Gabriele Gaupmann

Naloxone does not alter the perception of pain induced by electrical and thermal stimulation of the skin in healthy humans.

&NA; It has been hypothesized that, in the absence of acute or chronic pain, a tonically active system exists involving opioid peptides, which ensures a certain level of pain insensitivity. Although various studies have failed to support this concept, it has been reported that in conditions of both experimentally induced and clinical pain, high doses of the opioid antagonist naloxone induced a state of hyperalgesia and thus seemed to set off this hypothetical system. Lower doses were, however, without effect or even acted as analgesics. This study investigated the effect of 5 and 20 mg naloxone i.v., compared to placebo, on the perception of pain in healthy humans. Pain was induced by two methods, using electrical and thermal stimulation of the skin, which have previously been shown to be sensitive to the effects of opioid as well as of non‐steroidal anti‐inflammatory analgesics. Each of 12 males and 12 females participated in 3 experimental sessions, in which the treatments were administered double‐blind according to a Latin square design. Threshold and tolerance to electrically induced pain and threshold to thermally induced pain were measured at 30 min intervals for 90 min before and 90 min after drug administration. Electrical stimuli were square wave constant current impulses of linearly increasing intensity; thermal stimuli were of constant intensity and variable duration. Threshold and tolerance to electrically induced pain were not altered by either dose of naloxone, whereas the threshold to thermally induced pain was significantly higher after both 5 and 20 mg naloxone than after placebo, the effects of the two naloxone doses not differing from each other. Subjects who were relatively pain sensitive did not react differently to the pain stimuli after naloxone administration than did subjects who were relatively pain insensitive. These results, which are consistent with those of previous studies, cast further doubt on the validity of the concept that there is, in the absence of pain, a tonically active system involving endogenous opioids, which ensures a level of pain insensitivity.

Effects of cisapride on jejunal motor activity in fasting healthy humans

The effects of cisapride on jejunal interdigestive motor activity were studied in 12 healthy men participating in three experiments each. Five minutes after an activity front (phase III) they received, in random double-blind fashion, 10 mg of cisapride, 4 mg of cisapride, or saline placebo by intravenous injection. Motor activity was recorded for 4 h. A pneumohydraulic perfusion system and five catheters with orifices positioned 10-30 cm beyond the ligament of Treitz were used. Cisapride increased phase II-type activity (p less than 0.001) and reduced the number of activity fronts dose-dependently. Compared with phase II after placebo, the activity prevailing after cisapride was characterized by a significantly higher number and amplitude of contractions as well as by a significantly greater area under the pressure curve. Moreover, a significantly higher proportion of contractions was propagated aborally. Self-rated abdominal grumbling increased dose-dependently. Except for mild sedative effects, no side effects occurred. We conclude that cisapride induces a prolonged and highly propagative phase II-like jejunal motor activity in fasting humans.

Effects of oral cisapride on interdigestive jejunal motor activity, psychomotor function, and side-effect profile in healthy man

Intravenous cisapride was shown to induce a phase-2-like pattern of human interdigestive jejunal motor activity containing an increased number of propagated contractions. This study investigated the effects of oral cisapride in 12 fasting healthy males. Jejunal pressures were recorded by a pneumohydraulic system and five catheter orifices positioned 10–30 cm aborad the ligament of Treitz. Single oral doses of 5 and 10mg cisapride, administered 5 min after an activity front under random double-blind conditions, induced a phase-2-like jejunal motor pattern with a significantly higher number and amplitude of contractions and significantly more aborally propagated waves than placebo (P<0.001), while the number of subjects with activity fronts decreased with increasing dose. Five and 10mg cisapride administered tid for three days affected psychomotor function, subjective feelings, and side-effect frequency, apart from increases in systolic blood pressure and heart rate, no more than placebo. It is concluded that in fasting man, oral cisapride induces a highly propagative phase-2-like jejunal motor pattern causing only minor side effects.

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

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 aborad 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.

Effects of cisapride on postcibal jejunal motor activity

In the jejunum of fasting humans, cisapride induces a phase 2-like, highly propagative motor pattern. This study investigated cisaprides effects on the fed pattern of the jejunum. Starting 5 min after a phase 3 of the migrating motor complex, 18 healthy men received 5 or 10 mg cisapride or placebo orally in random double-blind fashion and ingested meals containing 1000 and 4200 kJ, respectively. Jejunal pressures were recorded pneumohydraulically with five catheter orifices 10–30 cm aborad the ligament of Treitz. After the 4200-kJ meal, total number and number of propagated contractions as well as area under the curve increased significantly more than after 1000 kJ. Following the 1000-kJ but not the 4200-kJ meal, 10 mg cisapride increased total number of contractions, number of propagated contractions, mean amplitude, and area under curve significantly more than placebo. Fed-pattern duration increased with the meals caloric content but was not influenced systematically by cisapride. In conclusion, cisapride stimulates jejunal motor activity and induces a propagative pattern after a 1000-kJ but not after a 4200-kJ meal, suggesting that it can produce no further stimulation when motor activity is near maximally enhanced already.

Effects of 3-days' intake of a sustained-release preparation of the nitric oxide donor, isosorbide dinitrate, on oesophageal motility

Nitric oxide plays an important role in gastrointestinal motility. We evaluated the effects of a sustained‐release preparation of the nitric oxide donor isosorbide dinitrate on swallow‐initiated oesophageal contractions and the lower oesophageal sphincter.

Esophageal Motor Abnormalities in Patients with Connective Tissue Diseases

Decreased contraction amplitudes in the smooth muscle esophagus and a decreased resting pressure of the lower esophageal sphincter (LOSP) are known to be common in progressive systemic sclerosis (PSS) and deficiencies in contraction strength of the striated muscle esophagus in polymyositis/dermatomyositis (PM/ DM). By contrast, only scarce information is available on esophageal activity in other connective tissue diseases. This study was aimed at evaluating esophageal motor activity in patients with a variety of such diseases diagnosed according to rigid criteria.