Search

Background: This study was conducted to develop a simplified Chinese version of the central sensitization inventory (CSI-CV) and to evaluate its reliability and validity. Methods: The CSI-CV was developed through a process involving the translation and back translation of the original CSI. Subsequently, experts reviewed and revised the content of the items to ensure their appropriateness. A total of 325 patients with knee osteoarthritis (KOA), who were scheduled to undergo total knee arthroplasty (TKA), completed the CSI-CV at a prominent orthopedic center in Xi'an, China. Afterward, a random selection of 100 participants was chosen for retesting after one week. The reliability and validity of the inventory were evaluated through exploratory factor analysis, correlation coefficient calculation and other methods. Results: The CSI-CV consists of 25 items in five dimensions (emotional distress, headache and jaw symptoms, physical symptoms, urological symptoms, and fatigue and sleep problems). The cumulative variance contribution rate was 75.3%, the Cronbach's α coefficient was 0.83, the Guttman split-half reliability coefficient was 0.88 and the intraclass correlation coefficient was 0.965. The CSI-CV scores correlated moderately with the total scores of the brief pain inventory (r = 0.506), Western Ontario and McMaster Universities Osteoarthritis Index (r = 0.466) and EuroQoL Group's five-dimension questionnaire (r = 0.576). Conclusions: The findings demonstrate that the CSI was successfully trans-culturally adapted into a simplified Chinese version (CSI-CV) that was reliable and valid for Chinese-speaking patients who awaiting TKA for KOA. [ABSTRACT FROM AUTHOR]

Background: Controversy remains regarding predictors of surgical outcomes for patients with lumbar spinal stenosis (LSS). Pain sensitization may be an underlying mechanism contributing to LSS surgical outcomes. Further, obesity is associated with dissatisfaction and poorer outcomes after surgery for LSS. Therefore, this study aimed to examine the relationship between central sensitization (CS), visceral fat, and surgical outcomes in LSS. Methods: Patients with LSS were categorized based on their central sensitization inventory (CSI) scores into low- (CSI < 40) and high- (CSI ≥ 40) CSI subgroups. The participants completed clinical outcome assessments preoperatively and 12 months postoperatively. Results: Overall, 60 patients were enrolled in the study (28 men, 32 women; mean age: 62.1 ± 2.8 years). The high-CSI group had significantly higher mean low back pain (LBP), leg pain, and leg numbness visual analogue scale (VAS) scores than the low-CSI group (p < 0.01). The high-CSI group had a significantly higher mean visceral fat area than the low-CSI group (p < 0.01). Postoperatively, LBP VAS score was significantly worse in the high-CSI group. Relative to preoperatively, postoperative leg pain and leg numbness improved significantly in both groups. Conclusions: We believe that neuro decompression can be effective for LSS surgical outcomes in patients with CS; nonetheless, it should be approached with caution owing to the potential for worsening LBP. Additionally, visceral fat is an important indicator suggesting the involvement of CS. [ABSTRACT FROM AUTHOR]

Background: Central sensitization (CS) is becoming increasingly recognized as a significant factor in many chronic pain conditions, including knee osteoarthritis (KOA) and chronic low back pain (CLBP). Yet it presently remains unclear how strong is the involvement of CS in KOA and CLBP and which factors are involved in CS in these two chronic disabling diseases. Methods: This is a cross-sectional study in which included a total of 178 patients with KOA and 118 patients with CLBP. Inclusion criteria for eligible participants for the KOA group were a confirmed diagnosis of KOA according to the American College of Rheumatology criteria, and for the CLBP group a chronic low back pain for more than 3 months. Subjects were excluded if they presented with a diagnosed psychiatric disorder or if they lacked the capacity to provide informed consent, understand study questionnaires or perform physical performance tests. In each group, were assessed; CS-related symptoms using the Central Sentization Inventory (CSI); demographic and clinical characteristics such as disease duration, pain intensity on a visual analog scale, self-reported function using the Lequesne index for KOA patients and the Oswestry Disability index for CLBP patients, and physical performance with the 6 minutes' walk test; as well as psychosocial risk factors using the Patient Health Questionnaire for depression (PHQ-9), the Generalized Anxiety Disorder (GAD-7) and the Pain Catastrophizing Scale (PCS). Results: CSI scores significantly correlated with pain intensity and disability in KOA and CLBP patients, and were highly correlated with self-reported symptoms of depression, anxiety and pain catastrophizing. Depression significantly predicted the CSI score in both groups. Conclusion: These findings provide further evidence for the impact of CS on pain, function and physical performance in KOA and CLBP patients. Psychosocial symptoms such as pain catastrophizing, anxiety and depression should also be considered as they are also associated with CS. [ABSTRACT FROM AUTHOR]

Objective: To investigate the brain structural correlates of postoperative axial pain (PAP) in degenerative cervical myelopathy (DCM) following posterior cervical decompression surgery. Methods: Structural images with high-resolution T1 weighting were collected from 62 patients with DCM and analyzed, in addition to 42 age/gender matched subjects who were healthy. Voxel-based morphometry (VBM) was analyzed, grey matter volume (GMV) was computed. One-way ANOVA was performed to reveal the GMV differences among DCM patients with PAP, patients without PAP and healthy controls (HC). Post-hoc analyses were conducted to identify the pair-wise GMV differences among these three groups. Analyses of correlations were conducted to uncover the link between clinical measurements and GMV variations. Last, support vector machine (SVM) was conducted to test the utility of GMV for classifying PAP and nPAP DCM patients. Results: Three main findings were observed: [1] Compared to healthy controls, DCM patients showed a significantly lower GMV in the precuneus preoperatively. DCM patients with PAP also exhibited a lower GMV within precuneus than those without; [2] In DCM patients with PAP, the precuneus GMV was inversely related to the postoperative pain intensity; [3] Moreover, successful classification between PAP and nPAP were observed via SVM based on precuneus GMV as features. Conclusion: In summary, our results indicate that precuneus GMV may be linked to PAP in DCM, and could be employed to forecast the emergence of PAP in DCM patients. [ABSTRACT FROM AUTHOR]

Background: Central sensitization is a condition in which even mild stimuli cause pain due to increased neuronal reactivity in the dorsal horn of the spinal cord. It is one of factors of chronic pain in patients with osteoarthritis. However, it is unknown whether central sensitization relates to clinical outcomes after total hip arthroplasty (THA). This study aimed to clarify whether preoperative central sensitization relates to the forgotten joint score-12 (FJS) after THA. Moreover, the secondary outcome was to identify which items in the FJS were most related by central sensitization. Methods: This retrospective analysis included 263 hips (263 patients; 51 males and 212 females) that underwent primary THA in our institute and were available for evaluation one year postoperatively. The average patient age was 64.8 ± 11.9 years. The Central Sensitization Inventory (CSI) part A, which is a patient-reported outcome, was used to measure preoperative central sensitization. The correlation between preoperative CSI and postoperative FJS and the association between postoperative FJS and preoperative CSI severity were determined. Moreover, difference in each FJS item was evaluated by CSI severity. Results: Twenty-six patients (9.9%) had central sensitization preoperatively. Preoperative CSI scores and postoperative FJS were negatively correlated (r = − 0.331, p < 0.0001). The postoperative FJS was significantly lower in patients with moderate or higher preoperative CSI severity than that in patients with subclinical or mild preoperative CSI severity (p < 0.05). FJS items with movement of daily life were significantly worse in the moderate or higher CSI severity compared with subclinical group (p < 0.05 or p < 0.01). Conclusion: Central sensitization prior to THA negatively related to postoperative FJS. In particular, the relationship of central sensitization was found to be significant in FJS items with movement, which would lead to lower patient satisfaction after THA. To get better postoperative outcomes in patients with preoperative central sensitization, improving central sensitization would be important. [ABSTRACT FROM AUTHOR]

Patients suffering from connective tissue disorders like Ehlers–Danlos syndrome hypermobility type/joint hypermobility syndrome (EDS-HT/JHS) may be affected by craniocervical instability (CCI). These patients experience myalgic encephalomyelitis, chronic fatigue, depression, extreme occipital-cervical pain, and severe widespread pain that is difficult to relieve with opioids. This complex and painful condition can be explained by the development of chronic neuroinflammation, opioid-induced hyperalgesia, and central sensitization. Given the challenges in treating such severe physical pain, we evaluated all the analgesic methods previously used in the perioperative setting, and updated information was presented. It covers important physiopathological aspects for the perioperative care of patients with EDS-HT/JHS and CCI undergoing occipital-cervical/thoracic fixation/fusion. Moreover, a change of paradigm from the current opioid-based management of anesthesia/analgesia in these patients to the perioperative opioid minimization strategies used by the authors was analyzed and proposed as follow-up considerations from our previous case series. These strategies are based on total-intravenous opioid-free anesthesia, multimodal analgesia, and a postoperative combination of anti-hyperalgesic coadjuvants (lidocaine, ketamine, and dexmedetomidine) with an opioid-sparing effect.Key points: Chronic neuroinflammation, neuronal damage and central sensitization are common pathways that cause severe widespread pain in patients with Ehlers–Danlos syndrome hypermobility type/joint hypermobility syndrome (EDS-HT/JHS) and craniocervical instability. The use of opioid-free anesthesia with propofol, ketamine, lidocaine, and dexmedetomidine is feasible in patients with EDS-HT/JHS who are to undergo occipital/cervical fixation, and the support of a service specialized in postoperative acute pain is essential for the viability of this management. Opioid-free anesthesia plus perioperative opioid-minimization management may reduce the postoperative pain in patients with EDS-HT/JHS that undergo occipital/cervical/thoracic fixation. Postoperative infusions of anti-hyperalgesic coadjuvants (lidocaine, ketamine, and dexmedetomidine) along with multimodal analgesia provide a significant opioid-sparing effect. However, more studies are needed to justify their use for more than 72 h in this type of patient. The perioperative opioid-minimization approach is a reasonable option for patients with EDS-HT/JHS suffering from gastrointestinal dysfunction, opioid-induced hyperalgesia, central sensitization and severe widespread pain. In the context of the perioperative opioid-minimization approach, methadone is the most suitable opioid for use as a rescue analgesic for severe pain owing to its anti-NMDA effect and its effect of reducing the reuptake of serotonin and norepinephrine. [ABSTRACT FROM AUTHOR]

One-fourth to one-third of women with endometriosis receiving first-line hormonal treatment lacks an adequate response in terms of resolution of painful symptoms. This phenomenon has been ascribed to "progesterone resistance", an entity that was theorized to explain the gap between the ubiquity of retrograde menstruation and the 10% prevalence of endometriosis among women of reproductive age. Nevertheless, the hypothesis of progesterone resistance is not free of controversies. As our understanding of endometriosis is increasing, authors are starting to set aside the traditionally accepted tunnel vision of endometriosis as a strictly pelvic disease, opening to a more comprehensive perspective of the condition. The question is: are patients not responding to first-line treatment because they have an altered signaling pathway for such treatment, or have we been overlooking a series of other pain contributors which may not be resolved by hormonal therapy? Finding an answer to this question is evermore impelling, for two reasons mainly. Firstly, because not recognizing the presence of further pain contributors adds a delay in treatment to the already existing delay in diagnosis of endometriosis. This may lead to chronicity of the untreated pain contributors as well as causing adverse consequences on quality of life and psychological health. Secondly, misinterpreting the consequences of untreated pain contributors as a non-response to standard first-line treatment may imply the adoption of second-line medical therapies or of surgery, which may entail non-negligible side effects and may not be free of physical, psychological and socioeconomic repercussions. The current narrative review aims at providing an overview of all the possible pain contributors in endometriosis, ranging from those strictly organic to those with a greater neuro-psychological component. Including these aspects in a broader psychobiological approach may provide useful suggestions for treating those patients who report persistent pain symptoms despite receiving first-line hormonal medical treatment. [ABSTRACT FROM AUTHOR]

Background: Pain is a major symptom in adolescents with hypermobility spectrum disorder or hypermobile Ehlers-Danlos syndrome. Although the underlying mechanism causing generalized pain in children with hypermobility spectrum disorder or hypermobile Ehlers-Danlos syndrome is unclear, central sensitization has been suggested as a possible explanation. The aim of this study was to explore the feasibility of a study protocol for a future case–control study, investigating features of central sensitization in adolescents with hypermobility spectrum disorder or hypermobile Ehlers-Danlos syndrome. Methods: Central sensitization features were measured in ten patients and nine healthy controls aged 13–17 years via experimental pain measurement quantifying primary and secondary hyperalgesia, endogenous pain modulation, and exercise-induced hyperalgesia. Descriptive statistics were used. Frequency, median, and range values were calculated. Results: Eleven out of 57 patients chose to participate. No control could be recruited through public schools. Therefore, a convenience sampling strategy was used for the recruitment of the control group. The process of assessing primary and secondary hyperalgesia, endogenous pain modulation, and exercise-induced hyperalgesia was well tolerated by all participants (patients and controls). When assessing endogenous pain modulation via conditioned pain modulation, two participants in the patient group and three in the control group did not achieve a pain experience ≥ 3 on the numerical rating scale when immersing their hands in cold water. Conclusion: This study investigated the feasibility, safety, and toleration of experimental pain measurements in adolescents with hypermobility spectrum disorder or hypermobile Ehlers-Danlos syndrome. Although the test protocol proved to be sufficiently feasible for use with the participant group, it will need to be adapted in the main study in order to obtain more reliable data. Recruitment, especially of participants for the control group, can be a major obstacle for future studies and requires careful planning. Trial registration: Researchweb.org, 270,501. Registered on 9 May 2019. [ABSTRACT FROM AUTHOR]

Background: The pathoanatomic cause of chronic low back pain (cLBP) cannot be identified for up to 90% of individuals. However, dysfunctional processing of endogenous nociceptive input, measured as conditioned pain modulation (CPM), has been associated with cLBP and may involve changes in neuronal gene expression. Epigenetic-induced changes such as DNA methylation (DNAm) have been associated with cLBP. Methods: In the present study, the relationship between CPM and DNAm changes in a sample of community-dwelling adults with nonspecific cLBP (n = 48) and pain-free controls (PFC; n = 50) was examined using reduced representation bisulfite sequencing. Gene ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied to identify key pathways involved in efficient versus deficient CPM. Results: Based on CPM efficiency, we identified 6006 and 18,305 differentially methylated CpG sites (DMCs) with q values < 0.01 among individuals with cLBP and PFCs, respectively. Most of the DMCs were hypomethylated and annotated to genes of relevance to pain, including OPRM1, ADRB2, CACNA2D3, GNA12, LPL, NAXD, and ASPHD1. In both cLBP and PFC groups, the DMCs annotated genes enriched many GO terms relevant to pain processing, including transcription regulation by RNA polymerase II, nervous system development, generation of neurons, neuron differentiation, and neurogenesis. Both groups also enriched the pathways involved in Rap1-signaling, cancer, and dopaminergic neurogenesis. However, MAPK-Ras signaling pathways were enriched in the cLBP, not the PFC group. Conclusions: This is the first study to investigate the genome-scale DNA methylation profiles of CPM phenotype in adults with cLBP and PFCs. Based on CPM efficiency, fewer DMC enrichment pathways were unique to the cLBP than the PFCs group. Our results suggest that epigenetically induced modification of neuronal development/differentiation pathways may affect CPM efficiency, suggesting novel potential therapeutic targets for central sensitization. However, CPM efficiency and the experience of nonspecific cLBP may be independent. Further mechanistic studies are required to confirm the relationship between CPM, central sensitization, and nonspecific cLBP. [ABSTRACT FROM AUTHOR]

Background: Cranial autonomic symptoms (CASs) during migraine attacks are reported to be quite common regardless of ethnicity. In our previous study investigating 373 migraineurs, we found that 42.4% of them had CASs. The patients with CASs more frequently had cutaneous allodynia than did those without CASs, and we speculated that CASs were associated with central sensitization. The present study searched for substantial evidence on the relationship between CASs and central sensitization in migraine patients.Methods: This was a prospective cross-sectional study. We studied a new independent cohort of 164 migraineurs who presented to the Tominaga Hospital Headache Center from July 2018 until December 2019. The clinical features of CASs according to the criteria in ICHD-3 (beta) were investigated. We also evaluated central sensitization based on the 25 health-related symptoms utilizing the validated central sensitization inventory (CSI), and each symptom was rated from 0 to 4 resulting a total score of 0-100.Results: The mean age was 41.8 (range: 20 to 77) years old. One hundred and thirty-one patients (78.9%) were women. Eighty-six of the 164 (52.4%) patients had at least 1 cranial autonomic symptom. The CSI score of the patients with ≥3 CASs reflected a moderate severity and was significantly higher than in those without CASs (41.9 vs. 30.7, p = 0.0005). The score of the patients with ≥1 conspicuous CAS also reflected a moderate severity and was significantly higher than in those without CASs (40.7 vs. 33.2, p = 0.013). The patients in the CSI ≥40 group had lacrimation, aural fullness, nasal blockage, and rhinorrhea, which are cranial autonomic parasympathetic symptoms, significantly more frequently than those in the CSI < 40 group.Conclusions: Migraine patients with CASs showed significantly greater central sensitization than those without such symptoms. In particular, cranial parasympathetic symptoms were more frequent in centrally sensitized patients than in nonsensitized patients, suggesting that cranial parasympathetic activation may contribute to the maintenance of central sensitization.Trial Registration: This study was retrospectively registered with UMIN-CTR on 29 Aug 2020 ( UMIN000041603 ). [ABSTRACT FROM AUTHOR]

Background: Persistent postural-perceptual dizziness (PPPD) is a chronic functional dizziness symptom triggered by psychological stress, but its pathophysiology is unknown. Central sensitization is considered the cause of functional diseases, such as medically unexplained symptoms, and is a psychosocially affected condition. However, the association between dizziness symptoms in PPPD and central sensitization remains unclear. Thus, we conducted a cross-sectional study on the relation between dizziness symptoms and central sensitization in PPPD. Methods: We recruited 61 outpatients with dizziness who met the PPPD diagnostic criteria. In addition to the evaluation of dizziness symptoms using the Dizziness Handicap Inventory, the participants were evaluated using the Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index, and Central Sensitization Inventory (CSI). A CSI score of 40 or higher was defined as central sensitization syndrome (CSS), and the severity of each condition in CSS and non-CSS participants was compared. We also evaluated the association between dizziness symptoms and central sensitization and coexisting symptoms using linear multiple regression analysis. Results: We analyzed the data of 50 valid responses (valid response rate of 82.0 percent). Compared with the non-CSS group, the CSS group had a higher degree of disability owing to dizziness and a higher rate of complications of anxiety and depression. The regression analysis results showed that the severity of central sensitization was a related factor that could enhance the dizziness symptoms of PPPD. Conclusions: Central sensitization may affect the dizziness symptoms of PPPD as an exacerbating factor. [ABSTRACT FROM AUTHOR]

Background: Central sensitization is an amplification of neuronal signaling within the central nervous system. The Central Sensitization Inventory was introduced in 2012. A Polish version of the CSI (CSI-Pol) was developed in 2019, but it was not psychometrically validated. The aim of this study was to validate the CSI-Pol in a sample of Polish-speaking patients with chronic spinal pain and compare them with a group of healthy control subjects.Methods: The CSI-Pol was administered to 151 patients with chronic spinal pain recruited from two centers. It was re-administered 7 days later. The psychometric properties were then evaluated, including test-retest reliability, construct validity, factor structure and internal consistency. We correlated the CSI-Pol with functional scales, depression and social support scales and compared CSI-Pol scores in the clinical subjects with 30 healthy control subjects recruited from medical staff and their families.Results: The CSI-Pol demonstrated excellent internal consistency (Cronbach's α =0,933) and test-retest reliability (Intraclass Correlation Coefficients - ICC =0.96), as well as significant positive associations with other patient-reported scales, including the Neck Disability Index (r = 0.593), Revised Oswestry Low Back Pain Disability Questionnaire (r = 0.422), and other measures of functional and depressive states. An exploratory factor analysis resulted in a 4-factor model. CSI-Pol scores in the clinical sample (35.27 ± 17.25) were significantly higher than the control sample (23.3 ± 8.9).Conclusion: The results of this study suggest that the CSI-Pol may be a useful clinical tool for assessing central sensitization related symptoms and guiding appropriate treatment in Polish-speaking patients with spinal pain. [ABSTRACT FROM AUTHOR]

Background: Previous studies have confirmed that the microglial activation and subsequent inflammatory responses in the trigeminal nucleus caudalis (TNC) are involved in the central sensitization of chronic migraine (CM). MicroRNA-155-5p has been shown to modulate the polarization of microglia and participate in inflammatory processes in a variety of neurological diseases. However, its role in CM remains unclear. The purpose of this study was to determine the precise role of miR-155-5p in CM.Methods: A model of CM in C57BL/6 mice was established by recurrent intraperitoneal injection of nitroglycerin (NTG). Mechanical and thermal hyperalgesia were evaluated by Von Frey filaments and radiant heat. The expression of miR-155-5p was examined by qRT-PCR, and the mRNA and protein levels of silent information regulator 1(SIRT1) were measured by qRT-PCR, Western blotting (WB) and immunofluorescence (IF) analysis. The miR-155-5p antagomir, miR-155-5p agomir, SRT1720 (a SIRT1 activator) and EX527 (a SIRT1 inhibitor) were administered to confirm the effects of miR-155-5p and SIRT1 on neuroinflammation and the central sensitization of CM. ELISA, WB and IF assays were applied to evaluate the expression of TNF-α, myeloperoxidase (MPO), IL-10, p-ERK, p-CREB, calcitonin gene-related peptide (CGRP), c-Fos and microglial activation. The cellular localization of SIRT1 was illustrated by IF.Results: After the NTG-induced mouse model of CM was established, the expression of miR-155-5p was increased. The level of SIRT1 was decreased, and partly colocalized with Iba1 in the TNC. The miR-155-5p antagomir and SRT1720 downregulated the expression of p-ERK, p-CREB, CGRP, and c-Fos, alleviating microglial activation and decreasing inflammatory substances (TNF-α, MPO). The administration of miR-155-5p agomir or EX527 exacerbated neuroinflammation and central sensitization. Importantly, the miR-155-5p agomir elevated CGRP and c-Fos expression and microglial activation, which could subsequently be alleviated by SRT1720.Conclusions: These data demonstrate that upregulated miR-155-5p in the TNC participates in the central sensitization of CM. Inhibiting miR-155-5p alleviates neuroinflammation by activating SIRT1 in the TNC of CM mice. [ABSTRACT FROM AUTHOR]

Background: Cough hypersensitivity is a major characteristic feature associated with several types of cough, including chronic cough, but its underlying mechanisms remain to be fully understood. Inflammatory mediators, such as prostaglandin E2 (PGE2), have been implicated in both peripheral induction and sensitization of the cough reflex. In this study, using a conscious guinea pig model of cough, we investigated whether PGE2 can sensitize the cough reflex via central actions and, if so, via which mechanisms.Methods: All drugs were administered by intracerebroventricular (i.c.v.) route and whole-body plethysmograph set-up was used for both induction, using aerosolized citric acid (0.2 M), and recording of cough. Immunohistochemistry was performed to confirm the expression of NaV 1.8 channels in the nucleus tractus solitarius (nTS).Results: We show that both PGE2 and the non-selective EP1/EP3 agonist, sulprostone, dose-dependently enhanced the citric acid-induced cough (P ≤ 0.001, P ≤ 0.01, respectively). Pretreatment with the EP1 antagonist, ONO-8130, did not affect the sulprostone-induced cough sensitization, whilst the EP3 antagonist, L-798,106, dose-dependently inhibited this effect (P ≤ 0.05). Furthermore, treatment with either the EP2 agonist, butaprost or the EP4 agonist, L-902,688, had no effect on cough sensitization. Additionally, pretreatment with either the TRPV1 antagonist, JNJ-17203212 or the TRPA1 antagonist, HC-030031, alone or in combination, nor with the NaV 1.1, 1.2, 1.3, 1.4, 1.6 and 1.7 channel blocker, tetrodotoxin, had any effect on the cough. In contrast, pretreatment with the NaV 1.8 antagonist, A-803467, dose-dependently inhibited this effect (P ≤ 0.05). Furthermore, NaV 1.8 channels were shown to be expressed in the nTS.Conclusion: Collectively, our findings show that PGE2 sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 but independently of TRPV1,TRPA1 and TTX-sensitive sodium channel activation. These results indicate that PGE2 plays an important role in central sensitization of the cough reflex and suggest that central EP3 receptors and/or NaVv 1.8 channels may represent novel antitussive molecular targets. [ABSTRACT FROM AUTHOR]

Introduction: Central sensitization (CS) may explain the persistence of symptoms in patients with chronic pain and persistent physical symptoms (PPS). There is a need for assessing CS in the consultation room. In a recently published systematic review, we made an inventory of tests for CS. In this study we aimed to assess which tests might have added value, might be feasible and thus be suitable for use in general practice. Methods: We conducted a Delphi study consisting of two e-mail rounds to reach consensus among experts in chronic pain and PPS. We invited 40 national and international experts on chronic pain and PPS, 27 agreed to participate. We selected 12 tests from our systematic review and additional searches; panellists added three more tests in the first round. We asked the panellists, both clinicians and researchers, to rate these 15 tests on technical feasibility for use in general practice, added value and to provide an overall judgement for suitability in general practice. Results: In two rounds the panellists reached consensus on 14 of the 15 tests: three were included, eleven excluded. Included were the Central Sensitization Inventory (CSI), pressure pain thresholds (PPTs) and monofilaments. No consensus was reached on the Sensory Hypersensitivity Scale. Conclusion: In a Delphi study among an international panel of experts, three tests for measuring CS were considered to be suitable for use in general practice: the Central Sensitization Inventory (CSI), pressure pain thresholds (PPTs) and monofilaments. [ABSTRACT FROM AUTHOR]

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., (© 2024. The Author(s).)

Background: Migraine stands as a prevalent primary headache disorder, with prior research highlighting the significant involvement of oxidative stress and inflammatory pathways in its pathogenesis and chronicity. Existing evidence indicates the capacity of Dl-3-n-butylphthalide (NBP) to mitigate oxidative stress and inflammation, thereby conferring neuroprotective benefits in many central nervous system diseases. However, the specific therapeutic implications of NBP in the context of migraine remain to be elucidated., Methods: We established a C57BL/6 mouse model of chronic migraine (CM) using recurrent intraperitoneal injections of nitroglycerin (NTG, 10 mg/kg), and prophylactic treatment was simulated by administering NBP (30 mg/kg, 60 mg/kg, 120 mg/kg) by gavage prior to each NTG injection. Mechanical threshold was assessed using von Frey fibers, and photophobia and anxious behaviours were assessed using a light/dark box and elevated plus maze. Expression of c-Fos, calcitonin gene-related peptide (CGRP), Nucleus factor erythroid 2-related factor 2 (Nrf2) and related pathway proteins in the spinal trigeminal nucleus caudalis (SP5C) were detected by Western blotting (WB) or immunofluorescence (IF). The expression of IL-1β, IL-6, TNF-α, Superoxide dismutase (SOD) and malondialdehyde (MDA) in SP5C and CGRP in plasma were detected by ELISA. A reactive oxygen species (ROS) probe was used to detect the expression of ROS in the SP5C., Results: At the end of the modelling period, chronic migraine mice showed significantly reduced mechanical nociceptive thresholds, as well as photophobic and anxious behaviours. Pretreatment with NBP attenuated nociceptive sensitization, photophobia, and anxiety in the model mice, reduced expression levels of c-Fos and CGRP in the SP5C and activated Nrf2 and its downstream proteins HO-1 and NQO-1. By measuring the associated cytokines, we also found that NBP reduced levels of oxidative stress and inflammation. Most importantly, the therapeutic effect of NBP was significantly reduced after the administration of ML385 to inhibit Nrf2., Conclusions: Our data suggest that NBP may alleviate migraine by activating the Nrf2 pathway to reduce oxidative stress and inflammation in migraine mouse models, confirming that it may be a potential drug for the treatment of migraine., (© 2024. The Author(s).)

Introduction: Little is known about the underlying biomechanical cause of low back pain (LBP). Recently, technological advances have made it possible to quantify biomechanical and neurophysiological measurements, potentially relevant factors in understanding LBP etiology. However, few studies have explored the relation between these factors. This study aims to quantify the correlation between biomechanical and neurophysiological outcomes in non-specific LBP and examine whether these correlations differ when considered regionally vs. segmentally. Methods: This is a secondary cross-sectional analysis of 132 participants with persistent non-specific LBP. Biomechanical data included spinal stiffness (global stiffness) measured by a rolling indenter. Neurophysiological data included pain sensitivity (pressure pain threshold and heat pain threshold) measured by a pressure algometer and a thermode. Correlations were tested using Pearson's product-moment correlation or Spearman's rank correlation as appropriate. The association between these outcomes and the segmental level was tested using ANOVA with post-hoc Tukey corrected comparisons. Results: A moderate positive correlation was found between spinal stiffness and pressure pain threshold, i.e., high degrees of stiffness were associated with high pressure pain thresholds. The correlation between spinal stiffness and heat pain threshold was poor and not statistically significant. Aside from a statistically significant minor association between the lower and the upper lumbar segments and stiffness, no other segmental relation was shown. Conclusions: The moderate correlation between spinal stiffness and mechanical pain sensitivity was the opposite of expected, meaning higher degrees of stiffness was associated with higher pressure pain thresholds. No clinically relevant segmental association existed. [ABSTRACT FROM AUTHOR]

Background: The Central Sensitization Inventory (CSI) is a screening tool designed to detect symptoms related to Central Sensitization (CS) and Central Sensitivity Syndromes (CSS) by measuring the degree of related phenomena. The objective of this study was to create a German, culturally-adapted version of the CSI and to test its psychometric properties.Methods: A German version of the CSI (CSI-GE) was developed, culturally-adapted, and pretested for comprehensibility. The psychometric properties of the resulting version were validated in a clinical study with chronic pain and pain-free control subjects. To assess retest reliability, the CSI-GE was administered twice to a subgroup of patients. Structural validity was tested using factor analyses. To investigate construct validity a hypotheses testing approach was used, including (1) correlations between the CSI-GE and several other well-established questionnaires as well as (2) an investigation of the CSI-GE discriminative power between different subgroups of participants believed to have different degrees of CS.Results: The CSI-GE showed excellent reliability, including high test-retest characteristics. Factor analyses confirmed a bi-factor dimensionality as has been determined previously. Analysing construct validity 6 out of 11 hypotheses (55%) were met. CSI-GE scores differentiated between subgroups according to expectations. Correlations between CSI-GE scores and other questionnaires suggested that none of the correlated constructs was identical, but there was overlap with other questionnaires based on symptom load. Several correlations did not fit with our current understanding of CS.Conclusion: The CSI-GE appears to be a reliable tool for measuring CS/CSS-related symptomatology. Whether this implies that the CSI-GE measures the degree of CS within an individual subject remains unknown. The resulting score should be interpreted cautiously until further clarification of the construct. [ABSTRACT FROM AUTHOR]

Background: Central Sensitization (CS) involves dysfunction in neurophysiological mechanisms that increase neuronal responses to both noxious and non-noxious stimuli in the central nervous system. The Central Sensitization Inventory (CSI) is considered the leading patient-reported outcome measure for assessing CS-related symptoms. The aim of this study was to translate and cross-culturally adapt the CSI into Finnish (CSI-FI) and to evaluate its psychometric properties.Methods: Translation and cross-cultural validation of the CSI was conducted according to established guidelines. The validation sample was 229 subjects, including 42 pain free controls and 187 subjects with chronic musculoskeletal pain. The CSI-FI was evaluated for internal consistency, test-retest reliability, exploratory factor analysis with maximum likelihood extraction, relationship with subject-reported outcome measures [Tampa scale of kinesiophobia (TSK), the Depression scale (DEPS), 5-level EQ-5D version (EQ-5 L-5D), Roland-Morris Disability Questionnaire (RMDQ), and Pain and Sleep Questionnaire Three-Item Index (PSQ-3)], pain history, subjective symptoms of dizziness, and CS-related diagnoses on CSI part B. Furthermore, we studied the ability of the CSI-FI to distinguish pain free controls, subjects with chronic pain in a single body area, and subjects with multisite chronic pain. In addition, we studied the relationship of CSI-FI scores with postural control on a force plate.Results: The CSI-FI demonstrated good internal consistency (0.884) and excellent test-retest reliability (0.933) with a 7 ± 1 day gap between test administrations. Exploratory factor analysis with maximum likelihood extraction yielded a one factor solution. Fair to good correlations were found between the CSI-FI and the TSK, DEPS, EQ-5 L-5D, RMDQ, and PSQ-3. Subjective symptoms of dizziness correlated better with CSI-FI scores than any of the CS-related diagnoses on CSI part B. Total CSI-FI scores successfully distinguished between pain free controls, subjects with chronic pain in a single body area, and subjects with multisite chronic pain. The multisite pain group reported significantly more dizziness symptoms than the other two groups. Force plate measurements showed no relationship between postural control and CSI-FI scores.Conclusion: The CSI-FI translation was successfully cross-culturally adapted and validated into Finnish. CSI-FI psychometric properties and scores were all in acceptable levels and in line with previous CSI validations. The CSI-FI appears to be a valid and reliable instrument for assessing CS-related symptomology in Finnish-speaking populations. [ABSTRACT FROM AUTHOR]

Background: Postoperative residual knee pain after total knee arthroplasty (TKA) is a significant factor that contributes to patient dissatisfaction. Patients with preoperative central sensitization (CS) may be more susceptible to unexplained chronic pain after TKA, and duloxetine has been reported to be effective in post-TKA pain control in patients with CS. However, there remains limited evidence to support this off-label use in routine clinical practice. Hence, we designed this randomized, placebo-controlled, triple-blind clinical trial to evaluate the effects of preoperative screening and targeted duloxetine treatment of CS on postoperative residual pain compared with the care-as-usual control group.Methods: This randomized controlled trial includes patients with knee osteoarthritis on a waiting list for primary unilateral TKA. Patients with preoperative CS will be randomly allocated to the perioperative duloxetine treatment group (duloxetine group) or the care-as-usual control group (placebo group). Patients in the duloxetine group will receive a half-dose of preemptive duloxetine (30 mg/day) for a week before surgery and a full-dose of duloxetine (60 mg/day) for six weeks after surgery. The primary outcome is the intensity of residual pain at six months after TKA, including the visual analogue scale, 11-point numeric rating scale, the sensory dimension of the brief pain inventory, and the pain subscale of the Knee injury and Osteoarthritis Outcome Score. The secondary outcome measures will include the pain and function related outcomes. All of the patients will be followed up at one, three, and six months after surgery. All adverse events will be recorded and immediately reported to the primary investigator and ethics committee to decide if the patient needs to drop out from the trial.Discussion: This clinical trial will convey the latest evidence of the efficacy and safety of the application of duloxetine in postoperative pain control in CS patients who are scheduled for TKA. The study results will be disseminated at national and international conferences and published in peer-reviewed journals.Trial Registration: Chinese Clinical Trial Registry ( http://www.chictr.org.cn ) registration number: ChiCTR2000031674 . Registered 07 April 2020. [ABSTRACT FROM AUTHOR]

Background: Central sensitization is an important pathophysiological mechanism of chronic migraine (CM). According to our previous studies, microglial activation and subsequent inflammation in the trigeminal nucleus caudalis (TNC) contribute to the central sensitization. The P2X7 receptor (P2X7R) is a purinergic receptor expressed in microglia and participates in central sensitization in chronic pain, but its role in CM is unclear. Numerous studies have shown that P2X7R regulates the level of autophagy and that autophagy affects the microglial activation and inflammation. Recently, autophagy has been shown to be involved in neuropathic pain, but there is no information about autophagy in CM. Therefore, the current study investigated the role of P2X7R in CM and its underlying mechanism, focusing on autophagy regulation.Methods: The CM model was established by repeated intraperitoneal injection of nitroglycerin (NTG) in mice. A Von Frey filament and radiant heat were used to assess the mechanical and thermal hypersensitivity. Western blotting and immunofluorescence assays were performed to detect the expression of P2X7R, autophagy-related proteins, and the cellular localization of P2X7R. To determine the role of P2X7R and autophagy in CM, we detected the effects of the autophagy inducer, rapamycin (RAPA) and P2X7R antagonist, Brilliant Blue G (BBG), on pain behavior and the expression of calcitonin gene-related peptide (CGRP) and c-fos. In addition, the effect of RAPA and BBG on microglial activation and subsequent inflammation were investigated.Results: The expression of P2X7R was increased and was mainly colocalized with microglia in the TNC following recurrent NTG administration. The autophagic flux was blocked in CM, which was characterized by upregulated LC3-II, and accumulated autophagy substrate protein, p62. RAPA significantly improved the basal rather than acute hyperalgesia. BBG alleviated both basal and acute hyperalgesia. BBG activated the level of autophagic flux. RAPA and BBG inhibited the activation of microglia, limited the inflammatory response, and reduced the expression of CGRP and c-fos.Conclusions: Our results demonstrate the dysfunction of the autophagic process in CM. Activated autophagy may have a preventive effect on migraine chronification. P2X7R contributes to central sensitization through mediating autophagy regulation and might become a potential target for CM. [ABSTRACT FROM AUTHOR]

Background: Energy metabolism disorders and neurogenic inflammation play important roles in the central sensitization to chronic migraine (CM). AMP-activated protein kinase (AMPK) is an intracellular energy sensor, and its activation regulates inflammation and reduces neuropathic pain. However, studies on the involvement of AMPK in the regulation of CM are currently lacking. Therefore, this study aimed to explore the mechanism underlying the involvement of AMPK in the central sensitization to CM., Methods: Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC). Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured. The expression of calcitonin gene-related peptide (CGRP) and cytokines, M1/M2 microglia, and NF-κB pathway activation were detected after the intervention., Results: Repeated NTG injections resulted in a gradual decrease in AMPK protein expression, and the negative regulation of AMPK by increased ubiquitin-like plant homeodomain and RING finger domain 1 (UHRF1) expression may counteract AMPK activation by increasing ADP/ATP. AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1β, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10. Moreover, AMPK in TNC was mainly located in microglia. AICAR could reduce the expression of inducible NO synthase (iNOS) in M1 microglia and increase the expression of Arginase 1 (Arg1) in M2 microglia by inhibiting the activation of NF-κB pathway., Conclusions: AMPK was involved in the central sensitization of CM, and the activation of AMPK reduced neuroinflammation in NTG-induced CM mice. AMPK may provide new insights into interventions for energy metabolism disorders and neurogenic inflammation in migraine., (© 2024. The Author(s).)

Background: Neuroinflammation, mediated by the activation of microglia, contributes to central sensitization, which is associated with the development of chronic migraine (CM). TREM1 receptors amplify the inflammatory response. However, their relationship to CM is unclear. Thus, this study endeavoured to elucidate the exact role of TREM1 in CM., Methods: Nitroglycerin (NTG) was repeatedly administered intraperitoneally to establish the CM model. Mechanical and thermal sensitivities were assessed using von Frey filaments and hot plate assays. Using Western blotting, TREM1, NF-κB pathway, NLRP3 inflammasome components, and proinflammatory cytokines were all detected. Immunofluorescence was used to examine the cellular distribution of TREM1 and NLRP3, the number of microglia, immunoreactivity, and morphological changes. We examined the effects of TREM1 antagonists (LR12) and NF-κB inhibitors (PDTC) on pain behaviour, as well as the production of c-fos and CGRP. Additionally, we investigated whether LR12 and PDTC affect the activation of microglia and the NLRP3 inflammasome. We synthesized siRNA and TREM1-overexpressing plasmids to transfect BV2 cells treated with LPS and normal BV2 cells and treated TREM1-overexpressing BV2 cells with PDTC. The NF-κB pathway, NLRP3 inflammasome components, and proinflammatory cytokines were quantified using Western blotting., Results: Following NTG administration, the expression of TREM1 was significantly upregulated and exclusively localized in microglia in the TNC, and was well co-localized with NLRP3. Furthermore, activation of the classical NF-κB pathway was observed. Pre-treatment with LR12 and PDTC effectively attenuated mechanical hypersensitivity, suppressed the expression of c-fos and CGRP, and inhibited NF-κB activity in CM mice. Additionally, inhibition of TREM1 and NF-κB activity mitigated NTG-induced microglia and NLRP3 activation, as well as proinflammatory cytokines production. In vitro, knockdown of TREM1 resulted in attenuated activation of the NF-κB pathway following lipopolysaccharide (LPS) treatment and reduced expression of NLRP3 inflammasome components as well as proinflammatory cytokines. After TREM1 overexpression, the NF-κB pathway was activated, NLRP3 inflammasome components and proinflammatory cytokines were upregulated, and PDTC reversed this phenomenon., Conclusions: Our findings suggest that TREM1 regulates microglia and NLRP3 activation via the NF-κB pathway, thereby contributing to central sensitization and implicating its involvement in chronic migraine pathogenesis., (© 2023. The Author(s).)

Background: Myofascial pain syndrome (MPS) is a prevalent chronic pain disorder primarily characterized by myofascial trigger points (MTrPs). There is limited knowledge on the pathophysiology and mechanisms underlying MTrP and its development. Research has previously demonstrated the identification of MTrPs using ultrasound and vibration sonoelastography, although there is some contradictory evidence regarding if MTrPs present as hyper or hypoechoic regions. Electromyography (EMG) investigations of MTrP have demonstrated that MTrPs are usually located proximal to innervation zones where the peak surface EMG signals are obtained from. Central sensitization has been proposed as the primary mechanism underlying MTrP development. Central sensitization is associated with hyperexcitability of neuronal responses to normal or noxious stimuli. There is a need for a study that measures ultrasound image textural changes and motor unit activity responses in the muscle following sensitization. The purpose of this study is to determine whether sensitizing healthy muscle using capsaicin induces a regional change in image texture variables within the specific and surrounding muscles, as well as the motor unit frequency and amplitude changes that accompany them. This is an exploratory trial that aims to provide preliminary evidence on whether central sensitization is a direct cause of taut band and MTrP development.Methods: Ethical approval was obtained from the University Health Network (UHN) Research Ethics Board. This proposed study is a single centered, factorial, randomized placebo-controlled trial with two independent variables, depth of capsaicin application and dose of capsaicin, for a total of six treatment arms and three control treatment groups.Discussion: This will be the first study that assesses the B-mode ultrasound image texture of induced sensitized muscles and will provide more evidence on muscle motor unit activity and regional changes of central sensitization. Findings from this study may support one of few hypotheses proposed delineating the involvement of central sensitization in the development of trigger points.Trial Registration: National Institutes of Health ClinicalTrials.gov NCT03944889 . Registered on May 07, 2019. [ABSTRACT FROM AUTHOR]

Temporomandibular disorder (TMD) is commonly comorbid with fibromyalgia syndrome (FMS). The incidence of these pain conditions is prevalent in women and prone to mental stress. Chronic pain symptoms in patients with FMS and myofascial TMD (mTMD) are severe and debilitating. In the present study, we developed a new animal model to mimic the comorbidity of TMD and FMS. In ovariectomized female rats, repeated forced swim (FS) stress induced mechanical allodynia and thermal hyperalgesia in the hindpaws of the 17β-estradiol (E2) treated rats with orofacial inflammation. Subcutaneous injection of E2, injection of complete Freund's adjuvant (CFA) into masseter muscles or FS alone did not induce somatic hyperalgesia. We also found that the somatic hyperalgesia was accompanied by upregulation of GluN1 receptor and serotonin (5-hydroxytryptamine, 5-HT)3A receptor expression in the dorsal horn of spinal cord at L4-L5 segments. Intrathecal injection of N-methyl-D-aspartic acid receptor (NMDAR) antagonist 2-amino-5-phosphonovaleric acid (APV) or 5-HT3 receptor antagonist Y-25130 blocked stress-induced wide-spreading hyperalgesia. These results suggest that NMDAR-dependent central sensitization in the spinal dorsal horn and 5-HT-dependent descending facilitation contribute to the development of wide-spreading hyperalgesia in this comorbid pain model. [ABSTRACT FROM AUTHOR]

Background: Only a small percentage of pediatric chest pain is of cardiac origin and the most common detected cause is musculoskeletal. Among musculoskeletal causes, acute chest pain is better described, with the causes of chronic pain not being adequately investigated in the literature. The aim of studuy is to evaluate the musculoskeletal causes of non-cardiac chest pain and investigate the relationship of chest pain with child abuse and central sensitization. Methods: Patients aged 12 to 18 years presenting with chest pain for at least 3 months were evaluated by a pediatric cardiologist and those without an organic pathology were referred to the physical medicine and rehabilitation clinic. In addition to detailed history and physical examination, juvenile fibromyalgia was questioned according to the 2016 revised diagnostic criteria of the American College of Rheumatology. The visual analog scale (to measure intensity of chest pain), the Central Sensitization Inventory (to evaluate the presence of central sensitization), the Hospital Anxiety Depression Scale (to determine depression and anxiety), the Childhood Trauma Questionnaire (to assess the presence of child abuse) were administered. Results: The study was completed with 64 patients. Twenty-six percent of patient (n = 17) were diagnosed with juvenile fibromyalgia, and central sensitization was detected in 34.4% (n = 22). Pain intensity, anxiety, depression and abuse scores were higher in patients with juvenile fibromyalgia than those without juvenile fibromyalgia and in patients with central sensitization compared to those without central sensitization (p < 0.001 for both). Higher scores of pain were related with child abuse [beta = 0.763, p < 0.001, (%95 CI, 4.397; 8.841)] and central sensitization of pain [beta = 0.382, p = 0.008 (95% CI: (0.986;6.231)] in regression analyses. Conclusion: In this study, juvenile fibromyalgia was detected as a cause of non-cardiac chest pain. Juvenile fibromyalgia or central sensitization may also indicate childhood abuse. [ABSTRACT FROM AUTHOR]

Background: Low back pain (LBP) is one of the greatest contributors to disability in the world and there is growing interest on the role of biomarkers in LBP. To purpose of this review was to analyze available evidence on the relationship between inflammatory biomarkers, clinical presentation, and outcomes in patients with acute, subacute and chronic non-specific low back pain (NSLBP).Methods: A search was performed in Medline, Embase, Cinahl and Amed databases. Studies which measured levels of inflammatory biomarkers in participants with NSLBP were included. Two reviewers independently screened titles and abstracts, full-texts, and extracted data from included studies. Methodological quality was assessed using the Newcastle Ottawa Quality Assessment Scale. Level of evidence was assessed using the modified GRADE approach for prognostic studies.Results: Seven primary studies were included in this review. All results assessed using the modified GRADE demonstrated low to very low quality evidence given the small number of studies and small sample. Three studies examined C-reactive protein (CRP), one of which found significantly higher CRP levels in an acute NSLBP group than in controls and an association between high pain intensity and elevated CRP. Three studies examined tumor necrosis factor alpha (TNF-α), two of which found elevated TNF-α in chronic NSLBP participants compared to controls. Two studies examined interleukin 6 (IL-6), none of which found a significant difference in IL-6 levels between NSLBP groups and controls. Two studies examined interleukin 1 beta (IL-β), none of which found a significant difference in IL-β levels between NSLBP groups and controls.Conclusions: This review found evidence of elevated CRP in individuals with acute NSLBP and elevated TNF-Α in individuals with chronic NSLBP. There are a limited number of high-quality studies evaluating similar patient groups and similar biomarkers, which limits the conclusion of this review. [ABSTRACT FROM AUTHOR]

Background: Central sensitisation is an important mechanism in migraine chronification. It is presumed to occur in second and third order neurons sequentially, resulting in an analogous spatial distribution of cutaneous allodynia with cephalic and extracephalic symptoms. We investigated whether allodynia, and its subtypes based on spatial distribution and type of stimulus, predict response to treatment in chronic migraine patients., Methods: This study was conducted as part of the CHARM study (NTR3440), a randomized, double-blind, placebo-controlled trial in chronic migraine patients with medication overuse. We included 173 patients. The presence of cutaneous allodynia at baseline was established with the Allodynia Symptom Checklist. Primary endpoint was reversion from chronic to episodic migraine., Results: Of all patients, 74.6% reported cutaneous allodynia. Absence of allodynia compared to presence of allodynia was predictive for reversion from chronic to episodic migraine, odds ratio (OR): 2.45 (95% CI: 1.03-5.84), p = 0.042. The predictive value was more pronounced when subdivided for spatial distribution, for participants without allodynia versus cephalic (OR: 4.16 (95% CI: 1.21-14.30), p = 0.024) and extracephalic (OR: 7.32 (95% CI: 1.98- 27.11), p = 0.003) allodynia. Mechanical, but not thermal, allodynia, was associated with outcome., Conclusions: Cutaneous allodynia, an important marker for central sensitization, likely has predictive value for treatment response in chronic migraine., (© 2023. Springer-Verlag Italia S.r.l., part of Springer Nature.)

Tension-type headache (TTH) and migraine are two common primary headaches distinguished by clinical characteristics according to the 3 rd edition of the International Classification of Headache Disorders. Migraine is identified by specific features such as being more prevalent in females, being aggravated by physical activity, certain genetic factors, having photophobia, phonophobia, nausea, vomiting, or aura, and responding to specific drugs. Nonetheless, TTH and migraine share some common characteristics, such as onset occurring in the 20 s, and being triggered by psychological factors like stress, moderate pain severity, and mild nausea in chronic TTH. Both conditions involve the trigeminovascular system in their pathophysiology. However, distinguishing between TTH and migraine in clinical practice, research, and epidemiological studies can be challenging, as there is a lack of specific diagnostic tests and biomarkers. Moreover, both conditions may coexist, further complicating the diagnostic process. This review aims to explore the similarities and differences in the pathophysiology, epidemiology, burden and disability, comorbidities, and responses to pharmacological and non-pharmacological treatments of TTH and migraine. The review also discusses future research directions to address the diagnostic challenges and improve the understanding and management of these conditions., (© 2023. The Author(s).)

Background: Pain is inherent in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and spondyloarthritis (SpA) and traditionally considered to be of nociceptive origin. Emerging data suggest a potential role of augmented central pain mechanisms in subsets of patients, thus, valid instruments that can identify underlying pain mechanisms are needed. The painDETECT questionnaire (PDQ) was originally designed to differentiate between pain phenotypes. The objectives were to evaluate the psychometric properties of the PDQ in patients with inflammatory arthritis by applying Rasch analysis and to explore the reliability of pain classification by test-retest.Methods: For the Rasch analysis 900 questionnaires from patients with RA, PsA and SpA (300 per diagnosis) were extracted from 'the DANBIO painDETECT study'. The analysis was directed at the seven items assessing somatosensory symptoms and included: 1) the performance of the six-category Likert scale; 2) whether a unidimensional construct was defined; 3) the reliability and precision of estimates. Another group of 30 patients diagnosed with RA, PsA or SpA participated in a test-retest study. Intraclass Correlation Coefficients (ICC) and classification consistency were calculated.Results: The Rasch analysis revealed: (1) Acceptable psychometric rating scale properties; the frequency distribution peaked in category 0 except for item 5, threshold calibration >10 observations per category, no disorder in the category measures for all items, scale category outfit Mnsq <2.0, small distances (<1.4 logits) between thresholds for category 1, 2 and 3 for all items. (2) The principal component analysis supported unidimensionality; the standardized residuals showed that 53.7% of total variance was explained by the measure and the magnitude of first contrast had an eigenvalue of 1.5, no misfitting items, clinical insignificant different item hierarchies across diagnoses (DIF < 0.5 logits). (3) A targeted item-person map, person and item separation indices of 1.88(reliability = 0.78), and 13.04 (reliability = 0.99). The test-retest revealed: ICC: RA 0.86(0.56-0.96), PsA 0.96(0.74-0.99), SpA 0.93(0.76-98), overall 0.94(0.84-0.98). Classification consistency was: RA 70%, PsA 80%, SpA 90%, overall 80%.Conclusion: The results support that the PDQ can be used as a classification instrument and assist identification of underlying pain-mechanisms in patients suffering from inflammatory arthritis. [ABSTRACT FROM AUTHOR]

Background: Chronic pain enhances sensory sensitivity and induces the biased development of psychological traits such as depression and pain catastrophizing, leading to the formation of heterogeneous conditions. Fluctuations in the sensory-related thresholds of non-injured sites (with normal peripheral tissue) in patients with chronic pain are thought to be related to central sensitization. The objectives of this study were to analyze the association between pain tolerance thresholds (PTTs) in non-injured sites and the psychological traits of patients with chronic pain and to evaluate the usefulness of PTT measures in assessments of pathological conditions related to chronic pain. Methods: This study included 57 patients with chronic pain. The PTTs were measured in non-injured sites with quantitative sensory testing (QST) with electrical stimulation and then classified with cluster analysis. The Short- Form McGill Pain Questionnaire was used to subjectively assess pain in the injured sites. The Minnesota Multiphasic Personality Inventory (MMPI) was used to assess the patients' psychological traits. Results: Based on the cluster analysis of PTTs, the patients were classified into a High-Sensitivity group and an Others group consisting of the remaining patients. The results of the MMPI profiles showed that the High-Sensitivity group included significantly more patients with the Neurotic Triad pattern and no patients with the Conversion V pattern. The scores of the hypochondriasis and hysteria scales were significantly lower in the High-Sensitivity group than in the Others group. Conclusions: This study indicated that patients with chronic pain can be classified according to PTTs in non-injured sites and suggests that patients with High-Sensitivity have characteristic psychological traits. Assessment of PTTs in non-injured sites would be useful for evaluating the psychological condition of patients with chronic pain. [ABSTRACT FROM AUTHOR]

Aims: Chronic migraine (CM) is a common neurological disorder with complex pathogenesis. Evidence suggests that pituitary adenylate cyclase-activating peptide (PACAP) induces migraine-like attacks and may be potential a new target for migraine treatment, but the therapeutic results of targeting PACAP and its receptors are not uniform. Therefore, the aim of this study was to investigate the regulatory effect of PACAP type I receptor (PAC1R) antagonist, PACAP6-38, on nitroglycerin (NTG)-induced central sensitization in a CM model., Methods: Sprague-Dawley (SD) rats received repeated injections of NTG to construct a CM model. Mechanical and thermal thresholds were measured using Von Frey filaments and hot plate tests. C-Fos expression was measured by western blotting and immunofluorescence staining to assess the central sensitization. PACAP6-38 was intracerebrally injected into the trigeminal nucleus caudalis (TNC), and then the changes in c-Fos, the synaptic-associated proteins, phospho-ERK1/2 (p-ERK1/2), phosphorylation of cyclic adenosine monophosphate response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) were detected. Transmission electron microscopy (TEM) and Golgi-Cox staining were used to observe the ultrastructure of synapses and dendritic structures of TNC neurons., Results: The results showed that PACAP and PAC1R expression were significantly raised in the TNC after repeated NTG injections. Additionally, PACAP6-38 treatment alleviated nociceptive sensitization, inhibited NTG-induced overexpression of c-Fos and synaptic-associated proteins in the TNC of CM rat, restored aberrant synaptic structures. Furthermore, the expression of ERK/CREB/BDNF pathway was depressed by PACAP6-38., Conclusions: Our results demonstrated that abnormal synaptic structure in the TNC of CM, which could be reversed by inhibition of PAC1R via down-regulating the ERK/CREB/BDNF signaling pathway. PACAP6-38 improves NTG-induced central sensitization by regulating synaptic plasticity in the TNC of CM rat, which may provide new insights into the treatments targeting PACAP/PAC1R in migraine., (© 2023. The Author(s).)

Background: Central sensitization has been widely accepted as an underlying pathophysiological mechanism of chronic migraine (CM), activation of cannabinoid type-1 receptor (CB1R) exerts antinociceptive effects by relieving central sensitization in many pain models. However, the role of CB1R in the central sensitization of CM is still unclear., Methods: A CM model was established by infusing inflammatory soup (IS) into the dura of male Wistar rats for 7 days, and hyperalgesia was assessed by the mechanical and thermal thresholds. In the periaqueductal gray (PAG), the mRNA and protein levels of CB1R and hyperpolarization-activated cyclic nucleotide-gated cation channel 2 (HCN2) were measured by qRT-PCR and western blotting. After intraventricular injection of Noladin ether (NE) (a CB1R agonist), ZD 7288 (an HCN2 blocker), and AM 251 (a CB1R antagonist), the expression of tyrosine phosphorylation of N-methyl-D-aspartate receptor subtype 2B (pNR2B), calcium-calmodulin-dependent kinase II (CaMKII), and phosphorylated cAMP-responsive element binding protein (pCREB) was detected, and central sensitization was evaluated by the expression of calcitonin gene-related peptide (CGRP), c-Fos, and substance P (SP). Synaptic-associated protein (postsynaptic density protein 95 (PSD95) and synaptophysin (Syp)) and synaptic ultrastructure were detected to explore synaptic plasticity in central sensitization., Results: We observed that the mRNA and protein levels of CB1R and HCN2 were both significantly increased in the PAG of CM rats. The application of NE or ZD 7288 ameliorated IS-induced hyperalgesia; repressed the pNR2B/CaMKII/pCREB pathway; reduced CGRP, c-Fos, SP, PSD95, and Syp expression; and inhibited synaptic transmission. Strikingly, the application of ZD 7288 relieved AM 251-evoked elevation of pNR2B, CGRP, and c-Fos expression., Conclusions: These data reveal that activation of CB1R alleviates central sensitization by regulating HCN2-pNR2B signaling in CM rats. The activation of CB1R might have a positive influence on the prevention of CM by mitigating central sensitization., (© 2023. The Author(s).)

Background: The goal of this observational, open-label, cohort study was to determine whether prophylactic migraine treatment with galcanezumab, a peripherally acting drug, alters the incidence of premonitory symptoms, and/or occurrence of headache after exposure to triggers or aura episodes in treatment-responders (≥ 50% reduction in monthly migraine days [MMD]), super-responders (≥ 70%), non-responders (< 50%) and super non-responders (< 30%)., Methods: Participants were administered electronic daily headache diaries to document migraine days and associated symptoms one month before and during the three months of treatment. Questionnaires were used to identify conscious prodromal and trigger events that were followed by headache prior to vs. after 3 months of treatment., Results: After 3 months of galcanezumab treatment, (a) the incidence of premonitory symptoms that were followed by headache decreased by 48% in the 27 responders vs. 28% in the 19 non-responders, and by 50% in the 11 super-responders vs. 12% in the 8 super non-responders; (b) the incidence of visual and sensory aura that were followed by headache was reduced in responders, non-responders, and super-responders, but not in super non-responders; (c) the number of triggers followed by headache decreased by 38% in responders vs. 13% in non-responders, and by 31% in super-responders vs. 4% in super non-responders; and (d) some premonitory symptoms (e.g., cognitive impairment, irritability, fatigue) and triggers (e.g., stress, sleeping too little, bright light, aura) were followed by headache only in super non-responders., Conclusions: Mechanistically, these findings suggest that even a mild decrease in migraine frequency is sufficient to partially reverse the excitability and responsivity of neurons involved in the generation of certain triggers and potentially premonitory symptoms of migraine., Trial Registration: ClinicalTrials.gov: NCT04271202. Registration date: February 10, 2020., (© 2023. The Author(s).)

Background: Several factors are believed to influence the development and experience of pain. Human clinical pain models are central tools, in the investigation of basic physiologic pain responses, and can be applied in patients as well as in healthy volunteers. Each clinical pain model investigates different aspects of the human pain response. Brief thermal sensitization induces a mild burn injury, resulting in development of primary hyperalgesia at the site of stimulation, and secondary hyperalgesia surrounding the site of stimulation. Central sensitization is believed to play an important role in the development of secondary hyperalgesia; however, a possible association of secondary hyperalgesia following brief thermal sensitization and other heat pain models remains unknown. Our aim with this study is to investigate how close the heat pain detection threshold is associated with the size of the area of secondary hyperalgesia induced by the clinical heat pain model: Brief thermal sensitization. Methods and design: We aim to include 120 healthy participants. The participants will be tested on two separate study days with the following procedures: i) Brief thermal sensitization, ii) heat pain detection threshold and iii) pain during thermal stimulation. Additionally, the participants will be tested with the Pain Catastrophizing Scale and Hospital Anxiety and Depression Scale questionnaires. We conducted statistical simulations based on data from our previous study, to estimate an empirical power of 99. 9 % with α of 0.05. We define that an R2 < 0.25 and predictive intervals larger than +/−150 cm2 are indications of a weak association. Discussion: The area of secondary hyperalgesia may serve as a quantitative measure of the central sensitization induced by cutaneous heat stimulation, and thus may be a biomarker of an individual's pain sensitivity. The number of studies investigating secondary hyperalgesia is growing; however basic knowledge of the physiologic aspects of secondary hyperalgesia in humans is still incomplete. We therefore find it interesting to investigate if HPDT, a known quantitative sensory test, is associated with areas of secondary hyperalgesia following brief thermal sensitization Trial registration: Clinicaltrials.gov (Identifier: NCT02527395). Danish Research Ethics Committee (Identifier: H-8-2014-012). Danish Data Protection Agency (Identifier: 30-1436). [ABSTRACT FROM AUTHOR]

Background: Central sensitization is modulated by the endogenous opioid system and plays a major role in the development and maintenance of pain. Recent animal studies performed following resolution of inflammatory pain showed reinstatement of tactile hypersensitivity induced by administration of a mu-opioid-antagonist, suggesting latent sensitization is mediated by endogenous opioids. In a recent crossover study in healthy volunteers, following resolution of a first-degree burn, 4 out of 12 volunteers developed large secondary areas of hyperalgesia areas after a naloxone infusion, while no volunteer developed significant secondary hyperalgesia after the placebo infusion. In order to consistently demonstrate latent sensitization in humans, a pain model inducing deep tissue inflammation, as used in animal studies, might be necessary. The aim of the present study is to examine whether a high-dose target-controlled naloxone infusion can reinstate pain and hyperalgesia following recovery from open groin hernia repair and thus consistently demonstrate opioid-mediated latent sensitization in humans.Methods/design: Patients submitted to unilateral, primary, open groin hernia repair will be included in this randomized, placebo-controlled, double-blind, crossover study. The experimental days take place 6-8 weeks after surgery, time-points at which patients are expected to be almost pain- free. Prior to administration of naloxone or placebo, the primary outcome (a summated measure of pain: at rest, during transition from supine to standing position, and evoked by pressure algometry) and the secondary outcomes (secondary hyperalgesia/allodynia, pressure pain thresholds, assessed at the surgical site and at the mirror-site in the contralateral groin, and, opioid withdrawal symptoms) will be assessed. These assessments will be repeated at each step of the target-controlled infusion of placebo or naloxone at estimated median (95 % CI) plasma concentrations of 344 ng/ml (130;567), 1059 ng/ml (400;1752) and 3196 ng/ml (1205;5276).Discussion: We aim to demonstrate opioid-mediated latent sensitization in a post-surgical setting, using pain as a clinical relevant variable. Impairment of the protective endogenous opioid system may play an important role in the transition from acute to chronic pain. In order to sufficiently block the endogenous opioid system, a high-dose target-controlled naloxone-infusion is used, in accordance with recent findings in animal studies.Trial Registration Number: Eudract: 2015-000793-36 (Registration date: 16 February 2015) Clinicaltrials.gov: NCT01992146 (Registration date: 12 December 2014). [ABSTRACT FROM AUTHOR]

Background: Spinal central sensitization is an important process in the generation and maintenance of visceral hypersensitivity. The release of brain-derived neurotrophic factor (BDNF) from the primary afferent neurons to the spinal cord contributes to spinal neuronal plasticity and increases neuronal activity and synaptic efficacy. The N-Methyl-D-aspartic acid (NMDA) receptor possesses ion channel properties, and its activity is modulated by phosphorylation of its subunits including the NMDA receptor 1 (NR1). Methods: Colonic inflammation was induced by a single dose of intracolonic instillation of tri-nitrobenzene sulfonic acid (TNBS). NR1 phosphorylation by BDNF in vivo and in culture was examined by western blot and immunohistochemistry. Signal transduction was studied by direct examination and use of specific inhibitors. Results: During colitis, the level of NR1 phospho-Ser896 was increased in the dorsal horn region of the L1 and S1 spinal cord; this increase was attenuated by injection of BDNF neutralizing antibody to colitic animals (36 μg/kg, intravenous (i.v.)) and was also reduced in BDNF+/− rat treated with TNBS. Signal transduction examination showed that the extracellular signal-regulated kinase (ERK) activation was not involved in BDNF-induced NR1 phosphorylation. In contrast, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway mediated BDNF-induced NR1 phosphorylation in vivo and in culture; this is an additional pathway to the phospholipase C-gamma (PLCγ) and the protein kinase C (PKC) that was widely considered to phosphorylate NR1 at Ser896. In spinal cord culture, the inhibitors to PLC (U73122), PKC (bisindolylmaleimide I), and PI3K (LY294002), but not MEK (PD98059) blocked BDNF-induced NR1 phosphorylation. In animals with colitis, treatment with LY294002 (50 μg/kg, i.v.) blocked the Akt activity as well as NR1 phosphorylation at Ser896 in the spinal cord. Conclusion: BDNF participates in colitis-induced spinal central sensitization by up-regulating NR1 phosphorylation at Ser896. The PI3K/Akt pathway, in addition to PLCγ and PKC, mediates BDNF action in the spinal cord during colitis. [ABSTRACT FROM AUTHOR]