Evidence for Japanese oriental ( Kampo ) medicines : how to utilise the evidence of Kampo medicine in daily practice

Introduction The evidence concerning Japanese oriental (Kampo) medicine has been accumulated over two decades. In this regard, many physicians use the Kampo formula in the field of primary health care in Japan. However, Kampo medicines have other paradigms that differ from Western medicine. Therefore, the characteristics and specificity of Kampo medicine must be comprehended while using them based on clinical evidence. This article provides a review of the recent clinical trials concerning Kampo medicines and the discussion on ‘how to utilise the evidence of Kampo Medicine’. Conclusion We have discussed the methods of using Kampo medicines and where the development of each use has reached. Where evidence has been used, specificity of Kampo medicine should be understood and evidence for this medicine is expected to increase in the near future. Introduction In Japan, at present, Kampo medicines are prescribed by many physicians, showing wide clinical applications from primary health care to the treatment of intractable diseases1–4. Within this background, there are two education-based factors. One of the factors is to intrigue the students with the question ‘Can you give an outline of traditional Japanese medicines?’, which was introduced in the medical education model core curriculum in March 2001, and certain Kampo medicine education began to be provided at 80 medical schools throughout the nation in 2007. The other factor is the advancement of the project for the standardisation of the contents of this education. Kampo treatment in daily clinics at present can be classified into three major forms: (1) the use of Kampo prescriptions according to the methodology of traditional medicine, (2) the administration of Kampo medicines based on the concept of diseases/pathological conditions in Western medicine and concept of elementary Kampo medicine and (3) the evidence-based administration of Kampo medicines. Forms (2) and (3) are observed in treatment by physicians other than Kampo specialists, and when no effects of administered Kampo drugs are observed, patients may be referred to specialists. Such differences in treatment forms according to systems for the evaluation of the pathological condition are not observed in Western medicine. In this article, we have given an outline of ‘evidence for Kampo medicines’ with a consideration of the aforementioned treatment forms observed at present, and have discussed the present status/specificity/methods of the use of evidence for Kampo medicines.


Introduction
In Japan, at present, Kampo medicines are prescribed by many physicians, showing wide clinical applications from primary health care to the treatment of intractable diseases [1][2][3][4] .Within this background, there are two education-based factors.One of the factors is to intrigue the students with the question 'Can you give an outline of tradi-tional Japanese medicines?',which was introduced in the medical education model core curriculum in March 2001, and certain Kampo medicine education began to be provided at 80 medical schools throughout the nation in 2007.The other factor is the advancement of the project for the standardisation of the contents of this education.
Kampo treatment in daily clinics at present can be classified into three major forms: (1) the use of Kampo prescriptions according to the methodology of traditional medicine, (2) the administration of Kampo medicines based on the concept of diseases/pathological conditions in Western medicine and concept of elementary Kampo medicine and (3) the evidence-based administration of Kampo medicines.Forms (2) and (3) are observed in treatment by physicians other than Kampo specialists, and when no effects of administered Kampo drugs are observed, patients may be referred to specialists.Such differences in treatment forms according to systems for the evaluation of the pathological condition are not observed in Western medicine.In this article, we have given an outline of 'evidence for Kampo medicines' with a consideration of the aforementioned treatment forms observed at present, and have discussed the present status/specificity/methods of the use of evidence for Kampo medicines.

Discussion
The author has referenced some of its own studies in this review.These referenced studies have been conducted in accordance with the Declaration of Helsinki (1964) and the protocols of these studies have been approved by the relevant ethics committees related to the institution in which they were performed.All human subjects, in these referenced studies, gave informed consent to participate in these studies.

Present status of evidence for Kampo medicines
When evidence is discussed, it should be understood that there are three stages for evidence, i.e., 'generate', 'convey', and 'use'.So-called evidence-based medicine (EBM) corresponds to 'use' among the three stages, and consists of four steps: (1) formulation (formulate a clear clinical question based on a patient's problem), (2) search of the literature (obtain information to answer the question), (3) critical appraisal (evaluate the evidence for its validity), and (4) application to patients (consider the applicability to each patient) 5 .In Western medicine, methodology for the fourth step in EBM has been discussed.However, to use evidence (perform EBM), efforts to 'generate' evidence are necessary.In Japan, although EBM has been practiced since the latter half of the 1990s, the accumulation of evidence for Kampo medicines is still inadequate.Since 2000, randomised-control trials (RCTs) have rapidly increased; however, due to the specificity of Kampo medicines, we consider that the clinical practice of Kampo medicine based on EBM is difficult at present.Although evidence may further accumulate in the future, clinical Kampo practice is basically performed according to the methodology of traditional medicine 6 , 7 .
The absence of a direct connection between evidence for Kampo medi-cines and clinical practice may lead to the opinion that the importance of 'generating' evidence becomes unclear.However, such an apprehension is unnecessary.This can be more readily understood by evaluating changes in the concept of EBM itself.Originally, EBM means to search for references, determine whether application to patients is possible, and perform treatment 8 .However, gradually, EBM has been more frequently used to indicate the level of the epidemiological and statistical guarantee of the effects of individual treatment contents.In other words, the meaning of the presence of evidence has been changing to the statistical guarantee of the objective effects of drugs on diseases being treated.In conferences in daily practice, questions arise such as 'Is there evidence?'This may mean 'Is there a statistical significance?' rather than 'Is it clinically applicable?' Since treatment with Kampo medicines differs among individuals, this statistical significance is insufficient at present.In clinical practice, evidence for Kampo medicines is extremely important in order to obtain a statistical significance for Kampo medicines or Kampo treatment.Besides, it must be still difficult to perform Kampo treatment, as described earlier in the Introduction, based on several evidences for Kampo formulae.To 'generate' and 'convey' evidence is more urgently necessary than to 'use' evidence for Kampo medicines.
Therefore, in June 2001, the Japan Society for Oriental Medicine established a special committee to promote EBM in Oriental medicine 9 .To 'convey' evidence for Kampo medicines, the committee has independently collected and organised RCTs since 1986 to the present and produced structured abstracts.There is quite a bit of evidence for Kampo medicines now.Structured abstracts and details of the collection of RCTs on Kampo medicines can be obtained on the home page of the Japan Society for Oriental Medicine 10 .There are 415 articles on Kampo medi-cines in January 2013, and further evidence is expected to accumulate in the future.

Specifi city of evidence in Kampo medicine
In Western medicine, RCTs are performed to evaluate the effects of certain drugs on certain diseases or associated symptoms, and evidence is obtained.Since Western medicine was born using the methodology of natural science, EBM is a rational methodology.However, for application to patients as mentioned in step 4 of the EBM, there is no established methodology.In Western medicine, the fourth step in EBM is considered to be the most important step, although this step has poor objectivity 11 .
In Kampo medicine, the problem in the practice of EBM is difficulty in performing RCTs to generate evidence compared with Western medicine 9 .Kampo medicines are used based on Kampo diagnosis ('sho', pattern/syndrome), and, therefore, even if the diagnosis based on Western medicine is the same, the Kampo medicines administered differ among patients (Figure 1b).RCTs, in which the same type of Kampo medicine is administered for the same disease, are dissociated from clinical Kampo practice.Therefore, there is a method of RCTs in which patients with the same disease based on Western medicine are classified according to 'sho' (stratification).Indeed, we previously clarified the effects of Kampo formulations with tonic effects in frail elderly subjects in a double-blind RCT 12 .In this RCT, we used a design to stratify patients according to their pathological condition based on Kampo medicine, and a design to establish a trial period with emphasis on individual differences.However, some cases do not require Kampo diagnosis.Since the symptoms of allergic rhinitis resemble the pathological condition requiring administration of shoseiryuto, RCT on allergic rhinitis-shoseiryuto can be performed, and evidence can be obtained (Figure 1a).
Additionally, it is very important to recognise the Kampo formula, which is a crude drug, as the 'one drug'.Natural science is based on the element-reductionism, so the action must be attributed to purified chemical element.In contrast, it is considered that the clinical efficacy must be evaluated via the crude drug in the health care of Kampo medicine.The representative Kampo formula (Keishinieppiittokaryojutsubu: KER) is demonstrated in Figure 2. KER is the common Kampo formula for the treatment in patients with rheumatoid arthritis (RA), and composed of 12 herbs: Atractylodis Lanceae Rhizoma, Hoelen, Gypsum Fibrosum, Zizyphi Fructus, Cinnamomi Cortex, Ephedrae Herba, Paeoniae Radix, Glycyrrhizae Radix, Zingiberis Rhizoma, Aconiti Tuber, Sinomeni Caulis et Rhizoma, Astragali Radix.

Methods for usage of evidence in Kampo medicine
Evidence for Kampo medicine obtained from RCTs is also used according to the 4 steps of EBM.There is sufficient evidence for the treatment of indefinite upper abdominal complaints 13 , postoperative intestinal obstruction 14 , dementia 15 , chronic hepatitis 16 and menstruation abnormalities 17 , and evidence for Kampo medicines in complementary therapy for various types of malignant tumours has also been accumulated 18 .Concerning these diseases, Kampo and Western medicines can be similarly administered without consideration of the pathological conditions based on traditional medicines specific to Kampo medicine.This is Form (3), and can be regarded as the clinical application of Kampo medicines, based on the diagnosis in Western medicine, but not Kampo diagnosis by traditional procedures.
However, it may be difficult to obtain adequate clinical effects with Kampo medicines using the aforementioned methods in Kampo clinical practice 7 .Although various Kampo medicines such as kososan (a Kampo formula) are administered for psychosomatic disorders, such as depressive moods and panic disorder, no evidence has been obtained.Although the presence of responders to Kampo medicines among patients with RA has been reported 19 , no RCTs on RA have been conducted.Thus, it may be necessary to recognise the differences between Kampo treatment and EBM of Kampo medicines (Figure 3).
Stratification is a method to structure the evidence for the use The herbs were mixed with 600 ml of water and boiled down to 300 ml, and then the aqueous extract was filtered through a sieve.The extract, called a decoction, was administered twice a day before breakfast and dinner.These herbs are covered by national health insurance in health care in Japan.

Figure 1 :
Figure 1: Diagnosis by Western Medicine and 'Sho' (traditional medical evaluation).(a) Since allergic rhinitis has often been treated successfully by shoseiryuto (one of the Kampo formulae), shoseiryuto may be administered to patients with allergic rhinitis without consideration of 'Sho'.In other words, the patients with allergic rhinitis resemble the target group of shoseiryuto.(b) In contrast, the indications for RA differ from KER (one of the Kampo formulae).The adaptation of one Kampo formula cannot cover the pathological conditions of RA.Therefore, one Kampo formula among many possible Kampo formulae must be selected in the treatment for RA.In addition, Yokuininto, Boiogito, Keishishakuyakuchimoto, Daibohuto and KER are Kampo formulae.Approximately, Yokuininto and Boiogito are applicable to the early RA with swollen joints, Keishishakuyakuchimoto and Daibohuto are administered to the advanced RA with frail joints.Keishinieppittokaryojutsubu is generally used for the RA patients in the middle period.

Figure 2 :
Figure 2: Twelve dried traditional herbs (a mixture) were used as KER.The herbs were mixed with 600 ml of water and boiled down to 300 ml, and then the aqueous extract was filtered through a sieve.The extract, called a decoction, was administered twice a day before breakfast and dinner.These herbs are covered by national health insurance in health care in Japan.

Figure 3 :
Figure 3: Medical examination and treatment for RA based on Kampo Medicine.(a) General Kampo medicine in daily practice.Various Kampo formulae are administered to patients with RA according to traditional medical education.Treatment with Kampo medicines differs among individuals with RA.(b) Special Kampo medicine to generate evidence supporting one Kampo formula.Patients who should appropriately receive administration of KER must be selected among RA patients.In clinical trials, this kind of clinical form is generally adopted.KER: Keishinieppiitokaryoujutubu (a Kampo formula).

Figure 4 :
Figure 4: Anti-cyclic citrullinated peptide antibodies (ACPA) levels at baseline in KER (Keishinieppiittokaryojutsubu, which is the representative Kampo formula for RA) responders and non-responders within the RA patients.KER responders had lower levels of ACPA at baseline than non-responders (p = 0.042, Mann-Whitney test).