A 35-year-old woman presents with recurrent episodes of abdominal pain, constipation, and a sense of incomplete emptying after defecation. She has a history of irritable bowel syndrome (IBS).
In patients with IBS, is tegaserod an appropriate therapy for treatment of abdominal pain and general dissatisfaction with bowel habits?
Background. IBS is a complex disorder that encompasses a wide profile of symptoms. Current drug treatments for IBS are of limited value, and many treatments target specific symptoms. Tegaserod, a 5-HT4 receptor partial agonist, has a novel mechanism of action in the treatment of IBS.
Objectives. The objective of this review1 was to evaluate the efficacy and tolerability of tegaserod in the treatment of IBS in patients 12 years of age and older.
Search Strategy. The authors searched MEDLINE (1966 to November 2002) and EMBASE (1980 to November 2002) using the key words “tegaserod,” “HTF 919,” “irritable bowel,” and “colonic diseases, functional.” The Cochrane Central Register of Controlled Trials, the Inflammatory Bowel Disease Review Group Specialized Trials Register, and Science Citation Index also were searched. Proceedings from the British Society of Gastroenterology Annual Meeting, and Digestive Disease Week (1998 to 2002) were searched by hand. Reference lists from relevant articles were reviewed. The manufacturer of tegaserod was contacted.
Selection Criteria. Randomized or quasi-randomized controlled trials that focused on clinical end points and compared tegaserod with placebo, no treatment, or any other intervention (pharmacologic or nonpharmacologic) in patients 12 years and older who had been diagnosed with IBS were considered for review.
Data Collection and Analysis. Study inclusion and exclusion, data extraction, and quality assessment were performed independently by two reviewers. Meta-analysis was performed when study populations, designs, outcomes, and statistical reporting allowed the valid combination of data. Eight short-term, placebo-controlled studies fulfilled the inclusion criteria. These studies were conducted predominantly in women. Seven studies evaluated the efficacy of tegaserod on global GI symptoms in patients with constipation-predominant IBS. One small study evaluated safety in patients with diarrhea-predominant IBS.
Primary Results. Compared with patients who received placebo, the relative risk (RR) of responding in terms of global relief of GI symptoms was significantly higher in patients who received tegaserod in dosages of 12 mg per day (RR, 1.19; 95 percent confidence interval [CI], 1.09 to 1.29) and 4 mg per day (RR, 1.15; 95 percent CI, 1.02 to 1.31), with numbers needed to treat (NNT) of 14 and 20, respectively. When patients who received tegaserod at any dosage (n = 4,040) were compared with patients who received placebo, the RR of responding was 1.17 (95 percent CI, 1.08 to 1.27), with an NNT of 17. Although the pooled results indicate a statistically significant benefit with tegaserod, the a priori minimal clinically important differences that were set in two of the four pooled studies were not reached. Tegaserod did not significantly improve patients’ individual symptoms of abdominal pain and discomfort, although a statistically significant improvement in bowel habits was noted in patients in the lower dosage group. There was a nonsignificant trend in favor of the 12-mg dosage.
When GI symptoms were assessed separately, symptoms indicative of GI motility, such as number of bowel movements and days without bowel movements, generally were improved in patients who received tegaserod, although the proportion of patients experiencing diarrhea was significantly higher in the 12-mg group than in the placebo group (RR, 2.75; 95 percent CI, 1.90 to 3.97), with a number needed to harm (NNH) of 20. The effects of tegaserod on GI symptoms such as bloating, stool consistency, and straining were not consistent across the studies.
Reviewers’ Conclusions. Tegaserod appears to improve the overall symptomatology of IBS, but there are few data on its effect on quality of life. More information is needed about its efficacy in men. It also would be of interest to know whether treatment with tegaserod leads—directly or indirectly—to changes in visceral sensitivity or psychopathology, which are considered important in the pathophysiology of this condition.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (http://www.cochrane.org)
Tegaserod offers modest improvement in global gastrointestinal (GI) symptoms in women with constipation-predominant IBS, without having significant effect on symptoms of abdominal pain and discomfort.
IBS is a chronic, relapsing condition encompassing a wide variety of GI symptoms, including abdominal pain and altered bowel habits. The condition affects 10 to 15 percent of the North American population and is twice as common in women as in men.2 The etiology is unknown, although motility disorders, visceral hypersensitivity, and sensitization of the central nervous system have been implicated. IBS is a clinical diagnosis of exclusion, and traditional treatments, such as bulking agents, anticholinergics, antispasmodics, antidiarrheals, and antidepressants, have targeted individual symptoms. Tegaserod, which stimulates smooth muscle within the GI tract and increases peristalsis and gut transit time, offers a new treatment option for the global symptoms of IBS.
Tegaserod in dosages of 12 mg daily has shown statistical significance in two studies, and a nonsignificant but beneficial trend in two additional randomized controlled studies, in the reduction of global GI symptoms. These self-reported subjective assessments asked patients to compare their GI symptoms before entering the trial with symptoms after initiating therapy. Patients in both treatment groups reported complete or considerable relief in GI symptoms.
Abdominal pain symptoms did not appear to be altered significantly, although beneficial trends were noted in some patients in both treatment groups. Patient satisfaction with bowel habits suggests that the lower dosage may be more efficacious, although a similar trend in patient satisfaction was noted in the higher dosage group.
Stool frequency and the number of days without bowel movements improved in patients in the 12-mg group. In one study, subjective scores of bloating, straining, and stool consistency decreased and stool frequency increased in the higher dosage group. However, these results were not consistent across all studies.
Tegaserod was well tolerated by most patients. The most common side effect was diarrhea, which was experienced significantly more often by patients in the higher dosage group (NNH, 20). Headache, abdominal pain, and nausea were experienced with increased frequency in this group as well, but this trend did not reach statistical significance. Cardiac effects were not apparent with this agent as they are with other partial 5-HT4 receptor agonist GI-motility agents such as cisapride. Three studies investigated the potential effect of QTc interval prolongation but did not identify an increase in frequency of ECG abnormalities between the high-dosage, low-dosage, and placebo groups.
Few data about tegaserod’s efficacy in men and its impact on quality of life exist. Longer-term studies are needed to determine the duration of treatment and the safety of this agent with prolonged use. Tegaserod appears to be an option for short-term relief of global GI symptoms in women with constipation-predominant IBS, but it does not affect their abdominal pain and discomfort.