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Opioid use disorder (OUD) treatment needs continue to outpace the capacity of existing treatment systems, with access to buprenorphine particularly constrained in many communities. Pharmacist involvement in medications for OUD (MOUD), including buprenorphine initiation and longitudinal management, has demonstrated feasibility and acceptability in select settings, yet widespread implementation remains limited by regulatory variability and fragmented care models. Pharmacies are highly accessible health care sites, and pharmacists’ scope of practice can be expanded through mechanisms such as collaborative pharmacy practice agreements (CPPAs)-a term used interchangeably in the literature with “collaborative practice agreement” and related variants-to support buprenorphine initiation and ongoing management. The CTN-0151 PharmValue project aims to develop a scalable, pharmacist-led CPPA model for MOUD that can be adapted across diverse state regulatory environments and pharmacy settings. Using a community-engaged research approach and a 50-state legal and regulatory review supplemented by a national expert survey, PharmValue will (1) engage community stakeholders to codevelop a model CPPA and care pathway for pharmacist-managed buprenorphine and (2) identify existing legal authorities and advocacy opportunities to expand pharmacist-managed MOUD care nationally. This protocol commentary describes the rationale, guiding frameworks, and key design decisions underlying the PharmValue model and outlines anticipated implementation challenges and future directions for evaluation and scale-up.

Related protocols: CTN-0151

American Indian and Alaska Native (AI/AN) communities experience a disproportionate burden of substance use disorders (SUDs) alongside persistent barriers to culturally responsive care and research participation. Despite this need, AI/AN populations remain underrepresented in substance use research, in part due to historical and ongoing systemic inequities, including research practices that have not adequately respected Tribal sovereignty or incorporated Indigenous knowledge systems. This commentary synthesizes research conducted within the National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) focused on AI/AN communities, identifies key lessons learned from this body of work, and offers recommendations for future research.

First, we provide an overview of CTN-supported studies involving AI/AN populations, highlighting both the diversity of substance use patterns across communities and the feasibility of conducting rigorous, culturally responsive research. Second, we synthesize lessons learned from these studies and related literature, including the importance of long-term relationship building, the need for culturally responsive research frameworks, structural barriers to implementation, and workforce and infrastructure challenges. Third, we present recommendations for the field, emphasizing the central role of community-based participatory research (CBPR) and Tribal participatory research (TPR), the integration of Indigenous knowledge systems, and the importance of Tribal data sovereignty and community-led dissemination.

Collectively, this commentary argues that sustainable progress in addressing SUDs among AI/AN populations requires a fundamental shift toward community-engaged, culturally responsive, and equity-focused research partnerships. The experiences of the CTN AI/AN Special Interest Group demonstrate that such approaches are not only feasible but essential for advancing both scientific knowledge and community health.

Related protocols: CTN-0020-A-1, CTN-0033-Ot-1, CTN-0033-Ot-2, CTN-0033-Ot-3, CTN-0033-Ot-4, CTN-0033-Ot-5, CTN-0044-A2, CTN-0078-Ot, CTN-0096, CTN-0096-A-1, CTN-0118, CTN-0123, CTN-0129

This is the primary outcomes paper for CTN-0101.

Background and aims:
Individuals who engage in illicit or nonmedical opioid use may have elevated risk of health and social consequences, including progression to opioid use disorder (OUD). Preventive interventions to reduce this risk are lacking. This trial tested the impact of a primary care-integrated collaborative care approach for reducing risky opioid use, defined as nonmedical use of prescription opioids or any use of illicit opioids.

Design: Cluster-randomized controlled trial randomized primary care providers (PCPs) and their patients into the Subthreshold Opioid Use Disorder Prevention (STOP) intervention or enhanced usual care (EUC).

Setting: Primary care clinics at 5 U.S. sites.

Participants:
PCPs and their patients were recruited January 2021–May 2023. A total of 119 PCP clusters (STOP=48, EUC=51) and 202 patients (STOP=88, EUC=114) enrolled. Eligible patients were adults (≥18 years) having current risky opioid use, without moderate–severe OUD. Patient participants were majority female (63.4%), white (70.8%) and non-Hispanic (96.5%), with a mean age of 55.7 [standard deviation (SD) = 12.7] years. At baseline, 63.4% of participants had moderate–severe pain (Brief Pain Inventory) and below average physical (79.2%) and mental (62.4%) health (SF-12).

Interventions: The STOP collaborative care intervention consisted of brief advice from the PCP about reducing risky opioid use, meetings with a clinic-embedded nurse care manager over 12 months and remote health coaching (2–6 sessions). Both groups received primary care treatment as usual and overdose risk reduction materials.

Measurements: The primary outcome was total days of risky opioid use, recorded from 6 monthly electronic surveys. A key secondary outcome was moderate–severe OUD at 6 and 12 months.

Findings: A total of 77 (87.5%) STOP and 107 (93.9%) EUC participants completed the 6-month assessment period. The primary outcome analysis used the Intention-to-Treat sample with multiple imputations of missing data. Mean days of risky opioid use at 180 days were lower in STOP than EUC [12.2 (SD = 27.73) vs. 15.5 (SD = 32.64)]; the difference between groups adjusted for baseline risky opioid use was not statistically significant (rate ratio 0.95, 95% confidence interval = 0.52–1.74). One STOP participant (1.1%) and 13 EUC participants (11.4%) developed moderate–severe OUD at 6 months, and 3 (3.4%) STOP and 6 (5.3%) EUC participants had moderate–severe OUD at 12 months (P<0.001).

Conclusions: This cluster-randomized controlled trial did not find evidence that the STOP intervention for reducing risky opioid use produced greater reductions over 6 months compared with enhanced usual care, though fewer intervention participants progressed to moderate–severe opioid use disorder. Patients had a high burden of pain and comorbidities that may present challenges to reducing opioid use.

Related protocols: CTN-0101

Substance use disorder (SUD) is a complex chronic condition requiring a multi-disciplinary approach to both research and treatment. Randomized controlled trials (RCTs) are gold standard methodologies for inferring causal relationships between an intervention and treatment outcomes but often face challenges in generalizability, scalability and real-world implementation. Target trial emulation (TTE) is a powerful methodological framework that uses observational or real-world data sources to emulate the methodology of these gold standard target trials to complement the learning from RCTs and enhance translation to real world evidence. An additional methodological innovation is the translational testing of clinical- and community-based digital health systems to provide new insights into SUD in the real world and provide scalable access to therapeutic resources.

To explore these methodological innovations in SUD research, the National Institute on Drug Abuse Center for the Clinical Trials Network convened a variety of experts for a virtual workshop titled “Target Trial Emulation in Observational Research and Translational Testing of Advanced Digital Health Tools for Substance Use Disorder Prevention and Treatment.” This article summarizes the discourse of the workshop, focused on three thematic areas: TTE using real-world healthcare data, SUD evidence from nationwide data sources that may be useful in TTE analyses, and translational testing of clinical- and community-based digital health systems. The workshop also highlighted various exemplars of digital health systems that demonstrate success in translational research addressing SUDs, key methodological and translational challenges, importance of rigorous study design, robust data linkages and expanding use of common data elements, and the integration of digital health tools to enhance causal inference and clinical impact. Future research directions are outlined to refine these approaches, address barriers, and maximize the utility of real-world data in shaping effective SUD prevention and treatment strategies.

Introduction: Despite rising concern about overdoses from fentanyl-adulterated cocaine, research on responses to adulteration among people who use cocaine (PWUC) is limited. We aimed to identify what risk mitigation strategies PWUC would engage in if they suspected fentanyl in their cocaine. Secondarily, we tested whether key individual differences were related to use of risk mitigation strategies.

Methods: A secondary analysis of an online study (CTN Protocol ID: CTN-0130) collected responses from 97 self-reported cocaine purchasers. Participants completed questionnaires on demographics and substance use and reported what they would do if they found out their cocaine might contain fentanyl. Participants selected from a list of behaviors (with a free response option). Responses were coded into a four-level variable: “no change,” “transfer risk,” “harm reduction,” and “abstain.”

Results: About 16.5% endorsed no change in their behavior, 14.4% endorsed transfer risk, 25.8% endorsed harm reduction, and 43.3% endorsed abstain. Of the 10 individual differences tested only cocaine use frequency and previous personal experience of overdose significantly related to selected behaviors. Further analysis showed those with more frequent cocaine use, or prior overdose experience were more likely to use cocaine normally or transfer risk rather than use harm reduction or abstain.

Conclusion: While 83.5% of our sample reported they would attempt to mitigate risk if they suspected fentanyl in their cocaine, participants with more frequent cocaine use or a prior overdose endorsed less use of typical harm reduction or abstention. This highlights the need to direct harm reduction interventions to PWUC to mitigate the fentanyl overdose risks.

Related protocols: CTN-0130

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

Purpose: Emergency Departments (ED) are important settings for initiating care following a non-fatal opioid overdose (NFOO). While ED-based interventions, including peer-led recovery support and initiation of medications for opioid use disorder (MOUD), are promising methods for reducing subsequent overdoses and mortality, randomized trials of ED-based overdose prevention or treatment- linkage interventions demonstrate that a substantial proportion of patients decline participation. The current secondary analysis is designed to characterize individuals who declined to participate in one such study.

Methods: Data were used from the Peer Intervention to Link Overdose Survivors to Treatment (PILOT) trial (CTN-0107), which was a multi-site study conducted in three US-based EDs that randomized participants to a 6-month peer-led overdose prevention intervention or treatment as usual in the ED. Demographics and clinical characteristics of those enrolled in PILOT (n = 150) were compared to those who declined to participate but completed a screening exit survey (ScrES; n = 46).

Results: Among those who declined study participation, 76% had experienced a prior overdose preceding the current overdose that brought them into the ED (58.7% within the past 72 h), 56.5% were not currently engaged in substance use treatment and among those, 65.4% expressed a desire for treatment. Odds of declining study participation decreased with age by 6% per year (OR = 0.94, 95% CI: 0.9, 0.99); those with any college experience had odds of declining at 3 times greater than those without a high school diploma (OR = 3.4, 95% CI: 1.2, 10.1). Those without health insurance had odds of declining nearly 3 times those with insurance (OR = 2.9, 95% CI: 1.2, 7.0). Frequently cited reasons for declining were a desire to leave the ED or feeling unwell (39.1%), lack of interest in research (30.4%) and a belief the intervention would not be helpful (17.4%).

Conclusions: Results from this analysis characterize ED patients declining to participate in peer-led overdose prevention research with the goals of enhancing future recruitment strategies and enrolling more representative samples to reduce subsequent overdoses. Future work is needed to determine how to better engage priority populations at critical touch points, while ensuring that interventions are flexible, patient-centered, and potentially offer remote access.

Related protocols: CTN-0107

Given the disproportionate impact of substance use on individuals, families, and communities from populations underrepresented in clinical trials, increasing their enrollment in treatment research is critical for ensuring that the findings inform policies and programs that are inclusive of all communities, thereby advancing health equity. However, since underrepresented groups continue to be underenrolled in clinical trials testing the efficacy and effectiveness of psychosocial treatments for substance use disorder, substance use researchers are still grappling with this challenge.

In this commentary, we describe rigorous methodological approaches, such as integrative data analysis (IDA) and related methods (e.g., moderated nonlinear factor analysis and propensity score weighting), that can help address the challenges posed by the underrepresentation of certain populations. By combining individual-level data from multiple studies into a pooled dataset, these methods increase sample size and statistical power while addressing covariate imbalance across treatment groups. We describe how we employed these methods to address the aims of our recently completed secondary data analysis project conducted within the National Drug Abuse Treatment Clinical Trial Network (CTN-0125; Integrative Data Analysis of CTN Studies to Examine the Impact of Psychosocial Treatments for Black People Who Use Cocaine and/or Opioids). Our study used these methods to pool and analyze data from nine completed CTN trials to assess the comparative effectiveness of psychosocial treatments for Black adults who use cocaine and/or opioids, a group underrepresented in registered trials of the NIDA. We illustrate the application of these methodological approaches in CTN-0125 and demonstrate how they complement each other to address unique analytic challenges. We describe how we addressed data harmonization challenges due to variations in data formats and inconsistencies or gaps in the supportive documentation available on the NIDA Data Share website. We conclude with recommendations for the research field on how to further address sample size and data integration challenges.

Related protocols: CTN-0125

Introduction: Moral injury is the psychological distress resulting from actions, or the lack thereof, which violate one’s moral or ethical code. There is a notable gap in literature exploring moral injury among substance use disorder (SUD) treatment and community service providers. Despite the lack of literature describing moral injury among the SUD workforce, moral injury was discussed extensively during meetings of the Community Representative Council (CIRCL) of the National Drug Abuse Treatment Clinical Trials Network (CTN), which engages community members within the CTN Nodes to understand perspectives of people with lived/living experience and those providing substance use services.

Methods: In response to this consistently raised topic, this commentary reviews the literature on moral injury related to the SUD workforce, as well as the perspectives of CIRCL members on the unique and persistent challenges faced by SUD treatment and community services providers.

Results: Members of CIRCL in the SUD treatment and community provider workforce consistently described experiencing morally injurious events, including acts of commission and omission, bearing witness, and observing betrayal from those in power. While some experiences are akin to those experienced by providers in other healthcare settings, some were unique to front-line SUD treatment and community services providers. These experiences caused intense experiences of guilt, isolation, and hopelessness, sometimes contributing to turnover.

Conclusions: Addressing moral injury among the SUD provider workforce may require unique mitigation and prevention strategies, potentially involving structural changes at the organizational, social, and policy levels that support the SUD treatment and community service workforce, ultimately improving not just the wellbeing of providers and patients, but the wellbeing of our communities.

Authentic community engagement requires partnership with those who share similar situations, concerns, or challenges. Community engagement in research can promote equitable representation, help inform important research questions and deliverables, and increase the likelihood of developing relevant and appropriate interventions that will be implemented and sustained. Established in 1999, the National Drug Abuse Treatment Clinical Trials Network (CTN) is a cooperative agreement within the National Institute on Drug Abuse (NIDA) and functions as a nationwide consortium of research scientists, treatment providers and other community members collaborating to improve care for substance use in communities across the US. The CTN is committed to community-engaged research. Developed in 2023, the CTN Community Representative Council (CIRCL) formed as a natural progression of this commitment, designed to systematically identify front line challenges warranting research and to recognize emerging community-based innovations – forms of “practice-based evidence” developed in response to real-world needs. CTN Nodes (regional hubs) nominated community members, many of whom are people with lived experience (PWLE) of substance use to serve as Council representatives to enhance the identification, communication, and dissemination of the needs and experiences of individuals served by CTN research across the US. This commentary provides an overview of CIRCL’s conceptualization and creation, operation, and impacts on CTN communities in its first year.

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: Stigma toward people with substance use disorders (SUD) remains a major barrier to care. There have been multiple calls to action to address SUD stigma in healthcare settings and other reviews have clarified the need for more rigorous effectiveness research. In addition to attention to effectiveness research, there is a need to attend to the implementation strategies used to deliver SUD stigma reduction interventions. Delineating discrete implementation strategies that have been used to address stigma will support future research efforts to arrive at the most optimal interventions to address SUD stigma.

Methods: We searched three databases and extracted data to identify interventions tested to reduce SUD stigma. We used the adapted Expert Recommendations for Implementing Change (ERIC) taxonomy to characterize the discrete implementation strategies used to support the adoption, implementation, sustainment, and scale-up (or spread) of each intervention.

Results: This scoping review synthesized 108 peer-reviewed studies reporting on interventions which to address SUD stigma among healthcare professionals. Most interventions were implemented in training environments, including higher education and continuing education settings, and focused on providing basic education on SUD broadly or opioid use disorder. Within interventions, educational and training implementation strategies were most prominent with 74% of studies using educational meetings and 39% distributing training materials. Far fewer studies used implementation strategies that used experiential approaches such interactive assistance, simulation, case-based learning, or contact with people with lived experience. Most studies (73%) reported reductions in stigmatizing attitudes, most often immediately post-intervention, though the need for higher study quality was notable.

Conclusions: Existing stigma-reduction interventions are overwhelmingly education-focused and primarily implemented in academic settings, with limited use of strategies that promote reflective learning, contact-based engagement, or organizational change. Future work should employ more rigorous designs that systematically test implementation strategies to create packaged SUD stigma reduction interventions optimized for effectiveness and implementation.

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

Despite comprising one-fifth of the population, individuals living in rural areas are underrepresented in clinical trials on substance use disorders (SUD). The inclusion of rural residents is critical to reducing disparities in health outcomes and improving adoption of evidence-based interventions for SUDs. The current commentary provides five guiding principles to assist researchers in including rural populations in trials. These principles emphasize including rural communities in the study design phase and throughout the research process, understanding the local rural context, consideration of operationalization of rural in research, suggested adaptions for research, and embracing opportunities for bi-directional and sustainable partnerships. When approached thoughtfully, research funding can catalyze rural capacity, foster durable partnerships, and enrich scientific inference to assist in establishing the evidence-base for SUD research.