National Institute on Drug Abuse Clinical Trials Network Meeting Report: Advancing Emergency Department Initiation of Buprenorphine for Opioid Use Disorder.

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.

A Quality Framework for Emergency Department Treatment of Opioid Use Disorder.

Emergency clinicians are on the front lines of responding to the opioid epidemic and are leading innovations to reduce opioid overdose deaths through safer prescribing, harm reduction, and improved linkage to outpatient treatment. Currently, there are no nationally recognized quality measures or best practices to guide emergency department quality improvement efforts, implementation science researchers, or policymakers seeking to reduce opioid-associated morbidity and mortality. To address this gap, in May 2017, the National Institute on Drug Abuse's Center for the Clinical Trials Network convened experts in quality measurement from the American College of Emergency Physicians' (ACEP's) Clinical Emergency Data Registry, researchers in emergency and addiction medicine, and representatives from federal agencies, including the National Institute on Drug Abuse and the Centers for Medicare & Medicaid Services. Drawing from discussions at this meeting and with experts in opioid use disorder treatment and quality measure development, we developed a multistakeholder quality improvement framework with specific structural, process, and outcome measures to guide an emergency medicine agenda for opioid use disorder policy, research, and clinical quality improvement.

Research Priorities to Improve Treatment of Patients Exposed to Xylazine-fentanyl: Rapid Communication from a National Institute on Drug Abuse Center for the Clinical Trials Network Meeting.

ABSTRACT: 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.

Extended-Release 7-Day Injectable Buprenorphine for Patients With Minimal to Mild Opioid Withdrawal.

Importance: Buprenorphine is an effective yet underused treatment for opioid use disorder (OUD). Objective: 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: 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: 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: 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: 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: 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: ClinicalTrials.gov Identifier: NCT04225598.

National Institute on Drug Abuse: Dissemination of Scientific Knowledge to Improve Adolescent Health.

The wide and effective dissemination of research findings is crucial to the mission of the National Institute on Drug Abuse (NIDA). This article describes NIDA dissemination efforts and resources that are available to inform clinicians, teens, families, and educators about youth and substance use. Resources that are available include content addressing facts about youth drug use, trends in use, and stigma, in addition to substance use disorder (SUD) prevention and treatment. Information is provided about resources such as infographics, research-based practice guides, training, educational events, and online videos. How input is solicited to inform dissemination efforts is described and future directions for NIDA's dissemination efforts are outlined.

National Institute on Drug Abuse: Dissemination of Scientific Knowledge to Improve Adolescent Health.

The wide and effective dissemination of research findings is crucial to the mission of the National Institute on Drug Abuse (NIDA). This article describes NIDA dissemination efforts and resources that are available to inform clinicians, teens, families, and educators about youth and substance use. Resources that are available include content addressing facts about youth drug use, trends in use, and stigma, in addition to substance use disorder (SUD) prevention and treatment. Information is provided about resources such as infographics, research-based practice guides, training, educational events, and online videos. How input is solicited to inform dissemination efforts is described and future directions for NIDA's dissemination efforts are outlined.

Early emergency department experience with 7-day extended-release injectable buprenorphine for opioid use disorder.

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.

Design of a pragmatic clinical trial to improve screening and treatment for opioid use disorder in primary care.

BACKGROUND: Opioid-related deaths continue to rise in the U.S. A shared decision-making (SDM) system to help primary care clinicians (PCCs) identify and treat patients with opioid use disorder (OUD) could help address this crisis. METHODS: In this cluster-randomized trial, primary care clinics in three healthcare systems were randomized to receive or not receive access to an OUD-SDM system. The OUD-SDM system alerts PCCs and patients to elevated risk of OUD and supports OUD screening and treatment. It includes guidance on OUD screening and diagnosis, treatment selection, starting and maintaining patients on buprenorphine for waivered clinicians, and screening for common comorbid conditions. The primary study outcome is, of patients at high risk for OUD, the percentage receiving an OUD diagnosis within 30 days of index visit. Additional outcomes are, of patients at high risk for or with a diagnosis of OUD, (a) the percentage receiving a naloxone prescription, or (b) the percentage receiving a medication for OUD (MOUD) prescription or referral to specialty care within 30 days of an index visit, and (c) total days covered by a MOUD prescription within 90 days of an index visit. RESULTS: The intervention started in April 2021 and continues through December 2023. PCCs and patients in 90 clinics are included; study results are expected in 2024. CONCLUSION: This protocol paper describes the design of a multi-site trial to help PCCs recognize and treat OUD. If effective, this OUD-SDM intervention could improve screening of at-risk patients and rates of OUD treatment for people with OUD.

Implementation Facilitation to Promote Emergency Department-Initiated Buprenorphine for Opioid Use Disorder.

Importance: Emergency department (ED)-initiated buprenorphine for the treatment of opioid use disorder (OUD) is underused. Objective: To evaluate whether provision of ED-initiated buprenorphine with referral for OUD increased after implementation facilitation (IF), an educational and implementation strategy. Design, Setting, and Participants: This multisite hybrid type 3 effectiveness-implementation nonrandomized trial compared grand rounds with IF, with pre-post 12-month baseline and IF evaluation periods, at 4 academic EDs. The study was conducted from April 1, 2017, to November 30, 2020. Participants were ED and community clinicians treating patients with OUD and observational cohorts of ED patients with untreated OUD. Data were analyzed from July 16, 2021, to July 14, 2022. Exposure: A 60-minute in-person grand rounds was compared with IF, a multicomponent facilitation strategy that engaged local champions, developed protocols, and provided learning collaboratives and performance feedback. Main Outcomes and Measures: The primary outcomes were the rate of patients in the observational cohorts who received ED-initiated buprenorphine with referral for OUD treatment (primary implementation outcome) and the rate of patients engaged in OUD treatment at 30 days after enrollment (effectiveness outcome). Additional implementation outcomes included the numbers of ED clinicians with an X-waiver to prescribe buprenorphine and ED visits with buprenorphine administered or prescribed and naloxone dispensed or prescribed. Results: A total of 394 patients were enrolled during the baseline evaluation period and 362 patients were enrolled during the IF evaluation period across all sites, for a total of 756 patients (540 [71.4%] male; mean [SD] age, 39.3 [11.7] years), with 223 Black patients (29.5%) and 394 White patients (52.1%). The cohort included 420 patients (55.6%) who were unemployed, and 431 patients (57.0%) reported unstable housing. Two patients (0.5%) received ED-initiated buprenorphine during the baseline period, compared with 53 patients (14.6%) during the IF evaluation period (P < .001). Forty patients (10.2%) were engaged with OUD treatment during the baseline period, compared with 59 patients (16.3%) during the IF evaluation period (P = .01). Patients in the IF evaluation period who received ED-initiated buprenorphine were more likely to be in treatment at 30 days (19 of 53 patients [35.8%]) than those who did not 40 of 309 patients (12.9%; P < .001). Additionally, there were increases in the numbers of ED clinicians with an X-waiver (from 11 to 196 clinicians) and ED visits with provision of buprenorphine (from 259 to 1256 visits) and naloxone (from 535 to 1091 visits). Conclusions and Relevance: In this multicenter effectiveness-implementation nonrandomized trial, rates of ED-initiated buprenorphine and engagement in OUD treatment were higher in the IF period, especially among patients who received ED-initiated buprenorphine. Trial Registration: ClinicalTrials.gov Identifier: NCT03023930.

Advancing emergency department-initiated buprenorphine.

Opioids are the main driver of drug overdose deaths in the United States, and there has been a marked increase in opioid-related overdoses during the COVID-19 public health emergency. Many emergency departments (EDs) across the country are implementing ED-initiated buprenorphine programs, and this is a method to address and prevent opioid overdoses. Resources are available to overcome barriers and take action.

A pilot study of the functionality and clinician acceptance of a clinical decision support tool to improve primary care of opioid use disorder.

OBJECTIVE: Most Americans with opioid use disorder (OUD) do not receive indicated medical care. A clinical decision support (CDS) tool for primary care providers (PCPs) could address this treatment gap. Our primary objective was to build OUD-CDS tool and demonstrate its functionality and accuracy. Secondary objectives were to achieve high use and approval rates and improve PCP confidence in diagnosing and treating OUD. METHODS: A convenience sample of 55 PCPs participated. Buprenorphine-waivered PCPs (n = 8) were assigned to the intervention. Non-waivered PCPs (n = 47) were randomized to intervention (n = 24) or control (n = 23). Intervention PCPs received access to the OUD-CDS, which alerted them to patients at potentially increased risk for OUD or overdose and guided diagnosis and treatment. Control PCPs provided care as usual. RESULTS: The OUD-CDS was functional and accurate following extensive multi-phased testing. PCPs used the OUD-CDS in 5% of encounters with at-risk patients, far less than the goal of 60%. OUD screening confidence increased for all intervention PCPs and OUD diagnosis increased for non-waivered intervention PCPs. Most PCPs (65%) would recommend the OUD-CDS and found it helpful with screening for OUD and discussing and prescribing OUD medications. DISCUSSION: PCPs generally liked the OUD-CDS, but use rates were low, suggesting the need to modify CDS design, implementation strategies and integration with existing primary care workflows. CONCLUSION: The OUD-CDS tool was functional and accurate, but PCP use rates were low. Despite low use, the OUD-CDS improved confidence in OUD screening, diagnosis and use of buprenorphine. NIH Trial registration NCT03559179. Date of registration: 06/18/2018. URL: https://clinicaltrials.gov/ct2/show/NCT03559179.

Emergency department patients with untreated opioid use disorder: A comparison of those seeking versus not seeking referral to substance use treatment.

BACKGROUND Little is known regarding the sociodemographic and clinical characteristics of emergency department (ED) patients with untreated opioid use disorder (OUD) and the relationship of those characteristics with whether they were seeking a referral to substance use treatment at the time of their ED visit. METHODS Using data collected from 2/2017-1/2019 from participants enrolled in Project ED Health (CTN-0069), we conducted a cross-sectional analysis of patients with untreated moderate to severe OUD presenting to one of four EDs in Baltimore, New York City, Cincinnati, or Seattle. Sociodemographic and clinical correlates, and International Classification of Diseases Tenth Revision (ICD-10) diagnosis codes related to opioid withdrawal, injection-related infection, other substance use, overdose, and OUD of those seeking and not seeking a referral to substance use treatment on presentation were compared using univariate analyses. RESULTS Among 394 study participants, 15.2 % (60/394) came to the ED seeking a referral to substance use treatment. No differences in age, gender, education, health insurance status or housing stability were detected between those seeking and not seeking referral to substance use treatment. Those seeking a referral to substance use treatment were less likely to have urine toxicology testing positive for amphetamine [17 % (10/60) vs 31 % (104/334), p = 0.023] and methamphetamine [23 % (14/60) vs 40 % (132/334), p = 0.017] compared to those not seeking a referral. CONCLUSION Most patients with untreated OUD seen in the EDs were not seeking a referral to substance use treatment. Active identification, treatment initiation, and coding may improve ED efforts to address untreated OUD.

The design and conduct of a randomized clinical trial comparing emergency department initiation of sublingual versus a 7-day extended-release injection formulation of buprenorphine for opioid use disorder: Project ED Innovation.

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-termSM Initiative, or NIH HEAL InitiativeSM efforts to increase access to medications for opioid use disorder (OUD). We use components of Implementation Facilitation to enhance adoption of ED-initiated buprenorphine (BUP) at approximately 30 sites. Subsequently we 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. We will compare the cost effectiveness of the two treatments on the primary outcome using the incremental cost-effectiveness ratio. We 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, we 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.

Developing a clinical decision support for opioid use disorders: a NIDA center for the clinical trials network working group report.

There is an urgent need for strategies to address the US epidemic of prescription opioid, heroin and fentanyl-related overdoses, misuse, addiction, and diversion. Evidence-based treatment such as medications for opioid use disorder (MOUD) are available but lack numbers of providers offering these services to meet the demands. Availability of electronic health record (EHR) systems has greatly increased and led to innovative quality improvement initiatives but this has not yet been optimized to address the opioid epidemic or to treat opioid use disorder (OUD). This report from a clinical decision support (CDS) working group convened by the NIDA Center for the Clinical Trials Network aims to converge electronic technology in the EHR with the urgent need to improve screening, identification, and treatment of OUD in primary care settings through the development of a CDS algorithm that could be implemented as a tool in the EHR. This aim is consistent with federal, state and local government and private sector efforts to improve access and quality of MOUD treatment for OUD, existing clinical quality and HEDIS measures for OUD or drug and alcohol use disorders, and with a recent draft grade B recommendation from the US Preventative Services Task Force (USPSTF) for screening for illicit drug use in adults when appropriate diagnosis, treatment and care services can be offered or referred. Through a face-to-face expert panel meeting and multiple follow-up conference calls, the working group drafted CDS algorithms for clinical care felt to be essential for screening, diagnosis, and management of OUD in primary care. The CDS algorithm was reviewed by addiction specialists and primary care providers and revised based on their input. A clinical decision support tool for OUD screening, assessment, and treatment within primary care systems may help improve healthcare delivery to help address the current epidemic of opioid misuse and overdose that has outpaced the capacity of specialized treatment settings. A semi-structured outline of clinical decision support for OUD was developed to facilitate implementation within the EHR. Further work for adaptation at specific sites and for testing is needed.

Implementation facilitation to promote emergency department-initiated buprenorphine for opioid use disorder: protocol for a hybrid type III effectiveness-implementation study (Project ED HEALTH).

BACKGROUND: Patients with opioid use disorder (OUD) frequently present to the emergency department (ED) after overdose, or seeking treatment for general medical conditions, their addiction, withdrawal symptoms, or complications of 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 challenge, we are evaluating the impact of implementation facilitation (IF) on the adoption of ED-initiated buprenorphine for OUD into practice. METHODS: This protocol describes a study that is being conducted through the National Institute on Drug Abuse's Center for the Clinical Trials Network. A hybrid type III effectiveness-implementation study design is 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-min "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 work with local stakeholders to tailor and refine a bundle of activities to meet the site's needs. The primary analyses 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, we will perform a cost-effectiveness analysis (CEA) to determine if the effectiveness benefits are worth the additional costs. DISCUSSION: Results will generate novel information regarding the impact of IF as a strategy to promote ED-initiated buprenorphine. TRIAL REGISTRATION: ClinicalTrials.gov NCT03023930 first posted 1/10/2017, https://clinicaltrials.gov/ct2/show/NCT03023930?term=0069&rank=1.

Self-report measures of medication adherence behavior: recommendations on optimal use.

Medication adherence plays an important role in optimizing the outcomes of many treatment and preventive regimens in chronic illness. Self-report is the most common method for assessing adherence behavior in research and clinical care, but there are questions about its validity and precision. The NIH Adherence Network assembled a panel of adherence research experts working across various chronic illnesses to review self-report medication adherence measures and research on their validity. Self-report medication adherence measures vary substantially in their question phrasing, recall periods, and response items. Self-reports tend to overestimate adherence behavior compared with other assessment methods and generally have high specificity but low sensitivity. Most evidence indicates that self-report adherence measures show moderate correspondence to other adherence measures and can significantly predict clinical outcomes. The quality of self-report adherence measures may be enhanced through efforts to use validated scales, assess the proper construct, improve estimation, facilitate recall, reduce social desirability bias, and employ technologic delivery. Self-report medication adherence measures can provide actionable information despite their limitations. They are preferred when speed, efficiency, and low-cost measures are required, as is often the case in clinical care.

DoD-NCCAM/NIH workshop on acupuncture for treatment of acute pain.

The Department of Defense (DoD) and the National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health (NIH) cosponsored a workshop that explored the possible benefits of acupuncture treatment for acute pain. One goal of the workshop was to establish a roadmap to building an evidence base on that would indicate whether acupuncture is helpful for treating active-duty military personnel experiencing acute pain. The workshop highlighted brief presentations on the most current research on acupuncture and acute pain mechanisms. The impact of various modifiers (stress, genetics, population, phenotypes, etc.) on acute pain pathways and response to acupuncture treatment was discussed. Additional presentations focused on common neural mechanisms, an overview of real-world experience with using acupuncture to treat traumatic acute pain, and best tools and methods specific for acupuncture studies. Three breakout groups addressed the gaps, opportunities, and barriers to acupuncture use for acute pain in military and trauma settings. Different models of effectiveness research and optimal research designs for conducting trials in acute traumatic pain were also discussed.