Treatment of irritable bowel syndrome

teaser

Jan Tack
MD PhD
Head of Clinic
Department of Gastroenterology
University Hospitals Leuven
Belgium
E:[email protected]

Irritable bowel syndrome (IBS) is a condition characterised by episodes of symptoms referring to the large bowel, in the absence of organic disease that readily explains the occurrence of symptoms.(1) There is heterogeneity amongst patients of IBS symptoms, which include abdominal pain or discomfort, bloating and disordered bowel habits. Relief of symptoms by defecation is a key feature of IBS. Furthermore, in at least a subset of patients, aggravation of abdominal symptoms occurs after a meal.(2) In addition, a number of noncolonic features, including upper gastrointestinal symptoms, urinary symptoms, low back pain and chronic fatigue, are also highly prevalent in IBS patients.(1)

Definition and subdivision according to stool pattern
There are no established diagnostic markers for IBS and, in clinical practice, diagnosis is based on the recognition of characteristic symptom patterns and the exclusion of organic disease. Mainly for the purpose of a more uniform selection of patients entering clinical trials, diagnostic criteria have been proposed. Historically, the first symptom criteria were proposed by Manning et al,(3)and these were adapted in the Rome I diagnostic criteria.(4) The currently accepted symptom criteria were proposed by the Rome II working team (see Box 1).(1) Whether or not these exact criteria are also useful in clinical practice is a matter of ongoing debate.(5,6) In clinical practice, for treatment stratification and for some clinical trials, IBS can be further subclassified according to the predominant bowel habit. One can distinguish IBS with constipation (IBS-C), IBS with diarrhoea (IBS-D) or IBS with alternating symptoms of both constipation and diarrhoea (IBS-A).

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Epidemiology
Studies have shown that the Rome criteria may have some diagnostic sensitivity and specificity.(6–8) This observation allows the use of the Rome criteria to study the prevalence and impact of IBS in the general population. In the largest study published on this topic to date, Hungin and colleagues applied random-digit dialling technology to conduct telephone interviews in more than 40,000 subjects 18 years of age and older in several European countries.(9) Using a structured questionnaire, the survey revealed that the overall prevalence of IBS ranges between 7 and 17%, depending on the country studied. Approximately two-thirds of subjects with IBS symptoms in the general population were females. When stringent standardised criteria were applied to subdivide individuals according to the stool pattern, 16% were assigned to the constipation-predominant category, 21% to the diarrhoea-predominant category and 63% to the alternating type.(9)

Impact of IBS
The morbidity and life expectancy in patients with IBS does not differ from that in the general population,(10) but many IBS patients suffer from a considerable impact on daily life and impairment of quality of life.(9,11) Patients with IBS experience symptoms that interfere with normal daily activities,(11) for which they repeatedly see physicians, and they have a higher number of days off work or school.(12) Direct medical costs in patients with IBS are significantly higher than those in a control population.(13)

Pathophysiology of IBS
The pathophysiology of IBS is incompletely understood, but several mechanisms may contribute to IBS symptoms. Over the last few decades, numerous hypotheses have been put forward to explain symptoms in IBS. Mechanisms that have been implicated include abnormal motility of the small or large bowel, inappropriately increased visceral sensitivity, sequellae of infection and (low-grade) inflammation and abnormalities of the central nervous system. However, considerable pathophysiological heterogeneity seems to exist, and IBS symptom pattern and severity are likely to be determined in a ­multifactorial way. Alterations in stool pattern observed in the irritable bowel syndrome seem to be related to intestinal and colonic transit times, with slower transit in IBS-C and more rapid transit in IBS-D.(14) Several recent studies from the Barcelona group have highlighted impaired colonic transit of gas in IBS patients and patients with symptoms of bloating.(15) Visceral hypersensitivity remains a key hypothesis for symptom generation in functional bowel disorders, including IBS. Several studies have shown that, in patients with IBS, balloon distension pressures or volumes required to induce pain from the rectosigmoid or colon are on average lower than in controls.(16–20) Somatic sensitivity does not seem to be enhanced in IBS patients.(20,21) Additional studies confirmed that rectal hypersensitivity is mainly a feature of IBS and not of other colonic or ­extracolonic disorders, and that the presence of hypersensitivity has good sensitivity and specificity for the diagnosis of IBS.(22,23) Hence, in addition to motility abnormalities, visceral hypersensitivity is considered a major mechanism in IBS.

IBS patients have more psychological and psychiatric disturbances than the general population, but less than psychiatric outpatients.(24,25) However, this association is nonspecific, as there is not a single psychological trait or psychiatric disorder that is common to all IBS patients. As only a minority of people with symptoms suggestive of IBS are seeking healthcare, it has been hypothesised that psychopathology does not determine symptoms but rather selects subjects that come to medical attention.(26) IBS patients experience more stress than asymptomatic controls,(27) and patients often report a temporal association between stress and aggravation of symptoms. Well-controlled studies are unfortunately lacking and, in a prospective study, a correlation with stress could only be found in 25% of the exacerbations of irritable bowel symptoms.(28)

Several recent studies have focused on the potential role of infection and inflammation in IBS. Both in retrospective and in prospective studies, it has now been well established that IBS may follow an acute intestinal infection.(29–34) A number of studies have reported signs of ongoing low-grade inflammation on rectal, colonic or ileal biopsies of IBS patients, and this is associated with increased counts of serotonin-containing enterochromaffin cells.(32,33,35,36) Studies investigating ­postprandial release of 5-HT in IBS demonstrated an increase in only a small subset of diarrhoea-predominant patients.(37–39) Decreased postprandial release of 5-HT has been reported in constipation-predominant IBS.(39)

Clinical approach to IBS
The challenge of diagnosing IBS is mainly in the exclusion of organic disease. It has been demonstrated that certain clinical features can be used to distinguish IBS from organic disease.(40) In patients with a typical history and no alarm symptoms, no added value for additional diagnostic testing has been shown.(40) Although routine blood tests are usually performed, their utility has not been proven. In areas with a high prevalence of coeliac disease, screening for endomysial or tissue transglutaminase antibodies seems logical, although their usefulness in a primary care setting has not been proven.(41) The same is true for examination of stools for parasites and ova. Although many patients report intolerance to dairy products, tests for lactase deficiency usually do not contribute to the diagnosis, and a trial of lactose elimination is to be recommended. Colorectal cancer is a major differential diagnosis, and screening is indicated in those with a family history.

Treatment options for IBS
Once the diagnosis of IBS has been made (after the initial examinations and exclusion of organic pathology), patients should be reassured and extensively informed about the nature of their complaints. A retrospective analysis from the Mayo Clinic suggests that reassurance and explanation have a significant clinical impact.(42) Although many physicians will prescribe dietary measures (a diet rich in fibre in constipated patients, reduced intake of carbohydrates in patients with diarrhoea or bloating), the value of these dietary interventions has been proven in a controlled study. Fibre supplements are traditionally prescribed to patients with constipation-predominant IBS, and they may improve constipation. To alleviate abdominal pain, fibre is not superior to placebo, and there is often an adverse influence on symptoms of abdominal pain, bloating or diarrhoea.(43) Alternatively, bulking agents such as ­psyllium or ­ispaghula can be prescribed, but their efficacy has not been proven.(44,45) In systematic reviews from the American College of Gastroenterology and from Switzerland, it was concluded that fibre is ­appropriate for the treatment of painless constipation but is not recommended for the treatment of IBS.(46,47) There is a surprising lack of evidence-based data on the efficacy of other laxatives in the treatment of IBS, and no randomised controlled trials have been published.

Antispasmodics cause relaxation of the intestinal smooth muscle cells, mostly by inhibiting the influx of calcium. Anticholinergics inhibit gastrointestinal motility by blocking muscarinic receptors on the intestinal smooth muscle. The American College of Gastroenterology review concluded that there were insufficient data to make a recommendation about the effectiveness of the anticholinergic or antispasmodic agents available in the USA.(46) Antispasmodics are more widely available and used more extensively in Europe than in the USA. Placebo-controlled studies show an inconsistent effect, but meta-analyses of smooth muscle relaxant studies suggest a benefit of these drugs on abdominal pain.(48) However, many of the controlled studies with antispasmodics were of short duration, included small numbers of patients and did not use the Rome diagnostic criteria. A recent Swiss meta-analysis concluded that there was insufficient evidence for the efficacy of specific antispasmodic drugs in IBS when only high-quality studies were taken into account, with the exception of otilonium bromide.(47) Otilonium bromide is one of the few antispasmodics for which recent controlled studies are available. Antispasmodics are generally well tolerated, although constipation has been cited as a complication in clinical trials; thus, they should be used with caution in patients with IBS-C or IBS-A.(46,47) Anticholinergic drugs often cause systemic anticholinergic side-effects, and effects in the long term have not been proven.

Loperamide, a synthetic opiate derivative widely used in Europe and available over the counter, is the only antidiarrhoeal agent that has been investigated in IBS. Although widely used in clinical practice, only few placebo- controlled trials of variable quality are available. These confirmed the effect of loperamide on stool frequency and in improving stool consistency, but no significant improvements in global IBS symptoms or abdominal pain or bloating were observed. Reviews concluded that loperamide may be effective for the treatment of diarrhoea, but there is no evidence for effectiveness in global IBS symptoms or pain.(46,47)

Tricyclic antidepressants are frequently used to treat patients with IBS, especially those with more severe or more refractory symptoms. Several placebo-controlled studies have confirmed the efficacy of low doses of tricyclic antidepressants in IBS.(49–51) The largest study that investigated the efficacy of tricyclic antidepressants was less clearly positive,(51) and a significant advantage was only found in patients who tolerated and continued the medication. The American College of Gastroenterology (ACG) review concluded that there was inadequate evidence to support the efficacy of tricyclic antidepressants for the improvement of global IBS symptoms. There was some limited evidence that tricyclic antidepressants may decrease abdominal pain, although they may cause constipation and should therefore be used with caution in IBS-C patients.(46) A Swiss review concluded that there was some limited evidence for their efficacy in patients with predominant abdominal pain and diarrhoea.(47) Tricyclic agents are non‑selective serotonin reuptake inhibitors, and they also have anticholinergic properties. It is unclear whether their effect in IBS is constituted by their anti‑cholinergic or by their serotonin reuptake inhibitor effects. Recent studies evaluating the selective serotonin reuptake inhibitors fluoxetin or sertralin failed to demonstrate a significantly favourable effect.(52,53) On the other hand, one study comparing psychotherapy and paroxetine for IBS treatment suggested the efficacy of paroxetine in providing overall symptom relief.(54) In a mechanistic study in healthy subjects, the selective serotonin reuptake inhibitor citalopram was found to decrease sensitivity to colonic distension and to inhibit the colonic response to feeding.(55) In a randomised crossover study in IBS patients without depression, citalopram was found to provide significant symptom relief over placebo.(56)

Because of the rather disappointing effects of standard medical treatment of IBS, and because of the association with psychological disturbances, several forms of psychotherapy have been applied. Few controlled trials have investigated dynamic psychotherapy, relaxation therapy, cognitive behavioural therapy and hypnotherapy. Although most studies reported superiority of these therapies, the role of psychotherapy in IBS remains unclear. It is unclear whether the outcome of these studies can be generalised, due to different criteria for patient selection, different definitions of IBS and selection of refractory patients with a higher likelihood of underlying psychological disturbances. In line with the conclusions of the ACG review, no trial has provided unequivocal evidence that psychological treatment is effective in the treatment of IBS.(46) However, there is some evidence that certain types of behavioural therapy might improve individual symptoms of IBS as well as psychological symptoms. This conclusion is similar to the recommendations of the Swiss review.(47)

Serotonin is a key neuromodulator and neuro­transmitter in the control of gastrointestinal sensori­motor function.(57,58) Several 5-HT receptors are expressed in the gastrointestinal tract, and they have been fruitful targets for new drug development. Antagonists at the 5-HT(3) receptor inhibit colonic transit time.(59) Clinical studies have established that the 5-HT(3) receptor antagonist alosetron improves stool pattern and provides relief of pain/discomfort in diarrhoea-predominant IBS.(60) Preliminary data suggest a similar potential for the 5-HT(3) receptor antagonist cilansetron.(61) Shortly after its introduction to the US market, alosetron was withdrawn due to suspected side-effects of colonic ischaemia.(62) The drug has now been reintroduced in a restricted-use programme in the USA but is unavailable elsewhere. Cilansetron is still undergoing regulatory agency evaluation.

Tegaserod, a partial agonist at the 5-HT(4) receptor, has been shown to promote small intestinal transit time and to enhance proximal colonic ­emptying in patients with constipation-predominant IBS.(63) Tegaserod also increases intestinal secretory reflexes and inhibits the nociceptive RIII pain reflex during painful rectal distention.(64,65) Several large-scale randomised controlled studies with ­tegaserod in constipation-predominant IBS have been conducted.(66–70) All these studies were 12-week trials and included patients who met the Rome criteria for IBS. All trials demonstrated statistically significant improvements in global IBS symptoms with ­tegaserod compared with placebo. Tegaserod-treated patients also experienced less bloating, less abdominal pain/discomfort and improved satisfaction with their bowel habits compared with placebo patients.

Tolerance of tegaserod in the clinical trials was excellent.(66–71) The most common adverse event is diarrhoea, which is generally mild and transient and reported by 2–10% of tegaserod patients, compared with 1–5% of placebo patients. A small number of cases of ischaemic colitis have been reported to be associated with the marketed use of tegaserod, although no causal relationship has been established.(72,73) Furthermore, the background incidence of ischaemic colitis is higher in IBS patients who experience IBS-like symptoms such as abdominal pain, bloating and constipation.(74) There is no evidence of increased prevalence of ischaemic ­colitis over the background prevalence with tegaserod, and no cases of ischaemic colitis have been found in placebo-controlled trials of tegaserod.(73) A study of safety and tolerability in patients with IBS-D found no associations between tegaserod use and increased incidence of adverse events, including diarrhoea and abdominal pain.(75) Both the ACG and a Swiss review concluded that tegaserod appears to be an effective and safe agent for the treatment of IBS-C. (46,47)

IBS is a chronic and recurrent disorder with fluctuations over time in many patients. Because of this episodic nature, patients often require repeated courses of treatment. Hence, it is important that pharmacological treatments can be repeated without a loss of efficacy, as was also published by the European Committee for Medicinal Products for Human Use in Points to consider on the evaluation of medicinal products for the treatment of irritable bowel syndrome.(76) Several 12-week treatment trials with tegaserod have documented a loss of treatment effect and symptom recurrence, although not as severe as at baseline, upon withdrawal of active treatment. In an open-label study carried out in the UK and aimed at comparing the effects of ­withdrawing tegaserod in comparison with continuous treatment, reintroduction of tegaserod in patients who relapsed after withdrawal provided symptom relief similar to that of the initial treatment.(77) A German open-label study, where retreatment with tegaserod was started in patients who experienced symptom recurrence following treatment withdrawal, showed that retreatment was as efficacious as the initial 12-week treatment period.(78)

An international prospective, double-blind, placebo-controlled, randomised retreatment trial with tegaserod was conducted in 2,660 women with IBS-C.(79) Initially, patients were randomised to receive either tegaserod 6mg twice weekly or placebo for one month. Patients with at least a partial response entered a treatment-free interval. Upon symptom recurrence, tegaserod-treated patients were re-randomised to tegaserod or placebo for an additional month. Both in the first and in the second treatment cycle, tegaserod was superior to placebo for the primary covariables of relief of IBS symptoms and relief of abdominal ­discomfort/pain.

Tegaserod was also superior to placebo for every secondary efficacy variable (relief of abdominal discomfort/pain, bloating and constipation, and stool frequency and consistency). Tegaserod produced greater satisfaction, work productivity and improved quality of life than placebo.

Conclusion
IBS is an extremely prevalent disorder with mixed underlying pathophysiology. Classical treatment approaches provide relief of single IBS symptoms only. The development of serotonergic drugs generated pharmacological approaches that provide relief of overall IBS symptoms. Tegaserod, a 5-HT(4) receptor agonist, has been shown to be an effective and safe agent for the treatment of IBS-C. Recent open-label studies suggest potential efficacy both in initial treatment and during retreatment with tegaserod. A randomised placebo-controlled retreatment trial with tegaserod in women with IBS-C confirmed the efficacy and safety of repeated tegaserod therapy in these patients.

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