O RI G I NAL ART I C L E GASTROINTESTINAL TRACT

Is the Addition of Sublingual Melatonin to Omeprazole

Superior to Omeprazole Alone in the Management of
Gastroesophageal Reflux Disease Symptoms: A Clinical Trial
Habib Malekpour1 , Amin Noori2 , Saeed Abdi3 , Mohammad Abbasinazari2 , Arash Mahboubi,4 , Mahdiye Abiyar Ghamsari2
1
Department of Gastroenterology and Hepatology, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2
Department of Clinical Pharmacy, Shahid Beheshti University of Medical Sciences Faculty of Pharmacy, Tehran, Iran
3
Department of Gastroenterology and Hepatology, Gastroenterology and Liver Diseases Research Center, Research Institute for
Gastroenterology and Liver Diseases Ayatollah Taleghani Hospital, Shahid Beheshti University of Medical Sciences Tehran, Iran
4
Department of Pharm​aceut​ics, P​harma​ceuti​cal Sciences Research Center, Shahid Beheshti University of Medical Sciences Faculty of
Pharmacy, Tehran, Iran

Cite this article as: Malekpour H, Noori A, Abdi S, Abbasinazari M, Mahboubi A, Abiyar Ghamsari M. Is the addition of sublingual
melatonin to omeprazole superior to omeprazole alone in the management of gastroesophageal reflux disease symptoms: A clinical
trial. Turk J Gastroenterol. 2023;34(12):1206-1211.

ABSTRACT
Background/Aims: Proton pump inhibitors are frequently used to treat gastroesophageal reflux disease, but their effect is restricted.
The present study aimed to investigate whether the addition of sublingual melatonin to omeprazole was effective in the treatment of
gastro gastroesophageal reflux disease symptoms.
Materials and Methods: This was a randomized double-blind clinical trial. A total of 78 patients with gastro gastroesophageal reflux dis-
ease were randomly allocated to either omeprazole 20 mg/d plus sublingual melatonin (3 mg/d) or omeprazole 20 mg/d plus placebo for
4 weeks. The selected patients had histories of heartburn and regurgitation and a score ≤32 on the Frequency Scale for the Symptoms
of gastroesophageal reflux disease (FSSG). The outcome measures for the assessment of treatment efficacy were heartburn, epigastric
pain and the Frequency Scale for the Symptoms of gastroesophageal reflux disease score. Safety and quality of life were evaluated in
the patients as the secondary outcomes too.
Results: Seventy-two out of 78 eligible patients completed this trial (35 in the melatonin group and 37 in the placebo group). Heartburn,
epigastric pain, and Frequency Scale for the Symptoms of gastroesophageal reflux disease score declined significantly in the melatonin
group compared to the placebo group (P = .04, P = .03, and P = .0001, respectively). Moreover, the quality of life score was significantly
higher in the melatonin group compared with the placebo group (P = .0001). Adverse events were similarly observed in the 2 groups
(P = .55), and there were no serious adverse events.
Conclusion: The combination of sublingual melatonin (3 mg/day) with omeprazole (20 mg/day) may be more effective than omeprazole
(20 mg/day) alone in the treatment of gastroesophageal reflux disease.
Keywords: Melatonin, omeprazole, GERD, sublingual, quality of life

INTRODUCTION significant therapeutic effects against GERD. In nearly

Gastroesophageal reflux disease (GERD) is one of the 30% of patients with a diagnosis of GERD, these drugs
most common digestive disorders worldwide. The preva- cannot improve their condition. The failure of PPI treat-
lence of this disease is estimated at 8%-33% in all age ment is an important challenge in the control and man-
groups in both males and females; it is also one of the agement of GERD. The reasons for this failure include
costliest digestive disorders.1 The most common diges- mutations in the H+/K+ ATPase coding gene, presence of
tive symptoms of GERD are heartburn and regurgitation, a polymorphism in the cytochrome p4502c19 enzyme,
while its atypical symptoms include chest pain, chronic nocturnal acid breakthrough, delayed stomach discharge.5
cough, pseudo-influenza symptoms, and sinusitis.2,3 Also considering pH testing, patients with diagnosis of
GERD are classified into 3 groups: those with unusual acid
Today, proton pump inhibitors (PPIs) are the most impor- reflux scores (nonerosive reflux disease), those with usual
tant group of drugs for reducing stomach acid secretion. acid reflux scores and a direct relation of symptom with
They are used for the treatment of many upper diges- reflux (acid-sensitive esophagus), and those with normal
tive disorders.4 Proton pump inhibitors exert the most reflux scores and no symptom related to reflux events

Corresponding author: Mohammad Abbasinazari, e-mail: [email protected]

Received: January 16, 2023 Accepted: March 22, 2023 Publication Date: September 29, 2023
DOI: 10.5152/tjg.2023.23021

Copyright @ Author(s) – Available online at https://www.turkjgastroenterol.org.

1206 Content of this journal is licensed under a Creative Commons Attribution (CC BY) 4.0 International License
Malekpour et al. Sublingual Melatonin in GERD Turk J Gastroenterol 2023; 34(12): 1206-1211

(functional heartburn). Data have been reported that the gastrointestinal disorders, with low bioavailability (about
patients with nonerosive GERD treated better with PPIs 15%) in the gastrointestinal tract.15 Attempts to increase
therapy than those in the other 2 groups.6 the bioavailability of melatonin seem rational to improve
the management of different diseases. Therefore, the
Melatonin is used to improve sleep disorders in many present study aimed to investigate the efficacy, safety,
countries. It is secreted in the pineal gland to control sleep and quality of life (QOL) of patients with GERD, who
patterns and in the enterochromaffin cells to improve the received sublingual melatonin, melatonin plus omepra-
digestive system motility.7 It has been postulated that zole, or placebo to control their symptoms.
low melatonin levels are effective in the aggregation of
GERD symptoms, as melatonin leads to diminished stom- MATERIALS AND METHODS
ach acid secretion and strengthens the lower esophageal This double-blind randomized clinical trial was approved
sphincter.8 by the ethics committees of nursing, midwifery, and phar-
macy schools of Shahid Beheshti University of Medical
Melatonin leads to the stimulation of melatonin type 2 Sciences (code: IR.SB​MU.PH​ARMAC​Y.REC​.1400​.168)​ and
(MT2) receptors in the duodenal enterocyte. Stimulation registered in the Iranian Registry of Clinical Trials (code:
of MT2 leads to increase of bicarbonate secretion; accord- IRCT2​01210​21011​192N1​2). Before initiating the clinical
ingly, they provide protection of the duodenal epithelium stages, melatonin and placebo were prepared and pack-
against stomach acids. Besides, stimulation of these recep- aged. Melatonin (3 mg) was prepared as sublingual tab-
tors reduces stomach acid secretion.9 Melatonin deficiency lets (Vana DarouGostar Pharmaceutical Company, Iran),
leads to increased nitric metabolites, along with the dimin- and the placebo was prepared at the pharmaceutical
ished antioxidant activity of enzymes.10 Additionally, it can laboratory of the Shahid Beheshti University of Medical
inhibit biosynthetic nitric oxide. The transient lower esoph- Sciences, with the same appearance as sublingual mel-
ageal sphincter relaxation is one of the main mechanisms atonin, according to the main drug formulation without
of GERD, where nitric acid plays a key role.11 melatonin.

Melatonin, by inhibiting oxygen activation through neu- The clinical stages of this study were initiated on May 1,
tralization of oxygen, functions as an antioxidant and free 2022 and continued until October 1, 2022. The patients
radical scavenger and consequently, exerts gastroprotec- were randomly assigned to either the melatonin or pla-
tive effects.12 A study by Kandil et al13 indicated that oral cebo group based on the table of random numbers. The
melatonin alone could reduce GERD symptoms (heart- patients, physician, and examiner were blinded to the
burn and epigastric pain). Moreover, in a study by Klupińsk drug or placebo during the trial. The patients in the mela-
et al14 melatonin administration improved the symptoms tonin group received 20 mg of omeprazole in the morn-
of functional dyspepsia. In previous studies, the oral tab- ing before breakfast plus 3 mg of sublingual melatonin at
let form of melatonin was used for the treatment of upper night. In the placebo group, the patients received 20 mg
of omeprazole in the morning before breakfast plus mela-
tonin placebo sublingually at night.
Main Points
• Acid suppression, especially proton pump inhibitors, is This study was performed on patients with mild to mod-
widely accepted as the cornerstone of medical treatment
of gastroesophageal reflux disease.
erate symptoms of GERD, who were referred to the
• It is estimated that around 30% of patients with diagnosis gastroenterology clinic of Shahid Beheshti Hospital as
of gastroesophageal reflux disease are refractory to proton outpatients. At baseline, the patients were explained
pump inhibitors so attempt for evaluation of new medica- about the study and the course of treatment, and volun-
tion for gastroesophageal reflux disease pharmacotherapy teers signed written informed consent forms for partici-
is necessary.
• Melatonin has been used for the treatment of gastro-
pation in this study. The inclusion criteria were as follows:
esophageal reflux disease symptoms successfully but diagnosis of GERD; age above 18 years; having complaints
there is a concern regarding poor bioavailability of melato- of heartburn and or regurgitation 2 days or more per week;
nin from gastrointestinal tract. So in the present trial, the and a score ≤32 on the Frequency Scale for the Symptoms
aim was to investigate whether the addition of sublingual of GERD (FSSG). In this questionnaire, the symptoms
melatonin to omeprazole was effective in the treatment of
gastroesophageal reflux disease symptoms.
associated with the severity of disease included heart-
burn, throat burning sensation, esophageal dysphagia,

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Turk J Gastroenterol 2023; 34(12): 1206-1211 Malekpour et al. Sublingual Melatonin in GERD

chest pain, and voice hoarseness, which were evaluated measured. The minimum level of statistical significance
in 20 items and scored based on a 0-4 Likert scale, with was set at P ≤ .05. The normal distribution of param-
higher scores indicating more severe symptoms.16 eters was evaluated using Kolmogorov–Smirnov test.
For comparison of the placebo and melatonin groups,
The exclusion criteria were as follows: history of sensi- samples t-test, Mann–Whitney test, and Pearson’s chi-
tivity to omeprazole or melatonin; patients with reflux square test were utilized. To calculate the sample size
symptoms with diagnosis of peptic ulcer and duodenal required for this study, the FSSG was used as the main
ulcer on endoscopy; pregnant or breastfeeding women; index. For the FSSG score to reach 10 in the melatonin
current use of drugs causing transient lower esophageal group and 12 in the placebo group within 1 month,18 at
sphincter relaxation (e.g., calcium channel blockers and least 35 patients were required for each group consid-
nitrates); patients with Child-Pugh C cirrhosis; patients ering a SD of 3, an alpha level of 0.05, and a beta value
with severe renal damage (Acute Kidney Injury Network of 80%.
[AKIN] classification stage 3); shift workers; patients
using medications with major interactions with omepra- RESULTS
zole or melatonin (e.g., fluvoxamine); patients using alter- In this study (5 months), 163 patients with GERD symp-
native or traditional medicines concurrently; and patients toms, who were referred to the clinic and willing to partic-
with severe symptoms (FSSG score >32). ipate in this research, were included; however, 85 patients
were removed based on the exclusion criteria. Out of 78
After selecting eligible volunteers for the study, demo- patients included in the study, 4 from the melatonin
graphic characteristics, including sex, age, smoking hab- group and 2 from the placebo group were excluded dur-
its, and body mass index (BMI), were recorded. Also, ing the study due to ADRs of the drug and lack of drug
before treatment, FSSG and QOL scores were calculated adherence. In the final analysis, 35 and 37 patients in the
for the patients. To evaluate QOL, the validated Persian melatonin and placebo groups were evaluated, respec-
version of Mayo-gastroesophageal reflux questionnaire tively. Figure 1 presents the process of patient recruit-
was employed. This questionnaire was completed before ment in this study. Also, Table 1 reports and compares
and after the study to evaluate the QOL of the patients. It the demographic characteristics of the patients in the 2
contained 25 items, with the scores ranging from 25 (the groups. Statistical analyses indicated no significant dif-
lowest QOL) to 175 (the highest QOL)16,17; in other words, ferences in terms of sex, BMI, and smoking habit (P = .81,
higher scores represented higher QOL. .43, and .76, respectively). However, the mean age of the

At baseline, the patients received the training needed to

optimize their lifestyle for controlling GERD symptoms
(e.g., consuming food at low volumes, but higher frequen-
cies per day, not consuming alcohol, not wearing tight
clothes, and avoiding lower esophageal sphincter loosen-
ing foods). Next, patients in the 2 groups took the medi-
cation or placebo for 4 weeks. After 4 weeks, they would
return to the gastroenterology clinic for reexamination.
In the second visit, they completed the FSSG and GERQ.
During 4 weeks, the patients were contacted at least
once a week to inquire about their adherence to medica-
tions, as well as possible adverse drug reactions (ADRs). If
ADRs were attributed to the drug or placebo, the patient
was recommended to stop taking the drug or placebo and
was excluded from the study.

Statistical Analysis
For data analysis, the Statistical Package for Social
Sciences (SPSS) version 26.0 (IBM Corp.; Armonk, NY,
USA) was used. For data comparison, mean ± SD was Figure 1. Flow diagram of the study.

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Malekpour et al. Sublingual Melatonin in GERD Turk J Gastroenterol 2023; 34(12): 1206-1211

Table 1. Demographic Characteristics of the Patients in Sublingual group, and this reduction was statistically significant (P =
Melatonin and Placebo Group (n = 72)
.04 and P = .03, respectively).
Sublingual
Melatonin Placebo The scores of FSSG and GERQ questionnaires were
(n = 35) (n = 37) P determined and compared between the melatonin and
Mean age (years) (±SD) 38.18 ± 13.28 35.62 ± 11.2 <.0001 placebo groups before and after the study. The FSSG
Sex scores were not significantly different between the 2
Female 19 19 .81
groups before treatment (P = .30). After 4 weeks and
at the end of the study, post-treatment FSSG score
Male 16 18
reduced in both groups; this reduction was significant
Body mass index (kg/m2) (±SD) 24. 53 ± 3.18 23.01 ± 3.58 .43 in both melatonin and placebo groups compared to the
Smoker baseline (P = .001 and P = .0001, respectively). The FSSG
No 28 31 .76 score was lower in the melatonin group compared to the
Yes 7 6
placebo group, and the difference was statistically sig-
nificant (P = .0001). In other words, the melatonin group
showed a greater FSSG score reduction compared to the
melatonin group was significantly lower than that of the placebo group.
placebo group (P = .0001).
Additionally, the GERQ scores of the 2 groups were
Table 2 outlines the number of patients with epigastric determined before and after the study, as shown in
pain and heartburn in each group before and after the Table 2. Statistical analysis revealed that the value of
study. Statistical analyses showed that the frequency this index was not significantly different between the
of patients with epigastric pain and heartburn did not 2 groups at baseline (P = .41). After 4 weeks, the GERQ
differ significantly before treatment (P = .59 and P = score increased more considerably in the melatonin
.48, respectively). However, at the end of the study, the group compared to the placebo group, and the differ-
number of patients with heartburn and epigastric pain ence was statistically significant (P = .0001). The main
reduced in the melatonin group compared to the placebo ADR was drowsiness in the 2 groups (5 cases in mela-
tonin and 3 cases in placebo group). Also nausea, vom-
iting, mouth dryness and headache have been reported
Table 2. Baseline and Secondary Outcomes in Sublingual Melatonin
and Placebo Group (n = 72) in some patients (less than 3 cases in any side effects).
Although the incidence of ADRs was higher in the mela-
Sublingual tonin group, no significant difference was found between
Melatonin the 2 groups (P = .55).
Group Placebo Group
(n = 35) (n = 37) P
Before treatment 32 31 .48 DISCUSSION
heartburn Although PPIs are the first-line treatment for GERD, con-
Before treatment 27 26 .59 sidering the high prevalence of GERD symptoms in Iran
epigastric pain
(10%-14.9%) and around the world (13%), besides the
After treatment 4 13 .04 high rates of disease relapse and chronicity, a high per-
heartburn
centage of patients do not respond to this type of treat-
After treatment 4 9 .03 ment, thereby highlighting the need for new compounds
epigastric pain
with minimal side effects.19-21 In recent years, studies have
Before treatment FSSG 23.48 ± 5.88 22.32 ± 4.76 .30 evaluated the role of melatonin in controlling the symp-
After treatment FSSG 10.02 ± 2.43 14.97 ± 3.28 .0001 toms of GERD. In this regard, Kandil et al13 conducted a
Before treatment 91.94 ± 13.04 94.86 ± 17.07 .41 study on 36 patients with GERD, who were assigned into
quality of life 4 groups of 9. The first group received omeprazole (20
After treatment quality 128.28 ± 10.20 115.10 ± 15.77 .0001 mg/d), the second group received melatonin (3 mg/d), the
of life third group received omeprazole plus melatonin concur-
FSSG, Frequency Scale for the Symptoms of gastroesophageal reflux rently, and the fourth group only received the placebo.
disease.
After 4 weeks, control of symptoms, such as heartburn

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and epigastric pain, was considerable in the omeprazole, Finally, the results of the current study indicated the
melatonin, and omeprazole plus melatonin groups com- greater effect of melatonin plus omeprazole versus
pared to the baseline. The efficacy of omeprazole alone omeprazole alone in the management of GERD symp-
was greater than melatonin, and the concurrent use of toms, such as heartburn, epigastric pain, and FSSG
melatonin and omeprazole was more effective than other score. Moreover, the simultaneous use of melatonin and
groups. Nevertheless, due to the small sample size, fur- omeprazole compared to omeprazole alone was associ-
ther trials are recommended. ated with greater improvements in the QOL of patients
after 4 weeks. In a review study by Bang et al,22 the use of
In a meta-analysis by Bang et al22 on studies evaluat- melatonin was associated with decreased sleep disorders,
ing the efficacy of melatonin in the treatment of GERD, which would indirectly reduce the symptoms of GERD.21
after reviewing medical databases, including EMBASE, Besides, Gurges et al27 reported that GERD is mostly
Cochrane, and PubMed, the efficacy of oral melato- associated with sleep disorders in patients. Since sleep
nin tablets in the management of GERD symptoms was improvement is one of the scoring indices in GERQ, the
reported. Since the bioavailability of oral melatonin tab- melatonin group was expected to obtain better scores
lets is below 15% in different studies,23,24 in this trial, to compared to the placebo group, which is consistent with
achieve a higher blood level of melatonin and desirable the results of the present study. Additionally, the current
therapeutic effects, the sublingual form of this drug was study showed that sublingual melatonin was not asso-
used. Considering the overlap between the symptoms ciated with serious ADRs and was well-tolerated by the
of upper digestive system diseases, including functional patients; the similar incidence rates of side effects in the
dyspepsia, a reliable questionnaire (FSSG) was used in 2 groups confirm this finding.
this study for the initial diagnosis and precise grading of
patients with GERD. This questionnaire can be used for Although this is the first study examining and comparing
evaluating the severity of disease and response to treat- the effects of sublingual melatonin addition to omepra-
ment, as well as diagnosis by the healthcare team and zole versus omeprazole alone, it has some limitations.
physicians.25 Unlike some previous research, assessments in this
study only included subjective parameters, while more
Numerous studies have reported a relationship between objective parameters, such as manometry, pH monitor-
plasma melatonin level and its efficacy in the treat- ing, and measurement of melatonin concentration, were
ment of upper digestive disorders. A study by Chojnacki not examined because of financial and time constraints
et al10 examining the effect of melatonin on Helicobacter to identify the relationship between plasma melatonin
pylori-induced dyspepsia, found that melatonin level was level and management of symptoms for confirmation of
significantly lower in the group of H. pylori plus dyspepsia the results. In our trial, the age was different significantly
(P < .001); after 6 months of treatment with melatonin, between the 2 groups. This may be related to the sample
the extent of improvement in dyspepsia symptoms was size of the trial. Randomization error (variability, impre-
47% in the placebo group and 84.3% in the treatment cision) can be overcome by increasing the sample size.
group. Although a positive effect of sublingual melatonin has
been observed in our trial, more sample sizes recommend
Since previous studies have suggested that the sublin- strongly in future trials. Future studies are highly recom-
gual form of melatonin can establish higher plasma lev- mended to address these shortcomings.
els,26 it might pose a risk to the significant alleviation of
digestive symptoms compared to its oral form with lower Ethics Committee Approval: This study was approved by Ethics
bioavailability. Accordingly, in this study, the sublingual Committee of Shahid Beheshti University of Medical Sciences
form of melatonin was used. To the best of our knowl- (Approval No: IR.sb​mu.ph​armac​y.rec​.1400​.168,​ Date: May 2021).
edge, no clinical study has yet investigated the effects of
Informed Consent: Written informed consent was obtained from
sublingual melatonin on controlling GERD symptoms. The
the patients who agreed to take part in the study.
present results based on FSSG showed that melatonin
significantly contributed to the alleviation of GERD symp- Peer-review: Externally peer-reviewed.
toms compared to the placebo (P = .001). Nevertheless,
in the placebo group, the symptoms diminished signifi- Author Contributions: Concept – N.A., M.A.; Design – M.H., A.M.;
cantly compared to the baseline, which is most probably Supervision – A.S., A.M.; Resources – A.G.M., M.A.; Materials – N.A.,
due to treatment with omeprazole. M.A.; Data collection – M.H., N.A., A.S., A.M., M.A., A.G.M.;

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Malekpour et al. Sublingual Melatonin in GERD Turk J Gastroenterol 2023; 34(12): 1206-1211

Analysis – A.M.; Literature review – A.M.; Writing – A.M., N.A.; Clinical 13. Kandil TS, Mousa AA, El-Gendy AA, Abbas AM. The potential
review – A.M., A.G.M. therapeutic effect of melatonin in gastro-esophageal reflux disease.
BMC Gastroenterol. 2010;10(1):7. [CrossRef]
Declaration of Interests: The authors have no conflict of interest to 14. Klupińska G, Poplawski T, Drzewoski J, et al. Therapeutic effect
declare. of melatonin in patients with functional dyspepsia. J Clin Gastroen-
terol. 2007;41(3):270-274. [CrossRef]
Funding: This study received no funding. 15. Bartoli AN, De Gregori S, Molinaro M, Broglia M, Tinelli C, Imberti R.
Bioavailability of a new oral spray melatonin emulsion compared
with a standard oral formulation in healthy volunteers. J Bioequiva-
REFERENCES lence Bioavailability. 2012;4(7):96-99.
1. Dent J, El-Serag HB, Wallander MA, Johansson S. Epidemiology of 16. Abdi S, Sargashteh Z, Abbasinazari M, Salamzadeh J, Mor-
gastro-oesophageal reflux disease: a systematic review. Gut. tazavi SA. Buccal buspirone as add–on therapy to omeprazole versus
2005;54(5):710-717. [CrossRef] omeprazole in treatment of gastroesophageal reflux diseases
2. Săraru ER, Enciu V, Peagu R, Fierb​inţea​nu-Br​atice​vici C. Advances (GERD). Iran J Pharm Res. 2020;19(4):113-120. [CrossRef]
in the diagnosis of GERD. Rom J Intern Med. 2021;59(1):3-9. 17. Nasseri S, Moghaddam RH, et al. Reliability, validity, and feasibility
[CrossRef] of the Mayo Gastro-Esophageal Reflux Questionnaire (GERQ) in a
3. Shaheen NJ, Hansen RA, Morgan DR, et al. The burden of gastro- Persian-speaking population. Iran J Public Health. 2008;37(2):64-69.
intestinal and liver diseases, 2006. Off J Am Coll Gastroenterol. 18. Abdi S, Sargashteh Z, Abbasinazari M, Salamzadeh J, Mor-
2006;101(9):2128-2138. [CrossRef] tazavi SA. Buccal buspirone as add-on Therapy to omeprazole versus
4. de Oliveira Torres JDF, de Souza Pereira R. Which is the best choice omeprazole in Treatment of gastroesophageal reflux diseases
for gastroesophageal disorders: melatonin or proton pump inhibi- (GERD). Iran J Pharm Res. 2020;19(4):113-120. [CrossRef]
tors? World J Gastrointest Pharmacol Ther. 2010;1(5):102-106. 19. Eusebi LH, Ratnakumaran R, Yuan Y, Solaymani-Dodaran M,
[CrossRef] Bazzoli F, Ford AC. Global prevalence of, and risk factors for, gastro-
5. Furuta T, Shirai N, Watanabe F, et al. Effect of cytochrome oesophageal reflux symptoms: a meta-analysis. Gut. 2018;67(3):430-
P4502C19 genotypic differences on cure rates for gastroesophageal 440. [CrossRef]
reflux disease by lansoprazole. Clin Pharmacol Ther. 2002;72(4):453- 20. Richter JE, Rubenstein JH. Presentation and epidemiology of
460. [CrossRef] gastroesophageal reflux disease. Gastroenterology. 2018;154(2):267-
6. Mittal R, Vaezi MF. Esophageal motility disorders and gastroe- 276. [CrossRef]
sophageal reflux disease [review]. N Engl J Med. 2020;383(20):1961- 21. Abbasinazari M, Panahi Y, Mortazavi SA, et al. Effect of a com-
1972. [CrossRef] bination of omeprazole plus sustained release Baclofen versus ome-
7. Locke 3rd GR, Talley NJ, Fett SL, Zinsmeister AR, Melton 3rd LJ. prazole alone on symptoms of patients with gastroesophageal reflux
Prevalence and clinical spectrum of gastroesophageal reflux: a pop- disease (GERD). Iran J Pharm Res. 2014;13(4):1221-1226.
ulation-based study in Olmsted County, Minnesota. Gastroenterol- 22. Bang CS, Yang YJ, Baik GH. Melatonin for the treatment of gas-
ogy. 1997;112(5):1448-1456. [CrossRef] troesophageal reflux disease; protocol for a systematic review and
8. Thor PJ, Krolczyk G, Gil K, Zurowski D, Nowak L. Melatonin and meta-analysis. Medicine. 2019;98(4):e14241. [CrossRef]
serotonin effects on gastrointestinal motility. J Physiol Pharmacol. 23. DeMuro RL, Nafziger AN, Blask DE, Menhinick AM, Bertino Jr JS.
2007;58(suppl 6):97-103. The absolute bioavailability of oral melatonin. J Clin Pharmacol.
9. Konturek PC, Konturek SJ, Hahn EG. Duodenal alkaline secretion: 2000;40(7):781-784. [CrossRef]
its mechanisms and role in mucosal protection against gastric acid. 24. Andersen LP, Werner MU, Rosenkilde MM, et al. Pharmacokinet-
Dig Liver Dis. 2004;36(8):505-512. [CrossRef] ics of oral and intravenous melatonin in healthy volunteers. BMC
10. Chojnacki C, Mędrek-Socha M, Konrad P, Chojnacki J, Błońska A. Pharmacol Toxicol. 2016;17(1):8. [CrossRef]
The value of melatonin supplementation in postmenopausal women 25. Takenaka R, Matsuno O, Kitajima K, et al. The use of frequency
with Helicobacter pylori-associated dyspepsia. BMC Womens Health. scale for the symptoms of GERD in assessment of gastro-oesopha-
2020;20(1):262. [CrossRef] geal reflex symptoms in asthma. Allergol Immunopathol (Madr).
11. Holloway RH. Systemic pharmacomodulation of transient lower 2010;38(1):20-24. [CrossRef]
esophageal sphincter relaxations. Am J Med. 2001;111(8):178S-185S. 26. Zetner D, Andersen LP, Rosenberg J. Pharmacokinetics of alter-
[CrossRef] native administration routes of melatonin: a systematic review. Drug
12. Tan DX, Manchester LC, Reiter RJ, Qi WB, Karbownik M, Calvo JR. Res. 2016;66(4):169-173. [CrossRef]
Significance of melatonin in antioxidative defense system: reac- 27. Gurges P, Murray BJ, Boulos MI. Relationship between gastroe-
tions and products. Biol Signals Recept. 2000;9(3-4):137-159. sophageal reflux disease and objective sleep quality. J Clin Sleep
[CrossRef] Med. 2022;18(12):2731-2738. [CrossRef]

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