The Korea n J ourna l of Inte rnal Me dic ine

Vol. 13, No. 1, Februa ry, 1998

Eff e ct s o f Le v o s u lp ir id e in P a t ie n t s w it h Fu n ct io n a l
Dy s p e p s ia Ac c o m p a n ie d
b y De la y e d G a s t r ic E m p t y in g

C h i- W o o k S o n g , M . D . , H o o n - J a e C h u n , M . D . , C h a n g - Du c k Kim , M . D .
Ho - S a n g Ry u , M . D . , J a e - G o l C h o e , M . D .* a n d J in - H a i Hy u n , M . D .
De p a rt m e nt o f Int e rn a l m e d ic in e a n d N u c le a r M e d ic in e *, In s t it u t e o f Dig e s t iv e
Dis e a s e a n d N ut rit io n , Ko re a U n iv e rs ity , Co lle g e o f M e d ic in e , S e o u l, Ko re a

O b j e c t iv e s : Le v o s u lp irid e is t h e le v o -e n a nt io m e r o f s u lp irid e , a w e ll- k n o w n a nt i-

e m e t ic , a nt id y s p e p t ic a n d a nt ip sy c h o t ic d ru g . T h is s t u d y w a s u n d e rt a k e n t o inv e s t ig at e
t h e e f f e c t s o f le v o s u lp irid e o n d y s p e p t ic sy m p t o m s a n d g a s t ric m o t o r f u n c t io n in a
g ro u p o f p at ie nt s w it h f u n ct io n a l d y s p e p s ia s h o w ing d e lay e d g a s t ric e m p ty ing .
M e t ho d : Fo rty tw o e lig ib le p a t ie nt s w e re e nt e re d in t o a 3 w e e k , d o u b le - b lin d
ra n d o m ize d c o m p a ris o n o f 2 5 m g o f le v o s u lp irid e o r p la c e b o t . i.d . . S y m p t o m a s s e s s -
m e nt a n d g a s t ric s c int ig ra p hy f o llo w ing t h e int a k e o f s c ra m b le d e g g s a n d w ic h , w e re
p e rf o rm e d in e a c h p a t ie nt b e f o re a n d af t e r t re a t m e nt .
Re s u lt s : T h e im p ro v e m e n t o f sy m p t o m s c o re in le v o s u lp irid e g ro u p w a s h ig h e r
t h a n t h e p la c e b o g ro u p (p＜ 0 . 0 5 ) . W e a s s e s s e d g lo b a l e f f ic a cy , w h ic h w a s e x c e lle nt in
1 (6 % ) , g o o d 1 1 (6 5 % ) , f a ir 4 ( 24 %) , n il 1 (6 % ) o f t h o s e re c e iv ing le v o s u lp irid e , a n d
f a ir 9 (6 0 %) , n il 5 (3 3 %) , p o o r 1 (6 % ) o f t h o s e re c e iv in g p la c e b o . Le v o s u lp irid e t e n d e d
t o b e m o re e f f e c t iv e t h a n p la c e b o in re lie v in g t h e d y s p e p t ic sy m p t o m s e s p e c ia lly in
t h e s u b g ro u p s o f d y s m o t ility - lik e (p＜ 0 . 0 5 ) a n d n o n s p e c if ic (p＜ 0 .0 5 ) a s c o m p a re d t o
o t h e r s u b g ro u p s (p = 0 . 16 ) . T h e re d u c t io n o f g a s t ric e m p ty ing t im e a f t e r le v o s u lp irid e
t re at m e nt w a s m o re m a rk e d t h a n Pla c e b o g ro u p (p＜ 0 . 0 5 ) . W e f o u n d a s ig n if ic a nt
c o rre la t io n b e tw e e n c h a n g e s o f sy m p t o m s c o re a n d g a s t ric e m p ty in g t im e ( r = 0 .4 7 ,
p = 0 . 0 1) . N o s e rio u s a d v e rs e e f f e c t s w e re re p o rt e d a f t e r a d m in is t ra t io n o f e it h e r
le v o s u lp irid e o r p la c e b o . O n ly tw o p at ie nt s re p o rt e d m ild s o m n o le n c e d u ring le v o s u l-
p irid e a d m in is t rat io n .
Co n c lu s io ns : Le v o s u lp irid e is e f f e ct iv e a n d w e ll t o le rat e d in p a t ie n t s w it h f u n c -
t io n a l d y s p e p s ia a c c o m p a n ie d by d e lay e d g a s t ric e m p ty ing . It s e f f ic a cy m ay b e re lat e d
t o it s a c t io n o n t h e g a s t ric m o t o r f u n ct io n by im p ro v in g t h e d e lay e d g a s t ric e m p ty ing .
───────────────────────────────────────────────────
Ke y W o rd s : Le v o s u lp ir id e , F u n ct io n a l d y s p e p s ia , Ga s t ric e m p ty in g

acute toxicity than both the racemic and dextro forms 2 - 4 ) .

INT R O D UC T IO N Due to its peripheral anti- dopaminegic action, levosul-
piride has a therapeutic role also in gastro- enterology as
Levosulpiride is the levo- enantiomer of sulpiride, a a modulator of the motor activity of the upper digestive
well- known antiemetic, antidyspeptic and antipsychotic tract5 - 1 1) . This double- blind, placebo- controlled study was
drug 1 ) . It has s hown greater central antidopaminergic undertaken to assess the efficacy of levosulpiride in
patients with functional dyspepsia accompanied by delay-
activity, antiemetic and antidyspeptic effects and lower
ed gastric emptying.
Address reprint requests to : Chi Wook S ong M.D. Depar-
tment of Internal Medicine, Korea University, College of
Medicine, 126- 1, 5Ka, Anam-Dong, Sung Buk-Ku. S eoul,
Korea

15
 C. W. S ONG, H.J. CHUN, C.D. KIM, H.S . R YU, J.G. CHOE, J.H. HYUN

selected for the study. Details of their dys pepsia histories,

MA T E R IA LS A N D MET HO D S
1. Patients
Forty two patients with functional dyspepsia accom-
panied by delayed gastric emptying were enrolled into the
study. The patients included 9 male and 33 female
patients with a mean age of 40 yr.(range 18- 64 yr.).
endoscopic findings, concomitant diseases, and current
drug treatments were recorded. Dyspeptic symptom
scores and the gastric half emptying time of a solid meal
were measured at the beginning of the study and after
3- week treatment of levosulpiride or placebo. Depending
on prevalent symptoms, patients with dyspepsia were
allocated into dysmotility- like, ulcer- like, reflux- like or
nonspecific dyspeps ia groups.

2. Inclus ion crite ria

5. Dys pe ptic symptom scoring
Outpatients with chronic or recurrent dyspepsia of
Dyspeptic symptoms were scored by the physician,
moderate to severe intensity were eligible for entry into
using a 4- point scale (0=absent; 1=mild; 2= moderate;
the study. The symptoms of dyspepsia included eructa-
3=severe), on entry and on completion of 3 week
tion, heartburn, regurgitation, early satiety, postprandial
treatment period. The physician and patient also made
bloating, anorexia, nausea, vomiting, epigastric pain or
independent global assessment of therapeutic efficacy,
soreness for more than 1 month. The subjects must have
indicated as excellent (complete relief of symptoms), good
at least one of the aforementioned symptoms with
(improvement with only occasional symptoms), fair (s light
moderate to severe intensity and also must have delayed
improvement with some persistence of symptoms), nil(no
gastric emptying to be eligible. Delayed gastric emptying
improvement) and poor (deterioration of symptoms).
was defined as the gastric half emptying time(T1/2) being
Adverse events were also assessed.
more than 100 minutes, according to gastric scintigraphic
measurements. The cut off value was established on the
basis of previous studies done in our laboratory and the 6. Meas ureme nt of gastric e mptying
normal range was 77.7± 12.1 minutes. Upper gastrointes-
A solid meal, scrambled egg sandwich, labeled with
tinal organic diseases were excluded by endoscopy, and
1mCi of Tc- 99m s ulfur colloid was administered, together
patients s howing typical symptoms of reflux disease such
with a orange juice. This standard meal provided about
as heartburn and regurgitation without any other
375Kcal. Thirty to sixty minutes before having their test
dyspeptic symptoms, or patients with reflux disease con-
meal and scintigraphy, a dose of levosulpiride/placebo
firmed by 24 hour esophageal pH study were excluded.
were administered to the patients . The data collection
None of the patients had a history of gastric surgery or
was started immediately after the meal in supine position
other physical conditions that could interfere with the
in a dual head gamma- camera. Both anterior and
performance or interpretation of the study. None of the
posterior images were taken simultaneously. The radioac-
female patients were pregnant or lactating and none had
tivity of the gastric area was recorded for 1 minute at
received drugs that could affect gastric motility during the
15- minute intervals for two hours. Throughout the study
week preceding the examination.
the examinees were allowed to move, but smoking,
eating and drinking were prohibited. The data were
3 . Allocation to treatme nt
corrected for the radio- isotope decay. The geometric
Levosulpiride 25mg t.i.d. or placebo were administered mean was calculated from the anterior and posterior data,
to 42 patients having functional dys pepsia with delayed then the gastric emptying curve was generated by least
gastric emptying for 3 weeks, randomly. In each subject, square fitting meth- od. The gastric half emptying time
the study medication was taken before the three main (T1/2) was defined as the time to be taken for one- half
meals. Concomitant use of antacids, antis pasmodics or of the test meal to be emptied.
other antidys peptic drugs was prohibited during the study.
7. Statistical ana lys is
4 . Study plan
To compare baseline with 3- week results, paired t
A medical examination was performed on the patients tests were conducted, and statistical s ignificance was

16
 EFFECTS OF LE VOS ULPIRIDE IN PA TIEN TS WITH FUNCTIONAL DYS PEPS IA
A CCOMPANIED B Y DELA YED GAS TRIC EMP TYING

established at the p＜0.05 level. Pearson correlation treatment in levosulpiride group were 10.8±4.5 and 5.2±
analysis was used for relations hip between changes of 3.2 respectively, whereas 9.3±3.4 and 8.7±3.9 in the
symptom score and gastric emptying time. placebo group(Fig. 1).

R E S U LT S

Forty two patients entered the trial. Their sex and age
distribution and pretreatment evaluation of total symptom
scores and gastric emptying time are presented in Table
1. According to the dys pe ps ia classification, 14 (33%) of

Ta ble 1. De mo g raphic a nd Pre tre atme nt Eva luatio n

of Patie nts Elig ible fo r Entry into The Tria l
Features Levosulpiride Placebo p- va lue
Age (yr) 40.9± 12.2 39.7± 16.3 NS
Sex (ma le :fe ma le) 4:17 5:16 NS
He ight (cm) 158.8± 6.3 16 1.3± 7.4 NS
We ight (kg) 52.5± 8.6 55.5± 9.6 NS
Tota l SS 10.8± 4.5 9.3± 3.4 NS Fig . 1. Tota l symptom scores before a nd afte r 3 wee ks of
GET (minute) 130.0±30.1 123.9±23.1 NS treatme nt with placebo or levosulpiride .
* : P＜0.05
SS; symptom score , GET; gastric e mptying time

The improvement of total symptom score of levo-

the 42 patients were diagnosed as having dysmotility- like
dyspeps ia, 4 (10%) ulcer- like, 4 (10%) reflux- like, and 20
(47%) nonspecific dys pepsia. 32 of 42 patients were
eligible for efficacy analys is, 17 patients were received
levosulpiride and 15 patients were received placebo.
1. Dys pe ptic symptom scoring
The total symptom score of baseline and 3- week after
s ulpiride group was higher than that of placebo group
(p=0.001). The global efficacy was assessed by physi-
cians as being excellent in 1 (6%), good 11 (65%), fair 4
(24%), nil 1 (6%) in the levos ulpiride group and fair in 9
(60%), nil 5 (33%) and poor 1 (6%) in the placebo group.
The patients assessments were similar, being excellent in
2 (12%), good 9 (53%), fair 3 (18%), nil 3 (18%) of those
receiving levosulpiride, and fair 4 (27%), nil 7 (47%), poor
4 (27%) of those receiving placebo(Fig. 2). Levosulpiride

Fig . 2 . Globa l eva luation afte r 3 wee ks of treatment with placebo or levosulpiride by phy-
s icia ns a nd patie nts .

17
 C. W. S ONG, H.J. CHUN, C.D. KIM, H.S . R YU, J.G. CHOE, J.H. HYUN

Fig . 3 . Improve ment of symptom scores before a nd afte r 3 weeks of treatme nt

with placebo or levosulpiride for the subgroups of functiona l dyspepsia . No
patie nts affected by reflux- like dyspepsia a re in the placebo group.
* : P＜0.05

showed a greater efficacy than placebo in relieving the

dyspeptic symptoms in the groups of dys motility- like
(p=0.02) and nonspecific (p=0.01)(Fig. 3).

2. Meas ure me nt of gastric e mptying

The gastric emptying time of baseline and 3- week

after treatment in levosulpiride group were 130.0±30.1
and 89.6±22.4 minutes respectively, whereas 123.9±23.1
and 106.1±23.6 minutes in the placebo group (Fig. 4).
The reduction of gastric emptying time in the levosulpiride
group was more marked than placebo group (p=0.01) (Fig.
5). There was a significant correlation between changes
of symptom score and changes in gastric emptying time Fig . 4 . Gastric emptying times before a nd afte r 3 wee ks
of treatme nt with placebo or levosulpiride .
(r=0.47, p=0.01).
GET : gastric emptying time
* : P＜0.05
3 . Adverse expe rie nces

No serious adverse effects were reported after admini-
stration of either levosulpiride or placebo. Only two pa-
tients reported mild somnolence during levosulpiride adm-
inistration.
D IS C US S IO N
Functional dyspepsia is very heterogeneous symptom
complex including nausea, vomiting, early satiety, post-
prandial fullness and epigastric pain without organic dis-
ease. The pathogenesis of dys peptic symptoms is
complex and still poorly understood and often related to
motor abnormalities of the upper gastro- intestinal tract.
Some cases of functional dys pepsia can be linked to
gastric motility disturbances with the frequency being
extremely variable (30- 60%)12 , 1 3 ) .
Recently, levosulpiride has been proposed in Europe
for therapy of psychotic, depressive and somatoform

18
 EFFECTS OF LE VOS ULPIRIDE IN PA TIEN TS WITH FUNCTIONAL DYS PEPS IA
A CCOMPANIED B Y DELA YED GAS TRIC EMP TYING

Fig . 5 . Improve me nt of gastric e mptying times before a nd afte r 3 wee ks of treatme nt with
placebo or levosulpiride for the subgroups of functiona l dyspepsia . No patie nts a re
affected by reflux- like dyspepsia in the placebo group.
GET : gastric e mptying time

disorders 14 ) and has also s hown that it is able to influence
gastric motor activity7 , 8 , 1 5 ) . The effect of levosulpiride on
gastric motility is quite the reverse of most drugs used for
the treatment of psychiatric disorders as most of these
drugs tend to decrease gastrointestinal motility. Therefore,
it is suggested that levosulpiride can control gastric
motility disturbances as well as controlling dyspeptic
symptoms from underlying depressive and somatoform
disorders . Levosulpiride is the active form of sulpiride that
blocks DA2 dopaminergic receptors at the central level
and at the s ubmucosal and myenteric plexus peripheral
level1 6 ) , which interacts with the cholinergic, adrenergic
and peptidergic fibers to regulate the motility of
gastrointestinal tract. Dopamine inhibits the cholinergic
neurons of the upper gastrointestinal tract and levosul-
piride acts as a prokinetic agent blocking the inhibition
and hence permitting a sustained cholinergic induced
contraction of smooth muscle cell in the myenteric plexus.
Several studies have shown that levosulpiride can incre-
ase interdigestive migrating motor complex (IMMC) by
means of manometry of gastric antrum 1 7 ) and also re-
duce the gastric emptying time measured by scinti-
graphy1 5 ) .
There are many studies about the effect of prokinetic
agents in the treatment of dyspeps ia 1 8 - 2 0 ) . The relief of
dyspeptic symptoms by these agents is superior to
placebo, however, the relief is not always accompanied
by an acceleration of gastric emptying2 1) . These results
s uggest that the subjective improvement of dyspeptic
symptoms may be the effect of drugs on central nervous
system. Furthermore, these discrepancies may be caused
by an inappropriate scoring system or technique to
evaluate functional dyspepsia.
There are a number of scoring systems for assessing
functional dyspepsia. So, in order to assess and evaluate
functional dyspepsia clearly, we used a modified scoring
system. For the grading of each symptoms, a diary table
was used. Once a day, the patient graded the intensity of
the symptoms on a scale of 0- 3. From this table, the
average grade for each symptoms could then be
calculated. Finally we used the total symptom score to
compare the effect before and after treatment of
levosulpiride or placebo.
In studying gastric motor function, there are a variety
of methods available, which in turn yield different results.
So far, to evaluate gastric motor function, gamma scinti-
graphy is the standard method because of its precision,
s implicity, and reproducibility. To achieve the best results
from gamma scintigraphy, solid bolus is used because it
is a better indicator of gastric motor function. A con-
venient measurement is the T1/2, or the time it takes for
one- half of the test meal to leave the stomach. Delayed

19
 C. W. S ONG, H.J. CHUN, C.D. KIM, H.S . R YU, J.G. CHOE, J.H. HYUN
gastric emptying is defined as gastric half emptying time
(T1/2) of more than 100 minutes (>mean＋2S D) accor-
ding to gastric scintigraphic measurements . This cut off
value was established on the basis of our laboratory
normal range, which is 77.7± 12.1 minutes.
The classification of functional dyspepsia has been
proposed as dys motility- like, reflux- like, ulcer- like and
nonspecific groups 2 1 ) . Although the class ification of func-
tional dyspeps ia patients into these groups was a purely
arbitrary and did not reflect the pathophysiologic mech-
anisms of functional dyspepsia, our results showed that
dysmotility- like and nonspecific groups had a more de-
layed gastric emptying than reflux- like and ulcer- like
groups. And levosulpiride improved dys peptic symptoms
greatly in dysmotility- like and nonspecific dyspepsia group
compared with placebo. However, we had some pro-
blems in sample size of reflux- and ulcer- like dyspeps ia
subgroup. The reasons why we had few patients in these
subgroups were probably due to inclusion criteria of these
subgroups. We excluded reflux- like dyspepsia if a patient
had typical reflux symptoms such as heartburn and
regurgitation without any other dys peptic symptoms or
gastroesophageal reflux disease confirmed by 24 hr
esophageal pH study. In a total group of functional dys-
pepsia accompanied by delayed gastric emptying, there
was a close relationship between changes of symptom
score and observed gastric emptying time.
After this trial, it has become necessary to compare
the effects of levosulpiride with other prokinetic agents.
Levosulpiride, when compared with metoclopramide or
domperidone, proved to be significantly more effective in
controlling chemotherapy- induced nausea and vomiting
and dyspeptic symptoms 7 , 2 2 ) . Also, it was well tolerated
and no extrapyramidal signs were observed.
Experimental studies and clinical controlled trials with
levosulpiride showed that it was extremely well tolerated
both in short and long term studies 9 , 1 1 , 2 3 ) . No side- effects
requiring intervention were recorded and laboratory tests,
electrocardiogram and arterial pressure were not modi-
fied 1 1 ) . As with other central antidopaminergic drugs,
levosulpiride can antagonize the inhibition of dopamine on
the prolactin producing cells of the anterior pituitary, thus
inducing a hypersecretioin of prolactin5 ) . However, in
humans , this effect is not dose- dependent, but rather
seems to be reduced after chronic treatment2 4 ) and in
most cases it does not induce clinical symptoms of
hyperprolactinemia.
In conclusion, our results suggest, by means of gastric
20
scintigraphy, that levosulpiride is able to stimulate gastric
motor activity during the digestive phase. Thus levosul-
piride appears to be an effective agent for the treatment
of functional dyspepsia with delayed gastric emptying.
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