Medetomidine, a veterinary α2-adrenergic agonist, has recently emerged as an adulterant in the non-medical opioid supply, yet human exposure has remained poorly characterized. We conducted a pragmatic retrospective cohort analysis utilizing chart review and liquid chromatography–tandem mass spectrometry (LC-MS/MS) toxicology testing on available urine samples from patients presenting to two hospitals in Philadelphia, PA, who fit two clinical phenotypes, intoxication or withdrawal. Samples also underwent glucuronidase pre-treatment to assess impact on the yield of medetomidine and xylazine metabolite detection. Testing identified universal exposure to medetomidine (58/58 samples) via the 3-hydroxy-medetomidine (3-OH-M) metabolite, post glucuronidase treatment and variable xylazine exposure (40/58 samples). Importantly, 32% of medetomidine exposures would have been missed without enzymatic pre-treatment. Patients exhibited two distinct clinical phenotypes: intoxication, characterized primarily by sedation; bradycardia; and often hypotension, and withdrawal, presenting with life-threatening tachycardia; hypertension and often encephalopathy. Notably, clinical phenotype correlated with urinary concentrations of 3-OH-M but not xylazine. These findings underscore the critical need for heightened clinical awareness and need for contemporaneous toxicologic screening mechanisms for medetomidine exposure, emphasizing its distinct clinical presentations and the potential public health implications posed by its widespread adulteration in illicit opioids.

Background/Objectives: Philadelphia has experienced a surge in illicit fentanyl adulterated with alpha-2 agonist sedatives. Initially, xylazine (“tranq”) was the predominant adulterant, and a novel 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. To assess whether a previously effective withdrawal management protocol retained efficacy after the emergence of medetomidine as the primary fentanyl adulterant in a community. 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 April 2025. Patients were divided into the xylazine era (September 2022–July 2024) and medetomidine era (August 2024–April 2025). The primary outcome was a 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, as well as the impact of a revised treatment protocol. Results: Among 1269 encounters with full data, 616 occurred during the xylazine era and 770 during the medetomidine era. Median COWS reduction was greater in the xylazine group (−9.0 vs. −4.0 points, p < 0.001), with more patients achieving symptom relief (COWS ≤ 4: 65.6% vs. 14.2%, p < 0.001). ICU admission occurred in 8.5% of xylazine era patients and 16.8% of medetomidine era patients (p < 0.001). Rates of AMA were higher during the medetomidine era as well (6.5% vs. 3.6%) (p = 0.038). Revision of treatment protocols showed promise. Conclusions: The protocol was significantly less effective during the medetomidine era, though a protocol change may be helping. Findings highlight the need to adapt withdrawal treatment protocols in response to changes in the illicit drug supply.

Medetomidine, a potent central acting α2 agonist, has emerged as a fentanyl adulterant in the non-medical opioid supply. Its use has been linked to a novel withdrawal syndrome that is often resistant to conventional treatment protocols. Four cases are presented exemplifying extreme, but increasingly common forms of this withdrawal syndrome. A literature review is provided demonstrating both the paucity of available literature as well as potential avenues for treatment and future research. As adulterants continue to proliferate in the illicit drug supply, clinicians should anticipate atypical withdrawal phenotypes and consider early intervention.

Background: Mitragynine pseudoindoxyl (MP) is a semi-synthetic kratom metabolite increasingly sold online and over-the-counter, marketed misleadingly as “kratom” or “7-OH,” despite lacking FDA approval and safety data in humans. Methods: This case report describes a 44-year-old male with polysubstance use history who developed opioid withdrawal symptoms after regular MP use (400 mg daily for pain management following neck injury). Vital signs, alcohol and opioid withdrawal scores and clinical outcomes were recorded. Results: The patient presented exhibiting symptoms of moderate opioid withdrawal in the absence of other opioid use. A buprenorphine macro-induction protocol was initiated. Following pre-treatment using chlorpromazine as an anti-emetic and diazepam to treat concomitant alcohol withdrawal, 32 mg buprenorphine were provided (16 mg × 2) on day one, with subsequent maintenance dosing and adjunctive medications. The patient demonstrated significant symptomatic improvement with decreased COWS scores and expressed interest in long-acting injectable buprenorphine maintenance therapy. Discussion: This represents the first documented case of suspected MP withdrawal successfully managed with buprenorphine macro-induction, demonstrating the potential efficacy of this approach for novel semi-synthetic kratom metabolites when standard withdrawal management protocols are insufficient. Further studies should evaluate long term outcomes and validate findings.

Background: Despite the emergence of medetomidine as the dominant adulterant in Philadelphia’s illicit opioid supply, coordinated public health responses are limited or non-existent in the literature. Thus, we summarize a recent Summit in Philadelphia of outpatient and inpatient service providers who specialize in the care of persons who use drugs to discuss medetomidine response readiness and building ongoing community readiness for potential destabilizing drug supply changes. Purpose: Describe a public health intervention that distributed information about practices across health care settings and mobilized key informants to identify and address barriers to treatment. Methods: Descriptive summary of the in-person Summit organized by the Division of Substance Use Prevention and Harm Reduction at the Philadelphia Department of Public Health and the Health Federation of Philadelphia’s Substance Use Response, Guidance, and Education program to review cases of medetomidine-associated withdrawal across outpatient, emergency department, hospital, and substance use treatment settings. Results: The authors reviewed the insights from attendees and grouped them into nine themes: overdose response, clinical recognition of withdrawal, monitoring withdrawal, treatment approach, patient care navigation, workforce development, testing and surveillance, mobile outreach, and reimbursement. The authors subsequently developed twelve summative recommendations to guide further public health interventions in Philadelphia and other communities where medetomidine may become a common adulterant in the drug supply. Conclusion: The insights gained regarding medetomidine withdrawal management will be shared with community organizations providing services to people who use drugs in Philadelphia and clarify specific barriers and areas for ongoing support. Other communities experiencing shifts in drug supply may benefit from this knowledge and similar information sharing colloquiums.

Emergency Department (ED) screening for substance use disorder (SUD) is limited by a lack of standardization and challenging clinical environments. Existing tools may be focused on informing clinicians rather than supporting patients. This study assessed a novel single-question screening tool to identify patients at risk of withdrawal and link those with opioid use disorder (OUD) to standardized treatment. A cross-sectional, retrospective study was conducted at two urban EDs in Philadelphia, PA, using electronic health record data between November 8, 2022, and February 28, 2025. Patients were included in the study if they arrived ambulatory to the emergency department, were aged 18 years and older, and able to answer screening questions. Demographic, encounter, screening response, disposition, and withdrawal order set utilization data were obtained. Data analysis was primarily descriptive, and bivariate associations were examined using odds ratios to assess the strength of relationships between key variables. 106,212 patient encounters met the inclusion criteria during the study period. 70,603 (66.5 %) of those patients answered the screening question. 4686 (6.6 %) patients answered affirmatively to a concern over withdrawal. 1512 patients (2.1 %) received medications from the opioid withdrawal order set, including 186 patients who did not express a withdrawal concern. Screening positive for a withdrawal concern was associated with a 2.28-fold increase in the odds of patient-directed discharge from the ED (OR = 2.28, 95 % CI = 2.10-2.47, p < .001). Patients who received the withdrawal protocol had significantly lower rates of patient-directed discharge (9.1 %) compared to those who screened positive for withdrawal overall (17.8 %) (OR = 0.41, 95 % CI: 0.33-0.51, p < .001). Use of a single-question ED screening tool to identify individuals in withdrawal and link them to withdrawal treatments may be an effective tool. Additional studies should assess barriers to screening and withdrawal treatment, and long-term outcomes of those who screen positive for withdrawal concern in the ED.