(61) Opioid Withdrawal and Autonomic Complications Associated with Medetomidine Adulteration

Background & Introduction: Medetomidine, a veterinary sedative not approved for human use, is an emerging adulterant in the illicit drug supply reported by our Philadelphia street drug checking programs (1) and detected in a series of patients with overdose in May 2024(2). The hallmark of these medetomidine overdose presentations was persistent somnolence despite naloxone and severe bradycardia (2). Between September 2024-January 2025, an increasing number of patients presented to 3 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). 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 syndrome (3,4). We aim to characterize this emerging clinical syndrome of opioid withdrawal complicated by severe autonomic findings that may be attributable to an abstinence syndrome associated with escalating medetomidine adulteration of the regional fentanyl supply.

Methods: Three health systems collaborated in data collection to describe this syndrome. We reviewed the medical records of a convenience sample of patients presenting between September 2024-January 2025 who were identified by addiction medicine and/or medical toxicology faculty at each institution. Patients were selected on the basis of an atypical and severe course of opioid withdrawal requiring hospitalization and charts were abstracted using a consensus derived data tool. Data elements included demographics, hospital course, ICU admission, intubation, dexmedetomidine use, peak vital sign abnormalities of BP (mm Hg) and heart rate (beats/min) and disposition.

Results: In total, 165 patient encounters were assessed across the three hospitals, with 55 from hospital A, 48 from hospital B and 62 from hospital C. The median age of the patient was 38 years [IQR 35-43], 70% identified as male. Patients identified as 62% White, 16% Black, 13% Hispanic and 7% other. 90% were admitted to the ICU at some point during their hospitalization, 23% of patients required intubation and mechanical ventilation and 83% of patients were treated with dexmedetomidine. The median max HR was 145/min [IQR=132-156], max median systolic BP was 195mmHg [IQR: 175-215], and the max median diastolic BP was 122 mmHg [IQR:109-136]. 45% of patients were discharged from the hospital, 32% left by patient directed discharge, 13% were transferred to rehabilitation and 10% were discharged in law enforcement custody. The others remain in the hospital at the time of this submission. Routine testing by hospital laboratories confirmed universal fentanyl exposure. Medetomidine metabolites have been detected via LC-MS/MS in urine samples performed in a select number of patients.

Conclusion & Discussion: We collaboratively describe an emerging phenomenon of opioid and suspected medetomidine withdrawal requiring hospitalization. Distinct findings include opioid withdrawal complicated by severe hypertension and tachycardia frequently requiring ICU care and intubation. Many patients received empiric dexmedetomidine infusions due to the pharmacologic similarity with medetomidine, in addition to full opioid agonists and opioid withdrawal adjunctive medication. The onset of this syndrome parallels the emergence of medetomidine in the fentanyl supply and has findings similar to a dexmedetomidine withdrawal syndrome. We acknowledge that occult concomitant benzodiazepine or alcohol withdrawal could account for the autonomic symptoms in a small number of these patients, although patient history and timelines did not support this. The use of dexmedetomidine and other sedation or specific antihypertensive agents requires additional study.

References: References
1) Franklin, F., Teixeira, D., Silva, D., & Laboy, C. (2024). Hospitals and behavioral health providers are reporting severe and worsening presentations of withdrawal among people who use drugs (PWUD) in Philadelphia. Division of Substance Use Prevention and Harm Reduction. Retrieved from https://hip.phila.gov/document/4874/PDPH-HAN-00444A-12-10-2024.pdf/
2) Kashyap, N, Glodjo T, Wong M, McKeever R, Hart B, Murphy LT. Emergence of Marked Bradycardia After Fentanyl Overdose in Philadelphia. North American Congress of Clinical Toxicology (NACCT) 2024 Abstracts, Clin Toxicol. 2024;62:sup2:1–174.

3) Pathan S, et al: Evaluation of dexmedetomidine withdrawal in critically ill adults. Journal of Critical Care 2021; 62:19-24

4) Bouajram RH, Bhatt K, Croci R, Baumgartner L, Puntillo K, Ramsay J, Thompson A. Incidence of Dexmedetomidine Withdrawal in Adult Critically Ill Patients: A Pilot Study. Crit Care Explor. 2019 Aug 9;1(8):e0035.