Digestive Diseases and Sciences, Vol. 36, No. I (Januao' I991), pp. 52-58

Visceral Perception in Health and Functional Dyspepsia Crossover Study of Gastric Distension with Placebo and Domperidone 9 M A R C B R A D E T T E , MD, P I E R R E P A R E , MD, F R C P C , P I E R R E D O U V I L L E , MD, F R C P C , and A N D R E E M O R I N , RN

The symptoms of functional dyspepsia are still unexplained. To evaluate the possible role of abnormal visceral perception, we studied the symptomatic responses and the pressure variations during progressive gastric distension in lO female healthy control subjects (mean age 33.6 years) and in lO female patients with functional dyspepsia (mean age 35.2 years). A rubber balloon was positioned 4 cm below the lower esophageal sphincter (LES) and inflated with progressively larger volumes of air by steps o f 50 ml; pressures at the gastric fundus and at the LES were continuously recorded by perfused manometric catheters. Each subject was studied on two separate occasions after randomized double-blind administration of either placebo or 20 mg o f domperidone. Symptomatic responses and the manometric data were analyzed at the time o f the initial recognition of distension (bloating step) and at the time of reporting pain or up to a maximum of 700 ml of balloon inflation (pain or 700-ml step). On placebo, the volumes o f gastric distension were more than two times lower in patients than in control subjects at the bloating step (185 +- 32 ml vs 470 +- 40 ml, P = 0.001) and at the pain or 700-ml step (265 +_54 ml vs 600 +- 34 ml, P < 0.005), while the pressure gradients (pressure at inflation steps minus baseline pressure before beginning inflation) were not statistically different between the two groups. On domperidone, the volumes at each of the two steps did 9not change in comparison to results on placebo except in healthy controls at the bloating step (470 +_40 ml on placebo vs 355 +_35 ml on domperidone, P < 0.001); however, there was a trend for pressure gradients to increase on domperidone in comparison to results on placebo. We conclude that patients with functional dyspepsia have a lower threshold both to the initial symptomatic recognition and to perception of pain during gastric distension and that domperidone might have an effect on the threshold of these conscious visceral sensations. This increased visceral perception may alone or w#h other abnormalities of the gastroduodenal tract explain the symptoms of functional dyspepsia. KEY WORDS: functional dyspepsia; essential dyspepsia; nonulcer dyspepsia; domperidone.

Manuscript received June 13, 1990; revised manuscript received August 22, 1990; accepted August 30, 1990. From the Division of Gastroenterology, Department of Medicine, H6tel-Dieu de Qu6bec Hospital, Laval University, Qu6bec, Canada. This study was supported in part by a grant from Janssen Pharmaceutica Inc., Canada. Address for reprint requests: Dr. Pierre Par6, H6tel-Dieu de Qu6bec, 11, C6te du Palais, Quebec, P.Q., Canada GIR 2J6.

52

Functional d y s p e p s i a is a relatively c o m m o n condition (1,2), and yet its cause is still u n k n o w n . The terms refer to d y s p e p s i a in which clinical evaluation fails to reveal organic or structural abnormalities in the upper gastrointestinal tract; the synd r o m e includes various s y m p t o m s of at least three m o n t h s ' duration, such as epigastric fullness or Digestive Diseases and Sciences, Vol. 36, No. 1 (January I991)

0163-2116/91/0100-0052506.50/0 ~f~ 1991 Plenum Publishing Corporation

GASTRIC VISCERAL PERCEPTION bloating after meals, early satiety, feeling of slow or r e t a r d e d digestion, nausea, and/or vomiting (3,

4). Recently, studies have d e m o n s t r a t e d abnormalities in the gastrointestinal function of m a n y of these patients. Myoelectric abnormalities presenting as t a c h y a r r h y t h m i a or tachycardia of the gastric pacem a k e r and abnormalities of the gastroduodenal motility have been described (5-8). Delayed gastric emptying of solids and liquids has been reported and is often clinically regarded as the cause of the s y m p t o m s (9-13). H o w e v e r , these abnormalities are not universal, and no relationship exists bet w e e n the degree of delay in gastric emptying and t h e severity of the s y m p t o m s (10-12). This suggests that the s y m p t o m s in functional dyspepsia are related to abnormalities in gastric function other than delayed gastric emptying alone. The role of emotional or psychological factors, although difficult to analyze, has been studied, but this c o m p o n e n t seems insufficient by itself to fully explain the s y n d r o m e (14, 15). The objective o f this study was to evaluate the s y m p t o m a t i c response and the m a x i m u m tolerance to gradually increasing gastric distension in patients with functional d y s p e p s i a and in healthy control subjects. D o m p e r i d o n e , a drug currently used and potentially effective in treating this condition (16), was introduced in a double-blind c r o s s o v e r design with a placebo, since the results were based on subjective visceral sensations. We speculated that patients with functional d y s p e p s i a might have a lower gastric threshold to recognize and/or to tolerate visceral distension as already described in patients with irritable colon s y n d r o m e (17) and in patients with idiopathic esophageal colic s y n d r o m e (18).

M A T E R I A L S AND M E T H O D S Patients and Healthy Controls. Ten patients and 10 control subjects, all female, were studied. The patients were referred to the gastroenterology clinic primarily for chronic dyspeptic symptoms: all had the diagnosis of functional dyspepsia based on symptoms of epigastric bloating or fullness after meals, a feeling of slow digestion and early satiety with or without epigastric pain, nausea, or vomiting. All patients had to have a normal esophagogastroduodenoscopy and ultrasound examination of the upper abdomen to be eligible for entry into the study. Patients with a history of peptic ulcer disease, or complaining of heartburn, dysphagia, or chest pain, or having had previous gastrointestinal surgery, or taking nonsteroidal antiinflammatory drugs were excluded. Patients Digestive Diseases and Sciences, Vol. 36, No. 1 (January 1991)

were otherwise healthy and free of any endocrine, neurologic, muscular, or collagen-vascular disease. Although all patients consulted with the chief complaint of dyspepsia, careful medical history elicited symptoms of irregular bowel habit and abdominal cramps in four of the 10 subjects. No specific investigation was performed in the 10 control volunteers who were healthy subjects free of any gastrointestinal symptoms. None were taking medication. No patients or control subjects had a past or present history of psychological distress. Evaluation for psychiatric disease included a Minnesota Multiphasic Personality Inventory (MMPI) test that was performed within one month after the completion of the study. These tests were analyzed blindly by a clinical psychologist. The two groups showed similar clinical characteristics: age of 33.6 --- 9.2 years and of 35.2 +- 8.1 years, height of 163 - 4.2 cm and of 162 --- 4.0 cm, and weight of 57 -+ 5.8 kg and of 60 -+ 9.1 kg in the control group and the patient group, respectively. There was one smoker in each group. The study was approved by the Clinical Research Review Board of Hrtel-Dieu de Qurbec Hospital in 1987. Written informed consent was obtained from all participating subjects. Instrumentation. The manometric probe consisted of four tubes, one connected to a rubber balloon (bag D-110/B, Clay-Adams Inc., New York) at the tip of the catheter and three for monitoring pressure changes at three different sites: the distal port was located 2 cm above the balloon connection for measuring intragastric pressure, the middle port at 4 cm above the balloon located at the gastric side of the lower esophageal sphincter, and the proximal port at 8 cm above the balloon in the lower esophagus. The lumens of these three manometric probes were connected via strain-gauge transducers (model P 23 Dd, Gould Inc., Medical Products Division, Oxnard, California) and capillary tubes to an infusion pump (model 975, Harvard Apparatus Co. Inc., Millis, Massachusetts) perfusing distilled water at room temperature at 0.15 ml/min. Electrical impulses were registered on a paper chart recorder (model MSPM macropolygraph, Gilson Medical Electronic Inc., Middleton, Wisconsin). During the study period, three balloons were used for air inflation and were verified before each experiment by measuring the displacement of 70 ml of distilled water placed in a graduated cylinder at two different volumes: the coefficients of variation on 40 readings were 0.7% and 0.8% for balloon inflations at 50 and 70 ml, respectively. Experimental Design and Procedure. Each of the subjects was asked not to take any medications known to have an effect on gastrointestinal motility for at least 48 hr prior to the study. No medication of any type was allowed 12 hr prior to the study. After an overnight fast, each control subject and each patient was given either two tablets of 10 mg of domperidone or matching placebo (randomized, double-blind) 15 min prior to intubation. The study was then repeated four to six weeks later using the alternate medication. During the period 0-5 min after intubation, subjects were placed supine in bed, head elevated at a 30~ angle, and the catheter was positioned with the balloon in the

53

BRADETTE ET A L B L O A T I N G STEP

800

B L O A T I N G STEP

P A I N O R 700 m l STEP

P A I N OR 700 m l S T E P

--r

. . . .

100 ~ ;

] i !

600

20

,00

~a

I

400 L

I 200

200

0

-I0

CD

CP

PP

GROUP

PD

CD

'

'

CP

PP

-

-

PD

GROUP

0 CD

CP

PP

~-PD

-I0

GROUP

CD

CP

PP

PD

GROUP

Fig 1. Median and 95% confidence intervals for results on volume and on pressure gradient at the bloating step and at the pain or 700-ml step. (CD = controls on domperidone, CP = controls on placebo, PP = patients on placebo, PD = patients on domperidone). fundus of the stomach by localizing the lower esophageal sphincter; the catheter was then fixed to the lower lip for the rest of the study. An observation period of 5 min followed (time 5 - t 0 min) to measure the baseline pressure, and at 10 min, a sham inflation was performed. At 15 min, the inflation began and was performed by successive increments of 50 mi without deflating the balloon between steps. F o r the first 300 ml, the inflations were maintained for 2 min and beyond 300 ml, the inflations were performed every 4 min. The subjects were not advised of inflation steps, and they could not see the examiner performing the distension. Immediately prior to the beginning of the experiment, subjects were given written information requesting them to advise the examiner of the first time they would recognize epigastric or upper abdominal discomfort of any type (bloating step since it usually consisted of bloating, fullness, or a blockage sensation). At no time during the procedure did the examiner suggest or inform of the subject's condition. Once the first symptomatic response was reported, the experiment was continued by successive inflations up to a maximum of 700 ml or until the subject felt a sensation of pain in the upper abdomen (pain or 700-ml step). After this second step had been completed, the balloon was deflated and the subject moved to the radiology department where the balloon was reinflated to the volume reported at the first symptomatic response. A plain film of the abdomen then was taken, with the subject in the supine position, to measure the greatest horizontal diameter of the balloon, and this ended the study. Analysis of Data. Pressure activity in the fundus of the stomach recorded in the manometric tracing was measured manually with a planimeter as the area under the curve for 30 sec at baseline and for each 30-sec period immediately following every 50-ml inflation of the balloon. Pressure changes were all expressed as the gradient variations in relation to baseline pressure (pressure at

54

inflation steps minus the baseline pressure). On the plain abdominal radiographic film taken at the bloating step, the longest horizontal diameter of the inflated gastric balloon was measured to make a calculated estimate of the gastric wall tension using the formula of the Laplace's law (tension is proportional to the pressure gradient • the radius of the inflated balloon divided by two). Statistical Analysis. Differences between groups were first analyzed by multiple-way analysis of variance with volume, pressure gradient, diameter, and variation in calculated tension at the bloating step. F o r the pain or 700-ml step, only volume and pressure change were available to analyze due to the study design. Thus, six analyses were made with the following independent variables: group + individuals (controls) + individuals (patients) + drug + sequence of the two experiments. This last factor was included to verify the potential learning effect of the first session on the second one. Since the study was relatively small, interaction terms were not considered in the model. The results of the multiple-way analysis of variance were consistent with standard two-tailed unpaired and paired (when appropriate) t tests. The statistical analysis was accomplished with the software Systat from Systat, Inc. (Evanston, Illinois 60201). Demographic data are expressed as mean +--s o of the mean. In tables, data are expressed as mean -+ sE from the mean. Figure 1 shows the median and its 95% confidence interval for volume and pressure gradient at the bloating step and at the pain or 700-ml step; in general, lack of overlap of the vertical bars between two groups indicates a significant difference. Differences in frequency of abnormalities or observations between groups were analyzed by F i s h e r ' s exact test. RESULTS F o r the p l a c e b o a n d d o m p e r i d o n e p h a s e s o f t h e s t u d y , the m e a n v o l u m e s at t h e b l o a t i n g s t e p a n d at Digestive Diseases and Sciences, Vol. 36, No. 1 (January I991)

GASTRIC

VISCERAL

PERCEPTION

TABLE 1. RESULTS OF EXPERIMENTS ON PLACEBO AND ON DOMPERIDONE IN HEALTHY CONTROLS AND IN PATIENTS (MEAN + SE)

Controls

Bloating step Volume (ml) Diameter (cm) Pressure gradient (cm2/30 sec) Tension variation(units) Pain or 700-ml step Volume (ml) Pressure gradient (cm2/30 sec)

Patients

Domperidone

Placebo

355 • 35(1)* 11.6 - 0.6 7.9 • 1.8

470 • 40 (2) 11.9 -- 0.3(3) 4.0 - 2.9

23.1 •

6.1

12.1 m 7.9

585 • 25 8.5 -+ 2.1

600 • 34 (4) 8.9 -- 3.1

Placebo 185 +- 32 8.8 • 0.6 4.8 -+ 1.7 . 10

•

3.3

265 -~ 54 4.1 • 1.8

Dornperidone 175 - 30 8.5 -+ 0.6 7.0 • 2.3 15.6•

5.7

360 • 79 13.3 -+ 3.9

*Difference b e t w e e n groups in j u x t a p o s e d c o l u m n s is statistically significant: (1) P < 0.001; (2) P = 0.001; (3) P = .002; (4) P < 0.005.

the pain or 700-ml step were markedly lower in patients than in healthy controls, while the manometric data were not statistically different (Table 1 and Figure 1). In healthy control subjects, the volume at the bloating step decreased significantly after domperidone treatment, while the increases in pressure gradient and i n variation of calculated tension were not statistically significant. At the pain or 700-ml step, there were no significant differences in volume and pressure gradient when healthy subjects received placebo or domperidone. In patients, the volume at the bloating step remained unchanged during domperidone treatment in comparison to placebo, while the increases in volume and in pressure gradient at the pain or 700-ml step were not statistically significant. Results of the multivariate statistical analysis are reported in Table 2. The predominant importance of the group under study, healthy controls vs patients, is clearly shown for volume of gastric distension at the bloating step and at the pain or 700-ml step, but there was no group effect on the pressure gradient. Administration of domperidone had a significant

effect only at the bloating step, and this was due to the results in healthy controls. The sequence of the experiments, placebo in the first or in the second study, had no effect on the volumes but affected the pressure gradient significantly at the pain or 700-m! pain step; there was also a trend towards a significant effect of order on these observations at the bloating step. During the experiments, all subjects except one control reported an initial nonpainful symptom; nine patients and six controls experienced epigastric or upper abdominal pain at or before distension to 700 ml of the gastric balloon. For volumes ~there was a strong correlation between results of the first experiment and those of the second experiment, at the bloating step (r = 0.78, P < 0.001) and at the pain or 700-ml step (r = 0.73, P < 0.001), consistent with a high degree of reproducibility in both groups. Analysis of the MMPI tests demonstrated definite abnormalities in seven of the 10 patients and in one of 10 healthy controls (Fisher's exact test, P = 0.02) Somatization was found in all seven patients, anxiety

TABLE 2. EFFECT OF INDEPENDENT VARIABLES ON RESULTS OBTAINED FOR VOLUME AND PRESSURE GRADIENT AT BLOATING STEP AND PAIN OR 700-ME STEP (EXTRACTS OF DATA FROM ANALYSIS OF VARIANCE)

Pain or 700-ml step

Bloating step F ratio Volume Group Domperidone Sequence of experiments P r e s s u r e gradient Group Domperidone S e q u e n c e of experiments

124.5 9.0 0.36

0.005 3.0 3.6

Digestive Diseases and Sciences, Vol. 36, No. I (January 1991)

P value < 0.000001 0.007 0.55

0.98 0.10 0.7

F ratio 62.6 1.3 0.5

0.0001 2.9 8.6

P value < 0.0001 0.27 0.49

0.99 0.10 0.009

55

BRADETTE ET AL in six patients and the control subject, hypochondria in three patients, and depression in two patients. DISCUSSION Our results show that female patients with functional dyspepsia have a strikingly lower threshold both to the onset of symptomatic recognition and to visceral perception of pain during gastric distension as compared to healthy female control subjects. The volume of gastric distension needed to produce this subjective response was twice as low in patients as compared to the volume needed to produce the same effect in healthy subjects. Dederding et al found that epigastric pain but not the initial sensation generated by gastric distension differed significantly between patients and controls (19). Their experiment involved deflating the balloon between steps, while our procedure of gradual and progressive distension of the stomach more closely resembles the effect of ingesting a meal. By investigating the response to isobaric gastric distension with an electronic barostat, Mearin et al (20) found that patients had a higher perception score than control subjects: this measurement more likely comprises a continuum of symptomatic response which gave results similar to ours. Gastric distension stimulates more than one kind of enteric receptor (21). For instance, receptive relaxation of the stomach is a vagovagal reflex of the parasympathetic nervous system with minimal central processing (22). Because only a few subjects were able to tolerate the increasing size of the gastric balloon, we were unable to validly analyze this reflex. However, preliminary data (19, 20, 23) show that the pressure-to-volume relationships during gastric distension are not different between patients with functional dyspepsia and controls, implying that the mechanism of receptive relaxation of the proximal stomach functions normally in these patients. On the o t h e r hand, the same form of stimulation is associated with a lower threshold of response regarding a conscious perception mediated by the sympathetic nerves (24). Although our estimated measurement of gastric wall tension is not necessarily representative of true muscle tone (21), pressure and tension variations at the time of eliciting symptoms were not different between controls and patients, suggesting that intrinsic myogenic tone was not increased in patients in comparison to healthy subjects. Therefore, this lower threshold of visceral perception in patients with

56

functional dyspepsia is probably the result of abnormal and increased sensitivity of the gastric nociceptive system, peripherally and/or centrally. Similar observations of lower threshold levels of pain without increased visceral pressure have been reported in other areas of the gastrointestinal tract such as in patients with esophageal colic syndrome (18) and in patients with spastic colon (17). The role of psychological factors and stress in patients with functional dyspepsia remains unclear (4). One study involving a large number of subjects (76 patients and 76 controls) reported psychological abnormalities more frequently in patients than in controls, but the absolute differences were small, suggesting that these factors were of minor importance (15). In a small number of subjectsl Lemann et al (23) found, as in our study, a high frequency of abnormal psychological traits in patients with functional dyspepsia. Furthermore, our analysis identified somatization and anxiety as the predominant abnormalities. These observations suggest that some specific types of psychological influence, rather than general behavior, might be important in patients with functional dyspepsia, at least at the time these patients seek medical consultation. The pharmacological therapy of functional dyspepsia has focused on gastrokinetic drugs since it has been thought that retarded gastric emptying is the cause of the symptoms (16). Domperidone is known to antagonize the dompamine effect on the gastric fundus (28) and to increase pressure and tension of the gastric wall by inhibiting the receptive relaxation of the proximal stomach (29). Indeed, during symptomatic distension of the gastric balloon, we observed a trend for the pressure gradient to become higher on domperidone in comparison to the results on placebo. In healthy controls, this effect was associated with a decrease in the volume of gastric distension needed to cause the initial symptomatic response but with no change in the volume needed to elicit pain. In patients, there was no significant change in the symptomatic volumes after domperidone treatment. As shown for gut responsiveness in irritable bowel syndrome (30), the effect of a drug in functional dyspepsia patients was qualitatively different from that in controls. It is thus possible that while receiving domperidone some subjects could tolerate higher pressure and tension of the gastric wall before signaling a symptomatic response. Domperidone might decrease the symptoms of these patients by keeping the volume of distension of the proximal Digestive Diseases and Sciences, Vol. 36, No. I (January 1991)

G A S T R I C V I S C E R A L PERCEPTION s t o m a c h s m a l l e r t h r o u g h a m o r e r a p i d solid- and l i q u i d - p h a s e g a s t r i c e m p t y i n g rate (31). M o r e o v e r , if g a s t r i c wall p r e s s u r e o r t e n s i o n r a t h e r than dist e n s i o n p e r s e is t h e p h y s i o l o g i c a l s t i m u l u s o f s e n Sation, t h e t h e r a p e u t i c effect o f the d r u g m i g h t involve modulation of conscious gastric perception by increasing the threshold of symptomatic recognition of visceral distension. In conclusion, patients with functional dyspepsia h a v e a l o w e r t h r e s h o l d to v i s c e r a l p e r c e p t i o n f o r both nonpainful and painful sensations during gast r i c d i s t e n s i o n . T h i s r e s p o n s e is p r o b a b l y the r e s u l t of increased sensitivity of the nociceptive system of t h e p r o x i m a l s t o m a c h ; d o m p e r i d o n e might h a v e an effect o n t h e t h r e s h o l d o f this s y m p t o m a t i c v i s c e r a l perception. This abnormal visceral sensation, alone o r in c o n j u n c t i o n with o t h e r a b n o r m a l i t i e s o f t h e gastroduodenal tract, may explain the symptoms of functional dyspepsia.

ACKNOWLEDGMENTS The authors thank Mr. Steven Lyco (Senior Medical Development Associate, Janssen Pharmaceutica Inc., Canada), Mr. Yves Julien (clinical psychologist), Dr. Marc Dorion (radiologist), and Mr. Paul E. Gregoire (laboratory technician) for their assistance and Mrs. Rachel Simard for her expert secretarial support.

REFERENCES I. Saunders JHB, Oliver RJ, Higson DL: Dyspepsia: Incidence of nonulcer disease in a controlled trial of ranitidine in general practice. Br Med J 292:665-668, 1986 2. Thompson WG: Nonulcer dyspepsia. Can Med Assoc J 130:565-569, 1984 3. Camilleri M, Thompson DG, Malagelada J-R: Functional dyspepsia. Symptoms and underlying mechanism. J Clin Gastroenterol 8:424-429, 1986 4. Talley N J, Phillips SF: Non-ulcer dyspepsia: Potential causes and pathophysiology. Ann Intern Med 108:865-879, 1988 5. You CH, Lee KY, Chey WY, Menguy R: Electrogastrographic study of patients with unexplained nausea, bloating, and vomiting. Gastroenterology 79:31 I-314, 1980 6. You CH, Lee KY, Chey WY: Gastric electromyography in normal and abnormal states in humans. In Functional Disorders of the Digestive Tract. Y Chey (ed). New York, Raven Press, 1983, pp 167--173 7. Chey WY, You CH, Lee KY, Menguy R: Gastric dysrythmia: Clinical aspects. In Functional Disorders of the Digestive Tract. WY Chey (ed). New York, Raven Press, 1983, pp 175-181 8. Malagelada )-R, Stanghellini V: Manometric evaluation of functional upper gut symptoms. Gastroenterology 88:12231231, 1985 9. Jian R. Ducrat F, Piedeloup C, Mary JY, Najean Y, Bernier J J: Measurement of gastric emptying in dyspeptic patients: Digestive Diseases and Sciences, Vol. 36. No. I (January 1991)

10.

I1.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21. 22.

23.

24. 25. 26.

Effect of a new gastrokinetic agent (cisapride). Gut 26:352358, 1985 da Rocha AFG. Zuccaro AM, Marquiotti M: Relationship between severity of clinical symptoms and delay in gastric emptying in chronic gastritis; studied with 99mTc-DTPA scintigraphy. Eur J Nucl Med 12:91-95, 1986 Talley~NJ, Shuter B, McCrudden G, Jones M, Hoschl R, Piper DW: Lack of association between gastric emptying of solids and symptoms in nonulcer dyspepsia. J Clin Gastroenterol 11:625-630, 1989 Jian R, Ducrat F, Ruskone A, Chaussade S, Rambaud JC, Modigliani R, Rain JD, Bernier J J: Symptomatic, radionuclide and therapeutic assessment of chronic idiopathic dyspeps!a. A double-blind placebo-controlled evaluation of cisapride. Dig Dis Sci 34:657-664, 1989 Wegener M, Borsch G, Schaffstein J, Reuter C, Leverkus F: Frequency of idiopathic gastric stasis and intestinal transit disorders in essential dyspepsia. J Clin Gastroenterol 11:163-168, 1989 Talley N J, Fung LH, Gilligan IJ, McNeil D, Piper DW: Association of anxiety, neuroticism, and depression with dyspepsia of unknown cause. A case-control study. Gastroenterology 90:886-892, 1986 Talley N J, Piper DW: Major life event stress and dyspepsia of unknown cause: A case control study. Gut 27:127-134, 1986 Dobrilla G, Comberlato M, Steele A, Vallaperta P: Drug treatment of functional dyspepsia. A recta-analysis of randomized controlled clinical trials. J Clin Gastroenterol 11:167-177, 1989 Ritchie J: Pain from distension of the pelvic colon by inflating a balloon in the irritable colon syndrome. Gut 14:125-132, 1973 Ritchter JE, Barish CF, Castell DO: Abnormal sensory perception in patients with esophageal chest pain. Gastroenterology 91:845-852, 1986 Dederding JP, Lemann M, Jian R, Rambaud JC: Study of sensory perception and adaptation to distension of prox!mal stomach in chronic idiopathic dyspepsia. Gastroenterology 94:91A, 1988 Mearin F, Cucala M, Azpiroz F, Malagelada J-R: Origin of gastric symptoms in functional dyspepsia. Gastroenterology 96:337A, 1989 Leek BR: Abdominal and pelvic visceral receptors. Br Med Bull 33:163-168, 1977 Ewart WR: Gut-brain-gut: Action or reaction? In Nerves and the Gastrointestinal Tract. MV Singer, H Goebell (ed). Boston, MTP Press Limited. 1989, pp 333-343 Lemann M, Dederding JP, Jian R, Flouri6 B, Franchisseur C, Rambaud JC: Abnormal sensory perception to gastric distension in patients with chronic idiopathic dyspepsia--the irritable stomach. Gastroenterology 96:294A, 1989 Klish WJ: Visceral pain. In Functional Disorders of the Digestive Tract. WY Chey (ed). New York, Raven Press, 1983, pp 237-243 McMahon TP, Tichter JE: Non-cardiac chest pain (NCCP) and irritable bowel syndrome (IBS): 1. Part of a continuum? Gastroenterology 90:1546A, 1986 Clouse RE, Eckert TC: Gastrointestinal symptoms of patients with esophageal contraction abnormalities. Dig Dis Sci 31:236-240, 1986

57

B R A D E T T E ET A L 27. Stark GA, McMahon TP, Tichter JE: increasing evidence for the irritable gut syndrome. Gastroenterology 92:1652A, 1987 28. Valenzuela JE, Liu DP: The effect of variations in intragastric pressure and gastric emptying of a saline meal in humans. Scand J Gastroenterol 17:293-296, 1982 29. Emanuel MB: The pharmacology and clinical uses of d0mperidone. Clin Res Rev 3:15-33, 1983

58

30. Shannon S, Hollingsworth J, Cook IJ, Collins SM: Effect of trimebutine on postprandial colonic motor activity in healthy subjects and patients with irritable bowel syndrome. J Gastrointest Motil 1:9-14, 1989 31. Horowitz M, Harding PE, Chatterton BE, Collins PJ, Shearman DJC: Acute and chronic effects of domperidone on gastric emptying in diabetic autonomic neuropathy. Dig Dis Sci 30:1-9, 1985

Digestive Diseases and Sciences, Vol. 36, No. 1 (January 1991)