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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

Aims: This study aimed to examine within and between effects of the relationship between depression, using the Beck Depression Inventory (BDI), and cocaine craving, using the visual analog craving scale (VAS), over time.

Methods: Data from the NIDA Clinical Trial Network Study Cocaine Use Reduction with Buprenorphine (CTN-0048) were used in a secondary analysis (CTN-0148). Random-effects regression modelling was used to examine relationships between participants’ depressive symptoms and their cocaine craving over time.

Results: A total of 301 participants with past-year DSM-IV criteria for cocaine and opioid use disorder were analyzed (21.6% female, 10.3% Hispanic, 66.4% Black) being treated with placebo or buprenorphine+naloxone. Craving significantly decreased over time (B = −1.11, 95% CI [-1.21, −1.02], p < 0.001). Depression emerged as a significant within-person predictor of craving over time (B = 0.93, 95% CI [0.76, 1.09], p<0.001), indicating that when a person’s BDI score increased by one point from their own mean, their craving increased by 0.71 units. Between-person differences in average BDI did not have significant effects (p>0.05), indicating that depression scores across participants did not significantly predict differences in craving.

Conclusions: These findings highlight depression as a dynamic, time-varying clinical marker of heightened craving risk and suggest that monitoring and addressing increases in depressive symptoms during treatment may help mitigate craving spikes and potentially reduce vulnerability in returning to use.

Related protocols: CTN-0148

This presentation provided a brief summary of the CTN-0135 study, Buprenorphine Treatment Engagement and Induction Problems Among Individuals Using Fentanyl, which aimed to determine whether there are regional variations in the prevalence of fentanyl use and problems initiating buprenorphine/naloxone. A secondary purpose was to characterize the specific problems that clinicians are encountering when initiating BUP treatment in patients using fentanyl and to determine how standard clinical protocols are being modified to engage patients in treatment, which was carried out via a survey administered to 396 clinicians.

The study team wanted to explore other dissemination strategies besides publishing in peer-reviewed journals in order to better share the results with a broader audience. To that end, they decided to develop an online data dashboard, which they developed using Shiny Apps. A second survey was sent out to original participants who had opted in for future contact (n=364) to ask questions about the dashboard, including questions about general usability, basic demographics, and some open-ended items.

Responses to the dashboard were positive, with 84.4% reporting they were at least “somewhat satisfied” with the dashboard. 91.7% found the study results to be relevant to clinical practice, and 77.7% said they would be likely to use a data dashboard to learn about study results. Strengths of the dashboard noted in the open-ended questions included “simplicity and ease of use,” while opportunities for improvement included “color scheme, scrolling reduction, and font sizes.”

Overall, the data dashboard evaluation results suggest it is a feasible dissemination strategy for a clinical audience: easy to use, something clinicians would recommend to colleagues, and clinically relevant. Future work should integrate users into the development process and consider visualization literacy as well as computer skills.

Find the Trends in Drug Use Study Dashboard here.

Related protocols: CTN-0135

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

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

This is the primary outcomes article for CTN-0080-A-2. Introduction: Racial and ethnic inequities persist in medication treatment initiation and adherence for pregnant and postpartum people with opioid use disorder (OUD). Our objective was to understand the experiences of “positive outliers,” specifically pregnant and postpartum people of color with OUD who utilized medication treatment and engaged in a randomized clinical trial for buprenorphine despite historical, cultural, and structural barriers.

Methods: We conducted two sets of semi-structured qualitative interviews. First, trained peers with lived expertise as mothers in recovery interviewed individuals who identified with a non-white race and/or ethnicity and enrolled in the Medication Treatment for OUD in Expectant Mothers (MOMs) trial (NCT03918850). Second, we interviewed principal investigators, clinicians, and research coordinators from the 13 MOMs trial sites. We used an inductive thematic approach informed by the Social Ecological Model of Racism and Anti-Racism. Transcripts were double-coded and reviewed until consensus was reached. Preliminary findings from participant and staff interviews were merged and triangulated with peers to inform theme development.

Results: We completed 17 interviews with MOMs trial participants from 7 sites. Participants identified as Hispanic (29%), Black non-Hispanic (24%), multi-racial Hispanic (18%), multi-racial non-Hispanic (18%), and American Indian, Native Hawaiian, or Pacific Islander (12%). Thirty-two interviews with trial staff were also completed. Three themes emerged: (1) Although some participants expected racist treatment and research exploitation, all participants interviewed reported non-discriminatory, non-judgmental care within the MOMs trial; (2) Compassionate care, frequent, personalized, and integrated encounters, and emotional support helped counteract prior stigmatizing and discriminatory health care interactions, enabling participants of color to feel particularly supported, trusted, and empowered during the MOMs trial; and (3) Despite pervasive cultural stigma around addiction and concerns about taking an investigational drug while pregnant, participants expressed that pregnancy status, care team trust, and transparent communication with MOMs trial staff encouraged medication utilization and adherence.

Conclusion: Facilitators of successful engagement in the MOMs trial and retention in medication treatment among pregnant and postpartum people of color with OUD included non-judgmental care, sustained trust, and frequent contact. Key perinatal OUD clinical interventions and trial improvements include personalized communication and scheduling flexibility to promote engagement of marginalized populations.

Related protocols: CTN-0080-A-2

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

Background and objectives: Patients using fentanyl have worse treatment outcomes; however, little is known about other drugs that complicate treatment.

Methods: A national survey (n = 396) was conducted for CTN-0135 using a random sample of clinicians waivered to prescribe buprenorphine in the United States. This study reports the results of a single survey item on clinicians’ perceptions of other drugs, besides IMF, complicating treatment.

Results: Clinicians reported methamphetamine (86.4%), synthetic cannabinoids (42.7%), and xylazine (41.4%) were complicating treatment; reports varied by geographic region.

Conclusions and scientific significance: Rapid clinician surveys can provide real-time data on changing patterns of drug use’s impact treatment outcomes.

Related protocols: CTN-0135