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Abstract: 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

Abstract:

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

Abstract:

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

Abstract:

Background: The National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) has supported clinical trials of substance use disorder (SUD) interventions for 25 years. This review describes the use of implementation outcomes across CTN trials, characterizes outcomes included, and identifies gaps and potential opportunities to strengthen implementation research within the CTN and the field of SUD treatment.

Methods: This systematic review included active or completed studies listed on the CTN Dissemination Library webpage as of August 18, 2021, and approved by the CTN for development by January 1, 2022. Study summaries and protocols were reviewed if they: 1) measured at least one implementation outcome and 2) examined a practice change, intervention, or process. Extracted data elements included trial design characteristics, implementation frameworks, and outcome assessment domains informed by the RE-AIM and Proctor Implementation Outcomes Frameworks.

Results: 114 protocols were considered, 42 full-text protocols were screened, and 25 were included for data extraction. Start dates of trials spanned a 20-year period (2004–2024) with latter studies including more implementation outcomes. Fidelity (n = 29) and reach/penetration (n = 26) were the most included implementation outcomes. Equity was not identified in any protocols. Methods of defining, capturing, and evaluating outcomes data varied across trials and outcomes.

Conclusions: The inclusion of implementation outcomes increased over time, perhaps reflecting a growing emphasis on implementation research. Incorporating measures of equity could advance knowledge about differential receipt or effectiveness of SUD interventions. Future research should seek to improve the consistency and comprehensiveness in descriptions of implementation science elements.

Related protocols: CTN-0016, CTN-0056, CTN-0062-Ot, CTN-0064, CTN-0065, CTN-0069, CTN-0074, CTN-0074-A-1, CTN-0075, CTN-0076-Ot, CTN-0079, CTN-0079-A-1, CTN-0088, CTN-0090, CTN-0091, CTN-0095, CTN-0096, CTN-0097, CTN-0098, CTN-0099, CTN-0102, CTN-0103, CTN-0107, CTN-0116, CTN-0121

Abstract:

Buprenorphine is an effective yet underused treatment for opioid use disorder (OUD). The goal of this study, part of CTN-0099 (Emergency Department-INitiated bupreNOrphine and VAlidaTIOn Network Trial: ED-INNOVATION), was to evaluate the feasibility (acceptability, tolerability, and safety) of 7-day injectable extended-release buprenorphine in patients with minimal to mild opioid withdrawal.

This nonrandomized trial comprising 4 emergency departments in the Northeast, mid-Atlantic, and Pacific geographic areas of the US included adults aged 18 years or older with moderate to severe OUD and Clinical Opiate Withdrawal Scale (COWS) scores less than 8 (minimal to mild), in which scores range from 0 to 7, with higher scores indicating increasing withdrawal. Exclusion criteria included methadone-positive urine, pregnancy, overdose, or required admission. Outcomes were assessed at baseline, daily for 7 days by telephone surveys, and in person at 7 days. Patient recruitment occurred between July 13, 2020, and May 25, 2023.

The intervention was injection of a 24-mg dose of a weekly extended-release formulation of buprenorphine (CAM2038) and referral for ongoing OUD care. Primary feasibility outcomes included the number of patients who (1) experienced a 5-point or greater increase in the COWS score or (2) transitioned to moderate or greater withdrawal (COWS score =13) within 4 hours of extended-release buprenorphine or (3) experienced precipitated withdrawal within 1 hour of extended-release buprenorphine. Secondary outcomes included injection pain, satisfaction, craving, use of nonprescribed opioids, adverse events, and engagement in OUD treatment.

A total of 100 adult patients were enrolled (mean [SD] age, 36.5 [8.7] years; 72% male). Among the patients, 10 (10.0% [95% CI, 4.9%-17.6%]) experienced a 5-point or greater increase in COWS and 7 (7.0% [95% CI, 2.9%-13.9%]) transitioned to moderate or greater withdrawal within 4 hours, and 2 (2.0% [95% CI, 0.2%-7.0%]) experienced precipitated withdrawal within 1 hour of extended-release buprenorphine. A total of 7 patients (7.0% [95% CI, 2.9%-13.9%]) experienced precipitated withdrawal within 4 hours of extended-release buprenorphine, which included 2 of 63 (3.2%) with a COWS score of 4 to 7 and 5 of 37 (13.5%) with a COWS score of 0 to 3. Site pain scores (based on a total pain score of 10, in which 0 indicated no pain and 10 was the worst possible pain) after injection were low immediately (median, 2.0; range, 0-10.0) and after 4 hours (median, 0; range, 0-10.0). On any given day among those who responded, between 29 (33%) and 31 (43%) patients reported no cravings and between 59 (78%) and 75 (85%) reported no use of opioids; 57 patients (60%) reported no days of opioid use. Improving privacy (62%) and not requiring daily medication (67%) were deemed extremely important. Seventy-three patients (73%) were engaged in OUD treatment on day 7. Five serious adverse events occurred that required hospitalization, of which 2 were associated with medication.

Conclusions: This nonrandomized trial of the feasibility of a 7-day buprenorphine injectable in patients with minimal to mild opioid withdrawal (COWS scores, 0-7) found the formulation to be acceptable, well tolerated, and safe in those with COWS scores of 4 to 7. This new medication formulation could substantially increase the number of patients with OUD receiving buprenorphine.

Related protocols: CTN-0099

Abstract:

Opioid overdose deaths in 2021 were the highest ever, driven by fentanyl and polysubstance use. The aim of this study was to characterize drug use, assessed by urine drug screens (UDSs), in patients with untreated opioid use disorder (OUD) presenting to 28 emergency departments (EDs) nationally and by region.

Researchers analyzed UDSs from patients enrolled in the CTN-0099 ED-INNOVATION (Emergency Department-Initiated Buprenorphine Validation) trial between July 12, 2020 and March 9, 2022. Participants were adult ED patients with OUD not engaged in addiction treatment with a UDS positive for an opioid, but negative for methadone. Sites were divided into “East” and “West” regions.

A UDS was available for all 925 enrolled participants, 543 from East and 382 from West. Fentanyl was in 702 specimens (76%) (n = 485 [89%] East vs. n = 217 [57%] West; p < 0.01) and was the only opioid in 269 (29%). After fentanyl, the most common opioids were morphine (presumably heroin; n = 411 [44%]; n = 192 [35%] East vs. n = 219 [57%] West; p < 0.01) and buprenorphine (n = 329 [36%]; n = 186 [35%] East vs. n = 143 [37%] West; p = 0.32). The most common drugs found with opioids were stimulants (n = 545 [59%]), tetrahydrocannabinol (n = 417 [45%]), and benzodiazepines (n = 151 [16%]). Amphetamine-type stimulants were more common in West (n = 209 [55%] vs. East (n = 125 [23%]). Cocaine was more common in East (n = 223 [41%]) vs. West (n = 82 [21%]). The presence of multiple drugs was common (n = 759 [82%]).

Conclusions: Most participants had UDS specimens containing multiple substances; a high proportion had fentanyl, stimulants, and buprenorphine. Regional differences were noted. Given the increased risk of death with fentanyl and polysubstance use, ED providers should be providing risk reduction counseling, treatment, and referral.

Related protocols: CTN-0099

Abstract:

This study aimed to discover computationally-derived phenotypes of opioid-related patient presentations to the ED via clinical notes and structured electronic health record (EHR) data. It was a retrospective study of ED visits from 2013–2020 across ten sites within a regional healthcare network participating in CTN-0099. The authors derived phenotypes from visits for patients 18 years of age or older with at least one prior or current documentation of an opioid-related diagnosis. Natural language processing was used to extract clinical entities from notes, which were combined with structured data within the EHR to create a set of features. Latent dirichlet allocation was performed to identify topics within these features. Groups of patient presentations with similar attributes were identified by cluster analysis.

In total 82,577 ED visits met inclusion criteria. The 30 topics were discovered ranging from those related to substance use disorder, chronic conditions, mental health, and medical management. Clustering on these topics identified nine unique cohorts with one-year survivals ranging from 84.2–96.8%, rates of one-year ED returns from 9–34%, rates of one-year opioid event 10–17%, rates of medications for opioid use disorder from 17–43%, and a median Carlson comorbidity index of 2–8. Two cohorts of phenotypes were identified related to chronic substance use disorder, or acute overdose.

Conclusions: These results indicate distinct phenotypic clusters with varying patient-oriented outcomes which provide future targets better allocation of resources and therapeutics. This highlights the heterogeneity of the overall population, and the need to develop targeted interventions for each population.

Related protocols: CTN-0099

Abstract:

Identifying patient risk factors leading to adverse opioid-related events (AOEs) may enable targeted risk-based interventions, uncover potential causal mechanisms, and enhance prognosis. In this study, part of CTN-0099, the authors aimed to discover patient diagnosis, procedure, and medication event trajectories associated with AOEs using large-scale data mining methods. The individual temporally preceding factors associated with the highest relative risk (RR) for AOEs were opioid withdrawal therapy agents, toxic encephalopathy, problems related to housing and economic circumstances, and unspecified viral hepatitis, with RR of 33.4, 26.1, 19.9, and 18.7, respectively. Patient cohorts with a socioeconomic or mental health code had a larger RR for over 75% of all identified trajectories compared to the average population. By analyzing health trajectories leading to AOEs, researchers discover novel, temporally-connected combinations of diagnoses and health service events that significantly increase risk of AOEs, including natural histories marked by socioeconomic and mental health diagnoses.

Conclusion: In this study, researchers examined the temporal sequencing of diagnoses, procedures and prescriptions as risk factors leading to an adverse opioid event. Using a data driven approach, they show how large-scale healthcare records can be leveraged to extract risk factors for future research, inform guidelines for practitioner prescribing of opioids and importantly highlights the incidences where further assessments and services are needed to address the patient’s overall health.

Related protocols: CTN-0099

Abstract:

Emergency department-initiated buprenorphine (BUP) for opioid use disorder is an evidence-based practice, but limited data exist on BUP initiation practices in real-world settings. We sought to characterize protocols for BUP initiation among a geographically diverse sample of emergency departments (EDs).

In December 2020, researchers reviewed prestudy clinical BUP initiation protocols from all EDs participating in CTN-0099 Emergency Department-INitiated bupreNOrphine VAlidaTION (ED-INNOVATION). They then abstracted information on processes for identification of treatment-eligible patients, BUP administration, and discharge care.

All participating ED-INNOVATION sites across 22 states submitted protocols; 31 protocols were analyzed. Identification of treatment-eligible patients: Most EDs 22 (71%) relied on clinician judgment to determine appropriateness of BUP treatment with only 7 (23%) requiring decision support tools or diagnosis checklists. Before BUP initiation, 27 (87%) protocols required a documented Clinical Opiate Withdrawal Scale (COWS) score; 4 (13%) required a clinical diagnosis of withdrawal with optional COWS score. Twenty-seven (87%) recommended a minimum COWS score of 8 for ED-initiated BUP. BUP administration: Initial BUP dose ranged from 2–16 mg (mode = 4). For continued withdrawal symptoms, 27 (87%) protocols recommended an interval of 30–60 minutes between first and second BUP dose. Total BUP dose in the ED ranged from 8 to 32 mg. Discharge care: Twenty-eight (90%) protocols recommended a BUP prescription (mode 16 mg daily) at discharge. Naloxone prescription and/or provision was suggested in 23 (74%) protocols.

Conclusions: In this geographically diverse sample of EDs, protocols for ED-initiated BUP differed between sites. Future work should evaluate the association between this variation and patient outcomes.

Related protocols: CTN-0099

Abstract:

ED-INNOVATION (Emergency Department-INitiated bupreNOrphine VAlidaTION) is a Hybrid Type-1 Implementation-Effectiveness multisite emergency department (ED) study funded through The Helping to End Addiction Long-term^SM Initiative, or NIH HEAL Initiative^SM, efforts to increase access to medications for opioid use disorder (OUD). In this study, researchers use components of Implementation Facilitation to enhance adoption of ED-initiated buprenorphine (BUP) at approximately 30 sites. Subsequently, they compare the effectiveness of two BUP formulations, sublingual (SL-BUP) and 7-day extended-release injectable (CAM2038, XR-BUP) in a randomized clinical trial (RCT) of approximately 2000 patients with OUD on the primary outcome of engagement in formal addiction treatment at 7 days.

Secondary outcomes assessed at 7 and 30 days include self-reported opioid use, craving and satisfaction, health service utilization, overdose events, and engagement in formal addiction treatment (30 days) and receipt of medications for OUD (at 7 and 30 days).

A sample size of 1000 per group provides 90% power at the 2-sided significance level to detect a difference in the primary outcome of 8% and accommodates a 15% dropout rate.

Researchers will compare the cost effectiveness of the two treatments on the primary outcome using the incremental cost-effectiveness ratio. They will also conduct an ancillary study in approximately 75 patients experiencing minimal to no opioid withdrawal who will undergo XR-BUP initiation. If the ancillary study demonstrates safety, they will expand the eligibility criteria for the RCT to include individuals with minimal to no opioid withdrawal. The results of these studies will inform implementation of ED-initiated BUP in diverse EDs which has the potential to improve treatment access.

Related protocols: CTN-0099

Abstract:

Patients with opioid use disorder (OUD) frequently present to the emergency department (ED) after overdose, or seeking treatment for medical conditions, their addiction, withdrawal symptoms, or complications from injection drug use, such as soft tissue infections. ED-initiated buprenorphine has been shown to be effective in increasing patient engagement in treatment compared with brief intervention with a facilitated referral or referral alone. However, adoption into practice has lagged behind need. To address this implementation change, we are evaluating the impact of implementation facilitation (IF) on the adoption of ED-initiated buprenorphine for OUD into practice.

This article describes a study that is being conducted through the NIDA Clinical Trials Network (CTN-0099). A hybrid type III effectiveness-implementation study design is being used to evaluate the effectiveness of a standard educational dissemination strategy versus IF on implementation (primary) and effectiveness (secondary) outcomes in four urban, academic EDs. Sites start with a standard 60-minute “Grand Rounds” educational intervention describing the prevalence of ED patients with OUD, the evidence for opioid agonist treatment and for innovative interventions with ED-initiated buprenorphine, followed by a 1-year baseline evaluation period.

Using a modified stepped wedge design, sites are randomly assigned to the IF intervention, which is guided by the Promoting Action on Research Implementation in Health Services (PARiHS) framework to assess evidence, context, and facilitation-related factors impacting the adoption of ED-initiated buprenorphine.

During the 6 months of IF through the 1-year IF evaluation period, external facilitators will work with local stakeholders to tailor and refine a bundle of activities to meet the site’s needs. The primary analyses will compare the baseline evaluation period to the IF evaluation period (n=120 patients with untreated OUD enrolled during each period) on (1) rates of provision of ED-initiated buprenorphine by ED providers with referral for ongoing medication (implementation outcome) and (2) rates of patient engagement in addiction treatment on the 30th day after the ED visit (effectiveness outcome). Finally, researchers will perform a cost-effectiveness analysis (CEA) to determine if the effectiveness benefits are worth the additional costs.

Conclusions: The ED is rapidly being identified as a “24/7/365” site to combat the opioid crisis by offering access to medications for opioid use disorder treatment. Sustainable, evidence-based practice implementation is a complex and challenging process. This study has the potential to identify an implementation strategy that can be translated to other EDs, thereby increasing the adoption of ED-initiated buprenorphine into practice, narrowing the gap between OUD identification and treatment.

Related protocols: CTN-0099