Effect of Metoclopramide on Gastrointestinal Motility in Man

A Manometric Study

Martin Eisner, MD

The effect of metoclopramide on intraluminal pressure of the human gastro- intestinal tract was studied by means of tubes and radiopills. Intravenous meto- clopramide, 20 mg, stimulates pressure in the stomach, and small and large intestine, but not in the sigmoid and rectum. Metoclopramide induces vigorous antral contractions that are followed by duodenal pressure waves which exhibit a particular phasic activity. During this activity, the radiopill passes rapidly through the small intestine. A reciprocal correlation between pressure and movement of the radiopiil was found in the small intestine; no correlation could be detected in the large intestine.

T h e effect of m e t o c l o p r a m i d e on mot i l i - ty of the gas t ro in t e s t ina l t rac t has been s tud ied in e x p e r i m e n t s (1-3) wi th i so la ted smooth muscle p r e p a r a t i o n s of an ima l s (4); in r ad io log ic e x a m i n a t i o n s (5-7) in man , by obse rv ing gastr ic e m p t y i n g t ime (8) a n d by m e a s u r i n g pressure in the gas t r ic an- t r um (9-10). T h e s e s tudies have demon- s t ra ted tha t m e t o c l o p r a m i d e s t imu la t e s gas- t r ic mot i l i ty , and p r o m o t e s gas t r ic emp-

ty ing and smal l i n t e s t ina l t ransi t , whereas no effect was f o u n d in the large in tes t ine in

vivo. T h e mode of a c t i on of meto-

c l o p r a m i d e is d i f ferent f rom tha t of o the r

pha r m aco log i c agents. Its effect is pa rasym- pa t icomet ic , b u t d i f ferent f rom ace ty lcho l ine

and chol ines terase i n h i b i t o r s (4). I t sensi-

tizes smoo th musc le to ace ty lcho l ine in v i t ro (4), a n d p r o b a b l y involves ac t i va t i on of

i n t r a m u r a l cho l ine rg ic neu rons in an ima l s

(1). T h e presen t s tudy dea ls w i th the effect

From the Department of Gastroenterology, Medi- zinische Universitiitsklinik, Bfirgerspital, Basel, Swit- zerland.

Address for reprint requests: Martin Eisner, MD, Medizinische Universithtsklinik, Basel, Switzerland.

of m e t o c l o p r a m i d e on i n t r a l u m i n a l pres- sure in the h u m a n s tomach, smal l a n d large in tes t ine , since m e a s u r e m e n t s of in t ra - l u m i n a l pressure are c u r r e n t l y used to de- t e rmin e d r u g effects on gas t ro in t e s t i na l m o t i l i t y in v ivo (11, 12).

METHODS AND MATERIALS Twenty-eight patients who were not affected by

gastrointestinal disease were studied. Prior to the study, all underwent radiologic examination of the gastrointestinal tract, which was normal. All pa- tients were on a normal diet. No preparation was necessary except for gastroduodenal intubation, after patients had fasted for at least 6 hours. Intubation was performed under local anesthesia of the pharynx.

Intraluminal pressure was recorded with pres- sure-sensitive telemetering capsules (radiopills, t3), and with tubes, Radiopitls* (length 25 mm, diame- ter 8 mm) were used for measurements of gastric, small intestinal and colonic pressures. The radiopill signal was monitored by a modified Heathkit FM-receiver t (SEM) and was recorded on a multi- channel Beckman Offner R 4 Dynograph. Open-

*EIL Type 70D, Electronic Instruments Ltd, Rich- mond, Surrey, England.

tSelig Electromagnetics Ltd, London NW 3, Eng- land.

Digestive Diseases, VoL 16, No. 5 (May 1971) 409

ended water-filled polyvinyl tubes ( in ternal d iame- ter 1.2 ram) wi th side open ings were used in the s tomach and d u o d e n u m . T r i p l e - l u m e n tubes were used for s imu l t aneous record ing f rom three differ- en t levels. T h e dis tance be tween the openings was ad jus ted to the i n t e n d e d measu remen t s . T h e three tubes were b o u n d together a n d were passed into the s tomach or the d u o d e n u m , so tha t pressure was m e a s u r e d e i ther f rom three levels w i th in the s tom- ach, or s imul t aneous ly f rom the a n t r u m and duo- d e n u m . T h e tubes were per fused con t inuous ly wi th tap water.

A system of three m i n i a t u r e ba l loon- t ipped (dia- me te r 5 ram) tubes, 5 cm apar t , was used in the s igmoid colon and rec tum. T h e tubes were placed t h r o u g h a s igmoidoscope u p to 20 cm f rom the anal marg in . T u b e s were connected to the m u l t i c h a n n e l recorder by S ta tham P 23-transducers . S imul taneous records f rom tubes a n d radiopil l were ob ta ined in some pat ients . T h e posi t ion of the tubes and pills at the beg inn ing a n d end of each s tudy was deter- m i n e d fluoroscopically. T a b l e 1 gives the n u m b e r of s tudies in each pa r t of the gas t ro in tes t ina l tract.

Design of Study and Analysis After the tubes were placed or the radiopil l

swallowed, a res t ing per iod of at least 30 m i n u t e s was allowed. An in t r avenous inject ion of physiologic sal ine was then given, followed 5 m i n u t e s later by metoc lopramide , 20 m g in 4 ml, given in t ravenous- ly. Record ing con t inued for at least 20 minu tes .

EISNER

Pat ients were screened before the sal ine injection, a n d 10 m i n u t e s af ter me toc lopramide was given.

I n t r a l u m i n a l pressure was analyzed for four con- secutive periods of 5 m i n u t e s each: Period 1 - rest ing period; Period 2--placebo (saline injection) ; Period 3 - -metoc topramide (first 5 minu tes ; and Period 4 - -metoc lopramide (second 5 minutes) . Pressure activity is expressed in te rms of a moti l i ty index (11) (MI) . In gastric and colonic records, the MI is the s u m of the products of ampl i t ude and d u r a t i on of each wave, divided by 5 ( t ime in minutes ) .

S (dura t ion × ampl i tude) MI =

5

In duodena l and smal l in tes t ina l records, the MI is the product of the sum of the ampl i tudes and the n u m b e r of waves, divided by 5:

S (ampli tudes) × No. of waves MI =

5

T h e significance of differences between the observa- t ion periods was calculated by means of the Student ' s t test for pai red samples. Each pat ient acted as his own control. T h e level of significance was P < 0.05.

RESULTS Statistical Analysis (Table 2)

lVIetoclopramide increased intraluminal pressure in the body of the stomach when pressure was measured by tubes, but had

Table 1. No. of Studies in Each Part of the Gastrointestinal Tract

Tube and pill, Location Tube Pill simultaneously Total'No.

Stomach Body 8 6 3 14 Antrum 5 3 I 8

t 3 Duodenum 6 J

i I 10" 12 Small intestine 6 Colon 2 5 ~ 7

8t Sigmoid 8 ~ 8 Rectum 10 10

* Seven the small

17 Three

were not included in the statistical analysis, because the pill moved from the stomach into intestine. were not included because the pill moved from the i leum into the colon.

410 Digestive Diseases, Vol. 16, No. 5 (May 1971)

I~ETOCLOPRAMIDE EFFECT

no influence on the pressure measured by the radiopill (Fig 1). It stimulated in- traluminal pressure measured by tubes or pill in the gastric antrum (Fig 2), duo- denum and small intestine (Fig 3), and colon (Fig 4). In the sigmoid colon, the effect was not significant, and no effect was demonstrable in the rectum (Fig 4).

S t o m a c h

Intraluminal pressure in the body was low during the resting and placebo peri-

ods. Metoclopramide increased intraluminal pressure by increasing the ampli tude of gastric pressure waves (Fig 5). T h e influ- ence of metoclopramide on the frequency of gastric pressure waves is unpredictable. Pills failed to record an effect, because they escaped into an area of low pressure when a pressure wave arrived. T h e effect of me- toclopramide was rapid and of short dura- tion; it lasted less than 5 minutes in 3 of 8 cases (Fig 1).

In the antrum, in all cases, pressure

Table 2. Statistical Comparison of Motility Index of the Four Periods of Analysis

Control 4- placebo Location Control vs placebo Placebo vs MI* vs MI* 4- MIt

Stomach Body

Tubes P > 0.5 P < 0.01 P < 0.001 Pills P > 0.2 P > 0.2 P > 0.2

Antrum P > 0.2 P < 0.01 P < 0.05 Small intestine

(including duodenum) P > 0.3 P < 0.01 P < 0.05 Colon P > 0.2 P < 0.05 P < 0.001 Sigmoid P > 0.05 P > 0.05 P > 0.05 Rectum P > 0.5 P > 0.5 P > 0.5

P value measured according to Student's t test. * First 5 minutes after metoclopramide is given. t Second 5 minutes after metoclopramide is given.

Fig 1, Effect of rnetoclopramide on body 200 of stomach expressed in terms of a motility index, Each column represents one of four consecutive periods of measurements (C, ~ 150 control; P, placebo; M u metoclopramide >, first 5 minutes; M 2, metoclopramide second "_- 100 5 minutes). Closed circles, radiopiIIs; open circles, tubes. Motility indices of every

50 patient are connected by lines.

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Digestive Diseases, Vol. 16, No. 5 (May 1971) 411

EISNER

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412 Digestive Diseases, Vol. 16, No. 5 (May 1971)

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Fig 6. Continuous record from tube in third part of duodenum. Metoclopramide induces bouts of high pressure waves with silent intervals. Subsiding activity is stimulated by intraduodenai injection of 20 ml water.

waves with a frequency of about 3/min, and low ampli tude were recorded in the resting and placebo periods, dur ing 20-100% of the time. T h e motil i ty index .increased af- ter metoclopramide due to the higher am- pli tude of the pressure waves. T h e drug effect persisted for more than I0 minutes in

3 of 5 cases (Fig 2). T h e number o[ radio- pill studies was small (3), so that no statisti- cal evaluation was possible. Seven studies are not included in this analysis, because the radiopills entered the duodenum or moved backward in the gastric fundus dur- ing the observation period. Simultaneous

414 Digestive Diseases, Vol, 16, No. 5 (May 1971)

METOCLOPRAMIDE EFFECT

records from three levels within the stom- ach revealed stimulation of pressure, lead- ing to peristaltic waves of high amplitude after injection of metoclopramide (Fig 5).

D u o d e n u m a n d S m a l l I n t e s t i n e

The stimulatory effect of meto- dopramide was seen, whether the resting pressure was high or low (Fig 3). Meto- clopramide induced a particular type of pressure activity in the duodenum. Bouts of high waves, consisting of 6-8 waves (duration 5-8 seconds each, amplitude I0 to over 50 mmHg), occurred three to four tifaes in 5 minutes, with silent intervals (Fig 6). After returning to the preinjection level, similar bouts of activity could be induced by intraluminal injection of fluid, proximal to the tip of the recording tube. The radiopill recorded the same pressure waves as did the tubes, when its position was unchanged (Fig 7). When the radiopill passed rapidly through the small intestine, it recorded little pressure (Fig 8), either be- cause the pressure in the distal small intes- tine was actually tow, or because the radio- pill was riding ahead of a pressure wave. Simultaneous antral and duodenal pressure recordings showed that an antral contrac- tion was usually followed by a bout of duo- denal pressure waves (Fig 9).

Colon

Variation in resting pressure, and re- sponse to metoclopramide between individ- uals was large (Fig 4). The position of the radiopill during the study changed little, and no correlation could be established between pressure and movement. Figure l0 is an example of rapid and marked stimu- lation of intraluminal pressure by meto- clopramide. The pattern of motility, after metoclopramide was given, appeared simi- lar to the usual colonic motility.

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Digestive Diseases, Vol. 16, No. 5 (May 1971) 415

EISNER

JEJUN M I | 0 ¢m H20

ILEUM

Fig 8. Continuous record from radiopill in small intestine. Subsiding pressure after metoclopramide corresponds with rapid transit. Before injection of saline, pill was in left upper quadrant. Twenty minutes later, it was in right lower quadrant medial to air-filled cecum.

S i g m o i d and R e c t u m

Although pressure was increased in 5 of 8 cases after treatment with meto- clopramide, its effect in the sigmoid was statistically not significant (0.05 < P < 0.1). This is due to the large variation in control and placebo period pressure. Meto- clopramide had no effect in the rectum.

S y m p t o m s I n d u c e d by M e t o c l o p r a m i d e

Metoclopramide was generally well toler- ated. Four patients felt increased bowel activity, and 3 complained of abdominal discomfort. One patient, who later was found to have gallstones, had severe colic 1 minute after injection of metoclopramide. A patient with chronic obstructive lung disease had an attack of dyspnea which

lasted 12 minutes, after injection of meto- clopramide.

D I S C U S S I O N

Our results demonstrate that meto- clopramide stimulated 'intraluminal pres- sure activity in the stomach, duodenum, small intestine and colon. When the drug is given intravenously, its effect is felt rapidly and is of short duration. It is regularly seen in pressure tracings from the stomach and small intestine, and in some but not all recordings from the large intestine. The effect is most marked in the gastric antrum and in the proximal small intesti.ne. This is in agreement with radiologic observations (5-7), wherein deep, regular peristaltic waves in the stomach, and dilatation and

416 Digestive Diseases, Vol. 16, No. 5 (May 1971)

METOCLOPRAMIDE EFFECT

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rapid transit through the small intestine are seen, whereas no effect ca.n be detected in the large intestine.

The increase in ampli tude of the gastric pressure waves leads to the vigorous gastric peristalsis seen by the radiologist. Our rec- ords of the use of open-ended tubes showed an .increase in antral contractions after metoclopramide is given, but this increase was not as impressive as that recorded with balloons (I0).

Gastroduodenal Correlat ion

A correlation between gastric and duo- denal pressure waves induced by meto- clopramide has been demonstrated in dogs (3). We have confirmed this observation in man. Coordinat ion of antral waves to duo- denal wave complexes is one remarkable effect of metoclopramide. It is probably the manometr ic equivalent of the short gastric emptying time (8, 9). Is the pressure activi- ty in the duodenum due to increased deliv- ery of gastric contents? When the effect of metoclopramide on the duodenum has ap- parently subsided, a small amount of fluid, given proximal to the tip of the recording tube, induces the same type of pressure waves. This indicates that at least part of the effect of metoclopramide is bound to the contents in the lumen of the gastro- intestinal tract. One of the stimuli of gas- trointestinal motility is the filling of the lumen, probably caused by stimulation of stretch receptors in the gastrointestinal wall (14). Our results could be interpreted as indicating an increase in sensitivity of these receptors as a result of treatment with metoclopramide.

From in vitro experiments, a similar mode of action of metoclopramide has also been postulated--ie , that metoclopramide sensitized smooth muscle to acetylcholine (4). From experiments, with animals, it was

Digestive Diseases, Vol. 16, No. 5 (May 1971) 417

EISNER

C O L O N ~ ' i v

I i [ ..... • . 1 MIN 2Omg Met o¢lopra mick~/~ [[1i

Fig I0. Continuous record from radiopill in colon. Metoclopramide induces marked pressure increase. Pill position during observation was steady.

concluded that metoclopramide might in- volve activation of intramural cholinergic neurons (1).

Pressure Propuls ion In te r re la t ionsh ip

T h e simultaneous recording of pressure, measured by tubes and the radiopill, and the fluoroscopic observation of pill move- ments showed impor tant differences be- tween the two methods. T h e radiopill moves freely in the gastrointestinal lumen, and records pressure only when its move- ments are inhibi ted-- ie , when the gas- trointestinal segment in which the radiopill is located is closed by a contraction of the gastrointestinal wall, above and below (15, 16). In the gastric fundus and body, the pressure waves do not close the lumen, and the radiopill failed to record existing pres- sure waves. In the small intestine, it was found that the radiopill sometimes records

the same pressure as do the tubes. The position of the pill was then steady. In other cases, the radiopill recorded little pressure, contrary to that recorded by the tube; and the pill had passed into the ileum during the observation period, sug- gesting that the lumen of the gastrointes- tinal tract was continuously open before the pill entered it.

Our results confirm that motility of an intestinal segment cannot be understood from pressure measurements in this seg- ment alone, but that the pressure in the adjacent proximal and distal segments of the intestine is of equal importance (15, 16).

R E F E R E N C E S

1. Jacoby HI, Brodie DA: Gastrointestinal ac- tions of metoclopramide. Gastroenterology 52:676, 1967

2. Tinker J, Cox AG: Effect of metoclopra-

418 Digestive Diseases, Vol. 16, No, 5 (May 1971)

METOCLOPRAMIDE EFFECT

mide on transport in the small intestine of the dog. Gut 10:986, 1969

3. Johnson AG: The action of metodopramide on the canine stomach, duodenum, and gall-bladder. Brit J Surg 56:696, 1969

4. Eisner M: Gastrointestinal effects of meto- ctopramide in man. In vitro experiments with human smooth muscle preparation. Brit Med J 4:679, 1968

5. Chevrot L, Roux G, Menard JC: Mdtoclo- pramide et routine radiologique digestive. Sem Hop Paris 41:1802, 1965

6. Justin-Besan~on L, Grivaux M, Wattez E: L'6preuve au m6toclopramide en radiologie digestive. Bull Soc Med Hop Paris 114:721, 1964

7. James WB, Hume R: Action of metoclo- pramide on gastric emptying and small bowel transit time. Gut 9:203, 1968

8. Connell AM, George JD: Effect of meto- clopramide on gastric function in man. Gut 10:687, 1969

9. Howarth FH, Cockel R, Hawkins CE: The effect of metoclopramide on gastric motility. Gastroenterology 54:487, 1968, abstr

10. Wagner T, Schmid E: Ueber die Wirkung von oral appliziertem Metoclopramid auf die Motilit~it des rnenschlichen Magens. Z Gastroenterlologie 7:373, 1969

11. Misiewicz J J, Wal ler SL, Eisner M: Motor responses of human gastrointestinal tract to 5-hydroxy-tryptamine in vivo and in vitro. Gut 7:208, 1966

12. Connell AM: Recording of intestinal mo- tility: routine or research? Gut 8:527, 1967

13. Connell AM, McCall J, Misiewicz JJ, et al: Observation on the clinical use of the radiopill . Brit Med J ii:771, 1963

I4. Youmans WB: Neural regulation of gastric and intestinal motility. Amer J Med 13:209, 1952

15: Edwards DAVit: Techniques and interpreta- tions of measurements of gastrointestinal pressures. Ann Roy Coll Surg Eng 37:275, 1965

16. Texter EC: Pressure and transit in the small intestine: the concept of propulsion and peripheral resistance in the alimentary canal. Amer J Dig Dis 13:443, 1968

Digestive Diseases, Vol. 16, No. 5 (May 1971) 419