Current and emerging pharmacotherapeutic options for irritable bowel syndrome.

Drugs DOI 10.1007/s40265-014-0292-7

REVIEW ARTICLE

Current and Emerging Pharmacotherapeutic Options for Irritable Bowel Syndrome Jose L. Barboza • Nicholas J. Talley Baharak Moshiree

•

Springer International Publishing Switzerland 2014

Abstract Treatment of irritable bowel syndrome (IBS) is challenging for both primary care physicians and gastroenterologists because of the heterogeneity of the patient population and the multifactorial pathophysiologies responsible for the symptoms in IBS. This review focuses on the current and emerging pharmacological treatments for IBS. Many of the current medications used to treat this disorder have distinct properties such as efficacy for different symptoms, safety profiles, contraindications, costs, dosing regimens, treatment duration and long-term data. All of these factors, in addition to patient preference and cognitive, food and environmental triggers, must be considered prior to any medication selection. This review will focus on randomized controlled trials with a general uniformity in study design, a rigorous patient selection and appropriate treatment durations. We will also discuss other exciting emerging treatments for IBS such as the l-opioid receptor (agonists and antagonists), selective j-opioid receptor agonists, anti-inflammatory drugs, serotonergic agents, bile acid modulators and intestinal bile acid

transporters, which may prove promising in treating our patients.

J. L. Barboza (&) University of South Florida College of Pharmacy, 12901 Bruce B. Downs Blvd. MDC30, Tampa, FL 33612, USA e-mail: [email protected]

1 Introduction

N. J. Talley University of Newcastle, Callaghan, NSW 2308, Australia N. J. Talley Mayo Clinic, Jacksonville, FL, USA B. Moshiree Division of Gastroenterology, University of Miami Miller School of Medicine, 1120 NW 14th Street, Miami, FL 33136, USA

Key Points Irritable bowel syndrome (IBS) is a complex and heterogeneous gastrointestinal disorder with several distinct biopsychosocial pathophysiologies, which must be addressed for adequate treatment. Recent randomized controlled trials and metaanalyses have evaluated the traditional and currently available new therapies for IBS. Various emerging therapies are being investigated for the treatment of IBS, which not only improve stool frequency and consistency but also improve pain and bloating in IBS.

Irritable bowel syndrome (IBS) is defined as a chronic functional gastrointestinal (GI) disorder characterized by symptoms of abdominal pain associated with altered bowel habits in the absence of known organic disease [1]. Although it is considered a syndrome and not a disease, patients with IBS have decreased work productivity and diminished quality of life [2], with resultant increased total healthcare costs between 35 and 59 % higher than those of patients without IBS [3]. In the USA, the cost of IBS is estimated at $1.56 billion in indirect costs and $1.35 billion

J. L. Barboza et al.

in direct costs [4]. Although the prevalence of IBS is estimated to average 11 % globally [5], the prevalence can vary depending on the diagnostic criteria used and the global location, ranging from 7 % in Southeast Asia to as high as 21 % in South America [5]. The optimal method used to diagnose IBS remains a matter of controversy, and in clinical practice it is often a diagnosis made on the basis of symptom-based criteria [1]. The latest diagnostic criteria agreed upon by a group of experts in the field of gastroenterology—the Rome III criteria—were designed in 2006 for the purpose of establishing some certainty in the diagnosis of IBS, avoiding unnecessary use of diagnostic procedures and treatments, for patient reassurance about their diagnosis, and also for the purpose of standardizing recruitment in clinical trials [6, 7]. This review references clinical trials that have used different diagnostic criteria, including the Manning [8], Rome I [9], Rome II [10] and Rome III [11] criteria. See Table 1 for the specific definitions of each criteria. Given the advancing discovery of distinct pathophysiological mechanisms underlying symptoms in IBS, symptom-based criteria alone have been criticized for making a positive diagnosis [12]. This dire need for better diagnostic studies of IBS is supported by a recent study in 1,848 adult patients presenting to secondary care practices for symptoms of IBS. The study found the sensitivity, specificity, positive likelihood ratio and negative likelihood ratio for the Rome III criteria to be 68.8 %, 79.5 %, 3.35 and 0.39, respectively, with the Rome II criteria having higher sensitivity (95.8 %) but lower specificity (70.6 %) than the Rome III criteria. This lack of adequate diagnostic measures, combined with the heterogeneity of the IBS population—which is perhaps due to the different pathophysiological mechanisms involved—leads to difficulty in comparison across clinical trials. The various postulated pathophysiological mechanisms include altered GI motility, visceral hypersensitivity, altered faecal flora, inflammation, increased intestinal permeability, bacterial overgrowth syndrome, genetic predisposition and food sensitivity [1]. Furthermore, even symptoms within the Rome III criteria can vary, ranging from constipation to diarrhoea, with some patients switching between the two. As such, IBS is divided into specific subtypes based on the predominant stool form, which has driven pharmacological trials. Figure 1 outlines the pathophysiological targets for IBS and the current and emerging pharmacotherapy options for each. These subtypes, according to the Rome III criteria, are IBS with diarrhoea (IBS-D), IBS with constipation (IBS-C), mixed IBS (IBS-M) and un-subtyped IBS (IBS-U) [6]. A challenge in drug development is targeting both the pathophysiology of the syndrome in each patient population and carefully recruiting a specific subgroup of the IBS

population in order to gain therapeutic benefit over placebo [13]. Unfortunately, thus far, given the lack of a distinct aetiology of the symptoms, the treatment of IBS is largely based on controlling symptoms and not reversing the underlying putative pathophysiological disturbances. Treatment options have been broad and include a combination of the following: pharmacological agents, dietary measures and psychological interventions, given the strong association of symptoms with stress and the comorbidity of IBS with anxiety disorders and depression. Psychological therapies, such as gut-directed hypnotherapy and cognitive–behavioural therapy, have also yielded positive results in patients with moderate to severe IBS [14]. Given that several causes may be responsible for the symptoms of IBS, no one drug will likely target all of these mechanisms. Inherent problems exist in reviewing the current clinical evidence for the treatment of IBS. These include difficulties in comparing the many randomized controlled trials (RCTs), given variable patient selection and the fact that studies are often underpowered. Notably, the placebo rates found in IBS treatment trials are high, averaging 40 % (range 16–71 %, confidence interval [CI] 35.9–44.4), which may reflect inconsistent study quality as well as variable stringency of the primary endpoints applied [15]. Experts debate whether meta-analyses should guide clinical management of patients [13]. Ford and Moayyedi found several errors in meta-analyses, which included inclusion of ineligible trials, as well as failure to include eligible trials, and data extraction errors [13]. Lastly, clinical trials evaluating therapeutic options for IBS, especially those prior to the introduction of the Rome I criteria in 1989, have contained flaws in trial design and lacked standardization of inclusion/exclusion criteria, duration of therapy, study endpoints and IBS diagnostic criteria [1]. This review attempts to discuss these differences in trial design between RCTs and includes important studies with ‘high-quality’ design. Acknowledging the potential pitfalls of published clinical trials, our review focuses on the pharmacological agents found by using MEDLINE/PubMed, Web of Science, and the Cochrane databases, with an emphasis on evidence from phase 2b and phase 3 placebo-controlled RCTs. Many of the studies that are discussed used a form of the Global Improvement Scale (GIS), which is a validated 7-point Likert scale whereby patients answer the following question [16]: ‘‘Compared to the way you usually felt during the 3 months before you entered the study, are your IBS symptoms over the past 4 weeks substantially worse, moderately worse, slightly worse, no change, slightly improved, moderately improved, or substantially improved?’’ The pharmacological recommendations in this review are based on the American College of

Current and Emerging Pharmacotherapeutic Options Table 1 Diagnostic criteria for irritable bowel syndrome (IBS) Manning [8]

Rome I (1989) [9]

Rome II (1999) [10]

Rome III* (2006) [11]

2 (or 3) or more of the following symptoms:

At least 3 months of continuous/ recurrent symptoms of abdominal pain or discomfort:

C12 weeks (not necessarily consecutive) in the past 12 months with abdominal discomfort or pain

Recurrent abdominal pain or discomfort on at least 3 days/month in the past 3 months associated with C2 of the following:

• Pain relieved by bowel movement

• Relieved with defecation

With C2 of the following:

• Improvement on defecation

• Abdominal distension

• OR

• Relieved with defecation

• Change in stool frequency

• Looser bowel movements with pain

• Associated with a change in stool frequency or consistency

• Change in stool frequency

• Change in form of stool

• More frequent bowel movements with pain

With C2 of the following on C25 % of days/occasions:

• Change in form of stool

• Mucus with stools

• Altered stool frequency

Symptoms that cumulatively support the diagnosis:

• Sensation of incomplete evacuation

• Altered stool form • Altered stool passage

Abnormal stool frequency Abnormal stool form

• Passage of mucus

Abnormal stool passage

• Bloating or feeling of abdominal distension

Passage of mucus Bloating or feeling of abdominal distension

The table lists the diagnostic criteria for IBS based on the Manning (1978) [8], Rome I (1989) [9], Rome II (1999) [10] and Rome III (2006) [11] criteria for IBS * Criteria met for the past 3 months, with onset of symptoms C6 months before diagnosis

Gastroenterology (ACG) Task Force on IBS [1], systematic reviews taking into account a European treatment perspective [17] and recommendations by the US Food and Drug Administration (FDA).

2 All IBS Subtypes 2.1 Fibre Fibre is commonly used, especially by general practitioners, as an initial agent to treat mainly IBS-C, although it has been shown to improve global symptoms in all IBS subtypes [18]. Fibre may work by increasing the absorption of liquids into the GI tract, thereby promoting peristalsis, and it also increases stool bulk and softness, and intraluminal pressure. Many fibre supplements, including psyllium, bran, polycarbophil, methylcellulose and wheat dextrin, have been studied for the treatment of IBS. One such study conducted in the Netherlands evaluated the use of psyllium and bran fibres as compared with placebo in patients with all IBS subtypes presenting to primary care practices [19]. The breakdown of IBS subtypes

was IBS-C: 56 %, IBS-D: 25 % and IBS-M: 19 %. The investigators found that psyllium resulted in significant clinical improvement in adequate relief of abdominal pain or discomfort, for at least 2 out of 4 weeks, compared with placebo. The percentage of patients experiencing relief of pain or discomfort in the first month was 53 % with psyllium compared with 29 % with placebo (relative risk [RR] 1.66, CI 1.19–2.31; number needed to treat [NNT] 4.2), and 46 % with psyllium compared with 29 % with placebo in the second month (RR 1.44, CI 1.04–2.00; NNT 5.9). Unfortunately, extended use of fibre for up to 3 months did not result in significant symptom relief compared with placebo (RR 1.32, CI 0.91–1.95). The use of bran did not result in significantly higher response rates compared with placebo. A subgroup analysis of patients with IBS-C only showed comparable results. The limitations of the study included the lack of blinding of clinicians and the use of non-standardized diagnostic criteria for IBS, with 61 % of the diagnoses based on practitioner opinion. Systematic reviews evaluating fibre therapy have reached different conclusions depending on the diagnostic criteria used in the analysis and the type of fibre agents studied. One example is a Cochrane Review by Ruepert

J. L. Barboza et al. Fig. 1 Pharmacotherapeutic targets in irritable bowel syndrome (IBS). Each of the possible pathophysiological mechanisms for IBS is listed with possible therapies for each target underneath. These mechanisms include the following: visceral hypersensitivity, central nervous system (CNS) desensitization, food allergies and sensitivities, immune dysregulation and altered gut flora, altered gut motility and secretion, and peripheral pain targets. ASA aminosalicylic acid, FODMAP Fermentable, Oligosaccharides, Disaccharides, Monosaccharides And Polyols, IBAT ileal bile acid transporter, PEG polyethylene glycol

et al. [20], which concluded that fibre is no better than placebo in relieving abdominal pain or in improving global assessment or symptom scores in patients with IBS. This review combined data on multiple sources of fibre without stratifying the results to specific fibre agents. Combining the results for all fibre agents may have masked any positive evidence for an individual agent. An alternate meta-analysis by Ford et al., which also evaluated RCTs in IBS, resulted in a different conclusion [18]. This metaanalysis included trials that assessed either global assessments of cure, improvement of symptoms, or cure of or improvement of abdominal pain. It found that psyllium was effective in treating persistent IBS symptoms, compared with placebo (RR 0.78, CI 0.63–0.96; NNT 6). The benefit

seen with psyllium likely drove the conclusion, as bran, methylcellulose and polycarbophil did not improve IBS symptoms as compared with placebo. Adverse effects from fibre include bloating, abdominal distension and pain—the exact symptoms for which it is recommended to treat IBS. Although fibre initiation can cause bloating if it is given at high doses initially, gradually titrating the dose of fibre and concomitantly administering it with liquids is a good approach in practice. Patients with trouble swallowing, gastroparesis, obstruction or strictures should avoid fibre supplementation [21]. In general, psyllium improves global symptoms in all IBS subtypes and can be considered a first-line pharmacological agent in patients with mild to moderate IBS symptoms.

Current and Emerging Pharmacotherapeutic Options

2.2 Antispasmodics

3.

Antispasmodics are commonly used as initial agents to treat IBS when the predominant symptom is pain, or as an adjunct to a medication for either constipation or diarrhoea, depending on the IBS subtype. Smooth-muscle spasm in the colon has been confirmed in IBS [22], and it is postulated that antispasmodics relax these smooth muscles. The antispasmodics include otilonium, hyoscine, pinaverium, trimebutine, cimetropium, dicyclomine, alverine, mebeverine, pirenzipine, prifinium, propinox, hyosciamine, dicyclomine and the combination cimetropium/dicyclomine. The availability and formulations of the antispasmodics varies in different countries. Caution must be used in assessing the evidence for antispasmodic use in IBS, as the overall quality of trials is generally poor. The limitations of existing studies, many of which were published prior to 2000, include the variety of different agents and formulations, lack of adherence to standardized criteria in diagnosis of IBS, and lack of a defined study endpoint. Meta-analyses have evaluated trials involving antispasmodics; however, these studies have not isolated a particular subtype of IBS that may benefit more from their use. One such meta-analysis done by Ruepert et al. [20] concluded that antispasmodics improved abdominal pain and global symptom scores, compared with placebo; abdominal pain was improved in 58 % of patients taking antispasmodics versus 46 % of patients on placebo (RR 1.32, CI 1.12–1.55; NNT 7), and global assessment improved in 57 % on antispasmodics versus 39 % on placebo (RR 1.86, CI 1.25–1.77; NNT 3). A subgroup analysis showed the following with respect to each specific antispasmodic:

4.

1.

2. 3. 4.

The cimetropium/dicyclomine combination benefited global symptoms but did not provide benefit in abdominal pain specifically. Pinaverium improved global symptoms and abdominal pain. Otilonium benefited global symptoms. Trimebutine improved abdominal pain but did not significantly improve global symptoms.

A more recent meta-analysis evaluated the use of antispasmodics in RCTs that measured either global assessments, improvement of other IBS symptoms, or relief or improvement of abdominal pain [18]. The use of antispasmodics resulted in lower rates of persistent symptoms, compared with placebo. In this analysis, the rates of persistent IBS symptoms after treatment were as follows: 1. 2.

Cimetropium at 19 % compared with placebo at 53 % (RR 0.38, CI 0.20–0.71; NNT 3) Pinaverium at 28 % compared with placebo at 61 % (RR 0.47, CI 0.33–0.67; NNT 3)

Hyoscine at 29 % compared with placebo at 46 % (RR 0.63, CI 0.51–0.78; NNT 3.5) Otilonium at 51 % compared with placebo at 71 % (RR 0.55, CI 0.31–0.97; NNT 4.5)

In another double-blind RCT in patients with IBS, the antispasmodic otilonium resulted in improvement in episodes of abdominal pain, severity of abdominal bloating and global efficacy [23]. This trial used the Rome II criteria and included patients with IBS-D (26 %), IBS-C (31 %) and IBS-M (43 %). Compared with placebo, otilonium 40 mg three times daily reduced the weekly frequency of episodes of abdominal pain (-0.90 ± 0.88 versus -0.65 ± 0.91; p = 0.03) and the severity of abdominal pain (-1.2 ± 1.2 versus -0.9 ± 1.1; p = 0.02), and increased the global efficacy scores as measured by patient assessment (1.3 ± 1.1 versus 1.0 ± 1.1; p = 0.047) at 15 weeks. In addition, during a 10-week follow-up period, a higher withdrawal rate due to symptom relapse was seen in the placebo group as compared with the otolinium group (27 versus 10 %; p = 0.0089) [23]. An additional study in Asia showed promising results with use of otilonium and mebeverine [24]. This doubleblind RCT, performed in patients with IBS diagnosed using the Rome II criteria in Taiwan, found that the abdominal pain/discomfort frequency score was decreased with otilonium and mebeverine as compared with patients’ baseline values. This study is noteworthy, as it was the first published study that evaluated otolinium in an Asian population. No significant differences between otilonium and mebeverine were seen in terms of efficacy. A weakness of this study was the lack of a placebo arm. Adverse effects and precautions differ with the various antispasmodic agents. Common adverse reactions include dry mouth, dizziness and blurred vision with anticholinergic agents available in the USA. Precautions with anticholinergics include glaucoma, obstructive uropathy, myasthenia gravis, obstructive GI tract disease, paralytic ileus, intestinal atony in older or debilitated patients, toxic megacolon and unstable cardiovascular status. Although strong evidence behind the use of antispasmodics is lacking, a reasonably good safety profile and availability leave them as an initial agent of choice in treating abdominal pain in any subtype of IBS. Peppermint oil is a naturally occurring carminative, which blocks Ca2? channels, resulting in smooth-muscle relaxation. Multiple small trials have evaluated the use of peppermint oil, which have lacked power or statistical significance. A meta-analysis conducted by Khanna et al. [25] evaluated nine placebo-controlled RCTs, which included 726 patients with IBS; peppermint oil resulted in greater improvement of global IBS symptoms (69 versus 31 %; RR 2.23, CI 1.78–2.81) and a greater number of


patients were relieved of abdominal pain with peppermint oil (57 % versus 27 %; RR 2.14, CI 1.64–2.79). A greater number of patients taking peppermint oil experienced at least one adverse effect, compared with placebo (22 versus 13 %; RR 1.73, CI 1.27–2.36). The events encountered were mild and transient, and included heartburn most commonly, dry mouth, belching, peppermint taste and smell, rash, dizziness, headache, increased appetite and a cold perianal sensation. 2.3 Antidepressants Antidepressants are used to treat severe pain and bowel dysfunction associated with IBS, and good evidence exists that they can benefit global IBS symptoms and possibly improve bowel habits in IBS-C or IBS-D through their dual effects on the brain and the gut. Centrally acting agents such as antidepressants may improve the dysregulation of neuroenteric pathways that lead to development of IBS. In addition to this rationale, which relates to their use in directly modulating pain centrally, they can also be used to treat possible underlying concomitant psychiatric disorders such as depression and anxiety [26–28]. Notably, different classes of antidepressants cause different effects on GI transit, which can be strategically used to target specific subtypes of IBS. For example, the tricyclic antidepressants (TCAs), including imipramine, slow colonic transit in IBS-D through anticholinergic actions. In contrast, the selective serotonin reuptake inhibitors (SSRIs), such as paroxetine, have prokinetic actions on the small intestine [29] and theoretically may benefit IBSC. It is generally presumed that TCAs may perform better in treating IBS-D and SSRIs may perform better in treating IBS-C, but firm evidence is lacking. The strength of the anticholinergic properties of TCAs depends on the subclass; tertiary amines are metabolized to secondary amines (e.g., amitriptyline and imipramine are metabolized to nortriptyline and desipramine, respectively). Tertiary amines are considered to have stronger anticholinergic activity. Several trials have now been done using TCAs to treat pain in IBS. The largest of these trials evaluated desipramine in female patients with functional bowel disorders (80 % of patients were diagnosed with IBS). Desipramine resulted in higher response rates compared with placebo (60 versus 47 %); however, this difference did not yield a statistically significant difference in the intention-to-treat analysis (p = 0.16) [30]. However, a significant increase in response rates with desipramine was noted in the per protocol analysis (p = 0.01) and after subjects with nondetectable desipramine blood levels were excluded from the desipramine group (p = 0.002). Patients were not stratified by IBS subtype.

SSRIs have also shown promising results for use in IBS. Paroxetine has helped global improvement of symptoms but may not help with pain in IBS. Other SSRIs such as fluoxetine and citalopram may help with abdominal pain in patients with IBS-C. In patients with dominant symptoms of anxiety or obsessive compulsive behaviour, SSRIs may be the preferred type of antidepressant. Other classes of antidepressants, e.g. serotonin norepinephrine reuptake inhibitors (SNRIs) such as duloxetine, have also been used to treat IBS and dyspepsia; however, only open-label studies and pilot studies exist that support their use for IBS [31]. Antipsychotics and other antidepressants such as mirtazapine and buspirone have not been studied in randomized trials but have been advocated for use in IBS [32]. Meta-analyses have strongly supported the use of antidepressants in IBS in general, although a specific IBS subtype has not shown benefit with antidepressants, likely because subtypes have not always been specified in trials. One meta-analysis that included RCTs in primary, secondary and tertiary care settings evaluated the use of antidepressants compared with placebo and psychological therapies compared with usual clinical care in IBS [33]. The study found that both SSRIs and TCAs reduced the number of patients with persistent IBS symptoms (RR 0.66, CI 0.57–0.78; NNT 4). However, despite their benefit, adverse effect rates were higher with antidepressant use (18.1 %) compared with placebo (9.2 %). The most common adverse effects reported were drowsiness and dizziness. Another meta-analysis, the Cochrane Review, concluded that SSRIs and TCAs were more effective than placebo in improving abdominal pain and global assessment, and in symptom improvement [21]. Improvement of abdominal pain occurred in 54 % of patients with antidepressants versus 37 % with placebo (p = 0.03; NNT = 5), improvement of global assessment occurred in 59 % with antidepressants versus 39 % with placebo (p \ 0.001; NNT = 4) and improvement of symptom scores occurred in 53 % with antidepressants versus 26 % with placebo (p = 0.001; NNT = 4). RCTs evaluating antidepressant use in IBS suggest that the true benefit may depend on the specific medication and patient population studied. Given the vast number of studies with different antidepressants used and different trial designs, it may be beneficial to review each antidepressant individually. Paroxetine [34], fluoxetine [35, 36], citalopram [37], amitriptyline [38] and imipramine [39] have all shown some benefit in treating IBS in double-blind RCTs compared with placebo (see Table 2 for the descriptions, methods and results of these trials). In clinical practice, low doses of antidepressants are used, which are far below the depression treatment levels and are incrementally increased to an optimal level of benefit and continued for 6–12 months or longer if needed.

Current and Emerging Pharmacotherapeutic Options Table 2 Antidepressants in irritable bowel syndrome (IBS): double-blind randomized placebo-controlled trials Trial and study design

Results

Paroxetine (SSRI) [34]

Primary endpoint: no difference in pain scores between paroxetine CR and placebo

Medication dosing: Paroxetine CR 12.5–50 mg daily (n = 36) Placebo (n = 36)

Secondary endpoint: global improvement and severity ratings were better with paroxetine compared with placebo

Diagnosis: Rome II criteria Length of trial: 12 weeks Other: IBS subtype not categorized Fluoxetine (SSRI) [35] Medication dosing: Fluoxetine 20 mg daily Placebo Length of trial: 6 weeks

Primary endpoint: fluoxetine 20 mg daily did not significantly improve abdominal pain scores after 6 weeks compared with placebo Other GI symptoms, global symptom relief and psychological symptoms were not improved as compared with placebo

Diagnosis: Rome I Other: IBS subtype not categorized Fluoxetine (SSRI) [36] Medication dosing: Fluoxetine 20 mg

Endpoint: fluoxetine was more effective than placebo in decreasing abdominal discomfort and bloating, improved stool consistency and increased the number of bowel movements compared with placebo (p \ 0.05)

Placebo 44 patients (number of patients in each group not reported) Length of trial: 12 weeks Diagnosis: Rome II, IBS-C Diagnostic studies: colonoscopy Citalopram (SSRI) [37] Medication dosing: Citalopram 20 mg for 3 weeks and 40 mg for 3 weeks Placebo for 6 weeks 23 patients, crossover trial Length of trial: 6 weeks

Primary endpoint (measured by patient questionnaire): citalopram significantly improved abdominal pain, bloating, impact of symptoms on daily life and overall wellbeing compared with placebo after 6 weeks of treatment (p \ 0.05) Other: changes in depression or anxiety scores were not related to symptom improvement

Diagnosis: Rome II Diagnostic studies: routine biochemistry and colonoscopy within 5 years Other: inclusion of all IBS subtypes. Subtype breakdown: 4 patients with IBS-C, 5 with IBS-D and 16 with IBS-M Amitriptyline (TCA) [38] Medication dosing: Amitriptyline 10 mg daily Placebo Length of trial: 2 months Diagnosis: Rome II, IBS-D Diagnostic studies: standard laboratory and radiological tests, and rectosigmoidoscopy

Amitriptyline resulted in greater reduction in the incidence of loose stools and feeling of incomplete defecation (p \ 0.05), and greater complete response defined as loss of all symptoms, compared with placebo (68 versus 28 %; p = 0.01) Adverse effects were similar in the two groups

J. L. Barboza et al. Table 2 continued Trial and study design

Results

Imipramine (TCA) and citalopram (SSRI) [39]

Primary outcome: neither citalopram nor imipramine significantly improved global IBS symptoms compared with placebo, with relief rates of 69 % with citalopram, 100 % with imipramine and 69 % with placebo (p = 0.80)

Medication dosing: Imipramine 50 mg daily Citalopram 40 mg daily Placebo Length of trial: 12 weeks Diagnosis: Rome II Other: patients were stratified into IBS subgroups, and IBS-D was the most common subtype in each group

Imipramine resulted in a greater significant improvement in bowel symptom severity rating for interference (p = 0.05) and distress (p = 0.02), but improvements in pain were not seen A greater number of patients dropped out of the imipramine group, with completion rates of 71 % for citalopram, 50 % for imipramine and 81 % for placebo

Listing of the antidepressants used to treat IBS. Primary outcomes, methods and results of major randomized double-blind placebo-controlled trials of antidepressants used in IBS are included above CR controlled release, GI gastrointestinal, IBS-C irritable bowel syndrome with constipation, IBS-D irritable bowel syndrome with diarrhoea, IBS-M mixed IBS, SSRI selective serotonin reuptake inhibitor, TCA tricyclic antidepressant

Adverse effects caused by antidepressants include insomnia, restlessness, sexual dysfunction, nausea, constipation and diarrhoea, the latter two depending on the specific antidepressant used. Additionally, TCAs can cause dose-related adverse events including sedation, orthostatic hypotension, erectile dysfunction and cardiotoxicity. TCAs can be fatal in an overdose setting, thus prompting the aforementioned studies to evaluate SSRIs instead. However, the doses used to treat IBS pain are lower than the doses used to treat depression and are therefore safer in treating IBS. These are usually administered at bedtime, given their sedating effects. With SSRI use, concomitant use of medications that increase serotonin levels, such as ondansetron, ganisteron, metoclopramide or tramadol, can lead to serotonin syndrome and should be avoided. SSRIs produce more insomnia, agitation, sexual dysfunction and diarrhoea and are better tolerated in the morning. Moreover, antidepressants have a potential risk of suicidality in patients under 24 years of age with major depressive disorder, thus this group of patients should be monitored closely for worsening depression or unusual changes in behaviour when initiating antidepressants or increasing doses. Despite these pitfalls, SSRIs and TCAs are well tolerated in the treatment of pain in IBS, and different agents can be selected depending on the IBS subtype [21, 33]. For patients with severe pain due to IBS, a combination of psychotherapy and antidepressants may lead to a more favourable outcome [40]. Using data from a large multicentre trial comparing desipramine, cognitive–behavioural therapy and placebo in the treatment of functional bowel disorders, the determinants of good clinical response were found to be not the individual therapy but patients’ confidence in their

treatments, control over their illness and symptoms, improved quality of life and positive bonding with study personnel—and not their individual IBS symptoms. Patients’ perception of symptom control outweighed the actual clinical variables studied, such as pain and bowel frequency. These findings imply combining pharmacotherapy with psychological and behavioural therapies such as cognitive–behavioural therapy, hypnosis and stress management [33]. Moreover, treatment with psychological therapy can benefit patients even when the treatment period ends. 2.4 Probiotics Probiotics are a safe pharmacological option for the treatment of IBS. Current data demonstrate that patients with IBS are more likely to have modestly increased small intestinal bacteria than the general population but not at the levels seen in small intestinal bacterial overgrowth syndrome [41–43]. Alteration in the normal intestinal microbiome may then cause increased fermentation of food, producing methane, bile acid malabsorption, changes in intestinal motor and sensory function, and mucosal immune activation [44]. The purpose of prescribing probiotics in IBS, therefore, is to modulate the intestinal microbiota. Several RCTs have evaluated the use of probiotics for treatment of IBS. One large meta-analysis, which included RCTs in patients with IBS diagnosed on the basis of a doctor’s opinion or symptom-based diagnostic criteria, found that probiotics were better overall than placebo at reducing IBS symptoms (RR 0.71, CI 0.57–0.88; NNT 4) [45]. No individual probiotic, however, was statistically better than placebo. These probiotics included


Lactobacillus, Bifidobacterium, Streptococcus and combinations of probiotics. The authors cautioned that there was potential publication bias and over-representation of small positive studies, which may have reduced the NNT reported. Another meta-analysis also included RCTs in adults with IBS diagnosed by the Manning or Rome II criteria and looked at improvement of IBS symptoms with single or combination probiotics compared with placebo [46]. This meta-analysis singled out two studies showing that specifically the probiotic containing Bifidobacterium infantis 35624 showed significant improvement over placebo in improving the composite score of abdominal pain/discomfort, bloating/distension and/or bowel movement difficulty (p \ 0.05). None of the other probiotics were found to significantly improve IBS symptoms. Other RCTs published after the completion of the aforementioned meta-analyses further support the use of probiotics in patients with IBS. For example, in a doubleblind RCT in patients with IBS diagnosed using the Rome III criteria in South Korea, a combination of the probiotics Bifidobacterium longum, Bifidobacterium bifidum, Lactobacillus acidophilus, Lactobacillus rhamnosus and Streptococcus thermophilus, given for 4 weeks, provided greater relief of IBS symptoms compared with placebo (68.0 versus 37.5 %; p \ 0.05) [47]. Lactobacillus plantarum 299v has been studied in a double-blind RCT [48], showing reduced abdominal pain frequency compared with placebo (R = 1.01 ? 0.77 versus 1.71 ? 0.93; p \ 0.05) pain severity (R = 0.68 ? 0.53 versus 0.92 ? 0.57; p \ 0.05) and even bloating. Yogurt products containing probiotics have also been studied, although many of the studies are small and have limitations in design or are underpowered. For example, a double-blind RCT in patients with IBS-C or IBS-M in central England evaluated global assessment of symptom relief provided by dairy yogurt products with the probiotic Bifidobacterium lactis versus yogurt without probiotics twice daily for 4 weeks [49]. The trial found that this specific probiotic added to yogurt products did not result in symptom relief at 4 weeks compared with placebo (57 versus 53 %; p = 0.71), but a benefit was seen with longterm use of the yogurt in the 8- and 12-week analysis (p = 0.03 at 8 weeks and p = 0.004 at 12 weeks). This trial was also limited by high dropout rates, with 39, 48 and 55 % dropout rates at 4, 8 and 12 weeks, respectively. Several limitations in trials of probiotics for treating IBS exist because the study designs have used probiotics with different species, strains, doses, combinations and regimens [1]. At this time, a consensus regarding a probiotic of choice does not exist. Adverse side effects have not been reported but may include flatulence and bloating that subside with continued use. Overall, probiotics in general, and specifically Bifidobacterium alone or in combination, may

be beneficial in improving symptoms of IBS in a subset and offer a safe and tolerable initial choice. 2.5 Multi-Herbal Drugs The preparations STW5 (Iberogast) and STW5II (modified Iberogast) are herbal products containing plant extracts that have shown efficacy in improving IBS symptoms. The exact mechanism of action of these agents is unknown [50]. STW5 is composed of the following nine plant extracts: bitter candytuft, chamomile flower, peppermint leaves, caraway fruit, liquorice root, lemon balm leaves, celandine herbs, angelica root and milk thistle fruit. The multi-herbal drug STW5II contains bitter candytuft, chamomile flower, peppermint leaves, caraway fruit, liquorice root and lemon balm leaves. Neither is available in the USA; however, they can be obtained as an over-the-counter (OTC) product worldwide, and patients can order this online from international sources. The recommended dose for STW5 and STW5II is 20 drops three times daily, based on low-quality trial designs, most of which are funded by the manufacturing company. STW5 has been mostly studied in functional dyspepsia, with a limited number of trials supporting its use in IBS, as discussed below [51]. One industry-sponsored double-blind RCT evaluated the efficacy of three different herbal preparations—STW5, STW5 II and bitter candytuft (a component of STW5 and STW5II)—as compared with placebo in patients with IBS by assessing IBS symptom scores and abdominal pain [52]. Overall, both STW5 and STW5II improved IBS symptom scores and abdominal pain as compared with placebo after 2 weeks (p = 0.0085 and 0.0006, respectively) and after 4 weeks (p = 0.001 and 0.0003, respectively). The overall improvement in symptom scores with STW5 and STW5II was 15–25 % better than that seen with placebo. The dose administered for all medications was 20 drops three times daily. However, candytuft did not improve IBS symptom scores or abdominal pain compared with placebo. No serious adverse events were reported in any of the groups. The study is limited, however, as it combined patients with IBS-D, IBS-M and IBS-C, the patients were not stratified according to their IBS subtype, and the study had low statistical power. Other flaws of the study are that the investigator’s judgment most often designated patient tolerability as ‘‘good’’ or ‘‘very good’’, not a validated questionnaire administered to each patient. On the basis of investigator-determined tolerability, the investigators concluded that STW and STWII may be effective in the treatment of IBS regardless of symptom predominance. Minimal adverse events are reported with STQ5 and STW5II. In clinical practice, STW5 and STW5II are safe and well tolerated by patients and may help symptoms of mild IBS-C on the basis of their mechanism of action on gut transit [52].


2.6 Melatonin Melatonin is an OTC medication commonly used to treat sleep onset latency but has been shown to improve pain related to IBS. The exact mechanism of action for its benefits in IBS are unknown; however, patients with functional abdominal pain are reported to have decreased urinary excretion of melatonin and decreased amplitude of circadian rhythm compared with healthy individuals, which suggests a melatonin deficiency in IBS [53]. Melatonin has also been shown to exert excitatory and inhibitory effects in the gut. Although this mechanism is not understood completely, it is thought to work by blocking nicotinic channels and/or by interacting with Ca2?-activated K? channels [54]. A placebo-controlled RCT by Song et al. [55] evaluated the use of melatonin 3 mg taken at bedtime for 2 weeks in 40 patients with IBS-C, IBS-D and IBS-M. Patients were diagnosed using the Rome II criteria and also had sleep disturbance. The study found that melatonin decreased the mean abdominal pain score (2.35 versus 0.70; p \ 0.001) and increased the mean rectal threshold (8.9 versus -1.2 mmHg; p \ 0.01) but did not show beneficial effects on bloating, stool type, stool frequency, or anxiety and depression scores. No patients reported adverse effects from the medication during this trial. Another placebo-controlled RCT conducted in Singapore evaluated melatonin given at 3 mg per day. The crossover study included 17 female patients with IBS receiving either melatonin or placebo for 8 weeks with a 4-week washout period in between. The percentage of patients reaching mild-excellent improvement was also higher with melatonin (88 versus 47 %; p = 0.04). Changes in mean sleep, anxiety and depression scores were similar between the melatonin group and the placebo group. Only one adverse effect—sleepiness—was noted in the melatonin group, but the patient also reported it while in the placebo arm. Both of the trials showed benefit with melatonin in IBS regardless of its effects on sleep.

3 IBS-C 3.1 Osmotic Laxatives The osmotic laxative polyethylene glycol (PEG) is a commonly recommended OTC medication for the treatment of IBS-C and has been shown to increase the frequency of bowel movements. Osmotic laxatives such as glycerin, lactulose, sorbitol, magnesium tablets and milk of magnesium improve constipation by producing an osmotic gradient in the intestinal lumen, thereby increasing stool frequency and consistency. Despite several available OTC osmotic laxatives used to treat constipation, only PEG has

been studied in RCTs for treatment of IBS-C, although the pain in IBS is not improved even with this osmotic laxative. PEG can be administered once or twice daily at a dose of 17 g. The current evidence for use of PEG in IBS-C and not constipation alone is limited and conflicting. One small RCT in adolescents with IBS-C showed that PEG improved stool frequency but did not improve abdominal pain compared with baseline values. However, the aim of this small study was to compare PEG as the control medication with the study drug, tegaserod [56]. Another double-blind RCT found that PEG plus electrolytes improved the mean number of spontaneous bowel movements per day compared with placebo in a 4-week trial period (4.4 ± 2.6 versus 3.11 ± 1.9) [57]. Patients on PEG had improvement of the mean severity of abdominal pain scores compared with placebo. In contrast, a double-blind RCT compared the effects of PEG on fasting and postprandial perception of rectal distension and symptoms in patients with IBS-C and found that PEG was no better than placebo [58]. Common side effects with PEG include abdominal pain, bloating and diarrhoea. Although osmotic laxatives such as PEG have been shown to improve stool consistency and frequency, they may not necessarily improve abdominal pain; therefore, in patients with severe IBS-C symptoms and pain, another treatment regimen may be more beneficial to treat the combination of pain and constipation. 3.2 Chloride Channel Activator: Lubiprostone Lubiprostone is a chloride channel activator. Although the mechanism of action of lubiprostone is not completely understood, it is postulated that it activates the CIC-2 chloride channels in the apical portion of the intestine to stimulate chloride-rich fluid secretion into the intestinal lumen, thus improving faecal transit. Lubiprostone is FDA approved to treat IBS-C in the USA for use in women aged C18 years at a dose of 8 lg twice daily and 24 lg twice daily for constipation alone. Strong evidence supporting the use of lubiprostone comes from two large combined 12-week double-blind phase 3 RCTs [59]. In 1,171 patients with IBS-C, they found that more patients taking lubiprostone had improved symptoms, using the GIS, as compared with placebo (17 versus 10 %; p = 0.001). Although these low improvement rates have been criticized, they are most likely explained by the very stringent primary endpoints used. In addition, since women accounted for 92 % of the combined population in these studies, the FDA did not approve lubiprostone’s use in men, because of insufficient evidence. Later, an open-label extension study in patients with IBS showed that lubiprostone maintained safety and the patient response rate for up to 52 weeks [60].


Side effects associated with lubiprostone include diarrhoea and nausea [59, 60]. In cases of treatment failure with the 8 lg dosage, it may be prudent to titrate to 24 lg twice daily—the dose approved for chronic constipation. However, a dose-dependent increased risk of nausea exists with lubiprostone at the 24 lg twice daily dose in up to 30 % of patients [61]. 3.3 Guanylate Cyclase-C Agonist: Linaclotide Linaclotide is a locally acting guanylate cyclase-C agonist, which increases intestinal fluid and electrolyte secretion, thereby improving the symptoms of IBS-C. Linaclotide has been approved by the European Medical Agency for treating moderate to severe IBS-C and by the FDA for IBSC and at a dose range of 145–290 lg orally. Linaclotide binds to the guanylate cyclase-C on the intestinal epithelium, increasing cyclic guanosine monophosphate (cGMP) [62], which then causes secretion of chloride and bicarbonate ions in the intestinal lumen while inhibiting sodium absorption. This causes an increase in intestinal fluid secretion, thereby increasing transit time. Linaclotide also increases extracellular cGMP, which has been shown to reduce the mechanosensitivity of colonic nociceptors in animal models, perhaps accounting for the decreased visceral hypersensitivity and abdominal pain in IBS [63]. Linaclotide also has low systemic bioavailability, which results in low rates of adverse effects. Two large landmark trials show evidence for linaclotide’s use in IBS-C. One is a parallel double-blind RCT of 800 patients with IBS-C diagnosed using the Rome II criteria, who were administered linaclotide 290 lg daily versus placebo for 12 weeks [64]. This trial used the FDA’s strict IBS-C endpoints, defined as a 30 % improvement in the average daily worst abdominal pain score and an increase by C1 complete spontaneous bowel movement from baseline for at least 50 % of the weeks assessed. Both endpoints were statistically improved with linaclotide compared with placebo (34 versus 21 %; p \ 0.0001; NNT 8). In addition, the use of linaclotide resulted in a greater reduction of abdominal pain compared with placebo (50 versus 37.5 %; p = 0.0003) for at least 75 % of the weeks. Patients taking linaclotide also had a greater increase of spontaneous bowel movements from baseline compared with placebo (49 versus 30 %; p \ 0.0001) for at least 75 % of the weeks. Moreover, linaclotide resulted in improvement compared with placebo in the following secondary endpoints: bloating, abdominal discomfort and bowel function. As expected, diarrhoea was seen more commonly in the group taking linaclotide (5.7 versus 0.3 % of those taking placebo). A similar double-blind RCT of 804 patients with IBS-C, which was completed in 2010, evaluated linaclotide 290 lg

daily compared with placebo [65]. The primary and secondary endpoints were analyzed over the first 12 weeks, then patients were followed up for 26 weeks. The investigators found that subjects taking linaclotide had a greater response to the FDA’s IBS-C endpoint compared with those taking placebo (34 versus 14 %; p \ 0.0001; NNT 5.1). The use of linaclotide resulted in a greater reduction of abdominal pain compared with placebo (48.9 versus 34.5 %; CI 4.7–13.1; NNT 7). Patients taking linaclotide also had a greater increase in the number of complete spontaneous bowel movements, compared with baseline, than patients taking placebo (48 versus 23 %; CI 3.2–5.4; NNT 4). Additionally, linaclotide treatment led to a statistically significant improvement in the secondary endpoints—abdominal pain, abdominal discomfort, abdominal bloating, stool frequency, stool consistency and severity of straining—even at 26 weeks. Diarrhoea was again the only adverse effect significantly greater in patients taking linaclotide than in those taking placebo, and it occurred in 19.7 % as compared with 2.5 %, respectively. Linaclotide is contraindicated in children aged B6 years and should be avoided in those aged \18 years, given the lack of available evidence in paediatrics. In summary, linaclotide has been shown to improve symptoms of IBS-C and abdominal pain, and it resulted in minimal systemic effects in two major trials; therefore, it is a reasonable option for treating IBS-C. 3.4 Serotonin 5-HT4 Receptor Agonists Serotonin 5-HT4 receptor agonists (5HT4-RAs) are effective in treating symptoms of IBS-C, but they are not approved in the USA at this time. The GI tract hosts 95 % of the serotonin available in the body, and activation of these receptors in the GI tract stimulates the peristaltic reflex, enhances intestinal secretions and reduces visceral hypersensitivity [66], making 5HT4-RAs a viable treatment option in treating patients with IBS-C. The 5HT4-RA tegaserod has been widely studied and improved global IBS-C symptoms [67], but it was removed from the US market in 2007 because of increased cardiovascular events. Later, a larger observational cohort study found conflicting information in regard to tegaserod’s safety [68]. Tegaserod remains available with FDA authorization and through investigational new drug (IND) approval for emergency use for life-threatening events or situations serious enough to warrant hospitalization [69]. Prucalopride is a selective 5HT4-RA that does not affect the 5-HT1 or hERG channel, thus minimizing cardiovascular effects [70]. It is approved by the European Medicines Agency for the treatment of chronic constipation but is not FDA approved. Three separate phase 3 trials have


shown prucalopride to be efficacious in chronic constipation over a 12-week course of treatment [70–72], but RCTs evaluating its use in IBS are still underway. One small study sponsored by Janssen Pharmaceuticals showed that prucalopride increased gastric, small-bowel and ascending colon emptying in patients with chronic constipation and IBS-C patients; however, a breakdown stating which patients had chronic constipation versus IBS-C was not provided [73]. Another 5HT4-RA, renzapride, failed to show efficacy over placebo in treating IBS-C, resulting in cessation of development by the manufacturer [74, 75]. There is no available 5HT4-RA with proven safety and efficacy in treating IBS; however, others currently in phase 2b studies, such as ATI-7505 and Velusetrage (TD-5108), may prove useful for treating IBS-C [76].

4 IBS-D 4.1 Anti-Diarrhoeal: Loperamide The anti-diarrhoeal loperamide is a l-opioid agonist used to treat patients with IBS-D. This OTC anti-diarrhoeal benefits patients with IBS-D by slowing colonic transit and decreasing bowel frequency, without sedation as it does not cross the blood–brain barrier. Loperamide is typically dosed at 2 mg, but a dosing of 2–4 mg prior to an episode of faecal urgency may be considered. Relatively little evidence exists for use of loperamide to treat IBS-D. Additionally, most existing trials were published prior to 2000 and contain limitations, including the lack of standardized diagnosis and treatment efficacy, lack of categorizing patients into IBS subtype and a short study duration. Two RCTs have evaluated patients with IBS-D [77, 78]. Both trials showed that loperamide improved stool consistency, with a 100 % improvement with loperamide compared with placebo, 20–45 % (p = 0.006), but overall IBS symptoms were not improved. A second double-blind RCT evaluating the use of loperamide compared with placebo in patients with IBS found that loperamide improved stool consistency (32 %) and decreased defecation frequency (36 %) and intensity of pain (30 %) during a 5-week treatment [79]. The loperamide group reported more nocturnal abdominal pain that was not seen in the placebo group. Another small, double-blind, crossover RCT evaluated loperamide in patients with IBS who failed to respond to bran supplementation [80] and found that loperamide improved small-bowel transit (p = 0.001), whole-gut transit (p = 0.01), diarrhoea (p = 0.01) and urgency (p = 0.01) as compared with placebo. Others have shown that loperamide may be beneficial in IBS-D for up to 13 weeks [78]. Common adverse effects with loperamide use include constipation, abdominal cramping and

nausea. It is contraindicated in acute dysentery. In summary, loperamide can be effective in improving stool consistency, urgency and defecation frequency; however, abdominal pain is likely not improved. 4.2 Antibiotics Rifaximin is a semi-synthetic antibiotic shown to improve global IBS symptoms in patients with IBS-D [81]. Rifaximin has low oral bioavailability, with less than 0.4 % of it detected in blood and urine after oral administration [82]. Rifaximin covers a broad spectrum of coverage including Gram-negative, Gram-positive and anaerobic bacteria and is commonly used for treatment of traveller’s diarrhoea and occasionally Clostridium difficile. The dose of rifaximin used to treat IBS is typically 550 mg administered orally twice or three times daily for 2 weeks. The exact regimen for rifaximin, and in particular the frequency of use, has not been established. Two landmark trials—TARGET 1 and TARGET 2— showed the benefit of rifaximin in IBS-D [83]. The combined studies evaluated 1,260 patients with IBS without constipation diagnosed using the Rome II criteria and found that oral rifaximin 550 mg given three times daily for 14 days improved global IBS symptoms for at least 2 out of 4 weeks after treatment as compared with placebo (40.7 versus 31.7 % improvement rates; p \ 0.001); the NNT for global IBS symptoms was 11. IBS-related abdominal pain, loose or watery stools, and bloating also significantly improved with rifaximin compared with placebo for at least 2 of the first 4 weeks. Improvements in IBS global symptoms, IBS-related abdominal pain, bloating, and loose or watery stools continued at 10 weeks posttreatment (p = 0.001). Furthermore, the side effect profile with rifaximin was similar to that of placebo. A recent meta-analysis evaluated the use of rifaximin compared with placebo in treating IBS and found that rifaximin was more efficacious than placebo in improving global IBS symptoms (odds ratio 1.57, CI 1.22–2.01; NNT 10.2) [84]. This meta-analysis compared differences between the trials and found that studies with higher cumulative rifaximin doses resulted in higher response rates, which supports the use of rifaximin 550 mg three times daily instead of twice daily. Other antibiotics such as neomycin [85] and metronidazole [86] have shown similar benefits in treating IBS; however, they have not been compared with rifaximin, and future well-designed trials are needed. Despite the potential benefits of antibiotic therapy, antibiotic resistance is a concern when antibiotics are used for chronic conditions, although evidence linking rifaximin with drug resistance is lacking. One retrospective chart review found that [75 % of patients re-treated up to 5 times with rifaximin successfully responded without a


decrease in the duration or effect with subsequent treatments, which suggests that there is little resistance to oral rifaximin [87]. Unfortunately, the high re-treatment rate suggests that symptoms of IBS are not cured by rifaximin, as is classically the case with traveller’s diarrhoea, therefore the course of treatment is unknown. Another limitation of rifaximin therapy is the medication cost—a 2-week treatment of rifaximin 550 mg three times daily is estimated to cost $1,100 in the USA. Commonly reported adverse reactions with rifaximin include flatulence, abdominal pain, tenesmus, faecal incontinence, nausea and headaches. However, on the basis of a pooled analysis of RCTs using rifaximin in IBS, the rates of GI-associated adverse events, drug-related adverse events and infections were found to be similar to those observed with placebo [88]. Overall, rifaximin can improve global IBS symptoms in patients with IBS without constipation and is associated with minimal adverse effects and persistent improvement up to 10 weeks after a 2-week treatment period. 4.3 Serotonin 5-HT3 Receptor Antagonists The serotonin 5-HT3 receptor antagonist alosetron is the only available serotonergic approved by the FDA for the treatment of women with severe IBS-D. Other 5-HT3 receptor antagonists include ramosetron, which is available in multiple countries in Asia for the treatment of IBS, and ondansetron, a widely available medication used commonly to treat nausea. 5-HT3 receptors are ion channels distributed throughout the GI tract, which regulate visceral pain, colonic transit and GI secretions; 5-HT3 inhibition slows colonic transit time, reduces gastrocolic reflexes, decreases chloride and water secretion, increases colonic compliance and reduces intestinal sensitivity to distension causing pain [89]. Alosetron was first introduced into the US market in February 2000 but was later voluntarily withdrawn in November of the same year, given an associated risk of ischaemic colitis. The FDA reintroduced alosetron in June 2002 with restricted access for women with severe IBS-D who have failed conventional therapy. The recommended dose of alosetron is 0.5 mg twice daily, and the response to treatment should be re-assessed at 4 weeks to determine whether a dose titration to 1 mg twice daily is recommended. Four weeks after the dose titration, patient response should be re-assessed to consider discontinuation of the medication if it does not provide adequate benefit. Multiple well-designed RCTs have shown benefit with alosetron for IBS-D treatment. One double-blind RCT evaluated 647 female patients with IBS-D diagnosed using the Rome I criteria and found that a greater number of patients taking alosetron 1 mg twice daily reported

adequate relief for all 3 months of treatment compared with placebo (41 versus 29 %, a difference of 12 %, CI 4.7–19.2) [90]. Alosetron also decreased urgency and stool frequency, while increasing stool firmness. Higher rates of constipation were seen with alosetron compared with placebo (30 versus 3 %), which resulted in higher dropout rates from the alosetron group compared with the placebo group (24 versus 16 %). Another double-blind RCT evaluating 801 non-constipated, mostly IBS-D female patients (98 %) found that alosetron 1 mg twice daily resulted in a greater proportion of days with satisfactory control of faecal urgency compared with placebo (73 versus 57 %; p \ 0.001). In addition, a greater number of patients taking alosetron had improvement in IBS global symptoms as compared with those taking placebo at 12 weeks (76 versus 44 %; p \ 0.001). IBS global responders had more days with satisfactory control of urgency at week 12, firmer stools, fewer stools per day and fewer days with incomplete evacuation, compared with non-responders. Lastly, abdominal pain can even improve with alosetron [91]. Camilleri et al. found that a higher proportion of patients taking alosetron reported adequate relief of pain for 3 months compared with those taking placebo (43 versus 26 %; p \ 0.001). Improvement was observed by the end of the fourth week and persisted throughout the study period. The FDA approved alosetron for women, given a disproportionally large number of women compared with men in the clinical trials. However, a double-blind RCT evaluated the use of alosetron in men with IBS-D at doses of 0.5, 1, 2 and 4 mg twice daily compared with placebo and found that it does benefit men [92]. Adequate relief of IBS pain during the treatment phase was seen in 53 % of patients taking alosetron 1 mg twice daily compared with 40 % of those in the placebo group (p = 0.04). A metaanalysis evaluating all three double-blind RCTs in men with IBS found that a larger number of men taking alosetron had adequate relief from IBS pain as compared with placebo (CI 1.02–1.47; p = 0.03) [92]. Safety data from the FDA alosetron risk management plan has shown that the rates of ischemic colitis were only 0.95 cases per 1,000 patient-years and the rates of complications of constipation were 0.36 cases per 1,000 patientyears [93]. No mesenteric ischemia, surgeries, transfusions or deaths occurred in patients with ischemic colitis, and none of the cases of constipation were associated with toxic megacolon, perforation, surgeries, transfusions or deaths. Although high-quality data exist that support use of alosetron in IBS-D to improve global IBS symptoms and pain relief with minimal risks, clinicians must use caution in regard to potential adverse events with alosetron use. Other 5-HT3 antagonists have also shown benefit in IBS. For example, ramosetron, based on phase 2b RCTs, has


been shown to improve global symptoms of IBS, including abdominal pain, and bowel habits in men and women with IBS-D when given at a dose of 5 lg daily for 12 weeks [94]. The effect on global IBS symptoms was seen at week 1 and maintained through 12 weeks, with 47 % response rates with ramosetron as compared with 27 % with placebo (p \ 0.001). Additionally, ramosetron significantly improves stool consistency compared with placebo in male patients with IBS-D when the Rome III criteria are used [95]. Ramosetron is not yet currently available in North America or Europe. Another 5-HT3 under investigation for use in IBS is ondansetron. A double-blind RCT, which evaluated 120 subjects with IBS-D over 3 weeks, showed that ondansetron improved stool consistency compared with placebo [96]. The mean difference in stool form between ondansetron and placebo was -0.9 using the Bristol Stool form score (CI -1.1 to -0.6; p \ 0.001). The study showed multiple additional benefits with ondansetron use, which also resulted in fewer days with urgency (p \ 0.001), lower urgency scores (p \ 0.001), reduced frequency of defecation (p = 0.002), less bloating (p = 0.002) and a decreased symptom severity score (p = 0.001). Pain scores were not significantly different from those observed with placebo, however. Again, the GI side effects with ondansetron included constipation. 4.4 Emerging Therapies Emerging therapies in the pipeline, at various phases of development, are focused on the different pathophysiologies of IBS. These agents are either already indicated for use in other GI disorders and are being expanded for use in IBS, or they are new medications targeting the several postulated mechanisms resulting in symptoms of IBS. A summary of the various treatments for IBS-C and IBS-D is illustrated further in Table 3. Promising new treatments for IBS-C include the newer serotonergic agents such as naronapride and velusetrag, which are potent agonists of 5-HT4 receptors and have been shown in two phase 2 RCTs to accelerate colonic transit and improve abdominal pain in patients with chronic constipation. Both have similar safety profiles to prucalopride [97]. Another novel group of agents for the treatment of chronic idiopathic constipation and potentially IBS-C are the bile acid modulators such as chenodeoxycholate and elobixibat—an ileal bile acid transporter (IBAT) inhibitor—which have been shown to promote intestinal secretion and improve the number of spontaneous bowel movements in IBS [98]. Bile acids are excreted into the biliary system and the small intestine after being synthesized in the liver and play a major role in absorption of dietary lipids, fat-soluble vitamins and cholesterol. Later,

they are reabsorbed through the apical lumen IBATs in the terminal ileum, and they later enter the enterohepatic pathway through the portal vein. A reduction in bile acid synthesis can lead to constipation [99] and, conversely, then inhibition of IBAT leads to a reduction in reabsorption of ileal bile acids, which then increases proximal colonic motility. RCTs in patients with IBS-C have demonstrated that ileocolonic delivery of chenodeoxycholate at doses of 500 and 1,000 mg a day accelerates bowel transit, leading to increased bowel frequency in IBS-C. Elobixibat is a one such novel IBAT inhibitor with promising evidence for the treatment of both chronic idiopathic constipation and IBSC. RCTs using elobixibat (15 and 10 mg) in patients with chronic constipation have shown improved colonic transit and an increase in the frequency of spontaneous bowel movements but not bowel frequency. Trials in IBS-C are pending at this time. For the treatment of IBS-D, several newer options are being evaluated. The anti-inflammatory 5-aminosalicylic acid (5ASA) derivatives, including mesalamine, are under investigation for treatment of post-infectious IBS, given a body of evidence in the literature suggesting the presence of increased intestinal permeability and inflammation, including changes in peripheral and tissue cytokine levels, and increased enterochromafin cells and activated T lymphocytes in the colon of patients with post-infectious IBS [100–102]. Two RCTs comparing mesalamine with placebo in patients with IBS-D were presented at the 2014 Digestive Diseases Week [101, 102]. While one trial (n = 68) showed no significant improvement of the primary outcome of stool frequency or secondary measures of abdominal pain and overall relief of symptoms in IBS after a 12-week treatment phase [101], another RCT (n = 185) showed a trend towards overall patient satisfaction in improvement of abdominal pain and bloating, although the results were not statistically significant [102]. Whether larger RCTs will prove mesalamine to be of benefit in treatment of IBS is yet to be determined. Other emerging treatments are the benzodiazepine modulators such as dextofisopam, which affect autonomic function—both GI motor and sensory activity. RCTs using dextofisopam have shown adequate relief of IBS symptoms compared with placebo in patients with IBS-D [103]. Other exciting treatments for IBS include the selective l-opioid receptor agonists asimadoline and the mixed agonist/antagonist eluxadoline. They reduce GI transit by decreasing the contractility of the intestines and by inhibiting intestinal secretions. These agents relieve pain and improve diarrhoea in patients with IBS-D [104, 105]. Although large RCTs in un-subtyped IBS have not shown asimadoline to improve pain/discomfort as compared with placebo [105], patients with IBD-D experienced significant improvement in adequate relief of IBS pain (47 %)

Medication

Elobixibat and others

Velusetrag (TD-5108) Chenodeoxycholate

Naronapride (ATI-7505)

Aminosalicylic acid derivative [100–102]

Mesalamine

Pharmacotherapeutic options for IBS-D

IBAT inhibitors [99]

Bile acid modulator [98]

5HT4-RAs [97]

Pharmacotherapeutic options for IBS-C

Drug class

Anti-inflammatory agent. May provide benefit in post-infectious IBS as a PPAR-c agonist resulting in modulation of inflammatory cytokine production and TNF activation while decreasing transcriptional activity of NK-jB. Results in inhibition of prostaglandins and leukotrienes, and a decrease of interleukin-1

Stimulate colonic motility and secretion by reducing reabsorption of bile acids at the distal ileum through inhibition of IBAT

Promotes intestinal secretion and motility in proximal colon, activates adenylate cyclase, increases mucosal permeability and inhibits apical Cl-/OH- exchange. Genetic variations in negative feedback inhibition of bile acid synthesis may affect acceleration of colonic transit

Simulate the peristaltic reflex, enhance intestinal secretions and reduce visceral hypersensitivity

Mechanism of action

Mesalazine has been shown to decrease faecal bacteria and rebalance microbiota. In a 12-week double-blind RCT of 20 patients with postinfective IBS, mesalamine did not improve IBS global symptoms, abdominal pain, bloating, stool urgency, stool consistency or quality of life [100]. Although this trial did not find a difference, mesalamine may have positive effects on IBS, as this trial was underpowered, with 5 % power to find a 20 % improvement over placebo in the primary outcomes. Two additional RCTs did not show significant improvements with mesalamine compared with placebo [101, 102]

Elobixibat showed benefit over placebo in colonic transit time, loose stool consistency, constipation rating, ease of stool passage and reduction of straining in 36 females with functional constipation in a double-blind RCT. Elobixibat 20 mg improved colonic transit at 24 h compared with placebo (p = 0.04). Although improvement was seen with the 15 mg dose, it was not statistically significant (p = 0.18); however, colonic transit was significantly improved with both the 15 and 20 mg doses (p = 0.002 and 0.001, respectively). Loose stool consistency improved with the 15 and 20 mg doses (p \ 0.005)

Chenodeoxycholate was evaluated in 36 female patients with IBS-C in a placebo-controlled double-blind RCT for 4 days and resulted in improved colonic transit (p = 0.005) and ascending colon emptying time (p = 0.028) compared with placebo. Loose stools, increased stool frequency and ease of passage were also significantly improved with chenodeoxycholate. Lower abdominal cramping/pain, diarrhoea and nausea were increased with chenodeoxycholate compared with placebo. Of note, lower abdominal cramping/pain rates were 45 and 42 % with chenodeoxycholate 500 and 1,000 mg respectively, compared with 0 % in the placebo group (p = 0.01)

Naronapride and velusetrag showed improvements in achieving C3 spontaneous bowel movements in patients with chronic constipation compared with placebo. There is limited evidence in IBS at this time

Rationale for development

Table 3 Emerging therapies for the treatment of irritable bowel syndrome with diarrhoea (IBS-D), IBS with constipation (IBS-C) and IBS-related pain


Eluxadoline

Asimadoline

Mixed visceral lopioid receptor agonist/ antagonist [104]

Selective visceral j-opioid receptor agonist [105]

CFTR chloride ion channel and CaCC chloride ion channel inhibitor [106]

Crofelemer

Pharmacotherapeutic options for IBS-related pain

Dextofisopam

Medication

Benzodiazepine modulator [103]

Drug class

Table 3 continued

Use of crofelemer was evaluated in a double-blind placebo-controlled RCT in 242 patients with IBS-D for 12 weeks [106]. The primary endpoint was a responder for improvement in stool consistency. Crofelemer did not show significant improvement in stool consistency, stool frequency, urgency or adequate relief. An improvement with crofelemer 500 mg was seen in female patients with IBS-D in pain- and discomfort-free days at 3 months (26.1 versus 10.6 %; p = 0.0076). A statistically significant benefit was not seen in month 1 or 2, and there was no benefit in male patients with IBS-D

Asimadoline was evaluated in a placebo-controlled double-blind RCT of 596 patients with IBS (IBS-D, IBS-D and alternating IBS) for 12 weeks with a primary endpoint of the number of months of adequate relief of IBS pain or discomfort [105]. In patients with IBS-D and moderate baseline pain, asimadoline 0.5 mg resulted in a significant improvement in the total number of months with adequate relief of IBS pain or discomfort (46.7 versus 20.0 %), adequate relief of IBS symptoms (46.7 versus 23.0 %), pain scores (week 12: -1.6 versus -0.7), pain-free days (42.9 versus 18.0 %), urgency and stool frequency (-2.3 versus -0.3). Statistically significant improvement was not seen in patients with IBS, only in those with IBS-D and alternating IBS

Selective j-opioid receptor agonist. Peripherally restricted at doses \5 mg, reduces nociceptive reflex associated with peripheral antinociceptive properties

Regulates fluid secretion and water loss due to diarrhoea and normalizes chloride ion and water flow in the GI tract by inhibiting the cAMP-stimulated CFTR chloride ion channel and the CaCC in the luminal membrane

Eluxadoline was evaluated in 807 patients with IBS-D in a phase 2 double-blind placebo-controlled RCT for 12 weeks [104]. The primary endpoint was a mean reduction in the pain score from baseline of C30 % and of at least 2 points on a 0–10 scale and a stool consistency score of 3 or 4 on the Bristol Stool Scale (1–7) for at least 66 % of daily entries during that week, at week 4. More patients receiving eluxadoline 25 mg (12.0 %) or 200 mg (13.8 %) met the primary endpoint compared with placebo (5.7 %; p \ 0.05). Greater improvements in bowel movement frequency and urgency, global symptoms, quality of life and adequate relief of assessments were seen with eluxadoline 100 and 200 mg (p \ 0.05 for all)

Dextofisopam was compared with placebo, measuring the number of months of adequate relief of IBS symptoms in 140 patients with IBS-D (78 % of patients) or alternating IBS in a double-blind RCT for 12 weeks. Patients taking dextofisopam had a greater number of months (1.7 months) of adequate relief of IBS symptoms compared with placebo (1.3 months; p = 0.033), a 14 % advantage in relief of symptoms over 3 months [103]. The difference between the groups remained statistically significant throughout the study, but the effect diminished with time. Patients taking dextofisopam experienced more abdominal pain (12 versus 4 %) and headaches (12 versus 5 %) compared with placebo


Reduces GI transit and faecal output by reducing contractility of intestinal tissue, and inhibits neurogenically mediated secretion

Mechanism is not completely understood. Binds to the 2-3benzodiazepine receptor, which may affect autonomic function, including GI motor and sensory activity

Mechanism of action


Pregabalin

Multiple medications, initial studies with chlorphenamine

Second-generation a2d ligand [108, 109]

Histamine-1 receptor antagonists [110]

Exact mechanism of action is unknown; however, it may bind potently to the auxiliary protein associated with voltage-gated calcium channels, reducing depolarization-induced calcium influx at the nerve terminals, and consequently the release of several excitatory neurotransmitters, glutamate, noradrenaline, substance P and CGRP. These neurotransmitters are thought to provide benefit in IBS Patients with IBS have low-grade inflammation, increased mast cells and exaggerated histamine release in the colonic mucosa. Blocking histamine decreases response to pain in experimental models

Replenishes hippocampal glutamate–glutamine

Mechanism of action

In a small trial of 12 patients with IBS, chlorphenamine showed different responses in sympathetic vasomotor tone between patients with IBS and controls. Chlorphenamine increased histaminergic activity in patients with IBS

In patients with fibromyalgia, pregabalin has been demonstrated to improve pain and function compared with placebo and is well tolerated [108]. In patients with IBS and rectal hypersensitivity, pregabalin increased sensory thresholds from baseline for first sensation (p = 9.945), desire to defecate (p = 0.008), pain (p = 0.048) and rectal compliance (p = 0.0001) as compared with placebo [109]

Niddam et al. [107] showed a reduction in hippocampal glutamate– glutamine in patients with IBS. This suggests that there may be abnormal hippocampal glutamatergic neurotransmission in patients with IBS compared with controls, possibly due to (1) hippocampal remodelling and (2) altered modulatory feedback to the hippocampus


5HT4-RA 5-HT4 receptor antagonist, CaCC calcium-activated chloride ion channel, cAMP cyclic adenosine monophosphate, CFTR cystic fibrosis transmembrane conductance regulator, CGRP calcitonin gene-related peptide, Cl-/OH- chloride/hydroxide, GI gastrointestinal, IBAT ileal bile acid transporter, NK-jB nuclear factor j-light-chain-enhancer of activated B cells, PPAR-c peroxisome proliferator-activated receptor-c, RCT randomized controlled trial, TNF tumour necrosis factor

Glutamate

Medication

Non-essential amino acid [107]

Drug class

Table 3 continued



Altered Bowel Motility: IBS-C Psyllium, osmotic laxatives (PEG), sorbitol/lactulose, lubiprostone, linaclotide, 5HT4 receptor agonists, STW5 Emerging Therapies •IBAT

Altered Bowel Motility: IBS-D Rifaximin, loperamide, psyllium, 5HT3 receptor antagonists Emerging Therapies: •Bile acid sequestrants •Crofelemer •ASA derivatives

Altered Bowel Motility Pain: Antispasmodics, antidepressants, probiotics, STW5, melatonin Emerging Therapies •Mixed visceral Muopioid receptor agonists/antagonists, •Pregabalin •Selective visceral Kopioid receptor agonists •H1 receptor antagonists •NK receptor antagonists

Pain

Bloating Bloating: Antispasmodics, antiflatulents, probiotics, linaclotide, rifaximin, antidepressants: citalopram, fluoxetine

Fig. 2 Treatments for irritable bowel syndrome (IBS) by predominant symptoms (altered bowel motility, pain, bloating). For symptoms of altered bowel motility, the treatments are separated on the basis of symptoms of diarrhoea (IBS-D) or constipation (IBS-C). Some of the

emerging therapies are also provided with respect to each of these IBS symptoms. ASA aminosalicylic acid, IBAT ileal bile acid transporter, NK neurokinin, PEG polyethylene glycol, STW5 Iberogast

compared with placebo (20 %), and reduced stool frequency [105]. Eluxadoline was evaluated in a phase 2 study of 807 patients with IBS-D [104]. Eluxadoline at doses of 25 mg and 200 mg resulted in a greater number of patients achieving clinical response at week 4 (12 and 14 %, respectively, versus 6 % with placebo; p \ 0.05 for all). In addition, improvements in stool frequency, urgency, global symptoms, quality of life and adequate relief of IBS symptoms were seen with eluxadoline 100 and 200 mg (p \ 0.05 for all). Another treatment for IBS-D is the drug crofelemer, which has been shown to normalize chloride ion channel and water flow in the GI tract and therefore regulates fluid secretion and water loss by inhibiting ion channels in the luminal membrane [106]. However, crofelemer did not improve bowel frequency when compared with placebo, although an improvement in pain/discomfort was seen in females with IBS-D. Other treatments for abdominal pain in IBS have also been explored. The agents under study include glutamate, which may remodel abnormal hippocampal glutamatergic neurotransmission, which may be disturbed in patients with IBS [107], and pregabalin, an a-2-d ligand already used for

treatment of fibromyalgia [108, 109]. Another group of medications, the histamine-1 receptor antagonists, may block histamine and, by altering the response to sympathetic vasomotor tone, may then decrease pain thresholds in IBS [110]. Several new agents are now being evaluated for treatment of IBS, and they need to be studied in rigorously designed RCTs using stringent criteria for the recruitment of subjects with well-defined control groups, strict safety measures, long-term durations and, ideally, validated IBS diagnostic criteria and biomarkers, which do not yet exist. Figure 2 summarizes these new treatments discussed for IBS subtypes and specific symptoms.

5 Conclusion IBS is a complex GI disorder with a heterogeneous patient population and symptom profile, a lack of validated diagnostic criteria and a complex pathophysiological basis. All of these elements cause the management of IBS to be challenging. Treating IBS requires effective communication between healthcare providers and patients in addition


to early identification of psychological comorbidities. A careful initial evaluation and patient interview can help guide treatment strategies. One must consider a patient’s symptoms and consider the properties of the different pharmacological agents, including the mechanism of action, efficacy, dosing regimen, safety profiles, contraindications, cost and long-term data. This increase in agents and information has further armed practitioners with better tools to manage this challenging disease. Acknowledgments Our sincere thanks to Glen Whelan, Pharm.D., for help with the figures in our manuscript. Funding and Conflicts Statement Jose Barboza has no conflicts of interest to report. Baharak Moshiree has received grants and consulting fees/honorarium from Prometheus Laboratory and has no other conflicts of interest to report. Nicholas Talley has received grant/research support from Abbott Pharmaceuticals, Ironwood, Janssen, Prometheus, Rome III Study, Salix liS Study, Takeda, and owns patents for biomarkers of irritable bowel syndrome.

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Irritable bowel syndrome: current and emerging treatment options.

New and Emerging Treatment Options for Irritable Bowel Syndrome.

Irritable bowel syndrome: emerging paradigm in pathophysiology.

Constipation-predominant irritable bowel syndrome: a review of current and emerging drug therapies.

Current and emerging treatments for irritable bowel syndrome with constipation and chronic idiopathic constipation: focus on prosecretory agents.

New and emerging therapies for the treatment of irritable bowel syndrome: an update for gastroenterologists.

Irritable bowel syndrome: a concise review of current treatment concepts.

Letter: Irritable-bowel syndrome.

Ondansetron and irritable bowel syndrome.

Irritable bowel syndrome.

Irritable bowel syndrome.

Rifaximin: irritable bowel syndrome.

Diet and irritable bowel syndrome.

Irritable bowel syndrome.

Irritable bowel syndrome.

Psychological Interventions for Irritable Bowel Syndrome and Inflammatory Bowel Diseases.

Emerging Pharmacologic Therapies for Constipation-predominant Irritable Bowel Syndrome and Chronic Constipation.

Irritable bowel syndrome and diet.

Homeopathy for treatment of irritable bowel syndrome.

Oral hyoscine butylbromide for irritable bowel syndrome?

Oral hyoscine butylbromide for irritable bowel syndrome?

Carotid artery stenting: current and emerging options.

Birdshot uveitis: current and emerging treatment options.

Probiotic Yeast Therapy for Irritable Bowel Syndrome.