Escitalopram is a weak inhibitor of the CYP2D6-catalyzed O-demethylation of (+)-tramadol but does not reduce the hypoalgesic effect in experimental pain.
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.
Noehr-Jensen
L
L
Institute of Public Health, Clinical Pharmacology, University of Southern Denmark, Odense, Denmark. lnjensen@health.sdu.dk
Zwisler
S T
ST
Larsen
F
F
Sindrup
S H
SH
Damkier
P
P
Brosen
K
K
D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001711:Biotransformation; D015283:Citalopram / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003640:Dealkylation; D004311:Double-Blind Method; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D010146:Pain / Q000517:prevention & control*; D010147:Pain Measurement; D012025:Reflex, Pupillary / Q000187:drug effects; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014147:Tramadol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
D000701:Analgesics, Opioid; D015283:Citalopram; D019389:Cytochrome P-450 CYP2D6; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D017367:Selective Serotonin Reuptake Inhibitors; D014147:Tramadol; C080580:O-demethyltramadol