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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

This editorial in JAMA describes the outcomes and implications of the primary outcomes paper for CTN-0099, the ED-INNOVATION trial, which compared the use of a 7-day extended-release buprenorphine injection to 7 days of sublingual buprenorphine for patients in the ED presenting with opioid use disorder and found no difference in treatment engagement at 7 days or 30 days among the two groups. They also reported low rates of precipitated withdrawal in both groups, despite a high rate of fentanyl use.

In the context of an ongoing public health emergency related to drug toxicity deaths, emergency department visits are undeniably important opportunities to identify people with high-risk opioid use and engage them in care. Increasing access to evidence-based harm reduction and treatment options for people with OUD in EDs is a crucial aspect of the response to this public health emergency.

Increasing the choices of opioid agonist therapies available in EDs is important. Providers should be careful to monitor their own biases regarding which approach might work best for an individual patient (for example, many providers might assume an injection is the easiest or best approach for a patient, while the patient may feel differently).

This study provides further evidence that EDs can and must lead ED-specific studies and initiatives that confirm best practices and increase access to lifesaving opioid agonist therapies. The way forward requires that clinician-scientists continue to foster a discussion of what is possible in EDs, while prioritizing patient-centered decision-making and consent, and clearly establishing both safety and benefit of interventions prior to implementation.

Related protocols: CTN-0099

This is the primary outcomes article for CTN-0099.

Importance: Extended-release injectable buprenorphine may expand the reach of initiating medications for opioid use disorder in high-risk and hard-to-reach individuals who visit the emergency department (ED) and can be administered in low levels of withdrawal.

Objective: To compare the effect of ED-initiated 7-day extended-release injectable buprenorphine vs sublingual buprenorphine on treatment engagement at 7 days.

Design, Setting, and Participants: Multicenter randomized clinical trial enrolling adult patients presenting to the ED with untreated opioid use disorder and a Clinical Opiate Withdrawal Scale (COWS) score of 4 or higher across 29 EDs in the US from July 12, 2020, to August 21, 2024. Final follow-up was completed on October 24, 2024.

Interventions: Patients were randomized to receive a 24-mg injection of extended-release buprenorphine (equivalent to 16 mg/d) or sublingual buprenorphine, which included either self-administration instructions if the COWS score was less than 8 or administration of 8 mg of sublingual buprenorphine in the ED if the COWS score was 8 or higher. All sublingual buprenorphine group patients received a 7-day prescription for 16 mg/d. Both groups were provided referral for ongoing medication with a scheduled appointment within 7 days.

Main Outcomes and Measures: Engagement in opioid use disorder treatment on day 7 was the primary outcome. Secondary outcomes included engagement at 30 days, precipitated withdrawal and overdose events, craving scores, days of illicit opioid use, and patient satisfaction with treatment.

Results: Among 2000 patients randomized, 6 who were enrolled twice were excluded, resulting in 991 in the extended-release group and 1003 in the sublingual group. The median age was 37 (IQR, 30-47) years, 68% were male, 31% had an initial COWS score of 4 to 7, and 76% tested positive for fentanyl. The adjusted proportion of engagement in opioid use disorder treatment at 7 days was 40.5% with extended-release buprenorphine vs 38.5% with sublingual buprenorphine (adjusted difference, 1.6%; 95% CI, −2.8% to 6.0%). Engagement at 30 days was similar, with adjusted proportions of 43.8% with extended-release buprenorphine vs 44.9% with sublingual buprenorphine (adjusted difference, −1.5%; 95% CI, −6.2% to 3.2%). Precipitated withdrawal was rare: 6 (0.6%) with extended-release buprenorphine and 8 (0.8%) with sublingual buprenorphine. Overdose events within 30 days occurred in 18 participants (2.3%) in each group. Patients receiving extended-release buprenorphine reported lower mean craving scores at 7 days vs those receiving sublingual buprenorphine (scale, 0-100; mean score, 26.5 vs 30.2, respectively; adjusted mean difference, −3.85; 95% CI, −7.08 to −0.63), fewer days of illicit opioid use in the past 7 days (adjusted ratio of means, 0.77; 95% CI, 0.68-0.95), and better treatment satisfaction scores (scale, 1-5; adjusted mean difference, 0.13; 95% CI, 0.01-0.25).

Conclusions and Relevance: No difference was detected in opioid use disorder treatment engagement on day 7 between the 7-day extended-release and sublingual buprenorphine groups. Both buprenorphine formulations were well tolerated; precipitated withdrawal was rare despite a high prevalence of fentanyl.

Related editorial: Moe J, et al. Buprenorphine in the ED — Balancing access, safety, and autonomy. JAMA 2026 (in press).

Related protocols: CTN-0099

Randomized clinical trials (RCTs) typically report patient-oriented outcomes. However, site engagement in RCTs requires substantial investment in personnel, training, and institutional resources, which may have lasting effects on personnel and institutional culture. Additionally, engagement in research has been associated with improved health care performance at the institutional level, including in prior studies at substance use treatment centers within the National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN). Nonetheless, little has been reported about downstream effects of site participation for emergency department (ED)-based studies, including investigator professional advancements and institution-wide improvements in clinical practice. This commentary piece describes individual- and site-level benefits associated with participation in the Emergency Department-Initiated Buprenorphine and Validation Network Trial (ED-INNOVATION, CTN-0099).

Related protocols: CTN-0099

Introduction: Hospitalizations are common among people with opioid use disorder (OUD). While hospitalizations represent opportunities to engage patients and offer treatment, they are also destabilizing events associated with an increased risk of death in the post-hospitalization period.

Methods: We conducted a retrospective cohort study within the Veterans Health Administration including all Veterans with OUD who experienced at least one medical hospitalization between January 2011 and December 2021 (part of CTN-0087). We examined which patient-level clinical and demographic factors were associated with all-cause and opioid-related mortality within 0-30 and 0-365 days following an index medical hospitalization.

Results: The cohort included 90,920 Veterans with OUD who experienced one or more medical hospitalizations during the study period. Median age was 58 years, and 93% were male. Older age (adjusted Odds Ratio [aOR] range 30d: 1.50-2.66; 1y: 1.58-3.28), higher medical complexity (aOR range 30d: 2.11-6.23; 1y: 1.96-7.34), multiple substance use disorders (SUD; aOR 30d: 1.81 (95% CI 1.44, 2.27) 1y: 1.48 [95% CI 1.36, 1.62]), and length of hospitalization (aOR 30d: 6.78 [95% CI 4.85, 9.47] 1y: 3.45 [95% CI 2.96, 4.01]) were associated with increased all-cause mortality following hospitalization. Homelessness (aOR 30d: 0.75 [95% CI 0.63, 0.90]; 1y: 0.85 [95 % CI 0.80, 0.91]), depression (aOR 1y: 0.89 [95 % CI 0.84, 0.95]), bipolar disorder (aOR 1y: 0.88 [95% CI 0.82, 0.94]), buprenorphine receipt (aOR 1y: 0.79 [95% CI 0.69, 0.91]), and service connection (aOR 30d: 0.76 [95% CI 0.60, 0.97] 1y: 0.64 [95 % CI 0.59, 0.70]) were associated with reduced all-cause mortality. Younger age (aOR range 30d: 3.21-5.24; 1y: 2.71-2.38), homelessness (aOR 1y: 1.40 [95% CI 1.20, 1.63]), and multiple SUD (aOR 1y: 1.78 [95% CI 1.33, 2.38]) were among factors associated with increased opioid-related mortality after hospitalization. Black race (aOR 1y: 0.61 [95% CI 0.50, 0.74]) and higher service connection (aOR 30d: 0.41 [95 % CI 0.21, 0.81]; 1y: 0.53 [95% CI 0.43-0.66]) were associated with reduced opioid-related mortality after hospitalization.

Conclusions: Several patient-level factors were associated with increased all-cause mortality (e.g., length of hospital stay), reduced all-cause mortality (e.g., homelessness), increased opioid-related mortality (e.g., multiple SUD), and reduced opioid-related mortality (e.g., service connection) after hospitalization. This information provides a roadmap for future development and study of tailored supports and risk stratification tools to enhance post-hospitalization transitional care for patients with OUD.

Related protocols: CTN-0087

Background: Adoption of ED-initiated buprenorphine for opioid use disorder has been slow despite evidence of its effectiveness. Implementation facilitation (IF) is an evidence-based implementation strategy to promote adoption of new practices within clinical settings. The Clinical Trials Network (CTN)-0069 Project ED Health” study evaluated whether provision of ED-initiated buprenorphine with referral for community-based medication for opioid use disorder (MOUD) increased after IF. We identified the health system resources required to conduct IF and sustain ED-initiated buprenorphine with referral for community-based MOUD and then calculated the financial costs associated with using those resources.

Methods: We estimated costs using nationally representative employee values of the formative evaluation and other IF-related resources (e.g., focus groups, clinician education, and academic detailing), using microcosting analysis to capture quantitative data and assign nationally-representative costs based on Drug Abuse Treatment Cost Analysis Program (DATCAP). The study data was collected from 2017 to 2020 from four sites. We calculated costs per site for three distinct phases: pre-implementation, IF, and sustainment.

Results: The mean, per-site, costs were: pre-implementation = $27,753 (range: $25,859$27,821), IF = $53,558 (range: $48,417-$59,468) and annual sustainment = $226,822(range: $104,871-$339,100), which resulted in a mean per-patient cost of $115 assuming an average of 195 patients identified with untreated OUD, per-month, across sites.

Conclusions: The microcosting analysis revealed the resources and costs involved in implementing ED-initiated buprenorphine programs at various sites. Understanding the different ways each site customized the IF strategy can improve adoption to this initiative. Interpreting the costs during the intervention and what it takes to sustain it will help decision makers address uncertainty and promote increased acceptance of implementing these practices in the context of potential benefits that this approach can provide.

Related protocols: CTN-0069

Introduction:
Primary care patients with opioid use disorder (OUD) may receive treatment in primary care clinics or co-located specialty addiction treatment models. To help guide operational leaders in organizing OUD care delivery systems, we described rates of OUD medication treatment among primary care patients in PRimary care Opioid Use Disorders treatment (PROUD, CTN-0074) trial intervention clinics and four primary care clinics not in the trial because they already had OUD treatment programs in place (exemplar clinics).

Methods:
Primary care patients seen at six PROUD trial intervention clinics that implemented the Massachusetts model of office-based addiction treatment (PROUD clinics) and four exemplar clinics (two co-located specialty models; two primary care models with universal prescribing, in which all primary care providers were expected to treat OUD) were compared. Primary outcomes were person-years (PY) of medication treatment for OUD with buprenorphine or extended-release naltrexone during follow up (3/2018–2/2020) and changes from baseline (3/2016–2/2018).

Results:
Baseline primary care samples included 109,196 patients in PROUD clinics and 101,631 patients in exemplar clinics. Baseline OUD treatment rates varied across exemplar clinics (range: 10.9 to 328.7 PY per 10,000 primary care patients) but were higher than in PROUD clinics at baseline (3.9 PY per 10,000), with exemplar clinics with primary care models (established 2005 and 2017) providing the highest treatment rates to their primary care patients. During follow-up, PROUD clinics nearly tripled treatment, to 14.4 PY per 10,000, whereas most exemplar clinics increased treatment by less than 10% but still had higher treatment rates (range: 12.0 to 359.4 PY per 10,000).

Conclusions:
Primary care OUD treatment rates varied markedly. Exemplar clinics in which all primary care providers were expected to treat OUD had the highest treatment rates at baseline and follow-up, suggesting that universal prescribing is a promising approach to increasing OUD treatment in primary care.

Related protocols: CTN-0074

Background: Opioid use disorder (OUD) during pregnancy is a leading contributor to peripartum morbidity and mortality, with overdose deaths rising significantly in recent years. Despite the identification of various factors associated with overdose events, including social, demographic, psychiatric, and neonatal outcomes, the relative contributions of these factors to peripartum overdose history (or lack thereof) remain unclear. Thus, this study aims to characterize factors associated with lifetime opioid-involved overdose events among currently pregnant individuals receiving buprenorphine (BUP) treatment for OUD.

Methods: Treatment-seeking pregnant individuals with an estimated gestational age of 6 to 30 weeks were enrolled in a large multisite randomized controlled trial evaluating 2 BUP formulations for OUD. Participant baseline demographic, substance use, and mental health data were collected using validated measures, and random forest modeling identified key factors associated with lifetime opioid overdose events.

Results: The 140 pregnant participants (Mage = 31.2 years, SD = 4.7; 87.1% White) reported an average of 8.7 years (SD = 5.8) of opioid use, with 92.1% endorsing lifetime prescription opioid use and 82.9% reporting heroin use. The average lifetime number of nonfatal opioid overdose events was 4.8 (SD = 12.1); an overdose was reported by 55% of the sample (n = 77). Random forest analysis (area under the receiver operating characteristic curve = 0.797) incorporating sociodemographic, substance use, and mental health characteristics found that the most important factors associated with lifetime overdose events were, in order, lifetime heroin use, trauma exposure, reliance on partners or parents for financial support, depressive symptoms, and lifetime cocaine use.

Conclusions: These findings underscore the critical need to address substance use, co-occurring mental health, and socioeconomic challenges that are associated with previous opioid overdose. Identifying and targeting key modifiable overdose risk factors can inform the development of tailored interventions to improve outcomes for this population.

Related protocols: CTN-0080

This is the primary outcomes article for CTN-0135.

Importance: Anecdotal accounts suggest an increase in problems initiating buprenorphine (BUP) treatment among individuals using illicitly manufactured fentanyl. Limited empirical data illuminate these challenges.

Objective: To determine the prevalence of clinician-reported problems initiating BUP treatment among patients using fentanyl and describe clinical strategies used to overcome engagement challenges.

Design, setting, and participants: For this survey study, an online survey was pilot tested and refined with a convenience sample of physicians. The final survey included 96 items and took less than 15 minutes to complete. The survey queried patients’ use of fentanyl, BUP induction problems (precipitated or prolonged withdrawal), strategies to overcome induction problems, clinician characteristics, and practice characteristics. Eligible clinicians initiated BUP for at least 10 patients with opioid use disorder in the past year and at least 1 patient in the past 90 days. The survey was live from June 2, 2023, to March 18, 2024.

Main outcome and measures: The main outcome of interest was precipitated and/or prolonged opioid withdrawal. Descriptive statistics are reported, and logistic regression was used to identify factors associated with BUP initiation problems.

Results: A random sample of physicians and advanced practice clinicians in the US Drug Enforcement Administration (DEA) registrant dataset from October 2022 (n = 3141) were invited to participate; of 2485 eligible for inclusion, 649 (26.1%) completed the prescreen survey. Of 421 (64.9%) eligible to complete the survey, the final sample included 396 (94.1%) clinicians who completed at least 50% of the survey items. Of 390 participants, 284 (72.8%) reported problems when initiating BUP in patients using fentanyl, with 242 of 394 (61.4%) reporting patients’ experiencing precipitated withdrawal. A total of 264 or 392 participants (67.3%) reported modifying their standard induction procedures, changing how they counsel patients, or changing both medication and counseling protocols. In multivariable modeling, clinicians were more likely to report problems initiating BUP in patients if they had a DEA waiver to treat more than 100 patients (OR, 1.92; 95% CI, 1.08-3.40), vs those waivered to treat fewer patients; if they reported at least 75% of their patients using fentanyl (OR, 6.31; 95% CI, 2.59-15.35), vs no patients; or if they inducted patients in noninpatient settings (OR, 2.79; 95% CI, 1.39-5.61), vs inpatient settings.

Conclusions and relevance: In this survey study of clinician-reported problems initiating BUP treatment, clinicians working in high-volume noninpatient settings reported more problems initiating BUP in patients using fentanyl, and many reported changing their clinical practices in response to these problems. Further research is warranted to match alternate BUP induction strategies by clinical settings.

Related protocols: CTN-0135