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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

Optimizing opioid use disorder treatment with naltrexone or buprenorphine

Rudolph, Kara E.; Diaz, Iván; Luo, Sean X.; Rotrosen, John; Nunes, Edward V.
Background: Relapse rates during opioid use disorder (OUD) treatment remain unacceptably high. It is possible that optimally matching patients with medication type would reduce risk of relapse. Our objective was to learn a rule by which to assign type of medication for OUD to reduce risk of relapse, and to estimate the extent to which risk of relapse would be reduced if such a rule were used. Methods: This was a secondary analysis of an open-label randomized controlled, 24-week comparative effectiveness trial of injection extended-release naltrexone (XR-NTX), delivered approximately every 28 days, or daily sublingual buprenorphine-naloxone (BUP-NX) for treating OUD, 2014"“2017 (N = 570). Outcome was a binary indicator of relapse to regular opioid use during the 24 weeks of outpatient treatment. Results: We found that applying an estimated individualized treatment rule"”i.e., a rule that assigns patients with OUD to either XR-NTX or BUP-NX based on their individual characteristics in such a way that risk of relapse is minimized"”would reduce risk of relapse by 24 weeks by 12% compared to randomly assigned treatment. Conclusions: The number-needed-to-treat with the estimated treatment rule to prevent a single relapse is 14. A simpler, alternative estimated rule in which homeless participants would be treated with XR-NTX and stably housed participants would be treated with BUP-NX performed similarly. These results provide an estimate of the amount by which a relatively simple change in clinical practice could be expected to improve prevention of OUD relapse.
ISSN: 0376-8716
CID: 5009422

Is extended release naltrexone superior to buprenorphine-naloxone to reduce drinking among outpatients receiving treatment for opioid use disorder? A secondary analysis of the CTN X:BOT trial

Roache, John D; Pavlicova, Martina; Campbell, Aimee; Choo, Tse-Hwei; Peavy, Michelle; Kermack, Andrea S; Nunes, Edward V; Rotrosen, John
BACKGROUND:The randomized X:BOT trial showed that following induction, sublingual agonist (buprenorphine-naloxone, BUP-NX) or antagonist injection (extended release naltrexone, XR-NTX) produced similar benefits for reducing opioid relapse in injection users with opioid use disorder. Given that XR-NTX reduces drinking in alcohol use disorder (AUD), we completed a secondary analysis of the X:BOT sample of patients successfully inducted onto treatment to determine if XR-NTX (n=204) was superior to BUP-NX (n=270) to reduce drinking or heavy drinking in patients with opioid use disorder. METHODS:Timeline follow-back recorded standard drink units consumed. Mixed-models regression examined monthly frequencies of any drinking or heavy drinking over 6 months of treatment and proportional hazard survival examined time to first drink. RESULTS:Both treatment groups reduced drinking from baseline to post-treatment (small to medium effect), but no differences between groups were detected. However, only 29% (n=136) of the sample had AUD and 19% (n=26/136) of those were abstinent before treatment. Analysis of a subsample enriched for possible drinking included n=136 with an AUD diagnosis plus n=43 who did not have AUD, but reported at least one day of heavy drinking prior to study. Even so, this subsample still reported only 32% of days of any drinking with a median of only 13% of days designated as "heavy". Within this subsample, the BUP-NX group reported greater mean drinks per drinking day than did the XR-NTX group at baseline (p=0.03); however, there were no other significant group differences in drinking observed before, during, or at the end of treatment. CONCLUSIONS:An overall improvement in drinking occurred for treatment of OUD using both agonist and antagonist approaches indicating that the hypothesis that XR-NTX would be superior to BUP-NX was not supported. The study is limited by low levels of comorbid AUD or heavy drinking observed in X:BOT trial participants seeking treatment for opioid use disorder.
PMID: 34698397
ISSN: 1530-0277
CID: 5042342

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

Reductions in tobacco use in naltrexone, relative to buprenorphine-maintained individuals with opioid use disorder: Secondary analysis from the National Drug Abuse Treatment Clinical Trials Network

Montgomery, LaTrice; Winhusen, Theresa; Scodes, Jennifer; Pavlicova, Martina; Twitty, Dylanne; Campbell, Aimee N C; Wang, An Li; Nunes, Edward V; Rotrosen, John
BACKGROUND:Smoking prevalence in individuals with opioid use disorder (OUD) is over 80%. Research suggests that opioid use significantly increases smoking, which could account for the strikingly low smoking-cessation rates observed in both methadone- and buprenorphine-maintained patients, even with the use of first-line smoking-cessation interventions. If opioids present a barrier to smoking-cessation, then better smoking outcomes should be observed in OUD patients treated with extended-release naltrexone (XR-NTX, an opioid antagonist) compared to those receiving buprenorphine (BUP-NX, a partial opioid agonist). METHODS:The current study is a secondary analysis of a 24-week, multi-site, open-label, randomized clinical trial conducted within the National Drug Abuse Treatment Clinical Trials Network comparing the effectiveness of XR-NTX vs. BUP-NX for adults with OUD. Longitudinal mixed effects models were used to determine if there was a significant reduction in cigarette use among daily smokers successfully inducted to treatment (n = 373) and a subset of those who completed treatment (n = 169). RESULTS:Among daily smokers inducted onto OUD medication, those in the XR-NTX group smoked fewer cigarettes per day (M = 11.36, SE = 0.62) relative to smokers in the BUP-NX group (M = 13.33, SE = 0.58) across all study visits, (b (SE) = -1.97 (0.55), p < .01). Results were similar for the treatment completers. CONCLUSIONS:OUD patients treated with XR-NTX reduced cigarette use more than those treated with BUP-NX, suggesting that XR-NTX in combination with other smoking cessation interventions might be a better choice for OUD smokers interested in reducing their tobacco use.
PMID: 34118716
ISSN: 1873-6483
CID: 4936712

Comparison of Methods for Alcohol and Drug Screening in Primary Care Clinics

McNeely, Jennifer; Adam, Angéline; Rotrosen, John; Wakeman, Sarah E; Wilens, Timothy E; Kannry, Joseph; Rosenthal, Richard N; Wahle, Aimee; Pitts, Seth; Farkas, Sarah; Rosa, Carmen; Peccoralo, Lauren; Waite, Eva; Vega, Aida; Kent, Jennifer; Craven, Catherine K; Kaminski, Tamar A; Firmin, Elizabeth; Isenberg, Benjamin; Harris, Melanie; Kushniruk, Andre; Hamilton, Leah
Importance/UNASSIGNED:Guidelines recommend that adult patients receive screening for alcohol and drug use during primary care visits, but the adoption of screening in routine practice remains low. Clinics frequently struggle to choose a screening approach that is best suited to their resources, workflows, and patient populations. Objective/UNASSIGNED:To evaluate how to best implement electronic health record (EHR)-integrated screening for substance use by comparing commonly used screening methods and examining their association with implementation outcomes. Design, Setting, and Participants/UNASSIGNED:This article presents the outcomes of phases 3 and 4 of a 4-phase quality improvement, implementation feasibility study in which researchers worked with stakeholders at 6 primary care clinics in 2 large urban academic health care systems to define and implement their optimal screening approach. Site A was located in New York City and comprised 2 clinics, and site B was located in Boston, Massachusetts, and comprised 4 clinics. Clinics initiated screening between January 2017 and October 2018, and 93 114 patients were eligible for screening for alcohol and drug use. Data used in the analysis were collected between January 2017 and October 2019, and analysis was performed from July 13, 2018, to March 23, 2021. Interventions/UNASSIGNED:Clinics integrated validated screening questions and a brief counseling script into the EHR, with implementation supported by the use of clinical champions (ie, clinicians who advocate for change, motivate others, and use their expertise to facilitate the adoption of an intervention) and the training of clinic staff. Clinics varied in their screening approaches, including the type of visit targeted for screening (any visit vs annual examinations only), the mode of administration (staff-administered vs self-administered by the patient), and the extent to which they used practice facilitation and EHR usability testing. Main Outcomes and Measures/UNASSIGNED:Data from the EHRs were extracted quarterly for 12 months to measure implementation outcomes. The primary outcome was screening rate for alcohol and drug use. Secondary outcomes were the prevalence of unhealthy alcohol and drug use detected via screening, and clinician adoption of a brief counseling script. Results/UNASSIGNED:Patients of the 6 clinics had a mean (SD) age ranging from 48.9 (17.3) years at clinic B2 to 59.1 (16.7) years at clinic B3, were predominantly female (52.4% at clinic A1 to 64.6% at clinic A2), and were English speaking. Racial diversity varied by location. Of the 93,114 patients with primary care visits, 71.8% received screening for alcohol use, and 70.5% received screening for drug use. Screening at any visit (implemented at site A) in comparison with screening at annual examinations only (implemented at site B) was associated with higher screening rates for alcohol use (90.3%-94.7% vs 24.2%-72.0%, respectively) and drug use (89.6%-93.9% vs 24.6%-69.8%). The 5 clinics that used a self-administered screening approach had a higher detection rate for moderate- to high-risk alcohol use (14.7%-36.6%) compared with the 1 clinic that used a staff-administered screening approach (1.6%). The detection of moderate- to high-risk drug use was low across all clinics (0.5%-1.0%). Clinics with more robust practice facilitation and EHR usability testing had somewhat greater adoption of the counseling script for patients with moderate-high risk alcohol or drug use (1.4%-12.5% vs 0.1%-1.1%). Conclusions and Relevance/UNASSIGNED:In this quality improvement study, EHR-integrated screening was feasible to implement in all clinics and unhealthy alcohol use was detected more frequently when self-administered screening was used at any primary care visit. The detection of drug use was low at all clinics, as was clinician adoption of counseling. These findings can be used to inform the decision-making of health care systems that are seeking to implement screening for substance use. Trial Registration/ Identifier: NCT02963948.
PMID: 34014326
ISSN: 2574-3805
CID: 4894872

Association between methadone or buprenorphine use during medically supervised opioid withdrawal and extended-release injectable naltrexone induction failure

Shulman, Matisyahu; Choo, Tse-Hwei; Scodes, Jennifer; Pavlicova, Martina; Wai, Jonathan; Haenlein, Patrick; Tofighi, Babak; Campbell, Aimee N C; Lee, Joshua D; Rotrosen, John; Nunes, Edward V
BACKGROUND:Extended-release naltrexone (XR-NTX) is an effective maintenance treatment for opioid use disorder, but induction from active opioid use is a challenge as individuals must complete detoxification before induction. We aimed to determine whether use of methadone or buprenorphine, long acting agonist opioids commonly used for detoxification, were associated with decreased likelihood of induction onto XR-NTX. METHODS:We performed a secondary analysis of a large open-label randomized trial of buprenorphine versus XR-NTX for treatment of individuals with opioid use disorder recruited from eight short term residential (detoxification) units. This analysis only included individuals randomized to the XR-NTX arm of the trial (N = 283). The method of detoxification varied according to usual practices at each inpatient program. Logistic regression models estimating the log-odds of induction onto XR-NTX were fit, with detoxification regimen received as the predictor. RESULTS:In the unadjusted logistic regression model, detoxification drug received (either methadone or buprenorphine) was significantly associated with decreased likelihood of induction onto XR-NTX compared to receiving non-opioid detoxification (Overall: P < 0.001); buprenorphine vs non-opioid detoxification: OR (95% CI) = 0.32 (0.15-0.67); methadone vs non-opioid detoxification: OR (95% CI) = 0.23 (0.11-0.46). After controlling for site as a random effect, the association of detoxification drug with induction success lost statistical significance. CONCLUSIONS:Use of agonist medication during detoxification was associated with XR-NTX induction failure. Medication choice was determined by each site's clinical practice and therefore this association could not be separated from other site level variables. CLINICAL TRIAL REGISTRATION/BACKGROUND:NCT02032433.
PMID: 33771287
ISSN: 1873-6483
CID: 4830232

Correlates of opioid abstinence after randomization to buprenorphine-naloxone versus injectable naltrexone in a multi-site trial [Meeting Abstract]

Greiner, M; Campbell, A; Nunes, E; Pavlicova, M; Rotrosen, J; Shulman, M; Scodes, J; Lee, J D; Novo, P; Choo, T -H
This activity is a paper presentation on a secondary analysis of factors associated with opioid abstinence three months following the treatment trial. While abstinence is not required for improvement in opioid use outcomes, better understanding of abstinence-related factors can inform efforts to facilitate stable recovery for opioid-dependent individuals. XXBackground(s): Opioid use disorder (OUD) is associated with substantial mortality. There are effective treatments in reducing opioid use and overdose events. However, many patients that successfully initiate OUD pharmacotherapy will discontinue treatment within the first few weeks or months. Upon treatment discontinuation, patients are at risk for relapse and overdose, however, not all patients relapse. There is a need to better understand predictors of relapse and abstinence after medication discontinuation. XXObjective(s): 1) Demonstrate general understanding of effective treatments for OUD and current barriers to treatment retention. 2) Describe factors associated with opioid abstinence from this secondary analysis. 3) Identify limitations in analyses and interpreting results. XXMethod(s): This secondary analysis examines correlates of opioid abstinence in 428 participants at week 36 follow-up from the National Drug Abuse Treatment Clinical Trials Network CTN-0051) X:BOT trial. X:BOT randomized participants to buprenorphine-naloxone (BUP-NX) or extended-release injectable naltrexone (XR-NTX) for up to 24 weeks of outpatient treatment. Study medications were discontinued at study completion or relapse. Follow-up assessments in the community were done at weeks 28 and 36. XXResult(s): Participants had higher odds of being abstinent at week 36 if randomized to XR-NTX compared with BUP-NX (odds ratio [OR] [95% confidence interval [CI]] = 2.47 [1.63, 3.74]), were on XR-NTX at follow-up compared with those off medication (OR = 2.33 [1.40, 3.90]), had longer time to relapse (OR = 1.04 [1.02, 1.07]), successfully inducted onto study medication compared with those who failed induction (OR = 3.16 [1.45, 6.92]), had longer time on study medication (OR = 1.03[1.01, 1.05]), and had more abstinent weeks during the trial (OR = 1.04 [1.02, 1.07]). XXConclusion(s): In general, participants that had better outcomes during the treatment trial were found to be abstinent from opioids at follow-up in the community. This included successful induction onto study medication, longer time on medication, greater time to relapse, and more abstinent weeks. While abstinence is not required for improvement in opioid use outcomes, better understanding of abstinence-related factors can inform efforts to facilitate stable recovery for opioid-dependent individuals. Scientific Significance: There is a need to better understand predictors of relapse and abstinence after medication discontinuation in order to better advise patients that may discontinue medications. Barriers to treatment retention and sustained abstinence are factors generally considered to be proxies for greater disease severity. Less is understood about factors associated with sustained abstinence
ISSN: 1521-0391
CID: 4928772

Naturalistic follow-up after a trial of medications for opioid use disorder: Medication status, opioid use, and relapse

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
AIM/OBJECTIVE:This report examined naturalistic opioid use outcomes and utilization of medications for opioid use disorder (MOUD) 36 weeks post-randomization in the National Drug Abuse Treatment Clinical Trials Network (CTN) Extended-Release Naltrexone (XR-NTX) versus Buprenorphine-Naloxone (BUP-NX) for Opioid Treatment trial (CTN-0051, X:BOT). DESIGN/METHODS:X:BOT was a multisite, randomized, 24-week comparative effectiveness trial of BUP-NX (N = 287) and XR-NTX (N = 283). Study medications were discontinued following treatment completion, relapse, or dropout. Participants were encouraged to continue MOUD. This report examined opioid use outcomes in 428 (75%) of the 570 participants who attended the 36-week follow-up visit. SETTING AND PARTICIPANTS/METHODS:Adults with opioid use disorder recruited from 8 community treatment programs across the United States. MEASUREMENTS/METHODS:Outcomes included medication status (on/off MOUD), type of MOUD (BUP-NX, XR-NTX, or methadone), abstinence from non-prescribed opioids, opioid use days, relapse, and other substance use 30 days prior to the 36-week visit. Relapse was defined as opioid use for 4 consecutive weeks or 7 consecutive days in the past month. Baseline and clinical variables included opioid use severity, intravenous drug use, study medication assignment, and induction status. FINDINGS/RESULTS:Of the 428 participants who completed the 36-week visit, 225 (53%) of participants were receiving MOUD and 203 (47%) were not. Compared to those off medication, participants on medication had fewer opioid use days (4.4 days (SD 9.0) versus 9.8 days (SD 12.1)), fewer met relapse criteria (37 (16.4%) versus 79 (38.9%)), and reported less stimulant use (34 (15.2%) versus 56 (27.7%)) and sedative use (14 (6.3%) versus 31 (15.3%)). There was no difference in abstinence rates between those on or off MOUD. A greater proportion of participants on XR-NTX (47 (53.4%) of 88 participants) were abstinent from non-prescribed opioids compared to those on buprenorphine (28 (23.3%) of 120 participants). CONCLUSIONS:Naturalistic outcomes data showed that despite potential barriers to continuing treatment in the community, about half of individuals were on opioid use disorder pharmacotherapy at follow-up and those on medication generally had better outcomes. Future research should explore barriers and facilitators to treatment retention in community settings; and developing interventions tailored to improve treatment engagement and adherence.
PMID: 34098301
ISSN: 1873-6483
CID: 4898252

Implementation facilitation to introduce and support emergency department-initiated buprenorphine for opioid use disorder in high need, low resource settings: protocol for multi-site implementation-feasibility study

McCormack, Ryan P; Rotrosen, John; Gauthier, Phoebe; D'Onofrio, Gail; Fiellin, David A; Marsch, Lisa A; Novo, Patricia; Liu, David; Edelman, E Jennifer; Farkas, Sarah; Matthews, Abigail G; Mulatya, Caroline; Salazar, Dagmar; Wolff, Jeremy; Knight, Randolph; Goodman, William; Hawk, Kathryn
BACKGROUND:For many reasons, the emergency department (ED) is a critical venue to initiate OUD interventions. The prevailing culture of the ED has been that substance use disorders are non-emergent conditions better addressed outside the ED where resources are less constrained. This study, its rapid funding mechanism, and accelerated timeline originated out of the urgent need to learn whether ED-initiated buprenorphine (BUP) with referral for treatment of OUD is generalizable, as well as to develop strategies to facilitate its adoption across a variety of ED settings and under real-world conditions. It both complements and uses methods adapted from Project ED Health (CTN-0069), a Hybrid Type 3 implementation-effectiveness study of using Implementation Facilitation (IF) to integrate ED-initiated BUP and referral programs. METHODS:ED-CONNECT (CTN 0079) was a three-site implementation study exploring the feasibility, acceptability, and impact of introducing ED-initiated BUP in rural and urban settings with high-need, limited resources, and different staffing structures. We used a multi-faceted approach to develop, introduce and iteratively refine site-specific ED clinical protocols and implementation plans for opioid use disorder (OUD) screening, ED-initiated BUP, and referral for treatment. We employed a participatory action research approach and use mixed methods incorporating data derived from abstraction of medical records and administrative data, assessments of recruited ED patient-participants, and both qualitative and quantitative inquiry involving staff from the ED and community, patients, and other stakeholders. DISCUSSION/CONCLUSIONS:This study was designed to provide the necessary, time-sensitive understanding of how to identify OUD and initiate treatment with BUP in the EDs previously not providing ED-initiated BUP, in communities in which this intervention is most needed: high need, low resource settings. TRIAL REGISTRATION/BACKGROUND:The study was prospectively registered on (NCT03544112) on June 01, 2018: .
PMID: 33750454
ISSN: 1940-0640
CID: 4822352