Xylazine: Difference between revisions

(Add MedicationDose entry for atropine)
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*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>
*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>
*'''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>
*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)
*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"/>
*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"/>
*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
*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"/>
*α₂ selectivity of 160:1 over α₁ (compare to [[clonidine]] at 220:1)<ref name="StatPearls"/>
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===Mechanism of Action===
===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 '''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)
*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)
*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"/>
*Potentiates opioid-induced respiratory depression through an unclear mechanism; animal studies suggest xylazine may blunt compensatory hyperoxic responses to fentanyl<ref name="Sue2024"/>
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''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"/>
''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
*CNS depression: sedation, lethargy, coma
*'''Respiratory depression:''' bradypnea, apnea (potentiated by co-ingested opioids)
*Respiratory depression: bradypnea, apnea (potentiated by co-ingested opioids)
*'''Bradycardia'''
*Bradycardia
*'''Hypotension''' (typically sustained; may be preceded by transient hypertension)
*Hypotension (typically sustained; may be preceded by transient hypertension)
*'''Miosis'''
*Miosis
*'''Hypothermia'''
*Hypothermia
*Dry mouth
*Dry mouth
*Hyperglycemia
*Hyperglycemia
*Areflexia
*Areflexia
*'''Prolonged sedation''' compared to opioid-only overdose — should raise suspicion for xylazine involvement
*Prolonged sedation compared to opioid-only overdose — should raise suspicion for xylazine involvement


===Key Distinguishing Feature: Poor Response to Naloxone===
===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
*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
*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===
===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>
*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
*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>
*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
*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"/>
*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
*Wounds are not intrinsically infected but are at risk for superinfection
*If untreated, may require surgical debridement or, rarely, amputation
*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
*Ask about skin wounds in patients presenting with opioid overdose — this may be the first clue to xylazine exposure
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==Evaluation==
==Evaluation==
===Workup===
===Workup===
*'''Fingerstick glucose''' (rule out [[hypoglycemia]]; xylazine itself can cause hyperglycemia)
*Fingerstick glucose (rule out [[hypoglycemia]]; xylazine itself can cause hyperglycemia)
*'''[[ECG]]''' — assess for [[bradycardia]], heart blocks, [[QT prolongation]] (if [[methadone]] co-ingestion suspected)
*[[ECG]] — assess for [[bradycardia]], heart blocks, [[QT prolongation]] (if [[methadone]] co-ingestion suspected)
*'''Cardiac monitoring''' — continuous telemetry
*Cardiac monitoring — continuous telemetry
*'''Temperature''' — assess for [[hypothermia]]
*Temperature — assess for [[hypothermia]]
*'''[[CXR]]''' — if concern for aspiration or [[noncardiogenic pulmonary edema]]
*[[CXR]] — if concern for aspiration or [[noncardiogenic pulmonary edema]]
*'''[[Acetaminophen]] level, [[salicylate]] level''' — standard toxicology screen for co-ingestion
*[[Acetaminophen]] level, [[salicylate]] level — standard toxicology screen for co-ingestion
*'''[[VBG]] or [[ABG]]''' — if significant respiratory depression
*[[VBG]] or [[ABG]] — if significant respiratory depression
*'''[[BMP]]''' — glucose, renal function, electrolytes
*[[BMP]] — glucose, renal function, electrolytes
*'''[[CK]]''' — if prolonged immobilization (concern for [[rhabdomyolysis]])
*[[CK]] — if prolonged immobilization (concern for [[rhabdomyolysis]])
*'''[[Lactate]]''' — if concern for end-organ hypoperfusion from prolonged hypotension
*[[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
*[[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)
*Skin exam — inspect for necrotic ulcerations (may be present on extremities even remote from injection sites)


===Diagnosis===
===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'''
*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"/>
*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
*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"/>
*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
*Xylazine test strips (for checking drug supply) are available through some harm reduction programs; these test the drug product, not the patient


==Management==
==Management==
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===Airway and Breathing===
===Airway and Breathing===
*'''Airway protection''' and '''ventilatory support''' are the '''top priority'''
*Airway protection and ventilatory support are the top priority
*Provide '''BVM ventilation''' and supplemental O₂ as needed
*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"/>
*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]])
**Use standard naloxone dosing (see [[Opioid toxicity]])
**Expect a partial or blunted response compared to opioid-only overdoses
**Expect a partial or blunted response compared to opioid-only overdoses
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===Cardiovascular===
===Cardiovascular===
*'''[[Bradycardia]]:'''
*[[Bradycardia]]:
**'''[[Atropine]]''' 0.5-1 mg IV; may repeat q3-5 min (max 3 mg)
**[[Atropine]] 0.5-1 mg IV; may repeat q3-5 min (max 3 mg)
**Transcutaneous or transvenous '''pacing''' if refractory to atropine
**Transcutaneous or transvenous pacing if refractory to atropine
*'''[[Hypotension]]:'''
*[[Hypotension]]:
**'''IV crystalloid''' bolus (e.g. 500-1000 mL [[normal saline]] or [[Lactated Ringer's]])
**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)
**[[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
*Transient hypertension may occur early and generally does not require treatment unless severe/symptomatic


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


===Hyperglycemia===
===Hyperglycemia===
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===Skin Wounds===
===Skin Wounds===
*Perform thorough skin exam on all patients with suspected xylazine exposure
*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"/>
*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
*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
*Consult wound care or surgery for deep or extensive wounds
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===Harm Reduction at Discharge===
===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
*[[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
*Xylazine test strips (where available): enable users to test drug supply
*'''Fentanyl test strips'''
*Fentanyl test strips
*'''Education:''' counsel that xylazine-adulterated opioids may cause prolonged sedation and that naloxone alone may not fully reverse overdose
*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
*'''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]])
*[[Buprenorphine]] initiation: offer ED-initiated buprenorphine for patients with [[opioid use disorder]] (see [[Opioid toxicity]])


===Investigational Reversal Agents===
===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"/>
*'''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
*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
*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
*None of these agents should be administered outside of a clinical trial or toxicology consultation


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


==Medication Dosing==
==Medication Dosing==

Latest revision as of 09:30, 22 March 2026

Background

  • Xylazine (trade names: Rompun, AnaSed, Sedazine) is an α₂-adrenergic agonist approved only for veterinary use as a sedative, analgesic, and muscle relaxant[1]
  • Not a controlled substance at the federal level (though some states have begun scheduling it); requires only a veterinary prescription to purchase[2]
  • Increasingly found as an adulterant in the illicit drug supply, most commonly mixed with fentanyl ("tranq dope") and in heroin/cocaine mixtures ("speedballs")[3]
  • 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[2]
  • Not reversed by naloxone; however, naloxone should still be administered in all suspected overdoses because opioid co-ingestion is nearly universal[2]
  • Routes of use: injection (most common), insufflation (snorting), smoking, ingestion
  • α₂ selectivity of 160:1 over α₁ (compare to clonidine at 220:1)[1]
  • 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[4]

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)[1]
  • 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[4]
  • 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, dexmedetomidine)[5][1]

  • 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[2][6]
  • Can occur at injection sites and at distant sites on the body
  • Reported even in individuals who snort or smoke xylazine (do not inject)[7]
  • 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[4]
  • 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[2]
  • 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[2][8]
  • Tapering α₂-agonists over 5-7 days may be appropriate; evidence is limited

Differential Diagnosis

Sedative/hypnotic toxicity

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[1]
  • 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[1]
  • 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.[2][1]

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[2]
    • 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:
  • 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[4][6]
  • 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[4]

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[1]
  • 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[1]
  • 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

Atropine 0.5-1mg IV, may repeat q3-5min (max 3mg) IV

See Also

External Links

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Xylazine Toxicity. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Gupta R, Holtgrave DR, Ashburn MA. Xylazine — Medical and Public Health Imperatives. N Engl J Med. 2023;388(24):2209-2212.
  3. ↑ 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.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Sue KL, Hawk K. Clinical considerations for the management of xylazine overdoses and xylazine-related wounds. Addiction. 2024;119(4):606-608.
  5. ↑ 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.
  6. ↑ 6.0 6.1 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.
  7. ↑ National Institute on Drug Abuse. Xylazine. Updated September 18, 2024.
  8. ↑ Ehrman-Dupre R, et al. Management of Xylazine Withdrawal in a Hospitalized Patient: A Case Report. J Addict Med. 2022;16(5).
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