National Institute on Drug Abuse Clinical Trials Network Meeting Report: Managing Patients Exposed to Xylazine-Adulterated Opioids in Emergency, Hospital and Addiction Care Settings.

Used as a veterinary sedative and not approved for human use, xylazine has been increasingly linked with opioid overdose deaths in the United States. A growing number of people have been exposed to xylazine in the illicit opioid supply (especially fentanyl) or in other drugs, particularly in some areas of the Northeast. Xylazine is an α-2 adrenergic agonist that decreases sympathetic nervous system activity. When combined with fentanyl or heroin, it is purported to extend the duration of the opioid's sedative effect and to cause dependence and an associated withdrawal syndrome; however, data to support these concerns are limited. Despite the escalating frequency of detection of xylazine in people with nonfatal and fatal opioid overdose, direct links to these outcomes have not been identified. Because the strongest causal link is to fentanyl coexposure, ventilatory support and naloxone remain the cornerstones of overdose management. Xylazine is also associated with severe tissue injury, including skin ulcers and tissue loss, but little is known about the underlying mechanisms. Nonetheless, strategies for prevention and treatment are emerging. The significance and clinical effects of xylazine as an adulterant is focused on 4 domains that merit further evaluation: fentanyl-xylazine overdose, xylazine dependence and withdrawal, xylazine-associated dermal manifestations, and xylazine surveillance and detection in clinical and nonclinical settings. This report reflects the Proceedings of the National Institute on Drug Abuse Center for the Clinical Trials Network convening of clinical and scientific experts, federal staff, and other stakeholders to describe emerging best practices for treating people exposed to xylazine-adulterated opioids. Participants identified scientific gaps and opportunities for research to inform clinical practice in emergency departments, hospitals, and addiction medicine settings.

First-Year Medical Students' Perceptions of Stigma Toward People With Opioid Use Disorder Before and After an Educational Intervention.

BACKGROUND: Stigma among medical trainees toward people with opioid use disorder (OUD) compounds the problems associated with opioid addiction. People with OUD who experience overt and implicit stigma from healthcare providers are less likely to seek and receive treatment, further restricting their access to already limited resources. The objective of our study was to assess an educational strategy to mitigate stigma toward people with OUD among first-year medical students. METHODS: This study assessed perceptions of stigma toward people with OUD among first-year medical students using an adaptation of a brief, validated opioid stigma scale before and after an educational intervention. The intervention consisted primarily of a recorded panel in which people with a history of OUD shared their experiences with stigma followed by small group discussions. RESULTS: After the educational intervention, students were more likely to respond that (1) they believed most people held negative beliefs about people with OUD and (2) they personally disagreed with negative statements about people with OUD. CONCLUSIONS: Educational interventions addressing stigma toward people with OUD are potentially effective and should be integrated into medical curricula. Such interventions are a crucial part of the effort to improve the medical care of people with OUD.

Mapping Buprenorphine Access at Philadelphia Pharmacies.

OBJECTIVES: Buprenorphine is not reliably stocked in many pharmacies, and pharmacy-level barriers may deter patients from opioid use disorder care. We surveyed all outpatient pharmacies in Philadelphia to describe variation in buprenorphine access and developed a map application to aid in identifying pharmacies that stock the medication. METHODS: Using a dataset from the Bureau of Professional and Occupational Affairs, we conducted a telephone survey of operating outpatient pharmacies (N = 422) about their buprenorphine stocking and dispensing practices. We used ArcGIS Pro 3.0.3 to join US Census Bureau ZIP code-level race and ethnicity data, conduct descriptive analyses, and create a map application. RESULTS: We collected data from 351 pharmacies (83% response rate). Two hundred thirty-eight pharmacies (68%) indicated that they regularly stock buprenorphine; 6 (2%) would order it when a prescription is sent. Ninety-one (26%) said that they do not stock or order buprenorphine, and 16 (5%) were unsure. We identified 137 "easier access" pharmacies (39%), meaning they regularly stock buprenorphine, dispense to new patients, and have no dosage maximums. Zip codes with predominantly White residents had a median (interquartile range) of 3 (2-4) "easier access" pharmacies, and those with predominantly Black residents a median (interquartile range) of 2 (1-4.5). Nine zip codes had no "easier access" pharmacies, and 3 had only one; these 3 zip codes are areas with predominantly Black residents. CONCLUSIONS: Buprenorphine access is not equitable across Philadelphia and a quarter of pharmacies choose not to carry the medication. Our map application may be used to identify pharmacies in Philadelphia that stock buprenorphine.

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.

Leveraging a Learning Collaborative Model to Develop and Pilot Quality Measures to Improve Opioid Prescribing in the Emergency Department.

The American College of Emergency Physicians (ACEP) Emergency Medicine Quality Network (E-QUAL) Opioid Initiative was launched in 2018 to advance the dissemination of evidence-based resources to promote the care of emergency department (ED) patients with opioid use disorder. This virtual platform-based national learning collaborative includes a low-burden, structured quality improvement project, data benchmarking, tailored educational content, and resources designed to support a nationwide network of EDs with limited administrative and research infrastructure. As a part of this collaboration, we convened a group of experts to identify and design a set of measures to improve opioid prescribing practices to provide safe analgesia while reducing opioid-related harms. We present those measures here, alongside initial performance data on those measures from a sample of 370 nationwide community EDs participating in the 2019 E-QUAL collaborative. Measures include proportion of opioid administration in the ED, proportion of alternatives to opioids as first-line treatment, proportion of opioid prescription, opioid pill count per prescription, and patient medication safety education among ED visits for atraumatic back pain, dental pain, or headache. The proportion of benzodiazepine and opioid coprescribing for ED visits for atraumatic back pain was also evaluated. This project developed and effectively implemented a collection of 6 potential measures to evaluate opioid analgesic prescribing across a national sample of community EDs, representing the first feasibility assessment of opioid prescribing-related measures from rural and community EDs.

Self-reported Xylazine Experiences: A Mixed-methods Study of Reddit Subscribers.

OBJECTIVES: Xylazine is an α 2 -agonist increasingly prevalent in the illicit drug supply. Our objectives were to curate information about xylazine through social media from people who use drugs (PWUDs). Specifically, we sought to answer the following: (1) What are the demographics of Reddit subscribers reporting exposure to xylazine? (2) Is xylazine a desired additive? And (3) what adverse effects of xylazine are PWUDs experiencing? METHODS: Natural language processing (NLP) was used to identify mentions of "xylazine" from posts by Reddit subscribers who also posted on drug-related subreddits. Posts were qualitatively evaluated for xylazine-related themes. A survey was developed to gather additional information about the Reddit subscribers. This survey was posted on subreddits that were identified by NLP to contain xylazine-related discussions from March 2022 to October 2022. RESULTS: Seventy-six posts were extracted via NLP from 765,616 posts by 16,131 Reddit subscribers (January 2018 to August 2021). People on Reddit described xylazine as an unwanted adulterant in their opioid supply. Sixty-one participants completed the survey. Of those who disclosed their location, 25 of 50 participants (50%) reported locations in the Northeastern United States. The most common route of xylazine use was intranasal use (57%). Thirty-one of 59 (53%) reported experiencing xylazine withdrawal. Frequent adverse events reported were prolonged sedation (81%) and increased skin wounds (43%). CONCLUSIONS: Among respondents on these Reddit forums, xylazine seems to be an unwanted adulterant. People who use drugs may be experiencing adverse effects such as prolonged sedation and xylazine withdrawal. This seemed to be more common in the Northeast.

Xylazine Adulteration of the Heroin-Fentanyl Drug Supply : A Narrative Review.

Xylazine is an animal sedative, approved by the U.S. Food and Drug Administration, that is commonly used in veterinary medicine and is not approved for human use. Since 2016, xylazine has consistently appeared in the illicitly manufactured fentanyl supply and has significantly increased in prevalence, likely due to its low cost, easy availability, and presumed synergistic psychoactive effect. Clinical experience along with the available pertinent research were used to review xylazine adulteration of the drug supply and provide guidance on the care of patients exposed to xylazine. This review discusses xylazine pharmacology, animal and human clinical effects, and what is known to date about care of patients experiencing acute overdose, xylazine-fentanyl withdrawal, and xylazine-associated wounds.

URINE TOXICOLOGY PROFILES OF EMERGENCY DEPARTMENT PATIENTS WITH UNTREATED OPIOID USE DISORDER: A MULTI-SITE VIEW.

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.

Association of Urine Fentanyl Concentration With Severity of Opioid Withdrawal Among Patients Presenting to the Emergency Department.

BACKGROUND AND AIMS: Fentanyl is involved in most US drug overdose deaths and its use can complicate opioid withdrawal management. Clinical applications of quantitative urine fentanyl testing have not been demonstrated previously. The aim of this study was to determine whether urine fentanyl concentration is associated with severity of opioid withdrawal. DESIGN: This is a retrospective cross-sectional study. SETTING: This study was conducted in 3 emergency departments in an urban, academic health system from January 1, 2020, to December 31, 2021. PARTICIPANTS: This study included patients with opioid use disorder, detectable urine fentanyl or norfentanyl, and Clinical Opiate Withdrawal Scale (COWS) recorded within 6 hours of urine drug testing. MEASUREMENTS: The primary exposure was urine fentanyl concentration stratified as high (>400 ng/mL), medium (40-399 ng/mL), or low (<40 ng/mL). The primary outcome was opioid withdrawal severity measured with COWS within 6 hours before or after urine specimen collection. We used a generalized linear model with γ distribution and log-link function to estimate the adjusted association between COWS and the exposures. FINDINGS: For the 1127 patients in our sample, the mean age (SD) was 40.0 (10.7), 384 (34.1%) identified as female, 332 (29.5%) reported their race/ethnicity as non-Hispanic Black, and 658 (58.4%) reported their race/ethnicity as non-Hispanic White. For patients with high urine fentanyl concentrations, the adjusted mean COWS (95% confidence interval) was 4.4 (3.9-4.8) compared with 5.5 (5.1-6.0) among those with medium and 7.7 (6.8-8.7) among those with low fentanyl concentrations. CONCLUSIONS: Lower urine fentanyl concentration was associated with more severe opioid withdrawal, suggesting potential clinical applications for quantitative urine measurements in evolving approaches to fentanyl withdrawal management.

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.

Impact of Universal Screening and Automated Clinical Decision Support for the Treatment of Opioid Use Disorder in Emergency Departments: A Difference-in-Differences Analysis.

STUDY OBJECTIVE: Emergency department (ED)-initiated buprenorphine improves outcomes in patients with opioid use disorder; however, adoption varies widely. To reduce variability, we implemented a nurse-driven triage screening question in the electronic health record to identify patients with opioid use disorder, followed by targeted electronic health record prompts to measure withdrawal and guide next steps in management, including initiation of treatment. Our objective was to assess the impact of screening implementation in 3 urban, academic EDs. METHODS: We conducted a quasiexperimental study of opioid use disorder-related ED visits using electronic health record data from January 2020 to June 2022. The triage protocol was implemented in 3 EDs between March and July 2021, and 2 other EDs in the health system served as controls. We evaluated changes in treatment measures over time and used a difference-in-differences analysis to compare outcomes in the 3 intervention EDs with those in the 2 controls. RESULTS: There were 2,462 visits in the intervention hospitals (1,258 in the preperiod and 1,204 in the postperiod) and 731 in the control hospitals (459 in the preperiod and 272 in the postperiod). Patient characteristics within the intervention and control EDs were similar across the time periods. Compared with the control hospitals, the triage protocol was associated with a 17% greater increase in withdrawal assessment, using the Clinical Opioid Withdrawal Scale (COWS) (95% CI 7 to 27). Buprenorphine prescriptions at discharge also increased by 5% (95% CI 0% to 10%), and naloxone prescriptions increased by 12% points (95% CI 1% to 22%) in the intervention EDs relative to controls. CONCLUSION: An ED triage screening and treatment protocol led to increased assessment and treatment of opioid use disorder. Protocols designed to make screening and treatment the default practice have promise in increasing the implementation of evidence-based treatment ED opioid use disorder care.

Barriers to opioid use disorder treatment: A comparison of self-reported information from social media with barriers found in literature.

Introduction: Medications such as buprenorphine and methadone are effective for treating opioid use disorder (OUD), but many patients face barriers related to treatment and access. We analyzed two sources of data-social media and published literature-to categorize and quantify such barriers. Methods: In this mixed methods study, we analyzed social media (Reddit) posts from three OUD-related forums (subreddits): r/suboxone, r/Methadone, and r/naltrexone. We applied natural language processing to identify posts relevant to treatment barriers, categorized them into insurance- and non-insurance-related, and manually subcategorized them into fine-grained topics. For comparison, we used substance use-, OUD- and barrier-related keywords to identify relevant articles from PubMed published between 2006 and 2022. We searched publications for language expressing fear of barriers, and hesitation or disinterest in medication treatment because of barriers, paying particular attention to the affected population groups described. Results: On social media, the top three insurance-related barriers included having no insurance (22.5%), insurance not covering OUD treatment (24.7%), and general difficulties of using insurance for OUD treatment (38.2%); while the top two non-insurance-related barriers included stigma (47.6%), and financial difficulties (26.2%). For published literature, stigma was the most prominently reported barrier, occurring in 78.9% of the publications reviewed, followed by financial and/or logistical issues to receiving medication treatment (73.7%), gender-specific barriers (36.8%), and fear (31.5%). Conclusion: The stigma associated with OUD and/or seeking treatment and insurance/cost are the two most common types of barriers reported in the two sources combined. Harm reduction efforts addressing barriers to recovery may benefit from leveraging multiple data sources.

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.

An analysis of cannabinoid hyperemesis syndrome Reddit posts and themes.

INTRODUCTION: Reddit hosts a large active community of members dedicated to the discussion of cannabinoid hyperemesis syndrome. We sought to describe common themes discussed and the most frequently mentioned triggers and therapies for cannabinoid hyperemesis syndrome exacerbations in the Reddit online community. METHODS: Data collected from six subreddits were filtered using natural language processing to curate posts referencing cannabinoid hyperemesis syndrome. Based on a manual review of posts, common themes were identified. A machine learning model was trained using the manually categorized data to automatically classify the themes for the rest of the posts so that their distributions could be quantified. RESULTS: From August 2018 to November 2022, 2683 unique posts were collected. Thematic analysis resulted in five overall themes: cannabinoid hyperemesis syndrome-related science; symptom timing; cannabinoid hyperemesis syndrome treatment and prevention; cannabinoid hyperemesis syndrome diagnosis and education; and health impacts. Additionally, 447 trigger and 664 therapy-related posts were identified. The most commonly mentioned triggers for cannabinoid hyperemesis syndrome episodes included: food and drink (n = 62), cannabinoids (n = 45), mental health (e.g., stress, anxiety) (n = 27), and alcohol (n = 22). Most commonly mentioned cannabinoid hyperemesis syndrome therapies included: hot water/bathing (n = 62), hydration (n = 60), antiemetics (n = 42), food and drink (n = 38), gastrointestinal medications (n = 38), behavioral therapies (e.g., meditation, yoga) (n = 35), and capsaicin (n = 29). DISCUSSION: Reddit posts for cannabinoid hyperemesis syndrome provide a valuable source of community discussion and individual reports of people experiencing cannabinoid hyperemesis syndrome. Mental health and alcohol were frequently reported triggers within the posts but are not often identified in the literature. While many of the therapies mentioned are well documented, behavioral responses such as meditation and yoga have not been explored by the scientific literature. CONCLUSIONS: Knowledge shared via online social media platforms contains detailed information on self-reported cannabinoid hyperemesis syndrome disease and management experiences, which could serve as valuable data for the development of treatment strategies. Further longitudinal studies in patients with cannabinoid hyperemesis syndrome are needed to corroborate these findings.

Personalized risk communication and opioid prescribing in association with nonprescribed opioid use: A secondary analysis of a randomized controlled trial.

BACKGROUND: To determine the impact of personalized risk communication and opioid prescribing on nonprescribed opioid use, we conducted a secondary analysis of randomized controlled trial participants followed prospectively for 90 days after an emergency department (ED) visit for acute back or kidney stone pain. METHODS: A total of 1301 individuals were randomized during an encounter at four academic EDs into a probabilistic risk tool (PRT) arm, a narrative-enhanced PRT arm, or a general risk information arm (control). In this secondary analysis, both risk tool arms were combined and compared with the control arm. We used logistic regressions to determine associations between receiving personalized risk information, receiving an opioid prescription in the ED, and nonprescribed opioid use in general and by race. RESULTS: Complete follow-up data were available for 851 participants; 23.3% (n = 198) were prescribed opioids (34.2% of White vs. 11.6% of Black participants, p < 0.001). Fifty-six (6.6%) participants used nonprescribed opioids. Participants in the personalized risk communication arms had lower nonprescribed opioid use odds (adjusted odds ratio [aOR] 0.58, 95% confidence interval [CI] 0.4-0.83). Black versus White participants had greater nonprescribed opioid use odds (aOR 3.47, 95% CI 2.05-5.87, p < 0.001). Black participants who were prescribed opioids had a lower marginal probability of using nonprescribed opioids versus those who were not (0.06, 95% CI 0.04-0.08, p < 0.001 vs. 0.10, 95% CI 0.08-0.11, p < 0.001). The absolute risk difference in nonprescribed opioid use for Black and White participants, respectively, in the risk communication versus the control arm, was 9.7% and 0.1% (relative risk ratio 0.43 vs. 0.95). CONCLUSIONS: Among Black but not White participants, personalized opioid risk communication and opioid prescribing were associated with lower odds of nonprescribed opioid use. Our findings suggest that racial disparities in opioid prescribing-which have been previously described within the context of this trial-may paradoxically increase nonprescribed opioid use. Personalized risk communication may effectively reduce nonprescribed opioid use, and future research should be designed specifically to explore this possibility in a larger cohort.

Self-reported Xylazine Experiences: A Mixed Methods Study of Reddit Subscribers.

Objectives: Xylazine is an alpha-2 agonist increasingly prevalent in the illicit drug supply. Our objectives were to curate information about xylazine through social media from People Who Use Drugs (PWUDs). Specifically, we sought to answer the following: 1) what are the demographics of Reddit subscribers reporting exposure to xylazine? 2) is xylazine a desired additive? and 3) what adverse effects of xylazine are PWUDs experiencing? Methods: Natural Language Processing (NLP) was used to identify mentions of "xylazine" from posts by Reddit subscribers who also posted on drug-related subreddits. Posts were qualitatively evaluated for xylazine-related themes. A survey was developed to gather additional information about the Reddit subscribers. This survey was posted on subreddits that were identified by NLP to contain xylazine-related discussions from March 2022 to October 2022. Results: 76 posts mentioning xylazine were extracted via NLP from 765,616 posts by 16,131 Reddit subscribers (January 2018 to August 2021). People on Reddit described xylazine as an unwanted adulterant in their opioid supply. 61 participants completed the survey. Of those that disclosed their location, 25/50 (50%) participants reported locations in the Northeastern United States. The most common eoute of xylazine use was intranasal use (57%). 31/59 (53%) reported experiencing xylazine withdrawal. Frequent adverse events reported were prolonged sedation (81%) and increased skin wounds (43%). Conclusions: Among respondents on these Reddit forums, xylazine appears to be an unwanted adulterant. PWUDs may be experiencing adverse effects such as prolonged sedation and xylazine withdrawal. This appeared to be more common in the Northeast.