Melatonin in Pediatric FD Population

Study Overview
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Brief Summary
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There are two specific aims in this study. Specific Aim 1: Determine if melatonin results in a higher grade of clinical response than does placebo in children with functional dyspepsia (FD). Hypothesis: treatment of FD with melatonin will result in a higher grade of clinical response than will treatment with a placebo. Specific Aim 2: Evaluate the relationship between changes in sleep and improvement in pain in pediatric patients with functional dyspepsia receiving melatonin. Hypothesis: There will be no association between improvement in pain and improvement in sleep in children with functional dyspepsia receiving melatonin.

Detailed Description
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Recurrent abdominal pain is present in a significant proportion of the pediatric population at large. Often times, no clear organic cause for pain will be found, and these children are diagnosed with functional abdominal pain. Of the children with functional abdominal pain, many are classified as having functional dyspepsia (FD). Functional dyspepsia is defined as persistent or recurrent pain or discomfort centered in the upper abdomen (above the umbilicus) that is unrelated to a change in stool frequency or form and not exclusively relieved by defecation. There have been only a few placebo controlled trials of medications in children with abdominal pain and none in children specifically with functional dyspepsia and uninvestigated mucosal inflammation. There is increasing evidence suggesting that melatonin plays a role in pain modulation. Melatonin is produced by the pineal gland and is recognized for its regulation of sleep and circadian functions. Less widely recognized is melatonin's production in other parts of the body; such as in the digestive system and in immune cells including mast cells. The total amount of melatonin in the digestive system exceeds that of the pineal gland and blood. Within the digestive tract, melatonin is produced in the enterochromaffin cells. It exerts both excitatory and inhibitory effects on the enteric nervous system as well as possessing anti-inflammatory and immunomodulatory properties. In a rat model of reflux esophagitis, melatonin demonstrated multiple effects on the esophageal mucosa. These included decreased lipid peroxidation (oxidative degradation of lipids in cell membranes which leads to cell damage), replenished superoxide dismutase and glutathione (improved defense of the mucosa), and decreased expression of T helper 1 cytokines (pro-inflammatory cytokines) while not altering anti inflammatory cytokines. These effects may account for the reduction in pain in adults with irritable bowel syndrome (IBS) and dyspepsia during a trial of melatonin therapy. In a study of adults with IBS in association with sleep disturbances, patients were given melatonin 3mg or placebo at bedtime for two weeks. Compared with the placebo group, the group who received melatonin had significantly lower mean abdominal pain scores while sleep parameters were not influenced. In a study of adults with functional dyspepsia, twelve weeks of melatonin (5 mg taken at bedtime) resulted in 56.6% of patients having complete resolution of symptoms and 30% having partial improvement, while only 6.7% of the patients who received placebo experienced any improvement in symptoms. Melatonin has not been previously studied in children with abdominal pain. Evaluation of its effects is warranted as melatonin would be a very safe and inexpensive alternative treatment.

Official Title
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The Therapeutic Effect of Melatonin in Pediatric Patients With Functional Dyspepsia

Conditions
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Dyspepsia

Intervention / Treatment
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* Dietary Supplement: Melatonin
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients seen in the GI clinic with a diagnosis of functional dyspepsia as defined by Rome III criteria. Persistent pain despite acid suppression at therapeutic doses for at least 4 weeks Patients ages 8-17 years, inclusive. Exclusion Criteria: Patients currently using melatonin. Patients who have previously had endoscopy. Initiation of a treatment plan that includes one or more of the following medications in the last 4 weeks Opiates Tramadol Gabapentin Benzodiazepines

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Melatonin<br>Melatonin All participants will receive a 5 mg. dose of melatonin before bed for a period of two weeks during study period. | Dietary Supplement: Melatonin<br>* Comparison between melatonin and placebo (2 weeks each) with active and placebo crossover during the study period of 34-36 days.<br>* Other names: Melatonin 5 mg.;|
| Placebo Comparator: Placebo<br>Placebo All participants will receive a placebo comparative in substance, color, and flavor, before bed for two weeks during the study. | Dietary Supplement: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Grade of clinical response to Melatonin in children with functional dyspepsia | The overall positive response rate (grade 3-5) will be compared between melatonin and placebo by the McNemar test. | 35 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in sleep in pediatric patients with functional dyspepsia receiving melatonin | The mean sleep latency and mean sleep duration from sleep diary and actigraphy data will be compared between baseline and therapy for melatonin and placebo, respectively, using the paired Student's t test. | 35 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Functional Dyspepsia, Melatonin, Pain, Actigraphy and Pain