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Therap Adv Gastroenterol. 2009 May; 2(3): 169–181.
PMCID: PMC2779541
NIHMSID: NIHMS123101

Therapeutic Advances in Functional Gastrointestinal Disease: Irritable Bowel Syndrome

Abstract

Reported prevalence rates of irritable bowel syndrome (IBS) are between 8% to 20% in the US general population with an average medical expenditure of US$1.35 billion direct and US$205 million indirect costs. Current pathophysiologic theories are based on abnormalities of both the brain and gut, thus setting a new stage for current and future therapeutic approaches. There are numerous treatment options in IBS acting centrally and peripherally by influencing motility and visceral sensitivity. Clinical evidence is variable; however, newer emerging treatments are being evaluated using better-designed clinical trials. Accurate assessment of IBS drug efficacy is still hampered by heterogeneity of the IBS population. Novel methods such as pharmacogenomics or brain imaging may be helpful in the future to better understand and characterize IBS patient subtypes, and this in turn will lead to more specific and efficient therapeutic options. Patient subpopulation measurement of side effects is also a clinical challenge and further understanding could improve treatment efficacy by enhancing the patient compliance.

Keywords: irritable bowel syndrome, drug therapy, efficacy, side effects

Introduction

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder centered on pain symptoms and changes in bowel habits such as constipation and diarrhea. It is also associated with cramping and bloating for at least 6 months prior to diagnosis (Rome III criteria). Reported prevalence rates of IBS are between 8% and 20% in the US general population with a 2:1 female to male ratio [Muller-Lissner et al. 2001]. This results in an average medical expenditure of US$1.35 billion direct and US$205 million indirect costs [Inadomi et al. 2003]. The pathophysiology of IBS is considered to be multifactorial, generated by a complex interplay between genetic, psychosocial and environmental factors that impact the patient's life quality, by producing abnormalities in central nervous system processing as well as in the periphery where they generate abnormal motility and secretory activity [Roka et al. 2007; Vassallo et al. 1992].

IBS was believed to be mainly a peripheral condition; however, current pathophysiologic theories are centered on the abnormalities of both the brain and gut, thus setting a new stage for current and future therapeutic approaches [Mayer et al. 2002]. Medications can improve the symptoms in IBS by targeting biochemical and physical mechanisms in the periphery (i.e. anticholinergic drugs, laxatives, antidiarrheals, antispasmodic drugs), or possibly with a dual mechanism at the periphery and at a central level (i.e. selective serotonin reuptake inhibitors (SSRIs), serotonin receptor modulators, tricyclic antidepressants, neurokinin antagonists, opioid drugs). This review aims to assess the developing IBS pharmacological armamentarium that is based upon emerging research in neuroenteric biology (Table 1).

Table 1.
Possible therapeutic approaches in the treatment of irritable bowel syndrome.

The IBS clinical trials that led to FDA drug approvals showed statistically significant improvement of symptoms when the effect on patients was compared with healthy controls but the clinical response rate in the population was rarely over 75%. For example, Camilleri et al. [2000] found a total benefit of 41% in IBS patients with a therapeutic gain of 12% when compared with placebo, and a number needed to treat of 7. A French survey reported that 87% of patients diagnosed with IBS used medication at some point but only about half (47%) noticed an improvement [Dapoigny et al. 2004]. These clinical trial results suggest that despite a significant clinical response this effect may be less evident when applied to a broader population of IBS patients. Another limitation that decreases overall use and efficacy of IBS medications is their side-effect profiles, with reports of ischemic colitis or cardiovascular problems in some cases.

Predominantly central-acting drugs

Selective serotonin reuptake inhibitors

SSRIs potentiate the effect of serotonin because they inhibit its reuptake in the presynaptic compartment, thus increasing the quantity available to act on postsynaptic receptors. Because serotonin is a neuromediator highly involved in cortical processes, its modulation is widely used in the treatment of mood disorders, anxiety and a variety of somatoform conditions such as fibromyalgia [Arnold et al. 2007], IBS [Spiller, 2007], and functional dyspepsia [Harasiuk et al. 2007]. The SSRIs mechanism of action to improve the symptoms of IBS is still controversial. These drugs interact mainly at a central level by balancing the emotional-affective compartment that may be involved [Guthrie et al. 2003].

Creed and coworkers showed that both psychotherapy and the SSRI paroxetine can improve pain symptomatology in IBS patients; however, it is not clear if the beneficial effect of SSRIs is due to improvement of pain symptoms or through improvement of depression [Creed et al. 2008, 2003]. In one of the largest randomized controlled trials of tricyclic antidepressants (TCAs) in 431 patients with functional bowel disorders, the beneficial effects of TCAs not related to dosage. Treatment was more effective in females with moderate disease and no depression than in those with severe disease and depression [Halpert et al. 2005]. Thus, the efficacy of these psychotropic drugs in IBS is still unclear.

Despite the evidence of the antinociceptive effects of the SSRIs in non-GI conditions such as premenstrual dysphoric disorder and fibromyalgia [Wassem et al. 2002; Romano et al. 1999], a study assessing specifically viscerosensitive changes in rats exposed to colonic distensions failed to prove any difference [Kall et al. 2007]. Similarly, a number of studies in IBS and healthy subjects failed to demonstrate a reduction in pain perception during rectal balloon distensions after an SSRI was administered [Talley et al. 2008; Tack et al. 2006; Kuiken et al. 2003].

To date, the largest randomized placebo uncontrolled study assessing the effects of SSRI in the IBS population reported a significant improvement of pain symptoms (p50.001) and physical component score (p50.001) in 86 patients compared with another IBS sample that received standard treatment care [Creed et al. 2003]. Talley et al. [2008] found that citalopram improved bowel symptoms in patients with IBS but did not have any effect specifically on pain symptoms. The same investigators found also that when compared to the TCAs, the SSRIs had less efficacy on the psychological component.

There is also some evidence that the SSRIs may influence gut motility in animals [Coates et al. 2006] and in humans, decreasing the orocecal transit times and increasing the colonic motility index, the amplitudes of the contractions and the colonic compliance [Tack et al. 2006; Chial et al. 2003].

It is unclear at the moment if patients with IBS receive a real overall benefit from SSRI treatment. Probably, because of their important psychotropic action, this drug family could be very effective in selected IBS populations. Their prokinetic activity could make them a suitable treatment option for the IBS-C subtype. They have a better safety profile than TCAs, which is another reason to consider them in selected IBS patients. To date, there is no FDA-approved SSRI for treating IBS, and the efficacy of these drugs should be further assessed. Ongoing studies with escitalopram and citalopram will help to clarify the benefit of this drug family for patients with IBS.

Central and peripheral-acting drugs

Neurokinin receptor antagonists

Neurokinin-receptor (NKR) antagonists are a novel class of substances that possess a variety of actions centrally and in the periphery by blocking the activity of kinins at specific receptors. There are three types of neurokinin receptors – differentiated by their characteristic functions and coding genes – and specific agonists and antagonists acting on them. Kinins are involved in the pathology of functional digestive disorders such as functional dyspepsia [Stanghellini et al. 2003], IBS and functional vomiting [Andrews, 1999] – for example, administration of neurokinin A (NKA)-induced IBS-like symptoms in healthy subjects. There is also evidence of NKR increased expression associated with visceral hypersensitivity [Lecci et al. 2004] and stress [Toulouse et al. 2000], which may explain the rationale of using NKR antagonists in conditions such as IBS. At the moment, the potential of these compounds is under research and data about their future clinical utility is evolving.

NK1R (neurokinin 1 receptor) antagonists could be of benefit in improving pain in IBS because of their demonstrated multiple roles at the GI level. TAK-637, one of the most researched NK1R antagonists diminished the secretory activity induced with a NK agonist in isolated nonin-flamed colonic mucosal sheets [Venkova and Greenwood-Van Meerveld, 2004]. In another study, TAK-637 diminished the colonic motility induced with substance P and an NK1 agonist but did not change the motility patterns in the nonstimulated colon [Okano et al. 2001]. Intriguingly, Onori et al. [2003] found an antipropulsive effect on distal colon with the administration of two other NK1R antagonists: MEN-10930 and SR-140333 in vitro. Visceral hypersensitivity induced with colonic distensions and acetic acid administration were significantly diminished by TAK-637, suggesting the involvement of NK1 in nociception but also the potential of NK1R antagonists in treating visceral pain conditions [Okano et al. 2002]. Data regarding the antinociceptive role of NK1R in humans is limited, with only one study showing a trend in reducing emotional responses to rectal balloon distensions after a 7-day trial of ezlopitant in 14 IBS patients [Lee, 2000].

NK2R antagonists act by specifically blocking NK2 receptors located in the muscularis mucosa and propria of the ileum and colon [Renzi et al. 2000]. A number of animal studies demonstrated that NK2R antagonists (SR489968, napadutant) can decrease pain symptoms generated with intrarectal balloon stimulation acting centrally [Julia et al. 1994] or in the periphery perhaps acting directly at a primary afferents level [Toulouse et al. 2000] by diminishing their firing rate [Lecci et al. 2004]. There is also evidence in animals that NK2R antagonists act at the GI level by reducing contraction amplitudes [Mule et al. 2000]. NK2R antagonists also inhibit secretory activity generated with intrarectal balloon distensions by acting at central or peripheral levels [Eutamene et al. 1997].

The antinociceptive effect of the NK2R antagonist, nepadutant, was also demonstrated in visceral pain models with intraluminal injection of glycerol in which the sensitization was diminished (unpublished data) [Lecci et al. 2004]. Lordal et al. [2001] also reported that nepadutant reduced the motility-stimulating effects induced with NKA on amplitude and frequency of contractions in 34 human subjects. Even though two of the subjects developed IBS-like symptoms after NKA administration, the authors did not specifically assess pain symptom reduction after the NK2R antagonist was also injected. Despite evidence of the potential for NK2R antagonists, there is no molecule as yet from this class that has been approved by the FDA for the treatment of IBS. NK3R antagonists bind with specificity to NK3 receptors that are particularly located in the GI tract at the level of submucosal and myenteric neural plexuses [Wang et al. 2002] where they are involved in excitability augmentation [Bertrand and Galligan, 1995].

Consistent with the actions of other classes of NKR antagonists, high doses of NK3R antagonists (SR142801 and SR 222200) manifest an inhibitory kinetic activity on isolated distal colon segments [Onori et al. 2001]. NK3R antagonists also have a significant antinociceptive role as demonstrated by animal and human experiments. Kamp et al. [2001] reported that NK3R antagonists but not NK1R or NK2R antagonists reduced the visceromotor response to noxious colorectal distention in rats. Similar results were reported by Fioramonti et al. [2003] who found that talnetant and SB-235375 decreased nocicep-tion in rats experiencing isobaric distensions by acting at a peripheral level. However, this antino-ciceptive effect of talnetant was not demonstrated in humans experiencing painful colonic stimulation [Houghton et al. 2007].

Even though there is intense basic science research to support drug development of neuro-kinin modulators, its translation into clinical effect on human subjects has not been entirely exploited yet. While neurokinin modulators are an exciting area for their potential, to date there is no FDA-approved medication from this class nor are there any active phase III trials.

Serotonin receptor modulators

Serotonin (5-hydroxytryptamine, 5-HT) modulators represent another class of drugs that has been rapidly evolving despite the fact that the role of serotonin in the control of GI function is incompletely understood [Gershon and Tack, 2007]. These molecules have a broad variety of complex effects on the GI tract resulting from their interaction with five subtypes of receptors located at the GI level: 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT7 that have different functional characteristics, are coded by different genes and are activated by specific agonists and antagonists.

5-HT3 modulators

This is one of the most well documented classes used in the treatment of IBS. The 5-HT3 receptors are located postsynaptically at the level of excitatory motor neurons and vagal afferents, mediating digestive related activities such as emesis, motility, secretion and visceral sensitivity. In animals, administration of 5-HT3 agonists produced an increase in colonic motility [Nagakura et al. 1996] while in humans it induced an increase of secretions and stimulation of vagal afferents, increasing visceral sensitivity [Fujita et al. 2005]. More importantly, the 5-HT3 antagonists have demonstrated relatively opposite actions in animal studies, such as decreasing visceral sensitivity by a central mechanism [Miranda et al. 2006], and significantly inhibiting colonic motility [Sanger and Wardle, 1994].

The actions of 5-HT3 receptor antagonists are widely documented in humans with alosetron, one of the members of this class, which had been approved for the treatment of IBS-D in females. Two brain-imaging studies [Nakai et al. 2005; Mayer and Bradesi, 2003] support that alosetron-treated IBS patients experience a reduction of visceral pain perception consistent with the reduction of cortical activity in auto-nomic networks. Serotoninergic regions of cortical activity are different between males and females, possibly showing that greater alosetron efficacy in female patients with IBS could be due also to central mechanisms [Nakai et al. 2005].

Alosteron is the only 5-HT3 antagonist currently FDA approved for the treatment of IBS-D in females for whom it induces significant improvement of GI symptoms such as abdominal pain and discomfort, urgency, stool frequency and consistency at 1 and 12 weeks’ timepoints [Camilleri et al. 2001; Lembo et al. 2001]. The largest meta-analysis to date by Andresen et al. [2007] found that for global improvement of GI symptoms, the alosetron risk ratio was 1.55 and slightly higher for the partial 5-HT3 antagonist, cilansetron (1.66). The pooled average number to treat was 4.2. Of note, this meta-analysis suggested that pain and discomfort improved in both men and women with diarrhea and nonconstipated IBS types. The most frequent reported side effect was constipation (20–30% of patients). There was a lower frequency of constipation in the d-IBS subgroup. Similarly, a study by Chang et al. [2005] showed that alose-tron had a significant effect in pain relief in men but not in most of the GI symptoms such as urgency or bloating.

The most concerning side effect experienced with alosetron is ischemic colitis, due to a yet unclear mechanism, with an incidence of 0.15% [Chang et al. 2006]. For concerns regarding reported cases of ischemic colitis and severe constipation, FDA suspended alosetron from the market in November 2000 and reintroduced it under a restricted access program in June 2002.

Cilansetron is not FDA approved for the treatment of IBS despite a large phase III trial showing clinical benefit. The main issue for its clinical use, after weighing its clinical benefit and side-effect profile, are challenges of this drug class regarding safety labeling and possible risk reduction programs. Another molecule with potential for the treatment of IBS is ramosetron (YM060), which has entered a phase III trial.

Pumosetrag (MKC-733, DDP-733) is in a phase IIb trial. It acts like a 5-HT3 partial agonist with prokinetic properties, which may give it some potential as a treatment for IBS-C [Evangelista, 2007].The drug is minimally absorbed by GI cells and as a result, more of the product remains available at the intestinal level. This is an important issue because the drug can have less systemic side effects compared with other serotonin modulators [Evangelista, 2007]. In a randomized, double-blind, placebo-controlled doseranging study, pumosetrag was administered three times per day for 28 days in four treatment groups: 0.2, 0.5, 0.8 and 1.4 mg. Trial results demonstrated favorable effects in 53.8% of subjects with the 1.4mg dose compared with 15.4% of subjects in the placebo group [Paterson, 2008a]. Adverse events occurred with similar frequency in all treatment groups and the majority were mild or moderate.

DDP225 is in clinical trials for d-IBC and has a unique combination of noradrenaline reup-take inhibition and 5-HT3 antagonism in one orally administered compound. In a randomized, double-blind, placebo-controlled trail, 87 females with IBS-D were randomized to placebo and different doses of DDP225 once daily for 8 weeks. The study showed beneficial effects on slowing motility and improving visceral pain, especially in subjects who received 1 mg daily for 8 weeks [Paterson, 2008b]. DDP225 was well tolerated with side effects similar to placebo [Paterson, 2008b].

5-HT4 modulators

These are also a subclass with a high impact on IBS treatment. 5-HT4 receptors are distributed throughout the entire GI tract, specifically in the presynaptic segment of the neuromuscular junction [Kindt and Tack 2007] where they manifest an active action in intestinal motility. In animals, 5-HT4 agonists have a prokinetic effect by stimulating acetylcholine release and enhancing bicarbonate and chloride secretion at a mucosal level as suggested by numerous studies [Tuo et al. 2004; Budhoo et al. 1996]. There is also evidence of the stimulatory effect of intra-luminal secretion and motility after administration of 5-HT4 agonists in human subjects [Prins et al. 2000].

Clinical evidence suggested that drugs in this class are effective in the treatment of specific subpopulations of IBS patients. Tegaserod, a 5-HT4 partial agonist, is currently approved by the FDA under restricted availability in the treatment of IBS-C. A meta-analysis by Evans and colleagues found that the relative risk to be a IBS-C responder was 1.19 and significant with a number needed to treat of 14 if the considered endpoint was GI symptoms relief. The relative risk for IBS-C to improve pain and discomfort was 1.16 (95% confidence interval, 0.89–1.51 not significant), but these results were from a pooled analysis of only three studies that reported visual analog pain scores.

From August 2002 to March 2004 there have been 20 reports that the use of tegaserod may be associated with ischemic colitis, but the presence of confounding factors such as IBS that could independently increase the incidence did not ultimately support this association. Because of concerns of ischemic cardiovascular events such as angina, heart attacks and strokes in 0.1% of the population treated with tegaserod versus 0.01% in those given placebo, the drug was withdrawn from the market in 2007 and its use restricted.

Another drug holding promise in the treatment of IBS-C is prucalopride, currently in phase III trials and preregistration [De Maeyer et al. 2008]. This drug significantly increased the number of weekly stools in healthy subjects from 7.1 to 11.5 [Prins et al. 2000] and also increased spontaneous stool frequency in 74 functionally constipated women [Emmanuel et al. 2002] demonstrating a promising utility in IBS-C. A phase IIb study found also that renzapride, a full 5-HT4 agonist, generated significant improvement in bowel movement frequency and stool consistency but not in pain and discomfort in a cohort of men and women with IBS-C [George et al. 2008]. Further assessment of this drug in the treatment of IBS is needed.

The 5-HT4 modulators are a very well researched class. Despite their high efficacy in treating IBS, their future presence in the market is uncertain because of their side-effect profile. In the future, potential 5-HT4 candidates might have to be refined to act more locally, so that systemic side effects can be minimized.

Drugs with opioid action

Among the five types of opioid receptors documented to date, mu, kappa and delta receptors seem to have the highest impact on gut activity [Holzer, 2004]. Mu-agonists inhibit colonic propulsive activity in rats by acting on specific receptors located on the Dogiel type I motor and interneurone parts of the enteric nervous system where they diminish neurotransmitter release [Hicks et al. 2004; Wood and Galligan, 2004]. There is evidence that some mu-agonists such as diphenoxylate and loperamide could inhibit diarrhea through a direct antisecretory action on the epithelial cell [Awouters et al. 1993].

The activity of a mu-antagonist, alvimopan, to accelerate colonic transit in healthy volunteers, and also improve symptoms in patients with postoperative ileus [Delaney et al. 2005; Viscusi et al. 2006] indicates a potential benefit of this class of drugs in IBS-C. To date, a preliminary study failed to show any improvement in chronic nonopioid constipated subjects after administration of alvimopan [Kelleher, 2006]. Concerns have been raised after a phase III clinical trial showing that alvimopan administration can be associated with a risk of cardiovascular events (1.12% placebo versus 2.6% in alvimopan-treated patients) and neoplasms (two patients given placebo (0.7%) versus 15 patients given alvimopan [2.8%] GSK and Adolor Announce Preliminary Results from Phase 3 Safety Study of Alvimopan (Entereg/Entrareg), April 2007). Currently, alvimopan is not approved by the FDA and is under extended review until more data clarifies any safety issues.

In contrast to mu-antagonists, which may operate through motility mechanisms, the kappa-agonists seem to target nociception more specifically. Recently, there is strong clinical evidence that asimadoline, a kappa-agonist, induced significant pain remission (unadjusted p50.003) 2h after its administration in females with IBS-mixed type without significant adverse effects (www. drugs.com, November 2008). Fedotozine, another drug from the same class significantly increased the pain threshold rectal stimulation (p¼0.0078) with an average of 6.0 mmHg in 14 IBS patients after it was administered intravenously, without modifying colonic compliance or tone. The authors of this study [Delvaux et al. 1999] concluded that kappa-agonists act mainly by reducing the afferent neuronal signal and not by influencing colonic compliance.

The use of kappa-agonists has clearly a high potential for the benefit of IBS patients and they may be a good treatment option. The absence of any major effect on motility makes these drugs a good alternative mainly in alleviating pain in all types of IBS. An important point to consider in the development of this class of drugs is limiting the central effect while maximizing their peripheral potency.

Neurotrophins

The neutrophin family is composed of a number of factors such as brain-derived neurotrophic factor (BDNF), neurotrophin (NT)-3 and NT-4 coded by different genes and with a well described role in neural development, including the enteric nervous system [Parkman et al. 2003; Coulie et al. 2000]. There is evidence from animal studies that administration of neurotrophins can induce somatic [Shu and Mendell, 1999] and visceral [Delafoy et al. 2006] hyperal-gesia in rats. Delafoy et al. [2006] demonstrated that intraperitoneal administration of 10 and 100 ?yg of BDNF significantly reduced the pain threshold from 40.4 mmHg to 21.5 mmHg (p50.001), respectively in rats exposed to rectal balloon stimulation. Of note, anti-BDNF antibodies administered post-BDNF and significantly reduced colonic pain thresholds.

Another important aspect of neurotrophins is their effect on colonic motility. In humans, BDNF and NF-3 induced accelerated colonic transit and improved bowel frequency in 87 patients with functional constipation [Parkman et al. 2003; Coulie et al. 2000]. The most frequent side effect noted was injection site reactions that had no relationship with the dose administered. A possible suggested mechanism for BDNF to influence motility patterns is an enhancing effect on 5-HT and CGRP molecules that further potentiates the peristaltic reflex [Grider et al. 2006].

Based on these findings, the neurotrophins seem to hold promise for the treatment of IBS, most probably IBC-C, because of their documented effect in augmenting peristalsis. Currently, there is no FDA-approved compound from this class or active clinical study to assess their benefit in IBS but further research in this area is anticipated.

Corticotropin-releasing hormone antagonists

Corticotropin-releasing hormone (CRH) is a 41 amino acid polypeptide secreted from the pituitary which further stimulates the secretion of ACTH and beta-endorphins [Vale et al. 1981]. CRH acts on two types of receptors coded by different genes with affinity for distinct mammalian ligands from the CRH molecule family. Evidence in animals suggests that CRH family ligands have a significant effect on colonic motility and sensitivity. Intraventricular administration of these molecules increased propulsive activity in rats [Martinez et al. 2004]. Colonic hypersensitivity was induced with intraventri-cular administration of CRF while centrally delivered antalarmin, a CRH-1 antagonist, decreased significantly (p50.01) the visceromo-tor response to 30mmHg balloon distensions in rats [Greenwood-Van Meerveld et al. 2005]. The central CRH-stimulated colonic activity could be mediated through activation of the para-sympathetic system [Tache et al. 2004].

There is also evidence that CRH agonists influence colonic motility and sensitivity by a direct action in the periphery on myenteric and sub-myenteric neurons [Sharara et al. 2006]. In humans, intravenous CRH increased the colonic motility index in controls and IBS subjects but the IBS group was significantly more affected (p50.05) than the control group [Fukudo et al. 1998]. Peripherally administered CRH decreased the pain threshold and increased the sensation of discomfort in seven healthy volunteers [Lembo et al. 1996]. Peripheral administration of a CRH-antagonist, alpha-helical CRH (9-41) normalized brain activity as recorded with EEG in ten IBS patients that experienced rectal balloon distensions, thus unveiling a possible central mechanism [Tayama et al. 2007].

These outcomes suggest that a CRH/CRH-receptor system may be involved in the pathophy-siology of IBS and could be a possible target in the treatment of this condition. Because of their inhibitory action on motility and algesia, the CRH receptor antagonists acting at the colo-nic level could be designed for the treatment of the IBS-D. Currently, there is an active phase II clinical trial evaluating the efficacy and safety of a CRF-1 receptor antagonist, GW876008, in patients with IBS.

Somatostatin analogs

Somatostatin is a peptidic hormone and together with its analogs has been reported to be beneficial in a variety of GI disorders such as diarrhea, dumping-syndrome, endocrine tumors or variceal bleeding [Corleto et al. 2006]. Somatostatin and its analogs act on specific receptors located in circular and longitudinal colonic smooth muscle as shown by animal and human studies [Corleto et al. 1998; McKeen et al. 1994]. Corleto et al. [2006] demonstrated that somatostatin analogs have an important relaxant effect on colonic motility mediated by subtype 1 SS receptor found on the circular layer and subtype 2 SS found in the longitudinal layer. In isolated rat colonic strips, somatostatin agonists have antisecretory properties [Emery et al. 2002].

As well as a direct effect on motility patterns, intravenous injection of octreotide, a somatostatin analog, significantly reduced maximum pain thresholds in healthy subjects from 211 + 13 ml with placebo to 362 +25 ml with octreotide (p50.01) and in IBS patients from 102+ 10 ml with placebo to 202 + 25 ml with octreotide (p50.05) [Hasler et al. 1993]. The authors of this study concluded that the putative mechanism for decreased visceral sensitivity could be a neural inhibition in the peripheral sensory nerves but a central analgesic effect cannot be excluded because SS analogs can cross the blood-brain barrier [Banks et al. 1990].

The studies in this area are very preliminary and there is no current therapy involving somatostatin analogs in IBS therapy or active studies to assess their efficacy for IBS. Because of their documented effect on motility and in reducing pain perception, the SS analogs are another class with high potential to be exploited in the future.

Drugs acting predominantly in the periphery

Antibiotics

Many of the symptoms present in IBS are relatively similar to those seen in small intestinal bacterial overgrowth - that is, bloating, diarrhea or loose stools – leading to the theory that IBS could be generated by an abnormal bacterial colonization of the bowel. Considering this rationale, a number of researchers have assessed the efficacy of diverse antibiotics in improving symptoms in patients with IBS. The most thoroughly studied drug, rifaximin, has been shown to improve bloating and global symptoms in 40.5% of an IBS cohort of patients versus 18.2% of the IBS cohort that received placebo (p ¼ 0.04) [Sharara et al. 2006]. One of the limitations of this study was that the cohort considered was heterogeneous without a very clear separation between IBS and patients with small intestine bacterial overgrowth. [Pimentel et al. 2006b] found that the global improvement percentage 8.5 weeks after treatment for abdominal pain, diarrhea, bloating and constipation was significantly higher (p ¼0.02) in 43 patients that received rifaximin versus 44 who received placebo. Neomycin also produced a significant global improvement of 36.7% in 16 IBS-C patients versus 5% in 17 patients given placebo (p50.001) – the probable effect was a reduction in methanogenic bacterial proliferation [Pimentel et al. 2006a].

There is no antibiotic approved for the treatment of IBS, but these findings suggest that in selected populations where there is a causality between IBS symptoms and abnormalities of the gut microbial flora, this class of drugs may be of benefit and should be considered a treatment option.

Selective chloride channel activators

The first representative of this class, lubipros-tone, is a bicyclic fatty acid that activates selectively type-2 chloride channels (CIC-2) at the level of intestinal epithelium, producing an increase of intraluminal secretion of isotonic fluid without altering overall the serum electrolyte levels in the body [Cuppoletti et al. 2004]. Very recently, a phase II study [Johanson et al. 2008] was reported that assessed the efficacy of lubiprostone in the treatment of IBS on a sample of 195 patients with IBS-C. This study found that daily doses of 16, 32 and 48mg are associated with significant improvement of abdominal discomfort and pain at 1 and 2 months of treatment (p50.05). The same dosages induced significant improvement of straining and severity of constipation at 1, 2 and 3 month time points (p50.01). The dosage that showed the optimal combination between efficacy and safety was 16 mg/day. This dosage has been proposed for use in further IBS studies with this drug. The most frequent adverse effects associated with lubiprostone (16 mg/day) were nausea and diarrhea experienced by 19% and 14%, respectively, of the cohort.

Currently, the selective chloride channel activators are FDA approved in the treatment of the chronic idiopathic constipation. Lubiprostone has been considered as an efficient option for IBS-C because of its limited side-effect profile. Its mechanisms of action are most likely peripheral, possibly by improving bowel function. FDA approval for this drug class in the treatment of IBS-C is pending.

Peripheral receptor modulators

Linaclotide is a new first-in-class compound in phase IIb study for treatment of IBS-C or chronic constipation. It is an agonist of the guanylate cyclase type-c transmembrane receptor (GC-C) that is located predominantly on the luminal surface of enterocytes throughout the small intestine and colon [Andresen et al. 2007]. Once the drug is bound to the extracellular domain of GC-C, it activates the receptor which leads to cGMP-dependent inhibition of Naβ/Hβ exchange and activation of the cystic fibrosis transmembrane regulator resulting in water, chloride, and bicarbonate secretion in the intestine.

Linaclotide showed efficacy in a double-blind, placebo-controlled, randomized, multiple repeat-dose study in which 100mg and 1000 mg daily for 5 days was compared with placebo in patients with IBS-C. There was a significant acceleration in colonic transit and a change in stool consistency at the high dosage [Andresen et al. 2007]. It appeared to be safe and well tolerated even at the high dosage [Andresen et al. 2007]. The most common adverse event was diarrhea; however, there was no associated dehydration or electrolyte abnormality [Lembo, 2008].

Cholecystokinin (CCK) antagonists

Cholecystokinin (CCK) is a polypeptide secreted in the duodenum and jejunum, inducing contractions of the gallbladder, stimulating pancreatic enzyme secretion and inhibiting gastric emptying [Walsh, 1994]. CCK acts mainly on two different types of receptors located in the periphery but also at the CNS level. The GI actions of CCK are mediated through the CCK-1 receptor.

Chey et al. [2001] demonstrated that intravenous administration of the CCK-8 agonist increased colonic amplitude contractions and the motility index in ten IBS patients to a greater extent than in a similar number of controls, suggesting a higher reactivity in IBS patients. In a phase II clinical trial, administration of the CCK antagonist, deoxiglumide (200 mg), delayed proximal colonic transit significantly in 18 IBS-C patients when compared with 18 controls, without any relief of IBS symptoms. The authors of this study concluded that CCK-1 antagonists might not be significant modulators in IBS-C and may be considered in the treatment of IBS-D. However, another phase II pilot study demonstrated significant improvement of abdominal pain and discomfort in IBS patients, after 12 weeks of 200 mg/day dexloxiglumide [D'Amato, 1999].

Even though CCK antagonists seem to have a potential benefit in the treatment of IBS, data in the literature is contradictory and this drug class needs further research. Currently, there are phase III randomized trials recruiting male and female subjects, that will assess the efficacy of oral dexloxiglumide in improving symptoms and quality of life in IBS-C patients. A potential limitation with the use of CCK antagonists could be induction of gallbladder stasis and possible cholelithiasis [Talley, 2003].

Newly developed natural products

Crofelemer is a new medicinal product extracted from the plant Croton lechleri, which reduces excess intraluminally secreted fluid by inhibiting chloride ion transport through the intestinal membrane. This property supports the rationale to use this compound in conditions characterized by increased transit such as diarrhea or IBS-D.

In a phase IIa double-blind clinical study, 246 males and females with IBS-D experienced a significant improvement of pain symptoms (p ¼ 0.02) but not of stool consistency and frequency after 12 weeks of treatment with clofelemer versus placebo. The treatment was beneficial in women but not in men, but this may have been confounded by the small number of males in the study. There have been no noteworthy side effects with clofelemer, which makes it a good option for further clinical study. Currently, clofelemer is in phase IIb clinical trials for further assessment of its efficacy in IBS-D.

Conclusion

There are numerous currently available treatment options in IBS acting centrally and peripherally by influencing motility and visceral sensitivity. Clinical evidence is variable though the emerging treatments are being evaluated using better clinical design. Despite more sophisticated approaches, an accurate assessment of IBS drug efficacy is still hampered by the heterogeneity of the IBS population. Novel methods such as pharmacogenomics or brain imaging may be helpful in the future for a better understanding and characterization of IBS patient subtypes, which will consequently give way for more specific and effective therapeutic options. Patient subpopulation measurement of side effects also remains a clinical challenge and a better understanding of the issues could improve treatment efficacy by enhancing patient compliance.

Conflict of interest statement

None declared.

Contributor Information

Alexandru Gaman, Massachusetts General Hospital, Gastrointestinal Unit, Harvard Medical School, Boston, MA, USA.

Maria Cristina Bucur, Massachusetts General Hospital, Gastrointestinal Unit, Harvard Medical School, Boston, MA, USA.

Braden Kuo, Massachusetts General Hospital, Gastrointestinal Unit, Harvard Medical School, Boston, MA, USA ; gro.srentrap@oukb.

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