Article Text

Acupuncture for the treatment of gastro-oesophageal reflux disease: a systematic review and meta-analysis
1. Jiajie Zhu1,2,
2. Yu Guo2,
3. Shan Liu3,
4. Xiaolan Su2,
5. Yijie Li1,
6. Yang Yang2,
7. Liwei Hou2,
8. Guishu Wang1,
9. Jiaxin Zhang1,
10. Jiande JD Chen4,
11. Qingguo Wang3,
12. Ruhan Wei5,
13. Wei Wei2
1. 1 Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
2. 2 Department of Gastroenterology, Beijing Key Laboratory of Functional Gastrointestinal Disorders Diagnosis and Treatment of Traditional Chinese Medicine, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, China
3. 3 Basic Medical College, Beijing University of Chinese Medicine, Beijing, China
4. 4 Division of Gastroenterology and Hepatology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA
5. 5 Cleveland State University, Cleveland, Ohio, USA
1. Correspondence to Professor Wei Wei, Beijing Key Laboratory of Functional Gastrointestinal Disorders Diagnosis and Treatment of Traditional Chinese Medicine, Wangjing Hospital, China Academy of Chinese Medical Sciences, No. 6 Wangjing Zhonghuan Road, Chaoyang District, Beijing 100102, China; sxxtyy{at}sina.com

## Abstract

Background Gastro-oesophageal reflux disease (GORD) is one of the most common diseases presenting to gastroenterology clinics. Acupuncture is widely used as a complementary and alternative treatment for patients with GORD.

Objective To explore the effectiveness of acupuncture for the treatment of GORD.

Methods Four English and four Chinese databases were searched through June 2016. Randomised controlled trials investigating the effectiveness of manual acupuncture or electroacupuncture (MA/EA) for GORD versus or as an adjunct to Western medicine (WM) were selected. Data extraction and quality evaluation were performed by two authors independently and RevMan 5.2.0 was used to analyse data.

Results A total of 12 trials involving 1235 patients were included. Meta-analyses demonstrated that patients receiving MA/EA combined with WM had a superior global symptom improvement compared with those receiving WM alone (relative risk (RR) 1.17, 95% CI 1.09 to 1.26; p=0.03; six studies) with no significant heterogeneity (I2=0%, p=0.41). Recurrence rates of those receiving MA/EA alone were lower than those receiving WM (RR 0.42,95% CI 0.29 to 0.61; p<0.001; three studies) with low heterogeneity (I2=7%, p=0.34), while global symptom improvement (six studies) and symptom scores (three studies) were similar (both p>0.05). Descriptive analyses suggested that acupuncture also improves quality of life in patients with GORD.

Conclusion This meta-analysis suggests that acupuncture is an effective and safe treatment for GORD. However, due to the small sample size and poor methodological quality of the included trials, further studies are required to validate our conclusions.

Trial registration number PROSPERO Systematic review registration no. CRD42016041916.

• Electroacupuncture
• GASTROENTEROLOGY
• Gastroenterology
• ACUPUNCTURE

## Introduction

Gastro-oesophageal reflux disease (GORD) is a disorder in which gastric contents reflux recurrently into the oesophagus, causing troublesome symptoms and/or complications.1 The prevalence of GORD in Western countries is high, ranging from 8.8–40%.2 3 It is also rising in Asian areas.4 GORD is associated with chronic cough, laryngitis and asthma1 as well as obstructive sleep apnoea.5 In addition to a potentially serious impact on quality of life, GORD imposes a huge burden on society with direct and indirect costs of US$4188 and$8741, respectively, per patient annually in the USA.6

While there are several established treatments for GORD, evidence of efficacy remains limited. Since GORD is closely related to lifestyle factors, lifestyle modification forms the basis of clinical management.1 However, for various reasons, compliance with lifestyle modification is low in most patients.1 Proton pump inhibitors (PPIs) are perceived to be the most effective treatment; however, long-term courses of treatment increase the risks of osteoporosis, Clostridium difficile infection and community-acquired pneumonia.7 In addition, the economic cost is high; approximately \$10 billion are spent on PPIs in the USA annually.8 Meanwhile, surgery is effective only in a subset of GORD patients, is limited by the experience of surgeons1 and is not helpful in reducing the risk of development of malignancy in cases of Barrett’s oesophagus.9

Over the last decade, a pronounced decline has been seen in drug development, accompanied by a dramatic increase in the testing of novel non-medical therapeutic techniques.10 Acupuncture, an effective alternative therapy, has been widely used in a number of gastrointestinal disorders including GORD. For instance, adding acupuncture to standard-dose PPI reportedly achieved better results than doubling the PPI dose in patients who had failed standard-dose PPIs.11 Since then, several other studies have investigated the effectiveness of acupuncture for GORD; however, no consensus has been reached. Moreover, to our knowledge, no systematic review or meta-analysis of trials of acupuncture for GORD has been conducted to date. Accordingly, the aim of this study was to perform a meta-analysis of trials examining the effectiveness of acupuncture for GORD.

## Methods

The protocol for this systematic review was prospectively registered in the PROSPERO (International Prospective Register of Systematic Reviews) database (reference no. CRD42016041916), which is openly accessible at http://www.crd.york.ac.uk/PROSPERO.

### Inclusion/exclusion criteria

#### Types of studies

Randomised controlled trials (RCT) assessing the effectiveness of manual acupuncture (MA) or electroacupuncture (EA) for patients with GORD were included.

#### Types of participants

Patients diagnosed with GORD aged between 18 and 70 years.

#### Types of interventions

MA/EA, used alone or combined with Western medicine (WM), needed to have been administered in the treatment groups. Control groups needed to have only received WM, which had to be the same as that provided as an adjunct to MA/EA (where applicable). No limitations were placed on treatment duration.

#### Types of outcome measures

The primary outcome measurement was global symptom improvement. Secondary outcomes included symptom score, quality of life (measured using the 36-item Short Form Health Survey (SF-36)), recurrence rate and adverse events.

### Search strategy

Two researchers searched four English language electronic databases (PubMed, Web of Science, the Cochrane Library and Embase) and four Chinese language electronic databases (Chinese Biomedicine (CBM), China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP) and the WanFang Database) from their inception through June 2016. Conference proceedings and dissertations containing unpublished trials were also searched via the CNKI and WanFang databases. English and Chinese were applied as language restrictions.

The following search terms (and their Chinese equivalents for the Chinese databases) were used individually and in combination, depending on which database was searched: ‘acupuncture’, ‘electroacupuncture’, ‘erosive esophagitis’, ‘gastroesophageal reflux disease’, ‘non-erosive reflux disease’, ‘GERD’, ‘GORD’, ‘gastro oesophageal reflux disease’, ‘nonerosive esophagitis’ and ‘endoscopically negative reflux disease’. The search strategy for Pubmed was as follows:

#1 Search (acupuncture(Title/Abstract)) OR electroacupuncture(Title/Abstract)

#2 Search (((((((‘erosive esophagitis’[Title/Abstract]) OR ‘gastroesophageal reflux disease’[Title/Abstract]) OR ‘non-erosive reflux disease’[Title/Abstract]) OR GERD[Title/Abstract]) OR GORD[Title/Abstract]) OR ‘gastro oesophageal reflux disease’[Title/Abstract]) OR ‘nonerosive esophagitis’[Title/Abstract]) OR ‘endoscopically negative reflux disease’[Title/Abstract]

#3 Search English (Language).

### Study selection and data extraction

Study selection and data extraction were independently carried out by two researchers. Detailed information including population, baseline characteristics, details of the interventions and outcome measurements were extracted to form a conclusive table. Any divergences were resolved by discussion and consensus with a third researcher.

#### Assessment of risk of bias

Using the Cochrane risk of bias tool, the methodological qualities of the included trials were evaluated by two researchers.12 The contents included random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, selective reporting, incomplete outcome data and ‘other bias’. For the latter, diagnostic/inclusion/exclusion criteria and baseline comparability were considered. Risk of bias was classified as low, high or unclear. Disagreements were resolved through discussion and consensus with a third researcher.

### Data synthesis and analysis

RevMan 5.3 (Cochrane, London, UK) was used to analyse the data. Dichotomous data were expressed as relative risk (RR) and continuous variables as mean difference (MD) with 95% CI. Both the χ2 test and I2 statistics were used for the assessment of heterogeneity.13 A fixed effects model was used if there was no obvious heterogeneity (I2 <50% or p>0.1) and a random effects model was used if significant heterogeneity existed (50% <I2<80% or p<0.05). A descriptive analysis was implemented if the heterogeneity was substantial (I2 >80% or p<0.01).14 Subgroup analyses for different treatment methods were performed when the necessary data were available.

## Results

### Study selection

A total of 178 citations were identified during the initial search and 12 articles were finally selected (figure 1).

Figure 1

Flow chart and study selection. CBM, Chinese Biomedicine; CNKI, China National Knowledge Infrastructure; VIP, Chinese Scientific Journals Database.

### Study characteristics

The 12 articles included 11 journal papers11 15–24 and one dissertation25 with a total of 1235 patients (640 and 595 in the treatment and control groups, respectively). Among them, two studies (one conducted in the USA11 and one in China20) were published in English. The remaining studies were all conducted in China and published in Chinese. All of the trials had two arms, except one trial16 that had three arms, namely EA, WM and a combined group (EA+WM). Six studies15 17 22–25 used MA and the other six studies11 16 18–21 utilised EA. Five studies15 18 20 21 25 applied MA/EA alone in the trial groups, while six studies11 17 19 22–24 combined MA/EA with WM and one16 included both types of comparison in view of its three-arm design, as described above. Detailed information is provided in table 1 and table S1 (see online supplementary material).

### Supplementary Material

Supplementary data
Table 1

Characteristics of the included studies

### Methodological quality

All articles included in the analysis were designed as randomised studies. Five studies11 18 20 21 25 used random number tables or lists, while the others did not detail the specific methods of randomisation. An attempt to contact the authors to clarify the method did not generate any responses. As there was no sham intervention in any of the included studies, participant blinding was not deemed to be applicable. Two trials21 25 reported dropout rates of patients but failed to perform intention-to-treat (ITT) analyses (figure 2). All trials reported all outcome measurements mentioned in the Methods, and were therefore deemed to be at low risk of attrition bias. For other sources of bias, all studies were rated as unclear risk because of the lack of registration information.

Figure 2

Methodological quality assessment of the risk bias for each included study.

### Global symptom improvement

All 12 trials11 15–25 reported on the primary outcome measure. A total of 1205 patients (625 and 580 in the treatment and control groups, respectively) were included in the analysis. Figure 3 shows the results of the meta-analyses of trials comparing MA/EA versus WM and MA/EA as an adjunct to WM, respectively. There were 402 patients in total that used MA/EA alone. The pooled results showed that MA/EA was equivalent to WM at treating GORD (RR 1.05, 95% CI 0.98 to 1.12; p=0.15) with low heterogeneity (I2=21%, p=0.28). When MA/EA combined with WM was compared against use of WM alone, a significant improvement in global symptom score was observed (RR 1.17, 95% CI 1.09 to 1.26; p=0.03) with no significant heterogeneity (I2=0%, p=0.41).

Figure 3

Forest plots of global symptom improvement in subgroups of patients with gastro-oesophageal reflux disease (GORD) treated with manual acupuncture or electroacupuncture (MA/EA) compared with Western medicine (WM) (1.9.1), and patients treated with MA/EA as an adjunct to WM (1.9.2), respectively.

### Symptom score

Three studies20 21 25 used symptom scores to assess the severity of GORD. As detailed in figure S1 (see online supplementary material), the pooled results demonstrated that MA/EA was equivalent to WM in terms of its effect on symptom scores (SMD −0.02, 95% CI −0.18 to 0.14; p=0.84) with no significant heterogeneity (I2=0%, p=0.87).

### Recurrence rate

Three studies19 22 25 reported on recurrence rate. As shown in figure 4, compared directly with WM, MA/EA reduced the recurrence rate of GORD (RR 0.42, 95% CI 0.29 to 0.61; p<0.001) with low heterogeneity (I2=7%, p=0.34).

Figure 4

Forest plot of recurrence rate in patients with gastro-oesophageal reflux disease (GORD) treated with manual acupuncture or electroacupuncture (MA/EA) compared with Western medicine (WM).

### Quality of life

Three studies11 20 21 evaluated quality of life using the SF-36; however, the presence of substantial heterogeneity prevented pooling of results. Dickman et al 11 found that the scores of all eight dimensions of the SF-36 with the single exception of vitality were improved by treatment with MA, whereas treatment with double-dose PPI was only associated with a slight improvement in physical and social function. Inter-group comparison also demonstrated that the MA treatment was associated with superior improvements in general health (55.0±18.0 vs 41.9±20.0, p=0.025) and body pain (57.0±31.1 vs 40.9±19.3, p=0.020) scores. Zhang et al 21 found that EA treatment had equivalent effects to WM treatment at the end of the intervention period, but superior effects during the 48 week follow-up period, with greater improvements in role physical (67±13 vs 55±21), role emotional (72±36 vs 64±18), vitality (71±23 vs 62±41) and body pain (84±20 vs 64±50) scores (all p<0.05). The results of the second study Zhang et al 20 were similar, with superior improvements in role physical (66.52±13.29 vs 54.87±11.34), role emotional (71.59±35.54 vs 63.55±27.74) and body pain (83.56±19.92 vs 73.85±39.51) scores (all p<0.05).

Adverse events were reported in five of the studies. Zhang et al 20 reported mild diarrhoea in three patients receiving WM during the initial stages of treatment, which spontaneously resolved within 5 days. Zhang et al 21 also identified two cases of mild diarrhoea in the WM group that improved spontaneously. One patient in the WM group withdrew from the study by Liu et al 25 due to nausea and abdominal pain. Dickman et al 11 mentioned a case of mild wrist pain that resolved within 2 weeks without any specific treatment in the MA group. By contrast, Liu et al 17 and Zhang et al 19 reported no adverse events.

### Publication bias

As shown in figure S2, our funnel plot analysis suggested that there may be a slight publication bias among the included studies (see online supplementary material).

## Discussion

### Main findings

This meta-analysis investigated the effectiveness of MA/EA (used alone or combined with WM) in the treatment of GORD relative to WM. The results showed that MA/EA was associated with a lower recurrence rate of symptoms (RR 0.42) and higher quality of life when directly compared with WM and that there were minimal reported adverse events. Furthermore, when MA/EA was combined with WM there was a significant increase in global symptom improvement. The results also suggest that MA/EA alone is equivalent to WM in terms of both global symptom improvement and reduction of symptom scores (with no significant differences observed between the two groups), although we cannot be certain of this fact because the included RCTs were designed as superiority trials rather than equivalence trials.

### Interpretation

Dysfunctional motility, reflected by decreased lower oesophageal sphincter pressure (LESP), increased transient lower oesophageal relaxation (TLESR) and decreased oesophageal clearance capacity, is believed to contribute greatly to the development of GORD.26 EA has been shown to have a regulatory effect on oesophageal motility. In cats with lower oesophageal sphincter myotomy, an increase in LESP and peak amplitude of oesophageal peristalsis was seen after EA at ST36.27 In normal cats, EA at PC6 also led to a significant reduction in the frequency of TLESR induced by gastric distension.28 In addition, a clinical study demonstrated that the frequency of TLESR was reduced by approximately 40% following EA at PC6.29

Acidity is another major cause of GORD and is closely related to the frequency of symptoms and severity of oesophagitis.30 Zhang et al 20 used oesophageal pH monitoring to show that the duration of oesophageal acid exposure (pH <4) was significantly decreased from 18% to 10% after 6 weeks of EA treatment.

In the past, acid reflux was thought to be the major contributor to GORD. With more modern testing techniques, oesophageal hypersensitivity has gained increasing attention and is considered to be a key reason for failure to respond to PPIs.31 In addition, several publications have focused on the effects of MA/EA on visceral hypersensitivity in irritable bowel syndrome.32 33 It is believed that MA/EA has a modulatory effect on oesophageal sensory thresholds,28 but the specific mechanisms involved are in need of further study.

### Strengths and limitations

There are several strengths to our study. To the best of our knowledge, this is the first published systematic review and meta-analysis to investigate the effectiveness and safety of acupuncture in the treatment of GORD. Several outcome measures were used to comprehensively evaluate effectiveness and safety. Furthermore, a standardised protocol was developed a priori and registered in the PROSPERO  database. However, there are also limitations to this meta-analysis. First, the trials included in the analysis were limited and the sample sizes were relatively small. Second, 11 out of 12 trials were carried out in China and 10 studies were published in Chinese. Accordingly, there is a high risk of publication bias (as suggested by our funnel plot analysis). Last, but not least, the methodological quality of the included studies was generally poor.

### Implications for further research

Based on this meta-analysis, several issues need be addressed in order to improve the methodological quality of future clinical studies. First, a sample size calculation should be performed before enrolment. Second, an attempt at double-blinding could be made using sham MA/EA, in order to control for non-specific effects of needling and placebo effects. Third, the randomisation procedure, allocation concealment and blinding methods should be explicitly described and fully reported. Fourth, withdrawal/dropout during the study should be clearly reported and an ITT analysis should be used. Finally, all clinical trials should be prospectively registered and a link to the protocol should be provided in the published article.

## Conclusion

This meta-analysis suggests that MA and EA improve recurrence rates compared with WM when used alone, and lead to greater global symptom improvement when used as an adjunct to WM in patients with GORD. They may also have a positive impact on quality of life. Although there is evidence to support the use of MA/EA alone, greater therapeutic gains may be achieved when combined with WM. Due to the generally small sample size and poor methodological quality of the included studies, a definitive conclusion is not possible and hence our findings should be interpreted with caution. Further studies with improved design, larger sample sizes and longer periods of follow-up are needed.

### Supplementary Material

Supplementary data

View Abstract

## Footnotes

• Contributors JZ and YG contributed equally to this research. WW, JZ and YG designed the review protocol. JZ, YG, SL and YL carried out the literature search. XS, YY, LH, GW and JZ contributed to data extraction. JZ, YG and WW contributed to quality assessment. JZ and YG performed the analyses and drafted the paper. JJDC, QW, RW and WW revised the paper.

• Funding This research was supported by the Fund Sponsorship of the Capital Public Health Project (grant no. Z151100003915144), National Natural Science Foundation of China (grant no. 81573806 and 81403389).

• Competing interests None declared.

• Patient consent This is a systematic review and meta-analysis.

• Provenance and peer review Not commissioned; externally peer reviewed.

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