Background and Aim Tramadol is one of the most used analgesics worldwide and occupies an important role in perioperative and chronic pain management. Unlike many other opioids, tramadol has a distinctive pharmacodynamic profile, acting not only as a weak µ-opioid receptor agonist but also as a serotonin and norepinephrine reuptake inhibitor. These serotonergic properties raise questions about its potential influence on platelet function and coagulation, since serotonin is a key mediator of platelet aggregation and vascular tone. While the effects of NSAIDs, paracetamol, and metamizole on platelet activity are well documented, the impact of tramadol remains poorly understood and inconsistently reported. Previous studies have shown contradictory findings, ranging from enhanced aggregation to delayed clot formation, underscoring the need for systematic evaluation. The aim of this study was to investigate the effect of tramadol on platelet function at various concentrations, both alone and in combination with other drugs commonly administered concomitantly, such as metamizole, ibuprofen, and fentanyl. Methods This single-center laboratory study was conducted at the Medical University of Graz following ethics approval (IRB00002556) and ClinicalTrials.gov registration (NCT05237492). Thirty-three healthy adult volunteers were enrolled after informed consent. Exclusion criteria included anticoagulant therapy, history of coagulopathy, or ongoing therapy with opiates. Blood samples were collected and platelet-rich plasma prepared for analysis by light transmission aggregometry (LTA), the reference method for platelet function testing. Tramadol was titrated in concentrations ranging from 500 to 9000 ng/ml. Additional experiments tested tramadol (200 ng/ml) in combination with metamizole (300–900 µg/ml), ibuprofen (60–180 µg/ml), or fentanyl (3000–9000 ng/ml). Aggregation was induced by standard agonists including ADP, collagen, arachidonic acid, ristocetin, and TRAP. Statistical analyses included Friedman’s test for non-parametric repeated measures, Kendall’s W for effect size estimation, and post-hoc comparisons where appropriate. Results Baseline platelet aggregation values were consistent across controls. Tramadol alone, even at supratherapeutic concentrations, did not produce statistically significant changes in platelet aggregation with any agonist tested (ADP: p=0.284; collagen: p=0.382; TRAP: p=0.502; ristocetin: p=0.404; arachidonic acid: p=0.121). Effect sizes were small to moderate. In contrast, tramadol combined with metamizole demonstrated significant reductions in platelet aggregation after ADP (p=0.015), collagen (p=0.016), and ristocetin activation (p=0.027), with large effect sizes (Kendall’s W up to 0.775). Similarly, tramadol with ibuprofen produced significant inhibitory effects under ADP (p=0.021), arachidonic acid (p=0.013), and collagen activation (p=0.038). No statistically significant differences were observed with tramadol–fentanyl combinations, though trends toward reduced aggregation were noted in some assays (p-values 0.058–0.126). Conclusion In this ex vivo study, tramadol alone did not significantly alter platelet aggregation across multiple pathways, supporting the null hypothesis. However, when combined with metamizole or ibuprofen, tramadol was associated with an inhibitory effect on platelet function, whereas fentanyl showed no relevant interaction. This potential interaction warrants consideration in perioperative pain management, especially in patients at elevated bleeding risk. Future clinical studies with larger sample sizes are necessary to confirm these results and to assess their translation into in vivo settings.
The Influence of Tramadol on Platelet´s Function
Zoidl, P. (Autor/-in). 2026
Studienabschlussarbeit: Dissertation