Evaluating the analgesic effect of a new generation of precision sodium channel modulators, including relutrigine, vormatrigine and PRAX-1451, across preclinical and human pain models.

Voltage-gated sodium (Na_V) channels are key mediators of pain signaling. Conventional sodium channel blockers (SCBs) provide analgesia for several peripheral and central pain states, but are limited by poor tolerability. Relutrigine, vormatrigine and PRAX-1451 demonstrate superior selectivity for pathologic states, and potential therapeutic utility in pain. Emerging evidence in epilepsy points to improved efficacy and tolerability over standard SCBs, supporting their exploration as analgesics.

Acute pain: Formalin – Analgesic activity was assessed by measuring paw licking in CD-1 mice following acute injection of dilute formalin into the right hind-paw plantar surface. Incision Pain – Reversal of mechanical allodynia was assessed using paw withdrawal thresholds in Sprague-Dawley rats following hind-paw incision.

Neuropathic pain: Chronic Constriction Injury – Reversal of mechanical allodynia was assessed using PWT in Sprague-Dawley rats following surgical sciatic nerve constriction. Oxaliplatin-Induced Peripheral Neuropathy (OIPN) – Reversal of cold allodynia was assessed in C57BL/6J mice using the acetone test (relutrigine) or in Sprague-Dawley rats using a cold immersion test (vormatrigine) following oxaliplatin pretreatment.

Translational model: PRAX-1451 effects were evaluated in healthy volunteers using Nerve Excitability Threshold Tracking (NETT) and the PainCart test battery as human biomarkers of Na_V-mediated analgesic mechanisms.

Relutrigine and vormatrigine demonstrated dose-dependent efficacy across acute and neuropathic pain models, with protection comparable to positive controls. In OIPN, cold allodynia reversal reflected potent inhibition of oxaliplatin-enhanced persistent sodium currents by relutrigine. In healthy volunteers, PRAX-1451 significantly reduced axonal excitability across NETT parameters, confirming Na_V target engagement, while nociceptive thresholds remained unchanged.

Preclinical and human data demonstrate selective Na_V modulation by relutrigine, vormatrigine, and PRAX-1451, supporting their potential as well-tolerated analgesics targeting peripheral NaV dysfunction, and advancing a translational platform for next-generation pain therapeutics.