Efficacy of Trimebutine Maleate in the Treatment of Functional Dyspepsia in Childhood

Address for correspondence Alexander A. Nijevitch PO Box 4894, Ufa-57, 450057, Russia E-mail: aanj@rambler.ru How to cite this article ? Nijevitch AA, Akhmadeeva EN, Sataev UV, Idrisov B. Effi cacy of Trimebutine Maleate in the Treatment of Functional Dyspepsia in Childhood. J Nepal Paediatr Soc 2013;33(2):158-162. Efficacy of Trimebutine Maleate in the Treatment of Functional Dyspepsia in Childhood


Introduction
P aediatric functional gastrointestinal disorders in childhood include a combination of chronic or recurrent symptoms and are not explained by structural or biochemical abnormalities 1 .The most common complaint among children until the age of 15 is a recurrent abdominal pain (RAP) 2 .Only in 5-10% of the children RAP symptom has an underlying organic nature associated with the complaint 3 .Among the children with functional dyspepsia (FD), RAP was determined in 70% patients 2 .The Rome III committee defi ned FD as the presence of complex of symptoms including epigastric pain and meal-induced dyspeptic symptoms, comprising a large number of non-painful symptoms (postprandial fullness, early satiety, abdominal bloating, belching and postprandial nausea) in the absence of any organic, systemic or metabolic disease that may explain the symptoms.Any combination of these symptoms may intermittently occur over time 4 .Thus, dyspepsia is an extremely common condition in paediatric practice 4 .Over 50% of dyspeptic patients in childhood alongside with RAP suffered from nausea, vomiting, bloating, early satiety and nocturnal awakening 2,5 .Nevertheless, the "dyspepsia" term is non-specifi c and is often used to describe non-identical symptoms and complaints in different groups of patients.Nowadays, FD remains a clinically important problem in paediatrics associated with considerable health and the experience of signifi cant decrease in quality of life.
The etiology and pathogenesis of FD remain still unclear and have not been fully elucidated 21 .
Several factors have been proposed in individual patients: delay in gastric and small bowel transit time, decreased postprandial gastric volume accommodation, augmented visceral sensitivity and perception.Disturbed gastrointestinal functions are believed to play an important role in the development of FD-associated symptoms in adolescents 5,6 .
Unfortunately, pharmacological treatments for patients with FD remain unsatisfactory.Standard empirical treatment with antisecretory drugs or prokinetic agents demonstrated heterogeneous results in different clinical trials 7,8,9 .
Very limited and confl icting clinical information is available regarding opioid agonists for FD treatment 8,10,11,12 .Trimebutine maleate (TM), an encephalinergic receptor ligand [3,4,5-trimethoxybenzoic acid 2-(dimethilamino)-2 phenylbutylester] acts as an agonist on peripheral μ, k-and δ-opiate receptors by triggering phase III of the migrating motor complex 13 .TM has been reported to have a dual action on gastric motility: 1) a stimulatory effect on the hypomotile gastrointestinal tract; 2) an inhibitory effect on the hypermotile tract 14 .TM modifi es gastric motility by an increase in frequency of slow wave of peristalsis and blocks cholinergic transmission and Ca 2+ infl ux1 5,16 .Few clinical and experimental studies suggest a benefi cial effect of TM on gastric emptying and propulsive electromechanical activity in the gastrointestinal tract 14,17 and local anesthetic property, which is 17 times more potent than classic drug lidocaine 18,19 .The experience of TM usage in childhood is very restricted, furthermore it is one of the few paediatric drug approved by the Ministry of Health in Russia and the only one approved by Ethical Committee of our hospital where given research was conducted 9 .The aim of this study was to assess the effectiveness of TM for the treatment of paediatric FD patients.

Materials and methods
This was a prospective, open-label study conducted on February, 2011 through February, 2012.The study was carried out in a tertiary center setting.During the above mentioned period, 161 paediatric outpatients 12-17 years of age (mean age 13.7+1.3years; 93 girls, 68 boys), who consecutively referred to our unit (Outpatient Department of Children Republican Hospital, Ufa, Russia) with persistent upper abdominal dyspeptic complaints, were considered for the study.The initial evaluation included the standard tests (complete blood count, sedimentation rate, urinalysis, liver and pancreatic profi les, stool cultures and stool examination for ova and parasites).Before endoscopy, pancreatitis, cholecystitis and anatomical abnormalities were excluded using abdominal ultrasonography.All patients or their parents (if subject was younger than 14 years old) approved an informed consent prior to the procedure.The presence of chronic infl ammatory bowel disease, lactose malabsorption and celiac disease was assessed by means of standard diagnostic procedures.Esophageal pH monitoring was performed in selected patients.
Upper gastrointestinal endoscopy is a routine examination for RAP patients with persistent symptoms in our hospital.We used endoscopy to rule out H. pylori associated diseases (gastritis, duodenitis, peptic ulcer disease), esophagitis and celiac disease in the study group.
Endoscopy was performed via an Olympus GIF XP20 endoscope (Olympus Optical, Tokyo, Japan) after overnight fasting and without any prior local medication.During endoscopy, four biopsy samples (from antrum and body) were obtained to estimate the mucosal infl ammation and H. pylori presence.Histologic examination of sections was performed with HE and Giemsa staining.The patients with organic disease (esophagitis, H. pylori-associated gastritis, peptic ulcer disease, pancreatitis, infl ammatory bowel disease), or other forms of gastrointestinal functional disorders (irritable bowel syndrome), parasitic infestation (ascariasis, giardiasis) were excluded from the study.Also, the patients were excluded, who had received previous treatment with PPI, bismuth salts, prokinetics, antibiotics, non-steroidal anti-infl ammatory drugs (NSAID) or medications known to affect gastrointestinal motility.
Subject inclusion criteria's were three of the following symptoms (recurrent epigastric pain or mealinduced dyspeptic symptoms): postprandial fullness, upper abdominal bloating (and belching), early satiety and nausea with having onset at least 6 months prior to the appointment and presented at least twice a week within the preceding 3 months.So all of the FD patients (n=92) were included.Trimedat ® (trimebutine maleate) (Valenta Pharmaceutica, Shchelokovo, Russia) was administered during 3 weeks at the entry of the study, according to the conditions of use established in the products technical form (100 or 200 mg of TM per tablet).The dose was 200 mg three times daily.Fully informed consent of the patients (or their parents) was obtained for every procedure that was performed.Approval of the study protocol by the Ethics Committee of Children's Republican Hospital was not obtained because the study medication was a commercialized product and was prescribed for approved indications of use.Both verbal and printed instructions were given to all the patients and their parents.The instructions comprised dosage, symptoms assessment scale, possible side effects, et cetera.For ethical reasons, no placebo group was included.
A detailed history and physical examination were obtained from each patient before endoscopy.Information about the symptoms was collected via a dedicated questionnaire completed by children and their parents.The severity of symptoms was graded from 0 to 3 (0= no symptoms, 1= easily tolerable/mild, 2= affecting normal daily activities/moderate, and 3=preventing normal daily activities/severe).The study included 2 visits.The fi rst visit with initial evaluation was at the study entry.The fi nal visit was performed and examination was repeated in 6 months after the management period completion (after the last dose of the drug).At the end of the 3 weeks treatment, all the patients were asked for assessment of compliance and side effects.Compliance was graded as excellent of over 80% of the provided drug had been used, fair if 60-80% had been used and poor if less than 60% had been used.
The signifi cance of difference in categorized data was tested by the Wilcoxon test.For the test, a p-value under 0.05 was considered to have statistical signifi cance.

Results
This was a single center study.The diagnosis of FD was confi rmed in 92 patients (57.14%).Compliance was excellent in the majority of the patients (83.6%, 77 children), good in 13 (14.1%)and fair in 2 (2.2%) of the patients.There were no side effects or adverse reactions, caused by the drug, which lead to disconfi rmation or modifi cation of the treatment regimen.Three patients were lost to follow up.
The management results are presented in Table 1.Response to the treatment can be considered as satisfactory.The best results were obtained in resolution of epigastric pain, postprandial fullness and early satiety, nausea and belching (p<0.05).Complete relief of symptoms occurred in 83 (90.22%) outpatients in the present study.

Discussion
Functional dyspepsia is a long-lasting gastrointestinal disorder with a very good prognosis 22 .However, recent investigations suggest that many children with RAP demonstrated well response to reassurance, but continue to suffer from the symptoms in adulthood 20 .
Optimal initial evaluation of FD syndrome patients is debatable 7 .In our opinion, although ulcer-like symptoms are not reliable as a predicting marker of peptic ulcer, endoscopy is indispensable in separation of organic disease (for example H. pylori infection or celiac disease) from functional gastrointestinal disorder, such as FD.H. pylori infection may play an important role in dyspeptic symptoms development in paediatric patients 23 .At the same time, some previous studies indicate that H. pyloriinfected children cannot be differentiated from those who are not on the basis of their presenting symptoms 24 .Obviously, immediate upper gastrointestinal endoscopy may present the most cost-effective approach in this case.The opposite option is an empiric therapy with antisecretory or prokinetic drugs.Unfortunately, antisecretory drugs (H 2 -receptor antagonists or PPI) can only be helpful with the patients with acid-related dyspeptic symptoms 25 .Since nearly 40% patients with FD demonstrated delay in gastric emptying, prokinetics is often employed in the FD treatment.Gastric emptying does not response to PPI treatment 26 , and PPIs use in the patients with FD-associated motility disorders will make no sense 4,27 .At the same time, modern studies do not fi nd any association between gastric emptying and epigastric pain, early satiety, bloating or nausea 28 .Unfortunately, wide use of standard prokinetics such as metoclopramide and domperidone in childhood is very limited owing to their side effects, including dystonic reaction and extrapyramidal disorders 29 .Based on lack of clarity, pharmacotherapy for FD varies widely 30 .Symptom-guided empiric treatment strategies have shown mixed results 27 .The chronic abdominal pain of FD is diffi cult to treat.PPIs have a signifi cantly smaller effect on visceral pain compared to some prokinetic drugs 4 .Furthermore, recently competent recommendations have been presented, showing that there are no convincing data on the use of prokinetic drugs in children with FD 29 .TM has been used in many western countries for the treatment of functional gastrointestinal disorders 31 .TM [2-dimethylamino-2-phenylbutyl-3,4,5trimethoxybenzoat hydrogen maleate] is a non-selective agonist of peripheral μ-, k-and δ-opioid receptors 18 .The mechanisms by which TM is benefi cial in FD patients remain incompletely understood 32 .It has been postulated that the association of weak opioid property of TM with sodium channel blockade and strong local anesthetic properties explains the effectiveness of TM in abdominal pain treatment 18 .At the same time 1 , through opiate receptors, TM mediate release of gastrointestinal peptides, such as motilin, and modulation of the release of other peptides, including vasoactive intestinal peptide, gastrin and glucagon 33 .TM has a safe toxicological profi le and demonstrates excellent tolerability 32 .There is no evidence to reveal that TM acts at the level of the central nervous system and crosses the blood-brain barrier 19 .
Painful dyspepsia is a main indication for TM as well as irritable bowel syndrome and esophagitis 34,35,36,37 .Recently, a Chinese study 10 has shown high effi cacy of TM in FD treatment.A four week course of TM treatment demonstrated a signifi cant decrease in scores of postprandial fullness, early satiation, abdominal pain and total score of symptoms of FD (p<0.05) in comparison with probiotic management.TM in our study has revealed an excellent effectiveness in FD symptoms relief in paediatric patients.TM was well tolerated and encouraged good compliance.Unfortunately, our study has several important limitations.The fi rst is a relatively low number of study patients.The second is an open-label design and absence of a placebo group or a group of comparison.Another limitation is a very short followup period.Relief of symptoms was assessed over a 6 months period, whereas FD is a chronic condition often persisting for many years 4 .These limitations should be taken in account when considering the results of our survey.

Conclusion
Despite all the limitations in our work, we regard further investigations of TM in paediatrics is necessary.It is important to develop a safe, well-tolerated and evidence-based therapy for children suffering from dyspeptic syndrome and recurrent abdominal pain, as well as to provide high level of their quality of life.A universal approach to the treatment of FD-associated symptoms in childhood has not been developed because the pathophysiologic mechanisms of FD are heterogeneous and probably different for children and adults.

Table 1 :
Comparison of clinical symptoms before and after treatment