Exploring the brain gut axis in irritable bowel syndrome specific emphasis on stress and melatonin

Part I

Literature Review and Hypothesis






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Chapter 1

Spectrum of Irritable Bowel
Syndrome and Brain-Gut Axis









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1.1 Introduction

The irritable bowel syndrome (IBS) is a common disorder producing abdominal

pain, bloating and altered bowel habits, which can be associated with significant
disability and health care costs. IBS is defined by symptoms, which are markedly
influenced by psychological factors and stressful life situations, in the absence of
structural pathology. No life threatening or significant disease such as infections,
inflammatory bowel disease or bowel cancer have been found in majority of IBS
patients on appropriate investigations. With the accumulation of knowledge from
epidemiology, physiology, psychology and neuroscience during the last decade, IBS
is now believed to result from a dysregulation of brain-gut axis which involves the
alterations in intestinal motor, sensory, and central nervous system (CNS).
The histories of patients with IBS show considerable variation in symptom
experience and behavior. Though most of these patients only have relatively mild to
moderate symptoms, some suffer severe symptoms that can restrict social activities
and substantially reduce quality of life and cause serious consequence. It can affect
employment, leisure travel, sexual function, diet and co-morbid with sleep,
depression and anxiety. Patients with IBS have three times work absenteeism than
other employees (Drossman et al, 1993), and based on the large proportion of the
population affected, IBS patients consume tremendous healthcare services. IBS
accounts for an estimated 2.4-3.5 million physician visits per year in the United States
(Everhart and Renault, 1991) and for an estimated 2.2 million medication
prescriptions (Sandler, 1990). Patients with IBS undergo numerous diagnostic tests

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and procedures (many unnecessary), and may retain a maladaptive illness belief that
some other diagnosis is still being missed. Some of them are also more likely to
undergo surgery (Longstreth et al, 1990).
The cost of health services for patients with IBS is significantly higher than that for
controls and is estimated at eight billion dollars per year for the white population of
the United States (Talley et al, 1995). Because of poor understanding of the cause of
the disorder, lack of common-accepted diagnostic criteria and a biopsychosocial
model of the disease, there is still no encouraging strategy for cure and the optimal

treatment for IBS remains controversial. As such, we face many problems and
challenges and there is clearly a need for more research on this disorder.

1.2 Epidemiology
In general, large epidemiological studies from United States, United Kingdom, and
China show that IBS affects about 11%-20% of people in the community (Farthing,
1995). The prevalence of IBS varies across different epidemiological studies;
presumably due to the diversity of definitional criteria, differences in the specific
questions used to elicit the information, different target population and other factors.
A survey using Manning criteria found that 22% of the British population aged
between 20 and 90 years have IBS (Jones and Lydeard, 1992). Another study using
the same diagnostic criteria but in a different age group (30 to 64 years), reported a
prevalence of approximately 17% (Talley et al, 1991). Using the more restrictive
Rome criteria, IBS symptoms was only detected in 9.4% of the United States
population (Drossman et al, 1993).

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It has also been documented that only a proportion of those with IBS symptoms
consult physicians. While a study done by Talley et al (1991) reported that only 14%
of patients with IBS symptoms had consulted a physician, a survey conducted by
Jones and Lydeard (1992) revealed that only one-third IBS patients had seen a doctor
for their symptoms.
There are marked differences in the prevalence of IBS in women as compared with
men. IBS affects females approximately twice as often as males. In the U.S.
Householder Survey (Drossman et al, 1993), IBS was present in 14.5% of women but
in only 7.7% of men. Similar differences in prevalence have been reported in other
studies from western countries (Hislop, 1971; Talley et al, 1991; Heaton et al, 1992;
Jones and Lydeard, 1992). Contrary to findings by the abovementioned studies done
in the western countries, studies from India and Sri lanka reported a preponderance of
men having IBS (Kapoor et al,1985; Mendis et al, 1982). The disparity of IBS

prevalence between the western and Indian reports may be attributed to different
healthcare seeking tendency between men and women in the two different societies
(Thompson et al, 1989).

1.3 Etiology and pathophysiology
The pathophysiology of IBS remains largely unknown. Several mechanisms have
been postulated as the basis for the cause and development of IBS. These mechanisms
include dysregulation of brain-gut interactions, psychological factors, abnormal
motility, enhanced visceral sensitivity and autonomic system imbalance. However, no
mechanism unique to IBS has been identified.

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1.3.1 The brain-gut axis
Currently, more and more attention has been put on the dysregulation of brain-gut
interactions. The brain-gut axis refers to the continuous back and forth interactions of
information and feedback that take place between the gastrointestinal tract, and the
brain and spinal cord. These interrelated feedback circuits can influence brain
processes and bowel functions including pain perception, gut sensitivity, secretions,
inflammatory responses, and motility. The brain-gut circuits can be activated by an
external or internal factor or stimulus that makes a demand on the system, such as a
stressful event. Symptoms, such as abdominal pain and altered motility and bowel
habits in IBS patients can arise from dysregulation of activity in one or more of the
stations in the bidirectional communication pathways between the GI system (the
enteric nervous system, ENS) and the spinal cord and brain (the central nervous
system, CNS).
Through the use of modern imaging techniques, such as positron emission
tomography (PET) and functional magnetic resonance imaging (fMRI), researchers
have been able to evaluate cerebral blood flow or oxygen desaturation respectively, in
areas of active brain functioning in response to real or anticipated pain from visceral
balloon distention. A fMRI study found increased anterior cingulated cortex (ACC)

activation in IBS patients compared to healthy controls as well as activation of
prefrontal, insular and thalamus in most subjects in response to painful rectal
distention (Mertz et al, 2000). However, using PET, it was also revealed that unlike
healthy controls, IBS patients failed to activate the ACC during painful rectal

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distention (Silverman et al, 1997). Such differences might suggest these findings are
related to anxiety and uncertainty among the patients. In spite of these inconsistent
results, these data at least provided an objective evidence to support the hypothesis of
the dysregulation of brain-gut communication, and such dysregulation are especially
manifested in the abnormal descending pain inhibitory modulation.
Numerous neurotransmitters found in the brain and gut act as messengers that
regulate brain-gut communication under stress. These messengers, including
serotonin (5-HT), cholecystokinin, substance P, enkephalins, calcitonin gene related
polypeptide, nitric oxide, and others, have varied and integrated effects on pain
modulation, gastrointestinal motility, emotional behavior, and immunity (Mayer and
Gebhart, 1994). Given the complex relationship between inflammatory mediators, gut
hypersensitivity, motility, and pain experience, the results of recent research strongly
suggest that alterations in neuroimmune and neuroendocrine communications at the
enteric and CNS levels may trigger a series of events that gives rise to chronic
changes in visceral sensitivity and central mechanisms controlling pain, as evidence
of dysregulation of the brain-gut axis. Several kinds of events could trigger the
dysregulation of the brain-gut axis in patients with IBS. Among these are
psychological experiences, such as life stress, psychological co-morbidity, or sexual
and physical abuse, and inflammation (Drossman et al, 1996; Gwee et al, 1999).

1.3.2 Stress
Stress, defined as an acute threat to the homeostasis of an organism by real
(physical, ‘interoceptive’; e.g. gut infection, cold water immersion, visceral distention)

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or perceived (psychological, ‘exteroceptive’; e.g. dichotomous listening, mental
arithmetic, life events) events, initiates adaptive physiologic and behavioral changes
that serve to defend the stability of the internal environment (Monnikes et al, 2001;
Selye,1998; Selye, 1976; Chrousos and Gold, 1992). Certain physical and
psychological stresses have been associated with the onset or symptom exacerbation
in functional gastrointestinal disorders (FGD), especially IBS. Such association in
patients with IBS was observed in some well-designed surveys (Gwee et al, 1999;
Bennett and Tennant et al, 1998; Whitehead et al, 1992; Welgan et al 1985). Patients
with FGD are exposed to one or more stressors much more often than normal controls
(98% versus 36%) (Bennett and Piesse et al, 1998). Meanwhile, the symptoms are
improved with the acquisition of more effective stress management skills (Guthrie et
al, 1993; Shaw et al, 1991). Furthermore, evidences from animal studies have shown
that various stressors caused delayed gastric emptying, inhibited small bowel transit
and accelerated colonic transit (Williams et al, 1988; Tache et al, 1999; Tsukada et al,
2002). Some investigators also observed increased responses of distal colonic motility
in response to stress in IBS patients (Welgan et al, 1988; Fukudo et al, 1993;
Narducci et al, 1985).
Recently, a study group reported decreased rectal pain thresholds in patients with
IBS but not in normal controls during acute laboratorial physical (cold water hand
immersion) and psychological (dichotomous listening) stress (Murray et al, 2004). By
contrast, a variety of stressful stimuli has been shown to produce analgesia, a
phenomenon often referred to as stress-induced analgesia (SIA) (Bodnar, 1986;
Hayes and Katayama, 1986; Watkins et al, 1982). Studies using different stressors

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(e.g. cold stress pain, ischemic pain and noxious heat) significantly produced
analgesia in healthy subjects (Washington et al, 2000; Willer et al, 1989; Pertovaara
et al, 1982). However, this “stress inhibiting pain” phenomenon has never been
reported in patients with IBS. Taken together, all these data may imply an altered

stress regulatory mechanism in IBS patients, especially endogenous pain modulation,
which change the sensory and motility of the bowel. These changes in turn could
cause visceral hyperalgesia, abdominal symptoms and altered stool habits.
Compared with the knowledge in physiology, the role of central functions in stress
and thereby the interactions between neural networks and gut remains poorly
understood. Sawchenko et al pointed out that there are some similar principal circuits
underlying the stress response in spite of the different types of stress (Sawchenko and
Li, 2000). The limbic forebrain including the lateral and medial prefrontal cortex,
hippocampus, and amygdale may participate in central processing psychological
stress (Sawchenko and Li, 2000). A recent study observed significant group
differences in the frontal brain among healthy controls and IBS patients with respect
to the event-related potentials in the brain during exposure to everyday words with
emotional content (Blomhoff et al, 2000). Using electroencephalograms (EEG),
Nomura et al also showed significantly greater EEG abnormality in the IBS patients
(29.2%) than in the controls (4.2%) under mental arithmetic stress and the
administration of neostigmine (Nomura et al, 1999).
All these data suggest a possible involvement of the CNS in the pathophysiology of
IBS, especially under the stress situation.


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1.3.3 Psychopathology
Some chronic and acute psychosocial factors including early life experiences,
conditioning factors (Levy et al, 2000; Whitehead et al, 1994), psychological stress
(which has been introduced in the section 1.3.1), personal and social coping systems
(Drossman et al, 2000), and psychological distress and co-morbidity, are important in
the pathophysiology of IBS. A whole variety of chronic psychopathologies have been
described in secondary care IBS patients although anxiety and depression are by far
the commonest, accounting for at least 60% (Whitehead and Crowell, 1991) of them.
Abnormal illness behavior and illness attitude have also been reported as being more

common in IBS than healthy controls (Drossman et al, 1988; Levy et al, 2000).
Compared with healthy controls, patients with IBS are observed to have higher scores
for anxiety, depression, hostile feelings, sadness, interpersonal sensitivity, as well as
more sleep disturbance (Whitehead et al, 1980; Svedlund et al, 1985; Gomborone et
al, 1995; Ford et al, 1987). All of these factors could cause chronic stress in IBS
subjects. This opinion was furthere supported by the finding that many patients with
IBS have counterproductive coping styles, such as cognitions that "catastrophize"
symptoms and life events (Drossman et al, 2000). In another study, psychological
factors were reported to predict the development IBS after an episode of acute
gastroenteritis in previously asymptomatic individuals (Gwee et al, 1999). The
prevalence of psychiatric diagnoses in IBS ranges between 40% and 100% depending
on the population, settings, and diagnostic criteria (Hochstrasser and Angst, 1996;
Drossman et al, 2000). However, part of these findings maybe overestimated because
the data are drawn from patients who are selectively referred to medical centers. It

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was found that persons with IBS who do not see physicians are psychologically
similar to normal subjects, and conversely, frequent clinic attenders have a high
frequency of psychosocial disturbance (Drossman et al, 1997; Drossman et al, 1988;
Smith et al, 1990). Hence, psychosocial factors not only influence the individual’s
illness seeking behavior but also may affect the way in which symptoms are
perceived and evaluated.

1.3.4 Altered motility
Abnormal bowel motility has been found in patients with IBS since long time ago
(Harding, 1951), and IBS has also been long considered as a motility disorder. Early
studies suggested abnormal electrical control activity in the colon of IBS patients
(Snape, 1976). Compared to healthy controls, both a reduction in and an increase in
the number of contractions per minute were found in IBS patients (Snape, 1976).
Accelerated transit in the colon was observed in some diarrhea predominant IBS

patient; on the other hand, delayed transit was found in some constipation
predominant IBS patients (Cann et al, 1983; Bassotti et al, 1988). Recently, a study
suggested that IBS patients have impaired transit and tolerance to intestinal gas and
this anomaly has been cited as a possible mechanism for pain and bloating which are
commonly observed in IBS patients (Serra et al, 2001). Furthermore, abnormal
motility patterns have also been found in other regions of the gastrointestinal tract,
such as the small bowel in IBS patients. (Kellow and Phillips, 1987). The transit time
through the small bowel was observed to be accelerated in diarrhea predominant IBS
patient, but delayed in constipation predominant IBS patients (Cann et al, 1983).

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However, the types of motility patterns seen in the colon and small intestine of IBS
patients are qualitatively similar to the contractions seen in healthy controls. Most
stool weights in IBS patients lie within the normal range in spite of their fast transit,
and this phenomenon was even found in diarrhea predominant IBS patients
(Arffmann et al, 1985; Cann et al, 1984; Vassallo et al, 1992).
In addition to the differences between IBS patients and healthy controls in the basal
motility pattern, patients with IBS have exaggerated intestinal motor in response to
environmental or enteric stimuli. Colonic activity is significantly accelerated in IBS
patients when they experience psychological stress (kendall et al,1990; Fukudo and
Suzuki, 1987). Eating a meal stimulates colonic activity, and gastrocolonic reflex is
prolonged and exaggerated in IBS (Sullivan et al, 1978; Rogers et al, 1989).
Moreover, these exaggerated responses to eating are found to be associated with
abdominal pain (Sullivan et al, 1978). Rectal distention studies also show a greater
increase in colonic motor activity in IBS patients compared to healthy controls
(Whitehead et al, 1990). Pharmacologic stimulation of the bowel with
cholecystokinin generated more contractile response in IBS patients than in healthy
controls and this exaggerated response was shown to persist (Harvey and Read, 1973).
In summary, although IBS patients have motility abnormalities, none of them are
specific for IBS. In fact, many abnormal motor patterns observed in IBS patients are

also found in healthy subjects (McKee and Quigley, 1993; Cann et al, 1983). Thus
abnormal motor patterns are not diagnostic for IBS (McKee and Quigley, 1993;
Drossman et al, 1997). Furthermore, these abnormal motility patterns neither
correlate with IBS symptoms nor are they sufficient to explain many of the symptoms

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associated with IBS. Therefore, nowadays, abnormal motility is usually no longer
considered the primary cause of IBS and it is generally believed that other
mechanisms may also be involved.

1.3.5 Visceral hypersensitivity
The studies in rectosigmoid balloon distention and the above mentioned non-
specific gut motility changes in IBS patients shifted the attention of researchers to
alterations in visceral sensations, i.e. visceral hypersensitivity in the 1970s. The
finding that IBS patients have lower pain thresholds was first described in rectal and
sigmoid colon using rectosigmoid balloon distention test (Ritchie, 1973). Thereafter,
similar results were also found elsewhere of the gastrointestinal tract including the
descending colon, small intestine (Kellow and Phillips, 1987), stomach and
esophagus (Trimble et al, 1995). Other than these gastrointestinal tract
hypersensitivity, the complain of extra-intestinal manifestations such as headaches,
breathlessness, chest pain, fatigue, dysuria and dyspaneuria were often found in IBS
patients (Whorwell et al, 1986; Talley et al, 1991; Jones and Lydeard, 1992). All
these data may suggest that IBS patients may either have a lowered sensory threshold
or have a tendency of apprehension to pain and other symptoms. This hypersensitivity
is specific to visceral stimulation because somatic pain thresholds to extreme cold or
transcutaneous electrical stimulation are not lower in IBS patients when compared to
healthy controls (Whitehead et al, 1990; Cook et al, 1987). However, a response bias
should not be omitted, because IBS patients are much more likely to show an

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increased hypersensitivity when the rectum is distended in a predictable increasing
volume sequence than in a random iterative method.
IBS patients may be prone to developing sensitization because repetitive painful
balloon distention in the sigmoid colon induced hypersensitivity in the rectum of IBS
patients but not healthy controls (Munakata et al, 1997). Such sensitization seems to
occur at the level of the lumbar dorsal horn neurons because the dorsal horn neurons
in the spinal cord receive converging signals from the sigmoid colon and rectal
splanchnic afferents.
In summary, the pathophysiological mechanism of IBS remains to be clearly
elucidated. However, an integrated model which attempts to synthesize the factors
discussed above has been pointed out (Figure 1-1) (Drossman, 1998; Ringel et al,
2001). In this model, IBS is neither a simple physiological nor a simple psychological
illness. It results from a dysregulation of brain-gut interactions that affect intestinal as
well as central and peripheral neurological function, mediated through
neuroendocrine and neuroimmunological pathways. Psychosocial factors do not cause
IBS but influence the expression of the symptoms and illness behavior (Ringel et al,
review, 2001).







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Figure 1-1 Conceptual model for irritable bowel syndrome. (Adapted from Ringel et
al, 2001)




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1.4 Diagnosis
A correct diagnosis of IBS is of crucial importance because it reassures patients
about the favorable prognosis of their disease and places the basis for a therapeutic
strategy on controlling the predominant symptom (e.g. constipation, diarrhea,
alternating bowel and pain/bloating). The diagnosis of IBS is based on recognizing
clinical symptoms consistent with it and on modest efforts to exclude other/organic
diseases, because there are no positive physical findings or biological markers for IBS
(Drossman et al, 1997; Ringel et al, 2001).
In 1978, Manning et al described several key abdominal symptoms, now referred to
as 'Manning criteria', that were more likely to be present in the IBS than in organic
abdominal disease (Manning et al, 1978) (Table 1-1). Kruis et al added other criteria,
including a requirement for symptoms to have been present for more than two years
and the use of symptom complexes that increase the chances of making a positive
clinical diagnosis (Kruis et al, 1984). These symptom criteria were integrated later
into other scoring systems. The Rome I, and more recently, the Rome II criteria are
the results of multinational ad hoc consensus workshops (Thompson et al, 1999)
(Table 1-1). Notably, factor analysis data proved that IBS can be defined by a cluster
of three symptoms which represent the core of Rome II criteria. Although the Rome
criteria are becoming more popular and have been accepted by many regulatory
authorities, the Manning criteria are better validated. Both Rome I and II criteria
proved to be valuable in identifying similar proportions of IBS patients in the general
population; however, Rome I criteria allowed the identification of higher numbers of

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IBS patients in referral centers than Rome II. It is not known why Rome I and II work
similarly in the community but yield different results in referral centers. It is probable
that inappropriate use and/or intrinsic limitations of diagnostic criteria may be
responsible for this discrepancy. Overall, the general view is that the Rome II criteria
are extremely valuable as research tool rather than useful criteria in daily practice (De
Giorgio et al, review, 2004). Furthermore, table 1-2 summarizes the main studies that
should be considered according to the patient's predominant symptom.

















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Table 1-1 Symptom-based criteria so far established for the diagnosis of IBS

Manning
Pain relieved by defecation
More frequent stools at the onset of pain
Looser stools at the onset of pain
Visible abdominal distension
Passage of mucus
Feeling of incomplete evacuation
Rome I
Abdominal pain or discomfort for at least 3 months with at least 1 of the
following symptoms:
relieved with defecation
associated with change in frequency of stools
Associated with change in form of stools and two or more of the following
symptoms:
altered stool frequency and/or form
altered stool passage
passage of mucus
bloating or abdominal distension
Rome II
Abdominal pain or discomfort for at least 12 weeks in 12 months with at least
two of the following symptoms:
relieved with defecation
associated with change in frequency of stools
Associated with change in form of stools with the following symptoms
supporting IBS:
altered stool frequency and/or form
altered stool passage
passage of mucus
bloating or abdominal distension

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TABLE 1-2 Further evaluation of irritable bowel syndrome optional studies
(Adapted with permission from Ringel et al, 2001)

Constipation-predominant IBS
Colonic transit time (e.g. Sitzmark study)
Anorectal manometry and rectal balloon expulsion
Electromyography
Defecography
Diarrhea-predominant IBS
Stool tests (e.g. volume, electrolytes, fat, white count, osmotic gap, and pH)
Breath tests for bacterial overgrowth
Intestine absorption function tests (e.g. D-xylose)
Small bowel radiograph (partial obstruction, inflammatory bowel disease)
Upper endoscopy with duodenal aspirate (Giardia) and biopsy (celiac sprue,
Whipple's, and lymphoma)
Colonic biopsies (collagenous/lymphocytic colitis)
Serum hormones/peptides (i.e. Gastrin, VIP, 5HIAA)
Stool and urine analysis for laxative
Discomfort/pain-predominant IBS
Upright abdominal X-ray (chronic pancreatitis and chronic idiopathic pseudo-
obstruction)
Small bowel radiograph (partial obstruction, inflammatory bowel disease)
Additional abdominal imaging studies (i.e. X-ray, ultrasound, computerized
tomography, magnetic resonance)
Serum amylase (chronic pancreatitis)

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1.5 Treatment
The treatment of IBS involves both pharmacological and non-pharmacological
approaches, the latter of which

appear to have the best long term results, particularly
in terms of dietary and psychotherapy treatments.

1.5.1 Non-pharmacological treatment approach

1.5.1.1 Construction of good therapeutic relationship
Once the diagnosis of IBS is established, an effective physician patient
relationship is crucial for setting the basis of a beneficial pharmacological approach.
This includes effective communication, appropriate reassurance, and patient
education about the condition and its consequences (Drossman et al, 1999).
Physicians should explain to patients the nature of their condition, treatment options,
and impact of anxiety and stress on symptoms. Evidence indicates that a positive
interaction with

patients with discussion of precipitating factors, diagnosis,

and
treatment has been shown to reduce the number of return

visits (Owens et al, 1995).

1.5.1.2 Life style and dietary modification
Many IBS patients benefit from dietary changes, lifestyle changes, and health-

promoting behaviors. Some patients with mild IBS symptoms may not require
prescription medications after appropriate changes in life style and diet. Identifying
offending dietary substances (e.g. lactose, caffeine, fatty foods, alcohol, gas-
producing foods, sorbitol) and making dietary modifications can help some patients.
An increased dietary fiber intake is one of the most common recommendations in

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constipation-predominant IBS. Potentially, fibers may be beneficial in constipated
IBS patients because of their ability to reduce the transit time through the entire
alimentary tract and intestinal wall tension by decreasing intracolonic pressure
(Muller-Lissner, 1988). However, physicians should keep in mind that patients may
get excessive on dietary restriction which may turn out to be potentially dangerous for
them. Psychological stressors, which are known to maintain and exacerbate
symptoms, should be sought and managed with supportive advice or lifestyle
modification. Simple life style modifications such as exercise and defecating patterns
may help individual patients.
1.5.1.3 Psychological treatment
Psychological treatment, including cognitive behavioral therapy, psychotherapy,
relaxation and hypnosis, may represent a valid therapeutic option, at least in a sub-
group of patients with IBS. A small relaxation therapy showed a reduction in
symptoms and consultations (Jones et al, 2000). Biofeedback in conjunction with
relaxation therapies has also shown some benefit (Lynch and Zamble, 1989; Neff and
Blanchard, 1987), but these study results may be biased by the effects of good
relationship between therapist and patients due to methodology shortcomings. The
role of cognitive behavioral therapy and hypnotherapy has not been clearly defined,
although small studies suggest some response with symptom improvement (Whorell,
1987; Payne and Blanchard, 1995). But another randomized trial showed
hypnotherapy as one of the most valuable non-pharmacological treatment in IBS,
with benefit lasting longer than 12 months (Francis and Houghton, 1996).
It should be

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recognized that the availability of these psychological therapies is limited and their
use should be restricted to certain most difficult cases.

1.5.2 Pharmacological treatment
The multiple symptoms that are so characteristic of IBS have proven to be a hurdle
in the treatment of the condition. Current pharmacological treatment of IBS is only
aimed at controlling the predominant symptoms: abdominal pain/bloating,

diarrhoea,
or constipation (Camilleri et al, 2002); therefore, it has limited efficacy overall
(Camilleri and Choi, 1999). Patients should be informed that any prescribed
compound should be taken only during symptom recurrence rather than chronically.

1.5.2.1 Abdominal pain and bloating
The most common medications used for management of pain in IBS patients are
the antispasmodics, which include three major subclasses, namely anti-muscarinics
smooth muscle relaxants and calcium channel blockers (De Giorgio et al, 2004). The
final effect of all these compounds is to evoke smooth muscle relaxation and hence
reduction of gut wall tension. A therapeutic trial of an antimuscarinic drug, given
before meals, may be beneficial in patients who have episodes of abdominal pain
after eating, but randomized clinical trials demonstrated little, if any, advantage over
placebo, and significant risk of mild side effects (Jaiwala et al, 2000). The British
Society of Gastroenterology suggests that antidepressants are currently the most
effective drugs for IBS. In treating underlying depression, antidepressants can modify
gut motility and alter visceral nerve responses (Jones et al, 2000). Low doses of

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antidepressants were found to be effective in alleviating chronic or severe abdominal

pain. This effect is independent of their psychotrophic effects and can be achieved at
lower doses and a shorter time interval than for that used for patients with psychiatric
disorders (Clouse, 1994).

1.5.2.2 Constipation
High fiber diet is frequently recommended for constipation predominant IBS
patients. Increasing intake

of a range of different dietary "fibers" including those
from

cereals, fruits, and vegetables have been shown to increase stool weight and
accelerate gut transit (Jones et al, 2000). Wheat bran, at doses

of 10 g to 30 g, is the
best known and probably the most effective

fiber supplement. Some clinical trials
showed that fibers were no better than placebo in overall symptom relief, whereas
symptoms such as pain and distension worsened (Snook and Shepherd, 1994).
However, most studies reported a significant improvement in constipation if
sufficient quantities of fiber are consumed (Cann et al, 1984).
Several new drugs that act on 5HT4 receptors (tegaserod and prucalopride), M3
muscarinic receptors (darifenacine and zamifenacin), and CCK receptors
(loxiglumide) appear promising for relief of constipation as well as abdominal pain
and bloating in IBS patients (Scarpignato and Pelosini, 1999). These drugs are
currently under clinical trials. Meanwhile, the current options for treatment of
constipation in IBS remain bulk-forming agents (psyllium, methylcellulose),
hyperosmotic laxatives (lactulose, sorbitol, and PEG solution), and stool softeners
(Ringel et al, 2001).

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1.5.2.3 Diarrhea
Loperamide (2-4 mg) is used for treatment of diarrhea-predominant IBS, especially
in patients who also have incontinence. As an opioid analogue, loperamide exerts an
inhibitory effect on intestinal peristalsis and fluid secretion by interacting with enteric
neurons. Therefore, it can decrease intestinal transit time, increase intestinal
absorption, and strengthen rectal tone (Thompson et al, 2000). It is documented that
loperamide significantly ameliorates diarrhea, urgency and faecal soiling (Jailwala et
al, 2000), although it has no effect on other IBS-related symptoms such as pain and
bloating (Read et al, 1982).








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Chapter 2

Role of Stress in IBS and Brain-
Gut Axis

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