Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is...

119
Patient Reported Effects of Treatments for Irritable Bowel Syndrome A Retrospective Study Zillan Neiron 307223159 Supervisors: Mrs Wendy Stuart-Smith, BSc DipEd, MNutDiet, APD Dr Anne Swain, Dip Nutr Diet, PhD Chief Dietitian, Allergy Unit, RPAH Dr Robert Loblay, MBBS, FRACP, PhD Director, Allergy Unit, RPAH Allergy Unit Department of Clinical Immunology Royal Prince Alfred Hospital, Sydney Date of Submission: 1 st November, 2012

Transcript of Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is...

Page 1: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

Patient Reported Effects of

Treatments for Irritable Bowel Syndrome

A Retrospective Study

Zillan Neiron 307223159

Supervisors:

Mrs Wendy Stuart-Smith, BSc DipEd, MNutDiet, APD

Dr Anne Swain, Dip Nutr Diet, PhD Chief Dietitian, Allergy Unit, RPAH

Dr Robert Loblay, MBBS, FRACP, PhD

Director, Allergy Unit, RPAH

Allergy Unit Department of Clinical Immunology Royal Prince Alfred Hospital, Sydney

Date of Submission: 1st November, 2012

Page 2: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

2

Declaration

The candidate, Zillan Neiron hereby declares that none of the work presented in this essay

has been submitted to any other University or Institution for a higher degree and that to

the best of her knowledge contains no material written or published by another person,

except where due reference is made in the text.

Signature  ………………………………………………………………………

Date  ……………………………………………………………………………….

Candidate: Zillan Neiron

Student Identification Number: 307223159

Page 3: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

3

Patient Reported Effects of Treatments for Irritable Bowel Syndrome

Abstract

Aim: The aim of the present study was to investigate the current management practices used for

irritable bowel syndrome (IBS), focusing on patient reported long term efficacies of trialed

therapies.

Methods: An email with a link to an online questionnaire was sent to all patients with

gastrointestinal symptoms who attended the Royal Prince Alfred Hospital (RPAH) Allergy Unit,

between November 2000 and June 2012. Questions focused on therapies trialed by the patients

and long term outcomes of these therapies. Responses were analysed using Excel and Stata.

Results: Data from 249 patients was analysed. Reported efficacy of treatments was varied. Eighty-

five percent of patients reported diet modification, specifically in the form of eliminating specific

chemicals, as the most effective treatment. Medication, especially gastric acid inhibitors, was also

important. Common probiotics were not reported to provide long term benefit. Modified fibre

diets showed mixed results, although data was incomplete. Reported challenges with specific

chemicals caused patients a variety of gastrointestinal and non-gastrointestinal symptoms, of

which  salicylates  provoked  the  greatest  number  of  patients’  symptoms.

Page 4: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

4

Conclusions: The reported efficacy of different treatments had a consistent theme, that diet

modification provides the greatest gastrointestinal symptomatic relief. The Elimination Diet and

Challenge protocol at RPAH has shown to be the most efficacious reported form of treatment.

Key words: diet, gastrointestinal symptoms, irritable bowel syndrome (IBS), salicylates.

Page 5: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

5

Introduction

Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting

10-20% of the adult population.1, 2 It is characterised by recurring symptoms of abdominal pain or

discomfort, bloating and altered bowel function in the absence of structural, inflammatory, or

biochemical abnormalities.3, 4 The pathophysiology of IBS is still being determined and includes a

complex interaction between altered GI motility, visceral hypersensitivity, altered brain-gut

function, low grade inflammation, psychosocial stress and intestinal microbes.5-7

The majority of patients with IBS perceive their symptoms to be diet related8 with many reporting

exacerbation of their symptoms immediately following food ingestion.9 Reported trigger foods

include milk and milk products, wheat products, caffeine, certain meats, cabbage and other

brassicas, onion, peas, beans, hot spices and fried foods.9 Dietary trials have produced mixed

results, offering minimal guidance to manage IBS symptoms. It has recently been suggested that

removing poorly absorbed, short chain, rapidly fermentable carbohydrate foods will prevent gas

production resulting from fermentation within the gastrointestinal tract and inhibit an osmotic

effect that may cause IBS symptoms.10 These groups of molecules are referred to as FODMAPs,

which stands for Fermentable Oligo-, Di- and Mono-saccharides and Polyols. Fructose, fructans,

lactose, sorbitol and xylitol are some examples of these carbohydrates.

It has also been hypothesised that natural and added food chemicals, including salicylates, amines

and glutamates, preservatives and colourings, some whole foods including wheat, dairy and soy,

the well-described  ‘windy  foods’  (e.g.  brassicas,  legumes)  may exacerbate symptoms experienced

by patients with IBS. In patients attending the Royal Prince Alfred Hospital (RPAH) Allergy Unit,

Page 6: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

6

dietary triggers of IBS are identified using the Elimination Diet and challenge protocol. The

‘elimination’   phase   involves   the   removal/reduction  of   certain  natural   foods, food chemicals and

additives (known to  elicit  adverse  reactions)   from  the  patient’s  diet   for  a  number of weeks until

symptoms settle to a stable baseline. The patient is then challenged with these foods and food

chemicals, either in the form of food or double blinded placebo controlled capsules to determine

what the patient reacts to. The patient then carefully liberalises their diet to determine their

threshold of reactivity in order to manage symptoms and maintain nutritional adequacy. Thus the

aim is to identify and limit intake of trigger chemicals/foods only as much as required to manage

symptoms.

The aim of this study is to retrospectively investigate the management history of patients

presenting to the RPAH Allergy Unit with IBS symptoms between the years 2000-2012.

Page 7: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

7

Methods

Study Design

This is a retrospective study of patients who attended the RPAH Allergy Unit between November

2000 and June 2012 with gastrointestinal symptoms. Many of the patients followed or are

currently following the Elimination Diet and challenge protocol for identification and management

of their dietary triggers. The study protocol was approved by the Sydney Local Health District

(SLHD) RPAH Zone ethics committee. All patients gave online informed consent, including to

patient record access.

Subjects

Patients were selected for inclusion in the study if they had attended the RPAH Allergy Unit

presenting with gastrointestinal symptoms, aged 18 years or over, between the November 2000

and June 2012. One thousand, one hundred and seventy-three subjects were identified and sent

an email outlining the purpose of the study and inviting them to complete an online Survey

Monkey questionnaire. Between 12 September, 2012, and 10 October, 2012, 249 patients

completed the questionnaire.

Questionnaire

The gastrointestinal symptom questionnaire (Appendix III) was constructed for the use of

retrospectively collecting the  patients’ symptoms, interventions and trialed therapies before and

after attending the RPAH Allergy Unit. The questionnaire was updated from a previous paper-

based questionnaire, in a similar study conducted by the RPAH Allergy Unit (Stuart-Smith W, 2000,

unpublished data), to reflect current therapies. The questionnaire for this study was implemented

Page 8: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

8

using an online survey software tool known as Survey Monkey consisting of 56 questions.

Questions required a mixture of closed and open responses.

Data Processing and Analysis

Patient data and text results from the online Survey Monkey questionnaire were entered into a

Microsoft Office Excel 2007 spreadsheet by the investigator. Analysis of the data and text was

performed using the Excel spreadsheet. When recording text responses to treatments, only a

definite   indication  of   improvement  was  taken  as  a   ‘yes’.  Blanks  were  treated  as  a   ‘no’  response.  

Graphs were generated from the spreadsheet data. Mean, median and age range of patients were

calculated using the RPAH Allergy Unit database and Stata version 12 statistical analysis program.

Patients’  symptom severity, symptom frequency and reactions to challenges were analysed using

Stata.

Page 9: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

9

Results

Response Rate

Of 1156 questionnaires sent via an email invitation with a link, 249 (21.5%) were completed.

Participants only filled out relevant sections of each question; hence data for each question differs

in the total number for analysis.

Demographics

The sample comprised 56 (22.5%) males and 193 (77.5%) females. The mean population age was

41.5 years (45 years for males, 39 years for females; range 18-90 years). The median population

age was 39 years (47.5 years for males, 37 years for females).

Symptoms

The symptom severity and frequency decreased for all symptoms over the study period (Figure 1).

Only patients who recorded severity and frequency before and after were included. The majority

of patients had their initial visit in 2011 (Appendix IV). The most severe symptom reported was

fatigue. The most frequently reported symptom was abdominal discomfort. The symptoms that

improved most in severity were abdominal pain, bloating, abdominal discomfort and stomach

cramps. The symptom improving most in frequency was bloating, followed by abdominal

discomfort, stomach cramps and stomach pain. Sixty-two  percent  (n=149)  of  patients’  symptoms

of stomach pain, cramps and discomfort were relieved upon defecation.

Page 10: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

10

Figure 1. Mean Symptom Severity and Frequency of Patients with Gastrointestinal Symptoms.

Mean severity and frequency axis refers to the participants rating of their experienced symptom severity and frequency within a range. Symptom severity ranges from 0-3 where 0 = none 1 = mild (aware of symptoms, but easily tolerated) 2 = moderate (bad enough to cause interference with daily life or usual activity) 3 = severe (incapacitating, with inability to work/take part in usual activities). Symptom frequency ranges from 0-4 where 0 = never, 1= less than 1 month, 2 = monthly, 3 = weekly and 4 = daily.

0

1

2

3

Mea

n Se

verit

y /

Freq

uenc

y

Symptom Severity Symptom Frequency

Page 11: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

11

Medical tests

Prior to presentation at the RPAH Allergy Unit the majority of patients (68.2%) had undergone

some form of medical testing to rule out any other organic disease, including colonoscopy/biopsy

(63.5%), endoscopy (62.9%), thyroid function test (49.4%), ultra-sound (41.8%), stool examination

(40.6%), CT-scan of abdomen (31.1%), small bowel biopsy (21.2%), dissacharidase assay (lactase)

(12.9%) and 3-day fecal fat collection (9.4%). On average, patients had undergone 1.7 medical

tests.

Page 12: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

12

Therapies

Table 1. Efficacy of therapies trialed by patients for gastrointestinal symptoms. Therapy Type Trialed

n= (%n) Still Effective

n= (%n) Medications

(n=127) Gastric Acid Inhibitor 40 (31.5) 31 (77.5)

Anti-inflammatory 14 (11.0) 8 (57.1)

Laxative 11 (8.7) 7 (63.6)

Antibiotic 8 (6.3) 3 (37.5)

Anti-depressant 7 (5.5) 3 (42.8)

Anti-spasmodic 7 (5.5) 5 (71.4)

Anti-diarrhoeal 5 (4.0) 3 (60.0)

Relaxation (n=55)

Golf/Other Exercise 24 (43.6) 13 (54.2)

Meditation 21 (38.2) 11 (52.4)

Decreasing workload 18 (32.7) 14 (77.8)

Taking time by self 18 (32.7) 12 (66.7)

Positive thinking 15 (27.3) 10 (66.7)

Deep breathing 15 (27.3) 10 (66.7)

Natural (n=83)

Herbal tea 38 (45.8) 16 (42.1)

Herbal remedies 38 (45.8) 11 (28.9)

Massage 25 (30.1) 14 (56.0)

Meditation 16 (19.3) 7 (43.8)

Antibiotic therapy 14 (16.9) 6 (42.9)

Colonic irrigation 7 (8.4) 1 (14.3)

Aromatherapy 7 (8.4) 2 (28.6)

Exercise (n=60)

Walking 34 (56.7) 21 (61.8)

Yoga 12 (20.0) 7 (58.3)

Running 10 (16.7) 8 (80.0)

Swimming 10 (16.7) 3 (30.0)

Sport 8 (13.3) 7 (87.5)

Pilates 7 (11.7) 5 (71.4)

Probiotics/Prebiotics/

Fermented Foods (n=160)

Probiotics 91(56.9) -

Prebiotics 6 (3.8) -

Fermented Foods 63 (39.4) -

Page 13: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

13

Medications

Forty-two percent of 164 patients had been prescribed medication to assist their gastrointestinal

symptoms, stress or anxiety.

Relaxation Therapy

Thirty-two percent (n=171) of patients were advised to decrease the stress in their life. Exercise

was the commonest therapy (Appendix V).

Natural Therapy

Just over half (50.9%) of 163 patients had used natural therapies to relieve symptoms. Herbal teas

and herbal remedies were the most trialed therapies (Table 1). Massage and meditation were

reported to relieve symptoms of muscle pain, sleeplessness, fatigue, headaches, stress and

improved their ability to relax.

Exercise

Forty-nine (37%) of 160 patients had used exercise to relieve symptoms. Walking was the most

common type trialed (Appendix VII). Exercise was found to assist with bloating (40.8%),

constipation (28.6%), stress (16.3%), bowel movements, gas and pain (14.3%) and general

wellbeing (12.2%).

Probiotics and Prebiotics

Of 158 patients, 67.1% had trialed probiotics and 19.3% of 140 had trialed prebiotics. The

commonly trialed probiotics were Inner Health Plus (56%), Yakult (32%) and IBS Support (27%)

Page 14: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

14

(Appendix VI). Efficacy of this therapy was low with less than half of those trialing them finding

probiotics beneficial. Specific preparations of Lactobacillus (n=14) and Bifidobacteria (n=8) were

reportedly the most effective with 42.9% and 62.5% respectively finding them beneficial but

numbers in these groups are very small. Ten percent experienced adverse effects from probiotics

such as diarrhoea, nausea, cramping, headache and itching.

Fermented Foods

Thirty-two percent of patients (n=157) trialed fermented foods to relieve symptoms. Yoghurt was

most commonly trialed (n=48), although 20.8% found it effective (Appendix VI).

Fibre

Forty-eight percent of 155 patients were advised to increase the fibre content of their diet, while

21% of 142 were advised to decreased dietary fibre. However baseline fibre intake levels were not

quantified in the survey. Fruit was the most commonly trialed form of fibre, with at least 30%

reporting improved symptoms and ongoing benefit (Table 2). One patient reported exacerbation

of symptoms, while 4 patients felt no change. Pulses and lentils were the least modified form of

fibre. Constipation and bloating were the symptoms most improved by altering dietary fibre. Six

patients reported symptom improvements due to reduction in intake of salicylate-containing

forms   of   fibre.   Removal   of   gluten/wheat   and   fibre   in   the   form   of   ‘wind   producing   vegetables’  

(namely cabbage, leek and onion) were also reported to alleviate symptoms.

Page 15: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

15

Table 2. Fibre Intake of Patients with Gastrointestinal Symptoms. Fibre Type Trialed Increased Intake Decreased Intake Still Benefitting

Fruit (total amount)

45 29 16 24

Pears 36 28 8 17 Apples 34 16 18 18 Banana 24 12 12 13 Avocado 21 8 13 10 Grapes 19 5 14 9 Kiwifruit 20 9 11 12 Vegetables (total) 21 4 17 10 Broccoli 34 28 6 18 Cabbage 27 15 12 15 Brussels sprouts 23 8 15 9 Onion 21 8 13 9 Leek 27 7 20 10 Garlic 21 12 9 9 Peas 29 14 15 16 Green beans 21 7 14 11 Bok choy 23 15 8 11 Beetroot 12 6 6 8 Grains†   15 6 9 8 Pulses and lentils (total)

30 14 16 16

Lentils 25 15 10 12 Chickpeas 22 12 10 10 Kidney beans 15 6 9 9 Baked beans 16 7 9 11 Bran 19 6 13 11 Bulking  agents‡ 20 10 10 11

†Includes  breads,  pasta  and  rice.  ‡Includes  Metamucil  and  psyllium  husks.

Diet Modifications

Almost 70% of 151 patients had trialed dietary modifications with benefit in 34% prior to

presentation at the RPAH Allergy Unit. The most common trialed diets were milk-free, gluten-free

and wheat-free, with around half of patients still continuing these diets and finding them

beneficial (Table 3). Fifteen patients specified avoidance of cabbage, broccoli, legumes, cauliflower,

nuts,   beans,  dried   fruit,   onions,   garlic   and  Brussels   sprouts  of   the   ‘windy   foods’.   Seven  patients  

who reported avoidance of rich foods specified fatty foods, cream, oil and chocolate to be

Page 16: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

16

beneficial. Water consumption was reportedly increased to 1-3 litres per day. Advice regarding

dietary modifications came from Doctors (39%), Dietitians (48%), Naturopaths (15%) and other

sources.

Table 3. Diets and Diet Modifications Trialed by Patients with Gastrointestinal Symptoms.

Diet Type Trialed Still Continuing Still Benefitting

Yeast-free 36 16 8 Sugar-free 30 10 7 Hypoglycaemia 5 2 1 Wheat-free 61 29 23 Gluten-free 64 33 25 Milk-free 70 34 30 Soy-free 21 13 9 Egg-free 7 4 1 Nut-free 13 4 3 ‘acid-food’  avoidance 27 16 12 ‘rich-food’  avoidance 24 14 10 ‘windy-food’  avoidance 31 17 12 FODMAPs 14 8 6 Increase water consumption 46 24 20 Vitamin/mineral supplementation

33 18 12

Yakult/acidophilus yoghurt 29 8 5 Food combining 8 1 1 Raw food 5 4 4 Organic 17 7 2 Food timing 3 4 1 Liver-cleansing 11 1 0 Diet from Naturopath 10 1 0

Page 17: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

17

Elimination Diet

Of 149 patients, 78% changed their diet after attending the RPAH Allergy Unit. Seventy-five

percent of those who started the RPAH Elimination Diet improved. Eighty-three participants

completed challenges: 53% food, 6% capsule and 41% both food and capsule challenges. On

challenge milk/dairy (55%), salicylates (52.5%), amines (50%), preservatives (47.5%),

glutamates/MSG (45%), additives (45%), gluten (40%) and wheat (38.8%) were the commonest

triggers  (Figure  2).  Salicylates  provoked  the  greatest  number  of  patients’  symptoms  (Appendix  VIII).  

The most common symptoms reported on challenge were: wind/bloating, stomach pain/cramp

and diarrhoea/constipation (Appendix IX).

Page 18: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

18

Figure 2. Elimination Diet Challenge Effects on Gastrointestinal and Non-Gastrointestinal Symptoms.

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Additives

Preservatives

Benzoates

Nitrates

Propionates

Sorbates

Sulfites

Antioxidants

Milk

Artificial Colours

Colour 160b

Lactose

Wheat

Gluten

Salicylates

Amines

Glutamate/MSG

Percent of Patients

Nausea/Vomiting Indigestion/Reflux Wind/Bloating Stomach Pain/Cramp

Diarrhoea/Constipation Mouth Ulcers Hives/Swelling Eczema

Headache/Migraine Fatigue Muscle/Joint Ache Sinus Problems

Bladder/Vaginal Other

n=36

n=40

n=42

n=32

n=10

n=22

n=31

n=8

n=44

n=25

n=28

n=38

n=36

n=9

n=10

n=18

n=10

Page 19: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

19

Ranking Treatments

One hundred and twenty-three patients ranked the effectiveness of the treatments they had

trialed (Appendix X). Eighty-five percent found dietary modification was the most effective

treatment. The most   frequently   cited   ‘most   effective’   treatment  was   the  RPAH Elimination Diet

(47.2%), gluten-free diet (7.3%), medications (6.5%), FODMAPs diet (4.9%) and lactose-free diet

(4.1%) being the most cited. A high fibre diet, exercise, dairy-free diet, probiotics and surgery were

the least effective.

Page 20: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

20

Discussion

General Discussion

In this present study on IBS, patients reported an overall reduction in symptom severity and

frequency over time after attending the RPAH Allergy Unit (the Unit) for management of their

symptoms. These improvements are similar to those of a previous retrospective study conducted

at the Unit, where patients reported a 30% reduction in symptom severity and frequency for all

symptoms (Stuart-Smith W, 2000, unpublished data).

It is estimated that 10% of people with IBS seek medical advice and are mostly managed by

primary care.11 Those who consult secondary care report more severe gastrointestinal symptoms

and increased levels of psychological disturbance compared to those who do not.12 Patients who

have attended the Unit, a tertiary care institution, have already seen either a Gastroenterologist or

General Practitioner. Results show that two-thirds of these patients have undergone some kind of

medical testing in relation to their gastrointestinal symptoms before referral to the Unit. As part of

the assessment process, patients seen at the Unit are screened by the physicians to rule out other

organic diseases.

The reported  prescribed  medications  for  patients’  symptoms  were similar to that reported in the

literature. Interestingly 77.5% of these patients were prescribed gastric acid inhibitors, of which

80.6% found them effective for reflux. However, reflux is not cited as a symptom of IBS in the

Rome III criteria. In addition there is no indication for the use of gastric acid inhibitors as a

treatment for IBS symptoms, but for gastro-oesophageal reflux disease (GORD). It is unknown

whether these patients have reflux and IBS, or whether gastric acid inhibitors are prescribed to

Page 21: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

21

assist with symptom complaints. It is possible reflux regularly occurs concurrently with IBS and

practitioners may need to consider the whole gastrointestinal tract as irritable as opposed to just

the bowels. This would benefit from further research.

Exercise was found to be the most effective relaxation therapy. This is in line with the fact that

physical activity improves IBS symptoms,13 increases gastrointestinal motility,14 gas transit and

decreases bloating.15 Relaxation therapy was found to be effective in a high proportion of patients.

Interestingly, diet was listed as a form of relaxation therapy, although diet was not an option

provided within the question on relaxation. Given patients with IBS find exacerbation of symptoms

upon ingestion of offending food,16 that when restricted reduce symptoms,17 it is understandable

these patients find diet a form of relaxation. Modification of diet may help alleviate their

symptoms, in turn reducing patient distress and helping them to relax. This finding is consistent

with the previous study conducted at the Unit (Stuart-Smith W, 2000, unpublished data).

The reported efficacy of some natural therapies was similar to results present in the literature. The

majority of patients trialing herbal tea specified peppermint tea. The antispasmodic effect of

peppermint18 may be the reason for 42% of patients in this study finding it effective. Types of

herbal remedies trialed were not specified by patients and therefore it is difficult to draw

conclusions, however data suggests that herbal medicine may be effective in improving IBS

symptoms.19 Seven patients reported symptom exacerbation with either herbal tea or remedies,

of  which  3  reported  ‘allergic’  reactions.  Exacerbation  of  symptoms  reported  by  patients  are  likely  

to be a result of very high sources of salicylates or other bioactive compounds in the patient

specified peppermint or chamomile teas and Chinese herbs. Meditation was reportedly beneficial

Page 22: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

22

in approximately 50% of patients, consistent with other studies. Meditation has been shown to

improve symptoms and sustain effects for up to 1 year. 20, 21 Hypnotherapy has been found to

provide positive long-term results with reduction in IBS symptoms,22 with a high percentage of

patients finding it worthwhile even if they had not responded to it.23 However in contrast to the

literature it was not reported by any patients as a form of treatment. This could be resultant of

possible expense of hypnotherapy and/or lack of knowledge of its therapeutic effects.

Inner Health Plus, Yakult and IBS Support were the most common probiotics trialed. Although

numbers are small, it is interesting that a higher proportion found single strain Lactobacillus and

Bifidobacteria more beneficial than the commonly trialed probiotic mixes. The literature has

indicated  that  not  all  probiotics  are  equivalent  (right  down  to  ‘strain’  level)  and  provide  the  same  

benefits,24-26 which is seen in this study. Whilst a higher proportion of patients are still using

probiotics, on average 16.2% of them are still finding them beneficial. Current research regarding

probiotics is still identifying the most effective organisms for a given patient, if at all, bearing in

mind that different types appear to improve different symptoms.27-31 It is suggested that probiotics

should be used as a supplement to standard therapy and not a therapy on its own.25, 32 Fermented

foods are a growing area of interest, particularly in naturopathy, for treatment of various ailments.

A number of patients trialed yoghurt for its management of symptoms, even though fermented

foods are not cited as a form of therapy for IBS. This may parallel the   ‘newness’   of   interest   in  

fermented foods.

Responses to fibre intake were mixed but overall patients found altering their dietary fibre was

beneficial. However due to the questionnaire design it was difficult to determine whether an

Page 23: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

23

increased or decreased intake provided benefit. Studies have concluded that fibre has no/limited

benefits for patients who have IBS with constipation.33 Therefore the inconclusive results are

consistent with the literature. It would be interesting for future research to determine the

predominant symptoms (constipation or diarrhoea) of patients benefitting from fibre. Some

patients found professional advice regarding   amounts   of   fibre   to   consume   ‘confusing’   and  

‘contradictory’. One  patient  had  been  advised  to  ‘eat  some  higher-fibre products, but reduce fruit

in  the  evening’.  General  avoidance  of  fibre  or  avoidance  of  specific  types,  such  as  the  ‘windy  foods’  

were reported by patients as a result of their personal experience. Some patients reported no

change or exacerbation of symptoms from fibre intake, a possible effect of insoluble fibre.34

Reasons for avoidance of fibre went beyond the fibre per se, and included the presence in fibre-

containing foods of gluten (in breads and cereals) and salicylates, which caused symptom

exacerbation. Fruits, vegetables, cereals and grains (and their products) may contain salicylates,

amines or glutamates, or indeed other added chemicals such as colours, flavours or additives.35

Increasing fibre-rich foods will result in an increased intake of these chemical compounds,

potentially beyond threshold in sensitive patients, exacerbating symptoms.35

There is a significant amount of information on the FODMAPs diet in the literature and it is often

the standard dietary intervention used by dietitians with this group (after ensuring basic healthy

eating principles).36-39 In contrast to the literature, avoidance of windy foods was found to be

beneficial in 12 patients, while 6 patients reported a benefit from the FODMAPs diet. Given that

the FODMAPs diet excludes windy foods, gluten, fructose and artificial sweeteners, this is an

interesting result. In those attending the Unit, 42.9% found the FODMAPs diet effective. It is

possible that other patients with IBS trialing the FODMAPs diet found it beneficial and as a result

Page 24: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

24

did not attend the Unit. It is possible that those who trialed the FODMAPs diet and found it

beneficial, but subsequently attended the Unit, sought further relief for their symptoms.

The results show a lactose-free diet was cited as an effective treatment by 4.1% of patients. This is

not surprising as following the ingestion of lactose symptoms such as bloating, flatulence,

abdominal discomfort, nausea and loose stools can be experienced, due to lactase insufficiency.33

Although lactose may exist in healthy individuals and patients with IBS,40 it is important to

determine if lactose intolerance is present in every patient. A milk-free diet was shown to have a

beneficial effect on 42.9% of patients. In addition a reaction to milk/dairy challenges was reported

most frequently. Milk contains numerous proteins and chemicals that patients with IBS may be

intolerant to.40 Milk also contains casein which coagulates in the stomach and is hard to digest,

which may cause symptoms.41 Therefore the results are consistent with the literature where milk

and milk products have been reported as offending foods.16

Interestingly, the number of patients reporting continuation of variously modified diets exceeds

the number of patients reporting a benefit. This could be due to patients feeling if they continue

the modified diets they will eventually receive a benefit.

The results show that the Elimination Diet can be effective in improving symptoms, a result

consistent with the previous study (Stuart-Smith W, 2000, unpublished data). Salicylates provoked

the greatest variety of symptoms: indigestion/reflux, mouth ulcers, hives/swelling, fatigue,

muscle/joint ache and bladder/vaginal problems. Wheat and gluten were most frequently

implicated in wind/bloating, stomach pain/cramps and diarrhoea/constipation. Amines,

Page 25: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

25

glutamates and gluten caused the greatest number of patients to report nausea/vomiting, while

milk was generally the most commonly cited problem food and the most common cause of

eczema and sinus problems. Additives, preservatives and amines were the most likely to provoke

headaches/migraines. On average patients reacted to 5.5 chemicals, to varying degrees.

Interestingly challenges to food chemicals affected a wide range of non-gastrointestinal symptoms

in addition to their non-gastrointestinal symptoms. This is consistent with the IBS literature where

patients with IBS often have concomitant central nervous system and skin symptoms.42

Food is a complex chemical mixture where one food item contains numerous chemicals and one

food chemical can be found in a variety of foods. The Elimination Diet and challenge protocol

allows   identification  of  a  patient’s  specific  triggers.  Therefore,  targeted  and  systematic challenge

of food chemicals is vital for appropriate identification of potential food triggers. For example

bread contains gluten and other wheat components, but also may contain milk (including lactose),

soy, salicylates, amines and glutamates and potentially thousand of other chemicals. However, if a

patient believes symptom exacerbation occurs after the ingestion of gluten, they might exclude all

foods containing gluten (e.g. bread, pizza, cake, biscuits and cereal). If symptoms are relieved with

this dietary change, it cannot be concluded with any certainty which chemical caused the

symptoms without specific challenges. This kind of ad hoc change is common advice, particularly

from naturopaths, but it rarely accompanied challenges. From a dietetic perspective this is of great

concern as it is not only very limiting to the patient, but is potentially not providing a balanced

adequate diet, sometimes entirely removing core food groups.

Page 26: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

26

It is possible that patients may trial numerous therapies at one time. The result is that it is not

possible to determine what is responsible for any change in symptom severity or frequency. In

those patients who utilise capsule challenges, these challenges are to single chemicals, double-

blinded and controlled, providing circumstances for the patient are unchanged (e.g. illness or

breaking the diet), the responses will be reproducible. Some patients noted that they had avoided

certain chemicals they had reactions to altogether, while a low or limited intake of chemicals

causing symptoms was reported by 19 patients. The idea of the Elimination Diet is to identify

thresholds and liberalise accordingly. It is possible that some patients are too early in the

Elimination Diet process to commence liberalising their diet, or are too afraid to experience

symptoms and are content with avoiding certain chemicals.

IBS is not a syndrome. It has multiple etiologies. For patients with food intolerance the reactions to

food and food chemicals are different for each patient; every patient reacts differently; the level of

sensitivity is different for each patient; the severity and frequency of symptoms are different;

personal dietary preferences and lifestyle are different. Therefore not one diet is therapeutic for

all patients with IBS. Each patient needs to be treated individually for their trigger(s) to be

determined and to develop an individual plan. This may be a long process of trial and error as well

as combining a number of therapies. Besides the poor quality of a number of studies, a lack of

reproduction of many studies, short duration and small patient numbers, one of the main reasons

for conflicting data is probably that different people respond differently.

Page 27: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

27

Limitations of the study

For natural, relaxation, probiotics, fermented foods and fibre therapies exact dose and duration of

therapy were not reported by all patients. Details provided by patients of therapies trialed were

also vague. Some patients reported throughout the questionnaire that their therapy was initially

effective however not effective anymore. Duration of therapy impacts efficacy and further

research needs to be conducted to look into the period of time patients are trialing therapies.

The questionnaire was not filled out completely by all patients. There was no requirement for all

parts of a question to be completed before the patient moved on. Therefore many questions were

left blank and although medical records may have assisted in this, they were not accessed at the

time. Recall bias plays an important part in this study in that some therapies were trialed over a

decade ago and patient memory may have been impacted, which may explain the incompletion of

the questionnaire.

The study utilises a selective sample population of patients attending the Unit in the past 12 years

for  management  of  gastrointestinal  symptoms  and  whose  details  were  retrieved  from  the  Unit’s  

database. Most would live within or near the Central Sydney Local Health District. It is quite

possible that the cohort is not representative (e.g. socioeconomic demographics, disease severity,

etc) of the greater IBS population, and this needs to be taken into account.

Due to limited experience with the platform (Survey Monkey), the questionnaire was not designed

optimally meaning that results were more difficult to interpret and analyse. This is well illustrated

by the fibre question where both increased intake and decreased intake were part of the same

Page 28: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

28

question. This resulted in unclear answers as to what patients found beneficial and were still using.

Survey Monkey can incorporate logistics within the questionnaire to prevent incompletion of

questions.

The study results demonstrate the significant role of food intolerance in a cohort of patients

presenting to a specialist clinic with gastrointestinal symptoms. It also demonstrates that of all

therapies the Elimination Diet is the most effective form of treatment for IBS in this cohort, an

effect which outlasts what may be expected from the placebo effect. Once patients have identified

chemicals that cause their symptoms they can modify their diets accordingly to suit their lifestyles.

The study also shows that reflux amongst other upper gastrointestinal symptoms may be common

in IBS patients and suggests that practitioners need to recognise that IBS may be a condition of the

whole gastrointestinal tract in some patients and not just a combination of bowel symptoms.

Page 29: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

29

Acknowledgments

The authors wish to acknowledge all the patients with IBS and who were involved in the study.

Thank you to the Royal Prince Alfred Hospital Allergy Unit, the staff and in particular Mrs Wendy

Stuart-Smith (APD), Dr Anne Swain (Chief Dietitian) and Dr Robert Loblay (Director) for their

guidance and assistance. Thank you to Tim Watkins for assistance with statistical data analysis.

Contributions to the study

Zillan Neiron: contributed to the study design, data collection and analysis, to writing and

reviewing the manuscript and applying or ethics approval.

Wendy Stuart Smith: contributed to study design, writing and reviewing the manuscript and

applying for ethics approval.

Anne Swain: contributed to study design, writing and reviewing the manuscript and applying for

ethics approval.

Robert Loblay: contributed to applying for ethics.

Tim Watkins: contributed to analysis of the data.

Page 30: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

30

References

1. Gwee KA, Wee S, Wong ML, Png DJ. The prevalence, symptom characteristics, and impact

of irritable bowel syndrome in an asian urban community. Am J Gastroenterol. 2004

May;99(5):924-31.

2. Wilson S, Roberts L, Roalfe A, Bridge P, Singh S. Prevalence of irritable bowel syndrome: a

community survey. Br J Gen Pract. 2004 Jul;54(504):495-502.

3. Brandt LJ, Chey WD, Foxx-Orenstein AE, Schiller LR, Schoenfeld PS, Spiegel BM, et al. An

evidence-based position statement on the management of irritable bowel syndrome. Am J

Gastroenterol. 2009 Jan;104 Suppl 1:S1-35.

4. Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Muller-Lissner SA.

Functional bowel disorders and functional abdominal pain. Gut. 1999 Sep;45 Suppl 2:II43-7.

5. Gunnarsson J, Simren M. Peripheral factors in the pathophysiology of irritable bowel

syndrome. Dig Liver Dis. 2009 Nov;41(11):788-93.

6. Ohman L, Simren M. New insights into the pathogenesis and pathophysiology of irritable

bowel syndrome. Dig Liver Dis. 2007 Mar;39(3):201-15.

7. Ohman L, Simren M. Pathogenesis of IBS: role of inflammation, immunity and

neuroimmune interactions. Nat Rev Gastroenterol Hepatol. 2010 Mar;7(3):163-73.

8. Simren M, Barbara G, Flint HJ, Spiegel BM, Spiller RC, Vanner S, et al. Intestinal microbiota

in functional bowel disorders: a Rome foundation report. Gut. 2012 Jul 10.

9. Simren M, Mansson A, Langkilde AM, Svedlund J, Abrahamsson H, Bengtsson U, et al.

Food-related gastrointestinal symptoms in the irritable bowel syndrome. Digestion.

2001;63(2):108-15.

Page 31: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

31

10. Gibson PR, Shepherd SJ. Evidence-based dietary management of functional

gastrointestinal symptoms: The FODMAP approach. J Gastroenterol Hepatol. 2010 Feb;25(2):252-8.

11. Thompson WG, Heaton KW, Smyth GT, Smyth C. Irritable bowel syndrome in general

practice: prevalence, characteristics, and referral. Gut. 2000 Jan;46(1):78-82.

12. Thompson WG, Heaton KW, Smyth GT, Smyth C. Irritable bowel syndrome: the view from

general practice. Eur J Gastroenterol Hepatol. 1997 Jul;9(7):689-92.

13. Johannesson E, Simren M, Strid H, Bajor A, Sadik R. Physical activity improves symptoms in

irritable bowel syndrome: a randomized controlled trial. Am J Gastroenterol. 2011

May;106(5):915-22.

14. Oettle GJ. Effect of moderate exercise on bowel habit. Gut. 1991 Aug;32(8):941-4.

15. Villoria A, Serra J, Azpiroz F, Malagelada JR. Physical activity and intestinal gas clearance in

patients with bloating. Am J Gastroenterol. 2006 Nov;101(11):2552-7.

16. Simren M, Abrahamsson H, Bjornsson ES. An exaggerated sensory component of the

gastrocolonic response in patients with irritable bowel syndrome. Gut. 2001 Jan;48(1):20-7.

17. Halpert A, Dalton CB, Palsson O, Morris C, Hu Y, Bangdiwala S, et al. What patients know

about irritable bowel syndrome (IBS) and what they would like to know. National Survey on

Patient Educational Needs in IBS and development and validation of the Patient Educational Needs

Questionnaire (PEQ). Am J Gastroenterol. 2007 Sep;102(9):1972-82.

18. Hills JM, Aaronson PI. The mechanism of action of peppermint oil on gastrointestinal

smooth muscle. An analysis using patch clamp electrophysiology and isolated tissue pharmacology

in rabbit and guinea pig. Gastroenterology. 1991 Jul;101(1):55-65.

19. Liu JP, Yang M, Liu YX, Wei ML, Grimsgaard S. Herbal medicines for treatment of irritable

bowel syndrome. Cochrane Database Syst Rev. 2006(1):CD004116.

Page 32: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

32

20. Keefer L, Blanchard EB. The effects of relaxation response meditation on the symptoms of

irritable bowel syndrome: results of a controlled treatment study. Behav Res Ther. 2001

Jul;39(7):801-11.

21. Keefer L, Blanchard EB. A one year follow-up of relaxation response meditation as a

treatment for irritable bowel syndrome. Behav Res Ther. 2002 May;40(5):541-6.

22. Lindfors P, Unge P, Nyhlin H, Ljotsson B, Bjornsson ES, Abrahamsson H, et al. Long-term

effects of hypnotherapy in patients with refractory irritable bowel syndrome. Scand J

Gastroenterol. 2012 Apr;47(4):414-20.

23. Lindfors P, Unge P, Arvidsson P, Nyhlin H, Bjornsson E, Abrahamsson H, et al. Effects of

gut-directed hypnotherapy on IBS in different clinical settings-results from two randomized,

controlled trials. Am J Gastroenterol. 2012 Feb;107(2):276-85.

24. Brenner DM, Moeller MJ, Chey WD, Schoenfeld PS. The utility of probiotics in the

treatment of irritable bowel syndrome: a systematic review. Am J Gastroenterol. 2009

Apr;104(4):1033-49; quiz 50.

25. Moayyedi P, Ford AC, Talley NJ, Cremonini F, Foxx-Orenstein AE, Brandt LJ, et al. The

efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut. 2010

Mar;59(3):325-32.

26. Spiller R. Review article: probiotics and prebiotics in irritable bowel syndrome. Aliment

Pharmacol Ther. 2008 Aug 15;28(4):385-96.

27. Dolin BJ. Effects of a proprietary Bacillus coagulans preparation on symptoms of diarrhea-

predominant irritable bowel syndrome. Methods Find Exp Clin Pharmacol. 2009 Dec;31(10):655-9.

Page 33: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

33

28. Kim HJ, Camilleri M, McKinzie S, Lempke MB, Burton DD, Thomforde GM, et al. A

randomized controlled trial of a probiotic, VSL#3, on gut transit and symptoms in diarrhoea-

predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2003 Apr 1;17(7):895-904.

29. Kim HJ, Vazquez Roque MI, Camilleri M, Stephens D, Burton DD, Baxter K, et al. A

randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel

syndrome with bloating. Neurogastroenterol Motil. 2005 Oct;17(5):687-96.

30. Nobaek S, Johansson ML, Molin G, Ahrne S, Jeppsson B. Alteration of intestinal microflora

is associated with reduction in abdominal bloating and pain in patients with irritable bowel

syndrome. Am J Gastroenterol. 2000 May;95(5):1231-8.

31. O'Mahony L, McCarthy J, Kelly P, Hurley G, Luo F, Chen K, et al. Lactobacillus and

bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine

profiles. Gastroenterology. 2005 Mar;128(3):541-51.

32. Nikfar S, Rahimi R, Rahimi F, Derakhshani S, Abdollahi M. Efficacy of probiotics in irritable

bowel syndrome: a meta-analysis of randomized, controlled trials. Dis Colon Rectum. 2008

Dec;51(12):1775-80.

33. Heizer WD, Southern S, McGovern S. The role of diet in symptoms of irritable bowel

syndrome in adults: a narrative review. J Am Diet Assoc. 2009 Jul;109(7):1204-14.

34. Ford AC, Talley NJ, Spiegel BM, Foxx-Orenstein AE, Schiller L, Quigley EM, et al. Effect of

fibre, antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome:

systematic review and meta-analysis. BMJ. 2008;337:a2313.

35. Swain A, Soutter, V., Loblay, R. RPAH Elimination Diet Handbook with food and shopping

guide2011.

Page 34: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

34

36. Barrett JS, Gearry RB, Muir JG, Irving PM, Rose R, Rosella O, et al. Dietary poorly absorbed,

short-chain carbohydrates increase delivery of water and fermentable substrates to the proximal

colon. Aliment Pharmacol Ther. 2010 Apr;31(8):874-82.

37. Ong DK, Mitchell SB, Barrett JS, Shepherd SJ, Irving PM, Biesiekierski JR, et al. Manipulation

of dietary short chain carbohydrates alters the pattern of gas production and genesis of symptoms

in irritable bowel syndrome. J Gastroenterol Hepatol. 2010 Aug;25(8):1366-73.

38. Shepherd SJ, Gibson PR. Fructose malabsorption and symptoms of irritable bowel

syndrome: guidelines for effective dietary management. J Am Diet Assoc. 2006 Oct;106(10):1631-9.

39. Shepherd SJ, Parker FC, Muir JG, Gibson PR. Dietary triggers of abdominal symptoms in

patients with irritable bowel syndrome: randomized placebo-controlled evidence. Clin

Gastroenterol Hepatol. 2008 Jul;6(7):765-71.

40. Foundation TG. Understanding Lactose Intolerance. In: Foundation TG, editor.2002.

41. Garcia-Talavera Espin NV, Gomez Sanchez MB, Zomeno Ros AI, Nicolas Hernandez M,

Gonzalez Valverde FM, Gomez Ramos MJ, et al. Comparative study of two enteral feeding

formulas in hospitalized elders: casein versus soybean protein. Nutricion hospitalaria : organo

oficial de la Sociedad Espanola de Nutricion Parenteral y Enteral. 2010 2010;25(4):606-12.

42. Tobin MC, Moparty B, Farhadi A, DeMeo MT, Bansal PJ, Keshavarzian A. Atopic irritable

bowel syndrome: a novel subgroup of irritable bowel syndrome with allergic manifestations.

Annals of allergy, asthma & immunology : official publication of the American College of Allergy,

Asthma, & Immunology. 2008 2008;100(1):49-53.

Page 35: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

35

Appendices

Appendix I Irritable Bowel Syndrome Literature Review

(2000-2012)

Appendix II Rome Criteria III

Appendix III Questionnaire

Appendix IV Time Frame of RPAH Patient Visits

Appendix V Ranked Relaxation Therapies

Appendix VI Probiotics, Prebiotics and Fermented Foods

Appendix VII Exercise Efficacy Ranking

Appendix VIII RPAH Elimination Diet Challenge Reactions (Compound Effects on Symptoms)

Appendix IX RPAH Elimination Diet Challenge Reactions (Symptoms Affected by Compounds)

Appendix X Patient Efficacy Ranking

Page 36: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

36

Appendix I: Irritable Bowel Syndrome Literature Review (2000-2012) Introduction

Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide. It is

characterised by recurring symptoms of abdominal pain or discomfort, bloating and altered bowel

function (constipation, diarrhoea, or both) in the absence of structural, inflammatory, or biochemical

abnormalities.1, 2 IBS affects 10-20% of the adult population3, 4 and the numerous gastrointestinal

symptoms cause significant morbidity, quality of life impairment, disruption to daily activities resulting

in significant healthcare costs.5-7 Prevalence of IBS is higher in women and relatively stable according to

geography and criteria used to define its presence.8

The etiology is poorly understood and many factors are involved, including gut hypersensitivity, low

grade mucosal inflammation, disturbed colonic motility and previous gastrointestinal infection.9 Due to

lack of reliable biological markers or complete understanding of the pathophysiology, IBS is currently

defined  by  clinical  criteria  and  by  exclusion  of  ‘organic’  disease.6, 10

Symptoms

IBS is characterised by symptomatic flare ups and a high rate of transition to other functional

gastrointestinal disease over the long term.11 The most bothering symptom of IBS is abdominal pain,

followed by bloating, abdominal distension and gas.12 The abdominal pain of IBS is visceral in nature,

typically episodic and unpredictable. Periods of pain recur over a range of 2-8 days, mixed with a few

pain-free days.13 However in some cases painful periods may be prolonged. The abdominal pain of IBS is

associated with a disturbed bowel habit, where the frequency and consistency of bowel movements

Page 37: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

37

change.14 These symptoms are often associated with a reduced quality of life and are therefore a

frequent reason to seek medical care.12, 15

Diagnosis and Subtypes of IBS

The lack of sensitivity and specificity of symptoms to diagnose IBS led to the development of several sets

of diagnostic criteria.16 The first attempt, the Manning criteria, published in 1978 lasted over 30 years.16

The Rome criteria, with three versions (Rome I, II and III) were developed as studies found the sensitivity

and specificity of the Manning criteria low.16 Currently the definition and sub-classification of IBS is given

by the Rome III criteria, which was introduced in 20066(Appendix II). This criterion defines a number of

symptoms including abdominal pain, change in stool frequency, stool consistency or relief of pain upon

defecation, bloating, flatulence, passage of mucus, straining, urgency or incomplete evacuation,

allowing for diagnosis. However despite the criteria, it is often difficult to compare research studies as

different forms of the criteria are used.

The Rome III criteria groups patients into different subtypes based on the predominant stool consistency

which is recognized as a marker of intestinal transit time.17-19 Hence different subtypes are thought to

reflect different pathophysiological mechanisms. Four subtypes are defined: IBS with constipation (IBS-

C), IBS with diarrhoea (IBS-D), IBS with mixed type (IBS-M) and IBS unsubtyped (IBS-U).20 IBS-D is the

most frequent subtype, followed by IBS-U, IBS-C and IBS-M.21 Alternating IBS (IBS-A) is defined as a

subgroup of patients experiencing both periods of diarrhoea and constipation over time.20 The Rome III

committee6 recommends  prospective  subtyping  by  self  reporting  of  the  patient’s  stool  pattern  using  the  

Bristol Stool Scale (BSS).22 However, no recommendations exist on the optimal length of self reporting

and no specification of time period required to define IBS-A 20.

Page 38: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

38

Subtyping is required to appropriately select and describe study populations in research. However it is

also used in clinical settings to help recommend diagnostic tests and treatment based on the

predominant stool pattern.1, 6, 14, 23-25 A study evaluating the stability of IBS subtypes found that changes

may occur over time mainly between IBS-C or IBS-D and IBS-U.20 Although a predominant IBS subtype

still existed.20

The severity of IBS is determined by symptom reports and behaviours of the patient, rather than by

blood test or histopathological markers in the bowel.26 IBS   must   be   understood   from   the   patient’s  

personal experience and perceived illness severity.26 It is the severity levels that determine clinical

diagnostic and treatment decisions. However if clinicians rely exclusively on patient reports of severity,

unnecessary intensive investigations or treatments may occur.26 Severity should not primarily be based

on individual symptoms such as abdominal pain, but on a broader multi-component construct, including

health-related quality of life, psychosocial factors, health care utilisation behaviours, and burden of

illness associated with IBS.26, 27 Therefore severity needs to reflect more on the IBS generally as opposed

to the intensity of symptoms.

Quality of Life and Health Care Burden

IBS is a chronic condition that has been associated with psychiatric co-morbidity, reduced quality of life,

work absenteeism, and impaired social functioning.26 The impact of IBS symptoms on daily functioning

and quality of life can be considerable and comparable to chronic diseases such as congestive heart

failure, hepatic cirrhosis, renal insufficiency and diabetes.28 Significant impairment in health-related

quality of life is most pronounced in energy/fatigue, role limitations caused by physical health problems,

bodily pain and health perceptions.5

Page 39: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

39

In a European survey (2003) annually patients with IBS spent 3.9 days in bed (corresponding figure for

those without IBS, 2.7), 5.5 days on sick leave from work (3.1 days), 8.4 days visiting a doctor or nurse

(5.2 days) and 10.2 days when work activities had to be cut short (4.8 days).29 In 2000, a study in the US

found that compared with subjects who did not have IBS, patients with IBS had significantly more

outpatient visits (medical, surgery and emergency), were hospitalised more often and had more

outpatient prescriptions.30 Total annual costs (direct and indirect) of IBS in the United States in 2000

were estimated to be approximately $30 billion excluding prescription and over-the-counter drugs

costs.31 The cost associated with IBS and its impact on patients’   lives   is  partly due to the inability to

effectively manage symptoms which vary greatly among patients.32

Patients with IBS have reported the integration of IBS into their lives to the extent that it becomes part

of their identity.33 They utilise strategies to manage their symptoms daily and events which threaten the

routine coping strategies have caused stress and exacerbation of symptoms.33 Patients create

individualised strategies that incorporate advice from their doctor.33 A study looking at the benefit-risk

trade off found that women subjects were willing to accept higher risks of serious adverse events in

return for treatments offering better symptom control.34 This indicates the desperation patients with IBS

have for symptomatic relief to improve quality of life.

Epidemiology

The Rome criteria have led to greater uniformity in epidemiological studies of IBS and have facilitated

comparisons among population subgroups. Estimates of the prevalence of IBS among adults are based

on population surveys. Most surveys have been conducted in developed countries and reflect the

prevalence of IBS in those cultures.35 The last comprehensive review of the prevalence and

epidemiology of IBS in North America, in which five population-based prevalence studies were evaluated,

Page 40: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

40

was conducted in 2002.36 The prevalence of IBS varies among countries due mainly to the use of

different criteria utilised to define it; the pooled global prevalence has been estimated at 11%.37 The

prevalence ranged from 3-20%, with most studies between 10% and 15%.38 There is a higher proportion

of women who develop IBS compared to men, (2:1), and onset of IBS symptoms occurred mainly in

patients younger than 45 years and also in the elderly.38

Pathophysiology

The pathophysiological mechanisms of IBS are not completely known, however it appears to be linked to

a complex interaction between altered gastrointestinal (GI) motility, visceral hypersensitivity, altered

brain-gut function, low grade inflammation, psychosocial stress and intestinal microbes.39-41

Altered Gastrointestinal Motility

Observations of motility in the stomach, small intestine, colon and rectum in patients with IBS are

generally qualitatively similar to those of healthy controls; 25-75% of patients with IBS show motility

abnormalities.9 In the ileum, colon and rectum, patients with IBS exhibit an exaggerated response to a

variety of provocative stimuli including meals, distention, stress, cholecystokinin, neostigmine and

corticotrophin-releasing hormone (CRH).9 No comparable pattern of hyper-reactivity has been

demonstrated in the proximal small intestine and stomach, where the response to stress changes

(inhibition of contractions) alters from the response to meals (increase in contractions).9

Although accelerated transit appears in diarrhoea and slowed transit appears in constipation, there is no

consensus regarding patterns of motility. In patients with IBS exhibiting diarrhoea and abdominal pain,

there are more significant high-amplitude spreading contractions compared to those seen in healthy

controls.9 These high-amplitude contractions are more likely to be related to a sensation of pain.9

Page 41: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

41

Visceral Hypersensitivity

The threshold to report pain is below the normal range in 50%-70% of patients with IBS, as well as their

enhanced perception of visceral events including intestinal contraction and gas.23 Patients with IBS have

an increased sensitivity to stimuli arising from the gut wall and colonic distension compared with healthy

volunteers, known as visceral hypersensitivity.42, 43 Visceral hypersensitivity is an important

pathophysiological mechanism underlying symptom generation in IBS and is present in 33-65% of

patients with IBS and contributes to abdominal pain/discomfort.44

A significant factor involved in the initiation and exacerbation of IBS is stress.45 Animal studies have

demonstrated that stress is an important trigger leading to visceral hypersensitivity, which involves the

release of corticotrophin releasing hormone (CRH)46 and subsequent mast cell activation.47

Seventy-seven percent of patients with IBS showed a significantly increased area of mucosa occupied by

mast cells compared with controls in a study investigating visceral hypersensitivity and microscopic

inflammation.43 Activation of mast cells leads to increased mucosal permeability and increased exposure

of the mucosal immune system to intraluminal antigens.43 Furthermore, mast cell mediators are potent

chemotaxic agents that contribute to increased influx of immune cells. These mediators have been

found to spontaneously be released in patients with IBS43 and sensitise visceral afferent nerves.48 As

these mediators are inflammatory it is proposed that a microscopic inflammation may play a role in

visceral hypersensitivity, with an increased number of mast cells and T cells found in mucosal biopsies

from IBS patients.42 Also mast cells have been shown to be in proximity to visceral afferent nerves in IBS

patients49 which is significantly correlated with severity and frequency of abdominal pain/discomfort.43

Page 42: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

42

Altered Brain-Gut Axis

The relationship between neural and immunological networks within the gut and the communication

between the gut and central nervous system, is often known as the brain-gut axis (BGA).50 The gut is

connected to the central nervous system (CNS) through the autonomic nervous system in a bidirectional

way.38 This connection allows for transmission of emotional states from the CNS to the gut and

perception of GI changes (including pain, contractions and bloating) to the CNS.51 In addition to

perception of GI changes, signals from the GI tract influence the brain and can exert changes in motility,

secretion and immune function.52 The axis is therefore a vital communication system for healthy

regulation of food intake, digestion, gut sensations and bowel movement control. Structural and

functional disruptions in the BGA may cause changes in perceptual and reflexive responses of the

nervous system and has been implicated in IBS.53 IBS-D is thought to be associated with increased

motility patterns while IBS-C with decreased motility.9

Independent of connections from the CNS, the gut is able to release the neurotransmitters serotonin

and acetylcholine as part of the enteric nervous system (ENS).54 The role of serotonin in intestinal motor

and secretory function has instigated the hypothesis that altered serotonin signaling can lead to either

constipation or diarrhoea in IBS.55 Serotonin is released from the GI mucosa to stimulate acetycholine

release which initiates GI motility.56 The main serotonin receptors involved in ENS communication are 5-

HT3 and 5-HT4 receptors.57 5-HT3 receptors signal changes in intestinal motility and operate as the main

neurotransmitter connecting to the CNS, whereas 5-HT4 receptors transmit signals to effector

acetycholine neurons. It has been demonstrated that a decrease in serotonin reuptake transporter

(SERT) located within the intestinal mucosa,58 consistently leads to dysfunction of GI motility through

increased serotonin concentrations.59 Increased concentrations of serotonin stimulate 5-HT3 and 5-HT4

Page 43: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

43

receptors leading to dysregulated contractions and dilations of the intestinal tract. Weakening of this

signaling cascade has been implemented for the treatment of IBS.38

Low Grade Inflammation

IBS has been viewed as a localised low grade inflammatory disorder with mast cells playing a crucial

role.60 The gut-associated immune system is upregulated in IBS, confirmed by increased inflammatory

cytokines such as interleukins 1, 6 and 1061 and increased activated mast cells, CD3+ve, CD4+ve and

CD8+ve T cells.41 There is a change in the microbial gut colonies in IBS62 and the types of microflora

colonising the gut have a role in regulating immunity.63

Furthermore, upregulated GI associated immune tissue stimulates the release of enterochromaffin cells

and other cells that release serotonin and histamine resulting in GI symptoms.64 Inflammation can result

in opening of tight junctions between enterocytes with the movement of large proteins across the GI

lumen.64 These large proteins act as antigens and lead to antibody production.65 The combination of an

activated immune system, altered gut microbiota and release of serotonin and histamine affecting GI

symptoms in patients with IBS show how a low grade inflammation may be a pathophysiological

mechanism.

Psychosocial Stress

Psychological and social factors (stressful life events or psychological distress) during life may influence

digestive function, symptom perception, illness behaviour and consequently health outcome, daily

function and quality of life.66 Psychological distress and major life events are frequently present in IBS

and are in some part responsible for certain outcomes. On the other hand visceral pain can influence

central pain perception, mood and behaviour.67 Data has shown that environmental factors and

Page 44: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

44

psychosocial stressors such as a history of being psychologically abused, less than 6 hours of sleep per

night and an irregular diet, can influence the progression from a healthy individual to a patient with

IBS.68 Also data has shown that anxiety disorders, depression69 and somatisation70 are risk factors for IBS.

Depression is the most common psychiatric diagnosis in patients with IBS with a prevalence of 31.4%

and 17.5% in controls.71 Depressive disorders have been found to be more common in patients with IBS

than patients with similar symptoms, organic GI diseases or healthy controls.71 In addition to depression,

higher levels of neuroticism and anxiety are seen in patients with IBS compared to the general

population.72 In light of the data psychological status, in particular stress, appears to be associated with

IBS.

Microbiota

The human body is inhabited by a complex community of microbes, collectively known as microbiota.73

The majority of these are found in the GI tract. Bacteria may be involved in IBS through the metabolic

capacity of the luminal microbiota and its potential to influence the host-via immune-microbial

interaction.74 A study aimed at evaluating intestinal microbial populations by examining fecal microbiota

found that patients with IBS have a different composition of microbiota compared to healthy controls,75

however there was no explanation how this might be so and how this interacts with IBS symptoms and

health.

IBS may develop post infective gastroenteritis (PI-IBS) which depletes commensal microbiota76 that

normally inhibits pathogen colonisation.77 Onset of new IBS symptoms after infective gastroenteritis is

reported by 6%-17% of patients with IBS.78 Up to 57% of patients continue to have altered bowel

function 6 years after recovery of an acute episode.63 A meta-analysis indicated an increased risk of

developing IBS 1 year after bacterial gastroenteritis, an effect still evident after 36 months.79 Broad

Page 45: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

45

spectrum antibiotics are another cause for the depletion of commensal microbiota, with an increased

risk of PI-IBS associated with antibiotic use.80 Exposure to broad spectrum antibiotics, particularly

macrolides or tetracyclines, may be associated with IBS development.81 Studies have therefore shown

that depletion of commensal microbiota via numerous ways may develop IBS despite method of

microbiota depletion.

Genetics

Epidemiological studies of familial aggregation82 and twins83 have suggested a genetic aspect to IBS.

However there are no published genome-wide correlation studies in functional GI or motility disorders

specifically focusing on genetic epidemiology and pharmacogenetics.

The best studied polymorphisms are those related to serotonin signalling in the brain-gut axis, including

serotonin transporter (SERT) and several 5-HT receptors. The 5-HTTLPR polymorphism (for serotonin

transporter-linked polymorphic region) in the promoter region of serotonin transporter gene SLC6A4 is

the most studied polymorphism in IBS. However recent meta-analysis found no clear association

between 5-HTTLPR and the clinical phenotype of IBS.84

Familial aggregation has been reproducibly shown in several clinic-based studies of patients with IBS.82,

85-87 However, clustering of IBS in families does not necessarily indicate a genetic basis, as it could also

result from environmental exposures shared in a household, including diet or lifestyle behaviours

exposure to adverse life events within the family, learned cognitions about disease and illness behaviour,

or shared exposure to microorganisms.82, 88 A study conducted on 6060 twin pairs (117 monozygotic and

164 dizygotic twins) showed that concordance for IBS was significantly greater in monozygotic twins

than in dizygotic twins. Hence having a mother or father with IBS was an independent predictor of IBS

Page 46: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

46

status, which was stronger than having a twin with IBS, suggesting that social learning (what an

individual learns from those in his or her environment) may also have an influence on the development

of IBS than genetics.89

Food Allergy

The   term   ‘food   allergy’   refers to an adverse immunologic response to the protein in foods.90 These

responses are based on the development of immunoglobulin E (IgE)-type antibodies to a food

constituent. IgE-mediated food allergies are rare in adults with typically rapid reactions after ingestion of

nuts, shellfish, or fish.90 IgE mediated reactions are generally not responsible for IBS symptoms.91

Treatment and Management

IBS has historically been managed mainly by physicians focusing on normalising bowel habits and

treating pain pharmacologically.92 Medication (antispasmodics, bulking agents, laxatives or

antidepressants), diet and lifestyle alterations have been the main therapeutic options for treatment.93

Management is often based on severity of disease, and the patient and practitioner preferences.

Pharmacological Drugs

Alosetron - Alosetron (5-hydroxytryptamine 3), is a 5-HT3 receptor antagonist used for the treatment of

diarrhoea-predominant irritable bowel syndrome (IBS-D) in women. Clinical trials with alosetron showed

significant efficacy, especially in improving fecal urgency, stool frequency and consistency.94 However

cases of ischemic colitis (IC) and complications of constipation (CoC) associated with its use lead to its

withdrawal in 2000.95 As a result of patient advocacy, it was reintroduced in 2002 with a risk

management plan to limit availability to women with severe IBS-D.95

Page 47: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

47

Tegaserod - Tegaserod is a partial agonist of the 5-HT4 receptor that has been shown to provide

improvements in global IBS symptoms and constipation in female patients with IBS-C.9 However reports

of cerebrovascular and cardiac events with Tegaserod usage led to it being removed from the USA

market in 2007.

Prucalopride - Prucalopride is full 5-HT4 agonist with high affinity and selectivity. It has demonstrated

treatment in IBS-C.96 Prucalopride accelerates colonic transit improving bowel function and frequency in

patients with chronic constipation. As a result is has shown to improve satisfaction of bowel movements,

decrease perceived severity of constipation and improve constipation related quality of life.96

Lubiprostone - Lubiprostone is a bicyclic fatty-acid derivative of prostaglandin E1.97 It is a highly specific

luminal activator of Type-2 chloride channels (ClC-2), a transmembrane protein believed to have a role

in IBS-C and constipation. As lubiprostone activates ClC-2, an efflux of chloride ions followed by sodium

ions into the lumen of the GI tract, result in the efflux of water into the lumen.97 Lubiprostone has

shown to improve frequency and consistency of stools, reducing discomfort, straining and severity of

abdominal pain.97 However its adverse effects include nausea, diarrhoea and abdominal pain.97

Crofelemer - Crofelemer belongs to a class of polyphenols that has an antisecretory mechanism of

action. It reduces excess chloride ion secretion via the cystic fibrosis transmembrane conductance-

regulator channel.98 By reducing excess chloride ion secretion, crofelemer decreases excess fluid in the

intestines, and therefore reduce diarrhoea symptoms in IBS-D. In an evaluation study, improvements in

pain and discomfort in females were reported. However no significant change was noticed in

consistency, frequency and urgency to defecate.99 As Crofelemer did not show benefit on bowel

function in this study, further studies are required to assess it as a visceral analgesic effect.

Page 48: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

48

Antispasmodics

The idea that pain in IBS is a result of colonic spasm has led to the use of antispasmodics.1 Commonly

used antispasmodics include otilonium, hyoscine, cimetropium, pinaverium and peppermint oil due to

their anticholinergic or relaxatory effects on smooth muscle. Systematic reviews have supported the

efficacy and use of antispasmodics for IBS treatment.1 Otilonium, cimetropium, hyoscine and pinaverium

have been shown to significantly reduce the risk of persistent symptoms after treatment, while

trimebutine appears to have no benefit compared to placebo in treating IBS.100 The biological rationale

for the efficacy of antispasmodics is unclear, but research has shown that patients with IBS-D have a

reduced colon diameter as well as accelerated small bowel transit.101 Therefore antispasmodics may act

by reducing colonic contraction and transit time resulting in decreased pain and stool frequency.

Antibiotics

The use of antibiotics was initially based on the assumption that small intestinal bacterial overgrowth

(SIBO) was a common phenomenon in IBS. This led to the investigation of antimicrobials whose

spectrum activity was appropriate for this indication, such as neomycin and rifaximin.102 Although it has

now been established that SIBO is not a major factor in IBS,103 initial trials with neomycin improved

global IBS symptoms by 50% compared to placebo treated patients.104 However neomycin has been

shown to produce clinical resistance quickly.105 Alternatively the poorly absorbed rifaximin has shown

efficacy in at least two randomised controlled clinical trials,102, 106 with a low incidence of resistance and

few side effects.107 Rifaximin has been shown to improve bloating and abdominal pain after 10 weeks of

treatment.108 A short course of antibiotics for IBS symptoms may be useful, but perhaps only in patients

with altered intestinal microbiota.109 Longer term treatment responsiveness, antibiotic resistance and

the efficacy of re-treatment needs to be investigated.110

Page 49: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

49

Tricyclic Antidepressants (TCAs) and Selective Serotonin reuptake inhibitors (SSRIs)

TCAs and SSRIs have been utilised for their modulation of hyperalgesia rather than their psychotropic

effects.111, 112 TCAs have shown to be effective in treating neuropathic pain, while SSRIs appear to

improve the effectiveness of endogenous pain inhibition systems.111 Data has shown that both drug

classes were equally effective in improving IBS symptoms, 112 however TCAs have indicated variable

effects on abdominal pain and uncertain tolerability.109

Psychological Treatment

There are a number of psychological therapies employed to treat IBS, of which cognitive behavioural

therapy (CBT), mindfulness, gut directed hypnotherapy and brief psychodynamic therapy have achieved

promising results.113 A study on patients with IBS showed treatment with CBT for 8 weeks in conjunction

with medical treatment increased mental health of patients more so than those receiving medical

treatment alone.114 CBT demonstrated a reduction in IBS symptoms in combination with medical

treatment and as a single form of treatment.114 Recognition and treatment of anxiety and depression in

patients with IBS using psychotropic drugs and CBT, may require special.115 However a major clinical

disadvantage of psychological treatments for IBS is that they are not widely available for patients and

are relatively expensive.116

Hypnotherapy

Gut-directed hypnotherapy has been shown to have positive long-term results with reduction of IBS

symptoms, in turn improving quality of life and work productivity after treatment.117 It is based on

muscular and mental relaxation utilising general hypnotic suggestions to either focus on symptoms or

distract from them.117 Individually adapted suggestions are used to bring forward a deeper feeling of

being able to control symptoms.117 In a randomised controlled trial using gut-directed hypnotherapy,

Page 50: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

50

the severity of GI symptoms, sensory symptoms and bowel habits were reduced.118 The symptom

reduction in the gut-directed hypnotherapy group was maintained 1 year post treatment.118

A retrospective study on 208 patients with IBS investigating the long term effects of gut-directed

hypnotherapy had 87% of patients considering the gut-directed hypnotherapy worthwhile.117 A

proportion of patients that did not respond to the treatment still found it worthwhile hence gut-directed

hypnotherapy may positively affect the ability of patients to cope with IBS symptoms.117 This study

found that patients with IBS responding favourably to hypnotherapy reported a reduction in visits to

gastroenterologists and GPs for GI symptoms.117

Probiotics

Probiotics are live microorganisms which when administered in sufficient amounts presents a health

benefit on the host, with lactobacilli and bifidobacteria being the most commonly used.119 Probiotics can

be packaged in many formulations containing either one organism or a mixture. The modes of action of

probiotics are believed to act through increasing barrier function of intestinal epithelium, inhibition of

pathogenic bacteria binding to intestinal epithelial cells, acidification of the colon and suppression of

growth of pathogens, alteration of immunity, inhibition of visceral hypersensitivity, change in mucosal

response to stress and improving bowel dysmotility.120 However, not all probiotics are the same and the

effect of one probiotic strain cannot be extrapolated to another.121-123

A probiotic preparation must contain sufficient quantities of microbes and requires enzyme and acid

resistance with good mucosal adherence being advantageous. It is not apparent which organisms are

most effective as some reduce bloating and flatulence,124-126 others improve bowel frequency,127 and

some have a positive effect on global symptom scores.62, 128-133 The safety of probiotics in IBS is

Page 51: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

51

acceptable, however some aggravate symptoms.134 Currently the strongest evidence to support overall

efficacy in IBS comes from Bifidobacterium infantis 35624 at a dose of 1x108 cfu/day taken for at least 4

weeks.132 Two meta-analysis studies both concluded probiotics improve symptoms of IBS and therefore

can be used as a supplement to standard therapy.122, 135

Prebiotics

Prebiotics are defined as non-digestible but fermentable foods that beneficially affect the host by

selectively stimulating the growth and activity of one species, or a limited number of species of bacteria

in the colon, especially Lactobacilli and Bifidobacteria.136 Among the most extensively studied prebiotics

are the inulin-type fructans, which are linked by [beta]-(2-1) bonds which prevent their digestion by

upper intestinal enzymes, and fructo-oligosaccharides. Both are present in considerable amounts in

many edible fruits and vegetables, including wheat, onion, chicory, garlic, leeks, artichokes and bananas.

Due to their chemical structure, prebiotics are not absorbed in the small intestine, but are fermented in

the colon by endogenous bacteria, releasing energy and producing metabolic substrates, with lactic acid

and short-chain carboxylic acids as end products of the fermentation.

One study utilising a specially developed prebiotic, a trans-galactooligosaccharide (t-GOS), produced

from Bifidobacterium bifidum NCIMB 41171 was examined on 60 patients with IBS.137 Following

prebiotics treatment, proportions of Bifidobacterium species in faeces was increased. It was found that

t-GOS performed better than the placebo in relieving flatulence and bloating, and   improving  subjects’  

global assessment scores. This study supports the idea that this specific prebiotic produced beneficial

effects   on   some   individuals   with   IBS   symptoms   and   promoted   the   growth   of   ‘good’   bacteria  

(Bifidobacteria).

Page 52: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

52

The ideal duration of probiotic and prebiotic therapy is unknown. Most studies have been short term

and those that have shown a benefit have relapsed soon after therapy cessation as the microbiota

reverts to normal.138 Thus, a lifelong therapy with prebiotics or probiotics may be necessary for patients

with IBS who respond to this type of therapy.131, 139

Symbiotic mixtures

Theoretically certain probiotics at the correct dose and in the appropriate formulation can assist to re-

establish an appropriate balance of intestinal microbiota. This can lead to a better digestive and

intestinal function and therefore improve gastrointestinal symptoms.140 A mixture of probiotics and

prebiotics, called symbiotic should apply a synergistic benefit as the prebiotic substrate enhances the

probiotic organisms.141 A randomised double blinded study showed that a symbiotic mixture has a

beneficial effect in reducing the severity of flatulence in IBS patients with a lack of adverse effects.

However it did not provide overall satisfactory respite of abdominal flatulence and bloating.12

Placebo effect

A placebo is usually described as an inactive substance or form of sham therapy which is identical in

appearance and method of administration to the active treatment. Clinical trials of treatment for IBS

present significant challenges due to a high and variable placebo response ranging from 0%-84%, which

is greater than most treatment effects.142 High placebo rates make it difficult to detect therapeutic gain

and are major concerns for both study design and result interpretation.143

Patient-practitioner interaction has been proposed to affect the placebo response.144 This demonstrates

the necessity for patients with IBS to have a positive patient-practitioner relationship in conjunction

with other forms of treatment to help further reduce symptom severity.

Page 53: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

53

Complementary and Alternative Therapies

Many patients with IBS have turned to complementary and alternative medicine (CAM),145 such as

herbal supplements/tea, massage therapy, biofeedback, acupuncture, yoga, reflexology and

aromatherapy.146 For most of these, few or no published studies exist and those that do are often poorly

conducted. However acupuncture and herbal medicines have been studied extensively. A Cochrane

systematic review of herbal medicine treatment was conducted evaluating the effectiveness in treating

IBS and concluded that herbal medicines may be effective in improving IBS symptoms; however future

high quality studies are required.147

Acupuncture

A study conducted on patients with IBS using acupuncture or sham acupuncture found a significant

improvement in global quality of life.148 However a similar study found no statistical difference between

groups.149 In general current evidence does not support the use of acupuncture for the treatment of

IBS.148 The apparent effect though is likely due to placebo and may be predicted by high coping capacity

and low sleep quality in individual patients.148

Meditation and Reflexology

Meditation is a mind-body medicine commonly used to treat various psychological and pain disorders

such as headache, fibromyalgia, lower back pain, anxiety, depression and cancer pain. A pilot study

assessed a relaxation response meditation program in 16 patients with IBS who were asked to practice

the taught meditation at home regularly.150 A significant improvement was seen in flatulence, bloating

and diarrhoea, which were sustained with continued meditation at 1-year follow-up.151 These two

studies show that relaxation may play a role in relieving IBS symptoms which can be continued for a long

period of time. Reflexology on the other hand has not been able to demonstrate the same effects as

Page 54: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

54

relaxation. A trial using reflexology foot massage and non-reflexology foot massage as a control,

showed no significant difference in bowel symptoms.152 In addition a systematic review found that

reflexology was not effective in treating other diseases, therefore current evidence does not support the

use of this treatment for any medical condition, including IBS.153

Herbal Therapies

A variety of herbal therapies are available for IBS symptoms. However their efficacies vary greatly, and

especially with a high placebo affect within the IBS population some such as Aloe Vera does not show a

significant effect. 154 The Curcuma longa, extracted from turmeric has shown to decrease IBS prevalence

and reduce abdominal pain/discomfort when taken daily for 8 weeks by approximately 22%. However,

there was no placebo control in this study,155 so no conclusions can be drawn.

Cynara scolymus (Artichoke leaf extract) has shown a significant fall in symptoms after treatment and an

improvement in quality of life in patients with IBS and dypepsia.156 Cynara scolymus has been reported

to affect intestinal microbiota as it is a source of inulin. It has been found to be a substrate for selective

growth of beneficial gut bacteria such as Bifidobacteria and Lactobacilli.157 Cynara scolymus also has an

antispasmodic activity which could also contribute to its positive effect.158

Hypericum perforatum (St  John’s  Wort) is a popular herbal medicine for the treatment of depression and

potentially beneficial in managing IBS by altering psychological stress and serotonin.159 A trial evaluating

the efficacy of Hypericum perforatum showed it reduced overall bowel symptom score from baseline,

however resulted in lower efficacy for IBS treatment compared with the placebo.160

Page 55: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

55

Mentha x piperita (Peppermint Oil) has effects on smooth muscle, reducing colonic contractility and pain

as a result of its calcium channel blocking activity.161 In a prospective, randomised, double-blind, placebo

controlled clinical study 79% of patients taking an enteric coated oil capsule experienced an alleviation

of the severity of abdominal pain.162 Eighty-three percent reported less abdominal distension, 83%

exhibited a reduction in stool frequency, 73% had fewer borborygmi and 79% had less flatulence.162

Results for the placebo were less than half for the corresponding symptoms.162 Another herbal therapy,

STW 5 (Iberogast), composed of hydroethanolic extracts of nine herbs has demonstrated a reduction in

total abdominal pain and IBS symptom scores more so than the placebo.163 It appears it may directly

acts on the epithelium through enteric neuron activation and has a prosecretory effect.164

These herbal therapies are a few examples of new (and in the case of peppermint oil existing) herbal

therapies that may be used currently by patients with IBS. Peppermint oil and STW 5 have shown

greater effects than their comparative placebos and are hence possibly alternative or adjunct forms of

treatment.

IgG based food elimination diet

The antibody, immunoglobulin G (IgG), has been implicated in food-related responses in IBS, particularly

IgG4 which has been demonstrated to be elevated in patients with IBS.165 Two centres have reported

significant symptomatic responses among some patients with IBS who have undergone diets eliminating

offending foods based on a base-line IgG antibody profile.165-167 However, IgG antibodies to food are

common in the normal population and not exclusive to patients with IBS.166 When foods are removed

based on IgG testing, symptoms may improve. However, as foods are complex chemically, the intake of

many other compounds is significantly reduced, and the improvement may be due to the reduction of

these other compounds. The Australasian Society of Clinical Immunology and Allergy (ASCIA) states that

Page 56: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

56

‘there   is   no   credible   evidence   that  measuring   IgG   antibodies   is   useful   for   diagnosing   food   allergy   or  

intolerance, nor that IgG antibodies  cause  symptoms’.  

Dietary Modifications

Food Intolerance

Subjective food intolerance is defined as symptoms related to intake of food with or without objective

findings, and is reported by 25-65% of patients with IBS.168 Food intolerance has been linked with

immunological, allergic, toxic and psychiatric mechanisms, however the etiology is poorly understood.167

Many patients with IBS describe the exacerbation of their symptoms immediately following food

ingestion,168 which include the sudden onset of abdominal cramps and urgency to defecate. More than

60% of IBS patients report worsening of symptoms after meals, 28% of these within 15 minutes after

eating and 93% within 3 hours.169 Reported offending foods are milk and milk products, wheat products,

caffeine, certain meats, cabbage, onion, peas, beans, hot spices and fried foods.168 As a result many

patients with IBS restrict their intake of certain foods to control symptoms,170 which instigates concerns

regarding the nutritional adequacy of their diet. However, a 2005 population-based survey comparing

dietary consumption of specific food items and nutrients between individuals with IBS or dyspeptic

symptoms to those without, found no difference in consumption of the suspected offending foods.171

No differences were observed for the intake of calories, fibre, protein, iron, calcium, niacin, and vitamins

C, D, E, niacin, B1, B2, B6 and B12 between groups.171

The use of Elimination diets may help patients with IBS identify foods that trigger their symptoms.

Patients are put on a diet consisting of few foods and beverages believed to be least likely to trigger IBS

symptoms.142 If symptoms stop or diminish significantly on the elimination diet, on food or food group is

added back into the diet gradually.142 If no symptoms return with reintroduction of a food, that food

Page 57: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

57

stays in the diet while others continue to be added. Return of symptoms after the addition of a food

leads to it being withheld. Ideally double-blind testing of trigger foods are conducted by providing the

triggering food and placebo, but this is rarely done. Response rates of elimination diets range from 6%-

58% .145 The literature on elimination diets is variable, due to the labourious nature of the diets, the

type or quantity of foods restricted, the level of restriction, the types of testing, and the range of

symptom responses to the suspect foods for each individual. Foods are complex and contain numerous

bioactive substances, and if testing is only done with whole foods, it is not possible to isolate the

particular compound causing a reaction. Of some reported triggers, histamine, a component in cheeses,

has been reported to cause diarrhoea and flatulence,172 and perhaps may be necessary to avoid/limit if

causing symptoms. Coffee may behave as a colonic stimulant causing upset in some patients, so

excluding/limiting coffee or caffeine containing products should be considered.173 Numerous other

foods and components may cause symptoms which is why it is not surprising that 63% of patients are

interested in knowing what food to avoid.174

The discussion of food, smell of food, or even sham feeding has been shown to lead to an increased

colonic motor activity and demonstrates that gut activation can take place prior to food ingestion.175

This is known as the cephalic response. As increased colonic motor activity has been shown to be

strongly related with abdominal pain in patients with IBS, it is crucial to recognise that the process of

eating, despite the component of food may exacerbate IBS symptoms.175 Beside the cephalic response,

interactions between nutrient intake, motility and visceral sensation may lead to IBS symptoms. For

example lipid has been found to increase colonic sensitivity and change the pattern of viscerosomatic

pain referral in IBS.176

Page 58: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

58

Bulking agents and Fibre

Fibre supplementation is the most extensively and carefully studied dietary treatment for IBS, although

a heterogeneous patient population and strong placebo effect have been the studies shortcomings.142

Bulking agents increase stool frequency by adding water and bulk to stool. Calcium polycarbophil, fibre,

ispaghula husk, methylcellulose and wheat bran are the most commonly used as first treatment for IBS.

Studies have concluded that fibre either has no efficacy or possibly limited benefits for patients who

have IBS with constipation.142

Ligaarden et al. showed a higher intake of vegetables was associated with an increased severity in IBS-C

and IBS-A, while a higher intake of fruits and berries associated with the severity of symptoms in IBS-

D.134 Brussels sprouts, beans and prunes have been reported to produce gas due to fermentation, which

some patients with IBS report to handle poorly.177 Some fruits may exert a laxative effect due to their

carbohydrate composition, which may suggest a cause for symptoms in IBS-D.178

A systematic review and meta-analysis examining the type of fibre, showed that wheat bran (insoluble

fibre) was no more effective in treating IBS than placebo or a low fibre diet.100 The use of insoluble fibre

is discouraged because of concerns that it may exacerbate symptoms.100, 179 The beneficial effect of fibre

seemed to be limited to ispaghula husk (soluble fibre), which only reached marginal statistical

significance in one study.100 In general the studies show how variable the effects of fibre and particularly

type of fibre can be. What may be beneficial for one individual may not be for another, and may even

exacerbate symptoms. The same type of fibre may have different effects on different patients. Hence it

is recommended that if fibre is going to be added to the diet, it should be started at low doses and

slowly titrated up to 20g to 30g per day as it can exacerbate abdominal pain, bloating and intestinal

gas.180

Page 59: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

59

Gluten

Recent   attention   has   been   given   to   ‘gluten   sensitivity’,  which  may   present  with   IBS   or   dyspepsia-like

symptoms without an enteropathy or positive tissue transglutaminase antibodies, which are the

diagnostic determinants for Coeliac disease.181 GI symptoms in these patients improve once gluten has

been excluded from the diet,181 and it has been shown that patients with IBS exhibit more symptoms

upon gluten re-challenge compared to patients receiving placebo.182 However the gluten challenges

were gluten-free muffins and gluten-free breads.182 Due to the nature of the gluten-challenge, i.e. not

being pure gluten, patients symptoms could have been a result of reactions to other chemicals within

the  muffins  or  breads.  Giving  a  ‘whole  food’  to  a  patient  as  a  challenge  does  not  test  for  one  particular  

chemical, but a range, making it impossible to conclude that one chemical was the trigger.

Lactose

Lactose is a disaccharide that cannot be absorbed in the small bowel until it is split by the enzyme

lactase.183 Lactose intolerance is a broad term used for individuals who have difficulty digesting lactose

due to a deficiency of lactase in the intestinal mucosa.142, 183 The amount of enzyme produced is usually

low and many will tolerate a small dose (10-12g) without symptoms developing.183 Hence exceeding this

small dose, equivalent to a 250mL glass of milk, symptoms will develop. The prevalence of lactose

intolerance varies widely across ethnic groups, being more prevalent in Indo-Asian populations and

those groups who traditionally have a non-dairy diet. Individuals with and without IBS may report

increased symptoms such as bloating, flatulence, abdominal discomfort, nausea and loose stools,

following ingestion of lactose-containing foods, such as milk and ice-cream.142 Therefore lactose

intolerance does not appear to be a cause of IBS or more prevalent in this group than the general

population.142 As lactose intolerance can imitate IBS symptoms, or be a coexistent condition, it is

Page 60: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

60

important to establish whether it is a factor, especially in patients where symptoms are associated with

dairy products.184

Fat

A consistent finding is that IBS symptoms are exacerbated by the consumption of large and irregular

meals high in fat. This could possibly result from an exaggerated gastro-colonic response and

gastrointestinal sensitivity after a fatty meal.185, 186 However there is no clear evidence that high-fat

meals cause symptom exacerbation, given no prospective, randomised controlled trial of a low-fat diet

for IBS treatment has been conducted.

FODMAPs

Fermentable oligosaccharides, dissacharide, monosaccharide and polyols (FODMAPs) are short-chain

carbohydrates that have common functional properties in that they are poorly absorbed, osmotically

active178 and quickly fermented by bacteria.187 FODMAPs include fructans, raffinose, lactose, polyols and

galactans and have the potential to cause IBS symptoms such as bloating and diarrhoea. Galactans are

present in onions, legumes, cabbage and sprouts, while fructans are found in wheat, onions, spring

onions, shallots, leeks, artichokes and chicory.188, 189 Fermentation of these substrates results in gas

production and increased fluid load.187

It is hypothesised that FODMAPs trigger gastrointestinal symptoms in people with visceral

hypersensitivity or abnormal motility by inducing luminal distension via osmotic effects and gas

production resulting from rapid fermentation by bacteria in the intestine.187 A randomised placebo-

controlled trial showed that patients with IBS respond well symptomatically to restriction of FODMAP

intake.189 Breath hydrogen testing was utilised to identify which specific sugars behave as FODMAPs in

Page 61: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

61

the individual.190 However it has been shown that the capacity to absorb fructose (a FODMAP) is

considerably varied.191 If the capacity is exceeded symptoms such as wind, bloating and loose/watery

motions are may be experienced.191 Up to 50% of healthy individuals can exceed their fructose

absorptive capacity and have a positive hydrogen breath test with 25g fructose. This has shown to

increase to 80% of healthy individuals exceeding their fructose absorptive capacity with 50g fructose.191

The fructose absorptive capacity and gas production has shown to be equivalent between health

individuals and patients with IBS.191 Only in those with IBS are there additional symptoms due to altered

muscle tone and motility patterns and visceral hypersensitivity.191 Hence IBS is not a result of FODMAP

intolerance as the restriction of FODMAPs will benefit both healthy individuals and patients with IBS.

Essentially FODMAPs are prebiotics and may promote the growth of beneficial bacteria and similarly

produce improvements in IBS symptoms. However the amount of FODMAPs consumed with prebiotic

intent requires trial and error to not exacerbate symptoms.

Glutamate

A study conducted on 57 patients with fibromyalgia and IBS investigated the effects of monosodium

glutamate (MSG) and aspartame after a 4-week diet excluding these chemicals.192 Of the 37 patients

that completed the diet 84% reported that more than 30% of their symptoms had resolved.192

Challenges resulted in a significant return of symptoms and decreased quality of life in regards to IBS

symptoms. This study shows that the effect of glutamate in the diet is more pronounced than the

placebo effect, indicating it that glutamate can cause IBS symptoms.192 Therefore it might be beneficial

to exclude/limit glutamate from the diet if it can be shown to be a trigger for symptoms in a particular

patient.

Page 62: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

62

Physical Activity

It has been proposed that physical activity stimulates and increases gastrointestinal motility,193

enhances gas clearance and reduces bloating in patients with IBS.194 Patients with chronic constipation

have demonstrated decreased colonic transit time and improved defecation patterns when starting

regular physical activity.195 IBS patients with a more sedentary lifestyle report more symptoms than

those who are physically active.196 Overall physical activity improves IBS symptoms.197 However the role

of intensity, type of activity, frequency and duration needs to be explored as in endurance athletes

exercise can have adverse effects such as an urge to defecate, diarrhoea and gastrointestinal cramps.198

Conclusion

The etiology of IBS is complex and most likely involving a range of mechanisms interacting with one

another as opposed to a single mechanism. Current treatments available include drugs, psychotherapy,

herbal therapy, relaxation, diet modification and physical activity, and perhaps a mixture depending on

the  patient’s  symptom  severity/symptom frequency, and their personal preferences. However given all

form of treatment, it is diet that over two-thirds of patients report as triggering onset of GI symptoms.

So essentially should it not be diet that is utilised as a main form of treatment for this population group?

Studies have shown diet to help improve symptoms; however there are fewer studies on diet and IBS

compared to drug treatment. Perhaps not all patients with IBS want to be taking drugs indefinitely for

symptom relief. In conclusion more thorough research into foods that trigger GI symptoms needs to be

conducted and considered a major player in symptom management.

Page 63: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

63

References

1. Brandt LJ, Chey WD, Foxx-Orenstein AE, Schiller LR, Schoenfeld PS, Spiegel BM, et al. An

evidence-based position statement on the management of irritable bowel syndrome. Am J

Gastroenterol. 2009 Jan;104 Suppl 1:S1-35.

2. Thompson WG, Longstreth GF, Drossman DA, Heaton KW, Irvine EJ, Muller-Lissner SA.

Functional bowel disorders and functional abdominal pain. Gut. 1999 Sep;45 Suppl 2:II43-7.

3. Gwee KA, Wee S, Wong ML, Png DJ. The prevalence, symptom characteristics, and impact of

irritable bowel syndrome in an asian urban community. Am J Gastroenterol. 2004 May;99(5):924-31.

4. Wilson S, Roberts L, Roalfe A, Bridge P, Singh S. Prevalence of irritable bowel syndrome: a

community survey. Br J Gen Pract. 2004 Jul;54(504):495-502.

5. Gralnek IM, Hays RD, Kilbourne A, Naliboff B, Mayer EA. The impact of irritable bowel syndrome

on health-related quality of life. Gastroenterology. 2000 Sep;119(3):654-60.

6. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel

disorders. Gastroenterology. 2006 Apr;130(5):1480-91.

7. Mertz HR. Irritable bowel syndrome. N Engl J Med. 2003 Nov 27;349(22):2136-46.

8. Lovell RM, Ford AC. Effect of gender on prevalence of irritable bowel syndrome in the

community: systematic review and meta-analysis. Am J Gastroenterol. 2012 Jul;107(7):991-1000.

9. Drossman DA, Camilleri M, Mayer EA, Whitehead WE. AGA technical review on irritable bowel

syndrome. Gastroenterology. 2002 2002;123(6):2108-31.

10. Guidelines--Rome III Diagnostic Criteria for Functional Gastrointestinal Disorders. J

Gastrointestin Liver Dis. 2006 Sep;15(3):307-12.

11. Rey E, Talley NJ. Irritable bowel syndrome: novel views on the epidemiology and potential risk

factors. Dig Liver Dis. 2009 Nov;41(11):772-80.

Page 64: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

64

12. Cappello C, Tremolaterra F, Pascariello A, Ciacci C, Iovino P. A randomised clinical trial (RCT) of a

symbiotic mixture in patients with irritable bowel syndrome (IBS): effects on symptoms, colonic transit

and quality of life. Int J Colorectal Dis. 2012 Aug 12.

13. Hahn B, Watson M, Yan S, Gunput D, Heuijerjans J. Irritable bowel syndrome symptom patterns:

frequency, duration, and severity. Dig Dis Sci. 1998 Dec;43(12):2715-8.

14. Spiller RC, Thompson WG. Bowel disorders. Am J Gastroenterol. 2010 Apr;105(4):775-85.

15. Ringel Y, Williams RE, Kalilani L, Cook SF. Prevalence, characteristics, and impact of bloating

symptoms in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2009 Jan;7(1):68-72;

quiz 3.

16. Mearin F, Lacy BE. Diagnostic criteria in IBS: useful or not? Neurogastroenterology and motility :

the official journal of the European Gastrointestinal Motility Society. 2012 2012;24(9):791-801.

17. Coletta M, Di Palma L, Tomba C, Basilisco G. Discrepancy between recalled and recorded bowel

habits in irritable bowel syndrome. Aliment Pharmacol Ther. 2010 Jul;32(2):282-8.

18. Deiteren A, Camilleri M, Bharucha AE, Burton D, McKinzie S, Rao AS, et al. Performance

characteristics of scintigraphic colon transit measurement in health and irritable bowel syndrome and

relationship to bowel functions. Neurogastroenterol Motil. 2010 Apr;22(4):415-23, e95.

19. O'Donnell LJ, Virjee J, Heaton KW. Detection of pseudodiarrhoea by simple clinical assessment

of intestinal transit rate. BMJ. 1990 Feb 17;300(6722):439-40.

20. Engsbro AL, Simren M, Bytzer P. Short-term stability of subtypes in the irritable bowel syndrome:

prospective evaluation using the Rome III classification. Aliment Pharmacol Ther. 2012 Feb;35(3):350-9.

21. Yao X, Yang YS, Cui LH, Zhao KB, Zhang ZH, Peng LH, et al. Subtypes of irritable bowel syndrome

on Rome III criteria: a multicenter study. J Gastroenterol Hepatol. 2012 Apr;27(4):760-5.

22. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J

Gastroenterol. 1997 Sep;32(9):920-4.

Page 65: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

65

23. American Gastroenterological Association medical position statement: irritable bowel syndrome.

Gastroenterology. 2002 Dec;123(6):2105-7.

24. Mayer EA. Clinical practice. Irritable bowel syndrome. N Engl J Med. 2008 Apr 17;358(16):1692-9.

25. Spiller R, Aziz Q, Creed F, Emmanuel A, Houghton L, Hungin P, et al. Guidelines on the irritable

bowel syndrome: mechanisms and practical management. Gut. 2007 Dec;56(12):1770-98.

26. Drossman DA, Chang L, Bellamy N, Gallo-Torres HE, Lembo A, Mearin F, et al. Severity in irritable

bowel syndrome: a Rome Foundation Working Team report. Am J Gastroenterol. 2011

Oct;106(10):1749-59; quiz 60.

27. Lembo A, Ameen VZ, Drossman DA. Irritable bowel syndrome: toward an understanding of

severity. Clinical gastroenterology and hepatology : the official clinical practice journal of the American

Gastroenterological Association. 2005 2005;3(8):717-25.

28. Frank L, Kleinman L, Rentz A, Ciesla G, Kim JJ, Zacker C. Health-related quality of life associated

with irritable bowel syndrome: comparison with other chronic diseases. Clin Ther. 2002 Apr;24(4):675-

89; discussion 4.

29. Hungin AP, Whorwell PJ, Tack J, Mearin F. The prevalence, patterns and impact of irritable

bowel syndrome: an international survey of 40,000 subjects. Aliment Pharmacol Ther. 2003 Mar

1;17(5):643-50.

30. Longstreth GF, Wilson A, Knight K, Wong J, Chiou CF, Barghout V, et al. Irritable bowel syndrome,

health care use, and costs: a U.S. managed care perspective. Am J Gastroenterol. 2003 Mar;98(3):600-7.

31. Sandler RS, Everhart JE, Donowitz M, Adams E, Cronin K, Goodman C, et al. The burden of

selected digestive diseases in the United States. Gastroenterology. [; Research Support, Non-U.S. Gov't].

2002 2002;122(5):1500-11.

32. Trinkley KE, Nahata MC. Treatment of irritable bowel syndrome. J Clin Pharm Ther. 2011

Jun;36(3):275-82.

Page 66: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

66

33. Farndale R, Roberts L. Long-term impact of irritable bowel syndrome: a qualitative study. Prim

Health Care Res Dev. 2011 Jan;12(1):52-67.

34. Johnson FR, Hauber AB, Ozdemir S, Lynd L. Quantifying women's stated benefit-risk trade-off

preferences for IBS treatment outcomes. Value Health. 2010 Jun-Jul;13(4):418-23.

35. Ringel Y, Sperber AD, Drossman DA. Irritable bowel syndrome. Annu Rev Med. 2001;52:319-38.

36. Brandt LJ, Bjorkman D, Fennerty MB, Locke GR, Olden K, Peterson W, et al. Systematic review on

the management of irritable bowel syndrome in North America. Am J Gastroenterol. 2002 Nov;97(11

Suppl):S7-26.

37. Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a meta-

analysis. Clin Gastroenterol Hepatol. 2012 Jul;10(7):712-21 e4.

38. Grundmann O, Yoon SL. Irritable bowel syndrome: epidemiology, diagnosis and treatment: an

update for health-care practitioners. J Gastroenterol Hepatol. 2010 Apr;25(4):691-9.

39. Gunnarsson J, Simren M. Peripheral factors in the pathophysiology of irritable bowel syndrome.

Dig Liver Dis. 2009 Nov;41(11):788-93.

40. Ohman L, Simren M. New insights into the pathogenesis and pathophysiology of irritable bowel

syndrome. Dig Liver Dis. 2007 Mar;39(3):201-15.

41. Ohman L, Simren M. Pathogenesis of IBS: role of inflammation, immunity and neuroimmune

interactions. Nat Rev Gastroenterol Hepatol. 2010 Mar;7(3):163-73.

42. Barbara G, Stanghellini V, De Giorgio R, Cremon C, Cottrell GS, Santini D, et al. Activated mast

cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome.

Gastroenterology. 2004 Mar;126(3):693-702.

43. Braak B, Klooker TK, Wouters MM, Welting O, van der Loos CM, Stanisor OI, et al. Mucosal

immune cell numbers and visceral sensitivity in patients with irritable bowel syndrome: is there any

relationship? Am J Gastroenterol. 2012 May;107(5):715-26.

Page 67: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

67

44. Posserud I, Syrous A, Lindstrom L, Tack J, Abrahamsson H, Simren M. Altered rectal perception in

irritable bowel syndrome is associated with symptom severity. Gastroenterology. 2007 Oct;133(4):1113-

23.

45. Mayer EA, Naliboff BD, Chang L, Coutinho SV. V. Stress and irritable bowel syndrome. Am J

Physiol Gastrointest Liver Physiol. 2001 Apr;280(4):G519-24.

46. Schwetz I, McRoberts JA, Coutinho SV, Bradesi S, Gale G, Fanselow M, et al. Corticotropin-

releasing factor receptor 1 mediates acute and delayed stress-induced visceral hyperalgesia in

maternally separated Long-Evans rats. Am J Physiol Gastrointest Liver Physiol. 2005 Oct;289(4):G704-12.

47. van den Wijngaard RM, Klooker TK, Welting O, Stanisor OI, Wouters MM, van der Coelen D, et al.

Essential role for TRPV1 in stress-induced (mast cell-dependent) colonic hypersensitivity in maternally

separated rats. Neurogastroenterol Motil. 2009 Oct;21(10):1107-e94.

48. Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature. 2001 Sep

13;413(6852):203-10.

49. Piche T, Saint-Paul MC, Dainese R, Marine-Barjoan E, Iannelli A, Montoya ML, et al. Mast cells

and cellularity of the colonic mucosa correlated with fatigue and depression in irritable bowel syndrome.

Gut. 2008 Apr;57(4):468-73.

50. Collins SM, Bercik P. The relationship between intestinal microbiota and the central nervous

system in normal gastrointestinal function and disease. Gastroenterology. 2009 May;136(6):2003-14.

51. Kern MK, Shaker R. Cerebral cortical registration of subliminal visceral stimulation.

Gastroenterology. 2002 Feb;122(2):290-8.

52. Mayer EA, Naliboff BD, Craig AD. Neuroimaging of the brain-gut axis: from basic understanding

to treatment of functional GI disorders. Gastroenterology. 2006 Dec;131(6):1925-42.

53. Clarke G, Quigley EM, Cryan JF, Dinan TG. Irritable bowel syndrome: towards biomarker

identification. Trends Mol Med. 2009 Oct;15(10):478-89.

Page 68: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

68

54. Gershon MD. Nerves, reflexes, and the enteric nervous system: pathogenesis of the irritable

bowel syndrome. J Clin Gastroenterol. 2005 May-Jun;39(5 Suppl 3):S184-93.

55. Atkinson W, Lockhart S, Whorwell PJ, Keevil B, Houghton LA. Altered 5-hydroxytryptamine

signaling in patients with constipation- and diarrhea-predominant irritable bowel syndrome.

Gastroenterology. 2006 Jan;130(1):34-43.

56. Brehmer A, Croner R, Dimmler A, Papadopoulos T, Schrodl F, Neuhuber W.

Immunohistochemical characterization of putative primary afferent (sensory) myenteric neurons in

human small intestine. Auton Neurosci. 2004 May 31;112(1-2):49-59.

57. Taniyama K, Makimoto N, Furuichi A, Sakurai-Yamashita Y, Nagase Y, Kaibara M, et al. Functions

of peripheral 5-hydroxytryptamine receptors, especially 5-hydroxytryptamine4 receptor, in

gastrointestinal motility. J Gastroenterol. 2000;35(8):575-82.

58. Wade PR, Chen J, Jaffe B, Kassem IS, Blakely RD, Gershon MD. Localization and function of a 5-

HT transporter in crypt epithelia of the gastrointestinal tract. J Neurosci. 1996 Apr 1;16(7):2352-64.

59. Coates MD, Mahoney CR, Linden DR, Sampson JE, Chen J, Blaszyk H, et al. Molecular defects in

mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and

irritable bowel syndrome. Gastroenterology. 2004 Jun;126(7):1657-64.

60. Mayer EA, Collins SM. Evolving pathophysiologic models of functional gastrointestinal disorders.

Gastroenterology. 2002 Jun;122(7):2032-48.

61. Chadwick VS, Chen W, Shu D, Paulus B, Bethwaite P, Tie A, et al. Activation of the mucosal

immune system in irritable bowel syndrome. Gastroenterology. 2002 Jun;122(7):1778-83.

62. O'Mahony L, McCarthy J, Kelly P, Hurley G, Luo F, Chen K, et al. Lactobacillus and

bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles.

Gastroenterology. 2005 Mar;128(3):541-51.

Page 69: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

69

63. Walker AF, Middleton RW, Petrowicz O. Artichoke leaf extract reduces symptoms of irritable

bowel syndrome in a post-marketing surveillance study. Phytother Res. 2001 Feb;15(1):58-61.

64. Drisko J, Bischoff B, Hall M, McCallum R. Treating irritable bowel syndrome with a food

elimination diet followed by food challenge and probiotics. J Am Coll Nutr. 2006 Dec;25(6):514-22.

65. Walker WA. Role of nutrients and bacterial colonization in the development of intestinal host

defense. J Pediatr Gastroenterol Nutr. 2000;30 Suppl 2:S2-7.

66. Drossman DA. The functional gastrointestinal disorders and the Rome III process.

Gastroenterology. 2006 Apr;130(5):1377-90.

67. Levy RL, Olden KW, Naliboff BD, Bradley LA, Francisconi C, Drossman DA, et al. Psychosocial

aspects of the functional gastrointestinal disorders. Gastroenterology. 2006 Apr;130(5):1447-58.

68. Fujii Y, Nomura S. A prospective study of the psychobehavioral factors responsible for a change

from non-patient irritable bowel syndrome to IBS patient status. Biopsychosoc Med. 2008;2:16.

69. Sykes MA, Blanchard EB, Lackner J, Keefer L, Krasner S. Psychopathology in irritable bowel

syndrome: support for a psychophysiological model. J Behav Med. 2003 Aug;26(4):361-72.

70. Van Oudenhove L, Vandenberghe J, Vos R, Holvoet L, Tack J. Factors associated with co-morbid

irritable bowel syndrome and chronic fatigue-like symptoms in functional dyspepsia.

Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility

Society. 2011 2011 Jun (Epub 2011 Jan;23(6):524-e202.

71. Whitehead WE, Palsson OS, Levy RL, Von Korff M, Feld AD, Turner MJ. Comorbid psychiatric

disorders in irritable bowel (IBS) and inflammatory bowel disease (IBD). Gastroenterology. 2003

Apr;124(4):A398-A.

72. Lee S, Wu J, Ma YL, Tsang A, Guo WJ, Sung J. Irritable bowel syndrome is strongly associated

with generalized anxiety disorder: a community study. Aliment Pharmacol Ther. 2009 Sep 15;30(6):643-

51.

Page 70: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

70

73. Young VB, Schmidt TM. Overview of the gastrointestinal microbiota. Adv Exp Med Biol.

2008;635:29-40.

74. Parkes GC, Brostoff J, Whelan K, Sanderson JD. Gastrointestinal microbiota in irritable bowel

syndrome: their role in its pathogenesis and treatment. Am J Gastroenterol. 2008 Jun;103(6):1557-67.

75. Rajilic-Stojanovic M, Biagi E, Heilig HG, Kajander K, Kekkonen RA, Tims S, et al. Global and deep

molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome.

Gastroenterology. 2011 Nov;141(5):1792-801.

76. Lupp C, Robertson ML, Wickham ME, Sekirov I, Champion OL, Gaynor EC, et al. Host-mediated

inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae.

Cell Host Microbe. 2007 Sep 13;2(3):204.

77. Barthel M, Hapfelmeier S, Quintanilla-Martinez L, Kremer M, Rohde M, Hogardt M, et al.

Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis

model that allows analysis of both pathogen and host. Infect Immun. 2003 May;71(5):2839-58.

78. Longstreth GF, Hawkey CJ, Mayer EA, Jones RH, Naesdal J, Wilson IK, et al. Characteristics of

patients with irritable bowel syndrome recruited from three sources: implications for clinical trials.

Aliment Pharmacol Ther. 2001 Jul;15(7):959-64.

79. Thabane M, Kottachchi DT, Marshall JK. Systematic review and meta-analysis: The incidence and

prognosis of post-infectious irritable bowel syndrome. Aliment Pharmacol Ther. 2007 Aug 15;26(4):535-

44.

80. Barbara G, Stanghellini V, Berti-Ceroni C, De Giorgio R, Salvioli B, Corradi F, et al. Role of

antibiotic therapy on long-term germ excretion in faeces and digestive symptoms after Salmonella

infection. Aliment Pharmacol Ther. 2000 Sep;14(9):1127-31.

81. Villarreal AA, Aberger FJ, Benrud R, Gundrum JD. Use of broad-spectrum antibiotics and the

development of irritable bowel syndrome. WMJ. 2012 Feb;111(1):17-20.

Page 71: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

71

82. Saito YA, Zimmerman JM, Harmsen WS, De Andrade M, Locke GR, 3rd, Petersen GM, et al.

Irritable bowel syndrome aggregates strongly in families: a family-based case-control study.

Neurogastroenterol Motil. 2008 Jul;20(7):790-7.

83. Lembo A, Zaman M, Jones M, Talley NJ. Influence of genetics on irritable bowel syndrome,

gastro-oesophageal reflux and dyspepsia: a twin study. Aliment Pharmacol Ther. 2007 Jun

1;25(11):1343-50.

84. Van Kerkhoven LA, Laheij RJ, Jansen JB. Meta-analysis: a functional polymorphism in the gene

encoding for activity of the serotonin transporter protein is not associated with the irritable bowel

syndrome. Aliment Pharmacol Ther. 2007 Oct 1;26(7):979-86.

85. Kanazawa M, Endo Y, Whitehead WE, Kano M, Hongo M, Fukudo S. Patients and nonconsulters

with irritable bowel syndrome reporting a parental history of bowel problems have more impaired

psychological distress. Dig Dis Sci. 2004 Jun;49(6):1046-53.

86. Levy RL, Whitehead WE, Von Korff MR, Feld AD. Intergenerational transmission of

gastrointestinal illness behavior. Am J Gastroenterol. 2000 Feb;95(2):451-6.

87. Locke GR, 3rd, Zinsmeister AR, Talley NJ, Fett SL, Melton LJ, 3rd. Familial association in adults

with functional gastrointestinal disorders. Mayo Clin Proc. 2000 Sep;75(9):907-12.

88. Kalantar JS, Locke GR, 3rd, Zinsmeister AR, Beighley CM, Talley NJ. Familial aggregation of

irritable bowel syndrome: a prospective study. Gut. 2003 Dec;52(12):1703-7.

89. Levy RL, Jones KR, Whitehead WE, Feld SI, Talley NJ, Corey LA. Irritable bowel syndrome in twins:

heredity and social learning both contribute to etiology. Gastroenterology. 2001 Oct;121(4):799-804.

90. American Gastroenterological Association medical position statement: guidelines for the

evaluation of food allergies. Gastroenterology. 2001 2001;120(4):1023-5.

91. Park MI, Camilleri M. Is there a role of food allergy in irritable bowel syndrome and functional

dyspepsia? A systematic review. Neurogastroenterol Motil. 2006 Aug;18(8):595-607.

Page 72: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

72

92. Akehurst R, Kaltenthaler E. Treatment of irritable bowel syndrome: a review of randomised

controlled trials. Gut. 2001 Feb;48(2):272-82.

93. Staudacher HM, Whelan K, Irving PM, Lomer MC. Comparison of symptom response following

advice for a diet low in fermentable carbohydrates (FODMAPs) versus standard dietary advice in

patients with irritable bowel syndrome. J Hum Nutr Diet. 2011 Oct;24(5):487-95.

94. Camilleri M, Chey WY, Mayer EA, Northcutt AR, Heath A, Dukes GE, et al. A randomized

controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhea-

predominant irritable bowel syndrome. Arch Intern Med. 2001 Jul 23;161(14):1733-40.

95. Lucak S. Irritable bowel syndrome and ischemic colitis: evidence supporting the increased use of

alosetron. Therap Adv Gastroenterol. 2012 Jul;5(4):215-8.

96. Camilleri M, Kerstens R, Rykx A, Vandeplassche L. A placebo-controlled trial of prucalopride for

severe chronic constipation. N Engl J Med. 2008 May 29;358(22):2344-54.

97. Lacy BE, Chey WD. Lubiprostone: chronic constipation and irritable bowel syndrome with

constipation. Expert Opin Pharmacother. 2009 Jan;10(1):143-52.

98. Fischer H, Machen TE, Widdicombe JH, Carlson TJS, King SR, Chow JWS, et al. A novel extract SB-

300 from the stem bark latex of Croton lechleri inhibits CFTR-mediated chloride secretion in human

colonic epithelial cells. Journal of ethnopharmacology. 2004 2004;93(2-3):351-7.

99. Mangel AW, Chaturvedi P. Evaluation of crofelemer in the treatment of diarrhea-predominant

irritable bowel syndrome patients. Digestion. [; Randomized Controlled Trial; Research Support, Non-U.S.

Gov't]. 2008 2008 (Epub 2008 Dec;78(4):180-6.

100. Ford AC, Talley NJ, Spiegel BM, Foxx-Orenstein AE, Schiller L, Quigley EM, et al. Effect of fibre,

antispasmodics, and peppermint oil in the treatment of irritable bowel syndrome: systematic review and

meta-analysis. BMJ. 2008;337:a2313.

Page 73: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

73

101. Marciani L, Foley S, Hoad CL, Campbell E, Totman JJ, Cox E, et al. Accelerated small bowel transit

and contracted transverse colon in diarrhoea-predominant irritable bowel syndrome (IBS-D): Novel

insights from magnetic resonance imaging (MRI). Gastroenterology. 2007 Apr;132(4):A141-A.

102. Pimentel M, Park S, Mirocha J, Kane SV, Kong Y. The effect of a nonabsorbed oral antibiotic

(rifaximin) on the symptoms of the irritable bowel syndrome: a randomized trial. Ann Intern Med. 2006

Oct 17;145(8):557-63.

103. Ford AC, Spiegel BM, Talley NJ, Moayyedi P. Small intestinal bacterial overgrowth in irritable

bowel syndrome: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2009

Dec;7(12):1279-86.

104. Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces

symptoms of irritable bowel syndrome. Am J Gastroenterol. 2000 Dec;95(12):3503-6.

105. Basseri RJ, Weitsman S, Barlow GM, Pimentel M. Antibiotics for the treatment of irritable bowel

syndrome. Gastroenterol Hepatol (N Y). 2011 Jul;7(7):455-93.

106. Lembo A, Zakko SF, Ferreira NL, Ringel Y, Bortey E, Courtney K, et al. Rifaximin for the treatment

of diarrhea-associated irritable bowel syndrome: Short term treatment leading to long term sustained

response. Gastroenterology. 2008 Apr;134(4):A545-A.

107. Yang J, Lee HR, Low K, Chatterjee S, Pimentel M. Rifaximin versus other antibiotics in the

primary treatment and retreatment of bacterial overgrowth in IBS. Dig Dis Sci. 2008 Jan;53(1):169-74.

108. Pimentel M, Lembo A, Chey WD, Zakko S, Ringel Y, Yu J, et al. Rifaximin therapy for patients with

irritable bowel syndrome without constipation. N Engl J Med. 2011 Jan 6;364(1):22-32.

109. Olden KW. Targeted therapies for diarrhea-predominant irritable bowel syndrome. Clin Exp

Gastroenterol. 2012;5:69-100.

110. Tack J. Antibiotic therapy for the irritable bowel syndrome. N Engl J Med. 2011 Jan 6;364(1):81-2.

Page 74: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

74

111. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev.

2007(4):CD005454.

112. Ford AC, Talley NJ, Schoenfeld PS, Quigley EM, Moayyedi P. Efficacy of antidepressants and

psychological therapies in irritable bowel syndrome: systematic review and meta-analysis. Gut. 2009

Mar;58(3):367-78.

113. Lackner JM, Mesmer C, Morley S, Dowzer C, Hamilton S. Psychological treatments for irritable

bowel syndrome: a systematic review and meta-analysis. J Consult Clin Psychol. 2004 Dec;72(6):1100-13.

114. Mahvi-Shirazi M, Fathi-Ashtiani A, Rasoolzade-Tabatabaei SK, Amini M. Irritable bowel syndrome

treatment: cognitive behavioral therapy versus medical treatment. Arch Med Sci. 2012 Feb 29;8(1):123-

9.

115. Pinto C, Lele MV, Joglekar AS, Panwar VS, Dhavale HS. Stressful life-events, anxiety, depression

and coping in patients of irritable bowel syndrome. J Assoc Physicians India. 2000 Jun;48(6):589-93.

116. Asare F, Storsrud S, Simren M. Meditation over Medication for Irritable Bowel Syndrome? On

Exercise and Alternative Treatments for Irritable Bowel Syndrome. Curr Gastroenterol Rep. 2012

Aug;14(4):283-9.

117. Lindfors P, Unge P, Nyhlin H, Ljotsson B, Bjornsson ES, Abrahamsson H, et al. Long-term effects

of hypnotherapy in patients with refractory irritable bowel syndrome. Scand J Gastroenterol. 2012

Apr;47(4):414-20.

118. Lindfors P, Unge P, Arvidsson P, Nyhlin H, Bjornsson E, Abrahamsson H, et al. Effects of gut-

directed hypnotherapy on IBS in different clinical settings-results from two randomized, controlled trials.

Am J Gastroenterol. 2012 Feb;107(2):276-85.

119. Guarner F, Requena T, Marcos A. Consensus statements from the Workshop "Probiotics and

Health: Scientific evidence". Nutr Hosp. 2010 Sep-Oct;25(5):700-4.

Page 75: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

75

120. Aragon G, Graham DB, Borum M, Doman DB. Probiotic therapy for irritable bowel syndrome.

Gastroenterol Hepatol (N Y). 2010 Jan;6(1):39-44.

121. Brenner DM, Moeller MJ, Chey WD, Schoenfeld PS. The utility of probiotics in the treatment of

irritable bowel syndrome: a systematic review. Am J Gastroenterol. 2009 Apr;104(4):1033-49; quiz 50.

122. Moayyedi P, Ford AC, Talley NJ, Cremonini F, Foxx-Orenstein AE, Brandt LJ, et al. The efficacy of

probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut. 2010 Mar;59(3):325-

32.

123. Spiller R. Review article: probiotics and prebiotics in irritable bowel syndrome. Aliment

Pharmacol Ther. 2008 Aug 15;28(4):385-96.

124. Kim HJ, Camilleri M, McKinzie S, Lempke MB, Burton DD, Thomforde GM, et al. A randomized

controlled trial of a probiotic, VSL#3, on gut transit and symptoms in diarrhoea-predominant irritable

bowel syndrome. Aliment Pharmacol Ther. 2003 Apr 1;17(7):895-904.

125. Kim HJ, Vazquez Roque MI, Camilleri M, Stephens D, Burton DD, Baxter K, et al. A randomized

controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating.

Neurogastroenterol Motil. 2005 Oct;17(5):687-96.

126. Nobaek S, Johansson ML, Molin G, Ahrne S, Jeppsson B. Alteration of intestinal microflora is

associated with reduction in abdominal bloating and pain in patients with irritable bowel syndrome. Am

J Gastroenterol. 2000 May;95(5):1231-8.

127. Dolin BJ. Effects of a proprietary Bacillus coagulans preparation on symptoms of diarrhea-

predominant irritable bowel syndrome. Methods Find Exp Clin Pharmacol. 2009 Dec;31(10):655-9.

128. Enck P, Zimmermann K, Menke G, Muller-Lissner S, Martens U, Klosterhalfen S. A mixture of

Escherichia coli (DSM 17252) and Enterococcus faecalis (DSM 16440) for treatment of the irritable bowel

syndrome--a randomized controlled trial with primary care physicians. Neurogastroenterol Motil. 2008

Oct;20(10):1103-9.

Page 76: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

76

129. Guglielmetti S, Mora D, Gschwender M, Popp K. Randomised clinical trial: Bifidobacterium

bifidum MIMBb75 significantly alleviates irritable bowel syndrome and improves quality of life--a

double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2011 May;33(10):1123-32.

130. Kajander K, Hatakka K, Poussa T, Farkkila M, Korpela R. A probiotic mixture alleviates symptoms

in irritable bowel syndrome patients: a controlled 6-month intervention. Aliment Pharmacol Ther. 2005

Sep 1;22(5):387-94.

131. Kajander K, Myllyluoma E, Rajilic-Stojanovic M, Kyronpalo S, Rasmussen M, Jarvenpaa S, et al.

Clinical trial: multispecies probiotic supplementation alleviates the symptoms of irritable bowel

syndrome and stabilizes intestinal microbiota. Aliment Pharmacol Ther. 2008 Jan 1;27(1):48-57.

132. Whorwell PJ, Altringer L, Morel J, Bond Y, Charbonneau D, O'Mahony L, et al. Efficacy of an

encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J

Gastroenterol. 2006 Jul;101(7):1581-90.

133. Williams EA, Stimpson J, Wang D, Plummer S, Garaiova I, Barker ME, et al. Clinical trial: a

multistrain probiotic preparation significantly reduces symptoms of irritable bowel syndrome in a

double-blind placebo-controlled study. Aliment Pharmacol Ther. 2009 Jan;29(1):97-103.

134. Ligaarden SC, Axelsson L, Naterstad K, Lydersen S, Farup PG. A candidate probiotic with

unfavourable effects in subjects with irritable bowel syndrome: a randomised controlled trial. BMC

Gastroenterol. 2010;10:16.

135. Nikfar S, Rahimi R, Rahimi F, Derakhshani S, Abdollahi M. Efficacy of probiotics in irritable bowel

syndrome: a meta-analysis of randomized, controlled trials. Dis Colon Rectum. 2008 Dec;51(12):1775-80.

136. Roberfroid M. Prebiotics: the concept revisited. J Nutr. 2007 Mar;137(3 Suppl 2):830S-7S.

137. Depeint F, Tzortzis G, Vulevic J, I'Anson K, Gibson GR. Prebiotic evaluation of a novel

galactooligosaccharide mixture produced by the enzymatic activity of Bifidobacterium bifidum NCIMB

Page 77: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

77

41171, in healthy humans: a randomized, double-blind, crossover, placebo-controlled intervention study.

Am J Clin Nutr. 2008 Mar;87(3):785-91.

138. Agrawal A, Houghton LA, Morris J, Reilly B, Guyonnet D, Goupil Feuillerat N, et al. Clinical trial:

the effects of a fermented milk product containing Bifidobacterium lactis DN-173 010 on abdominal

distension and gastrointestinal transit in irritable bowel syndrome with constipation. Aliment Pharmacol

Ther. 2009 Jan;29(1):104-14.

139. Kajander K, Krogius-Kurikka L, Rinttila T, Karjalainen H, Palva A, Korpela R. Effects of multispecies

probiotic supplementation on intestinal microbiota in irritable bowel syndrome. Aliment Pharmacol Ther.

2007 Aug 1;26(3):463-73.

140. Gibson GR, Probert HM, Loo JV, Rastall RA, Roberfroid MB. Dietary modulation of the human

colonic microbiota: updating the concept of prebiotics. Nutr Res Rev. 2004 Dec;17(2):259-75.

141. Schrezenmeir J, de Vrese M. Probiotics, prebiotics, and synbiotics--approaching a definition. Am

J Clin Nutr. 2001 Feb;73(2 Suppl):361S-4S.

142. Heizer WD, Southern S, McGovern S. The role of diet in symptoms of irritable bowel syndrome in

adults: a narrative review. J Am Diet Assoc. 2009 Jul;109(7):1204-14.

143. Patel SM, Stason WB, Legedza A, Ock SM, Kaptchuk TJ, Conboy L, et al. The placebo effect in

irritable bowel syndrome trials: a meta-analysis. Neurogastroenterol Motil. 2005 Jun;17(3):332-40.

144. Kelley JM, Lembo AJ, Ablon JS, Villanueva JJ, Conboy LA, Levy R, et al. Patient and practitioner

influences on the placebo effect in irritable bowel syndrome. Psychosomatic medicine. [Comparative

Study; ; Research Support, N.I.H., Extramural]. 2009 2009 Sep (Epub 2009 Aug;71(7):789-97.

145. Hussain Z, Quigley EM. Systematic review: Complementary and alternative medicine in the

irritable bowel syndrome. Aliment Pharmacol Ther. 2006 Feb 15;23(4):465-71.

Page 78: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

78

146. van Tilburg MA, Palsson OS, Levy RL, Feld AD, Turner MJ, Drossman DA, et al. Complementary

and alternative medicine use and cost in functional bowel disorders: a six month prospective study in a

large HMO. BMC Complement Altern Med. 2008;8:46.

147. Liu JP, Yang M, Liu YX, Wei ML, Grimsgaard S. Herbal medicines for treatment of irritable bowel

syndrome. Cochrane Database Syst Rev. 2006(1):CD004116.

148. Schneider A, Enck P, Streitberger K, Weiland C, Bagheri S, Witte S, et al. Acupuncture treatment

in irritable bowel syndrome. Gut. 2006 May;55(5):649-54.

149. Lembo AJ, Conboy L, Kelley JM, Schnyer RS, McManus CA, Quilty MT, et al. A treatment trial of

acupuncture in IBS patients. Am J Gastroenterol. 2009 Jun;104(6):1489-97.

150. Keefer L, Blanchard EB. The effects of relaxation response meditation on the symptoms of

irritable bowel syndrome: results of a controlled treatment study. Behav Res Ther. 2001 Jul;39(7):801-11.

151. Keefer L, Blanchard EB. A one year follow-up of relaxation response meditation as a treatment

for irritable bowel syndrome. Behav Res Ther. 2002 May;40(5):541-6.

152. Tovey P. A single-blind trial of reflexology for irritable bowel syndrome. Br J Gen Pract. 2002

Jan;52(474):19-23.

153. Ernst E. Is reflexology an effective intervention? A systematic review of randomised controlled

trials. Med J Aust. 2009 Sep 7;191(5):263-6.

154. Davis K, Philpott S, Kumar D, Mendall M. Randomised double-blind placebo-controlled trial of

aloe vera for irritable bowel syndrome. Int J Clin Pract. 2006 Sep;60(9):1080-6.

155. Bundy R, Walker AF, Middleton RW, Booth J. Turmeric extract may improve irritable bowel

syndrome symptomology in otherwise healthy adults: a pilot study. J Altern Complement Med. 2004

Dec;10(6):1015-8.

156. Bundy R, Walker AF, Middleton RW, Marakis G, Booth JC. Artichoke leaf extract reduces

symptoms of irritable bowel syndrome and improves quality of life in otherwise healthy volunteers

Page 79: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

79

suffering from concomitant dyspepsia: a subset analysis. J Altern Complement Med. 2004

Aug;10(4):667-9.

157. Costabile A, Kolida S, Klinder A, Gietl E, Bauerlein M, Frohberg C, et al. A double-blind, placebo-

controlled, cross-over study to establish the bifidogenic effect of a very-long-chain inulin extracted from

globe artichoke (Cynara scolymus) in healthy human subjects. Br J Nutr. 2010 Oct;104(7):1007-17.

158. Emendorfer F, Bellato F, Noldin VF, Cechinel-Filho V, Yunes RA, Delle Monache F, et al.

Antispasmodic activity of fractions and cynaropicrin from Cynara scolymus on guinea-pig ileum. Biol

Pharm Bull. 2005 May;28(5):902-4.

159. Rahimi R, Nikfar S, Abdollahi M. Efficacy and tolerability of Hypericum perforatum in major

depressive disorder in comparison with selective serotonin reuptake inhibitors: a meta-analysis. Prog

Neuropsychopharmacol Biol Psychiatry. 2009 Feb 1;33(1):118-27.

160. Saito YA, Rey E, Almazar-Elder AE, Harmsen WS, Zinsmeister AR, Locke GR, et al. A randomized,

double-blind, placebo-controlled trial of St John's wort for treating irritable bowel syndrome. Am J

Gastroenterol. 2010 Jan;105(1):170-7.

161. Hills JM, Aaronson PI. The mechanism of action of peppermint oil on gastrointestinal smooth

muscle. An analysis using patch clamp electrophysiology and isolated tissue pharmacology in rabbit and

guinea pig. Gastroenterology. 1991 Jul;101(1):55-65.

162. Liu JH, Chen GH, Yeh HZ, Huang CK, Poon SK. Enteric-coated peppermint-oil capsules in the

treatment of irritable bowel syndrome: a prospective, randomized trial. J Gastroenterol. 1997

Dec;32(6):765-8.

163. Madisch A, Holtmann G, Plein K, Hotz J. Treatment of irritable bowel syndrome with herbal

preparations: results of a double-blind, randomized, placebo-controlled, multi-centre trial. Aliment

Pharmacol Ther. 2004 Feb 1;19(3):271-9.

Page 80: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

80

164. Krueger D, Gruber L, Buhner S, Zeller F, Langer R, Seidl S, et al. The multi-herbal drug STW 5

(Iberogast) has prosecretory action in the human intestine. Neurogastroenterol Motil. 2009

Nov;21(11):1203-e110.

165. Zar S, Mincher L, Benson MJ, Kumar D. Food-specific IgG4 antibody-guided exclusion diet

improves symptoms and rectal compliance in irritable bowel syndrome. Scand J Gastroenterol. 2005

Jul;40(7):800-7.

166. Atkinson W, Sheldon TA, Shaath N, Whorwell PJ. Food elimination based on IgG antibodies in

irritable bowel syndrome: a randomised controlled trial. Gut. 2004 Oct;53(10):1459-64.

167. Zar S, Kumar D, Benson MJ. Food hypersensitivity and irritable bowel syndrome. Aliment

Pharmacol Ther. 2001 Apr;15(4):439-49.

168. Simren M, Mansson A, Langkilde AM, Svedlund J, Abrahamsson H, Bengtsson U, et al. Food-

related gastrointestinal symptoms in the irritable bowel syndrome. Digestion. 2001;63(2):108-15.

169. Chey WD, Olden K, Carter E, Boyle J, Drossman D, Chang L. Utility of the Rome I and Rome II

criteria for irritable bowel syndrome in U.S. women. Am J Gastroenterol. 2002 Nov;97(11):2803-11.

170. Halpert A, Dalton CB, Palsson O, Morris C, Hu Y, Bangdiwala S, et al. What patients know about

irritable bowel syndrome (IBS) and what they would like to know. National Survey on Patient

Educational Needs in IBS and development and validation of the Patient Educational Needs

Questionnaire (PEQ). Am J Gastroenterol. 2007 Sep;102(9):1972-82.

171. Saito YA, Locke GR, 3rd, Weaver AL, Zinsmeister AR, Talley NJ. Diet and functional

gastrointestinal disorders: a population-based case-control study. Am J Gastroenterol. 2005

Dec;100(12):2743-8.

172. Wohrl S, Hemmer W, Focke M, Rappersberger K, Jarisch R. Histamine intolerance-like symptoms

in healthy volunteers after oral provocation with liquid histamine. Allergy Asthma Proc. 2004 Sep-

Oct;25(5):305-11.

Page 81: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

81

173. Rao SS, Welcher K, Zimmerman B, Stumbo P. Is coffee a colonic stimulant? Eur J Gastroenterol

Hepatol. 1998 Feb;10(2):113-8.

174. Austin GL, Dalton CB, Hu Y, Morris CB, Hankins J, Weinland SR, et al. A very low-carbohydrate

diet improves symptoms and quality of life in diarrhea-predominant irritable bowel syndrome. Clin

Gastroenterol Hepatol. 2009 Jun;7(6):706-8 e1.

175. Chey WY, Jin HO, Lee MH, Sun SW, Lee KY. Colonic motility abnormality in patients with irritable

bowel syndrome exhibiting abdominal pain and diarrhea. Am J Gastroenterol. 2001 May;96(5):1499-506.

176. Simren M, Abrahamsson H, Bjornsson ES. Lipid-induced colonic hypersensitivity in the irritable

bowel syndrome: the role of bowel habit, sex, and psychologic factors. Clin Gastroenterol Hepatol. 2007

Feb;5(2):201-8.

177. Agrawal A, Whorwell PJ. Review article: abdominal bloating and distension in functional

gastrointestinal disorders--epidemiology and exploration of possible mechanisms. Aliment Pharmacol

Ther. 2008 Jan 1;27(1):2-10.

178. Barrett JS, Gearry RB, Muir JG, Irving PM, Rose R, Rosella O, et al. Dietary poorly absorbed,

short-chain carbohydrates increase delivery of water and fermentable substrates to the proximal colon.

Aliment Pharmacol Ther. 2010 Apr;31(8):874-82.

179. Bijkerk CJ, de Wit NJ, Muris JW, Whorwell PJ, Knottnerus JA, Hoes AW. Soluble or insoluble fibre

in irritable bowel syndrome in primary care? Randomised placebo controlled trial. BMJ. 2009;339:b3154.

180. Miller V, Lea R, Agrawal A, Whorwell PJ. Bran and irritable bowel syndrome: the primary-care

perspective. Dig Liver Dis. 2006 Oct;38(10):737-40.

181. Verdu EF. Editorial: Can gluten contribute to irritable bowel syndrome? The American journal of

gastroenterology. 2011 2011;106(3):516-8.

182. Biesiekierski JR, Newnham ED, Irving PM, Barrett JS, Haines M, Doecke JD, et al. Gluten causes

gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-

Page 82: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

82

controlled trial. The American journal of gastroenterology. 2011 2011 Mar (Epub 2011 Jan;106(3):508-14;

quiz 15.

183. Foundation TG. Understanding Lactose Intolerance. In: Foundation TG, editor.2002.

184. Adeyemo MA, Chang L. New treatments for irritable bowel syndrome in women. Women's

health (London, England). 2008 2008-Nov;4(6):605-23.

185. Simren M, Abrahamsson H, Bjornsson ES. An exaggerated sensory component of the

gastrocolonic response in patients with irritable bowel syndrome. Gut. 2001 Jan;48(1):20-7.

186. Simren M, Agerforz P, Bjornsson ES, Abrahamsson H. Nutrient-dependent enhancement of

rectal sensitivity in irritable bowel syndrome (IBS). Neurogastroenterol Motil. 2007 Jan;19(1):20-9.

187. Ong DK, Mitchell SB, Barrett JS, Shepherd SJ, Irving PM, Biesiekierski JR, et al. Manipulation of

dietary short chain carbohydrates alters the pattern of gas production and genesis of symptoms in

irritable bowel syndrome. J Gastroenterol Hepatol. 2010 Aug;25(8):1366-73.

188. Shepherd SJ, Gibson PR. Fructose malabsorption and symptoms of irritable bowel syndrome:

guidelines for effective dietary management. J Am Diet Assoc. 2006 Oct;106(10):1631-9.

189. Shepherd SJ, Parker FC, Muir JG, Gibson PR. Dietary triggers of abdominal symptoms in patients

with irritable bowel syndrome: randomized placebo-controlled evidence. Clin Gastroenterol Hepatol.

2008 Jul;6(7):765-71.

190. Barrett JS, Irving PM, Shepherd SJ, Muir JG, Gibson PR. Comparison of the prevalence of fructose

and lactose malabsorption across chronic intestinal disorders. Aliment Pharmacol Ther. 2009 Jul

1;30(2):165-74.

191. Skoog SM, Bharucha AE, Zinsmeister AR. Comparison of breath testing with fructose and high

fructose corn syrups in health and IBS. Neurogastroenterology and motility : the official journal of the

European Gastrointestinal Motility Society. [Comparative Study; ; Randomized Controlled Trial; Research

Page 83: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

83

Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't]. 2008 2008 May (Epub 2008

Jan;20(5):505-11.

192. Holton KF, Taren DL, Thomson CA, Bennett RM, Jones KD. The effect of dietary glutamate on

fibromyalgia and irritable bowel symptoms. Clin Exp Rheumatol. 2012 Jul 4.

193. Oettle GJ. Effect of moderate exercise on bowel habit. Gut. 1991 Aug;32(8):941-4.

194. Villoria A, Serra J, Azpiroz F, Malagelada JR. Physical activity and intestinal gas clearance in

patients with bloating. Am J Gastroenterol. 2006 Nov;101(11):2552-7.

195. De Schryver AM, Keulemans YC, Peters HP, Akkermans LM, Smout AJ, De Vries WR, et al. Effects

of regular physical activity on defecation pattern in middle-aged patients complaining of chronic

constipation. Scand J Gastroenterol. 2005 Apr;40(4):422-9.

196. Lustyk MK, Jarrett ME, Bennett JC, Heitkemper MM. Does a physically active lifestyle improve

symptoms in women with irritable bowel syndrome? Gastroenterol Nurs. 2001 May-Jun;24(3):129-37.

197. Johannesson E, Simren M, Strid H, Bajor A, Sadik R. Physical activity improves symptoms in

irritable bowel syndrome: a randomized controlled trial. Am J Gastroenterol. 2011 May;106(5):915-22.

198. Moses FM. The effect of exercise on the gastrointestinal tract. Sports Med. 1990 Mar;9(3):159-

72.

Page 84: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

84

Appendix II: Rome Criteria III Rome Foundation

Diagnostic criterion* for Irritable Bowel Syndrome:

Recurrent abdominal pain or discomfort**at least 3 days/month in the last 3 months associated

with two or more of the following:

1. Improvement with defecation

2. Onset associated with a change in stool frequency

3. Onset associated with a change in stool form (appearance)

*Criterion fulfilled for the last 3 months with symptom onset at least 6 months prior to

diagnosis

**  ‘Discomfort’  means  an  uncomfortable  sensation  not  described  as  pain.

In pathophysiology research and clinical trials, a pain/discomfort frequency of at least 2 days a

week during screening evaluation is recommended for subject eligibility.

Reference: Rome Foundation. Rome III Diagnostic Criteria for Functional Gastrointestinal Disorders; 2006. (Also available from: http://www.romecriteria.org/assets/pdf/19_RomeIII_apA_885-898.pdf), accessed on 25 October 2012

Page 85: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

85

Appendix III: Questionnaire

Page 86: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

86

Page 87: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

87

Page 88: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

88

Page 89: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

89

Page 90: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

90

Page 91: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

91

Page 92: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

92

Page 93: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

93

Page 94: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

94

Page 95: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

95

Page 96: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

96

Page 97: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

97

Page 98: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

98

Page 99: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

99

Page 100: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

100

Page 101: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

101

Page 102: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

102

Page 103: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

103

Page 104: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

104

Page 105: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

105

Page 106: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

106

Page 107: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

107

Page 108: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

108

Page 109: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

109

Appendix IV: Year of Initial RPAH Allergy Unit Patient Visit

Figure. A1. Time period between initial RPAH visit and current survey of patients with gastrointestinal symptoms.

1 0 2 2

8

2 3 6

16

10

25

67

26

0

10

20

30

40

50

60

70

80

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

No.

of P

atie

nts

Years

Page 110: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

110

Appendix V: Ranked Relaxation Therapies

Figure. A2. Ranked relaxation therapies by patients in relation to gastrointestinal symptom improvements.

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Therapy 1 (n= 47)

Therapy 2 (n= 33)

Therapy 3 (n=27)

Perc

ent o

f Pat

ient

s

Ranked Relaxation Therapy

Exercise

Diet

Meditation

Deep Breathing

Positive Thinking

Delegation

Talking to friends

Relaxation

Time Alone

Page 111: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

111

Appendix VI: Probiotics, Prebiotics and Fermented Foods Table A1. Common Probiotics, Prebiotics and Fermented Foods utilised by participants for relief of gastrointestinal symptoms and efficacy. Product Trialed Effective Still

Using Still

Benefitting

Prob

iotic

s†

Inner Health Plus 54 14 7 5 IBS Support 26 8 4 2 Symbiotique 0 1 0 0 Lactobacillus 14 6 4 4 Bifidobacteria 8 5 4 4 Vaalia Innergy yoghurt 7 3 2 1 Danone Activia yoghurt 11 5 4 2 SKI Activ yoghurt 12 4 5 2 Yakult 30 6 6 2

Prebiotic†

EcoBloom 6 3 3 2

Ferm

ente

d Fo

ods‡

Yoghurt 48 16 17 10 Kefir 5 0 2 0 Kimchi 5 0 0 0 Kombucha 1 1 0 0 Miso 8 1 2 0 Umeboshi 0 0 0 0 Sauerkraut 3 1 0 0 Tempeh 3 0 0 0 Pickles (including Carrots/Beets)

7 1 0 0

Pickled Ginger 9 2 0 0

For the treatment of gastrointestinal symptoms number of patients responded to the questions on the use   of   Probiotics†   and   Prebiotics†   is   97 in total. Number of patients responded to questions of Fermented  Foods‡  is  63.

Page 112: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

112

Appendix VII: Exercise Efficacy Ranking

Figure A3. Ranked exercise types by patients for symptomatic relief of gastrointestinal symptoms.

0

10

20

30

40

50

60

70

Exercise 1 Exercise 2 Exercise 3

Num

ber o

f Pat

ient

s

Exercise Rank

Walking

Other

Yoga

Swimming

Running

Pilates

Gym

Page 113: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

113

Appendix VIII: RPAH Elimination Diet Challenge Reactions (Compound Effects on Symptoms)

Figure A4. Symptoms experienced by patients reacting to chemical compounds.

0 5

10 15 20 25 30

No.

of P

atie

nts

Milk

0 5

10 15 20 25

No.

of P

atie

nts

Wheat

0 5

10 15 20 25

No.

of P

atie

nts

Gluten

0 5

10 15 20 25

No.

of P

atie

nts

Salicylates

0 5

10 15 20 25

No.

of P

atie

nts

Amines

0

5

10

15

20

No.

of P

atie

nts

Glutamates/MSG

Page 114: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

114

Figure A4. Symptoms experienced by patients reacting to chemical compounds.

0

5

10

15

20

No.

of P

atie

nts

Additives

0

5

10

15

20

No.

of P

atie

nts

Preservatives

0 1 2 3 4 5 6

No.

of P

atie

nts

Benzoates

0 2 4 6 8

10 12

No.

of P

atie

nts

Nitrates

0 1 2 3 4 5 6

No.

of P

atie

nts

Propionates

0 1 2 3 4 5

No.

of P

atie

nts

Sorbates

Page 115: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

115

Figure A4. Symptoms experienced by patients reacting to chemical compounds.

0 2 4 6 8

10 12

No.

of P

atie

nts

Sulfites

0 0.5

1 1.5

2 2.5

3 3.5

4 4.5

No.

of P

atie

nts

Antioxidants

0 2 4 6 8

10 12 14

No.

of P

atie

nts

Artificial Colours

0 1 2 3 4 5 6 7

No.

of P

atie

nts

Colour 160b

0

5

10

15

20

No.

of P

atie

nts

Lactose

Page 116: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

116

Appendix IX: RPAH Elimination Diet Challenge Reactions (Symptoms Affected by Compounds) Figure A5. RPAH Elimination Diet challenges causing symptoms in patients reacting to chemical compounds.

0 2 4 6 8

10 12 14 16

No.

of P

atie

nts

Nausea/Vomiting

0 2 4 6 8

10 12 14 16

No.

of P

atie

nts

Indigestion/Reflux

0

5

10

15

20

25

No.

of P

atie

nts

Wind/Bloating

0

5

10

15

20

25

No.

of P

atie

nts

Stomach Pain/Cramp

0 5

10 15 20 25 30

No.

of P

atie

nts

Diarrhoea/Constipation

0 1 2 3 4 5 6 7

No.

of P

atie

nts

Mouth Ulcers

Page 117: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

117

Figure A5. RPAH Elimination Diet challenges causing symptoms in patients reacting to chemical compounds.

0 2 4 6 8

10 12

No.

of P

atie

nts

Hives/Swelling

0 1 2 3 4 5 6

No.

of P

atie

nts

Eczema

0

5

10

15

20

No.

of P

atie

nts

Headache/Migraine

0

5

10

15

20 N

o. o

f Pat

ient

s

Fatigue

0

5

10

15

No.

of P

atie

nts

Muscle/Joint Ache

0

5

10

15

No.

of P

atie

nts

Sinus Problems

Page 118: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

118

Figure A5. RPAH Elimination Diet challenges causing symptoms in patients reacting to chemical compounds.

0 1 2 3 4 5 6 7 8

No.

of P

atie

nts

Bladder/Vaginal

0 2 4 6 8

10 12

No.

of P

atie

nts

Other

Page 119: Patient Reported Effects of Treatments for Irritable Bowel ... · Irritable bowel syndrome (IBS) is the most common gastrointestinal disorder worldwide affecting 10-20% of the adult

119

Appendix X: Patient Efficacy Ranking

Figure. A3. Patient reported efficacy of trialed therapies in relation to gastrointestinal symptoms.

47.2

17.9

7.3 6.5 4.9 4.1

2.4 2.4 1.6 1.6 0.8 0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

40.0

45.0

50.0

Perc

ent o

f Pat

ient

Therapy