Irritable Bowel Syndrome: Diagnosis, Psychology, and Treatment [Reprint 2020 ed.] 9783110813722, 9783110149128

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Irritable bowel syndrome

Irritable bowel syndrome Diagnosis, psychology, and treatment

Edited by

P. Denis

w Walter de Gruyter DE

G Berlin • New York 1995

Editor Prof. Dr. P. Denis G r o u p e de B i o c h e m i e et de Physiopathologie Digestive et Nutritionelle ( G B P D N ) , C H U Rouen F-76031 Rouen Cedex France

Deutsche Bibliothek

—

Cataloging-in-Publication-Data

Irritable bowel syndrome : diagnosis, psychology, and treatment / ed. by P. Denis. — Berlin ; New Y o r k : de Gruyter, 1 9 9 5 ISBN 3 - 1 1 - 0 1 4 9 1 2 - 5 N E : Denis, Philippe [Hrsg.]

© Copyright 1 9 9 5 by Walter de G r u y t e r &C C o . , Berlin. All rights reserved, including those o f translation into foreign languages. N o part o f this b o o k may be reproduced in any form — by p h o t o p r i n t , microfilm o r any other means n o r transmitted n o r translated into a machine language without written permission f r o m the publisher. M e d i c a l science is constantly developing. Research and clinical experience e x p a n d our k n o w l e d g e , especially with regard to t r e a t m e n t and medication, For dosages and applications mentioned in this w o r k , the reader may rely on the authors, editors and publisher having taken great pains to ensure that these indications reflect the standard o f knowledge at the time this w o r k w a s completed. Nevertheless, all users are requested to check the p a c k a g e leaflet o f the m e d i c a t i o n , in order to determine for themselves whether the r e c o m m e n t a t i o n s given for the dosages or the likely contraindications differ f r o m those given in this b o o k . T h i s is especially true for medication which is seldom used o r has recently been put on the m a r k e t and for medication whose application has been restricted by the G e r m a n Ministry o f H e a l t h . T h e q u o t a t i o n o f registered names, trade names, trade m a r k s , etc. in this copy does not imply, even in the absence o f a specific statement that such names are e x e m p t from laws and regulations protecting trade m a r k s , etc. and therefore free for general use. Typesetting: Arthur Collignon G m b H , Berlin. — Printing: G e r i k e G m b H , Berlin. — Binding: Dieter M i k o l a i , Berlin. — Printed in G e r m a n y .

Authors

M. Delvaux, Dr. Gastroenterology Unit CHU Rangueil F-31054 Toulouse France

A. Morbey, Dr. Gastroenterol. Dept. Curry Cabral Hopital Lisbon Portugal

P. Denis, Prof. Dr. Groupe de Biochemie et de Physiopathologie Digestive et Nutritionelle (GBPDN), CHU Rouen F-76031 Rouen Cedex France

M. van Outryve, Dr. Gastro-Enterologie Grétrystraat 33 B-2018 Antwerpen Belgium

A. den Hertog, Prof. Dr. Rijksuniversiteit Groningen Vokgroep Farmacologie/Klinische Farmacologie NL-9713 BZ Groningen Netherlands H. Malchow, Prof. Dr. Klinikum Leverkusen D-51375 Leverkusen Germany

J. Weber, Prof. Groupe de Biochemie et de Physiopathologie Digestive et Nutritionelle (GBPDN) CHU Rouen F-76031 Rouen Cedex France

Contents

Introduction P. Denis

1

Diagnosis of irritable bowel syndrome H. Malchow

3

Psychosocial profile of patients with irritable bowel syndrome J. Weber, P. Denis

13

Awareness of IBS by patients and physicians A. Morbey

19

Pharmacological aspects of mebeverine and antispasmodics as related to irritable bowel syndrome A. den Hertog

25

A new mebeverine formulation in clinical practice M. Delvaux

31

Risk-benefit ratio of IBS treatment: data from a high dose mebeverine study M. van Outryve

37

Introduction P. Denis

T h e round table organized by S O L V A Y Pharma to present a new formulation of mebeverine enabled the participants to review and update the present status of irritable bowel syndrome (IBS), a particularly frequent cause f o r the consulting of gastroenterologists. This round table had three major objectives: the definition of IBS, its management and its medical treatment. International data on IBS diagnosis were reviewed by H . M a l c h o w . This confirmed the clear consensus shared by some of the participants about the clinical criteria on which the diagnosis of IBS is usually based. T h e place of colonoscopy in diagnostic strategy w a s widely discussed. While the participants readily agreed on its value when a risk factor f o r cancer w a s present, a consensus seemed less easy to reach f o r other cases. In this matter, it is still diffucult to formulate a precise recommendation. Functional investigations do remain the subject of emotional reactions. Because they are unable to bring an immediate improvement in the diagnosis of IBS, some of the participants considered them to be useless. For others, they are necessary as they seem to contribute to a better understanding of the symptoms and, therefore, to improve our knowledge of the pathophysiology of this syndrome. In the immediate future, functional investigations will likely be restricted to clinical research and to a better understanding of the mechanisms of drug action and medical treatment. T h e second topic concerned the management of patients with IBS. T h e participants easily reached agreement on the absolute necessarity of a close relationship between physician and patient for the medical treatment. In a sense, the manner in which the medical treatment is prescribed may be as important as the prescription itself. T h e request f o r additional investigations is sometimes more a part of this understanding between physician and patient than a component of the rational strategy f o r evaluating the patient's condition: sometimes colonoscopy may be prescribed more to reduce the patient's fear of cancer than to assess his lesions. Occasionally, the necessary relationship between physician and patient may "infiltrate" the logical recommendations of a diagnostic approach. T h e chronicity of this syndrome is the second characteristic to be taken into account in the management of patients with IBS and w a s discussed at length during this meeting. A s clearly explained by A . Morbey, the physician tries more to control the symptoms than to cure them. T h e participants agreed that

2

P. Denis

physicians, in order to control the course of IBS, must first have an understanding approach vis-à-vis their patients and also see them regularly (the optimal periodicity of these visits being difficult to establish) and inform them about their disorder. When patient's are correctly informed they may indeed contribute to a better management of their symptoms. Achieving an understanding attitude may be easier for the physician if he better understands the personality of his patient. T h e semiometric survey presented by J . Weber suggests that the physician's approach should be adjusted to the major symptom manifested by the patient. In this survey, it was observed that the patient's personality varied with the dominant symptoms: constipation, diarrhea or bloating. Constipated patients seem to grant more importance to values such as harmony and loyalty, suggesting that the physician should adopt a maternal attitude. In the case of patients with diarrhea, the physician should abandon the idea of giving strict directions to the patient, and instead provide more information about IBS, as patients with diarrhea appear to be more independently minded, freedom loving and ask for advice but refuse orders. Bloated patients, on the contrary, are orderly persons, keen on moral values, they will therefore expect their physician to be rational and self-assertive. They would like to understand their symptoms and tend to request examinations with a pathophysiological orientation. They wish to receive strict directives based on physiopathological mechanisms. T h e last part of this round table dealt with the pharmacological mechanisms of drug action in the various methods used to treat these patients and recent reports based on two studies on mebeverine. Four major points emerged from the debate carried out by the participants about these treatments: T h e drugs used in IBS must be effective without showing atropinic side effects or an interaction with the central nervous system as underlined by A. den Hertog speaking about the pharmacology of IBS drugs. T h e trend toward new galenic formulations reducing the number of doses seems to be very promising, ensuring the compliance of patients who suffer from chronic disorders such as IBS, as was suggested by M . Delvaux and M . van Outryve in their reports on the results of two studies on the new slow-release formulation of mebeverine. It is necessary to indicate if the antalgic effect of a drug is due to its action on the motility of the intestinal wall or its sensitivity. T h e time during which a drug should initially be prescribed for acute symptomatology and the efficacy of a long-term treatment are still unclear.

Diagnosis of irritable bowel syndrome H.

Malchow

It is nearly as complicated to speak on the diagnosis of irritable bowel syndrome as on the therapy for irritable bowel syndrome, because there are no positive criteria for diagnosis, but rather only exclusion criteria. At first it is necessary to take the medical history of the patient, and the patient will talk about abdominal distension, that he does not feel well in his abdomen and has relief of abdominal pain with defecation. This holds true for 30% to 40% of all patients. Most patients have more frequent bowel movements and report looser stools with the onset of abdominal pain. There is a long list of symptoms for irritable bowel syndrome (tab. 1). Abdominal pain is not easily characterized, it is very often on the left side of the abdomen, it may be on the upper-left or lower-left side of the abdomen, and the patient may report distension. Bloating is another feature of this disease, and there is nearly no patient who does not suffer from bloating. Some patients have previously had surgery, but it is not known whether abdominal surgery really causes the development of irritable bowel syndrome or whether the patients had been operated upon with the wrong diagnosis. Patients very often have food intolerance, but the diagnosis of food intolerance, too, is very complicated and it is nearly impossible for most practitioners to make a good diagnosis of it. Another symptom which is very often found in irritable bowel syndrome is diarrhea. Diarrhea may be watery, or it may only occur in the form of loose stool. Other patients complain of constipation, or they complain of diarrhea alternating with constipation and irregular stools. And when they inspect their stools, they see mucus and think that they have a severe disease, at least worse than irritable bowel syndrome. Mostly women, but also men, show an abuse of laxatives. Another feature of irritable bowel syndrome is nocturnal

Table 1

• • • • • • •

Symptoms of IBS

Abdominal pain Bloating and/or abdominal distension Abdominal surgery in the history Food intolerance Diarrhea Constipation Diarrhea alternating with constipation

• • • • • •

Irregular stools Mucus on stools Abuse of laxatives Nocturnal well-being Vegetative signs Psychological abnormalities

4

H. Malchow

well-being, where the patient does not feel the symptoms when he sleeps. Some patients have vegetative signs and some patients have psychic abnormalities. There are criteria available to make a positive diagnosis of irritable bowel syndrome. The most accepted are the criteria from Manning (tab. 2), including abdominal distension, relief of pain with bowel movement, more frequent stools with the onset of pain, or looser stools with onset of pain, the passage of mucus, and the sensation of incomplete evacuation. The Manning criteria have been validated by other researchers. Table 2 • • • • • •

Manning

criteria

Abdominal distension Relief of pain with bowel movement More frequent stools with onset of pain Looser stools with onset of pain Passage of mucus Sensation of incomplete evacuation

For clinical studies, the Kruis' score has been discussed as an alternative. This score has two parts. The first part has to be filled out by the patient (tab. 3), where the patient is asked "Did you come because of abdominal pain?", "Do you suffer from flatulence?" and "Do you suffer from bowel movement irregularities?" The second question, "Have you suffered from your complaints for more than two years?" shows that irritable bowel syndrome is a syndrome which is present in the patient for his whole life. The third question is " H o w can your abdominal pain be described: burning, cutting, very strong, terrible, feeling of pressure, dull, boring, not so bad?" The most patients with irritable bowel syndrome can describe their pain very well. The last question to the patient is "Have you noticed alternating constipation and diarrhea?" Points were given for these questions. Table 3

Kruis' index for diagnosis of IBS

Questions to be answered by the patient 1. Did you come because of abdominal pain? Do you suffer from flatulence? Do you suffer from irregularities of bowel movement?

34

2. Have you suffered from your complaints for more than two years?

16

3. H o w can your abdominal pain be described: burning, cutting, very strong, terrible, feeling of pressure, dull, boring, not so bad?

23

4. Have you noticed alternating constipation and diarrhea?

14

Diagnosis o f irritable bowel syndrome

5

T h e second part of the Kruis' score for the diagnosis of irritable bowel syndrome (tab. 4) has to be filled out by the physician and the physician has to check whether, for example, there are abnormal physical findings and/or a history which are pathognomonic for any diagnosis other than irritable bowel syndrome. In this case, 47 points are subtracted. Other parameters are E S R , leucocytosis, hemoglobin and blood in the stool. A positive diagnosis of irritable bowel syndrome is made when the score is 4 4 or greater. T h e method is not easily applicable in normal clinical practice, but it is good for studies of irritable bowel syndrome. Table 4

Kruis' index for diagnosis of IBS

C h e c k list to be filled out by the d o c t o r 1. A b n o r m a l physical findings and/or history p a t h o g n o m o n i c for any diagnosis other than IBS

47

2. E S R > 2 0 mm/2 hr

13

3. Leucocytosis > 10.000/ccm

50

4 . H e m o g l o b i n female < 12 g/dl male < 1 4 g/dl

98

5 . History o f b l o o d in stool

98

A score of a 4 4 is indicative o f IBS

Tab. 5 shows the long list for the differential diagnosis of irritable bowel syndrome. We can divide it into two groups, patients with diarrhea, and patients with constipation. Infectious diarrhea has to be excluded. This is normally done either by the case history or by stool cultures. Inflammatory bowel disease, Crohn's disease, or ulcerative colitis, have to be excluded, too, as well as pancreatic insufficiency and short bowel syndrome. It has to be asked whether

Table 5 • • • • • • • • • •

Differential

diagnosis of IBS — presenting

Infectious diarrhea IBD Pancreas insufficiency S h o r t bowel syndrome Abuse of laxatives Rectal c a r c i n o m a Carcinoid syndrome Verner M o r r i s o n syndrome Zollinger Ellison syndrome Hyperthyreosis

with diarrhea — • • • • • • • • •

Blind loop syndrome Lactase insufficiency Celiac disease Food allergies Whipple's disease Intestinal l y m p h o m a I m m u n e deficiency Amyloidosis D i a b e t i c enteropathy

6

H. Malchow

there is an abuse of laxatives. Rectal carcinoma and carcinoid syndrome and the other aspects on the list must be checked. A similar list is possible for the patients showing constipation and abdominal pain, appendicitis, gall stone disease or cholecystitis, peptic ulcers, gastric tumors, colonic tumors and pancreatic tumors (tab. 6). Table 6 • • • • • • • •

Differential

diagnosis of IBS — presenting

Diverticulitis Appendicitis Gall stone disease/cholecystitis Peptic ulcer Gastric tumors Porphyria Colonic tumors Pancreas tumors

with constipation • • • • • • •

and abdominal

pain —

Lead intoxication Tabes dorsalis Mesenteric vessel disease Hernia Endometriosis Coronary heart disease Urogenital disease

At present, the positive diagnostic criteria generally accepted and described for irritable bowel syndrome are: abdominal pain or discomfort relieved with defecation or associated with a change in frequency or consistency of stools (tab. 7); an irregular pattern of defecation at least 25% of the time consisting of three or more of the following: altered stool frequency, altered stool form (hard loose or watery), and altered stool passage (straining or urgency, feeling of incomplete evacuation, and the passage of mucus), and bloating or feeling of abdominal distension. These are the so-called Rome criteria which base on the Manning Criteria. First published after a 1988 consensus conference in Rome. For the diagnosis it is necessary to look at the case history (tab. 8) and to determine whether typical symptoms have been present for at least three months, i. e. to exclude infections and diseases with a sudden onset. Symptoms suggesting organic disease should be excluded, e. g., pain on awakening from sleep. A typical symptom of irritable bowel syndrome is that the patient is comfortable during the night with regard to pain and diarrhea. Patients with Table 7

Diagnostic

criteria for IBS: Rome

criteria

Continuous or recurrent symptoms for at least three months of: 1. abdominal pain or discomfort, relieved with defecation, or associated with a change in frequency or consistency of stool; and 2. an irregular (varying) pattern of defecation at least 25% of the time (three or more of): altered stool frequency; altered stool form (hard or loose/watery stool); altered stool passage (straining or urgency, feeling of incomplete evacuation); passage of mucus; bloating or feeling of abdominal distension.

Diagnosis of irritable bowel syndrome Table 8

Suggested components

of the evaluation

of patients with symptoms

7

of IBS

Component features History taking

Determine whether typical symptoms have been present for at least three months Check for the presence of the Rome criteria Exclude symptoms suggestive of organic disease • pain on awaking from sleep • pain that interferes with normal sleep patterns • diarrhea that awakens the patient from sleep • visible or occult blood in the stool • weight loss • fever Investigate the patient's dietary history to exclude lactase insufficiency or excessive use of sorbitol, fructose or aspartame Review medications for gastrointestinal side effects Identify psychosocial factors precipitating presentation Consider depression or panic disorders

irritable bowel syndrome are normally in good health and don't experience weight-loss or fever. Fever, like blood in the stool, is a symptom of an organic inflammatory disease or of malignancy. The patient's dietary history should be investigated to exclude lactase insufficiency or excessive use of sorbitol, fructose or aspartame. This is important because nowadays there are so many foods which contain sorbitol, fructose or aspartame, especially so-called diet food and/or diet drinks. A physical examination is also necessary for the diagnosis (tab. 9), as well as a complete blood count of erythrocyte sedimentation rate and flexible sigmoidoscopy. Table 9

Suggested components

of the evaluation

of patients with symptoms

of IBS

Component features Physical examination Other studies

-

Perform a complete blood count Measure erythrocyte sedimentation rate Conduct chemistry panel Perform flexible sigmoidoscopy If diarrhea is the predominant symptom: • examine stool for ova and parasites, fecal leucocytes and excessive fat Assess thyroid function Perform sigmoidoscopic biopsy

8

H. Malchow

Other diagnoses have to be considered for patients with symptoms of irritable bowel syndrome (tab. 10). Table 10

Diagnoses

that may need to be considered

in patients with symptoms

of IBS

Diagnosis

Cause

Neoplasia

colonic adenocarcinoma, villous adenoma

Inflammatory bowel disease

ulcerative colitis, Crohn's disease

Vascular insufficiency

abdominal angina, ischemic colitis

Chronic constipation

drugs, pseudo-obstruction, idiopathy

Complications of constipation

fecal impaction, intermittent sigmoid volvulus, megacolon

Chronic diarrhea

drugs, celiac disease, bacterial overgrowth

Intestinal parasites

giardiasis

Lactase deficiency (lactose intolerance) Gynecological disorders

endometriosis

Psychiatric disorders

depression, somatisation, anxiety, panic disorders

In summary, the diagnosis of irritable bowel syndrome relies on the recognition of characteristic symptom patterns. Equally important is the exclusion of organic structural disease.

References Manning, A. P., Thompson, W. G., Heaton, K. W., Morris, A. F.: Towards positive diagnosis of the irritable bowel. Br. Med. J. 2: 6 5 3 - 6 5 4 , 1978 Kruis, W., Thieme, Ch., Weinzierl, M., Schiissler, P., Holl, J., Paulus, W.: A diagnostic score for the irritable bowel syndrome (Its value in the exclusion of organic disease). Gastroenterology 87: 1 - 7 , 1984 Whorwell, P. J., McCallum, M., Creed, F. H., Roberts, C. T.: Non-Colonic features of irritable bowel syndrome. Gut 27: 3 7 - 4 0 , 1986 Drossman, D. A., Thompsen, W. G., Talley, N. J., Funch-Jensen, P., Janssens, J., Whitehead, W. E.: Identification of sub-groups of functional gastrointestinal disorders. Gastroenterology International 3: 1 5 9 - 1 7 2 , 1990 Talley, N. J., Zinsmeister, A. R., van Dyke, C., Melton, L. J.: Epidemiology of colonic symptoms and the irritable bowel syndrome. Gastroenterology 101: 927—934, 1991 Cullingford, G. L., Coffey, J. F., Carr-Locke, D. L.: Irritable bowel syndrome: Can the patient's response to colonoscopy help with diagnosis? Digestion 52: 209—213, 1992

Discussion Denis: Thank you very much, Professor Malchow, for your very clear presentation. I totally agree with you that the difficulty is the absence of positive criteria for

Diagnosis of irritable bowel syndrome

9

the diagnosis of IBS. As I understood, you made a differentiation between chronic constipation and IBS? Malcbow: Yes, I think most gastroenterologists do. There is a difference between chronic constipation and IBS, because patients with chronic constipation only suffer from the symptom of constipation and not from symptoms of pain and, occasionally, distension. Denis: I agree with you, but I think there is generally a confusion between chronic constipation and IBS, and about the criteria for including patients in the study. Malcbow: Yes, but I think the Rome criteria with their six points differentiate patients with irritable bowel syndrome from the patients with chronic constipation. Throughout the world, the Manning criteria are very well accepted as the socalled positive diagnosis of irritable bowel syndrome and I would recommend them, too. van

Outryve:

Would you propose making a repeat colonoscopy in irritable bowel syndrome, and, if so, after how many years? Or do you find it is not necessary? Machow: I did not recommend colonoscopy for the diagnosis of irritable bowel syndrome because in all the literature I have read no one recommends a total colonoscopy for the diagnosis of irritable bowel syndrome. If you ask me what I do personally, I coloscope each patient who comes to me with symptoms originating from the colon. After the diagnosis of irritable bowel syndrome (including colonoscopy) I treat the patients. If I don't succeed within several months, or several years, or if the symptom pattern changes, then I repeat colonoscopy, but I don't recommend repeating a colonoscopy after two years. Denis: What is your opinion from your practice, Dr. van Outryve? van

Outryve:

Well, I do about the same as you do. In patients of less than fifty years of age, I do left colonoscopy or an X-ray with an enema, but when a patient is older

10

H. Malchow

than fifty, I never make a diagnosis of colonic disease or of IBS without performing a total colonoscopy. And I have to recognize that even in patients for whom I had made a diagnosis, I sometimes find two or three years later a colonic tumor, especially on the right hemicolon, that I probably missed. So in patients older than fifty years of age I find it safer at the start of the treatment to be sure there is no organic colonic disease at all, because in our region, I think in Germany the percentages are about the same, colonic cancer is still increasing in frequency. We are always afraid to miss a colonic tumor, especially in older patients. Malchow: One can discriminate between men and women. If you have a man who is forty or a little older, and he presents symptoms of irritable bowel syndrome for the first time, I would recommend colonoscopy, too. In women it might be quite a bit different and you could wait until fifty years of age. Morbey: If we talk about colonoscopy, it's an very invasive technique. But I think that it is completely indispensable to exclude an organic disease, even if patients are young. In our country (Portugal), colonic cancer is increasing not only in old people, but also in the middle-aged and sometimes in young persons, so I never lose an opportunity to do a coloscopy. Once an organic disease is excluded, I then affirm that the patient has IBS and I treat him accordingly. van Outryve: Do you have any experience with IBS in children? Because it seems to be quite a common disease in children, too. And how is the diagnostic work-up in children? Malchow: Yes, I'm a gastroenterologist and so I don't see children very often, but I'm aware that children do have this syndrome, and I think that diagnosis has to be made as in adults. But I think colonoscopy is not necessary as a first step. If they don't respond to any kind of treatment, then you have to diagnose the patient again, even if they are children. van Outryve: Let me ask another question. There is a concordance between IBS and urological symptoms and bladder diseases. Do we have any experience with that?

Diagnosis o f irritable bowel syndrome

11

Malcbow: I have only had experience with a few patients, no scientific experience. But I have had scientific experience with a combination of irritable bowel syndrome and inflammatory bowel disease. Sometimes patients with ulcerative colitis also have the feature of irritable bowel syndrome and they respond very well if you combine both forms of treatment, e. g. sulfasalazine and mebeverine.

Denis: We discussed the clinical diagnosis of IBS. Another problem is to include patients in pharmacological studies. What is your opinion on the physiological criteria for including patients in a pharmacological study? Physiological criteria cannot replace clinical data, but physiological data can be complementary to clinical classification.

Malcbow: Yes, such criteria might facilitate special kinds of studies. If you want to show that a substance is effective, then you may be able to show it much easier by criteria like balloon distension and pain sensation. But for the F D A or Institut fur Arzneimittelforschung you have to present a study showing that the patient has improved in terms of therapy goals and not in terms of physiological goals. So you have to validate such physiological signs with therapeutic goals and aims, something which is always very difficult.

Psychosocial profile of patients with irritable bowel syndrome J. Weber, P. Denis

All physicians who manage patients with irritable bowel syndrome (IBS) are under the impression that these patients have a special psychological profile and the psychological origin of IBS is usually accepted. Several authors have characterized the psychological profile of these patients through tests from which a personality profile may be obtained [1 — 4]. These psychological profiles show a difference between the personality of patients with IBS and that of normal subjects. This difference is observed in the following scales: hypochondria, depression, conversion hysteria, schizophrenia and ego strength. Conversely, the various profiles do not differ in relation to the dominant symptom (diarrhea, constipation, bloating) (tab. 1). G . Devroede [3] has shown with a discriminating analysis that the M M P I test (Minnesota multiphysic personality inventory) could separate, in 83% of the cases, constipated patients who had only a delayed transit (defined as a non-constant increase of the transit during the last two years) from those whose constipation was caused by colonic inertia (defined as an increased colonic transit in the ascending colon during the last two years). Similarly, using a closely related test (Hopkins symptom check list), Wald [5] has demonstrated that constipated patients with IBS had psychopathological scores higher than those of controls. Table 1

Personality

scores found

higher in IBS patients

than

Talley — pain — diarrhea — constipation

— — — —

hypochondriasis depression hysteria schizophrenia

Drossman — diarrhea

— hypochondriasis/depression — hysteria, psychasthenia — schizophrenia

Devroede — constipation

— hypochondriasis — hysteria — masculinity

controls

14

J. Weber, P. Denis

Those with a normal transit, however, had a more disturbed psychopathological profile t h a n t h o s e w i t h a delayed-colonic transit, as if h a v i n g a m e a s u r a b l e d y s f u n c t i o n of colonic motricity does p r o t e c t against p s y c h o p a t h o l o g i c a l disorders. F u r t h e r m o r e , using the M M P I test, G . D e v r o e d e [3] has s h o w n the presence of a p s y c h o s o m a t i c V (hysteria, depression, h y p o c h o n d r i a ) w h i c h is c h a r acteristic of p a t i e n t s w i t h IBS. Anxiety c o u l d be o n e of the m e c h a n i s m s e x p l a i n i n g this s i t u a t i o n . D e v r o e d e [3] has d e m o n s t r a t e d a c o r r e l a t i o n b e t w e e n a delayed colonic transit a n d the level of anxiety. F u r t h e r m o r e , Klauser [6] has indicated t h a t , t h r o u g h b i o f e e d b a c k , n o r m a l subjects were able t o slow d o w n their colonic transit. Given these findings, it is indeed t e m p t i n g t o c o n c l u d e t h a t a relation exists b e t w e e n IBS a n d a psychological p r o b l e m . A review of the literature reveals, h o w e v e r , t h a t t h e situation is n o t so clear-cut a n d t h a t this impression m u s t t e m p e r e d . a) T h e psychological p r o f i l e of p a t i e n t s w i t h IBS is q u i t e d i f f e r e n t f r o m t h a t of psychiatric p a t i e n t s [4]. T h e s e results suggest t h a t p a t i e n t s w i t h IBS are n o t psychiatric patients. b) T h e psychological profile of p a t i e n t s w i t h IBS is n o t different f r o m t h a t of p a t i e n t s w i t h f u n c t i o n a l disorders (e.g., non-ulcer dyspepsia [4]) o r o r g a n i c lesions w i t h similar s y m p t o m s , as s h o w n by Enck [2] a n d Smith [7]. Furtherm o r e , w e have seen t h a t the psychological profile of p a t i e n t s w i t h IBS did n o t vary in relation to the d o m i n a n t s y m p t o m (diarrhea, c o n s t i p a t i o n , bloating). Given these c i r c u m s t a n c e s , the psychological profile of p a t i e n t s w i t h IBS could c o r r e s p o n d t o the similar profile of p a t i e n t s w i t h c h r o n i c s y m p t o m s , w h e t h e r of f u n c t i o n a l or o r g a n i c origin. C h r o n i c d i s o r d e r s have an i m p a c t on the personality, b u t a p a r t i c u l a r p e r s o n a l ity does n o t explain s y m p t o m s . D r o s s m a n [1] and Creed [8] suggest the i m p o r t a n c e of life events t o explain the personality of subjects w i t h IBS. T h e s e events m a y b e l o n g to the socioprofessional sphere or be related t o the familial or m a r i t a l experience of the p a t i e n t . Sexual aggression a n d physical violence seem t o play an i m p o r t a n t role f o r D r o s s m a n [9] a n d Leroi [10]. In fact, a possible c o n n e x i o n b e t w e e n sexual p r o b l e m s a n d IBS has been suggested by G u t h r i e [11] a n d Weber [12]. In such cases, the p a r t i c u l a r personality of p a t i e n t s w i t h IBS could m i r r o r m o r e their p s y c h o c u l t u r a l experience t h a n a special p s y c h o p a t h o l o g y . T h e study of the sociocultural profile c o u l d t h e n o f f e r a m e a n s for the u n d e r s t a n d i n g these patients. Clearly, the psychological p r o f i l e of p a t i e n t s w i t h IBS m a y be related to their s o c i o d e m o g r a p h i c profile. A representative s a m p l e of 10,000 subjects aged 15 years or over w a s polled by S O F R E S , a French institution. Female p a t i e n t s , w i t h IBS aged 35 to 65 years or elder, w e r e c h o s e n . T h e i r s y m p t o m s w e r e t h e

Psychosocial profile of patients

15

usual ones: constipation, diarrhea, abdominal bloating, isolated or in association (fig. 1). They were asked to answer a semiometric questionnaire. 25% 21 %

constipation

Fig. 1

Symptoms

diarrhea

21 %

abd. bloating

of IBS patients from semiometric

19%

all three symptoms

analysis.

What is semiometry? Words are charged with moral values for individuals, in whom they induce pleasant or unpleasant feelings. Semiometry is a way to analyse the affective content of words. A score was attributed to each word from very unpleasant to very pleasant (tab. 2). A list of 2 1 0 words was proposed. They were representative of what is usually considered as common in a Western society, i. e. words that are suggestive, sensitive but not consensual, and semantically stable. For example, words such as soft, modesty, war, precious, wild, sacrifice, moderation were among those selected for this list (tab. 3). Table 2

Significance

attributed

to each word chosen for the semiometric

Very disagreeable

:

M o d e r a t e l y disagreeable

:

—2

Slightly disagreeable

:

—1

N o sensation

:

0

Slightly agreeable

:

+1

analysis

—3

M o d e r a t e l y agreeable

:

+2

Very agreeable

:

+3

T h e results were analysed by principal components, showing three main axes: order—freedom, conflict—harmony, love—indifference (fig. 2). Some words were chosen more often by patients with IBS than by controls. T h e former selected words between order and harmony. For example, they underscored words suggesting anxiety, breaking and conflict. Conversely, they overscored words suggesting being and seeming, maternal influence, introversion and spiritual concerns. They feared conflict and distress and needed affective comfort.

16

J. Weber, P. Denis

Table 3

Example of words chosen

Soft Modesty War Precious

-3 -3 -3 -3

Wild Sacrifice Moderation

-3 -3 -3

Three

Fig. 2

and

their

-2 -2

tributed

significance 0

0

-2

0 0

-2 -2 -2 -2

0 0

0

+1 + 1 + 1 + 1 + 1 +1 + 1

+2 +2 + 2 + 2

+2 + 2 + 2

+3 +3 +3 +3 + 3 + 3 + 3

axes

The three axes of semiometric

analysis.

Patients with IBS w h o were mostly constipated overscored words ranging between love and harmony. Constipated patients underscored the same words as patients with IBS, but m o r e markedly so when they referred to anxiety, breaking and conflict. In the same manner, they overscored words suggesting being and seeming, affective h a r m o n y and dreams. T h e sociocultural profile of constipated patients with IBS may be summarized this way: they are very sensitive to the views of the others (especially their physician), they overscore familiar harm o n y values, they need maternal love and understanding. Diarrheic patients overscored words related to the concept of freedom. Diarrheic patients with IBS have a teenage personality refusing coercion, showing their own feelings through rebellion or dreams. T h e y underscored words suggesting authority, social standard values and rationality. T h e y overscored words suggesting dispute, freedom, impulse and hallucinations. In summary, diarrheic patients with IBS were anti-conformist persons. T h e y need advice, not orders. Patients with abdominal bloating overscored words placed between order and harmony. Patients with IBS w h o complained o f abdominal bloating have an introverted personality with some difficulty to adjust to the reality of daily life. T h e y underscored words suggesting anxiety, action and free self-expression. T h e y overscored words suggesting being and seeming, distinction, transcendence and affective standards. Patients with IBS and abdominal bloating have the following sociocultural type of personality: they need standards, they feel

Psychosocial profile of patients

17

reassured by the power of medical authorities, they expect a straight medical diagnosis and a precise form of treatment. The major point of this study is that patients with IBS are looking for order if they have abdominal bloating, love and harmony if they are constipated and freedom if they are diarrheic, but none chose conflict! In summary, the psychological profiles of patients with IBS differ from those of psychiatric patients and normal subjects. It could be related to the sociocultural profile. The semiometric analysis suggests that it is important to take into account the sociocultural profile which seems to be related to the symptoms of patients with IBS.

References [1] D r o s s m a n , D . A., M c K e e , D . C . , Sandler, R . S., Mitchell, C. M . , G r a m e r , E. M . ,

Lowman,

B . C . , Burger, A. L.: Psychosocial factors in the irritable b o w e l syndrome. A multivariate study o f patients and non-patients with irritable bowel syndrome. G a s t r o e n t e r o l o g y 9 5 : 7 0 1 — 7 0 8 , 1988 [2] E n c k , P., W h i t e h e a d , W. E., Schuster, M . M . , W i e n b e c k , M . : Clinical symptoms, psychopathology and intestinal motility in patients with 'irritable b o w e l ' . Z . G a s t r o e n t e r o l . 2 7 : 3 5 7 — 3 6 1 , 1989 [3] Devroede, G . , G i r a r d , G . , B o u c h o u c h a , M . , Roy, T., B l a c k , R . , C a m e r l a i n , M . , Pinard, G . , Schang, J . C . , A r h a n , P.: Idiopathic constipation by c o l o n i c dysfunction, relationship with personality and anxiety. Dig. Dis. Sci. 3 4 : 1 4 2 8 - 1 4 3 3 , 1 9 8 9 [4] Talley, N . J . , Phillips, S. F., Bruce, B., Twomey, C. K., Zinsmeister, A. R . , M e l t o n , III, L. J . : Relation a m o n g personality and s y m p t o m s in non ulcer dyspepsia and the irritable bowel syndrome. G a s t r o e n t e r o l o g y 9 9 : 3 2 7 — 3 3 3 , 1 9 9 0 [5] Wald, A., Hinds, J . P., C a m a n a , B. J . : Psychological and physiological characteristics o f patients with severe idiopathic constipation. G a s t r o e n t e r o l o g y 9 7 : 9 3 2 — 9 3 7 , 1 9 8 9 [6] Klauser, A. G . , Voderholzer, W. A., Heinrich, C . A., Schinlbeck, N . E., Muller-Lissner, S. A.: Behavioral modification o f c o l o n i c function. C a n constipation be learned? Dig. Dis. Sci. 10: 1 2 7 1 - 1 2 7 5 , 1990 [7] Smith, R . C . , G r e e n b a u m , D . S., Vancouver, J . B., Henry, R . C . , Reinhart, M . A., G r e e n b a u m , R . B., D e a n , H . A., M a y l e , J . E.: Psychosocial factors are associated with health care seeking rather than diagnosis in irritable bowel syndrome. G a s t r o e n t e r o l o g y 98: 2 9 3 — 3 0 1 , 1 9 9 0 [8] Creed, E , Craig, T., Farmer, R . : Functional a b d o m i n a l pain, psychiatric illness, and life events. Gut 29: 2 3 5 - 2 4 2 , 1989 [9] D r o s s m a n , D . A., Ieserman, J . , N a c h m a n , G . , Li, Z . , G l u c k , H . , Toomey, T. C . , Mitchell, M . : Sexual and physical abuse in w o m e n with functional or organic gastrointestinal disorders. Ann. Int. M e d . 1 1 3 : 8 2 8 - 8 3 3 ,

1990

[10] Leroi, A. M . , Berkelmans, I., Denis, P., H e m o n d , M . , Devroede, G . : Anismus as a m a r k e r o f sexual abuse: consequences o f abuse on anorectal motility. Dig. Dis. Sci. submitted 1 9 9 5 [11] Guthrie, E., Creed, F. H . , W h o r w e l l , P. J . : Severe sexual dysfunction in w o m e n with the irritable bowel syndrome: c o m p a r i s o n with i n f l a m m a t o r y bowel disease and duodenal ulceration. Br. Med. J . 2 9 5 : 5 7 7 - 5 7 8 , 1 9 8 7 [12] Weber, J . , D u c r o t t e , P., T o u c h a i s , J . Y., Roussignol, C . , Denis, P.: Biofeedback training for constipation in adults and children. Dis. C o l o n . R e c t u m 3 0 : 8 4 4 — 8 4 6 , 1 9 8 7

18

J. Weber, P. Denis

Discussion van

Outryve:

Our patients very often tell us that their emotional disturbances are not the reason for the symptoms, but rather the consequence "I do feel the pain, doctor, and because I feel pain, I get anxious". What is your answer to that? Denis: May I suggest two groups of IBS patients. I think that there is a group of IBS patients in whom anxiety is a consequence of the symptoms. I think they are relatively easy to treat, because when they are symptom-free they also feel well. And there is another group of IBS patients who remain in a poor state even when the symptoms disappear, and even when the physiological criteria disappear. But I think it is difficult to say that anxiety is always a consequence of the symptoms. van

Outryve:

What is the influence of the glands? A very interesting study of IBS showed a marked increase of cortisone excretion in females after meals. Can this also influence the psychological profile? Weber: I think that cortisone augmentation is correlated with stress and anxiety. Stress and anxiety are common in IBS patients and so cortisone may modify the psychological profile.

Awareness of IBS by patients and physicians A. Morbey

Irritable bowel syndrome is often refered to as IBS, but is also designated, although improperly, by other names such as "irritable colon", "spastic colon" and "spastic colitis". It is one of the most common problems that physicians face in their practice. It is also the most frequent digestive tract disorder referred to the gastroenterologist in the industrialized world. IBS affects millions of people, at least 1 5 % to 2 0 % of the general population, though most suffers do not seek medical attention for their symptoms. It appears to be equally common in young, middle-aged and elderly healthy western people. However, people in their thirties and forties are the most affected. In western societies, female suffers of IBS outnumber men by a ratio of approximately 2 to 1. In eastern societies, like Sri Lanka, China, Japan and India it is just the opposite; men outnumber women by precisely the same ratio. This difference seems to be sociocultural rather than biological: for example, in India, it is more acceptable for men rather than for women to express somatic symptoms. The incidence of IBS showed no significant differences between racial groups. IBS is not associated with hospitalization and usually does not lead to surgery. However, the patient's quality of life can be very seriously compromised. In fact, as a professor of psychiatry from the University of Baltimore described: "this syndrome won't kill anyone, although some victims occasionally wish it would". Many IBS sufferers feel miserable, some even feel as though their life is threatened. For most patients, IBS tends to be a chronic condition that flares up from time to time: when the symptoms become distressing their life style is disrupted, although usually only temporarily. After the common cold, IBS seems to be the second leading cause of absenteeism from work. In 1990, as a result of a consensus meeting in Rome, an international commission published criteria to define IBS, which have become known as the Rome criteria: Continuous or recurrent symptoms for at least three months of: 1. abdominal pain or discomfort, relieved with defecation, or associated with a change in frequency or consistency of stool; and 2. an irregular (varying) pattern of defecation at least 2 5 % of the time (three or more of):

20

A. Morbey

altered stool frequency; altered stool form (hard or loose/watery stool); altered stool passage (straining or urgency, feeling of incomplete evacuation); passage of mucus; bloating or feeling of abdominal distension. According to these criteria, IBS is a disturbance of the bowel function characterised by abdominal discomfort, even pain, bloating and abnormal bowel movements sometimes producing urgency and diarrhea that may often alternate with constipation. Physicians and patients cannot be aware of IBS and its problems if they do not understand the causes of this disorder. For a long time, it was thought IBS could be related to severe inflammatory bowel disease, such as Crohn's disease or ulcerative colitis: however, in these diseases, one can actually see the abnormalities in the mucosa. They also cause bleeding, anemia, weight loss, fever, that cannot be explained by IBS where no physical abnormalities are found. Nowadays, we know that there is a group of conditions affecting the bowel from the esophagus to the rectum for which no specific cause has been found. These conditions are called "functional" bowel disorders as opposed to the "inflammatory" bowel diseases. IBS is one of these functional digestive disorders whose cause is not completely understood. The recent advances in gastrointestinal motility allow us to say that IBS sufferers have some altered patterns of bowel motility. Manometric abnormalities have been described, although they are neither constant nor specific. The gut and the brain are very closely linked: they develop from the same part of the human embryo and remain linked through a large nucleus (locus ceruleus). So, the rich nerve supply of the gut shares with the brain many of the same nerve endings and the chemical transmitters. This is why the intestinal tract is called the "little brain". Local neurohumoral troubles as well as personality disturbances can induce sensitivity disorders, psychological stress or emotional arousal. Actually, several reports indicate that the symptomatology of IBS patients is due to hypersensitive and hyperreactive mechanisms of the bowel. Many researchers in the area of physiology and gastrointestinal motility have shown that IBS sufferers compared to healthy controls seem to have an enhanced perception of physiological intestinal motility. That is to say: • higher sensitivity to bowel distension or pain perception in their small and large intestine. These researchers have been testing the increased sensitivity to bowel distension in order to establish a correlation between abdominal pain and the visible distension due to abdominal bloating, two important

Awareness of IBS by patients and physicians

21

IBS symptoms already mentioned. This testing is far from clinical reality. Certain drugs, food and medical investigations such as colonoscopy (inflating the whole colon) may help to demonstrate hypersensitivity. However, two questions are still to be investigated: • the electromyographic and manometric patterns clearly related with painful distension still have to be defined and uniformly accepted by all researchers. In fact, several motility patterns in various subforms of IBS, specially measured by 24-hour ambulatory measurements, demonstrate a great heterogeneity in intestinal tract motility. • the sensitivity and specificity of the research methods have to be confirmed in both unselected and symptomatically selected IBS sufferers. The investigations on IBS patients to date allow us to conclude that: 1. the concept of "hypersensitive and hyperreactive gut" is a widely accepted hypothesis in the pathophysiology of IBS. 2. hypersensitive, hyperreactive bowel is nonspecific for most varying stimuli. 3. symptoms are not necessarily always related to altered motor activity. When the physician is aware of the IBS definition and understands the problematics of its pathophysiology, he is able not only to make the diagnosis but also to face the questions that his patients ask him. Why do not all IBS patients consult a doctor? IBS sufferers who do seek medical attention represent 25% to 50% of the referrals to gastroenterologists. Several epidemiological studies have found in those seeking care a higher prevalence of intestinal symptoms and personality deviations. The explanation for this undoubtedly has a sociocultural and psychological nature. What kind of questions should we expect from IBS sufferers seeking care? H o w should the physician respond? People with an irritable bowel syndrome need help and the demonstration of interest, especially those who are guarded and defensive because of previously frustrating experiences. Physicians have to be patient and inspire confidence as well as being firm and persistent. The main risk for IBS patients is the doubt which hovers over the disease entity and can be responsible for patient anxiety, leading to fear, expensive investigations and undesirable effects of medication, even in the form of not taking it. If the patient's complaints remain unchanged at the second medical visit, alternative diagnoses should be considered, although unjustified investigations are to be avoided. The physician should explain to the patient, then, why the new diagnoses considered were also rejected. After a patient-centered interview that should not be directive or judgmental, and after a careful examination and cost-efficient investigation, the diagnosis can be well established. The conditions for the patient accepting that he has an

22

A. Morbey

irritable bowel syndrome have been created. T h e doctor-patient

relationship

has begun and its further development needs to be gently and carefully fostered to be effective. IBS is a really challenging condition for both doctors and patients. T h e r e are no roles, but continued empathy with the patient is important. O f t e n , in each visit if necessary, the patient should be invited to ask questions and discuss concepts and doubts about his symptoms. H e should also be encouraged to talk with relatives w h o might provide useful information. T h e patient has to be educated and reassured in order to alleviate his anxiety stemming from the symptomatology itself and to gain confidence in the physician. T h e physician also needs to get to k n o w his patient and it is important to help the patient understand that: • he has a benign, chronic and recurrent intestinal m o t o r disorder. Sometimes, it is helpful to use examples o f other chronic disorders such as diabetes or hypertension as an analogy for diseases that c a n n o t be cured, but can be controlled. • multiple factors influence this disorder, including: — emotional stress, — drugs (for example, harsh chemical laxatives), — dietary products (like dietary fats, food additives, artificial sweeteners that can cause bloating, discomfort and diarrhea). Controlled clinical trials to date have failed to provide a universally agreed upon approach to therapy. In fact, no m a j o r advances in treatment can occur until the aethiopathogenesis is better understood. In any event, the management approach is only possible, as we already mentioned, if the doctor-patient relationship is strong. T h i s may even consist in involving the patient in choosing the treatment (telling him for example: "let me suggest some treatments for you to consider"). T h e treatment approach has to be individualized and based on c o m m o n sense, on an understanding of the patient's predominant symptom pattern and on the psychological factors that influenced the symptoms and prompted the visit to the physician. Physicians must be guided by the old dictum: " P r i m u m non n o c e r e " . First we are obliged to exclude organic disease efficiently and safely, then to cure sometimes, to relieve often and to c o m f o r t always. Drugs certainly play an important role, in medical management. We can use antispasmodics, opiate analogues, stimulant laxatives, antidepressants and tranquilizers. T h e i r prescription depends on the severity and nature of the symptomatology as well as the psychosocial determinants of the patient's illness behaviour.

A w a r e n e s s of IBS by p a t i e n t s a n d p h y s i c i a n s

23

Dietary management is also frequently recommended: • high fiber supplementation is advisable if constipation predominates in the symptomatology. • restricted diet is recommended for patients with diarrhea-predominant IBS or alternating diarrhea and constipation. All these measures may encounter the problem of patient noncompliance. This is why psychotherapy and/or other psychological treatment approaches are of great benefit. They reduce psychological stress in order to relieve abdominal pain, to normalize bowel habits and to obtain greater acceptability from patients. Recurrence is more easily accepted by people affected by IBS than the feeling, even if it is incorrect, of an inappropriate diagnosis or inadequate treatment. For this reason, return visits should continue on a regular basis in order to: • assure continued interest; • offer support for better compliance with therapeutic alternatives with the possibility of modifying the therapeutic regimen and in order to avoid automedication; • avoid a sense of abandonment that very often leads the patient to look for another doctor; • finally, encourage the patient to engage in his daily activities to be more active and independent in the management of his disorder. Finally, support should be given to patient organizations, e. g. the International Foundation for Bowel Dysfunction, based in Milwaukee, WI, USA, which: • work directly with functional bowel disorders; • offer support and educational services to IBS sufferers, their families and the general population. Encouraging people to become a member of this nonprofit educational and research organization is a very worthwhile way to make patients and physicians aware of the problems of irritable bowel syndrome.

References Guthrie, E. A., Creed, F. H., Whorwell, P. J., Tomenson B.: Outpatients with irritable bowel syndrome: a comparison of first time and chronic attenders. Gut 33: 361 — 363, 1992 Heaton, K. W., O'Donnell, L. J., Braddon, F. E. M., Mountford, R. A., Hughes, A. O., Cripps, P. J.: Symptoms of irritable bowel syndrome in a British urban community: consulters and nonconsulters. Gastroenterology 102: 1962-1967, 1992 Kettell, J., Jones, R., Lydeard, S.: Reasons for consultation in irritable bowel syndrome. Br. J. General Pract. 42: 4 5 9 - 4 6 1 , 1992 Kellow, J. E., Evans, P. E.: Management of irritable bowel syndrome. J. Gastroenterol. Hepatol. 8: 2 8 7 - 2 9 3 , 1992

24

A. Morbey

Discussion van

Outryve:

In which cases do you refer your patients to a psychiatrist for bio-feedback therapy and do your patients easily accept referral to psychiatrists? In our practice it is quite difficult. The patients prefer to be treated by a gastroenterologist rather than by a psychiatrist. Morbey: That is a very good question. It is my opinion that very few patients who are IBS sufferers have to be sent to the psychiatrist. But if I have one of these cases, my relationship to the patient is strong enough to convince him that he should go and see the psychiatrist, though he remains linked to me, to my consultation. We have to take the responsibility on us of saying to the patient "Go and see what the psychiatrist is going to do with you and how much you are going to improve with him, and then come and tell me what happened." The few I have sent to the psychiatrist I didn't lose, and I have had very good results. You asked me about bio-feedback. Some of my patients from the motility department I work in were referred to bio-feedback. However, it's still too early for us to describe our experience and the results. Denis: What do you think about inclusion of manometry in a pharmacological study? Morbey: I think we should work much more in the field of gastrointestinal motility with manometry. Of course pharmacological studies always have to accompany manometric procedures. Denis: I agree with you. Any further questions? Outryve: What about the use of psychotropic drugs? They can aggravate constipation. Morbey: I don't like them at all. They aggravate constipation a lot and also they don't keep the patient sufficiently enough aware of what is happening to him. I use them very little.

Pharmacological aspects of mebeverine and antispasmodics as related to irritable bowel syndrome A. den Hertog

The intestinal tract consists of a longitudinal and a circular muscle layer. Pacemaker cells in the circular muscle layer of the colon generate the basic rhythmic activity, or slow waves, conducted in the distal direction (fig. 1). The motor activity of the smooth muscle cells is modulated by extrinsic and intrinsic nervous systems and by local hormones and peptides. Extrinsic sympathetic and parasympathetic fibres, under control of the central nervous system, and the intrinsic nervous system, the plexus myentericus, located in between the circular and longitudinal muscle layer, are mainly involved in the regulation of the motoractivity of the intestine. The plexus submucosa is particularly important in activating secretory processes. This complex regulating system determines the local contractile state of the colon (fig. 2). The slow waves generated by pacemaker cells are represented by depolarization, causing spike activity and a concomitant contraction of the smooth muscle cells (fig. 3) [1]. The transmitters released by the respective nerve endings and the hormones produced locally stimulate specific receptors on the smooth and muscle cells. Receptor stimulation causes depolarization (acetylcholine, ACh) or hyperpolarization (noradrenaline, NOR) of the cells depending on the receptor

longitudinal muscle myenteric plexus circular muscle submucosal plexus submucosa

mucosa

Fig. 1

Schematic

representation

of the structure

of the intestinal

wall.

26

A. den Hertog Parasympathetic pathway

Sympathetic pathway

T

J_

I j

Extrinsic nervous regulation

Myenteric plexus j S u b m u c o s a l plexus j pressure/stretch / c h e m o s e n s o r s |

Intrinsic nervous regulation

IT-

Smooth muscle cells

Longitudinal muscle Circular m u s c l e

Fig. 2

Neural regulation of smooth

muscle cell

activity.

depolarization

r\ J \J

r-\I r\ -

\r

/ \ J

\

I

contraction

Fig. 3 Electrical and mechanical activity of the circular smooth muscle cells of the intestine the action of acetylcholine (ACh) and noradrenaline (NOR) respectively.

and

stimulated. Polarization is induced by changing the ionflux across the smooth muscle cell membrane by (in)activation of the concomitant ion channels (fig. 4). Depolarization is superimposed on the slow waves, resulting in enhanced spiking in the muscle cells (depolarization) and a pronounced contraction. In contrast, hyperpolarization causes a decrease in spike activity and relaxation. Thus, modulation of the contractile performance of the colon is achieved by blocking or stimulating discrete receptors or by the polarization of the smooth muscle cells (fig. 4). Irritable bowel syndrome might be due to an extensive contracted or possibly relaxed state, in particular of the circular muscle cells. The extrinsic parasympathetic or sympathetic nervous system, respectively, may contribute to the contractile state resulting in colon spasm. Intrinsic reflex responses elicited by the contractile state of the colon via stretch and pressure transducers are also part

Pharmacological aspects of mebeverine and antispasmodics

'1 '^

1

V / I ' ^ ' I -

¿¿¿¿Ai±

I

intrinsic nerve

Co2*

ACh

No*

27

extracellular

JTTTL*-'1

•¡Vv

membrane

1 Depolarization

cytoplasm

Depolarization

Contraction

Fig. 4 Schematic representation of the cellular events resulting in contraction muscle. (Na+: sodium ions, Ca2+: calcium ions, ACh: acetylcholine).

of intestinal

smooth

of the process. Pharmacological treatment of this syndrome requires modification of the contractile state of the colon by a local action of the d r u g to prevent side effects. Such an action can be obtained by a readily metabolized d r u g changing the polarization of s m o o t h muscle cells via a direct effect on the ion channels in the cell m e m b r a n e or indirectly by interaction with specific receptor sites. To enhance colon activity in case of extensive relaxation, the contribution of the inhibitory neural regulation can be limited, otherwise the excitatory mechanism has to be stimulated. Blocking the inhibitory d o p a m i n e receptors in the intrinsic system (domperidone, metoclopramide) will result in an increased motility. Increased activity is also achieved by facilitating the release of acetylcholine f r o m the intrinsic nerves by the locally acting drug cisapride [2, 3], T h e contractile state of the colon can be diminished by limiting calcium entry via voltage dependent channels (pinaverium bromide), by blocking the acetylcholine sensitive receptors on the s m o o t h muscle cells (atropine-like substances) a n d / o r by hyperpolarizing the s m o o t h muscle cell directly. Mebeverine, a P-phenylethylamine derivative, is readily metabolized into inactive mebeverine alcohol and veratric acid, which implies that side effects are unlikely [4], Mebeverine has unexpected effects on the intestinal tract concerning limitation of muscle contraction. This c o m p o u n d showed, besides local anaesthetic action at relative high concentrations [5], a limitation of the a m o u n t of available

28

A. den Hertog

calcium mobilized on r e c e p t o r s t i m u l a t i o n (fig. 5) a n d a direct h y p e r p o l a r i z a tion of the s m o o t h muscle cell m e m b r a n e by decreasing s o d i u m p e r m e a b i l i t y a n d c o n s e q u e n t l y inhibiting spike activity in the intestinal t r a c t (fig. 6) [6]. T h i s last aspect implies t h a t the basic contractile state of t h e colon is limited by t h e reducing of s o d i u m leakage of the s m o o t h muscle cell m e m b r a n e . T h i s reduction in activity caused by m e b e v e r i n e is i n d e p e n d e n t of n e u r a l m o d u l a t i o n , because it affects t h e e f f e c t o r o r g a n o r s m o o t h muscle cells directly. potassium channel closed

Fig. 5

Mebeverine

blocks the refilling of calcium

Fig. 6

Mebeverine

blocks sodium

channels.

depots.

Pharmacological aspects of mebeverine and antispasmodics

29

Cellular activity is determined by the effectiveness of receptor stimulation, second messengers, ion channels and the contractile mechanism. Regulation of the final activity of the intestinal tract by drugs acting directly on the smooth muscle cells is favored in view of the complexity of the neural regulation. It is noted that the action of a drug is defined by its acutal effect on the target organ. Medication, however, often means a long-term treatment of the organism with the drug. Long-lasting exposure to the drug may change the cellular responsiveness by "chronic" modification of the cellular components involved. This aspect needs more attention and requires a study on cellular responsiveness after long-term pharmacological treatment.

References [1] Barajas-Lôpez, C., Huizinga, J. D.: Different mechanisms of contraction generation in circular muscle of canine colon. Am. J. Physiol. 256: G 5 7 0 - G 5 8 0 , 1989 [2] Schuurkes, J. A. J., Van Nueten, J. M., Van Daele, P. G.: Motor stimulating properties of cisapride on isolated gastrointestinal preparations of the guinea-pig. J. Pharmacol. Exp. Ther. 234: 7 7 5 - 7 8 3 , 1985 [3] Den Hertog, A., Van den Akker, J.: The effect of cisapride on smooth muscle cells of guineapig taenia caeci. Eur. J. Pharmacol. 126: 31 — 35, 1986 [4] Linder, A., Selzer, H., Claassen, V., Gans, P., Offringa, O. R., Zwagemakers, J. M. A.: Pharmacological properties of mebeverine, a smooth muscle relaxant. Arch. Int. Pharmacodyn. 145: 3 7 8 - 3 9 5 , 1963 [5] Den Hertog, A., Van den Akker, J.: Modification of a r r e c e p t o r - o p e r a t e d channels by mebeverine in smooth muscle cells of guinea-pig taenia caeci. Eur. J. Pharmacol. 138: 367—374, 1987 [6] Den Hertog, A., Van den Akker, J.: The action of mebeverine and metabolites on mammalian non-myelinated nerve fibres. Eur. J. Pharmacol. 139: 353 — 355, 1987

Discussion Denis: Thank you, Professor den Hertog. Are there any questions? Weber: In one of your slides you show an excitatory potential with acetylcholine action, and you show, too, inhibitory drugs and potential with a depolarization of the membrane. Does mebeverine have this inhibitory drug potential? den Hertog: Yes, mebeverine brings the whole activity down to a lower level, but it does not influence the slow waves which continue forever. However, you can lower

30

A. den Hertog

the whole excitability of the cells by influencing the sodium channel. When you use mebeverine you can expect spiking to decrease because of the lowering of the excitability of the cells. Denis: In studies, mebeverine reduces colonic activity, but predominantly when the level of colonic activity in patients is high. Could you explain this observation? den

Hertog:

Yes, it depends on the relationship between the memory potential and the sensitivity of the calcium channel to opening up by depolarization. Mebeverine acts indirectly on the calcium channel via the sodium channel as I have demonstrated. Denis: The problem is: "Does a reduction of activity modify the transit time?" Have you an opinion, Dr. Morbey? Morbey: Yes, I agree. The point of Prof, den Hertog's presentation is that sensitivity and reactivity are lowered and that we can get some advantages for abdominal bloating and for pain distension.

A new mebeverine formulation in clinical practice M. Delvaux

Introduction Irritable bowel syndrome is a well characterized condition amongst functional digestive disorders. It is also the most frequent reason for referral of patients to the gastroenterologist. Mebeverine acts as an antispasmodic agent, mainly on the digestive smooth muscle. Its effectiveness has been established for a long time in the treatment of IBS. Since it is devoid of any anticholinergic action, mebeverine does not induce the side effects commonly seen with other antispasmodic drugs: mouth dryness, visual disturbances, dysuria. Mebeverine is now available in a new dosage form: mebeverine microgranules in 200 mg capsules. Pharmacokinetic studies with this new dosage have shown that it allows delivery of mebeverine progressively throughout the intestine by a slow release formulation. The present clinical study was designed to evaluate the efficacy, safety and tolerance of mebeverine 200 mg b. i. d. in the treatment of patients with IBS.

Patients and method Patients with IBS were included in an open 12-week-study. IBS was defined according to the Rome criteria as the presence of abdominal pain and/or transit disturbances and/or abdominal distension. These patients were 38 men and 32 women with a mean age of 52 years (extremes: 20—85). They had symptoms related to IBS for an average of 5.6 years. Sixty-two percent of them were not taking any treatment for IBS at time of entry into the study. Mebeverine 200 mg capsules were administred twice daily, before breakfast and dinner, i. e. at an interval of about 12 hours. Patients were followed-up monthly in consultations where they were given a questionnaire evaluating the intensity of their symptoms and clinically examined. All adverse events were also recorded. The main symptoms — abdominal pain, transit abnormalities and abdominal distension — were evaluated on a 4grade scale: symptom not present, slight, moderate or severe. The overall impression of the benefit felt by the patients was also recorded as "symptoms

32

M . Delvaux

disappeared,

markedly

improved,

slightly

improved,

unchanged,

slightly

worsened or markedly worsened".

Results Amongst the 7 0 patients enrolled in the trial, 58 completed the study according to the protocol. Six patients dropped out and 6 were lost during follow-up. Four patients dropped out of the study because of treatment inefficacy and 2 because of side effects. Treatment

efficacy

At the time of entry in the trial, the majority of patients complained of moderate to severe abdominal pain. At the first follow-up visit (4 weeks), abdominal pain had become slight or even disappeared in most patients (fig. 1). This favorable outcome of the treatment was still pronounced at the 8-week control since the intensity of abdominal pain was further decreased in most of patients. By contrast, no additional benefit was obtained when the treatment was for another 4-week period beyond 56 days. Overall, abdominal pain completely disappeared in 6 1 . 4 % of cases and was markedly improved in 2 0 . 0 % . A clear clinical benefit was thus obtained in 8 1 . 4 % of patients treated with mebeverine 2 X 2 0 0 mg for 12 weeks (fig. 2). Transit disturbances were present in almost all patients at the first visit and consisted primarily of mild to moderate constipation (fig. 3). Transit abnormalities were improved in 8 0 % of patients at the end of the first 4-week period of treatment and were further significantly improved during the second 4-week period.

Fig. 1

Evolution of abdominal

pain.

A n e w m e b e v e r i n e f o r m u l a t i o n in c l i n i c a l p r a c t i c e

33

% of patient 80 Q

Abdominal pom

Ë 3 Bloating r j Transit disturbance

| disappeared

Fig. 2

Assessment

Fig. 3

Evolution

marked slight improvement improvement

of efficacy

of bowel

based on symptoms

unchanged

after 12

slight worsening

marked worsening

weeks.

habits.

Mebeverine caused abdominal distension to disappear in 62.2% and improve in 20% of cases (fig. 4). As was observed for abdominal pain and transit disturbances, the initial clinical benefit observed after 4 weeks was again observed after 8 weeks of treatment. The mean time to obtain relief of symptoms was 13 days. In the overall assessment of the therapeutic benefit, the fact that at 12 weeks the symptoms had completely disappeared in 57% of patients and improved in 28.6% of them, indicates an overall satisfactory result in 85.6% of cases (fig. 5). Tolerance Tolerance of mebeverine was good in 87% of cases. One patient was withdrawn because of ineffectiveness. Mebeverine did not cause significant changes in he-

34

M . Delvaux (r

3

-

DO

Fig. 4

D 28

Evolution of abdominal

D5S

D 84

bloating.

unchanged

Fig. 5

Overall efficacy on symptoms

after 12 weeks.

matological nor biological parameters which were measured at the beginning and at the end of the study in all patients. Mild changes observed in some biological parameters could not be definitely attributed to the treatment.

Conclusion This study clearly demonstrates that the new long-acting formulation of mebeverine at the dose of 200 mg b. i. d. is an effective therapy of irritable bowel syndrome. Clinical benefit is characterized by an improvement of symptoms

A n e w m e b e v e r i n e f o r m u l a t i o n in clinical p r a c t i c e

35

after a few days of treatment. Relief of symptoms is marked after 28 days of therapy and is even more pronounced after 56 days. Mebeverine proved effective in this study in about 85% of patients who experienced relief from abdominal pain, bloating and transit disturbances. At this dosage, mebeverine was well tolerated and safe, given the very low frequency and the mild nature of adverse events.

References Tasman-Jones, C.: Mebeverine in patients with the irritable bowel syndrome: double blind study. N Z . Med. J. 77: 2 3 2 - 2 3 4 , 1973 Prout, B. J.: The treatment of irritable bowel syndrome: two doses of mebeverine compared. The practitioner 227: 1607-1608, 1983 Den Hertog, A., Van den Akker, J.: Modification of al-receptor-operated channels by mebeverine in smooth muscle cells of guinea-pig taenia caeci. Eur. J. Pharmacol. 138: 367—374, 1987 Inauen, W., Halter, F.: Clinical efficacy, safety and tolerance of mebeverine slow release (200 mg) versus mebeverine tablets in patients with irritable bowel syndrome. Drug Invest. 8: 234—240, 1994

Discussion Denis: Why does it take so long before the action of mebeverine is completed? Delvaux: We can't speak about what happens during the first three or four weeks, because the first consultation was after four weeks. It is very difficult to evaluate this period, because the diary book was summarized at day 28. But if we look at the individual histories of the patients, we were able to show that significant improvement of symptoms occurred during the first or the second week of treatment. Weber: In your study you had many male subjects. Did you find a difference in improvement between male and female subjects? Delvaux: No.

Risk-benefit ratio of IBS treatment: data from a high dose mebeverine study M . van

Outryue

Abstract In our study, mebeverine was administered in a dose of 800 mg a day, which is twice the normal dose in irritable bowel syndrome. T h e safety and efficacy of a new mebeverine microgranula formulation was compared with standard plain mebeverine in this high dose treatment of 60 patients suffering from irritable bowel syndrome. Patients with a score of at least 4 4 on the Kruis scale were randomized into a two-period crossover trial. Each treatment period lasted for 6 weeks, during which the patients took mebeverine plain 135 mg, 2 capsules t. i . d . , or mebeverine microgranules in 2 0 0 mg capsules, 2 capsules b. i. d. After 6 weeks of each treatment both treatments were evaluated as "effective" or "very effective" by both the patients and the investigator in more than 8 0 % of the cases. Regarding general clinical improvement, more than 7 0 % of all patients improved within three weeks of the first treatment. An additional improvement was reported after the next three weeks. Abdominal pain was still present in more than 5 0 % of the patients, but with much lower intensity compared to baseline. Mean scores of efficacy were very similar for both treatments after 3 and 6 weeks (2.0 for mebeverine plain vs. 1.9 for mebeverine 2 0 0 m g ) . T h e statistical comparison of all scores between the two formulations did not show a significant difference at any time. Very few adverse events were noted and a causal relationship to the tested medications was judged as unlikely or impossible. Compliance was close to 1 0 0 % for most of the patients. T h e results of the present study allow us to conclude that mebeverine microgranules in 2 0 0 mg capsules presents equivalent efficacy and tolerance to mebeverine plain in the treatment of the irritable bowel syndrome, while allowing two intakes instead of three. Moreover, the high dose of 800 mg a day provoked no major side effects or toxicity.

Introduction Irritable bowel syndrome is a complex but frequent syndrome. T h e clinical picture is based upon symptoms of abdominal pain and disturbed defecation

38

M. van Outryve

(diarrhea or constipation) and symptoms of bloatedness and distension, continuous or recurrent for at least 3 months. Traditionally, the diagnosis is made by excluding other organic disorders. Besides drug therapy, lifestyle improvements and dietary changes should be undertaken. Clinical trials have demonstrated the efficacy of mebeverine hydrochloride in the treatment of irritable bowel syndrome. It is a musculotropic drug, whose mode of action is based on a decrease of the calcium availability in the smooth muscle. Mebeverine has an antispasmodic activity and a regulatory effect on the bowel function. In long-term treatment, mebeverine is usually given at a dose of 135 mg t. i. d., but it can be increased to 270 mg t. i. d. if necessary. The slow-release formulation of the mebeverine microgranules in 200 mg capsules can reduce the number of daily intakes from three to two. The objective of this study was to compare the safety and efficacy of slowrelease mebeverine with standard plain mebeverine, both administered at a high dose of 800 mg a day. The risk-benefit ratio of this high dose mebeverine was assessed in the treatment of IBS patients. Other clinical studies have already demonstrated the efficacy of mebeverine administered at a lower dose of 400 mg a day.

Patients and

methods

A double-blind randomized and crossover study was carried out in two centers in Belgium (Dr. Mayeur in Boussu and Dr. van Outryve in Antwerp). Of the 72 patients initially enrolled in the study, 12 were excluded after the placebo baseline week. Finally, 60 out-patients (43 women and 17 men) were randomized into the two-period crossover trial. The age of the patients ranged from 18 to 80 years, with a mean of 49 years. The diagnosis of irritable bowel syndrome was made with the diagnostic scale of Kruis. Only patients with a score of at least 44 on this scale were included in the study. All of these patients had been treated with placebo for 1 week and did not respond to this placebo treatment. The placebo responders, with less than two episodes of abdominal pain during the placebo treatment period, were excluded from the study. The 60 patients finally included in the study were to be treated for 12 weeks. A first group "A" was initially treated for 6 weeks with mebeverine 200 mg in doses of 2 capsules in the morning and evening and with 2 placebo capsules at noon. They thus took a daily dose of mebeverine 200 mg of 800 mg. After this initial treatment for 6 weeks, these patients received treatment "B", also for a period of 6 weeks. Treatment "B" consisted of 2 capsules of mebeverine plain 135 mg, t. i. d. During this period, the daily dose of plain mebeverine was thus 810 mg. The other group of 30 patients first received treatment "B" of mebeverine plain 135 mg, two capsules t. i. d. for 6 weeks. Afterwards they received treatment

Data from a high dose mebeverine study

39

" A " of mebeverine 2 0 0 mg two capsules b. i. d., with two placebo capsules at noon for 6 weeks. In this way, all the patients received in fact the same treatment, but in two crossover periods. Evaluations of efficacy, tolerance and compliance were made before and after the placebo week and after 3, 6, 9 and 12 weeks of treatment. At each visit, the general clinical impression (GCI) was assessed using a five-point scale (1: no symptoms, 2: light disease, 3: mild disease, 4: severe disease, 5: incapacitating disease). T h e general clinical improvement (GCIm) was evaluated at each visit from visit 2 to visit 6 using a three-point scale (1: improvement, 2: unchanged, 3: worsening). At the end of each treament period (weeks 6 and 12), the treatment was evaluated by both the patient and the investigator (—1: worsening, 0: not effective, + 1: slightly effective, + 2 : effective, + 3 : very effective). T h e main parameters of efficacy were the patients' and investigators' efficacy assessments and the G C I and G C I m after 6 weeks of treatment. T h e scores of the different IBS symptoms and of the G C I and G C I m after 3 weeks of treatment were considered as secondary parameters. Abdominal pain, ballooning, flatulence, constipation, diarrhea or alternating stool pattern were assessed at each visit for their intensity and their frequency. Tolerance was evaluated on the basis of clinical history, clinical examination and biological tests. Hematology, serum chemistry and hepatic enzymes were measured at selection and after 6 weeks of treatment. Any adverse event that emerged during treatment was reported, specifying the type, date of onset, duration, severity and relationship with the tested treatment. Statistics All statistical tests were two-sided, at a 5 % level of significance. Descriptive statistics were calculated for the demographic characteristics of patients at selection. T h e scores of efficacy, G C I , G C I m , the intensity and frequency of the symptoms were compared beteen the two formulations after 3 and 6 weeks using the Mann-Whitney-Wilcoxon rank test adapted to crossover design by Koch. T h e efficacy was also tested for each formulation separately using a Wilcoxon's signed rank test to compare the G C I , G C I m and symptoms scores after 3 and 6 weeks of treatment to baseline values.

Results Compliance O f the 60 patients included in the study, 55 were evaluated after 3 weeks of both treatments. Fifty-three could be evaluated after 6 weeks of both treatments. As

40

M. van Outryve

drop-outs, we mention 4 patients with treatment failure after 3 weeks (2 patients in each treatment group). Another 2 patients dropped out for unknown reasons. One patient left the study because of side effects, which in our opinion were not related to the treatment. After a thorough clinical and biological examination, no pathology could be discovered in this patient. Global

efficacy

After 6 weeks of treatment, the global efficacy of the treatment was assessed by the patient. The results of the assessment are given in figure 1, expressed in percentages. Both treatment forms (mebeverine plain and mebeverine 200 mg) were regarded as "effective" or "very effective" in more than 80% of the cases. No patient's condition worsened during the study and less than 5% of the patients considered the treatment "not effective". When comparing both formulations, no statistically significant difference was found (P > 0.40). _

68

E o ^ j mebeverine

plain

i