TY - JOUR

T1 - High-dose naloxone, an experimental tool uncovering latent sensitisation: pharmacokinetics in humans.

AU - Papathanasiou, Theodoros

AU - Springborg, Anders

AU - Kongstad, Kenneth Thermann

AU - Stærk, Dan

AU - Møller, Kirsten

AU - Taylor, Bradley K.

AU - Lund, Trine Meldgaard

AU - Werner, Mads Utke

PY - 2019

Y1 - 2019

N2 - BackgroundNaloxone, 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.MethodsEight 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.ResultsThree- 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.ConclusionsA 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

AB - BackgroundNaloxone, 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.MethodsEight 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.ResultsThree- 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.ConclusionsA 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

U2 - 10.1016/j.bja.2018.12.007

DO - 10.1016/j.bja.2018.12.007

M3 - Journal article

C2 - 30915992

VL - 123

SP - e204-e214

JO - British Journal of Anaesthesia

JF - British Journal of Anaesthesia

SN - 0007-0912

IS - 2

ER -