You’re working a red team overnight and a patient with opioid use disorder presents after a fall. He’s concerned about MSK pain and reports his last opioid use was this morning. You order some plain films and analgesia, and move to the next room. An hour later, you go back to discuss the imaging results and you barely recognize him.
He’s diaphoretic, tachycardic, and vomiting. You give him fluids, methadone, and zofran, but despite these treatments there’s no improvement. It looks like opioid withdrawal . . . but are you missing something? Is there more we can offer to help this patient? Let’s talk about it on this week’s Pharm & Cheese.
BACKGROUND
Since the early 2000s, alpha-2 agonists have been slowly infiltrating the illicit drug supply. Their muscle relaxing, analgesic, and sedative properties make enticing adulterants, stretching the drug supply while enhancing its effects. The best-known example here is xylazine (aka tranq), which was identified in the drug supply in the early 2000s. By 2023, xylazine was detected in nearly the entire illicit fentanyl supply in Philadelphia.6
Another alpha-2 agonist, medetomidine, a medication with no FDA-approved uses in humans, was first noted in Chicago in 2024. The Chicago department of public health reported findings from January 2024 - June 2025, noting that 8% of the sampled drug supply included xylazine while 6% included medetomidine.5 These adulterants have only risen in popularity since, making them relevant to the EM clinician.
ALPHA-2 AGONIST INTOXICATION
Alpha-2 agonists decrease the release of catecholamines, including epinephrine and dopamine, causing profound sedation along with bradycardia, hypothermia, hypotension, and occasionally respiratory depression. Given the overlapping toxidrome with opioids, these adulterants are tricky to identify. One clue that these adulterants are on board is if you see prolonged sedation and respiratory depression despite naloxone administration. Other clues suggesting medetomidine intoxication may include dose dependent mydriasis (rather than the classic miosis seen in pure opioid OD), hallucinations, extreme dry mouth, hypothermia, and tremors and myoclonus—of which this last finding can be seen in both overdose and withdrawal.2,4
Medetomidine is particularly potent compared to xylazine, with a substantially higher selectivity and affinity for alpha-2 receptors. Initially, stimulation of vascular smooth muscles causes vasoconstriction and elevated systemic vascular resistance with reflex bradycardia, but as the central sympathetic suppression takes over, persistent bradycardia and hypotension dominate the clinical picture.
As with most things in tox, treatment here is largely supportive. Most patients respond to fluids, but in rare cases you may have to break out the atropine and vasopressors. While naloxone will not reverse medetomidine, it is recommended in suspected severe overdose given common cross contamination in fentanyl and other opioid derivatives. Resolution of intoxication typically occurs over 3-6 hours.6
WOUNDS
I would be remiss if I didn’t mention the notorious xylazine-associated wounds here. These lesions are most commonly seen among those who inject, often developing at or distal to injection sites. However, even those who exclusively insufflate or smoke can get these wounds.1 The wound often starts as a dark discoloration before progression to a dry eschar, and eventual deep necrosis with exposed underlying structures.
It was previously thought that ischemia from vasoconstriction was the culprit here, but recent evidence suggests that xylazine disrupts skin integrity via epithelial kappa opioid receptors, potentially explaining why these wounds are unique to xylazine and not seen with other alpha-2 agonists.3
Management ranges from local wound care, to debridement, possible antibiotics, and sometimes amputation in the worst cases. Thankfully, in those who manage to quit, the majority of cases can fully heal.7,8
WITHDRAWAL
With its short half life, withdrawal from medetomidine can progress rapidly, within just 4-6 hours from last use! This is much faster than opioid withdrawal and can clue you in to the diagnosis. Initially patients may experience anxiety, tremors, and flushing. This is followed by emesis, lots of emesis, that’s unfortunately often refractory to treatment. As it progresses, patients may develop severe tachycardia and hypertension, and in the worst cases delirium, PRES, or cardiomyopathy. In comparison, drugs with xylazine adulterants seem to have much less severe withdrawal profiles.6
TREATMENT
Treating medetomidine withdrawal can be quite challenging. For refractory emesis, dopamine agents will likely be your friend as zofran often fails. Consider Droperidol 1.25 - 2.5mg IV/IM or Prochloperazine 10mg IV/IM. Make sure to monitor QTc as you go!
The cornerstone of treatment here is to replace the alpha-2 agonists you’ve lost. Clonidine is often the go-to, but high doses may be required to achieve a response. Published protocols as linked here, recommend Clonidine 0.3mg every 20 minutes for up to 2-3 doses in the first hour (max 0.6 - 0.9mg), holding for hypotension. Afterwards, additional Clonidine can be administered based on severity. Consider Clonidine 0.1–0.2 mg orally 3–4 times daily as needed, held for BP <90/60 mmHg or HR <60 bpm.Transdermal clonidine can be started early, but note that it takes 2-3 days to achieve therapeutic levels. Guanfacine 2mg q8 hours can be added as adjunctive therapy. Utilize benzos prn for agitation.
If all else fails, fight fire with fire. Severe cases may require a call to our ICU colleagues for a dexmedetomidine, aka Precedex, drip.6
CONCLUSION
So you give your patient some droperidol which improves the emesis long enough to tolerate some PO clonidine, but his vital signs fail to improve as he becomes increasingly more agitated. Soon enough he’s headed to the unit on a Precedex drip where he slowly improves over the next few days. Just remember the next time you have a patient with a gnarly wound or suspected opioid withdrawal that comes on suddenly and isn’t responding to the typical treatments, consider these sneaky adulterants may just be the culprits.
Sources
Jawa R, Mackin S, Zheng Y, et al. Drug use practices and wound care experiences in the age of xylazine adulteration. Drug Alcohol Depend. 2024;263:112390. doi:10.1016/j.drugalcdep.2024.112390.
Sue, K.L. and Hawk, K. (2024), Clinical considerations for the management of xylazine overdoses and xylazine-related wounds. Addiction, 119: 606-608. https://doi.org/10.1111/add.16388
Robertson, T. F., Horn, A., Smith, F. M., & Huttenlocher, A. (2026). Evidence that xylazine disrupts skin homeostasis by acting on epithelial cells through the kappa opioid receptor. Disease Models & Mechanisms, 19, dmm052600. https://doi.org/10.1242/dmm.052600
Watkins, J. M., Hahn, R., Dempsey, M., & Hohmann, A. G. (2026). Xylazine exacerbates fentanyl-induced respiratory depression and prevents rescue by naloxone in mice. Psychopharmacology. https://doi.org/10.1007/s00213-026-07031-w
Chicago Department of Public Health. Carfentanil Identified in Chicago's Drug Supply. Health Alert Network; August 8, 2025. Accessed June 9, 2026. https://www.chicagohan.org
Lynch MJ, Pizon AF, Yealy DM. Emergence of medetomidine in the illicit drug supply: implications for emergency care and withdrawal management. Ann Emerg Med. 2026;87(6):709-716. doi:10.1016/j.annemergmed.2025.12.004.
Vaile, J, Connolly, W, Zavitsanos, A, et al. Xylazine-Associated Wounds: A Scoping Review of Clinical Presentation and Management. Adv Skin Wound Care. 2026;39(4):E185-E193. doi:10.1097/ASW.0000000000000436.
Makhoul, A. T., Morales, C. Z., Card, E. B., Goldshore, M. A., Morris, J. B., Levin, L. S., Wink, J. D., Fischer, J. P., Lin, I. C., & Kovach, S. J. (2026). Surgical Management of Xylazine-Associated Wounds: A Retrospective Review and Algorithmic Approach. Annals of Plastic Surgery, 96(5S), S359–S364. https://doi.org/10.1097/SAP.0000000000004616
Authored by Dr Samson Frendo (PGY4) and Dr Theresa Kim (EM faculty, toxicologist)