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.

Patients presenting to the ED with nonfatal drug overdose: Self-reported history of overdose and naloxone use.

BACKGROUND: In the context of polysubstance use and fentanyl detection in non-opioid drugs supplies (e.g., cocaine, methamphetamine), it is important to re-evaluate and expand our understanding of which populations are at high risk for fatal drug overdoses. The primary objective of this pilot study was to gather data from the ED to characterize the population presenting with drug overdose, including demographics, drug use patterns and comorbidities, to inform upstream overdose prevention efforts. METHODS: A consecutive sample of ED patients undergoing treatment for non-fatal overdose were prospectively recruited for study participation at the time of ED visit. Participants reported history of substance use over the past six months, recent and lifetime overdose, and naloxone receipt and administration history. RESULTS: A total of 76 eligible participants were enrolled over the course of seven months. Participants reported high rates of opioid (56%), stimulant (56%), and cannabis use (59%). Self-reported polysubstance use, defined as self-reported use of more than one substance, was 83%. Of enrolled participants, 64% reported at least one overdose and 39% reported three or more lifetime overdoses prior to their index overdose ED visit. Participants with no self-reported intentional opioid use (n = 32) in the past six months had fentanyl positive urine drug screen 84% of the time versus 89% in the overall study population (n = 74). Participants who did not report opioid use in the past six months were less likely to possess (34% vs. 55%) or to know how to acquire (50% vs. 74%) naloxone compared to participants with self-reported history of opioid use. CONCLUSION: This study demonstrated high rates of fentanyl exposure on toxicology testing at time of overdose across all participants including study participants without self-reported intentional opioid use. Data gathered in the ED at time of overdose can be used to inform upstream naloxone distribution and public health initiatives.

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.

Provider and administrator attitudes and experiences with implementing telebuprenorphine during the COVID-19 pandemic: a mixed-methods survey.

Introduction: This mixed-methods study assessed buprenorphine provider and administrator perceptions and experiences in offering telebuprenorphine during the COVID-19 pandemic. Methods: Semi-structured interviews were conducted between June 2021 and September 2021 among telebuprenorphine providers and administrators (N=16) and assessed for program design and implementation strategies, clinical workflow, patient-level factors influencing program entry and retention, and challenges and solutions to improving clinical care. Results: Clinician (n=15) and administrator (n=1) participants identified changes to clinical workflow, including increased administrative tasks to confirm patient receipt of prescribed medications, completion of referrals to community- or specialty treatment, and locating available pharmacies and laboratory services. Challenges consisted of staff redeployment to COVID-19 related responsibilities, prior authorization requirements for buprenorphine prescriptions, billing structures that under-reimbursed for telephone or video visits, and concerns with changes in government regulations. Strategies to improving telebuprenorphine included offering "hotlines" to facilitate same-day visits, expanding between-visit support, establishing workflows with community pharmacies to ensure seamless dispensing of buprenorphine, co-location of behavioral health providers, and distributing donated mobile phones to patients. Suggested technologies for enhancing care included text messaging (75%) and smartphone applications (56.3%). Conclusions: Findings from this study highlight considerable heterogeneity in the delivery of telebuprenorphine services.

Cannabis Use Patterns and Whole-Blood Cannabinoid Profiles of Emergency Department Patients With Suspected Cannabinoid Hyperemesis Syndrome.

STUDY OBJECTIVES: The objectives of this study were to characterize the detailed cannabis use patterns (eg, frequency, mode, and product) and determine the differences in the whole-blood cannabinoid profiles during symptomatic versus asymptomatic periods of participants with suspected cannabinoid hyperemesis syndrome recruited from the emergency department (ED) during a symptomatic episode. METHODS: This is a prospective observational cohort study of participants with symptomatic cyclic vomiting onset after chronic cannabis use. Standardized assessments were conducted to evaluate for lifetime and recent cannabis use, cannabis use disorder, and cannabis withdrawal symptoms. Quantitative whole-blood cannabinoid testing was performed at 2 times, first when symptomatic (ie, baseline) and at least 2 weeks after the ED visit when asymptomatic. The differences in cannabinoid concentrations were compared between symptomatic and asymptomatic testing. The study was conducted from September 2021 to August 2022. RESULTS: There was a difference observed between delta-9-tetrahydrocannabinol metabolites, but not the parent compound during symptomatic episodes and asymptomatic periods. Most participants (84%) reported using cannabis > once per day (median 3 times per day on weekdays, 4 times per day on weekends). Hazardous cannabis use was universal among participants; the mean cannabis withdrawal discomfort score was 13, indicating clinically significant rates of cannabis withdrawal symptoms with cessation of use. Most participants (79%) previously tried to stop cannabis use, but a few (13%) of them had sought treatment. CONCLUSION: Patients presenting to the ED with cannabinoid hyperemesis syndrome have high cannabis use disorder scores. Further studies are needed to better understand the influence of THC metabolism and concentrations on symptomatic cyclic vomiting.

Implementation and Uptake of the Massachusetts Drug Supply Data Stream: A Statewide Public Health-Public Safety Partnership Drug Checking Program.

CONTEXT: The illicit drug supply is rapidly evolving. Equally important to gathering drug supply data for monitoring is timely sharing of information with people who use drugs, the providers who care for them, law enforcement partners, and public health stakeholders so that efforts to avoid harmful substances, take preventive actions, and better target interventions can occur. PROGRAM: The Massachusetts Drug Supply Data Stream (MADDS) is the country's first statewide community drug checking program. Founded on public health-public safety partnerships, MADDS collects remnant drug packaging and paraphernalia with residue from people who use drugs and noncriminal samples from partnering police departments. MADDS tests samples using simultaneous immunoassay fentanyl test strips, Fourier-transform infrared spectrometry (FTIR), and off-site laboratory testing by gas chromatography-mass spectrometry (GC/MS). Results are accessible to community programs and municipalities, while trend analyses inform public health for cross-site alerts and informational bulletins. IMPLEMENTATION: MADDS was launched statewide in 2020 and rapidly expanded to a multisite program. Program staff approached communities and met with municipal police and community partners to secure written agreements to host drug checking. Community partners designed sample collection consistent with their pandemic era workflows. Consultations with stakeholders gathered feedback on design and deliverables. EVALUATION: The program tests sample donations on-site from community agencies and police departments, incorporates review by a medical toxicologist for health and safety concerns, crafts stakeholder-specific communications, and disseminates English, Spanish, and Portuguese language materials. For 2020, a total of 427 samples were tested, of which 47.1% were positive for fentanyl. By early 2021, MADDS detected shifts in cocaine purity, alerted communities of a new toxic fentanyl analogue and a synthetic cannabinoid contaminant, and confirmed the increase of xylazine (a veterinary sedative) in Massachusetts. DISCUSSION: Community drug checking programs can be collaboratively designed with public health and public safety to generate critical health and safety information for people who use drugs and the communities where they live.

Tele-buprenorphine for emergency department overdose visit follow up and treatment initiation.

INTRODUCTION: An ED visit for opioid overdose may be a person's only contact with the medical and behavioral health care systems and is an important opportunity to reduce risk of subsequent overdose and death. While ED initiatives to engage people with opioid use disorder (OUD) are being increasingly implemented, there are significant gaps in the receipt of services at the time of the ED encounter. METHODS: This is a retrospective cohort study of an outreach pilot project providing real-time telehealth delivered buprenorphine initiation and referral to community harm reduction and addiction treatment services via a follow up telephone call to patients after an ED visit for an opioid overdose. RESULTS: From January 2020 to April 2021 there were 606 patients with an ED visit for an opioid overdose eligible for a callback. Of the 606 eligible patients, 254/645 (42%) patients could be contacted and accepted service and/or treatment referrals. Fifteen patients were connected same-day to a buprenorphine prescriber for a telehealth encounter and, of connected patients, nine received a buprenorphine prescription. CONCLUSION: A post-ED follow up telephone call protocol is an opportunity to improve treatment engagement and access to buprenorphine for patients at high risk for opioid overdose and death.

What Do You Know About Maryjane? A Systematic Review of the Current Data on the THC:CBD Ratio.

Background: Ratios of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) impact metabolism and therapeutic effects of cannabis. Currently, no states with legalized medical or recreational cannabis consider ratios THC:CBD in regulations. Objective: Determine what THC:CBD ratios are selected for use in clinical cannabis trials and what is the rationale. Methods: This is a systematic literature review of Central, CINAHL, Embase, PsycInfo, and PubMed of the last 10 years of English language medical cannabis publications highlighting THC:CBD ratios. Included were clinical studies of products containing and listing both THC and CBD ratios, percentages, or weighted amounts. Case reports and series, abstracts, reviews, and meta-analysis were excluded. Non-human, non-therapeutic, or studies examining approved cannabis pharmaceuticals were excluded. Results: Four hundred and seventy-nine (479) unique references were found, of which 11 met inclusion criteria. THC:CBD ratios listed and/or calculated: 1:0, 22:1, 2:1, 1:1, 1:2, 1:6, 1:9, 1:20, 1:33, 1:50, and 0:1. Rationale for ratios selected was often not listed, or simply trivialized as the ratios available to patients in the area, or ratios that were pharmaceutically available throughout the study country. One study compared ratios of high and low THC:CBD, but did not specify the ratios. Conclusion: The medical and scientific communities have not drawn substantive conclusions nor thoroughly explored THC:CBD ratios for "best practice" treatment of different disease processes and their sequelae. While there is evidence that cannabis provides medical benefits, research is lacking on standardization of medical cannabis use in modern medical practices.

Opioid Withdrawal Precipitated by Long-Acting Antagonists.

BACKGROUND: Precipitated opioid withdrawal (POW) after opioid antagonist administration can be challenging to manage in the emergency department (ED), particularly if caused by a long-acting opioid antagonist such as naltrexone. There are no evidence-based guidelines to assist in safely and efficiently managing patients with this syndrome. OBJECTIVE OF REVIEW: To review current practice on the treatment of long-acting antagonist POW and make recommendations on the treatment of this complex disease process. METHODS: A literature search of opioid withdrawal cases precipitated by naltrexone was done using PubMed. One of the authors screened all the results of this search by title and abstract, leading to a final count of 27 articles that were reviewed in full by all authors. English language cases that involved precipitated opioid withdrawal from a long-acting opioid antagonist were included. Data were extracted, including the precipitant involved and dose, severity of opioid withdrawal, treatments rendered, and response to treatment. In all cases where symptoms and signs were described, a Clinical Opiate Withdrawal Scale score was calculated based on the information available. RESULTS: Twenty-seven papers were included. Naltrexone alone was the primary antagonist reported in 19 of the papers, extended-release naltrexone in two, naltrexone-morphine combination in two, and nalmefene in four. Treatment most commonly included fluid replacement, benzodiazepines, antiemetics, and clonidine. Full opioid agonist treatment, although often suggested, was poorly described. Buprenorphine successfully reduced the severity and duration of withdrawal in several cases. No standardized response scale was used, and response to treatment ranged from 3 to 48 h prior to resolution of clinical effects. CONCLUSIONS: Management of POW from long-acting antagonists is a complex problem with little formal evaluation of treatment options. There is not currently a sufficiently robust body of literature to support an evidence-based guideline. However, use of intravenous fluids, antiemetics, and benzodiazepines is commonly reported as successful and seems to be a reasonable approach until this process is better studied. A treatment strategy using partial agonists such as buprenorphine is emerging and may represent a safe and effective treatment pathway for these patients.

Substances in Counterfeit Prescription Pills Seized by Law Enforcement, 2017-2022.

This study examines substances identified during testing of counterfeit prescription pills seized by law enforcement in Rhode Island from 2017 to 2022.

Comparative Analysis of Opioid Queries on Erowid.org: An Opportunity to Advance Harm Reduction.

BACKGROUND: Many individuals who use opioids turn to online resources to gather information on effects, availability, and safety. OBJECTIVE: Describe opioid index page views on Erowid.org to assess trends in public interest in particular opioids. METHODS: Retrospective analysis of Erowid.org site traffic was performed to identify unique average daily visits to opioid pages. All data was normalized to that of visits to the heroin index page. Average daily visits to the index pages of each of 6 commonly abused opioids were assessed during the period of 2009 to 2015. Similarly, visits to 15 distinct opioid index pages at 5 time points (July, October 2014 and Jan, April, and July 2015) were described. RESULTS: From 2009 to 2015 a decrease in the number of page visits versus heroin (1.00) occurred for hydrocodone (0.87 to 0.59, -32%), oxycodone (1.38 to 0.99, -28%), and morphine (0.26 to 0.25, -6%). Increases in page visits compared to heroin occurred for fentanyl (0.18 to 0.47, +157%), tramadol (0.43 to 0.88, +106%), hydromorphone (0.19 to 0.24, +29%), and oxymorphone (0.11 to 0.13, +18%). Indexed to heroin (1.00) average opioid page visit frequencies from July 2014 to July 2015 were highest for oxycodone (1.02) and tramadol (0.81). Conclusion/Importance: Oxycodone and tramadol represent the greatest number of Erowid.org opioid page visits compared to heroin. The largest increase in visits over the study periods was for fentanyl and tramadol. The relationship of page visits on Erowid.org creates a unique opportunity for real-time evaluation of emerging drug trends and epidemiological study.

Notes from the Field: Cardiac Dysrhythmias After Loperamide Abuse - New York, 2008-2016.

Loperamide is an over-the-counter antidiarrheal with opioid-receptor agonist properties. Recommended over-the-counter doses (range = 2-8 mg daily) do not produce opioid effects in the central nervous system because of poor oral bioavailability and P-glycoprotein efflux* of the medication (1); recent reports suggest that large doses (50-300 mg) of loperamide produce euphoria, central nervous system depression, and cardiotoxicity (2-4). Abuse of loperamide for its euphoric effect or for self-treatment of opioid withdrawal is increasing (5). Cases of loperamide abuse reported to the Upstate New York Poison Center and New York City Poison Control Center were analyzed for demographic, exposure, clinical, and laboratory characteristics. Cases of intentional loperamide abuse reported to the National Poison Database System (NPDS) also were analyzed for demographic, dose, formulation, and outcome information.

Refractory Hypoglycemia Due to Sulfonylurea Contamination of Illicit Opioid Medications.

Illicit drug supply adulteration can heighten the risk for adverse health outcomes. Sulfonylurea medications are widely used in the treatment of diabetes mellitus (DM). Unintentional or intentional overdose of sulfonylureas can cause refractory hypoglycemia. This case report describes a 62-year-old male patient who presented to the emergency department (ED) after being found on the ground with signs of mild trauma. He was noted to be persistently hypoglycemic despite boluses of intravenous dextrose, a dextrose infusion, and oral nutrition. The patient did report purchase and oral ingestion of pills sold as oxycodone and that the pill shape and color were different from his usual supply. The patient was empirically treated with octreotide resulting in normalization of his serum glucose. Testing demonstrated a serum glipizide concentration six times the reporting range. This case represents unintentional sulfonylurea exposure in the setting of non-prescribed oxycodone use, resulting in hypoglycemia refractory to intravenous dextrose and oral nutrition. Octreotide is an additional potential treatment for this condition. As in this case, ingestion of street drugs may present a potential source of sulfonylurea exposure. Opioid contamination with sulfonylureas has not been widely reported in the literature and knowledge about this potential exposure is important for the prompt recognition and treatment of these patients by emergency physicians.

Buprenorphine prescribing and treatment accessibility in response to regulation changes due to the COVID-19 public health emergency.

BACKGROUND: In 2021, over 80,000 fatal overdoses occurred in the United States. Since 2020, the federal government has enacted multiple regulatory changes around buprenorphine prescribing for opioid use disorder (OUD) to increase access to buprenorphine. This study aims to explore trends in buprenorphine treatment initiation pre- and post-public health emergency to evaluate changes in the context of X-waiver relaxations and telehealth allowances. METHODS: In a cross-sectional study, all RI residents who filled a buprenorphine prescription at a pharmacy in Rhode Island (RI), Massachusetts, and Connecticut between January 2017 and December 2023 were obtained from the RI Prescription Drug Monitoring Program (PDMP). The study excluded buprenorphine products not approved for OUD treatment from the analysis. Identified individuals had initiated buprenorphine for OUD during the study period if they did not have a prior prescription or if they had >30 days without buprenorphine exposure between their prescriptions. Spearman's rank correlation tests were used to identify significant associations between outcomes and regulation changes. RESULTS: The average number of patients dispensed buprenorphine did not significantly change over the study period, however the average number of initiates significantly decreased (ρ = -0.38255, p = .0003). The average number of providers prescribing CII-CV substances in RI has increased 3.4 % over the study period. The average percentage of prescribers in the PDMP prescribing buprenorphine for OUD doubled (ρ = 0.96075, p < .0001). CONCLUSION: Though efforts have been made to increase buprenorphine initiation, buprenorphine initiates remain well below pre-PHE levels. Efforts must continue to eliminate existing barriers to treatment and improve access to individuals seeking treatment.

"It gets you high as a kite but not unsick": Characterizations of and responses to a changing local drug supply by people who use drugs in Rhode Island.

BACKGROUND: The North American overdose crisis has continued at unprecedented rates with more than 100,000 overdose deaths occurring in the United States (US) in 2022. Overdose deaths have increasingly been polysubstance-involved, with novel substances (e.g., xylazine) complicating overdose risk and health outcomes. Understanding the effects of-and responses to-a changing drug supply among people who use drugs is critical to modifying harm reduction strategies to be more responsive to people's needs. METHODS: This qualitative study draws on data collected from May to December 2022 in Rhode Island. Data include in-depth interviews with 50 people who use drugs and observational fieldwork in spaces frequented by participants (e.g., encampments, drop-in centers). Qualitative data were analyzed thematically drawing on concepts of situated rationality. RESULTS: Participants described significant changes in the drug supply, with many attributing these transitions to COVID-19. Most participants characterized the local supply as "synthetic" with textures, color, and taste evolving. Notably, participants emphasized adverse outcomes related to available supplies, including during use (e.g., intense burning sensations) and post-consumption (e.g., heavy sedation, ongoing withdrawal, necrosis). Given the complex supply, participants highlighted the increased risk of overdose and shared how they altered their use practices to manage evolving health risks. CONCLUSION: Our results underscore how people who use drugs characterized the local drug supply, including perceived changes to supply contents. Implementing and scaling up harm reduction interventions that reduce risk and reinforce the agency of people who use drugs are urgently needed to effectively address the overdose crisis.

Trends in recurrent overdose and treatment initiation following emergency department visits for opioid overdose between 2016 and 2021.

BACKGROUND: Overdose remains a pressing public health concern in the United States, particularly with the emergence of fentanyl and other potent synthetic opioids in the drug supply. We evaluated trends in recurrent overdose and opioid use disorder (OUD) treatment initiation following emergency department (ED) visits for opioid overdose to inform response efforts. METHODS: This retrospective cohort study used electronic health record and statewide administrative data from Rhode Island residents who visited EDs for opioid overdose between July 1, 2016, and June 30, 2021, a period with fentanyl predominance in the local drug supply. The primary outcome was recurrent overdose in the 365 days following the initial ED visit. OUD treatment initiation within 180 days following the initial ED visit was considered as a secondary outcome. Trends in study outcomes were summarized by year of the initial ED visit. RESULTS: Among 1745 patients attending EDs for opioid overdose, 20 % (n=352) experienced a recurrent overdose within 365 days, and this percentage was similar by year (p=0.12). Among patients who experienced any recurrent overdose, the median time to first recurrent overdose was 88 days (interquartile range=23-208), with 85 % (n=299/352) being non-fatal. Among patients not engaged in OUD treatment at their initial ED visit, 33 % (n=448/1370) initiated treatment within 180 days; this was similar by year (p=0.98). CONCLUSIONS: Following ED visits for opioid overdose in Rhode Island from 2016-2021, the one-year risk of recurrent overdose and six-month treatment initiation rate remained stable over time. Innovative prevention strategies and improved treatment access are needed.

Statewide Variation in Cannabinoid Regulations.

As a growing number of states legalize the use of cannabinoids for medical and non-medical purposes, there continues to be large gaps in the understanding of appropriate dosing, impact on health, and the state's role in regulation of products. Here, we present a summary of 2022 cannabis regulations by state to evaluate for the presence of THC:CBD ratios, maximum THC concentration or content within products, specific caps for cannabis possession, and requirements for testing for cannabinoid content and/or contaminants such as pesticides and heavy metals. These results are presented in Map 1 and Table 1 and demonstrate substantial variation among product THC content, purchasing limits, and quality measurements across the country. Finally, we note there is currently no centralized data collection platform for this set of information between states as cannabis use evolves, creating poor transparency between consumers and state regulators.

"I still partly think this is bullshit": A qualitative analysis of cannabinoid hyperemesis syndrome perceptions among people with chronic cannabis use and cyclic vomiting.

BACKGROUND: Cannabis is the most widely used psychoactive substance in the United States (US), with reported use patterns increasing among adults in recent years. Cannabinoid hyperemesis syndrome (CHS) has been one concern related to increased cannabis use patterns. US emergency departments have reported an increase of CHS cases over the last decade, yet little is known about CHS. This study explores the experiences of people with chronic cannabis use and cyclic vomiting and their perceptions of CHS. METHODS: Semi-structured interviews were conducted with 24 people recruited from a prospective cohort of patients presenting to Rhode Island emergency departments with symptomatic cyclic vomiting and chronic cannabis use. Data were analyzed thematically using NVivo. FINDINGS: Participants characterized their cyclic vomiting as related to food and alcohol consumption patterns, stress, and existing gastrointestinal issues. Despite recurrent episodes of cyclic vomiting, nausea, and abdominal pain, many participants remained uncertain whether their symptoms were driven by cannabis. Many participants relied on at-home research to assess their symptoms and seek out management approaches. Clinical treatment recommendations focused on cannabis cessation. However, most participants felt clinical recommendations failed to consider the complexity and challenge of stopping cannabis use given the chronicity of use and therapeutic benefits some perceived cannabis to have. CONCLUSIONS: Although cannabis cessation is the only reported CHS cure to date, additional clinical and non-clinical treatment approaches are needed to better support people with chronic cannabis use and cyclic vomiting to meet their ongoing needs.