Safety Evaluator Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration Potomac, United States
Background: Xylazine, an alpha-2 receptor agonist approved for sedation and analgesia in the veterinary setting, has been increasingly detected in the illicit drug supply.
Objectives: The objective of this case-series was to identify potential safety concerns associated with xylazine use in humans.
Methods: For this retrospective case-series, the authors searched the Food and Drug Administration (FDA) Adverse Events Reporting System, America’s Poison Centers’ National Poison Data System, Toxicology Investigators Consortium Core registry, and published medical literature for reports describing any intentional xylazine exposure (XE) from January 1, 2000, through December 31, 2021. Cases were assessed for information about concomitant medications, signs and symptoms of acute and chronic toxicity, reversal with naloxone, and evidence of physical dependence.
Results: Among 112 identified cases, the median patient age was 35.5 years, with 71% of patients being male and 92% originating from the United States. Common concomitant medications included fentanyl (59%), cocaine (31%), and heroin (25%). In cases describing acute toxicity symptoms (N=36), the most common adverse events were central nervous system (CNS) depression (83.3%), bradycardia (63.9%), respiratory depression (61.1%), and hypotension (41.7%). Sixteen cases indicated naloxone (average and median doses of 3.5 mg and 2 mg, respectively) had been administered (route not provided) to reverse symptoms. Eleven cases reported no response following naloxone administration, two reported a partial response in the context of likely multi-substance use, and three did not provide adequate information regarding response. Although most patients with acute toxicity (80.6%) recovered without sequalae, two died and two experienced persistent sequelae (amputation, anoxic brain injury). Six cases described chronic XE, commonly in combination with heroin and cocaine. Chronic XE was associated with severe skin necrosis in two cases, necessitating amputation. Chronic XE also resulted in physical dependence, as evidenced by withdrawal symptoms (anxiety, tremor) that occurred when xylazine was discontinued, and persisted despite treatment with buprenorphine or methadone reported in five chronic XE cases.
Conclusions: Related to these findings, the FDA issued a communication to healthcare professionals highlighting specific concerns. First, acute xylazine toxicity resembles the opioid toxidrome and is often found in combination with fentanyl, cocaine, and heroin. Second, naloxone did not readily reverse xylazine-associated CNS or respiratory depression. Finally, chronic XE use may lead to severe skin ulcerations and withdrawal symptoms not managed by typical opioid use disorder pharmacotherapy.
