Skip to main content
Log in

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

  • Pharmacoepidemiology and Prescription
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G (2008) Pharmacology and management of the vitamin K antagonists: American college of chest physicians evidence-based clinical practice guidelines (8th Edition). Chest 133(6 Suppl):160S–198S

    Article  PubMed  CAS  Google Scholar 

  2. Veeger NJ, Piersma-Wichers M, Tijssen JG, Hillege HL, van der Meer J (2005) Individual time within target range in patients treated with vitamin K antagonists: main determinant of quality of anticoagulation and predictor of clinical outcome. A retrospective study of 2300 consecutive patients with venous thromboembolism. Br J Haematol 128(4):513–519

    Article  PubMed  Google Scholar 

  3. Steffensen FH, Kristensen K, Ejlersen E, Dahlerup JF, Sorensen HT (1997) Major haemorrhagic complications during oral anticoagulant therapy in a Danish population-based cohort. J Intern Med 242(6):497–503

    Article  PubMed  CAS  Google Scholar 

  4. Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D’Angelo A et al (1996) Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet 348(9025):423–428

    Article  PubMed  CAS  Google Scholar 

  5. Oake N, Jennings A, Forster AJ, Fergusson D, Doucette S, van Walraven C (2008) Anticoagulation intensity and outcomes among patients prescribed oral anticoagulant therapy: a systematic review and meta-analysis. CMAJ 179(3):235–244

    PubMed  Google Scholar 

  6. Holbrook AM, Pereira JA, Labiris R, McDonald H, Douketis JD, Crowther M et al (2005) Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 165(10):1095–1106

    Article  PubMed  CAS  Google Scholar 

  7. Jobski K, Behr S, Garbe E (2011) Drug interactions with phenprocoumon and the risk of serious haemorrhage: a nested case–control study in a large population-based German database. Eur J Clin Pharmacol 67(9):941–951

    Google Scholar 

  8. Madsen H, Rasmussen JM, Brosen K (1997) Interaction between tramadol and phenprocoumon. Lancet 350(9078):637

    Article  PubMed  CAS  Google Scholar 

  9. Scher ML, Huntington NH, Vitillo JA (1997) Potential interaction between tramadol and warfarin. Ann Pharmacother 31(5):646–647

    PubMed  CAS  Google Scholar 

  10. Sabbe JR, Sims PJ, Sims MH (1998) Tramadol-warfarin interaction. Pharmacotherapy 18(4):871–873

    PubMed  CAS  Google Scholar 

  11. Dumo PA, Kielbasa LA (2006) Successful anticoagulation and continuation of tramadol therapy in the setting of a tramadol-warfarin interaction. Pharmacotherapy 26(11):1654–1657

    Article  PubMed  Google Scholar 

  12. Boeijinga JK, van Meegen E, van den Ende R, Schook CE, Cohen AF (1998) Lack of interaction between tramadol and coumarins. J Clin Pharmacol 38(10):966–970

    PubMed  CAS  Google Scholar 

  13. Gaist D, Sorensen HT, Hallas J (1997) The Danish prescription registries. Dan Med Bull 44(4):445–448

    PubMed  CAS  Google Scholar 

  14. WHO Collaborating Centre for Drug Statistics Methodology (2010) Guidelines for ATC classification and DDD assignment 2011. Oslo

  15. Pedersen CB (2011) The danish civil registration system. Scand J Public Health 39(7 Suppl):22–25

    Article  PubMed  Google Scholar 

  16. Diagnose- og operationskoder [in Danish]; [Last updated 5/1/2011]. Available from: http://diagnosekoder.dk/.

  17. International Statistical Classification of Diseases and Related Health Problems 10th Revision Version for 2007; [Last updated 4/5/2006; citeret 18/3/2011]. Available from: http://apps.who.int/classifications/apps/icd/icd10online/.

  18. Meegaard PM, Holck LH, Pottegard A, Madsen H, Hallas J (2012) Excessive anticoagulation with warfarin or phenprocoumon may have multiple causes. Dan Med J 59(2):A4383

    PubMed  Google Scholar 

  19. Rothman K (2002) Epidemiology: an introduction. New York, NY: Oxford University Press Inc. Measuring disease occurrence and causal effects. 24–56.

  20. Hallas J, Gaist D, Bjerrum L (1997) The waiting time distribution as a graphical approach to epidemiologic measures of drug utilization. Epidemiology 8(6):666–670

    PubMed  CAS  Google Scholar 

  21. Williams RL (2000) A note on robust variance estimation for cluster-correlated data. Biometrics 23:645–646

    Article  Google Scholar 

  22. Bjerre LM, LeLorier J (2000) Expressing the magnitude of adverse effects in case–control studies: “the number of patients needed to be treated for one additional patient to be harmed”. BMJ 320(7233):503–506

    Article  PubMed  CAS  Google Scholar 

  23. Hallas J, Dall M, Andries A, Andersen BS, Aalykke C, Hansen JM et al (2006) Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case–control study. BMJ 333(7571):726

    Article  PubMed  Google Scholar 

  24. Lynge E, Sandegaard JL, Rebolj M (2011) The danish national patient register. Scand J Public Health 39(7 Suppl):30–33

    Article  PubMed  Google Scholar 

  25. Zhang Q, Bal-dit-Sollier C, Drouet L, Simoneau G, Alvarez JC, Pruvot S et al (2011) Interaction between acetaminophen and warfarin in adults receiving long-term oral anticoagulants: a randomized controlled trial. Eur J Clin Pharmacol 67(3):309–314

    Article  PubMed  CAS  Google Scholar 

  26. Lægemiddelstyrelsen. Medstat.dk; [Last updated 25/5/2011; citeret 2/2/2012]. Available from: http://www.medstat.dk.

  27. Hernandez-Diaz S, Rodriguez LA (2000) Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation: an overview of epidemiologic studies published in the 1990s. Arch Intern Med 160(14):2093–2099

    Article  PubMed  CAS  Google Scholar 

  28. Penning-van Beest FJ, van Meegen E, Rosendaal FR, Stricker BH (2001) Characteristics of anticoagulant therapy and comorbidity related to overanticoagulation. Thromb Haemost 86(2):569–574

    PubMed  CAS  Google Scholar 

  29. Cadiou G, Varin R, Levesque H, Grassi V, Benichou J, Tiret I et al (2008) Risk factors of vitamin K antagonist overcoagulation. A case–control study in unselected patients referred to an emergency department. Thromb Haemost 100(4):685–692

    PubMed  CAS  Google Scholar 

  30. Hedenmalm K, Lindh JD, Sawe J, Rane A (2004) Increased liability of tramadol-warfarin interaction in individuals with mutations in the cytochrome P450 2D6 gene. Eur J Clin Pharmacol 60(5):369–372

    Article  PubMed  CAS  Google Scholar 

  31. Pedersen RS, Damkier P, Brosen K (2005) Tramadol as a new probe for cytochrome P450 2D6 phenotyping: a population study. Clin Pharmacol Ther 77(6):458–467

    Article  PubMed  CAS  Google Scholar 

  32. Ufer M (2005) Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. Clin Pharmacokinet 44(12):1227–1246

    Article  PubMed  CAS  Google Scholar 

  33. Palareti G, Cosmi B (2009) Bleeding with anticoagulation therapy - who is at risk, and how best to identify such patients. Thromb Haemost 102(2):268–278

    PubMed  CAS  Google Scholar 

  34. Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S (2007) Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 115(21):2689–2696

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Rasmus Steen Pedersen, Michael Due Larsen and Søren Ilsøe Moreno for valuable comments on the manuscript.

Conflicts of interest

Jesper Hallas has received fees for teaching from the Danish Association of the Pharmaceutical Industry and research grants from Nycomed, MSD and Pfizer. The remaining authors declare that they have no potential conflicts of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Anton Pottegård.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pottegård, A., Meegaard, P.M., Holck, L.H. et al. 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 69, 641–646 (2013). https://doi.org/10.1007/s00228-012-1363-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-012-1363-x

Keywords

Navigation