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

Discussion

Melatonin, a close derivative of serotonin (5-hydroxytryptamine, 5-HT),^[13] is a hormone initiating sleep in humans^[14] and a powerful scavenger of free radicals. It is more effective than several well-known vitamins.^[15] The pineal gland is the major source of melatonin in the peripheral circulation, producing melatonin in a distinct circadian fashion, with peak levels occurring during the night.^[13] Melatonin has been also detected in entero-endocrine (EE) cells of gastro-intestinal tract (GIT) wall, where this indole may act via endocrine, paracrine and/or luminal pathway through G-protein coupled receptors.^[16] Following pinealectomy, the light/dark cycle of plasma melatonin levels disappears, while its daytime blood concentrations are attenuated but sustained mainly due to its release from the GIT, and therefore, a part of blood melatonin has a source in the digestive system, especially during daytime.^[17]

In the present study, the mean melatonin level was significantly lower in all patients in comparison to control group at baseline evaluation. This observation is in agreement with Klupiñska et al^[18] who found that in patients with GERD and recurrent duodenal ulcers, melatonin concentration was lower than in healthy subjects and concluded that high or relatively correct secretion of melatonin is sufficient to prevent peptic changes in esophageal and duodenal mucosa. In addition, Bubenik et al.^[19] demonstrated that pigs with chronic gastric ulcers exhibited lower contents of melatonin in the gastric mucosa and in the blood suggesting that these spontaneous ulcers originate from the local deficiency of the indole.

However, Otsuka et al.^[20] reported that acute stress induced gastric lesions in rats are accompanied by increased plasma melatonin. The proposed explanation for the rise in melatonin is that its production increases under stressful stimuli in both, experimental animals and human as suggested by Karasek and Winczyk.^[21]

For the clinical purposes, some investigators measure serum concentration of melatonin twice, that is at 9.00 a.m. (light period) and 2.00 a.m. (dark period) and the differences in the day/night patterns taken for evaluation.^[22] The interests of gstroenterologists mainly focused on studies on melatonin nocturnal secretion. In other investigations, melatonin concentration in blood measured at three points of time: at 10.00 p.m., 2.00 a.m. and 6.00 a.m. as done in our study as during these hours the influence of food intake on enterohormones secretion is negligible. On the other hand, at bedtime the patients often complain of recurrent symptoms of GERD that largely disturb their sleep.^[17] It was also noted that pharmacologically administered low and high doses of melatonin have been found to be with very low or no toxicity.^[23]

The current study also evaluates the role of the recently used antiulcer drug melatonin, the widely used antiulcer drug omeprazole and the combination of both drugs in the treatment of GERD. We used an oral fast release melatonin at a dose of 3 mg/day for 4 and 8 weeks. Werbach^[24] found that melatonin up to 6 mg at bedtime may be an effective treatment for GERD with fewer and less serious adverse effects. It was found that treatment of GERD with melatonin, omeprazole or both was duration dependent. Patients treated with melatonin for four weeks and patients treated with omeprazole for four weeks showed incomplete improvement of GERD symptoms. These findings are in agreement with Gavert and Harvey.^[25] Moreover, in patients treated with melatonin for eight weeks and patients treated with melatonin and omeprazole for four weeks, there was complete improvement of GERD symptoms as heartburn and epigastric pain. These findings were in agreement with Pereira^[26] who reported that dietary supplementation containing melatonin and L-tryptophan, which is a substrate for melatonin biosynthesis in patients with GERD, resulted in remarkable remission of GERD symptoms in the majority of treated patients. The clinical remission of GERD was comparable with that obtained by classical treatment using omeprazole. It was concluded that the formulation containing melatonin or its precursor, tryptophan, promotes regression of GERD symptoms without any side effects and may be useful in the GERD therapy. Melatonin has also been studied in alleviating GERD. In a head-to-head comparison, the researchers gave 175 patients standard treatment with the prescription drug omeprazole, while 176 received a supplement containing melatonin, its precursor L-tryptophan, and B vitamins, over a 40-day treatment period. All patients in the supplement group reported complete regression of symptoms by the end of the study, compared with only 66% in the drug-treated group. Again, no significant side effects were reported in the supplemented patients.^[26]

Although many studies were carried out to evaluate the role of melatonin in GERD based on its effect in alleviation of GERD symptoms only, the review of literature showed that no previous studies were based on endoscopic findings besides the clinical improvement.

In the present study, also signs were improved including lower esophageal sphincter (LES) pressure (from 10 ± 1.58 and, 10.3 ± 1.68 mmHg in the pretreated patients to 16.5 ± 0.6, and 14.1 ± 0.5 mmHg in patients treated with melatonin for 8 weeks and patients treated with melatonin and omeprazole for 4 weeks respectively). In addition, residual pressure (from 0.012 ± 0.52, and, 0.012 ± 0.44 in the pretreated patients to 0.32 ± 0.013, and, 0.21 ± 0.016 mmHg patients treated with melatonin for 8 weeks and patients treated with melatonin and omeprazole for 4 weeks respectively). Besides, relaxation duration (from 6.8 ± 0.12, and 6.8 ± 0.16 seconds in the pretreated patients to 5.3 ± 0.12, and 5.8 ± 0.13 seconds in patients treated with melatonin for 8 weeks and patients treated with melatonin and omeprazole for 4 weeks respectively), relaxation % (from 86 ± 0.87, and 85 ± 1.58% in pretreated patients to 95 ± 0.9 and 90 ± 1.23% in patients treated with melatonin for 8 weeks and patients treated with melatonin and omeprazole for 4 weeks respectively). However, the pH, 5 cm above the level of LES, was elevated from 2.3 ± 0.36, 2.1 ± 0.38 and 1.98 ± 0.37 in pretreated patients to 5.9 ± 0.65, 5.9 ± 0.48 and 6.1 ± 0.55 in patients treated with melatonin for 8 weeks, patients treated with omeprazole for 4 weeks and patients treated with melatonin and omeprazole for 4 weeks respectively).

It was believed that melatonin protects against GERD by increasing blood flow and anti-inflammatory molecules in the esophageal mucous, thus preventing significant esophageal injury.^[27] Although, Sener-Muratoglu et al.^[28] previously compared the antiulcer and gastro duodenal protective mechanism of famotidine, omeprazole and melatonin and their results revealed that the three drugs have gastroduodenal protective action but famotidine and omeprazole have lowering effects on gastric acidity (antisecrotory activity) whereas melatonin has no effect on this parameter but famotidine and omeprazole were not efficient as antioxidant as melatonin.

However, others concluded that the esophagoprotective activity of melatonin against GERD might be related to the inhibitory effect of this indole on gastric acid secretion and due to stimulation of gastrin release, which might attenuate the gastro-esophageal reflux by stimulation of the contractile activity of the lower esophageal sphincter.^[29]

In the present study, there was a significant increase in the pH with a significant decrease in BAO and a significant increase in serum gastrin after melatonin therapy compared to pretreatment levels. While patients treated with omeprazole alone or combined with melatonin showed a significant increase in PH and serum gastrin level with a significant decrease in BAO than melatonin alone, however, the combined therapy showed a non-significant increase in serum gastrin or BAO compared with omeprazole alone.

These protective effects were accompanied by gradual increase in plasma melatonin levels suggesting that topical melatonin exerts a local protective action on gastric mucosa, acting via circulation following its absorption form the gut. The results of our study revealed that melatonin has a role in the improvement of GERD as detected in patients treated with melatonin for 8 weeks and in patients treated with melatonin and omeprazole for 4 weeks. Meanwhile, omeprazole alone has a better effect on gastric acidity than melatonin alone as the clinical improvement started at the fourth week of treatment with omeprazole and was completed at the eighth week. On the other hand, with melatonin alone the improvement started at the fourth week and was completed at the eighth week of treatment but it was significantly less effective than omeprazole. It was found that melatonin accelerates the clinical and endoscopic improvement when combined with omeprazole as improvement in combination therapy was completed at shorter duration (at the fourth week) with no further increase in serum gastrin level. Our results were in agreement with Bandyopadhyay et al.^[30] who stated that melatonin prevented gastric damage and when compared with already marketed anti-ulcer drugs such as ranitidine and omeprazole, melatonin was found to be more effective than ranitidine but less effective than omeprazole in preventing stress ulcer. They also demonstrated that co-treatment of GERD with melatonin at a low dose synergistically increases the efficacy of omeprazole in preventing stress induced lesion. This may be important, as giving omeprazole at lower doses would reduce the severity of their side effects. Rieter et al.^[31] reported that melatonin when combined with other anti ulcer drugs like omeprazole has a beneficial effect as it accelerates the healing effects of omeprazole and shortens the duration of treatment. Therefore, melatonin reduces the side effects and increases the efficacy of omeprazole.

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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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