, 306 were inducted, and 179 were transfers already on buprenorphine. Post-induction (n = 306), week 1 drop-out was 17%. Rates of any induction-related AE were 12%; serious adverse events, 0%; precipitated withdrawal, 3%; prolonged withdrawal, 4%. Treatment retention was a median 38 weeks (range 0-320) for inductions, compared to 110 (0-354) weeks for transfers and 57 for the entire clinic population. Older age, later years of first clinic visit (vs. 2006-2007), and baseline heroin abstinence were associated with increased treatment retention overall. CONCLUSIONS: Unobserved "home" buprenorphine induction in a public sector primary care setting appeared a feasible and safe clinical practice. Post-induction treatment retention of a median 38 weeks was in line with previous naturalistic studies of real-world office-based opioid treatment. Low threshold treatment protocols, as compared to national guidelines, may compliment recently increased prescriber patient limits and expand access to buprenorphine among public sector opioid use disorder patients.
PMID: 28245872
ISSN: 1940-0640
CID: 2471132

Target trial emulation for comparative effectiveness research with observational data: Promise and challenges for studying medications for opioid use disorder

Christine, Paul J; Lodi, Sara; Hsu, Heather E; Bovell-Ammon, Benjamin; Yan, Shapei; Bernson, Dana; Novo, Patricia; Lee, Joshua D; Rotrosen, John; Liebschutz, Jane; Walley, Alexander Y; Larochelle, Marc R
Medications for opioid use disorder (MOUD) increase retention in care and decrease mortality during active treatment; however, information about the comparative effectiveness of different forms of MOUD is sparse. Observational comparative effectiveness studies are subject to many types of bias; a robust framework to minimize bias would improve the quality of comparative effectiveness evidence. This paper discusses the use of target trial emulation as a framework to conduct comparative effectiveness studies of MOUD with administrative data. Using examples from our planned research project comparing buprenorphine-naloxone and extended-release naltrexone with respect to the rates of MOUD discontinuation, we provide a primer on the challenges and approaches to employing target trial emulation in the study of MOUD.
PMID: 38519819
ISSN: 1360-0443
CID: 5641042

Jail-based medication for opioid use disorder and patterns of reincarceration and acute care use after release: A sequence analysis

Lim, Sungwoo; Cherian, Teena; Katyal, Monica; Goldfeld, Keith S; McDonald, Ryan; Wiewel, Ellen; Khan, Maria; Krawczyk, Noa; Braunstein, Sarah; Murphy, Sean M; Jalali, Ali; Jeng, Philip J; Rosner, Zachary; MacDonald, Ross; Lee, Joshua D
BACKGROUND:Treatment with methadone and buprenorphine medications for opioid use disorder (MOUD) during incarceration may lead to better community re-entry, but evidence on these relationships have been mixed. We aimed to identify community re-entry patterns and examine the association between in-jail MOUD and a pattern of successful reentry defined by rare occurrence of reincarceration and preventable healthcare utilization. METHODS:Data came from a retrospective, observational cohort study of 6066 adults with opioid use disorder who were incarcerated in New York City jails and released to the community during 2011-14. An outcome was community re-entry patterns identified by sequence analysis of 3-year post-release reincarceration, emergency department visits, and hospitalizations. An exposure was receipt of in-jail MOUD versus out-of-treatment (42 % vs. 58 %) for the last 3 days before discharge. The study accounted for differences in baseline demographic, clinical, behavioral, housing, and criminal legal characteristics between in-jail MOUD and out-of-treatment groups via propensity score matching. RESULTS:This study identified five re-entry patterns: stability (64 %), hospitalization (23 %), delayed reincarceration (7 %), immediate reincarceration (4 %), and continuous incarceration (2 %). After addressing confounding, 64 % and 57 % followed the stability pattern among MOUD and out-of-treatment groups who were released from jail in 2011, respectively. In 2012-14, the prevalence of following the stability pattern increased year-by-year while a consistently higher prevalence was observed among those with in-jail MOUD. CONCLUSIONS:Sequence analysis helped define post-release stability based on health and criminal legal system involvement. Receipt of in-jail MOUD was associated with a marker of successful community re-entry.
PMID: 38072387
ISSN: 2949-8759
CID: 5589462

Misclassification of overdose events in the X:BOT study - Authors' reply [Letter]

Lee, Joshua D; Nunes, Edward V; Van Veldhuisen, Paul; Lindblad, Robert; Rotrosen, John
PMID: 37480935
ISSN: 1474-547x
CID: 5536282

Patient Perceptions of Integrating Meditation-based Interventions in Office-based Opioid Treatment with Buprenorphine: A Mixed-methods Survey

Tofighi, Babak; Marini, Christina; Lee, Joshua D; Garland, Eric L
INTRODUCTION:Recent findings support the provision of meditation-based interventions (MBIs) in primary care. However, the acceptability of MBI among patients prescribed medications for opioid use disorder (eg, buprenorphine) in primary care remains unclear. This study assessed experiences and preferences for adopting MBI among patients prescribed buprenorphine in office-based opioid treatment (OBOT). METHODS:This 23-item, semistructured cross-sectional survey was administered by study staff to patients enrolled in OBOT (N = 72) and consisted of demographic and clinical characteristics, perceptions, experiences with MBI, and preferred strategies to access MBI to support their treatment on buprenorphine. RESULTS:Most participants reported practicing at least 1 category of MBI (90.3%) on at least a daily (39.6%) or weekly (41.7%) basis including (1) spiritual meditation (eg, centering prayer; 67.7%); (2) nonmantra meditation (eg, comfortable posture; 61.3%); (3) mindfulness meditation (eg, mindfulness-based stress reduction; 54.8%); and (4) mantra meditation (eg, transcendental meditation; 29.0%). Interest in MBI was motivated by improving one's general health and well-being (73.4%), treatment outcomes with medications for OUD (eg, buprenorphine; 60.9%), and relationships with others (60.9%). Perceived clinical benefits of MBI included reduced anxiety or depression symptoms (70.3%), pain (62.5%), illicit substance or alcohol use (60.9%), cravings for illicit substances (57.8%), and opioid-related withdrawal symptoms (51.6%). CONCLUSIONS:Findings from this study indicate high acceptability for adopting MBI among patients prescribed buprenorphine in OBOT. Further research is needed to assess the efficacy of MBI to improve clinical outcomes among patients initiating buprenorphine in OBOT.
PMID: 37788602
ISSN: 1935-3227
CID: 5634912

Secondary Analysis of Agreement Between Negative Timeline Follow Back Report and Negative Urine Toxicology in a Large Trial of Individuals with Opioid Use Disorder

Shulman, Matisyahu; Choo, Tse-Hwei; Scodes, Jennifer; Pavlicova, Martina; Novo, Patricia; Campbell, Aimee N C; Greiner, Miranda; Lee, Joshua D; Rotrosen, John; Nunes, Edward V
OBJECTIVES/OBJECTIVE:Timeline follow-back (TLFB) is a self-report measure commonly used as a method of assessing historical drug use in both clinical and research settings. Our study considered rates of agreement between TLFB and an objective biological assay of opioid use. METHODS:We calculated the rates of agreement between negative report of opioid use for the most recent 8 days on TLFB and urine toxicology (UTOX) results in a large multisite opioid use disorder treatment trial. RESULTS:In total, 3986 assessments were provided by trial participants with both UTOX and TLFB during weeks 1 to 12, 2716 during weeks 13 to 24, and 325 at week 28. Rates of disagreement between negative TLFB and positive opioid UTOX were 2.33% of all assessments (21.68% of those with positive UTOX) over weeks 1 to 12, 2.06% of all assessment (25.00% of those with positive UTOX) over weeks 13 to 24, and 9.85% of all assessments (26.02% of those with positive UTOX) at week 28. CONCLUSIONS:Negative TLFB seems to be generally associated with negative results on urine toxicology.
PMID: 37195799
ISSN: 1935-3227
CID: 5544262

Trajectories of depression among patients in treatment for opioid use disorder: A growth mixture model secondary analysis of the XBOT trial

Vest, Noel; Wenzel, Kevin; Choo, Tse-Hwei; Pavlicova, Martina; Rotrosen, John; Nunes, Edward; Lee, Joshua D; Fishman, Marc
BACKGROUND AND OBJECTIVES/OBJECTIVE:To inform clinical practice, we identified subgroups of adults based on levels of depression symptomatology over time during opioid use disorder (OUD) treatment. METHODS:Participants were 474 adults in a 24-week treatment trial for OUD. Depression symptoms were measured using the 17-item Hamilton Depression Rating Scale (HAM-D) at nine-time points. This was a secondary analysis of the Clinical Trials Network Extended-Release Naltrexone versus Buprenorphine for Opioid Treatment (XBOT) trial using a growth mixture model. RESULTS:Three distinct depression trajectories were identified: Class 1 High Recurring-10% with high HAM-D with initial partial reductions (of HAM-D across time), Class 2 Persistently High-5% with persistently high HAM-D, and Class 3 Low Declining-85% of the participants, with low HAM-D with early sustained reductions. The majority (low declining) had levels of depression that improved in the first 4 weeks and then stabilized across the treatment period. In contrast, 15% (high recurring and persistently high) had high initial levels that were more variable across time. The persistently high class had higher rates of opioid relapse. DISCUSSION AND CONCLUSIONS/CONCLUSIONS:In this OUD sample, most depressive symptomatology was mild and improved after medication treatment for opioid use disorder (MOUD). Smaller subgroups had higher depressive symptoms that persisted or recurred after the initiation of MOUD. Depressive symptoms should be followed in patients initiating treatment for OUD, and when persistent, should prompt further evaluation and consideration of antidepressant treatment. SCIENTIFIC SIGNIFICANCE/CONCLUSIONS:This study is the first to identify three distinct depression trajectories among a large clinical sample of individuals in MOUD treatment.
PMID: 36645265
ISSN: 1521-0391
CID: 5464722

The real unmet need: A multifactorial approach for identifying sensitized kidney candidates with low access to transplant

Maldonado, Angela Q; Bradbrook, Keighly; Sjöholm, Kristoffer; Kjellman, Christian; Lee, Joshua; Stewart, Darren
BACKGROUND:At the start of 2020, the kidney waiting list consisted of 2526 candidates with a calculated panel reactive antibody (CPRA) of 99.9% or greater, a cohort demonstrated in published research to have meaningfully lower than average access to transplantation even under the revised kidney allocation system (KAS). METHODS:This was a retrospective analysis of US kidney registrations using data from the OPTN [Reference (]. The period-prevalent study cohort consisted of US kidney-alone registrations who waited at least 1 day between April 1, 2016, when HLA DQ-Alpha and DP-Beta unacceptable antigen data became available in OPTN data collection, to December 31, 2019. Poisson rate regression was used to model deceased donor kidney transplant rates per active year waiting and using an offset term to account for differential at-risk periods. Median time to transplant was estimated for each IRR group using the Kaplan-Meier method. Sensitivity analyses were included to address geographic variation in supply-to-demand ratios and differences in dialysis time or waiting time. RESULTS:In this study, we found 1597 additional sensitized (CPRA 50-<99.9%) candidates with meaningfully lower than average access to transplant when simultaneously taking into account CPRA and other factors. In combination with CPRA, candidate blood type, Estimated Post-Transplant Survival Score (EPTS), and presence of other antibody specificities beyond those in the current, 5-locus CPRA were found to influence the likelihood of transplant. CONCLUSION:In total, this suggests approximately 4100 sensitized candidates are on the waiting list who represent a community of disadvantaged patients who may benefit from progressive therapies and interventions to facilitate incompatible transplantation. Though associated with higher risks, such interventions may nevertheless be more attractive than remaining on dialysis with the associated accumulation of mortality risk over time.
PMID: 36841966
ISSN: 1399-0012
CID: 5507792