Dose dependent effects of fentanyl on indomethacin-induced gastric damage

Whilst developing a rat model for studies of gastric protection, we noticed that the anaesthetic agent 'Hypnorm', containing the opiate fentanyl 0.315 mg/ml and the butyrophenone fluanisone 10mg/ml, was itself protective against indomethacin-induced damage: unrestrained animals given indomethacin (20 mg/kg) subcutaneously had an ulcer score of 9 ± 1 mm 2 , compared with 1 ± 1 mm 2 in animals pre-treated with Hypnorm (0.8 ml/kg) and then given indomethacin (p < 0.01). Further investigation showed this effect to be due to fentanyl-inhibiting gastric acid secretion: doses of fentanyl (90 and 180 μg/kg) which decreased indomethacin-induced damage also caused a rise in intragastric pH from 2.7 ± 0.6 in controls to 5.1 ± 0.8 and 5.0 ± 0.8, respectively. However, the response of fentanyl varied depending on the dose given: fentanyl, 3.6 μg/kg did not affect indomethacin-induced damage, 8 ± 2 vs. 9 ± 1 mm 2 ; fentanyl, 18 μg/kg potentiated damage, 15 ± 4 mm 2 (p < 0.05), whereas fentanyl, 90 μg/kg and 180 μg/kg decreased damage, 2 ± 1 mm 2 and 0.1 ± 0.1 mm 2 , respectively (p < 0.01). Neither the butyrophenone haloperidol (8.3mg/kg) nor the α-adrenergic receptor antagonist phenoxybenzamine (3 mg/kg) protected against indomethacin-induced damage. We conclude that fentanyl affects intragastric pH and can both potentiate and protect against indomethacin-induced damage. Furthermore, the potentiation of gastric damage by fentanyl occurred at doses similar to those used for human anesthesia, so clinical studies are suggested.