The calmodulin (CaM) inhibitor trifluoperazine (TFP) can produce analgesia when given intrathecally to rats, however the mechanism is not known. We asked whether TFP could modulate the Na_v1.7 sodium channel, which is highly expressed in the peripheral nervous system and plays an important role in nociception. We show that 500 nM and 2 µM TFP induce major decreases in Na_v1.7 and Na_v1.4 current amplitudes and that 2 µM TFP causes hyperpolarizing shifts in the steady-state inactivation of Na_v1.7 and Na_v1.4. CaM can bind to the C-termini of voltage-gated sodium channels and modulate their functional properties; therefore we investigated if TFP modulation of sodium channels was due to CaM inhibition. However, the TFP inhibition was not replicated by whole-cell dialysis of a calmodulin inhibitory peptide, indicating that major effects of TFP do not involve a disruption of CaM-channel interactions. Rather, our data shows that TFP inhibition is state-dependent and that the majority of the TFP inhibition depends on specific amino-acid residues in the local anesthetic receptor site in sodium channels. TFP was also effective in vivo in causing motor and sensory blockade after subfascial injection to the rat sciatic nerve. The state-dependent block of Na_v1.7 channels with nanomolar concentrations of TFP raises the possibility that TFP, or TFP analogs, might be useful for regional anesthesia and pain management, and could be more potent than traditional local anesthetics.