Kory S. London

Drug supply monitoring programs commonly describe novel substances in binary terms: a substance is either present or absent, and its presence alone defines risk. Medetomidine, a veterinary imidazole alpha-2 agonist anesthetic, has been detected as an adulterant in illegally manufactured fentanyl across the United States, and reports of medetomidine toxicity have been similarly widespread. Yet its severe withdrawal syndrome has emerged in communities more gradually, with many unaffected. The environmental-health concept of dose-response offers a plausible explanation for this geographic mismatch. Some harms follow a linear relationship where any exposure carries risk, and that risk rises in proportion to dose. Opioid overdose and medetomidine toxicity fit this pattern. Others may follow a threshold relationship, appearing only once exposure surpasses a critical level. Medetomidine withdrawal fits the threshold pattern because tolerance, and therefore withdrawal, require sustained exposure of sufficient dose and duration. Where it has appeared, the withdrawal syndrome has strained local hospital systems. Preliminary review of hospital billing data and community drug-checking results suggests that hospital utilization rose only after medetomidine’s prevalence and potentially concentration in the local supply crossed a threshold. Current evidence supporting application of this dose-response theory to medetomidine withdrawal is hypothesis-generating. Further work linking drug-supply prevalence and concentration data to well-defined, drug-specific clinical outcomes could support a surveillance system that lets public health and hospital stakeholders anticipate drug-related harms before they become widespread, using evidence-based thresholds.

Objectives: Medetomidine, a veterinary alpha-2-adrenergic agonist, has emerged as a dominant adulterant in the Philadelphia illicit opioid supply, producing a severe withdrawal syndrome requiring significant inpatient support. We developed an intravenous dexmedetomidine protocol for intermediate care units (IMCU) and describe the safety and feasibility of delivering this care outside the intensive care unit (ICU). Methods: A retrospective descriptive analysis of patients who received dexmedetomidine under an IMCU orderset for alpha-2 withdrawal was conducted at two urban medical centers in Philadelphia, PA, from April 2024 to February 2026. Encounters were classified as protocol-concordant or protocol-discordant by dosing and level of support; the concordant cohort was primary. Variables included demographics and addiction consult status. Outcomes included length of stay (hospital and IMCU), ICU admission, rapid response team activation, intubation, and discharge disposition. Results: Of 487 encounters, 449 (92.2%) were protocol-concordant and 38 (7.8%) protocol-discordant. All subsequent results describe the protocol-concordant cohort (n=449) unless otherwise noted. The cohort was predominantly male (58.1%) with a mean age of 41.8 years. Median hospital stay was 6.0 days and median IMCU stay was 2.2 days. ICU admission was not required in 50.1% of encounters. Rapid response team activation occurred in 38 encounters (8.5%), the majority for escalating withdrawal management. Patient-directed discharge occurred in 41.4% of encounters. Conclusions: An IMCU dexmedetomidine protocol deployed across seven monitored units at 2 hospitals offers a replicable framework for managing medetomidine withdrawal while potentially mitigating critical care capacity challenges. Identified opportunities include modification of titration and dosing strategies and further investment in addiction consult infrastructure.

Purpose of Review: Medetomidine is a veterinary α2-adrenergic agonist that has been an adulterant of illicitly manufactured opioids since 2022. We review its pharmacology, detection, intoxication, withdrawal, and management, and assess why severe withdrawal has emerged in some regions but not others. Recent Findings: Medetomidine has spread through North American drug markets yet evades most toxicology testing. Roughly two hundred times more potent than xylazine, with greater α2 selectivity and imidazoline-1 activity, it causes intoxication resembling other α2 agonists: sedation and bradycardia. The dominant clinical problem is withdrawal: autonomic dysregulation, intractable vomiting, and encephalopathy frequently requiring intensive care. Treatment requires multimodal α2-agonist therapy, often escalating to parenteral dexmedetomidine. Where it is established, withdrawal encounters and hospital admissions have risen. Summary: We hypothesize that both local prevalence and drug concentration determine where withdrawal appears. This syndrome exposes gaps in both assessment and treatment; prospective multicenter research, a validated withdrawal instrument, and integrated addiction-critical care models are needed.

Background: The rapid emergence of alpha-2 agonist adulterants (xylazine, medetomidine) in some illicit fentanyl supplies has transformed opioid withdrawal presentations and introduced challenges with induction of medications for opioid use disorder (MOUD). This study compared outcomes of a standardized opioid withdrawal order set across 2 emergency departments with differing operational profiles, stratified by the predominant adulterant in the regional fentanyl supply. Methods: Retrospective analysis of all encounters utilizing a standardized withdrawal order set at an academic referral center and a community hospital in Philadelphia, PA, from September 2022 through December 2025. Encounters were stratified into xylazine-predominant (September 2022 through July 2024) and medetomidine-predominant (August 2024 through December 2025) eras. The primary outcome was the rate of premature departure disposition. Secondary outcomes included MOUD receipt in the emergency department and clinical presentation patterns. Results: A total of 3877 encounters were included (3086 academic; 791 community). Monthly visits more than doubled across the era transition at both sites. Withdrawal-related chief complaints increased from 16.2% to 42.7%, with a corresponding shift in primary diagnosis toward opioid withdrawal. Premature departure rates did not differ across eras, but were higher at the academic center (7.4% vs 3.3%; adjusted OR 2.40, 95% CI 1.58-3.64) and varied significantly by arrival time, with evening and overnight arrivals showing higher rates ( P = .006). Overall MOUD receipt declined from 46.8% to 27.9% (OR 2.27, P < .001) across the era transition. Conclusions: Encounters for withdrawal treatment surged during a period of drug supply adulteration. Increased visits and a decline in MOUD uptake coincided with medetomidine emergence. Premature departures in this cohort were most associated with operational factors, including treatment site and arrival time, and not era.

Objectives: To quantify the impact of the adulterated fentanyl supply, through the eras of xylazine and medetomidine predominance, on critical care charges associated with treatment of opioid withdrawal. Methods: A longitudinal retrospective analysis was conducted at 2 intensive care units (ICUs) in Philadelphia, PA, USA, from April 1, 2017, to September 30, 2025. Primary outcomes included median per quarter and per patient charges and median quarterly ICU admissions with a primary or secondary ICD-10 diagnosis of opioid withdrawal (F11.23) from Q2 2017 to Q3 2025. These dates were correlated with quarterly drug supply adulterant prevalence reports by the Philadelphia Department of Public Health (PDPH). Secondary outcomes included ICU length of stay. Results: Median quarterly ICU charges for F11.23 increased from $1,383,688 (1,138,614–1,602,562), during the period when the drug supply only included fentanyl (BX), to $2,883,659 (2,625,205–3,466,314) during the period of xylazine dominance (XE), to $17,168,020 (11,302,464–19,963,551) (H=23.50, P P =0.167). Conclusions: The adulteration of synthetic opioids with medetomidine was associated with a dramatic increase in ICU admissions and charges related to opioid withdrawal diagnoses. These changes represent a substantial public health challenge that may require systematic changes to health system resource allocation and withdrawal protocols.

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: 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 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. 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 x 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 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.

Introduction: Take-home naloxone (THN) programs in emergency departments (ED) can reduce opioid overdose deaths by providing naloxone directly to at-risk patients before discharge. However, sustainable models that integrate reimbursement and workflow alignment remain limited. Methods: A reimbursable ED-led THN program was developed across a large regional health system. The program used electronic health record (EHR)–integrated ordering, on-site kit dispensing, and third-party insurance billing when available. Kits were stocked in automated medication dispensing systems and supplemented by city-provided stock for uninsured patients. Pilot outcomes included kits dispensed and reimbursement rates across eight participating EDs. Results: A total of 2,520 naloxone kits were dispensed across eight EDs between January 2019–December 2024, with a total of 6,551 encounters with decision support prompting naloxone ordering (31.6% of eligible). The proportion of kits reimbursed by insurance rose from 46% in 2019 to 95% by 2025. In total, 89.9% of kits were reimbursed either by insurance or public supply (the rest paid by the hospital system). Kit distribution grew from 99 in 2019 to 702 in 2024, reflecting expanded site participation, improved workflows, and greater staff engagement. Conclusion: A reimbursable ED-led naloxone program can increase access to life-saving medication for patients at risk of opioid overdose. Integrating take-home naloxone distribution into EHR workflows, leveraging insurance billing, and partnering with public health agencies offers a sustainable, low-barrier model that other health systems can adopt.

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.