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European Journal of Clinical Pharmacology

, Volume 74, Issue 12, pp 1547–1553 | Cite as

Pharmacodynamics and arteriovenous difference of intravenous naloxone in healthy volunteers exposed to remifentanil

  • Ida Tylleskar
  • Arne Kristian Skulberg
  • Sissel Skarra
  • Turid Nilsen
  • Ola Dale
Pharmacodynamics
  • 118 Downloads

Abstract

Purpose

Pharmacodynamic studies of naloxone require opioid agonism. Steady state condition may be achieved by remifentanil TCI (target controlled infusion). Opioid agonism can be measured by pupillometry. It is not known whether there are arteriovenous concentration differences for naloxone. The aim was thus to further develop a model for studying pharmacokinetic/pharmacodynamic aspects of naloxone and to explore whether a significant arteriovenous concentration difference for naloxone in humans was present.

Methods

Relevant authorities approved this study. Healthy volunteers (n = 12) were given 1.0 mg intravenous (IV) naloxone after steady state opioid agonism was obtained by TCI of remifentanil (1.3 ng/ml). Opioid effect was measured by pupillometry. Arterial and venous samples were collected simultaneously before and for 2 h after naloxone administration for quantification of naloxone and remifentanil.

Results

Arterial remifentanil was in steady state at 12 min. One milligram IV naloxone reversed the effect of remifentanil to 93% of pre-opioid pupil-size within 4 min. The estimated duration of antagonism was 118 min. At that time, the concentration of naloxone was 0.51 ng/ml. The time course of arterial and venous serum concentrations for naloxone was similar, although arterial AUC (area under the curve) was slightly lower (94%) than the venous AUC (p = 0.03). There were no serious adverse events.

Conclusion

Onset of reversal by IV naloxone was rapid and lasted 118 min. The minimum effective concentration was 0.5 ng/ml. Using TCI remifentanil to obtain a steady-state opioid agonism may be a useful tool to compare new naloxone products.

Keywords

Pharmacodynamics Naloxone Remifentanil Pharmacokinetics Arteriovenous difference 

Notes

Acknowledgements

The authors wish to thank the Intensive Care Unit, St. Olavs hospital, Trondheim University Hospital, for the use of their facilities for conduction of the study, and the anaesthesiologists Pål Klepstad, Ole Kristian Rolfseng and Johan Arnt Hegvik for their aid with arterial cannulation. We are grateful for the Clinical Research Facility, St. Olavs hospital, Trondheim University Hospital and their nurses for assistance with the study. Thanks to Unit for Applied Clinical Research, NTNU, for assistance with GCP monitoring. The naloxone and remifentanil analyses were provided by the Proteomics and Metabolomics Core Facility, PROMEC, NTNU.

Funding information

The Clinical Research Facility, the Unit for Applied Clinical Research and PROMEC are funded by the Faculty of Medicine and Health Sciences, NTNU and the Central Norway Regional Health Authority. This study was supported by grants from the Faculty of Medicine and Health Sciences at NTNU, The Research Council of Norway and Felles Forskningsutvalg, NTNU/St. Olavs hospital, Trondheim University Hospital, Norway.

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 a naloxone nasal spray formulation. 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. Farma Industry AS (sister company to dne pharma) has recently gained market approval in 12 european countries for this spray, containing 1.4 mg Naloxone-HCl. 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_2545_MOESM1_ESM.pdf (38 kb)
Supplementary file 1 (PDF 37 kb)

References

  1. 1.
    Staahl C, Upton R, Foster DJ, Christrup LL, Kristensen K, Hansen SH et al (2008) Pharmacokinetic-pharmacodynamic modeling of morphine and oxycodone concentrations and analgesic effect in a multimodal experimental pain model. J Clin Pharmacol 48(5):619–631CrossRefGoogle Scholar
  2. 2.
    Harris SC, Perrino PJ, Smith I, Shram MJ, Colucci SV, Bartlett C, Sellers EM (2014) 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(4):468–477CrossRefGoogle Scholar
  3. 3.
    Friedman MS, Manini AF (2016) Validation of criteria to guide prehospital naloxone administration for drug-related altered mental status. J Med Toxicol 12(3):270–275CrossRefGoogle Scholar
  4. 4.
    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):100–108CrossRefGoogle Scholar
  5. 5.
    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):941–953CrossRefGoogle Scholar
  6. 6.
    Rollins MD, Feiner JR, Lee JM, Shah S, Larson M (2014) Pupillary effects of high-dose opioid quantified with infrared pupillometry. Anesthesiology 121(5):1037–1044CrossRefGoogle Scholar
  7. 7.
    Loimer N, Hofmann P, Chaudhry HR (1994) Nasal administration of naloxone is as effective as the intravenous route in opiate addicts. Int J Addict 29(6):819–827CrossRefGoogle Scholar
  8. 8.
    Loimer N, Hofmann P, Chaudhry HR (1992) Nasal administration of naloxone for detection of opiate dependence. J Psychiatr Res 26(1):39–43CrossRefGoogle Scholar
  9. 9.
    Gufford BT, Ainslie GR, White JR, Layton ME, Padowski JM, Pollack GM, Paine MF (2017) Comparison of a New Intranasal Naloxone Formulation to Intramuscular Naloxone: Results from Hypothesis-generating Small Clinical Studies. Clin Transl Sci 10:380–386CrossRefGoogle Scholar
  10. 10.
    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):1460–1473CrossRefGoogle Scholar
  11. 11.
    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):427–438CrossRefGoogle Scholar
  12. 12.
    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):242–249CrossRefGoogle Scholar
  13. 13.
    Rentsch KM, Kullak-Ublick GA, Reichel C, Meier PJ, Fattinger K (2001) Arterial and venous pharmacokinetics of intravenous heroin in subjects who are addicted to narcotics. Clin Pharmacol Ther 70(3):237–246CrossRefGoogle Scholar
  14. 14.
    Moksnes K, Fredheim OM, Klepstad P, Kaasa S, Angelsen A, Nilsen T, Dale O (2008) Early pharmacokinetics of nasal fentanyl: is there a significant arterio-venous difference? Eur J Clin Pharmacol 64(5):497–502CrossRefGoogle Scholar
  15. 15.
    Hermann DJ, Egan TD, Muir KT (1999) Influence of arteriovenous sampling on remifentanil pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 65(5):511–518CrossRefGoogle Scholar
  16. 16.
    Skulberg AK, Tylleskar I, Nilsen T, Skarra S, Salvesen Ø, Sand T, Loftsson T, Dale O (2018) Pharmacokinetics and -dynamics of intramuscular and intranasal naloxone in healthy volunteers. Eur J Clin Pharmacol 74(7):873–883CrossRefGoogle Scholar
  17. 17.
    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):1289–1297CrossRefGoogle Scholar
  18. 18.
    Brzezinski M, Luisetti T, London MJ (2009) Radial artery cannulation: a comprehensive review of recent anatomic and physiologic investigations. Anesth Analg 109(6):1763–1781CrossRefGoogle Scholar
  19. 19.
    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):101–110CrossRefGoogle Scholar
  20. 20.
    Norwegian Medicines Agency. Remifentanil Ultiva 2 mg - Summary of Product Characteristics [updated 28.03.2014Google Scholar
  21. 21.
    Minto CF, Schnider TW, Egan TD, Youngs E, Lemmens HJ, Gambus PL et al (1997) Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I Model development. Anesthesiology 86(1):10–23CrossRefGoogle Scholar
  22. 22.
    Minto CF, Schnider TW, Shafer SL (1997) Pharmacokinetics and pharmacodynamics of remifentanil. II Model application. Anesthesiology 86(1):24–33CrossRefGoogle Scholar
  23. 23.
    The Association of Anaesthetists of Great Britain and Ireland. AAGBI Safety Guidelines, Pre- operative Assessment and Patient Preparation. Verma R, editor2010Google Scholar
  24. 24.
    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(5):555–562CrossRefGoogle Scholar
  25. 25.
    Bender J, van den Elshout J, Selinger K, Broeders G, Dankers J, van der Heiden C (1999) Determination of remifentanil in human heparinised whole blood by tandem mass spectrometry with short-column separation. J Pharm Biomed Anal 21(3):559–567CrossRefGoogle Scholar
  26. 26.
    Dadgar D, Burnett PE, Choc MG, Gallicano K, Hooper JW (1995) Application issues in bioanalytical method validation, sample analysis and data reporting. J Pharm Biomed Anal 13(2):89–97CrossRefGoogle Scholar
  27. 27.
    Shah VP, Midha KK, Dighe S, McGilveray IJ, Skelly JP, Yacobi A et al (1991) Analytical methods validation: bioavailability, bioequivalence and pharmacokinetic studies. Conference report. Eur J Drug Metab Pharmacokinet 16(4):249–255CrossRefGoogle Scholar
  28. 28.
    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):1243–1253CrossRefGoogle Scholar
  29. 29.
    McDonald R, Lorch U, Woodward J, Bosse B, Dooner H, Mundin G et al (2018) Pharmacokinetics of concentrated naloxone nasal spray for opioid overdose reversal: Phase I healthy volunteer study. Addiction 113(3):484–493CrossRefGoogle Scholar
  30. 30.
    Kharasch ED, Hoffer C, Whittington D (2004) Influence of age on the pharmacokinetics and pharmacodynamics of oral transmucosal fentanyl citrate. Anesthesiology 101(3):738–743CrossRefGoogle Scholar
  31. 31.
    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):1417–1427CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  1. 1.Department of Circulation and Medical ImagingNTNU - Norwegian University of Science and TechnologyTrondheimNorway
  2. 2.Clinic of Emergency Medicine and Prehospital Care, St. Olavs hospital, Trondheim University HospitalTrondheimNorway
  3. 3.Division of Emergencies and Critical Care, Department of AnaesthesiologyOslo University HospitalOsloNorway
  4. 4.Department of Research and Development, St. Olavs hospitalTrondheim University HospitalTrondheimNorway

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