REVIEW
Metoclopramide: Pharmacology and Clinical Application
RIYADALBIBI, M.D.; and RICHARD W. McCALLUM, M.D.; New Haven, Connecticut
Metoclopramide antagonizes the effect of dopamine in the
central nervous system and other organ systems.
Metoclopramide's effect on the medullary chemoreceptor
trigger zone makes it useful as a routine anti-emetic and
in preventing vomiting induced by antineoplastic drugs,
particularly cisplatin. Metoclopramide's gastrointestinal
smooth muscle stimulatory effects are related to its ability
to antagonize the inhibitory neurotransmitter, dopamine;
to augment acetylcholine release and sensitize the
muscarinic receptors of the gastrointestinal smooth
muscle; and to coordinate gastric-pyloric-small intestinal
motor function. The indications for which metoclopramide
is approved in the United States are reviewed. Adverse
effects, which may occur in up to 2 0 % of patients, include
drowsiness, lassitude, and akathisia; all are usually mild,
transient, and reversible. Tremor, dystonic reactions, and
extrapyramidal effects are infrequent; breast
enlargement, galactorrhea, and menstrual irregularities
are related to prolactin release.
M E T O C L O P R A M I D E ( methoxy-2-chloro-5 -procainamide )
(Reglan; A. H. Robins Co., Richmond, Virginia) has
been studied in this country for 8 years. This scientific
evaluation has led to a better understanding of the role of
dopamine in the gastrointestinal tract and the potential
therapeutic value of dopamine antagonists in the treatment of smooth muscle disorders. As a medication initially introduced in Europe 15 years ago for the treatment of nausea and vomiting in pregnancy, this drug now
has wide applications in a number of organ systems apart
from the gastrointestinal tract, particularly in the endocrine system. The investigations in the United States over
the last 8 years also provided a stimulus for the development of new dopamine antagonists with selective peripheral smooth muscle effects that may have future therapeutic value.
Metoclopramide is a new generation of dopamine antagonist first described by Justin-Bescanon and associates
(1) in the early 1960's, 10 years after the synthesis of
procainamide. Both drugs are derived from substituted
benzene compounds with para-aminobenzoic acid as the
parent compound. The two drugs differ in that procainamide lacks the 5-chloro and 2-methoxy aryl substituents
(Figure 1). However, there is a great difference in their
pharmacodynamics in that metoclopramide effects the
gastrointestinal smooth muscle, as well as being a powerful centrally acting anti-emetic; procainamide is a wellknown local anesthetic with recently appreciated anti-arrythmic properties ( 2 ) .
Mechanisms and Actions of Metoclopramide
Metoclopramide's effect on gastrointestinal smooth
• F r o m t h e D e p a r t m e n t of Internal Medicine, Section of Gastroenterology, Yale
University School of Medicine; N e w Haven, Connecticut.
86
muscle is not entirely understood. Metoclopramide lowers the pressure threshold for the occurrence of the peristaltic reflex, reduces the appearance of fatigue, and enhances the frequency and amplitude of the longitudinal
muscle contractions (3, 4 ) . Metoclopramide's uniqueness
lies in its ability to coordinate gastric, pyloric, and duodenal motor activity to result in net aboral movement. This
aspect is not completely understood but separates metoclopramide's effects from nonspecific cholinergic-like
stimulation of upper gastrointestinal smooth muscle, and
is a good explanation for the clinical difference seen in
the therapeutic effects of metoclopramide on gastric emptying compared to bethanechol ( 5 ) .
CHOLINERGIC PROPERTIES
Metoclopramide is not a cholinomimetic in the usual
sense; it does not increase gastric acid secretion (6-8) or
stimulate endogenous gastrin release ( 9 ) . Metoclopramide's effects on gastric emptying may be seen after vagotomy (6-8, 10), although atropine reduces or abolishes
its upper gastrointestinal smooth muscle actions (11-13).
In humans, 10 /^g/kg of atropine blocks the action of
metoclopramide, 10 mg intravenously ( 1 4 ) . This fact
suggests that metoclopramide's mechanism of action depends on intramural cholinergic neurons (7, 11). There
is evidence that metoclopramide, unlike conventional
cholinergic compounds, needs intrinsic stores of acetylcholine (15-18). Postsynaptic activity results from the
drug's ability to augment acetylcholine release from postganglionic cholinergic nerve terminals and to sensitize
the muscarinic receptors of gastrointestinal smooth muscles ( 1 1 , 13). Clinically, metoclopramide's effects seem
more pronounced on the proximal rather than distal
bowel, but it has more effect in vitro on colonic than on
proximal smooth muscle (11, 13).
DOPAMINE ANTAGONISM
It appears that some of the gastrointestinal smooth
muscle actions of metoclopramide are due to antagonism
of the inhibitory neurotransmitter, dopamine (19, 20). It
is known that dopamine exerts effects in both the central
and peripheral portions of the nervous system; the existence of specific dopamine receptors has been established
pharmacologically. Dopamine does not cross the bloodbrain barrier, but levodopa, the precursor of dopamine, is
able to penetrate the central nervous system where it is
decarboxylated to dopamine. Specific dopamine receptors
have also been identified in the gastrointestinal tract
(particularly in the stomach and exocrine pancreas), renal, mesenteric, coronary, and cerebral vasculatures
(19). In the gastrointestinal tract, dopamine is regarded
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© 1983 American College of Physicians
as an inhibitory neurotransmitter; however, the existence
of actual dopaminergic neurons has not been clearly established in man (21). Levodopa inhibits metoclopramide stimulation of the lower esophageal sphincter in man
(22), and also inhibits gastric emptying of a mixed solidliquid meal in normal persons (23). Metoclopramide antagonizes this latter effect, returning gastric emptying to
normal. In subemetic doses, apomorphine (a dopamine
agonist) results in gastric stasis, spasm of the pylorus and
duodenum, and constipation (24). Metoclopramide
blocks these effects, probably by antagonizing dopamine
or through cholinergic or serotonergic modulation. Metoclopramide accelerates gastric emptying by increasing
tone and amplitude of antral contractions, relaxing the
pyloric sphincter and duodenal bulb, while increasing
peristalsis of the duodenum and jejunum and accelerating
intestinal transit time from the duodenum to the ileocecal
valve (25-27).
In addition to its ability to enhance upper gastrointestinal smooth muscle motor function, metoclopramide may
also increase gastric emptying through inhibition of receptive relaxation of the gastric fundus (28). This study
of vagally innervated gastric pouches of dogs implied that
metoclopramide partially blocked receptive relaxation resulting in increased liquid and solid food emptying (28).
This fact may help explain the actions of metoclopramide
in patients with chronic gastric stasis after gastric resection surgery where gastric emptying can be accelerated
by metoclopramide in the absence of an antrum (29).
There is some evidence that cholinergic transmission
can be modulated by dopamine. This fact is particularly
evident in the central nervous system, but less clearly
defined in the periphery (10). A similar relationship may
exist in upper gastrointestinal smooth muscle and mediate some of metoclopramide's actions.
DIRECT EFFECT ON SMOOTH MUSCLE
There is evidence that suggests one of metoclopramide's mechanisms of action may be directly on smooth
muscle. Metoclopramide's effect on the lower esophageal
sphincter of the opossum is not abolished by tetrodotoxin
or atropine (30). This in-vitro preparation used large
doses of metoclopramide, and whether this result can be
extrapolated to its use in humans is not clear. In the
isolated gastric smooth muscle of the guinea pig, Hay
(18) showed that tetrodotoxin and hexamethonium reversed metoclopramide potentiation of extrinsic acetylcholine action. This reversal indicates that the action of
metoclopramide depends on the release of acetylcholine
from postganglionic nerve endings rather than a direct
effect on the muscle.
CENTRAL ANTI-EMETIC EFFECT
Metoclopramide's potent central anti-emetic activities
may contribute to its clinical effectiveness because therapeutic success is not always correlated with an improvement in gastric emptying. In high doses, apomorphine
can produce nausea and vomiting by stimulating the medullary chemoreceptors trigger zone. Phenothiazine and
metoclopramide are effective in preventing apomorphine-
Figure 1. Chemical structure of metoclopramide (2-methoxy-5chloro-procainamide).
induced vomiting (31). This property of metoclopramide
is viewed as supplementary and complimentary to its gastrointestinal smooth muscle effects in clinical situations
with nausea and vomiting.
Absorption, Metabolism, and Excretion
Metoclopramide is used as a dihydrochloride monohydrate. Pharmacokinetic studies suggest that the drug is
well-absorbed and rapidly excreted with a short half-life,
60 to 90 minutes in the rat and dog, and about 4 hours in
humans. The drug's onset of action is 1 to 3 minutes after
intravenous doses, 3 to 5 minutes after intramuscular injection. Maximal plasma levels of 84 n g / m L occur within
20 to 30 minutes of oral intake, although the peak metoclopramide plasma concentration during intravenous administration was 221 n g / m L (both 20 mg doses). Peak
change in lower esophageal sphincter pressure correlated
weakly with peak plasma metoclopramide concentrations
(22). Metoclopramide is weakly bound to serum protein,
rapidly distributed in most tissue, and highly soluble in
water and ethanol. A 1% aqueous solution stored in colored containers should be stable for up to 5 years (32).
In humans, most metoclopramide is excreted either
unchanged in the urine or is conjugated to sulfate or glucuronide in the bile. In most other species studied, N-deethylation is a major pathway for metoclopramide metabolism. In humans, there is only partial metabolism by this
pathway and most of the drug ( 8 0 % ) is excreted unchanged in the urine in 24 hours (33). In the brain, metoclopramide is localized in the area postrema that contains the chemoreceptor trigger zone for vomiting. Impaired renal function prolongs the drug's half-life and
this fact has to be considered when treating patients with
chronic renal failure. The dosage should be no more than
half the normally recommended dose of 40 mg. On the
other hand, dialysis completely clears the drug and
would result in the need for extra doses during renal dialysis treatments (34). Recommendations may include 10
mg doses immediately after dialysis.
Clinical Uses and Trials
GASTROESOPHAGEAL REFLUX
Several clinical studies have shown that metoclopramide increases the resting tone of the lower esophageal
sphincter (35-37). Cohen and associates (35) reported
that both oral and intravenous administration led to a
dose-related increase in pressure in normal subjects and
patients with gastroesophageal reflux. Dose response
curves for oral administration showed greater absolute
responsiveness in normal subjects as compared to patients, but the accepted oral dose of 10 mg resulted in a
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Figure 2. Mean lower esophageal sphincter pressure (LESP) in mm
Hg in 15 patients with gastroesophageal reflux before and for 6 0
minutes after oral administration of metoclopramide, 10 and 2 0
mg; bethanechol 2 5 mg; and placebo.
mild increase in pressure that was not consistent in all
patients. McCallum and associates (5) showed that metoclopramide, 20 mg orally, produced a greater increase
in lower esophageal sphincter pressure than either metoclopramide, 10 mg, or bethanechol, 25 mg, in gastroesophageal reflux patients (Figure 2 ) . Serum gastrin concentrations were not altered by any of the drugs and, unlike
bethanechol, metoclopramide does not increase gastric
acid secretion (6-8).
There are conflicting reports about the effect of metoclopramide on the amplitude of peristaltic contractions in
the body of the esophagus and on esophageal acid clearance. Only one study reported an increase in peristaltic
amplitude and improvement in acid clearance (37). Other studies were not able to confirm these results (36, 38).
Delayed gastric emptying of solids or liquids could be
one of the mechanisms that increases the volume of gastroduodenal contents available for reflux into the esophagus. It was previously reported that gastric emptying of
an isotope-labeled semi-solid meal was delayed in a significant percentage of patients with gastroesophageal reflux (39). Behar and Ramsby (40) reported that patients
with reflux esophagitis have a decreased number of antral
contractions and a lower cumulative antral activity index
using a perfused catheter system, whereas gastric emptying using an isotope-labeled semi-solid meal was normal.
A recent report shows that when a specific marker for the
solid food component of a meal is evaluated, gastric emptying is delayed in a significant number ( 5 7 % ) of adult
patients with gastroesophageal reflux disease (41). At the
same time, liquid (water) emptying is normal. These
data suggest that many reflux esophagitis patients have
an,antral motility disturbance contributing to the pathophysiology of their disease. It is conceivable that duodenogastric reflux and accompanying gastritis may induce
an antral motility disturbance, or that impairment of antral function and delayed gastric emptying is part of a
spectrum of abnormalities that include duodenal and pyloric dysfunction.
This appreciation of delayed gastric emptying, usually
subclinical but sometimes related to nausea, vomiting,
33
and epigastric discomfort in reflux patients, suggests the
possibility that a mechanical approach to accelerate gastric emptying and stimulate upper gastrointestinal
smooth muscle is indicated in the treatment of reflux esophagitis. A recent report shows that bethanechol, an
agent used in gastroesophageal reflux treatment because
it enhances lower esophageal sphincter pressure, has no
reliable effect on increasing the rate of gastric emptying
in reflux esophagitis patients, whereas metoclopramide,
with similar effects on lower esophageal sphincter pressure, was also able to significantly accelerate gastric emptying and return it to normal in a group of reflux esophagitis patients with delayed emptying (5, 38). In infants that fail to thrive or with pulmonary aspiration,
delayed gastric emptying of an isotope-labeled cow's milk
formula meal has been reported, implying that abnormal
motor function of the gastric fundus may be a significant
factor in the pathogenesis of gastroesophageal reflux, of
infancy (42). Whether metoclopramide increases this delayed gastric emptying in these infants had not been studied.
Behar and Biancani (43) compared the effects of single
doses of metoclopramide, 15 mg, aluminum hydroxide,
30 mL, and placebo in 15 patients with reflux esophagitis.
Oral metoclopramide was found to be significantly more
effective than antacid in reducing the cumulative duration of reflux. Metoclopramide increased resting lower
esophageal sphincter pressure in all 15 patients for at
least 1 hour, and prevented gastroesophageal reflux after
an intragastric acid load.
Three recent double-blind studies have shown that metoclopramide improves symptoms of gastroesophageal reflux. McCallum and associates (44), in a double-blind 8week crossover study in 30 patients, showed that metoclopramide treatment resulted in significantly greater
symptomatic improvement than during placebo. BrightAsare and El-Bassoussi (45) compared the efficacy of
cimetidine, metoclopramide, and placebo and found that
both cimetidine and metoclopramide were more effective
than placebo. Winnan and associates (38) studied 19 patients for a 4-week period comparing metoclopramide
with placebo and antacid. Metoclopramide was more effective than the combination of placebo and moderate
doses of antacid, 56 g/d, in improving the symptoms of
gastroesophageal reflux, although objective parameters
for healing were not improved. Despite encouraging results in short-term trials, the role of metoclopramide
maintenance therapy in the long-term management of reflux remains uncertain, pending appropriate controlled
studies.
Gastric Prokinetic Effects
Gastric stasis, characterized by upper abdominal discomfort, distension, bloating, early satiety, nausea, and
vomiting, may be associated with a number of clinical
states that include surgical vagotomy with or without accompanying gastric resection, diabetes mellitus with visceral neuropathy, gastrointestinal pseudo-obstruction,
gastroesophageal reflux, systemic sclerosis involving the
gastrointestinal tract, anorexia nervosa, as well as idio-
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pathic gastric stasis. A number of studies have established that metoclopramide significantly accelerates gastric emptying (46). Both Eisner (11) and Johnson (47)
reported that metoclopramide has a pronounced effect
increasing contraction amplitude and frequency in the
antrum. Our experience with this agent confirms these
reports, using a perfused catheter system in the antrum
(Figure 3).
Diabetic Gastroparesis
The term gastroparesis diabeticorum was coined by
Kassander in 1958 (48); he also emphasized that a number of diabetic patients with delayed gastric emptying
may be asymptomatic. The exact incidence of the problem is still unknown and reports of the frequency vary
because of different patient samples, as well as the limitations of quantitating delayed gastric emptying by radiologic techniques. In general, gastroparesis is not sex-related and occurs in long-term diabetic patients who are
insulin-dependent and usually have a peripheral neuropathy and evidence of other complications of diabetes mellitus. There is not always a good correlation between the
degree of gastric stasis and symptoms. Some patients
with severe gastric stasis have few symptoms which suggests that control of day-to-day glucose fluctuations can
contribute to unrecognized gastric emptying problems.
Investigators have concluded that changes in gastric
emptying initially assumed to reflect "autovagotomy"
were not reproducible by simple surgical vagotomy in
non-diabetic patients. Malagelada and associates (27)
found that interdigestive motor cycles were absent in the
stomach but intact in the small bowel of patients with
diabetic and post-vagotomy gastroparesis. The function
of these interdigestive cycles is thought to be that of an
"intestinal housekeeper" which may explain the formation of bezoars in patients with chronic gastroparesis. It
is also possible that decreased acid secretion in patients
with longstanding diabetes (49) may play a role in slowing gastric emptying.
Fox and Behar (14) compared the effect of metoclopramide on diabetic patients and normal subjects. Intravenous metoclopramide did not alter the rate of antral
contractions or the total cumulative antral activity in patients with diabetic gastroparesis although it increased
the cumulative antral activity in normal subjects and in
diabetic patients without gastroparesis. This pharmacologic study was based on a single intravenous injection.
There are studies that suggest that the visceral neuropathy may result from abnormal metabolism in unregulated diabetic patients. The accumulation of myoinositol
at nerve endings and structural changes reported in the
postganglionic sympathetic fibers are related to this hypothesis.
Several brief communications reported favorable results with the use of oral metoclopramide in the treatment of diabetic gastroparesis (50-52). These were not
controlled studies, although objective evidence of improved gastric emptying was shown. Metzger and colleagues (29) did a double-blind crossover design trial in
five patients that showed that emptying was better in pa-
Figure 3. A continuously perfused catheter system in the antrum of
the stomach measures contractions (in mm Hg) at 3 cm intervals,
basally and 10 minutes after intravenous administration of metoclopramide, 10 mg. Metoclopramide increased the amplitude and
frequency (contractions/minute) of antral and duodenal contractions.
tients treated with metoclopramide. Campbell and associates (53) studied gastric emptying in 12 diabetic patients
and 20 non-diabetic control subjects. Both intravenous
and oral metoclopramide produced symptomatic improvement and restored gastric emptying to normal. Perkell and associates (46), in a double-blind trial of symptomatic gastric stasis patients, measuring gastric emptying using a suboptimal method (a "barium burger"), saw
improvement in 10 of 14 patients on metoclopramide and
4 of 40 on placebo.
Other investigators have reported less favorable results. Soergel and associates (54) showed that metoclopramide did not alter the emptying of solid or liquid
components of the test meal, and ten diabetic patients
had subjective improvement without change in their
emptying after 4 to 6 weeks. The number of long-term
patients studied was small and a single-blind trial design
was used. Saltzman and co-workers (55), in a doubleblind trial of 13 patients, showed that both parenteral
and oral metoclopramide significantly increased gastric
emptying of an isotope-labeled semi-solid meal (Figure
4 ) , and that chronic oral metoclopramide therapy significantly improved symptoms of gastric stasis in these
patients compared to placebo (Figure 5). Despite symptomatic relief, some patients had little change in their
emptying, implying that some clinical efficacy can be
attributed to the central effects of metoclopramide on the
chemoreceptor trigger zone.
Plasma metoclopramide levels may be useful in monitoring patient responses. Chronic oral ingestion in diabetic patients causes sustained plasma levels ranging from 40
to 100 n g / m L , 6 hours after metoclopramide, 10 mg orally. Little initial change occurs after acute oral intake.
These levels are approximately half of the peak concentration achieved after parenteral administration.
Postsurgical Gastroparesis
Functional gastric outlet obstruction is defined as the
inability of the stomach to empty solids and sometimes
liquids through a mechanically patent gastroenteric stoma into the upper small intestine more than 4 weeks after
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t-igure 4 . Percentage (mean ± SEM) of isotope remaining in the
stomach in seven patients with chronic gastric stasis accompanying
diabetes mellitus before and after receiving chronic oral metoclopramide therapy. The meal used was an isotope-labeled egg salad
sandwich. Patients clinically improved on oral metoclopramide
therapy had a significantly accelerated mean gastric emptying rate
after 6 0 and 9 0 minutes (p < 0 . 0 5 ) compared to their pre-treatment baseline day, although a faster rate was not seen in all patients. The improved gastric emptying was still slower than the rate
for normal subjects (n = 2 6 ) ingesting this meal.
tion after vagotomy. Eight patients received metoclopramide and were able to function on a standard postvagotomy diet. Nine patients received placebo and were
unable to retain anything orally, but had prompt relief
after they were given metoclopramide.
McCallum and associates (62), in a double-blind study
on ten patients who had either vagotomy and gastric resection or vagotomy and pyloroplasty for duodenal ulcer
2 months or more before the study, showed that parenteral and oral metoclopramide significantly improved the
gastic emptying of a isotope-labeled semi-solid meal (Figure 6). Chronic oral metoclopramide, 10 mg four times a
day, when compared to placebo, significantly improved
the symptoms of chronic gastric stasis during a doubleblind crossover trial (Figure 7 ) . As in diabetic gastroparesis, most of these studies used the patients' symptomatic
relief as a criterion and some of the responses may be
explained by the central effect of metoclopramide as an
anti-emetic drug.
Idiopathic Gastric Stasis
surgery. Gastric emptying abnormalities may persist for
months or years with an overall incidence of from 0.5%
to 3 % . The cause is thought to be related to interruption
of the gastric pacemaker and basal electrical rhythm by
resection of part of the stomach, together with the effect
of vagotomy. The incidence of impaired gastric emptying
may rise to 8% in patients who have truncal vagotomy
accompanying a gastric drainage procedure if there has
been chronic pyloric outlet obstruction in the stomach
before surgery. Approximately 2 5 % of patients developing severe functional gastric outlet obstruction immediately after surgical treatment for peptic ulcer disease need
exploratory surgery to rule out mechanical obstruction.
The mortality rate for repeated surgery may be as high as
12% (56).
Several double-blind trials have shown metoclopramide to be effective in both acute and postsurgical stasis.
Stadaas and Aune (57), in 1971, first noted that metoclopramide relieved the symptoms of gastric stasis in people
after peptic ulcer surgery, and in 1972 (58) reported that
these symptoms worsened when metoclopramide was discontinued. Hancock and associates (59) studied patients
with acute and chronic gastric retention using an isotopelabeled solid meal. Patients with delayed gastric emptying after vagotomy responded to metoclopramide. Metzger and coworkers (29, 60) found that parenteral metoclopramide was effective in improving chronic gastric retention in patients who had had an antrectomy. Davidson
and associates (61) studied 20 patients with severe
chronic gastric retention after surgery for peptic ulcer
disease who received oral metoclopramide. Excellent or
good relief of symptoms was achieved in 4 5 % of the patients, fair relief in 2 5 % , and no change in symptoms in
3 0 % . Gastric manometric studies showed a return of gastric contractions after an intramuscular injection of metoclopramide in patients who had no contractions, and augmentation of contractions in patients with weak contractions before metoclopramide. In 1978, McClelland and
Horton (56) studied 17 patients with acute gastric reten90
Some patients with typical symptoms of gastric stasis,
and delayed gastric emptying of an isotope-labeled solid
meal, are categorized as having idiopathic gastric stasis
without apparent cause. Possible contributing factors include gastroesophageal reflux disease, either clinically apparent or latent, where a significant portion of patients
have an associated delay in solid food emptying suggesting antral motor disturbance (41-44). In addition, achlorhydria, with or without pernicious anemia, results in ab-
Figure 5. Symptoms of gastric stasis in 13 patients with diabetic
gastroparesis. A comparison between placebo treatment (hatched
bars) and metoclopramide (black bars) during a 3-week doubleblind crossover trial shows those symptoms
significantly
(p < 0 . 0 5 ) improved by metoclopramide compared to placebo.
White bars = basal period.
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Figure 6. Percentage (mean ± SEM) of isotope remaining in stomach before and after oral and parenteral metoclopramide in seven
patients with chronic gastric stasis after gastric surgery. The meal
used was an isotope-labeled egg salad sandwich. Both routes of
administration of metoclopramide significantly accelerated gastric
emptying after 9 0 minutes (p < 0 . 0 5 ) compared to the baseline.
normally slow gastric emptying of solids with normal liquid emptying (63). Finally, tachygastria or antral dysrhythmias has been reported, where, instead of the usual
basal electrical rhythm of three cycles/minute, showing
the maximum frequency of peristaltic contractions that
can occur, electrical activity of greater than six cycles/
minute was present regularly or intermittently in some
patients (64-66). Metoclopramide is indicated as initial
treatment in patients with idiopathic gastric stasis and
there have been reports of improvement (46).
Gastric Ulcer
In one hypothesis for the cause of gastric ulcer disease,
delay in gastric emptying is regarded as an important
factor. Data from studies done by Dragstedt (67) suggest
that delayed gastric emptying in dogs induced by pyloric
narrowing caused the formation of gastric ulcers. Two
large studies (68, 69) of patients have shown that either
clinical or radiologic evidence of gastric retention can be
found in 3 0 % and 6 4 % , respectively, of patients with
gastric ulcer disease. Garrett and associates (70), studying antral motility, found that patients with gastric ulcers
had decreased activity during the active phase of the ulcer and an indication that healing may be associated with
a return to normal. Recently, a study by Miller and associates (71) showed that delayed gastric emptying could
be denned using isotope-labeled meals in patients with
gastric ulcers near the incisura. Metoclopramide significantly stimulated gastric emptying in these patients. Although clinical trials are lacking, the study raises the
question of whether an agent (metoclopramide) that
stimulated upper gastrointestinal smooth muscle activity
and decreased duodeno-gastric (bile) reflux may be valuable in treating gastric ulcer disease.
Anorexia Nervosa
The cause of anorexia nervosa is unknown; the hypotheses include phobic response to food, disturbed psycho-
sexual development, perceptual and conceptual disturbances, distorted relations with parents, and an affective
disorder. Hypothalamic dysfunction (72, 73) and abnormal central dopamine receptors (74) have been proposed
as a possible basis for the pathophysiology of the disorder. Upper gastrointestinal symptoms are frequently
present in this disorder. Patients with anorexia nervosa
may have nausea, vomiting, abdominal pain, diarrhea,
constipation, heartburn, belching, distension, and early
satiety. A gastric emptying disturbance can be shown in
80% of patients, using isotope-labeled meals defining the
solid food and liquid components (75). The gastric emptying abnormality has been localized to the solid food
component with normal liquid emptying, suggesting that
an antral motility disturbance may be present. Whether
the abnormality is a primary effect or an epiphenomenon
related to weight loss and consequent malnutrition, with
its associated psychological changes, has not been defined. Metoclopramide increased the rate of gastric emptying in anorexia nervosa patients with delayed emptying
(75, 76), and may have a role in the future in the therapeutic management of anorexia nervosa.
Pseudo-obstruction
Pseudo-obstruction has been used to describe patients
with classic signs and symptoms of bowel obstruction
without an apparent mechanical cause of ileus. Pseudoobstruction has been associated with diseases that involve
the bowel wall, such as scleroderma and amyloidosis, and
is also seen in myxedema, hypoparathyroidism, and myotonic dystrophy. Transient obstruction may occur in patients with pancreatitis, heart failure, uremia, and electrolyte imbalance. The term chronic idiopathic pseudoobstruction is applied to patients with no apparent underlying disease. Motility studies have shown infrequent or
absent peristaltic activity in the esophagus, decreased
lower esophageal sphincter pressure, and hypomotility of
the proximal small bowel. Attempts to stimulate motor
activity by intraluminal instillation of acetylcholine or
Figure 7. Comparison of symptom scores in ten patients with
chronic postsurgical gastric stasis receiving metoclopramide and
placebo in a randomized, double-blind 3-week crossover trial. During metoclopramide use, the symptom scores were significantly reduced (p < 0 . 0 5 ) compared to placebo during each of the 3 weeks.
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intravenous neostigmine have been unsuccessful. It is
conceivable that metoclopramide could improve motor
activity in these patients; however, Lipton and Knauer
(77) reported that metoclopramide has no advantage
over placebo. This action may be explained by the fact
that some patients with pseudo-obstruction have severe
visceral myopathy (78) rather than neuropathy, and any
direct effect of metoclopramide on muscle function is
negated. In-vitro studies have shown that metoclopramide increased the magnitude and number of contractions
in colonic muscle preparation from both animals and
people ( 3 ) . Metoclopramide may be useful in patients
with colonic hypomotility, including diabetes and scleroderma, and controlled trials are needed.
bulb, reduces the time needed to pass barium and small
bowel capsules for biopsy specimens (84, 85). Controlled
radiologic studies in patients receiving barium meals have
shown that intravenous or subcutaneous metoclopramide
significantly increases the rate of gastric emptying and
reduces small bowel transit time as compared to placebo.
James and Hume (86) studied 217 patients having barium examinations; these untreated patients had persistent
gastric stasis and no movement of barium through the
pylorus even 1 to 2 hours after ingestion. Intravenous
metoclopramide produced rapid gastric emptying, and
the barium was at or beyond the cecum within 1 hour in
59 of 83 patients.
Postoperative Ileus
Nausea and Vomiting
Metoclopramide is effective in preventing apomorphine-induced vomiting in humans (31). It is more effective than prochlorperazone, as effective as trimethobenzamine, but significantly superior to perphenazine ( 2 ) . The
anti-emetic property is probably via a direct effect on the
chemoreceptor trigger zone by blocking dopamine receptors. Uncontrolled studies in the treatment of a wide variety of conditions associated with nausea and vomiting
have indicated a success rate of about 8 0 % to 9 0 % . In a
double-blind study of 12 patients with chronic renal failure, there was an improvement in nausea in 3 of the 24week periods on placebo compared with 13 of 24 drug
periods ( 7 9 ) . Metoclopramide is probably effective in
treating emesis during pregnancy and labor. A doubleblind comparison of metoclopramide, placebo, and prochlorperazine showed good to fair response in 7 9 % of
women treated with metoclopramide (80). There are no
reports of dysmorphogenic effects in animals due to metoclopramide; however, it should not be given in the first
trimester because its effects on the fetus have not been
established.
Metoclopramide is currently being evaluated for its efficacy in the treatment of nausea and vomiting secondary
to antineoplastic drugs, particularly cisplatin (cis-platin u m ) . Two clinical pilot studies (81, 82) showed that
metoclopramide may be an effective agent for controlling
cisplatin-induced vomiting. A recent randomized doubleblind trial in patients with advanced cancer treated with
cisplatin showed that high dose intravenous metoclopramide (up to 10 m g / k g body weight during the study
period) was superior to placebo and to prochlorperazine
in reducing the volume of emesis and was more effective
than placebo in shortening the duration of nausea and
vomiting (83). It should not be concluded, however, that
metoclopramide would be as effective against all chemotherapeutic drugs. It is thought that different mechanisms exist for emesis, and anti-emetics may exert their
effects through different physiologic pathways. Furthermore, this high dose should be used with great caution
and not in any other clinical setting.
Diagnostic Radiology and Intubation
Metoclopramide, by shortening the duration of small
bowel transit and relaxation of the pylorus and duodenal
92
Davidson and associates (87) studied 115 patients who
had had a laparotomy with and without gastrointestinal
anastomosis in a randomized, double-blind study using
metoclopramide and placebo. Less nausea and vomiting,
and a better tolerance to solid food was achieved in the
metoclopramide-treated group. However, no statistically
significant difference was found in other parameters such
as abdominal pain, return of bowel sounds, passage of
flatus, and stools. Other investigators have shown even
better results (88). Further controlled observations are
needed before the indications and role of metoclopramide, if any, in postoperative ileus can be defined.
Metoclopramide and the Endocrine System
Metoclopramide has a potential use in evaluating pituitary hypothalamic function. Dopamine inhibits the release of prolactin from the anterior pituitary gland by
stimulating the secretion of prolactin inhibitory factor
from the hypothalamus (19). Metoclopramide increases
prolactin by blocking dopamine (89), and pretreatment
with levodopa inhibits the prolactin response to metoclopramide. Sowers and associates (90) compared the effect
of metoclopramide on prolactin release with that of thyrotropin releasing hormone and chlorpromazine in 11 euthyroid men. The peak response of serum prolactin and
the maximal increment were greater after the administration of metoclopramide than after either thyrotropin releasing hormone or chlorpromazine (Figure 8). Metoclopramide also produced a small increase in serum thyrotropin and small reduction of serum growth hormone,
luteinizing hormone, and follicle-stimulating hormone.
Cohen and associates (91) reported an increase in
growth hormone levels in ten hypogonadal men after 10
mg intravenous administration of metoclopramide.
Dopamine exerts a suppressive effect on aldosterone
secretion analogous to the effect on prolactin (92), but
the exact site, while not known, is probably central dopaminergic receptors (93). It was shown that parenteral
metoclopramide increased plasma aldosterone levels, although there was no correlation between the changes in
aldosterone and prolactin concentrations, suggesting that
prolactin was not the mediator of this increase. There
were no significant changes in plasma renin activity, potassium, or Cortisol after metoclopramide. Hypertension
and hypokalemia have not been reported as side effects of
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oral metoclopramide therapy, probably because higher
plasma concentrations of metoclopramide are necessary
to increase aldosterone levels compared to changes in
prolactin, and these plasma concentrations are not attained by oral administration.
Other Factors
Clinical experience suggests that metoclopramide may
also be effective in a variety of disorders, including intractable cases of hiccups, vertigo, migraine headaches ( 2 ) ,
stimulation of lactation in the postpartum period, and in
orthostatic hypotension (94). However, further controlled observations are needed in these areas. Metoclopramide may be useful in treating the neurogenic bladder
because it has similar actions as bethanechol, which has
been used with some success for this condition (95). Like
phenothiazines, metoclopramide has minimal antipsychotic properties in the doses used for the clinical indications that have been discussed.
Side Effects
Some adverse effects may occur if metoclopramide is
given in the usual therapeutic doses. Side effects have
been reported in up to 20% of patients, but are usually
mild, transient, and reversible after withdrawal of the
drug. Drowsiness and lassitude are the commonest, being
reported in up to 10% of patients. Feelings of anxiety,
agitation, or motor restlessness may occur; they are doserelated, and are more frequent after intravenous administration. Urticaria or maculopapular rash may rarely occur. Extrapyramidal side effects are uncommon. True dystonic reactions occur in only about 1 % of patients and
include trismus, torticollis, facial spasms, opisthotonos,
and oculogyric crises. These reactions disappear within
24 hours after withdrawal of metoclopramide (96). Parkinson symptoms of tremor, rigidity, and akinesia are
rarely seen, except after excessive doses or in patients
with decreased renal function. Children are particularly
susceptible to developing symptoms resembling parkinsonism (97) that respond rapidly to anti-parkinson
drugs, such as intramuscular diazepam or benztropin.
Metoclopramide is a potent stimulant of prolactin release. Long-term administration may lead to breast enlargement or nipple tenderness, galactorrhea, and menstrual disorders in some patients.
Metoclopramide should not be given to patients receiving monoaminoxidase inhibitors, tricyclic antidepressants, or sympathomimetics. Metoclopramide should not
be given in combination with phenothiazines, butyrophenones, or orthiazanthenes, and should not be given to
patients with epilepsy or extrapyramidal syndromes. Although metoclopramide has been safely given to parkinsonian patients, both to enhance levodopa absorption and
decrease levodopa-induced nausea and vomiting (98),
this use must be viewed cautiously pending further investigations. Studies in patients with heart disease have
shown that large intravenous doses of metoclopramide
have no significant effect on intracardiac conduction or
blood pressure. Large doses prevent experimentally induced cardiac arrhythmia in animals and produce slight
Figure 8. Prolactin responses in n g / m L (mean ± SEM) in 11 euthyroid men after administration at 0 time of oral metoclopramide,
10 mg; intravenus methyl-thyrotropin-releasing hormone, 1 0 0 mg;
intravenous thyrotropine-releasing hormone, 5 0 0 mg; or intramuscular chlorpromazine, 5 0 mg.
and transient decreases in blood pressure ( 2 ) . Metoclopramide also decreases the serum concentration of digoxin by promoting its transit through the upper gastrointestinal tract (99). Metoclopramide may rarely cause hypertensive crises by unmasking unsuspected pheochromocytoma (100).
Dosage
The usual oral dosage of metoclopramide in adults is
10 mg, 20 to 30 minutes before meals, and at bedtime.
Dosage up to 80 mg/d can be tolerated, but the incidence
of side effects increases above 40 mg. For diagnostic procedures in adults, metoclopramide, 20 mg, can be given
orally 30 minutes before the procedure or parenterally,
10 to 20 mg 5 minutes before examination. The total
daily dose in children should not exceed 0.5 mg/kg body
weight. For infants, a liquid form of administration is
available.
Approved Indications for Clinical Use
For the past 2 years, parenteral metoclopramide has
been approved to facilitate tube placement into the stomach and small bowel, and also to accelerate small bowel
transit and minimize fluoroscopic examination time in
patients having small bowel series. As of December 1980,
the Federal Drug Administration ( F D A ) approved the
use of oral metoclopramide for patients with diabetic gastric stasis. In January 1981, the FDA's Gastrointestinal
Advisory Committee approved metoclopramide for
short-term use in gastroesophageal reflux disease and final F D A clearance was obtained in May 1982. Marketing
for this use will presumably begin in early 1983. The
injectable form of metoclopramide for use in decreasing
nausea and vomiting induced by cisplatin cancer chemotherapy has been approved on a "fast track" basis by the
FDA. Future major indications for metoclopramide include
other forms of gastric stasis, as well as postoperative nausea
and vomiting, and will be submitted for F D A approval.
Albibi and McCallum
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• Metoclopramide
93
• Requests for reprints should be addressed to Richard W. McCallum,
M.D.; Yale University School of Medicine, Gastroenterology Section, 92
LMP, 333 Cedar Street; New Haven, CT 06510.
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