The global impact of IBS: time to think about IBS-specific models of care?

Abstract

Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal (GI) disorder that can significantly erode the quality of life (QoL) of sufferers and places a major cost burden on healthcare services. This paper reviews the literature on the impact of IBS on healthcare services and society, including a recent report on the subject, in order to formulate a plan for the future. A completely different model of care for these patients is recommended based on this review and the experience of the two authors who have been treating patients with functional GI disorders for 20 and 35 years, respectively.

Keywords

burden IBS model of care

Introduction

Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder characterised by the presence of recurrent abdominal pain in association with abnormalities in stool frequency and form.¹ The prevalence of IBS is approximately 10% in Western countries and, due to its chronic relapsing course, up to 50% of patients consult a physician for these symptoms.² Early studies have suggested a low prevalence of IBS in developing countries, but more recent research has shown an increasing prevalence in newly developed and developing economies as they become more ‘westernised.’ IBS is more common in females and people of working age.^1,3

According to the predominant bowel habit, defined by stool consistency and form, IBS patients are divided into subgroups which include IBS with diarrhoea (IBS-D), with constipation (IBS-C) and with mixed diarrhoea and constipation (IBS-M).¹ The World Gastroenterology Organisation has reported that up to one-third of cases are IBS-C, one third are IBS-D and a third to a half of cases are IBS-M.⁴

The pathogenesis of IBS is still unclear but several mechanisms have been implicated in the pathophysiology of symptoms. These include altered GI motility, increased visceral sensitivity, abnormal processing of visceral sensations by the central nervous system, psychological abnormalities, altered mucosal immune activation and, more recently, increased intestinal permeability or an altered gut flora.⁵

A recent study evaluated the behaviour of IBS symptoms, using diaries over a 21-day period while patients were not on any treatment. The results showed that in the majority of Rome III-defined patients with moderate severity (according to an IBS severity score), symptoms were episodic.⁶ Abdominal pain was present for about half of the days and substantially overlapped with bloating episodes. The average duration of pain episodes was 3.1 days and bloating episodes was 3.5 days. The average duration of diarrhoea episodes was 2.1 days while that of constipation was 4.5 days. When pain, constipation and diarrhoea are collectively taken into account, IBS symptom episodes occur for nearly two-thirds (62.9%) of the time and patients with IBS-C have the highest proportion of days with symptoms. They also have a greater proportion of total days with pain compared with IBS-D patients. In IBS-D there is a more clear cut association between pain and occurrence of diarrhoea. This suggests a possible pathophysiological link between the gut dysfunction and the symptom. However, this seems less clear in IBS-C but pain could be related to the absence of bowel movements resulting from either increased non-propulsive or reduced motor activity. The bowel habit appears to be more stable in IBS-C than IBS-D patients,⁶ who complain of unpredictability of bowel movements⁷ as well as experiencing urgency more often (76.9%) than patients with IBS-C (34.7%).⁸

It has been suggested that with regard to severity of IBS, 40% of individuals are mild, 35% are moderate and the remaining 25% are severe.⁹ Severity of IBS is determined by symptom reports and behaviours rather than by blood tests or histopathological markers. It is currently best defined as a “biopsychosocial composite of patient-reported GI and extra-intestinal symptoms, degree of disability, and illness related perceptions and behaviours”. Considering the complexities involved in defining severity and the subjectivity of patient reporting, this parameter is difficult to measure and currently there is no universal consensus on what constitutes mild, moderate or severe symptoms. However, a simple and frequently used tool to assess IBS severity is represented by the IBS symptom severity score (IBS-SSS).¹⁰

The treatment of patients with IBS, regardless of predominant bowel habit, normally starts with reassurance, education about the disorder and dietary or lifestyle advice, with the important aim of creating a good doctor–patient relationship.¹ Pharmacological treatment of IBS has traditionally involved combining drugs acting on pain (antispasmodics) with those active on either constipation (laxatives) or diarrhoea (loperamide).¹ Antidepressants are used for those not responding to initial therapy.¹ More recently, new drugs treating both pain and an altered bowel habit have been approved such as linaclotide for IBS-C and eluxadoline for IBS-D.¹

A recent report facilitated by a pharmaceutical company and co-authored by one of the authors of the current review, states that IBS represents a major burden for healthcare services and society mainly because its management is far from ideal.¹¹ The current review aims to summarise and critically review the relevant aspects emerging from this report, as well as other literature, to suggest a possible model of care for these patients in line with the experience of the two authors who have been treating functional GI patients for 20 and 35 years, respectively.

The burden of IBS on healthcare systems

As highlighted in one of the most complete reviews on this subject, differences in how healthcare systems are organised and financed are likely to lead to variation in the number of people with IBS choosing to consult and who they consult.¹² Moreover, some patients may choose to self-fund a physician visit and the price difference may affect who they choose to consult and how much further healthcare they utilise. However, the trends in utilisation remain broadly similar across most countries.¹²

It has been reported that only up to 50% of IBS patients seek medical advice¹² and the majority of these consultations (90%) are with a general practitioner (GP).¹² It is also known that about one in 20 patients seen by GPs have a functional bowel disorder with IBS being the most frequent condition they see.¹³ IBS patients have been reported to repetitively consult their GP and this can be as much as 10 times before or even after the first specialist consultation in the UK.¹⁴ A third of patients are referred to secondary care and when this takes place two-thirds of cases are referred to a physician and the remainder to a surgeon.¹⁵ IBS accounts for up to 50% of consultations with gastroenterologists.¹⁶ Patients with a formal diagnosis of IBS have been reported to have an increased number of consultations per year, both in primary and secondary care, as compared with patients without this diagnosis (8.6–9.0 versus 4.6).¹⁷ Up to 85% of IBS patients undergo an investigation, with the most frequent being an abdominal ultrasound (approximately half) and a colonoscopy (approximately one-third).¹² Moreover, they have more visits to the emergency room and episodes of hospitalisation compared with those without IBS¹² and receive twice as many appendectomies or hysterectomies, and two to three times as many cholecystectomies.^18,19

Overall, primary care visits account for up to 30% of the total direct healthcare costs for patients with IBS, while inpatient care accounts for another 25–30%.¹² Furthermore, as these patients use a variety of medications, either over-the-counter or prescribed, these costs need to be added to those of the healthcare system. These patients also use other approaches such as complementary therapies which add to the cost of IBS to the patient themselves. Obviously, the costs of prescribed medications are more easily estimated and it has been shown that between 33–91% of IBS patients receive at least one and on average three to seven prescriptions a year.¹² As compared with people without IBS, this represents two or three more prescriptions over a year, with antispasmodics and laxatives being the most frequently prescribed.¹²

In a study looking at resource utilisation across six European countries (France, Germany, Italy, Spain, Sweden and the UK) in patients with IBS-C, it was observed that the mean annual direct cost of IBS was 1363 Euros per patient. This includes the cost of medication, diagnostic tests, hospitalisations, medical consultations with specialists and nurses, and medical consultations with general/family doctors.²⁰ In the UK it has been calculated that IBS accounts for about 0.1% of the total National Health Service cost.¹² Interestingly, it is estimated that the total cost (direct and indirect) of IBS is comparable to that of other long-term diseases with a similar prevalence, such as asthma, migraine, hypertension or congestive heart failure.²¹

The burden of IBS on society

Calculating the burden to society means evaluating the impact this condition has on the welfare of the whole of society, including education, social services and industry.¹² With regard to the latter, the effect of an illness is considered in terms of loss of productivity within the workplace, either as absenteeism or presenteeism.¹² Presenteeism is assessed by asking people how much of the time while at work they feel they are not performing at their best as a result of their illness.¹² It is a difficult parameter to measure as it is subjective and is dependent on how an individual interprets this question.¹²

There have been relatively few studies dealing with the cost that IBS represents to society but from the data available it appears that patients with IBS are twice as likely to take time off work as those without (absenteeism) and also have high rates of presenteeism and impairment in performing daily activities regardless of IBS subtype.^17,22

In the UK and US, patients with IBS take an average of between 8.5 and 21.6 days off work in a year.²³ It has been estimated that absenteeism and presenteeism due to IBS amounts to an annual loss per patient of $748 in Canada (1996),²⁴ US$335 in UK²⁵ and $812 in Iran.²⁶ In 2005, a US banking organisation calculated that their total productivity loss attributable to IBS was $7737 per patient annually irrespective of bowel habit subtype.²⁷ In Denmark, the median annual cost due to absenteeism was $1508 per IBS patient.²⁸

Looking at factors influencing work impairment, the severity of IBS has been found to be a significant predictor of the proportion of work and activity impairment, overall work impairment and missed work time.²⁹ Interestingly, time off work and work impairment for IBS seems to be greater than for ‘legitimate’ diseases such as asthma or psychiatric disorders such as social phobia.²¹ However, it has been reported that in only 60% of cases do employers recognize this as a valid reason for absence.³⁰

Also to be considered as costs to society are those related to those caring for or living with people with IBS. It has been reported that the burden on these individuals is comparable to that of partners of people with dementia and greater than that of carers of terminal cancer patients.³¹

The burden of IBS on patient quality of life

Quality of life (QoL) is usually measured by questionnaires which normally incorporate the emotional, social and physical dimensions of the life of an individual. For research purposes, this can be recorded in a variety of ways such as a score from very poor to excellent or even in terms of the degree to which a patient might trade life expectancy in order to improve their health. QoL can be measured using generic instruments generalised to all conditions or disease specific instruments such as those designed specifically for IBS.¹² European and North American IBS studies have shown relatively consistent reductions in overall mean patient-reported QoL scores (e.g. EQ-5D rating scale) versus the general population.¹² However, the degree of IBS impact on QoL components may differ between IBS populations in different countries. Therefore, the full understanding of the impact of IBS on QoL is difficult to determine. For example, IBS patients from Mexico reported significantly lower scores on ‘body image’ and ‘health worry,’ and a substantial ‘interference with activities’ in the overall score compared with patients from North Carolina, USA.³²

Symptom severity, especially in relation to bowel function or abdominal pain, has been shown to have the most important effect on reducing QoL in IBS.^33,34 Patients with IBS report uncertainty and unpredictability, with loss of freedom, spontaneity, social contacts, and feelings of fearfulness, shame and embarrassment. Psychological symptoms have an additive effect on reducing QoL.³³ Moreover, the lack of understanding by family, friends, and physicians of the effects of the disorder on the individual and the reality of their emotions and adaptive behaviours further complicates the life of these patients.³⁴ A US survey (n = 350) found that two-thirds of respondents reported missing an average of over 10 activities or social events over a three month period due to IBS, equivalent to one activity per week.³⁵

A study of 243 Rome III-diagnosed patients that evaluated IBS-specific QoL using the IBS-QoL questionnaire suggested that IBS-D and IBS-M patients have lower IBS-QoL than IBS-C patients.³⁶ Indeed, they reported more interference with daily activities and food avoidance than patients with IBS-C. In contrast, different IBS subtypes did not differ in the remaining subscales: dysphoria, health worries, sexual health and body image.

Interestingly, European and North American IBS studies have demonstrated that the reduction in overall mean EQ-5D scores (0.62–0.75) is similar to those observed in other organic GI disorders, such as inflammatory bowel disease (IBD) (0.77–0.92), coeliac disease (0.82–0.84) and potentially treatable colorectal cancer (0.76–0.85).¹²

An aspect almost never considered, is the impact on IBS patients of out-of-pocket costs, loss of earnings and the effect on their partner or relatives.¹² As already reported above, IBS patients frequently use over-the-counter medications, complementary medicine or choose to pay for private consultations and these costs have never been assessed. Furthermore, the costs of absenteeism have always been considered from the perspective of the employer but not as loss of earnings for patients, who have even been reported to completely stop work in about 12% of cases.¹² Indeed, the burden of IBS extends beyond patients to family members, friends and carers. Studies have demonstrated that QoL can be lower in partners than the patients themselves and IBS partners report higher burden scores than partners of healthy controls.³¹ Many partners say they have not gone on holiday for many years or not even gone out to a restaurant. Once again, higher IBS illness severity is seen to be associated with higher partner burden. When it comes to relationships about one-third of IBS partners believed that IBS frequently interfered with their sexual relationship.³¹ This correlated with the partner’s perception that patients use IBS as an excuse to avoid sex. In a study evaluating sexual function in IBS women as compared with IBD and patients with duodenal ulcer, it has been demonstrated that, excluding psychiatric comorbidities, 77% of IBS patients report sexual dysfunction as compared with 29% of IBD and 14% of patients with ulcers.³⁷

To illustrate the impact of IBS on patients, it is worth noting that 13.5% of patients would be willing to accept at least a 1/1000 chance of death and 10.1% would accept at least a 1/1000 risk of serious or permanent side effects from a medication to achieve perfect health. Those with the greatest degree of IBS severity were those that were most likely to accept risk.³⁸ In secondary and tertiary care, IBS is also associated with a significant risk of suicide which is unrelated to any co-existent depression.³⁹

Conclusions concerning the global impact of IBS and limitations of the current literature

Looking at these data, it is clear that in terms of burden for the healthcare system most of the costs are driven by repetitive GP consultations or emergency care and inpatient stays. There are also the costs of unnecessary investigations as well as many hidden costs related to the use of other medications and complementary treatments. The latter increase the costs for patients but, if reimbursed, add to the costs to the healthcare system.

In terms of the burden on society, these patients represent a cost as a result of being off work more frequently than colleagues without a functional GI disorder and even those with organic diseases with a similar prevalence in the population. Presenteeism and reduced work productivity can also add to the costs of disease but currently there are no reliable estimates of this in relation to IBS. In addition, better instruments for capturing these issues need to be developed.

From the above, it is clear that the total burden of IBS on the patient, their partners, their relatives and society has not yet been fully evaluated, although it is already apparent that it is just as bad as that of organic disease. We still need more information on absenteeism and presenteeism in IBS patients and whether attendance and productivity at work is also affected in their partners and relatives. These issues could indicate a cost to society that, to date, has been completely ignored.

It is important to underline that this picture of the global impact of IBS is based on relatively few, mostly retrospective, studies frequently with methodological issues. The current gaps in the literature need to be filled with high quality studies.

However, in the meantime, is there anything we can do?

Let us try to put IBS into the context of real world clinical practice

The diagnosis of IBS relies on criteria developed by experts in the field which are called the Rome criteria.¹ They have now reached a fourth edition and are currently primarily used to identify IBS patients for clinical trials and have been frequently perceived as too difficult to apply in clinical practice.¹ Moreover, the recently released Rome IV criteria have been criticised as found to be more restrictive than the Rome III ones. Applying these criteria, indeed, the prevalence of IBS is reported as 5.7% compared with 10.7% using Rome III.⁴⁰ Does this mean that 50% of those patients diagnosed with IBS by the Rome III method do not now have IBS? Of course not. This difference was brought about by the apparently minor change of requiring pain three times a month for Rome III compared with once a week for Rome IV.⁴⁰ In contrast the elimination of discomfort from the criteria and the requirement that changes in the frequency or consistency of stools need to be temporally related with abdominal pain but not necessarily follow it, did not contribute significantly to the reduction in prevalence of IBS from Rome III to Rome IV.⁴⁰ It is, therefore, possible that Rome IV criteria identify patients with more severe and frequent symptoms and future studies will have to clarify this aspect.⁴⁰ However, for the time being, it would be probably best to use the Rome IV criteria, especially as they have been shown to have very good specificity.⁴⁰ They are still somewhat cumbersome to use but this should soon be overcome by internet aides that are being developed to be available at the point of care.⁴⁰ In any case, it should be noted that these criteria in general do actually reflect how clinicians identify these patients. The presence of chronic symptoms for >6 months of abdominal pain, relieved or related to defaecation, and associated with changes in stool consistency strongly raise the possibility of IBS. If this is then associated with negative results from limited investigations, often with the observation that symptoms can worsen with stress, the diagnosis can be made with some confidence. In a recent study it has been shown that a combination of the absence of nocturnal defaecation, a high somatisation score on the Patient Health Questionnaire-12 (PHQ-12), a normal haemoglobin and a normal C-reactive protein (CRP) results in a positive likelihood ratio of 7–17 and a specificity for symptom-based Rome III criteria for IBS of ⩾95%.⁴¹ Once the diagnosis is clear then these patients can be treated according to ‘guidelines’ using evidence-based treatments suggested by the Rome IV committee.¹

But, if this is so simple, where is the problem?

First-line physicians working in busy, pressured clinical practice need to know exactly which tests are necessary and which are superfluous in a patient in whom they suspect IBS. In addition, they need to know in what order to introduce treatment options, bearing in mind that availability of some medications varies considerably between countries. Another critical decision is when to refer patients to secondary care. This is likely to be a general gastroenterologist and, in an ideal world, there should also be available a gastroenterologist specialising in functional GI disorders to whom more challenging patients can be referred for further treatment and possibly more specialised investigation.

Based on the experience of the two co-authors of the present review, taking into account the Rome criteria and what is feasible in the real world clinical practice of GPs, at least in Europe, first-line screening should include: a full blood count, CRP, liver function tests, electrolytes, ferritin, thyroid-stimulating hormone and a coeliac screen. A stool sample for faecal calprotectin is advisable in any situation where there is a possibility of IBD and stool analysis for an infective or parasitic cause should be considered when appropriate. In patients with rectal bleeding or who are over the age of 50, or in whom there is a suspicion of colonic malignancy, referral for appropriate investigation is mandatory. Following negative screening, GPs could start a first-line treatment based on reassurance, education about the disorder and lifestyle advice. Simple and practical dietary advice as suggested by the UK Dietitian Association⁴² is nearly always useful and pharmacological treatment should be considered if necessary. The latter could be an antispasmodic, possibly associated with a laxative in IBS-C or with an anti-diarrhoea medication in IBS-D. Using an evidence-based approach, peppermint oil is worth considering and is also widely available in European countries.⁴³ Hyoscine is useful for episodes of acute pain and opiates should be avoided at all costs.⁴⁴ Availability of antispasmodics does vary across different countries but, where available, otilonium, pinaverium and cimetropium bromide can be used.⁴³ However, it should be remembered that the actual evidence on antispasmodics, although positive, is based on a rather poor quality literature.⁴³ In addition, we do not have any information about the effect of antispasmodics in different IBS subgroups.⁴³ With regard to laxatives, macrogol is the most cost-effective agent which has been shown to benefit constipation both in the short and long-term⁴³ but has not been shown to necessarily relieve abdominal pain.⁴³ Loperamide is the most frequently used medication for diarrhoea and there is some evidence of benefit in these patients, even though it does not relieve abdominal pain.⁴³ Duration of treatment depends upon the frequency and intensity of symptoms.⁴³ Consequently, ‘as necessary’ use of antispasmodics may be all that is required but when patients have continuous symptoms, more prolonged and regular treatment may be needed. Fortunately, antispasmodics are safe and, therefore, if long-term use is required this should not be a cause for concern. The response to treatment can be assessed by simply asking for a subjective evaluation by patients, however, or if a more objective assessment is felt important, the IBS-SSS provides this in a questionnaire which can be completed very quickly.¹⁰

This approach, combined with GP education (provision of teaching sessions as well as an IBS diagnosis and management algorithm supplied on a desktop app) has been recently demonstrated to be cost-effective and to reduce secondary care referral in the UK.⁴⁵

If this approach to treatment fails to bring about a satisfactory improvement, or if there is any diagnostic uncertainty, then referral to secondary care needs to be considered.

Time to think about IBS-specific models of care?

In recent years, there has been a strong trend towards sub-specialist care for individual conditions, such as IBD.⁴⁶ Patients with IBD are now managed by a team of people led by a gastroenterologist with specific expertise in the management of this condition. This multidisciplinary team will include specialist nurses, pharmacists, dieticians and, where necessary, dedicated surgeons. Indeed, it would be considered inappropriate these days for a gastroenterologist to manage these patients entirely on their own.

In contrast, there are no similar models of care for functional bowel disorders, despite IBS being 10 times as common as IBD.¹ There are guidelines on the management of IBS¹ but no information on how the overall care of these patients should be provided.

Experience in treating IBS patients suggests that they exhibit an even more complex pattern of disease than IBD and, so far, there are far less effective treatments.⁴⁷ In the absence of biological markers for functional GI disorders, it is necessary for the functional gastroenterologist to know which investigations are most appropriate, interpret the patient’s symptoms and decide on an appropriate course of management. Regrettably, there is a great shortage of functional gastroenterologists at present and we urgently need to develop ways of attracting suitable applicants to this sub-specialty. The modern gastroenterologist tends to be very ‘technical’ favouring an investigational and interventional approach to their specialty. This is partly due to the fact that this is what is required by the modern hospital in order to cope with the huge numbers of patients requiring endoscopic and related interventional techniques. However, 50% of the gastroenterologist’s workload consists of functional GI disorders and yet these conditions are given very little time in medical school training. If we are going to solve the problem of providing good care to patients with functional GI disorders the process has to start in medical schools where these conditions are given equal emphasis to other, what are currently considered, more ‘serious’ conditions. It is unlikely that a patient with IBS has ever featured in a final medical student examination and, therefore, students are unlikely to have knowledge of such conditions high on their agenda.

Over recent years there has been considerable progress in improving our understanding of the pathogenesis and pathophysiological mechanisms of functional GI disorders¹ and this has been assisted by the development of new ways of assessing gut function, such as high resolution manometry and magnetic resonance imaging^48,49 and, no doubt, further techniques will be forthcoming in the future. This has also been associated with important work on evidence-based assessment of the efficacy of the drugs used to treat these patients, which has helped to clarify their role in the management of IBS. It has also helped to identify gaps in our knowledge which need addressing.⁴⁷ Hopefully, this progress will result in internationally agreed guidelines on management as now seen in IBD and it is encouraging to see that the US Food and Drug Administration and European Medicines Agency are now gradually harmonising their approach to functional GI disorders which will reduce the confusion that surrounds these conditions for so many gastroenterologists and results in patients placing a huge burden on healthcare systems and society worldwide.

Given the large numbers of patients with GI disorders, in particular IBS, a case could be made for the creation of functional GI centres of excellence where the more severe forms of the condition could be referred. Such centres could also provide training programmes for functional gastroenterologists. This would allow more research to take place as well as the provision of more sophisticated investigation and the development of new investigational techniques and, hopefully, biological markers. The role of surgery in functional GI disorders remains very controversial and a centre of excellence where surgeons and functional gastroenterologists could work closely together would enable the role of surgery in these conditions to be far better defined. This could significantly reduce the burden of ‘surgical cripples’ who are currently seen in many tertiary care centres. Inappropriate surgery, and even investigation, can also result from the fact that patients with IBS and other functional GI disorders often complain of a range of non-colonic symptoms. These include constant tiredness, low backache, chest pain, urinary symptoms, as well as gynaecological symptoms.¹ If these symptoms are more prominent than the GI symptoms, the GP may refer the patient to the wrong speciality where interventions that are not necessary can take place.

Another advantage of functional GI centres would be the development of a model of care which includes collaboration with specialists who deal with functional disorders in other systems, such as fibromyalgia and pelvic pain. The psychological aspects of functional disorders rarely need the help of a psychiatrist but psychologists could play a pivotal role in care as well as helping to develop behavioural treatments which have been consistently shown to be effective in reducing symptoms. Lastly, such centres could even provide a ‘hub and spoke’ approach to treatment with specialist nurses rotating into general practices in order to try and treat patients early in the hope that they do not get into the secondary and tertiary care spiral.

For a variety of reasons, including revolutionary new treatments, the prevalence of some diseases is likely to dramatically decline in the future. If the medical workforce does not respond to this change it is possible that there could be a surplus of consultants in some specialties and deficiencies in others, especially those that are currently less popular. In gastroenterology, IBD is almost inevitably going to come under better control in the not-too-distant future and consequently, the burden of functional GI disorders is proportionately going to become greater and greater. It is, therefore, essential that steps are taken to try and make functional GI disorders, as well as functional disorders in other specialities, more attractive to young doctors. This will need a concerted effort from specialists and patient organisations to encourage better engagement in this area from medical schools, governments, medical charities and pharmaceutical companies.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare the following conflicts of interest. Maura Corsetti is a speaker for Shire and Menarini and is a consultant for Allergan.

Peter Whorwell has acted as a consultant for, or received research grant support from, the following pharmaceutical companies in the last 5 years: Almirall Pharma, Boehringer–Ingelheim, Chr. Hansen, Danone Research, Ironwood Pharmaceuticals, Salix, Shire UK, Sucampo Pharmaceuticals and Allergan.

References

Lacy

Mearin

Chey

et al . Bowel disorders. Gastroenterology. Epub ahead of print 18 February 2016. DOI: 10.1053/j.gastro.2016.02.031.

Cremonini

Talley

NJ.

Irritable bowel syndrome: epidemiology, natural history, health care seeking and emerging risk factors. Gastroenterol Clin North Am 2005; 34: 189–204.

Gwee

KA.

Irritable bowel syndrome in developing countries: a disorder of civilization or colonization?

Neurogastroenterol Motil 2005; 17: 317–324.

World Gastroenterology Organisation Global Guidelines. Irritable bowel syndrome: a global perspective. Updated September 2015, www.worldgastroenterology.org/guidelines/global-guidelines/irritable-bowel-syndrome-ibs/irritable-bowel-syndrome-ibs-english.

Camilleri

Lasch

Zhou

Irritable bowel syndrome: methods, mechanisms, and pathophysiology. The confluence of increased permeability, inflammation, and pain in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 2012; 303: G775– G785.

Palsson

Baggish

Whitehead

WE.

Episodic nature of symptoms in irritable bowel syndrome. Am J Gastroenterol 2014; 109: 1450–1460.

Atarodi

Rafieian

Whorwell

PJ.

Faecal incontinence - the hidden scourge of irritable syndrome: a cross sectional study. BMJ Open Gastroenterology 2014; 1: 1–6.

Hellström

Saito

Bytzer

et al . Characteristics of acute pain attacks in patients with irritable bowel syndrome meeting Rome III criteria. Am J Gastroenterol 2011; 106: 1299–1307.

Drossman

Chang

Bellamy

et al . Severity in irritable bowel syndrome: a Rome Foundation Working Team report. Am J Gastroenterol 2011; 106: 1749–1759.

10.

Francis

Morris

Whorwell

PJ.

The irritable bowel severity scoring system: a simple method of monitoring irritable bowel syndrome and its progress. Aliment Pharmacol Ther 1997; 11: 395–402.

11.

IBS Global Impact Report. ISBN: 978-0-9956022-0-5, https://allergan-web-cdn-prod.azureedge.net/allerganuk/allerganukzinc/media/allergan-uk/uk_global_ibs_impact_report.pdf (2016, accessed February 2017).

12.

Canavan

West

Card

Review article: the economic impact of the irritable bowel syndrome. Aliment Pharmacol Ther 2014; 40: 1023–1034.

13.

Talley

NJ.

Functional gastrointestinal disorders as a public health problem. Neurogastroenterol Motil 2008; 20: 121–129.

14.

Canavan

West

Card

Calculating total health service utilisation and costs from routinely collected electronic health records using the example of patients with irritable bowel syndrome before and after their first gastroenterology appointment. Pharmacoeconomics 2016; 34: 181–194.

15.

Spiller

Aziz

Creed

et al . Guidelines on the irritable bowel syndrome: mechanisms and practical management. Gut 2007; 56: 1770–1798.

16.

Gunn

Cavin

Mansfield

JC.

Management of irritable bowel syndrome. Postgrad Med J 2003; 79: 154–158.

17.

Allergan data on file INT/0567/2016b. Prepared October 2016, www.allergan.com.

18.

Hungin

APS

Whorwell

Tack

et al . The prevalence, patterns and impact of irritable bowel syndrome: an international survey of 40 000 subjects. Aliment Pharmacol Ther 2003; 17: 643–650.

19.

Longstreth

Yao

JF.

Irritable bowel syndrome and surgery: a multivariable analysis. Gastroenterology 2004; 126: 1665–1673.

20.

Coffin

Follet

Mackinnon

et al . The burden of moderate-to-severe irritable bowel syndrome with constipation (Ibs-C) In France: a comparison with the European results from the Ibis-C observational study. Value Health 2015; 18: A632.

21.

Cash

Sullivan

Barghout

Total costs of IBS: employer and managed care perspective. Am J Manag Care 2005; 11: S7–S16.

22.

Sayuk

Wolf

Chang

Comparison of symptoms, healthcare utilization, and treatment in diagnosed and undiagnosed individuals with diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol. Epub ahead of print 17 January 2017. DOI: 10.1038/ajg.2016.574.

23.

Maxion-Bergemann

Thielecke

Abel

et al . Costs of irritable bowel syndrome in the UK and US. Pharmacoeconomics 2006; 24: 21–37.

24.

Bentkover

Field

Greene

et al . The economic burden of irritable bowel syndrome in Canada. Can J Gastroenterol 1999; 13(Suppl. A): 89A–96A.

25.

Creed

Ratcliffe

Fernandez

et al . Health-related quality of life and health care costs in severe, refractory irritable bowel syndrome. Ann Intern Med 2001; 134: 860–881.

26.

Roshandel

Rezailashkajani

Shafaee

et al . A cost analysis of functional bowel disorders in Iran. Int J Colorectal Dis 2007; 22: 791–799.

27.

Dean

Aquilar

Barghout

et al . Impairment in work productivity and health-related quality of life in patients with IBS. Am J Manag Care 2005; 11: 17–26.

28.

Begtrup

Engsbro

Kjeldsen

et al . A positive diagnostic strategy is noninferior to a strategy of exclusion for patients with irritable bowel syndrome. Clin Gastroenterol Hepatol 2013; 11: 956–962.

29.

Reilly

Bracco

Ricci

J-F

et al . The validity and accuracy of the Work Productivity and Activity Impairment questionnaire–irritable bowel syndrome version (WPAI:IBS). Aliment Pharmacol Ther 2004; 20: 459–467.

30.

Silk

DB.

Impact of irritable bowel syndrome on personal relationships and working practices. Eur J Gastroenterol Hepatol 2001; 13: 1327–1332.

31.

Wong

Drossman

Weinland

et al . Partner burden in irritable bowel syndrome. Clin Gastroenterol Hepatol 2013; 11: 151–155.

32.

Schmulson

Ortiz

Mejia-Arangure

et al . Further validation of the IBS-QOL: female Mexican IBS patients have poorer quality of life than females from North Carolina. Dig Dis Sci 2007; 52: 2950–2955.

33.

Lee

Guthrie

Robinson

et al . Functional bowel disorders in primary care: factors associated with health-related quality of life and doctor consultation. J Psychosom Res 2008; 64: 129–138.

34.

Drossman

Chang

Schneck

et al . A focus group assessment of patient perspectives on irritable bowel syndrome and illness severity. Dig Dis Sci 2009; 54: 1532–1541.

35.

Hulisz

The burden of illness of irritable bowel syndrome: current challenges and hope for the future. J Manag Care Pharm 2004; 10: 299–309.

36.

Singh

Staller

Barshop

et al . Patients with irritable bowel syndrome-diarrhea have lower disease-specific quality of life than irritable bowel syndrome-constipation. World J Gastroenterol 2015; 21: 8103–8109.

37.

Guthrie

Creed

Whorwell

PJ.

Severe sexual dysfunction in women with the irritable bowel syndrome: comparison with inflammatory bowel disease and duodenal ulceration. Br Med J (Clin Res Ed) 1987; 295: 577–578.

38.

Drossman

Morris

Schneck

et al . International survey of patients with IBS: symptom features and their severity, health status, treatments, and risk taking to achieve clinical benefit. J Clin Gastroenterol 2009; 43: 541–550.

39.

Miller

Hopkins

Whorwell

PJ.

Suicidal ideation in patients with Irritable Bowel Syndrome. Clinical Gastroenterol Hepatol 2004; 2: 1064–1068.

40.

Whitehead

Palsson

Simrén

Irritable bowel syndrome: what do the new Rome IV diagnostic guidelines mean for patient management?

Expert Rev Gastroenterol Hepatol 2017; 11: 281–283.

41.

Sood

Camilleri

Gracie

et al . Enhancing diagnostic performance of symptom-based criteria for irritable bowel syndrome by additional history and limited diagnostic evaluation. Am J Gastroenterol 2016; 111: 1446–1454.

42.

IBS Food Fact Sheet. The association of UK dietitians, www.bda.uk.com/foodfacts/IBSfoodfacts.pdf.

43.

Ford

Moayyedi

Lacy

et al . Task Force on the Management of Functional Bowel Disorders. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol 2014; 109(Suppl. 1): S2–S26.

44.

Pearson

Pollard

Whorwell

PJ.

Avoiding analgesic escalation and excessive healthcare utilization in severe irritable bowel syndrome: a role for intramuscular anticholinergics?

Therap Adv Gastroenterol 2014; 7: 232–237.

45.

Williams

Barclay

Benneyworth

et al . Using best practice to create a pathway to improve management of irritable bowel syndrome: aiming for timely diagnosis, effective treatment and equitable care. Frontline Gastroenterol 2016; 7: 323–330.

46.

Mowat

Cole

Windsor

et al . Guidelines for the management of inflammatory bowel disease in adults. Gut 2011; 60: 571–607.

47.

Corsetti

Whorwell

Novel pharmacological therapies for irritable bowel syndrome. Expert Rev Gastroenterol Hepatol 2016; 10: 807–815.

48.

Corsetti

Pagliaro

Demedts

et al . Pan-colonic pressurizations associated with relaxation of the anal sphincter in health and disease: a new colonic motor pattern identified using high-resolution manometry. Am J Gastroenterol. Epub ahead of print 6 September 2016. DOI: 10.1038/ajg.2016.341.

49.

Lam

Chaddock

Marciani Laurea

et al . Distinct abnormalities of small bowel and regional colonic volumes in subtypes of irritable bowel syndrome revealed by MRI. Am J Gastroenterol. Epub ahead of print 13 December 2016. DOI: 10.1038/ajg.2016.538.