View source for Xylazine

==Background==
*Xylazine (trade names: Rompun, AnaSed, Sedazine) is an '''α₂-adrenergic agonist''' approved '''only for veterinary use''' as a sedative, analgesic, and muscle relaxant<ref name="StatPearls">Xylazine Toxicity. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.</ref>
*'''Not a controlled substance''' at the federal level (though some states have begun scheduling it); requires only a veterinary prescription to purchase<ref name="NEJM2023">Gupta R, Holtgrave DR, Ashburn MA. Xylazine — Medical and Public Health Imperatives. N Engl J Med. 2023;388(24):2209-2212.</ref>
*Increasingly found as an adulterant in the illicit drug supply, most commonly mixed with [[fentanyl]] ("tranq dope") and in heroin/cocaine mixtures ("speedballs")<ref name="Friedman2022">Friedman J, Montero F, Bourgois P, et al. Xylazine spreads across the US: A growing component of the increasingly synthetic and polysubstance overdose crisis. Drug Alcohol Depend. 2022;233:109380.</ref>
*Street names: "tranq," "tranq dope," "sleep cut," "zombie drug," "Anestecia de Caballo" (Puerto Rico)
*The White House Office of National Drug Control Policy declared fentanyl mixed with xylazine an '''emerging threat''' to the United States in April 2023<ref name="NEJM2023"/>
*Not reversed by [[naloxone]]; however, naloxone should still be administered in all suspected overdoses because opioid co-ingestion is nearly universal<ref name="NEJM2023"/>
*Routes of use: injection (most common), insufflation (snorting), smoking, ingestion
*α₂ selectivity of 160:1 over α₁ (compare to [[clonidine]] at 220:1)<ref name="StatPearls"/>
*Estimated half-life in humans: 23-50 minutes per FDA; however, clinical effects may last 8-72 hours, likely due to redistribution and co-ingestions<ref name="Sue2024">Sue KL, Hawk K. Clinical considerations for the management of xylazine overdoses and xylazine-related wounds. Addiction. 2024;119(4):606-608.</ref>

===Mechanism of Action===
*Activation of '''presynaptic α₂a and α₂c''' receptors in the CNS → decreased norepinephrine and dopamine release → sedation (locus ceruleus) and analgesia (dorsal horn)<ref name="StatPearls"/>
*Activation of peripheral α₂b receptors on vascular smooth muscle → vasoconstriction (may explain skin wound pathology)
*At high doses, can activate α₁ and α₂b receptors → paradoxical hypertension (usually transient, followed by sustained hypotension)
*Potentiates opioid-induced respiratory depression through an unclear mechanism; animal studies suggest xylazine may blunt compensatory hyperoxic responses to fentanyl<ref name="Sue2024"/>
*No activity at opioid receptors — this is why naloxone does not reverse xylazine effects

==Clinical Features==
===Acute Toxicity===
''Clinical presentation is similar to other centrally acting α₂-agonists (e.g. [[clonidine toxicity|clonidine]], [[dexmedetomidine]])''<ref name="ACEP2024">Love JS, Levine M, Aldy K, et al. Opioid overdoses involving xylazine in emergency department patients: a multicenter study. Clin Toxicol. 2023;61(3):173-180.</ref><ref name="StatPearls"/>

*CNS depression: sedation, lethargy, coma
*Respiratory depression: bradypnea, apnea (potentiated by co-ingested opioids)
*Bradycardia
*Hypotension (typically sustained; may be preceded by transient hypertension)
*Miosis
*Hypothermia
*Dry mouth
*Hyperglycemia
*Areflexia
*Prolonged sedation compared to opioid-only overdose — should raise suspicion for xylazine involvement

===Key Distinguishing Feature: Poor Response to Naloxone===
*Suspect xylazine when a patient with apparent [[opioid toxicity]] has an incomplete or absent response to adequate naloxone dosing
*Patient may have partial improvement in respiratory depression (due to reversal of co-ingested opioid) but remain significantly sedated and bradycardic

===Xylazine-Associated Skin Wounds===
*Severe, necrotic skin ulcerations that are a hallmark of chronic xylazine use<ref name="NEJM2023"/><ref name="McFadden2024">McFadden R, Wallace-Keeshen S, Petrillo Straub K, et al. Xylazine-associated wounds: Clinical experience from a low-barrier wound care clinic in Philadelphia. J Addict Med. 2024;18(1):9-12.</ref>
*Can occur at injection sites and at distant sites on the body
*Reported even in individuals who snort or smoke xylazine (do not inject)<ref name="NIDA2024">National Institute on Drug Abuse. Xylazine. Updated September 18, 2024.</ref>
*Wounds may progress to deep necrotic ulcers with eschar; can involve underlying tendons, bone
*Pathophysiology is poorly understood; likely involves peripheral vasoconstriction, obliterative vascular injury from repeated injection, and possible locally toxic extravasation<ref name="Sue2024"/>
*Wounds are not intrinsically infected but are at risk for superinfection
*If untreated, may require surgical debridement or, rarely, amputation
*Ask about skin wounds in patients presenting with opioid overdose — this may be the first clue to xylazine exposure

===Xylazine Withdrawal===
*Patients with chronic use may develop physiological dependence<ref name="NEJM2023"/>
*Withdrawal symptoms can include: anxiety, agitation, irritability, diaphoresis, insomnia
*Limited data on management; some centers use [[clonidine]], [[lofexidine]], or [[dexmedetomidine]] infusions (ICU setting) to treat withdrawal<ref name="NEJM2023"/><ref>Ehrman-Dupre R, et al. Management of Xylazine Withdrawal in a Hospitalized Patient: A Case Report. J Addict Med. 2022;16(5).</ref>
*Tapering α₂-agonists over 5-7 days may be appropriate; evidence is limited

==Differential Diagnosis==
*[[Opioid toxicity]] (most common co-ingestion)
*[[Clonidine toxicity]] (very similar presentation)
*[[Organophosphate toxicity]] (miosis, bradycardia, respiratory depression — but typically with copious secretions, SLUDGE)
*[[Sedative/hypnotic toxicity]]
*[[Beta-blocker toxicity]] (bradycardia, hypotension)
*[[Calcium channel blocker toxicity]] (bradycardia, hypotension)
*[[Hypothermia]]
*[[Hypoglycemia]]
*Pontine hemorrhage ([[CVA]] — miosis, coma)
*[[Carbon monoxide toxicity]]

{{Sedatve/hypnotic toxicity types}}

==Evaluation==
===Workup===
*Fingerstick glucose (rule out [[hypoglycemia]]; xylazine itself can cause hyperglycemia)
*[[ECG]] — assess for [[bradycardia]], heart blocks, [[QT prolongation]] (if [[methadone]] co-ingestion suspected)
*Cardiac monitoring — continuous telemetry
*Temperature — assess for [[hypothermia]]
*[[CXR]] — if concern for aspiration or [[noncardiogenic pulmonary edema]]
*[[Acetaminophen]] level, [[salicylate]] level — standard toxicology screen for co-ingestion
*[[VBG]] or [[ABG]] — if significant respiratory depression
*[[BMP]] — glucose, renal function, electrolytes
*[[CK]] — if prolonged immobilization (concern for [[rhabdomyolysis]])
*[[Lactate]] — if concern for end-organ hypoperfusion from prolonged hypotension
*[[Utox]] (standard urine drug screen) — will not detect xylazine or fentanyl; useful to identify other co-ingestions
*Skin exam — inspect for necrotic ulcerations (may be present on extremities even remote from injection sites)

===Diagnosis===
*Primarily clinical: suspect xylazine when a patient presents with opioid-like toxidrome (miosis, respiratory depression, bradycardia) and has a poor or incomplete response to naloxone
*Standard urine immunoassay drug screens do '''not''' detect xylazine<ref name="StatPearls"/>
*Newer immunoassay-based xylazine tests are being developed but are not widely available as point-of-care tests
*Definitive detection requires gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS); turnaround time is days, so this does '''not''' guide acute ED management<ref name="StatPearls"/>
*Xylazine test strips (for checking drug supply) are available through some harm reduction programs; these test the drug product, not the patient

==Management==
''There is '''no specific antidote''' for xylazine in humans. Management is '''supportive care'''.''<ref name="NEJM2023"/><ref name="StatPearls"/>

===Airway and Breathing===
*Airway protection and ventilatory support are the top priority
*Provide BVM ventilation and supplemental O₂ as needed
*Administer [[naloxone]] — will not reverse xylazine effects but will treat the nearly universal opioid co-ingestion<ref name="NEJM2023"/>
**Use standard naloxone dosing (see [[Opioid toxicity]])
**Expect a partial or blunted response compared to opioid-only overdoses
*[[Intubation]] if patient cannot protect airway or has persistent apnea despite naloxone
*Prolonged respiratory support may be required (effects can last hours)

===Cardiovascular===
*[[Bradycardia]]:
**[[Atropine]] 0.5-1 mg IV; may repeat q3-5 min (max 3 mg)
**Transcutaneous or transvenous pacing if refractory to atropine
*[[Hypotension]]:
**IV crystalloid bolus (e.g. 500-1000 mL [[normal saline]] or [[Lactated Ringer's]])
**[[Norepinephrine]] infusion if refractory to fluids (preferred given α-agonist mechanism of injury and concurrent vasodilation)
*Transient hypertension may occur early and generally does not require treatment unless severe/symptomatic

===Hypothermia===
*Active rewarming measures as indicated (see [[Hypothermia]])

===Hyperglycemia===
*Usually self-limited; monitor glucose
*Treat with [[insulin]] only if severely elevated with clinical consequence

===Skin Wounds===
*Perform thorough skin exam on all patients with suspected xylazine exposure
*Wound care: keep wounds moist, clean, and covered; chemical or enzymatic debridement of eschar often preferred over surgical debridement by patients<ref name="Sue2024"/><ref name="McFadden2024"/>
*Assess for signs of superinfection (purulence, spreading erythema, cellulitis) and treat with antibiotics if indicated
*Consult wound care or surgery for deep or extensive wounds
*Connecting patient to outpatient wound care follow-up is critical
*Initiating or increasing [[buprenorphine]] or [[methadone]] may help reduce injection frequency and promote wound healing<ref name="Sue2024"/>

===Harm Reduction at Discharge===
*[[Naloxone]] distribution: Provide or direct to OTC Narcan (4 mg nasal spray); naloxone will not reverse xylazine but will address opioid component of polysubstance overdose
*Xylazine test strips (where available): enable users to test drug supply
*Fentanyl test strips
*Education: counsel that xylazine-adulterated opioids may cause prolonged sedation and that naloxone alone may not fully reverse overdose
*'''Never Use Alone''' hotline: encourage patients to have someone present when using
*[[Buprenorphine]] initiation: offer ED-initiated buprenorphine for patients with [[opioid use disorder]] (see [[Opioid toxicity]])

===Investigational Reversal Agents===
*'''Atipamezole:''' potent α₂-antagonist used as a veterinary reversal agent for xylazine; was briefly approved for human use (1970-2017) but is '''no longer FDA-approved''' for humans; active clinical investigation is underway<ref name="StatPearls"/>
*Yohimbine: natural α₂-antagonist; has reversed xylazine effects in animal models; not approved for this indication in humans
*Tolazoline: α₂-antagonist used in veterinary medicine; not approved for this use in humans
*None of these agents should be administered outside of a clinical trial or toxicology consultation

==Disposition==
*'''Observation:''' Prolonged observation is warranted; effects of xylazine may last '''8-72 hours''', significantly longer than most opioids<ref name="StatPearls"/>
*Admit if:
**Persistent respiratory depression requiring supplemental O₂ or ventilatory support
**Hemodynamically unstable (refractory bradycardia, hypotension requiring vasopressors)
**Hypothermia requiring active rewarming
**Significant skin wounds requiring inpatient wound care or surgical consultation
**Concern for ongoing withdrawal requiring α₂-agonist taper
*Consider discharge only if:
**Hemodynamically stable and asymptomatic for a minimum of 4-6 hours after last intervention
**Ambulatory, GCS 15, RR >12, HR >50, SpO₂ >92% on room air
**Skin wounds (if present) have been assessed with outpatient wound care follow-up arranged
**Naloxone and harm reduction supplies provided
**Warm handoff to addiction services offered (if applicable)
*Lower threshold for admission than with opioid-only overdose given prolonged and unpredictable duration of effects

==Medication Dosing==
{{MedicationDose
| drug = Atropine
| dose = 0.5-1mg IV, may repeat q3-5min (max 3mg)
| route = IV
| context = Symptomatic bradycardia
| indication = Xylazine
| population = Adult
}}

==See Also==
*[[Opioid toxicity]]
*[[Clonidine toxicity]]
*[[Naloxone]]
*[[Opioid withdrawal]]
*[[Fentanyl]]
*[[Buprenorphine]]

==External Links==
*[https://nida.nih.gov/research-topics/xylazine NIDA - Xylazine Overview]
*[https://www.cdc.gov/overdose-prevention/media/pdfs/2024/07/Xylazine-Clinical-Management-and-Harm-Reduction.pdf CDC - Xylazine Clinical Management and Harm Reduction Fact Sheet (2024)]
*[https://www.nejm.org/doi/full/10.1056/NEJMp2303120 NEJM - Xylazine: Medical and Public Health Imperatives (2023)]
*[https://www.acep.org/toxicology/newsroom/may-2024/xylazine-a-confounding-adulterant ACEP Toxicology Section - Xylazine: A Confounding Adulterant (2024)]

==References==
{{reflist|2}}

[[Category:Toxicology]]