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

Vulvodynia is a chronic pain condition, without clearly identifiable and visible causes, associated with disability, sexual disfunction, and impaired quality of life. It is frequently under-reported and under-diagnosed, resulting in significant emotional burden. The pathophysiology of vulvodynia is complex and multidimensional. According to the integrated biopsychosocial model, main triggers of vulvodynia may be biological (infectious or inflammatory conditions inducing severe or prolonged nociceptive or neuropathic pain, genetic predisposition, hormonal imbalance), psychological (depression, anxiety), sexual (traumatic experiences, unhealthy intimate relationship), and social (adverse childhood experiences). The diagnostic approach is based on accurate medical history exploring the characteristics and timing of vulvar pain, as well as the presence of other chronic pain conditions that are often comorbid. Pelvic examination (vulvar and vaginal appearance, cotton swab test for vulvar sensitivity, pelvic floor evaluation) supports the diagnosis and excludes secondary vulvar pain disorders. Considering that pain is a complex human experience within a multidimensional frame, the best therapeutic strategy should be multidisciplinary encompassing different therapeutic targets. Pharmacological therapies have anti-nociceptive, neuromodulating, and anti-inflammatory purposes and include both topical and systemic treatments (antidepressants, anticonvulsants, hormonal creams). Physical therapy consists of pelvic floor physiotherapy, electrostimulation, and neuromodulation techniques, while cognitive behavioral therapy, psychosexual intervention, and neurobiological education address the psychosocial dimension of vulvodynia. If results are insufficient, a surgical approach is allowed. We present a clinical case linking amelioration of vulvodynia to a training program to increase muscle mass, especially in the lower limbs, in a girl reporting an eating disorder.

Migraine is a primary headache disorder recognized by the World Health Organization as one of the most poorly understood and debilitating neurological conditions impacting global disability. Chronic pain disorders are more frequently diagnosed among cisgender women than men, suggesting that female sex hormones could be responsible for mediating chronic pain, including migraine and/or that androgens can be protective. This review discusses the major gonadal hormones, estrogens, progesterone, and testosterone in the context of molecular mechanisms by which they play a role in migraine pathophysiology. In addition, the literature to date describing roles of minor sex hormones including prolactin, luteinizing hormone, follicular stimulating hormone, and gonadotropin releasing hormone in migraine are presented. Because transgender and gender non-conforming (trans*) individuals are an underserved patient population in which gender-affirming sex hormone replacement therapy (HRT) is often medically necessary to align biological sex with gender identity, results from cisgender patient populations are discussed in the context of these major and minor sex hormones on migraine incidence and management in trans* patients.

Background: Central sensitisation is an important mechanism in migraine chronification. It is presumed to occur in second and third order neurons sequentially, resulting in an analogous spatial distribution of cutaneous allodynia with cephalic and extracephalic symptoms. We investigated whether allodynia, and its subtypes based on spatial distribution and type of stimulus, predict response to treatment in chronic migraine patients. Methods: This study was conducted as part of the CHARM study (NTR3440), a randomized, double-blind, placebo-controlled trial in chronic migraine patients with medication overuse. We included 173 patients. The presence of cutaneous allodynia at baseline was established with the Allodynia Symptom Checklist. Primary endpoint was reversion from chronic to episodic migraine. Results: Of all patients, 74.6% reported cutaneous allodynia. Absence of allodynia compared to presence of allodynia was predictive for reversion from chronic to episodic migraine, odds ratio (OR): 2.45 (95% CI: 1.03–5.84), p = 0.042. The predictive value was more pronounced when subdivided for spatial distribution, for participants without allodynia versus cephalic (OR: 4.16 (95% CI: 1.21–14.30), p = 0.024) and extracephalic (OR: 7.32 (95% CI: 1.98- 27.11), p = 0.003) allodynia. Mechanical, but not thermal, allodynia, was associated with outcome. Conclusions: Cutaneous allodynia, an important marker for central sensitization, likely has predictive value for treatment response in chronic migraine. [ABSTRACT FROM AUTHOR]

Chronic pain is highly prevalent in the pediatric population. Many factors are involved in the transition from acute to chronic pain. Currently, there are conceptual models proposed, but they lack a mechanistically sound integrated theory considering the stages of child development. Objective biomarkers are critically needed for the diagnosis, risk stratification, and prognosis of the pathological stages of pain chronification. In this article, we summarize the current evidence on mechanisms and biomarkers of acute to chronic pain transitions in infants and children through the developmental lens. The goal is to identify gaps and outline future directions for basic and clinical research toward a developmentally informed theory of pain chronification in the pediatric population. At the outset, the importance of objective biomarkers for chronification of pain in children is outlined, followed by a summary of the current evidence on the mechanisms of acute to chronic pain transition in adults, in order to contrast with the developmental mechanisms of pain chronification in the pediatric population. Evidence is presented to show that chronic pain may have its origin from insults early in life, which prime the child for the development of chronic pain in later life. Furthermore, available genetic, epigenetic, psychophysical, electrophysiological, neuroimaging, neuroimmune, and sex mechanisms are described in infants and older children. In conclusion, future directions are discussed with a focus on research gaps, translational and clinical implications. Utilization of developmental mechanisms framework to inform clinical decision-making and strategies for prevention and management of acute to chronic pain transitions in children, is highlighted. [ABSTRACT FROM AUTHOR]

It has long been recognized that men and women have different degrees of susceptibility to chronic pain. Greater recognition of the sexual dimorphism in chronic pain has resulted in increasing numbers of both clinical and preclinical studies that have identified factors and mechanisms underlying sex differences in pain sensitization. Here, we review sexually dimorphic pain phenotypes in various research animal models and factors involved in the sex difference in pain phenotypes. We further discuss putative mechanisms for the sexual dimorphism in pain sensitization, which involves sex hormones, spinal cord microglia, and peripheral immune cells. Elucidating the sexually dimorphic mechanism of pain sensitization may provide important clinical implications and aid the development of sex-specific therapeutic strategies to treat chronic pain. [ABSTRACT FROM AUTHOR]

Objective Widespread pain hypersensitivity and enhanced temporal summation of pain (TSP) are commonly reported in patients with complex regional pain syndrome (CRPS) and discussed as proxies for central sensitization. This study aimed to directly relate such signs of neuronal hyperexcitability to the pain phenotype of CRPS patients. Methods Twenty-one CRPS patients and 20 healthy controls (HC) were recruited. The pain phenotype including spatial pain extent (assessed in % body surface) and intensity were assessed and related to widespread pain hypersensitivity, TSP, and psychological factors. Quantitative sensory testing (QST) was performed in the affected, the contralateral and a remote (control) area. Results CRPS patients showed decreased pressure pain thresholds in all tested areas (affected: t(34)  = 4.98, P  < .001, contralateral: t(35) = 3.19, P  = .005, control: t(31) = 2.65, P  = .012). Additionally, patients showed increased TSP in the affected area (F(3,111) = 4.57, P  = .009) compared to HC. TSP was even more enhanced in patients with a high compared to a low spatial pain extent (F(3,51) = 5.67, P  = .008), suggesting pronounced spinal sensitization in patients with extended pain patterns. Furthermore, the spatial pain extent positively correlated with the Bath Body Perception Disturbance Scale (ρ = 0.491; P  = .048). Conclusions Overall, we provide evidence that the pain phenotype in CRPS, that is, spatial pain extent, might be related to sensitization mechanism within the central nociceptive system. This study points towards central neuronal excitability as a potential therapeutic target in patients with more widespread CRPS. [ABSTRACT FROM AUTHOR]

A bidirectional causal relationship has been established between temporomandibular disorders (TMDs) and chronic headaches. Recent advances in the neurobiology of chronic pain offer a framework for understanding the comorbidity between these two conditions that might reside in the shared biomolecular mechanisms of peripheral and central sensitization. The initiation of these processes is inflammatory in nature and is most likely mediated by key molecules, including calcitonin gene-related peptide (CGRP). This scoping review proposes that CGRP-mediated neuroinflammation in the trigeminal ganglion may partly explain the biomolecular bidirectional link between TMDs and chronic headaches. Finally, clinical implications of this neuropathologic process are briefly discussed. [ABSTRACT FROM AUTHOR]

Background: Chronic postsurgical pain (CPSP) worsens patients' mortality, morbidity, and quality of life. Cardiopulmonary bypass is mandatory for cardiac surgery, but it induces intense inflammation. The presence of inflammation is a crucial part of pain sensitization. An extreme inflammatory response due to cardiopulmonary bypass might cause a high prevalence of CPSP after cardiac surgery. We hypothesized that the prevalence and severity of CPSP are higher in patients after on-pump coronary artery bypass graft (CABG) surgery than in those after off-pump CABG surgery. Methods: This prospective, observational study was performed on a cohort from a randomized trial (on-pump CABG: 81 patients, off-pump CABG: 86 patients). A questionnaire about the severity of surgical wound pain that evaluated pain with the numerical rating scale (NRS) was filled out by the patients. NRS responses for current pain, peak pain in the last 4 weeks, and average pain in the last 4 weeks were evaluated. The main outcomes were the severity of CPSP as evaluated using the NRS and the prevalence of CPSP. CPSP was defined as pain with an NRS score > 0. Differences in severity between groups were analyzed using multivariate ordinal logistic regression models adjusted for age and sex, and differences in prevalence between groups were analyzed using multivariate logistic regression models adjusted for age and sex. Results: The questionnaire return rate was 77.0%. During a median follow-up of 17 years, 26 patients complained of CPSP (on-pump CABG: 20 patients, off-pump CABG: 6 patients). Ordinal logistic regression showed that the NRS response for current pain (odds ratio [OR] 2.34; 95% CI 1.12–4.92; P = 0.024) and the NRS response for peak pain in the last 4 weeks (OR 2.71; 95% CI 1.35–5.42; P = 0.005) were significantly higher in patients who underwent on-pump CABG surgery than in those who underwent off-pump CABG. Logistic regression showed that on-pump CABG surgery was an independent predictor of CPSP (OR 2.59; 95% CI 1.06–6.31; P = 0.036). Conclusions: The prevalence and severity of CPSP are higher in patients with on-pump CABG surgery than in those with off-pump CABG surgery. [ABSTRACT FROM AUTHOR]

A significant number of rotator cuff tear (RCT) patients developed chronic shoulder pain that did not correspond to physiological changes. Central sensitization syndrome (CSS) is a neurophysiological adaptation process that can result in hypersensitivity to peripheral stimuli. Although there is evidence of an association between CSS and musculoskeletal problems, no studies have focused on the association between CSS and RCT. The primary purpose of this study was to examine the prevalence of CSS in patients with RCT. The secondary purpose was to document the associated conditions and comorbidity that were associated with the CSS. This was a cross-sectional study of patients with RCT who completed the Central Sensitization Inventory (CSI). Patients with score of ≥ 40/100 were considered positive for CSS. Demographic and clinical data and CSI results were collected to analyze the prevalence and associated factors of CSS in RCT patients. A total of 404 RCT patients were included, and the CSS prevalence was 39.4%. Compared to the non-CSS group, the CSS group had an odds ratio of 4.13 (95% CI, 2.70–6.32; p＜0.001) for ages 51–60, 3.07 (95% CI, 2.00–4.69; p＜0.001) for symptoms lasting more than 6 months, 6.08 (95% CI, 3.90–9.47; p＜0.001) for nonphysical laborers, 3.69 (95%CI, 2.42–5.61; p＜0.001) for long head of biceps (LHB) abnormality, 2.93 (95% CI, 1.93–4.45; p＜0.001) for concurrent shoulder stiffness, 4.82 (95% CI, 2.55–9.10; p＜0.001) for anxiety or panic episodes, and 2.11 (95% CI, 1.12, 4.00; p＜0.001) for depression. The prevalence of CSS in patients with RCT was relatively high at 39.4%. The CSS was associated with higher age, female gender, and clinical findings of symptoms lasting over six months, nonphysical laborers, abnormal LHB, concurrent shoulder stiffness, anxiety, and depression. [ABSTRACT FROM AUTHOR]

Patients suffering from connective tissue disorders like Ehlers–Danlos syndrome hypermobility type/joint hypermobility syndrome (EDS-HT/JHS) may be affected by craniocervical instability (CCI). These patients experience myalgic encephalomyelitis, chronic fatigue, depression, extreme occipital-cervical pain, and severe widespread pain that is difficult to relieve with opioids. This complex and painful condition can be explained by the development of chronic neuroinflammation, opioid-induced hyperalgesia, and central sensitization. Given the challenges in treating such severe physical pain, we evaluated all the analgesic methods previously used in the perioperative setting, and updated information was presented. It covers important physiopathological aspects for the perioperative care of patients with EDS-HT/JHS and CCI undergoing occipital-cervical/thoracic fixation/fusion. Moreover, a change of paradigm from the current opioid-based management of anesthesia/analgesia in these patients to the perioperative opioid minimization strategies used by the authors was analyzed and proposed as follow-up considerations from our previous case series. These strategies are based on total-intravenous opioid-free anesthesia, multimodal analgesia, and a postoperative combination of anti-hyperalgesic coadjuvants (lidocaine, ketamine, and dexmedetomidine) with an opioid-sparing effect.Key points: Chronic neuroinflammation, neuronal damage and central sensitization are common pathways that cause severe widespread pain in patients with Ehlers–Danlos syndrome hypermobility type/joint hypermobility syndrome (EDS-HT/JHS) and craniocervical instability. The use of opioid-free anesthesia with propofol, ketamine, lidocaine, and dexmedetomidine is feasible in patients with EDS-HT/JHS who are to undergo occipital/cervical fixation, and the support of a service specialized in postoperative acute pain is essential for the viability of this management. Opioid-free anesthesia plus perioperative opioid-minimization management may reduce the postoperative pain in patients with EDS-HT/JHS that undergo occipital/cervical/thoracic fixation. Postoperative infusions of anti-hyperalgesic coadjuvants (lidocaine, ketamine, and dexmedetomidine) along with multimodal analgesia provide a significant opioid-sparing effect. However, more studies are needed to justify their use for more than 72 h in this type of patient. The perioperative opioid-minimization approach is a reasonable option for patients with EDS-HT/JHS suffering from gastrointestinal dysfunction, opioid-induced hyperalgesia, central sensitization and severe widespread pain. In the context of the perioperative opioid-minimization approach, methadone is the most suitable opioid for use as a rescue analgesic for severe pain owing to its anti-NMDA effect and its effect of reducing the reuptake of serotonin and norepinephrine. [ABSTRACT FROM AUTHOR]

Tension-type headache (TTH) and migraine are two common primary headaches distinguished by clinical characteristics according to the 3rd edition of the International Classification of Headache Disorders. Migraine is identified by specific features such as being more prevalent in females, being aggravated by physical activity, certain genetic factors, having photophobia, phonophobia, nausea, vomiting, or aura, and responding to specific drugs. Nonetheless, TTH and migraine share some common characteristics, such as onset occurring in the 20 s, and being triggered by psychological factors like stress, moderate pain severity, and mild nausea in chronic TTH. Both conditions involve the trigeminovascular system in their pathophysiology. However, distinguishing between TTH and migraine in clinical practice, research, and epidemiological studies can be challenging, as there is a lack of specific diagnostic tests and biomarkers. Moreover, both conditions may coexist, further complicating the diagnostic process. This review aims to explore the similarities and differences in the pathophysiology, epidemiology, burden and disability, comorbidities, and responses to pharmacological and non-pharmacological treatments of TTH and migraine. The review also discusses future research directions to address the diagnostic challenges and improve the understanding and management of these conditions. [ABSTRACT FROM AUTHOR]

Although the prevalence of cancer pain is 47% after treatment, cancer pain is often underestimated, and many patients are undertreated. The complexity of cancer pain contributes to the lack of its management. Recently, as the mechanism of cancer pain, it has become clear that central sensitization (CS) influences chronic pain conditions and the transition from acute to chronic pain. In this state-of-the-art review, we summarized the association of CS or central sensitivity syndrome with pain and the treatment for pain targeting CS in cancer survivors. The management of patients with CS should not only focus on tissue damage in either the affected body regions or within the central nervous system; rather, it should aim to target the underlying factors that sustain the CS process. Pain neuroscience education (PNE) is gaining popularity for managing chronic musculoskeletal pain and could be effective for pain and CS in breast cancer survivors. However, there is a study that did not demonstrate significant improvements after PNE, so further research is needed. Precision medicine involves the classification of patients into subgroups based on a multifaceted evaluation of disease and the implementation of treatment tailored to the characteristics of each patient, which may play a central role in the treatment of CS. [ABSTRACT FROM AUTHOR]

Purpose of this review: Referred pain is a common but less understood symptom that originates from somatic tissues. A comprehensive recognition of referred pain is important for clinicians when dealing with it. The purpose of this study is to summarize the current understanding of referred pain, including its pathogenesis, characteristics, diagnosis, and treatment. Recent findings: Referred pain arises not only from pathologies primarily involving local tissue but also from lesions in distant structures. Central sensitization of convergent neurons and peripheral reflexes of dichotomizing afferent fibers are two theories proposed to explain the pathological mechanism of referred pain. Because syndromes related to referred pain of different origins overlap each other, it is challenging to define referred pain and identify its originating lesions. Although various approaches have been used in the diagnosis and treatment of referred pain, including conservative treatment, blockade, radiofrequency, and surgery, management of referred pain remains a clinical challenge. Summary: Unlike radicular pain and neuropathic pain, referred pain is a less studied area, despite being common in clinics. Referred pain can derive from various spinal structures, and blockage helps identify the primary pathology. Due to the heterogeneity of referred pain, treatment outcomes remain uncertain. Further studies are needed to improve our understanding of referred pain. [ABSTRACT FROM AUTHOR]

Fibromyalgia is a complex and heterogeneous clinical syndrome, mainly characterized by the presence of widespread pain, possibly associated with a variety of other symptoms. Fibromyalgia can have an extremely negative impact on the psychological, physical and social lives of people affected, sometimes causing patients to experience dramatically impaired quality of life. Nowadays, the diagnosis of fibromyalgia is still clinical, thus favoring diagnostic uncertainties and making its clear identification challenging to establish, especially in primary care centers. These difficulties lead patients to undergo innumerable clinical visits, investigations and specialist consultations, thus increasing their stress, frustration and even dissatisfaction. Unfortunately, research over the last 25 years regarding a specific biomarker for the diagnosis of fibromyalgia has been fruitless. The discovery of a reliable biomarker for fibromyalgia syndrome would be a critical step towards the early identification of this condition, not only reducing patient healthcare utilization and diagnostic test execution but also providing early intervention with guideline-based treatments. This narrative article reviews different metabolite alterations proposed as possible biomarkers for fibromyalgia, focusing on their associations with clinical evidence of pain, and highlights some new, promising areas of research in this context. Nevertheless, none of the analyzed metabolites emerge as sufficiently reliable to be validated as a diagnostic biomarker. Given the complexity of this syndrome, in the future, a panel of biomarkers, including subtype-specific biomarkers, could be considered as an interesting alternative research area. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effect of treatment with anti‐calcitonin gene–related peptide (CGRP; receptor) antibodies on visual hypersensitivity in patients with migraine. Background: Increased visual sensitivity can be present both during and outside migraine attacks. CGRP has been demonstrated to play a key role in light‐aversive behavior. Methods: In this prospective follow‐up study, patients treated for migraine with erenumab (n = 105) or fremanezumab (n = 100) in the Leiden Headache Center were invited to complete a questionnaire on visual sensitivity (the Leiden Visual Sensitivity Scale [L‐VISS]), pertaining to both their ictal and interictal state, before starting treatment (T0) and 3 months after treatment initiation (T1). Using a daily e‐diary, treatment effectiveness was assessed in weeks 9–12 compared to a 4‐week pre‐treatment baseline period. L‐VISS scores were compared between T0 and T1. Subsequently, the association between the reduction in L‐VISS scores and the reduction in monthly migraine days (MMD) was investigated. Results: At 3 months, the visual hypersensitivity decreased, with a decrease in mean ± standard deviation (SD) ictal L‐VISS (from 20.1 ± 7.7 to 19.2 ± 8.1, p = 0.042) and a decrease in mean ± SD interictal L‐VISS (from 11.8 ± 6.6 to 11.1 ± 7.0, p = 0.050). We found a positive association between the reduction in MMD and the decrease in interictal L‐VISS (β = 0.2, p = 0.010) and the reduction in ictal L‐VISS (β = 0.3, p = 0.001). Conclusion: A decrease in visual hypersensitivity in patients with migraine after treatment with anti‐CGRP (receptor) antibodies is positively associated with clinical response on migraine. [ABSTRACT FROM AUTHOR]

One-fourth to one-third of women with endometriosis receiving first-line hormonal treatment lacks an adequate response in terms of resolution of painful symptoms. This phenomenon has been ascribed to "progesterone resistance", an entity that was theorized to explain the gap between the ubiquity of retrograde menstruation and the 10% prevalence of endometriosis among women of reproductive age. Nevertheless, the hypothesis of progesterone resistance is not free of controversies. As our understanding of endometriosis is increasing, authors are starting to set aside the traditionally accepted tunnel vision of endometriosis as a strictly pelvic disease, opening to a more comprehensive perspective of the condition. The question is: are patients not responding to first-line treatment because they have an altered signaling pathway for such treatment, or have we been overlooking a series of other pain contributors which may not be resolved by hormonal therapy? Finding an answer to this question is evermore impelling, for two reasons mainly. Firstly, because not recognizing the presence of further pain contributors adds a delay in treatment to the already existing delay in diagnosis of endometriosis. This may lead to chronicity of the untreated pain contributors as well as causing adverse consequences on quality of life and psychological health. Secondly, misinterpreting the consequences of untreated pain contributors as a non-response to standard first-line treatment may imply the adoption of second-line medical therapies or of surgery, which may entail non-negligible side effects and may not be free of physical, psychological and socioeconomic repercussions. The current narrative review aims at providing an overview of all the possible pain contributors in endometriosis, ranging from those strictly organic to those with a greater neuro-psychological component. Including these aspects in a broader psychobiological approach may provide useful suggestions for treating those patients who report persistent pain symptoms despite receiving first-line hormonal medical treatment. [ABSTRACT FROM AUTHOR]

Background: Excessive use of headache treatments often leads to the development, progression and exacerbation of primary headache, which is defined as medication overuse headache (MOH). A significant pathophysiological mechanism of MOH is central sensitization. Recent evidence suggests that central sensitization in chronic headache is a result of inflammatory responses mediated by microglial activation in the trigeminal nucleus caudalis (TNC). However, it is unknown whether microglial activation has an impact on the central sensitization of MOH. Accordingly, the goal of this research was to determine how microglial activation and the P2X7R/NLRP3 inflammasome signaling pathway in the TNC contribute to the pathogenesis of MOH. Methods: Repeated intraperitoneal injection of sumatriptan (SUMA) was used to establish a mouse model of MOH. Basal mechanical hyperalgesia was evaluated using von Frey filaments. As central sensitization biomarkers, the c-Fos and CGRP expression levels were measured by immunofluorescence analysis. We estimated the expression of microglial biomarkers (Iba1 and iNOS) within the TNC by qRT-PCR, western blotting and immunofluorescence analysis. To elucidate the effect of microglial activation and the P2X7/NLRP3 signaling pathway on central sensitization in MOH, we evaluated whether the microglia-specific inhibitor minocycline, the P2X7R-specific antagonist BBG and the NLRP3-specific inhibitor MCC950 altered SUMA-caused mechanical hyperalgesia. Furthermore, we examined c-Fos and CGRP expression within the TNC following individual injections of these inhibitors. Results: Repeated SUMA injection induced basal mechanical hyperalgesia, increased c-Fos and CGRP levels, and activated microglia within the TNC. Inhibiting microglial activation with minocycline prevented the emergence of mechanical hyperalgesia and cut down c-Fos and CGRP expression. Immunofluorescence colocalization analysis revealed that P2X7R was predominantly co-localized with microglia. The levels of P2X7R and the NLRP3 inflammasome were elevated by repeated SUMA injection, and blocking P2X7R and NLRP3 inhibited mechanical hyperalgesia and cut down c-Fos and CGRP expression within the TNC. Conclusion: Based on the current findings, inhibiting microglial activation could reduce central sensitization caused by chronic SUMA treatment via the P2X7R/NLRP3 signaling pathway. The clinical management of MOH may benefit from a novel strategy that inhibits microglial activation. [ABSTRACT FROM AUTHOR]

Background: Pain is a major symptom in adolescents with hypermobility spectrum disorder or hypermobile Ehlers-Danlos syndrome. Although the underlying mechanism causing generalized pain in children with hypermobility spectrum disorder or hypermobile Ehlers-Danlos syndrome is unclear, central sensitization has been suggested as a possible explanation. The aim of this study was to explore the feasibility of a study protocol for a future case–control study, investigating features of central sensitization in adolescents with hypermobility spectrum disorder or hypermobile Ehlers-Danlos syndrome. Methods: Central sensitization features were measured in ten patients and nine healthy controls aged 13–17 years via experimental pain measurement quantifying primary and secondary hyperalgesia, endogenous pain modulation, and exercise-induced hyperalgesia. Descriptive statistics were used. Frequency, median, and range values were calculated. Results: Eleven out of 57 patients chose to participate. No control could be recruited through public schools. Therefore, a convenience sampling strategy was used for the recruitment of the control group. The process of assessing primary and secondary hyperalgesia, endogenous pain modulation, and exercise-induced hyperalgesia was well tolerated by all participants (patients and controls). When assessing endogenous pain modulation via conditioned pain modulation, two participants in the patient group and three in the control group did not achieve a pain experience ≥ 3 on the numerical rating scale when immersing their hands in cold water. Conclusion: This study investigated the feasibility, safety, and toleration of experimental pain measurements in adolescents with hypermobility spectrum disorder or hypermobile Ehlers-Danlos syndrome. Although the test protocol proved to be sufficiently feasible for use with the participant group, it will need to be adapted in the main study in order to obtain more reliable data. Recruitment, especially of participants for the control group, can be a major obstacle for future studies and requires careful planning. Trial registration: Researchweb.org, 270,501. Registered on 9 May 2019. [ABSTRACT FROM AUTHOR]

Aims: Chronic migraine (CM) is a common neurological disorder with complex pathogenesis. Evidence suggests that pituitary adenylate cyclase-activating peptide (PACAP) induces migraine-like attacks and may be potential a new target for migraine treatment, but the therapeutic results of targeting PACAP and its receptors are not uniform. Therefore, the aim of this study was to investigate the regulatory effect of PACAP type I receptor (PAC1R) antagonist, PACAP6-38, on nitroglycerin (NTG)-induced central sensitization in a CM model. Methods: Sprague–Dawley (SD) rats received repeated injections of NTG to construct a CM model. Mechanical and thermal thresholds were measured using Von Frey filaments and hot plate tests. C-Fos expression was measured by western blotting and immunofluorescence staining to assess the central sensitization. PACAP6-38 was intracerebrally injected into the trigeminal nucleus caudalis (TNC), and then the changes in c-Fos, the synaptic-associated proteins, phospho-ERK1/2 (p-ERK1/2), phosphorylation of cyclic adenosine monophosphate response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) were detected. Transmission electron microscopy (TEM) and Golgi-Cox staining were used to observe the ultrastructure of synapses and dendritic structures of TNC neurons. Results: The results showed that PACAP and PAC1R expression were significantly raised in the TNC after repeated NTG injections. Additionally, PACAP6-38 treatment alleviated nociceptive sensitization, inhibited NTG-induced overexpression of c-Fos and synaptic-associated proteins in the TNC of CM rat, restored aberrant synaptic structures. Furthermore, the expression of ERK/CREB/BDNF pathway was depressed by PACAP6-38. Conclusions: Our results demonstrated that abnormal synaptic structure in the TNC of CM, which could be reversed by inhibition of PAC1R via down-regulating the ERK/CREB/BDNF signaling pathway. PACAP6-38 improves NTG-induced central sensitization by regulating synaptic plasticity in the TNC of CM rat, which may provide new insights into the treatments targeting PACAP/PAC1R in migraine. [ABSTRACT FROM AUTHOR]

The P2Y 2 receptor agonist, diquafosol sodium, is commonly used to treat the signs and symptoms of dry eye disease (DE) patients. Although diquafosol improves tear film stability, the neural mechanisms underlying the reduction in ocular pain are not well defined. This study determined if repeated application of diquafosol reduces the sensitization of nociceptive neurons in the lower trigeminal brainstem nuclear complex (TBNC) via peripheral P2Y 2 mechanisms in a rat model for DE. Diquafosol was applied to the ocular surface daily for 28 days, starting at day 0 or day 14, after exorbital gland removal. The number of eyeblinks, P2Y 2 -immunoreactive neurons in the trigeminal ganglion (TG), and correlates of TBNC neural excitability (i.e., cFos protein and phosphorylated extracellular signal-regulated kinase (pERK) expression) were assessed in male rats. Diquafosol increased spontaneous tear volume and reduced the number of ocular surface-evoked eyeblinks in DE rats. Fluorogold-labeled TG neurons that supply the cornea expressed P2Y 2. The number of P2Y 2 -immunoreactive neurons was increased in DE rats and suppressed by diquafosol. Diquafosol also reduced the number of cFos- and pERK-immunoreactive neurons in the TBNC in DE rats. These findings suggest that diquafosol, regardless of late-phase treatment, relieves ocular nociception in DE by reducing peripheral P2Y 2 expression. • The P2Y 2 receptor agonist, diquafosol sodium, enhanced tear volume in dry eye rats. • Diquafosol sodium (Dq) decreases P2Y 2 expression in the TG of dry eye rats. • TG neurons innervating to the cornea express P2Y 2. • Dq attenuates corneal hypersensitivity in dry eye regardless of the treatment phase. • Dq attenuates central sensitization of neuronal activity in dry eye. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. Central sensitization (CS) is defined as an increased nociceptive responsiveness due to sensitization of neurons in the central nervous system, usually the result of prolonged nociceptive input or a disease state associated with noxious inputs (eg, polyarthritis). The concept of CS has recently been adopted in clinical assessments of chronic pain, but its diagnosis in humans may now include a wide range of hypervigilant responses. The purpose of this review is to ascertain whether self-report questionnaires linked with CS are associated with enhanced nociceptive responses or whether they measure sensitivity in a broader sense (ie, emotional responses). According to our published, PROSPERO-registered review protocol (CRD42021208731), a predefined search of studies that involve the Central Sensitization Inventory (CSI) or Pain Sensitivity Questionnaire (PSQ), correlated with either nociceptive sensory tests or emotional hypervigilance was conducted on MEDLINE, PsycINFO, and Web of Science. Correlations between the CSI or PSQ with our primary outcomes were extracted and meta-analysed. A review of 66 studies totalling 13,284 participants found that the CSI (but not the PSQ) strongly correlated with psychological constructs: depression, anxiety, stress, pain catastrophising, sleep, and kinesiophobia. The CSI and PSQ showed weak or no correlations with experimental measures of nociceptive sensitivity: pain thresholds, temporal summation, or conditioned pain modulation. The PSQ did, however, correlate strongly with phasic heat and tonic cold pain tests. The studies reviewed did not provide sufficient evidence that self-report measures reflect a canonical understanding of CS. The CSI more closely reflects psychological hypervigilance than increased responsiveness of nociceptive neurons. [ABSTRACT FROM AUTHOR]

Background: Vulvodynia is defined as a chronic idiopathic vulvar pain condition. This study aimed to investigate the effect of central sensitization on the prognosis of neuromodulator treatment for vulvodynia. Method: A total of 105 patients with vulvodynia who underwent pelvic mapping pain exploration were included and scored according to the Convergence PP Criteria for pelvic pain and central sensitization. The patients were treated according to chronic pelvic pain guidelines, and their response to treatment was evaluated. Results: A total of 35 out 105 patients (33%) with vulvodynia had central sensitization, which was associated with comorbidities, dyspareunia, pain with micturition, and pain with defecation. Dyspareunia and pain with defecation were independent prognostic factors for central sensitization. Patients with central sensitization experienced more pain during intercourse, urination, or defecation, had more comorbidities, and responded worse to treatment. They required more treatment, with a longer response time (over 2 months). Patients with localized vulvodynia were treated with physiotherapy and lidocaine, while patients with generalized vulvodynia were treated with neuromodulators. Amitriptyline was effective in treating patients with generalized spontaneous vulvodynia and dyspareunia. Conclusions: Overall, this study highlights the importance of considering central sensitization in the diagnosis and treatment of vulvodynia and the need for individualized treatment based on the patient's symptoms and underlying mechanisms. Vulvodynia patients with central sensitization had more pain during intercourse, urination, or defecation, and responded worse to treatment, requiring more time and medication. [ABSTRACT FROM AUTHOR]

Objective Complex regional pain syndrome (CRPS) is associated with a range of sensory disturbances on the symptomatic side of the body but whether this includes olfaction is uncertain. To clarify this, the aims of this study were to compare ratings of intensity and hedonic appeal of household odorants in CRPS patients and controls, and to determine whether ratings differed between the symptomatic and contralateral sides within the sample of patients. Methods Six odorants (vanilla, fish sauce, vinegar, eucalyptus, almond essence and acetone) were presented sequentially in random order on cottonwool buds held in the midline approximately 1 cm from both nostrils in 37 CRPS patients and 21 pain-free controls. Each odor was rated for intensity and hedonic appeal, and participants reported whether the odor was stronger and/or smelt different on one side than the other. Results The odorants smelt worse for patients than controls (P  < .05 for the symptomatic and contralateral sides) but neither the intensity nor the unpleasantness of the odorants was greater on the symptomatic than contralateral side in the group as-a-whole. Conclusions These findings suggest that the trigeminal component of olfaction interacts bilaterally with pain-sensitized circuits in the thalamus or higher cortical centers to distort odor perception in patients with CRPS. This aberrant process appears to differ from the mechanism that underlies hemilateral hyperalgesia in other sensory modalities. [ABSTRACT FROM AUTHOR]

Study Design.: Double-blinded, prospective laboratory animal study. Objective.: To examine whether intraoperative spinal cord stimulation (SCS) inhibits the development of spine surgery–induced hypersensitivity. Summary of Background Data.: Managing postoperative pain after spine surgery is challenging, and as many as 40% of patients may develop failed back surgery syndrome. Although SCS has been shown to effectively reduce chronic pain symptoms, it is unknown whether intraoperative SCS can mitigate the development of central sensitization that causes postoperative pain hypersensitivity and potentially leads to failed back surgery syndrome after spine surgery. Materials and Methods.: Mice were randomly stratified into three experimental groups: (1) sham surgery, (2) laminectomy alone, and (3) laminectomy plus SCS. Secondary mechanical hypersensitivity was measured in hind paws using von Frey assay one day before and at predetermined times after surgery. In addition, we also performed a conflict avoidance test to capture the affective-motivational domain of pain at selected time points postlaminectomy. Results.: Mice that underwent unilateral T13 laminectomy developed mechanical hypersensitivity in both hind paws. Intraoperative SCS applied to the exposed side of the dorsal spinal cord significantly inhibited the development of hind paw mechanical hypersensitivity on the SCS-applied side. Sham surgery did not produce any obvious secondary mechanical hypersensitivity in the hind paws. Conclusions.: These results demonstrate that spine surgery for unilateral laminectomy induces central sensitization that results in postoperative pain hypersensitivity. Intraoperative SCS after laminectomy may be able to mitigate the development of this hypersensitivity in appropriately selected cases. [ABSTRACT FROM AUTHOR]

Carpal tunnel syndrome (CTS) has been traditionally classified as primarily a neuropathic condition with or without pain. Precision medicine refers to an evidence-based method of grouping patients based on their susceptibility to biology, prognosis of a particular disease, or in their response to a specific treatment, and tailoring specific treatments accordingly. In 2021, the International Association for the Study of Pain (IASP) proposed a grading system for classifying patients into nociceptive, neuropathic, or nociplastic phenotypes. This position paper presents data supporting the possibility of subgrouping individuals with specific CTS related-pain into nociceptive, neuropathic, nociplastic or mixed-type phenotypes. Carpal tunnel syndrome is a neuropathic condition but can also be comorbid with a nociplastic pain condition. The presence of extra-median symptoms and the development of facilitated pain processing seem to be signs suggesting that specific CTS cases can be classified as the nociplastic pain phenotype. The clinical responses of therapeutic approaches for the management of CTS are inconclusive. Accordingly, the ability to identify the predominant pain phenotype in patients with CTS could likely be problematic for producing efficient treatment outcomes. In fact, the presence of a nociplastic or mixed-type pain phenotype would explain the lack of clinical effect of treatment interventions targeting the carpal tunnel area selectively. We propose a clinical decision tree by using the 2021 IASP classification criteria for identifying the predominant pain phenotype in people with CTS-related pain, albeit CTS being a priori a neuropathic pain condition. The identification of a nociplastic-associated condition requires a more nuanced multimodal treatment approach to achieve better treatment outcomes. [ABSTRACT FROM AUTHOR]

AbstractNeuroinflammation is implicated in the development and maintenance of persistent pain states, but there are limited data linking cerebrospinal fluid (CSF) inflammatory mediators with neurophysiological pain processes in humans. In a prospective observational study, CSF inflammatory mediators were compared between patients with osteoarthritis (OA) who were undergoing total hip arthroplasty due to disabling pain symptoms (n = 52) and pain-free comparison controls (n = 30). In OA patients only, detailed clinical examination and quantitative sensory testing were completed. Cerebrospinal fluid samples were analyzed for 10 proinflammatory mediators using Meso Scale Discovery platform. Compared to controls, OA patients had higher CSF levels of interleukin 8 (IL-8) (P = 0.002), intercellular adhesion molecule 1 (P = 0.007), and vascular cell adhesion molecule 1 (P = 0.006). Osteoarthritis patients with central sensitization possibly indicated by arm pressure pain detection threshold

Central sensitization is the mechanism of nociplastic pain and leads to an overemphasized response to a painful stimulus (hyperalgesia) or pain to stimuli that do not otherwise cause pain (allodynia). Persistent nociceptive pain is a risk factor for nociplastic pain, which can often occur in isolation or combination with other types of pain, most often in patients with chronic musculoskeletal pain (osteoarthritis, lumbar and cervical syndrome, fibromyalgia, rheumatoid arthritis, complex regional pain syndrome, tendinopathy, etc.). Diagnosis of central sensitization is established through clinical examination, questionnaires and quantitative sensory testing (QST), which serves to assess and quantify sensory functions, i.e., determine the threshold for detection of sensory stimuli (heat-cold, pressure, vibration). Conditioned Pain Modulation (CPM) testing is important for clarifying pain modulation profiles, which can be pro-nociceptive (less effective CPM facilitation) and anti-nociceptive (effective, inhibitory CPM effect). In the pronociceptive modulation profile that is common in patients with musculoskeletal disorders, there is a higher risk of developing chronic pain, a higher prevalence of pain conditions and higher pain associated with injury. CPM testing is also important in the individualization of drug therapy for pain, based on predicting the effectiveness of drugs in the treatment.

Key points DCM patients exhibited pain hypersensitivity preoperatively compared to healthy participants. The pain hypersensitivity is associated with postoperative axial pain intensity in DCM. MCC ALFF could be used to predict occurrence of PAP in DCM.

Allyson Shrikhande,1,2 Soha Patil,1,2 Merzia Subhan,1,2 Erika Moody,1,2 Janaki Natarajan,1,2 Yogita Tailor,1,2 Marjorie Mamsaang,1,2 Neha James,1,2 Kimberlee Leishear,1,2 Rakhi Vyas,1,2 Sandra Sandhu,1,2 Tayyaba Ahmed,1,2 Rosemarie Filart,1,2 Gabrielle Daniel,1,2 Iris Kerin Orbuch,3,4 Yaniv Larish,1,2 Lora Liu1,2 1Pelvic Rehabilitation Medicine Clinical Research Foundation, West Palm Beach, FL, USA; 2The Feinstein Institute for Medical Research, Manhasset, NY, USA; 3Providence St John’s Hospital, Santa Monica, CA, USA; 4Advanced Gynecologic Laparoscopy Center, Los Angeles, CA, USACorrespondence: Allyson Shrikhande, Email AShrikhande@pelvicrehabilitation.comPurpose: The purpose of this paper is to evaluate the efficacy of a multimodal, outpatient neuromuscular protocol in treating remaining sensitization and myofascial pain in endometriosis patients post-surgical excision.Patients and Methods: A retrospective longitudinal study was conducted for women aged 22 to 78 with a history of surgically excised endometriosis. 60 women with an average duration of pain of 8.63 ± 7.65 years underwent a treatment protocol consisting of ultrasound guided trigger point injections, peripheral nerve blocks, and pelvic floor physical therapy for 6 weeks. Concomitant cognitive behavioral therapy once weekly for a total of 12 weeks was also undertaken. Pain intensity and pelvic functionality were assessed at new patient consults and 3-month follow ups using Visual Analogue Scale (VAS) and Functional Pelvic Pain Scale (FPPS).Results: At new patient consults, average VAS and FPPS were 7.45 ± 2.11 (CI 6.92– 7.98) and 14.35 ± 6.62 (CI 12.68 − 16.02), respectively. At 3-month follow ups, average VAS and FPPS decreased to 4.12 ± 2.44 (CI 3.50– 4.73; p < 0.001) and 10.3 ± 6.55 (CI 8.64– 11.96; p < 0.001), respectively. Among FPPS categories, sleeping, intercourse, and working showed the highest statistical significance.Conclusion: Data suggests the multimodal protocol was effective in treating the remaining underlying sensitization and myofascial pain seen in Endometriosis patients post-surgical excision, particularly in decreasing pain and improving function during work and intercourse.Keywords: chronic pelvic pain, peripheral sensitization, central sensitization, myofascial dysfunction

Abstract Background Rheumatoid arthritis patients usually suffer from arthritic chronic pain. However, due to an incomplete understanding of the mechanisms underlying autoimmune disorders, the management of arthritic pain is unsatisfactory. Here, we investigated the analgesic effect and underlying mechanism of the natural flavonoid naringenin (NAR) in collagen-induced arthritis (CIA) pain. Methods NAR was injected (i.p.) once per day for 42 days after initial immunization, and rats were sacrificed on the 28th (the 21st day after final immunization, PID 21) and 42nd days (PID 35). The inflammatory factors, central sensitization indicators, and CRMP2 phosphorylation, as well as the anti-rheumatoid activity and analgesic effect of NAR, were further investigated. Results We found that NAR decreased the arthritis score and paw swelling, as well as the mechanical and thermal pain. The immunofluorescence results also showed a dose dependent effect of NAR on reducing the expressions of spinal cFos, IBA-1, and GFAP on the 28th (PID 21) and 42nd day (PID 35). NAR decreased the phosphorylation of CRMP2 S522 and the expression of the kinase CDK5 in the spinal dorsal horn, but pCRMP2 Y479 was unchanged. In addition, CRMP2 was co-localized with NEUN, but not IBA-1 or GFAP, indicating the involvement of neural CRMP2 phosphorylation in CIA-related pain. Finally, CRMP2 S522 phosphorylation selective inhibitor (S)-lacosamide also alleviated arthritic pain. Conclusions Taken together, our results demonstrate that NAR alleviates inflammation and chronic pain in CIA model, which might be related to its inhibition of neuronal CRMP2 S522 phosphorylation, potentially mitigating the central sensitization. Our study provide evidence for the potential use of NAR as non-opioid-dependent analgesia in arthritic pain.

Abstract Background Although cross-sectional and cohort data suggest that higher serum blood glucose levels in patients with knee osteoarthritis (KOA) are associated with more severe knee symptoms, little is known about the longitudinal relationship between serum blood glucose and knee symptoms, particularly considering central sensitization (CS) comorbidity, which also worsens knee symptoms. Methods We evaluated the longitudinal relationship between serum blood glucose and knee symptoms by dividing the cohort of patients with KOA into those with and without CS. We hypothesized that higher serum blood glucose levels would worsen knee symptoms. A total of 297 participants (mean age: 59.6 years; females: 211; average BMI: 23.7 kg/m2) were enrolled in this study. At baseline, plain radiographs of the bilateral knee joints were evaluated according to the Kellgren–Lawrence grade (KLG). All participants exhibited at least a KLG ≥ 2 in each knee. At baseline, fasting blood glucose (FBG) and Central Sensitization Inventory-9 (CSI-9) were evaluated; ≥ 10 points on the CSI-9 was defined as CS+. Knee injury and Osteoarthritis Outcome Score (KOOS) was evaluated at baseline and at 1-year follow-up; the change in KOOS (ΔKOOS) was calculated by subtracting the KOOS at baseline from that at the 1-year follow-up. Multiple linear regression analysis was conducted with ΔKOOS as the dependent variable and FBG at baseline as the independent variable, adjusted for age, sex, BMI, and CSI-9 at baseline. Results Of the 297 subjects, 48 (16.2 %) were defined as CS+. In the CS − group, there was no association between FBG levels at baseline and ΔKOOS. In contrast, FBG at baseline was negatively associated with ΔKOOS pain (B = − 0.448; p = 0.003), ADL (B = − 0.438; p = 0.003), and sports (B = − 0.706; p = 0.007). Conclusions In patients with radiographic KOA and CS, higher blood glucose levels were associated with deteriorated knee symptoms during the 1-year follow-up. Healthcare providers should pay attention to controlling blood glucose, particularly in patients with KOA and concurrent CS, to mitigate their knee symptoms. Study design Retrospective cohort study (evidence level: III).

Morten Rune Blichfeldt-Eckhardt,1– 3 Dorte Aalund Olsen,4 Rikke Fredslund Andersen,4 Palle Toft,3,5 Laila Bendix2 1Department of Anesthesiology, Vejle Hospital, Vejle, Denmark; 2Multidiciplinary Pain Center of Southern Denmark, Department of Anesthesiology and Intensive Care, Odense University Hospital, Odense, Denmark; 3Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 4Department of Biochemistry and Immunology, Vejle Hospital, Vejle, Denmark; 5Department of Anesthesiology and Intensive Care, Odense University Hospital, Odense, DenmarkCorrespondence: Morten Rune Blichfeldt-Eckhardt, Multidisciplinary Pain Center of Southern Denmark, Department of Anesthesiology and Intensive Care, Odense University Hospital, Heden 9, Indgang 200, Odense, DK-5000, Denmark, Tel +4565414721, Fax +45 6541 3026, Email mr.be@rsyd.dkPurpose: Chronic, abdominal pain remains a problem in a subset of patients after cholecystectomy. The cause is often obscure but central sensitization may be an important component and could theoretically be mediated by spinal PGE2, which is regulated by several cytokines. The aim of the study was to examine cerebrospinal fluid (CSF) of participants with post cholecystectomy syndrome and healthy volunteers for signs of PGE2 and cytokine mediated central sensitization.Patients and Methods: In phase 1 of the study, 83 subjects were included for DNA analysis, eight of these subjects with post cholecystectomy syndrome. We examined the SNPs rs5275, rs16944 and rs1800795 from the Cox-2, IL-1β and IL-6 genes respectively. In phase 2 of the study, we examined concentrations of PGE2-metabolite (PGEM), IL-1β and IL-6 in CSF and plasma from 6 patients with post cholecystectomy syndrome and visceral hyperalgesia and 11 pain free volunteers.Results: We found a significant difference in distribution of the rs5275 SNP of the Cox-2 enzyme (CT-genotype=88% in pain group, 45% in pain free group, TT-genotype=0 in pain group, 41% in pain free group, p=0.05) but not in the other SNPs. PGEM, but not IL-6, was significantly elevated in CSF of the pain group (3.6 pg/mL, sd=1.9 vs 2.1 pg/mL, p=0.03), IL-1β was undetectable.Conclusion: We found elevated PGEM levels in CSF of patients with post cholecystectomy syndrome and visceral hyperalgesia, suggesting a central, possibly inflammatory component to the pain, and overrepresentation of the CT-genotype in the rs5275 SNP in the Cox2 gene, suggesting overexpression of Cox2 as a possible cause for elevated PGEM levels.Keywords: T8473, visceral pain, post cholecystectomy syndrome, hyperalgesia, central sensitization

Back pain can be caused by various etiological factors, and its development is mediated by various pathogenetic mechanisms. Anatomical structures that can participate in the formation of pain include muscles, fascia, ligaments, tendons, facet joints, intervertebral discs and vertebrae. Changes in the central pain modulation system are an important factor in the development of chronic low back pain (LBP). Accumulating evidence allows us to consider LBP not as a series of isolated unrelated episodes, but as a long-term condition with a variable course. In the practice of a rheumatologist, LBP can occur as a manifestation of the underlying disease or as a comorbid pathology on the background of rheumatic pathology. In this case, it may be difficult to determine the activity of the underlying disease and the effectiveness of the therapy.

Vivian Santiago,1 Malvin N Janal,2 Dane B Cook,3,4 Karen G Raphael1 1Department of Oral & Maxillofacial Pathology, Radiology & Medicine, New York University College of Dentistry, New York, NY, USA; 2Department of Epidemiology and Health Promotion, New York University College of Dentistry, New York, NY, USA; 3Research Service, William S. Middleton Memorial Veterans Hospital, Madison, WI, USA; 4Department of Kinesiology, University of Wisconsin-Madison School of Education, Madison, WI, USACorrespondence: Vivian Santiago, Department of Oral & Maxillofacial Pathology, Radiology & Medicine, New York University College of Dentistry, 137th East 25th Street, Rm 731, New York, NY, 10010, USA, Tel +1 212 998-9419, Email vs1555@nyu.eduPurpose: Mechanisms underlying myofascial temporomandibular disorder (mTMD) are poorly understood. One theory is dysfunction in the central mediation of pain, specifically in enhanced facilitatory pain modulation. Because mechanisms leading to central sensitization may differ for joint and muscle pain, this study of mTMD addressed phenotypic heterogeneity by temporomandibular (TM) joint pain in the examination of quantitative sensory testing (QST).Patients and Methods: The stimulus dependent increase in second pain (temporal summation (TS)) and associated aftersensations (AS) were examined across groups of women with mTMD with TM joint pain and without, and a demographically matched control group.Results: TS was slightly more evident in mTMD without joint pain vs with (p = 0.035), but AS were most robustly persistent in the group with joint pain vs without (p < 0.002).Conclusion: While both subgroups demonstrated evidence of central sensitization relative to controls on one of two measures, differences in QST results, if replicated, may point to possible differences in the mechanisms that yield central sensitization. Alternatively, it may represent methodological artifacts that need to be addressed. Therefore, greater consideration should be given to symptom-based phenotypes in studies examining TS and AS.Keywords: endogenous pain modulation, facilitatory pain modulation, central sensitization, muscle pain, wind-up