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

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 (NaV) and potassium (KV) conductances. We analyze the roles of peripheral NaV isoforms (NaV1.7, NaV1.8, NaV1.9) as drivers of pathological firing and discuss the translational trajectory of NaV inhibitors, ranging from the recent clinical approval of NaV1.8-selective small molecules to the ongoing challenges facing NaV1.7-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 KV7 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.