A Review of Alpha-2 Adrenergic Agents Implicated in Opioid Use Disorder

Opioid use disorder (OUD) has been recognized for many years as a leading public health emergency in the United States, costing almost 80,000 Americans their lives in 2023. Recently, fentanyl, the predominant synthetic opioid implicated in OUD, has begun to be adulterated with the alpha-2 adrenergic receptor (α₂AR) agonists xylazine and medetomidine. This has a profound effect on the treatment of suspected overdoses, as naloxone, which reverses fentanyl overdoses, does not reverse α₂ agonist overdoses, and there are no FDA-approved treatments for overdoses with an α₂ agonist. Xylazine is spreading rapidly through the illicit drug supply in the United States, and to further complicate efforts to mitigate its effects, xylazine users frequently experience necrotic wounds which are difficult to treat. In this review, we comprehensively examined literature sources to compile information on the pharmacology, chemistry, pharmacokinetics, and toxicities of α₂AR agonists that are implicated in OUD. We hope that this summary will provide a perspective on the way forward in combating the issue of α₂ agonist-adulterated opioids and lead to the discovery of drugs as reversal agents for α₂ agonist overdoses.