OBJECTIVE -Pathophysiology explaining pain in diabetic neuropathy (DN) is still unknown.RESEARCH DESIGN AND METHODS -Thirty patients with peripheral DN (17 men and 13 women; mean age 52.4 Ϯ 2.5 years) were investigated. Fifteen patients had neuropathic pain, and 15 patients were free of pain. Patients were followed over 2 years and examined at the beginning and thereafter every 6 months. Clinical severity and painfulness of the DN were assessed by the neuropathy impairment score and visual analog scales (VASs). Cold and warm perception thresholds as well as heat pain thresholds were obtained for evaluation of A␦-and C-fibers. Nerve conduction velocities (NCVs) and vibratory thresholds were recorded for analysis of thickly myelinated fibers. Moreover, for assessment of cardiac vagal function, heart rate variability (HRV) was evaluated. In order to reduce day-to-day variability of pain, mean values of the five time points over 2 years were calculated and used for further analysis. Data were compared with an age-and sex-matched control group of healthy volunteers.RESULTS -There were significant differences regarding electrophysiological studies, HRV and quantitative sensory testing (QST) between patients and healthy control subjects (P Ͻ 0.001). Generally, patients with neuropathic pain were indistinguishable from pain-free patients. In the pain group, however, VAS pain ratings were correlated to the impairment of small-fiber function (cold detection thresholds, P ϭ 0.02; warm detection thresholds, P ϭ 0.056).CONCLUSIONS -Intensity of pain in painful DN seems to depend on small nerve fiber damage and deafferentation.
Diabetes Care 27:2386 -2391, 2004D iabetic neuropathy (DN) is the most frequent neuropathy in western countries and affects ϳ60% of all diabetic patients (1). About 13% of patients with DN report neuropathic pain (2), which includes spontaneous pain such as burning feet or dysesthesia (3). Unfortunately, there are no predictors for the development of pain as a symptom of DN. The intensity of pain may vary substantially within days or weeks. There are mood, seasonal, social, and daily activity influences that modify pain intensity or pain-coping strategies (4). This variability complicates the quantification of clinical neuropathic pain. The detailed mechanisms leading to neuropathic pain are not specific for DN and may even vary between patients. The most important mechanisms are the accumulation of sodium channels on injured axons (5), sympatho-afferent coupling (6), disinhibition of nociception (7), and peripheral or central sensitization (8). However, the predominant pathophysiology in painful DN is unknown (9).Tests to analyze nerve function in DN include assessment of sensory and motor nerve conduction velocity (NCV), quantitative sensory testing (QST) for different afferent fiber classes (10), analysis of heart rate variability (HRV) for vagal function, and sudomotor axon reflexes for peripheral sympathetic fibers (11). Histological data can be obtained from nerve or skin biopsies (12). However, ...