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

T Lilius; E Kangas; M Niemi; P Rauhala; E Kalso

doi:10.1016/j.bja.2017.11.081

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

Br J Anaesth. 2018 Apr;120(4):818-826. doi: 10.1016/j.bja.2017.11.081. Epub 2017 Dec 2.

Authors

T Lilius¹, E Kangas², M Niemi³, P Rauhala², E Kalso⁴

Affiliations

¹ Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; HUSLAB, Helsinki University Hospital, Helsinki, Finland. Electronic address: tuomas.lilius@helsinki.fi.
² Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
³ Department of Clinical Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; HUSLAB, Helsinki University Hospital, Helsinki, Finland.
⁴ Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Anaesthesiology, Intensive Care Medicine, and Pain Medicine, Pain Clinic, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

PMID: 29576122
DOI: 10.1016/j.bja.2017.11.081

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 Sprague-Dawley 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 chromatography-tandem 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 oxycodone-tolerant 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.

Keywords: anaesthetics; analgesics; dissociative; ketamine; morphine; opioid; oxycodone; pain; tolerance.

MeSH terms

Analgesics / pharmacology*
Analgesics, Opioid / pharmacology*
Animals
Drug Interactions
Drug Tolerance / physiology*
Ketamine / analogs & derivatives
Ketamine / pharmacology*
Male
Models, Animal
Morphine / pharmacology*
Oxycodone / pharmacology*
Rats
Rats, Sprague-Dawley

Substances

Analgesics
Analgesics, Opioid
Ketamine
Morphine
Oxycodone
norketamine