Decreased Effectiveness of a Novel Opioid Withdrawal Protocol Following the Emergence of Medetomidine as a Fentanyl Adulterant

Background: Philadelphia has experienced a surge in illicit fentanyl adulterated with alpha-2 agonist sedatives. Initially, xylazine (“tranq”) was the predominant adulterant, and a multimodal withdrawal protocol was effective at mitigating symptoms. However, since mid-2024, medetomidine—a more potent sedative—has largely supplanted xylazine. Clinicians have reported more severe, treatment-resistant opioid withdrawal during this transition. Objectives: To assess whether the previously effective withdrawal management protocol retained efficacy after the emergence of medetomidine. Methods: We conducted a retrospective cohort study of patients receiving protocol-based opioid withdrawal treatment at two emergency departments in Philadelphia between September 2022 and March 2025. Patients were divided into the xylazine era (Sept 2022–July 2024) and medetomidine era (Aug 2024–Mar 2025). The primary outcome was change in Clinical Opioid Withdrawal Scale (COWS) score from pre- to post-treatment. Secondary outcomes included rates of discharge against medical advice (AMA) and ICU admission. Results: Among 1269 encounters, 616 occurred during the xylazine era and 653 during the medetomidine era. Median COWS reduction was greater in the xylazine group (−9.0 vs −5.0 points, p < 0.0001), with more patients achieving symptom relief (COWS ≤ 4: 65.6% vs 14.2%, p < 0.0001). ICU admission occurred in 10.6% of xylazine-era patients and 25.7% of medetomidine-era patients. AMA rates were higher during the medetomidine era (6.5% vs 3.6%). Conclusions: The protocol was significantly less effective during the medetomidine era. Findings highlight the need to adapt withdrawal treatment protocols in response to changes in the illicit drug supply.