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Review article: the treatment of functional abdominal bloating
and distension
M. Schmulson* & L. Chang
*Laboratory of Liver, Pancreas and
Motility (HIPAM), Department of
Experimental Medicine-Faculty of
Medicine, Universidad Nacional Auto-
noma de Mexico (UNAM), Mexico.
Center for Neurobiology of Stress,
Division of Digestive Diseases, David
Geffen School of Medicine at UCLA,
Los Angeles, CA, USA.
Correspondence to:
Dr L. Chang, Center for Neurobiology
of Stress, 10945 Le Conte Avenue,
PVUB 2114, Los Angeles, CA
90095-6949, USA.
E-mail: [email protected]
Publication data
Submitted 4 October 2010
First decision 26 October 2010
Resubmitted 8 February 2011
Accepted 3 March 2011
EV Pub Online 29 March 2011
This commissioned review article was
subject to full peer-review.
SUMMARY
Background
Abdominal bloating and distension are common symptoms in patients withfunctional gastrointestinal disorders (FGIDs), however, relatively little is
known about their treatment.
Aim
To review the treatment trials for abdominal bloating and distension.
Methods
A literature review in Medline for English-language publications through
February 2010 of randomised, controlled treatment trials in adults. Study
quality was assessed according to Jadad’s score.
Results
Of the 89 studies reviewed, 18% evaluated patients with functional dyspep-sia, 61% with irritable bowel syndrome (IBS), 10% with chronic constipa-
tion and 10% with other FGIDs. No studies were conducted in patients
diagnosed with functional abdominal bloating. The majority of trials inves-tigated the efficacy of prokinetics or probiotics, although studies are hetero-
geneous with respect to diagnostic criteria and outcome measures. In
general, bloating and ⁄ or distension were evaluated as secondary endpoints
or as individual symptoms as part of a composite score rather than as pri-
mary endpoints. A greater proportion of IBS patients with constipation
reported improvement in bloating with tegaserod vs. placebo (51% vs. 40%,P < 0.0001) and lubiprostone (P < 0.001). A greater proportion of noncon-
stipating IBS patients reported adequate relief of bloating with rifaximin vs.placebo (40% vs. 30%, P < 0.001). Bloating was significantly reduced with
the probiotics, Bifidobacterium infantis 35624 (1 · 108 dose vs. placebo:
)
0.71 vs.)
0.44, P < 0.05) and B. animalis (live vs. heat-killed:)0.56 Æ 1.01 vs. )0.31 Æ 0.87, P = 0.03).
Conclusions
Prokinetics, lubiprostone, antibiotics and probiotics demonstrate efficacy for
the treatment of bloating and ⁄ or distension in certain FGIDs, but other
agents have either not been studied adequately or have shown conflicting
results.
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ª 2011 Blackwell Publishing Ltd 1071doi:10.1111/j.1365-2036.2011.04637.x
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INTRODUCTION
Bloating is a common symptom that is reported by 6%
to 31% of the general population.1–3 It is usually consid-
ered the subjective sensation that is associated with
abdominal distension, i.e. the visible increase in abdomi-
nal girth,4, 5 which is considered more of an objective
sign. In a population-based study in Olmsted County in
the United States, the age and gender-adjusted overall
prevalence for bloating was 19% and 9% for visible
abdominal distension.6
Bloating is a common complaint in patients with
functional gastrointestinal disorders (FGIDs). In a U.S.
study of a mixed population recruited from an academic
university clinic and advertisement, of 542 patients with
irritable bowel syndrome (IBS), 76% of patients reported
abdominal bloating.7 Moreover, in a cross-sectional study
among employees of a Veterans Affairs Health Care
Center in the United States, of which 39% were men,
bloating was reported by 35% of individuals with non-
constipating IBS, 23% with nondiarrhoea IBS and 42%
with non-investigated dyspepsia.8
However, studies suggest that while bloating and dis-
tension are related, they are two separate symptoms. For
example, in the above mentioned study in an academic
university clinic, 24% reported having bloating only and
76% had both bloating and visible abdominal distension.7
IBS patients with bloating and distension had a higher
female-to-male ratio, constipation predominance, symp-
tom severity and less diurnal variation compared with
those with bloating only. Patients with bloating with and
without distension reported that symptoms progressively
worsened during the day and were relieved by defecation
or gas passage.7 Approximately 50% of the subjects ful-
filling modified Rome II criteria for dyspepsia reported
bloating, while almost half of this group also had visible
abdominal distension. In addition, subjects with dyspep-
sia were two times more likely to have bloating alone or
distension alone when compared with controls.6 In
another U.S. study, distension defined by the presence of
both bloating and visible abdominal distension was more
prevalent than bloating alone in IBS and functional dys-pepsia (FD), but bloating alone was more common than
distension in functional constipation.6
Bloating has been considered a secondary criterion for
IBS and FD according to the Rome I classification9 and
a supportive symptom for IBS in the Rome II and III
diagnostic criteria.10, 11 Despite being a common symp-
tom of several FGIDs,12 the Rome classification includes
Functional Bloating as an independent entity. The name
has changed from Functional Abdominal Bloating both
in Rome I and II9, 10 to Functional Bloating in Rome III
(Table 1).11 This diagnosis is made in patients with
symptoms of bloating who do not meet the diagnostic
criteria of IBS, FD or other FGIDs.
The pathophysiological mechanisms associated with
abdominal bloating and distension are poorly under-
stood. Bloating and distension together with eructation,
aerophagia and flatulence, have been attributed to exces-
sive intestinal gas accumulation.13, 14 Other proposed
underlying mechanisms include impaired small intestinal
handling of gas,15 impaired clearance from the proximal
colon,16 psychological factors,17 fluid retention,18 food
intolerance and carbohydrate malabsorption,4, 19 increase
in lumbar lordosis,5, 20 weakness of abdominal wall mus-
culature,21 altered sensorimotor function,22 small intesti-
nal bacterial overgrowth and altered gut microflora.23
Although bloating and distension are very common
symptoms, they are considered challenging to treat in
clinical practice. Relatively little is known about the effi-
cacy of treatments for these symptoms. Therefore, we
reviewed the literature of treatment interventions for
bloating and distension in patients with FGIDs.
METHODS
A literature search was performed on PubMed in the
Medline database using the following terms: ‘bloating
syndrome’, ‘functional abdominal bloating’, ‘abdominal
bloating’, ‘bloating’, ‘abdominal distension’, ‘flatulence’
and ‘gases’. These were combined using the AND opera-
tor, with studies identified with the following terms:‘therapeutics’, ‘combined modality therapy’, ‘complemen-
tary therapies’, ‘drug therapy’, ‘therapies, investigational’,
‘psychotherapy’, ‘behavior therapy’, ‘cognitive therapy’,
‘surfactants’, ‘antifoaming agents’, ‘anti-bacterial
agents’, ‘antibiotics’, ‘probiotics’, ‘prebiotics’, ‘dietary sup-
plements’, ‘pancreatic enzymes’, ‘antispasmodics’ and
‘parasympatholytics’. Searching limits included humans,
men and women, randomised controlled trials, all adults
Table 1 | Rome III Diagnostic criteria for functional
bloating11
Must include both of the following:
1. Recurrent feeling of bloating or visible distension at least
3 days a month in the last 3 months
2. Insufficient criteria for FD, IBS or other FGID
Criteria fulfilled for the last 3 months with symptom onset atleast 6 months prior to diagnosis.
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aged 18 or older and English language. The search
included all articles published in the past (no starting
date restrictions) to a publication cut-off date of Febru-
ary 2010. A total of 167 articles were retrieved. The titles
and abstracts were reviewed by the authors to select only
those articles that analysed the effect of treatment on
bloating and ⁄ or distension in FGIDs, excluding those
that did not meet eligibility. We also performed manual
searches of reference lists from relevant articles to iden-
tify other manuscripts which may have been missed by
the search strategy.
Eighty-five articles were reviewed in detail. Of these,
five were not included: one was a duplicate publication,24
two did not report the treatment response on bloat-
ing 25, 26 and two could not be retrieved in full text. 27, 28
There were two recently published articles that were not
identified by the search, but that analysed the efficacy of
renzapride and linaclotide on bloating and were therefore
added.29, 30 Three additional articles were identified by manual search of references from other articles.31–33
Moreover, two multicentre, placebo-controlled trials that
were recently published in abstract form were also
reviewed.34–36 Thus, a total of 87 articles were included
in the review . Two of the studies were published in full
text while preparing this article, therefore their references
were updated.30, 36 Of the identified articles, 63%
included patients with IBS, 16% with dyspepsia, 10%
with chronic constipation and 10% with symptoms of
other FGIDs. There were no studies conducted in
patients specifically diagnosed with Functional Abdomi-nal Bloating or Functional Bloating. We also did not
identify any psychological or behavioural treatment stud-
ies that measured their efficacy on bloating or distension.
The quality of reporting of each clinical trial was
graded according to Jadad’s scale from 0 to 5. 37 A score
of ‡4 was considered to be of high quality. Accordingly,
each article was assessed based on three methodological
items: randomisation, concealment of treatment and
intention-to-treat analysis and withdrawals. In the case
of articles published in abstract form, we did not include
the Jadad’s scale, as these formats do not provide all thenecessary information.
RESULTS
Dietary interventions
The osmotic load within the bowel lumen may contrib-
ute to abdominal distension38 and candidate substrates
that are highly fermentable are poorly absorbed short
chain carbohydrates called Fermentable Oligosaccharides,
Disacharides, Monosacharides and Polyols (FODM-
APs).33 Patients with IBS and fructose malabsorption
who had reported symptomatic relief to a low FODM-
APs diet, were re-challenged with one of four test sub-
stances: fructans, fructose, fructans and fructose, or
glucose in low, medium or high doses in a crossover
design study (supplementary Table S1). Bloating severity
scores increased with fructans, fructose and a mixture of
both in a dose dependent manner and were significantly
greater than that with glucose, suggesting the benefit of
the low FODMAPs diet for bloating in IBS.
Antifoaming ⁄ surfactants
One of the earliest pharmacological treatments used to
relieve bloating and distension was antifoaming agents,
which are thought to alter the elasticity of the gas bub-
bles and ease the passage of flatus (supplementary Table
S1). A very small study in 41 patients with upper GI
symptoms, such as heartburn, feeling fullness, bloating,gas and upset stomach, reported that simethicone was
significantly superior to placebo in decreasing the fre-
quency and severity of gas, distension ⁄ stiffness and
bloating.39 A recent multicentre trial evaluated the com-
bination of simethicone and activated charcoal in
patients consulting general practitioners for abdominal
fullness, bloating, nausea and slow digestion.40 Patients
with diagnostic symptoms of gastro-oesophageal reflux
or IBS were included as long as these symptoms were
not the predominant ones. However, patients with long-
standing dyspepsia who had undergone endoscopic orimaging explorations within the previous 2 years were
excluded. Compared with placebo, the intensity of full-
ness, bloating and sensation of slow digestion were sig-
nificantly decreased after 90 days with the active
treatment.
Antispasmodics
Smooth muscle spasm has been thought to contribute to
symptom generation in FGIDs and therefore antispasmo-
dics have been used.40, 41 In many parts of the world,
these agents remain the first-line treatment for FGIDs.42
Trimebutine has been traditionally considered an anti-
spasmodic, but its mechanism of action is not well
understood. It is an opioid agonist that acts on j, l and
d receptors of the enteric nervous system and modulates
the release of motilin and other peptides.43 Two studies
evaluated its effect on bloating in IBS (supplementary
Table S1).44, 46 The first study reported data from three
trials. Two of the trials were crossover, placebo-con-
trolled trials, but treatment durations lasted only 3 days
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with a trimebutine dose of 100 or 200 mg three times
daily respectively. In the first trial, bloating decreased
with trimebutine but not with placebo and patients
reported higher satisfaction with trimebutine. However,
in the second trial, there was no difference in the
patients’ preference for trimebutine or placebo, which
was the study’s main outcome assessment.44 The third
trial compared 2 weeks of trimebutine and mebeverine
(another antispasmodic with anticholinergic properties)45
in patients with mostly moderate to severe abdominal
distension. Both groups reported equal improvement in
abdominal distension.44 Another very small study also
showed that trimebutine, but not placebo, decreased
bloating and the patients’ treatment satisfaction scores.46
Octilonium bromide (OB) is a quaternary ammonium
compound selectively acting on the smooth muscle of
the distal GI tract by interfering with the Ca 2+ ions nec-
essary for the electromechanical coupling.47 An earlier,
very small study found that OB significantly reduced theseverity of bloating during the 4-week treatment period
compared wity placebo, but the difference was marginal
at the end of the study (supplementary Table S1).48 A
larger, 15-week study reported significant but comparable
reductions in distension scores for both the OB and pla-
cebo groups.49 The authors subsequently published a
supplementary post hoc analysis of the same data, report-
ing that OB was significantly superior to placebo in the
rates of monthly (at least 2 of 4 weeks ⁄ month) and
weekly responses of abdominal gas and distension
relief.50 Another study compared the combination of OBand a 10 to 15-g fibre diet with a 20-g fibre diet plus 10-
g bran supplement without OB over 24 months. A
greater reduction in distension was demonstrated in the
OB with fibre group, but this was not sustained during
the follow-up period.51 However, this study did not
clearly state whether patients received treatment during
the first 12 months of the study and the number of
patients who remained in the study during the follow-up
period. A recent multinational trial in patients with IBS
reported that bloating severity decreased significantly
more with OB than with placebo.34 The adverse eventprofile was similar in both groups and tolerability was
excellent.
Peppermint oil is a natural volatile oil that is consid-
ered a spasmolytic agent due to its calcium influx block-
ing effect.52 Two studies evaluated the efficacy of enteric
coated peppermint in IBS (supplementary Table S1).
One study included predominantly men (60%) with IBS
and demonstrated a significant reduction in abdominal
distension in 83% of patients on peppermint oil com-
pared to 29% of those on placebo.52 The second placebo-
controlled study was conducted in IBS patients with neg-
ative lactose and lactulose breath tests and coeliac serolo-
gies and reported a significant decrease in bloating and
distension after 4 weeks of treatment for both groups,
but a significantly greater improvement with peppermint
oil.53
In summary, antispasmodics have shown some effi-
cacy in the treatment of bloating, but most of the trials
included small sample sizes and analyssed the efficacy
within each treatment group rather than between active
treatment and placebo. In addition, the majority of these
articles were of low quality. Therefore, it is difficult to
make definitive conclusions on the efficacy of this family
of agents. Moreover, the mechanism by which these
agents can improve bloating and distension is unclear,
but it is possible that they may have an analgesic effect
by decreasing intestinal smooth muscle contractility. Lar-
ger studies are warranted.
Bulking agents
Bulking agents have been traditionally used as first-line
therapy in IBS and chronic constipation. The efficacy of
ispaghula husk (psyllium) was studied in IBS patients, of
which half were classified as IBS-C (supplementary Table
S1). After 3 months, both ispaghula and placebo simi-
larly decreased the frequency and severity of bloating.
However, whole gut transit time decreased only with is-
paghula.54 The efficacy of calcium polycarbophil, a syn-
thetic hydrophilic colloid, was compared with placebo ina small crossover study in IBS (supplementary Table S1).
At the end of the study, patients were asked to express
an overall preference, and those with bloating favoured
polycarbophil more strongly than placebo. However,
there were no significant differences in the bloating
severity scores between those taking polycarbophil and
placebo.55
Osmotic laxatives
With regard to osmotic laxatives, polyethylene glycol
(PEG) 3350 is an inert polymer that has shown to benontoxic, absorbed only in trace amounts and is water
soluble.56 PEG 3350 has been approved for the short-
term treatment of chronic constipation.56 Improvement
of constipation would be expected to help reduce bloat-
ing and distension. The efficacy of PEG for bloating was
studied in one high quality trial that included patients
with chronic constipation who met Rome II criteria but
were also taking medications associated with at least a
3% incidence of constipation.57 Both PEG and placebo
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relieved bloating in a similar fashion, despite the fact that
78% of the PEG-treated patients no longer met the
symptom criteria for constipation vs. 39% of those on
placebo (supplementary Table S2).57
Stimulants of fluid secretion
Lubiprostone enhances fluid secretion into the gut lumen
by activating the type-2 chloride channels (ClC-2)
located in the apical area of the enteric epithelial cells.
The activation of the ClC-2 induces the negatively
charged chloride ions to enter the lumen and the posi-
tively charged sodium ions passively diffuse through the
intracellular spaces to balance chloride, allowing water to
follow passively into the lumen.58 Although lubiprostone
at a dose of 24 mcg twice daily was shown to accelerate
small intestinal and colonic transit in healthy volun-
teers,59 a dose of 24 mcg once daily increased the colonic
motor function without a statistical significance.60 Results
of two phase 3 trials in IBS-C (supplementary Table S2),
reported a significantly greater improvement in the
bloating severity score compared with baseline in the
lubiprostone group than that observed in the placebo
group at month 2.32 Five percent of the subjects reported
nausea as an adverse event. As for chronic constipation
(supplementary Table S2), patients treated with lubipro-
stone for 4 weeks reported significant improvements in
bloating at weeks 2 and 3 compared with those taking
placebo.61
Linaclotide (MD-1100) is a novel agonist of the gua-
nylate cyclase-C receptors on the luminal surface of intestinal enterocytes that is minimally absorbed and has
shown to increase fluid secretion and transit in animal
models.30 Linaclotide was shown to accelerate ascending
colon emptying half-time and overall colonic transit at
48 h but not overall transit at 24 h. 62 In a dose-ranging,
phase 2b study in chronic constipation, linaclotide signif-
icantly improved the severity of bloating.30 In addition,
there was a significantly greater proportion of patients
taking linaclotide who reported a decrease in bloating
compared with placebo (supplementary Table S2). How-
ever, there was not a dose-dependent effect, perhaps dueto relatively low baseline scores, which decreases the abil-
ity of linaclotide to improve bloating, i.e. a ‘floor-effect’.
Two phase 3 clinical trials conducted in 1272 patients
with modified Rome II criteria for functional constipa-
tion that were recently published in abstract form per-
formed within group comparisons for change in bloating
severity.35 Bloating severity significantly decreased from
baseline with both the 133 and 266 mcg doses of linaclo-
tide, but not with placebo.35
In summary, in studies of high quality of reporting,
lubiprostone demonstrated efficacy in bloating in FGIDs
with constipation. More information is needed regarding
the efficacy of linaclotide on bloating compared with pla-
cebo. It is possible that the secretory properties and the
ability to accelerate intestinal transit play a role in their
effect on bloating symptoms.
Prokinetics
Disturbances in GI motility may contribute to the patho-
genesis of bloating and distension by interfering with the
movement of gas.5 Hence, there is a rationale for the use
of prokinetics for the treatment of these symptoms.
Cholinergic pathways are the main ones implicated in
regulating GI motility. Neurotransmitters such as seroto-
nin (5-HT) via 5-HT4 receptors and others acting through
dopamine and motilin receptors have also been
implicated.63
Dopamine antagonists. Three dopamine antagonists have
been studied in dyspepsia (supplementary Table S3): (i)
metoclopramide, a centrally acting dopamine antagonist
that enhances the local effect of acetylcholine on the gas-
tric smooth muscle, (ii) levosulpiride, an antagonist of
central and peripheral dopamine receptors and (iii) dom-
peridone, a peripheral dopamine antagonist.64 In a small
trial in patients with dyspeptic symptoms, metoclopra-
mide had no effect on abdominal distension.65 In
patients with dysmotility-like FD, both levosulpiride and
cisapride (another prokinetic agent with 5-HT4 proper-ties), significantly improved bloating at doses that accel-
erate gastric emptying in FD and gastroparesis.66 Side
effects were more common with levosulpiride, but more
patients with cisapride had to withdraw from the study
because of side effects such as anxiety, tachycardia, dizzi-
ness and even bloating.
Domperidone demonstrated a significant improvement
in the ‘postprandial flatulence’ symptom cluster (i.e.
abdominal swelling, feeling full after a heavy meal, and
eructation) when compared with baseline in patients with
dyspepsia and IBS symptoms (supplementary Table S3).67
By contrast, another study conducted in IBS patients, who
had symptoms that persisted for at least 6 months and
were present on at least 3 days per week, reported more
days per week with distension on domperidone but not
with placebo. Domperidone had no significant effect on
gastric emptying, small bowel or whole gut transit times.68
Muscarinic antagonists. Acotiamide hydrochloride trihy-
drate is a novel gastric motility modulator that partly exerts
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its prokinetic effect by enhancing acetylcholine release via
antagonism of the M1 and M2 muscarinic receptors in
addition to inhibiting acetylcholinesterase activity.69 In
patients with Rome II positive FD, improvement in bloat-
ing severity with acotiamide was not related to enhanced
gastric emptying or accommodation or to decreased gastric
sensitivity (supplementary Table S3) and therefore the
underlying mechanism responsible for the effect on bloat-
ing needs to be determined.70 Two serious adverse events
reported with the 50 mg three times daily dosage were bili-
ary colic and angina pectoris. Both resolved at the end of
the study and were considered unlikely related to the medi-
cation.70
5HT 4 agonists. Cisapride exerts its prokinetic effect by
enhancing the release of acetylcholine at the myenteric
plexus and acting on 5-HT4 receptors.71, 72 It also has 5-
HT2 and 5-HT3 antagonist effects. Five placebo-controlled
studies conducted in patients with dyspepsia in severalcountries,71–75 evaluated the efficacy of cisapride on bloat-
ing (supplementary Table S3). Overall, cisapride appears
to reduce bloating in patients with symptoms of FD. How-
ever, none of the studies were rated to be of high quality.
In IBS, the efficacy of cisapride on bloating symptoms
is inconsistent (supplementary Table S3). In IBS-C
patients treated with cisapride 5 mg three times daily
with an increase to 10 mg three times daily if there was
no improvement, no differences were found in the sever-
ity of bloating compared with placebo.76 This study was
rated to be of higher quality than two other studies, bothof which demonstrated efficacy with cisapride. One of
the two studies found that patients reported a significant
but similar improvement in bloating severity both with
cisapride and placebo, but there was a greater proportion
of patients without bloating with cisapride.76 The other
trial in IBS-C found that distension improved with both
cisapride and placebo. However, the improvement was
significantly greater with cisapride, mainly due to a
greater reduction in the frequency of complete disap-
pearance of distension.78 Taken together, cisapride
appears to reduce bloating and distension in patientswith FD, but there is conflicting evidence on its effect on
bloating in IBS-C.
Tegaserod, is a selective 5-HT4 receptor partial agonist
that has been shown to accelerate orocecal transit times
in IBS-C patients.79 Two identical placebo-controlled tri-
als were conducted in women with dyspepsia symptoms
consisting of mid-upper abdominal discomfort character-
ised by at least two of the following symptoms: postpran-
dial fullness, early satiety and ⁄ or bloating.80 There was a
significant improvement in bloating with tegaserod vs.
placebo in one of the trials but a trend for an effect in
the other one (supplementary Table S3).
Four placebo-controlled high quality studies81–84 eval-
uated the efficacy of tegaserod in patients with IBS-C or
IBS without diarrhoea (supplementary Table S3). These
studies reported either a trend82, 83 or a significant81, 84
improvement in bloating with tegaserod. Another study
evaluated the efficacy and safety of tegaserod given dur-
ing an initial and subsequent repeated treatment period
in women with IBS-C.84 Patients with at least a partial
response (satisfactory relief of either overall IBS symp-
toms or abdominal discomfort ⁄ pain for ‡2 of the first 4
treatment weeks) during the initial treatment period
entered a treatment-free interval. During this treatment-
free interval, a gradual recurrence of symptoms occurred
in some patients after both tegaserod and placebo.
Patients who experienced symptom recurrence entered a
repeated treatment period. Those previously treated withtegaserod were re-randomised to tegaserod or placebo for
one additional month and those previously on placebo
were mock randomised to tegaserod. Tegaserod was supe-
rior to placebo in relieving overall symptoms, abdominal
pain ⁄ discomfort and bloating during both treatment peri-
ods.84
With regard to chronic constipation, studies were
more consistent in demonstrating a significant decrease
in the bothersomeness of bloating with tegaserod, but
not with placebo (supplementary Table S3).85–87 How-
ever, bloating and distension were also reported asadverse events in both treatment groups.86, 87
In summary, tegaserod appears to have some efficacy
on bloating symptoms in various FGIDs, but the results
less consistent in FD and nondiarrhoea predominant IBS
as they are in chronic constipation. All of the studies were
of high quality. It is important to note that tegaserod is
unavailable in many parts of the world because of cardio-
vascular safety concerns and it is only available in certain
countries under a restricted access program.88, 89
Macrolides. In patients with FD and delayed gastricemptying, an intravenous one-time dose of erythromycin
(supplementary Table S3) enhanced gastric emptying for
solids and liquids compared with saline. Bloating was the
only meal induced symptom that improved.90
Colchicine. This agent has been evaluated in chronic con-
stipation due to its side effect of diarrhoea. It accelerates
GI motility and increases secretion.91 In a crossover
design, placebo-controlled study in 16 patients with
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chronic idiopathic constipation refractory to standard
medical therapy (supplementary Table S3), an increase in
the number of spontaneous bowel movements with accel-
eration of the colonic transit was found with colchicine,
but there were no differences in bloating scores compared
with placebo.91
Other serotonergic agents
Serotonin (5-HT) is an important neurotransmitter that
modulates gut function and more than 95% in the
human body is present in the enteric nervous system.63
It is considered to be involved not only in GI motility
and secretion but also in visceral perception.92 Therefore,
it may be related to the generation of abdominal disten-
sion and bloating. There are at least four 5-HT receptors
that have been associated with the GI physiology in
humans, including 5-HT1, 5-HT2, 5-HT3 and 5-HT4. In
addition, several agents that target these receptors have
been developed for functional and motility disorders of the GI tract.93
5-HT 1 agonists. Sumatriptan is a specific 5-HT1 receptor
agonist that induces relaxation of the gastric fundus in
FD. In a study of 30 patients with dyspeptic symptoms
and negative upper GI endoscopy, an acute subcutaneous
dose with sumatriptan or placebo, administered twice
48 h apart, concluded that sumatriptan improved the
gastric distension-induced nausea in both dyspeptic
patients and controls, but did not reduce bloating, pain
or heartburn.94 In a recent 4-week study in patients withFD and visceral hypersensitivity to gastric distension or
with impaired accommodation, the 5-HT1A receptor ago-
nist R-13769695 failed to relieve bloating (supplementary
Table S4). Both studies were of low quality.
5-HT 3 antagonists and others. Although 5-HT3 antago-
nists have demonstrated efficacy in nonconstipating IBS,
they have not been shown to improve bloating. 96 Ondan-
setron is a highly selective 5-HT3 antagonist that was
assessed in patients with IBS-D (n = 28) and IBS-C
(n = 20) and demonstrated no significant effect onabdominal distension.97 In addition, three alosetron stud-
ies98–100 did not show any significant efficacy of the sec-
ondary variable of bloating in IBS patients with
predominantly diarrhoea symptoms (supplementary
Table S4). However, bloating is not reported to be a pre-
dominantly bothersome or severe symptom by IBS-D
patients compared with IBS-C patients.101 The efficacy
and safety of renzapride, a full 5-HT4 agonist, 5-HT3
antagonist and a weak partial 5-HT2b antagonist, was
recently assessed in a high quality, 12-week, phase 3,
dose-ranging multinational trial in 1798 women with
IBS-C.29 The sensation of bloating improved in all
groups with a limited superiority of the 2 mg twice daily
dose of renzapride over placebo (supplementary Table
S4).
Selective serotonin reuptake inhibitors
On the basis that both psychological factors and seroto-
nin receptors as mediators of visceral hypersensitivity
and motor function are involved in the pathogenesis of
FGIDs, it is plausible to believe that selective serotonin
reuptake inhibitors (SSRIs) can be effective as visceral
analgesics and therefore improve symptoms such as
bloating.102, 103 Two high-quality, but small studies com-
pared fluoxetine with placebo in patients with IBS (sup-
plementary Table S4). The first study did not find any
significant differences in the proportion of patients
reporting bloating after 6 weeks of treatment comparedwith baseline within the fluoxetine and placebo
groups.102 The second one demonstrated a significant
decrease in the proportion that reported bloating inter-
fering with daily activities with fluoxetine but not pla-
cebo.103 Paroxetine was also evaluated in IBS patients
who did not respond to a high fibre diet. Paroxetine was
considered to be effective a priori if there was the pres-
ence of at least 30% difference in the proportion of
patients who reported a decrease in bloating. No differ-
ence was found with paroxetine compared with pla-
cebo.104 However, in a small randomised, crossoverdesigned study, citalopram significantly decreased the
number of days with bloating after 3 and 6 weeks of
treatment as well as the severity of bloating compared
with placebo.31 Although all of these studies had a high
quality of reporting, larger studies with SSRIs together
with better trial designs are needed to determine the
effectiveness of these agents for the treatment of bloating
and distension. Notably, there were no studies identified
that assessed the effect of tricyclic antidepressants on
bloating ⁄ distension and this needs to be explored.
Opioid agents
Endogenous opioids have been shown to regulate GI
motility and can modulate visceral sensitivity along the
digestive tract.105 In addition, opioid receptors closely
interact with the 5-HT4 receptors in the enteric nervous
system and opioid antagonists have synergistic effects
with 5-HT4 agonists on bowel motility.106, 107 Fedoto-
zine, a peripheral kappa receptor agonist, was studied in
a dose-ranging trial in patients with FD symptoms for 6
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weeks. Compared with placebo, fedotozine at doses of 30
and 70 mg tid significantly decreased postprandial full-
ness and bloating scores (supplementary Table S5).108 In
a dose-ranging, placebo-controlled study in patients with
IBS symptoms, 30 mg of fedotozine was superior to
placebo in relieving maximal daily abdominal bloating
measured as a secondary variable (supplementary Table
S5).109 Naloxone is a high affinity l-opioid receptor
competitive antagonist with a lower affinity for j- and d
receptors. In a very small, placebo-controlled trial in
IBS-C and IBS-A patients, naloxone was not associated
with a significant change in bloating scores compared
with placebo (supplementary Table S5).110 The quality of
reporting of these studies was good.
Antidiarrhoeal agents
The efficacy of antidiarrhoeals has been assessed for the
treatment of IBS symptoms including bloating. For
example, lidamidine is an agonist of the alpha-2 recep-tors located presynaptically on colonic nerves, inhibiting
the release of acetylcholine. However, its main effect
appears to be the inhibition of secretion rather than
motility.111 A small crossover study of lidamidine vs.
placebo in 62 patients with IBS and distension (IBS-D:
26%, IBS-C: 33%, IBS-A: 41%) reported no change in
abdominal distension in either group (supplementary
Table S5).112 Another small trial in Romania compared
the efficacy of diosmectite, a natural silicate of aluminium
and magnesium used as an intestinal adsorbent, with the
mu receptor agonist loperamide, in patients with func-tional diarrhoea. Diosmectite, but not loperamide,
reduced bloating severity (supplementary Table S5).113
Antibiotics
Based on the presumption that the production of the so
called ‘gas-related’ symptoms is either from bacterial fer-
mentation of carbohydrates in the colon, altered gut flora
or small bowel bacterial overgrowth (SIBO), it is reason-
able to hypothesise that antibiotics can relieve bloating
and distension.4 Rifaximin is an antibiotic that lacks
intestinal absorption and is highly active even againstanaerobes.114 The efficacy of rifaximin vs. activated char-
coal was tested in a group of 34 patients with FGIDs
according to Rome I criteria. Although the specific disor-
ders were not described, the patients complained of
excessive passage of flatus, bloating, abdominal discom-
fort or pain not explained by structural or biochemical
abnormalities.115 Rifaximin at a dose of 400 mg twice
daily, but not charcoal, significantly reduced the H2
excretion on the lactulose hydrogen breath test and over-
all severity of symptoms (supplementary Table S6).
While rifaximin was associated with a reduction in the
mean number of flatus episodes and abdominal girth,
there was no change in bloating.115 By contrast, in a lar-
ger study by Sharara et al.116 of 124 patients with pre-
dominantly bloating and excessive flatulence with
negative lactulose hydrogen breath tests, rifaximin at a
dose of 400 mg twice daily was associated with signifi-
cant global symptom relief and reduction in bloating
scores compared with placebo (supplementary Table S6).
In the subset of seventy patients who fulfilled criteria for
IBS, rifaximin was also superior to placebo in relieving
bloating.
In a study conducted in IBS patients by Pimentel
et al.,117 rifaximin at a dose of 400 mg three times daily
for 10 days was superior to placebo in reducing the
bloating severity score during the 10-week follow-up per-
iod (supplementary Table S6). This improvement
remained after controlling for the higher baselineabdominal pain in the rifaximin group. Two recently
completed phase 3 multicentre trials compared the effi-
cacy of rifaximin at a dose of 550 mg three times daily
and placebo for 14 days in patients with nonconstipating
IBS.36 Adequate relief of IBS symptom of bloating was a
key secondary endpoint. The pooled results showed that
a significantly greater proportion of patients taking rifax-
imin reported adequate relief of bloating than those tak-
ing placebo (40% vs. 30%). These studies suggest that
rifaximin improves bloating in patients with FGIDs.
Probiotics, prebiotics and symbiotics
Colonic bacteria can generate intestinal gas through fer-
mentation of undigested materials, therefore, an imbal-
ance in gut microbiota may produce or exacerbate
bloating or distension.118 Some bacterial groups are more
prone to gas production than others, including Entero-
bacteriaceae and Clostridia,119 and to abnormal patterns
of short chain fatty acids.120 Hence, modification of the
microbiota may improve gas-related symptoms. Probiot-
ics are defined by the World Health Organization as live
micro-organisms that when administered in adequateamounts confer a health benefit on the host.121 They are
nonpathogenic microbial food supplements of human
origin that enter the GI tract in an active form improv-
ing its intestinal microbial balance and can have positive
effects on gut physiology and immunology.122 Prebiotics
are nondigestible food ingredients that beneficially affect
the host by promoting the growth and improving sur-
vival of probiotics residing in the colon. Prebiotics
include oligosaccharides (OS) and fructooligosaccharides
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(FOS). Finally, symbiotics are the combination of pro-
biotics and prebiotics.123 Several probiotics, prebiotics
and symbiotics have been evaluated in FGIDs and some
studies have assessed their efficacy for bloating and
distension.
Probiotics
Lactobacillus. One placebo-controlled study conducted
in IBS patients showed a beneficial effect on bloating,
while three other studies did not (supplementary Table
S6). Lactobacillus casei strain GG showed no effect vs.
placebo in IBS patients complaining of abdominal dis-
tension.118 Similarly, L. plantarum administered in a
rose-hip drink mixed with an oatmeal soup in patients
with IBS reportedly had no effect on bloating, but the
data were not shown.124 Lactobacillus reuteri, a major
component of lactobacillus that can decrease the intesti-
nal pH to a level that is unfavourable to most patho-
genic bacteria, significantly improved all analysed variables over time in IBS patients but there were no dif-
ferences in bloating compared with placebo.125 Lactoba-
cillus sporogenes ⁄ Bacillus coagulans (Bc) has been used in
food preparation products and it is classified as a lactic
acid bacillus.126 IBS patients allocated to Bc GBI-30
6086 , but not placebo, with higher baseline severity
scores for bloating significantly achieved improvement
during all 7-weekly comparisons.127
Compared with placebo, L. casei Shirota failed to
demonstrate differences in the occurrence or degree of
bloating compared with baseline in patients with chronicconstipation (supplementary Table S6).128 The same pro-
biotic was studied in adults not fulfilling criteria for any
GI diagnosis and found no difference in the Gastrointes-
tinal Symptoms Rating Scale (GSRS)-flatus score but
there was a trend in the distension subscore (supplemen-
tary Table S6). There was also no difference in the
Severity of Dyspepsia Assessment (SODA)-bloating sub-
score.129
Bifidobacterium spp. Two studies have demonstrated the
efficacy of B. infantis 35624 for bloating, flatulenceand ⁄ or distension in IBS patients irrespective of the
bowel habit subtype (supplementary Table S6).130, 131
Bifidobacterium animalis DN-173 010 has been shown to
decrease orocecal and colonic transit times.132 In a large
scale, controlled, 6-week trial in 267 primary care
patients with IBS-C, both live and heat-killed B. animalis
DN-173 010 significantly improved bloating; however,
the effect was greater with live B. animalis DN-173 010
at the third week. The authors speculated that heat-killed
probiotic may not be a true placebo and may have thera-
peutic properties that could have influenced the high
‘placebo’ response.133 Fermented milk containing B. lactis
DN-173 010 was studied in women with minor GI
symptoms but without any specific disorder.134 Com-
pared with controls, the B. lactis DN-173 010 group
reported greater improvements in the general well-being
and frequency of flatulence but not in bloating (supple-
mentary Table S6).
Probiotic mixtures. Kajander et al.135 hypothesised that a
mixture of probiotics could show greater efficacy than a
single probiotic in IBS, because of its multifactorial aeti-
ology. They compared the efficacy of a mixture that
included L. rhamnosus GG, L. rhamnosus LC705,
B. breve 99 and Propionibacterium freudenreichii ssp.
shermanii JS with placebo in IBS (supplementary Table
S6). The beneficial effects of these lactobacillus spp.
includes immunomodulation and prevention and treat-ment of diarrhoea, while Propionibacterium can alleviate
constipation.136, 137 During the 6-month treatment per-
iod, patients were allowed to continue their previous IBS
medications (fibre supplements, laxatives, antidiarrhoeals,
antispasmodics, antiflatulence agents and ⁄ or antidepres-
sants). At the end of the trial, the total symptom score
that included abdominal pain, distension, flatulence and
borborygmi was significantly lower with the probiotics
vs. placebo, with a median reduction of 42% vs. 6%
respectively. However, there was no difference in the
individual symptom of distension (supplementary TableS6).135
Two studies evaluated the effectiveness of VSL#3, a
mixture containing strains of three lyophilised species,
Bifidobacterium, Lactobacillus and Streptococcus (supple-
mentary Table S6). In the first study conducted in IBS-D
patients, there was a significant reduction in bloating
scores compared with baseline with VSL#3, but there
was only a trend compared with placebo.138 In a second
study in patients with significant bloating, there was no
significant difference in the reduction of bloating with
VSL#3 or placebo.139 Because of the difficulty in enroll-ing patients, only half completed the 8-week trial and a
third completed only 4 weeks.139
In summary, the efficacy of probiotics on bloating
symptoms has not been consistently demonstrated. Most
of the studies are relatively small and there is variability
in the quality of reporting. However, in high quality
studies, B. infantis 35624 and B. animalis appear to have
potential efficacy while Lactobacillus spp., B. lactis and
VSL#3 do not.
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Prebiotics
Fructooligosaccharides are nondigestible OS that are rap-
idly fermented into short-chain fatty acids in the colon,
mainly by bifidobacteria, promoting the growth of the
bacteria and stimulating colonic peristalsis.140 Compared
with placebo, FOS had no significant effect on distension
in IBS patients and those on FOS complained more of
flatulence.140 The quality of reporting in this study was
good. A novel prebiotic, B-GOS, composed of trans-
galactooligosaccharide mixture produced from the activity
of galactosyltransferase from B. bifidum NCIMB 41171 on
lactose, was recently evaluated in a pilot study in IBS. After
4 weeks, the prebiotic, particularly at the higher dose, sig-
nificantly enhanced faecal bifidobacteria, evaluated by
fluorescent in situ hybridisation using synthetic oligonu-
cleotide probes. Bloating improved with the 3.5 g ⁄ day
dose but worsened with 7.0 g ⁄ day (supplementary Table
S6). This study had a low quality of reporting.141
Symbiotics
A study in IBS-A patients analysed the efficacy of SCM-
III, a preparation of L. acidophilus, L. helveticus and
bifidobacteria in a vitamin and phytoextracts-enriched
medium, compared with the same dosage of the heat
inactivated symbiotic which served as the control.142
SCM-III significantly improved the intensity of the bloat-
ing sensation compared with baseline and the control
preparation at 6 weeks but was not distinguishable from
the control arm at 12 weeks (supplementary Table S6).
The quality of this study was rated as low. In patientswith symptoms of FGIDs, but who did not meet criteria
for any of the specific FGIDs diagnosis, the efficacy of
five combinations of intestinal microflora fermented in
substrates from whole plants, plants juices and minerals
were explored, but no conclusive evidence on their effi-
cacy could be made (supplementary Table S6).126
Complementary and alternative medicine
Herbal remedies. Carmint, a herbal medicine that is
thought to have antispasmodic, carminative and sedative
effects, was studied in a relatively small, but high quality IBS study (supplementary Table S7). Although bloating
severity and frequency decreased with carmint compared
with placebo, the confounding effect of other medica-
tions was not taken into account in this trial.143 In
another high quality study, Saito et al.144 compared the
efficacy of the herbal remedy St John’s Wort and placebo
on bloating in IBS patients. The effect of St. John’s Wort
on bloating was not significantly different than placebo.
Also, a Tibetan blend of 15 herbs was studied in IBS and
showed a within group improvement in the percentage
of patients reporting moderate to severe abdominal dis-
tension at 12 weeks with this formula, but there was no
difference compared with placebo.145 Finally, moxibus-
tion is a traditional Chinese medicine in which the moxa
leaf is pulverised and processed into a stick and then lit
and held over specific acupuncture points to warm them
and stimulate blood flow and energy. It was used in con-
junction with acupuncture in a small study in IBS.146 A
composite score that included bloating improved 52%
with moxibustion vs. 1.7% with sham ⁄ placebo.146
Although this study was designed according to the 2001
version of the Consolidated Standards of Reporting Tri-
als (CONSORT)147 and the 2002 Standards for Reporting
Interventions in Controlled Trial of Acupunture
(STRICTA) guidelines,148 it only had an intermediate
quality of reporting (supplementary Table S7).
Other therapies
Melatonin is a sleep promoting agent that is largely
secreted in the GI tract.149, 150 It is involved in the diges-
tive pathophysiology, but the exact mechanism of action
by which it regulates the gastrointestinal motility is not
well understood.151 Because sleep disturbances are com-
mon in IBS and melatonin can regulate sleep as well as
the bowel function, it has been studied in this disorder.
However, melatonin did not produce any effects on
bloating in patients with IBS and sleep disturbances,
although it decreased abdominal pain and increased the
rectal pain thresholds without influencing the sleepparameters.152 In addition, a pilot study in IBS showed
that hypnotherapy was superior to placebo in improving
the mean weekly distension score. This difference
reached significance by the fourth week of treatment.153
Taking into consideration the higher female preva-
lence of FGIDs such as FD, IBS and constipation-related
symptoms,154, 155 and increased bloating at the time of
menses,156 it has been suggested that ovarian hormones
play a role in these symptoms. The efficacy of leuprolide
acetate, a gonadotropin-releasing hormone, in relieving
GI symptoms including bloating was assessed in twostudies comparing 3 or 4 months treatment with
3.75 mg intramuscular administration vs. placebo.157, 158
The studies were conducted in women with symptoms of
nausea, vomiting, early satiety, anorexia, bloating and
distension that were unresponsive to conventional thera-
pies. The first trial reported that leuprolide significantly
improved the bloating score compared with baseline
while placebo did not. The second trial showed similar
improvements in both groups (supplementary Table S7).
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CONCLUSIONS
To the best of our knowledge, this is the first comprehen-
sive review on the treatment of bloating and distension.
We have found that at least two-thirds of the studies were
conducted in IBS patients in whom these symptoms were
evaluated as secondary variables. Less than 5% of the
treatment trials were performed in patients specifically
complaining of bloating and ⁄ or distension. Therefore, the
studies may not have been sufficiently powered to detect
significant differences in bloating and distension. In addi-
tion, many of the earlier trials performed within group
analyses of efficacy and not between group analyses and
therefore no definitive conclusions can be drawn from
their results. More importantly, the optimal patient
reported outcome measures to detect a treatment
response for bloating and visible abdominal distension
have yet to be determined. Moreover, it seems highly
likely that there is publication bias and negative trials are
less likely to be published, particularly with respect to
symptoms that are subjective and secondary outcome
measures such as bloating and distension.
The large majority of trials investigated the efficacy of
prokinetics and probiotics and the studies are heteroge-
neous in terms of the patient population, diagnostic cri-
teria for the FGIDs and outcome measures. The available
evidence suggests that currently there is no treatment
that has unequivocally proven to be effective for abdomi-
nal bloating or distension. Overall, some efficacy has
been demonstrated with 5HT4 agonists (cisapride in FD
and tegaserod in chronic constipation and IBS-C), lubi-prostone in both chronic constipation and IBS-C, rifaxi-
min in patients with predominantly bloating, as well as
in IBS and certain probiotics such as Bifantis 35624 and
B. animalis. While there are inconsistent results with the
other therapies, most have not been evaluated in well-
designed, appropriately sized trials that have employed
rigorous statistical analyses or in well-characterised
patient populations. Future studies need to develop valid
patient reported endpoints for bloating and distension,
evaluate these symptoms as primary outcome measures
and determine predictors of treatment response.
ACKNOWLEDGEMENTS
Declaration of personal interests: Dr Schmulson has
served as a consultant for Procter and Gamble, Novartis
and Schering-Plough. He has served as a speaker for
Nycomed, Schering-Plough, Novartis and Mayoli-Spin-
dler, and has received research funding from Nycomed
and Nestle. Dr Chang has served as a consultant for
Takeda, Forest, Rose Pharma, GlaxoSmithKline, Iron-
wood, Salix, Ocera and Movetis. She has received
research funding from Takeda, Rose Pharma and Prome-
theus. Declaration of funding interests: This study was
supported in part by grant PAPIIT, IN-210010 of
DGAPA, Universidad Nacional Autonoma de Mexico
(UNAM).
SUPPORTING INFORMATION
Additional Supporting Information may be found in the
online version of this article:
Table S1. Dietary interventions, antifoaming and
bulking agents for the treatment of bloating and disten-
sion.
Table S2. Osmotic laxatives and stimulants of fluid
secretion for the treatment of bloating and distension.
Table S3. Prokinetics for the treatment of bloating
and distension.
Table S4. Other serotoninergic agents and SSRI’s for
the treatment of bloating and distension.
Table S5. Opioid agonists and antidiarrhoeal agents
for the treatment of bloating and distension.
Table S6. Antibiotics, probiotics, prebiotics and sym-biotics for the treatment of bloating and distension.
Table S7. Complementary and alternative medicine
and other therapies for the treatment of bloating and
distension.
Please note: Wiley-Blackwell are not responsible for
the content or functionality of any supporting materials
supplied by the authors. Any queries (other than missing
material) should be directed to the corresponding author
for the article.
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