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Gonzalez-Ibarra F, Cruz-Ruiz M, Llanes JM, Achem SR, Fass R. The Role of Psychological Factors in Noncardiac Chest Pain of Esophageal Origin. J Neurogastroenterol Motil 2024; 30:272-280. [PMID: 38972864 PMCID: PMC11238108 DOI: 10.5056/jnm23166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Revised: 01/17/2024] [Accepted: 03/10/2024] [Indexed: 07/09/2024] Open
Abstract
Background/Aims Noncardiac chest pain (NCCP) of esophageal origin is a challenging clinical problem of diverse etiology that affects more than 80 million Americans yearly. We assess the prevalence and impact of psychological disorders on NCCP of esophageal origin, describe possible mechanisms associated with this condition, and review psychological therapy options. Methods Online search using PubMed and Medline from January 1, 1966, to April 30, 2023. Results Psychological disorders have been reported in up to 79% of patients with NCCP of esophageal origin. Several psychological disturbances have been identified with this condition, including depression, anxiety, panic disorder, phobias, and obsessive-compulsive and somatoform disorders. It is unclear whether the psychological disorders trigger the chest pain or vice versa. Multiple psychological mechanisms have been linked to chest pain and may contribute to its pathogenesis and severity. These mechanisms include cardiophobia, poor coping strategies, negative social problem solving, stress and perceived control, hypervigilance to cardiopulmonary sensations, altered pain perception, and alexithymia. Psychological therapies for NCCP of esophageal origin include cognitive behavioral therapy, hypnotherapy, physical and relaxation training, breathing retraining, and alternative medicine. Among the therapeutic options, cognitive behavioral therapy has been shown to be an effective treatment for NCCP of esophageal origin. Conclusion This review raises awareness about the high prevalence of psychological disorders in NCCP of esophageal origin and highlights the need for clinical trials and trained therapists to address the management of this taxing clinical problem.
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Affiliation(s)
| | | | - Joel Murillo Llanes
- Department of Research, Sinaloa Health Services, Women’s Hospital, Sinaloa, Mexico
| | - Sami R Achem
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| | - Ronnie Fass
- Digestive Health Center, Division of Gastroenterology and Hepatology, MetroHealth Medical Center, Cleveland, OH, USA
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2
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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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3
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Mermelstein J, Chait Mermelstein A, Chait MM. Proton pump inhibitor-refractory gastroesophageal reflux disease: challenges and solutions. Clin Exp Gastroenterol 2018; 11:119-134. [PMID: 29606884 PMCID: PMC5868737 DOI: 10.2147/ceg.s121056] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
A significant percentage of patients with gastroesophageal reflux disease (GERD) will not respond to proton pump inhibitor (PPI) therapy. The causes of PPI-refractory GERD are numerous and diverse, and include adherence, persistent acid, functional disorders, nonacid reflux, and PPI bioavailability. The evaluation should start with a symptom assessment and may progress to imaging, endoscopy, and monitoring of esophageal pH, impedance, and bilirubin. There are a variety of pharmacologic and procedural interventions that should be selected based on the underlying mechanism of PPI failure. Pharmacologic treatments can include antacids, prokinetics, alginates, bile acid binders, reflux inhibitors, and antidepressants. Procedural options include laparoscopic fundoplication and LINX as well as endoscopic procedures, such as transoral incisionless fundoplication and Stretta. Several alternative and complementary treatments of possible benefit also exist.
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Affiliation(s)
- Joseph Mermelstein
- Gasteroenterology and Nutrition Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alanna Chait Mermelstein
- Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maxwell M Chait
- Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
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4
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Determinants of the Association between Non-Cardiac Chest Pain and Reflux. Am J Gastroenterol 2017; 112:1671-1677. [PMID: 29016562 DOI: 10.1038/ajg.2017.288] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 08/08/2017] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Gastroesophageal reflux is considered to be the most common gastrointestinal cause of non-cardiac chest pain (NCCP). It remains unclear why some reflux episodes in the same patient cause chest pain while others do not. To understand more about the mechanisms by which reflux elicits chest pain, we aimed to identify factors which are important in triggering chest pain. METHODS In this multicenter study, 120 patients with NCCP were analyzed using 24-h pH-impedance monitoring. In the patients with a positive association between reflux and chest pain, the characteristics of the reflux episodes which were followed by a chest pain episode were compared with chest pain-free reflux episodes. RESULTS Using 24-h pH-impedance monitoring, 40% of the NCCP patients were identified as having reflux as a possible cause of their chest pain. Reflux episodes that were associated with chest pain had a higher proximal extent (P=0.007), a higher volume clearance time (P=0.030), a higher 15-minute acid burden (P=0.041), were more often acidic (P=0.011), had a lower nadir pH (P=0.044), and had a longer acid duration time (P=0.027) than reflux episodes which were not followed by chest pain. Patients who experienced typical reflux symptoms were more likely to have reflux as the cause of their chest pain (52 vs. 31.4%, P=0.023). CONCLUSIONS The presence of a larger volume of acid refluxate for a longer period of time appears to be an important determinant of perceiving a reflux episode as chest pain. 24-h pH-impedance monitoring is an important tool in identifying gastroesophageal reflux as a potential cause of symptoms in patients with NCCP.
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5
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Min YW, Rhee PL. Esophageal hypersensitivity in noncardiac chest pain. Ann N Y Acad Sci 2016; 1380:27-32. [PMID: 27496289 DOI: 10.1111/nyas.13182] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 06/13/2016] [Accepted: 06/20/2016] [Indexed: 01/04/2025]
Abstract
Noncardiac chest pain (NCCP) is an often-encountered clinical problem. Although many patients suffer from persistent or recurrent chest pain, treatment remains a challenge owing to its various possible etiologies. Gastroesophageal reflux disease (GERD) is the most common cause of NCCP. In GERD-related NCCP, proton pump inhibitor treatment appears to be effective. However, the pathophysiology remains to be fully elucidated in NCCP patients without GERD. Treatment for non-GERD-related NCCP has been aimed at esophageal motility disorders and visceral hypersensitivity. As there is growing evidence that esophageal visceral hypersensitivity plays a role in NCCP, pain modulators have become the mainstay of therapy in patients with non-GERD-related NCCP. However, there is an unmet need for the treatment of esophageal hypersensitivity in NCCP due to modest evidence for the benefit of pain modulators, including antidepressants, in non-GERD-related NCCP. Recent studies have demonstrated that esophageal mast cell infiltration and impaired mucosal integrity are related to visceral hypersensitivity in patients with NCCP. Thus, esophageal mast cell stabilization and restoration of esophageal mucosal integrity could be considered potential therapeutic targets in selected NCCP patients with hypersensitivity. However, further observations are necessary to shed light on esophageal hypersensitivity in NCCP.
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Affiliation(s)
- Yang Won Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Poong-Lyul Rhee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
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6
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Zhao J, Gregersen H. Diabetes-induced mechanophysiological changes in the esophagus. Ann N Y Acad Sci 2016; 1380:139-154. [PMID: 27495976 DOI: 10.1111/nyas.13180] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 06/17/2016] [Accepted: 06/20/2016] [Indexed: 12/13/2022]
Abstract
Esophageal disorders are common in diabetes mellitus (DM) patients. DM induces mechanostructural remodeling in the esophagus of humans and animal models. The remodeling is related to esophageal sensorimotor abnormalities and to symptoms frequently encountered by DM patients. For example, gastroesophageal reflux disease (GERD) is a common disorder associated with DM. This review addresses diabetic remodeling of esophageal properties and function in light of the Esophagiome, a scientifically based modeling effort to describe the physiological dynamics of the normal, intact esophagus built upon interdisciplinary approaches with applications for esophageal disease. Unraveling the structural, biomechanical, and sensory remodeling of the esophagus in DM must be based on a multidisciplinary approach that can bridge the knowledge from a variety of scientific disciplines. The first focus of this review is DM-induced morphodynamic and biomechanical remodeling in the esophagus. Second, we review the sensorimotor dysfunction in DM and how it relates to esophageal remodeling. Finally, we discuss the clinical consequences of DM-induced esophageal remodeling, especially in relation to GERD. The ultimate aim is to increase the understanding of DM-induced remodeling of esophageal structure and sensorimotor function in order to assist clinicians to better understand the esophageal disorders induced by DM and to develop better treatments for those patients.
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Affiliation(s)
- Jingbo Zhao
- Giome Academia, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
| | - Hans Gregersen
- GIOME, Department of Surgery, Prince of Wales Hospital and Chinese University of Hong Kong, Shatin, Hong Kong SAR.,GIOME, College of Bioengineering, Chongqing University, Chongqing, China
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Emerenziani S, Ribolsi M, Guarino MPL, Balestrieri P, Altomare A, Rescio MP, Cicala M. Acid reflux episodes sensitize the esophagus to perception of weakly acidic and mixed reflux in non-erosive reflux disease patients. Neurogastroenterol Motil 2014; 26:108-14. [PMID: 24118616 DOI: 10.1111/nmo.12239] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2013] [Accepted: 08/29/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND Non-erosive reflux disease (NERD) patients are more sensitive than erosive esophagitis patients to weakly acidic reflux and to the presence of gas in the refluxate. Intra-esophageal acid perfusion sensitizes esophageal receptors to mechanical and chemical stimuli. METHODS To establish whether acid sensitization plays a role in the perception of weakly acidic and mixed reflux episodes, 29 NERD patients, responders and 14 non-responders to proton pump inhibitors (PPIs), underwent pH-impedance monitoring. Non-responders repeated the study while on PPIs. To assess the effect of acid exposure on symptom perception, the time period with pH below 4 was measured in 15- and 30-minute time-windows preceding the onset of each reflux episode. KEY RESULTS Considering weakly acidic and mixed refluxes, both in responder and non-responder patients (off PPIs), the symptomatic refluxes were preceded by a significantly higher cumulative acid exposure than the asymptomatic refluxes. In all patients, following acid reflux, the percentage of symptomatic weakly acidic reflux episodes was significantly higher than that of asymptomatic refluxes. Non-responder patients, off-treatment, were characterized by a lower proportion of weakly acidic reflux and mixed reflux episodes. In the non-responder patients on PPI, only mixed and weakly symptomatic reflux episodes were preceded by a higher cumulative acid exposure. CONCLUSIONS & INFERENCES In NERD patients, spontaneous acid reflux enhances subsequent reflux perception, regardless of acidity or liquid/mixed composition of episodes; in non-responder patients on PPIs, only the perception of mixed and weakly acidic reflux episodes seems to be mediated by a preceding acid exposure.
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Affiliation(s)
- S Emerenziani
- Unit of Digestive Disease, Campus Bio Medico University, Roma, Italy
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8
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Fass R, Achem SR. Noncardiac chest pain: epidemiology, natural course and pathogenesis. J Neurogastroenterol Motil 2011; 17:110-23. [PMID: 21602987 PMCID: PMC3093002 DOI: 10.5056/jnm.2011.17.2.110] [Citation(s) in RCA: 123] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2011] [Revised: 03/17/2011] [Accepted: 03/28/2011] [Indexed: 12/24/2022] Open
Abstract
Noncardiac chest pain is defined as recurrent chest pain that is indistinguishable from ischemic heart pain after a reasonable workup has excluded a cardiac cause. Noncardiac chest pain is a prevalent disorder resulting in high healthcare utilization and significant work absenteeism. However, despite its chronic nature, noncardiac chest pain has no impact on patients' mortality. The main underlying mechanisms include gastroesophageal reflux, esophageal dysmotility and esophageal hypersensitivity. Gastroesophageal reflux disease is likely the most common cause of noncardiac chest pain. Esophageal dysmotility affects only the minority of noncardiac chest pain patients. Esophageal hypersensitivity may be present in non-GERD-related noncardiac chest pain patients regardless if esophageal dysmotility is present or absent. Psychological co-morbidities such as panic disorder, anxiety, and depression are also common in noncardiac chest pain patients and often modulate patients' perception of disease severity.
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Affiliation(s)
- Ronnie Fass
- Section of Gastroenterology, Department of Medicine, Southern Arizona VA Health Care System, Tucson, Arizona, USA.
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9
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Wang K, Duan LP, Zeng XZ, Liu JY, Xu-Chu W. Differences in cerebral response to esophageal acid stimuli and psychological anticipation in GERD subtypes--an fMRI study. BMC Gastroenterol 2011; 11:28. [PMID: 21439078 PMCID: PMC3073936 DOI: 10.1186/1471-230x-11-28] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2010] [Accepted: 03/26/2011] [Indexed: 12/14/2022] Open
Abstract
Background To evaluate whether there are differences in the cerebral response to intraesophageal acid and psychological anticipation stimuli among subtypes of gastroesophageal reflux disease (GERD). Methods Thirty nine patients with GERD and 11 healthy controls were enrolled in this study after gastroscopy and 24 hr pH monitoring. GERD subjects were divided into four subgroups: RE (reflux esophagitis), NERD+ (non-erosive reflux disease with excessive acid reflux), NERD-SI+ (normal acid exposure and positive symptom index) and NERD-SI+ (normal acid exposure and negative symptom index, but responded to proton pump inhibitor trial). Cerebral responses to intraesophageal acid and psychological anticipation were evaluated with fMRI. Results During intraesophageal acid stimulation, the prefrontal cortex (PFC) region was significantly activated in all subgroups of GERD; the insular cortex (IC) region was also activated in RE, NERD+ and NERD-SI- groups; the anterior cingulated cortex (ACC) region was activated only in RE and NERD-SI- groups. The RE subgroup had the shortest peak time in the PFC region after acid was infused, and presented the greatest change in fMRI signals in the PFC and ACC region (P = 0.008 and P = 0.001, respectively). During psychological anticipation, the PFC was significantly activated in both the control and GERD groups. Activation of the IC region was found in the RE, NERD-SI+ and NERD-SI- subgroups. The ACC was activated only in the NERD-SI+ and NERD-SI- subgroups. In the PFC region, the NERD-SI- subgroup had the shortest onset time (P = 0.008) and peak time (P < 0.001). Compared with actual acid infusion, ACC in RE and IC in NERD+ were deactivated while additional areas including the IC and ACC were activated in the NERD-SI+ group; and in NERD-SI- group, onset-time and peak time in the PFC and IC areas were obviously shorter in induced anticipation than in actual acid infusion. Conclusions The four subgroups of GERD patients and controls showed distinctly different activation patterns and we therefore conclude GERD patients have different patterns of visceral perception and psychological anticipation. Psychological factors play a more important role in NERD-SI+ and NERD-SI- groups than in RE and NERD+ groups.
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Affiliation(s)
- Kun Wang
- Department of Gastroenterology, Peking University Third Hospital, Beijing, 100191, PR China
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10
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Abstract
Noncardiac chest pain (NCCP) is not only a difficult disorder to define but is also complex in characterization and treatment. Patients with NCCP are a challenge to primary care and subspecialty services such as cardiology and gastroenterology. NCCP is often a heterogeneous disorder with many potential causes including gastroenterologic diagnoses. This article presents the current evidence for gastroesophageal reflux disease as a cause of NCCP and highlights the best currently available tests for this group of patients.
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Affiliation(s)
- Amanke C Oranu
- Division of Gastroenterology, Hepatology and Nutrition, Center for Swallowing and Esophageal Disorders, Vanderbilt University Medical Center, TVC 1660, Nashville, TN 37232-5280, USA
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11
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Banerjee B, Medda BK, Schmidt J, Zheng Y, Zhang Z, Shaker R, Sengupta JN. Altered expression of P2X3 in vagal and spinal afferents following esophagitis in rats. Histochem Cell Biol 2009; 132:585-97. [PMID: 19784665 DOI: 10.1007/s00418-009-0639-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/02/2009] [Indexed: 11/28/2022]
Abstract
Purinergic P2X(3) receptors are predominantly expressed in small diameter primary afferent neurons and activation of these receptors by adenosine triphosphate is reported to play an important role in nociceptive signaling. The objective of this study was to investigate the expression of P2X(3) receptors in spinal and vagal sensory neurons and esophageal tissues following esophagitis in rats. Two groups of rats were used including 7 days fundus-ligated (7D-ligated) esophagitis and sham-operated controls. Esophagitis was produced by ligating the fundus and partial obstruction of pylorus that initiated reflux of gastric contents. The sham-operated rats underwent midline incision without surgical manipulation of the stomach. Expressions of P2X(3) receptors in thoracic dorsal root ganglia (DRGs), nodose ganglia (NGs), and esophageal tissues were evaluated by RT-PCR, western blot and immunohistochemistry. Esophageal neurons were identified by retrograde transport of Fast Blue from the esophagus. There were no significant differences in P2X(3) mRNA expressions in DRGs (T1-T3) and NGs between 7D-ligated and sham-operated rats. However, there was an upregulation of P2X(3) mRNA in DRGs (T6-T12) and in the esophageal muscle. At protein level, P2X(3) exhibited significant upregulation both in DRGs and in NGs of rats having chronic esophagitis. Immunohistochemical analysis exhibited a significant increase in P2X(3) and TRPV1 co-expression in DRGs and NGs in 7D-ligated rats compared to sham-operated rats. The present findings suggest that chronic esophagitis results in upregulation of P2X(3) and its co-localization with TRPV1 receptor in vagal and spinal afferents. Changes in P2X(3) expression in vagal and spinal sensory neurons may contribute to esophageal hypersensitivity following acid reflux-induced esophagitis.
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Affiliation(s)
- Banani Banerjee
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
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12
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Gastroesophageal reflux disease is associated with the C825T polymorphism in the G-protein beta3 subunit gene (GNB3). Am J Gastroenterol 2009; 104:281-5. [PMID: 19174793 DOI: 10.1038/ajg.2008.139] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Visceral hypersensitivity is involved in the etiology of reflux symptoms. Familial clustering and twin studies demonstrated a genetic predisposition to gastroesophageal reflux disease (GERD). G-protein-coupled receptors (GPCRs) mediate the response to acid, neurotransmitters and humoral factors modulating esophageal sensory function. Thus, polymorphisms in G-proteins are putative genetic factors contributing to GERD manifestation. A functional polymorphism in the G-protein beta3 subunit gene (GNB3) is associated with functional dyspepsia (FD), in which visceral hypersensitivity is implicated in symptom generation. We evaluated the association of the GNB3 C825T polymorphism with GERD and GERD subgroups classified according to esophageal acid exposure time, symptom-reflux correlation, or coexistence of FD and/or irritable bowel syndrome (IBS) symptoms. METHODS In total, 363 GERD patients, defined as having esophageal pH < 4 > or = 6% of time and/or symptom index (SI) > or = 50% or symptom association probability (SAP) > or = 95%, participated. In addition, 373 healthy controls free of gastrointestinal symptoms were studied. Genotyping was performed by molecular beacon assay. RESULTS The CT genotype was more prevalent in GERD patients relative to healthy controls (adjusted odds ratio (OR)=1.43, 95% CI 1.04-1.98). GERD patients sensitive to physiological amounts of reflux displayed a higher OR (1.59), as did GERD patients with a positive symptom association score (1.50). The strongest association was detected in patients without concomitant FD and/or IBS symptoms (OR=1.66). CONCLUSIONS GERD is associated with GNB3 C825T. The results for GERD subgroups support the hypothesis that enhanced perception of reflux events, as a consequence of the increased signal transduction upon GPCR activation associated with the 825T allele, underlies this association.
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13
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Banerjee B, Medda BK, Zheng Y, Miller H, Miranda A, Sengupta JN, Shaker R. Alterations in N-methyl-D-aspartate receptor subunits in primary sensory neurons following acid-induced esophagitis in cats. Am J Physiol Gastrointest Liver Physiol 2009; 296:G66-77. [PMID: 18974310 PMCID: PMC2636931 DOI: 10.1152/ajpgi.90419.2008] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The excitatory amino acid glutamate plays an important role in the development of neuronal sensitization and the ionotropic N-methyl-d-aspartate receptor (NMDAR) is one of the major receptors involved. The objective of this study was to use a cat model of gastroesophageal reflux disease (GERD) to investigate the expression of the NR1 and NR2A subunits of NMDAR in the vagal and spinal afferent fibers innervating the esophagus. Two groups of cats (Acid-7D and PBS-7D) received 0.1 N HCl (pH 1.2) or 0.1 M PBS (pH 7.4) infusion in the esophagus (1 ml/min for 30 min/day for 7 days), respectively. NR1 splice variants (both NH(2) and COOH terminals) and NR2A in the thoracic dorsal root ganglia (DRGs), nodose ganglia (NGs), and esophagus were evaluated by RT-PCR, Western blot, and immunohistochemistry. Acid produced marked inflammation and a significant increase in eosinophil peroxidase and myeloperoxidase contents compared with PBS-infused esophagus. The NR1-4 splice variant gene exhibited a significant upregulation in DRGs and esophagus after acid infusion. In DRGs, NGs, and esophagus, acid infusion resulted in significant upregulation of NR1 and downregulation of NR2A subunit gene expression. A significant increase in NR1 polypeptide expression was observed in DRGs and NGs from Acid-7D compared with control. In conclusion, long-term acid infusion in the cat esophagus resulted in ulcerative esophagitis and differential expressions of NR1 and NR2A subunits. It is possible that these changes may in part contribute to esophageal hypersensitivity observed in reflux esophagitis.
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Affiliation(s)
- Banani Banerjee
- Division of Gastroenterology and Hepatology and Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Bidyut K. Medda
- Division of Gastroenterology and Hepatology and Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Yue Zheng
- Division of Gastroenterology and Hepatology and Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Heather Miller
- Division of Gastroenterology and Hepatology and Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Adrian Miranda
- Division of Gastroenterology and Hepatology and Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Jyoti N. Sengupta
- Division of Gastroenterology and Hepatology and Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Reza Shaker
- Division of Gastroenterology and Hepatology and Division of Pediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Milwaukee, Wisconsin
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Ang D, Sifrim D, Tack J. Mechanisms of heartburn. ACTA ACUST UNITED AC 2008; 5:383-92. [PMID: 18542113 DOI: 10.1038/ncpgasthep1160] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2008] [Accepted: 04/18/2008] [Indexed: 02/07/2023]
Abstract
Heartburn is a typical symptom of GERD. The spectrum of diseases associated with GERD includes reflux esophagitis, Barrett's esophagus and nonerosive reflux disease (NERD). Although acid reflux is the classic cause of heartburn in patients with erosive esophagitis, the relationship between acid and heartburn is far from clear, especially in patients with NERD. Strong evidence exists that weakly acidic reflux and/or non-acid-related events have a significant role in the generation of heartburn. In addition to the role of nonacidic refluxate components, activation of mechanoreceptors and chemoreceptors, and a possible role for central and peripheral sensitization, has been described. Although patients with erosive esophagitis respond well to acid-suppressive therapy, the same does not hold true for those with NERD. NERD represents a major clinical problem, and its management remains a challenge. Discussion of NERD focuses on the mechanisms that cause chest pain in this subgroup of patients. Improved understanding of the pathogenesis underlying heartburn in patients with GERD, in particular those with NERD, will shape our understanding of this condition. Such understanding will serve as a platform for further research and allow additional therapies to be developed for this increasingly encountered clinical condition.
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Affiliation(s)
- Daphne Ang
- Department of Gastroenterology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Herestraat 49, 3000 Leuven, Belgium
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15
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Qin C, Farber JP, Foreman RD. Intraesophageal chemicals enhance responsiveness of upper thoracic spinal neurons to mechanical stimulation of esophagus in rats. Am J Physiol Gastrointest Liver Physiol 2008; 294:G708-16. [PMID: 18187515 DOI: 10.1152/ajpgi.00477.2007] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Esophageal hypersensitivity is one of the most common causes of noncardiac chest pain in patients. In this study, we investigated whether exposure of the esophagus to acid and other chemical irritants affected activity of thoracic spinal neurons responding to esophageal distension (ED) in rats. Extracellular potentials of single thoracic (T3) spinal neurons were recorded in pentobarbital sodium-anesthetized, -paralyzed, and -ventilated male rats. ED (0.2 or 0.4 ml, 20 s) was produced by water inflation of a latex balloon placed orally into the middle thoracic region of the esophagus. The chemicals were administered via a tube that was passed through the stomach and placed in the thoracic esophagus. To irritate the esophagus, 0.2 ml of HCl (0.01 N), bradykinin (10 microg/ml), or capsaicin (10 microg/ml) were injected for 1-2 min. Only neurons excited by ED were included in this study. Results showed that intraesophageal instillation of HCl, bradykinin, and capsaicin increased activity in 3/20 (15%), 7/25 (28%), and 9/20 (45%) neurons but enhanced excitatory responses to ED in 9/17 (53%), 8/15 (53%), and 7/11 (64%) of the remaining spinal neurons, respectively. Furthermore, intraesophageal chemicals were more likely to enhance the responsiveness of low-threshold neurons than high-threshold neurons to the esophageal mechanical stimulus. Normal saline (pH 7.4, 0.2 ml) or vehicle instilled in the esophagus did not significantly affect activity or ED responses of neurons. We conclude that enhanced responses of thoracic spinal neurons to ED by the chemically challenged esophagus may provide a possible pathophysiological basis for visceral hypersensitivity in patients with gastroesophageal reflux and/or esophagitis.
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Affiliation(s)
- Chao Qin
- Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190, USA.
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Cheung TK, Lim PWY, Wong BCY. Noncardiac chest pain--an Asia-Pacific survey on the views of primary care physicians. Dig Dis Sci 2007; 52:3043-8. [PMID: 17436083 DOI: 10.1007/s10620-007-9764-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2006] [Accepted: 01/03/2007] [Indexed: 02/08/2023]
Abstract
Noncardiac chest pain (NCCP) is common and has a significant impact on health care. Primary care physicians (PCPs)' attitudes, clinical approach, preference of diagnostic tests, referral patterns, and comfort in managing patients with NCCP in the Asia-Pacific region are not known. Consequently, we performed this survey in the Asia-Pacific region. The self-completed questionnaire was sent to PCPs in the Asia-Pacific region. A 28-item questionnaire contained questions on demographic information, characteristics of practice, preferences of diagnostic tests, referral patterns, treatment plans, and opinion on Helicobacter pylori and NCCP. A total of 108 (74%) PCPs returned the questionnaire. A mean of 18% of the patients were diagnosed with NCCP by PCPs in the past 6 months. Ninety-four percent of PCPs had treated NCCP patients in the last 6 months. Only 38% of the PCPs were comfortable in diagnosing NCCP but 85.2% believed that they should manage NCCP patients. PCPs in Malaysia and Philippines were more likely to refer patients to subspecialists. Fifty-seven and four-tenths percent of PCPs believed that H. pylori infection plays a role in the development of NCCP. The study demonstrates clearly that the understanding, diagnostic strategies, and treatment strategies of NCCP in the Asia-Pacific region are suboptimal and thus highlights the importance of educational and training programs tailored for PCPs in NCCP.
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Affiliation(s)
- Ting Kin Cheung
- Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong
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Tipnis NA, Rhee PL, Mittal RK. Distension during gastroesophageal reflux: effects of acid inhibition and correlation with symptoms. Am J Physiol Gastrointest Liver Physiol 2007; 293:G469-74. [PMID: 17556589 DOI: 10.1152/ajpgi.00019.2007] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
We studied spontaneous gastroesophageal reflux (GER)-induced esophageal distension using ultrasound imaging and its role in the genesis of esophageal symptoms before and during esomeprazole therapy. Ten controls and 10 GER disease (GERD) patients were studied by combined impedance, esophageal pH, manometry, and ultrasonography before and during esomeprazole therapy. Physiological data and symptoms were recorded for 2 h following a standardized meal. From ultrasound images, the esophageal cross-sectional area (CSA) at the peak of GER-induced distension was determined and compared between controls vs. patients, symptomatic vs. asymptomatic GER episodes, and before vs. during esomeprazole in GERD patients. The mean lumen CSA is greater in the patients than controls (271 +/- 71 mm(2) vs. 163 +/- 56 mm(2), P = 0.001) but not different among asymptomatic reflux episodes, and those associated with regurgitation (290 +/- 110 mm(2)) or heartburn (271 +/- 67 mm(2)). Eight chest pain episodes associated with reflux revealed a tendency toward larger mean esophageal distension (459 +/- 40 mm(2)) compared with asymptomatic reflux (268 +/- 70 mm(2), P = 0.058). Following esomeprazole treatment, most GER episodes were nonacidic and asymptomatic except in two patients in whom cyclical reflux was associated with large esophageal distensions. Esomeprazole did not alter the lumen CSA during GER. Esophageal distension is greater in the GERD subjects compared with controls; however, it is unlikely that the GER-induced distension of the esophagus plays a significant role in the genesis of heartburn sensation. Esomeprazole therapy does not alter the GER-induced distension of the esophagus.
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Affiliation(s)
- Neelesh A Tipnis
- Division of Gastroenterology, San Diego Veterans Affairs Health Care System and University of California, San Diego, California 92161, USA
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Banerjee B, Medda BK, Lazarova Z, Bansal N, Shaker R, Sengupta JN. Effect of reflux-induced inflammation on transient receptor potential vanilloid one (TRPV1) expression in primary sensory neurons innervating the oesophagus of rats. Neurogastroenterol Motil 2007; 19:681-91. [PMID: 17640184 DOI: 10.1111/j.1365-2982.2007.00947.x] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
A possible mechanism of oesophageal hypersensitivity is the acid-induced activation of transient receptor potential vanilloid receptor 1 (TRPV1) in the primary sensory neurons. We investigated TRPV1 expression and its colocalization with substance P (SP) and isolectin B4 (IB4)-positive cells in the thoracic dorsal root ganglia (DRGs) and nodose ganglia (NGs) of rats with reflux-induced oesophagitis (RO). RO was developed by fundus ligation and partial obstruction of the pylorus of Sprague-Dawley rats. Four groups of rats were used; fundus ligated acute (RO 48 h), chronic 7 days (RO 7D), RO 7D + omeprazole (7D + Omz, 40 mg kg(-1), i.p.) and sham-operated controls. Immunohistochemical analysis of TRPV1, SP and IB4 expression were carried out in spinal cord (SC), DRGs and NGs. RO rats exhibited significant inflammation and increase in TRPV1-ir and SP-ir expressions in the SC, DRGs and NGs. The maximum colocalization of TRPV1 and SP was observed in RO 7D rats, but Omz prevented inflammation and over expression of TRPV1 and SP. TRPV1-ir significantly increased in IB4-positive cells in DRGs and SC, but not in the NGs. Results document that acid-induced oesophagitis increases TRPV1 expression in both SP- and IB4-positive sensory neurons. The over expression of TRPV1 may contribute to oesophageal hypersensitivity observed in gastro-oesophageal reflux disease (GORD).
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Affiliation(s)
- B Banerjee
- Division of Gastroenterology and Hepatology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
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Hammer J, Vogelsang H. Characterization of sensations induced by capsaicin in the upper gastrointestinal tract. Neurogastroenterol Motil 2007; 19:279-87. [PMID: 17391244 DOI: 10.1111/j.1365-2982.2007.00900.x] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Intraluminal capsaicin induces perception in the jejunum, but chemosensitivity of proximal gastrointestinal regions is unclear. Our aim was to evaluate the quality of perception induced by intraluminal capsaicin in different regions of the upper gastrointestinal tract. Healthy volunteers received either an oral tube for distension and capsaicin perfusion of the mid-duodenum or jejunum or swallowed a capsule containing 0.75 mg capsaicin powder. Graded questionnaires evaluated quality and severity of sensations during distensions, capsaicin infusion and 30 min after ingestion of capsaicin capsules respectively. Duodenal capsaicin induced sensations at lower doses than jejunal capsaicin (P < 0.05). Most prominent sensations evoked by capsaicin infusion were pressure, cramps, pain and nausea; nausea and warmth were more intense during capsaicin infusion than distension (P < 0.05,for the duodenum and jejunum), pain was more intense during distension (P < 0.05, duodenum only). Gastric ingestion of capsaicin capsules mainly induced sensations of pressure, heartburn and warmth. Capsaicin application into the upper gastrointestinal tract reproducibly induced upper abdominal sensation. Qualitative features distinguished chemically from mechanically induced sensations, but both sensitivity for chemical and mechanical stimulation decreased along the intestine. Activation of chemical pathways could be a useful human pain model activating nociceptors apart from mechanical stimulation.
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Affiliation(s)
- J Hammer
- Abteilung für Gastroenterologie und Hepatologie, Medical University of Vienna, Vienna, Austria.
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Remes-Troche JM, Maher J, Mudipalli R, Rao SSC. Altered esophageal sensory-motor function in patients with persistent symptoms after Nissen fundoplication. Am J Surg 2007; 193:200-5. [PMID: 17236847 DOI: 10.1016/j.amjsurg.2006.10.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2006] [Revised: 10/30/2006] [Accepted: 10/30/2006] [Indexed: 01/27/2023]
Abstract
BACKGROUND The pathophysiology of persistent gastroesophageal reflux disease (GERD) symptoms after antireflux surgery is unclear. We assessed esophageal sensorimotor function in patients with GERD before and after Nissen fundoplication (NF). METHODS Sensory and biomechanical properties were evaluated before surgery using impedance planimetry in 17 GERD patients and 16 healthy volunteers. All patients underwent standard laparoscopic NF. Eight GERD patients with persistent symptoms after surgery underwent repeat evaluations at least 12 months after surgery. RESULTS At baseline, GERD patients had lower thresholds for first perception (P < .001), discomfort (P < .001), and pain (P < .001) compared with controls. The esophagus was more reactive (P = .001) and less distensible (P = .04) in patients than controls. After NF, in patients with persistent symptoms, the sensory thresholds were unchanged (P > .05) but esophageal wall reactivity decreased (P = .001), and distensibility improved (P = .025). CONCLUSIONS NF improves esophageal biomechanical dysfunction but not the underlying hypersensitivity. Visceral hypersensitivity of the esophagus may explain persistent symptoms after NF.
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Affiliation(s)
- Jose M Remes-Troche
- Section of Neurogastroenterology, Division of Gastroenterology-Hepatology, Department of Internal Medicine, University of Iowa Carver College of Medicine, 200 Hawkins Dr, 4612 JCP, Iowa City, IA 52242, USA
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21
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Drewes AM, Pedersen J, Reddy H, Rasmussen K, Funch-Jensen P, Arendt-Nielsen L, Gregersen H. Central sensitization in patients with non-cardiac chest pain: a clinical experimental study. Scand J Gastroenterol 2006; 41:640-9. [PMID: 16754535 DOI: 10.1080/00365520500442559] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Patients with non-cardiac chest pain (NNCP) suffer from unexplained and often intractable pain which can pose a major clinical problem. The aim of this study was to investigate nociceptive processing in NNCP patients and their response to experimentally acid-induced oesophageal hyperalgesia using a multimodal stimulation protocol. MATERIAL AND METHODS Ten highly selected patients with NCCP (mean age 43 years, 1 M) were compared with an age- and gender-matched group of 20 healthy subjects. After preconditioning, the distal oesophagus was painfully distended with a balloon using "impedance planimetry". This method assesses the luminal cross-sectional area of the oesophagus based on the electrical impedance of the fluid inside the balloon. The baseline distensions were done before and after pharmacological relaxation of the smooth muscle with 20 mg butylscopolamine. After baseline distensions, a series of up to 10 mechanical stimuli was performed (temporal summation). The stimulations were repeated after sensitization of the oesophagus induced by acid perfusion. The sensory intensities were assessed during the stimulations and the referred pain area was mapped. RESULTS At baseline distensions, no differences were seen between patients and controls before and after relaxation of the smooth muscles. The patients tolerated fewer repeated distensions than controls (4.8+/-0.5 versus 9.1+/-0.9; p=0.04) and had an increased size of the referred pain areas to the mechanical stimulations (32.9+/-6.2 versus 64.9+/-18.3 cm2; p=0.01). After sensitization with acid, the patients developed hyperalgesia (p<0.001), whereas no significant changes were seen in controls. CONCLUSIONS NCCP patients showed facilitated central pain mechanisms (temporal summation and visceral hyperalgesia after sensitization). This could be used in the diagnosis and understanding of the symptoms in these patients.
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Affiliation(s)
- Asbjørn Mohr Drewes
- Centre for Visceral Biomechanics and Pain, Department of Gastroenterology, Aalborg Hospital, Aalborg, Denmark.
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22
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Iovino P, Angrisani L, Galloro G, Consalvo D, Tremolaterra F, Pascariello A, Ciacci C. Proximal stomach function in obesity with normal or abnormal oesophageal acid exposure. Neurogastroenterol Motil 2006; 18:425-32. [PMID: 16700721 DOI: 10.1111/j.1365-2982.2006.00768.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
There is an increased prevalence of gastro-oesophageal reflux and symptoms in obese patients. Information about the proximal stomach in obese patients with reflux is lacking. Gastric volume and compliance are similar between obese and lean subjects. To study the proximal stomach function and perception in obese patients with normal or abnormal oesophageal acid exposure, thirty-one obese patients, with normal or abnormal oesophageal acid exposure, underwent medical evaluation of oesophageal and gastrointestinal symptoms by a questionnaire and measurement of proximal stomach function and perception by an electronic barostat and a standardized questionnaire. Nineteen obese patients had abnormal oesophageal acid exposure. The percentage of total time with pH <4 is significantly related to the presence of hiatal hernia, the oesophageal intensity-frequency symptom score and gender, i.e. higher percentage in men. The perception cumulative score was significantly different between patients with normal and abnormal oesophageal acid exposure after adjusting for covariates (gender, body mass index, age, minimal distending pressure, gastric tone and gastric compliance). Gastric tone and compliance were significantly related to the perception cumulative score. In conclusion, patients with abnormal oesophageal acid exposure have increased gastric perception. A significant relation among gastric tone, gastric compliance and upper gastrointestinal sensations was shown.
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Affiliation(s)
- P Iovino
- Dipartimento di Chirurgia Generale, Geriatria, Oncologica e Tecnologie Avanzate, University of Naples Federico II, Naples, Italy.
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Drewes AM, Arendt-Nielsen L, Funch-Jensen P, Gregersen H. Experimental human pain models in gastro-esophageal reflux disease and unexplained chest pain. World J Gastroenterol 2006; 12:2806-17. [PMID: 16718803 PMCID: PMC4087795 DOI: 10.3748/wjg.v12.i18.2806] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Methods related to experimental human pain research aim at activating different nociceptors, evoke pain from different organs and activate specific pathways and mechanisms. The different possibilities for using mechanical, electrical, thermal and chemical methods in visceral pain research are discussed with emphasis of combinations (e.g., the multimodal approach). The methods have been used widely in assessment of pain mechanisms in the esophagus and have contributed to our understanding of the symptoms reported in these patients. Hence abnormal activation and plastic changes of central pain pathways seem to play a major role in the symptoms in some patients with gastro-esophageal reflux disease and in patients with functional chest pain of esophageal origin. These findings may lead to an alternative approach for treatment in patients that does not respond to conventional medical or surgical therapy.
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Affiliation(s)
- Asbjørn Mohr Drewes
- Center for Visceral Biomechanics and Pain, Department of Medical Gastroenterology, Aalborg University Hospital, DK-9000 Aalborg, Denmark.
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Sami SAK, Rössel P, Dimcevski G, Nielsen KD, Funch-Jensen P, Valeriani M, Arendt-Nielsen L, Drewes AM. Cortical changes to experimental sensitization of the human esophagus. Neuroscience 2006; 140:269-79. [PMID: 16631315 DOI: 10.1016/j.neuroscience.2006.02.031] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2005] [Revised: 01/17/2006] [Accepted: 02/05/2006] [Indexed: 12/24/2022]
Abstract
Topographical organization in the neocortex shows experience-dependent plasticity. We hypothesized that experimental sensitization of the esophagus results in changes of the topographical distribution of the evoked potentials and the corresponding dipole source activities to painful stimulation. An endoscopic method was used to deliver 35 electrical stimuli at the pain threshold to a fixed area of the mucosa in 10 healthy volunteer men and women. The stimulations were repeated after 30 min (reproducibility experiment), and after 60 min following perfusion of 200 ml 0.1 N hydrochloric acid (sensitization experiment). During stimulation the electroencephalogram was recorded from 64 surface electrodes. The sensitization resulted in a decrease in the pain threshold (F=6.2; P=0.004). The topographic distribution of the evoked potentials showed reproducible negative (N1, N2) and positive (P1, P2) components. After acid perfusion a reduced latency and a change in localization was seen for the P1 subdivided into frontal and occipital components (F=29.5, P<0.001; F=53.7, P<0.001). Furthermore the sensitization resulted in a reduction of the latency for P2 (F=6.2, P=0.009). The source analysis showed consistent dipolar activity in the bilateral opercular-insular cortex before and after acid perfusion. For the anterior cingulate dipole there was a reduction in latency (P=0.03) and a posterior shift (P=0.0002) following acid perfusion. The findings indicate that short-term sensitization of the esophagus results in central neuroplastic changes involving the cingulate gyrus, which also showed pathological activation in functional diseases of the gut, thus reflecting the importance of this region in visceral pain and hyperalgesia.
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Affiliation(s)
- S A K Sami
- Center for Sensory-Motor Interactions, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark
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25
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Anderson SHC, Yadegarfar G, Arastu MH, Anggiansah R, Anggiansah A. The relationship between gastro-oesophageal reflux symptoms and achalasia. Eur J Gastroenterol Hepatol 2006; 18:369-74. [PMID: 16538107 DOI: 10.1097/00042737-200604000-00009] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIMS Patients with achalasia can experience heartburn, which may be misinterpreted as gastro-oesophageal reflux disease (GORD), leading to a delay in diagnosis and subsequent treatment. We investigated the relationship between gastro-oesophageal reflux (GOR) and reflux symptoms in a large cohort of patients with achalasia. METHODS The symptoms of all patients with a manometric diagnosis of achalasia made over the past 15 years were studied. The types of treatment, onset and pattern of heartburn, lower oesophageal sphincter pressure (LOSP) and 24-h oesophageal pH studies were compared. RESULTS A total of 110 out of 225 untreated (48.9%) and 57 out of 99 treated (57.6%) patients experienced heartburn. An oesophageal pH study was performed on 80 patients and GOR was found in only six out of 57 untreated (10.5%) and 10 out of 23 treated (43.5%) patients. A low LOSP (<10 mmHg) was associated with an increased risk of GOR [odds ratio (OR) 14.2; 95% confidence interval (CI) 1.6-128.7; P<0.02). Treated patients were also more likely to develop GOR (OR 7.9; 95% CI 2.0-32.1; P<0.005). Neither the LOSP nor previous treatment was, however, a predictor of heartburn. The timing of the onset of dysphagia and heartburn was categorized in 111 patients. There was no significant difference in mean (or median) LOSP between these three groups, indicating that the LOSP is unlikely to predict the occurrence of symptoms. CONCLUSIONS Heartburn is common in patients with untreated and treated achalasia, but is a poor predictor of GORD. Such patients should always be investigated with a 24-h oesophageal pH study to clarify the presence of GORD.
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Affiliation(s)
- Simon H C Anderson
- Department of Gastroenterology, Guy's and St Thomas' Hospital, London SE1 7EH, UK
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Yang M, Li ZS, Xu XR, Fang DC, Zou DW, Xu GM, Sun ZX, Tu ZX. Characterization of cortical potentials evoked by oesophageal balloon distention and acid perfusion in patients with functional heartburn. Neurogastroenterol Motil 2006; 18:292-9. [PMID: 16553584 DOI: 10.1111/j.1365-2982.2006.00761.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Oesophageal visceral hypersensitivity is thought to be important in generating symptoms in functional heartburn (FH). However, the neurophysiological mechanisms involved are poorly understood. The aim of this study was to compare the characteristics of oesophageal cortical evoked potentials (CEPs) induced by balloon distension and acid perfusion in FH and controls. We studied 21 FH patients and 12 healthy volunteers. Oesophageal mechanical stimulation was performed using the specially constructed mechanical pump. CEPs were recorded using the 10-20 international system of electroencephalogram recording. Oesophageal distention elicited recognizable, reproducible and muti-peak CEPs. CEP latencies for N1, P1 and N2 components were significantly shorter (P = 0.016, P = 0.003 and P = 0.031, respectively) in FH than in controls before perfusion. Acid perfusion significantly decreased the latencies of N1, P1 and N2 (P = 0.022, P = 0.007 and P = 0.041, respectively) and significantly increased the amplitude of P1-N2 components (P = 0.020) in FH patients, but not in controls. In conclusion, cortical evoked potential responses evoked by oesophageal distention and acid perfusion were greater in FH than in controls, suggesting that dysfunction of visceral neural pathways and/or alterations in cortical processing may produce and mediate oesophageal hypersensitivity in FH. These findings provide the evidence that central sensitization contributes to the development and maintenance of oesophageal hypersensitivity.
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Affiliation(s)
- M Yang
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China
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Abstract
The close anatomical relations of the heart and oesophagus, and the similarity of symptoms attributable to disorders of either organ, often lead to diagnostic difficulty in patients with chest pain. A definitive diagnosis of non-cardiac chest pain attributable to oesophageal reflux or spasm is hampered, both by the need for prolonged ambulatory monitoring of pH, manometry, and endoscopy, and by the common occurrence of asymptomatic reflux and spasm, and the corresponding difficulty in linking an episode of reflux or spasm with an episode of pain. Moreover, some patients with non-cardiac chest pain and normal tests of oesophageal structure and function have centrally mediated hypersensitivity, both within and without the oesophagus. Rather than proceed with investigations, in the absence of symptoms to suggest structural disease of the oesophagus, it would be reasonable to attempt symptomatic treatment with a proton pump inhibitor or an antidepressant.
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Affiliation(s)
- M Heatley
- Department of Cardiology, Singleton Hospital, Swansea, Wales
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28
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Abstract
Various underlying mechanisms have been described in patients with non-cardiac chest pain (NCCP). By far, gastroesophageal reflux disease (GERD) is the most common cause and thus requires initial attention when patients with NCCP are managed. Esophageal dysmotility can be demonstrated in 30% of the NCCP patients, but appears to play a very limited role in symptom generation. A significant number of patients with NCCP lack any evidence of GERD and have been consistently shown to have reduced perception thresholds for pain. Peripheral and/or central sensitization have been suggested to be responsible for visceral hypersensivity in NCCP patients. Further understanding of the underlying mechanisms for pain in patients with NCCP will likely improve our current therapeutic approach.
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Affiliation(s)
- Daniel Van Handel
- The Neuro-Enteric Clinical Research Group, Department of Medicine, Section of Gastroenterology, Southern Arizona VA Health Care System and University of Arizona Health Sciences Center, Tucson, AZ 85723-0001, USA
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29
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Lee YC, Wang HP, Chiu HM, Huang SP, Tu CH, Wu MS, Lin JT. Patients with functional heartburn are more likely to report retrosternal discomfort during wireless pH monitoring. Gastrointest Endosc 2005; 62:834-41. [PMID: 16301022 DOI: 10.1016/s0016-5107(05)00317-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2004] [Revised: 06/24/2004] [Accepted: 12/29/2004] [Indexed: 02/08/2023]
Abstract
BACKGROUND Although the wireless Bravo pH system is effective, some patients experience retrosternal sensations possibly caused by esophageal sensitivity that may complicate clinical application. METHODS Ambulatory pH of 40 consecutive patients with GERD who had erosive esophagitis or nonerosive reflux disease, were monitored for 2 days with the Bravo system. Results were stratified and compared on the basis of self-awareness of the intraesophageal capsule. RESULTS Pathologic acid reflux was diagnosed in 20 patients and normal reflux was diagnosed in 20 patients. Seventeen patients (42.5%) reported retrosternal discomfort, and 12 of them (70.6%) had normal reflux. Patients with retrosternal discomfort were less likely to have moderate endoscopic esophagitis, i.e., Los Angeles classification grades B, C, and D endoscopic esophagitis (p = 0.006), and were less likely to have significantly elevated esophageal acid exposure (p = 0.0036) than those who did not perceive the discomfort. Reported discomfort was not associated with age, gender, or the presence of endoscopic esophagitis. CONCLUSIONS The negative correlation between Bravo-capsule-induced retrosternal discomfort and esophageal-acid exposure indicates modified mechanical afferent nerve function after long-term acid stimulation. Capsule-induced retrosternal discomfort in the presence of normal acid exposure suggests functional heartburn.
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Affiliation(s)
- Yi-Chia Lee
- Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
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30
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Abrahão LJ, Lemme EMO. [Role of esophageal provocative tests in the investigation of patients with chest pain of undetermined origin]. ARQUIVOS DE GASTROENTEROLOGIA 2005; 42:139-45. [PMID: 16200248 DOI: 10.1590/s0004-28032005000300003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
BACKGROUND Traditional methods employed in esophageal investigation of patients with chest pain of undetermined origin includes upper endoscopy, esophageal manometry and pH monitoring. These methods many times disclose abnormalities that can only be enrolled as the possible cause of chest pain. Provocative tests can reproduce pain in the laboratory, establishing its esophageal origin. OBJECTIVES Determine the positivity of acid perfusion test, edrophonium and balloon distension in patients with chest pain of undetermined origin and compare with results of traditional exams, establishing the gain for the diagnosis of esophageal pain. RESULTS Forty patients with chest pain of undetermined origin (normal coronary angiography), 80% female, mean age of 54.7 years were submitted to traditional exams and provocative tests. Upper endoscopy disclosed erosive esophagitis in two (5%) and peptic ulcer in one (2.5%), esophageal manometry was abnormal in 60%. pH monitoring was abnormal in 14 (35%) with a positive symptom index in 7. Chest pain was considered of proved esophageal origin by traditional exams in 7 (17.5%) patients with a positive symptom index and of probable esophageal origin in 19 (47.5%) being 8 with gastroesophageal reflux disease and 11 abnormal esophageal motility. In 14 (35%) an esophageal origin could not be demonstrated. The acid perfusion test was positive in 10 (25%), edrophonium test in 8 (20%) and balloon distension test in 15 (37.5%) and at least one provocative test was positive in 23 (57.5%) patients. The introduction of provocative tests allowed the diagnosis of proved esophageal pain in 12 of 19 (63.1%) patients with probable esophageal pain and in 6 of 14 (42.8%) with normal or inconclusive traditional exams what represented a diagnostic gain of 45% (18/40). Two patients had negative provocative tests and a positive symptom index, making a total of 25 (62.5%) patients with proved esophageal pain.
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Affiliation(s)
- Luiz J Abrahão
- Serviço de Gastroenterologia, Hospital Universitário Clementino Fraga Filho, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ.
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31
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Drewes AM, Reddy H, Staahl C, Pedersen J, Funch-Jensen P, Arendt-Nielsen L, Gregersen H. Sensory-motor responses to mechanical stimulation of the esophagus after sensitization with acid. World J Gastroenterol 2005; 11:4367-74. [PMID: 16038036 PMCID: PMC4434664 DOI: 10.3748/wjg.v11.i28.4367] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Sensitization most likely plays an important role in chronic pain disorders, and such sensitization can be mimicked by experimental acid perfusion of the esophagus. The current study systematically investigated the sensory and motor responses of the esophagus to controlled mechanical stimuli before and after sensitization.
METHODS: Thirty healthy subjects were included. Distension of the distal esophagus with a balloon was performed before and after perfusion with 0.1 mol/L hydrochloric acid for 30 min. An impedance planimetry system was used to measure cross-sectional area, volume, pressure, and tension during the distensions. A new model allowed evaluation of the phasic contractions by the tension during contractions as a function of the initial muscle length before the contraction (comparable to the Frank-Starling law for the heart). Length-tension diagrams were used to evaluate the muscle tone before and after relaxation of the smooth muscle with butylscopolamine.
RESULTS: The sensitization resulted in allodynia and hyperalgesia to the distension volumes, and the degree of sensitization was related to the infused volume of acid. Furthermore, a nearly 50% increase in the evoked referred pain was seen after sensitization. The mechanical analysis demonstrated hyper-reactivity of the esophagus following acid perfusion, with an increased number and force of the phasic contractions, but the muscle tone did not change.
CONCLUSION: Acid perfusion of the esophagus sensitizes the sensory pathways and facilitates secondary contractions. The new model can be used to study abnormal sensory-motor mechanisms in visceral organs.
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Affiliation(s)
- Asbjørn-Mohr Drewes
- Center for Biomechanics and Pain, Department of Medical Gastroenterology, Aalborg Hospital, DK-9000 Aalborg, Denmark.
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32
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Zentilin P, Accornero L, Dulbecco P, Savarino E, Savarino V. Air swallowing can be responsible for non-response of heartburn to high-dose proton pump inhibitor. Dig Liver Dis 2005; 37:454-7. [PMID: 15893286 DOI: 10.1016/j.dld.2004.06.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2004] [Accepted: 06/09/2004] [Indexed: 12/11/2022]
Abstract
Intraluminal electrical impedance is a novel technique, which is able for the first time to provide a qualitative assessment of refluxed material moving from the stomach to the oesophagus. In other words, the presence of air can be differentiated from that of liquid, because the former is characterised by high and the latter by low impedance compared with baseline. Moreover, the combined measurement of electrical impedance and pH-metry permits to distinguish acid from non-acid liquid reflux. One of the most important clinical applications of this method is to assess the reasons for poor response of GORD patients to high-dose proton pump inhibitors. This case report describes the results of impedance in the evaluation of a young woman, who did not respond to twice-daily doses of rabeprazole. She continued to complain of heartburn as major symptom and impedance allowed us to clarify that it was not related to acid or non-acid reflux, but to air swallowing. Therefore, this technique identified aerophagia to be responsible for persistent heartburn despite high-dose proton pump inhibitor and prevented the adoption of more aggressive, but probably unuseful therapies, such as the surgical one.
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Affiliation(s)
- P Zentilin
- Department of Internal Medicine, University of Genoa, Viale Benedetto XV, n. 6, 16132 Genoa, Italy
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33
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Abstract
Heartburn is a symptom complex that has traditionally been accepted as an acid-mediated event and a reliable indicator of gastroesophageal reflux disease. Recently, however, these concepts have been questioned because patients with endoscopy-negative "heartburn" have lower response rates to acid suppression with proton pump inhibitors than do patients with endoscopy-positive "heartburn," ie, erosive esophagitis. As explanation for this, 3 different mechanisms have been proposed to explain the occurrence of heartburn in the endoscopy-negative setting. They are: esophageal visceral hypersensitivity, sustained esophageal contractions, and abnormal tissue resistance. In this report, we review the observations in support of each concept and propose a means for reconciling them under one hypothesis: abnormal tissue resistance. Essential to this review and to the conclusions drawn about the pathogenesis of heartburn in nonerosive reflux disease is a reaffirmation of the definition of reflux-associated "heartburn" as an acid-mediated event requiring "relief by antacids" as a necessary component of the history.
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Affiliation(s)
- William J Barlow
- Tulane University Health Sciences Center, Department of Medicine SL-35, 1430 Tulane Avenue, New Orleans, Louisiana 70112, USA
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34
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Medda BK, Sengupta JN, Lang IM, Shaker R. Response properties of the brainstem neurons of the cat following intra-esophageal acid–pepsin infusion. Neuroscience 2005; 135:1285-94. [PMID: 16165290 DOI: 10.1016/j.neuroscience.2005.07.016] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2005] [Revised: 06/24/2005] [Accepted: 07/01/2005] [Indexed: 11/16/2022]
Abstract
Studies in humans have documented that acute acid infusion into the esophagus leads to decrease in threshold for sensations to mechanical distension of the esophagus. It is not known whether acid infusion leads to sensitization of brainstem neurons receiving synaptic input from vagal afferent fibers innervating the esophagus. The aim of this study was to investigate the correlation of responses of vagal afferents and brainstem neurons after acute infusion of acid (0.1 N HCl)+pepsin (1 mg/ml) into the esophagus of cats. The vagal afferent fibers (n=20) exhibited pressure-dependent increase in firing to graded esophageal distension (5-80 mm Hg). Infusion of acid+pepsin into the esophagus produced a significant increase in ongoing resting firing of five of 16 fibers (31%) tested. However, their responses to graded esophageal distension did not change when tested 30 min after infusion. Pepsin infusion did not change the resting firing and response to esophageal distension (n=4). Twenty-one brainstem neurons were recorded that responded in an intensity-dependent manner to graded esophageal distension. Responses of 12 excited neurons were tested after intra-esophageal acid+pepsin infusion. Neurons exhibited a decrease in threshold for response to esophageal distension and increase in firing after acid+pepsin infusion. The sensitization of response after intra-esophageal acid remained unaffected after cervical (C1-C2) spinal transection (n=3). Results indicate that the esophageal distension-sensitive neurons in the brainstem exhibit sensitization of response to esophageal distension after acute acid+pepsin exposure. The sensitization of brainstem neurons is possibly initiated by increased spontaneous firing of the vagal afferent fibers to acid+pepsin, but not to sensitized response of vagal distension-sensitive afferent fibers to esophageal distension. Results also indicate that spinal pathway does not contribute to sensitization of brainstem neurons.
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Affiliation(s)
- B K Medda
- MCW Dysphagia Institute and Division of Gastroenterology and Hepatology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA
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35
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Zimmerman J. Irritable bowel, smoking and oesophageal acid exposure: an insight into the nature of symptoms of gastro-oesophageal reflux. Aliment Pharmacol Ther 2004; 20:1297-303. [PMID: 15606391 DOI: 10.1111/j.1365-2036.2004.02216.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND In gastro-oesophageal reflux disease, oesophageal acid exposure correlates with symptoms but explains only a small fraction of their variance. AIMS To elucidate the effects of irritable bowel syndrome and smoking on gastro-oesophageal reflux disease symptoms and to clarify whether they modulate the relationship between oesophageal acid exposure and symptoms. METHODS The relationship between oesophageal acid exposure, irritable bowel syndrome (Rome I criteria), smoking status and symptoms was investigated in patients with a normal gastroscopy who underwent a 24-h oesophageal pH monitoring. RESULTS Of 256 patients with gastro-oesophageal reflux disease, 16% were smokers and 50% met the criteria for irritable bowel syndrome (irritable bowel syndrome+). The extent of oesophageal acid exposure was unrelated to smoking or irritable bowel syndrome status. Oesophageal acid exposure, irritable bowel syndrome status and current smoking independently predicted symptoms. Irritable bowel syndrome and smoking modulated the effect of oesophageal acid exposure on symptoms: oesophageal acid exposure was predictive of symptoms only in non-smokers. However, irritable bowel syndrome was a significant predictor of symptoms both in smokers and in non-smokers. Smoking was associated with symptoms only in irritable bowel syndrome+, while oesophageal acid exposure was associated with symptoms irrespective of irritable bowel syndrome status. CONCLUSIONS In patients with non-erosive gastro-oesophageal reflux disease, smoking and irritable bowel syndrome independently predicted symptoms, without affecting the extent of oesophageal acid exposure. The relationship between oesophageal acid exposure and symptoms was affected significantly, and in opposite directions, by smoking and irritable bowel syndrome.
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Affiliation(s)
- J Zimmerman
- Gastroenterology Unit, Hadassah-Hebrew University Medical Centre, Jerusalem, Israel.
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36
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Abstract
Originally, sensory testing of the esophagus included the acid perfusion test and the edrophonium test, which were developed to assess patients with non-cardiac chest pain. In the last 2 decades interest in functional esophageal disorders has increased and thus further understanding of the underlying mechanisms of esophageal pain required development of new sensory testing techniques. Balloon distension using a computerized electronic device, electrical stimulation and impedance planimetry have generated important information about esophageal sensory thresholds for pain in different disease states. Intraluminal ultrasonography has been used to determine the physiologic changes of the muscle wall of the esophagus during perception of typical esophageal symptoms. Central evaluation of patients undergoing esophageal stimulation has recently been introduced to assess cerebral activation in different esophageal disorders. However, many studies using esophageal sensory testing are afflicted with significant design flaws, making interpretation of the results very difficult. This is primarily due to lack of recognition of factors that can modulate esophageal sensation.
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Affiliation(s)
- Ronnie Fass
- Neuro-Enteric Clinical Research Group, Department of Medicine, Section of Gastroenterology, Southern Arizona VA Health Care System, Tucson, Arizona 85723, USA.
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Lee KJ, Demarchi B, Demedts I, Sifrim D, Raeymaekers P, Tack J. A pilot study on duodenal acid exposure and its relationship to symptoms in functional dyspepsia with prominent nausea. Am J Gastroenterol 2004; 99:1765-73. [PMID: 15330916 DOI: 10.1111/j.1572-0241.2004.30822.x] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Duodenal hypersensitivity to acid and decreased duodenal clearance of exogenous acid have been reported in functional dyspepsia (FD). However, the relevance of these abnormalities to spontaneous duodenal acid exposure and dyspeptic symptoms in FD is unknown. AIMS To determine spontaneous duodenal acid exposure and its relationship with symptoms, duodenal sensitivity to acid, and the effects of a 5-HT(3) receptor antagonist on duodenal responses to acid in FD. METHODS Eleven FD patients with prominent nausea and 11 healthy controls underwent 24-h ambulatory duodenal pH monitoring with assessment of dyspeptic symptoms. On the next day, duodenal bolus infusions of 5 ml of acid and normal saline were given in a randomized double-blind manner and repeated after ondansetron or a placebo. RESULTS Nighttime duodenal acid exposure was similar, but FD patients had lower duodenal pH and higher duodenal % time (pH < 4) than controls during the daytime and in the second postprandial 2 h (p < 0.05). Seven patients (64%) with duodenal acid exposure above the normal range had higher severity scores for several dyspeptic symptoms including nausea. However, the symptom severity was poorly or weakly correlated to duodenal pH, and brief duodenal acid infusion did not affect any symptoms. Duodenal responses to exogenous acid were unaffected by 5-HT(3) receptor antagonism. CONCLUSIONS Spontaneous duodenal acid exposure is increased in a subset of FD patients with prominent nausea, and this is associated with more severe dyspeptic symptoms. However, a direct relationship between duodenal acid exposure and symptom severity is lacking.
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Affiliation(s)
- Kwang-Jae Lee
- Division of Gastroenterology, Department of Internal Medicine, University Hospital Gasthuisberg, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium
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38
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Abstract
Symptoms arising from the esophagus are produced generally in one of two ways: through stimulation of chemosensitive-nociceptors (eg, through excess esophageal exposure to refluxed gastric acid or the resulting inflammation arising in acid-damaged tissue) or through stimulation of mechanosensitive nociceptors (eg, through repeated deformation or distension of the esophageal wall resulting from peristaltic or lower esophageal sphincter dysfunction). These symptoms are usually attributed in most patients to such well recognized conditions as reflux esophagitis, achalasia,etc. that subsequently result in the delivery of specific and effective treatment.However, a subset of patients exists in which the etiology of "similar-sounding symptoms" remains obscure and their responses to standard specific treatments poor. Now recognized as among this group of patients are those with visceral hypersensitivity. Visceral hypersensitivity is not itself a disease but a definable aberrant sensory response (allodynia or hyper-algesia) to end-organ stimulation. Such an aberrant sensory response is neither specific for nor limited to the esophagus, and the etiopathogenesis for its development within this organ is unknown. Nonetheless, esophageal symptoms as a manifestation of visceral hypersensitivity are increasingly recognized and worthy of attention because they identify a disorder that responds to treatment aimed at the end organ's nociceptors or their neuroanatomic pathways within the CNS.
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Affiliation(s)
- Roy C Orlando
- Tulane University Medical School, 1430 Tulane Avenue, New Orleans, LA 70112-2699, USA.
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39
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Abstract
Visceral hypersensitivity is a common cause of NCCP. Mechanoreceptors appear to be important in the pathophysiology of NCCP, although chemoreceptors also appear to play a significant role. The processing of visceral information and possibly the development of central sensitization may be important in NCCP, although the pathophysiology of NCCPremains poorly understood.
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Affiliation(s)
- Anthony J Lembo
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Hospital, Dana 501, 330 Brookline Avenue, Boston, MA 02215, USA.
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40
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Drewes AM, Schipper KP, Dimcevski G, Petersen P, Andersen OK, Gregersen H, Arendt-Nielsen L. Multi-modal induction and assessment of allodynia and hyperalgesia in the human oesophagus. Eur J Pain 2004; 7:539-49. [PMID: 14575667 DOI: 10.1016/s1090-3801(03)00053-3] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Experimental pain models based on single stimuli have to some degree limited visceral pain studies in humans. Hence, the aim of this study was to investigate the effect of multi-modal visceral pain stimuli of the oesophagus in healthy subjects before and after induction of visceral hyperalgesia. We used a multi-modal psychophysical assessment regime and a neurophysiological method (nociceptive reflex) for the characterisation of the experimentally induced hyperalgesia. METHODS A probe for multi-modal (cold, warm, electrical, and mechanical) visceral stimulation was positioned in the lower part of the oesophagus in eleven healthy subjects. Mechanical stimuli were applied as distensions with a bag, which also had electrodes mounted for electrical stimulation. Thermal stimulation with temperatures from 0 to 60 degrees C was applied with re-circulating water in the bag. To assess the interaction between visceral and somatic pathways, the nociceptive withdrawal reflex to electrical stimuli at the ankle was measured with and without simultaneous mechanical oesophageal distension to painful levels. Finally, the oesophageal sensitisation was induced by perfusion with hydrochloric acid. Multimodal responses (pain threshold, stimulus response function, size of nociceptive reflex, and referred pain areas) were assessed before and after the induced hyperalgesia. RESULTS The multi-modal psychophysical responses and reflex sizes were assessed twice before sensitisation, and the parameters were reproducible. Sensitisation of the oesophagus resulted in hyperalgesia to electrical and mechanical stimuli (29 and 35% decrease in pain threshold) and allodynia to cold and warmth stimuli (11% increase in sensory rating). After sensitisation, the referred pain area to mechanical stimuli increased more than 300% with a change in the localisation of the referred pain to all stimuli, and the amplitude of nociceptive reflex increased 100%, all indicating the presence of central hyperexcitability. CONCLUSIONS Visceral hyperalgesia/allodynia can be induced experimentally and assessed quantitatively by the newly introduced multi-modal psychophysical assessment approach. The significant changes of the experimentally evoked referred pain patterns and of the nociceptive reflex evoked from a distant somatic structure indicate that even short-lasting visceral hyperalgesia can generate generalised sensitisation.
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Affiliation(s)
- Asbjørn Mohr Drewes
- Center for Visceral Biomechanics and Pain, Departments of Medical and Surgical Gastroenterology, Aalborg University Hospital, DK-9000 Aalborg, Denmark.
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Lee KJ, Vos R, Janssens J, Tack J. Influence of duodenal acidification on the sensorimotor function of the proximal stomach in humans. Am J Physiol Gastrointest Liver Physiol 2004; 286:G278-84. [PMID: 12760903 DOI: 10.1152/ajpgi.00086.2003] [Citation(s) in RCA: 101] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Decreased acid clearance and increased exposure to acid of the duodenum have been reported in a subset of functional dyspepsia patients. However, the mechanism by which increased duodenal acid exposure may affect symptoms is unclear. The aim of the present study was to investigate the effects of duodenal acidification on proximal gastric tone and mechanosensitivity in humans. An infusion tube with a pH electrode attached was positioned in the second part of the duodenum, and a barostat bag was located in the gastric fundus. In 12 healthy subjects, fundic tone and sensitivity to distensions were assessed before and during duodenal infusion of 0.1 N hydrochloric acid or saline in a randomized, double-blind design. In 10 healthy subjects, meal-induced accommodation was measured during duodenal infusion of acid or saline. Acid infusion in the duodenum significantly increased fundic compliance and decreased fasting fundic tone. This was accompanied by a significant decrease in the pressures and the corresponding wall tensions at the thresholds for discomfort. During infusion of acid, significantly higher perception and symptom scores were obtained for the same distending pressures. The meal-induced fundic relaxation was significantly smaller during acid infusion compared with saline infusion. In conclusion, duodenal acidification induces proximal gastric relaxation, increases sensitivity to gastric distension, and inhibits gastric accommodation to a meal. Through these mechanisms, increased duodenal acid exposure may be involved in the pathogenesis of dyspeptic symptoms.
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Affiliation(s)
- Kwang-Jae Lee
- Department of Internal Medicine, University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium
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Tack J, Fass R. Review article: approaches to endoscopic-negative reflux disease: part of the GERD spectrum or a unique acid-related disorder? Aliment Pharmacol Ther 2004; 19 Suppl 1:28-34. [PMID: 14725576 DOI: 10.1111/j.0953-0673.2004.01835.x] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Endoscopic-negative reflux disease (ENRD) is the most common presentation of gastro-oesophageal reflux disease (GERD)-affecting up to 70% of these individuals. In the last three decades therapeutic studies have focused solely on the treatment of patients with erosive oesophagitis. However, more recent studies have shifted our attention to defining, understanding and treating those with ENRD. GERD has traditionally been approached as a spectrum with ENRD at the mild end and complicated GERD (i.e. patients with erosive oesophagitis, stricture and Barrett's oesophagus) being at the other end, suggesting that patients' disease may progress over time along the spectrum. Current data indicate that ENRD should be approached as a unique entity rather than a part of the GERD spectrum and that over time only a few patients with ENRD will develop GERD-related complications. Patients with ENRD are a heterogenous group of patients with different aetiologies for their heartburn symptoms, including motor events, reflux of acidic or nonacidic gastric contents, minute changes in intraesophageal pH (pH < 4), mucosal hypersensitivity, and emotional or psychological abnormalities. By dropping the spectrum concept, which emphasizes oesophageal mucosal injury, we can focus our attention on the specific mechanisms that lead to symptom generation in each of the three unique groups of GERD (ENRD, erosive oesophagitis and Barrett's oesophagus) and on the specific therapeutic modalities that benefit each of these individual groups. Acid suppressive therapy with proton pump inhibitors is highly effective in healing erosions and controlling symptoms in those with erosive oesophagitis. In those with ENRD the resolution or control of heartburn with proton pump inhibitor therapy is greater than that with placebo or H2 receptor antagonist, but not as consistent nor as impressive as the results observed in studies of patients with erosive oesophagitis. By considering the mechanisms involved in ENRD symptom generation, future studies that include high-dose proton pump inhibitors, promotility agents (alone or in combination with proton pump inhibitors), transient lower oesophageal sphincter reducers, or pain modulators (e.g. tricyclic antidepressant agents) may prove beneficial.
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Affiliation(s)
- J Tack
- Department of Gastroenterology, University Hospitals, Leuven, Belgium.
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43
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Abstract
BACKGROUND & AIMS Changes in visceral sensation contribute to the development of dyspepsia. Nonhuman models have previously focused on responses to mechanical stimulation. We studied the response to acid stimulation in the normal and inflamed stomach in rats. METHODS A balloon and gastrostomy catheter were implanted into the stomach. Electromyographic responses to gastric balloon distention or acid administration through the gastrostomy were recorded from the acromiotrapezius muscle. To characterize chemonociceptive pathways, 0.75 mL HCl (0.05-0.3 N) or saline were given intragastrically in controls and animals after vagotomy, splanchnic nerve resection, or chemical denervation with capsaicin. The effect of inflammation was examined after induction of mild diffuse gastritis using iodoacetamide or creating gastric ulcers by injecting 60% acetic acid for 45 seconds into a clamped area of the stomach. RESULTS Visceromotor electromyographic responses increased within 2 minutes after HCl administration (0.15 and 0.3 mol/L) but not saline or lower acid concentrations. Vagotomy and pretreatment with capsaicin but not splanchnic nerve resection abolished this response. Prior acid administration did not acutely sensitize animals to subsequent gastric distention. Gastritis and gastric ulcers enhanced the visceromotor responses to intragastric acid. CONCLUSIONS In awake rats, visceromotor responses to intragastric acid are quantifiable, reliable, and reproducible. Aversive responses to acute noxious chemical stimuli primarily require vagal but not spinal sensory pathways. Injury-induced sensitization to intragastric acid administration is consistent with a potential role of chemical stimulation in triggering dyspeptic symptoms.
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Affiliation(s)
- Kenneth Lamb
- Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
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44
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Drewes AM, Gregersen H, Arendt-Nielsen L. Experimental pain in gastroenterology: a reappraisal of human studies. Scand J Gastroenterol 2003; 38:1115-30. [PMID: 14686714 DOI: 10.1080/00365520310004399] [Citation(s) in RCA: 135] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Affiliation(s)
- A M Drewes
- Center for Visceral Biomechanics and Pain, Dept. of Medical Gastroenterology, Aalborg University Hospital, Denmark.
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45
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Drewes AM, Schipper KP, Dimcevski G, Petersen P, Gregersen H, Funch-Jensen P, Arendt-Nielsen L. Gut pain and hyperalgesia induced by capsaicin: a human experimental model. Pain 2003; 104:333-41. [PMID: 12855343 DOI: 10.1016/s0304-3959(03)00039-3] [Citation(s) in RCA: 83] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Human experimental visceral pain models using chemical stimulation are needed for the study of visceral hyperexcitability. Our aim was to stimulate the human gut with chemical activators (capsaicin, glycerol) and measure quantitatively the induced hyperexcitability to painful mechanical gut distension. Ten otherwise healthy subjects with an ileostoma participated. Increasing volumes of capsaicin 50 microg/ml (0.25, 0.5, 0.75, 1.0, 1.5, 2.0, and 3 ml), glycerol (2.5, 5, and 10 ml) or saline (2.5, 5, and 10 ml) intermingled with sham stimuli were randomly applied to the ileum via the stomal opening at three occasions separated by a week. After each application, pain intensity, qualities, and referred pain area were assessed together with the pain threshold to distension of the proximal gut. 'Boring' and 'hot' pain were evoked in all subjects by low doses (median 0.5 ml) of capsaicin. The median pain onset, peak pain, and pain duration were 55, 85, and 420 s, respectively. Referred somatic pain developed around the stomal opening with a correlation between the pain area and pain intensity. After application of capsaicin, significant hyperalgesia was found to distension of the gut (a 28% reduction pressure in pain threshold). No significant manifestations were found after application of glycerol and saline. Application of capsaicin to the human ileum induces pain and mechanical hyperalgesia. Specific activation of nociceptors in the gut mucosa provides new possibilities to study clinical relevant visceral pain mechanisms.
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Affiliation(s)
- Asbjørn Mohr Drewes
- Laboratory for Visceral Pain and Biomechanics, Department of Medical and Surgical Gastroenterology, Aalborg Hospital, 9000 Aalborg, Denmark.
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Stanghellini V, De Ponti F, De Giorgio R, Barbara G, Tosetti C, Corinaldesi R. New developments in the treatment of functional dyspepsia. Drugs 2003; 63:869-92. [PMID: 12678573 DOI: 10.2165/00003495-200363090-00003] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Functional dyspepsia is a clinical syndrome defined by chronic or recurrent pain or discomfort in the upper abdomen of unknown origin. Although generally accepted, investigators differently interpret this definition and clinical trials are often biased by inhomogeneous inclusion criteria. The poorly defined multifactorial pathogenesis of dyspeptic symptoms has hampered efforts to develop effective treatments. A general agreement exists on the irrelevant role played by Helicobacter pylori in the pathophysiology of functional dyspepsia. Gastric acid secretion is within normal limits in patients with functional dyspepsia but acid related symptoms may arise in a subgroup of them. Proton pump inhibitors appear to be effective in this subset of patients with dyspepsia. Non-painful dyspeptic symptoms are suggestive of underlying gastrointestinal motor disorders and such abnormalities can be demonstrated in a substantial proportion of patients. Postprandial fullness and vomiting have been associated with delayed gastric emptying of solids, and early satiety and weight loss to postcibal impaired accommodation of the gastric fundus. Prokinetics have been shown to exert beneficial effects, at least in some patients with dyspepsia. In contrast, drugs enhancing gastric fundus relaxation have been reported to improve symptoms, although conflicting results have also been published. An overdistended antrum may also generate symptoms, but its potential pathogenetic role and the effects of drugs on this abnormality have never been investigated formally. Visceral hypersensitivity plays a role in some dyspeptic patients and this abnormality is also a potential target for treatment. Both chemo- and mechanoreceptors can trigger hyperalgesic responses. Psychosocial abnormalities have been consistently found in functional digestive syndromes, including dyspepsia. Although useful in patients with irritable bowel syndromes (IBS), antidepressants have been only marginally explored in functional dyspepsia. Among the new potentially useful agents for the treatment of functional dyspepsia, serotonin 5-HT(4) receptor agonists have been shown to exert a prokinetic effect. Unlike motilides, 5-HT(4) receptor agonists do not appear to increase the gastric fundus tone and this may contribute to improve symptoms. 5-HT(3) receptor antagonists have been investigated mainly in the IBS and the few studies performed in functional dyspepsia have provided conflicting results. Also, kappa-opioid receptor agonists might be useful for functional digestive syndromes because of their antinociceptive effects, but available results in functional dyspepsia are scanty and inconclusive. Other receptors that represent potential clinical targets for antagonists include purinoceptors (i. e., P2X2/3 receptors), NMDA receptors (NR2B subtype), protease-activated receptor-2, the vanilloid receptor-1, tachykinin receptors (NK(1)/NK(2)) and cholecystokinin (CCK)(1) receptors.
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Affiliation(s)
- Vincenzo Stanghellini
- Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy.
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Strigo IA, Bushnell CM, Boivin M, Duncan GH. Psychophysical analysis of visceral and cutaneous pain in human subjects. Pain 2002; 97:235-246. [PMID: 12044620 DOI: 10.1016/s0304-3959(02)00023-4] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Clinical evidence suggests that cutaneous and visceral pain differ in sensory, affective, and motivational realms, yet there has been little comparative characterization of these types of pain. This study uses psychophysical measures to compare directly visceral and cutaneous pain and sensitivity. Healthy subjects (10 males, seven females, age 19-29) evaluated perceptions evoked by balloon distention of the distal esophagus and contact heat on the upper chest. Subjects gave continuous ratings of pain intensity using an on-line visual analog scale (VAS), reported maximum pain intensity and unpleasantness on printed VASs, chose phrases from the McGill Pain Questionnaire and Spielberger State-Trait Anxiety Inventory, and drew the area of perceived sensation. For esophageal distention, the threshold for pain intensity was higher than that observed for unpleasantness, whereas for contact heat, pain and unpleasantness thresholds did not differ for either phasic (10s) or tonic (36s) stimulus application. The relative unpleasantness, calculated as the difference between the unpleasantness and the intensity ratings, was higher during esophageal distention than during either phasic or tonic cutaneous heat; this difference in relative unpleasantness was seen at all intensities of esophageal stimulation. Subjects chose significantly more affective words and reported more anxiety during visceral pain than during phasic cutaneous heat pain. A similar tendency was observed when visceral pain was compared to tonic cutaneous heat pain. Subjects also chose a wider range of words to describe visceral than cutaneous pain. On-line VAS ratings revealed greater pain sensation after stimulus termination during visceral than during phasic cutaneous pain; likewise, a similar tendency was observed between visceral and tonic cutaneous pain. Finally, visceral pain led to a more spatially diffuse sensation and was referred to the entire chest and sometimes to the back. Our results show that visceral pain is more unpleasant, diffuse, and variable than cutaneous pain of similar intensity, independent of the duration of the presented stimuli. The data suggest the likelihood of both similarities and differences in the neural substrates underlying visceral and cutaneous pain.
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Affiliation(s)
- Irina A Strigo
- Department of Physiology McGill University, Montreal, Quebec, Canada, H3G 1Y6 Department of Anesthesia, Anesthesia Research Unit, Room 1225, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada, H3G 1Y6 Département de gastroenétrologie, Faculté de médecine, Université de Montréal, Montreal, Quebec, Canada, H3C 3J7 Département de stomatologie, Faculté de médecine dentaire, Université de Montréal, Montreal, Quebec, Canada, H3C 3J7 Centre de recherche en sciences neurologiques, Faculté de médecine dentaire, Université de Montréal, Montreal, Quebec, Canada, H3C 3J7
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Abstract
GOALS Review of research directions in the etiology, evaluation, and treatment of patients with noncardiac chest pain. The author proposes a combined practical approach to noncardiac chest pain that incorporates these findings, which is useful in a clinical practice setting. BACKGROUND Several major schools of thought have emerged in the etiology of noncardiac chest pain: acid reflux, motor disorder, altered pain threshold/hypersensitivity, and association with psychiatric dysfunction. There is significant overlap among these. Occult gastroesophageal reflux disease (GERD) is more common than motor disorders and is found in 30% to 40% of these patients; a subset has hypersensitivity, with a normal pH profile. Esophageal motility testing and endoscopy have a more limited role than 24-hour pH testing. Impedance planimetry and balloon sensory provocative testing remain research tools. Provocative testing with hydrochloric acid or edrophonium is less helpful than pH monitoring. Gastroesophageal reflux disease-induced chest pain requires high-dose long-term proton pump inhibitors (PPIs): at least 4 to 8 weeks. Psychotropics are superior to placebo, both in patients with and without psychiatric dysfunction. RESULTS The author found combined PPIs and psychotropics helpful in patients with esophageal hypersensitivity and GERD, although supporting data is scant. CONCLUSIONS A brief 1-week high-dose PPI challenge, i.e., omeprazole test, may be cost-effective in a primary care setting. However, this approach may not be useful in a referral setting, where pH data and diary assessment of associated symptoms provide useful management help. A behavioral model approach, with early emphasis on patient education, integrated with physiologic data helps the most.
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Affiliation(s)
- V Alin Botoman
- Department of Gastroenterology, Cleveland Clinic Florida, Weston, Florida 33331, USA.
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Abstract
OBJECTIVE Many patients with functional (noncardiac) chest pain exhibit both hypersensitivity and motor dysfunction of the esophageal wall. We aimed to determine whether the sensory or motor dysfunction plays an important role in the pathogenesis of chest pain. METHODS We performed graded balloon distentions of the esophagus using impedance planimetry in 16 consecutive patients with chest pain and otherwise normal cardiac and esophageal evaluations and in 13 healthy controls. In those patients who experienced chest pain with balloon distention, the test was repeated after atropine was given. Sensory and biomechanical parameters were measured. RESULTS Balloon distention reproduced typical chest pain in 13/16 patients (81%) and at lower (p < 0.01) sensory thresholds than controls. Pain was reproduced in all 13 patients and at lower (p < 0.05) sensory thresholds after atropine. Also, after atropine, the esophageal cross-sectional area and wall tension increased (p < 0.05), the tension/strain association shifted to the right (p < 0.05), and reactivity decreased (p < 0.002) relative to results before atropine or in healthy controls (i.e., the esophageal wall relaxed and became more deformable). CONCLUSIONS Even after relaxing the esophageal wall, most patients experienced chest pain and at lower sensory thresholds. Hence, hyperalgesia rather than motor dysfunction appears to be the predominant mechanism for functional chest pain of esophageal origin.
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Affiliation(s)
- S S Rao
- Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, USA
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Abstract
OBJECTIVES Nutcracker esophagus is a manometric pattern that is commonly seen in patients with functional (noncardiac) chest pain. However, this pattern is often unassociated with pain. Consequently, the pathophysiology of chest pain in these patients is unclear. METHODS We prospectively examined the sensory perception and biomechanical properties of the esophagus in 10 patients with chest pain and a nutcracker esophagus, along with those properties in 12 healthy controls using impedance planimetry. RESULTS Stepwise balloon distentions reproduced typical chest pain in 9/10 (90%) patients. The threshold for chest pain was lower (p < 0.05) in patients than in controls (mean +/- SD 43+/-5 vs 62+/-4 cm H2O) but only 2/12 controls experienced pain. The thresholds for first perception and moderate discomfort were also lower (18+/-8 vs 30+/-11 cm H2O, p < 0.01 and 28+/-9 vs 62+/-5 cm H2O, p < 0.001) in patients than in controls, but only 3/12 controls experienced moderate discomfort. The esophageal reactivity to balloon distention was higher in patients than in controls (p < 0.001). The tension-strain curve shifted to the left in the patient group when compared to that in the controls (p < 0.05). CONCLUSIONS Patients with a nutcracker esophagus demonstrate a hypersensitive and stiff esophagus. Because balloon distention reproduced their chest pain, visceral hyperalgesia of the esophagus may be relevant to the pathogenesis of their pain. Balloon distention test may be more useful in the evaluation of patients with functional chest pain and a nutcracker esophagus.
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Affiliation(s)
- V R Mujica
- Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, USA
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