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1 Role of Carbon Dioxide-Releasing Suppositories in the Treatment of Chronic Functional Constipation A Double-Blind, Randomised, Placebo-Controlled Trial M. Lazzaroni; V. Casini; G. Bianchi Porro Authors and Disclosures M. Lazzaroni, V. Casini and G. Bianchi Porro, Gastrointestinal Unit, L. Sacco University Hospital, Milan, Italy Disclosure: The authors have no potential conflicts of interest that are directly relevant to the contents of this article. Posted: 08/10/2005; Clin Drug Invest. 2005;25(8): Adis Data Information BV Physician Rating: Abstract and Introduction 1 / 9

2 Abstract Objective: Treatment of chronic functional constipation is difficult. Both oral and topical laxatives may fail to adequately relieve symptoms, and there is risk of adverse effects such as functional or structural changes in the intestine, together with electrolyte disturbances. The aim of this study was to evaluate the efficacy and safety of a suppository that combines sodium bicarbonate and potassium bitartrate in a polyethylene glycol base to generate approximately 175mL of carbon dioxide (CO 2 ). This release distends the rectal ampulla, thereby stimulating peristalsis and a subsequent bowel movement. Patients and Methods: This was a prospective, crossover, double-blind, randomised, placebo-controlled, sequential study of outpatients with chronic functional constipation. Each patient received two suppositories of identical appearance, containing active drug or placebo. The sequence of active drug-placebo (sequence 1) or placebo-active drug (sequence 2) was randomised in groups of eight. The second suppository was taken 7 days after the first. The following parameters were evaluated and scored: evacuation time, type of evacuation, feeling of emptying of the rectal ampulla, stool characteristics, anal complaints, abdominal pain and overall patient assessment. Results: A total of 29 patients entered the study. According to a restricted sequential plan, a statistical significance (p < 0.05) in favour of the active drug was reached after 26 patients. A positive response within 30 minutes of introduction of the suppository occurred in 51.7% and 6.9% of patients treated with the active drug and placebo, respectively (p = ). Normal evacuation occurred in 65.5% and 24.1% of patients treated with the active drug and placebo, respectively (p = 0.004). Normal stool consistency was found in 44.8% and 7.2% of patients treated with the active drug and placebo, respectively (p = 0.04). Patient assessment of treatment as satisfactory occurred in 51.7% and 20.7% of subjects treated with the active drug and placebo, respectively (p = 0.029). Only a trend in favour of the active drug was observed with regard to feeling of incomplete evacuation, and active drug was comparable to placebo with regard to anal and abdominal tolerability Conclusion: The CO 2 -releasing suppository may represent an alternative to rectal laxatives for the relief of chronic functional constipation. The data obtained in this study indicate that CO 2-releasing suppositories may be usefully and safely employed in the treatment of patients at risk for electrolyte disorders such as the elderly or patients with renal or cardiovascular disorders. Introduction Treatment of chronic functional constipation is a difficult challenge. In more severe forms of the condition, both bulking agents and oral laxatives may fail to adequately relieve symptoms, while introducing the risk of adverse effects such as abdominal pain, functional or structural changes in the intestine (increased apoptosis of colonic epithelial cells), electrolyte disturbances and abdominal distension. [1] 2 / 9

3 The combination of oral and rectal laxatives such as stimulating suppositories, hyperosmolar enemas and faecal softening agents may contribute to satisfactory emptying of the rectum by reducing straining at stool. The results are, however, unpredictable [2] and there is evidence that stimulating suppositories and hyperosmolar enemas are not as completely harmless as they have been believed to be. [3] The present investigation was carried out to evaluate the efficacy and safety of a suppository that combines sodium bicarbonate and potassium bitartrate, in a polyethylene glycol base, to generate approximately 175mL of carbon dioxide (CO 2 ). [4,5] This release distends the rectal ampulla, thereby stimulating peristalsis and a subsequent bowel movement, usually within 30 minutes of introduction.suppositories, hyperosmolar enemas and faecal softening agents may contribute to satisfactory emptying of the rectum by reducing straining at stool. The results are, however, unpredictable [2] and there is evidence that stimulating suppositories and hyperosmolar enemas are not as completely harmless as they have been believed to be. [3] The present investigation was carried out to evaluate the efficacy and safety of a suppository that combines sodium bicarbonate and potassium bitartrate, in a polyethylene glycol base, to generate approximately 175mL of carbon dioxide (CO 2 ). [4,5] This release distends the rectal ampulla, thereby stimulating peristalsis and a subsequent bowel movement, usually within 30 minutes of introduction. Patients and Methods Patients Outpatients >18 years of age with chronic functional constipation defined according to R ome II criteria [6] were enrolled in the study. All patients had normal haematological and biochemical test results, and were ineligible for the study if organic disease of the upper and lower gastrointestinal tract in the last year had not been ruled out by endoscopy or x-rays. 3 / 9

4 Other exclusion criteria were: drug-induced constipation; central or peripheral neurological abnormalities; metabolic and endocrine disorders (diabetes mellitus, porphyria, hypothyroidism, hyper- parathyroidism and hypercalcaemia); acute or chronic hepatic and/or renal disorders; and previous anorectal surgery. It was a prerequisite that female patients enrolled in the study were not pregnant or breast-feeding, and were postmenopausal, surgically sterilised or using adequate contraception. Evaluation Criteria The following parameters were evaluated: a. Evacuation time, evaluated on a three-point scale as follows: 1 = <15 minutes, 2 = >15 minutes but <30 minutes, 3 = >30 minutes; b. Characteristics of evacuation, evaluated on a two-point scale as follows: 1 = normal, 2 = difficult; c. Feeling of emptying of the rectum, evaluated on a two-point scale as follows: 1 = complete, 2 = incomplete; d. Characteristics of the stools, evaluated on a three-point scale as follows: 1 = normal, 2 = soft; 3 = hard; e. Anal complaints, evaluated on a four-point scale as follows: 1 = absent, 2 = anal itch, 3 = anal irritation, 4 = anal pain; f. Abdominal pain, evaluated on a four-point scale as follows: 1 = absent, 2 = mild, 3 = moderate, 4 = severe; and g. Patient's overall assessment, evaluated on a two-point scale as follows: 1 = satisfied, 2 = not satisfied. Using this evaluation system, an overall score ranging from a minimum of 8 (positive effect) to a maximum of 20 (no effect) was obtained. The active drug was considered superior to the placebo if a score at least 3 points lower than that of the placebo was reached. If the score was 2 points or less lower, the active drug and the placebo were considered equivalent. Treatment In this crossover, prospective, double-blind, randomised, placebo-controlled, sequential study, each patient received two suppositories of identical appearance, containing either active drug (CEO-two, Beutlich, Inc., Niles, IL, USA) 1 or placebo. The sequence of active drug-placebo (sequence 1) or placebo-active drug (sequence 2) was randomised in groups of eight. The second suppository was taken 7 days after the first. Evaluation scores and all adverse events were recorded in a daily diary. Use of oral laxatives and rectal administration of enemas or suppositories was not permitted in the 2 days prior to administration of the study medication. Patients were also encouraged to take about 30g of non-starch polysaccharide daily. Within 48 hours of the end of treatment, patients were again interviewed and compliance with treatment, clinical status and diary cards were evaluated. Ethics 4 / 9

5 The study was approved by the local Ethics Committee of the L. Sacco University Hospital, Milan, Italy. All study participants provided written informed consent prior to the start of the study. Statistical Evaluation A restricted sequential plan with upper, lower and middle boundaries (according to Armitage [7] ) was applied with the following specifications: type I error alpha: 0.05; power (1 minus beta): 0.95; proportion of preferences in favour of the active drug (theta value) 0.80; null hypothesis 50; maximum size of trial 40 pairs of treatments. The trial was completed as soon as the trial results plot reached one of the boundaries. If the upper boundary was reached first, the active drug was significantly superior to placebo; if the lower boundary was reached first, placebo was significantly superior to active drug; if the middle boundary was reached this was considered as no evidence of a treatment difference. Statistical analysis was also carried out using Student's t-test, the chi-square (? 2 ) test (with Yates' correction) and Fisher's exact test when needed. Scores were analysed by means of Koch's non-parametric test for crossover trials. A p-value <5% was considered significant. Results Patients A total of 29 patients entered the study. The two groups were similar in mean age, sex distribution and previous treatment with laxatives other than bulk agents ( table I ). Efficacy The upper boundary was reached when patient #26 expressed the fifteenth valid preference for the active drug, thus showing that the active suppository was significantly superior to the placebo (p < 0.05) [figure 1]. 5 / 9

6 Figure 1. Sequential plan of the study according to Armitage.[7] The upper boundary was reached when patient #2 Figure 1. Sequential plan of the study according to Armitage.[7] The upper boundary was reached when patient #26 expressed the fifteenth valid preference for the active drug, thereby showing significant superiority of the active suppository over placebo (p < 0.05). Evacuation Time. A positive response occurred within 30 minutes of introduction of the suppository (score 1 plus 2) in 51.7% (15 of 29) of the patients treated with the active drug; the percentage after placebo was 6.9% (2 of 29). This difference was significant (p = ) [ table II ]. A score of 1 (positive response within 15 minutes) was recorded in 7 of 29 (24.1%) patients treated with active drug but in no patients treated with placebo. The median scores on the evacuation time scale after active drug and placebo were 2.43 and 2.96, respectively (p < 0.001). Evacuation Characteristics. Normal evacuation was reported by 19 of 28 (65.5%) and 7 of 29 (24.1%) patients treated with the active drug and placebo, respectively (p = 0.004) [ ta ble II ]. Analysis of scores according to Koch's criteria showed a statistically significant difference in favour of the active drug. Feeling of Emptying of the Rectum. A feeling of incomplete evacuation was reported by 16 of 29 patients (55.2%) after the active drug and 23 of 29 (79.3%) after placebo (p = 0.093) [ table II ]. Stool Characteristics. Normal consistency of the stools was reported in 13 of 29 (44.8%) and in 5 of 29 (7.2%) of patients treated with the active drug and placebo, respectively (p = 0.04) [ table II ]. However, no difference was observed in the analysis of median scores because of a statistically significant carryover effect. Patients' Overall Assessment. Treatment was assessed as satisfactory by 15 of 29 6 / 9

7 (51.7%) and 6 of 29 (20.7%) patients treated with the active drug and placebo, respectively (p = 0.029) [ table II ]. A significant difference in favour of the active drug was also observed in relation to median scores. Safety Anorectal Complaints. No symptoms were reported by 25 of 29 (86.2%) patients after the active drug and 26 of 29 patients (89.7%) after placebo; local irritation occurred in 4 of 29 patients after active drug and in 3 of 29 patients after placebo ( table II ). The median scores according to sequence of administration were similar. Abdominal Pain. No symptoms were reported by 18 of 29 (62.1%) patients after the active drug and 23 of 29 patients (79.3%) after placebo (p = 0.249); moderate pain was reported by 2 of 29 (6.8%) patients after the active drug. In no case was severe abdominal pain reported ( table II ). The median scores according to sequence of administration were similar. Discussion Most experts recommend that patients with chronic functional constipation first increase their intake of dietary fibre. [8] Fibre intake may be increased by changing the composition of the diet or by adding medicinal fibre or bulk-forming agents. Although increasing dietary fibre can increase stool frequency and bulk, it may lead to increased bloating and may be unhelpful in patients with severe colonic inertia or dyschezia. [9,10] Moreover, it has been observed that patients complaining of constipation do not eat less dietary fibre than matched healthy control subjects. [11,12] In most chronically constipated patients, oral laxatives are administered alone or, particularly in patients with outlet obstruction constipation, combined with rectal stimulating suppositories, hyper- osmolar enemas or faecal softening agents. In most cases rectal laxatives are widely used for long periods without any medical controls. However, the effect on the rectal mucosa of long-term administration of such agents has not been studied. [13] There are occasional severe adverse reactions due to inadvertent introduction and retention of large volumes of water enema or hypertonic solutions. [14] Metabolic effects are potentially dangerous in small children or in adults with cardiovascular or renal impairment. [1] 7 / 9

8 Rectal laxatives may stimulate contraction by distension or chemical action (stimulation). Action, mainly by distension, is observed after a saline or water enema. Water does not induce adverse effects on the mucosa, but if large volumes (1-2L) are retained, dangerous water intoxication may occur. [13] Sodium phosphate enemas act by distension and stimulation. They are usually successful in the treatment of occasional rectal evacuation, but their long-term use may induce mild to severe lesions in the rectal mucosa. [15] Furthermore, if there is any disorder that prevents prompt evacuation, use of phosphate enemas can lead to dangerous hyper- phosphataemia and hypocalcaemic tetanus in children or patients with renal impairment. [16,17] Glycerine and bysacodil exert a stimulating effect, but the latter may produce marked changes in epithelial cells to varying depths within the crypts. [15] The availability of a suppository that stimulates bowel movements without the risk of passage of large liquid stools, water retention or mucosal damage may represent an interesting alternative to the current rectal laxatives, particularly in patients at risk because of age or organic disease. The active drug combines sodium bicarbonate and potassium bitartrate, in a polyethylene glycol base, to generate approximately 175mL of CO 2. [4,5] CO 2 is an important component of intestinal gas, which, in physiological conditions, is produced by fermentative degradation of carbohydrates and cellulose. In adequate amounts, CO 2 stimulates peristalsis, increases microcirculation permeability without histopathological damage, and promotes defaecation. The choice of the duration of washout period from laxatives in this study was arbitrary. However, we believe that a 2-day washout from laxatives other than bulk-forming laxatives was sufficient to minimise the influence of laxatives on the study drug. Furthermore, the number of patients taking laxatives in the two arms of the study was similar. 8 / 9

9 No stratification by age was performed in this study. While this might have provided useful clinical information, the patient series was too small to have allowed valid statistical conclusions to be drawn regarding any possible effects of patient age on treatment. The results of our study appear to confirm the clinical usefulness of the product under investigation. When compared with placebo, the active drug significantly decreased evacuation time: a bowel movement occurred within 15 minutes of introduction of the suppository in 24% of patients, and within 30 minutes in 52% of patients. The corresponding figures after placebo were significantly lower (0% and 7%, respectively). The active drug also reduced straining during bowel movements in 66% of patients, and improved stool characteristics in 45% of patients. No difference between the active drug and placebo was noted in the feeling of emptying of the rectal ampulla. This finding is not easy to explain, but may indicate a residual effect of distension of the ampulla by CO 2. It is also worth noting that overall patient assessment of clinical efficacy was significantly in favour of the active drug: 52% of patients expressed a preference for the active drug compared with 21% for placebo. The active drug was well tolerated. The percentage of anal complaints was similar to that for placebo (14% vs 11% of cases). Abdominal pain was reported as mild in 31% of patients and moderate in 7% of patients after the active drug; these figures were not significantly different to those after placebo. Conclusion The active drug is an interesting alternative to rectal laxatives, when administered alone or combined with oral laxatives, for the relief of chronic functional constipation. In our opinion, the compound acts on mechanisms that do not involve risks of mucosal damage or electrolyte imbalance and can be proposed for short-term treatment even in patients at risk for electrolyte disorders, such as, for instance, the elderly or patients with renal or cardiovascular impairment. Long-term use in such patients, however, warrants further study. 9 / 9