Concurrent use of tramadol and oral vitamin K antagonists and the risk of excessive anticoagulation: a register-based nested case-control study

Eur J Clin Pharmacol. 2013 Mar;69(3):641-6. doi: 10.1007/s00228-012-1363-x. Epub 2012 Jul 31.


Objectives: The objective was to assess whether the concurrent use of tramadol and vitamin K antagonists (VKAs) leads to an increased risk of excessive anticoagulation.

Design: The study was designed as a case-control study, nested within users of VKA and with tramadol use as our main exposure. We used conditional logistic regression to control for potential confounders.

Setting: Prescription data from primary care were obtained from Odense Pharmacoepidemiological Database (OPED). Information about hospital admissions was obtained from the patient administrative system of Funen County (FPAS).

Subjects: Both cases and controls were selected from users of VKA. Cases were defined by being hospitalised with a main diagnosis indicating excessive anticoagulation. For each case, we selected 15 controls among VKA users, matched by age and sex.

Main outcome measure: Odds ratio for experiencing excessive anticoagulation attributable to the use of tramadol.

Results: A total of 178 patients were included, 30 of which were exposed to tramadol, along with 2643 controls, 114 of which were exposed to tramadol. The adjusted odds-ratio for experiencing excessive anticoagulation during use of tramadol was 3.1 (1.9-5.2). This corresponds to, on average, one excess case per 250 treatment years (CI 125-584). The result is potentially confounded by concomitant paracetamol use and the presence of acute illness.

Conclusion: Caution is advised when using tramadol in patients using VKA, and if possible, an alternative pain-medication should be used.

MeSH terms

  • Administration, Oral
  • Aged
  • Aged, 80 and over
  • Analgesics, Opioid / adverse effects*
  • Anticoagulants / administration & dosage
  • Anticoagulants / adverse effects*
  • Blood Coagulation / drug effects*
  • Case-Control Studies
  • Confounding Factors, Epidemiologic
  • Denmark
  • Drug Interactions
  • Drug Prescriptions
  • Female
  • Hemorrhage / blood
  • Hemorrhage / chemically induced*
  • Humans
  • Logistic Models
  • Male
  • Odds Ratio
  • Patient Selection
  • Registries
  • Risk Assessment
  • Risk Factors
  • Tramadol / adverse effects*
  • Vitamin K / antagonists & inhibitors*


  • Analgesics, Opioid
  • Anticoagulants
  • Vitamin K
  • Tramadol