Atipamezole merits investigation for use in human α‐2 agonist toxicity

First responders and emergency physicians are facing a dynamic challenge in the ability to effectively treat patients after illicit opioid overdose because of a rapidly evolving adulterant profile. The adulteration of illicitly purchased opioids with α-2-agonists, such as the veterinary sedatives xylazine and medetomidine, has rapidly proliferated recently [1, 2]. This trend has complicated the clinical management of opioid overdoses, as α-2-agonists independently produce profound central nervous system depression, bradycardia and respiratory compromise [2, 3]. The adulteration of fentanyl with xylazine has reached unprecedented levels in many regions of the United States (US). Xylazine has been increasingly detected in fatal opioid overdoses [4, 5]. The number of drug overdose deaths involving xylazine was 102 in 2018 and 3468 in 2021, increasing from 0.03 per 100 000 population to 1.06 over the same time period [6]. Simultaneously, other α-2-agonists such as medetomidine have been increasingly detected in illegally manufactured opioids since 2022 [7]. These drugs not only potentiate the sedative and respiratory depressant effects of opioids, but may also contribute to non-fatal complications such as skin ulcerations and bradyarrhythmias [8, 9]. Although naloxone effectively reverses the opioid toxicity component of sedation and respiratory depression, there is no approved antidote in humans for these clinical effects caused by α-2-agonist toxicity, and treatment is limited to supportive measures [9]. Conversely, a rapidly effective α-2 reversal agent exists in the veterinary pharmacopeia. Atipamezole is a selective α-2-adrenergic antagonist approved for veterinary use to reverse sedation from sedatives such as xylazine and medetomidine [10]. It rapidly and effectively reverses sedation and bradycardia in animals, and limited case reports and preclinical studies suggest it may have similar efficacy in humans [11-13]. Atipamezole offers a promising pharmacologic intervention for human use. A treatment pathway has been devised based on human and animal data in the setting of acute overdose from veterinary xylazine formulations [14]. Although high dose (10 mg IV) naloxone has been used for acute clonidine overdose in children, this dose is 5 to 100 times greater than recommended doses for opioid toxicity reversal, and would precipitate severe opioid withdrawal in patients with opioid dependence [15, 16]. In contrast, atipamezole could provide clinicians with a targeted reversal agent for α-2-agonist toxicity, conceptually similar to naloxone for opioid overdose or flumazenil for benzodiazepine-related sedation. However, without formal clinical trials and US Food and Drug Administration approval, its application in human toxicology remains largely theoretical. Patients who may benefit from atipamezole include those who received adequate naloxone to reverse opioid toxicity, but with continued hemodynamic or central nervous system effects from α-2-agonist toxicity (e.g. hypoperfusion, loss of airway reflexes, deep or prolonged coma). Potential efficacy outcomes include mental status improvement as measured by improvement of Richmond Agitation-Sedation Scale or Glasgow Coma Scale scores, improvement of hemodynamics parameters, mortality rates, intubation rates or change in disposition from the emergency department. Potential safety outcomes include precipitation of a withdrawal syndrome, requirement for sedation or occurrence of dysrhythmias or hypertensive emergencies. Given this context, we encourage the toxicology research community, in collaboration with regulatory bodies and pharmaceutical sponsors, to initiate clinical investigations into the efficacy and safety of atipamezole in humans. Adam Blumenberg: Conceptualization; writing—original draft; writing—review and editing. Laurén Murphy: Conceptualization; writing—original draft; writing—review and editing. None.