European Journal of Clinical Pharmacology

, Volume 74, Issue 7, pp 873–883 | Cite as

Pharmacokinetics and -dynamics of intramuscular and intranasal naloxone: an explorative study in healthy volunteers

  • Arne Kristian Skulberg
  • Ida Tylleskar
  • Turid Nilsen
  • Sissel Skarra
  • Øyvind Salvesen
  • Trond Sand
  • Thorsteinn Loftsson
  • Ola Dale
Clinical Trial



This study aimed to develop a model for pharmacodynamic and pharmacokinetic studies of naloxone antagonism under steady-state opioid agonism and to compare a high-concentration/low-volume intranasal naloxone formulation 8 mg/ml to intramuscular 0.8 mg.


Two-way crossover in 12 healthy volunteers receiving naloxone while receiving remifentanil by a target-controlled infusion for 102 min. The group were subdivided into three different doses of remifentanil. Blood samples for serum naloxone concentrations, pupillometry and heat pain threshold were measured.


The relative bioavailability of intranasal to intramuscular naloxone was 0.75. Pupillometry showed difference in antagonism; the effect was significant in the data set as a whole (p < 0.001) and in all three subgroups (p < 0.02–p < 0.001). Heat pain threshold showed no statistical difference.


A target-controlled infusion of remifentanil provides good conditions for studying the pharmacodynamics of naloxone, and pupillometry was a better modality than heat pain threshold. Intranasal naloxone 0.8 mg is inferior for a similar dose intramuscular. Our design may help to bridge the gap between studies in healthy volunteers and the patient population in need of naloxone for opioid overdose.

Trial registration NCT02307721


Naloxone Intranasal Pharmacodynamics Pharmacokinetics Drug overdose Remifentanil 



The Clinical Research Facility, St. Olavs Hospital, Trondheim University Hospital, conducted the study, and the Unit for Applied Clinical Research, NTNU, assisted with GCP monitoring and provided the Internet-based randomisation. The naloxone analysis were provided by the Proteomics and Metabolomics Core Facility, PROMEC, NTNU. These infrastructures are all funded by the Faculty of Medicine, NTNU, and the Central Norway Regional Health Authority. This study was supported by grants from the Liaison Committee for Education, Research and Innovation in Central Norway and the Joint Research Committee between St. Olavs Hospital, Trondheim University Hospital, and the Faculty of Medicine and Health Sciences, NTNU, Norway. Anders Åsberg, School of Pharmacy, University of Oslo, has given teaching on pharmacokinetics.

Author contributions

OD was principal investigator and contributed to all aspects of this study. AKS and IT has written the manuscript, designed the research protocol, conducted the research and analysed data. ØS has performed the mixed model statistical analysis. TN and SS has analysed serum samples and prepared data for PK analysis. TS has designed the HPT measurement program. TL has been pivotal in the development of the IN naloxone formulation, the fundament of this study. All authors have reviewed the final draft of the text.

Compliance with ethical standards

Conflict of interest

Norwegian University of Science and Technology (NTNU) and its subsidiary Technology Transfer Office (TTO) have a licencing agreement with Den norske Eterfabrikk (DnE) regarding the naloxone formulation studied. DnE has sent an application for marketing authorization for a drug for human consumption. NTNU, TTO and Ola Dale (OD) have financial benefit from these contracts. OD has been engaged by DnE as Principle Investigator in a pharmacokinetic study of naloxone for which OD receives no personal honorarium. DnE has compensated OD for two travels from Trondheim to Oslo.

Arne Kristian Skulberg (AKS) has signed a non-compete contract with DnE lasting the duration of his PhD program (estimated 2018). This does not limit AKS right to publish results and he receives no royalties or other financial benefits from DnE/NTNU. Other authors declare they have no conflicts of interest.

Supplementary material

228_2018_2443_MOESM1_ESM.docx (21 kb)
ESM 1 (DOCX 21 kb)


  1. 1.
    United Nations Office on Drugs and Crime (2016) World drug report. United Nations publication, Sales No. E.16.XI.7Google Scholar
  2. 2.
    Rudd RA, Aleshire N, Zibbell JE, Gladden RM (2016) Increases in drug and opioid overdose deaths—United States, 2000–2014. MMWR Morb Mortal Wkly Rep 64(50–51):1378–1382. CrossRefPubMedGoogle Scholar
  3. 3.
    Clarke SF, Dargan PI, Jones AL (2005) Naloxone in opioid poisoning: walking the tightrope. Emerg Med J 22(9):612–616. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    World Health Organization (2014) Community management of opioid overdose Substance Use:Google Scholar
  5. 5.
    Strang J, McDonald R, Tas B, Day E (2016) Clinical provision of improvised nasal naloxone without experimental testing and without regulatory approval: imaginative shortcut or dangerous bypass of essential safety procedures? Addiction 111(4):574–582. CrossRefPubMedGoogle Scholar
  6. 6.
    Dale O (2016) Ethical issues and stakeholders matter. Addiction 111(4):587–589. CrossRefPubMedGoogle Scholar
  7. 7.
    Dowling J, Isbister GK, Kirkpatrick CM, Naidoo D, Graudins A (2008) Population pharmacokinetics of intravenous, intramuscular, and intranasal naloxone in human volunteers. Ther Drug Monit 30(4):490–496. PubMedCrossRefGoogle Scholar
  8. 8.
    Kerr D, Kelly AM, Dietze P, Jolley D, Barger B (2009) Randomized controlled trial comparing the effectiveness and safety of intranasal and intramuscular naloxone for the treatment of suspected heroin overdose. Addiction 104(12):2067–2074. CrossRefPubMedGoogle Scholar
  9. 9.
    Costantino HR, Illum L, Brandt G, Johnson PH, Quay SC (2007) Intranasal delivery: physicochemical and therapeutic aspects. Int J Pharm 337(1–2):1–24. CrossRefPubMedGoogle Scholar
  10. 10.
    Dale O, Hoffer C, Sheffels P, Kharasch ED (2002) Disposition of nasal, intravenous, and oral methadone in healthy volunteers. Clin Pharmacol Ther 72(5):536–545. CrossRefPubMedGoogle Scholar
  11. 11.
    Pond SM, Tozer TN (1984) First-pass elimination. Basic concepts and clinical consequences. Clin Pharmacokinet 9(1):1–25. CrossRefPubMedGoogle Scholar
  12. 12.
    ADAPT Pharma NARCAN® (naloxone hydrochloride) nasal spray—PRESCRIBING INFORMATION. Accessed 22. FEBRUARY 2016 2016
  13. 13.
    Tylleskar I, Skulberg AK, Nilsen T, Skarra S, Jansook P, Dale O (2017) Pharmacokinetics of a new, nasal formulation of naloxone. Eur J Clin Pharmacol 73:1–8. CrossRefGoogle Scholar
  14. 14.
    Macleod DB, Habib AS, Ikeda K, Spyker DA, Cassella JV, Ho KY, Gan TJ (2012) Inhaled fentanyl aerosol in healthy volunteers: pharmacokinetics and pharmacodynamics. Anesth Analg 115(5):1071–1077. CrossRefPubMedGoogle Scholar
  15. 15.
    Harris SC, Perrino PJ, Smith I, Shram MJ, Colucci SV, Bartlett C, Sellers EM (2013) Abuse potential, pharmacokinetics, pharmacodynamics, and safety of intranasally administered crushed oxycodone HCl abuse-deterrent controlled-release tablets in recreational opioid users. J Clin Pharmacol 54:468–477. CrossRefPubMedGoogle Scholar
  16. 16.
    Staahl C, Upton R, Foster DJ, Christrup LL, Kristensen K, Hansen SH, Arendt-Nielsen L, Drewes AM (2008) Pharmacokinetic-pharmacodynamic modeling of morphine and oxycodone concentrations and analgesic effect in a multimodal experimental pain model. J Clin Pharmacol 48(5):619–631. CrossRefPubMedGoogle Scholar
  17. 17.
    Gufford BT, Ainslie GR, Padowski JM, Layton ME, White JR, Paine MF (2015) A novel human model to assess reversal of opioid effects. Clin Pharmacol Ther 97:S13–S14. CrossRefGoogle Scholar
  18. 18.
    Stoops WW, Lofwall MR, Nuzzo PA, Craig LB, Siegel AJ, Walsh SL (2012) Pharmacodynamic profile of tramadol in humans: influence of naltrexone pretreatment. Psychopharmacology 223(4):427–438. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Shram MJ, Silverman B, Ehrich E, Sellers EM, Turncliff R (2015) Use of remifentanil in a novel clinical paradigm to characterize onset and duration of opioid blockade by Samidorphan, a potent mu-receptor antagonist. J Clin Psychopharmacol 35(3):242–249. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Loimer N, Hofmann P, Chaudhry HR (1992) Nasal administration of naloxone for detection of opiate dependence. J Psychiatr Res 26(1):39–43CrossRefPubMedGoogle Scholar
  21. 21.
    Meissner K, Avram MJ, Yermolenka V, Francis AM, Blood J, Kharasch ED (2013) Cyclosporine-inhibitable blood-brain barrier drug transport influences clinical morphine pharmacodynamics. Anesthesiology 119(4):941–953. CrossRefPubMedGoogle Scholar
  22. 22.
    Rollins MD, Feiner JR, Lee JM, Shah S, Larson M (2014) Pupillary effects of high-dose opioid quantified with infrared pupillometry. Anesthesiology 121(5):1037–1044. CrossRefPubMedGoogle Scholar
  23. 23.
    Kharasch ED, Francis A, London A, Frey K, Kim T, Blood J (2011) Sensitivity of intravenous and oral alfentanil and pupillary miosis as minimal and noninvasive probes for hepatic and first-pass CYP3A induction. Clin Pharmacol Ther 90(1):100–108. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Friedman MS, Manini AF (2016) Validation of criteria to guide prehospital naloxone administration for drug-related altered mental status. J Med Toxicol 12(3):270–275. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Gustorff B, Felleiter P, Nahlik G, Brannath W, Hoerauf KH, Spacek A, Kress HG (2001) The effect of remifentanil on the heat pain threshold in volunteers. Anesth Analg 92(2):369–374CrossRefPubMedGoogle Scholar
  26. 26.
    Kim TE, Kim KP, Shin D, Chung YJ, Price J, Mistry P, Jang IJ, Yu KS (2012) Assessment of the analgesic effect of remifentanil using three pain models in healthy Korean volunteers: a randomized, controlled study. Basic Clin Pharmacol Toxicol 110(6):518–523. CrossRefPubMedGoogle Scholar
  27. 27.
    Lenz H, Raeder J, Draegni T, Heyerdahl F, Schmelz M, Stubhaug A (2011) Effects of COX inhibition on experimental pain and hyperalgesia during and after remifentanil infusion in humans. Pain 152(6):1289–1297. CrossRefPubMedGoogle Scholar
  28. 28.
    Comelon M, Raeder J, Stubhaug A, Nielsen CS, Draegni T, Lenz H (2016) Gradual withdrawal of remifentanil infusion may prevent opioid-induced hyperalgesia. Br J Anaesth 116(4):524–530. CrossRefPubMedGoogle Scholar
  29. 29.
    American Society of Anasthesiologists. ASA Physical Classification System.
  30. 30.
    Brown RL, Leonard T, Saunders LA, Papasouliotis O (1998) The prevalence and detection of substance use disorders among inpatients ages 18 to 49: an opportunity for prevention. Prev Med 27(1):101–110. CrossRefPubMedGoogle Scholar
  31. 31.
    Health Products Regulatory Authority Ireland Summary of product characteristics Naloxone B Braun.
  32. 32.
    Boyer EW (2012) Management of opioid analgesic overdose. N Engl J Med 367(2):146–155. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    GlaxoSmithKline UK Ltd Ultiva Injection SmPC. Datapharm. Accessed 27 june 2017
  34. 34.
    Minto CF, Schnider TW, Egan TD, Youngs E, Lemmens HJ, Gambus PL, Billard V, Hoke JF, Moore KH, Hermann DJ, Muir KT, Mandema JW, Shafer SL (1997) Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology 86(1):10–23CrossRefPubMedGoogle Scholar
  35. 35.
    AAGBI Safety Guidelines, Pre- operative Assessment and Patient Preparation (2010). The Association of Anaesthetists of Great Britain and Ireland,Google Scholar
  36. 36.
    US Food and Drug Administration (2001) Statistical approaches to establishing bioequivalence. Guidance for industryGoogle Scholar
  37. 37.
    Olofsen E, van Dorp E, Teppema L, Aarts L, Smith TW, Dahan A, Sarton E (2010) Naloxone reversal of morphine- and morphine-6-glucuronide-induced respiratory depression in healthy volunteers: a mechanism-based pharmacokinetic-pharmacodynamic modeling study. Anesthesiology 112(6):1417–1427. CrossRefPubMedGoogle Scholar
  38. 38.
    Middleton LS, Nuzzo PA, Lofwall MR, Moody DE, Walsh SL (2011) The pharmacodynamic and pharmacokinetic profile of intranasal crushed buprenorphine and buprenorphine/naloxone tablets in opioid abusers. Addiction 106(8):1460–1473. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Yu EH, Tran DH, Lam SW, Irwin MG (2016) Remifentanil tolerance and hyperalgesia: short-term gain, long-term pain? Anaesthesia 71(11):1347–1362. CrossRefPubMedGoogle Scholar
  40. 40.
    Rosow CE, Gomery P, Chen TY, Stefanovich P, Stambler N, Israel R (2007) Reversal of opioid-induced bladder dysfunction by intravenous naloxone and methylnaltrexone. Clin Pharmacol Ther 82(1):48–53. CrossRefPubMedGoogle Scholar
  41. 41.
    Kharasch ED, Hoffer C, Whittington D (2004) Influence of age on the pharmacokinetics and pharmacodynamics of oral transmucosal fentanyl citrate. Anesthesiology 101(3):738–743CrossRefPubMedGoogle Scholar
  42. 42.
    Krieter P, Chiang N, Gyaw S, Skolnick P, Crystal R, Keegan F, Aker J, Beck M, Harris J (2016) Pharmacokinetic properties and human use characteristics of an FDA-approved intranasal naloxone product for the treatment of opioid overdose. J Clin Pharmacol 56(10):1243–1253. CrossRefPubMedGoogle Scholar
  43. 43.
    McDonald R, Lorch U, Woodward J, Bosse B, Dooner H, Mundin G, Smith K, Strang J (2017) Pharmacokinetics of concentrated naloxone nasal spray for opioid overdose reversal: phase I healthy volunteer study. Addiction 113:484–493. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    McDonald R, Danielsson Glende O, Dale O, Strang J (2017) International patent applications for non-injectable naloxone for opioid overdose reversal: exploratory search and retrieve analysis of the PatentScope database. Drug Alcohol Rev 37:205–215. CrossRefPubMedGoogle Scholar
  45. 45.
    Evzio Full prescribing information (2014)Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Arne Kristian Skulberg
    • 1
    • 2
  • Ida Tylleskar
    • 1
  • Turid Nilsen
    • 1
  • Sissel Skarra
    • 1
  • Øyvind Salvesen
    • 3
  • Trond Sand
    • 4
    • 5
  • Thorsteinn Loftsson
    • 6
  • Ola Dale
    • 1
    • 7
  1. 1.Department of Circulation and Medical Imaging, Faculty of Medicine and Health SciencesNTNU-Norwegian University of Science and TechnologyTrondheimNorway
  2. 2.Department of Anaesthesiology and Critical CareOslo University HospitalOsloNorway
  3. 3.Department of Public Health and Nursing, Faculty of Medicine and Health SciencesNTNU-Norwegian University of Science and TechnologyTrondheimNorway
  4. 4.Department of Neuromedicine and Movement Science, Faculty of Medicine and Health SciencesNTNU-Norwegian University of Science and TechnologyTrondheimNorway
  5. 5.Department of Neurology and Clinical Neurophysiology, St. Olavs HospitalTrondheim University HospitalTrondheimNorway
  6. 6.Department of Pharmaceutical SciencesUniversity of IcelandReykjavikIceland
  7. 7.Department of Research, St. Olavs HospitalTrondheim University HospitalTrondheimNorway

Personalised recommendations