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 (Na _V ) and potassium (K _V ) conductances. We analyze the roles of peripheral Na _V isoforms (Na _V 1.7, Na _V 1.8, Na _V 1.9) as drivers of pathological firing and discuss the translational trajectory of Na _V inhibitors, ranging from the recent clinical approval of Na _V 1.8-selective small molecules to the ongoing challenges facing Na _V 1.7-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 _V 7 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.