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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

Perceptions and experiences toward extended-release buprenorphine among persons leaving jail with opioid use disorders before and during COVID-19: an in-depth qualitative study

Cheng, Anna; Badolato, Ryan; Segoshi, Andrew; McDonald, Ryan; Malone, Mia; Vasudevan, Kumar; Badiei, Beita; Sugarman, Allison; Macdonald, Ross; Mangat, Jasdeep; Giftos, Jonathan; Lee, Joshua D; Tofighi, Babak
BACKGROUND:Extended-release buprenorphine (XRB) offers a novel approach to sustained monthly treatment for people who use opioids in criminal justice settings (CJS). This study explores the experiences of adults receiving XRB as a jail-to-community treatment. METHODS AND FINDINGS:In-depth qualitative interviews were conducted among adult participants with opioid use disorder (OUD; n  = 16) who were recently released from NYC jails and maintained on XRB after switching from daily sublingual buprenorphine (SLB). Interviews elaborated on the acceptability and barriers and facilitators of XRB treatment pre- and post-release. Interviews were audio recorded, transcribed, and analyzed for content related to factors influencing XRB treatment uptake and community reentry. Important themes were grouped into systems, medication, and patient-level factors. Key systems-level factors influencing initiation of XRB in jail included an alternative to perceived stigmatization and privacy concerns associated with daily in-jail SLB administration and less concerns with buprenorphine diversion. In-jail peer networks positively influenced participant adoption of XRB. XRB satisfaction was attributed to reduced in-jail clinic and medication administration visits, perceived efficacy and blockade effects upon the use of heroin/fentanyl following release, and averting the risk of criminal activities to fund opioid use. Barriers to retention included post-injection withdrawal symptoms and cravings attributed to perceived suboptimal medication dosing, injection site pain, and lack of in-jail provider information about the medication. CONCLUSION:Participants were generally favorable to XRB initiation in jail and retention post-release. Further studies are needed to address factors influencing access to XRB in criminal justice settings, including stigma, ensuring patient privacy following initiation on XRB, and patient-, provider-, and correctional staff education pertaining to XRB. Trial Registration Identified: NCT03604159.
PMID: 35093164
ISSN: 1940-0640
CID: 5153262

A Mixed-Methods Evaluation of the Feasibility of a Medical Management-Based Text Messaging Intervention Combined With Buprenorphine in Primary Care

Tofighi, Babak; Durr, Meghan; Marini, Christina; Lewis, Crystal F; Lee, Joshua D
Background/UNASSIGNED:Mobile health (mHealth) tools offer an effective and personalized approach to enhance chronic disease management and may partially offset provider-level barriers to increasing buprenorphine prescribing in primary care. This study assessed the feasibility of integrating a text messaging-based medical management tool (TeMeS) in primary care among patients initiating buprenorphine. Methods/UNASSIGNED:TeMeS messages are categorized per the medical management model, programed in a HIPAA-compliant texting software (Apptoto©), and delivered in a tiered fashion over 8-weeks to patients. This mixed-methods evaluation of TeMeS utilized key stakeholder feedback (patients, physicians, administrators, nursing), text messaging software process measures, thematic analysis of patient participant text message content, and electronic administrative data (eg, appointment adherence, treatment retention) at 2-months. Results/UNASSIGNED:The study team approached 65 patients and n = 14 (21%) were ineligible or declined to participate in the study. Most eligible participants owned a smartphone (90%), responded to at least one text query (88%) over an average of 24 days, and few requested to stop receiving texts (6%). Participant text replies included responses to cognitive behavioral therapy-based queries (13.8%), confirming or rescheduling appointments (6.1%), and insurance, pharmacy, or clinical issues pertaining to buprenorphine dispensation or dosing (2%). Suggestions for design modifications included personalizing message content and adjusting message frequency per patient risk of illicit opioid reuse, use of video-based informational content, and real-time provider and staff support for emergent issues. Conclusion/UNASSIGNED:Our findings highlight the acceptability, feasibility, and high rates of engagement of utilizing text messaging to enhance self-management among patients initiating buprenorphine treatment.
PMID: 35356483
ISSN: 1178-2218
CID: 5219952

Injecting Opioid Use Disorder Treatment in Jails and Prisons: The Potential of Extended-release Buprenorphine in the Carceral Setting

Berk, Justin; Del Pozo, Brandon; Rich, Josiah D; Lee, Joshua D
As the opioid overdose cases rise, policy-makers and researchers should target interventions to populations at highest risk. Incarceration serves as a risk factor for opioid overdose (Gan et al. Addiction 2021) and a large portion of recent overdose deaths have had encounters in the criminal justice system. Medications for opioid use disorder in the criminal justice system can save lives, though unique administrative barriers in jails and prisons hinder access. As facilities expand medications for opioid use disorder access (due to new legislation and court rulings across states), extended-release buprenorphine offers an opportunity to overcome these barriers including logistics of administration, diversion concern, patient stigma, and an increased bridge of treatment during re-entry to the community. As extended-release buprenorphine has practical advantages in correctional health delivery, future research and policy discussions should investigate its optimal role in treating opiate addiction in a carceral setting.
PMID: 34954747
ISSN: 1935-3227
CID: 5107942

Cost-effectiveness implications of increasing the efficiency of the extended-release naltrexone induction process for the treatment of opioid use disorder: a secondary analysis

Murphy, Sean M; Jeng, Philip J; McCollister, Kathryn E; Leff, Jared A; Jalali, Ali; Shulman, Matisyahu; Lee, Joshua D; Nunes, Edward V; Novo, Patricia; Rotrosen, John; Schackman, Bruce R
BACKGROUND AND AIMS/OBJECTIVE:In a US randomized-effectiveness trial comparing extended-release naltrexone (XR-NTX) with buprenorphine-naloxone (BUP-NX) for the prevention of opioid relapse among participants recruited during inpatient detoxification (CTN-0051), the requirement to complete opioid detoxification prior to initiating XR-NTX resulted in lower rates of initiation of XR-NTX (72% XR-NTX versus 94% BUP-NX). DESIGN/METHODS:This was a retrospective secondary analysis of CTN-0051 trial data, including follow-up data over 24-36 weeks. SETTING/METHODS:Eight community-based, inpatient-detoxification and follow-up outpatient treatment facilities in the United States. PARTICIPANTS/METHODS:A total of 283 participants randomized to receive XR-NTX. MEASUREMENTS/METHODS:Efficiency was estimated using a multivariable generalized structural equation model to explore simultaneous determinants of XR-NTX induction and induction duration (detoxification + residential days). Cost-effectiveness was estimated from the health-care sector perspective and included expected costs and quality-adjusted life-years (QALYs). FINDINGS/RESULTS:Treatment site was the only modifiable factor that simultaneously increased the likelihood of XR-NTX induction and decreased induction duration. Incorporating the higher predicted probability of XR-NTX induction, and fewer predicted days of detoxification and subsequent residential treatment into the cost-effectiveness framework, reduced the incremental average 24-week total cost of XR-NTX treatment from $5317 more than that of BUP-NX (P = 0.01) to a non-statistically-significant difference of $1016 (P = 0.63). QALYs gained remained similar across arms. CONCLUSION/CONCLUSIONS:Adopting an efficient model of extended-release naltrexone initiation could result in extended-release naltrexone and buprenorphine-naloxone being of comparable economic value from the health-care sector perspective over 24-36 weeks for patients seeking treatment for opioid use disorder at an inpatient detoxification facility.
PMID: 33950535
ISSN: 1360-0443
CID: 4874032

Comparison of Treatment Retention of Adults With Opioid Addiction Managed With Extended-Release Buprenorphine vs Daily Sublingual Buprenorphine-Naloxone at Time of Release From Jail

Lee, Joshua D; Malone, Mia; McDonald, Ryan; Cheng, Anna; Vasudevan, Kumar; Tofighi, Babak; Garment, Ann; Porter, Barbara; Goldfeld, Keith S; Matteo, Michael; Mangat, Jasdeep; Katyal, Monica; Giftos, Jonathan; MacDonald, Ross
Importance/UNASSIGNED:Extended-release buprenorphine (XRB), a monthly injectable long-acting opioid use disorder (OUD) treatment, has not been studied for use in corrections facilities. Objective/UNASSIGNED:To compare treatment retention following release from jail among adults receiving daily sublingual buprenorphine-naloxone (SLB) vs those receiving XRB. Design, Setting, and Participants/UNASSIGNED:This open-label, randomized comparative effectiveness study included 52 incarcerated adults in New York City observed for 8 weeks postrelease between June 2019 and May 2020. Participants were soon-to-be-released volunteers from 1 men's and 1 women's jail facility who had OUDs already treated with SLB. Follow-up treatment was received at a primary care clinic in Manhattan. Data were analyzed between June 2020 and December 2020. Interventions/UNASSIGNED:XRB treatment was offered prior to release and continued monthly through 8 weeks after release. SLB participants continued to receive daily directly observed in-jail SLB administration, were provided a 7-day SLB supply at jail release, and followed up at a designated clinic (or other preferred clinics). Main Outcomes and Measures/UNASSIGNED:Buprenorphine treatment retention at 8 weeks postrelease. Results/UNASSIGNED:A total of 52 participants were randomized 1:1 to XRB (26 participants) and SLB (26 participants). Participants had a mean (SD) age of 42.6 (10.0) years; 45 participants (87%) were men; and 40 (77%) primarily used heroin prior to incarceration. Most participants (30 [58%]) reported prior buprenorphine use; 18 (35%) reported active community buprenorphine treatment prior to jail admission. Twenty-one of 26 assigned to XRB received 1 or more XRB injection prior to release; 3 initiated XRB postrelease; and 2 did not receive XRB. Patients in the XRB arm had fewer jail medical visits compared with daily SLB medication administration (mean [SD] visits per day: XRB, 0.11 [0.03] vs SLB, 1.06 [0.08]). Community buprenorphine treatment retention at week 8 postrelease was 18 participants in the XRB group (69.2%) vs 9 in the SLB group (34.6%), and rates of opioid-negative urine tests were 72 of 130 tests in the XRB group (55.3%) and 50 of 130 tests in the SLB group (38.4%). There were no differences in rates of serious adverse events, no overdoses, and no deaths. Conclusions and Relevance/UNASSIGNED:XRB was acceptable among patients currently receiving SLB, and patients had fewer in-jail clinic visits and increased community buprenorphine treatment retention when compared with standard daily SLB treatment. These results support wider use and further study of XRB as correctional and reentry OUD treatment. Trial Registration/ Identifier: NCT03604159.
PMID: 34495340
ISSN: 2574-3805
CID: 5011982

Long-acting buprenorphine vs. naltrexone opioid treatments in CJS-involved adults (EXIT-CJS)

Waddell, Elizabeth Needham; Springer, Sandra A; Marsch, Lisa A; Farabee, David; Schwartz, Robert P; Nyaku, Amesika; Reeves, Rusty; Goldfeld, Keith; McDonald, Ryan D; Malone, Mia; Cheng, Anna; Saunders, Elizabeth C; Monico, Laura; Gryczynski, Jan; Bell, Kathleen; Harding, Kasey; Violette, Sandra; Groblewski, Thomas; Martin, Wendy; Talon, Kasey; Beckwith, Nicole; Suchocki, Andrew; Torralva, Randy; Wisdom, Jennifer P; Lee, Joshua D
The EXIT-CJS (N = 1005) multisite open-label randomized controlled trial will compare retention and effectiveness of extended-release buprenorphine (XR-B) vs. extended-release naltrexone (XR-NTX) to treat opioid use disorder (OUD) among criminal justice system (CJS)-involved adults in six U.S. locales (New Jersey, New York City, Delaware, Oregon, Connecticut, and New Hampshire). With a pragmatic, noninferiority design, this study hypothesizes that XR-B (n = 335) will be noninferior to XR-NTX (n = 335) in retention-in-study-medication treatment (the primary outcome), self-reported opioid use, opioid-positive urine samples, opioid overdose events, and CJS recidivism. In addition, persons with OUD not eligible or interested in the RCT will be recruited into an enhanced treatment as usual arm (n = 335) to examine usual care outcomes in a quasi-experimental observational cohort.
PMID: 33865691
ISSN: 1873-6483
CID: 5066472

Corrigendum to "Naturalistic follow-up after a trial of medications for opioid use disorder: Medication status, opioid use, and relapse" [Journal of Substance Abuse Treatment 131 (2021) 108447]

Greiner, Miranda G; Shulman, Matisyahu; Choo, Tse-Hwei; Scodes, Jennifer; Pavlicova, Martina; Campbell, Aimee N C; Novo, Patricia; Fishman, Marc; Lee, Joshua D; Rotrosen, John; Nunes, Edward V
PMID: 34366203
ISSN: 1873-6483
CID: 5006082