Behavioral Pharmacology of Opioid/Xylazine Mixtures

PROJECT SUMMARY The opioid crisis continues despite the availability of several FDA approved medications for treating opioid abuse and overdose. This public health crisis has worsened significantly over the past several years with the COVID-19 pandemic and the increased availability of fentanyl and related ultra-potent analogs. Recently, there has been a marked rise in overdose deaths involving opioids and xylazine, a non-opioid with sedative, analgesic, and muscle relaxant properties and authorized only for veterinary use. It remains unclear why use of opioid/xylazine mixtures has increased so rapidly. Use of xylazine might be intentional in some situations but not others as it is commonly found as an adulterant in other drugs. Having agonist properties at alpha-2 adrenergic receptors, xylazine decreases release of norepinephrine and dopamine, and causes drowsiness, hypotension, bradycardia, hypothermia, respiratory depression, and coma as well as soft tissue damage that can lead to necrotic skin lesions. Xylazine shares many effects with opioids, increasing the risk of adverse effects, including fatal overdose, when combined with an opioid. Anecdotal reports suggest that xylazine enhances the reinforcing and subjective effects of opioids and diminishes the severity of opioid withdrawal which might contribute to increased use; however, these hypotheses have not been tested experimentally. In the case of overdose, treatment with naloxone (Narcan®) blocks only the effects of the opioid, thus additional measures are required to successfully treat opioid/xylazine overdose. Repeated exposure to xylazine might also lead to physical dependence and withdrawal, and it remains unclear whether xylazine alters opioid withdrawal. Though medications are approved for reversing effects of xylazine in veterinary care, there are currently no approved medications for treating xylazine overdose or withdrawal in humans. Proposed studies use well- established methods and a highly translational species to improve our understanding of interactions between opioids and xylazine as well as to elucidate factors contributing to the use of opioid/xylazine mixtures, which will help to drive the discovery of safe and effective treatments.