Chlorpromazine is a phenothiazine derivative which is primarily used for schizophrenia and occasionally for migraine. Because Na(v)1.7 plays an important role in pain sensation, we investigated whether chlorpromazine blocks the human Na(v)1.7 (hNa(v)1.7) sodium current in HEK293 cells stably expressing hNa(v)1.7 using the whole-cell patch-clamp technique. The peak current of hNa(v)1.7 was reduced by chlorpromazine in a concentration-dependent manner with a half-maximal inhibitory concentration of 25.9 +/- 0.6 mu M and a Hill coefficient of 2.3 +/- 0.1. The calmodulin inhibitory peptide did not abolish the blockade of hNa(v)1.7 currents by chlorpromazine. The blockade of hNa(v)1.7 currents by chlorpromazine was completely and repeatedly reversible after washout. The half-maximal voltage of activation of hNa(v)1.7 was not changed by chlorpromazine. However, chlorpromazine caused hyperpolarized the steady-state inactivation of hNa(v)1.7. The recovery from inactivation in the presence of chlorpromazine was slower than in the absence of chlorpromazine. Chlorpromazine also showed strong use-dependent inhibition of the hNa(v)1.7 current. Our results demonstrate that chlorpromazine blocks the hNa(v)1.7 current in concentration-, state- and use-dependent manners and suggest that it merits further study for potential use in pain management. (C) 2016 Elsevier Ireland Ltd. All rights reserved.