Responsiveness of central sensitization-related measures in older people with chronic low back pain.

Chaihu-Shugan-San alleviates functional dyspepsia by inhibiting central sensitization and regulating glutamate metabolism via NMDAR/CaMKII signaling pathway.

Neck-specific exercises are commonly used in the management of temporomandibular disorders (TMD); however, the additional role of aerobic training remains unclear. Given the involvement of central pain mechanisms in TMD and the effects of aerobic exercise on pain modulation, its potential adjunctive value warrants further investigation. To evaluate the additional effects of aerobic training to neck exercises on pain intensity, neck disability, and related outcomes in women with chronic TMD. Randomized controlled trial. Fifty-eight women with chronic TMD were randomized into: (1) neck exercises (CG; n=30); or (2) neck exercises plus aerobic training (EG; n=28). Primary outcomes were orofacial pain intensity (VAS) and neck disability (NDI). Secondary outcomes were pressure pain thresholds (PPTs), jaw function (MFIQ), self-efficacy (CPSS), and oral health-related quality of life (OHIP-14). Repeated-measures ANOVA and multilevel mixed modelling (MLM) were used for analysis. Both groups improved over time in pain intensity, neck disability, and secondary outcomes, with no statistically significant differences between groups. Within-group effect sizes for pain intensity were large in the EG (g=1.43) and in the CG (g=1.08) after treatment. The MLM models indicated that NDI, CPSS and OHIP-14 explained part of the variation in pain intensity, and central sensitization, OHIP-14, and CPSS explained part of the variation for neck disability. Moderate-intensity aerobic exercise did not yield statistically significant additional benefits compared with performing neck exercises alone. However, it remains important to explore other types of aerobic exercise for managing TMD.

This review aimed to examine the role of the amygdala as a central hub in the pathophysiology of chronic pain, with a specific focus on fibromyalgia and migraine. We synthesize evidence on how structural, functional, and neurochemical alterations within amygdala-centered circuits contribute to pain amplification, emotional dysregulation, and central sensitization, and discuss their implications for circuit-based therapeutic strategies. A comprehensive, theory-driven literature synthesis was conducted, integrating findings from neuroimaging, neuromodulation, molecular neuroscience, and clinical studies. We examined alterations in amygdala structure, function, and connectivity with cortical and brainstem regions involved in nociceptive processing, emotional regulation, and descending pain modulation. Pharmacological and non-pharmacological interventions targeting limbic-brainstem circuits were also analyzed. Converging evidence indicates that both fibromyalgia and migraine are associated with significant volumetric, functional, and connectivity-related alterations of the amygdala. These changes are characterized by limbic hyperexcitability and aberrant coupling with the prefrontal cortex, hypothalamus, periaqueductal gray (PAG), and rostral ventromedial medulla (RVM), biasing descending pain control toward facilitation rather than inhibition. This network reorganization amplifies both the sensory and affective dimensions of pain and promotes symptom persistence. Neurochemical dysregulation-encompassing glutamatergic, monoaminergic, GABAergic, and peptidergic systems-further sustains maladaptive plasticity within amygdala-centered circuits. Emerging therapeutic approaches, including cognitive-behavioral interventions, neuromodulation, pharmacological modulation, and immersive technologies, show potential to reshape dysfunctional limbic-cortical networks and attenuate pain amplification. The amygdala emerges as a key integrative node linking nociceptive, emotional, and autonomic processes in fibromyalgia and migraine. Through its influence on descending pain modulatory systems, amygdala-centered circuits play a critical role in pain chronification and affective sensitization. These findings support a circuit-based framework for chronic pain, highlighting the amygdala as a promising target for individualized, multimodal therapeutic strategies aimed at restoring adaptive emotional-nociceptive integration.

This editorial examines the constraints and novel approaches to management of cervical spondylosis patients with generalized anxiety disorder. Cervical spondylosis is a prevalent degenerative illness that often coexists with generalized anxiety disorder, which can cause pain and diminishing functional capacity. The loop of pain, anxiety, and inflammation diminishes the effectiveness of standard medications and rehabilitation, resulting from the interaction of neuroinflammation, central sensitization, and maladaptive pain processing. Electroacupuncture (EA), integrating traditional acupuncture with low-frequency electrical stimulation, has the capacity to modify pain and inflammatory pathways. EA stimulates the release of endogenous opioids, regulates cytokines such as interleukin (IL)-6 and tumor necrosis factor-alpha, and increases anti-inflammatory markers including IL-10 and transforming growth factor-β. It also augments motor and sensory functions, alleviates inflammation, and rehabilitates cognitive processes. Throughout an eight-week trial, a recent study showed that EA significantly reduced back pain, disability, and anxiety, while simultaneously decreasing inflammatory biomarkers, indicating strong connections between symptom relief and biochemical improvement. EA alleviates the pain-anxiety loop, enhancing its use as an adjunct therapy by targeting inflammation. EA is a multimodal strategy that improves quality of life, reduces reliance on pharmaceuticals, corresponds with mechanism-based therapy, and is clinically safe. Moreover, its advantageous safety profile yields socioeconomic benefits by lowering healthcare costs, enabling workforce reintegration, and improving access to adjunct medicines. This editorial advocates for the incorporation of EA into clinical practice to optimize treatment outcomes, enhance quality of life in certain patient populations, and improve symptom management.

Chronic iodine excess is associated with increased serum thyrotropin (TSH) levels. We assessed the independent and interactive effects of iodine-excess transition outcomes and aging on TSH levels over 20-year follow-up. The original prospective cohort study started in 1999 and focused on three communities in North China (n = 1176). Based on the iodine status transition over the 20-year period, the euthyroid participants were categorized into groups according to urinary iodine concentrations (UIC): continuous iodine sufficiency (UIC 100-299 μg/L) (SI-SI, n = 261), from iodine excess (UIC >299 μg/L) to iodine deficiency (UIC <100 μg/L) (EI-DI, n = 145), from iodine excess to iodine sufficiency (EI-SI, n = 530), and continuous iodine excess (EI-EI, n = 240), respectively. During 1999-2004, the baseline median TSH levels were positively associated with the initial UIC levels. After 20 years, for participants with negative thyroid antibodies, the three iodine-excess groups all exhibited elevated median TSH levels (SI-SI 1.81 mU/L vs. EI-DI 2.19 mU/L vs. EI-SI 2.08 mU/L vs. EI-EI 2.01 mU/L), an increased prevalence of mild subclinical hypothyroidism (SCH) with TSH <10.0 mU/L (SI-SI 5.3% vs. EI-DI 11.2% vs. EI-SI 12.3% vs. EI-EI 9.4%) and reduced central thyroid hormone sensitivity compared with the SI-SI group (p < 0.05). However, the EI-EI group had the lowest TSH rising degree (SI-SI 0.32 mU/L [24.57%] vs. EI-DI 0.47 mU/L [24.56%] vs. EI-SI 0.45 mU/L [37.52%] vs. EI-EI 0.21 mU/L [14.18%], p < 0.05). Repeated-measures analysis revealed that aging was primarily related to a stable increase in TSH. Iodine-excess transition outcomes were also associated. Furthermore, a significant interaction effect existed between aging and different iodine-excess transition outcomes, modulating the TSH rising degree. Alleviation of iodine excess promoted aging-related TSH elevation, whereas persistent iodine excess suppressed aging-related TSH elevation. However, among participants with positive thyroid antibodies, no significant interaction effect above was observed. By comparison, there was a greater prevalence of SCH, especially an obvious high prevalence of severe SCH under persistent iodine excess. Elevated TSH levels induced by chronic iodine excess cannot be downregulated by reducing iodine intake. In nonautoimmune contexts, an interaction effect between iodine status and aging synergistically modulates the TSH rising degree. Iodine excess contributes to mild SCH and is correlated with high baseline TSH levels.

Excessive consumption of high-fat diets is linked to peripheral insulin resistance, neuroinflammation, and obesity. While dietary methionine restriction improves peripheral metabolic health, its effectiveness in attenuating central insulin resistance and neuroinflammation, especially in a sex-dependent manner, remains unclear. This study investigates whether methionine restriction can mitigate high-fat diet-induced alterations in insulin resistance and neuroinflammation in male and female mice and explores the role of endogenous fibroblast growth factor 21 (FGF21) in mediating these effects. We utilized wild-type and Fgf21 knockout (Fgf21-/-) mice to assess the impact of methionine restriction on body composition, insulin sensitivity, central insulin signaling, and neuroinflammation. methionine restriction reduced body weight and adiposity in males, regardless of diet or genotype. In females, methionine restriction reduced weight gain under high-fat diet conditions in both genotypes but had limited effects on female adiposity. Methionine restriction improved insulin sensitivity in WT mice, but this effect was absent in Fgf21-/- mice, highlighting the importance of FGF21. Likewise, methionine restriction enhanced hepatic insulin signaling in WT males, but not Fgf21-/- males. In contrast, methionine restriction had minimal impact on insulin signaling in the liver or brain of female mice. Methionine restriction decreased neuroinflammatory gene expression in the hippocampus of males following the high-fat diet, a process dependent on FGF21. These findings demonstrate that methionine restriction confers sex-specific protection against high-fat diet-induced metabolic disturbances, with FGF21 playing a critical role in both peripheral and central insulin sensitivity, particularly in males. Future studies should further elucidate the molecular mechanisms underlying the sex-specific effects of methionine restriction and the role of FGF21 in mediating these responses.

Peripheral cannabinoid receptor activation attenuates frostbite-induced chronic pain via modulation of TRP channels, neuroinflammation, and autophagy.

ABSTRACT Background and Purpose Chronic pain affects approximately 63% of people with multiple sclerosis (pwMS), contributing to fatigue, depression, anxiety, poor sleep, reduced quality of life, and cognitive decline. Within the biopsychosocial model, music therapy has emerged as a promising intervention to address these complex symptoms. This study aims to examine the effects of heart rate‐synchronized music therapy combined with motor imagery practice on pain, autonomic and cognitive functions, and psychosocial outcomes in patients with pwMS. We hypothesize that the combined intervention will lead to greater improvements than music therapy alone or routine care. Methods A double‐blind, randomized, and three‐arm parallel trial will be conducted with 45 patients with pwMS experiencing chronic pain. Participants will be randomly assigned to one of three groups: (1) heart rate‐synchronized music therapy combined with motor imagery, (2) heart rate‐synchronized music therapy alone, or (3) a control group receiving routine care. Interventions will be delivered twice weekly for 8 weeks, with each session lasting 20–30 min. The experimental groups will receive music therapy via videoconferencing. Assessments will be conducted at baseline, post‐intervention (week 8), and follow‐up (week 12). The primary outcome is pain intensity. Secondary outcomes include neuropathic pain, central sensitization, heart rate variability, anxiety, depression, fatigue, sleep quality, quality of life, and cognitive function. Sample size was calculated using G*Power; HRV data will be analyzed with Kubios software. Statistical analyses will be performed using SPSS and GraphPad Prism 10. Results Following randomization, baseline data will be collected. Blinded assessors will evaluate all outcomes at follow‐up points. An independent researcher will perform statistical analyses to assess changes across time and between groups. Discussion This study may provide evidence supporting a novel, non‐pharmacological, and telehealth‐compatible intervention for chronic pain in pwMS. Trial Registration NCT06800144, 24th January 2025

Effect of perioperative preemptive analgesia on hippocampal GABAA receptor α1/α5 balance in aged mild cognitive impairment rats.

Development of a Central Sensitization Inventory short form using data from twenty-three countries.

To highlight key factors required to optimize multi-mechanistic approaches with oral combination treatments for the acute management of a migraine attack. Given the complex multi-factorial nature of migraine, combining treatments with different mechanisms of action should improve outcomes compared to monotherapies, but this has not been demonstrated with all treatment combinations. For this narrative review, we searched PubMed using combinations of these terms: migraine, acute treatment, combination therapy, fixed-dose combination therapy, multi-mechanistic treatment, pharmacokinetics, and pharmacodynamics. All articles considered relevant were included. None of the existing migraine acute treatments as monotherapy effectively treat the key pathophysiological processes of migraine completely. Many patients do not achieve 2-h pain freedom, which is key to avoiding migraine recurrence, medication overuse leading to chronification, and migraine-related disability. The development of combination approaches has led to only two combinations with demonstrated superiority over their individual components: aspirin/acetaminophen/caffeine and sumatriptan/naproxen sodium. The latter is the most effective proven combination treatment because it targets peripheral activation of central pain pathways during the early migraine stages and central sensitization that develops later, independent of peripheral input. Other triptan/nonsteroidal anti-inflammatory drug combinations with higher efficacy as monotherapies could be more effective than sumatriptan/naproxen sodium, particularly if their pharmacokinetic profiles align with the vasoactive mediators of peripheral and central sensitization that they target. Combination treatments with different mechanisms of action targeting key distinct pathophysiological processes of migraine may be more effective than monotherapies, particularly if their pharmacokinetic profiles are optimized to target those processes at the right time. Further research in this area is warranted.

Background/Objectives: Fibromyalgia is a chronic pain syndrome influenced by both physical and psychological factors, but their interaction remains unclear. We evaluated tools combining physical and emotional dimensions to characterise fibromyalgia and assess associations with persistent physical symptoms (PPS) and the emotional distress in its clinical interpretation. Methods: This cross-sectional study included 1588 patients referred to the Pain Management Unit, Complejo Asistencial Universitario de León. Fibromyalgia cases had a prior diagnosis to referral using the 2019 ACTTION-American Pain Society Pain Taxonomy diagnostic criteria. At the first consultation, participants completed a standardized protocol including sociodemographic variables, a Central Sensitization Inventory Part B checklist of previously physician-diagnosed physical and psychological conditions, and the visual analogue scale for pain, the Modified Somatic Perception Questionnaire (MSPQ), and the Zung Self-Rating Depression Scale. The Distress and Risk Assessment Method (DRAM) was used to integrate MSPQ and Zung data. Results: Women had higher odds of fibromyalgia (p = 0.003). Fibromyalgia was associated with PPS (p < 0.001), with chronic fatigue predominating in women (p < 0.001) and neck injury/whiplash in men (p = 0.005). The MSPQ had the highest OR among the instruments evaluated (overall: p < 0.001; women: p < 0.001; men: p = 0.005). Fibromyalgia status differed by DRAM category (nominal model, p < 0.001), suggesting higher odds in the Depressive and Somatic categories compared with Normal. Conclusions: In our sample, sex was associated with fibromyalgia and PPS profiles; PPS profiles were also associated with fibromyalgia. The MSPQ appeared to be among the most informative instruments, and its integration with Zung through the DRAM may have potential utility for psychosomatic risk profiling in fibromyalgia, warranting further study.

Background: Neuropathic pain represents a growing global burden and has been selected by the IASP as the Global Year Topic for 2026. The implementation of the ICD-11 has redefined chronic pain taxonomy (MG30), necessitating an update in the clinical management of the most prevalent neuropathies. Objective: To synthesize recent updates regarding definitions, diagnostic criteria, molecular pathophysiology, and pharmacological and interventional treatment for Trigeminal Neuralgia (TN), Persistent Idiopathic Facial Pain (PIFP), Postherpetic Neuralgia (PHN), and Painful Diabetic Neuropathy (PDN). Methods: A structured literature review was conducted using PubMed, Cochrane, Embase, and Scielo databases. Clinical guidelines (EAN, IASP, ADA) and recent meta-analyses were analyzed to establish levels of evidence, NNT (Number Needed to Treat), and NNH (Number Needed to Harm). Results: TN classification is evolving towards an MRI-based stratification, while maintaining sodium channel blockers as the Gold Standard (NNT 1.7). The term "Atypical Facial Pain" is being abandoned in favor of PIFP, emphasizing central sensitization mechanisms. For PDN and PHN, sensory phenotyping is prioritized to distinguish between "irritable nociceptor" versus "deafferentation" profiles, guiding the use of gabapentinoids, dual inhibitors (SNRIs), and high-concentration topical therapies (8% capsaicin). Conclusions: Contemporary management is transitioning from a purely etiology-based approach to a mechanism-based approach (precision medicine). The implementation of the ICD-11 and clinical phenotyping are essential to optimize therapeutic efficacy.

Psychosocial correlates of central sensitization and kinesiophobia: the role of Type D personality in fibromyalgia - a cross-sectional study.

To analyse the relationship between central sensitivity to thyroid hormones (THs) and liver fibrosis in a euthyroid population. Central TH sensitivity indices, including the thyroid feedback quantile-based index (TFQI), thyroid stimulating hormone index (TSHI), and thyrotropin thyroxine resistance index (TT4RI), were calculated according to TH levels. Liver stiffness measurement (LSM) values were determined by liver shear wave quantification ultrasonography, and statistical analysis of the above data was conducted. Compared with those in the LSM < 7.3kPa group, the TFQI, TSHI, and TT4RI in the LSM ≥ 7.3kPa group significantly increased (P < 0.001). Trend tests of multiple regression equations indicated that the LSM was positively correlated with the TT4RI (β = 0.413, P < 0.001). In the sex subgroups, the LSM was positively correlated with the TT4RI (β = 0.425, P = 0.03) and TSHI (β = 0.015, P = 0.027) in females; in the age subgroups, the LSM was positively correlated with the TT4RI (inflection point: 8.4kPa, β = 0.324, P = 0.01) and TSHI (inflection point: 8.3kPa, β = 0.01, P = 0.022) before the inflection points in the age < 65 years group; and in the BMI subgroups, the LSM was positively correlated with the TT4RI (inflection point: 5.9kPa, β = 0.437, P = 0.008), TSHI (inflection point: 6.8kPa, β = 0.013, P = 0.008) and TFQI (inflection point: 6.8kPa, β = 0.007, P = 0.045) in the BMI < 30kg/m2 group. Central TH sensitivity decreases as the degree of fibrosis increases in the euthyroid population, particularly among females, individuals aged < 65 years, and those with a BMI < 30kg/m2 within certain ranges.

The Impact of Targeted Endometriosis Treatment On Patients With Central Sensitization: Systematic Review and Meta Analysis.

Purpose: To investigate the effect of corneal flap margin space width after femtosecond laser–assisted laser in situ keratomileusis (FS-LASIK) on corneal nerve regeneration using in vivo confocal microscopy (IVCM). Methods: This study assessed 46 consecutive patients who underwent FS-LASIK surgery. Routine examinations after myopic laser surgery were performed. IVCM was performed before and after surgery to observe the flap margin space and regeneration of the corneal subbasal nerve. The average of corneal flap margin space was calculated. Patients were divided into two groups: the wide-space group (&gt; 20 µm) and the narrow-space group (⩽ 20 µm). Central and peripheral (average of 3-, 6-, and 9-o'clock positions) corneal sensitivity was tested by the Cochet–Bonnet esthesiometer and corneal subbasal nerve regeneration was quantitatively analyzed. Results: Postoperatively at days 1 to 90, the incision edge of the narrow-space group showed a high-density linear structure without obvious epithelial cells filling in the space, and the corneal nerve gradually grew from the outside of the flap through the incision edge to the inside of the flap. In the wide-space group, obvious epithelial cells filling in the space were observed from 1 day postoperatively, and the corneal nerve grew less from the outside of the flap through the incision edge to the inside of the flap. There was no significant intergroup difference in the central corneal nerve fiber length. However, the peripheral corneal nerve fiber length in the narrow-space group was significantly higher at both 30 and 90 days postoperatively. No statistically significant differences were observed between groups in central and peripheral corneal sensitivity. There was no significant difference in spherical equivalent between groups at each time point. Conclusions: Although the postoperative flap margin space significantly affects corneal nerve regeneration, it does not influence corneal sensitivity or the refractive outcome after FS-LASIK.

Perioperative Treatment of Neuropathic Pain (Nerve SPACE 2025).

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease characterized by complex pain mechanisms that extend beyond inflammation. Although inflammatory nociceptive pain - primarily mediated by pro-inflammatory cytokines - represents the classic pathway and therapeutic target, many patients continue to experience pain despite suppression of inflammation. This residual pain often reflects non-inflammatory processes, including nociplastic and neuropathic pain. Central sensitization, a key mechanism of nociplastic pain, contributes to pain amplification and poor response to treatment. Fibromyalgia, considered the typical phenotype of nociplastic pain, can co-occur with axSpA and is associated with increased symptom burden and reduced efficacy of anti-inflammatory therapies. Neuropathic pain, albeit less common, can result from structural complications and requires targeted therapeutic approaches. In addition, biological sex differences further influence pain perception and treatment outcomes: female patients report more widespread pain, show higher rates of central sensitization and have a worse response to biologic therapies than male patients. Current treatment paradigms are effective for inflammation-driven symptoms but often fail to address the broader spectrum of pain phenotypes in axSpA. Future work should include the development of biomarkers to differentiate pain mechanisms, the refinement of assessment tools and the evaluation of multimodal therapies that target both inflammation and pain processes. This evolving understanding necessitates a shift from an inflammation-centric to a mechanism-informed approach to pain management in axSpA.