• Romina Klimas, Diana Witticke, Sarah El Fallah, and Gerd Mikus.
• University of Heidelberg, Department of Clinical Pharmacology and Pharmacoepidemiology, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany.
• Expert Opin Drug Metab Toxicol. 2013 May 1;9(5):517-28.

ObjectiveOxycodone (OC) is an opioid which exerts its analgesic effect through µ-receptors in the brain. It is metabolized through CYP450 enzymes and some of the metabolites show pharmacological activity. The aim of this investigation is to research the contribution of the metabolites of OC to its overall analgesic effect. A further aim was to elucidate the role of drug-drug interactions and CYP2D6 polymorphism.Research Design And MethodsThe authors performed a literature search to identify published information on: blood concentrations of OC and metabolites, protein binding, blood-brain-barrier behavior and opioid receptor affinity. The authors then calculated the contribution of OC and metabolites to the overall analgesic effect.ResultsOC itself is responsible for 83.02 and 94.76% of the analgesic effect during p.o. and i.v. administration, respectively. Oxymorphone (OM), which has a much higher affinity for the µ-receptor, only plays a minor role (15.77 and 4.52% for p.o. and i.v., respectively). Although the CYP2D6 genotype modulates OM pharmacokinetics, OC remains the major contributor to the overall analgesic effect.ConclusionThis article's calculations demonstrate that OC itself is responsible for the analgesic effect. Although OM and noroxymorphone have much higher µ-receptor affinity than the parent drug, the metabolite concentrations at the site of action are very low. This suggests that there is a minimal analgesic effect from these metabolites.

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