Medetomidine
Medetomidine, an alpha-2 agonist not approved for human use, is an emerging drug adulterant that was found in 72% of illicit opioid samples by Philadelphia street drug checking programs in Q4 2024. During the same time frame, detection of xylazine (previously the most common adulterant), decreased from 98% to just 31% of samples. This represents a large shift in the regional opioid supply, one which has caused significant changes in the presentation of patients experiencing opioid overdose and withdrawal. It is important to note that fentanyl remained present in 100% of tested samples during this time period.
- used in veterinary sedation/analgesia
- an equal mixture of two enantiomers, dexmedetomidine and levomedetomidine (inactive)
- highly selective and potent alpha-2 agonist (100x more than xylazine)
- known to cause bradycardia and hypotension in animals
Medetomidine Overdose
Medetomidine was first noted to be clinically significant in a cluster of overdoses at several Philadelphia hospitals in Spring 2024. A case series from Temple University Hospital describes patients who were brought to the ED by ambulance with persistent lethargy (despite naloxone by EMS or bystanders) and bradycardia (heart rates 20-50 beats/min). Details of these overdoses involving medetomidine can be reviewed below:
- All patients were male, ages 30-61 years old
- Most patients were given naloxone by bystanders in the field, which did not successfully reverse depressed mental status. Only one patient required naloxone to reverse respiratory depression, which was suspected to be an effect of fentanyl.
- Hypotension was uncommon, only seen in 18% of cases.
- In the cases involving hypotension, vasopressors were not required and blood pressure normalized with IV fluids alone.
- After reversal of hypoxia and respiratory depression, patients were noted to be persistently bradycardic with sustained heart rates below 50bpm.
- Atropine was never required but was given once by EMS
- Patients with persistent bradycardia had serum testing to confirm medetomidine, fentanyl and xylazine concentrations
Courtesy of Temple University Health: Neena Kashyap, MD, Talia Glodjo, MD, Matthew Wong, MD, Rita McKeever MD, Brendan Hart MD, and Lauren Murphy
See table below for details of this case series:
Courtesy of Temple University Health: Neena Kashyap, MD, Talia Glodjo, MD, Matthew Wong, MD, Rita McKeever MD, Brendan Hart MD, and Lauren Murphy
Medetomidine Withdrawal
Between September 2024-January 2025, an increasing number of patients presented to three health systems in Philadelphia with fentanyl withdrawal complicated by profound autonomic signs in the absence of benzodiazepine, barbiturate, or alcohol use. All patients needed inpatient hospitalization and the majority were managed in an intensive care unit (ICU). Nearly all required treatment with dexmedetomidine.
The syndrome parallels the onset and case descriptions of patients who develop dependence (or withdrawal from) the related enantiomer, dexmedetomidine, with a resultant rebound autonomic withdrawal syndrome.
Key components of this new drug withdrawal syndrome that is suspected to be secondary to medetomidine withdrawal include:
- severe hypertension and tachycardia (complications such as PRES and NSTEMI have been observed in some patients)
- intractable nausea and vomiting
- anxiety and agitation
- tremor without clonus or hyperreactivity
Importantly, these findings have been refractory to increasing doses of opioids (e.g. hydromorphone, methadone, oxycodone, fentanyl), sedatives (e.g. lorazepam, diazepam, midazolam, phenobarbital, propofol, haloperidol, droperidol), and adjunctive opioid and xylazine withdrawal medications (ketamine, clonidine, tizanidine, ondansetron).
Clinical Recommendations for Managing Medetomidine Withdrawal
You can download our ICU medetomidine-fentanyl withdrawal management strategy here.
Note: Availability of different medications depends on level of care; e.g. dexmedetomidine is typically available only in the ED and ICU settings. Strategy and approach may vary depending on setting.
(1) Long and short-acting opioids
Rationale: High quantities of fentanyl remain prevalent in the illicit opioid supply and opioid withdrawal remains a primary concern
(2) Alpha-2 agonist (clonidine, tizanidine, dexmedetomidine)
Rationale: Drug checking reports a high prevalence of medetomidine, a potent alpha-2 agonist, in the illicit opioid supply
Patients who are tolerating oral medications can first be treated with clonidine +/- tizanidine. Clonidine patches can be considered for those who are not tolerating oral medications, though it should be noted that dosing of individual patches is low and onset of action is delayed. Escalation to dexmedetomidine, which has been used to treat dexmedetomidine withdrawal and has been effective in managing critically ill patients with medetomidine withdrawal, may be necessary if the patient is not tolerating oral medications or if clonidine/tizanidine is ineffective.
(3) Ketamine
Rationale: Regionally supported adjunctive in patients experiencing fentanyl and/or xylazine withdrawal
(4) Aggressive antiemetic therapy (olanzapine, prochlorperazine, thorazine)
Rationale: Intractable nausea and vomiting that is refractory to traditional first-line agents such as ondansetron has been observed in patients with medetomidine withdrawal. These agents may also be helpful in managing agitation.
(5) Antihypertensive agents
Rationale: Severe hypertension may persist despite aggressive treatment with the above therapies. End-organ dysfunction (i.e. hypertensive emergency) has been common, possibly due to a low prevalence of chronic hypertension in this patient population. Early initiation of antihypertensive agents is warranted if the patient has signs of end-organ dysfunction.
(6) Additional adjunctive medications for opioid withdrawal (hydroxyzine, imodium, acetaminophen, NSAIDs, etc.)
Rationale: High quantities of fentanyl remain prevalent in the illicit opioid supply and opioid withdrawal remains a primary concern
References
de Andrade Horn P, Berida TI, Parr LC, Bouchard JL, Jayakodiarachchi N, Schultz DC, Lindsley CW, Crowley ML. Classics in Chemical Neuroscience: Medetomidine. ACS Chem Neurosci. 2024 Nov 6;15(21):3874-3883. doi: 10.1021/acschemneuro.4c00583. Epub 2024 Oct 15. PMID: 39405508; PMCID: PMC11587509.
Sinclair MD. A review of the physiological effects of alpha2-agonists related to the clinical use of medetomidine in small animal practice. Can Vet J. 2003 Nov;44(11):885-97. PMID: 14664351; PMCID: PMC385445.
https://hip.phila.gov/document/4874/PDPH-HAN-00444A-12-10-2024.pdf/
