Impact of the CYP2D6 genotype on post-operative intravenous oxycodone analgesia S. T. ZWISLER 1,2 , T. P. ENGGAARD 1,2 , S. MIKKELSEN 1 , K. BROSEN 2 and S. H. SINDRUP 3 1 Department of Anaesthesiology and Intensive Care, Odense University Hospital, Odense, Denmark, 2 Clinical Pharmacology, Institute of Public Health, University of Southern Denmark, Denmark and 3 Department of Neurology, Odense University Hospital, Odense, Denmark Background: Oxycodone is a semi-synthetic opioid with a m-receptor agonist-mediated effect in several pain con- ditions, including post-operative pain. Oxycodone is metabolized to its active metabolite oxymorphone by O-demethylation via the polymorphic CYP2D6. The aim of this study was to investigate whether CYP2D6 poor metabolizers (PMs) yield the same analgesia post-opera- tively from intravenous oxycodone as extensive metabo- lizers (EMs). Methods: Two hundred and seventy patients undergoing primarily thyroid surgery or hysterectomy were included and followed for 24 h post-operatively. The CYP2D6 genotype was blinded until study procedures had been completed for all patients. All patients received intravenous oxycodone as pain treatment for 24 h post-operatively and morphine 5 mg was used as escape medication. A responder was characterized as a patient without the need for escape medica- tion and a positive evaluation in a questionnaire 24 h post- operatively. Results: Twenty-four patients were PM (8.9%) and 246 were EM (91.1%). One PM (4.17%, CI 5 0.1–21.1) was a non- responder and 42 EM (17.07%, CI 5 12.6–22.4) were non- responders. The non-responder rate did not differ between the two genotypes (P 5 0.14). There was no difference in the total consumption of oxycodone between the two geno- types (EM 5 14.7 mg, CI 5 13.0–16.4 and PM 5 13.0 mg, CI 5 8.9–17.0, P 5 0.42). The mean oxymorphone/oxyco- done ratios were 0.0031 and 0.00081 in the EMs and PMs, respectively (Po0.0001). Conclusion: This study showed for the first time in patients that the oxymorphone formation depends on CYP2D6, but we found no difference in the post-operative analgesic effect of intravenous oxycodone between the two CYP2D6 genotypes. Accepted for publication 8 July 2009 r 2009 The Authors Journal compilation r 2009 The Acta Anaesthesiologica Scandinavica Foundation O XYCODONE is a semi synthetic opioid with effects in both acute and chronic pain condi- tions. 1–3 Oxycodone is generally considered to be a m-opioid agonist 4,5 with a lower affinity for the receptor than morphine. 6 However, it has also been suggested that oxycodone interacts with k-opioid receptors. 7 Active metabolites could also be im- portant for the analgesic effect and side effects. Oxycodone is metabolized in the liver by O- and N- demethylation, 6-ketoreduction and conjugation with glucuronic acid (Fig. 1). The N-demethylation via CYP3A4 is quantitatively the most important route, but the metabolite noroxycodone has only a weak antinociceptive effect. 8 The O-demethylation to oxymorphone mainly via CYP2D6 9 only ac- counts for approximately 11% of the metabolism of oxycodone, but oxymorphone has a m-receptor affinity 10–40 times higher than oxycodone and is itself a very potent antinociceptive drug. 10 Noroxy- morphone, the metabolite of noroxycodone and oxymorphone, is also a m-receptor agonist, but recent studies have revealed the lack of an antino- ciceptive effect of noroxymorphone after systemic administration. 11 Local formation of oxymorphone via CYP2D6 expressed in the brain 12 could theore- tically make this quantitatively less important me- tabolic pathway important for the analgesic effect, because oxycodone may be actively transported over the blood–brain barrier 13 and its formation may be in close relation to the m-opioid receptor. 14 Blocking CYP2D6 in humans by oral doses of quinidine caused a reduction in the oxymorphone concentration, but the study did not include eva- luation of the analgesic effect. 15 Because of a genetic polymorphism, the popula- tion can be divided into four groups according to the CYP2D6 genotype: poor metabolizers (PM) with two non-functional alleles, intermediate 232 Acta Anaesthesiol Scand 2010; 54: 232–240 Printed in Singapore. All rights reserved r 2009 The Authors Journal compilation r 2009 The Acta Anaesthesiologica Scandinavica Foundation ACTA ANAESTHESIOLOGICA SCANDINAVICA doi: 10.1111/j.1399-6576.2009.02104.x