Download Options for patients with irritable bowel syndrome

Neurogastroenterol Motil (2004) 16, 701–711
doi: 10.1111/j.1365-2982.2004.00550.x
Options for patients with irritable bowel syndrome:
contrasting traditional and novel serotonergic therapies
J. F. JOHANSON
Department of Medicine, University of Illinois College of Medicine, Rockford, IL, USA
pation and diarrhoea [IBS-A]).4 Well-established
diagnostic criteria are used to identify patients for
clinical trials,4 but, in practice, a global definition of
abdominal discomfort associated with altered bowel
habits is more appropriate and clinically useful.1
The economic burden inflicted by IBS on both
society and the health care system is tremendous,
compared with that imposed by asthma, hypertension
and stroke.5,6 The chronic and episodic nature of IBS
symptoms accounts for up to 3.7 million doctor visits7
and more than two million prescriptions annually.8
Direct (e.g. doctor visits, outpatient care, diagnostic
tests) and indirect (e.g. work absenteeism and
decreased productivity) costs associated with IBS are
estimated at $30 billion (adjusted for 1999 and 2000
dollars, respectively) per year.7,8
Symptoms experienced by persons with IBS significantly impact quality-of-life.9 Studies using general or
disease-specific quality-of-life instruments have consistently shown that the health status of those with IBS
is poorer than that of the general population.10–12
Quality-of-life scores of IBS patients are directly correlated with their responses to therapy,12 and management of multiple IBS symptoms is important for
overall improvement in patient well-being.
Until recently, treatment options for IBS have been
limited by poor efficacy, poorly tolerated adverse
effects or both. Research into the pathophysiology of
IBS, which has uncovered the potential role of serotonin (5-HT), has led to the development of two
serotonergic agents for the treatment of patients with
IBS. This paper reviews the traditional single symptom-based treatment options for IBS and the novel
serotonergic agents that target multiple IBS symptoms
through pharmacological action in serotonin receptors.
Abstract This article reviews the efficacy and tolerability of traditional therapies for irritable bowel syndrome (IBS) and concludes that they are limited by
both poor efficacy and adverse effects. Serotonin, a
neurotransmitter found mainly in the gut, appears to
represent a link in IBS pathophysiological processes –
altered gut motility, abnormal intestinal secretion and
visceral hypersensitivity. Recently, available treatments for IBS have targeted serotonin receptors that
are involved in motor, sensory and secretory functions
of the gut. Serotonergic agents, such as alosetron
(a 5-HT3 receptor antagonist) and tegaserod (a selective
5-HT4 receptor partial agonist), provide global relief of
the multiple symptoms of IBS with diarrhoea and IBS
with constipation, respectively, and represent important additions to the IBS treatment armamentarium.
Keywords alosetron, constipation, irritable bowel
syndrome, serotonin, tegaserod, treatment.
OVERVIEW
Irritable bowel syndrome (IBS) is one of the most common gastrointestinal (GI) disorders, with a prevalence of
up to 20% in the United States.1 It is the most common
diagnosis made by gastroenterologists (28% of total) and
accounts for 12% of diagnoses made by primary care
doctors.2,3 In North America, IBS affects twice as many
women as men, and patients are generally between the
ages of 30 and 50 years when they first consult a doctor.2
Irritable bowel syndrome is considered a functional
bowel disorder characterized by abdominal discomfort
or pain associated with altered bowel function (constipation [IBS-C], diarrhoea [IBS-D] or alternating constiAddress for correspondence
John F. Johanson MSc, MD, Rockford Gastroenterology
Associates, 401 Roxbury Road, Rockford, IL 61107, USA.
Tel: 815-397-7340; fax: 815-397-2156;
e-mail: [email protected]
Received: 30 September 2003
Accepted for publication: 1 April 2004
2004 Blackwell Publishing Ltd
TRADITIONAL IBS THERAPIES
Despite their limitations, many patients continue
to rely on traditional pharmacological and non-pharmacological treatments that target individual IBS
701
J. F. Johanson
Neurogastroenterology and Motility
examined the efficacy of these compounds for relieving
the pain and discomfort associated with IBS.16–18 The
two meta-analyses found that five16 and six17 smooth
muscle relaxants have proven clinical efficacy in IBS
without significant adverse reactions. In the systematic review, 13 studies, including seven high-quality
trials, found these smooth muscle relaxants to be
effective for abdominal pain;18 significant improvement in constipation was reported in two of the highquality trials. However, these agents are not available
in the United States.
Although dicyclomine and hyoscyamine are available in the United States for the treatment of IBS
patients, clinical trials examining these agents have
had numerous methodological flaws. Moreover, they
have demonstrated inconsistent efficacy, making evidence-based assessment of efficacy difficult.1,18 Of the
three trials evaluating dicyclomine, only one (40 mg
four times daily) demonstrated significant symptom
improvement compared with placebo. At this high
dose, however, close to 70% of patients experienced
adverse effects.20 In their systematic review of all
evidence available for these agents, the ACG FGID
Task Force concluded that the data are insufficient to
allow a meaningful evaluation of the effectiveness of
these agents.1
Tricyclic antidepressants have been used in low doses
(i.e. lower than those used for depression) to alleviate the
abdominal pain or discomfort associated with IBS.19,21
The mechanistic evidence that they alter motor or
sensory function is limited and their effects may reflect a
central action. A meta-analysis of eight clinical trials in
which five TCAs were used to treat IBS patients showed
these agents to be effective in reducing pain-related
symptoms. However, these trials were not adequately
blinded, included small numbers of patients and were of
relatively short duration (averaging only 46 patients and
6 weeks). In addition, many were crossover trials, which
are suboptimal in that the effects of the drug may not be
completely washed out before the patient is Ôcrossed
overÕ to the control.13
A systematic review of the six published clinical
trials with TCAs indicated that, in general, these trials
were not sufficiently powered for statistically valid
conclusions to be drawn, and they suffered from
suboptimal methodologies (e.g. not using Rome criteria
for enrolling patients, short durations of therapy and
high dropout rates); thus, the validity of their results is
in question. Overall, the data are inadequate to
conclude whether TCAs are more effective than
placebo in providing global relief of IBS symptoms.1 A
recent trial of desipramine did not show benefit over
placebo in the intent-to-treat analysis.22
symptoms (Table 1). Traditional IBS management
approaches often rely on combinations of dietary
changes, antispasmodics, antidiarrhoeals, laxatives,
antidepressants and analgesics. However, the efficacy
(Table 2),1,13–18 safety and tolerability of these treatments have not been examined in well-controlled
clinical trials. The American College of Gastroenterology (ACG) Functional Gastrointestinal Disorders
(FGID) Task Force, performed a systematic review of
the efficacy and safety of traditional therapies and
found none of these agents demonstrated level I
evidence (i.e. randomized, controlled trials with
P-values <0.05, adequate sample sizes and appropriate
methodology) to support their use in the treatment of
IBS.1 It is important to note that the levels of evidence
used by the Task Force were defined to ensure that
level I randomized, controlled trials had few limitations, thereby minimizing type I errors, and were
adequately powered to minimize type II errors. Thus, if
a trial did show a significant difference between
treatment and placebo, it is unlikely that this finding
was due to biased study design. Moreover, if the trial
did not show a significant difference between treatment and placebo, it would be unlikely that this
finding was due to an inadequate sample size of
patients. In addition, few studies of traditional therapies measure global relief of symptoms as an efficacy
variable. Global symptom relief was identified by the
Rome Committee to be the primary outcome measure
incorporating the key symptoms of IBS, allowing the
patient to integrate the contributions of multiple
symptoms into a single global clinical rating. To date,
there has been no compelling evidence that combining
multiple modalities is effective in treating patients
with IBS. Furthermore, the adverse effects of some
treatments for IBS may outweigh their potential benefits.
Antispasmodics and antidepressants
Traditional medications evaluated in published clinical trials for the treatment of IBS-related abdominal
pain or discomfort include antispasmodics and tricyclic antidepressants (TCAs). Some antispasmodics (e.g.
cimetropium bromide) directly relax intestinal smooth
muscle; others (e.g. dicyclomine) act indirectly via
anticholinergic effects.19
Smooth muscle relaxants have been evaluated in a
number of double-blind, randomized, placebo-controlled clinical trials with IBS patients. Three systematic reviews – two meta-analyses of 26 and 23
randomized, controlled trials, respectively, and a systematic review of 16 randomized, controlled trials –
702
2004 Blackwell Publishing Ltd
2004 Blackwell Publishing Ltd
Abdominal pain/
discomfort
Traditional
Antispasmodics
Dicyclomine
Hyoscyamine
703
Constipation (stool
frequency, stool
consistency)
1. Urgency
2. Diarrhoea
Serotonergic agonists/antagonists
Tegaserod
1. Abdominal pain/
discomfort
2. Constipation
3. Bloating
Bulking agents/fibre
Psyllium Calcium
polycarbophil
Wheat bran
Ispaghula/poloxamer
Corn fibre
Wheat fibre
Ispaghula husk
Antidiarrhoeal
Loperamide
Tricyclic antidepressants
Desipramine
Abdominal pain/
Trimipramine
discomfort
Doxepin
Amitriptyline
Targeted
symptom(s)
Therapy
1. Global IBS symptoms
2. Individual symptoms
(e.g. abdominal pain/
discomfort, bloating,
stool frequency,
satisfaction with
bowel habits)
1. Global IBS
symptomsà
2. GI symptoms
(e.g. abdominal pain,
bowel movements)
1. SGA
2. Abdominal pain/
distension
3. Diarrhoea
4. Urgency
GI symptoms (e.g.
abdominal pain,
vomiting, mucus
in stool, belching)
1. Individual IBS
symptoms
2. Symptom
improvement
3. Global IBS
4. symptoms
Study
assessment(s)
Table 1 Traditional and recently approved IBS pharmacotherapies
1. Acceptable
duration
(12 weeks)
2. Large samples
(520–1519)
3. Optimal study
design (12–13)
1. Short duration (3–12
weeks, most
<8 weeks)
2. Small samples
(most <30)
3. Suboptimal study
design (5–9)
1. Short duration
(3–5 weeks)
2. Small samples
(30–90)
3. Suboptimal study
design (5–7)
1. Short duration
(4–8 weeks)
2. Small samples
(most £31)
3. Suboptimal study
design (quality
score: 5–6)
1. Short duration
(£8 weeks)
2. Small samples (29–96)
3. Suboptimal study
design (quality
score : 5–7)
4. Inconsistent
effectiveness
Study
assessment
Grade A recommendation:
more effective than
placebo in providing
global relief of IBS
symptoms in female
patients with IBS-C
Grade B recommendation:
not more effective
than placebo in providing
global relief of IBS symptoms
Grade B recommendation:
improves diarrhoea;
not more effective than
placebo in providing global
relief of IBS symptoms
Grade B recommendation:
not more effective than
placebo in providing
global relief of IBS
symptoms. TCAs
improve abdominal
pain in IBS patients
Grade B recommendation:
insufficient data for
recommendation about
effectiveness of
antispasmodic
agents available in
the United States
Evidence-based
classification*1
May cause mild,
transient diarrhoea
Limited adverse effect data,
precluding evidence-based
conclusions
Increased fibre intake
may worsen bloating
and abdominal pain/
discomfort in patients
with IBS
Limited adverse effects data,
precluding evidencebased conclusions
Constipation and fatigue
have been documented
May cause anticholinergic
adverse effects at
higher doses
Should be used
cautiously in patients
with constipation
Evidence-based assessment
of adverse effects1
Volume 16, Number 6, December 2004
Efficacy and tolerability of IBS therapies
Serious, sometimes fatal,
constipation-associated
complications
(e.g. ischaemic colitis)
Neurogastroenterology and Motility
The most common adverse effects among patients
using low-dose TCAs for IBS-related abdominal pain
include fatigue, dry mouth, sedation, weight gain,
difficulty with urination and constipation.2 TCAs
should, therefore, be used with caution in IBS-C patients
and may be most beneficial for patients with IBS-D.19
Other limitations of these agents include a possible
6-week lag before therapeutic effects are seen 23 and the
requirement of continual use for maintenance of
effect.19
IBS, irritable bowel syndrome; IBS-C, irritable bowel syndrome with constipation; IBS-D, irritable bowel syndrome with diarrhoea; SGA, Subject’s Global Assessment; TCA,
tricyclic antidepressant. *Evidence-based recommendations: Grade A – evidence based on a minimum of two randomized, controlled trials with P < 0.05, adequate sample
size, and appropriate methodology. Grade B – evidence based on randomized, controlled trials with P > 0.05 and/or inadequate sample size and/or inappropriate methodology. Range 0–13. àDefinition of global symptoms was poorly defined in many studies.
Alosetron
1. Abdominal pain/
discomfort
2. Fecal urgency
3. Diarrhoea
1. Global IBS
symptoms
2. Individual symptoms
(e.g. abdominal pain,
fecal urgency, stool
consistency, stool
frequency,
satisfaction with
bowel habits)
1. Acceptable duration
(12 weeks)
2. Large samples
(370–801)
3. Optimal study
design (12)
Grade A recommendation:
more effective than
placebo in providing
global relief of
IBS symptoms
in female patients
with IBS-D
May cause
constipation
J. F. Johanson
Antidiarrhoeals
The antidiarrhoeal agent most commonly used for IBSD patients is loperamide, which works by binding to
opiate receptors.19 Loperamide improves diarrhoea,
urgency, and fecal soiling in IBS-D patients by slowing
intestinal transit, enhancing absorption of intestinal
water and ions, and strengthening the resting tone of
the anal sphincter.19,21,24
An evidence-based review of loperamide indicated
that suboptimal trial design has limited assessment of
its efficacy.1 Although loperamide appears to be an
effective treatment for diarrhoea, it is not more effective than placebo in treating IBS-associated abdominal
pain or in providing global relief of IBS symptoms.1
Fibre and laxatives
Patients with IBS-C are often advised to increase
dietary fibre intake or to take commercially available
fibre products such as psyllium or calcium polycarbophil.24 Fibre has been shown to decrease whole-gut
transit time in persons with mild transit delays,
thereby alleviating constipation.19 However, in most
instances of moderate-to-severe constipation, fibre
provides little therapeutic benefit.
Although fibre can be effective in alleviating constipation, its value for IBS patients remains unclear.
Randomized crossover trials of fibre use in IBS patients
did not show differences in symptom improvement
between active treatment and control groups.25,26 The
benefits of fibre for constipation have been achieved
mainly with high doses (20–30 g day)1), which are
associated with an increased incidence of adverse
effects.19 Moreover, fibre frequently aggravates the
bloating, distension and abdominal pain associated
with IBS.19 In fact, a recent systematic review of 17
studies concluded that the benefits of fibre in the
treatment of global IBS symptoms are marginal and
fibre has no effect on the relief of abdominal pain.27
Thus, the benefit of fibre in IBS patients is dubious –
fibre and bulking agents do not appear to be more
704
2004 Blackwell Publishing Ltd
Volume 16, Number 6, December 2004
Efficacy and tolerability of IBS therapies
Table 2 Efficacy of traditional therapies for IBS
Therapy
No. of trials
NNT*
Agents tested
Outcome measurements
Antispasmodics
26 trials16
23 trials17
16 trials18
3.7
5.6
1.6–6.7
Global improvement,
individual symptom
improvement (abdominal
pain/discomfort, abdominal
distension, constipation, transit)
Antidepressants
11 trials13
3.2 (95% CI,
2.1–6.5)
Antidiarrhoeal
agents
One trial18
3.6
Cimetropium
Mebeverine
Dicyclomine
Trimebutine
Rociverine
Diltiazem
Pinaverium
Otilonium
Pirenzepine
Pirifinium
Amitriptyline
Cloipramine
Desipramine
Doxepin
Trimipramine
Mianserin
Loperamide
Bulking
agents
Three trials18
2.2–3.5
Tegaserod
Four trials
(phase III)15
10 (95% CI,
7.1–20)
Alosetron
Six trials14
7 (95% CI,
5.7–9.4)
Psyllium
Coarse bran
Concentrated fibre
Corn fibre
Polycarbophil
Ispaghula husk
6 mg b.i.d.
tegaserod
Alosetron
Global improvement, individual
symptom improvement (abdominal
pain/discomfort, diarrhoea/constipation,
ability to work)
Global improvement (stool frequency,
stool consistency, abdominal
pain/discomfort), diarrhoea improvement
Global improvement, individual symptom
improvement (stool passage, satisfaction
with bowel movements, constipation,
stool frequency, abdominal pain, bloating)
Global IBS symptom improvement
(abdominal pain/discomfort, bloating,
constipation), individual symptom
improvement (abdominal pain/discomfort,
bloating, stool frequency)
Global IBS symptom improvement
(abdominal pain, diarrhoea, urgency),
individual symptom improvement
*Global assessment.
effective than placebo in providing global relief of IBS
symptoms.1
Laxatives prescribed for IBS-C patients include
osmotic laxatives (e.g. polyethylene glycol, lactulose
and magnesium-containing products), stimulant laxatives (e.g. bisacodyl or cascara) and emollients (e.g.
docusate). With the exception of polyethylene glycol,
the efficacy of laxatives has not been established in
randomized, controlled trials in the United States,
although their effectiveness in relieving constipation is
generally well accepted. However, some medications
in this class (e.g. lactulose) can worsen symptoms
common to IBS, such as bloating and cramping, and
excessive use can lead to diarrhoea and dehydration.
Long-term laxative use, especially of stimulant laxatives, generally is not recommended.19 Finally,
laxatives do not treat IBS-associated abdominal pain
or discomfort.19
2004 Blackwell Publishing Ltd
Behavioural therapy
Increasing evidence indicates that behavioural therapy
may benefit IBS patients, particularly those with
co-morbid psychiatric conditions (e.g. depression or
severe anxiety) – estimated to be approximately 18% of
IBS patients in the community.28 In one study,
23 patients with IBS were assessed before and after
12 weeks of hypnotherapy focused on the GI system;
the results suggest that hypnotherapy improves abnormal sensory perception in IBS patients, while leaving
normal sensation unchanged.29 The benefits of psychotherapy were evaluated by the FGID Task Force,
whose members examined clinical trials that compared
behavioural treatments (e.g. psychotherapy, hypnotherapy and relaxation) with placebo.1 Most clinical
trials published to date suggest that behavioural therapy is more effective than placebo in alleviating
705
J. F. Johanson
Neurogastroenterology and Motility
individual IBS symptoms.1 However, numerous limitations in study design make difficult the determination of efficacy of behavioural therapy in the
treatment of IBS patients. A recently reported, well
designed trial of cognitive behavioural therapy (CBT) vs
education demonstrated that CBT was efficacious.22
PATHOPHYSIOLOGICAL BASIS FOR
SEROTONERGIC AGENTS IN IRRITABLE
BOWEL SYNDROME
A number of discoveries over the past several years
have shed new light on the pathophysiology of IBS and
have focused attention on processes that regulate
bowel sensorimotor responses and visceral pain perception. A unifying theory is that IBS involves dysregulation of the brain–gut axis. The enteric nervous
system (ENS) operates semi autonomously in controlling intrinsic bowel functions (both motility and
secretion) and is modified centrally by the central
nervous system (CNS), which supplies extrinsic sympathetic and parasympathetic innervation to the GI
tract via the autonomic nervous system.31,32 Disruptions along the brain–gut communication path likely
cause the various symptoms of IBS, such as altered gut
motility, abnormal intestinal secretion and visceral
hypersensitivity.33,34
The neurotransmitter serotonin is a common link
among these three processes – GI motility (peristaltic
reflex), secretion and perception of visceral pain.
Serotonin is an important signalling molecule in the
ENS,31 and the GI tract is the largest source of
serotonin in mammals; 95% is synthesized, stored
and secreted in the gut.33,34 Serotonin acts on several
receptors, including the 5-HT1P, 5-HT3and 5-HT4
receptor subtypes localized in the gut, mediating
numerous GI tract functions,33,34 such as stimulation
of secretory and peristaltic reflexes (via intrinsic sensory neurones) and modulation of visceral sensation
(via extrinsic sensory neurones and vagal spinal afferent neurones).34 Its diverse activity in modulating
these processes is believed to be pivotal in the
normalization of GI function, making 5-HT receptors
and their associated neuronal pathways important
targets for IBS-specific drugs.
WHAT DO PATIENTS THINK OF
TRADITIONAL IBS THERAPIES
It is not surprising that IBS patients are often dissatisfied with the efficacy and tolerability of traditional
treatment options that address single symptoms. In a
survey conducted by the International Foundation for
Functional Gastrointestinal Disorders, 350 IBS patients
(chosen randomly from a database of IBS patients in the
United States) responded to questions regarding their
IBS symptoms, the impact of these symptoms on their
lifestyles and their satisfaction with treatment.9
Eighty-eight per cent of the respondents reported using
prescription medications (antispasmodics and antidepressants being among the most common) at some
point; 78 and 64% acknowledged using over-the-counter laxatives or antidiarrhoeals, respectively.
Less than half (45%) of patients surveyed believed
their prescription IBS medications were effective, and
40% reported being dissatisfied with their current IBS
medications or remedies. Dissatisfaction was related
primarily to lack of effectiveness, although adverse
effects, likely resulting from long-term use and the
interaction of multiple medications, also contributed
to patient dissatisfaction. Of those persons taking prescription medications, 62% reported adverse effects.9
The results of a recent study reviewing utilization
trends of GI medications by IBS patients support the
hypothesis that patient dissatisfaction leads to the
use of multiple medications, switching of medications, and repeated doctor visits. In this study, 5960
outpatient service claims records from 1995 to 1997
for the 12 months following an initial diagnosis of IBS
were analysed.30 The results indicated that 53% of
patients used prescription GI medications continuously throughout the year following IBS diagnosis –
36% used monotherapy and 64% used polytherapy.
Among IBS patients using multiple IBS therapies,
22% switched from one drug to another, and 42%
augmented the originally prescribed drug with another GI medication from a different drug class. In
the year after the index diagnosis, expenditures
related to outpatient services and pharmaceuticals
were higher for polytherapy users who switched and
augmented
treatment
than
for
monotherapy
patients.30
GI motility and secretion
Irritable bowel syndrome patients have demonstrated
increased intestinal motility in response to both
intrinsic (e.g. food intake) and environmental factors
(e.g. stress).35 In general, 5-HT3 receptors are associated
with excitation in the GI tract, resulting in increased
motility, secretion and sensation.33 5-HT3 antagonists,
therefore, slow colonic transit and increase fluid
absorption, thus improving symptoms of IBS-D.
5-HT4 receptors mediate both excitatory or inhibitory
effects on gut function.33,34 In vitro studies indicate
that 5-HT4 receptors are essential mediators of the
peristaltic reflex and synthetic 5-HT4 receptor agonists
706
2004 Blackwell Publishing Ltd
Volume 16, Number 6, December 2004
Efficacy and tolerability of IBS therapies
have been found to increase gut motility.36 Although
the mechanism underlying the development of IBS is
unknown, one hypothesis is that patients with
different bowel symptoms differ in colonic 5-HT
concentration 37 and/or perhaps in 5-HT receptor
composition.38,39
Intestinal secretion, which is also mediated by
5-HT3 and 5-HT4 receptors, can be modulated by synthetic agonists or antagonists.33 Antagonism of 5-HT3
receptors leads to decreased fluid secretion and 5-HT4
receptor agonism results in increased intestinal fluid
and electrolyte secretion.33,40,41
Alosetron
Alosetron hydrochloride is currently indicated for use
in women with severe diarrhoea-predominant IBS in
whom traditional therapy has failed. Initial trials
demonstrated that alosetron decreased gut transit in
non-IBS and IBS subjects,50 increased fluid absorption
by normal human intestine43 and reduced pain perception upon rectal distension in IBS patients.51 These
pharmacodynamic effects are believed to be the reason
for alosetron’s effective alleviation of multiple IBS
symptoms, including abdominal pain and discomfort,
diarrhoea, and urgency.
Two large, randomized, placebo-controlled, clinical
trials comprising 1273 women assessed the efficacy of
alosetron 1 mg twice daily for 12 weeks among
patients with diarrhoea-predominant IBS.52,53 A comparator trial of 623 women with IBS assessed alosetron
1 mg twice daily vs the antispasmodic mebeverine.54
Significantly more subjects treated with alosetron
reported adequate relief of abdominal pain and discomfort for all 3 months of treatment compared with those
receiving placebo/comparator treatment.52–54 Alosetron also improved stool consistency and decreased
stool frequency and bowel urgency compared with
placebo. However, in the single study that examined
the effects of alosetron on bloating, no statistically
significant difference was observed between the two
groups during the 12-week treatment course.53 Constipation was the most common adverse effect reported
in these trials 52–54 and may be expected to occur in up
to 25% of patients treated continually. Approximately
10% of patients taking alosetron withdrew prematurely because of constipation-related adverse events.53
Alosetron 1 mg twice daily was also assessed in a
placebo-controlled clinical trial of 801 women with
severe diarrhoea-predominant IBS – enrolled patients
experienced symptoms of urgency on at least 50% of
days at study entry.55 Compared with placebo, subjects
taking alosetron had a significantly greater proportion
of days with satisfactory control of urgency, as well as
greater global improvement in IBS symptoms. Alosetron-treated subjects also showed improvement in
bowel symptoms compared with those receiving placebo.
The most common adverse effects, which were
reported in at least 1% of IBS patients taking alosetron
in clinical trials, included constipation, abdominal
discomfort/pain and nausea. In patients receiving alosetron 1 mg twice daily, constipation was generally mildly
to moderately severe and transient (typically occurring
as a single episode during the first month of treatment);
it resolved on its own or with an interruption in
Visceral hypersensitivity
Irritable bowel syndrome patients also appear to differ
from controls in the way the CNS processes colorectal
pain stimulation.42,43 It is interesting to note that this
hypersensitivity to distension is not restricted to the
distal bowel – IBS patients experience hypersensitivity
to distension throughout the entire GI tract. Therefore,
abnormal neurosensory function may occur in both the
CNS and the peripheral nervous system in IBS
patients.30 Alosetron, a 5HT3 antagonist, changes the
pattern of blood flow during noxious rectal distension
activating centres that downregulate pain sensation.44,45
Serotonin appears to be involved in modulating
visceral hypersensitivity in IBS patients. Results from
animal studies suggest that 5-HT3 receptors mediate
visceral nocioceptive signals via spinal vagal afferent
neurones.46 Painful colonic distension from visceral
stimuli leads to increased CNS activation that is
inhibited in a dose-dependent manner by 5-HT3 receptor antagonism.46
Similarly, 5-HT4 receptors are believed to mediate
visceral sensation and perception in experimental
animals. The firing rate of rectal spinal afferents
decreases in response to slow pressure distension when
a 5-HT4 receptor agonist is applied.47 Moreover, 5-HT4
receptor agonism inhibits the visceral pain responses
and afferent signalling induced by rectal distension.48
Data from human studies also suggest they alter reflex
sensory responses.49
SEROTONERGIC AGENTS: ALOSETRON
AND TEGASEROD
The preclinical studies described previously led to the
clinical development and approval of two medications
for the treatment of IBS: alosetron, a 5-HT3 receptor
antagonist, and tegaserod, a selective 5-HT4 receptor
agonist.
2004 Blackwell Publishing Ltd
707
J. F. Johanson
Neurogastroenterology and Motility
well as in the single symptoms of abdominal pain/
discomfort, number of bowel movements and stool
consistency.62,63 Significant improvement in daily
bloating scores was also observed in two of these
trials,61,62 and one study showed that tegaserod-treated
patients experienced a significant reduction in the
number of days with straining, compared with controls.61 More recently, the efficacy of tegaserod was
evaluated in randomized controlled trials among
Asian-Pacific and Nordic populations with IBS whose
primary bowel habits were not diarrhoea. In both
studies, patients received either tegaserod 6 mg b.i.d. or
placebo for 12 weeks. The results showed that the
mean proportion of patients with overall satisfactory
relief was statistically significantly greater in the
tegaserod group compared with placebo for the majority of the study period.64,65 Reductions in the number
of days with at least moderate abdominal pain/discomfort, bloating, no bowel movements and hard/lumpy
stools were also greater in the tegaserod group.64
Tegaserod was well tolerated, with diarrhoea and
headache being the most frequently reported adverse
effects.40,61,62 In the 12-week trials, diarrhoea occurred
in 9 and 4% of patients treated with tegaserod and
placebo, respectively. The diarrhoea was typically mild
and transient, causing less than 2% of subjects to
withdraw prematurely. Headaches occurred more frequently among those taking tegaserod (15% vs 12%),
but the incidence of migraine headaches was similar
between the two treatment groups.
The long-term safety of tegaserod has been assessed
in a multicentre, open-label, clinical trial of patients
with IBS-C.66 The most common adverse effects
related to tegaserod were mild and transient diarrhoea
(10.1%), headache (8.3%), abdominal pain (7.4%) and
flatulence (5.5%). The adverse effects profile, clinical
laboratory evaluations, vital signs and electrocardiogram recordings revealed no evidence of any unexpected adverse effects and suggested that tegaserod
treatment was safe over a 12-month period.66
Because IBS patients may alternate between constipation and diarrhoea, the safety of tegaserod in patients
with IBS-D was also examined. 67 In a randomized,
placebo-controlled, double-blind trial comparing
patients with IBS-D receiving either placebo or 4 or
12 mg of tegaserod per day, no complications of
diarrhoea or serious adverse effects were reported.
When data from the two tegaserod groups were pooled,
the overall frequency of diarrhoea was similar among
patients receiving tegaserod (33%) and placebo (35%).67
Tegaserod has also been shown to be devoid of
untoward electrocardiographic effects. Recent studies
have evaluated its cardiac safety profile. One analysed
treatment. However, serious complications such as
constipation requiring hospitalization or ischaemic
colitis have been reported in clinical studies and in
postmarketing experience.41
These serious complications occurred in approximately one of 1000 patients. The cumulative incidence
of ischaemic colitis in women taking alosetron was
two of 1000 patients during 3 months and three of 1000
patients during 6 months. Long-term safety data have
yet to be established.41
Alosetron was reintroduced in the United States in
November 2002 after it had been voluntarily withdrawn from the marketplace in 2001 and is now
indicated only for women with severe diarrhoeapredominant IBS for whom conventional IBS therapies
have failed. A number of restrictions have been
imposed on those prescribing alosetron, including
mandatory doctor training and certification. Patients
must also sign consent forms confirming the severity
of their symptoms and their understanding of the
potential risks associated with alosetron therapy.
While undergoing treatment, patients should be monitored for the development of severe constipation or
ischaemic colitis. In addition, alosetron should be used
cautiously in patients with hepatic insufficiency
because of its extensive metabolism by the liver.41
Tegaserod
The selective 5-HT4 receptor agonist tegaserod is
indicated for women with IBS whose primary bowel
symptom is constipation. Tegaserod is the first in a
novel class of drugs (aminoguanidine indoles) designed
to be similar in structure to serotonin and to act
selectively at 5-HT4 receptors in the GI tract.
Tegaserod accelerates overall GI transit in healthy
subjects 56 and promotes gastric emptying, small bowel
transit and colonic transit in IBS-C patients.57,58
Tegaserod was found to reduce the firing rate of spinal
afferents in vivo,47,59 supporting its role in the modulation of visceral sensitivity. Tegaserod also increased
fecal water and intestinal secretion in female subjects.60
The efficay of tegaserod has been evaluated in
several large, multicentre, randomized, double-blind,
placebo-controlled trials.40,61,62 In these trials, patients
with IBS-C received placebo or tegaserod (2 or 6 mg
twice daily) for 12 weeks. Two of the trials included
4-week follow-up without medication.40,61 When compared with placebo, tegaserod 6 mg twice daily produced statistically significant improvement in the
Subject’s Global Assessment (a validated 5-point ordinal scale) of relief (overall symptom improvement), as
708
2004 Blackwell Publishing Ltd
Volume 16, Number 6, December 2004
Efficacy and tolerability of IBS therapies
electrocardiographic data (11 535 electrocardiograms)
from 2516 IBS patients participating in various clinical
trials (receiving tegaserod 2 or 6 mg twice daily or
placebo); the other analysed data from a study of
36 healthy male patients (receiving tegaserod
0.8–20 mg day)1 intravenously). Clinical trial results
revealed that tegaserod was no more likely than
placebo to result in an electrocardiographic abnormality, and no serious dysrhythmias were reported. In
healthy volunteers, no cardiac effects were noted, even
when drug plasma concentrations reached 100 times
those observed after a typical therapeutic dose (12 mg
day)1).68
Tegaserod is classified as pregnancy category B.40
Although animal studies have indicated that tegaserod
does not impair fertility or cause fetal harm at
concentrations 15 to 51 times those expected at
recommended doses, no adequate, well-controlled
studies have been undertaken in pregnant women.40
Because experience drawn from clinical trials regarding
tegaserod and pregnancy has been limited (15 unintended pregnancies on tegaserod and five on placebo),
tegaserod is not recommended during pregnancy.69 Use
in nursing mothers must be evaluated carefully as well;
it is not known whether tegaserod is excreted in
human milk, but it is excreted in the milk of lactating
rats with high milk-to-plasma ratios.40
Adding alosetron and tegaserod to the armamentarium of treatments for patients with IBS offers patients
the option of therapies that target IBS-specific pathophysiological pathways. Although this focus may help
to provide global relief of the multiple symptoms of IBS
for patients, it is a first step. These therapies do not
address all the needs of all patients with IBS and more
work in the area of IBS management needs to be done
in order to provide all IBS patients with optimal
treatment of their symptoms. It is important to note,
however, that even in the clinical trials that show
these medications to be superior to placebo or other
comparators, the proportion of patients with global
relief rarely reaches 70%. It is clear, therefore, that
there is still room for improvement in IBS therapy.
SUMMARY AND CONCLUSIONS
Until recently, no drugs targeted IBS-specific pathophysiological pathways or the multiple symptoms of
IBS. Patients are often dissatisfied with the efficacy and
adverse effect profiles of traditional therapies. This
leads to multiple doctor visits and frequent medication
switching or augmentation – factors that often lead to
increased medical costs. Alosetron and tegaserod represent a step in the right direction for the treatment of
patients with IBS by providing these patients with
options for treating the multiple and varied symptoms
of IBS, resulting in global symptom improvement.
The future management of IBS appears promising in
that agents now in clinical development will follow
the lead of serotonergic modulators in targeting the
multiple symptoms of IBS.
SUPPORT FOR THE USE OF
SEROTONERGIC AGENTS IN THE
TREATMENT OF PATIENTS WITH IBS
In addition to evaluating traditional IBS therapies, the
FGID Task Force used an evidence-based approach to
evaluate the published tegaserod and alosetron clinical
trials.1 Based on study methodologies and clinical trial
evidence, tegaserod and alosetron were the only IBS
therapies to receive grade A recommendations from the
Task Force. This is not surprising given the fact that
criteria for determining optimal study design were
published relatively recently. Nevertheless, the Task
Force concluded that, when compared with placebo,
these agents provided significant global relief of symptoms of IBS-C and IBS-D, respectively.
Results of a recent meta-analysis of six alosetronrandomized, placebo-controlled clinical trials are analogous with the conclusions of the ACG FGID Task
Force, providing further evidence to support the efficacy of alosetron in women with diarrhoea-predominant
IBS.14 The meta-analysis used the Quality of Reports of
Meta-analyses statement guidelines for ensuring quality of the analysis.70
2004 Blackwell Publishing Ltd
REFERENCES
1 Brandt LJ, Locke GR, Olden K et al. An evidence-based
approach to the management of irritable bowel syndrome
in North America. Am J Gastroenterol 2002; 97(Suppl.):
S1–28.
2 Drossman DA, Camilleri M, Mayer EA, Whitehead WE.
AGA technical review on irritable bowel syndrome. Gastroenterology 2002; 123: 2108–31.
3 Mitchell CM, Drossman DA. Survey of the AGA membership relating to patients with functional gastrointestinal disorders. Gastroenterology 1987; 92: 1282–4.
4 Thompson WG, Longstreth GF, Drossman DA, Heaton
KW, Irvine EJ, Muller-Lissner SA. Functional bowel disorders and functional abdominal pain. Gut 1999; 45(Suppl.
II): II43–7.
5 American Heart Association. 2002 Heart and Stroke Statistical Update Dallas, TX: American Heart Association,
2002: 1–35.
6 Druss BG, Marcus SC, Olfson M, Tanielian T, Elinson L,
Pincus HA. Comparing the national economic burden of
709
J. F. Johanson
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Neurogastroenterology and Motility
24 Rosemore JG, Lacy BE. Irritable bowel syndrome: basis of
clinical management strategies. J Clin Gastroenterol 2002;
35(Suppl.): S37–44.
25 Cook IJ, Irvine EJ, Campbell D, Shannon S, Reddy SN,
Collins SM. Effect of dietary fiber on symptoms and
rectosigmoid motility in patients with irritable bowel
syndrome: a controlled, crossover study. Gastroenterology
1990; 98: 66–72.
26 Lucey MR, Clark ML, Lowndes J, Dawson AM. Is bran
efficacious in irritable bowel syndrome? A double blind
placebo controlled crossover study. Gut 1987; 28: 221–5.
27 Bijkerk CJ, Muris JVM, Knottnerus JA, Hoes AW, De Wit
NJ. Systematic review: the role of different types of fibre in
the treatment of irritable bowel syndrome. Aliment
Pharmacol Ther 2004; 19: 245–51.
28 Walker EA, Katon WJ, Jemelka RP, Roy-Bryne PP.
Comorbidity of gastrointestinal complaints, depression,
and anxiety in the Epidemiologic Catchment Area (ECA)
Study. Am J Med 1992; 92: 26S–30.
29 Lea R, Houghton LA, Calvert EL et al. Gut-focused hypnotherapy normalizes disordered rectal sensitivity in
patients with irritable bowel syndrome. Aliment Pharmacol Ther 2003; 17: 635–42.
30 Zacker C, Albers LA, Chawla A, Wang S.Drug utilization
patterns in patients with irritable bowel syndrome. Presented at: Drug Information Association Annual Meeting,
June 22, 2000, San Diego, CA.
31 Hunt RH. Evolving concepts in the pathophysiology of
functional gastrointestinal disorder. J Clin Gastroenterol
2002; 35(Suppl.): S2–6.
32 Wood JD. Neuropathophysiology of irritable bowel syndrome. J Clin Gastroenterol 2002; 35(Suppl.): S11–22.
33 Crowell MD. The role of serotonin in the pathophysiology
of irritable bowel syndrome. Am J Manag Care 2001;
7(Suppl. 8): S252–60.
34 Gershon MD. Review article: roles played by 5-hydroxytryptamine in the physiology of the bowel. Aliment
Pharmacol Ther 1999; 13(Suppl. 2): 15–30.
35 Ringel Y, Drossman DA. Irritable bowel syndrome: classification and conceptualization. J Clin Gastroenterol
2002; 35(Suppl.): S7–10.
36 Grider JR, Foxx-Orenstein AE, Jin JG. 5-Hydroxytryptamine4 receptor agonists initiate the peristaltic reflex in
human, rat, and guinea pig intestine. Gastroenterology
1998; 115: 370–80.
37 Miwa J, Echizen H, Matsueda K, Umeda N. Patients with
constipation-predominant irritable bowel syndrome (IBS)
may have elevated serotonin concentrations in colonic
mucosa as compared with diarrhea-predominant patients
and subjects with normal bowel habits. Digestion 2001;
63: 188–94.
38 Spiller RC. Role of nerves in enteric infection. Gut 2002;
51: 759–62.
39 Linden DR, Chen JX, Gershon MD, Sharkey KA, Mawe
GM. Serotonin availability is increased in mucosa of guinea pigs with TNBS-induced colitis. Am J Physiol Gastrointest Liver Physiol 2003; 285: G207–16.
40 Novartis Pharmaceuticals Corporation. Zelnorm (tegaserod maleate) Prescribing Information East Hanover, NJ:
Novartis Pharmaceuticals Corporation, 2002.
41 GlaxoSmithKline. Lotronex (alosetron hydrochloride)
Prescribing Information Research Triangle Park, NC:
GlaxoSmithKline, 2002.
five chronic conditions. Health Aff (Milwood) 2001; 20:
233–41.
American Gastroenterological Association. The Burden of
Gastrointestinal Diseases Bethesda, MD: American
Gastroenterological Association, 2001: 1–86 (available at:
http://www.gastro.org/pdf/burden-report.pdf).
Martin R, Barron JJ, Zacker C. Irritable bowel syndrome:
toward a cost-effective management approach. Am J
Manag Care 2001; 7(Suppl. 8): S268–75.
International Foundation for Functional Gastrointestinal
Disorders. IBS in the Real World Survey Milwaukee, WI:
International Foundation for Functional Gastrointestinal
Disorders, 2002: 1–19.
Gralnek IM. Health care utilization and economic issues
in irritable bowel syndrome. Eur J Surg 1998; 164(Suppl.):
73–6.
Frank L, Kleinman L, Rentz A, Ciesla G, Kim JJ, Zacker C.
Health-related quality of life associated with irritable
bowel syndrome: comparison with other chronic diseases.
Clin Ther 2002; 24: 675–89.
El Serag HB, Olden K, Bjorkman D. Health-related quality
of life among persons with irritable bowel syndrome: a
systematic review. Aliment Pharmacol Ther 2002; 16:
1171–85.
Jackson JL, O’Malley PG, Tomkins G, Balden E, Santoro J,
Kroenke K. Treatment of functional gastrointestinal disorders with antidepressant medications: a meta-analysis.
Am J Med 2000; 108: 65–72.
Cremonini F, Delgado-Aros S, Camilleri M. Efficacy of
alosetron in irritable bowel syndrome: a meta-analysis of
randomized controlled trials. Neurogastroenterol Motil
2003; 15: 79–86.
Schoenfeld P, Chey WD, Drossman D, Kim HM, Thompson WG. Effectiveness and safety of tegaserod in the
treatment of irritable bowel syndrome: a meta-analysis of
randomized control trials. Gastroenterology 2002;
122(Suppl.): A465.
Poynard T, Naveau S, Mory B, Chaput JC. Meta-analysis of
smooth muscle relaxants in the treatment of irritable
bowel syndrome. Aliment Pharmacol Ther 1994; 8: 499–
510.
Poynard T, Regimbeau C, Benhamou Y. Meta-analysis of
smooth muscle relaxants in the treatment of irritable
bowel syndrome. Aliment Pharmacol Ther 2001; 15: 355–
61.
Jailwala J, Imperiale TF, Kroenke K. Pharmacologic treatment of the irritable bowel syndrome: a systematic review
of randomized, controlled trials. Ann Intern Med 2000;
133: 136–47.
Lembo T, Rink R. Current pharmacologic treatments of
irritable bowel syndrome. Participate 2002; 11: 1–4.
Page JG, Dirnberger GM. Treatment of the irritable bowel
syndrome with bentyl (dicyclomine hydrochloride). J Clin
Gastroenterol 1981; 3: 153–6.
Camilleri M. Review article: clinical evidence to support
current therapies of irritable bowel syndrome. Aliment
Pharmacol Ther 1999; 13(Suppl. 2): 48–53.
Drossman DA, Toner BB, Whitehead WE et al. Cognitivebehavioral therapy versus education and desipramine
versus placebo for moderate to severe functional bowel
disorders. Gastroenterology 2003; 125: 19–31.
Wald A. Psychotrophic agents in irritable bowel syndrome.
J Clin Gastroenterol 2002; 35(Suppl.): S53–7.
710
2004 Blackwell Publishing Ltd
Volume 16, Number 6, December 2004
Efficacy and tolerability of IBS therapies
57 Prather CM, Camilleri M, Zinsmeister AR, Thomforde G,
McKinzie S. Tegaserod accelerates orocecal transit in
patients with constipation-predominant irritable bowel
syndrome. Gastroenterology 2000; 118: 463–8.
58 Petrig C, Templeton J, Matzinger D, Ruegg P, Beglinger C,
Degen L. Effect of tegaserod on gastrointestinal transit in
male and female subjects. Gut 2002; 51(Suppl. III): A138.
59 Schikowski A, Mathis C, Thewiben M, Ross HG, Pak MA,
Enck P. Dose-dependent modulation of rectal afferent
sensitivity by a 5-HT4 receptor agonist. Gastroenterology
1999; 116(Suppl. 2): A643.
60 Petrig C, Templeton J, Matzinger D, Ruegg P, Beglinger C,
Degen L. Effect of tegaserod on faecal water and electrolyte
secretion in male and female subjects. Gut 2002; 51(Suppl.
III): A249.
61 Novick J, Miner P, Krause R et al. A randomized, doubleblind, placebo-controlled trial of tegaserod in female
patients suffering from irritable bowel syndrome with
constipation. Aliment Pharmacol Ther 2002; 16: 1877–
88.
62 Muller-Lissner SA, Fumagalli I, Bardhan KD et al. Tegaserod, a 5-HT4receptor partial agonist, relieves symptoms
in irritable bowel syndrome patients with abdominal pain,
bloating and constipation. Aliment Pharmacol Ther 2001;
15: 1655–66.
63 Lefkowitz MP, Ruegg P, Shi Y, Dunger-Baldauf C. Relief of
overall gastrointestinal symptoms and abdominal pain and
discomfort as outcome measures in a clinical trial of
irritable bowel syndrome with tegaserod. Gastroenterology 1999; 116: A1027.
64 Kellow J, Lee OY, Chang FY et al. An Asia-Pacific, double
blind, placebo controlled, randomized study to evaluate
the efficacy, safety, and tolerability of tegaserod in patients
with irritable bowel syndrome. Gut 2003; 52: 671–6.
65 Nyhlin H, Bang C, Elsborg L et al. Tegaserod is an effective
and safe therapy for irritable bowel syndrome in a Nordic
population. Gastroenterology 2003; 124(Suppl. 1): A389.
66 Tougas G, Snape WJ, Otten MH et al. Long-term safety of
tegaserod in patients with constipation-predominant
irritable bowel syndrome. Aliment Pharmacol Ther 2002;
16: 1701–8.
67 Fidelholtz J, Smith W, Rawls J et al. Safety and tolerability
of tegaserod in patients with irritable bowel syndrome and
diarrhea symptoms. Am J Gastroenterol 2002; 97: 1176–
81.
68 Morganroth J, Ruegg PC, Dunger-Baldauf C, AppelDingemanse S, Bliesath H, Lefkowitz M. Tegaserod, a
5-hydroxytryptamine type 4 receptor partial agonist, is
devoid of electrocardiographic effects. Am J Gastroenterol
2002; 97: 2321–7.
69 Appel-Dingemanse S. Clinical pharmacokinetics of tegaserod, a serotonin 5-HT(4) receptor partial agonist with
promotile activity. Clin Pharmacokinet 2002; 41: 1021–
42.
70 Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup
DF. Improving the quality of reports of meta-analyses of
randomized controlled trials: the QUOROM statement.
Onkologie 2000; 23: 597–602.
42 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: 64–72.
43 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: 842–8.
44 Chang L, Berman S, Mayer EA et al. Brain responses to
visceral and somatic stimuli in patients with irritable bowel syndrome with and without fibromyalgia. Am J
Gastroenterol 2003; 98: 1354–61.
45 Naliboff BD, Berman S, Chang L et al. Sex-related differences in IBS patients: central processing of visceral stimuli. Gastroenterology 2003; 124: 1738–47.
46 Kozlowski CM, Green A, Grundy D, Boissonade FM,
Bountra C. The 5-HT3 receptor antagonist alosetron
inhibits the colorectal distention induced depressor
response and spinal c-fos expression in the anaesthetised
rat. Gut 2000; 46: 474–80.
47 Mathis C, Schikowski A, Thewiben M, Ross HG, Pak MA,
Enck P. Modulation of rectal spinal afferent sensitivity via
5-HT4 receptors. Neurogastroenterol Motil 1998; 10: 459.
48 Schikowski A, Thewissen M, Mathis C, Ross HG, Enck P.
Serotonin type-4 receptors modulate the sensitivity of
intramural mechanoreceptive afferents of the cat rectum.
Neurogastroenterol Motil 2002; 14: 221–7.
49 Coffin B, Farmachidi JP, Rueegg P, Bastie A, Bouhassira D.
Tegaserod, a 5-HT4 receptor partial agonist, decreases
sensitivity to rectal distension in healthy subjects. Aliment Pharmacol Ther 2003; 17: 577–85.
50 Houghton LA, Foster JM, Whorwell PJ. Alosetron, a 5-HT3
receptor antagonist, delays colonic transit in patients with
irritable bowel syndrome and healthy volunteers. Aliment
Pharmacol Ther 2000; 14: 775–82.
51 Delvaux M, Louvel D, Mamet JP, Campos-Oriola R,
Frexinos J. Effect of alosetron on responses to colonic
distension in patients with irritable bowel syndrome.
Aliment Pharmacol Ther 1998; 12: 849–55.
52 Camilleri M, Northcutt AR, Kong S, Dukes GE, McSorley
D, Mangel AW. Efficacy and safety of alosetron in women
with irritable bowel syndrome: a randomized, placebocontrolled trial. Lancet 2000; 355: 1035–40.
53 Camilleri M, Chey WY, Mayer EA et al. A randomized
controlled clinical trial of the serotonin type 3 receptor
antagonist alosetron in women with diarrhea-predominant
irritable bowel syndrome. Arch Intern Med 2001; 161:
1733–40.
54 Jones RH, Holtmann G, Rodrigo L et al. Alosetron relieves
pain and improves bowel function compared with mebeverine in female nonconstipated irritable bowel syndrome
patients. Aliment Pharmacol Ther 1999; 13: 1419–27.
55 Lembo T, Wright RA, Bagby B et al. Alosetron controls
bowel urgency and provides global symptom improvement
in women with diarrhea-predominant irritable bowel
syndrome. Am J Gastroenterol 2001; 96: 2662–70.
56 Degen L, Matzinger D, Maecke H et al. Tegaserod (HTF
919), a partial 5-HT4 receptor agonist, accelerates gastrointestinal (GI) transit. Gastroenterology 2000; 118: A845.
2004 Blackwell Publishing Ltd
711