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

## TL;DR

This review discusses how alpha-2 adrenergic agents like xylazine and medetomidine are complicating opioid use disorder treatment and overdose reversal.

## Contribution

The paper provides a comprehensive review of alpha-2 adrenergic agents in the context of opioid use disorder and their impact on overdose treatment.

## Key findings

- Xylazine and medetomidine are increasingly contaminating the opioid supply, complicating overdose treatment.
- Naloxone is ineffective against alpha-2 agonist overdoses, and no FDA-approved reversal agents exist.
- Xylazine use is associated with severe complications like necrotic wounds.

## Abstract

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.