Table of Contents  

Farmer and Ruffle: Irritable bowel syndrome

Introduction

Functional gastrointestinal disorders (FGIDs) are a heterogeneous group of disorders that include irritable bowel syndrome (IBS), functional dyspepsia and functional chest pain. FGIDs represent a considerable unmet need in modern gastroenterological practice, accounting for more than 40% of all new referrals to general gastroenterological outpatient clinics, although 83% of patients are managed in primary care.1,2 FGID can be defined as

variable combinations of chronic or recurrent gastrointestinal symptoms which are not explained by structural or biochemical abnormalities

Drossman DA. Rome III: the functional gastrointestinal disorders. 2006.3

Importantly, the processes that underpin the development and maintenance of symptoms in FGID remain incompletely understood. This unfortunately ties to a current paucity of efficacious treatments and inevitably results in symptom chronicity, patient anxiety and dissatisfaction, overinvestigation, recurrent consultations and significant morbidity. Therefore, it is not surprising that the socioeconomic impact is considerable through reduced health-related quality of life and increased absenteeism.4 Direct and indirect associated health care costs have been estimated to be in the order of $34 billion in the seven largest western health care economies.3,5 This review focuses on the epidemiology, aetiology, clinical features, differential diagnosis and clinical management of IBS.

Irritable bowel syndrome

Various terms including ‘nervous colitis’ and ‘spastic colon’ have been used in the past to describe the constellation of systems that are currently referred to as IBS. The contemporaneous understanding of IBS conceptualizes its pathophysiology, with aspects arising peripherally from the gut and centrally from the brain. Despite a considerable research effort affording to the identification of objective biomarkers, IBS remains a symptom-based diagnosis. The Rome Foundation, an international committee of experts, has sought to systematize the diagnosis of IBS with the aim of improving homogeneity within both the research and clinical sphere.6

Epidemiology

Irritable bowel syndrome affects approximately 5–20% of individuals worldwide.7,8 There is a paucity of studies examining the incidence of new cases of IBS, although one large United Kingdom-based study of 580 000 primary care patients reported 4 new cases per 1000 population per annum.9 The peak incidence is in 18- to 34-year-olds but declines with increasing age.2 Considering that the prevalence is around 25 times that of its incidence, IBS is often a lifelong condition and is associated with a significant diminution in work productivity and health-related quality of life.10 Furthermore, the prevalence of symptoms compatible with IBS varies significantly over time, and is convoluted by a strong geographical effect.11 For example, whilst prevalence is estimated at 12% in northern Europe and North America, IBS is nearly twice as common in South America (21%) and less common in southeast Asia (7%).12

Clinical features of irritable bowel syndrome

The characteristic clinical features of IBS are recurrent abdominal pain and/or discomfort, associated with an alteration in stool frequency or consistency and relief with defecation. In contrast to other causes of abdominal pain, pain in IBS is frequently relieved by defecation and is induced by eating, the latter presumably as a sequela of the gastrocolic reflex inducing colonic contractions.13 Extra-gastrointestinal (GI) features are also prevalent and include lassitude, headache, dysmenorrhoea and deep dyspareunia. Whilst symptoms characteristically wax and wane, patients typically report pain or discomfort approximately 3 days per week, which often occurs in clusters.14 IBS is currently subdivided based upon predominant bowel habit and is grouped as IBS with constipation (IBS-C), IBS with diarrhoea (IBS-D), IBS mixed (IBS-M) (with alternating bowel habit) and IBS unclassified (IBS-U) (Figure 1). Ford and Talley11 previously documented IBS-D to be the most common subtype, formulating a pooled prevalence of 40%, whilst IBS-M was the least common, encompassing 23%. Furthermore, IBS-C is significantly more common in women, whilst IBS-D is more common in men.11 The diagnostic criteria for IBS are proposed by the Rome working group (Table 1), which include symptoms of recurrent abdominal pain or discomfort associated with a marked change in bowel habit for at least 6 months, with symptoms experienced for at least 3 days a month for the past 3 months.3,15

FIGURE 1

The different subtypes of IBS are classified according to the predominant bowel habit: IBS-C, IBS-D, IBS-M and IBS-U.

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TABLE 1

The Rome III definition of IBS

Rome III criteria for the diagnosis of IBS
Recurrent abdominal pain or discomfort for at least 3 days a month in the past 3 months, associated with two or more of the following*:
  • Improvement with defecation

  • Onset associated with a change in frequency of stool

  • Onset associated with a change in form (appearance) of stool

* Criteria fulfilled for the past 3 months with symptom onset at least 6 months before diagnosis.

‘Discomfort’ means an uncomfortable sensation not described as pain.

Gut pain or discomfort is a central defining feature of IBS. Moreover, of the symptoms experienced, untreated chronic gut pain is the symptom most likely to prompt a patient to seek medical advice, although it is often the most difficult for the clinician to successfully treat.16 IBS accounts for between 40% and 60% of outpatient referral to the gastroenterology clinic17,18 and thus, with such a considerable burden of disease, the development of a complete understanding of the underlying pathophysiology of this complex disorder remains the prerequisite step on the road to the development of efficacious treatments.

Aetiology

Genetic influences

A number of studies have reported the clustering of IBS within families, thereby suggesting a degree of heritability.1921 Twin studies have shown the genetic heritability to range between 22% and 57%.22 The concordance rate for IBS among monozygotic compared with dizygotic twins is thought to be between 33% and 13%, respectively.19,2325 Nevertheless, despite the consistent observation of familial clustering differences and zygosity, such observations, in part, could potentially be accounted for by environmental factors such as social learning.26,27 To date, several candidate genes have been investigated in IBS, including the serotonin transporter SLC6A4, 5-hydroxytryptamine 2A (5-HT2A) receptor, noradrenaline transporter, alpha-2A and 2C adrenergic receptor, V-type voltage-gated sodium channels and various inflammatory genes such as interleukin-10 (IL-10), transforming growth factor-β1, tumour necrosis factor-alpha and the β3 subunit G protein.28 However, the results of candidate gene approach studies are often not reproduced in independent cohorts, which is often a consequence of underpowered small studies.

To combat the limitations of underpowered IBS genetic studies, large population-based genome-wide association studies (GWASs) represent one of the most exciting potential avenues for delineating the genetic factors that contribute to the development of IBS, although a prerequisite step is the further definition of the clinical phenotype based upon pathophysiological features rather than purely symptom-based criteria. Certain groups have made considerable progress in elucidating the genetic factors that influence disease development and severity by GWAS methodology. Numerous genetic factors affecting IBS symptomology (including colonic motility factors) have now been published, including genetics regarding post-infectious IBS (PI-IBS),29 endocannabinoid metabolism30 and local colonic immune function.31 As a recent example, a GWAS of more than 500 IBS cases (matched against almost 5000 healthy controls), published in 2014, revealed that a locus on chromosome 7 (7p22.1) was associated with consistent IBS risk effects.32 This locus includes the coding sequence for the KDEL endoplasmic reticulum protein retention receptor 2 (KDELR2) and glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein.32 There is a drive to fully elucidate both the genetics underpinning the pathophysiology and the pharmacogenetics of IBS to ascertain certain difficulties in its treatment.33 In order to address many of these shortcomings, a European collaboration has recently been set up to improve homogeneity in sampling and technical methods, from which it is hoped that significant progress will be made (GENes in Irritable Bowel Syndrome Research Network EURope, www.GENIEUR.eu).

Infection

Irritable bowel syndrome can also occur after an enteric infection; termed PI-IBS.34 Whilst the overwhelming majority of individuals who develop bacterial gastroenteritis have acute self-limiting symptoms, approximately 4–32% of patients develop IBS-like symptoms that outlast the initial infection. Interestingly, personality traits such as neuroticism have been shown as independent risk factors for symptom chronicity in these instances.35 IBS symptoms have been documented after infection with a variety of enteric pathogens, including Campylobacter, Salmonella and Shigella strains and Escherichia coli.36 Indeed, public health disasters, such as the E. coli outbreak in Walkerton, Ontario, have afforded researchers the opportunity to prospectively study the natural history, pathophysiology and genetic susceptibility of PI-IBS at the population level.37 Although there is an absence of universally applicable pathophysiological features, intestinal inflammation, alterations in GI motility and mucosal permeability have all been implicated in the pathophysiology of PI-IBS.

Visceral hypersensitivity

Currently, the germane hypothesis that has been proposed to account for chronic abdominal pain in IBS is visceral hypersensitivity. It has been over 40 years since Ritchie38 first observed that patients with IBS have a heightened sensitivity to mechanical distension of the gut, which has been subsequently termed ‘visceral hypersensitivity’ (Figure 2).38 The epiphenomenon of visceral hypersensitivity has spawned a considerable research effort aimed at identifying the underlying molecular mechanisms responsible.

FIGURE 2

The concept of visceral hypersensitivity. In this study, Whitehead et al.46 distended a rectosigmoid balloon in healthy controls (blue line) and patients with IBS (red line). IBS patients reported pain at lower distension volumes than healthy controls, thereby suggesting that the viscera is mechanically hypersensitive.

8-3-7-fig2.jpg

Psychological factors

Psychological comorbidities such as depression, somatization and hypochondriasis are associated with IBS.15,39 Using animal models, studies have shown that adverse early life events, such as maternal separation, are risk factors for the development of chronic abdominal pain in adulthood.40 For humans, adverse events associated with IBS include a history of sexual abuse, especially in childhood (which has been shown to alter visceral pain sensitivity), as well as physical abuse.4145 Not unsurprisingly, increased levels of psychiatric comorbidity are seen in tertiary care IBS clinics compared with community populations.

Gut microbiota

As a consequence of advances in gene sequencing over the last decade, quantification of the human microbiota, the majority of which reside in the colon (≈ 1014 organisms), has become possible.47,48 The gut is sterile prior to birth, but is vertically inoculated from the mother during delivery with subsequent establishment of the diverse microbiota ecosystem during the first year of life. Furthermore, significant refinement of the microbiota throughout life occurs whereby genetics, ethnicity, diet and environment are influential.49 Whilst the microbiota has a role in protection from external pathogens and metabolism, it has also shown to yield far more complex roles. Moreover, the gut microbiota have been shown to influence cognitive functions, including learning, memory and decision-making.50 The development of culture-independent techniques has facilitated considerable advances in ascertaining the role of the microbiota in different IBS subtypes.51 A recent study by Jeffery et al.52 performed pyrosequencing analysis of the composition of faecal microbiota and demonstrated two species-specific subtypes of IBS, which were independent of symptom-based classification. The first of these showed a microbial composition similar to normal, while the second was characterized by an increase in Firmicutes-associated taxa with a relative depletion of Bacteroides-related taxa. The implication of these data is that, in the future, GI microbial enterotyping may facilitate stratifications of IBS subpopulations. Presently, however, such methods have limited practicality as a routine clinical biomarker as they are both resource and labour intensive.53 Pimentel et al.54 have reported the combined results of two phase III trials evaluating the utility of the non-absorbable antibiotic rifaximin (Targaxan®/Xifaxanta®, Norgine Pharmaceuticals, Middlesex, UK) in non-constipated IBS, demonstrating a small but significant improvement in the relief of global symptoms, bloating, abdominal pain and loose or watery stools. The potential therapeutic activity of rifaximin in IBS warrants further investigation and replication in larger, controlled studies, addressing the need for retreatment.

Faecal microbiota transplantation (FMT) has received considerable attention recently, particularly in the treatment of Clostridium difficile. It has been shown that FMT is significantly more effective for the treatment of recurrent C. difficile infection than the use of vancomycin.55 Given the role of the microbiota in IBS, a number of preliminary case reports and retrospective studies, examining the efficacy of FMT in the treatment of IBS, have demonstrated promising results, although to date there are no prospective, randomized, double-blinded, placebo-controlled trials.56

Differential diagnosis

Patients displaying the typical features of IBS, in the absence of alarm or red flag symptoms (Table 2), can be confidently diagnosed with IBS without recourse to multiple investigations. Given the relative lack of specificity of symptoms in IBS, the differential diagnosis is broad and includes lactose intolerance, giardiasis, coeliac disease, inflammatory bowel disease, bile acid malabsorption and food allergies. Screening investigations for patients presenting with diarrhoea typically include a full blood count, assessment of inflammatory markers (such as erythrocyte sedimentation rate and/or C-reactive protein), serum ferritin and vitamin B12 and serological testing for coeliac disease (antitissue transglutaminase antibodies); furthermore, testing for CA-125 should be considered in women.

TABLE 2

Alarm symptoms that would prompt further investigation

Alarm symptoms
Abnormalities on clinical examination
Weight loss
Rectal bleeding or masses
Nocturnal symptoms
History of recent antibiotic use
Raised inflammatory markers
Family history of colorectal carcinoma or ovarian cancer

Stool microscopy may be helpful in diagnosing chronic enteric infections such as giardiasis, although these are uncommon in western populations of IBS patients. In elderly patients, endoscopic imaging of the colon is required in order to exclude microscopic colitis, which is common and can account for up to 20% of unexplained diarrhoea in patients aged over 70 years.57

Bile acid malabsorption is also an important differential diagnosis of IBS, since the clinical response to bile acid sequestrants is high in this group. Interestingly, a recent meta-analysis reported by Slattery et al.58 revealed that 28.7% of those meeting the Rome II or III criteria for IBS in actuality had bile acid malabsorption (Figure 3). These results have important implications for the interpretation of previous research in IBS-D and in future guideline development.

FIGURE 3

Forest plot of the pooled proportions of bile acid malabsorption in prospective studies using the Rome II/III criteria. These results demonstrate that the overall pooled proportion was pooled rate was 28.1% (95% confidence interval 22.6–34%). Adapted from Slattery et al.58

8-3-7-fig3.jpg

Management of irritable bowel syndrome

Given the incomplete understanding of the pathophysiology underpinning IBS, treatment can be difficult. Central to a successful outcome is the doctor–patient relationship, hereinafter referred to as the therapeutic relationship. In particular, validation of a patient’s symptoms in a supportive environment is an absolute cornerstone of treatment. It is not uncommon to encounter patients who have experienced negative attitudes towards their symptoms from health care professionals given the lack of an objective diagnostic biomarker. This observation frequently leads to a breakdown in the therapeutic relationship, and thus patients are often disenchanted. It is our opinion that the development of a therapeutic relationship and patient education are the cornerstones for successful management of such patients. Similarly, treatment options, and their underlying rationale, should be discussed in detail. The clinician and the patient should also agree upon, and set, reasonable treatment goals in the context of regular outpatient reviews. In this context, it is important not to underestimate the role of the wider multidisciplinary team, such as colleagues in psychiatry, psychology and dietetics. The absolute regularity of such reviews may be limited by local service provision, but these reviews do permit definition of response or non-response, facilitate earlier escalation of intervention as appropriate and, importantly, leave patients with a sense of confidence that their symptoms are being taken seriously. Although such an approach is resource intensive, over the longer term it is likely to be cost effective. Moreover, the majority of IBS patients will not need such a fastidious approach, and therefore it can be reserved for recalcitrant cases.

In addition to these general approaches, various interventions have been suggested beneficial, including lifestyle measures and pharmacological and psychological treatments. Furthermore, the National Institute for Health and Care Excellence has very recently published updated clinical guidelines for the management of IBS.59 A central aspect of pharmacological management is the stratification of patients into the predominant subtype of IBS, which aids in clinical decision-making. A management algorithm is shown in Figure 4.

FIGURE 4

A suggested management algorithm for IBS. *Unlicensed medication. FODMAP, fermentable oligosaccharides, disaccharides, monosaccharides and polyols; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. Note: Linaclotide (Constella®, Almirall, Barcelona, Spain).

8-3-7-fig4.jpg

Lifestyle and dietary interventions

There are numerous aspects of patient lifestyle that may be modified for symptomatic improvement. Patients should be given written information that details the importance of self-help measures to manage their symptoms, but should also be counselled to take exercise and to create time to relax within their schedules. Patients often report that certain dietary components can exacerbate symptoms and therefore their diet and nutrition should be assessed. General advice includes taking regular meals, drinking at least eight cups of fluid per day and limiting caffeinated drinks to three cups per day.

The role of avoidance of certain dietary components has generated considerable interest in the role of FODMAPs in the symptomology of IBS. FODMAPs are fermentable carbohydrates, which induce intraluminal gaseous distension and exert an osmotic effect. Moreover, recent evidence suggests that diets differing in FODMAP content exert marked effects on the composition of the gut microbiota.60 Foods high in FODMAPS include fruits such as apples, peaches, nectarines, lactose-containing substances, legumes and artificial sweeteners (products with sorbitol, as in sugar-free chewing gum, should be avoided in diarrhoeal disease).59 In a well-designed randomized controlled crossover trial, patients with IBS had a reduction in bloating, abdominal pain and flatus with greater satisfaction with stool consistency.61 Furthermore, a recent study has reported that dietitian-led FODMAP group education is clinically effective and may represent significant cost savings over individually administered advice.62

Pharmacotherapy

Elucidation of optimum pharmacotherapy has proven difficult in IBS, not least because of a particularly high placebo response rate (≈ 40%63), which is likely to influence trial results. That being said, the utilization of numerous compounds, including antispasmodic drugs, antidepressants and antibiotic/probiotics, is suggested to be efficacious and is included in the most recent UK clinical guidelines.59 Antispasmodic drugs largely compete with acetylcholine at post-ganglionic vagal nerve endings, and therefore reduce the strength of smooth muscle contraction, reducing abdominal pain. A recent Cochrane database systematic review has highlighted imetropium/dicyclomine, peppermint oil (which also inhibits smooth muscle contraction albeit by calcium channel blockade), pinaverium and trimebutine to also be beneficial in reducing IBS symptoms.64

Constipation-predominant irritable bowel syndrome

In those with IBS-C, simple laxatives such as senna and docusate (Docusol®, Typharm, Norwich, UK) are often effective in managing symptoms, in addition to lifestyle measures. However, lactulose is often poorly tolerated, because of worsening of bloating, and is therefore not advocated. Linaclotide is a minimally absorbed peptide guanylate cyclase-C agonist, and is recommended as second-line therapy in patients who have symptoms for more than 12 months. The mechanism of action of linaclotide is shown in Figure 5. Notably, linaclotide has an important effect on colonic nociceptors and therefore reduces pain, which is a central feature of IBS.65 Two well-designed phase III randomized controlled trials demonstrated that linaclotide is effective in reducing abdominal pain, bloating and bowel symptoms.66,67

FIGURE 5

A schematic illustration of the secretory mechanism of action of linaclotide. Intraluminal linaclotide binds to the guanylate cyclase-C receptor stimulating the production of cyclic guanosine monophosphate (cGMP) leading to activation of protein kinase II (PKGII) and phosphorylation (P) of the cystic fibrosis transmembrane conductance regulator (CFTR) and secretion of chloride (Cl) and bicarbonate (HCO3) into the lumen which is followed by sodium (Na+) and water (H2O). This increases intestinal transit. cGMP also inhibits the afferent pain fibres to leading to analgesia.

8-3-7-fig5.jpg

Diarrhoea-predominant irritable bowel syndrome

Loperamide exerts an antidiarrhoeal effect through the inhibition of peristalsis, leading to prolongation of gut transit time through its action as a mu (µ)-opioid receptor agonist, although it does not cross the blood–brain barrier. Thus, it is frequently used as a first-line agent in IBS-D. Although loperamide has no benefit on overall symptoms in IBS, it does reduce stool frequency and defecatory urgency and improves stool consistency.68

It has also been proposed that 5-HT3 receptor antagonists may be effective in the management of treating IBS-D symptoms, given that serotonin is a major gut mediator in afferent nerve signalling and prokinetic activity. 5-HT3 receptor antagonists block 5-HT-induced vagal stimulation, and IBS-D has been associated with 5-HT abnormalities, including increased 5-HT-containing enteroendocrine cells,69 increased post-prandial 5-HT release70 and reduced serotonin transporter mRNA in the colon.71,72 Previously, the 5-HT3 receptor antagonist alosetron (Lotronex®, Prometheus Laboratories, San Diego, CA, USA) was approved for use in IBS-D, failing success with conventional therapy; however, it has since been withdrawn because of complaints of constipation and, in rare cases, ischaemic colitis.73 Consequently, other 5-HT3 receptor antagonists have been investigated, and a recent placebo-controlled crossover trial encompassing 120 IBS-D patients has shown that ondansetron significantly improves IBS symptoms, including reduced urgency within 7 days of treatment, but also has an enhanced safety profile.74 Similarly, another 5-HT3 receptor antagonist, ramosetron (Iribo®, Astellas Pharma, Tokyo, Japan), has been shown to improve stool consistency in male patients with IBS-D.75

Different prospective anti-inflammatory therapies have been proposed including 5-aminosalicylates such as mesalazine.76 Early research has suggested that mesalazine is an efficacious therapy,77 although other studies have found conflicting results.78 More recently, two large randomized multicentre-controlled trials of mesalazine for IBS did not demonstrate superiority over a placebo in the satisfactory relief of abdominal pain and distention.79,80

Low-dose antidepressants

Low-dose TCAs are recommended as a second-line treatment for those patients in whom laxatives, loperamide or antispasmodics have not reduced symptoms. The exact mechanisms by which TCAs exert their analgesic effects are yet to be completely understood, although they are well known to inhibit reuptake of noradrenaline and 5-HT, as well as influence both histaminergic and cholinergic transmission. It has been postulated that the analgesic mechanism of TCA is by retarding GI transit, treating comorbid anxiety and depression, and by modulating both ascending visceral sensory afferents and central transmission.81 In a meta-analysis, Ford et al.82 identified nine clinical trials, which had studied 575 patients.82 Of the 319 patients who had received active treatment, 41.4% had continued symptoms compared with 59.8% of those treated with placebo. This equated to a relative risk (reduction) of IBS symptoms persisting of 0.68 (95% confidence interval 0.56–0.83) in those treated with TCA. It is our clinical practice to commence with low-dose amitriptyline, for example 5 mg at night, titrating it up to the desired therapeutic dose as this strategy minimizes side-effects such as tiredness, dry mouth and constipation. Considering that constipation is a side-effect, it is recommend that amitriptyline is used in patients with IBS-D.83

Selective serotonin reuptake inhibitors are thought to selectively block the presynaptic serotonin reuptake transporter, thereby increasing the quantity of serotonin within the synaptic space. Tack et al.84 evaluated the effect of the SSRI citalopram in 23 IBS patients in a crossover design that compared 6 weeks of treatment with a placebo. Citalopram was found to significantly reduce abdominal pain in comparison with the placebo; an effect that was independent of drug-induced changes in anxiety and depression. These promising initial results need to be replicated in a larger cohort of patients with IBS, but they suggest that SSRIs have efficacy in treating visceral pain associated with IBS. A frequently encountered side-effect of SSRIs is diarrhoea, and thus this class of intervention can be helpful in those with IBS-C.

As mentioned above, the role of the psychiatrist is critically important in the management of IBS patients, and in particular those in whom symptoms are resistant to standard therapies. In such patients, coexistent psychiatric diagnoses may exist that warrant expert evaluation and treatment.

Manipulation of the microbiota

Given the wealth of research surrounding alterations in the gut microbiota in IBS, the utilization of antibiotics or indeed probiotics may be of use. It has been proposed that modulation of GI bacterial composition may alter the clinical course.11 Moreover, a large placebo-controlled trial of rifaximin, which included in excess of 1200 IBS patients, has shown significant symptomatic improvement in those whom were allocated the treatment, although the numbers needed to treat and harm were 10.6 and 8971, respectively54,85 Meta-analytic data have suggested that probiotics are useful in treating IBS, particularly in reducing pain and symptom severity, although it has been highlighted that inconsistencies in study designs have rendered it difficult to understand their true utility.11,86,87

Psychological therapies

Meta-analytic evidence has demonstrated that psychological treatments, as a class of interventions per se, are effective in reducing symptoms of IBS.88 Behavioural therapies, including cognitive behavioural therapy (CBT), dynamic psychotherapy and hypnotherapy all alleviate the symptoms associated with IBS. The role of CBT was specifically addressed by Lackner et al.,89 where patients with moderate to severe IBS were randomized to receive psychotherapist-delivered CBT, self-administered CBT or usual care. Those who received therapist or self-administered CBT had superior reporting rates of relief from abdominal pain, in comparison with those receiving usual care (60.9% or 72% vs. 7.4%, respectively). Gut-focused hypnotherapy, whereby the aim is to reassure the patient of their symptoms with the aid of hypnosis, improves GI symptoms through cognitive changes in function, thereby influencing sensitivity or spasm. The use of hypnotherapy has been evaluated in a number of studies. Whorwell et al.90 demonstrated significant improvement in abdominal pain in a cohort of patients with refractory IBS, and a recent Cochrane review concluded hypnotherapy to be more efficacious than the current standard of care. Moreover, in a very recent report of 1000 patients with refractory IBS symptoms, hypnotherapy provided important therapeutic gains in symptom scores, abdominal pain and quality of life.91 Given the relatively high burden of side-effects associated with more traditional pharmacological therapies, hypnotherapy represents an excellent treatment option. Unfortunately, however, limited therapist availability often restricts accessibility for patients.

Future directions

The pharmacotherapeutic pipeline for IBS is currently proving a fertile area with a number of novel compounds in active phase II and III development. In IBS-C, plecanatide (Synergy Pharmaceuticals, New York, NY, USA), another guanylate cyclase-C agonist, and A3309 (Albireo, Gothenburg, Sweden), an ileal bile acid transporter, are demonstrating considerable promise in early-phase clinical trials.92,93 Phase II studies of eluxadoline (Viberzi®, Actavis, Dublin, Ireland), a locally active, mixed µ-opioid receptor agonist/delta (δ)-opioid receptor antagonist, have provided early efficacy data in the management of IBS-D.94

Conclusions

Irritable bowel syndrome remains a prevalent, multifactorial, enigmatic and vexatious disorder. Its diagnosis relies on the identification of a characteristic symptom pattern coupled with the exclusion of other organic disorders. In reality, however, it is likely that IBS represents a number of distinct pathophysiological processes that culminate in identical clinical phenotypes. Whilst the diverse management options available offer the potential to improve symptoms, further work is warranted on the individualization of therapeutic interventions. Nevertheless, despite the clinical burden of IBS, it remains a fruitful area of gastroenterological practice and clinical research.

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