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Comparing methods of naloxone administration: A narrative review

Shawn E. Fellows, PharmD, Alexander J. Coppola, BS, EMT-B, PharmD, Mona A. Gandhi, PharmD


The effectiveness and safety of naloxone for the reversal of opioid toxicity are reviewed. A literature search was performed using PubMed, the Cochrane Library, CINAHL, and Medline. Clinical trials comparing either the clinical efficacy or pharmacokinetic/pharmacodynamic properties displayed by intravenous, intramuscular, intranasal, subcutaneous, and nebulized naloxone were included; however, trials with primary endpoints evaluating oral or endotracheal naloxone were excluded. Naloxone was shown to be clinically effective via all routes of administration, when compared to either baseline or control. The inconsistencies in data regarding the relative outcome comparisons between administration methods were likely due to differences in concentrations of naloxone preparations and method of administration for the same route of delivery between different studies. Choice of route depends on the environment in which the opioid toxicity occurs, individual patient characteristics, and provider preference.


naloxone, administration, pharmacokinetics

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Hedegaard H, Warner M, Chen LH: Rates of drug poisoning deaths involving heroin,* by selected age and racial/ethnic groups—United States, 2002 and 2011. MMWR Morb Mortal Wkly Rep. 2014; 63: 581-584.

Centers for Disease Control and Prevention: Deaths: Final Data for 2013. 2013. National Vital Statistics Reports 64.

Kochanek KD, Murphy SL, Xu J, et al.: Mortality in the United States, 2013. NCHS Data Brief. 2014; 178: 1-8.

Centers for Disease Control and Prevention, National Center for Health Statistics: Multiple Cause of Death 1999-2013 on CDC WONDER Online Database. 2015.

Inocencio TJ, Carroll NV, Read EJ, et al.: The economic burden of opioid-related poisoning in the United States. Pain Med. 2013; 14: 1534-1547.

Faul M, Dailey MW, Sugerman DE, et al.: Disparity in naloxone administration by emergency medical service providers and the burden of drug overdose in US rural communities. Am J Public Health. 2015; 105(suppl 3): e26-e32.

Evzio (naloxone) [package insert]. Richmond, VA: kaleo, Inc. 2014.

Wermeling DP: Review of naloxone safety for opioid overdose: Practical considerations for new technology and expanded public access. Ther Adv Drug Saf. 2015; 6: 20-31.

Weinstein SH, Pfeffer M, Schor JM, et al.: Absorption and distribution of naloxone in rats after oral and intravenous administration. J Pharm Sci. 1973; 62: 1416-1419.

Goldfrank L, Lewis G, Weisman RS, et al.: A dosing nomogram for continuous infusion intravenous naloxone. Ann Emerg Med. 1986; 15: 566-570.

Berkowitz BA: The relationship of pharmacokinetics to pharmacological activity: Morphine, methadone and naloxone. Clin Pharmacokinet. 1976; 1: 219-230.

Sabzghabaee AM, Eizadi-Mood N, Yaraghi A, et al.: Naloxone therapy in opioid overdose patients: Intranasal or intravenous? A randomized clinical trial. Arch Med Sci. 2014; 10: 309-314.

Merlin MA, Saybolt M, Kapitanyan R, et al.: Intranasal naloxone delivery is an alternative to intravenous naloxone for opioid overdoses. Am J Emerg Med. 2010; 28: 296-303.

Doe-Simkins M, Walley AY, Epstein A, et al.: Saved by the nose: Bystander-administered intranasal naloxone hydrochloride for opioid overdose. Am J Public Health. 2009; 99: 788-791.

Schuh KJ, Walsh SL, Bigelow GE, et al.: Buprenorphine, morphine and naloxone effects during ascending morphine maintenance in humans. J Pharmacol Exp Ther. 1996; 278: 836-846.

Lanier RK, Lofwall MR, Mintzer MZ, et al.: Physical dependence potential of daily tramadol dosing in humans. Psychopharmacology. 2010; 211: 457-466.

Buajordet I, Naess A-C, Jacobsen D, et al.: Adverse events after naloxone treatment of episodes of suspected acute opioid overdose. Eur J Emerg Med. 2004; 11: 19-23.

Kim HK, Nelson LS: Reducing the harm of opioid overdose with the safe use of naloxone: A pharmacologic review. Expert Opin Drug Saf. 2015; 14: 1137-1146.

Wang RI, Wiesen RL, Lamid S, et al.: Rating the presence and severity of opiate dependence. Clin Pharmacol Ther. 1974; 16: 653-658.

Dowling J, Isbister GK, Kirkpatrick CMJ, et al.: Population pharmacokinetics of intravenous, intramuscular, and intranasal naloxone in human volunteers. Ther Drug Monit. 2008; 30: 490-496.

Kelly A-M, Kerr D, Dietze P, et al.: Randomised trial of intranasal versus intramuscular naloxone in prehospital treatment for suspected opioid overdose. Med J Aust. 2005; 182: 24-27.

Weber JM, Tataris KL, Hoffman JD, et al.: Can nebulized naloxone be used safely and effectively by emergency medical services for suspected opioid overdose? Prehosp Emerg Care. 2012; 16: 289-292.

Sporer KA, Firestone J, Isaacs SM: Out-of-hospital treatment of opioid overdoses in an urban setting. Acad Emerg Med. 1996; 3: 660-667.

Clarke SFJ, Dargan PI, Jones AL: Naloxone in opioid poisoning: walking the tightrope. Emerg Med J. 2005; 22: 612-616.

Olofsen E, van Dorp E, Teppema L, et al.: Naloxone reversal of morphine- and morphine-6-glucuronide-induced respiratory depression in healthy volunteers. Anesthesiology. 2010; 112: 1417-1427.

Wanger K, Brough L, Macmillan I, et al.: Intravenous vs subcutaneous naloxone for out-of-hospital management of presumed opioid overdose. Acad Emerg Med. 1998; 5: 293-299.

ASHP: FDA Approves First Intranasal Naloxone Product. Available at Accessed June 7, 2016.

Weiss ES, Makary MA, Wang T, et al.: Prevalence of bloodborne pathogens in an urban, university-based general surgical practice. Ann Surg. 2005; 241: 803-807; discussion 807-809.

Loimer N, Hofmann P, Chaudhry HR: Nasal administration of naloxone for detection of opiate dependence. J Psychiatr Res. 1992; 26: 39-43.

Loimer N, Hofmann P, Chaudhry HR: Nasal administration of naloxone is as effective as the intravenous route in opiate addicts. Int J Addict. 1994; 29: 819-827.

Barton ED, Ramos J, Colwell C, et al.: Intranasal administration of naloxone by paramedics. Prehosp Emerg Care. 2002; 6: 54-58.

Barton ED, Colwell CB, Wolfe T, et al.: Efficacy of intranasal naloxone as a needleless alternative for treatment of opioid overdose in the prehospital setting. J Emerg Med. 2005; 29: 265-271.

Robertson TM, Hendey GW, Stroh G, et al.: Intranasal naloxone is a viable alternative to intravenous naloxone for prehospital narcotic overdose. Prehosp Emerg Care. 2009; 13: 512-515.

Kerr D, Kelly A-M, Dietze P, et al.: Randomized controlled trial comparing the effectiveness and safety of intranasal and intramuscular naloxone for the treatment of suspected heroin overdose. Addiction. 2009; 104: 2067-2074.

NARCAN® nasal spray (naloxone) [package insert]. Radnor, PA: Adapt Pharma, Inc. 2016.

Costantino HR, Illum L, Brandt G, et al.: Intranasal delivery: Physicochemical and therapeutic aspects. Int J Pharm. 2007; 337: 1-24.

Grassin-Delyle S, Buenestado A, Naline E, et al.: Intranasal drug delivery: An efficient and non-invasive route for systemic administration: Focus on opioids. Pharmacol Ther. 2012; 134: 366-379.

Mycyk MB, Szyszko AL, Aks SE: Nebulized naloxone gently and effectively reverses methadone intoxication. J Emerg Med. 2003; 24: 185-187.

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: 585-588.

Karras DJ, Levy DB, Domingo L, et al.: Research forum abstracts. Ann Emerg Med. 1998; 32: S1-S62.

Hussain A, Anwar H, Ryohei K, et al.: Nasal absorption of naloxone and buprenorphine in rats. Int J Pharm. 1984; 21: 233-237.

Wyse J, DeHart MP: Intranasal naloxone compositions and methods of making and using same. US patent 20150174061A1. 2015.

Born J, Lange T, Kern W, et al.: Sniffing neuropeptides: A transnasal approach to the human brain. Nat Neurosci. 2002; 5: 514-516.

Chapman CD, Frey WH 2nd, Craft S, et al.: Intranasal treatment of central nervous system dysfunction in humans. Pharm Res. 2013; 30: 2475-2484.

Westin UE, Boström E, Gråsjö J, et al.: Direct nose-to-brain transfer of morphine after nasal administration to rats. Pharm Res. 2006; 23: 565-572.

Ruigrok MJR, de Lange ECM: Emerging insights for translational pharmacokinetic and pharmacokinetic-pharmacodynamic studies: Towards prediction of nose-to-brain transport in humans. AAPS J. 2015; 17: 493-505.



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