Variation in Opioid Agonist Dosing in Clinical Trials by Race and Ethnicity.

Importance: Racial and ethnic disparities in access to treatment and quality of treatment for opioid use disorder (OUD) have been identified in usual care settings. In contrast, disparities in treatment quality within clinical trials are relatively unexamined. Objective: To estimate racial and ethnic differences in the dose of opioid agonist treatment for OUD in the first 4 weeks of treatment in clinical trials. Design, Setting, and Participants: This cohort study performed analysis of the methadone and buprenorphine treatment arms of 3 trials conducted by the National Institute on Drug Abuse Clinical Trials Network between May 2006, and January 31, 2017, at multiple Clinical Trials Network sites across the US. Trial participants who were randomized to and initiated buprenorphine or methadone treatment and who identified as Hispanic, non-Hispanic Black, or non-Hispanic White were included in the present study. Data were analyzed from November 1, 2023, to August 5, 2024. Exposure: Combined race and ethnicity as self-classified by the patient at trial enrollment. Main Outcomes and Measures: The maximum daily dose of buprenorphine or methadone received in each week for the first 4 weeks of treatment. The mean dose and the percentage of patients receiving a higher dose (buprenorphine ≥16 mg and methadone ≥60 mg) were compared across race and ethnicity groups. Results: A total of 1748 patients (1263 who initiated buprenorphine and 485 who initiated methadone treatment) were included in the analysis (1168 [66.8%] male; median age, 33 [IQR, 26-45] years). Of these, 138 patients (7.9%) identified as Black, 273 (15.6%) as Hispanic, and 1337 (76.5%) as White. In week 4, Black patients received buprenorphine doses 2.5 (95% CI -4.6 to -0.5) mg lower and methadone doses 16.7 (95% CI, -30.7 to -2.7) mg lower compared with White patients, after standardizing by age and sex. In week 4, the percentage of patients receiving a higher dose of medication (buprenorphine ≥16 mg; methadone ≥60 mg) was 16.9 (95% CI, -31.9 to -1.9) points lower for Black patients compared with White patients. Hispanic and White patients received similar buprenorphine doses; Hispanic patients received lower methadone doses than White patients. Conclusions and Relevance: In this cohort study of data from 3 clinical trials, White patients generally received higher doses of medication than Black patients. Future research is needed to understand the mechanisms of and interventions to reduce disparities in OUD treatment quality and how such disparities impact generalizability of trial results.

The Concept of Treatment-Refractory Addiction: Implications for Addiction Treatment Systems and Research.

ABSTRACT: The concept of treatment-refractory addiction, proposed by Eric Strain in this edition of the Journal, has the potential to invigorate the field of addiction treatment and research by focusing on a phenomenon that is familiar to any clinician treating patients with substance use disorders, namely, the patient who does not experience sufficient improvement from standard treatments. An analogy is drawn to the concept of treatment-resistant depression and the STAR*D study, which demonstrated an algorithmic approach to treatment, where if the first antidepressant medication tried did not result in remission from depression, subsequent trials of medications or cognitive behavioral therapy doubled the proportion of patients achieving remission. Recognizing treatment-refractory addiction challenges our field to develop analogous, stepwise, algorithmic approaches to treatment of substance use disorders, moving away from siloed treatment programs toward integrated treatment systems where alternative treatments are available, offering the kind of personalized, tailored forms of care used in the treatment of most other chronic illnesses. Like in STAR*D, research could focus on samples of patients who have not benefitted from initial trials of standard addiction treatments, addressing the key clinical question of what to do next when previous treatments fail.

Medications for opioid use disorder: Predictors of early discontinuation and reduction of overdose risk in US military veterans by medication type.

AIM: This study: (1) estimated the effect of early discontinuation of medication for opioid use disorder (MOUD) on overdose probability and (2) measured the relationship between patient characteristics and early discontinuation probability for each MOUD type. DESIGN, SETTING AND PARTICIPANTS: This was a retrospective cohort using electronic health record data from the US Veterans Healthcare Administration. Participants were veterans initiating MOUD with buprenorphine (BUP), methadone (MET) or extended-release naltrexone (XR-NTX) from fiscal years 2012-19. A total of 39 284 veterans met eligibility with 22 721 (57.8%) initiating BUP, 12 652 (32.2%) initiating MET and 3911 (10.0%) initiating XR-NTX. MEASUREMENTS: Measurements (1) determined whether the veteran experienced an overdose in the 365 days after MOUD initiation (primary) and (2) early discontinuation of MOUD, defined as discontinuation before 180 days (secondary). We assumed that unobserved patient characteristics would jointly influence the probability of discontinuation and overdose. and estimated the joint distribution with a bivariate probit model. FINDINGS: We found that 9.0% of BUP initiators who experienced an overdose above the predicted 3.9% had no veteran-discontinued BUP early; findings for XR-NTX were similar, with 12.2% of initiators overdosing above the predicted 4.5%, but this was statistically inconclusive. We found no relationship between early discontinuation and overdose for MET initiators, probably due to the high risk of both events. The patient characteristics included in our post-estimation exploratory analysis of early discontinuation varied by MOUD type, with between 14 (XR-NTX) and 25 (BUP) tested. The only characteristics with at least one level showing a statistically significant change in probability of early discontinuation for all three MOUD types were geography and prior-year exposure to psychotherapy, although direction and magnitude varied. CONCLUSION: Early discontinuation of buprenorphine, and probably extended-release naltrexone, appears to be associated with a greater probability of experiencing a fatal or non-fatal overdose among US veterans receiving medication for opioid use disorder (MOUD); methadone does not show the same association. There is no consistent set of characteristics among early discontinuers by MOUD type.

Comparative effectiveness of extended-release naltrexone and sublingual buprenorphine for treatment of opioid use disorder among Medicaid patients.

BACKGROUND AND AIMS: Extended-release naltrexone (XR-NTX) and sublingual buprenorphine (SL-BUP) are both approved for opioid use disorder (OUD) treatment in any medical setting. We aimed to compare the real-world effectiveness of XR-NTX and SL-BUP. DESIGN AND SETTING: This was an observational active comparator, new user cohort study of Medicaid claims records for patients in New Jersey and California, USA, 2016-19. PARTICIPANTS/CASES: The participants were adult Medicaid patients aged 18-64 years who initiated XR-NTX or SL-BUP for maintenance treatment of OUD and did not use medications for OUD in the 90 days before initiation. Our cohort included 1755 XR-NTX and 9886 SL-BUP patients. MEASUREMENTS: We examined two outcomes up to 180 days after medication initiation: (1) composite of medication discontinuation and death and (2) composite of overdose and death. FINDINGS: In adjusted analyses, treatment with XR-NTX was more likely to result in discontinuation or death by the end of follow-up than treatment with SL-BUP: cumulative risk 75.9% [95% confidence interval (CI) = 73.9%, 77.9%] versus 62.2% (95% CI = 61.2%, 63.2%), respectively (risk difference = 13.7 percentage points, 95% CI = 11.4, 16.0). There was minimal difference in the cumulative risk of overdose or death by the end of follow-up: XR-NTX 3.9% (95% CI = 3.0%, 4.8%) versus SL-BUP 3.3% (95% CI = 2.9%, 3.7%); risk difference = 0.5 percentage points, 95% CI = -0.4, 1.5. Results were consistent across sensitivity analyses. CONCLUSIONS: Medicaid patients in California and New Jersey, USA, receiving treatment for opioid use disorder stayed in treatment longer on sublingual buprenorphine than on extended-release naltrexone, but the risk of overdose was similar. Most patients in this study discontinued medication within 6 months, regardless of which medication was initiated.

Missed Opportunities for Preexposure Prophylaxis Initiation in Hospitalized Persons With Opioid Use Disorder and Infectious Diseases.

Hospitalizations are increasing among persons who use opioids, secondary to overdose and infections. Our study identified acute hospitalization as a reachable moment for engaging people who use drugs in increased screening and education about human immunodeficiency virus risk and prevention (preexposure prophylaxis).

Predictors of urine toxicology and other biologic specimen missingness in randomized trials of substance use disorders.

BACKGROUND: High levels of missing outcome data for biologically confirmed substance use (BCSU) threaten the validity of substance use disorder (SUD) clinical trials. Underlying attributes of clinical trials could explain BCSU missingness and identify targets for improved trial design. METHODS: We reviewed 21 clinical trials funded by the NIDA National Drug Abuse Treatment Clinical Trials Network (CTN) and published from 2005 to 2018 that examined pharmacologic and psychosocial interventions for SUD. We used configurational analysis-a Boolean algebra approach that identifies an attribute or combination of attributes predictive of an outcome-to identify trial design features and participant characteristics associated with high levels of BCSU missingness. Associations were identified by configuration complexity, consistency, coverage, and robustness. We limited results using a consistency threshold of 0.75 and summarized model fit using the product of consistency and coverage. RESULTS: For trial design features, the final solution consisted of two pathways: psychosocial treatment as a trial intervention OR larger trial arm size (complexity=2, consistency=0.79, coverage=0.93, robustness score=0.71). For participant characteristics, the final solution consisted of two pathways: interventions targeting individuals with poly- or nonspecific substance use OR younger age (complexity=2, consistency=0.75, coverage=0.86, robustness score=1.00). CONCLUSIONS: Psychosocial treatments, larger trial arm size, interventions targeting individuals with poly- or nonspecific substance use, and younger age among trial participants were predictive of missing BCSU data in SUD clinical trials. Interventions to mitigate missing data that focus on these attributes may reduce threats to validity and improve utility of SUD clinical trials.

Examining the Impact of the Innovative Opioid Court Model on Treatment Access and Court Outcomes for Court Participants.

OBJECTIVE: The opioid intervention court (OIC) is an innovative, pre-plea treatment court to facilitate rapid linkage to medications for opioid use disorder (MOUD) for people at risk of overdose. This study compares participants in OIC and participants with opioid use problems in a traditional drug treatment court model on (i) initiation for any substance use (SU) treatment, (ii) initiation of MOUD, (iii) number of days to MOUD initiation, and (iv) retention in the OIC program/retention on MOUD. METHODS: We used administrative court records from n = 389 OIC and n = 229 drug court participants in 2 counties in New York State. Differences in outcomes by court were assessed using logistic, multinomial, or linear regressions. RESULTS: After adjusting for current charge severity, gender, race/ethnicity, age, and county, OIC participants were no more likely to initiate any SU treatment but were significantly more likely to initiate MOUD (81.2% OIC vs 45.9% drug court, P < 0.001) and were more quickly linked to any SU treatment (hazard ratio = 1.68, 95% confidence interval = 1.35-2.08) and MOUD (hazard ratio = 4.25, 95% confidence interval = 3.23-5.58) after starting the court. Retention in court/MOUD was higher among drug court participants and may speak to the immediate sanctions (eg, jail) for noncompliance with drug court directives as compared with opioid court, which does not carry such immediate sanctions for noncompliance. CONCLUSIONS: These analyses suggest that the new OIC model can more rapidly link participants to treatment, including MOUD, as compared with traditional drug court model, and may demonstrate improved ability to immediately stabilize and reduce overdose risk in court participants.

Extended-Release Injection vs Sublingual Buprenorphine for Opioid Use Disorder With Fentanyl Use: A Post Hoc Analysis of a Randomized Clinical Trial.

Importance: Fentanyl has exacerbated the opioid use disorder (OUD) and opioid overdose epidemic. Data on the effectiveness of medications for OUD among patients using fentanyl are limited. Objective: To assess the effectiveness of sublingual or extended-release injection formulations of buprenorphine for the treatment of OUD among patients with and without fentanyl use. Design, Setting, and Participants: Post hoc analysis of a 24-week, randomized, double-blind clinical trial conducted at 35 outpatient sites in the US from December 2015 to November 2016 of sublingual buprenorphine-naloxone vs extended-release subcutaneous injection buprenorphine (CAM2038) for patients with OUD subgrouped by presence vs absence of fentanyl or norfentanyl in urine at baseline. Study visits with urine testing occurred weekly for 12 weeks, then 6 times between weeks 13 and 24. Data were analyzed on an intention-to-treat basis from March 2022 to August 2023. Intervention: Weekly and monthly subcutaneous buprenorphine vs daily sublingual buprenorphine-naloxone. Main Outcomes and Measures: Retention in treatment, percentage of urine samples negative for any opioids (missing values imputed as positive), percentage of urine samples negative for fentanyl or norfentanyl (missing values not imputed), and scores on opiate withdrawal scales and visual analog craving scales. Results: Of 428 participants, 123 (subcutaneous buprenorphine, n = 64; sublingual buprenorphine-naloxone, n = 59; mean [SD] age, 39.1 [10.8] years; 75 men [61.0%]) had evidence of baseline fentanyl use and 305 (subcutaneous buprenorphine, n = 149; buprenorphine-naloxone, n = 156; mean [SD] age, 38.1 [11.1] years; 188 men [61.6%]) did not have evidence of baseline fentanyl use. Study completion was similar between the fentanyl-positive (60.2% [74 of 123]) and fentanyl-negative (56.7% [173 of 305]) subgroups. The mean percentage of urine samples negative for any opioid were 28.5% among those receiving subcutaneous buprenorphine and 18.8% among those receiving buprenorphine-naloxone in the fentanyl-positive subgroup (difference, 9.6%; 95% CI, -3.0% to 22.3%) and 36.7% among those receiving subcutaneous buprenorphine and 30.6% among those receiving buprenorphine-naloxone in the fentanyl-negative subgroup (difference, 6.1%; 95% CI, -1.9% to 14.1%), with significant main associations of baseline fentanyl status and treatment group. In the fentanyl-positive subgroup, the mean percentage of urine samples negative for fentanyl during the study was 74.6% among those receiving subcutaneous buprenorphine vs 61.9% among those receiving sublingual buprenorphine-naloxone (difference, 12.7%; 95% CI, 9.6%-15.9%). Opioid withdrawal and craving scores decreased rapidly after treatment initiation across all groups. Conclusions and Relevance: In this post hoc analysis of a randomized clinical trial of sublingual vs extended-release injection buprenorphine for OUD, buprenorphine appeared to be effective among patients with baseline fentanyl use. Patients with fentanyl use had fewer opioid-negative urine samples during the trial compared with the fentanyl-negative subgroup. These findings suggest that the subcutaneous buprenorphine formulation may be more effective at reducing fentanyl use. Trial Registration: ClinicalTrials.gov Identifier: NCT02651584.

Rapid Initiation of Injection Naltrexone for Opioid Use Disorder: A Stepped-Wedge Cluster Randomized Clinical Trial.

Importance: Injectable extended-release (XR)-naltrexone is an effective treatment option for opioid use disorder (OUD), but the need to withdraw patients from opioid treatment prior to initiation is a barrier to implementation. Objective: To compare the effectiveness of the standard procedure (SP) with the rapid procedure (RP) for XR-naltrexone initiation. Design, Setting, and Participants: The Surmounting Withdrawal to Initiate Fast Treatment with Naltrexone study was an optimized stepped-wedge cluster randomized trial conducted at 6 community-based inpatient addiction treatment units. Units using the SP were randomly assigned at 14-week intervals to implement the RP. Participants admitted with OUD received the procedure the unit was delivering at the time of their admission. Participant recruitment took place between March 16, 2021, and July 18, 2022. The last visit was September 21, 2022. Interventions: Standard procedure, based on the XR-naltrexone package insert (approximately 5-day buprenorphine taper followed by a 7- to 10-day opioid-free period and RP, defined as 1 day of buprenorphine at minimum necessary dose, 1 opioid-free day, and ascending low doses of oral naltrexone and adjunctive medications (eg, clonidine, clonazepam, antiemetics) for opioid withdrawal. Main Outcomes and Measures: Receipt of XR-naltrexone injection prior to inpatient discharge (primary outcome). Secondary outcomes included opioid withdrawal scores and targeted safety events and serious adverse events. All analyses were intention-to-treat. Results: A total of 415 participants with OUD were enrolled (mean [SD] age, 33.6 [8.48] years; 205 [49.4%] identified sex as male); 54 [13.0%] individuals identified as Black, 91 [21.9%] as Hispanic, 290 [69.9%] as White, and 22 [5.3%] as multiracial. Rates of successful initiation of XR-naltrexone among the RP group (141 of 225 [62.7%]) were noninferior to those of the SP group (68 of 190 [35.8%]) (odds ratio [OR], 3.60; 95% CI, 2.12-6.10). Withdrawal did not differ significantly between conditions (proportion of days with a moderate or greater maximum Clinical Opiate Withdrawal Scale score (>12) for RP vs SP: OR, 1.25; 95% CI, 0.62-2.50). Targeted safety events (RP: 12 [5.3%]; SP: 4 [2.1%]) and serious adverse events (RP: 15 [6.7%]; SP: 3 [1.6%]) were infrequent but occurred more often with RP than SP. Conclusions and Relevance: In this trial, the RP of XR-naltrexone initiation was noninferior to the standard approach and saved time, although it required more intensive medical management and safety monitoring. The results of this trial suggest that rapid initiation could make XR-naltrexone a more viable treatment for patients with OUD. Trial Registration: ClinicalTrials.gov Identifier: NCT04762537.

Optimizing Contingency Management with Reinforcement Learning.

Contingency Management (CM) is a psychological treatment that aims to change behavior with financial incentives. In substance use disorders (SUDs), deployment of CM has been enriched by longstanding discussions around the cost-effectiveness of prized-based and voucher-based approaches. In prize-based CM, participants earn draws to win prizes, including small incentives to reduce costs, and the number of draws escalates depending on the duration of maintenance of abstinence. In voucher-based CM, participants receive a predetermined voucher amount based on specific substance test results. While both types have enhanced treatment outcomes, there is room for improvement in their cost-effectiveness: the voucher-based system requires enduring financial investment; the prize-based system might sacrifice efficacy. Previous work in computational psychiatry of SUDs typically employs frameworks wherein participants make decisions to maximize their expected compensation. In contrast, we developed new frameworks that clinical decision-makers choose actions, CM structures, to reinforce the substance abstinence behavior of participants. We consider the choice of the voucher or prize to be a sequential decision, where there are two pivotal parameters: the prize probability for each draw and the escalation rule determining the number of draws. Recent advancements in Reinforcement Learning, more specifically, in off-policy evaluation, afforded techniques to estimate outcomes for different CM decision scenarios from observed clinical trial data. We searched CM schemas that maximized treatment outcomes with budget constraints. Using this framework, we analyzed data from the Clinical Trials Network to construct unbiased estimators on the effects of new CM schemas. Our results indicated that the optimal CM schema would be to strengthen reinforcement rapidly in the middle of the treatment course. Our estimated optimal CM policy improved treatment outcomes by 32% while maintaining costs. Our methods and results have broad applications in future clinical trial planning and translational investigations on the neurobiological basis of SUDs.

Discontinuation of medication treatment for opioid use disorder after a successful course: The discontinuation phase of the CTN-0100 (RDD) trial.

INTRODUCTION AND BACKGROUND: Buprenorphine, and extended-release naltrexone, are effective in decreasing opioid use, morbidity and mortality. The available evidence suggests that these medications should be used for long term treatment; however, patients often ask how long they need to be on medication, and whether it would be safe to discontinue. There are sparse data to guide us. The CTN-0100 trial will address this gap in our knowledge by studying participants who have decided to discontinue buprenorphine and extended-release naltrexone for OUD. RESEARCH DESIGN AND METHODS: The trial is a multicenter, randomized, non-blinded study. Participants are stable adult volunteers, on sublingual buprenorphine, extended-release buprenorphine, or extended-release naltrexone, expressing an interest in discontinuing medication. Participants on buprenorphine must be stable for at least 1 year and participants on extended-release naltrexone must be stable for at least 6 months. Participants are engaged in the study for up to 96 weeks, including a flexible taper period, and are then transitioned to follow-up within the trial. All participants are randomly assigned to the study Medical Management (MM) or to MM plus Connections (CHESS health) digital smartphone application aimed at recovery and abstinence (MMD). Sublingual Buprenorphine participants are also randomized (2 × 2 design) to a taper using either sublingual or extended-release buprenorphine. DISCUSSION/CONCLUSION: It is hoped that this trial will provide a rich source of data on management of patients discontinuing medication for opioid use disorder (MOUD) to inform future research and practice. The trial will shed light on which strategies are most likely to lead to long-term success (absence of relapse), and what participant characteristics distinguish those who can safely discontinue MOUD from those who remain at risk of relapse should they discontinue. CLINICALTRIALS: gov Identifier: NCT04464980.

Effect of the Communities that HEAL intervention on receipt of behavioral therapies for opioid use disorder: A cluster randomized wait-list controlled trial.

BACKGROUND: The U.S. opioid overdose crisis persists. Outpatient behavioral health services (BHS) are essential components of a comprehensive response to opioid use disorder and overdose fatalities. The Helping to End Addiction Long-Term® (HEALing) Communities Study developed the Communities That HEAL (CTH) intervention to reduce opioid overdose deaths in 67 communities in Kentucky, Ohio, New York, and Massachusetts through the implementation of evidence-based practices (EBPs), including BHS. This paper compares the rate of individuals receiving outpatient BHS in Wave 1 intervention communities (n = 34) to waitlisted Wave 2 communities (n = 33). METHODS: Medicaid data included individuals ≥18 years of age receiving any of five BHS categories: intensive outpatient, outpatient, case management, peer support, and case management or peer support. Negative binomial regression models estimated the rate of receiving each BHS for Wave 1 and Wave 2. Effect modification analyses evaluated changes in the effect of the CTH intervention between Wave 1 and Wave 2 by research site, rurality, age, sex, and race/ethnicity. RESULTS: No significant differences were detected between intervention and waitlisted communities in the rate of individuals receiving any of the five BHS categories. None of the interaction effects used to test the effect modification were significant. CONCLUSIONS: Several factors should be considered when interpreting results-no significant intervention effects were observed through Medicaid claims data, the best available data source but limited in terms of capturing individuals reached by the intervention. Also, the 12-month evaluation window may have been too brief to see improved outcomes considering the time required to stand-up BHS. TRIAL REGISTRATION: Clinical Trials.gov http://www. CLINICALTRIALS: gov: Identifier: NCT04111939.

Prevalence of Opioid Use Disorder and Opioid Overdose Rates Among People With Mental Illness.

OBJECTIVE: The authors examined the prevalence and correlates of co-occurring opioid use disorder and opioid overdose among individuals receiving psychiatric services. METHODS: This was a cross-sectional study of adults with continuous enrollment in New York State Medicaid who received at least one psychiatric service in 2020 (N=523,885). Logistic regression models were used to examine the correlates of both opioid use disorder and overdose. RESULTS: In the study sample, the prevalence rate of opioid use disorder was 8.1%; within this group, 7.7% experienced an opioid overdose in the study year. Opioid use disorder rates were lower among younger (18-24 years; 2.0%) and older (≥65 years; 3.1%) adults and higher among men (11.1%) and among those residing in rural areas (9.9%). Compared with Whites (9.4%), opioid use disorder rates were lower for Asian Americans (2.0%, adjusted odds ratio [AOR]=0.22) and Blacks (6.8%, AOR=0.76) and higher for American Indians (13.2%, AOR=1.43) and Hispanics (9.6%, AOR=1.29). Individuals with any substance use (24.9%, AOR=5.20), posttraumatic stress (15.7%, AOR=2.34), bipolar (14.9%, AOR=2.29), or anxiety (11.3%, AOR=2.18) disorders were more likely to have co-occurring opioid use disorder; those with conduct (4.5%, AOR=0.51), adjustment (7.4%, AOR=0.88), or schizophrenia spectrum (7.4%, AOR=0.87) disorders were less likely to have opioid use disorder. Those with suicidality (23.9%, AOR=3.83) or economic instability (23.7%, AOR=3.35) had higher odds of having opioid use disorder. Overdose odds were higher among individuals with suicidality (34.0%, AOR=6.82) and economic instability (16.0%, AOR=2.57). CONCLUSIONS: These findings underscore the importance of providing opioid use disorder screening and treatment for patients receiving psychiatric services.

Comparative effectiveness of extended release naltrexone and sublingual buprenorphine for treatment of opioid use disorder among Medicaid patients.

Aims: To compare the real-world effectiveness of extended release naltrexone (XR-NTX) and sublingual buprenorphine (SL-BUP) for the treatment of opioid use disorder (OUD). Design: An observational active comparator, new user cohort study. Setting: Medicaid claims records for patients in New Jersey and California, 2016-2019. Participants/Cases: Adult Medicaid patients aged 18-64 years who initiated XR-NTX or SL-BUP for maintenance treatment of OUD and did not use medications for OUD in the 90-days before initiation. Comparators: New initiation with XR-NTX versus SL-BUP for the treatment of OUD. Measurements: We examined two outcomes up to 180 days after medication initiation, 1) composite of medication discontinuation and death, and 2) composite of overdose and death. Findings: Our cohort included 1,755 XR-NTX and 9,886 SL-BUP patients. In adjusted analyses, treatment with XR-NTX was more likely to result in discontinuation or death by the end of follow-up than treatment with SL-BUP: cumulative risk 76% (95% confidence interval [CI] 75%, 78%) versus 62% (95% CI 61%, 63%), respectively (risk difference 14 percentage points, 95% CI 13, 16). There was minimal difference in the cumulative risk of overdose or death by the end of follow-up: XR-NTX 3.8% (95% CI 2.9%, 4.7%) versus SL-BUP 3.3% (95% 2.9%, 3.7%); risk difference 0.5 percentage points, 95%CI -0.5, 1.5. Results were consistent across sensitivity analyses. Conclusions: Longer medication retention is important because risks of negative outcomes are elevated after discontinuation. Our results support selection of SL-BUP over XR-NTX. However, most patients discontinued medication by 6 months indicating that more effective tools are needed to improve medication retention, particularly after initiation with XR-NTX, and to identify which patients do best on which medication.

An Approach to Enhancing Medication Treatment for Opioid Use Disorder in the HEALing Communities Study.

The HEALing (Helping to End Addiction Long-term) Communities Study (HCS) aims to test the effectiveness of the Communities That HEAL intervention in decreasing opioid overdose deaths in 67 communities across four U.S. states. This intervention enlists a collaborative team of researchers, academic experts, and community coalitions to select and implement interventions from a menu of evidence-based practices, including medications for opioid use disorder (MOUD). The HCS's New York team developed an integrated network systems (INS) approach with a mapping tool to coach coalitions in the selection of strategies to enhance medication treatment. With the INS approach, community coalitions develop a map of service delivery venues in their local county to better engage people with medication treatment wherever this need arises. The map is structured around core services that can provide maintenance MOUD and satellite services, which include all settings where people with opioid use disorder are encountered and can be identified, possibly given medication, and referred to core programs for ongoing MOUD care. This article describes the rationale for the INS mapping tool, with a discussion framed by the consolidated framework for implementation research, and provides a case example of its application.

Mixed amphetamine salts-extended release (MAS-ER) as a behavioral treatment augmentation strategy for cocaine use disorder: A randomized clinical trial.

Psychosocial interventions remain the primary strategy for addressing cocaine use disorder (CUD), although many individuals do not benefit from these approaches. Amphetamine-based interventions have shown significant promise and may improve outcomes among individuals continuing to use cocaine in the context of behavioral interventions. One hundred forty-five adults (122 males) who used cocaine a minimum of 4 days in the prior month and met the criteria for a CUD enrolled in a two-stage intervention. All participants received a computer-delivered skills intervention and contingency management for reinforcing abstinence for a 1-month period. Participants demonstrating less than 3 weeks of abstinence in the first month were randomized to receive mixed amphetamine salts-extended release (MAS-ER) or placebo (80 mg/day) for 10 weeks under double-blind conditions. All participants continued with the behavioral intervention. The primary outcome was the proportion of individuals who achieved 3 consecutive weeks of abstinence as measured by urine toxicology confirmed self-report at the study end. The proportion of participants demonstrating 3 consecutive weeks of abstinence at study end did not differ between the medication groups: MAS-ER = 15.6% (7/45) and placebo = 12.2% (5/41). Participants who received MAS-ER reported greater reductions in the magnitude of wanting cocaine, although no group differences were noted in either the perceived improvement or the frequency of wanting cocaine. Retention rates were greater for both medication groups compared to behavioral responders. Overall, augmenting a behavioral intervention with MAS-ER did not significantly increase the abstinence rate among individuals continuing to use cocaine following a month of behavioral therapy alone. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Individual-Level Risk Prediction of Return to Use During Opioid Use Disorder Treatment.

Importance: No existing model allows clinicians to predict whether patients might return to opioid use in the early stages of treatment for opioid use disorder. Objective: To develop an individual-level prediction tool for risk of return to use in opioid use disorder. Design, Setting, and Participants: This decision analytical model used predictive modeling with individual-level data harmonized in June 1, 2019, to October 1, 2022, from 3 multicenter, pragmatic, randomized clinical trials of at least 12 weeks' duration within the National Institute on Drug Abuse Clinical Trials Network (CTN) performed between 2006 and 2016. The clinical trials covered a variety of treatment settings, including federally licensed treatment sites, physician practices, and inpatient treatment facilities. All 3 trials enrolled adult participants older than 18 years, with broad pragmatic inclusion and few exclusion criteria except for major medical and unstable psychiatric comorbidities. Intervention: All participants received 1 of 3 medications for opioid use disorder: methadone, buprenorphine, or extended-release naltrexone. Main Outcomes and Measures: Predictive models were developed for return to use, which was defined as 4 consecutive weeks of urine drug screen (UDS) results either missing or positive for nonprescribed opioids by week 12 of treatment. Results: The overall sample included 2199 trial participants (mean [SD] age, 35.3 [10.7] years; 728 women [33.1%] and 1471 men [66.9%]). The final model based on 4 predictors at treatment entry (heroin use days, morphine- and cocaine-positive UDS results, and heroin injection in the past 30 days) yielded an area under the receiver operating characteristic curve (AUROC) of 0.67 (95% CI, 0.62-0.71). Adding UDS in the first 3 treatment weeks improved model performance (AUROC, 0.82; 95% CI, 0.78-0.85). A simplified score (CTN-0094 OUD Return-to-Use Risk Score) provided good clinical risk stratification wherein patients with weekly opioid-negative UDS results in the 3 weeks after treatment initiation had a 13% risk of return to use compared with 85% for those with 3 weeks of opioid-positive or missing UDS results (AUROC, 0.80; 95% CI, 0.76-0.84). Conclusions and Relevance: The prediction model described in this study may be a universal risk measure for return to opioid use by treatment week 3. Interventions to prevent return to regular use should focus on this critical early treatment period.

Clinical Implications of the Relationship Between Naltrexone Plasma Levels and the Subjective Effects of Heroin in Humans.

BACKGROUND: Extended-release naltrexone (NTX) is an opioid antagonist approved for relapse prevention after medical withdrawal. Its therapeutic effect is dependent on the NTX plasma level, and as it decreases, patients may lack protection against relapse and overdose. Therefore, identifying the minimally effective NTX level needed to block opioid-induced subjective effects has important clinical implications. METHODS: This secondary, individual-level analysis of data collected in a human laboratory study was conducted to evaluate the relationship between NTX levels and subjective effects of an intravenously administered 25-mg challenge dose of heroin in non-treatment-seeking participants with opioid use disorder (N = 12). Subjective ratings of drug liking using a 100-mm visual analog scale (VAS) and NTX levels were measured across 6 weeks after participants received a single injection of either extended-release NTX 192 mg (N = 6) or 384 mg (N = 6). Cubic spline mixed-effects models were used to provide 95% prediction intervals for individual changes in liking scores as a function of NTX levels. RESULTS: Naltrexone levels above 2 ng/mL blocked nearly all VAS ratings of drug liking after intravenous heroin administration. Participants with NTX levels ≥ 2 ng/mL had minimal (≤20 mm) changes from placebo in VAS ratings of drug liking based on 95% prediction intervals. In contrast, NTX levels < 2 ng/mL were associated with greater variability in individual-level subjective responses. CONCLUSIONS: In clinical practice, a plasma level range of 1 to 2 ng/mL is considered to be therapeutic in providing heroin blockade. The current findings suggest that a higher level (>2 ng/mL) may be needed to produce a consistent blockade.

Retention and critical outcomes among new methadone maintenance patients following extended take-home reforms: a retrospective observational cohort study.

Background: Approximately 1800 opioid treatment programs (OTPs) in the US dispense methadone to upwards of 400,000 patients with opioid use disorder (OUD) annually, operating under longstanding highly restrictive guidelines. OTPs were granted novel flexibilities beginning March 15, 2020, allowing for reduced visit frequency and extended take-home doses to minimize COVID exposure with great variation across states and sites. We sought to use electronic health records to compare retention in treatment, opioid use, and adverse events among patients newly entering methadone maintenance in the post-reform period in comparison with year-ago, unexposed, controls. Methods: Retrospective observational cohort study across 9 OTPs, geographically dispersed, in the National Institute of Drug Abuse (NIDA) Clinical Trials Network. Newly enrolled patients between April 15 and October 14, 2020 (post-COVID, reform period) v. March 15-September 14, 2019 (pre-COVID, control period) were assessed. The primary outcome was 6-month retention. Secondary outcomes were opioid use and adverse events including emergency department visits, hospitalizations, and overdose. Findings: 821 individuals were newly admitted in the post-COVID and year-ago control periods, average age of 38.3 (SD 11.1), 58.9% male. The only difference across pre- and post-reform groups was the prevalence of psychostimulant use disorder (25.7% vs 32.9%, p = 0.02). Retention was non-inferior (60.0% vs 60.1%) as were hazards of adverse events in the aggregate (X2 (1) = 0.55, p = 0.46) in the post-COVID period. However, rates of month-level opioid use were higher among post-COVID intakes compared to pre-COVID controls (64.8% vs 51.1%, p < 0.001). Moderator analyses accounting for stimulant use and site-level variation in take-home schedules did not change findings. Interpretation: Policies allowing for extended take-home schedules were not associated with worse retention or adverse events despite slightly elevated rates of measured opioid use while in care. Relaxed guidelines were not associated with measurable increased harms and findings could inform future studies with prospective trials. Funding: USDHHSNIDACTNUG1DA013035-15.

Integrating Text Messaging in a Low Threshold Telebuprenorphine Program for New York City Residents with Opioid Use Disorder during COVID-19: A Pilot Randomized Controlled Trial.

BACKGROUND: Pragmatic innovations are needed to optimize clinical outcomes among people who use opioids initiating buprenorphine. This pilot randomized controlled trial assessed the feasibility of integrating text messaging in a low threshold telebuprenorphine bridge program for people who use opioids during the COVID-19 pandemic. METHODS: Eligible adult patients with opioid use disorder inducted on buprenorphine (N = 128) in the NYC Health+Hospitals Virtual Buprenorphine Clinic between May and November 2020 were randomized to an automated texting intervention based on the medical management model versus treatment as usual. A participant feedback survey was administered at 8 weeks (n = 18). Primary outcomes consisted of acceptability (eg, study enrollment, engagement with the intervention) and feasibility (eg, lack of phone number and/or mobile phone ownership) of integrating texting in clinical care. A secondary outcome included retention in treatment at week 8 (ie, active buprenorphine prescription within the prior 7 days). RESULTS: Nearly all eligible patients consented to enroll in the study (90.8%) and few were excluded because of lack of mobile phone ownership (n = 27, 14.6%). Requests to discontinue receipt of texts (n = 6, 9.4%) was attributed to excessive message frequency, perceived lack of relevancy, and reduced interest in the intervention. Respondents completing the follow-up feedback survey were generally satisfied with the frequency of software-generated messages (14/18, 77.8%) and half shared text content with peers (9/18, 50%). There were no perceived issues with privacy, intrusiveness, or ease of use. Retention did not differ between participants randomized to the texting (M = 5.23 weeks, SD = 3.41) and treatment as usual groups (M = 4.98 weeks, SD = 3.34) at week 8 ( P = 0.676). CONCLUSIONS: This pilot randomized controlled trial confirms high acceptability and feasibility of integrating an automated texting tool in a telebuprenorphine bridge program. Future studies should assess whether text messaging may be efficacious when combined with staff contact and content addressing social determinants of health.