AbstractSodium channel inhibitor drugs decrease pathological hyperactivity in various diseases including pain syndromes, myotonia, arrhythmias, nerve injuries and epilepsies. Inhibiting pathological but not physiological activity, however, is a major challenge in drug development. Sodium channel inhibitors exert their effects by a dual action: they obstruct ion flow (“block”), and they alter the energetics of channel opening and closing (“modulation”). Ideal drugs would be modulators without blocking effect, because modulation is inherently activity-dependent, therefore selective for pathological hyperactivity. Can block and modulation be separated? It has been difficult to tell, because the effect of modulation is obscured by conformation-dependent association/dissociation of the drug. To eliminate dynamic association/dissociation, we used a photoreactive riluzole analog which could be covalently bound to the channel; and found, unexpectedly, that drug-bound channels could still conduct ions, although with modulated gating. The finding that non-blocking modulation is possible, may open a novel avenue for drug development because non-blocking modulators could be more specific in treating hyperactivity-linked diseases.