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Introduction: For the downstream nociceptive processing of elite athletes, recent studies indicate that athletes probably tolerate more pain as compared with a normally active population. Phenotyping the nociceptive processing of athletes in different types of endurance sports can provide insight into training-specific effects, which may help in understanding the long-term effects of specific exercise., Methods: Twenty-six elite endurance athletes from the disciplines of rowing, triathlon, and running and 26 age- and sex-matched, recreationally active control subjects who participated in the subjective pain perception and processing of standardized noxious stimuli were investigated by EEG. This included standardized heat pain thresholds (HPT) and contact heat-evoked potentials from heat stimulation, measured with EEG as well as pinprick-evoked potentials from mechanical stimulation., Results: After noxious stimulation, athletes showed a higher activation of the event-related spectral perturbation (ERSP) patterns in the N2P2 EEG response at the Cz Electrode compared with the controls. After noxious contact heat stimulation, triathletes had a higher ERSP activation compared with the controls, whereas the rowers had a higher ERSP activation after noxious mechanical stimulation. Also, HPT in triathletes were increased despite their increased central activation after thermal stimulation. We found a correlation between increased HPT and training hours and years, although athletes did not differ within these variables., Conclusions: Although we were able to identify differences between athletes of different endurance sports, the reasons and implications of these differences remain unclear. The study of sport-specific somatosensory profiles may help to understand the mechanisms of exercise-related long-term effects on pain processing and perception. Furthermore, sport-specific somatosensory effects may support the personalization of exercise interventions and identify risk factors for chronic pain in elite athletes., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American College of Sports Medicine.)

Introduction: The possibility of balancing career and family is meanwhile a central concern for most physicians when choosing a job. The aim of this study was to identify current barriers and opportunities for physician education and career planning., Methods: This cross-sectional study was conducted as an online survey between 11/2021 and 02/2022 and targeted physicians at all career levels in Germany who were members of a clinical professional association. Alternative and consent questions were used to assess experiences/attitudes toward various aspects of life and career planning, as well as alternative work and parental leave models, depending on gender, specialty, and hierarchical level., Results: The majority of the 2060 participants were female (69%) and had children (66%). Many childless residents reported that they felt they had to choose between children and a career. The majority of female residents, specialists and attending physicians (Ø 55.5%) stated that they had experienced career losses as a result of taking parental leave, while most men did not share this experience (Ø 53.7%). 92% of all participants agreed with the statement that men and women have different career opportunities. Job-sharing models were considered feasible at all levels of the hierarchy by an average of 55.6% of all medical executives., Conclusion: Parenthood and the use of parental leave and part-time work appear to have a significant impact on the career paths of those surveyed. Although the majority of directors of medical training programs are open to job-sharing models, further measures are needed in order to equalize career opportunities for men and women., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2024 Oberberg et al.)

Abstract: Paradoxical heat sensation (PHS) is the perception of warmth when the skin is cooled. Paradoxical heat sensation rarely occurs in healthy individuals but more frequently in patients suffering from lesions or disease of the peripheral or central nervous system. To further understand mechanisms and epidemiology of PHS, we evaluated the occurrence of PHS in relation to disease aetiology, pain levels, quantitative sensory testing parameters, and Neuropathic Pain Symptom Inventory (NPSI) items in patients with nervous system lesions. Data of 1090 patients, including NPSI scores from 404 patients, were included in the analysis. We tested 11 quantitative sensory testing parameters for thermal and mechanical detection and pain thresholds, and 10 NPSI items in a multivariate generalised linear model with PHS, aetiology, and pain (yes or no) as fixed effects. In total, 30% of the neuropathic patients reported PHS in contrast to 2% of healthy individuals. The frequency of PHS was not linked to the presence or intensity of pain. Paradoxical heat sensation was more frequent in patients living with polyneuropathy compared with central or unilateral peripheral nerve lesions. Patients who reported PHS demonstrated significantly lower sensitivity to thermal perception, with lower sensitivity to normally painful heat and cold stimuli. Neuropathic Pain Symptom Inventory scores were lower for burning and electric shock-like pain quality for patients with PHS. Our findings suggest that PHS is associated with loss of small thermosensory fibre function normally involved in cold and warm perception. Clinically, presence of PHS could help screening for loss of small fibre function as it is straightforward to measure or self-reported by patients., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Botulinum toxin has been used for decades in the treatment of a variety of painful diseases. Botulinum toxin not only blocks neuromuscular transmission, but also the secretion of neuropeptides, such as substance P, glutamate and calcitonin gene-related peptide (CGRP) and thus inhibits neurogenic inflammation. In addition, it has a modulatory pain-relieving effect via retrograde transport into the central nervous system. In addition to approval for the treatment of dystonia or spasticity, onabotulinum toxin A is also approved for the prophylaxis of chronic migraine if the oral prophylactic migraine medication has had an insufficient effect or has not been tolerated. In addition, botulinum toxin is also recommended in guidelines as a third-line treatment for neuropathic pain, but in Germany this is an off-label application. This article provides an overview of the current clinically relevant areas of application of botulinum toxin in the field of pain medicine., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Diagnosis and treatment of patients with immune-mediated neuropathies is challenging due to the heterogeneity of the diseases., Objectives: To assess similarities and differences in the current care of patients with immune-mediated polyneuropathies in specialized centers in Germany within the German neuritis network "Neuritis Netz"., Material and Methods: We conducted a cross-sectional survey of nine neurological departments in Germany that specialize in the care of patients with immune-mediated neuropathies. We assessed the diagnosis, the approach to diagnostic work-up and follow-up, typical symptoms at manifestation and progression of the disease, and treatment data., Results: This report includes data from 1529 patients per year treated for immune-mediated neuropathies, of whom 1320 suffered from chronic inflammatory demyelinating polyneuropathy (CIDP). Diagnostic work-up almost always included nerve conduction studies, electromyography, and lumbar puncture in accordance with current guidelines. The use of ultrasound, biopsy, and MRI varied. The most important clinical parameter for therapy monitoring in all centers was motor function in the clinical follow-up examinations. A wide range of different immunosuppressants was used for maintenance therapy in about 15% of patients., Conclusions: These data provide important epidemiological insights into the care of patients with immune-mediated neuropathies in Germany. The further development of specific recommendations for treatment and follow-up examinations is necessary to ensure a uniform standard of patient care. This effort is greatly facilitated by a structured collaboration between expert centers such as Neuritis Netz., (© 2022. The Author(s).)

Increased exercise loads, as observed in elite athletes, seem to modulate the subjective pain perception in healthy subjects. The combination of electroencephalography (EEG) and standardized noxious stimulation can contribute to an objective assessment of the somatosensory stimulus processing. We assessed the subjective pain ratings and the electroencephalogram (EEG)-based response after standardized noxious mechanical and thermal stimuli as well as during conditioned pain modulation (CPM) in 26 elite endurance athletes and compared them to 26 recreationally active controls. Elite endurance athletes had consistently stronger somatosensory responses in the EEG to both mechanical and thermal noxious stimuli than the control group. We observed no significant group differences in the subjective pain ratings, which may have been influenced by our statistics and choice of stimuli. The CPM testing revealed that our conditioning stimulus modulated the subjective pain perception only in the control group, whereas the EEG indicated a modulatory effect of the conditioning stimulus on the spectral response only in the athletes group. We conclude that a higher activation in the cortical regions that process nociceptive information may either be an indicator for central sensitization or an altered stimulus salience in the elite endurance athletes' group. Our findings from our CPM testing were limited by our methodology. Further longitudinal studies are needed to examine if exercise-induced changes in the somatosensory system might have a critical impact on the long-term health of athletes., (© 2022. The Author(s).)

Background: Pain occurs in the majority of patients with late onset Pompe disease (LOPD) and is associated with a reduced quality of life. The aim of this study was to analyse the pain characteristics and its relation to a small nerve fiber involvement in LOPD patients., Methods: In 35 patients with LOPD under enzyme replacement therapy without clinical signs of polyneuropathy (19 females; 51 ± 15 years), pain characteristics as well as depressive and anxiety symptoms were assessed using the PainDetect questionnaire (PDQ) and the hospital anxiety and depression scale (HADS), respectively. Distal skin biopsies were analysed for intraepidermal nerve fiber density (IENFD) and compared to age- and gender-matched reference data. Skin biopsies from 20 healthy subjects served as controls to assure validity of the morphometric analysis., Results: Pain was reported in 69% of the patients with an average intensity of 4.1 ± 1.1 on the numeric rating scale (NRS; anchors: 0-10). According to PDQ, neuropathic pain was likely in one patient, possible in 29%, and unlikely in 67%. Relevant depression and anxiety symptoms occurred in 31% and 23%, respectively, and correlated with pain intensity. Distal IENFD (3.98 ± 1.95 fibers/mm) was reduced in 57% of the patients. The degree of IENFD reduction did not correlate with the durations of symptoms to ERT or duration of ERT to biopsy., Conclusions: Pain is a frequent symptom in treated LOPD on ERT, though a screening questionnaire seldom indicated neuropathic pain. The high frequency of small nerve fiber pathology in a treated LOPD cohort was found regardless of the presence of pain or comorbid risk factors for SFN and needs further exploration in terms of clinical context, exact mechanisms and when developing novel therapeutic options for LOPD., (© 2022. The Author(s).)

Objectives: Aim of the review is to summarize the knowledge about the sensory function and pain modulatory systems in posttraumatic headache and discuss its possible role in patients with posttraumatic headache., Background: Posttraumatic headache is the most common complication after traumatic brain injury, and significantly impacts patients' quality of life. Even though it has a high prevalence, its origin and pathophysiology are poorly understood. Thereby, the existing treatment options are insufficient. Identifying its mechanisms can be an important step forward to develop target-based personalized treatment., Methods: We searched the PubMed database for studies examining pain modulation and/or quantitative sensory testing in individuals with headache after brain injury., Results: The studies showed heterogenous alterations in sensory profiles (especially in heat and pressure pain perception) compared to healthy controls and headache-free traumatic brain injury-patients. Furthermore, pain inhibition capacity was found to be diminished in subjects with posttraumatic headache., Conclusions: Due to the small number of heterogenous studies a distinct sensory pattern for patients with posttraumatic headache could not be identified. Further research is needed to clarify the underlying mechanisms and biomarkers for prediction of development and persistence of posttraumatic headache.

Abstract: The pathophysiology of pain in neuropathy is complex and may be linked to sensory phenotypes. Quantitative sensory testing, a standardized method to evaluate sensory profiles in response to defined stimuli, assesses functional integrity of small and large nerve fiber afferents and central somatosensory pathways. It has revealed detailed insights into mechanisms of neuropathy, yet it remains unclear if pain directly affects sensory profiles. The main objective of this study was to investigate sensory profiles in patients with various neuropathic conditions, including polyneuropathy, mononeuropathy, and lesions to the central nervous system, in relation to self-reported presence or absence of pain and pain sensitivity using the Pain Sensitivity Questionnaire. A total of 443 patients (332 painful and 111 painless) and 112 healthy participants were investigated. Overall, loss of sensation was equally prevalent in patients with and without spontaneous pain. Pain thresholds were equally lowered in both patient groups, demonstrating that hyperalgesia and allodynia are just as present in patients not reporting any pain. Remarkably, this was similar for dynamic mechanical allodynia. Hypoalgesia was more pronounced in painful polyneuropathy, whereas hyperalgesia was more frequent in painful mononeuropathy (compared with painless conditions). Self-reported pain sensitivity was significantly higher in painful than in painless neuropathic conditions. Our results reveal the presence of hyperalgesia and allodynia in patients with central and peripheral lesions of the somatosensory system not reporting spontaneous pain. This shows that symptoms and signs of hypersensitivity may not necessarily coincide and that painful and painless neuropathic conditions may mechanistically blend into one another., (Copyright © 2020 International Association for the Study of Pain.)

Pain is a common symptom accompanying the coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Nonspecific discomfort such as sore throat and body ache are frequent. Parainfectious pain such as headache, myalgia, or neuropathic pain has also been reported. The latter seems to be associated with an autoimmune response or an affection of the peripheral neuromuscular system or the central nervous system because of the viral infection. Furthermore, chronic pain can be a complication of intensive care unit treatment due to COVID-19 itself (such as intensive care-acquired weakness) or of secondary diseases associated with the SARS-CoV-2 infection, including Guillain-Barré syndrome, polyneuritis, critical illness polyneuropathy, or central pain following cerebrovascular events. Data on long-lasting painful symptoms after clinically manifest COVID-19 and their consequences are lacking. In addition, preexisting chronic pain may be exacerbated by limited and disrupted health care and the psychological burden of the COVID-19 pandemic. Medical providers should be vigilant on pain during and after COVID-19., Competing Interests: The authors have no conflict of interest to declare., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Background: Conditioned pain modulation (CPM) evaluates the effect of a painful conditioning stimulus (CS) on a painful test stimulus (TS). Using painful cutaneous electrical stimulation (PCES) as TS and painful cold water as CS, the pain relief was paralleled by a decrease in evoked potentials (PCES-EPs). We now aimed to compare the effect of CPM with cognitive distraction on PCES-induced pain and PCES-EP amplitudes., Methods: PCES was performed using surface electrodes inducing a painful sensation of 60 (NRS 0-100) on one hand. In a crossover design healthy subjects (included: n = 38, analyzed: n = 23) immersed the contralateral hand into 10 °C cold water (CS) for CPM evaluation and performed the 1-back task for cognitive distraction. Before and during the CS and 1-back task, respectively, subjects rated the pain intensity of PCES and simultaneously cortical evoked potentials were recorded., Results: Both CPM and cognitive distraction significantly reduced PCES-EP amplitudes (CPM: 27.6 ± 12.0 μV to 20.2 ± 9.5 μV, cognitive distraction: 30.3 ± 14.2 µV to 13.6 ± 5.2 μV, p < 0.001) and PCES-induced pain (on a 0-100 numerical rating scale: CPM: 58 ± 4 to 41.1 ± 12.3, cognitive distraction: 58.3 ± 4.4 to 38.0 ± 13.0, p < 0.001), though the changes in pain intensity and PCES-amplitude did not correlate. The changes of the PCES-EP amplitudes during cognitive distraction were more pronounced than during CPM (p = 0.001)., Conclusions: CPM and cognitive distraction reduced the PCES-induced pain to a similar extent. The more pronounced decrease of PCES-EP amplitudes after distraction by a cognitive task implies that both conditions might not represent the general pain modulatory capacity of individuals, but may underlie different neuronal mechanisms with the final common pathway of perceived pain reduction.

Background: Nociplastic pain has been recently introduced as a third mechanistic descriptor of pain arising primarily from alterations of neural processing, in contrast to pain due to tissue damage leading to nociceptor activation (nociceptive) or due to lesion or disease of the somatosensory nervous system (neuropathic). It is characterized by hyperalgesia and allodynia, inconsistency and reversibility, as well as dynamic cross-system interactions with biological and psychobehavioral factors. Along with this renewed understanding, functional pain disorders, also classified as chronic primary pain, are being reframed as biopsychosocial conditions that benefit from multimodal treatment., Objective: To summarize the current understanding of nociplastic pain and functional pain disorders, with a focus on conditions that are common in neurology practice., Methods: This was a narrative literature review., Results: Chronic back pain, fibromyalgia syndrome and complex regional pain syndrome are best understood within a biopsychosocial framework of pain perception that considers structural factors (predispositions and sequelae) and psychobehavioral mechanisms. Although pain is often the primary complaint, it should not be the only focus of treatment, as accompanying symptoms such as sleep or mood problems can significantly impact quality of life and offer useful leverage points for multimodal treatment. Analgesic pharmacotherapy is rarely helpful on its own, and should always be imbedded in a multidisciplinary setting.

This study investigated the clinical characteristics and somatosensory profiles of patients suffering from leprosy in Mumbai, India. A cross-sectional deep profiling study was conducted in 86 patients with leprosy (with and without pain) using an extensive battery of phenotyping measures including structured clinical examination, psychological state (General Health Questionnaire [GHQ-12]), and a quality-of-life condition-specific instrument (Brief Pain Inventory-short form). Quantitative sensory testing was performed according to the protocol of the German Research Network on Neuropathic Pain (DFNS) to assess the somatosensory profiles in the ulnar nerve innervation territory of all participants (dorsum of the hand). Reference data from 50 healthy Indian subjects were within the range of published DFNS values. Somatosensory profiles in leprosy patients with clinically or electroneurographically diagnosed neuropathy (with and without pain) revealed a profile of sensory loss to thermal and tactile stimuli combined with preservation of vibration and deep pressure detection. Sensory gain phenomena were not generally observed in patients with leprosy. In the group of subclinical neuropathy, a high degree of impaired thermal sensation was found, which could be clinically deployed to enhance identification of leprosy neuropathy at an early stage. Quantitative sensory testing can effectively document leprosy-associated neuropathy but does not distinguish between patients with or without pain. Patients with leprosy and neuropathic pain reported a poor quality of life and less psychological well-being compared with the pain-free patients with leprosy neuropathy., Competing Interests: Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Hyperalgesia and allodynia are frequent in neuropathic pain. Some pain questionnaires such as the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) and the Neuropathic Pain Scale (NPS) include self-assessment or bedside testing of hyperalgesia/allodynia. The aim of this study was to determine to what extent LANSS and NPS data are congruent with findings on quantitative sensory testing (QST). Self-reported presence of dynamic mechanical allodynia (DMA) and descriptors of hot, cold, or deep ongoing pain (the NPS and LANSS) as well as bedside findings of mechanical allodynia (LANSS) were compared with signs of DMA and thermal hyperalgesia on QST in 617 patients with neuropathic pain. Self-reported abnormal skin sensitivity (LANSS) showed a moderate concordance with DMA during bedside test (67.9%, κ = 0.391) or QST (52.8%, κ = 0.165). Receiver operating curve analysis for self-reported DMA yielded similar area-under-the-curve values for the LANSS (0.65, confidence interval: 0.59%-0.97%) and NPS (0.71, confidence interval: 0.66%-0.75%) with high sensitivity but low specificity. Self-reported deep pain intensity was higher in patients with blunt pressure hyperalgesia, but not in patients with DMA or thermal hyperalgesia. No correlations were observed between self-reported hot or cold pain quality and thermal hyperalgesia on QST. Self-reported abnormal skin sensitivity has a high sensitivity to identify patients with DMA, but its low specificity indicates that many patients mean something other than DMA when reporting this symptom. Self-reported deep pain is related to deep-tissue hypersensitivity, but thermal qualities of ongoing pain are not related to thermal hyperalgesia. Questionnaires mostly evaluate the ongoing pain experience, whereas QST mirrors sensory functions. Therefore, both methods are complementary for pain assessment.

Background: One of the main goals of novel, noninvasive imaging techniques like high-resolution nerve ultrasound (HRUS) and corneal confocal microscopy (CCM) is the prediction of treatment response for patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)., Methods: A total of 17 patients with CIDP were examined prospectively at baseline and every 9 months over a period of 18 months using CCM to quantify corneal nerve degeneration markers and immune cell infiltration as well as HRUS to detect changes of the cross-sectional area (CSA) of the peripheral nerves. Additionally, skin biopsy of the distal and proximal leg as well as quantitative sensory testing were performed at the first follow-up visit., Results: A value of more than 30 total corneal cells/mm 2 in CCM at baseline identified patients with clinical progression with a sensitivity/specificity of 100% in our cohort. Corneal nerve fiber density and length remained low and stable over the study period and intra-epidermal fiber density was markedly reduced in the majority of the patients. Furthermore, an increase in Bochum ultrasound score (BUS), which summarizes the CSA of the ulnar nerve in Guyons' canal, the ulnar nerve in the upper arm, the radial nerve in the spiral groove and the sural nerve between the gastrocnemius muscle, and a maximum BUS of 4 at study initiation identified patients with disease progression (sensitivity 80%, specificity 88%)., Conclusions: BUS and corneal total cell infiltration seem to represent early markers for clinical progression in CIDP, thus having the potential to identify at-risk patients and impact treatment decisions., Competing Interests: Conflicts of interest: Nina Kumowski, Lynn Eitner, Tineke Greiner, Anna Lena Fisse and Adnan Labedi report no disclosures. Dietrich Sturm received funding from the Ruhr University, Bochum (FoRUM-Program). Kalliopi Pitarokoili received travel funding and speaker honoraria from Biogen Idec, Novartis and Bayer Schering Pharma and funding from the Ruhr University, Bochum (FoRUM-Program). R. Gold has received consultation fees and speaker honoraria from Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis and TEVA. He also acknowledges grant support from Bayer Schering, Biogen Idec, Merck Serono, Sanofi-Aventis and TEVA, none related to this manuscript. Elena K. Enax-Krumova is member of the German Research Network on Neuropathic pain e.V. (BMBF, grants 01EM0107 & 01EM0502), members of the European Collaboration, which has received support from the Innovative Medicines Initiative Joint Undertaking, under grant agreement no 11507, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies (AstraZeneca, Pfizer, Esteve, UCB-Pharma, Sanofi-Aventis, Grünenthal, Eli Lilly und Boehringer Ingelheim) inkind contribution, was supported by intramural funding of the Ruhr University Bochum (FoRUM: grant number K046-10, Heinemann Award 2013) and has received a travel grant from Mundipharma GmbH and Bayer Vital GmbH, speaker fees from Grünenthal GmbH and Pfizer GmbH. Christoph Maier has received honoraria for speaking and advisory board membership from Gruenenthal, MSD, Köhler Chemie, Mundipharma, Pfizer, and Wyeth. Martin Tegenthoff has received speaker honoraria from Pfizer, Novartis and Mundipharma. He also acknowledges a grant support from Genzyme, not related to this manuscript. Tobias Schmidt-Wilcke received consulting fees from Daiichi Sankyo. Min-Suk Yoon has received speaker honoraria from CSL Behring and Grifols, a scientific grant from CSL Behring, none related to this manuscript.

Objectives: Spinal cord and peripheral nerve stimulation (SCS/PNS) may alleviate chronic pain; however, the underlying mechanisms remain controversial. The aim of this observational study was to assess sensory changes in the ON-conditions and OFF-conditions to obtain insights into the mechanism of analgesic effects of SCS/PNS., Materials and Methods: We contacted 85 patients and selected 28 patients with sufficient pain relief by SCS (n=15) or PNS (n=13) to assess their ongoing pain intensity (Numerical Rating Scale, 0 to 10), pain thresholds using Quantitative Sensory Testing (DFNS-protocol), and conditioned pain modulation (CPM) in a nonrandomized manner 2 to 4 hours after SCS/PNS deactivation (OFF-condition) and during stimulation (ON-condition). For each patient, the number of abnormally decreased pain thresholds, the presence of dynamic mechanical allodynia, and/or increased pain sensitivity was additionally totaled OR summed., Results: In the ON-condition, pain intensity decreased (Numerical Rating Scale SCS: 6.5±2.1 vs. 3.7±2.3, P<0.01; PNS: 6.2±1.4 vs. 4±1.9, P<0.01), but this did not correlate with any single sensory parameter. However, for SCS, the total number of parameters indicating hyperalgesia was significantly reduced in the ON-condition (45 vs. 23, P=0.001). A smaller CPM effect in the OFF-condition correlated with a greater CPM improvement during stimulation (SCS: r=-0.741, P=0.002; PNS: r=-0.773, P=0.003), independently from the spontaneous pain intensity., Discussion: The analgesic effect of SCS/PNS did not correlate with changes of single sensory parameters, but SCS/PNS reduced the number of abnormal hyperalgesic findings disregarding the kind of applied stimuli, suggesting a general antihyperalgesic effect. In addition, stimulation improved the endogenous pain inhibition. Both findings indicate that SCS/PNS may modulate central circuits.

Background and Aims: Cold pressor test was recently reported to significantly reduce painful cutaneous electrical stimulation (PCES)-induced pain and corresponding evoked potentials (PCES-EPs), but whether this reduction is an effect of conditioned pain modulation (CPM) remains unknown. To what extent these findings are confounded by habituation is also unknown. We thus compared the effect of CPM and habituation on PCES-induced pain and PCES-EPs and analysed whether increased attention by a random change of electric stimulation would intensify this possible habituation effect., Methods: Three custom-built concentric surface electrodes were used to induce a pain intensity of 60 on a 0-100 numerical rating scale (NRS) among 29 healthy subjects (age 20-35y, 16 females). PCES-EPs (including P0N1 and N1P1 amplitudes, N1 latencies) were assessed over Cz. Group A received 14 min of electrical stimulation with constant intensity followed by 14 min of electrical stimulation with variable intensities, group B vice versa. Afterwards, subjects perceived cold-water pain (10 °C) contralaterally as conditioning stimulus to assess CPM. Statistical analysis was conducted with ANOVA and t-test., Results: In both groups, N1 latencies remain unchanged, but the intensity of PCES-induced pain (12 ± 17%; p < 0.01) and N1P1 amplitudes of PCES-EPs (10 ± 16%; p < 0.05) decreased significantly during the 14-min PCES with constant current intensity. CPM also significantly reduced pain ratings (36 ± 19%; p < 0.001) and amplitudes (37.2 ± 15.8%), p < 0.001). A significant decline of P0N1 amplitudes occurred only during CPM (18 ± 61%; p < 0.001)., Conclusion: We found a significant effect of habituation on PCES-induced pain and PCES-EPs, although the effect of CPM was significantly larger and could not be explained by habituation alone., Significance: Painful cutaneous electrical stimulation leads to moderate habituation of pain and evoked potential amplitudes, but the conditioned pain modulation effect using this method is significantly larger, which might indicate a different mechanism in central processing., (© 2018 European Pain Federation - EFIC®.)

As an indirect approach to relate previously identified sensory phenotypes of patients suffering from peripheral neuropathic pain to underlying mechanisms, we used a published sorting algorithm to estimate the prevalence of denervation, peripheral and central sensitization in 657 healthy subjects undergoing experimental models of nerve block (NB) (compression block and topical lidocaine), primary hyperalgesia (PH) (sunburn and topical capsaicin), or secondary hyperalgesia (intradermal capsaicin and electrical high-frequency stimulation), and in 902 patients suffering from neuropathic pain. Some of the data have been previously published. Randomized split-half analysis verified a good concordance with a priori mechanistic sensory profile assignment in the training (79%, Cohen κ = 0.54, n = 265) and the test set (81%, Cohen κ = 0.56, n = 279). Nerve blocks were characterized by pronounced thermal and mechanical sensory loss, but also mild pinprick hyperalgesia and paradoxical heat sensations. Primary hyperalgesia was characterized by pronounced gain for heat, pressure and pinprick pain, and mild thermal sensory loss. Secondary hyperalgesia was characterized by pronounced pinprick hyperalgesia and mild thermal sensory loss. Topical lidocaine plus topical capsaicin induced a combined phenotype of NB plus PH. Topical menthol was the only model with significant cold hyperalgesia. Sorting of the 902 patients into these mechanistic phenotypes led to a similar distribution as the original heuristic clustering (65% identity, Cohen κ = 0.44), but the denervation phenotype was more frequent than in heuristic clustering. These data suggest that sorting according to human surrogate models may be useful for mechanism-based stratification of neuropathic pain patients for future clinical trials, as encouraged by the European Medicines Agency.

Background: Conditioned pain modulation (CPM) evaluates the pain modulating effect of a noxious conditioning stimulus (CS) on another noxious test stimulus (TS), mostly based solely on subjective pain ratings. We used painful cutaneous electrical stimulation (PCES) to induce TS in a novel CPM-model. Additionally, to evaluate a more objective parameter, we recorded the corresponding changes of cortical evoked potentials (PCES-EP)., Methods: We examined the CPM-effect in 17 healthy subjects in a randomized controlled cross-over design during immersion of the non-dominant hand into 10 °C or 24 °C cold water (CS). Using three custom-built concentric surface electrodes, electrical stimuli were applied on the dominant hand, inducing pain of 40-60 on NRS 0-100 (TS). At baseline, during and after CS we assessed the electrically induced pain intensity and electrically evoked potentials recorded over the central electrode (Cz)., Results: Only in the 10 °C-condition, both pain (52.6 ± 4.4 (baseline) vs. 30.3 ± 12.5 (during CS)) and amplitudes of PCES-EP (42.1 ± 13.4 μV (baseline) vs. 28.7 ± 10.5 μV (during CS)) attenuated during CS and recovered there after (all p < 0.001). In the 10 °C-condition changes of subjective pain ratings during electrical stimulation and amplitudes of PCES-EP correlated significantly with each other (r = 0.5) and with CS pain intensity (r = 0.5)., Conclusions: PCES-EPs are a quantitative measure of pain relief, as changes in the electrophysiological response are paralleled by a consistent decrease in subjective pain ratings. This novel CPM paradigm is a feasible method, which could help to evaluate the function of the endogenous pain modulation processes., Trial Registration: German Clinical Trials Register DRKS-ID: DRKS00012779 , retrospectively registered on 24 July 2017.

In a recent cluster analysis, it has been shown that patients with peripheral neuropathic pain can be grouped into 3 sensory phenotypes based on quantitative sensory testing profiles, which are mainly characterized by either sensory loss, intact sensory function and mild thermal hyperalgesia and/or allodynia, or loss of thermal detection and mild mechanical hyperalgesia and/or allodynia. Here, we present an algorithm for allocation of individual patients to these subgroups. The algorithm is nondeterministic-ie, a patient can be sorted to more than one phenotype-and can separate patients with neuropathic pain from healthy subjects (sensitivity: 78%, specificity: 94%). We evaluated the frequency of each phenotype in a population of patients with painful diabetic polyneuropathy (n = 151), painful peripheral nerve injury (n = 335), and postherpetic neuralgia (n = 97) and propose sample sizes of study populations that need to be screened to reach a subpopulation large enough to conduct a phenotype-stratified study. The most common phenotype in diabetic polyneuropathy was sensory loss (83%), followed by mechanical hyperalgesia (75%) and thermal hyperalgesia (34%, note that percentages are overlapping and not additive). In peripheral nerve injury, frequencies were 37%, 59%, and 50%, and in postherpetic neuralgia, frequencies were 31%, 63%, and 46%. For parallel study design, either the estimated effect size of the treatment needs to be high (>0.7) or only phenotypes that are frequent in the clinical entity under study can realistically be performed. For crossover design, populations under 200 patients screened are sufficient for all phenotypes and clinical entities with a minimum estimated treatment effect size of 0.5.

Pain-related evoked potentials (PREP) is an established electrophysiological method to evaluate the signal transmission of electrically stimulated A-delta fibres. Although prerequisite for its clinical use, test-retest-reliability and side-to-side differences of bilateral stimulation in healthy subjects have not been examined yet. We performed PREP twice within 3-14days in 33 healthy subjects bilaterally by stimulating the dorsal hand. Detection (DT) and pain thresholds (PT) after electrical stimulation, the corresponding pain ratings, latencies of P0, N1, P1 and N2 components and the corresponding amplitudes were assessed. Impact of electrically induced pain intensity, age, sex, and arm length on PREP was analysed. MANOVA, t-Test, interclass correlation coefficient (ICC), standard error of measurement (SEM), smallest real difference (SRD), Bland-Altmann-Analysis as well as ANCOVA were used for statistical analysis. Measurement from both sides on both days resulted in mean N1-latencies from 142.39±18.12ms to 144.03±16.62ms and in mean N1P1-amplitudes from 39.04±12.26μV to 40.53±12.9μV. Analysis of a side-to-side effect showed for the N1-latency a F-value of 0.038 and for the N1P1-amplitude of 0.004 (p>0.8). We found intraclass correlation coefficients (ICC) from 0.88 to 0.93 and a standard error of measurement (SEM)<10% of mean values for all measurements concerning the N1-Latency and N1P1-amplitude. Intraclass correlation coefficients, standard error of measurement and Bland-Altman-Analyses revealed excellent test-retest-reliability for N1-latency and N1P1-amplitude without systematic error and there was no side-to-side effect on PREP. N1-latency (r=0.35, p<0.05) and N1P1-amplitude (r=-0.45, p<0.05) correlated with age and additionally N1-latency correlated with arm length (r=0.45, p<0.001). In contrast, pain intensity during the stimulation had no effect on both N1-latency and N1P1-amplitude. In summary, PREP showed high test-retest-reliability and negligible side-to-side differences concerning the commonly used parameters N1-latency and N1P1-amplitude., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: In unilateral neuropathic pain. e.g. after peripheral nerve injury, both positive and negative sensory signs occur often, accompanied by minor but equally directed contralateral sensory changes. To mimic this feature, we experimentally aimed to induce concomitant c-fibre sensitization and block in healthy subjects and analyzed the bilateral sensory changes by quantitative sensory testing (QST) using the protocol of the German Research Network on Neuropathic Pain., Methods: Twenty eight healthy subjects were firstly randomized in 2 groups to receive either topical capsaicin (0.6%, 12 cm 2 , application duration: 15 min.) or a lidocaine/prilocaine patch (25/25 mg, 10 cm 2 , application duration: 60 min.) on the right volar forearm. Secondly, 7-14 days later in the same area either at first capsaicin (for 15 min.) and immediately afterwards local anesthetics (for 60 min.) was applied (Cap/LA), or in inversed order with the same application duration (LA/Cap). Before, after each application and 7-14 days later a QST was performed bilaterally., Statistics: Wilcoxon-test, ANOVA, p < 0.05., Results: Single application of 0,6% capsaicin induced thermal hypoesthesia, cold hypoalgesia, heat hyperalgesia and tactile allodynia. Lidocaine/prilocaine alone induced thermal and tactile hypoesthesia as well as mechanical and cold hypoalgesia, and a heat hyperalgesia (to a smaller extent). Ipsilaterally both co-applications induced a combination of the above mentioned changes. Significant contralateral sensory changes occurred only after the co-application with concomitant sensitization and hypoesthesia and comprised increased cold (Cap/LA, LA/Cap) and mechanical detection as well as cold pain threshold (LA/Cap)., Conclusion: The present experimental model using combined application of capsaicin and LA imitates partly the complex sensory changes observed in patients with unilateral neuropathic pain and might be used as an additional surrogate model. Only the concomitant use both agents in the same area induces both positive and negative sensory signs ipsilaterally as well as parallel contralateral sensory changes (to a lesser extent)., Trial Registration: ClinicalTrials.gov Identifier NCT01540877 , registered on 23 February 2012.

Objective: The most prominent sensory sign of the complex regional pain syndrome (CRPS) is blunt hyperalgesia, but longitudinal studies on its relation to the outcome of long-term multimodal treatment are lacking., Methods: We examined 24 patients with CRPS type I using standardized Quantitative Sensory Testing on the affected hand and the contralateral hand at baseline and 6 months following treatment. Somatosensory evoked potentials after single and paired-pulse stimulation of the median nerve were performed to assess the paired-pulse suppression (n = 19). Treatment response at follow-up was defined as pain relief > 30% and improved hand function. Statistics: Wilcoxon test, Pearson correlation., Results: At baseline, similar to previous studies, the pressure pain threshold (PPT) was significantly decreased and the pain response to repeated pinprick stimuli was significantly increased, while all detection thresholds were within the normal range without any difference between the later treatment responders and non-responders. After 6 months of treatment, the PPT increased significantly in the whole study group. However, the pressure hyperalgesia improved only in treatment responders (n = 17, P  < 0.05), whereas there was no improvement in non-responders (n = 7). The rest of the sensory profile remained nearly unchanged. There was a correlation between the paired-pulse suppression and the PPT only at follow-up (r = 0.49, P  < 0.05), but not at baseline, where low pressure pain threshold was associated with impaired paired-pulse suppression., Conclusion: Thus, the persistence of blunt hyperalgesia seems to be associated with impaired paired-pulse suppression, both representing maladaptive central nervous changes in CRPS, which may account for the treatment non-response in this subgroup., (© 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: Conditioned Pain Modulation (CPM) is often used to assess human descending pain inhibition. Nine different studies on the test-retest-reliability of different CPM paradigms have been published, but none of them has investigated the commonly used heat-cold-pain method. The results vary widely and therefore, reliability measures cannot be extrapolated from one CPM paradigm to another. Aim of the present study was to analyse the test-retest-reliability of the common heat-cold-pain method and its correlation to pain thresholds., Methods: We tested the short-term test-retest-reliability within 40 ± 19.9 h using a cold-water immersion (10 °C, left hand) as conditioning stimulus (CS) and heat pain (43-49 °C, pain intensity 60 ± 5 on the 101-point numeric rating scale, right forearm) as test stimulus (TS) in 25 healthy right-handed subjects (12females, 31.6 ± 14.1 years). The TS was applied 30s before (TSbefore), during (TSduring) and after (TSafter) the 60s CS. The difference between the pain ratings for TSbefore and TSduring represents the early CPM-effect, between TSbefore and TSafter the late CPM-effect. Quantitative sensory testing (QST, DFNS protocol) was performed on both sessions before the CPM assessment., Statistics: paired t-tests, Intraclass correlation coefficient (ICC), standard error of measurement (SEM), smallest real difference (SRD), Pearson's correlation, Bland-Altman analysis, significance level p < 0.05 with Bonferroni correction for multiple comparisons, when necessary., Results: Pain ratings during CPM correlated significantly (ICC: 0.411…0.962) between both days, though ratings for TSafter were lower on day 2 (p < 0.005). The early (day 1: 16.7 ± 11.7; day 2: 19.5 ± 11.9; ICC: 0.618, SRD: 20.2) and late (day 1: 1.7 ± 9.2; day 2: 7.6 ± 11.5; ICC: 0.178, SRD: 27.0) CPM effect did not differ significantly between both days. Both early and late CPM-effects did not correlate with the pain thresholds., Conclusions: The short-term test-retest-reliability of the early CPM-effect using the heat-cold-pain method in healthy subjects achieved satisfying results in terms of the ICC. The SRD of the early CPM effect showed that an individual change of > 20 NRS can be attributed to a real change rather than chance. The late CPM-effect was weaker and not reliable.

Background: Recently published systematic reviews came to different conclusions with respect to the efficacy, tolerability and safety of cannabinoids for treatment of chronic neuropathic pain., Material and Methods: A systematic search of the literature was carried out in MEDLINE, the Cochrane central register of controlled trials (CENTRAL) and clinicaltrials.gov up until November 2015. We included double-blind randomized placebo-controlled studies (RCT) of at least 2 weeks duration and with at least 9 patients per treatment arm comparing medicinal cannabis, plant-based or synthetic cannabinoids with placebo or any other active drug treatment in patients with chronic neuropathic pain. Clinical endpoints of the analyses were efficacy (more than 30 % or 50 % reduction of pain, average pain intensity, global improvement and health-related quality of life), tolerability (drop-out rate due to side effects, central nervous system and psychiatric side effects) and safety (severe side effects). Using a random effects model absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables. The methodological quality of RCTs was rated by the Cochrane risk of bias tool., Results: We included 15 RCTs with 1619 participants. Study duration ranged between 2 and 15 weeks. Of the studies 10 used a plant-derived oromucosal spray with tetrahydrocannabinol/cannabidiol, 3 studies used a synthetic cannabinoid (2  with nabilone and 1  with dronabinol) and 2 studies used medicinal cannabis. The 13 studies with parallel or cross-over design yielded the following results with 95 % confidence intervals (CI): cannabinoids were superior to placebo in the reduction of mean pain intensity with SMD - 0.10 (95 % CI - 0.20- - 0.00, p = 0.05, 13 studies with 1565 participants), in the frequency of at least a 30 % reduction in pain with an RD of 0.10 [95 % CI 0.03-0.16, p = 0.004, 9 studies with 1346 participants, number needed to treat for additional benefit (NNTB) 14, 95 % CI 8-45] and in the frequency of a large or very large global improvement with an RD of 0.09 (95 % CI 0.01-0.17, p = 0.009, 7 studies with 1092 participants). There were no statistically significant differences between cannabinoids and placebo in the frequency of at least a 50 % reduction in pain, in improvement of health-related quality of life and in the frequency of serious adverse events. Patients treated with cannabinoids dropped out more frequently due to adverse events with an RD of 0.04 [95 % CI 0.01-0.07, p = 0.009, 11 studies with 1572 participants, number needed to treat for additional harm (NNTH) 19, 95 % CI 13-37], reported central nervous system side effects more frequently with an RD of 0.38 (95 % CI 0.18-0.58, p = 0.0003, 9 studies with 1304 participants, NNTH 3, 95 % CI 2-4) and psychiatric side effects with an RD of 0.11 (95 % CI 0.06-0.16, p < 0.0001, 9 studies with 1304 participants, NNTH 8, 95 % CI 7-12)., Conclusion: Cannabinoids were marginally superior to placebo in terms of efficacy and inferior in terms of tolerability. Cannabinoids and placebo did not differ in terms of safety during the study period. Short-term and intermediate-term therapy with cannabinoids can be considered in selected patients with chronic neuropathic pain after failure of first-line and second-line therapies.

Background: Topical high-dose capsaicin acting on TRPV1 receptors and inducing an intraepidermal decrease in the small nerve fibre count is effective in treating neuropathic pain (NP). Sensory changes after capsaicin application, their correlation with pain relief and their role as possible predictors of response have been insufficiently analysed. We hypothesized a positive correlation between pain relief and increase in the warmth detection threshold (WDT), indicating loss of C-fibre function, and higher response rates in patients with preserved C-fibre function or heat hyperalgesia before application., Methods: Quantitative Sensory Testing (DFNS protocol) was conducted in 20 unilaterally treated patients with peripheral NP (peripheral nerve injury: n = 14, polyneuropathy: n = 4, postherpetic neuralgia: n = 2) before and 2, 4, 6 and 8 weeks after application of capsaicin (8%) in this open-label study. Response was defined as ≥30% or ≥2 (Numeric Rating Scale: 0-10) decrease of current pain at any follow-up compared to baseline., Results: In all patients, WDT significantly increased 8 weeks after capsaicin application, but did not correlate with pain relief in responders (n = 10, r = 0.179, p = 0.141). Before treatment, responders showed significantly higher z-values for the cold (CPT, +0.7 ± 1.1 vs. -0.4 ± 0.9) and mechanical pain threshold (MPT; 0.7 ± 2.5 vs. -1.2 ± 1.3), but did not differ from non-responders regarding WDT or heat pain threshold. A sum of the z-values for CPT and MPT >0.8 before treatment identified responders with 100% specificity and 70% sensitivity., Conclusions: Efficacy of capsaicin does not correlate with the induced loss of function of small fibres, measured by QST. Presence of cold and pinprick hyperalgesia seems to be predictive of response to capsaicin (8%)., (© 2015 European Pain Federation - EFIC®)

Quantitative Sensory Testing (QST) is a psychophysical method assessing the somatosensory nervous system. A premise for comparable results between laboratories is standardized testing. Its quality can be proven by analyzing healthy subjects, because their results should lie within confidence intervals estimated from large database samples. However, it is unclear how many abnormal values can be tolerated. Based on a binomial distribution, a tool for assessing samples of healthy subjects was developed to detect inclusion errors (inclusion of nonhealthy subjects) or measuring errors (inaccuracies in single QST parameters). Sensitivity and specificity of detecting inclusion errors were assessed in 431 healthy subjects and 833 patients with neuropathic pain syndromes from the German Research Network on Neuropathic Pain (DFNS) database. Measuring errors were simulated by raising all absolute values in a single parameter by 0.5 SD. We calculated optimal cutoff values for group sizes of 16 healthy subjects, as implemented in the DFNS certification procedures. The algorithm was applied in the certification process of 18 European QST laboratories. With a specificity of 95% and a sensitivity of 60%, inclusion errors can be assumed for ≥4 abnormal values per subject, whereas ≥6 abnormal values per QST parameter and laboratory indicate measuring errors. Subsequently, in the certification process of 5 of 18 centers, inclusion or measuring errors were detected. In most cases, inclusion errors were verified and reasons for measuring errors were illuminated by the centers. This underlines the usefulness and validity of our tool in quality assurance of QST laboratories using the DFNS protocol.

Clinical and human experimental pain studies often include so-called "healthy" controls in investigations of sensory abnormalities, using quantitative sensory testing (QST) as an outcome measure. However, the criteria for what is considered "healthy" vary among the different studies and between study centers and investigators, partly explaining the high variability of the results. Therefore, several aspects should be considered during inclusion of healthy volunteers in QST-based trials to have homogenous groups of healthy controls with less variability between human experimental studies, so that results are less likely to be false negative or false positive because of subject-related factors. The EUROPAIN and NEUROPAIN consortia aimed to define factors influencing the variability in selection of healthy subjects in QST-based studies before the start of both projects and to give recommendations how to minimize it based on the current literature and expertise of the participants. The present suggestions for inclusion criteria of healthy volunteers into QST-based trials describe a 2-level approach including standardized questionnaires enabling the collection of relevant information on sociodemographic data, medical history, current health status, coping strategies in dealing with pain, and the motivation of the volunteer to participate in the study. These suggestions are believed to help researchers interpret their results in comparison with others and improve the quality of clinical studies including healthy volunteers as controls or in human experimental pain studies. They aim to reduce any confounding factors. Furthermore, the acquired information will allow post hoc analyses of variance for different potential influencing factors.

Purpose of Review: The purpose of this review was to provide an update on the diagnostic tools for neuropathic pain for clinical practice., Recent Findings: The new definition of neuropathic pain by the International Association for the Study of Pain requires confirmation of a lesion or disease affecting the somatosensory system. In addition to traditional diagnostic procedures, for example, nerve conduction studies, skin biopsies depict morphological alteration and/or rarefication of the small intraepidermal nerve fibers and were recently used to identify small fiber abnormalities, for example, in patients with fibromyalgia or sarcoidosis. Quantitative sensory testing assesses the somatosensory function including both peripheral and central pathways. A recent consensus statement discussed its diagnostic value. Corneal confocal microscopy is a noninvasive method enabling in-vivo assessment of the small nerve fibers in the cornea and also seems to identify patients at risk for developing diabetic neuropathy at an early stage and to reflect the improvement of neuropathy after treatment. Further promising methods are the microneurography and nociceptive evoked potentials; however, they are technically challenging and their diagnostic value for clinical practice has yet to be confirmed., Summary: For diagnosing neuropathic pain, confirmation of a lesion or disease affecting the somatosensory system is needed. Better clinical phenotyping will hopefully enable individualized mechanism-based treatment of neuropathic pain.

Background: Patients with complex regional pain syndrome type I (CRPS I) show a cortical reorganization with contralateral shrinkage of cortical maps in S1. The relevance of pain and disuse for the development and the maintenance of this shrinkage is unclear., Objective: Aim of the study was to assess whether short-term pain relief induces changes in the cortical representation of the affected hand in patients with CRPS type I., Study Design: Case series analysis of prospectively collected data., Methods: We enrolled a case series of 5 consecutive patients with CRPS type I (disease duration 3 - 36 months) of the non-dominant upper-limb and previously diagnosed sympathetically maintained pain (SMP) by reduction of the pain intensity of more than > 30% after prior diagnostic sympathetic block. We performed fMRI for analysis of the cortical representation of the affected hand immediately before as well as one hour after isolated sympathetic block of the stellate ganglion on the affected side., Statistics: Wilcoxon-Test, paired t-test, P < 0.05., Results: Pain decrease after isolated sympathetic block (pain intensity on the numerical rating scale (0 - 10) before block: 6.8 ± 1.9, afterwards: 3.8 ± 1.3) was accompanied by an increase in the blood oxygenation level dependent (BOLD) response of cortical representational maps only of the affected hand which had been reduced before the block, despite the fact that clinical and neurophysiological assessment revealed no changes in the sensorimotor function., Limitations: The interpretation of the present results is partly limited due to the small number of included patients and the missing control group with placebo injection., Conclusions: The association between recovery of the cortical representation and pain relief supports the hypothesis that pain could be a relevant factor for changes of somatosensory cortical maps in CRPS, and that these are rapidly reversible.