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Treatments targeting putative mechanisms in irritable bowel syndrome

Abstract

The pathophysiology of irritable bowel syndrome (IBS) is heterogeneous; it is possible for several mechanisms to be disturbed in the same patient. Isolating a single target for pharmacological manipulation is also difficult because of the complexity and overlap of the neural circuitry in the enteric and central nervous system. This review summarizes the rationale and efficacy of current and future therapies for IBS, on the basis of putative pathophysiological models. The modulation of gastrointestinal sensorimotor function, intestinal gas handling, the gastrocolonic reflex, neurohormonal stress responses, central processing of afferent information, and microbial flora are the current frontiers for experimental therapeutics for IBS. Patients presumed to have POSTINFECTIOUS IBS have also been targeted as a distinct group. In the very near future, it is unlikely that a single drug will come to the fore as a suitable and successful treatment for everyone with IBS, but new data on potential therapeutic targets lend hope for the improved long-term management of IBS. Disease modification rather than just symptom-based treatments must remain the goal.

Introduction

Irritable bowel syndrome (IBS) is a poorly understood yet frequently encountered problem in clinical practice; in the US, IBS accounts for more than a third of the referrals to a gastroenterologist.1 IBS is defined by the presence of abdominal discomfort or pain associated with disturbed defecation,1 and symptom-based diagnostic criteria (the Rome criteria) provide a positive clinical diagnosis.1

The pathophysiology of IBS is probably heterogeneous, and encompasses abnormal gastrointestinal motility, altered visceral perception, excess intestinal gas, altered intestinal microbial flora, an exaggerated neurohormonal stress response and disturbed central processing of visceral stimuli; infections and psychosocial factors are probably predisposing factors for the development of IBS.1

The choice of therapy for IBS has traditionally been based on the predominant bowel symptom. It has proven difficult to identify any optimal single pharmacological therapeutic targets, however, in part because of the complex innervation of the gut and the occurrence of multiple pathophysiological disturbances.2 For example, serotonergic drugs alter gut motor function, which improves some of the colonic symptoms of IBS but aggravates others, depending on the receptor being modulated.2 This review summarizes current and future therapeutic strategies for the treatment of IBS on the basis of putative pathophysiological models (Figure 1).

Figure 1: Localization of potential relevant molecular targets in irritable bowel syndrome with the specific classes of agents discussed in this Review.
figure1

Experimental and currently used agents for the treatment of irritable bowel syndrome (IBS) target the putative brain–gut dysfunction at multiple sites. It is unclear whether postinfectious IBS will stand as an entity to treat separately. CCK-A, cholecystokinin A receptor; Cox-2, cyclo-oxygenase-2; CRF-1, corticotropin releasing factor 1; CRH, corticotropin releasing hormone; NSAIDs, non-steroidal anti-inflammatory drugs; SSRIs, selective serotonin reuptake inhibitors.

Modulation of gastrointestinal motor function

Manometric studies in small numbers of patients have indicated that clustered small intestinal contractions and high amplitude pressure waves might correlate with pain in IBS.3 Although there is no hallmark motor abnormality in this disorder, about 40% of patients with either constipation-predominant or diarrhea-predominant IBS do have abnormalities in gastrointestinal transit.4 In patients with diarrhea-predominant IBS, a greater number of high amplitude colon-propagated contractions have been reported, whereas in patients with constipation-predominant IBS the number might be reduced.5 These motor abnormalities are reflected by accelerated whole-gut and colonic transit in diarrhea-predominant IBS,6 and delayed colonic transit in constipation-predominant IBS.7 Altering gastrointestinal transit is therefore the target of several pharmacological therapies.

Serotonergic agents

Modulation of serotonin (5-hydroxytryptamine or 5-HT) receptors in the gut has long been known to affect gastrointestinal motility and transit.8 The pharmacodynamic effects that delay or accelerate colonic and small-bowel transit have been harnessed to try to relieve the IBS symptoms of diarrhea and constipation.

Alosetron is a 5-HT3 receptor antagonist that provides greater global symptom improvement in female patients with diarrhea-predominant IBS compared with placebo.9 The average number needed to treat (NNT) with alosetron is 7 (95% CI 5.7–9.4)9 and its effects can be attributed to a reduction in colonic transit,10 an effect on visceral compliance or sensation,10 or central analgesia.11 The safety profile of alosetron is a clinical consideration. Alosetron frequently causes severe constipation (number needed to harm = 3.9, 95% CI 3.6–4.3), and reports of drug-related ischemic colitis (incidence in large trials circa 0.1%), surgery for severe constipation and bowel perforation prompted the manufacturer's voluntary withdrawal of alosetron from the market in 2000. Since June 2002, alosetron has been available in the US as part of a restricted access program and the starting dose reduced to 1 mg daily (from 1 mg twice daily). It is unclear why the drug works better in women. Functional polymorphisms of the serotonin transporter gene have been associated with a greater delay in colonic transit on administration of alosetron.12

Cilansetron is a 5-HT3 receptor antagonist with the same presumed mechanism of action as alosetron. It has shown efficacy in male and female patients with non-constipated IBS at 1 mg, 6 mg and 16 mg doses,13 but cases of ischemic colitis have been reported. There are currently no data to explain why cilansetron seems to be efficacious in patients of both sexes, whereas alosetron might be more efficacious in women. Evidence is currently being gathered to better define the incidence of ischemic colitis in patients receiving cilansetron. Other 5-HT3 antagonists such as tropisetron and YM-114 also remain to be evaluated for diarrhea-predominant IBS.

The partial 5-HT4 agonist tegaserod increases coordinated motor function in the small intestine; it accelerates gastric emptying, small-bowel and colonic transit,14 and in healthy volunteers decreases visceral sensitivity during rectal distension.15 The NNT for tegaserod in constipation-predominant IBS is between 8 and 14,16 and the 6 mg dose twice daily seems optimal. Similarly to the alosetron trials, most patients enrolled in the tegaserod trials were female, and therefore any benefit in males with IBS has not been established.

Cisapride is a 5-HT4 agonist and partial 5-HT3 antagonist that accelerates gastric emptying, small bowel and colonic transit.17 Placebo-controlled studies with cisapride in patients with IBS have shown conflicting results. No clinically relevant benefit from cisapride was found in placebo-controlled trials in patients with constipation-predominant IBS.18 Cisapride was withdrawn from the market in 2001 because of associated rare fatal cardiac arrhythmias and is not available for the treatment of IBS or other motility disorders except on a compassionate use basis in individual cases in the US.

Renzapride is a new 5-HT4 receptor agonist and a 5-HT3 receptor antagonist. It accelerates transit and improves stool consistency and ease of passage versus placebo in constipation-predominant IBS,19 suggesting that the 5-HT4 action is dominant. The efficacy of renzapride, however, has yet to be firmly established, and its side effects need further characterization.

The selective 5-HT4 agonist prucalopride was associated with increased stool frequency and reduced time to first evacuation in a 4-week trial of chronic constipation.20 Data on IBS are lacking, however, and concerns about carcinogenicity and cardiac toxicity in animals have halted further development of this drug.

Other serotonergic agents with potential prokinetic action that have not yet been tested in constipation-predominant IBS include the 5-HT4 agonists norcisapride, mosapride, ML-1035 and E3620, and the 5-HT3 agonist MKC-733. 5-HT4 receptor antagonists with potential antidiarrheal action, such as piboserod and sulamserod, have also not been tested in IBS.

Dopamine receptor antagonists

Itopride is a dopamine D2 receptor antagonist and an antiacetylcholinesterase with a structural resemblance to cisapride. It has been used as a gastroprokinetic in studies in patients with functional dyspepsia and is currently available on the market in Japan. Phase III studies show it is devoid of cardiac side effects. Studies on its effect on small-bowel and colonic motor function are underway.

Opioid antagonists

Opioid analgesics have a constipating effect, which led to the testing of opioid antagonists as a treatment for constipation-predominant IBS. An oral form of naloxone was shown to have a small but nonsignificant symptom benefit in patients with IBS for pain, bloating, straining and urgency.21 Alvimopan is a peripheral μ-opioid receptor antagonist effective in postoperative ileus; its effect on gastrointestinal transit in humans is currently being studied.

Cannabinoids

The cannabinoid receptor subtype CB1 is present in the human small and large intestine: when activated, inhibition of the excitatory cholinergic system, which is associated with reduced motility, has been observed.22 Modulation of the cannabinoid receptor could therefore serve a dual therapeutic purpose: cannabinoid receptor antagonists, such as SR141716A, could enhance phasic motor activity in the colon, whereas cannabinoid receptor agonists might reduce hyperalgesia,23 secondary to their effects on visceral afferent pathways. Studies with cannabinoid receptor modulators in functional bowel disorders are therefore awaited with interest.

Neurotrophins

Recombinant human neurotrophic factor-3 (r-metHuNT-3) is a neurotrophin that modulates synaptic transmission, survival and maturation of several neuronal subpopulations. A 2-week, placebo-controlled pharmacodynamic study of r-metHuNT-3 in patients with chronic constipation showed that it accelerated overall colonic transit, increased frequency of defecation and facilitated passage of stools.24 In a subsequent dose-ranging, phase II study of 107 patients with chronic constipation, a 9 mg dose of r-metHuNT-3 was found to be effective in increasing spontaneous, complete and total bowel movements, in softening of stool and improving ease of passage versus placebo.25 Whether these findings will apply to patients with constipation-predominant IBS needs to be addressed.

Reduction of intestinal gas

Excessive retention of gas in the intestines is potentially responsible for the predominant symptoms of bloating and distension. These symptoms have been attributed to impaired gas clearance with excess gas pooling, visceral hypersensitivity with normal amounts of gas, excessive production of gas owing to bacterial overgrowth or an abnormal response to fat in the duodenum after meals.26

No convincing evidence is available to support the efficacy of gas-absorbing substances, such as charcoal or simethicone, as a treatment for IBS. In a proof-of-concept physiological study of 28 patients with predominant bloating (of whom 14 had IBS), intravenous neostigmine cleared intraduodenally infused gas, and provided relief of bloating and distension.27 Pyridostigmine is a longer-acting cholinesterase inhibitor than neostigmine and has less muscarinic effects; it might therefore be more suitable for such an approach.

In patients with IBS, physiological concentrations of intestinal lipids cause excessive inhibition of gas transit,26 and this is a possible novel target for intervention. The role of low fat diets has not been tested, however, and the neurohormonal response to the presence of fat in the duodenum is complex. Antagonism of the neuropeptide cholecystokinin (CCK) is one potential therapeutic avenue (see below).

Bacterial overgrowth of the small intestine in patients with IBS has been associated with excessive gas, alterations in gut sensorimotor function, excessive orthosympathetic activation and hyperimmunity.28 In short-term trials, the treatment of presumed bacterial overgrowth with antibiotics showed symptom responses as high as 75%.29 The placebo responses in these trials were unusually low,29 however, and testing for bacterial overgrowth of the small intestine with the lactulose breath test is neither sensitive nor specific. These results must therefore be viewed with great caution.

Modulation of an exaggerated gastrocolonic response

An abnormal increase in colonic motility following the presence of food in the duodenum—an excessive gastrocolonic response—has been associated with postprandial symptoms in patients with IBS. The gastrocolonic response is mediated either by mechanoreceptors activated by distension of the stomach or by chemoreceptors activated by the presence of nutrients in the duodedum.30 CCK, a neuropeptide released by ENDOCRINE I CELLS within the duodenal and jejunal mucosa, mediates a component of the reflex after the delivery of food to the small bowel.

Dexloxiglumide is a potent CCK-1 receptor antagonist. The results of a 12-week, placebo-controlled, phase II trial indicate that a dose of 200 mg/day of dexloxiglumide was associated with a higher proportion of improvement in abdominal pain and discomfort in female patients with IBS with constipation.31 More recent pharmacodynamic data in IBS, however, show that dexloxiglumide delays rather than accelerates transit in the ascending colon,32 and an unpublished large clinical trial of dexloxiglumide in IBS showed no significant effects on symptoms.

Modulation of visceral hypersensitivity

Visceral hypersensitivity is common in patients with IBS, and it has been proposed as a 'biological marker' of the syndrome.33 Indeed, the pressure threshold for pain measured during distensions with a RECTAL BAROSTAT are generally significantly lower for patients with IBS compared with healthy controls (mean values 30.4 ± 6.7 mm Hg versus 44.5 ± 5 mmHg, respectively).34 Although testing for visceral hypersensitivity is not routine in clinical practice, these measurements have been assessed in experimental proof-of-concept trials of different visceral analgesics. Physiological testing of visceral sensation is helpful for understanding the mechanisms of new drugs, but its use is not recommended to direct drug choice in clinical practice.2

Opioid agonists

Opioid agonists inhibit intestinal secretion and delay transit. For example, loperamide is efficacious for diarrhea in patients with IBS; however, it does not provide significant relief from abdominal pain in patients with IBS.35

Asimadoline is a kappa opioid agonist with peripheral antinociceptive properties that reduces colonic sensation during non-noxious distensions in health,36 and, in patients with IBS, increases the pressure thresholds for pain.37 The clinical testing of kappa opioid agonists is therefore promising, focusing on IBS patients with abdominal pain as their predominant symptom.

Neurokinin receptor modulators

The neurokinin (subclasses NK1, NK2 and NK3) receptors for tachykinin peptides are involved in visceral sensitivity. As such, targeting NK receptors to modulate sensorimotor function of the gut is currently considered a potential treatment modality for IBS. The potential beneficial effects of NK antagonism in IBS could include reduction of visceral afferent output, central effects (such as anti-anxiety properties) as well as reduction of colonic inflammation and antisecretory effects.

The NK1 antagonist aprepitant has been shown to be efficacious in providing relief from chemotherapy-induced emesis, an effect that is probably related to vagal afferent inhibition, but this agent has not been tested in IBS. CJ-11974, another NK1 antagonist, reduced patient anger related to rectal balloon distension in a preliminary IBS study.38

The NK2 receptor antagonists nepadutant and saredutant dose-dependently reduced fecal excretion and abdominal contractions induced by colorectal distensions, a proxy for IBS in animal studies. However, no data are available on the effects of NK2 receptor modulation in patients with IBS. The selective NK3 receptor antagonists talnetant and SB-235375 reduced visceral sensation in animal studies without altering visceral compliance;39 human studies of the effects of NK3 antagonism on visceral sensitivity are under way.

Alpha-2 agonists

Adrenergic dysfunction could underlie some of the motility and sensation disturbances of IBS. Certain functional polymorphisms in alpha-2 adrenoceptors have been associated with constipation-predominant IBS.40 In healthy controls, the α2-receptor agonist clonidine reduces colonic motor activity in the fasting state and pain thresholds during colorectal distensions with the rectal barostat.41 Clonidine has also been found to increase visceral compliance without altering colonic motility,42 indicating that it might be particularly useful in patients with urgency as their predominant symptom. In one study, of patients with diarrhea-predominant IBS, 0.1 mg clonidine twice daily was significantly better than placebo in terms of bowel dysfunction, but these effects did not correlate with modulation of colonic transit.43 Moreover, clonidine has side effects (e.g. hypotension) that often prevent its use for the treatment of IBS. Lidamidine, another α2-receptor agonist, was no better than placebo in reducing the frequency and severity of abdominal pain and bloating in patients with IBS.44

Altering the colonic microbial flora

The possibility that an 'unfavorable' gut flora might predispose to certain gastrointestinal symptoms, such as abdominal bloating and flatulence, has long been hypothesized on the basis of the gas-producing ability of certain bacterial species. Antibiotics have been tested in those patients with IBS and presumed bacterial overgrowth.2 In addition, PROBIOTICS have been proposed for use in patients with IBS to restore any imbalance of the bowel flora and disruptions of gut permeability. Probiotics are appealing agents given their ease of administration and the well-demonstrated safety of most probiotic microbial species. The data available, however, suggest that there is, at most, a limited benefit for individual IBS symptoms.45 Abdominal bloating has been the most consistently improved symptom, but no global relief from IBS has been observed. More research is needed to determine the optimal microbial strains (for viability, kinetics and interaction with gut physiology) and the optimal dosages to be tested in IBS.

Postinfectious IBS

Between 7% and 30% of patients have persistent colonic symptoms after the disappearance of the causal microorganism (POSTINFECTIOUS IBS).46 In some patients, this has been linked to persistent microscopic inflammation, with a higher proportion of ENTEROCHROMAFFIN CELLS and altered release of serotonin, and increased numbers of activated T cells, putatively leading to disturbed sensorimotor function.47 In one animal model of postinfectious IBS, steroids and non-steroidal anti-inflammatory drugs prevented the occurrence of abnormal motor responses;48 however, a 3-week placebo-controlled trial of high-dose prednisolone in patients with presumed postinfectious IBS was negative.49 Nonetheless, these initial negative data should not discourage exploration of other experimental therapeutic options in patients with postinfectious IBS, such as cyclo-oxygenase-2 (Cox-2) inhibition.

Modulation of central processing of afferent traffic and exaggerated neurohormonal responses to stress

The mechanisms by which antidepressants might provide symptom relief for patients with IBS could lie both centrally and peripherally. In addition to their effect on psychiatric comorbidity in IBS, antidepressants have central analgesic properties and might influence the cortical processing of noxious visceral stimuli. Peripherally, some antidepressants modulate gut sensorimotor function. Venlafaxine, a serotonin and adrenergic reuptake inhibitor, reduced colonic compliance and tended to reduce pressure-induced pain thresholds versus placebo.50 Results with the other selective serotonin reuptake inhibitors (for example, sertraline, fluoxetine and buspirone), however, have been somewhat disappointing.50 Paroxetine was better than usual care in terms of health-related quality-of-life endpoints in patients with IBS, but not abdominal pain.51 Similar results were reported in another trial of paroxetine, in patients with IBS that was unresponsive to a high fiber diet versus placebo.52

The mean NNT for global IBS improvement with TRICYCLIC ANTIDEPRESSANTS has been reported to be 3 (95% CI 2–7).53 In a recent, large and well-conducted trial, desipramine was superior to placebo in the PER-PROTOCOL ANALYSIS, but not in the INTENTION TO TREAT ANALYSIS, for patients with moderate to severe IBS.54

The search for antidepressants with the most favorable pharmacodynamic effect for the treatment of IBS continues. On the basis of current data, however, antidepressants cannot be recommended as first-line agents for the treatment of IBS.

Increased stress responsiveness, resulting in the excessive release of neurohormones and autonomic dysfunction, has been postulated to be a key alteration in patients with IBS.47 Corticotrophin releasing factor (CRF) is a stress hormone that affects colonic sensorimotor function,47 and a CRF antagonist could therefore limit the effects of an exaggerated response to stress. Astressin, a selective CRF-1 receptor antagonist, reduced visceral discomfort induced in animals: intracerebral injection of this compound in rats abolished the usual CRF-induced changes in gut motor function.55 In humans, intravenous CRF induced duodenal dysmotility and abdominal symptoms, and a greater response was observed in patients with IBS compared with healthy volunteers.56 Alpha-helical corticotropin releasing hormone (CRH), a non-selective CRH receptor antagonist, suppressed rectal motility and pain induced by electrical stimulation in 10 patients with IBS.57 Taken together, these data indicate that CRF-1 and CRH receptors are a potential target of major relevance for the treatment of IBS.

Conclusions

The experimental testing of new treatments for IBS presents many challenges. Despite the lack of a definite pathophysiological explanation for all symptoms of IBS, the principle of using biological endpoints as targets for the development of novel drugs is logical and probably valid. A comprehensive understanding of a drug's pharmacodynamic mechanisms, however, does not guarantee its success for treating the clinical manifestations of IBS. The number of prospective new drugs in the pipeline is large, but the number of possible pharmacological targets is even larger. Given the clinical heterogeneity of IBS and the lack of understanding of its etiology, however, it seems unlikely that any single drug will combat all of the clinical features of IBS in the very near future. The search for disease-modifying drugs as opposed to symptomatic therapy is also in its infancy.

Review criteria

The electronic databases MedLine (1966–2004) and EMBASE (1988–2004) were searched for articles relevant to experimental treatment and pathophysiologic mechanisms of irritable bowel syndrome. Our search criteria included the following keywords: irritable bowel, functional, functional bowel, diarrhea, constipation, therapy, pharmacological and pathophysiology. The search was limited to papers published in English. We reviewed clinical trials (open-label and placebo-controlled), meta-analyses, systematic reviews and mechanistic experimental studies. Both authors participated in the process of retrieval and critical selection of the evidence.

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Correspondence to Nicholas J Talley.

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NJ Talley declares that he has received research support from Merck, Forest, AstraZeneca, Novartis, and Solvay. He has acted as a consultant for AstraZeneca, Axcan, EBMed, Gianconda, and Theravance.

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Cremonini, F., Talley, N. Treatments targeting putative mechanisms in irritable bowel syndrome. Nat Rev Gastroenterol Hepatol 2, 82–88 (2005). https://doi.org/10.1038/ncpgasthep0096

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