담적

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: 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: The demand for complementary and alternative medicine for the management of functional dyspepsia (FD) is increasing due to the insufficient efficacy of conventional treatment options. In Asia, the Chinese herbal medicine formula Banxia-xiexin tang (BXT) has been used to treat FD.

Methods: We searched 11 digital medical databases on 1 September 2021. Randomized controlled trials (RCTs) that investigated the efficacy of BXT or combination therapy (BXT plus Western medicines) for FD were selected. The outcome parameters were total clinical efficacy rate (TCE), motilin level, symptom checklist-90-revised (SCL-90-R), and visual analog scale (VAS) for dyspepsia and adverse events. Cochrane risk of bias tool 2.0 (RoB 2) was used for the quality assessment of included studies.

Results: The meta-analysis comprised 57 RCTs with 5,525 participants. BXT was more efficacious, with a higher TCE than Western medicine. Combination therapy (BXT plus Western medicine) also resulted in a higher TCE than Western medicine. Combination therapy improved motilin levels and psychological symptoms to a greater extent than Western medicine, evidenced by a higher SCL-90-R score. However, no significant difference in VAS scores was observed between the BXT and placebo groups. BXT and combination therapy were associated with fewer adverse events than Western medicine or placebo.

Conclusion: Our findings suggest that BXT and its combination therapy may be an effective and safe alternative treatment for FD. More RCTs with better methodologies are required to strengthen this evidence.

Systematic Review Registration: [https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019123285], identifier [CRD42019123285].

3.1 Selection of study: The initial search identified 504 studies, of which 83 duplicates were excluded. After screening the titles and abstracts, 340 studies were excluded. Fifteen studies were excluded because 14 did not meet the inclusion criteria, and one presented inaccurate data. Finally, 66 studies were included, and 57 were selected for the meta-analysis (Figure 1).

3.2 Characteristics of included studies: We included 66 studies published between 2001 and 2021. All articles were RCTs and parallel-design studies. Four studies were written in English and 62 in Chinese. Three randomized trials were conducted in Korea and 63 in China. BXT was compared with Western medicine in 51 RCTs. In 10 articles, combination therapy (BXT plus Western medicine), and Western medicine were compared. BXT was also compared with a placebo in five RCTs. The total number of patients included in the meta-analysis was 5,615. In each study, 31–200 patients were included. Table 1 shows a summary of the analyzed RCTs.

3.3 Assessment of risk of bias: Figure 2 shows the quality assessment results of the 57 studies selected for this meta-analysis using the RoB 2 tool. Table 2 shows the ratings for the individual domains at the study level for the 66 included studies.

3.3.1 Bias arising from the randomization process: Concerns were raised in 55 of the RCTs. These randomization studies did not report the sequence of allocation concealment. Two studies (; ) used a center-controlled method to randomize participants and were assessed to have a low RoB.

3.3.2 Bias due to deviations from intended interventions: Three trials (;; ) had low RoB because the participants and personnel were blinded to the placebo. Fifty-five studies had high RoB because participants and those delivering the interventions were aware of their assigned interventions. Deviations from the intended intervention occurred in these studies because of the trial context and group balance, which probably affected the outcome.

3.3.3 Bias due to missing outcome data: conducted a per-protocol analysis and had a high RoB. However, the other studies had a low RoB. Fifty-four trials did not have missing patients. conducted an intention-to-treat analysis, while had one missing patient before administering the test drug.

3.3.4 Bias in measurement of the outcome: While three RCTs (;; ) blinded outcome assessment, 54 did not report blinding of statistical analyses, and the outcome assessment was probably influenced by knowledge of the intervention received.

3.3.5 Bias in selection of the reported result: Two RCTs (; ) with published study protocols had a low RoB. The remaining 55 studies were biased due to insufficient information.

3.3.6 Overall bias: Of the 57 studies included in this meta-analysis, two had a low risk, one had a moderate risk, and 54 had a high overall RoB.

3.4 Primary outcome: total clinical efficacy rate: This systematic review examined the efficacy of BXT and combination therapy (BXT plus Western medicine) in treating FD using TCE.

3.4.1 BXT versus western medicine: Western medicine groups were subdivided into PK agent groups, such as domperidone, trimebutine maleate, mosapride, and cisapride, as well as combinations of the PK and PPI groups. BXT was more efficacious than domperidone (RR: 1.19; 95% CI:1.11–1.21; p < 0.001), trimebutine maleate (RR: 1.24; 95% CI: 1.15–1.33; p < 0.001), mosapride (RR: 1.18; 95% CI: 1.13 to 1.24; p < 0.001), and combinations of PK and PPI (RR: 1.20; 95% CI: 1.12–1.29; p < 0.001). Heterogeneity was not significant in the trimebutine maleate (p = 0.99; I 2 = 0%), mosapride (p = 0.89; I 2 = 0%), or the combination of the PK and PPI groups (p = 0.31; I 2 = 16%).

In the integrated analysis of the five groups, 43 RCTs with 4,183 patients were included. They showed that BXT was more efficacious than Western medicine against FD (RR: 1.19; 95% CI: 1.15–1.23; p < 0.001) and had moderate heterogeneity (p = 0.02; I 2 = 33%) (Figure 3).

3.4.2. Combination of BXT and western medicine versus western medicine: The Western medicine group was divided into two subgroups: domperidone and mosapride. The combination of BXT and Western medicine was more efficacious than domperidone (RR: 1.16; 95% CI: 1.06–1.27; p = 0.002) and mosapride (RR: 1.21; 95% CI: 1.10–1.33; p < 0.001). Heterogeneity was insignificant in either subgroup (p = 0.66, I 2 = 0%; p = 0.79, I 2 = 0%).

Six studies with 601 patients were analyzed by integrating the subgroups. Combination therapy (BXT plus Western medicine) was more efficacious (RR: 1.18; 95% CI: 1.11–1.26; p < 0.001) and had lower heterogeneity (p = 0.88; I 2 = 0%) than Western medicine (Figure 4).

3.5 Motilin: The meta-analysis included only plasma motilin levels (pg/ml) measured using radio-immunoassays before meals. Analysis of three RCTs with 286 participants showed that combination therapy (BXT plus Western medication) was more efficacious than Western medicine alone in boosting motilin secretion (MD: 96.89; 95% CI: 82.49–111.30; p < 0.001). Western medicine groups included domperidone, mosapride, and a combination of mosapride, omeprazole, amitriptyline (on demand), and clarithromycin (on demand). Heterogeneity was high (p < 0.001; I 2 = 0%) (Figure 5).

3.6 Symptom checklist-90-revised: Two studies (; ) compared combination therapy (BXT plus domperidone) with domperidone alone and used the SCL-90-R to evaluate psychological symptoms. These studies included 166 patients. The SCL-90-R has nine subscales. Combination therapy (BXT plus domperidone) was more efficacious than domperidone alone in all aspects of the SCL-90-R.

The somatization score was significantly lower in the combination therapy group (BXT plus domperidone) than in the domperidone group (MD: –13.51; 95% CI: [–14.52]—[–12.49]; p < 0.001). Obsessive-compulsive symptoms improved remarkably in the combination therapy group (BXT plus domperidone) than in the domperidone group (MD: –10.63; 95% CI: [–12.05]- [–9.20]; p < 0.001), and interpersonal sensitivity was found to be more significantly improved in the combination therapy group than in the domperidone group (MD: –11.08; 95% CI: [–12.16] -[–10.01]; p < 0.001). Depression scores were significantly lower in the combination therapy group (BXT plus domperidone) than in the domperidone group (MD: –13.00; 95% CI: [–14.39]—[–11.60]; p < 0.001). Combination therapy (BXT plus domperidone) was found to be remarkably more efficacious against anxiety than domperidone (MD: –14.14; 95% CI: [–21.01]—[ −7.27]; p < 0.001) and reduced hostile symptoms more significantly than domperidone (MD: –7.46; 95% CI: [–8.47]—[–6.45]; p < 0.001). Combination therapy (BXT plus domperidone) was more efficacious in reducing phobic anxiety than domperidone (MD: –8.97; 95% CI [–10.00] - [–7.94]; p < 0.001). The paranoid ideation score was significantly lower in the combination therapy group (BXT plus domperidone) than in the domperidone group (MD: –12.19; 95% CI: [–13.25]—[–11.14]; p < 0.001). Combination therapy (BXT plus domperidone) was more efficacious in reducing the psychoticism score than domperidone (MD: –13.09; 95% CI [–14.42] - [–11.77]; p < 0.001) (Figure 6).

3.7 Visual analog scale: Three RCTs (;; ) with 179 participants compared the BXT and placebo groups using the VAS. No significant difference was observed between the BXT and placebo groups (MD: –4.31; 95% CI: [–17.40]—[–8.77]; p = 0.52). Heterogeneity was high (p = 0.01; I 2 = 78%) (Figure 7).

3.8 Subgroup analysis: Chaizhi-BXT versus western medicine: In this meta-analysis, the modified BXT group was integrated with the BXT group. A subgroup analysis was performed to minimize heterogeneity in the experimental groups. Three RCTs (;; ) with 240 participants showed that Chaizhi-BXT had a significantly higher TCE than Western medicine (RR: 1.25; 95% CI: 1.09–1.43; p = 0.001) (Figure 8).

3.9 Adverse events: Of the 66 studies, 54 did not report any adverse events. The experimental group included BXT and Western medicine, and the control group included Western medicine and placebo. Two articles (; ) reported no adverse events, and one reported the number of occurrences alone. The remaining nine RCTs reported mild adverse events. The number of adverse events was significantly lower in the experimental group than in the control group (RR: 0.53; 95% CI: 0.35–0.81; p = 0.003) (Figure 9).

Relatively mild adverse events such as nausea, vomiting, diarrhea, abdominal pain, acid reflux, epigastric fullness, dizziness, headache, urticaria, and insomnia were reported in the experimental groups. Adverse events in the control group were similar to those in the experimental groups and were mostly mild. However, reported intestinal obstruction (n = 1) due to progressive aggravation of constipation in the Western medicine (mosapride and estazolam) group.

3.10 Publication bias: Figure 10 shows a funnel plot of TCE comparing BXT and Western medicine. It is possible that smaller studies with lower estimates of benefits have not been published. However, the asymmetry is difficult to equate with publication bias because most of the included RCTs were published in Chinese, and the overall methodological quality of the studies was low.

3.11 Level of evidence: Table 3 shows the level of evidence for each outcome. Regarding TCE, BXT was more efficacious than Western medicine against FD. Because of the high RoB, the level of evidence was moderate. In the subgroup analysis, the level of evidence for BXT was lower than that of domperidone, considering the unexplained heterogeneity. The level of evidence for BXT was lower than that of cisapride due to unexplained heterogeneity and the small sample size. Combination therapy (BXT plus Western medicine) was more efficacious than Western medicine against FD. A high RoB led to a moderate level of evidence. In the subgroup analysis, the level of evidence was low because of the small sample size. Combination therapy (BXT plus Western medicine) was more efficacious than Western medicine alone in boosting motilin secretion. Because of the high RoB and the small sample size, the level of evidence was low. Combination therapy (BXT plus domperidone) had significantly better efficacy than domperidone in all aspects of the SCL-90-R. The level of evidence was low because of the high RoB and small sample size. The VAS scores showed no significant differences between the BXT and placebo groups. The RoB was low in the VAS; however, the small sample size led to a moderate level of evidence. The number of adverse events was significantly lower in the experimental group than in the control group. The level of evidence was moderate because of the high RoB.

Prokinetics is one of the therapeutic agents for functional and motility disorders of the stomach. However, its efficacy is limited. Kampo medicine is a unique medical system that was developed in Japan. In Kampo medicine, herbal medicine is prescribed based on the patient’s condition. Therefore, even for functional and motility disorders of the stomach, some herbal medicines are considered as a therapeutic option. Recently, there has been an increase in evidence for the efficacy or the mechanism of herbal medicine for functional and motility disorders of the stomach. Among these, rikkunshito is a well-studied herbal medicine that could be used as an alternative to prokinetics. In this review, we discuss the possibilities of rikkunshito for functional dyspepsia with its prokinetic and non-prokinetic effects and provide an overview of their current use with a focus on their therapeutic mechanism.

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).