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Background and aims: Female, Hispanic, and Black patients with opioid use disorder (OUD) are less likely to receive OUD medication treatment than other patients. The PROUD (PRimary care Opioid Use Disorders treatment) trial demonstrated that implementation of primary care (PC) nurse care management increases OUD medication treatment compared with usual care (UC). This study assessed whether the PROUD intervention’s effect differed across sex, race and ethnicity.

Design: Secondary analyses of cluster-randomized implementation trial.

Setting: 12 PC clinics (2 per health system) in five states in the USA, randomized to UC or intervention, stratified by health system.

Participants: PC patients 16-90 years old.

Intervention: Three strategies to implement office-based addiction treatment (OBAT) by nurse care managers: (1) full-time nurse salary; (2) nurse training and technical assistance from expert nurses at Boston Medical Center; (3) ≥3 PC providers willing to prescribe buprenorphine. Nurses were trained in the Massachusetts model of OBAT which includes lowering barriers to OUD treatment, assessing and educating patients, supporting initiation of medications for OUD and providing ongoing medical management, in collaboration with PC providers.

Measurements: The primary outcome was a clinic-level measure of OUD treatment defined as patient-years of OUD treatment per 10 000 PC patients based on orders and procedures for buprenorphine or extended-release naltrexone from electronic health records and insurance claims (hereafter ‘OUD treatment’).

Findings: The mean numbers of patients seen by intervention and UC clinics at baseline were 18 485 and 22 557, respectively. Female patients comprised 60% of the total PC population in intervention clinics and 64% in UC clinics; Asian, Black, Hispanic or smaller racial groups comprised 61% of the PC population in intervention clinics, and 70% in UC clinics. Compared with UC, the intervention increased OUD treatment for male patients [adjusted difference: 13.7 patient-years; 95% confidence interval (CI) = 5.8-21.7], but not female patients (2.9; 95% CI = -4.3 to 10.2); effect modification test, F (1,14) = 4.77; P = 0.046. Exploratory analyses suggest that differences in the intervention’s effect on receipt of any OUD treatment in female and male patients, rather than differences in the duration of OUD treatment, may account for findings. There was no significant effect modification by race or ethnic group [effect modification test F (4,44) = 1.50; P = 0.218].

Conclusions: Primary care clinics that implement office-based addiction treatment by nurses increase patient-years of opioid use disorder (OUD) treatment in male but not female patients. Exploratory findings suggest that differences in the proportion of patients treated for OUD, rather than differences in the duration of OUD treatment, account for observed differences across groups.

Related protocols: CTN-0074

Introduction: The ability for people living with stimulant use disorder to live meaningful lives requires not only abstinence from addictive substances, but also healthy engagement with their community, lifestyle practices, and overall health. The Treatment Effectiveness Assessment (TEA) assesses components of recovery consisting of four functional domains: substance use, health, lifestyle, and community. This secondary data analysis of 403 participants with severe methamphetamine use disorder tested the reliability and validity of the TEA.

Methods: Participants were enrolled in the Accelerated Development of Additive Pharmacotherapy Treatment (ADAPT-2) for methamphetamine use disorder. The study used total TEA and domain scores at baseline to assess factor structure and internal consistency, as well as construct validity related to substance cravings (visual analog scale [VAS]), quality of life (quality-of-life assessment [QoL]), mental health (Patient Health Questionnaire-9 [PHQ-9], Concise Health Risk Tracking Scale Self-Report [CHRT-SR16]), and social support (CHRT-SR16).

Results: Individual TEA items showed moderate to large correlations with each other (r = 0.27-0.51; p < .001), and strong correlations to the total score (r = 0.69-0.78; p < .001). Internal consistency was strong (coefficient α = 0.73 [0.68-0.77]; coefficient ω = 0.73 [0.69-0.78]). Construct validity was acceptable, with the strongest correlation between the TEA Health item and the general health status item on the QoL (r = 0.53, p < .001).

Conclusions: TEA has acceptable levels of reliability and validity supporting prior similar findings in a sample of participants with moderate to severe methamphetamine use disorder. Results from this study provide support for its use in assessing clinically meaningful changes beyond simply reduced substance use.

Related protocols: CTN-0068

Background and objectives: People with opioid use disorder (OUD) who are in safety-sensitive occupations are often not allowed to work if taking methadone or buprenorphine due to concerns about cognitive impairment from opioid agonist effects. Naltrexone, an antagonist which lacks opioid agonist effects, has fewer restrictions. However, comparisons of neurocognitive effects across treatments are limited.

Methods: This post hoc analysis examined observed Trailmaking Test (TMT) difference scores and Stroop Color-Word accuracy and interference scores at 4, 8, 16, and 24 weeks after treatment initiation with either extended-release injection naltrexone (XR-NTX) (N=283) or sublingual buprenorphine-naloxone (BUP-NX) (N=287) in a randomized, nonblinded, trial of patients with OUD. Scores were compared between medication groups across time points with linear mixed-effects regression.

Results: There were no significant effects of medication group or time for either the TMT or the Stroop tests. TMT difference scores at baseline were 48.40±24.12 (XR-NTX) and 48.26±25.45 seconds (BUP-NX), with model-estimated means (SE) across post-initiation time points: XR-NTX: 37.53 (1.62); BUP-NX: 37.80 (1.51); difference: -0.26 (1.59), P=0.87; 95% CI [-3.38, 2.86]. Stroop Color-Word accuracy and interference scores at baseline were 49.65 (XR-NTX) versus 50.88 (BUP-NX) and 51.11 (XR-NTX) versus 51.68 (BUP-NX), respectively. Model estimated means (SE) across post-initiation timepoints were: accuracy: XR-NTX: 56.54 (0.90); BUP-NX: 56.22 (0.75); difference: 0.33 (0.73), P=0.65; 95% CI [-1.1, 1.76]; interference: XR-NTX: 54.15 (0.76); BUP-NX: 54.67 (0.73); difference: -0.52 (0.62), P=0.41; 95% CI [-1.74, 0.70].

Conclusions: Neurocognitive performance did not significantly differ between patients with OUD treated with XR-NTX or BUP-NX. These results suggest that absolute restrictions on buprenorphine use in safety-sensitive occupations may be unwarranted. Individual cognitive assessments may still be appropriate based on specific job demands.

Related protocols: CTN-0051

The interrelatedness of mental health status and HIV-related outcomes is well-documented. However, the long-term relationship between psychological distress and health outcomes among persons with HIV, co-diagnosed with substance use disorders (SUD), is understudied. We measured psychological distress among men and women with HIV who use drugs, using a low-burden instrument, and tested its effect, longitudinally, on HIV and substance use-related outcomes. Recently hospitalized, adult men and women co-diagnosed with HIV and SUD were surveyed for psychological distress, using the 18-item Brief Symptom Inventory (BSI-18). We tested the short-term (6 months) and long-term (12 months) effect of psychological distress on HIV-related and substance use-related outcomes. Psychological distress predicted higher engagement with SUD treatment and higher substance use, which decreased rapidly, and significantly, over time. No significant relationship was found between psychological distress and HIV viral load suppression. Using brief and easy to administer measures, early detection of psychological distress among persons with HIV and SUD, could avert negative, long-term health consequences-warranting further investigation of interventions that address mental health challenges faced by this population.

Related protocols: CTN-0049

Introduction: Screening for unhealthy alcohol and drug use is recommended in primary care, and effective implementation requires understanding patients’ perspectives. Failure to identify and address potential differences in attitudes toward screening across demographic groups may result in care gaps, but research examining this is limited.

Methods: We surveyed 977 adult patients in 9 primary care clinics that participated in a screening implementation study (CTN-0062-Ot). The survey collected demographics and attitudes toward screening/discussion of alcohol/drug use in primary care. We described responses overall and compared across age, gender, race, and ethnicity using Chi-square/Fisher’s exact tests.

Results: Mean age was 51.1 years, and the sample was 39% male, 61% female, 72% White non-Hispanic, 11% Hispanic, 10% Black non-Hispanic, and 6% other/unknown race non-Hispanic. Most participants across all demographic groups reported supportive attitudes. Comfort reporting drug use was lower among young, male, Black non-Hispanic, and Hispanic patients, and comfort with screening overall was lower among middle-aged, Black non-Hispanic, and Hispanic patients.

Conclusions: Results suggest that screening/discussion of alcohol/drug use in primary care is generally highly acceptable to patients across demographic groups. Strategies are needed to increase comfort and alleviate concerns about how medical information will be used, particularly among middle-aged, Black, and Hispanic patients.

Related protocols: CTN-0062-OT

Many common estimators in machine learning and causal inference are linear smoothers, where the prediction is a weighted average of the training outcomes. Some estimators, such as ordinary least squares and kernel ridge regression, allow for arbitrarily negative weights, which improve feature imbalance but often at the cost of increased dependence on parametric modeling assumptions and higher variance. By contrast, estimators like importance weighting and random forests (sometimes implicitly) restrict weights to be non-negative, reducing dependence on parametric modeling and variance at the cost of worse imbalance. In this paper, we propose a unified framework that directly penalizes the level of extrapolation, replacing the current practice of a hard non-negativity constraint with a soft constraint and corresponding hyperparameter. We derive a worst-case extrapolation error bound and introduce a novel “bias-bias-variance” tradeoff, encompassing biases due to feature imbalance, model misspecification, and estimator variance; this tradeoff is especially pronounced in high dimensions, when positivity is poor. We then develop an optimization procedure that regularizes this bound while minimizing imbalance and outline how to use this approach as a sensitivity analysis for dependence on parametric modeling assumptions. We demonstrate the effectiveness of our approach through synthetic experiments and a real-world application, involving the generalization of randomized controlled trial estimates to a target population of interest.

Related protocols: CTN-0027

Randomized clinical trials are considered the gold standard for informing treatment guidelines, but results may not generalize to real-world populations. Generalizability is hindered by distributional differences in baseline covariates and treatment–outcome mediators. Approaches to address differences in covariates are well established, but approaches to address differences in mediators are more limited. Here, we consider the setting where trial activities that differ from usual-care settings (e.g., monetary compensation and follow-up visits frequency) affect treatment adherence. When treatment and adherence data are unavailable for the real-world target population, we cannot identify the mean outcome under a specific treatment assignment (i.e., mean potential outcome) in the target population. Therefore, we propose a sensitivity analysis in which a parameter for the relative difference in adherence to a specific treatment between the trial and the target, possibly conditional on covariates, must be specified. We discuss options for specification of the sensitivity analysis parameter based on external knowledge, including setting a range or specifying a probability distribution from which to repeatedly draw parameter values (i.e., use Monte Carlo sampling). We introduce two estimators for the mean counterfactual outcome in the target, which incorporate this sensitivity parameter, a plug-in estimator, and a one-step estimator that is double robust and supports the use of machine learning for estimating nuisance models. Finally, we apply the proposed approach to the motivating application where we transport the risk of relapse under two different medications for the treatment of opioid use disorder from a trial to a real-world population.

Related protocols: CTN-0051

Background: Active depression and/or anxiety (D/A) symptoms among pregnant individuals with opioid use disorder (OUD) may impact the efficacy of new OUD medication treatment formulations.

Methods: We conducted an exploratory secondary analysis of an intent-to-treat, parallel group, randomized trial that compared the effectiveness of injectable extended-release buprenorphine (XR-BUP) to sublingual (SL-BUP). Participants included pregnant adults (N=140) seeking or receiving buprenorphine for OUD treatment. A total of 52.1% (n=73) of participants screened positive for active D/A symptoms at baseline, assessed using the Hospital Anxiety and Depression Scale. The primary outcome of illicit opioid abstinence, measured by urine drug screens, was assessed from baseline through one-year postpartum. We also assessed buprenorphine adherence, opioid craving, and withdrawal during the same period. We employed descriptive statistics to characterize baseline population characteristics and longitudinal multiple regression to test treatment effects across time.

Results: Opioid abstinence during pregnancy was higher in the XR-BUP group than the SL-BUP group who were D/A positive (group difference=12.5%, p=0.03) compared to D/A negative (group difference=6.7%, p=0.27). Withdrawal was lower during the postpartum period in the XR-BUP group than the SL-BUP group for those D/A positive (group difference −2.9, p<0.01) compared to those D/A negative (group difference= −0.7, p=0.47). We observed a time effect for decreases in the proportion of participants who were D/A positive during pregnancy (Odds Ratio=0.27, p<0.01).

Conclusions: Among pregnant individuals with OUD and co-occurring D/A symptoms, XR-BUP may confer greater benefits related to opioid abstinence and reduced withdrawal symptoms compared to SL-BUP.

Related protocols: CTN-0080

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

Buprenorphine treatment for opioid use disorder (OUD) is highly effective in decreasing opioid use, risk of opioid overdose, and death, but retention is challenging. Buprenorphine does not always eliminate illicit opioid use and craving and does not treat stimulant or other substance co-use, nor common comorbid sleep problems. Tirzepatide, a glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, may help address substance use and sleep problems. The National Drug Abuse Treatment Clinical Trials Network (CTN) is conducting a 9-site outpatient, intent-to-treat, two-arm, double-blind, randomized controlled trial: Evaluation of Tirzepatide as an Adjunct to Buprenorphine for the treatment of OUD (TAB). The primary objective is to evaluate the effect of tirzepatide, relative to placebo, as an adjunct to buprenorphine on retention and on substance-related and sleep outcomes in adults with OUD. The primary outcome is 6-month buprenorphine treatment retention. The key secondary outcome is proportion of illicit opioid-negative urine samples over the 6-month treatment period. Approximately 310 adults with moderate-severe OUD who recently started buprenorphine will be recruited and randomized 1:1 to tirzepatide or placebo, balancing on site and buprenorphine formulation (transmucosal vs extended-release). Participants will be administered study medication, receive Fitbits to track sleep, and attend weekly research visits through 6 months post-randomization with longer research visits occurring at 1, 3, and 6 months. A follow-up visit at week 30 will collect final safety measures. This paper describes the rationale and study design for TAB, the first randomized trial to test tirzepatide for the treatment of OUD.

Related protocols: CTN-0152

The EXPLORE toolkit is a resource designed to support researchers and frontline workers addressing substance use in the Borderlands. It addresses equity, stigma, and participation barriers, promoting culturally sensitive and community-centered research practices.

This toolkit is an ideal tool for clinical trials researchers and community health workers who are interested in learning more about how to engage underrepresented populations in clinical trials research in Southern New Mexico and beyond.

Related protocols: CTN-0133

The PATHS toolkit, a product of CTN-0080, offers evidence-based educational resources about the use of medication to treat opioid use disorder (OUD) during and after pregnancy. Resources include an introductory video, a range of printable downloads (flyers, discussion guide, factsheets, posters, and a workbook), and social media downloads to make dissemination of the tools easy and effective.

The toolkit is available in English and Spanish, and also includes a version culturally tailored for American Indian/Alaska Native communities.

This is the primary outcomes paper for CTN-0133.

Background: Underrepresented communities in the Southwestern United States Borderlands region face disproportionate substance use disorder (SUD) burdens yet remain largely excluded from clinical trials. No existing resource integrates health beliefs, research literacy, and vulnerability frameworks to support diverse community engagement in SUD clinical trials.

Methods: We developed the Exploring Health Beliefs for Community Engagement and Diversity in Clinical Trials (EXPLORE) Toolkit through a multi-phase process (2021-2024) including systematic review of existing toolkits, domain development, platform design, individual interviews (n = 10), and two rounds of theater testing with community health workers serving Hispanic communities in Southern New Mexico (n = 60) and American Indian communities in Northern New Mexico (n = 25). Pre/post surveys assessed feasibility, acceptability, community interest, and research literacy. Ripple Effects Mapping evaluated the development process.

Results: Domain-specific toolkit importance ratings averaged 4.48-4.61 on a 5-point scale; 79% of participants rated the toolkit “very important” for promoting culturally competent research, and 64% were “very likely” to recommend it. Post-theater testing scores improved for perceived feasibility of conducting clinical research in participants’ communities (pre: 7.19 vs. post: 7.94, 10-point scale) and research terminology understanding (pre: 7.97 vs. post: 8.74). Qualitative themes included cultural appropriateness, the role of community gatekeepers, and confidentiality concerns in rural and border communities.

Conclusions: The EXPLORE Toolkit demonstrates promise for bridging researcher-community gaps in SUD clinical trials. Findings highlight the value of interdisciplinary, community-centered development and the need for ongoing cultural adaptation.

Find the EXPLORE Toolkit here!

Related protocols: CTN-0133

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.

This webinar, sponsored by the Northwest ATTC and the Western States Node of the NIDA CTN, summarized what makes women’s treatment for substance use disorder (SUD) unique from men’s treatment and highlighted key issues when providing treatment to pregnant and parenting women with opioid use and other SUDs.