British Journal of Clinical
Pharmacology
Adverse effects reported in the use of gastroesophageal reflux disease treatments in children: a 10 years literature review
Shlomi Cohen,1,2,3 Mirjam Bueno de Mesquita1,2 & Francis B. Mimouni2,3,4
1The Pediatric Gastroenterology unit, 2Department of Pediatrics,
4Division of Neonatology, Shaare Zedek Medical Center, Jerusalem, Israel
DOI:10.1111/bcp.12619
Correspondence
Dr Shlomi Cohen, MD, Pediatric Gastroenterology Unit,
Children’s Hospital, Tel Aviv Medical Center, 6 Weizman Street, Tel Aviv, 64239,
Israel.
Tel.: + 972 3 697 4515
Fax: + 972 3 697 4181
Keywords
antacids, children, gastroesophageal reflux disease, histamine H2 receptor antagonists, metoclopramide,
prokinetics, proton pump inhibitors
Received
14 October 2014
Accepted
26 February 2015
Accepted Article
Published Online
5 March 2015
Gastroesophageal reflux (GER) is commonly observed in children, particularly during the first year of life. Pharmacological therapy is mostly reserved for symptomatic infants diagnosed with GER disease (GERD), usually as defined in a recent consensus statement. The purpose of the present article was to review the reported adverse effects of pharmacological agents used in the treatment of paediatric GERD. We conducted this review using the electronic journal database Pubmed and Cochrane database systematic reviews using the latest
Introduction
Gastroesophageal reflux (GER) is commonly observed in children, particularly during the first year of life. Up to 65% of infants regurgitate stomach contents at least once a day at the age of
complicated GER, or GER disease (GERD), usually as defined in a recent consensus statement [2].
The purpose of the present article was to review re- ported AEs of pharmacological agents commonly used in the treatment of paediatric GERD.
Search strategy
We conducted the present review using the electronic jour- nal database Pubmed and Cochrane database systematic reviews, using the latest
© 2015 The British Pharmacological Society |
Br J Clin Pharmacol / |
S. Cohen et al.
31 December 2012). Our search strategy included the fol- lowing keywords: omeprazole, esomeprazole, lansoprazole, pantoprazole, ranitidine, cimetidine, famotidine, nizatidine, domperidone, metoclopramide, betanechol, erythromycin, baclofen and alginate. For each search and for each pharmacological agent we used the term: ’AND GERD’ in order to retrieve only the side effects of these agents when used to treat GERD (and no other therapeutic indication). In order to limit our search to articles related to the paediatric population, we used Pubmed’s own filter of: ’child: birth– 18 years’, ’humans only’, published in English. We also scrutinized the citations of the retrieved articles for any references not identified by our search. All full articles were reviewed and included only randomized controlled trials retrieved from our Pubmed search, or from our search of the references found in the articles. All AEs reported were recorded by drug and by article, without exception. Below is a summary of our search, on a
Results
Proton pump inhibitors (PPIs)
PPIs are the most frequently prescribed medications for the treatment of adults and children with GERD. Their effectiveness for the treatment of peptic conditions in the paediatric population is well established [3]. The effectiveness of PPIs relates to their structure, which must undergo acidic activation within the parietal cell to allow the PPI to be ionized and form covalent disulfide bonds with cysteine residues of the
Esomeprazole Esomeprazole is the
A total of 69 articles on esomeprazole were retrieved. Only 12 were found to be relevant, in that they addressed a paediatric population treated for GERD
Table 1
Proton pump inhibitors
articles were excluded because of mislabelling (dealing with an adult population), because the indication for ther- apy was not GERD, because they were not original articles (reviews mostly) or because they did not report AEs.
The cumulative sample size of all these studies was 764 paediatric patients, ranging in age from 0 to 17 years (five studies dealt with patients <1 year).The studies were difficult to combine as the doses used ranged from 0.5 mg
Omeprazole A total of 133 articles on omeprazole were retrieved but only 10 were relevant
|
Esomeprazole |
Omeprazole |
Lansoprazole |
Pantoprazole |
Rabeprazole |
Number of articles identified |
69 |
133 |
54 |
34 |
39 |
Number of paediatric articles |
12 |
10 |
9 |
6 |
2 |
Sample size |
764 |
318 |
620 |
340 |
52 |
Placebo controlled studies |
309 |
295 |
207 |
128 |
52 |
|
|
|
|
|
|
2 / Br J Clin Pharmacol
flatulence in one (0.3%); somnolence in three (0.9%); constipation in six (1.9%); arthralgia in three (0.9%); and headache in one patient (0.3%).
Lansoprazole
Pantoprazole
Rabeprazole Rabeprazole has a greater antisecretory potency relative to equivalent doses of the above- mentioned PPIs [42]. We retrieved 39 articles on
Gastroesophageal reflux disease in children
rabeprazole but only two were paediatric RCTs and were retained for analysis [43, 44]. The cumulative sample size was 52 outpatients, ranging from 1 to 16 years of age; doses used ranged from 0.14 mg
H2 receptor antagonists (H2RAs)
H2RAs act by reducing
Ranitidine Ranitidine is the most commonly used H2RA.
Table 2
H2 receptor antagonists
|
|
|
|
|
|
Ranitidine |
Cimetidine |
Famotidine |
Nizatidine |
Number of |
28 |
0 |
7 |
3 |
articles identified |
|
|
|
|
Number of |
4 |
0 |
0 |
1 |
paediatric articles |
|
|
|
|
Sample size |
245 |
0 |
0 |
210 |
Placebo- controlled studies |
17 |
0 |
0 |
210 |
|
|
|
|
|
Br J Clin Pharmacol / 3
S. Cohen et al.
firmly established as in one large study of 91 children [24] the proportion having at least one AE was 59%, while in another large study of 102 patients the proportion was 4% [46]. There were no serious AEs reported in any of the studies. All other reported AEs were mild, and included abdominal pain in one (1.7%); diarrhoea or gastroenteritis in 43 (74%); headache in two (3.4%); somnolence in one (1.7%); and pneumonia in 11 (19%).
Canani et al. [24] reported on 186 subjects, aged
Cimetidine Cimetidine is rarely used clinically as there are concerns about its effect on cytochrome P450 and consequent multiple drug interactions, as well as interference with vitamin D metabolism and endocrine function [48]. We could not find any prospective studies of paediatric patients with GERD exposed to cimetidine reporting AEs.
Famotidine Famotidine is an alternative H2RA; it is not licensed for use in children in the UK but is licensed in the US. Seven articles on famotidine were retrieved but only one dealt with paediatric patients with GERD; the focus of this article [49] was on the pharmacokinetics of famotidine and AEs were not reported systematically.
Nizatidine Nizatidine is a competitive, reversible, H2RA. It has a much lower drug interaction potential than cimetidine and a lower risk of
Table 3
Prokinetics
12/292 (4%), diarrhoea in nine (3%), pharyngitis in 12 (4%), cough or URTI in 40 (14%), vomiting in nine (3%), somnolence in one (0.3%) and eczema in one (0.3%).
Prokinetics Table 3 shows the results of the search in terms of the number of publications identified and selected, and the cumulative patient number.
Metoclopramide Metoclopramide blocks dopamine and serotonin receptors, and has sympathomimetic activity.
Betanechol Bethanechol is a muscarinic receptor agonist that has been shown to increase the tone of the lower oesophageal sphincter. No paediatric studies on this molecule were reported in the
Domperidone Domperidone is a prokinetic agent [57], through its action as a peripheral
|
Metoclopramide |
Betanechol |
Domperidone |
Erythromycin |
Baclofen |
Number of articles identified |
28 |
0 |
15 |
8 |
7 |
Number of paediatric articles |
0 |
0 |
4 |
0 |
2 |
Sample size |
0 |
0 |
120 |
0 |
38 |
0 |
0 |
28 |
0 |
30 |
|
|
|
|
|
|
|
4 / Br J Clin Pharmacol
Erythromycin Erythromycin is a macrolide antibiotic that increases gastrointestinal motility by acting as a motilin receptor agonist [62]. Eight articles on erythromycin were retrieved but none was relevant, in that they were either reviews or did not deal with paediatric subjects.
Cisapride Cisapride is a prokinetic agent but, as of 14 July 2000, it has been withdrawn from the market because of at least 341 reports of heart rhythm abnormalities, including 80 deaths [63].
Baclofen
Thickening agents (Alginate)
Alginate contains sodium and magnesium alginate; it acts as a feed thickener by increasing the viscosity of feeds and, together with sodium/potassium bicarbonate in the presence of gastric acid, forms a ’foam raft’ to neu- tralize gastric acid (providing symptomatic relief) and to reduce oesophageal irritation [66]. We retrieved 20 arti- cles on the use of alginate but only two were found to be relevant [67, 68]. The cumulative sample size was 73 preterm infants, ranging in age from 0 to 30 days, with doses ranging from 0.25 ml
Discussion
Many studies have shown that H2RAs and PPIs are effective in suppressing gastric acid production and relieving oesophagitis in children. The current review has allowed us to determine the relative safety of
Gastroesophageal reflux disease in children
pharyngeal pain or pneumonia is related to GERD (directly or indirectly) or to lansoprazole [31].
However, the most used H2RA, ranitidine, is well known for its ability to lead to tachyphylaxis, which seri- ously restricts its
A
Br J Clin Pharmacol / 5
S. Cohen et al.
children’ [74]. At this time, thickening agents have not been studied adequately in the paediatric population, both in terms of efficacy and AEs, so their routine use cannot be recommended as independent agents [70].
The weaknesses of the research carried out in the field of GERD therapy so far include a relatively low number of drug trials conducted in the paediatric age group, as com- pared with the much larger number of adult studies; and combined sample sizes that were too small in nearly all the included articles, for all medications, that we studied. Finally, the reporting quality of many of the studies retrieved in our search was very poor, which may have significantly affected the results, a phenomenon almost universally described when dealing with AE reporting [75].
Thus, our recommendations are that the primum non nocere (’first, do no harm’) rule should also apply to pae- diatric GERD. We suggest that the use of GERD medica- tions should be used only after nonpharmacological measures have been taken with incomplete success, to infants and children with significant symptoms, and that the use of such medications in ’happy spitter’ infants should be avoided. The use of the minimum number of
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