Hypervigilance for innocuous tactile stimuli in patients with fibromyalgia: an experimental approach

Background: Hypervigilance, i.e., excessive attention, is often invoked as a potential explanation for the observation that many individuals with fibromyalgia show a heightened sensitivity to stimulation in various sensory modalities, such as touch and hearing. Compelling evidence for this assumption is, however, lacking. The aim of the present study was to investigate the presence of somatosensory hypervigilance in patients with fibromyalgia. Methods: Fibromyalgia patients (n=41) and a matched control group (n=40) performed a tactile change detection task in which they had to detect whether there was a change between two consecutively presented patterns of tactile stimuli presented to various body locations. The task was performed under two conditions: in the unpredictable condition, tactile changes occurred equally often at all possible body locations; in the predictable condition, the majority of tactile changes occurred at one specific body location. Results: It was hypothesized that the fibromyalgia group would show better tactile change detection in the unpredictable condition and when changes ocurred at unexpected locations in the predictable condition. The results did not support this hypothesis. In neither condition was the fibromyalgia group better than the control group in detecting tactile changes. Conclusions: No evidence was found to support the claim that patients with fibromyalgia display somatosensory hypervigilance. This finding challenges the idea of hypervigilance as a static feature of fibromyalgia and urges for a more dynamic view in which hypervigilance emerges in situations when bodily threat is experienced

A systematic review and meta-analysis of the prevalence of small fiber pathology in fibromyalgia: Implications for a new paradigm in fibromyalgia etiopathogenesis

Objectives: Fibromyalgia is a condition which exhibits chronic widespread pain with neuropathic pain features and has a major impact on health-related quality of life. The pathophysiology remains unclear, however, there is increasing evidence for involvement of the peripheral nervous system with a high prevalence of small fiber pathology (SFP). The aim of this systematic literature review is to establish the prevalence of SFP in fibromyalgia. Methods: An electronic literature search was performed using MEDLINE, EMBASE, PubMed, Web of Science, CINAHL and the Cochrane Library databases. Published full-text, English language articles that provide SFP prevalence data in studies of fibromyalgia of patients over 18years old were included. All articles were screened by two independent reviewers using a priori criteria. Methodological quality and risk of bias were evaluated using the critical appraisal tool by Munn et al. Overall and subgroup pooled prevalence were calculated by random-effects meta-analysis with 95% CI. Results: Database searches found 935 studies; 45 articles were screened of which 8 full text articles satisfied the inclusion criteria, providing data from 222 participants. The meta-analysis demonstrated the pooled prevalence of SFP in fibromyalgia is 49% (95% CI: 38–60%) with a moderate degree of heterogeneity, (I2= 68%). The prevalence estimate attained by a skin biopsy was 45% (95% CI: 32–59%, I2= 70%) and for corneal confocal microscopy it was 59% (95% CI: 40–78%, I2= 51%). Conclusion: There is a high prevalence of SFP in fibromyalgia. This study provides compelling evidence of a distinct phenotype involving SFP in fibromyalgia. Identifying SFP will aid in determining its relationship to pain and potentially facilitate the development of future interventions and pharmacotherapy

Thermal Quantitative Sensory Testing in Fibromyalgia Patients

Publisher Copyright: © 2015 by Marija Mihailova. Copyright: Copyright 2015 Elsevier B.V., All rights reserved.Fibromyalgia (FM) is a chronic disorder manifested by diffuse musculoskeletal pain, fatigue, sleep, and emotional disturbance. The disorder is probably associated with dysfunction of C and A delta peripheral nerve fibres. Thermal quantitative sensory testing (QST) was used to analyse thinly myelinated A delta fibres and nonmylinated C fibres, which function in the nociceptive sensory system, and the spinothalamic pathway. The observation that FM pain has neuropathic nature increased the value of QST as an additional diagnostic tool. The research group included 51 patients. Somatic symptoms were assessed using the Fatigue Severity Score (FSS), Fibromyalgia Impact Questionnaire (FIQ) and American College of Rheumatology (ACR) 2010 year diagnostic criteria. QST was performed by using thermal stimulus at wrist and feet. QST results were compared with 20 non-FM controls matched for age and sex. FM patients showed significant alteration of thermal perception and pain threshold compared with that in healthy controls, which demonstrated possible neuropathic pain nature in FM patients. Changes were more expressed in warm perception and heat pain threshold, which probably indicates that in FM patients C fibres are more damaged and warm perception and warm pain threshold are more sensitive, which may be used as FM diagnostics. We also found statistically significant negative correlations between warm and cold perception thresholds and between heat and cold pain thresholds, reflecting central sensitization or a defective pain inhibitory system.publishersversionPeer reviewe

Harmonizing neuropathic pain research: outcomes of the London consensus meeting on peripheral tissue studies

Neuropathic pain remains difficult to treat, with drug development hampered by an incomplete understanding of the pathogenesis of the condition, as well as a lack of biomarkers. The problem is compounded by the scarcity of relevant human peripheral tissues, including skin, nerves, and dorsal root ganglia. Efforts to obtain such samples are accelerating, increasing the need for standardisation across laboratories. In this white paper, we report on a consensus meeting attended by neuropathic pain experts, designed to accelerate protocol alignment and harmonization of studies involving relevant peripheral tissues. The meeting was held in London in March 2024 and attended by 28 networking partners, including industry and patient representatives. We achieved consensus on minimal recommended phenotyping, harmonised wet laboratory protocols, statistical design, reporting, and data sharing. Here, we also share a variety of relevant standard operating procedures as supplementary protocols. We envision that our recommendations will help unify human tissue research in the field and accelerate our understanding of how abnormal interactions between sensory neurons and their local peripheral environment contribute towards neuropathic pain

Proinflammatory cytokine levels in fibromyalgia patients are independent of body mass index

<p>Abstract</p> <p>Background</p> <p>Fibromyalgia (FM) is characterized by chronic, widespread muscular pain and tenderness and is generally associated with other somatic and psychological symptoms. Further, circulatory levels of proinflammatory cytokines (IL-1β, TNF-α, and IL-6) may be altered in FM patients, possibly in association with their symptoms. Recently, rises in BMI have been suggested to contribute to increased circulating levels of proinflammatory cytokines in FM patients. Our aim was to measure the circulatory levels of proinflammatory cytokines to determine the influence of BMI on these levels in FM patients and healthy volunteers (HVs). In Spanish FM patients (n = 64) and HVs (n = 25), we measured BMI and serum concentrations of proinflammatory cytokines by capture ELISA.</p> <p>Findings</p> <p>There were significant differences in BMI levels between FM patients (26.40 ± 4.46) and HVs (23.64 ± 3.45) and significant increase in IL-6 in FM patients (16.28 ± 8.13 vs 0.92 ± 0.32 pg/ml) (P < 0.001). IL-1β and TNF-α decreased in FM patients compared with HVs. By ANCOVA, there was no significant association between BMI and TNF-α (F = 0.098, p = 0.75) or IL-6 (F = 0.221, p = 0.63) levels in FM patients.</p> <p>Conclusions</p> <p>Our analysis in FM patients of BMI as a covariate of proinflammatory cytokines levels showed that serum TNF-α and IL-6 levels are independent of BMI. Further studies are necessary to dissect these findings and their implication in future therapeutic approaches for FM patients.</p

Inducible nitric oxide synthase inhibition by 1400W limits pain hypersensitivity in a neuropathic pain rat model

Peripheral neuropathic pain (PNP), resulting from injury to or dysfunction of a peripheral nerve, is a major health problem that affects 7–8% of the population. It is inadequately controlled by current drugs and is characterized by pain hypersensitivity, which is believed to be attributable to sensitization of peripheral and CNS neurons by various inflammatory mediators. Here we examined, in a rat model of PNP: (i) whether reducing levels of nitric oxide (NO) with 1400W, a highly selective inhibitor of inducible NO synthase (iNOS), would prevent or attenuate pain hypersensitivity; and (ii) the effects of 1400W on plasma concentrations of several cytokines that are secreted after iNOS upregulation during chronic pain states. The L5 spinal nerve axotomy (SNA) model of PNP was used, and 1400W (20 mg kg−1) was administered i.p . at 8 h intervals for 3 days starting at 18 h post‐SNA. Changes in plasma concentrations of 12 cytokines in SNA rats treated with 1400W were examined using multiplex enzyme‐linked immunosorbent assay. The SNA rats developed behavioural signs of mechanical and heat hypersensitivity. Compared with the vehicle/control, 1400W significantly: (i) limited development of mechanical hypersensitivity at 66 h post‐SNA and of heat hypersensitivity at 42 h and at several time points tested thereafter; and (ii) increased the plasma concentrations of interleukin (IL)‐1α, IL‐1β and IL‐10 in the SNA rats. The findings suggest that 1400W might exert its analgesic effects by reducing iNOS and altering the balance between the pro‐inflammatory (IL‐1β and IL‐1α) and anti‐inflammatory (IL‐10) cytokines and that therapies targeting NO or its enzymes might be effective for the treatment of PNP

NOV/CCN3 attenuates inflammatory pain through regulation of matrix metalloproteinases-2 and -9

<p>Abstract</p> <p>Background</p> <p>Sustained neuroinflammation strongly contributes to the pathogenesis of pain. The clinical challenge of chronic pain relief led to the identification of molecules such as cytokines, chemokines and more recently matrix metalloproteinases (MMPs) as putative therapeutic targets. Evidence points to a founder member of the matricial CCN family, NOV/CCN3, as a modulator of these inflammatory mediators. We thus investigated the possible involvement of NOV in a preclinical model of persistent inflammatory pain.</p> <p>Methods</p> <p>We used the complete Freund's adjuvant (CFA)-induced model of persistent inflammatory pain and cultured primary sensory neurons for <it>in vitro </it>experiments. The mRNA expression of NOV and pro-inflammatory factors were measured with real-time quantitative PCR, CCL2 protein expression was assessed using ELISA, MMP-2 and -9 activities using zymography. The effect of drugs on tactile allodynia was evaluated by the von Frey test.</p> <p>Results</p> <p>NOV was expressed in neurons of both dorsal root ganglia (DRG) and dorsal horn of the spinal cord (DHSC). After intraplantar CFA injection, NOV levels were transiently and persistently down-regulated in the DRG and DHSC, respectively, occurring at the maintenance phase of pain (15 days). NOV-reduced expression was restored after treatment of CFA rats with dexamethasone. <it>In vitro</it>, results based on cultured DRG neurons showed that siRNA-mediated inhibition of NOV enhanced IL-1β- and TNF-α-induced MMP-2, MMP-9 and CCL2 expression whereas NOV addition inhibited TNF-α-induced MMP-9 expression through β₁integrin engagement. <it>In vivo</it>, the intrathecal delivery of MMP-9 inhibitor attenuated mechanical allodynia of CFA rats. Importantly, intrathecal administration of NOV siRNA specifically led to an up-regulation of MMP-9 in the DRG and MMP-2 in the DHSC concomitant with increased mechanical allodynia. Finally, NOV intrathecal treatment specifically abolished the induction of MMP-9 in the DRG and, MMP-9 and MMP-2 in the DHSC of CFA rats. This inhibitory effect on MMP is associated with reduced mechanical allodynia.</p> <p>Conclusions</p> <p>This study identifies NOV as a new actor against inflammatory pain through regulation of MMPs thus uncovering NOV as an attractive candidate for therapeutic improvement in pain relief.</p

Regulation of peripheral blood flow in Complex Regional Pain Syndrome: clinical implication for symptomatic relief and pain management

Background. During the chronic stage of Complex Regional Pain Syndrome (CRPS), impaired microcirculation is related to increased vasoconstriction, tissue hypoxia, and metabolic tissue acidosis in the affected limb. Several mechanisms may be responsible for the ischemia and pain in chronic cold CPRS. Discussion. The diminished blood flow may be caused by either sympathetic dysfunction, hypersensitivity to circulating catecholamines, or endothelial dysfunction. The pain may be of neuropathic, inflammatory, nociceptive, or functional nature, or of mixed origin. Summary. The origin of the pain should be the basis of the symptomatic therapy. Since the difference in temperature between both hands fluctuates over time in cold CRPS, when in doubt, the clinician should prioritize the patient's report of a persistent cold extremity over clinical tests that show no difference. Future research should focus on developing easily applied methods for clinical use to differentiate between central and peripheral blood flow regulation disorders in individual patients