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  • Review Article
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Status of peripheral sodium channel blockers for non-addictive pain treatment

Nature Reviews Neurology volume 16, pages 689–705 (2020)Cite this article

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Abstract

The effective and safe treatment of pain is an unmet health-care need. Current medications used for pain management are often only partially effective, carry dose-limiting adverse effects and are potentially addictive, highlighting the need for improved therapeutic agents. Most common pain conditions originate in the periphery, where dorsal root ganglion and trigeminal ganglion neurons feed pain information into the CNS. Voltage-gated sodium (NaV) channels drive neuronal excitability and three subtypes — NaV1.7, NaV1.8 and NaV1.9 — are preferentially expressed in the peripheral nervous system, suggesting that their inhibition might treat pain while avoiding central and cardiac adverse effects. Genetic and functional studies of human pain disorders have identified NaV1.7, NaV1.8 and NaV1.9 as mediators of pain and validated them as targets for pain treatment. Consequently, multiple NaV1.7-specific and NaV1.8-specific blockers have undergone clinical trials, with others in preclinical development, and the targeting of NaV1.9, although hampered by technical constraints, might also be moving ahead. In this Review, we summarize the clinical and preclinical literature describing compounds that target peripheral NaV channels and discuss the challenges and future prospects for the field. Although the potential of peripheral NaV channel inhibition for the treatment of pain has yet to be realized, this remains a promising strategy to achieve non-addictive analgesia for multiple pain conditions.

Key points

  • NaV1.7, NaV1.8 and NaV1.9 are voltage-gated sodium channels preferentially expressed in the peripheral nervous system, which could enable them to be inhibited without central and cardiac adverse effects.

  • Gain-of-function mutations in NaV1.7, NaV1.8 and NaV1.9 cause pain and loss-of-function mutations in NaV1.7 result in a loss of pain sensation, which validates these channels as targets for pain treatment.

  • NaV1.7-selective blockers have shown promise in rodent models of pain but clinical studies of these compounds have yielded mixed results.

  • NaV1.8-selective blockers are also under development and early clinical trials of one agent seem promising, although formal results have yet to be published.

  • Attempts to develop NaV1.9-selective blockers have lagged because of difficulties in generating NaV1.9 expression systems but recent advances could overcome this challenge.

  • The optimization of solubility, plasma protein binding and penetration of the blood–nerve and blood–brain barriers might improve the efficacy of peripheral sodium channel-targeting compounds; future prospects include building blockers from alternative molecular scaffolds, gene therapy, targeting channel trafficking and pharmacogenomics.

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Fig. 1: DRG neurons: peripheral drivers of pain pathways.
Fig. 2: Contribution of sodium channels to action potentials in peripheral sensory neurons.
Fig. 3: Chemical structures of investigated NaV1.7 and NaV1.8 blockers.

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Acknowledgements

The authors acknowledge grants from the Rehabilitation Research Service, Department of Veterans Affairs (B9253-C), NIH/NIGMS Medical Scientist Training Program T32GM007205 (M.A. and G.P.H.) and 5T32GM086287 (P.R.E.), and the Department of Anaesthesiology (P.R.E.). The authors also thank Sulayman Dib-Hajj, Simon Tate and John Hunter for helpful comments.

Review criteria

Although this article is not intended to be a systematic review of all peripheral sodium channel blockers, PubMed was searched for “selective Nav1.7 blocker”, “selective Nav1.8 blocker” and “selective Nav1.9 blocker”. Identified compounds were then subsequently searched in PubMed, ClinicalTrials.gov and on company webpages. Additionally, the authors are familiar with this subject area and consulted with experts in the field regarding current investigational therapeutics and future considerations.

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Authors and Affiliations

  1. Department of Neurology, Yale University School of Medicine, New Haven, CT, USA

    Matthew Alsaloum, Grant P. Higerd & Stephen G. Waxman

  2. Center for Neuroscience & Regeneration Research, Yale University, West Haven, CT, USA

    Matthew Alsaloum, Grant P. Higerd, Philip R. Effraim & Stephen G. Waxman

  3. Center for Rehabilitation Research, VA Connecticut Healthcare System, West Haven, CT, USA

    Matthew Alsaloum, Grant P. Higerd, Philip R. Effraim & Stephen G. Waxman

  4. Yale Medical Scientist Training Program, Yale School of Medicine, New Haven, CT, USA

    Matthew Alsaloum & Grant P. Higerd

  5. Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, CT, USA

    Matthew Alsaloum

  6. Department of Anesthesiology, Yale School of Medicine, New Haven, CT, USA

    Philip R. Effraim

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The authors contributed equally to all aspects of the article.

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Correspondence to Stephen G. Waxman.

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Competing interests

S.G.W. has received research funding from Pfizer, has served as a consultant or adviser to Alnylam Pharmaceuticals, Amgen, Biogen, Chromocell, Exicure, GlaxoSmithKline, Eli Lilly Research, Sangamo Therapeutics, and Redpin Therapeutics, and serves on the Scientific Advisory Boards of SiteOne Therapeutics and OliPass. All other authors declare no competing interests.

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Glossary

Central sensitization

A state of neuronal excitability and increased synaptic efficacy of CNS nociceptors that results in hyperalgesia and allodynia.

Neuromas

Bulb-shaped tangled masses of regenerating nerve fibres that act as sites of ectopic action potential generation.

Crossover study

A trial in which each participant receives both the control treatment and test treatment consecutively; for example, one group will receive the control treatment followed by the test treatment, whereas another group will receive the test treatment followed by the control treatment.

Parallel-group study

A study in which participants are randomly assigned to receive one of two or more treatments.

Withdrawal trial

A trial in which all participants receive the test treatment for a specified period of time, after which participants are randomly assigned to receive either placebo or a continuation of the test treatment.

Enriched enrollment

A trial in which all participants receive the test treatment for a specified period of time, after which only participants who responded to the test treatment continue with the trial and are randomly assigned to receive either placebo or a continuation of the test treatment.

Rheobase

The minimum current amplitude of infinite duration required to generate an action potential.

Double-dummy

A study in which all participants receive both placebo and the intervention in alternating periods, with the aim of providing additional insurance against bias when the placebo and intervention can only be provided in visibly different formulations.

Half-maximal inhibitory concentration

(IC50). The concentration of a compound necessary to achieve 50% inhibition of a biological process.

Dose-ranging study

A clinical trial that tests the safety or efficacy of multiple doses of a drug to establish a reasonable therapeutic dose for subsequent clinical trials.

Charcot joints

Progressive denervation-induced degeneration of a weightbearing joint.

Epitope tag

A biological structure that can be recognized by an antibody.

Optogenetic tools

Genetic constructs that enable the perturbation of biology using light.

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Alsaloum, M., Higerd, G.P., Effraim, P.R. et al. Status of peripheral sodium channel blockers for non-addictive pain treatment. Nat Rev Neurol 16, 689–705 (2020). https://doi.org/10.1038/s41582-020-00415-2

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