Nonaddictive Analgesia: New Approaches That Target the Hodgkin-Huxley NaV/KV Dyad.

Abstract

Chronic pain represents a massive global health burden that is exacerbated by the limitations and liabilities of opioid therapies. This review examines the biophysical basis of nociceptor excitability, framed by the Hodgkin-Huxley dyad of opposing voltage-gated sodium (Na_V) and potassium (K_V) conductances. We analyze the roles of peripheral Na_V isoforms (Na_V1.7, Na_V1.8, Na_V1.9) as drivers of pathological firing and discuss the translational trajectory of Na_V inhibitors, ranging from the recent clinical approval of Na_V1.8-selective small molecules to the ongoing challenges facing Na_V1.7-targeted programs. Beyond canonical pore blockers, we evaluate emerging modalities, including state-dependent cannabinoid modulation, targeted protein degradation, and genetic interventions. Complementing these excitatory targets, we discuss K_V7 channel activators as molecular brakes capable of buffering hyperexcitability. Finally, we propose that rational comodulation of this dyad offers a mechanistically grounded pathway toward effective, nonaddictive analgesia.