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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.

ABSTRACT Objective Subjects and Methods Results Conclusions To investigate the relationship between biological, psychological, and social factors underlying Burning Mouth Syndrome (BMS).A case (n = 40) and control (n = 42) study containing 80 variables was examined using two network models based on regularized partial correlations (n = 82).The structure of the associative pathways with the BMS was revealed. Direct associations involved Gastrointestinal Alterations (0.23), Vitamin D Deficiency (0.29), Musculoskeletal Alterations (0.29), Symptom Severity Score 2 (SSS2) (0.22), Cortisol Variation (0.10), Interpersonal Sensitivity (0.04), Hostility (0.03). Global Severity Index, Symptom Severity Score 1, Psychoticism, Obsession‐Compulsion, Depression, Anxiety, and Somatization were indirectly related. The SSS2 was the most influential on BMS accuracy.Gastrointestinal alterations and vitamin D deficiency show a significant influence on BMS while cortisol mediates in multiple associative pathways between musculoskeletal alterations, gastrointestinal alterations, vitamin D deficiency, non‐restorative sleep, fatigue, and cognitive problems. In addition to anxiety and depression, psychoticism, interpersonal sensitivity, and hostility stand out as psychological factors that seem to be related to a lack of vitamin D. None of the factors studied seem to have a relevant predictive potential for BMS, except for nonspecific symptoms of central sensitization. [ABSTRACT FROM AUTHOR]

Background: Chronic migraine (CM) is a serious neurological disorder. Central sensitization is one of the important pathophysiological mechanisms underlying CM, and microglia-induced neuroinflammation conduces to central sensitization. Triggering receptor expressed on myeloid cells 2 (TREM2) is presented solely in microglia residing within the central nervous system and plays a key role in neuroinflammation. Metformin has been shown to regulate inflammatory responses and exert analgesic effects, but its relationship with CM remains unclear. In the study, we investigated whether metformin modulates TREM2 to improve central sensitization of CM and clarified the potential molecular mechanisms. Methods: A CM mouse model was induced by administration of nitroglycerin (NTG). Behavioral evaluations were conducted using von Frey filaments and hot plate experiments. Western blot and immunofluorescence techniques were employed to investigate the molecular mechanisms. Metformin and the SYK inhibitor R406 were administered to mice to assess their regulatory effects on neuroinflammation and central sensitization. To explore the role of TREM2-SYK in regulating neuroinflammation with metformin, a lentivirus encoding TREM2 was injected into the trigeminal nucleus caudalis (TNC). In vitro experiments were conducted to evaluate the regulation of TREM2-SYK by metformin, involving interventions with LPS, metformin, R406, siTREM2, and TREM2 plasmids. Results: Metformin and R406 pretreatment can effectively improve hyperalgesia in CM mice. Both metformin and R406 significantly inhibit c-fos and CGRP expression in CM mice, effectively suppressing the activation of microglia and NLRP3 inflammasome induced by NTG. With the administration of NTG, TREM2 expression gradually increased in TNC microglia. Additionally, we observed that metformin significantly inhibits TREM2 and SYK expression in CM mice. Lv-TREM2 attenuated metformin-mediated anti-inflammatory responses. In vitro experiments, knockdown of TREM2 inhibited LPS-induced SYK pathway activation and alleviated inflammatory responses. After the sole overexpression of TREM2, the SYK signaling pathway is activated, resulting in the activation of the NLRP3 inflammasome and an increased expression of pro-inflammatory cytokines; nevertheless, this consequence can be reversed by R406. The overexpression of TREM2 attenuates the inhibition of SYK activity mediated by metformin, and this effect can be reversed by R406. Conclusions: Our findings suggest that metformin attenuates central sensitization in CM by regulating the activation of microglia and NLRP3 inflammasome through the TREM2-SYK pathway. [ABSTRACT FROM AUTHOR]

Background: Migraine is the fourth most common cause of disability in women and the eighth most common cause in men. Central sensitization phenomena predispose to chronic migraine and are generally more pronounced in women. Objective: The aim of this retrospective observational study was to look for sex differences in a population of migraine subjects attending a tertiary headache center, focusing on symptoms of central sensitization such as allodynia and pericranial tenderness. Methods: This study is based on data collected at a tertiary headache center between January 1, 2018, and December 31, 2022. The clinical interview included the main features of migraine, allodynia, a disability questionnaire, the pericranial tenderness score, and anxiety and depression scales. Results: We selected a total of 1,087 migraine subjects (233 men). Osmophobia predominated in women, as did nausea. Disability scores, headache intensity, allodynia, anxiety, and depression predominated in women, without menopausal age playing a role. The frequency of symptomatic medication use was similar in both sexes. Allodynia score was the largest discriminating factor between women and men. Conclusions: Women with migraine are more likely than men to report acute allodynia, nausea, and osmophobia and are also more likely to be anxious, depressed, and disabled. These features appear to be independent of fertile age and are probably related to sex-specific genetic characteristics. These symptoms represent a tendency toward sensory hypersensitivity and central sensitization that should be carefully assessed in both women and men with migraine with a view to possibly predicting chronic development. [ABSTRACT FROM AUTHOR]

Background: Patellofemoral pain (PFP) is a common multifactorial condition in young and physically active people. Objective: The occurrence of central sensitization may play an important role in sensory disturbance. This study was designed to investigate, in patients with chronic PFP, the presence of disturbances in tactile acuity with central sensitization. Methods: Thirty patients with chronic PFP and 30 matched healthy controls entered this cross-sectional study. Graphesthesia (numerical score), two-point discrimination (mm), and point-to-point sensation (mm) were assessed in all participants. Results: The results of between-group comparisons showed that there were significant differences between the involved knee in patients with chronic PFP and healthy participants in graphesthesia (median = 13 [case], 19 [control]; p <.001), two-point discrimination (median = 25.8 [case], 20.3 [control]; p <.001), and point-to-point sensation (median = 14.5 [case], 6.2 [control]; p <.001). There was also a significant difference in graphesthesia between the non-involved knee in patients with chronic PFP and healthy participants (median = 17 [case], 19 [control]; p =.003). The results of within-group comparisons revealed a significant difference in graphesthesia, two-point discrimination, and point-to-point sensation between the involved and non-involved knee in patients with chronic PFP (p <.001). Moreover, there was a positive correlation between two-point discrimination and pain in patients with chronic PFP (r = 0.446, p =.014). Conclusion: The findings of this study reveal that there is a sensory deficit in patients with chronic PFP. Because sensory information is necessary for motor control and pain perception, we can assume that clinical symptoms in these patients are related to sensory deficits. [ABSTRACT FROM AUTHOR]

Background Neuropathic-like pain, fatigue, cognitive difficulty, catastrophizing, anxiety, sleep disturbance, depression and widespread pain associate with a single factor in people with knee pain. We report the Central Aspects of Pain questionnaire (CAP) to characterize this across painful musculoskeletal conditions. Methods CAP was derived from the 8-item CAP-Knee questionnaire, and completed by participants with joint pain in the Investigating Musculoskeletal Health and Wellbeing survey. Subgroups had OA, back pain or FM. Acceptability was evaluated by feedback and data missingness. Correlation coefficients informed widespread pain scoring threshold in relation to the other items, and evaluated associations with pain. Factor analysis assessed CAP structure. Intraclass Correlation Coefficient (ICC) between paper and electronic administration assessed reliability. Friedman test assessed score stability over 4 years in people reporting knee OA. Results Data were from 3579 participants (58% female, median age 71 years), including subgroups with OA (n  = 1158), back pain (n  = 1292) or FM (n  = 177). Across the three subgroups, ≥10/26 painful sites on the manikin scored widespread pain. Reliability was high [ICC = 0.89 (95% CI 0.84–0.92)] and CAP scores fit to one- and two-factor model, with a total CAP score that was associated with pain severity and quality (r = 0.50–0.72). In people with knee pain, CAP scores were stable over 4 years at the group level, but displayed significant temporal heterogeneity within individual participants. Conclusions Central aspects of pain are reliably measured by the CAP questionnaire across a range of painful musculoskeletal conditions, and is a changeable state. [ABSTRACT FROM AUTHOR]

AbstractDeafferentation is an umbrella term that includes several clinical conditions. The exact mechanism is not yet known, and the different clinical conditions do not necessarily share common pathophysiology. It includes both non-painful and painful conditions, including cancer pain conditions. Clinical presentation can be immediate or delayed, sometimes years after the causative lesion. Patients experience neuropathic pain symptoms in an area of abnormal or absent sensation. Laboratory tests show denervation and loss of function. Pain management strategies can be directed toward alleviating symptoms rather than eradication. The site of origin of the pain can help decide the treatment modalities to be tried. Gabapentinoids, antidepressants, and sodium channel blockers can be used. This type of pain is typically opioid-nonresponsive, but some patients may benefit. Neuronal destructive procedures are indicated for brachial plexus avulsion injuries. Spinal cord stimulation, dorsal root entry zone rhizotomy, deep brain thalamic stimulation, and motor cortex stimulation have been suggested for the management of the complex clinical conditions under the umbrella of deafferentation. [ABSTRACT FROM AUTHOR]

Neuropathic pain, arising from lesions of the somatosensory nervous system, presents with diverse symptoms including ongoing pain, paroxysmal pain, and provoked pain, usually accompanied by sensory deficits. Understanding the pathophysiological mechanisms behind these symptoms is crucial for targeted treatment strategies. Neurophysiological techniques such as nerve conduction studies, reflexes, and evoked potentials help elucidate these mechanisms by assessing large myelinated non-nociceptive fibres and small nociceptive fibres. This argumentative review highlights the importance of tailored neurophysiological assessments for improving our understanding of the pathophysiological mechanisms behind neuropathic pain symptoms. [ABSTRACT FROM AUTHOR]

[Display omitted] • Abnormal activation of Group I mGluRs induces central sensitization. • Blocking Group Ⅰ mGluRs can alleviate neuropathic pain. • The existing Group I mGluRs orthosteric site antagonists have limitations. • Allosteric Modulators exhibit natural advantages due to allosteric modulation. • Structure based drug discovery may promote drug discovery targeting Group I mGluRs. Neuropathic pain (NP) is a widespread public health problem that existing therapeutic treatments cannot manage adequately; therefore, novel treatment strategies are urgently required. G-protein-coupled receptors are important for intracellular signal transduction, and widely participate in physiological and pathological processes, including pain perception. Group I metabotropic glutamate receptors (mGluRs), including mGluR1 and mGluR5, are predominantly implicated in central sensitization, which can lead to hyperalgesia and allodynia. Many orthosteric site antagonists targeting Group I mGluRs have been found to alleviate NP, but their poor efficacy, low selectivity, and numerous side effects limit their development in NP treatment. Here we reviewed the advantages of Group I mGluRs negative allosteric modulators (NAMs) over orthosteric site antagonists based on allosteric modulation mechanism, and the challenges and opportunities of Group I mGluRs NAMs in NP treatment. This article aims to elucidate the advantages and future development potential of Group I mGluRs NAMs in the treatment of NP. [ABSTRACT FROM AUTHOR]

BACKGROUND: 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. OBJECTIVE: The present study aimed to investigate the impact of HACS on treatment outcomes of transforaminal epidural steroid injection (TFESI). METHODS: 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. RESULTS: 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). CONCLUSION: The presence of HACS has a negative effect on pain scores, disability, and mental state in patients undergoing TFESI. [ABSTRACT FROM AUTHOR]

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

The appearance of contralateral effects after unilateral injury has been shown in various experimental pain models, as well as in clinics. They consist of a diversity of phenomena in contralateral peripheral nerves, sensory ganglia, or spinal cord: from structural changes and altered gene or protein expression to functional consequences such as the development of mirror-image pain (MP). Although MP is a well-documented phenomenon, the exact molecular mechanism underlying the induction and maintenance of mirror-like spread of pain is still an unresolved challenge. MP has generally been explained by central sensitization mechanisms leading to facilitation of pain impulse transfer through neural connections between the two sides of the central nervous system. On the contrary, the peripheral nervous system (PNS) was usually regarded unlikely to evoke such a symmetrical phenomenon. However, recent findings provided evidence that events in the PNS could play a significant role in MP induction. This manuscript provides an updated and comprehensive synthesis of the MP phenomenon and summarizes the available data on the mechanisms. A more detailed focus is placed on reported evidence for peripheral mechanisms behind the MP phenomenon, which were not reviewed up to now. [ABSTRACT FROM AUTHOR]

Central pain sensitivity (CS) is defined as an increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold inputs. The main aim of this paper is to investigate if and how specific psychological constructs are related with CS burden in patients with chronic headache (CH). Specifically, research question 1 explores the association of temperament, personality, childhood adversities, defense mechanisms and mental pain with CS burden. Research question 2 aims to test the role of the best predictors of CS burden in affecting the quality of life (QoL) using path analysis. A total of 508 women with CH completed a psycho-diagnostic survey. Results showed that higher levels of low sensory threshold (β = 0.200), bodily threat traumatic experiences (β = 0.156), neurotic defenses (β = 0.109) and mental pain (β = 0.343) emerged as the best predictors of higher CS burden. The model presented demonstrated a satisfactory fit (GFI = 0.984; NFI = 0.966; CFI = 0.979; RMSEA = 0.056 [95% CI 0.028–0.085]) with large and medium effect sizes on physical (−0.654) and psychological QoL (−0.246). The study showed a key role of psychological dimensions in CS burden levels and their relationships with QoL in CH patients. From a clinical perspective, these results suggest the importance of evaluating the level of CS burden during the clinical assessment for chronic pain conditions such as CH, since it may contribute to guide patients to tailored psychological and medical treatments, thereby saving time and costs on diagnostic procedures for chronic pain. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between sacroiliac joint (SIJ) involvement and central sensitization (CS) in patients with axial spondyloarthritis (axSpA). Patients and Methods: Twenty-four patients with axSpA were included in this study. CS was investigated via pressure pain threshold (PPT), temporal summation (TS), conditional pain modulation (CPM), and the central sensitization inventory (CSI). Sacroiliac joint involvement was assessed using the magnetic resonance imaging (MRI)-based Canadian Spondyloarthritis Research Consortium (SPARCC) scoring system. CS-related parameters and SPARCC score correlations were analyzed. Results: The median (IQR) sacroiliac PPT score for the right SIJ was calculated as 17.47 (4.43) and 17.67 (4.57) for the left SIJ. In the TS measurement, the right SIJ TS median (IQR) value was calculated as 4.0 (3.5) and 4.0 (2.75) for the left side. The median (IQR) value was 149.67 (107.5) for CPM and 45.0 (27.75) for CSI. The median (IQR) sacroiliac inflammation score was calculated as 3.0 (8.75), and the median (IQR) structural score was calculated as 7.0 (11.5). No correlation was found between SPARCC scores and PPT, TS, CPM, and CSI values. Conclusion: In axSpA patients, there was no association observed between pain sensitivity measures and sacroiliac involvement. Further comprehensive studies are required, taking into account the complex nature of CS. [ABSTRACT FROM AUTHOR]

Aim: Evaluate the efficacy and safety ® (olokizumab) in patients with rheumatoid arthritis (RA) in real‐world clinical practice, with a targeted assessment of patient report outcomes (PRO) and central sensitization. Methods: An open‐label observational non‐interventional study was conducted, enrolling 183 patients with moderate and severe RA activity. All patients received OKZ 64 mg SC as injections every 4 weeks (Q4W) with methotrexate. The patients' follow‐up period was 24 weeks or less. RA activity (DAS28‐CRP), pain severity (NRS), patient global assessment (PGA, NRS), functional impairment (NRS), fatigue (FACIT‐F), central sensitization (central sensitization inventory, CSI), and symptoms of neuropathic pain (PainDETECT) were evaluated. Results: The study cohort was comprised of 144 patients. And 39 patients were lost to follow‐up, refused OKZ treatment, or were not dosed with OKZ for administrative reasons. In 6 months, DAS28‐CRP decreased to 3.3 ± 0.9 (p <.001) and statistically significant reductions in pain intensity, PGA, functional impairment, and fatigue were achieved. Pain intensity decreased as early as 2 days after the first OKZ administration (p <.05). The number of patients with CSI >40 in 24 weeks decreased from 71.0% to 21.0% (p <.001), with PainDETECT >18 – from 21.5% to 13.2%. NSAIDs use decreased from 70.8% to 33.8% (р <.001), steroids – from 54.2% to 32.6%. AEs were reported in 14.2% patients, serious events were observed in three patients. Conclusion: OKZ is effective in reducing RA activity and controlling chronic pain related to dysfunction of the nociceptive system. [ABSTRACT FROM AUTHOR]

Key summary points: Aim: This study investigates differences in self-reported signs of central sensitization and pressure pain threshold in individuals with knee osteoarthritis and sarcopenia. Findings: Patients with knee osteoarthritis had significantly increased central sensitization inventory-9 scores compared with those with sarcopenia, but there was no significant difference in pressure pain threshold between patients with knee osteoarthritis and patients with sarcopenia. In addition, comparing sarcopenia and non-sarcopenia in community-based older-age participants, pressure pain threshold was significantly lower in those with sarcopenia, but there was no significant difference in central sensitization inventory-9. Message: The interpretation of the Central Sensitization Inventory-9 (CSI-9) and Pressure Pain Threshold (PPT) may differ in the context of knee osteoarthritis and sarcopenia, potentially affecting the assessment of central sensitization and Central Sensitization Syndrome (CSS), with the responsiveness of these measures varying according to the specific disease condition. Purpose: Neuroinflammation, which occurs in knee osteoarthritis and sarcopenia, has attracted attention as a mechanism of central sensitization, but the relationship between central sensitization and these conditions has not been widely studied. This study investigates differences in self-reported signs of central sensitization and pressure pain threshold in individuals with knee osteoarthritis and sarcopenia. Methods: We examined 340 patients (mean age ± standard deviation: 76 ± 5.9, women were 86.9%) with knee osteoarthritis scheduled to undergo total knee arthroplasty. For comparison, 129 community-dwelling older people (mean age ± standard deviation: 76 ± 5.5, women were 68.9%) individuals without a history of knee osteoarthritis or any other diagnosed illnesses were matched for age and sex. We assessed central sensitization inventory-9, pressure pain threshold, pain-related factors, skeletal muscle mass index, and hand grip strength. ANCOVA using 2 (patients with knee osteoarthritis and community older people without knee osteoarthritis) × 2 (sarcopenia and robust) was performed to assess outcome measurements. Results: The prevalence of sarcopenia among patients with knee osteoarthritis was 50.3%. ANCOVA revealed an interaction effect for the central sensitization inventory-9. For the main effect of knee osteoarthritis, there was a significant difference in central sensitization inventory-9, and for the main effect of sarcopenia, there was a significant difference in pressure pain threshold. Conclusions: Discrepancies in the evaluation of central sensitization were identified between knee osteoarthritis and sarcopenia. Individuals with knee osteoarthritis had elevated score of self-reported indications of central sensitization, whereas sarcopenic patients had reduced pressure pain thresholds. [ABSTRACT FROM AUTHOR]

Breast cancer represents the most common type of malignant neoplasm worldwide. Advances in diagnosis and treatment have increased the life expectancy of patients. However, the sequelae associated with the treatment of the disease such as chronic pain, kinesiophobia and loss of physical function in breast cancer survivors (BCS) are a long-term health problem. Therapeutic strategies are required for the treatment of chronic sequelae in this population. To evaluate the effectiveness of a pain neuroscience education (PNE) and therapeutic exercise (TE) for the treatment of chronic sequelae in BCS. Quasi-experimental repeated measures study. The intervention lasted 9 weeks, with 3 educational and 24 exercise sessions. Pain frequency and intensity (VAS scale), neuropathic pain (DN4), kinesiophobia level (TSK-11V), central sensitization (CSI-Sp), functionality of the affected arm (ULFI-Sp) and active joint range (ROM) with goniometry were measured at baseline, 3rd, 6th and 9th week. Statistical analysis included Friedman's test and ANOVA according to normality criteria. A total sample of 26 BCS participate in the study. Significant statistical changes were found from the 3rd week of treatment in the frequency and intensity of pain, kinesiophobia and neuropathic pain (p < 0.05). All variables had significant changes at the 9th week (p = 0.001). The results of the present investigation suggest that the combination of PNE and TE are effective in treating sequelae at short term in BCS with chronic pain. [ABSTRACT FROM AUTHOR]

Background/Objectives: Fibromyalgia (FM) is a syndrome characterized by widespread chronic pain as the primary symptom. Neurophysiological pain mechanisms, such as the function of the descending inhibitory system, are impaired in this condition. The main objective of this study was to compare the results of two paradigms to evaluate CPM in women with FM. The secondary objective was to correlate the results of each CPM paradigm with the clinical status of patients with FM. Methods: One hundred and three FM women were divided into two groups: fifty patients diagnosed with FM were assigned to the conditioned pain modulation (CPM) group using a cold pressor stimulus, and fifty-three patients were assigned to the CPM group using the ischemic pressure stimulus. The main outcome measures were pain intensity, disability, mechanical hyperalgesia, and CPM. Results: The primary analysis revealed significant differences between the results obtained from the different CPM protocols. Poorer outcomes in the cold pressor test correlated with higher pain intensity and a greater disability index. Conclusions: Pain modulation abnormalities in FM patients were evident when using either the cold pressor or ischemic pressure stimuli to establish the CPM paradigm. The cold pressor conditioning stimulus elicited a stronger response than the ischemic pressure stimulus in FM patients. [ABSTRACT FROM AUTHOR]

Abstract Background Chronic migraine (CM) is a serious neurological disorder. Central sensitization is one of the important pathophysiological mechanisms underlying CM, and microglia-induced neuroinflammation conduces to central sensitization. Triggering receptor expressed on myeloid cells 2 (TREM2) is presented solely in microglia residing within the central nervous system and plays a key role in neuroinflammation. Metformin has been shown to regulate inflammatory responses and exert analgesic effects, but its relationship with CM remains unclear. In the study, we investigated whether metformin modulates TREM2 to improve central sensitization of CM and clarified the potential molecular mechanisms. Methods A CM mouse model was induced by administration of nitroglycerin (NTG). Behavioral evaluations were conducted using von Frey filaments and hot plate experiments. Western blot and immunofluorescence techniques were employed to investigate the molecular mechanisms. Metformin and the SYK inhibitor R406 were administered to mice to assess their regulatory effects on neuroinflammation and central sensitization. To explore the role of TREM2-SYK in regulating neuroinflammation with metformin, a lentivirus encoding TREM2 was injected into the trigeminal nucleus caudalis (TNC). In vitro experiments were conducted to evaluate the regulation of TREM2-SYK by metformin, involving interventions with LPS, metformin, R406, siTREM2, and TREM2 plasmids. Results Metformin and R406 pretreatment can effectively improve hyperalgesia in CM mice. Both metformin and R406 significantly inhibit c-fos and CGRP expression in CM mice, effectively suppressing the activation of microglia and NLRP3 inflammasome induced by NTG. With the administration of NTG, TREM2 expression gradually increased in TNC microglia. Additionally, we observed that metformin significantly inhibits TREM2 and SYK expression in CM mice. Lv-TREM2 attenuated metformin-mediated anti-inflammatory responses. In vitro experiments, knockdown of TREM2 inhibited LPS-induced SYK pathway activation and alleviated inflammatory responses. After the sole overexpression of TREM2, the SYK signaling pathway is activated, resulting in the activation of the NLRP3 inflammasome and an increased expression of pro-inflammatory cytokines; nevertheless, this consequence can be reversed by R406. The overexpression of TREM2 attenuates the inhibition of SYK activity mediated by metformin, and this effect can be reversed by R406. Conclusions Our findings suggest that metformin attenuates central sensitization in CM by regulating the activation of microglia and NLRP3 inflammasome through the TREM2-SYK pathway. Graphical Abstract

Purpose: Exacerbations of osteoarthritis (OA) pain significantly impair activities of daily living and walking, thereby reducing quality of life. Despite various treatments, persistent pain remains a challenge, particularly in patients with hip OA, where pain perception mechanisms extend beyond nociceptive pain. This study examined the pain characteristics in patients with hip OA, with an emphasis on neuropathic pain and central sensitization (CS). Methods: A total of 421 patients scheduled for unilateral total hip arthroplasty were analyzed using the painDETECT score and Central Sensitization Inventory to classify the pain types as nociceptive (Noc), CS, neuropathic (Neu), or neuropathic with CS (NeuCS). Results: The results indicated that 72.9% of patients experienced Noc pain, while 5.0% experienced combined NeuCS pain. The Neu and NeuCS groups exhibited significantly lower modified Harris Hip Score and EuroQol-5 Dimensions Questionnaire (EQ-5D) scores than the Noc group, indicating worse clinical outcomes and quality of life. Neu pain was more intense at rest, and when combined with CS it significantly diminished the quality of life. Conclusion: These findings highlight the need for mechanism-based pain treatment strategies, such as Neu pain and CS components, which independently and cumulatively affect clinical scores and quality of life. This study highlights the importance of early recognition and targeted treatment of these pain mechanisms in patients with hip OA. Future research should focus on evaluating therapeutic interventions for Neu pain and CS to optimize patient outcomes.

Abstract Neuropathic pain, arising from lesions of the somatosensory nervous system, presents with diverse symptoms including ongoing pain, paroxysmal pain, and provoked pain, usually accompanied by sensory deficits. Understanding the pathophysiological mechanisms behind these symptoms is crucial for targeted treatment strategies. Neurophysiological techniques such as nerve conduction studies, reflexes, and evoked potentials help elucidate these mechanisms by assessing large myelinated non-nociceptive fibres and small nociceptive fibres. This argumentative review highlights the importance of tailored neurophysiological assessments for improving our understanding of the pathophysiological mechanisms behind neuropathic pain symptoms.

Chronic pain poses a multifaceted and prevalent challenge that significantly affects an individual's quality of life. Sensory mechanisms, behavioural components (kinesiophobia and catastrophising), and social factors can influence pain perception in both younger and older populations. Moreover, the mechanisms underlying these altered pain phenotypes require further investigation in order to plan appropriate treatment. While Pain Neuroscience Education (PNE) has proven effective in managing chronic pain and previous research has been conducted on PNE physiotherapeutic techniques, there remains insufficient evidence on the efficacy of these adjunctive treatments. The objective of the present systematic review and meta-analysis was to evaluate the evidence for the efficacy of PNE + PT (PNE+) on pain as a primary outcome and 12 other psychosocial variables as secondary outcomes in patients with different pain mechanisms, and whether PNE+ could be applied to painful diabetic neuropathy. A thorough literature search was conducted in the database Scopus, MEDLINE/PubMed, ScienceDirect, CINAHL, and Web of Science, using keywords like "Pain Neuroscience Education", and "Chronic Pain" from 2010 to 2024 based on inclusion and exclusion criteria. Twenty of the 2558 studies that underwent screening qualified for a meta-analysis and 24 of them for a systematic review. Cochrane Risk of Bias 2 was used to assess the quality of the studies. Forest plots were generated using the Revman 5.3 software. Studies that predominantly addressed central sensitization and neuropathic pain demonstrated moderate-to good-quality evidence. The review findings indicate that PNE+ is effective in reducing experienced pain intensity and experienced pain interference on the Visual Analogue Scale (VAS: SMD -0.70, 95% CI -1.26 to −0.14), Numerical Pain Rating Scale (NPRS SMD -1.71, 95% CI -2.34 to −1.08), reduced kinesiophobia (Tampa scale of Kinesiophobia: SMD -5.29, 95% CI -7.33 to −3.25), and catastrophizing (pain catastrophizing scale: −3.82, 95% CI -6.44 to −1.21). PNE + has been found to be an effective intervention for reducing perceived pain experience, pain interference and other psychosocial variables in the management of chronic pain with different pain mechanisms. Most studies have focused on central sensitization, urging future research to explore PNE+ efficacy in neuropathic pain, such as painful diabetic neuropathy. CRD42023451101. • To plan PNE +, identify the pain mechanism type, duration and risk severity. • Stories and metaphors in PNE + should have personal relevance to patient's context. • First de-educate the misconceptions of pain, then educate. • There is no fixed PNE program as each individual has unique pain experience. • Integrated PNE + could improve quality of life and psychosocial outcomes. [ABSTRACT FROM AUTHOR]

Pain is a sensory and emotional experience. How did Pat Wall, founding editor of the journal PAIN and recognized pain guru, view the relation between the brain and the experience of pain? He was certain what it is not. It is not impulses in peripheral nociceptors that light up neurons in a central pain nucleus. Rather, it is a complex "signature" of brain activity normally driven by sensory stimuli, but in the event of pathology also from ectopic sources in injured nerves and associated dorsal root ganglia. Pain signatures are modulated in many ways: suppressed by gate control and descending brain pathways, augmented by peripheral and central sensitization, and massaged by abundant central feedback and feedforward loops. Pain experience is a complex function of a conscious brain. Ultimately, to understand pain is to understand conscious perception. [ABSTRACT FROM AUTHOR]

Abstract Galcanezumab, a monoclonal antibody targeting the calcitonin gene-related peptide pathway (CGRP mAb), acts peripherally due to its large size. However, recent studies have suggested that CGRP mAbs may also have a central mode of action. This study aimed to evaluate the central effects of galcanezumab on migraine central sensitization.This prospective real-world study was conducted at three headache centers in Japan between May 2021 and May 2022. Patients treated with galcanezumab for migraines were included in the study. The primary outcome was the change in the validated Central Sensitization Inventory (CSI) score from baseline to six months of treatment. We also assessed changes in the Allodynia Symptom Checklist (ASC-12) score. Eighty-six patients with migraine (73 female and 13 male) were analyzed. At 6 months, CSI and ASC-12 scores were significantly reduced compared to baseline (CSI: 36.0 vs. 29.3, p

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.

The study aims to investigate the relationship between serum hornerin levels and disease severity and pain scores and to evaluate hornerin’s potential as a biomarker and its role in understanding the etiopathogenesis of fibromyalgia (FM).The study included 36 female patients diagnosed with FM and 36 healthy female volunteers, matched for age and body mass index (BMI). Disease functional status and pain intensity in FM were assessed using the Fibromyalgia Impact Questionnaire (FIQ) and Visual Analog Scale (VAS), respectively. Serum hornerin levels were measured using a commercial ELISA kit.The mean age and BMI were 47.08 ± 9.76 and 27.17 ± 4.19 in the patient group and 43.61 ± 12.40 and 25.43 ± 5.25 in the control group. Serum hornerin levels averaged 2.64 ± 0.50 ng/mL in the patient group and 2.33 ± 0.49 ng/mL in the control group, showing significantly higher levels in the FM group (p=0.009). The median VAS score for FM patients was 8.0 (6.25–10) cm, and the mean FIQ score was 61.64 ± 15.09. The cutoff value for hornerin was determined to be 2.44 ng/mL (with 63.9 % sensitivity and 61.1 % specificity). A positive correlation was found between serum hornerin levels and BMI values.Elevated hornerin levels were observed in FM cases. Hornerin has the potential to be explored as a biomarker for diagnosing FM. [ABSTRACT FROM AUTHOR]

Galcanezumab, a monoclonal antibody targeting the calcitonin gene-related peptide pathway (CGRP mAb), acts peripherally due to its large size. However, recent studies have suggested that CGRP mAbs may also have a central mode of action. This study aimed to evaluate the central effects of galcanezumab on migraine central sensitization.This prospective real-world study was conducted at three headache centers in Japan between May 2021 and May 2022. Patients treated with galcanezumab for migraines were included in the study. The primary outcome was the change in the validated Central Sensitization Inventory (CSI) score from baseline to six months of treatment. We also assessed changes in the Allodynia Symptom Checklist (ASC-12) score. Eighty-six patients with migraine (73 female and 13 male) were analyzed. At 6 months, CSI and ASC-12 scores were significantly reduced compared to baseline (CSI: 36.0 vs. 29.3, p < 0.001; and ASC-12: 5.55 vs. 4.26, p < 0.01). Furthermore, these effects were observed as early as three months of treatment. In this study, we demonstrated the real-world efficacy of galcanezumab in improving central sensitization in migraine, with significant effects seen in the early phase of treatment.Please check and confirm whether the corresponding author mail ID is correctly processed We checked it. And, please kindly re-check !!!! !!! To use this Article for commercial purposes should be okay.!!! We asked you to publish this article with the following license; Creative Commons licence CC BY: This licence allows readers to copy, distribute and transmit the Article as long as it is attributed back to the author. Readers are permitted to alter, transform or build upon the Article, and to use the Article for commercial purposes.Please confirm the inserted city name is correct in affiliation 3 and amend if necessary.Checked.Per style, a structured abstract is not allowed so we have changed the structured abstract to an unstructured abstract. Please check and confirm.We Checked. And again, please kindly make sure the followings; !!! Please kindly re-check !!! To use this Article for commercial purposes should be okay.!!! We asked you to publish this article with the following license; Creative Commons licence CC BY: This licence allows readers to copy, distribute and transmit the Article as long as it is attributed back to the author. Readers are permitted to alter, transform or build upon the Article, and to use the Article for commercial purposes. Trial registration: This study was registered with UMIN-CTR on May 2, 2021 (UMIN000044096). [ABSTRACT FROM AUTHOR]

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]

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]

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]

Background/Objectives: Psoriatic arthritis (PsA) is an inflammatory rheumatic disease characterized by peripheral arthritis, enthesitis, spondylitis and psoriasis. The objective of this study was to examine the prevalence of central sensitization (CS) and its impact on the clinical and functional aspects of PsA. Methods: Adult patients with PsA according to the Classification of Psoriatic Arthritis (CASPAR) criteria were included in this cross-sectional observational study. The Central Sensitization Inventory (CSI) was used to assess the presence of CS. The study evaluated the impact of CS on individuals by analyzing many factors including demographic information, laboratory findings, clinical features, disease activity, quality of life, severity of sleeplessness, frequency of depression and anxiety. The patients were categorized into distinct groups based on the existence and intensity of CS, and a comparative analysis was conducted on their respective outcomes. Results: A total of 103 PsA patients with a mean age of 43.2 (SD: 6.7) years and including 42 (40.8%) males were included. The mean CSI score was 45.4 (SD: 15.1), and 67 (65.1%) patients had CS. The logistic regression analysis revealed that the variables Psoriasis Area Severity Index (PASI), General Anxiety Disorder-7 (GAD-7), and Insomnia Severity Index (ISI) exhibit considerable predictive power in relation to the outcome variable CS (p < 0.05). PASI was observed as the most important variable in predicting CS (OR 9.70 95% CI: 1.52–62.21). Conclusions: CS has demonstrable efficacy in influencing laboratory, clinical, and functional markers among individuals with PsA. When assessing pain sensitivity in these patients, it is important to take into account the presence of CS. [ABSTRACT FROM AUTHOR]

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. [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. Chronic pain has been investigated in pathophysiology and different mechanisms underlying this condition has been described. Despite the plentiful literature regarding this topic and the different pharmacological treatments proposed, patients often referred inadequate relief from medication. The aim of this narrative review was to investigate the different rehabilitative approach in the management of chronic pain and their efficacy. Methods. A systematic narrative review has been conducted considering randomize controlled trials and systematic reviews published within the past 5 years. Results. 13 papers on chronic pain and 6 papers on nociplastic pain has been described in the main aspects analyzed. Conclusions. No one treatment appears to be more effective than another but often it is the combination of several treatments that gives the best results. More studies, evaluating in particular specific exercises with clear proprioceptive elements, should be conducted to best analyzed their role in the management of chronic pain. Clin Ter 2024; 175 (5):337-345 doi: 10.7417/CT.2024.5139 [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]

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]

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]

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]

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]