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This review explores the application of the conservative management model for pain to sports-related concussions (SRCs), framing concussions as a distinct form of pain syndrome with a pathophysiological foundation in central sensitization. Drawing parallels with proven pain management models, we underscore the significance of a proactive approach to concussion management. Recognizing concussions as a pain syndrome allows for the tailoring of interventions in alignment with conservative principles. This review first covers the epidemiology and controversies surrounding prolonged concussion recovery and persistent post-concussion symptoms (PPCS). Next, the pathophysiology of concussions is presented within the central sensitization framework, emphasizing the need for early intervention to mitigate the neuroplastic changes that lead to heightened pain sensitivity. Five components of the central sensitization process specific to concussion injuries are highlighted as targets for conservative interventions in the acute period: peripheral sensitization, cerebral metabolic dysfunction, neuroinflammation, glymphatic system dysfunction, and pain catastrophizing. These proactive interventions are emphasized as pivotal in accelerating concussion recovery and reducing the risk of prolonged symptoms and PPCS, in line with the philosophy of conservative management.

Introduction: Previously, 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. Methods: TS 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). Results: An 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. Conclusion: Our 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. [ABSTRACT FROM AUTHOR]

Introduction: Nociplastic pain (NP), classified as a third type of pain alongside nociceptive and neuropathic pain, is chronic pain arising from the amplification of nociceptive stimuli through central sensitization, despite the absence of tissue damage, sensory nerve damage, or disease. An important clinical feature of NP is that it is not only associated with pain but also with sensory hypersensitivity to sound and light and cognitive dysfunction, including mood and attention disorders. Recent studies have suggested that depression and developmental disorders, such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), coexist with NP at high frequency. Additionally, cognitive impairment in individuals with NP may be associated with these psychiatric comorbidities. However, to our knowledge, there are no reports on (1) multidimensional evaluation and diagnostic details of abdominal NP in adults with ADHD/ASD; (2) how ADHD drugs and antidepressants are administered when ADHD and depression coexist with NP; and (3) how central sensitization, brain function, and family relationship problems underlying NP are altered by treatments of ADHD and depression. Case presentation: Herein, we present the case of a 51-year-old woman with abdominal NP. She developed severe right lower abdominal pain and underwent a thorough medical examination; however, the physical, medical cause remained unknown, making treatment challenging. Additionally, she took time off work as she began to complain of insomnia and anxiety. She was referred to our pain center, where a diagnosis of depression, ADHD, and ASD was confirmed, and treatment with ADHD medication was initiated. While ADHD medications alone did not yield sufficient improvement, a combination of methylphenidate and the antidepressant venlafaxine eventually led to improvements in abdominal NP, depression, ADHD symptoms, central sensitization, and family relationship issues. During treatment, cerebral blood flow in the anterior cingulate, prefrontal, and parietal cortices also improved. Conclusion: The treatment of comorbid depression is important while treating NP, and venlafaxine may be effective, especially in cases of comorbid ADHD/ASD. Screening for developmental disorders and depression is required in patients with abdominal NP. [ABSTRACT FROM AUTHOR]

According to the neurocognitive model of attention to pain, when the attentional resources invested in a task unrelated to pain are high, limited cognitive resources can be directed toward the pain. This is supported by experimental studies showing that diverting people's attention away from acute pain leads to experiencing less pain. Theoretical work has suggested that this phenomenon may present a top-down modulatory mechanism for persistent pain as well. However, conclusive empirical evidence is lacking. To fill this gap, we used a preregistered, double-blind, between-subject study design to investigate whether performing a tailored, demanding, and engaging working memory task unrelated to pain (difficult) vs a task that requires less mental effort to be performed (easy), could lead to lower development of secondary hypersensitivity--a hallmark of central sensitization. Eighty-five healthy volunteers, randomly assigned to one of the 2 conditions, performed a visual task with a different cognitive load (difficult vs easy), while secondary hypersensitivity was induced on their nondominant forearm using high-frequency stimulation. To assess the development of secondary hypersensitivity, sensitivity to mechanical stimuli was measured 3 times: T0, for baseline and 20 (T1) and 40 (T2) minutes after the procedure. We did not observe any significant difference in the development of secondary hypersensitivity between the 2 groups, neither in terms of the intensity of mechanical sensitivity nor its spatial extent. Our results suggest that a top-down modulation through attention might not be sufficient to affect pain sensitization and the development of secondary hypersensitivity. [ABSTRACT FROM AUTHOR]

Neuropathic pain is a common pain syndrome, which seriously affects the quality of life of patients. The mechanism of neuropathic pain is complex. Peripheral tissue injury can trigger peripheral sensitization; however, what really plays a key role is the sensitization of the central nervous system. Central sensitization is a key factor in the perception of chronic pain. Central sensitization refers to the increased sensitivity of the central nervous system to pain treatment, which is related to the change of the functional connection mode of the neural network. The current study aims to reveal the basic molecular mechanisms of central sensitization, including the involvement of P2 purine X4 receptor and brain-derived neurotrophic factor. In terms of treatment, although there are drugs and physical therapy, the accuracy of targeting is limited and the efficacy needs to be further improved. Future therapeutic strategies may involve the development of new drugs designed to specifically inhibit the central sensitization process. This article focuses on the effector molecules involved in central sensitization, aiming to elucidate the pathogenesis of neuropathic pain and provide a basis for the development of more effective treatment models. [ABSTRACT FROM AUTHOR]

Objectives Central pain mechanisms may be prominent in a considerable subset of rheumatology patients with persistent pain. Several self-report instruments have been used in previous research to infer the presence and severity of central sensitization (CS) that stem from different definitions or approaches of CS. The current study aimed to evaluate and quantify the overlap of actual symptoms measured among self-report measures of CS in rheumatology. Methods We used Fried's (2017) comprehensive systematic approach to analyse the content of five commonly used or typical self-report measures (Generalized Pain Questionnaire, Pain Sensitivity Questionnaire, Central Sensitization Inventory, Central Aspects of Pain in the Knee scale and the painDETECT) used in rheumatology research and to visualize and quantify the overlap in symptoms measured. Results The five instruments together measured 39 different symptoms, most of which could be grouped into nociplastic pain manifestations (7 symptoms), neuropathic pain qualities (5 symptoms), and psychosomatic symptoms and emotional distress (25 symptoms). Most symptoms (74.4%) were unique to a single instrument. Thermal allodynia was the most frequently measured symptom across the different instruments, assessed in four of the measures. Average content overlap was very low and ranged from no overlap at all to moderate overlap (Jaccard index = 0.43) between pairs of instruments. Conclusion There is high heterogeneity and limited overlap in the content of self-report measures used to infer central pain sensitization. This may lead to results that are specific to the particular instrument and may limit the generalizability and comparability of study findings in rheumatology research. [ABSTRACT FROM AUTHOR]

Background: Fibromyalgia (FM) is a complex multidimensional disorder primarily characterized by chronic widespread pain, significantly affecting patients' quality of life. FM is associated with some clinical signs found with quantitative sensory testing (QST), sleep disturbance, or psychological problems. This study aims to explore the associations between pressure pain thresholds (PPTs), conditioned pain modulation (CPM), clinical status, and sleep quality in FM patients, offering insights for better clinical management and assessment tools. Methods: This secondary analysis utilized data from a clinical trial involving 129 FM patients. Various assessments, including the Fibromyalgia Impact Questionnaire (FIQ), Pain Catastrophizing Scale (PCS), State-Trait Anxiety Inventory (STAI), and Jenkins Sleep Scale (JSS), were employed to evaluate the clinical and psychological status and sleep quality. PPTs and CPM were measured to understand their relationship with clinical parameters. Results: Our findings revealed that PPTs and CPM are not significantly associated with the clinical status or sleep quality of FM patients. Instead, pain catastrophizing and anxiety state showed a stronger correlation with the impact of fibromyalgia and sleep disturbances. These results highlight the importance of psychological and cognitive factors in managing FM. Conclusions: The study suggests that while PPTs and CPM may not be reliable biomarkers for clinical status in FM, the use of comprehensive assessments including FIQ, PCS, STAI, and JSS can provide a more accurate evaluation of patients' condition. These tools are cost-effective, can be self-administered, and facilitate a holistic approach to FM management, emphasizing the need for personalized treatment plans. [ABSTRACT FROM AUTHOR]

Human assumed central sensitization (HACS) is a potential pathophysiological mechanism underlying a group of musculoskeletal disorders. HACS may negatively influence the outcomes of surgical or interventional procedures. The present study aimed to investigate the impact of HACS on treatment outcomes of transforaminal epidural steroid injection (TFESI). Patients who received fluoroscopy-guided single-level lumbosacral TFESI between January 2020 and January 2021 were included in the study. The patients were divided into two groups with respect to the existence of HACS. Patients were assessed before the procedure, at the third week, and at the third month after the procedure. The presence of HACS was investigated by central sensitization inventory (CSI). The Numerical Rating Scale (NRS), Oswestry Disability Index (ODI), and Beck Depression Inventory (BDI) were used for patient assessment. A total of 65 patients were included in the study. Thirty-one of the patients had HACS. There was no difference between the groups in terms of demographic data. Significant improvement in NRS was found at 3rd week and 3rd month compared to the baseline. BDI and ODI scores were also significantly reduced at the end of 3 months (p< 0.001). NRS scores at all time points were significantly lower in patients without HACS (p< 0.05). The presence of HACS has a negative effect on pain scores, disability, and mental state in patients undergoing TFESI. [ABSTRACT FROM AUTHOR]

Recently, we showed that while atogepant—a small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist—does not fully prevent activation of meningeal nociceptors, it significantly reduces a cortical spreading depression (CSD)-induced early response probability in C fibres and late response probability in Aδ fibres. The current study investigates atogepant effect on CSD-induced activation and sensitization of high threshold (HT) and wide dynamic range (WDR) central dura-sensitive trigeminovascular neurons. In anaesthetized male rats, single-unit recordings were used to assess effects of atogepant (5 mg/kg) versus vehicle on CSD-induced activation and sensitization of HT and WDR trigeminovascular neurons. Single cell analysis of atogepant pretreatment effects on CSD-induced activation and sensitization of central trigeminovascular neurons in the spinal trigeminal nucleus revealed the ability of this small molecule CGRP receptor antagonist to prevent activation and sensitization of nearly all HT neurons (8/10 versus 1/10 activated neurons in the control versus treated groups, P = 0.005). In contrast, atogepant pretreatment effects on CSD-induced activation and sensitization of WDR neurons revealed an overall inability to prevent their activation (7/10 versus 5/10 activated neurons in the control versus treated groups, P = 0.64). Unexpectedly however, in spite of atogepant's inability to prevent activation of WDR neurons, it prevented their sensitization (as reflected their responses to mechanical stimulation of the facial receptive field before and after the CSD). Atogepant' ability to prevent activation and sensitization of HT neurons is attributed to its preferential inhibitory effects on thinly myelinated Aδ fibres. Atogepant's inability to prevent activation of WDR neurons is attributed to its lesser inhibitory effects on the unmyelinated C fibres. Molecular and physiological processes that govern neuronal activation versus sensitization can explain how reduction in CGRP-mediated slow but not glutamate-mediated fast synaptic transmission between central branches of meningeal nociceptors and nociceptive neurons in the spinal trigeminal nucleus can prevent their sensitization but not activation. [ABSTRACT FROM AUTHOR]

Chronic pain is a prevalent condition with a multifaceted pathogenesis, where epigenetic modifications, particularly DNA methylation, might play an important role. This review delves into the intricate mechanisms by which DNA methylation and demethylation regulate genes associated with nociception and pain perception in nociceptive pathways. We explore the dynamic nature of these epigenetic processes, mediated by DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) enzymes, which modulate the expression of pro- and anti-nociceptive genes. Aberrant DNA methylation profiles have been observed in patients with various chronic pain syndromes, correlating with hypersensitivity to painful stimuli, neuronal hyperexcitability, and inflammatory responses. Genome-wide analyses shed light on differentially methylated regions and genes that could serve as potential biomarkers for chronic pain in the epigenetic landscape. The transition from acute to chronic pain is marked by rapid DNA methylation reprogramming, suggesting its potential role in pain chronicity. This review highlights the importance of understanding the temporal dynamics of DNA methylation during this transition to develop targeted therapeutic interventions. Reversing pathological DNA methylation patterns through epigenetic therapies emerges as a promising strategy for pain management. [ABSTRACT FROM AUTHOR]

Endometriosis, often associated with chronic pelvic pain, can lead to anxiety and depression. This study investigates the role and mechanism of Glycine receptor alpha 3 (Glrα3) in the central sensitization of pain in endometriosis, aiming to identify new therapeutic targets. Using a Glrα3 knockout mouse model of endometriosis, we employed behavioral tests, qPCR, immunofluorescence, Nissl staining, MRI, and Western blot to assess the involvement of Glrα3 in central pain sensitization. Our results indicate that endometriosis-induced hyperalgesia and anxiety–depressive-like behaviors are linked to increased Glrα3 expression. Chronic pain in endometriosis leads to gray matter changes in the sensory and insular cortices, with Glrα3 playing a significant role. The inhibition of Glrα3 alleviates pain, reduces neuronal abnormalities, and decreases glial cell activation. The absence of Glrα3 effectively regulates the central sensitization of pain in endometriosis by inhibiting glial cell activation and maintaining neuronal stability. This study offers new therapeutic avenues for the clinical treatment of endometriosis-related pain. [ABSTRACT FROM AUTHOR]

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 < 0.01), lowly positively correlated with pain catastrophization (r = 0.332, p = 0.017) and anxiety (r = 0.492, p < 0.01), but not depression (r = 0.207, p = 0.132). Multiple linear regression analysis showed that kinesiophobia (B = 1.308, p < 0.01) and anxiety (B = 1.806, p = 0.02) were significant positive predictors of CSI score. Conclusions: The findings confirm some of our hypotheses. Accordingly, the findings inferred that the CSI does not seem to respond to CPM effect in patients with CNP effectively. In addition, CSI score was associated with cognitions and psychological factors, of which kinesiophobia and anxiety were effective predictors. In clinical practice, pain-related cognitions and psychological factors should be fully considered to manage neck pain efficiently. [ABSTRACT FROM AUTHOR]

Pain control and patient satisfaction after total knee arthroplasty (TKA) have room for improvement. While studies have reported better analgesic outcomes with antidepressants like duloxetine in patients who do not have central sensitivity (CS), we undertook this trial to determine the short and midterm analgesic role of low-dose duloxetine in patients who do not have CS. This prospective, double-blinded, randomized, placebo-controlled trial was conducted in 106 patients undergoing single-setting, bilateral TKA under spinal anesthesia. There were 2 matched groups, with one given 20 mg of duloxetine and the other given a placebo (similar in appearance and weight) from preoperative day 2 to postoperative day 28. Follow-ups were scheduled at 48-hours, 1-week, 2-weeks, 4-weeks, and 3-months. Pain was measured using a visual analogue scale at rest and visual analogue scale at mobilization (mVAS). Secondary measures included additional non-steroidal anti-inflammatory drug consumption, patient satisfaction, and safety profile. The visual analogue scale at rest in the duloxetine group was better in the first 48 hours (6.38 ± 1.32 versus 7.02 ± 0.99; P =.017), 1-week (4.76 ± 1.24 versus 5.89 ± 1.06; P <.001), and 2-weeks (3.34 ± 1.19 versus 4.26 ± 1.02; P <.001) follow-up. The mVAS remained significantly higher in the duloxetine group in the first 48 hours (7.23 ± 1.12 versus 8.21 ± 0.69; P <.001), 1-week (5.83 ± 1.11 versus 6.82 ± 0.92; P <.001), and 2 weeks (3.70 ± 0.89 versus 4.60 ± 1.03; P <.001) follow-up. Both outcomes became comparable from 4-week follow-up onward. Patient satisfaction (8.44 ± 1.68 versus 7.17 ± 1.04; P <.001) and additional non-steroidal anti-inflammatory drug consumption (2,770 ± 533.05 versus 3,566.04 ± 464.54; P <.001) were better in the duloxetine group, with a comparable safety profile. In patients who did not have CS, persistent pain after bilateral TKA can be managed safely and successfully by a daily dose of 20 mg Duloxetine, improving patient satisfaction and analgesic consumption in the acute postoperative phase. [ABSTRACT FROM AUTHOR]

Individuals with chronic pain due to knee osteoarthritis (OA) are insufficiently physically active, and alterations of facilitatory and inhibitory nociceptive signaling are common in this population. Our objective was to examine the association of these alterations in nociceptive signaling with objective accelerometer-based measures of physical activity in a large observational cohort. We used data from the Multicenter Osteoarthritis Study. Measures of peripheral and central pain sensitivity included pressure pain threshold at the knee and mechanical temporal summation at the wrist, respectively. The presence of descending pain inhibition was assessed by conditioned pain modulation (CPM). Physical activity was quantitatively assessed over 7 days using a lower back-worn activity monitor. Summary metrics included steps/day, activity intensity, and sedentary time. Linear regression analyses were used to evaluate the association of pain sensitivity and the presence of descending pain inhibition with physical activity measures. Data from 1873 participants was analyzed (55.9% female, age = 62.8 ± 10.0 years). People having greater peripheral and central sensitivity showed lower step counts. CPM was not significantly related to any of the physical activity measures, and none of the exposures were significantly related to sedentary time. In this cohort, greater peripheral and central sensitivity were associated with reduced levels of objectively-assessed daily step counts. Further research may investigate ways to modify or treat heightened pain sensitivity as a means to increase physical activity in older adults with knee OA. [ABSTRACT FROM AUTHOR]

Although the pathophysiology of fibromyalgia syndrome has been better understood in recent decades, a unified model of its pathogenesis and an effective therapeutic approach are still far from being realized. The main aim of this article will be to delve into the fundamental mechanisms of the pathophysiology of fibromyalgia conceptualized as stress intolerance syndrome. Using the biopsychosocial model of chronic pain syndromes, we will describe the potential role of the attachment system, C-tactile fibers, and oxytocinergic system dysfunction in the pathophysiology of fibromyalgia syndrome and other central sensitivity syndromes. At the end of the article, the therapeutic implications of this new global and translational pathophysiological model will be briefly discussed. [ABSTRACT FROM AUTHOR]

Background: Patients with vestibular migraine (VM) exhibit higher levels of central sensitization and share similar disorder characteristics with migraine with vestibular symptoms (MwVS), except in terms of disability. These patients experience fluctuating mechanical pain thresholds and persistent vestibular symptoms even without a migraine attack. Objective: This study aimed to investigate whether interictal allodynia or hyperalgesia can differentiate between VM, MwVS, and migraine only. Methods: We conducted a cross-sectional study of patients with episodic migraine aged between 18 and 65 years, categorized into three groups. A questionnaire was used to collect and compare demographic and clinical variables. Interictal widespread pressure hyperalgesia (IWPH) was evaluated using the Manual Tender Point Survey. Patients with tender point counts ≥7 were classified as having IWPH. Results: The study included 163 patients: 31 with VM, 54 with MwVS, and 78 with migraine without vestibular symptoms (migraine only). We found that aura (p = 0.042, odds ratio 3.50, 95% confidence interval 1.26-10.4), tender point count (p < 0.001, d = 0.889, median difference = 2), and IWPH (p = 0.002, odds ratio 5.3, 95% confidence interval 1.80-17.2) were significantly associated with VM compared to MwVS. Aura and IWPH were significantly associated with VM. However, there were no significant associations observed for interictal allodynia or hyperalgesia between the other two groups. Conclusion: IWPH and aura are associated with VM, indicating their potential roles in its pathogenesis. These findings may contribute to the differential diagnosis and management of migraine, potentially leading to targeted treatment strategies. [ABSTRACT FROM AUTHOR]

Posttraumatic headache (PTH) is common following traumatic brain injury and impacts quality of life. We investigated descending pain modulation as one possible mechanism for PTH and correlated it to clinical measures. Pain-related evoked potentials (PREP) were recorded in 26 PTH-patients and 20 controls after electrical stimulation at the right hand and forehead with concentric surface electrodes. Conditioned pain modulation (CPM) was assessed using painful cutaneous electric stimulation (PCES) on the right hand as test stimulus and immersion of the left hand into 10 °C-cold water bath as conditioning stimulus based on changes in pain intensity and in amplitudes of PCES-evoked potentials. All participants completed questionnaires assessing depression, anxiety, and pain catastrophising. PTH-patients reported significantly higher pain ratings during PREP-recording in both areas despite similar stimulus intensity at pain threshold. N1P1-amplitudes during PREP and CPM-assessment were lower in patients in both areas, but statistically significant only on the hand. Both, PREP-N1-latencies and CPM-effects (based on the N1P1-amplitudes and pain ratings) were similar in both groups. Patients showed significantly higher ratings for anxiety and depression, which did not correlate with the CPM-effect. Our results indicate generalized hyperalgesia for electrical stimuli in both hand and face in PTH. The lacking correlation between pain ratings and EEG parameters indicates different mechanisms of pain perception and nociception. [ABSTRACT FROM AUTHOR]

Clinical Scenario: Pain is a common symptom experienced by individuals who sustain an acute lateral ankle sprain and can continue to persist among those who develop chronic ankle instability. Most rehabilitation protocols for individuals with acute ankle sprains or chronic ankle instability focus on restoring physical impairments and have largely omitted any pain-relieving therapies. This impairment-based focus has led pain to be an understudied symptom among individuals with an ankle sprain history. Overlooking the role of pain has also left clinicians with little insight into whether pain experienced after an ankle sprain is local (i.e., peripheral sensitization) or widespread (i.e., central sensitization). Understanding the pain profiles for those with an ankle sprain history may represent an unexploited area for clinicians and future research to improve health outcomes for this patient population. Clinical Question: Is there evidence to suggest that pain mechanosensitivity levels are different between those with and without a history of lateral ankle sprain? Summary of Key Findings: The literature was systematically searched for Level 4 evidence or higher. The search yielded two cross-sectional case-control studies and one cross-sectional study that met the inclusion and exclusion criteria. Based on the available evidence, pain mechanosensitivity levels are lower across ligamentous stabilizers immediately after an acute ankle sprain and over lower extremity neuromuscular structures among individuals with chronic ankle instability. ClinicalBottom Line: There is weak evidence to support an ankle sprain history can affect local pain mechanosensitivity levels of structures surrounding the ankle but not at distant locations. Strength of Recommendation: Level 4 evidence is available according to the Center for Evidence-Based Medicine. [ABSTRACT FROM AUTHOR]

The insula and dorsal anterior cingulate cortex (dACC) are core brain regions involved in pain processing and central sensitization, a shared mechanism across various chronic pain conditions. Methods to modulate these regions may serve to reduce central sensitization, though it is unclear which target may be most efficacious for different measures of central sensitization. Objective/Hypothesis: Investigate the effect of low-intensity focused ultrasound (LIFU) to the anterior insula (AI), posterior insula (PI), or dACC on conditioned pain modulation (CPM) and temporal summation of pain (TSP). N = 16 volunteers underwent TSP and CPM pain tasks pre/post a 10 min LIFU intervention to either the AI, PI, dACC or Sham stimulation. Pain ratings were collected pre/post LIFU. Only LIFU to the PI significantly attenuated pain ratings during the TSP protocol. No effects were found for the CPM task for any of the LIFU targets. LIFU pressure modulated group means but did not affect overall group differences. LIFU to the PI reduced temporal summation of pain. This may, in part, be due to dosing (pressure) of LIFU. Inhibition of the PI with LIFU may be a future potential therapy in chronic pain populations demonstrating central sensitization. The minimal effective dose of LIFU for efficacious neuromodulation will help to translate LIFU for therapeutic options. • Low-intensity focused ultrasound (LIFU) can non-invasively target subregions of the insula and anterior cingulate. • LIFU to the posterior insula reduced pain ratings during temporal summation of pain but not conditioned pain modulation. • Estimated in vivo pressure varies across participants and brain targets and may help explain LIFU's effects. [ABSTRACT FROM AUTHOR]

Pain sensitivity is the main finding of central sensitization (CS) and can occur in patients with chronic shoulder pain. However, there is limited evidence concerning the distribution of pain sensitivity in shoulders, forearms, and legs in patients with CS associated with chronic shoulder pain. The present study aimed to determine the distribution of pain sensitivity in patients with CS associated with chronic subacromial pain syndrome (SPS). This cross-sectional study included 58 patients with chronic SPS and CS (patient group) and 58 healthy participants (control group). The presence of CS was determined using the Central Sensitization Inventory (CSI). To determine the distribution of pain sensitivity, pressure pain threshold (PPT) measurements were performed from the shoulders, forearms, and legs. There was no significant difference between the two groups in terms of sociodemographic data (p > 0.05). The patient group had a significantly higher CSI score (p < 0.001) and lower PPTs in all regions (p < 0.05) than the control group. Unlike the control group, the patient group had lower PPTs on the affected side for the shoulder [mean difference (MD) 95% confidence interval (CI): 1.2 (−1.7 to −0.6)], forearm [MD 95% CI: 1.1 (−1.7 to −0.6)], and leg [MD 95% CI: 0.9 (−1.4 to −0.3)] compared with the contralateral side (p < 0.001). Pain sensitivity is more pronounced in the affected shoulder and the forearm and leg located on this side than in those on the contralateral side in patients with CS associated with chronic SPS. • Pain sensitivity occurs in shoulders, forearms, and legs in patients with central sensitization associated with chronic subacromial pain syndrome. • Pain sensitivity is more pronounced in the forearm and leg on the side of the painful shoulder than in the symmetrical ones on the contralateral side. • The difference in pain pressure threshold between the distal and proximal regions is similar to that of healthy people. [ABSTRACT FROM AUTHOR]

Introduction: Aromatase inhibitor (AI)-induced musculoskeletal symptoms (AIMSS) can decrease health-related quality of life and lead to discontinuation of AI therapy for postmenopausal women with breast cancer (BC). Although central sensitization (CS) may contribute to AIMSS, the relevance of CS-related symptoms to AIMSS has not been fully clarified. This study aimed to investigate the relationship between AIMSS and CS-related symptoms in women with BC who received AI therapy. Methods: This cross-sectional study recruited women who underwent BC surgery before at least 1 year and were taking AI for at least 6 months. Participants were assessed for joint pain and CS-related symptoms using the central sensitization inventory (CSI). The severity of CS-related symptoms was classified into three groups, and the prevalence of AIMSS was calculated. Multiple logistic regression analysis was used to assess the relationship between AIMSS and factors of possible relevance to AIMSS, including CSI severity. Results: Of the 73 women who were included in this study, 31 (42.4%) were categorized into the AIMSS group and 42 (57.6%) into the non-AIMSS group. Participants with a history of chemotherapy and higher CSI score were significantly more likely to have AIMSS. Multiple logistic regression analysis showed that a history of chemotherapy (odds ratio = 4.21) and higher CSI severity (odds ratio = 13.43) had significantly associated with AIMSS. Conclusion: CS-related symptoms assessed using CSI may be strongly associated with AIMSS. Further longitudinal studies to investigate the causal relationship and effectiveness of CS-targeted interventions are needed to prevent and treat AIMSS effectively. [ABSTRACT FROM AUTHOR]

Background: The insula and dorsal anterior cingulate cortex (dACC) are core brain regions involved in pain processing and central sensitization, a shared mechanism across various chronic pain conditions. Methods to modulate these regions may serve to reduce central sensitization, though it is unclear which target may be most efficacious for different measures of central sensitization.Objective/Hypothesis: Investigate the effect of low-intensity focused ultrasound (LIFU) to the anterior insula (AI), posterior insula (PI), or dACC on conditioned pain modulation (CPM) and temporal summation of pain (TSP). Methods: N = 16 volunteers underwent TSP and CPM pain tasks pre/post a 10 min LIFU intervention to either the AI, PI, dACC or Sham stimulation. Pain ratings were collected pre/post LIFU. Results: Only LIFU to the PI significantly attenuated pain ratings during the TSP protocol. No effects were found for the CPM task for any of the LIFU targets. LIFU pressure modulated group means but did not affect overall group differences. Conclusions: LIFU to the PI reduced temporal summation of pain. This may, in part, be due to dosing (pressure) of LIFU. Inhibition of the PI with LIFU may be a future potential therapy in chronic pain populations demonstrating central sensitization. The minimal effective dose of LIFU for efficacious neuromodulation will help to translate LIFU for therapeutic options.

Abstract Posttraumatic headache (PTH) is common following traumatic brain injury and impacts quality of life. We investigated descending pain modulation as one possible mechanism for PTH and correlated it to clinical measures. Pain-related evoked potentials (PREP) were recorded in 26 PTH-patients and 20 controls after electrical stimulation at the right hand and forehead with concentric surface electrodes. Conditioned pain modulation (CPM) was assessed using painful cutaneous electric stimulation (PCES) on the right hand as test stimulus and immersion of the left hand into 10 °C-cold water bath as conditioning stimulus based on changes in pain intensity and in amplitudes of PCES-evoked potentials. All participants completed questionnaires assessing depression, anxiety, and pain catastrophising. PTH-patients reported significantly higher pain ratings during PREP-recording in both areas despite similar stimulus intensity at pain threshold. N1P1-amplitudes during PREP and CPM-assessment were lower in patients in both areas, but statistically significant only on the hand. Both, PREP-N1-latencies and CPM-effects (based on the N1P1-amplitudes and pain ratings) were similar in both groups. Patients showed significantly higher ratings for anxiety and depression, which did not correlate with the CPM-effect. Our results indicate generalized hyperalgesia for electrical stimuli in both hand and face in PTH. The lacking correlation between pain ratings and EEG parameters indicates different mechanisms of pain perception and nociception.

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.

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.

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

Background: Central sensitization is one of the pivotal pathological mechanisms in chronic migraine (CM). Silent information regulator 1 (SIRT1) was shown to be involved in CM, but its specific mechanism is unclear. Reactive oxygen species (ROS) are increasingly regarded as important signaling molecules in several models of pain. However, studies about the role of ROS in the central sensitization of CM model are rare. We thus explored the specific process of SIRT1 involvement in the central sensitization of CM, focusing on the ROS pathway. Methods: Inflammatory soup was repeatedly administered to male Sprague-Dawley rats to establish a CM model. The SIRT1 expression level in trigeminal nucleus caudalis (TNC) tissues was assessed by qRT-PCR and Western blotting analysis. The levels of ROS were detected by a Tissue Reactive Oxygen Detection Kit, DHE staining, and the fluorescence signal intensity of 8-OHdG. A ROS scavenger (tempol), a SIRT1 activator (SRT1720), a SIRT1 inhibitor (EX527), and a mitochondrial fission inhibitor (Mdivi-1) were used to investigate the specific molecular mechanisms involved. NMDAR2B, CGRP, ERK, and mitochondrial fission-related protein were evaluated by Western blotting, and the CGRP level in frozen sections of the TNC was detected via immunofluorescence staining. Results: After repeated inflammatory soup infusion and successful establishment of the CM rat model, SIRT1 expression was found to be significantly reduced, accompanied by elevated ROS levels. Treatment with Tempol, SRT1720, or Mdivi-1 alleviated allodynia and reduced the increase in NMDAR2B phosphorylation and CGRP and ERK phosphorylation in the CM rat. In contrast, EX527 had the opposite effect in CM rat. SRT1720 and EX527 decreased and increased ROS levels, respectively, in CM rats, and tempol reversed the aggravating effect of EX527 in CM rats. Furthermore, the regulatory effect of SIRT1 on ROS may include the involvement of the mitochondrial fission protein DRP1. Conclusion: The results indicate the importance of SIRT1 in CM may be due to its role in regulating the production of ROS, which are involved in modulating central sensitization in CM. These findings could lead to new ideas for CM treatment with the use of SIRT1 agonists and antioxidants. [ABSTRACT FROM AUTHOR]

Neuropathic pain arises from injuries to the nervous system in diseases such as diabetes, infections, toxicity, and traumas. The underlying mechanism of neuropathic pain involves peripheral and central pathological modifications. Peripheral mechanisms entail nerve damage, leading to neuronal hypersensitivity and ectopic action potentials. Central sensitization involves a neuropathological process with increased responsiveness of the nociceptive neurons in the central nervous system (CNS) to their normal or subthreshold input due to persistent stimuli, leading to sustained electrical discharge, synaptic plasticity, and aberrant processing in the CNS. Current treatments, both pharmacological and non-pharmacological, aim to alleviate symptoms but often face challenges due to the complexity of neuropathic pain. Neuromodulation is emerging as an important therapeutic approach for the treatment of neuropathic pain in patients unresponsive to common therapies, by promoting the normalization of neuronal and/or glial activity and by targeting cerebral cortical regions, spinal cord, dorsal root ganglia, and nerve endings. Having a better understanding of the efficacy, adverse events and applicability of neuromodulation through pre-clinical studies is of great importance. Unveiling the mechanisms and characteristics of neuromodulation to manage neuropathic pain is essential to understand how to use it. In the present article, we review the current understanding supporting dorsal root ganglia and spinal cord neuromodulation as a therapeutic approach for neuropathic pain. [ABSTRACT FROM AUTHOR]

Introduction and Hypothesis: Bladder pain syndrome (BPS) is a debilitating condition characterised by exaggerated bladder sensations and altered bladder function. It is still unknown whether the condition is a peripheral sensory problem or due to abnormal central sensory processing as seen in central sensitisation. This systematic review, which followed a published and Prospective Register of Systematic Reviews-registered protocol (CRD42021229962), is aimed at establishing the scope of central sensitisation in patients with BPS to aid optimal management and treatment. Methods: Four databases were searched, and appraisal of the identified studies was conducted by two independent reviewers based on eligibility criteria: patients with BPS being investigated for central sensitisation with or without comparison of controls, English-language articles, full text and publication in a peer-reviewed journal. The Methodological Index for non-Randomised Studies was used to determine study quality. We identified 763 papers in total, with 15 studies included in the final analysis. All studies were observational and had a low risk of bias. Measures included in the evaluation of CS were questionnaires, urodynamics, and quantitative sensory testing methods. Results: There was evidence of central sensitisation in patients with BPS in all papers evaluated (15 out of 15). In addition, more significant central sensitisation correlated with severe disease presentation (3 out of 3 papers) and concomitant chronic pain conditions (5 out of 5 papers). Conclusions: Central sensitisation plays an integral role in BPS patient pathology. Many secondary measures are used to evaluate this condition. Stratification of patients based on their pathology (peripheral, central or a combination of the two) will aid in implementing an individualised management strategy. [ABSTRACT FROM AUTHOR]

The objective of this study is to determine whether the change in pain intensity over time differs between somatosensory functioning evolution profiles in knee osteoarthritis (KOA) patients undergoing total knee arthroplasty (TKA). This longitudinal prospective cohort study, conducted between March 2018 and July 2023, included KOA patients undergoing TKA in four hospitals in Belgium and the Netherlands. The evolution of the Knee Injury and Osteoarthritis Outcome Score (KOOS) subscale pain over time (baseline, 3 months, and 1 year post-TKA scores) was the outcome variable. The evolution scores of quantitative sensory testing (QST) and Central Sensitization Inventory (CSI) over time (baseline and 1 year post-TKA scores) were used to make subgroups. Participants were divided into separate normal, recovered, and persistent disturbed somatosensory subgroups based on the CSI, local and widespread pressure pain threshold [PPT] and heat allodynia, temporal summation [TS], and conditioned pain modulation [CPM]. Linear mixed model analyses were performed. Two hundred twenty-three participants were included. The persistent disturbed somatosensory functioning group had less pronounced pain improvement (based on CSI and local heat allodynia) and worse pain scores 1 year post-TKA (based on CSI, local PPT and heat allodynia, and TS) compared to the normal somatosensory functioning group. This persistent group also had worse pain scores 1 year post-TKA compared to the recovered group (based on CSI). The study suggests the presence of a "centrally driven central sensitization" subgroup in KOA patients awaiting TKA in four of seven grouping variables, comprising their less pain improvement or worse pain score after TKA. Future research should validate these findings further. The protocol is registered at clinicaltrials.gov (NCT05380648). [ABSTRACT FROM AUTHOR]

Background: Central sensitization has a major role in health-related parameters in musculoskeletal conditions. There is still a lack of understanding regarding the impact of central sensitization on the interpretation of disease activity and functional disability in primary Sjögren's syndrome (pSS). Methods: The Central Sensitization Inventory (CSI) was used to screen for central sensitization. Disease-related parameters, including objective tests, medication use, the EULAR SS Patient Reported Index (ESSPRI), and the EULAR SS Disease Activity Index (ESSDAI), were assessed. Functionality, quality of life, sleep, and mental health were evaluated by the Health Assessment Questionnaire-Disability Index (HAQ-DI), Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), Jenkins Sleep Evaluation Scale (JSS), and Hospital Anxiety and Depression Scale (HADS), respectively. The effect of central sensitization on functionality and disease activity measures was assessed by regression analyses. Results: The frequency of central sensitization was 65% in patients with pSS (n = 60). Patients with central sensitization had higher HAQ-DI, ESSPRI, HADS, and JSS and lower SF-36 subdomain scores (p < 0.05 for all). A significant positive correlation was observed between the CSI score and the ESSPRI, JSS, HAQ-DI, and HADS scores (Spearman's rho ranging from 0.342 to 0.739). The multiple regression analysis indicated that CSI was independently associated with HAQ-DI (adjusted R2 = 0.19, B = 0.01) and ESSPRI (adjusted R2 = 0.45, B = 0.08) (p < 0.001 for all). Conclusion: This study confirms that central sensitization has a major impact on functionality and the interpretation of self-reported disease activity in pSS. When devising strategies for the management of patients with pSS, it is crucial to consider these close relationships. Key Points • The frequency of central sensitization accompanying primary Sjögren's syndrome is considerable. • Central sensitization was independently associated with functionality and self-reported disease activity assessment. • This close association leads to challenges in functionality, evaluating treatment response, and planning or switching between therapies in primary Sjögren's syndrome. [ABSTRACT FROM AUTHOR]

Chronic nonbacterial osteitis (CNO) is a rare musculoskeletal disease causing chronic bone pain. It is known that chronic musculoskeletal pain may involve other mechanisms than nociceptive pain only. We investigate the prevalence of neuropathic and nociplastic pain in adult CNO and their association with clinical characteristics and treatment outcomes. Survey study among the Dutch adult CNO cohort (n = 84/195 participated), including PAIN-detect for neuropathic pain, and the Central Sensitization Inventory (CSI), Fibromyalgia Rapid Screening Tool (FiRST), and ACTTION-APS Pain Taxonomy (AAPT) for nociplastic pain. Clinical characteristics and CNO-related bone pain scores were compared between patients with exclusive nociceptive pain and those with nociceptive pain plus neuropathic and/or nociplastic pain (mixed pain). 31% (95% CI 21–41) of patients classified as likely having neuropathic pain according to PAIN-detect. 53% (41–64) of patients displayed central sensitization on CSI, 61% (50–72) screened positive for fibromyalgia on FiRST and 14% (7–23) of patients fulfilled the AAPT criteria, all indicative of nociplastic pain. Mixed pain was associated with longer diagnostic delay (mean difference 2.8 years, 95% CI 0.4–5.2, p = 0.023), lower educational level (72% versus 20%, p < 0.001), and opioid use (37% versus 13%, p = 0.036). Despite comparable disease severity and extent, patients with mixed pain reported significantly higher CNO-related bone pain scores. This study demonstrates the high prevalence of mixed pain in adult CNO, in which neuropathic and nociplastic pain exist alongside nociceptive inflammatory bone pain. Disease burden in CNO may extend beyond inflammatory activity, highlighting the need for a multifaceted management approach. [ABSTRACT FROM AUTHOR]

Purpose: The primary aim of this cross-sectional study is to examine the prevalence of pain phenotypes in breast cancer survivors (BCS). A secondary aim entails examining whether health related quality of life differs between the main pain phenotypes in BCS. Methods: BCS who experienced chronic pain were asked to complete the numeric pain rating scale for pain, Margolis pain diagram, and short form 36 (SF-36). Following administration of questionnaires and quantitative sensory examinations were applied. To determine the prevalence of the predominant type of pain, a recently proposed classification system by the Cancer Pain Phenotyping (CANPPHE) Network was used. Results: Of the 86 female participants, 19 (22.09%) had dominant neuropathic pain, 18 (20.93%) had dominant nociceptive pain and 14 (16.28%) had dominant nociplastic pain. 35 participants (40.70%) were classified as having mixed pain. One-way ANOVA revealed a significant difference between the four pain groups for the SF-36 general health (F = 3.205, p = 0.027), social functioning (F = 4.093, p = 0.009), and pain (F = 3.603, p = 0.017) subscale scores. Conclusion: This study found that pain in BCS was mostly of mixed phenotype, followed by predominantly neuropathic and nociplastic pain. Furthermore, it was found that, compared to BCS with predominant neuropathic and nociceptive pain, BCS with predominant nociplastic pain have lower health related quality of life in the areas of bodily pain and social functioning. [ABSTRACT FROM AUTHOR]

Central sensitization is an important pathophysiological mechanism underlying chronic migraine (CM). Previous studies have shown that microglial activation and subsequent inflammation in the trigeminal nucleus caudalis (TNC) contribute to central sensitization. Toll-like receptor 2 (TLR2) is a receptor expressed on the membrane of microglia and participates in central sensitization in inflammatory and chronic pain; however, its role in CM is unclear. Therefore, this study investigated TLR2 involvement in CM in detail. Mice treated with recurrent nitroglycerin (NTG) were used as a CM model. Hyperalgesia was assessed using a 50% paw mechanical threshold and a 50% periorbital threshold on a Von Frey filament pain meter. Western blotting and immunofluorescence analyses were used to detect the expression of TLR2, microglia, c-fos and CGRP in TNC. The expression of inflammatory factors (IL-6, IL-1β、 IL-10、TNF-α and IFN-β1) was detected using quantitative real-time polymerase chain reaction (qRT-PCR). A selective TLR2 antagonist (C29) was systematically administered to observe its effect on hyperalgesia, microglia activation and the expression of c-fos, CGRP and inflammatory factors. Recurrent administration of NTG resulted in acute and chronic hypersensitivity, accompanied by upregulation of TLR2 expression and microglial activation in TNC. C29 partially inhibited pain hypersensitivity. C29 suppressed microglial activation induced by NTG administration. Inhibition of TLR2 reduced the expression of c-fos and CGRP in TNC after NTG treatment. C29 inhibited the expression of inflammatory mediators in TNC. These data showed that microglial TLR2 plays a critical role in the pathogenesis of CM by regulating microglial activation in TNC. [ABSTRACT FROM AUTHOR]

Background/aim: Data on the role of central sensitization in hemodialyzed patients are scarce. The aim was to identify the impact of central sensitization on quality of life and elucidate the risk factors for the development of central sensitization in patients receiving hemodialysis. Methods: Central sensitization, quality of life, psychological well-being, and sleep were assessed by the Central Sensitization Inventory (CSI), abbreviated version of the World Health Organization Quality of Life Instrument (WHOQOL-BREF), Hospital Anxiety and Depression Scale (HADS), and Jenkins Sleep Evaluation Scale (JSS), respectively. The effect of central sensitization on quality of life and the predictors of the development of central sensitization were assessed by regression analyses. Results: The frequency of central sensitization was 48% in the study population (n = 100). Patients with central sensitization had significantly higher pain intensity, worse sleep quality, and more impaired psychological status (p < 0.05 for all). The CSI score negatively affected all quality of life domains on its own (p < 0.001 for all, adjusted R2 ranged from 0.17 to 0.47). Dialysis vintage (OR, 0.8; 95% CI, 0.7 to 1.0), pain (OR, 1.5; 95% CI, 1.1 to 2.0), JSS (OR, 1.3; 95% CI, 1.1 to 1.5), and HADS-total (OR, 1.1; 95% CI, 1.0 to 1.2) were determined as the independent risk factors for central sensitization (p < 0.05 for all). Conclusion: This study confirms that given the high frequency of central sensitization and its significant negative impact on quality of life, the presence of central sensitization should be investigated in patients undergoing hemodialysis. [ABSTRACT FROM AUTHOR]

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]