Sutcliffe S. Epidemiology Studies

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Sutcliffe S. Epidemiology Studies

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Issue 18 - March 2020
This e-newsletter - published the CPRA to keep the medical-scientific and patient communities abreast of research advances on Chronic Overlapping Pain Conditions (COPCs) - contains abstracts of studies on the epidemiology, pathophysiology and clinical management of COPCs published between October 2019 and March 2020. Prior issues are available on our website, http://www.cpralliance.org. To read the CPRA's White Paper, click here. Please direct any questions or comments to the CPRA's Director, Christin Veasley - [email protected] If you are not already on our mailing list would like to sign up to receive future issues of COPCs Research Advances, click here.
In this Issue...
National Multi-Site Studies Pathophysiology Studies Epidemiology Studies Clinical Studies
About the Chronic Pain Research Alliance
NATIONAL MULTI-SITE STUDIES
Changes in whole body pain intensity and widespreadness during urologic chronic pelvic pain syndrome flares-Findings from one site of the MAPP study. Xu T, Lai HH, Pakpahan R, Vetter J, Andriole GL, Bradley C, Naliboff BD, Colditz GA, Sutcliffe S. Neurourol Urodyn. 2019 Nov;38(8):2333-2350. doi: 10.1002/nau.24150.
OBJECTIVE: To investigate changes in whole body pain during urologic chronic pelvic pain syndrome (UCPPS) flares. MATERIALS AND METHODS: UCPPS participants at one site of the multidisciplinary approach to the study of chronic pelvic pain research network reported their daily flare status and pain levels in 7 pelvic/genital and 42 extrapelvic body areas (scale = 0-10) for 10 days at baseline and during their first flare. Linear mixed models and conditional logistic regression were used to investigate symptom changes during flares. Analyses were stratified by chronic overlapping pain condition (COPC) status. RESULTS: Fifty-five out of 60 participants completed the study, 27 of whom provided information on both nonflare (n=281) and flare (n=208)

days. Pelvic/genital pain intensity (mean change = 3.2 of 10) and widespreadness (mean=1/48) increased significantly during flares for all participants (all P interaction > .1), whereas extrapelvic pain intensity increased significantly only among participants with COPCs (mean=2.09; p interaction < .0001). Pelvic/genital and extrapelvic pain also varied on nonflare days but symptom fluctuations were generally less than/equal to 1 point (80.0%-100% of participants). Increases of greater than/equal to 2 points in pelvic/genital pain intensity (odds ration (OR)=22.0, 95% confidence interval (CI)=4.0118.6) and greater than/equal to 1 point in the urination-related pain (OR=9.10, 95% CI=1.74-47.7) were independently associated with flare onset for all participants. CONCLUSION: Our observations of extrapelvic pain increases during flares for patients with COPCs and our independent associations between pelvic/genital/urination-related pain intensity and flare onset may provide insight into mechanisms underlying flare development (eg, common biologic pathways between UCPPS phenotypes and flares), flare management (eg, local vs systemic therapies by COPC status), and patient flare definitions.
The Quebec Low Back Pain Study: a protocol for an innovative 2-tier provincial cohort. Page GM, Lacasse A, Quebec Back Pain Consortium (in alphabetical order), Beaudet N, Choiniere M, Deslauriers S, Diatchenko L, Dupuis L, Gregoire S, Hovey R, Leclair E, Leonard G, Meloto CB, Montagna F, Parent A, Rainville P, Roy JS, Roy M, Ware MA, Wideman TH, Stone LS. Pain Rep. 2019 Dec 19;5(1):e799. doi: 10.1097/PR9.0000000000000799.
INTRODUCTION: The neurobiological mechanisms underlying recovery from or persistence of low back pain (LBP) remain misunderstood, limiting progress toward effective management. We have developed an innovative two-tier design to study the transition from acute to chronic LBP. The objective of the first tier is to create a provincial web-based infrastructure to recruit and monitor the trajectory of individuals with acute LBP. The objective of the second tier is to fuel hypothesis-driven satellite data collection centers with specialized expertise to study the role of biomechanical, epigenetic, genetic, neuroanatomical, ontological, physiological, psychological, and socioeconomic factors in LBP chronicity. METHODS: This article describes the first tier of the protocol: establishment of the Core Dataset and Cohort. Adults with acute LBP will be recruited through networks, media, and health care settings. A web-based interface will be used to collect self-reported variables at baseline and at 3, 6, 12, and 24 months. Acute LBP will be defined according to the Dionne 2008 consensus. Measurements will include the Canadian minimum data set for chronic LBP research, DN4 for neuropathic pain, comorbidities, EQ-5D-5L for quality of life, and linkage with provincial medico-administrative databases. The primary outcome will be the transition to chronic LBP, as defined by Deyo 2014. Secondary outcomes include health care resource utilization, disability, sick leave, mood, and quality of life. PERSPECTIVE: This study brings together diverse research expertise to investigate the transition from acute to chronic LBP, characterize the progression to recovery or chronicity, and identify patterns associated with that progression.
PATHOPHYSIOLOGY STUDIES
The link between chronic pain and Alzheimer's disease. Cao S, Fisher DW, Yu T, Dong H. J Neuroinflammation. 2019 Nov 6;16(1):204. doi: 10.1186/s12974-019-1608-z.
Chronic pain often occurs in the elderly, particularly in the patients with neurodegenerative disorders such as Alzheimer's disease (AD). Although studies indicate that chronic pain correlates with cognitive decline, it is unclear whether chronic pain accelerates AD pathogenesis. In this review, we provide evidence that supports a

link between chronic pain and AD and discuss potential mechanisms underlying this connection based on currently available literature from human and animal studies. Specifically, we describe two intertwined processes, locus coeruleus noradrenergic system dysfunction and neuroinflammation resulting from microglial pro-inflammatory activation in brain areas mediating the affective component of pain and cognition that have been found to influence both chronic pain and AD. These represent a pathological overlap that likely leads chronic pain to accelerate AD pathogenesis. Further, we discuss potential therapeutic interventions targeting noradrenergic dysfunction and microglial activation that may improve patient outcomes for those with chronic pain and AD.
Why do multiple sclerosis and migraine coexist? Hamamci M, Gocmen AY, Say B, Alpua M, Badem ND, Ergun U, Ertugrul Inan L. Mult Scler Relat Disord. 2020 Jan 16;40:101946. doi: 10.1016/j.msard.2020.101946.
BACKGROUND: Migraine coexistence, which is high in multiple sclerosis (MS), is reported. To better understand the etiology of the coexistence of MS and migraine and the outcomes of this relationship, the vitamin D, vitamin D-binding protein (VITDBP), vitamin D receptor (VITDR), high-sensitivity C-reactive protein (hs-CRP), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), total antioxidant status (TAS), total oxidant status (TOS), and Oxidative Stress Index (OSI) values were examined in patients with the coexistence of relapsing-remitting multiple sclerosis (RRMS) and migraine. METHODS: This study was conducted between January 1, 2019, and July 25, 2019, at the neurology and biochemistry clinics of two different tertiary hospitals simultaneously. Overall, 50 RRMS patients with migraine, 50 RRMS patients without migraine, and 50 healthy volunteers were included in the study. The participants' vitamin D, VITDBP, VITDR, hs-CRP, SOD, CAT, GSH-Px, TAS, TOS, and OSI values were measured. RESULTS: The vitamin D and VITDR values of the RRMS patients with migraine were lower than those of the RRMS patients without migraine (respectively, p = 0.014, p < 0.001). There was no significant difference between the RRMS patients with and without migraine in terms of their VITDBP values (p = 0.570). The SOD, CAT, GSH-Px, and TAS values of the RRMS patients with migraine were lower than those without migraine (all p < 0.001). The hs-CRP and TOS values of the RRMS patients with migraine were higher than those without migraine (all p<0.001). CONCLUSION: To the best of our knowledge, this is the first study on this topic to date. Based on the results, our study may shed light on the etiopathogenesis of the coexistence of MS and migraine and new treatments. However, more studies are needed to better understand the etiology of this relationship and its negative effects.
Cross-disorder analysis of endometriosis and its comorbid diseases reveals shared genes and molecular pathways and proposes putative biomarkers of endometriosis. Vargas E, Aghajanova L, Gemzell-Danielsson K, Altmae S, Esteban FJ. Reprod Biomed Online. 2020 Feb;40(2):305-318. doi: 10.1016/j.rbmo.2019.11.003.
RESEARCH QUESTION: Women with endometriosis are considered to be at higher risk of several chronic diseases, such as autoimmune disorders, gynaecological cancers, asthma/atopic diseases and cardiovascular and inflammatory bowel diseases. Could the study of endometriosis-associated comorbidities help to identify potential biomarkers and target pathways of endometriosis? DESIGN: A systematic review was performed to identify all possible endometriosisassociated comorbid conditions. Next, this list of disorders was coded into MeSH terms, and the gene expression profiles were downloaded from the Phenopedia database and subsequently analysed following a systems biology approach. RESULTS: The results identified a group of 127 candidate genes that were recurrently expressed in endometriosis and its closest comorbidities and that were defined as 'endometriosis sibling disorders' (ESD). The enrichment analysis showed that these candidate genes are principally involved in immune and drug responses, hormone

metabolism and cell proliferation, which are well-known hallmarks of endometriosis. The expression of ESD genes was then validated on independent sample cohorts (n=2017 samples), in which the involvement of 16 genes (AGTR1, BDNF, C3, CCL2, CD40, CYP17A1, ESR1, IGF1, IGF2, IL10, MMP1, MMP7, MMP9, PGR, SERPINE1 and TIMP2) in endometriosis was confirmed. Several of these genes harbour polymorphisms that associate to either endometriosis or its comorbid conditions. CONCLUSIONS: The study results highlight the molecular processes underlying the aetiopathogenesis of endometriosis and its comorbid conditions, and identify putative endometriosis biomarkers.
Bioinformatics analysis of gene and microRNA targets for fibromyalgia. Qiu Y, Zhang TJ, Meng LB, Cheng XT, Hua Z. Clin Exp Rheumatol. 2020 Feb 14. [Epub ahead of print]
OBJECTIVES: Fibromyalgia (FM) is the most common chronic pain disease in middleaged women. Patients may also complain of migraine, irritable bowel syndrome and depression, which seriously affect their work and life, causing huge economic losses to society. However, the pathogenesis of FM is still controversial and the effect of the current treatment is far from satisfactory. METHODS: Differentially expressed genes (DEGs) and miRNAs (DEMs) were found between FM and normal blood samples. The pathway and process enrichment analysis of the genes were performed. Proteinprotein interaction network were constructed. Hub genes were found and analysed in The Comparative Toxicogenomics Database. RESULTS: A total of 102 genes were up-regulated and 46 down-regulated, 206 miRNAs down-regulated, and 15 upregulated in FM. CD38, GATM, HDC, FOS were found as candidate genes. These genes were significantly associated with musculoskeletal disease, mental disorder, immune system disease. There was partial overlap between metformin therapy-related genes and FM-related genes. CONCLUSIONS: We found DEGs and DEMs in FM patients through bioinformatics analysis, which may be involved in the occurrence and development of FM and serve as potential targets for diagnosis and treatment.
Pain condition and sex differences in the descending noradrenergic system following lateral hypothalamic stimulation. Jeong Y, Wagner MA, Ploutz-Snyder RJ, Holden JE. IBRO Rep. 2019 Dec 17;8:11-17. doi: 10.1016/j.ibror.2019.12.003.
The lateral hypothalamus (LH) is known to modulate nociception via the descending noradrenergic system in acute nociception, but less is known about its role in neuropathic pain states. In naïve females, LH stimulation produces opposing effects of α-adrenoceptors, with α2-adrenoceptors mediating antinociception, while pronociceptive α1-adrenoceptors attenuate the effect. Whether this opposing response is seen in neuropathic conditions or in naïve males is unknown. We used a mixed factorial design to compare male and female rats with chronic constriction injury (CCI) to naïve rats, measured by Total Paw Withdrawal (TPW) responses to a thermal stimulus. Rats received one of three doses of carbachol to stimulate the LH followed by intrathecal injection of either an α1- or an α2-adrenoceptor antagonist (WB4101 or yohimbine, resp.) or saline for control. Overall, naïve rats showed a more pronounced opposing alpha-adrenergic response than CCI rats (p < 0.04). Naïve male and female rats demonstrated antinociception following α1-adrenoceptor blockade and hyperalgesia following α2-adrenoceptor blockade. Male CCI rats also showed dose dependent effects from either WB4101 or yohimbine (p < 0.05), while female CCI rats had significant antinociception from WB4101 (p < 0.05), but no effect from yohimbine. These results support the idea that peripheral nerve damage differentially alters the descending noradrenergic modulatory system in male and female rats, and notably, that female CCI rats do not show antinociception from descending noradrenergic input. These findings are suggestive that clinical therapies that recruit the descending

noradrenergic system may require a different approach based on patient gender.
Activation of transposable elements in immune cells of fibromyalgia patients. Ovejero T, Sadones O, Sanchez-Fito T, Almenar-Perez E, Espejo JA, Martin-Martinez E, Nathanson L, Oltra E. Int J Mol Sci. 2020 Feb 18;21(4). pii: E1366. doi: 10.3390/ijms21041366.
Advancements in nucleic acid sequencing technology combined with an unprecedented availability of metadata have revealed that 45% of the human genome constituted by transposable elements (TEs) is not only transcriptionally active but also physiologically necessary. Dysregulation of TEs, including human retroviral endogenous sequences (HERVs) has been shown to associate with several neurologic and autoimmune diseases, including Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS). However, no study has yet addressed whether abnormal expression of these sequences correlates with fibromyalgia (FM), a disease frequently comorbid with ME/CFS. The work presented here shows, for the first time, that, in fact, HERVs of the H, K and W types are overexpressed in immune cells of FM patients with or without comorbid ME/CFS. Patients with increased HERV expression (N = 14) presented increased levels of interferon (INF-β and INF-γ) but unchanged levels of TNF-α. The findings reported in this study could explain the flu-like symptoms FM patients present with in clinical practice, in the absence of concomitant infections. Future work aimed at identifying specific genomic loci differentially affected in FM and/or ME/CFS is warranted.
Plasma tryptophan and kynurenine in females with temporomandibular disorders and fibromyalgia-An exploratory pilot study. Barjandi G, Louca Jounger S, Lofgren M, Bileviciute-Ljungar I, Kosek E, Ernberg M. J Oral Rehabil. 2020 Feb;47(2):150-157. doi: 10.1111/joor.12892.
BACKGROUND: Both temporomandibular disorders myalgia (TMDM) and fibromyalgia (FM) have been linked to central and peripheral changes in serotonin availability. The precursor of serotonin, tryptophan (TRP), is mainly catabolised via another pathway to produce kynurenine (KYN), but whether changes of this pathway are present in TMDM and FM are still unclear. OBJECTIVE: The aim was to explore blood plasma concentrations of TRP and KYN in TMDM and FM in an attempt to identify novel associations for future research. METHODS: Plasma of 113 female participants (17 TMDM, 40 FM and 56 healthy pain-free controls) were analysed for TRP and KYN concentrations. The degradation of TRP via the KYN pathway was indicated by the KYN to TRP ratio (KYN/TRP). Pain intensities were assessed with the Graded Chronic Pain Scale (GCPS) and Visual Analogue Scale (VAS). Psychological symptoms were evaluated using the Hospital Anxiety and Depression Scale (HADS), Patient Health Questionnaire (PHQ-9) and General Anxiety Disorder scale (GAD-7). RESULTS: In TMDM there was a negative correlation between TRP and pain intensity (rs = -0.55 P = .023) and positive correlations between KYN/TRP and pain intensity (rs = 0.59 P = .013). In FM, KYN/TRP was negatively correlated with anxiety symptoms (rs = -0.36 P = .022) and a trend towards significantly lower TRP levels was found compared to controls (P = .05). CONCLUSION: The association between KYN/TRP and pain intensity as well as anxiety ratings in this small exploratory study may indicate that KYN/TRP could be a relevant indicator for symptom severity in TMDM and FM. Further investigations of the KYN pathway in chronic myalgia are warranted.
Altered microbiome composition in individuals with fibromyalgia. Minerbi A, Gonzalez E, Brereton NJB, Anjarkouchian A, Dewar K, Fitzcharles MA, Chevalier S, Shir Y. Pain. 2019 Nov;160(11):2589-2602. doi: 10.1097/j.pain.0000000000001640.

Fibromyalgia (FM) is a prevalent syndrome, characterised byy chronic widespread pain, fatigue, and impaired sleep, that is challenging to diagnose and difficult to treat. The microbiomes of 77 women with FM and that of 79 control participants were compared using 16S rRNA gene amplification and whole-genome sequencing. When comparing FM patients with unrelated controls using differential abundance analysis, significant differences were revealed in several bacterial taxa. Variance in the composition of the microbiomes was explained by FM-related variables more than by any other innate or environmental variable and correlated with clinical indices of FM. In line with observed alteration in butyrate-metabolising species, targeted serum metabolite analysis verified differences in the serum levels of butyrate and propionate in FM patients. Using machine-learning algorithms, the microbiome composition alone allowed for the classification of patients and controls (receiver operating characteristic area under the curve 87.8%). To the best of our knowledge, this is the first demonstration of gut microbiome alteration in nonvisceral pain. This observation paves the way for further studies, elucidating the pathophysiology of FM, developing diagnostic aids and possibly allowing for new treatment modalities to be explored.
Feeling down? A systematic review of the gut microbiota in anxiety/depression and irritable bowel syndrome. Simpson CA, Mu A, Haslam N, Schwartz OS, Simmons JG. J Affect Disord. 2020 Jan 22;266:429-446. doi: 10.1016/j.jad.2020.01.124.
Background Anxiety/depression and irritable bowel syndrome (IBS) are highly prevalent and burdensome conditions, whose co-occurrence is estimated between 44 and 84%. Shared gut microbiota alterations have been identified in these separate disorders relative to controls; however, studies have not adequately considered their comorbidity. This review set out to identify case-control studies comparing the gut microbiota in anxiety/depression, IBS, and both conditions comorbidly relative to each other and to controls, as well as gut microbiota investigations including measures of both IBS and anxiety/depression. Methods Four databases were systematically searched using comprehensive search terms (OVID Medline, Embase, PsycINFO, and PubMed), following PRISMA guidelines. Results Systematic review identified 17 studies (10 human, 7 animal). Most studies investigated the gut microbiota and anxiety/depression symptoms in IBS cohorts. Participants with IBS and high anxiety/depression symptoms had lower alpha diversity compared to controls and IBSonly cohorts. Machine learning and beta diversity distinguished between IBS participants with and without anxiety/depression by their gut microbiota. Comorbid IBS and anxiety/depression also had higher abundance of Proteobacteria, Prevotella/Prevotellaceae, Bacteroides and lower Lachnospiraceae relative to controls. Limitations A large number of gut microbiota estimation methods and statistical techniques were utilized; therefore, meta-analysis was not possible. Conclusions Welldesigned case-control and longitudinal studies are required to disentangle whether the gut microbiota is predicted as a continuum of gastrointestinal and anxiety/depression symptom severity, or whether reported dysbiosis is unique to IBS and anxiety/depression comorbidity. These findings may inform the development of targeted treatment through the gut microbiota for individuals with both anxiety/depression and IBS.
Critical evaluation of animal models of visceral pain for therapeutics development: A focus on irritable bowel syndrome. Johnson AC, Farmer AD, Ness TJ, Greenwood-Van Meerveld B. Neurogastroenterol Motil. 2019 Dec 13:e13776. doi: 10.1111/nmo.13776.
The classification of chronic visceral pain is complex, resulting from persistent inflammation, vascular (ischemic) mechanisms, cancer, obstruction or distension, traction or compression, and combined mechanisms, as well as unexplained functional

mechanisms. Despite the prevalence, treatment options for chronic visceral pain are limited. Given this unmet clinical need, the development of novel analgesic agents, with defined targets derived from preclinical studies, is urgently needed. While various animal models have played an important role in our understanding of visceral pain, our knowledge is far from complete. Due to the complexity of visceral pain, this document will focus on chronic abdominal pain, which is the major complaint in patients with disorders of the gut-brain interaction, also referred to as functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). Models for IBS are faced with challenges including a complex clinical phenotype, which is comorbid with other conditions including anxiety, depression, painful bladder syndrome, and chronic pelvic pain. Based upon the multifactorial nature of IBS with complicated interactions between biological, psychological, and sociological variables, no single experimental model recapitulates all the symptoms of IBS. This position paper will contextualize chronic visceral pain using the example of IBS and focus on its pathophysiology while providing a critical review of current animal models that are most relevant, robust, and reliable in which to screen promising therapeutics to alleviate visceral pain and delineate the gaps and challenges with these models. We will also highlight, prioritize, and come to a consensus on the models with the highest face/construct validity.
Association between irritable bowel syndrome and allergic diseases: To make a case for aeroallergen. Loo EXL, Wang Y, Siah KTH. Int Arch Allergy Immunol. 2020;181(1):31-42. doi: 10.1159/000503629.
Irritable bowel syndrome (IBS) is a functional gastrointestinal disease and the most common cause of prolonged abdominal pain and bowel disturbances in the developed world. While initially thought to be functional or psychosomatic in nature, IBS is now recognized as a heterogeneous group of conditions. A subset of IBS patients and patients with allergic diseases share some characteristic inflammatory features. In fact, atopic children show an increased likelihood of developing IBS as adults. Given these findings, a subset of IBS may be suffering from allergy-related gut diseases. In this review, we present the allergy-related comorbidities of IBS, including genetic, environmental, and immunologic factors. We discuss studies demonstrating an increased sensitization of IBS patients to aeroallergens compared to food allergens. We then postulate potential pathophysiological mechanisms underlying both IBS and aeroallergens in the gut, followed by potential implications in the screening and treatment of allergies in IBS patients.
MicroRNAs as biomarkers of pain intensity in patients with chronic fatigue syndrome. Al-Rawaf HA, Alghadir AH, Gabr SA. Pain Pract. 2019 Nov;19(8):848-860. doi: 10.1111/papr.12817.
BACKGROUND: Numerous experimental models have shown that microRNAs (miRNAs) play an important role in regulating pain processing in clinical pain disorders. In this study, we evaluated a set of miRNAs as diagnostic biomarkers of pain intensity in adolescents with chronic fatigue syndrome (CFS). We then correlated the expression of these miRNAs with the levels of inflammatory markers and pain-related comorbidities in adolescents with CFS and healthy controls (HCs). METHODS: A total of 150 adolescents, 12 to 18 years of age, participated in this study between April 2016 and April 2017. The participants were classified into 2 groups: adolescents with CFS (n = 100) and HCs (n = 50). Reverse-transcription polymerase chain reaction was used to evaluate the expression of miR-558, miR146a, miR-150, miR-124, and miR-143. Immunoassay analysis was used to assess the levels of immune inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and cyclooxygenase-2 (COX-2). RESULTS: Adolescents with CFS showed significantly higher pain thresholds than comparable nonfatigued HCs. Ability to enjoy life and relations with others were the parameters least influenced by pain in CFS

patients. Differential expression of miR-558, miR-146a, miR-150, miR-124, and miR143 was significantly downregulated and notably interfered with pain intensity and frequency in patients with CFS. Also, the expression of these miRNAs was significantly correlated with that of IL-6, TNF-α, and COX-2, which have been shown to mediate pain intensity in patients with CFS. Girls with CFS showed significantly decreased expression levels of these miRNAs compared with the levels of boys with CFS. Girls with CFS also showed increased expression of the inflammatory painrelated markers IL-6, TNF-α, and COX-2 compared with the levels of boys with CFS. CONCLUSIONS: The intensity and consequences of pain were influenced by differential expression of miR-558, miR-146a, miR-150, miR-124, and miR-143, which was directly associated with higher expression of the immune inflammatory-related genes TNFα, IL-6, and COX-2 in adolescents with CFS. Further studies of larger patient cohorts will help clarify the role of miRNAs in the pathogenesis of CFS.
Sex as a biological variable in irritable bowel syndrome. Gamilleri M. Neurogastroenterol Motil. 2020 Jan 13:e13802. doi: 10.1111/nmo.13802.
BACKGROUND: The pathophysiology and mechanisms of irritable bowel syndrome (IBS) involve both central and peripheral mechanisms that result in altered perception, as well as changes in bowel functions. These dysfunctions are associated with motor, sensory, immune, barrier, and intraluminal perturbations, including the microbiota, and their products and endogenous molecules with bioactive properties. There is evidence that these mechanisms are altered in both females and males. However, there is also increasing evidence that sex is a biological variable that impacts a number of aspects of the mechanisms, epidemiology, and manifestations of IBS. PURPOSE: The objective of this article is to review the evidence of the differences among genders of the following factors in IBS: the brain-gut axis and sex hormones, epidemiology, diagnostic criteria and prognosis, pain perception, colonic transit, abdominal distension, overlap with urogynecological conditions, psychologic issues, anorexia, fibromyalgia, serotonin, and responsiveness to treatment of IBS. It is important to consider the variations attributable to sex in order to enhance the management of patients with IBS and the research of mechanisms involved in IBS.
Co-occurrence of pain syndromes. Affaitati G, Costantini R, Tana C, Cipollone F, Giamberardino MA. J Neural Transm (Vienna). 2019 Nov 29. doi: 10.1007/s00702-019-02107-8.
Many pain conditions in patients tend to co-occur, influencing the clinical expressions of each other in various ways. This paper summarizes the main concurrent pain conditions by analyzing the major interactions observed. In particular, co-occurrence will be examined in: visceral pain (especially ischemic heart disease, irritable bowel syndrome, dysmenorrhea / endometriosis and urinary pain), fibromyalgia, musculoskeletal pain and headache. Two concurrent visceral pains from internal organs sharing at least part of their central sensory projection can give rise to viscero-visceral hyperalgesia, i.e., enhancement of typical pain symptoms from both districts. Visceral pain, headache and musculoskeletal pains (myofascial pain from trigger points, joint pain) can enhance pain and hyperalgesia from fibromyalgia. Myofascial pain from trigger points can perpetuate pain symptoms from visceral pain conditions and trigger migraine attacks when located in the referred pain area from an internal organ or in cervico-facial areas, respectively. The pathophysiology of these pain associations is complex and probably multifactorial; among the possible processes underlying the mutual influence of symptoms recorded in the associations is modulation of central sensitization phenomena by nociceptive inputs from one or the other condition. A strong message in these pain syndrome cooccurrence is that effective treatment of one of the conditions can also improve symptoms from the other, thus suggesting a systematic and thorough evaluation of

the pain patient for a global effective management of his/her suffering.
Neuroimmunology: What role for autoimmunity, neuroinflammation, and small fiber neuropathy in fibromyalgia, chronic fatigue syndrome, and adverse events after human papillomavirus vaccination? Ryabkova VA, Churilov LP, Shoenfeld Y. Int J Mol Sci. 2019 Oct 18;20(20). pii: E5164. doi: 10.3390/ijms20205164.
Fibromyalgia is a disorder characterized by chronic widespread pain and non-pain symptoms, such as fatigue, dysautonomia, and cognitive and sleep disturbances. Its pathogenesis and treatment continue to be the subject of debate. We highlight the role of three mechanisms-autoimmunity, neuroinflammation, and small fiber neuropathy-in the pathogenesis of the disease. These mechanisms are shown to be closely interlinked (also on a molecular level), and the review considers the implementation of this relationship in the search for therapeutic options. We also pay attention to chronic fatigue syndrome, which overlaps with fibromyalgia, and propose a concept of "autoimmune hypothalamopathy" for its pathogenesis. Finally, we analyze the molecular mechanisms underlying the neuroinflammatory background in the development of adverse events following HPV vaccination and suggesting neuroinflammation, which could exacerbate the development of symptoms following HPV vaccination (though this is hotly debated), as a model for fibromyalgia pathogenesis.
Painful interactions: Microbial compounds and visceral pain. van Thiel IAM, Botschuijver S, de Jonge WJ, Seppen J. Biochim Biophys Acta Mol Basis Dis. 2020 Jan 1;1866(1):165534. doi: 10.1016/j.bbadis.2019.165534.
Visceral pain, characterized by abdominal discomfort, originates from organs in the abdominal cavity and is a characteristic symptom in patients suffering from irritable bowel syndrome, vulvodynia or interstitial cystitis. Most organs in which visceral pain originates are in contact with the external milieu and continuously exposed to microbes. In order to maintain homeostasis and prevent infections, the immune- and nervous system in these organs cooperate to sense and eliminate (harmful) microbes. Recognition of microbial components or products by receptors expressed on cells from the immune and nervous system can activate immune responses but may also cause pain. We review the microbial compounds and their receptors that could be involved in visceral pain development.
A subgroup of chronic low back pain patients with central sensitization. Aoyagi K, He J, Nicol AL, Clauw DJ, Kluding PM, Jernigan S, Sharma NK. Clin J Pain. 2019 Nov;35(11):869-879. doi: 10.1097/AJP.0000000000000755.
BACKGROUND: Our knowledge of central sensitization (CS) in chronic low back pain (CLBP) is limited. 2011 fibromyalgia criteria and severity scales (2011 FM survey) have been used to determine FM positive as a surrogate of CS. The major features of CS including widespread hyperalgesia and dysfunction of the descending inhibitory pathways can be identified by pressure pain threshold (PPT) and conditioned pain modulation (CPM) tests. The purpose of the study was to examine neurophysiological characteristics and psychosocial symptoms in a subgroup of FM-positive CLBP compared with FM-negative CLBP patients. METHODS: A total of 46 participants with CLBP and 22 pain-free controls completed outcome measures of the 2011 FM survey, PPT and CPM tests, and psychosocial questionnaires. Differences between FMpositive and FM-negative CLBP participants on these measures and correlations were analyzed. RESULTS: The 2011 FM survey identified 22 (48%) participants with CLBP as FM positive. FM-positive CLBP participants showed lower PPT values of the thumbnail (P=0.011) and lower back (P=0.003), lower CPM values of the thumbnail

(P=0.002), and more sever pain catastrophizing, anxiety, and depression symptoms (P<0.05) than FM-negative CLBP participants. The 2011 FM scores were significantly correlated with the PPT and CPM values of the thumbnail and with psychosocial symptoms (p<0.001). DISCUSSION: Our findings suggest a subgroup of CLBP patients exhibiting with signs and symptoms of CS. Associations between subjective and objective CS measures indicate that the 2011 FM survey can be utilized to identify the presence of CS in CLBP in clinical practice.
Exploring the neural correlates of touch and pain in women with provoked vestibulodynia. Sutton KS, Yessick LR, Wild CJ, Chamberlain SM, Pukall CF. Pain. 2019 Dec 10. doi: 10.1097/j.pain.0000000000001778.
Group differences in touch and pain thresholds-and their neural correlates-were studied in women with provoked vestibulodynia (PVD; N = 15), a common subtype of vulvodynia (chronic vulvar pain), and pain-free control women (N = 15). Results from quantitative sensory testing and self-report measures indicated that, as compared with control participants, women with PVD exhibited allodynia (ie, pain in response to a normally nonpainful stimulus) and hyperalgesia (ie, an increased response to a normally painful stimulus) at vulvar and nonvulvar sites. In addition, brain imaging analyses demonstrated reduced difference scores between touch and pain in the S2 area in women with PVD compared with control participants, supporting previous findings of allodynia in women with PVD. There were no significant reductions in difference scores between touch and pain for regions related to cognitive and affective processing of painful stimuli. The results of this study contribute important information to the general pain and vulvodynia literatures in elucidating the specific sensorimotor neural mechanisms that underlie hyperalgesia in a chronic pain population. These results have implications for differentiating neural processing of touch and pain for women with and without PVD. Future research should attempt to examine alterations related to hyperalgesia in commonly comorbid conditions of PVD.
EPIDEMIOLOGY STUDIES
Persistent, consistent, and extensive: The trend of increasing pain prevalence in older Americans. Zimmer Z, Zajacova A. J Gerontol B Psychol Sci Soc Sci. 2020 Jan 14;75(2):436-447. doi: 10.1093/geronb/gbx162.
OBJECTIVES: Assess trends in pain prevalence from 1992 to 2014 among older U.S. adults and by major population subgroups, and test whether the trends can be explained by changes in population composition. METHODS: Health and Retirement Study data include information on any pain, pain intensity, and limitations in usual activities due to pain. Average annual percent change in prevalence is calculated for any and for 2 levels of pain-mild/moderate and nonlimiting and severe and/or limitingacross demographic and socioeconomic characteristics, and for those with and without specific chronic conditions. Generalized linear latent and mixed models examine trends adjusting for covariates. RESULTS: Linear and extensive increases in pain prevalence occurred across the total population and subgroups. The average annual percent increase was in the 2%-3% range depending upon age and sex. Increases were consistent across subgroups, persistent over time, and not due to changes in population composition. Without increases in educational attainment over time, pain prevalence increases would be even higher. DISCUSSION: The increases in pain prevalence among older Americans are alarming and potentially of epidemic proportions. Population-health research must monitor and understand these
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