The Potential Therapeutic Effect of Melatonin in Gastro-esophageal Reflux Disease

Tharwat S Kandil; Amany A Mousa; Ahmed A El-Gendy; Amr M Abbas

BMC Gastroenterol. 2010;10:7

Methods

Sixty subjects "60", suffering from GERD symptoms, were attending the outpatient clinics of the Gastro-Enterology Center and Specialized Medical Hospital. Informed consent was obtained from all patients to be included in the study, after explanations of the nature of the disease and treatment options. All patients signed an informed consent to be included in our study. This paper was approved by the local ethical committee of Mansoura University Hospital, General Surgery Department.

All individuals were subjected to thorough history taking including: history of drug intake, epigastric pain, upper gastrointestinal bleeding (hematemesis and/or melena), dyspeptic manifestations and heartburn. They were also subjected to clinical examination with special stress on: (a) General examination: pulse, blood pressure and temperature. (b) Chest and heart examination. (c) Local abdominal examination for the state of the liver, spleen and the presence or absence of ascites. They also underwent laboratory investigations: Complete blood picture, Urine and stool analysis and Liver function tests including serum albumin, bilirubin, alanine transaminase enzyme (ALT), aspartate transaminase enzyme (AST). The patients excluded from our study were; patients with cardiac disease, patients with renal affection, and patients with liver diseases (drug induced, autoimmune disease and viral hepatitis). In addition, patients on the drugs known to affect the GIT motility (phenothiazines, anticholinergics, nitrates or calcium channel blockers) excluded during the time of conduction of the study or the preceding two weeks. After exclusion, 45 subjects were selected for evaluation by: a) Endoscopic Investigation: subjects were subjected to upper gastrointestinal endoscopy for visualization of the mucosa of esophagus and stomach for the presence of mucosal ulceration. b) Record of esophageal motility by Smart graph analysis software lab motility system Sandhill 8 - channels esophageal manometry. Manometric recording systems rely on computers for data acquisition display and analysis. This manometric recording was done by using station pull through technique at 5 minutes intervals. The most important aspect of Lower Esophageal Sphincter (LES) pressure measurement is that of LES relaxation. Subjects with duodenal, gastric ulcers or functional dyspepsia were excluded and finally 27 subjects with GERD were selected to complete the study compared with nine healthy volunteers who matched with age and sex as controls or reference.

After admission the following was done: (a) blood samples for measuring serum melatonin levels taken at 10.00 p.m., 2.00 a.m. and 6.00 a.m. After collecting the sample, the blood centrifuged and serum thus was obtained and frozen at the temperature of minus 80°C. Melatonin concentration was measured with ELISA method using the Lab system Multiscan and antibodies of the Immuno-Biological Laboratories (catalogue RE 54021).^[8] (b)An ambulatory digitrapper was used to perform 24 hours pH-metry measurement by UP S2020 Orion MMS Holland pH-metry. The pH probe was positioned 5 cm above the position of the LES. The data were collected using De-meester (DM) score; gastroesophageal reflux considered as a drop in esophageal PH below "4" and the percentage reflux in 24 hours calculated for each patient.^[9]

Basal Acid Output (BAO)

At the end of each pH-metry monitoring period, the electrode was removed and BAO was measured during one hour through a naso-gastric tube inserted at the most dependent part of the stomach. The correct position of the tube was checked by the water recovery test. Patients were laid in a semi-recumbent position on their left side. Gastric secretion was aspirated continuously by gentle manual suction and collected in 15-minute samples after discarding the first 15-minute collection corresponding to the emptying of the stomach. The concentration of H⁺ ions was determined on each sample by a titrimetric method with NaOH 0.1N and expressed in millimoles H⁺ per litre. BAO is the sum of the four 15-minute outputs and is expressed in mmol H⁺/h.

Determination of Serum Gastrin Levels

The serum gastrin concentration was measured by a radioimmunoassay method using C-terminal-directed antibodies equally reactive to little gastrins (G-17) and big gastrins G-34. Serum Gastrin was expressed in picograms per milliliter.

Groups: The subjects selected were classified into four groups: Group I included nine healthy normal subjects and was considered the control group. Group II included nine patients suffering from GERD; receiving melatonin alone for treatment of GERD in a dose of 3 mg once daily at the bedtime.^[10] Group III included nine patients suffering from GERD, receiving omeprazole alone for treatment of GERD in a dose of 20 mg twice daily.^[11] Group IV included nine patients suffering from GERD receiving omeprazole and melatonin for treatment of GERD in the same dose of each of them. The three patient groups were re-evaluated after 4 weeks and 8 weeks of treatment.

Statistical Analysis

The statistical analysis was performed using the SPSS statistical Package version 13.0 (SPSS, Chicago, IL, USA). To compare the data, the recorded values were expressed as means and standard deviation (Mean ± SD). The minimal level of significance was identified at p < 0.05.^[12]

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This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Cite this: The Potential Therapeutic Effect of Melatonin in Gastro-esophageal Reflux Disease - Medscape - Jan 18, 2010.

Table 1. Comparison of control subjects and patients pretreated with melatonin, omeprazole and both (n = 9)
	control	Pretreatment with melatonin	Pretreatment with omeprazole	Pretreatment with melatonin and omeprazole
Symptoms:
1-Heart burn:
Yes	0	7	7	8
Duration(months)		1.3 ± 0.4	1.2 ± 0.3	1.4 ± 0.4
2-Epigastric pain:
Yes	0	6	6	6
Duration(months)		1.4 ± 0.5	1.3 ± 0.4	1.3 ± 0.4
A)LES Study:
1-LES pressure(mmHg)	22.8 ± 1.3	10 ± 1.58^a	10.5 ± 2.86^a	10.3 ± 1.68^a
2-Residual pressure (mmHg)	0.4 ± 0.01	0.012 ± 0.52^a	0.1 ± 0.064^a	0.012 ± 0.44^a
3-Relaxation duration (seconds)	5.0 ± 0.1	6.8 ± 0.12^a	6.5 ± 2.74^a	6.8 ± 0.16^a
4-Relaxation %	100 ± 0.00	86 ± 0.87^a	87.2 ± 0.17^a	85 ± 1.58^a
C) PH (at 5 cm above the LES):	7.8 ± 0.4	2.3 ± 0.36^a	2.1 ± 0.38^a	1.98 ± 0.37^a
D) BAO (mmol/h)	2.6 ± 0.6	24.7 ± 0.5^a	25.1 ± 0.6^a	24.9 ± 0.7^a
E) Serum Gastrin(pg/ml)	41.8 ± 7.1	22.1 ± 4.2^a	21.5 ± 4.6^a	21.9 ± 4.7^a
D) Melatonin level at day time (pg/ml):	36.1 ± 2.3	18.2 ± 5.54^a	18.5 ± 3.75^a	18.3 ± 3.8^a

a: p < 0.05 relative to control

Table 2. Effects of melatonin on patients with GERD group II (n = 9)
	Pretreatment with melatonin	4 weeks Post treatment with melatonin	8 weeks Post treatment with melatonin
Symptoms:
1-Heart burn:
Yes	7	3 (57.1%)	0 (100%)
Duration(months)	1.3 ± 0.4
2-Epigastric pain:
Yes	6	3 (50%)	1 (83%)
Duration(months)	1.4 ± 0.5
B)LES Study:
1-LES pressure(mmHg)	10 ± 1.58	14.5 ± 1.58^a	20.2 ± 1.56 ^ab
2-Residual pressure (mmHg)	0.012 ± 0.52	0.2 ± 0.016	0.32 ± 0.013^a
3-Relaxation duration (seconds)	6.8 ± 0.12	5.9 ± 0.16 ^a	5.3 ± 0.12 ^a
4-Relaxation %	86 ± 0.87	90 ± 0.86 ^a	100 ± 0.00 ^ab
C) PH (at 5 cm above the LES):	2.3 ± 0.36	5.2 ± 0.5 ^a	6.7 ± 0.65 ^ab
D) BAO (mmol/h)	24.7 ± 0.5	20.1 ± 0.4 ^a	16.6 ± 0.6 ^ab
E) Serum Gastrin(pg/ml)	22.1 ± 3.2	27.2 ± 2.3 ^a	32.3 ± 2.1 ^ab
D) Melatonin level at day time (pg/ml):	18.2 ± 5.54	28.26 ± 2.26 ^a	34.5 ± 2.35 ^ab

a: p < 0.05 relative to pretreatment with melatonin
b: p < 0.05 relative to 4 weeks post treatment with melatonin

Table 3. Effects of omeprazole on patients with GERD Group III (n = 9)
	Pretreatment with omeprazole	4 weeks Post treatment with omeprazole	8 weeks Post treatment with omeprazole
A) Symptoms:
1-Heart burn:
Yes	7	2 (71.4%)	0 (100%)
Duration(months)	1.2 ± 0.3
2-Epigastric pain:
Yes	6	2	0
Duration(months)	1.3 ± 0.4	(66.7%)	(100%)
B)LES Study:
1-LES pressure(mmHg)	10.5 ± 2.86	10.4 ± 4.05	10.5 ± 2.85
2-Residual pressure (mmHg)	0.1 ± 0.064	0.2 ± 0.15	0.1 ± 0.07
3-Relaxation duration (seconds)	6.5 ± 2.74	6.3 ± 2.7	6.3 ± 2.65
4-Relaxation %	87.2 ± 0.17	87.3 ± 0.25	87.1 ± 0.1
C) PH (at 5 cm above the LES):	2.1 ± 0.38	5.9 ± 0.48^a	7.2 ± 0.32^ab
D) BAO (mmol/h)	25.1 ± 0.6	17.2 ± 0.7^a	11.5 ± 0.6^ab
E) Serum Gastrin (pg/ml)	21.5 ± 4.6	32.1 ± 2.1^a	35.9 ± 1.8^ab
D) Melatonin level at day time (pg/ml):	18.5 ± 3.75	19.2 ± 3.47	17.9 ± 3.72

a: p < 0.05 relative to pretreatment with melatonin
b: p < 0.05 relative to 4 weeks Post treatment with melatonin

Table 4. Effects of melatonin and omeprazole on patients with GERD group IV (n = 9)
	Pretreatment with melatonin and omeprazole	4 weeks Post treatment with melatonin and omeprazole	Post 8 weeks treatment with melatonin and omeprazole
A) Symptoms:
1-Heart burn:
Yes	8	1(87.5%)	0 (100%)
Duration(months)	1.4 ± 0.4
2-Epigastric pain:
Yes	6	1(83.3%)	0 (100%)
ration(months)	1.3 ± 0.4
B) LES Study:
1-LES pressure(mmHg)	10.3 ± 1.68	14.5 ± 1.26^a	20.5 ± 1.22^ab
2-Residual pressure (mmHg)	0.012 ± 0.44	0.21 ± 0.016	0.33 ± 0.016^a
3-Relaxation duration (seconds)	6.8 ± 0.16	5.8 ± 0.13^a	5.2 ± 0.12^a
4-Relaxation %	85 ± 1.58	90 ± 1.23^a	100 ± 0.00^ab
C) PH (at 5 cm above the LES):	1.98 ± 0.37	6.1 ± 0.55^a	7.5 ± 0.31^ab
D) BAO (mmol/h)	24.9 ± 0.7	15.8 ± 0.9^a	10.2 ± 0.9^ab
E) Serum Gastrin (pg/ml)	21.9 ± 4.7	33.6 ± 2.7^a	36.8 ± 2.1^ab
D) Melatonin level at day time (pg/ml):	18.3 ± 3.8	28.83 ± 1.82^a	34.5 ± 2.35^ab

a: p < 0.05 relative to pretreatment with melatonin
b: p < 0.05 relative to 4 weeks Post treatment with melatonin

Table 5. Comparison of the three treated groups with GERD
	Melatonin	Omeprazole	Melatonin and Omeprazole	P value
	Melatonin	Omeprazole	Melatonin and Omeprazole	P1	P2	P3
A)Symptoms:
Heart burn:
control	0	0	0
pretreatment:
yes	7	7	8
duration (months)	1.3 ± 0.4	1.2 ± 0.3	1.4 ± 0.4
4 weeks
8 weeks	3(57.1%)	2(71.4%)	1(87.5%)
	0(100%)	0(100%)	0(100%)
Epigastric pain:
-control	0	0	0
pretreatment:
yes	6	6	6
duration (months)	1.4 ± 0.5	1.3 ± 0.4	1.3 ± 0.4
4 weeks	3(50%)	2(66.7%)	1(83.3%)
8 weeks	1(83%)	0(100%)	0(100%)
B) LES Study:				P1	P2	P3
1-LES pressure(mmHg)
control	22.8 ± 1.3	22.8 ± 1.3	22.8 ± 1.3	0.9	0.9	0.9
pretreatment:	10 ± 1.58	10.5 ± 2.86	10.3 ± 1.68	0.65	0.7	0.86
4 weeks	14.5 ± 1.58	10.4 ± 4.05	14.5 ± 1.26	0.006	0.468	0.002
8 weeks	20.2 ± 1.56	10.5 ± 2.85	20.5 ± 1.22	0.000	0.68	0.000
2-Residual pressure (mmHg)				P1	P2	P3
- control	0.4 ± 0.01	0.4 ± 0.01	0.4 ± 0.01	1.0	1.0	1.0
pretreatment:	0.012 ± 0.52	0.1 ± 0.064	0.012 ± 0.44	0.578	1.00	0.556
4 weeks	0.2 ± 0.016	0.2 ± 0.15	0.21 ± 0.016	1.00	0.198	0.198
8 weeks	0.32 ± 0.013	0.1 ± 0.07	0.33 ± 0.016	0.000	0.08	0.000
3-Relaxation duration (seconds)				P1	P2	P3
control	5.0 ± 0.1	5.0 ± 0.1	5.0 ± 0.1	1.0	1.0	1.0
pretreatment::	6.8 ± 0.12	6.5 ± 2.74	6.8 ± 0.16	0.747	1.000	0.747
4 weeks	5.9 ± 0.16	6.3 ± 2.7	5.8 ± 0.13	0.662	0.153	0.585
8 weeks	5.3 ± 0.12	6.3 ± 2.65	5.2 ± 0.12	0.747	0.102	0.059
4-Relaxation %				P1	P2	P3
control	100 ± 0.00	100 ± 0.00	100 ± 0.00	1.0	1.0	1.0
pretreatment:	86 ± 0.87	87.2 ± 0.17	85 ± 1.58	0.12	0.116	0.14
4 weeks	90 ± 0.86	87.3 ± 0.25	90 ± 1.23	0.1	1.000	0.1
8 weeks	100 ± 0.00	87.1 ± 0.1	100 ± 0.00	0.01	1.00	0.01
C) PH (at 5 cm above the LES):				P1	P2	P3
control:	7.8 ± 0.4	7.8 ± 0.4	7.8 ± 0.4	1.0	1.0	1.0
pretreatment:	2.3 ± 0.36	2.1 ± 0.38	1.98 ± 0.37	0.1	0.1	0.1
4 weeks	5.2 ± 0.5	5.9 ± 0.48	6.1 ± 0.55	0.008	0.002	0.09
8 weeks	6.7 ± 0.65	7.2 ± 0.32	7.5 ± 0.31	0.01	0.008	0.1
D) BAO(mmol/h)				P1	P2	P3
- control:	2.6 ± 0.6	2.6 ± 0.6	2.6 ± 0.6	1.0	1.0	1.0
pretreatment:	24.7 ± 0.5	25.1 ± 0.6	24.9 ± 0.7	0.1	0.1	0.1
4 weeks	20.1 ± 0.4	17.2 ± 0.7	15.8 ± 0.9	0.008	0.002	0.09
- 8 weeks	16.6 ± 0.6	11.5 ± 0.6	10.2 ± 0.9	0.01	0.008	0.1
E) Serum Gastrin(pg/ml)				P1	P2	P3
control:	41.8 ± 7.1	41.8 ± 7.1	41.8 ± 7.1	1.0	1.0	1.0
pretreatment:	22.1 ± 4.2	21.5 ± 4.6	21.9 ± 4.7	0.1	0.1	0.1
4 weeks	27.2 ± 2.3	32.1 ± 2.1	33.6 ± 2.7	0.008	0.002	0.09
- 8 weeks	32.3 ± 2.1	35.9 ± 1.8	36.8 ± 2.1	0.01	0.008	0.1
D) Melatonin level at day time (pg/ml):				P1	P2	P3
control	36.1 ± 2.3	36.1 ± 2.3	36.1 ± 2.3	1.0	1.0	1.0
pretreatment:	18.2 ± 5.54	18.5 ± 3.75	18.3 ± 3.8	0.1	0.665	0.472
4 weeks	28.26 ± 2.26	19.2 ± 3.47	28.83 ± 1.82	0.000	0.55	0.000
8 weeks	34.5 ± .35	17.9 ± 3.72	34.5 ± 2.35	0.000	1.00	0.000

P1: group III versus group II
P2: group IV versus group II
P3: group IV versus group III

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