Curcumin analogue NL04 inhibits spinal cord central sensitization in rats with bone cancer pain by inhibiting NLRP3 inflammasome activation and reducing IL-1ß production.

The management and therapy of bone cancer pain (BCP) remain formidable clinical challenges. Curcumin and its analogues have been shown to have anti-inflammatory and analgesic properties. In the present study, we investigated the efficacy of curcumin analogue NL04 (NL04) in modulating inflammation in spinal dorsal horn (SDH), thereby exploring its potential to reduce central sensitization of BCP in a rat model. Differing doses of NL04 and curcumin were administered intrathecally either once (on day 12 of BCP) or over seven consecutive days (from day 6-12 of BCP). Results indicated that the ED50 for NL04 and curcumin ameliorating BCP-induced mechanical hyperalgesia is 49.08 µg/kg and 489.6 µg/kg, respectively. The analgesic effects at various doses of NL04 lasted between 4 and 8 h, with sustained administration over a week maintaining pain relief for 1-4 days, while also ameliorating locomotor gait via gait analysis and reducing depressive and anxiety-like behaviors via open-field and light-dark transition tests. The analgesic effects at various doses of curcumin lasted 4 h, with sustained administration over a week maintaining pain relief for 0-2 days. ELISA, Western blotting, qPCR, and immunofluorescence assays substantiated that intrathecal administration of NL04 on days 6-12 of BCP dose-dependently lowered spinal IL-1ß and IL-18 levels and significantly reduced the expression of IKKß genes and proteins, as well as the downstream cleavage of the trans-Golgi network (TGN). Whole-cell patch-clamp results demonstrated that NL04 inhibits potassium ion efflux in rat primary spinal neurons. Thus, NL04 exhibits significant analgesic effects in a BCP rat model by downregulating IKKß expression and inhibiting neuronal potassium ion efflux, which, in turn, suppresses the activation of NLRP3 inflammasomes and reduces IL-1ß production, potentially ameliorating pain management in BCP.

5-HT3a receptor contributes to neuropathic pain by regulating central sensitization in a rat with brachial plexus avulsion.

PURPOSE: As a frequently occurring complication resulting from brachial plexus avulsion (BPA), neuropathic pain significantly impacts the quality of life of patients and places a substantial burden on their families. Recent reports have suggested that the 5-HT3a receptor may play a role in the development and regulation of neuropathic pain. The current study aimed to explore the involvement of the 5-HT3a receptor in neuropathic pain resulting from BPA in rats. METHODS: A rat model of neuropathic pain was induced through brachial plexus avulsion (BPA). The pain thresholds of the rats were measured after BPA. The spinal dorsal horn (SDH) of rats was collected at day 14 after surgery, and the expression and distribution of the 5-HT3a receptor were analyzed using immunohistochemistry and western blotting. The expression levels of various factors related to central sensitization were measured by western blot, including c-Fos, GFAP, IBA-1, IL-1ß and TNF-α. The effects of 5-HT3a receptor antagonists on hyperalgesia were assessed through behavioral tests after intrathecal administration of ondansetron. Additionally, at 120 min postinjection, the SDH of rats was acquired, and the change of expression levels of protiens related to central sensitization were measured by western blot. RESULTS: BPA induced mechanical and cold hypersensitivity in rats. The 5-HT3a receptor was increased and mainly distributed on neurons and microglia in the SDH after BPA, and the level of central sensitization and expression of inflammatory factors, such as c-Fos, GFAP, IBA-1, IL-1ß and TNF-α, were also increased markedly. Ondansetron, which is a selective 5-HT3a receptor antagonist, reversed the behavioral changes caused by BPA. The antagonist also decreased the expression of central sensitization markers and inflammatory factors. CONCLUSION: The results suggested that the 5-HT3a receptor is involved in neuropathic pain by regulating central nervous system sensitization in a rat brachial plexus avulsion model. Targeting the 5-HT3a receptor may be a promising approach for treating neuropathic pain after brachial plexus avulsion.

Frequency of idiopathic intracranial hypertension with ultrasound in patients with fibromyalgia: Relation with function, central sensitization, and neuropathic pain.

OBJECTIVE: The purpose of this study was to evaluate the prevalence of idiopathic intracranial hypertension (IIH) in fibromyalgia (FMS) patients by utilizing ultrasound to measure the optic nerve sheath diameter (ONSD), a marker of elevated intracranial pressure and also to investigate the relationship with function, fatigue, quality of life (QOL), central sensitization (CS) and neuropathic pain. METHODS: The study encompassed 80 female FMS patients and 75 healthy controls. Ultrasound was employed to measure the average ONSD in both groups. Conditions potentially elevating intracranial pressure were ruled out following neurological assessments. Pain (via visual analog scale, VAS), function (revised Fibromyalgia Impact Questionnaire, r-FIQ), QOL (Short Form-36, SF-36), fatigue (fatigue severity scale, FACIT), CS (Central Sensitization Scale), and neuropathic pain (Douleur Neuropathique-4) were evaluated. RESULTS: The average ONSD was significantly higher in the patient group than the control group. Patients with ONSD >5.5 mm consistent with IIH were categorized as Group 1 (n = 54, 67.5%), while those with a diameter of 5.5 mm and below-formed Group 2. VAS pain (p = .033) and FIQ-R scores (p = .033) were significantly higher in Group 1 than Group 2. Headache was found more common in Group 1. CONCLUSION: This study unveils a substantial occurrence (67.5%) of IIH in FMS patients, suggesting shared pathophysiological mechanisms contributing to symptoms like fatigue, headache, and cognitive dysfunction. Additionally, these findings implicate heightened functional impairment, CS, headache, and fatigue in FMS patients with IIH.

Association between smoking and central sensitization pain: a web-based cross-sectional study.

PURPOSE: This study aimed to investigate whether smoking is an independent risk factor for central sensitization syndrome (CSS) in individuals with pain as measured by the Central Sensitization Inventory (CSI). METHODS: In 2020, we conducted an Internet survey targeting 2000 ordinary residents of Japan (aged 20-69 years) who had pain symptoms from October to November 2020. A multiple regression analysis was performed on the association between smoking status (nonsmokers and current smokers; Brinkman index) and CSI values. Moreover, compared to nonsmokers, the relative risk (RR) of the CSI cut-off score of 40 points or higher among current smokers was calculated using a modified Poisson regression model. Covariates included age, sex, body mass index, marital status, equivalized income, exercise habits, history of hypertension, history of hyperlipidemia, history of diabetes, pain chronicity, and Pain Catastrophizing Scale score. RESULTS: This study analyzed 1,822 individuals (1,041 men and 781 women). Among those experiencing pain, current smoking was associated with the increase in CSI values (ß = 0.07). The Brinkman index was also significantly associated with the increase in CSI values (ß = 0.06). Current smoking also increased the risk of being over the CSI cut-off score, with a relative risk (RR) of 1.29 (95% confidence intervals, 1.04-1.60). Younger age, being women, experiencing chronic pain, and higher pain catastrophizing thinking were also significantly associated with increased CSS severity, independent of smoking status. CONCLUSION: Smoking is an independent risk factor for CSS. This indicates that smoking may be an important factor in the management of central pain disorders.

Relationship Between Central Sensitization-Related Symptoms and Pain-Related Disability After Cervical Spine Surgery: A Structural Equation Model.

BACKGROUND: It is unknown if central sensitization (CS)-related symptoms have an intermediate role that might explain how disability develops from pain after cervical spinal surgery. AIMS: The study aim was to investigate the role of CS-related symptoms in the relationship between pain and disability reported after cervical spinal surgery. DESIGN: Cross-sectional study. SETTINGS: Tertiary care spinal surgery center. PARTICIPANTS/SUBJECTS: The participants included individuals with a cervical degenerative condition who had undergone surgery. METHODS: The following patient-reported outcome measures were evaluated: (1) Numerical Rating Scale; (2) Neck Disability Index; and (3) Short Form of the Central Sensitization Inventory. A hypothesized model containing the CS-related symptoms and the relationships between pain and disability was constructed and tested by structural equation modeling. RESULTS: Questionnaires were mailed to 280 individuals, and responses were obtained from 145 participants. Of these respondents, 99 (68.3%) were males and 46 (31.7%) were females, with a mean age of 64.4 ± 12.3 years. The latent variable for pain, represented by the neck (coefficient: 0.856, p < .001) and upper limb pain (0.568, p < .001), influenced CS-related symptoms (coefficient: 0.504, p < .001). Pain directly affected disability (coefficient: 0.497, p < .001) and indirectly through CS-related symptoms. Bootstrap analysis confirmed this indirect effect (point estimate: 2.85, 95% confidence interval: 1.04 to 6.30, p = .04). CONCLUSIONS: The results revealed that neck and upper limb pain affected disabilities both directly and through CS-related symptoms. Future research should focus on the efficacy of biopsychosocial approaches for patients after cervical spine surgery with a high risk of disability due to CS-related symptoms.

The Effect of Central Sensitization on Postoperative Neurocognitive Dysfunction in Hospitalized Elderly Patients: A Prospective Cohort Clinical Trial.

OBJECTIVE: To investigate whether central sensitization (CS) in elderly patients was a predictive risk factor for postoperative neurocognitive dysfunction (PNCD). METHODS: One hundred and thirty-three aged patients undergoing total knee arthroplasty (TKA) who received femoral nerve block and general anesthesia were recruited in this research and prospectively assigned into two groups according to the Central Sensitization Inventory (CSI) score: group C (n = 106, CSI score less than 40) and group CS (n = 27, CSI score higher than 40). Scores of Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Confusion Assessment Method (CAM), Numerical Rating Scale (NRS) and Quality of recovery-40 (QoR-40) questionnaires were assessed. Basic information and clinical records of all participants were also collected. RESULTS: PNCD occurred in 24 (22.6%) of patients in group C and 16 (59.3%) in group CS (p < .05). Multivariate logistic regression analysis revealed that patients with CSI score ≥40 before surgery exhibited higher risk of PNCD after adjustment for other risk factors (p < .05). Compared to group C, the pre- and post-operative NRS scores, pain duration, the WOMAC score, and propofol consumptions for anesthesia induction were significantly increased in group CS (p < .05). CONCLUSION: Hospitalized elderly patients with clinical symptoms of CS scores may have increased risk of PNCD following TKA.

Central Sensitisation Syndrome: A Frequent Finding in Women with Pelvic Floor Symptoms Without Evident Urogenital Prolapse.

INTRODUCTION AND HYPOTHESIS: Women with central sensitisation syndrome (CSS) experience poorer subjective post-operative outcomes even after successful pelvic floor reconstruction. This study tests the hypothesis that women with pelvic floor symptoms (PFS) without relevant pelvic organ prolapse (POP), are more likely to have CSS. METHODS: A questionnaire was sent to women who participated in the POP-UP study in 2017. The POP-UP study evaluated POP in 247 women 16 years after laparoscopic or vaginal hysterectomy. POP-Q data and Pelvic Floor Distress Inventory (PFDI-20) results were used and supplemented with CSS-specific questionnaires. A Central Sensitisation Inventory (CSI) score above 40 implicates CSS. Women were divided into groups based on POP beyond the hymen in relation to the PFDI-20 score. Outcomes of women with PFS and without POP (called 'group 1') were compared with the rest of the cohort (groups 2-4; women without PFS and/or with POP). RESULTS: A total of 136 women were included in the analysis. A CSI score above 40 was present in 16 out of 42 women of group 1 (37%) versus 11 out of 93 women of groups 2-4 (12%), p < 0.0001. Passive coping was more prevalent in group 1 (p = 0.039), and more deviations in somatisation, depression, anxiety and distress were found in group 1 (p values of < 0.0001, 0.018, 0.003 and 0.002 respectively). CONCLUSIONS: This study suggests that CSS might be more prevalent in women with PFS without relevant POP. More awareness of CSS and valid individual counselling may overcome unnecessary surgery for POP and help in setting realistic expectations.

Questionnaires for the Assessment of Central Sensitization in Endometriosis: What Is the Available Evidence? A Systematic Review with a Narrative Synthesis.

It has been suggested that central sensitization (CS) may be involved in the failure of standard medical and surgical treatment to relieve endometriosis-related pain. However, there is no gold standard for the diagnosis of CS, and self-reported questionnaires are used as diagnostic surrogates. The main objective of this review was to identify all CS questionnaires used in clinical endometriosis studies. The secondary objective was to qualitatively analyze strengths and weaknesses of each questionnaire. A PubMed and EMBASE systematic literature search conducted in April 2023 using the terms "endometriosis; central pain; central sensitization; questionnaire; patient-reported outcome measure; screening tool" identified 122 publications: six articles were included in the review. The Central Sensitization Inventory (CSI) is the most frequently used questionnaire for the detection of CS in patients with endometriosis. It has been validated in patients with endometriosis, in whom it appears to have good psychometric proprieties. The Fibromyalgia Survey Questionnaire (FSQ) has also been used, although it has not been specifically validated in endometriosis patients. The debate regarding these questionnaires' construct validity is still open and will be so until a gold standard diagnostic tool for CS is found. In fact, some authors argue these questionnaires are measuring psychological vulnerability and a hypervigilant state that is associated with pain, rather than CS itself. However, their use should not be discouraged as they are able to identify chronic pain patients which warrant further attention and who may benefit from broader treatment strategies.

Central Sensitization in Psoriatic Arthritis: Relationship With Composite Measures of Disease Activity, Functional Disability, and Health-Related Quality of Life.

OBJECTIVE: To investigate the prevalence of central sensitization (CS) in patients with psoriatic arthritis (PsA) and its association with disease activity and patient-reported outcome measures. METHODS: This cross-sectional study included adults with PsA without coexisting fibromyalgia (FM). Patients underwent a clinimetric assessment to collect variables regarding disease activity, quality of life (QOL), functional ability, impact of disease, and CS. Spearman ρ was used to examine the relationship between CS Inventory (CSI) scores and other variables. A multivariate analysis was performed to determine the independent contribution of each variable to the 12-item Psoriatic Arthritis Impact of Disease (PsAID-12) score. RESULTS: One hundred fifty-seven patients were enrolled. Of them, 45.2% scored a CSI ≥ 40, indicating a high probability of CS. Significant correlations were found between CSI and disease activity, as evaluated by Disease Activity in Psoriatic Arthritis score and Psoriatic Arthritis Disease Activity Score (ρ 0.587 and ρ 0.573, respectively), between CSI and the Health Assessment Questionnaire (ρ 0.607), and between CSI and the 36-item Short Form Health Survey physical component summary and mental component summary scores (ρ -0.405 and ρ -0.483, respectively). In multivariate analysis, CSI score was the principal independent variable (P < 0.001) contributing to PsAID-12 score. CONCLUSION: Patients with PsA with symptoms of CS had higher disease activity, worse functional ability, and worse QOL. The presence of CS is the major contributor in the impact of disease.

Central Sensitization and Neuropathic Pain Cumulatively Affect Patients Reporting Inferior Outcomes Following Total Knee Arthroplasty.

UPDATE: This article was updated on November 17, 2023, because of previous errors, which were discovered after the preliminary version of the article was posted online. On page 102, the text that had read "In a post hoc analysis of the preoperative results, Group 1 showed significantly inferior WOMAC pain, function, and total scores compared with Group 4 (p < 0.05 for all). Groups 2 and 3 showed worse preoperative WOMAC pain, function, and total subscores compared with Group 4 (p < 0.05 for all). These results remained the same at 2 years after surgery." now reads "In a post hoc analysis of the preoperative results, Groups 1, 2, and 3 showed significantly inferior WOMAC pain, function, and total scores compared with Group 4 (p < 0.05 for all). At 2 years postoperatively, Group 1 showed inferior WOMAC pain, function, and total scores compared with the other groups (p < 0.05 for all). Also, Groups 2 and 3 had worse WOMAC pain, function and total scores compared with Group 4 (p < 0.05 for all)." Also, on page 106, the title of Table IV, which had previously read "Inter-Group Comparison of Preoperative Scores (Post Hoc Analysis)" now reads "Inter-Group Comparison of Postoperative Scores (Post Hoc Analysis)."

Available studies on the relationship between central sensitization and neuropathic pain, and on their association with patient-reported outcome measures (PROMs), following total knee arthroplasty (TKA) are insufficient. The purpose of the present study was to investigate this association. A total of 316 patients who underwent primary unilateral TKA for the treatment of end-stage osteoarthritis (OA) of the knee were enrolled. Central sensitization was defined as a score of ≥40 on the Central Sensitization Inventory. Neuropathic pain was defined as a score of ≥19 on the painDETECT Questionnaire (PDQ). PROMs were also evaluated on the basis of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score preoperatively and at 2 years postoperatively. The patients were divided into 4 groups: Group 1 had both central sensitization and neuropathic pain, Group 2 had central sensitization only, Group 3 had neuropathic pain only, and Group 4 had neither central sensitization nor neuropathic pain. Preoperative and postoperative PROMs were compared among the groups. All individuals who participated in the study were Asian, especially Korean. Fifty-five patients (17.4%) had both central sensitization and neuropathic pain, 68 (21.5%) had central sensitization only, 35 (11.1%) had neuropathic pain only, and 158 (50.0%) had neither condition. All WOMAC subscores showed significant differences among the 4 groups before and after surgery (p < 0.05 for all). In a post hoc analysis of the preoperative results, Groups 1, 2, and 3 showed significantly inferior WOMAC pain, function, and total scores compared with Group 4 (p < 0.05 for all). At 2 years postoperatively, Group 1 showed inferior WOMAC pain, function, and total scores compared with the other groups (p < 0.05 for all). Also, Groups 2 and 3 had worse WOMAC pain, function and total scores compared with Group 4 (p < 0.05 for all). Each condition, central sensitization and neuropathic pain, was associated with inferior PROMs following TKA. Furthermore, patients with both central sensitization and neuropathic pain showed worse PROMs compared with patients with either condition alone or without either condition. Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Influence of radiological factors, psychosocial factors, and central sensitization-related symptoms on clinical symptoms in patients with lumbar spinal canal stenosis.

BACKGROUND: No study to date has concurrently evaluated the impact of radiological factors, psychosocial factors, and central sensitization (CS) related symptoms in a single lumbar spinal canal stenosis (LSS) patient cohort. OBJECTIVE: To investigate the associations between these factors and clinical symptoms in LSS patients. METHODS: We recruited 154 patients with LSS scheduled for surgery. Patient-reported outcome measures and imaging evaluation including clinical symptoms, psychosocial factors, CS-related symptoms, and radiological classifications. Spearman's rank correlation coefficient and multiple regression analyses were employed. RESULTS: Spearman's correlation revealed CS-related symptoms positively correlated with low back pain (r= 0.25, p< 0.01), leg pain (r= 0.26, p< 0.01), and disability (r= 0.32, p< 0.01). Pain catastrophizing positively correlated with leg pain (r= 0.23, p< 0.01) and disability (r= 0.36, p< 0.01). Regression analysis showed that pain catastrophizing was associated with disability (ß= 0.24, 95%CI = 0.03-0.18), and CS-related symptoms with low back pain (ß= 0.28, 95%CI = 0.01-0.09). Radiological classifications were not associated with clinical symptoms. CONCLUSION: Our findings suggest that psychosocial factors and CS-related symptoms, rather than radiological factors, seem to contribute to clinical symptoms in patients with LSS.

Cross-cultural adaptation and validation for central sensitization inventory: based on Chinese patients undergoing total knee arthroplasty for knee osteoarthritis.

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.

Low central sensitisation inventory score is associated with better post-operative outcomes of osteotomy around the knee.

PURPOSE: The purpose of this study was to investigate the potential association between central sensitisation inventory (CSI) scores and post-operative patient-reported outcomes (PROs) in patients underwent osteotomy around the knee (OAK), with a CSI cut-off score specific for knee osteoarthritis. METHODS: CSI scores were collected from 173 patients who underwent OAK, along with their knee injury and osteoarthritis outcome score (KOOS) and pain numeric rating scale (NRS) scores. Patients were divided into high-CSI score group and low-CSI score group with a cut-off score of 17. Multivariate linear regression was performed to test the association between CSI scores and post-operative outcomes. Pre-surgery KOOS and NRS scores and the rate of attainment of minimal clinically important difference (MCID) of KOOS scores was analysed as secondary outcomes. RESULTS: Low-CSI score group had significantly higher post-operative KOOS scores and lower pain NRS scores compared to the high-CSI score group (< p = 0.01) after adjusting for confounding factors. For pre-operative scores, only the KOOS-Symptom score was significantly different between the groups (64.7 ± 20.1 when CSI < 17 vs.55.1 ± 19.7 when CSI ≥ 17; p = 0.008). The low-CSI score group had significantly higher MCID achievement rates of KOOS-Pain, Symptom, and ADL than the high-CSI score group (86% vs. 68%; 74% vs. 55%; 86% vs. 67%, respectively; P < 0.05). CONCLUSIONS: This study established an association between post-operative CSI scores ≥ 17 and poorer outcomes following OAK, highlighting the potential value of the CSI in identifying patients in need of more comprehensive peri-operative pain management. LEVEL OF EVIDENCE: Level III. Retrospective comparative study.

Association of central sensitization, visceral fat, and surgical outcomes in lumbar spinal stenosis.

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.

Central sensitization negatively influences the level of disability in female patients with anterior knee pain.

PURPOSE: To define the prevalence of Central Sensitization (CS) in patients with Anterior Knee Pain (AKP) and determine whether there is an association between CS and the magnitude of pain, disability, quality-of-life and psychological impairment. METHODS: The data of a total of 44 AKP female patients with a mean age of 27.7 years (15-50) recruited consecutively from hospital outpatient knee clinics were prospectively included in this study. The patients had no antecedents of knee trauma or surgery and no history of injury or disease of the nervous system. There were also 50 healthy female controls with a mean age of 26.1 years (16-46). CS was evaluated using the Central Sensitization Inventory (CSI). Quality-of-life was evaluated using the EuroQoL-5D questionnaire. Self-reporting of clinical pain intensity was obtained using the Visual Analogue Scale. The Kujala Knee Scale and IKDC form were used to evaluate disability. Anxiety and depression were evaluated using the Hospital Anxiety and Depression Subscale (HAD). Kinesiophobia was measured with the Tampa Scale for Kinesiophobia (TSK-11) and catastrophizing by means of the Pain Catastrophizing Scale (PCS). RESULTS: Sixteen AKP patients (36%), and 2 (4%) of the healthy controls presented with central sensitization (p < 0.01). AKP patients with CS have a greater degree of disability based on the Kujala Scale and higher levels of anxiety and depression than AKP patients without CS. The score of AKP patients in the CSI correlated weakly with disability and quality of life and moderately with anxiety and depression. However, no association was seen between CSI score and pain intensity, nor with catastrophizing and kinesiophobia. A multivariate logistic regression analysis showed that only depression was statistically significant in the prediction of the presence of CS (odds ratio 1.45; 95% CI 1.07 to 1.96). CONCLUSIONS: AKP patients have a significantly higher prevalence of CS in comparison with what has been reported for the general population. This finding suggests the presence of altered pain modulation in a subgroup of AKP patients. LEVEL OF EVIDENCE: Level III.

The crosstalk of the pathophysiologic models in fibromyalgia.

Fibromyalgia (FM) is a heterogeneous condition with various mechanisms (endotype) and manifestations (phenotypes). Many worthy endeavors have been dedicated to exploring the main trajectories of FM pathogenesis, depicted as the models of FM development. The Imbalance of Threat and Soothing Systems (FITSS) model, which is an advancing psychosocial form of the "central sensitization" model, and autonomic nervous system (ANS) model, besides new discoveries of potential pathways for FM development such as autoimmunity, small fiber pathology, and gut-brain axis currently comprise all our knowledge assets about FM pathogenesis. The pathophysiology of fibromyalgia is too complex to justify with one model, one main loop of pathogenesis, and one terminator. It appears that the variable FM models could justify some phenotypes of FM. Currently, our knowledge about FM pathogenesis and trying to match the different pathways and links mimic solving a puzzle in the hands of beginners. Until unraveling many missed interconnections and formulas between numerous scrambled pieces of the FM puzzle, proposing an integrated model seems not possible. This review focuses on the main trajectories of FM pathogenesis proposed thus far and tries to illuminate the crosstalking between them. We also propose the subgrouping FM into more homogenous categories based on the endotype-phenotype characteristics. It could provide a more pragmatic approach toward understanding of the diverse network of FM pathogenesis as well as the personalized stratification of FM. Key Points • The disentangled nature of FM pathogenesis escapes from embracing under one integrated model. • There appears to be no way for formulizing FM pathogenesis except the acknowledgment of the different pathways and their crosstalk explored as yet. • Acknowledging the different endotypes/phenotypes of FM spectrum and classifying them into more homogenous groups can help to the pragmatic approach to FM.

Negative correlation between central sensitization and forgotten joint score-12 after total hip arthroplasty.

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.

Evaluation of a scoring system for the detection of central sensitization among women with chronic pelvic pain.

BACKGROUND: Central sensitization is frequently associated with chronic pelvic pain and requires specific management. The pain is described as hypersensitivity to an innocuous stimulus that is both widespread and persistent. However, no study has evaluated if central sensitization can be measured objectively with neurophysiological tests in the pelvic and perineal area to prove this concept in women with chronic pelvic pain. OBJECTIVE: This study aimed to evaluate nociceptive thresholds (primary objective) and spatial and temporal diffusion of pain among women with chronic pelvic pain and high or low scores of central sensitization. STUDY DESIGN: This prospective, assessor-blinded, comparative study compared a cohort of women with chronic pelvic pain and a high (>5/10; n=29) vs low (<5/10; n=24) score of sensitization according to the Convergences PP criteria. Participants underwent a noninvasive bladder sensory test, a rectal barostat test, and a muscular (algometer) and a vulvar (vulvagesiometer) sensory test. Poststimulation pain (minutes), quality of life (Medical Outcomes Study 36-Item Short Form Survey), and psychological state, comprising anxiety (State-Trait Anxiety Inventory), depression (Beck Depression Inventory Short Form), and catastrophizing (Pain Catastrophizing Scale), were assessed. RESULTS: The participants mostly suffered from endometriosis (35.8%), irritable bowel syndrome (35.8%), bladder pain syndrome (32.1%), and vestibulodynia (28.3%). Baseline characteristics were similar. Women with a high sensitization score had more painful diseases diagnosed (2.7±1.3 vs 1.6±0.8; P=.002) and suffered for longer (11±8 vs 6±5 years; P=.028) than participants with a low score. The bladder maximum capacity was equivalent between participants (399±168 vs 465±164 mL; P=.18). However, the pain felt at each cystometric threshold was significantly increased in women with a high sensitization score. No difference was identified for the rectal pain pressure step (29.3±5.5 vs 30.7±6.5 mm Hg; P=.38). Rectal compliance was decreased in women with a high sensitization score with a considerable increase in pain felt. The average of pain pressure thresholds at the 5 vulvar sites tested was decreased in these participants (162.5±90.5 vs 358.7±196.5 g; P=.0003). Similar results were found for the average of the pain pressure thresholds at 6 muscles tested (1.34±0.41 vs 2.63±1.52 kg/m2; P=.0002). A longer period was needed for patients with high sensitization score to obtain a VAS <3 out of 10 after the stimulation of the bladder (4.52±5.26 vs 1.27±2.96 minutes; P=.01), the rectum (3.75±3.81 vs 1.19±1.23 minutes; P=.009), and the muscles (1.46±1.69 vs 0.64±0.40 minutes; P=.002). The psychological state was equivalent between groups. No association was found between the sensory thresholds and the psychological state results. The physical component of the quality of life score was reduced in women with high sensitization score (P=.0005), with no difference in the mental component. CONCLUSION: Using neurophysiological tests, this study showed that there are objective elements to assess for the presence of central sensitization, independently of psychological factors.

PACAP6-38 improves nitroglycerin-induced central sensitization by modulating synaptic plasticity at the trigeminal nucleus caudalis in a male rat model of chronic migraine.

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.