Aliment Pharmacol Ther 2004; 20 (Suppl. 2): 10–22.
Diagnosis and therapy of irritable bowel syndrome
R. DE GIORGIO, G . BARBAR A, V. STAN GHELLIN I, C. CREMON, B. SA LVIOLI, F. DE PO NTI* &
R. COR INALDESI
Departments of Internal Medicine and Gastroenterology and *Pharmacology, University of Bologna, Italy
SUMMARY
Irritable bowel syndrome (IBS) is one of the most
common gut functional diseases, affecting 10–20% of
people worldwide. Although most patients do not seek
medical help, the disease accounts for huge costs for
both patients and health-care systems and worsens
significantly patients’ quality of life. Diagnosis is based
on the identification of symptoms according to Man-
ning, Rome I and Rome II criteria and exclusion of
alarm indicators. IBS symptoms overlap with those of
coeliac disease, lactose intolerance, food allergies and
bile salt malabsorption. The treatment of IBS is centred
INTRODUCTION
Irritable bowel syndrome (IBS), one of the most
common diseases in gastrointestinal clinical practice,
is defined classically as a chronic disorder characterized
by abdominal pain/discomfort and disturbed defecation
not explained by structural and biochemical abnormal-
ities.1–5 The social impact of IBS on the general
population is extremely high, as this syndrome affects
10–20% of people worldwide and reduces quality of
life.4, 6, 7 These patients represent a considerable burden
for society because of direct (e.g. public health-care use,
drug consumption) and indirect (e.g. absenteeism from
work and lack of productivity) costs.8–10 Hence, the
need to develop appropriate diagnostic and therapeutic
approaches for IBS has grown considerably in the recent
past. Several insightful papers, reviews and working
Correspondence to: Dr R. De Giorgio, Department of Internal Medicine and
Gastroenterology, St Orsola Hospital, Building no. 5, Via Massarenti,
9-40138, Bologna, Italy.
E-mail: deg@orsola-malpighi.med.unibo.it
10
on an excellent doctor–patient relationship along with
drugs targeting the predominant symptom, especially
during exacerbations. Current pharmacological remed-
ies are unsatisfactory due to the high number of patients
complaining of lack of response and/or symptom
recurrence. Although useful in some IBS patients, the
validity of psychotherapy deserves further investigation.
A wide array of potentially useful drugs are currently
under consideration in pre-clinical trials. A better
understanding of the pathogenetic mechanisms under-
lying IBS may help to develop more effective drugs for
this disease.
team reports have illustrated different strategies to
manage patients with IBS (for review see1–5).
A proposed approach includes a positive diagnosis by
means of accurate symptom analysis, few laboratory
tests (avoiding useless and costly examinations) and a
therapeutic trial,2 which may be of benefit to the
patient, also considering the high placebo response
(from 20–70%) found in this syndrome.11–13 Exclusion
of alarm symptoms is considered mandatory. These are
also referred to as Ôred flagsÕ and include age > 50 years,
nocturnal symptoms awaking the patient from sleep,
refractory diarrhoea, rectal bleeding or evidence of
anaemia, hypoalbuminaemia, significant weight loss,
fever, abnormal physical examination (e.g. palpable
abdominal mass), progressive and severe non-fluctu-
ating symptoms, history of antibiotic use and family
history of colon cancer or inflammatory bowel dis-
ease.1–5 Clearly, testing is necessary in the case of any
red flag and/or evidence of positive family history; the
appropriate examinations should be discussed and
planned with the patient at the first consultation. None

2004 Copyright Blackwell Publishing Ltd
 CLINICAL FEATURES AND TREATMENT OF IBS 11

the less, the distinction between organic and functional
diseases represents one of the most difficult tasks not
only in general practice but also in the specialist setting.
In order to overcome this problem, experts formed
consensus groups to identify symptom-based criteria
useful to differentiate IBS from organic diseases.
The aim of this review article is 2-fold: (1) to focus on
the main diagnostic criteria for IBS and related possible
pitfalls; and (2) to tackle appropriate therapeutic approa-
ches and potential pathophysiological targets.
MAIN EPIDEMIOLOGICAL FEATURES OF IBS
For the purpose of this work, we will review only the
major epidemiological aspects of IBS which may help to
provide the framework for a correct clinical approach to
IBS patients (for more details on the epidemiology and
socio-economic impact of IBS the reader is referred to
in-depth reviews, e.g.1, 2).
IBS is an extremely common disease as it affects up to
24% of women and up to 19% of men of the adult
population in the USA and Europe.14 These findings
reflect the tremendous impact of IBS on social costs due
to health-care use, drug consumption and absenteeism
from work. For example, it has been estimated that the
social indirect costs for IBS are similar to those reported
for influenza.2, 8–10 The exact prevalence of IBS is
poorly defined, probably because of the different defini-
tions and clinical criteria (see below) used to define the
syndrome. For instance, Saito et al.15 compared Man-
ning vs. Rome II criteria to evaluate the prevalence of
IBS in a community in Olmsted County (MN, USA). The
results showed substantial variability, as the age- and
gender-adjusted prevalence was 20.4% using two
symptoms of the Manning criteria, whereas it was
8.5% using three defecation disorders in the Rome II
criteria. The percentage of agreement for both the
criteria used was > 90%. Similarly, the incidence of IBS
is unknown, although it can be expected to be around
0.2% per year based on clinical diagnosis of the
syndrome.16 This finding certainly underestimates the
real incidence of IBS as only one in three patients seek
doctors. IBS is commonly believed to be a female disease;
depending on the type of the sample, women are 3–4
times more commonly affected than men in the clinical
setting, whereas this estimate becomes 2 : 1 in the
community.16 The reason why women appear to be
more prone than men to IBS is unknown, although
health-seeking behaviour and other factors may play a
role in this gender predominance (Table 1).17–22 On the
other hand, in eastern countries, either no gender
difference (e.g. in Taiwan)23 or male predominance (e.g.
in India)17 has been reported.
THE CLINICAL DIAGNOSIS OF IBS: FROM MANNING
TO ROME CRITERIA
Making a correct diagnosis of IBS is of crucial import-
ance because it reassures patients about the favourable
prognosis of their disease and places the basis for a
therapeutic strategy on controlling the predominant
symptom (e.g. constipation, diarrhoea, alternating
bowel and pain/bloating). However, the distinction
between IBS and other organic diseases is not an easy
one, for several reasons. First, physicians, especially
general practitioners, are not confident enough with the
use of positive symptom criteria (see below) to detect
IBS, implying that in this setting, IBS remains a
diagnosis of exclusion. Secondly, the lack of a Ôbiological
markerÕ for IBS corroborates the concerns experienced
by most physicians about the certainty of their diagnosis
and may probably explain, at least in part, the high

Table 1. Putative factors for female sex predominance in health-care request for IBS

Factor Meaning Reference

Cultural background Women seek medical aid more frequently than men in Unruh, 1996
western countries
Stress and psychological abnormalities Women are more sensitive to psychological distress Lydiard, 2001
and life event stress
Sex hormones Female steroids are known to affect visceral sensitivity and Berkley, 1997;
decrease pain threshold Ruigomez et al. 2003
Different brain serotonin synthesis Possible sex-related difference in neurotransmitter synthesis Nishizawa et al. 1997
(i.e. serotonin) in the central nervous system which may
account for visceral perception and illness behaviour

2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20 (Suppl. 2), 10–22
12 R. DE GIORGIO et al.
percentage of patients with functional bowel disorders
referred to consultants in specialized centres (up to
60%).1–5 Thirdly, symptoms complained of by IBS
patients are not specific for the syndrome and are
characterized by a significant inter- and intra-individual
variability (i.e. symptoms vary considerably among
patients and within a single patient over time). These
factors may contribute to the doubts that physicians
have of missing an organic disease.
In an attempt to facilitate a correct diagnostic
approach to IBS, over the years groups of experts have
developed clinical measures based on positive symptom
analysis. In 1978, Manning and colleagues were the
first to propose key symptoms, now referred to as
ÔManning criteriaÕ, to help the diagnosis of IBS.24 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 (Table 2).25, 26 The Rome II
working group (the Rome III criteria are currently in
progress) defined IBS as Ô…a group of functional bowel
disorders in which abdominal discomfort or pain is
associated with defecation or a change in bowel habit,
and with features of disordered defecationÕ.26 Notably,
factor analysis data proved evidence that IBS can be
defined by a cluster of three symptoms which represent
the core of Rome II criteria (see Table 2). Although
Rome criteria have now gained popularity, being used
in several clinical studies and adopted by regulatory
authorities, the Manning criteria have been better
validated. Indeed, Manning criteria have been found
to discriminate IBS from other organic disorders of the
gastrointestinal tract with sensitivity and specificity
rates ranging from 58 to 81% and 67 to 87%,
respectively.4, 27, 28 Vanner et al.29 compared Rome I
criteria to the consultant’s final diagnosis, which was
considered as the gold standard for IBS identification in
this study. The results showed that Rome I had a
sensitivity of 65% and, in the absence of red flags, the
specificity was 98%. Thus, positive Rome I criteria along
with absence of alarm indicators have a very high
predictive value for identifying patients with IBS and, on
the other hand, the risk of missing organic diseases
appears to be low. Both Rome I and II criteria proved to
be valuable in identifying similar proportions of IBS
patients in the general population;30, 31 however, Rome
I criteria allowed the identification of higher numbers of
IBS patients compared to Rome II in referral centres.32, 33
The reason why Rome I and II work similarly in the

2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20 (Suppl. 2), 10–22
Table 2. 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 irritable bowel syndrome:
altered stool frequency and/or form
altered stool passage
passage of mucus
bloating or abdominal distension
community and yield different results in referral centres
remains unknown. 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. Probably, the advent of the next Rome III
criteria will improve this bias and will favour the
development of more adequate clinical measures useful
not only for research purposes, but also for the
identification and management of IBS patients in
clinical practice. None the less, we believe that Manning
or Rome II can guide doctors towards a positive
diagnosis of IBS if combined with an accurate history
evaluation, physical examination and, particularly,
exclusion of alarm symptoms suggestive of an underly-
ing organic disease. These considerations apply more
effectively to the clinical setting of referral centres than
to general practice, where looser definitions of IBS are
commonly used. Finally, the identification of risk factors
 CLINICAL FEATURES AND TREATMENT OF IBS 13

Table 3. Risk and commonly associated factors in IBS

Risk/associated factor Specific evidence

Genetic factors
Sex
Psychosocial factors
Drugs
History of previous
gastroenteritis
No direct evidence; however, a genetic imbalance between pro- and anti-inflammatory cytokines may be
responsible for a Ôminimal inflammationÕ, likely involved in the pathogenesis of IBS symptoms
IBS is more common in women; there is more medical consultation among women
> men; menstrual cycle may play a role in symptom exacerbation
Co-existence of anxiety and depression; personality abnormalities and stress in IBS aggravate symptoms
and make the patient more keen to seek medical support
Non-steroidal anti-inflammatory drugs and antibiotics may elicit IBS symptoms
Established aetiological factor in subsets of IBS and other functional disorders

for IBS may also be useful to facilitate diagnosis
(Table 3).1–5
DIAGNOSTIC PITFALLS AND DIFFERENTIAL
DIAGNOSIS
Based on the general understanding that functional
symptoms experienced by IBS patients overlap greatly
with other gastrointestinal diseases, physicians are often
faced by the dilemma of whether the patient should be
first treated or tested. Moreover, if the second option (i.e.
test the patient) would be the best choice to avoid the risk
of missing alternative diagnosis, then the question that
arises in daily practice is which patient should undergo
testing. A clinical scenario which exemplifies the chal-
lenge of clinical practice is given by patients presenting
with diarrhoea, a symptom related to either IBS (diar-
rhoea-predominant IBS) or a variety of underlying
disorders including coeliac disease, lactose intolerance,
food allergies and other conditions. Obviously the solu-
tion of this problem, i.e. what is the best to do in this case,
is far from established. Again, the general experts’
consensus indicate that if a patient is diagnosed to have
IBS according to symptom-based criteria in the absence of
red flags, then no further investigations are need. This
hypothetical patient should be given a therapeutic trial
(based on predominant symptom) and possibly tested
only if refractory to treatment. Recent data, however,
suggest a critical evaluation of this strategy. Indeed, Cash
et al.34 showed that among patients fulfilling the Rome II
criteria for IBS, the pre-test probability to identify
inflammatory bowel disease, colorectal cancer or infec-
tious diarrhoea was less than 1%. However, the pre-test
probability of coeliac disease in these patients was 10
times higher than the prevalence of coeliac disease in the
general population.34 These results indicate that
diagnostic tests performed in IBS patients defined accord-
ing to Rome II are not likely to unravel underlying
organic disorders, but coeliac disease. Sanders et al.35
performed a controlled study based on 300 consecutive
new patients meeting the Rome II criteria and screened
them for coeliac disease with antibody testing. The results
showed that 66 of 300 patients with IBS had positive
antibody results, of whom 14 had histologically proven
coeliac disease (4.8%) compared to two control subjects,
who turned out to be positive for coeliac disease (0.7%)
[odds ratio ¼ 7 (95% CI 1.7–28.0)].35 According to these
results, serological screening for coeliac disease should
be conducted in IBS patients referred to secondary
care centres. In this regard, the American
Gastroenterological Association guidelines for IBS recom-
mend serological tests for coeliac disease (i.e. antibody
anti-tissue transglutaminase) in any patients with
IBS, especially those with diarrhoea-predominant IBS.3
The two main conditions that should be considered in
the differential diagnosis of IBS are inflammatory bowel
disease in young patients and colorectal carcinoma in
older patients, whereas parasitic and bacterial infections
represent a major clinical challenge in developing
countries.2 An accurate physical examination along
with few targeted investigations will help to exclude
organic (e.g. structural, metabolic or infectious) dis-
eases. Special consideration should be made for gut
inflammation, which recent clinical and experimental
data from our and other groups indicate may be
involved in the pathogenesis of IBS symptoms.36, 37
Furthermore, histological analyses of colonic mucosal
biopsies may also reveal 10% of microscopic colitis that
would be missed using symptom-based criteria alone.38
Other gastrointestinal disorders that should be consid-
ered in the differential diagnosis of IBS have been
reviewed by a panel of experts (for review, see39) and we

2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20 (Suppl. 2), 10–22
14 R. DE GIORGIO et al.
will cover only briefly the major conditions that must be
taken into consideration by practising physicians.
Lactose and other carbohydrate malabsorptions
The role of sugar malabsorption in the pathogenesis of
IBS is still a debated problem. In fact, demographic data
show that the prevalence of IBS patients with sugar
malabsorption is similar to that found in controls.2
The diagnosis of lactose intolerance can be achieved
with breath testing following the administration of 50 g
of lactose, although the test may be limited by a low
sensitivity and specificity.40 Symptoms, such as diar-
rhoea and bloating, can typically be reproduced by
lactose intake and reduced following lactose exclusion
from the diet. Lactose malabsorption may co-exist with
IBS. Indeed, lactose malabsorption can be detected in
about 25% of patients with IBS. Furthermore, lactose
ingestion evokes symptoms in about 25% of IBS.41–45
Nevertheless, a lactose-free diet is effective in improving
symptoms only in about 10% of IBS patients.45 In
addition to lactose other carbohydrates, such as sorbitol
(a sweetener used in sucrose-free dietary products) and
fructose, may precipitate IBS symptoms. Ingestion of 5 g
of sorbitol and 25 g of fructose have been found to
induce symptoms more commonly in IBS patients than
in controls (44.3% vs. 3.5%).42, 43, 46 Notably, the dose
of carbohydrates that evokes symptoms in IBS is lower
than that required to trigger symptoms in healthy
volunteers.
In conclusion, the diagnosis of carbohydrate mal-
absorption is based on hydrogen excretion with breath
testing after oral challenge of the sugar which is
thought to evoke IBS-like symptoms. If this test is
positive, then the offensive sugar should be excluded
from the diet. However, it is still debated whether all IBS
patients should undergo breath testing for carbohydrate
malabsorption.
Food allergies
This term indicates immune-mediated forms of adverse
reactions evoked by some foods. The exposure of
allergenic substances to the intestinal mucosa triggers
IgE- and non-IgE-mediated mechanisms which stimu-
late the release of histamine and other mediators from
mast cells. The released pool of chemical messengers
may deeply affect gut neuro-muscular functions and
hence induce the occurrence of symptoms overlapping

2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20 (Suppl. 2), 10–22
those of IBS (e.g. diarrhoea and abdominal pain). The
prevalence of food allergies has been estimated to be
0.3–7.5% in children and 1.3–2% in adults.47 These
figures may be underestimated, however, as methods
used currently to detect food allergies are still debatable
and hampered by low sensitivity and specificity.48 The
impact of food allergies on IBS is still largely undefined
and studies are awaited in this field. Thus, the diagnosis
of food allergies in patients with IBS remains poorly
defined. If a food allergy is recognized, an exclusion diet
may be of benefit for IBS patients. Too-restrictive diets
are unadvisable, based on a wide positivity of allergic
tests. A therapeutic trial with sodium chromoglycate
can also be attempted, but only limited evidence of its
efficacy has been produced so far.49, 50
Bile salt malabsorption
This disorder is characterized by IBS-like symptoms such
as abdominal pain and watery stools that are not
associated with a previous intestinal resection, vagoto-
my or cholecystectomy. The pathophysiology of bile salt
malabsorption has been reviewed recently.51 If a patient
presents with watery diarrhoea with a stool weight up to
900 g per day, then bile salt malabsorption can be
suspected. To substantiate the existence of this condition
several tests can be attempted, including assay of bile salt
in the faeces (> 250 g per day in disease state)52 and
scintigraphic assessment measuring the degree of
retention and excretion of 75SeHCAT (75-selenium-
homotaurocholic acid) at 30 min and 7 days following
the examination (normally the retention is > 15%).53, 54
These examinations, however, are necessarily performed
in secondary or tertiary referral centres and therefore
cannot be considered for routine screening. A more
simplistic approach is based on a therapeutic trial
with the bile salt sequestering drug cholestiramine, if
tolerated by the patient. In conclusion, a bile salt
malabsorption should be sought in patients with diar-
rhoea-predominant IBS in whom diarrhoea is partic-
ularly severe and unresponsive to classic treatment.
NON-PHARMACOLOGICAL AIDS IN THE
TREATMENT OF IBS
General considerations and patient stratification
Patients with IBS encompass a wide spectrum of disease
severity which needs to be evaluated to address a

correct management. Indeed, the analysis of the nature
and severity of symptoms, correlation of symptoms to
food intake and/or bowel habit changes, degree of gut
functional impairment, and the presence of psychologi-
cal abnormalities and psychiatric comorbidity allow for
a differentiation of IBS patients into three main
categories, i.e. mild, moderate and severe.55, 56 Most
patients (approximately 70%) experience mild symp-
toms and treatment is directed to target pharmacolog-
ically the underlying altered gut sensorimotor function;
other patients with moderate symptoms (25%) have an
intermittent, although disabling, symptom pattern. The
symptoms complained of by these patients relate to gut
sensorimotor dysfunction and psychological/psychiatric
disturbances, hence treatment is based on the use of
agents targeting gut dysfunction along with low-dose
antidepressants and psychological support if needed;
finally, a minority of patients (5%) suffers from severe
symptoms often refractory to medications. Patients with
such severe forms of IBS require referral to specialized
centres; they often manifest psychiatric comorbidity
(anxiety, depression) and psychological problems (pre-
vious history of sexual abuse, poor coping) which may
benefit from antidepressants and psychiatric/psycholo-
gical support.
Non-pharmacological aids
Once the diagnosis of IBS is established, an effective
physician–patient relationship is crucial for setting the
basis of a beneficial pharmacological approach. The
fundamentals of this relationship rely on the doctor as
Ôkey-playerÕ able to: (i) listen carefully to the patient and
estimate her/his understanding of the disease and
concerns; (ii) reassure her/him on the benign nature
(i.e. absence of alarm symptoms, normal physical
examination) of the illness; (iii) provide an explanation
of what IBS is and Ôwhat is wrong in the bellyÕ (i.e.
simple description of the potential mechanisms leading
to symptoms); and (iv) also provide a ÔroleÕ to the
patient, who should be actively involved in the treat-
ment.1–3 Evidence indicates that this approach leads to
a reduced number of health-care visits.57 Psychological
stressors, which are known to maintain and exacerbate
symptoms, should be sought and managed with sup-
portive advice or lifestyle modification. Dietary review,
with the recommendation to avoid caffeine and foods
that the patient recognizes as symptom-triggers, along
with a reduction of fat intake (known to markedly

2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20 (Suppl. 2), 10–22
CLINICAL FEATURES AND TREATMENT OF IBS 15
contribute to disturbed gut functions, such as sensation
and motor reflexes), is a reasonable approach in patients
with IBS. This simple strategy prevents an excessive
dietary restriction which may turn out to be potentially
dangerous for the patient. Notably, previous studies
indicated that restriction diets did not show any efficacy
in IBS.58 Specific dietary indications should be aimed at
reducing/eliminating excessive intake of fructose or
sorbitol in patients with diarrhoea; increasing ade-
quately dietary fibre in subjects with constipation; and,
finally, avoiding fermenting foods, i.e. beans, cabbage
and cauliflower, may be useful to patients with
predominant bloating.59
Fibre supplementation
An increased dietary fibre intake (i.e. cellulose, hemi-
cellulose pectins and lignins) is one of the most common
recommendations in constipation-predominant IBS.
Potentially, fibres may be beneficial in constipated IBS
patients because of their ability to reduce the transit
time of the entire alimentary tract (thus improving
intestinal peristalsis and therefore bowel movements)
and intestinal wall tension by decreasing intracolonic
pressure (this latter effect may contribute to visceral
pain relief).60 Nevertheless, published clinical trials (i.e.
wheat bran) showed that fibres were no better than
placebo in overall symptom relief, whereas symptoms
such as pain and distension worsened.61, 62 Bran is
usually not well tolerated by patients with IBS. More
recent meta-analysis data confirmed the concept that
fibre supplements are not superior to placebo, although
they could be effective for improving constipation.63 In
conclusion, fibre may be prescribed in constipated IBS,
although its use should be introduced gradually into the
dietary regimen.
Psychological treatment
The approaches to psychological treatment, including
cognitive behavioural therapy, psychotherapy, relaxa-
tion and hypnosis, may represent a valid therapeutic
option, at least in a sub-group of patients with IBS.
Potential candidates who benefit from psychological
measures are patients with pain and predominant
diarrhoea, psychiatric comorbidity and intermittent
pain aggravated by stressful events or anxiety.64 On
the other hand, patients with chronic abdominal pain
do not appear to be responsive to psychotherapy.64
16 R. DE GIORGIO et al.
Meta-analysis results indicate that psychological treat-
ment was better than standard therapy in eight studies,
whereas it did not prove efficacy in five studies.65
However, most of these studies have significant method-
ological shortcomings (i.e. lack of blinding, no control
with placebo and patients entering studies are those
referred to tertiary centres) and therefore the actual
efficacy of psychotherapy in IBS deserves further data.
Randomized trials showed hypnotherapy as one of the
most valuable nonpharmacological treatment in IBS,
with benefit lasting longer than 12 months.66 Further
results are awaited with this approach.
PHARMACOLOGICAL APPROACHES TO IBS
General considerations
The pharmacological treatment of IBS is aimed at
controlling the dominant symptom, i.e. constipation,
diarrhoea and pain/bloating.2, 59, 67 Physicians need to
inform patients that any prescribed compound should
be taken only during symptom recurrence rather than
chronically. Although a variety of drugs belonging to
different pharmacological classes (i.e. anticholinergic or
antispasmodics, opioid derivatives, laxatives, antidepres-
sants and serotonin receptor modulating agents) have
therapeutic potential for IBS, the efficacy of these
compounds turned out to be limited in clinical trials,
probably because of methodological inadequacies inclu-
ding undefined, unclear or questionable entry criteria,
limited number of patients, high dropout rate, short
duration of study and improper use of statistical
analysis.68 These biases have been considered by
investigators, and recent trials appear to be better
designed with appropriate patient selection/sub-groups,
exclusion of gut disorders overlapping with IBS and,
finally, definition of clear, clinically relevant therapeutic
Ôend-pointsÕ.
The following sections will briefly review the main
classes of drugs used in IBS treatment as emerged by
clinical trials and meta-analysis.
Antispasmodics
Currently available antispasmodics belong to three
major subclasses, namely anti-muscarinics (e.g. cimetr-
opium, prifinium), smooth muscle relaxants (e.g. tiropr-
amide, papaverine-like agents that directly inhibit
smooth muscle contractility by increasing cAMP levels

2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20 (Suppl. 2), 10–22
or interfering with the intracellular calcium pool) and
calcium channel blockers (e.g. nifedipine or pinaverium
that are especially l-type calcium channel blockers).69
The final effect of all these compounds is to evoke
smooth muscle relaxation and hence reduction of gut
wall tension. Antispasmodics are indicated in IBS as
these patients have increased postprandial colonic
motility, which often manifests with diarrhoea and
cramp-like abdominal pain.
The abundant literature on antispasmodic agents in
IBS has been pooled and evaluated in different valuable
meta-analysis. Critical issues emerging from meta-
analysis studies concerned the poor quality of most
trials (i.e. characterized by lack of appropriate blinding,
a significant number of dropouts at follow-up, short
duration and unclear end-points) and this has limited
our understanding on the actual efficacy of antispasmo-
dics. According to two recent meta-analyses, the overall
effect of these compounds is superior to placebo in
reliving global symptoms and pain (odds ratio for benefit
¼ 2.1), although they had no effect on diarrhoea and
constipation.63, 70 Antispasmodics, taken about 30 min
before meals, can be effective in controlling postprandial
cramps and diarrhoea and they should be recommended
for this specific therapeutic target. Although no formal
studies have assessed the efficacy of sublingual
antispasmodics, their use appears indicated especially
for as-needed regimens.2, 59 Possible side effects of
anticholinergic compounds, including dry mouth,
blurred vision and urinary hesitancy, may occur, but
they are generally mild and well tolerated by patients.
Peppermint oil has been proposed as a remedy for IBS,
although five placebo-controlled studies did not show
any clinical efficacy for this treatment.71
Antidiarrhoeals
This class of drugs includes opioid analogues, such as
loperamide, which are known to exert an inhibitory
effect on intestinal peristalsis and fluid secretion by
interacting with enteric neurones. Clinical trials showed
that loperamide significantly ameliorates diarrhoea,
urgency and faecal soiling,63 although it has no effect
on other IBS-related symptoms such as pain and
bloating.72 Compared to codeine and diphenoxylate,
loperamide does not cross the blood–brain barrier and
this feature makes it a relatively safe drug employed
extensively in general practice and clinical trials (at a
dose of 2–4 mg up to four times per day). None the less,

loperamide should not be used chronically to avoid
rebound constipation, and its best prescription is
as-needed medication during exacerbation of diarrhoea.
As mentioned previously, colestyramine can be also
used to treat IBS patients in whom bile salt malabsorp-
tion may contribute to or be directly responsible for
diarrhoea.73
Antidepressants
Tricyclic antidepressants (e.g. amitriptyline, desimipr-
amine, imipramine, doxepin) have been proposed in
the management of functional gastrointestinal syn-
dromes, especially IBS. The conceptual basis for their
use in IBS patients is centred on three main aspects,
including treatment of co-existing psychological abnor-
malities (depression, anxiety), reduction of central pain
perception of stimuli conveyed by sensory afferent
nerves pathways and ability to target gut sensorimotor
dysfunction.74 According to a recent meta-analysis,
tricyclic antidepressants proved to be helpful in IBS
patients with a number needed to treat of 3.2.75 In
these trials, tricyclic psychotropic agents were used at
lower dosages (10–25 mg for amitriptyline and 50 mg
for desimipramine) than those prescribed for treating
depression, thus implying that their effects are not
necessarily related to those responsible for the antide-
pressant effect. Tricyclic antidepressants are best
prescribed for periods of 2–3 months, rather than an
as-needed regimen, and typical candidates for this
treatment are patients with frequently recurrent or
chronic symptoms, especially pain and diarrhoea. The
only non-tricyclic compound tested so far in a clinical
trial is mianserine, which proved to be as effective as
tricyclic antidepressants.75 Because of their anticholin-
ergic effects, tricyclic antidepressants can evoke con-
stipation, but also dry mouth, somnolence and urinary
retention, which may hamper the use and efficacy of
these drugs.
Selective serotonin re-uptake inhibitors (SSRIs; e.g.
fluoxetine, paroxetine), which lack anticholinergic side
effects, may be a valuable alternative to tricyclic
antidepressants for the treatment of IBS and other
functional bowel disorders,76 and indeed SSRIs may
have a prokinetic effect. SSRIs are advisable for IBS
patients with psychiatric comorbidity (i.e. depression).
In a recent study by Creed et al.,77 the SSRI paroxetine
(20 mg per day) and psychotherapy (eight individual
sessions) were compared to routine care by a

2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20 (Suppl. 2), 10–22
CLINICAL FEATURES AND TREATMENT OF IBS 17
practitioner or a gastroenterologist in patients with
severe IBS. The results showed that both psychotherapy
(69% of patients) and paroxetine (50%) were better
than routine management in improving the physical
aspects of health-related quality of life in IBS and that
the beneficial effect of both psychotherapy and paroxe-
tine was less expensive than routinary treatment. This
study indicated that paroxetine, as well as psychother-
apy, can be a cost–effective treatment for patients with
severe IBS. Nevertheless, further studies with SSRI are
needed to establish their use in IBS.
SSRIs
The rationale for the use of serotonin (5-hydroxytrip-
tamine, 5-HT) receptor agonists and antagonists in IBS
is based on the evidence that this biogenic amine, which
is released by enteroendocrine (i.e. enterochromaffin-
like), enteric neurones and other non-neuronal sources,
possesses a wide array of established motor effects on
the gut and can lead to hyperalgesia in several
experimental models.78 5-HT modulates its effects on
the gastrointestinal tract through binding with several
receptor subtypes termed 5-HT1, 5HT2, 5-HT3, 5-HT4,
and 5-HT7 (for reviews, see 79, 80). For the purpose of
the present paper we will focus on 5-HT3 and 5-HT4
receptors because they are the most extensively studied
in gastroenterology and for their relevance to IBS
treatment.
Alosetron is a 5-HT3 receptor antagonist approved by
the Food and Drug Administration (FDA) for the
treatment of diarrhoea-predominant IBS in female
patients resistant to conventional anti-diarrhoic agents.
This drug affects extrinsic afferent sensory neurones
projecting to the gut and intrinsic enteric neuro-
neuronal reflexes.81 Thus, the final effect induced by
alosetron is a delayed gut transit time and an increase
in visceral perception threshold, which makes this
compound valuable for treating diarrhoea-predominant
IBS.82
Six major multicentre, randomized, placebo-controlled
studies83–88 were included in a recent meta-analysis
comprising 1762 patients treated with alosetron vs.
1356 with placebo.89 Most of the enrolled patients
were female (93%) with diarrhoea-predominant IBS
(75%). The pooled adjusted odds ratio for the end-point
adequate relief of pain or global symptom improvement
was 1.81 (95% CI 1.57–2.10), with an average
number of seven patients needed to treat. The effective
18 R. DE GIORGIO et al.
dose of 1 mg b.i.d. of alosetron (12 weeks in each
study) successfully relieved pain, discomfort and diar-
rhoea in female IBS patients. No beneficial effect was
reported in male patients. The safety profile indicated
that the most commonly experienced symptom was
constipation (one of four patients), whereas the
prevalence of presumed ischaemic colitis in the alose-
tron-treated group was 0.1%. From these meta-analy-
sis data it can be concluded that the 5-HT3 antagonist
alosetron is advisable in selected female patients with
severe pain and diarrhoea refractory to conventional
therapies. A special consideration should be reserved
for the study of Jones et al.84 (based on 623 non-
constipated females with IBS) in which alosetron 1 mg
b.i.d. was more effective than the antispasmodic
mebeverine 135 mg t.d.s.
Cilansetron is another 5-HT3 antagonist currently
undergoing clinical trials and only little information is
currently available in the published literature.90
5-HT4 receptor agonists are known to evoke a potent
prokinetic effect throughout the gastrointestinal tract.
The most extensively studied 5-HT4 receptor agonists
include cisapride, tegaserod and prucalopride. Cisapride,
however, has been withdrawn from the market because
of its well-known potential to evoke ventricular
arrhythmias and prolongation of the QT interval
through blockade of HERG K+ channels.91 In contrast,
second-generation 5-HT4 receptor agonists, i.e. tegas-
erod, mosapride and prucalopride, seem to be devoid of
anti-arrhythmic properties and at least two of them
(tegaserod, prucalopride) may be more active at the
colonic level than cisapride.92 Among 5-HT4 receptor
agonists, tegaserod, prucalopride and mosapride have
undergone clinical trials. Tegaserod is approved by the
FDA (not yet in the European Union) for the treatment
of constipation-predominant IBS in women. A meta-
analysis of seven studies in 4040 female IBS patients
with predominant constipation showed that tegaserod
was superior to placebo at the dosages of 12 mg
(relative risk of being a responder of 1.19; 95% CI
1.09–1.29) and 4 mg (relative risk of being a responder
of 1.15; 95% CI 1.02–1.31), with a number of 14 and
20 needed to treat, respectively.93 Thus, tegaserod
proved to be useful in constipation-predominant IBS,
although further studies are awaited.
Prucalopride is being investigated for a range of
conditions including constipation-predominant IBS
and slow transit constipation with higher efficacy
compared to placebo.

2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20 (Suppl. 2), 10–22
Antibiotics and probiotics
The rationale for antibiotics in IBS arises from data
showing that functional symptoms may be related to an
underlying small bowel bacterial overgrowth.94 Fur-
thermore, Pimentel et al. investigated 111 patients with
IBS and found that most of them (84%) had a small
bowel overgrowth as identified by positive lactulose
breath test. Patients were then randomized in a double-
blind fashion for the non-absorbable antibiotic neomy-
cin (500 mg per day for 10 days) or placebo for 1 week.
Treatment with neomycin was significantly superior to
placebo in improving IBS symptoms (35% of patients vs.
11.4%, respectively).95 However, because of the short
follow-up (7 days), the absence of information concern-
ing the duration of the beneficial effect evoked by
neomycin, and methodological drawbacks intrinsic to
the lactulose breath test (low sensitivity, 16.7% and
specificity, 70%),96 the therapeutic value of neomycin
in IBS remains questionable. On the other hand,
Di Stefano et al.97 assessed the efficacy of rifaximin, a
rifamycin derivative, on intestinal gas production and
related intestinal symptoms and found that this non-
absorbable antibiotic significantly reduced both H2
excretion and overall severity of symptoms in 34
functional bowel disease patients. Confirmatory studies
are now awaited.
In addition to antibiotics, probiotics have also been
tested to treat changes of intestinal microflora, a
potential pathogenetic mechanism contributing to IBS
symptoms. The probiotics used included either single
strains of Lactobacilli or a mixture of Bifidobacteria, and
Lactobacilli and one strain of Streptococcus (namely,
VSL#3). However, randomized controlled trials yielded
controversial results,98–103 with four of six studies
showing beneficial effects. Probiotic-related improve-
ment included daily symptom scores98, 99 or single
symptoms such as abdominal pain,99, 100 flatulence100
and bloating.103 In conclusion, probiotics may be useful
in IBS; however, conclusive evidence of their efficacy is
still needed.
FUTURE DRUGS
An impressive knowledge on molecular biology, phys-
iology and pharmacology of the gastrointestinal tract is
in the process of being translated into a clinical
perspective. This advancement is expected to foster the
development of novel drugs potentially useful for the

treatment of IBS patients. A long list of products are in
the pipeline, including cholecystokinin 1 receptor
antagonists, tachykinin-1, -2 and -3 receptor antago-
nists, opiate receptor j-agonists and l-antagonists,
a2-adrenergic agonists, muscarinic-3 receptor antago-
nists, cortocotrophin-releasing factor receptor type 1,
cannabinoid receptor 1, somatostatin analogues, chlor-
ide channel openers and others, are currently under
investigation (for review see,67,104). Although these
agents have a variety of effects, they mainly modulate
gut sensorimotor function.
CONCLUSIONS
IBS has a tremendous impact on society, being a
major cause of morbidity worlwide. Over the years,
experts have identified symptom-based criteria to ease
the diagnosis of IBS and avoid the risk of missing
organic disease. Thus, Manning, Rome I and Rome II
criteria have been established and their use, together
with an accurate exclusion of alarm symptoms, is
currently considered the best approach for diagnosing
IBS patients. The pathophysiology of the symptoms
related to IBS remains poorly understood and this has
limited the development of targeted therapeutic agents.
Hence, management is aimed at controlling the
predominant symptom (i.e. diarrhoea, constipation,
alternating bowel and pain/bloating) with non-phar-
macological and pharmacological measures. Sympto-
matic treatment is based on cautionary increase in
fibre intake for patients with predominant constipa-
tion, on-demand opioid agents for diarrhoea and,
finally, low-dose antidepressants, antispasmodics and
other non-conventional therapeutic options such as
psychotherapy, for management of pain. Serotonin
receptor modulators, especially 5-HT3 antagonists and
5-HT4 agonists, represent new therapeutic options for
IBS. A variety of other new drugs are also currently
under investigation. It is likely that the better
elucidation of the mechanisms underlying IBS will
bring the drugs currently under investigational assess-
ment to the clinical foreground. Whether innovative
techniques, i.e. pharmacogenomic, or clinical strat-
egies, i.e. identification of biological markers to sub-
group patients, will improve the management of IBS is
a future perspective. The combination of these approa-
ches will probably pave the way to a better manage-
ment of patients with functional bowel disorders,
including IBS.

2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20 (Suppl. 2), 10–22
CLINICAL FEATURES AND TREATMENT OF IBS 19
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