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This study aimed to assess, using multiple regression analyses, the roles of lower esophageal sphincter, esophageal contractile and transport function, hiatal hernia, age, sex, and body mass for esophageal acid exposure in upright and recumbent postures and for esophagitis. In 116 patients with reflux symptoms, acid exposure was recorded by 24-hr pH monitoring, motility manometrically, bolus transport scintigraphically, hiatal hernia and esophagitis endoscopically. In upright posture, the percentage time at pH <4 increased significantly with higher body mass index and lower distal esophageal amplitude, the number of episodes >5 min at pH <4 with lower distal amplitude, slower transport, and higher body mass, and the longest episode at pH <4 with lower distal amplitude. In recumbency, the percentage time at pH <4 increased with lower percentage of effective esophageal contraction waves and male sex, and the number of episodes and the longest episode with lower percentage effective waves. The severity of esophagitis augmented with slower supine transport and male sex. In both postures, acid exposure and esophagitis seem to be determined primarily by impaired esophageal motility and the ensuing slow bolus transport rather than by compromised lower esophageal sphincter function and the presence and size of a hiatal hernia.

Previous studies in diabetic patients suggested a relationship between delayed gastric emptying and increased ingesta retention in either proximal or distal stomach, but the determinants underlying these abnormalities remained obscure. We aimed at assessing the impact of cardiovascular autonomic neuropathy, blood glucose concentration, long-term glycemic control, and other factors in 34 type I and 43 type II diabetic patients (ages 21-67 and 34-81 years, respectively). Emptying was slower (P < 0.04) in type I diabetic patients than in 20 healthy control subjects (ages 23-63 years). Patients with autonomic neuropathy (N = 45) had slower gastric emptying (P < 0.02) and retained more in the distal stomach (P < 0.0001) than patients without neuropathy (N = 32). Multiple regression analyses revealed that slow emptying and increased distal retention were significantly associated with autonomic neuropathy (P < 0.043, P < 0.0002), whereas blood glucose, glycemic control, diabetes duration, age, and other factors had no discernible influence. Thus, both slow emptying and increased distal ingesta retention seem primarily referable to autonomic neuropathy.

Aims: To evaluate the impact of total and proximal stomach emptying on 24 hour and postprandial reflux as well as the number of reflux episodes per hour in relation to the impact of lower oesophageal sphincter (LOS) pressure, and oesophageal contractile and clearance function., Methods: Seventy one outpatients (37 female, 34 male; age 23-82 years) with symptoms suggestive of both delayed gastric emptying and reflux referred for further investigations participated in the study. Gastric emptying of a semisolid 1168 kJ meal and oesophageal clearance of a water bolus (supine) were recorded scintigraphically, reflux by 24 hour pH monitoring, and oesophageal motility manometrically., Results: Slow proximal but not slow distal or total stomach emptying correlated with increased 24 hour and postprandial acid exposure and increased number of reflux episodes/hour. No relationship was found between total or proximal emptying and LOS resting pressure, oesophageal contraction amplitude, percentage of failed contractions, or clearance. Multiple linear regression analyses showed that slow proximal emptying and low LOS pressure contributed significantly to both 24 hour (p=0.0007 and p=0. 0001) and two hour postprandial acid exposure (p=0.007 and p=0.0001). In contrast, the rate of total emptying contributed to neither 24 hour nor postprandial acid exposure., Conclusion: Our data suggest that in contrast with total stomach emptying, the rate of proximal stomach emptying contributes to the extent of 24 hour as well as postprandial acid exposure and the number of reflux episodes/hour.

Aims: 5-hydroxytryptamine3 receptor antagonists act antiemetically and slow colonic transit. This study evaluated effects of the high-affinity 5-HT3 antagonist, cilansetron, on fasting, meal-and anticholinesterase-stimulated phasic contractile activity of the human sigmoid colon as well as on bowel habits and stool consistency., Methods: Five female and seven male healthy volunteers received, during three 7 day periods separated by 7 day wash-out periods, 4 mg cilansetron, 8 mg cilansetron or placebo three times daily orally under random, double-blind, crossover conditions. On day 8 of each treatment period, motility 20-40 cm from the anal verge was recorded using five pressure sensors spaced at 5 cm intervals. After a basal 30 min, subjects swallowed a further dose of the scheduled treatment; 60 min later, blood was taken for the determination of plasma cilansetron levels. Thereafter, subjects ingested a 4200 kJ meal and 250 ml sweetened mallow tea (166 kJ); 90 min after meal onset, 1 mg neostigmine was administered intramuscularly and motility recording was continued for 60 min, Results: Phasic contractile activity and intraluminal base-line pressure increased postprandially and more so after neostigmine. With cilansetron, the area under the pressure curve as the primary outcome variable and the number of contractions were significantly greater than with placebo (P = 0.005), amplitude and duration of contractions and base-line pressure were not affected. The effects of the two cilansetron dosages did not differ. With cilansetron, stool tended to become firmer. No adverse effects were observed. Plasma levels were highest with 8 mg cilansetron., Conclusions: Cilansetron slightly augments meal-stimulated and markedly neostigmine-stimulated phasic motility of the sigmoid colon. When administered over 7 days, it tends to increase stool consistency and is well tolerated.

Aims/hypothesis: Hyperglycaemia that is induced short-term slows gastric emptying in healthy subjects and patients with diabetes mellitus. Little information is available on the impact of longer-lasting, naturally occurring blood glucose increases and their reduction to euglycaemic values. We studied the relation between gastric emptying and pre-prandial and postprandial blood glucose concentrations in patients with Type II (non-insulin-dependent) diabetes mellitus and secondary failure to respond to oral hypoglycaemic treatment (a) before readjusting hypoglycaemic therapy and (b) 1 week thereafter., Methods: We studied 9 female and 1 male patient (age 60-78 years, BMI 21.9-32.5 kg/m2, diabetes duration 3-33 years, HbA1c 8.8-13.2%). Gastric emptying of a radiolabelled semisolid 1168 kJ meal was recorded scintigraphically., Results: Blood glucose concentration pre-prandial and postprandial was considerably lower subsequent to than before therapy readjustment in all patients (fasting, 7.9 mmol/l+/-1.5 SD vs 11.7+/-1.7 mmol/l; 60 min postprandial, 11.7+/-2.0 vs 15.4+/-2.2 mmol/l). By contrast, gastric emptying was unchanged (residual radioactivity in stomach 50 min postprandial 65.7+/-14.1% vs 66.5+/-12.9%). There was no relation between emptying and either fasting blood glucose concentration or its postprandial increase., Conclusion/interpretation: The data do not support a major impact of actual, longer-lasting, naturally occurring blood glucose concentrations upon the rate of gastric emptying in patients with Type II diabetes.

In insulin-dependent diabetes mellitus, slow gastric emptying may make absorption unpredictable and foster glycemic instability. Cisapride accelerates emptying, but controlled long term studies are scarce, and effects on glycemic control unknown. We investigated, in patients with insulin-dependent diabetes mellitus and unstable glycemia, the effects of 10 mg cisapride 4 times daily for 8 weeks vs. placebo on glycemic control and gastric emptying under random, cross-over, double blind conditions. In 14 patients with delayed and 9 with nondelayed emptying, blood glucose variability over 28-week treatment periods separated by a 4-week wash-out and gastric emptying of a semisolid 1168-kJ meal immediately after the treatment periods were assessed. Cisapride did not affect glycemic control [SD of within-patient mean blood glucose, 4.2 mmol/L +/-0.1 (+/- SEM) vs. 4.0+/-0.1 mmol/L after placebo; hemoglobin A1c, 8.3+/-0.2% vs. 8.5+/-0.2%]. Emptying was faster after cisapride than after placebo in 8 of 14 patients with delayed vs. 7 of 9 with nondelayed emptying (P = NS) and in 11 of 15 without vs. 4 of 8 with cardiovascular autonomic neuropathy (P = NS). Autonomic neuropathy prevailed in 7 of 14 patients with delayed and 1 of 9 with nondelayed emptying. Blood glucose immediately before and during assessment of emptying was unrelated to the emptying rate, whereas blood glucose increases over fasting levels were greater with faster emptying (P<0.002). In conclusion, cisapride's effects were not different from those of placebo on glycemic control and gastric emptying, it did not differently affect patients with delayed vs. nondelayed emptying, and it slightly accelerated emptying (P = NS) in patients without, but not in those with, cardiovascular autonomic neuropathy. Blood glucose levels before and during assessment of emptying did not affect emptying, but the glucose rise over fasting levels was greater with faster emptying.

Background: The globus sensation has been widely regarded as psychogenic, but organic disorders were found to be etiologically significant., Objective: To investigate the structural, functional, psychological, and psychiatric factors possibly eliciting the globus sensation and influencing its course., Methods: Eighty-eight patients, 67 women and 21 men (aged 22-71 years), referred to 2 tertiary care centers underwent history taking, otolaryngological examination, pharyngoesophageal videofluoroscopy and manometry, psychosocial evaluation, psychometric tests, psychiatric interview, and when indicated, esophagogastroduodenoscopy, esophageal bolus transport, gastroesophageal reflux, and gastric emptying studies. According to revealed disorders, therapy was initiated, and the outcome was studied., Results: Only 15 patients had normal pharyngoesophageal function; of these 15, 6 had chronic tonsillitis or pharyngitis, 3 had thyroid adenomata, 4 had cervical spondylosis, and 1 each had dry oropharyngeal mucosa and chronic bronchitis. Of the other 73 patients, 2 had pharyngeal dysfunction, 24 had achalasia, 1 had diffuse esophageal spasms, 3 had "nutcracker esophagus," 30 had nonspecific esophageal motor disorders, and 13 had gastroesophageal reflux. Psychometry revealed no more anxiety and depression than in general medical outpatients. Of 58 patients interviewed, 37 met criteria for psychiatric disorders. Psychometric scores and psychiatric characteristics were unrelated to the sensation's course. Therapy was recommended, but only 26 patients were treated accordingly; 22 received nonspecific treatment. Follow-up 3 to 59 months later revealed that the sensation had vanished in 13 patients who had received specific treatment, 5 who had received nonspecific treatment, and 6 who had received no treatment; it was alleviated in 10 who had received specific treatment, 13 who had received nonspecific treatment, and 9 who had received no treatment; and it was unchanged in 3 who had received specific treatment, 5 who had received nonspecific treatment, and 23 patients who had received no treatment., Conclusions: Pharyngoesophageal disorders may be sensed only vaguely, inducing the globus sensation. Psychological and psychiatric characteristics could be relevant to the discomfort experienced but are unlikely to be etiologically significant.

Background: 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., Methods: Twelve healthy men, aged 23-32 years, received, at 1-week intervals and under random double-blind conditions, for 3 days either 20 mg isosorbide dinitrate, 40 mg isosorbide dinitrate or placebo twice daily (b.d.). One hour after a further dose on day 4, oesophageal motility was recorded for 30 min using a multilumen catheter with a Dent sleeve straddling the lower oesophageal sphincter and side-hole openings 0, 3, 6 and 9 cm proximal to the sleeve. Contractile responses to twelve 5-mL water swallows were evaluated., Results: Amplitude, duration, propagation velocity and onset latency of oesophageal contractions were not affected by either dosage of isosorbide dinitrate. Lower oesophageal sphincter resting pressure was significantly lower after 40 mg (15.1 mmHg +/- 1.2 S.E.M.) and 20 mg isosorbide dinitrate b.d. (15.0 +/- 1.0 mmHg) than after placebo (17.9 +/- 1.7 mmHg; P < 0.025). Headache was reported by all subjects on 40 mg isosorbide dinitrate, seven subjects on 20 mg and by one on placebo., Conclusions: Twenty and 40 mg sustained-release isosorbide dinitrate twice daily had no effect on swallow-initiated oesophageal contractions but decreased lower oesophageal sphincter resting pressure.

Background: Evidence has accumulated that nitric oxide is involved in the regulation of gastrointestinal motor activity. We investigated whether nitric oxide derived from a sustained-release isosorbide dinitrate (Cedocard retard) had an effect on gastric emptying and on subjective feelings., Methods: Twelve healthy males aged 23-32 years received at weekly intervals, for 3 days twice daily, either 20 mg isosorbide dinitrate, 40 mg isosorbide dinitrate, or placebo, under random double-blind conditions. After a further dose on day 4, subjects ate a 1168 kJ semisolid meal, the emptying of which was recorded scintigraphically for 50 min., Results: Neither dosage of isosorbide dinitrate had an effect on emptying which differed from the effect of placebo and the effects of the two dosages were the same. The radioactivity remaining in the stomach 50 min postprandially was 68.5% +/- 4.5 S.E.M. after placebo, 65.4 +/- 5.6% after 20 mg isosorbide dinitrate and 66.1 +/- 4.4% after 40 mg isosorbide dinitrate. With 40 mg isosorbide dinitrate, all 12 subjects complained of persistent headache, whereas only slight headache was reported by 7 subjects on 20 mg isosorbide dinitrate and by 1 subject on placebo., Conclusion: Twenty and 40 mg doses of sustained-release isosorbide dinitrate twice daily had no effect on the gastric emptying of a semisolid meal, but dose-dependently induced headaches.

Objective: To investigate whether autonomic neuropathy or hyperglycemia plays a crucial etiological role in gastric retention of ingesta frequently found in type I diabetic patients., Research Design and Methods: We investigated the gastric emptying of a radiolabeled semisolid 1,168 kJ meal in 38 female and 45 male patients (age 18-75 years; illness duration 3-46 years). None took drugs affecting gastrointestinal motility. Fasted patients underwent tests of cardiovascular autonomic and peripheral nerve function. Blood glucose levels were determined before and after the scintigraphic recording of gastric emptying., Results: The percentage of meal remaining in the stomach at the end of the 50-min recording time was related significantly to the patients' degree of cardiovascular autonomic neuropathy [r (81) = 0.235, P < 0.028] but not to their degree of peripheral neuropathy, preprandial blood glucose level, HbA1c indicative of glycemic control, diabetes duration, and age. The patients' mean residual percentage of meal was significantly greater than that of 48 healthy subjects, that is, 71.1 +/- 15.1 vs. 53.5 +/- 13.1% [means +/- SD; t (129) = 6.48, P < 0.0001]. The healthy individuals' mean residual percentage + 2 SD was exceeded in 22 patients., Conclusions: Slow gastric emptying in patients with type I diabetes seems related to the degree of autonomic neuropathy but not to peripheral neuropathy, actual blood glucose, and glycemic control.

Objective: To evaluate the outcomes of patients with achalasia who had undergone myotomy and an antireflux operation because dilatations had not yielded satisfactory results., Design: Retrospective analysis., Setting: University-based tertiary care center., Patients: Of 39 patients who met inclusion criteria, 18 female patients and 18 male patients (age range; 17-85 years; median age, 54 years; range of time elapsed since operation, 1-22 years; median time, 6 years) could be studied. Antireflux operations included 360 degrees fundoplications in 27 patients, anterior hemifundoplications in 5 and other procedures in 4., Main Outcome Measures: Dysphagia for solid foods and liquids, regurgitation, heartburn, retrosternal pain and body weight., Results: Excellent, good, and fair results of myotomy and antireflux operation were encountered in 14, 3, and 6 patients, respectively, and poor or absent results in the remaining 13 patients. The resting pressure of the lower esophageal sphincter was significantly lower at follow-up than preoperatively, and this was associated with reduced dysphagia for solid foods in 14 patients and for liquids in 16 of 17 patients., Conclusions: Myotomy and antireflux operation yielded excellent to fair results in 23 patients in whom dilatations had not facilitated swallowing. Poor results in the remaining 13 patients seemed to be attributable to the 360 degrees fundoplication performed in 12 of them. In these patients, a further surgical intervention seemed to be indicated.

Objective: The sensitivity of radionuclide bolus transport and videofluoroscopic studies to confirm manometrically revealed achalasia was investigated prospectively in 77 patients with symptoms indicative of disordered esophageal motor function., Methods: The studies were performed in random order and were analyzed blindly by strict diagnostic criteria. Transport of radiolabeled water was recorded for 2 min with patients supine. Videofluoroscopy assessed three swallows in prone oblique and one in upright position. Manometry employed four pressure sensors in the esophageal body and the Dent sleeve in the lower esophageal sphincter., Results: Radionuclide and videofluoroscopic studies confirmed 25 and 15, respectively, of 37 manometrically diagnosed achalasias and provided indications for the disorder in another 8 and 16 patients. Using information from both studies increased the sensitivity to detect achalasia from 68% and 41%, respectively, to 73%, and increased detection of disordered esophageal motor function from 81% and 74% to 92%., Conclusion: Radionuclide and videofluoroscopic studies represent valuable and complementary, although relatively insensitive, procedures to detect achalasia.

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.

Thirty consecutive patients with globus sensation who were referred to a psychosomatic clinic prospectively underwent otolaryngological, videokinematographic, and manometric examinations of pharynx and esophagus to evaluate whether morphological abnormalities or motility disorders underlay their symptom. When indicated by findings, 24-hour pH-metry, scintigraphy of bolus transport, and esophagogastroscopy were performed. Seven patients were shown to have achalasia, 10 had "hypochalasia" (lower esophageal sphincter relaxation less than 75% with esophageal contraction abnormalities but no complete distal aperistalsis), and 1 had diffuse esophageal spasms; 2 patients had also hyperplastic lingual tonsils, 1 had tonsillitis, and 1 had a cervical spondylophyte. Nutcracker esophagus and nonspecific contraction abnormalities were found in 7 patients, and gastroesophageal reflux with esophagitis and a low lower esophageal sphincter resting pressure was found in 1; only 3 patients had normal esophageal motility. None had volunteered dysphagic symptoms at primary evaluation. Psychometric investigations in consenting patients showed no higher mean scores for state and trait anxiety, depression, hysteria, and hypochondriasis than in general medical outpatients. Esophageal motor disorders may, before giving rise to dysphagia, be sensed more vaguely and induce the globus sensation. However, only disappearance of the sensation after treatment allows inferring an etiological significance of such a disorder.

The evaluation of agents potentially accelerating gastric emptying in gastric stasis syndromes is time-consuming. Since a previous study showed that emptying is slowed after antecedent fat ingestion and intravenous cisapride abolishes this effect, we investigated whether emptying delayed by fat incorporated into a meal is reversed by cisapride and thus could serve as a model for such evaluations. Twelve healthy males received, under double-blind conditions, 30 mg cisapride rectally or placebo, and 3 hr thereafter a semisolid meal of low (9.2 g) or high (37.9 g) fat content. The sequence of combinations placebo/low-fat meal, placebo/high-fat meal, and cisapride/high-fat meal was randomized. Gastric emptying and antral motility were recorded scintigraphically. After placebo/high-fat, emptying was significantly slower (P less than 0.05) than after placebo/low-fat. After cisapride/high-fat, emptying was significantly faster (P less than 0.01) than after placebo/high-fat and similar to that after placebo/low-fat. Antral motility was little affected. The slow emptying of a high-fat meal thus seems a suitable model for the evaluation of prokinetic drug effects.

The selective 5-HT3 receptor antagonist, ICS 205-930 (Sandoz), has potent effects on gastrointestinal motor activity in vitro and in vivo. This double-blind, crossover study compared the effects of 20 mg of ICS 205-930 infused intravenously with those of a placebo on the motor activity of the oesophageal body and the lower oesophageal sphincter (LOS). Each of twelve healthy young men participated in two recording sessions one week apart. Oesophageal pressures were recorded using a catheter assembly with orifices 2, 5, 8, 11, and 14 cm above the oral border of the LOS and a Dent sleeve for measurement within the LOS. During and after the infusion of ICS 205-930, amplitude and duration of swallow-initiated contractions in the smooth muscle oesophagus increased slightly, the area under the curve as a measure of contraction strength being significantly greater than after placebo (P less than 0.05). LOS resting pressure increased slightly during ICS 205-930 infusion and was significantly higher than it was in the case of the placebo (P less than 0.001). Propagation velocity of contractions, incidence of tertiary contractions and relaxation of LOS upon swallowing remained unaffected. ICS 205-930 was well tolerated. It is concluded that ICS 205-930 has slight but distinct stimulatory effects on contraction strength in the smooth muscle oesophagus and LOS resting pressure.

1. The selective 5-HT3 receptor antagonist, ICS 205-930 (Sandoz), has been reported to have potent effects on gastric smooth muscle in vivo and to enhance gastric emptying in animals and in man. 2. This study investigated the effects of ICS 205-930 on fat-delayed gastric emptying of a semisolid meal and antral motor activity in humans. 3. Twelve healthy men participated in each of three studies in which 10 or 20 mg of ICS 205-930 or placebo were infused i.v. in a random double-blind fashion. Gastric emptying and antral motor activity were studied scintigraphically. 4. Gastric emptying was not altered after 10 mg but slower after 20 mg of ICS 205-930 than after placebo. Emptying after 20 mg of ICS 205-930 was significantly slower than after 10 mg of ICS 205-930. 5. Antral contraction amplitude was slightly lower after 20 mg of ICS 205-930 than after placebo, whereas the effects of 10 mg ICS 205-930 did not differ from those of placebo. 6. The results suggest that the investigated doses of ICS 205-930 have only slight effects on gastric motor activity of healthy young men, with 20 mg reducing the rate of emptying.

Previous studies showed that symptoms of oesophageal motor disorders can be misinterpreted as indicating anorexia nervosa and that in primary anorexia nervosa gastric motility is frequently impaired. We investigated in 32 women with bulimia nervosa whether symptoms of oesophageal motor disorders could be obscured by or be mistaken as forming part of bulimic behaviour, and whether impaired gastric motility was frequent as well. Oesophageal motility was normal in 18 of 26 patients studied, another four had incomplete lower oesophageal sphincter relaxation. Two patients had vigorous achalasia and each one achalasia and diffuse oesophageal spasm, all of whom experienced two types of vomiting: one self-induced and one involuntary, in which the vomit was non-acidic and tasted as the preceding meal. Gastric emptying of a semisolid meal was studied in all patients except of the eight with oesophageal motor abnormalities. Emptying was significantly slower than in healthy controls and grossly delayed in nine of 24 patients. Antral contraction amplitudes were lower and increased less postcibally than in controls. In conclusion (i) bulimic behaviour can obscure symptoms of oesophageal motor disorders and (ii) gastric emptying is frequently delayed in bulimia nervosa.

In the jejunum of fasting humans, cisapride induces a phase 2-like, highly propagative motor pattern. This study investigated cisapride's 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 aboard 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 meal's 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.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

1. Ro 15-8081 (Hoffmann-La Roche, Basle, Switzerland) is a novel mixed 5-HT/noradrenaline uptake inhibitor producing potent antinociceptive effects in animal pain models. 2. In healthy man, two models with electrically and thermally induced pain, respectively, have been shown to reliably discriminate between the effects of opioid as well as of antipyretic analgesics and placebo. 3. This study investigated the effects of single oral doses of 10, 25, and 50 mg Ro 15-8081 in comparison with 60 mg codeine and placebo on threshold and tolerance to electrically induced pain and on threshold to thermally induced pain. Furthermore, the effects on psychomotor function, self-rated subjective feelings, and side effect profile were studied. 4. Twenty healthy males participated each in five experiments in which they received, in random double-blind fashion, each of the treatments. Every experiment comprised two series of measurements before and twelve after drug administration, carried out at 30 min intervals. 5. Ro 15-8081 produced marked elevations of threshold and tolerance to electrically and of threshold to thermally induced pain. The effects of all doses of Ro 15-8081 were significantly superior to those of placebo. Threshold and tolerance to electrically induced pain were not affected differently by the three doses of Ro 15-8081, whereas the threshold to thermally induced pain was elevated significantly more by 50 mg than by 10 and 25 mg Ro 15-8081. 6. Codeine 60 mg had a more rapid onset of action and greater maximal effects than Ro 15-8081.(ABSTRACT TRUNCATED AT 250 WORDS)

1. ICS 205-930 (Sandoz) is a selective antagonist at 5-hydroxytryptamine3 receptors and exerts marked effects on gastrointestinal motility in animals. 2. This study investigated, under random double-blind conditions, the effects of 10 and 20 mg ICS 205-930 infused intravenously in comparison with placebo on colonic motor activity. 3. Twelve healthy men participated each in three studies in which they received, in random double-blind fashion, each of the treatments. Colonic pressures were recorded pneumohydraulically with four catheter orifices 20-40 cm from the anal verge. Treatments were administered after a basal 30 min. One hour later, subjects ingested a 4200 kJ meal and 90 min thereafter, 1 mg neostigmine was administered intramuscularly and recording continued for another 90 min. 4. After both doses of ICS 205-930, the number of contractions as averaged over the entire recording time was slightly but significantly higher than after placebo. 5. After 10 mg but not after 20 mg ICS 205-930, amplitude of contractions and area under the curve as averaged over the entire recording time were significantly higher than after placebo. 6. ICS 205-930 induced few and mild side effects, but significantly more self-rated drowsiness and tiredness than placebo.