The relationship among pain, sensory loss, and small nerve fibers in diabetes.
OBJECTIVE
Many individuals with diabetes experience neuropathic pain, often without objective signs of large-fiber neuropathy. We examined intraepidermal nerve fibers (IENFs) to evaluate the role of small nerve fibers in the genesis of neuropathic pain.


METHODS
Twenty-five diabetic subjects with neuropathic pain and 13 without were studied. The pain was present for at least 6 months for which no other cause could be found. Punch skin biopsies were obtained from the distal leg. IENFs were stained using antibody to protein gene product 9.5 and counted with confocal microscopy. Neuropathy was graded by vibration perception and cold detection thresholds and the Michigan Neuropathy Screening Instrument.


RESULTS
In the total cohort, IENF density was significantly lower in those with pain compared with those without (3 [1-6] vs. 10 [3-19], respectively, P = 0.02). There were significant inverse correlations between IENF and severity of neuropathy, with the pain group having a flatter gradient than their pain-free counterparts (P < 0.02). The difference in IENF density was greatest in subjects with less objective evidence of neuropathy (P < or = 0.01).


CONCLUSIONS
More severe loss of IENF is associated with the presence of neuropathic pain only in those with little or no objective sign of neuropathy. Thus, loss of IENF cannot explain pain in all cases, suggesting that different mechanisms underpin the genesis of pain at various stages of neuropathy.
Sorensen
Lea
L
Diabetes Centre, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia. lea@email.cs.nsw.gov.au
Molyneaux
Lynda
L
Yue
Dennis K
DK
D000368:Aged; D001706:Biopsy; D003929:Diabetic Neuropathies / Q000175:diagnosis / Q000473:pathology*; D004817:Epidermis / Q000294:innervation*; D005260:Female; D005528:Foot; D006801:Humans; D008297:Male; D008875:Middle Aged; D009412:Nerve Fibers / Q000473:pathology*; D010146:Pain / Q000473:pathology*; D014110:Touch; D014732:Vibration