The Impact of Xylazine on Overdose Response

Xylazine is a non-scheduled, centrally-acting alpha 2 agonist that is structurally similar to clonidine.¹ It is approved for use exclusively in veterinary medicine, primarily as a horse and large animal tranquilizer, resulting in profound sedation and muscle relaxation.

Xylazine may impact the response to naloxone and can lead to severe wounds in individuals who are using unregulated substances. Additionally, pharmacists and health care providers should be familiar with the management of xylazine overdose and withdrawal.

In recent years, xylazine has increasingly been found as an active cut in the unregulated drug supply, including heroin, fentanyl, cocaine, methamphetamine, and counterfeit prescription pills.² Although not a controlled substance federally, several states have moved to schedule xylazine.

Originally limited to Philadelphia and commonly referred to as “tranq” on the streets, xylazine has now been discovered in unregulated substances throughout the United States. Between 2010 and 2015, only 2% of opioid overdose deaths in Philadelphia also involved xylazine, and by 2019, that number had increased to 1 in 3.³

Sedation with xylazine can be profound and last for 8 hours or longer. People experiencing an overdose from unregulated substances often have a mixture of opioids, stimulants, sedatives, and other drugs in their system.

For example, in May 2022, a baggie sold as fentanyl for injection in Providence, Rhode Island, was found to contain fentanyl, acetylfentanyl, acrylfentanyl, para-fluorofentanyl, xylazine, tramadol, methadone, phenacetin, ketamine, acetaminophen, lidocaine, nicotine, and caffeine.⁴ Naloxone will work to restore breathing from opioid-induced respiratory depression, but will not reverse the effects of xylazine or other sedatives.

This may affect overdose response counseling provided by pharmacists as the focus of naloxone administration should be to restore breathing. Naloxone should not be dosed more frequently than every 2 minutes, nor after a person begins breathing in an effort to induce responsiveness, as excessive doses of naloxone may worsen precipitated withdrawal and vomiting. People experiencing extended sedation should be placed on their side in the recovery position, to minimize the risk of aspiration from emesis, and provided with soft material padding on bony areas in contact with the ground such their head, hips, ankles, shoulders, knees and/or heels.⁵

Deep necrotic wounds from tissue hypoxia, typically located on the outer aspects of the forearms, thighs and/or shins, have been associated with xylazine use. These wounds are caused by peripheral vasoconstriction and are not directly associated with the site of drug injection.

Signs of xylazine toxicity include bradycardia, miosis, sedation and hypotension. No antidote is currently available, and xylazine overdose should be treated with supportive measures to maintain blood pressure, airway patency, and heart rate.

Atropine, low-dose epinephrine, oxygen/intubation, fluid, and/or norepinephrine may be employed as supportive measures for xylazine overdose.⁶ Xylazine withdrawal appears similar to that seen with benzodiazepines, with the potential for prolonged anxiety and irritability, and management may include dexmedetomidine, clonidine, or tizanidine.

References

1. Xylazine - United States Department of Justice. February 2021. Accessed October 28, 2022. https://www.deadiversion.usdoj.gov/drug_chem_info/Xylazine.pdf.
2. National Institute on Drug Abuse.Xylazine. Accessed October 28, 2022. https://nida.nih.gov/research-topics/xylazine
3. Kounang N. How Xylazine, a veterinary tranquilizer, is making overdoses even riskier. CNN. Published March 17, 2022. Accessed October 28, 2022.https://www.cnn.com/2022/03/17/health/xylazine-tranq-overdose/index.html
4. Local Drug Sample Testing Update. Accessed October 28, 2022. https://preventoverdoseri.org/local-drug-supply.
5. Johnson J, Pizzicato L, Johnson C, Viner K. Increasing presence of xylazine in heroin and/or fentanyl deaths, Philadelphia, Pennsylvania, 2010-2019. Inj Prev. 2021;27(4):395-398. doi:10.1136/injuryprev-2020-043968
6. Xylazine. Michigan Department of Health and Human Services. Published 2019. Accessed July 28, 2022. https://www.michigan.gov/-/media/Project/Websites/mdhhs/Folder3/Folder68/Folder2/Folder168/Folder1/Folder268/Xylazine03042019.pdf?rev=5ac99b3753314429889096f654978fd1