Placebo responses undoubtedly exist in laxative trials. For example here are results from a trial in which constipated children were randomly assigned to either placebo (n=19) or cisapride (n=17):

Treatment success was judged to have occurred in 76% of the cisapride group and 37% of the placebo group (p<0.03) (Nurko et al., 2000).

The systematic review of laxative trials conducted by Tramonte's group (Tramonte et al., 1997) concluded that laxative medication of whatever kind increased stool frequency by about 1.5 per week compared with placebo. Study limitations prevented clear conclusions about the relative efficacy of different laxative classes.

In the light of these conclusions, which were largely echoed by the authors of a systematic review of laxative trials in the elderly (Petticrew, Watt and Sheldon, 1997), there must now be a doubt over whether it is ethical to conduct Phase 2 or certainly Phase 3 laxative comparisons against placebo. A placebo comparison is appropriate when there is doubt as to whether any effective therapy for the condition in question exists. In the case of constipation, it is clear that a number of effective treatments exist. What we are unsure of is their relative worth. Clinical practice needs evidence not whether a laxative preparation is better than placebo, but whether it is better than any other laxative preparation, in terms not only of efficacy but also of acceptability and economics.

Like the previous question, this is a matter not only of pharmacology but also of ethics. Some stimulant laxatives undergo hepatic recirculation that prolongs their effects, making a one-week washout period appropriate before commencing another agent. On the other hand there is likely to be individual variation in the duration of action of the drug and the previous dose might not have been effective anyway. A phase with no medication (or with placebo) exposes the subject to the risk of distressing existing constipation.

An alternative sometimes used is to provide an initial run-in phase in which specified oral and rectal laxative measures are used in order to clear the bowel so that there is a "level playing field" at the start of the trial. Practically, it is often not possible in a clinical study to adopt either of these practices. Instead, the trial duration may be made long enough that carry-over effects are likely to be insignificant in the overall result, or in a crossover trial the order of treatments is randomized and statistical allowance made for order or period effects. In a parallel group trial, patients may be allowed to continue their previous medication in addition to the test drug, varying its dose according to their bowel function. Such variations can then be an outcome measure for the trial.

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