The opioid tramadol blocks the cardiac sodium channel Nav1.5 in HEK293 cells

Aims Opioids are associated with increased risk of sudden cardiac death. This may be due to their effects on the cardiac sodium channel (Na(v)1.5) current. In the present study, we aim to establish whether tramadol, fentanyl, or codeine affects Na(v)1.5 current. Methods and results Using whole-cell patch-clamp methodology, we studied the effects of tramadol, fentanyl, and codeine on currents of human Na(v)1.5 channels stably expressed in HEK293 cells and on action potential (AP) properties of freshly isolated rabbit ventricular cardiomyocytes. In fully available Na(v)1.5 channels (holding potential -120 mV), tramadol exhibited inhibitory effects on Na(v)1.5 current in a concentration-dependent manner with an IC50 of 378.5 +/- 33.2 mu M. In addition, tramadol caused a hyperpolarizing shift of voltage-gated (in)activation and a delay in recovery from inactivation. These blocking effects occurred at lower concentrations in partially inactivated Na(v)1.5 channels: during partial fast inactivation (close-to-physiological holding potential -90 mV), IC50 of Na(v)1.5 block was 4.5 +/- 1.1 mu M, while it was 16 +/- 4.8 mu M during partial slow inactivation. The tramadol-induced changes on Na(v)1.5 properties were reflected by a reduction in AP upstroke velocity in a frequency-dependent manner. Fentanyl and codeine had no effect on Na(v)1.5 current, even when tested at lethal concentrations. Conclusion Tramadol reduces Na(v)1.5 currents, in particular, at close-to-physiological membrane potentials. Fentanyl and codeine have no effects on Na(v)1.5 current.