Comment

The pharmacological treatment of irritable bowel syndrome (IBS) is currently far from satisfactory and there have been no new drug developments for many years. Recently, there has been a surge of interest in serotonin and the gut with particular emphasis, where IBS is concerned, on 5-HT₃ and 5-HT₄ receptors. A number of agonists and antagonists of these receptors are now under investigation and alosetron (a 5-HT₃ antagonist) was the first to reach the market in the USA.

In the study reported here which was confined to women, alosetron was found to be significantly superior to placebo in providing “adequate relief of pain/discomfort” in patients with diarrhoea and improving bowel function in patients with both diarrhoea and an alternating bowel habit. A particularly noteworthy feature was that the advantage of alosetron was promptly lost when treatment was stopped, suggesting a real effect. The main side effect of treatment was constipation but one case of ischaemic colitis was also reported.

IBS is notorious for its disparate symptomatology1 and the varying importance that patients place on a particular symptom.2 Thus defining a primary outcome measure for trials is fraught with difficulties, an issue which has recently been addressed by the Rome II Consensus Conference.3 It was suggested that a global outcome measure that integrates the key symptoms is probably the most preferable. Thus the “adequate relief of pain/discomfort” used in this study does not quite meet this standard but this trial was designed before the publication of Rome II.

Clinical trials in IBS have to have strict entry criteria and thus are only conducted on a small sample of patients. For instance, in this study, nearly half of the patients considered for entry were not eligible for randomisation. Thus trials such as these are undertaken on the “tip of the IBS iceberg” and very different results, which could be better or worse, may be forthcoming when the drug reaches the market place.

It is likely that new drug developments, as in this case, are likely to be directed to particular subgroups of the disorder. This is a crucial point as generations of doctors are used to prescribing the currently available medications to all forms of IBS without having to think about targeting symptoms. Thus there could be a temptation to try any new drug on “all comers”. This could prove to be a major problem with the 5-HT₃ antagonists where even in the carefully controlled conditions of a trial they caused constipation in 30% of patients. It is therefore vital that the pharmaceutical companies carefully address the issue of inappropriate prescribing which could lead to potentially serious consequences. Fortunately, this is unlikely to be a major problem for drugs that enhance transit, such as the 5-HT₄ agonists, where further loosening of an already loose bowel habit should not be too troublesome. We will also need to know much more about the gender effects of these drugs as there will be a strong temptation to try them in men. In addition, it will be interesting to see if there are any subtle differences in the activities of apparently similar 5-HT₃ antagonists and 5-HT₄ agonists which might be clinically exploitable.

Although IBS can severely impair quality of life,4 it is not a life threatening condition and therefore any potential new medication has to be much safer than might be acceptable for other indications. In addition, all new drugs are likely to be more expensive and thus increase the costs of treating IBS. Authorities are therefore likely to require evidence of superiority over existing drugs in addition to placebo and, where 5-HT₃ antagonists are concerned, may even demand comparisons with low dose tricyclic antidepressants which are being used increasingly in diarrhoea predominant IBS.

Unfortunately, alosetron has recently been withdrawn from the market in the USA because of further cases of ischaemic colitis. It remains to be determined whether this is a side effect confined to alosetron or represents a class effect common to all 5-HT₃ antagonists. If it is the latter, then this could present problems for all of the other 5-HT₃ antagonists in development. So far, no such similar adverse events have been reported for drugs active on the 5-HT₄ receptor.