Escitalopram is a weak inhibitor of the CYP2D6-catalyzed O-demethylation of (+)-tramadol but does not reduce the hypoalgesic effect in experimental pain

Clin Pharmacol Ther. 2009 Dec;86(6):626-33. doi: 10.1038/clpt.2009.154. Epub 2009 Aug 26.

Abstract

Tramadol is O-demethylated to the active metabolite (+)-O-desmethyltramadol ((+)-M1) via CYP2D6, an enzyme that is weakly inhibited by escitalopram. We investigated the possibility of a pharmacokinetic (PK) and pharmacodynamic (PD) effect of escitalopram on tramadol metabolism. Fifteen healthy subjects completed this randomized, double-blind, three-phase, crossover trial. Combinations of escitalopram 20 mg/day or placebo together with tramadol 150 mg or placebo were used. Blood samples for pharmacokinetics were drawn at 0-24 h after medication. The analgesic effect of (+)-M was assessed by the cold pressor test (CPT) (area under effect curve, 1-12 h after medication (AUEC(1-12))). The median area under plasma concentration-time curve extrapolated to infinity (AUC(0-infinity)) of (+)-M1 was 2.75 micromol/l.h after placebo pretreatment compared with 1.95 micromol/l.h after escitalopram (P = 0.0027). The mean AUEC(1-12) of CPT were 4,140 and 4,388 cm.s after placebo and escitalopram, respectively (P = 0.71). Although escitalopram is a weak inhibitor of CYP2D6, it does not impair the analgesic effect of tramadol.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / blood
  • Analgesics, Opioid / pharmacokinetics*
  • Biotransformation
  • Citalopram / administration & dosage
  • Citalopram / blood
  • Citalopram / pharmacokinetics*
  • Cross-Over Studies
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP2D6 Inhibitors*
  • Dealkylation
  • Double-Blind Method
  • Drug Interactions
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / blood
  • Enzyme Inhibitors / pharmacokinetics*
  • Female
  • Humans
  • Male
  • Pain / prevention & control*
  • Pain Measurement
  • Reflex, Pupillary / drug effects
  • Selective Serotonin Reuptake Inhibitors / administration & dosage
  • Selective Serotonin Reuptake Inhibitors / blood
  • Selective Serotonin Reuptake Inhibitors / pharmacokinetics*
  • Tramadol / administration & dosage
  • Tramadol / analogs & derivatives
  • Tramadol / blood
  • Tramadol / pharmacokinetics*
  • Young Adult

Substances

  • Analgesics, Opioid
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Enzyme Inhibitors
  • Serotonin Uptake Inhibitors
  • Citalopram
  • O-demethyltramadol
  • Tramadol
  • Cytochrome P-450 CYP2D6