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Investigation and Outcomes

During fall 2024, in response to emerging awareness of a newly recognized medetomidine withdrawal syndrome, addiction medicine and medical toxicology faculty members at three Philadelphia health systems (health systems A, B, and C) began maintaining a list of patients identified with the syndrome, including those they had helped care for or provided consultation for, as well as patients referred by other health care providers. The faculty members reviewed electronic health records of patients who were admitted to the three health systems during September 1, 2024–January 31, 2025, and whose withdrawal syndrome was characterized by severe signs and symptoms that were not resolved by established treatment protocols for fentanyl and xylazine withdrawal. Overall, 165 patients were identified who demonstrated one or more signs or symptoms such as agitation, anxiety, severe hypertension, tachycardia, tremor without clonus or hyperreflexivity, and vomiting, resistant to increasing doses of opioids (e.g., fentanyl, hydromorphone, methadone, or oxycodone), sedatives (e.g., diazepam, droperidol, haloperidol, lorazepam, midazolam, phenobarbital, or propofol), and adjunctive opioid and xylazine withdrawal medications (clonidine, ketamine, olanzapine, ondansetron, or tizanidine) (2). Median age was 38 years (IQR = 33–43 years). This evaluation was reviewed and approved by the institutional review boards of health systems A, B, and C.

Among the 165 patients, 150 (91%) required intensive care unit (ICU) care, including 39 (24%) who received endotracheal intubation (Table). A total of 137 (83%) patients were treated with and responded to dexmedetomidine* infusion, a drug eventually recognized as potentially effective; medetomidine is an enantiomer^† of dexmedetomidine, and prolonged dexmedetomidine exposure can induce a withdrawal syndrome manageable with controlled weaning from the drug. Traditional dosages of dexmedetomidine (0.2–1.5 μg/kg/hr) (3) were used and titrated to control symptoms or sedate patients with intubation. In a majority of patients requiring dexmedetomidine, the drug was titrated to a maximum dosage of 1.5 μg/kg/hr. Duration of infusion varied, depending on the patient. Use of oral alpha-2 agonists, such as clonidine, was limited because of vomiting. Patients were also treated with antihypertensive medications titrated to blood pressure levels ≤180/120 mm Hg. Complications secondary to severe hypertension or tachycardia included altered mental status with computed tomography (CT)- or magnetic resonance imaging (MRI)-documented posterior reversible encephalopathy syndrome^§ in three patients, and non-ST elevation myocardial infarction (NSTEMI) secondary to demand ischemia (insufficient blood supply to meet the heart’s oxygen demand) with positive high-sensitivity troponin, indicating potential damage to the heart muscle in a substantial number of patients^¶. Findings of severe withdrawal syndromes typically associated with other sedatives (alcohol, barbiturate, or benzodiazepine), such as seizures or hallucinations, were infrequent. Routine testing of specimens from all 165 patients by hospital laboratories confirmed universal fentanyl exposure. Testing for medetomidine or its metabolites using liquid phase chromatography with mass spectrometry was available at health system A; all 55 patients treated at health system A received a positive test result for 3-hydroxy medetomidine.

Preliminary Conclusions and Actions

The syndrome described in this report is similar to that described among ICU patients with days-long exposure to dexmedetomidine, an enantiomer of medetomidine, who experience an autonomic withdrawal syndrome with vomiting and agitation when dexmedetomidine is discontinued (4,5). In the patients described in this report, these signs and symptoms were not resolved by increasing doses of medications previously effective in managing fentanyl and xylazine withdrawal; however, they were responsive to dexmedetomidine, as described in the management of dexmedetomidine withdrawal (4,5). Health care providers and public health agencies need to be aware of this life-threatening withdrawal syndrome because it can require substantial escalations in care compared with the typical opioid and xylazine withdrawal syndromes. Public health agencies should consider testing for medetomidine in their regional drug supplies.