Tramadol as a Voltage-Gated Sodium Channel Blocker ofPeripheral Sodium Channels Na v 1.7 and Na v 1.5

ABSTRACT

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 Na v1.7 or the cardiac sodium channel Na v1.5. The half-maximal inhibitory concentration of tramadol was 0.73 mM for Na v1.7 and 0.43 mM for Na v1.5 at a holding potential of –100 mV. The blocking effects of tramadol were completely reversible. Tramadol shifted the steady-state inactivation curves of Na v1.7 and Na v1.5 toward hyperpolarization. Tramadol also slowed the recovery rate from the inactivation of Na v1.7 and Na v1.5 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 Na v1.7 or show cardiotoxicity by blocking Na v1.5. 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.