Small Fiber Functionality in Patients with Diabetic Neuropathic Pain

ÜNAL ÇEVİK I., ORHAN D., ACAR ÖZEN N. P., Mamak-Ekinci E. B.

PAIN MEDICINE, vol.22, no.9, pp.2068-2078, 2021 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 22 Issue: 9
  • Publication Date: 2021
  • Doi Number: 10.1093/pm/pnab150
  • Journal Name: PAIN MEDICINE
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, CINAHL, EMBASE, MEDLINE, Psycinfo, SportDiscus
  • Page Numbers: pp.2068-2078
  • Keywords: C-fibers, Axon-Flare Reflex, Histamine, Capsaicin, Skin Biopsy, AXON REFLEX FLARE, QUESTIONNAIRE, PHENOTYPE, DIAGNOSIS, LDIFLARE, VALIDITY, DN4
  • Hacettepe University Affiliated: Yes


Objectives. Diabetic neuropathic pain is associated with small fiber neuropathy. We aimed to assess the functionality of small fibers in patients with diabetes by using a practical method. Design. Patients with impaired glucose tolerance (IGT), diabetic neuropathic pain (DNP), type II diabetes mellitus without neuropathic pain, and healthy control were included. Axon-reflex flare responses were induced by the intradermal application of capsaicin and histamine at the distal leg. The associated flare characteristics (flare areas and flare intensities) were recorded by using Laser Speckle Contrast Analysis (LASCA). The pain and itch responses were rated while performing LASCA. To verify the structural properties of the small fibers, proximal and distal skin biopsies were performed. Results. DN4, MNSI, NRS, evoked-burning pain scores, and HbA1c levels were the highest in the DNP group. Compatible with length-dependent neuropathy, the distal skin PGP9.5-positive intraepidermal nerve fiber densities (IENFDs) were the lowest, whereas TRPV1-positive IENFDs were the highest in patients with DNP. The distal leg LASCA data showed hypo-functionality in both patients with IGT and DNP and association with disease severity. Conclusions. There is an unmet need to practically assess the functionality of small fibers in patients with pain. In this study, a practical and objective method that does not need special expertise for the measurement of the functional properties of small fibers by using axon-flare responses is presented. The LASCA method could potentially facilitate a practical, quick (within 5 minutes), and very early diagnosis of small fiber hypo-functionality in both patients with IGT and DNP.