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Objectives: Chronic musculoskeletal pain is associated with decreased parasympathetic and increased sympathetic activity in the autonomic nervous system. The objective of this study was to determine the associations between objective measures of heart rate variability (a measure of autonomic nervous system function), actigraphy (a measure of activity and sleep quality), respiration rates, and subjective patient‐reported outcome measures (PROMs) of central sensitization, kinesiophobia, disability, the effect of pain on sleep, and life quality. Methods: Thirty‐eight study subjects were divided into two subgroups, including low symptoms of central sensitization (n = 18) and high symptoms of central sensitization (n = 20), based on patient‐reported scores on the Central Sensitization Inventory (CSI). Heart rate variability (HRV) and actigraphy measurements were carried out simultaneously in 24 h measurement during wakefulness and sleep. Results: A decrease in HRV during the first 2 h of sleep was stronger in the low CSI subgroup compared to the high CSI subgroup. Otherwise, all other HRV and actigraphy parameters and subjective measures of central sensitization, disability, kinesiophobia, the effect of pain on sleep, and quality of life showed only little associations. Discussion: The high CSI subgroup reported significantly more severe symptoms of disability, kinesiophobia, sleep, and quality of life compared to the low CSI subgroup. However, there were only small and nonsignificant trend in increased sympathetic nervous system activity and poorer sleep quality on the high central sensitization subgroup. Moreover, very little differences in respiratory rates were found between the groups. [ABSTRACT FROM AUTHOR]

Background: Controversy exists with the presence of alterations in descending pain inhibition mechanisms in patients with non‐specific neck pain (NSNP). The aim of the present study was to evaluate the status of conditioned pain modulation CPM, remote pressure pain thresholds (PPT), and psychological factors in a specific subgroup of patients with NSNP such as young adult students. In addition, possible associations between CPM, psychological factors, and pain characteristics were analyzed. Methods: Thirty students with recurrent or chronic NSNP and 30 pain‐free students were included in this cross‐sectional study. The following measures were assessed: CPM, remote PPT, psychological factors (depression, anxiety, pain catastrophizing, and kinesiophobia), pain characteristics (duration, intensity, severity of chronic pain, interference with daily life), and central sensitization inventory (CSI). Results: No significant differences were found in the efficacy of CPM between students with chronic or recurrent NSNP and pain‐free students (β coefficient = −0.67; 95% CI = −1.54, 0.20). However, students with pain showed a significantly higher remote PPT (mean difference = −1.94; 95% CI = −2.71, −1.18). and a greater presence of anxious (mean difference = 6; 95% CI = 2, 9) and depressive symptoms (mean difference = 8.57; 95% CI = 3.97, 13.16). In addition, significant moderate or strong correlations were found between CPM and pain intensity (partial r = 0.41), pain catastrophizing and mean pain intensity (r = 0.37), grade (r = 0.50), and interference of pain (r = 0.57), kinesiophobia and disability (r = 0.38), and depression and CSI (r = 0.39). Conclusions: Young adult students with chronic or recurrent NSNP present remote hyperalgesia and symptoms of depression and anxiety but not dysfunctional CPM. [ABSTRACT FROM AUTHOR]

Aim: To examine central sensitization (CS), and to investigate the relationship between CS, and urinary symptom severity, and quality of life (QoL) in women with overactive bladder (OAB). Materials and Methods: A total of 144 women with OAB included the study. CS with the Central Sensitization Inventory (CSI), urinary symptom with the Overactive Bladder Questionnaire‐Version 8 (OAB‐V8), bladder diary and Patients' Perception of Intensity of Urgency Scale (PPIUS) and QoL with the King's Health Questionnaire (KHQ) were assessed. Results: It was found that 47.9% (n = 69) of women with OAB had CS. It was observed that the CSI score was related to the OAB‐V8 score (ρ = 0.327; p < 0.001) and the average number of voids/day (ρ = 0.291; p < 0.001). Additionally, urgency severity was higher in women with OAB with CS than in women with OAB without CS (p = 0.006). There was a relationship between the CSI score and KHQ‐incontinence impact (ρ = 0.250; p = 0.012), KHQ‐personal relationship (ρ = 0.253; p = 0.002), KHQ‐sleep/energy (ρ = 0.180; p = 0.031), KHQ‐emotional state (ρ = 0.310; p < 0.001) and KHQ‐severity measurement scores (ρ = 0.391; p < 0.001). Conclusion: In this study, it was observed that the majority of women with OAB had CS. It was found that more severe symptoms of CS were associated with worse urinary symptom severity and QoL in these patients. It may be beneficial to evaluate CS in the management of OAB and to consider CS when determining treatment strategies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and Purpose: Nociplastic pain due to central sensitization (CS) is common in people suffering from chronic pain, but no clinical practice guideline is available in rehabilitative settings for patients' management. The aim of this study is to achieve expert consensus on physiotherapy competencies in the management of people with nociplastic pain and suspected CS mechanisms. Methods: A web‐based Delphi process was employed. Experts in the rehabilitation field were recruited following pre‐defined eligibility criteria. Following completion of three Delphi rounds, the final list of competencies was generated. Results: In all, 23 participants were recruited. They all completed Round 1 (23/23, 100%), twenty Round 2 and Round 3 (20/23, 87%). Following Round 1, seven areas were identified by the panel as crucial for CS physiotherapy management; 19 competencies out of 40 reached the consensus between experts, and nine additional competencies were added to Round 2 following literary review. Round 2 identified the agreement for all the 29 competencies. During Round 3, all the experts confirmed the final list generated through the consensus process. Discussion: An agreement between experts was found for the final list of competencies that a physiotherapist should implement every time it approaches people with suspected CS mechanisms. Further research is needed to support the clinical utility of our findings and their applicability in daily practice. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effect of treatment with anti‐calcitonin gene–related peptide (CGRP; receptor) antibodies on visual hypersensitivity in patients with migraine. Background: Increased visual sensitivity can be present both during and outside migraine attacks. CGRP has been demonstrated to play a key role in light‐aversive behavior. Methods: In this prospective follow‐up study, patients treated for migraine with erenumab (n = 105) or fremanezumab (n = 100) in the Leiden Headache Center were invited to complete a questionnaire on visual sensitivity (the Leiden Visual Sensitivity Scale [L‐VISS]), pertaining to both their ictal and interictal state, before starting treatment (T0) and 3 months after treatment initiation (T1). Using a daily e‐diary, treatment effectiveness was assessed in weeks 9–12 compared to a 4‐week pre‐treatment baseline period. L‐VISS scores were compared between T0 and T1. Subsequently, the association between the reduction in L‐VISS scores and the reduction in monthly migraine days (MMD) was investigated. Results: At 3 months, the visual hypersensitivity decreased, with a decrease in mean ± standard deviation (SD) ictal L‐VISS (from 20.1 ± 7.7 to 19.2 ± 8.1, p = 0.042) and a decrease in mean ± SD interictal L‐VISS (from 11.8 ± 6.6 to 11.1 ± 7.0, p = 0.050). We found a positive association between the reduction in MMD and the decrease in interictal L‐VISS (β = 0.2, p = 0.010) and the reduction in ictal L‐VISS (β = 0.3, p = 0.001). Conclusion: A decrease in visual hypersensitivity in patients with migraine after treatment with anti‐CGRP (receptor) antibodies is positively associated with clinical response on migraine. [ABSTRACT FROM AUTHOR]

Exercise‐induced hypoalgesia (EIH) has been found to vary widely within individuals with chronic neck pain (NP). Research has suggested that the presence of central sensitization within a subgroup of individuals with chronic NP might be a mediating factor to explain the relationship between exercise and improvements in patient‐reported outcomes. Furthermore, recent work has found that lactate might play a role in the development and maintenance of chronic pain. The immediate effect of a single bout of physical exercise on central sensitization in individuals with chronic NP and the relationship between lactate concentration, central sensitization and pain sensitivity are to be investigated. Eighty adult participants with chronic NP will be recruited for this randomized crossover trial. Outcome measures, including temporal summation, conditioned pain modulation, EIH and lactate concentration, will be assessed before and after low‐ and high‐intensity bicycling exercise. The outcomes of this study will provide new insights into the mechanistic effect of exercise on central sensitization in individuals with chronic NP and have the potential to add important information to the current exercise prescription guidelines for individuals with chronic NP. This study has been approved by the Human Research Ethics Committee, The University of Adelaide (H‐2022‐082) and registered in the Australian New Zealand Clinical Trials Registry (ACTRN12622000642785p). [ABSTRACT FROM AUTHOR]

Background: Irritable bowel syndrome (IBS) is characterized as a central sensitization syndrome (CSS), a group of conditions including fibromyalgia, chronic fatigue, and restless leg syndrome (RLS) among others with frequent comorbidities of anxiety, depression, and chemical sensitivity. The prevalence of comorbid conditions and their impact on IBS symptom severity and quality of life in rural community populations has not been described. Methods: We administered a cross‐sectional survey to patients with a documented CSS diagnosis in rural primary care practices to evaluate the relationship between CSS diagnoses, quality of life, symptom severity, and interactions with healthcare providers utilizing validated questionnaires. Subgroup analysis was performed on the IBS cohort. Mayo Clinic IRB approved the study. Key Results: Seven hundred seventy‐five individuals out of 5000 completed the survey (15.5% response rate) with 264 (34%) reporting IBS. Only 3% (n = 8) of IBS patients reported IBS alone without comorbid CSS condition. Most respondents reported overlapping migraine (196, 74%), depression (183, 69%), anxiety (171, 64%), and fibromyalgia (139, 52%). IBS patients with more than two comorbid CS condition showed significantly higher symptom severity with linear increase. Quality of life was lower in IBS with comorbid conditions, particularly in patients with IBS and RLS (mean EQ5‐D 0.36 vs. 0.8 in IBS only, p < 0.01). Quality of life declined as number of comorbid conditions increased. Conclusions & Inferences: Patients with IBS often have multiple CS disorders which increases symptom severity and lowers quality of life. Understanding the impact of multiple CSS diagnoses and treating these as a global condition may improve patient experience. [ABSTRACT FROM AUTHOR]

Dry eye disease (DED) affects nearly 55% of people worldwide; several studies have proposed that central sensitization and neuroinflammation may contribute to the developing corneal neuropathic pain of DED, while the underlying mechanisms of this contribution remain to be investigated. Excision of extra orbital lacrimal glands established the dry eye model. Corneal hypersensitivity was examined through chemical and mechanical stimulation, and open field test measured the anxiety levels. Restingstate fMRI is a method of functional magnetic resonance imaging (rs‐fMRI) was performed for anatomical involvement of the brain regions. The amplitude of low‐frequency fluctuation (ALFF) determined brain activity. Immunofluorescence testing and Quantitative real‐time polymerase chain reaction were also performed to further validate the findings. Compared with the Sham group, ALFF signals in the supplemental somatosensory area, secondary auditory cortex, agranular insular cortex, temporal association areas, and ectorhinal cortex brain areas were increased in the dry eye group. This change of ALFF in the insular cortex was linked with the increment in corneal hypersensitivity (p < 0.01), c‐Fos (p < 0.001), brain‐derived neurotrophic factor (p < 0.01), TNF‐α, IL‐6, and IL‐1β (p < 0.05). In contrast, IL‐10 levels (p < 0.05) decreased in the dry eye group. DED‐induced corneal hypersensitivity and upregulation of inflammatory cytokines could be blocked by insular cortex injection of Tyrosine Kinase receptor B agonist cyclotraxin‐B (p < 0.01) without affecting anxiety levels. Our study reveals that the functional activity of the brain associated with corneal neuropathic pain and neuroinflammation in the insular cortex might contribute to dry eye‐related corneal neuropathic pain. [ABSTRACT FROM AUTHOR]

Introduction: Exercise is the most recommended treatment for chronic low back pain (CLBP) and is effective in reducing pain, but the mechanisms underlying its effects remain poorly understood. Exercise‐induced hypoalgesia (EIH) may play a role and is thought to be driven by central pain modulation mechanisms. However, EIH appears to be disrupted in many chronic pain conditions and its presence in people with CLBP remains unclear. As people suffering from chronic pain often exhibit psychological factors and central sensitization symptoms influencing pain perception, EIH might be associated with these factors. Objective: The aim of this study is to compare the level of EIH between participants with and without CLBP following back and wrist exercises and to assess the associations between EIH, psychological factors, and symptoms of central sensitization (using the central sensitization inventory ‐ CSI) in CLBP. Method: Twenty‐eight participants with CLBP and 23 without pain were recruited. Pressure pain thresholds (PPT) were measured at 4 sites (2 bony sites = capitate, S1|2 muscle sites = wrist flexors, lumbar erector spinae) before and after each of two exercises (wrist flexion and lumbar extension). Exercise‐induced hypoalgesia was defined as percent change in PPT from pre‐ to post‐exercise. Participants with CLBP also completed questionnaires to measure psychological factors (e.g., kinesiophobia, catastrophizing, anxiety, and self‐efficacy) and symptoms of central sensitization (CSI), and correlations with EIH were calculated. Results: After wrist exercise, EIH measured at the muscle sites was lower in the CLBP group compared with the pain‐free group (p = 0.047) but no differences were found at bony sites (p = 0.49). No significant differences for EIH were observed following back exercise at muscle sites (p = 0.14) or at bony sites (p = 0.65). Exercise‐induced hypoalgesia was not correlated with any psychological factors or with the CSI score. Conclusion: The lower EIH following wrist exercises may represent an alteration in pain modulation control in CLBP. However, psychological factors and central sensitization symptoms may not explain the differences observed. [ABSTRACT FROM AUTHOR]

Diseases of joints are among the most frequent causes of chronic pain. In the course of joint diseases, the peripheral and the central nociceptive system develop persistent hyperexcitability (peripheral and central sensitization). This review addresses the mechanisms of spinal sensitization evoked by arthritis. Electrophysiological recordings in anesthetized rats from spinal cord neurons with knee input in a model of acute arthritis showed that acute spinal sensitization is dependent on spinal glutamate receptors (AMPA, NMDA, and metabotropic glutamate receptors) and supported by spinal actions of neuropeptides such as neurokinins and CGRP, by prostaglandins, and by proinflammatory cytokines. In several chronic arthritis models (including immune‐mediated arthritis and osteoarthritis) spinal glia activation was observed to be coincident with behavioral mechanical hyperalgesia which was attenuated or prevented by intrathecal application of minocycline, fluorocitrate, and pentoxyfylline. Some studies identified specific pathways of micro‐ and astroglia activation such as the purinoceptor‐ (P2X7‐) cathepsin S/CX3CR1 pathway, the mobility group box‐1 protein (HMGB1), and toll‐like receptor 4 (TLR4) activation, spinal NFκB/p65 activation and others. The spinal cytokines TNF, interleukin‐6, interleukin‐1β, and others form a functional spinal network characterized by an interaction between neurons and glia cells which is required for spinal sensitization. Neutralization of spinal cytokines by intrathecal interventions attenuates mechanical hyperalgesia. This effect may in part result from local suppression of spinal sensitization and in part from efferent effects which attenuate the inflammatory process in the joint. In summary, arthritis evokes significant spinal hyperexcitability which is likely to contribute to the phenotype of arthritis pain in patients. [ABSTRACT FROM AUTHOR]

Background and Purpose: Sleep problems are common in individuals with chronic low back pain (CLBP). Central sensitization (CS) is present in a subgroup of individuals with CLBP. However, our knowledge about whether sleep quality varies between the subgroups of CLBP is limited. Therefore, we sought to examine whether the subgroup of CLBP with CS has poorer sleep quality than the subgroup without CS. Methods: 2011 Fibromyalgia Survey (2011 FM survey) was used as a surrogate measure of CS to divide the CLBP participants into two subgroups: CLBP with CS and CLBP without CS. We also created a CS index comprising a set of quantitative sensory testing measures (i.e., pressure pain thresholds, conditioned pain modulation) to evaluate pain sensitivity. Sleep quality was assessed with Pittsburgh Sleep Quality Index (PSQI). Group differences about PSQI and CS index and associations between sleep quality and CS across the groups were analyzed. Results: We included 60 participants with CLBP and 23 healthy controls (HCs). Overall, 80% of the participants with CLBP presented with poor sleep quality. Participants with CLBP with CS showed significantly higher PSQI scores (poorer sleep) than participants with CLBP without CS and HCs (p < 0.05). Both the 2011 FM survey and CS index were significantly correlated with sleep quality (r = 0.5870, p < 0.001 and r = −0.264, p = 0.04). Logistic regression models revealed that the FM status (odds ratio (OR) = 6.00, p = 0.02 [95% confidence interval: 1.31–42.1]), but not the CS index (OR = 1.11, p = 0.79 [95% CI: 0.48–2.71]) was associated with PSQI. After adjusting covariates, the results remained similar but became non‐significant for the FM status. Discussion: We found that sleep problems were more common and severe in those who exhibited signs of CS. Thus, clinicians may consider using 2011 FM survey to identify those with CS and co‐existing sleep problems. [ABSTRACT FROM AUTHOR]

Objectives: Signals from inflamed tooth pulp activate thalamic neurons to evoke central sensitization. We aimed to gain insights into the mechanisms mediating the early phase of pulpal inflammation‐induced thalamic neural and glial activation. Materials and Methods: Pulpal inflammation was induced via the application of mustard oil (MO) to the upper first molar of Wistar rats with local anesthesia (LA) or saline injection. After 0.5, 1, 2, and 24 hr, contralateral thalami were subjected to microarrays, a real‐time polymerase chain reaction and immunohistochemistry to identify differentially expressed genes and assess potassium voltage‐gated channel subfamily A member 1 (Kv1.1)‐expressing axons and glial fibrillary acidic protein (GFAP)‐expressing astrocytes. Results: The Kv1.1 gene (Kcna1) was down‐regulated and the density of Kv1.1‐expressing axons decreased in non‐anesthetized rats, but not in anesthetized rats 1 hr after the MO treatment. The density of GFAP‐expressing astrocytes increased in both groups until 24 hr after the MO treatment, with a greater increase being observed in the saline‐injection group than in the LA group. Conclusions: MO induced the transient down‐regulation of Kcna1, transiently reduced the density of Kv1.1‐expressing axons, and increased astrocytes in thalami within 1 hr of pulpal application. These results suggest central sensitization represented by neuronal hyperexcitability and astrocyte activation. [ABSTRACT FROM AUTHOR]

Aims: There is no clear pathophysiologic evidence determining how long overactive bladder (OAB) medication should be continued. We, therefore, investigated the effect of mirabegron using cessation (CES) or continuation (CON) treatment in an OAB animal model. Methods: Female C57BL/6 mice were divided into four groups (N = 8 each): Sham, OAB, CES, and CON groups. The OAB‐like condition was induced by three times weekly intravesical instillations of KCl mixture with hyaluronidase. After the last intravesical instillation for inducing OAB, mirabegron (2 mg/kg/day) was administered in CES and CON groups for 10 and 20 days, respectively. Final experiments were carried out on 20 days from the last intravesical instillation in all groups. After cystometry, mRNA levels of bladder muscarinic, β‐adrenergic, and P2X purinergic receptors were measured to investigate bladder efferent and afferent activity. In addition, mRNA levels of CCL2 and CCR2 in L6‐S1 dorsal root ganglia (DRG) were measured to assess afferent sensitization. Immunofluorescent staining of CX3CR1, GFAP, and CCR2 in the L6 spinal cord was also conducted to investigate glial activation and central sensitization. Results: OAB mice showed bladder overactivity evidenced by decreased intercontraction interval (3.56 ± 0.51 vs. 5.76 ± 0.95 min in sham mice), increased non‐voiding contractions (0.39 ± 0.11 vs. 0.13 ± 0.07/min in sham mice), and inefficient voiding (72.1 ± 8.6% vs. 87.1 ± 9.5% in sham mice). Increased M2, M3, β2, β3, P2X2, P2X3, P2X4, and P2X7 levels in the bladder and increased CCL2 and CCR2 in DRG indicate bladder efferent and afferent hyperexcitability. In addition, CX3CR1, GFAP, and CCR2 in the L6 spinal cord were upregulated in OAB mice. However, the CON group exhibited reduced β2, β3, P2X2, P2X3, P2X4, and P2X7 levels in the bladder, reduced CCL2 and CCR2 in DRG, which are markers of afferent hyperexcitability, and reduced immunoreactivities of CX3CR1, GFAP, and CCR2 in the L6 spinal cord, which are markers of the central sensitization. Moreover, the CON group showed better improvements in nonvoiding contractions (0.16 ± 0.09 vs. 0.44 ± 0.17/min) and voiding efficiency (93.9 ± 7.4% vs. 76.5 ± 13.1%) and reductions in bladder β3 receptors and CCL2 of L6‐S1 DRG, and immunoreactivities of CX3CR1 and GFAP in the L6 spinal cord compared to the CES group. Conclusions: Continuous mirabegron treatment seems to prevent central sensitization and, thus, might be desirable for long‐term disease control of OAB. [ABSTRACT FROM AUTHOR]

Objectives: The clinical utility of combining the central sensitization (CS) inventory (CSI) with the pressure pain threshold (PPT) in assessing the effect of central sensitization on pain is unknown. This study aimed to investigate the effects of CSI, PPT, and their interaction on pain and the characteristics of clinical symptoms in patients with chronic musculoskeletal pain grouped according to the CSI score and PPT value. Method: A total of 187 participants with chronic musculoskeletal pain were recruited. PPT, brief pain inventory, widespread pain index, pain catastrophizing scale, EuroQol‐5 dimension, and CSI were assessed. Multiple regression analyses were performed using pain intensity and interference scores as dependent variables and the CSI score and PPT value as independent variables. Hierarchical cluster analysis was also performed to classify the participants into subgroups according to the CSI score and PPT value. Following the classification, pain‐related characteristics and health‐related QOL were compared among the subgroups. Results: Multiple regression analyses demonstrated that only the CSI score significantly affected pain intensity and interference. As a result of the cluster analysis, three groups were identified: cluster 1 (n = 61, CSI low/PPT low group), cluster 2 (n = 78, CSI low/PPT high group), and cluster 3 (n = 48, CSI high/PPT low group). The CSI high/PPT low group had a higher incidence of pain‐related symptoms than the CSI low group regardless of the PPT value. Conclusions: Combined CSI and PPT may not fully allow a detailed classification of pain‐related characteristics. The CSI may be clinically more useful for assessing the effect of CS on pain‐related symptoms. [ABSTRACT FROM AUTHOR]

Background: Central sensitization (CS), defined as the amplification of neural signaling within the CNS that elicits pain hypersensitivity, is thought be a characteristic of several chronic pain conditions. Maladaptive body awareness is thought to contribute and maintain CS. Less is known about the relationship between CS and adaptive body awareness. Purpose: This cross‐sectional study investigated relationships among self‐reported adaptive body awareness (Multidimensional Interoceptive Awareness Scale‐2; MAIA‐2), CS‐related symptoms (Central Sensitization Inventory; CSI), and pain intensity and further delineate potential direct and indirect links among these constructs. Methods: Online surveys were administered to 280 individuals with chronic pain reporting elevated CSI scores. Strategic sampling targeted respondents to reflect the 2010 census. Pearson's correlations characterized overall relationship between variables. Multiple regression analyses investigated potential direct links. A path analysis assessed mediational effects of CS‐related symptoms on the relationship between adaptive body awareness and pain intensity. Results: CSI demonstrated strong, inverse correlations with some MAIA‐2 subscales, but positive correlations with others. Higher CSI scores predicted greater pain intensity (b = 0.049, p ≤ 0.001). Two MAIA‐2 subscales, Not‐Distracting (b = −0.56, p ≤ 0.001) and Not‐Worrying (b = −1.17, p ≤ 0.001) were unique predictors of lower CSI. Not‐Distracting (b = −0.05, p = 0.003) and Not‐Worrying (b = −0.06, p = 0.007) uniquely predicted lower pain intensity. CSI completely mediated the relationship between adaptive body awareness and pain intensity [point estimate = −0.04; 95% bootstrap confident intervals (CI) = −0.05 to −0.02]. Conclusions: Findings also support future research to explore causal relationships of variables. Findings suggest that frequency of attention to bodily sensations is distinct from cognitive‐affective appraisal of bodily sensation, and the two distinct higher order processes may have divergent influences on perceived pain and CS‐related symptoms. Results also support future research to explore causal relationships of variables. [ABSTRACT FROM AUTHOR]

A significant proportion of patients do not experience relief from pain during the early postsurgical period after joint arthroplasty and are at risk for developing chronic pain. The objectives of this study were to identify biopsychosocial factors associated with acute postsurgical pain trajectories and with pain intensity and interference after 1, 3, and 12 months. Two hundred ten patients listed for joint arthroplasty filled a presurgical battery of questionnaires assessing presurgical pain intensity, catastrophizing, emotional distress, state anxiety and depression, self‐efficacy, central sensitization, and executive functions. From the day after surgery, they were asked to fill a 7‐day diary, including questions about postsurgical pain and postsurgical state catastrophizing. Finally, they provided data about pain intensity and interference after 1, 3, and 12 months. Predictors of acute pain trajectories were investigated using multilevel growth curve analysis. Results showed that central sensitization was a predictor of the intercept of pain trajectories and daily postsurgical catastrophizing was a significant covariate of pain intensity in the acute phase. Analyses of follow‐up data showed that central sensitization was a predictor of pain intensity and pain interference at 3 and 12 months, that emotional distress was related with pain intensity and interference at 1 month, and with pain interference at 3 months, and that cognitive flexibility was associated with pain interference at 1 month. Assessment of these factors could enable to identify patients at risk for worse outcomes and to plan targeted treatments to be implemented during the patient's inward stay. [ABSTRACT FROM AUTHOR]

Background and Purpose: The manipulation of sensory conditions and attentional demand affect the postural sway in older adults with knee osteoarthritis (KOA). However, it is not known if emotional and sensitization status affects postural sway in this population. This study aimed to test if older adults with mild and moderate knee osteoarthritis with symptoms of depression and high sensitization would change the profile of postural sway. Methods: Design: A cross‐sectional study was undertaken. Participants: The center of pressure parameters of 30 older adults with mild and moderate knee osteoarthritis and 15 healthy controls were evaluated under different conditions manipulating the visual and attentional demand. We used the pressure pain threshold to measure the sensitization status. Furthermore, we applied the Beck Depression Inventory index to assess emotional status. Results: Manipulating the visual demand affected the center of pressure parameters for both groups, without differences between them. Compared to the healthy control group, the knee osteoarthritis group presented with worse scores on the Beck Depression Inventory, lower pressure pain threshold scores, and the correlations between the symptoms of depression and sensitization status ranged from weak to moderate. Finally, in the knee osteoarthritis group, we observed few and weak significant associations between the center of pressure parameters and the Beck Depression Inventory and the pressure pain threshold scores. Discussion: Emotional and sensitization status seem not to be more associated with the center of pressure of older adults with mild to moderate KOA than healthy adults. Thus, it suggests that this population can safely maintain postural sway, irrespective of depression symptoms and high sensitization. [ABSTRACT FROM AUTHOR]

Background: Proinflammatory mechanisms are implicated in pain states. Recent research indicates that patients with osteoarthritis (OA) with signs of central sensitization exhibit elevated cerebrospinal fluid (CSF) levels of interferon gamma‐induced protein 10 (IP‐10), Fms‐related tyrosine kinase 1 (Flt‐1), and monocyte chemoattractant protein 1 (MCP‐1). Methods: The current prospective cohort study, including 15 patients with OA, primarily aimed to evaluate associations among alterations in CSF IP‐10, Flt‐1, MCP‐1, and pain sensitization following total hip arthroplasty (THA). Participants provided CSF and blood samples for analysis of 10 proinflammatory mediators, and underwent detailed clinical examination and quantitative sensory testing, immediately preoperative and 18 months after surgery. Results: Neurophysiological measures of pain showed markedly reduced pain sensitivity long‐term postoperative. Increases in remote site pressure pain detection thresholds (PPDTs) and decreased temporal summation indicated partial resolution of previous central sensitization. Compared to preoperative, CSF concentrations of IP‐10 were increased (p = 0.041), whereas neither Flt‐1 (p = 0.112) nor MCP‐1 levels changed (p = 0.650). Compared to preoperative, plasma concentrations of IP‐10 were increased (p = 0.006), whereas interleukin (IL)‐8 was decreased (p = 0.023). Subjects who exhibited increases in arm PPDTs above median showed greater increases in CSF IP‐10 compared to those with PPDT increases below median (p = 0.028). Analyses of plasma IP‐10 and IL‐8 indicated higher levels of peripheral inflammation were linked to decreased pressure pain thresholds (unadjusted β = −0.79, p = 0.006, and β = −118.1, p = 0.014, respectively). Conclusions: THA leads to long‐term decreases in pain sensitivity, indicative of resolution of sensitization processes. Changes in CSF and plasma levels of IP‐10, and plasma IL‐8, may be associated with altered pain phenotype. [ABSTRACT FROM AUTHOR]

Background: Central sensitization has been suggested as an explanation of the wide range of gastrointestinal and extraintestinal symptoms commonly seen in irritable bowel syndrome (IBS). In this study, the presence and level of central sensitization, and its association to gastrointestinal (GI) symptoms were explored in IBS in comparison with control groups. Methods: We investigated patients with IBS (n = 215), chronic pain disorders (n = 36), and inflammatory bowel disease (IBD) (n = 40) and volunteers without chronic diseases (n = 112). The Central Sensitization Inventory (CSI) was translated and validated in Swedish and used together with the Highly Sensitive Person (HSP) scale to measure the presence and level of central sensitization. Furthermore, severity of GI symptoms (GSRS‐IBS and IBS‐SSS), and anxiety and depression (HAD) were determined. Key results: The Swedish translation of CSI demonstrated excellent validity. Central sensitization, defined by validated cut‐off levels for CSI and HSP, was common in the whole cohort (40% and 28%) and in IBS (57% and 35%). Study participants with central sensitization had more severe GI symptoms, anxiety and depression, than participants without central sensitization. Strong associations were seen between CSI and GI symptom severity in the whole cohort (GSRS‐IBS: partial η2 = 0.455, p < 0.001; IBS‐SSS: partial η2 = 0.408, p < 0.001), with decreasing strength in patients with chronic pain, IBD, IBS, and volunteers. Conclusion and Inferences: Central sensitization was common in IBS and associated with GI symptom severity, but with stronger associations in chronic pain disorders and IBD. This implies that other mechanisms may be of equal or greater importance for GI symptom severity in IBS. [ABSTRACT FROM AUTHOR]

Introduction: One of the most widely used instruments to identify symptoms that may be related to central sensitization is the Central Sensitization Inventory (CSI). Although this instrument has been translated and validated in Spanish patients with chronic musculoskeletal pain, no psychometric analysis has been carried out in breast cancer survivors. The aim of this study was to perform a psychometric analysis of the Spanish version of the Central Sensitization Inventory (CSI‐Sp) in Spanish breast cancer survivors. Materials and Methods: A validation study was carried out in 183 breast cancer survivors. A psychometric analysis of internal consistency, factor structure, and test‐retest reliability of the CSI‐Sp was performed. Internal consistency was determined using Cronbach's alpha. Test‐retest reliability was evaluated using the Intraclass Correlation Coefficient (ICC) Type 2.1. Exploratory factor analysis was used to determine the internal structure of the questionnaire. Results: The internal consistency was high (α = 0.91). The test‐retest reliability was satisfactory with excellent values (ICC 2.1 = 0.95). The exploratory factor analysis yielded a one factor structure explaining the 33.88% of total variance. Conclusions: The CSI‐Sp has demonstrated to be a psychometrically strong measure for assessing central sensitization symptoms in breast cancer survivors based on internal consistency, test‐retest reliability, and structural validity. Further studies that analyze other measurement properties in different Spanish clinical populations are needed. [ABSTRACT FROM AUTHOR]

Both spinal tumor necrosis factor (TNF) and interleukin‐6 (IL‐6) contribute to the development of "mechanical" spinal hyperexcitability in inflammatory pain states. Recently, we found that spinal sensitization by TNF was significantly reduced by blockade of spinal IL‐6 signaling suggesting that IL‐6 signaling is involved in spinal TNF effects. Here, we explored whether spinal interleukin‐1β (IL‐1β), also implicated in inflammatory pain, induces "mechanical" spinal hyperexcitability, and whether spinal IL‐1β effects are related to TNF and IL‐6 effects. We recorded the responses of spinal cord neurons to mechanical stimulation of the knee joint in vivo and used cellular approaches on microglial and astroglial cell lines to identify interactions of IL‐1β, TNF, and IL‐6. Spinal application of IL‐1β in anesthetized rats modestly enhanced responses of spinal cord neurons to innocuous and noxious mechanical joint stimulation. This effect was blocked by minocycline indicating microglia involvement, and significantly attenuated by interfering with IL‐6 signaling. In the BV2 microglial cell line, IL‐1β, like TNF, enhanced the release of soluble IL‐6 receptor, necessary for spinal IL‐6 actions. Different to TNF, IL‐1β caused SNB‐19 astrocytes to release interleukin‐11. The generation of "mechanical" spinal hyperexcitability by IL‐1β was more pronounced upon spinal TNF neutralization with etanercept, suggesting that concomitant TNF limits IL‐1β effects. In BV2 cells, TNF stimulated the release of IL‐1Ra, an endogenous IL‐1β antagonist. Thus, spinal IL‐1β has the potential to induce spinal hyperexcitability sharing with TNF dependency on IL‐6 signaling, but TNF also limited IL‐1β effects explaining the modest effect of IL‐1β. [ABSTRACT FROM AUTHOR]

Objectives: The COVID‐19 crisis is a significant stressor worldwide. The physical and emotional condition of individuals with pain sensitization syndromes who are experiencing the pandemic may worsen. This study investigated the contribution of life changes due to the coronavirus to emotional distress in individuals with a diagnosis of chronic central sensitization pain and tested whether the associations between level of pain and sensitization were independent of or mediated by emotional distress. Methods: Spanish individuals with chronic pain (N = 362) completed an online survey on direct or indirect exposure to the consequences of COVID‐19, pain intensity, and emotional distress. They also completed central sensitization questionnaires. Results: An association was found between changes in daily routines and pain intensity, emotional distress, and sensitization scores. Correlations were found between emotional distress, sensitization, and pain intensity. Significant predictors of emotional distress were age, difficulty in receiving medical care, changes in daily routines, and diminished social support. Emotional distress did not mediate the association between sensitization and pain intensity. Conclusion: Due to the COVID‐19 situation, individuals with central sensitization pain syndromes may be at higher risk of developing psychological distress. Interdisciplinary interventions involving psychologists are urgently needed to provide this population with appropriate health care. [ABSTRACT FROM AUTHOR]

Purpose: To explore the effects of chronic, uncontrolled glaucoma on pressure sensitivity in dogs before and after enucleation of the painful globe. Methods: Client‐owned dogs undergoing enucleation for chronic glaucoma with no other sources of pain were enrolled. Normal dogs of similar breeds and skull morphology were enrolled as controls. Craniofacial ratio (CFR) and relative palpebral fissure width (RPFW) were assessed in all patients. Serial mechanical quantitative sensory testing (QST) was performed the day before surgery, and 14, 30, 60, and 120 days after surgery. QST consisted of electronic Von Frey (eVF), and blunt algometry (BA) performed above and below the nonglaucomatous eye, the metacarpus, and metatarsus. Cochet‐Bonnet esthesiometry (CB) was also performed on the remaining eye. Results: Twelve dogs (6 per group) were included. Compared to baseline values, sensitivity tended to decrease over time (increased thresholds) in treatment dogs while it stayed constant or increased slightly in control dogs. The difference in change from baseline sensitivity between control and treatment groups was significant at day 120 using BA at supraorbital (P =.0153), infraorbital (P =.0209), and metacarpal sites (P =.007) and overall (P =.0470). This divergence was also significant using CB (P =.0470) on the opposite cornea. As patient CFR and RPFWV increased, both eVF (P =.005‐.023) and BA (P =.004‐.041) increased. Conclusions: Sensitivity to mechanical stimuli decreased both locally and at remote sites in dogs following enucleation for painful chronic glaucoma. Cranial conformation is associated with differences in sensitivity. [ABSTRACT FROM AUTHOR]

Central sensitization is the potential pathogenesis of chronic migraine (CM) and is related to persistent neuronal hyperexcitability. Dysfunction of excitatory amino acid transporter 2 (EAAT2) leads to the accumulation of glutamate in the synaptic cleft, which may contribute to central sensitization by overactivating glutamate N‐methyl‐D‐aspartate receptors and enhancing synaptic plasticity. However, the therapeutic potential of CM by targeting glutamate clearance remains largely unexplored. The purpose of this study was to investigate the role of EAAT2 in CM central sensitization and explore the effect of EAAT2 expression enhancer LDN‐212320 in CM rats. The glutamate concentration was measured by high‐performance liquid chromatography in a rat model of CM. Then, q‐PCR and western blots were performed to detect EAAT2 expression, and the immunoreactivity of astrocytes was detected by immunofluorescence staining. To understand the effect of EAAT2 on central sensitization of CM, mechanical and thermal hyperalgesia and central sensitization‐associated proteins were examined after administration of LDN‐212320. In addition, the expression of synaptic‐associated proteins was examined and Golgi‐Cox staining was used to observe the dendritic spine density of trigeminal nucleus caudalis neurons. Also, the synaptic ultrastructure was observed by transmission electron microscope (TEM) to explore the changes of synaptic plasticity. In our study, elevated glutamate concentration and decreased EAAT2 expression were found in the trigeminal nucleus caudalis of CM rats, administration of LDN‐212320 greatly up‐regulated the protein expression of EAAT2, alleviated hyperalgesia, decreased the concentration of glutamate and the activation of astrocytes. Furthermore, reductions in calcitonin gene‐related peptide, substance P(SP), and phosphorylated NR2B were examined after administration of LDN‐212320. Moreover evaluation of the synaptic structure, synaptic plasticity‐, and central sensitization‐related proteins indicated that EAAT2 might participate in the CM central sensitization process by regulating synaptic plasticity. Taken together, up‐regulation of EAAT2 expression has a protective effect in CM rats, and LDN‐212320 may have clinical therapeutic potential. Cover Image for this issue: https://doi.org/10.1111/jnc.14769. [ABSTRACT FROM AUTHOR]

Chronic overlapping pain conditions (COPCs) are conditions that share several clinical characteristics and symptomatology, are usually considered idiopathic in nature, and are frequently comorbid. Currently, there are no established inclusion criteria to determine which conditions should be included under this umbrella term despite different systems proposed. Persistent dentoalveolar pain disorder (PDAP), also referred to as atypical odontalgia and thought to be a component of persistent idiopathic facial pain, is a chronic pain condition that manifests as a persistent tooth pain or pain over a dentoalveolar site formerly occupied by a tooth in the absence of detectable pathology during clinical or radiological examination. PDAP is considered idiopathic in nature, and its pathophysiological mechanisms are not fully understood. Our objective was to investigate whether PDAP fits the conceptual paradigm of COPC given its characteristics and commonalities with other COPC, based on published literature identified through a scoping review. We found that PDAP fits 16 out of 18 common characteristics among COPCs, and based on this finding, we discuss the implications of PDAP being considered a COPC. [ABSTRACT FROM AUTHOR]

Objectives: The goal of the present study was to explore additional evidence of validity of the Serbian version of the Central Sensitization Inventory (CSI), a patient‐reported outcome measure of symptoms that have been found to be associated with central sensitization (CS). The CSI has been found to be psychometrically sound, and has demonstrated evidence of convergent and discriminant validity in numerous published studies and in multiple languages. Methods: CSI data were collected from 399 patients with chronic pain who had various diagnoses and from 146 pain‐free controls. In addition, the patient sample completed a battery of validated patient‐reported outcome measures of sleep problems, cognitive problems, pain catastrophizing, pain‐related fear‐avoidance, decreased quality of life, and decreased perception of social support. Six patient subgroups were formed, with presumably different levels of CS (including those with fibromyalgia, multiple pain sites, and localized pain sites). Results: Significant differences were found in total CSI scores among the controls and patient subgroups. Those with fibromyalgia and multiple pathologies scored highest and the control subjects scored lowest. Other patient‐reported CS‐related symptom dimensions were significantly correlated with total CSI scores. When the patients were divided into CSI severity subgroups (from subclinical to extreme), the severity of these other symptom dimensions increased with the severity of CSI scores. Conclusions: The current study successfully demonstrated additional evidence of the convergent and discriminant validity of the Serbian version of the CSI. [ABSTRACT FROM AUTHOR]

Objective: To clarify the detailed clinical characteristics of cranial autonomic symptoms (CAS) of Japanese patients with migraine and to get insight into the pathophysiological implications. Background: Recent studies reported that CAS in migraine is causing diagnostic confusion with cluster headache or sinus headache; however, most reports have concerned Caucasians, and Asian data are scarce. The regional differences in the clinical characteristics of primary headaches between Caucasians and Asians have also been revealed recently. Method: This was a cross‐sectional study. We investigated 373 patients with migraine in a tertiary headache center with face‐to‐face interviews. Results: According to our findings, 158/373 (42.4%) patients with migraine had CAS and were characterized by more frequent cutaneous allodynia than those without CAS, suggesting the contribution of central sensitization; however, there were no statistically significant differences in pulsating pain or motion sensitivity as signs of peripheral sensitization. In contrast to the previous study, osmophobia was found to be significantly related to CAS. Conclusion: CAS in patients with migraine is common not only in Caucasians but also in Asians. Central sensitization seems to contribute more than peripheral sensitization to CAS manifestation, and osmophobia might be noteworthy among Asian patients with migraine. To avoid a misdiagnosis, we emphasize the need for comments on CAS in the international classification of headache disorders migraine criteria. [ABSTRACT FROM AUTHOR]

Background: Central sensitization (CS) is a form of neuroplasticity characterized by changes in the neural sensitivity, responsiveness, and/or output that are not contingent on peripheral input nor activity-dependent. CS is characterized by activation of unmyelinated C-fibers resulting in a cascade of events at molecular and cellular levels which eventuate into generation of synaptic currents at rest. CS, therefore, contributes to heightened generalized pain sensitivity, further complicates the process of reaching a diagnosis, and increases the possibility of treatment failure. BODY: Trigeminal nerve is the main sensory supplier of the anterior part of the head, including the intraoral structures. Primary afferent nociceptors of the trigeminal nerve and low threshold mechanoreceptors synapse with wide dynamic range (WDR) neurons in the pons. This multifaceted network of nerve interactions which is further complicated by the modulatory circuits that can suppress or heighten the activity of WDR neurons is one of the main contributors to CS. The importance of CS in orofacial pain disorders is emphasized in the context of chronic pain development. As for all chronic pain conditions, it is crucial to consider the biopsychosocial aspects of chronic orofacial pain in managing this diverse group of conditions. This review highlights current understanding of the biopsychosocial model and central mechanisms contributing to the pathogenesis of chronic orofacial pain. [ABSTRACT FROM AUTHOR]

Background: Central sensitization may be present in some patients with hip osteoarthritis (OA), often reflected as widespread pain. We examine the association between pain extent with signs of central sensitization and other clinical and psychological features in patients with hip OA. Methods: Thirty patients with hip OA were recruited for this cross‐sectional observational study. Participants completed pain drawings on a digital tablet, which displayed frontal and dorsal views of the body. The pain extent (%) for each participant was determined by combining the frontal and dorsal pixels shaded and dividing by the total pixels of the body chart area. Participants completed patient‐reported outcome measures to assess for signs and symptoms of central sensitization and psychosocial factors. Quantitative sensory testing including pain pressure thresholds (PPTs) and thermal pressure thresholds was performed at points anatomically local and distant from the hip. Results: Women had significantly greater pain extent (6.71%) than men (2.65%) (z = −2.76, P < 0.01). Across all participants, increased pain extent was significantly associated with higher scores on the Widespread Pain Index (r2 = 0.426, P < 0.05), painDETECT questionnaire (r2 = 0.394, P < 0.05), and Pain Catastrophizing Scale (r2 = 0.413, P < 0.05), and with lower PPTs at the thenar eminence (r2 = −0.410, P < 0.05), vastus lateralis (r2 = −0.530, P < 0.01), vastus medialis (r2 = 0.363, P < 0.05), and greater trochanter (r2 = −0.373, P < 0.05). Conclusions: Greater pain extent was associated with several measures of signs and symptoms of central sensitization in patients with hip OA. These results support the utility of the pain drawing for identifying signs of central sensitization in patients with hip OA. [ABSTRACT FROM AUTHOR]

Background: Musculoskeletal conditions are well documented in inflammatory bowel disease (IBD). However, whether IBD activity influences musculoskeletal pain experiences is uncertain. Central sensitization has been proposed in patients with IBD who are suffering from persistent pain. Identification of central sensitization symptomology using the Central Sensitization Inventory (CSI) has been reported in many pain‐related disorders. Aims of this study were to explore predictive relationships between IBD activity and musculoskeletal pain experiences (severity/interference), and the mediating effects of the CSI. Methods: A cross‐sectional online survey was performed exploring self‐reported musculoskeletal pain in adults with IBD. Survey questionnaires included IBD activity indices, numeric rating scales, PROMIS Pain Interference, and the CSI. Linear regression was used to examine the relationship between active IBD and pain experiences. Simple and serial mediation analyses were used to explore mediation models: independent variable (IBD activity), dependent variables (severity/interference), and mediators (CSI/severity). Results: 208 adults with IBD, 18 to 88 years of age, reported musculoskeletal pain. Regression analysis identified IBD activity as a significant predictor of worse pain severity (R2 = 0.039, P < 0.005) and interference (R2 = 0.067, P < 0.001). Simple mediation showed a significant indirect effect from CSI scores between IBD activity and pain severity. Serial mediation analysis showed a significant indirect effect from CSI scores and pain severity, between IBD activity and pain interference. Conclusion: Active IBD demonstrated a positive association with worse musculoskeletal pain experiences. The CSI demonstrated significant mediation between active IBD and pain severity. Additionally, the CSI and pain severity demonstrated significant mediation between active IBD and pain interference. This suggests that symptoms of central sensitization significantly influence musculoskeletal pain experiences in IBD. [ABSTRACT FROM AUTHOR]

N6‐methyladenosine (m6A) modification in RNA has been implicated in diverse biological processes. However, very little is currently known about its role in nociceptive modulation. Here, we found that the level of spinal m6A modification was significantly increased in a mouse model of Complete Freund's Adjuvant (CFA)‐induced chronic inflammatory pain, which was accompanied with the augmentation of methyltransferase‐like 3 (METTL3) expression in the spinal cord. Knockdown of spinal METTL3 prevented and reversed CFA‐induced pain behaviors and spinal neuronal sensitization. In contrast, overexpression of spinal METTL3 produced pain behaviors and neuronal sensitization in naive mice. Moreover, we found that METTL3 positively modulated the pri‐miR‐65‐3p processing in a microprocessor protein DiGeorge critical region 8‐dependent manner. Collectively, our findings reveal an important role of METTL3‐mediated m6A modification in nociceptive sensitization and provide a novel perspective on m6A modification in the development of pathological pain. [ABSTRACT FROM AUTHOR]

Introduction: Topical capsaicin is commonly employed to experimentally induce central sensitization (CS) in humans. While previous studies have investigated the effect of skin preheating on the sensitizing effect of capsaicin, no studies have compared the synergistic effect of skin preheating on the magnitude of sensitization via topical capsaicin within the first 30 minutes of application. We tested the hypothesis that skin preheating potentiates the sensitizing effect of topical capsaicin by evoking a larger region of secondary hyperalgesia vs. topical capsaicin alone. Methods: Twenty young, healthy subjects each received topical capsaicin (Zostrix HP 0.075%) only (CAP), topical capsaicin with preheating (CAP + HEAT), and topical nonsensitizing placebo cream (CON) in a crossover design. Capsaicin and placebo creams were applied to a 50 cm2 area of the dorsal forearm. The CAP + HEAT session also included a 10‐minute preheating session. Regions of secondary hyperalgesia were assessed using mechanical brush allodynia testing, and skin temperature was assessed via infrared thermography. Outcomes were normalized to baseline and compared at 10, 20, and 30 minutes after cream application. Results: The CAP + HEAT session led to a significantly larger area of secondary hyperalgesia compared to the CAP session as measured by brush allodynia (CON: 0 ± 0 cm; CAP: 2.08 ± 0.45 cm; CAP + HEAT: 3.70 ± 0.46 cm; P < 0.05) and skin temperature (CON: −2.92% ± 0.03%; CAP: −0.63% ± 0.09%; CAP + HEAT: 2.50% ± 0.11%; (of baseline) P < 0.05). Conclusion: Preheating amplifies the sensitizing effect of topical capsaicin within 30 minutes of application. The heat–capsaicin technique may be employed to assess differing magnitudes of CS induction and enables future studies investigating the development and progression of CS in humans. [ABSTRACT FROM AUTHOR]

Background: Sensitivity‐related trait characteristics involving physical and emotional sensitivities and high trait anxiety personality types have been observed in individuals with nonspecific chronic low back pain (NSCLBP). High trait sensitivity to sensory stimulation combined with interpretation biases based on personality type may contribute to the development of central sensitization (CS) symptoms. To date, there is limited research that has considered both sensitivity levels and personality type in NSCLBP with CS. The purpose of this study was to investigate (1) relationships between trait sensory profiles, trait anxiety, and CS symptoms, and (2) the predictive capacity of sensory profiles, trait anxiety, and personality types on CS symptoms in people with NSCLBP. Methods: This was a cross‐sectional observational study using 4 self‐report measures on adults (N = 165, mean age = 45 ± 12 [standard deviation] years) from physiotherapy clinics in England, Ireland, and New Zealand. Inclusion: NSCLBP > 6 months, age 18 to 64 years, predominant CS pain presentation, no other pathology. Parametric and nonparametric correlation statistics and regression analyses were used. Results: Positive correlations were found between central sensitization inventory (CSI) scores and sensory hypersensitivity profiles and trait anxiety. CSI score increases could be predicted by sensory‐sensitive, low‐registration profiles; trait anxiety scores; and extreme defensive high anxious personality type. Conclusions: Trait sensory hyper‐ and/or hyposensitivity and high trait anxiety–related personality type characteristics predict the extent of CS symptoms in people with NSCLBP. Further investigation is required to establish causality between these characteristics and CS symptoms. [ABSTRACT FROM AUTHOR]

Introduction: The differentiation between acute and chronic pain can be insufficient for appropriate pain management. The aim of this study was to evaluate the prevalence of the predominant pain type (nociceptive, neuropathic, or central sensitization [CS] pain) in breast cancer survivors (BCS) with chronic pain. The secondary aims were to examine (1) differences in health‐related quality of life (HRQoL) between the different pain groups; and (2) the associations between patient‐, disease‐, and treatment‐related factors and the different pain types. Methods: To determine the prevalence of the predominant type of pain, a recently proposed classification system was used. BCS were asked to complete the VAS for pain, Douleur Neuropathique 4 Questionnaire, Margolis Pain Diagram, Central Sensitization Inventory, and Short Form 36 (SF‐36). Results: Ninety‐one BCS participated, among whom 25.3% presented neuropathic pain, 18.7% nociceptive pain, and 15.4% CS pain. Mixed pain was found in 40.6%. A significant intergroup difference in HRQoL was found for SF‐36 "general health" (P = 0.04). The odds for the presence of CS rather than nociceptive pain are 26 times higher in patients exposed to hormone therapy in comparison to the nonexposed (odds ratio 25.95, 95% confidence interval 1.33 to 504.37, P = 0.03). Conclusion: Neuropathic pain is most frequent in BCS. Strong associations were found between CS pain and hormone therapy. [ABSTRACT FROM AUTHOR]

Purpose: The relationship between exposure to abuse and interstitial cystitis/bladder pain syndrome (IC/BPS) is well‐documented. However, studies have yet to examine posttraumatic stress disorder (PTSD), which develops following exposure to trauma and worsens health outcomes in chronic pain. We aimed to assess the prevalence and impact of PTSD in patients with IC/BPS, including their relation to genitourinary symptom presentation and widespread pain phenotype. Materials and Methods: We recruited 202 participants with chronic pain from an academic medical center and classified 64 individuals as IC/BPS based on validated epidemiological criteria. Participants completed self‐reported questionnaires assessing trauma exposure, PTSD symptoms, emotional distress, pain, and urinary symptoms. Wilcoxon rank‐sum tests assessed study aims comparing IC/BPS to other chronic pain. Results: Although elevated, IC/BPS trauma exposure rates were equivalent to that of other chronic pain conditions in the sample. Despite this equivalence, in comparison, IC/BPS patients had significantly higher rates of PTSD symptoms, with 42% meeting provisional diagnostic criteria for PTSD. Among IC/BPS, those meeting provisional criteria for PTSD had significantly higher incidence of lifetime sexual abuse, childhood trauma, and presentations consistent with the widespread pain phenotype. In IC/BPS, there was no association between PTSD and genitourinary symptoms, but provisional PTSD was associated with more pain, emotional distress, and poorer quality of life. Conclusions: We recommend that patients with IC/BPS and widespread pain have ongoing screening and monitoring of PTSD. We recommend using trauma‐informed care practices with these patients to increase trust and safety, which could improve treatment compliance and follow‐up. [ABSTRACT FROM AUTHOR]

Synopsis: Alpha‐2‐macroglobulin shows potential for use as an adjunctive treatment option for chronic pelvic pain syndrome when injected into Alcock's canal using a hydrodissection technique. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Symptoms of central sensitization (CS) have been described in patients with chronic spinal pain (CSP). Although a gold standard to diagnose CS is lacking, psychophysical pain measures are often used. The Central Sensitization Inventory (CSI) is proposed as an alternative method and indirect tool for the evaluation of CS symptomatology. The aim of the current study was to evaluate the convergent validity of the CSI by investigating the association with psychophysical pain measures and self‐reported measures of current pain intensity, quality of life, disability, and catastrophizing in CSP patients. Methods: One hundred sixteen patients with nonspecific CSP were included in the present study. Patients completed the CSI, were subjected to pressure pain thresholds (PPTs) and a conditioned pain modulation (CPM) paradigm, and completed questionnaires for current pain intensity, quality of life, pain disability, and pain catastrophizing. Results: Higher CSI scores were weakly correlated with lower PPTs (−0.276 ≤ r ≤ −0.237; all P ≤ 0.01) and not with CPM efficacy (r = 0.017; P = 0.858). Higher CSI scores were moderately correlated with higher current pain intensity (r = 0.320; P < 0.001), strongly correlated with lower physical (r = −0.617; P < 0.001) and emotional (r = −0.635; P < 0.001) quality of life, and moderately correlated with higher pain disability (r = 0.472; P < 0.001) and higher pain catastrophizing (r = 0.464; P < 0.001). Conclusion: The CSI was weakly associated with PPTs and not with CPM efficacy in CSP patients. Moderate to strong associations were found with current pain intensity, quality of life, disability, and catastrophizing. The current results illustrate that the CSI does not reflect a direct measure of CS, yet is a representation of general distress, possible originating from CS symptoms. [ABSTRACT FROM AUTHOR]

Abstract: The current manuscript reviews approaches for phenotyping central sensitization (CS). The manuscript covers the concept of diagnostic phenotyping, use of endophenotypes, biomarkers, and symptom clusters. Specifically, the components of CS that include general sensory sensitivity (assessed by quantitative sensory testing) and a symptom cluster denoting sleep difficulties, pain, affect, cognitive difficulties, and low energy (S.P.A.C.E.). Each of the assessment domains are described with reference to CS and their presence in chronic overlapping pain conditions (COPCs)—conditions likely influenced by CS. Chronic overlapping pain conditions likely represent clinical diagnostic phenotypes of CS. Components of CS can also be assessed using QST or self‐report instruments designed to assess single elements of CS or more general composite indices. [ABSTRACT FROM AUTHOR]

Medical interventions alone have been largely unsuccessful in treating and curing disorders characterized by chronic pain like central sensitivity syndromes (CSS; e.g., fibromyalgia, chronic migraine, temporomandibular disorders, irritable bowel syndrome). In this article, we discuss how a biopsychosocial perspective adds to understanding people's experiences with chronic pain. A biopsychosocial perspective examines how biological, psychological, social, and contextual factors work independently and jointly to influence the experience, maintenance, and exacerbation of CSS and their symptoms. We highlight several key psychological and social factors relevant to many people who live with CSS, while also emphasizing the heterogeneity in people's experiences, life courses, and symptoms. Furthermore, we emphasize that the psychological, social, and contextual factors that we include are best characterized as contributors to chronic pain experience rather than causes of it. [ABSTRACT FROM AUTHOR]

The goal of this study was to study central sensitization (CS)‐related symptoms in breast cancer (BC) survivors and to find if there are differences in clinical and functional variables. In this cross‐sectional study, 25 women aged between 32 and 69 years participated. CS pain was measured with the Central Sensitization Inventory (CSI). Forty points was considered the cutoff value. Cancer‐related fatigue (CRF), Quality of life, functional capacity, and handgrip strength (HGS) was assessed. A 60% of BC survivors showed a CSI score from 0 to 40, while the rest 40% of women had a score higher than 40, CSI scores being 38.35 ± 14.54 points in the whole sample. Significant differences were found in functional capacity, CRF and QoL (p < .011). However, there were no differences in HGS (p = .089). This is the first study to report BC survivors CS‐related symptoms. The high CS‐related symptoms group showed differences in some symptoms and functional capacity in this population. Future research including a wider sample and more variables related to pain should be carried out. [ABSTRACT FROM AUTHOR]

Abstract: Background and objective: Central sensitization (CS) is a phenomenon associated with several medical diagnoses, including postcancer pain, low back pain, osteoarthritis, whiplash, and fibromyalgia. CS involves an amplification of neural signaling within the central nervous system that results in pain hypersensitivity. The purpose of this systematic review was to gather published studies of a widely used outcome measure (the Central Sensitization Inventory [CSI]), determine the quality of evidence these publications reported, and examine the measurement properties of the CSI. Databases and data treatment: Four databases were searched for publications from 2011 (when the CSI was developed) to July 2017. The Consensus‐Based Standards for the Selection of Health Measurement Instruments (COSMIN) checklist was applied to evaluate methodological quality and risk of bias. In instances when COSMIN did not offer a scoring system for measurement properties, qualitative analyses were performed. Results: Fourteen studies met inclusion criteria. Quality of evidence examined with the COSMIN checklist was determined to be good to excellent for all studies for their respective measurement property reports. Interpretability measures were consistent when publications were analyzed qualitatively, and construct validity was strong when examined alongside other validated measures relating to CS. Conclusions: An assessment of the published measurement studies of the CSI suggest the tool generates reliable and valid data that quantify the severity of several symptoms of CS. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: It has been increasingly recognized that many chronic pain conditions are associated with central sensitization (CS). The Central Sensitization Inventory (CSI) is a potentially useful tool for screening patients whose presenting symptoms are suspected of being related to CS, so that additional diagnostic evaluation can be performed and appropriate treatment can be initiated. The original English version is currently not available in Serbian. Methods: The CSI was translated into Serbian (CSI‐Serb) and then psychometrically evaluated in a sample of 363 chronic pain subjects. Results: The CSI‐Serb showed a high degree of internal consistency (Cronbach's α = 0.909), excellent test‐retest reliability (intraclass correlation coefficient type 2.1 = 0.947), and a significant goodness of fit test result (χ2 = 888.44; P < 0.001). A factor analysis confirmed a 4‐factor solution, as found by the original authors of the CSI, with all items retained. Higher CSI‐Serb scores were associated with higher pain severity and longer pain duration. Total CSI scores distinguished between 3 subject groups with presumably different levels of CS, including fibromyalgia (53.3, SD = 11.2), chronic regional pain only (29.7, SD = 11.6), and a pain‐free control group (20.9, SD = 9.1). Conclusions: The results of the present study indicate strong psychometric properties, including evidence of convergent and discriminant validity, of the CSI‐Serb. These results correspond with those of other translated versions of the CSI that have been psychometrically evaluated and published. Due to the current interest in CS, and its relationship with many chronic pain conditions, it is anticipated that the CSI‐Serb will benefit Serbian‐speaking clinicians in the evaluation of patients with chronic pain conditions. [ABSTRACT FROM AUTHOR]

Abstract: Background: Impaired pain inhibitory and enhanced pain facilitatory mechanisms are repeatedly reported in patients with central sensitization pain. However, the exact effects of frequently prescribed opioids on central pain modulation are still unknown. Methods: A randomized, double‐blind, placebo‐controlled cross‐over trial was carried out. Ten chronic fatigue syndrome (CFS)/fibromyalgia (FM) patients, 11 rheumatoid arthritis (RA) patients and 20 controls were randomly allocated to the experimental (10 mg morphine or 0.2 mg/mL Naloxone) and placebo (2 mL Aqua) group. Pressure pain thresholds (PPTs) and temporal summation at the Trapezius and Quadriceps were assessed by algometry. Conditioned pain modulation (CPM) efficacy and deep tissue pain pressure were assessed by adding ischemic occlusion at the opposite upper arm. Results: Deep tissue pain pressure was lower and temporal summation higher in CFS/FM (P = 0.002 respectively P = 0.010) and RA patients (P = 0.011 respectively P = 0.047) compared to controls at baseline. Morphine had only a positive effect on PPTs in both patient groups (P time = 0.034). Accordingly, PPTs increased after placebo (P time = 0.015), and no effects on the other pain parameters were objectified. There were no significant effects of naloxone nor nocebo on PPT, deep tissue pain, temporal summation or CPM in the control group. Conclusions: This study revealed anti‐hyperalgesia effects of morphine in CFS/FM and RA patients. Nevertheless, these effects were comparable to placebo. Besides, neither morphine nor naloxone influenced deep tissue pain, temporal summation or CPM. Therefore, these results suggest that the opioid system is not dominant in (enhanced) bottom‐up sensitization (temporal summation) or (impaired) endogenous pain inhibition (CPM) in patients with CFS/FM or RA. [ABSTRACT FROM AUTHOR]

Abstract: Brain alterations are hypothesized to be present in patients with chronic whiplash‐associated disorders (CWAD). The aim of this case–control study was to examine alterations in cortical thickness and white matter (WM) structure, and the presence of brain microhemorrhages in a patient group encountering chronic neck pain of traumatic origin (i.e., CWAD) when compared with a patient group characterized by nontraumatic chronic neck pain [i.e., chronic idiopathic neck pain (CINP)], and healthy controls. Furthermore, we aimed to investigate associations between brain structure on one hand and cognitive performance and central sensitization (CS) on the other hand. T1‐weighted, diffusion‐weighted and T2*‐weighted magnetic resonance images of the brain were acquired in 105 women (31 controls, 37 CINP, 37 CWAD) to investigate regional cortical thickness, WM structure, and microhemorrhages, respectively. Next, cognitive performance, and CS encompassing distant hyperalgesia and conditioned pain modulation (CPM) efficacy were examined. Cortical thinning in the left precuneus was revealed in CWAD compared with CINP patients. Also, decreased fractional anisotropy, together with increased values of mean diffusivity and radial diffusivity could be observed in the left cingulum hippocampus and tapetum in CWAD compared with CINP, and in the left tapetum in CWAD patients compared with controls. Moreover, the extent of WM structural deficits in the left tapetum coincided with decreased CPM efficacy in the CWAD group. This yields evidence for associations between decreased endogenous pain inhibition, and the degree of regional WM deficits in CWAD. Our results emphasize the role of structural brain alterations in women with CWAD compared with CINP. [ABSTRACT FROM AUTHOR]

Chronicity and recurrence in musculoskeletal shoulder pain are highly prevalent and can possibly be attributed to the concept of central sensitization. Available studies suggest a role for central sensitization in explaining chronic shoulder pain, but so far a comprehensive quantitative sensory testing (QST) protocol has not been used. The aim of this study was to gain knowledge on sensory processing and central pain modulatory mechanisms in patients suffering from chronic shoulder pain using such a QST protocol. Fifty study participants, including chronic shoulder pain patients and healthy controls, underwent a standardized, comprehensive psychophysical testing procedure. A static adapted QST protocol (including pressure algometry, vibration and mechanical detection) was applied. Thereafter, all subjects underwent dynamic measures of temporal summation and conditioned pain modulation. Questionnaires assessing psychosocial factors were completed by each subject. No significant differences (P >= .05) were found between patients and controls based on pressure algometry, vibration detection, mechanical detection, temporal summation, and conditioned pain modulation. Moderate positive correlations (r = .5) were found between pressure pain thresholds (PPTs) and the amount of sports participation. Weak‐to‐moderate negative correlations (r = −.3 à −.5) were found between PPTs and psychosocial factors such as pain catastrophizing. Based on these findings, we can conclude that central sensitization is no characteristic feature in chronic musculo‐skeletal shoulder pain but can be present in individual cases. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Central sensitization (CS) implies increased sensitivity of the nervous system, resulting in increased pain sensitivity as well as widespread pain. Recently, the Central Sensitization Inventory (CSI) was developed to assess symptoms of CS and central sensitivity syndromes. The aim of this study was to examine the convergent validity of the CSI by comparing the outcome to psychosocial factors and clinical features of CS. Methods: In a cross‐sectional explorative study, patients with chronic pain completed multiple questionnaires, including the CSI, Pain Catastrophizing Scale, and Symptom Checklist 90, for psychological distress, duration of pain, intensity of pain, widespread pain, and lateralization of pain. Based on bivariate correlations, relevant predictors of CS were selected and used to fit an exploratory structural equation model (SEM) of CS. Results: In total, 114 patients with chronic pain were included, 56.1% being women. The average pain duration was 88 months. The mean total score on the CSI was 36.09 (15.26). The CSI was strongly related to known contributing and related factors of CS. SEM analysis showed that both psychological distress and widespread pain contributed significantly to the variance in symptoms of CS in patients with chronic pain. Conclusion: In this study, the convergent validity of the CSI was measured with demonstration of a strong relationship between contributing factors and clinical features of CS. These findings of convergent validity, considering former studies of the CSI, underline the use of the questionnaire in the clinical practice. [ABSTRACT FROM AUTHOR]

Objective The current study examined pain and neurogenic inflammation responses to topical capsaicin during the interictal period (between headache) and their relationship with plasma oxytocin in individuals with migraine. Background Individuals with migraine can experience generalized (extracephalic) hyperalgesia, which can persist even between headache attacks. Elevated levels of plasma and cerebrospinal fluid oxytocin have been observed during migraine attacks, oxytocin levels being positively associated with the intensity of migraine symptoms. However, whether oxytocin plays a role in the mechanisms of generalized pain sensitization and neurogenic inflammation during the interictal period has not been studied yet. Understanding migraineurs' interictal pain phenotype and endogenous oxytocin might help identify individuals who would benefit from intranasal oxytocin treatment. Methods Thirty-two subjects with migraine and 26 healthy controls underwent pain testing. The current study compared capsaicin-induced pain, central sensitization (areas of secondary mechanical allodynia and hyperalgesia), and neurogenic inflammation (capsaicin-induced flare) responses on the nondominant volar forearm between migraineurs and healthy controls. Additionally, we studied plasma oxytocin levels and their relationship to migraine symptoms, experimental pain and affect. Results The results indicated a significant group effect ( P = .019): Migraineurs reported greater capsaicin-induced pain unpleasantness ( M = 1.2, SD = 1.4) on a 0-10 scale and showed larger areas of flare (LnM = 2.8, SD = 0.4) than healthy controls ( M = 0.5, SD = 0.8; LnM = 2.6, SD = 0.4; ps < .032). In a subgroup analysis, enhanced capsaicin-induced pain unpleasantness was found in the chronic ( P = .007), but not the episodic ( Ps > .200), migraineurs. The oxytocin levels were elevated in migraineurs and accounted for 18% of the group difference in capsaicin-induced pain unpleasantness. Within migraineurs, interictal oxytocin levels were negatively associated with psychological distress ( Ps < .030). However, during the interictal period, pain sensitivity in extracephalic regions and plasma oxytocin levels were unrelated to migraine symptom parameters ( Ps > .074). Lastly, the results found no group difference in areas of secondary mechanical allodynia and hyperalgesia ( Ps >.298). Conclusion The current study revealed that individuals with migraine exhibit enhanced extracephalic capsaicin-induced pain unpleasantness and flare responses during interictal periods. In addition, migraineurs, especially those with chronic migraine, had slightly elevated interictal oxytocin levels compared to controls, which was associated with their affective component of experimental pain. Therefore, treatment targeting affective pain during the interictal period may help to reduce generalized pain in migraine. Furthermore, endogenous increases in oxytocin may be a compensatory mechanism that may help decrease affective distress in migraineurs. The therapeutic effects of intranasal oxytocin may benefit migraineurs by reducing their affective distress. [ABSTRACT FROM AUTHOR]

Introduction: An increased response to painful stimuli without spontaneous pain suggests a role of central hyperexcitability of pain pathways in the pathogenesis of myofascial pain syndrome (MPS). In this study we aimed to test the hypothesis that spinal pain pathways are affected in MPS. We used cutaneous silent period (CSP) parameters to demonstrate the hyperexcitability of spinal pain pathways in MPS.Methods: Twenty-nine patients diagnosed with MPS and 30 healthy volunteers were included in the study. The CSP recordings were performed in the right upper and left lower extremities.Results: In both upper and lower extremities, patients had prolonged CSP latencies (P = 0.034 and P = 0.049 respectively) and shortened CSP durations (P = 0.009 and P = 0.008, respectively).Discussion: Delayed and shortened CSP in MPS patients implies dysfunction in the inhibitory mechanism of the spinal/supraspinal pain pathways, suggesting central sensitization in the pathogenesis of MPS and supporting our research hypothesis. Muscle Nerve 57: E24-E28, 2018. [ABSTRACT FROM AUTHOR]

Introduction: Pain is a major symptom in adolescents with generalized Hypermobility Spectrum Disorder (HSD) or Hypermobile Ehlers-Danlos Syndrome (hEDS) (1). Central sensitization (CS) of pain has been suggested as a possible explanation (2). The aim of this study was to investigate the feasibility of a study protocol investigating features of CS in adolescents with HSD or hEDS for further studies. Introduction: Pain is a major symptom in adolescents with generalized Hypermobility Spectrum Disorder (HSD) or Hypermobile Ehlers-Danlos Syndrome (hEDS) (1). Central sensitization (CS) of pain has been suggested as a possible explanation (2). The aim of this study was to investigate the feasibility of a study protocol investigating features of CS in adolescents with HSD or hEDS for further studies. Results: All three measurements were well tolerated by all participants (patients and control). When measuring endogenous pain modulation through CPM, there were five participants (patients and control), who did not experience pain when immersing their hand in the cold water and as such a CPM reaction was not achieved. Discussion: The test protocols proved to have a good feasibility but there is a need to adapt the protocol to obtain more reliable data in the main study. For example, reduction of the water sample temperature. Process evaluation: One suggestion for improving the study is to add additional measurements for example time required for examinations, time required for completing the questionnaire. [ABSTRACT FROM AUTHOR]