Faculty Bibliography

IMPORTANCE/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: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. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT04225598.

INTRODUCTION/BACKGROUND:Treatment of opioid use disorder (OUD) with buprenorphine is safe and effective, but Emergency Department-initiated buprenorphine (ED BUP) uptake is suboptimal. As part of a randomized clinical trial (RCT), we evaluated Implementation Facilitation (IF)'s impact on EDs' readiness to provide ED BUP. METHODS:From February 2020 to May 2024, we surveyed 31 ED Medical Directors (MDs) and site-Principal Investigators (PIs) across 33 Emergency Department-INitiated bupreNOrphine VAlidaTION (ED-INNOVATION) sites (29 of which proceeded to RCT enrollment) at three time points: pre-IF (baseline), early-IF (pre-enrollment), and late-IF (post-enrollment). We collected 10-point Likert scale ratings and performed linear regression modeling and correlation analysis to evaluate relationships between readiness, barriers, facilitators, and readiness changes over time. RESULTS:Across 31 responses for the three time points, mean readiness increased pre-IF to early-IF (6.29 vs. 8.23, p < 0.0001) and pre-IF to late-IF (6.29 vs. 8.39, p < 0.0001). We observed decreases in 13/15 barriers and increases in 13/19 facilitators. When examining relationships between changes in readiness, barriers, and facilitators, the strongest relationships were follow-up treatment availability (r = 0.64, p = 0.0001), prescribing practices knowledge (r = -0.64, p = 0.001); insurance coverage (r = -0.52, p = 0.002); nursing support (r = -0.48, p = 0.01); and knowledge about addiction and its treatment (r = 0.47, p = 0.007); weak relationships were length of stay impact (r = 0.02, p = 0.92), trained clinicians (r = 0.02, p = 0.91), and social complexity (r = -0.10, p = 0.60). CONCLUSIONS:IF was associated with improved readiness, decreases in barriers and an increase in facilitators of ED BUP. When faced with limited resources, these findings can help inform prioritization of addressable barriers and facilitators to improve readiness for ED BUP.

STUDY OBJECTIVE/OBJECTIVE:To characterize opioid and nonopioid drug use in the week following emergency department (ED)-initiated extended-release buprenorphine (XR-BUP) treatment using both self-reported data and urine drug screens (UDS). METHODS:This study uses data collected during a nonrandomized clinical trial of patients with untreated opioid use disorder (OUD), testing the safety and feasibility of initiating XR-BUP in patients presenting with minimal to mild withdrawal. The study was conducted from July 2020 to May 2023 across four urban academic EDs in the Northeast, Mid-Atlantic, and Pacific regions of the United States. A total of 100 participants, 18 years or older with OUD defined by DSM-5 criteria, a clinical opiate withdrawal scale (COWS < 8), and a positive opioid urine screen were included. Individuals with recent MOUD treatment, presentation for overdose, or concurrent methadone use were excluded. All participants received a single subcutaneous injection of 24 mg XR-BUP (CAM2038) during their ED visit. The primary outcomes were self-reported daily opioid and nonopioid drug use over 7 days postinjection using daily Qualtrics surveys and UDS results on day 7. RESULTS:Among participants who received XR-BUP and completed daily surveys, 98% reported at least one opioid-free day, and 63% reported no opioid use across all 7 days. Day 7 UDS results showed decreased detection of opioids, stimulants, and benzodiazepines. Reported polysubstance use also declined over the observation period. CONCLUSIONS:ED-initiated XR-BUP was associated with substantial reductions in opioid and polysubstance use during the first week post-discharge, supporting its role in early overdose risk mitigation and highlighting its value as an ED-based intervention for opioid use disorder. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov Identifier: NCT03658642.

IMPORTANCE/UNASSIGNED:Buprenorphine is an effective yet underused treatment for opioid use disorder (OUD). OBJECTIVE/UNASSIGNED:To evaluate the feasibility (acceptability, tolerability, and safety) of 7-day injectable extended-release buprenorphine in patients with minimal to mild opioid withdrawal. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED: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. INTERVENTION/UNASSIGNED:Injection of a 24-mg dose of a weekly extended-release formulation of buprenorphine (CAM2038) and referral for ongoing OUD care. MAIN OUTCOMES AND MEASURES/UNASSIGNED: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. RESULTS/UNASSIGNED: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 AND RELEVANCE/UNASSIGNED: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. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT04225598.

As the opioid overdose epidemic escalates, there is an urgent need for treatment innovations to address both patient and clinician barriers when initiating buprenorphine in the emergency department (ED). These include insurance status, logistical challenges such as the ability to fill a prescription and transportation, concerns regarding diversion, and availability of urgent referral sites. Extended-release buprenorphine (XR-BUP) preparations such as a new 7-day injectable could potentially solve some of these issues. We describe the pharmacokinetics of a new 7-day XR-BUP formulation and the feasibility of its use in the ED setting. We report our early experiences with this medication (investigational drug CAM2038), in the context of an ongoing clinical trial entitled Emergency Department-Initiated BUP VAlidaTION (ED INNOVATION), to inform emergency clinicians as they consider incorporating this medication into their practice. The medication was approved by the European Medicines Agency in 2018 and the U.S. Food and Drug Administration in 2023 for those 18 years or older for the treatment of moderate to severe opioid use disorder (OUD). We report our experience with approximately 800 ED patients with OUD who received the 7-day XR-BUP preparation in the ED between June 2020 and July 2023.

BACKGROUND:Opioid overdose deaths in 2021 were the highest ever, driven by fentanyl and polysubstance use. OBJECTIVE:The aim of the 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. METHODS:We 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. RESULTS: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.

Opioid use disorder and opioid overdose deaths are a major public health crisis, yet highly effective evidence-based treatments are available that reduce morbidity and mortality. One such treatment, buprenorphine, can be initiated in the emergency department (ED). Despite evidence of efficacy and effectiveness for ED-initiated buprenorphine, universal uptake remains elusive. On November 15 and 16, 2021, the National Institute on Drug Abuse Clinical Trials Network convened a meeting of partners, experts, and federal officers to identify research priorities and knowledge gaps for ED-initiated buprenorphine. Meeting participants identified research and knowledge gaps in 8 categories, including ED staff and peer-based interventions; out-of-hospital buprenorphine initiation; buprenorphine dosing and formulations; linkage to care; strategies for scaling ED-initiated buprenorphine; the effect of ancillary technology-based interventions; quality measures; and economic considerations. Additional research and implementation strategies are needed to enhance adoption into standard emergency care and improve patient outcomes.

STUDY OBJECTIVE/OBJECTIVE:We hypothesized that implementation facilitation would enable us to rapidly and effectively implement emergency department (ED)-initiated buprenorphine programs in rural and urban settings with high-need, limited resources and dissimilar staffing structures. METHODS:This multicenter implementation study employed implementation facilitation using a participatory action research approach to develop, introduce, and refine site-specific clinical protocols for ED-initiated buprenorphine and referral in 3 EDs not previously initiating buprenorphine. We assessed feasibility, acceptability, and effectiveness by triangulating mixed-methods formative evaluation data (focus groups/interviews and pre/post surveys involving staff, patients, and stakeholders), patients' medical records, and 30-day outcomes from a purposive sample of 40 buprenorphine-receiving patient-participants who met research eligibility criteria (English-speaking, medically stable, locator information, nonprisoners). We estimated the primary implementation outcome (proportion receiving ED-initiated buprenorphine among candidates) and the main secondary outcome (30-day treatment engagement) using Bayesian methods. RESULTS:Within 3 months of initiating the implementation facilitation activities, each site implemented buprenorphine programs. During the 6-month programmatic evaluation, there were 134 ED-buprenorphine candidates among 2,522 encounters involving opioid use. A total of 52 (41.6%) practitioners initiated buprenorphine administration to 112 (85.1%; 95% confidence interval [CI] 79.7% to 90.4%) unique patients. Among 40 enrolled patient-participants, 49.0% (35.6% to 62.5%) were engaged in addiction treatment 30 days later (confirmed); 26 (68.4%) reported attending one or more treatment visits; there was a 4-fold decrease in self-reported overdose events (odds ratio [OR] 4.03; 95% CI 1.27 to 12.75). The ED clinician readiness increased by a median of 5.02 (95% CI: 3.56 to 6.47) from 1.92/10 to 6.95/10 (n(pre)=80, n(post)=83). CONCLUSIONS:The implementation facilitation enabled us to effectively implement ED-based buprenorphine programs across heterogeneous ED settings rapidly, which was associated with promising implementation and exploratory patient-level outcomes.

BACKGROUND:Alcohol and drug use (substance use) is a risk factor for crash involvement. OBJECTIVES:To assess the association between substance use and crash injury severity among older adults and how the relationship differs by rurality/urbanicity. METHODS:We pooled 2017-2021 cross-sectional data from the United States National Emergency Medical Service (EMS) Information System. We measured injury severity (low acuity, emergent, critical, and fatal) predicted by substance use, defined as self-reported or officer-reported alcohol and/or drug use. We controlled for age, sex, race/ethnicity, road user type, anatomical injured region, roadway crash, rurality/urbanicity, time of the day, and EMS response time. We performed a partial proportional ordinal logistic regression and reported the odds of worse injury outcomes (emergent, critical, and fatal injuries) compared to low acuity injuries, and the predicted probabilities by rurality/urbanicity. RESULTS:Our sample consisted of 252,790 older adults (65 years and older) road users. Approximately 67%, 25%, 6%, and 1% sustained low acuity, emergent, critical, and fatal injuries, respectively. Substance use was reported in approximately 3% of the population, and this proportion did not significantly differ by rurality/urbanicity. After controlling for patient, crash, and injury characteristics, substance use was associated with 36% increased odds of worse injury severity. Compared to urban areas, the predicted probabilities of emergent, critical, and fatal injuries were higher in rural and suburban areas. CONCLUSION:Substance use is associated with worse older adult crash injury severity and the injury severity is higher in rural and suburban areas compared to urban areas.