Effects of the prodrug loperamide oxide, loperamide, and placebo on jejunal motor activity

Abstract

This crossover, double-blind study investigated the effects of single oral doses of the prodrug loperamide oxide, which is reduced gradually to loperamide in the intestine, and loperamide on jejunal motor activity in 12 fasting healthy men. Five minutes after a phase III of the migrating motor complex (MMC), 2 mg loperamide oxide, 4 mg loperamide oxide, 4 mg loperamide, or placebo were administered. Thereafter, motor activity 10-30 cm abroad the ligament of Treitz was recorded with five catheter orifices at 3-cm intervals over 4 hr. Number of contractions and area under curve increased significantly with 4 mg loperamide and 4 mg loperamide oxide, the increases with loperamide oxide occurring more gradually. Placebo and 2 mg loperamide oxide had no discernible effects. With both 4 mg loperamide and 4 mg loperamide oxide, phase I of the MMC was slightly prolonged and phase II and the time from drug administration to the onset of the first phase III slightly shortened. The percentage of aborally propagated contractions in phase II increased with all active treatments, whereas the occurrence of phases III was not altered.

Treatment of opioid-induced gut dysfunction

“…The first strategy is to target opioid receptors in the gut, a possibility that has long been accomplished by the development of loperamide. The antidiarrhoeal action of this compound is predominantly mediated by µ-opioid receptors and is restricted to the gut because loperamide is poorly absorbed and fails to cross the blood-brain barrier at concentrations needed to produce analgesia [6,30,62]. The second strategy is to inhibit enkephalinases that degrade endogenous opioids once they have been released from neurons or other cells in the GI tract.…”

“…In the canine gut, µ-opioid receptor agonists have a biphasic excitatory and inhibitory influence on the migrating myoelectrical complex [27], and transit in the human colon is retarded by activation of µ-opioid (but not κ-opioid) receptors [28,29]. Other studies have shown that activation of µ-opioid receptors in the human gut can increase pyloric tone, induce pyloric (as well as duodenojejunal phasic) pressure activity and elevate the resting anal sphincter pressure [30,31]. The relative contribution of these multiple effects to opioid-induced constipation is not clear [7].…”

Objectives of the meeting: think opiates

“…As an introduction to the more mechanistic reviews to follow, it is important to summarize the information available in the literature. In humans, studies have focused on the effects of three specific opioid receptors on visceral antinociception and motility: the µ‐, δ‐ and κ‐opioid receptors 1–13 …”

“…µ‐receptor‐selective opiates retard gastric, small bowel and colonic transit 12,13 . Migrating motor complex (MMC)‐like activity fronts are induced in the proximal and distal small bowel 9–11 …”

Pharmacology of Opioids and their Effects on Gastrointestinal Function

“…Furthermore, exogenous opioids inhibit water and electrolyte secretion in addition to increased fl uid absorption ( Figures 2 and 3 ). Th ese activities have been exploited therapeutically to manage diarrhea; for example, the action of loperamide is predominantly mediated by μ -opioid receptors and is primarily restricted to the gut due to its inability to cross the blood -brain barrier at concentrations needed to produce analgesia ( 52 ). However, in patients without diarrhea, the antisecretory eff ect of opioids combines with their antipropulsive action to cause constipation.…”