Targeting neurovascular dysfunction in diabetic neuropathic pain: a review of mechanism-based pharmacotherapy beyond gabapentinoids.

Abstract

Background: Diabetic neuropathic pain (DNP) is a condition that affects about 20-30% of people with diabetes, significantly reducing health-related quality of life and having a significant economic impact on healthcare economics. Although conventional "gold standard" treatments such as gabapentinoids, serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs) are widely used in the clinic, a substantial number of patients have poor results with these medications in terms of the quality of their analgesia or their systemic side effects.

Objective: In order to overcome these drawbacks, this review examines the status of the current pharmacotherapy and evaluates the new classes of drugs in late-stage clinical development.

Methods: A thorough search of PubMed, Google Scholar, the Cochrane Library, and ClinicalTrials.gov (2015-2025) of randomised controlled trials and meta-analyses reveals a clear ceiling effect for the traditional gabapentinoids in terms of therapeutic benefit.

Results: On the other hand, new mechanistically targeted therapies like selective Nav1.7 sodium channel blockers, alternative voltage-gated calcium channel ligands, and angiotensin II AT2 receptor antagonists show therapeutic potential and achieve marked improvement in pain scores while maintaining improved safety profiles. Moreover, new lines of therapy are emerging with the incorporation of advanced non-systemic and integrative treatments such as the development of nanotechnology-based drug delivery systems, phytoconstituents with therapeutic properties, structured physical exercise and advanced neuromodulation therapies, which are aimed at reducing the effect of neuroinflammation and microvascular damage.

Conclusion: Finally, modern management of DNP is shifting to a mechanism-based approach. A change from a generic, empirical drug prescription to a more precise, individual-based approach to drug prescription (phenotypic pain profile) has great potential to improve therapeutic outcomes, especially for refractory diabetic neuropathy.