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

Abstract

Background and aims Opioids are associated with increased risk of sudden cardiac death. This may be due to their effects on the cardiac sodium channel (Nav1.5) current. In the present study, we establish whether tramadol, fentanyl, or codeine affect Nav1.5 current. Methods Using whole-cell patch-clamp methodology, we studied the effects of tramadol, fentanyl, and codeine on currents of human Nav1.5 channels stably expressed in HEK293 cells, and on action potential (AP) properties of freshly isolated rabbit ventricular cardiomyocytes. Results In fully-available Nav1.5 channels (holding potential –120 mV), tramadol exhibited inhibitory effects on Nav1.5 current in a concentration-dependent manner with an IC50 of 378.5 ± 33.2 μM. 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 Nav1.5 channels: during partial fast-inactivation (close-to-physiological holding potential –90 mV), IC50 of Nav1.5 block was 4.5 ± 1.1 μM, while it was 16 ± 4.8 μM during partial slow-inactivation. The tramadol-induced changes on Nav1.5 properties were reflected by a reduction in AP upstroke velocity in a frequency-dependent manner. Fentanyl and codeine had no effect on Nav1.5 current, even when tested at lethal concentrations. Conclusion Tramadol reduces Nav1.5 currents, in particular, at close-to-physiological membrane potentials. Fentanyl and codeine have no effects on Nav1.5 current.

Opioids-Induced Long QT Syndrome: A Challenge to Cardiac Health

“…Methadone is also present to inhibit the function of NaV1.5 channels through interaction with LA-binding [ 47 ]. Similarly, tramadol reduces NaV1.5 currents, in particular, at close-to-physiological membrane potentials [ 57 ]. However, no functional effect of buprenorphine on NaV1.5 channels could be detected at clinically relevant concentrations [ 15 ].…”