High-dose naloxone, an experimental tool uncovering latent sensitisation : pharmacokinetics in humans
(2019) In British Journal of Anaesthesia 123(2). p.204-214- 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... (More)
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.
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- author
- Papathanasiou, Theodoros ; Springborg, Anders Deichmann ; Kongstad, Kenneth Thermann ; Staerk, Dan ; Møller, Kirsten ; Taylor, Bradley Kenneth ; Lund, Trine Meldgaard and Werner, Mads Utke LU
- organization
- publishing date
- 2019-01-18
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- central sensitisation, chronic pain, endogenous opioids, naloxone, opioid receptor antagonist, pharmacokinetics
- in
- British Journal of Anaesthesia
- volume
- 123
- issue
- 2
- pages
- 204 - 214
- publisher
- Elsevier
- external identifiers
-
- scopus:85060082638
- pmid:30915992
- ISSN
- 0007-0912
- DOI
- 10.1016/j.bja.2018.12.007
- language
- English
- LU publication?
- yes
- id
- 73d7a618-7578-4b3b-8ebe-4e5f472b1d04
- date added to LUP
- 2019-01-29 14:40:59
- date last changed
- 2024-04-15 21:44:46
@article{73d7a618-7578-4b3b-8ebe-4e5f472b1d04,
abstract = {{<p>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<sup>−1</sup>). 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.</p>}},
author = {{Papathanasiou, Theodoros and Springborg, Anders Deichmann and Kongstad, Kenneth Thermann and Staerk, Dan and Møller, Kirsten and Taylor, Bradley Kenneth and Lund, Trine Meldgaard and Werner, Mads Utke}},
issn = {{0007-0912}},
keywords = {{central sensitisation; chronic pain; endogenous opioids; naloxone; opioid receptor antagonist; pharmacokinetics}},
language = {{eng}},
month = {{01}},
number = {{2}},
pages = {{204--214}},
publisher = {{Elsevier}},
series = {{British Journal of Anaesthesia}},
title = {{High-dose naloxone, an experimental tool uncovering latent sensitisation : pharmacokinetics in humans}},
url = {{http://dx.doi.org/10.1016/j.bja.2018.12.007}},
doi = {{10.1016/j.bja.2018.12.007}},
volume = {{123}},
year = {{2019}},
}