Opioid toxicity

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Background

A two milligram dose of fentanyl powder (on pencil tip).
  • Natural derivatives: Heroin, Morphine, Codeine, Hydrocodone, Oxycodone (+ UDS)
  • Semi-synthetic: Hydromorphone, Buprenorphine
  • Synthetic: Fentanyl, Methadone, Meperidine, Tramadol, Dextromethorphan (often - UDS)
  • Illicit fentanyl and fentanyl analogues now account for the majority of opioid overdose deaths in the United States[1]
  • Respiratory depression is the cause of virtually all mortality from opioid toxicity
  • Obtain acetaminophen levels in all cases of combination opioid-acetaminophen (Percocet, Norco) overdoses
  • When prescribing opioid pain relievers in the ED, discuss co-ingestion of other depressants (alcohol involved in 1/5 of opioid related deaths)[2]
  • In addition to common co-ingestions, consider adulterants:
    • Xylazine ("tranq"): α2-adrenergic agonist increasingly found in the illicit opioid supply; causes CNS/respiratory depression and bradycardia that does not respond to naloxone[3]
    • Amphetamines, anticholinergics, benzodiazepines, hypnotics, heavy metals
  • In the year after an ED visit for an opioid overdose, >5% die and >19% will experience another opioid overdose[4]

Clinical Features

Common

  • Miosis (may be absent with co-ingestion of sympathomimetics or anticholinergics, and with meperidine or tramadol)
  • Nausea/vomiting
  • Respiratory depression (↓ RR, ↓ tidal volume, apnea)
  • Mental status depression

Uncommon

Fentanyl-Specific Considerations

  • Rapid onset of respiratory depression; may progress to apnea and cardiac arrest within minutes
  • Chest wall rigidity ("wooden chest syndrome") can occur with rapid IV fentanyl administration; may impair BVM ventilation
  • May require higher and repeated doses of naloxone compared to other opioids[6]
  • Fentanyl test strips can be provided as part of harm reduction at discharge

Xylazine ("Tranq") Considerations

  • α₂-adrenergic agonist; not reversed by naloxone[3]
  • Causes bradycardia, hypotension, respiratory depression, and prolonged sedation
  • Should be suspected when a patient does not respond appropriately to adequate naloxone dosing
  • Management is supportive care: airway management, ventilation, atropine for symptomatic bradycardia, IV fluids for hypotension
  • Associated with necrotic skin ulcerations at distant injection sites

Differential Diagnosis

Sedative/hypnotic toxicity

Evaluation

Management

Airway Protection and Ventilatory Management

  • BVM ventilation is the first priority — provide respiratory support while preparing naloxone
  • BVM and naloxone administration may prevent need for intubation
  • If chest wall rigidity present (fentanyl): naloxone, or neuromuscular blockade + intubation

Naloxone (Narcan)

Repeat every 2-5 minutes as needed. If no response after a total of 10mg, strongly consider an alternative diagnosis. Onset: IV almost immediate (1-2 min); IN/IM 3-5 min. Duration of action: 20-90 min (redosing will be necessary for most overdoses, especially with long-acting opioids or fentanyl)

Dosing

IV/IM/IO
  • If apneic or near-apneic: 2 mg IV (may start with 0.4 mg and rapidly escalate)
  • If opioid-naïve with mild-moderate respiratory depression: 0.4 mg IV
  • If opioid-dependent with mild-moderate respiratory depression: 0.04-0.05 mg IV ("push-dose Narcan"), titrate to respiratory effort rather than consciousness to minimize precipitated withdrawal
  • Fentanyl overdoses frequently require higher initial doses (2-4 mg) and repeated dosing[6]
Intranasal (IN)
  • 4 mg IN (one spray in one nostril using prefilled device); may repeat in alternate nostril in 2-3 min
  • This is the dose available OTC (see below)
  • Higher-dose formulation: 8 mg IN (Kloxxado) also FDA-approved
Intramuscular (IM)
  • 0.4 mg IM if no IV access; may repeat q2-5 min
Infusion
  • Indicated if patient responded to bolus and requires repeat administration
    • Step 1: Determine the "wake-up dose" (total bolus required to restore adequate ventilation)
    • Step 2: Infuse 2/3 of the wake-up dose per hour in D5W or NS
    • Step 3: Give an additional half the initial bolus 15 minutes after starting the infusion to maintain steady-state
    • Monitor closely and titrate to respiratory effort

GI Decontamination

  • Activated charcoal x1 if opioid ingestion occurred within 1 hr (only if airway is protected)
  • Whole bowel irrigation may be considered for body packers/stuffers

Disposition

Heroin/Short-Acting Opioid Intoxication

  • Can consider discharge 1-2 hr[7] after last dose of naloxone if all are true:
    • Ambulatory without assistance
    • O₂ sat >92% (room air)
    • RR >10
    • HR >50
    • Normal temp
    • GCS 15

Non-Heroin/Long-Acting Opioid Intoxication

  • Consider discharge after 4-6 hr observation
  • Methadone toxicity: observe for 12-24 hr (half-life up to 60 hours; risk of recurrent respiratory depression)
  • Extended-release formulations (e.g. OxyContin, fentanyl patches): prolonged observation (≥12 hr)

Naloxone at Discharge

Narcan 4 mg nasal spray was approved by the FDA for over-the-counter (OTC) sale without a prescription in March 2023.[8] A second OTC product (RiVive 3 mg nasal spray) was also approved in July 2023.

  • Every patient discharged after an opioid overdose or with risk factors for overdose should receive or be directed to obtain take-home naloxone[9]
  • OTC Narcan is available at pharmacies, convenience stores, grocery stores, gas stations, and online without a prescription[8]
  • Prescription naloxone products (injectable, higher-dose IN) remain available
  • Example counseling: "Deliver 1 spray (4 mg) to one nostril if signs of opioid overdose. May repeat in other nostril in 2-3 min. Call 911 immediately."

Populations at risk who should receive naloxone:[9]

  • Discharged from the ED after opioid intoxication or poisoning
  • Receiving high doses of opioids or undergoing chronic pain management
  • Receiving rotating opioid medication regimens
  • History of substance use disorder with legitimate need for analgesia
  • Using extended/long-acting opioid preparations
  • Completing mandatory opioid detoxification or abstinence programs
  • Recent release from incarceration with history of opioid use
  • Co-prescribed benzodiazepines with opioids
  • Household members or close contacts of individuals using opioids

ED-Initiated Buprenorphine for Opioid Use Disorder

See also: Opioid withdrawal, Buprenorphine

ACEP consensus recommendations (2021) recommend that emergency physicians offer to initiate buprenorphine treatment in appropriate ED patients with opioid use disorder (OUD) and provide direct linkage to ongoing treatment.[10]

  • No X-waiver is required since the Mainstreaming Addiction Treatment (MAT) Act of 2023; any DEA-licensed practitioner can prescribe buprenorphine for OUD[11]
  • ED-initiated buprenorphine is associated with significantly increased engagement in addiction treatment and decreased illicit opioid use at 30 days compared to referral alone[12]
  • Standard initiation: Patient must be in mild-moderate withdrawal (COWS ≥8-12) before first dose
    • Starting dose: buprenorphine/naloxone 4 mg/1 mg SL
    • Re-dose 4 mg/1 mg SL q1-2h as needed for persistent withdrawal symptoms
    • Typical day-1 total: 8-16 mg
  • Discharge prescription: buprenorphine/naloxone up to 16 mg SL daily with warm handoff to outpatient addiction medicine or primary care for continued prescribing within 24-72 hours
  • All patients with OUD, regardless of interest in buprenorphine, should receive harm reduction supplies: take-home naloxone, fentanyl test strips (where legal), and connection to community resources


Naloxone (Narcan) 2 mg IV (apneic/near-apneic); or 0.4 mg IV (opioid-naïve, mild-mod); or 0.04-0.05 mg IV (opioid-dependent); repeat q2-5min PRN IV/IM/IO (onset 1-2 min (IV), 3-5 min (IN/IM), duration 20-90 min) (max 10 mg total (consider alt diagnosis if no response)) Naloxone (Narcan) 4 mg intranasal (may repeat q2-3min) IN (onset 3-5 min, duration 20-90 min) — OTC nasal spray available; may need higher/repeated doses for fentanyl Naloxone (Narcan) 0.1 mg/kg IV/IM/IO (max 2 mg); or 0.1 mg/kg IN via nasal atomizer IV/IM/IO/IN (max 2 mg per dose) Naloxone (Narcan) Continuous infusion: 2/3 of effective bolus dose per hour IV drip — For long-acting opioid OD or recurrent sedation; titrate to respiratory effort Buprenorphine 4 mg SL initial; may give additional 4 mg SL after 1-2 hours (total 8-16 mg on day 1) SL — No X-waiver required since MAT Act 2023; must be in mild-moderate withdrawal (COWS ≥8)

See Also

External Links

References

  1. ↑ Centers for Disease Control and Prevention. Drug Overdose Deaths in the United States, 2001-2021. NCHS Data Brief, No. 457. Dec 2022.
  2. ↑ Jones CM, Paulozzi LJ, Mack KA. Alcohol Involvement in Opioid Pain Reliever and Benzodiazepine Drug Abuse–Related Emergency Department Visits and Drug-Related Deaths — United States, 2010. CDC MMWR. October 10, 2014 / 63(40);881-885.
  3. ↑ 3.0 3.1 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. ↑ Davis C, Carr D, Glenn M, Samuels E. Legal Authority for Emergency Medical Services to Increase Access to Buprenorphine Treatment for Opioid Use Disorder. Ann Emerg Med. 2021;78(1):102–107.
  5. ↑ Sporer KA and Dorn E. Heroin-related noncardiogenic pulmonary edema: a case series. Chest. 2001; 120(5):1628-32.
  6. ↑ 6.0 6.1 Carpenter J, Murray BP, Atti S, Moran TP, Yancey A, Morgan B. Naloxone Dosing After Opioid Overdose in the Era of Illicitly Manufactured Fentanyl. J Med Toxicol. 2020;16(1):41-48.
  7. ↑ Willman MW, Liss DB, Schwarz ES, Mullins ME. Do heroin overdose patients require observation after receiving naloxone? Clin Toxicol (Phila). 2017;55(2):81-87.
  8. ↑ 8.0 8.1 U.S. Food and Drug Administration. FDA Approves First Over-the-Counter Naloxone Nasal Spray. March 29, 2023.
  9. ↑ 9.0 9.1 ACEP Policy Statement. "Naloxone Prescriptions by Emergency Physicians." Approved by ACEP Board of Directors October 29, 2015.
  10. ↑ Hawk K, Hoppe J, Ketcham E, et al. Consensus Recommendations on the Treatment of Opioid Use Disorder in the Emergency Department. Ann Emerg Med. 2021;78(3):434-442.
  11. ↑ Consolidated Appropriations Act, 2023 (H.R. 2617), Section 1262 - Mainstreaming Addiction Treatment Act.
  12. ↑ D'Onofrio G, O'Connor PG, Pantalon MV, et al. Emergency Department-Initiated Buprenorphine/Naloxone Treatment for Opioid Dependence: A Randomized Clinical Trial. JAMA. 2015;313(16):1636-44.
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