Eur opean Rev iew for Med ical and Pharmacol ogical Sci ences 2010; 14: 155-162 Octatropine methyl bromide and diazepam combination (Valpinax ®) in patients with irritable bowel syndrome: a multicentre, randomized, placebo-controlled trial

F. PACE ‡, A. MAURANO ^, C. CIACCI**, V. SAVARINO †, A. ATTILI*, G. IAQUINTO ^^ , E. MAGNI §, G. BIANCHI PORRO ‡

‡Institute of Gastroenterology, School of Medicine, "Luigi Sacco" Hospital, University of Milan (Italy) ^Service of Digestive Endoscopy, “G. da Procida” Hospital, Salerno (Italy) **Department of Clinical and Experimental Medicine, “Federico II” University, Naples (Italy) †Department of Internal Medicine and Medical Specialties, School of Medicine, University of Genova (Italy) Department of Clinical Medicine and Gastroenterology, School of Medicine, “Sapienza University”, Rome (Italy) ^^ Division of Gastroenterology, “S. Giuseppe Moscati” Hospital, Avellino (Italy) §Crinos S.p.A., Medical Direction (Italy)

Abstract. – Objective: To investigate the the design of a clinical trial, since it does not con - efficacy and tolerability of octatropine methyl sider disease activity level on admission. bromide plus diazepam (Valpinax ®) in patients with irritable bowel syndrome (IBS). Key Words: Materials and Methods: We conducted a ran - Diazepam, Irritable bowel syndrome, Octatropine; domized, double-blind, multicentre study in 186 Tropanes. patients aged 18-65 years with IBS diagnosed ac - cording to Rome II criteria. Following a 2-week washout period, patients received octatropine plus diazepam 40 mg/2.5 mg twice daily or place - bo for 6 weeks. The primary efficacy endpoint Introduction was response to a weekly question: “did you have satisfactory relief of your abdominal pain The term irritable bowel syndrome (IBS) refer and discomfort during the last week?” Other end - to a well recognized complex of symptoms aris - points included abdominal swelling, abdominal pain and discomfort, symptom severity, and the ing from interactions of the intestine, the psyche number of bowel movements. A prespecified sub - and, possibly, luminal factors. IBS is a disorder group analysis was conducted in patients with an characterized by cramping, abdominal pain, abdominal pain and discomfort score ≥3. bloating, constipation, and diarrhoea, and causes Results: The primary efficacy endpoint showed a great deal of discomfort and distress. As many a tendency towards a statistically significant bene - as 20% of the adult population has symptoms of fit for octatropine plus diazepam over placebo among patients with a baseline abdominal pain IBS, making it one of the most commonly diag - and discomfort score of ≥3 (3 vs. 0 patients; p = nosed disorders. IBS is more common in women 0.059). Octatropine plus diazepam demonstrated than in men and presents before the age of 35 in significant improvements from baseline in all pa - approximately 50% of those affected 1-4 . In most rameters assessed, but not compared with place - patients, symptoms can be controlled with diet, bo. Adverse events were reported in 15.1% of pa - stress management, and prescribed medications. tients receiving octatropine plus diazepam. However, for some people IBS can be disabling. Conclusions: Patients with IBS and an abdomi - nal pain and discomfort score of ≥3, who may be They may be unable to work, attend social 5-7 considered in the active phase of the disease, events, or travel even short distances . may derive some benefits from octatropine plus Abdominal pain, bloating, and discomfort are diazepam. This study highlights that Rome II cri - the main symptoms of IBS. However, symptoms teria should be considered with particular care in can vary from person to person and from time to

Corresponding Author : Fabio Pace, MD; e-mail: [email protected] 155 F. Pace, A. Maurano, C. Ciacci, V. Savarino, A. Attili, G. Iaquinto, E. Magni, G. Bianchi Porro time. Some patients experience constipation or vious studies have established the therapeutic ef - infrequent bowel movements. These patients fre - ficacy of the octatropine plus diazepam combina - quently report straining and cramping when try - tion product over octatropine and diazepam ing to have a bowel movement but either cannot monotherapy in IBS patients 15,16 . eliminate stools or can eliminate only a small The present study was designed to evaluate amount. If they are able to have a bowel move - and confirm the clinical efficacy of the combina - ment, there may be mucus in it. Diarrhoea is also tion of octatropine and diazepam in patients suf - common among patients with IBS, resulting in fering from IBS diagnosed according to the re - frequent, loose and watery stools 4. Patients with cent Rome II criteria 17 . diarrhoea frequently feel an urgent and uncon - trollable need to have a bowel movement. The symptoms of IBS may subside for a few months at a time and then return, while some patients re - Material and Methods port a constant worsening of symptoms over time. Study Design The specific cause for IBS is currently unclear This was a 6-week randomized, double-blind, and motility disorders of the gut have been pro - parallel-group, placebo-controlled, multicenter posed as the cause in the past. More recently, de - study. The study was performed according to the rangement of visceral sensitivity has been sug - principles of the Declaration of Helsinki and gested. It has recently been reported that sero - Good Clinical Practice. The study protocol was tonin is linked with normal gastrointestinal (GI) designed according to EMEA guidelines for functioning. The majority of serotonin in the treatments for IBS 18 and was approved by the body (95%) is located in the GI tract and the re - Ethics Committees at all participating centres. maining 5% is found in the brain. Cells that line All patients gave their written informed consent the inside of the bowel work as transporters and to participate in the study. carry serotonin out of the GI tract. People with IBS, however, have diminished receptor activity, Patients causing abnormal levels of serotonin to exist in IBS outpatients aged between 18 and 65 years the GI tract 8-10 . As a result, patients with IBS ex - were recruited from 15 hospital centres in Italy. perience problems with bowel movement, motili - IBS had to be diagnosed more than one year be - ty and sensation, having more sensitive pain re - fore the recruitment. All patients were screened ceptors in their GI tract. In addition, people with according to Rome II criteria for IBS 17 . These are IBS frequently suffer from depression and anxi - that patients had previously experienced abdomi - ety, which can worsen symptoms. Similarly, the nal discomfort/pain with two of the following symptoms associated with IBS can cause a per - characteristics: (a) relief with defecation; (b) on - son to feel depressed and anxious 11 . set associated with a change in stool frequency; The usual treatment of IBS includes increased or (c) onset associated with a change in stool dietary fibre intake for constipation, loperamide form, for at least 12 weeks (not necessarily con - for diarrhoea, and antispasmodics or low-dose secutive) during the previous 12 months. At antidepressants for pain relief 12 . Nevertheless, the baseline, IBS severity was evaluated using a 100 efficacy of some currently available treatment re - mm visual analogical scale and a score between mains to be clearly established because of the 30 and 50 mm was required for inclusion in the poor design of clinical trials, such as lack of study . Exclusion criteria were: chronic severe placebo control and double blinding 13,14 . constipation with less than one stool per week; Octatropine methyl bromide (octatropine) is a previous history of GI surgery (except appendec - quaternary ammonium antimuscarinic agent that tomy, cholecystectomy or hemorrhoidectomy); has been used for many years to relieve visceral other GI diseases (except hemorrhoids and un - spasm and is widely used in relieving the pain complicated diverticula), as assessed by ultra - caused by smooth muscle spasm in IBS. Di - sonography, colonoscopy or rectoscopy; a recent azepam is a benzodiazepine with anxiolytic, history of drug or alcohol abuse; intolerance to sedative and muscle-relaxant properties. Octat - lactose; severe psychiatric disorders; aspartate ropine in combination with diazepam aminotransferase or alanine aminotransferase (Valpinax ®) is widely used in Italy for the treat - greater than twice the upper limit of normal; use ment and relief of symptoms related to IBS. Pre - of other investigational drugs within three

156 Octatropine plus diazepam in irritable bowel syndrome months of the screening visit; and female pa - Tolerability was assessed at week 3 and 6 by tients not using adequate contraceptive precau - evaluating the incidence and severity of reported tions. Concomitant use of any medication that adverse events, and the relationship of these ad - could affect GI motility was not permitted during verse events to study medication. the study. Limited use of laxatives such as glyc - erine, and diosmectite to treat diarrhoea, was al - Statistical Analyses lowed in rare cases and under the supervision of Between-group comparisons of endpoints the investigator. Patients recorded every con - were performed using Fisher’s exact test, Student comitant drug taken during the study period in t test, or Chi square test, where appropriate. Pub - their diary and were instructed to follow their lished literature for octatropine plus diazepam usual diet, including any alimentary restriction. shows a success rate of 80% (95% confidence in - tervals 62.47-97.53). As a prudential rule, sample Study Protocol size calculation was done using the hypothesis of The study consisted of a 2-week wash-out pe - 70% success rate with octatropine plus diazepam riod followed by a 6-week double-blind treat - and 50% with placebo. Using alfa 0.05 and beta ment period. Patients who met the inclusion cri - 0.20, an estimated sample size of 103 patients teria at control visit 1 entered a 2-week screening per treatment group was required. phase during which they received placebo and filled out a daily diary recording the severity of abdominal pain, number of evacuations, and stool consistency. At the baseline visit (week 0, Results control visit 2), patients were randomly allocated in a 1:1 ratio to receive treatment with octat - Patients ropine/diazepam 40 mg/2.5 mg combination A total of 206 patients were screened and the product twice-daily or placebo for 6 weeks with 186 patients who correctly completed daily diary control visit 3 occurring in week 3 and visit 4 at records and provided consent entered the ran - the end of treatment week 6. Treatment numbers domized treatment period. Of these, 16 patients were assigned consecutively in ascending order. (9 in the active group and 7 in the placebo group) The randomization list, in blocks of 4, was gen - discontinued the study prematurely (7 for con - erated by a computer system independently of sent withdrawal, 4 for adverse events or lack of the investigator and study sponsor. The codes compliance, 3 for loss at follow-up or protocol were kept confidential until the end of the study. violation, and 2 for insufficient response). In to - EMEA guidelines state that the patient’s global tal, 170 patients concluded the study and were assessment of symptoms and abdominal discom - considered for statistical analysis; 83 patients re - fort should be used as endpoints in clinical trials in ceived octatropine plus diazepam and 87 patients IBS 18 . In this study, the primary efficacy endpoint received placebo. Patients’ disposition during the was therapeutic success, assessed by patients’ re - study is shown in Figure 1. There were no statis - sponse to a weekly question: “did you have satis - tically significant differences at baseline among factory relief of your abdominal pain and discom - the two treatment groups for any of the key de - fort during the last week?” Other efficacy end - mographic features (Table I). In total, 10 patients points included abdominal swelling (measured (10.9%) in the active group and 14 patients with a digital scale: no = 0; very mild = 1; mild = (14.9%) in the placebo group had pain and dis - 2; moderate = 3; severe = 4; very severe = 5), ab - comfort of at least moderate intensity. dominal pain and discomfort (measured with a digital scale: no = 0; very mild = 1; mild = 2; Efficacy moderate = 3; severe = 4; very severe = 5), and In total, 59 patients in the active group and 59 number of bowel movements per day. These were patients in the placebo group experienced thera - assessed on a daily basis by the patient noting re - peutic success, with no significant between-group sults on a semiquantitative scale, different for each difference seen. However, when only patients with parameter, and discussing the daily diary with the pain and discomfort of at least moderate intensity investigator at each control visit. were analyzed, there was a tendency towards sig - A subgroup analysis was conducted in patients nificantly more patients receiving octatropine plus with an abdominal pain and discomfort of mod - diazepam experiencing therapeutic success com - erate or higher intensity (i.e. a score ≥3). pared with placebo ( p =0.059; Figure 2).

157 F. Pace, A. Maurano, C. Ciacci, V. Savarino, A. Attili, G. Iaquinto, E. Magni, G. Bianchi Porro

Figure 1. Patients’ disposi - Assessed for eligibility tion during the study. (n= 206)

Excluded (n = 20) Enrollment Not giving consent (n = 16) Not satisfying inclusion Randomization criteria (n = 4) (n = 186)

Allocated to Allocated to placebo octatropine/diazepam Allocation (n = 94) (n = 87)

Consent withdrawal Consent withdrawal (n = 4) (n = 3) Adverse events or no Follow-up Adverse events or no compliance (n = 2) compliance (n = 2) Loss at follow-up or protocol Insufficient response violation (n = 3) (n = 2)

Analyzed (per-protocol) Analyzed (per-protocol) (n = 83) Analysis (n = 87)

Abdominal swelling score (Figure 3) was sig - so, compared with baseline (octatropine/diazepam nificantly reduced at week 6 compared with base - 1.24 ± 0.90 at baseline vs. 1.13 ± 0.70 at week 6; line values in both groups (octatropine/diazepam placebo 1.31 ± 0.97 vs. 1.25 ± 0.62). 1.85 ± 1.02 at baseline vs. 1.30 ± 1.01 at week 6; The subgroup analysis conducted in patients placebo 1.72 ± 1.19 vs. 1.20 ± 1.08; both p with pain and discomfort of moderate, severe or <0.001 ). This reduction was already significant very severe intensity showed that 6 weeks’ treat - after three weeks ( p <0.05) , but no significant be - ment with octatropine/diazepam resulted in a 43% tween-group differences were observed at either reduction in the severity score compared with a time point. Abdominal pain and discomfort was 32% reduction in placebo recipients. These results also significantly reduced at study end compared failed to reach statistical significance ( p =0.43); with baseline values in both groups (octat - however, they showed a positive therapeutic trend ropine/diazepam 1.65 ± 0.95 at baseline vs. 1.19 in the group of actively treated patients (Figure 5). ± 0.96 at week 6; placebo 1.60 ± 1.15 vs. 1.12 ± 1.01; both p <0.005) ( Figure 4) . The difference Tolerability between week 3 and baseline was not statistically The combination of octatropine plus diazepam significant in either group, although a trend to - was well tolerated. In total, 60 patients (34.9%) wards a reduction was evident. No significant be - experienced an adverse event, 26 in the octat - tween-group differences were observed. ropine plus diazepam group (15.1%) and 34 in The number of bowel movements was also re - the placebo group (19.8%). Of these, only 12 and duced in both groups, although not significantly 18 adverse events in the respective groups were

158 Octatropine plus diazepam in irritable bowel syndrome

Table I. Baseline demographics.

Octatropine/diazepam Placebo All patients (n = 92) (n = 94) (n = 186)

Male/female (%) 29/63 (31.5/68.5) 45/49 (47.9/52.1) 74/112 (39.8/60.2) Age (mean ± SD, years) 39.9 ± 11.5 41.8 ± 11.5 40.8 ± 11.5 Height (mean ± SD, cm) 166.4 ± 7.9 169.1 ± 8.9 167.8 ± 8.5 Weight (mean ± SD, kg) 63.5 ± 11.4 68.2 ± 13.8 65.9 ± 12.8 BMI (mean ± SD, kg/m 2) 22.87 ± 3.06 23.77 ± 3.49 23.32 ± 3.30 No alcohol use, n (%) 51 (55.3) 46 (48.9) 97 (52.5) No smokers, n (%) 70 (76.1) 77 (81.9) 147 (79.0) Dietary restrictions (n) Low salt 101 Low calorie 134 Low fat 448 Pain/discomfort during run-in period Intensity (mean ± SD) 1.68 ± 0.93 1.62 ± 1.14 1.65 ± 1.04 Days (mean ± SD) 10.86 ± 3.94 10.31 ± 4.20 10.58 ± 4.07 Abdominal swelling during run-in period Intensity (mean ± SD) 1.91 ± 1.03 1.75 ± 1.18 1.83 ± 1.11 Days (mean ± SD) 10.90 ± 4.0 10.46 ± 4.30 10.68 ± 4.14 Bowel movements/day (mean ± SD) 1.26 ± 0.87 1.30 ± 0.95 1.28 ± 0.91 Patients with active disease (pain 10 (10.9) 14 (14.9) 24 (12.9) and discomfort score ≥3 at inclusion visit), n (%)

SD = standard deviation. considered by the physician to be drug related. The most common adverse events reported dur - ing the treatment period were mild-to-moderate abdominal pain, asthenia, cephalea, abdominal swelling, nausea, and vomiting. The only severe adverse events were one case of abdominal Octatropine+diazepam (n = 83) swelling, nausea and epigastralgia reported by a Placebo (n = 87)

Placebo e Octatropine/diazepam r o c s

g n i l l e w s

l a s n t i n m e i o t d a P b A

Baseline Week 3 Week 6 Success No success Figure 3. Effect of 6 weeks’ treatment with octatropine Figure 2. Therapeutic success among patients with an ab - plus diazepam or placebo on abdominal swelling scores in dominal pain/discomfort score of ≥3 at baseline treated for 6 patients with irritable bowel syndrome. p <0.05 for week 3 weeks with octatropine plus diazepam or placebo ( p =0.059 vs. baseline; p <0.001 for week 6 vs baseline in the octat - for octatropine plus diazepam vs. placebo). ropine plus diazepam group.

159 F. Pace, A. Maurano, C. Ciacci, V. Savarino, A. Attili, G. Iaquinto, E. Magni, G. Bianchi Porro

Discussion Octatropine+diazepam (n = 83) Placebo (n = 87) IBS is a chronic condition which can be im - proved but not completely resolved by drug ther - apy. Few studies have provided convincing evi - e r

o dence for the efficacy of drug treatment for IBS. c s

This can be attributed to the lack of objective t r

o markers of improvement in IBS and the large f

m placebo response, which is often associated with o c

s subjective diseases such as IBS and confounds i d

/ interpretation of potential clinical benefit. n i

a The present study was designed to evaluate the p

l clinical efficacy of the combination of octat - a ® n

i ropine plus diazepam (Valpinax ) for the symp - m

o tomatic treatment of IBS. Patients were selected d

b according to Rome II criteria, having experi - A enced abdominal discomfort/pain for at least 12 weeks (not necessarily consecutive) during the Baseline Week 3 Week 6 12 months before entering the study. Patients had also to meet inclusion and exclusion criteria sug - Figure 4. Effect of 6 weeks’ treatment with octatropine gested by EMEA guidelines available at the time plus diazepam or placebo on abdominal pain/discomfort of the study 18 . Treatment with octatropine plus scores in patients with irritable bowel syndrome. p <0.001 for week 6 vs. baseline in both groups. diazepam significantly reduced abdominal swelling, pain and discomfort, and the number of bowel movements relative to baseline, but this patient receiving octatropine plus diazepam and difference was not significant compared with one case of abdominal pain reported by a placebo placebo. recipient. Only two patients discontinued treat - A pre-specified subgroup analysis was con - ment due to an adverse event. No deaths oc - ducted in patients with abdominal pain and dis - curred during the study. comfort of moderate, severe, or very severe inten - sity at baseline. This symptom is considered as a key feature of IBS, according to EMEA guide - lines 18 , and we may speculate that these patients Placebo are in an active phase of disease. Interestingly, Octatropine/diazepam only a very low number of patients met this crite - rion. In this small population, some subjects re - e r

o ceiving octatropine plus diazepam achieved thera - c s

peutic success compared with no patients receiv - t r

o ing placebo, and the between-group difference f

m approached significance. Between-group statisti - o c

s cal significance may not have been reached be - i d

/ cause of the low number of patients included in n i

a this sub-analysis. This observation is also sup - p

l ported by the trend towards a reduction in the a n

i severity of pain and discomfort in octatropine

m plus diazepam patients compared with placebo re - o d

b cipients (between-group difference 11%). A The beneficial role of muscle relaxants in IBS has been demonstrated in a meta-analysis, which Baseline Week 3 Week 6 suggested that these agents are beneficial in IBS patients with abdominal pain as a predominant Figure 5. Effect of 6 weeks’ treatment with octatropine 14 plus diazepam or placebo on abdominal pain/discomfort symptom . In another meta-analysis of 23 ran - scores in patients with irritable bowel syndrome and an ab - domized, controlled trials of other muscle relax - dominal pain/discomfort score of ≥3 at baseline. ants including cimetropium bromide, hyoscine

160 Octatropine plus diazepam in irritable bowel syndrome butyl bromide, mebeverine, otilium bromide, the quality of life, including depression and anxi - pinaverium bromide and trimebutine, these ety. Another possible limitation could be the use agents were associated with a global improve - of a placebo control in the presence of other ther - ment in 56% of patients compared with 38% of apies However, the European guidelines consider placebo recipients ( p <0.001) 19 . the use of placebo as the most appropriate con - Our study did not exclude IBS patients free of trol, since pharmacological therapies are sympto - any symptom of abdominal discomfort/pain at matic 18 . the time of study enrollment. As such, we may In conclusion, this study suggests the thera - hypothesize that some patients may have entered peutic efficacy of octatropine plus diazepam for the randomized treatment period in a quiescent reducing the predominant symptoms of IBS, es - phase. Moreover, in most IBS patients, symp - pecially in patients with abdominal pain and dis - toms are intermittent, with severe symptomatic comfort of at least moderate intensity. However, episodes followed by symptom-free days. These further trials are needed to provide more infor - results suggest that IBS patients who take part in mation on the therapeutic activity of octatropine clinical trials should only be recruited when they plus diazepam. Future experimental design are in an active phase of the disease, and always should consider only patients in the active phase according to Rome II criteria or the more recent of the disease to more accurately determine effi - Rome III criteria 20 . cacy. Although the study design followed the EMEA guidelines for IBS trials 18 and conse - quently considered the Rome II diagnostic crite - ria as the basis for subject enrollment, it did not take into consideration the activity level of the References syndrome on admission to the study. The inclu - sion of patients without symptoms may be a flaw 1) TALLEY NJ, Z INSMEISTER AR, V AN DYKE C, M ELTON LJ in the study design and prevent demonstration of 3RD . Epidemiology of colonic symptoms and the a favourable drug effect. It is evident that it is irritable bowel syndrome. Gastroenterology 1991; difficult to demonstrate the improvement of 101: 927-934. pain/discomfort in subjects that present with only 2) DROSSMAN DA, L I Z, A NDRUZZI E, T EMPLE RD, T ALLEY minor or no symptoms at baseline. Rome II crite - NJ, T HOMPSON WG, W HITEHEAD WE, J ANSSENS J, ria may be impractical when considering patients FUNCH -J ENSEN P, C ORAZZIARI E, et al. US household - er survey of functional gastrointestinal disorders for screening in a clinical trial as there is the high prevalence, sociodemography and health impact. risk of including patients with a “silent” disease Dig Dis Sci 1993; 38: 1569-1580. status. On the other hand, to include only sub - 3) CAMILLERI M, C HOI MG . Irritable bowel syndrome. jects with a high level of discomfort/pain on ad - Aliment Pharmacol Ther 1997; 11: 2-15. mission would increase the sample size beyond 4) DROSSMAN DA, W HITEHEAD WE, C AMILLERI M. Irritable reasonable limits for any phase III to IV study. In bowel syndrome: a technical review for practice this study, symptomatic patients accounted for guideline development. Gastroenterology 1997; approximately 10% of the enrolled population; 112: 2120-2137. therefore, in order to obtain a subset of 200 sub - 5) LEONG SA, B ARGHOUT V, B IRNBAUM HG, T HIBEAULT CE, jects with a pain/discomfort score of ≥3 in the BEN -H AMADI R, F RECH F, O FMAN JJ. The economic present study, 2000 Rome II subjects would have consequences of irritable bowel syndrome: a US needed to be enrolled. employer perspective. Arch Intern Med 2003; 163: Another limitation of this study is the “subjec - 929-935. tive” evaluation of efficacy endpoints. However, 6) DELVAUX M. Functional disorders of irritable bowel the study was conducted in accordance with syndrome in Europe. Aliment Pharmacol Ther EMEA guidelines current at the time 18 . These 2003; 18(suppl): 75-79. guidelines state that no widely accepted and vali - 7) HAHN BA, K IRCHDOERFER LJ, F ULLERTON S, M AYER E. dated clinical outcomes are available for the eval - Patient-perceived severity of irritable bowel syn - drome in relation to symptoms, health resource uation of IBS patients. A patient’s global assess - utilisation and quality of life. Aliment Pharmacol ment of efficacy endpoints is therefore consid - Ther 1997; 11: 553-559. ered as an effective surrogate of validated clinical 8) ZIGHELBOIM J, T ALLEY NJ, P HILLIPS SF, H ARMSEN WS, parameters. Moreover, this subjective evaluation ZINSMEISTER AR . Visceral perception in irritable bow - takes into account the effects of the therapy on el syndrome. Rectal and gastric responses to dis -

161 F. Pace, A. Maurano, C. Ciacci, V. Savarino, A. Attili, G. Iaquinto, E. Magni, G. Bianchi Porro

tention and serotonin type 3 antagonism. Dig Dis 19) POYNARD T, R EGIMBEAU C, B ENHAMOU Y. Meta-analy - Sci 1995; 40: 819-827. sis of smooth muscle relaxants in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther 9) HAMMER J, P HILLIPS SF, T ALLEY NJ, C AMILLERI M. Effect 2001; 15: 355-361. of a 5-HT3 antagonist (ondansetron) on rectal sensitivity and compliance in health and the irrita - 20) DROSSMANN DA. The functional gastrointestinal ble bowel syndrome. Aliment Pharmacol Ther disorders and the Rome III process. Gastroen - 1993; 7: 543-552. terology 2006; 130: 1377–1390.

10) GERSHON MD. Review article: role played by 5-hy - droxytryptamine in the physiology of the bowel. ––––––––––––––––– –– Aliment Pharmacol Ther 1999; 13(suppl 2): 15- Acknowledgements 30.

11) CAMILLERI M, C HOI MG. Review article: irritable The authors would like to thank the following Princi - bowel syndrome. Aliment Pharmacol Ther 1997; pal Investigators involved in this study: Prof. Gabriele 11: 3-15. Bianchi Porro, Dr. Angelo Pera, Prof. Adolfo Attili, Prof. Giacomo C. Sturniolo, Dr. Gaetano Iaquinto, Dr. 12) THOMSON WG, L ONGSTRETH GF, D ROSSMAN DA, Giorgio Minoli, Prof. Sergio Vigneri, Dr. Clara Vir - HEATON KW, I RVINE EJ, M ULLER -L ISSNER SA. Function - gilio, Dr. Attilio Maurano, Dr. Gabriele Bazzocchi, al bowel disorders and functional abdominal pain. Prof. Vincenzo Savarino, Dr. Mario del Piano, Dr. En - Gut 1999; 45(Suppl 2): 1143-1147. rico Colombo, Dr. Uomo Generoso, Prof. Carolina 13) AKEHURST R, K ALTENHALER E. Treatment of irritable Ciacci. bowel syndrome: a review of randomised con - trolled trials. Gut 2001; 48: 272-282. The co-ordinating centre for this study was Cattedra di Gastroenterologia Ospedale Universitario Luigi Sacco, 14) JAILWALA J, I MPERIALE TF, K ROENKE K. Pharmacologic Milano (Italy). The study italian centres were as fol - treatment of the irritable bowel syndrome: a sys - lows: Divisione di Gastroenterologia, Ospedale Mauri - tematic review of randomised, controlled trials. ziano, Torino; Dipartimento di Medicina Clinica e Ga - Ann Intern Med 2000; 133: 136-147. stroenterologia Università la Sapienza, Roma; Divisio - 15) BARBARA L, M IGLIOLI M. Treatment of irritable bowel ne di Gastroenterologia, Azienda Ospedaliera, Padova; disease. A double blind trial of the anticholinergic Divisione di Gastroenterologia Azienda Ospedaliera S. octatropine methylbromide (Valpin) alone or with G. Moscati, Avellino; Unità operativa di Gastroentero - the tranquillizer diazepam (Valpinax). Clin Trials J logia, Azienda ospedaliera, Valduce, Como; Servizio di 1979; 16: 140-146. Gastroenterologia Università di Palermo; Reparto di Gastroenterologia ospedale L, Curro, Catania; Ambula - 16) GUSLANDI M, E VANGELISTA A, T ESTONI PA, Tittobello A. torio di Endoscopia digestiva Presidio ospedaliero G. Clinical evaluation of octatropine methyl-bromide da Procida Salerno; Ambulatorio diagnostica e riabili - plus diazepam (Valpinax) in the treatment of irrita - tazione disordini viscerali, Montecatone Bologna; Di - ble bowel disease. Clin Trials J 1981; 18: 138-144. partimento di Medicina interna e Specialità mediche, Genova; Divisione di Gastroenterologia Azienda Ospe - 17) DROSSMAN DA, C ORAZZIARI E, T ALLEY NJ, et al. Rome II – The functional Gastrointestinal Disorders; Di - dale Maggiore, Novara; Servizio di Gastroenterologia agnosis, Pathophysiology and Treatment: a Multi - Ospedale G. Salvini, Garbagnate, Milano; Dipartimen - national Consensus. McLeon VA; Degnon Associ - to di Medicina Interna, Ospedale Cardarelli Napoli; Di - ates, 2000: 360. partimento di Medicina Clinica e Sperimentale Univer - sità Federico II Napoli. 18) EUROPEAN AGENCY FOR THE EVALUATION OF MEDICINAL PRODUCTS . Points to consider on the evaluation of English language assistance for the preparation of this medicinal products for the treatment of irritable manuscript was provided by Tracy Harrison, Nila bowel syndrome. March 2003. Available from URL: Bhana, and Neil Reynolds, Wolters Kluwer Medical http://www.emea.europa.eu/pdfs/human/ewp/0785 Communications. This assistance was funded by 97en.pdf. Accessed 27th February 2009. Crinos SpA.

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