Ibs

Aliment Pharmacol Ther 2004; 20 (Suppl. 2): 10–22.

Diagnosis and therapy of irritable bowel syndrome R. DE GIORGIO, G . BARBAR A, V. STAN GHELLIN I, C. CREMON, B. SA LVIOLI, F. DE PO NTI* & R. COR INALDESI Departments of Internal Medicine and Gastroenterology and *Pharmacology, University of Bologna, Italy

SUMMARY

Irritable bowel syndrome (IBS) is one of the most common gut functional diseases, affecting 10–20% of people worldwide. Although most patients do not seek medical help, the disease accounts for huge costs for both patients and health-care systems and worsens significantly patients’ quality of life. Diagnosis is based on the identification of symptoms according to Manning, Rome I and Rome II criteria and exclusion of alarm indicators. IBS symptoms overlap with those of coeliac disease, lactose intolerance, food allergies and bile salt malabsorption. The treatment of IBS is centred

INTRODUCTION

Irritable bowel syndrome (IBS), one of the most common diseases in gastrointestinal clinical practice, is defined classically as a chronic disorder characterized by abdominal pain/discomfort and disturbed defecation not explained by structural and biochemical abnormalities.1–5 The social impact of IBS on the general population is extremely high, as this syndrome affects 10–20% of people worldwide and reduces quality of life.4, 6, 7 These patients represent a considerable burden for society because of direct (e.g. public health-care use, drug consumption) and indirect (e.g. absenteeism from work and lack of productivity) costs.8–10 Hence, the need to develop appropriate diagnostic and therapeutic approaches for IBS has grown considerably in the recent past. Several insightful papers, reviews and working Correspondence to: Dr R. De Giorgio, Department of Internal Medicine and Gastroenterology, St Orsola Hospital, Building no. 5, Via Massarenti, 9-40138, Bologna, Italy. E-mail: [email protected]

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on an excellent doctor–patient relationship along with drugs targeting the predominant symptom, especially during exacerbations. Current pharmacological remedies are unsatisfactory due to the high number of patients complaining of lack of response and/or symptom recurrence. Although useful in some IBS patients, the validity of psychotherapy deserves further investigation. A wide array of potentially useful drugs are currently under consideration in pre-clinical trials. A better understanding of the pathogenetic mechanisms underlying IBS may help to develop more effective drugs for this disease.

team reports have illustrated different strategies to manage patients with IBS (for review see1–5). A proposed approach includes a positive diagnosis by means of accurate symptom analysis, few laboratory tests (avoiding useless and costly examinations) and a therapeutic trial,2 which may be of benefit to the patient, also considering the high placebo response (from 20–70%) found in this syndrome.11–13 Exclusion of alarm symptoms is considered mandatory. These are also referred to as Ôred flagsÕ and include age > 50 years, nocturnal symptoms awaking the patient from sleep, refractory diarrhoea, rectal bleeding or evidence of anaemia, hypoalbuminaemia, significant weight loss, fever, abnormal physical examination (e.g. palpable abdominal mass), progressive and severe non-fluctuating symptoms, history of antibiotic use and family history of colon cancer or inflammatory bowel disease.1–5 Clearly, testing is necessary in the case of any red flag and/or evidence of positive family history; the appropriate examinations should be discussed and planned with the patient at the first consultation. None
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the less, the distinction between organic and functional diseases represents one of the most difficult tasks not only in general practice but also in the specialist setting. In order to overcome this problem, experts formed consensus groups to identify symptom-based criteria useful to differentiate IBS from organic diseases. The aim of this review article is 2-fold: (1) to focus on the main diagnostic criteria for IBS and related possible pitfalls; and (2) to tackle appropriate therapeutic approaches and potential pathophysiological targets. MAIN EPIDEMIOLOGICAL FEATURES OF IBS

For the purpose of this work, we will review only the major epidemiological aspects of IBS which may help to provide the framework for a correct clinical approach to IBS patients (for more details on the epidemiology and socio-economic impact of IBS the reader is referred to in-depth reviews, e.g.1, 2). IBS is an extremely common disease as it affects up to 24% of women and up to 19% of men of the adult population in the USA and Europe.14 These findings reflect the tremendous impact of IBS on social costs due to health-care use, drug consumption and absenteeism from work. For example, it has been estimated that the social indirect costs for IBS are similar to those reported for influenza.2, 8–10 The exact prevalence of IBS is poorly defined, probably because of the different definitions and clinical criteria (see below) used to define the syndrome. For instance, Saito et al.15 compared Manning vs. Rome II criteria to evaluate the prevalence of IBS in a community in Olmsted County (MN, USA). The results showed substantial variability, as the age- and gender-adjusted prevalence was 20.4% using two symptoms of the Manning criteria, whereas it was 8.5% using three defecation disorders in the Rome II

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criteria. The percentage of agreement for both the criteria used was > 90%. Similarly, the incidence of IBS is unknown, although it can be expected to be around 0.2% per year based on clinical diagnosis of the syndrome.16 This finding certainly underestimates the real incidence of IBS as only one in three patients seek doctors. IBS is commonly believed to be a female disease; depending on the type of the sample, women are 3–4 times more commonly affected than men in the clinical setting, whereas this estimate becomes 2 : 1 in the community.16 The reason why women appear to be more prone than men to IBS is unknown, although health-seeking behaviour and other factors may play a role in this gender predominance (Table 1).17–22 On the other hand, in eastern countries, either no gender difference (e.g. in Taiwan)23 or male predominance (e.g. in India)17 has been reported. THE CLINICAL DIAGNOSIS OF IBS: FROM MANNING TO ROME CRITERIA

Making a correct diagnosis of IBS is of crucial importance because it reassures patients about the favourable prognosis of their disease and places the basis for a therapeutic strategy on controlling the predominant symptom (e.g. constipation, diarrhoea, alternating bowel and pain/bloating). However, the distinction between IBS and other organic diseases is not an easy one, for several reasons. First, physicians, especially general practitioners, are not confident enough with the use of positive symptom criteria (see below) to detect IBS, implying that in this setting, IBS remains a diagnosis of exclusion. Secondly, the lack of a Ôbiological markerÕ for IBS corroborates the concerns experienced by most physicians about the certainty of their diagnosis and may probably explain, at least in part, the high

Table 1. Putative factors for female sex predominance in health-care request for IBS Factor

Meaning

Reference

Cultural background

Women seek medical aid more frequently than men in western countries

Unruh, 1996

Stress and psychological abnormalities

Women are more sensitive to psychological distress and life event stress

Lydiard, 2001

Sex hormones

Female steroids are known to affect visceral sensitivity and decrease pain threshold

Berkley, 1997; Ruigomez et al. 2003

Different brain serotonin synthesis

Possible sex-related difference in neurotransmitter synthesis (i.e. serotonin) in the central nervous system which may account for visceral perception and illness behaviour

Nishizawa et al. 1997


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percentage of patients with functional bowel disorders referred to consultants in specialized centres (up to 60%).1–5 Thirdly, symptoms complained of by IBS patients are not specific for the syndrome and are characterized by a significant inter- and intra-individual variability (i.e. symptoms vary considerably among patients and within a single patient over time). These factors may contribute to the doubts that physicians have of missing an organic disease. In an attempt to facilitate a correct diagnostic approach to IBS, over the years groups of experts have developed clinical measures based on positive symptom analysis. In 1978, Manning and colleagues were the first to propose key symptoms, now referred to as ÔManning criteriaÕ, to help the diagnosis of IBS.24 These symptom criteria were integrated later into other scoring systems. The Rome I, and more recently the Rome II, criteria are the results of multinational ad hoc consensus workshops (Table 2).25, 26 The Rome II working group (the Rome III criteria are currently in progress) defined IBS as Ô…a group of functional bowel disorders in which abdominal discomfort or pain is associated with defecation or a change in bowel habit, and with features of disordered defecationÕ.26 Notably, factor analysis data proved evidence that IBS can be defined by a cluster of three symptoms which represent the core of Rome II criteria (see Table 2). Although Rome criteria have now gained popularity, being used in several clinical studies and adopted by regulatory authorities, the Manning criteria have been better validated. Indeed, Manning criteria have been found to discriminate IBS from other organic disorders of the gastrointestinal tract with sensitivity and specificity rates ranging from 58 to 81% and 67 to 87%, respectively.4, 27, 28 Vanner et al.29 compared Rome I criteria to the consultant’s final diagnosis, which was considered as the gold standard for IBS identification in this study. The results showed that Rome I had a sensitivity of 65% and, in the absence of red flags, the specificity was 98%. Thus, positive Rome I criteria along with absence of alarm indicators have a very high predictive value for identifying patients with IBS and, on the other hand, the risk of missing organic diseases appears to be low. Both Rome I and II criteria proved to be valuable in identifying similar proportions of IBS patients in the general population;30, 31 however, Rome I criteria allowed the identification of higher numbers of IBS patients compared to Rome II in referral centres.32, 33 The reason why Rome I and II work similarly in the

Table 2. Symptom-based criteria so far established for the diagnosis of IBS Manning Pain relieved by defecation More frequent stools at the onset of pain Looser stools at the onset of pain Visible abdominal distension Passage of mucus Feeling of incomplete evacuation Rome I Abdominal pain or discomfort for at least 3 months with at least 1 of the following symptoms: relieved with defecation associated with change in frequency of stools Associated with change in form of stools and two or more of the following symptoms: altered stool frequency and/or form altered stool passage passage of mucus bloating or abdominal distension Rome II Abdominal pain or discomfort for at least 12 weeks in 12 months with at least two of the following symptoms: relieved with defecation associated with change in frequency of stools Associated with change in form of stools with the following symptoms supporting irritable bowel syndrome: altered stool frequency and/or form altered stool passage passage of mucus bloating or abdominal distension

community and yield different results in referral centres remains unknown. It is probable that inappropriate use and/or intrinsic limitations of diagnostic criteria may be responsible for this discrepancy. Overall, the general view is that the Rome II criteria are extremely valuable as research tool rather than useful criteria in daily practice. Probably, the advent of the next Rome III criteria will improve this bias and will favour the development of more adequate clinical measures useful not only for research purposes, but also for the identification and management of IBS patients in clinical practice. None the less, we believe that Manning or Rome II can guide doctors towards a positive diagnosis of IBS if combined with an accurate history evaluation, physical examination and, particularly, exclusion of alarm symptoms suggestive of an underlying organic disease. These considerations apply more effectively to the clinical setting of referral centres than to general practice, where looser definitions of IBS are commonly used. Finally, the identification of risk factors


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Table 3. Risk and commonly associated factors in IBS Risk/associated factor

Specific evidence

Genetic factors

No direct evidence; however, a genetic imbalance between pro- and anti-inflammatory cytokines may be responsible for a Ôminimal inflammationÕ, likely involved in the pathogenesis of IBS symptoms IBS is more common in women; there is more medical consultation among women > men; menstrual cycle may play a role in symptom exacerbation Co-existence of anxiety and depression; personality abnormalities and stress in IBS aggravate symptoms and make the patient more keen to seek medical support Non-steroidal anti-inflammatory drugs and antibiotics may elicit IBS symptoms Established aetiological factor in subsets of IBS and other functional disorders

Sex Psychosocial factors Drugs History of previous gastroenteritis

for IBS may also be useful to facilitate diagnosis (Table 3).1–5 DIAGNOSTIC PITFALLS AND DIFFERENTIAL DIAGNOSIS

Based on the general understanding that functional symptoms experienced by IBS patients overlap greatly with other gastrointestinal diseases, physicians are often faced by the dilemma of whether the patient should be first treated or tested. Moreover, if the second option (i.e. test the patient) would be the best choice to avoid the risk of missing alternative diagnosis, then the question that arises in daily practice is which patient should undergo testing. A clinical scenario which exemplifies the challenge of clinical practice is given by patients presenting with diarrhoea, a symptom related to either IBS (diarrhoea-predominant IBS) or a variety of underlying disorders including coeliac disease, lactose intolerance, food allergies and other conditions. Obviously the solution of this problem, i.e. what is the best to do in this case, is far from established. Again, the general experts’ consensus indicate that if a patient is diagnosed to have IBS according to symptom-based criteria in the absence of red flags, then no further investigations are need. This hypothetical patient should be given a therapeutic trial (based on predominant symptom) and possibly tested only if refractory to treatment. Recent data, however, suggest a critical evaluation of this strategy. Indeed, Cash et al.34 showed that among patients fulfilling the Rome II criteria for IBS, the pre-test probability to identify inflammatory bowel disease, colorectal cancer or infectious diarrhoea was less than 1%. However, the pre-test probability of coeliac disease in these patients was 10 times higher than the prevalence of coeliac disease in the general population.34 These results indicate that

diagnostic tests performed in IBS patients defined according to Rome II are not likely to unravel underlying organic disorders, but coeliac disease. Sanders et al.35 performed a controlled study based on 300 consecutive new patients meeting the Rome II criteria and screened them for coeliac disease with antibody testing. The results showed that 66 of 300 patients with IBS had positive antibody results, of whom 14 had histologically proven coeliac disease (4.8%) compared to two control subjects, who turned out to be positive for coeliac disease (0.7%) [odds ratio ¼ 7 (95% CI 1.7–28.0)].35 According to these results, serological screening for coeliac disease should be conducted in IBS patients referred to secondary care centres. In this regard, the American Gastroenterological Association guidelines for IBS recommend serological tests for coeliac disease (i.e. antibody anti-tissue transglutaminase) in any patients with IBS, especially those with diarrhoea-predominant IBS.3 The two main conditions that should be considered in the differential diagnosis of IBS are inflammatory bowel disease in young patients and colorectal carcinoma in older patients, whereas parasitic and bacterial infections represent a major clinical challenge in developing countries.2 An accurate physical examination along with few targeted investigations will help to exclude organic (e.g. structural, metabolic or infectious) diseases. Special consideration should be made for gut inflammation, which recent clinical and experimental data from our and other groups indicate may be involved in the pathogenesis of IBS symptoms.36, 37 Furthermore, histological analyses of colonic mucosal biopsies may also reveal 10% of microscopic colitis that would be missed using symptom-based criteria alone.38 Other gastrointestinal disorders that should be considered in the differential diagnosis of IBS have been reviewed by a panel of experts (for review, see39) and we


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will cover only briefly the major conditions that must be taken into consideration by practising physicians. Lactose and other carbohydrate malabsorptions The role of sugar malabsorption in the pathogenesis of IBS is still a debated problem. In fact, demographic data show that the prevalence of IBS patients with sugar malabsorption is similar to that found in controls.2 The diagnosis of lactose intolerance can be achieved with breath testing following the administration of 50 g of lactose, although the test may be limited by a low sensitivity and specificity.40 Symptoms, such as diarrhoea and bloating, can typically be reproduced by lactose intake and reduced following lactose exclusion from the diet. Lactose malabsorption may co-exist with IBS. Indeed, lactose malabsorption can be detected in about 25% of patients with IBS. Furthermore, lactose ingestion evokes symptoms in about 25% of IBS.41–45 Nevertheless, a lactose-free diet is effective in improving symptoms only in about 10% of IBS patients.45 In addition to lactose other carbohydrates, such as sorbitol (a sweetener used in sucrose-free dietary products) and fructose, may precipitate IBS symptoms. Ingestion of 5 g of sorbitol and 25 g of fructose have been found to induce symptoms more commonly in IBS patients than in controls (44.3% vs. 3.5%).42, 43, 46 Notably, the dose of carbohydrates that evokes symptoms in IBS is lower than that required to trigger symptoms in healthy volunteers. In conclusion, the diagnosis of carbohydrate malabsorption is based on hydrogen excretion with breath testing after oral challenge of the sugar which is thought to evoke IBS-like symptoms. If this test is positive, then the offensive sugar should be excluded from the diet. However, it is still debated whether all IBS patients should undergo breath testing for carbohydrate malabsorption. Food allergies This term indicates immune-mediated forms of adverse reactions evoked by some foods. The exposure of allergenic substances to the intestinal mucosa triggers IgE- and non-IgE-mediated mechanisms which stimulate the release of histamine and other mediators from mast cells. The released pool of chemical messengers may deeply affect gut neuro-muscular functions and hence induce the occurrence of symptoms overlapping

those of IBS (e.g. diarrhoea and abdominal pain). The prevalence of food allergies has been estimated to be 0.3–7.5% in children and 1.3–2% in adults.47 These figures may be underestimated, however, as methods used currently to detect food allergies are still debatable and hampered by low sensitivity and specificity.48 The impact of food allergies on IBS is still largely undefined and studies are awaited in this field. Thus, the diagnosis of food allergies in patients with IBS remains poorly defined. If a food allergy is recognized, an exclusion diet may be of benefit for IBS patients. Too-restrictive diets are unadvisable, based on a wide positivity of allergic tests. A therapeutic trial with sodium chromoglycate can also be attempted, but only limited evidence of its efficacy has been produced so far.49, 50 Bile salt malabsorption This disorder is characterized by IBS-like symptoms such as abdominal pain and watery stools that are not associated with a previous intestinal resection, vagotomy or cholecystectomy. The pathophysiology of bile salt malabsorption has been reviewed recently.51 If a patient presents with watery diarrhoea with a stool weight up to 900 g per day, then bile salt malabsorption can be suspected. To substantiate the existence of this condition several tests can be attempted, including assay of bile salt in the faeces (> 250 g per day in disease state)52 and scintigraphic assessment measuring the degree of retention and excretion of 75SeHCAT (75-seleniumhomotaurocholic acid) at 30 min and 7 days following the examination (normally the retention is > 15%).53, 54 These examinations, however, are necessarily performed in secondary or tertiary referral centres and therefore cannot be considered for routine screening. A more simplistic approach is based on a therapeutic trial with the bile salt sequestering drug cholestiramine, if tolerated by the patient. In conclusion, a bile salt malabsorption should be sought in patients with diarrhoea-predominant IBS in whom diarrhoea is particularly severe and unresponsive to classic treatment.

NON-PHARMACOLOGICAL AIDS IN THE TREATMENT OF IBS

General considerations and patient stratification Patients with IBS encompass a wide spectrum of disease severity which needs to be evaluated to address a


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correct management. Indeed, the analysis of the nature and severity of symptoms, correlation of symptoms to food intake and/or bowel habit changes, degree of gut functional impairment, and the presence of psychological abnormalities and psychiatric comorbidity allow for a differentiation of IBS patients into three main categories, i.e. mild, moderate and severe.55, 56 Most patients (approximately 70%) experience mild symptoms and treatment is directed to target pharmacologically the underlying altered gut sensorimotor function; other patients with moderate symptoms (25%) have an intermittent, although disabling, symptom pattern. The symptoms complained of by these patients relate to gut sensorimotor dysfunction and psychological/psychiatric disturbances, hence treatment is based on the use of agents targeting gut dysfunction along with low-dose antidepressants and psychological support if needed; finally, a minority of patients (5%) suffers from severe symptoms often refractory to medications. Patients with such severe forms of IBS require referral to specialized centres; they often manifest psychiatric comorbidity (anxiety, depression) and psychological problems (previous history of sexual abuse, poor coping) which may benefit from antidepressants and psychiatric/psychological support. Non-pharmacological aids Once the diagnosis of IBS is established, an effective physician–patient relationship is crucial for setting the basis of a beneficial pharmacological approach. The fundamentals of this relationship rely on the doctor as Ôkey-playerÕ able to: (i) listen carefully to the patient and estimate her/his understanding of the disease and concerns; (ii) reassure her/him on the benign nature (i.e. absence of alarm symptoms, normal physical examination) of the illness; (iii) provide an explanation of what IBS is and Ôwhat is wrong in the bellyÕ (i.e. simple description of the potential mechanisms leading to symptoms); and (iv) also provide a ÔroleÕ to the patient, who should be actively involved in the treatment.1–3 Evidence indicates that this approach leads to a reduced number of health-care visits.57 Psychological stressors, which are known to maintain and exacerbate symptoms, should be sought and managed with supportive advice or lifestyle modification. Dietary review, with the recommendation to avoid caffeine and foods that the patient recognizes as symptom-triggers, along with a reduction of fat intake (known to markedly

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contribute to disturbed gut functions, such as sensation and motor reflexes), is a reasonable approach in patients with IBS. This simple strategy prevents an excessive dietary restriction which may turn out to be potentially dangerous for the patient. Notably, previous studies indicated that restriction diets did not show any efficacy in IBS.58 Specific dietary indications should be aimed at reducing/eliminating excessive intake of fructose or sorbitol in patients with diarrhoea; increasing adequately dietary fibre in subjects with constipation; and, finally, avoiding fermenting foods, i.e. beans, cabbage and cauliflower, may be useful to patients with predominant bloating.59 Fibre supplementation An increased dietary fibre intake (i.e. cellulose, hemicellulose pectins and lignins) is one of the most common recommendations in constipation-predominant IBS. Potentially, fibres may be beneficial in constipated IBS patients because of their ability to reduce the transit time of the entire alimentary tract (thus improving intestinal peristalsis and therefore bowel movements) and intestinal wall tension by decreasing intracolonic pressure (this latter effect may contribute to visceral pain relief).60 Nevertheless, published clinical trials (i.e. wheat bran) showed that fibres were no better than placebo in overall symptom relief, whereas symptoms such as pain and distension worsened.61, 62 Bran is usually not well tolerated by patients with IBS. More recent meta-analysis data confirmed the concept that fibre supplements are not superior to placebo, although they could be effective for improving constipation.63 In conclusion, fibre may be prescribed in constipated IBS, although its use should be introduced gradually into the dietary regimen. Psychological treatment The approaches to psychological treatment, including cognitive behavioural therapy, psychotherapy, relaxation and hypnosis, may represent a valid therapeutic option, at least in a sub-group of patients with IBS. Potential candidates who benefit from psychological measures are patients with pain and predominant diarrhoea, psychiatric comorbidity and intermittent pain aggravated by stressful events or anxiety.64 On the other hand, patients with chronic abdominal pain do not appear to be responsive to psychotherapy.64


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Meta-analysis results indicate that psychological treatment was better than standard therapy in eight studies, whereas it did not prove efficacy in five studies.65 However, most of these studies have significant methodological shortcomings (i.e. lack of blinding, no control with placebo and patients entering studies are those referred to tertiary centres) and therefore the actual efficacy of psychotherapy in IBS deserves further data. Randomized trials showed hypnotherapy as one of the most valuable nonpharmacological treatment in IBS, with benefit lasting longer than 12 months.66 Further results are awaited with this approach.

PHARMACOLOGICAL APPROACHES TO IBS

General considerations The pharmacological treatment of IBS is aimed at controlling the dominant symptom, i.e. constipation, diarrhoea and pain/bloating.2, 59, 67 Physicians need to inform patients that any prescribed compound should be taken only during symptom recurrence rather than chronically. Although a variety of drugs belonging to different pharmacological classes (i.e. anticholinergic or antispasmodics, opioid derivatives, laxatives, antidepressants and serotonin receptor modulating agents) have therapeutic potential for IBS, the efficacy of these compounds turned out to be limited in clinical trials, probably because of methodological inadequacies including undefined, unclear or questionable entry criteria, limited number of patients, high dropout rate, short duration of study and improper use of statistical analysis.68 These biases have been considered by investigators, and recent trials appear to be better designed with appropriate patient selection/sub-groups, exclusion of gut disorders overlapping with IBS and, finally, definition of clear, clinically relevant therapeutic Ôend-pointsÕ. The following sections will briefly review the main classes of drugs used in IBS treatment as emerged by clinical trials and meta-analysis. Antispasmodics Currently available antispasmodics belong to three major subclasses, namely anti-muscarinics (e.g. cimetropium, prifinium), smooth muscle relaxants (e.g. tiropramide, papaverine-like agents that directly inhibit smooth muscle contractility by increasing cAMP levels

or interfering with the intracellular calcium pool) and calcium channel blockers (e.g. nifedipine or pinaverium that are especially l-type calcium channel blockers).69 The final effect of all these compounds is to evoke smooth muscle relaxation and hence reduction of gut wall tension. Antispasmodics are indicated in IBS as these patients have increased postprandial colonic motility, which often manifests with diarrhoea and cramp-like abdominal pain. The abundant literature on antispasmodic agents in IBS has been pooled and evaluated in different valuable meta-analysis. Critical issues emerging from metaanalysis studies concerned the poor quality of most trials (i.e. characterized by lack of appropriate blinding, a significant number of dropouts at follow-up, short duration and unclear end-points) and this has limited our understanding on the actual efficacy of antispasmodics. According to two recent meta-analyses, the overall effect of these compounds is superior to placebo in reliving global symptoms and pain (odds ratio for benefit ¼ 2.1), although they had no effect on diarrhoea and constipation.63, 70 Antispasmodics, taken about 30 min before meals, can be effective in controlling postprandial cramps and diarrhoea and they should be recommended for this specific therapeutic target. Although no formal studies have assessed the efficacy of sublingual antispasmodics, their use appears indicated especially for as-needed regimens.2, 59 Possible side effects of anticholinergic compounds, including dry mouth, blurred vision and urinary hesitancy, may occur, but they are generally mild and well tolerated by patients. Peppermint oil has been proposed as a remedy for IBS, although five placebo-controlled studies did not show any clinical efficacy for this treatment.71 Antidiarrhoeals This class of drugs includes opioid analogues, such as loperamide, which are known to exert an inhibitory effect on intestinal peristalsis and fluid secretion by interacting with enteric neurones. Clinical trials showed that loperamide significantly ameliorates diarrhoea, urgency and faecal soiling,63 although it has no effect on other IBS-related symptoms such as pain and bloating.72 Compared to codeine and diphenoxylate, loperamide does not cross the blood–brain barrier and this feature makes it a relatively safe drug employed extensively in general practice and clinical trials (at a dose of 2–4 mg up to four times per day). None the less,


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loperamide should not be used chronically to avoid rebound constipation, and its best prescription is as-needed medication during exacerbation of diarrhoea. As mentioned previously, colestyramine can be also used to treat IBS patients in whom bile salt malabsorption may contribute to or be directly responsible for diarrhoea.73 Antidepressants Tricyclic antidepressants (e.g. amitriptyline, desimipramine, imipramine, doxepin) have been proposed in the management of functional gastrointestinal syndromes, especially IBS. The conceptual basis for their use in IBS patients is centred on three main aspects, including treatment of co-existing psychological abnormalities (depression, anxiety), reduction of central pain perception of stimuli conveyed by sensory afferent nerves pathways and ability to target gut sensorimotor dysfunction.74 According to a recent meta-analysis, tricyclic antidepressants proved to be helpful in IBS patients with a number needed to treat of 3.2.75 In these trials, tricyclic psychotropic agents were used at lower dosages (10–25 mg for amitriptyline and 50 mg for desimipramine) than those prescribed for treating depression, thus implying that their effects are not necessarily related to those responsible for the antidepressant effect. Tricyclic antidepressants are best prescribed for periods of 2–3 months, rather than an as-needed regimen, and typical candidates for this treatment are patients with frequently recurrent or chronic symptoms, especially pain and diarrhoea. The only non-tricyclic compound tested so far in a clinical trial is mianserine, which proved to be as effective as tricyclic antidepressants.75 Because of their anticholinergic effects, tricyclic antidepressants can evoke constipation, but also dry mouth, somnolence and urinary retention, which may hamper the use and efficacy of these drugs. Selective serotonin re-uptake inhibitors (SSRIs; e.g. fluoxetine, paroxetine), which lack anticholinergic side effects, may be a valuable alternative to tricyclic antidepressants for the treatment of IBS and other functional bowel disorders,76 and indeed SSRIs may have a prokinetic effect. SSRIs are advisable for IBS patients with psychiatric comorbidity (i.e. depression). In a recent study by Creed et al.,77 the SSRI paroxetine (20 mg per day) and psychotherapy (eight individual sessions) were compared to routine care by a

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practitioner or a gastroenterologist in patients with severe IBS. The results showed that both psychotherapy (69% of patients) and paroxetine (50%) were better than routine management in improving the physical aspects of health-related quality of life in IBS and that the beneficial effect of both psychotherapy and paroxetine was less expensive than routinary treatment. This study indicated that paroxetine, as well as psychotherapy, can be a cost–effective treatment for patients with severe IBS. Nevertheless, further studies with SSRI are needed to establish their use in IBS. SSRIs The rationale for the use of serotonin (5-hydroxytriptamine, 5-HT) receptor agonists and antagonists in IBS is based on the evidence that this biogenic amine, which is released by enteroendocrine (i.e. enterochromaffinlike), enteric neurones and other non-neuronal sources, possesses a wide array of established motor effects on the gut and can lead to hyperalgesia in several experimental models.78 5-HT modulates its effects on the gastrointestinal tract through binding with several receptor subtypes termed 5-HT1, 5HT2, 5-HT3, 5-HT4, and 5-HT7 (for reviews, see 79, 80). For the purpose of the present paper we will focus on 5-HT3 and 5-HT4 receptors because they are the most extensively studied in gastroenterology and for their relevance to IBS treatment. Alosetron is a 5-HT3 receptor antagonist approved by the Food and Drug Administration (FDA) for the treatment of diarrhoea-predominant IBS in female patients resistant to conventional anti-diarrhoic agents. This drug affects extrinsic afferent sensory neurones projecting to the gut and intrinsic enteric neuroneuronal reflexes.81 Thus, the final effect induced by alosetron is a delayed gut transit time and an increase in visceral perception threshold, which makes this compound valuable for treating diarrhoea-predominant IBS.82 Six major multicentre, randomized, placebo-controlled studies83–88 were included in a recent meta-analysis comprising 1762 patients treated with alosetron vs. 1356 with placebo.89 Most of the enrolled patients were female (93%) with diarrhoea-predominant IBS (75%). The pooled adjusted odds ratio for the end-point adequate relief of pain or global symptom improvement was 1.81 (95% CI 1.57–2.10), with an average number of seven patients needed to treat. The effective


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dose of 1 mg b.i.d. of alosetron (12 weeks in each study) successfully relieved pain, discomfort and diarrhoea in female IBS patients. No beneficial effect was reported in male patients. The safety profile indicated that the most commonly experienced symptom was constipation (one of four patients), whereas the prevalence of presumed ischaemic colitis in the alosetron-treated group was 0.1%. From these meta-analysis data it can be concluded that the 5-HT3 antagonist alosetron is advisable in selected female patients with severe pain and diarrhoea refractory to conventional therapies. A special consideration should be reserved for the study of Jones et al.84 (based on 623 nonconstipated females with IBS) in which alosetron 1 mg b.i.d. was more effective than the antispasmodic mebeverine 135 mg t.d.s. Cilansetron is another 5-HT3 antagonist currently undergoing clinical trials and only little information is currently available in the published literature.90 5-HT4 receptor agonists are known to evoke a potent prokinetic effect throughout the gastrointestinal tract. The most extensively studied 5-HT4 receptor agonists include cisapride, tegaserod and prucalopride. Cisapride, however, has been withdrawn from the market because of its well-known potential to evoke ventricular arrhythmias and prolongation of the QT interval through blockade of HERG K+ channels.91 In contrast, second-generation 5-HT4 receptor agonists, i.e. tegaserod, mosapride and prucalopride, seem to be devoid of anti-arrhythmic properties and at least two of them (tegaserod, prucalopride) may be more active at the colonic level than cisapride.92 Among 5-HT4 receptor agonists, tegaserod, prucalopride and mosapride have undergone clinical trials. Tegaserod is approved by the FDA (not yet in the European Union) for the treatment of constipation-predominant IBS in women. A metaanalysis of seven studies in 4040 female IBS patients with predominant constipation showed that tegaserod was superior to placebo at the dosages of 12 mg (relative risk of being a responder of 1.19; 95% CI 1.09–1.29) and 4 mg (relative risk of being a responder of 1.15; 95% CI 1.02–1.31), with a number of 14 and 20 needed to treat, respectively.93 Thus, tegaserod proved to be useful in constipation-predominant IBS, although further studies are awaited. Prucalopride is being investigated for a range of conditions including constipation-predominant IBS and slow transit constipation with higher efficacy compared to placebo.

Antibiotics and probiotics The rationale for antibiotics in IBS arises from data showing that functional symptoms may be related to an underlying small bowel bacterial overgrowth.94 Furthermore, Pimentel et al. investigated 111 patients with IBS and found that most of them (84%) had a small bowel overgrowth as identified by positive lactulose breath test. Patients were then randomized in a doubleblind fashion for the non-absorbable antibiotic neomycin (500 mg per day for 10 days) or placebo for 1 week. Treatment with neomycin was significantly superior to placebo in improving IBS symptoms (35% of patients vs. 11.4%, respectively).95 However, because of the short follow-up (7 days), the absence of information concerning the duration of the beneficial effect evoked by neomycin, and methodological drawbacks intrinsic to the lactulose breath test (low sensitivity, 16.7% and specificity, 70%),96 the therapeutic value of neomycin in IBS remains questionable. On the other hand, Di Stefano et al.97 assessed the efficacy of rifaximin, a rifamycin derivative, on intestinal gas production and related intestinal symptoms and found that this nonabsorbable antibiotic significantly reduced both H2 excretion and overall severity of symptoms in 34 functional bowel disease patients. Confirmatory studies are now awaited. In addition to antibiotics, probiotics have also been tested to treat changes of intestinal microflora, a potential pathogenetic mechanism contributing to IBS symptoms. The probiotics used included either single strains of Lactobacilli or a mixture of Bifidobacteria, and Lactobacilli and one strain of Streptococcus (namely, VSL#3). However, randomized controlled trials yielded controversial results,98–103 with four of six studies showing beneficial effects. Probiotic-related improvement included daily symptom scores98, 99 or single symptoms such as abdominal pain,99, 100 flatulence100 and bloating.103 In conclusion, probiotics may be useful in IBS; however, conclusive evidence of their efficacy is still needed. FUTURE DRUGS

An impressive knowledge on molecular biology, physiology and pharmacology of the gastrointestinal tract is in the process of being translated into a clinical perspective. This advancement is expected to foster the development of novel drugs potentially useful for the


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treatment of IBS patients. A long list of products are in the pipeline, including cholecystokinin 1 receptor antagonists, tachykinin-1, -2 and -3 receptor antagonists, opiate receptor j-agonists and l-antagonists, a2-adrenergic agonists, muscarinic-3 receptor antagonists, cortocotrophin-releasing factor receptor type 1, cannabinoid receptor 1, somatostatin analogues, chloride channel openers and others, are currently under investigation (for review see,67,104). Although these agents have a variety of effects, they mainly modulate gut sensorimotor function.

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CONCLUSIONS

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IBS has a tremendous impact on society, being a major cause of morbidity worlwide. Over the years, experts have identified symptom-based criteria to ease the diagnosis of IBS and avoid the risk of missing organic disease. Thus, Manning, Rome I and Rome II criteria have been established and their use, together with an accurate exclusion of alarm symptoms, is currently considered the best approach for diagnosing IBS patients. The pathophysiology of the symptoms related to IBS remains poorly understood and this has limited the development of targeted therapeutic agents. Hence, management is aimed at controlling the predominant symptom (i.e. diarrhoea, constipation, alternating bowel and pain/bloating) with non-pharmacological and pharmacological measures. Symptomatic treatment is based on cautionary increase in fibre intake for patients with predominant constipation, on-demand opioid agents for diarrhoea and, finally, low-dose antidepressants, antispasmodics and other non-conventional therapeutic options such as psychotherapy, for management of pain. Serotonin receptor modulators, especially 5-HT3 antagonists and 5-HT4 agonists, represent new therapeutic options for IBS. A variety of other new drugs are also currently under investigation. It is likely that the better elucidation of the mechanisms underlying IBS will bring the drugs currently under investigational assessment to the clinical foreground. Whether innovative techniques, i.e. pharmacogenomic, or clinical strategies, i.e. identification of biological markers to subgroup patients, will improve the management of IBS is a future perspective. The combination of these approaches will probably pave the way to a better management of patients with functional bowel disorders, including IBS.

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