소화불량

Background: Functional dyspepsia (FD) is a disorder that presents with chronic dyspepsia, which is not only very common but also highly affects quality of life of the patients. In Japan, FD became a disease name for national insurance in 2013, and has been gradually recognized, though still not satisfactory. Following the revision policy of Japanese Society of Gastroenterology (JSGE), the first version of FD guideline was revised this time.

Method: Like previously, the guideline was created by the GRADE (grading of recommendations assessment, development and evaluation) system, but this time, the questions were classified to background questions (BQs, 24 already clarified issues), future research questions (FRQs, 9 issues cannot be addressed with insufficient evidence), and 7 clinical questions that are mainly associated with treatment.

Results and Conclusion: These revised guidelines have two major features. The first is the new position of endoscopy in the flow of FD diagnosis. While endoscopy was required to all cases for diagnosis of FD, the revised guidelines specify the necessity of endoscopy only in cases where organic disease is suspected. The second feature is that the drug treatment options have been changed to reflect the latest evidence. The first-line treatment includes gastric acid-secretion inhibitors, acetylcholinesterase (AChE) inhibitors (acotiamide, a prokinetic agent), and Japanese herbal medicine (rikkunshito). The second-line treatment includes anxiolytics /antidepressant, prokinetics other than acotiamide (dopamine receptor antagonists, 5-HT4 receptor agonists), and Japanese herbal medicines other than rikkunshito. The patients not responding to these treatment regimens are regarded as refractory FD.

Background: Epidemiological studies suggest considerable overlap between functional dyspepsia (FD) and irritable bowel syndrome (IBS). To date, no surveys have been performed to investigate the clinical overlap between these two disorders using Rome III criteria. Our aim was to investigate the prevalence and risk factors for the overlap of FD and IBS based on Rome III criteria in a large clinical sample.

Methods: Consecutive patients at the general gastroenterology outpatient clinic were requested to complete a self-report questionnaire. FD and IBS were defined by Rome III criteria.

Results: Questionnaires were returned by 3014 patients (52.8% female, 89% response rate). FD-IBS overlap was observed in 5.0% of the patients, while 15.2% and 10.9% of the patients were classified as FD alone and IBS alone, respectively. Compared with non-IBS patients, the odds ratio of having FD among IBS patients was 2.09 (95% CI: 1.68–2.59). Patients with FD-IBS overlap had higher severity scores for the postprandial fullness symptom (2.35 ± 1.49 vs. 1.72 ± 1.59, P < 0.001) and overall FD symptom (6.65 ± 2.88 vs. 5.82 ± 2.76, P = 0.002) than those with FD alone. The only independent risk factor for FD-IBS overlap vs. FD alone was the presence of postprandial fullness symptom (OR 2.67, 95% CI: 1.34–5.31).

Conclusion: Clinical overlap of FD and IBS according to Rome III criteria is very common. One risk factor for FD-IBS overlap is the presence of postprandial fullness symptom. This study provides clues for future pathophysiological studies of FD and IBS.

Sample characteristics: Of the 3379 eligible patients, 3014 patients completed questionnaires (response rate 89.2%). Overall, 47.2% (1422 patients) of the respondents were male with the mean (± s.d.) age of 43.2 (± 15.9) years and a range of 18–97 years. Among non-respondents, 47.6% were males with a mean (± s.d.) age of 44.0 (± 16.0) with a range of 20–95 years. There was no significant difference between the responders and non-responders with respect to sex or age.

Demographic and symptomatic characteristics of FD-IBS overlap versus FD alone and versus IBS alone: The demographic and symptomatic characteristics of patients with FD-IBS overlap, FD alone and IBS alone are shown in Tables 1 and 2. Overlap between FD and IBS according to Rome III criteria was very common in clinical practice, as summarized in Figure 1; in addition, 24.8% (151/608) of FD patients and 31.5% (151/480) of IBS patients fulfilled the diagnostic criteria of the other disorder. There was no significant difference with respect to sex or age among FD alone, IBS alone and FD-IBS overlap groups. The odds ratio [the ratio of the odds of having IBS among those with FD to the odds of having IBS among those without FD, or the ratio of the odds of having FD among those with IBS to the odds of having FD among those without IBS] was 2.09 (95% CI: 1.68–2.59).

More patients with PDS alone had IBS than those with EPS alone (26.5% vs. 18.3%, P = 0.039). Patients with FD-IBS overlap were more likely to be classified as the PDS+EPS subtype (33.8% vs. 24.1%, P = 0.02), had more frequent presence of the postprandial fullness symptom (76.2% vs. 58.2%, P < 0.001) and higher severity scores for the postprandial fullness symptom (2.35 ± 1.49 vs. 1.72 ± 1.59, P < 0.001) and overall FD symptom (6.65 ± 2.88 vs. 5.82 ± 2.76, P = 0.002) than those with FD alone. In addition, they were less likely to be classified as the EPS alone subtype (27.2% vs. 40.0%, P = 0.004) compared to patients classified as FD alone (Table 1). Demographic features and patterns of symptom and subtype were not significantly different between patients with FD-IBS overlap and IBS alone (Table 2).

Potential risk factors for FD-IBS overlap: Table 1 summarizes the comparison of variables in patients with FD-IBS overlap relative to those with FD alone. Of the dichotomously classified potential correlates of the probability of overlap, the presence of postprandial fullness symptom (P < 0.001), epigastric burning symptom (P = 0.11) and EPS alone subtype (P = 0.004) were included in the multivariate logistic regression analysis. Of these, only the presence of postprandial fullness (OR 2.67, 95% CI: 1.34–5.31, P = 0.005) had a statistically significant and independent effect on the probability of having overlap in the final logistic model (Table 3).

Table 2 summarizes the comparison of variables in patients with FD-IBS overlap relative to those of patients with IBS alone. Male gender (P = 0.17) and subtypes of IBS-M (P = 0.12) and non-IBS-D (P = 0.08) were included in multivariate logistic regression analysis after the univariate analysis. As shown in Table 4, none of these variables were identified as risk factors for FD-IBS clinical overlap vs. IBS alone in the final logistic model.

The vagus nerve represents the main component of the parasympathetic nervous system, which oversees a vast array of crucial bodily functions, including control of mood, immune response, digestion, and heart rate. It establishes one of the connections between the brain and the gastrointestinal tract and sends information about the state of the inner organs to the brain via afferent fibers. In this review article, we discuss various functions of the vagus nerve which make it an attractive target in treating psychiatric and gastrointestinal disorders. There is preliminary evidence that vagus nerve stimulation is a promising add-on treatment for treatment-refractory depression, posttraumatic stress disorder, and inflammatory bowel disease. Treatments that target the vagus nerve increase the vagal tone and inhibit cytokine production. Both are important mechanism of resiliency. The stimulation of vagal afferent fibers in the gut influences monoaminergic brain systems in the brain stem that play crucial roles in major psychiatric conditions, such as mood and anxiety disorders. In line, there is preliminary evidence for gut bacteria to have beneficial effect on mood and anxiety, partly by affecting the activity of the vagus nerve. Since, the vagal tone is correlated with capacity to regulate stress responses and can be influenced by breathing, its increase through meditation and yoga likely contribute to resilience and the mitigation of mood and anxiety symptoms.

Background: Herbal medicine is widely used for the treatment of functional dyspepsia (FD) in East Asian countries. We aimed to analyze the prescription patterns of herbal medicine for patients with FD in Korean medicine clinical settings through the analysis of national health insurance claims data over the past 10 years and to check how herbal medicine has been used for FD within the scope of national health insurance.

Methods: All prescription data claimed to the Health Insurance Review and Assessment Service with the diagnosis of FD and herbal medicine prescriptions in 2010–2019 were reviewed. We estimated the demographics, clinical characteristics, and annual prescription amount and cost of each herbal medicine. Frequent comorbidities of FD were investigated by analyzing the frequency of the Korean standard classification of diseases codes used together with FD.

Results: In total, 19,388,248 herbal medicine prescriptions were identified. Herbal medicine prescriptions were mostly claimed by women, the elderly, outpatients at Korean medicine clinics, and national health insurance; the number increased every year. The most frequently prescribed herbal medicine was Pingwei-san (Pyeongwi-san) (31.12%), followed by Xiangshapingwei-san (Hyangsapyeongwi-san) (23.20%), Qiongxia-tang (Gungha-tang) (6.31%), and Banxiaxiexin-tang (Banhasasim-tang) (6.25%). The total cost of herbal medicine prescriptions increased every year, and it was highest for Xiangshapingwei-san (Hyangsapyeongwi-san) (19.37%), followed by Banxiaxiexin-tang (Banhasasim-tang) (17.50%) and then Pingwei-san (Pyeongwi-san) (15.63%). Musculoskeletal and connective tissue diseases including low back pain and myalgia were the commonest comorbidities associated with FD.

Conclusion: This is the first study to investigate the disease burden and actual prescription pattern of herbal medicine for FD using claim data. Future clinical research and related healthcare policies should be established based on our study.

3.1. Selection Process of Target Prescriptions: In total, 123,506,249 prescriptions (medications, procedures, etc.) included K30 in either the primary or first secondary diagnosis in Korean medical institutions. Among them, 19,428,028 prescriptions included herbal medicines. After excluding prescriptions of individual herbs, only the prescriptions that corresponded to the predefined 56 herbal formulas (mixed extracts) were selected for analysis. Finally, 19,388,248 herbal medicine prescriptions from 3,687,700 patients were included in the analysis.

3.2. Demographics and Clinical Characteristics: The study population comprising 3,687,700 FD patients—1,105,503 men (29.98%) and 2,582,197 women (70.02%)—showed a mean age (standard deviation) of 49.17 (22.02) years. Regarding the type of medical institution, Korean medical clinics issued most (n = 19,152,474 [98.58%]) of the 19,388,248 herbal medicine prescriptions issued during the study period. Stratification by the type of health insurance showed that the NHI covered most of the herbal medicine prescriptions (n = 18,539,775 [95.62%]). In addition, most hospital visits were made by outpatients (n = 19,341,996, 99.76%). The mean prescription period and cost were 1.68 days and approximately ₩1,880 KRW, respectively (Table 1).

3.3. Number of Herbal Medicine Prescriptions for FD Stratified by Sex, Age, and Year: A sex-stratified comparison of the number of herbal medicine prescriptions showed that approximately three times more women (n = 14,414,514, 74.3%) than men (n = 4,973,734, 25.7%) received these prescriptions. Age-stratified analysis showed that the number of herbal medicine prescriptions tended to increase proportionally with age: patients in their 70s accounted for the most prescriptions (n = 6,745,042; 34.8%), followed by those in their 60s (n = 4,430,108; 22.8%); thus, subjects in their 60s and 70s accounted for more than half of all herbal medicine prescriptions (Figure 1). The total number of herbal medicine prescriptions steadily increased throughout the study period and, in particular, increased 5.5-fold from 2010 (n = 536,372) to 2019 (n = 2,914,167). A similar trend was observed in the age-stratified analyses; the upward trend was particularly evident in subjects aged 60 or older (Figure 2).

3.4. Number and Cost of Frequently Prescribed Herbal Medicines for FD Based on the Year: According to the number of herbal medicine prescriptions for FD that were submitted in claims to the HIRA over 10 years, Pingwei-san (Pyeongwi-san) was the most prescribed medication, accounting for 31.12% (n = 6,033,229) of all prescriptions. Xiangshapingwei-san (Hyangsapyeongwi-san) was the second most prescribed agent (n = 4,497,837; 23.20%), followed by Qiongxia-tang (Gungha-tang; n = 1,222,565; 6.31%), Banxiaxiexin-tang (Banhasasim-tang; n = 1,210,996; 6.25%), and Erchen-tang (Yijin-tang; n = 1,169,238; 6.03%) (Figure 3). The year-wise comparison showed that Pingwei-san (Pyeongwi-san) was the most prescribed medicine across all years during the study period except 2010. The total cost of herbal medicine prescriptions was highest for Xiangshapingwei-san (Hyangsapyeongwi-san) at ₩7,051,079,037 KRW (19.37%), followed by Banxiaxiexin-tang (Banhasasim-tang; ₩6,370,364,917 KRW, 17.50%), Pingwei-san (Pyeongwi-san; ₩5,687,566,199 KRW, 15.63%), Neixiao-san (Naeso-san; 2,335, ₩428,678 KRW, 6.42%), and Buzhongyiqi-tang (Bojungikgi-tang; ₩1,905,819,409 KRW, 5.24%) (Figure 4). The total cost of 56 herbal medicine prescriptions for the treatment of FD during the 10-year study period was ₩36,399,342,776 KRW (Supplement 2).

3.5. Frequent Comorbidities of FD: This study cohort comprised 21,771,403 comorbidities in total that were associated with the FD code (K30). Among them, M code (Diseases of the Musculoskeletal System and Connective Tissue) accounted for most (57.05%; n = 12,420,825) comorbidities, followed by the R code (Symptoms, Signs, and Abnormal Clinical and Laboratory Findings, Not Elsewhere Classified; 11.39%), S code (Injury, Poisoning, and Certain Other Consequences of External Causes; 9.82%), U code (Codes for Special Purposes; 8.07%), G code (Diseases of the Nervous System; 4.49%), J code (Diseases of the Respiratory System; 3.89%), and K code (Diseases of the Digestive System; 1.75%). The commonest comorbidity was lower back pain (M545; n = 3,225,059), followed by myalgia (M791; n = 1,390,267), muscle strain (M626; n = 1,118,574), joint pain (M255; n = 870,202), and pain localized to the upper abdomen (R101; n = 796,848) (Table 2). When the K30 code was the primary, secondary, or primary and secondary diagnosis, the ranking of comorbidities showed a similar trend. However, when the K30 code was the primary, the U code (Codes for special purposes, encompassing diseases name in Oriental medicine, disease patterns/syndromes in Oriental medicine, and disease patterns/syndromes of Four-Constitution Medicine) comprised the most frequent comorbidity. In particular, the “spleen qi deficiency pattern (U680)” and “food-retention disorder (U280)” were frequently reported when the K30 code was the primary or secondary diagnosis (Supplement 3).

Background: Prokinetic is the first-line conventional treatment for functional dyspepsia (FD) in Asia despite potential adverse events. Chinese herbal medicine (CHM) may be an effective and safe substitution. This network meta-analysis (NMA) aimed to evaluate the comparative effectiveness of different CHM formulae for FD against prokinetics.

Methods: Seven international and Chinese databases were searched from their inception to July 2020 for randomised controlled trials (RCTs) on CHM versus prokinetics. Data from each RCT were first pooled using random-effect pairwise meta-analyses and illustrated as risk difference (RD) or standardised mean difference (SMD) with 95% confidence interval (CI). Random-effect NMAs were then performed to evaluate the comparative effectiveness of CHM formulae and displayed as RD with 95% CI or SMD with 95% credible interval (CrI). The GRADE partially contextualised framework was applied for NMA result interpretation.

Results: Twenty-six unique CHM formulae were identified from twenty-eight RCTs of mediocre quality. Pairwise meta-analyses indicated that CHM was superior to prokinetics in alleviating global symptoms at 4-week follow-up (pooled RD: 0.14; 95% CI: 0.10–0.19), even after trim and fill adjustment for publication bias. NMAs demonstrated that Modified Zhi Zhu Decoction may have a moderate beneficial effect on alleviating global symptoms at 4-week follow-up (RD: 0.28; 95% CI: − 0.03 to 0.75). Xiao Pi Kuan Wei Decoction may have a large beneficial effect on alleviating postprandial fullness (SMD: − 2.14; 95% CI: − 2.76 to 0.70), early satiety (SMD: − 3.90; 95% CI: − 0.68 to − 0.42), and epigastric pain (SMD: − 1.23; 95% CI: − 1.66 to − 0.29). No serious adverse events were reported.

Conclusion: Modified Zhi Zhu Decoction and Xiao Pi Kuan Wei Decoction may be considered as an alternative for patients unresponsive to prokinetics. Confirmatory head-to-head trials should be conducted to investigate their comparative effectiveness against prokinetics.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13020-021-00556-6.

Study selection and characteristics: A total of 1,927 citations were yielded from the literature search. 1,572 titles and abstracts were screened after deduplication. 110 potential full-texts then proceeded to further eligibility assessment. Finally, twenty-eight RCTs were included in this study. Selection process is illustrated in Fig. 1.

All RCTs were conducted in China, with only one of them published in English, and spanned 2004 to 2019 (Table 1). A total of 2,736 participants took part in the twenty-eight trials, with an average sample size of 98 (range, 56–202). Average age of the participants ranged from 24.0 to 54.6 years. Duration of their FD symptoms ranged from less than one year to over twenty-four years. Participants in twenty-three trials were diagnosed by the Rome III criteria, while those in the other five trials were diagnosed by the Rome II criteria. Fifteen out of twenty-eight RCTs adopted TCM diagnostic pattern as part of their inclusion criteria (Table 1). Nine unique TCM diagnostic patterns were included: food stagnation, liver qi invading the stomach, liver depression and spleen deficiency, cold-heat complex, liver qi depression, spleen deficiency and qi stagnation, spleen-stomach weakness, spleen qi deficiency, and spleen deficiency and dampness-heat.

Twenty-six unique CHM formulae were studied in the twenty-eight RCTs (Table 2). TCM function(s) of the CHM formulae corresponded to the diagnostic pattern(s) adopted in the fifteen RCTs according to TCM theories. Twenty-one formulae were compared against domperidone in twenty-three RCTs, with Liu Wei An Xiao Capsule and He Wei Decoction studied in two RCTs respectively. Five formulae were compared against mosapride in five RCTs. Treatment duration ranged from two to six weeks. Twenty trials had a length of follow-up of four weeks, while seven and one trials had a 2-week follow-up and 6-week follow-up, respectively.

Risk of bias assessment: The overall risk of bias among the included studies was mediocre, with none of them being at low risk, twenty-four having some concerns, and four being at high risk [Additional file 1: Appendix 2]. Those having some concerns did not implement blinding for trial participants, carers, and people delivering interventions. Moreover, they did not report details on allocation sequence generation or provide information on whether the data were analysed following a pre-specified analysis plan. For those at high risk of bias, despite limitations described, they did not report details on baseline differences groups.

Pairwise meta-analysis: Six pairwise meta-analyses were conducted to compare CHM with prokinetics in alleviating global symptoms, postprandial fullness, early satiety, and epigastric pain (Figs. 2, 3).

Alleviation of global symptoms: Compared to prokinetics, CHM had a stronger effect in alleviating global symptoms at 4-week follow-up (20 RCTs; pooled RD: 0.14; 95% CI: 0.10–0.19; p < 0.00001; I2 = 56%; low-quality of evidence) (Table 3). CHM was also superior to domperidone alone (17 RCTs; pooled RD: 0.16; 95% CI: 0.10–0.21; p < 0.00001; I2 = 57%; low-quality of evidence). Substantial heterogeneity was observed in both results. No significant difference was found between CHM and mosapride (3 RCTs; pooled RD: 0.07; 95% CI: − 0.03 to 0.17; p = 0.19; I2 = 34%; low-quality of evidence). At 2-week follow-up, CHM was more effective than prokinetics (7 RCTs; pooled RD: 0.14; 95% CI: 0.04–0.23; p = 0.005; I2 = 73%; moderate-quality of evidence) and domperidone alone (6 RCTs; pooled RD: 0.11; 95% CI: 0.02–0.20; p = 0.01; I2 = 61%; moderate-quality of evidence). High-level heterogeneity existed in both pooling results. The MCID of 0.20 RD was not met by any comparisons above.

Alleviation of postprandial fullness: When compared with prokinetics, CHM showed a stronger effect in alleviating postprandial fullness at 4-week follow-up (8 RCTs; pooled SMD: − 1.08; 95% CI: − 1.64 to − 0.51; p = 0.0002; I2 = 90%; moderate-quality of evidence) (Table 4), with the effect size exceeded the MCID of − 0.50 SMD. CHM was also superior to domperidone (6 RCTs; pooled SMD: − 0.81; 95% CI: − 1.37, − 0.24; p = 0.005; I2 = 88%; low-quality of evidence) and mosapride alone (6 RCTs; pooled SMD: − 1.97; 95% CI: − 3.79, − 0.16; p = 0.03; I2 = 93%; very low-quality of evidence). Substantial heterogeneity was detected in all results.

Alleviation of early satiety: There was no significant difference between CHM and domperidone in alleviating early satiety at 4-week follow-up (4 RCTs; pooled SMD: − 1.19; 95% CI: − 2.40 to 0.10; p = 0.05; I2 = 96%; very low-quality of evidence) (Table 4). High-level heterogeneity was observed in this comparison.

Alleviation of epigastric burning: No significant difference was found between CHM and domperidone in alleviating epigastric burning at 4-week follow-up (4 RCTs; pooled SMD: − 1.93; 95% CI: − 4.29 to 0.43; p = 0.11; I2 = 97%; very low-quality of evidence) (Table 4). High-level heterogeneity existed for this meta-analysis.

Alleviation of epigastric pain: CHM was more effective than domperidone in alleviating epigastric pain at 4-week follow-up (4 RCTs; pooled SMD: − 0.84; 95% CI: − 1.10 to − 0.58; p < 0.00001; I2 = 23%; low-quality of evidence), with moderate-level heterogeneity (Table 4). The effect size was higher than the MCID of − 0.50 SMD.

Sensitivity analysis: Sensitivity analysis comparing pooled results from “studies with some concerns over risk of bias” and “studies at high risk of bias” is illustrated in Fig. 4. There was no significant subgroup difference (p = 0.18) between the two groups, implying that the difference in risk of bias level did not influence the pooled results on global symptom alleviation at 4-week.

Publication bias assessment: Judging from visual inspection of contour-enhanced funnel plots [Additional file 1: Appendix 3a–3b], evidence of funnel plot asymmetry was observed, indicating the potential presence of publication bias favouring CHM in alleviating global symptoms at 4-week follow-up, as compared to all prokinetics and domperidone alone. After applying the trim and fill adjustment, CHM remained to be superior to prokinetics (adjusted RD: 0.10; 95% CI: 0.05–0.15) and domperidone alone (adjusted RD: 0.12; 95% CI: 0.06–0.17) (Table 3).

Network meta-analysis: Five star-shaped networks were devised to illustrate comparison networks of CHM formulae in alleviating global symptoms, postprandial fullness, early satiety, and epigastric pain against domperidone (Figs. 5, 6, 7). Another star-shaped network was used to illustrate the comparison network of CHM formulae in alleviating global symptoms against mosapride [Fig. 10]. The quality of evidence supporting each network is illustrated in Additional file 1: Appendix 4–9.

Alleviation of global symptoms: In the NMA of seventeen RCTs, no specific CHM formula was significantly better than domperidone or other CHM formulae in the network in alleviating global symptoms at 4-week follow-up (Table 5). Nevertheless, according to the partially contextualised framework, Modified Zhi Zhu Decoction (RD: 0.28; 95% CI: − 0.03 to 0.75) may have a moderate beneficial effect in alleviating global symptoms at 4-week, comparing to domperidone. It was the best-ranked intervention in the network (SUCRA: 0.85), as supported by low certainty of evidence (Table 6).

Similarly, in the NMA of six RCTs, no specific CHM formula was significantly superior to domperidone or other CHM formulae in the network in alleviating global symptoms at 2-week. Under the partially contextualised framework, both Cai Hu Shu Gan Powder (RD: 0.16; 95% CI: − 0.06 to 0.50) and Wei Kang Ping Decoction (RD: 0.16; 95% CI: − 0.07 to 0.49) may have a small beneficial effect in alleviating global symptoms at 2-week, as compared to domperidone. They were the best-ranked intervention in the network (SUCRA: 0.79), as supported by low certainty of evidence (Table 7).

In the NMA of three RCTs, no specific CHM formula was significantly more effective than mosapride or other CHM formulae in the network in alleviating global symptoms at 2-week (Table 8). According to the partially contextualised framework, Da Li Tong Granules (RD: 0.12; 95% CI: − 0.05 to 0.35) may have a small beneficial effect in alleviating global symptoms at 2-week, when compared to mosapride. It was the best-ranked intervention in the network (SUCRA: 0.85), as supported by low certainty of evidence (Table 9).

Alleviation of postprandial fullness: In the NMA of six RCTs, no specific CHM formulae were significantly superior to domperidone or other CHM formulae in alleviating postprandial fullness at 4-week (Table 5). However, based on the partially contextualised framework, Xiao Pi Kuan Wei Decoction (SMD: − 2.14; 95% CrI: − 2.76 to 0.70) may have a large beneficial effect on postprandial fullness alleviation at 4-week follow-up. It was the best-ranked intervention in the network (SUCRA: 0.85), and this finding was supported by low certainty of evidence (Table 10).

Alleviation of early satiety: In the NMA of four RCTs, Xiao Pi Kuan Wei Decoction was significantly more effective than domperidone in alleviating early satiety at 4-week follow-up (SMD: − 3.90; 95% CrI: − 0.68 to − 0.42) (Table 5). Under the partially contextualised framework, Xiao Pi Kuan Wei Decoction may have a large beneficial effect on early satiety alleviation at 4-week follow-up. It was the best-ranked intervention in the network (SUCRA: 0.92), as supported by low certainty of evidence (Table 10).

Background and Aims: Functional dyspepsia (FD) is closely associated with gut–brain interaction disorder (DGBI), characterized by the interaction of gastrointestinal symptoms and central nervous system dysregulation. Chinese herbal medicine (CHM) has a good concurrent effect in the treatment of FD, especially for patients with concurrent psychological disorders. A meta-analysis was designed to evaluate the efficacy and safety of CHMs in the treatment of FD.

Methods: The PubMed, Embase, Cochrane Library, Web of Science, Chinese Biological Medical Database (CBM), Wanfang Data, China National Knowledge Infrastructure (CNKI), and China Science and Technology Journal Database (VIP) were searched to collect randomized controlled trials of FD treated with CHM. The retrieval time limit is from the establishment of the database till 11 April 2022. Two researchers independently searched databases, screened documents, extracted data, and evaluated the risk of bias of included studies. RevMan 5.4 software was used for meta-analysis.

Results: A total of 11 studies including 951 patients were included. The study was divided into two parts. The first part included 5 clinical trials, including 471 patients. The experimental group was treated only with CHM and the control group was only treated with placebo. The results of first part showed that the total effective rate of CHM in the treatment of FD was higher than that in the placebo group (84.5 vs. 49.4%) [relative risk (RR) = 1.76; 95% confidence interval (CI) (1.13, 2.75); P = 0.01]. In addition, CHM treatment could reduce the total symptom score [standardized mean difference (SMD) = −10.05; 95% CI (−13.50, −6.59); Z = 5.70; P < 0.0001] and depression score [SMD = −7.68; 95% CI (−14.43, −0.94); Z = 2.23; P = 0.03]. The second part included 6 clinical trials, including 480 patients. The experimental group was only treated with CHM and the control group was treated with prokinetic agents combined with flupentixol melitracen (deanxit). The results of second part showed that the total effective rate of CHM in the treatment of FD was higher than that of the control group (92.6 vs. 78.8%) [RR = 1.17; 95% CI (1.09, 1.26), P < 0.0001]. In addition, CHM treatment could reduce HAMA score [mean difference (MD) = −3.19; 95% CI (−3.79, −2.59); Z = 10.40; P < 0.00001], HAMD score [MD = −4.32; 95% CI (−6.04, −2.61); Z = 4.94; P < 0.00001], and gastric emptying rate [MD = 12.62; 95% CI (5.84, 19.40); Z = 3.65; P = 0.0003]. The results of the two parts of the meta-analysis showed no serious adverse reactions, and there was no significant difference in the adverse reactions between the experimental group and the control group [MD = 1.14; 95% CI (0.53, 2.42); Z = 0.33; P = 0.74]; [MD = 0.14; 95% CI (0.01, 2.67); Z = 1.30; P = 0.19].

Conclusion: The current evidence shows that CHM treatment has great potential and safety in alleviating the symptoms of FD and improving the psychological disorders of anxiety and depression in patients with FD. Limited by the quantity and quality of the included studies and other biases, the above conclusions need more high-quality studies to be verified.

Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier [CRD42022311129].

Retrieval Results: A total of 185 studies were obtained through preliminary search, including 140 in CNKI, 1 in Wanfang, 13 in PubMed, 3 in VIP, 25 in Cochrane, and 3 in Web of Science. First, we removed 14 duplicate documents. Second, 152 articles were excluded by reading the literature titles and abstracts, and 8 articles were excluded by reading the full text. Finally, 11 studies were included in the meta-analysis (;;;;;;;;;; ). Among them, there are five studies (;;;; ) on CHM vs. placebo and six studies (;;;;; ) on CHM vs. prokinetics + deanxit (Figure 1).

Basic Characteristics of Included Studies: A total of 11 RCTs were selected. Among them, there are five studies on CHM vs. placebo, one from Japan and the rest (;;; ) from China. Four (;;; ) of all studies were published in English and one in Chinese.

There are six studies of CHM vs. prokinetics + deanxit, all from China and published in Chinese. The 951 participants in the 11 RCTs were divided into the following 2-part studies, and the number of participants in each study ranged from 43 to 118. Of the 11 studies involved, 2 (; ) were multicenter studies, and the number of participating research centers ranged from 9 to 56. The basic information of the 11 studies included in the analysis is shown in Table 1. The specific drug composition of Chinese medicine compounds involved in the study is shown in Table 2.

Risk of Bias Assessment: All the inclusion trials were randomized, but some of them did not describe the specific randomization method, hence the evaluation was “unclear.” Some of these inclusion trials did not describe blindness. Among them, trials that neither described randomization method nor blindness were considered high risk, and the others were evaluated as “unclear.” Complete details of the bias risk assessment are shown in Figures 2, 3.

Meta Results / Total Effective Rate / Chinese Herbal Medicine vs. Placebo Group: Among the five studies included, three studies (;; ) reported the total effective rate. There were a total of 341 cases, of which 181 cases were in the Chinese medicine compound treatment group. Of these, 153 cases were reported effective (84.5%). Of the 160 cases in the placebo control group, of which 79 cases were effective (49.4%).

The heterogeneity test showed high heterogeneity (P = 0.006, I2 = 80%); therefore, a randomized effect model was adopted. The results showed that the therapeutic effect of CHM was significantly better than that of placebo on the overall symptom improvement [RR = 1.76; 95% confidence interval (CI) (1.13, 2.75), P = 0.01] (Figure 4).

Chinese Herbal Medicine vs. Western Medicine Group: Six studies (;;;;; ) all reported the total clinical effective rate. Totaling 480 cases, 244 cases were in the Chinese medicine compound treatment group. Of these, 226 cases were effective (92.6%), and of the 236 cases in the control group, 186 cases were effective (78.8%).

The comprehensive analysis showed low heterogeneity (I2 = 0, P = 0.98), and a fixed-effects model was used. The comprehensive results showed that the effective rate of the CHM was significantly better than that of the control group, and the difference was statistically significant [RR = 1.17; 95% CI (1.09, 1.26), P < 0.0001] (Figure 5).

Total Symptom Score / Chinese Herbal Medicine vs. Placebo Group: A total of 4 studies (;;; ), including 381 participants compared total symptom scores. The comprehensive analysis showed high heterogeneity (I2 = 98%), and a random-effects model was used. The comprehensive results showed that the CHM could effectively reduce the total symptom score [SMD = −10.05; 95% CI (−13.50, −6.59); Z = 5.70; P < 0.00001] (Figure 6).

Depression Scale / Chinese Herbal Medicine vs. Placebo Group: Three studies (;; ) including 341 investigators compared post-treatment depression scores. The heterogeneity test showed high heterogeneity (P < 0.00001, I2 = 99%); therefore, a randomized effect model was adopted. Two of the studies used the HAMD score (; ) and one study used the HADS score. The comprehensive results showed that the CHM could effectively reduce the depression score [SMD = −7.68; 95% CI (−14.43, −0.94); Z = 2.23; P = 0.03] (Figure 7).

Two other studies also evaluated depression improvement. According to results, the JX pill group had a greater improvement in the HAMD total score from baseline to 4 weeks than the placebo group, but the difference was not significant [mean between-group difference, −0.7 points (95% CI, −1.8 to −0.3); P = 0.093]. showed that compared with the placebo group, the effective rate of the CHM group was significantly increased (68.75 vs. 37.50%, P < 0.05). The cure rates of the CHM group were significantly higher than those of the placebo group (27.08% vs. 0, P < 0.05).

Chinese Herbal Medicine vs. Western Medicine Group: Six studies (;;;;; ) including 480 investigators compared HAMD scores after treatment. The comprehensive analysis showed high heterogeneity (I2 = 98%), and a random-effects model was used. The comprehensive results showed that the CHM could effectively reduce the HAMD score [MD = −4.32; 95% CI (−6.04, −2.61); Z = 4.94; P < 0.00001] (Figure 8).

HAMA Score / Chinese Herbal Medicine vs. Placebo Group: Only evaluated anxiety. The results showed that JX pill had a greater improvement in the HAMA scores from baseline to 4 weeks than the placebo group, but the difference was not significant [mean between-group difference, −0.3 points (95% CI, −1.3 to −0.7); P = 0.446].

Chinese Herbal Medicine vs. Western Medicine Group: Three studies (;; ) including 254 investigators compared HAMA scores after treatment. The comprehensive analysis showed high heterogeneity (I2 = 80%), and a random-effects model was used. The comprehensive results showed that the CHM could effectively reduce the HAMA score [MD = −3.19; 95% CI (−3.79, −2.59); Z = 10.40; P < 0.00001] (Figure 9).

Gastric Emptying Rate / Chinese Herbal Medicine vs. Western Medicine Group: Three studies (;; ) involving six articles reported the gastric emptying rate. All studies used radioimaging. The heterogeneity test showed high heterogeneity (P < 0.00001, I2 = 97%); thus, the randomized effect model was adopted. The combined results showed that the Chinese herbal formula could effectively reduce the gastric emptying rate [MD = 12.62; 95% CI (5.84, 19.40); Z = 3.65; P = 0.0003] (Figure 10).

Adverse Reactions / Chinese Herbal Medicine vs. Placebo Group: All 5 studies reported drug safety evaluations and included a total of 561 patients. In study, eight cases of adverse reactions occurred in the GHM group, including three cases of dry mouth, two cases of dizziness, one case of loss of appetite, one case of nausea, and one case of gastrointestinal discomfort. There were seven cases of adverse reactions in the placebo group, including nausea two cases, one case of insomnia, one case of fatigue, three cases of constipation. In, one participant in the CHM group reported slight diarrhea, one participant reported mild constipation, and one participant had abnormal liver function (ALT, 108.7 U/L; AST, 63.7 U/L); no specific adverse reactions were reported in the placebo group. The comprehensive results showed that the incidence of adverse reactions was 4.68% in the CHM group and 3.44% in the placebo group, with no significant difference between the two groups [MD = 1.14; 95% CI (0.53, 2.42); Z = 0.33; P = 0.74] (Figure 11).

Chinese Herbal Medicine vs. Western Medicine Group: Out of the six studies (;;; ), four conducted drug safety evaluation. Among them mentioned only in the abstract that there were no adverse reactions in either group during the study period. conducted a 6-month follow-up, and the result was that there were no serious adverse reactions in both groups. During treatment, two patients in the control group had mild dizziness, one patient had dry mouth and slight bitterness, and no adverse reactions occurred in the treatment group. During the study, no adverse reactions occurred in both groups. None of the reported adverse reactions affected the course of treatment. The comprehensive results showed that there was no significant difference in the occurrence of adverse reactions between the two groups [MD = 0.14; 95% CI (0.01, 2.67); Z = 1.30; P = 0.19] (Figure 12).