Linköping University Medical Dissertations

No. 974

Irritable Bowel Syndrome

Diagnostic Symptom Criteria
and Impact of Rectal Distensions on
Cortisol and Electrodermal Activity

Susanna Walter

Division of Gastroenterology and Hepatology

Department of Molecular and Clinical Medicine
Faculty of Health Sciences Linköping University
SE-581 85 Linköping, Sweden

Linköping 2006
Susanna Walter, 2006

ISBN 91-85643-24-6
ISSN 0345-0082

Printed in Sweden by LiU-Tryck AB, Linköping

To Bent and Fridolf
ABSTRACT
In a population prevalence questionnaire study we demonstrated that constipation and fecal
incontinence are common problems in the general Swedish population with a similar
magnitude as in other Western countries. 95.6% of the population had between three bowel
movements per day and three per week. Constipation was mostly defined by “hard stools” and
“the need of using laxatives”.
Irritable Bowel Syndrome (IBS) is characterized by abdominal pain/discomfort and abnormal
bowel habits. The diagnostic criteria of IBS are based on clinical symptoms. Division of IBS
patients into symptom subgroups appears important as their bowel symptoms are
characterized by heterogeneity. International criteria to subgroup IBS (Rome II) are based on
expert consensus and not on evidence. We investigated the variation of stool consistency and
defecatory symptoms in 135 IBS patients by symptom diary cards. Most patients had
alternating stool consistency. When subgroups were based on stool consistency, all kinds of
defecatory symptoms (straining, urgency, and feeling of incomplete evacuations) were
frequently present in all subgroups. Stool frequency was in the normal range in the majority
of patients. We propose that IBS subgroups should be based on stool consistency. We suggest
that Rome II supportive criteria must be reconsidered as the determination of presence or
absence of specific symptoms does not work as an instrument for categorization of IBS
patients into diarrhoea-and constipation-predominant. We also propose that abnormal stool
frequency should be excluded to define subgroups of IBS. Alternating stool consistency and
presence of different defecatory symptoms, regardless of stool consistency should be included
as criteria for IBS.
Stress is known to play an important role in the onset and modulation of IBS symptoms. From
experimental studies there is evidence for a stress-dependent alteration of visceral sensitivity.
The biological mechanisms responsible for the causal link between stress and IBS symptoms
are not completely understood, but the hypothalamic-pituitary-adrenocortical axis and the
autonomous nervous system seem to play a prominent role in the pathophysiology of IBS. We
investigated visceral sensitivity and the effect of repeated maximal tolerable rectal distensions
on salivary cortisol levels and skin conductance in patients with IBS, chronic constipation and
healthy volunteers.
We found that the expectancy of the experimental situation per se (provocation of bowel
symptoms by rectal distensions) compared to non-experimental days at home measured as
salivary cortisol had a high impact on the level of arousal in IBS. IBS patients had higher skin
conductance values than controls in the beginning of distension series and lower rectal
thresholds for first sensation, urge and discomfort than healthy controls and constipation
patients. IBS patients demonstrated habituation to repeated subjective maximal tolerable
rectal distensions according to sympathetic activity although patients continued to rate their
discomfort as maximal. Constipation patients had lower sympathetic activity than IBS
patients before and during repeated rectal distensions. None of the groups demonstrated a
significant increase in cortisol after repetitive rectal distensions.
We conclude that Rome II supportive criteria for IBS should be reconsidered according to our
findings. IBS patients are more sensitive to pre-experimental stress than healthy controls and
patients with constipation. This should be considered in the design of experimental IBS
studies. IBS patients habituated to subjective maximal tolerable, repetitive rectal distensions
with decreasing sympathetic activity. Since responses to repeated stimuli of close-to-pain
intensities are resistant to habituation this finding could be caused by psychological influences
on perception, that is, perceptual response bias.

5
6
PAPERS

This thesis is based on the following papers, which are referred to in the text by their Roman
numerals:

I. A population-based study on bowel habits in a Swedish community: prevalence

of faecal incontinence and constipation
Walter S, Hallböök O, Gotthard R, Bergmark M, Sjödahl R
Scand J Gastroenterol. 2002 Aug;37(8):911-6.

II. Subgroups of irritable bowel syndrome: a new approach

Walter SA, Skagerström E, Bodemar G
Eur J Gastroenterol Hepatol. 2004 Oct;16(10):991-4.

III. New criteria for irritable bowel syndrome based on prospective symptom
evaluation
Walter SA, Ragnarsson G, Bodemar G
Am J Gastroenterol. 2005 Nov;100(11):2598-9.

IV. Pre-experimental stress in patients with irritable bowel syndrome: high cortisol
values already before symptom provocation with rectal distensions
Walter SA, Aardal-Eriksson E, Thorell L-H, Bodemar G, Hallböök O
Neurogastroenterol & Motil. 2006; (18): 1069- 1077

V. Sympathetic activity during repeated maximal rectal distensions in patients with

irritable bowel syndrome and constipation
Walter SA, Bodemar G, Hallböök O, Thorell L-H
Submitted

7
8
CONTENTS

Page

ABSTRACT 5

PAPERS 7

CONTENTS 9

INTRODUCTION 11

Normal bowel habits 11

The prevalence of self reported constipation 11
The prevalence of self reported fecal incontinence 12
The prevalence of irritable bowel syndrome (IBS) 12

Diagnostic symptom criteria for IBS 16

Manning criteria 16
Kruis criteria 16
Rome I criteria 16
Rome II criteria 17
Rome II supportive criteria 17
Results of earlier IBS symptoms studies from Linköping 17

Pathophysiological aspects of IBS 19

Visceral hypersensitivity 19
Stress 20
Cortisol 21
Autonomic dysfunction 22
Skin conductance 22
Psychosocial aspects 22

AIMS 23

SUBJECTS AND METHODS 25

Paper I 25
Paper II 25
Paper III 26
Papers IV and V 27
Subjects 27
Methods 28
Statistical methods 31
Ethics 31

9
RESULTS 33

Paper I 33
General results 33
Constipation 35
Fecal incontinence 37

Papers II and III 39

Papers IV and V 43

Symptoms 43
Psychiatric ratings 44
Rectal manovolumetry 46
Cortisol 47
Skin conductance during maximal repetitive
Rectal distensions 49

GENERAL DISCUSSION 53

Population prevalence study 53

Constipation 53
Fecal incontinence 54
General aspects 54

Diary card symptom studies of IBS patients 54

Comments on newly published Rome III criteria 56

Impact of repetitive rectal distensions on salivary cortisol

and skin conductance 58

Patients with IBS 58

Patients with constipation 59

CONCLUSIONS 61

APPENDIX 62

SUMMARY IN SWEDISH 65

ACKNOWLEDGEMENTS 67

REFERENCES 69

10
INTRODUCTION

Normal bowel habits

There have been several attempts to study what are “normal” bowel habits. 1 2 3 4 5 6 7 8 9 10 In
1965 Connell et al. found that 99.3% of people had between three bowel movements per day
and three per week. 1 This was confirmed in a later study by Drossman et al. 3 Today a stool
frequency within this range is still considered to be normal.11 Ragnarsson and Bodemar found
that the majority of patients with irritable bowel syndrome (IBS) had a bowel movement
frequency within this “normal” range. 12 Obviously, normal bowel frequency does not exclude
bowel disturbances. Heaton et al. found, in a prospective diary card study, that only 40% of
men and 33% of women had a regular 24-hour bowel habit cycle 5 and concluded that normal
bowel function is experienced by less than half of the population. Bowel habits are reported to
be influenced by several factors such as gender, 4 5, 13 14 15 age, 5 16 race,4 13 diet,17 18 stress, 3
or physical activity 4 and may therefore differ between different cultures and countries. It
seems to be somewhat unclear how to interpret the term “normal bowel habits”. It may also be
difficult to translate the results of international population prevalence studies of bowel habits
to Swedish conditions. A better understanding of bowel function in the general population
would be useful to evaluate patients with gastrointestinal complaints.

The prevalence of self-reported constipation

One common gastrointestinal complaint is constipation. In North American population

prevalence studies, constipation ranged from 1.9% to 27.2%, with most estimates from 12%
to 19%.19 Everhart and co-workers found in a population sample by face-to-face interview
that 20.8% of women and 8.0% of men reported constipation.4 In the same study 9.1 % of
women and 3.2% of men reported three or fewer bowel movements per week. People thus
consider low stool frequency as one among other symptoms when they consider themselves
constipated. Most epidemiological studies have relied upon self-reported constipation, in
which the subjects have simply been asked whether they are constipated or not. 20 The
concept of constipation is complicated by disagreement among patients and doctors about its
nature.11 The value of self-reported constipation has been questioned as it cannot reliably
differ between functional constipation and bowel outlet delay. 20 Moreover, there is an overlap
of subjects reporting constipation and having IBS. Mearin et al. found that 66% of patients
with IBS who fulfilled symptom criteria for IBS according to expert consensus (Rome I 21)
and 57% who fulfilled symptom criteria for IBS according to expert consensus (Rome II 22)
considered themselves to have constipation.23 In conclusion, results of constipation
prevalence studies have to be interpreted carefully with respect to how subjects define
constipation. Moreover, there seems to be a large overlap between self-reported constipation
and IBS.

11
The prevalence of fecal incontinence

Another gastrointestinal problem that is common and may have a devastating impact on
quality of life is fecal incontinence.24 25 26 27 28 The prevalence of fecal incontinence is
estimated to be between 11-15%. 29 Prevalence figures heavily rely on the definition of
severity and frequency of leakage events. Unfortunately only 5%-27% of patients with this
condition consult their doctors about this problem 30 31 and consequently physicians should
ask about the symptoms. 32 However, Nelson et al. found by telephone interview that 2.2% of
an American population had anal incontinence including soiling and incontinence of gas. 33
This could be an underestimation because of people’s reluctance to report these symptoms.
The overall prevalence in another American study was as high as 18.4%. 34 The prevalence of
fecal incontinence is higher in older than in younger people. 35 Functional bowel disorders
including IBS may account for a large portion of fecal incontinence, although evidence data
are limited.36 37 Other risk factors for fecal incontinence are diarrhoea, diabetes, older age,
neurological disorders, high body mass index, obstetric anal sphincter injury, poor overall
health and previous hysterectomy.32 On this background there are probably large international
differences in the prevalence of fecal incontinence.

The prevalence of irritable bowel syndrome (IBS)

Population prevalence rates of IBS vary widely. Mearin et al. showed that the stricter the
criteria, the lower the prevalence of IBS. 38 The IBS prevalence varied between 2.1%
(according to Rome II 39) and 12.1% (according to Manning 40) in the same population
dependent on the criteria used. But even if the same criteria are used (Rome II), the IBS
prevalence still can vary between different population prevalence studies, from 3.3% in Spain
38
to 35% in Mexico 41 (Table 1).

To study whether the international differences are real or apparent, Hungin et al. studied IBS
prevalence in eight European countries, using the Manning, Rome I and Rome II criteria. The
overall prevalence of current IBS symptoms across Europe was 9.6 % with a range from 6.2%
in the Netherlands to 12% in UK and Italy. 15 The prevalence of subjects who had a formal
diagnosed IBS varied from 1.7% in Germany to 11.5% in Italy. In the same study the highest
overall prevalence rate was obtained with the Manning criteria (6.5%) followed by the Rome I
(4.2%) and the Rome II criteria (2.9%). They also found that IBS seems to be more common
in women, even if different criteria are used.

IBS is a disorder with a chronic relapsing course. 39 In a follow-up study using Rome II
criteria, Williams et al. found that 52% no longer met the IBS criteria two years after the first
survey.42 They concluded that Rome II criteria are limited in capturing fluctuations of disease
over time. Ragnarsson and Bodemar studied IBS patients in a follow-up after seven years 43
using diary cards. Although there was a general decrease in pain and straining and increase of
normal stools, they found that the abdominal symptoms remained fairly unchanged. However,
35% of patients (n=20) did not take part in the follow-up study, limiting the conclusions that
may be drawn from the results.

12
In conclusion, the epidemiology of IBS depends on the criteria used to classify it; the stricter
the criteria, the lower the prevalence of the disease. 44 However, there are still large
international differences even when the same criteria (Rome II) are used. It remains an open
question to what extent these international differences are real, dependent on cultural factors
or study designs. One common major factor of these epidemiologic studies is the use of
questionnaires, which leads to recall bias,45 and the absence of prospective documentation of
symptoms on diary cards.

Table 1: Epidemiologic prevalence studies for irritable bowel syndrome

Author Year Country Sample Method IBS IBS

prevalence criteria

Thompson 1980 Great 301 apparently Questionnaire 13.6% Manning

et al. 2 Britain healthy criteria
subjects
Drossman 1982 United 789 students Questionnaire 17.1% Manning
et al. 3 States and hospital criteria
employees
Jones 1992 Great Random Questionnaire Ca 25% Manning
et al. 46 Britain sample criteria
2280 subjects
Agreus 1995 Sweden Population Questionnaire 12.5%
et al. 47 sample 1290
subjects
Talley 2001 New Cohort of Questionnaire 12.7% Manning
et al. 48 Zealand Young adults
n= 1290 4.3% Rome II
Mearin 2001 Spain 2000 subjects Personal 3.3% Rome II
et al. 23 interviews

Bommelaer 2002 France 11 131 Questionnaire & 4% Rome I

et al. 49 subjects interview

Icks 2002 Germany Random Questionnaire 12.5%

et al. 50 sample
2400 subjects
Kwan 2002 Hong Random Telephone 6.6% Rome II
et al. 51 Kong sample interview
1000 subjects
Hungin 2003 Europe 40 000 Telephone 11.5% Manning,
et al. 15 (eight subjects interview Rome I or
countries) Rome II

13
Table 1 (continuation)

Author Year Country Sample Method IBS IBS

prevalence criteria

Lu 2003 Taiwan 2865 subjects Questionnaire 22.1% Rome II

et al. 52 receiving a
health check
Tan 2003 Malaysia 533 healthy Questionnaire 15.8% Rome I
et al. 53 students

Hoseini-Asl 2003 Iran Random Questionnaire 5.8% Rome II

et al. 54 sample
5492 subjects
Gwee 2004 Singapore Random Face-to-face 8.6% Rome II
et al. 55 sample interview
3000
households
Celebi 2004 Turkey Random Face-to-face 6.3% Rome II
et al. 56 sample interview with
1900 subjects questionnaire
Bommelaer 2004 France 8221 subjects Questionnaire 1.1% Rome II
et al. 57

Wilson 2004 Great Random Questionnaire 10.5% Rome II

et al. 58 Britain sample
4807 subjects
Hungin 2005 United Random Screening 14.1% Manning,
et al. 59 States sample telephone Rome I or
5009 subjects interview Rome II
Yilmaz 2005 Turkey Random Face-to-face 10.2% Rome II
et al. 60 selection interview
3000 subjects
Wigington 2005 United 990 subjects Questionnaire 9.6% Rome II
et al. 61 States

Sperber 2005 Israeli 737 rural Interview 5.8% Rome II

et al. 62 Bedouin subjects
society 1018 urban 9.4%
subjects
Schmulson 2006 Mexico 324 healthy Questionnaire 35% Rome II
et al. 41 City volunteers

Vandvik 2006 Norway 4622 subjects Questionnaire 8.4% Rome II

et al. 63

Boyce 2006 Australia 1225 subjects Questionnaire 8.9% Rome I

et al. 64 Rome II

14
Diagnostic symptom criteria for IBS

Manning criteria
The diagnosis of IBS is based on clinical symptoms. The first attempt to find unifying criteria
was in 1978 when Manning and co-workers 40 studied 109 unselected patients who were
referred to gastroenterology or surgery clinics with abdominal pain and/or change in bowel
habit. Thirty-two of them got the diagnosis IBS. Based on a questionnaire with 15 questions
about bowel symptoms, they found that four symptoms were more common in IBS patients
than in patients with organic diseases:

x pain eased after bowel movement

x looser stools at onset of pain
x more frequent bowel movements at onset of pain
x abdominal distension

Later the Manning criteria were criticized as they apply to women and were not considered of
diagnostic value for men.65 66 Moreover, only one of the four Manning criteria (abdominal
distension) distinguished patients with IBS from patients with inflammatory bowel disease.67

Kruis et al. criteria

In another attempt, Kruis and co-workers 68 compared 108 patients with IBS and 299 patients
with organic disease. The following symptoms, evaluated by questionnaire, were more
common in IBS:
x abdominal pain
x flatulence
x bowel irregularity
x the presence of symptoms for more than two years
x diarrhoea alternating with constipation

Rome I criteria
Rome I criteria 21 were largely drawn from the Manning and Kruis data.65 (Table 2)

Table 2: Rome 1 criteria for IBS 21

Continuous or recurrent symptoms of:

1) Abdominal pain relieved by defecation or associated with a change in frequency or
consistency of stools, and/or
2) Disturbed defecation (two or more of):
Altered stool frequency
Altered stool form
Altered stool passage (straining, urgency, or feeling of incomplete
evacuation)
Passage of mucus
Usually with bloating or feeling of incomplete distension

15
Rome II criteria
In 1998 an expert consensus called “the Rome Working Team” changed the definition and
diagnostic criteria for IBS with the intension to improve clarity and international consistency,
based on existing evidence. The Rome II criteria are presented in Table 3. The studies to
support the changes of the criteria according to the consensus document 39 are listed in
Table 5. Beside the study of Manning there are two more patient studies with 104 69 and 156
70
patients, respectively, that have explored the symptoms of IBS patients. Both studies as
well as the other studies are based on questionnaires, not on prospective recording of
symptoms on diary cards.

Rome II supportive criteria

Because of the heterogeneity of the symptoms in IBS,71 subgrouping appears meaningful.
Subgroups of patients with irritable bowel syndrome (IBS) are likely to respond differently to
existing and evolving therapies.72 Rome II supportive criteria (Table 4) recommend the use of
specific symptoms to classify patients into diarrhoea- or constipation-predominant IBS. They
propose that patients with diarrhoea-predominant IBS should have more than three bowel
movements a day or loose stools or urgency and that patients with constipation-predominant
IBS should have fewer than three bowel movements a week or hard or lumpy stools or
straining during a bowel movement. Patients belonging to one subgroup should not have any
of the items present in the other subgroup.

Rome II supportive criteria are based on expert opinions, not on evidence. Our clinical
impression was that IBS patients often have an alternating stool consistency. Criteria for an
IBS subgroup with alternating stool consistency are missing in Rome II. Furthermore, our
clinical impression and results obtained in trials was that almost all patients with IBS have
some proportions of all defecatory symptoms and stool frequency seemed to be independent
of stool consistency.

Results of earlier IBS symptoms studies from Linköping

Paper II and III of the present thesis is the continuation of the work of Ragnarsson and
Bodemar. 43 73 Ragnarsson and Bodemar showed that pain is temporally related to eating but
not to defecation in IBS patients. 74 Patients define constipation and diarrhoea on the basis of
stool consistency, not frequency, which is in the normal range in the majority of patients. 12
Patients can be divided into subgroups and the symptoms remain fairly unchanged over time.
43
Compared with controls, the patients are distinguished by pain, bloating and stools with
straining and feeling of incomplete evacuation.75

General aspects of symptom records

IBS is a diagnosis based on symptom reports. Heterogeneity of symptoms in IBS is a well
known problem. Symptom evaluation by diary card is superior to questionnaires and
minimizes the phenomena of recall.45 Moreover, IBS patients might have a peculiar
confirmatory bias for negative material 76 leading to bias when grading their symptoms
retrospectively. In a majority of clinical studies, inclusion of IBS patients are performed by
symptom questionnaires. Usually a description of patients’ symptoms is absent with a
reference that patient inclusion fulfils defined criteria (Manning, Rome I or Rome II).
Unfortunately those criteria are not sufficiently evidence-based and criticism of them is
growing.

16
Table 3: Rome II diagnostic criteria* for IBS 22

At least 12 weeks or more, which need not be consecutive, in the preceding 12 months of
abdominal discomfort or pain that has two out of three features:
(1) Relieved with defecation; and/or
(2) Onset associated with a change in frequency of stool; and or
(3) Onset associated with a change in form (appearance) of stool.

Symptoms that cumulatively support the diagnosis of Irritable Bowel Syndrome

- Abnormal stool frequency (for research purposes “abnormal” may be defined
as greater than three bowel movements per day and less than three bowel
movements per week);
- Abnormal stool form (lumpy/hard or loose/watery stool);
- Abnormal stool passage (straining, urgency, or feeling of incomplete
evacuation);
- Passage of mucus;
- Bloating or feeling of abdominal distension.

* In the absence of structural or metabolic abnormalities to explain the symptoms


Table 4: Rome II Supportive Symptoms of IBS to subclassify IBS original* and additional
criteria from the revised version ** 65

(1) Fewer than three bowel movements a week

(2) More than three bowel movements a day
(3) Hard or lumpy stool
(4) Loose (mushy) or watery stools
(5) Straining during a bowel movement
(6) Urgency (having a rush to have a bowel movement)
(7) Feeling of incomplete bowel movement
(8) Passing mucus (white material) during a bowel movement
(9) Abdominal fullness, bloating or swelling

Diarrhoea-predominant
1 or more of 2, 4, or 6 and none of 1, 3, or 5;*
or: 2 or more of 2, 4, or 6 and one of 1 or 5. (3. Hard or lumpy stools do not qualify)**
Constipation-predominant
1 or more of 1, 3, or 5 and none of 2, 4, or 6;*
or: 2 or more of 1, 3, or 5 and one of 2, 4, or 6.**

17



Table 5: Rome II criteria for IBS is based on studies given in the table, according to the
Rome II Multinational Consensus Document 39

Author Year Journal Study Subjects Inclusion Method

Type criteria
Manning 1978 British Medical Patient 109 Patients referred to Questionnaire
et al.40 Journal study unselected gastroenterology or
patients, 32 surgery clinics with
of them got abdominal pain and/or
the change in bowel habit
diagnosis
IBS
Harvey 1987 Lancet Long- 104 IBS Manning criteria Questionnaire
et al.69 term patients
follow-up
study on
patients
Whitehead 1990 Gastroenterology Factor Two Women consulting for Questionnaire
et al.77 analysis samples contraception and
on non- (n=351, women belonging to
patients n=149) of church women’s
female society were invited
adults
Taub 1995 Digestive Factor 1344 male Female and male Questionnaire
et al.78 Diseases and analysis and female African-Americans
Sciences on non- adults and Caucasians
patients
Thompson 1997 European Journal Patient 156 IBS Patients with Questionnaire
et al.70 of study patients diagnosis IBS not
Gastroenterology based on specific
criteria
Longstreth 1997 Digestive Review
et al.79 Diseases and
Sciences













18
Pathophysiological aspects of IBS

The current view on the pathophysiology of IBS is that of interactions between different
biological and psychological factors. Visceral hyperalgesia, altered motility, disturbances of
the brain-gut axis, abnormal central processing, autonomic and hormonal events, genetic and
environmental factors, postinfectious sequels, and psychological disturbances such as
dysfunctional coping, stress and psychiatric disorders are variably involved in IBS. 11 In the
present study we focus on visceral hypersensitivity, cortisol and sympathetic activity.

Visceral hypersensitivity
In 1973, Ritchie was the first to show that IBS patients report pain at lower volume when a
balloon was inflated in the lumen of the bowel. 80 81 Later studies demonstrated that IBS
patients in general perceive pain at lower rectal pressures or volumes than healthy controls. 51
82 83 84 51, 85 86 87 88
However some studies have not been able to show significant differences
between patients and controls according to thresholds for pain or discomfort and for non-
painful rectal distensions. 81 89, 90 Differences of visceral sensitivity between subgroups of
IBS have been reported but with inconsistent results. 91 92 93 94 95 In IBS patients visceral
hypersensitivity has also been measured in the esophagus. 96 In a recent study it was found
that visceral intolerance to distension appears organ-specific in patients exhibiting a specific
site of symptoms. 97 IBS patients do not have a general hypersensitivity to pain apart from
visceral hypersensitivity. 98 At least half of IBS patients perceive stimuli over wider referral
areas of the abdomen than healthy subjects 99 and lidocaine application into the rectum before
barostat procedure reduces the visceral hyperalgesia. 100

Several factors can influence the visceral sensitivity. IBS patients often have postprandial
abdominal symptoms. 101 102 An increased sensitivity of the rectum after a meal is seen in IBS
patients but also in healthy volunteers. 75 103 A fatty meal can increase rectal sensitivity in
both controls and IBS patients 104 and lipid administration in the duodenum leads to a marked
reduction in colonic perception thresholds in IBS patients compared to controls. 105 Rectal
hypersensitivity in IBS patients can also be induced by repetitive sigmoid stimulation.94 106
Psychological factors, including stress, influence pain thresholds in patients with IBS. 81
Hypnotic relaxation increased the distension volume of the bowel required to induce
discomfort, while anger reduced this threshold compared with relaxation in healthy controls.
88 107
Hypnotherapy is effective in the treatment of IBS. 108 Mental stress increases the
subjective feeling of pain during sigmoid distensions in healthy volunteers. 109

The cause of visceral hypersensitivity is not completely understood. Studies have shown
evidence for abnormalities in afferent neurons, 84 abnormal peripheral visceral receptors, 110
hyperexcitability of spinal nociceptive processes, 111 abnormal endogenous pain inhibitory
mechanisms 91 and a heightened pain sensitivity of the brain-gut axis in IBS. 112 There is also
evidence for a specific brain activation in patients with IBS not only during noxious rectal
distension but also during the anticipation of rectal pain. 113 In functional brain studies IBS
patients have shown an augmented activation in the dorsal portion of the anterior cingulated
cortex in association with increased subjective pain reports to rectal stimuli. These data do not
necessarily indicate a cerebral etiology for visceral hypersensitivity; they could reflect a
normal cerebral response to a heightened incoming sensory signal. 99 Studies of visceral
hypersensitivity in IBS patients represent both neural and cognitive functions. A rectal
distension causes principally two processes in the brain, that is, registration of the sensory

19
signal and perception-related cognitive processes. 114 Recently, the effect of small and
therefore unperceived rectal distensions on brain activity has been tested to minimize the
influence of cognitive processes related to the experimental stimulus. IBS patients showed a
larger functional Magnetic Resonance Imaging (f-MRI) activity volume in the brain in
response to these unperceived rectal distensions, confirming the presence of neural circuitry
hypersensitivity. 115

Manovolumetry
Manovolumetric investigation methods of reservoir organs were developed in the 1960s and
1970s. 116 117 The apparatus often used for manovolumetry is called a barostat. The barostat
can measure motor functions, such as motility of gastrointestinal reservoirs like the rectum. 118
The barostat is also used to estimate the extent of hypersensitivity and to provoke symptoms
in IBS. 119 120, 121 122 It has even been suggested as a diagnostic instrument for IBS. 82 83 123
The methodology of measuring rectal sensitivity in patients with IBS has been improved in
recent years by standardization of distension protocols and technical development of the
barostat. 124 125 126 127 One of these distension protocols is called “tracking technique”. The
tracking technique was described by Whitehead et al. in 1997. 128 It was developed to
circumvent the problem of susceptibility to psychological influences. 81 124 “Nonperceptual
factors, such as prior learning and the anticipated consequences of reporting pain, can affect
the threshold at which pain is reported. Some subjects may report pain at low intensity of
stimulation to insure that they do not experience harm, whereas other subjects may deny pain
even at levels of stimulation that cause tissue damage because they want to appeal strong or
stoical.” 81 With the tracking technique the distension of the rectum is either increased or kept
the same as long as the patient does not report pain or maximal tolerable distension. When the
patient reports pain or maximal tolerable distension, the next distension is either decreased or
remains the same. Whether the next distension is changed or remains the same is determined
by a random process.

Stress
Stress is known to play an important role in the onset and modulation of IBS symptoms. 129,
130 128 131 132
From experimental studies there is evidence for a stress-dependent alteration of
visceral sensitivity. 133 134 135 The biological mechanisms responsible for the causal link
between stress and IBS symptoms are not completely understood, but the hypothalamic-
pituitary-adrenocortical axis and the autonomous nervous system seem to play a prominent
role in the pathophysiology of IBS. 99 133 136 In rats, stress by “the neonatal maternal
deprivation model” is known to trigger long-term alterations in gut transit-time, colonic
epithelial barrier function, and mucosal immunity. 137 One main finding in these animals was
that basal plasma adrenocorticotrophic hormone and corticosterone concentrations were
significantly elevated. 138 Pre-treatment of the separated rats with a corticotrophin-releasing
hormone antagonist abolished the stress-induced mucosal changes of the intestine, indicating
that neonatal trauma can induce phenotypic changes in adulthood, including enhanced
vulnerability of the gut mucosa to stress, via mechanisms involving peripherally located
corticotrophin-releasing hormone receptors. 139 There is also evidence that corticotrophin-
releasing hormone receptor activation prevents colorectal-induced visceral pain in rats. 140

Human data also show that corticotrophin-releasing hormone is an important mediator of the
central stress response and seems to play an important role for the colonic motility and
visceral perception. Fukudo et al. showed that IBS patients had a greater colonic motility than
controls after corticotrophin-releasing hormone injection. 141 Sagami et al. found that

20
peripheral administration of a corticotrophin-releasing hormone receptor antagonist improved
gastrointestinal motility, visceral perception, and negative mood in response to gut
stimulation. 142 Posserud et al. found that basal corticotrophin-releasing hormone levels were
lower in IBS patients and increased significantly during stress in patients but not in controls.
134

Cortisol
Cortisol was first isolated from the adrenal cortex in the 1930s by Kendall 143 and
Reichstein.144 Cortisol is a corticosteroid hormone produced by the adrenal cortex. The
synthesis of cortisol from cholesterol is stimulated by adrenocorticotropic hormone from the
anterior lobe of the pituitary gland. Adrenocorticotrophic hormone is in turn stimulated by
corticotropin-releasing hormone released by the hypothalamus. The basal hypothalamic-
pituitary-adrenocortical axis activity is regulated by a pulsative corticotrophin-releasing
hormone secretion leading to a cortisol peak level before awakening and a decrease
throughout the day reaching its nadir in the late evening. 145

Psychological or physiological stress results in increased cortisol secretion from the adrenal
cortex within ten minutes of the stress situation. 146 This process requires a normal function of
the hypothalamic-pituitary-adrenocortical axis. In response to psychological stress,
corticotrophin-releasing hormone release is controlled by central neurotransmittors such as
norepinephrine and serotonin and in response to infection corticotrophin-releasing hormone
containing neurons respond to proinflammatory cytokines such as interleukin 1, 6 and tumor
necrosis factor alfa. 147

Cortisol has a broad spectrum of effects in many tissues to maintain homeostasis under
conditions of strain. 148 149 Changed levels have been observed in connection with
psychological stress, 150 151 fear, pain, depression, 152 posttraumatic stress disorder,149 physical
exertion or physiological conditions such as intake of a meal, 148 hypoglycemia, premenstrual
syndrome, 153 fever, trauma, or surgery. 154 Measurement of salivary free cortisol is widely
used in experimental studies to evaluate the activation of the hypothalamic-pituitary-
adrenocortical axis. 150

Several studies have reported increased cortisol or an overactivation of the hypothalamic-

pituitary-adrenocortical axis in IBS patients. 147 155 156 157 According to IBS symptom
subgroups, there are contradicting results. Elsenbruch and co-workers found elevated cortisol
levels in diarrhoea-predominant IBS compared to constipation-predominant IBS 158 and Dinan
and co-workers found that cortisol was elevated in all IBS subgroups (diarrhoea-predominant,
constipation-predominant and alternators), although the elevation was most marked in the
constipation subgroup. 147 Other studies have not found any differences between IBS patients
and controls. 134 159

In conclusion there is evidence for a dysregulation of the hypothalamic-pituitary-

adrenocortical axis in IBS patients both during stress and non-stress conditions.

21
Autonomic dysfunction
The autonomic nervous system regulates vegetative processes such as heart rate, blood
pressure, body temperature and motility of the gut and modulates these homeostatic functions
to meet behavioural demands. Dysfunction or imbalance of the autonomic nervous system is
associated with gastrointestinal symptoms in IBS, 160 but the results of studies have been
inconsistent. 157 161 162 163 164 165 166 167 168

Aggarwal et al. demonstrated that patients with constipation-predominant IBS had cholinergic
abnormalities, whereas patients with diarrhoea-predominant IBS had adrenergic
abnormalities. 161 Abnormal cholinergic function in IBS was also demonstrated by other
investigators. 168 169 170 Some investigators found evidence for increased sympathetic activity
in IBS patients 157, 160 165 whereas others did not find any differences in autonomic response.
171
Alterations of the autonomic function may increase susceptibility to gastrointestinal
symptoms. 172 It is unclear whether the autonomic alterations in IBS are a primary
phenomenon or merely reflect dysregulations in the bidirectional interactions of the central
and enteric nervous system. 99

Skin conductance
Afferent neurons from the sympathetic axis of the autonomous nervous system innervate
eccrine sweat (sudomotor) glands, and their activity leads to measurable changes in skin
conductance, termed electrodermal activity. 173 174 The palmar and plantar regions are very
sensitive to psychological processes such as emotion, alertness and attention. 152 Changes in
skin conductance are strongly linearly related to changes in the number of active eccrine
sweat glands, 175 changes in sympathetic sudomotor nerve activity upon stimulation 176 and
changes in the amount of water evaporation from the skin under skin conductance
measurement. 177
Stress and anxiety represent high levels of arousal and emotion-related sympathetic activity,
which can be manifested as increased electrodermal activity 178 and electodermal reactivity to
repeated stimulation.179 This connection enables electrodermal activity to be used as an
objective index of emotional behaviour, for example, as an indicator of fear conditioning. By
fear conditioning is meant that a neutral stimulus is temporarily paired with an aversive
stimulus. The neutral stimulus becomes predictive of the aversive stimulus and will elicit
arousal responses that can be measured as increased electrodermal activity. 180 Fear
conditioning may occur without conscious awareness. 181 The first conditioning experiment
performed referred to the gastrointestinal tract, and demonstrated the possibility of producing
conditioned autonomic visceral responses to external neutral stimuli. 182 Skin conductance has
been measured in IBS patients but studies are few and results have been inconsistent. 160 169 183
184 185

Psychosocial aspects
Patients with IBS experience significant impairment of health-related quality of life compared
with the general population. 58 186 Psychological disturbances are generally more common in
IBS patients with more severe symptoms who seek medical care. 187 188 189 Among them, there
is a high prevalence of anxiety, mood and somatoform disorders, 190 191 sleep disturbances, 192
and fatigue. 193 Psychiatric disorders such as depression and anxiety are not viewed as causes
for IBS 48 but as comorbid factors that may influence the patient's response to symptoms. IBS
patients who are not health-care seekers do not show any appreciable differences in
psychological disturbances from the general population. 194

22
AIMS

x To investigate bowel habits in the general Swedish population with focus on

constipation and fecal incontinence.

x To investigate the variation of stool consistency and defecatory symptoms in IBS

patients with the help of symptom records from diary cards

x To validate the Rome II supportive criteria for IBS and to identify subgroups based on
symptom diary card records

x To propose alternative criteria for IBS based on evidence from prospective studies of
symptoms with diary cards

x To investigate visceral sensitivity in patients with IBS, chronic constipation and

healthy volunteers

x To investigate the effect of maximal tolerable rectal distensions on salivary cortisol

levels in patients with IBS, chronic constipation and healthy volunteers

x To investigate whether the expectancy of the experimental situation per se

(provocation of bowel symptoms by rectal distensions) has a higher impact on the
level of arousal in IBS patients compared to patients with constipation and healthy
volunteers.

x To investigate skin conductance activity before and during repetitive rectal distensions
at subjective maximal tolerable pressure in patients with irritable bowel syndrome and
chronic constipation compared to healthy volunteers

x To investigate if IBS patients habituate or sensitize to repeated rectal maximal

distensions, measured with skin conductance during repetitive rectal distensions

23
24
SUBJECTS AND METHODS

Paper I

A questionnaire was mailed to a random sample of 2000 residents between the age of 31 and
76 years in the county of Östergötland with mixed rural and urban population. For this the
Swedish population register and a random generator were used. The questionnaire had not
been validated before. It was coded and reminder letters were sent once to non-responders.
The translated questionnaire is given in the Appendix .

Paper II

The symptom diary cards (Figure 1) of 60 IBS patients (22 men), who had kept daily records
of their abdominal symptoms during 40 days were analysed. The same diary card recordings
were earlier used and validated in a study by Ragnarsson and Bodemar. 12 74
Patients were included according to the Rome 1 criteria and the absence of organic disease.
They were referred by primary care physicians to our unit, department of gastroenterology.
Each patient underwent an extensive interview and a thorough physical examination. All
patients were seen or contacted during a follow-up period of at least two years to ascertain
that no organic disease had been subsequently diagnosed.
Patients had been asked to define stool consistency as “loose, normal, hard or very hard
stools, with separate hard lumps like nuts” for every bowel movement. Patients had also
recorded corresponding defecatory symptoms (urge, straining and feeling of incomplete
evacuation) and episodes of pain and bloating.

25
Figure 1: Symptom diary card (IBS)
Hours: 06 08 10 12 14 16 18 20 22 24 02 04 06

Note meals with X

Note when you have abdominal pain with: X---X
and score the intensity of the pain with number
written above the line.
(please see below).
Hours: 06 08 10 12 14 16 18 20 22 24 02 04 06
Note bowel movements with circle (O). Write
number inside the circle.
(please see below) .
Did you have to rush to the toilet ?
Yes/No
Did you have to strain passing stool?
Yes/No
Did you have the feeling that you could empty
the bowel completely?
Yes/No
Intensity of pain: Stool consistency:
1: X---1---X light pain 1: loose stool
2: X---2---X intermediate pain that can be disregarded 2: normal stool
3: X---3---X intensive, unbearable pain 3: hard stool
4: very hard stool, with separate hard lumps like nuts

Paper III

The results of paper III are based on the symptom diary cards of three patient populations.
Sixty patients are the same as in study II. Fifty patients are the same as in another earlier study
by Ragnarsson and Bodemar 195 and these patients were also included after getting the
diagnosis by a gastroenterologist. They also fulfilled Rome I criteria for IBS. Twenty-five
patients and controls are the same as in study IV and V.

The following diary card data were used: Number of stools, number of bowel movements
with urgency, straining and feeling of incomplete evacuation, number of stools with loose,
normal or hard consistency, pain and bloating (number of episodes or total number of hours of
pain and bloating).

We defined subgroups based on stool consistency and associations to defecatory symptoms

were investigated. Patients were also classified into subgroups according to Rome II
supportive criteria.

26
Papers IV and V

Subjects

IBS patients
Twenty-seven patients with IBS (4 men, 23 women, mean age 41 years, range 22–73 years)
were studied. Patients were referred by primary care physicians working in the primary
catchment area of the University Hospital of Linköping. All patients fulfilled Rome 1 criteria
for IBS. Exclusion criteria were the presence of additional conditions such as organic
abdominal disease, progressive weight loss, medication that could affect the gastrointestinal
system, metabolic, neurological and current psychiatric disorders.

Patients were interviewed and examined by a gastroenterologist. Blood samples were taken
from all patients for analysis of haemoglobin, leucocytes, platelets, C-reactive protein, alanine
aminotransferase, aspartate aminotransferase, albumin, blood glucose, T4, TSH and stool
examination for occult blood. All patients underwent sigmoidoscopy or colonoscopy. Other
examinations were performed when required to exclude any organic disease.

The IBS patients had had symptoms for median 15 years, range 3–50 years. Two IBS patients
remembered that symptoms started after gastroenteritis. Start of symptoms in 17 patients had
no connection to gastroenteritis and eight patients did not remember. All IBS patients
recorded their bowel symptoms prospectively on diary cards for 14 days before entering the
study. During diary card registration any intake of bulking agents was continued but other
medication that could affect bowel function was not allowed.

Constipation patients
Thirteen patients with constipation (all women, mean age 50 years, range 32-60 years) were
studied. Patients were referred by the primary care physicians in the primary catchment area
of the University Hospital of Linköping. Patients were evaluated by a gastroenterologist. All
of them fulfilled the Rome II criteria 39 for functional constipation (Table 6). Symptoms were
recorded on diary cards. Blood samples were taken from all patients for analysis of
haemoglobin, leucocytes, platelets, C-reactive protein, alanine aminotransferase, aspartate
aminotransferase, albumin, calcium, blood glucose, T4, thyroid stimulating hormone and stool
examination for occult blood. All patients had a colonoscopy or barium enema before entry
into the study.

Control group
The control group consisted of 18 healthy subjects with no history of gastrointestinal disease
(4 men, 14 women, mean age 42 years, range 22-72 years) who were recruited by
announcement. Controls were interviewed by a gastroenterologist and recorded their bowel
habits on diary cards.

27
Table 6: The Rome II diagnostic criteria for constipation

At least 12 weeks, which need not be consecutive , in the preceding 12 months of two or
more of:
1) Straining in > ¼ defecations;
2) Lumpy or hard stools stools in > ¼ defecations;
3) Sensation of incomplete evacuation in > ¼ stools;
4) Sensation of anorectal obstruction/blockage in > ¼ of stools;
5) Manual maneuvers to facilitate > ¼ defecations;
6) < 3 defecations/week
Loose stools are not present, and there are insufficient criteria for IBS

Methods

Psychiatric ratings
The Comprehensive Psychiatric Rating Scale for Self-Assessment is a self-rating scale for
affective syndromes containing 19 items covering symptoms of depression, anxiety and
obsessive-compulsive syndromes.196 Each item contains a description of the symptom at four
defined levels of severity. Three additional intermediate levels were used, resulting in a
seven-point scale. This self-rating scale is an instrument to estimate temporary psychological
distress.197 The questionnaire was sent to the patients between two and three weeks before the
experiment, to be filled in at home.

Barostat and manovolumetry

The electronic barostat (Dual Drive Barostat, Distender series II, G&J Electronics Inc.,
Toronto, Canada) was connected to a computer. Distension protocols were created by using
the Protocol Plus Deluxe (V 4.2 R) program. An external computer using the Protocol Plus
data scanner (V 1.9) recorded the information. The rectal balloon catheter consisted of a
highly compliant polyethylene bag (maximal volume 520 ml) which was attached to a
polyethylene tube. Maximal infusion rate was 40 ml/s. The method of rectal manovolumetry
is described elsewhere.198

Distension Protocol
Intermittent phasic stimulations with distension duration of 60 sec were used. The time
interval between distensions was 30 sec. Pressure increments were 5 mmHg. The subjects had
to grade their sensation 15 sec after start of each distension by using four parameters: 1 = no
sensation; 2 = first sensation/some sensation; 3 = urge to defecate; 4 = maximal
discomfort/pain.

When the subjects reported maximal discomfort the barostat computer randomly reduced the
next distension by 5 mmHg or repeated the same distension level. When subjects had reported
maximal discomfort or pain three times at the same pressure level, this level was defined as
maximal tolerable distension level (tracking technique).124

28
After the level of maximal tolerable distension had been determined, it was repeated five
times with a duration of 30 sec each. The time between each distension was 30 sec. The
subjects continued to grade their symptoms. When the subjects had increasing discomfort or
pain, the distension series was interrupted.

Salivary cortisol measurements

Because of the non-invasive simple sampling procedure, the analytical simplicity and the
stability of the samples, salivary cortisol was chosen as a stress marker. A commercial
enzyme, immunoassay, designed for the analysis of salivary cortisol, was used (Salimetrics,
Eletrabox). The Salivette test tube (Sarstedt, Nuembrecht, Germany) method for saliva
sampling was used. The procedure of saliva collection is described earlier.199 Pre- and post-
experimental cortisol values were calculated in relation to baseline cortisol measured close to
the same time of day on a normal day in the subject’s usual environment. Cortisol values were
evaluated by an independent expert in clinical chemistry (E.A-E).

Assessment of cortisol circadian variation

Patients and controls were instructed to collect saliva at 8 am, 1 pm, 3 pm and 10 pm on a
normal day in their usual environment. Samples were sent to our laboratory by mail within
four days. The midday samples were taken at 1 pm and 3 pm because the laboratory
experiment was performed close to the same times of the day. Subjects were instructed not to
eat, drink, or smoke for 60 minutes before sampling.

Skin conductance measurement

The MP100 from BIOPAC Systems Inc., Santa Barbara, California, USA was used for
continuous measurement of the skin conductance by a GSR100B amplifier during the whole
experiment.

The skin conductance was measured according to a standard method, 173 i.e. by a constant
voltage of 0.5V applied over two Ag-AgCl (Neuroline 70001-A, Medicotest A/S, Ølstykke,
Denmark) electrodes on the toe-tips of the second and third toes of the non-dominant foot.
The resulting signal is expressed in units of conductance.

The analogue signals from the amplifiers were converted to digital by the A/D converter
MP100, sending 16-bit digitalized skin conductance values over a serial port to a computer at
a rate of 250Hz per channel and stored on hard disk. Predefined sections of the skin
conductance curves were selected visuo-manually off line according to a curve-dependent
standard set of rules for scoring skin conductance. These skin conductance curves were then
computed automatically by the commercially available standard signal processing programme
AcqKnowledge 3.7.3, from BIOPAC Systems Inc. All skin conductance data were analysed
without knowledge of subject identity or category.

Scoring skin conductance

Skin conductance measures were expressed in microSiemens (PS). Skin conductance
variables are explained and shown in Figure 2. For each of the five repetitive distensions the
following variables were derived: (1) The SCLb: skin conductance baseline level at start of
each distension; (2) The SCR1a: the amplitude of the first skin conductance response within a
latency window of 2 to 8 sec from the start of rectal pressure increase; and (3) the SCRmax: the
difference between the maximal skin conductance level (SCLmax) and the skin conductance
baseline level (SCLb), provided that this difference emanates from a skin conductance
increase that starts within a latency window of 2 to 32 sec from the start of rectal distension,

29
i.e. during the whole time period of rectal distension. In addition, the SCLb was also measured
before the barostat investigation. The usual latency criterion for a first skin conductance
response to a distinct stimulus is 1–4 sec.174 However, due to the increment time of the
balloon distension to target pressure level, this up-to-8-sec wide latency window was applied
for the SCR1a of this study.

The definitions of skin conductance response habituation and sensitisation were a statistically
significant skin conductance response decrement and increment, respectively, over repeated
rectal distensions using Friedman’s non-parametric test for repeated measures.

9000.00

8500.00

SCLmax
8000.00

7500.00

SCRmax
7000.00

SCR1a 6500.00

SCLb 6000.00

SC DC offset (3.24 uS)

5500.00

4000.00
60000.0
50000.0
Start of distension Distension 40000.0
30000.0
20000.0
10000.0
-0.0000
-0.0000
1300.0 1305.0 1310.0 1315.0 1320.0 1325.0 1330. 1335.0 1340.0 1345.0
seconds

Figure 2: Example of skin conductance reactivity (uS) during a subjective maximal rectal distension.
Parameters chosen for analysis of skin conductance are shown. Abbreviations: SCR1a: Amplitude of
the initial SC Response within the latency window 1 – 8 s from start of distension; SCLb: Baseline SC
Level at start of SCR1 or if no SCR1, at start of distension; SCLmax: Maximal SC level of a SC increase
if started within the latency window of 1 to 31 s from start of distension; SCRmax: Maximal SC
Response, i.e. the SCLmax relative to the SCLb.

Experimental protocol
At midday (at about 1 pm) after a fasting period of four hours, the subjects came to our unit
without bowel preparation. After a 15-minute rest in a quiet room, given the possibility to
read light literature, salivary samples for cortisol analysis were taken. They were then served
400 ml of a liquid high-calorie nutritional solution (Fortimel Nutricia Nordic) containing 40 g
protein, 41.2 g carbohydrate and 8.2 g fat (= 400 kcal).

After finishing their meal, subjects were placed in left lateral position and the balloon catheter
was inserted into the rectum. After positioning the balloon the subjects turned around lying on
their back in a comfortable position. Then, the electrodes for skin conductance were applied.
After initial instructions about the distension protocol, the examiner was always present
during the study but communication with the subject was avoided during measurement. An

30
initial distension of 20 mmHg was performed to unfold the balloon. The subject had no visual
or auditory cues to anticipate the magnitude of the distensions. The duration of the barostat
procedure was between 25 and 35 minutes. After completion of the distension protocol,
salivary samples for cortisol analysis were taken.

Statistical methods

For all studies the statistical significance level was set to D 0.05.
Study I: Chi-square tests were used to calculate differences in bowel habits between women
and men, older and younger. The Kruskall-Wallis test was used to investigate any association
between individual symptoms. Results of study II and III were expressed as mean confidence
interval and median and interquartile range.To compare groups, the Kruskall-Wallis test and
the Mann-Whitney U test were used. Results of studies IV and V were expressed as mean,
standard error of mean (SEM), standard deviation (SD), median and interquartile range.
Nonparametric tests were used to test differences in each group, to compare day x time
interactions between groups (VI), and to compare groups (Wilcoxon's Sign Rank Test, Mann-
Whitney U-test and Kruskal Wallis test). Repeated measures in paper V were calculated by
the Friedman test. Correlations were calculated with the Spearman rank correlation coefficient
(rho). Initial covariance analyses with subject category as factor and age as co-variate were
used to evaluate if age was associated with cortisol values or with SC values in paper VI or V,
respectively.

Ethics
The studies were carried out in accordance with the Helsinki declaration. The Research Ethics
Committee, Faculty of Health Sciences, Linköping University, Sweden approved the studies.
Oral informed consent was obtained from each patient. For further details, see separate paper
I-V.

31
32
RESULTS

Paper I

General results
The overall response rate was 80.5% (69 % answered directly and 11.5% after one reminder
letter). Median age was 52 years (range 31-76) and the male-to female ratio was 1:1.12
(male:female). 95.6% had between three bowel movements per day and three per week and
this is in accordance with other studies.1 3 10 3.1 % reported to have fewer than three bowel
movements per week and 1.4% more than three bowel movements per day. The majority of
people (84%) managed to empty their bowels within 15 minutes. For the subjects’ opinions
about how the bowel function affects general well-being and daily activities see Figures 3-5.

Effect on general well being and daily activities

100
Daily activity
Gen well being
75
Percent

50

25

0
Not at all A little Quite a bit A lot

Figure 3: The subjects’ opinions about how the bowel function affects general well-being and
daily activities. Percentages of the total number of answers are given.

33
 General well being

10.0
Men
Women
7.5
Percent

5.0

2.5

0.0
31-45 46-60 60-75
Age-class

Figure 4: Age and sex distribution of the subjects’ opinions that the bowel function affects
general well-being “quite a bit” or “a lot”. Percentages of the total number of answers in each
subgroup are given.

Daily activities

4
Men
Women
3
Percent

0
31-45 46-60 60-75
Age-class
Figure 5: Age and sex distribution of the subjects’ opinions that the bowel function affects
daily activities “quite a bit” or “a lot”. Percentages of the total number of answers in each
subgroup are given.

34
Constipation
In the present study 5.7% of women and 2% of men considered themselves to be constipated
“often” or “always”. (Figure 6) For a more detailed age and gender distribution see Table 7.
When subjects were included who considered themselves to be constipated “sometimes” the
prevalence was 19.8% for women and 8.3% for men.

In the present study subjects’ opinions on what they meant with constipation varied and
infrequent bowel movements were in a greater extent by women than by men considered to be
a symptom of constipation. Table 8. Self- reported constipation was most often related to hard
stools but also to difficulties withstanding the urge to defecate, the need to strain, the use of
laxatives and to incontinence for gas and soiling. Self reported constipation had a significantly
negative impact on general well-being. Straining at bowel movement (at least 25% of the
times) was reported by 53% of the population (women 61.2% and men 43.9 %). Straining at
bowel movement at least 50% of times was reported by 5.7% of the population.

Constipation
10
Men
8 Women

6
Percent

0
31-45 46-60 60-75
Age-class

Figure 6: Age and sex distribution of subjects reporting constipation “often” or always”.
Percentages of the total number of answers in each subgroup are given.

35
Table 7: Proportion of bowel habits according to age class and gender. Refers to answers to
the questionnaire (Appendix)

women women women men men men total

31-45 y 46-60 y 61-76 y 31-45 y 46-60 y 61-76 y n=1609
n=277 n=300 n=274 n=248 n=297 n=213
consider themselves to be constipated “often“ 5.1% 4.7% 7.4% 1.2% 2.7% 2.4% 4%
or “always“
bowel movements three times or less a week 5.1% 3.1% 4.8% 1.6% 1.6% 1.9% 3,1 %
needing to strain at 50% of bowel movements 7.2% 7.4% 9.5% 2% 4.1% 3.2% 5.7%
or more often
”often“ wake up at night time needing to pass a 0.3% 0% 0% 0% 0.3% 0% 0.1%
motion.
”never“ or “sometimes“ able to empty the 4.7% 2.7% 5.1% 3.6% 3.1% 1% 3.4%
bowels in less than 15 minutes
use of medication to be able to open their 9.8% 11.1% 22.1% 2.8% 4.7% 8.5% 9.9%
bowels at least every fourth time
”never“ or “sometimes“ able to withstand urge 18.7% 25.6% 20 % 11.9% 12.1% 17.7% 17.8%
to defecate for 15 minutes
”never“ or “sometimes“ able to break wind 3.3% 2.4% 6.2% 1.6% 2.3% 3.7% 3.3%
without soiling underclothes
involuntary leakage of wind more often than 8.1% 11.5% 22.6% 16.8% 13.3% 13.9% 14.8%
once a week
involuntary leakage of solid faeces more often 0 % 0% 0.7% 0% 0.3% 1% 0.3%
than once a week
involuntary leakage of loose faeces more often 0.4% 1.6% 4% 0.8% 1% 2% 1.6%
than once a week
soiling underclothes more often than once a 2.6% 5% 8.9% 6.5% 5.5% 6.6% 5.8%
week
bowel function affects well-being “quite much“ 6.6% 4.4% 9.5% 2.8% 6.1% 3.7% 5.7%
or “a lot“
bowel function affects daily activities “quite 1.9% 1.7% 3.6% 0.8% 3.1% 1.9% 2.2%
much“ or “a lot“

Table 8: Opinions on what men and women mean by the word „constipation“. Percentages of
the total number of answers (n=1610). Multiple answers could be given, see Table 1, question
16.

women men
hard stools 43.7% 43%
straining in connection with 23.8% 24.3%
bowel movement
pain when passing a motion 23.1% 22.4%
Infrequent bowel movements 41% 21%
Needing to use laxatives 58.3% 56.2%

36
Use of laxatives
9.9% of the population use medication to achieve a bowel movements at least every fourth
time. For a more detailed age and gender distribution see Figure 7

Laxative use

25
Men
20 Women

15
Percent

10

0
31-45 46-60 60-75
Age-class

Figure 7: Age and sex distribution of subjects using laxatives at least every fourth time to
open the bowels. Percentages of the total number of answers in each subgroup are given.

Fecal incontinence
Among the total population, 10.9% of women and 9.7% of men reported leakage of faeces
more often than once a month when the consistency was loose. With solid fecal consistency
the rate of leakage was 1.4% and 0.4% for women and men respectively. Soiling occurred
significantly more often than once a month in 21.0% of men and 14.5% of women. In the age
group 31- 45 years it was 17.8% for men and 9.9% for women (Figure 8). Daily involuntary
leakage of gas was found in 5.9% of men and 4.9% of women (Figure 9). Overall 10%
sometimes woke up during night time by the need of passing a motion and 4.5% could never
withstand the urge to pass a motion longer than 15 minutes.
For differences in bowel habits and symptoms between younger and older men and women
also see Table 7
All types of incontinence (for gas, soiling, loose stool and solid stool) had a significantly
negative impact on general well-being. Incontinence (all types) was also related to difficulties
in withstanding the urge to defecate. Incontinence for gas and soiling was related to
constipation but incontinence for loose and solid faeces was not.

37
 Soiling more often than once per week

9
8
Men
7
Women
6
Percent

5
4
3
2
1
0
31-45 46-60 60-75
Age-class

Figure 8: Age and sex distribution of subjects having soiling more often than once per week.
Percentages of the total number of answers in each subgroup are given.

Gas incontinence more often than once per week

25
Men
20 Women

15
Percent

10

0
31-45 46-60 60-75
Age-class

Figure 9: Age and sex distribution of subjects having gas incontinence more often than once
per week. Percentages of the total number of answers in each subgroup are given.

38
Papers II and III

The results of the 60 IBS patients from paper II are included in the results of the 135 patients
in paper III; therefore we mainly report the results of study III.

All patients, but no control subjects, suffered from abdominal pain and/or discomfort and
almost all patients had bloating or abdominal distension. Symptoms of abdominal pain and
bloating are shown in Table 9.

114 patients had between three bowel movements per day and three per week. Eighteen
patients had more than 21 stools per week and three patients less than three stools per week.
This means that 84,4 % had between three bowel movements per day and three per week with
no major differences in stool frequencies between subgroups (Table 10).

The main subgroup according to stool form consisted of 51 patients with alternating loose,
normal and hard stools, more than 10% of each kind. Other subgroups (for definition see
Table 10) were loose-stool predominant, hard-stool predominant, loose-normal, hard-normal
and normal. Our results show that almost all patients had alternating stool consistency. All
kinds of defecatory symptoms (urgency, straining and feeling of incomplete evacuation)
occurred in all subgroups (Table 10, Figures 10-13). The degree of pain and bloating was
unrelated to subgroup.

In this study only 12 out of 135 patients could be classified into subgroups according to Rome
II supportive criteria (original Rome II supportive criteria, Table 4), as the majority of patients
had urgency combined with hard stools or straining even if stools were loose.

Table 9: IBS patients of study II-V. Episodes and hours of pain and bloating are shown.

Subjects Days of Pain Hours of pain Hours of Bloating

(n) symptom episodes median bloating episodes
recording median (range) median median
(n) (range) (range) (range)
IBS patients 60 40 23 (0-86) 92 (0-960) 22 (0-81)
study II and III
IBS patients 50 7 7 (0-22) 21 (0-153) 21 (0-105)
study III
IBS patients 25 14 15 (0-54) 47 (1-173) 47 (0-209) 12 (0-58)
study III, IV and V
Controls 18 14 0 0 0 0
study IV and V

39
Table 10: IBS Subgroups based on stool consistency

Stool Loose- Loose stool Hard stool Loose- Hard- Normal Controls
consistency normal- Predominant predominant normal Normal Stools
hard
Subgroup >10% hard t50% loose t50% hard 10-50% 10-50% <10%
Definition and >10% and <10% and <10% loose, hard, loose,
loose hard stools loose stools <10% hard <10% <10%
stools and t50% loose and hard
normal t50% stools
stools normal
stools
Subjects (n) 51 43 10 19 8 4 18
Bowel 11 14 8 11 9 11 7
movements (1-36) (7-58) (1-35) (5-20) (3-21) (8-15) (4-16)
n/week *
% loose 32.7 75.0 0 30.0 5.9 1.0 6.5
stools** (21.6-52.4) (62.2-96.1) (0-3.9) (24.5-37.0) (0-7.1) (0-21.7)
% normal 33.3 20.0 37.2 65.0 71.4 93.6 90.8
stools** (17.0-44.2) (4.5-37.5) (3.0-42.0) (61.8-73.7) (63.3-78.9) (66.7-100)
% hard 27.3 0 62.8 0 24.8 2.0 0
stools** (16.1-38.2) (0-2.3) (51.9-95.0) (0-5.3) (18.5-32.2) (0-10.8)
% stools 33.3 53.6 50.0 17.0 7.7 8.5 0
with (21.8-62.5) (17.2-74.5) (4.0-98.5) (1.0-34.9) (0-18.0) (0-17.8)
urge**
% stools 40.0 37.5 77.9 23.0 40.4 70.0 8.7
with (22.5-64.0) (4.3-65.5) (55.0-96.2) (12.6-57.3) (21.6-83.0) (0-34.4)
straining**
% stools with 58.0 38.8 78.4 38.9 25.6 37.3 0
incomplete (35.7-83.5) (14.2-74.5) (65.5-92.0) (10.1-61.5) (14.4-52.7) (0-2.7)
evacuation**
* Number of bowel movements per week is expressed in median (range)
**Data expressed in median of percentages (25-75 percentile range)

40
 IBS subgroup with alternating
loose and hard stools (n=51)
100

80

60 urge
%

straining
40
incomplete evacuation
20

Figure 10: Proportions of defecatory symptoms in IBS patients with

more than 10% hard stools and more than 10% loose stools. Mean values
and 95% confidence intervals are shown.

loose-stool predominant IBS (n=43)

100

80

60 urge
%

straining
40
incomplete evacuation
20

Figure 11: Proportions of defecatory symptoms in IBS patients with

less than 10% hard stools and more than 50% loose stools. Mean values
and 95% confidence intervals are shown.

41
 hard-stool predominant IBS (n=10)
100

80

60 urge
%

straining
40
incomplete evacuation
20

Figure 12: Proportions of defecatory symptoms in IBS patients with

more than 50% hard stools and less than 10% loose stools. Mean values
and 95% confidence intervals are shown.

IBS subgroup with alternating

loose and normal stools (n=19)
100

80

60 urge
%

straining
40
incomplete evacuation
20

Figure 13: Proportions of defecatory symptoms in IBS patients with

less than 10% hard stools, more than 10%loose stools and
50% normal stools. Mean values and 95% confidence intervals are shown.

42
Papers IV and V

Symptoms
For bowel habits and abdominal symptoms see Table 11. One IBS diary card registration was
lost during the study. All IBS patients had episodes of abdominal pain during diary card
recording. Their bowel habits were highly disturbed, with alternating stool consistency in
combination with defecatory symptoms. Five constipation patients completed their diary card
recordings following the instructions given. Diary cards of six constipation patients could not
be evaluated because of daily use of laxatives: Two patients used water enemas, two patients
bisacodyl, one patient lactulose and one patient large doses of macrogol. Two constipation
patients did not complete their recordings.

Table 11: Bowel symptoms according to the diary card recording during 14 days. Stools forms and
defaecatory symptoms are expressed in proportions of the total number of bowel movements.

Median (range) IBS Controls Constipation

(n=26) (n= 18) (n=5)*
Stools per week 11 (3-29.5) 7.5 (3.5-16) 2.5 (1-13.5)
Loose stools % 36 (0-96) 6 (0-50) 0 (0-0)
Hard stools % 21 (0-81) 0 (0-22) 80 (0-100)
Normal stools % 36 (0-93) 91 (50-100) 20 (0-27)
Urgency % 39 (0-100) 0 (0-37) 0 (0-20)
Straining % 36 (0-91) 9 (0-74) 100 (60-100)
Feeling of incomplete evacuation % 57 (0-100) 0 (0-58) 47 (0-100)
Episodes of abdominal pain per week 7.5 0 0.5
(0.5-27) (0-7)
Hours of pain per week 23.5 0 2.5
(0.5-86.5) (0-120)
Episodes of bloating per week 5.5 0 1
(0-8) (0-8)
Hours of bloating per week 23.5 0 4
(0-104.5) (0-150)
Days without bowel movement per 0.5 0.75 4.5
week (0-3) (0-3.5) (0-6)

*Patients using laxatives and/or enemas constantly during diary card recording
were excluded in this table.

43
Psychiatric ratings
The IBS and constipation patients had significantly higher “Comprehensive Psychiatric
Rating Scale for Self-Assessment” scores for depression (p < 0.0001 and p = 0.007), anxiety
(p < 0.0001 and p = 0.005), physical disability (p < 0.0001 and p = 0.03) and obsessional
compulsive symptoms (p = 0.003 and p = 0.008) than controls, respectively (Figure 14 a-d).
There was no significant correlation between rating scores and skin conductance measures or
bowel symptoms in any of the groups. In IBS patients the ratings (anxiety, depression and
obsessive compulsive symptoms) were all significantly positively intercorrelated (rho̓ = 0.45–
0.78).

30
CPRS score

20

10

0
IBS Control Constipation

Figure 14 a: Depression: IBS patients and constipation patients had significantly higher
Comprehensive Psychiatric Rating Scale for Self-Assessment (CPRS-SA) scores for depression than
controls (p<0.0001 and p=0.007) (Mann-Whitney U-test).

30
CPRS score

20

10

0
IBS Control Constipation

Figure 14 b: Anxiety: IBS patients had significantly higher CPRS-SA scores for anxiety than patients
with constipation (p=0.02) and controls (p<0.0001). Patients with constipation had significantly higher
anxiety scores than controls (p=0.005) (Mann-Whitney U-test).

44
 3
CPRS score

0
IBS Control Constipation

Figure 14 c: IBS patients had significantly higher CPRS-SA scores for physical disability than
patients with constipation (p=0.03) and controls (p<0.0001). Patients with constipation had
significantly higher disability scores than controls (p=0.017) (Mann-Whitney U-test).

4
CPRS score

0
IBS Control Constipation

Figure 14 d: IBS patients and constipation patients had significantly higher CPRS-SA scores for
obsessional compulsive symptoms than controls (p=0.003 and p=0.008) (Mann-Whitney U-test).

45
Rectal Manovolumetry

Distension protocol 1
Mean maximal tolerable rectal distension pressure for IBS patients was 38 mmHg (SD 8.3),
for controls 55 mmHg (SD 6.4), and for patients with constipation 53 mmHg (SD 10.1).
The IBS patients had lower rectal distension pressure thresholds for first sensation, urge and
maximal tolerable distension than the patients with constipation (p=0.0164, p=0.0023,
p=0.0003) and the controls (p=0.0366, p=0.0008, p<0.0001), as shown in Figure 15. There
was no significant difference in sensation thresholds between patients with constipation and
controls. IBS patients had significantly lower rectal volumes than the two other groups at first
sensation, urge and maximal tolerable distension (Figure 16). IBS patients had significantly
lower rectal compliance than patients with constipation and controls (p<0.05).
Nine healthy volunteers, two patients with IBS and three with constipation did not reach
maximal tolerable pressure in distension protocol 1 due to the safety level of the barostat
device, which allowed pressures up to 60 mmHg. These subjects continued distension
protocol 2 with “submaximal tolerable pressure”, i.e. 60 mmHg. The exclusion of subjects
with submaximal pressure levels from the statistical analyses did not change the conclusions
about differences between groups.

Distension protocol 2
Most patients and controls continued to grade their rectal symptoms as maximal tolerable
except for one constipation patient who discontinued because of increasing discomfort. There
was no significant change of symptoms in any of the groups. There was a significant increase
in rectal volumes in all groups from distensions 1–5 (p<0.0001) (Friedman).

60
IBS (n=27)
50
Controls (n=18)
Pressure (mmHg)

40 *** Constipation (n=13)

30
**
20
*
10

0
First Urge Maximal
sensation tolerable
pressure

Figure 15: Mean rectal thresholds for first sensation, urge and maximal tolerable pressure. The
standard error of mean is shown in the bars. IBS patients had significantly lower thresholds (first
sensation, urge, maximal tolerable pressure) compared to patients with constipation (p= 0.0164, p=
0.0023, p= 0.0003) and controls (p= 0.0366, p= 0.0008, p< 0.0001) (Mann-Whitney U-test). There
was no significant difference between patients with constipation and controls.

46
 400
IBS (n=27)
Controls (n=18)
300
Volume (ml)
Constipation (n=13)
**
200

100 ***
*
0
First Urge Maximal
sensation tolerable
pressure

Figure 16: Mean rectal volumes at first sensation, urge and maximal tolerable pressure. The standard
error of mean is shown in the bars. IBS patients had significantly lower volumes at first sensation,
urge and maximal tolerable pressure compared to patients with constipation (p= 0.0170, p= 0.0005, p=
0.0004) and controls (p= 0.015, p< 0.0001, p= 0.0002) (Mann-Whitney U-test). There was no
significant difference between patients with constipation and controls.

Cortisol
Cortisol data from two IBS patients, five constipation patients and three controls were
incomplete because of non-compliance when taking saliva samples at home or because of lost
samples. One IBS patient was excluded because of very high salivary cortisol values but
further examination could not verify high cortisol values or any endocrinological abnormality.
All calculations according to cortisol analysis were based on those subjects that had complete
cortisol data, i.e. 24 IBS patients, 15 controls and 8 patients with constipation.

Initial covariance analyses with subject category as factor and age as co-variate showed that
age did not statistically significantly explain differences in cortisol values. Therefore
variations in age were not taken into account in subsequent statistical analyses of cortisol
values.

IBS patients, but not constipation patients and controls, had significantly higher cortisol
concentrations during the afternoon when the barostat experiment was performed (before and
after barostat procedure) compared to similar times (1 pm: p=0.0034; 3 pm: p=0.0002) on an
ordinary day in their usual environment Figure 17, (Table 12). There was no significant
difference in salivary cortisol levels before compared to after rectal distensions in patients or
in controls (Figure 17). The cortisol level changes from pre-experimentally to post-
experimentally did not differ significantly from the change from 1 pm to 3 pm between the
groups. There was no statistically significant difference between the groups according to
salivary cortisol values at 8 am, 1 pm, 3 pm and 10 pm, measured at home (Table 12). There
was no significant correlation within the groups between bowel symptoms, cortisol values,
barostat measurements or psychometric testing results.

47
 7
** IBS (n=24)
6 ** Controls (n=15)
cortisol (nmol/l)

5 Constipation (n=8)
4

0
st

pm

pm
e
pr

po

3
Figure 17: Salivary cortisol levels pre-experimentally (pre), post-experimentally (post) and in their
usual environment at similar times (1 pm) and (3 pm). IBS patients had higher salivary cortisol values
pre-experimentally (p=0.0034) and post-experimentally (p=0.0002) than at similar times (1 and 3 pm)
in their usual environment (Wilcoxons Sign Rank test). Mean values and standard error are shown.

Table 12: Means (standard deviations) of salivary cortisol at 8 am, 1 pm, 3 pm and 10 pm at home on
an ordinary day. There were no significant differences between IBS patients and controls.

Salivary cortisol (nmol/l) IBS Control Constipation

8 am 8.26 (3.70) 7.84 (3.03) 8.36 (3.13)
1 pm 4.05 (1.77) 4.73 (2.17) 4.55 (1.36)
3 pm 3.20 (1.65) 3.59 (1.60) 3.57 (1.15)
10 pm 2.32 (2.09) 2.47 (3.09) 2.47 (2.23)
Pre-experimental 5.28 (2.21) 4.59 (1.92) 4.80 (1.92)
Post-experimental 5.85 (3.47) 4.59 (3.06) 4.80 (1.69)

48
Skin conductance during repetitive maximal rectal distensions

Skin conductance data of one IBS patient, two controls and two patients with constipation
could not be analysed because of data collection artefacts. Initial covariance analyses with
subject category as factor and age as covariate showed that age did not statistically
significantly explain group differences in skin conductance measures. There was no statistical
difference between men and women according to skin conductance values in the IBS and
control group. Consequently, variations in age and gender were not taken into account in
subsequent statistical analyses.

IBS patients had consistently significantly higher baseline skin conductance (SCLb) than the
patients with constipation before the start of the barostat examination (p=0.014), and before
the five rectal repetitive distensions (p=0.0008; p=0.0014; p=0.0013; p=0.0007; p=0.0004);
see Figure 18. Patients with constipation had significantly lower baseline skin conductance
(SCLb) than controls before the first (p=0.048), fourth (p=0.034) and fifth (p=0.034)
distensions. This difference persisted after excluding men from analysis. There was no
significant difference in SCLb between patients with IBS and controls. There was no
statistically significant increase or decrease in baseline skin conductance in any of the groups
over the course of the distensions. The exclusion of subjects who did not reach maximal
tolerable rectal pressure levels from the statistical analyses did not change the conclusions
about differences between groups.

The IBS patients had significantly higher maximal skin conductance response (SCRmax) than
patients with constipation at the second (p=0.039), third (p=0.04) and fourth (p=0.014)
distension (Figure 19). There was no significant difference in SCRmax between the IBS and
controls, nor was there any difference in SCRmax between the constipation and the control
groups.

The IBS patients had significantly higher values of initial skin conductance response (SCR1a)
than patients with constipation and controls at the second rectal distension (p=0.022 and
p=0.046, respectively). There was no significant difference between patients with constipation
and controls. There was a significant SCR1a decrement over the distensions 1–5 within the
IBS group and within the constipation group, but not within the control group (Figure 20).
When individuals with submaximal distension thresholds were excluded from analysis there
was still a significant SCR1a decrement over distensions 1–5 within the IBS patients
(p=0.0015), but not within the constipation or control groups.

49
 10.0
IBS (n=26)
Control (n=16)
(microSiemens)

7.5
Constipation (n=11)
SCL-b

5.0

2.5

0.0
t

5
ar

on

on

on

on

on
st

si

si

si

si

si
en

en

en

en

en
st

st

st

st

st
di

di

di

di

di

Figure 18: Mean skin conductance (SC) at start of the barostat examination and baseline values
(SCLb) between the five repetitive rectal distensions. The standard error of mean is shown in the bars.
The IBS patients had significantly higher SC levels overall than patients with constipation (p=0.014
(start); p=0.0008; p=0.0014; p=0.0013; p=0.0007; p=0.0004 (distensions 1-5)) (Mann-Whitney U-
test). Patients with constipation had significantly lower values than controls before first (p=0.048),
fourth (p=0.034) and fifth (p=0.034) distension (Mann-Whitney U-test). There was no significant
difference between patients with IBS and controls. The Friedman test for repeated measures was not
significant in any of the groups for distensions 1-5.

50
 1.5
IBS (n=26)
Control (n=16)
(microSiemens) Constipation (n=11)
SCRmax
1.0

0.5

0.0
1

5
on

on

on
on

on
i

i
ns

ns

ns

ns

ns
e

e
st

st

st

st

st
di

di

di

di

di
Figure 19: Amplitude of the maximal skin conductance (SC) responses to the repetitive rectal
distensions 1-5, (SCRmax 1-5). The standard error of mean is shown in the bars. The IBS patients had
significantly higher values than patients with constipation at the second (p=0.039), third (p=0.04) and
fourth (p=0.014) distension (Mann-Whitney U-test). There was no significant difference between
controls and IBS patients and between controls and constipation patients. The Friedman test for
repeated measures was not significant in any of the groups for distensions 1-5.

1.0
IBS (n=26)
(microSiemens)

Control (n=16)
Constipation (n=11)
SCR1a

0.5

0.0
1

5
2

3
on

on

on
on

on
si

si

si

si

si
en

en

en

en

en
st

st
st

st

st
di

di

di

di

di

Figure 20: Mean skin conductance (SC) first response amplitude to the repetitive rectal distensions 1-
5, (SCR1a 1-5). The standard error of mean is shown in the bars. The IBS patients had higher values
than patients with constipation and controls at the second distension (p=0.022 and p=0.046
respectively) (Mann-Whitney U-test). There was no significant difference between patients with
constipation and controls. The Friedman test for repeated measures showed a significant decrease of
SC values from distension 1 to 5 for IBS patients (p<0.0001) and patients with constipation (p=0.019)
but not for controls.

51
52
GENERAL DISCUSSION

Population prevalence study

Constipation
We have shown that self-reported constipation is a common gastrointestinal complaint in the
Swedish population. 19.8% of women and 8.3% of men considered themselves to be
constipated “sometimes”, “often” or “always”. This is in accordance with an American study
by Everhart et al. which found that 20.1% of women and 8.0% of men reported constipation.4

In an Australian study the prevalence of self-reported constipation was about 10% higher than
in the present study, that is, 26.6% in middle-aged (45-50 years) and 27.0% in older women
(70-75 years).200 This might be a true difference as both studies used similar questions about
constipation.

Most results of constipation prevalence studies cannot be compared with each other since
different definitions, symptom criteria and study designs are used. In a Canadian study the
overall prevalence of self-reported constipation was 27.2% but only 16.7% and 14.9% had
functional constipation according to Rome I and II criteria, respectively. For all three
definitions, the rate for women was close to twice that for men.201 Also in the present study
the prevalence of constipation, in accordance with some earlier reports, was highest in elderly
women. 22 202 203

Probert and co-workers studied the constipation prevalence according to self-reported

constipation, slow colonic transit and Rome-1 criteria for constipation. They found that the
constipation prevalence by each definition was about 8% but overlap between those three
definitions was only 2%. 204 Harari et al. found that 5.7% of older persons (>60 years)
reported constipation “always or mostly” and 38% “sometimes or rarely”. They also found
that self-reported constipation was highly related to straining, hard stool consistency and
fewer than three stools per week but feeling of incomplete evacuation, bloating and pain were
less strongly associated.203 In a study of young people not seeking healthcare, Sandler et al.
found that 7.3% of subjects reported constipation greater than 25% of the time and they most
commonly defined constipation as straining and hard stools. 13 Apart from the need to take
laxatives, most subjects in the present study defined constipation as hard stools, 43.7% of
women and 43% of men. Infrequent bowel movements were considered a constipation
symptom by 41% of women and 21% of men and straining was considered a symptom of
constipation by 24% of women and men.

According to our study the prevalence of self-reported constipation is high, 19.8% for women
and 8.3% for men. 5.7% of women and 2.0% of men considered themselves constipated
“often” or “always”.

53
Straining at bowel movement
Straining at bowel movement (at least 25% of the time) was reported by 53% of the
population (women 61.2% and men 43.9%) and straining at bowel movement at least 50% of
times was reported by 5.7% of the population. Straining >1/4 of defecations is one of six
criteria of functional constipation according to Rome II criteria. 39
In our study the majority of people reported “straining” >1/4 of defecations but in the same
population the self-reported prevalence of constipation (often or always) was only 4%.

In a study of Bellini et al. 5% of women and 1% of men recorded straining at 25% of the
bowel movements or more often. 10 The corresponding data of the present study were 61.2%
for women and 43.9% for men. Bellini and co-workers used a four-week daily diary instead of
questionnaire. This may be a more valid method than questionnaire and indicates that subjects
in the present study may have overreported their straining symptoms. However, the subjects
in Bellini’s study were not from a random sample of the population and the sample size was
smaller (n=204) than in the present study. Moreover, subjects were recruited as persons who
perceived their bowel function as normal. Thompson et al. found in a questionnaire survey
that overall 10.3% of subjects had to strain greater than a quarter of bowel movement
occasions.2 Also their subjects did not come from a random sample of the population and the
sample size was only 301.

Fecal incontinence
The present study shows that fecal incontinence is a common problem in the population. This
is in accordance with other studies, even if results can vary depending on study design and
criteria used. 6 30 33 34 One striking finding in the present study was the gender difference in
prevalence of soiling, especially in the younger age group. Soiling occurred more often than
once a month in 21.0% of men between 31 and 45 years although this group is expected to
have the best anal sphincter function.

General aspects
One limitation of paper I is that the analysis relied on questionnaires and diary cards were not
used. Another limitation is that we did not investigate confounding factors such as
gastrointestinal disease or surgical procedures. On the other hand, this study is strictly
population-based with a high response rate. The high response rate was probable due to our
decision not to include very old and young people among whom we expected a lower
response rate. We used the Swedish population register which is unique, without bias of
socio-economic status, thus allowing valid epidemiological studies. We chose a population
area with mixed rural and urban components.

Diary card symptom studies of IBS patients

In paper II and III all patients suffered from abdominal pain and/or discomfort and almost all
patients had bloating or abdominal distension. Chronic or recurrent abdominal pain and
discomfort are the key features of IBS 11 39 40 in combination with disturbed bowel habits and
in absence of organic disease. The present prospective diary card studies have been performed
to characterize these key features in detail. One main finding of the present study was that IBS
patients had straining even with loose stools and urgency with hard stools. Therefore only 12
out of 135 patients could be classified into subgroups according to Rome II supportive

54
criteria. This erratic relationship between defecatory symptoms and stool consistency has also
been described in IBS patients by Heaton et al. 71 We suggest that IBS subgroups should be
based either on stool consistency or defecatory symptom but not on both.

In the present study the majority of patients with IBS had varying stool forms although the
degree of variation differed. The patients of the largest subgroup had often loose, hard and
normal stools and therefore the largest degree of variation. The patients of the other subgroups
had one dominating type of stool form but still had some degree of variation. Therefore we
consider that alternating stool consistency should be a major criterion for IBS. The existence
of an alternating subgroup is supported by many studies. 59 205 206 Several researchers have
included IBS patients with alternating IBS with reference to the Rome criteria although
specific criteria for alternating IBS are missing. 93 134 160 Since both specific criteria for and
symptom description of patients with alternating IBS are missing in Rome II, the validity of
those studies could be questioned. This phenomenon has also been addressed by Drossman et
al. who state that not fulfilling Rome criteria for diarrhoea-predominant IBS or constipation-
predominant IBS does not necessarily mean it is an alternating stool pattern. 207

Rome II supportive criteria uses stool frequency as an item to subgroup patients into diarrhoea
or constipation-predominant IBS. In our study of 135 patients with IBS who daily recorded
their symptoms prospectively on diary cards, the majority of patients (84.4%) had between
three bowel movements per day and three per week with no major differences in stool
frequencies between subgroups (Table 11). This range of bowel movements is considered
normal in the general population. Earlier Ragnarsson and Bodemar demonstrated that IBS
patients define constipation (hard stools) and diarrhoea (loose stools) on the basis of stool
consistency, not frequency. 12

According to our data (Table 11), the great majority of IBS patients has alternating stool
consistency during registration. Subgroups should be formed by proportions of stool
consistency and data should be collected by prospective symptom registration on diary cards.
The 51 of 135 patients who had mixed loose, normal and hard stools clinicians would
considered to have mixed stool pattern. The 43 patients with mostly loose stools could be
called diarrhoea-predominant and the 10 patients with mostly hard stools constipation-
predominant. The remaining 31 patients who had predominantly normal stools would
probably be considered as diarrhoea-like or constipation-like as they still have some
proportion of either loose or hard stools. We do not suggest that our single centre study
should be the basis for subgroup definition for IBS, but we argue that stool consistency should
be the basis for subgrouping and diary cards should be the basis to collect this information at
least in studies. Symptom evaluation in research must be as carefully performed as the very
extensive pathophyiologic examination now reported in IBS patients.

Ragnarsson and Bodemar showed earlier that pain is temporally related to eating but not to
defecation in IBS patients. 74 The symptom “pain relieved by defecation“ was not among
those typical for IBS in a study of Kay & Jörgensen either,208 who studied an unselected
population to define common abdominal symptom clusters in the population. They defined an
IBS symptom cluster with presence of abdominal pain and distension combined with
borborygmi or alternating stool consistency or both.

In conclusion, we propose that symptom criteria for IBS should be changed according to the
present evidence (see Table 13). Moreover, symptom subgroups should be based on stool
consistency.

55
Table 13: Proposed symptom criteria for irritable bowel syndrome based on prospective
daily symptom records of 135 IBS patients.

Chronic or recurrent symptoms of abdominal discomfort or pain combined with

disturbed bowel habits:

(1) Alternating stool consistency and/or

(2) Some degree of defecatory symptoms of urgency, straining and feeling of incomplete
evacuation regardless of proportions of stools with loose, hard or normal consistency.

Supportive criteria for IBS

x Postprandial onset or worsening of pain and /or discomfort
x Bloating and/or feeling of abdominal distension
x Most IBS patients will have a normal stool frequency
(< 3 / day and > 3 / week).

Comments on newly published Rome III criteria

Recently revised Rome III symptom criteria for IBS 11 (Table 14) are supported by the
findings of the present studies. The Rome committees now recommend that diarrhoea,
constipation and mixed IBS subtypes should be based on a simple classification derived from
stool consistency and not anymore from defecatory symptoms or frequency. Changes in Rome
III criteria compared to Rome II criteria are apart from the results of Ragnarsson and Bodemar
12, 74
mainly based on three trials. 23 206, 207

56
Table 14: Rome III diagnostic criteria for IBS 11

Rome III diagnostic criteria* for IBS 11

Recurrent abdominal pain or discomfort ** at least three days per month in the last three
months associated with two or more of the following:

1. Improved with defecation

2. Onset associated with a change in frequency of stool
3. Onset associated with a change in form (appearance) of stool

* Criteria fulfilled for the last three months with symptom onset at least six months prior to
diagnosis

** Discomfort means an uncomfortable sensation not described as pain. In pathophysiology

research and clinical trials, a pain/discomfort frequency of at least two days a week during
screening evaluation for subject eligibility.

Rome III: Subtyping IBS by Predominant Stool Pattern

1. IBS with constipation (IBS-C) — hard or lumpy stools t25% and loose
(mushy) or watery stools < 25% of bowel movements.
2. IBS with diarrhoea (IBS-D) — loose (mushy) or watery stools t25% and hard
or lumpy stools < 25% of bowel movements.
3. Mixed IBS (IBS-M) — hard or lumpy stools t25% and loose (mushy) or
watery stools t25% of bowel movements.
4. Unsubtyped IBS — insufficient abnormality of stool consistency to meet
criteria for IBS-C, D or M.

57
Impact of repetitive rectal distensions on salivary
cortisol and skin conductance
We investigated visceral sensitivity and the effect of maximal tolerable rectal distensions on
salivary cortisol levels and skin conductance (measure of sympathetic activity) in patients
with IBS, chronic constipation, and healthy volunteers.

Patients with IBS

The IBS patients demonstrated (a) pre-experimental stress according to increased salivary
levels of cortisol which was not found in patients with constipation or controls; (b)
habituation to repeated subjective maximal tolerable rectal distensions according to
decreasing skin conductance values, although patients continued to rate their discomfort as
maximal; (c) higher skin conductance values than controls in the beginning of distension
series; (d) higher skin conductance values than constipation patients before and during
repeated rectal distensions; (e) lower rectal distension thresholds for first sensation, urge and
discomfort than healthy controls and constipation patients; and (f) no further significant
increase in cortisol after repetitive rectal distensions.

The pre-experimentally high cortisol level indicates that IBS patients were more stressed in
relation to their “normal” state of arousal at home than controls and constipation patients
before start of the rectal distensions. This higher level of stress is also mirrored by larger
initial skin conductance baseline values and response to rectal distensions in the beginning of
the repetitive rectal distension series. We think that this higher degree of arousal in IBS
compared to controls represents a higher degree of discomfort, anxiety or hypervigilance,
probably due to aversive feelings prior to the experiment.

Other investigators have also shown that IBS patients are more stressed than controls just
before start of an experiment. Murray and his group studied the effect of acute psychological
and physical stress on autonomic activity and visceral sensitivity in IBS patients. Patients
reported significantly higher levels of stress than controls already before onset of
experimental stress and they also demonstrated a visceral hypersensitivity. 133 Hightened pre-
experimental arousal was also measured by Dickhaus et al. 159 and Posserud et al. 134 who
found increased norepinephrine values before the experiment with rectal distensions.

Skin conductance activity is closely linked to distinct brain regions with distinct anatomical
contributions to the control of this electrodermal activity. The ventromedial prefrontal cortex
is involved in anticipatory electrodermal activity responses, whereas the amygdala is
implicated in electrodermal activity response to learned associations between stimuli and
reinforcement such as fear conditioning.180 The amygdala is known to play a critical role in
linking external stimuli to defence networks. 209 Mayer et al. demonstrated recently that IBS
patients show greater activation of the amygdala during rectal distensions than patients with
ulcerative colitis. 210

Lower visceral pain thresholds in IBS could be caused, at least in part, by psychological
influences on perception, that is, perceptual response bias. To circumvent this problem,
manovolumetry techniques such as the tracking technique used in this study have been
developed. 124 In the present study we found low rectal distension thresholds for both non-
painful stimuli and maximal discomfort in IBS patients. This finding would support a

58
biological basis for visceral hypersensitivity so far as the tracking technique really is able to
circumvent perceptional response bias.

The fact that the electrodermal response to distension habituated, indicates that there is a
psychophysiological mechanism behind the visceral hypersensitivity. From earlier studies we
know that sympathetic responses, such as electrodermal activity, to stimuli of moderate
intensity habituate, while responses to repeated stimuli of close to pain intensities are resistant
to habituation.211 Perhaps IBS patients in the present study unintentionally may have chosen
lower pre-pain rectal pressures as maximally tolerable. This might be the result of
conditioning by earlier painful rectal examinations or colonoscopies.

Emotional experience of pain could set up a memory loop which may be activated by the
anorectal test situation.212The habituation of skin conductance represents a decrease of the
arousal response in IBS patients during repeated distensions. Probably the healthy controls do
not habituate because their maximal tolerable rectal distension thresholds are close to pain.

This interpretation is supported by the results of Naliboff et al., who studied the effect of
several repeated rectal distension assessments on perceptual responses in IBS patients over 12
months. 213 In the beginning and in the end of this period a positron emission tomography was
performed to study regional brain activation. IBS patients had a gradual increase
(normalisation) of discomfort thresholds over time although their bowel symptoms during the
year remained steady. Anticipation of an aversive rectal stimulus was seen in the first positron
emission tomography session but not in the last. While brain activity in the sensory processing
areas of the brain remained unchanged, activation of limbic and paralimbic circuits related to
vigilance and arousal for aversive events showed significant changes. This occured during
both actual rectal distension and anticipation of distension, suggesting a decrease in visceral
hypervigilance as a primary underlying factor for the perceptual change. Probably their results
were due to a habituation process with a decrease in hypervigilance to the repeated rectal
distensions over time. However, as autonomous responses were not recorded during their
study, they have no objective measure of arousal to confirm the hypothesis of habituation.
Our study of skin conductance as a measure of sympathetic activity was able to study the
level of arousal. During repetitive rectal distensions we found a decrease of sympathetic
reactivity. This support the findings of Naliboff et al. that visceral hypersensitivity is not a
constant feature in IBS patients and indeed habituation may lead to normalization of the
visceral perceptual response over time.214

In the present study the IBS patients had higher scores in psychological ratings than controls
and there were correlations between anxiety, depression and obsessive compulsive symptoms,
indicating a non-specific psychological characteristic of the IBS patients. Cortisol levels or
SC values were not related to any of the specific psychological items among the IBS patients.
Because of the two to three-week time span between the ratings of possibly temporary
psychological variables and the experiment, a conclusion of absence of relationship between
rated anxiety and cortisol levels should be considered as tentative.

Patients with constipation

The main findings for constipation patients were: (1) the constipation patients had
significantly lower mean baseline SC compared to both the IBS patients and controls; (2) the
maximal SC response to rectal distensions did not differ significantly between constipation
patients and controls, but constipation patients had significantly lower values than IBS

59
patients; and (3) the amplitude of the initial SC response decreased successively over the five
repetitive distensions in patients with constipation but not in controls.

The significant habituation of the SC response and significantly lower SC baseline levels in
the constipation group when compared with controls suggest that the constipation patients
were not stressed by the barostat investigation per se, and that the stimuli were perceived as
moderate despite choosing similar maximal pressures as controls. These results suggest that
the constipation group is not as sympathetically active and reactive as healthy controls and
IBS patients.

Emmanuel and co-workers found that patients with idiopathic constipation had a reduction in
rectal mucosal blood flow. They conclude that this would provide evidence for a decreased
sympathetic drive affecting both colonic transit and mucosal blood flow, or a deficit in the
normal cholinergic drive.215Our findings support the theory of an inhibition of the sympathetic
drive in constipated subjects.

The significantly lower skin conductance baseline levels in the constipation group, as
compared to the normal and the IBS groups, indicates a physiological and maybe also
psychological state in constipation patients which has to be explained. In any case, our results
support the necessity for differentiation between IBS and constipation patients in scientific
research and strongly argue for careful assessment of symptoms to categorize patients
correctly.

60
CONCLUSIONS

Paper I: In the Swedish population the prevalence of self-reported constipation and fecal
incontinence was high with a similar magnitude as in other Western countries. 95.6% of the
population had between three bowel movements per day and three per week. Constipation
was mostly defined by “hard stools” and “the need of using laxatives”.

Paper II and III: Alternating stool consistency and presence of different defecatory symptoms
regardless of stool consistency should be included as criteria for IBS. IBS subgroups should
be based on stool consistency. Rome II supportive criteria should be reconsidered as the
determination of presence or absence of specific symptoms does not work as an instrument
for categorization of IBS patients into diarrhoea- and constipation-predominant. Moreover
abnormal stool frequency should be excluded to define subgroups of IBS.

Papers IV and V: The expectancy of the experimental situation per se (provocation of bowel
symptoms by rectal distensions) compared to non-experimental days at home measured as
cortisol had a high impact on the level of arousal in IBS. IBS patients are more sensitive to
pre-experimental stress than healthy controls and patients with constipation. This should be
considered in the design of experimental IBS studies.
IBS patients had higher skin conductance values than controls in the beginning of distension
series. IBS patients had visceral hypersensitivity both according to maximal and sub-maximal
rectal distension pressures. IBS patients habituated to subjective maximal tolerable, repetitive
rectal distension with decreasing sympathetic activity. Since responses to repeated stimuli of
close-to-pain intensities are resistant to habituation this finding could be caused by
psychological influences on perception, that is, perceptual response bias.

61
APPENDIX
Questionnaire

1. Do you consider yourself constipated?

a) Never, or very rarely
b) Yes, sometimes
c) Yes, often
d) Yes, always
2. How often do you move your bowels?
a) More than three times a day
b) Approximately two to three times a day
c) Approximately once a day
d) Approximately three times a week
e) Approximately once every five days
f) Less often

3. Do you wake up at night time needing to move your bowels?

a) No, never
b) Yes, sometimes
c) Yes, often
d) Yes, every night

4. Do you need to strain when moving your bowels?

a) Rarely (less than every fourth time)
b) Sometimes (at least every fourth but not as much as every second time)
c) Often (at least half of the time but not every time)
d) Always (every or at least nearly every time)

5. Can you manage to empty your bowels in less than 15 minutes?

a) Yes, always
b) Yes, often
c) Yes, sometimes
d) No, never
6. Do you need medication to be able to open your bowels?
a) No, never or nearly never
b) Yes, sometimes (at least every fourth but not every second time)
c) Yes, often (at least every second but not every time)
d) Yes, always (or nearly every time)

7. What kind of medication? Please specify:

62
8. Can you withstand the urge to pass a motion longer than 15 minutes?
a) Yes, always
b) Yes, often
c) Yes, sometimes
d) No, never

9. Can you break wind without soiling your underclothes?

a) Yes, always
b) Yes, often
c) Yes, sometimes
d) No, never

10. Does it happen that you break wind involuntarily?

a) No, never
b) Yes, between once a month and once a week
c) Yes, between once a week and once a day
d) Yes, daily
11. Does it happen that you leak when the motion is loose?
a) No, never
b) Yes, between once a month and once a week
c) Yes, between once a week and once a day
d) Yes, daily
12. Does it happen that you have a leakage even if the motion is not loose?
a) No, never
b) Yes, between once a month and once a week
c) Yes, between once a week and once a day
d) Yes, daily
13. Do you have problems with soiling your underclothes?
a) No, never
b) Yes, between once a month and once a week
c) Yes, between once a week and once a day
d) Yes, daily
14. Does your bowel function adversely affect your general well-being?
a) Not at all
b) A little
c) Quite a bit
d) A lot

63
15. Does your bowel function adversely affect your daily activities?
a) Not at all
b) A little
c) Quite a bit
d) A lot
16. There is a variety of concepts of what it means to be constipated. What does constipation
mean to you? Multiple answers may be given.
a) Hard stools
b) Straining in connection with bowel movement
c) Pain when passing a motion
d) Infrequent bowel movements
e) Needing to use laxatives

64
SAMMANFATTNING PÅ SVENSKA

Arbete I är en enkätundersökning som mäter förekomsten av förstoppning och

avföringsinkontinens i befolkningen. Ett frågeformulär med 16 frågor om tarmtömningsvanor har
skickats till 2000 kvinnor och män i åldrarna 31-76 år, slumpvis utvalda via befolkningsregistret i
Östergötland. I frågeformuläret ingick även två frågor om hur tarmfunktionen påverkar
livskvaliteten och dagliga aktiviteter. Svarsfrekvensen var 80.5%. Resultaten visade att 95.6% av
befolkningen har mellan tre tarmtömningar per dag och tre per vecka. 5.7% av kvinnorna och 2%
av männen upplever sig ofta eller alltid förstoppade. De flesta definierar förstoppning som hård
avföringskonsistens och/eller behovet av att använda laxermedel. 10.9% av kvinnorna och 9.7% av
männen har avföringsläckage om avföringskonsistensen är lös. Ofrivillig gasavgång förekommer
hos 14.8% av befolkningen. Kvinnor i åldergruppen 61-76 har oftare avföringsinkontinens än
yngre kvinnor och män. 6.5% av männen och 2.6% av kvinnorna i åldersgruppen 31-45 år har
besvär med fuktläckage från ändtarmen minst varje vecka
Sammanfattningsvis är både förstoppning och avföringsinkontinens vanliga problem i
befolkningen. Vi visade också att tarmsymptomen har en negativ effekt på det allmänna
välbefinnandet och dagliga aktiviteter.

Irritable Bowel Syndrome (IBS) kännetecknas av buksmärta/obehag och avikande tarmvanor.

IBS är en funktionell gastrointestinal störning och kan för närvarande inte förklaras av anatomiska
eller biokemiska avvikelser. Diagnosen baseras uteslutande på symptom som är mycket varierande
i karaktär. Försök har gjorts att dela in patienter med IBS i undergrupper med avseende på
symptom för att lättare kunna standardisera inklusionskriterier till studier och behandlingar.
”Rome II supportive criteria” är ett sådant försök som baseras på åsikter i en expertgrupp.
I arbete II och III har ”Rome II supportive criteria” validerats med hjälp av magdagböcker där 135
IBS patienter i detalj har registrerat sina symptom. IBS patienterna inkluderades utifrån klassiska
IBS kriterier (Rome I). Majoriteten kunde inte klassificeras i undergrupper enligt dessa nya
”supportive criteria” då patienterna hade alla typer av symptom vid tarmtömning (trängning,
krystning, känsla av ofullständig tömning) oberoende av avföringskonsistens. Undergruppering
föreslås istället vara baserad på avföringskonsistens. Baserat på detta och tidigare
Linköpingsstudier föreslås i rapporten att nya symptomkriterier för IBS bör ersätta de idag
använda Rome II kriterierna.

Vid IBS finns samverkan mellan stress och debut eller försämring av mag-tarmsymptom. I
experimentella studier har man sett samband mellan en ändrad känslighet i tarmen, mätt med
rektalballong, och utsöndring av stresshormoner. Det är dock oklart om själva
undersökningssituationen på laboratoriet kan påverka och därmed vara en ”confounding factor” för
IBS patienter avseende stresspåslag. I arbete IV mättes saliv-kortisol, som ett mått på stress, före
och efter maximala rektala ballongdistensioner hos patienter med IBS, kronisk förstoppning och
friska kontrollpersoner. För att studera hur själva laboratoriesituationen påverkade patienterna
genomfördes även basala saliv-kortisol mätningar i hemmiljö. Jämfört med mätningar som utförts i
deras hemmiljö visade mätningarna i sjukhusmiljö att endast IBS patienterna var mer stressade
före undersökningen. Ballongdistensionerna ledde inte till någon signifikant stegring av
stresshormon i någon av grupperna. IBS patienterna hade känslighetströsklar för distension av
rektum som var lägre än patienterna med förstoppning och kontroller. Slutsatsen blev att man bör
ta hänsyn till IBS patienternas högre stressnivå vid bedömningen av jämförelser med andra
patientgrupper.

65
IBS är associerat till en dysfunktion i det autonoma nervsystemet. Förändringar i hudkonduktans är
direkt korrelerade till svettkörtel- och sympatikusaktivitet. I en tidigare studie har man funnit att
IBS patienter har ett generellt ökat hudkonduktanssvar (skin conductance response) vid upprepade
distensioner i sigmoideum men det framgår inte hur sympatikussvaret mera specifikt ter sig vid
upprepning av stimulus. För att bättre karakterisera den överkänsligheten i tarmen mättes i arbete
V den initiala hudkonduktansen och den maximala hudkonduktansen för varje rektaldistension.
Dessutom mättes basalvärdet före varje distension. IBS patienter hade en högre basal
sympatikusaktivitet än förstoppningspatienter samt habituerade avseende sympatikusaktivitet till
upprepade subjektivt maximala rektaldistensioner. Detta betyder att IBS patienter hade ett större
stresspåslag i samband med undersökningen än förstoppningspatienter och det troligen finns en
psykologisk komponent som påverkar känsligheten i tarmen hos IBS patienter.

66
ACKNOWLEDGEMENTS

I wish to express my sincere gratitude and appreciation to all who helped me to complete
this thesis.

I especially want to thank:

x My supervisor, Associate Professor Olof Hallböök, for introducing me to the world of

anorectal physiology, for invaluable scientific guidance, for well-founded criticism,
for helping me keep focused on writing, and last but not least for good friendship.

x My supervisor and mentor, Professor Göran Bodemar, for his invaluable support,
unlimited generosity, teaching, enthusiasm and encouragement. He has always found
the time to follow the many different problems I have encountered during this study
with a never failing helpfulness, interest and patience.

x Associate Professor Lars-Håkan Thorell for introducing me to the field of

psychophysiology, and sharing with me his great knowledge and accuracy in scientific
work, his patience and friendly mind and great sense of humour which were essential
for completing this work.

x Ritva Johansson for excellent and professional help in performing the manovolumetric
measures, invaluable help in organising the study and careful concern for the patients.

x Patients and healthy volunteers for their time, interest and cooperation.

x Professor Eva Swahn, my mentor and friend since 1997 for being there whenever I
needed, whether it be for professional or private reasons. She has generously
supported me with good advice in all kinds of situations.

x Professor Rune Sjödahl for his extensive knowledge and experience, generous support
and creating an inspiring research atmosphere.

x Elisabeth Aardahl Eriksson for invaluable expertise on salivary cortisol.

x Associate Professor Magnus Ström for constructive discussions, warm support and
valuable help in organizing practical details around this thesis.

x Dr Gudmundur Ragnarsson for all the excellent research about IBS symptoms in
Linköping.

x Associate Professor Mikael Thyberg for introducing me to scientific work. His

enthusiasm and patience were of great value.

x Ricci Gotthard and Monica Bergmark, for initiating the population prevalence study.

67
x Ann-Katrine Ryn for always creating a warm atmosphere and for her considerable
ability to help our patients.

x Elisabeth Kaminsky for valuable help processing skin conductance data.

x My colleagues and friends at the department of Gastroenterology and Hepatology for

all their support.

x Mathias for being a good friend, for all support and for introducing me into the world
of computers many years ago.

x All the girls in Honey Jam, our charming Ladies Orchestra, Rydskogen Joymakers,
Michaela and all other friends for reminding me of other valuable aspects of life.

x Stella, my dog, for forcing me out in all kinds of weather and Björn & Solvej who
helped me taking care of her.

x Ulf, Ute, Heidi, Björg, Oma, Karin and Dagmar for their invaluable help with all sorts
of matters.

x My parents for their continuous support and for always being there when I needed
them.

x Bent for sharing my life and Fridolf our wonderful son.

68
REFERENCES
1. Connell AM, Hilton C, Irvine G, Lennard-Jones JE, Misiewicz JJ. Variation of
bowel habit in two population samples. Br Med J 1965;5470:1095-9.

2. Thompson WG, Heaton KW. Functional bowel disorders in apparently healthy

people. Gastroenterology 1980;79(2):283-8.

3. Drossman DA, Sandler RS, McKee DC, Lovitz AJ. Bowel patterns among
subjects not seeking health care. Use of a questionnaire to identify a population
with bowel dysfunction. Gastroenterology 1982;83(3):529-34.

4. Everhart JE, Go VL, Johannes RS, Fitzsimmons SC, Roth HP, White LR. A
longitudinal survey of self-reported bowel habits in the United States. Dig Dis
Sci 1989;34(8):1153-62.

5. Heaton KW, Radvan J, Cripps H, Mountford RA, Braddon FE, Hughes AO.
Defecation frequency and timing, and stool form in the general population: a
prospective study. Gut 1992;33(6):818-24.

6. Talley NJ, O'Keefe EA, Zinsmeister AR, Melton LJ, 3rd. Prevalence of
gastrointestinal symptoms in the elderly: a population-based study.
Gastroenterology 1992;102(3):895-901.

7. Harari D, Gurwitz JH, Avorn J, Bohn R, Minaker KL. Bowel habit in relation to
age and gender. Findings from the National Health Interview Survey and
clinical implications. Arch Intern Med 1996;156(3):315-20.

8. Chen LY, Ho KY, Phua KH. Normal bowel habits and prevalence of functional
bowel disorders in Singaporean adults--findings from a community based study
in Bishan. Community Medicine GI Study Group. Singapore Med J
2000;41(6):255-8.

9. Bassotti G, Bellini M, Pucciani F, et al. An extended assessment of bowel habits

in a general population. World J Gastroenterol 2004;10(5):713-6.

10. Bellini M, Alduini P, Bassotti G, et al. Self-perceived normality in defecation

habits. Dig Liver Dis 2006;38(2):103-8.

11. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC.
Functional bowel disorders. Gastroenterology 2006;130(5):1480-91.

12. Ragnarsson G, Bodemar G. Division of the irritable bowel syndrome into

subgroups on the basis of daily recorded symptoms in two outpatients samples.
Scand J Gastroenterol 1999;34(10):993-1000.

13. Sandler RS, Drossman DA. Bowel habits in young adults not seeking health
care. Dig Dis Sci 1987;32(8):841-5.

69
14. Meier R, Beglinger C, Dederding JP, et al. Influence of age, gender, hormonal
status and smoking habits on colonic transit time. Neurogastroenterol Motil
1995;7(4):235-8.

15. Hungin AP, Whorwell PJ, Tack J, Mearin F. The prevalence, patterns and
impact of irritable bowel syndrome: an international survey of 40,000 subjects.
Aliment Pharmacol Ther 2003;17(5):643-50.

16. Graff J, Brinch K, Madsen JL. Gastrointestinal mean transit times in young and
middle-aged healthy subjects. Clin Physiol 2001;21(2):253-9.

17. Cummings JH, Branch W, Jenkins DJ, Southgate DA, Houston H, James WP.
Colonic response to dietary fibre from carrot, cabbage, apple, bran. Lancet
1978;1(8054):5-9.

18. Davies GJ, Crowder M, Reid B, Dickerson JW. Bowel function measurements
of individuals with different eating patterns. Gut 1986;27(2):164-9.

19. Higgins PD, Johanson JF. Epidemiology of constipation in North America: a

systematic review. Am J Gastroenterol 2004;99(4):750-9.

20. Talley NJ, Weaver AL, Zinsmeister AR, Melton LJ, 3rd. Functional constipation
and outlet delay: a population-based study. Gastroenterology 1993;105(3):781-
90.

21. Thompson WG, Dotevall G, Drossman D, Heaton KW, Kruis W. Irritable bowel
syndrome: Guidelines for the diagnosis. Gastroenterology International
1989;2:92-5.

22. Drossman DA. The functional gastrointestinal disorder and the Rome II process.
Gut 1999;45 (Suppl II):II1-II5.

23. Mearin F, Balboa A, Badia X, et al. Irritable bowel syndrome subtypes

according to bowel habit: revisiting the alternating subtype. Eur J Gastroenterol
Hepatol 2003;15(2):165-72.

24. Bharucha AE, Zinsmeister AR, Locke GR, et al. Prevalence and burden of fecal
incontinence: a population-based study in women. Gastroenterology
2005;129(1):42-9.

25. Melville JL, Fan MY, Newton K, Fenner D. Fecal incontinence in US women: a
population-based study. Am J Obstet Gynecol 2005;193(6):2071-6.

26. Siproudhis L, Pigot F, Godeberge P, Damon H, Soudan D, Bigard MA.

Defecation disorders: a French population survey. Dis Colon Rectum
2006;49(2):219-27.

27. Perry S, Shaw C, McGrother C, et al. Prevalence of faecal incontinence in adults

aged 40 years or more living in the community. Gut 2002;50(4):480-4.

70
28. Lynch AC, Dobbs BR, Keating J, Frizelle FA. The prevalence of faecal
incontinence and constipation in a general New Zealand population; a postal
survey. N Z Med J 2001;114(1142):474-7.

29. Macmillan AK, Merrie AE, Marshall RJ, Parry BR. The prevalence of fecal
incontinence in community-dwelling adults: a systematic review of the
literature. Dis Colon Rectum 2004;47(8):1341-9.

30. Enck P, Gabor S, Von Ferber L, Rathmann W, Erckenbrecht JF. [Prevalence of

fecal incontinence and degree of information possessed by family physicians
and health insurance]. Z Gastroenterol 1991;29(10):538-40.

31. Whitehead WE. Diagnosing and managing fecal incontinence: if you don't ask,
they won't tell. Gastroenterology 2005;129(1):6.

32. Kuehn BM. Silence masks prevalence of fecal incontinence. Jama

2006;295(12):1362-3.

33. Nelson R, Norton N, Cautley E, Furner S. Community-based prevalence of anal

incontinence. Jama 1995;274(7):559-61.

34. Johanson JF, Lafferty J. Epidemiology of fecal incontinence: the silent

affliction. Am J Gastroenterol 1996;91(1):33-6.

35. Pretlove SJ, Radley S, Toozs-Hobson PM, Thompson PJ, Coomarasamy A,

Khan KS. Prevalence of anal incontinence according to age and gender: a
systematic review and meta-regression analysis. Int Urogynecol J Pelvic Floor
Dysfunct 2006;17(4):407-17.

36. Crowell MD, Lacy BE, Schettler VA, Dineen TN, Olden KW, Talley NJ.
Subtypes of anal incontinence associated with bowel dysfunction: clinical,
physiologic, and psychosocial characterization. Dis Colon Rectum
2004;47(10):1627-35.

37. Varma MG, Brown JS, Creasman JM, et al. Fecal Incontinence in Females
Older Than Aged 40 Years: Who is at Risk? Dis Colon Rectum 2006.

38. Mearin F, Badia X, Balboa A, et al. Irritable bowel syndrome prevalence varies
enormously depending on the employed diagnostic criteria: comparison of
Rome II versus previous criteria in a general population. Scand J Gastroenterol
2001;36(11):1155-61.

39. Rome I. Rome II: A Multinational Consensus Document on Functional

Gastrointestinal Disorders. Gut 1999;45(Supplement 11).

40. Manning AP, Thompson WG, Heaton KW, Morris AF. Towards positive
diagnosis of the irritable bowel. Br Med J 1978;2(6138):653-4.

71
41. Schmulson M, Ortiz O, Santiago-Lomeli M, et al. Frequency of functional
bowel disorders among healthy volunteers in Mexico City. Dig Dis 2006;24(3-
4):342-7.

42. Williams RE, Black CL, Kim HY, et al. Stability of irritable bowel syndrome
using a Rome II-based classification. Aliment Pharmacol Ther 2006;23(1):197-
205.

43. Ragnarsson G. Abdominal symptoms and anorectal function in outpatients with

the irritable bowel syndrome (IBS). Linköping University Medical Dissertation
2000;No. 651(Paper 3).

44. Read NW. IBS--it all depends where you draw the line. Scand J Gastroenterol
2001;36(11):1121-2.

45. Manning AP, Wyman JB, Heaton KW. How trustworthy are bowel histories?
Comparison of recalled and recorded information. British Medical Journal
1976;2:213-4.

46. Jones R, Lydeard S. Irritable bowel syndrome in the general population. Bmj
1992;304(6819):87-90.

47. Agreus L, Svardsudd K, Nyren O, Tibblin G. Irritable bowel syndrome and

dyspepsia in the general population: overlap and lack of stability over time.
Gastroenterology 1995;109(3):671-80.

48. Talley NJ, Howell S, Poulton R. The irritable bowel syndrome and psychiatric
disorders in the community: is there a link? Am J Gastroenterol
2001;96(4):1072-9.

49. Bommelaer G, Dorval E, Denis P, et al. Prevalence of irritable bowel syndrome

in the French population according to the Rome I criteria. Gastroenterol Clin
Biol 2002;26(12):1118-23.

50. Icks A, Haastert B, Enck P, Rathmann W, Giani G. Prevalence of functional

bowel disorders and related health care seeking: a population-based study. Z
Gastroenterol 2002;40(3):177-83.

51. Kwan CL, Diamant NE, Mikula K, Davis KD. Characteristics of rectal
perception are altered in irritable bowel syndrome. Pain 2005;113(1-2):160-71.

52. Lu CL, Chen CY, Lang HC, et al. Current patterns of irritable bowel syndrome
in Taiwan: the Rome II questionnaire on a Chinese population. Aliment
Pharmacol Ther 2003;18(11-12):1159-69.

53. Tan YM, Goh KL, Muhidayah R, Ooi CL, Salem O. Prevalence of irritable
bowel syndrome in young adult Malaysians: a survey among medical students. J
Gastroenterol Hepatol 2003;18(12):1412-6.

72
54. Hoseini-Asl MK, Amra B. Prevalence of irritable bowel syndrome in
Shahrekord, Iran. Indian J Gastroenterol 2003;22(6):215-6.

55. Gwee KA, Wee S, Wong ML, Png DJ. The prevalence, symptom characteristics,
and impact of irritable bowel syndrome in an asian urban community. Am J
Gastroenterol 2004;99(5):924-31.

56. Celebi S, Acik Y, Deveci SE, et al. Epidemiological features of irritable bowel
syndrome in a Turkish urban society. J Gastroenterol Hepatol 2004;19(7):738-
43.

57. Bommelaer G, Poynard T, Le Pen C, et al. Prevalence of irritable bowel

syndrome (IBS) and variability of diagnostic criteria. Gastroenterol Clin Biol
2004;28(6-7 Pt 1):554-61.

58. Wilson S, Roberts L, Roalfe A, Bridge P, Singh S. Prevalence of irritable bowel

syndrome: a community survey. Br J Gen Pract 2004;54(504):495-502.

59. Hungin AP, Chang L, Locke GR, Dennis EH, Barghout V. Irritable bowel
syndrome in the United States: prevalence, symptom patterns and impact.
Aliment Pharmacol Ther 2005;21(11):1365-75.

60. Yilmaz S, Dursun M, Ertem M, Canoruc F, Turhanoglu A. The epidemiological

aspects of irritable bowel syndrome in Southeastern Anatolia: a stratified
randomised community-based study. Int J Clin Pract 2005;59(3):361-9.

61. Wigington WC, Johnson WD, Minocha A. Epidemiology of irritable bowel

syndrome among African Americans as compared with whites: a population-
based study. Clin Gastroenterol Hepatol 2005;3(7):647-53.

62. Sperber AD, Friger M, Shvartzman P, et al. Rates of functional bowel disorders
among Israeli Bedouins in rural areas compared with those who moved to
permanent towns. Clin Gastroenterol Hepatol 2005;3(4):342-8.

63. Vandvik PO, Lydersen S, Farup PG. Prevalence, comorbidity and impact of
irritable bowel syndrome in Norway. Scand J Gastroenterol 2006;41(6):650-6.

64. Boyce PM, Talley NJ, Burke C, Koloski NA. Epidemiology of the functional
gastrointestinal disorders diagnosed according to Rome II criteria: an Australian
population-based study. Intern Med J 2006;36(1):28-36.

65. Drossman DA, al. e. ROME II. The Functional Gastrointestinal Disorders.
Diagnosis, Pathophysiology and Treatment: A Multinational Concencus.
McLean, VA, USA 2000;second edition.

66. Smith RC, Greenbaum DS, Vancouver JB, et al. Gender differences in Manning
criteria in the irritable bowel syndrome. Gastroenterology 1991;100(3):591-5.

67. Thompson WG. Gastrointestinal symptoms in the irritable bowel compared with
peptic ulcer and inflammatory bowel disease. Gut 1984;25(10):1089-92.

73
68. Kruis W, Thieme C, Weinzierl M, Schussler P, Holl J, Paulus W. A diagnostic
score for the irritable bowel syndrome. Its value in the exclusion of organic
disease. Gastroenterology 1984;87(1):1-7.

69. Harvey RF, Mauad EC, Brown AM. Prognosis in the irritable bowel syndrome:
a 5-year prospective study. Lancet 1987;1(8539):963-5.

70. Thompson WG. Gender differences in irritable bowel symptoms. Eur J

Gastroenterol Hepatol 1997;9(3):299-302.

71. Heaton KW, Ghosh S, Braddon FEM. How bad are the symptoms and bowel
dysfunction of patients with the irritable bowel syndrome? A prospective,
controlled study with emphasis on stool form. Gut 1991;32:73-9.

72. Whitehead EW. Patient subgroups in irritable bowel syndrome that can be
defined by symptom evaluation and physical examination. Am J Med 1999;107
(5A):33S-9S.

73. Bodemar G, Ragnarsson G. [Irritable bowel syndrome. Survey of definitions,

differential diagnosis and pathogenesis]. Lakartidningen 2001;98(7):666-71.

74. Ragnarsson G, Bodemar G. Pain is temporally related to eating but not to

defaecation in the irritable bowel syndrome (IBS). Patients' description of
diarrhea, constipation and symptom variation during a prospective 6-week
study. Eur J Gastroenterol Hepatol 1998;10(5):415-21.

75. Ragnarsson G, Hallbook O, Bodemar G. Abdominal symptoms and anorectal

function in health and irritable bowel syndrome. Scand J Gastroenterol
2001;36(8):833-42.

76. Gomborone JE, Dewsnap PA, Libby GW, Farthing MJG. Selective affective
biasing in recognition memory in the irritable bowel syndrome. Gut
1993;34:1230-3.

77. Whitehead WE, Crowell MD, Bosmajian L, et al. Existence of irritable bowel
syndrome supported by factor analysis of symptoms in two community samples.
Gastroenterology 1990;98(2):336-40.

78. Taub E, Cuevas JL, Cook EW, 3rd, Crowell M, Whitehead WE. Irritable bowel
syndrome defined by factor analysis. Gender and race comparisons. Dig Dis Sci
1995;40(12):2647-55.

79. Longstreth GF. Irritable bowel syndrome. Diagnosis in the managed care era.
Dig Dis Sci 1997;42(6):1105-11.

80. Ritchie J. Pain from distension of the pelvic colon by inflating a balloon in the
irritable colon syndrome. Gut 1973;14(2):125-32.

74
81. Whitehead WE, Palsson OS. Is rectal pain sensitivity a biological marker for
irritable bowel syndrome: psychological influences on pain perception.
Gastroenterology 1998;115(5):1263-71.

82. Mertz H, Naliboff B, Munakata J, Niazi N, Mayer EA. Altered rectal perception
is a biological marker of patients with irritable bowel syndrome.
Gastroenterology 1995;109(1):40-52.

83. Bouin M, Plourde V, Boivin M, et al. Rectal distention testing in patients with
irritable bowel syndrome: Sensitivity, specitivity, and predictive values of pain
sensory thresholds. Gastroenterology 2002;122(7):1771-7.

84. Lembo T, Munakata J, Mertz H, et al. Evidence for the hypersensitivity of

lumbar splanchnic afferents in irritable bowel syndrome. Gastroenterology
1994;107:1686-96.

85. Whitehead WE, Holtkotter B, Enck P, et al. Tolerance for rectosigmoid

distention in irritable bowel syndrome. Gastroenterology 1990;98(5 Pt 1):1187-
92.

86. Steens J, Van Der Schaar PJ, Penning C, Brussee J, Masclee AA. Compliance,
tone and sensitivity of the rectum in different subtypes of irritable bowel
syndrome. Neurogastroenterol Motil 2002;14(3):241-7.

87. Bradette M, Delvaux M, Staumont G, Fioramonti J, Bueno L, Frexinos J.

Evaluation of colonic sensory thresholds in IBS patients using a barostat.
Definition of optimal conditions and comparison with healthy subjects. Dig Dis
Sci 1994;39(3):449-57.

88. Prior A, Colgan SM, Whorwell PJ. Changes in rectal sensitivity after
hypnotherapy in patients with irritable bowel syndrome. Gut 1990;31(8):896-8.

89. Whitehead WE, Crowell MD, Davidoff AL, Palsson OS, Schuster MM. Pain
from rectal distension in women with irritable bowel syndrome: relationship to
sexual abuse. Dig Dis Sci 1997;42(4):796-804.

90. Naliboff BD, Munakata J, Fullerton S, et al. Evidence for two distinct perceptual
alterations in irritable bowel syndrome. Gut 1997;41:505-12.

91. Wilder-Smith CH, Schindler D, Lovblad K, Redmond SM, Nirkko A. Brain

functional magnetic resonance imaging of rectal pain and activation of
endogenous inhibitory mechanisms in irritable bowel syndrome patient
subgroups and healthy controls. Gut 2004;53(11):1595-601.

92. Prior A, Maxton DG, Whorwell PJ. Anorectal manometry in irritable bowel
syndrome: differences between diarrhoea and constipation predominant
subjects. Gut 1990;31(4):458-62.

75
93. Kuiken SD, Lindeboom R, Tytgat GN, Boeckxstaens GE. Relationship between
symptoms and hypersensitivity to rectal distension in patients with irritable
bowel syndrome. Aliment Pharmacol Ther 2005;22(2):157-64.

94. Schmulson M, Chang L, Naliboff B, Lee OY, Mayer EA. Correlation of

symptom criteria with perception thresholds during rectosigmoid distension in
irritable bowel syndrome patients. Am J Gastroenterol 2000;95(1):152-6.

95. Zuo XL, Li YQ, Shi L, et al. Visceral hypersensitivity following cold water
intake in subjects with irritable bowel syndrome. J Gastroenterol
2006;41(4):311-7.

96. Trimble KC, Farouk R, Pryde A, Douglas S, Heading RC. Heightened visceral
sensation in functional gastrointestinal disease is not site-specific. Evidence for
a generalized disorder of gut sensitivity. Dig Dis Sci 1995;40(8):1607-13.

97. Bouin M, Lupien F, Riberdy M, Boivin M, Plourde V, Poitras P. Intolerance to

visceral distension in functional dyspepsia or irritable bowel syndrome: an organ
specific defect or a pan intestinal dysregulation? Neurogastroenterol Motil
2004;16(3):311-4.

98. Rossel P, Drewes AM, Petersen P, Nielsen J, Arendt-Nielsen L. Pain produced

by electric stimulation of the rectum in patients with irritable bowel syndrome:
further evidence of visceral hyperalgesia. Scand J Gastroenterol
1999;34(10):1001-6.

99. Kellow JE, Azpiroz F, Delvaux M, et al. Applied principles of

neurogastroenterology: physiology/motility sensation. Gastroenterology
2006;130(5):1412-20.

100. Verne GN, Robinson ME, Vase L, Price DD. Reversal of visceral and cutaneous
hyperalgesia by local rectal anesthesia in irritable bowel syndrome (IBS)
patients. Pain 2003;105(1-2):223-30.

101. Ragnarsson G, Bodemar G. Pain is temporally related to eating but nor to

defaecation in the irritable bowel syndrome (IBS). Patients´description of
diarrhoea , constipation and symptom variation during a prospective 6-week
study. Eur J Gastroenterol Hepatol 1998;10:415-21.

102. Simren M, Mansson A, Langkilde AM, et al. Food-related gastrointestinal

symptoms in the irritable bowel syndrome. Digestion 2001;63(2):108-15.

103. Musial F, Crowell MD, Kalveram K, Enck P. Nutrient ingestion increases rectal
sensitivity in humans. Am J Gastroenterol 1994;92:2073-9.

104. Ragnarsson G, Hallböök O, Bodemar G. Abdominal Symptoms and Anorectal

Function in Health and Irritable Bowel Syndrome. Scandinavian Journal of
Gastroenterology 2001;8:833-42.

76
105. Simrén M, Abrahamsson H, Björnsson ES. An exaggerated sensory component
of the gastrocolonic response in patients with irritable bowel syndrome. Gut
2001;48:20-7.

106. Munakata J, Naliboff B, Harraf F, et al. Repetitive sigmoid stimulation induces

rectal hyperalgesia in patients with irritable bowel syndrome. Gastroenterology
1997;112:55-63.

107. Houghton LA, Calvert EL, Jackson NA, Cooper P, Whorwell PJ. Visceral
sensation and emotion: a study using hypnosis. Gut 2002;51(5):701-4.

108. Wilson S, Maddison T, Roberts L, Greenfield S, Singh S. Systematic review: the

effectiveness of hypnotherapy in the management of irritable bowel syndrome.
Aliment Pharmacol Ther 2006;24(5):769-80.

109. Ford MJ, Camilleri M, Zinsmeister AR, Hanson RB. Psychosensory modulation
of colonic sensation in the human transverse and sigmoid colon.
Gastroenterology 1995;109(6):1772-80.

110. Coates MD, Mahoney CR, Linden DR, et al. Molecular defects in mucosal
serotonin content and decreased serotonin reuptake transporter in ulcerative
colitis and irritable bowel syndrome. Gastroenterology 2004;126(7):1657-64.

111. Coffin B, Bouhassira D, Sabate JM, Barbe L, Jian R. Alteration of the spinal
modulation of nociceptive processing in patients with irritable bowel syndrome.
Gut 2004;53(10):1465-70.

112. Mertz H, Morgan V, Tanner G, et al. Regional cerebral activation in irritable

bowel syndrome and control subjects with painful and nonpainful rectal
distention. Gastroenterology 2000;118(5):842-8.

113. Silverman DH, Munakata JA, Ennes H, Mandelkern MA, Hoh CK, Mayer EA.
Regional cerebral activity in normal and pathological perception of visceral
pain. Gastroenterology 1997;112(1):64-72.

114. Sidhu H, Kern M, Shaker R. Absence of increasing cortical fMRI activity

volume in response to increasing visceral stimulation in IBS patients. Am J
Physiol Gastrointest Liver Physiol 2004;287(2):G425-35.

115. Lawal A, Kern M, Sidhu H, Hofmann C, Shaker R. Novel evidence for

hypersensitivity of visceral sensory neural circuitry in irritable bowel syndrome
patients. Gastroenterology 2006;130(1):26-33.

116. Martinson J. Studies on the efferent vagal control of the stomach. Acta Physiol
Scand Suppl 1965;255:1-24.

117. Sundin T, Carlsson CA. Reconstruction of severed dorsal roots innervating the
urinary bladder. An experimental study in cats. I. Studies on the normal afferent
pathways in the pelvic and pudendal nerves. Scand J Urol Nephrol
1972;6(2):176-84.

77
118. Hallböök O. Colonic pouch anastomosis after rectal excision for cancer.
Linköping University Medical Dissertation 1996;504.

119. Simrén M, Ringstrom G, Björnsson ES, Abrahamsson H. Treatment with

hypnotherapy reduces the sensory and motor component of the gastrocolonic
response in irritable bowel syndrome. Psychosomatic Medicine 2004;66(2):233-
8.

120. Naliboff BD, Derbyshire SWG, Munakata J, Chang L, Mayer EA. Cerebral
Activation in Patients with Irritable Bowel Syndrome and Control Subjects
During Rectosigmoid Stimulation. Psychosomatic Medicine 2001;63:365-75.

121. Wilder-Smith CH, Schindler D, Lovblad K, Redmond SM, Nirkko A. Brain

functional magnetic resonance imaging of rectal pain and activation of
endogenous inhibitory mechanisms in irritable bowel syndrome patient
subgroups and healthy controls. Gut 2004;53:1595-601.

122. Ragnarsson G, Hallböök O, Bodemar G. Abdominal Symptoms Are Not Related

to Anorectal Function in the Irritable Bowel Syndrome. Scand J Gastroenterol
1999;3:250-8.

123. Dong WZ, Zou DW, Li ZS, et al. Study of visceral hypersensitivity in irritable
bowel syndrome. Chin J Dig Dis 2004;5(3):103-9.

124. Whitehead WE, Delvaux M. Standardization of Barostat Procedures for Testing

Smooth Muscle Tone and Sensory Thresholds in the Gastrointestinal Tract.
Digestive Diseases and Sciences 1997;42:223-41.

125. Hammer HF, Phillips SF, Camilleri M, Hanson RB. Rectal tone, distensibility,
and perception: reproducibility and response to different distensions. Am J
Physiol 1998;37:G584-G90.

126. Schaar van der PJ, Lamers CHBW, Masclee AAM. The Role of the Barostat in
Human Research and Clinical Practice. Scand J Gastroenterol 1999;34 suppl
230:52-63.

127. Delvaux M. Alterations of sensori-motor functions of the digestive tract in the

pathophysiology of irritable bowel syndrome. Best Pract Res Clin Gastroenterol
2004;18(4):747-71.

128. Whitehead WE, Crowell MD, Robinson JC, Heller BR, Schuster MM. Effects of
stressful life events on bowel symptoms: subjects with irritable bowel syndrome
compared with subjects without bowel dysfunction. Gut 1992;33(6):825-30.

129. Mayer EA, Naliboff BD, Chang L, Coutinho SV. Stress and the gastrointestinal
tract, V. Stress and irritable bowel syndrome. Am J Physiol Gastrointest Liver
Physiol 2001;280:G519-24.

78
130. Dancey CP, Taghavi M, Fox RJ. The relationship between daily stress and
symptoms of irritable bowel syndrome: A time-series approach. Journal of
Psychosomatic Research 1998;44:537-45.

131. Tache Y, Martinez V, Million M, Rivier J. Corticotropin-releasing factor and the

brain-gut motor response to stress. Can J Gastroenterol 1999;13 Suppl A:18A-
25A.

132. Bennet EJ, Tennant CC, Piesse C, Badcock C-A, Kellow JE. Level of chronic
life stress predicts clinical outcome in irritable bowel syndrome. Gut
1998;43:256-61.

133. Murray CD, Flynn J, Ratcliffe L, Jacyna MR, Kamm MA, Emmanuel AV.
Effect of acute physical and psychological stress on gut autonomic innervation
in irritable bowel syndrome. Gastroenterology 2004;127(6):1695-703.

134. Posserud I, Agerforz P, Ekman R, Bjornsson ES, Abrahamsson H, Simren M.

Altered visceral perceptual and neuroendocrine response in patients with
irritable bowel syndrome during mental stress. Gut 2004;53(8):1102-8.

135. Mönnikes H, Tebbe JJ, Hildebrandt M, et al. Role of Stress in Functional

Gastrointestinal Disorders. Dig Dis 2001;19:201-11.

136. Tache Y, Monnikes H, Bonaz B, Rivier J. Role of CRF in stress-related

alterations of gastric and colonic motor function. Ann N Y Acad Sci
1993;697:233-43.

137. Barreau F, Ferrier L, Fioramonti J, Bueno L. Neonatal maternal deprivation

triggers long term alterations in colonic epithelial barrier and mucosal immunity
in rats. Gut 2004;53(4):501-6.

138. Rots NY, de Jong J, Workel JO, Levine S, Cools AR, De Kloet ER. Neonatal
maternally deprived rats have as adults elevated basal pituitary-adrenal activity
and enhanced susceptibility to apomorphine. J Neuroendocrinol 1996;8(7):501-
6.

139. Soderholm JD, Yates DA, Gareau MG, Yang PC, MacQueen G, Perdue MH.
Neonatal maternal separation predisposes adult rats to colonic barrier
dysfunction in response to mild stress. Am J Physiol Gastrointest Liver Physiol
2002;283(6):G1257-63.

140. Million M, Wang L, Wang Y, et al. CRF2 receptor activation prevents

colorectal distension induced visceral pain and spinal ERK1/2 phosphorylation
in rats. Gut 2006;55(2):172-81.

141. Fukudo S, Nomura T, Hongo M. Impact of Corticotropin-releasing hormone on

gastrointestinal motility and adrenocorticotropic hormone in normal controls
and patients with irritable bowel syndrome. Gut 1998;42:845-9.

79
142. Sagami Y, Shimada Y, Tayama J, et al. Effect of a corticotropin releasing
hormone receptor antagonist on colonic sensory and motor function in patients
with irritable bowel syndrome. Gut 2004;53(7):958-64.

143. Mason HL, Myers CS, Kendall EC. The chemistry of crystalline substances
isolated from the suptrarenal gland. J Biol Chem 1936;114:613-31.

144. Reichstein T. Über Bestandteile der Nebennieren-Rinde. VI. Trennungsmethode

sowie Isolierung der Substanzen Fa, H and J. Helv Chim 1936;Acta, 19:1107-
26.

145. Gallagher TF, Yoshida K, Roffwarg HD, Fukushima DK, Weitzman ED,
Hellman L. ACTH and cortisol secretory patterns in man. J Clin Endocrinol
Metab 1973;36(6):1058-68.

146. Aguilera G, Rabadan C. Vasopressinergic regulation of the hypothalamic-

pituitary-adrenal axis: Implications for stress adaption. Regul Pept 2000;96 (1-
2):23-9.

147. Dinan TG, Quigley EM, Ahmed SM, et al. Hypothalamic-pituitary-gut axis
dysregulation in irritable bowel syndrome: plasma cytokines as a potential
biomarker? Gastroenterology 2006;130(2):304-11.

148. Rask E. Neuroendocrine studies in obesity and insulin resistance. Linköping

University Medical Dissertation 2002;No 772.

149. Aardal E. Salivary cortisol and posttraumatic stress reactions. Linköping

University Medical Dissertation 2002;No 705.

150. Kudielka BM, Buske-Kirschbaum A, Hellhammer DH, Kirschbaum C. HPA

axis responses to laboratory psychosocial stress in healthy elderly adults,
younger adults, and children: impact of age and gender.
Psychoneuroendocrinology 2004;29(1):83-98.

151. Yehuda R, Martin TL, Southwick SM, Shaffer D, Giller EL. Lymphocyte
Glucocorticoid Receptor Number in Posttraumatic Stress Disorder. Am J
Psychiatry 1991;148:499-504.

152. Thorell LH. Electrodermal activity in depressive patients. Linköping University

Medical Dissertation 1987;No. 249.

153. Odber J, Cawood EH, Bancroft J. Salivary cortisol in women with and without
perimenstrual mood changes. J Psychosom Res 1998;45(6):557-68.

154. Riad M, Mogos M, Thangathurai D, Lumb PD. Steroids. Curr Opin Crit Care
2002;8(4):281-4.

155. Elsenbruch S, Thompson JJ, Hamish MJ, Exton MS, Orr WC. Behavioral and
physiological sleep characteristics in women with irritable bowel syndrome. Am
J Gastroenterol 2002;97(9):2306-14.

80
156. Patacchioli FR, Angelucci L, Dell'Erba G, Monnazzi P, Leri O. Actual stress,
psychopathology and salivary cortisol levels in the irritable bowel syndrome
(IBS). J Endocrinol Invest 2001;24:173-7.

157. Heitkemper M, Jarrett M, Cain K, et al. Increased urine catecholamines and

cortisol in women with irritable bowel syndrome. Am J Gastroenterol
1996;91(5):906-13.

158. Elsenbruch S, Orr WC. Diarrhea- and constipation-predominant IBS patients

differ in postprandial autonomic and cortisol responses. Am J Gastroenterol
2001;96(2):460-6.

159. Dickhaus B, Mayer EA, Firooz N, et al. Irritable bowel syndrome patients show
enhanced modulation of visceral perception by auditory stress. Am J
Gastroenterol 2003;98(1):135-43.

160. Tillisch K, Mayer EA, Labus JS, Stains J, Chang L, Naliboff BD. Sex specific
alterations in autonomic function among patients with irritable bowel syndrome.
Gut 2005;54(10):1396-401.

161. Aggarwal A, Cutts TF, Abell TL, et al. Predominant symptoms in irritable
bowel syndrome correlate with specific autonomic nervous system
abnormalities. Gastroenterology 1994;106(4):945-50.

162. Elsenbruch S, Orr WC. Diarrhea-and constipation-predominant IBS patients

differ in postprandial autonomic and cortisol responses. American Journal of
Gastroenterology 2001;96:460-6.

163. Elsenbruch S, Lovallo WR, Orr WC. Psychological and Physiological

Responses to Postprandial Mental Stress in Women With the Irritable Bowel
Syndrome. Psychosomatic Medicine 2001;63:805-13.

164. Payne A, Blanchard EB, Holt CS, Schwarz SP. Physiological reactivity to
stressors in irritable bowel syndrome patients, inflammatory bowel disease
patients and non-patient controls. Behav Res Ther 1992;30(3):293-300.

165. Karling P, Nyhlin H, Wiklund U, Sjoberg M, Olofsson BO, Bjerle P. Spectral

analysis of heart rate variability in patients with irritable bowel syndrome. Scand
J Gastroenterol 1998;33(6):572-6.

166. Adeyemi EO, Desai KD, Towsey M, Ghista D. Characterization of autonomic

dysfunction in patients with irritable bowel syndrome by means of heart rate
variability studies. Am J Gastroenterol 1999;94(3):816-23.

167. Waring WS, Chui M, Japp A, Nicol EF, Ford MJ. Autonomic cardiovascular
responses are impaired in women with irritable bowel syndrome. Clinical
Gastroenterology 2004;38(8):658-63.

81
168. van Orshoven NP, Andriesse GI, van Schelven LJ, Smout AJ, Akkermans LM,
Oey PL. Subtle involvement of the parasympathetic nervous system in patients
with irritable bowel syndrome. Clin Auton Res 2006;16(1):33-9.

169. Lee CT, Chuang TY, Lu CL, Chen CY, Chang FY, Lee SD. Abnormal vagal
cholinergic function and psychological behaviors in irritable bowel syndrome
patients: a hospital-based Oriental study. Dig Dis Sci 1998;43(8):1794-9.

170. Munakata J, Mayer EA, Chang L, et al. Autonomic and neuroendocrine

response to rectosigmoid stimulation. Gastroenterology 1998;114:A808.

171. Elsenbruch S, Lovallo WR, Orr WC. Psychological and physiological responses
to postprandial mental stress in women with the irritable bowel syndrome.
Psychosom Med 2001;63(5):805-13.

172. Heitkemper M, Jarrett M, Bond E. Irritable bowel syndrome: more than a gut
feeling. J Wound Ostomy Continence Nurs 2002;29(4):202-9.

173. Fowles DC, Christie MJ, Edelberg R, Grings WW, Lykken DT, Venables PH.
Committee report. Publication recommendations for electrodermal
measurements. Psychophysiology 1981;18(3):232-9.

174. Boucsein W. Electrodermal Activity. New York, Plenum Press 1992.

175. Thomas PE, Korr IM. Relationship Between Sweat Gland Activity and
Electrical Resistance of the Skin. Med& Biol Eng& Comput 1957;10:505-10.

176. Lidberg L, Wallin BG. Sympathetic Skin Nerve Discharges in Relation to

Amplitude of Skin Resistance Responses. Psychophysiology 1981;18:268-70.

177. Nilsson L. Relationship between evoked skin-conductance response and

evaporative-water-loss response following acoustic stimulation. Med& Biol
Eng& Comput 1982;20:678-92.

178. Payne A, Blanchard EB, Holt CS, Schwarz SP. Physiological reactivity to
stressors in irritable bowel syndrome patients, inflammatory bowel disease
patients and non-patient controls. Behav Res Ther 1992;30:293-300.

179. Lader MH, Wing L. Physiological measures, sedative drugs, and morbid
anxiety. London: Oxford University Press 1966.

180. Critchley HD. Electrodermal responses: what happens in the brain.

Neuroscientist 2002;8(2):132-42.

181. Ohman A, Soares JJ. On the automatic nature of phobic fear: conditioned
electrodermal responses to masked fear-relevant stimuli. J Abnorm Psychol
1993;102(1):121-32.

182. Pavlov IP. Conditioned reflexes. New York: Dover 1927.

82
183. Palsson OS, Turner MJ, Johnson DA, Burnelt CK, Whitehead WE. Hypnosis
treatment for severe irritable bowel syndrome: investigation of mechanism and
effects on symptoms. Dig Dis Sci 2002;47(11):2605-14.

184. Bernstein CN, Niazi N, Robert M, et al. Rectal afferent function in patients with
inflammatory and functional intestinal disorders. Pain 1996;66(2-3):151-61.

185. Tousignant-Laflamme Y, Goffaux P, Bourgault P, Marchand S. Different

Autonomic Responses to Experimental Pain in IBS Patients and Healthy
Controls. J Clin Gastroenterol 2006;40(9):814-20.

186. Gralnek IM, Hays RD, Kilbourne A, Naliboff B, Mayer EA. The impact of
irritable bowel syndrome on health-related quality of life. Gastroenterology
2000;119(3):654-60.

187. Osterberg E, Blomquist L, Krakau I, Weinryb RM, Asberg M, Hultcrantz R. A

population study on irritable bowel syndrome and mental health. Scand J
Gastroenterol 2000;35(3):264-8.

188. Talley NJ, Spiller R. Irritable bowel syndrome: a little understood organic bowel
disease? Lancet 2002;360(9332):555-64.

189. Barbara G, De Giorgio R, Stanghellini V, Cremon C, Salvioli B, Corinaldesi R.

New pathophysiological mechanisms in irritable bowel syndrome. Aliment
Pharmacol Ther 2004;20 Suppl 2:1-9.

190. Drossman DA, Creed FH, Olden KW, Svedlund J, Toner BB, Whitehead WE.
Psychosocial aspects of the functional gastrointestinal disorders. Gut 1999;45
Suppl 2:II25-30.

191. Sjodin I, Svedlund J. Psychological aspects of non-ulcer dyspepsia: a

psychosomatic view focusing on a comparison between the irritable bowel
syndrome and peptic ulcer disease. Scand J Gastroenterol Suppl 1985;109:51-8.

192. Svedlund J, Sjodin I, Dotevall G, Gillberg R. Upper gastrointestinal and mental

symptoms in the irritable bowel syndrome. Scand J Gastroenterol
1985;20(5):595-601.

193. Simren M, Abrahamsson H, Svedlund J, Bjornsson ES. Quality of life in

patients with irritable bowel syndrome seen in referral centers versus primary
care: the impact of gender and predominant bowel pattern. Scand J
Gastroenterol 2001;36(5):545-52.

194. Drossman DA. The functional gastrointestinal disorders and the Rome III
process. Gastroenterology 2006;130(5):1377-90.

195. Ragnarsson G, Hallbook O, Bodemar G. Abdominal symptoms are not related to

anorectal function in the irritable bowel syndrome. Scand J Gastroenterol
1999;34(3):250-8.

83
196. Svanborg P, Åsberg M. A new self-rating scale for depression and anxiety states
based on Comprehensive Psychopathological Rating Scale. Acta Psychiatr
Scand 1994;89:21-8.

197. Weinryb RM, Österberg E, Blomquist L, Hultcrantz R, Krakau L, Åsberg M.

Psychological Factors in Irritable Bowel Syndrome: a Population-based Study of
Patients, Non-patients and Controls. Scand J Gastroenterol 2003;38:503-10.

198. Hallböök O, Sjödahl R. Techniques of rectal compliance measurement.

Seminars in Colon & Rectal Surgery 1992;3:88-91.

199. Aardal E, Holm A-C. Cortisol in Saliva- Reference Ranges and Relation to
Cortisol in Serum. Eur J Clin Chem Biochem 1995;33:927-32.

200. Chiarelli P, Brown W, McElduff P. Constipation in Australian women:

prevalence and associated factors. Int Urogynecol J Pelvic Floor Dysfunct
2000;11(2):71-8.

201. Pare P, Ferrazzi S, Thompson WG, Irvine EJ, Rance L. An epidemiological

survey of constipation in canada: definitions, rates, demographics, and
predictors of health care seeking. Am J Gastroenterol 2001;96(11):3130-7.

202. Erckenbrecht JF. [The epidemiology of constipation]. Z Gastroenterol

2000;Suppl 1:3-5.

203. Harari D, Gurwitz JH, Avorn J, Bohn R, Minaker KL. How do older persons
define constipation? Implications for therapeutic management. J Gen Intern Med
1997;12(1):63-6.

204. Probert CS, Emmett PM, Cripps HA, Heaton KW. Evidence for the ambiguity
of the term constipation: the role of irritable bowel syndrome. Gut
1994;35(10):1455-8.

205. Guilera M, Balboa A, Mearin F. Bowel habit subtypes and temporal patterns in
irritable bowel syndrome: systematic review. Am J Gastroenterol
2005;100(5):1174-84.

206. Tillisch K, Labus JS, Naliboff BD, et al. Characterization of the alternating
bowel habit subtype in patients with irritable bowel syndrome. Am J
Gastroenterol 2005;100(4):896-904.

207. Drossman DA, Morris CB, Hu Y, et al. A prospective assessment of bowel habit
in irritable bowel syndrome in women: defining an alternator. Gastroenterology
2005;128(3):580-9.

208. Kay L, Jorgensen T. Redefining abdominal syndromes. Results of a population-

based study. Scand J Gastroenterol 1996;31(5):469-75.

209. LeDoux J. The emotional brain, fear, and the amygdala. Cell Mol Neurobiol
2003;23(4-5):727-38.

84
210. Mayer EA, Berman S, Suyenobu B, et al. Differences in brain responses to
visceral pain between patients with irritable bowel syndrome and ulcerative
colitis. Pain 2005;115(3):398-409.

211. Graham FK. Habituation and Dishabituation of Responses Innervated by the

Autonomic Nervous System. HVS peeke &MJHerz (Eds), New York: Academic
Press 1973(Habituation):163-216.

212. Read NW. Rectal distention: from sensation to feeling. Gastroenterology

2000;118(5):972-4.

213. Naliboff BD, Berman S, Suyenobu B, et al. Longitudinal change in perceptual

and brain activation response to visceral stimuli in irritable bowel syndrome
patients. Gastroenterology 2006;131(2):352-65.

214. Aziz Q. Visceral hypersensitivity: fact or fiction. Gastroenterology

2006;131(2):661-4.

215. Emmanuel AV, Kamm MA. Laser Doppler flowmetry as a measure of extrinsic
colonic innervation in functional bowel disease. Gut 2000;46(2):212-7.

85