Differential effect of lacosamide on Nav1.7 variants from responsive and non-responsive patients with small fibre neuropathy

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 Nav1.7 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 Nav1.7 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 Nav1.7 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 Nav1.7 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 Nav1.7 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 Nav1.7 variants.

Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels

“…3. Recently a clinical trial has found lacosamide to be efficacious in reducing pain and well-being of SFN patients with SCN9A mutations [27]; however, the effect was linked to subset of SCN9A mutations [74].…”

Pharmacotherapeutic Options for Managing Neuropathic Pain: A Systematic Review and Meta-Analysis

“…The anticonvulsant lacosamide, acting on Nav1.3, Nav1.7, and Nav1.8 channels, was tested in patients with Nav1.7-mutation-related small-fibre neuropathy, with promising findings in a subgroup of patients [ 33 ]. Labau and colleagues, using voltage-clamp recordings, found a preferential effect of lacosamide on Nav1.7 variants in patients who were responsive to lacosamide via a hyperpolarizing shift in the voltage dependence of both fast and slow inactivation and enhancement of use-dependent inhibition [ 53 ]. In addition, recent studies have shown that carbamazepine, at clinically achievable concentrations, acts via a new mode of action as an activation modulator of select mutant Nav1.7 channels [ 54 , 55 ].…”

Characterization of Vixotrigine, a Broad-Spectrum Voltage-Gated Sodium Channel Blocker

“…Experiments in recombinant systems suggest carbamazepine affects these mutant channels by modulating inactivation as opposed to restoring normal channel activation. Likewise, a recent study identified a striking correlation between lacosamide modulation of Nav1.7 mutation channels in patients and clinical efficacy (Labau et al, 2020). These observations suggest that the underlying molecular driver of pathologic neural activity may constrain the efficacy of Nav blockers based on their particular mechanism of action.…”