A study of bloating symptomatology, the role of gastrointestinal transit and the response to treatment with the 5 HT4 receptor agonist in patients with bloating predominant irritable bowel syndrome

A STUDY OF BLOATING SYMPTOMATOLOGY, THE ROLE OF GASTROINTESTINAL TRANSIT AND THE RESPONSE TO TREATMENT WITH THE 5-HT4 RECEPTOR AGONIST IN PATIENTS WITH BLOATING PREDOMINANT IRRITABLE BOWEL SYNDROME YANG MEI (MBBS, CSU) A THESIS SUBMITTED FOR THE DEGREE OF MASTER OF SCIENCE DEPARTMENT OF MEDICINE NATIONAL UNIVERSITY OF SINGAPORE 2006 ACKNOWLEDGEMENTS I would like to express my sincere thanks to my supervisors, Professor Ho Khek Yu and Professor Gwee Kok Ann, for their invaluable advice and guidance throughout the course of this project. I would also thank Dr. Shuter Borys for his great support in scan data analysis. Many thanks to Ms.Luo Fenfang, Ms.Ng Siew Mei, Mr. Jerry Lara and other staff in Nuclear Medicine Department, NUH for their kind help in technical support in bran scan. I greatly appreciate Dr Song Guanghui for his important advice and suggestion. I would also thank Ms Guo Yaling, Ms Adeline Chow, Ms Betty Tan and Mr Lui Kai Foo for their support, help and friendship. I would like to thank Miss Shila Rosli, Miss Shiela Pulmones for their kind help in technical support, patient recruitment and financial management. At last, special thanks to my loved husband, daughter and my parents for their love and encouragement. i CONTENTS Page Title Acknowledgements i Contents ii Summary vi Chapter Introduction 1.1 Irritable Bowel Syndrome (IBS) 1.1.1 Overview 1.1.2 Epidemiology 1.1.3 Diagnosis of IBS 1.1.3.1 Diagnosis Criteria 1.1.3.2 Diagnostic Strategy 1.1.4 Pathophysiology of IBS 11 1.1.4.1 Altered motility 11 1.1.4.2 Visceral Hypersensitivity 12 1.1.4.3 Psychopathology 14 1.1.4.4 Stress 15 1.1.4.5 The brain-gut interaction 18 1.1.5 Treatment 21 1.1.5.1 Non-pharmacological therapies 21 1.1.5.2 Pharmacological treatment 23 1.2 Bloating in IBS 27 ii 1.2.1 Overview 27 1.2.2 Pathophysiology of bloating 29 1.2.2.1 Mechanisms of distorted sensation 29 1.2.2.2 Mechanisms of physical abdominal expansion 30 1.2.2.3 Mechanisms of abdominal muscular activity 33 1.3 The role of Serotonin in IBS 34 1.3.1 Synthesis, distribution and metabolism of Serotonin 35 1.3.2 Serotonin in GIT 37 1.3.3 Effects of 5-HT4 agonist on IBS 38 1.4 Hypothesis and Aims 41 Chapter Symptom Profile in Irritable Bowel Syndrome Patients with Bloating 43 2.1 Introduction 44 2.2 Subjects and methods 45 2.2.1 Subjects 45 2.2.2 Methods 47 2.2.3 Statistical analysis 48 2.3 Results 49 2.3.1 Demographic Characteristics 49 2.3.2 Characteristics of the sensation of bloating 50 2.3.3 Bowel habits 54 2.3.4 Symptom score and HAD score 56 2.3.5 Survey of IBS education 58 iii 2.4 Discussion 59 Chapter Impaired Intestine Transit in Non-Diarrhea Irritable Bowel Syndrome Patients with Bloating 64 3.1 Introduction 65 3.2 Subjects and methods 67 3.2.1 Subjects 67 3.2.2 Procedure 68 3.2.3 Scintigraphic analysis 70 3.2.4 Statistical analysis 71 3.3 Results 73 3.3.1 Demographic characteristics 73 3.3.2 Transit times 75 3.3.3 Bloating symptom and girth measurement 82 3.4 Discussion 84 Chapter Effect of 5-HT4 Agonist Tegaserod on Non-Diarrhea IBS with Bloating –A Randomized, Double Blind, Placebo Controlled Study 89 4.1 Introduction 90 4.2 Subjects and methods 92 4.2.1 Subjects 92 4.2.2 Methods 93 4.2.3 Statistical analysis 96 4.3 Results 4.3.1 Demographic characteristics 97 97 iv 4.3.2 Symptoms characteristics in treatment groups 98 4.3.3 Transit measurements 104 4.4 Discussion 110 Chapter References 115 Appendix Appendix A Gastrointestinal Symptoms Questionnaire Appendix B Hospital Anxiety and Depression (HAD) Scale Appendix C Symptoms Score Appendix D Bowel Diary v Summary Irritable bowel syndrome (IBS) is a chronic disorder with symptoms of abdominal pain, discomfort or bloating associated with alterations in bowel habits without organic disease. Bloating is a troublesome and poorly understood symptom in IBS. It has been suggested that impaired gut motility and altered sensitivity may be the mechanism of bloating. We thus hypothesized that 1) bloating predominant IBS patients in Asia have delayed intestinal transit; and 2) tegaserod could improve bloating and intestine transit in these patients. Therefore, the objective of this study is to investigate the symptomatology of bloating, the role of gastrointestinal transit and effect of tegaserod in non-diarrhea IBS patients with bloating. In the first part of this thesis, the symptoms profiles of non-diarrhea IBS patients with bloating were assessed. It was showed that there were more common complaints with upper abdominal bloating associated with moderate bowel disturbance in these patients. Using psychological questionnaires, these IBS patients were observed to have higher HAD scores than healthy controls. Additionally, the results of IBS education survey suggested that more IBS health education and health-care costs about IBS should be provided to Asian patients. vi The second part of this thesis was to investigate the gastrointestinal transit in non-diarrhea IBS patients with bloating and normal controls, using radioscintigraphic method. The results showed these bloating IBS patients had significant slower small bowel transit than normal controls. However, there were no significant differences in the gastric emptying half-time and ileocaecal transit times between the IBS patients and normal controls. Meanwhile, it was found that majority of these IBS patients and none of the normal controls reported bloating during the scan. In the third part of this thesis, the effect of 5-HT4 receptor agonist Tegaserod was investigated in a randomized, double blind and controlled study. Compared with placebo, administration of oral tegaserod 6mg twice a day for two weeks significantly alleviated bloating symptom in non-diarrhea IBS patients with bloating. It was also showed partial improvement in bowel habits after tegaserod treatment. On the other hand, tegaserod accelerates small bowel transit time without any effect on gastric emptying and ileocaecal transit time. Moreover, the improvement of bloating score is positively correlated to the decrease of small bowel transit time in tegaserod group. In conclusion, we demonstrated that non-diarrhea IBS patients with bloating in Asia presented with upper abdominal bloating, moderate bowel disturbance and vii higher HAD scores than normal controls. Moreover, these patients have impaired small intestinal transit. Tegaserod mg b.i.d alleviated the bloating symptoms and bowel disturbance. In addition, tegaserod significantly accelerated small bowel transit in bloating predominant IBS patients compared with placebo. 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Aliment Pharmacol Ther 2002;16:1867-76 125 Appendix A Gastrointestinal Symptoms Questionnaire • • • • • • “Often” refers to a frequency of at least 25% of the time “Severity” of symptoms refers to the severity of at least 50% of episodes = None = Mild (awareness of symptoms, no interference with daily activities, can be ignored) = Moderate (some interference with daily activities, cannot be ignored, but can continue with work/daily activities) = Severe ( disabling, unable to conduct a range of daily activities, affects concentration on work and daily activities) Upper GUT Symptoms 1. Did you often notice a sour or acid tasting fluid at the back of your throat? ‰ None ‰ Mild ‰ Moderate ‰ Severe 2. Did you often have heartburn or chest pain? ‰ None ‰ Mild ‰ Moderate ‰ Severe 3. Did you often have difficulty swallowing? ‰ None ‰ Mild ‰ Moderate ‰ Severe 4. Did you often have a feeling of wanting to throw up? ‰ None ‰ Mild ‰ Moderate ‰ Severe 5. Did you often throw up? ‰ None ‰ Mild ‰ Moderate ‰ Severe 6. Did you often experience discomfort or pain in the abdomen after meals? ‰ None ‰ Mild ‰ Moderate ‰ Severe 7. Did your stomach often become over-filled soon after starting to eat, out of proportion to the size of the meal? ‰ None ‰ Mild ‰ Moderate ‰ Severe 8. Did you often have a sensation of persistence of food in the stomach? ‰ None ‰ Mild ‰ Moderate ‰ Severe 9. Did you often experience bloating or distension of the abdomen? ‰ None ‰ Mild ‰ Moderate ‰ Severe Abdominal Pain 10. Did you often have an ache or pain in your abdomen? ‰ None ‰ Mild ‰ Moderate ‰ Severe 11. Where you usually feel the pain? Which of these often makes the pain better? 13. Belching ‰ Yes ‰ No 14. Vomiting ‰ Yes ‰ No 15. Passing motion ‰ Yes ‰ No 16. Passing flatus ‰ Yes ‰ No When you have the pain, are your bowel movements often: 17. More frequent? ‰ Yes ‰ No 18. Less frequent? ‰ Yes ‰ No 19. Loose or watery? ‰ Yes ‰ No 20. Harder? ‰ Yes ‰ No Bloating 21. Did you have bloating in your abdomen? ‰ None ‰ Mild ‰ Moderate ‰ Severe 22. Where you usually feel the bloating? Which of these makes the bloating better? 23. Belching ‰ Yes ‰ No 24. Vomiting ‰ Yes ‰ No 25. Passing motion ‰ Yes ‰ No 26. Passing flatus ‰ Yes ‰ No When you have the bloating, are your bowel movements often: 27. More frequent? ‰ Yes ‰ No 28. Less frequent? ‰ Yes ‰ No 29. Loose or watery? ‰ Yes ‰ No 30. Harder? ‰ Yes ‰ No 31. When is your bloating worse? ‰ On waking ‰ Morning ‰ Afternoon ‰ Evening ‰ At night 32. Are there any known precipitating factors for the bloating? ‰ Yes please specify : _____________________________ ‰ No 33. Is your bloating visible distension? ‰ Yes ‰ No Bowel Habits 34. How would you describe your usual bowel pattern in the last one month? ‰ Normal ‰ Constipated ‰ Diarrhoea ‰ Alternating constipation/diarrhoea Did you often have bowel movements: 35. Less than times per week? ‰ Yes ‰ No 36. More than 21 times a week (or times a day)? ‰ Yes ‰ No With regard to your stools, were they often: 37. Loose or watery ‰ None ‰ Mild ‰ Moderate ‰ Severe 38. Hard or pellety ‰ None ‰ Mild ‰ Moderate ‰ Severe 39. Did you often see mucus in your stools? ‰ Yes ‰ No 40. Did you often strain to have a bowel movement? ‰ Yes ‰ No 41. After finishing a bowel movement, did you often feel there was still stool that needed to be passed? ‰ None ‰ Mild ‰ Moderate ‰ Severe 42. Did you often experience an urgent need to open your bowels that made you rush to the toilet? ‰ None ‰ Mild ‰ Moderate ‰ Severe Appendix B Hospital Anxiety and Depression (HAD) Scale 1) Doctors are aware that emotions play an important part in most illnesses. This questionnaire is designed to help your doctor to know how you are feeling. 2) Please read each item, then place a tick ( ) in the box which comes closest to how you have been feeling during the past week. 3) Don’t take too long over your replies; your immediate reaction to each item will probably be more accurate than a long thought out response I feel tense or wound up: □ Most of the time □ A lot of the time □ Time to time □ Not at all *I feel as if I am slowed down: □ Nearly all the time □ Very often □ Sometimes □ Not at all *I still enjoy the things I used to enjoy: □ Definitely as much □ Not quite so much □ Only a little □ Hardly at all I get a sort of frightened feeling like butterflies in the stomach: □ Not at all □ Occasionally □ Quite often □ Very often I get a sort of frightened feeling as if something awful is about to happen: □ Very definitely and quite badly □ Yes, but not too badly □ A little, but it does not worry me □ Not at all *I have lost interest in my appearance: □ Definitely □ I not take so much care as I should □ I may not take quite as much care □ I take just as much care as ever *I can laugh and see the funny side of things: □ As much as I always could □ Not quite as much now □ Definitely not so much now □ Not at all I feel restless as if I have to be on the move: □ Very much indeed □ Quite a lot □ Not very much □ Not at all Worrying thoughts go through my mind: □ A great deal of the time □ A lot of the time □ From time to time but not too often □ Only occasionally *I look forward with enjoyment to things: □ As much as ever I did □ Rather less than I used to □ Definitely less than I used to □ Hardly at all *I feel cheerful: □ Not at all □ Not often □ Sometimes □ Most of the time I get sudden feelings of panic: □ Very often indeed □ Quite often □ Not very often □ Not at all I can sit at ease and feel relaxed: □ Definitely □ Usually □ Not often □ Not at all *I can enjoy a good book or radio or TV programmer: □ Often □ Sometimes □ Not often □ Very seldom Scoring: Even questions (with*) are for depression. Odd questions are for anxiety. Score each separately. A score of or more is significant, a score of 11 or more highly significant. Appendix C Symptoms Score For the symptoms which you experience at least days per week, please choose the symptom scores that best describe the symptoms. (Please tick in the appropriate box) = none Symptom score (Likert scale) = mild = 3= moderate moderate severe = severe abdominal pain abdominal fullness bloating belching nausea flatus Appendix D 10 [...]... increases water and ion absorption, decrease intestinal transit time and increases anal sphincter tone (Viera et al, 2002) Several clinical trials showed that loperamide significantly ameliorates diarrhea, urgency and faecal soiling, although it has no effect on other IBS-related symptoms such as pain and bloating (Jailwala et al, 2000& Read et al, 1982) Compared to codeine and diphenoxylate, loperamide... for the treatment of diarrheapredominant IBS in female patients resistant to conventional anti-diarrhoic agents 5- HT4 receptor agonists 24 5- HT4 receptor agonists are known to evoke a potent prokinetic effect throughout the gastrointestinal tract Stimulation of 5- HT4 increases colonic transit time and inhibits visceral sensitivity The most extensively studied 5- HT4 receptor agonists include cisapride,... defecation associated with change in frequency of stools Associated with change in form of stools with the following symptoms supporting irritable bowel syndrome: altered stool frequency and/ or form altered stool passage passage of mucus bloating or abdominal distension 7 1.1.3.2 Diagnostic Strategy Clinical presentation The predominant symptom of IBS is abdominal pain/ discomfort associated with a change... reduce the transit time of the entire alimentary tract and intestinal wall tension by decreasing intracolonic pressure (Muller, 1988) However, the ability of dietary fiber to alleviate abdominal pain and diarrhea has been disappointing It seems that IBS patients 21 with diarrhea -predominant symptoms have greatest number of adverse food reactions Simple dietary advice is inexpensive and harmless and may... on the role of abnormal motility in the pathogenesis of IBS A number of motor abnormalities have been described in the colon and small intestine of IBS patients Patients with predominant symptom of diarrhea seem to have accelerated whole gut and colonic transit times Conversely, decreased transit was revealed in patients who have constipation predominant IBS (Cann et al, 1983) Intestinal transit studies... abdominal bloating in the month before the interview (Sandler et al, 2000) Studies revealed that abdominal bloating is second only to abdominal pain as the most frequently reported symptom in IBS (Manning et al, 1978 & Maxton et al, 1989) Bloating, as with most functional gastrointestinal symptoms, is much more frequent in women than in men (Chang et al 2001 & Sandler et al, 2000) The severity of bloating. .. stress management, and relaxation techniques Further treatments are based on the type and severity of symptoms 25 Constipation -predominant Mild Diarrhea -predominant Pain -predominant Education, reassurance, stress management, and relaxation techniques Guar gum, fiber, exercise Trial diet excluding Increased fluid intake lactose and caffeine; Other dietary changes Antispasmodic agent Moderate pepermint, Osmotic... common and bothersome abdominal complaint in patients with IBS, and it impairs quality of life However, it is an ambiguous term that alludes both to the subjective sensation and to the objective abdominal distention (Azpitoz& Malagelada, 20 05) To some patients, bloating refer to a subjective sensation of fullness or pressure inside the abdomen To some individuals, bloating represents abdominal distension,... suggest that the transit of food through the ileocaecal region may be associated with pain and bloating (Cann et al, 1983; Trotman et al, 1986) Recently, a study found that IBS patients has impaired transit and tolerance to intestinal gas and this has been cited as a possible mechanism for bloating which commonly experienced in IBS patients( Serra et al, 2001) Similarly study demonstrated that rectal distension... neuromodulatory peptides, which including corticotrophin releasing factor (CRF), vasoactive intestinal peptide (VIP), serotonin, calcitonin gene-related polypeptide (CGRP), acetylcholine, substance P, nitric oxide, cholecystokinin, and the enkephalins (Kirkup et al, 2001) In particular, serotonin (5- HT) is a major messenger in the GI tract Two of 5- HT receptors, 5- HT3 and 5- HT4 appear to play an important role . A STUDY OF BLOATING SYMPTOMATOLOGY, THE ROLE OF GASTROINTESTINAL TRANSIT AND THE RESPONSE TO TREATMENT WITH THE 5- HT4 RECEPTOR AGONIST IN PATIENTS WITH BLOATING PREDOMINANT IRRITABLE BOWEL. be the mechanism of bloating. We thus hypothesized that 1) bloating predominant IBS patients in Asia have delayed intestinal transit; and 2) tegaserod could improve bloating and intestine transit. transit in these patients. Therefore, the objective of this study is to investigate the symptomatology of bloating, the role of gastrointestinal transit and effect of tegaserod in non-diarrhea IBS