Ketamine and norketamine attenuate oxycodone tolerance markedly less than that of morphine : from behaviour to drug availability

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Lilius , T , Kangas , E , Niemi , M , Rauhala , P & Kalso , E 2018 , ' Ketamine and norketamine attenuate oxycodone tolerance markedly less than that of morphine : from behaviour to drug availability ' , British Journal of Anaesthesia , vol. 120 , no. 4 , pp. 818-826 . https://doi.org/10.1016/j.bja.2017.11.081

Title: Ketamine and norketamine attenuate oxycodone tolerance markedly less than that of morphine : from behaviour to drug availability
Author: Lilius, T.; Kangas, E.; Niemi, M.; Rauhala, P.; Kalso, E.
Contributor organization: HUSLAB
Medicum
Department of Clinical Pharmacology
Department of Pharmacology
Faculty of Medicine
University of Helsinki
Clinicum
Pekka Rauhala / Principal Investigator
Eija Kalso / Principal Investigator
Department of Diagnostics and Therapeutics
Anestesiologian yksikkö
HUS Perioperative, Intensive Care and Pain Medicine
Date: 2018-04
Language: eng
Number of pages: 9
Belongs to series: British Journal of Anaesthesia
ISSN: 0007-0912
DOI: https://doi.org/10.1016/j.bja.2017.11.081
URI: http://hdl.handle.net/10138/299449
Abstract: Background: Ketamine attenuates morphine tolerance by antagonising N-methyl-D-aspartate receptors. However, a pharmacokinetic interaction between morphine and ketamine has also been suggested. The interaction between oxycodone and ketamine is unclear. We studied the effects of ketamine and norketamine on the attenuation of morphine and oxycodone tolerance focusing on both the pharmacodynamic and pharmacokinetic interactions. Methods: Morphine 9.6 mg day(-1) or oxycodone 3.6 mg day(-1) was delivered to SpragueeDawley rats by subcutaneous pumps. Once tolerance had developed, the rats received subcutaneous injections of ketamine or norketamine. Tail-flick, hot-plate, and rotarod tests were performed. Drug concentrations were measured with high-performance liquid chromatographyetandem mass spectrometry. Results: Anti-nociceptive tolerance to morphine and oxycodone developed similarly by Day 6. Acute ketamine 10 mg kg(-1) and norketamine 30 mg kg(-1) attenuated morphine tolerance for 120 and 150 min, respectively, whereas in oxycodonetolerant rats the effect lasted only 60 min. Both ketamine and norketamine increased the brain and serum concentrations of morphine, and inhibited its metabolism to morphine-3-glucuronide, whereas oxycodone concentrations were not changed. Morphine, but not oxycodone, pretreatment increased the brain and serum concentrations of ketamine and norketamine. Ketamine, but not norketamine, significantly impaired the motor coordination. Conclusions: Ketamine and norketamine attenuated morphine tolerance more effectively than oxycodone tolerance. Ketamine and norketamine increased morphine, but not oxycodone brain concentrations, which may partly explain this difference. Norketamine is effective in attenuating morphine tolerance with minor effects on motor coordination. These results warrant pharmacokinetic studies in patients who are co-treated with ketamine and opioids.
Subject: anaesthetics
dissociative
analgesics
opioid
ketamine
morphine
oxycodone
pain
tolerance
NMDA RECEPTOR ANTAGONIST
ANTINOCICEPTIVE TOLERANCE
HEALTHY-VOLUNTEERS
PERSISTENT PAIN
RODENT MODELS
INHIBITION
RAT
GLUCURONIDATION
DEPENDENCE
PHARMACOKINETICS
3126 Surgery, anesthesiology, intensive care, radiology
Peer reviewed: Yes
Rights: cc_by_nc_nd
Usage restriction: openAccess
Self-archived version: publishedVersion


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