Differential effect of lacosamide on Na _v1.7 variants from responsive and non-responsive patients with small fibre neuropathy

Abstract

Lacosamide, an anti-epileptic drug that targets sodium channels, reduces pain in a subset of patients with small fibre neuropathy caused by mutations in Na _v1.7 sodium channels. Labau et al. provide biophysical data that may explicate why a subset of Na _v1.7 variants differentially respond to treatment with lacosamide.

Abstract

Small fibre neuropathy is a common pain disorder, which in many cases fails to respond to treatment with existing medications. Gain-of-function mutations of voltage-gated sodium channel Na _v1.7 underlie dorsal root ganglion neuronal hyperexcitability and pain in a subset of patients with small fibre neuropathy. Recent clinical studies have demonstrated that lacosamide, which blocks sodium channels in a use-dependent manner, attenuates pain in some patients with Na _v1.7 mutations; however, only a subgroup of these patients responded to the drug. Here, we used voltage-clamp recordings to evaluate the effects of lacosamide on five Na _v1.7 variants from patients who were responsive or non-responsive to treatment. We show that, at the clinically achievable concentration of 30 μM, lacosamide acts as a potent sodium channel inhibitor of Na _v1.7 variants carried by responsive patients, via a hyperpolarizing shift of voltage-dependence of both fast and slow inactivation and enhancement of use-dependent inhibition. By contrast, the effects of lacosamide on slow inactivation and use-dependence in Na _v1.7 variants from non-responsive patients were less robust. Importantly, we found that lacosamide selectively enhances fast inactivation only in variants from responders. Taken together, these findings begin to unravel biophysical underpinnings that contribute to responsiveness to lacosamide in patients with small fibre neuropathy carrying select Na _v1.7 variants.