Clinical considerations for the management of xylazine overdoses and xylazine‐related wounds

This editorial reviews literature on xylazine as well as major clinical considerations for treatment and management of suspected xylazine-involved overdoses and xylazine-related wounds. The clinical presentation and management of xylazine overdoses in the emergency setting are covered. Finally, it presents important programmatic considerations for improving care of people using xylazine. Xylazine, an α-2 agonist with a chemical structure similar to phenothiazines and pharmacologic similarities to clonidine, tizanidine and dexmedetomidine, is a substance used in veterinary medicine known to cause sedation, analgesia and muscle relaxation, and it has increasingly become present in the United States (US) illicit drug supply over the last 5 years 1-3. The Food and Drug Administration (FDA) has recently issued clinical guidance on xylazine 4 and the Office of National Drug Control and Policy has also issued additional clinical recommendations with policy and research guidance 5. Xylazine initially was studied as a potential anesthetic or sedative-hypnotic agent, however, early trials in humans were limited by severe hypotension and central nervous system depression 6. Xylazine was approved for veterinary use in 1972. In the early 2000s, xylazine was reported in Puerto Rico among people injecting heroin; at the time, it was noted to cause large skin wounds and profound sedative effects that differed from opioid intoxication 7, 8. Clinical effects of xylazine in humans have been mostly derived from case reports. Currently, most xylazine overdoses are concomitant with fentanyl 1, 9. However, xylazine in and of itself can be fatal: one review article reported 21 non-fatal and 22 fatal cases involving xylazine; several fatalities were intentional overdoses of xylazine in combination with alcohol or benzodiazepines 10. The effects of xylazine poisoning in humans are largely driven by the decreased release of norepinephrine and dopamine in the central nervous system. Bradycardia, central nervous system depression, respiratory depression, hyperglycemia, miosis, hypothermia, premature ventricular contractions and transient hypertension followed by sustained hypotension have been reported, from central and peripheral reduction in sympathetic tone, including increased vagal tone 10-12. Time to onset of clinical effect is minutes, with an estimated half-life of 23 to 50 minutes per the FDA 4, however, duration of effects in large animals has been typically 3 to 4 hours 12. Given overlap in clinical presentation of opioids and xylazine overdoses, mixed overdose presentations are often indistinguishable on presentation, with the exception that naloxone, may partially improve the respiratory rate or miosis without improvement of mental status. In these situations, treatment is primarily supportive, including vital sign monitoring, supplemental oxygen, intravenous fluids and/or vasopressors and endotracheal intubation when needed. Extrapolation from what is known about pharmacologically similar medications (i.e. dexmedetomidine, clonidine) has been an important factor in our developing understanding of xylazine-associated deaths. Intranasal or IV naloxone should be given as indicated every 2 to 3 minutes if there is improvement in mental status to reverse any opioid involvement, alongside oxygen and ongoing circulation support as needed. There are no known human reversal agents for xylazine overdose, although yohimbine and tolazoline are used as reversal agents in horses 13. Although xylazine testing could be an important component for patient education and clinician decision making, urine toxicology testing is rarely available during an acute overdose event, and therefore, is unlikely to change pre-hospital or emergency clinician management. The combination of opioids and xylazine likely potentiates sedation and respiratory depression, however, the exact mechanism of xylazine in these processes is unclear. Animal studies suggest that the presence of xylazine blunts the compensatory hyperoxic phase of the biphasic oxygen response that had been identified in rats exposed to fentanyl or heroin alone 14, thereby eliminating a protective central nervous system compensatory mechanism 15. However, in a recent large prospective, multicenter cohort of individuals presenting to emergency departments with opioid overdose, cardiac arrest and coma were significantly less common in those testing positive for xylazine than for opioids alone, which may be related to lower comparative opioid content in samples containing xylazine or different patterns of use 16. Although xylazine may cause an opioid overdose like toxidrome on its own in the absence of fentanyl, the extent to which xylazine is replacing more potent fentanyl in the illicit drug supply and the downstream impact that may have on day-to-day drug use patterns and overdose risk is poorly understood. Additional studies are needed to better delineate the role of xylazine in overdose deaths. Diagnosing and managing xylazine-related wounds relies on a high index of suspicion, a thorough history of substance use and diagnosis of potential substance use disorders, and familiarity with local xylazine prevalence. Much of what is known about management is based on case reports only because of no known trials in humans. These wounds are primarily noted at or around the site of previous injection, with necrosis or black eschar formation at the site within 1 to 3 days of injection 17. It is not clear how small wounds become confluent into larger body surface area wounds. Potential pathophysiology involves peripheral vasoconstrictive effects of xylazine, impairing wound healing, obliterative vascular damage from repeated injection, locally toxic extravasation or an immunologic phenomenon. Similar to burns or wounds with larger body surface area, they could be a risk for superinfection, but are not intrinsically infected. Once wounds are recognized as potentially xylazine-related, efforts to help patients cease injection drug use into or near the wound are critical. In many cases, this involves initiating or increasing doses of medication to treat opioid use disorder (e.g. buprenorphine or methadone), harm reduction strategies to decrease injection episodes, switch route of administration to intranasal and consistent access to wound care supplies and education. Keeping the wound moist, clean and covered at all times is imperative. In our clinical experience, chemical or enzymatic debridement of eschar is often preferred by patients over surgical debridement; we advise patients to avoid drying agents like alcohol swabs. Keeping the wound covered at all times with petrolatum gauze, antimicrobial dressings and self-adhesive wraps or large bandages is recommended. Currently, it is not clear at this time whether xylazine dependence 18 and withdrawal 19 are diagnostic entities, although reported symptoms of anxiety and restlessness have been managed with analogue agents such as dexmetometidine, clonidine or adjunct benzodiazepines. It is not known if xylazine is impacting the difficulty of initiating medication for opioid use disorder or people's ability to enter treatment programs; however, some patients have anecdotally conveyed being turned away from programs because of xylazine wounds or have not entered treatment for fear their xylazine dependence will go untreated. There is also fear that stigma related to xylazine wounds could prevent patients from seeking help from healthcare professionals. There are urgent research, clinical and policy considerations surrounding xylazine in humans. Increased testing for xylazine, low barrier access and affordable, therapeutic doses of medication treatment for opioid use disorder, as well as expanded access to harm reduction services, including drug checking, overdose prevention centers, safer opioid supply programs and wound care supplies, are essential considerations moving forward. Kimberly L. Sue: Conceptualization (equal); writing—original draft (equal); writing—review and editing (equal). Kathryn Hawk: Conceptualization (equal); writing—original draft (equal); writing—review and editing (equal). The authors acknowledge harm reduction programs and the National Survivors Union who have shared their experiences with caring for people with xylazine wounds and responding to xylazine-involved overdoses. K.L.S. has no conflicts of interest to declare. K.H. has research funding from the Elevance Foundation and the Foundation for Opioid Response Efforts. Data sharing is not applicable to this article as no new data were created or analyzed in this study.