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ObjectivePain persistence following knee replacement (KR) occurs in ∼20-30% of patients. Although several studies have identified preoperative risk factors for persistent post-KR pain, few have focused on post-KR contributing factors. We sought to determine whether altered nociceptive signaling and other peripheral nociceptive drivers present post-operatively contribute to post-KR pain.DesignWe included participants from the Multicenter Osteoarthritis Study who were evaluated ∼12 months after KR. We evaluated the relation of measures of pain sensitivity [pressure pain threshold (PPT), temporal summation (TS), and conditioned pain modulation (CPM)] and the number of painful body sites to post-KR WOMAC knee pain, and of the number of painful sites to altered nociceptive signaling using linear or logistic regression models, as appropriate.Results171 participants (mean age 69 years, 62% female) were included. TS was associated with worse WOMAC pain post-KR (β ​= ​0.77 95% CI:0.19-1.35) and reduced odds of achieving patient acceptable symptom state (aOR ​= ​0.54 95%CI:0.34-0.88). Inefficient CPM was also associated with worse WOMAC pain post-KR (β ​= ​1.43 95% CI:0.15-2.71). In contrast, PPT was not associated with these outcomes. The number of painful body sites present post-KR was associated with TS (β ​= ​0.05, 95% CI:0.01, 0.05).ConclusionsPost-KR presence of central sensitization and inefficient descending pain modulation was associated with post-KR pain. We also noted that presence of other painful body sites contributes to altered nociceptive signaling, and this may thus also contribute to the experience of knee pain post-KR. Our findings provide novel insights into central pain mechanisms and other peripheral pain sources contributing to post-KR persistent knee pain.

Relevance. The phenomenon of central sensitization occurs when physiological activity in nociceptive pathways increases and leads to abnormal sensitivity; it is defined as “increased sensitivity of nociceptive neurons of the central nervous system to their normal or subthreshold afferent input,” according to the definition provided by the International Association for the Study of Pain (IASP). The excitability of spinal cord neurons significantly modifies the gain of the somatosensory system. Chronic pain syndromes, anxiety-depressive disorder, sleep disorders are currently very common in the population, significantly reducing the quality of life of the population; the pathogenesis of these nosologies lies in central sensitization. Objective. To study the clinical manifestations of central sensitization in patients with episodic migraine associated with neck pain or cervicogenic headache. Materials and methods. The longitudinal prospective study included 180 patients, divided into 3 groups: 1) patients with a combination of migraine and cervicogenic headache – 60 people (study group); 2) patients with a combination of migraine and cervicalgia diagnoses – 60 people (control group); 3) patients diagnosed with migraine without complaints of pain and limitation of movements in the cervical spine – 60 people (additional group). Results. In patients with migraine and comorbid cervical headache, more pronounced central sensitization was revealed when compared with comorbid cervicalgia. Myofascial pain syndrome involving the trapezius and temporal muscles can resolve on its own with specific migraine therapy with monoclonal antibodies, however, to relieve tension and soreness in the masseter and inferior oblique muscles, the addition of therapeutic exercises and gentle manual techniques is more effective. Taking into account the identified direct relationships of moderate strength between the number of painful points of exit of the trigeminal nerve, the muscles of the pericranial region involved, as well as the effect of treatment of migraine attacks with monoclonal antibodies, it can be concluded that central sensitization is more pronounced when the masseter and inferior oblique muscles are involved. Conclusions. During examination of patients with migraine with comorbid active cervicalgic factor or even if it is absence, it is necessary to make a thorough examination of the facial and cranioverebral region muscles, even in the absence of patient complaints of pain in the face or neck, and also prescribe specific therapeutic exercises to increase the effectiveness of treatment. In all patients with migraine, regardless of chronicity, it is necessary to assess the intensity of central sensitization for timely and more complete provision of medical care.

Abstract Introduction Chronic neck pain (CNP) is a global public health problem, with high prevalence and absenteeism rates. Central sensitization (CS) as a basis for chronic pain may play an essential role in its development and progression. It is often comorbid with low conditioned pain modulation (CPM) effects, cognitions, and psychological problems. Objectives The purposes of this study were to (1) explore the relationship between pain-related cognitions and psychological factors, CPM effects, and the central sensitization inventory (CSI) scores; and (2) determine whether cognitions and psychological factors can predict CSI scores and CPM effects in individuals with CNP. Methods Fifty-four individuals with CNP were recruited for this cross-sectional study. The following outcome measures were evaluated: The CSI (screening tool) was compared with the cold pressor test (CPT), which was the psychophysical test used to assess the CPM; neck pain intensity using the visual analogue scale (VAS), as well as pain-related cognitions (including kinesiophobia and pain catastrophization) and psychological states (including anxiety and depression) using self-report questionnaires. Results CSI score was not associated with the CPM effect (r = 0.257, p > 0.05), and no cognitions or psychological factors were associated with CPM (p > 0.05), but CSI score was moderately positively correlated with kinesiophobia (r = 0.554, p

Rani Othman, Abdulrahman Mohammed Bajaber, Anas Mohammed Alhabshi, Majed Albadi, Rawan Aldhabi, Muataz Almaddah, Abdullah Alqarni Physical Therapy Department, King Abdulaziz University, Jeddah, Saudi ArabiaCorrespondence: Rani Othman, Email rhothman@kau.edu.saBackground: Central sensitization (CS) has been proposed as a possible contributor to persistent shoulder pain. Measures of sensitivity, such as quantitative sensory tests (QSTs) and sensitivity to movements evoked pain (SMEP), have been increasingly used to investigate CS in a wide range of painful conditions. However, there is a lack of data on whether QST and SMEP are reliable among individuals with shoulder pain. Therefore, the present study aimed to investigate the intra-rater test–retest reliability of QST and SMEP in individuals with chronic shoulder pain.Materials and Methods: Forty-seven individuals with chronic shoulder pain were enrolled in the study. The QST measures, including pressure pain threshold (PPT) and mechanical temporal summation (MTS), were tested, and SMEP was measured with a lifting task. Relative and absolute reliability were analyzed using intraclass correlation coefficients (ICC 3,1) and standard error of the measurement (SEM), respectively.Results: The results showed that the ICC coefficients for all sensitivity measures were moderate to good, ranging from 0.63 to 0.86. The SEM% for the QST measures at all sites ranged from 21.4% to 36%, with TS at the forearm demonstrating a high SEM% (greater than 30%). The SMEP measure also showed a high SEM% (46%).Conclusion: The results showed that the sensitivity measures had moderate to good reliability among individuals with shoulder pain. Acceptable limits of accuracy of measurements were demonstrated for TS and PPT measures, while SMEP demonstrated high error, highlighting the need for further refinement of this measure among these populations.Keywords: shoulder pain, quantitative sensory testing, sensitive to movement evoked pain, central sensitization, reliability

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

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

Modern pathogenetic therapy of inflammatory rheumatic diseases (IRD) is aimed not only at reducing disease activity (although achieving remission and low disease activity remains the main goal of treatment), but also at eliminating as quickly and completely as possible the main symptoms that cause a decrease in the quality of life of patients. Particular importance is attached to effective control of chronic pain – the main and most distressing manifestation of IRD. To solve this problem, the pathogenesis of chronic pain in IRD continues to be actively studied, aimed at finding new ”targets” of pharmacotherapy. Thus, the role of central sensitization (CS) and comorbid fibromyalgia in the formation of clinical manifestations of IRD is now clearly proven. Signs of CS, depending on the instrument of its detection, are determined in 20–40% of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA).Interleukin (IL) 17 plays a fundamental role in the development of chronic pain in IIRD. This cytokine takes a leading position in the development of the ”cytokine cascade”, inducing the synthesis of various cytokines and chemokines, as well as chemotaxis and activation of neutrophils and T cells. Induction of synthesis of inflammatory mediators (including prostaglandin E2) determines the role of IL-17 in activation of nociceptors and their sensitization. IL-17 also takes an active part in neuroimmune interactions by activating glia cells and affecting receptors present on the membrane of neurons of the posterior horns of the spinal cord. This defines the role of IL-17 as one of the inductors of CS development. Pharmacologic blockade of IL-17 is a known pathway to suppress the activity of IIRPs such as PsA and AxSpA. However, this mechanism also allows for significant effects on chronic pain. In particular, the IL-17 inhibitor ixekizumab has shown high analgesic potential in a series of studies in PsA and AxSpA (SPIRIT-P1 and SPIRIT-P2, COAST V and COAST W). It is important to note that this drug demonstrated a very rapid analgesic effect: pain intensity was significantly reduced already 7 days after the first injection. These data suggest a specific effect of ixekizumab on the nociceptive system, independent of the anti-inflammatory effect. This fact allows us to consider ixekizumab as a drug of choice for the treatment of patients with PsA and AxSpA who experience severe pain and have signs of CS and fibromyalgia.

Central sensitization and neuropathic pain may develop in rheumatological diseases. This study aimed to investigate the presence of central sensitization and neuropathic pain in patients with rheumatoid arthritis (RA). We used the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) questionnaire to evaluate neuropathic pain (NP) in patients with RA. The presence of central sensitization in patients was evaluated using the central sensitization inventory (CSI). Demographic and clinical data were obtained from patients and interviews. Beck Depression Scale (BDS) was used to evaluate the mood of the patients, and the Short Form-36 (SF-36) quality of life scale was used to evaluate the quality of life. A total of 104 patients participated in our study, and 33 (31.7%) of them were found to be NP. CSI scores indicated central sensitization in 41 (39.4%) of the patients. A positive significant relationship was detected between LANSS and Visual Analog Scale (VAS), BDI, and Disease Activity Score 28 (DAS28). Central sensitization (CS) and neuropathic pain (NP) significantly contribute to functional disability in RA patients. Central sensitization and neuropathic pain significantly contribute to functional disability in patients experiencing neuropathic pain, with CS having a detrimental impact on their quality of life. Thus, it is imperative to consider neuropathic pain and CS during disease monitoring and follow-up. [Med-Science 2024; 13(3.000): 699-705]

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

Introduction Spondyloarthritis (SpA) is a common rheumatic inflammatory disease and can impact patients’ work productivity. We aimed to evaluate the impact of pain catastrophizing and central sensitization on work outcomes in young SpA patients and determine the predictive factors of work productivity loss. Material and methods We performed a cross-sectional study over 6 months. We included patients aged between 18 and 50 years old, diagnosed with axial or peripheral SpA. Pain catastrophizing and central sensitization were assessed using the Pain Catastrophizing Scale (PCS) and Central Sensitization Inventory (CSI) questionnaire, respectively. Impact of SpA on work productivity and activity impairment during and out-side of work was measured with the Work Productivity and Activity Impairment Questionnaire (WPAI: Spondyloarthritis). Results A total of 72 patients were enrolled, with a median age of 39 years (28.3–46), 65.3% men, and 54.4% working patients. Median scores of activity impairment outside of work, and work productivity loss were 50% (40–70), and 50% (40–60), respectively. Median absenteeism and presenteeism scores were 0% (IQR 0–7), and 100% (IQR 86.5–100), respectively. Regarding work-related outcomes: activity impairment was positively correlated with CSI and PCS; presenteeism was significantly associated with male sex ( p = 0.009); and work productivity loss was positively associated with anxiety, depression, and poor quality of life. Multivariate regression analysis identified predictive factors of work productivity loss: male sex, poor quality of life, and prolonged morning stiffness. Conclusions Assessment of the impact of pain catastrophizing and central sensitization on work-related outcomes in patients with SpA is important to understand the burden of illness and to identify early those in need of interventions in clinical practice.

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

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

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

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

Chronic pain is primarily conceptualized as a disease in its own right when it is associated with emotional distress and functional impairment. Pathophysiologically, dysfunction of the cortico-mesolimbic connectome is of major importance, with overlapping signals in the nociceptive and stress systems. The endocannabinoid system plays an important role in the central processing of nociceptive signals and regulates the central stress response. Clinically, there is moderate evidence that cannabis-based medicines (CBM) can contribute to a significant reduction in pain, especially the associated pain affect, and improvement in physical function and sleep quality in a proportion of patients with chronic pain. The analgesic effect appears to be largely independent of the cause of pain. In this context, CBM preferentially regulates stress-associated pain processing. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the presence and severity of central sensitization (CS) and its associations with clinical measures and quality of life (QoL) in individuals with a history of paralytic poliomyelitis with and without post-polio syndrome (PPS). Methods: In this cross-sectional study, we included 98 individuals with a history of poliomyelitis, in whom 82 (83.6%) met the criteria of PPS. We used CS Inventory (CSI) to evaluate the presence and severity of CS. We evaluated the severity of fatigue, pain, polio-related impairments, and QoL using a Numerical Rating Scale in addition to Fatigue Severity Scale, Self-reported Impairments in Persons with late effects of Polio rating scale (SIPP), and Nottingham Health Profile (NHP). Results: CS was present in 52.4% of patients with PPS, of which 63% are classified as severe to extreme. Those with CS reported more severe symptoms, more polio-related impairments, and worse QoL than those without CS. Severity of CS showed significant positive correlations with severity of fatigue, pain, SIPP, and NHP scales in those with PPS. CSI did not indicate CS in any of those without PPS. Conclusion: CS was present in more than half of the individuals with PPS and correlated with more severe pain, fatigue, and more polio-related impairments, in addition to poorer QoL. These findings suggest that CS may contribute to the clinical picture in a subgroup of individuals with PPS. Thus, identification and appropriate management of CS patients may potentially help alleviate their symptoms and improve their QoL. [ABSTRACT FROM AUTHOR]

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

BACKGROUND: Central sensitization cannot be demonstrated directly in humans. Therefore, studies used different proxy markers (signs, symptoms and tools) to identify factors assumed to relate to central sensitization in humans, that is, Human Assumed Central Sensitization (HACS). The aims of this systematic review were to identify non-invasive objective markers of HACS and the instruments to assess these markers in patients with fibromyalgia (FM). METHODS: A systematic review was conducted with the following inclusion criteria: (1) adults, (2) diagnosed with FM, and (3) markers and instruments for HACS had to be non-invasive. Data were subsequently extracted, and studies were assessed for risk of bias using the quality assessment tools developed by the National Institute of Health. RESULTS: 78 studies (n = 5234 participants) were included and the findings were categorized in markers identified to assess peripheral and central manifestations of HACS. The identified markers for peripheral manifestations of HACS, with at least moderate evidence, were pain after-sensation decline rates, mechanical pain thresholds, pressure pain threshold, sound 'pressure' pain threshold, cutaneous silent period, slowly repeated evoked pain sensitization and nociceptive flexion reflex threshold. The identified markers for central manifestations of HACS were efficacy of conditioned pain modulation with pressure pain conditioning and brain perfusion analysis. Instruments to assess these markers are: pin-prick stimulators, cuff-algometry, repetitive pressure stimulation using a pressure algometer, sound, electrodes and neuroimaging techniques. CONCLUSIONS: This review provides an overview of non-invasive markers and instruments for the assessment of HACS in patients with FM. Implementing these findings into clinical settings may help to identify HACS in patients with FM. [ABSTRACT FROM AUTHOR]

Chronic postsurgical pain (CPSP) following total knee arthroplasty (TKA) and total hip arthroplasty (THA) is a prevalent complication of joint replacement surgery which has the potential to decrease patient satisfaction, increase financial burden, and lead to long-term disability. The identification of risk factors for CPSP following TKA and THA is challenging but essential for targeted preventative therapy. Recent meta-analyses and individual studies highlight associations between elevated state anxiety, depression scores, preoperative pain, diabetes, sleep disturbances, and various other factors with an increased risk of CPSP, with differences observed in prevalence between TKA and THA. While the etiology of CPSP is not fully understood, several factors such as chronic inflammation and preoperative central sensitization have been identified. Other potential mechanisms include genetic factors (e.g., catechol-O-methyltransferase (COMT) and potassium inwardly rectifying channel subfamily J member 6 (KCNJ6) genes), lipid markers, and psychological risk factors (anxiety and depression). With regards to therapeutics and prevention, multimodal pharmacological analgesia, emphasizing nonopioid analgesics like acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), has gained prominence over epidural analgesia. Nerve blocks and local infiltrative anesthesia have shown mixed results in preventing CPSP. Ketamine, an N-methyl-D-aspartate (NMDA)-receptor antagonist, exhibits antihyperalgesic properties, but its efficacy in reducing CPSP is inconclusive. Lidocaine, an amide-type local anesthetic, shows tentative positive effects on CPSP. Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) have mixed results, while gabapentinoids, like gabapentin and pregabalin, present hopeful data but require further research, especially in the context of TKA and THA, to justify their use for CPSP prevention. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the effectiveness of balance exercises on functional status, pain, balance, and central sensitization in patients with knee osteoarthritis (OA). Patients diagnosed with bilateral Kellgren–Lawrence grade ≥ 2 primary knee OA and associated central sensitization were included in the study. Patients were randomized into two groups. Both groups were provided with verbal and written information on knee OA. In addition, the intervention group received a supervised balance exercise program for 6 weeks, 3 days a week on alternating days. The outcome measures were the changes in the Central Sensitization Inventory (CSI), Visual Analog Scale (VAS) pain, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Berg Balance Scale, and Y Balance Test. Evaluations were performed at baseline, immediately after treatment (6th week) and at 12th week. The study included 40 patients, 20 patients in each group. At the end of the treatment period (6th week), the improvement in CSI score, WOMAC pain, WOMAC physical function, WOMAC total score, Y Balance Test scores, and VAS pain during activity was significantly greater in the intervention group than that in the control group (p < 0.001). Regarding the changes from baseline to the 12th week, the intervention group experienced greater improvement in most of the outcome measures. Yet, the change in WOMAC pain score, Berg Balance Scale score, and VAS pain at rest was similar between the study groups (p = 0.05, p = 0.257, and p = 0.385, respectively). A two-model multiple linear regression analysis revealed that the changes in VAS pain (during activity) after the treatment and at follow-up [(p = 0.004, adjusted R2: 0.346) and (p = 0.002, adjusted R2: 0.391), respectively], as well as changes in WOMAC pain from baseline to follow-up (p = 0.020, ΔR2 = 0.245) significantly affected central sensitization. However, changes in Y Balance Test and WOMAC total scores did not appear to have a significant impact on the improvement in central sensitization (p > 0.05). Balance exercises may provide improvement in central sensitization, functional status, and dynamic balance among patients with knee OA. The improvement in central sensitization depends mostly on the pain relief effect of balance exercises. [ABSTRACT FROM AUTHOR]

To investigate the effects of a high frequency strengthening program on function, pain, and pain sensitization in female runners with chronic patellofemoral pain (PFP). Cross-sectional study. University laboratory. Thirty female runners (mean age 32 ± 8.1 years) with chronic PFP completed an 8-week home strengthening program. Variables assessed at baseline, 8-weeks, and 12 weeks included single leg step down test (SLSD), pain, Anterior Knee Pain Scale (AKPS), University of Wisconsin Running Injury and Recovery Index (UWRI), and quantitative sensory testing. There was large and statistically significant improvement at 8 and 12 weeks for average knee pain (η p 2 = 0.334, p < 0.001), worst knee pain (η p 2 = 0.351, p < 0.001), SLSD (η p 2 = 0.161, p = 0.001), AKPS (η p 2 = 0.463, p < 0.001), and UWRI (η p 2 = 0.366, p < 0.001). A medium to large effect and statistically significant improvement in pressure pain threshold testing was found for all local and remote structures (η p 2 range, 0.110 to 0.293, range p < 0.001 to p = 0.009) at 8 and 12 weeks. There was a significant decrease in local and remote hyperalgesia via mechanical and thermal pain sensitivity testing in female runners with chronic PFP. There was a large effect and significant improvement in self-reported pain and function. • Improved pain with high frequency strengthening in female runners with chronic PFP. • Primary and secondary hyperalgesia improved with strengthening at 8 and 12 weeks. • No change for measures of central pain facilitation and central pain inhibition. [ABSTRACT FROM AUTHOR]

While preoperative psychological distress is known to predict risk for worse total knee arthroplasty (TKA) outcomes, distress may be too broad and nonspecific a predictor in isolation. We tested whether there are distinct preoperative TKA patient types based jointly on psychological status and measures of altered pain processing that predict adverse clinical outcomes. In 112 TKA patients, we preoperatively assessed psychological status (depression, anxiety, and catastrophizing) and altered pain processing via a simple quantitative sensory testing protocol capturing peripheral and central pain sensitization. Outcomes (pain, function, opioid use) were prospectively evaluated at 6 weeks and 6 months after TKA. Cluster analyses were used to empirically identify TKA patient subgroups. There were 3 distinct preoperative TKA patient subgroups identified from the cluster analysis. A low-risk (LR) group was characterized by low psychological distress and low peripheral and central sensitization. In addition, 2 subgroups with similarly elevated preoperative psychological distress were identified, differing by pain processing alterations observed: high-risk centralized pain and high-risk peripheral pain. Relative to LR patients, high-risk centralized pain patients displayed significantly worse function and greater opioid use at 6 months after TKA (P values <.05). The LR and high-risk peripheral pain patient subgroups had similar 6-month outcomes (P values >.05). Among patients who have psychological comorbidity, only patients who have central sensitization were at elevated risk for poor functional outcomes and increased opioid use. Central sensitization may be the missing link between psychological comorbidity and poor TKA clinical outcomes. Preoperative testing for central sensitization may have clinical utility for improving risk stratification in TKA patients who have psychosocial risk factors. [ABSTRACT FROM AUTHOR]

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Objective: Sleep disturbances are common in migraine patients and affect quality of life. Central sensitization (CS) is likely to play a role in the increased severity and chronicity of migraine. We hypothesized that the number of comorbid sleep problems would affect headache-related disability through the effects of central sensitization (CS). Methods: We performed a cross-sectional study including 215 consecutive patients with migraine. Insomnia was defined as a Pittsburgh Sleep Quality Index (PSQI) global score greater than 5. Probable REM sleep behavior disorder (pRBD) was defined as an RBD screening score of 5 or greater. Excessive daytime sleepiness (EDS) was defined as an Epworth Sleepiness Scale score of 10 or higher. Suspected sleep apnea (SA) was defined as patients with snoring or sleep apnea witnessed 3 or more nights a week. CS was assessed by the Central Sensitization Inventory (CSI). Results: Restless legs syndrome, insomnia, EDS, SA and pRBD were observed in 25.6%, 71.6%, 34.4%, 10.2%, and 21.4%, respectively, of the patients. At least one sleep problem was present in 87.0% of the patients. According to the results of the multinomial logistic regression analysis with no sleep problems as a reference, after we corrected for adjustment factors, the Migraine Disability Assessment (MIDAS) score significantly increased when three or more comorbid sleep problems were present. According to our mediation analysis, an increased number of sleep problems had a direct effect on the MIDAS score after we adjusted for other variables, and the CSI score was indirectly involved in this association. Conclusion: The present study showed an association between migraine-related disability and the burden of multiple sleep problems, which was partially mediated by CS. [ABSTRACT FROM AUTHOR]

[Display omitted] • BDNF from microglia drives neuropathic pain. • Peripheral BDNF drives chronic inflammatory pain. • BDNF does not drive pain in females. In males but not in females, brain derived neurotrophic factor (BDNF) plays an obligatory role in the onset and maintenance of neuropathic pain. Afferent terminals of injured peripheral nerves release colony stimulating factor (CSF-1) and other mediators into the dorsal horn. These transform the phenotype of dorsal horn microglia such that they express P2X4 purinoceptors. Activation of these receptors by neuron-derived ATP promotes BDNF release. This microglial-derived BDNF increases synaptic activation of excitatory dorsal horn neurons and decreases that of inhibitory neurons. It also alters the neuronal chloride gradient such the normal inhibitory effect of GABA is converted to excitation. By as yet undefined processes, this attenuated inhibition increases NMDA receptor function. BDNF also promotes the release of pro-inflammatory cytokines from astrocytes. All of these actions culminate in the increase dorsal horn excitability that underlies many forms of neuropathic pain. Peripheral nerve injury also alters excitability of structures in the thalamus, cortex and mesolimbic system that are responsible for pain perception and for the generation of co-morbidities such as anxiety and depression. The weight of evidence from male rodents suggests that this preferential modulation of excitably of supra-spinal pain processing structures also involves the action of microglial-derived BDNF. Possible mechanisms promoting the preferential release of BDNF in pain signaling structures are discussed. In females, invading T-lymphocytes increase dorsal horn excitability but it remains to be determined whether similar processes operate in supra-spinal structures. Despite its ubiquitous role in pain aetiology neither BDNF nor TrkB receptors represent potential therapeutic targets. [ABSTRACT FROM AUTHOR]

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

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: Neuroinflammation and maladaptive neuroplasticity play pivotal roles in migraine (MIG), trigeminal autonomic cephalalgias (TAC), and complex regional pain syndrome (CRPS). Notably, CRPS shares connections with calcitonin gene-related peptide (CGRP) in its pathophysiology. This study aims to assess if the documented links between CRPS and MIG/TAC in literature align with clinical phenotypes and disease progressions. This assessment may bolster the hypothesis of shared pathophysiological mechanisms. Methods: Patients with CRPS (n = 184) and an age-/gender-matched control group with trauma but without CRPS (n = 148) participated in this case–control study. Participant answered well-established questionnaires for the definition of CRPS symptoms, any headache complaints, headache entity, and clinical management. Results: Patients with CRPS were significantly more likely to suffer from migraine (OR: 3.23, 95% CI 1.82–5.85), TAC (OR: 8.07, 95% CI 1.33–154.79), or non-classified headaches (OR: 3.68, 95% CI 1.88–7.49) compared to the control group. Patients with MIG/TAC developed CRPS earlier in life (37.2 ± 11.1 vs 46.8 ± 13.5 years), had more often a central CRPS phenotype (60.6% vs. 37.0% overall) and were three times more likely to report allodynia compared to CRPS patients with other types of headaches. Additionally, these patients experienced higher pain levels and more severe CRPS, which intensified with an increasing number of headache days. Patients receiving monoclonal antibody treatment targeting the CGRP pathway for headaches reported positive effects on CRPS symptoms. Conclusion: This study identified clinically relevant associations of MIG/TAC and CRPS not explained by chance. Further longitudinal investigations exploring potentially mutual pathomechanisms may improve the clinical management of both CRPS and primary headache disorders. Trial registration: German Clinical Trials Register (DRKS00022961). [ABSTRACT FROM AUTHOR]

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

IntroductionObjectiveMethodsResultsConclusionAcute lower back pain can lead to neuroplastic changes in the central nervous system, and symptoms of central sensitization after 12 weeks. While sensory sensitivity has been shown to predict symptoms of central sensitization, trait sensory profiles may be prognostic in the persistence of central sensitization symptoms in low back pain over time.To examine sensory profiles as prognostic symptoms of central sensitization in people with acute low back pain.A longitudinal type 2 prognostic factor research study was performed according to the PROGRESS framework. Baseline and 12-week follow-up measures were taken using the Adolescent/Adult Sensory Profile and the Central Sensitization Inventory measures. Study participants were consecutively included from primary care physiotherapy practices. Univariable, and multivariable regression analyses were performed to adjust sensory profiles based on previous history of low back pain, baseline Central Sensitization Inventory scores, level of pain, disability, age, and duration of low back pain.After adjustment, the sensory profiles of Low Registration B = 0.44, 95%CI (0.18, 0.70), Sensation Seeking B = 0.38, 95%CI (0.19, 0.57), Sensory Sensitive B = 0.49, 95%CI (0.25, 0.74), Sensation Avoiding B = 0.40, 95% CI (0.15, 0.65) was significantly associated with the persistence of central sensitization symptoms (N = 103).Sensory profiles may predict symptoms of central sensitization after 12 weeks in people with acute low back pain. [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]

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 (β = 0.24, 95%CI = 0.03–0.18), and CS-related symptoms with low back pain (β = 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. [ABSTRACT FROM AUTHOR]

Except when surgery is the only option because of organ damage, the presence of suspicious lesions, or the desire to conceive, women with endometriosis-associated pain often face a choice between medical and surgical treatment. In theory, the description of the potential benefits and potential harms of the two alternatives should be standardized, unbiased, and based on strong evidence, enabling the patient to make an informed decision. However, doctor's opinion, intellectual competing interests, local availability of specific services and (mis)information obtained from social media, and online support groups can influence the type of advice given and affect patients' choices. This is compounded by the paucity of robust data from randomized controlled trials, and the anxiety of distressed women who are eager to do anything to alleviate their disabling symptoms. Vulnerable patients are more likely to accept the suggestions of their healthcare provider, which can lead to unbalanced and physician-centred decisions, whether in favour of either medical or surgical treatment. In general, treatments should be symptom-orientated rather than lesion-orientated. Medical and surgical modalities appear to be similarly effective in reducing pain symptoms, with medications generally more successful for severe dysmenorrhoea and surgery more successful for severe deep dyspareunia caused by fibrotic lesions infiltrating the posterior compartment. Oestrogen–progestogen combinations and progestogen monotherapies are generally safe and well tolerated, provided there are no major contraindications. About three-quarters of patients with superficial peritoneal and ovarian endometriosis and two-thirds of those with infiltrating fibrotic lesions are ultimately satisfied with their medical treatment although the remainder may experience side effects, which may result in non-compliance. Surgery for superficial and ovarian endometriosis is usually safe. When fibrotic infiltrating lesions are present, morbidity varies greatly depending on the skill of the individual surgeon, the need for advanced procedures, such as bowel resection and ureteral reimplantation, and the availability of expert colorectal surgeons and urologists working together in a multidisciplinary approach. The generalizability of published results is adequate for medical treatment but very limited for surgery. Moreover, on the one hand, hormonal drugs induce disease remission but do not cure endometriosis, and symptom relapse is expected when the drugs are discontinued; on the other hand, the same drugs should be used after lesion excision, which also does not cure endometriosis, to prevent an overall cumulative symptom and lesion recurrence rate of 10% per postoperative year. Therefore, the real choice may not be between medical treatment and surgery, but between medical treatment alone and surgery plus postoperative medical treatment. The experience of pain in women with endometriosis is a complex phenomenon that is not exclusively based on nociception, although the role of peripheral and central sensitization is not fully understood. In addition, trauma, and especially sexual trauma, and pelvic floor disorders can cause or contribute to symptoms in many individuals with chronic pelvic pain, and healthcare providers should never take for granted that diagnosed or suspected endometriosis is always the real, or the sole, origin of the referred complaints. Alternative treatment modalities are available that can help address most of the additional causes contributing to symptoms. Pain management in women with endometriosis may be more than a choice between medical and surgical treatment and may require comprehensive care by a multidisciplinary team including psychologists, sexologists, physiotherapists, dieticians, and pain therapists. An often missing factor in successful treatment is empathy on the part of healthcare providers. Being heard and understood, receiving simple and clear explanations and honest communication about uncertainties, being invited to share medical decisions after receiving detailed and impartial information, and being reassured that a team member will be available should a major problem arise, can greatly increase trust in doctors and transform a lonely and frustrating experience into a guided and supported journey, during which coping with this chronic disease is gradually learned and eventually accepted. Within this broader scenario, patient-centred medicine is the priority, and whether or when to resort to surgery or choose the medical option remains the prerogative of each individual woman. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The purpose of this study was to describe the relationship between behavioral and psychological traits with indicators of central sensitization in female runners with patellofemoral pain (PFP), and to determine if behavioral and psychological traits improve with strength training. Cross-sectional study. University laboratory. Twenty-eight active females (mean age 32 ± 8.1 years) with PFP completed testing at baseline, 8 weeks (post intervention), and 12 weeks. Behavioral and psychological questionnaires included the General Anxiety Disorder-7, Patient Health Questionairre-9, Pain Catastrophizing Scale, Tampa Scale of Kinesiophobia-11, and Central Sensitization Inventory. Quantitative sensory testing (QST) measures were also collected. After baseline testing, subjects were instructed in a hip and knee strengthening intervention to be completed twice daily over 8 weeks. A statistically significant improvement was found at 12 weeks for anxiety (p =.015; ηp (Boling et al., 2010) = 0.099) and kinesiophobia (p =.041; ηp (Boling et al., 2010) = 0.076). There was no significant improvement for depression, catastrophizing, or subjective central sensitization. No significant correlations were found between any of the behavioral and psychological questionnaires with baseline QST variables. No relationship was found for behavioral and psychological characteristics with QST measures in female runners with persistent PFP. • Female runners with PFP report mild anxiety and mild depression. • Female runners with PFP report lower anxiety and kinesiophobia after exercise. • No correlation found between QST measures and behavioral/psychological traits. [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]

Central sensitization (CS) involves amplified central nervous system (CNS) signaling and several biochemical changes which lead to pain hypersensitivity. Data on the effects of CS are limited in orthopaedics and has been associated with reported levels of postoperative pain after hip arthroscopy. Patients over the age of 18 who underwent hip arthroscopy with preoperative as well as 2-year postoperative functional outcome scores were identified through the Multicenter Arthroscopic Study of the Hip (MASH) database. Patient demographics, procedure information, as well as patient reported outcome measures (PROMs) were collected along with CS index scores. 34 patients met inclusion criteria for our study. Preop MCS and iHOT as well as Postop MCS, showed moderate to strong negative correlations with CSI scores (−0.607, −0.573, and −0.756, respectively). VAS, PCS and MSC scores were significantly different preoperatively to postoperatively, ensuring alleviation of pain after hip arthroscopy. Subgroup analysis by stratifying CSI scores into 1 SD below the mean, within 1 SD of the mean, and above 1 SD showed significant differences across all 3 groups for preoperative MCS (p < 0.001), postoperative MCS (p = 0.001), and PSEQ2 (p = 0.015). Postoperative VAS pain approached significance but did not meet criteria of p < 0.05 (p = 0.062). Increased postoperative CSI scores directly correlated with decreased preoperative and postoperative MCS scores and worse preoperative resilience. Recognizing the influence of CS on pain perception and resilience on coping with adversity in the recovery period may guide orthopaedic surgeons in developing comprehensive treatment plans to continue to improve surgical outcomes in hip arthroscopy. IV. [ABSTRACT FROM AUTHOR]

OBJECTIVE: This study aimed to investigate the effects of central sensitization (CS) on pain sensitivity, disease activity, neuropathic symptoms and quality of life (QoL) in patients with rheumatoid arthritis (RA). METHODS: Sixty patients diagnosed with RA according to the American College of Rheumatology and the European League Against Rheumatism (ACR/EULAR) 2010 classification criteria were included in the study. Patient assessment tools included visual analog scale (VAS) for pain, algometer for pain pressure threshold (PPT), disease activity score in 28 joints (DAS-28) for disease activity (DA), central sensitization inventory (CSI) for CS and rheumatoid arthritis QoL questionnaire for QoL. RESULTS: Central sensitization was identified in 29 (48.3%) patients. Although erythrocyte sedimentation rate (ESR), C-reactive protein and swollen joint count were comparable between patients with or without CS, higher VAS, tender joint count and DAS-28 scores were observed in patients with CS (all p<0.05). Pain pressure thresholds (PPT) at the wrist (PPTW) and the trapezius muscle (PPTT) were lower in patients with CS (p=0.004, p=0.001, respectively). It was found that neuropathic pain components increased and quality of life decreased as CSI scores increased (all p=0.000). CONCLUSION: The presence of CS leads to pain sensitivity as well as overestimation of disease activity in RA patients. The presence of CS should not be overlooked in RA patients to avoid overtreatment for inflammation and to determine the treatment need for nociplastic pain. [ABSTRACT FROM AUTHOR]

Central sensitisation is defined as a multifactorial etiopathogenetic condition involving an increase in the reactivity of nociceptive neurons and alterations in pain transmission and perception in the central nervous system. Patients may present with widespread chronic pain, fatigue, sleep disturbance, dizziness, psychological (e.g., depression, anxiety, and anger) and social impairment. Pain can be spontaneous in onset and persistence, characterised by an exaggerated response and spread beyond the site of origin, and sometimes triggered by a non-painful stimulus. Whole-body cryostimulation (WBC) could be an adjuvant therapy in the management of this type of pain because of its global anti-inflammatory effect, changes in cytokines and hormone secretion, reduction in nerve conduction velocity, autonomic modulation, and release of neurotransmitters involved in the pain pathway. In several conditions (e.g., fibromyalgia, rheumatoid arthritis, and chronic musculoskeletal pain), WBC affects physical performance, pain perception, and psychological aspects. Given its multiple targets and effects at different organs and levels, WBC appears to be a versatile adjuvant treatment for a wide range of conditions of rehabilitation interest. Further research is needed to fully understand the mechanisms of analgesic effect and potential actions on pain pathways, as well as to study long-term effects and potential uses in other chronic pain conditions. [ABSTRACT FROM AUTHOR]

Though there is growing awareness of the overrepresentation of autistic patients in chronic pain clinics, potential adaptations for the assessment and treatment of chronic pain in this population have not yet been established. To address this gap, a retrospective review of electronic medical records and discussions by an interdisciplinary pain treatment team were summarized to inform potential biopsychosocial factors affecting the presentation, assessment, and treatment of chronic pain in autistic youth. Our sample included a record review of 95 patients receiving treatment in an interdisciplinary outpatient pediatric pain clinic. Results indicated that 9% (n = 9) of the patients presented to the clinic with a prior diagnosis of autism, but an additional 21% (n = 20) were identified as likely meeting criteria for autism based on the clinical assessment of the developmental history, behaviors observed during the clinical encounter(s), and expert clinical judgment, suggesting that the prevalence rate of autism may be closer to 30% in our outpatient pediatric pain clinic. Over half (52%) of the autistic youth presented to the clinic with widespread pain, 60% identified as female, and 6% identified as gender expansive or transgender. Qualitative insights revealed that most of the autistic patients had co-occurring sensory-processing challenges and difficulty in describing their pain, emotions, and somatic experiences and exhibited cognitive inflexibility and social challenges. We summarize our team's clinical reflections on how autism-relevant biopsychosocial vulnerability factors may contribute to the experience of pain in autistic youth and propose treatment targets and adaptations for the assessment and treatment of pain in this population. Finally, we recommend the need for interventions focused on sensorimotor integration, especially for autistic youth, and describe how pain clinics may be particularly helpful for identifying and supporting autistic females, for whom the potential role of autism in pain experiences had not been considered until receiving treatment in our clinic. [ABSTRACT FROM AUTHOR]

IntroductionPreviously, we had observed that immediate pain reduction after one acupuncture treatment was associated with high temporal summation of pain (TS) at a pain free control site and younger age in a mixed population of chronic pain patients. The aim of the present study was to verify these results in chronic non-specific low back pain (LBP) and to collect pilot data on the association between TS and the response to an acupuncture series.MethodsTS at a pain free control site (back of dominant hand) and at the pain site was quantified by the pin-prick induced wind-up ratio (WUR) in 60 LBP patients aged 50 years or younger. Response to one acupuncture treatment was assessed by change in pain intensity and pressure pain threshold (PPT) at the pain site. The primary hypothesis was that a high TS (WUR > 2.5) would be associated with a clinically relevant reduction in pain intensity of at least 30%. In study part two, 26 patients received nine additional treatments. Response to the acupuncture series was assessed by the pain intensity during the last week, the PPT and the Hannover functional ability questionnaire (FFbH-R).ResultsAn immediate reduction in pain intensity of at least 30% was frequent irrespective of TS at the control site (low vs. high TS 58% vs. 72%, p = 0.266). High TS at the pain site was also not significantly associated with a clinically relevant immediate reduction in pain intensity (low vs. high TS 46% vs. 73%, p = 0.064). The PPT was not changed after one acupuncture treatment. Study part two did not reveal a consistent association between TS at the control site and any of the outcome measures but also a trend toward a higher chance for a clinically relevant response along with low TS at the pain site.ConclusionOur results do not suggest an important role of TS for predicting a clinically important acupuncture effect or the response to a series of 10 acupuncture treatments in patients with chronic non-specific LBP. Overall high response rates imply that acupuncture is a suitable treatment option for LBP patients irrespective of their TS.

Hemisphere functional lateralization is a prominent feature of the human brain. However, it is not known whether hemispheric lateralization features are altered in end-stage knee osteoarthritis (esKOA). In this study, we performed resting-state functional magnetic imaging on 46 esKOA patients and 31 healthy controls (HCs) and compared with the global and inter-hemisphere network to clarify the hemispheric functional network lateralization characteristics of patients. A correlation analysis was performed to explore the relationship between the inter-hemispheric network parameters and clinical features of patients. The node attributes were analyzed to explore the factors changing in the hemisphere network function lateralization in patients. We found that patients and HCs exhibited “small-world” brain network topology. Clustering coefficient increased in patients compared with that in HCs. The hemisphere difference in inter-hemispheric parameters including assortativity, global efficiency, local efficiency, clustering coefficients, small-worldness, and shortest path length. The pain course and intensity of esKOA were positively correlated with the right hemispheric lateralization in local efficiency, clustering coefficients, and the small-worldness, respectively. The significant alterations of several nodal properties were demonstrated within group in pain-cognition, pain-emotion, and pain regulation circuits. The abnormal lateralization inter-hemisphere network may be caused by the destruction of regional network properties.

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

Zhiyun Zhang, Hao Zheng, Qingquan Yu, Xianghong Jing Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of ChinaCorrespondence: Xianghong Jing, Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China, Email jxhtjb@263.netAbstract: The spinal dorsal horn (SDH) transmits sensory information from the periphery to the brain. Wide dynamic range (WDR) neurons within this relay site play a critical role in modulating and integrating peripheral sensory inputs, as well as the process of central sensitization during pathological pain. This group of spinal multi-receptive neurons has attracted considerable attention in pain research due to their capabilities for encoding the location and intensity of nociception. Meanwhile, transmission, processing, and modulation of incoming afferent information in WDR neurons also establish the underlying basis for investigating the integration of acupuncture and pain signals. This review aims to provide a comprehensive examination of the distinctive features of WDR neurons and their involvement in pain. Specifically, we will examine the regulation of diverse supraspinal nuclei on these neurons and analyze their potential in elucidating the mechanisms of acupuncture analgesia.Keywords: WDR neurons, spinal dorsal horn, pain, central sensitization, receptive fields, DNIC, acupuncture analgesia