Treatment of irritable bowel syndrome.

Irritable bowel syndrome is characterised by diverse symptoms including abdominal pain, altered bowel function (increased bowel frequency, constipation), bloating, abdominal distension, the sensation of incomplete evacuation, and the increased passage of mucus. No unifying hypothesis explains all these symptoms, and no single agent will alleviate all components of the symptom complex. The currently favoured model to explain the symptoms includes central and end organ components. These may be combined into an integrated hypothesis that incorporates psychological factors (stress, distress, affective disorder) and dysfunction of the gut (disorders of motility, visceral hypersensitivity). Current standard drug treatment generally entails a symptom directed approach with drugs aimed at pain, constipation, and diarrhoea. Development of new drugs has focused mainly on agents that modify the effects of 5-hydroxytryptamine (5-HT) in the gut. Alternatives to this single receptor approach exist, although not all patients respond to educational and psychological interventions, and treatment with drugs will remain an option for nonresponders. As a mediator of the motor and secretory responses to the ingestion of food, 5-HT has an important physiological role. Growing evidence shows that some aspects of the pathophysiology of irritable bowel syndrome may affect the 5-HT axis. Specific 5-HT3 and 5-HT4 receptors have been identified as therapeutic targets. Alosetron and cilansetron, which are 5-HT3 receptor antagonists, were devised to reduce pain and retard transit and therefore be beneficial in irritable bowel syndrome that manifests predominantly as diarrhoea. Randomised controlled trials indicate that both have some efficacy in patients with diarrhoea predominant irritable bowel syndrome, although alosetron is effective only in women. Although alosetron was licensed in the United States in 2000, it was subsequently withdrawn because many patients developed ischaemic colitis and severe constipation. Many of these patients required admission to hospital, and three of them died. Ischaemic colitis has also been reported with cilansetron and seems likely to be a class specific adverse effect. Recent evidence shows that ischaemic colitis may be increased in patients with irritable bowel syndrome, and that this may be influencing the effect of alosetron adversely. The Food and Drug Administration, however, has challenged this position. The second problem relates to whether the statistically significant therapeutic gain of about 12% over placebo translates into a clinically important benefit for patients with irritable bowel syndrome. A group of experts has advised that a 10-15% therapeutic gain would be appropriate for a new drug for irritable bowel syndrome, although this statement seems to lack evidence. Tegaserod, a 5-HT4 receptor partial agonist and a prokinetic in the gut, is effective in women with constipation predominant irritable bowel syndrome. The therapeutic gain over placebo varied substantially in different trials at 5-20%, again raising the question whether this is a clinically important effect and whether a similar therapeutic gain might be obtained with a simple laxative or soluble fibre. A Cochrane review confirms the drug’s efficacy in improving the overall symptoms in irritable bowel syndrome, with a number needed to treat between 14 and 20, but finds no effect on individual symptoms of pain and discomfort. Tegaserod is now available in the United States and some other countries for the treatment of constipation predominant irritable bowel syndrome in women. It is still under evaluation by the European Agency for Evaluation of Medicinal Products. Tegaserod has also been linked to ischaemic colitis, but this assertion has been rebutted on the basis that this merely represents the incidence in the general population. The science linking 5-HT and irritable bowel syndrome is appealing, and some progress has been made in translating this knowledge into new treatments, however, we still have no pharmacological intervention that will resolve all aspects of the symptom complex of irritable bowel syndrome in men and women. An agent directed at a single gut receptor is unlikely to cure irritable bowel syndrome. What other options might be worth exploring? The importance of psychosocial factors in the development of irritable bowel syndrome has been recognised for decades. Psychological interventions (psychotherapy, short and long term hypnotherapy, cognitive behaviour therapy) and antidepressants (low and conventional doses) are effective. Cognitive behaviour therapy has an impressive therapeutic gain of 33% over control. Multidisciplinary education and comprehen-