Focus on Otilonium Bromide

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Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2012; 16: 25-37 The use of anti-spasmodics in the treatment of irritable bowel syndrome: focus on otilonium bromide

F. FORTE, M. PIZZOFERRATO, L. LOPETUSO, F. SCALDAFERRI

Department of Internal Medicine, Division of Gastroenterology, School of Medicine, Catholic University of the Sacred Heart, Rome (Italy)

Abstract. – Objective: Aim of this review is disorder in gastroenterology practice. It is char - to summarize the studies carried out, with particu - acterized by an inconstant association of symp - lar interest in those who dealt with otilonium bro - toms like abdominal pain or discomfort associat - mide, in treatment of IBS (Irritable Bowel Syn - drome). ed with disorders of bowel movement (constipa - Discussion: IBS is a frequent gastrointestinal tion or diarrhea) and/or or symptoms such as disease, characterized by a combination of sever - bloating and abdominal distension. The social al symptoms including abdominal pain or discom - impact of this disease is significantly high, with fort, flatulence and problems related to bowel important limitation in quality of life and produc - habits (constipation and/or diarrhea). It affects tivity, increased absenteeism from work and rele - about 15% of the western population, with a nega - vant costs for health systems because of repeti - tive impact on the quality of life and also on health 1-3 care costs. In relation to such important complexi - tive diagnostic test and therapies . IBS is a com - ty and negative impact, therapeutic options are plex disease, in which the wide range of symp - still very limited and most of the pharmacological toms cannot be always attributed to the numerous compounds, validated for short term use, are only pathological mechanisms hypothesized. That is partially controlling symptoms. Among those, an - the main reason of the lacking of an appropriate ti-spasmodics are commonly used in clinical set - specific etiologic therapy 2,3 . tings. Despite a discrete literature in support of these drugs, systematic collections of clinical evi - dence to support the use of anti-spasmodics and Epidemiology and Pathogenesis of IBS in particular the use of otilonium bromide in Precise estimation of IBS epidemiology is course of IBS are scarce. complex due to several reasons: the variety of Results and Conclusions: Otilonium bromide is factors involved in its pathogenesis, the diagnos - a systemically poorly absorbed antispasmodic, tic difficulties due to the absence of specific and which has shown clear efficacy compared to place - reproducible examinations or markers, the vari - bo, in controlling symptoms related to IBS. Otiloni - um bromide was effective also in comparison to ety of used criteria, the variability of clinical other drugs, such as pinaverium bromide and manifestations as well as the division of medical mebeverine, with a favorable tolerability profile. Fur - management in self-medication (71-80%), family ther studies are necessary to better define duration medicine (20-29%) and referral centers (1%), in of treatment and maximum therapeutic dose. the absence of a common database. Despite this, it is commonly recognized that IBS is a wide - Key Words: spread disease, with high prevalence in western Irritable bowel syndrome, Anti-spasmodics, Otiloni - countries and in women (M/F 1:2) 1,4 . Prevalence um bromide . of the disease depends on the diagnostic criteria used 1,3 , varying from 2.5%, when considering on - ly 1 of the 6 Manning’s criteria described below, to 37% adopting all 6 criteria 1 or 10% with 3 cri - teria 1. It is generally accepted, however, that IBS Introduction affects 10-15% of western population 2,3,5,6 . His - torically IBS has been considered a functional is - Irritable bowel syndrome (IBS) represents the sue, without any clear evidence of anatomical or most frequently encountered functional digestive metabolic or inflammatory or infectious damage,

Corresponding Author: Franco Scaldaferri, MD; e-mail: [email protected] 25 F. Forte, M. Pizzoferrato, L. Lopetuso, F. Scaldaferri so involving primarily a distorted perception and in IBS pathogenesis, sustaining the vicious circle processing of pain. Modern understandings are of immune activation – altered response to stress considering IBS as a multifactorial disease, and inflammation. Low grade intestinal inflam - where genetic factors, inflammatory changes mation in IBS patients, and in particular the acti - caused by gastrointestinal infections, nutrition, vation of neurons mediated by the release of and psychosocial aspects play a crucial role 1-3 . In tryptase from mast cell, could be responsible of this complex system of events, gastrointestinal visceral hypersensitivity through the direct acti - motility disorders also play a role, determining vation of trans membrane protein called neuronal an exaggerated response to the ingestion of food receptors-2 activated by proteinase (PAR2). That and/or stressful events 1. could be one of the possible mechanisms respon - It seems clear, nowadays, that patients with di - sible for alteration in pain perception 21,22 as well arrhea have an increased intestinal motility and as induction of chronic pain 23,24 in IBS patients. accelerated bowel transit, while those with con - Furthermore , IBS patients seem to display a hy - stipation display reduced motility and bowel peractivity of posterior horns of spinal cord transit 1. Furthermore, IBS patients seem to dis - which could also be responsible for lower ex - play visceral hypersensitivity, which consists in tremities skin hyperalgesia, because of the con - increased sensitivity to mechanical stimulation of vergence of nociceptive inputs of lower extremi - the bowel, alteration observed in approximately ties with viscerosomatic ones 21,25,26 . Micro-in - 2/3 of IBS patients 1. The involvement of central flammation could also influence serotonin path - and peripheral mechanisms can also support the ways. presence of a chronic pain in IBS patients 1. Serotonin can directly affect gastrointestinal Food allergy diagnosis (prevalence < 1-2%) motility and sensitivity through its 7 receptor excludes by definition the diagnosis of IBS. subtypes, which can be found in the brain as well Some studies, on the contrary, support the role of as in enterochromaffin gastrointestinal cells 27 . food intolerance in IBS pathogenesis, although IBS patients, particularly diarrhea type, have methods for intolerance evaluation are not al - been shown to display an increased number of ways correct. Among food intolerance, lactose enterochromaffin cells which produce serotonin intolerance plays a possible important role in IBS following intestinal micro-inflammation; that is pathogenesis. Various types of stress predispose the main reason of the use of tegaserod, partial IBS and facilitate the onset of symptoms in chil - agonist 5HT4, in IBS with constipation or alos - dren 7 through the activation of pituitary-adrenal etron antagonist 5HT3, in the variety with diar - axis or pituitary disorders, mediated by corti - rhea. To make the situation more complicated cotrophin release factor (CRF), the hypothalamic there is the fact that in IBS patients a reduction in stress hormone responsible for behavioral, auto - proteins for serotonin reuptake further extends nomic, immune and visceral stress events. IBS the effect of serotonin 27-29 . patients display an increased response to stress Intestinal micro-inflammation is probably with a high production of CRF 8-10 . Upon CRF re - maintained by intestinal antigenic factors such as lease 11,12 , Substance P (SP) and Peptide Related food, bacteria, fungi in the presence of increased to the Gene of Calcitonin (PRGC) 13,14 are re - intestinal permeability at least partly related to leased and are responsible to an increase in in - the activation of PAR2, responsible for the tight testinal permeability, greater bacterial adhesion junctions alteration and mast cells alterations. It to the mucosa and increased bacterial transloca - has been shown that probiotics and prebiotics can tion to the spleen 15 . At morphological level both actively act on these mechanisms, partially con - in rats and humans there is a load of mitochondr - trolling IBS related symptoms 30,31 . ial swelling enterocytes, infiltration immune, mu - IBS adults and children display an altered in - cous depletion and degranulation of mast testinal microflora compared to general popula - cells 9,16,17 . These changes persist in the animal tion, probably the result of incorrect eating habits even after removal of the stressful factor because or prolonged antibiotic therapy. of the ability of mast cells to change their inter - More than 60% of IBS patients recognize in action with neurons 14,18 . The same effects have certain type of foods the triggering event of been observed in humans 19,20 . A bidirectional symptoms while elimination of certain foods in synergism stress-inflammation can further sus - some studies has shown efficacy in reducing tain these disorders. In fact , it is generally agreed symptoms 32 . However, despite these reports, de - that micro-inflammation plays an important role spite the efficacy of disodium chromoglycate that

26 The use of anti-spasmodics in the treatment of irritable bowel syndrome inhibits the degranulation of mast cells 33,34 , there Table II. Criteria Rome III* for the diagnosis of irritable are still many doubts about the real role of elimi - bowel syndrome. ( Adapted from Spiller R et al) 1. nation diets in treating IBS. Finally, another important concause of symp - Abdominal pain or discomfort applicant for at least 3 days a month in the last 3 months, associated with 2 or toms in IBS is small intestine bacterial over - more of these factors: growth (SIBO). This condition could be cause of • Improvement with defecation several IBS symptoms including bloating, pain • Occurrence associated with a change in the frequency and could evoke an inflammatory response of evacuations through more complex neuro-endocrine-im - • Occurrence associated with a change in the appearance munological local alterations. (shape) of faeces The complex relationships of all these factors *Criteria satisfied in the last 3 months with the onset of and mechanisms described above can be sum - symptoms at least 6 months before the diagnosis. marised in a pathogenic model of IBS that cur - °Discomfort means an unpleasant sensation, not definable rently remains a fascinating working hypothesis. as pain.

Clinical Symptoms as Cornerstone in the Diagnosis of IBS tion, urgency of stimulus, sense of incomplete Main problems related to IBS management are evacuation and expulsion of mucus in the feces 1. represented by the diagnostic accuracy and pre - The late or sometimes not done IBS diagnosis cise definition 4. IBS could be classified on the or incorrect management of patients with irrita - base of bowel symptoms in diarrhea (D) type, ble bowel syndrome has a huge impact on health constipation (C) type and mixed (M) diarrhea care spending 2,4,6,36,37 with an annual cost per pa - and constipation type 3,35 . tient extremely higher than comparable subjects First attempts to define the diagnostic criteria without disease 6,38 . For example, a survey from for irritable bowel syndrome date back to 1970 US on the costs of medical care delivered on an and to the work of Manning et al (Table I )1,4 . outpatient basis showed an annual cost of US $ Subsequently , a more precise definition of 4,000 for an IBS patient and of US $ 2,700 for a IBS and more valid diagnostic criteria, from control, determining a difference of 49% 6. IBS Rome 1990 criteria to Rome II criteria in 1999, absorbs around the 28% of the consultations in have been developed. The most recent Rome gastroenterology and represents 12% of those re - III criteria shown in Table II 1, elaborated in alized on an outpatient basis 3. It has been esti - 2006, have changed only slightly previous doc - mated that in 1998 3.65 million gastroenterologi - uments . cal visits for irritable bowel syndrome have been Crucial symptom for IBS is pain, or abdomi - carried out 6. nal “discomfort”, clearly related to intestinal The irritable bowel syndrome has strong so - function, which is typically relieved by defeca - cial-economic impact in that consumption of tion (suggesting an origin from colon) or associ - health care resources are accompanied by the lack ated with changes in the form of stool (thus sug - of work, and the low quality of life 3. It has been gesting a correlation with intestinal transit) 1. Fre - calculated that in a year the absences from work quent symptoms in irritable bowel syndrome, but among the subjects with irritable bowel syndrome not included in the diagnostic criteria are: bloat - are three times those of corresponding controls: ing, anomalies in the form of feces, increase in 13.4 to 4.9 days 5,6 . An important element that the number of evacuations, effort during defeca - contributes to the high medical expenditure in pa - tients with irritable bowel syndrome is represent - ed by co-morbidity: in fact these patients consult Table I. Manning’s criteria for the diagnosis of irritable 1 a doctor for a large quantity of symptoms, either bowel syndrome. ( Adapted from Spiller R et al) . related to the gastrointestinal tract or not 37 . Patients with irritable bowel syndrome under - 1 Pain relieved by defecation go medical examinations twice as compared to 2 Evacuations more frequent at the onset of pain controls and 78% of visits in most were not relat - 3 Soft feces before the onset of pain ed to gastric disease 37 . Co-morbidity tends to be 4 Evident abdominal distension more marked in relation to psychiatric diagnosis: 5 Emission of mucus from anus in any case, the mental disorder influences but 6 Sense of incomplete evacuation does not explain the co-morbidity 37 .

27 F. Forte, M. Pizzoferrato, L. Lopetuso, F. Scaldaferri

Therapeutic Approach in Irritable Bowel Anti-spasmodics Medicines for Syndrome (IBS) the Treatment of Irritable Bowel The need for effective therapy in the management Syndrome (IBS) of irritable bowel syndrome is an absolute priority This paper will present a review of clinical tri - for modern gastroenterology 3. However, the com - als and meta-analyses which are judged to be of plex pathogenesis, the complex diagnostic definition high quality on the use of anti-spasmodics, com - and the lack of a specific pathway are shared by var - pared to placebo or other drugs 3. At the end of ious forms of irritable bowel and make the identifi - this review, a possible use will be proposed, cation of pharmacological target very difficult 3. based on the evidence, of the various classes of Symptomatic treatment represents today the drugs studied in specific clinical conditions. main target of pharmacological therapy, for both The first meta-analysis of randomized studies the abdominal pain and the altered intestinal transit on the efficacy of antispasmodics in the treat - (constipation, diarrhea), and, on reflection, for the ment of IBS patients was conducted by Poynard consequences of the latter, such as flatulence and et al and published in 1994 39 . In this meta-analy - incontinence 2,3 . The therapeutic approach must sis 5 active drugs were identified as being with - take into account the intensity of the symptoms, out significant side effects: cimetropium bro - the size of the medical intervention and the degree mide, pinaverium bromide, trimebutine, otiloni - of associated psychosocial diseases 3. The treatment um bromide, mebeverine 39 . must be based on reassurance, education and modi - Subsequently, a second more recent meta- fication of diet and lifestyle, as well, of course, on analysis was published in 2002 by Poynard et al 40 , the appropriate pharmacotherapy 3. highlighting 6 active drugs without significant The pharmaceutical categories today routinely side effects. In this study the Authors have con - used in the management of IBS include anti-spas - sidered only randomised double-blind, placebo- modics, prokynetics, alosetron, tegasetron antide - controlled studies, published as extended work. pressants, antibiotics, prebiotics and intestinal an - Total number of patients treated accounted ap - ti-inflammatory 3. Among these , antidepressants proximately to 1888 while 943 patients received are especially effective in IBS patients of the diar - placebo. Main endpoint was represented by clini - rhea type. Tegaserod and aloserod are mainly ef - cal improvement, as reported in Table III 40 . fective in the female population, the first is used Results demonstrated the therapeutic value of in constipation variant and the second in the diar - antispasmodics in pharmacological treatment of rheal. The loperamide may be used in the treat - IBS patients 40 , with Odd ’s ratio and risk reduc - ment of irritable bowel syndrome in patients tion significantly in favor of active treatment without abdominal pain and with diarrhea 3. compared to placebo (Table IV )40 .

Table III. Main features of meta-analysis of Poynard et al on the effectiveness of antispasmodics. (Adapted from Poynard T, et al) 40 .

Design studies Randomized, double-blind, placebo-controlled

Number of studies evaluated 23 Type of studies Clinical, published as articles (no abstracts or letters Period of publication Since 1965 (mebeverine) and 1999 (otilonium bromide) Main endpoint Overall improvement Other endpoints Improvement of abdominal pain Improvement of constipation Improvement of intestinal transit Improvement of abdominal distension % of patients without side effects Assessment Qualitative and quantitative Treatments considered Antispasmodics without significant side effects Drugs considered Cimetropium bromide (5 studies) mebeverine (5 studies) otilonium bromide (4 studies), trimebutine (4 studies) hyoscine 0.1 mg butylbromide (3 studies), pinaverium bromide (2 studies) Casuistry At least 51% of patients with IBS in each study Patients 1888 (active drug) 943 (placebo)

28 The use of anti-spasmodics in the treatment of irritable bowel syndrome

Considering separately each drug, a remark - sion 4. The treatment success was defined as the able variability in clinical response could be ob - reduction from baseline in at least one unit of served, in particular, in relation to the parameters scores 4. of overall effectiveness (range of response from Admission to 15 weeks of treatment was 31% to 11%) and control of pain 40 . Although a reached for 325 patients (100 males and 225 fe - direct comparison between the various drugs is males), 160 of which received otilonium bromide not possible and it is not the main objective of and 165 placebo 4. Results showed that treatment the proposed meta-analyses, it could be observed with otilonium bromide significantly reduced ab - that otilonium bromide was particularly effective dominal pain (frequency of episodes) at 10 and when compared to placebo, in the resolution of 15 weeks ( p < 0.05 and < 0.001, respectively) symptoms 40 (Figures 1, 2) . compared with the placebo treatment (Figure 3) 4. In the study, the reduction in the overall score Otilonium Bromide in the Treatment of of abdominal pain was significantly in favor of Irritable Bowel Syndrome (IBS) otilonium bromide, as shown in Figure 4 4. The first study which demonstrated the effica - Number of patients with reduced frequency of cy of otilonium bromide in patients with IBS, di - abdominal pain was greater in the group treated arrhea variant, is that of Battaglia et al., evaluat - with otilonium bromide compared to placebo, with ing a wide italian population 4. statistically significant differences ( p < 0.01) In this randomized, double-blind, placebo- (Odd’s ratio 1.87, 95% CI 1.20-2.91) (Figure 5) 4. controlled parallel-group study, conducted in 23 Considering abdominal pain, the success of Italian Centers, 378 IBS patients (121 males and therapy was significantly more frequent in group 257 females) were enrolled 4. The treatment was of patients treated with otilonium bromide com - provided for 15 weeks with otilonium bromide pared to placebo ( p < 0.05 ) (Odd ’s ratio 1.67, 40 mg tid or placebo, with controls at 5, 10 and 95% CI 1.05-2.65) (Figure 6) 4. 15 weeks 4. The evaluation of the efficacy was Otilonium bromide exerted a favorable effect based on three main symptoms (abdominal pain, in the management of several physical signs as - abdominal distension, disorders in the defeca - sociated to IBS, as the tenderness of the colon tion), and to each of them a score was assigned 4. and other parameters reported in Figure 7 4. Abdominal pain was measured in frequency Finally, the improvement of the well-being (number of episodes: none, 3 or more, from 4 to state and the judgment of the investigator signifi - 7) and intensity (absent, mild-to-moderate, se - cantly favored otilonium bromide versus placebo vere and very severe); overall score was calculat - (p < 0.01 and p < 0.05 , respectively) (Figure 8) 4. ed by multiplying frequency for the intensity 4. A Recently (2011), the results of a multicentre similar calculation applied to abdominal disten - (34 Centres), double-blind, randomized, parallel-

Table IV. Results of meta-analysis of Poynard et al on effectiveness of antispasmodics in the global population. (Adapted from Poynard T, et al) 40 .

Studies included 21 Overall improvement % patients 56% active drugs (n = 927) 38% placebo (n = 925) Odd’s ratio 2.13 ( p < 0.001, 95% CI 1.77-2.58) Risk reduction 22% ( p < 0.001, 95% CI 13-32) Significant differences in favor of active drugs Improvement in pain % patients 53% active drugs (n = 567) 41% placebo (n = 568) Odd’s ratio 1.65 ( p < 0.001, 95% CI 1.30-2.10) Risk reduction 18% ( p < 0.001, 95% CI 7-28) Significant differences in favor of active drugs Improvement of abdominal distension % patients 44% active drugs (n = 442) 35% placebo (n = 443) Odd’s ratio 1.46 ( p < 0.001, 95% CI 1.30-2.10) Risk reduction 18% ( p < 0.001, 95% CI 7-28) Significant differences in favor of active drugs

29 F. Forte, M. Pizzoferrato, L. Lopetuso, F. Scaldaferri

Figure 1. Meta-analysis of 21 studies on the effectiveness of antispasmodics in the treatment of IBS patients: results ex - pressed as percentage of patients with overall improvement. (Adapted from Poynard T, et al) 40 .

30 The use of anti-spasmodics in the treatment of irritable bowel syndrome group, placebo-controlled study have been pub - Patients who completed the 15-week sched - lished 41 . uled period were subsequently allocated to a 10- Otilonium bromide versus at the dose of 40 week follow-up, without receiving any drug mg tid, has been compared with placebo in a therapy. large patient population of 365 patients with irri - At the end of the treatment, statistically signif - table bowel syndrome, diagnosed according to icant differences were observed in favour of Rome II criteria. Out of them, 179 patients were otilonium bromide versus placebo for both, the assigned to 15 weeks of treatment with otilonium primary endpoint (frequency of abdominal pain bromide and 177 to placebo. episodes) and two secondary endpoints (bloating

Figure 2. Meta-analysis of 21 studies on the effectiveness of antispasmodics in the treatment of IBS patients: results ex - pressed as percentage of patients with improvement of abdominal pain. (Adapted from Poynard T, et al) 40 .

31 F. Forte, M. Pizzoferrato, L. Lopetuso, F. Scaldaferri

strated the efficacy of otilonium bromide in symptom control in patients with irritable bowel syndrome 41 . Furthemore , the above study suggests that the effect of otilonium bromide can persist even after discontinuation of this drug 41 . More precisely, there was evidence that the results obtained with otiloni - um bromide at the end of the treatment period, as for reduction of abdominal pain, were long lasting, persisting also during the follow-up. In fact, it has been reported in the placebo group a high inci - dence of withdrawals, due to symptom recur - rences, with statistically significant differences in comparison with otilonium bromide: 27% versus 10%, p = 0.0089. Similarly, the probability for the patient to stay symptom-free in the post-treatment phase was significantly higher in the otilonium bromide group versus placebo (Figure 9) 41 . As a concluding remark, it is worthy to notice that the persistence of the effect of otilonium bro - mide after its withdrawal, can be of major impor - tance in clinical management of IBS, particularly when adopting an intermittent drug regimen 41 . In conclusion, clinical trials of otilonium bro - mide 4,42,43 and meta-analyses described abov e3,39,40 Figure 3. The frequency of abdominal pain: changes in the score in the 2 treatment groups, otilonium bromide 40 mg have shown a good efficacy of this drug versus tid or placebo. (Adapted from Battaglia G, et al 4). placebo in the treatment of IBS, with significant differences on many endpoints. Otilonium bromide resulted effective not only severity and patient assessment of global effica - against placebo but also toward some other treat - cy) (Table V ). ments 44,45 . Although the most frequent dietary ad - These data generally confirm what already ob - vices suggest to patients with IBS to adopt diets served in previous clinical studies, which demon - rich in fibers, there is no evidence of their real

Figure 4. Reduction in the overall score of abdominal pain in the 2 treatment groups, otilonium bromide 40 mg tid or place - bo. (Adapted from Battaglia G, et al 4).

32 The use of anti-spasmodics in the treatment of irritable bowel syndrome

Figure 5. Number of patients with reduced abdominal pain intensity in two groups: otilonium bromide 40 mg tid vs Figure 6. Efficacy of therapy: reduction of symptoms score placebo. (Adapted from Battaglia G, et al 4). in two groups: otilonium bromide 40 mg tid vs placebo. (Adapted from Battaglia G, et al 4). beneficial effects 1. Indeed, a search in this sense, distension toward pre-treatment significantly pointed out that a high fiber content of cereals higher respect to the results of the diet alone at may also be associated with a worsening of the end of 24 months of follow-up ( p < 0.01) 44 . symptoms in 55% of cases 1. In 40 patients with irritable bowel syndrome, In 114 patients with irritable bowel syndrome, otilonium bromide displayed significant im - otilonium bromide 40 mg tid (n = 61) was more provement in symptoms compared to pinaverium effective than a diet that included daily 20 g of bromide 45 . Otilonium bromide (20 mg tid) result - fiber and 10 g of bran (n = 53) 44 . The drug has ed equally effective to cimetropium bromide (50 led to an improvement in pain and abdominal mg bid), in double-blind evaluation for the period

Figure 7. Otilonium bromide efficacy in reducing IBS physical signs in two groups: otilonium bromide 40 mg tid vs placebo. (Adapted from Battaglia G, et al 4).

33 F. Forte, M. Pizzoferrato, L. Lopetuso, F. Scaldaferri

Otilonium bromide is a chemical product com - posed by quaternary ammonium, a compound with direct antispasmodic action on distal gas - trointestinal tract 4. The drug is also able to act on cholinergic pathways, neurokines receptors and calcium channels, leading to an efficient muscular relaxation, resulting in effects on intestinal motili - ty, pain perception and visceral sensitivity 47-49 . More precisely otilonium bromide counteracts muscarinic receptors, including those for the acetylcholine, blocking the stimulating action of this transmitter 47 . Otilonium bromide acts on the calcium channels, by modifying the flows from intra- and extra-cellular deposits at the level of abdominal smooth muscle 47-49 . Otilonium bro - mide inhibits, in addition, tachichinine receptors and neurochines involved in motility and intesti - nal algesia 50,51 . Otilonium bromide enhances, finally, the thresh - 47-49 Figure 8. Comparison between otilonium bromide 40 mg old of sensitivity to detente rectum-sigmoidian . tid and placebo in improving well-being status (10-point Otilonium bromide is poorly absorbed systemical - VAS) and physician rating of effectiveness. (Adapted from ly: acts , therefore , mainly at local level without sig - Battaglia G, et al. 4). of 6 weeks on 40 patients with irritable bowel syndrome 46 . Both treatments resulted in a significant reduc - tion in the severity of abdominal pain and of scores assigned to bowel habits 46 . Two important aspects must be emphasized: first of all, the cimetropium bromide is an antispasmodic highly active 47 and secondly in this study otilonium bromide was used at a particularly low dose, about half compared to that normally adopted i.e. 40 mg tid. The association of otilonium bromide and ben - zodiazepines such as diazepam, may represent a useful alternative to the use of antispasmodics in monotherapy, as they can further improve the beneficial effects of the drug on gastrointestinal system by controlling anxiety 2. The clinical effectiveness of otilonium bro - Figure 9. Impact of otilonium bromide on the probability mide can be determined by several mechanisms for the patient to be free from long-term recurrences of of action, determined by the presence of several symptoms: results of the 10 weeks of follow-up after the 15 receptors and chemical mediators 4,47-49 . weeks of treatment. ( Adapted from Clavé P, et al 41 ).

Table V. Efficacy of otilonium bromide versus placebo in 365 patients with irritable bowel syndrome: results at the end of 15- week treatment. (Adapted from Clavé P et al) 41 .

Reduction of abdominal Reduction of Patient assessment pain frequency bloating severity of global efficacy

Otilonium bromide 40 mg tid –0.90 ± 0.88 –1.20 ± 1.20 1.13 ± 1.20 Placebo –0.65 ± 0.90 –0.90 ± 1.10 0.90 ± 1.10 Statistical significance p = 0.038 p = 0.02 p = 0.047

34 The use of anti-spasmodics in the treatment of irritable bowel syndrome nificant side effects 4,47 . In a recent review on tolera - References bility and safety of drugs currently in use in IBS treatment, it has been emphasized the lack of infor - 1) SPILLER R, A ZIZ Q, C REED F, E MMANUEL A, H OUGHTON mation about drugs metabolism for the majority of L, H UNGIN P, J ONES R, K UMAR D, R UBIN G, T RUDGILL pharmacological treatments, while there is no N, W HARWELL P. Guidelines on the irritable bowel syndrome: mechanisms and practical manage - shortage of information about the evaluations of ef - ment. Gut 2007; 56: 1770-1798. fectiveness 35 . In order to go deeper in these data, 2) SPINELLI A. Irritable bowel syndrome. Clin Drug In - our systematic review is meant to be carried out in vest 2007; 27: 15-33. 3. Lesbros-Pantoflickova D, the literature according to strict criteria, highlight - Michetti P, Fried M, Beglinger C, Blum AL. 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