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.

Opioid and Benzodiazepine Co-Prescribing Trends from the Emergency Department from 2012 to 2019: A National Analysis.

BACKGROUND: In 2016, the U.S. Food and Drug Administration (FDA) issued its strongest safety warning ("Black Box Warning") for concomitant use of prescription opioids and benzodiazepines due to overdose deaths. OBJECTIVE: Our objective was to look at trends of opioid and benzodiazepine co-prescribing in the emergency department (ED) using national data, because recent data are sparse. METHODS: This is a retrospective review of data collected by the National Hospital Ambulatory Medical Care Survey between 2012 and 2019. Our primary outcome was to determine whether there was a trend in ED visits when opioids and benzodiazepines were co-prescribed at discharge. We also compared the rate of visits when co-prescribing occurred before (2012-2015) and after (2017-2019) the 2016 FDA warning. We identified commonly co-prescribed benzodiazepines and opioids, and the rate of naloxone co-prescribing. We used descriptive statistics and bivariate tests to describe data. RESULTS: Between 2012 and 2019, there were 4,489,613 ED visits (0.41% of ED visits) when benzodiazepines and opioids were co-prescribed. There was no trend in the rate of co-prescribing overall, but a decrease in visits after the 2016 FDA Black Box Warning (2012-2015: mean 0.49%; 2017-2019: mean 0.29%; p < 0.0001). There were 7980 ED visits (0.18%) when naloxone was co-prescribed for these visits within this time frame and an increase over time (p < 0.001). CONCLUSIONS: Our study found that between 2012 and 2019, there was no overall reduction in co-prescribing of opioids and benzodiazepines across EDs nationwide, but a decrease after the 2016 Black Box Warning.

American College of Medical Toxicology and the American Academy of Clinical Toxicology position statement: nalmefene should not replace naloxone as the primary opioid antidote at this time.

BACKGROUND: Nalmefene is a potent opioid antagonist that has recently been reintroduced in the United States to treat known or suspected opioid overdose. NALMEFENE CLINICAL TRIAL DATA: The injection formulation, which had been withdrawn in 2008, was reintroduced in 2022, and in 2023 the United States Food and Drug Administration approved a new intranasal formulation of nalmefene. Because nalmefene had been previously approved for use in 1995 via injection, the new intranasal formulation did not require new clinical data as it was approved under an Abbreviated New Drug Application. Inherent to this abbreviated approval process, intranasal nalmefene was not studied in patients currently suffering opioid overdose. NALOXONE AND NALMEFENE: Nalmefene also has unique characteristics compared with naloxone, the current standard opioid antidote. Nalmefene has a higher affinity for opioid receptors and a longer duration of action than naloxone. Comparative effectiveness data regarding naloxone and nalmefene are sparse, and it is unclear if the inherent properties of nalmefene are beneficial in opioid overdose. We have decades of experience using naloxone safely and effectively as the primary opioid antidote, even in cases of fentanyl and fentanyl analog overdoses. There is, however, evidence to suggest nalmefene may result in more prolonged and severe opioid withdrawal than naloxone, which could be harmful to patients. POSITION: As nalmefene is untested in the current clinical environment of synthetic opioid overdoses and has the potential to cause harm via prolonged withdrawal, it is the opinion of the American College of Medical Toxicology and the American Academy of Clinical Toxicology that nalmefene should not replace naloxone as the primary opioid antidote at this time. RECOMMENDATIONS: We recommend additional clinical studies of nalmefene, administered via all approved routes, be conducted in a comparative fashion with naloxone, and that safety and effectiveness outcomes be evaluated before nalmefene is recommended as a primary opioid antidote.

Impact of the COVID-19 pandemic on emergency department alcohol intoxication presentations and positive screens for problem drinking.

Our aim was to assess the changes in patients presenting with acute alcohol intoxications or positive screens for problem drinking during the COVID-19 pandemic compared to before the pandemic in a seven-hospital health system. A retrospective chart review of emergency department (ED) visits from seven hospitals in the Washington, DC/Baltimore, and MD area from January 2019 to June 2021 is provided. The health system utilizes a validated system for Screening, Brief Intervention, and Referral to Treatment (SBIRT) for ED patients. We evaluated trends in patients who had a positive SBIRT screen for problem drinking (AUDIT-C score ≥ 3 in women, 4 in men), alcohol misuse (≥5), and those presenting with acute alcohol intoxication before March 2020 and during the early COVID pandemic period. There were 510 648 patients who were screened, ranging from ages of 16 to 95 years during the study period. There was an overall increase in patients who screened positive for problem drinking, alcohol misuse, and acute intoxications. While there was an overall decrease in the total number of ED visits during the start of the pandemic, which later increased near prepandemic levels, alcohol-related presentations as a percentage of total visits increased during the early pandemic period. There was an overall decrease in ED visits during the COVID-19 pandemic study period; problem drinking and acute intoxication presentation held steady, leading to an overall increase in proportion compared to pre-COVID-19 levels. Future research should focus on lessons learned during this time and should navigate the postpandemic care of patients with AUD. There was an increase in the proportion of ED visits for alcohol intoxications and positive screens for problem drinking during the COVID-19 pandemic in our seven-hospital system.

Management of Acetaminophen Poisoning in the US and Canada: A Consensus Statement.

Importance: The US and Canada currently have no formal published nationwide guidelines for specialists in poison information or emergency departments for the management of acetaminophen poisoning, resulting in significant variability in management. Objective: To develop consensus guidelines for the management of acetaminophen poisoning in the US and Canada. Evidence Review: Four clinical toxicology societies (America's Poison Centers, American Academy of Clinical Toxicology, American College of Medical Toxicology, and Canadian Association of Poison Control Centers) selected participants (n = 21). Led by a nonvoting chairperson using a modified Delphi method, the panel created a decision framework and determined the appropriate clinical management of a patient with acetaminophen poisoning. Unique to this effort was the collection of guidelines from most poison centers in addition to systematic collection and review of the medical literature. Comments from review by external organizations were incorporated before the guideline was finalized. The project began in March 2021 and ended in March 2023. Findings: The search retrieved 84 guidelines and 278 publications. The panel developed guidelines for emergency department management of single or repeated ingestion of acetaminophen. In addition, the panel addressed extended-release formulation, high-risk ingestion, coingestion of anticholinergics or opioids, age younger than 6 years, pregnancy, weight greater than 100 kg, and intravenous acetaminophen use. Differences from current US practice include defining acute ingestion as an ingestion presentation from 4 to 24 hours after overdose was initiated. A revised form of the Rumack-Matthew nomogram was developed. The term massive ingestion was replaced with the term high-risk ingestion and denoted by a specific nomogram line. Other recommendations include specific criteria for emergency department triage, laboratory evaluation and monitoring parameters, defining the role of gastrointestinal decontamination, detailed management of acetylcysteine treatment, associated adverse effects, and stopping criteria for acetylcysteine treatment, as well as criteria for consultation with a clinical toxicologist. Finally, specific treatment considerations, including acetylcysteine dosing, fomepizole administration, and considerations for extracorporeal elimination and transplant evaluation, were addressed. Conclusions and Relevance: This qualitative study provides a consensus statement on consistent evidence-based recommendations for medical, pharmacy, and nursing education and practice to optimize care of patients with acetaminophen poisoning.

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.

Systematic Review of Naloxone Dosing and Adverse Events in the Emergency Department.

BACKGROUND: Experts recommend using the lowest effective dose of naloxone to balance the reversal of opioid-induced respiratory depression and avoid precipitated opioid withdrawal, however, there is no established dosing standards within the emergency department (ED). OBJECTIVES: The aim of this review was to determine current naloxone dosing practice in the ED and their association with adverse events. METHODS: We conducted a systematic review by searching PubMed, Cochrane, Embase, and EBSCO from 2000-2021. Articles containing patient-level data for initial ED dose and patient outcome had data abstracted by two independent reviewers. Patients were divided into subgroups depending on the initial dose of i.v. naloxone: low dose ([LD], < 0.4 mg), standard dose ([SD], 0.4-2 mg), or high dose ([HD], > 2 mg). Our outcomes were the dose range administered and adverse events per dose. We compared groups using chi-squared difference of proportions or Fisher's exact test. RESULTS: The review included 13 articles with 209 patients in the results analysis: 111 patients in LD (0.04-0.1 mg), 95 in SD (0.4-2 mg), and 3 in HD (4-12 mg). At least one adverse event was reported in 37 SD patients (38.9%), compared with 14 in LD (12.6%, p < 0.0001) and 2 in HD (100.0%, p = 0.16). At least one additional dose was administered to 53 SD patients (55.8%), compared with 55 in LD (49.5%, p < 0.0001), and 3 in HD (100.0%, p = 0.48). CONCLUSIONS: Lower doses of naloxone in the ED may help reduce related adverse events without increasing the need for additional doses. Future studies should evaluate the effectiveness of lower doses of naloxone to reverse opioid-induced respiratory depression without causing precipitated opioid withdrawal.

Efficacy and tolerability of oral morphine versus oxycodone/acetaminophen for analgesia in the emergency department.

OBJECTIVE: Oxycodone/acetaminophen is one of the most commonly prescribed medications for pain management in the emergency department (ED) despite its high abuse liability. Our objective was to determine whether oral immediate-release morphine is as effective and well tolerated as oral oxycodone/acetaminophen for pain relief in stable ED patients. DESIGN: This is a prospective comparative study in which stable adult patients with acute painful conditions who had either oral morphine (15 or 30 mg) or oxycodone/acetaminophen (5/325 mg or 10/650 mg) ordered for them at the discretion of a triage physician were recruited. SETTING: This study took place in an urban, academic ED from 2016 to 2019. PARTICIPANTS: Seventy-three percent of the subjects were between the ages of 18 and 59, 57 percent were female, and 85 percent were African American. Most presented with abdominal, extremity, or back pain. Patient characteristics were similar between treatment groups. INTERVENTIONS: Of the 364 enrolled patients, 182 were given oral morphine and 182 were given oxycodone/acetaminophen at the discretion of the triage provider. They were asked to rate their pain score prior to receiving analgesia and at 60 and 90 minutes after administration. MAIN OUTCOME MEASURES: We examined pain scores, adverse effects, overall satisfaction, willingness to accept the same treatment again, and the need for additional analgesia. RESULTS: There was no difference in satisfaction reported by patients who received morphine versus oxycodone/acetaminophen: 15.9 percent vs 16.5 percent were very satisfied, 31.9 percent vs 26.4 percent were somewhat satisfied, and 23.6 percent vs 22.5 percent were not satisfied, p = 0.56. Secondary outcomes also showed no significant difference: net change in pain score -2 vs -2 at 60 and 90 minutes, p = 0.91 and p = 0.72, respectively; adverse effects 20.9 percent vs 19.2 percent, p = 0.69; need for further analgesia 9.3 percent vs 7.1 percent, p = 0.44; willingness to accept analgesic again 73.1 percent vs 78.6 percent, p = 0.22. CONCLUSIONS: Oral morphine is a feasible alternative to oxycodone/acetaminophen for analgesia in the ED.

Public health and medical preparedness for mass casualties from the deliberate release of synthetic opioids.

The large amounts of opioids and the emergence of increasingly potent illicitly manufactured synthetic opioids circulating in the unregulated drug supply in North America and Europe are fueling not only the ongoing public health crisis of overdose deaths but also raise the risk of another type of disaster: deliberate opioid release with the intention to cause mass harm. Synthetic opioids are highly potent, rapidly acting, can cause fatal ventilatory depression, are widely available, and have the potential to be disseminated for mass exposure, for example, if effectively formulated, via inhalation or ingestion. As in many other chemical incidents, the health consequences of a deliberate release of synthetic opioid would manifest quickly, within minutes. Such an incident is unlikely, but the consequences could be grave. Awareness of the risk of this type of incident and preparedness to respond are required to save lives and reduce illness. Coordinated planning across the entire local community emergency response system is also critical. The ability to rapidly recognize the opioid toxidrome, education on personal protective actions, and training in medical management of individuals experiencing an opioid overdose are key components of preparedness for an opioid mass casualty incident.

A national analysis of ED presentations for early pregnancy and complications: Implications for post-Roe America.

BACKGROUND: Most obstetric emergencies are initially managed in the emergency department (ED). The Supreme Court decision of Dobbs v. Jackson Women's Health Organization, overturning Roe v. Wade, in June 2022, eliminated constitutional protection of abortion rights, allowing states to swiftly enact laws that can greatly change reproductive medicine. In this post-Roe landscape, the ambiguity and uncertainty being imposed on clinicians regarding the legality of certain interventions may have catastrophic effects. To understand and plan for the changes that will come and attempt to mitigate adverse outcomes, the authors first assessed the current state of pregnancy-related complication care in the ED setting. This study utilized data obtained from the National Hospital Ambulatory Medical Care Survey (NHAMCS) to evaluate trends in pregnancy-related ED visits from 2016 to 2020 that could be impacted by restricted abortion access and trigger laws. The authors subsequently analyzed the legislative changes and translated the pertinent ones to dispel misunderstandings and provide a framework for appropriate medical practice. METHODS: The retrospective study utilized data from the NHAMCS database from 2016 to 2020, encompassing an estimated total of 4,556,778 pregnancy-related ED visits. NHAMCS is a multi-stage probabilistic sample collected by the National Center for Health Statistics (NCHS) at the Centers for Disease Control and Prevention (CDC) using an annual survey of EDs in the United States. All data were summarized using descriptive statistics such as proportions and 95% confidence intervals Furthermore, the supreme court decision was analyzed in addition to multiple state laws and legal texts. The findings were summarized and discussed. RESULTS: The majority (79.4%) of all studied visits were for patients between the ages of 18-34 years, capturing those in peak reproductive years. This age group also comprised of the bulk (76.4%) of visits for pathologic pregnancies, including ectopic and molar pregnancies, and 79.8% of visits for a spontaneous miscarriage or threatened miscarriage in early pregnancy. Black patients accounted for 25.7%, white patients 70.1%. Regarding ethnicity, patients were separated into Hispanic and non-Hispanic, with Hispanic patients comprising 27% of all ED visits for included diagnoses between 2016 and 2020. Most visits for complications following an induced abortion occurred in the south (70.8%) and were nearly twice as likely to occur in non-metropolitan areas. Approximately 18% patients presenting with a pathologic pregnancy required admission to the hospital and approximately 50% of those visits for pathologic pregnancies and visits for bleeding in pregnancy had a procedure in the ED (49.8% and 49.5%). There were 111,264 estimated visits in which methotrexate was administered, amounting to approximately 1 in 7 visits for ectopic or molar pregnancy. In this data set, approximately 14,000 miscarriage and early bleeding patients received misoprostol. CONCLUSION: Pregnancy-related ED visits comprise of a significant proportion of emergency care. As it relates to many of the trends previously elucidated on, the true extent of the burden cannot be predicted. It must be emphasized that contrary to popular belief, Dobbs v. Jackson does not prohibit termination of pregnancy in the setting of life-threatening conditions to the mother, including ectopic pregnancy, preeclampsia, and others, but the resultant uncertainty and ambiguity surrounding the constitutional change is leading to an over-compliance of the law, necessarily obstructing reproductive health care. The authors recommend that physicians be mindful of the rapidly-evolving laws in their particular state, and to also practice in accordance with Emergency Medical Treatment and Active Labor Act (EMTALA). Patient safety must be prioritized.