Acetorphan is an orally active inhibitor of
enkephalinase (EC 3.4.24.11) with antidiarrhoeal activity in rodents apparently through protection of endogenous
enkephalins and a purely antisecretory mechanism. Its antidiarrhoeal activity in man was assessed in an experimental model of
cathartic induced secretory diarrhoea as well as in acute diarrhoea of presumed infectious origin. In six healthy volunteers receiving
castor oil and pretreated with
acetorphan or placebo in a crossover controlled trial, the
drug significantly decreased the number and weight of stools passed during 24 hours. About 200 outpatients with severe acute diarrhoea (more than five stools per day) were included in a randomised double blind study of
acetorphan against placebo. The significant antidiarrhoeal activity of
acetorphan was established using a variety of criteria: (i) the duration of both diarrhoea and treatment were diminished; (ii) no
acetorphan treated patient withdrew from the study whereas five dropped out because of worsening in the placebo group; (iii) the frequency of symptoms associated with diarrhoea--for example,
abdominal pain or distension,
nausea and
anorexia--remaining after two weeks was nearly halved; (iv) using visual analogue scales
acetorphan treatment was found more effective than placebo by both investigators and patients. There was statistically no significant difference between
acetorphan and placebo in respect of side effects, particularly
constipation, which often accompanies the antidiarrhoeal activity of
mu opioid receptor agonists this difference is attributable to the lack of antipropulsive activity of
acetorphan in man. The efficacy and tolerance of
acetorphan suggest that
enkephalinase inhibition may represent a novel therapeutic approach for the symptomatic management of acute secretory diarrhoea without impairing intestinal transit.