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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. Correspo ndence to: Dr L. Chang, Center for Neurobiology of Stress, 10945 Le Conte Avenue, PVUB 2114, Los Angeles, CA 90095-6949, USA. E-mail: linchang@uc la.edu 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 with functi ona l gas troint est ina l dis orders (FGI Ds) , howeve r, rel ati vel y lit tle is known about their treatment. Aim To review the treatment trials for abdominal bloating and distension. Methods A lit erature rev iew in Medlin e for Eng lis h-l ang uag e pub lic ations thr oug h Feb ruar y 2010 of randomise d, con tro lled tre atment tri als 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- tio n and 10% wit h other FGIDs. No studie s were con duc ted in pati ent s diagnosed with functional abdominal bloating. The majority of trials inves- tigated the efcacy of prokinetics or probiotics, although studies are hetero- gene ous wi th respect to di agno sti c crit er ia and outcome me as ure s. 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- mar y endpoi nts. A gre ate r pro por tion of IBS pat ien ts wit h con stipation 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 signicantly reduced with the probi otics, Bido bacter ium infant is 35624 (1 · 10 8 dos e vs. pla ceb o: )0 .7 1 v s. )0.44, P < 0.05) an d B. anima li s (live vs. heat-k il le d: )0.56 Æ 1.01 vs. )0.31 Æ 0.87, P = 0.03). Conclusions Prokinetics, lubiprostone, antibiotics and probiotics demonstrate efcacy for the treatment of blo ati ng and   ⁄  or dis ten sion in cer tai n FGIDs, but other agents have either not been studied adequately or have shown conicting results.  Aliment Pharmacol Ther 2011; 33: 1071–1086 ª 2011 Blackwell Publishing Ltd 1071 doi:10.1111/j.1365-2036.2011.04637.x Alimentary Pharmacology and Therapeutics

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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.

  Aliment Pharmacol Ther 2011; 33: 1071–1086

ª 2011 Blackwell Publishing Ltd 1071doi:10.1111/j.1365-2036.2011.04637.x

Alimentary Pharmacology and Therapeutics

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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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