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

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)
• 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
• 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)

• 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
• Can occur at injection sites and at distant sites on the body
• Reported even in individuals who snort or smoke xylazine (do not inject)
• 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
• 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
• 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
• 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

Sedative/hypnotic toxicity

• Absinthe
• Barbiturates
• Benzodiazepines
  • Flunitrazepam (Rohypnol)
• Chloral hydrate
• Gamma hydroxybutyrate (GHB)
• Baclofen toxicity
• Opioids
  • Lomotil toxicity
  • Loperamide toxicity
• Toxic alcohols
  • Ethanol
  • Ethylene glycol
  • Isopropyl alcohol
  • Methanol
• Xylazine 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
• 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
• 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.

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
  • 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
• 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

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
• 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
• 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

• Opioid toxicity
• Clonidine toxicity
• Naloxone
• Opioid withdrawal
• Fentanyl
• Buprenorphine

External Links

• NIDA - Xylazine Overview
• CDC - Xylazine Clinical Management and Harm Reduction Fact Sheet (2024)
• NEJM - Xylazine: Medical and Public Health Imperatives (2023)
• ACEP Toxicology Section - Xylazine: A Confounding Adulterant (2024)