CYP2D6 genotype dependent oxycodone metabolism in postoperative patients.

Ulrike M Stamer,Frank Musshoff,Lan Zhang,Malte Book,Lutz E Lehmann,Frank Stuber,Balraj Mittal

doi:10.1371/journal.pone.0060239

Ulrike M Stamer, Frank Musshoff + Show 5 more

Open Access

https://doi.org/10.1371/journal.pone.0060239

Copy DOI

Abstract

BackgroundThe impact of polymorphic cytochrome P450 CYP2D6 enzyme on oxycodone's metabolism and clinical efficacy is currently being discussed. However, there are only spare data from postoperative settings. The hypothesis of this study is that genotype dependent CYP2D6 activity influences plasma concentrations of oxycodone and its metabolites and impacts analgesic consumption.MethodsPatients received oxycodone 0.05 mg/kg before emerging from anesthesia and patient-controlled analgesia (PCA) for the subsequent 48 postoperative hours. Blood samples were drawn at 30, 90 and 180 minutes after the initial oxycodone dose. Plasma concentrations of oxycodone and its metabolites oxymorphone, noroxycodone and noroxymorphone were analyzed by liquid chromatography-mass spectrometry with electrospray ionization. CYP2D6 genotyping was performed and 121 patients were allocated to the following genotype groups: PM (poor metabolizer: no functionally active CYP2D6 allele), HZ/IM (heterozygous subjects, intermediate metabolizers with decreased CYP2D6 activity), EM (extensive metabolizers, normal CYP2D6 activity) and UM (ultrarapid metabolizers, increased CYP2D6 activity). Primary endpoint was the genotype dependent metabolite ratio of plasma concentrations oxymorphone/oxycodone. Secondary endpoint was the genotype dependent analgesic consumption with calculation of equianalgesic doses compared to the standard non-CYP dependent opioid piritramide.ResultsMetabolism differed between CYP2D6 genotypes. Mean (95%-CI) oxymophone/oxycodone ratios were 0.10 (0.02/0.19), 0.13 (0.11/0.16), 0.18 (0.16/0.20) and 0.28 (0.07/0.49) in PM, HZ/IM, EM and UM, respectively (p = 0.005). Oxycodone consumption up to the 12th hour was highest in PM (p = 0.005), resulting in lowest equianalgesic doses of piritramide versus oxycodone for PM (1.6 (1.4/1.8); EM and UM 2.2 (2.1/2.3); p<0.001). Pain scores did not differ between genotypes.ConclusionsIn this postoperative setting, the number of functionally active CYP2D6 alleles had an impact on oxycodone metabolism. The genotype also impacted analgesic consumption, thereby causing variation of equianalgesic doses piritramide : oxycodone. Different analgesic needs by genotypes were met by PCA technology in this postoperative cohort.

Highlights

While morphine represents the standard analgesic in a postoperative setting, other opioids might be suitable or even advantageous
One-hundred-thirty-one patients scheduled for elective major abdominal surgery or thoracotomy gave written informed consent and were instructed in the details of the study, the use of the patient-controlled analgesia (PCA) device and the numeric rating scale for pain intensities (NRS: 0 denotes no pain, 100 denotes worst pain imaginable)
In patients receiving oxycodone for postoperative analgesia after major surgery, the CYP2D6 genotype influenced the ratio of plasma concentrations of oxymorphone/oxycodone as well as analgesic consumption via PCA during the first 12 postoperative hours

Summary

Introduction

While morphine represents the standard analgesic in a postoperative setting, other opioids might be suitable or even advantageous. Intravenous oxycodone is not a standard opioid for postoperative pain management in most countries, including Germany. As polymorphic cytochrome P450 enzymes (CYP) are involved in the metabolism, a pharmacogenetic impact on oxycodone’s efficacy is discussed [1,2,3]. Formation of the active metabolite oxymorphone depends on CYP2D6, whereas N-demethylation by CYP3A via the major pathway produces noroxycodone, a metabolite with weak antinociceptive properties. Both metabolites, oxymorphone and noroxycodone, are further degraded to noroxymorphone by CYP2D6 and CYP3A. The impact of polymorphic cytochrome P450 CYP2D6 enzyme on oxycodone’s metabolism and clinical efficacy is currently being discussed. The hypothesis of this study is that genotype dependent CYP2D6 activity influences plasma concentrations of oxycodone and its metabolites and impacts analgesic consumption

Methods

Results

Discussion

Conclusion