Written by: Eunice Armato-Barone, MD

Edited by: Jonathan Kobles, MD


Background and Epidemiology

  • Drug overdose is the leading cause of unintentional death in the United States, and in 2021, 75% of those deaths involved opioids.
  • Opioid-related deaths have dramatically increased in the last decade, from 7 per 100,000 deaths in 2011 to 25 per 100,000 deaths in 2021.
  • Naloxone (Narcan) is an opioid antagonist that can effectively reverse opioid toxicity.

Pathophysiology of Naloxone

  • Naloxone is a competitive inhibitor at all opioid receptor sites (mu (μ), kappa (κ), and delta (δ)) but is most potent at the μ receptor.
  • It is the activation of the μ receptors that causes the central nervous system (CNS) and respiratory depression seen in opioid overdose, accounting for the mortality associated with opioid use. 

Clinical Presentation of Opioid Overdose

  • CNS depression, including euphoria, sedation, altered mentation, lethargy, and coma
  • Respiratory depression, including bradypnea, apnea, cyanosis, hypoxia, and hypercapnia
  • Miosis (aka “pin-point pupils”)
  • Potential hemodynamic compromise including bradycardia and hypotension



  • An opioid overdose should be considered in any patient presenting with lethargy, miotic pupils, and signs of respiratory depression. 
  • Empiric treatment with Naloxone should be considered in cases of undifferentiated coma or cardiac arrest, given the potential life-saving benefits with minimal risk associated with naloxone administration.
  • Response to Naloxone is diagnostic of opioid toxicity.
  • Following the reversal of opioid toxicity, patients should be placed on a cardiac monitor with pulse oximetry and end-tidal CO2 monitoring to observe for hemodynamic instability and recurrent bradypnea, apnea, or hypercapnia.


  • Patients presenting with signs of life-threatening opioid overdose, including apnea, respiratory failure, coma, or cardiac arrest, should be treated immediately with the following:
    • 2 mg Naloxone IV
    • 4 mg Naloxone IN
  • Patients presenting with signs of respiratory depression without respiratory failure may have a nuanced approach to opioid toxicity reversal.
    • The goal of opioid reversal with Naloxone is to restore appropriate respiration while avoiding withdrawal. 
      • Goal respiratory rate (RR): ≥ 10 breaths/min
    • Narcan should not be administered solely to awaken a patient to their baseline mental status in the absence of respiratory depression or hypercarbia.


Naloxone Administration and Dosing

Route of Administration

  • Intravenous or Intraosseus
  • Intramuscular or Subcutaneous
  • Intranasal
  • Inhalation/Nebulized
  • Titratable Drip


Intravenous or Intraosseus:

  • Preferred in the hospital setting

Adult Dosing

  • Opioid-dependent patients: 0.04 mg
  • Opioid-naïve patients: 0.4 mg

Onset of Action: 1-2 mins

  • Repeat and titrate up dose every 2-3 mins until the desired effect

Duration of Action: 20-90 mins, depending on the dose

Special Considerations

  • Most IV naloxone preparations come in 1mg/mL or 0.4 mg/mL vials.
  • 1 mL of 0.4 mg/mL naloxone + 9 mL of NS or D5W will produce 10 mL of 0.04 mg/mL naloxone.


Intramuscular or Subcutaneous:

Adult Dosing:

  • Same as intravenous dosing above

Onset of Action: 5-6 mins

Duration of Action: 20-90 mins, depending on the dose

Special Considerations:

  • Duration of action of Naloxone, when given IM/subQ, may be slightly longer than when the same dose is given IV.



Adult Dosing:

  • Commercial nasal sprays (i.e., Narcan) are generally available as 4 mg/0.1 mL (4 mg/nasal spray) preparation
  • Can use atomizer device with 1 mg/mL injectable formulation to administer 0.1 mg-1.0 mg (0.1 mL-1.0 mL) per nare as desired

Onset of Action: 3-4 mins

Duration of Action: 2-6 hours, dose-dependent

Special Considerations:

  • The bioavailability of intranasal Naloxone is about 40-50%.


Inhalational / Nebulized:

Adult Dosing:

  • 2 mg naloxone mixed with 3 mL NS

Onset of Action: 5 mins

Duration of Action: Not extensively studied

Special Considerations:

  • Avoid in patients with severe respiratory depression as this route necessitates spontaneous breaths to be effective.
  • Generally not a recommended route, as in this method, Naloxone can easily be over- or under-dosed, and dosing achieved to improve respiratory status may be unclear. As such, the duration of action is not well described.


Naloxone Drip:

  • Consider in patients requiring two or more naloxone boluses and in patients known to have used long-acting opioids, such as methadone.
  • Naloxone drip is not indicated in patients who have failed to demonstrate a response to naloxone bolus.
  • Initiation and Maintenance of Naloxone drip :
    • Determine the “wake-up” dose, the total bolus amount of Naloxone needed to achieve improved respiration.
    • Administer 2/3 of the wake-up dose per hour as a drip (i.e., if a patient requires 0.12 mg of Naloxone to “wake up,” start the naloxone drip at 0.08 mg/hr).
    • For patients who develop recurrent respiratory depression while on a naloxone drip, administer ½ of the wake-up dose as a bolus (repeat as necessary) and increase the drip by 50% (using the above patient example, bolus 0.06 mg of Naloxone and restart drip at 0.12 mg/hr).
    • For patients who begin to demonstrate symptoms or evidence of opioid withdrawal while on a naloxone drip, pause the drip and treat withdrawal symptoms. Frequently reassess for recurrence of respiratory depression and re-dose 50% of the initial bolus, if needed. Consider restarting the drip at 50% of the initial rate.


Potential Complications

Induced Opioid Withdrawal

  • Management is primarily supportive care (anti-emetics for nausea and vomiting, verbal de-escalation for agitation or anxiety).
  • Avoid treating agitation with high doses of long-acting anxiolytics such as benzodiazepines, as the effects of this may last longer than the effect of Naloxone. Respiratory depression from opioid intoxication may reoccur, and benzodiazepines may compound this.

Non-Cardiogenic Pulmonary Edema 

  • Although rare, Opioid overdose can lead to Non-Cardiogenic Pulmonary edema, including progression to Acute Respiratory Distress Syndrome (ARDS). 
    • The mechanism of non-cardiogenic pulmonary edema is poorly understood but has been theorized to be secondary to a surge in catecholamines occurring in the presence of hypoxia or apnea.
    • It is also possible that rapid reversal with Naloxone unmasks an existing opioid-induced ARDS.
  • The risk of Non-Cardiogenic Pulmonary Edema is increased in patients who are opioid-tolerant, hypercapnia, or rapidly reversed. 
  • When possible, a low-dose naloxone strategy and optimization of hypoxia/hypercapnia prior to naloxone administration may mitigate the risk of non-cardiogenic pulmonary edema.
  • For further discussion on the management of non-cardiac pulmonary edema and ARDS: https://coreem.net/podcast/episode-195-ards/ 


Next Steps and Disposition

  • All opioid-intoxicated patients who require Naloxone should be observed for at least 2 hours in the ED. 4-6 hours of observation is recommended for all patients who received high doses of Naloxone.
    • Numerous studies have attempted to identify patient characteristics suitable for shorter observation periods, such as a 1-hour observation strategy; however, these studies have repeatedly revealed a non-insignificant rate of adverse events.
  • Patients with opioid toxicity secondary to long-acting opioids (methadone) should be observed for 12-24 hours.
  • All patients requiring an ongoing naloxone infusion should be admitted to the ICU.
  • Emergency Department initiation of medication-assisted treatment of Opioid Use Disorder (including buprenorphine and methadone) has proven to be an effective tool in reducing mortality in patients with opioid use disorder.
  • Upon discharge, take-home intranasal Naloxone should be dispensed to all patients who present with an opioid-related complaint or have a history of active opioid use disorder.


Take-Home Points

  • Opioid overdose deaths are preventable with timely use of Naloxone.
  • Naloxone administration should be reserved for evidence of respiratory depression, not to restore normal mentation.
  • In the hospital setting, using a low-dose IV naloxone titration strategy when appropriate to manage opioid-induced respiratory depression minimizes the risk of opioid withdrawal and may reduce adverse outcomes, including Non-Cardiogenic Pulmonary Edema.
  • Consider a continuous infusion of Naloxone in patients requiring multiple doses of Naloxone or with suspected long-acting opioid intoxication.
  • Ventilate patients adequately prior to naloxone administration to avoid an increase in catecholamines, which can lead to non-cardiac pulmonary edema and ARDS.



  1. Centers for Disease Control and Prevention. Accidents or Unintentional Injuries. National Center for Health Statistics. Published November 5, 2023. Accessed February 26, 2024. https://www.cdc.gov/nchs/fastats/accidental-injury.htm
  2. Centers for Disease Control and Prevention. Understanding the Opioid Overdose Epidemic. Opioids. Published August 8, 2023. Accessed February 26, 2024. https://www.cdc.gov/opioids/basics/epidemic.html
  3. National Institutes of Health. How Naloxone Saves Lives in Opioid Overdose. National Institute on Drug Abuse. Published April 11, 2019. Accessed February 26, 2024. https://nida.nih.gov/videos/how-naloxone-saves-lives-in-opioid-overdose
  4. Nelson LS, Howland MA, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. Goldfrank’s Toxicologic Emergencies. 11th ed. McGraw-Hill Education; 2019:519-544.
  5. Tintinalli JE. Tintinalli’s Emergency Medicine. 9th ed. Mcgraw-Hill Education; 2020:1232-1238.
  6. Kim HK, Nelson LS. Reversal of Opioid-Induced Ventilatory Depression Using Low-Dose Naloxone (0.04 mg): a Case Series. J Med Toxicol. 2016;12(1):107-110. doi:10.1007/s13181-015-0499-3
  7. Connors NJ, Nelson LS. The Evolution of Recommended Naloxone Dosing for Opioid Overdose by Medical Specialty. J Med Toxicol. 2016;12(3):276-281. doi:10.1007/s13181-016-0559-3
  8. Wanger K, Brough L, Macmillan I, Goulding J, MacPhail I, Christenson JM. Intravenous vs subcutaneous Naloxone for out-of-hospital management of presumed opioid overdose. Acad Emerg Med. 1998;5(4):293-299. doi:10.1111/j.1553-2712.1998.tb02707.x
  9. Naloxone: Drug Information. UpToDate. Accessed February 26, 2024. https://www.uptodate.com/contents/naloxone-drug-information?source=mostViewed_widget
  10. Emergent. NARCAN® (Naloxone Hydrochloride) Nasal Spray Full Prescribing Information.; 2020:1-17. Accessed February 26, 2024. https://narcan.com/hubfs/Gen2-Prescribing-Information.pdf?hsLang=en
  11. Baumann BM, Patterson RA, Parone DA, et al. Use and efficacy of nebulized Naloxone in patients with suspected opioid intoxication. Am J Emerg Med. 2013;31(3):585-588. doi:10.1016/j.ajem.2012.10.004
  12. Goldfrank L, Weisman RS, Errick JK, Lo MW. A dosing nomogram for continuous infusion of intravenous Naloxone. Ann Emerg Med. 1986;15(5):566-570. doi:10.1016/s0196-0644(86)80994-5
  13. Duberstein JL, Kaufman DM. A clinical study of an epidemic of heroin intoxication and heroin-induced pulmonary edema. Am J Med. 1971;51(6):704-714. doi:10.1016/0002-9343(71)90298-1
  14. Sporer KA, Dorn E. Heroin-related noncardiogenic pulmonary edema: a case series. Chest. 2001;120(5):1628-1632. doi:10.1378/chest.120.5.1628
  15. Schwartz JA, Koenigsberg MD. Naloxone-induced pulmonary edema. Ann Emerg Med. 1987;16(11):1294-1296. doi:10.1016/s0196-0644(87)80244-5
  16. Prough DS, Roy R, Bumgarner J, Shannon G. Acute pulmonary edema in healthy teenagers following conservative doses of intravenous Naloxone. Anesthesiology. 1984;60(5):485-486. doi:10.1097/00000542-198405000-00018
  17. Mills CA, Flacke JW, Miller JD, Davis LJ, Bloor BC, Flacke WE. Cardiovascular effects of fentanyl reversal by Naloxone at varying arterial carbon dioxide tensions in dogs. Anesth Analg. 1988;67(8):730-736.