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

Background

Gastro esophageal reflux Disease (GERD) is defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications.^[1] Symptoms of GERD occur in approximately 14 to 20% of the population on at least a weekly basis. Symptoms of GERD may result in a large burden on employers through increased absenteeism and decreased performance while remaining at work impaired by health problems.^[2]

Even though over 50 years have passed since the discovery of melatonin, the knowledge on its physiological function is still not complete. The results of the researches have provided the evidence that melatonin is synthesized not only in the pineal gland, but also in different organs. A special attention has been directed to the digestive tract where total quantity of melatonin is considerably greater than in the pineal gland.^[3] It was calculated that the gastrointestinal tract contains at least 400 times melatonin than the pineal gland.^[4] Although pineal melatonin acts prevalently in an endocrine capacity, extra-pineal melatonin may act as an autocrine or a paracrine hormone.^[5] It protects gastric mucosa against destructive activity of free radicals in stress-induced ulcers and due to non-steroidal anti-inflammatory drugs and other gastrotoxic agents.^[6] Furthermore, Kato et al.^[7] demonstrated the inhibitory action of melatonin on secretion of HCL and pepsin. Only a few studies on gastrointestinal role of melatonin have been carried out on humans.

In view of melatonin's known gut regulatory functions, antidepressant and anxiolytic properties, and its potentially beneficial effects on brain gut axis, it was hypothesized that melatonin might serve as an effective agent for treating GERD.

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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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