Nonsteroidal anti-inflammatory drug-induced visible and invisible small intestinal injury

Abstract

Permeation of the small intestinal mucosa is a key mechanism in the induction of enteropathy. We investigated the effect of rebamipide in healthy subjects with diclofenac-induced small intestinal damage and permeability. In this crossover study, each treatment period was 1 week with a 4-week washout period. Diclofenac (75 mg/day) and omeprazole (20 mg/day) plus rebamipide (300 mg/day) or placebo were administered. Capsule endoscopy and a sugar permeability test were performed on days 1 and 7 in each period. Ten healthy subjects were enrolled. Small intestinal injuries were observed on day 7 in 6 of 10 subjects in both groups. Urinary excretion of administered lactulose increased from 0.30% to 0.50% of the initial dose during the first treatment period in the placebo group, and from 0.13% to 0.33% in the rebamipide group. Despite recovery from small-intestinal mucosal damage, the increased permeability in both groups resulted in sustained high levels of lactulose (0.50% to 1.06% in the placebo group and 0.33% to 1.12% in the rebamipide group) through the 4-week washout period. Diclofenac administration induced enteropathy and hyperpermeability of the small intestine. The sustained hyperpermeability during the washout period may indicate the presence of invisible fragility.

Keywords: diclofenac; healthy subjects; permeability; rebamipide; small intestinal damage.

Fig. 1

Study protocol —Crossover design—.

Fig. 2

Changes in sugar excretion. Permeability was described as percent of the initial dose according to the following formula: excretion of sugar in urine (mg/ml) × urine volume (ml)/quantity of sugar loading (mg) × 100. Changes in excretion of sugars were defined as differences between the baseline and day 7 levels.

Fig. 3

Time course of lactulose excretion in urine. Closed circles represent the placebo group, and open circles represent the rebamipide group. Diclofenac use is associated with a linear increase of lactulose urinary excretion level during the washout period despite the recovery from small intestinal injury.