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.RESEARCH DESIGN AND 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 ϭ 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 Ͻ 0.02). The difference in IENF density was greatest in subjects with less objective evidence of neuropathy (P Յ 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. Diabetes Care 29:883-887, 2006P eripheral neuropathy is a common complication of both type 1 and type 2 diabetes (1). Most commonly, it manifests as sensory loss, which predisposes subjects to foot abnormalities and high risk of ulceration. However, it has been reported that between 4 and 33% of subjects with diabetes suffer from the painful type of neuropathy, which can become chronic and produce unremitting pain for which there is little satisfactory treatment (2-4).It is known that pain transmission in peripheral nerves occurs along the small A␦ and C-type fibers (5,6). However, conventional clinical investigation of individuals with painful diabetic neuropathy is usually limited to nerve conduction studies that measure large-nerve fiber function. The results of these tests are often normal and unable to provide an explanation for the presence of pain (7,8). This conundrum reflects a common clinical observation that pain is often present in the absence of objective signs of neuropathy. Even in the presence of abnormal nerve conduction studies, some individuals may experience pain while others with the same degree of electrophysiological abnormalities are completely asymptomatic. It is commonly assumed that more specific testing of small-fiber function may better discriminate those with or without pain, but several studies, including our own, have shown this not to be the case (9 -11). However, in view of the pivotal role played by small nerve fibers in the transmission of pain sensation, further studies are obviously of importance.Direct examination of int...

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OBJECTIVE—Magnetic resonance spectroscopy (MRS) (specifically, 1H-MRS) has been used to show changes in the brain following peripheral nerve injury in subjects without diabetes. This study used 1H-MRS to examine the brain in subjects with or without painful diabetic neuropathy. RESEARCH DESIGN AND METHODS—Twenty-six diabetic subjects (12 with and 14 without chronic neuropathic pain) were compared, with 18 subjects without diabetes and pain. The left thalamus, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC) were assessed using 1H-MRS. RESULTS—In the DLPFC, diabetic subjects had a decrease in N-acetyl aspartate (NAA) and creatine relative to the control group. In the thalamus, there was a reduction of NAA in the diabetic group with pain compared with that in patients with diabetes and no pain. CONCLUSION—Subjects with diabetes have metabolite differences in the brain compared with control subjects. Subjects with painful neuropathy showed reduced NAA in the thalamus, which may explain the genesis of pain in some cases.