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

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.

Keywords: central sensitisation; chronic pain; endogenous opioids; naloxone; opioid receptor antagonist; pharmacokinetics.

Fig 1

Observed concentration–time profiles for naloxone and naloxone-3-glucuronide (N3G) after high-dose naloxone infusion. Solid lines present the population predicted trajectory for the simple body weight proportional model (red), Dowling's model (blue), and Yassen's model (orange)., Thin red lines present the individual post hoc trajectories based on the simple body weight proportional model. The inset presents the period after infusion discontinuation (i.e. time interval 76–334 min) where the distribution and elimination kinetics are most evident (note the log-concentration scale). Only predictions based on the simple PK model are presented for simplicity.

Fig 2

Goodness-of-fit plots presenting the population and individual predicted naloxone concentrations for the simple body weight proportional model and the complex model with body weight linearly related to V2_Nxvs time and observed naloxone concentrations. The black line is the line of identity and the red line is a linear regression.

Fig 3

Goodness-of-fit plots presenting the population and individual predicted naloxone-3-glucuronide (N3G) concentrations for the simple body weight proportional model and the complex model with body weight linearly related to V2_Nxvs time and observed N3G concentrations. The black line is the line of identity and the red line is a linear regression.

Fig 4

Comparison of infusion rate (left), target-controlled infusion (TCI) predicted naloxone concentrations (middle) and cumulative naloxone dose over time (right) for TCI driven by the simple body weight proportional model (NONMEM) (red), Dowling's model (blue) and Yassen's model (orange). A 40 min infusion of naloxone at a target plasma concentration of 1000 ng ml⁻¹ was simulated for a 70 kg subject for all models (solid line), and an 80 kg (dashed line) and 90 kg (medium dashed line) subject for the new model. The maximum infusion rate (8 mg min⁻¹) was chosen in order to obtain the target naloxone concentration within 10 min for a 70 kg subject when evaluated using the simple model. Only predictions based on the simple PK model are presented for simplicity.

Fig 5

Simulated population profiles for a typical 70 kg individual based on the simple body weight proportional model for naloxone and naloxone-3-glucuronide. The dosing schemes are based on two published reports., Prediction in red: i.v. bolus of naloxone (5 μg kg⁻¹, 2 min), followed by an initial infusion of 40 μg kg⁻¹ h⁻¹ over 20 min and a secondary infusion of 20 μg kg⁻¹ h⁻¹ over 8 min. Prediction in blue: i.v. bolus of naloxone (4 mg, 20 s), followed by a naloxone infusion of 7 μg kg⁻¹ h⁻¹ over 16.7 min.