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Three Part Question

For [infants with symptoms of GOR] is [domperidone as effective as or more effective than standard therapy] at [improving symptoms]?

Clinical Scenario

As a paediatric registrar you are presented with a 4-month-old baby in paediatric outpatients. His mum describes him as having large vomits up to 30 min after most feeds, and recently he has seemed reluctant to feed. He is exclusively breast fed, and is gaining weight appropriately and otherwise thriving. He has previously been investigated for his vomiting and you conclude that he has gastr­oeosphageal reflux without complications (GOR).

In the first instance, positioning and thickened, small frequent feeds would be advised. The latter suggestion is not without difficulty for mothers exclusively breast feeding. As the mother is describing vomiting at least six times per day, but no signs suggestive of pain at present, could a pro-kinetic alone such as domperidone improve these symptoms?

Search Strategy

Medline (1948–March 2011) and Embase (1947–March 2011) were searched. Cochrane database of systematic reviews was also searched.
keywords (infant or child) and (gastro-oesophageal reflux or gastro-oesophageal reflux) and (domperidone or Motilium), limited to the English language.

Search Outcome

A total of 137 articles were found of which seven were relevant: six papers were identified after review of abstracts, and a further paper from referenced citations. These are summarised in the table.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Pritchard et al, 2005	Children aged 0–18 years, with GOR or regurgitation receiving at least 1 week of oral domperidone, placebo or non-surgical treatments, with at least one of: symptoms of GOR; presence of any adverse events; occurrence of clinical complications of GOR; weight change.	Systematic Review	Four trials identified, which are described in this table. Evidence is limited; there is no robust evidence of efficacy for the treatment of GOR with domperidone in children.	No adverse events
Bines et al, 1992	17 children (aged 5 months–12 year) with pH probe recording ‘confirmed’ GOR unresponsive to non-pharmacological therapy treated with domperidone 0.6 mg/kg/tds or placebo for 4 weeks. Second open label phase.	Blinded randomised placebo-controlled study	Effective reduction of pH probe measured reflux episodes but no symptomatic improvement or in any other objective pH metric data.	No significant difference in symptom diary. Decrease of 25% in reflux episodes in the 2 h after a meal in all 17 patients (p<0.01).	Small cohort. Loss of 2 patients unexplained. Heterogeneous groups at baseline: mean ages of 3.6 years in the treatment group and 2.4 years in controls. 69 baseline pH reflux episodes in the treatment group and 16 in the control group. Not clear how randomised. pH monitor data from 2 h after meals only reported.
Carroccio et al, 1994	80 children (aged 1–18 months) with GOR ‘confirmed’ by radiological and pH metric investigation. Group A: domperidone 0.3 mg/kg/premeal plus magnesium hydroxide and aluminum hydroxide; group B: domperidone plus alginate; group C: domperidone plus placebo; group D: two placebos. All for 8 weeks.	Blinded randomised placebo-controlled study	Domperidone plus magnesium hydroxide and aluminum hydroxide is more effective than other combinations studied at improving GOR and objective pH metric results. ‘Cured or improved’: group A 20/20; group B 16/20; group C 16/20; group D 10/20.	Group C (domperidone) had a reduced number of reflux episodes (median 59 to median 48.5; p<0.009). However, no other significant difference in outcomes (measured and reported) found between domperidone alone and placebo.	Continued use of non-pharmacological measures. Small number per group. Clinical severity score used to stratify and ensure similarity between groups. Blinding continued during interpretation of results. Symptom assessment not clearly defined.
De Loore et al, 1979	47 children (aged 3 weeks–8 years) with chronic, excessive regurgitation/vomiting and nausea. Treated with domperidone 0.3 mg/kg/tds, metoclopramide 0.3 mg/kg/tds or placebo for 2 weeks	Blinded randomised placebo-controlled study	Significant symptomatic relief of patients treated with domperidone.	At 2 weeks, 75% of the domperidone group, 43% of the metoclopramide group and 7% of controls not vomiting. End of trial assessment did not reach significance for dompridone versus metoclopramide, but did for both drugs against placebo (p<0.001).	Identical looking preparations for all three groups which were small. Randomisation method not stated. Investigator rated symptoms, blinding of investigator not detailed. Baseline age differences in groups (9 months vs 6 months) and range from neonate to 8 years.
Clara et al, 1979	32 children (aged 2.5 months–10 years) with chronic regurgitation/vomiting. Treated with domperidone 0.3 mg/kg/tds or placebo for 2 weeks. Increased to 0.6 mg/kg/tds for 7 of the 14 in the treatment group with poor response	Blinded randomised placebo-controlled study	Response	93% Of domperidone group had ‘good’ or ‘excellent’ response versus 33% of controls (p<0.05).	Small cohort. Median age 4 years in treatment group and 6 years in control.
Hegar et al, 2009	20 infants (aged 2–9 months) with symptoms and signs of GOR not controlled with optimisation of feeding regimen. Treated with domperidone (0.8 mg/kg/day) or cisapride (0.8 mg.kg/day) for 4 weeks. Symptom diary and pH monitoring	Pilot prospective randomised study (without blinding), no placebo control group	Efficacy of the two drugs comparable for regurgitation symptoms. Cisapride more effective for acid reflux (directly measured). Domperidone has better safety profile.	Median frequency of regurgitation in the domperidone group reduced from 4.8 (range 4.2–10.57) to 1.25 (range 0.2–5.6) (p=0.001).	No control group, not possible to state that improvement in regurgitation is significantly greater than would be expected with time. Other interventions to improve symptoms were discontinued during the trial.
Cresi et al, 2008	28 term and preterm neonates admitted to a neonatal pathology centre with clinical GORD, not responding to conservative management. Treated with domperidone 0.3 mg/kg/bd for 24 h or no treatment. Oesophageal pH monitoring.	Randomised controlled study. Non-blinded	No evidence of the benefit of domperidone in the neonatal population.	Initial reduction in pH probe measured reflux frequency and increase in reflux duration not maintained to last 8 h period.	Babies were kept at 30° supine, feeds not thickened. 8% Of tracing eliminated for ‘artefacts or interruptions’, no results on symptoms reported. No blinding; 24 h only; only neonates.

Comment(s)

GOR in infancy is a common disorder encountered in paediatric practice. The reported prevalence varies widely from 20% to 67% in the literature (Nelson), the prognosis is very good, and prevalence peaks at 4 months, after which the majority of children are symptom free by 1–2 years of age(Carre). When treatment is needed, positioning and thickening of feeds is the recommended first line management in most clinical practice, as suggested by ESPGAN.. Since the hypothesised pathogenesis for GOR in young babies includes inappropriate relaxation of the lower oesophageal sphincter (Omari, Davidson). pro-kinetics to intensify oesophageal peristalsis and accelerate gastric emptying have also been used widely. Prior to its withdrawal, cisapride was the mainstay of this treatment despite equivocal evidence of efficacy (Ausgood), with other drugs such as domperidone and erythromycin adopted later.

Investigation in this area is made problematic by the suggestions that objective measurements such as oesophageal pH monitoring and manometry correlate poorly with symptoms (Vandenplas) and that outcomes measured by symptom reporting are liable to subjectivity. In addition, there are variable definitions of what constitutes abnormal vomiting or regurgitation.

The ‘best fit’ answer to this clinical question found was the systematic review undertaken by Pritchard et al in 2005. They identified four randomised control trials (three of which were also identified by the above search strategy). The trials are described as having variable methodological quality and heterogeneous populations, interventions and outcome measures recorded. The results presented for each study were also disparate. The authors conclude that there is no robust evidence for the efficacy of domperidone for the treatment of GOR in young children and suggest further study is required. To address our clinical question the individual studies were examined, and information for the last trial (Clara) extracted from abstracts and data presented in the systematic review.

Of the first two studies, Bines et al randomly allocated 17 children to domperidone or placebo for a 4-week period. They found significant changes (p<0.01, 25% decrease) in the pH metric recordings for reflux episodes but no other measured, or symptom, changes. Carroccio et al randomly allocated 80 children to one of four groups relevant to this question. In the group which received domperidone and a placebo, they report a significant reduction (from a median of median 59 to a median of 48.5; p<0.009) in measured reflux episodes but no decrease for any other pH metric data or symptom reporting.

De Loore et al randomly allocated 47 children to receive domperidone, metoclopramide or placebo, and found improvements in symptom score and ‘nausea’ for both drugs investigated (p<0.001) compared to placebo; no details are provided regarding symptom assessment (including that of nausea in infants). Clara et al reported that 93% of 37 infants and children randomly allocated to domperidone had symptomatic improvement compared to placebo over a 2-week period (p<0.05); no details on symptom assessment, methodology or blinding beyond allocation were presented.

Two small and dissimilar trials were undertaken after the review by Pritchard et al. Cresi et al recorded 24 h oesophageal pH monitoring data in inpatient neonates openly allocated to domperidone or no treatment. They found no significant improvement in objective outcome measures. In contrast, Hegar et al found improvement in symptoms and some oesophageal pH metric data in infants with GOR treated for 4 weeks with domperidone openly compared with cisapride.

With the addition of the two more recent studies to those identified by Pritchard et al in 2005, the results are still somewhat disparate. Study design, definitions of diagnosis, use of controls, objectivity of outcome measures, use of concomitant treatments and the duration and dose of drug treatments used all differ, and, where applicable, there is little analysis of ‘infants’ as a subgroup. The studies present little convincing evidence for the efficacy of domperidone in infants with GOR. The only consensus between these studies is that no adverse events were reported; however, since the total sample size is small and the accumulated treatment period short at 608 patient weeks (excluding Cresi et al from ‘patient weeks’ as their patients were only treated for 24 h), this information cannot be taken as proof of safety.

In answer to this clinical question, given current evidence, it is not possible to support the use of domperidone in the treatment of uncomplicated gastroeosphageal reflux in infancy. The numbers found here are too small to engender confidence regarding the safety of domperidone in this usually benign and self-limiting condition. The advice in our current scenario has to be that the best management options are the use of positioning, small frequent feeds and thickeners, with reassurance and a ‘watch and wait’ policy also reasonable.

Editor Comment

Information was not gathered directly from the original paper by Clara et al as it proved impossible to obtain a copy of the article from local resources, the British Library or the publishers.

bd, twice a day; GOR, gastro-oesophageal reflux; GORD, gastro-oesophageal reflux disease; tds, three times a day.

Clinical Bottom Line

There is insufficient evidence for the efficacy of domperidone in uncomplicated infantile gastro-oesophageal reflux without complications.

References

1. Pritchard DS, Baber N, Stephenson T. Should domperidone be used for the treatment of gastro-oesophageal reflux in children? Systematic review of randomized controlled trials in children aged 1 month to 11 years old. Br J Clin Pharmacol 2005;59:725–9
2. Bines JE, Quinlan JE, Treves S, et al. Efficacy of domperidone in infants and children with gastroesophageal reflux. J Pediatr Gastroenterol Nutr 1992;14:400–5.
3. Carroccio A, Iacono G, Montalto G, et al. Domperidone plus magnesium hydroxide and aluminum hydroxide: a valid therapy in children with gastroesophageal reflux. A double-blind randomized study versus placebo. Scand J Gastroenterol 1994;29:300–4.
4. De Loore L, Van Ravenstayn H. Domperidone drops in the symptomatic treatment of chronic paediatric vomiting and regurgitation. A comparison with metoclopramide. Postgrad Med J 1979;55(Suppl 1):40–2.
5. Clara R. Chronic regurgitation and vomiting treated with domperidone. A multicenter evaluation. Acta Paediatric Belg 1979;32:203–7.
6. Hegar B, Alatas S, Advani N, et al. Domperidone versus cisapride in the treatment of infant regurgitation and increased acid gastro-oesophageal reflux: a pilot study. Acta Paediatr 2009;98:750–5.
7. Cresi F, Marinaccio C, Russo MC, et al. Short-term effect of domperidone on gastroesophageal reflux in newborns assessed by combined intraluminal impedance and pH monitoring. J Perinatol 2008;28:766–70.
8. Nelson SP, Chen EH, Syniar GM, et al. Prevalence of symptoms of gastroesophageal reflux during infancy. A pediatric practice-based survey. Pediatric Practice Research Group. Arch Pediatr Adolesc Med 1997;151:569–72.
9. Carre IJ. Clinical significance of gastro-oesophageal reflux. Arch Dis Child 1984;59:911–2.
10. Vandenplas Y, Ashkenazi A, Belli D, et al. A proposition for the diagnosis and treatment of gastro-oesophageal reflux disease in children: a report from a working group on gastro-oesophageal reflux disease. Working Group of the European Society of Paediatric Gastro-enterology and Nutrition (ESPGAN). Eur J Pediatr 1993;152:704–11.
11. Omari TI, Barnett CP, Benninga MA, et al. Mechanisms of gastro-oesophageal reflux in preterm and term infants with reflux disease. Gut 2002;51:475–9.
12. Davidson G. The role of lower esophageal sphincter function and dysmotility in gastroesophageal reflux in premature infants and in the first year of life. J Pediatr Gastroenterol Nutr 2003;37 Suppl 1:S17–22.
13. Ausgood C, MacLennon S. Cisapride treatment for gastroesophageal reflux in children (Cochrane Review). The Cochrane Library, Issue 3. Oxford: Update Software, 2000
14. Vandenplas Y, Sacré-Smits L. Gastro-oesophageal reflux in infants. Evaluation of treatment by pH monitoring. Eur J Pediatr 1987;146:504–7.