Tramadol as a Voltage-Gated Sodium Channel Blocker of Peripheral Sodium Channels Nav1.7 and Nav1.5

Tramadol is an opioid analog used to treat chronic and acute pain. Intradermal injections of tramadol at hundreds of millimoles have been shown to produce a local anesthetic effect. We used the whole-cell patch-clamp technique in this study to investigate whether tramadol blocks the sodium current in HEK293 cells, which stably express the pain threshold sodium channel Nav1.7 or the cardiac sodium channel Nav1.5. The half-maximal inhibitory concentration of tramadol was 0.73 mM for Nav1.7 and 0.43 mM for Nav1.5 at a holding potential of -100 mV. The blocking effects of tramadol were completely reversible. Tramadol shifted the steady-state inactivation curves of Nav1.7 and Nav1.5 toward hyperpolarization. Tramadol also slowed the recovery rate from the inactivation of Nav1.7 and Nav1.5 and induced stronger use-dependent inhibition. Because the mean plasma concentration of tramadol upon oral administration is lower than its mean blocking concentration of sodium channels in this study, it is unlikely that tramadol in plasma will have an analgesic effect by blocking Nav1.7 or show cardiotoxicity by blocking Nav1.5. However, tramadol could act as a local anesthetic when used at a concentration of several hundred millimoles by intradermal injection and as an antiarrhythmic when injected intravenously at a similar dose, as does lidocaine.

Automated summary

This study investigated the blocking effects of tramadol on sodium currents in HEK293 cells expressing Nav1.7 and Nav1.5 channels. Tramadol inhibited both channels with IC50 values of 0.73 mM and 0.43 mM, respectively. Tramadol also shifted the steady-state inactivation curves, slowed the recovery rate, and induced stronger use-dependent inhibition. The plasma concentration of tramadol upon oral administration is unlikely to block Nav1.7 or Nav1.5 effectively, but it may act as a local anesthetic or antiarrhythmic agent at high concentrations by injection.