Gut, 1990,31,355-358 355 Longterm treatment of irritable bowel syndrome with cimetropium bromide: a double blind placebo Gut: first published as 10.1136/gut.31.3.355 on 1 March 1990. Downloaded from controlled clinical trial G Dobrilla, B P Imbimbo, L Piazzi, G Bensi Abstract The aim of this study was to evaluate the many reviewed could offer convincing evidence efficacy of cimetropium bromide, a new anti- in favour of the efficacy of any therapy tested in muscarinic compound, in relieving symptoms treating irritable bowel syndrome. of patients with irritable bowel syndrome over Cimetropium bromide is a new antispasmodic a three month period. Seventy consecutive agent selectively acting on the gut by antagonising outpatients were given cimetropium (50 mg tid) acetylcholine at the smooth muscle muscarinic or placebo according to a double blind, ran- receptors." 12 Unlike other antimuscarinics it has domised, parallel groups design. Symptoms minimal effects on vascular receptors, so it has were evaluated initially and at monthly inter- no appreciable untoward effects.'3 vals up to the end of the study period. One The aim of this study was to assess the efficacy patient receiving placebo withdrew because of of cimetropium bromide in improving the treatment failure. Pain score decreased by 40, symptoms of irritable bowel syndrome over 66,85% in the cimetropium group, at the end of three months - a longer period than usual. the first, second and third months respectively, compared with 26, 32 and 52% reductions among controls (p=0 0005). At the end of Methods treatment there was a 86% reduction in the number of abdominal pain episodes per day in PATIENTS the cimetropium group compared with 50% in This trial was a double blind, randomised, the placebo group (p=0-001). Constipation placebo controlled, parallel groups study. It and diarrhoea scores decreased by 59 and 49% included a two week screening period and a three in the cimetropium treated patients, compared month test period, during which each patient http://gut.bmj.com/ with 37 and 39% in controls, the differences was randomly assigned to drug or placebo. between being not significant. At the end of Irritable bowel syndrome was diagnosed after the study 89% of the patients treated with all other organic causes for the symptoms had cimetropium considered themselves as globally been excluded by the results of complete clinical improved as opposed to 69% in the placebo examinations (including rectosigmoidoscopy group (p=0 039). The corresponding 95% con- and double contrast enemas) and the usual fidence intervals for the differences between laboratory tests (erythrocyte sedimentation rate, on September 24, 2021 by guest. Protected copyright. the proportion of improved patients in the two complete blood count, serum transaminases, groups were from 11% to 29%. Six patients alkaline phosphatase, cholesterol, plasma pro- taking cimetropium complained of slight dry teins, electrophoresis, plasma urea, electrolytes, mouth. The results of this study showed that calcium, thyroid tests, urinalaysis, stool exam- cimetropium bromide is effective in relieving ination for occult blood, ova and parasites and pain in patients with irritable bowel syndrome. stool culture, lactase intolerance). When appro- priate, such additional investigations as upper abdominal ultrasonography, total colonoscopy, Despite its favourable prognosis, irritable bowel and oesophagogastroduodenoscopy were per- syndrome (IBS) is a social problem and up to formed and showed nothing abnormal. 20% of the population are affected.' Half of Only patients with bowel alterations and the patients referred to gastroenterologists have episodes of abdominal pain, usually cramp like irritable bowel syndrome.2 and in lower abdominal quadrants, lasting for at Gastroenterology Anticholinergics, antispasmodics, laxatives, least two months, were considered eligible for Division and Service of and bulking agents, have all been used but no the study. Between October 1984 and April 1986 Pathophysiology and benefits have been clearly shown.3 4 Many studies, 128 patients referred to our outpatient depart- Digestive Endoscopy, General Regional aimed at proving drug efficacy, have failed ment were diagnosed as having irritable bowel Hospital, Bolzano, Italy mainly because of the good response to placebo syndrome. Of these, 89 patients conformed to G Dobrilla shown by these patients: placebo response rates the inclusion criteria; of these, 12 patients were B P Imbimbo L Piazzi were sometimes over 70%.5-7 The placebo effects, excluded because they did not give informed G Bensi however, tend to decrease with time8 so that the TABLE I Scoresfor severity ofabdominal pain and Correspondence to: Prof duration of the study treatment is crucial for a abdominal distension Giorgio Dobrilla, Divisione di correct evaluation of the efficacy of any drug. Gastroenterologia, Servizio di Patofisiologia ed Endoscopia Most studies were too short to produce good 0=absent Digestiva, Ospedale Generale results.9 1=mild (symptom cannot be ignored, but does not influence daily Regionale di Bolzano, 39100 activities) Bolzano, Italy. A critical review of a large number of trials 2 = moderate (symptom influencesconcentration on daily activities) in irritable bowel was recently pub- 3=severe (symptom markedly influences daily activities except Accepted for publication syndrome the most elementary) 23 May 1989 lished'" concluding that not a single study of the 356 Dobrilla, Imbimbo, Piazzi, Bensi consent and seven who were uncooperative or TABLE II Characteristics ofthe patients unreliable. The remaining 70 patients were randomly assigned to either the drug group or Placebo Cimetropium p the placebo group. Sex Gut: first published as 10.1136/gut.31.3.355 on 1 March 1990. Downloaded from male/female 11/24 12/23 NS During the baseline screening phase, patients Age (yrs) received a diary card and were instructed to median 45 45 NS range 22-63 24-67 record the number ofabdominal painful episodes Duration ofdisease (yrs) and the severity of abdominal pain, abdominal median 3 0 3 0 NS range 0-2-15-0 04-20-0 distension, constipation, and diarrhoea. Diar- Previous treatments rhoea was defined as loose to liquid stools more (yes/no) 15/20 16/19 NS Bowel habits frequent than three times per day, constipation constipation 12 14 was considered as straining with harder stools diarrhoea 12 13 NS alternating const/diarr 9 8 less frequent than three times per week. Because Habits the patients' descriptions of frequency of defae- smoking (yes/no) 14/21 11/24 NS alcohol (yes/no) 18/17 18/17 NS cation are unreliable,'4 however, severity of coffee (yes/no) 34/1 30/5 NS constipation and diarrhoea was arbitrarily scored, fibres (yes/no) 4/31 5/30 NS taking into account subjective discomfort, on a laxative (yes/no) 6/29 7/28 NS four point scale: 0=none, 1 = mild, 2=moderate, 3=severe. Severity of pain and abdominal dis- tension was scored as shown in Table I. The with the NWA STATPAK statistical package.'6 attending physician recorded patients' evalua- tions of their symptoms and made a physical examination of the abdomen to assess the pres- Results ence of pain on palpation, and contracted colon. One patient in the placebo group withdrew from This baseline period was also regarded as a the study because of treatment failure. He was washout phase from any drug interference with included in the analysis according to the inten- symptoms ofirritable bowel syndrome. tion to treat approach. Patients in the placebo At the end of the baseline period patients group returned 8-9 (1-3)% of the assigned treat- admitted to the study were randomly allocated to ment tablets, while patients on cimetropium receive cimetropium bromide 50 mg tablets tid returned 8-2 (O 8)% ofgiven tablets. or placebo tablets tid before meals for three The patients in the two treatment groups were months. No other drugs were allowed during comparable as regards their personal data and this treatment period. medical history (Table II). During the treatment period patients con- http://gut.bmj.com/ tinued to record symptoms and came for monthly checkups. At these visits they handed in their SYMPTOMS diaries and were given new ones. Median scores Figures 1 and 2 show frequency and severity of for severity of symptoms during the previous abdominal pain of the two groups during treat- treatment week were recorded by the attending ment. In the placebo group the number of physician and considered for statistical analysis. painful episodes per day dropped during the first New treatment tablets were dispensed and un- month, but did not improve further significantly. on September 24, 2021 by guest. Protected copyright. used tablets were returned and counted; another decreases were and 50% physical examination was done to check pain on The percentage 35, 43, palpation and presence ofcontracted colon. respectively at the first, second and third month At the end of the treatment period patients attended the final visit during which a retrospec- tive overall assessment since the baseline visit 3- (better, same, worse) was recorded. The study was conducted according to the Declaration of Helsinki. w (0 | * * jPlacebo c 0--- Cimetropium STATISTICAL ANALYSIS E 2- Symptom scores and the number ofdaily painful episodes were compared within groups by the 'aV Friedman test, and between groups by the us 0 Mann-Whitney U-test. Percentage differences 'a between these variables at baseline and monthly 0 .0 visits were calculated from mean values for the z - treatment groups. Presence or absence ofpain on palpation and contracted colon were compared z by Fisher's exact test. Overall assessment of treatment were compared by the X2 test. The 95% confidence intervals for differences between the proportion of improved patients in the two groups and standard errors of proportions were 6, I. 2. 3. calculated according to standard procedures.'5 Values of to or less than 0-05 Time (months) p equal (two-sided) Figure 1: Mean numbers ofpain episodes per dayfor the were considered significant.