Use of tramadol and the risk of bleeding complications in patients on oral anticoagulants: a systematic review and meta-analysis

Purpose This systematic review and meta-analysis aimed to determine whether tramadol intake increases the risk of bleeding in patients receiving oral anticoagulants. Methods This systematic review was registered on PROSPERO, CRD42022327230. We searched PubMed and Embase up to 14 April 2022, and references and citations of included studies were screened. Comparative and non-comparative studies exploring bleeding complications among adult patients on oral anticoagulants and tramadol were included. Risk of bias was assessed using an adaptation of the Drug Interaction Probability Scale for case reports and case series and the Newcastle–Ottawa Scale for comparative studies. A meta-analysis was performed for the risk of serious bleeding (leading to hospitalisation or death) associated with tramadol in patients on vitamin K antagonists. Results A total of 17 studies were included: 1 case series, 12 case reports, 2 case–control studies and 2 cohort studies. Most of the studies described tramadol-vitamin K antagonists’ concomitant use; one case–control study also assessed dabigatran and rivaroxaban; one case report involved dabigatran. Among case reports/series, a total of 33 patients had a bleeding complication while using tramadol and an oral anticoagulant. The 4 comparative studies reported an increased bleeding risk during tramadol and vitamin K antagonist intake which was statistically significant in one study; the pooled risk ratio of serious bleeding was 2.68 [95% CI: 1.45 to 4.96; p < 0.001]. Conclusion This systematic review confirms an association between tramadol use and risk of bleeding in patients on vitamin K antagonists. Evidence is too limited to assess whether this risk extends to patients on direct oral anticoagulants, and further studies are needed.