Reduced intraepidermal nerve fiber density in patients with chronic ischemic pain in peripheral arterial disease.

Chronic ischemic pain in peripheral arterial disease (PAD) is a leading cause of pain in the lower extremities. A neuropathic component of chronic ischemic pain has been shown independent of coexisting diabetes. We aimed to identify a morphological correlate potentially associated with pain and sensory deficits in PAD. Forty patients with symptomatic PAD (Fontaine stages II-IV), 20 with intermittent claudication (CI), and 20 with critical limb ischemia (CLI) were enrolled; 12 volunteers served as healthy controls. All patients were examined using pain scales and questionnaires. All study participants underwent quantitative sensory testing (QST) at the distal calf and skin punch biopsy at the distal leg for determination of intraepidermal nerve fiber density (IENFD). Additionally, S100 beta serum levels were measured as a potential marker for ischemic nerve damage. Neuropathic pain questionnaires revealed slightly higher scores and more pronounced pain-induced disability in CLI patients compared to CI patients. QST showed elevated thermal and mechanical detection pain thresholds as well as dynamic mechanical allodynia, particularly in patients with advanced disease. IENFD was reduced in PAD compared to controls (P<0.05), more pronounced in the CLI subgroup (CLI: 1.3 ± 0.5 fibers/mm, CI: 2.9 ± 0.5 fibers/mm, controls: 5.3 ± 0.6 fibers/mm). In particular, increased mechanical and heat pain thresholds negatively correlated with lower IENFD. Mean S100 beta levels were in the normal range but were higher in advanced disease. Patients with chronic ischemic pain had a reduced IENFD associated with impaired sensory functions. These findings support the concept of a neuropathic component in ischemic pain.

Test order of quantitative sensory testing facilitates mechanical hyperalgesia in healthy volunteers.

UNLABELLED: Quantitative sensory testing (QST) has become a widely used method to evaluate different submodalities of the somatic sensory system (predominantly) in patients with neuropathic pain. QST consists of 7 tests measuring 13 parameters in order to assess and quantify the perception of temperature, touch, pain, pressure, and vibration. The German Research Network on Neuropathic Pain implemented a standardized QST protocol including a defined testing order of the measurements. Accordingly, subjects tested with QST undergo thermal before mechanical testing. In the present study, we investigated the effect of testing order on the results of QST. Twenty healthy subjects were tested twice, 1 week apart with 2 different QST testing orders: the standardized testing order according to the German Research Network on Neuropathic Pain and a modified testing order in which mechanical stimuli were applied before thermal stimuli. For the test protocol that began with thermal testing, subjects exhibited signs of an increased mechanical perception: The mechanical pain sensitivity was significantly increased (P = .001, Wilcoxon test) for each pinprick stimulator and the mechanical pain threshold was lowered by a factor of 2 when compared with the modified testing order in which mechanical parameters were tested at the beginning of the session without prior thermal stimulation. Thermal parameters were the same for both test-order paradigms. These data indicate that preceding mild thermal stimulation might lead to a sensitization to mechanical stimuli and thus to mechanical hyperalgesia. Alternative habituation mechanisms in the modified testing order resulting from repeated pinprick stimulation at the beginning should also be debated. QST is a helpful diagnostic tool but interpretation should be done with consideration of interaction between test parameters. Reference data are only valid in the testing order from which they are obtained. PERSPECTIVE: Present data showed that mechanical hyperalgesia followed thermal testing. This article demonstrates that the test order of quantitative sensory testing is relevant in interpreting the results obtained. Reference values are suitable in the test order from which they are obtained.