Full text of DOI:10.1078/09447110260571580

Phytomedicine 9: 373–376, 2002
Urban & Fischer Verlag
http://www.urbanfischer.de/journals/phytomed
©
Phytomedicine
A comparative study between excess-dose users
and regular-dose users of rhubarb contained
in Kampo medicines
N. Mantani, T. Kogure, S. Sakai, M. Kainuma, Y. Kasahara, A. Niizawa, Y. Shimada,
and K. Terasawa
Department of Japanese Oriental Medicine , Faculty of Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan
Summary
With prolonged use of rhubarb-containing Kampo medicines, some patients come to ask for high-
dose rhubarb because of deteriorated reactivity to rhubarb. We divided patients into two groups in
terms of rhubarb-dose, and compared clinical backgrounds between regular-dose group and ex-
cess-dose group. Patients who were treated with rhubarb-containing Kampo extracts (manufac-
tured prescriptions) or Kampo formulae (decoctions) for more than 12 months were enrolled. These
two groups were compared for age, sex, shape of stool, abdominal symptoms, existence of hemor-
rhoids, Kampo diagnosis of abdomen, past stimulant laxative use, duration of stimulant laxative use
before the first administration of rhubarb, duration of rhubarb use in our hospital, and initial exis-
tence of stimulant pain caused by taking stimulant laxatives for the first time. No significant differ-
ence was shown between the two groups in terms of age, duration of stimulant laxative-use before
the first prescription of rhubarb, shape of stool, abdominal symptoms, existence of hemorrhoids, or
duration of rhubarb-use. However, most patients in the regular-dose group had initial stimulant
pain of the abdomen upon taking stimulant laxatives for the first time, but most patients in the ex-
cess-dose group did not (p < 0.001). All patients except one in the regular dose group had the sign of
“
umbilical region tenderness on pressure”, but half of the excess-dose group did not have it (p =
0.041). Based on these findings, the absence of “initial stimulant pain” and the absence of “umbilical
region tenderness on pressure” may predict increasing or excess use of rhubarb, and long-term use
of rhubarb should be discouraged more strongly in the patients without these signs.
Key words: Kampo medicine, herb, rhubarb, (Rheum palmatum) Rhei Rhizoma, lazy bowel syndrome,
laxative abuse
ꢀ
Introduction
Anthranoid-containing herbal medicines such as senna,
Kampo medicines containing rhubarb (Rhei Rhi-
aloe, cascara, frangula, and rhubarb are used as stimu- zoma, Rheum palmatum L.) are sometimes used for
lant laxatives (Siegers, 1992). These drugs are currently long-term treatment of patients with chronic diseases
recommended for short-term treatment (1–2 weeks), be- including chronic functional constipation. In the field
cause melanosis coli and neuronal degeneration in the of Kampo medicine, rhubarb is not only a laxative but
colon, “lazy bowel” syndrome, may occur in patients also an anti-inflammatory or a tranquilizer (Terasawa,
who use stimulant laxatives for a long time (Friedman 1993). Rhubarb is also used for improving “Oketsu”
and Isselbacher, 1994). In these patients, deteriorated syndrome (syndrome caused by blood stagnation).
reactivity to stimulant laxatives is sometimes an omen However, even with the traditional manner of rhubarb-
of neuronal degeneration in the colon (Ikeda, 1992).
use, some patients with prolonged use come to ask for
0
944-7113/02/09/05-373 $ 15.00/0

3
74
N. Mantani et al.
high-dose rhubarb because of deteriorated reactivity to count and serum electrolyte analysis. Patient who did
rhubarb. We divided patients into a regular-dose group not undergo these examinations or patients with an
and an excess-dose group, and compared the clinical identifiable cause of constipation, including constipat-
backgrounds between the two groups. The aim of this ing medicines, were excluded from this study.
study were to analyze risk factors of increasing or ex-
cess use of rhubarb.
Patients were divided into an excess-dose and a reg-
ular-dose group. We defined patients as “regular dose”
if a Kampo extract (manufactured prescription) were
used within the stated dose recommended for each ex-
tract by the Ministry of Health and Welfare (Japan), or
if 1g or less of rhubarb was added to Kampo formulae
ꢀ
Patients and Methods
Among the outpatients of Johetsu General Hospital (Jo-
hetsu, Japan) affiliated with our department, we includ-
ed in the study group all patients who were treated with
rhubarb-containing Kampo extracts (manufactured
prescriptions) or Kampo formulae (decoctions) for
more than 12 months and visited the hospital between
January and June 2001. In Japan, Kampo medicines are
prescribed with either forms Kampo extracts or Kampo
formulae. The existence of identifiable cause of consti-
pation was studied by stool testing for occult blood
and/or laboratory studies including a complete blood
(
decoctions). We defined as “excess-dose” when more
than the recommended dose of manufactured Kampo
extracts was used or any rhubarb-containing laxa-
tives were used in addition to the maximum dose of a
manufactured Kampo extract, or when more than 1 g of
rhubarb was added to Kampo decoctions.
Firstly, we examined the transition in rhubarb dose
using medical records from the first visit until the study
period in regular-dose group and excess-dose group
(
analyzed by Wilcoxon signed-ranks test). Secondly,
the two groups were compared for age, sex, shape of
stool (small and hard stool or not), abdominal symp-
toms, existence of hemorrhoids, Kampo diagnosis of
abdomen, past stimulant laxative use, duration of stim-
ulant laxative use before the first administration of
rhubarb, duration of rhubarb use in our hospital, and
initial existence of stimulant pain caused by taking
stimulant laxatives for the first time. Categorical vari-
ables were compared by Fisher’s exact test or Mann-
Whitney’s U test, and continuous variables were com-
pared by Student’s t-test. P-value less than 0.05 was
considered statistically significant.
ꢀ
Results
Fig. 1. Rhubarb dose contained in Kampo extracts (manu-
factured prescriptions) of the regular-dose group ( ) and the
excess-dose group ( ). Initial rhubarb dose and current
rhubarb dose are shown. (a: p = 0.917, b: p = 0.043)
Among the outpatients, 28 patients diagnosed with
chronic functional constipation were enrolled in this
study. In 15 of these patients, a regular dose of laxa-
tives was used, and in 13 patients an excess-dose of
laxatives was used during the study period. In daily
practice, the dose of rhubarb was decided by the sub-
ject’s physicians according to subject’s demand. No
conscious intervention was performed in the prescrip-
tion of rhubarb.
The initial rhubarb dose contained in manufactured
Kampo extracts (Figure 1) and Kampo decoctions
(
Figure 2) was higher in the excess-dose group than
that in the regular-dose group. Before the first adminis-
tration of rhubarb in our hospital, half of the patients in
the excess-dose group had continuously taken high-
dose stimulant laxatives (data not shown). In these pa-
tients, the initial dose of rhubarb was inevitably high.
Moreover, in the excess-dose group, the rhubarb-use
increased significantly during the period from the first
Fig. 2. Rhubarb dose contained in Kampo formulae (decoc-
tions) of the regular-dose group ( ) and the excess-dose
group ( ). Initial rhubarb dose and current rhubarb dose are
shown. (a: p = 0.179, b: p = 0.028)

Study between excess-dose users and regular-dose users
375
Table 1. Background and clinical features in the regular-dose group and the excess-dose group.
Regular dose
(N = 15)
Excess dose
(N = 13)
Total
(N = 28)
Pvalue
Clinical feature
number of users with events (%)
Age
Sex
49.1
0
51.3
2 (15.4%)
50.1
2
0.692
male
female
15 (100%)
8 (53.3%)
7.9
11 (84.6%)
8 (61.5%)
10.6
26
16
9.2
34.9
13
13
17
6
9
9
12
7
Past stimulant laxative-use
Duration of stimulant laxative-use (years)
Duration of rhubarb use (months)
Stimulant pain
Small and hard stool
Abdominal fullness
0.662
0.563
0.227
<0.001
0.431
0.489
0.262
0.505
0.945
30.5
39.9
12 (80.0%)
8 (53.3%)
10 (66.7%)
2 (13.3%)
4 (26.7%)
4
1 (7.7%)
5 (38.5%)
7 (53.8%)
4 (7.7%)
5 (38.5%)
5
Accelerated bowel movement
Increased abdominal gas
"Abdominal tension"
excess
balanced
reduced
8
3
4
4
"
"
Umbilical region tenderness on pressure"
Lower abdominal tenderness on pressure"
14 (93.3%)
2 (13.3%)
4 (26.7%)
8 (61.5%)
3 (23.1%)
4 (30.8%)
22
5
8
0.041
0.502
0.811
Hemorrhoids
prescription of rhubarb until the study period, in sharp bined herbs may cooperatively affect patients with con-
contrast to the regular dose group (Figures 1, 2). stipation. Some herbs may act as wetting laxatives and
No significant difference was shown between the some as osmotic laxatives, and rhubarb acts as a stimu-
two groups in terms of age, duration of stimulant laxa- lant laxative. For example, Toukaku-johki-to (Tao he
tive-use before the first prescription of rhubarb, dura- cheng qi tang) used to treat some patients in this study
tion of rhubarb-use in our hospital, shape of stool contains Tonin (Persicae semen), Keihi (Cinnamomi
(
small and hard stool or not), abdominal symptoms, or cortex), Bosho (Natrium sulfuricum), Kanzo (Gly-
existence of hemorrhoids (Table 1). Only two factors, cyrrhizae radix) and rhubarb. Bosho, Na SO , is an os-
2
4
“
initial stimulant pain” and “umbilical region tender- motic agent. Tonin and Kanzo may affect like wetting
ness on pressure” were significantly different between agents (Terasawa, 1993). As a result of the cooperative
the two groups. Most patients in the regular-dose group effects, Kampo medicines containing rhubarb may not
had initial stimulant pain of the abdomen upon taking necessarily cause deteriorated reactivity to themselves,
stimulant laxatives for the first time, but most patients as shown in the regular-dose group. In this study, we
in the excess-dose group did not (p < 0.001). All pa- should consider effects of other component herbs in
tients except one in the regular dose group had the sign Kampo medicines except rhubarb. Toukaku-johki-to
of “umbilical region tenderness on pressure”, but half was administered to about half patients both in the reg-
of the excess-dose group did not have (p = 0.041).
ular-dose group and in the excess-dose group, and
other Kampo medicines administered to the regular-
dose group were similar to those administered to the
excess-dose group. Therefore, other component herbs
except rhubarb may not have caused the difference in
ꢀ
Discussion
In the field of “Western“ medicine, the long-term use rhubarb dose between the two groups.
of stimulant laxatives is discouraged (Friedman and Is-
In contrast to the regular-dose group, the rhubarb-
selbacher, 1994). In the field of Kampo medicine, dose in the excess-dose group significantly increased
rhubarb-containing medicines are sometimes used for a during the period from the first prescription of rhubarb
long time. This discrepancy between the two fields of until the study period. The initial rhubarb-dose in
medicine led us to this study.
Kampo extracts and Kampo formulae was higher in the
Kampo medicines containing rhubarb were used excess-dose group than that in the regular-dose group.
within the recommended dose range in half of the en- This difference in the initial dose may not have affected
rolled patients even with prolonged use. Kampo the subsequent course of the rhubarb-dose, because the
medicines are composed of several herbs, and the com- subsequent rhubarb-dose in the excess-dose group in-

3
76
N. Mantani et al.
creased greatly even in patients started with low-dose increased intestinal motility. Therefore, the symptom
rhubarb. Half of the patients in the excess-dose group “initial stimulant pain” may be related to the sign “um-
had taken high-dose stimulant laxatives before the first bilical region tenderness on pressure” to some degree.
prescription of rhubarb, therefore, some initial condi-
tions of the patients in the excess-dose group may have absence of “initial stimulant pain” and the absence of
caused the increasing use of rhubarb.
“umbilical region tenderness on pressure” may predict
In any case, based on the findings of this study, the
In this study, the absence of “initial stimulant pain” increasing or excess use of rhubarb, and long-term use
was predictive of the increasing use of rhubarb. Pa- of rhubarb should be more strongly discouraged in pa-
tients who experienced stimulant pain may have con- tients without these signs. Although no physiological
trolled laxative-use by themselves, and Kampo doctors studies (e.g. colonic transit time, cinedefecography,
may have been reluctant to increase the rhubarb-dose anal manometry, anal electromyography, etc.) were
for these patients. However, the absence of “initial performed in the present study, these findings may
stimulant pain” may be related to some specific and in- offer useful suggestion on long-term rhubarb use in
trinsic condition of the intestine, for example, potential daily practice. To optimize the use of rhubarb, further
neuronal dysfunction of the intestine. Excess-dose type experimental studies of the mechanism of anthranoids’
patients seems to be insensitive to the stimulation of effects and a larger population study to confirm the
the intestine by rhubarb, whereas regular-dose type pa- findings made in this study are warranted.
tients seems to be sensitive to it. We can adopt another
hypothesis that the proportion of some intestinal bacte-
ria have affected the increase of rhubarb dose. A previ-
ous study demonstrated that the laxative potential of
sennoside A, B is influenced by the particular bacteria
in the large intestine of each individual (Akao et al.,
ꢀ
References
Akao T, Che OM, Kobashi K, Yang L, Hattori M, Namba T
(1994) Isolation of a human intestinal anaerobe Bifidobac-
terium sp. -Strain SEN, capable of hydrolyzing Sennidins.
Appl Environ Microbiol 60: 1041–1043
1
994; Takada et al., 1998).
Patients’ complaints are usually highly valued in
Friedman LS, Isselbacher KJ (1994) Diarrhea and constipa-
tion. In: Isselbacher,K.J., Braunwald, E., Wilson, J.D.,
Martin, J.B., Fauci, A.S., Kasper, D.L., eds. Harrison’s
principles of internal medicine. 13 th ed. New York: Mc-
Graw-Hill
Guang JY(2001) The mode of thinking in Chinese clinical
medicine: characteristics, steps, and forms. Clinical
Acupuncture and Oriental Medicine 2: 23–28
Kampo diagnosis and treatment (Tarasawa, 1993;
Guang, 2001); therefore, rhubarb-use is likely to be
perceived as unsuitable for patients with stimulant pain
caused by rhubarb. However, this study revealed that
the use of rhubarb in the patients with stimulant pain
did not increase even after long-term use, suggesting
that rhubarb-use may be more suitable for patients with
stimulant pain than for patients without it.
Ikeda M (1992) Constipation. Diagnosis & Treatment 80
Suppl: 144–146
Another factor, the sign of “umbilical region tender-
ness on pressure” was absent in half of the patients of Mikage M (1996) Studies of Rhei Rhizoma. Jp J Orient Med
the excess-dose group. According to the Kampo theory,
the sign of “umbilical region tenderness on pressure” is
a sign of the “Oketsu” syndrome (syndrome caused by
blood stagnation) (Terasawa, 1993). Long ago, rhubarb
was originally used as an agent to treat “Oketsu” syn-
drome (Mikage, 1996). Thus, “umbilical region tender-
ness on pressure” is an indication for the use of
rhubarb-containing Kampo medicines in the view of
Kampo medicine. The significant difference we ob-
served between the two groups in terms of “umbilical
region tenderness on pressure” may be related to these
Kampo theories.
47: 411–418
Siegers CP (1992) Anthranoid laxatives and colorectal can-
cer. Tips 13: 229–231
Takada M (1998) Relation of human intestinal flora and
SHO: efficiency and differences among individuals. Prog.
Med. 18: 759–767, (In Japanese with English abstract)
Terasawa K (1993) Kampo (Japanese-Oriental) medicine,
First ed. Tokyo: K K Standerd McIntyre
ꢀ
Address
Other hypotheses can be proposed : 1) in patients N. Mantani M.D., Ph.D., Department of Japanese Ori-
with stimulant pain, a low threshold of pain may affect ental Medicine , Faculty of Medicine, Toyama Medical
the presence of “umbilical region tenderness on pres- and Pharmaceutical University, 2630 Sugitani, Toyama
sure”, 2) if the phenomenon of “umbilical region ten- 930-0194, Japan
derness on pressure” is caused by intra-lumenal stagna- Tel: ++81-76-434-7393; Fax: ++81-76-434-0336;
tion, stimulant laxatives may cause such pain through e-mail: nmantani@showa.gunma-u.ac.jp