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Durcan C, Hossain M, Chagnon G, Perić D, Girard E. Mechanical experimentation of the gastrointestinal tract: a systematic review. Biomech Model Mechanobiol 2024; 23:23-59. [PMID: 37935880 PMCID: PMC10901955 DOI: 10.1007/s10237-023-01773-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 09/10/2023] [Indexed: 11/09/2023]
Abstract
The gastrointestinal (GI) organs of the human body are responsible for transporting and extracting nutrients from food and drink, as well as excreting solid waste. Biomechanical experimentation of the GI organs provides insight into the mechanisms involved in their normal physiological functions, as well as understanding of how diseases can cause disruption to these. Additionally, experimental findings form the basis of all finite element (FE) modelling of these organs, which have a wide array of applications within medicine and engineering. This systematic review summarises the experimental studies that are currently in the literature (n = 247) and outlines the areas in which experimentation is lacking, highlighting what is still required in order to more fully understand the mechanical behaviour of the GI organs. These include (i) more human data, allowing for more accurate modelling for applications within medicine, (ii) an increase in time-dependent studies, and (iii) more sophisticated in vivo testing methods which allow for both the layer- and direction-dependent characterisation of the GI organs. The findings of this review can also be used to identify experimental data for the readers' own constitutive or FE modelling as the experimental studies have been grouped in terms of organ (oesophagus, stomach, small intestine, large intestine or rectum), test condition (ex vivo or in vivo), number of directions studied (isotropic or anisotropic), species family (human, porcine, feline etc.), tissue condition (intact wall or layer-dependent) and the type of test performed (biaxial tension, inflation-extension, distension (pressure-diameter), etc.). Furthermore, the studies that investigated the time-dependent (viscoelastic) behaviour of the tissues have been presented.
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Affiliation(s)
- Ciara Durcan
- Zienkiewicz Centre for Modelling, Data and AI, Faculty of Science and Engineering, Swansea University, Swansea, SA1 8EN, UK
- Université Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, 38000, Grenoble, France
| | - Mokarram Hossain
- Zienkiewicz Centre for Modelling, Data and AI, Faculty of Science and Engineering, Swansea University, Swansea, SA1 8EN, UK.
| | - Grégory Chagnon
- Université Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, 38000, Grenoble, France
| | - Djordje Perić
- Zienkiewicz Centre for Modelling, Data and AI, Faculty of Science and Engineering, Swansea University, Swansea, SA1 8EN, UK
| | - Edouard Girard
- Université Grenoble Alpes, CNRS, UMR 5525, VetAgro Sup, Grenoble INP, TIMC, 38000, Grenoble, France
- Laboratoire d'Anatomie des Alpes Françaises, Université Grenoble Alpes, Grenoble, France
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2
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Broers C, Geeraerts A, Boecxstaens V, Van Houtte B, Geysen H, Peersman N, Vermeersch P, Vanuytsel T, Tack J, Pauwels A. The role of serotonin in the control of esophageal sensitivity assessed by multimodal stimulation in health. Neurogastroenterol Motil 2021; 33:e14057. [PMID: 33280212 DOI: 10.1111/nmo.14057] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 10/22/2020] [Accepted: 11/17/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Esophageal hypersensitivity is considered an important pathophysiological mechanism in refractory gastroesophageal reflux disease (GERD) patients. Serotonin (5-HT) plays an important role in the regulation of GI (gastrointestinal) secretion, motility and sensitivity. Previous studies found that altered 5-HT availability has no clear effects on esophageal/GI sensations. Our aim was therefore to investigate the role of 5-HT in esophageal sensitivity in healthy volunteers (HV). METHODS Esophageal sensitivity to thermal, mechanical, electrical, and chemical stimuli was assessed in 3 different placebo-controlled studies. In the first study, the effect of citalopram (40 mg; 5-HT reuptake inhibitor; intravenous) was investigated (n = 14). In the second study, the effect of buspirone (20 mg; 5HT1A agonist; oral) was investigated (n = 10). In the third study, acute tryptophan depletion (ATD) was used to decrease 5-HT levels to investigate the effect of reduced 5-HT availability on esophageal sensitivity (n = 15). KEY RESULTS No difference was observed in esophageal sensitivity after the administration of citalopram or buspirone (all p > 0.06). In contrast, pain perception threshold to chemical stimulation was increased after ATD (p = 0.017, Cohen's d+ = 0.67). No effect was found on the first perception or pain tolerance threshold. ATD had no influence on esophageal sensitivity to thermal, mechanical, and electrical stimulation compared with placebo. CONCLUSIONS AND INFERENCES ATD, which induces 5-HT depletion, significantly decreased pain perception threshold during chemical stimulation, without affecting sensitivity to mechanical, thermal, or electrical stimulation. These findings confirm the involvement of 5-HT in the control of esophageal acid sensitivity, but identifying the receptors involved requires more ligands and studies.
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Affiliation(s)
- Charlotte Broers
- Translational Research Centre for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - Annelies Geeraerts
- Translational Research Centre for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - Veerle Boecxstaens
- Translational Research Centre for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - Brecht Van Houtte
- Translational Research Centre for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - Hannelore Geysen
- Translational Research Centre for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - Nele Peersman
- Clinical Department of Laboratory Medicine, University Hospital Leuven, Leuven, Belgium
| | - Pieter Vermeersch
- Clinical Department of Laboratory Medicine, University Hospital Leuven, Leuven, Belgium
| | - Tim Vanuytsel
- Translational Research Centre for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - Jan Tack
- Translational Research Centre for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
| | - Ans Pauwels
- Translational Research Centre for Gastrointestinal Disorders, University of Leuven, Leuven, Belgium
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Evans DW, De Nunzio AM. Controlled manual loading of body tissues: towards the next generation of pressure algometer. Chiropr Man Therap 2020; 28:51. [PMID: 33012288 PMCID: PMC7534174 DOI: 10.1186/s12998-020-00340-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Accepted: 08/07/2020] [Indexed: 11/23/2022] Open
Abstract
Assessing the responses of body tissue subjected to mechanical load is a fundamental component of the clinical examination, psychophysical assessments and bioengineering research. The forces applied during such assessments are usually generated manually, via the hands of the tester, and aimed at discreet tissue sites. It is therefore desirable to objectively quantify and optimise the control of manually applied force. However, current laboratory-grade manual devices and commercial software packages, in particular pressure algometer systems, are generally inflexible and expensive. This paper introduces and discusses several principles that should be implemented as design goals within a flexible, generic software application, given currently available force measurement hardware. We also discuss pitfalls that clinicians and researchers might face when using current pressure algometer systems and provide examples of these. Finally, we present our implementation of a pressure algometer system that achieves these goals in an efficient and affordable way for researchers and clinicians. As part of this effort, we will be sharing our configurable software application via a software repository.
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Affiliation(s)
- Davidk W Evans
- Centre of Precision Rehabilitation for Spinal Pain, School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, B15 2TT, UK. .,Research Centre, University College of Osteopathy, 275 Borough High Street, London, SE1 1JE, UK.
| | - Alessandro Marco De Nunzio
- LUNEX International University of Health, Exercise and Sports, 50, avenue du Parc des Sports, L-4671, Differdange, Luxembourg
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4
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Wu PI, Sloan JA, Kuribayashi S, Gregersen H. Impedance in the evaluation of the esophagus. Ann N Y Acad Sci 2020; 1481:139-153. [PMID: 32557676 DOI: 10.1111/nyas.14408] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Revised: 05/09/2020] [Accepted: 05/14/2020] [Indexed: 12/16/2022]
Abstract
The aim of this paper is to review esophageal electrical impedance technologies and to discuss the use of these technologies for physiological measurements, diagnostics, and therapy of esophageal disease. In order to develop a better understanding of the pathophysiology of and improve the diagnosis of esophageal disorders, such as gastroesophageal reflux disease (GERD) and achalasia, several new diagnostic tests, including intraluminal impedance, esophageal mucosal impedance, and the functional luminal imaging probe, have been developed. These technologies have proven valuable for assessment of the esophagus in recent years. They provide information on esophageal flow properties, mucosal integrity, lumen shape, and distensibility in esophageal disorders, in particular for GERD and achalasia. Despite their promise and novel clinical studies, the potential of these technologies has been far from realized. New multidisciplinary approaches will contribute to our understanding and interpretation of esophageal impedance data and disease mechanisms.
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Affiliation(s)
- Peter I Wu
- Department of Gastroenterology and Hepatology, St George Hospital, University of New South Wales, Sydney, New South Wales, Australia
| | - Joshua A Sloan
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Shiko Kuribayashi
- Department of Gastroenterology and Hepatology, Gunma University Hospital, Maebashi, Japan
| | - Hans Gregersen
- GIOME, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
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5
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Suciu A, Popa SL, Dumitrascu DL. Upper Gastrointestinal Sensitization And Symptom Generation. J Med Life 2019; 12:316-321. [PMID: 32025247 PMCID: PMC6993284 DOI: 10.25122/jml-2019-0111] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 11/20/2019] [Indexed: 12/29/2022] Open
Abstract
Functional gastrointestinal disorders (FGIDs) are a highly prevalent group of heterogeneous disorders, and their diagnostic criteria are symptom-based, with the absence of anatomical and biochemical abnormalities of the gastrointestinal tract. Chronic visceral symptoms are common both in patients with an identifiable organic disease but also in FGID patients. Patients suffering from upper gastrointestinal functional disorders typically present with various symptoms such as early satiety, postprandial fullness, bloating, nausea, vomiting, and epigastric pain. Considering their increasing prevalence, difficulties in diagnosis, and low quality of life, FGIDs have become an emerging problem in gastroenterology. We aimed to provide an updated summary of pathways involved in visceral sensitization. We examined the recent literature searching for evidence of the most important studies about the mechanisms underlying gastrointestinal symptom generation and sensitization.
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Affiliation(s)
| | - Stefan-Lucian Popa
- Second Medical Department “Iuliu Hatieganu” University of Medicine and Pharmacy Cluj-Napoca, Romania
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6
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Designing and conducting proof-of-concept chronic pain analgesic clinical trials. Pain Rep 2019; 4:e697. [PMID: 31583338 PMCID: PMC6749910 DOI: 10.1097/pr9.0000000000000697] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 09/24/2018] [Accepted: 09/26/2018] [Indexed: 02/07/2023] Open
Abstract
Introduction: The evolution of pain treatment is dependent on successful development and testing of interventions. Proof-of-concept (POC) studies bridge the gap between identification of a novel target and evaluation of the candidate intervention's efficacy within a pain model or the intended clinical pain population. Methods: This narrative review describes and evaluates clinical trial phases, specific POC pain trials, and approaches to patient profiling. Results: We describe common POC trial designs and their value and challenges, a mechanism-based approach, and statistical issues for consideration. Conclusion: Proof-of-concept trials provide initial evidence for target use in a specific population, the most appropriate dosing strategy, and duration of treatment. A significant goal in designing an informative and efficient POC study is to ensure that the study is safe and sufficiently sensitive to detect a preliminary efficacy signal (ie, a potentially valuable therapy). Proof-of-concept studies help avoid resources wasted on targets/molecules that are not likely to succeed. As such, the design of a successful POC trial requires careful consideration of the research objective, patient population, the particular intervention, and outcome(s) of interest. These trials provide the basis for future, larger-scale studies confirming efficacy, tolerability, side effects, and other associated risks.
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7
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Broers C, Boecxstaens V, Deloose E, Tack J, Pauwels A. The optimal order of stimulation modalities and reproducibility of the multimodal esophageal stimulation paradigm. Neurogastroenterol Motil 2019; 31:e13475. [PMID: 30246470 DOI: 10.1111/nmo.13475] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2017] [Revised: 08/22/2018] [Accepted: 08/28/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Esophageal hypersensitivity can be triggered by different stimuli. We use a multimodal stimulation model to study esophageal sensitivity to four sensory modalities: thermal, mechanical, electrical, and chemical stimulation. The optimal order of these stimulations needs further validation. METHODS Esophageal sensitivity to thermal (heated saline solution), mechanical (balloon distention), electrical (block pulses with electrodes), and chemical stimulation (acid solution, 0.1 N HCl) was assessed in 10 subjects. In one session, thermal stimulation was performed first, followed by mechanical stimulation ("original protocol"). In a second session, mechanical stimulation was performed first, followed by temperature stimulation ("reversed protocol"). Besides, the impact of balloon distention speed (25 mL/min vs 50 mL/min) during mechanical stimulation was evaluated. Secondly, in order to establish reproducibility, independent control sessions of multimodal stimulations in 15 healthy volunteers were used retrospectively. KEY RESULTS A significant difference in pain perception threshold for thermal stimulation was found between the original and reversed protocol (P = 0.046), indicating that mechanical stimulation can sensitize the esophagus to thermal stimulation. Balloon distention rate had no impact on sensitivity thresholds for mechanical stimulation. Concerning the reproducibility, there were no differences for thermal, mechanical, electrical, and chemical stimulation in any of the control sessions. CONCLUSIONS The optimal order of the multimodal stimulation protocol was to start with the thermal stimulation, followed by mechanical, electrical, and chemical stimulation. The optimal balloon distention rate was 25 mL/min. Multimodal esophageal stimulation generates reproducible perception scores in health and therefore provides a reliable method to assess esophageal sensitivity changes after interventions that may alter esophageal sensitivity.
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Affiliation(s)
- Charlotte Broers
- Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Veerle Boecxstaens
- Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.,Department of Oncology, Abdominal Surgical Oncology, KU Leuven, Leuven, Belgium
| | - Eveline Deloose
- Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Jan Tack
- Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.,Department of Gastroenterology, Leuven University Hospitals, Leuven, Belgium
| | - Ans Pauwels
- Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
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8
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Führer M, Dejaco C, Kopp B, Hammer J. Gastric administration of garlic powder containing the trpa1- agonist allicin induces specific epigastric symptoms and gastric relaxation in healthy subjects. Neurogastroenterol Motil 2019; 31:e13470. [PMID: 30238636 DOI: 10.1111/nmo.13470] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 08/20/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND TRPA1 is an excitatory ion channel and is involved in sensory processes including thermal nociception and inflammatory pain. The allicin in garlic is a strong activator of the TRPA1 channel. AIM To evaluate the effect of intragastric garlic powder containing allicin on perception, gastric tone, and mechanosensitivity. METHODS An infusion-barostat balloon assembly was used for infusion of test solutions, for distension, and to measure proximal gastric compliance and tone. After an initial open label dose finding with 1 g, 2 g, 3.75 g, and 7.5 g commercially available garlic powder, a bolus of 2 g garlic powder (11 mg allicin)/60 mL H2 O was considered to induce moderate but constant sensation and was used hereafter in a placebo-controlled, single-dose, double-blind, randomized study in 7 volunteers to evaluate gastric sensation, tone, and mechanosensitivity. KEY RESULTS Bolus injection of garlic caused immediate epigastric symptoms, mean aggregate symptom scores (AUC in 15 minutes) were 106 ± 49 vs. 35 ± 30 after placebo (P = 0.01). Garlic induced significant epigastric pressure, stinging, and warmth (P < 0.01 vs. placebo), while intensity of cramps, satiety, nausea, and pain was not significantly different to placebo (P > 0.05). Garlic induced an immediate, short lived fundic relaxation (balloon volume 627 ± 349 mL vs. -145 ± 120 mL; P < 0.02). No effect of allicin on proximal gastric mechanosensitivity and compliance was observed (NS). CONCLUSION AND INFERENCES Garlic containing allicin induces immediate epigastric symptoms of pressure, stinging, and warmth and induces fundic relaxation but does not influence mechanosensitivity or compliance. TRPA1 is a receptor that is involved in gastric sensation and motility.
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Affiliation(s)
- Martina Führer
- Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Clemens Dejaco
- Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Brigitte Kopp
- Department of Pharmacognosy, University of Vienna, Vienna, Austria
| | - Johann Hammer
- Department of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
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9
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Hoff DAL, McMahon B, Gregersen H. Esophageal multimodal stimulation and sensation. Ann N Y Acad Sci 2018; 1434:210-218. [DOI: 10.1111/nyas.13730] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 03/16/2018] [Accepted: 03/21/2018] [Indexed: 12/17/2022]
Affiliation(s)
- Dag Arne Lihaug Hoff
- Division of Gastroenterology and Hepatology, Department of Medicine, Ålesund HospitalMøre and Romsdal Hospital Trust Ålesund Norway
| | - Barry McMahon
- Trinity Academic Gastroenterology Group (TAGG)Trinity College and Tallaght Hospital Dublin Ireland
| | - Hans Gregersen
- Department of Surgerythe Chinese University of Hong Kong Shatin Hong Kong
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10
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Blevins CH, Iyer PG, Vela MF, Katzka DA. The Esophageal Epithelial Barrier in Health and Disease. Clin Gastroenterol Hepatol 2018; 16:608-617. [PMID: 28652128 DOI: 10.1016/j.cgh.2017.06.035] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 06/15/2017] [Accepted: 06/19/2017] [Indexed: 02/07/2023]
Abstract
Dysfunction in the esophageal epithelial barrier function is a major source for morbidity. To better understand the pathophysiologic pathways of the diseases associated with barrier dysfunction, including gastroesophageal reflux disease, eosinophilic esophagitis, Barrett's esophagus, and obesity, it is important to understand the esophageal epithelial embryologic development, microscopic anatomy with a special focus on the barrier structure and function, extraepithelial defense mechanisms, and how these change in the diseased state. In recent years, significant progress has been made in elucidating the esophageal barrier structure and function both in vitro and in vivo. This has enhanced the understanding of mechanisms of disease, and may also allow identification of therapeutic targets that can help in the management of these diseases. This review provides a detailed discussion regarding the esophageal epithelial barrier structure and function, the current and historical techniques used to study the barrier, and how it is affected by common esophageal diseases.
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Affiliation(s)
- Christopher H Blevins
- Division of Gastroenterology and Hepatology, Mayo Clinic Minnesota, Rochester, Minnesota
| | - Prasad G Iyer
- Division of Gastroenterology and Hepatology, Mayo Clinic Minnesota, Rochester, Minnesota.
| | - Marcelo F Vela
- Division of Gastroenterology and Hepatology, Mayo Clinic Arizona, Scottsdale, Arizona
| | - David A Katzka
- Division of Gastroenterology and Hepatology, Mayo Clinic Minnesota, Rochester, Minnesota
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11
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Gregersen H, Lo KM. What Is the Future of Impedance Planimetry in Gastroenterology? J Neurogastroenterol Motil 2018; 24:166-181. [PMID: 29605974 PMCID: PMC5885717 DOI: 10.5056/jnm18013] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 02/09/2018] [Indexed: 12/13/2022] Open
Abstract
The gastrointestinal (GI) tract is efficient in transporting ingested material to the site of delivery in healthy subjects. A fine balance exists between peristaltic forces, the mixing and delivery of the contents, and sensory signaling. This fine balance is easily disturbed by diseases. It is mandatory to understand the pathophysiology to enhance our understanding of GI disorders. The inaccessibility and complex nervous innervation, geometry and mechanical function of the GI tract make mechanosensory evaluation difficult. Impedance planimetry is a distension technology that assesses luminal geometry, mechanical properties including muscle dynamics, and processing of nociceptive signals from the GI tract. Since standardized models do not exist for GI muscle function in vivo, models, concepts, and terminology must be borrowed from other medical fields such as cardiac mechanophysiology. The review highlights the impedance planimetric technology, muscle dynamics assessment, and 3 applied technologies of impedance planimetry. These technologies are the multimodal probes that assesses sensory function, the functional luminal imaging probe that dynamically measures the geometry of the lumen it distends, and Fecobionics that is a simulated feces providing high-resolution measurements during defecation. The advanced muscle analysis and 3 applied technologies can enhance the quality of future interdisciplinary research for gaining more knowledge about mechanical function, sensory-motor disorders, and symptoms. This is a step in the direction of individualized treatment for GI disorders based on diagnostic subtyping. There seems to be no better alternatives to impedance planimetry, but only the functional luminal imaging probe is currently commercially available. Wider use depends on commercialization of the multimodal probe and Fecobionics.
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Affiliation(s)
- Hans Gregersen
- GIOME, Department of Surgery, The Chinese University of Hong Kong, Shatin, Hong Kong.,California Medical Innovations Institute, San Diego, California, USA
| | - Kar Man Lo
- GIOME Doublecove, Wu Kai Sha, New Territories, Hong Kong
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12
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Broers C, Melchior C, Van Oudenhove L, Vanuytsel T, Van Houtte B, Scheerens C, Rommel N, Tack J, Pauwels A. The effect of intravenous corticotropin-releasing hormone administration on esophageal sensitivity and motility in health. Am J Physiol Gastrointest Liver Physiol 2017; 312:G526-G534. [PMID: 28336550 DOI: 10.1152/ajpgi.00437.2016] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 03/09/2017] [Accepted: 03/13/2017] [Indexed: 02/08/2023]
Abstract
Esophageal hypersensitivity is important in gastroesophageal reflux disease (GERD) patients who are refractory to acid-suppressive therapy. Stress affects visceral sensitivity and exacerbates heartburn in GERD. Peripheral CRH is a key mediator of the gut stress response. We hypothesize that CRH increases esophageal sensitivity and alters esophageal motility in health. Esophageal sensitivity to thermal, mechanical, electrical, and chemical stimuli was assessed in 14 healthy subjects after administration of placebo or CRH (100 μg iv). Perception scores were assessed for first perception, pain perception threshold (PPT), and pain tolerance threshold (PTT). Esophageal motility was investigated by high-resolution impedance manometry, before and after CRH and evaluated by distal contractile integral (DCI) and intrabolus pressure (IBP). Pressure flow analysis assessed bolus clearance (impedance ratio), degree of pressurization needed to propel bolus onward (IBP slope), and pressure flow (pressure flow index, PFI). Stress and mood were assessed during the study. Sensitivity to mechanical distention was increased after CRH compared with placebo (PPT: P = 0.0023; PTT: P = 0.0253). CRH had no influence on the other stimulations. DCI was increased for all boluses (liquid, P = 0.0012; semisolid, P = 0.0017; solid, P = 0.0107). Impedance ratio for liquid (P < 0.0001) and semisolid swallows (P = 0.0327) decreased after CRH. IBP slope increased after CRH for semisolid (P = 0.0041) and solid (P = 0.0003) swallows. PFI increased for semisolid (P = 0.0017) and solid swallows (P = 0.0031). CRH increased esophageal sensitivity to mechanical distention, not to the other stimulation modalities. CRH increased esophageal contractility and tone, decreased LES relaxation, increased esophageal bolus pressurization, improved esophageal bolus clearance, and increased pressure flow.NEW & NOTEWORTHY This is the first study to address the effect of corticotropin-releasing hormone (CRH) on esophageal sensitivity and alterations in motility in health. CRH administration increased esophageal sensitivity to mechanical distention. This effect is accompanied by an increase in esophageal contractility and tone and a decrease in lower esophageal sphincter relaxation. CRH increased esophageal bolus pressurization, improved esophageal bolus clearance, and increased pressure flow. The changes in esophageal contractile properties may underlie the increased sensitivity to mechanical distention after CRH.
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Affiliation(s)
- Charlotte Broers
- Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, KU Leuven, Belgium
| | - Chloé Melchior
- Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, KU Leuven, Belgium.,Institut National de la Santé et de la Recherche Médicale, UMR 1073, Institute for Research and Innovation in Biomedicine, Normandy University, Rouen, France; and.,Physiology and Gastroenterology Department, Rouen University Hospital, France
| | - Lukas Van Oudenhove
- Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, KU Leuven, Belgium
| | - Tim Vanuytsel
- Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, KU Leuven, Belgium.,Department of Gastroenterology, Leuven University Hospitals, Leuven, Belgium
| | - Brecht Van Houtte
- Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, KU Leuven, Belgium
| | - Charlotte Scheerens
- Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, KU Leuven, Belgium.,Experimental Oto-Rhino-Laryngology, Department of Neurosciences, KU Leuven, Belgium
| | - Nathalie Rommel
- Experimental Oto-Rhino-Laryngology, Department of Neurosciences, KU Leuven, Belgium
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, KU Leuven, Belgium; .,Department of Gastroenterology, Leuven University Hospitals, Leuven, Belgium
| | - Ans Pauwels
- Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, KU Leuven, Belgium
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13
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Lottrup C, Krarup AL, Gregersen H, Ejstrud P, Drewes AM. Patients with Barrett's esophagus are hypersensitive to acid but hyposensitive to other stimuli compared with healthy controls. Neurogastroenterol Motil 2017; 29. [PMID: 27891754 DOI: 10.1111/nmo.12992] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2016] [Accepted: 10/18/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND Esophageal hyposensitivity has been observed in Barrett's esophagus and may contribute to its pathophysiology. However, studies are few, in particular those assessing different sensory modalities. We aimed to compare esophageal sensitivity to multimodal stimulation in patients with Barrett's esophagus and in healthy controls. METHODS Twenty-three patients with Barrett's esophagus and 12 healthy controls were examined. A multimodal probe was placed in the lower esophagus. Mechanical, thermal, and electrical stimulation was applied followed by an acid perfusion test with 0.1 N hydrochloric acid. KEY RESULTS Compared with controls, patients were hyposensitive to mechanical distension, heat, and electrical stimulation (all P<.05), but hypersensitive to acid (mean tolerated acid volume 57% lower, P=.001). A linear correlation between acid hypersensitivity and lower baseline impedance was found (P<.001). Patients had longer esophageal acid exposure time than controls (median acid exposure time 18 vs 5%, P=.03). Asymptomatic patients (no reflux symptoms at baseline) were hyposensitive to mechanical distension, electrical stimulation, and acid perfusion (all P<.05) compared with symptomatic patients. CONCLUSIONS & INFERENCES Patients with Barrett's esophagus exhibited acid hypersensitivity but hyposensitivity to other stimuli. Lower mucosal baseline impedance, a likely surrogate marker for impaired mucosal integrity, may explain the selective hypersensitivity to acid. On the other hand, the concurrent hyposensitivity may theoretically be explained by changes in central pain modulation. Patients with Barrett's esophagus seem to compose symptomatic and asymptomatic subgroups, showing different esophageal sensory profiles.
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Affiliation(s)
- C Lottrup
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.,Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.,Department of Medicine, North Denmark Regional Hospital, Hjørring, Denmark
| | - A L Krarup
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.,Department of Medicine, North Denmark Regional Hospital, Hjørring, Denmark
| | - H Gregersen
- GIOME, Department of Surgery, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong SAR
| | - P Ejstrud
- Department of Surgery, Aalborg University Hospital, Aalborg, Denmark
| | - A M Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark.,Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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14
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Abstract
The Rome IV diagnostic criteria delineates 5 functional esophageal disorders which include functional chest pain, functional heartburn, reflux hypersensitivity, globus, and functional dysphagia. These are a heterogenous group of disorders which, despite having characteristic symptom profiles attributable to esophageal pathology, fail to demonstrate any structural, motility or inflammatory abnormalities on standard clinical testing. These disorders are associated with a marked reduction in patient quality of life, not least considerable healthcare resources. Furthermore, the pathophysiology of these disorders is incompletely understood. In this narrative review we provide the reader with an introductory primer to the structure and function of esophageal perception, including nociception that forms the basis of the putative mechanisms that may give rise to symptoms in functional esophageal disorders. We also discuss the provocative techniques and outcome measures by which esophageal hypersensitivity can be established.
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15
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Gregersen H, Liao D, Brasseur JG. The Esophagiome: concept, status, and future perspectives. Ann N Y Acad Sci 2016; 1380:6-18. [PMID: 27570939 DOI: 10.1111/nyas.13200] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 07/13/2016] [Accepted: 07/14/2016] [Indexed: 12/23/2022]
Abstract
The term "Esophagiome" is meant to imply a holistic, multiscale treatment of esophageal function from cellular and muscle physiology to the mechanical responses that transport and mix fluid contents. The development and application of multiscale mathematical models of esophageal function are central to the Esophagiome concept. These model elements underlie the development of a "virtual esophagus" modeling framework to characterize and analyze function and disease by quantitatively contrasting normal and pathophysiological function. Functional models incorporate anatomical details with sensory-motor properties and functional responses, especially related to biomechanical functions, such as bolus transport and gastrointestinal fluid mixing. This brief review provides insight into Esophagiome research. Future advanced models can provide predictive evaluations of the therapeutic consequences of surgical and endoscopic treatments and will aim to facilitate clinical diagnostics and treatment.
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Affiliation(s)
- Hans Gregersen
- GIOME, College of Bioengineering, Chongqing University, China. .,GIOME, Department of Surgery, Prince of Wales Hospital, College of Medicine, Chinese University of Hong Kong, Hong Kong SAR.
| | - Donghua Liao
- GIOME Academy, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - James G Brasseur
- Aerospace Engineering Sciences, University of Colorado, Boulder, Colorado
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16
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17
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Ravages of Diabetes on Gastrointestinal Sensory-Motor Function: Implications for Pathophysiology and Treatment. Curr Gastroenterol Rep 2016; 18:6. [PMID: 26768896 DOI: 10.1007/s11894-015-0481-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Symptoms related to functional and sensory abnormalities are frequently encountered in patients with diabetes mellitus. Most symptoms are associated with impaired gastric and intestinal function. In this review, we discuss basic concepts of sensory-motor dysfunction and how they relate to clinical findings and gastrointestinal abnormalities that are commonly seen in diabetes. In addition, we review techniques that are available for investigating the autonomic nervous system, neuroimaging and neurophysiology of sensory-motor function. Such technological advances, while not readily available in the clinical setting, may facilitate stratification and individualization of therapy in diabetic patients in the future. Unraveling the structural, mechanical, and sensory remodeling in diabetes disease is based on a multidisciplinary approach that can bridge the knowledge from a variety of scientific disciplines. The final goal is to increase the understanding of the damage to GI structures and to sensory processing of symptoms, in order to assist clinicians with developing an optimal mechanics based treatment.
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18
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Brock C, McCallum RW, Gyawali CP, Farmer AD, Frøkjaer JB, McMahon BP, Drewes AM. Neurophysiology and new techniques to assess esophageal sensory function: an update. Ann N Y Acad Sci 2016; 1380:78-90. [DOI: 10.1111/nyas.13175] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 06/10/2016] [Accepted: 06/15/2016] [Indexed: 12/19/2022]
Affiliation(s)
- Christina Brock
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital and Clinical Institute; Aalborg University; Aalborg Denmark
| | - Richard W. McCallum
- Department of Internal Medicine; Texas Tech University Health Sciences Center; El Paso Texas
| | - C. Prakash Gyawali
- Division of Gastroenterology; Washington University School of Medicine; St. Louis Missouri
| | - Adam D. Farmer
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital and Clinical Institute; Aalborg University; Aalborg Denmark
- Centre for Digestive Diseases, Blizard Institute, Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry; Queen Mary University of London; London United Kingdom
- Department of Gastroenterology; University Hospitals of North Midlands; Stoke on Trent United Kingdom
| | - Jens Brøndum Frøkjaer
- Mech-Sense, Department of Radiology, Aalborg University Hospital and Clinical Institute; Aalborg University; Aalborg Denmark
| | - Barry P. McMahon
- Department of Medical Physics and Clinical Engineering; Tallaght Hospital and Trinity College; Dublin Ireland
| | - Asbjørn Mohr Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital and Clinical Institute; Aalborg University; Aalborg Denmark
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19
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Brock C, Gregersen H, Gyawali CP, Lottrup C, Furnari M, Savarino E, Novais L, Frøkjaer JB, Bor S, Drewes AM. The sensory system of the esophagus--what do we know? Ann N Y Acad Sci 2016; 1380:91-103. [DOI: 10.1111/nyas.13205] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 07/19/2016] [Accepted: 07/19/2016] [Indexed: 12/13/2022]
Affiliation(s)
- Christina Brock
- Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital and Clinical Institute; Aalborg University; Aalborg Denmark
| | - Hans Gregersen
- GIOME and the Key Laboratory for Biorheological Science and Technology of Ministry of Education, College of Bioengineering; Chongqing University; Chongqing China
| | - C. Prakash Gyawali
- Division of Gastroenterology; Washington University School of Medicine; St. Louis Missouri
| | - Christian Lottrup
- Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital and Clinical Institute; Aalborg University; Aalborg Denmark
- Department of Medicine; North Jutland Regional Hospital; Hjørring Denmark
| | - Manuele Furnari
- Division of Gastroenterology, Department of Internal Medicine; University of Genoa; Genoa Italy
| | - Edoardo Savarino
- Division of Gastroenterology, Department of Surgery, Oncology and Gastroenterology; University of Padua; Padua Italy
| | - Luis Novais
- Neurogastroenterology and Gastrointestinal Motility Laboratory, Nova Medical School; Universidade Nova de Lisboa; Lisbon Portugal
| | - Jens Brøndum Frøkjaer
- Mech-Sense, Department of Radiology, Aalborg University Hospital and Clinical Institute; Aalborg University; Aalborg Denmark
| | - Serhat Bor
- Department of Gastroenterology; Ege University School of Medicine; Bornova Izmir Turkey
| | - Asbjørn Mohr Drewes
- Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital and Clinical Institute; Aalborg University; Aalborg Denmark
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20
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Farmer AD, Brock C, Frøkjaer JB, Gregersen H, Khan S, Lelic D, Lottrup C, Drewes AM. Understanding the sensory irregularities of esophageal disease. Expert Rev Gastroenterol Hepatol 2016; 10:907-14. [PMID: 26890720 DOI: 10.1586/17474124.2016.1155984] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Symptoms relating to esophageal sensory abnormalities can be encountered in the clinical environment. Such sensory abnormalities may be present in demonstrable disease, such as erosive esophagitis, and in the ostensibly normal esophagus, such as non-erosive reflux disease or functional chest pain. In this review, the authors discuss esophageal sensation and the esophageal pain system. In addition, the authors provide a primer concerning the techniques that are available for investigating the autonomic nervous system, neuroimaging and neurophysiology of esophageal sensory function. Such technological advances, whilst not readily available in the clinic may facilitate the stratification and individualization of therapy in disorders of esophageal sensation in the future.
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Affiliation(s)
- Adam D Farmer
- a Mech-Sense , University Hospital Aalborg , Aalborg , Denmark.,b Centre for Digestive Diseases, Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine & Dentistry, Queen Mary University of London , London , UK.,c Department of Gastroenterology , University Hospitals of North Midlands , Stoke on Trent , UK
| | - Christina Brock
- a Mech-Sense , University Hospital Aalborg , Aalborg , Denmark
| | - Jens Brøndum Frøkjaer
- a Mech-Sense , University Hospital Aalborg , Aalborg , Denmark.,d Department of Radiology , Aalborg University Hospital , Aalborg , Denmark
| | - Hans Gregersen
- e GIOME, Key Laboratory for Biorheological Science and Technology , College of Bioengineering, Chongqing University , Chongqing , China
| | - Sheeba Khan
- c Department of Gastroenterology , University Hospitals of North Midlands , Stoke on Trent , UK
| | - Dina Lelic
- a Mech-Sense , University Hospital Aalborg , Aalborg , Denmark
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21
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Farmer AD, Franchina M, Gregersen H, Penagini R, Shaker A, Soffer E. Provocative testing of the esophagus and its future. Ann N Y Acad Sci 2016; 1380:33-47. [DOI: 10.1111/nyas.13109] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 04/21/2016] [Accepted: 04/25/2016] [Indexed: 12/25/2022]
Affiliation(s)
- Adam D. Farmer
- Centre for Digestive Diseases, Wingate Institute of Neurogastroenterology, Blizard Institute, Barts and the London School of Medicine & Dentistry; Queen Mary University of London; London United Kingdom
- Department of Gastroenterology; University Hospitals of North Midlands; Stoke on Trent Staffordshire United Kingdom
| | - Marianna Franchina
- Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi of Milan and Gastroenterology and Endoscopy Unit; Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico; Milan Italy
| | - Hans Gregersen
- GIOME, College of Bioengineering; Chongqing University; Chongqing China
- Department of Surgery; Prince of Wales Hospital; Shatin Hong Kong SAR
| | - Roberto Penagini
- Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi of Milan and Gastroenterology and Endoscopy Unit; Fondazione IRCCS Cà Granda - Ospedale Maggiore Policlinico; Milan Italy
| | - Anisa Shaker
- Department of Medicine; University of Southern California; Los Angeles California
| | - Edy Soffer
- Department of Medicine; University of Southern California; Los Angeles California
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22
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Martel M, Olesen A, Jørgensen D, Nielsen L, Brock C, Edwards R, Drewes A. Does catastrophic thinking enhance oesophageal pain sensitivity? An experimental investigation. Eur J Pain 2016; 20:1214-22. [DOI: 10.1002/ejp.845] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/17/2015] [Indexed: 12/12/2022]
Affiliation(s)
- M.O. Martel
- Department of Anesthesiology & Pain Medicine; Brigham & Women's Hospital; Harvard Medical School; Boston USA
| | - A.E. Olesen
- Mech-Sense; Department of Gastroenterology & Hepatology; Aalborg University Hospital; Denmark
- Department of Drug Design and Pharmacology; Faculty of Health and Medical Sciences; University of Copenhagen; Denmark
| | - D. Jørgensen
- Mech-Sense; Department of Gastroenterology & Hepatology; Aalborg University Hospital; Denmark
- Center for Sensory-Motor Interaction (SMI); Department of Health Science and Technology; Aalborg University; Denmark
| | - L.M. Nielsen
- Mech-Sense; Department of Gastroenterology & Hepatology; Aalborg University Hospital; Denmark
- Department of Drug Design and Pharmacology; Faculty of Health and Medical Sciences; University of Copenhagen; Denmark
| | - C. Brock
- Mech-Sense; Department of Gastroenterology & Hepatology; Aalborg University Hospital; Denmark
- Department of Drug Design and Pharmacology; Faculty of Health and Medical Sciences; University of Copenhagen; Denmark
| | - R.R. Edwards
- Department of Anesthesiology & Pain Medicine; Brigham & Women's Hospital; Harvard Medical School; Boston USA
| | - A.M. Drewes
- Mech-Sense; Department of Gastroenterology & Hepatology; Aalborg University Hospital; Denmark
- Department of Clinical Medicine; Aalborg University; Denmark
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23
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Drewes AM, Søfteland E, Dimcevski G, Farmer AD, Brock C, Frøkjær JB, Krogh K, Drewes AM. Brain changes in diabetes mellitus patients with gastrointestinal symptoms. World J Diabetes 2016; 7:14-26. [PMID: 26839652 PMCID: PMC4724575 DOI: 10.4239/wjd.v7.i2.14] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Revised: 09/14/2015] [Accepted: 10/27/2015] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus is a common disease and its prevalence is increasing worldwide. In various studies up to 30%-70% of patients present dysfunction and complications related to the gut. To date several clinical studies have demonstrated that autonomic nervous system neuropathy and generalized neuropathy of the central nervous system (CNS) may play a major role. This systematic review provides an overview of the neurodegenerative changes that occur as a consequence of diabetes with a focus on the CNS changes and gastrointestinal (GI) dysfunction. Animal models where diabetes was induced experimentally support that the disease induces changes in CNS. Recent investigations with electroencephalography and functional brain imaging in patients with diabetes confirm these structural and functional brain changes. Encephalographic studies demonstrated that altered insular processing of sensory stimuli seems to be a key player in symptom generation. In fact one study indicated that the more GI symptoms the patients experienced, the deeper the insular electrical source was located. The electroencephalography was often used in combination with quantitative sensory testing mainly showing hyposensitivity to stimulation of GI organs. Imaging studies on patients with diabetes and GI symptoms mainly showed microstructural changes, especially in brain areas involved in visceral sensory processing. As the electrophysiological and imaging changes were associated with GI and autonomic symptoms they may represent a future therapeutic target for treating diabetics either pharmacologically or with neuromodulation.
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24
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Abstract
Nordic research on gastrointestinal motility has since 1965 made substantial contributions to our current understanding of gastrointestinal function. During the last decade, the term neurogastroenterology has widened the concept of motility research into the study of gastrointestinal sensory-motor function, including the complex central nervous system interaction. The discovery of a non-adrenergic non-cholinergic (NANC) innervation of the gut in the sixties was made by considerable contributions from the Nordic countries with the Martinson group in Sweden as central innovators. Important discoveries regarding the intramural nerve ganglia as mediators of the autonomic nervous input has also been produced from this research. In clinical motility research, the study of the migrating motor complex in the small bowel has revealed its ability to act as a retroperistaltic pump in the proximal duodenum (Sweden) and its important role for gut microbial homeostasis (Norway). Also in the development of methodology to study gut sensory-motor function, the Nordic countries has contributed. Examples are the physical characteristics of the esophageal manometry catheter (Denmark), the use of ultrasound for assessment of gastric function (Norway), a temporary electrical stimulation method in patients with severe nausea and vomiting (Sweden), a rectal barostat method for clinical evaluation of recto-anal function and a colonic transit time method utilizing radio-opaque markers (Sweden). In later years, the research collaborations have increasingly become worldwide in a manner making it less easy to define pure Nordic contributions.
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Affiliation(s)
- Hans Törnblom
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg , Gothenburg , Sweden
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25
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Brock C, Brokjaer A, Drewes AM, Farmer AD, Frøkjaer JB, Gregersen H, Lottrup C. Neurophysiology of the esophagus. Ann N Y Acad Sci 2015; 1325:57-68. [PMID: 25266015 DOI: 10.1111/nyas.12515] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on the methods and characteristics of esophageal afferents in humans; the pitfalls in characterization of mechanosensitive afferents; the sensitization of esophageal afferents in human studies; the brain source modeling in the understanding of the esophagus-brain axis; the use of evoked brain potentials in the esophagus; and measuring descending inhibition in animal and human studies.
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Affiliation(s)
- Christina Brock
- Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
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26
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27
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Abstract
Dramatic progress has been made over the past decade in the sophistication and availability of equipment to test esophageal motility and sensation. High-resolution esophageal manometry and impedance have moved from the research clinic into clinical practice. Some of the testing is costly and time consuming, and requires extensive experience to perform the testing and properly interpret the results. These sensory studies are valuable in the interpretation of clinical problems, and provide important research information. Clinicians should evaluate the research studies to advance their understanding of the pathophysiology of the esophagus.
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Affiliation(s)
- Salman Nusrat
- Section of Digestive Disease and Nutrition, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Philip B Miner
- Division of Gastroenterology, Department of Medicine, Oklahoma Foundation for Digestive Research, Oklahoma University School of Medicine, 525 Northwest 9th Street, Suite 325, Oklahoma City, OK 73102, USA.
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28
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Liao D, Krarup AL, Lundager FH, Drewes AM, Gregersen H. Quantitative differences between primary and secondary peristaltic contractions of the esophagus. Dig Dis Sci 2014; 59:1810-6. [PMID: 24682721 DOI: 10.1007/s10620-014-3070-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Accepted: 02/07/2014] [Indexed: 01/25/2023]
Abstract
BACKGROUND AND AIMS Differences in contraction characteristics between primary and secondary peristalsis have only been scarcely studied. Recently new measures of contractile activity in the human esophagus were developed. The study aims were to use combined manometry and impedance planimetry [pressure-cross-sectional area (P-CSA)] recordings from healthy volunteers to examine esophageal peristalsis, and, furthermore, to investigate the effect of the motility enhancing drug erythromycin to study differential effects on the two types of contractions. METHODS Sixteen healthy volunteers participated in the study [mean age 23 (range, 19-34) years, 6 females]. An esophageal probe with a bag for CSA measurement was positioned 10 cm above the lower esophageal sphincter. Bag volume was increased stepwise from 5 to 25 ml before and after intravenous infusion of 250 mg erythromycin. Swallow-evoked primary and distension-evoked secondary esophageal peristalsis were compared with regard to (1) pressure amplitude, (2) CSA amplitude, (3) preload tension (wall tension before an evoked contraction), (4) contractile tension, and (5) work outputs. RESULTS Primary peristalsis induced more efficient contractions as the contraction amplitudes, work output and contractile tension were higher compared to secondary peristalsis (P < 0.001). Erythromycin induced change in CSA during distension-evoked secondary peristalsis (CSA before 212.9 ± 26.8 vs. after 180.5 ± 23.3, P < 0.05). The sensitivity to esophageal distension increased with the distending volume both before and during erythromycin. The sensitivity was not changed by erythromycin (P = 0.6). CONCLUSIONS Esophageal primary peristaltic contractions were more forceful with longer duration, and higher work output compared to secondary peristalsis contractions. Erythromycin affected peristalsis only to a minor degree.
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Affiliation(s)
- Donghua Liao
- Giome Academia, Institute of Clinical Medicine, Aarhus University Hospital, Skejby, Brendstrupgaardsvej, 8200, Aarhus, Denmark,
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29
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Arendt-Nielsen L, Madsen H, Jarrell J, Gregersen H, Drewes AM. Pain evoked by distension of the uterine cervix in women with dysmenorrhea: evidence for central sensitization. Acta Obstet Gynecol Scand 2014; 93:741-8. [DOI: 10.1111/aogs.12403] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Accepted: 04/10/2014] [Indexed: 12/15/2022]
Affiliation(s)
- Lars Arendt-Nielsen
- Center for Sensory-Motor Interactions (SMI); Department of Health Science and Technology; School of Medicine; Aalborg University; Aalborg Denmark
| | - Hans Madsen
- Department of Obstetrics and Gynecology; Aalborg University Hospital; Aalborg Denmark
| | - John Jarrell
- Calgary Chronic Pain Centre and Department of Obstetrics and Gynecology; University of Calgary; Calgary Alberta Canada
| | - Hans Gregersen
- Mech-Sense; Department of Gastroenterology; Aalborg University Hospital; Aalborg Denmark
| | - Asbjørn M. Drewes
- Center for Sensory-Motor Interactions (SMI); Department of Health Science and Technology; School of Medicine; Aalborg University; Aalborg Denmark
- Mech-Sense; Department of Gastroenterology; Aalborg University Hospital; Aalborg Denmark
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30
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Reeves JW, Al-Zinaty M, Woodland P, Sifrim D, Aziz Q, Birch MJ. Sensiprobe—a miniature thermal device incorporating Peltier technology as a diagnostic tool for studying human oesophageal sensitivity. Physiol Meas 2014; 35:1265-77. [DOI: 10.1088/0967-3334/35/7/1265] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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31
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Arendt-Nielsen L, Nielsen TA, Gazerani P. Translational pain biomarkers in the early development of new neurotherapeutics for pain management. Expert Rev Neurother 2014; 14:241-54. [PMID: 24490970 DOI: 10.1586/14737175.2014.884925] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Translation of the analgesic efficacy of investigational neurotherapeutics from pre-clinical pain models into clinical trial phases is associated with a high risk of failure. Application of human pain biomarkers in early stages of clinical trials can potentially enhance the rate of successful translation, which would eventually reduce both length and costs of drug development after the pre-clinical stage. Human pain biomarkers are based on the standardized activation of pain pathways followed by the assessment of ongoing and paroxysmal pain, plus evoked responses which can be applied to healthy individuals and patients prior to and after pharmacological interventions. This review discusses the rationality and feasibility of advanced human pain biomarkers in early phases of drug development for pain management which is still an unmet medical need.
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Affiliation(s)
- Lars Arendt-Nielsen
- Department of Health Science and Technology, Center for Sensory-Motor Interaction (SMI), Aalborg University, Fredrik Bajers Vej 7D-3, 9220 Aalborg East, Denmark
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32
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Altomare A, Luca Guarino Sara Emerenziani MP, Cicala M, Drewes AM, Krarup AL, Brock C, Lottrup C, Frøkjaer JB, Souza RF, Nardone G, Compare D. Gastrointestinal sensitivity and gastroesophageal reflux disease. Ann N Y Acad Sci 2013; 1300:80-95. [PMID: 24117636 DOI: 10.1111/nyas.12236] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
This paper reports on gastrointestinal sensitivity, including on the role of refluxate volume on the perception of reflux symptoms; experimental pain models that mimic mechanisms and symptoms of pain associated with esophageal diseases; the potential role of the acid receptor TRPV1 in the genesis of gastroesophageal reflux disease (GERD) symptoms; and roles for ATP and the purine and pyrimidine receptor subfamilies P1, P2X, and P2Y in the pathogenesis of GERD symptoms.
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Affiliation(s)
- Annamaria Altomare
- Department of Digestive Disease, Campus Bio-medico University, Rome, Italy
| | | | - Michele Cicala
- Department of Digestive Disease, Campus Bio-medico University, Rome, Italy
| | - Asbjørn Mohr Drewes
- Mech-Sense, Departments of Gastroenterology & Radiology, Aalborg University Hospital, Aalborg, Denmark
| | - Anne Lund Krarup
- Mech-Sense, Departments of Gastroenterology & Radiology, Aalborg University Hospital, Aalborg, Denmark
| | - Christina Brock
- Mech-Sense, Departments of Gastroenterology & Radiology, Aalborg University Hospital, Aalborg, Denmark
| | - Christian Lottrup
- Mech-Sense, Departments of Gastroenterology & Radiology, Aalborg University Hospital, Aalborg, Denmark
| | - Jens Brøndum Frøkjaer
- Mech-Sense, Departments of Gastroenterology & Radiology, Aalborg University Hospital, Aalborg, Denmark
| | - Rhonda F Souza
- Departments of Medicine, University of Texas Southwestern Medical Center and the VA North Texas Health Care System, Dallas, Texas
| | - Gerardo Nardone
- Department of Clinical and Experimental Medicine, Gastroenterology Unit, University "Federico II,", Naples, Italy
| | - Debora Compare
- Department of Clinical and Experimental Medicine, Gastroenterology Unit, University "Federico II,", Naples, Italy
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Krarup AL, Liao D, Gregersen H, Drewes AM, Hejazi RA, McCallum RW, Vega KJ, Frazzoni M, Frazzoni L, Clarke JO, Achem SR. Nonspecific motility disorders, irritable esophagus, and chest pain. Ann N Y Acad Sci 2013; 1300:96-109. [PMID: 24117637 DOI: 10.1111/nyas.12244] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
This paper presents commentaries on whether Starling's law applies to the esophagus; whether erythromycin affects esophageal motility; the relationship between hypertensive lower esophageal sphincter and vigorous achalasia; whether ethnic- and gender-based norms affect diagnosis and treatment of esophageal motor disorders; health care and epidemiology of chest pain; whether normal pH excludes esophageal pain; the role of high-resolution manometry in noncardiac chest pain; whether pH-impedance should be included in the evaluation of noncardiac chest pain; whether there are there alternative therapeutic options to PPI for treating noncardiac chest pain; and the usefulness of psychological treatment and alternative medicine in noncardiac chest pain.
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Affiliation(s)
- Anne Lund Krarup
- Mech-Sense, Department of Gastroenterology, Aalborg University, Aalborg, Denmark
| | - Donghua Liao
- Mech-Sense, Department of Gastroenterology, Aalborg University, Aalborg, Denmark
| | - Hans Gregersen
- Mech-Sense, Department of Gastroenterology, Aalborg University, Aalborg, Denmark
| | - Asbjørn Mohr Drewes
- Mech-Sense, Department of Gastroenterology, Aalborg University, Aalborg, Denmark
| | - Reza A Hejazi
- Department of Internal Medicine, Texas Tech University Health Sciences Center, El Paso, Texas
| | - Richard W McCallum
- Department of Internal Medicine, Texas Tech University Health Sciences Center, El Paso, Texas
| | - Kenneth J Vega
- Division of Digestive Diseases and Nutrition, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Marzio Frazzoni
- Fisiopatologia Digestiva, Nuovo Ospedale S. Agostino, Modena, Italy
| | | | - John O Clarke
- Division of Gastroenterology, Johns Hopkins University, Baltimore, Maryland
| | - Sami R Achem
- Mayo College of Medicine, Mayo Clinic, Jacksonville, Florida
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Woodland P, Sifrim D, Krarup AL, Brock C, Frøkjaer JB, Lottrup C, Drewes AM, Swanstrom LL, Farmer AD. The neurophysiology of the esophagus. Ann N Y Acad Sci 2013; 1300:53-70. [DOI: 10.1111/nyas.12238] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Philip Woodland
- Neurogastroenterology Group, Barts and The London School of Medicine and Dentistry; Queen Mary University of London; London United Kingdom
| | - Daniel Sifrim
- Neurogastroenterology Group, Barts and The London School of Medicine and Dentistry; Queen Mary University of London; London United Kingdom
| | - Anne Lund Krarup
- Mech-Sense, Department of Gastroenterology; Aalborg Hospital; Aarhus University; Aarhus Denmark
| | - Christina Brock
- Mech-Sense, Department of Gastroenterology; Aalborg Hospital; Aarhus University; Aarhus Denmark
| | - Jens Brøndum Frøkjaer
- Mech-Sense, Department of Gastroenterology; Aalborg Hospital; Aarhus University; Aarhus Denmark
| | - Christian Lottrup
- Mech-Sense, Department of Gastroenterology; Aalborg Hospital; Aarhus University; Aarhus Denmark
| | - Asbjørn Mohr Drewes
- Mech-Sense, Department of Gastroenterology; Aalborg Hospital; Aarhus University; Aarhus Denmark
| | | | - Adam D. Farmer
- Department of Gastroenterology, Shrewsbury & Telford Hospitals NHS Trust; Princess Royal Hospital; Apley Castle Telford Shropshire United Kingdom
- Neurogastroenterology Group, Blizard Institute of Cell & Molecular Science; Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine & Dentistry; Queen Mary University of London; London United Kingdom
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Krarup AL, Gunnarsson J, Brun J, Poulakis A, Edebo A, Ringström G, Drewes AM, Simrén M. Exploration of the effects of gender and mild esophagitis on esophageal pain thresholds in the normal and sensitized state of asymptomatic young volunteers. Neurogastroenterol Motil 2013; 25:766-e580. [PMID: 23822673 DOI: 10.1111/nmo.12172] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2013] [Accepted: 05/22/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND Clinical data suggest gender differences in gastrointestinal pain, but very little experimental data exist. Esophageal painful thresholds to mechanical, thermal, electric, and chemical stimuli can be measured with the esophageal multimodal pain model. The aim was to measure the effect of gender and mild esophagitis on esophageal pain perception. METHODS Thirty-five healthy asymptomatic volunteers [19 men, median age 29 (22-56 years)] underwent upper GI endoscopy, 24 h pH/impedance measurement, and multimodal esophageal pain stimulation before and after sensitization with acid. Stimulus intensities at painful thresholds were recorded. KEY RESULTS Men had higher pain thresholds (PT) to mechanical stimulation (mean volume: men 20.9 ± 10 mL vs women 15.2 ± 6.8 mL, P = 0.02) and more men tolerated the maximum acid challenge (58% vs 20%, P = 0.03). There were no differences between genders for PT to (1) thermal stimulation [mean stimulation time (men, women): heat; 20 ± 5 s vs 21 ± 6 s or cold; 33.3 ± 20.1 s vs 20.7 ± 21.4 s, P > 0.2], (2) electrical current (mean current: men 17.6 ± 9.2 mA vs women 12.9 ± 3.7 mA, P = 0.11), or (3) acid volume [median volume: men 200 (20;200) mL vs women 133 (40;200) mL, P = 0.2]. Fifteen asymptomatic subjects had mild esophagitis (10 men, all Los Angeles A). There were no differences in esophageal PT between subjects with normal endoscopy or mild esophagitis (all P > 0.3). CONCLUSIONS & INFERENCES The effects of gender and mild esophagitis on esophageal multimodal pain perception have been measured in asymptomatic volunteers. The study suggests that gender, not mild esophagitis, tends to influence mechanical and chemical esophageal pain.
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Affiliation(s)
- A L Krarup
- Department of Internal Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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Liao D, Villadsen GE, Gregersen H. Distension-evoked motility analysis in human esophagus. Neurogastroenterol Motil 2013; 25:407-12, e296-7. [PMID: 23360205 DOI: 10.1111/nmo.12081] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Accepted: 12/11/2012] [Indexed: 01/11/2023]
Abstract
BACKGROUND The major function of the esophagus is to transport food from the mouth to the stomach by peristaltic muscle action. However, only few techniques exist for detailed evaluation of motor activity of the esophagus in vivo. The aim of this study is to use distension combined with manometry and impedance planimetry [pressure-cross-sectional area (P-CSA) recordings] to assess esophageal peristaltic motor function in terms of the mechanical energy output, and to examine the change in the motor activity of the esophagus in response to butylscopolamine, an anticholinergic drug known to impair the smooth muscle contraction in the gastrointestinal tract. METHODS The probe with CSA measurements was positioned 7 cm above the lower esophageal sphincter in 16 healthy volunteers before and during butylscopolamine administration. Distension-evoked esophageal peristalsis was analyzed using P-CSA data during distension up to pressures of 5 kPa. The P-CSA, work output (area of the tension-CSA curves), and propulsive tension were analyzed. KEY RESULTS The wave-like peristalsis resulted in P-CSA loops consisting of relaxation and contraction phases. The work increased with the distension pressure (from 1311 ± 198 to 16 330 ± 1845 μJ before butylscopolamine vs from 2615 ± 756 to 11 404 ± 1335 μJ during butylscopolamine administration), and propulsive tension increased from 18.7 ± 1.9 to 88.5 ± 5.5 N m(-1) before the drug and from 23.1 ± 3.9 to 79.5 ± 3.3 N m(-1) during butylscopolamine administration). Significantly, lower values were found during butylscopolamine administration compared with the distension before using the drug (P < 0.01). CONCLUSIONS & INFERENCES Esophageal muscle properties during peristalsis can be assessed in vivo in terms of mechanical energy output parameters. Butylscopolamine impaired muscle contraction which could be detected as altered contraction parameters. The analysis can be further used as an adjunct tool of the combined manometry and impedance planimetry recordings to derive advanced esophageal motor function parameters for studying the physiological and pathophysiological mechanical consequences of esophageal contractions.
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Affiliation(s)
- D Liao
- Mech-Sense, Department of Gastroenterology and Surgery, Aalborg University Hospital, Aalborg, Denmark.
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Krarup AL, Ny L, Gunnarsson J, Hvid-Jensen F, Zetterstrand S, Simrén M, Funch-Jensen P, Hansen MB, Drewes AM. Randomized clinical trial: inhibition of the TRPV1 system in patients with nonerosive gastroesophageal reflux disease and a partial response to PPI treatment is not associated with analgesia to esophageal experimental pain. Scand J Gastroenterol 2013; 48:274-84. [PMID: 23320520 DOI: 10.3109/00365521.2012.758769] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Many patients with nonerosive reflux disease (NERD) have insufficient relief on proton pump inhibitors (PPIs). Some patients have a hypersensitive esophagus and may respond to transient receptor potential vanilloid 1 (TRPV1) antagonists. Aim. To investigate the effect of the TRPV1 antagonist AZD1386 on experimental esophageal pain in NERD patients. MATERIAL AND METHODS Enrolled patients had NERD and a partial PPI response (moderate-to-severe heartburn or regurgitation ≥3 days/week before enrolment despite ≥6 weeks' PPI therapy). Fourteen patients (21-69 years, 9 women) were block-randomized into this placebo-controlled, double-blinded, crossover study examining efficacy of a single dose (95 mg) of AZD1386. On treatment days, each participant's esophagus was stimulated with heat, distension, and electrical current at teaching hospitals in Denmark and Sweden. Heat and pressure pain served as somatic control stimuli. Per protocol results were analyzed. RESULTS Of 14 randomized patients, 12 were treated with AZD1386. In the esophagus AZD1386 did not significantly change the moderate pain threshold for heat [-3%, 95% confidence interval (CI), -22;20%], distension (-11%, 95% CI, -28;10%), or electrical current (6%, 95% CI, -10;25%). Mean cutaneous heat tolerance increased by 4.9°C (95% CI, 3.7;6.2°C). AZD1386 increased the maximum body temperature by a mean of 0.59°C (95% CI, 0.40-0.79°C), normalizing within 4 h. CONCLUSIONS AZD1386 had no analgesic effect on experimental esophageal pain in patients with NERD and a partial PPI response, whereas it increased cutaneous heat tolerance. TRPV1 does not play a major role in heat-, mechanically and electrically evoked esophageal pain in these patients. ClinicalTrials.gov identifier: D9127C00002.
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Affiliation(s)
- Anne Lund Krarup
- Mech-Sense, Department of Gastroenterology and Hepatology, Aarhus University Hospital, Aalborg, Denmark.
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Olesen AE, Kristensen K, Staahl C, Kell S, Wong GY, Arendt-Nielsen L, Drewes AM. A population pharmacokinetic and pharmacodynamic study of a peripheral κ-opioid receptor agonist CR665 and oxycodone. Clin Pharmacokinet 2013; 52:125-37. [PMID: 23212610 DOI: 10.1007/s40262-012-0023-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
BACKGROUND Peripherally acting opioids, particularly peripheral κ-opioid agonists, may be effective for treating visceral pain by activating receptors expressed on afferent nerves within the gut. OBJECTIVE The objective of this study was to investigate the pharmacokinetic/pharmacodynamic profile of a novel peripherally selective κ-opioid agonist, CR665 (JNJ-38488502), and compare it to that of oxycodone, a non-selective brain-penetrant opioid. METHODS In a randomized, placebo-controlled, double-blind, three-way crossover study, healthy male volunteers were administered CR665 (0.36 mg/kg, intravenous), oxycodone (15 mg, oral) or placebo (intravenous and oral), followed by assessment of visceral pain tolerance thresholds (VPTT) measured as volume of water (mL) in the bag placed on an oesophageal probe. Plasma drug concentration data were used to generate pharmacokinetic models, which were then used to fit the VPTT data using NONMEM(®) VI to generate population pharmacokinetic/pharmacodynamic models. RESULTS CR665 kinetics were optimally fitted with a two-compartment model, while oxycodone kinetics were best described by a one-compartment model with transit compartment absorption feeding directly into the central compartment. For both drugs, the plasma concentration effects on VPTT were best fit by a direct linear model, i.e. without the concentration-analgesia delay characteristic of brain-penetrant opioids. The slope of oxycodone (0.089 mL per ng/mL) was steeper than that of CR665 (0.0035 mL per ng/mL) for the plasma drug concentration acting on the VPTT. CONCLUSION The results are consistent with the peripheral selectivity of CR665, as well as the possibility that peripheral actions of oxycodone contribute to its visceral analgesic efficacy.
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Affiliation(s)
- Anne E Olesen
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark.
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Remes-Troche JM, Attaluri A, Chahal P, Rao SS. Barostat or dynamic balloon distention test: which technique is best suited for esophageal sensory testing? Dis Esophagus 2012; 25:584-9. [PMID: 22168228 PMCID: PMC4038032 DOI: 10.1111/j.1442-2050.2011.01294.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Esophageal sensation is commonly assessed by barostat-assisted balloon distension (BBD) or dynamic balloon distension (DBD) technique, but their relative merits are unknown. Our aim was to compare the usefulness and tolerability of both techniques. Sixteen healthy volunteers (male/female = 6/10) randomly underwent graded esophageal balloon distensions, using either BBD (n= 8) or DBD (n= 8). BBD was performed by placing a 5-cm long highly compliant balloon attached to a barostat, and DBD by placing a 5-cm long balloon attached to a leveling container. Intermittent phasic balloon distensions were performed in increments of 6 mm Hg. Sensory thresholds and biomechanical properties were assessed and compared. Sensory thresholds for first perception (mean ± standard deviation; 21 ± 6 vs. 21.2 ± 5, mm Hg, P= 0.9), discomfort (38 ± 8 vs. 35 ± 9, P= 0.5), and pain (44 ± 4 vs. 45 ± 3, P= 0.7) were similar with BBD and DBD techniques. However, more subjects tolerated DBD (7/8, 88%) when compared with BBD (4/8, 50%). Forceful expulsion of balloon into stomach (n= 4), pulling around the mouth (n= 4), chest discomfort (n= 2) and retching (n= 2) were overlapping reasons for intolerance with BBD. Esophageal wall distensibility was similar with both techniques. Both techniques provided comparable data on biomechanical properties. However, DBD was better tolerated than BBD for evaluation of esophageal sensation. Hence, we recommend DBD for performing esophageal balloon distension test.
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Affiliation(s)
- Jose M. Remes-Troche
- Division of Neurogastroenterology and Motility, Department of Internal Medicine and Clinical Translational Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa,Digestive Physiology and Motility Department, Medical-Biological Research Institute, University of Veracruz, Mexico
| | - Ashok Attaluri
- Division of Neurogastroenterology and Motility, Department of Internal Medicine and Clinical Translational Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Premjit Chahal
- Division of Neurogastroenterology and Motility, Department of Internal Medicine and Clinical Translational Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Satish S.C. Rao
- Division of Neurogastroenterology and Motility, Department of Internal Medicine and Clinical Translational Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa
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McMahon BP, Rao SSC, Gregersen H, Kwiatek MA, Pandolfino JE, Drewes AM, Krarup AL, Lottrup C, Frøkjaer JB. Distensibility testing of the esophagus. Ann N Y Acad Sci 2011; 1232:331-40. [PMID: 21950823 DOI: 10.1111/j.1749-6632.2011.06069.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The following contains commentaries on distensibility testing using the functional lumen imaging probe (FLIP); the use of the distention test of the esophageal body in the clinic diagnosis of noncardiac chest pain; the functional lumen imaging in gastroesophageal reflux disease-impaired esophagogastric junction; a multimodal pain model for the esophagus; the rationale for distensibility testing; and further developments in standardized distension protocols.
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Affiliation(s)
- Barry P McMahon
- Department of Medical Physics & Clinical Engineering and Trinity College, Adelaide & Meath Hospital, Dublin, Ireland
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Falk GW, Jacobson BC, Riddell RH, Rubenstein JH, El-Zimaity H, Drewes AM, Roark KS, Sontag SJ, Schnell TG, Leya J, Chejfec G, Richter JE, Jenkins G, Goldman A, Dvorak K, Nardone G. Barrett's esophagus: prevalence-incidence and etiology-origins. Ann N Y Acad Sci 2011; 1232:1-17. [PMID: 21950804 DOI: 10.1111/j.1749-6632.2011.06042.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Although the prevalence of Barrett's esophagus (BE) is rising no data exist for racial minorities on prevalence in the general population. Minorities have a lower prevalence than Caucasians, and yet age, smoking, abdominal obesity, and Helicobacter pylori are all risk factors. Metabolic changes induced by adipocytokines and the apparently strong association between obesity, central adiposity, and BE may lead to reconsideration of some aspects of the natural history of BE. There is lack of experimental evidence on acid sensitivity and BE, which is hyposensitive compared to esophageal reflux disease. Reactive nitrogen and oxygen species lead to impaired expression of tumor suppressor genes, which can lead to cancer development; thus, antioxidants may be protective. Gastroesophageal reflux disease may be considered an immune-mediated disease starting at the submucosal layer; the cytokine profile of the mucosal immune response may explain the different outcome of gastroesophageal reflux.
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Affiliation(s)
- Gary W Falk
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
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Arendt-Nielsen L, Hoeck HC. Optimizing the early phase development of new analgesics by human pain biomarkers. Expert Rev Neurother 2011; 11:1631-1651. [DOI: 10.1586/ern.11.147] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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Gregersen H, Drewes AM, Frøkjaer JB, Krarup AL, Lottrup C, Farmer AD, Aziz Q, Hobson AR. Mechanism-based evaluation and treatment of esophageal disorders. Ann N Y Acad Sci 2011; 1232:341-8. [DOI: 10.1111/j.1749-6632.2011.06068.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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The pain system in oesophageal disorders: mechanisms, clinical characteristics, and treatment. Gastroenterol Res Pract 2011; 2011:910420. [PMID: 21826137 PMCID: PMC3150142 DOI: 10.1155/2011/910420] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2011] [Accepted: 05/23/2011] [Indexed: 12/14/2022] Open
Abstract
Pain is common in gastroenterology. This review aims at giving an overview of pain mechanisms, clinical features, and treatment options in oesophageal disorders. The oesophagus has sensory receptors specific for different stimuli. Painful stimuli are encoded by nociceptors and communicated via afferent nerves to the central nervous system. The pain stimulus is further processed and modulated in specific pain centres in the brain, which may undergo plastic alterations. Hence, tissue inflammation and long-term exposure to pain can cause sensitisation and hypersensitivity. Oesophageal sensitivity can be evaluated ,for example, with the oesophageal multimodal probe. Treatment should target the cause of the patient's symptoms. In gastro-oesophageal reflux diseases, proton pump inhibitors are the primary treatment option, surgery being reserved for patients with severe disease resistant to drug therapy. Functional oesophageal disorders are treated with analgesics, antidepressants, and psychological therapy. Lifestyle changes are another option with less documentation.
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The esophageal multimodal pain model: normal values and degree of sensitization in healthy young male volunteers. Dig Dis Sci 2011; 56:1967-75. [PMID: 21221787 DOI: 10.1007/s10620-010-1546-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2010] [Accepted: 12/18/2010] [Indexed: 02/06/2023]
Abstract
BACKGROUND Sensory changes are thought to be involved in gastro-esophageal reflux disease (GERD). The esophageal multimodal pain model can be used to investigate sensations in response to distension, heat, electric current and acid. AIMS The aim of this study was to provide normal values for this model in the normal state and in the acid induced sensitized state. METHODS Fifty-three healthy men (20-38 years old) underwent esophageal stimulation with distension, heat and electrical current before and after sensitization with 0.1 N HCl acid. Stimulus intensities at painful and non-painful thresholds and referred pain areas were measured. The percentage of individual participants sensitized to each modality was calculated. In 22 subjects the pre-acid tests were repeated on three subsequent visits. RESULTS To reach moderate pain, subjects tolerated mean distension of 29.1 ± 11 mL, heat stimulation time of 141 ± 33 s, and mean current of 17.6 ± 6.4 mA. After acid exposure, significantly reduced thresholds were observed for mechanical (24%), heat (11%) and electrical (14%) stimulation (P values < 0.05). The percentage of subjects sensitized, defined as reductions in thresholds of ≥10% or ≥20% after acid perfusion, was as follows: for distension 77%/62%, for heat 48%/28%, and for current 58%/44%. The model showed good reliability (intra-class correlations >0.6). CONCLUSIONS Normal values for healthy young men are now provided for the normal and the sensitized state. The percentage of subjects sensitized after acid stimulation are thoroughly documented, and depends on stimulation type and the cut-off value chosen.
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Krarup AL, Ny L, Astrand M, Bajor A, Hvid-Jensen F, Hansen MB, Simrén M, Funch-Jensen P, Drewes AM. Randomised clinical trial: the efficacy of a transient receptor potential vanilloid 1 antagonist AZD1386 in human oesophageal pain. Aliment Pharmacol Ther 2011; 33:1113-22. [PMID: 21410733 DOI: 10.1111/j.1365-2036.2011.04629.x] [Citation(s) in RCA: 109] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Many patients with gastro-oesophageal reflux disease (GERD) are hypersensitive to heat and acid and may respond insufficiently to standard treatment. Antagonists of the heat and acid receptor 'transient receptor potential vanilloid 1'(TRPV1) are a potential drug class for GERD treatment. AIM To investigate the effect of a TRPV1 antagonist (AZD1386) on experimentally induced oesophageal pain. METHODS Twenty-two healthy men (20-31 years) participated in this randomised, placebo-controlled, double-blinded, crossover study examining the effects of a single-dose oral AZD1386 (30 and 95 mg). Subjects were block-randomised. On treatment days, participants were stimulated with painful heat, distension, electrical current and acid in the oesophagus. Heat and pressure pain on the forearm were somatic control stimuli. DATA ANALYSIS intention-to-treat. RESULTS A total of 21 participants completed the protocol and 1 voluntarily discontinued. In the oesophagus, both 30 and 95 mg of AZD1386 increased pain thresholds to heat stimuli 23% [95% confidence interval (CI): 10-38%] and 28%, respectively (CI: 14-43%). The skin heat tolerance was increased 2.1 °C (CI: 1.1-3.2 °C) after 30 mg AZD1386 and 4.0 °C (CI: 3.0-5.0 °C) after 95 mg. Heat analgesia persisted for 2.5 h. Pain thresholds to the other stimuli were unaffected by AZD1386. 50% reported 'feeling cold' and body temperature increased in all subjects exposed to 30 and 95 mg AZD1386 (mean increase 0.4±0.3 °C and 0.7±0.3 °C, respectively, P<0.05). CONCLUSIONS AZD1386 increased oesophageal and skin heat pain thresholds and had a safe adverse-event profile. This drug class may have a potential for treatment of GERD.
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Affiliation(s)
- A L Krarup
- Mech-Sense, Department of Gastroenterology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark
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Krarup AL, Olesen SS, Funch-Jensen P, Gregersen H, Drewes AM. Proximal and distal esophageal sensitivity is decreased in patients with Barrett’s esophagus. World J Gastroenterol 2011; 17:514-21. [PMID: 21274382 PMCID: PMC3027019 DOI: 10.3748/wjg.v17.i4.514] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2010] [Revised: 09/18/2010] [Accepted: 09/25/2010] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate sensations to multimodal pain stimulation in the metaplastic and normal parts of the esophagus in patients with Barrett’s esophagus (BE).
METHODS: Fifteen patients with BE and 15 age-matched healthy volunteers were subjected to mechanical, thermal and electrical pain stimuli of the esophagus. Both the metaplastic part and the normal part (4 and 14 cm, respectively, above the esophago-gastric junction) were examined. At sensory thresholds the stimulation intensity, referred pain areas, and evoked brain potentials were recorded.
RESULTS: Patients were hyposensitive to heat stimulation both in the metaplastic part [median stimulation time to reach the pain detection threshold: 15 (12-34) s vs 14 (6-23) s in controls; F = 4.5, P = 0.04] and the normal part of the esophagus [median 17 (6-32) s vs 13 (8-20) s in controls; F = 6.2, P = 0.02]. Furthermore, patients were hyposensitive in the metaplastic part of the esophagus to mechanical distension [median volume at moderate pain: 50 (20-50) mL vs 33 (13-50) mL in controls; F = 5.7, P = 0.02]. No indication of central nervous system abnormalities was present, as responses were comparable between groups to electrical pain stimuli in the metaplastic part [median current evoking moderate pain: 13 (6-26) mA vs 12 (9-24) mA in controls; F = 0.1, P = 0.7], and in the normal part of the esophagus [median current evoking moderate pain: 9 (6-16) mA, vs 11 (5-11) mA in controls; F = 3.4, P = 0.07]. Furthermore, no differences were seen for the referred pain areas (P-values all > 0.3) or latencies and amplitudes for the evoked brain potentials (P-values all > 0.1).
CONCLUSION: Patients with BE are hyposensitive both in the metaplastic and normal part of esophagus likely as a result of abnormalities affecting peripheral nerve pathways.
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Olesen AE, Staahl C, Arendt-Nielsen L, Drewes AM. Different effects of morphine and oxycodone in experimentally evoked hyperalgesia: a human translational study. Br J Clin Pharmacol 2011; 70:189-200. [PMID: 20653672 DOI: 10.1111/j.1365-2125.2010.03700.x] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * Previous studies using short-lasting experimental pain stimulations in healthy volunteers have shown differences in opioid effects regarding visceral pain stimulations. However, these differences can be more pronounced in patients due to a sensitized pain system. Therefore, the aim of the present study was to mimic the clinical situation by investigating opioid effects on experimental pain in healthy volunteers after experimentally evoked hyperalgesia. WHAT THIS STUDY ADDS? * We now know that morphine and oxycodone exerts different effects in the sensitized pain system as we found a greater analgesic effect of oxycodone in response to skin, muscle and oesophageal pain stimulation. This supports clinicians' experiences that oxycodone can be superior to morphine in the treatment of some pain conditions. The evoked hyperalgesia bridged findings from studies in healthy volunteers to patients, and new fundamental knowledge on different analgesic effects in hyperalgesia was found. AIM Similar analgesics may have different analgesic potencies especially in patients in whom the pain system is sensitized. The aim was to investigate different opioid effects on experimental pain after the sensitized pain system was mimicked evoking hyperalgesia in healthy volunteers. METHODS Twenty-four healthy volunteers were randomized to treatment with morphine (30 mg orally) and oxycodone (15 mg orally) or placebo in a double-blind crossover study. Hyperalgesia was induced by oesophageal perfusion with acid and capsaicin. Several exploratory endpoints were studied using skin heat, muscle pressure and oesophageal mechanical, heat and electrical stimulation. Effects on pain from deeper structures were considered most important. RESULTS Different analgesic potencies were found. Oxycodone had a greater analgesic effect than morphine attenuating pain from: (i) heat stimulation of skin (P= 0.016); difference between the means of 0.39 degrees C, 95% CI 0.22, 2.09. (ii) muscle pressure (P < 0.001); difference between the means of 11.93kPa, 95% CI 5.4, 18.5. (iii) oesophageal heat stimulation (P < 0.001); difference between the means of 38.54 cm(2), 95% CI 15.37, 61.71 and (iv) oesophageal electrical stimulation (P= 0.016); difference between the means of 6.69mA, 95% CI 1.23, 12.13. CONCLUSION After sensitization of the pain system different analgesic potencies of morphine and oxycodone were found in response to skin, muscle and oesophageal pain stimulation, in which oxycodone had a greater effect. As similar differential analgesic potencies of the two opioids have been found in patients with chronic pain, the experimental hyperalgesia model bridged findings from studies in healthy volunteers to patients.
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Affiliation(s)
- Anne Estrup Olesen
- Mech-Sense, Department of Gastroenterology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark.
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The hypersensitive esophagus: pathophysiology, evaluation, and treatment options. Curr Gastroenterol Rep 2011; 12:417-26. [PMID: 20669058 DOI: 10.1007/s11894-010-0122-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Visceral hypersensitivity plays a key role in the pathogenesis of esophageal functional disorders such as functional heartburn and chest pain of presumed esophageal origin (noncardiac chest pain). About 80% of patients with unexplained noncardiac chest pain exhibit lower esophageal sensory thresholds when compared to controls during esophageal sensory testing (ie, esophageal barostat, impedance planimetry). Such information has led to prescription of peripherally and/or centrally acting therapies for the management of these patients. This review summarizes and highlights recent and significant findings regarding the pathophysiology, evaluation, and treatment of the hypersensitive esophagus, a central factor in functional esophageal disorders.
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Takemura Y, Furuta S, Hirayama S, Miyashita K, Imai S, Narita M, Kuzumaki N, Tsukiyama Y, Yamazaki M, Suzuki T, Narita M. Upregulation of bradykinin receptors is implicated in the pain associated with caerulein-induced acute pancreatitis. Synapse 2010; 65:608-16. [DOI: 10.1002/syn.20880] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2010] [Accepted: 09/23/2010] [Indexed: 01/01/2023]
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