Altered pain processing in patients with type 1 and 2 diabetes: systematic review and meta-analysis of pain detection thresholds and pain modulation mechanisms.

The first signs of diabetic neuropathy typically result from small-diameter nerve fiber dysfunction. This review synthesized the evidence for small-diameter nerve fiber neuropathy measured via quantitative sensory testing (QST) in patients with diabetes with and without painful and non-painful neuropathies. Electronic databases were searched to identify studies in patients with diabetes with at least one QST measure reflecting small-diameter nerve fiber function (thermal or electrical pain detection threshold, contact heat-evoked potentials, temporal summation or conditioned pain modulation). Four groups were compared: patients with diabetes (1) without neuropathy, (2) with non-painful diabetic neuropathy, (3) with painful diabetic neuropathy and (4) healthy individuals. Recommended methods were used for article identification, selection, risk of bias assessment, data extraction and analysis. For the meta-analyses, data were pooled using random-effect models. Twenty-seven studies with 2422 participants met selection criteria; 18 studies were included in the meta-analysis. Patients with diabetes without symptoms of neuropathy already showed loss of nerve function for heat (standardized mean difference (SMD): 0.52, p<0.001), cold (SMD: -0.71, p=0.01) and electrical pain thresholds (SMD: 1.26, p=0.01). Patients with non-painful neuropathy had greater loss of function in heat pain threshold (SMD: 0.75, p=0.01) and electrical stimuli (SMD: 0.55, p=0.03) compared with patients with diabetes without neuropathy. Patients with painful diabetic neuropathy exhibited a greater loss of function in heat pain threshold (SMD: 0.55, p=0.005) compared with patients with non-painful diabetic neuropathy. Small-diameter nerve fiber function deteriorates progressively in patients with diabetes. Because the dysfunction is already present before symptoms occur, early detection is possible, which may assist in prevention and effective management of diabetic neuropathy.