Sensitization Research Articles

Association of Quadratus Lumborum Muscle Stiffness with Chronic Low Back Pain Features: An Observational Study

Background and Objectives: Low back pain (LBP) is highly prevalent and often associated with altered muscle function, including in the quadratus lumborum (QL) muscle. While some studies have highlighted the clinical relevance of QL muscle stiffness in LBP, the findings remain inconsistent, and the role of this parameter in relation to clinical severity indicators is not well understood. Considering the high prevalence of myofascial trigger points among patients, objectively and reliably quantifying QL stiffness and its association with other clinical parameters could improve the identification of early stages of the condition before other alterations become apparent. Therefore, this study aimed to explore the association between QL stiffness and multiple indicators of LBP severity. Materials and Methods: A cross-sectional observational study was conducted involving the participation of seventy-six patients suffering from chronic LBP. An ultrasound scanner with shear-wave elastography (SWE) was used to determine the participants’ QL stiffness. Additional information was collected on LBP-associated pain intensity, disability, central sensitization, and quality of life. Results: QL muscle stiffness was negatively correlated with pain intensity (p < 0.01) and central sensitization (p < 0.01), and it was positively correlated with physical quality of life (p < 0.01). Muscle stiffness influenced the variance in pain intensity along with physical quality of life, central sensitization, and chronicity (together explaining 49% of the variance) but did not explain the variance in central sensitization. Conclusions: Assessing QL muscle stiffness in patients with LBP is recommended, as greater muscle softness is linked to higher pain intensity, central sensitization, and poorer physical quality of life. Regression analyses further highlighted that QL stiffness helps explain the variance in pain intensity, physical quality of life, central sensitization, and chronicity, but it did not directly affect the central sensitization variance.

Somatosensory and clinical profiles of patients with spine-related and clinical framework-based neck-arm pain.

Spine-related neck-arm pain is heterogeneous and may present on a spectrum between nociceptive and neuropathic pain. A recently developed mechanism-based clinical framework for spine-related pain distinguishes between spinally referred pain without neurological deficits (somatic referred pain, heightened nerve mechanosensitivity, radicular pain), with neurological deficits (radiculopathy), and mixed-pain presentations. This study investigated differences in somatosensory and clinical profiles of patients with unilateral spine-related neck-arm pain grouped according to the clinical framework. Patients (n = 113) underwent a clinical examination, after which they were classified into a subgroup(s). They completed questionnaires to assess function (Neck Disability Index), psychosocial factors (Tampa Scale of Kinesiophobia, pain catastrophizing scale, Depression, anxiety, and stress scale), neuropathic pain (Douleur neuropathique 4), and central sensitization features (Central Sensitization Inventory). Standardized quantitative sensory testing (QST) was performed over the maximal pain area and contralateral side. The radiculopathy group showed a significant loss of function on the symptomatic vs asymptomatic side in cold (P = 0.024) and warm detection (P = 0.004), thermal sensory limen (P = 0.001), mechanical detection (P = 0.001), increased windup ratio (P = 0.014), and cold hyperalgesia (P = 0.049). No other subgroup showed significant side differences in QST parameters. Symptom descriptors, such as burning (P < 0.031), tingling (P < 0.018), pins and needles (P < 0.031), numbness (P < 0.016), spontaneous pain (P < 0.001), and electric pain/shock (P < 0.026) were more common in the radicular/radiculopathy groups compared with the somatic/mechanosensitivity groups. There were no differences in psychosocial parameters between the groups. The phenotypic profiles support the construct of the clinical examination and patient classification and its application in clinical practice according to a clinical framework for spine-related pain.

The Interplay Between Chronic Pelvic Pain and Pelvic Organ Prolapse.

Chronic pelvic pain (CPP) affects approximately 26% of the world's female population and has various proposed etiologies. This manuscript aims to review concepts related to pelvic organ prolapse (POP) and CPP, encompassing its etiology, risk factors, clinical findings, and pain management. A narrative review was performed using MeSH terms and text words on PubMed, and the Cochrane Database of Systematic Reviews through May 2024. A total of 33 references were used to address the questions posed in this review. Specific risk factors for CPP associated with POP include pain antedating POP onset, POP surgery duration, and extent of soft tissue trauma. Studies indicate that uterosacral ligament repair performed during surgical interventions for POP correction has alleviated CPP symptoms whether performed vaginally or laparoscopically. Women with preexisting CPP or central sensitization syndrome (CSS) undergoing pelvic reconstructive surgery for POP may experience less favorable postoperative outcomes compared to those without preexisting pain conditions. These outcomes include lower patient satisfaction, less resolution of discomfort, and poorer improvement in urinary symptoms. On the basis of current evidence, surgeries for POP correction, especially those involving the uterosacral ligament, have shown a positive impact on reducing pelvic pain. However, untreated CPP is associated with lower satisfaction and less improvement in outcomes after POP surgery regarding pelvic symptoms and quality of life. Screening for and treating CPP conditions prior to POP surgery should be prioritized.Pain management of CPP should be addressed preoperatively, perioperatively, and postoperatively.

Evaluation of Inadequate Response to Ultrasound-Guided Subacromial Corticosteroid Injection in Shoulder Impingement Syndrome: Treatment Failure or Central Sensitization?: Central Sensitization in Injection Response.

To evaluate whether central sensitization (CS), pain catastrophizing, and psychological factors are associated with inadequate response to ultrasound-guided subacromial corticosteroid injection (SCI) in patients with chronic shoulder impingement syndrome (SIS). This study was designed as a prolective observational study, combining analytical cross-sectional and prospective elements to evaluate associations and treatment responses. Secondary care outpatient clinic. A total of 72 patients aged 18-75 years with SIS and at least 6 months of shoulder pain, planned to undergo ultrasound-guided SCI, were included in the study. Not applicable. Treatment response was defined as a ≥50% reduction in pain (VAS) at 4 weeks post-injection. The presence of central sensitization was assessed using the Central Sensitization Inventory (CSI) and Pressure Pain Threshold (PPT) via algometry (ipsilateral deltoid, contralateral deltoid, and contralateral vastus lateralis). Negative thoughts related to pain were evaluated with the Pain Catastrophizing Scale (PCS), and mood status was assessed using the Hospital Anxiety and Depression Scale (HADS). 48 patients (responders) experienced ≥50% VAS reduction, while 24 (non-responders) did not. Non-responders had significantly higher CSI (p=0.000), HADS-depression (p=0.001), and HADS-anxiety (p=0.000) scores. PPT values were significantly lower in non-responders at ipsilateral deltoid (p=0.030), contralateral deltoid (p=0.045), and contralateral vastus lateralis (p=0.036). CSI was significantly correlated with PPT at ipsilateral deltoid (r=-0.400, p=0.001), contralateral deltoid (r=-0.354, p=0.002), and contralateral vastus lateralis (r=-0.442, p=0.000); PCS total score (r=0.449, p=0.000); HADS-depression score (r=0.572, p=0.000); and HADS-anxiety score (r=0.618, p=0.000). CSI was the most predictive factor for non-response (AUC=0.755, 95% CI: 0.635-0.875). Multivariate analysis identified CSI as an independent predictor (p=0.022), with a predictive accuracy of 72.2%. Inadequate response to SCI in chronic SIS is strongly associated with CS, psychological distress, and altered pain perception. Integrating CS-targeted interventions into treatment strategies may improve outcomes.

Gender differences in clinical presentations and sensory profiles in patients with fibromyalgia: implications of peripheral and central mechanisms.

Fibromyalgia has a high female predominance and research work has been focussing mainly on women. We aimed to answer (1) gender differences in pain scores and quality of life, (2) any gender-specific subgroups defined by quantitative sensory testing (QST), and (3) correlations of QST parameters with pain intensity and questionnaire scores. We evaluated clinical presentations and QST profiles from 38 male and 38 age-matched female patients. Women reported significantly higher scores in average daily pain, daily sleep interference score, average weekly pain, weekly sleep interference score, and revised fibromyalgia impact questionnaire (rFIQ). Based on LOGA classification, L0G2, mechanical allodynia or hyperalgesia without abnormal sensory loss, was the most common QST subtype which accounted for 28.9% of men and 26.3% of women. Approximately 34.2% of men and 26.3% of women displayed loss of function of small fibres with an increased cold or warm detection threshold. Cold detection threshold was negatively correlated with pain intensity and functional impairment, suggesting a peripheral mechanism. Central sensitization, defined as allodynia and hyperalgesia to thermal or mechanical stimuli, was found in two-thirds of male and female patients. Mechanical pain sensitivity was positively correlated with the severity of pain and associated symptoms in women, but not men. There was a marked gender difference in reported pain and quality of life. We have confirmed that central sensitization is a major mechanism for women. Our data suggested an important role of small fibre pathology in both men and women.

Fibromyalgia: do I tackle you with pharmacological treatments?

Pharmacological approaches are frequently proposed in fibromyalgia, based on different rationale. Some treatments are proposed to alleviate symptoms, mainly pain, fatigue, and sleep disorder. Other treatments are proposed according to pathophysiological mechanisms, especially central sensitization and abnormal pain modulation. Globally, pharmacological approaches are weakly effective but market authorization differs between Europe and United States. Food and Drug Administration-approved medications for fibromyalgia treatment include serotonin and noradrenaline reuptake inhibitors, such as duloxetine, and pregabalin (an anticonvulsant), which target neurotransmitter modulation and central sensitization. Effect of analgesics, especially tramadol, on pain is weak, mainly on short term. Low-dose naltrexone and ketamine are gaining attention due their action on neuroinflammation and depression modulation, but treatment protocols have not been validated. Moreover, some treatments should be avoided due to the high risk of abuse and severe side effects, especially opioids, steroids, and hormonal replacement.

Molecular hydrogen reduces dermatitis-induced itch, diabetic itch and cholestatic itch by inhibiting spinal oxidative stress and synaptic plasticity via SIRT1-β-catenin pathway in mice.

Chronic itch which is primarily associated with dermatologic, systemic, or metabolic disorders is often refractory to most current antipruritic medications, thus highlighting the need for improved therapies. Oxidative damage is a novel determinant of spinal pruriceptive sensitization and synaptic plasticity. The resolution of oxidative insult by molecular hydrogen has been manifested. Herein, we strikingly report that both hydrogen gas (2%) inhalation and hydrogen-rich saline (5mL/kg, intraperitoneal) injection prevent and alleviate persistent dermatitis-induced itch, diabetic itch and cholestatic itch. Hydrogen therapy reverses the decrease of spinal SIRT1 expression and antioxidant enzymes (SOD, GPx and CAT) activity after dermatitis, diabetes and cholestasis. Furthermore, hydrogen reduces spinal ROS generation, oxidation products (MDA, 8-OHdG and 3-NT) accumulation, β-catenin acetylation and dendritic spine density in persistent itch models. Spinal SIRT1 inhibition eliminates antipruritic and antioxidative effects of hydrogen, while SIRT1 agonism attenuates chronic itch phenotype, spinal β-catenin acetylation and mitochondrial damage. β-catenin inhibitors are effective against chronic itch via reducing β-catenin acetylation, blocking ERK phosphorylation and elevating antioxidant enzymes activity. Hydrogen treatment suppressed dermatitis and cholestasis mediated spontaneous excitatory postsynaptic currents in vitro. Additionally, hydrogen impairs cholestasis-induced the enhancement of cerebral functional connectivity between the right primary cingulate cortex and bilateral sensorimotor cortex, as well as bilateral striatum. Taken together, this study uncovers that molecular hydrogen protects against chronic pruritus and spinal pruriceptive sensitization by reducing oxidative damage via up-regulation of SIRT1-dependent β-catenin deacetylation in mice, implying a promising strategy in translational development for itch control.

N-Methyl-D-aspartate receptor antagonists for the prevention of chronic postsurgical pain: a narrative review.

The N-methyl-D-aspartate receptor (NMDAR) has been linked to the development of chronic postsurgical pain (CPSP), defined as pain after surgery that does not resolve by 3 months. Once the combination of a painful stimulus and glutamate binding activates the NMDAR, calcium influx triggers signaling cascades that lead to processes like central sensitization and CPSP. Three of the most widely studied perioperative NMDAR antagonists include ketamine, magnesium, and methadone, with ketamine having garnered the greatest amount of attention. While multiple studies have found improved analgesia in the acute postoperative period, fewer studies have focused on long-term outcomes and those that have are often underpowered for CPSP or have not included those patients at highest risk. Existing meta-analyses of ketamine for CPSP are inconsistent in their findings, and studies of magnesium and methadone are even more limited. Overall, the evidence supporting NMDAR antagonists for CPSP is weak and we recommend that future studies focus on high-risk patients and potentially include combinations of NMDAR antagonists administered together for the longest duration feasible. The results of ongoing trials could have a major influence on the overall direction of the evidence supporting NMDAR antagonists in preventing CPSP.

Mechanisms of chronic postsurgical pain.

Chronic pain after surgery, also known as chronic postsurgical pain (CPSP), is recognized as a significant public health issue with serious medical and economic consequences. Current research on CPSP underscores the significant roles of both peripheral and central sensitization in pain development and maintenance. Peripheral sensitization occurs at the site of injury, through the hyperexcitability of nerve fibers due to surgical damage and the release of inflammatory mediators. This leads to increased expression of pronociceptive ion channels and receptors, such as transient receptor potential and acid-sensing ion channels (ASIC), enhancing pain signal transmission. Central sensitization involves long-term changes in the central nervous system, particularly in the spinal cord. In this context, sensitized spinal neurons become more responsive to pain signals, driven by continuous nociceptive input from the periphery, which results in an enhanced pain response characterized by hyperalgesia and/or allodynia. Key players in this process include N-methyl-D-aspartate receptor and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, along with proinflammatory cytokines and chemokines released by activated glia. These glial cells release substances that further increase neuronal excitability, maintaining the sensitized state and contributing to persistent pain. The activation of antinociceptive systems is required for the resolution of pain after surgery, and default in these systems may also be considered as an important component of CPSP. In this review, we will examine the clinical factors underlying CPSP in patients and the mechanisms previously established in preclinical models of CPSP that may explain how acute postoperative pain may transform into chronic pain in patients.

The psychological and physiological effects of a virtual reality-based treatment program in female patients with fibromyalgia syndrome: A randomized controlled trial

ABSTRACT The study aims to evaluate the effects of virtual reality (VR) programs on disease activity, central sensitization, kinesiophobia, body awareness, and pain catastrophizing in patients with fibromyalgia syndrome (FMS). Twenty-nine with FMS were randomized into the VR group or the control group (CG). FMS patients in the VR group were included in the VR-based relaxing treatment for 4 weeks, with one session per week. The progressive muscle relaxation technique and the breath-counting exercise were taught to participants in the CG. The Fibromyalgia Impact Questionnaire (FIQ), Central Sensitization Inventory Short-Form (CSI-SF), TAMPA, Pain Catastrophizing Scale (PCS), and Body Awareness Questionnaire (BAQ) were evaluated. Additionally, in the VR group, the Galvanic Skin Response (GSR), Simulator Sickness Questionnaire (SSQ), pain, stress, and exhaustion were assessed during each session. Post-treatment, the VR group showed significantly greater improvements than the CG in FIQ, CSI-SF, PCS, and BAQ (p < 0.05). Effect sizes in the VR group, except for TAMPA, ranged from large to very large (Cohen’s d = 0.993–1.350). Although GSR scores decreased post-treatment, this reduction was not statistically significant (p > 0.05). Additionally, symptoms of SSQ, pain, stress, and exhaustion were notably reduced in the VR group. we recommend the widespread use of this innovative treatment approach in FMS patients.

Chronic postsurgical pain and transitional pain services: a narrative review highlighting European perspectives.

Chronic postsurgical pain (CPSP) is a significant, often debilitating outcome of surgery, impacting patients' quality of life and placing a substantial burden on healthcare systems worldwide. CPSP (pain persisting for more than 3 months postsurgery) leads to both physical and psychological distress. Recognized as a distinct chronic pain entity in International Classification of Diseases, 11th Revision, CPSP enables better reporting and improved management strategies. Despite advancements in surgical care, CPSP remains prevalent, affecting 5%-85% of patients, with higher rates following thoracotomies, amputations, mastectomies and joint replacements. The acute to chronic pain transition involves complex interactions between peripheral and central mechanisms, with central sensitization playing a key role. Identifying high-risk patients is crucial for prevention, with factors such as surgical type, nerve injury, neuropathic elements in acute postoperative pain, and psychosocial conditions being significant contributors. Current pain management strategies, including multimodal therapy and regional anesthesia, show limited effectiveness in preventing CPSP. Neuromodulation interventions, though promising, are not yet established as preventive modalities. Transitional pain services (TPSs) offer a comprehensive, multidisciplinary approach to managing CPSP and reducing opioid dependence, addressing both physical and psychosocial aspects of functional recovery. While promising results have been seen in Canada and Finland, TPSs are not yet widely implemented in Europe. There is also growing interest in pain biomarkers, through initiatives such as the A2CPS program, aiming to improve CPSP prediction and develop targeted interventions. Future research should focus on large-scale studies integrating various factors to facilitate CPSP prediction, refine prevention strategies and reduce its long-term impact.

Blood proteomics and multimodal risk profiling of human volunteers after incision injury: A translational study for advancing personalized pain management after surgery.

A significant number of patients develop chronic pain after surgery, but prediction of those who are at risk is currently not possible. Thus, prognostic prediction models that include bio-psycho-social and physiological factors in line with the complex nature of chronic pain would be urgently required. Here, we performed a translational study in male volunteers before and after an experimental incision injury. We determined multi-modal features ranging from pain characteristics and psychological questionnaires to blood plasma proteomics. Outcome measures included pain intensity ratings and the extent of the area of hyperalgesia to mechanical stimuli surrounding the incision, as a proxy of central sensitization. A multi-step logistic regression analysis was performed to predict outcome measures based on feature combinations using data-driven cross-validation and prognostic model development. Phenotype-based stratification resulted in the identification of low and high responders for both outcome measures. Regression analysis revealed prognostic proteomic, specific psychophysical, and psychological features. A combinatorial set of distinct features enabled us to predict outcome measures with increased accuracy compared to using single features. Remarkably, in high responders, protein network analysis suggested a protein signature characteristic of low-grade inflammation. Alongside, in silico drug repurposing highlighted potential treatment options employing antidiabetic and anti-inflammatory drugs. Taken together, we present here an integrated pipeline that harnesses bio-psycho-physiological data for prognostic prediction in a translational approach. This pipeline opens new avenues for clinical application with the goal of stratifying patients and identifying potential new targets, as well as mechanistic correlates, for postsurgical pain.

Nociceptor-localized KCC2 suppresses brachial plexus avulsion-induced neuropathic pain and related central sensitization

Lack in understanding of the mechanism on brachial plexus avulsion (BPA)-induced neuropathic pain (NP) is the key factor restricting its treatment. In the current investigation, we focused on the nociceptor-localized K+-Cl− cotransporter 2 (KCC2) to investigate its role in BPA-induced NP and related pain sensitization. A novel mice model of BPA on the middle trunk (C7) was established, and BPA mice showed a significant reduction in mechanical withdrawal threshold of the affected fore- and hind- paws without affecting the motor function through CatWalk Gait analysis. Decreased expression of KCC2 in dorsal root ganglion (DRG) was detected through Western blot and FISH technology after BPA. Overexpression of KCC2 in DRG could reverse the hyperexcitability of DRG neurons and alleviate the pain of BPA mice synchronously. Meanwhile, the calcium response signal of the affected SDH could be significantly reduced through above method using spinal cord fiber photometry. The synthesis and release of brain-derived neurotrophic factor (BDNF) was also proved reduction through overexpression of KCC2 in DRG, which indicates BDNF can also act as the downstream role in this pain state. As in human-derived tissues, we found decreased expression of KCC2 and increased expression of BDNF and TrκB in avulsed roots of BPA patients compared with normal human DRGs. Our results indicate that nociceptor-localized KCC2 can suppress BPA-induced NP, and peripheral sensitization can be regulated to reverse central sensitization by targeting KCC2 in DRG at the peripheral level through BDNF signaling. The consistent results in both humanity and rodents endow great potential to future transformation of clinical practice.

PIEZO2 Proton Affinity and Availability May Also Regulate Mechanical Pain Sensitivity, Drive Central Sensitization and Neurodegeneration

PIEZO2 Proton Affinity and Availability May Also Regulate Mechanical Pain Sensitivity, Drive Central Sensitization and Neurodegeneration

Chronic pain syndrome in musculoskeletal diseases-how different are fibromyalgia and long Covid?-Part 1

Chronic pain is a common problem in rheumatology. Nociceptive pain is distinguished from neuropathic and nociplastic pain. Mechanistically, the former is explained by persistent inflammation, for example. Included in the second category is nerve damage of various causes. In contrast, nociplastic pain is not caused by tissue damage or a lesion in the somatosensory nerve system. It is caused by an altered sensation of pain through the modulation of stimulus processing. The concept of central sensitization, together with further neurobiological and psychosocial mechanisms, best explains such pain conditions. Fibromyalgia (FM) plays a big part in rheumatology- on the one hand, as a differential diagnosis, and on the other, because the management of inflammatory rheumatic conditions is made more difficult by the simultaneous occurrence of FM. In the context of the coronavirus pandemic, persistent pain syndromes with similarities to FM have been described after COVID-19 infection. There is an increasing scientific controversy whether the so-called long Covid syndrome is an actual entity or "only" a variant of FM. This discussion and the current state of knowledge on the problem are the subject of this review.

Brain activation patterns and dopaminergic neuron activity in response to conspecific advertisement calls in reproductive vs. non-reproductive male plainfin midshipman fish (Porichthys notatus).

The plainfin midshipman fish (Porichthys notatus) relies on the production and reception of social acoustic signals for reproductive success. During spawning, male midshipman produce long duration advertisement calls to attract females, which use their auditory sense to locate and access calling males. While seasonal changes based on reproductive state in inner-ear auditory sensitivity and frequency encoding in midshipman is well documented, little is known about reproductive-state dependent changes in central auditory sensitivity and auditory neural responsiveness to conspecific advertisement calls. Previous research indicates that forebrain dopaminergic neurons are preferentially active in response to conspecific advertisement calls and during female auditory-driven behavior in the breeding season. These dopamine neurons project to both the inner ear and central auditory nuclei and contribute to regulation of inner-ear auditory sensitivity based on reproductive state. The present study tested the hypothesis that exposure to the male advertisement call would elicit differential activation in auditory brain nuclei and in the forebrain auditory-projecting dopaminergic nucleus in reproductive vs. non-reproductive male midshipman. Fish were collected during the spring reproductive and winter non-reproductive months and were exposed to a playback of the advertisement call or ambient noise (control). Immunohistochemistry identified activated neurons (pS6-ir; proxy for neural activation) in midbrain and forebrain auditory and dopaminergic nuclei. Our results revealed that in key auditory and dopaminergic areas, the greatest activation (most pS6-ir cells) occurred in reproductive males exposed to the advertisement call.

Impact of repeated low-level red-light therapy on axial length, refraction, and macular retinal blood flow density in adolescents with mild to moderate myopia.

In order to evaluate the effectiveness of repeated low-level red-light (RLRL) therapy on stabilizing axial elongation and refractive changes in adolescents with mild to moderate myopia. In addition, we also examined whether RLRL therapy affects retinal blood flow density in the macular region, a factor previously unstudied in this context. Conducted at a single clinical site, this retrospective, single-arm study followed participants over six months, with assessments at baseline, 1 month, 3 months, and 6 months. The primary outcomes included axial length and spherical equivalent refraction (SER) changes. Secondary assessments included retinal blood flow density (superficial and deep macular layers), white-to-white corneal diameter, central corneal thickness, intraocular pressure (IOP), corneal curvature, light sensitivity, and peripheral retinal thickness. There were 32 enrolled participants (mean age = 11.5 ± 1.72) in the current study. The spherical equivalent (SER) remained relatively stable over the first three months, but it significantly improved at six months, changing from -2.39 ± 2.21 D at baseline to -2.01 ± 2.12 D (P < 0.05). However, the axial length also showed minimal variation across follow-up visits, indicating stable eye growth with no substantial elongation throughout the study period. Furthermore, RLRL therapy resulted in stable measurements across primary and secondary outcomes (all P > 0.05), with no significant changes over the six months. There were no obvious side effects following the treatment. Low-energy red light therapy shows promise as a non-invasive approach for stabilizing myopia in adolescents, with no observed compromise to retinal blood flow density. Further longitudinal research is needed to validate these findings and support clinical recommendations for myopia management.

Effect of biopsychosocial comprehensive chronic pain management physiotherapy practice protocol in patients with chronic musculoskeletal pain-a randomised control trial

Background: Chronic musculoskeletal pain (CMP) is a common condition treated by physiotherapists. Many existing treatments focus mainly on biomedical aspects, which have limited effectiveness and do not align with clinical practice guidelines that advocate for a biopsychosocial (BPS) approach. To address this issue, a new physiotherapy protocol has been developed that incorporates pain neurophysiological education, cognitive behaviour modification, and self-management strategies. This protocol will undergo clinical trial evaluation and has the potential to transform physiotherapy practices in line with these guidelines. Methods: A randomised, single-centre clinical trial will be carried out to compare the effect of a comprehensive CMP management (CCPM) which consists of 16 sessions weekly twice for 8 weeks neuroscience education program (4 sessions, 4 hrs) cognitive behaviour modification program (6 sessions, 6 hrs), self-management strategies (4 sessions, 4 hrs) and revision of the program (2 sessions, 2 hrs) along with usual care physiotherapy treatment for thrice weekly for 8 weeks, with standardised physiotherapy thrice weekly for 8 weeks as control group. The study aims to evaluate the effect of CCPM intervention on central sensitisation, as well as on fear avoidance, pain, disability, and pain self-efficacy The outcome variables will be measured at the beginning of the intervention and after 8 weeks. Discussions: The Physiotherapy practice must adopt a multi-dimensional pathway of treatment that considers all the bio-psychosocial factors during treatment sessions, rather than just following a bio-model pathway of management. Trial registration: CTRI/2023/05/053340 [Registered on: 31/05/2023]

Improvement in Central Sensitization Following Total Knee Arthroplasty Is Associated With Severe Preoperative Pain and Affects Postoperative Quality ofLife:A Retrospective Study.

Central sensitization (CS) is associated with quality of life (QOL) after total knee arthroplasty (TKA). However, how CS changes after TKA and whether these changes have clinical relevance remain unclear. Therefore, this study was conducted to identify changes in CS after TKA and to assess the clinical significance of these changes. This retrospective study was conducted on 92 patients between January 2021 and May 2023. CS severity was quantified using the Central Sensitization Inventory (CSI). One year after TKA, the patients were divided into groups based on whether CS severity improved by ≥ 1 level (improved group) or did not improve (non-improved group). The differences in preoperative and postoperative characteristics of patients in the two groups were analyzed. These characteristics included demographics, underlying diseases, physical examinations, and the Hospital for Special Surgery (HSS) knee score. QOL improvement was compared based on two different minimal clinically important changes (MIC) in the Short-Form Health Survey (SF-36). Continuous variables were compared using Student's t-test or the Mann-Whitney U-test. The chi-squared test was used to compare categorical variables. The postoperative CS severity in patients was significantly lower compared to preoperative levels (p < 0.001). The improved group exhibited a lower HSS knee pain score (p < 0.001). Out of the eight SF-36 scales, five showed significantly greater improvement in the improved group compared to the non-improved group. The mean postoperative increases in scores for all eight SF-36 scales exceeded the MIC in the improved group, whereas half of the scales fell below the MIC in the non-improved group. CS showed improvement after TKA, particularly in patients with more severe preoperative pain. This improvement appears to be correlated with the improvement in QOL after TKA.

Multiple lesion inductions intensify central sensitization driven by neuroinflammation in a mouse model of endometriosis.

Endometriosis is an inflammatory disease associated with chronic pelvic pain (CPP). Growing evidence indicates that endometriotic lesions are not the sole source of pain. Instead, central nervous system (CNS) dysfunction created by prolonged peripheral and central sensitization plays a role in developing endometriosis-associated CPP. This study investigated how CPP is established using a multiple lesion induction mouse model of endometriosis, as repeated retrograde menstruation is considered underlying endometriosis pathogenesis. We generated endometriosis-like lesions by injecting endometrial tissue fragments into the peritoneal cavity in mice. The mice received a single (1x) or multiple inductions (6x) to simulate recurrent retrograde menstruation. Lesion development, hyperalgesia by behavioral testing, signs of peripheral sensitization, chronic inflammation, and neuroinflammation were examined with lesions, peritoneal fluids, dorsal root ganglia (DRG), spinal codes, and brain. Multiple lesion inductions increased lesion numbers and elevated abdominal and hind paw hypersensitivity compared to single induction mice. Elevated persistent glial cell activation across several brain regions and/or spinal cords was found in the multiple induction mice. Specifically, IBA1+ microglial soma size was increased in the hippocampus and thalamus. IBA1+ cells were abundant in the cortex, hippocampus, thalamus, and hypothalamus of the multiple induction mice. GFAP+ astrocytes were mainly elevated in the hippocampus. Elevated TRPV1, SP, and CGRP expressions in the DRG were persistent in the multiple induction mice. Furthermore, multiple inductions induced the severe disappearance of TIM4 hi MHCII lo residential macrophages and the influx of increased proinflammatory TIM4 lo MHCII hi macrophages in the peritoneal cavity. The single and multiple inductions elevated secreted TNFα, IL-1β, and IL-6 levels in the peritoneal cavity at 2 weeks. Elevated cytokine levels returned to the pre-induction levels in the single induction mice at 6 weeks; however, they remained elevated in the multiple induction mice. Our results indicate that the repeatedly occurring lesion inductions (=mimic retrograde menstruation) can be a peripheral stimulus that induces nociceptive pain and creates composite chronic inflammatory stimuli to cause neuroinflammation and sensitize the CNS. The circuits of neuroplasticity and stimulation of peripheral organs via a feedback loop of neuroinflammation may mediate widespread endometriosis-associated CPP.