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Herbal Medicine for the Treatment of Non-Erosive Reflux Disease: A Systematic Review and Meta-Analysis Protocol

Article information

J Int Korean Med. 2023;44(6):1176-1185
Publication date (electronic) : 2023 December 30
doi : https://doi.org/10.22246/jikm.2023.44.6.1176
1 Dept. of Clinical Korean Medicine, Graduate School of Kyung Hee University
2 Dept. of Digestive Diseases, College of Korean Medicine, Kyung Hee University
3 Dept. of Korean Internal Medicine, Kyung Hee University College of Korean Medicine, Kyung Hee University Hospital at Gangdong
4 Division of Digestive Diseases, Dept. of Korean Internal Medicine, Kyung Hee University Korean Medicine Hospital
·Corresponding author: Seok-Jae Ko Dept. of Korean Internal Medicine, Kyung Hee University College of Korean Medicine, Kyung Hee University Hospital at Gangdong, Dongnam-ro 892, Gangdong-gu, Seoul, Korea TEL: 02-440-6245 E-mail: kokokoko119@daum.net
Received 2023 November 16; Revised 2023 December 21; Accepted 2023 December 22.

Abstract

Introduction:

Non-erosive reflux disease (NERD) is the most common subtype of gastroesophageal reflux disease (GERD). This study aims to synthesize evidence on the efficacy and safety of various herbal medicines for the treatment of NERD.

Methods and analysis:

Ten electronic databases will be examined: MEDLINE (via PubMed), Cochrane Central Register of Controlled Trials, Embase, Allied and Complementary Medicine Database, China National Knowledge Infrastructure Database, Citation Information by Nii, Korean Medical Database, Korean Studies Information Service System, National Digital Science Library, and Oriental Medicine Advanced Searching Integrated System. All randomized controlled trials published from inception to May 2023 that meet the eligibility criteria will be selected. Two independent researchers will extract data, such as publication year, study design, intervention details, outcome measures, main results, and adverse events. The risk of bias and quality of evidence will be assessed, and subgroup analyses will be performed according to the type of control intervention and herbal medicine. The analysis process will be conducted using Review Manager 5.4 software.

Discussion:

This review will present a summary and rationale for herbal medicine’s effectiveness in treating NERD. The findings of this review can help those who want to apply herbal medicine to the treatment of NERD.

Systematic review registration:

PROSPERO registration number CRD42023423052.

I. Introduction

Gastroesophageal reflux disease (GERD) is one of the most commonly diagnosed chronic gastrointestinal disorders and is characterized by regurgitation of stomach contents back into the esophagus. Based on the endoscopic and histopathological appearance, there are several phenotypes of GERD, such as non-erosive reflux disease (NERD), erosive esophagitis, and Barrett’s esophagus. NERD accounts for the most prevalent type among them1. Symptoms induced by the regurgitation of gastric juice associated with NERD, even without inflammatory lesions on the mucous membrane of the esophagus, can contribute to lowering the patients’ quality of life and generating severe heartburn2,3. Conventional treatment options currently include lifestyle modifications, medical, surgical, and endoluminal therapy4. Proton pump inhibitor (PPI) therapy is the most widely used method that can be tried in medical therapy. However, evidence for the effectiveness of PPIs in the treatment of NERD has not been sufficiently established5,6. Herbal medicine can serve as a viable alternative for treating NERD, particularly when Western medicine fails to provide desired results, such as in cases of PPI-refractory reflux disease or when dose reduction is preferred. There have been various types of reports, such as case reports, randomized controlled trials (RCT), and systematic reviews that confirmed the efficacy and safety of herbal medicine treatment on GERD and NERD7-10. A meta-analysis confirming the efficacy and safety of traditional treatment of NERD was conducted in 201811. However, the databases searched were limited to English and Chinese, and trials involving Western medicine in the intervention group were excluded. Therefore, we aimed to search for more recent and extensive trials relevant to herbal medicine treatment of NERD and conduct subgroup analyses to synthesize the current state of evidence on the efficacy of herbal medicine in treating NERD.

II. Methods and analysis

This systematic review and meta-analysis aimed to identify, synthesize, and analyze the evidence on the efficacy and safety of herbal medicines for NERD. The systematic review and meta-analysis will be conducted according to the Cochrane Handbook for Systematic Reviews of Interventions12. The protocol for this systematic review is based on the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guideline13, and is registered in the International Prospective Register of Systematic Review (PROSPERO) with registration number CRD42023423052.

1. Search strategy

We will search the following 10 electronic databases from inception to May 2023 without language or publication date restrictions: MEDLINE (via PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), Embase, Allied and Complementary Medicine Database (AMED), China National Knowledge Infrastructure Database (CNKI), Citation Information by Nii (CiNii), Korean Medical Database (Kmbase), Korean Studies Information Service System (KISS), National Digital Science Library (NDSL), Oriental Medicine Advanced Searching Integrated System (OASIS). The search term will consist of a combination of controlled terms such as Medical Subject Headings (MeSH) and free text words related to “non-erosive reflux disease”, “herbal medicine”, or “traditional medicine”. The search strategy for MEDLINE is shown in Table 1.

Search strategy for Medline via PubMed

2. Eligibility criteria

The following eligibility criteria will be applied to select the appropriate studies for inclusion in this review.

1) Types of studies

RCTs and quasi-RCTs in humans will be included. Other than RCTs, such as case reports, retrospective studies, reviews, and animal studies will be excluded.

2) Types of participants

Patients diagnosed with NERD will be included, and those diagnosed with any organic disease associated with symptoms other than GERD or NERD will be excluded. There will be no restriction on demographic characteristics, such as race or gender, but studies involving only non-adults under the age of 19 years will be excluded.

3) Types of interventions

Studies involving any type of herbal medicine, such as a decoction, pill, tablet, capsule, or powder administered orally as an intervention, will be included. There will be no restrictions on the number of herbs that comprise the formula, and studies using herbal medicines consisting of only one herb as an intervention will also be included. Studies comparing herbal medicine with any type of control intervention will be included: herbal medicine alone, herbal medicine combined with Western medicine versus Western medicine alone, herbal medicine versus placebo formulation, and herbal medicine versus no treatment. However, studies that involved other traditional treatment methods, such as acupuncture or moxibustion with herbal medicine as the main intervention in the treatment group and studies that included herbal medicine as an intervention in both the control and treatment groups, will be excluded.

4) Types of outcome measures

The primary outcome will be the total efficacy rate. Symptom scores and quality of life examined by self-response questionnaires such as reflux diagnostic questionnaire score, gastroesophageal reflux disease questionnaire, short-form 36 health survey score, and recurrence rates will be secondary outcomes.

3. Study selection

Two researchers (MK and CP) will independently examine the titles and abstracts of all retrieved studies in the first phase of screening. In the second phase, researchers will undergo a full-text screening process. Disagreements between the two researchers will be resolved through a discussion with a senior researcher (S-JK). Duplicates among the studies will be identified by study characteristics such as author names, publication year, trial registration number, intervention, or participants during the screening process, and multiple reports will be removed. The selection process will be shown in the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) flow diagram (Fig. 1). Selected studies that meet the eligibility criteria above will undergo data extraction process. Data management will be performed using Endnote X20 software program.

Fig. 1

Flow chart of the search process.

CENTRAL : Cochrane Central Register of Controlled Trials, AMED : Allied and Complementary Medicine Database, CNKI : China National Knowledge Infrastructure Database, CiNii : Citation Information by Nii, Kmbase : Korean Medical Database, KISS : Korean Studies Information Service System, NDSL : National Digital Science Library, OASIS : Oriental Medicine Advanced Searching Integrated System

4. Data extraction

Data extraction will be performed by two independent researchers (MK and CP), and data will be recorded in a pre-defined form. The extracted data will include the basic characteristics of the study, such as authors’ name, year of publication, study design, information about participants, details of the intervention, outcome measures, main results, and adverse events. Details of the intervention will include the type of herbal medicine, and duration and frequency of treatment.

III. Meta-analysis

1. Assessment of the risk of bias

The quality of all selected studies will be assessed using the Cochrane risk-of-bias tool for randomized trials individually14. Biases in the random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting will be checked. Each domain will be judged as low, uncertain, or high.

2. Data synthesis and analysis

Results such as the overall efficacy rate from the treatment and control groups will be compared. Dichotomous data will be presented as risk ratios (RR) with a 95% confidence intervals (CI); continuous data will be presented as mean difference (MD) or standardized mean difference (SMD) with a 95% CI15. Statistical analyses will be conducted using Review Manager program (RevMan) version 5.4.. A narrative summary will be provided if the studies are not appropriate for quantitative synthesis.

Statistical heterogeneity of the studies will be measured using I2 statistics; if it is over 50%, it will be considered to have significant heterogeneity16. Fixed- or random- effects models will be used for the meta-analysis. In addition, a funnel plot will be used to assess publication bias in terms of the primary outcome.

3. Assessment of meta-biases

The quality of evidences from the included studies will be assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. The risks of bias, imprecision, inconsistency, indirectness, and publication bias will be assessed and graded as high, moderate, low, or very low17.

4. Subgroup analyses

A subgroup analysis will be performed based on the type of control intervention or type of herbal medicine used. Differences will be compared according to the type of Western medicine and whether herbal medicine is combined with Western medicine or used alone.

IV. Discussion

NERD is the most common type of GERD. It is defined as the absence of mucosal lesions confirmed by endoscopy and represents up to 60% of all patients with reflux symptoms18. Medical treatment of patients with NERD is based on gastric acid- suppressive drugs such as PPIs. Although PPI therapy is the most effective method for treating GERD, the response rates to PPIs are lower in patients than in those with other phenotypes of GERD19. This systematic review and meta-analysis will assess the efficacy and safety of herbal medicines for the treatment of NERD.

Herbal medicines can be a helpful option for the treatment of reflux disease, especially in cases that do not respond to conventional medical treatments, including proton pump inhibitors. Various herbal medicines can alleviate the symptoms of non-erosive reflux disease in patients with symptoms such as heartburn20,21. In this study, we will investigate clinical trials published from the inception of herbal medicine treatment for NERD, and synthesize recent evidence of its efficacy.

Ethics and dissemination

Since this study do not include individual patient data, ethical approval is not required. The results of this systematic review will be disseminated via peer-reviewed journal publication or conference presentations.

Acknowledgements

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Contributors

Both MK and CP contributed to the conceptualization of the review. Both J-WP and JK contributed to the development of the search strategy and design of the analysis plan. MK wrote the initial draft of the manuscript. S-JK reviewed and edited the final manuscript. All the authors have read and approved the final version of the manuscript.

Funding

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (No. 2022R1C1C1004937) to S.J.K..

This funding source had no role in the design of this study and will not play any role during its execution, analysis, interpretation of the data, or decision to submit the results.

References

1. Fass R, Frazier R. The Role of Dexlansoprazole Modified-Release in the Management of Gastroesophageal Reflux Disease. Therap Adv Gastroenterol 2017;10(2):243–51.
2. Zhang JX, Ji MY, Song J, Lei HB, Qiu S, Wang J, et al. Proton Pump Inhibitor for Non-Erosive Reflux Disease:A Meta-Analysis. World J Gastroenterol 2013;19(45):8408–19.
3. El-Serag HB, Sweet S, Winchester CC, Dent J. Update on the Epidemiology of Gastro-Oesophageal Reflux Disease:A Systematic Review. Gut 2014;63(6):871–80.
4. Antunes C, Aleem A, Curtis SA. Gastroesophageal Reflux Disease. StatPearls [Internet] 2023;
5. Scarpignato C. Poor Effectiveness of Proton Pump Inhibitors in Non-Erosive Reflux Disease:The Truth in the End! Neurogastroenterol Motil 2012;24(8):697–704.
6. Woodland P, Sifrim D. Management of Gastro- Oesophageal Reflux Disease Symptoms That Do Not Respond to Proton Pump Inhibitors. Curr Opin Gastroenterol 2013;29(4):431–6.
7. Sadeghi F, Mohammad S, Sepehri B, Khodaie L, Monirifar H, Mirghafourvand M. Effects of Herbal Medicine in Gastroesophageal Reflux Disease Symptoms:A Systematic Review and Meta-Analysis. Tradit Med Res 2020;5(6):464–75.
8. Tominaga K, Iwakiri R, Fujimoto K, Fujiwara Y, Tanaka M, Shimoyama Y, et al. Rikkunshito Improves Symptoms in PPI-Refractory GERD Patients:A Prospective, Randomized, Multicenter Trial in Japan. J Gastroenterol 2012;47(3):284–92.
9. Dai Y, Zhang Y, Li D, Ye J, Chen W, Hu L. Efficacy and Safety of Modified Banxia Xiexin Decoction (Pinellia Decoction for Draining the Heart) for Gastroesophageal Reflux Disease in Adults:A Systematic Review and Meta-Analysis. Evidence-based Complement Altern Med 2017;2017:9591319.
10. Los UMDECDE. A Clinical Case Report of Non- Erosive Reflux Disease Treated with Traditional Oriental Medicine. Korean J Orient Intern Med 2006;27(4):991–8.
11. Xiao J, Yang Y, Zhu Y, Qin Y, Li Y, Fu M, et al. Efficacy and Safety of Traditional Chinese Medicine on Nonerosive Reflux Disease:A Meta-Analysis of Randomized Controlled Trials. Evidence-based Complement Altern Med 2018;2018:1505394.
12. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA, et al. Cochrane Handbook for Systematic Reviews of Interventions Version 6.3(Updated August 2022). Cochrane 2022;
13. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 Statement:An Updated Guideline for Reporting Systematic Reviews. BMJ 2021;:372.
14. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2:A Revised Tool for Assessing Risk of Bias in Randomised Trials. BMJ 2019;366:1–8.
15. Andrade C. Understanding Relative Risk, Odds Ratio, and Related Terms:As Simple as It Can Get. J Clin Psychiatry 2015;76(7):e857–61.
16. Melsen WG, Bootsma MC, Rovers MM, Bonten MJ. The Effects of Clinical and Statistical Heterogeneity on the Predictive Values of Results from Meta-Analyses. Clin Microbiol Infect 2014;20(2):123–9.
17. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE:An Emerging Consensus on Rating Quality of Evidence and Strength of Recommendations. BMJ 2008;336(7650):924–6.
18. Karamanolis GP, Tutuian R. Role of Non-Acid Reflux in Patients with Non-Erosive Reflux Disease. Ann Gastroenterol 2013;26(2):100–3.
19. Sigterman KE, van Pinxteren B, Bonis PA, Lau J, Numans ME. Short-Term Treatment with Proton Pump Inhibitors, H2-Receptor Antagonists and Prokinetics for Gastro-Oesophageal Reflux Disease-like Symptoms and Endoscopy Negative Reflux Disease. Cochrane Database Syst Rev 2013;2013(5):CD002095.
20. Tominaga K, Kato M, Takeda H, Shimoyama Y, Umegaki E, Iwakiri R, et al. A Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Rikkunshito for Patients with Non-Erosive Reflux Disease Refractory to Proton-Pump Inhibitor:The G-PRIDE Study. J Gastroenterol 2014;49(10):1392–405.
21. Li BS, Li ZH, Tang XD, Zhang LY, Zhao YP, Bian LQ, et al. A Randomized, Controlled, Double-Blinded and Double-Dummy Trial of the Effect of Tongjiang Granule on the Nonerosive Reflux Disease of and Gan-Wei Incoordination Syndrome. Chin J Integr Med 2011;17(5):339–45.

Appendices

【PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) 2015 checklist : recommended items to address in a systematic review protocol*

From: Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart L, PRISMA-P Group. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015 Jan 2;349(jan02 1):g7647.

Pre-defined Data Extraction Form

Article information Continued

Table 1

Search strategy for Medline via PubMed

No. Search strategy
#1. gastroesophageal reflux[MeSH Terms]

#2. gastric acid reflux[tiab] OR acid reflux, gastric[tiab] OR reflux, gastric acid[tiab] OR gastric acid reflux disease[tiab]

#3. gastro-esophageal reflux disease[tiab] OR gastro esophageal reflux disease[tiab] OR gastro-esophageal reflux diseases[tiab] OR reflux disease, gastro-esophageal[tiab]

#4. gastro-oesophageal reflux[tiab] OR gastro oesophageal reflux[tiab] OR reflux, gastro-oesophageal[tiab]

#5. gastroesophageal reflux disease[tiab]

#6. GERD[tiab] OR reflux, gastroesophageal[tiab] OR esophageal reflux[tiab] OR gastro-esophageal reflux[tiab] OR gastro esophageal reflux[tiab] OR reflux, gastro-esophageal[tiab]

#7. #1 OR #2 OR #3 OR #4 OR #5 OR #6

#8. non erosive[tiab] OR non-erosive[tiab] OR nonerosive[tiab] OR non erosion[tiab] OR non-erosion[tiab] OR NERD[tiab] OR non erosive reflux disease[tiab] OR non-erosive reflux disease[tiab] OR nonerosive reflux disease[tiab] OR non erosion reflux disease[tiab] OR non-erosion reflux disease[tiab]

#9. #7 OR #8

#10. herbal medicine[MeSH Terms]

#11. medicine, herbal[tiab] OR herb*[tiab]

#12. plants, medicinal[MeSH Terms] OR plant extracts[MeSH Terms]

#13. medicine, traditional[MeSH Terms] OR medicine, korean traditional[MeSH Terms] OR medicine, chinese traditional[MeSH Terms] OR medicine, east asian traditional[MeSH Terms]

#14. korean[tiab] OR chinese[tiab] OR east asian[tiab] OR japanese[tiab]

#15. tradition*[tiab]

#16. #14 AND #15

#17. traditional[tiab] OR chinese[tiab] OR herbal[tiab]

#18. medicine[tiab]

#19. #17 AND #18

#20. medicine, kampo[MeSH Terms]

#21. complementary therapies[MeSH Terms]

#22. drugs, chinese herbal[MeSH Terms]

#23. tang[tiab] OR decoction[tiab] OR formula*[tiab] OR herbal formula[tiab] OR granule[tiab] OR syrup[tiab] OR san[tiab] OR hwan[tiab] OR capsule[tiab] OR powder[tiab] OR tablet[tiab]

#24. #10 OR #11 OR #12 OR #13 OR #16 OR #19 OR #20 OR #21 OR #22 OR #23

#25. randomized controlled trial[pt]

#26. controlled clinical trial[pt]

#27. randomized[tiab] OR randomised[tiab]

#28. randomly[tiab]

#29. clinical[tiab]

#30. trial*[tiab]

#31. clinical trial[tiab]

#32. #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31

#33. #9 AND #24 AND #32

MeSH : medical subject headings, tiab : title/abstract, GERD : gastroesophageal reflux disease, NERD : non-erosive reflux disease, pt : publication type

Fig. 1

Flow chart of the search process.

CENTRAL : Cochrane Central Register of Controlled Trials, AMED : Allied and Complementary Medicine Database, CNKI : China National Knowledge Infrastructure Database, CiNii : Citation Information by Nii, Kmbase : Korean Medical Database, KISS : Korean Studies Information Service System, NDSL : National Digital Science Library, OASIS : Oriental Medicine Advanced Searching Integrated System

【PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) 2015 checklist : recommended items to address in a systematic review protocol*

Section and topic Item No Checklist item Reported on Page #
ADMINISTRATIVE INFORMATION
Title :
Identification 1a Identify the report as a protocol of a systematic review 1
Update 1b If the protocol is for an update of a previous systematic review, identify as such N/A
Registration 2 If registered, provide the name of the registry (such as PROSPERO) and registration number 2
Authors :
Contact 3a Provide name, institutional affiliation, e-mail address of all protocol authors; provide physical mailing address of corresponding author 1
Contributions 3b Describe contributions of protocol authors and identify the guarantor of the review 11
Amendments 4 If the protocol represents an amendment of a previously completed or published protocol, identify as such and list changes; otherwise, state plan for documenting important protocol amendments N/A
Support :
Sources 5a Indicate sources of financial or other support for the review 12
Sponsor 5b Provide name for the review funder and/or sponsor 12
Role of sponsor or funder 5c Describe roles of funder(s), sponsor(s), and/or institution(s), if any, in developing the protocol 12
INTRODUCTION
Rationale 6 Describe the rationale for the review in the context of what is already known 3
Objectives 7 Provide an explicit statement of the question(s) the review will address with reference to participants, interventions, comparators, and outcomes (PICO) 3
METHODS
Eligibility criteria 8 Specify the study characteristics (such as PICO, study design, setting, time frame) and report characteristics (such as years considered, language, publication status) to be used as criteria for eligibility for the review 3-7
Information sources 9 Describe all intended information sources (such as electronic databases, contact with study authors, trial registers or other grey literature sources) with planned dates of coverage 3-4
Search strategy 10 Present draft of search strategy to be used for at least one electronic database, including planned limits, such that it could be repeated 5-6
Study records:
Data management 11a Describe the mechanism(s) that will be used to manage records and data throughout the review 7-8
Selection process 11b State the process that will be used for selecting studies (such as two independent reviewers) through each phase of the review (that is, screening, eligibility and inclusion in meta-analysis) 7-8
Data collection process 11c Describe planned method of extracting data from reports (such as piloting forms, done independently, in duplicate), any processes for obtaining and confirming data from investigators 10
Data items 12 List and define all variables for which data will be sought (such as PICO items, funding sources), any pre-planned data assumptions and simplifications 10
Outcomes and prioritization 13 List and define all outcomes for which data will be sought, including prioritization of main and additional outcomes, with rationale 10
Risk of bias in individual studies 14 Describe anticipated methods for assessing risk of bias of individual studies, including whether this will be done at the outcome or study level, or both; state how this information will be used in data synthesis 10
Data synthesis 15a Describe criteria under which study data will be quantitatively synthesised 10
15b If data are appropriate for quantitative synthesis, describe planned summary measures, methods of handling data and methods of combining data from studies, including any planned exploration of consistency (such as I2, Kendall’s τ) 10
15c Describe any proposed additional analyses (such as sensitivity or subgroup analyses, meta-regression) 10-11
15d If quantitative synthesis is not appropriate, describe the type of summary planned 10
Meta-bias(es) 16 Specify any planned assessment of meta-bias (es) (such as publication bias across studies, selective reporting within studies) 10
Confidence in cumulative evidence 17 Describe how the strength of the body of evidence will be assessed (such as GRADE) 10
*

It is strongly recommended that this checklist be read in conjunction with the PRISMA-P Explanation and Elaboration (cite when available) for important clarification on the items. Amendments to a review protocol should be tracked and dated. The copyright for PRISMA-P (including checklist) is held by the PRISMA-P Group and is distributed under a Creative Commons Attribution Licence 4.0.

Pre-defined Data Extraction Form

No. First author (year) Language Participants (n) M:F Diagnosis criteria Invervention (n) Control (n) Treatment period Outcome measure Main results Side effects
Age Content Content Main statistics
1