The hypoalgesic effect of tramadol in relation to CYP2D6.
Tramadol inhibits norepinephrine reuptake, stimulates serotonin release, and acts with mu-opioid receptors by way of its metabolite (+)-M1. Formation of M1 seems to depend on the genetic polymorphic CYP2D6. The analgesic effect of 2 mg/kg tramadol was evaluated in 15 extensive and 12 poor metabolizers of sparteine in two parallel, randomized, double-blind, placebo-controlled crossover studies that used experimental pain models. In extensive metabolizers, tramadol increased pressure pain detection (p = 0.03) and tolerance (p = 0.06) thresholds, as well as thresholds for eliciting nociceptive reflexes, after single (p = 0.0002) and repeated (p = 0.06) stimulation of the sural nerve. Peak pain and pain area in the cold pressor test were reduced (p = 0.0006 and 0.0009). In poor metabolizers, only thresholds to pressure pain tolerance (p = 0.02) and nociceptive reflexes after single stimulation (p = 0.04) were increased and the reflex threshold was less increased in poor metabolizers than in extensive metabolizers (p = 0.02). The serum concentration of (+)-M1 2 to 10 hours after tramadol ranged from 10 to 100 ng/L in extensive metabolizers, whereas in poor metabolizers serum concentrations of (+)-M1 were below or around the detection limit of 3 ng/ml. It is concluded that formation of (+)-M1 by way of CYP2D6 is important for the effect of tramadol on experimental pain.
Poulsen
L
L
Department of Clinical Pharmacology, Institute of Medical Biology, Odense University, Denmark.
Arendt-Nielsen
L
L
Brøsen
K
K
Sindrup
S H
SH
D000328:Adult; D000701:Analgesics, Opioid / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D003080:Cold Temperature / Q000009:adverse effects; D018592:Cross-Over Studies; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D010146:Pain / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D017288:Pain Threshold / Q000187:drug effects*; D011312:Pressure / Q000009:adverse effects; D012016:Reference Values; D012018:Reflex / Q000187:drug effects; D013034:Sparteine / Q000378:metabolism; D014147:Tramadol / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*
D000701:Analgesics, Opioid; D013034:Sparteine; D014147:Tramadol; D019389:Cytochrome P-450 CYP2D6