How does sodium channel blockade reduce pain?
Voltage-gated sodium channels are upregulated after nervous system injury and disease, resulting in spontaneous and elicited pain. In addition, gain- and loss-of-function mutations in a specific sodium channel subtype, Nav 1.7, have been linked to the pain syndromes primary erythromelalgia and congenital insensitivity to pain, respectively. Sodium channels blockers have been used for decades to treat chronic neuropathic pain (lidocaine, mexilitine, lamotrigine). However, they have not been very successful due to nonselectivity for sodium channel subtypes, resulting in dose limiting side effects. There is emerging interest in selective blockers to sodium channel subtypes specific to the pain pathways. As these subtypes are not present in heart tissue or the CNS, they are better tolerated and likely will provide better analgesia. Nav 1.3, Nav 1.7, Nav 1.8, and Nav 1.9 are specific channels that have been implicated in pain signaling. The most promising channels are the Nav 1.7 and Nav 1.8 subtypes. Both systemic and intrathecal agents are being developed that affect the function of these Nav channel subtypes.