Quantitative assessment of small-fiber dysfunction

Berfelo et al. [2] investigated the utility of intra-epidermal electrical stimulation (IES) to assess nociceptive detection thresholds (NDT) and evoked potentials (EPs) in diabetic patients with (DMp) and without (DM) painful neuropathy. Their results demonstrated significant alterations in NDT and EP responses among patients with painful neuropathy, suggesting that IES-derived electrophysiological parameters can objectively capture small-fiber dysfunction. These findings support the use of IES as a valuable adjunctive tool in the diagnostic evaluation of painful diabetic polyneuropathy, offering a more precise and quantifiable assessment of sensory fiber impairment.

Mechanistic foundations supporting targeted treatment

Novel pharmacological candidates

Interventional and device-based therapies

Matejowsky et al. [10] present a comprehensive review of interventional strategies for managing refractory NP, encompassing spinal cord stimulation (SCS), intrathecal drug delivery systems (IDDS), peripheral nerve stimulation, and various ablative or destructive procedures. The authors synthesize evidence indicating that SCS and IDDS offer superior analgesic outcomes compared to conventional systemic pharmacotherapy, particularly in patients with treatment-resistant NP. They underscore the critical role of appropriate patient selection, interdisciplinary management, and systematic long-term outcome monitoring in maximizing therapeutic benefit. Safety remains a central concern in interventional pain management, and this is especially pertinent in the NP population, where invasive techniques carry specific risks and must be carefully balanced against potential benefits [11].

This integrative, mechanism-targeted approach aligns with current clinical paradigms that prioritize individualized treatment strategies based on precise diagnostic phenotyping. However, the field still faces a major challenge in the rigorous validation of existing assessment tools. Addressing this gap, one study in this special issue validated the Chinese version of the painDETECT questionnaire, confirming its strong reliability, internal consistency, and discriminative accuracy for identifying NP. These findings support its clinical applicability as a culturally adapted screening instrument for Chinese-speaking populations [12]. Given that painDETECT is among the most widely utilized tools for the diagnosis of NP in both clinical and research contexts, its robust cross-cultural validation is of particular significance [13–15].

Challenges and future directions

Despite substantial advances in the understanding and management of NP, several significant challenges remain unresolved. Translational research must effectively bridge the gap between preclinical discoveries and clinical implementation. For example, while IES offers promising objective measures of small-fiber function, normative reference data and validation across a range of NP phenotypes are essential for its broader clinical adoption. Similarly, the therapeutic potential of S1R modulators must be confirmed through clinical trials employing patient-centered endpoints to establish both efficacy and safety. Neuroplasticity-based treatments, particularly serotonergic psychedelics, show emerging promise but require rigorous randomized controlled trials with standardized protocols and long-term follow-up to determine their clinical utility. In parallel, the incorporation of neuromodulatory interventions such as SCS and IDDS into clinical practice necessitates additional high-quality evidence regarding their long-term effectiveness, cost-efficiency, appropriate patient selection criteria, and safety profile. Furthermore, while mechanism-based treatment algorithms offer a rational framework for individualized care, prospective validation in real-world settings is imperative to substantiate their clinical applicability and optimize treatment outcomes in diverse patient populations.

Conclusion

The collective works presented in this special issue constitute a multi-dimensional advance in NP research. By integrating objective diagnostics, mechanism-based therapies, novel pharmacological modalities, and refined interventional techniques, they mark a substantial step toward personalized, effective, and durable NP management. Future efforts should prioritize rigorous clinical validation, multidisciplinary care models, and dynamic patient stratification to fully translate these insights into improved clinical outcomes.