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Background and objectives: Patients using fentanyl have worse treatment outcomes; however, little is known about other drugs that complicate treatment.

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

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

In response to the rapid escalation in the detection of xylazine in the unregulated drug supply, in April 2023, the White House designated fentanyl contaminated with xylazine an “emerging threat.” The National Institute on Drug Abuse Center for Clinical Trials Network convened a multidisciplinary meeting of stakeholders, federal staff members, researchers, and clinicians caring for patients with fentanyl and xylazine exposures. This convening focused on the most critical areas of concern with the goal of describing current practices and a xylazine-fentanyl research agenda. Discussions focused on the domains of epidemiology and laboratory detection, xylazine withdrawal and overdose, and dermal manifestations. The authors were involved in planning and moderating the program and providing a summary of the proceedings.

Recordings from this event can be found in the CTN Dissemination Library.

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

In response to the rapid escalation in the detection of xylazine in the unregulated drug supply, in April 2023, the White House designated fentanyl contaminated with xylazine an “emerging threat.” The National Institute on Drug Abuse (NIDA) Center for the Clinical Trials Network (CCTN) convened health care professionals and federal partners to review current practices in xylazine-related testing, treatment, and wound care to inform evolving best-practices in the field. This convening focused on the most critical areas of concern with the goal of rapidly identifying current practices and a xylazine-opioid research agenda.

Session 1: Pharmacology and Clinical Manifestations of Withdrawal and Overdose

Presenters focus on current knowledge of xylazine’s pharmacology, clinical outcomes of xylazine-exposed patients who present in the emergency department (ED), and the signs and symptoms of xylazine withdrawal—as well as their treatment.

• Xylazine Pharmacology – Joseph D’Orazio, M.D., Temple University School of Medicine and Giacomo Gianotti, D.V.M., D.V.Sc., DACVAA
• Xylazine Withdrawal, Opioid Withdrawal, and Medication Induction –
  Matthew Salzman, M.D.
• Opioid Overdoses Involving Xylazine in Emergency Department Patients: A Multicenter Study – Jennifer Love, M.D
• Manifestations of Xylazine and Fentanyl Withdrawal in a Hospital Cohort – Maggie Lowenstein, M.D., M.S.H.P., and Ashish Thakrar, M.D.Session 2: Xylazine WoundsLittle is understood about xylazine wounds (generally seen on the arms and legs) or satellite wounds (i.e., distinct injuries not at an injection site). Presenters describe how care is being provided for patients in the community—as individuals with open wounds are often turned away from inpatient drug treatment centers and shelters—and surgical management over the long term.
  • Hands On: Care Provided in the Community –
    Stephanie Klipp, R.N., CARN, CAAP, CRS
  • Surgical: Managing Complex Wounds Long-Term – Lisa Rae, M.D.

  
  Session 3: Testing

  Commercial testing of the illicit drug supply has increased significantly, which raises many questions. Speakers discuss how patients view the usefulness of xylazine tests, a state-wide program that checks the illicit drug supply, and a research collaborative for drug testing with rapid sharing of results.

  • Patient Perspectives and Utility of Xylazine Test Strips – Megan K. Reed, Ph.D., M.P.H.
  • State-wide Drug Testing in Rhode Island: Xylazine –
    Rachel Wightman, M.D.
  • Xylazine Testing for Harm Reduction and Clinical Care –
    Edward R. Sisco, Ph.D.

  
  Roundtable Discussion and Wrap Up

  Drs. Perrone, Haroz, and Thakrar lead a discussion in which participants generate several high-priority research questions in the areas of (1) pharmacology and clinical manifestations of withdrawal and overdose, (2) xylazine wounds, and (3) testing. Aidan Hampson, Ph.D., describes NIDA’s Notice of Special Interest (NOSI), Xylazine: Understanding its Use and the Consequences (NOT-DA-24-009). The purpose of the NOSI is to encourage research on the prevalence and consequences of xylazine use, as well as its treatment—including overdose alone or in combination with other drugs.