Isoform-Specific NaV Modulation in Painful Chemotherapy-Induced Neuropathy: Promise, Limitations, and a Clinical Agenda.

Painful chemotherapy-induced peripheral neuropathy (CIPN) is highly prevalent and functionally disabling yet remains largely refractory to current treatments. Isoform-specific modulation of voltage-gated sodium channels (NaV), particularly NaV1.8, has emerged as a promising strategy to reduce nociceptor hyperexcitability. The recent approval of the NaV1.8-selective inhibitor suzetrigine for acute postoperative pain demonstrates the feasibility of highly selective peripheral sodium-channel inhibition, although its indication is currently restricted to acute pain and its relevance for chronic neuropathic conditions remains uncertain. However, painful CIPN is mechanistically heterogeneous, shaped by oxidative stress, mitochondrial dysfunction, neuroinflammation, activation of transient receptor potential channels, axonal degeneration, and central sensitization. These multidimensional pathways raise important questions about whether NaV selectivity alone can provide meaningful benefit in a condition where neuronal hyperexcitability represents only one component of a broader pathophysiological network. Evidence from sodium-channel-targeted analgesics, including the partial efficacy of NaV1.7 inhibitors and the functional redundancy among NaV1.7, NaV1.8, and NaV1.9, further underscores the limitations of monotherapy approaches. This Current Opinion argues that isoform-specific NaV modulation should be embedded within a broader translational framework. Priorities include mechanistic phenotyping aligned with chemotherapy class, integration of functional and molecular biomarkers, and adoption of patient-centered endpoints. Furthermore, multimodal strategies combining NaV modulators with agents targeting oxidative stress, mitochondrial dysfunction, immune activation, or cytoskeletal injury-alongside mechanism-based rehabilitation and neuromodulation-may offer more realistic therapeutic benefit. By situating NaV modulation within these multidimensional strategies and incorporating pharmacogenetic insights into NaV variants associated with painful neuropathies, the field may move beyond technological promise toward interventions that meaningfully improve outcomes for patients living with painful CIPN.