Pharmacokinetic considerations for community-based dosing of nasal naloxone in opioid overdose in adults

References

• UNODC. Opioid overdose. UNODC World Drug Report August 4th 2021.
   Google Scholar
• Uuskula A, Jarlais DD, Vorobjov S. The fentanyl epidemic in Estonia: opportunities for a comprehensive public health response. Lancet Psychiatry. 2019;6(12):985.
   PubMedGoogle Scholar
• Boyer EW. Management of opioid analgesic overdose. N Engl J Med. 2012 Jul 12;367(2):146–155.
   PubMedGoogle Scholar
• Rzasa Lynn R, Galinkin JL. Naloxone dosage for opioid reversal: current evidence and clinical implications. Ther Adv Drug Saf. 2018 Jan;9(1):63–88.
   PubMed Web of Science ®Google Scholar
• Kim HK, Nelson LS. Reducing the harm of opioid overdose with the safe use of naloxone: a pharmacologic review. Expert Opin Drug Saf. 2015 Jul;14(7):1137–1146.
   PubMed Web of Science ®Google Scholar
• Neale J, Strang J. Naloxone–does over-antagonism matter? Evidence of iatrogenic harm after emergency treatment of heroin/opioid overdose. Addiction. 2015 Oct;110(10):1644–1652.
   PubMed Web of Science ®Google Scholar
• Strang J, Darke S, Hall W, et al. Heroin overdose: the case for take-home naloxone. BMJ. 1996 Jun 8;312(7044):1435–1436.
   PubMedGoogle Scholar
• Strang J, McDonald R, Campbell G, et al. Take-home naloxone for the emergency interim management of opioid overdose: the public health application of an emergency medicine. Drugs. 2019 Sep;79(13):1395–1418.
   PubMed Web of Science ®Google Scholar
• Strang J. Take-home naloxone and the prevention of deaths from heroin overdose: pursuing strong science, fuller understanding, greater impact. Eur Addict Res. 2021 Dec;28:1–15.
   PubMedGoogle Scholar
• Strang J, Powis B, Best D, et al. Preventing opiate overdose fatalities with take-home naloxone: pre-launch study of possible impact and acceptability. Addiction. 1999 Feb;94(2):199–204.
   PubMed Web of Science ®Google Scholar
• Strang J, Manning V, Mayet S, et al. Family carers and the prevention of heroin overdose deaths: unmet training need and overlooked intervention opportunity of resuscitation training and supply of naloxone. Drugs: Education, Prevention and Policy. 2009;15(2):211–218.
   Google Scholar
• Nadel J. Clinical and regulatory perspectives on naloxone products intended for use in the community. October 15th 2016.
   Google Scholar
• Strang J, McDonald R, Tas B, et al. Clinical provision of improvised nasal naloxone without experimental testing and without regulatory approval: imaginative shortcut or dangerous bypass of essential safety procedures? Addiction. 2016 Apr;111(4):574–582.
   PubMed Web of Science ®Google Scholar
• Krieter PA, Chiang CN, Gyaw S, et al. Comparison of the pharmacokinetic properties of naloxone following the use of FDA-approved intranasal and intramuscular devices versus a common improvised nasal naloxone device. J Clin Pharmacol. 2019 Aug;59(8):1078–1084.
   PubMedGoogle Scholar
• McDonald R, Strang J. Are take-home naloxone programmes effective? SYSTEMATIC REVIEW UTILIZING APPLICATION OF THE BRADFORD HILL CRITERIA. Addiction. 2016 Jul;111(7):1177–1187.
   PubMed Web of Science ®Google Scholar
• Razaghizad A, Windle SB, Filion KB, et al. The effect of overdose education and naloxone distribution: an umbrella review of systematic reviews. Am J Public Health. 2021 Aug;111(8):e1–e12.
   PubMedGoogle Scholar
• Volkow ND, Frieden TR, Hyde PS, et al. Medication-assisted therapies–tackling the opioid-overdose epidemic. N Engl J Med. 2014 May 29 370(22):2063–2066
   PubMedGoogle Scholar
• Hertz S. Naloxone for outpatient use: data required to support an NDA. Division of anesthesia a, and addiction products. CDEReditor, 2012, see Supplementary Material
   Google Scholar
• Chou R, Korthuis PT, McCarty D, et al. Management of suspected opioid overdose with naloxone in out-of-hospital settings: a systematic review. Ann Intern Med. 2017 Dec 19;167(12):867–875.
   PubMedGoogle Scholar
• Skulberg AK, Tylleskar I, Valberg M, et al. Comparison of intranasal and intramuscular naloxone in opioid overdoses managed by ambulance staff: a double-dummy, randomised, controlled trial. Addiction. 2022 Feb;8:1–10. •• First double-blinded RCT of an approved naloxone spray in opioid overdose.
   Google Scholar
• WHO Guidelines Approved by the Guidelines Review Committee. Community management of opioid overdose. Geneva: World Health Organization; 2014.
   Google Scholar
• Sutter ME, Gerona RR, Davis MT, et al. Fatal fentanyl: one pill can kill. Acad Emerg Med. 2017 Jan;24(1):106–113.
   PubMed Web of Science ®Google Scholar
• Somerville NJ, O’Donnell J, Gladden RM, et al. Characteristics of fentanyl overdose - Massachusetts, 2014-2016. MMWR Morb Mortal Wkly Rep. 2017 Apr 14 66(14):382–386
   PubMedGoogle Scholar
• Poklis J, Poklis A, Wolf C, et al. Postmortem tissue distribution of acetyl fentanyl, fentanyl and their respective nor-metabolites analyzed by ultrahigh performance liquid chromatography with tandem mass spectrometry. Forensic Sci Int. 2015 Dec;257:435–441.
   PubMed Web of Science ®Google Scholar
• Foldes FF, Lunn JN, Moore J, et al. N-Allylnoroxy-morphone: a new potent narcotic antagonist. Am J Med Sci. 1963;245:23–30.
   PubMed Web of Science ®Google Scholar
• Kaufman JJ, Semo NM, Koski WS. Microelectrometric titration measurement of the pKa’s and partition and drug distribution coefficients of narcotics and narcotic antagonists and their pH and temperature dependence. J Med Chem. 1975 Jul;18(7):647–655.
   PubMedGoogle Scholar
• Fujimoto JM. Isolation of naloxone-3-glucuronide from human urine. Proc Soc Exp Biol Med. 1970 Jan;133(1):317–319.
   PubMedGoogle Scholar
• Fishman J, Roffwarg H, Hellman L. Disposition of naloxone-7,8,3H in normal and narcotic-dependent men. J Pharmacol Exp Ther. 1973 Dec;187(3):575–580.
   PubMed Web of Science ®Google Scholar
• Weinstein SH, Pfeffer M, Schor JM. Metabolism and pharmacokinetics of naloxone. Adv Biochem Psychopharmacol. 1973;8:525–535.
   PubMedGoogle Scholar
• Papathanasiou T, Springborg AD, Kongstad KT, et al. High-dose naloxone, an experimental tool uncovering latent sensitisation: pharmacokinetics in humans. Br J Anaesth. 2019 Aug;123(2):e204–e214.
   PubMedGoogle Scholar
• Tylleskar I, Skarra S, Skulberg AK, et al. The pharmacokinetic interaction between nasally administered naloxone and the opioid remifentanil in human volunteers. Eur J Clin Pharmacol. 2021 Jul 29;77:1901–1908. https://doi.org/10.1007/s00228-021-03190-1.
   Google Scholar
• Nasser AF, Heidbreder C, Liu Y, et al. Pharmacokinetics of sublingual buprenorphine and naloxone in subjects with mild to severe hepatic impairment (child-pugh classes A, B, and C), in hepatitis C virus-seropositive subjects, and in healthy volunteers. Clin Pharmacokinet. 2015 Aug;54(8):837–849.
   PubMed Web of Science ®Google Scholar
• Brennscheidt U, Brunnmuller U, Proppe D, et al. Pharmacokinetics of tilidine and naloxone in patients with severe hepatic impairment. Arzneimittelforschung. 2007;57(2):106–111.
   PubMedGoogle Scholar
• Skulberg AK, Tylleskar I, Nilsen T, et al. Pharmacokinetics and -dynamics of intramuscular and intranasal naloxone: an explorative study in healthy volunteers. Eur J Clin Pharmacol. 2018 Jul;74(7):873–883.
   PubMedGoogle Scholar
• Skulberg AK, Asberg A, Khiabani HZ, et al. Pharmacokinetics of a novel, approved, 1.4-mg intranasal naloxone formulation for reversal of opioid overdose-a randomized controlled trial. Addiction. 2019 May;114(5):859–867.
   PubMed Web of Science ®Google Scholar
• Edward EGR, Kelley G, Smith A, et al. Pharmacokinetics of 2.0 mg intranasal and intramuscular naloxone HCl administration and the impact of vasoconstrictor use on the bioavailability of intranasal naloxone HCl. Pain Med. 2016 Feb;17(2):e1.
   PubMedGoogle Scholar
• Yassen A, Olofsen E, Romberg R, et al. Mechanism-based PK/PD modeling of the respiratory depressant effect of buprenorphine and fentanyl in healthy volunteers. Clin Pharmacol Ther. 2007 Jan;81(1):50–58.
   PubMed Web of Science ®Google Scholar
• Lotsch J. Pharmacokinetic-pharmacodynamic modeling of opioids. J Pain Symptom Manage. 2005 May;29(5 Suppl):S90–103.
   PubMed Web of Science ®Google Scholar
• Olofsen E, van Dorp E, Teppema L, et al. Naloxone reversal of morphine- and morphine-6-glucuronide-induced respiratory depression in healthy volunteers: a mechanism-based pharmacokinetic-pharmacodynamic modeling study. Anesthesiology. 2010 Jun;112(6):1417–1427.
   PubMed Web of Science ®Google Scholar
• Ngai SH, Berkowitz BA, Yang JC, et al. Pharmacokinetics of naloxone in rats and in man: basis for its potency and short duration of action. Anesthesiology. 1976 May;44(5):398–401.
   PubMedGoogle Scholar
• Berkowitz BA. The relationship of pharmacokinetics to pharmacological activity: morphine, methadone and naloxone. Clin Pharmacokinet. 1976;1(3):219–230.
   PubMedGoogle Scholar
• Albeck H, Woodfield S, Kreek MJ. Quantitative and pharmacokinetic analysis of naloxone in plasma using high-performance liquid chromatography with electrochemical detection and solid-phase extraction. J Chromatogr B. 1989;488(2):435–445.
   Google Scholar
• Tylleskar I, Skulberg AK, Nilsen T, et al. Naloxone nasal spray - bioavailability and absorption pattern in a phase 1 study. Tidsskr Nor Laegeforen. 2019 Sep 24;139(13). https://doi.org/10.4045/tidsskr.19.0162.
   Google Scholar
• Dietze P, Jauncey M, Salmon A, et al. Effect of intranasal vs intramuscular naloxone on opioid overdose: a randomized clinical trial. JAMA Network Open. 2019 Nov 1 2(11):e1914977.
   PubMedGoogle Scholar
• McDonald R, Danielsson Glende O, Dale O, et al. International patent applications for non-injectable naloxone for opioid overdose reversal: exploratory search and retrieve analysis of the PatentScope database. Drug Alcohol Rev. 2018 Feb;37(2):205–215.
   PubMedGoogle Scholar
• EVZIO®. Highlights of prescribing information. , 2016 http://www.evzio.com/hcp/about-evzio/safety-and-usability.php .
   Google Scholar
• Edwards E, Gunn R, Kelley G, et al. Naloxone 0.4 mg bioavailability FNaloxone 0.4 mg bioavailability following a single injection with a novel naloxone auto-injector, EVZIOTM in healthy adults, with reference to a standard syringe and intramuscular following a single injection with a novel naloxone auto-injector, EVZIOTM, in healthy adults, with reference to a standard syringe and intramuscular needle. Pain Med. 2015;16(3):608.
   Google Scholar
• Smith K, Hopp M, Mundin G, et al. Low absolute bioavailability of oral naloxone in healthy subjects. Int J Clin Pharmacol Ther. 2012 May;50(5):360–367.
   PubMed Web of Science ®Google Scholar
• Strang J, McDonald R, Alqurshi A, et al. Naloxone without the needle - systematic review of candidate routes for non-injectable naloxone for opioid overdose reversal. Drug Alcohol Depend. 2016 Jun 1;163:16–23. https://doi.org/10.1016/j.drugalcdep.2016.02.042.
   Google Scholar
• Harris DS, Mendelson JE, Lin ET, et al. Pharmacokinetics and subjective effects of sublingual buprenorphine, alone or in combination with naloxone: lack of dose proportionality. Clin Pharmacokinet. 2004;43(5):329–340.
   PubMed Web of Science ®Google Scholar
• Weinberg DS, Inturrisi CE, Reidenberg B, et al. Sublingual absorption of selected opioid analgesics. Clin Pharmacol Ther. 1988 Sep;44(3):335–342.
   PubMed Web of Science ®Google Scholar
• Preston KL, Bigelow GE, Liebson IA. Effects of sublingually given naloxone in opioid-dependent human volunteers. Drug Alcohol Depend. 1990 Feb;25(1):27–34.
   PubMed Web of Science ®Google Scholar
• Alqurshi A, Kumar Z, McDonald R, et al. Amorphous formulation and in vitro performance testing of instantly disintegrating buccal tablets for the emergency delivery of naloxone. Mol Pharm. 2016 May 2 13(5):1688–1698.
   PubMedGoogle Scholar
• Dale O, Hjortkjaer R, Kharasch ED. Nasal administration of opioids for pain management in adults. Acta Anaesthesiol Scand. 2002 Aug;46(7):759–770.
   PubMedGoogle Scholar
• 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 Oct;29(3):265–271.
   PubMed Web of Science ®Google Scholar
• 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 Oct-Dec;13(4):512–515.
   PubMed Web of Science ®Google Scholar
• Middleton LS, Nuzzo PA, Lofwall MR, et al. The pharmacodynamic and pharmacokinetic profile of intranasal crushed buprenorphine and buprenorphine/naloxone tablets in opioid abusers. Addiction. 2011 Aug;106(8):1460–1473.
   PubMed Web of Science ®Google Scholar
• Dowling J, Isbister G K, Kirkpatrick C M, Naidoo D and Graudins A. (2008). Population Pharmacokinetics of Intravenous, Intramuscular, and Intranasal Naloxone in Human Volunteers. Therapeutic Drug Monitoring, 30(4), 490–496. https://doi.org/10.1097/FTD.0b013e3181816214
   PubMed Web of Science ®Google Scholar
• Tylleskar I, Skulberg AK, Nilsen T, et al. Pharmacokinetics of a new, nasal formulation of naloxone [journal article]. Eur J Clin Pharmacol. 2017 May;73(5):555–562.
   PubMed Web of Science ®Google Scholar
• Krieter P, Chiang N, Gyaw S, et al. Pharmacokinetic properties and human use characteristics of an FDA-approved intranasal naloxone product for the treatment of opioid overdose. J Clin Pharmacol. 2016 Oct;56(10):1243–1253.
   PubMed Web of Science ®Google Scholar
• McDonald R, Lorch U, Woodward J, et al. Pharmacokinetics of concentrated naloxone nasal spray for opioid overdose reversal: phase I healthy volunteer study. Addiction. 2018 Mar;113(3):484–493.
   PubMed Web of Science ®Google Scholar
• Loimer N, Hofmann P, Chaudhry HR. Nasal administration of naloxone for detection of opiate dependence. J Psychiatr Res. 1992 Jan;26(1):39–43.
   PubMedGoogle Scholar
• 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(6):819–827.
   PubMed Web of Science ®Google Scholar
• Clarke SF, Dargan PI, Jones AL. Naloxone in opioid poisoning: walking the tightrope. Emerg Med J. 2005 Sep;22(9):612–616.
   PubMed Web of Science ®Google Scholar
• Madah-Amiri D, Clausen T, Lobmaier P. Rapid widespread distribution of intranasal naloxone for overdose prevention. Drug Alcohol Depend. 2017 Apr 1; 173:17–23.https://doi.org/10.1016/j.drugalcdep.2016.12.013
   Google Scholar
• Buajordet I, Naess AC, Jacobsen D, et al. Adverse events after naloxone treatment of episodes of suspected acute opioid overdose. Eur J Emerg Med. 2004 Feb;11(1):19–23.
   PubMed Web of Science ®Google Scholar
• Avetian GK, Fiuty P, Mazzella S, et al. Use of naloxone nasal spray 4 mg in the community setting: a survey of use by community organizations. Curr Med Res Opin. 2018 Apr;34(4):573–576.
   PubMed Web of Science ®Google Scholar
• Moustaqim-Barrette A, Papamihali K, Williams S, et al., Adverse events related to bystander naloxone administration in cases of suspected opioid overdose in British Columbia: an observational study. PLoS One. 16(10): e0259126. 2021. .
   PubMed Web of Science ®Google Scholar
• Farkas A, Lynch MJ, Westover R, et al. Pulmonary complications of opioid overdose treated with naloxone. Ann Emerg Med. 2020 Jan;75(1):39–48.
   PubMed Web of Science ®Google Scholar
• Tas B, Jolley CJ, Kalk NJ, et al. Heroin-induced respiratory depression and the influence of dose variation: within-subject between-session changes following dose reduction. Addiction. 2020 Oct;115(10):1954–1959.
   PubMed Web of Science ®Google Scholar
• Darke S, Duflou J. The toxicology of heroin-related death: estimating survival times. Addiction. 2016 Sep;111(9):1607–1613.
   PubMed Web of Science ®Google Scholar
• McClain DA, Hug CCJ. Pharmacodynamics of opiates. Int Anesthesiol Clin. 1984;22(4):75–94.
   PubMedGoogle Scholar
• Kelly E, Sutcliffe K, Cavallo D, et al. The anomalous pharmacology of fentanyl. Br J Pharmacol. 2021 May 24. DOI:https://doi.org/10.1111/bph.15573.
   Google Scholar
• Burns G, DeRienz RT, Baker DD, et al. Could chest wall rigidity be a factor in rapid death from illicit fentanyl abuse? Clin Toxicol (Phila). 2016 Jun;54(5):420–423.
   PubMed Web of Science ®Google Scholar
• Torralva R, Janowsky A. Noradrenergic mechanisms in fentanyl-mediated rapid death explain failure of naloxone in the opioid crisis. J Pharmacol Exp Ther. 2019 Nov;371(2):453–475.
   PubMedGoogle Scholar
• Miner NB, Schutzer WE, Zarnegarnia Y, et al. Fentanyl causes naloxone-resistant vocal cord closure: a platform for testing opioid overdose treatments. Drug Alcohol Depend. 2021 Oct 1;227:108974. https://doi.org/10.1016/j.drugalcdep.2021.108974.
   Google Scholar
• Dale O, Hoffer C, Sheffels P, et al. Disposition of nasal, intravenous, and oral methadone in healthy volunteers. Clin Pharmacol Ther. 2002 Nov;72(5):536–545.
   PubMed Web of Science ®Google Scholar
• Gal TJ. Naloxone reversal of buprenorphine-induced respiratory depression. Clin Pharmacol Ther. 1989 Jan;45(1):66–71.
   PubMedGoogle Scholar
• E VD, Yassen A, Sarton E, et al. Naloxone reversal of buprenorphine-induced respiratory depression. Anesthesiology. 2006 Jul;105(1):51–57.
   PubMedGoogle Scholar
• Kim HK, Nelson LS. Reversal of Opioid-Induced Ventilatory Depression Using Low-Dose Naloxone (0.04 mg): a Case Series. J Med Toxicol. 2016 Mar;12(1):107–110.
   PubMed Web of Science ®Google Scholar
• Kim HK, Nelson LS. Management of opioid analgesic overdose. N Engl J Med. 2012 Oct 4;367(14):1371–1372. author reply 1372-3
   PubMedGoogle Scholar
• McDermott C, Collins NC. Prehospital medication administration: a randomised study comparing intranasal and intravenous routes. Emerg Med Int. 2012;2012:476161.
   PubMedGoogle Scholar
• Tylleskar I, Gjersing L, Bjornsen LP, et al. Prehospital naloxone administration - what influences choice of dose and route of administration? BMC Emerg Med. 2020 Sep 5;20(1):71.
   PubMedGoogle Scholar
• Massachusetts Department of Public Health. Data brief: opioid-related overdose deaths among Massachusetts residents 2020 [cited 2020 15th March]. Available from: https://www.mass.gov/doc/opioid-related-overdose-deaths-among-ma-residents-june-2020/download
   Google Scholar
• Tas B, McDonald R, Commentary on Darke & Duflou. Heroin-related deaths-identifying a window for intervention. Addiction. 2016 Sep;111(9):1614–1615.
   PubMedGoogle Scholar
• Bardsley R. Higher naloxone dosing may be required for opioid overdose. Am J Health Syst Pharm. 2019 Oct 30; 76(22):1835–1837.
   PubMedGoogle Scholar
• Weiner SG, Mitchell PM, Temin ES, et al. Use of intranasal naloxone by basic life support providers. Prehosp Emerg Care. 2017 May-Jun;21(3):322–326.
   PubMed Web of Science ®Google Scholar
• Klebacher R, Harris MI, Ariyaprakai N, et al. Incidence of naloxone redosing in the age of the new opioid epidemic. Prehosp Emerg Care. 2017 Nov-Dec;21(6):682–687.
   PubMed Web of Science ®Google Scholar
• Thompson J, Salter J, Bui P, et al. Safety, efficacy, and cost of 0.4-mg versus 2-mg intranasal naloxone for treatment of prehospital opioid overdose. Ann Pharmacother. 2021;6:10600280211030918.
   Google Scholar
• Faul M, Lurie P, Kinsman JM, et al. Multiple naloxone administrations among emergency medical service providers is increasing. Prehosp Emerg Care. 2017 Jul-Aug;21(4):411–419.
   PubMed Web of Science ®Google Scholar
• Bell A, Bennett AS, Jones TS, et al. Amount of naloxone used to reverse opioid overdoses outside of medical practice in a city with increasing illicitly manufactured fentanyl in illicit drug supply. Subst Abus. 2019 Mar 20;40(1):52–55.
   PubMed Web of Science ®Google Scholar
• Carpenter J, Murray BP, Atti S, et al. Naloxone dosing after opioid overdose in the era of illicitly manufactured fentanyl. J Med Toxicol. 2020 Jan;16(1):41–48.
   PubMed Web of Science ®Google Scholar
• Mahonski SG, Leonard JB, Gatz JD, et al. Prepacked naloxone administration for suspected opioid overdose in the era of illicitly manufactured fentanyl: a retrospective study of regional poison center data. Clin Toxicol (Phila). 2020 Feb;58(2):117–123.
   PubMed Web of Science ®Google Scholar
• Kim HK, Connors NJ, Mazer-Amirshahi ME. The role of take-home naloxone in the epidemic of opioid overdose involving illicitly manufactured fentanyl and its analogs. Expert Opin Drug Saf. 2019 Jun;18(6):465–475.
   PubMed Web of Science ®Google Scholar
• Armenian P, Vo KT, Barr-Walker J, et al. Fentanyl, fentanyl analogs and novel synthetic opioids: a comprehensive review. Neuropharmacology. 2018 May 15 134(Pt A):121–132
   PubMedGoogle Scholar
• Moss RB, Carlo DJ. Higher doses of naloxone are needed in the synthetic opioid era. Subst Abuse Treat Prev Policy. 2019 Feb 18; 14(1):6
   PubMedGoogle Scholar
• Coruh B, Tonelli MR, Park DR. Fentanyl-induced chest wall rigidity. Chest. 2013 Apr;143(4):1145–1146.
   PubMed Web of Science ®Google Scholar
• Tomassoni AJ, Hawk KF, Jubanyik K, et al. Multiple fentanyl overdoses - new haven, connecticut. MMWR Morb Mortal Wkly Rep. June 23, 2016 66(4):107–111
   PubMedGoogle Scholar
• McDonald R, Breidahl S, Abel-Ollo K, et al. Take-home naloxone kits: attitudes and likelihood-of-use outcomes from a European survey of potential overdose witnesses. Eur Addict Res. 2022 Feb;3:1–6.
   Google Scholar
• Smart R, Davis CS. Reducing opioid overdose deaths by expanding naloxone distribution and addressing structural barriers to care. Am J Public Health. 2021 Aug;111(8):1382–1384.
   PubMedGoogle Scholar
• Skolnick P. Treatment of overdose in the synthetic opioid era. Pharmacol Ther. 2021 Oct;9:108019.
   Google Scholar
• Hasan N, Imran M, Kesharwani P, et al. Intranasal delivery of Naloxone-loaded solid lipid nanoparticles as a promising simple and non-invasive approach for the management of opioid overdose. Int J Pharm. 2021 Apr 15;599:120428. https://doi.org/10.1016/j.ijpharm.2021.120428.
   Google Scholar
• Evzio FULL PRESCRIBING INFORMATION: food and Drugs Administration; [updated 04/2014; cited 2014 7. september]. Available from: http://www.webcitation.org/6g1VdDwWl
   Google Scholar
• Kloxxado TM. Prescribing information. 2021 April.
   Google Scholar
• Base de Données Publique des Médicaments. NALSCUE 0,9 mg/0,1 ml, Résumé des caractéristiques du produit, 2020 [cited 2020 5 october]. Available from: http://base-donnees-publique.medicaments.gouv.fr/affichageDoc.php?specid=60855566&typedoc=R
   Google Scholar