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

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

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