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Published: October 2006
ADR update

Evidence For Tramadol-Warfarin Interaction

Prescriber Update 27(2): 23-24.
October 2006

Ruth Savage, Medical Assessor, CARM, New Zealand Pharmacovigilance Centre, Dunedin

Local and international case reports provide evidence of an interaction between oral tramadol and warfarin in some individuals, leading to an elevated International Normalised Ratio (INR) and in some instances bruising or haemorrhage.  The mechanism has not been determined.  The interaction usually occurs 3-4 days after tramadol is commenced in patients stabilised on warfarin.  The decrease in INR after tramadol is withdrawn may take several days.  Where it is necessary to prescribe tramadol with warfarin there should be close monitoring of the INR, especially during the first week of treatment with tramadol.

CARM reports show marked increases in INR

Up to 31 July 2006, the Centre for Adverse Reactions Monitoring (CARM) had received a total of 116 reports of suspected adverse reactions to tramadol.  Three of these reports were of increased International Normalised Ratio (INR), ranging from 7.0 to 12.3 occurring when oral tramadol was given to patients taking warfarin.  Two patients were symptomatic: one with petechiae and one with melaena.  Onset time after tramadol was commenced was one, two and seven days.  A fourth patient taking warfarin was found to have bruising and a haematoma eight days after commencing tramadol.

The extent to which tramadol contributed to the elevated INR in the four patients is not entirely clear as one patient may have taken an incorrect dose of warfarin and the other three were also prescribed antibiotics.  However, tramadol seemed the most likely cause in two of these cases.

Published case reports provide further evidence

Firmer evidence of an interaction with oral tramadol can be found in two published case reports.1,2  A 76-year-old man had been on a stable dose of warfarin for six months when he developed purpura and was found to have an INR of 7.3.  He had been taking tramadol 50mg three times daily for one month.  There had been no other changes to his prescribed medication, and he had not taken any over-the-counter medicines.1  A 61-year-old woman on a stable regime of medicines including warfarin had recently finished taking tramadol 50mg six hourly for two weeks.  She presented with extensive bruising of the right upper arm, and was found to have an INR of 10.6.  Warfarin was withheld for three days until her INR reduced sufficiently for the warfarin to be reinstated, although initially a lower dose was required.2

Similar reports in Australia

Case reports published in 2004 by the Australian Adverse Drug Reactions Advisory Committee (ADRAC) detail 11 reports of elevated INR or haemorrhage when tramadol was taken with warfarin.3  The median onset time after addition of tramadol to stabilised warfarin therapy was four (range 3-7) days, with the exception of one outlier at six weeks.  Five reports described recovery within 1-4 days of tramadol being discontinued, with or without reduction in the dose of warfarin.  Two patients, aged 76 and 88 years, died of haemorrhagic stroke.

The interaction may occur in a sub-group of patients

In a pharmacodynamic study4 of the effect of oral tramadol on INR in 19 patients stabilised on phenprocoumon (a coumarin anticoagulant), two patients had clinically significant increases in INR to 6.0 and 7.3, respectively, while taking tramadol.  However, the mean difference in INR for all participants did not reach statistical significance.  The mechanism of the interaction is unclear, but these results suggest that the interaction may be associated with a variation in metabolism and that only a sub-group of patients will be affected.  This possibility is supported by the small number of case reports in the Australian database compared with total prescriptions for oral tramadol.3

Increased INR monitoring necessary when tramadol prescribed with warfarin

Although the mechanism has not been elucidated, there is evidence for an interaction between oral tramadol and warfarin in some, but probably not all, individuals.  The CARM case reports, where antibiotics were also implicated, are a reminder that more than one interaction may be occurring.  The interaction between tramadol and warfarin is documented in the product information for tramadol.5-7  It is unclear whether the interaction occurs with injectable tramadol.3

Close monitoring of the INR should be undertaken when it is necessary to prescribe tramadol for patients taking warfarin, especially during the first week of treatment with tramadol.

Competing interests (author): none declared.

References
  1. Scher ML, Huntington NH, Vitillo JA. Potential interaction between tramadol and warfarin. Ann Pharmacotherapy 1997;31:646-647.
  2. Sabbe JR, Sims PJ, Sims MH. Tramadol-warfarin interaction. Pharmacotherapy 1998;18(4):871-873.
  3. Adverse Drug Reactions Advisory Committee (ADRAC), Australia. Tramadol-warfarin interaction. ADRAC Bulletin 2004;23(4).
  4. Boeijinga JK, van Meegan E, van den Ende R. Lack of interaction between tramadol and coumarins. J Clin Pharmacol 1998;38:966-970.
  5. CSL (New Zealand) Limited. Tramal (tramadol) data sheet October 2005. www.medsafe.govt.nz/profs/Datasheet/t/TramalcapSRtabinjoraldrops.pdf
  6. Pharmaco (NZ) Limited. Zytram BD (tramadol) data sheet 20 February 2006. www.medsafe.govt.nz/profs/Datasheet/z/ZytramBDtab.pdf
  7. AFT Pharmaceuticals Ltd. Tramadol data sheet 8 December 2005. www.medsafe.govt.nz/profs/Datasheet/t/TramadolHydrochloridecap.pdf