The Clinical Effectiveness of Acupuncture for Patients with Insomnia and Functional Gastrointestinal Diseases: A Meta-Analysis of Randomized Controlled Trials

Dixiang Zhong¹, Mei Han², Ting Hong¹, Yuanyuan Qi¹, Wendan Xue¹, Mengyun Zhu¹, Zheyou Chu¹, Minrou Xu¹ and Yingchun Miao1^{1* *}Correspondence: Yingchun Miao1, Department of Traditional Chinese medicine, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China, Email:

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Introduction

Insomnia refers to a subjective experience of dissatisfaction with sleep time and/or quality, despite proper sleeping opportunities and sleeping environment, characterized by falling asleep and sleep maintenance disorders, and abnormal daytime social functions (Sleep Disorder Society, 2012; American Psychiatric Association, 2013). About one third of adults have insomnia symptoms, and 45.5% subjects in China have experienced different degrees of insomnia (Sleep Disorder Society, 2012; American Psychiatric Association, 2013; Soldatos CR, et al., 2005). Insomnia increases the risk of many health problems, for example cardiovascular diseases (Li M, et al., 2014), obesity and diabetes (Anothaisintawee T, et al., 2016; Chan WS, et al., 2018), depression and anxiety (Hertenstein E, et al., 2019) and functional gastrointestinal diseases (Andreev DN, et al., 2021; Wang B, et al., 2018) and etc. Thus, insomnia brings about a heavy burden to individual and society.

Functional Gastrointestinal Disorders (FGIDs) are a kind of non-organic diseases characterized by the presence of chronic and recurrent gastrointestinal symptoms (Drossman DA and Hasler WL, 2016; Black CJ, et al., 2020). FGIDs are mainly represented by Irritable Bowel Syndrome (IBS), Functional Constipation (FC) and Functional Dyspepsia (FD). From the most recent global epidemiology study, an estimated 40% of the world population suffer from FGIDs (Sperber AD, et al., 2021), and the prevalence rate in China is 34.4%, which affects the life quality of people and increases the medical burden (Sperber AD, et al., 2021).

The comorbidity of insomnia and functional gastrointestinal diseases is widespread. Many insomnia patients have Functional Gastrointestinal Disorders, and insomnia is also often found in patients with functional gastrointestinal disease usually (Hyun MK, et al., 2019; Lei WY, et al., 2019), which is also mentioned in the classic book Huangdi Neijing (The Yellow Emperor’s Canon of Internal Medicine) “stomach disharmony leading to restless sleep” in thousands of years ago (Tian DH, 2005).

As for the comorbidity of insomnia and functional gastrointestinal diseases, modern medicine study also provides a theoretical basis through the understanding of Brain-Gut Axis (BGA) (Tait C and Sayuk GS, 2021). The BGA dysfunction may be the pathological basis and the brain-gut peptides such as 5-Hydroxytryptamine (5-HT) is the material basis of patients with insomnia and FGIDs (Jiang W and Wang CJ, 2021). Until now, there is no consensus on the effective treatment for patients with insomnia and FGIDs. At present, the clinical methods for patients with insomnia and FGIDs are mainly symptomatic treatment.

The treatment of insomnia includes drug therapy and non-drug therapy. Although non-drug therapies such as cognitive behavioral therapy and stimulation control therapy are recommended for insomnia by the guide, hypnotics are still needed to achieve better sleep quality for these patients (Lou BX and Oks M, 2021; Shang ZJ, et al., 2021), among which the most common adverse reactions of hypnotics include dizziness, dry mouth, loss of appetite, constipation, etc. Especially for patients with insomnia and FGIDs, gastrointestinal adverse reactions will aggravate gastrointestinal symptoms (China Sleep Research Institute, 2021).

Currently, the medicine treatment of FGIDs is mainly symptomatic treatment with drugs, but there are still some problems (Black CJ, et al., 2020). For example, the proton pump inhibitor is widely used as the first-line therapy for FD (Wauters L, et al., 2021; Suzuki H, 2021), but some scholars have found that it may cause insomnia in patients (Lu Y, 2020; Zhou XL, et al., 2022). For patients with insomnia and FGIDs, while treating gastrointestinal diseases, it may increase the risk of insomnia.

In short, there are many contradictions in clinical treatment, and it is urgent to find new treatment methods. For the comorbidity of insomnia and FGIDs, acupuncture has the characteristics of rapid effect, strong tolerance, low recurrence rate and high safety. A large number of studies have shown that acupuncture is effective and safe in the treatment of insomnia or FGIDs (Feng H, et al., 2020; Fang QQ, et al., 2021; Wang XY, et al., 2021). Tui Na has the function of dredging channels and collaterals, and is widely used in the treatment of insomnia or FGIDs (Wang XY, et al., 2021; Feng G, et al., 2019; You Y, et al., 2021; Larussa T, et al., 2019). Acupuncture combined with Tui Na therapy is a more common treatment for patients with insomnia and FGIDs in clinical practice.

In recent years, several related studies have mentioned the problems of clinical treatment and found the clinical treatment methods, acupuncture and Tui Na, but these still lack high-quality clinical evidence to prove whether acupuncture or Tui Na is effective. Therefore, in our study, we first analyze the difference of curative effect between acupuncture and western medicine in treating patients with insomnia and FGIDs. Furthermore, we compared the efficacy of acupuncture alone with acupuncture combined with Tui Na in treating patients with insomnia and FGIDs to provide evidence-based basis for clinical practice.

Materials and Methods

We followed the methods of Feng G, et al., 2019.

Protocol and registration

The review protocol was conducted under the guidance of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and this system review had been registered on Prospero (CRD42022343673).

Inclusion criteria

Participants: Adult patients who met the diagnostic criteria for insomnia and FGIDs (Diagnostic and Statistical Manual of Mental Disorders (DSM- 5) and Chinese Classification of Mental Disorders (CCMD-3) were used as the diagnostic criteria for insomnia, and Rome II, Rome III or Rome IV were used as diagnostic criteria for FGIDs).

Intervention measures: Firstly, the treatment group was treated with acupuncture alone, while the control group was treated with benzodiazepines; furtherly, the treatment group was treated with acupuncture combined with Tui Na, while the control group was treated with acupuncture alone.

Outcome indicators: Pittsburgh Sleep Quality Index (PSQI) scores for the insomnia and FGIDs related assessment indicators.

Study type: Randomized Controlled Trials (RCTs) published in Chinese and English.

Exclusion criteria

• The data in RCTs did not meet the insomnia and FGIDs diagnostic criteria.
• The treatment group was treated with non-acupuncture, and the control group was treated with placebo, sham acupuncture, or non-benzodiazepines.
• Outcomes reported incompletely no PSQI scale score or missing data.
• Duplication of the study.

Literature search

Two authors (Dixiang Zhong and Ting Hong) separately searched eight databases from their inception to June 1, 2022 at the same time: PubMed, Excerpta Medica Database (EMBASE), the Cochrane Library, Web of science, China National Knowledge Infrastructure (CNKI), Wanfang Database, China Science Technology Journal Database, SinoMed Database. The details of the search strategy of PubMed were shown in Appendix.

Screening and data extraction

Two researchers (Yuanyuan Qi and Wendan Xue) independently screened RCTs according to the inclusion-exclusion criteria. Then, three researchers (Mengyun Zhu, Zheyou Chu, and Minrou Xu) separately extracted data from eligible RCTs. The extracted data included the authors, year of publication, sample size, characteristics of participants (age and sex, etc.), intervention measures, and outcome indicators. If differing opinions arose, a third researcher (Yingchun Miao) was consulted. Yingchun Miao conducted the search, Mei Han evaluated the abstract.

Risk of bias

The methodological quality of these included RCTs will be scored by two researchers (Dixiang Zhong and Ting Hong) according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins J and Green S, 2011). The following seven items were assessed: Random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. Tree levels were used to evaluate the quality of the method: “Low risk of bias” (+), “high risk of bias” (-), and “unclear risk of bias” (?). If disagreement was seen in the assessments, this was resolved through discussion with a more experienced researcher (Yingchun Miao).

Data synthesis

The meta-analysis was conducted using RevMan (5.3) and Stata 16.0 software. Outcome indicators of insomnia and FGIDs were all continuous variables, so we used the Mean Difference (MD) and 95% Confidence Interval (CI) to represent the difference between the groups. We tested heterogeneity using the I square (I2) and p value (p), and if p<0.1 or I2>50%, it was assumed that the heterogeneity was significant and the random-effects model was selected. Otherwise, the fixed-effects model was validated, and the sources of heterogeneity were explored using subgroup analysis or sensitivity analysis. If the number of included RCTs was enough, the inverted funnel plot will be used to evaluate the impact of publication bias.

Results

Literature search

A total of 1,902 related articles were collected via the search strategy. After excluding 124 duplicate studies, 1778 articles remained, and after the multilayer screening, 9 RCTs (Xu F, et al., 2019; Ren ML, et al., 2017; Xu F, et al., 2013; Liang FJ, et al., 2020; Feng WT, 2017; Zhu LP and Ji N, 2019; Wang ZH, 2019; Wang Y, 2021; Gao YD, 2018) were included in this review. More details of literature search are shown in Figure 1.

Figure 1: Study flow diagram

Study characteristics

We included 9 RCTs with 984 participants, 492 participants in the intervention group and 492 participants in the control group. 4 RCTs (Xu F, et al.,2019; Ren ML, et al., 2017; Xu F, et al., 2013; Liang FJ, et al., 2020) compared acupuncture with benzodiazepines. 5 RCTs (Feng WT, 2017; Zhu LP and Ji N, 2019; Wang ZH, 2019; Wang Y, 2021; Gao YD, 2018) compared acupuncture alone with acupuncture combined with Tui Na. The duration of treatment varied from 3 weeks to 1 month, 1 RCT did not mention it (Zhu LP and Ji N, 2019). 3 RCTs (Xu F, et al., 2019; Liang FJ, et al., 2020; Zhu LP and Ji N, 2019) did not mention the mean course. More details are shown in Table 1.

Table 1: Characteristics of included Randomized Clinical Trials (RCTs)

Methodological quality evaluation

5 RCTs (Xu F, et al., 2019; Ren ML, et al., 2017; Xu F, et al., 2013; Liang FJ, et al., 2020; Wang ZH, 2019; Wang Y, 2021) reported the right randomization methods, while the remaining 4 RCTS (Xu F, et al., 2013; Liang FJ, et al., 2020; Wang ZH, 2019; Gao YD, 2018) did not mention how to produce the random sequence. None of the articles reported allocation concealment and blinding of outcome assessment. Due to the characteristics of acupuncture, it was hard to blind doctors and patients. So, we assessed all of them as ‘high’ risk. Only one RCT (Liang FJ, et al., 2020) reported the outcome indicators of insomnia and FGIDs, while the remaining 8 RCTs (Xu F, et al., 2019; Ren ML, et al., 2017; Xu F, et al., 2013; Feng WT, 2017; Zhu LP and Ji N, 2019; Wang ZH, 2019; Wang Y, 2021; Gao YD, 2018) only reported the PSQI. The detailed methodological quality evaluation is shown in Figures 2 and 3.

Figure 2: Risk of bias. Note: (): Low risk of bias; (): Unclear risk of bias; (): High risk of bias

Figure 3:Risk of bias summary.

Results of meta-analysis

In these included 9 RCTs, all 9 RCTs reported PSQI score, and 1 RCT (Liang FJ, et al., 2020) reported FGIDs related assessment indicators.

PSQI score: In a comparison between the acupuncture group with the benzodiazepines group, 4 RCTs (Xu F, et al., 2019; Ren ML, et al., 2017; Xu F, et al., 2013; Liang FJ, et al., 2020) reported the PSQI score involving a total of 526 participants. Meta-analysis showed that acupuncture group was more effective than benzodiazepines group after treatment (MD-2.60, 95% CI (-4.95, -0.25), I2=96%) (Figure 4).

Figure 4:Forest plot of Pittsburgh Sleep Quality Index (PSQI) (acupuncture compared with western medicine).

In a comparison between the acupuncture group with acupuncture combined with Tui Na group, 5 RCTs (Feng WT, 2017; Zhu LP and Ji N, 2019; Wang ZH, 2019; Wang Y, 2021; Gao YD, 2018) were included the PSQI score involving a total of 458 participants. Meta-analysis showed that acupuncture combined with Tui Na group was more effective than acupuncture group after treatment (MD-2.48, 95% CI (-2.64, -2.33), I2=14%) (Figure 5).

Figure 5:Forest plot of PSQI (acupuncture combined with Tui Na compared to acupuncture alone).

FGIDs related assessment indicators: One RCT (Liang FJ, et al., 2020) (total 60 participants) compared the acupuncture group with benzodiazepines group reported FGIDs related assessment indicators such as 5-HT and Vasoactive Intestinal Peptide (VIP). The results of 5-HT and VIP showed that there was a significant difference between acupuncture group and benzodiazepines group.

Sensitive analysis and publication bias: For PSQI score, comparing acupuncture group with benzodiazepines group, the heterogeneity was major among the studies (I²=96%>50%). But we did not find the heterogeneity source through the sensitivity analysis. More details of the sensitive analysis are shown in Figure 6. Considering the heterogeneity may come from the lack of included literature, the difference of acupuncture point selection, manipulation and intervention measures in the control group.

Figure 6:Sensitivity analysis of acupuncture vs. western medicine.

Discussion

Summary of results

We analyze the effect of acupuncture for patients with insomnia and FGIDs. Meta-analysis showed that the acupuncture group was better than the western medicine group in improving the sleep quality and regulating the level of brain-gut peptide for patients with insomnia and FGIDs, and acupuncture combined with Tui Na group is superior to acupuncture group in improving the sleep quality.

Possible mechanisms of acupuncture or Tui Na therapy for insomnia and FGIDs

Our review showed that acupuncture and acupuncture combined with Tui Na therapy appeared to be effective for patients with insomnia and functional gastrointestinal diseases. It is necessary to discuss the possible mechanisms of acupuncture or Tui Na therapy for insomnia and FGIDs. The possible mechanisms may be explained by Traditional Chinese Medicine (TCM) and modern medicine respectively. In TCM theory, the main and general cause of insomnia and FGIDs is the disharmony and imbalance of yin-yang, and qi-blood (Liu JC, et al., 2021). The possible mechanism of acupuncture and Tui Na for insomnia and FGIDs is that acupuncture and Tui Na can dredge channel and restore the harmony and balance of Yin-yang, Qi-blood. Modern medicine provides a certain basis for this comorbidity of insomnia and FGIDs through the understanding of Brain- Gut Axis (BGA) (Wang XY, et al., 2021; Hou LW, et al., 2020). Studies have shown that the brain-gut interaction mainly involves four ways: Microbiome, inflammation, nerve and endocrine (Ferrara M, et al., 2022). The four ways involve many material base, for example intestinal microbiome (Jackson ML, et al., 2015; Nishida K, et al., 2017), pro-inflammatory factors (Interleukin-1 (IL-1), Tumor Necrosis Factor (TNF)) (Joscelyn J and Kasper LH, 2014; Yehuda S, et al., 2009; Xiao HS and Liu L, 2021; Ren L, 2006), neurotransmitters (γ-Aminobutyric Acid (GABA) and Glutamic acid (Glu)) (Julio-Pieper M, et al., 2013), brain-gut peptides (Somatostatin (SS), Melatonin (MT) and 5- Hydroxytryptamine (5-HT)), and etc.

Acupuncture can regulate the levels of TNF-α, IL-25, GABA, Glu, SS, 5-HT and improve the diversity of intestinal flora in patients with acupuncture and FGIDs. Tui Na can improve the sleep quality and gastrointestinal function of patients by regulating neurotransmitters. Acupuncture combined with Tui Na can improve gastrointestinal symptoms by regulating the abundance of intestinal flora and SS level. In addition, acupuncture combined with Tui Na can improve sleep quality by regulating the levels of IL-6, TNF-α, and 5-HT.

Conclusion

Acupuncture and acupuncture combined with Tui Na can both improve the sleep quality of patients with insomnia and functional gastrointestinal diseases, and the efficacy of acupuncture combined with Tui Na is better than acupuncture alone. Practitioners could recommend this therapy to patients with insomnia and FGIDs according to the condition. However, it is not clear whether it can improve gastrointestinal symptoms. More high-quality clinical trials are needed to provide more powerful and comprehensive evidence in the future.

Limitations and Implications

As we mentioned above, the comorbidity of insomnia and FGIDs is common in clinic, but there is no effective treatment. Clinical practice and studies have found that acupuncture and Tui Na have a certain effect for patients with insomnia and FGIDs. So, we evaluate the effect of acupuncture and Tui Na for patients with insomnia and FGIDs, and furtherly provide evidence-based basis for clinical practice.+

Limitations

Although all literatures mentioned randomness, only five literatures described the correct random sequence generation method, and none of the nine literatures described the distribution result hiding and the blind method of outcome evaluator, all of which could cause selection bias. There are great differences in acupuncture point selection and manipulation, and the frequency and times of acupuncture treatment are not uniform. Especially, there are great differences between acupuncture intervention treatment and western medicine treatment in the control group, and some Tui Na treatment details are not clearly reported, which affects the homogeneity of the literature included in this study. Only one RCT mentioned the FGIDs related assessment indicators.

Implications for clinical practice

This meta-analysis study shows that acupuncture and acupuncture combined with Tui Na were effective for patients suffering from insomnia and FGIDs. Clinicians could recommend this therapy to patients, and finally make decisions based on various factors, such as the experience of doctors, the preferences of patients, etc. In addition, most of the included studies neglected the evaluation of the efficacy of gastrointestinal function, so we suggest that future researches should report the effects both of sleep and gastrointestinal function for patients with insomnia and FGIDs.

Declarations

The data supporting this meta-analysis are from previously reported studies and datasets, which have been cited. The processed data are available from the corresponding author upon request.

Data availability

The data supporting this meta-analysis are from previously reported studies and datasets, which have been cited. The processed data are available from the corresponding author upon request.

Authors’ contributions

The paper was drafted by Dixiang Zhong and revised by Yingchun Miao and Mei Han. The search strategy was performed by Dixiang Zhong and Ting Hong. Yuanyuan Qi and Wendan Xue independently screened the potential studies. Mengyun Zhu, Zheyou Chu, and Minrou Xu extracted data from the included studies and completed the data synthesis, Yingchun Miao offered arbitration in case of disagreement. All authors contributed to the interpretation of the results and gave their final approval for the version to be published.

Acknowledgments

The authors sincerely thank Guiyu Feng, Dongzhimen Hospital, Beijing University of Chinese Medicine, for helping to guide the design of research methods. This work was supported by Beijing ENN Fund for Chinese Medicine (2018-XAJLJJ-020).

Supplementary materials

The search strategy of PUBMED database as an example.

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