Download Itopride in the Treatment of Dysmotility

Received: July 2010
Accepted: September 2010
ORIGINAL ARTICLE
Itopride in the Treatment of Dysmotility-like Functional Dyspepsia:
A Randomized, Placebo-Controlled Trial
Sebastian Saji
Department of Gastroenterology, Government Medical College, Trichur, India
ABSTRACT
Background and Objectives: The treatment of patients with functional dyspepsia remains unsatisfactory, though
prokinetic drugs are widely used for treatment of functional dyspepsia. We designed a randomized, placebo-controlled trial
to assess the efficacy and safety of a new prokinetic drug itopride hydrochloride, a dopamine D2 antagonist with antiacetylcholinesterase effects, in patients with dysmotility-like functional dyspepsia.
Methods: Sixty-seven eligible patients were enrolled and were randomly assigned to receive either itopride 10 mg three
times a day or placebo for a period of 4 weeks. Patients were re-assessed at 2 and 4 weeks for improvement in dyspepsiaspecific symptom score (pain/discomfort, fullness, bloating, early satiety, and nausea/vomiting), global symptom score and
and the effect on subjective global assessment of relief. Adverse events also were recorded.
Results: The symptom scores prior to treatment were comparable in the both groups. After completion of 2-week and 4week treatment, the symptom scores were significantly lower in the itopride group compared to the placebo group (11.2 ±
4.0 vs 15.03±4.2; p = 0.0003) and (9.3±4.1 vs 14.4±5.8; p = 0.0004), respectively. The subjective assessment of global relief
was significantly higher in the itopride group (11 of 33patients) compared to 1 of 34 patients in the placebo group.
Conclusions: Itopride is superior to placebo in the treatment of functional dyspepsia having bloating and fullness as their
predominant symptoms. It can be used safely in this subset of patients where proton pump inhibitors may not be very
effective.(J Dig Endos 2010;1(4):171-75)
Key words: Itopride - Functional dyspepsia - Placebo
Introduction
Chronic or relapsing dyspeptic symptoms that occur in
absence of clinically identifiable structural lesions are called
1
functional dyspepsia. Dyspepsia is a common problem
encountered in clinical practice. Dyspepsia by definition is
not one symptom but a constellation of symptoms which
include bloating, early satiety, post prandial fullness, nausea,
2
anorexia, heartburn, regurgitation and burping. Treatment
approaches that have been tested include use of anti secretory
agents, prokinetic agents and H.pylori eradication. But the
3
benefits of such approaches have been modest. About 40%
of patients with functional dyspepsia suffer from delayed
gastric emptying or disturbed gastrointestinal function which
Journal of Digestive Endoscopy 2010;1(4):171-75
4
is believed to play a role in development of symptoms.
Meta-analysis by Moayyedi et al demonstrated that patients
with dysmotility symptoms (bloating, early satiety, post
5
prandial fullness) do not respond to anti secretory treatment.
In this sub group of patients prokinetic agents like cisapride
has demonstrated superiority over placebo.6-8 But safety
profile of these agents are major concern which restricts their
use.9,10 So there is a strong need for identifying an effective
Reprints requests and correspondence:
Sebastian Saji
Assistant professor and Head of the Department
Department of Gastroenterology,
Government Medical College, Trichur, India
E-mail: [email protected]; Phone -09846831368
171
Itopride in the Treatment of Dysmotility
Sebastian Saji
and safe prokinetic agent.
Itopride is one such drug with gastroprokinetic action
due to its dual mode of action viz. dopamine D2 receptor
11
antagonist and acetylcholine esterase inhibition. This will
lead to increased levels of acetylcholine in upper gastrointes12
tinal tract leading to stimulation of gastric motility. As
itopride has no affinity for 5HT4 receptors it has no undesir13
able cardiac effects. Since it is not metabolized by
cytochrome p450 enzyme it does not have any significant
14
drug interactions.
Little is known about the dose response of itopride in
these functional dyspepsia patients with dysmotility symptoms as their predominant complaint. Efficacy of itopride in
15
various populations also has to be determined.
Hence we aimed to study the efficacy and safety of
itopride in patients with functional dyspepsia having bloating
and post prandial fullness as their predominant symptom.
Materials and Methods
Study design
The present study was a randomized double blind
placebo-controlled trial conducted in the Department of
Gastroenterology between January 2006 to December 2006.
The study was approved by institutional ethics committee.
All patients enrolled for the study gave written informed
consent for the study.
Patient populations
16,17
Patients who satisfied Rome II criteria
in the age
group of 18 to 60 yrs with predominant bloating and post
prandial fullness were eligible for the study. Functional
dyspepsia was diagnosed if persistent upper abdominal
discomfort was present. Discomfort was characterized by
presence of early satiety, post prandial fullness and bloating
present for at least 12 weeks in a period of 12 months, without
an identifiable structural or biochemical abnormality to
which it can be attributed.
Exclusion criteria were: organic gastrointestinal or systemic
diseases; diabetes mellitus; pregnancy or lactation; previous
abdominal surgery (except appendectomy); mental disorders; and the use of drugs interfering with gastrointestinal
motility, cardiac disease, hypersensitivity reactions, predominant reflux symptoms, unwilling for follow up and those on
medication altering gut function (macrolides). Consecutive
patients who satisfied the strict inclusion criteria were only
included.
Dyspeptic symptom scoring
Before the patients could be included in the trial,
demographic data and baseline symptoms were recorded in a
proforma. Individual symptoms were assessed using
modified mean global severity index (Dyspepsia severity
18
index of De Luca et al) a validated scoring system. A total of
172
five following symptoms were evaluated prior to enrolment
and 2-week and 4-week after treatment: (1) upper abdominal
pain or discomfort (2) post prandial fullness, (3) bloating, (4)
early satiety and (5) nausea/vomiting. Each symptom was
graded according to the intensity and frequency on a 4-point
score from zero to three. Adding together we get the total
score of each symptom and adding all the scores we get the
global dyspepsia symptom score. By dividing the global
dyspepsia symptom score by 5 we get the mean global
dyspepsia score. The intensity of discomfort was scored as: 0,
no discomfort; 1, mild discomfort; 2, moderate discomfort;
and 3, severe discomfort. The frequency was scored as: 0,
never; 1, 1-2 days a week; 2, 3–4 times per week; 3, 5 or more
times per week.
A complete physical examination and routine blood
investigations (hemogram, blood glucose, urea and
creatinine, liver function tests, serum electrolytes) were done
to rule out organic diseases. All the patients underwent upper
gastrointestinal endoscopy and ultrasonography to rule out a
structural cause for the symptoms. Electrocardiogram was
performed before the drug was administered and corrected
QT interval calculated.
Randomization and blinding
Randomization was done using random table allocation. Group A received Itopride 50mg thrice daily half an
hour before major meals (itopride group) and Group B
received identical looking placebo tablets three times daily
before major meals in a double blind fashion for 4 weeks
(placebo group). The drugs were dispensed only for 2 weeks
at a time so as to check the dyspepsia symptom score, sideeffects and compliance by means of pill count at review visit.
Outcome measures
Patients were reviewed every 2 weeks. At each visit
symptom scores were calculated and subjective global
assessments of relief of symptoms were also calculated. Any
adverse events occurring were also recorded. At the end of 4
weeks an ECG was taken. If at review patient had intractable
symptoms only antacids were allowed to take.
19
Subjective global assessment (SGA) of relief was
assessed by answering following questions. Please consider
how you felt in the past 2 weeks with regard to your functional dyspepsia symptoms in particular overall well being
and symptoms of abdominal discomfort, bloating, post
prandial fullness, early satiety and nausea. Compared to the
way you usually felt before entering the study, how would
you rate your relief of symptoms during past 2 weeks?
Possible answers were: completely relieved; considerably
relieved; some what relieved; unchanged; or worse.
Bloating and fullness are considered as two most
important symptoms of functional dyspepsia evaluated in our
study. We evaluated the severity of bloating and fullness after
food intake as important end points. Only those who became
completely symptom free and markedly improved were
Journal of Digestive Endoscopy 2010;1(4):171-75
Itopride in the Treatment of Dysmotility
Sebastian Saji
taken as improvement in our study.
Outcome variables – change in symptom score and
SGA of relief at 2 and 4 weeks of treatment were the outcome
variables assessed in our study
Statistical analysis
It was done using SPSS version 10. Data were expressed
as mean ± SD Comparison between itopride and placebo
was done using paired‘t’ test and Wilcoxon signed rank test. p
value of less than 0.05 was accepted as statistically significant.
Itopride
Results
Ninety-two patients were screened for the study; of
them 67 patients with predominant bloating and post
prandial fullness were included in the study. Thirty-three
patients were randomly assigned to receive itopride and 34
were assigned to receive placebo. There were seven drop
outs, three in the itopride and four in the placebo groups. Six
of them (3 each in itopride and placebo groups) did not return
for follow up. One patient had met with an accident. The
data reported are only for the intent-to-treat population. An
overview of the trial is illustrated in Figure 1. The baseline
demographics of the patients were comparable in both
treatment groups (Table 1).
Placebo
18
16
14
12
10
8
*
6
*
4
2
0
Visits
1
2 weeks
2
4 weeks
3
Subjective global assessment of relief
After 2 weeks of treatment 5 patients in itopride group
and one patient in placebo group had grade 1 or 2 SGA of
relief. After completion of treatment 11 patients in itopride
group and one patient in placebo group had significant
improvement in symptoms assessed by SGA of relief.
Adverse events
Response to treatment
The symptom scores prior to the initiation of treatment
was comparable in both groups (16.9±3.7 in the itopride
group and 16.7±4.3 in the placebo group). After 2 weeks of
treatment the symptom score was significantly lower
(11.2±4.0) in itopride group compared to the placebo group
(15.03±4.2; p = 0.0003) After completion of treatment the
decrease in symptom score was significant (p=0.0004) with
9.3±4.1 in the itopride group and 14.4±5.8 in the placebo
group. (Figure 2)
Journal of Digestive Endoscopy 2010;1(4):171-75
No major adverse effects were noted during the study.
Two patients in the itopride group developed adverse effects
consisting of aphthous ulceration and abdominal discomfort
in one patient each. Constipation occurred in five patients in
the placebo group. ECG taken prior to treatment and after
treatment did not show any prolongation of corrected QT
interval.
Discussion
Disturbance in gastrointestinal motility and sensory
function are believed to play a key role in development of
20,21,22
symptoms in patients with functional dyspepsia.
Itopride is known to exert prokinetic effect by way of
173
Itopride in the Treatment of Dysmotility
antidopaminergic and anti acetylcholine esterase action and
so have effects on gastric accommodation and gastric
hypersensitivity. The symptoms of bloating and post prandial
fullness are linked to gastric accommodation and hypersensitivity. Hence itopride giving significant relief of bloating and
fullness in patients with functional dyspepsia is tenable.
There are only very few randomized double blind
placebo controlled trials of itopride available in the literature.
Most of the studies are on patients with functional dyspepsia.
None of the studies have compared the efficacy of itopride in
subgroup of patients with predominant bloating and fullness.
That too in one of the large studies, itopride had shown
significant improvements in symptoms of functional
23
dyspepsia.
But some studies did not report significant difference
24
in relief of symptom when compared to placebo. But this
may be due to inclusion of all patients with functional
dyspepsia instead of those with predominant dysmotiliy.
There are no studies available in the literature in which
itopride has been tried in the subgroup of patients with
predominant dysmotility symptoms. Itopride has also been
25
26
compared with domperidone as well as with mosapride
and was found to have better efficacy and tolerability.
This trial had strict entry criteria (only those with
predominant bloating and fullness) and application of valid
outcome measures. Those with predominant reflux symptoms were excluded from the study, as they may have
response to prokinetics.
The data shows that itopride is effective in this sub
group of functional dyspepsia patients when compared to
placebo. We observed a statistically significant difference in
symptom score of patients with functional dyspepsia
(predominant bloating and distention) in the itopride group
when compared to the placebo group as early as 2 weeks after
initiation of treatment. This statistically significant difference
in the symptom score persisted at completion of treatment.
Our results showed an advantage for itopride in patient’s
overall satisfactory relief from functional dyspepsia symptoms measured by SGA of relief, a validated efficacy measure
that assess the impact of treatment on functional dyspepsia
related symptoms.
Sebastian Saji
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Conclusion
In summary results of our study shows that itopride is
superior to placebo in the treatment of functional dyspepsia
having bloating and fullness as their predominant symptoms.
It can be used safely in this subset of patients where proton
pump inhibitors may not be very effective.
References
1.
174
Richter JE. Dyspepsia organic causes and differential
characteristics from functional dyspepsia. Scan J
Gastroenterol Suppl. 1991;182:11-6.
15.
16.
17.
Mark Feldman, Lawrence S. Freidman, Lawrence J.Brandt.
Sleisenger and Fordtran’s Gastrointestinal disease 8th edition
Chapter 7 Dyspepsia by Kenneth R. McQuaid Page 121
Saunders.
Holtman G, Talley N J. Functional dyspepsia – current
treatment recommendations. Drugs 1993;45:918-30.
Talley NJ. Functional dyspepsia should treatment be targeted
on disturbed physiology? Aliment Pharmacol Ther 1995;
9:107-15.
Moayyedi P, Delaney BC, Vakil N, Forman D, Talley NJ. The
efficacy of proton pump inhibitors in nonulcer dyspepsia: a
systematic review and economic analysis. Gastroenterology
2004; 127: 1329-37.
Ta l l e y N J , Va k i l N B , M o a y y e d i P. A m e r i c a n
Gastroenterological Association technical review on the
evaluation of dyspepsia. Gastroenterology 2005;129:1756-80.
Dobrilla G, Comberlato M, Steele A, Vallaperta P. Drug
treatment of functional dyspepsia: a meta-analysis of
randomized controlled clinical trials. J Clin Gastroenterol
1989;11:169-77.
Veldhuyzen van Zanten SJ, Jones MJ,Verlinden M, Talley NJ.
Efficacy of cisapride and domperidone in functional (non
ulcer) dyspepsia: a meta-analysis. Am J Gastroenterol 2001;
96: 689-96.
Gupta S, Kapoor V, BM Gupta, Kapoor B, Verma U, Gupta V.
Effect of Itopride hydrochloride on QT interval in adult
healthy volunteers Clinical Pharmacology JK Practitioner
2005;12:207-10.
Ohki R, Takahashi M, Mizuno O, Fujikawa H Mitsuhashi T,
Katsuki T, Ikeda U et al. Torsades de pointes ventricular
tachycardia induced by mosapride and flecainide in the
presence of hypokalemia. Pacing Clin Electophysiol 2001;
24:119-21.
Kaikiuchi M, Saito T. Pharmacological evaluation of Itopride
hydrochloride with regard to drug induced arrhythmia. Jpn
Pharmacol Ther 1997;25:811-7.
Iwanaga Y, Miyashita N, Saito T, Morikawa K, Itoh Z. Gastroprokinetic effect of a new benzamide derivative itopride and
its action mechanisms in conscious dogs. Jpn J Pharmacol
1996;71:129-37.
Pasricha PJ. Prokinetic agents, antiemetics agents used
inirritable bowel syndrome. In: Hardman JG et al (eds.),
Goodman and Gilman’s. The Pharmacological Basis of
Therapeutics, 10th edition, New York, McGraw Hill Book
Inc.2001; pp 1021.
Mushiroda T, Douya R, Takahara E, Nagata O. The involvement of flavin containing monooxygenase but not CYP3A4 in
metabolism of itopride hydrochloride, a gastrokinetic agent:
comparison with cisapride and mosapridecitrate. Drug Metab
Dispos 2000;28:1231-37.
Chiba T, Tokunaga Y, Ikeda K, Takagi R, Chishima R, Terui T,
Kudara N et al. Effects of itopride hydrochloride and
ranitidine in patients with functional dyspepsia: comparison
between prokinetic and acid suppression therapies.
Hepatogastroenterology 2007;54(78):1878-81.
Talley NJ, Stanghellini V, Heading RC, Koch KL, Malagelada
JR, Tytgat GN. Functional gastroduodenal disorders. Gut
1999;45:Suppl 2: II37–42.
Drossman DA. The Rome II modular questionnaire. In:
Drossman DA, Corazziari E, Talley NJ, Thompson WG,
Journal of Digestive Endoscopy 2010;1(4):171-75
Itopride in the Treatment of Dysmotility
18.
19.
20.
21.
Whitehead WE, eds Rome II - The functional gastrointestinal
disorders: Diagnosis, pathophysiology and treatment: A
multinational consensus. McLean VA: Degnon Associates
2000:360
DeLuca C, Zagari RM , Pozzato P, Fiorini T, Ricciardiello L,
Martuzzi C, Roda E,. Measuring dyspesia: A new severity
index validated in Bologna. Dig Liver Dis 2004;36:806-10.
Muller-Lissner S, Koch G, Talley NJ, Drossman D, Rueegg P,
Dunger-Baldauf C, Lefkowitz M. Subject’s global assessment of relief on IBS related symptoms in clinical trials. J Clin
Epidemiol 2003;56:310-6.
Holtmann G, Gschossmann J, Neufang-Huber J, Gerken G,
Talley NJ. Differences in gastric mechanosensory function
after repeated ramp distensions in non consulters with
dyspepsia and healthy controls. Gut 2000;47:332-6.
Holtmann G, Talley NJ, Mitchell H, Hazell S. Antibody
response to specific H. pylori antigens in functional dyspepsia, duodenal ulcer disease, and health. Am J Gastroenterol
1998;93:1222-7.
Sebastian Saji
22.
23.
24.
25.
26.
Zighelboim J, Talley NJ. What are functional bowel disorders? Gastroenterology 1993;104:1196-201. [Erratum,
Gastroenterology 1993;105:649].
Holtmann G, Talley NJ, Liebregts T, Adam B, Parow C. A
placebo-controlled trial of itopride in functional dyspepsia. N
Engl J Med 2006;354:832-40.
Talley NJ, Tack J, Ptak T, Gupta R, Giguère M. Itopride in
functional dyspepsia: results of two phase III multicentre,
randomised, double-blind, placebo-controlled trials. Gut
2008;57:740-6. Epub 2007 Oct 26.
Sawant P, Das HS, Desai N, Kalokhe S, Patil S. Comparative
evaluation of the efficacy and tolerability of itopride hydrochloride and domperidone in patients with non-ulcer
dyspepsia. J Assoc Physicians India 2004;52:626-8.
Amarapurkar DN, Rane P. Randomised, double-blind,
comparative study to evaluate the efficacy and safety of
ganaton (itopride hydrochloride) and mosapride citrate in the
management of functional dyspepsia. J Indian Med Assoc
2004;102:735-7, 760.
Source of support: Nil; Conflict of interest: none declared
Journal of Digestive Endoscopy 2010;1(4):171-75
175