The Relationship Among Pain, Sensory Loss, and Small Nerve Fibers in Diabetes

Abstract

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...

Surrogate Markers of Small Fiber Damage in Human Diabetic Neuropathy

“…This finding is, of course, in contrast with several studies that have demonstrated a reduction in IENF density in patients with impaired glucose tolerance, but it must be remembered that these patients also had painful neuropathy (12). Indeed, it may be that pain is related to loss of IENFs as shown in a recent study in which diabetic patients with painful neuropathy had a significant reduction in IENFD compared with diabetic patients with painless neuropathy (29). Several studies have attempted to address whether there is a relationship between the severity of neuropathy and the degree of IENF loss.…”

“…However, it is important to note that all patients had severe neuropathy as they were undergoing pancreas transplantation. Similarly, a recent study has also demonstrated an association between IENFD and vibration perception threshold; however, the majority of patients in that study also had moderate to severe neuropathy (29). Another study has shown a correlation between loss of IENF and the severity of neuropathy assessed using electrophysiology and QST (28).…”

Abnormal LDIflare but Normal Quantitative Sensory Testing and Dermal Nerve Fiber Density in Patients with Painful Diabetic Neuropathy

“…Lauria et al (19) found reduced IENFD in a study of six patients with painful diabetic neuropathy compared with that in normal control subjects. In another study of patients with neuropathic pain, Sorensen et al (20) paradoxically found more severe IENFD loss compared with that in those with PLN. From this finding, they concluded that loss of IENFD cannot explain genesis of pain in all patients.…”

Three-dimensional Imaging of Nociceptive Intraepidermal Nerve Fibers in Human Skin Biopsies

“…At present, the most commonly used protocol only measures the densities of nerve fibers that penetrate the basement membrane of the epidermis; it does not take into consideration axonal branching and/or morphological changes of the nerves. In addition, current IENFD analysis has not been shown to correlate IENFD with the presence of pain in PN 15 .…”