ReviewArticle - Hindawi Publishing CorporationKo Nishimura, 1 YoshihiroImazu,1 HeidrunReissenweber,3 andClaudiaM.Witt2 1 CenterforKampo Medicine, Keio University Schoolof Medicine,Shinjuku-ku,

Hindawi Publishing CorporationEvidence-Based Complementary and Alternative MedicineVolume 2011, Article ID 513842, 19 pagesdoi:10.1093/ecam/neq067

Review Article

Traditional Japanese Kampo Medicine: Clinical Researchbetween Modernity and Traditional Medicine—The State ofResearch and Methodological Suggestions for the Future

Kenji Watanabe,1 Keiko Matsuura,1 Pengfei Gao,1 Lydia Hottenbacher,2 Hideaki Tokunaga,1

Ko Nishimura,1 Yoshihiro Imazu,1 Heidrun Reissenweber,3 and Claudia M. Witt2

1 Center for Kampo Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan2 Institute for Social Medicine, Epidemiology and Health Economics, Charité University Medical Center, 10098 Berlin, Germany3 Research Unit for Japanese Phytotherapy (Kampo), Department of Internal Medicine, University of Munich, Munich, Germany

Correspondence should be addressed to Claudia M. Witt, [email protected]

Received 12 October 2009; Accepted 13 May 2010

Copyright © 2011 Kenji Watanabe et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

The Japanese traditional herbal medicine, Kampo, has gradually reemerged and 148 different formulations (mainly herbal extracts)can be prescribed within the national health insurance system. The objective of this article is to introduce Kampo and to presentinformation from previous clinical studies that tested Kampo formulae. In addition, suggestions on the design of future researchwill be stated. The literature search was based on a summary, up until January 2009, by the Japanese Society of Oriental Medicineand included only those trials which were also available in either Pubmed or ICHUSHI (Japan Medical Abstracts Society). Weincluded 135 studies, half of these studies (n = 68) used a standard control and 28 a placebo control. Thirty-seven trials werepublished in English [all randomized controlled trials (RCTs)] and the remaining articles were in Japanese only. The sample size formost studies was small (two-third of the studies included less than 100 patients) and the overall methodological quality appeared tobe low. None of the studies used Kampo diagnosis as the basis for the treatment. In order to evaluate Kampo as a whole treatmentsystem, certain aspects should be taken into account while designing studies. RCTs are the appropriate study design to test efficacyor effectiveness; however, within the trial the treatment could be individualized according to the Kampo diagnosis. Kampo is acomplex and individualized treatment with a long tradition, and it would be appropriate for further research on Kampo medicineto take this into account.

1. Background

1.1. Historical Background. Japanese traditional herbalmedicine (Kampo medicine) obtained the unique featuresobserved today during its phase of long historical develop-ment in Japan. In Japan, the administration of crude herbaldrug formulations dates back by more than 1500 years.Recent decades have seen a revival of Kampo medicine inmedical practice, accompanied by a scientific reevaluationand critical examination of its relevance in modern healthcare [1].

The term “Kampo”, which literally means “method fromthe Han period (206 BC to 220 AD) of ancient China”,refers to its origin from ancient China. The basic therapeutichandbook for the application of herbal prescriptions was

the Shang han lun. During the Edo-period from 1600onwards, the specific Japanese characteristics of Kampotook shape. The seclusion of Japan from the outside worldled to ever increasing differences from the predominantlyChinese concepts. The huge variety of the thousands ofChinese crude drugs was reduced to ∼300, those being themost efficacious drugs which were subsequently combinedinto ∼300 prescriptions. From a pragmatic point of view,Japanese physicians criticized the highly theoretical andspeculative nature of Chinese medicine as being inadequateto meet the problems of every-day practice. The strongestcritique came from Yoshimasu Todo in the 18th centurywho wrote: “In clinical medicine, we should only rely onwhat we actually have observed by examination of thepatient”. For Yoshimasu Todo, one way to gain data on

2 Evidence-Based Complementary and Alternative Medicine

the condition of the body was to examine the abdomen, forwhich he developed a refined palpation technique (fukushin)[2]. The results of the abdominal palpation should giveadditional clinical information in order to select the mostappropriate herbal prescription for the patient. YoshimasuTodo’s pragmatic attitude and his abdominal palpation as adiagnostic procedure has had a strong influence on Kampotherapy right up until the present day [3].

It is not surprising that many Japanese physicians weredrawn towards medical techniques from the West to improvetheir therapeutic options in surgery, but most of them con-tinued to use traditional Kampo prescriptions for treatingproblems of internal medicine until the 19th century. Atthe end of the 19th century, it became obvious that for theurgent medical problems of that time, infectious diseases andacute surgical problems, Western medicine had better tools.The German system of medical education was adopted. In1876, the government passed a regulation that all physicianswere required to study Western medicine. The practice ofKampo was not forbidden but greatly inhibited and graduallydeclined [4]. However, after the Second World War, thefirst modern Kampo specialists carried on the traditionsfrom the Edo-period. This revival of Kampo took placewithin a context dominated by modern Western medicine.The pragmatic and reductive approach of restricting Kampotherapy to clinically meaningful components helped tofacilitate its gradual integration into modern medicine.Modern industrial society, in combination with longer lifeexpectancy, has caused a shift in the predominant diseasepatterns, bringing to the therapeutic forefront chronicand degenerative diseases, functional and psychosomaticdisorders and the multimorbidity of the elderly. Theseprovide the main indications for the use of herbal drugs,not only with respect to treatment, but also for prevention[5].

Although rooted in Chinese tradition, Kampo medicineis not the same as modern traditional Chinese medicine(TCM). TCM emphasizes the traditional concepts of EastAsian natural philosophy, such as Yin and Yang and the the-ory of the five elements. Japanese Kampo favors diagnosticmethods that directly relate the symptoms to the therapy,bypassing speculative concepts. The vast array of crude drugshas been reduced in Kampo and also the quantity of eachdrug in the formulation is much lower. While Kampo stilluses traditional prescriptions, TCM also tends to create newdrug combinations [6].

1.2. Usage and Integration into Modern Medicine. Kampotraditional prescriptions have been included in the JapaneseNational Health Insurance drug list since 1971. A totalof 148 Kampo herbal prescriptions are able to be fundedto date. The application of Kampo has steadily increasedand according to a survey by the Journal Nikkei Medical,more than 70% of physicians prescribe Kampo drugs today[7]. The Japan Society for Oriental Medicine is the biggestsociety for Kampo medicine and has 8600 members and2600 certified board members. In 2001, Kampo educationfor medical students was incorporated into ‘the model core

curriculum’ by the Japanese Ministry of Education, Culture,Sports, Science and Technology [6].

The development of modern ready-to-use forms wasdirectly related to the enormous increase in Kampo usage,mainly as spray-dried granular extracts of the originalformulae. They have increasingly replaced the traditionaldecoction of the crude drugs, even though they are alsocovered by the national insurance system. Besides beingsimple to administer, industrial production has enabledseveral other advantages. The quality control of the purityas well as toxicity is standardized in Japan, followingthe Japanese pharmacopoeia and internationally establishedregulations for Good Manufacturing Practice (GMP) andGood Laboratory Practice (GLP). The standardization ofthe main components has become possible and this is aprecondition of clinical research. Today, extract preparationsmake up to 95% of the Japanese Kampo market.

In Western countries, herbal therapies originating inother cultural areas, mainly Chinese herbal medicine aspart of TCM, are receiving increasing interest. In theUSA, TCM is still far more visible than Kampo. Thepractitioners practice herbal therapy often in combinationwith acupuncture, which is often a mixture of Chinese,Japanese and Korean acupuncture styles. Kampo drugs areonly available over the counter, meeting Japanese GMPcriteria. Since Japanese pharmaceutical companies havestarted clinical trials in the USA, several drugs have alreadybeen registered as investigational new drugs (IND) by theFood and Drug Administration. Safety and toxicity datafrom Japan are generally accepted by the US and Europeanagencies.

In Europe, especially in Germany, there is a long-termtradition of herbal medicine, and there is growing interestin Chinese phytotherapy and Japanese Kampo is also gettingmore and more attention. However, there is a shortage ofdoctors specialized in Japanese Kampo.

1.3. Background of Kampo. Kampo is an individualizedtreatment system where the overall condition of the patientand their constitution are of real importance; additionally,Kampo has a holistic therapeutic approach, as the mindand body are seen as one entity. The therapeutic aim isto relieve symptoms and to restore harmony in bodilyfunctions. The treatment regime is based on symptoms. Forthe determination of the appropriate herbal prescription, thephysician carries out a thorough investigation of the com-plaints and symptoms of the patient, including taking theirtemperature, examining sensation, weakness or sweating,symptoms which are not often primarily taken into accountin conventional medicine. The physical examination includesabdominal palpation, tongue inspection and pulse diagnosis.This provides additional information concerning the stateof the disease, by gathering the amount and distribution ofki (vital energy), ketsu (blood) and sui (body fluid). Thesubjective complaints and the symptoms observed by thephysician are combined to an individual symptom profile, aKampo diagnosis (sho), which leads to the selection of theappropriate prescription [8]. It may happen that patients

Evidence-Based Complementary and Alternative Medicine 3

Table 1: Summary of Kampo clinical studies (1987–2007).

RCT Quasi-RCT Cross-over designComparative study(non-randomized)

Total

Kampo versus either notreatment or a differentKampo formula

31 1 4 3 39

Kampo versus placebo 22 0 2 4 28

Kampo versus standardtreatment

53 5 4 6 68

Total 106 6 10 13 135

with the same conventional diagnosis obtain different pre-scriptions (same diagnosis but different treatments), orpatients with different conventional diagnoses are prescribedthe same formula (same treatment for different diagnoses).

Japanese physicians with limited education in Kampodiagnostics tend to apply the formulations according toconventional Western diagnoses. This makes sense for somelimited indications, if the formula for the Kampo sho is closeto the conventional diagnosis. However, in most cases, thetraditional individual approach, where each patient receivestheir appropriate prescription, is the preferred option. Forexample, diseases that are expected to respond to the formulaKakkonto are diagnosed as Kakkonto-sho and it naturallyfollows that Kakkonto is prescribed in such cases.

These special conditions have made clinical research inthe field of Kampo medicine more complex than the researchon conventional drugs. The World Health Organization WestPacific Regional Office (WHO/WPRO) has put considerableefforts into standardizing East Asian traditional medicine[9]. WHO headquarters is considering incorporating theinternational classification of Traditional Medicine, East Asia(ICTM EA) into International Classification of Diseases(ICD)-11. ICD-11 is planned to be finalized in 2014 andscheduled to be approved by the WHO assembly in 2015.Japan proposes a double coding system of the ICD codes,that is, the conventional diagnosis code together with thetraditional diagnosis (or pattern) code. This will allowintegration into the conventional medical system withoutloosing the traditional information. The Kampo pattern(sho) codes have already been published in Japanese [10].

2. Information Available on Clinical Research

Our search was based on an evidence report of Kampotreatment made by the Japanese Society of Oriental Medicine(JSOM) which included 320 clinical trials between 1986 and2008. [11]. This report includes Kampo trials available in theCochrane register [12], ICHUSHI (Japan Medical AbstractsSociety) [13] and the database from the Japan KampoMedicines Manufacturer Association [14]. In this reviewonly those studies were included, which used granulateformulations and were based on the drug regulation thatwas introduced in 1986. Liquid formulations and decoctionswere excluded. Only peer-reviewed research from the JSOMdatabase were included, which were also available in PubMed[15] or ICHUSHI [13]. A total of 135 trials, published

between 1988 and 2007, were identified and summarizedTable 1. These publications were extracted by two researchersfluent in both English and Japanese. Subsequently, they werediscussed with two senior researchers (a Kampo specialistfrom Japan and a research methodologist from Germany).We classified Kampo clinical studies into three categories(Tables 2, 3, and 4):

(i) Kampo compared with either no treatment or differ-ent Kampo formula.

(ii) Kampo compared with placebo.

(iii) Kampo compared with standard treatment.

Among the 135 clinical studies, 106 were randomizedcontrolled trials (RCTs), 6 quasi-RCTs and 10 were cross-over studies. There were 13 non-randomized comparativestudies. Among the 106 RCTs, 23 studies were placebo-controlled. More than two thirds of the studies used onlyKampo as verum, whereas in 38 studies, Kampo was usedin addition to the standard treatment. Almost half of thestudies (n = 68) used a standard control, 28 used a placebocontrol, 24 had no treatment control and in 15, anotherKampo formula was used as a control Table 1.

The sample size varied between 4 patients in the smalleststudy and 2069 patients in the largest. Most of the studieswere small. Two thirds included less than 100 patientsand the overall quality was low. Thirty-five trials werepublished in English and the remaining studies were inJapanese. The spectrum of diagnoses was diverse. The mostcommon diagnosis was asthma (ICD J 45.0 and J 45.9),which was evaluated in nine studies. Many of the trials hadlow methodological quality (small sample size and unclearconcealment) and thus a publication bias is to be expected.With respect to the methodology, it is interesting to notethat in all studies summarized here, the treatment was basedon the Western diagnosis only. A Kampo diagnosis was notmentioned in any of the trials. However, one trial seemedto be more individually based, using seven different Kampoformula in the verum group [134].

3. Suggestions for Future Research

3.1. Relevant Research Questions. The research availablefollowed a Western approach and concentrated on singleWestern diagnoses treated with one Kampo formula. SinceKampo is a comprehensive and complex treatment system


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och

uek

kito

Hio

kiet

al.(

2004

)[5

5]E

E66

.9(o

besi

ty)

RC

T81

RD

B2

KP

bofu

tsu

shos

an

Suzu

kiet

al.(

2005

)[5

6]E

F03

(dem

enti

a)R

CT

30R

DB

3K

Pgo

shaj

inki

gan

,ch

otos

an

Iwas

akie

tal

.(20

04)

[57]

EF0

3(d

emen

tia)

RC

T33

RD

B2

KP

hac

him

ijiog

an

Nag

akie

tal

.(20

03)

[58]

EH

16.1

(ker

atit

is)

RC

T75

RD

B3

KP

gosh

ajin

kiga

n

Ara

kaw

aet

al.(

2006

)[5

9]E

I10

(ess

enti

alhy

pert

ensi

on)

RC

T20

4R

DB

2K

Por

enge

doku

to

Nak

amu

raet

al.(

2000

)[6

0]J

I95.

1(O

rth

osta

tic

hypo

ten

sion

)

RC

T-

cros

sov

er10

RSB

2K

Pgo

reis

an

Kaj

iet

al.(

2001

)[6

1]J

J00

(acu

ten

asop

har

yngi

tis)

RC

T25

0R

DB

2K

Psh

osai

koto

Bab

a(1

995)

[62]

JJ3

0.4

(alle

rgic

rhin

itis

)R

CT

217

ED

B2

KP

shos

eiry

uto

Miy

amot

oet

al.(

2001

)[6

3]J

J40

(bro

nch

itis

)R

CT

192

RD

B2

KP

shos

eiry

uto

Ura

taet

al.(

2002

)[6

4]E

J45.

0(b

ron

chia

last

hm

a)R

CT

-cr

oss

over

33R

DB

2K

Psa

ibok

uto

Nis

hiz

awa

etal

.(20

01)

[65]

JJ4

5.0

(bro

nch

iala

sth

ma)

RC

T32

RD

B2

KP

Saib

oku

toin

hal

atio

n

Nis

hiz

awa

etal

.(20

01)

[66]

JJ4

5.0

(bro

nch

iala

sth

ma)

RC

T74

RD

B2

KP

Saib

oku

toin

hal

atio

n

Iwas

akie

tal

.(20

07)

[67]

EJ6

9.0

(pn

eum

onit

is)

RC

T95

RD

B2

KP

han

gen

kou

boku

to

Har

asaw

aet

al.(

1998

)[6

8]J

K31

.9(d

ysm

otili

ty-l

ike

dysp

epsi

a)R

CT

296

RD

B2

KP

rikk

un

shit

o

Sasa

kiet

al.(

1998

)[6

9]J

K58

(irr

itab

lebo

wel

syn

drom

e)R

CT

204

ED

B2

KP

keis

hik

ash

akuy

aku

to

Miy

osh

iet

al.(

1994

)[7

0]J

K59

.0(c

onst

ipat

ion

)R

CT

146

ED

B3

KP

daio

kan

zoto

Itoh

etal

.(20

02)

[71]

EK

91.3

(pos

t-op

erat

ive

ileu

s)R

CT

24R

SB2

KP

daik

ench

uto

Taka

gaki

etal

.(20

00)

[72]

JK

91.3

(par

alyt

icile

us)

RC

T21

RSB

2K

Pda

iken

chu

to

Nis

hiz

awa

etal

.(20

04)

[73]

E/J

M35

.0(S

icca

syn

drom

e)R

CT

229

RD

B2

KP

baku

mon

doto

Aok

iet

al.(

2001

)[7

4]E

N39

.9(u

rody

nam

icst

udi

es)

RC

T-

cros

sov

er19

RSB

2K

Pm

aobu

shis

aish

into


Ta

ble

3:C

onti

nu

ed.

Au

thor

(Yea

r)(N

)R

efer

ence

Lan

guag

eIC

D10

code

(dis

ease

nam

e)D

esig

nC

ases

(N)

Ran

dom

izat

ion

Blin

din

gG

rou

ps(N

)In

terv

enti

onC

ontr

olK

ampo

trea

tmen

t

Ku

mad

aet

al.(

1999

)[7

5]J

R25

.2(m

usc

lecr

amps

)R

CT

126

RD

B2

KP

shak

uyak

uka

nzo

to

Oda

guch

iet

al.(

2006

)[7

6]E

/JR

51(h

eada

che)

RC

T53

RD

B2

KP

gosh

uyu

to

Sato

het

al.(

2005

)[7

7]E

R54

(sen

ilem

usc

lew

eekn

ess)

RC

T13

RD

B3

KP

hoc

hu

ekki

to

Ham

azak

iet

al.(

2007

)[7

8]E

Z01

.8(a

djuv

ant

effec

tto

vacc

inat

ion

)R

CT

36R

DB

2K

Ph

och

uek

kito

Taka

has

hie

tal

.(20

07)

[79]

EZ

01.8

(ser

um

amin

oac

idco

nce

ntr

atio

n)

RC

T-

cros

sov

er18

RSB

3K

Pro

kum

igan

Saru

wat

arie

tal

.(20

04)

[80]

EZ

01.8

(CO

PD

)R

CT

-cr

oss

over

26R

DB

2K

Pba

kum

ondo

to

Isob

eet

al.(

2003

)[8

1]E

Z01

.9(r

etin

albl

ood

flow

)

RC

T-

cros

sov

er12

RD

B2

KP

hac

him

ijiog

an

J:Ja

pan

ese;

E:

En

glis

h;R

:ra

ndo

miz

atio

n;

E:

enve

lops

;D

B:

dou

ble

blin

d;SB

:si

ngl

ebl

ind;

K:

Kam

po;

SK:

Stan

dard

+K

ampo

;S:

Stan

dard

;N

T:

no

trea

tmen

t;P

:pl

aceb

o;IC

D:

Inte

rnat

ion

alC

lass

ifica

tion

ofD

isea

ses,

Kam

potr

eatm

ent

incl

ude

son

lyfo

rmu

lae

prod

uce

daf

ter

1986

,IC

Dco

des

deta

ilsht

tp:/

/app

s.w

ho.in

t/cl

assi

fica

tion

s/ap

ps/i

cd/i

cd10

onlin

e/,

dosa

geof

the

Kam

pofo

rmu

lae

http

://w

ww

.jsom

.or.

jp/m

edic

al/e

bm/i

nde

x.ht

ml.


Ta

ble

4:K

ampo

clin

ical

stu

dies

com

pari

ng

Kam

pow

ith

stan

dard

trea

tmen

t.

Au

thor

(Yea

r)R

efer

ence

Lan

guag

eIC

D10

(dis

ease

)D

esig

nC

ases

(N)

Ran

dom

izat

ion

Blin

din

gG

rou

ps(N

)In

terv

enti

onC

ontr

olK

ampo

trea

tmen

t

Sasa

kiet

al.(

2006

)[8

2]J

C18

.9(g

astr

oen

teri

cca

nce

r)R

CT

168

No

No

2SK

S,K

juze

nta

ihot

o

Sasa

kiet

al.(

2007

)[8

3]J

C18

.9(c

ance

rch

emot

her

apy)

RC

T16

8N

oN

o2

SKS,

Kju

zen

taih

oto

Ada

chi(

1988

)[8

4]J

C50

.9(a

dvan

ced

brea

stca

nce

r)R

CT

74E

No

2SK

Sju

zen

taih

oto

Yam

amot

oet

al.(

2003

)[8

5]J

D25

.9(u

teri

ne

aden

omyo

sis)

RC

T24

RN

o2

SKS

keis

hib

uku

ryog

an

Aka

seet

al.(

2003

)[8

6]J

D50

.0(a

nem

iadu

eto

ute

rin

em

yom

a)R

CT

25R

No

2K

Sto

kish

akuy

aku

san

Aoe

(200

7)[8

7]J

D50

.8(i

ron

defi

cien

cyan

emia

)R

CT

120

RN

o3

SKS

juze

nta

ihot

o

Yan

agib

orie

tal

.(19

95)

[88]

JD

50.9

(Iro

nde

fici

ency

anem

ia,)

RC

T39

ESB

2SK

Sn

injin

yoei

to

Aoe

etal

.(20

00)

[89]

JD

62(a

cute

post

hae

mor

rhag

ican

emia

)R

CT

57R

No

2SK

Sju

zen

taih

oto

Aoe

etal

.(19

99)

[90]

JD

62(a

cute

post

hae

mor

rhag

ican

emia

)R

CT

90R

No

3SK

Sju

zen

taih

oto,

nin

jinyo

eito

Azu

ma

etal

.(19

94)

[91]

JE

10-E

14(n

on-i

nsu

lin-d

epen

den

tdi

abet

esm

ellit

us)

RC

T18

EN

o2

SKS

seis

hin

ren

shii

n

Yam

ano

etal

.(19

95)

[92]

JE

78.5

(hyp

erlip

idae

mia

)R

CT

92E

No

3SK

S,N

Tda

isai

koto

Sasa

kiet

al.(

1991

)[9

3]J

E78

.5(h

yper

lipid

aem

ia)

RC

T40

RN

o3

SKS

dais

aiko

to

Ish

ida

etal

.(19

99)

[94]

JF4

1.9

(an

xiet

ydi

sord

er,

un

spec

ified

)R

CT

15R

No

2SK

Ssa

ibok

uto

Yam

agiw

aan

dFu

jita

(200

7)[9

5]J

F45.

3(a

bnom

alse

nsa

tion

)qu

asi-

RC

T86

RN

o2

KS

rikk

un

shit

o

Mar

uyam

a(2

006)

[96]

JG

43.9

(mig

rain

e,u

nsp

ecifi

ed)

RC

T-

cros

sov

er28

RN

o2

KS

gosh

uyu

to

Kim

ura

etal

.(19

91)

[97]

JG

51.3

(fac

ials

pasm

)R

CT

20R

No

2SK

Ssh

akuy

aku

kan

zoto

Seki

ne

etal

.(20

03)

[98]

JG

54.4

(lu

mbo

sacr

alro

otdi

sord

ers)

RC

T-

cros

sov

er20

RN

o2

KS

gosh

ajin

kiga

n

Inou

e(2

001)

[99]

JH

65.0

(acu

tese

rou

sot

itis

med

ia)

Cas

eC

ontr

ol34

No

No

2K

Ssh

osei

ryu

to,

eppi

kaju

tsu

to

Mat

sush

ita

etal

.(19

95)

[100

]J

I67.

9,I6

7.8,

I10

(cer

ebro

vasc

ula

rdi

seas

e,hy

pert

ensi

on)

RC

T22

EN

o2

KS

chot

osn

Aki

yam

aet

al.(

2001

)[1

01]

JI7

3.0

(ray

nau

d’s

syn

drom

e)C

ase

Con

trol

49N

oN

o2

SKS

toki

shak

uyak

usa

n,

oren

gedo

kuto


Ta

ble

4:C

onti

nu

ed.

Au

thor

(Yea

r)R

efer

ence

Lan

guag

eIC

D10

(dis

ease

)D

esig

nC

ases

(N)

Ran

dom

izat

ion

Blin

din

gG

rou

ps(N

)In

terv

enti

onC

ontr

olK

ampo

trea

tmen

t

Fujim

orie

tal

.(20

01)

[102

]J

J00

(pos

tin

fect

ion

sco

ugh

)R

CT

25R

No

2K

Sba

kum

ondo

to

Kim

oto

and

Ku

roki

(200

5)[1

03]

JJ1

0(i

nfl

uen

za)

Cas

eC

ontr

ol19

No

No

2SK

Sm

aoto

Ku

boet

al.(

2007

)[1

04]

EJ1

0.1

(typ

eA

infl

uen

zain

fect

ion

)qu

asi-

RC

T37

No

No

2SK

Sm

aoto

Kat

oet

al.(

2005

)[1

05]

JJ4

4.9

(ch

ron

icob

stru

ctiv

epu

lmon

ary

dise

ase)

RC

T31

EN

o2

SKS

seih

aito

Tats

um

iet

al.(

2009

)[1

06]

EJ4

4.9

(ch

ron

icob

stru

ctiv

epu

lmon

ary

dise

ase)

RC

T71

EN

o2

KS

hoc

hu

ekki

to

Nis

hiz

awa

etal

.(20

04)

[107

]J

J45.

0(b

ron

chia

last

hm

a)R

CT

161

RN

o2

KS

shin

bito

inh

alat

ion

Nis

hiz

awa

etal

.(20

03)

[108

]J

J45.

0(b

ron

chia

last

hm

a)R

CT

114

RN

o2

KS

shin

bito

inh

alat

ion

Nis

hiz

awa

etal

.(20

02)

[109

]J

J45.

0(b

ron

chia

last

hm

a)R

CT

107

RN

o2

KS

saib

oku

to

Nis

hiz

awa

etal

.(20

02)

[110

]J

J45.

0(b

ron

chia

last

hm

a)R

CT

94R

No

2K

Ssa

ibok

uto

inh

alat

ion

Ega

shir

aan

dN

agan

o(1

993)

[111

]E

J45.

9(b

ron

chia

last

hm

a)R

CT

112

ESB

2SK

Ssa

ibok

uto

Mik

amo

etal

.(20

07)

[112

]J

J98.

9(r

espi

rato

ryin

fect

ion

)R

CT

116

No

No

3SK

Sju

mih

aido

kuto

,kak

koto

,ke

ish

ito,

koso

san

,sh

osai

koto

,hoc

hu

ekki

to

Um

emot

oet

al.(

2007

)[1

13]

JK

11.7

(dry

mou

th)

RC

T10

0N

oN

o3

KS

baku

mon

doto

Yam

ada

etal

.(19

98)

[114

]J

K14

.6(g

loss

odyn

ia)

RC

T10

4R

No

2K

Ssa

ibok

uto

Kat

oet

al.(

2005

)[1

15]

JK

21.0

(gas

tro-

oeso

phag

eal

refl

ux

dise

ase

wit

hoe

soph

agit

is)

RC

T19

EN

o2

SKS

han

geko

boku

to

Koi

de(2

006)

[116

]J

K21

.9(g

astr

o-oe

soph

agea

lre

flu

xdi

seas

ew

ith

out

oeso

phag

itis

)R

CT

118

No

No

3SK

,KS,

Kri

kku

nsh

ito

Hig

uch

iet

al.(

1999

)[1

17]

EK

26.9

(Hel

icob

acte

rpy

lori

)R

CT

63R

No

2SK

Sgo

shuy

uto

Yam

agu

chia

nd

Koi

de(2

007)

[118

]J

K30

(dys

peps

ia)

RC

T12

0E

No

3K

Sri

kku

nsh

ito

Nis

hiz

awa

etal

.(20

04)

[119

]J

K59

.0(c

onst

ipat

ion

)R

CT

318

RN

o2

SKS

kum

ibin

roto

Nak

ajim

aet

al.(

2003

)[1

20]

JK

73.9

(ch

ron

ich

epat

itis

)R

CT

100

EN

o3

KS,

Ksh

osai

koto

Nak

ajim

aet

al.(

1999

)[1

21]

JK

73.9

(ch

ron

ich

epat

itis

)R

CT

99R

No

2SK

Ssh

osai

koto


Ta

ble

4:C

onti

nu

ed.

Au

thor

(Yea

r)R

efer

ence

Lan

guag

eIC

D10

(dis

ease

)D

esig

nC

ases

(N)

Ran

dom

izat

ion

Blin

din

gG

rou

ps(N

)In

terv

enti

onC

ontr

olK

ampo

trea

tmen

t

Tara

o(2

007)

[122

]J

K73

.9(c

hro

nic

hep

atit

is)

RC

T15

6N

oN

o2

KK

shos

aiko

to,j

uze

nta

ihot

o

Oku

ma

(199

3)[1

23]

JL

70.0

(cn

evu

lgar

is)

RC

T26

8R

No

5K

S,K

jum

ihai

doku

to,

oren

gedo

kuto

Nis

hiz

awa

etal

.(20

04)

[124

]J

M35

.0(s

icca

syn

drom

e)R

CT

847

RN

o2

KS

baku

mon

doto

Nis

hiz

awa

etal

.(20

03)

[125

]J

M35

.0(S

icca

syn

drom

e)R

CT

756

RN

o2

KS

baku

mon

doto

Nis

hiz

awa

etal

.(20

02)

[126

]J

M35

.0(S

icca

syn

drom

e)R

CT

105

CN

o2

KS

baku

mon

doto

Hay

ash

iet

al.(

1994

)[1

27]

JM

48.0

(spi

nal

sten

osis

)Q

uas

i-R

CT

27R

No

2K

Sh

ach

imiji

ogan

Mae

jima

and

Kat

ayam

a(2

004)

[128

]J

M48

.02

(ch

ron

iclu

mba

rpa

in)

RC

T89

RN

o3

KS,

Kgo

shaj

inki

gan

,sh

uch

ibu

shim

atsu

Nis

hiz

awa

etal

.(20

07)

[129

]J

N32

.8(o

vera

ctiv

ebl

adde

r)R

CT

704

No

No

2K

Sgo

shaj

inki

gan

Iwab

uch

i(20

00)

[130

]J

N93

.9(d

ysfu

nct

ion

alu

teri

ne

blee

din

g)C

ase

Con

trol

183

No

No

2K

Sky

uki

kyog

aito

Taka

mat

su(2

006)

[131

]J

N95

.1(m

enop

ausa

lsy

ndr

ome)

Qu

asi-

RC

T17

0N

oN

o2

KS

toki

shak

uyak

usa

n,

kam

ish

oyos

anke

ish

ibu

kury

ogan

Ush

iroy

ama

etal

.(2

005)

[132

]E

N95

.8(m

enop

ausa

lsy

ndr

ome)

RC

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with a traditional approach, many research questions stillneed to be investigated. Kampo has been used for hundredsof years and is well integrated into the Japanese healthcare system, therefore it should be taken into account usingan appropriate research strategy. When performing clinicalresearch identical questions must be addressed for every newtreatment, as well as for traditional treatments, which arealready on the market:

(i) For whom and what is it used to treat?

(ii) Is it safe?

(iii) Is it superior to placebo?

(iv) Is it superior or equivalent to conventional standardtreatment?

For traditional treatments, the order of research ques-tions should differ from conventional drug research, becausetraditional treatments are already widely available [150].First, knowledge is needed regarding who will benefit fromthe treatment and which diseases the treatment is intendedto treat, as well as how it is to be administered. In addition, itwould be helpful to get an idea as to whether the patientsimprove under the treatment not to mention the essentialsafety assessment.

All of these questions could be answered using aprospective observational study which evaluates these aspectsin usual care. This has been done for other traditionaltreatments such as homeopathy [151–153], and is cur-rently being carried out for Kampo at the Keio University[154]. This computer-based self-assessment system is dividedinto two domains. One is the patients’ self-assessment atevery visit using a visual analogue scale (VAS) and theother domain is an assessment by the physician. Datafrom both sources are combined and analyzed using datamining. The advantage of this system is that data iscollected in a real-life setting. Also, Kampo values subjectivecomplaints. This computer-based, self-assessment system,allows data incorporation of patient’s subjective outcomemeasures.

Objective outcome measures which are often used inexperimental RCTs are sometimes separated from subjectivefeelings. Kampo physicians value subjective complaints anddiagnose sho not only based on objective findings, but alsofrom the subjective complaints. The evaluation of the Kampotreatment by the physician is sometimes decided based on thesubjective symptoms. Current Kampo clinical research hasnot taken this aspect into account. Due to the individualizedtreatment approach of Kampo, subjective outcome measuresare relevant and should always be considered while planninga study. In addition to databases, some authors have alsosuggested that more individual single-case research includingN of one trials would be suitable to reflect Kampo medicine[155, 156]. The main motivation to perform clinical researchon traditional treatments is for justification purposes, mostplacebo-controlled trials on Kampo do not reflect the use ofKampo in usual practice and are therefore not helpful whenmaking medical decisions in daily practice.

3.2. Testing for Superiority over Placebo. Previous researchhas followed the principles of conventional drug researchby testing the superiority of a single Kampo formula over aplacebo for a clearly defined conventional diagnosis. An RCTfrom 1998, for example, compared Rikkunshito with a kindof placebo (low dose of the same formula) for the treatmentof dyspepsia [68]. Results from this kind of trial are helpfulfor the integration of a single formula into conventionalcare. A formula that has proven efficacy in a conventionaldrug trial could be used in the future without any Kampoknowledge. However, this provides no information aboutKampo as a whole treatment system.

Nevertheless, this kind of research does not representthe traditional Kampo treatment. A traditional treatment isled from the Kampo diagnosis (by taking a patient history,abdominal examination, tongue and pulse diagnosis). If theaim of a clinical trial is to ask whether Kampo treatment in atraditional way is efficacious or not, the traditional treatmentsystem has to be taken into account. For this purpose, anadditional Kampo diagnosis with the conventional diagnosiscould be used for choosing the appropriate Kampo medicine.There are two options; the first excludes the influences ofthe Kampo diagnostic procedure and the study could beperformed in a similar way as suggested for the placebo-controlled study. When this design is used, the Kampodiagnosis is performed for all patients before randomization,although it is only needed for the group that actually receivesKampo.

The first design is that Kampo diagnoses and anappropriate treatment could be used for stratification withinthe randomization process (see Figure 1). This design isespecially useful for pilot trials or smaller studies to proveKampo as an individualized treatment system. This trialdesign allows for an individual Kampo treatment accordingto the Kampo diagnosis. However, it also means that arange of different formulae will be administered. In order toensure blinding, it might be necessary to prepare an adequateplacebo for each formula, if they differ in appearance, smelland taste. In this type of trial, the patients should notonly be blinded for the treatment, but they should alsonot receive any information about their Kampo diagnosis.Designs like this have already been used for homeopathy[157].

For many Western diagnoses, more than two Kampodiagnoses are common. Different patterns would result in alarger number of subgroups and some of these might be toosmall to have enough statistical power for subgroup analysis.For this reason, it makes sense to use the pooled patternsfor primary analysis and to pre-specify subgroup analysisfor the more common patterns. Another possibility, whichmight be easier to handle for the trial process, is to usethe Kampo diagnosis as additional inclusion criteria and torecruit only those patients with relevant Kampo diagnosisfor the formula under research. An example for this canbe seen in the study by Kobayashi [158]. When using thisdesign, it must be recognized that a large number of patientsmay need to be screened. In addition, the results are lessrepresentative for the Western diagnosis and integration intoconventional care might be more difficult, because Western


Placebo

Placebo 2 (n = 50)

Placebo 1 (n = 50)

Kamishoyosan (n = 50)

Qi stagnation/depression pattern (n = 100)

Keishibukuryogan (n = 50)

Stagnant blood pattern (n = 100)

Verum

Kampo diagnosis andtreatment defined

Randomization Treatment

Western inclusion andexclusion criteria

ICDN95.1

Figure 1: Combining the Western and Kampo diagnosis for a placebo-controlled trial: to evaluate the efficacy of Kampo drug treatment, forexample, for menopausal symptoms (ICD N95.1).

Standard

Placebo 1 (n = 100)

Kamishoyosan (n = 50)Diagnosis: qi stagnation/depression pattern

Treatment: Keishibukuryogan (n = 50)Diagnosis: stagnatant blood pattern

Kampo

Kampo diagnosis

Randomization

Western inclusion andexclusion criteria

n = 100

n = 100

ICD N95.1

Figure 2: Combining the Western and Kampo diagnosis for a standard care controlled trial: to evaluate the effectiveness of Kampo as awhole treatment system, for example, for menopausal symptoms (ICD N95.1).

trained doctors could not differentiate between the differentKampo diagnoses.

3.3. Testing for Non-Inferiority or Superiority over StandardCare. Doctors and patients want to know whether it is betterto use Kampo instead of, or in addition to conventionaltreatment. Depending on its causality or external validity,the main focus of these studies could be performed moreexperimentally (homogenous patients and clearly definedtreatment protocols) or more pragmatically (heterogeneouspatients and a treatment which represents usual care)[159]. Especially for chronic diseases where a more complextreatment is needed [160], a pragmatic study design to testKampo as an additional treatment could provide usefulinformation for decision making. Similarly for the suggestedplacebo-controlled study designs, it is possible to use anindividualized Kampo treatment within these studies.

The second possibility is to see the diagnostic procedureas part of the Kampo treatment, and the diagnostic proce-dure be used only on the Kampo group after randomizationFigure 2. Study designs shown in Figures 1 and 2 are used toanswer different research questions. The first option focuseson the treatment effects of the drug, whereas the secondoption provides a broader picture and evaluates Kampoas a whole treatment system, which consists of both thediagnostic procedure and the drug treatment.

3.4. Taking Patient Expectations into Account. Patient pref-erences and patient expectation can play a role in com-plementary and alternative medicine trials. Two systematicreviews suggest that the influence of patient expectationson outcomes is related to both within-group changes andbetween-group differences [161, 162]. This has already beenshown for acupuncture [163]. If the patients in a Kampo


trial have higher expectations of a positive outcome thanthe “average” patient, then this could result in within-group changes that are larger than in a more representativesample. High expectations might also be associated withhigh response rates and improved outcomes in the placebo-controlled group. This could result in a ceiling effect makingit more difficult to detect a significant difference betweenverum and placebo. Different strategies are available todeal with this problem, such as: including a run-in phase,stratification for randomization and measuring expectation.A simple tool for measuring aspects of expectations atbaseline is to ask questions such as: “How effective do youexpect the treatment to be?” with responses such as “veryeffective”, “effective”, “slightly effective”, “not effective” or“don’t know”. These data could be used to make adjustmentsin the primary data analysis.

4. Conclusion

Kampo is a holistic and individualized treatment with a longtradition and future research is required to take this intoaccount. RCT is the appropriate study design for testingefficacy or effectiveness, however within such a study, thetreatment should be individualized according to the Kampodiagnosis.

Funding

This work was supported by Grant-in-Aide for Researchon Applied Use of Statistics and Information, Healthand Labour Sciences Research and Clinical Research forDevelopment of Preventive Medicine and New Therapeuticsfrom Ministry of Health, Labour and Welfare of Japan.This work was also supported by the Center for ClinicalTrials, Japan Medical Association. Claudia Witts’ Chair forComplementary Medicine is endowed by the Carstens-Foundation. Research grant for doctoral candidates from theGerman Academic Exchange Service (DAAD) to L. H.

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ReviewArticle - Hindawi Publishing CorporationKo Nishimura, 1 YoshihiroImazu,1 HeidrunReissenweber,3 andClaudiaM.Witt2 1 CenterforKampo Medicine, Keio University Schoolof Medicine,Shinjuku-ku,