High-dose naloxone, an experimental tool uncovering latent sensitisation: pharmacokinetics in humans. (August 2019)

• Record Type: Journal Article
• Authors: Papathanasiou, Theodoros; Springborg, Anders Deichmann; Kongstad, Kenneth Thermann; Staerk, Dan; Møller, Kirsten; Taylor, Bradley Kenneth; Lund, Trine Meldgaard; Werner, Mads Utke
• Is Part Of: British journal of anaesthesia. Volume 123:Number 2(2019)
• Page Start: e204
• Page End: e214
• Publication Date: 2019-08
• Subjects: central sensitisation -- chronic pain -- naloxone -- pharmacokinetics -- opioid receptor antagonist -- endogenous opioids; Anesthesiology -- Periodicals; Anesthesia -- Periodicals; 617.9605
• DOI: 10.1016/j.bja.2018.12.007
• Languages: English
• ISSNs: 0007-0912

Abstract

Abstract: 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.