Drugs targeting specific sodium channels

Opioids, although effective for acute postoperative pain, are associated with a number of harms
Other analgesics used across the spectrum of pain conditions are only modestly efficacious, and newer analgesics are necessary

Voltage-gated sodium channels are transmembrane proteins essential for generating action potentials in excitable cells
Mammalian voltage-gated sodium channels consist of:

An ⍺-subunit (Na_v); constitutes the transmembrane core protein of the channel
β-proteins; contribute to targeting, anchoring the channels at specific membrane sites, and modulate the ⍺-subunit

There are nine alpha-subunit subtypes (Na_v1.1 - 1.9) encoded for by different genes (SCN1A-5A and SCN8A-11A)
They are further classified based on their reaction to tetrodotoxin (TTX) as either:

Existing drugs acting on sodium channels may have beneficial effects including anaesthetic, analgesic, anti-arrhythmic or anti-epileptic properties
However, they are poorly selective for Na_v subtypes and therefore come with potentially (severe) adverse effects
Some existing drugs have demonstrated a degree of selectivity, such as:

Lacosamide is effective in treating a genetic painful sensory neuropathy in patients with a particular Na_v1.7 variant
Oxcarbazepine is effective in patients with peripheral neuropathic pain demonstrating an 'irritable nociceptor' phenotype maintained by (probably) sodium-channel-mediated neuronal excitability

Na_v1.7 and 1.8 have generated attention as potential therapeutic targets owing to their preferential expression in subsets of primary sensory neurones

Na_v1.7

Receptor activation contributes to amplification of generator potentials, particularly at sensory nerve endings
It brings the membrane potential to the threshold required for Na_v1.8 activation, which itself is important in the synaptic transmission process

Na_v1.8

Na_v1.8 (SCN10A gene) is highly expressed in small-diameter nociceptors
It is also expressed in medium- and large-diameter neurones, but is not present in the adult human brain

It doesn't play a critical role in normal nociceptive function, but is involved in the pathophysiology of pain after neuronal and tissue injury, including visceral pain
Its action is characterised by slow activation and inactivation gating, a relatively depolarised activation threshold, and low channel conductance
It is postulated targeting Na_v1.8 will reduce hyperalgesia and allodynia (rather than anti-nociception per se)
It is resistant to inactivation by low temperatures, thus contributing to cold sensitivity and cold-induced pain

Role of Na_v1.7 and 1.8

Further evidence for the key role of these receptors comes in the form of genetic studies showing:

Gain-of-function mutations in Na_v1.7 are linked to both the painful hereditary neuropathy erythromelalgia and paroxysmal extreme pain disorder
Mild gain-of-function variants in Na_v1.7 and Na_v1.8 are found in a notable proportion of patients with idiopathic small fibre neuropathy
Loss-of-function mutations in Na_v1.7 lead to congenital insensitivity to pain
Knockdown models of Na_v1.8 in dorsal root ganglia prevents thermal and mechanical hypersensitivity in animal models of inflammatory and neuropathic pain

Drugs targeting Na_v1.7 and/or 1.8

Multiple drugs targeting Na_v1.7 have failed to progress beyond Phase II clinical trials due to lack of efficacy
A-803467 was a selective Na_v1.8 antagonist which showed promise in animal models, but was beset by poor oral pharmacokinetics
Suzetrigine (VX-548) is an allosteric inhibitor of Na_v1.8

Suzetrigine binds to the second voltage-sensitive domain (VSD2) of the Na_v1.8 channel at a site distinct from the pore region
It stabilises the closed state of the channel
It does not interfere/compete with local anaesthetics directly targeting the pore
Pharmaceutical-sponsored Phase III trials show promising results, demonstrating efficacy vs. placebo and comparative analgesia to other analgesics
Effects are relatively slow onset (8hrs post-insult in trials) which may limit use in the early post-operative setting
Trials demonstrate good tolerance of the drug, with the commonest adverse effects being minor
Some less common adverse effects may be of more concern such as rash, elevated muscle enzymes, spasms and exacerbation of arrhythmias
It is licensed by the FDA to treat moderate-severe acute pain in adults