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Background: Racial and ethnic inequities persist in perinatal opioid use disorder (OUD) care, with pregnant and postpartum people of color facing structural barriers to using medications to treat OUD (MOUD). Because access to clinical research is often mediated through treatment settings, these structural barriers may also shape who is reached, recruited, and retained in perinatal OUD trials. The Medication Treatment for OUD in Expectant Mothers trial (CTN-0080) provided an opportunity to assess how site-level and policy contexts influenced equitable recruitment, including gaps between projected and actual enrollment.

Methods: We employed a convergent parallel mixed-methods design integrating thematic analysis of semi-structured qualitative interviews with non-White and/or Hispanic trial participants and research staff, site survey data, state policy classifications, and administrative enrollment data from the 13 trial sites. We examined how clinical structures, staffing composition, and policy environments shaped equitable recruitment. For each site, we calculated a recruitment ratio (actual/expected non-White and/or Hispanic enrollment).

Results: Among the 13 trial sites, 3 exceeded projected recruitment of non-White and/or Hispanic participants, 7 fell below projections, and 2 enrolled no non-White and/or Hispanic participants. Recruitment ratios (actual/expected) ranged from 0.0 to 6.3. Sites that exceeded projections commonly reported the inclusion of peer clinical staff and integration of prenatal and OUD care and were more often located in states without mandated reporting of MOUD during pregnancy. Qualitative analyses of participant (n = 17) and research staff interviews (n = 32) identified themes of trust, representation, and lived experience, emphasizing their importance for equitable recruitment and engagement.

Conclusions: Equity in perinatal substance use disorder (SUD) research depends not only on inclusive trial design but also on the relational and policy conditions that build trust and enable participation. Beyond demographic targets, findings point to institutional practices, community partnerships, and supportive policy environments as actionable levers to promote equitable recruitment and engagement in perinatal SUD research.

Related protocols: CTN-0080, CTN-0080-A-1

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

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

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 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.

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.

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 session, Drs. Rossom and Hooker discussed the design and implementation of Opioid Wizard, a clinical decision support tool embedded in the EHR for primary care clinicians and developed as part of NIDA Clinical Trials Network protocol CTN-0095. The goal of the tool is to help clinicians identify, screen, diagnose and treat opioid use disorder (OUD).

They also discussed one of the supplements to CTN-0095, which tested a training to reduce stigma towards people with OUD among primary care clinicians.

Related protocols: CTN-0095

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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

Methadone is an essential tool for addressing opioid use disorder, especially with the prevalence of high-potency synthetic opioids in the drug supply. The current care delivery model in the United States with siloed methadone clinics has many limitations. Legislation has been proposed to expand access to methadone to office-based settings with pharmacy dispensing. Even with legal and regulatory changes, there are many practical barriers to implementation which include insurance coverage and patient cost, prior authorizations, and stocking of methadone.

Practical steps for clinicians and policymakers to take to overcome these barriers include ensuring insurance coverage for methadone, removing methadone from the algorithms that limit the amount of controlled substances pharmacies can order, and obtaining concentrated methadone formulations.

Related protocols: CTN-0131

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