Neuropathic Pain Secondary to Multiple Sclerosis: A Narrative Review.

Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system (CNS). Neuropathic pain in MS is a debilitating symptom that significantly impairs the quality of life for a substantial proportion of MS patients. Neuropathic pain in MS stems primarily from demyelination, axonal loss, CNS inflammation, and direct damage to the myelin sheath, leading to pain manifestations such as ongoing extremity pain, Lhermitte's phenomenon, and trigeminal neuralgia (TN). The pathophysiological mechanisms behind MS-related neuropathic pain are explored in this review, highlighting central sensitization, neural dysfunction, spinal thalamic tract dysfunction, and inflammatory processes that exacerbate neuronal damage. Neuropathic pain in MS necessitates comprehensive assessment tools and neurophysiological tests to differentiate neuropathic pain from other MS symptoms accurately. Treatment strategies for MS-related neuropathic pain encompass pharmacological interventions, including anticonvulsants and antidepressants, and emerging therapies targeting specific inflammatory processes. The review advocates for a holistic approach to management, incorporating innovative treatments and multidisciplinary strategies to address both the physical symptoms and psychosocial aspects of this disorder. This comprehensive overview underscores the importance of ongoing research into targeted therapies to improve patient outcomes and enhance the quality of life for those affected by MS.

SIRT1-regulated ROS generation activates NMDAR2B phosphorylation to promote central sensitization and allodynia in a male chronic migraine rat model.

Background: Central sensitization is one of the pivotal pathological mechanisms in chronic migraine (CM). Silent information regulator 1 (SIRT1) was shown to be involved in CM, but its specific mechanism is unclear. Reactive oxygen species (ROS) are increasingly regarded as important signaling molecules in several models of pain. However, studies about the role of ROS in the central sensitization of CM model are rare. We thus explored the specific process of SIRT1 involvement in the central sensitization of CM, focusing on the ROS pathway. Methods: Inflammatory soup was repeatedly administered to male Sprague-Dawley rats to establish a CM model. The SIRT1 expression level in trigeminal nucleus caudalis (TNC) tissues was assessed by qRT-PCR and Western blotting analysis. The levels of ROS were detected by a Tissue Reactive Oxygen Detection Kit, DHE staining, and the fluorescence signal intensity of 8-OHdG. A ROS scavenger (tempol), a SIRT1 activator (SRT1720), a SIRT1 inhibitor (EX527), and a mitochondrial fission inhibitor (Mdivi-1) were used to investigate the specific molecular mechanisms involved. NMDAR2B, CGRP, ERK, and mitochondrial fission-related protein were evaluated by Western blotting, and the CGRP level in frozen sections of the TNC was detected via immunofluorescence staining. Results: After repeated inflammatory soup infusion and successful establishment of the CM rat model, SIRT1 expression was found to be significantly reduced, accompanied by elevated ROS levels. Treatment with Tempol, SRT1720, or Mdivi-1 alleviated allodynia and reduced the increase in NMDAR2B phosphorylation and CGRP and ERK phosphorylation in the CM rat. In contrast, EX527 had the opposite effect in CM rat. SRT1720 and EX527 decreased and increased ROS levels, respectively, in CM rats, and tempol reversed the aggravating effect of EX527 in CM rats. Furthermore, the regulatory effect of SIRT1 on ROS may include the involvement of the mitochondrial fission protein DRP1. Conclusion: The results indicate the importance of SIRT1 in CM may be due to its role in regulating the production of ROS, which are involved in modulating central sensitization in CM. These findings could lead to new ideas for CM treatment with the use of SIRT1 agonists and antioxidants.

Effect of dry needling on pain and central sensitization in women with chronic pelvic pain: A randomized parallel-group controlled clinical trial.

Chronic pelvic pain (CPP) is a debilitating problem in women with clear evidence of myofascial dysfunction. It seems that Myofascial trigger points (MTrPs) contribute to the development of central sensitization (CS). This study aimed to investigate the effect of dry needling on pain and CS in women with CPP. Thirty-six women with CPP participated in this randomized controlled clinical trial and randomly assigned into three groups: dry needling group (DNG), placebo needling group (PNG) and control group (CG). The DNG received five sessions of DN using the "static needling", the PNG received non-penetrating method, and the CG did not receive any intervention. Assessment of outcomes including central sensitization inventory (CSI), short-form McGill pain questionnaire (SF-MPQ), electroencephalography (EEG), conditioned pain modulation (CPM), salivary cortisol concentration, 7-item general anxiety disorder scale (GAD-7), pain catastrophizing scale (PCS), and SF-36 questionnaire was performed pre-intervention, post-intervention, and three months post-intervention by a blind examiner. The result showed a significant group-by-time interaction for CSI, SF-MPQ, and PCS. There was a significant decrease in CSI score in post-intervention and three-months post-intervention compare to pre-intervention in the DNG and PNG. SF-MPQ-PPI score in DNG significantly decreased post-intervention. PCS-Total score decreased significantly post-intervention in DNG and PNG. No significant group-by-time interactions were observed for other variables. EEG results showed regional changes in the activity of frequency bands in both eye closed and eye open conditions. It seems that DN can affect central pain processing by removing the source of peripheral nociception. Trial registration: Iranian Registry of Clinical Trials (IRCT20211114053057N1, registered on: December 03, 2021. https://irct.behdasht.gov.ir/search/result?query=IRCT20211114053057N1).

Establishing central sensitization inventory cut-off values in Dutch-speaking patients with chronic low back pain by unsupervised machine learning.

BACKGROUND: Human Assumed Central Sensitization (HACS) is involved in the development and maintenance of chronic low back pain (CLBP). The Central Sensitization Inventory (CSI) was developed to evaluate the presence of HACS, with a cut-off value of 40/100. However, various factors including pain conditions (e.g., CLBP), contexts, and gender may influence this cut-off value. Unsupervised clustering approaches can address these complexities by considering diverse factors and exploring possible HACS-related subgroups. Therefore, this study aimed to determine the cut-off values for a Dutch-speaking population with CLBP based on unsupervised machine learning. METHODS: Questionnaire data covering pain, physical, and psychological aspects were collected from patients with CLBP and aged-matched healthy controls (HC). Four clustering approaches were applied to identify HACS-related subgroups based on the questionnaire data and gender. The clustering performance was assessed using internal and external indicators. Subsequently, receiver operating characteristic (ROC) analysis was conducted on the best clustering results to determine the optimal cut-off values. RESULTS: The study included 63 HCs and 88 patients with CLBP. Hierarchical clustering yielded the best results, identifying three clusters: healthy group, CLBP with low HACS level, and CLBP with high HACS level groups. The cut-off value for the overall groups were 35 (sensitivity 0.76, specificity 0.76). CONCLUSION: This study found distinct patient subgroups. An overall CSI cut-off value of 35 was suggested. This study may provide new insights into identifying HACS-related patterns and contributes to establishing accurate cut-off values.

Evaluation of the segmental distribution of pain sensitivity among patients with central sensitization associated with chronic subacromial pain syndrome: A cross-sectional study.

INTRODUCTION: Pain sensitivity is the main finding of central sensitization (CS) and can occur in patients with chronic shoulder pain. However, there is limited evidence concerning the distribution of pain sensitivity in shoulders, forearms, and legs in patients with CS associated with chronic shoulder pain. The present study aimed to determine the distribution of pain sensitivity in patients with CS associated with chronic subacromial pain syndrome (SPS). METHOD: This cross-sectional study included 58 patients with chronic SPS and CS (patient group) and 58 healthy participants (control group). The presence of CS was determined using the Central Sensitization Inventory (CSI). To determine the distribution of pain sensitivity, pressure pain threshold (PPT) measurements were performed from the shoulders, forearms, and legs. RESULTS: There was no significant difference between the two groups in terms of sociodemographic data (p > 0.05). The patient group had a significantly higher CSI score (p < 0.001) and lower PPTs in all regions (p < 0.05) than the control group. Unlike the control group, the patient group had lower PPTs on the affected side for the shoulder [mean difference (MD) 95% confidence interval (CI): 1.2 (-1.7 to -0.6)], forearm [MD 95% CI: 1.1 (-1.7 to -0.6)], and leg [MD 95% CI: 0.9 (-1.4 to -0.3)] compared with the contralateral side (p < 0.001). CONCLUSION: Pain sensitivity is more pronounced in the affected shoulder and the forearm and leg located on this side than in those on the contralateral side in patients with CS associated with chronic SPS.

Modulatory Processes in Craniofacial Pain States.

Pain is a common symptom associated with many disorders affecting the craniofacial tissues that include the teeth and their supporting structures, the jaw, face and tongue muscles, and the temporomandibular joint. Most acute craniofacial pain states are easily recognized and readily treated, but chronic craniofacial pain states (e.g., temporomandibular disorders [TMD], trigeminal neuropathies, and some headaches) may be especially challenging to manage successfully. This chapter provides an overview of the processes that underlie craniofacial pain, with a focus on the pain-modulatory mechanisms operating in craniofacial tissues and in the central nervous system (CNS), including the role of endogenous chemical processes such as those involving opioids. The chapter outlines in particular findings from preclinical studies that have provided substantial information about the neural as well as nonneural (e.g., glial) processes involved in the initiation, transmission, and modulation of nociceptive signals in the trigeminal system, and also draws attention to their clinical correlates. The increased understanding gained from these preclinical studies of how nociceptive signals can be modulated will contribute to improvements in presently available therapeutic approaches to manage craniofacial pain as well as to the development of novel analgesic approaches.

A Narrative Review of the Dorsal Root Ganglia and Spinal Cord Mechanisms of Action of Neuromodulation Therapies in Neuropathic Pain.

Neuropathic pain arises from injuries to the nervous system in diseases such as diabetes, infections, toxicity, and traumas. The underlying mechanism of neuropathic pain involves peripheral and central pathological modifications. Peripheral mechanisms entail nerve damage, leading to neuronal hypersensitivity and ectopic action potentials. Central sensitization involves a neuropathological process with increased responsiveness of the nociceptive neurons in the central nervous system (CNS) to their normal or subthreshold input due to persistent stimuli, leading to sustained electrical discharge, synaptic plasticity, and aberrant processing in the CNS. Current treatments, both pharmacological and non-pharmacological, aim to alleviate symptoms but often face challenges due to the complexity of neuropathic pain. Neuromodulation is emerging as an important therapeutic approach for the treatment of neuropathic pain in patients unresponsive to common therapies, by promoting the normalization of neuronal and/or glial activity and by targeting cerebral cortical regions, spinal cord, dorsal root ganglia, and nerve endings. Having a better understanding of the efficacy, adverse events and applicability of neuromodulation through pre-clinical studies is of great importance. Unveiling the mechanisms and characteristics of neuromodulation to manage neuropathic pain is essential to understand how to use it. In the present article, we review the current understanding supporting dorsal root ganglia and spinal cord neuromodulation as a therapeutic approach for neuropathic pain.

Indication for spinal sensitization in chronic low back pain: mechanical hyperalgesia adjacent to but not within the most painful body area.

Introduction: In 85% of patients with chronic low back pain (CLBP), no specific pathoanatomical cause can be identified. Besides primary peripheral drivers within the lower back, spinal or supraspinal sensitization processes might contribute to the patients' pain. Objectives: The present study conceptualized the most painful area (MP) of patients with nonspecific CLBP as primarily affected area and assessed signs of peripheral, spinal, and supraspinal sensitization using quantitative sensory testing (QST) in MP, a pain-free area adjacent to MP (AD), and a remote, pain-free control area (CON). Methods: Fifty-nine patients with CLBP (51 years, SD = 16.6, 22 female patients) and 35 pain-free control participants individually matched for age, sex, and testing areas (49 years, SD = 17.5, 19 female participants) underwent a full QST protocol in MP and a reduced QST protocol assessing sensory gain in AD and CON. Quantitative sensory testing measures, except paradoxical heat sensations and dynamic mechanical allodynia (DMA), were Z-transformed to the matched control participants and tested for significance using Z-tests (α = 0.001). Paradoxical heat sensations and DMA occurrence were compared between cohorts using Fisher's exact tests (α = 0.05). The same analyses were performed with a high-pain and a low-pain CLBP subsample (50% quantile). Results: Patients showed cold and vibration hypoesthesia in MP (all Ps < 0.001) and mechanical hyperalgesia (P < 0.001) and more frequent DMA (P = 0.044) in AD. The results were mainly driven by the high-pain CLBP subsample. In CON, no sensory alterations were observed. Conclusion: Mechanical hyperalgesia and DMA adjacent to but not within MP, the supposedly primarily affected area, might reflect secondary hyperalgesia originating from spinal sensitization in patients with CLBP.

Sleep disorders in patients with endometriosis; a cross-sectional study.

BACKGROUND: Endometriosis affects 10-15% of women of reproductive age and is considered a critical gynecological problem. Endometriosis causes pain and infertility, both of which can impair the patient's quality of life. Sleep disorders account for the most bothersome presentation of impaired quality of life. This study investigated the frequency and severity of sleep disorders in women with endometriosis. METHODS: In this analytical cross-sectional study, 665 women referred to three hospitals in Tehran, Rasool-e-Akram, Pars, and Nikan, were included (463 patients with endometriosis and 202 women without endometriosis). All of them were informed about the study design and the aim of the research, and then they were asked to sign the consent form and complete the Pittsburgh Sleep Quality Index (PSQI). After data gathering and entering, they were analyzed by SPSS version 22 and were considered significant with P < 0.05. RESULTS: The study population's mean age was 35.4 ± 7.9 years. The mean global PSQI score in the case group (endometriosis patients) was higher than in the control group (non-endometriosis patients) (10.6 vs. 7.1; P < 0.001). Patients with dyspareunia, dysuria, pelvic pain, and dyschezia had a significantly higher PSQI score (P < 0.05). CONCLUSION: According to the findings of the present study, the sleep quality in endometriosis patients is low, and there is a need to pay greater attention to these patients. This may result in some changes in the therapeutic strategies for this disease.

PaiNEd app. Assessing central sensitization in survivors of breast cancer: A reliability study.

Introduction: Pain is a common adverse event in survivors of breast cancer (sBCs). As there is no gold standard to assess pain experience predominantly related to central sensitization (CS) symptoms, we designed the PaiNEd app, which includes an algorithm to report whether patients are under predominant CS pain mechanisms. Objective: We aimed to assess the reliability of the PaiNEd app to estimate whether sBC pain experience is predominantly related to CS symptoms. Methods: An observational, descriptive reliability design was employed to assess the inter- and intrarater reliability of the PaiNEd app. This app includes an algorithm that considers the number of painful body parts and some questionnaires related to pain, such as the Numeric Pain-Rating Scale, the Brief Pain Inventory, the Tampa Scale for Kinesiophobia, the Pain Catastrophizing Scale, and the Central Sensitization Inventory (CSI). Results: A total of 21 sBCs with persistent pain were recruited. We observe a general trend of close agreement between the paper-based and app-based formats (ICCs ranged between 0.802 and 0.972; Cronbach's alpha ranged between 0.797 and 0.971). Test-retest reliabilities were moderate to excellent (ICCs ranged between 0.510 and 0.941; Cronbach's alpha ranged between 0.499 and 0.938). The agreement between the categorization of the CS algorithm and the CSI (cut-off point ≥ 40 for CS symptoms) was 95.24%. Conclusion: The PaiNEd app emerges as a robust tool for evaluating pain experience predominantly related to CS and pain-related symptoms in sBCs. Its demonstrated reliability not only bolsters its utility but also signifies its potential as a valuable asset for healthcare professionals engaged in pain education programs.

Temporal relationships between pain, functioning, and human assumed central sensitization in patients with chronic low back pain; a single-case design.

BACKGROUND: Interdisciplinary pain rehabilitation (IPR) aims to improve functioning in people with chronic low back pain (CLBP), and is not primary aimed at pain reduction. Many patients however also report a decrease in pain. An explanation could be that IPR results in a decrease in Central Sensitization (CS). As CS is not directly assessable in humans the term Human Assumed Central Sensitization (HACS) is used in this study. It is unknown whether a decrease in HACS precedes a decrease in pain and improved functioning or vice versa. OBJECTIVES: This study aimed to gain understanding into the temporal relationships between changes in pain, functioning, and HACS in patients with CLBP during IPR. DESIGN: Longitudinal observational small-N-study. METHOD: Twelve patients filled in frequently repeated self-reports 1 week before, during the 12-week IPR program, and 2 weeks after IPR. Pain was assessed by Visual Analogue Scale for pain (daily), functioning by Pain Disability Index (weekly) and Work Ability Score (daily), and HACS by Central Sensitization Inventory part A (bi-weekly). Analyses were performed by visual inspection and time series cross-correlation analyses. RESULTS: Visual inspection showed large fluctuations within and between individual participants in patterns over time. Cross-correlation analyses showed that in most participants, relationships between pain, functioning, and HACS were strongest when analyzed at the same time (55% of comparisons). Strength and direction of (strongest) correlations showed high interindividual variability (neg: 0.33-0.97; pos: 0.22-0.99). CONCLUSION: Overall, relationships between pain, functioning, and HACS did not show consistent temporality in patients with CLBP.

Implication of system xc- in neuroinflammation during the onset and maintenance of neuropathic pain.

BACKGROUND: Despite the high prevalence of neuropathic pain, treating this neurological disease remains challenging, given the limited efficacy and numerous side effects associated with current therapies. The complexity in patient management is largely attributed to an incomplete understanding of the underlying pathological mechanisms. Central sensitization, that refers to the adaptation of the central nervous system to persistent inflammation and heightened excitatory transmission within pain pathways, stands as a significant contributor to persistent pain. Considering the role of the cystine/glutamate exchanger (also designated as system xc-) in modulating glutamate transmission and in supporting neuroinflammatory responses, we investigated the contribution of this exchanger in the development of neuropathic pain. METHODS: We examined the implication of system xc- by evaluating changes in the expression/activity of this exchanger in the dorsal spinal cord of mice after unilateral partial sciatic nerve ligation. In this surgical model of neuropathic pain, we also examined the consequence of the genetic suppression of system xc- (using mice lacking the system xc- specific subunit xCT) or its pharmacological manipulation (using the pharmacological inhibitor sulfasalazine) on the pain-associated behavioral responses. Finally, we assessed the glial activation and the inflammatory response in the spinal cord by measuring mRNA and protein levels of GFAP and selected M1 and M2 microglial markers. RESULTS: The sciatic nerve lesion was found to upregulate system xc- at the spinal level. The genetic deletion of xCT attenuated both the amplitude and the duration of the pain sensitization after nerve surgery, as evidenced by reduced responses to mechanical and thermal stimuli, and this was accompanied by reduced glial activation. Consistently, pharmacological inhibition of system xc- had an analgesic effect in lesioned mice. CONCLUSION: Together, these observations provide evidence for a role of system xc- in the biochemical processes underlying central sensitization. We propose that the reduced hypersensitivity observed in the transgenic mice lacking xCT or in sulfasalazine-treated mice is mediated by a reduced gliosis in the lumbar spinal cord and/or a shift in microglial M1/M2 polarization towards an anti-inflammatory phenotype in the absence of system xc-. These findings suggest that drugs targeting system xc- could contribute to prevent or reduce neuropathic pain.

Environmental enrichment alleviates hyperalgesia by modulating central sensitization in a nitroglycerin-induced chronic migraine model of mice.

BACKGROUND: Chronic migraine (CM) is a debilitating neurofunctional disorder primarily affecting females, characterized by central sensitization. Central sensitization refers to the enhanced response to sensory stimulation, which involves changes in neuronal excitability, synaptic plasticity, and neurotransmitter release. Environmental enrichment (EE) can increase the movement, exploration, socialization and other behaviors of mice. EE has shown promising effects in various neurological disorders, but its impact on CM and the underlying mechanism remains poorly understood. Therefore, the purpose of this study was to determine whether EE has the potential to serve as a cost-effective intervention strategy for CM. METHODS: A mouse CM model was successfully established by repeated administration of nitroglycerin (NTG). We selected adult female mice around 8 weeks old, exposed them to EE for 2 months, and then induced the CM model. Nociceptive threshold tests were measured using Von Frey filaments and a hot plate. The expression of c-Fos, calcitonin gene-related peptide (CGRP) and inflammatory response were measured using WB and immunofluorescence to evaluate central sensitization. RNA sequencing was used to find differentially expressed genes and signaling pathways. Finally, the expression of the target differential gene was investigated. RESULTS: Repeated administration of NTG can induce hyperalgesia in female mice and increase the expression of c-Fos and CGRP in the trigeminal nucleus caudalis (TNC). Early exposure of mice to EE reduced NTG-induced hyperalgesia in CM mice. WB and immunofluorescence revealed that EE inhibited the overexpression of c-Fos and CGRP in the TNC of CM mice and alleviated the inflammatory response of microglia activation. RNA sequencing analysis identified that several central sensitization-related signaling pathways were altered by EE. VGluT1, a key gene involved in behavior, internal stimulus response, and ion channel activity, was found to be downregulated in mice exposed to EE. CONCLUSION: EE can significantly ameliorate hyperalgesia in the NTG-induced CM model. The mechanisms may be to modulate central sensitization by reducing the expression of CGRP, attenuating the inflammatory response, and downregulating the expression of VGluT1, etc., suggesting that EE can serve as an effective preventive strategy for CM.

Phenotyping of chronic pain in breast cancer survivors: an original study using the cancer pain phenotyping (CANPPHE) Network multidisciplinary international guidelines.

PURPOSE: The primary aim of this cross-sectional study is to examine the prevalence of pain phenotypes in breast cancer survivors (BCS). A secondary aim entails examining whether health related quality of life differs between the main pain phenotypes in BCS. METHODS: BCS who experienced chronic pain were asked to complete the numeric pain rating scale for pain, Margolis pain diagram, and short form 36 (SF-36). Following administration of questionnaires and quantitative sensory examinations were applied. To determine the prevalence of the predominant type of pain, a recently proposed classification system by the Cancer Pain Phenotyping (CANPPHE) Network was used. RESULTS: Of the 86 female participants, 19 (22.09%) had dominant neuropathic pain, 18 (20.93%) had dominant nociceptive pain and 14 (16.28%) had dominant nociplastic pain. 35 participants (40.70%) were classified as having mixed pain. One-way ANOVA revealed a significant difference between the four pain groups for the SF-36 general health (F = 3.205, p = 0.027), social functioning (F = 4.093, p = 0.009), and pain (F = 3.603, p = 0.017) subscale scores. CONCLUSION: This study found that pain in BCS was mostly of mixed phenotype, followed by predominantly neuropathic and nociplastic pain. Furthermore, it was found that, compared to BCS with predominant neuropathic and nociceptive pain, BCS with predominant nociplastic pain have lower health related quality of life in the areas of bodily pain and social functioning.

Associations of pain sensitivity and conditioned pain modulation with physical activity: findings from the Multicenter Osteoarthritis Study (MOST).

OBJECTIVE: Individuals with chronic pain due to knee osteoarthritis (OA) are insufficiently physically active, and alterations of facilitatory and inhibitory nociceptive signaling are common in this population. Our objective was to examine the association of these alterations in nociceptive signaling with objective accelerometer-based measures of physical activity in a large observational cohort. DESIGN: We used data from the Multicenter Osteoarthritis Study. Measures of peripheral and central pain sensitivity included pressure pain threshold at the knee and mechanical temporal summation at the wrist, respectively. The presence of descending pain inhibition was assessed by conditioned pain modulation (CPM). Physical activity was quantitatively assessed over 7 days using a lower back-worn activity monitor. Summary metrics included steps/day, activity intensity, and sedentary time. Linear regression analyses were used to evaluate the association of pain sensitivity and the presence of descending pain inhibition with physical activity measures. RESULTS: Data from 1873 participants was analyzed (55.9% female, age = 62.8 ± 10.0 years). People having greater peripheral and central sensitivity showed lower step counts. CPM was not significantly related to any of the physical activity measures, and none of the exposures were significantly related to sedentary time. CONCLUSIONS: In this cohort, greater peripheral and central sensitivity were associated with reduced levels of objectively-assessed daily step counts. Further research may investigate ways to modify or treat heightened pain sensitivity as a means to increase physical activity in older adults with knee OA.

Beyond Pain: The Effects of OnabotulinumtoxinA Therapy on Sensitization and Interictal Symptoms in Chronic Migraine.

Chronic migraine is a disease with a high burden on patients from both a working and quality of life point of view. The pathophysiology of this subtype of migraine is due to several factors, such as medication overuse. Nevertheless, the detrimental recurring of headache attacks with central and peripheral sensitization plays a central role and explains some additional symptoms complained about by these patients even in the interictal phase. OnabotulinumtoxinA is a therapy indicated for chronic migraine since it has proven to reduce peripheral sensitization, showing even efficacy on central symptoms. The aim of this narrative review is to present the current evidence regarding the effect of OnabotulinumtoxinA on sensitization and interictal symptoms.

Evaluation of Central Sensitisation in Bladder Pain Syndrome: A Systematic Review.

INTRODUCTION AND HYPOTHESIS: Bladder pain syndrome (BPS) is a debilitating condition characterised by exaggerated bladder sensations and altered bladder function. It is still unknown whether the condition is a peripheral sensory problem or due to abnormal central sensory processing as seen in central sensitisation. This systematic review, which followed a published and Prospective Register of Systematic Reviews-registered protocol (CRD42021229962), is aimed at establishing the scope of central sensitisation in patients with BPS to aid optimal management and treatment. METHODS: Four databases were searched, and appraisal of the identified studies was conducted by two independent reviewers based on eligibility criteria: patients with BPS being investigated for central sensitisation with or without comparison of controls, English-language articles, full text and publication in a peer-reviewed journal. The Methodological Index for non-Randomised Studies was used to determine study quality. We identified 763 papers in total, with 15 studies included in the final analysis. All studies were observational and had a low risk of bias. Measures included in the evaluation of CS were questionnaires, urodynamics, and quantitative sensory testing methods. RESULTS: There was evidence of central sensitisation in patients with BPS in all papers evaluated (15 out of 15). In addition, more significant central sensitisation correlated with severe disease presentation (3 out of 3 papers) and concomitant chronic pain conditions (5 out of 5 papers). CONCLUSIONS: Central sensitisation plays an integral role in BPS patient pathology. Many secondary measures are used to evaluate this condition. Stratification of patients based on their pathology (peripheral, central or a combination of the two) will aid in implementing an individualised management strategy.

Association of pruritus and chronic cough: an all of us database study.

PURPOSE: Based on a potential shared pathophysiology tied to mast cell activity and neurogenic inflammation that may link pruritus and chronic cough (CC), this study, leveraging the All of Us database, examines the association between the two conditions. MATERIALS AND METHODS: A nested case-control comparison was used to examine the association, identifying cases with SNOMED codes 418363000 (pruritus) and 68154008 (CC). Matching was performed on a 1:4 ratio by age, sex, and ethnicity using the MatchIt package in R, followed by maximum likelihood method to estimate odds ratios (ORs) and 95% confidence intervals from 2x2 contingency tables. RESULTS: CC patients (n = 2,388) were more than twice as likely to be diagnosed with pruritus (OR: 2.65) and pruritus patients (n = 22,496) were more than twice as likely to be diagnosed with CC (OR: 2.57), than respective matched controls. CONCLUSIONS: These results highlight the potential bidirectional relationship between CC and pruritus, suggesting possible shared immune and neural pathways. Treatments like difelikefalin and nalbuphine that modulate these pathways, alongside P2X3 targeting agents, are emerging as potential therapeutic approaches for itch and chronic cough given the possible interconnected pathophysiology. This study's insights into the associations between pruritus and CC may pave the way for targeted therapeutic strategies that address their shared mechanisms.

Electroacupuncture improves allodynia and central sensitization via modulation of microglial activation associated P2X4R and inflammation in a rat model of migraine.

Background: Recent studies have demonstrated that activated microglia were involved in the pathogenesis of central sensitization characterized by cutaneous allodynia in migraine. Activation of microglia is accompanied by increased expression of its receptors and release of inflammatory mediators. Acupuncture and its developed electroacupuncture (EA) have been recommended as an alternative therapy for migraine and are widely used for relieving migraine-associated pain. However, it remains rare studies that show whether EA exerts anti-migraine effects via inhibiting microglial activation related to a release of microglial receptors and the inflammatory pathway. Therefore, this study aimed to investigate EA' ability to ameliorate central sensitization via modulation of microglial activation, microglial receptor, and inflammatory response using a rat model of migraine induced by repeated epidural chemical stimulation. Methods: In the present study, a rat model of migraine was established by epidural repeated inflammatory soup (IS) stimulation and treated with EA at Fengchi (GB20) and Yanglingquan (GB34) and acupuncture at sham-acupoints. Pain hypersensitivity was further determined by measuring the mechanical withdrawal threshold using the von-Frey filament. The changes in c-Fos and ionized calcium binding adaptor molecule 1 (Ibal-1) labeled microglia in the trigeminal nucleus caudalis (TNC) were examined by immunflurescence to assess the central sensitization and whether accompanied with microglia activation. In addition, the expression of Ibal-1, microglial purinoceptor P2X4, and its associated inflammatory signaling pathway mediators, including interleukin (IL)-1ß, NOD-like receptor protein 3 (NLRP3), and Caspase-1 in the TNC were investigated by western blot and real-time polymerase chain reaction analysis. Results: Allodynia increased of c-Fos, and activated microglia were observed after repeated IS stimulation. EA alleviated the decrease in mechanical withdrawal thresholds, reduced the activation of c-Fos and microglia labeled with Ibal-1, downregulated the level of microglial purinoceptor P2X4, and limited the inflammatory response (NLRP3/Caspase-1/IL-1ß signaling pathway) in the TNC of migraine rat model. Conclusions: Our results indicate that the anti-hyperalgesia effects of EA ameliorate central sensitization in IS-induced migraine by regulating microglial activation related to P2X4R and NLRP3/IL-1ß inflammatory pathway.

Central sensitization significantly deteriorates functionality and the interpretation of self-reported disease activity in primary Sjögren's syndrome.

BACKGROUND: Central sensitization has a major role in health-related parameters in musculoskeletal conditions. There is still a lack of understanding regarding the impact of central sensitization on the interpretation of disease activity and functional disability in primary Sjögren's syndrome (pSS). METHODS: The Central Sensitization Inventory (CSI) was used to screen for central sensitization. Disease-related parameters, including objective tests, medication use, the EULAR SS Patient Reported Index (ESSPRI), and the EULAR SS Disease Activity Index (ESSDAI), were assessed. Functionality, quality of life, sleep, and mental health were evaluated by the Health Assessment Questionnaire-Disability Index (HAQ-DI), Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), Jenkins Sleep Evaluation Scale (JSS), and Hospital Anxiety and Depression Scale (HADS), respectively. The effect of central sensitization on functionality and disease activity measures was assessed by regression analyses. RESULTS: The frequency of central sensitization was 65% in patients with pSS (n = 60). Patients with central sensitization had higher HAQ-DI, ESSPRI, HADS, and JSS and lower SF-36 subdomain scores (p < 0.05 for all). A significant positive correlation was observed between the CSI score and the ESSPRI, JSS, HAQ-DI, and HADS scores (Spearman's rho ranging from 0.342 to 0.739). The multiple regression analysis indicated that CSI was independently associated with HAQ-DI (adjusted R2 = 0.19, B = 0.01) and ESSPRI (adjusted R2 = 0.45, B = 0.08) (p < 0.001 for all). CONCLUSION: This study confirms that central sensitization has a major impact on functionality and the interpretation of self-reported disease activity in pSS. When devising strategies for the management of patients with pSS, it is crucial to consider these close relationships. Key Points • The frequency of central sensitization accompanying primary Sjögren's syndrome is considerable. • Central sensitization was independently associated with functionality and self-reported disease activity assessment. • This close association leads to challenges in functionality, evaluating treatment response, and planning or switching between therapies in primary Sjögren's syndrome.