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Eur J Clin Pharmacol (2004) 60: 369372
DOI 10.1007/s00228-004-0783-7SHORT COMMUNICATIONKarin Hedenmalm Jonatan D. Lindh Juliette Sawe
Anders RaneIncreased liability of tramadolwarfarin interaction in individuals
with mutations in the cytochrome P450 2D6 geneReceived: 29 January 2004 / Accepted: 19 April 2004 / Published online: 10 June 2004
Springer-Verlag 2004Abstract Objective: This study aimed to investigate the
importance of cytochrome P450enzymes for the reported
interaction between tramadol and warfarin.Materials and methods: Cases of suspected interaction
between tramadol and warfarin resulting in International Normalised Ratios increases that were reported to
the Swedish Adverse Drug Reactions Advisory Committee until March 2003 were included. Ten cases had
been genotyped for known polymorphisms of CYP2D6,
CYP2C9 and CYP2C19.Results: Seven of ten patients carried defective CYP2D6
alleles (population prevalence 42.2%) (one-sided binomial test,P=0.07). A further patient received concomitant drug treatments that may have resulted in CYP2D6
enzyme inhibition.Conclusion: The liability to an interaction between
tramadol and warfarin may be related to the CYP2D6
activity.Keywords Tramadol Warfarin Cytochrome P450IntroductionMaterials and methodsSince 1965, Sweden has had a system for spontaneous
reporting of adverse drug reactions. Reporting to the
regional centres (at the Swedish departments of clinical
pharmacology) of the Swedish Adverse Drug Reactions
Advisory Committee (SADRAC) is compulsory for all
suspected new or serious adverse drug reactions. A
total of 17 cases of suspected interactions between
warfarin and tramadol leading to INR increases were
reported to SADRAC between the registration of
tramadol in 1995 and March 2003. The patients were
5889 years of age (mean 76.5 years). Ten of the
patients were males. Prior to initiation of tramadol
treatment, all patients had stable INR values within the
therapeutic range. Their warfarin doses varied from11.2 mg to 66.2 mg per week with a mean of 28.5 mgTramadol is a synthetic opioid analgesic that also
inhibits norepinephrine and serotonin reuptake [1].Several cases of suspected interaction between tramadol
and warfarin have been published [2, 3]. This resulted in
exaggerated anticoagulation and increased International
Normalised Ratios (INR). The mechanism of the interaction remains unknown but is important to study, as
warfarin is a widely used oral anticoagulant. Interactions with warfarin are typically attributed to metabolic
inhibition, additive anti-coagulation eects or, less
commonly, protein displacement. Tramadol is unlikely
to cause signicant displacement of warfarin due to its
low plasma...