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Irritable bowel syndrome is one of the most common functional gastrointestinal disorders, and is characterized by recurrent abdominal pain and discomfort, bloating and altered bowel function.1 It has been estimated in epidemiological studies that as many as 22% of people report symptoms consistent with irritable bowel syndrome.2 In clinical practice in Western countries, irritable bowel syndrome is generally reported more frequently by women.2, 3 The disease can have a significant impact on an individual’s quality of life, with profound social and economic consequences.4–6
The diagnosis of irritable bowel syndrome is challenging because of the lack of histopathological or biochemical markers to characterize the disorder.1, 7 Physicians therefore rely on exploring the symptomatology expressed by individual patients, the predominant symptom being abdominal pain or discomfort.1 The subclassification of irritable bowel syndrome patients by their primary symptoms can be clinically meaningful in order to select the appropriate treatment.2 In terms of bowel function, some patients may experience constipation more often and others diarrhoea more often. However, there is a large group of patients who alternate between constipation and diarrhoea during the course of their illness.8
The underlying mechanisms which contribute to the pathophysiology of irritable bowel syndrome are currently emerging with the advent of novel therapeutic agents. Recent methodological advances and interdisciplinary studies have led to a greater understanding of gastrointestinal physiology, in particular the interplay between the enteric and the central nervous system (the ‘brain–gut axis’). As a result, it is now accepted that disturbances in gastrointestinal motility and enhanced perception of visceral stimuli (visceral hypersensitivity) both make important contributions to irritable bowel syndrome symptoms.2, 7, 9
In the past, treatment decisions were often based on the patient’s individual symptoms because there was no single drug that was effective in relieving abdominal pain, bloating and constipation associated with irritable bowel syndrome.10 However, there is growing evidence that serotonin (5-HT), via its subtype 4 (5-HT4) receptors, plays a pivotal role in the maintenance of overall gastrointestinal motor function.11, 12 The advent of innovative 5-HT4 receptor agonists has demonstrated that 5-HT4 receptor stimulation can trigger the peristaltic reflex in both animal and human gastrointestinal tract.13 Moreover, recent studies performed in cats and rats suggest a modulating role of 5-HT4 receptors in visceral sensation.14, 15
Tegaserod [3-(5-methoxy-1H-indol-3-ylmethylene)- N-pentyl-carbazimidamide] hydrogen maleate is a new compound designed as a selective 5-HT4 receptor partial agonist.16, 17 Preclinical and clinical investigations have demonstrated that tegaserod can stimulate motility throughout the gastrointestinal tract.18–22 Partial agonists may have the effect of normalizing altered gastrointestinal motility and, in addition, may also modulate visceral sensation.14, 15 Therefore, tegaserod was investigated in the treatment of irritable bowel syndrome.
The purpose of this study was to evaluate the efficacy and safety of tegaserod in a large, international, randomized, placebo-controlled, double-blind, multicentre study in patients with symptoms of abdominal pain, bloating and constipation associated with irritable bowel syndrome.
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This study was designed to evaluate the effects of the novel selective 5-HT4 receptor partial agonist, tegaserod, on the multiple symptoms of irritable bowel syndrome. Patients with irritable bowel syndrome typically complain of abdominal pain and discomfort, bloating and altered stool frequency and consistency (constipation, diarrhoea or both). In this study, patients were characterized by a symptom profile of abdominal pain/discomfort, bloating and constipation. Both doses of tegaserod used in the study (2 mg b.d. and 6 mg b.d.) were effective against these symptoms and were well tolerated. However, the higher dose of tegaserod, 6 mg b.d., offered more consistent efficacy over time and across the major symptoms examined. The clinical benefits of tegaserod in relieving abdominal pain/discomfort and constipation were noted during the first week of treatment, demonstrating a rapid onset of action. These effects were sustained over the entire 12-week treatment period.
Improvement in the symptoms of irritable bowel syndrome has traditionally been difficult to quantify in clinical trials, because of the lack of biological markers in patients,1, 7 and the complex nature of the condition. Indeed, there has been much concern in recent years over the lack of an agreed universal end-point by which to classify responders in clinical trials. Assessing treatment effects by single variables, such as pain scores, is useful but may not provide an accurate reflection of the overall symptom improvement because individual symptoms can vary from patient to patient and from time to time.26 However, it has been reported that global assessments of efficacy allow the multiple symptoms of irritable bowel syndrome to be captured in a single measure.27 The global relief measure used in the pivotal tegaserod clinical trials (the SGA of Relief) takes into account the three central factors in irritable bowel syndrome: abdominal pain and discomfort, altered bowel function and overall well-being. Furthermore, the SGA of Relief has shown a high correlation with clinically relevant improvements in the daily diary measures of abdominal pain and bowel function.24 This finding is further substantiated by the results of this study.
Another problem commonly associated with irritable bowel syndrome clinical trials is the high placebo response rate. The placebo effect in our study varied between 25 and 40%, depending on the duration of treatment and the variable examined. This is consistent with placebo rates reported in previous clinical trials of functional gastrointestinal disorders,28, 29 and is thought to be due, at least in part, to the types of patients recruited in clinical trials and also the underlying variability of the severity of the disorder.25 The superiority of tegaserod, 6 mg b.d., over placebo (drug-placebo treatment difference) was 13.4% on the SGA of Relief after 12 weeks of treatment. In clinical practice, therefore, an absolute response rate of approximately 50% can be anticipated with tegaserod, 6 mg b.d. This effect is clinically meaningful, especially in view of the fact that no other treatment is available to simultaneously manage the multiple symptoms of abdominal pain and constipation associated with irritable bowel syndrome.
In the updated Rome criteria for functional gastrointestinal disorders (Rome II criteria), irritable bowel syndrome is defined as a group of symptoms in which abdominal discomfort or pain is associated with altered bowel function.1 It is pointed out that irritable bowel syndrome is a heterogeneous disorder and there is probably no pathophysiology common to all patients fulfilling the definition of irritable bowel syndrome. Hence, it is reasonable to tailor treatments towards the primary symptom pattern (e.g. abdominal pain, bloating and constipation) by using specific drugs with different pharmacodynamics to effectively treat the symptoms expressed.
Because of its known ability to increase intestinal motility,18–20 tegaserod was selected for clinical development in irritable bowel syndrome patients who experience abdominal pain, bloating and constipation. A previous study with tegaserod demonstrated a significant reduction in orocaecal transit times in irritable bowel syndrome patients with constipation.22 The effects of tegaserod on gastrointestinal motility were confirmed by the results of this study: patients treated with tegaserod showed an increase in stool frequency as early as the first week of treatment. This was accompanied by a significant improvement in stool consistency, the effects of which were also evident during the first week of treatment.
The pathogenesis of abdominal pain and discomfort in irritable bowel syndrome is understood to a lesser degree than the abnormal motility component. It has been previously reported that abnormal motility, intestinal distension and visceral hypersensitivity are among the most important underlying mechanisms.2, 30–32 Because most irritable bowel syndrome patients who suffer from constipation frequently complain about abdominal pain and bloating related to their bowel function,8 a beneficial effect of a prokinetic agent on these symptoms, via increased peristalsis, might be anticipated. Interestingly, the mixed 5-HT4 receptor agonist/5-HT3 receptor antagonist, cisapride, has proven gastro-prokinetic activity.33 It also improved constipation34 and appeared to improve irritable bowel syndrome symptoms in one study.35 However, the clinical efficacy of cisapride in irritable bowel syndrome patients could not be confirmed in a subsequent trial.36
In contrast, tegaserod is a selective 5-HT4 receptor partial agonist devoid of 5-HT3 receptor antagonist properties,17, 20 and therefore offers an innovative pharmacological profile. In animal models investigating the effect of tegaserod on visceral sensitivity, tegaserod triggered propagating motor activity in the gastrointestinal tract,13 reduced the firing rate in spinal rectal afferent nerves in the cat,14 and increased the pain threshold to colorectal distension in rats,15 thus suggesting a modulating role of the 5-HT4 receptor in nociception. It is tempting to speculate that these pharmacodynamic effects contributed to the therapeutic activity observed in the present study of irritable bowel syndrome. A visceral pain perception effect may correlate with the significant reduction in patients’ abdominal pain or discomfort compared with placebo.
Although not classed as one of the central diagnostic symptoms of irritable bowel syndrome, bloating (also known as a feeling of abdominal distension or fullness)37 is one of the key supportive symptoms.1 In a recent study evaluating the occurrence of various gastrointestinal symptoms in irritable bowel syndrome patients, Schmulson and colleagues identified bloating-type symptoms in 88.6% of irritable bowel syndrome patients with constipation.8 In the present study, tegaserod showed a favourable trend in reducing the number of days with significant abdominal bloating compared with placebo.
Tegaserod showed a highly favourable safety profile in this study. The overall incidence of adverse events in the two tegaserod treatment groups was similar to placebo. The only adverse event reported more frequently with tegaserod was diarrhoea (as defined/considered by patients). The diarrhoea typically occurred early during treatment, and quickly resolved without intervention or interruption of therapy. The early onset of diarrhoea in some patients is consistent with the rapid pharmacodynamic action of the drug. Tegaserod also showed a favourable cardiac safety profile, with no clinically relevant effects on electrocardiogram parameters, QTc interval or cardiac repolarization. Concern over the cardiac safety profile of gastro-prokinetic agents arose from the association of cisapride with rare disturbances in electrocardiogram parameters (such as prolonged QTc intervals), which may lead to potentially fatal dysrhythmias.38, 39