Ibs Cic Monograph Ajg Aug 2014

7262019 Ibs Cic Monograph Ajg Aug 2014

httpslidepdfcomreaderfullibs-cic-monograph-ajg-aug-2014 125

nature publishing groupVOLUME 109 SUPPLEMENT 1 AUGUST 2014S2

The American Journal of GASTROENTEROLOGY VOLUME 109 | SUPPLEMENT 1 | AUGUST 2014 wwwamjgastrocom

see related editorial on page x

Irritable bowel syndrome (IBS) and chronic idiopathic constipa-

tion ((CIC) also reerred to as unctional constipation) are two

o the most common unctional gastrointestinal disorders world-wide IBS is a global problem with anywhere rom 5 to 15 o the

general population experiencing symptoms that would satisy a

de1047297nition o IBS (12) In a systematic review on the global preva-

lence o IBS Lovell and Ford (1) documented a pooled prevalence

o 11 with all regions o the world suffering rom this disorder

at similar rates Given its prevalence the requency o symptoms

and their associated debility or many patients and the act that

IBS typically occurs in younger adulthood an important period

or urthering education embarking on careers andor raising

amilies the socioeconomic impact o IBS is considerable Tese

indirect medical costs are requently compounded by the direct

medical costs related to additional medical tests and the use o various medical and nonmedical remedies that may have limited

impact CIC is equally common in another systematic review

Suares and Ford (3) reported a pooled prevalence o 14 and also

noted that constipation was more common in emales in older

subjects and those o lower socioeconomic status (3) Chronic

constipation has also been linked to impaired quality o lie (4)

most notably among the elderly (5)

Neither IBS nor CIC are associated with abnormal radiologic

or endoscopic abnormalities nor are they associated with a

reliable biomarker diagnosis currently rests entirely thereore

on clinical grounds Although a number o clinical de1047297nitions

o both IBS and CIC have been proposed the criteria developed

through the Rome process currently in its third iteration havebeen those most widely employed in clinical trials and thereore

most relevant to any review o the literature on the management

o these disorders

According to Rome III IBS is de1047297ned on the basis o the pres-

ence of

Recurrent abdominal pain or discomort at least 3 daysmonthin the past 3 months associated with two or more o the ollowing

Improvement with deecation

Onset associated with a change in requency o stool

Onset associated with a change in orm (appearance) o stool

Tese criteria should be ul1047297lled or the past 3 months with

symptom onset at least 6 months beore diagnosis (6)

Rome III de1047297nes unctional constipation as the presence o

two or more o the ollowing

Straining during at least 25 o deecationsLumpy or hard stools in at least 25 o deecations

Sensation o incomplete evacuation or at least 25 o deeca-

tions

Sensation o anorectal obstructionblockage or at least 25

o deecations

Manual maneuvers to acilitate at least 25 o deecations

(eg digital evacuation support o the pelvic 1047298oor)

Fewer than three deecations per week

Furthermore loose stools are rarely present without the use

o laxatives and there are insuffi cient criteria or IBS Again these

criteria should be ul1047297lled or the past 3 months with symptom

onset at least 6 months beore diagnosis (6)In Rome III IBS is subtyped according to predominant bowel

habit as IBS with constipation (IBS-C) IBS with diarrhea (IBS-D)

mixed type (IBS-M) and unclassi1047297ed (IBS-U) Te de1047297nition o

bull

bull

bull

bullbull

bull

bull

bull

bull

American College of Gastroenterology Monograph on

the Management of Irritable Bowel Syndrome andChronic Idiopathic Constipation

Alexander C Ford MB ChB MD FRCP1 10 Paul Moayyedi BSc MB ChB PhD MPH FACG2 11 Brian E Lacy MD PhD FACG3 Anthony J Lembo MD4 Yuri A Saito MD MPH5 Lawrence R Schiller MD FACG6 Edy E Soffer MD FACG7 Brennan MR SpiegelMD FACG8 and Eamonn MM Quigley MD FACG9 for the Task Force on the Management of Functional Bowel Disorders

Am J Gastroenterol 2014 109S2ndashS26 doi101038ajg2014187

1 Leeds Gastroenterology Institute St Jamesrsquos University Hospital Leeds UK 2 Farncombe Family Digestive Health Research Institute Division of GastroenterologyMcMaster University Hamilton Ontario Canada 3 Dartmouth-Hitchcock Medical Center Lebanon New Hampshire USA 4 Harvard Medical School BethIsrael Deaconess Medical Center Boston Massachusetts USA 5 Mayo Clinic Rochester Minnesota USA 6 Baylor University Medical Center Digestive HealthAssociates of Texas Dallas Texas USA 7 Division of Gastroenterology Keck School of Medicine University of Southern California Los Angeles California USA8 UCLA School of Medicine UCLA VA Center for Outcomes Research and Education (CORE) Los Angeles California USA 9 Division of Gastroenterology andHepatology Houston Methodist Hospital and Weill Cornell Medical College Houston Texas USA 10 First author on the monograph but is not a member of theTask Force 11 Conducted systematic reviews with the support of AC Ford and carried out the technical analyses of the data independent of the Task ForceCorrespondence Eamonn MM Quigley MD FACG Chief Division of Gastroenterology amp Hepatology Houston Methodist Hospital and Weill Cornell MedicalCollege Houston Texas USA E-mail equigleyuccie

CME



copy 2014 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

SACG Monograph on IBS and CIC

bowel habit type is in turn based on the patientrsquos description o

stool orm by reerring to the Bristol Stool Scale (7) Te recogni-

tion that IBS sufferers segregate into subtypes according to pre-

dominant bowel habit together with research 1047297ndings suggesting

that IBS-C and IBS-D may be pathophysiologically distinct entities

(8ndash10) led to the development o therapies speci1047297cally directed at

each o these subtypes Nonetheless it is worth noting that symp-

toms may not be stable over a lietime and individuals may exhibit

one IBS subtype during a period and then a different IBS subtype

during another period in their lives

However although there is general awareness o the Rome

criteria they are inrequently employed in the assessment o

IBS and CIC in clinical practice (11) o provide more ldquoclinician

riendlyrdquo de1047297nitions as well as to permit inclusion o studies

that predated the Rome process American College o Gastro-

enterology ask Forces suggested the ollowing de1047297nitions in

prior systematic reviews

IBS is de1047297ned by abdominal discomfort associated with altered

bowel habits (12)Constipation is de1047297ned as a symptom-based disorder de1047297ned as

unsatisfactory defecation and is characterized by infrequent stools

diffi cult stool passage or both Diffi cult stool passage includes

straining a sense o diffi culty passing stool incomplete evacu-

ation hardlumpy stools prolonged time to stool or need or

manual maneuvers to pass stool CIC is de1047297ned as the presence o

these symptoms or at least 3 months (13)

It is important to note that the Rome III criteria state that i

ndividuals with chronic constipation do not ul1047297ll criteria or IBS

with pain or discomort being a major determinant in the latter

In practice a clear separation between CIC and IBS with constipa-

tion may be challenging and studies have shown not only consid-erable overlap between these entities (14ndash16) but also a signi1047297cant

tendency or patients to migrate between these diagnoses over

time (15) It is appropriate thereore that in this update o prior

American College o Gastroenterology monographs on IBS and

CIC these entities be addressed in the same exercise (121317)

Te goal o this exercise thereore was to update the most recent

systematic reviews commissioned by the American College o

Gastroenterology on IBS rom 2009 (17) and CIC rom 2005 (13)

METHODS

We have conducted a series o systematic reviews on the effi cacy

o therapy in IBS and CIC Tere have been several systematicreviews o therapy or IBS and CIC published in the past 5

years (18ndash22) Tere have been considerable data published in

the intervening time and hence we have thereore updated

all these systematic reviews o IBS and CIC and synthesized

the data including the inormation rom new trials where

appropriate

Te primary objective o this exercise was to assess the effi cacy

o available therapies in treating IBS and CIC compared with

placebo or no treatment Te secondary objectives included assess-

ing the effi cacy o available therapies in treating IBS according to

predominant stool pattern reported (IBS with constipation IBS

with diarrhea and mixed IBS) as well as assessing adverse events

with therapies or both IBS and CIC

Systematic review methodology

We evaluated manuscripts that studied adults (aged gt 16 years)

using any de1047297nition o IBS or CIC For IBS this included a cli-

nician-de1047297ned diagnosis the Manning criteria (23) the Kruis

score (24) or Rome I (25) II (26) or III (6) criteria For CIC

this included symptoms diagnosed by any o the Rome criteria

(62526) as well as a clinician-de1047297ned diagnosis We included

only parallel-group randomized controlled trials (RCs) com-

paring active intervention with either placebo or no therapy

Crossover trials were eligible or inclusion provided extractable

data were provided at the end o the 1047297rst treatment period beore

crossover

For IBS the ollowing treatments were considered

1 Diet and dietary manipulation

2 Fiber3 Interventions that modiy the microbiota probiotics prebiotics

antibiotics

4 Antispasmodics

5 Peppermint oil

6 Loperamide

7 Antidepressants

8 Psychological therapies including hypnotherapy

9 Serotonergic agents

10 Prosecretory agents

11 Polyethylene glycol

For CIC the ollowing were considered

1 Fiber

2 Osmotic and stimulant laxatives

3 5-H4 agonists


5 Bioeedback

6 Bile acid transporter inhibitors

7 Probiotics

Subjects needed to be ollowed up or at least 1 week o be

eligible trials needed to include one or more o the ollowing

outcome measures

(i) Global assessment o improvement in IBS or CIC symptoms

(ii) Improvement in abdominal pain or IBS

(iii) Global IBS symptom or abdominal pain scores or IBS

(iv) Mean number o stools per week during therapy or CIC

Search strategy for identification of studies

MEDLINE (1946 to October 2013) EMBASE and EMBASE

Classic (1947 to October 2013) and the Cochrane central register

o controlled trials were searched

Studies on IBS were identi1047297ed with the terms irritable bowel

syndrome and functional diseases colon (both as medical subject




S4 Ford et al

headings (MeSH) and ree text terms) and IBS spastic colon irri-

table colon and functional adj5 bowel (as ree text terms)

For RCs o dietary manipulation these were combined using

the set operator AND with studies identi1047297ed with the terms diet

fat-restricted diet protein-restricted diet carbohydrate-restricted

diet gluten-free diet macrobiotic diet vegetarian diet Mediterra-

nean diet fads gluten fructose lactose intolerance or lactose (both

as MeSH and ree text terms) or the ollowing ree text terms

FODMAP$ glutens food adj5 intolerance food allergy or food

hypersensitivity

For RCs o 1047297ber antispasmodics and peppermint oil these

were combined using the set operator AND with studies identi-

1047297ed with the terms dietary 1047297ber cereals psyllium methylcellulose

sterculia karaya gum parasympatholytics hyoscyamine scopo-

lamine trimebutine muscarinic antagonists or butylscopolammo-

nium bromide (both as MeSH and ree text terms) or the ollowing

ree text terms bulking agent psyllium 1047297ber 1047297ber husk bran

ispaghula wheat bran calcium polycarbophil spasmolytics spas-

molytic agents antispasmodics mebeverine alverine pinaveriumbromide otilonium bromide cimetropium bromide hyoscine butyl

bromide butylscopolamine peppermint oil or colpermin

For RCs o probiotics these were combined using the set oper-

ator AND with studies identi1047297ed with the terms Saccharomyces

Lactobacillus Bi1047297dobacterium Escherichia coli or probiotics (both

as MeSH and ree text terms) For RCs o prebiotics and synbiot-

ics these were combined using the set operator AND with stud-

ies identi1047297ed with the term prebiotic (both MeSH and ree text

terms) or synbiotic (both MeSH and ree text terms) For RCs o

antibiotics these were combined using the set operator AND with

studies identi1047297ed with the terms anti-bacterial agents penicillins

cephalosporins rifamycins quinolones nitroimidazoles tetracycline doxycycline amoxicillin cipro1047298oxacin metronidazole or tinidazole

(both as MeSH and ree text terms) or the ollowing ree text

terms antibiotic or rifamixin

For RCs o loperamide these were combined using the set

operator AND with studies identi1047297ed with the terms loperamide

or antidiarrheals (both as MeSH and ree text terms) or the ollow-

ing ree text terms imodium or lopex

For RCs o antidepressants and psychological therapies includ-

ing hypnotherapy these were combined using the set operator

AND with studies identi1047297ed with the terms psychotropic drugs

antidepressive agents antidepressive agents (tricyclic) desipramine

imipramine trimipramine doxepin dothiepin nortriptyline

amitriptyline selective serotonin reuptake inhibitors paroxetine sertraline 1047298uoxetine citalopram venlafaxine cognitive therapy

psychotherapy behavior therapy relaxation techniques or hypno-

sis (both as MeSH and ree text terms) or the ollowing ree text

terms behavioral therapy relaxation therapy or hypnotherapy

For RCs o serotonergic agents these were combined

using the set operator AND with studies identi1047297ed with the

terms serotonin antagonists serotonin agonists cisapride recep-

tors (serotonin 5-H 3 ) or receptors (serotonin 5-H

4 ) (both


5-H 3 5-H

4 alosetron cilansetron ramosetron prucalopride

mosapride or renzapride

For RCs o pro-secretory agents these were combined using

the set operator AND with studies identi1047297ed with the ollowing

ree text terms linaclotide or lubiprostone

For RCs o polyethylene glycol (PEG) these were combined

using the set operator AND with studies identi1047297ed with the term

polyethylene glycol (both as a MeSH and ree text term)

Studies on CIC were identi1047297ed with the terms constipation

or gastrointestinal transit (both as MeSH and ree text terms)

or functional constipation idiopathic constipation chronic

constipation or slow transit (as ree text terms) For the search

involving bioeedback the ree text terms dyssynergia pelvic

1047298oor dysfunction anismus and outlet obstruction were also

added

For RCs o 1047297ber these were combined using the set operator

AND with studies identi1047297ed with the terms dietary 1047297ber cellulose

plant extracts psyllium cereals plantago or methylcellulose (both

as MeSH and ree text terms) or the ollowing ree text terms 1047297ber

soluble 1047297ber insoluble 1047297ber bran ispaghula metamucil fybogel or

ispaghula For RCs o osmotic and stimulant laxatives these were com-

bined using the set operator AND with studies identi1047297ed with

the terms laxatives cathartics anthraquinones phenolphthaleins

indoles phenols lactulose polyethylene glycol senna plant senna

extract bisacodyl phosphates dioctyl sulfosuccinic acid magne-

sium magnesium hydroxide sorbitol poloxamer (both as MeSH

and ree text terms) or the ollowing ree text terms sodium

picosulphate docusate milk of magnesia danthron senna and

poloxalkol

For RCs o 5-H4 agonists these were combined using the set

operator AND with studies identi1047297ed with the terms serotonin

agonists receptors or serotonin 5-H 4 (both as MeSH and ree textterms) or the ollowing ree text terms prucalopride velusetrag or

naronapride



ree text terms lubiprostone or linaclotide

For RCs o bioeedback these were combined using the set

operator AND with studies identi1047297ed with the MESH terms

biofeedback and psychology and the ollowing ree text terms

biofeedback or neuromuscular training

For RCs o bile acid transporter inhibitors these were com-


the ollowing ree text terms bile acid transporter elobixibat or

A3309 For RCs o probiotics these were combined using the set oper-


Lactobacillus Bi1047297dobacterium E coli or probiotics (both as MeSH

and ree text terms) For RCs o prebiotics and synbiotics these

were combined using the set operator AND with studies identi1047297ed

with the term prebiotic (both MESH and ree text terms) or synbi-

otic (both MESH and ree text terms)

Te search was limited to humans No restrictions were

applied with regard to language o publication A recursive

search o the bibliography o relevant articles was also conducted

DDW (Digestive Diseases Week) and UEGW (United European





Methodology for assessing levels of evidence and grading

recommendations

We used the GRADE (Grading o Recommendations Assessment

Development and Evaluation) system or grading the quality

o evidence and strength o recommendation or each medical

intervention (32) Te system has been widely used in evidence-based guidelines and is endorsed by all major gastrointestinal

societies (httpwwwgradeworkinggrouporg) Te quality o the

evidence is based on the study design as well as the extent o risk

o bias inconsistency indirectness imprecision and publication

bias that exists or the evidence supporting the intervention (33)

Quality o evidence is described as high to very low depending

on the extent to which urther evidence would change the esti-

mate o treatment effect (Box 1 ) Te grading scheme also classi-

1047297es recommendations as strong or weak according to the quality

o the evidence applicability to all patient groups balance o

bene1047297ts and risks patient preerences and cost With this graded

recommendation the clinician receives guidance about whetheror not recommendations should be applied to most patients and

whether or not recommendations are likely to change in the uture

afer production o new evidence ldquoStrongrdquo recommendations

represent a ldquorecommendation that can apply to most patients in

most circumstances and further evidence is unlikely to change our

con1047297dence in the estimate of treatment effect rdquo Te summary o the

evidence or IBS is presented in Table 1 the reasons or the deci-

sion on the quality o that evidence in Table 2 and the reasons

or the strength o recommendation in Table 3 Similarly the

summary o the evidence or CIC is presented in Table 4 the

reasons or the decision on quality o the evidence in Table 5 and

the reasons or the strength o recommendation in Table 6

RESULTS

Irritable bowel syndrome

1 Diet and dietary manipulation in IBS

(a) Role of diet in IBS Although ood intake is one o the most

common precipitants o symptoms in IBS (34) responses to

ood ingestion and interactions with components o the diet

have not typically undergone rigorous evaluation in the context

o a blinded trial Based on their own experiences IBS sufferers

have generated their own theories to explain this phenomenon or

seek guidance rom other usually unsupported dietary remedies

Box 1 Interpretation of the grading of the quality of evidenceQuality of evidence InterpretationHigh Further research is very unlikely to change our

confidence in the estimate of effectModerate Further research is likely to have an important

impact on our confidence in the estimate of effectand may change the estimate

Low Further research is very likely to have an importantimpact on our confidence in the estimate of effectand is likely to change the estimate

Very low The estimate of effect is very uncertain

From httpwwwgradeworkinggrouporg

Gastroenterology Week) abstract books were hand searched

between 2000 and 2013 Authors o trial reports that did not

give enough detail or adequate data extraction were contacted

and asked to contribute ull data sets Experts in the 1047297eld were

contacted or leads on unpublished studies

rials were assessed or risk o bias according to the methods

described in the Cochrane handbook [27] using the ollowing

characteristics method used to generate the randomization

schedule method used to conceal treatment allocation implemen-

tation o masking completeness o ollow-up and conduct o an

intention-to-treat analysis

Eligibility quality and outcome data were extracted by the

lead reviewer (Alexander Ford) and by a masked second reviewer

(Paul Moayyedi) on to specially developed orms Any discrepancy

was resolved by discussion between the two reviewers in order

to reach a consensus Data were extracted as intention-to-treat

analyses where all dropouts were assumed to be treatment ailures

wherever trial reporting allowed this

Data synthesis

For IBS whenever possible any improvement of global IBS

symptoms as a binary outcome was taken as the primary

outcome measure I this was not available improvement in

abdominal pain was used For CIC any improvement of global

CIC symptoms as a binary outcome was taken as the primary

outcome measure Te impact o interventions was expressed

as a relative risk (RR) o IBS or CIC symptoms not improv-

ing together with 95 con1047297dence intervals (CIs) I there were

suffi cient data RRs were combined using the DerSimonian

and Laird random effects model (28) to give a more conserva-

tive estimate o the effi cacy o individual IBS therapies Forcontinuous data such as global IBS symptom scores or indi-

vidual IBS symptom scores a standardized mean difference

with 95 CIs was calculated It should be noted that some

treatments may be bene1047297cial in IBS or CIC because o the

effects on outcomes other than global symptoms or abdominal

pain but this was not evaluated and was outside o the scope

o this review

ests o heterogeneity were reported (29) When the test o

heterogeneity was signi1047297cant (P lt 010 andor I 2 gt 25) the

reasons or this were explored by evaluating differences in

study population study design or study end points in subgroup

analyses Publication bias or other causes o small study effects

were evaluated using tests or unnel plot asymmetry (30) wheresuffi cient studies were identi1047297ed (31)

Te number needed to treat (NN) which is the number o

patients who would need to receive active therapy over and

above the control therapy or one to experience an improvement

in symptoms and the number needed to harm (NNH) which

is the number o patients who would need to receive active

therapy over and above the control therapy or one to experi-

ence an adverse event were calculated as the inverse o the

risk difference rom the meta-analysis and checked using the

ormula NN = 100 RRR times BR where BR is baseline risk and

RRR is relative risk reduction




S6 Ford et al

(b) Role of dietary manipulation in IBS Specialized diets may

improve symptoms in individual IBS patients

Recommendation weak Quality of evidence very low

We identi1047297ed 12 RCs that evaluated dietary intervention in

IBS (43ndash54) Following exclusions due to nonextractable data

(46485052ndash54) lack o relevant symptom data (454951) and

an intervention lasting lt 1 week (46) three evaluable RCs

involving 230 patients remained (434447)

Te 1047297rst o these addressed the impact o gluten in IBS In a

double-blind placebo-controlled trial 34 patients with IBS were

randomized to either remain on a gluten-ree diet or to receive

16 gday o gluten on completion o an open gluten-ree run-in

phase (44) In the gluten group 68 (1319) reported that their

Many IBS patients commonly believe that they have an allergy

to certain oods although true ood allergies are uncommon in

IBS (35) Tus although the prevalence o true ood allergies inWestern societies is between 1 and 3 in adults surveys o gas-

trointestinal clinic patients ound that 30ndash50 believed that their

symptoms represented ood allergy or ood intolerance (35ndash37)

Most ood-related IBS symptoms appear to represent ood intol-

erance although only 11ndash27 o patients can accurately identiy

the presumed offending ood when re-challenged in a double-

blind manner (38) Based on their own experiences with ood and

despite a lack o objective evidence to incriminate a speci1047297c ood

studies have shown that a majority o IBS patients institute dietary

changes (39ndash41) sometimes to an extent that may compromise

their nutrition (42)

Table 1 Summary of results of monograph on interventions for IBS

Statement

No of

trials

No of

patients

RR symptoms

(95 CI)

NNT

(95 CI) Recommendation

Quality of

evidence

Specialized diets may improve symptoms in individualIBS patients

3 230 NA NA Weak Very low

Fiber provides overall symptom relief in IBS 14 906 086 (080ndash094) 10 (6ndash33) Weak Moderate

Psyllium but not bran provides overall symptom reliefin IBS (data presented for psyllium)

7 499 083 (073ndash094) 7 (4ndash25) Weak Moderate

There is insufficient evidence to recommendprebiotics or synbiotics in IBS


Taken as a whole probiotics improve globalsymptoms bloating and flatulence in IBS

23 2575 079 (070ndash089) 7 (4ndash125) Weak Low

Rifaximin is effective in reducing total IBS symptomsand bloating in IBS-D


Certain antispasmodics provide symptomaticshort-term relief in IBS


Peppermint oil is superior to placebo in improving IBS

symptoms


There is insufficient evidence to recommendloperamide for use in IBS

2 42 044 (014ndash142) NA Strong Very low

As a class antidepressants are effective in symptomrelief in IBS

17 1084 067 (058ndash077) 4 (3ndash6) Weak High

A variety of psychological interventions are effectivein improving IBS symptoms

32 2189 068 (061ndash076) 4 (3ndash5) Weak Very low

Alosteron is effective in females with IBS-D 8 4987 079 (069ndash090) 8 (5ndash17) Weak Moderate

Mixed 5-HT4 agonists 5-HT

3 antagonists are not more

effective than placebo at improving symptoms ofIBS-C

9 2905 096 (083ndash111) NA Strong Low

Linaclotide is superior to placebo for the treatmentof IBS-C

3 2028 080 (075ndash085) 6 (5ndash8) Strong High

Lubiprostone is superior to placebo for the treatmentof IBS-C

3 1366 091 (087ndash095) 125 (8ndash25) Strong Moderate

There is no evidence that polyethylene glycolimproves overall symptoms and pain in patientswith IBS


CI confidence interval 5-HT3 serotonin subtype 3 5-HT

4 serotonin subtype 4 IBS irritable bowel syndrome IBS-C IBS with constipation IBS-D IBS with diarrhea NA

not available NNT number needed to treat RR relative risk






S8 Ford et al

symptoms were not adequately controlled as compared with 615

(40) in the placebo group Continuous symptom scores or

abdominal pain bloating satisaction with stool consistency and

tiredness were statistically signi1047297cantly better in those who main-

tained a gluten-ree diet

Te second o these studies examined the contribution o ood

allergy or hypersensitivity as assessed not by immunoglobulin

(Ig) E antibodies but by IgG antibodies (43) In a double-blind

parallel-group trial 150 IBS patients were randomized to either

an exclusion diet based on the presence o IgG antibodies to vari-

ous oods or a sham diet Participants were ollowed or 12 weeks

and symptoms assessed using a global impact score and the IBS

severity score Compared with 1166 (17) in the sham diet

group (P = 014) 28 (1865) in the exclusion diet intervention

arm noted a signi1047297cant improvement in symptoms Te authors

reported marginal statistical signi1047297cance in those with high adher-

ence to their diet

Te third study examined the role o FODMAPs (ermentable

oligosaccharides disaccharides monosaccharides and polyols)Forty-one IBS patients were randomized to a low-FODMAP diet or

their regular (habitual) diet or 4 weeks (47) O those randomized

to the low-FODMAP diet 68 (1319) reported adequate control

o their symptoms compared with 522 (23) o the habitual diet

group (P = 0005) Stool consistency did not differ between groups

stool requency was less in the low-FODMAP diet group A signi1047297-

cant limitation o this study was the lack o blinding regarding the

dietary intervention

Summary Belatedly perhaps the role o dietary components in

the precipitation o symptoms or even in the basic pathogenesis

o IBS is now being addressed o date two mechanisms intole-

rance and hypersensitivity have been addressed in clinical trialsalthough it is highly plausible that other mechanisms (eg stimu-

lation o gut hormones and interactions with the microbiota) may

also be relevant to the effects o ood or ood components While

recognizing the challenges that any investigation o the role o an

individualrsquos diet or o a speci1047297c ood component in IBS present

the current data provide limited guidance on the role o diet in the

management o IBS Gluten-ree and low-FODMAP diets show

promise but their precise role(s) in the management o IBS need

to be de1047297ned

2 Fiber in IBS

Fiber provides overall symptom relief in IBS

Recommendation weak Quality of evidence moderate Psyllium but not bran provides overall symptom relief in IBS

Recommendation weak Quality of evidence moderate

Increased intake o dietary 1047297ber is requently recommended

to improve bowel unction or IBS particularly or constipation-

related symptoms However insoluble 1047297bers requently cause

bloating and abdominal discomort

In updating our prior systematic review (18) we identi1047297ed

two additional studies or a total o 14 RCs (55ndash69) involving

906 patients All but 1047297ve trials did not differentiate IBS by subtype

and only two restricted recruitment to IBS-C (5866) T a b l e 2

C o n t i n u e d

S t a t e m e n t

Q u a l i t y a s s e s s m e n t

S t u d y l i m i t a t i o n s

I n c o n s i s t e n c y

I n d i r e c t n e s s o f e v i d e n c e

I m p r e c i s i o n

R e p o r t i n g b i a s

M i x e d 5 - H T

4

a g o n i s t s 5 - H T

3

a n t a g o n i s t s a r e n o t m o r e

e f f e c t i v e t h a n p l a c e b o a t

i m p r o v i n g s y m p t o m s o f

I B S - C

L o w

O n l y o n e t r i a l w a s l o w r i s k o f b i a s a n d

t h i s s t u d y w a s n e g a t i v e

S

i g n i fi c a n t h e t e r o g e n e i t y b e t w e e n s t u d -

i e s t h a t w a s u n e x p l a i n e d

3

3

3

L i n a c l o t i d e i s s u p e r i o r t o

p l a c e b o f o r t h e t r e a t m e n t

o f I B S - C

H i g h

3

3

3

3

N o t e v a l u a b l e

L u b i p r o s t o n e i s s u p e r i o r t o


o f I B S - C

M o d e r a t e

O n e o t h e r R C T p e r f o r m e d b u t u n a b l e

t o o b t a i n d i c h o t o m o u s d a t a f r o m t h

e

c o m p a n y o r a u t h o r s

3

3

E f f e c t m o d e s t

3

T h e r e i s n o e v i d e n c e

t h a t p o l y e t h y l e n e g l y c o l

i m p r o v e s o v e r a l l s y m p t o m s

a n d p a i n i n p a t i e n t s w i t h

I B S

V e r y l o w

B o t h t r i a l s a r e u n c l e a r r i s k o f b i a s

R

C T s c a n n o t b e c o m b i n e d a s d i f f e r e n t

p

o p u l a t i o n s s t u d i e d

3

N o s t a t i s t i c a l l y s i g n i fi -

c a n t e f f e c t o n a b d o m i n a l

p a i n o r o v e r a l l s y m p -

t o m s

O v e r a l l n u m b e r

o f p a t i e n t s s t u d i e d w a s

s m a l l


G R A D E

G r a d i n g o f R e c o m m e n d a t i o n s A s s e s s m e n t D e v e l o p m e n t a n d E v a l u a t i o n 5 - H T

3 s e r o t o n i n

s u b t y p e 3 5 - H T

4 s e r o t o n i n s u b t y p e 4 I B S

i r r i t a b

l e b o w e l s y n d r o m e I B S - C

I B S w i t h c o n s t i p a t i o n I B S - D

I B S w i t h

d i a r r h e a R C T r a n d o m i z e d c o n t r o l l e d t r i a l

a C

h e c k m a r k s i n d i c a t e t h a t t h e c r i t e r i o n w a s f u l fi l l e d n o t a c o n c e r n





Table 3 Reasons for strength of recommendation for IBS therapies according to GRADE criteria

Statement

Recom-

mendation

Quality of

evidence All patient groups Benefits vs risks Patient values Costa

Specialized diets may improvesymptoms in individual IBS

patients

Weak Very low Likely to relate to onlysome IBS patients

Some diets are very strin-gent and difficult to follow

3 b 3

Fiber provides overall symptomrelief in IBS

Weak Moderate May only relate toIBS-C most trials did

not state type of IBSpatient

Fiber can cause bloatingand abdominal discomfort

Some patients donot like taking fiber

supplements

3

Psyllium but not bran provides

overall symptom relief in IBS

Weak Moderate May only relate to

IBS-C most trials didnot state type of IBS

patient

Fiber can cause bloating

and abdominal discomfort

Some patients do

not like taking fibersupplements

3

There is insufficient evidenceto recommend prebiotics or

synbiotics in IBS

Weak Very low Likely that only somepatients will respond

3 3 Can be expensiveto patients

Taken as a whole probiotics

improve global symptoms bloatingand flatulence in IBS

Weak Low Likely that only some

patients will respond3 3 Can be expensive

to patients

Rifaximin is effective in reducing

total IBS symptoms and bloatingin IBS-D

Weak Moderate Likely that only some

patients will respond

Antibiotic resistance of

GI flora a concern if usewidespread Long-term

efficacy uncertain

3 Can be expensive

to patients

Certain antispasmodics providesymptomatic short-term relief in

IBS

Weak Low 3 3 3 3

Peppermint oil is superior toplacebo in improving IBS

symptoms

Weak Moderate 3 3 3 3

There is insufficient evidence to

recommend loperamide for usein IBS

Strong Very low 3 3 3 3

As a class antidepressants are

effective in symptom relief in IBS

Weak High 3 Both TCA and SSRI asso-

ciated with adverse eventswith an NNH of 9

Some patients do not

like the idea of takingantidepressants

SSRIs can be

expensive TCAs areinexpensive

A variety of psychological interven-

tions are effective in improving IBSsymptoms

Weak Very low 3 Can be time intensive for

patients


like the concept ofpsychotherapy

Most psychothera-

peutic interventionsare expensive

Alosteron is effective in femaleswith IBS-D

Weak Moderate 3 Concerns regardingischemic colitis

3 Can be expensiveand not freelyavailable


3

antagonists are not more effective

than placebo at improving symp-toms of IBS-C

Strong Low 3 3 3 3

Linaclotide is superior to placebo

for the treatment of IBS-C

Strong High 3 3 3 Expensive

Lubiprostone is superior to placebofor the treatment of IBS-C

Strong Moderate 3 3 3 Expensive

There is no evidence that poly-ethylene glycol improves overall

symptoms and pain in patientswith IBS

Weak Very low Not clear whetherthis intervention is

effective

Not clear whether thisintervention is effective and

hence although adverseevents are rare cannotevaluate risks vs benefits

3 Can be moderatelyexpensive for

patients

GI gastrointestinal GRADE Grading of Recommendations Assessment Development and Evaluation 5-HT3 serotonin subtype 3 5-HT

4 serotonin subtype 4

IBS irritable bowel syndrome IBS-C IBS with constipation IBS-D IBS with diarrhea NNH number needed to harm SSRI selective serotonin reuptake inhibitorTCA tricyclic antidepressanta Cost was classified as expensive for the health service if the listed medication cost was gt $5 per day At this level an economic analysis ( 289) has shown there is lesscertainty that the drug is cost effective although it is important to emphasize that this will be cost effective for some patients but may not be for those with milder

symptomsb Check marks indicate that the criterion was fulfilled not a concern




10 Ford et al

Table 4 Summary of results of monograph on interventions for CIC

Statement

No of

trials

No of

patients

RR symptoms

(95 CI) NNT (95 CI) Recommendation

Quality of

evidence

Some fiber supplements increase stool frequencyin patients with CIC

3 293 025 (016ndash037) 2 (16ndash3) Strong Low

PEG is effective in increasing stool frequency andimproving stool consistency in CIC


Lactulose is effective in increasing stool frequencyand improving stool consistency in CIC


Sodium picosulfate and bisacodyl are effectivein CIC


Prucalopride is more effective than placebo atimproving symptoms of CIC


Linaclotide is effective in CIC 3 1582 084 (080ndash087) 6 (5ndash8) Strong High

Lubiprostone is effective in the treatment of CIC 4 651 067 (058ndash077) 4 (3ndash6) Strong High

Biofeedback is effective in CIC patients withdemonstrated evidence of pelvic floor dyssynergia


CI confidence interval CIC chronic idiopathic constipation NNT number needed to treat PEG polyethylene glycol RR relative risk

Table 5 Reasons for quality of evidence of assessment of data on CIC according to GRADE criteria

Statement

Quality

assessment Study limitations Inconsistency

Indirectness

of evidence Imprecision Reporting bias

Some fiber supplementsincrease stool frequency in

patients with CIC

Low All trials were unclearrisk of bias but did

show a marked effect

End points different evenin the studies that could be

combined

3 a Only a smallnumber of patients

studied

Not evaluable

PEG is effective in increasingstool frequency and improv-ing stool consistency in CIC

High All RCTs low risk ofbias and demonstratedstrong treatment effect

Moderate heterogeneitybetween studies

3 3 Not evaluable

Lactulose is effective inincreasing stool frequencyand improving stoolconsistency in CIC

Low Both trials at high riskof bias but there was astrong treatment effect


3 Only a smallnumber of patientsstudied with wide95 CIs

Not evaluable

Sodium picosulfate andbisacodyl are effective inCIC

Moderate Both trials low risk ofbias and strong treat-ment effect

Significant heterogeneitybetween studies

3 Modest number ofpatients studied foreach intervention

Not evaluable

Prucalopride is moreeffective than placebo atimproving symptoms of CIC

Moderate 5 8 Trials were low riskof bias and these stud-ies were also positive

Significant heterogeneitybetween studies that wasunexplained

3 3 3

Linaclotide is effective inCIC

High 3 3 3 3 3

Lubiprostone is effective inthe treatment of CIC

High Two trials low risk ofbias strong treatmenteffect

3 3 3 Not evaluable

Biofeedback is effective inCIC patients with demon-strated evidence of pelvicfloor dyssynergia

Low All three trials werehigh risk of bias butthe treatment effectwas marked

End points different evenin the studies that could becombined and interventionslightly different betweenstudies

3 Very modestnumber of patientsstudied

Not evaluable

CI confidence interval CIC chronic idiopathic constipation GRADE Grading of Recommendations Assessment Development and Evaluation PEG poly-ethylene glycol RCT randomized controlled triala Check marks indicate that the criterion was fulfilled not a concern





In the largest study to date 275 patients o whom 53ndash58 wereIBS-C and 19ndash29 were IBS-D were randomized to one o three

arms 10 g o the soluble 1047297ber psyllium 10 g o the insoluble 1047297ber

bran or 10 g o a placebo once daily or 12 weeks (57) During the

1047297rst month a signi1047297cantly greater proportion o patients receiv-

ing psyllium but not bran reported adequate symptom relie or

at least 2 weeks compared with placebo (57 vs 35 psyllium vs

placebo RR 160 95 CI 113ndash226) Bran was more effective than

placebo during the third month o treatment only (57 vs 32

170 112ndash257) Afer 3 months o treatment symptom severity

in the psyllium group was reduced by 90 points compared with

49 points in the placebo group (P = 003) and 58 points in the

bran group (P = 061 vs placebo) No differences were ound with

respect to quality o lie Dropout was most common in the brangroup most commonly because o exacerbation in IBS

Data on overall adverse events were only provided by six trials

(575860646569) Tese trials evaluated 566 patients but as

numbers o adverse events were so small in 5 o the trials pooling

o data was not carried out A total o 130 (388) o 335 patients

receiving 1047297ber reported adverse events compared with 63 (273)

o 231 in the placebo arms

Summary Although its use in the management o IBS is time

honored the status o 1047297ber in general in IBS is ar rom straight-

orward Insoluble 1047297bers may exacerbate symptoms and provide

little relie soluble 1047297bers and psyllium in particular provide relie

in IBS Tese latter effects appear to transcend expected bene1047297ts interms o relie o constipation

3 Interventions that modify the microbiota probiotics prebiotics

and antibiotics

Te suggestion that the gut bacteria could be relevant to IBS

1047297rst came rom the observation that a small although de1047297nite

proportion o individuals who suffer an episode o bacterial

gastroenteritis will go on to develop IBS de novo postinec-

tious IBS (70) Although bacterial ermentation has been linked

to bloating and 1047298atulence and changes in the microbiota have

been described in IBS the contribution o the microbiota to

these or other symptoms in IBS is unclear Tus although both

small intestinal bacterial overgrowth (SIBO) (71) and quantita-tive and qualitative changes in the ecal microbiota (72) have

also been linked to IBS (73) the overall contribution o SIBO to

IBS remains controversial (74) and 1047297ndings in relation to the

microbiota require con1047297rmation in larger patient populations

Prebiotics probiotics and prebioticndashprobiotic preparations

have been used or decades on an empirical basis by IBS suffer-

ers they have only recently been subjected to scrutiny in clini-

cal trials Te interpretation o probiotic studies in IBS remains

challenging as studies have employed different species strains

preparations and doses in various patient populations and ofen

in substandard trials

Table 6 Reasons for strength of recommendation for treatments of CIC according to GRADE criteria

Statement

Recommen-

dation

Quality of

evidence

All patient

groups Benefits vs risks Patient values Costa

Some fiber supplements increase stoolfrequency in patients with CIC

Strong Low 3 b Fiber can cause bloatingand abdominal discomfort


supplements

3

PEG is effective in increasing stoolfrequency and improving stoolconsistency in CIC

Strong High 3 3 3 Can be expensiveto patients

Lactulose is effective in increasingstool frequency and improving stoolconsistency in CIC

Strong Low 3 Lactulose can causebloating

3 3

Sodium picosulfate and bisacodyl areeffective in CIC

Strong Moderate 3 3 3 3

Prucalopride is more effective thanplacebo at improving symptoms of CIC


Linaclotide is effective in CIC Strong High 3 3 3 Expensive

Lubiprostone is effective in the treatmentof CIC


Biofeedback is effective in CIC patientswith demonstrated evidence of pelvicfloor dyssynergia

Weak Low 3 3 Some patients notreceptive to the ideaof biofeedback

Expensive

CIC chronic idiopathic constipation GRADE Grading of Recommendations Assessment Development and Evaluation PEG polyethylene glycola Cost was classified as expensive for the health service if the listed medication cost was gt $5 per day At this level an economic analysis (289) has shown thereis less certainty that drug is cost effective although it is important to emphasize that this will be cost effective for some patients but may not be for those withmilder symptomsb Check marks indicate that the criterion was fulfilled not a concern




12 Ford et al

pseudorandomized and included acupuncture in both study arms

(104) and hence we excluded these two studies (103104) Tere-

ore in total there were 35 RCs (83ndash102105ndash119) involving

3452 patients Fourteen trials were at low risk o bias (878991ndash

939799101105109ndash111118119) with the remainder being

unclear

Tere were 23 RCs involving 2575 patients (as reported on

Table 1 ) that gave outcomes as a dichotomous variable Probiotics

were statistically signi1047297cantly better than placebo (RR o IBS not

improving = 079 95 CI 070ndash089) with the NN o 7 (95 CI

4ndash125) Tere was statistically signi1047297cant heterogeneity between

studies A urther complicating actor in the assessment o probi-

otics was the use o a great variety o preparations Combination

probiotics as well as ormulations based on speci1047297c species (but

widely variable strains) Lactobacillus Bi1047297dobacterium Escherichia

and Streptococcus were assessed in individual trials Subanalysis

only demonstrated a signi1047297cant effect or combination probiot-

ics Lactobacillus plantarum DSM 9843 and E coli DSM17252 but

there was signi1047297cant heterogeneity between studies or the 1047297rsttwo and only one study or the third

Tere were 24 trials making 25 comparisons and assessing

2001 patients who reported improvement in global IBS symp-

tom scores or abdominal pain scores Tere was a statistically

signi1047297cant effect o probiotics in reducing symptoms with

no signi1047297cant heterogeneity Subanalysis on this occasion

revealed signi1047297cant effects or combinations o probiotics but

not or those containing Lactobacillus spp Bi1047297dobacterium spp

or Saccharomyces spp

Tere were 17 separate trials making 18 comparisons and con-

taining 1446 patients that reported the effect o probiotics on

bloating symptom scores Overall bloating scores were signi1047297-cantly reduced with probiotics but with signi1047297cant heterogeneity

between individual study results

In the 10 trials that assessed this outcome 1047298atulence scores were

signi1047297cantly lower with probiotics compared with placebo with no

signi1047297cant heterogeneity detected

Tere was no apparent bene1047297t detected or probiotics on urgency

in the six trials that assessed this symptom

otal adverse events were reported by 24 RCs containing 2407

patients Overall 201 (165) o 1215 patients allocated to probi-

otics experienced any adverse event compared with 164 (138) o

1192 assigned to placebo with the NNH o 35 (95 CI 16ndash362)

We identi1047297ed 6 RCs (120ndash124) involving 1916 participants

that evaluated antibiotic therapy in IBS patients wo trials eval-uating metronidazole (125) and riaximin (126) were excluded

as they did not provide extractable data A urther RC ( 127)

assessed Helicobacter pylori eradication therapy but was excluded

as it assessed symptoms 2 years afer a 1-week course o antibi-

otics Overall antibiotic therapy improved IBS symptoms com-

pared with placebo with no signi1047297cant heterogeneity between

studies One trial (124) evaluated neomycin in 111 patients

with a signi1047297cant effect in avor o neomycin (RR = 073 95

CI 056ndash096) with the NN o 5 (95 CI 3ndash33) Te remain-

ing 5 trials (120ndash123) evaluated riaximin in 1805 IBS patients

Tere was a statistically signi1047297cant bene1047297t in avor o the anti-

Although initial studies employing the lactulose hydrogen

breath test suggested that more than ldquothree quartersrdquo o all

IBS suerers had SIBO (75) subsequent studies have in gen-

eral ailed to conirm such a high prevalence o SIBO in IBS

(7374) hese divergent results may relate to problems inher-

ent to the lactulose breath hydrogen test that may provide an

overestimation o the true positive rate (73) Nevertheless this

inding provided a rationale or assessing antibiotics in IBS

Riaximin a nonabsorbable antibiotic has demonstrated ei-

cacy in clinical trials in IBS-D and although statistically signi-

icant improvements were demonstrated over placebo in global

IBS symptoms as well as in bloating it is important to note that

tests or SIBO were not perormed in these pivotal trials leav-

ing the mechanism o action o riaximin in IBS unclear (76)

(a) Prebiotics and synbiotics in IBS Tere is insuffi cient evidence to

recommend prebiotics or synbiotics in IBS


(b) Probiotics in IBS aken as a whole probiotics improve global

symptoms bloating and 1047298atulence in IBS

Recommendations regarding individual species preparations or

strains cannot be made at this time because o insuffi cient and con-

1047298icting data

Recommendation weak Quality of evidence low

(c) Antibiotics in IBS Te poorly absorbable antibiotic rifaximin is

effective at reducing total IBS symptoms and bloating in diarrhea-

predominant IBS


We identi1047297ed one RC that evaluated the prebiotic trans-

galactooligosaccharide in IBS (77) this study was excluded rom

urther analysis as the data were not extractable In relation to

probiotics it should be noted that changes in diet and intake

o dietary 1047297ber can exert prebiotic effects on gut microbiota

these are addressed in previous sections We identi1047297ed two trials

assessing 198 IBS patients that evaluated synbiotics vs control

preparations (7879) Both studies evaluated different products

We excluded two other RCs o synbiotics in IBS as data were

not extractable in one case (80) and in the second there was no

control arm (81)

Tere was one study that assessed dichotomous outcomes in

68 patients (79) Tere were 7 (206) o 34 patients assigned tosynbiotics with persistent symptoms compared with 30 (882)

o 34 assigned to control therapy (P lt 001) Both trials (7879)

assessed global IBS symptoms on a continuous scale in 185

patients there was no statistically signi1047297cant effect o synbiotics

in reducing IBS symptom scores even though both trials were

individually positive again because o signi1047297cant heterogeneity

We updated our previous systematic review and meta-analy-

sis on probiotics in IBS (2282) and identi1047297ed a total o 20 new

trials (83ndash102) However one o these was a ull publication o a

trial previously included in the original meta-analysis in abstract

orm (89103) and one trial in the original meta-analysis was





biotic (RR = 084 95 CI 078ndash090) with the NN o 9 (95 CI

6ndash125) Tere were three (122123) low risk o bias trials assess-

ing 1330 patients

Tree RCs reported adverse events (121122124) in 1456

patients Tere was no difference in overall adverse events between

the antibiotic and placebo groups (RR o adverse events = 070

95 CI 042ndash116)

Summary Although data accumulate to suggest a role or the

microbiota in IBS the primacy o any reported changes in enteric

populations in the pathogenesis o IBS remains to be con1047297rmed

Although at this time there is insuffi cient evidence to permit

a recommendation on the use o prebiotics or synbiotics in IBS

aggregated data do indicate a bene1047297cial effect or probiotics with

bloating and 1047298atulence appearing to be especially responsive

Tough recognizing the intrinsic differences that exist between

individual probiotic strains and the consumerrsquos desire to obtain

guidance on product selection limitations intrinsic to available

data as well as a lack o comparative studies severely limit onersquos

ability to recommend a particular strain or product at this timeTe antibiotic riaximin although not approved or this indication

by the Food and Drug Administration has shown modest but con-

sistent effi cacy in nonconstipated IBS and seems to be well toler-

ated and despite concerns regarding the long-term or repeated use

o an antibiotic has proven sae at least over the time periods in

which it has been evaluated

4 Antispasmodics in IBS

Antispasmodics have been used or decades on an empirical

basis in the treatment o IBS based on the assumption that gut

and especially colonic smooth muscle spasm contributes to IBS

symptoms and pain in particular hence the term spastic colon Certain antispasmodics (otilonium hyoscine cimetropium pina-

verium and dicyclomine) provide symptomatic short-term relief in

IBS Adverse events are more common with antispasmodics than

placebo


We identi1047297ed 23 RCs (606467128ndash147) evaluating 2154

patients with IBS Tere was considerable variation between

the studies concerning diagnostic and inclusion criteria dosing

schedule and study end points Only 3 studies used standard-

ized diagnostic criteria (Rome I or II) (131138140) whereas

all other 20 studies used author-de1047297ned IBS re1047298ecting the act

that most trials were conducted beore Rome de1047297nitions werepublished Te majority o trials did not differentiate between

the types o IBS patients recruited Overall the quality o trials

was poor with only 4 recruiting more than 100 patients Only

our trials (67131133144) reported an adequate method o

randomization and none reported on concealment o alloca-

tion although all were double blind Risk o bias was unclear

in all o the trials O the drugs used in the various studies only

hyoscine (6467146) and dicyclomine (142) are available in the

United States

Tis review shows that as a class antispasmodic therapy has a

statistically signi1047297cant effect in improving IBS symptoms with the

NN o 5 (95 CI 4ndash9) However the effect o individual anti-

spasmodics is variable and diffi cult to interpret as there are only a

small number o studies evaluating each o the 12 different drugs

available or review

With respect to individual agents otilonium (128129131

132138) hyoscine bromide (6467146) cimetropium bromide

(130134143) pinaverium bromide (133139147) and dicyclo-

mine hydrochloride (142) showed bene1047297cial effects with NNs o

5 3 3 3 and 4 respectively However some o these were evalu-

ated in as ew as just one study (142) and or those that were

assessed in multiple studies heterogeneity was a problem in some

instances

Mebeverine (one trial) trimebutine (three trials) pirenzipine

(one trial) alverine (one trial) rociverine (one trial) pri1047297nium

(one trial) and propinox (one trial) did not have a statistically sig-

ni1047297cant effect on IBS symptoms although the numbers o patients

studied were small

Fifeen trials included in this review reported adverse events

with either active drug or placebo In total 144 (163) o 883patients assigned to antispasmodics experienced adverse events

compared with 92 (104) o 882 allocated to placebo When data

were pooled the incidence o adverse events was signi1047297cantly

higher among those taking antispasmodics as compared with

placebo (RR o experiencing any adverse event = 161 95 CI

108ndash239) with the NNH o 20 (95 CI 95ndash333) Te most

common adverse events were dry mouth dizziness and blurred

vision but there were no serious adverse events reported in either

treatment arm in any o the trials

Summary Although many o the relevant clinical trials are old

and ar rom ideal in terms o quality antispasmodics as a cate-

gory are effective in IBS though their use may be limited by anti-cholinergic adverse events However not all antispasmodics have

been shown to be effective and studies on individual agents vary

in quality and outcome measures Furthermore the availability

o some o the more effective agents may be limited to certain

regions

5 Peppermint oil in IBS

Peppermint oil can be ound in various preparations available

through conventional or complementary venues Limited experi-

mental data suggest that it can relax smooth muscle but it may

also have effects via attenuation o visceral hypersensitivity and

modulation o pain sensation and hence its use or the treatment

o IBSPeppermint oil is superior to placebo in improving IBS symptoms

Te risk of adverse events is no greater with peppermint oil than with

placebo


We identi1047297ed 1047297ve RCs (148ndash152) involving 482 patients

Most trials did not differentiate between the types o IBS patients

recruited with only one study providing data on this (148) Tere

was only one RC at low risk o bias (152) with the remainder

being unclear Tis RC reported a less dramatic effect o pepper-

mint oil on IBS symptoms compared with placebo but this was




14 Ford et al

depressants having persistent abdominal pain ollowing treat-

ment as compared with 123 (728) o 169 subjects allocated to

placebo giving a RR o abdominal pain persisting o 062 (95 CI

043ndash088) but with considerable heterogeneity between studies

(I 2 = 724 P = 0001)

ricyclic antidepressants were studied in 11 RCs involving

744 patients (64156ndash158160163165ndash169) and active therapy

was associated with a reduction in IBS symptoms compared with

placebo with the NN o 4 Selective serotonin reuptake inhibi-

tors were studied in 7 RCs involving 356 patients (159161ndash164

170171) and active therapy was associated with a reduction in IBS

symptoms compared with placebo with the NN o 4

Only seven trials reported on overall adverse events vs pla-

cebo (157ndash160162166168) In total 65 (313) o 208 patients

assigned to antidepressants experienced adverse events as com-

pared with 33 (165) o 200 allocated to placebo When data


higher among those taking antidepressants as compared with

placebo (RR o experiencing any adverse event = 163 95 CI118ndash225) Te NNH was 9 (95 CI 5ndash111) Drowsiness and dry

mouth were more common in patients taking tricyclic antidepres-

sants than those on placebo

Summary Both tricyclic antidepressants and selective seroto-

nin reuptake inhibitors are effective in providing global symptom

relie and reducing pain in IBS Adverse events and patient as well

as physician acceptability have limited their use and in1047298uenced

our recommendation Available data other than adverse event

pro1047297le (eg constipating effects o tricyclic antidepressants)

do not permit guidance on patient selection or antidepressant

therapy

8 Psychological therapies including hypnotherapy in IBS

A variety of psychological interventions are effective in improving

IBS symptoms


We updated our previous systematic review and meta-analysis

on psychological therapies in IBS (20155) and identi1047297ed a total o

10 new papers containing 11 separate RCs thereby providing in

total 30 papers reporting 32 separate trials involving 2189 patients

(167172ndash200) Te quality o these trials was generally poor with

only 8 having a sample size o more than 100 (16717417517818

1189191194) Because o the nature o the intervention double-

blind studies would not have been possible but only our papersreported that investigators were blinded (167174175192) All o

the trials were at high risk o bias

Tere was a statistically signi1047297cant effect in avor o psycho-

logical therapies with the NN o 4 (95 CI 3ndash5) but with signi1047297-

cant heterogeneity between studies

In terms o the 10 different types o psychological therapies

evaluated the bene1047297ts were demonstrated or cognitive behav-

ioral therapy (NN o 3 (95 CI 2ndash6)) hypnotherapy (NN o

4 (95 CI 3ndash8) multi-component psychological therapy (NN

o 4 (95 CI 3 ndash7)) multi-component psychological therapy

administered via the telephone (NN o 5 (95 CI 3ndash17)) and

still statistically signi1047297cant Overall there was a statistically signi1047297-

cant effect in avor o peppermint oil compared with placebo with

the NN o 3 (95 CI 2ndash4) However there was signi1047297cant hetero-

geneity between results In these studies an enteric-coated prepa-

ration o peppermint oil was employed in doses ranging rom 187

to 225 mg tid

When data were pooled the incidence o adverse events was

not signi1047297cantly higher among those taking peppermint oil as

compared with placebo (RR o experiencing any adverse

event = 126 95 CI 075ndash212)

Summary In speci1047297c ormulations which may not be univer-

sally available peppermint oil is effective in IBS

6 Loperamide in IBS

Tere is insuffi cient evidence to recommend loperamide for use

in IBS

Recommendation strong Quality of evidence very low

Tere were two RCs (153154) involving 42 patients Tere wasno statistically signi1047297cant effect in avor o loperamide compared

with placebo Both trials stated the type o IBS patients recruited

with one study recruiting only IBS-M patients (153) and the other

only IBS-D (154)

Data on overall adverse events were provided in both trials

Tere were no adverse events in either arm in one trial (153) and

our adverse events in each arm o the other study (154)

Summary Although loperamide is an effective antidiarrheal

there is no evidence to support the use o loperamide or relie o

global symptoms in IBS

7 Antidepressants in IBS Antidepressants were 1047297rst introduced into the management o

IBS based on the observation that depression and anxiety were

requent comorbidities among IBS subjects seen in secondary and

tertiary care Subsequent studies suggested that in subdepression

doses these agents were effective in relieving pain o visceral

origin

Antidepressants (tricyclic antidepressants and selective serotonin

reuptake inhibitors) are effective in symptom relief in IBS

Side effects are common and may limit patient tolerance

Recommendation weak Quality of evidence high


on antidepressants in IBS (20) and identi1047297ed our urther papers(155) Overall there were 17 RCs (64156ndash171) evaluating 1084

patients Te majority o trials did not differentiate between the

type o IBS patients recruited with seven studies providing data

on this (159161162164ndash166170) one o which recruited only

IBS-C patients (164) and another only IBS-D patients (165) Only

three o the RCs were at low risk o bias (167169170) with the

remainder being unclear

Antidepressants were effective in treating IBS symptoms

with the NN o 4 (95 CI 3ndash6) Te effect o antidepressant

therapy on abdominal pain was reported by 7 RCs (158159161

164ndash166169) with 87 (467) o 182 patients receiving anti-





dynamic psychotherapy (NN o 35 (95 CI 2ndash25)) No signi1047297-

cant effects were evident or relaxation therapy sel-administered

cognitive behavioral therapy behavioral therapy delivered via the

internet stress management or mindulness meditation training

However the latter three have only been tested in one or two

RCs and thereore a de1047297nite lack o bene1047297t cannot be assumed

Only our trials (172178184187) used ldquoshamrdquo or ldquocontrolrdquo

psychological interventions as a comparison

Adverse events data were poorly reported by individual RCs

precluding any meaningul analysis

Summary Although issues relating to blinding and choice o

control intervention have complicated their evaluation a variety

o therapeutic approaches loosely aggregated under the term

ldquopsychological therapiesrdquo have been shown to be effective in IBS

Availability o skilled therapists experienced in the management

o IBS greatly limits their use


Serotonin (5-hydroxytryptamine (5-H)) plays a critical role ingastrointestinal secretion motility and sensation (201) and a vari-

ety o 5-H receptors have been targets or new drug development

in unctional gastrointestinal disorders (202) Te serotonin sub-

type 3 (5-H3 ) receptors have been shown to play an important

role in visceral pain and 5-H3 antagonists decrease painul sensa-

tions rom the gut and slow intestinal transit (203204) Alosetron

a selective 5-H3 antagonist was thereore evaluated in diarrhea-

predominant IBS and although it showed effi cacy instances o

severe constipation and ischemic colitis (205) led initially to its

withdrawal by the US Food and Drug Administration (FDA) It

was subsequently reintroduced by the FDA in a restricted manner

under a risk management plan or ldquowomen suffering with severediarrhea-predominant IBS that is disablingrdquo (httpwwwdagov

downloadsDrugsDrugSaetyPostmarketDrugSaetyInorma-

tionorPatientsandProvidersUCM227960pd accessed June 10th

2014) Te risk management plan was converted to a risk evalu-

ation and mitigation strategy in 2010 Other 5-H3 antagonists

such as cilansetron and ramosetron have never been introduced

into clinical practice

Te serotonin subtype 4 (5-H4 ) receptors are distributed through-

out the gastrointestinal tract and stimulation o these receptors

enhances intestinal secretion augments the peristaltic re1047298ex and

increases gastrointestinal transit (206207) egaserod is an amino-

guanidine-indole categorized as a partial selective 5-H4 agonist Te

FDA granted approval or the use o tegaserod in women with IBS withconstipation in July 2002 Because o possible cardiovascular adverse

effects tegaserod was withdrawn rom the US market in March 2007

egaserod is the only 5-H4 partial agonist that has been evaluated

in large prospective randomized controlled studies in IBS patients

As tegaserod is no longer available in the United States an updated

analysis o tegaserod effi cacy and saety has not been perormed Te

interested reader is reerred to the previous systematic review (19)

A number o selective 5-H4 agonists have been developed and have

shown effi cacy in constipation (eg prucalopride that is available in

Canada and the European Union) but no data are as yet available on

the effi cacy or saety o these agents or the treatment o IBS

(a) 5-H3 antagonists in IBS Alosteron is effective in females with

diarrhea-predominant IBS



sis (19) and identi1047297ed two new studies providing a total o 13

trials eligible containing 8173 patients or inclusion (208ndash220)

Only one trial was at low risk o bias (216) with the remainder

unclear All but one recruited nonconstipated IBS Most trials

recruited women only or predominantly women with the

exception o two Japanese studies where men predominated

(218219) and a US-based trial that recruited only men (213)

Overall there was a statistically signi1047297cant effect in avor o

5-H3 antagonists with the NN o 7 and signi1047297cant hetero-

geneity

Tere appeared to be no difference in effi cacy between the three

drugs alosetron (208210ndash214216) cilansetron (209215220) and

ramosetron (218219) within this class all proving effective with

NNs o 8 6 and 7 respectivelyTere were 9 studies (208210ndash214216218219) evaluat-

ing 5564 patients that provided total adverse event data 5-H3

antagonists had statistically signi1047297cantly more adverse events

than placebo (RR o any adverse event = 117 95 CI 108ndash125)

Te NNH was 11 (95 CI 8ndash17) Te main adverse event that

was more common with 5-H3 antagonists than with placebo was

constipation Ischemic colitis has been reported with alosetron

and it was withdrawn by the FDA in November 2001 In June

2002 the FDA announced the approval o a supplemental

New Drug Application that allowed restricted marketing o

alosetron to treat only women with severe diarrhea-predominant

IBS Te approval includes a risk management program (termeda risk evaluation and mitigation strategy since 2010) to ensure

patients and physicians are ully inormed o the theoretical risks

and possible bene1047297ts o alosetron (221)

(b) 5-H4 agonists in IBS No further analysis of these agents was

performed as there were no new data and tegaserod has been with-

drawn in most areas

(c) Mixed 5-H3 antagonists 5-H4 agonists Mixed 5-H 4

ago-

nists 5-H 3

antagonists are not more effective than placebo at

improving symptoms of constipation-predominant IBS

Recommendation strong Quality of evidence low

Te complex physiology involved in the generation o IBS symp-

toms is thought to represent an intricate balance o 5-H receptor

agonism and antagonism (201206207) Several agents classi1047297ed

as mixed 5-H3 antagonists5-H

4 agonists have been developed

or the treatment o IBS Tese are collectively and individually

reviewed below It should be noted that cisapride has not been

widely available since withdrawal rom the US market in July 2000

and that this drug was shown to be not more effective than placebo

in a recent meta-analysis (19)

A total o 9 double-blind placebo-controlled trials involv-

ing 2905 patients were eligible or inclusion (222ndash230) Four




16 Ford et al

95 CI 096ndash124) However diarrhea reported in all three trials

was signi1047297cantly more likely with linaclotide as compared with

placebo (RR = 662 95 CI 439ndash996) with the NNH o 6 (95

CI 55ndash8) Flatulence reported in two trials (232234) was also

signi1047297cantly more common with active therapy (RR = 227 95

CI 118ndash436) with the NNH o 50 (95 CI 23ndash167)

(b) Lubiprostone Lubiprostone is superior to placebo for the treat-

ment of constipation-predominant IBS

Recommendation strong Quality of evidence moderate

Lubiprostone activates the chloride channel type 2 (CIC-2) on

the apical surace o the intestinal epithelium Tis results in chlo-

ride and water 1047298ux into the intestinal lumen resulting in aster

transit through the small and large intestines

Four clinical trials o lubiprostone in IBS patients have been

reported in three separate papers (235ndash237) However one o

these was a mixed population o IBS and CIC patients (236)

Tree studies reported dichotomous data in 1366 IBS patients(235237) All trials were at low risk o bias Tere was a statis-

tically signi1047297cant effect in avor o lubiprostone as compared

with placebo with the NN o 125 (95 CI 8ndash25) and no sig-

ni1047297cant heterogeneity between the three individual trial results

Te quality o evidence was graded as moderate according to

GRADE criteria as the effect on overall IBS symptoms was mod-

est and the 95 CI or the RR was relatively close to a null effect

Furthermore dichotomous data or IBS patients rom one trial

were not available (236)

Data on overall adverse events were reported in all three trials

but pooled or the two trials reported in a single paper (235) In the

study by Johanson et al (237) adverse events were reported by 66o lubiprostone patients as compared with 58 o placebo but this

difference was not statistically signi1047297cant Nausea was also com-

moner (17 with lubiprostone compared with 4 with placebo)

but again this was not statistically signi1047297cant Te only adverse

event occurring more requently among those receiving lubipros-

tone was diarrhea (NNH = 10 95 CI 5ndash25) In the two studies

that pooled adverse events data (235) 50 and 51 o IBS patients

receiving lubiprostone and placebo respectively reported at

least one adverse event Diarrhea occurred in 6 o lubiprostone-

treated patients compared with 4 o those receiving placebo

Nausea was reported by 8 o those allocated to lubiprostone com-

pared with 4 o those assigned to placebo

Summary Te prosecretory agents linaclotide and lubiprostoneare effective in constipation-predominant IBS As both o these agents

were evaluated in comparison with placebo rather than ldquostandard

therapyrdquo their position in an IBS treatment algorithm (ie or those

who have ailed other treatments or as primary therapy) is diffi cult

to de1047297ne and complicated by lack o consensus on what ldquostandardrdquo

therapy should be in IBS given the limitations o data on other agents

11 PEG in IBS

Tere is no evidence that PEG improves overall symptoms and pain

in patients with IBS


studies each involved cisapride (223225227228) or renzapride

(222224226229) one study involved mosapride (230) Eight

trials recruited patients with constipation-predominant IBS

(222ndash225227ndash230) and one mixed IBS (226) Te methodological

quality o trials was low

Analysis o all nine studies revealed no statistically signi1047297cant

differences between placebo and mixed 5-H3 antagonists5-H

4

agonists or the treatment o IBS and signi1047297cant heterogeneity was

identi1047297ed between studies

In terms o individual agents neither renzapride (222224226

229) in constipation-predominant or mixed IBS nor mosapride

(230) showed signi1047297cant bene1047297t over placebo

Tere was no statistically signi1047297cant increase in adverse events

with mixed 5-H3 antagonists5-H

4 agonists as compared with

placebo

Summary O the various agonists and antagonists to serotonergic

receptors that have been developed and evaluated in IBS only aloset-

ron and ramosetron both 5-H3 antagonists are available (although

in certain regions only) and supported by evidence o effi cacyBecause o concerns regarding adverse events the use o alosetron

in the United States is limited to women with severe diarrhea-pre-

dominant IBS and can be prescribed only in the context o a careully

monitored program Ramosetron is approved or the management

o diarrhea-predominant IBS in Japan Korea and Tailand


(a) Linaclotide Linaclotide is superior to placebo for the treatment of

constipation-predominant IBS

Recommendation strong Quality of evidence high

Linaclotide is a 14-amino acid peptide structurally similar tohormones in the guanylin peptide amily Guanylin peptides are

endogenous hormones that assist in the regulation o intestinal

1047298uid and electrolyte homeostasis by binding to and activating

guanylate cyclase-C receptors on the lumen o intestinal epithe-

lium Activation o guanylate cyclase-C results in an increase o

cyclic guanosine monophosphate that triggers a series o events

leading to the activation o the cystic 1047297brosis transmembrane

conductance regulator that results in secretion o bicarbonate

and chloride into the lumen ollowed by sodium and water 1047298ux

into the intestinal lumen as well as modulation o pain afferent

sensors (231)

Tree randomized clinical trials in IBS patients were identi1047297ed

involving 2028 combined patients (232ndash234) All trials were at lowrisk o bias and there was no signi1047297cant heterogeneity between

individual trial results

Tere was a statistically signi1047297cant effect in avor o linaclotide

compared with placebo with the NN o 6 (95 CI 5ndash8) with no

signi1047297cant heterogeneity between studies Tere was a statistically

signi1047297cant effect in avor o linaclotide compared with placebo on

abdominal pain (NN o 8) but with signi1047297cant heterogeneity

between individual trial results

Data on overall adverse events were provided by two o the

three trials (232234) Overall adverse event rates were not higher

among those taking linaclotide compared with placebo (RR = 109





Combined data rom the three trials (243245246) suggested

that 1047297ber was bene1047297cial compared with placebo with the NN

o 2 (95 CI 16ndash3) and no statistically signi1047297cant heterogene-

ity between studies Although these trials could be combined or

analysis the de1047297nitions o improvement were all different and in

one trial (245) not all patients enrolled in the trial had the outcome

that was used to de1047297ne treatment success present at baseline Te

effect size given in this meta-analysis thereore needs to be treated

with extreme caution

In terms o individual ormulations among the three trials

(241243246) that studied psyllium including the largest iden-

ti1047297ed RC conducted by Fenn et al (243) although outcomes

varied between these RCs all reported signi1047297cant bene1047297ts with

psyllium

Lopez Roman et al (245) used 20 g o a soluble 1047297ber mixture o

inulin and maltodextrin administered as a dairy preparation and

reported signi1047297cant reductions in the proportion o patients with

straining during deecation sensation o incomplete evacuation or

sensation o obstruction with soluble 1047297ber In addition the numbero days between bowel movements was also signi1047297cantly reduced

wo trials reported on the effi cacy o insoluble 1047297ber in CIC

(242244) Te 24 patients recruited were allocated to receive 20 g

o bran per day or placebo No signi1047297cant bene1047297ts were noted with

bran (242) but rye bread was effective (244)

No single study reported total adverse events One trial reported

the number o patients in each trial arm who dropped out because

o adverse events (one with psyllium and two with placebo) (243)

Ashra et al (241) recorded individual adverse events with 18

o psyllium patients experiencing abdominal pain compared with

0 o placebo patients but no differences in back pain bloating

or cramping Finally there were higher combined symptom scoresor gastrointestinal side effects such as abdominal pain 1047298atulence

borborygmi and bloating with rye bread compared with low-1047297ber

toast (244)

Summary Fiber and soluble 1047297ber in particular are effective

in the management o chronic constipation Adverse events and

bloating distension 1047298atulence and cramping may limit the use

o insoluble 1047297ber especially i increases in 1047297ber intake are not

introduced gradually

2 Osmotic and stimulant laxatives in CIC

Osmotic laxatives contain poorly absorbed ions or molecules that

retain water in the intestinal lumen Osmotic agents used with

some requency include polyethylene glycol lactulose magnesiumhydroxide magnesium citrate magnesium sulate and sodium

phosphate

(a) Osmotic laxatives in CIC PEG is effective in improving symp-

toms of CIC


Lactulose is effective in improving symptoms of CIC


Five studies compared PEG with placebo (247ndash251) our

reported dichotomous data in 573 patients (247ndash250) with the

PEG is a large polymer that behaves as an osmotic laxa-

tive and although it is approved by the FDA or the treatment

o occasional constipation it has not been extensively studied

in patients with IBS-C One open-label study in 27 adolescents

with IBS-C suggested that PEG improved stool requency but

not pain (238) We identi1047297ed only two RCs (239240) o PEG

in IBS In one trial there was no statistically signi1047297cant effect on

bowel movements or discomort and pain (239) In the second

trial (240) which recruited 139 patients with IBS with constipa-

tion the mean increase in spontaneous bowel movements was

signi1047297cantly greater with PEG compared with placebo at 4 weeks

but there was no difference in effect on abdominal pain or dis-

comort Response rates de1047297ned as more than our spontane-

ous bowel movements per week with an increase o two or more

rom baseline and no worsening o abdominal pain or discom-

ort were signi1047297cantly higher with PEG (365 vs 175 with

placebo P lt 005) However there was no signi1047297cant difference

in the proportion o patients with a pain response de1047297ned as a

decrease by 10 or more rom baseline (619 vs 476 P gt 01)Adverse event rates were higher with PEG (388 vs 329) but

most o these were mild or moderate

Summary Tere is no evidence that PEG ormulations alleviate

pain or provide overall symptom relie in IBS

Chronic idiopathic constipation

1 Fiber in CIC

Some medicinal and dietary 1047297ber supplements increase stool

frequency in patients with chronic idiopathic constipation


Dietary 1047297ber is de1047297ned as carbohydrate polymers that areincapable o being digested in the normal small intestine and

are delivered to the colon Fiber can be part o ingested ood or

puri1047297ed and taken as a supplement (ldquomedicinal 1047297berrdquo) Fiber is

classi1047297ed as ldquosolublerdquo or ldquoinsolublerdquo depending on its interaction

with water Psyllium is the archetypical soluble 1047297ber bran is

insoluble

Psyllium husk is the outer coat o the psyllium seed (known

in India as ispaghula seed) rom the plant Plantago ovata It can

undergo bacterial ermentation in the colon thereby producing

gas and bloating Semisynthetic bulking agents less suscepti-

ble to ermentation include calcium polycarbophil and methyl-

cellulose Few studies have been done with bulking agents in

CIC and the quality o evidence about the use o these agentsis very low

Six trials met the criteria or inclusion in this review (241ndash246)

but a ormal meta-analysis was only possible with three trials

(243245246) and the remaining studies could not be analyzed

because o crossover design (241242) or a ailure to provide

dichotomous data or extraction (244) with uncertainty regard-

ing whether the study was truly random Four o the eligible tri-

als used soluble 1047297ber three used psyllium (241243246) and the

ourth used a combination o inulin and maltodextrose (245) wo

used insoluble 1047297ber wheat bran in one study (242) and rye bread

in the other (244)




18 Ford et al

Eight o these trials involved prucalopride (257ndash259261ndash265)

whereas one trial involved velusetrag (260) wo studies inves-

tigated the effects o prucalopride in patients either resistant to

or dissatis1047297ed with laxatives (258264) One study investigated

the effects o prucalopride in patients aged 65 years and older

(262) Doses ranged rom 05 to 4 mg daily studies lasted rom

4 to 12 weeks Five trials were considered to be at low risk o

bias (257260262263265)

In an analysis o all 9 trials 723 o patients (16912339) who

received 5-H4 agonists ailed to respond to therapy as compared

with 881 (10591202) o those allocated to placebo with the

NN o 6 (95 CI 5ndash8) Signi1047297cant heterogeneity was noted

between the studies

Analysis o the 8 prucalopride trials revealed that 711

(14542045) o patients treated with prucalopride ailed to

respond to therapy as compared with 874 (9571095) o

those randomized to placebo with the NN o 5 (95 CI 4ndash8)

Signi1047297cant heterogeneity was identi1047297ed between studies One

study perormed a subgroup analysis o those patients treatedwith prucalopride who had previously ailed laxatives (264) Te

authors reported that the effects o prucalopride were similar in

patients who had ailed other laxatives compared with the overall

population although a better comparator would have contrasted

those patients who did not use laxatives beore being enrolled in

the trial with those who did

Analysis o the one velusetrag trial revealed that 806 (237294)

o patients treated with velusetrag ailed to respond to therapy as

compared with 953 (102107) o those randomized to placebo

the NN was 7 (95 CI 5ndash11)

Eight trials reported total numbers o adverse events (257ndash260

262ndash265) these were more common in patients treated with 5-H4 agonists than with placebo (RR = 128 95 CI 111ndash148 NNH = 8

95 CI 5ndash16) Individual adverse events including headache

nausea and diarrhea were all more common in patients who used

5-H4 agonists compared with placebo Selective 5-H

4 agonists

were not associated with an increase in serious adverse event rates

(RR = 084 95 CI 057ndash125) and only 2 cardiovascular events

were reported (supraventricular tachycardia in one patient and

electrocardiogram signs o myocardial ischemia in the second)

(257265)

Summary Te 5-H4 agonists prucalopride and velusetrag are

effective in CIC with the ormer supported by considerably more

data o date the cardiac adverse events that bedeviled prior 5-H4

agonists have not emerged as a signi1047297cant issue neither is availablein the United States at this time

4 Prosecretory agents in CIC

(a) Linaclotide Linaclotide is effective in chronic idiopathic consti-

pation It is generally safe with the main adverse event being

diarrhea


Review o the literature demonstrated no new randomized

clinical trials since a previously published systematic review

and meta-analysis (21) In total three trials have been reported

NN o 3 (95 CI 2ndash4) All trials were at low risk o bias and there

was moderate heterogeneity between studies wo studies (252253)

evaluated lactulose compared with placebo in 148 patients with

the NN o 4 (95 CI 2ndash7) Both trials were at high risk o bias and

there was moderate heterogeneity between studies

rials with osmotic laxatives did not report on the total number

o adverse events Where reported (247248) the incidence o indi-

vidual adverse events including abdominal pain or headache did

not differ between active agent and placebo

(b) Stimulant laxatives in CIC Sodium picosulfate and bisacodyl are

effective in CIC


Stimulant laxatives appear to induce 1047298uid and electrolyte

secretion by the colon or induce peristalsis in the colon thereby

producing a bowel movement Stimulant laxatives include senna

bisacodyl castor oil cascara rhubarb and aloe

Both trials o stimulant laxatives containing 735 patientsreported dichotomous data and had a low risk o bias (254255) In

total 421 o all patients randomized to stimulant laxatives ailed

to respond to therapy as compared with 780 o those receiving

placebo with the NN o 3 (95 CI 2ndash35) and with statistically

signi1047297cant heterogeneity between studies

Only one RC reported total numbers o adverse events (254)

the RR o experiencing any adverse event with laxatives was 194

(95 CI 152ndash247 NNH = 3 95 CI 2ndash4) Diarrhea occurred sig-

ni1047297cantly more requently in the two trials (RR = 1375 95 CI

282ndash6714 NNH = 3 95 CI 2ndash6) (254255)

Summary Although supported by varying levels o evidence the

osmotic laxatives PEG and lactulose and the stimulant laxativessodium picosulate and bisacodyl have been shown to be effec-

tive in chronic constipation Other stimulant laxatives although

commonly used by sufferers have not been adequately studied

and cannot be recommended at this time Other laxatives have not

been ormally tested

3 5-H4 agonists in CIC

Prucalopride is more effective than placebo in improving symptoms

of CIC


Serotonin (5-H) plays a critical role in the gastrointestinal tract

and in1047298uences secretory motor and sensory unctions (256) Tereare seven major classes o serotonin receptor subtypes (5-H

1 minus 7 )

stimulation o the 5-H4 receptor enhances intestinal secretion

augments the peristaltic re1047298ex and increases gastrointestinal

transit (206207) Te 5-H4 receptor agonism has the potential

to improve symptoms o CIC Te selective 5-H4 agonists pruca-

lopride and velusetrag are reviewed below egaserod a selective

partial 5-H4 agonist was removed rom the US market in March

2007 because o possible adverse cardiovascular effects and will

not be discussed urther

Effi cacy We identi1047297ed 9 randomized placebo-controlled trials

o 5-H4 agonists in CIC involving 3441 patients (257ndash265)





in two separate publications (266267) involving a total o 1582

CIC patients All three trials were at low risk o bias Overall 860

(790) o 1089 patients receiving linaclotide ailed to respond

to therapy as compared with 468 (949) o 493 placebo patients

with the NN o 6 (95 CI 5ndash8) No signi1047297cant heterogeneity was

observed between studies

wo o the trials pooled adverse events data together (267)

precluding meta-analysis Overall 58 o linaclotide patients

experienced any adverse event compared with 52 o placebo

patients In the third trial adverse event rates were very similar

in number in both treatment arms (336 linaclotide vs 319

placebo) (266) Separate adverse events data or diarrhea in each

trial were obtained rom the authors as part o the meta-analysis

(21) Diarrhea was more common in patients receiving linaclotide

compared with placebo (RR = 308 95 CI 127ndash748 NNH = 12

95 CI 7ndash385)

(b) Lubiprostone Lubiprostone is effective in the treatment of chronic

idiopathic constipationRecommendation strong Quality of evidence high

We updated a previous meta-analysis on lubiprostone in CIC (21)

that had involved three trials o lubiprostone in CIC (268ndash270) We

ound two additional clinical trials o lubiprostone (236271) but

these two studies did not provide extractable dichotomous data

Afer contact with the authors we obtained dichotomous data or

one o these studies (271) but not the second (236) despite con-

tacting both the original authors and the manuacturers Tere-

ore this meta-analysis included our trials o lubiprostone in CIC

involving 651 patients in total wo trials were at low risk o bias

(270271)O the 364 patients receiving lubiprostone 453 ailed to

respond to therapy compared with 669 o 287 placebo patients

with the NN o 4 (95 CI 3ndash6) and no heterogeneity between

studies

Tree trials reported adverse events data (268ndash270) otal num-

bers o adverse events were signi1047297cantly higher with lubiprostone

(RR = 179 95 CI 121ndash265 NNH = 4 95 CI 3ndash6) Diarrhea

and nausea both occurred signi1047297cantly more requently with lubi-

prostone but no signi1047297cant difference in rates o abdominal pain

or headache were detected

Summary Te prosecretory agents linaclotide and lubiprostone

are effective in CIC and are well tolerated Tere have been no

comparative studies As both were evaluated in comparison withplacebo rather than ldquostandard therapyrdquo a recommendation regard-

ing their precise position in a CIC treatment algorithm (ie or

those who have ailed 1047297ber osmotic or stimulant laxatives or as

primary therapy) cannot be made at this time

5 Biofeedback in CIC

One o the potential causes o constipation is pelvic 1047298oor

dysunction or dyssynergia Either alterations in pelvic 1047298oor

anatomy or unction can result in impaired ability to dee-

cate effectively Deecation requires coordinated activity that

includes generation o intrarectal pressure and relaxation o the

internal and external anal sphincters perineal muscles as well

as the levator ani including the puborectalis muscle (272) Incor-

rect technique structural abnormalities (eg rectocele) and

pudendal and perineal nerve damage can contribute to incom-

plete deecation (273) Symptoms and signs include straining

incomplete evacuation and digital maneuvers Complications

can include rectal prolapse rectocele and anal 1047297ssures

ypical eatures o pelvic 1047298oor dyssynergia include incomplete

relaxation or paradoxical contraction o the anal canal paradoxical

contraction o the puborectalis muscle or uncoordinated move-

ment o the abdominal rectal and anal muscles As such the goals

o bioeedback are to provide a tailored approach to correction o

improper deecatory technique rained physical therapists use a

variety o techniques and tools to assess and correct underlying

technical abnormalities

Biofeedback performed by a trained and skilled therapist is effective

in relief of constipation symptoms in CIC patients with demonstrated

evidence of pelvic 1047298oor dyssynergia


A total o nine randomized clinical trials (274ndash282) o patients

with CIC with pelvic 1047298oor dyssynergia were identi1047297ed Six were

excluded because either they did not report a relevant outcome

(277) or data were not extractable (278) or they compared bio-

eedback with balloon-assisted training or different orms o

bioeedback (279ndash282) leaving three randomized clinical trials

(274ndash276) that evaluated 216 patients that compared bioeed-

back to a sham therapy or PEG laxative All trials were unclear

or at high risk o bias because o inability to blind participants to

the nature o the interventions or a lack o reporting o methods

used to generate the randomization schedule or conceal allo-cation Tere was a statistically signi1047297cant bene1047297t o bioeed-

back (RR constipation not improved = 033 95 CI 022ndash050)

with the NN o 2 (95 CI 16ndash4) and no statistically signi1047297cant

heterogeneity

None o the eligible trials (274ndash276) reported on adverse

events

Summary Although techniques may vary in precise methodo-

logical details bioeedback administered by a skilled and expe-

rienced therapist is in general effective in the management o

patients with CIC who have prominent eatures o pelvic 1047298oor

dyssynergia Access to such expertise limits the useulness o this

approach or many patients and their physicians

6 Bile acid transporter inhibitors in CIC

Te ileal bile acid transporter (IBA) inhibitor A3309 is a promising

new therapy for CIC

Grading not appropriate as no implication for current CIC manage-

ment

Te IBA is the most important transporter o the bile acid

reabsorption loop IBA inhibitors selectively inhibit the reuptake

o bile acids in the ileum resulting in increased secretion and

motor activity in the colon Recently the IBA inhibitor A3309

has been proposed as a potential treatment or CIC




20 Ford et al

We identi1047297ed 3 RCs o the bile acid transporter inhibitor A3309

in CIC involving 256 patients (283ndash285) All three trials were at

low risk o bias Varying doses o A3309 were employed ranging

rom as low as 01 mg to as high as 20 mg Responses were dose

dependent In the largest study to date (283) an increase o ge 1

complete spontaneous bowel movements per week over baseline

or 4 o the 8 weeks o the study was reported or 58 64 and 75

o those randomized to 5 10 and 15 mg o A3309 respectively

compared with 33 or placebo

Diarrhea was more common in the patients receiving A3309

compared with placebo (RR = 262 95 CI 072ndash956)

7 Probiotics in CIC

Tere is insuffi cient evidence to recommend probiotics in CIC


We identi1047297ed three trials evaluating probiotics in 245 CIC patients

(286ndash288) None o the eligible trials stated the method o randomi-

zation or concealment and one was an open design In two trials(286288) the risk o bias was deemed to be unclear and one (287)

had a high risk o bias Tere were two trials (286287) that reported

on improvement in constipation in 110 CIC patients Although both

trials were positive in avor o probiotics improving constipation

the pooled data were not statistically signi1047297cant (RR = 029 95 CI

007ndash112) in a random effects model as there was signi1047297cant heter-

ogeneity between the two trials Tere were two trials (287288) that

reported on mean number o bowel movements per week in 165

patients Tere was a signi1047297cant improvement in the mean number

o bowel movements per week (mean increase in bowel movements

per week in the symbiotic group = 149 95 CI 102ndash196)

CONFLICT OF INTEREST

Guarantor of the article Eamonn MM Quigley MD FACG

Speci1047297c author contributions AC Ford and P Moayyedi perormed

the meta-analyses and participated in writing and reviewing the

manuscript EMM Quigley BE Lacy YA Saito LR Schiller EE

Soffer BMR Spiegel and AJ Lembo together with P Moayyedi

developed all grading and recommendations and contributed to writ-

ing the manuscript All authors reviewed all drafs o the manuscript

and agreed with the 1047297nal version AC Ford is 1047297rst author on the

monograph but is not a member o the ask Force P Moayyedi

conducted systematic reviews with support o AC Ford and carried

out the technical analyses o the data independent o the ask Force

Financial support Unrestricted grants have been provided to theAmerican College o Gastroenterology rom Forest Laboratories

Ironwood Pharmaceuticals Nestleacute Health Science and Prometheus

Laboratories Te analysis that supports this monograph and its

writing were conducted on behal o the American College o

Gastroenterology and the ACG Institute or Clinical Research amp

Education by the ACG Functional Bowel Disorders ask Force

which had complete scienti1047297c and editorial control o its content and

whose work was supported exclusively by the ACG Institute Readers

should note that the work o the systematic review was conducted

and the writing o the IBSCIC monograph was completed beore

unding was obtained

Potential competing interests AC Ford has received grantresearch

support rom Almirall and GE Healthcare and is a consultant

speaker or Almirall GE Healthcare Mayoly Spindler Merck Sharp

amp Dohme and Shire Pharmaceuticals BE Lacy has served on

scienti1047297c advisory boards or Ironwood Pharmaceuticals akeda

Salix and Prometheus is a consultant to Furiex and receives grant

support rom the NIH or the unctional dyspepsia treatment trial

YA Saito has received research unding rom P1047297zer and Ironwood

Pharmaceuticals and is on the advisory board o Salix LR Schiller

has served on the speakersrsquo bureau or Forest Laboratories Iron-

wood Pharmaceuticals AbbottAbbvie akeda Salix and Santarus

Pharmaceuticals EE Soffer has served as a consultant and share-

holder or EndoStim BMR Spiegel has received grant support rom

akeda Ironwood Pharmaceuticals Teravance Amgen Shire and

Nestleacute Health Sciences is an advisor to Astellas and received con-

sulting ees rom Ironwood Pharmaceuticals and lecture ees rom

akeda EMM Quigley has served as a consultant andor on the

advisory board or Salix Almirall Ironwood Pharmaceuticals For-

est Laboratories ShireMovetis Janssen Rhythm PharmaceuticalsVibrant and Alimentary Health has served as a speaker or Procter

amp Gamble Almirall Janssen Alimentary Health and Shire has

received research support rom Rhythm Alimentary Health Vibrant

Pharma and Norgine and has been a non-executive director share-

holder and patent holder or Alimentary Health P Moayyedi has

served as a speaker or AstraZeneca Shire and Forest Laboratories

Canada has served as consultant andor on the advisory board or

Forest Laboratories Canada and his Chair at McMaster University

is unded in part by an unrestricted donation rom AstraZeneca to

McMaster University AJ Lembo has served as a consultant andor

on the advisory board or Ironwood Pharmaceuticals Forest Labora-

tories Salix Prometheus AstraZeneca and Furiex and has receivedresearch support rom Prometheus and Furiex

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irritable bowel syndrome a consensus statement o the World Gastro-enterology Organisation Summit ask Force on Irritable Bowel SyndromeJ Clin Gastroenterol 201246356ndash66

3 Suares NC Ford AC Prevalence o and risk actors or chronic idiopathicconstipation in the community systematic review and meta-analysisAm J Gastroenterol 20111061582ndash91

4 Belsey J Green1047297eld S Candy D et al Systematic review impact o constipa-tion on quality o lie in adults and children Aliment Pharmacol Ter201031938ndash49

5 Koloski NA Jones M Wai R et al Impact o persistent constipation onhealth-related quality o lie and mortality in older community-dwellingwomen Am J Gastroenterol 20131081152ndash8

6 Longstreth GF Tompson WG Chey WD et al Functional bowel disordersGastroenterology 20061301480ndash91

7 Lewis SJ Heaton KW Stool orm scale as a useul guide to intestinal transittime Scand J Gastroenterol 199732920ndash4

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10 Hughes PA Harrington AM Castro J et al Sensory neuro-immune inter-actions differ between irritable bowel syndrome subtypes Gut 201362 1456ndash65





11 Olasdottir LB Gudjonsson H Jonsdottir HH et al Irritable bowel syn-drome physiciansrsquo awareness and patientsrsquo experience World J Gastroen-terol 2012183715ndash20

12 Brandt LJ Bjorkman D Fennerty MB et al Systematic review on the man-agement o irritable bowel syndrome in North America Am J Gastroen-terol 200297 (11 Suppl) S7ndashS26

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2005100 (Suppl 1) S5ndashS2114 Shekhar C Monaghan PJ Morris J et al Rome III unctional constipation

and irritable bowel syndrome with constipation are similar disorders withina spectrum o sensitization regulated by serotonin Gastroenterology2013145749ndash57

15 Wong RK Palsson O urner MJ et al Inability o the Rome III criteria todistinguish unctional constipation rom constipation-subtype irritablebowel syndrome Am J Gastroenterol 20101052228ndash34

16 Zhao YF Ma XQ Wang R et al Epidemiology o unctional constipationand comparison with constipation-predominant irritable bowel syndromeTe Systematic Investigation o Gastrointestinal Diseases in China (SILC)Aliment Pharmacol Ter 2011341020ndash9

17 Brandt LJ Chey WD Foxx-Orenstein AE et al An evidence-basedsystematic review on the management o irritable bowel syndrome Am JGastroenterol 2009104 (Suppl I) S8ndashS35

18 Ford AC alley NJ Spiegel BMR et al Effect o 1047297bre antispasmodics andpeppermint oil in irritable bowel syndrome systematic review and meta-analysis BMJ 20083371388ndash92

19 Ford AC Brandt LJ Young C et al Effi cacy o 5-H3 antagonists and 5-H

4

agonists in irritable bowel syndrome systematic review and meta-analysisAm J Gastroenterol 20091041831ndash43

20 Ford AC alley NJ Schoeneld PS et al Effi cacy o antidepressants andpsychological therapies in irritable bowel syndrome systematic review andmeta-analysis Gut 200958367ndash78

21 Ford AC Suares NC Effect o laxatives and pharmacological therapies inchronic idiopathic constipation systematic review and meta-analysis Gut201160209ndash18

22 Moayyedi P Ford AC Brandt LJ et al Te effi cacy o probiotics in thetreatment o irritable bowel syndrome a systematic review Gut 201059325ndash32

23 Manning AP Tompson WG Heaton KW et al owards positive diagnosiso the irritable bowel BMJ 1978277653ndash4

24 Kruis W Tieme CH Weinzierl M et al A diagnostic score or the irritable

bowel syndrome Its value in the exclusion o organic disease Gastro-enterology 1984871ndash7

25 Drossman DA Tompson WG alley NJ Identi1047297cation o sub-groups ounctional gastrointestinal disorders Gastroenterology Intl 19903159ndash72

26 Tompson WG Longstreth GF Drossman DA et al Functional boweldisorders and unctional abdominal pain Gut 199945 (Suppl II) II43ndash7

27 Higgins JP Green S Cochrane handbook or systematic reviews ointerventions Version 502 wwwcochrane-handbookorg 2009

28 Dersimonian R Laird N Meta-analysis in clinical trials Control Clin rials19867177ndash88

29 Higgins JP Tompson SG Deeks JJ et al Measuring inconsistency inmeta-analyses BMJ 2003327557ndash60

30 Egger M Davey-Smith G Schneider M et al Bias in meta-analysis detectedby a simple graphical test BMJ 1997315629ndash34

31 Sterne JA Sutton AJ Ioannidis JP et al Recommendations or examiningand interpreting unnel plot asymmetry in meta-analyses o randomisedcontrolled trials BMJ 2011343d4002

32 Guyatt G Oxman AD Akl EA et al GRADE guidelines 1 Introduction-GRADE evidence pro1047297les and summary o 1047297ndings tables J Clin Epidemiol201164383ndash94

33 Balshem H Heland M Schunemann HJ et al GRADE guidelines 3 Rat-ing the quality o evidence J Clin Epidemiol 201164401ndash6

34 Simren M Mansson A Langkilde AM et al Food-related gastrointestinalsymptoms in the irritable bowel syndrome Digestion 200163108ndash15

35 Rona RJ Keil Summers C et al Te prevalence o ood allergy a meta-analysis J Allergy Clin Immunol 2007120638ndash46

36 Lack G Epidemiologic risks or ood allergy J Allergy Clin Immunol20081211331ndash6

37 Bhat K Harper A Gorard DA Perceived ood and drug allergies inunctional and organic gastrointestinal disorders Aliment Pharmacol Ter200216969ndash73

38 Young E Stoneham MD Petruckevitch A et al A population study o oodintolerance Lancet 19943431127ndash30

39 Heizer WD Southern S McGovern S Te role o diet in symptoms oirritable bowel syndrome in adults a narrative review J Am Diet Assoc20091091204ndash14

40 Monsbakken KW Vandvik PO Farup PG Perceived ood intolerance insubjects with irritable bowel syndrome--etiology prevalence and conse-quences Eur J Clin Nutr 200660667ndash72

41 Halpert A Dalton CB Palsson O et al What patients know about irritablebowel syndrome (IBS) and what they would like to know National Survey

on Patient Educational Needs in IBS and development and validation othe Patient Educational Needs Questionnaire (PEQ) Am J Gastroenterol20071021972ndash82

42 Hayes P Corish C OrsquoMahony E et al A dietary survey o patients with ir-ritable bowel syndrome J Hum Nutr Diet 201427 (Suppl 2) 36ndash47

43 Atkinson W Sheldon A Shaath N et al Food elimination based on IgGantibodies in irritable bowel syndrome a randomised controlled trial Gut2004531459ndash64

44 Biesiekierski JR Newnham ED Irving PM et al Gluten causes gastroin-testinal symptoms in subjects without celiac disease a double-blind rand-omized placebo-controlled trial Am J Gastroenterol 2011106508ndash14

45 King S Elia M Hunter JO Abnormal colonic ermentation in irritablebowel syndrome Lancet 19983521187ndash9

46 Ong DK Mitchell SB Barrett JS et al Manipulation o dietary short chaincarbohydrates alters the pattern o gas production and genesis o symptomsin irritable bowel syndrome J Gastroenterol Hepatol 2010251366ndash73

47 Staudacher HM Lomer MC Anderson JL et al Fermentable carbohydraterestriction reduces luminal bi1047297dobacteria and gastrointestinal symptomsin patients with irritable bowel syndrome J Nutr 20121421510ndash8

48 Bentley SJ Pearson DJ Rix KJ Food hypersensitivity in irritable bowelsyndrome Lancet 19832295ndash7

49 Carroccio A Brusca I Mansueto P et al Fecal assays detect hypersensitivityto cowrsquos milk protein and gluten in adults with irritable bowel syndromeClin Gastroenterol Hepatol 20119965ndash71

50 Shepherd SJ Parker FC Muir JG et al Dietary triggers o abdominalsymptoms in patients with irritable bowel syndrome randomizedplacebo-controlled evidence Clin Gastroenterol Hepatol 20086765ndash71

51 Vazquez Roque MI Camilleri M Smyrk et al A controlled trial ogluten-ree diet in patients with irritable bowel syndrome-diarrhea effectson bowel requency and intestinal unction Gastroenterology 2013144903ndash11

52 Halmos EP Power VA Shepherd SJ et al A diet low in FODMAPs reducessymptoms o irritable bowel syndrome Gastroenterology 201414667ndash75

53 Biesiekierski JR Peters SL Newnham ED et al No effects o gluten inpatients with sel-reported non-celiac gluten sensitivity afer dietaryreduction o ermentable poorly absorbed short-chain carbohydratesGastroenterology 2013145320ndash8

54 Berg LK Fagerli E Martinussen M et al Effect o ructose-reduced diet inpatients with irritable bowel syndrome and its correlation to a standardructose breath test Scand J Gastroenterol 201348936ndash43

55 Moayyedi P Quigley EM Lacy BE et al Te effect o 1047297ber supplementationon irritable bowel syndrome A systematic review and meta-analysisAm J Gastroenterol 2014 (in press)

56 Arthurs Y Fielding JF Double blind trial o ispaghulapoloxamer in theirritable bowel syndrome Ir Med J 198376253

57 Bijkerk CJ de Wit NJ Muris JW et al Soluble or insoluble 1047297bre in irritablebowel syndrome in primary care Randomised placebo controlled trialBMJ 2009339b3154

58 Fowlie S Eastwood MA Prescott R Irritable bowel syndrome assessmento psychological disturbance and its in1047298uence on the response to 1047297bresupplementation J Psychosom Res 199236175ndash80

59 Jalihal A Kurian G Ispaghula therapy in irritable bowel syndromeimprovement in overall well-being is related to reduction in boweldissatisaction J Gastroenterol Hepatol 19905507ndash13

60 Kruis W Weinzierl M Schussler P et al Comparison o the therapeuticeffects o wheat bran mebeverine and placebo in patients with the irritablebowel syndrome Digestion 198634196ndash201

61 Longstreth GF Fox DD Youkeles L et al Psyllium therapy in the irritablebowel syndrome a double-blind trial Ann Intern Med 19819553ndash6

62 Lucey MR Clark ML Lowndes JO et al Is bran effi cacious in irritablebowel syndrome A double blind placebo controlled crossover study Gut198728221ndash5

63 Manning AP Heaton KW Harvey RF et al Wheat 1047297bre and irritable bowelsyndrome a controlled trial Lancet 1977310417ndash8

64 Nigam P Kapoor KK Rastog CK et al Different therapeutic regimens inirritable bowel syndrome J Assoc Physicians India 1984321041ndash4




22 Ford et al

65 Prior A Whorwell P Double blind study o ispaghula in irritable bowelsyndrome Gut 1987281510ndash3

66 Rees G Davies J Tompson R et al Randomised-controlled trial o a 1047297bresupplement on the symptoms o irritable bowel syndrome J R Soc Health200512530ndash4

67 Ritchie JA ruelove SC reatment o irritable bowel syndrome withlorazepam hyoscine butylbromide and ispaghula husk BMJ 1979278376ndash8

68 Soltof J Krag B Gudmand-Hoyer E et al A double-blind trial o theeffect o wheat bran on symptoms o irritable bowel syndrome Lancet1976307270ndash2

69 Cockerell KM Watkins AS Reeves LB et al Effects o linseeds on thesymptoms o irritable bowel syndrome a pilot randomised controlledtrial J Hum Nutr Diet 201225435ndash43

70 Halvorson HA Schlett CD Riddle MS Postinectious irritable bowelsyndrome--a meta-analysis Am J Gastroenterol 20061011894ndash9

71 Lin HC Small intestinal bacterial overgrowth a ramework or under-standing irritable bowel syndrome JAMA 2004292852ndash8

72 Jeffrey IB Quigley EM Ohman L et al Te microbiota link to irritablebowel syndrome an emerging story Gut Microbes 20123572ndash6

73 Spiegel BM Questioning the bacterial overgrowth hypothesis in irritablebowel syndrome an epidemiologic and evolutionary perspective ClinGastroenterol Hepatol 20119461ndash9

74 Ford AC Spiegel BMR alley NJ et al Small intestinal bacterial over-growth in irritable bowel syndrome systematic review and meta-analysisClin Gastroenterol Hepatol 200971279ndash86

75 Pimentel M Chow EJ Lin HC Eradication o small intestinal bacterialovergrowth reduces symptoms o irritable bowel syndrome Am J Gastro-enterol 2000953503ndash6

76 Menees SB Maneerattanaporn M Kim HM et al Te effi cacy and saety oriaximin or the irritable bowel syndrome a systematic review and meta-analysis Am J Gastroenterol 201210728ndash35

77 Silk DB Davis A Vulevic J et al Clinical trial the effects o a trans-galac-tooligosaccharide prebiotic on aecal microbiota and symptoms in irritablebowel syndrome Aliment Pharmacol Ter 200929508ndash18

78 Min YW Park SU Jang YS et al Effect o composite yogurt enrichedwith acacia 1047297ber and Bi1047297dobacterium lactis World J Gastroenterol2012184563ndash9

79 suchiya J Barreto R Okura R et al Single-blind ollow up study on theeffectiveness o a symbiotic preparation in irritable bowel syndromeChin J Dig Dis 20045169ndash74

80 Bittner AC Croffut RM Stranahan MC Prescript-Assist probiotic-prebi-otic treatment or irritable bowel syndrome a methodologically oriented2-week randomized placebo-controlled double-blind clinical studyClin Ter 200527755ndash61

81 Andriulli A Neri M Loguercio C et al Clinical trial on the effi cacy oa new symbiotic ormulation Flortec in patients with irritable bowelsyndrome a multicenter randomized study J Clin Gastroenterol 200842(Suppl 3) S218ndash23

82 Ford AC Quigley EM Lacy BE et al Effect o prebiotics probiotics andsynbiotics in irritable bowel syndrome and chronic idiopathic constipationsystematic review and meta-analysis Am J Gastroenterol 2014 (in press)

83 Enck P Zimmerman K Menke G et al A mixture o Escherichia coli (DSM 17252) and Enterococcus faecalis (DSM 16440) or treatment o theirritable bowel syndrome - a randomized controlled trial with primarycare physicians Neurogastroenterol Motil 2008201103ndash9

84 Zeng J Li Y-Q Zuo X-L et al Clinical trial effect o active lactic acid bac-teria on mucosal barrier unction in patients with diarrhoea-predominantirritable bowel syndrome Aliment Pharmacol Ter 200828994ndash1002

85 Agrawal A Houghton LA Morris J et al Clinical trial the effects o aermented milk product containing Bi1047297dobacterium lactis DN-173 010on abdominal distension and gastrointestinal transit in irritable bowelsyndrome with constipation Aliment Pharmacol Ter 201329104ndash14

86 Enck P Zimmerman K Menke G et al Randomized controlled treatmenttrial o irritable bowel syndrome with a probiotic E-coli preparation(DSM17252) compared to placebo Z Gastroenterol 200947209ndash14

87 Hong KS Kang HW Im JP et al Effect o probiotics on symptoms inKorean adults with irritable bowel syndrome Gut Liver 20093101ndash7

88 Williams EA Stimpson J Wang D et al Clinical trial a multistrainprobiotic preparation signi1047297cantly reduces symptoms o irritable bowelsyndrome in a double-blind placebo-controlled study Aliment PharmacolTer 20092997ndash103

89 Simren M Ohman L Olsson J et al Clinical trial the effects o aermented milk containing three probiotic bacteria in patients with

irritable bowel syndrome - A randomized double-blind controlled studyAliment Pharmacol Ter 201031218ndash27

90 Choi CH Jo SY Park HJ et al A randomized double-blind placebo-controlled multicenter trial o Saccharomyces boulardii in irritable bowelsyndrome effect on quality o lie J Clin Gastroenterol 201145679ndash83

91 Guglielmetti S Mora D Gschwender M et al Randomised clinical trialBi1047297dobacterium bi1047297dum MIMBb75 signi1047297cantly alleviates irritable bowelsyndrome and improves quality o lie - a double-blind placebo-controlled

study Aliment Pharmacol Ter 2011331123ndash3292 Michail S Kenche H Gut microbiota is not modi1047297ed by randomized

double-blind placebo-controlled trial o VSL3 in diarrhea-predominantirritable bowel syndrome Probiotics Antimicrob Proteins 201131ndash7

93 Sondergaard B Olsson J Ohlson K et al Effects o probiotic ermentedmilk on symptoms and intestinal 1047298ora in patients with irritable bowelsyndrome a randomized placebo-controlled trial Scand J Gastroenterol201146663ndash72

94 Cha BK Jung SM Choi CH et al Te effect o a multispecies probioticmixture on the symptoms and ecal microbiota in diarrhea-dominantirritable bowel syndrome a randomized double-blind placebo-controlledtrial J Clin Gastroenterol 201246220ndash7

95 Cui S Hu Y Multistrain probiotic preparation signi1047297cantly reduces symp-toms o irritable bowel syndrome in a double-blind placebo-controlledstudy Int J Clin Exp Med 20125238ndash44

96 Dapoigny M Piche Ducrotte P et al Effi cacy and saety pro1047297le oLCR35 complete reeze-dried culture in irritable bowel syndromea randomized double-blind study World J Gastroenterol 2012182067ndash75

97 Ducrotte P Sawant P Jayanthi V Clinical trial Lactobacillus plantarum 299v (DSM 9843) improves symptoms o irritable bowel syndrome WorldJ Gastroenterol 2012184012ndash8

98 Farup PG Jacobsen M Ligaarden SC et al Probiotics symptoms andgut microbiota what are the relations A randomized controlled trialin subjects with irritable bowel syndrome Gastroenterol Res Pract20122012214102

99 Kruis W Chrubasik S Boehm S et al A double-blind placebo-controlledtrial to study therapeutic effects o probiotic Escherichia coli Nissle 1917 insubgroups o patients with irritable bowel syndrome Int J Colorectal Dis201227467ndash74

100 Ringel-Kulka Palsson OS Maier D et al Probiotic bacteria Lactobacillusacidophilus NCFM and Bi1047297dobacterium lactis Bi-07 versus placebo orthe symptoms o bloating in patients with unctional bowel disorders

a double-blind study J Clin Gastroenterol 201145518ndash25101 Begtrup LM de Muckadell OB Kjeldsen J et al Long-term treatment

with probiotics in primary care patients with irritable bowel syndrome - arandomised double-blind placebo controlled trial Scand J Gastroenterol2013481127ndash35

102 Roberts LM McCahon D Holder R et al A randomised controlled trialo a probiotic lsquounctional oodrsquo in the management o irritable bowelsyndrome BMC Gastroenterol 20131345

103 Simren M Lindh A Samuelsson L et al Effect o yoghurt containingthree probiotic bacteria in patients with irritable bowel syndrome (IBS)- a randomized double-blind controlled trial Gastroenterology 2007132(Suppl 1) A210

104 Long ZR Yu CH Yang Y et al [Clinical observation on acupuncturecombined with microorganism pharmaceutical preparations or treatmento irritable bowel syndrome o constipation type] Zhongguo Zhen Jiu200626403ndash5

105 Drouault-Holowacz S Bieuvelet S Burckel A et al A double blind rand-omized controlled trial o a probiotic combination in 100 patients withirritable bowel syndrome Gastroenterol Clin Biol 200832147ndash52

106 Gade J Torn P Paraghurt or patients with irritable bowel syndromeScand J Prim Health Care 1989723ndash6

107 Guyonnet D Chassany O Ducrotte P et al Effect o a ermented milk con-taining Bi1047297dobacterium animalis DN-173 010 on the health-related qualityo lie and symptoms in irritable bowel syndrome in adults in primarycare a multicentre randomized double blind controlled trial AlimentPharmacol Ter 200726475ndash86

108 Kajander K Hatakka K Poussa et al A probiotic mixture alleviatessymptoms in irritable bowel syndrome patients a controlled 6-monthintervention Aliment Pharmacol Ter 200522387ndash94

109 Kajander K Myllyluoma E Rajilic-Stojanovic M et al Clinical trial multi-species probiotic supplementation alleviates the symptoms o irritablebowel syndrome and stabilizes intestinal microbiota Aliment PharmacolTer 20082748ndash57





110 Kim HJ Camilleri M McKinzie S et al A randomized controlled trial o aprobiotic VSL3 on gut transit and symptoms in diarrhea-predominantirritable bowel syndrome Aliment Pharmacol Ter 200317895ndash904

111 Kim HJ Vazquez Roque MI Camilleri M et al A randomized control-led trial o a probiotic combination VSL3 and placebo in irritable bowelsyndrome with bloating Neurogastroenterol Motil 200517687ndash96

112 Kim YG Moon J Lee KM et al Te effects o probiotics on symptoms oirritable bowel syndrome Korean J Gastroenterol 200647413ndash9

113 Niedzielin K Kordecki H Birkeneld B A controlled double blind rand-omized study on the effi cacy o Lactobacillus plantarum 299V in patientswith irritable bowel syndrome Eur J Gastroenterol Hepatol 2001131143

114 Niv E Nafali Hallak R et al Te effi cacy o Lactobacillus reuteri ACC55730 in the treatment o patients with irritable bowel syndrome ndasha double blind placebo-controlled randomized study Clin Nutr 200524 925ndash31

115 Nobaek S Johansson M-L Molin G et al Alteration o intestinal micro1047298o-ra is associated with reduction in abdominal bloating and pain in patientswith irritable bowel syndrome Am J Gastroenterol 2000951231ndash8

116 OrsquoMahony L McCarthy J Kelly P et al Lactobacillus and bi1047297dobacterium in irritable bowel syndrome symptom responses and relationship tocytokine pro1047297les Gastroenterology 2005128541ndash51

117 Simren M Syrous A Lindh A et al Effects o Lactobacillus Plantarum 299V on symptoms and rectal sensitivity in patients with irritable bowelsyndrome (IBS) ndash a randomized double blind controlled trial Gastroen-

terology 2006130 (Suppl 1) A600118 Sinn DH Song JH Kim HJ et al Terapeutic effect o Lactobacillus acido-

philus -SDC 2012 2013 in patients with irritable bowel syndrome Dig DisSci 2008532714ndash8

119 Whorwell PJ Altringer L Morel J et al Effi cacy o an encapsulatedprobiotic Bi1047297dobacterium infantis 35624 in women with irritable bowelsyndrome Am J Gastroenterol 20061011581ndash90

120 Lembo A Zakko SF Ferreira NL et al Riaximin or the treatment odiarrhea-associated irritable bowel syndrome short term treatment lead-ing to long term sustained response Gastroenterology 2008134 (Suppl 1)545

121 Pimentel M Park S Mirocha J et al Te effect o a nonabsorbed oralantibiotic (riaximin) on the symptoms o the irritable bowel syndrome arandomized trial Ann Intern Med 2006145557ndash63

122 Pimentel M Lembo A Chey WD et al Riaximin therapy or patientswith irritable bowel syndrome without constipation N Engl J Med201136422ndash32

123 Sharara AI Aoun E Abdul-Baki H et al A randomized double-blindplacebo-controlled trial o riaximin in patients with abdominal bloatingand 1047298atulence Am J Gastroenterol 2006101326ndash33

124 Pimentel M Chow EJ Lin HC Normalization o lactulose breath testingcorrelates with symptom improvement in irritable bowel syndrome Adouble-blind randomized placebo-controlled study Am J Gastroenterol200398412ndash9

125 Nayak AK Karnad DR Abraham P et al Metronidazole relieves symp-toms in irritable bowel syndrome the conusion with so-called lsquochronicamebiasisrsquo Indian J Gastroenterol 199716137ndash9

126 Di Steano M ana P Mengoli C et al Colonic hypersensitivity is a majordeterminant o the effi cacy o bloating treatment in constipation-predomi-nant irritable bowel syndrome Intern Emerg Med 20116403ndash11

127 Moayyedi P Duffett S Mason S et al Te in1047298uence o antibiotics onirritable bowel syndrome a randomised controlled trial Gastroenterology2002122 (Suppl 4) A465

128 Baldi F Corinaldesi R Ferrarini F et al Clinical and unctional evaluationo octilonium bromide in the treatment o irritable bowel syndrome adouble-blind controlled trial Clin rials J 19832077ndash88

129 Castiglione F Daniele B Mazzacca G Terapeutic strategy or the irritablebowel syndrome Ital J Gastroenterol 199123 (Suppl 1) 53ndash5

130 Centonze V Imbibo BP Campanozzi F et al Oral cimetropium bromidea new antimuscarinic drug or long-term treatment o irritable bowelsyndrome Am J Gastroenterol 1988831262ndash6

131 Clave P Acalovschi M rianta1047297llidis JK et al Randomised clinical trialotilonium bromide improves requency o abdominal pain severity odistention and time to relapse in patients with irritable bowel syndromeAliment Pharmacol Ter 201134432ndash42

132 DrsquoArienzo A DrsquoAgostino L Lrsquoottilonio bromuro nel trattamento dellasiacutendrome del colon irritabile Rass Int Clin er 198060649ndash56

133 Delmont J Interet de lrsquoadjonction drsquoun antispasmodique musculotrope autraitement des constipations douloureuses des colopathies onctionnellespar le son Med Chir Dig 198110365ndash70

134 Dobrilla G Imbibo BP Piazzi L et al Long term treatment o irritablebowel syndrome with cimetropium bromide a double blind placebocontrolled clinical trial Gut 199031355ndash8

135 Fielding JF Double blind trial o trimebutine in the irritable bowel syn-drome Ir Med J 198073377ndash9

136 Ghidini O Saponati G Intrieri L Single drug treatment or irritablecolon rociverine versus trimebutine maleate Curr Ter Res Clin Exp198639541ndash8

137 Gilvarry J Kenny A Fielding JF Te non-effect o pirenzipine in dietaryresistant irritable bowel syndrome Ir J Med Sci 1989158262

138 Glende M Morselli-Labate AM Battaglia G et al Extended analysis o adouble blind placebo-controlled 15-week study with otilinium bromidein irritable bowel syndrome Eur J Gastroenterol Hepatol 2002141331ndash8

139 Levy C Charbonnier A Cachin M Pinaverium bromide and unctionalcolonic disease (double-blind study) Sem Hop Ter 197753372ndash4

140 Mitchell SA Mee AS Smith GD et al Alverine citrate ails to relievethe symptoms o irritable bowel syndrome results o a double-blindrandomized placebo-controlled trial Aliment Pharmacol Ter 2002161187ndash95

141 Moshal MG Herron M A clinical trial o trimebutine (Mebutin) in spasticcolon J Int Med Res 19797231ndash4

142 Page JG Dirnberger GM reatment o the irritable bowel syndromewith Bentyl (dicyclomine hydrochloride) J Clin Gastroenterol 19813153ndash6

143 Passaretti S Guslandi M Imbibo BP et al Effects o cimetropium bromideon gastrointestinal transit time in patients with irritable bowel syndromeAliment Pharmacol Ter 19893267ndash76

144 Piai G Mazzacca G Pri1047297nium bromide in the treatment o the irritablecolon syndrome Gastroenterology 197977500ndash2

145 Pulpeiro A Marti ML De Los Santos AR et al Propinox en sindrome deintestino irritable Prensa Med Argent 200087299ndash307

146 Schaer VE Ewe K Te treatment o irritable colon Effi cacy and toleranceo buscopan plus buscopan paracetamol and placebo in ambulatorypatients with irritable colon Fortschr Med 1990108488ndash92

147 Virat J Hueber D Colopathy pain and dicetel Prat Med 19874332ndash4148 Capanni M Surrenti E Biagini M et al Effi cacy o peppermint oil in the

treatment o irritable bowel syndrome a randomized controlled trialGazz Med Ital 2005164119ndash26

149 Cappello G Spezzaerro M Grossi L et al Peppermint oil (Mintoil) inthe treatment o irritable bowel syndrome a prospective double blindplacebo-controlled randomized trial Dig Liver Dis 200739530ndash6

150 Lech Y Olesen KM Hey H et al reatment o irritable bowel syndromewith peppermint oil A double-blind investigation with a placebo UgeskrLaeger 19881502388ndash9

151 Liu J-H Chen G-H Yeh H-Z et al Enteric-coated peppermint-oil capsulesin the treatment o irritable bowel syndrome a prospective randomizedtrial J Gastroenterol 199732765ndash8

152 Merat S Khalili S Mostajabi P et al Te effect o enteric-coated delayed-release peppermint oil on irr itable bowel syndrome Dig Dis Sci 2010551385ndash90

153 Hovdenak N Loperamide treatment o the irritable bowel syndromeScand J Gastroenterol 198713081ndash4

154 Lavo B Stenstam M Nielsen A-L Loperamide in treatment o irritablebowel syndrome - a double-blind placebo controlled study Scand JGastroenterol 198713077ndash80

155 Ford AC Quigley EM Lacy BE et al Effect o antidepressants and psycho-logical therapies including hypnotherapy in irritable bowel syndrome

systematic review and meta-analysis Am J Gastroenterol 2014 (in press)156 Bergmann M Heddergott A Schlosser Die therapie des colon irritabile

mit trimipramin (Herphonal) - Eine kontrollierte studie Z Klin Med1991461621ndash8

157 Boerner D Eberhardt R Metz K et al Wirksamkeit und vertraglichkeiteines antidepressivuns beim colon irritabile Terapiewoche 198838 201ndash8

158 Heener JD Wilder RM Wilson ID Irritable colon and depressionPsychosomatics 197819540ndash7

159 Kuiken SD ytgat GNJ Boeckxstaens GEE Te selective serotoninreuptake inhibitor 1047298uoxetine does not change rectal sensitivity andsymptoms in patients with irritable bowel syndrome a double-blindrandomized placebo-controlled study Clin Gastroenterol Hepatol20031219ndash28

160 Myren J Groth H Larssen SE et al Te effect o trimipramine in patientswith the irritable bowel syndrome a double-blind study Scand J Gastro-enterol 198217871ndash5




24 Ford et al

161 abas G Beaves M Wang J et al Paroxetine to treat irritable bowelsyndrome not responding to high 1047297ber diet a double-blind placebo-controlled trial Am J Gastroenterol 200499914ndash20

162 ack J Broekaert D Fischler B et al A controlled crossover study o theselective serotonin reuptake inhibitor citalopram in irritable bowel syn-drome Gut 2006551095ndash103

163 alley NJ Kellow JE Boyce P et al Antidepressant therapy (imipramineand citalopram) or irritable bowel syndrome a double-blind rand-omized placebo-controlled trial Dig Dis Sci 200853108ndash15

164 Vahedi H Merat S Rashidioon A et al Te effect o 1047298uoxetine in patientswith pain and constipation-predominant irritable bowel syndrome a double-blind randomized-controlled study Aliment Pharmacol Ter 200522381ndash5

165 Vahedi H Merat S Momtahen S et al Clinical trial the effect o amitripty-line in patients with diarrhea-predominant irritable bowel syndromeAliment Pharmacol Ter 200827678ndash84

166 Vij JC Jiloha RC Kumar N et al Effect o antidepressant drug (doxepin)on irritable bowel syndrome patients Indian J Psychiatry 199133243ndash6

167 Drossman DA oner BB Whitehead WE et al Cognitive-behavioraltherapy versus education and desipramine versus placebo or moderate tosevere unctional bowel disorders Gastroenterology 200312519ndash31

168 Abdul-Baki H El Hajj ElZahabi L et al A randomized controlled trialo imipramine in patients with irritable bowel syndrome World J Gastro-enterol 2009153636ndash42

169 Ghadir MR Habibinejad H Heidari A et al Doxepin is more effective

than nortriptyline and placebo or the treatment o diarrhea-predominantirritable bowel syndrome a randomized triple-blind placebo-controlledtrial ehran Univ Med J 201169352ndash8

170 Ladabaum U Sharabidze A Levin R et al Citalopram is not effectivetherapy or nondepressed patients with irritable bowel syndrome ClinGastroenterol Hepatol 2010842ndash8

171 Masand PS Pae C-U Krulewicz S et al A double-blind randomizedplacebo-controlled trial o paroxetine controlled-release in irritable bowelsyndrome Psychosomatics 20095078ndash86

172 Blanchard EB Schwarz SP Suls JM et al wo controlled evaluations omulticomponent psychological treatment o irr itable bowel syndromeBehav Res Ter 199230175ndash89

173 Blanchard EB Greene B Scharff L et al Relaxation training as a treatmentor irritable bowel syndrome Bioeedback Sel Regul 199318125ndash31

174 Boyce PM alley NJ Balaam B et al A randomized controlled trial ocognitive behavior therapy relaxation training and routine clinical careor the irritable bowel syndrome Am J Gastroenterol 2003982209ndash18

175 Creed F Fernandes L Guthrie E et al Te cost-effectiveness o psycho-therapy and paroxetine or severe irritable bowel syndrome Gastro-enterology 2003124303ndash17

176 Galovski E Blanchard EB Te treatment o irritable bowel syndromewith hypnotherapy Appl Psychophysiol Bioeedback 199823219ndash32

177 Greene B Blanchard EB Cognitive therapy or irritable bowel syndromeJ Consult Clin Psychol 199462576ndash82

178 Guthrie E Creed F Dawson D et al A controlled trial o psycho-logical treatment or the irritable bowel syndrome Gastroenterology1991100450ndash7

179 Heitkemper M Jarrett ME Levy RL et al Sel-management or womenwith irritable bowel syndrome Clin Gastroenterol Hepatol 20042585ndash96

180 Keeer L Blanchard EB Te effects o relaxation response meditation onthe symptoms o irritable bowel syndrome results o a controlled treat-ment study Behav Res Ter 200139801ndash11

181 Kennedy Jones R Darnley S et al Cognitive behaviour therapy in addi-

tion to antispasmodic treatment or irritable bowel syndrome in primarycare randomised controlled trial BMJ 2005331435ndash7

182 Lynch PM Zamble E A controlled behavioral treatment study o irritablebowel syndrome Behav Ter 198920509ndash23

183 Neff DF Blanchard EB A multi-component treatment or irritable bowelsyndrome Behav Ter 19871870ndash83

184 Payne A Blanchard EB A controlled comparison o cognitive therapyand sel-help support groups in the treatment o irr itable bowel syndromeJ Consult Clin Psychol 199563779ndash86

185 Sanders KA Blanchard EB Sykes MA Preliminary study o a sel-admin-istered treatment or irritable bowel syndrome comparison to a wait listcontrol group Appl Psychophysiol Bioeedback 200732111ndash9

186 Shaw G Srivastava ED Sadlier M et al Stress management or irritablebowel syndrome a controlled trial Digestion 19915036ndash42

187 Simren M Ringstrom G Bjornsson ES et al reatment with hypnotherapyreduces the sensory and motor component o the gastrocolonic responsein irritable bowel syndrome Psychosom Med 200466233ndash8

188 kachuk GA Graff LA Martin GL et al Randomized controlled trialo cognitive-behavioral group therapy or irritable bowel syndrome in amedical setting J Clin Psychol Med Settings 20031057ndash69

189 van der Veek PPJ van Rood YR Masclee AAM Clinical trial short- andlong-term bene1047297t o relaxation training or irritable bowel syndromeAliment Pharmacol Ter 200726943ndash52

190 Vollmer A Blanchard EB Controlled comparison o individual versusgroup cognitive therapy or irritable bowel syndrome Behav Ter19982919ndash33

191 Craske MG Wolitzky-aylor KB Labus J et al A cognitive-behavioraltreatment or irritable bowel syndrome using interoceptive exposure to visceral sensations Behav Res Ter 201149413ndash21

192 Gaylord SA Palsson OS Garland EL et al Mindulness training reducesthe severity o irr itable bowel syndrome in women results o a rand-omized controlled trial Am J Gastroenterol 20111061678ndash88

193 Hunt MG Moshier S Milonova M Brie cognitive-behavioral internettherapy or irritable bowel syndrome Behav Res Ter 200947797ndash802

194 Jarrett ME Cain KC Burr RL et al Comprehensive sel-managementor irritable bowel syndrome randomized trial o in-person vs combinedin-person and telephone sessions Am J Gastroenterol 20091043004ndash14

195 Lackner JM Jaccard J Krasner SS et al Sel-administered cognitivebehavior therapy or moderate to severe irr itable bowel syndromeclinical effi cacy tolerability easibility Clin Gastroenterol Hepatol 20086 899ndash906

196 Lindors P Unge P Arvidsson P et al Effects o gut-directed hypnotherapyon IBS in different clinical settings - results rom two randomizedcontrolled trials Am J Gastroenterol 2012107276ndash85

197 Ljotsson B Falk L Wibron Vesterlund A et al Internet-delivered exposureand mindulness based therapy or irritable bowel syndrome - a rand-omized controlled trial Behav Res Ter 201048531ndash9

198 Moser G ragner S Elwira Gajowniczek E et al Long-term successo GU-directed group hypnosis or patients with reractory irritablebowel syndrome a randomized controlled trial Am J Gastroenterol2013108602ndash9

199 Moss-Morris R McAlpine L Didsbury LP et al A randomized control-led trial o a cognitive behavioural therapy-based sel-managementintervention or irritable bowel syndrome in primary care Psychol Med20104085ndash94

200 Shinozaki M Kanazawa M Kano M et al Effect o autogenic training ongeneral improvement in patients with irritable bowel syndrome a rand-omized controlled trial Appl Psychophysiol Bioeedback 201035189ndash98

201 Gershon MD Review article serotonin receptors and transporters -- rolesin normal and abnormal gastrointestinal motility Aliment PharmacolTer 200420 (Suppl 7) 3ndash14

202 Spiller R Serotonergic modulating drugs or unctional gastrointestinaldiseases Br J Clin Pharmacol 20025411ndash20

203 Goldberg PA Kamm MA Setti-Carraro P et al Modi1047297cation o visceralsensitivity and pain in irritable bowel syndrome by 5-H3 antagonism(ondansetron) Digestion 199657478ndash83

204 Houghton LA Foster JM Whorwell PJ Alosetron a 5-H3 receptorantagonist delays colonic transit in patients with irritable bowel syndromeand healthy volunteers Aliment Pharmacol Ter 200014775ndash82

205 Miller DP Alredson Cook SF et al Incidence o colonic ischemiahospitalized complications o constipation and bowel surgery in relationto use o alosetron hydrochloride Am J Gastroenterol 2003981117ndash22

206 Grider JR Foxx-Orenstein AE Jin JG 5-Hydroxytryptamine4 receptoragonists initiate the peristaltic re1047298ex in human rat and guinea pig

intestine Gastroenterology 1998115370ndash80207 Prather CM Camilleri M Zinsmeister AR et al egaserod accelerates

orocecal transit in patients with constipation-predominant irritable bowelsyndrome Gastroenterology 2000118463ndash8

208 Bardhan KD Bodemar G Geldo H et al A double-blind randomizedplacebo-controlled dose-ranging study to evaluate the effi cacy o alosetronin the treatment o irritable bowel syndrome Aliment Pharmacol Ter20001423ndash34

209 Bradette M Moennikes H Carter F et al Cilansetron in irritable bowelsyndrome with diarrhea predominance (IBS-D) effi cacy and saety ina 6 month global study Gastroenterology 2004126 (Suppl 2) A42

210 Camilleri M Mayer EA Drossman DA et al Improvement in pain andbowel unction in emale irritable bowel patients with alosetron a 5-H

3

receptor antagonist Aliment Pharmacol Ter 1999131149ndash59211 Camilleri M Northcutt AR Kong S et al Effi cacy and saety o alosetron

in women with irritable bowel syndrome a randomised placebo-controlled trial Lancet 20003551035ndash40





212 Camilleri M Chey WY Mayer EA et al A randomized controlled clinical trialo the serotonin type 3 receptor antagonist alosetron in women with diarrhea-predominant irritable bowel syndrome Arch Intern Med 20011611733ndash40

213 Chang L Ameen VZ Dukes GE et al A dose-ranging phase II study othe effi cacy and saety o alosetron in men with diarrhea-predominantIBS Am J Gastroenterol 2005100115ndash23

214 Chey WD Chey WY Heath A et al Long-term saety and effi cacy oalosetron in women with severe diarrhea-predominant irritable bowelsyndrome Am J Gastroenterol 2004992195ndash203

215 Francisconi CF Drossman DA Mayer EA et al Interruption o daily acti- vities in cilansetron-treated patients with irritable bowel syndrome withdiarrhea-predominance (IBS-D) results rom a 16-week placebo-control-led rerandomization trial Gastroenterology 2006130 (Suppl 2) A600

216 Krause R Ameen V Gordon SH et al A randomized double-blindplacebo-controlled study to assess effi cacy and saety o 05 mg and 1 mgalosetron in women with severe diarrhea-predominant IBS Am J Gastro-enterol 20071021709ndash19

217 Lembo Wright RA Lotronex Investigator eam et al Alosetron controlsbowel urgency and provides global symptom improvement in womenwith diarrhea-predominant irritable bowel syndrome Am J Gastroenterol2001962662ndash70

218 Matsueda K Harasawa S Hongo M et al A phase II trial o the novel sero-tonin type 3 receptor antagonist ramosetron in Japanese male and emalepatients with diarrhea-predominant irritable bowel syndrome Digestion

200877225ndash35219 Matsueda K Harasawa S Hongo M et al A randomized double-blind

placebo-controlled clinical trial o the effectiveness o the novel serotonintype 3 receptor antagonist ramosetron in both male and emale Japanesepatients with diarrhea-predominant irritable bowel syndrome Scand JGastroenterol 2008431202ndash11

220 Miner P Stanton D Carter F et al Cilansetron in irritable bowel syndromewith diarrhea predominance (IBS-D) effi cacy and saety in a 3 month USstudy Am J Gastroenterol 200499 (Suppl) S277

221 httpwwwdagovdownloadsDrugsDrugSaetyPostmarketDrugSaety InormationorPatientsandProvidersUCM227960pd (accessed June 10th2014)

222 Camilleri M McKinzie S Fox J et al Effect o renzapride on transit inconstipation-predominant irritable bowel syndrome Clin GastroenterolHepatol 20042895ndash904

223 Farup PG Hovdenak N Wetterhus S et al Te symptomatic effect ocisapride in patients with irritable bowel syndrome and constipationScand J Gastroenterol 199833128ndash31

224 George AM Meyers NL Hickling RI Clinical trial renzapride therapyor constipation-predominant irritable bowel syndrome - multicentrerandomized placebo-controlled double-blind study in primary healthcaresetting Aliment Pharmacol Ter 200827830ndash7

225 Schutze K Brandstatter G Dragosics B et al Double-blind study othe effect o cisapride on constipation and abdominal discomort ascomponents o the irritable bowel syndrome Aliment Pharmacol Ter199711387ndash94

226 Spiller RC Meyers NL Hickling RI Identi1047297cation o patients with non-D non-C irritable bowel syndrome and treatment with renzapride anexploratory multicenter randomized double-blind placebo-controlledclinical trial Dig Dis Sci 2008533191ndash200

227 Van Outryve M Milo R oussaint J et al ldquoProkineticrdquo treatment o consti-pation-predominant irritable bowel syndrome a placebo-controlled studyo cisapride J Clin Gastroenterol 19911349ndash57

228 Ziegenhagen DJ Kruis W Cisapride treatment o constipation-predomi-nant irritable bowel syndrome is not superior to placebo J GastroenterolHepatol 200419744ndash9

229 Lembo AJ Cremonini F Meyers N et al Clinical trial renzapride treat-ment o women with irritable bowel syndrome and constipation - adouble-blind randomized placebo-controlled study Aliment PharmacolTer 201031979ndash90

230 Mansour NM Ghaith O El-Halabi M et al A prospective randomizedtrial o mosapride vs placebo in constipation-predominant irritable bowelsyndrome Am J Gastroenterol 2012107792ndash3

231 Forte LR Guanylin regulatory peptides structures biological activitiesmediated by cyclic GMP and pathobiology Regulat Pept 19998125ndash39

232 Chey WD Lembo AJ Lavins BJ et al Linaclotide or irritable bowel syndromewith constipation a 26-week randomized double-blind placebo-controlledtrial to evaluate effi cacy and saety Am J Gastroenterol 20121071702ndash12

233 Johnston JM Kurtz CB MacDougall JE et al Linaclotide improvesabdominal pain and bowel habits in a phase IIb study o patients with

irritable bowel syndrome and constipation Gastroenterology 20101391877ndash86

234 Rao S Lembo AJ Shiff SJ et al 12-week randomized controlled trialwith a 4-week randomized withdrawal period to evaluate the effi cacyand saety o linaclotide in irritable bowel syndrome with constipationAm J Gastroenterol 20121071714ndash24

235 Drossman DA Chey WD Johanson JF et al Clinical trial lubiprostone inpatients with constipation-associated irritable bowel syndrome - resultso two randomized placebo-controlled studies Aliment Pharmacol Ter200929329ndash41

236 Fukudo S Hongo M Kaneko H et al Effi cacy o lubiprostone in patientswith constipation with or without irritable bowel syndrome in Japanrandomized placebo-controlled and dose-1047297nding study Gastroenterology2010130 (Suppl 1) 1435ndash6

237 Johanson JF Drossman DA Panas R et al Clinical trial phase 2 studyo lubiprostone or irritable bowel syndrome with constipation AlimentPharmacol Ter 200827685ndash96

238 Khoshoo V Armstead C Landry L Effect o a laxative with and withouttegaserod in adolescents with constipation predominant irritable bowelsyndrome Aliment Pharmacol Ter 200623191ndash6

239 Awad RA Camacho S A randomized double-blind placebo-controlledtrial o polyethylene glycol effects on asting and postprandial rectal sensi-tivity and symptoms in hypersensitive constipation-predominant irritablebowel syndrome Colorectal Dis 2010121131ndash8

240 Chapman RW Stanghellini V Geraint M et al Randomized clinicaltrial macrogolPEG 3350 plus electrolytes or treatment o patients withconstipation associated with irritable bowel syndrome Am J Gastroenterol20131081508ndash15

241 Ashra W Park F Lo J et al Effects o psyllium therapy on stool character-istics colon transit and anorectal unction in chronic idiopathic constipa-tion Aliment Pharmacol Ter 19959639ndash47

242 Badiali D Corazziari E Habib FI et al Effect o wheat bran in treatment ochronic non-organic constipation A double-blind controlled trial Dig DisSci 199540349ndash56

243 Fenn GC Wilkinson PD Lee CE et al A general practice study o the effi -cacy o Regulan in unctional constipation Br J Gen Pract 198640192ndash7

244 Hongisto S-M Paajanen L Saxelin M et al A combination o 1047297bre-richrye bread and yoghurt containing Lactobacillus GG improves bowel unc-tion in women with sel-reported constipation Eur J Clin Nutr 200660 319ndash24

245 Lopez Roman J Martinez Gonzalvez AB Luque A et al Eecto de laingesta de un preparado lacteo con 1047297bra dietetica sobre el estrenimientocronic primario idiopatico] Nutr Hosp 20082312ndash9

246 Nunes FP Nunes CP Levis E et al A double-blind trial o a celandinaloevera and psyllium laxative preparation in adult patients with constipa-tion Rev Bras Med 200562352ndash7

247 Corazziari E Badiali D Habib FI et al Small volume isosmotic polyethyl-ene glycol electrolyte balanced solution (PMF-100) in treatment o chronicnonorganic constipation Dig Dis Sci 1996411636ndash42

248 Corazziari E Badiali D Bazzocchi G et al Long term effi cacy saety andtolerability o low daily doses o isosmotic polyethylene glycol electrolytebalanced solution (PMF-100) in the treatment o unctional chronic con-stipation Gut 200046522ndash6

249 DiPalma JA DeRidder PH Orlando RC et al A randomized placebo-controlled multicenter study o the saety and effi cacy o a new polyethyl-ene glycol laxative Am J Gastroenterol 200095446ndash50

250 DiPalma JA Cleveland MV McGowan J et al A randomized multicenter

placebo-controlled trial o polyethylene glycol laxative or chronic treat-ment o chronic constipation Am J Gastroenterol 20071021436ndash41

251 Baldonedo YC Lugo E Uzcategui AA et al Evaluation and use o polyeth-ylene glycol in constipated patients] G E N 199145294ndash7

252 Wesselius-De Casparis A Braadbaart S Bergh-Bohlken GE et al reat-ment o chronic constipation with lactulose syrup results o a double-blind study Gut 1968984ndash6

253 Sander JF Lactulose syrup assessed in a double-blind study in elderlyconstipated patients J Am Geriatr Soc 197826236ndash9

254 Kamm MA Mueller-Lissner S Wald A et al Oral bisacodyl is effective andwell-tolerated in patients with chronic constipation Clin GastroenterolHepatol 20119577ndash83

255 Mueller-Lissner S Kamm MA Wald A et al Multicenter 4-week double-blind randomized placebo-controlled trial o sodium picosulate inpatients with chronic constipation Am J Gastroenterol 2010105897ndash903

256 Kim DY Camilleri M Serotonin a mediator o the brain-gut connectionAm J Gastroenterol 2000952698ndash709



26 Ford et al

257 Camilleri M Kerstens R Rykx A et al A placebo-controlled trial o pruca-lopride or severe chronic constipation N Engl J Med 20083582344ndash54

258 Coremans G Kerstens R De Pauw M et al Prucalopride is effective inpatients with severe chronic constipation in whom laxatives ail to provideadequate relie Digestion 20036782ndash9

259 Emmanuel AV Roy AJ Nicholls J et al Prucalopride a systemic enterokineticor the treatment o constipation Aliment Pharmacol Ter 2002161347ndash56

260 Goldberg M Li Y-P Johanson JF et al Clinical trial the effi cacy and tolerabilityo velusetrag a selective 5-H

4 agonist with high intrinsic activity in chronic

idiopathic constipation ndash a 4-week randomized double-blind placebo-controlled dosendashresponse study Aliment Pharmacol Ter 2010321102ndash12

261 Miner PB Nichols Silvers DR et al Te effi cacy and saety o prucalo-pride in patients with chronic constipation Gastroenterology 1999116(Suppl) A1043

262 Muller-Lissner S Rykx A Kerstens R et al A double-blind placebo-controlled study o prucalopride in elderly patients with chronicconstipation Neurogastroenterol Motil 201022991ndash8

263 Quigley EMM Vandeplassche L Kerstens R et al Clinical trial theeffi cacy impact on quality o lie and saety and tolerability o prucalo-pride in severe chronic constipation - a 12-week randomized double-blind placebo-controlled study Aliment Pharmacol Ter 200929315ndash28

264 ack J Van Outryve M Beyens M et al Prucalopride (Resolor) in thetreatment o severe chronic constipation in patients dissatis1047297ed withlaxatives Gut 200958357ndash65

265 Ke M Zou D Yuan Y et al Prucalopride in the treatment o chronicconstipation in patients rom the Asia-Paci1047297c region a randomizeddouble-blind placebo-controlled study Neurogastroenterol Motil201224999ndashe541

266 Lembo AJ Kurtz CB MacDougall JE et al Effi cacy o l inaclotide orpatients with chronic constipation Gastroenterology 2010138886ndash95

267 Lembo AJ Schneier HA Shiff SJ et al wo randomized trials o linaclotideor chronic constipation N Engl J Med 2011365527ndash36

268 Barish CF Drossman D Johanson JF et al Effi cacy and saety o lubiprostonein patients with chronic constipation Dig Dis Sci 2010551090ndash7

269 Johanson JF Ueno R Lubiprostone a local ly acting chloride channelactivator in adult patients with chronic constipation a double-blindplacebo-controlled dose-ranging study to evaluate effi cacy and saetyAliment Pharmacol Ter 2007251351ndash61

270 Johanson JF Morton D Geene J et al Multicenter 4-week double-blindrandomized placebo-controlled trial o lubiprostone a locally-actingtype-2 chloride channel activator in patients with chronic constipationAm J Gastroenterol 2008103170ndash7

271 Rao S Meduri K uteja A et al Effects o lubiprostone on gastrointestinalsymptoms bowel unction and bowel satisaction in patients with metha-nogenic 1047298ora and chronic constipation Am J Gastroenterol 2012107(Suppl 1s) S712ndash3

272 Bharucha AE Pelvic 1047298oor anatomy and unction NeurogastroenterolMotil 200618507ndash19

273 Faubion SS Schuster L Bharucha AE Recognition and management ononrelaxing pelvic 1047298oor dysunction Mayo Clin Proc 201287187ndash93

274 Chiarioni G Whitehead WE Pezza V et al Bioeedback is superior tolaxatives or normal transit constipation due to pelvic 1047298oor dyssynergiaGastroenterology 2006130657ndash64

275 Heymen S Scarlett Y Jones K et al Randomized controlled trial showsbioeedback to be superior to alternative treatments or patients withpelvic 1047298oor dyssynergia-type constipation Dis Colon Rectum 200750428ndash41

276 Rao SS Seaton K Miller M et al Randomized controlled trial o bioeed-back sham eedback and standard therapy or dyssynergic deecationClin Gastroenterol Hepatol 20075331ndash8

277 Hart SL Lee JW Berian J et al A randomized controlled trial o anorectalbioeedback or constipation Int J Colorectal Dis 201227459ndash66

278 Simon MA Bueno AM Behavioural treatment o the dyssynergic deeca-tion in chronically constipated elderly patients a randomized controlledtrial Appl Psychophysiol Bioeedback 200934273ndash7

279 Glia A Gylin M Gullberg K et al Bioeedback retraining in patientswith unctional constipation and paradoxical puborectalis contractioncomparison o anal manometry and sphincter electromyography or eed-back Dis Colon Rectum 199740889ndash95

280 Koutsomanis D Lennard-Jones JE Roy AJ et al Controlled randomisedtrial o visual bioeedback versus muscle training without a visual displayor intractable constipation Gut 19953795ndash9

281 Heymen S Wexner SD Vickers D et al Prospective randomized trialcomparing our bioeedback techniques or patients with constipation

Dis Colon Rectum 1999421388ndash93282 Pourmomeny AA Emami MH Amooshahi M et al Comparing the

effi cacy o bioeedback and balloon-assisted training in the treatment odyssynergic deecation Can J Gastroenterol 20112589ndash92

283 Chey WD Camilleri M Chang L et al A randomized placebo-controlledphase IIb trial o a3309 a bile acid transporter inhibitor or chronicidiopathic constipation Am J Gastroenterol 20111061803ndash12

284 Simren M Bajor A Gillberg PG et al Randomised clinical trial the ilealbile acid transporter inhibitor A3309 vs placebo in patients with chronicidiopathic constipation--a double-blind study Aliment Pharmacol Ter20113441ndash50

285 Wong BS Camilleri M McKinzie S et al Effects o A3309 an ileal bileacid transporter inhibitor on colonic transit and symptoms in emaleswith unctional constipation Am J Gastroenterol 20111062154ndash64

286 Koebnick C Wagner I Leitzmann P et al Probiotic beverage containingLactobacillus casei Shirota improves gastrointestinal symptoms in patientswith chronic constipation Can J Gastroenterol 200317655ndash9

287 Sakai Makino H Ishikawa E et al Fermented milk containing Lacto-bacillus casei strain Shirota reduces incidence o hard or lumpy stools inhealthy population Int J Food Sci Nutr 201162423ndash30

288 Yang YX He M Hu G et al Effect o a ermented milk containingBi1047297dobacterium lactis DN-173010 on Chinese constipated womenWorld J Gastroenterol 2008146237ndash43

289 Bracco A Jonsson B Ricci J-F et al Economic evaluation o tegaserod vs placebo in the treatment o patients with irritable bowel syndrome ananalysis o the ENOR study Value in Health 200710238ndash46





bowel habit type is in turn based on the patientrsquos description o

stool orm by reerring to the Bristol Stool Scale (7) Te recogni-

tion that IBS sufferers segregate into subtypes according to pre-

dominant bowel habit together with research 1047297ndings suggesting

that IBS-C and IBS-D may be pathophysiologically distinct entities

(8ndash10) led to the development o therapies speci1047297cally directed at

each o these subtypes Nonetheless it is worth noting that symp-

toms may not be stable over a lietime and individuals may exhibit

one IBS subtype during a period and then a different IBS subtype

during another period in their lives

However although there is general awareness o the Rome

criteria they are inrequently employed in the assessment o

IBS and CIC in clinical practice (11) o provide more ldquoclinician

riendlyrdquo de1047297nitions as well as to permit inclusion o studies

that predated the Rome process American College o Gastro-

enterology ask Forces suggested the ollowing de1047297nitions in

prior systematic reviews

IBS is de1047297ned by abdominal discomfort associated with altered

bowel habits (12)Constipation is de1047297ned as a symptom-based disorder de1047297ned as

unsatisfactory defecation and is characterized by infrequent stools

diffi cult stool passage or both Diffi cult stool passage includes

straining a sense o diffi culty passing stool incomplete evacu-

ation hardlumpy stools prolonged time to stool or need or

manual maneuvers to pass stool CIC is de1047297ned as the presence o

these symptoms or at least 3 months (13)

It is important to note that the Rome III criteria state that i

ndividuals with chronic constipation do not ul1047297ll criteria or IBS

with pain or discomort being a major determinant in the latter

In practice a clear separation between CIC and IBS with constipa-

tion may be challenging and studies have shown not only consid-erable overlap between these entities (14ndash16) but also a signi1047297cant

tendency or patients to migrate between these diagnoses over

time (15) It is appropriate thereore that in this update o prior

American College o Gastroenterology monographs on IBS and

CIC these entities be addressed in the same exercise (121317)

Te goal o this exercise thereore was to update the most recent

systematic reviews commissioned by the American College o

Gastroenterology on IBS rom 2009 (17) and CIC rom 2005 (13)

METHODS

We have conducted a series o systematic reviews on the effi cacy

o therapy in IBS and CIC Tere have been several systematicreviews o therapy or IBS and CIC published in the past 5

years (18ndash22) Tere have been considerable data published in

the intervening time and hence we have thereore updated

all these systematic reviews o IBS and CIC and synthesized

the data including the inormation rom new trials where

appropriate

Te primary objective o this exercise was to assess the effi cacy

o available therapies in treating IBS and CIC compared with

placebo or no treatment Te secondary objectives included assess-

ing the effi cacy o available therapies in treating IBS according to

predominant stool pattern reported (IBS with constipation IBS

with diarrhea and mixed IBS) as well as assessing adverse events

with therapies or both IBS and CIC

Systematic review methodology

We evaluated manuscripts that studied adults (aged gt 16 years)

using any de1047297nition o IBS or CIC For IBS this included a cli-

nician-de1047297ned diagnosis the Manning criteria (23) the Kruis

score (24) or Rome I (25) II (26) or III (6) criteria For CIC

this included symptoms diagnosed by any o the Rome criteria

(62526) as well as a clinician-de1047297ned diagnosis We included

only parallel-group randomized controlled trials (RCs) com-

paring active intervention with either placebo or no therapy

Crossover trials were eligible or inclusion provided extractable

data were provided at the end o the 1047297rst treatment period beore

crossover

For IBS the ollowing treatments were considered

1 Diet and dietary manipulation

2 Fiber3 Interventions that modiy the microbiota probiotics prebiotics

antibiotics

4 Antispasmodics

5 Peppermint oil

6 Loperamide

7 Antidepressants

8 Psychological therapies including hypnotherapy



11 Polyethylene glycol

For CIC the ollowing were considered

1 Fiber

2 Osmotic and stimulant laxatives

3 5-H4 agonists


5 Bioeedback

6 Bile acid transporter inhibitors

7 Probiotics

Subjects needed to be ollowed up or at least 1 week o be

eligible trials needed to include one or more o the ollowing

outcome measures

(i) Global assessment o improvement in IBS or CIC symptoms

(ii) Improvement in abdominal pain or IBS

(iii) Global IBS symptom or abdominal pain scores or IBS

(iv) Mean number o stools per week during therapy or CIC

Search strategy for identification of studies

MEDLINE (1946 to October 2013) EMBASE and EMBASE

Classic (1947 to October 2013) and the Cochrane central register

o controlled trials were searched

Studies on IBS were identi1047297ed with the terms irritable bowel

syndrome and functional diseases colon (both as medical subject




S4 Ford et al










hypersensitivity








































4 ) (both


5-H 3 5-H















added














poloxalkol




naronapride



























recommendations



























RESULTS


































Data synthesis

















o this review




















S6 Ford et al




























Statement

No of

trials

No of

patients

RR symptoms

(95 CI)

NNT


Quality of

evidence















symptoms



























S8 Ford et al

















ence to their diet





















to be de1047297ned

2 Fiber in IBS












C o n t i n u e d

S t a t e m e n t







M i x e d 5 - H T

4


3




I B S - C

L o w



S



3

3

3



o f I B S - C

H i g h

3

3

3

3




o f I B S - C

M o d e r a t e



e


3

3


3





I B S

V e r y l o w


R


p


3




t o m s



s m a l l


G R A D E


3 s e r o t o n i n

s u b t y p e 3 5 - H T


i r r i t a b



I B S w i t h


a C







Statement

Recom-

mendation

Quality of



patients



3 b 3






supplements

3





patient



Some patients do


3


synbiotics in IBS







to patients







efficacy uncertain

3 Can be expensive

to patients


IBS

Weak Low 3 3 3 3


symptoms











SSRIs can be





patients



Most psychothera-






3



Strong Low 3 3 3 3









effective




patients








10 Ford et al


Statement

No of

trials

No of

patients

RR symptoms


Quality of

evidence

















Statement

Quality


Indirectness



patients with CIC




combined


studied

Not evaluable




3 3 Not evaluable





Not evaluable





Not evaluable




3 3 3


High 3 3 3 3 3



3 3 3 Not evaluable





Not evaluable































and antibiotics





















Statement

Recommen-

dation

Quality of

evidence

All patient





supplements

3





3 3










Expensive





12 Ford et al






unclear




































































1047298icting data




predominant IBS












control arm (81)



















ing 1330 patients




95 CI 042ndash116)

























placebo
















United States






available or review








instances





studied were small

















regions









placebo











14 Ford et al





(I 2 = 724 P = 0001)
























therapy



IBS symptoms

























to 225 mg tid







6 Loperamide in IBS


in IBS





only IBS-D (154)












origin





















































































geneity




















drawn in most areas


ago-

nists 5-H 3



















16 Ford et al














































11 PEG in IBS











4









placebo























sensors (231)






























psyllium


















toast (244)










phosphate


toms of CIC





























1 Fiber in CIC









insoluble

















in the other (244)




18 Ford et al








bias (257260262263265)





between the studies





















4 agonists





(257265)








diarrhea















effective in CIC





















been ormally tested



of CIC




1 minus 7 )






























95 CI 7ndash385)















studies



















































heterogeneity


events









new therapy for CIC


ment









20 Ford et al












7 Probiotics in CIC






































unding was obtained
























































4




















































22 Ford et al













































































































24 Ford et al






















































3

























































26 Ford et al








































S4 Ford et al










hypersensitivity








































4 ) (both


5-H 3 5-H















added














poloxalkol




naronapride



























recommendations



























RESULTS


































Data synthesis

















o this review




















S6 Ford et al




























Statement

No of

trials

No of

patients

RR symptoms

(95 CI)

NNT


Quality of

evidence















symptoms



























S8 Ford et al

















ence to their diet





















to be de1047297ned

2 Fiber in IBS












C o n t i n u e d

S t a t e m e n t







M i x e d 5 - H T

4


3




I B S - C

L o w



S



3

3

3



o f I B S - C

H i g h

3

3

3

3




o f I B S - C

M o d e r a t e



e


3

3


3





I B S

V e r y l o w


R


p


3




t o m s



s m a l l


G R A D E


3 s e r o t o n i n

s u b t y p e 3 5 - H T


i r r i t a b



I B S w i t h


a C







Statement

Recom-

mendation

Quality of



patients



3 b 3






supplements

3





patient



Some patients do


3


synbiotics in IBS







to patients







efficacy uncertain

3 Can be expensive

to patients


IBS

Weak Low 3 3 3 3


symptoms











SSRIs can be





patients



Most psychothera-






3



Strong Low 3 3 3 3









effective




patients








10 Ford et al


Statement

No of

trials

No of

patients

RR symptoms


Quality of

evidence

















Statement

Quality


Indirectness



patients with CIC




combined


studied

Not evaluable




3 3 Not evaluable





Not evaluable





Not evaluable




3 3 3


High 3 3 3 3 3



3 3 3 Not evaluable





Not evaluable































and antibiotics





















Statement

Recommen-

dation

Quality of

evidence

All patient





supplements

3





3 3










Expensive





12 Ford et al






unclear




































































1047298icting data




predominant IBS












control arm (81)



















ing 1330 patients




95 CI 042ndash116)

























placebo
















United States






available or review








instances





studied were small

















regions









placebo











14 Ford et al





(I 2 = 724 P = 0001)
























therapy



IBS symptoms

























to 225 mg tid







6 Loperamide in IBS


in IBS





only IBS-D (154)












origin





















































































geneity




















drawn in most areas


ago-

nists 5-H 3



















16 Ford et al














































11 PEG in IBS











4









placebo























sensors (231)






























psyllium


















toast (244)










phosphate


toms of CIC





























1 Fiber in CIC









insoluble

















in the other (244)




18 Ford et al








bias (257260262263265)





between the studies





















4 agonists





(257265)








diarrhea















effective in CIC





















been ormally tested



of CIC




1 minus 7 )






























95 CI 7ndash385)















studies



















































heterogeneity


events









new therapy for CIC


ment









20 Ford et al












7 Probiotics in CIC






































unding was obtained
























































4




















































22 Ford et al













































































































24 Ford et al






















































3

























































26 Ford et al










































recommendations



























RESULTS


































Data synthesis

















o this review




















S6 Ford et al




























Statement

No of

trials

No of

patients

RR symptoms

(95 CI)

NNT


Quality of

evidence















symptoms



























S8 Ford et al

















ence to their diet





















to be de1047297ned

2 Fiber in IBS












C o n t i n u e d

S t a t e m e n t







M i x e d 5 - H T

4


3




I B S - C

L o w



S



3

3

3



o f I B S - C

H i g h

3

3

3

3




o f I B S - C

M o d e r a t e



e


3

3


3





I B S

V e r y l o w


R


p


3




t o m s



s m a l l


G R A D E


3 s e r o t o n i n

s u b t y p e 3 5 - H T


i r r i t a b



I B S w i t h


a C







Statement

Recom-

mendation

Quality of



patients



3 b 3






supplements

3





patient



Some patients do


3


synbiotics in IBS







to patients







efficacy uncertain

3 Can be expensive

to patients


IBS

Weak Low 3 3 3 3


symptoms











SSRIs can be





patients



Most psychothera-






3



Strong Low 3 3 3 3









effective




patients








10 Ford et al


Statement

No of

trials

No of

patients

RR symptoms


Quality of

evidence

















Statement

Quality


Indirectness



patients with CIC




combined


studied

Not evaluable




3 3 Not evaluable





Not evaluable





Not evaluable




3 3 3


High 3 3 3 3 3



3 3 3 Not evaluable





Not evaluable































and antibiotics





















Statement

Recommen-

dation

Quality of

evidence

All patient





supplements

3





3 3










Expensive





12 Ford et al






unclear




































































1047298icting data




predominant IBS












control arm (81)



















ing 1330 patients




95 CI 042ndash116)

























placebo
















United States






available or review








instances





studied were small

















regions









placebo











14 Ford et al





(I 2 = 724 P = 0001)
























therapy



IBS symptoms

























to 225 mg tid







6 Loperamide in IBS


in IBS





only IBS-D (154)












origin





















































































geneity




















drawn in most areas


ago-

nists 5-H 3



















16 Ford et al














































11 PEG in IBS











4









placebo























sensors (231)






























psyllium


















toast (244)










phosphate


toms of CIC





























1 Fiber in CIC









insoluble

















in the other (244)




18 Ford et al








bias (257260262263265)





between the studies





















4 agonists





(257265)








diarrhea















effective in CIC





















been ormally tested



of CIC




1 minus 7 )






























95 CI 7ndash385)















studies



















































heterogeneity


events









new therapy for CIC


ment









20 Ford et al












7 Probiotics in CIC






































unding was obtained
























































4




















































22 Ford et al













































































































24 Ford et al






















































3

























































26 Ford et al








































S6 Ford et al




























Statement

No of

trials

No of

patients

RR symptoms

(95 CI)

NNT


Quality of

evidence















symptoms



























S8 Ford et al

















ence to their diet





















to be de1047297ned

2 Fiber in IBS












C o n t i n u e d

S t a t e m e n t







M i x e d 5 - H T

4


3




I B S - C

L o w



S



3

3

3



o f I B S - C

H i g h

3

3

3

3




o f I B S - C

M o d e r a t e



e


3

3


3





I B S

V e r y l o w


R


p


3




t o m s



s m a l l


G R A D E


3 s e r o t o n i n

s u b t y p e 3 5 - H T


i r r i t a b



I B S w i t h


a C







Statement

Recom-

mendation

Quality of



patients



3 b 3






supplements

3





patient



Some patients do


3


synbiotics in IBS







to patients







efficacy uncertain

3 Can be expensive

to patients


IBS

Weak Low 3 3 3 3


symptoms











SSRIs can be





patients



Most psychothera-






3



Strong Low 3 3 3 3









effective




patients








10 Ford et al


Statement

No of

trials

No of

patients

RR symptoms


Quality of

evidence

















Statement

Quality


Indirectness



patients with CIC




combined


studied

Not evaluable




3 3 Not evaluable





Not evaluable





Not evaluable




3 3 3


High 3 3 3 3 3



3 3 3 Not evaluable





Not evaluable































and antibiotics





















Statement

Recommen-

dation

Quality of

evidence

All patient





supplements

3





3 3










Expensive





12 Ford et al






unclear




































































1047298icting data




predominant IBS












control arm (81)



















ing 1330 patients




95 CI 042ndash116)

























placebo
















United States






available or review








instances





studied were small

















regions









placebo











14 Ford et al





(I 2 = 724 P = 0001)
























therapy



IBS symptoms

























to 225 mg tid







6 Loperamide in IBS


in IBS





only IBS-D (154)












origin





















































































geneity




















drawn in most areas


ago-

nists 5-H 3



















16 Ford et al














































11 PEG in IBS











4









placebo























sensors (231)






























psyllium


















toast (244)










phosphate


toms of CIC





























1 Fiber in CIC









insoluble

















in the other (244)




18 Ford et al








bias (257260262263265)





between the studies





















4 agonists





(257265)








diarrhea















effective in CIC





















been ormally tested



of CIC




1 minus 7 )






























95 CI 7ndash385)















studies



















































heterogeneity


events









new therapy for CIC


ment









20 Ford et al












7 Probiotics in CIC






































unding was obtained
























































4




















































22 Ford et al













































































































24 Ford et al






















































3

























































26 Ford et al










































S8 Ford et al

















ence to their diet





















to be de1047297ned

2 Fiber in IBS












C o n t i n u e d

S t a t e m e n t







M i x e d 5 - H T

4


3




I B S - C

L o w



S



3

3

3



o f I B S - C

H i g h

3

3

3

3




o f I B S - C

M o d e r a t e



e


3

3


3





I B S

V e r y l o w


R


p


3




t o m s



s m a l l


G R A D E


3 s e r o t o n i n

s u b t y p e 3 5 - H T


i r r i t a b



I B S w i t h


a C







Statement

Recom-

mendation

Quality of



patients



3 b 3






supplements

3





patient



Some patients do


3


synbiotics in IBS







to patients







efficacy uncertain

3 Can be expensive

to patients


IBS

Weak Low 3 3 3 3


symptoms











SSRIs can be





patients



Most psychothera-






3



Strong Low 3 3 3 3









effective




patients








10 Ford et al


Statement

No of

trials

No of

patients

RR symptoms


Quality of

evidence

















Statement

Quality


Indirectness



patients with CIC




combined


studied

Not evaluable




3 3 Not evaluable





Not evaluable





Not evaluable




3 3 3


High 3 3 3 3 3



3 3 3 Not evaluable





Not evaluable































and antibiotics





















Statement

Recommen-

dation

Quality of

evidence

All patient





supplements

3





3 3










Expensive





12 Ford et al






unclear




































































1047298icting data




predominant IBS












control arm (81)



















ing 1330 patients




95 CI 042ndash116)

























placebo
















United States






available or review








instances





studied were small

















regions









placebo











14 Ford et al





(I 2 = 724 P = 0001)
























therapy



IBS symptoms

























to 225 mg tid







6 Loperamide in IBS


in IBS





only IBS-D (154)












origin





















































































geneity




















drawn in most areas


ago-

nists 5-H 3



















16 Ford et al














































11 PEG in IBS











4









placebo























sensors (231)






























psyllium


















toast (244)










phosphate


toms of CIC





























1 Fiber in CIC









insoluble

















in the other (244)




18 Ford et al








bias (257260262263265)





between the studies





















4 agonists





(257265)








diarrhea















effective in CIC





















been ormally tested



of CIC




1 minus 7 )






























95 CI 7ndash385)















studies



















































heterogeneity


events









new therapy for CIC


ment









20 Ford et al












7 Probiotics in CIC






































unding was obtained
























































4




















































22 Ford et al













































































































24 Ford et al






















































3

























































26 Ford et al










































Statement

Recom-

mendation

Quality of



patients



3 b 3






supplements

3





patient



Some patients do


3


synbiotics in IBS







to patients







efficacy uncertain

3 Can be expensive

to patients


IBS

Weak Low 3 3 3 3


symptoms











SSRIs can be





patients



Most psychothera-






3



Strong Low 3 3 3 3









effective




patients








10 Ford et al


Statement

No of

trials

No of

patients

RR symptoms


Quality of

evidence

















Statement

Quality


Indirectness



patients with CIC




combined


studied

Not evaluable




3 3 Not evaluable





Not evaluable





Not evaluable




3 3 3


High 3 3 3 3 3



3 3 3 Not evaluable





Not evaluable































and antibiotics





















Statement

Recommen-

dation

Quality of

evidence

All patient





supplements

3





3 3










Expensive





12 Ford et al






unclear




































































1047298icting data




predominant IBS












control arm (81)



















ing 1330 patients




95 CI 042ndash116)

























placebo
















United States






available or review








instances





studied were small

















regions









placebo











14 Ford et al





(I 2 = 724 P = 0001)
























therapy



IBS symptoms

























to 225 mg tid







6 Loperamide in IBS


in IBS





only IBS-D (154)












origin





















































































geneity




















drawn in most areas


ago-

nists 5-H 3



















16 Ford et al














































11 PEG in IBS











4









placebo























sensors (231)






























psyllium


















toast (244)










phosphate


toms of CIC





























1 Fiber in CIC









insoluble

















in the other (244)




18 Ford et al








bias (257260262263265)





between the studies





















4 agonists





(257265)








diarrhea















effective in CIC





















been ormally tested



of CIC




1 minus 7 )






























95 CI 7ndash385)















studies



















































heterogeneity


events









new therapy for CIC


ment









20 Ford et al












7 Probiotics in CIC






































unding was obtained
























































4




















































22 Ford et al













































































































24 Ford et al






















































3

























































26 Ford et al








































10 Ford et al


Statement

No of

trials

No of

patients

RR symptoms


Quality of

evidence

















Statement

Quality


Indirectness



patients with CIC




combined


studied

Not evaluable




3 3 Not evaluable





Not evaluable





Not evaluable




3 3 3


High 3 3 3 3 3



3 3 3 Not evaluable





Not evaluable































and antibiotics





















Statement

Recommen-

dation

Quality of

evidence

All patient





supplements

3





3 3










Expensive





12 Ford et al






unclear




































































1047298icting data




predominant IBS












control arm (81)



















ing 1330 patients




95 CI 042ndash116)

























placebo
















United States






available or review








instances





studied were small

















regions









placebo











14 Ford et al





(I 2 = 724 P = 0001)
























therapy



IBS symptoms

























to 225 mg tid







6 Loperamide in IBS


in IBS





only IBS-D (154)












origin





















































































geneity




















drawn in most areas


ago-

nists 5-H 3



















16 Ford et al














































11 PEG in IBS











4









placebo























sensors (231)






























psyllium


















toast (244)










phosphate


toms of CIC





























1 Fiber in CIC









insoluble

















in the other (244)




18 Ford et al








bias (257260262263265)





between the studies





















4 agonists





(257265)








diarrhea















effective in CIC





















been ormally tested



of CIC




1 minus 7 )






























95 CI 7ndash385)















studies



















































heterogeneity


events









new therapy for CIC


ment









20 Ford et al












7 Probiotics in CIC






































unding was obtained
























































4




















































22 Ford et al













































































































24 Ford et al






















































3

























































26 Ford et al


































































and antibiotics





















Statement

Recommen-

dation

Quality of

evidence

All patient





supplements

3





3 3










Expensive





12 Ford et al






unclear




































































1047298icting data




predominant IBS












control arm (81)



















ing 1330 patients




95 CI 042ndash116)

























placebo
















United States






available or review








instances





studied were small

















regions









placebo











14 Ford et al





(I 2 = 724 P = 0001)
























therapy



IBS symptoms

























to 225 mg tid







6 Loperamide in IBS


in IBS





only IBS-D (154)












origin





















































































geneity




















drawn in most areas


ago-

nists 5-H 3



















16 Ford et al














































11 PEG in IBS











4









placebo























sensors (231)






























psyllium


















toast (244)










phosphate


toms of CIC





























1 Fiber in CIC









insoluble

















in the other (244)




18 Ford et al








bias (257260262263265)





between the studies





















4 agonists





(257265)








diarrhea















effective in CIC





















been ormally tested



of CIC




1 minus 7 )






























95 CI 7ndash385)















studies



















































heterogeneity


events









new therapy for CIC


ment









20 Ford et al












7 Probiotics in CIC






































unding was obtained
























































4




















































22 Ford et al













































































































24 Ford et al






















































3

























































26 Ford et al








































12 Ford et al






unclear




































































1047298icting data




predominant IBS












control arm (81)



















ing 1330 patients




95 CI 042ndash116)

























placebo
















United States






available or review








instances





studied were small

















regions









placebo











14 Ford et al





(I 2 = 724 P = 0001)
























therapy



IBS symptoms

























to 225 mg tid







6 Loperamide in IBS


in IBS





only IBS-D (154)












origin





















































































geneity




















drawn in most areas


ago-

nists 5-H 3



















16 Ford et al














































11 PEG in IBS











4









placebo























sensors (231)






























psyllium


















toast (244)










phosphate


toms of CIC





























1 Fiber in CIC









insoluble

















in the other (244)




18 Ford et al








bias (257260262263265)





between the studies





















4 agonists





(257265)








diarrhea















effective in CIC





















been ormally tested



of CIC




1 minus 7 )






























95 CI 7ndash385)















studies



















































heterogeneity


events









new therapy for CIC


ment









20 Ford et al












7 Probiotics in CIC






































unding was obtained
























































4




















































22 Ford et al













































































































24 Ford et al






















































3

























































26 Ford et al











































ing 1330 patients




95 CI 042ndash116)

























placebo
















United States






available or review








instances





studied were small

















regions









placebo











14 Ford et al





(I 2 = 724 P = 0001)
























therapy



IBS symptoms

























to 225 mg tid







6 Loperamide in IBS


in IBS





only IBS-D (154)












origin





















































































geneity




















drawn in most areas


ago-

nists 5-H 3



















16 Ford et al














































11 PEG in IBS











4









placebo























sensors (231)






























psyllium


















toast (244)










phosphate


toms of CIC





























1 Fiber in CIC









insoluble

















in the other (244)




18 Ford et al








bias (257260262263265)





between the studies





















4 agonists





(257265)








diarrhea















effective in CIC





















been ormally tested



of CIC




1 minus 7 )






























95 CI 7ndash385)















studies



















































heterogeneity


events









new therapy for CIC


ment









20 Ford et al












7 Probiotics in CIC






































unding was obtained
























































4




















































22 Ford et al













































































































24 Ford et al






















































3

























































26 Ford et al








































14 Ford et al





(I 2 = 724 P = 0001)
























therapy



IBS symptoms

























to 225 mg tid







6 Loperamide in IBS


in IBS





only IBS-D (154)












origin





















































































geneity




















drawn in most areas


ago-

nists 5-H 3



















16 Ford et al














































11 PEG in IBS











4









placebo























sensors (231)






























psyllium


















toast (244)










phosphate


toms of CIC





























1 Fiber in CIC









insoluble

















in the other (244)




18 Ford et al








bias (257260262263265)





between the studies





















4 agonists





(257265)








diarrhea















effective in CIC





















been ormally tested



of CIC




1 minus 7 )






























95 CI 7ndash385)















studies



















































heterogeneity


events









new therapy for CIC


ment









20 Ford et al












7 Probiotics in CIC






































unding was obtained
























































4




















































22 Ford et al













































































































24 Ford et al






















































3

























































26 Ford et al









































































































geneity




















drawn in most areas


ago-

nists 5-H 3



















16 Ford et al














































11 PEG in IBS











4









placebo























sensors (231)






























psyllium


















toast (244)










phosphate


toms of CIC





























1 Fiber in CIC









insoluble

















in the other (244)




18 Ford et al








bias (257260262263265)





between the studies





















4 agonists





(257265)








diarrhea















effective in CIC





















been ormally tested



of CIC




1 minus 7 )






























95 CI 7ndash385)















studies



















































heterogeneity


events









new therapy for CIC


ment









20 Ford et al












7 Probiotics in CIC






































unding was obtained
























































4




















































22 Ford et al













































































































24 Ford et al






















































3

























































26 Ford et al








































16 Ford et al














































11 PEG in IBS











4









placebo























sensors (231)






























psyllium


















toast (244)










phosphate


toms of CIC





























1 Fiber in CIC









insoluble

















in the other (244)




18 Ford et al








bias (257260262263265)





between the studies





















4 agonists





(257265)








diarrhea















effective in CIC





















been ormally tested



of CIC




1 minus 7 )






























95 CI 7ndash385)















studies



















































heterogeneity


events









new therapy for CIC


ment









20 Ford et al












7 Probiotics in CIC






































unding was obtained
























































4




















































22 Ford et al













































































































24 Ford et al






















































3

























































26 Ford et al






















































psyllium


















toast (244)










phosphate


toms of CIC





























1 Fiber in CIC









insoluble

















in the other (244)




18 Ford et al








bias (257260262263265)





between the studies





















4 agonists





(257265)








diarrhea















effective in CIC





















been ormally tested



of CIC




1 minus 7 )






























95 CI 7ndash385)















studies



















































heterogeneity


events









new therapy for CIC


ment









20 Ford et al












7 Probiotics in CIC






































unding was obtained
























































4




















































22 Ford et al













































































































24 Ford et al






















































3

























































26 Ford et al








































18 Ford et al








bias (257260262263265)





between the studies





















4 agonists





(257265)








diarrhea















effective in CIC





















been ormally tested



of CIC




1 minus 7 )






























95 CI 7ndash385)















studies



















































heterogeneity


events









new therapy for CIC


ment









20 Ford et al












7 Probiotics in CIC






































unding was obtained
























































4




















































22 Ford et al













































































































24 Ford et al






















































3

























































26 Ford et al
























































95 CI 7ndash385)















studies



















































heterogeneity


events









new therapy for CIC


ment









20 Ford et al












7 Probiotics in CIC






































unding was obtained
























































4




















































22 Ford et al













































































































24 Ford et al






















































3

























































26 Ford et al








































20 Ford et al












7 Probiotics in CIC






































unding was obtained
























































4




















































22 Ford et al













































































































24 Ford et al






















































3

























































26 Ford et al



















































4




















































22 Ford et al













































































































24 Ford et al






















































3

























































26 Ford et al








































22 Ford et al













































































































24 Ford et al






















































3

























































26 Ford et al

































































































24 Ford et al






















































3

























































26 Ford et al



























































































26 Ford et al





































Ibs Cic Monograph Ajg Aug 2014

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Transcript of Ibs Cic Monograph Ajg Aug 2014