The hypoalgesic effect of tramadol in relation to CYP2D6.

Abstract

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.

• Authors: L Poulsen, L Arendt-Nielsen, K Brøsen, S H Sindrup
• Journal: Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 60 Issue 6 Pg. 636-44 (Dec 1996) ISSN: 0009-9236 [Print] United States
• PMID: 8988065 (Publication Type: Clinical Trial, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics, Opioid
• Sparteine
• Tramadol
• Cytochrome P-450 CYP2D6

Topics

• Adult
• Analgesics, Opioid (blood, pharmacokinetics, pharmacology)
• Cold Temperature (adverse effects)
• Cross-Over Studies
• Cytochrome P-450 CYP2D6 (metabolism)
• Double-Blind Method
• Female
• Humans
• Male
• Pain (etiology, metabolism, prevention & control)
• Pain Threshold (drug effects)
• Pressure (adverse effects)
• Reference Values
• Reflex (drug effects)
• Sparteine (metabolism)
• Tramadol (blood, pharmacokinetics, pharmacology)