Influence of CYP2D6 activity on pre-emptive analgesia by the N-methyl-D-aspartate antagonist dextromethorphan in a randomized controlled trial of acute pain

Background: There is some evidence that dextromethorphan (DM) is effective as a preemptive analgesic agent. DM is mainly metabolized to dextrorphan (DOR) by CYP2D6 whose activity can be inhibited by pharmacologic intervention. Objectives: To investigate the efficacy of DM as a pre-emptive analgesic agent and describe the population pharmacokinetics in the presence of normal and poor CYP2D6 metabolism in acute post-operative pain. Study Design: Double blind, randomized, placebo-controlled trial Setting: Post-surgical analgesic consumption after knee ligament surgery, a setting of acute pain. Methods: Forty patients were randomized to a single oral dose of 50 mg quinidine or placebo, administered 12 hours before 50 mg DM. Patients were genotyped for the major CYP2D6 and ABCB1 variants and phenotyped for CYP2D6 using urine DM/DOR metabolic ratios and blood samples for population pharmacokinetic modeling. Results: Quinidine was effective in inhibiting CYP2D6 activity, with 2-fold reduction of DM to DOR biotransformation clearance, prolonged DM half-life, and increased DM systemic availability. Patients in the quinidine group required significantly less often NSAIDs than patients in the placebo group (35.3% vs. 75.0%, P = 0.022). The odds ratio for NSAID consumption in the placebo vs. quinidine group was 5.5 (95% confidence interval (CI) 1.3 - 22.7) at 48 hours after surgery. Limitations: While this study shows an impact of DM on pre-emptive analgesia and is mechanistically interesting, the findings need to be confirmed in larger trials. Conclusion: CYP2D6 inhibition by quinidine influenced the pre-emptive analgesic effectiveness of DM confirming that CYP2D6 phenotypic switch increases the neuromodulatory effect of oral dextromethorphan.