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Janika Krafthöfer,1 Sophie-Charlotte Fabig,1 Ralf Baron,1 Janne Gierthmühlen1,2 1Division of Neurological Pain Research and Therapy, Department of Neurology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Schleswig-Holstein, Germany; 2Department for Anesthesiology and Surgical Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Schleswig-Holstein, GermanyCorrespondence: Janika Krafthöfer, Division of Neurological Pain Research and Therapy, Department of Neurology, University Hospital Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, Haus D, Kiel, 24105, Germany, Tel +49 431 500 23911, Fax +49 431 500 20914, Email janika.krafthoefer@web.deBackground: Pain leads to activation of the autonomic nervous system and thus, among other things, to pupillary reflex dilation (PRD). Previous studies have already confirmed a correlation between the perception of pain and the pupillary reaction, measured using pupillometry. However, the previous study populations were under the influence of medication for analgesia in perioperative setting or suffered from pain. This study examines the relationship between pupillary reaction and pain perception in healthy controls and addresses the question of whether endogenous pain inhibition, clinically tested by conditioned pain modulation (CPM), can be quantified using pupillometry.Methods: Forty-two healthy volunteers (21 females, 21 males, mean age 27.9 ± 5.8 years, range 20– 39 years) were included in this study. The PRD, as a measure of the pupillary reaction (variance from the base diameter in percent), was investigated during baseline, heat application and during CPM testing and results compared to the reported pain intensity on the numerical rating scale (NRS).Results: The volunteers showed higher variances under painful conditions compared to the measurement at rest corresponding to higher sympathetic activity during pain. Volunteers with a higher variance, ie a stronger pupillary reaction, gave higher pain ratings than subjects with a lower pupil variance. However, there was no correlation between the NRS and PRD. PRD and pain ratings during CPM were significantly lower compared to heat pain application alone. However, there was no correlation between the calculated CPM effect and the PRD.Conclusion: Pupillometry is capable of objectively reflecting the pain response, eg pain relief through CPM testing. However, the CPM effect calculated from the subjective pain ratings and the objective PRD measurements is not associated suggesting that both measure different aspects of pain perception. It must be discussed whether the CPM effect can be the correct measure for the functionality of the pain system.Keywords: conditioned pain modulation, descending control, pupillary reaction, pain, sympathetic nervous system

KD Bharwani,1,* AB Kersten,1,* AL Stone,2 F Birklein,3 S Bruehl,2 M Dirckx,1 PD Drummond,4 J Gierthmühlen,5 A Goebel,6 L Knudsen,7 FJPM Huygen1 1Center for Pain Medicine, Department of Anesthesiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands; 2Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN, USA; 3Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany; 4Discipline of Psychology, College of Science, Health, Engineering and Education, Murdoch University, Perth, WA, Australia; 5Division of Neurological Pain Research and Therapy, Department Neurology, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany; 6Director of the Pain Research Institute Reader in Pain Medicine, University of Liverpool Honorary Consultant in Pain Medicine, Walton Centre NHS Foundation Trust, Liverpool, UK; 7The National Rehabilitation Centre for Neuromuscular Diseases, Aarhus, Denmark*These authors contributed equally to this workCorrespondence: KD Bharwani Tel +31107040704Email bharwani.kd@gmail.comPurpose: Several articles have claimed that complex regional pain syndrome (CRPS) does not exist. Although a minority view, it is important to understand the arguments presented in these articles. We conducted a systematic literature search to evaluate the methodological quality of articles that claim CRPS does not exist. We then examined and refuted the arguments supporting this claim using up-to-date scientific literature on CRPS.Methods: A systematic search was conducted in MEDLINE, EMBASE and Cochrane CENTRAL databases. Inclusion criteria for articles were (a) a claim made that CRPS does not exist or that CRPS is not a distinct diagnostic entity and (b) support of these claims with subsequent argument(s). The methodological quality of articles was assessed if possible.Results: Nine articles were included for analysis: 4 narrative reviews, 2 personal views, 1 letter, 1 editorial and 1 case report. Seven points of controversy were used in these articles to argue that CRPS does not exist: 1) disagreement with the label “CRPS”; 2) the “unclear” pathophysiology; 3) the validity of the diagnostic criteria; 4) CRPS as a normal consequence of immobilization; 5) the role of psychological factors; 6) other identifiable causes for CRPS symptoms; and 7) the methodological quality of CRPS research.Conclusion: The level of evidence for the claim that CRPS does not exist is very weak. Published accounts concluding that CRPS does not exist, in the absence of primary evidence to underpin them, can harm patients by encouraging dismissal of patients’ signs and symptoms.Keywords: complex regional pain syndrome, pathophysiology, treatment, chronic pain

Objective: The clinical relevance of pro- and hyperalgesic effects of opioids is still a matter of debate. Particularly for remifentanil, an increased postoperative need for analgesics has been demonstrated suggesting opioid-induced hyperalgesia as a possible cause. The aim of the study was therefore to investigate the effect of intraoperatively applied remifentanil compared to sufentanil on somatosensory thresholds investigated with the quantitative sensory testing (QST) battery of the German Research Network on Neuropathic Pain (DFNS).Research Design and Methods: Twenty-three patients undergoing surgery of the female breast were randomly assigned to intraoperative remifentanil (0.4 μg × kg-1 × min-1) or sufentanil (0.25 μg × kg-1 bolus, 0.15 μg × kg-1, repetition after 60 min) application. Anesthesia was maintained BIS-guided (Bispectral indexTM) with propofol and postoperative analgesia was ensured with paracetamol (max. 3 g/24 h). Quantitative sensory testing was performed in the region of dermatome Th 5 in the mid-axillary line preoperatively and 20 h postoperatively.Clinical Trial Registration: The study was registered at the German registry for clinical studies (DRKS00009002).Main Outcome Measures: Comparison of somatosensory thresholds before versus after surgery and application of intraoperative remifentanil or sufentanil.Results: Sixteen patients could be finally included in the analysis. No differences of mechanical or thermal detection or pain thresholds were observed between pre- and postoperative testing or between remifentanil and sufentanil.Conclusion: A change of somatosensory thresholds or a clinically relevant opioid-induced hyperalgesia in the selected small patient sample (segmental resections or mastectomy with or without sentinel lymph node biopsy, surgery length <90 minutes, sufficient postoperative pain medication with paracetamol due to rather low postoperative pain intensities) with remifentanil or sufentanil was not detected 20 h after surgery. [ABSTRACT FROM AUTHOR]

This study determined patterns of sensory signs in complex regional pain syndrome (CRPS) type I and II and peripheral nerve injury (PNI). Patients with upper-limb CRPS-I (n=298), CRPS-II (n=46), and PNI (n=72) were examined with quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain. The majority of patients (66%-69%) exhibited a combination of sensory loss and gain. Patients with CRPS-I had more sensory gain (heat and pressure pain) and less sensory loss than patients with PNI (thermal and mechanical detection, hypoalgesia to heat or pinprick). CRPS-II patients shared features of CRPS-I and PNI. CRPS-I and CRPS-II had almost identical somatosensory profiles, with the exception of a stronger loss of mechanical detection in CRPS-II. In CRPS-I and -II, cold hyperalgesia/allodynia (28%-31%) and dynamic mechanical allodynia (24%-28%) were less frequent than heat or pressure hyperalgesia (36%-44%, 67%-73%), and mechanical hypoesthesia (31%-55%) was more frequent than thermal hypoesthesia (30%-44%). About 82% of PNI patients had at least one type of sensory gain. QST demonstrates more sensory loss in CRPS-I than hitherto considered, suggesting either minimal nerve injury or central inhibition. Sensory profiles suggest that CRPS-I and CRPS-II may represent one disease continuum. However, in contrast to recent suggestions, small fiber deficits were less frequent than large fiber deficits. Sensory gain is highly prevalent in PNI, indicating a better similarity of animal models to human patients than previously thought. These sensory profiles should help prioritize approaches for translation between animal and human research. [ABSTRACT FROM AUTHOR]

Abstract: We aimed to investigate the genetic associations of neuropathic pain in a deeply phenotyped cohort. Participants with neuropathic pain were cases and compared with those exposed to injury or disease but without neuropathic pain as control subjects. Diabetic polyneuropathy was the most common aetiology of neuropathic pain. A standardised quantitative sensory testing protocol was used to categorize participants based on sensory profile. We performed genome-wide association study, and in a subset of participants, we undertook whole-exome sequencing targeting analyses of 45 known pain-related genes. In the genome-wide association study of diabetic neuropathy (N = 1541), a top significant association was found at the KCNT2 locus linked with pain intensity (rs114159097, P = 3.55 × 10-8). Gene-based analysis revealed significant associations between LHX8 and TCF7L2 and neuropathic pain. Polygenic risk score for depression was associated with neuropathic pain in all participants. Polygenic risk score for C-reactive protein showed a positive association, while that for fasting insulin showed a negative association with neuropathic pain, in individuals with diabetic polyneuropathy. Gene burden analysis of candidate pain genes supported significant associations between rare variants in SCN9A and OPRM1 and neuropathic pain. Comparison of individuals with the "irritable" nociceptor profile to those with a "nonirritable" nociceptor profile identified a significantly associated variant (rs72669682, P = 4.39 × 10-8) within the ANK2 gene. Our study on a deeply phenotyped cohort with neuropathic pain has confirmed genetic associations with the known pain-related genes KCNT2, OPRM1, and SCN9A and identified novel associations with LHX8 and ANK2, genes not previously linked to pain and sensory profiles, respectively., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Trigeminal neuralgia is characterized by severe, lightning-like attacks of pain, which are mandatory for the diagnosis. The pain typically occurs on one side and is often triggered by simply touching the face, chewing or talking. In acute exacerbations, this can also hinder food and fluid intake, resulting in a life-threatening clinical picture. A distinction is made between classical, secondary and idiopathic trigeminal neuralgia. For the diagnosis of trigeminal neuralgia, the medical history and imaging procedures are key for classification. The only active substances approved for the treatment of trigeminal neuralgia in Germany are carbamazepine and phenytoin, which is why off-label drugs often need to be used if there is no or insufficient effect or inacceptable side effects. Cooperation between research and clinical practice to improve the care of affected patients is therefore essential., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Abstract: It is still unclear how and why some patients develop painful and others painless polyneuropathy. The aim of this study was to identify multiple factors associated with painful polyneuropathies (NeuP). A total of 1181 patients of the multicenter DOLORISK database with painful (probable or definite NeuP) or painless (unlikely NeuP) probable or confirmed neuropathy were investigated clinically, with questionnaires and quantitative sensory testing. Multivariate logistic regression including all variables (demographics, medical history, psychological symptoms, personality items, pain-related worrying, life-style factors, as well as results from clinical examination and quantitative sensory testing) and machine learning was used for the identification of predictors and final risk prediction of painful neuropathy. Multivariate logistic regression demonstrated that severity and idiopathic etiology of neuropathy, presence of chronic pain in family, Patient-Reported Outcomes Measurement Information System Fatigue and Depression T-Score, as well as Pain Catastrophizing Scale total score are the most important features associated with the presence of pain in neuropathy. Machine learning (random forest) identified the same variables. Multivariate logistic regression archived an accuracy above 78%, random forest of 76%; thus, almost 4 out of 5 subjects can be classified correctly. This multicenter analysis shows that pain-related worrying, emotional well-being, and clinical phenotype are factors associated with painful (vs painless) neuropathy. Results may help in the future to identify patients at risk of developing painful neuropathy and identify consequences of pain in longitudinal studies., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Background: Fabry disease (FD) causes cold-evoked pain and impaired cold perception through small fiber damage, which also occurs in polyneuropathies (PNP) of other origins. The integrity of thinly myelinated fibers and the spinothalamic tract is assessable by cold-evoked potentials (CEPs). In this study, we aimed to assess the clinical value of CEP by investigating its associations with pain, autonomic measures, sensory loss, and neuropathic signs., Methods: CEPs were examined at the hand and foot dorsum of patients with FD ( n  = 16) and PNP ( n  = 21) and healthy controls ( n  = 23). Sensory phenotyping was performed using quantitative sensory testing (QST). The painDETECT questionnaire (PDQ), FabryScan, and measures for the autonomic nervous system were applied. Group comparisons and correlation analyses were performed., Results: CEPs of 87.5% of the FD and 85.7% of the PNP patients were eligible for statistical analysis. In all patients combined, CEP data correlated significantly with cold detection loss, PDQ items, pain, and autonomic measures. Abnormal CEP latency in FD patients was associated with an abnormal heart frequency variability item ( r  = -0.684; adjusted p  = 0.04). In PNP patients, CEP latency correlated significantly with PDQ items, and CEP amplitude correlated with autonomic measures ( r  = 0.688, adjusted p  = 0.008; r  = 0.619, adjusted p  = 0.024). Furthermore, mechanical pain thresholds differed significantly between FD (gain range) and PNP patients (loss range) ( p  = 0.01)., Conclusions: Abnormal CEPs were associated with current pain, neuropathic signs and symptoms, and an abnormal function of the autonomic nervous system. The latter has not been mirrored by QST parameters. Therefore, CEPs appear to deliver a wider spectrum of information on the sensory nervous system than QST alone., Competing Interests: DK reports a grant, non-financial support, and a personal fee for a podcast episode from Grünenthal GmbH outside this study. MS is a consultant for Takeda Pharmaceutical and Merz Pharma; she reports personal fees from Alnylam Pharmaceuticals, Sanofi Genzyme, Grünenthal GmbH, Amicus Therapeutics, and Akcea, outside the submitted work. JL has received personal fees from Pfizer OFG Germany GmbH. S-CF reports grants from Grünenthal GmbH, during the conduct of this study as well as personal fees from Grünenthal GmbH outside the submitted work (speaker fees). Furthermore, she received financial support from Pfizer OFG Germany GmbH (personal fees). JF reports a grant (FO 1311/1-1) from the German Research Foundation (DFG); personal fees and non-financial support from Grünenthal GmbH and Sanofi Genzyme GmbH, personal fees from Bayer, non-financial support from Novartis, outside the submitted work. SC-K has received honoraria from Amicus Therapeutics, Chiesi Farmaceutici, Sanofi, and Takeda Pharmaceuticals. JGa reports grants from Amicus Therapeutics, Takeda Pharmaceuticals, and Sanofi Genzyme. JGi reports speaker fees from TAD Pharma, Insignia, Lilly GmbH, and Neurotech GmbH; consultant fees from Omega Pharma and Certkom; and travel support from Novartis, Lilly GmbH and Teva, outside the submitted work. RB reports grants/research support [EU Projects: “Europain“ (115007). DOLORisk (633491), IMI Paincare (777500), German Federal Ministry of Education and Research (BMBF): Verbundprojekt: Frühdetektion von Schmerzchronifizierung (NoChro) (13GW0338C), German Research Network on Neuropathic Pain (01EM0903), Pfizer Pharma GmbH, Genzyme GmbH, Grünenthal GmbH, Mundipharma Research GmbH und Co. KG., Novartis Pharma GmbH, Alnylam Pharmaceuticals Inc., Zambon GmbH, Sanofi-Aventis Deutschland GmbH]; speaker fees (Pfizer Pharma GmbH, Genzyme GmbH, Grünenthal GmbH, Mundipharma, Sanofi Pasteur, Medtronic Inc. Neuromodulation, Eisai Co. Ltd., Lilly GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Astellas Pharma GmbH, Desitin Arzneimittel GmbH, Teva GmbH, Bayer-Schering, MSD GmbH, Seqirus Australia Pty. Ltd., Novartis Pharma GmbH, TAD Pharma GmbH, Grünenthal SA Portugal, Sanofi-Aventis Deutschland GmbH, Agentur Brigitte Süss, Grünenthal Pharma AG Schweiz, Grünenthal B.V. Niederlande, Evapharma, Takeda Pharmaceuticals International AG Schweiz, Ology Medical Education Netherlands, Ever Pharma GmbH, Amicus Therapeutics GmbH); and consultant fees (Pfizer Pharma GmbH, Genzyme GmbH, Grünenthal GmbH, Mundipharma Research GmbH und Co. KG, Allergan, Sanofi Pasteur, Medtronic, Eisai, Lilly GmbH, Boehringer Ingelheim Pharma GmbH&Co. KG, Astellas Pharma GmbH, Novartis Pharma GmbH, Bristol Myers Squibb, Biogenidec, AstraZeneca GmbH, Merck, Abbvie, Daiichi Sankyo, Glenmark Pharmaceuticals S.A., Seqirus Australia Pty. Ltd., Teva Pharmaceuticals Europe Niederlande, Teva GmbH, Genentech, Mundipharma International Ltd. UK, Astellas Pharma Ltd. UK, Galapagos NV, Kyowa Kirin GmbH, Vertex Pharmaceuticals Inc., Biotest AG, Celgene GmbH, Desitin Arzneimittel GmbH, Regeneron Pharmaceuticals Inc. USA, Theranexus DSV CEA Frankreich, Abbott Products Operations AG Schweiz, Bayer AG, Grünenthal Pharma AG Schweiz, Mundipharma Research Ltd. UK, Akcea Therapeutics Germany GmbH, Asahi Kasei Pharma Corporation, AbbVie Deutschland GmbH & Co. KG, Air Liquide Sante International Frankreich, Alnylam Germany GmbH, Lateral Pharma Pty Ltd., Hexal AG, Angelini, Janssen, SIMR Biotech Pty Ltd. Australien, Confo Therapeutics N. V. Belgium, Merz Pharmaceuticals GmbH, Neumentum Inc., F. Hoffmann-La Roche Ltd. Switzerland, AlgoTherapeutix SAS France). PH reports grants from BMBF, Medoc, and Zambon outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Kersebaum, Sendel, Lassen, Fabig, Forstenpointner, Reimer, Canaan-Kühl, Gaedeke, Rehm, Gierthmühlen, Baron and Hüllemann.)

Introduction: The immune system is believed to be important in the initiation and maintenance of chronic pain., Objectives: The aim was to investigate whether patients with chronic painful polyneuropathy (PP) differ in cytokine profiles of serum and/or cerebrospinal fluid (CSF) compared with pain-free controls., Methods: Thirty-nine patients (16 women and 23 men, mean age, 69.2 ± 12.7 years, range 41-92 years) with PP (mean duration 43 ± 48.3 months) were phenotyped with quantitative sensory testing and electroneurography, and serum and CSF samples were analyzed by 40-multiplexed, bead-based cytokine immunoassays. Results were compared with 36 age- and gender-matched patients with normal pressure hydrocephalus and absence of abnormal CSF findings., Results: Compared with controls, patients with PP had lower concentrations of several proinflammatory and anti-inflammatory chemokines and cytokines in CSF, and others showed the same tendency, among these were tumor necrosis factor-α (14.1 ± 10.0 vs 23.9 ± 16.4 pg/mL, P < 0.005), interleukin (IL)-2 (0.6 ± 0.4 vs 1.2 ± 0.6 pg/mL, P < 0.0001), IL-6 (4.7 ± 6.8 vs 7.3 ± 9 pg/mL, P = 0.001), and IL-10 (7.5 ± 6.8 vs 16.8 ± 19.2 pg/mL, P < 0.01), whereas no differences were observed in serum., Conclusion: Results suggest that (1) inflammatory mediators play a minor role in the maintenance of chronic pain in contrast to initiation of acute pain, (2) chemokines/cytokines are downregulated in chronic pain, or (3) chemokines/cytokines have a protective role for nerve regeneration that is disturbed in patients with chronic pain., Competing Interests: The authors have no conflict of interest to declare., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

Objective: During routine clinical evaluation, it can be challenging to differentiate between lumbar radiculopathy (RAD) and lower back pain with non-radicular somatic referred pain (SRP) or even axial non-radiating low back pain (LBP). The aim of this study was to characterize patients with RAD, axial LBP (aLBP), and SRP on the basis of somatosensory profiles., Methods: Patients with LBP (n = 54) were assessed with quantitative sensory testing in the area of LBP and, in cases of RAD, additionally in the area of projecting pain. Questionnaires (PainDETECT®, EuroQol-5D, Medical Outcomes Study Sleep Scale, Hannover Functional Ability Questionnaire for Back Pain, Roland Morris Disability Questionnaire, Short Form-12 Health Survey, and Hospital Anxiety and Depression Scale) were answered by all patients., Results: Patients with RAD (n = 12) had higher pain intensity scores (numeric rating scale: 5.7 ± 1.5 vs 4.1 ± 2.2; P < 0.05) and higher PainDETECT scores (14.6 ± 6.13 vs 9.7 ± 6.2; P < 0.05) than did patients with aLBP and SRP (n = 42). Patients with RAD had a more pronounced loss of small-fiber function, increased mechanical hyperalgesia, and a trend toward increased sensitivity to thermal pain in the area of LBP compared with patients with aLBP and SRP. Within patients with RAD, sensory profiles of the area of projecting pain and the area of LBP did not differ. Pressure pain hyperalgesia (measured by pressure pain threshold) and loss of mechanical detection (measured by mechanical detection threshold) in combination with the PainDETECT items numbness and prickling reached the best predictive value in detecting a radiculopathy., Conclusions: Patients with RAD demonstrated more somatosensory abnormalities than did patients with aLBP and SRP, including increased mechanical hyperalgesia and a loss of mechanical detection. The combination of pressure pain threshold, mechanical detection threshold, numbness, and prickling in the area of LBP can be a time-efficient tool to identify patients with RAD., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In the early phase of the COVID pandemic 2020, we demonstrated how patients with painful polyneuropathy, against our expectations, did not experience a deterioration of their neuropathic pain. We hypothesized that our assessed measures, that is, pain intensity and characteristics, emotional wellbeing, and everyday life, would deteriorate in the further course of the pandemic according to the phases of disaster management. Thus, the aim of our study was to investigate patients repeatedly under varying pandemic conditions from March until December 2020. Sixty-three patients were investigated with validated questionnaires (brief pain inventory [BPI], neuropathic pain symptom inventory [NPSI], pain catastrophizing scale [PCS], patient-reported outcomes measurement information system [PROMIS] pain interference/sleep disturbance/fatigue/ depression/anxiety, EuroQol 5 dimensions 5 level version [EQ-5D-5L]) and a pandemic-specific, self-designed questionnaire. The data from the beginning of the pandemic with severe restrictions, during summer with loosened regulations and from December 2020 with reinstalled, severe restrictions were compared with an observational design. Patients reported higher pain severity when restrictions were lower. Sleep, mood, and quality of life did not change in the course of the pandemic in the validated measures. Pain interference significantly decreased during the study independent from restrictions. Patients who reported medical disadvantages had a lower quality of life upon EuroQol 5 dimension (EQ-5D) and were significantly more worried about their health. The perception of pain intensity was dependent on pandemic severity. Sleep, mood, and quality of life did not change significantly in validated measures. Continued medical care seems decisive to prevent worsening of pain and quality of life., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: Neuropathic pain highly affects quality of life, well-being, and function. It has recently been shown based on cluster analysis studies that most patients with neuropathic pain may be categorized into 1 of 3 sensory phenotypes: sensory loss, mechanical hyperalgesia, and thermal hyperalgesia. If these phenotypes reflect underlying pathophysiological mechanisms, they may be more relevant for patient management than underlying neurological diagnosis or pain intensity. The aim of this study was thus to examine the impact of these sensory phenotypes on mental health, functionality, and quality of life. Data of 433 patients from the IMI/EuroPain network database were analyzed, and results of HADS-D/A, Pain Catastrophizing Scale, Euro Quality of Life 5D/-VAS, Brief Pain Inventory, and Graded Chronic Pain Scale between the sensory phenotypes were compared using multiple regression analysis. There was no difference in chronic pain grade, pain intensity, depression, or anxiety scores between phenotypes. Pain interference (Brief Pain Inventory) was higher (P = 0.002); self-reported health state lower (Euro Quality of Life 5D VAS, P = 0.02); and problems regarding mobility (P = 0.008), usual activities (P = 0.004), and self-care (P = 0.039) more prominent (EQ5-D) in the sensory loss compared with the thermal hyperalgesia phenotype. Patients with sensory loss also showed higher pain catastrophizing scores (P = 0.006 and 0.022, respectively) compared with the 2 other groups. Sensory phenotype is associated with the impact of neuropathic pain conditions on well-being, daily functionality, and quality of life but is less associated with pain intensity. These results suggest that the somatosensory phenotype should be considered for personalized pain management., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Abstract: During the past few years, the research of chronic neuropathic pain has focused on neuroinflammation within the central nervous system and its impact on pain chronicity. As part of the ERA-Net NEURON consortium, we aimed to identify immune cell patterns in the cerebrospinal fluid (CSF) of patients with herpes zoster neuralgia and patients with polyneuropathy (PNP), which may contribute to pain chronicity in these neuropathic pain conditions. Cerebrospinal fluid of 41 patients (10 herpes zoster and 31 PNP) was analyzed by flow cytometry identifying lymphocyte subsets: CD4+ (T-helper cells), CD8+ (cytotoxic T cells), CD19+ (B cells), and CD56+ (natural killer [NK]) cells. At baseline and at follow-up, the somatosensory phenotype was assessed with quantitative sensory testing. In addition, the patients answered epidemiological questionnaires and the PainDETECT questionnaire. Immune cell profiles and somatosensory profiles, as well as painDETECT questionnaire scores, were analyzed and correlated to determine specific immune cell patterns, which contribute to chronic pain. We found a negative correlation (P = 0.004, r = -0.596) between the frequency of NK cells and mechanical pain sensitivity (MPS), one of the most relevant quantitative sensory testing markers for central sensitization; a high frequency of NK cells correlated with low MPS. The analysis of the individual follow-up showed a worsening of the pain condition if NK-cell frequency was low. Low NK-cell frequency is associated with signs of central sensitization (MPS), whereas high NK-cell frequency might prevent central sensitization. Therefore, NK cells seem to play a protective role within the neuroinflammatory cascade and may be used as a marker for pain chronicity., (Copyright © 2021 International Association for the Study of Pain.)

Objective: To test whether contralateral sensory abnormalities in the clinically unaffected area of patients with unilateral neuropathic pain are due to the neuropathy or pain mechanisms., Methods: We analyzed the contralateral clinically unaffected side of patients with unilateral painful or painless neuropathy (peripheral nerve injury [PNI], postherpetic neuropathy [PHN], radiculopathy) by standardized quantitative sensory testing following a validated protocol. Primary outcome was the independent contribution of the following variables on the contralateral sensory function using generalized linear regression models: pain intensity, disease duration, etiology, body area, and sensory patterns in the most painful area., Results: Among 424 patients (PNI n = 256, PHN n = 78, radiculopathy n = 90), contralateral sensory abnormalities were frequent in both painful (n = 383) and painless (n = 41) unilateral neuropathy, demonstrating sensory loss for thermal and mechanical nonpainful stimuli and both sensory loss and gain for painful test stimuli. Analysis by etiology revealed contralateral pinprick hyperalgesia in PHN and PNI. Analysis by ipsilateral sensory phenotype demonstrated mirror-image pinprick hyperalgesia in both mechanical and thermal hyperalgesia phenotypes. Pain intensity, etiology, and affected body region predicted changes in only single contralateral somatosensory parameters. Disease duration had no impact on the contralateral sensory function., Conclusion: Mechanisms of sensory loss seem to spread to the contralateral side in both painful and painless neuropathies. Contralateral spread of pinprick hyperalgesia was restricted to the 2 ipsilateral phenotypes that suggest sensitization; this suggest a contribution of descending net facilitation from supraspinal areas, which was reported in rodent models of neuropathic pain but not yet in human patients., (© 2021 American Academy of Neurology.)

Introduction: Patients suffering from fibromyalgia syndrome (FMS) are heterogenous. They often present with sensory abnormalities and comorbidities., Objectives: We aimed to answer the following questions: (1) Is there a specific somatosensory profile in our patient cohort? (2) Can we detect subgroups characterized by a specific combination of sensory and psychological features? and (3) Do psychological parameters influence sensory signs?, Methods: In 87 patients with FMS quantitative sensory testing was performed on the hand and evaluated in combination with questionnaire results regarding pain, psychological comorbidities, sleep, and functionality., Results: Patients presented different somatosensory patterns, but no specific subgroups regarding sensory signs and psychological features were detected. Hypersensitivity for noxious mechanical and thermal stimuli and hyposensitivity for nonnoxious mechanical stimuli were the most prominent features. Thirty-one percent of patients showed signs of central sensitization as indicated by abnormally increased pinprick hyperalgesia or dynamic mechanical allodynia. Central sensitization was associated with higher pain intensities ( P < 0.001). Only a small influence of psychiatric comorbidities on mechanical pain sensitivity ( P = 0.044) and vibration detection ( P = 0.028) was found, which was partly associated with high pain intensities. A small subgroup of patients (11.4%) demonstrated thermal hyposensitivity (loss of small-fiber function)., Conclusion: Patients with FMS showed various somatosensory abnormalities. These were not significantly influenced by psychological comorbidities. Signs for central sensitization were detected in about one-third of patients and associated with higher pain intensities. This supports the notion of central sensitization being a major pathophysiological mechanism in FMS, whereas small-fiber loss may be less important., Competing Interests: S. Rehm reports grants from Pfizer GmbH Grant Number 9109 during the conduct of the study and personal fees from Bayer GmbH and non-financial support from Grünenthal outside the submitted work. J. Sachau reports consultant fees from Pfizer Pharma GmbH, travel support from Alnylam Pharmaceuticals Inc. and Pfizer, and speaker fees from Grünenthal GmbH outside the submitted work. J. Hellriegel reports personal fees and non-financial support from Pfizer and Grünenthal during the conduct of the study and personal fees and non-financial support from Pfizer and Grünenthal outside the submitted work. J. Forstenpointner reports grants from the German Research Foundation (DFG, FO 1311/1–1) during the conduct of the study; personal fees and non-financial support from Grünenthal GmbH, Sanofi Genzyme GmbH, personal fees from Bayer, and non-financial support from Novartis outside the submitted work. J. Gierthmühlen reports personal fees from TAD Pharma, Glenmark, Certkom, Pfizer, Grünenthal, Sanofi Pasteur, and Novartis outside the submitted work. R. Baron reports grants from Pfizer (Grant 9109) during the conduct of the study and grants and research support from EU Projects: “Europain” (115007), DOLORisk (633491), IMI-PainCare (777500). German Federal Ministry of Education and Research (BMBF): Verbundprojekt: Frühdetektion von Schmerzchronifizierung (NoChro) (13GW0338C), German Research Network on Neuropathic Pain (01EM0903), Pfizer Pharma GmbH, Genzyme GmbH, Grünenthal GmbH, Mundipharma Research GmbH und Co. KG., Novartis Pharma GmbH, Alnylam Pharmaceuticals Inc., Zambon GmbH, Sanofi-Aventis Deutschland GmbH speaker fees from Pfizer Pharma GmbH, Genzyme GmbH, Grünenthal GmbH, Mundipharma, Sanofi Pasteur, Medtronic Inc., Neuromodulation, Eisai Co.Ltd., Lilly GmbH, Boehringer Ingelheim Pharma GmbH & Co. KG, Astellas Pharma GmbH, Desitin Arzneimittel GmbH, Teva GmbH, Bayer-Schering, MSD GmbH, Seqirus Australia Pty. Ltd, Novartis Pharma GmbH, TAD Pharma GmbH, Grünenthal SA Portugal, Sanofi-Aventis Deutschland GmbH, Agentur Brigitte Süss, Grünenthal Pharma AG Schweiz, Grünenthal B.V. Niederlande, Evapharma, Takeda Pharmaceuticals International AG Schweiz, Ology Medical Education Netherlands, consultant fees from Pfizer Pharma GmbH, Genzyme GmbH, Grünenthal GmbH, Mundipharma Research GmbH und Co. KG, Allergan, Sanofi Pasteur, Medtronic, Eisai, Lilly GmbH, Boehringer Ingelheim Pharma GmbH&Co.KG, Astellas Pharma GmbH, Novartis Pharma GmbH, Bristol-Myers Squibb, Biogenidec, AstraZeneca GmbH, Merck, Abbvie, Daiichi Sankyo, Glenmark Pharmaceuticals S.A., Seqirus Australia Pty. Ltd, Teva Pharmaceuticals Europe Niederlande, Teva GmbH, Genentech, Mundipharma International Ltd. United Kingdom, Astellas Pharma Ltd. United Kingdom, Galapagos NV, Kyowa Kirin GmbH, Vertex Pharmaceuticals Inc., Biotest AG, Celgene GmbH, Desitin Arzneimittel GmbH, Regeneron Pharmaceuticals Inc. USA, Theranexus DSV CEA Frankreich, Abbott Products Operations AG Schweiz, Bayer AG, Grünenthal Pharma AG Schweiz, Mundipharma Research Ltd. United Kingdom, Akcea Therapeutics Germany GmbH, Asahi Kasei Pharma Corporation, AbbVie Deutschland GmbH & Co. KG, Air Liquide Sante International Frankreich, Alnylam Germany GmbH, Lateral Pharma Pty Ltd, Hexal AG, Angelini, SIMR Biotech Pty Ltd Australien, Confo Therapeutics N. V. Belgium, and Janssen, outside the submitted work. The remaining authors have no conflicts of interest to declare.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

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.)

Background: The serotonin receptor 2A (HTR2A) has been described as an important facilitation mediator of spinal nociceptive processing leading to central sensitization (CS) in animal models of chronic pain. However, whether HTR2A single nucleotide variants (SNVs) modulate neuropathic pain states in patients has not been investigated so far. The aim of this study was to elucidate the potential association of HTR2A variants with sensory abnormalities or ongoing pain in neuropathic pain patients., Methods: At total of 240 neuropathic pain patients and 253 healthy volunteers were included. Patients were phenotypically characterized using standardized quantitative sensory testing (QST). Patients and controls were genotyped for HTR2A g.-1438G > A (rs6311) and c.102C > T (rs6313). Genotype-related differences in QST parameters were assessed considering QST profile clusters, principal somatosensory components and sex., Results: There was an equal distribution of rs6313 and linked rs6311 between patients and controls. However, the rs6313 variant was significantly associated with a principal component of pinprick hyperalgesia and dynamic mechanical allodynia, indicating enhanced CS in patients with sensory loss (-0.34 ± 0.15 vs. +0.31 ± 0.11 vs., p < .001). In this cluster, the variant allele was also associated with single QST parameters of pinprick hyperalgesia (MPT, +0.64 ± 0.18 vs. -0.34 ± 0.23 p = .002; MPS, +0.66 ± 0.17 vs. -0.09 ± 0.23, p = .009) and ongoing pain was increased by 30%., Conclusions: The specific association of the rs6313 variant with pinprick hyperalgesia and increased levels of ongoing pain suggests that the HTR2A receptor might be an important modulator in the development of CS in neuropathic pain., Significance: This article presents new insights into serotonin receptor 2A-mediating mechanisms of central sensitization in neuropathic pain patients. The rs6313 variant allele was associated with increased mechanical pinprick sensitivity and increased levels of ongoing pain supporting a contribution of central sensitization in the genesis of ongoing pain providing a possible route for mechanism-based therapies., (© 2020 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Background: Previous studies have shown that not only pain intensity but also impairment of quality of life and functionality are important parameters for the evaluation of treatment of chronic low back pain patients. The aim of the study was to validate a specific self-questionnaire for symptom assessment and their influence on quality of life and functionality of chronic low back pain patients (Questionnaire for Symptom Assessment in Pain disorders for back pain patients, Q-SAP)., Methods: The self-questionnaire consists of two parts (for back and if applicable leg symptoms) and was tested in 152 chronic low back pain patients with and without radiculopathy. Test-retest reliability, exploratory factor analysis, convergent validity, criterion-related validity and the sensitivity to detect patient reported changes were investigated., Results: The questionnaire showed a good to excellent test-retest reliability. In the factor analysis nociceptive and neuropathic pain components could be separated and the highest convergent validities were shown for the painDETECT, EQ-5D-3L and the FFbH-R. The criterion-related validity showed concordance of QST and the Q-SAP Back for warmth induced pain and numbness. Regarding the sensitivity to patient-reported changes, a moderate correlation was found for both parts of the questionnaire., Conclusions: The Q-SAP was tested as a useful, valid and reliable tool. This new questionnaire records classical nociceptive and neuropathic pain symptoms of chronic low back pain patients depending on their local distribution. Furthermore, the questionnaire records the intensity of these symptoms and their influence on quality of life and functionality and can be used for the evaluation of treatment., Significance: The Q-SAP Back/Leg is a new self-questionnaire for CLBP patients with or without radiating leg pain that precisely assesses neuropathic and nociceptive symptoms. In contrast to other questionnaires, the Q-SAP Back/Leg evaluates not only symptom intensities but also their impact on the patient's quality of life and functionality. Furthermore, this questionnaire requests the symptoms depending on their anatomical distribution., (© 2020 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

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.)