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Chronic visceral pain is one of the most common reasons for patients with gastrointestinal disorders, such as inflammatory bowel disease or disorders of brain-gut interaction, to seek medical attention. It represents a substantial burden to patients and is associated with anxiety, depression, reductions in quality of life, and impaired social functioning, as well as increased direct and indirect health care costs to society. Unfortunately, the diagnosis and treatment of chronic visceral pain is difficult, in part because our understanding of the underlying pathophysiologic basis is incomplete. In this review, we highlight recent advances in peripheral pain signaling and specific physiologic and pathophysiologic preclinical mechanisms that result in the sensitization of peripheral pain pathways. We focus on preclinical mechanisms that have been translated into treatment approaches and summarize the current evidence base for directing treatment toward these mechanisms of chronic visceral pain derived from clinical trials. The effective management of chronic visceral pain remains of critical importance for the quality of life of suffers. A deeper understanding of peripheral pain mechanisms is necessary and may provide the basis for novel therapeutic interventions., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The management of chronic visceral pain related to Inflammatory Bowel Diseases or Irritable Bowel Syndrome is still a clinical problem and new therapeutic strategies continue to be investigated. In the present study, the efficacy of a pomegranate decoction and of its polysaccharide and ellagitannin components in preventing the development of colitis-induced abdominal pain in rats was evaluated. After colitis induction by 2,4-dinitrobenzenesulfonic acid (DNBS), the pomegranate decoction (300 mg kg -1 ), polysaccharides (300 mg kg -1 ), and ellagitannins (45 mg kg -1 ) were orally administered for 14 days. Repeated treatment with decoction reduced visceral hypersensitivity in the colitic animals both at 7 and 14 days. Similar efficacy was shown by polysaccharides, but with lower potency. Ellagitannins administered at dose equivalent to decoction content showed higher efficacy in reducing the development of visceral pain. Macroscopic and microscopic evaluations performed on the colon 14 days after the damage showed that all three preparations reduced the overall amount of mast cells, the number of degranulated mast cells, and the density of collagen fibers in the mucosal stroma. Although ellagitannins seem to be responsible for most of the beneficial effects of pomegranate on DNBS-induced colitis, the polysaccharides support and enhance its effect. Therefore, pomegranate mesocarp preparations could represent a complementary approach to conventional therapies for promoting abdominal pain relief.

Background: Visceral hypersensitivity plays a key role in the pathophysiology of chronic visceral pain like irritable bowel syndrome (IBS), which is significantly more prevalent in women. Possible sex differences in visceral sensitivity remain poorly studied. We assessed sex differences in visceral sensitivity and their association with subclinical symptoms, trait anxiety, and chronic stress in a large sample of healthy men and women., Methods: In 280 young healthy volunteers (50% female), visceral sensory and pain thresholds were determined using rectal balloon distensions. Gastrointestinal (GI) symptoms, chronic stress, and trait anxiety as IBS-related risk factors were assessed with questionnaires. Men and women were compared regarding visceral sensitivity and multiple regression analyses were conducted to evaluate the predictive value of sex and risk factors for visceral sensitivity. Subgroups with high, intermediate, and low sensitivity were compared regarding psychological and biological characteristics., Key Results: Men and women did not differ in sensory or pain thresholds or in IBS-related risk factors. In multiple regression analyses, no predictor of visceral sensitivity could be identified. While sensitivity subgroups differed in sensory and pain thresholds, the proportions of men and women were comparable, and groups did not differ in IBS-related risk factors., Conclusions and Inferences: Despite the large sample size, we found no evidence supporting sex differences in visceral sensitivity. At least in healthy young volunteers, our findings suggest that sex, GI symptoms, anxiety, or chronic stress do not contribute to altered visceral sensitivity., (© 2019 John Wiley & Sons Ltd.)

The intent of this article is to help clinicians to have practical knowledge and skills related to both assessment and pharmacotherapy of chronic pain in the seriously ill patients. Treating patients with chronic pain and progressive disease should include assessment of "total pain" (physical, psychological, and spiritual suffering) and the care givers as part of treatment team. Effective management of chronic pain starts with thorough assessment and diagnosis of the pain syndrome. A worldwide consensus endorses use of multimodal approach and opioid pharmacotherapy as the mainstay approach to moderate to severe pain in cancer and pain associated with serious illness., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: Fecal microbiota transfer (FMT) is suggested as a potential treatment for patients with irritable bowel syndrome (IBS). We aimed to study the effect of allogenic and autologous FMT on IBS symptoms, visceral sensitivity, and compositional changes in fecal and mucosa-adherent microbiota., Methods: Seventeen patients with IBS were randomized either to receive fecal material from a healthy donor (allogenic) or to receive their own fecal material (autologous). The fecal material was administered into the cecum by whole colonoscopy after bowel cleansing., Results: No significant differences were found between the allogenic and the autologous FMT regarding symptom scores. However, symptom scores of patients receiving allogenic fecal material significantly decreased after FMT compared with baseline (P = 0.02), which was not the case in the autologous group (P = 0.16). Visceral sensitivity was not affected except for a small beneficial effect on urge scores in the autologous group (P < 0.05). While both fecal and mucosa-adherent microbiota of some patients shifted to their respective donor's fecal microbiota, some patients showed no relevant microbial changes after allogenic FMT. Large compositional shifts in fecal and mucosa-adherent microbiota also occurred in the autologous group., Conclusions: This study showed that a single FMT by colonoscopy may have beneficial effects in IBS; however, the allogenic fecal material was not superior to the autologous fecal material. This suggests that bowel cleansing prior to the colonoscopy and/or processing of the fecal material as part of the FMT routine contribute to symptoms and gut microbiota composition changes in IBS.

Chronic visceral pain is a frequent and disabling condition. Despite high prevalence and impact, chronic visceral pain is not represented in ICD-10 in a systematic manner. Chronic secondary visceral pain is chronic pain secondary to an underlying condition originating from internal organs of the head or neck region or of the thoracic, abdominal, or pelvic regions. It can be caused by persistent inflammation, by vascular mechanisms or by mechanical factors. The pain intensity is not necessarily fully correlated with the disease process, and the chronic visceral pain may persist beyond successful treatment of the underlying cause. This article describes how a new classification of chronic secondary visceral pain is intended to facilitate the diagnostic process and to enable the collection of accurate epidemiological data. Furthermore, it is hoped that the new classification will improve the tailoring of patient-centered pain treatment of chronic secondary visceral pain and stimulate research. Chronic secondary visceral pain should be distinguished from chronic primary visceral pain states that are considered diseases in their own right.

In recent decades, much effort has been invested in scientific studies of objective and reliable assessment of pain in horses. Various types of pain assessment tools have been described and (partly) validated for different types of pain in horses. Currently, composite pain scales and facial expression-based pain scales seem to be the most promising tools for pain assessment in horses and numerous studies have recently been published on the use of these pain scales in horses. Therefore, this narrative review mainly focusses on these two types of pain scales and on the studies that have appeared describing these type of pain scales in horses. The extent to which these pain scales have been validated (sensitivity, specificity, inter-observer reliability etc.) and their potential use for clinical pain states is discussed. Possible future directions for new studies and their possible aid in assessing pain in hospitalised and ridden horses are presented. In this way, improved pain scoring could improve criteria used to evaluate the clinical efficacy of new analgesic drugs and techniques, potentially benefiting equine welfare., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Functional bowel disorder patients can suffer from chronic abdominal pain, likely due to visceral hypersensitivity to mechanical stimuli. As there is only a limited understanding of the basis of chronic visceral hypersensitivity (CVH), drug-based management strategies are ill defined, vary considerably, and include NSAIDs, opioids, and even anticonvulsants. We previously reported that the 1.1 subtype of the voltage-gated sodium (NaV; NaV1.1) channel family regulates the excitability of sensory nerve fibers that transmit a mechanical pain message to the spinal cord. Herein, we investigated whether this channel subtype also underlies the abdominal pain that occurs with CVH. We demonstrate that NaV1.1 is functionally upregulated under CVH conditions and that inhibiting channel function reduces mechanical pain in 3 mechanistically distinct mouse models of chronic pain. In particular, we use a small molecule to show that selective NaV1.1 inhibition (a) decreases sodium currents in colon-innervating dorsal root ganglion neurons, (b) reduces colonic nociceptor mechanical responses, and (c) normalizes the enhanced visceromotor response to distension observed in 2 mouse models of irritable bowel syndrome. These results provide support for a relationship between NaV1.1 and chronic abdominal pain associated with functional bowel disorders.

Background: Some consider that patients with visceral hypersensitivity may represent a separate entity within the IBS population not only from a pathophysiological but also from a clinical perspective. The aim of this prospective exploratory study was to assess whether characteristics of abdominal pain in IBS patients could be suggestive of hypersensitivity., Methods: This prospective study included consecutive IBS patients selected by Rome III criteria. Validated scores (IBS-SSS, Bristol stool scale, HADS) were used to phenotype patients who were also asked to describe the main location of their abdominal pain on a simple image (abdomen divided into 6 zones). Progressive isobaric rectal distensions were performed to demonstrate, with the ascending method of limits, allodynia (pain threshold lower than 24 mmHg)., Key Results: Fifty patients (women: 72%), 42.6 ± 15.7 years old, were included. Sub-types were IBS-D, IBS-C and IBS-M in 58%, 22% and 20% of cases, respectively. Allodynia was present in 18% of cases. Neither IBS-SSS nor intensity of pain was predictive of hypersensitivity. In hypersensitive patients, pain was more often located in one of the two iliac fossa (P = 0.02) and located outside these areas in only 11% of cases. The sensitivity and the specificity of this pain location to differentiate hyper from normosensitive patients were 0.89 and 0.59, respectively., Conclusions & Inferences: The location of pain is different between hyper and normosensitive IBS patients. Pain located outside one of the two iliac fossa suggests that the patient is normosensitive., (© 2018 John Wiley & Sons Ltd.)

Aim: To observe whether there are differences in the effects of electro-acupuncture (EA) and moxibustion (Mox) in rats with visceral hypersensitivity., Methods: EA at 1 mA and 3 mA and Mox at 43 °C and 46 °C were applied to the Shangjuxu (ST37, bilateral) acupoints in model rats with visceral hypersensitivity. Responses of wide dynamic range neurons in dorsal horns of the spinal cord were observed through the extracellular recordings. Mast cells (MC) activity in the colons of rats were assessed, and 5-hydroxytryptamine (5-HT), 5-hydroxytryptamine 3 receptor (5-HT3R) and 5-HT4R expressions in the colons were measured., Results: Compared with normal control group, responses of wide dynamic range neurons in the dorsal horn of the spinal cord were increased in the EA at 1 mA and 3 mA groups (1 mA: 0.84 ± 0.74 vs 2.73 ± 0.65, P < 0.001; 3 mA: 1.91 ± 1.48 vs 6.44 ± 1.26, P < 0.001) and Mox at 43 °C and 46 °C groups (43 °C: 1.76 ± 0.81 vs 4.14 ± 1.83, P = 0.001; 46 °C: 5.19 ± 2.03 vs 7.91 ± 2.27, P = 0.01). MC degranulation rates and the expression of 5-HT, 5-HT3R and 5-HT4R in the colon of Mox 46 °C group were decreased compared with model group (MC degranulation rates: 0.47 ± 0.56 vs 0.28 ± 0.78, P < 0.001; 5-HT: 1.42 ± 0.65 vs 7.38 ± 1.12, P < 0.001; 5-HT3R: 6.62 ± 0.77 vs 2.86 ± 0.88, P < 0.001; 5-HT4R: 4.62 ± 0.65 vs 2.22 ± 0.97, P < 0.001)., Conclusion: The analgesic effects of Mox at 46 °C are greater than those of Mox at 43 °C, EA 1 mA and EA 3 mA., Competing Interests: Conflict-of-interest statement: The authors declare no conflict of interest related to this study.

Objectives: Many patients with painful chronic pancreatitis (CP) have insufficient effect of treatment, and the prevalence of adverse effects is high. Consequently, alternatives to conventional management are needed. We aimed to study the effect of acupuncture in painful CP., Methods: This was a prospective, single-blinded, randomized crossover trial. Fifteen patients with CP were assigned to a session of acupuncture followed by sham stimulation or vice versa. Patients rated clinical pain scores daily on a 0 to 10 visual analogue scale (VAS) and completed the Patient Global Impression of Change. For mechanistic linkage, resting state electroencephalograms were recorded and quantified by spectral power analysis to explore effects on central pain processing., Results: Acupuncture, compared with sham stimulation, caused more pain relief (2.0 ± 1.5 VAS vs 0.7 ± 0.8 VAS; P = 0.009). The effect, however, was short, and after 1-week follow-up, there was no difference in clinical pain scores between groups (P = 1.0) or the rating of Patient Global Impression of Change (P = 0.8). Electroencephalogram spectral power distributions between sham and acupuncture were comparable between groups (all P > 0.6)., Conclusions: The study presents proof-of-concept for the analgesic effect of acupuncture in pancreatic pain. Although the effect was short lasting, the framework may be used to conceptualize future trials of acupuncture in visceral pain.

Background: Neural-immune-endocrine network mechanism has attracted increased attention in diarrhoea-predominant irritable bowel syndrome (IBS-D). Pre-clinical evidence indicates that nerve growth factor (NGF) mediates visceral hypersensitivity and gut barrier dysfunction, via interactions with mast cells and sensory nerve fibres., Aim: To explore the role of nerve growth factor, as well as mast cell-nerve growth factor-nerve interaction in IBS-D pathophysiology., Methods: In this cross-sectional study, IBS-D patients and healthy controls first underwent clinical and psychological assessments. Visceral sensitivity to rectal distension was tested. As gut barrier function markers, serum diamine oxidase and d-lactate were detected. Rectosigmoid biopsies were taken for the analyses of nerve growth factor expression, mast cell count and activation, and sensory nerve fibres expressing transient receptor potential vanilloid 1 and calcitonin gene-related peptide. Correlations between these parameters were examined in patients., Results: Thirty-eight IBS-D patients (28 males, 10 females; average age 30.2 years) and 20 healthy controls (12 males, 8 females; average age 26.8 years) participated in the study. The patients presented increased psychological symptoms, visceral hypersensitivity and impaired gut barrier function. NGF gene expression, mast cell count and sensory nerve fibres were significantly increased in the patients (P < 0.05). In correlation analysis, NGF expression was positively correlated with the disease severity, anxiety and serum diamine oxidase; visceral sensitivity thresholds were negatively associated with NGF expression (Bonferroni corrected P < 0.0029)., Conclusions: Elevated mucosal NGF may interact with mast cells and sensory nerve fibres, contributing to visceral hypersensitivity and impaired gut barrier function in IBS-D., (© 2016 John Wiley & Sons Ltd.)

Ion channels are expressed throughout the gastrointestinal system and regulate nearly every aspect of digestion, including fluid secretion and absorption, motility, and visceral sensitivity. It is therefore not surprising that in the setting of functional bowel disorders, such as irritable bowel syndrome (IBS), ion channels are often altered in terms of expression level and function and are a target of pharmacological intervention. This is particularly true of their role in driving abdominal pain through visceral hypersensitivity (VH), which is the main reason IBS patients seek medical care. In the study by Scanzi et al., in the current issue of this journal, they provide evidence that the T-type voltage-gated calcium channel (Ca v ) Ca v 3.2 is upregulated in human IBS patients, and is necessary for the induction of an IBS-like disease state in mice. In this mini-review, we will discuss the contribution of specific ion channels to VH in IBS, both in human patients and rodent models. We will also discuss how Ca v 3.2 may play a role as an integrator of multiple environmental stimuli contributing toward VH., (© 2016 John Wiley & Sons Ltd.)

This study presents the validation of two recently described pain scales, the Equine Utrecht University Scale for Composite Pain Assessment (EQUUS-COMPASS) and the Equine Utrecht University Scale for Facial Assessment of Pain (EQUUS-FAP), in horses with acute colic. A follow-up cohort study of 46 adult horses (n = 23 with acute colic; n = 23 healthy control horses) was performed for validation and refinement of the constructed scales. Both pain scales showed statistically significant differences between horses with colic and healthy control horses, and between horses with colic that could be treated conservatively and those that required surgical treatment or were euthanased. Sensitivity and specificity were good for both EQUUS-COMPASS (87% and 71%, respectively) and EQUUS-FAP (77% and 100%, respectively) and were not substantially influenced by applying weighting factors to the individual parameters., (Copyright © 2016. Published by Elsevier Ltd.)

Background: Irritable bowel syndrome (IBS) is a heterogeneous condition with a number of pathophysiological mechanisms that appear to contribute to symptom chronicity. One of these is altered pain sensitivity., Methods: Women between ages 18-45 were recruited the community. Of those enrolled, 56 had IBS and 36 were healthy control (HC) women. Participants completed questionnaires, kept a 4-week symptom diary and had a 12-h Holter placed to assess nighttime heart rate variability including high frequency power (HF), low frequency power (LF), and total power (TP). At mid-follicular phase approximately 80% of women completed a thermal pain sensitivity test with conditioned pain modulation and visceral pain sensitivity using a water load symptom provocation (WLSP) test., Key Results: As expected, daily abdominal pain was significantly higher in the IBS compared to HC group. There were no differences between the bowel pattern subgroups (IBS-diarrhea [IBS-D], IBS-constipation plus mixed [IBS-CM]). Thermal pain sensitivity did not differ between the IBS and the HC groups, but was significantly higher in the IBS-CM group than the IBS-D group. In the WLSP test, the IBS group experienced significantly more symptom distress than HCs and the IBS-CM group was higher than the IBS-D group. Heart rate variability indicators did not differ between the groups or IBS subgroups. Daily abdominal pain was positively correlated with LF and TP in the IBS group., Conclusions & Inferences: Despite similar levels of abdominal pain in IBS, the IBS-CM group demonstrated greater sensitivity to both thermal and visceral testing procedures., (© 2016 John Wiley & Sons Ltd.)

Objective: To determine the attitudes, opinions and knowledge of Italian veterinarians regarding abdominal visceral pain in canine practice., Study Design: Prospective online survey., Methods: An online questionnaire was created on a Google Form spreadsheet and the weblink was circulated to Italian veterinarians on several mailing lists. The questionnaire, which was available between November 2012 and July 2013, comprised 18 closed, semi-closed and open questions divided into five sections (aetiology, recognition and assessment, drug choices for canine visceral pain, general knowledge about pain management and desire for further education, and demographic information)., Results: A total of 527 responses to the questionnaire were completed. Pancreatitis (19%), gastroenteritis (17%) and gastrointestinal obstructions or foreign bodies (9%) were highlighted as the most frequent causes of abdominal visceral pain. Posture, gait and movement changes (32%) and physiological changes (31%) were commonly quoted for pain recognition and assessment. Most respondents (74%) did not use pain scoring systems. Pancreatitis and peritonitis were considered the most painful abdominal conditions. Opioids (40%), nonsteroidal anti-inflammatory drugs (21%) and tramadol (20%) were cited as drugs for the management of visceral pain. A large percentage of respondents (97%) believed that their knowledge regarding pain management required improvement. There is practitioner interest for more continuing education in the subject. Most respondents were women (66%), aged between 25 and 40 years (57%). Internal medicine (56%), surgery (34%) and anaesthesiology (29%) were the main three speciality areas of interest in this study., Conclusions and Clinical Relevance: This online survey represents the opinion of a small number of Italian veterinarians regarding the assessment and treatment of canine abdominal visceral pain. The results show that Italian veterinarians are aware of the main causes and clinical signs of canine visceral pain. Pain-scoring systems are not often used for the recognition and assessment of pain; however, according to these veterinarians, visceral pain is commonly diagnosed., (© 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.)

Background: Joint hypermobility syndrome describes a disorder in which musculoskeletal pain occurs in a generalized joint hypermobility substrate. The clinical picture comprises variable manifestations which involve mainly but not exclusively the musculoskeletal system, and evolve over the person's lifetime., Case Presentation: Describing the case of a 20-year-old female with generalized arthro-myalgias, persistent fatigue and troublesome visceral pain, we illustrate how a frequently ignored clinical sign such as joint hypermobility can be the keystone to clarify different simultaneous symptoms. All of the patient's physical complaints had been investigated separately during her previous medical examinations, and several tests repeatedly gave negative results. The patient received different diagnoses that describe only part of her problems, such as irritable bowel syndrome for visceral pain, fibromyalgia for arthralgias or depression for fatigue. These approaches gave rise to pharmacological or physical treatments which did not improve her quality of life in any way and in some instances worsened the situation. Pronounced joint hypermobility which led the patient to flex her joints excessively, causing subluxations in several districts, was the only sign overlooked., Conclusion: Exploring the patient's articular features in her clinical context led us to diagnose joint hypermobility syndrome, a complex and often ignored condition. The case highlights the utility of a multidisciplinary approach and coordinated interventions to define and manage this clinical entity.

Symptoms of irritable bowel syndrome (IBS) are common in population studies including chronic abdominal pain associated with altered bowel habits. Patients often have associated gastrointestinal and somatic symptoms suggesting a possible common contributing mechanism, but the heterogeneous symptom patterns of individual patients make generalizations difficult. The pathophysiology of IBS is incompletely understood but includes disturbances of the brain-gut axis. Central mechanisms are: the psychosocial history and environment, dysfunctional brain processing of peripheral signals attributed to the intestine including the enteric nervous system, the microbiome and the innate and adaptive immune system. As a result there is visceral hypersensitivity and disturbed intestinal secretory and motor activity. Some mechanisms of visceral pain hypersensitivity may overlap with other pain syndromes including fibromyalgia (FMS). Central Sensitization (CS) would offer a way to conceptualize an integration of life experience and psychologic response into a biopsychosocial framework of pathophysiology, diagnosis and treatment of IBS. Corticotropin-releasing factor, a principle regulator in the stress and pain response may contribute to a neuroendocrine mechanism for the brain-gut interaction. The positive diagnostic approach to IBS symptoms to avoid excess testing and enhance the patient-provider therapeutic relationship requires the recognition of the "cluster" of IBS symptoms while identifying "alarm" symptoms requiring specific attention. The severity of the symptoms and other individual psychosocial factors characterize patients who seek medical care. The presence of significant psychosocial comorbidities adds to the complexity of management which often requires a multidisciplinary approach. Several treatment options exist but no single method is effective for all the symptoms of IBS. The therapeutic benefit of the well-executed physician-patient relationship is considered essential to success in managing IBS symptoms over the long term.

Aim: To systematically evaluate the effect of intraperitoneal local anesthetic on pain characteristics after laparoscopic cholecystectomy (LC)., Methods: We searched MEDLINE, EMBASE, and the Cochrane Library. Randomized controlled trials in English that compared the effect of intraperitoneal administration of local anesthetics on pain with that of placebo or nothing after elective LC under general anesthesia were included. The primary outcome variables analyzed were the combined scores of abdominal, visceral, parietal, and shoulder pain after LC at multiple time points. We also extracted pain scores at resting and dynamic states., Results: We included 39 studies of 3045 patients in total. The administration of intraperitoneal local anesthetic reduced pain intensity in a resting state after laparoscopic cholecystectomy: abdominal [standardized mean difference (SMD) = -0.741; 95%CI: -1.001 to -0.48, P < 0.001]; visceral (SMD = -0.249; 95%CI: -0.493 to -0.006, P = 0.774); and shoulder (SMD = -0.273; 95%CI: -0.464 to -0.082, P = 0.097). Application of intraperitoneal local anesthetic significantly reduced the incidence of shoulder pain (RR = 0.437; 95%CI: 0.299 to 0.639, P < 0.001). There was no favorable effect on resting parietal or dynamic abdominal pain., Conclusion: Intraperitoneal local anesthetic as an analgesic adjuvant in patients undergoing laparoscopic cholecystectomy exhibited beneficial effects on postoperative abdominal, visceral, and shoulder pain in a resting state.

Although recognition of equine pain has been studied extensively over the past decades there is still need for improvement in objective identification of pain in horses with acute colic. This study describes scale construction and clinical applicability of the Equine Utrecht University Scale for Composite Pain Assessment (EQUUS-COMPASS) and the Equine Utrecht University Scale for Facial Assessment of Pain (EQUUS-FAP) in horses with acute colic. A cohort follow-up study was performed using 50 adult horses (n = 25 with acute colic, n = 25 controls). Composite pain scores were assessed by direct observations, Visual Analog Scale (VAS) scores were assessed from video clips. Colic patients were assessed at arrival, and on the first and second mornings after arrival. Both the EQUUS-COMPASS and EQUUS-FAP scores showed high inter-observer reliability (ICC = 0.98 for EQUUS-COMPASS, ICC = 0.93 for EQUUS-FAP, P <0.001), while a moderate inter-observer reliability for the VAS scores was found (ICC = 0.63, P <0.001). The cut-off value for differentiation between healthy and colic horses for the EQUUS-COMPASS was 5, and for differentiation between conservatively treated and surgically treated or euthanased patients it was 11. For the EQUUS-FAP, cut-off values were 4 and 6, respectively. Internal sensitivity and specificity were good for both EQUUS-COMPASS (sensitivity 95.8%, specificity 84.0%) and EQUUS-FAP (sensitivity 87.5%, specificity 88.0%). The use of the EQUUS-COMPASS and EQUUS-FAP enabled repeated and objective scoring of pain in horses with acute colic. A follow-up study with new patients and control animals will be performed to further validate the constructed scales that are described in this study., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: To examine rates and correlates of unemployment across distinct common chronic pain diagnoses., Methods: Data were analyzed from a sample of 2,382 patients with chronic pain in the Quebec Pain Registry (QPR). Patients were grouped into the following diagnostic categories based on their primary pain diagnosis recorded in the QPR: musculoskeletal pain; myofascial pain; neuropathic pain, and visceral pain. Analyses were performed to examine the associations between pain diagnosis, patient demographics, pain intensity, depressive symptoms, and unemployment status., Results: Pain diagnosis, age, marital status, education, pain intensity, and depressive symptoms were each significant unique predictors of unemployment status in a hierarchical logistic regression analysis; the addition of depressive symptoms in this model contributed to the greatest increment of model fit., Conclusions: Depressive symptoms are associated with unemployment across a number of common chronic pain conditions, even when controlling for other factors that are associated with unemployment in these patients. Depressive symptoms, as a modifiable factor, may thus be an important target of intervention for unemployed patients with chronic pain.

Metritis is a common disease in dairy cattle, but to our knowledge, no work has assessed pain associated with this disease. Tissue palpation is commonly used to assess pain in human and veterinary medicine. The objective of this study was to evaluate visceral pain responses during rectal palpation, with and without uterine palpation, in healthy cows and in cows diagnosed with metritis. A total of 49 Holstein dairy cows (mean ± standard deviation parity of 2.8±1.8) were subjected to systematic health checks every 3 d after parturition for 21 d, scoring for vaginal discharge (0 to 4); 13 cows showed a discharge score ≥2 during at least 1 health check and were classified as metritic, whereas 29 cows were classified as healthy and showed no sign of this or any other disease (including mastitis and lameness). Back arch and heart rate variability before examination and during palpation were recorded using video and heart rate monitors. Back arch (cm(2)) on the day of diagnosis was greater in metritic versus healthy cows (1,034±72 vs. 612±48cm(2)), and greater during rectal palpation with uterine palpation versus rectal palpation without uterine palpation (869±45 vs. 777±45cm(2)). Heart rate frequency domain analysis showed that the low-frequency portion was higher in cows with metritis versus healthy cows (16.5±1.2 vs. 12.9±1.0). Time domain analysis showed that the standard deviation between normal to normal interbeat intervals and the root mean square of successive differences both decreased during rectal palpation with uterine palpation versus rectal palpation without uterine palpation (1.9±0.1 vs. 2.5±0.1 and 1.3±0.1 vs. 1.7±0.1, respectively). Together, these results indicate that the inflammation associated with metritis is painful, and that the pain response can be detected during rectal palpation with and without uterine palpation. Rectal palpation with uterine palpation appears to be more aversive than rectal palpation without uterine palpation, suggesting that the former should be avoided when possible., (Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Visceral pain is a particularly difficult symptom to manage in patients with irritable bowel syndrome (IBS). Our aim was to examine whether noninvasive neurostimulation applied to the motor cortex or lumbosacral region can modulate human visceral sensation. Sixteen healthy adult volunteers and 10 patients with IBS were evaluated. Single-pulse lumbosacral magnetic stimulation (LSMS) or transcranial magnetic stimulation (TMS) was used to assess spinal root and cortical excitability as well as the effect of neurostimulation on anorectal sensation and pain, which were provoked by a local electrical stimulus. Initially, healthy volunteers received 6 stimulation paradigms in a randomised order (3 repetitive LSMS [1 Hz, 10 Hz, and sham]) and 3 repetitive TMS (1 Hz, 10 Hz, and sham) to investigate the effects on neural function and visceral sensation over 1 hour. The most effective cortical and spinal interventions were then applied in patients with IBS. Only 1-Hz rLSMS altered healthy anal motor excitability, increasing spinal (58 ± 12.3 vs 38.5 ± 5.7 μV, P = 0.04) but not cortical responses. Both 1-Hz rLSMS and 10-Hz repetitive transcranial magnetic stimulation increased healthy rectal pain thresholds for up to an hour after intervention (P < 0.05). When applied to patients with IBS, rectal pain thresholds were increased across all time points after both 1-Hz rLSMS and 10-Hz repetitive transcranial magnetic stimulation (P < 0.05) compared with sham. The application of magnetoelectric stimuli to the cortical and lumbosacral areas modulates visceral sensation in healthy subjects and patients with IBS. This proof-of-concept study provides supportive evidence for neurostimulation in managing functional gastrointestinal disorders.

Background & Aims: Chronic stress alters the hypothalamic-pituitary-adrenal axis, increases gut motility, and increases the perception of visceral pain. We investigated whether epigenetic mechanisms regulate chronic stress-induced visceral pain in the peripheral nervous systems of rats., Methods: Male rats were subjected to 1 hour of water avoidance stress each day, or given daily subcutaneous injections of corticosterone, for 10 consecutive days. L4-L5 and L6-S2 dorsal root ganglia (DRG) were collected and compared between stressed and control rats (placed for 1 hour each day in a tank without water). Levels of cannabinoid receptor 1 (CNR1), DNA (cytosine-5-)-methyltransferase 1 (DNMT1), transient receptor potential vanilloid type 1 (TRPV1), and EP300 were knocked down in DRG neurons in situ with small interfering RNAs. We measured DNA methylation and histone acetylation at genes encoding the glucocorticoid receptor (NR3C1), CNR1, and TRPV1. Visceral pain was measured in response to colorectal distention., Results: Chronic stress was associated with increased methylation of the Nr3c1 promoter and reduced expression of this gene in L6-S2, but not L4-L5, DRGs. Stress also was associated with up-regulation in DNMT1-associated methylation of the Cnr1 promoter and down-regulation of glucocorticoid-receptor-mediated expression of CNR1 in L6-S2, but not L4-L5, DRGs. Concurrently, chronic stress increased expression of the histone acetyltransferase EP300 and increased histone acetylation at the Trpv1 promoter and expression of the TRPV1 receptor in L6-S2 DRG neurons. Knockdown of DNMT1 and EP300 in L6-S2 DRG neurons of rats reduced DNA methylation and histone acetylation, respectively, and prevented chronic stress-induced increases in visceral pain., Conclusions: Chronic stress increases DNA methylation and histone acetylation of genes that regulate visceral pain sensation in the peripheral nervous system of rats. Blocking epigenetic regulatory pathways in specific regions of the spinal cord might be developed to treat patients with chronic abdominal pain., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The pathophysiology of irritable bowel syndrome (IBS) is complex and not fully understood, so the aim of this study was to evaluate whether visceral and somatic hypersensitivity, autonomic cardiovascular dysfunction, and low-grade inflammation of the gut wall are associated with diarrhea-predominant IBS (D-IBS). Sixty-two patients with D-IBS and 20 control subjects participated in the study. Using the ascending method of limits (AML) protocol, we demonstrated that D-IBS patients had significantly lower sensory thresholds compared with healthy controls (P<0.001). Using diverse methods, especially the ischemic sensitivity test, for the first time in China, we confirmed that D-IBS patients have somatic hypersensitivity. They had a significantly higher systolic blood pressure and heart rate after a cold stimulus, indicative of autonomic cardiovascular dysfunction. Compared with the control group, D-IBS patients had a significantly higher level of calprotectin (P<0.001). We also found significant correlations between visceral and somatic hypersensitivity, visceral hypersensitivity and autonomic cardiovascular dysfunction, and somatic hypersensitivity and autonomic cardiovascular dysfunction. Our findings may provide valuable suggestions for the treatment of D-IBS.

Aim: To systematically characterize specific pain patterns in the most frequent pancreatic diseases., Methods: Pain in patients with chronic pancreatitis (n = 314), pancreatic cancer (n = 469), and other pancreatic tumors (n = 249) including mucinous (n = 20) and serous cystadenoma (n = 31), invasive (n = 37) and non-invasive intraductal papillary mucinous neoplasia (IPMN; n = 48), low stage (n = 18) and high stage neuroendocrine neoplasia (n = 44), and ampullary cancer (n = 51) was registered and correlated with clinicopathological data. Survival times were estimated by the Kaplan-Meier method. Patients alive at the follow-up time were censored. Survival curves were compared statistically using the log-rank test., Results: Forty-nine point one percent of pancreatic cancer patients revealed no pain, whereas in chronic pancreatitis only 18.3% were pain free. In contrary, moderate/severe pain was registered in 15.1% in pancreatic cancer patients that was increased in chronic pancreatitis with up to 34.2%. Serous cystadenoma was asymptomatic in most cases (58.1%), whereas 78.9% of all mucinous cystadenoma patients suffered pain. In neuroendocrine neoplasia pain was not a key clinical symptom since 64% of low stage neuroendocrine neoplasia and 59% of high stage neuroendocrine neoplasia patients were pain free. Cancer localization in the pancreatic body and patients with malignant pancreatic neoplasms were associated with more severe pain. Tumor grading and stage did not show any impact on pain. Only in pancreatic cancer, pain was directly associated with impaired survival., Conclusion: Pancreatic pain depicts different patterns of abdominal pain sensation according to the respective pancreatic disorder and does not allow a unification of the term pancreatic pain.

Regional changes in brain structure have been reported in patients with altered visceral sensitivity and chronic abdominal pain, such as in irritable bowel syndrome. It remains unknown whether structural brain changes are associated with visceral sensitivity. Therefore, we present the first study in healthy individuals to address whether interindividual variations in gray matter volume (GMV) in pain-relevant regions correlate with visceral sensitivity. In 92 healthy young adults (52 female), we assessed rectal sensory and pain thresholds and performed voxel-based morphometry (VBM) to compute linear regression models with visceral sensory and pain thresholds, respectively, as independent variable and GMV in a priori-defined regions of interest (ROIs) as dependent variable. All results were familywise error (FWE) corrected at a level of PFWE<.05 and covaried for age. The mean (±SEM) rectal thresholds were 14.78±0.46mm Hg for first sensation and 33.97±1.13mm Hg for pain, without evidence of sex differences. Lower rectal sensory threshold (ie, increased sensitivity) correlated significantly with reduced GMV in the thalamus, insula, posterior cingulate cortex, ventrolateral and orbitofrontal prefrontal cortices, amygdala, and basal ganglia (all PFWE<.05). Lower rectal pain threshold was associated with reduced GMV in the right thalamus (PFWE=.051). These are the first data supporting that increased visceral sensitivity correlates with decreased gray matter volume in pain-relevant brain regions. These findings support that alterations in brain morphology not only occur in clinical pain conditions but also occur according to normal interindividual variations in visceral sensitivity., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Few studies have verified the validity of behavioral and physiological methods of pain assessment in cattle. This prospective, blinded, randomized controlled experimental study aimed to validate different methods of pain assessment during acute and chronic (up to 21 d postintervention) conditions in dairy cattle, in response to 3 analgesic treatments for traumatic reticuloperitonitis. Cerebrospinal fluid (CSF) biomarkers and mechanical sensitization were measured as indicators of centralized pain. Proteomics in the CSF were examined to detect specific (to pain intensity) and sensitive (responsive to analgesia) markers. Recordings of spontaneous behavior with video analysis, telemetered motor activity, pain scales, electrodermal activity, and plasma cortisol concentration were quantified at regular intervals. Cows were assigned to group 1 (n=4, standard control receiving aspirin), group 2 (n=5, test group receiving preemptive tolfenamic acid), or group 3 (n=3, positive control receiving preemptive multimodal analgesia composed of epidural morphine, plus tolfenamic acid and butorphanol). Rescue analgesia was administered as needed. Generalized estimating equations tested group differences and the influence of rescue analgesia on the measurements. All 3 groups demonstrated a long-term decrease in a CSF protein identified as transthyretin. The decrease in transthyretin expression inversely correlated with the expected level of analgesia (group 1<2<3). Moreover, in group 1, CSF noradrenaline decreased long term, cows were hypersensitive to mechanical stimulation, and they demonstrated signs of discomfort with higher motor activity and "agitation while lying" recorded from video analysis. Decreased "feeding behavior," observer-reported pain scales, electrodermal activity, and plasma cortisol concentration were inconsistent to differentiate pain intensity between groups. In summary, changes in CSF biomarkers and mechanical sensitization reflected modulation of central pain in dairy cows. The spontaneous behavior "agitation while lying" was the only behavioral outcome validated for assessing acute and chronic pain in this visceral pain model., (Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

In a clinical setting, diabetic autonomic complications (cardiac, gastrointestinal, urogenital, etc.) are often handled as separate entities. We investigated rectal sensitivity to heat, mechanical distension, and electrical stimulations in 20 patients with diabetes and symptoms of gastroparesis, to evaluate the extent of visceral neuronal damage. Furthermore, to evaluate the relation between the nervous structures we examined gastric emptying and cardiac autonomic function with the hypothesis being an association between these. We found that 60% of patients had delayed gastric empting. Rectal hyposensitivity was a general finding as they tolerated 67% higher thermal, 42% more mechanical, and 33% higher electrical current intensity compared to healthy controls. In patients, most heart rate variability parameters were reduced; they reported significantly more gastrointestinal symptoms and a reduced quality of life in all SF-36 domains. Shortened RR interval correlated with reduced rectal temperature sensitivity, and gastric retention rate was negatively associated with symptoms of nausea and vomiting. To conclude, in these patients with signs and symptoms of diabetic gastroparesis, rectal sensitivity was reduced, and heart rate variability was impaired. Thus, we suggest regarding diabetic autonomic neuropathy as a diffuse disorder. Symptoms of widespread autonomic dysfunction and sensory disorders should be expected and treated in these patients.

Background: Despite chronic pain being a feature of functional chest pain (FCP) its experience is variable. The factors responsible for this variability remain unresolved. We aimed to address these knowledge gaps, hypothesizing that the psychophysiological profiles of FCP patients will be distinct from healthy subjects., Methods: 20 Rome III defined FCP patients (nine males, mean age 38.7 years, range 28-59 years) and 20 healthy age-, sex-, and ethnicity-matched controls (nine males, mean 38.2 years, range 24-49) had anxiety, depression, and personality traits measured. Subjects had sympathetic and parasympathetic nervous system parameters measured at baseline and continuously thereafter. Subjects received standardized somatic (nail bed pressure) and visceral (esophageal balloon distension) stimuli to pain tolerance. Venous blood was sampled for cortisol at baseline, post somatic pain and post visceral pain., Key Results: Patients had higher neuroticism, state and trait anxiety, and depression scores but lower extroversion scores vs controls (all p < 0.005). Patients tolerated less somatic (p < 0.0001) and visceral stimulus (p = 0.009) and had a higher cortisol at baseline, and following pain (all p < 0.001). At baseline, patients had a higher sympathetic tone (p = 0.04), whereas in response to pain they increased their parasympathetic tone (p ≤ 0.008). The amalgamating the data, we identified two psychophysiologically distinct 'pain clusters'. Patients were overrepresented in the cluster characterized by high neuroticism, trait anxiety, baseline cortisol, pain hypersensitivity, and parasympathetic response to pain (all p < 0.03)., Conclusions & Inferences: In future, such delineations in FCP populations may facilitate individualization of treatment based on psychophysiological profiling., (© 2013 John Wiley & Sons Ltd.)

The pharmacotherapy for the treatment of pain is an active area of investigation. There are effective drugs to treat this problem, but there is also a need to find alternative treatments free of undesirable side effects. In the present work the capacity of a series of flavonoids to bind to the μ opioid receptor was evaluated. The most active compound, 3,3-dibromoflavanone (31), a synthetic flavonoid, presented a significant inhibition of the binding of the selective μ opioid ligand [(3)H]DAMGO, with a Ki of 0.846 ± 0.263 μM. Flavanone 31 was further synthesized using a simple and cheap procedure with good yield. Its in vivo effects in mice, after acute treatments, were studied using antinociceptive and behavioral assays. It showed no sedative, anxiolytic, motor incoordination effects or inhibition of the gastrointestinal transit in mice at the doses tested. It evidenced antinociceptive activity on the acetic acid-induced nociception, hot plate and formalin tests (at 10 mg/kg and 30 mg/kg). The results showed that the 5-HT2 receptor and the adrenoceptors seem unlikely to be involved in its antinociceptive effects. Naltrexone, a nonselective opioid receptors antagonist, totally blocked compound 31 antinociceptive effects on the hot plate test, but naltrindole (δ opioid antagonist) and nor-binaltorphimine (κ opioid antagonist) did not. These findings demonstrated that 3,3-dibromoflavanone (31), at doses that did not interfere with the motor performance, exerted clear dose dependent antinociception when assessed in the chemical and thermal models of nociception in mice and it seems that its action is related to the activation of the μ opioid receptor., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objectives: Abdominal pain in chronic pancreatitis (CP) may be visceral or nonvisceral in origin. Differential nerve block (DNB) distinguishes visceral from nonvisceral pain. Endoscopic ultrasound and other imaging tests (eg, computed tomography and magnetic resonance cholangiopancreatography) are used to diagnose and stage CP. However, it is not known whether structural changes predict the presence of visceral pain, which may better respond to endoscopic, surgical, or visceral nerve interventions. We investigated the correlation of pancreatic structural abnormalities evident on imaging tests with the presence of visceral pain on DNB., Methods: A retrospective study was performed. Our DNB database was queried for patients who underwent imaging testing for evaluation of upper abdominal pain. The patients were classified into 3 groups based on structural severity: (1) normal pancreatic imaging, (2) mild CP, and (3) severe CP. The rates of visceral pain in the 3 groups were compared using a χ² test., Results: Fifty-four patients were included. There was no significant difference in rates of visceral pain based on structural severity: 48% in normal, 60% in mild CP, 67% in severe CP (χ², P = 0.484)., Conclusions: The severity of structural changes of CP found on imaging tests does not predict the presence of visceral pain.

Background and Objectives: Quantitative sensory testing (QST) has proven to be an important instrument to characterize mechanisms underlying somatic and neuropathic pain disorders. However, its reliability has not previously been established in patients with visceral pain. We investigated the test-retest reliability of static and dynamic QST in patients with visceral pain due to chronic pancreatitis., Methods: Sixty-two patients (38 men, 53 [11] y) with painful chronic pancreatitis were included. Static QST comprised sensory thresholds for pressure and electrical stimulation performed in the ventral and dorsal T10 dermatomes (sharing spinal innervation with the pancreas, ie, pancreatic viscerotomes) and in 4 heterologous regions (control areas). Dynamic QST comprised conditioned pain modulation. Measurements were obtained from 2 subsequent test sessions separated by 1 week., Results: The reliability of static QST was generally high, with the best test-retest performance seen for pressure pain thresholds (intraclass correlation coefficients [ICC], 0.74) and electrical sensation thresholds (ICC, 0.66). In contrast, the reliability of dynamic QST was poor (ICC, 0.01). For static QST measures, the reliability was higher for pain thresholds compared with suprapain thresholds (P < 0.01). No differences between assessments in the pancreatic viscerotomes compared with heterologous regions were seen (P = 0.6)., Conclusions: Sensory thresholds in the pancreatic viscerotomes and control areas were reproducible over time. In contrast, dynamic QST measurements reflecting active central modulation of pain processing state (ie, conditioned pain modulation) were not stable over time and showed considerable variability. These factors should be taken into consideration in case QST is used to follow disease mechanisms, drug effects, or effects of pain intervention.

Growing evidence suggests that systemic immune activation plays a role in the pathophysiology of pain in functional bowel disorders. By implementing a randomized crossover study with an injection of endotoxin or saline, we aimed to test the hypothesis that endotoxin-induced systemic inflammation increases visceral pain sensitivity in humans. Eleven healthy men (mean ± standard error of the mean age 26.6 ± 1.1 years) received an intravenous injection of either lipopolysaccharide (LPS; 0.4 ng/kg) or saline on 2 otherwise identical study days. Blood samples were collected 15 min before and 1, 2, 3, 4, and 6h after injection to characterize changes in immune parameters including proinflammatory cytokines. Rectal sensory and pain thresholds and subjective pain ratings were assessed with barostat rectal distensions 2h after injection. LPS administration induced an acute inflammatory response indicated by transient increases in tumor necrosis factor alpha, interleukin 6, and body temperature (all P<.001). The LPS-induced immune activation increased sensitivity to rectal distensions as reflected by significantly decreased visceral sensory and pain thresholds (both P<.05) compared to saline control. Visceral stimuli were rated as more unpleasant (P<.05) and inducing increased urge to defecate (P<.01). Pain thresholds correlated with interleukin 6 at +1h (r=0.60, P<.05) and +3h (r=0.67, P<.05) within the LPS condition. This report is novel in that it demonstrates that a transient systemic immune activation results in decreased visceral sensory and pain thresholds and altered subjective pain ratings. Our results support the relevance of inflammatory processes in the pathophysiology of visceral hyperalgesia and underscore the need for studies to further elucidate immune-to-brain communication pathways in gastrointestinal disorders., (Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Introduction: The aim of the study is to present a compact employee attitude survey for companies within a health care management tool. Beside body pains work-related psychosocial risk factors as well as further influencing factors, are taken into consideration. The questionnaire was evaluated by 6 Bavarian companies., Method: Potential influencing factors on physical problems like back pain, neck- and shoulder tension, gastro-intestinal diseases and headache were examined by multiple analysis. Dissatisfaction with working conditions was also examined in the same way. All analyses were carried out age and sex adjusted., Results: Statistical analyses are based on 3,720 employees of 3 companies out of a total of 6 companies who answered the questionnaires. Response rates of the different companies ranged from 34 to 60%. Psychomental demands and psychosocial strains were found to be the strongest predictors for body pains as well as for dissatisfaction with working conditions., Conclusions: The introduced questionnaire is easy to implement within the framework of a company health care management. It has an holistic approach. We could demonstrate that this instrument is able to reveal multiple aspects of work-related body pain as well as multiple aspects of dissatisfaction with working conditions. Thus it is a starting point for the development of necessary measures for health promotion., (© Georg Thieme Verlag KG Stuttgart · New York.)