The objective of this study was to investigate the effects of the opioid loperamide and its recently synthesized pharmacologically inactive prodrug loperamide oxide on the anal sphincter. In a double-blind, placebo-controlled crossover study, anorectal manometry was performed in 12 healthy volunteers five hours after oral bolus application of 10 mg of loperamide, loperamide oxide, or placebo. Loperamide significantly increased the threshold volumes for minimal perception and urgency to defecate (P less than 0.05) and raised the volume required to abolish recovery of the rectoanal inhibitory reflex (P less than 0.05). These findings suggest that loperamide has a specific continence-improving action on the anal sphincter. However, anal resting pressure and maximal squeeze pressure were unaffected in our study and do not seem to be responsible for this effect. The effects under loperamide oxide showed a similar tendency but were without statistical significance.