title: Influence of CYP2D6 activity on pre-emptive analgesia by the N-methyl-D-aspartate antagonist dextromethorphan in a randomized controlled trial of acute pain.
abstract: BACKGROUND
  There is some evidence that dextromethorphan (DM) is effective as a pre-emptive analgesic agent.  DM is mainly metabolized to dextrorphan (DOR) by CYP2D6 whose activity can be inhibited by pharmacologic intervention.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  Double blind, randomized, placebo-controlled trial
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  CYP2D6 inhibition by quinidine influenced the pre-emptive analgesic effectiveness of DM confirming that CYP2D6 phenotypic switch increases the neuromodulatory effect of oral dextromethorphan.
authors: Division of Clinical Pharmacology and Toxicology & Multidisciplinary Pain Center, Geneva University Hospital, Geneva, Switzerland.
authors: Georg B
authors: GB
authors: Ehret
authors: Youssef
authors: Y
authors: Daali
authors: Jocelyne
authors: J
authors: Chabert
authors: Michela
authors: M
authors: Rebsamen
authors: Adriana
authors: A
authors: Wolff
authors: Alain
authors: A
authors: Forster
authors: Fouzia
authors: F
authors: Moursli
authors: Daniel
authors: D
authors: Fritschy
authors: Michel F
authors: MF
authors: Rossier
authors: Valérie
authors: V
authors: Piguet
authors: Pierre
authors: P
authors: Dayer
authors: Marianne
authors: M
authors: Gex-Fabry
authors: Jules A
authors: JA
authors: Desmeules
mesh_terms: D000293:Adolescent; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000328:Adult; D000698:Analgesia / Q000379:methods*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics / Q000378:metabolism*; D003915:Dextromethorphan / Q000627:therapeutic use*; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D016202:N-Methylaspartate; D010147:Pain Measurement; D010149:Postoperative Pain / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D011802:Quinidine / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000317:Adrenergic alpha-Antagonists; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018691:Excitatory Amino Acid Antagonists; D016202:N-Methylaspartate; D003915:Dextromethorphan; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine