Drugs and gastroesophageal reflux: not always effective and with some risks

Paediatricians have always dedicated great attention and several diagnostic-therapeutic tools in order to tackle the gastroesophageal reflux, especially in early childhood.
The most recent literature has scaled down the problem, attributing the gastroesophageal reflux to its paraphysiological nature and highlighting the few situations where the gastroesophageal reflux could really become a disease (the so-called gastroesophageal reflux disease, GERD).^1,2
In the meantime, prescriptions in children of gastric antisecretory agents, gastroprotectants and prokinetics have been multiplying in the world. Very often the symptoms have been treated more than the disease, with a frequent off-label use of the medications, even without clear evidences of their indication and effectiveness.^3,4
After cisapride’s withdrawn from the market (in 2000) for reported severe cardiotoxicity (80 deaths), the wide use of prokinetics continued with molecules that are less effective (in Italy domperidone) or which still have significant adverse effects (metoclopramide among the others).
At the same time protonic pump inhibitors, for their effectiveness in reducing gastric acid secretion and their favourable therapeutic profile, have been exponentially prescribed within the whole paediatric age, including prematures, newborns and infants.⁴ Prescriptions of protonic pump inhibitors for children less than one year old increased 4 times from 2000 to 2004 (71% were used within 6 months of age) and it increased of even 11 times from 2002 to 2009.^5,6
According to several authors, this data underline a scenario of poor therapeutic appropriateness^7,8 which is fostered by the overestimation of the gastroesophageal reflux phenomenon,^9,10 whose risks have been reported in literature.^3,4,11
Let us now consider the principal classes of drugs used for the treatment of the gastroesophageal reflux in the child and their safety profile.

PROKINETICS

Metoclopramide, domperidone, erythromycin and cisapride are considered pro kinetics.

Metoclopramide This drug is counter indicated for children before one year of age and it is indicated from 1 to 18 years of age for the prevention of “retarded nausea and vomit induced by chemotherapy as second line option”.
This medication increases the response of the first gastrointestinal tract to acetylcholine, strengthen the lower oesophageal sphincter and has been used for treating the gastroesophageal reflux disease also in paediatric age, despite the poor evidences supporting it.
Because of the significant adverse reactions (dystonic reactions, oculogyric crisis, irritability, dry mouth, vomit and apnoea, galactorrhoea and gynecomastia) registered by 1-35% of patients, metoclopramide is not currently indicated for the treatment of gastroesophageal reflux disease in children.
Domperidone Strengthens the lower oesophageal sphincter and has a prokinetic effect, but evidence of effectiveness in the gastroesophageal reflux disease are lacking. In newborns it can have a paradox effect increasing the episodes of gastroesophageal reflux, preventing the coordination of intestinal movements. Extrapyramidal effects are rare, but domperidone can cause irritability and colics in infants. The immaturity of the cytochrome P450 can increase the drug toxicity level and cases of QT interval prolongation have been reported.
Erythromycin Favours gastric emptying and induces phase III peristaltic movements that propagate from the stomach to the ileum. There are no evidences to support the indication for its use in the treatment of the gastroesophageal reflux disease in paediatric age.
Cisapride Is not anymore available on the market because of the severe QT interval prolongation effects; one isoform could become available again once its effectiveness and safety will have been studied.

PROTONIC PUMP INHIBITORS

The excessive use of protonic pump inhibitors in newborns and infants has been repeatedly reported and, especially, the risk that the reduction of acid defences and enteric motility could favour gastrointestinal and bronchopulmonary infections.¹² Omeprazole, esomeprazole, lansoprazole and pantoprazole are protonic pump inhibitors.

Omeprazole Indicated for children over one year of age and 10 kg of weight, this drug has been studied between 0 and 16 years of age. Mild adverse reactions have been reported (vomit, pharyngitis, constipation, arthralgia, drowsiness) in 34% of cases, with wide variability among the different studies.
Esomeprazole Isomer of omeprazole, with greater bioavailability and longer duration of action, it is registered for children over 12 years of age, but studies reported its use from 0 to 17 years of age and the FDA has authorised its use from one month of age for the treatment of erosive esophagitis. Mild adverse effects (headache, diarrhoea, abdominal pain, fever and vomit) are registered in 34.8% of cases. Severe adverse reactions are very rare (0.9%), mostly linked to the intravenous administration of the drug (catheter infection).
Lansoprazole Has to be avoided before one year of age and it is not authorized in children according to the data sheet of the product; there are studies of effectiveness from 0 to 18 years of age. It has caused adverse reactions in 44% of the treated cases, almost always of mild entity (upper respiratory tract infections, pharyngitis, laryngitis, sinusitis, bronchitis, otitis, nausea, vomit and headache). In 2.3% of cases the adverse events were significant (asthmatic crisis and pneumonia).
Pantoprazole Indicated over 12 years of age, adverse events have been reported (similar to those of the other protonic pump inhibitors) in at least 40% of treated paediatric cases. One case of severe pancreatitis was registered.

H2-ANTAGONISTS

Ranitidine is the most used H2-antagonist, even though the evidences of effectiveness in the treatment of gastroesophageal reflux are quite poor and the tendency to develop tachyphylaxis within few weeks of use limits its long term use. The frequency of adverse effects (headache, diarrhoea, drowsiness and pneumonia) is very variable in the different studies (from 4 to 59%) but it is well diffused the perception of a good safety profile. No serious adverse effects have been reported, but an increased risk of intestinal and respiratory infections¹² and necrotising enterocolitis for prematures have been reported.¹³

Advices for the clinical practice

As it clearly appears from the paediatric literature of gastroesophageal reflux, the principal point is the correct diagnosis of the real gastroesophageal reflux disease (especially in newborns and infants) and consequently a really necessary and effective treatment with a favourable benefit-risk ratio. Approximate diagnoses or not really convinced ones only lead to improper therapeutic approaches which may be useless or even harmful.
It should be reminded that prescribing off-label drugs to children, without well documented evidences of effectiveness, can expose the children to unjustified risks and the paediatricians to medical-legal consequences. It also should not be forgotten that there is quite a variety of non-pharmacological approaches (dietetic, behavioural and postural) that, in the less severe situations of gastroesophageal reflux, could help tackling and solving the symptoms with no adverse effects at all.