Commentary

Racecadotril is an antisecretory agent that inhibits intestinal encephalinases, resulting in an increase of endogenous encephalines, which decrease secretion of water and electrolytes into the gut lumen. Unlike loperamide, racecadotril is thought to have no direct effect on intestinal motility.

The study by Santos et al addresses a topic highly relevant to paediatric practice, given that diarrhoeal diseases continue to be among the leading causes of death in childhood globally. Disappointingly, the study failed to demonstrate a significant difference between children treated with ORS combined with racecadotril and a control group receiving ORS alone regarding stool frequency, duration of diarrhoea and number of medical consultations. The authors concluded that in children with moderate acute gastroenteritis who do not require admission, ‘racecadotril does not diminish the symptoms of diarrhea more rapidly than ORS alone’.

However, the study has a number of important limitations, which complicate the interpretation of these findings. First, neither the investigators nor the parents were blinded to treatment allocation. Second, stool frequency and consistency were recorded by the parents (as participants were treated as outpatients), rather than being monitored by the investigators, which would have been a more accurate approach. Finally, and most importantly, the loss to follow-up was high, with only 103 patients (58% of the study population included in the efficacy analysis) returning for the second assessment on day 7.

The sample size calculation provided in the manuscript, based on data from an earlier study by Cojocaru et al (reporting a reduction in median stool frequency of 28% with racecadotril),1 appears to suggest that 73 children were required in both study arms to detect a significant difference with 90% power. It is therefore likely that the study was insufficiently powered to identify moderate-size differences between the two treatment groups.

The findings reported by Santos et al appear to stand in contrast with the conclusions of a recent systematic review by Szajewska et al,2 evaluating the use of racecadotril in the treatment of acute diarrhoea in children. The data presented in this meta-analysis, which included three paediatric RCTs, suggest that racecadotril is associated with a significant reduction in stool output at 48 h. However, the cure rate at day 5 was no different to placebo in this meta-analysis. Notably, all three RCTs included in this review were conducted in an inpatient setting, and compliance with study medication is therefore likely to have been higher than in the study by Santos et al, which may account for some of the differences. Epidemiological differences related to the prevalence and spectrum of causative microbial agents between different study sites may also have played a role.

Undoubtedly, further data on the efficacy of racecadotril as treatment for gastroenteritis in paediatric outpatients are needed before this drug can be recommended for use in this setting. It appears prudent that future research in this area investigates clinically more meaningful primary outcome measures – such as hydration status, the need for hospital admission and the need for nasogastric or intravenous rehydration – rather than merely focusing on stool volume and frequency.