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

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

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. CLINICAL TRIALS REGISTRATION: NCT01992146.