title: Are poor metabolisers of sparteine/debrisoquine less pain tolerant than extensive metabolisers?
abstract: It has recently been shown that O-demethylation of the opioid drug codeine to morphine depends on the sparteine/debrisoquine oxygenase (CYP2D6) which in man exhibits genetic polymorphism. Morphine may be an endogenously formed substance in mammalians. Therefore, it may be hypothesized that the final step in an endogenous synthesis of morphine from codeine also depends on CYP2D6. CYP2D6, which is present in the liver and presumably also in the brain, is not expressed in subjects who are poor metabolisers of the sparteine/debrisoquine type. We have determined sensitivity to painful stimuli in 94 extensive metabolisers and 82 poor metabolisers of sparteine in 2 phasic (pain thresholds to heat and pressure) and 1 tonic (cold pressor test) experimental pain model. Extensive and poor metabolisers did not differ significantly in the 2 phasic pain models neither with respect to pain detection nor pain tolerance thresholds. However, for the cold pressor test, peak pain ratings and area under the pain rating-time curve during 2 min were significantly higher in poor than in extensive metabolisers (P = 0.0024 and 0.044). Furthermore, a substantially higher fraction of poor metabolisers prematurely withdrew their hand from the ice water during the cold pressor test due to intolerable pain (32 vs. 18%, P = 0.0545). We conclude that poor metabolisers of sparteine may be less tolerant to tonic pain than extensive metabolisers, and we hypothesize that this may be related to an inherited defect in endogenous synthesis of morphine via CYP2D6 in the brain.
authors.affiliation: Department of a Clinical Pharmacology, Odense University, OdenseDenmark Department of Medical Informatics, Aalborg University, AalborgDenmark.
authors.forename: Søren H
authors.initials: SH
authors.lastname: Sindrup
authors.forename: Lars
authors.initials: L
authors.lastname: Poulsen
authors.forename: Kim
authors.initials: K
authors.lastname: Brøsen
authors.forename: Lars
authors.initials: L
authors.lastname: Arendt-Nielsen
authors.forename: Lars F
authors.initials: LF
authors.lastname: Gram
mesh_terms: D000328:Adult; D001921:Brain / Q000201:enzymology; D003061:Codeine / Q000494:pharmacology; D003080:Cold Temperature; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003647:Debrisoquin / Q000378:metabolism*; D005260:Female; D006801:Humans; D008099:Liver / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010146:Pain / Q000201:enzymology / Q000378:metabolism* / Q000523:psychology; D010147:Pain Measurement / Q000187:drug effects; D010641:Phenotype; D013034:Sparteine / Q000378:metabolism*
chemical_list: D013034:Sparteine; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D019389:Cytochrome P-450 CYP2D6; D003061:Codeine; D003647:Debrisoquin