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Dr. Korthuis reviewed the biological basis of medications for OUD, presented recent data on the effects of buprenorphine on patient outcomes, and introduced tools for integrating buprenorphine treatment into your current setting.

Background: Cannabis is the most commonly used drug in the United States, and among people who use cannabis, polysubstance use is common and understudied. We aimed to examine the association of tetrahydrocannabinol (THC) positive urine drug screen (+UDS) with the odds of submitting a cocaine + UDS during cocaine use disorder treatment.

Methods: We conducted a secondary data analysis of a previously reported double-blind, placebo-controlled clinical trial, CTN0048. Participants meeting criteria for opioid abuse/dependence were assigned to receive extended-release naltrexone and one of three conditions of buprenorphine (placebo, 4 mg/day, 16 mg/day) for 8 weeks. Generalized estimating equations (GEE) were used to analyze urine samples (Liu et al., 2018) collected over time, examining the association between THC + UDS and cocaine + UDS during treatment.

Results: Participants (n = 301) averaged 46 (SD = 8.64) years of age, were majority male (78.41 %), non-Hispanic (89.70 %), and African American (66.45 %). GEE results indicated that patients who submitted THC + UDS had significantly higher odds of submitting cocaine + UDS compared to participants who submitted THC-negative UDS across the 25 time points examined (OR = 1.47, 95 % CI = 1.21–1.79, p = 0.00). Time (OR = 0.9998, 95 % CI: 0.9997, 0.9999, p = 0.018) and the covariate of sex assigned at birth (OR = 1.77, 95 % CI = 1.13–2.77, p = 0.013) were also significant in the model, indicating very small decreases in the odds of submitting a cocaine + UDS over time for all patients and 77 % higher odds of submitting cocaine + UDS for females.

Conclusion: THC + UDS was associated with increased odds of submitting a cocaine + UDS during treatment. Further investigation is needed to discern whether decreasing THC use will result in reduced cocaine use; however, these results suggest that it may be beneficial to counsel patients on cannabis use cessation both before and during treatment for cocaine use, as it is related to cocaine use treatment outcomes.

Related protocols: CTN-0048

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In this webinar, Erin Winstanley, PhD (University of Pittsburgh and West Virginia University, CTN Appalachian Node), described a NIDA Clinical Trials Network study, CTN-0135, examining clinician-reported challenges with initiating buprenorphine for people using fentanyl, including precipitated or prolonged withdrawal, patient reports that buprenorphine was ineffective, and patient preference for methadone. In response to these challenges, most clinicians surveyed reported modifying their standard induction protocols or patient counseling approaches. Clinicians treating larger patient volumes, seeing a high proportion of patients using fentanyl, or initiating treatment in non-inpatient settings were more likely to report difficulties starting patients on buprenorphine.

Related protocols: CTN-0135

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Retention on buprenorphine for opioid use disorder is known to be poor across health systems, despite established mortality benefits of treatment, and little is known about how to counsel patients who want to stop using buprenorphine or who have to stop due to barriers to ongoing care.

This webinar will consider what the evidence from a prescription opioid registry developed by NIDA Clinical Trials Network study CTN-0084 suggests for individuals who discontinue buprenorphine, including whether there was a length-of-treatment exposure associated with improved outcomes. Implications for patient education and shared decision-making will be considered. Understanding the optimal length of treatment after which individuals can safely discontinue buprenorphine could help patients better understand what treatment might look like at the outset, supporting informed decision-making and potentially improving both treatment retention and outcomes.

Related protocols: CTN-0084

Background and aims: US regulatory changes allowed for additional methadone take-home doses following COVID-19 onset. How dispensing practices changed and which factors drove variation remains unexplored. We determined daily methadone dispensing trajectories over six months before and after regulatory changes due to COVID-19 using state sequence analysis and explored correlates.

Design: Retrospective chart review of electronic health records.

Settings: Nine opioid treatment programs (OTPs) across nine US states.

Participants: Adults initiating treatment in 2019 (n = 328) vs. initiating 1 month after the COVID-19 regulatory changes of March 2020 (n = 376).

Measurements: Type of daily methadone medication encounter (in-clinic, weekend/holiday take-home, take-home, missed dose, discontinued) based on OTP clinic; cohort (pre vs. post-COVID-19); and patient substance use, clinical and sociodemographic characteristics.

Findings: Following COVID-19 regulatory changes, allotted methadone take-home doses increased from 3.5% to 13.8% of total person-days in treatment within the first 6 months in care. Clinic site accounted for the greatest variation in methadone dispensing (6.2% and 9.5% of the variation of discrepancy between sequences pre- and post-COVID-19, respectively). People who co-use methamphetamine had a greater increase in take-homes than people who did not use methamphetamine (from 3.7% pre-pandemic to 21.2% post-pandemic vs. 3.5% to 12.5%) and higher discontinuation (average 3.6 vs. 4.7 months among people who did not use methamphetamine pre-COVID-19; average 3.3 vs. 4.6 months post-COVID-19). In the post-COVID-19 cohort, females had a higher proportion of missed doses (17.2% vs. 11.9%) than males. People experiencing houselessness had a higher proportion of missed doses (19% vs. 12.3%) and shorter stays (average 3.5 vs. 4.5 months) when compared with those with stable housing.

Conclusion: Daily methadone dispensing trajectories in the US both before and following COVID-19 regulatory changes appeared to depend more on the opioid treatment programs’ practices than individual patient characteristics or response to treatment.

Related protocols: CTN-0112

Background: While medication for opioid use disorder (MOUD) is effective for a significant proportion of patients, many return to using opioids during treatment. Understanding which factors lead to successful treatment informs the development of implementation approaches that can improve outcomes. This manuscript and its accompanying website provide an applied introduction to interpretable machine learning for clinical investigators interested in predicting treatment response for people using MOUD.

Methods: This study, which uses data from CTN-0094, applied machine learning (ML) algorithms (K-Nearest Neighbors (KNN), logistic regression with and without regularization, Multivariate Additive Regression Splines (MARS), Support Vector Machines, Classification and Regression Trees (CART), Random Forest, Bayesian Additive Regression Trees (BART), Boosted Trees, Neural Networks) to predict failure of treatment in a collection of 2478 individuals who had participated in the three largest pragmatic, clinical trials of MOUD.

Results: All models produced Receiver Operating Characteristic Area Under the Curve (ROC AUC) estimates in the range of 0.62 to 0.67 using cross-validation data and the optimal model, random forest, achieved 0.65 using testing data. The algorithms nearly universally identified predictive features such as age, intravenous drug use days, study medication, and study site. Most algorithms also identified various aspects of smoking. Only the algorithms that detect complex non-linear trends identified details from timeline follow-back. One algorithm, BART, performed well while devaluing all treatment-specific details.

Conclusions: After explaining how to apply, compare, and contrast various ML workflows, the results show that while overall modeling performance is similar across the models developed, the use of different algorithms identifies different sets of predictive features. Previous research has not recognized some features as important for predicting treatment outcomes. A companion website introduces clinical investigators to the concepts and implementations this study presents. That site also provides a detailed annotated blueprint to fully replicate, or even expand, this work.

Related protocols: CTN-0094

Poster describing a study that examined type-specific medications for opioid use disorder (MOUD) awareness (i.e., heard of) and referral willingness among CBO providers and clients. The data was acquired via cross-sectional survey of 13 Southern U.S. CBOs in FL, GA, LA, MS, and TN. Analysis revealed that compared with methadone, buprenorphine and naltrexone awareness is lower for both providers and clients, though providers are more aware of all types of MOUD than clients. Additionally, providers report greater willingness to refer for buprenorphine and naltrexone than clients report willingness to be referred (especially for naltrexone).

This type of misalignment can hinder MOUD uptake, weaken provider-client linkage, and contribute to high overdose rates and limited provider and MOUD access in the South.

Related protocols: CTN-0082

Substance use can be a coping mechanism during stressful times. The United States opioid crisis worsened during the COVID-19 pandemic. This study looks at the effects of the pandemic on self-reported change in drug and alcohol use and medications for opioid use disorder (MOUD) and naloxone interest in a population and region hit hard by the opioid crisis—people who use illicit opioids (PWUO) and other drugs in the Southern United States. Cross-sectional data came from the National Institute on Drug Abuse Clinical Trials Network survey study CTN-0082. During the pandemic, participants (N=381) completed a survey about their pandemic-attributed increase, decrease, or no change in use of opioids, non-opioid drugs, or alcohol and interest in MOUD and naloxone. Data were analyzed using multinomial logistic regressions; regression models included potential contributing factors like sociodemographics, substance use frequency, and psychological distress. Results showed that most participants reported no change in: use of opioids (54%), non-opioid drugs (59%), or alcohol (64%) and interest in MOUD (60%) or naloxone (72%). Factors related to no change in relation to change in substance use and/or service interest included past 12-month substance use frequency, race, ethnicity, age, sex, and education.

Conclusions: We conclude that the lack of change in drug use and interest in MOUD and naloxone suggests stability amidst challenging times in our sample of PWUO in the Southern United States. Differences in outcomes based on sociodemographics and substance use frequency indicate the need for tailored services during future public health emergencies.

Related protocols: CTN-0082

Introduction: The initiation of buprenorphine for patients with opioid use disorder (OUD) in the emergency department (ED) has been associated with improved outcomes including reduced ED visits and increased treatment engagement. Though both standard-dose (8 mg buprenorphine equivalent) and high-dose (24 mg buprenorphine equivalent) strategies to initiate buprenorphine have been used in the ED, no prospective trials comparing outcomes among patients receiving these treatments have been reported.

Methods and analysis: This multisite randomised clinical trial (CTN-0145) is a multisite double-blind, double-dummy, randomised clinical trial enrolling 360 emergency department patients with moderate-to-severe OUD. Enrolled patients will be randomised to one of two study arms: standard-dose induction or high-dose induction, both provided in the ED. This study will engage, train and provide resources to five EDs throughout the US to recruit patients with untreated OUD into a randomised clinical trial. The primary aim is to evaluate the effects of the standard-dose induction and high-dose induction on rates of OUD treatment participation within 10 days post-randomisation. The secondary aims are to evaluate differences between standard-dose induction and high-dose induction on the outcomes of opioid craving, opioid withdrawal symptoms and illicit drug use assessed during 10 days post randomisation and evaluate the effects between treatment arms on rates of OUD treatment participation within 30 days post randomisation.

Ethics and dissemination: This study is funded by the National Institute on Drug Abuse and has been approved by the WCG Instutitional Review Board. It has been registered at clinicaltrials.gov. This study will inform the strategy for treatment initiation with buprenorphine among diverse ED settings and will provide ongoing evidence to support the safety and efficacy of initiating treatment for OUD in the ED.

Related protocols: CTN-0145

Objectives: To estimate all-cause and cause-specific mortality burden in patients who received medication treatment for opioid use disorder (OUD).

Methods: We (the CTN Health Systems Node) conducted a cohort study of 27,230 patients who received medications for opioid use disorder (MOUD), buprenorphine or naltrexone, matched 1:1 to individuals without MOUD from 4 US health systems in California, Colorado, and Michigan between 2012 and 2021. We calculated standardized mortality ratios (SMRs) with bootstrapped 95% CI to assess mortality burden.

Results: Patients who received treatment for OUD were 4 times more likely to die from any cause (SMR 4.37, 95% CI 3.80-4.64) and 37 times more likely to die from drug overdose (SMR 37.58, 95% CI 29.33-55.09; 41.6% of all deaths) compared to demographically similar individuals. Deaths from non-overdose causes showed modest but significant burden (SMR 2.68, 95% CI 2.31-2.86; 58.4% of deaths). The top contributors to non-overdose deaths were circulatory system diseases (SMR 3.06, 95% CI 1.73-3.63; 13.9% of deaths), other external causes (SMR 4.50, 95% CI 3.64-5.62; 11.3% of deaths), and cancers (SMR 1.59, 95% CI 1.30-1.86; 9.4% of deaths), which all showed elevated mortality.

Conclusions: Continued efforts are needed to prevent high burden of mortality from both overdose and non-overdose causes among patients with MOUD treatment.

Background: Rural communities face disproportionate rates of opioid use disorder (OUD) and overdose mortality but continue to be underrepresented in clinical research and underserved in access to medications for opioid use disorder (MOUD). Structural barriers including shortages of qualified providers, transportation challenges, and stigma limit uptake of evidence-based treatment. To address these gaps, the National Drug Abuse Treatment Clinical Trials Network (CTN) launched two pragmatic trials focused exclusively on rural populations: CTN-0102, a telemedicine (TM) feasibility study connecting rural primary care patients to external MOUD providers, and CTN-0102XR (RXR), a pilot randomized trial evaluating extended-release buprenorphine (Brixadi®) compared to sublingual buprenorphine-naloxone.

Objective: The article aims to describe the implementation of these two rural pragmatic trials, identify challenges encountered in study implementation, and present lessons learned. We applied frameworks from implementation science, including the Consolidated Framework for Implementation Research (CFIR) and the Expert Recommendations for Implementing Change (ERIC), to demonstrate how pragmatic trial implementation mirrors implementation of evidence-based programs and practices, and can benefit from established implementation frameworks and strategies.

Results: Across 13 rural clinics in 10 states, both trials demonstrated the feasibility of integrating MOUD into primary care settings through pragmatic study designs closely aligned with routine clinical workflows. Principal challenges included limited clinic research capacity, staff stigma toward OUD treatment, communication barriers between local clinics and external TM vendors, and variable digital access. Solutions included engaging local champions, co-developing workflows tailored to each clinic’s operations, simplifying technology requirements, and emphasizing bi-directional communication among clinic, research, and vendor teams. Continuous technical assistance and protocol flexibility and adaptation were crucial for sustaining engagement and aligning study procedures with clinical realities. Findings demonstrated that rural clinics can feasibly implement TM-based MOUD coordination and extended-release buprenorphine with adequate support and contextual adaptation.

Conclusions: Lessons from CTN-0102 and CTN-0102XR underscore that pragmatic trials in rural settings benefit from early contextual assessment, engagement of community stakeholders, adaptable protocols, and strong implementation support. Applying implementation science frameworks facilitates solutions to real-world barriers and enhances study sustainability. Future CTN efforts should continue to prioritize rural site inclusion, capacity building, and equitable access to evidence-based OUD treatment.

Related protocols: CTN-0102, CTN-0102-XR

Importance: Health plan disenrollment may interrupt treatment for opioid use disorder (OUD) and overall care, increasing risk for serious outcomes, including overdose and death. There is limited evidence on the association of disenrollment with all-cause and overdose mortality after initiating medications for OUD (MOUD) treatment.

Objective: To assess the association of health plan disenrollment with all-cause and overdose mortality in patients treated with MOUD.

Design, setting, and participants: This cohort study conducted by the CTN Health Systems Node, included privately and publicly insured patients aged 16 years or older who initiated buprenorphine or naltrexone for OUD treatment between January 1, 2012, and December 31, 2021, at 3 integrated health insurance and care delivery systems in 2 US states. Patients were followed up to 2 years until December 31, 2022. Data were analyzed July 2024 to November 2025.

Exposure: Health plan disenrollment following MOUD initiation.

Main outcomes and measures: All-cause mortality and drug-related and alcohol-related overdose mortality within 2 years of MOUD initiation ascertained from the National Death Index. Survival analyses were adjusted for patient sociodemographic and clinical characteristics.

Results: Among 20,011 patients (mean [SD] age 38.7 [15.1] years; 12 299 males [61.5%]) who were treated for OUD, 6948 (34.7%) experienced disenrollment and 586 (2.9%) died during follow-up. The crude rate was 15.3 (95% CI, 14.1-16.6) per 1000 person-years for all-cause mortality and 6.2 (95% CI, 5.4-7.0) per 1000 person-years for overdose mortality. Ever experiencing disenrollment showed elevated all-cause mortality (17.6 [95% CI, 14.9-20.8] vs 14.7 [95% CI, 13.4-16.1] per 1000 person-years) and overdose mortality (8.9 [95% CI, 7.1-11.3] vs 5.4 [95% CI, 4.7-6.3] per 1000 person-years) relative to remaining enrolled. In adjusted analyses, ever experiencing disenrollment was associated with increased hazards of all-cause (hazard ratio [HR], 1.51; 95% CI, 1.23-1.84) and overdose mortality (HR, 1.56; 95% CI, 1.17-2.09). Compared with remaining enrolled and receiving MOUD treatment, being disenrolled (HR, 4.34; 95% CI, 3.19-5.89) and being enrolled and not receiving MOUD treatment (HR, 4.19; 95% CI, 3.24-5.43) were associated with overall mortality.

Conclusions and relevance: In this cohort study of patients who initiated MOUD, experiencing health plan disenrollment was associated with increased mortality risk compared with remaining enrolled. Strategies are needed to improve continuity of health coverage and mitigate the elevated mortality risk during insurance transitions for patients receiving medications for OUD.

Medications for opioid use disorder (MOUD), such as methadone, buprenorphine, and extended-release naltrexone (XR-NTX), have been shown to reduce or eliminate opioid use and craving, protecting against opioid overdose and death. Stopping medication is associated with risk of relapse and potential overdose. Unsurprisingly, patients may desire to stop MOUD because of adverse effects, burden, or preference for recovery without medication, asking, “How long do I need to take medication?” Clinicians who treat OUD often encounter this uncomfortable risk-benefit discussion with patients who want to stop MOUD, hoping that the patients can do so successfully, while acknowledging the major risks. Prospective data are needed to inform those discussions. In designing one of the first clinical trials focused on MOUD discontinuation—the Discontinuation Phase of the Optimizing Retention, Duration, and Discontinuation Strategies for Opioid Use Disorder Pharmacotherapy (RDD) trial (NCT04464980)2—the investigators identified ethical issues that needed consideration in designing the study.

The authors of this Viewpoint are study investigators, including a social worker (S.E.P.) and 2 psychiatrists experienced with MOUD (R.D.W. and E.V.N.). In this Viewpoint, we describe those ethical challenges and our attendant solutions to inform the design of other studies of medication discontinuation, where discontinuing treatment could have grave consequences.

Related protocols: CTN-0100

Background: Rural communities continue to experience high overdose mortality rates and challenges retaining individuals with opioid use disorder (OUD) on medications for opioid use disorder (MOUD). The most recent formulation of injectable extended-release buprenorphine (XR-BUP) may improve treatment engagement and outcomes for people with OUD.

Objectives: The RXR study (CTN-0102-XR) aims to evaluate the feasibility of implementing XR-BUP in rural settings, acceptability of XR-BUP to clinic staff and patients, and effectiveness of XR-BUP compared with sublingual buprenorphine-naloxone (SL-BUP).

Study design and methods: This is an open-label randomized controlled trial (RCT) using intention-to-treat (ITT) analysis. Approximately 144 participants recruited from seven rural clinic sites will be randomized to receive XR-BUP or SL-BUP in a ratio of 2:1, and will receive study medication for 14 weeks. Participants in the XR-BUP condition will receive two weekly initiation dosages, followed by the target monthly dosage (128 mg) at Weeks 2, 6, and 10. Participants in the SL-BUP condition will receive medication on a similar schedule, with a target dose range of 16-24 mg/day. The main comparative effectiveness outcome measure is the number of monthly opioid negative urine drug screens (UDS) for non-prescribed opioids from Weeks 2-14. Feasibility and acceptability will be evaluated using mixed methods, combining participant survey and interview data from clinic administrators, providers, and patients.

Conclusions: If demonstrated to be feasible and acceptable to participants and staff and there is evidence of effectiveness for people with OUD in reducing opioid use, XR-BUP may be considered an important option for addressing OUD in rural settings.

Related protocols: CTN-0102-XR

This is the primary outcomes article for CTN-0080. Importance: Treating opioid use disorder (OUD) in pregnancy with sublingual buprenorphine is an evidence-based practice, but it has disadvantages that could be addressed with an extended-release formulation.

Objective: To evaluate the effectiveness and safety of extended-release buprenorphine vs sublingual buprenorphine for OUD in pregnancy through 12 months post partum.

Design, setting, and participants: This 2-group, open-label, noninferiority, randomized clinical trial was conducted between July 2, 2020, and October 30, 2024, among adults with OUD and a singleton pregnancy of 6 to 30 weeks’ gestational age at 13 outpatient cross-disciplinary peripartum OUD treatment sites.

Interventions: Randomization to sublingual or extended-release buprenorphine (weekly formulation during pregnancy, monthly formulation optional post partum if not breastfeeding).

Main outcomes and measures: The primary and key secondary outcomes were illicit opioid abstinence during pregnancy and the postpartum period, respectively, defined as the proportion of weekly collected urine samples negative for illicit opioids. If noninferiority was demonstrated at a margin of 0.15, testing for superiority was planned. Key secondary infant outcomes from medical records were opioid treatment for neonatal opioid withdrawal syndrome (NOWS; yes or no) and number of opioid treatment days for NOWS.

Results: Among 140 randomized participants, the mean (SD) age was 31.2 (4.6) years. There were 10 Black participants (7.1%), 10 Hispanic participants (7.1%), 116 (82.9%) White participants, and 14 participants (10.0%) who belonged to additional groups. All but 2 were already prescribed sublingual buprenorphine. Study completion was 98% through pregnancy (137 participants) and 81% through 12 months post partum (114 participants). Illicit opioid abstinence was higher during pregnancy for participants receiving extended-release vs sublingual buprenorphine (82.5% vs 72.6%; mean difference, 9.84 [95% CI, 1.72 to 17.95] percentage points; P = .009). Postpartum abstinence rates declined and were similar in both groups (60.2% vs 59.5%; mean difference, 0.65 [98% CI, -12.72 to 14.02] percentage points; P = .45). Those receiving extended-release buprenorphine experienced fewer serious adverse events during pregnancy (8.7% vs 26.8%; P = .007) and post partum (6.0% vs 18.6%; P = .04). Nonserious adverse events rates did not differ between groups, but more were deemed medication-related for extended-release participants during pregnancy (26.1% vs 7.0%; P = .003). Infants exposed to extended-release vs sublingual buprenorphine did not differ in need for opioid treatment (30.2% vs 26.5%; relative risk, 1.14 [98% CI, 0.54 to 1.99]; P = .64) or mean (SE) treatment days (10.9 [2.2] vs 14.8 [3.0] days; relative risk, 0.73 [98% CI, 0.36 to 1.51]; P = .28). At birth, extended-release-exposed neonates had larger mean (SE) head circumferences than those exposed to sublingual buprenorphine (34.0 [0.2] vs 33.4 [0.2] cm; mean difference, 0.63 [95% CI, -0.00 to 1.26] cm; P = .049).

Conclusions and relevance: The findings of this randomized clinical trial support weekly extended-release buprenorphine for OUD treatment during pregnancy.

Related protocols: CTN-0080