Efficacy of Rikkunshito, a Traditional Japanese Medicine

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□ ORIGINAL ARTICLE □

Efficacy of Rikkunshito, a Traditional Japanese Medicine(Kampo), in Treating Functional Dyspepsia

Hiroaki Kusunoki 1, Ken Haruma 2, Jiro Hata 3, Manabu Ishii 2, Tomoari Kamada 2,

Naohito Yamashita 1, Keisuke Honda 1, Kazuhiko Inoue 1, Hiroshi Imamura 3,

Noriaki Manabe 3, Akiko Shiotani 2 and Tsukasa Tsunoda 1

Abstract

Background Rikkunshito, a traditional Japanese (Kampo) medicine, is widely prescribed as an oral prepa-

ration for the treatment of functional dyspepsia (FD). In our previous study, we reported that extracorporeal

ultrasonography (US) is a useful technique for the assessment of the gastric accommodation reflex (AR) and

duodenogastric motility. In this study, we examined the effects of Rikkunshito on the gastroduodenal function

in patients with FD.

Methods Sixteen FD patients (median age, 45 y) underwent US, before and after 14 days of treatment with

Rikkunshito (7.5 g b.d.). For assessment of the AR, a cross-sectional area of the proximal stomach was mea-

sured after incremental ingestion of a liquid meal up to 400-mL. The expansion rate was used as the parame-

ter to determine the AR. Then, the gastric emptying rate (GER), motility index (MI), and reflux index (RI)

were evaluated using previously reported methods.

Results Although no significant changes were observed in the total score of the Gastrointestinal Symptom

Rating Scale (GSRS), the scores of 3 of the 15 symptoms of GSRS decreased significantly after treatment

with Rikkunshito. The expansion rate of the proximal stomach was significantly greater after treatment with

Rikkunshito than before the treatment. Although the GER and MI increased significantly, no significant dif-

ferences in the RI were observed after treatment with Rikkunshito.

Conclusion These observations suggested that Rikkunshito may be beneficial for the treatment of FD pa-

tients with impaired AR and gastric motility. These results also suggested that Rikkunshito has a therapeutic

potential for FD and GERD.

Key words: Rikkunshito, gastric accommodation reflex, gastroduodenal motility, ultrasound, traditional Japa-

nese medicine (Kampo)

(Inter Med 49: 2195-2202, 2010)(DOI: 10.2169/internalmedicine.49.3803)

Introduction

Functional dyspepsia (FD) is defined as the presence of

gastrointestinal symptoms such as epigastric pain, epigastric

burning, postprandial fullness, and early satiation in the ab-

sence of any organic, systemic, or metabolic disease.

On the basis of the Rome III criteria (1), FD is subdi-

vided into 2 diagnostic categories: 1) meal-induced

postprandial distress syndrome (PDS), which is character-

ized by postprandial fullness and early satiation, and 2) epi-

gastric pain syndrome (EPS), which is characterized by epi-

gastric pain and burning. These categories were proposed

under the assumption that the 2 types of FD might arise

from different underlying pathophysiological mechanisms. It

has been suggested that impaired accommodation reflex

１Department of General Medicine, Kawasaki Medical School, Kurashiki, ２Division of Gastroenterology, Department of Internal Medicine,

Kawasaki Medical School, Kurashiki and ３Division of Endoscopy and Ultrasound, Department of Clinical Pathology and Laboratory Medicine,

Kawasaki Medical School, Kurashiki

Received for publication April 13, 2010; Accepted for publication July 14, 2010

Correspondence to Dr. Hiroaki Kusunoki, [email protected]

Inter Med 49: 2195-2202, 2010 DOI: 10.2169/internalmedicine.49.3803

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(AR) of the proximal stomach and delayed gastric emptying

may play major roles in the pathogenesis of the PDS sub-

group (2). According to previous reports, these functional

abnormalities are observed in 15% to 50% of all FD pa-

tients (3, 4). Therefore, assessment of both the gastric AR

and gastroduodenal motility is essential for understanding

the pathogenesis of FD.

Rikkunshito is an orally administered Japanese herbal

(Kampo) preparation that is widely prescribed for patients

showing various gastrointestinal symptoms such as gastroe-

sophageal reflux (5, 6), dyspeptic symptoms of post gastro-

intestinal surgery (7, 8), and chemotherapy-induced nau-

sea (9). Rikkunshito is composed of 8 constituents: Glycyr-

rhizae radix (4.7%), Zingiberis rhizoma (2.3%), Atractylodis

lanceae rhizoma (18.6%), Zizyphi fructus (9.3%), Aurantii

nobilis pericarpium (9.3%), Ginseng radix (18.6%), Pinelliae

tuber (18.6%), and Hoelen (18.6%). Several studies have

shown that many Japanese herbal medicines, including Rik-

kunshito, improve gastroduodenal motility-related disorders

and are therefore clinically efficacious against FD to some

extent (10-14). However, few studies have been reported on

the action mechanism of this medicine in humans (15); al-

though Rikkunshito has been demonstrated to improve the

impairment in the gastric AR in vitro (16), no clinical re-

ports have been published on the effects of Rikkunshito on

the gastric AR.

In our previous study, we reported that extracorporeal ul-

trasonography (US) is a useful modality for the assessment

of meal-induced gastric AR, gastric emptying rate (GER),

antral contractions, and duodenogastric reflux

(DGR) (17-22). The aim of this study was to determine the

clinical effects of Rikkunshito on gastric AR and gastroduo-

denal motility in FD patients by using US.

Subjects and Methods

Study Subjects

Sixteen FD patients (10 men and 6 women; age range,

28-78 y; median age, 45 y) were enrolled in this study. All

of the patients were diagnosed with FD according to the

Rome III criteria. None of them had a history of diabetes

mellitus and gastrointestinal surgery; they were not under

any medications that could affect gastric motility. Smoking

was prohibited on the day before and on both days of ultra-

sonographic examination. Candidates infected with Helico-bacter pylori were not excluded from the study. The proto-

col for this study was approved by the Ethics Committee of

Kawasaki Medical School, and all participants gave prior in-

formed consent.

Study Methods

Changes in gastrointestinal symptoms

The changes in the gastrointestinal symptoms were evalu-

ated on the basis of the Gastrointestinal Symptom Rating

Scale (GSRS), Japanese edition (23). The GSRS is com-

posed of 15 items, each rated according to severity on a

scale of 1 (absence of the symptom) to 7 (maximal intensity

of the symptom) (23); thus, higher GSRS scores indicate

more severe symptoms. We used the total score and the 15

gastrointestinal symptoms of GSRS for evaluating the dys-

peptic symptoms. The GSRS questionnaire was administered

twice to each patient (before and after treatment with Rik-

kunshito).

Assessment of AR

The patients were examined by US, before and after 14

days of treatment with Rikkunshito (TJ-43; Tsumura, Tokyo,

Japan) administered at a dose of 7.5 g b.d. The patients

were asked to fast overnight and before the US examination,

they were asked to consume incremental amounts of up to

400-mL of a liquid meal (consommé soup, 13 kcal/400-mL)

through a straw. Thereafter, the cross-sectional area of the

proximal stomach was measured for assessment of the gas-

tric AR with the subjects lying on a bed in the supine posi-

tion. In order to obtain the largest cross-sectional area of the

proximal stomach, an US probe was positioned and main-

tained in the intercostal space of the left axilla (Fig. 1) of

the patient, with the spleen as the landmark for this view

(Fig. 2) as described previously (20-22). The cross-sectional

area of the proximal stomach was estimated by tracing its

mucosal side using built-in calipers for 1-2 minutes after the

meal ingestion. The expansion rate in the cross-sectional

area measured before and after treatment with the drug was

expressed as follows: “[(area of each volume after ingestion

- area before ingestion) ÷ area before ingestion] ×100 (%).”

Assessment of gastroduodenal motility

After the assessment of gastric AR, the patients were

asked to sit on a chair, reclining slightly backwards, and the

GER, antral contractions, and DGR were evaluated by US,

as described previously (17-20, 22). The US probe was po-

sitioned vertically to simultaneously visualize the antrum,

superior mesenteric artery, and abdominal aorta.

The antral area was estimated by tracing the mucosal side

of the antrum with built-in caliper at 1 minute and 15 min-

utes after ingestion of the liquid meal. The GER was ex-

pressed as follows: “[(antral area at 1 minute - antral area at

15 minutes) ÷ antral area at 1 minute] ×100 (%).” The fre-

quency of antral contractions was defined as the number of

contractions per 3 minutes. The amplitude of the antral con-

tractions was calculated from the maximal reduction in the

antral area for each contraction as follows: “[(antral area at

the time of relaxation - antral area at the time of contrac-

tion) ÷ antral area at the time of relaxation] ×100 (%)”. The

motility index (MI) was expressed as the product of the fre-

quency of contractions and mean amplitude.

To evaluate the DGR by color Doppler US, we positioned

the US probe at the level of the transpyloric plane to simul-

taneously visualize the antrum, pylorus, and proximal duo-

denum. The color gain, high-pass filter, and angle between


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Figure 1. The position of the ultrasonography probe to obtain the largest cross-sectional area of the proximal stomach. The probe was placed in the intercostal space of the left axilla.

Figure 2. Changes in the US images of the largest cross-sectional area of the proximal stomach after incremental ingestion of up to 400-mL of a liquid meal. The incremental changes in the area of the proximal stomach positively corresponded to the intake volumes. The spleen was used as the marker for this view. The cross-sectional area of the proximal stomach was evaluated by marking the mucosal side with built-in calipers.

the US beam and the transpyloric flow were standardized

for all measurements. The frequency of DGR was defined as

the amount of DGR obtained at a distance “x” (measured in

cm) of the color signal from the pylorus. The reflux index

(RI) was expressed as follows: “frequency of DGR × mean

intensity of DGR.

All of the evaluations were performed by one researcher

(Kusunoki H). The equipment used was an SSA-770A US

system (Toshiba, Nasu, Japan) with a 3.75-MHz curved ar-

ray scanner.

Statistical analysis

The data are expressed as mean ± SE. The statistical sig-

nificance of differences between the 2 groups was assessed


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Figure 3. Changes in the total score of GSRS. Although the total score of GSRS decreased after treatment with Rikkunshito, the differences were not statistically significant.

Table 1. Changes in the 15 Items of Gastrointestinal Symptoms of GSRS were Shown in the Table1. The Scores of Three Items of Gastrointestinal Symptoms (Abdominal Pains, Heartburn, and Abdominal Distension) of GSRS Decreased Significantly after Treatment with Rikkunshito.

using the Mann-Whitney’s test, the Wilcoxon test, or the

Student’s t-test. The difference was considered statistically

significant if p<0.05.

Results

Changes in gastrointestinal symptoms

Although the total score of GSRS decreased after treat-

ment with Rikkunshito, the differences were not statistically

significant (Fig. 3). However, the scores of 3 of the gastro-

intestinal symptoms of GSRS (abdominal pain, heartburn,

and abdominal distension) decreased significantly after treat-

ment with Rikkunshito (Table 1).

Assessment of AR

The expansion rate in the cross-sectional area of the

proximal stomach was significantly greater after treatment

with Rikkunshito than before the treatment (before treatment

vs. after treatment: after 100-mL ingestion, 2.20±0.28 vs.

3.27±0.45, p=0.034; after 200-mL ingestion, 3.69±0.57 vs.

6.51±1.39, p=0.007; after 300-mL ingestion, 5.13±0.97 vs.

9.08±2.06, p=0.017; and after 400-mL ingestion, 6.40±1.29)

vs. 11.29±2.48, p=0.017) (Fig. 4).

Assessment of gastroduodenal motility

Although the values of GER [before treatment vs. after

treatment: 57.9±5.7 vs. 72.3±5.4, p=0.010] and MI [7.93±

0.48 vs. 8.88±0.24, p=0.049] increased significantly after

Rikkunshito treatment, those of RI [18.8±3.1 vs. 15.3±3.0,

p=0.463] were not significantly different (Fig. 5). None of

the subjects had any adverse events that necessitated with-

drawal from the study.


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Figure 4. The expansion rate in the cross-sectional area measured before and after treatment with Rikkunshito was expressed as“[(area of each volume after ingestion － area of each volume before ingestion) ÷ area before ingestion] × 100 (%).” The expansion rate in the cross-sectional area of the proximal stomach was significantly greater after treatment with Rikkunshito than be-fore the treatment

Figure 5. Changes in the gastric emptying rate (GER), motility index (MI), and reflux index (RI) before and after treatment with Rikkunshito. Although the values of GER and MI increased significantly after Rikkunshito treatment, those of RI were not significantly different.


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Discussion

Traditional Japanese (Kampo) medicines are widely pre-

scribed in Japan for patients with various gastrointestinal

symptoms, and Rikkunshito is the most popular Kampo

medicine prescribed for the treatment of FD. Some clinical

studies have reported that Rikkunshito is efficacious in the

treatment of FD-related gastrointestinal (10-12, 14, 15) and

gastroesophageal reflux disease (GERD) symptoms (5, 6). In

the present study, we showed that the scores of 3 of the gas-

trointestinal symptoms of GSRS (abdominal pain, heartburn,

and abdominal distension) decreased significantly after treat-

ment with Rikkunshito. In this study, although we consid-

ered the symptoms individually, the present rating scale ap-

pears to be effective in assessing the degree of symptoms

and the changes before and after treatment. Our results were

consistent with those of previous studies, which suggested

that Rikkunshito may have a therapeutic potential for not

only FD patients with PDS but also FD patients with EPS

and GERD. All of the mechanisms underlying the effects of

Rikkunshito on these symptoms cannot be explained; how-

ever, improvement of AR, GER, and MI may contribute to

decreasing the GSRS score of 3 of the gastrointestinal

symptoms of GSRS. With regard to the effect of Rikkun-

shito on heartburn, Kawahara et al reported that Rikkunshito

reduces distal esophageal acid exposure by improving

esophageal acid clearance (6). However, since Rikkunshito

is composed of over 100 compounds, including 8 major

constituents, it is highly likely that this drug produces symp-

tomatic relief through an unknown prokinetic action. Addi-

tional mechanistic studies need to be performed in FD pa-

tients to conclusively determine the effects of Rikkunshito.

Previous studies have shown that Rikkunshito impairs the

adaptive AR in vitro (16); however, no reports have been

published on the clinical effects of Rikkunshito on AR. This

is the first clinical report showing that Rikkunshito enhanced

the meal-induced AR of the proximal stomach. In the pre-

sent study, we selected the cross-sectional area of the proxi-

mal stomach as a criterion for the assessment of gastric AR

by US (21, 22). The measurement of this criterion is simple

and easy. The efficacy of the previous methods that evalu-

ated the intragastric volume on the basis of the cross-

sectional area of the proximal stomach has been shown in

previous studies (21, 22). A previous study reported that

changes in the cross-sectional area of the proximal stomach

are significantly correlated with the changes in the gastric

volume caused by the ingestion of a liquid meal (21). Using

this method, we also reported that FD patients had impaired

gastric AR (21). Furthermore, Matsumoto et al (24) reported

that US and a pressure sensor can be used to assess the iso-

tonic expansion of the proximal stomach.

In the present study, all evaluations were performed by

the same researcher to prevent inter-observer variation. The

US probe was positioned and maintained in the same posi-

tion for all patients, and the expansion rate of the same area

was measured to assess the AR; this helped to prevent in-

consistencies in the results; however, the reproducibility of

the measurements was not adequately evaluated. In addition,

we selected and confirmed some landmarks to help maintain

the same view throughout the measurement (17-22). There-

fore, we believe that there were very few human errors of

measurement in this method.

Several devices such as the barostat and techniques such

as scintigraphy, single photon emission computed tomogra-

phy (SPECT), and magnetic resonance imaging have been

used to evaluate gastrointestinal functions (25-29) including

meal-induced gastric AR; however, these techniques often

have technical limitations and are too expensive or complex

for daily use. Hence, the use of the barostat is the standard

method for the assessment of AR in the proximal stomach

and has been used in several studies (4, 25, 30-33). How-

ever, this method is invasive and because the presence of

food in the stomach would interfere with the expansion of

the balloon of the barostat system, the value of the postpran-

dial gastric volume may be less than that recorded before

consuming the test meal (34). Similarly, the US method has

the same disadvantage as the barostat, i.e., it requires the pa-

tients to be in the supine position for partial distribution of

the liquid test meal in the proximal stomach. Therefore, the

US method also cannot be used to evaluate the AR with

normal gastric distribution of a liquid test meal. However,

we selected the US method for easy AR assessment.

Rikkunshito has reported improvement in delayed gastric

emptying in rats in vivo (35). However, there are few re-

ports discussing the clinical effects of Rikkunshito on gas-

troduodenal motility in humans (19). In a previous study by

Tatsuta and Ishii, 42 patients with FD were randomly di-

vided into the “Rikkunshito-treated” group and the

“Combizym-treated” group; they reported that Rikkunshito

enhances gastric emptying and provides significantly greater

relief from some symptoms than Combizym (11). In their

recent study, Kawahara et al demonstrated that administra-

tion of Rikkunshito results in symptomatic relief and im-

proves gastric emptying in patients with severe FD because

of delayed gastric emptying (6). In the present study, we

showed that Rikkunshito administration enhanced the meal-

induced AR of the proximal stomach, GER, and MI in pa-

tients with FD. Therefore, our results were consistent with

the reports of previous studies indicating that this drug has

an effect on gastric motility.

With regard to the role of Rikkunshito in the enhance-

ment of AR, GER, and MI, the precise mechanisms underly-

ing the effects of Rikkunshito on gastric AR and gastroduo-

denal motility are still unclear; however, the pharmacologi-

cal mechanisms and active ingredients of Rikkunshito have

been elucidated in part (16, 35). Factors associated with gas-

tric motility, such as gastric emptying and gastric AR, are

regulated by various effectors, including nitric oxide (NO),

5-hydroxytryptamine (5-HT), and its receptors. Studies have

shown that the prokinetic actions of Rikkunshito are medi-

ated by NO (16, 35, 36). Initially, the actions of Rikkun-


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shito were thought to be mediated via NO production alone

because it contains L-arginine, a substrate of NO, in its

water fraction. Subsequently, analysis of the fractional ex-

tracts of Rikkunshito revealed that the methanol fraction

contained an even more potent promoter of gastric motility,

namely, hesperidin (35). It was reported that hesperidin is

not a substrate of NO because it does not belong to the

guanidine group (37) and that it actually decreases NO pro-

duction (38). Thus, Rikkunshito and hesperidin were be-

lieved to promote gastric motility through a mechanism

other than that mediated by NO. However, in a recent study,

Tominaga et al (39) reported that Rikkunshito has no effect

on dopamine-induced gastrointestinal motility. They also re-

ported that Rikkunshito has 5-HT3-antagonist effects on gas-

tric motility. Initially, we believed that the role of Rikkun-

shito in promoting gastric motility may be mediated by

ghrelin because Rikkunshito elevates the low plasma ghrelin

levels that are induced by cisplatin (40). Some subsequent

studies (41-43) revealed that the pharmacological actions of

Rikkunshito in promoting gastric motility may be associated

with ghrelin. Therefore, our results corroborate the evidence

obtained by previous studies showing that Rikkunshito has

an effect on gastric motility.

In the present study, although we confirmed the gastric

prokinetic actions of Rikkunshito by US evaluation, Rikkun-

shito did not show any significant effect on DGR. The DGR

occurs as a result of the reversal of the original pressure

gradient between the duodenum and the antrum. The mecha-

nism underlying this phenomenon is unclear; the DGR may

be related to a duodenal brake caused by early gastric emp-

tying. Thus, a decrease in DGR reflects the normalization of

gastrointestinal coordination.

In summary, this study showed that Rikkunshito enhanced

meal-induced gastric AR, GER, and MI in patients with FD

and that the scores of three of the gastrointestinal symptoms

of GSRS (abdominal pain, heartburn, and abdominal disten-

sion) decreased significantly after treatment with Rikkun-

shito. These observations suggested that Rikkunshito may be

beneficial for the treatment of FD patients with impaired AR

and gastric motility. These results also suggested that Rik-

kunshito has a therapeutic potential for FD (both PDS and

EPS) and GERD.

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Efficacy of Rikkunshito, a Traditional Japanese Medicine