High-dose naloxone, an experimental tool uncovering latent sensitisation: pharmacokinetics in humans

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Background: Naloxone, an opioid receptor antagonist, is used as a pharmacological tool to detect tonic endogenous activation of opioid receptors in experimental pain models. We describe a pharmacokinetic model linking naloxone pharmacokinetics to its main metabolite after high-dose naloxone infusion. Methods: Eight healthy volunteers received a three-stage stepwise high-dose i.v. naloxone infusion (total dose 3.25 mg kg−1). Naloxone and naloxone-3-glucuronide (N3G) plasma concentrations were sampled from infusion onset to 334 min after infusion discontinuation. Pharmacokinetic analysis was performed using non-linear mixed effect models (NONMEM). The predictive performances of Dowling's and Yassen's models were evaluated, and target-controlled infusion simulations were performed. Results: Three- and two-compartment disposition models with linear elimination kinetics described the naloxone and N3G concentration time-courses, respectively. Two covariate models were developed: simple (weight proportional) and complex (with the shallow peripheral volume of distribution linearly increasing with body weight). The median prediction error (MDPE) and wobble for Dowling's model were –32.5% and 33.4%, respectively. For Yassen's model, the MDPE and wobble were 1.2% and 19.9%, respectively. Conclusions: A parent–metabolite pharmacokinetic model was developed for naloxone and N3G after high-dose naloxone infusion. No saturable pharmacokinetics were observed. Whereas Dowling's model was inaccurate and over-predicted naloxone concentrations, Yassen's model accurately predicted naloxone pharmacokinetics. The newly developed covariate models may be used for high-dose TCI-naloxone for experimental and clinical practice. Clinical trials registration: NCT01992146.


  • Theodoros Papathanasiou
  • Anders Deichmann Springborg
  • Kenneth Thermann Kongstad
  • Dan Staerk
  • Kirsten Møller
  • Bradley Kenneth Taylor
  • Trine Meldgaard Lund
  • Mads Utke Werner
Enheter & grupper
Externa organisationer
  • University of Copenhagen
  • University of Kentucky
  • Copenhagen University Hospital

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Anestesi och intensivvård
  • Farmaceutisk vetenskap


Sidor (från-till)e204-e214
TidskriftBritish Journal of Anaesthesia
Utgåva nummer2
Tidigt onlinedatum2019 jan 18
StatusPublished - 2019
Peer review utfördJa