¹Geneva University Hospital, Geneva, Switzerland

Abstract

Background: Oxycodone's (OX) major and minor metabolic routes (N- and O- demethylation) involve CYP3A4 and 2D6, respectively. We investigated their relative contribution on the antinociceptive effects of OX.

Methods: Randomized, double-blind, placebo-controlled, crossover, 5-arm, PK-PD study in 10 healthy genotyped males (1PM, 7EM, 2UM for CYP2D6, AmpliChip^TM Roche). They received orally placebo (P), single OX dose (0,2 mg/kg), OX 2h after CYP2D6 blockade with 100 mg quinidine (Q), OX 2h after CYP3A4 blockade with ketoconazole (K), or OX+Q+K. Naloxone (NX) iv was given 1.75h later. CYP2D6 (dextromethorphan) and CYP3A4 (midazolam) activity were assessed at each session. PK was followed for 24h and PD for 6h. Quantitative sensory testing using (thermal), nociceptive flexion reflex (electrical) (Viking IV, Madison USA), cold pressor test, and digital pupillometry (NeurOptics PLR-100) were performed.

Results: After OX alone, the peak supraspinal antinociceptive effect increased in EM (37% SEM19), the PM did not experience significant effect (4%) whereas both UM showed a clear-cut increase (49 & 108%, p<0.05). Antinociceptive effects were inversely correlated with pupil diameter. NX reversed all OX PD effects. CYP3A4 inhibition by K enhanced (2-fold) the magnitude of OX effect. Adverse events (nausea, vomiting, drowsiness, headache, hallucinations) were observed with K or in UM only.

Conclusion: Both CYP2D6 genotype and CYP3A4 activity exert a determinant role on PK, PD, and safety of OX.