Administration of tramadol or ibuprofen increases the INR level in patients on warfarin

Abstract

Case report Anticoagulation with the vitamin-K antagonist warfarin is widely used in cardiology to reduce the risk of thromboembolism in cardiac arrhythmias such as atrial fibrillation. The target international normalized ratio (INR) level should often be kept in the interval of 2.0-3.0, in order to diminish the risk of thromboembolism and decrease the risk of adverse effects such as hemorrhage. Monitoring of the INR is necessary [1]. A 74-year-old man was admitted to hospital with recurrence of atrial fibrillation. The patient had been suffering from paroxysmal atrial fibrillation for 5 years and was treated with warfarin. At the time of admission, the patient presented with the feeling of irregular heart rhythm, palpitations, shortness of breath, mild chest pain and with an ECG showing atrial fibrillation. The patient was biochemically screened. This included renal function parameters, electrolytes and thyroid-stimulating hormone. Because of chest pain, troponin Tand CK-MB were included. We found no bleeding of either the skin or the mucosa by physical examination. Finally, INR status was evaluated. The initial blood sample showed an increased INR of 5.8, otherwise the biochemical analysis was normal. Due to the increased INR, the warfarin treatment was immediately paused. We treated the atrial fibrillation of the patient successfully with direct current cardioversion. During the hospitalization, the patient’s preceding INRvalues and his medication was reviewed. We found that the elevation in INR-value was coincident with the prescription of tramadol, which was prescribed due to pain in the back. The patient’s INR-values were monitored on a regular basis. The patient was on 50 mg tramadol three times a day, for four days. He stopped the treatment due to reduced pain in the back. At this time, the INR was 5.3. The previous records of the INR showed that the patient had had steady INR-values in the interval 2.1–2.6 for more than 9 months. After the discontinuation of tramadol, the patient was treated with ibuprofen starting the next day. The dose was 400 mg three times a day until being hospitalized. During this approxmately one month period, the patient’s INR was measured on three occasions, the values being 4.4, 3.9 and 5.7. (Fig. 1). No other drugs were prescribed and no changes in the medication took place during this time. The patient received no potential inhibitors of cytochrome P450 2D6. We checked the Danish Prescription Database to confirm the data. The patient denies any use of over-the-counter drugs during this period. The pause with warfarin treatment and the discontinuation of NSAID treatment normalized the INR values within two days, and the patient was discharged in a good state of health, with sinus rhythm and with a nearly normalized INR value. The patient continued anticoagulation with the same dosage of warfarin as before admission, with periodic INR monitoring at his general practitioner. Reports of interaction between tramadol and warfarin are sparse. The PubMed database contains only a few reports regarding tramadol and warfarin interaction, while the interaction between the NSAID and warfarin is better elucidated. The NSAIDs inhibit platelet aggregation reversibley; the evidence is not substantial for ibuprofen itself, but for all inhibitors of the cyclooxygenase as a class, it is well documented [2–4]. The demonstrated interaction may indicate a pharmacokinetic interaction between warfarin and ibuprofen, leading to inhibition of the metabolism of warfarin. Both warfarin and ibuprofen are metabolized by cytochrome