Assessing the Feasibility of a Multimodal Approach to Pain Evaluation in Early Stages after Spinal Cord Injury.

This research evaluates the feasibility of a multimodal pain assessment protocol during rehabilitation following spinal cord injury (SCI). The protocol amalgamates clinical workup (CW), quantitative sensory testing (QST), and psychosocial factors (PSF) administered at 4 (T1), 12 (T2), and 24 (T3) weeks post injury and at discharge (T4). Molecular blood biomarkers (BB) were evaluated via gene expression and proteomic assays at T1 and T4. Different pain trajectories and temporal changes were identified using QST, with inflammation and pain-related biomarkers recorded. Higher concentrations of osteopontin and cystatin-C were found in SCI patients compared to healthy controls, indicating their potential as biomarkers. We observed altered inflammatory responses and a slight increase in ICAM-1 and CCL3 were noted, pointing towards changes in cellular adhesion linked with spinal injury and a possible connection with neuropathic pain. Despite a small patient sample hindering the correlation of feasibility data, descriptive statistical analyses were conducted on stress, depression, anxiety, quality of life, and pain interferences. The SCI Pain Instrument (SCIPI) was efficient in distinguishing between nociceptive and neuropathic pain, showing a progressive increase in severity over time. The findings emphasize the need for the careful consideration of recruitment setting and protocol adjustments to enhance the feasibility of multimodal pain evaluation studies post SCI. They also shed light on potential early adaptive mechanisms in SCI pathophysiology, warranting the further exploration of prognostic and preventive strategies for chronic pain in the SCI population.

Swiss QUality of life and healthcare impact Assessment in a Real-world Erenumab treated migraine population (SQUARE study): interim results.

BACKGROUND: The fully human monoclonal antibody erenumab, which targets the calcitonin gene-related peptide (CGRP) receptor, was licensed in Switzerland in July 2018 for the prophylactic treatment of migraine. To complement findings from the pivotal program, this observational study was designed to collect and evaluate clinical data on the impact of erenumab on several endpoints, such as quality of life, migraine-related impairment and treatment satisfaction in a real-world setting. METHODS: An interim analysis was conducted after all patients completed 6 months of erenumab treatment. Patients kept a headache diary and completed questionnaires at follow up visits. The overall study duration comprises 24 months. RESULTS: In total, 172 adults with chronic or episodic migraine from 19 different sites across Switzerland were enrolled to receive erenumab every 4 weeks. At baseline, patients had 16.6 ± 7.2 monthly migraine days (MMD) and 11.6 ± 7.0 acute migraine-specific medication days per month. After 6 months, erenumab treatment reduced Headache Impact Test (HIT-6™) scores by 7.7 ± 8.4 (p < 0.001), the modified Migraine Disability Assessment (mMIDAS) by 14.1 ± 17.8 (p < 0.001), MMD by 7.6 ± 7.0 (p < 0.001) and acute migraine-specific medication days per month by 6.6 ± 5.4 (p < 0.001). Erenumab also reduced the impact of migraine on social and family life, as evidenced by a reduction of Impact of Migraine on Partners and Adolescent Children (IMPAC) scores by 6.1 ± 6.7 (p < 0.001). Patients reported a mean effectiveness of 67.1, convenience of 82.4 and global satisfaction of 72.4 in the Treatment Satisfaction Questionnaire for Medication (TSQM-9). In total, 99 adverse events (AE) and 12 serious adverse events (SAE) were observed in 62 and 11 patients, respectively. All SAE were regarded as not related to the study medication. CONCLUSIONS: Overall quality of life improved and treatment satisfaction was rated high with erenumab treatment in real-world clinical practice. In addition, the reported impact of migraine on spouses and children of patients was reduced. TRIAL REGISTRATION: BASEC ID 2018-02,375 in the Register of All Projects in Switzerland (RAPS).

Local hyperexcitability of C-nociceptors may predict responsiveness to topical lidocaine in neuropathic pain.

We explored whether increased C-nociceptor excitability predicts analgesic effects of topical lidocaine in 33 patients with mono- (n = 15) or poly-neuropathy (n = 18). Excitability of C-nociceptors was tested by transcutaneous electrical sinusoidal (4 Hz) and half sine wave (single 500 ms pulse) stimulation delivered to affected and non-affected sites. Analgesic effects of 24 hrs topical lidocaine were recorded. About 50% of patients reported increased pain from symptomatic skin upon continuous 4 Hz sinusoidal and about 25% upon 500 ms half sine wave stimulation. Electrically-evoked half sine wave pain correlated to their clinical pain level (r = 0.37, p < 0.05). Lidocaine-patches reduced spontaneous pain by >1-point NRS in 8 of 28 patients (p < 0.0001, ANOVA). Patients with increased pain to 2.5 sec sinusoidal stimulation at 0.2 and 0.4 mA intensity had significantly stronger analgesic effects of lidocaine and in reverse, patients with a pain reduction of >1 NRS had significantly higher pain ratings to continuous 1 min supra-threshold sinusoidal stimulation. In the assessed control skin areas of the patients, enhanced pain upon 1 min 4 Hz stimulation correlated to increased depression scores (HADS). Electrically assessed C-nociceptor excitability identified by slowly depolarizing electrical stimuli might reflect the source of neuropathic pain in some patients and can be useful for patient stratification to predict potential success of topical analgesics. Central neuronal circuitry assessment reflected by increased pain in control skin associated with higher HADS scores suggest central sensitization phenomena in a sub-population of neuropathic pain patients.

Variability in clinical and neurophysiological evaluation of pain development following acute spinal cord injury: a case report.

INTRODUCTION: Chronic neuropathic pain (NeP) often develops following traumatic spinal cord injury (SCI). This case report explores variability in clinical and neurophysiological aspects of pain evaluation in early post-trauma stages. CASE PRESENTATION: A 34-year old female presenting with acute incomplete sensorimotor tetraplegia C4 AIS D was examined by neurological examination and pain assessment at three time points after acute trauma T1 (8 weeks), T2 (11 weeks), and T3 (24 weeks). Quantitative sensory testing (QST) and laser-evoked potentials (LEPs) were measured above (control area), at (area of NeP), and below (foot) the neurological level of injury (NLI). Musculo-skeletal and neuropathic pain were clinically present already during T1 but showed variations in localization and occurrence over time. Neuropathic pain classification varied between time points due to shifting of NLI. Above-level QST revealed minor, less pronounced abnormalities similar to at-level site. At-level QST (site of NeP) showed loss for thermal and mechanical detection thresholds but also gain of function for mechanical pain thresholds with a tendency of amelioration over time. QST below-level did not reveal remarkable changes over time. LEPs above- and below-level were within normal limits. At-level LEPs abolished after T1. DISCUSSION: In early stages post injury (up to 6 month) variations in pain presentation for both, musculo-skeletal and neuropathic pain as well as QST and LEP could be demonstrated. These findings suggest ongoing adaption mechanisms in sensory pathways, which require further exploration and may be relevant for prognostic and preventive strategies against the development of chronic neuropathic and nociceptive pain.

Multimodal sensory evaluation of neuropathic spinal cord injury pain: an experimental study.

STUDY DESIGN: An experimental study. OBJECTIVES: To investigate the changes in somatosensory functions using the combined application of quantitative sensory testing (QST), contact heat-evoked potentials (CHEPs) and laser-evoked potentials (LEPs) studies in individuals with spinal cord injury (SCI) in relation to neuropathic pain (NeP). SETTING: Centre for Pain Medicine, Swiss Paraplegic Centre, Nottwil, Switzerland. METHODS: Individuals with SCI were compared: 12 with NeP (SCI NeP) and 12 without NeP (SCI no NeP). Tools used were QST, CHEPs, LEPs and self-reported questionnaires. Tests were applied to the control (hand) and test (dermatome of altered sensation) sites, and compared to the able-bodied group. RESULTS: QST, LEPs and CHEPs assessments showed abnormalities both on the test and control sites, which did not differ between the groups with SCI. QST showed higher prevalence of allodynia in SCI NeP. CHEPs and LEPs demonstrated diminished amplitudes in both groups with SCI in comparison to able-bodied individuals. Only reaction time (RT) analysis revealed the difference of SCI NeP from the other two groups, expressed in partially preserved responses to the laser C-fibre stimulations. CONCLUSIONS: Combination of assessments in our study allowed to examine spinothalamic and dorsal column functions in individuals with SCI. Changes in QST, CHEPs and LEPs were detected below the level of injury independent of NeP and at the control site indicating modifications in sensory processing rostral to the spinal lesion. Analysis of RT during laser stimulation could be an essential component when evaluating the somatosensory functions related to NeP in persons with SCI.

Psychosocial resources and chronic pain in individuals with spinal cord injury: evidence from the second Swiss national community survey.

STUDY DESIGN: Cross-sectional. OBJECTIVE: To investigate the associations of a set of psychosocial resources with pain and pain-related factors in individuals with spinal cord injury (SCI) and chronic pain. SETTING: Community, Switzerland. METHODS: Data from 1,064 individuals with chronic pain who participated in the second community survey of the Swiss Spinal Cord Injury Cohort Study (Survey 2017) were analyzed. Multiple linear regression modeling was performed to test the hypotheses that higher levels of psychosocial resources (self-efficacy, self-esteem, purpose in life, optimism, hope, social support, sense of belonging) are negatively associated with pain intensity, pain interference and depressive symptoms. RESULTS: Higher self-esteem, optimism and hope were related to less pain interference and all psychosocial resources under study were negatively associated with depressive symptoms in final models. However, neither of the psychosocial resources was related to pain intensity when models were adjusted for pain interference and depressive symptoms. CONCLUSIONS: These findings strengthen the evidence that psychosocial resources can have an impact on pain interference and depressive symptoms as pain-related factors, and support the notion that psychosocial resources might be promising targets for pain interventions in individuals with SCI.

Somatosensory profiles in patients with non-specific neck-arm pain with and without positive neurodynamic tests.

Despite normal neurological integrity tests, some patients with non-specific neck-arm pain (NSNAP) have heightened nerve mechanosensitivity upon neurodynamic testing. The aim of this study was to determine whether or not a nerve dysfunction is present in patients with positive neurodynamic tests compared to those with negative neurodynamic tests or healthy controls. Somatosensory profiling using quantitative sensory testing (QST) was established in 40 consecutive patients with unilateral NSNAP; 23 had positive upper limb neurodynamic tests (ULNTPOS) and 17 had negative neurodynamic tests (ULNTNEG) and in 26 healthy controls. QST included measurement of thermal and mechanical detection and pain thresholds in the maximal pain area on the symptomatic side as well as the corresponding contralateral area. Fifty-seven percent of patients with NSNAP had positive neurodynamic tests. Somatosensory profiling revealed a loss of function phenotype in NSNAP patients compared to healthy controls both in the maximal pain area and asymptomatic side. Hyperalgesia (cold, heat and pressure) was present bilaterally in both NSNAP groups. Direct comparison between the patient groups revealed no significant differences in somatosensory profiles. However, the ULNTPOS group demonstrated sensory loss compared to healthy controls in more parameters than the ULNTNEG group. The ULNTNEG subgroup represented an intermediate phenotype between ULNTPOS patients and healthy controls in most detection thresholds as well as thermal and pressure pain thresholds. Even though patients with NSNAP present as a spectrum, it remains unclear whether the sensory changes are indicative of a nerve dysfunction/lesion or rather a marker of altered central pain processing.

Management of pain in individuals with spinal cord injury: Guideline of the German-Speaking Medical Society for Spinal Cord Injury.

Introduction: Pain is a prominent complication in spinal cord injury (SCI). It can either occur as a direct or as an indirect consequence of SCI and it often heavily influences the quality of life of affected individuals. In SCI, nociceptive and neuropathic pain can equally emerge at the same time above or below the level of injury. Thus, classification and grading of pain is frequently difficult. Effective treatment of SCI-related pain in general and of neuropathic pain in particular is challenging. Current treatment options are sparse and their evidence is considered to be limited. Considering these aspects, a clinical practice guideline was developed as basis for an optimized, comprehensive and standardized pain management in SCI-related pain. Methods: The German-Speaking Medical Society for Spinal Cord Injury (Deutschsprachige Medizinische Gesellschaft für Paraplegiologie - DMGP) developed a clinical practice guideline that received consensus from seven further German-speaking medical societies and one patient organization. The evidence base from clinical trials and meta-analyses was summarized and subjected to a structured consensus-process in accordance with the regulations of the Association of Scientific Medical Societies in Germany (AWMF) and the methodological requirements of the "German instrument for methodological guideline appraisal". Results: This consensus-based guideline (S2k classification according to the AWMF guidance manual and rules) resulted in seven on-topic statements and 17 specific recommendations relevant to the classification, assessment and therapy of pain directly or indirectly caused by SCI. Recommended therapeutic approaches comprise pharmacological (e.g. nonsteroidal anti-inflammatory drugs or anticonvulsants) and non-pharmacological (e.g. physical activity or psychotherapeutic techniques) strategies for both nociceptive and neuropathic pain. Discussion: Assessment of SCI-related pain is standardized and respective methods in terms of examination, classification and grading of pain are already in use and validated in German language. In contrast, valid, evidence-based and efficient therapeutic options are limited and ask for further clinical studies, ideally randomized controlled trials and meta-analyses.

Unexpectedly decreased plasma cytokines in patients with chronic back pain.

INTRODUCTION: Chronic back pain is one of the most important socioeconomic problems that affects the global population. Elevated levels of inflammatory mediators, such as cytokines, have been correlated with pain, but their role in chronic back pain remains unclear. The effectiveness of anti-inflammatory drugs seems to be limited for chronic back pain. The authors wanted to investigate the levels of inflammatory mediators in long-term medically treated patients with persistent chronic back pain. METHODS: Cytokine plasma levels of patients with chronic back pain (n=23), compared to pain-free healthy controls (n=30), were investigated by immunoassay. Patients with chronic back pain were exposed to long-term conservative medical therapy with physiotherapy and anti-inflammatories, also combined with antidepressants and/or muscle-relaxants. RESULTS: The patients with chronic back pain expressed lower levels of the chemokines MCP1, CCL5, and CXCL6 compared to pain-free healthy controls. Significantly lower concentrations of the anti-inflammatory cytokines, interleukin (IL)-4 and granulocyte-colony stimulating factor were also found. Interestingly, levels of proinflammatory cytokines (IL-2, IL-6, IL-1ß, tumor necrosis factor alpha), IL-10, granulocyte-macrophage colony-stimulating factor, and stromal cell-derived factor 1 alpha showed no significant differences between both groups. CONCLUSION: This decrease of inflammatory mediators in medically treated patients with chronic back pain is of unclear origin and might be either a long-term side effect of medical therapy or related to chronic pain. Further longitudinal research is necessary to elucidate the underlying cause of these findings.

Tuning in C-nociceptors to reveal mechanisms in chronic neuropathic pain.

OBJECTIVE: Develop and validate a low-intensity sinusoidal electrical stimulation paradigm to preferentially activate C-fibers in human skin. METHODS: Sinusoidal transcutaneous stimulation (4Hz) was assessed psychophysically in healthy volunteers (n = 14) and neuropathic pain patients (n = 9). Pursuing laser Doppler imaging and single nociceptor recordings in vivo in humans (microneurography) and pigs confirmed the activation of "silent" C-nociceptors. Synchronized C-fiber compound action potentials were evoked in isolated human nerve fascicles in vitro. Live cell imaging of L4 dorsal root ganglia in anesthetized mice verified the recruitment of small-diameter neurons during transcutaneous 4-Hz stimulation of the hindpaw (0.4mA). RESULTS: Transcutaneous sinusoidal current (0.05-0.4mA, 4Hz) activated "polymodal" C-fibers (50% at ∼0.03mA) and "silent" nociceptors (50% at ∼0.04mA), intensities substantially lower than that required with transcutaneous 1-ms rectangular pulses ("polymodal" ∼3mA, "silent" ∼50mA). The stimulation induced delayed burning (nonpulsating) pain and a pronounced axon-reflex erythema, both indicative of C-nociceptor activation. Pain ratings to repetitive stimulation (1 minute, 4Hz) adapted in healthy volunteers by Numeric Rating Scale (NRS) -3 and nonpainful skin sites of neuropathic pain patients by NRS -0.5, whereas pain even increased in painful neuropathic skin by approximately NRS +2. INTERPRETATION: Sinusoidal electrical stimulation at 4Hz enables preferential activation of C-nociceptors in pig and human skin that accommodates during ongoing (1-minute) stimulation. Absence of such accommodation in neuropathic pain patients suggest axonal hyperexcitability that could be predictive of alterations in peripheral nociceptor encoding and offer a potential therapeutic entry point for topical analgesic treatment. Ann Neurol 2018;83:945-957.

Successful spinal cord stimulation for neuropathic below-level spinal cord injury pain following complete paraplegia: a case report.

INTRODUCTION: Neuropathic pain is common in patients with spinal cord injury (SCI) and often difficult to treat. We report a case where epidural spinal cord stimulation (SCS) below the level of injury has been successfully applied in a patient with a complete spinal cord lesion. CASE PRESENTATION: A 53-year-old female presented with neuropathic below-level SCI pain of both lower legs and feet due to complete SCI below T5. Time and pain duration since injury was 2 years. Pain intensity was reported on numeric rating scale with an average of 7/10 (0 meaning no pain, 10 meaning the worst imaginable pain), but also with about 8-10 pain attacks during the day with an intensity of 9/10, which lasted between some minutes and half an hour. SCS was applied below the level of injury at-level T11-L1. After a successful 2 weeks testing period the pulse generator has been implanted permanently with a burst-stimulation pattern. The average pain was reduced to a bearable intensity of 4/10, in addition attacks could be reduced both in frequency and in intensity. This effects lasted for at least three months of follow-up. DISCUSSION: Even in case of complete SCI, SCS might be effective. Mechanisms of pain relief remain unclear. A modulation of suggested residual spinothalamic tract function may play a role. Further investigation has to be carried out to support this theory.

Chronic pain, depression and quality of life in individuals with spinal cord injury: Mediating role of participation.

OBJECTIVE: To test the hypotheses that: (i) pain is associated with depressive symptoms and quality of life; and (ii) participation restriction, satisfaction, and frequency mediate these relationships. DESIGN: Population-based, cross-sectional study. SUBJECTS/PATIENTS: Community-dwelling individuals with spinal cord injury (n = 1,549). METHODS: Hypotheses were tested in individuals with at least moderate chronic pain on the spinal cord injury - Secondary Conditions Scale (n = 834), applying structural equation modelling to data for spinal cord injury subgroups related to lesion severity (paraplegia, tetraplegia, complete, incomplete) and time since injury (≤ 10 vs ≥ 10 years). Model parameters included pain intensity (numerical rating scale), participation frequency, restriction, satisfaction (Utrecht Scale of Evaluation of Rehabilitation-Participation; USER-Participation), depressive symptoms (5-item Mental Health Index of the Short Form Health Survey; MHI-5), and 5 selected quality of life items (World Health Organization Quality of Life Scale; WHOQoL-BREF). RESULTS: Structural equation models confirmed associations of pain with depressive symptoms and quality of life, as well as the mediating role of participation restriction and low satisfaction with participation. These findings were apparent in individuals with tetraplegia or complete lesion and in those ≤ 10 years since paraplegia or incomplete injury. CONCLUSION: Unrestricted or satisfactory participation was found to be a crucial resource for individuals living less than 10 years with a more severe spinal cord injury, since it represents buffering potential for the negative effects of chronic pain on mental health and quality of life.

Nondermatomal somatosensory deficits in chronic pain are associated with cerebral grey matter changes.

OBJECTIVES: Widespread sensory deficits occur in 20-40% of chronic pain patients on the side of pain, independent of pain aetiology, and are known as nondermatomal sensory deficits (NDSDs). NDSDs can occur in absence of central or peripheral nervous system lesions. We hypothesised that NDSDs were associated with cerebral grey matter changes in the sensory system and in pain processing regions, detectable with voxel-based morphometry. METHODS: Twenty-five patients with NDSDs, 23 patients without NDSDs ("pain-only"), and 29 healthy controls were studied with high resolution structural MRI of the brain. A comprehensive clinical and psychiatric evaluation based on Diagnostic and Statistical Manual was performed in all patients. RESULTS: Patients with NDSDs and "pain-only" did not differ concerning demographic data and psychiatric diagnoses, although anxiety scores (HADS-A) were higher in patients with NDSDs. In patients with NDSDs, grey matter increases were found in the right primary sensory cortex, thalamus, and bilaterally in lateral temporal regions and the hippocampus/fusiform gyrus. "Pain-only" patients showed a bilateral grey matter increase in the posterior insula and less pronounced changes in sensorimotor cortex. CONCLUSIONS: Dysfunctional sensory processing in patients with NDSDs is associated with complex changes in grey matter volume, involving the somatosensory system and temporal regions.

Bilateral Sensory Changes and High Burden of Disease in Patients With Chronic Pain and Unilateral Nondermatomal Somatosensory Deficits: A Quantitative Sensory Testing and Clinical Study.

OBJECTIVES: Widespread sensory deficits resembling hemihypoesthesia occur in 20% to 40% of chronic pain patients on the side of pain, independent of pain etiology, and have been termed nondermatomal sensory deficits (NDSDs). Sensory profiles have rarely been investigated in NDSDs. MATERIALS AND METHODS: Quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain (DFNS) was performed in the face, hand, and foot of the painful body side and in contralateral regions in chronic pain patients. Twenty-five patients with NDSDs and 23 without NDSDs (termed the pain-only group) were included after exclusion of neuropathic pain. Comprehensive clinical and psychiatric evaluations were carried out. RESULTS: NDSD in chronic pain was associated with high burden of disease and more widespread pain. Only in the NDSD group were significantly higher thresholds for mechanical and painful stimuli found in at least 2 of 3 regions ipsilateral to pain. In addition, we found a bilateral loss of function for temperature and vibration detection, and a gain of function for pressure pain in certain regions in patients with NDSD. Sensory loss and gain of function for pressure pain correlated with pain intensity in several regions. DISCUSSION: This may indicate a distinct sensory profile in chronic non-neuropathic pain and NDSD, probably attributable to altered central pain processing and sensitization. The presence of NDSD in chronic non-neuropathic pain may be regarded as a marker for higher burden of pain disease.

Pain modulation is affected differently in medication-overuse headache and chronic myofascial pain - A multimodal MRI study.

Background Neuroimaging studies revealed structural and functional changes in medication-overuse headache (MOH), but it remains unclear whether similar changes could be observed in other chronic pain disorders. Methods In this cross-sectional study, we investigated functional connectivity (FC) with resting-state functional magnetic resonance imaging (fMRI) and white matter integrity using diffusion tensor imaging (DTI) to measure fractional anisotropy (FA) and mean diffusivity (MD) in patients with MOH ( N = 12) relative to two control groups: patients with chronic myofascial pain (MYO; N = 11) and healthy controls (CN; N = 16). Results In a data-driven approach we found hypoconnectivity in the fronto-parietal attention network in both pain groups relative to CN (i.e. MOH < CN and MYO < CN). In contrast, hyperconnectivity in the saliency network (SN) was detected only in MOH, which correlated with FA in the insula. In a seed-based analysis we investigated FC between the periaqueductal grey (PAG) and all other brain regions. In addition to overlapping hyperconnectivity seen in patient groups (relative to CN), MOH had a distinct connectivity pattern with lower FC to parieto-occipital regions and higher FC to orbitofrontal regions compared to controls. FA and MD abnormalities were mostly observed in MOH, involving the insula. Conclusions Hyperconnectivity within the SN along with associated white matter changes therein suggest a particular role of this network in MOH. In addition, abnormal connectivity between the PAG and other pain modulatory (frontal) regions in MOH are consistent with dysfunctional central pain control.

Effects of Current Density on Nociceptor Activation Upon Electrical Stimulation in Humans.

OBJECTIVES: Mechano-insensitive ("silent") nociceptors contribute to neuropathic pain. Their activation causes an axon-reflex erythema, but their high electrical excitation thresholds complicate their assessment, particularly in painful neuropathy. We therefore developed electrical stimulation paradigms for brief nociceptor activation and explored their sensitivity for clinical trials. METHOD: The local ethics committee approved the study protocol, and 14 healthy subjects were enrolled. Electrical stimuli were administered to ventral forearm and dorsum of the foot via self-adhesive 3 × 10 mm electrodes and a pair of blunted 0.4-mm-diameter platinum/iridium pin electrodes. Pain thresholds were determined and nociceptors activated at 1.5-fold pain threshold by 5 blocks delivering 10 pulses each and at randomized frequencies of 5 to 10 to 20 to 50 to 100 Hz, respectively. Axon reflex erythema and pain were recorded. RESULTS: Increased frequencies dose-dependently increased pain (P < 0.0001). Pin electrode stimulation was more painful than adhesive electrode stimulation (P < 0.04) particularly at the feet. Axon reflex erythema was significantly smaller at the feet than at the forearm (P < 0.0001). At both skin sites, pin electrode stimuli evoked significantly larger erythema (P < 0.05). CONCLUSIONS: Electrical stimulation at high current density using pin electrodes is a sensitive method for investigating "silent" nociceptors, which might therefore preferably be applied in neuropathic pain conditions.