April 1, 2022

Clinical Practice Guideline for Dementia 2017
Japanese Society of Neurology
Recommendation grade
1 (Strong): Recommend to “perform” or “not to perform”
2 (Weak): Propose to “perform” or “not to perform”
Strength of body of evidence
A: Strong B: Moderate
C: Weak D: Very weakCQ 3B-2: What are the effective non-pharmacological therapies andpharmacotherapy for agitation?

Recommendation: … For pharmacotherapy, atypical antipsychotics such as risperidone and aripiprazole
have been shown to be effective. Consider also to use Yokukansan (liver-inhibiting powder), tiapride,carbamazepine, sertraline, escitalopram, and trazodone. (2C)
Comments and evidence: … A multicenter study in Japan has reported the effectiveness of Yokukansan.1)

CQ 3B-3: What are the effective non-pharmacological therapies andpharmacotherapy for hallucinations and delusions?

Recommendation: … Yokukansan may also be considered. (2C)
Comments and evidence: … For drugs other than antipsychotics, Yokukansan has been reported to be effective ina small number of cases.2)

CQ 3C-10: What are the interventions for edema?

Answer: … Pay attention to the possibility of edema induced by drugs such as Yokukansan andantipsychotics, and consider discontinuation or dose reduction of the causative drugs as appropriate.
(C)
Comments and evidence: … In people with dementia, it is necessary to consider the possibility of edema induced bydrugs including antipsychotic drugs and Yokukansan,3) and to consider discontinuation or dose reduction of the causative
drug as appropriate.3) According to an observational study that examined the safety and efficacy of long-term use of
Yokukansan in 163 patients who had been prescribed Yokukansan for more than 6 months, edema appeared in 10.8%of the patients and many recovered by discontinuing Yokukansan with no need for treatment.3)

CQ 7-7: Are there any treatments for behavioral and psychological symptoms ofdementia (BPSD) and REM sleep behavior disorder (RBD) in dementia with Lewy
bodies (DLB)?

Recommendation: Although Yokukansan and atypical antipsychotics have been reported to be
therapeutic drugs for BPSD, sufficient consideration for safety is required. … Some case reports haveindicated that Yokukansan, ramelteon, and donepezil are effective when clonazepam cannot be used.
(2C)
Comments and evidence: … Yokukansan has been shown to be effective in improving NPI total score, hallucinations,
delusion, depression, and anxiety symptoms.4) Although Yokukansan does not cause extrapyramidal symptoms oranticholinergic symptoms, hypokalemia may occur occasionally which requires attention. … Case reports have indicatedthat Yokukansan,5) ramelteon, and donepezil were effective when clonazepam cannot be used due to adverse effects.
… A report also indicates the effectiveness of Yokukansan in improving total time and efficiency of sleep, and reducing
the number of arousals during sleep.6)
1) Mizukami K, et al. A randomized cross-over study of a traditional Japanese medicine (kampo), yokukansan, in the treatment of thebehavioural and psychological symptoms of dementia. Int J Neuropsychopharmacol. 12: 191-199, 2009.
2) Mizukami K. Pharmacotherapy for BPSD. Jpn J Gen Hosp Psychiatry. 23: 19-26, 2011. (In Japanese with English abstract)3) Okahara K, et al. Safety and efficacy evaluation of long-term treatment with a traditional Japanese medicine, Yokukansan, on behavioral
and psychological symptoms of dementia. Dementia Japan. 26: 196-205, 2012. (In Japanese)4) Iwasaki K, et al. Improvement in delusions and hallucinations in patients with dementia with Lewy bodies upon administration ofyokukansan, a traditional Japanese medicine. Psychogeriatrics. 12: 235-241, 2012.
5) Shinno H, et al. Successful treatment with Yi-Gan San for rapid eye movement sleep behavior disorder. Prog Neuropsychopharmacol
Biol Psychiatry. 32: 1749-1751, 2008.
6) Shinno H, et al. Effect of Yi-Gan San on psychiatric symptoms and sleep structure at patients with behavioral and psychological symptomsof dementia. Prog Neuropsychopharmacol Biol Psychiatry. 32: 881-885, 2008.
Department of Japanese Oriental Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama

April 1, 2022

Evidence-based Clinical Practice Guidelines for Functional Dyspepsia (FD) 2021
2nd Edition
The Japanese Society of Gastroenterology
Grading Scale of Strength of Evidence
A: High quality evidence (High)
B: Moderate quality evidence (Moderate)
C: Low quality evidence (Low)
D: Very low quality evidence (Very Low)
Grading Scale of Strength of Recommendation
1: Strong recommendation
Recommend to "implement"
2: Weak recommendation
Propose to "implement"

Recommend to “do not implement"
Propose to “do not implement”

CQ 4-4: Are Kampo medicines effective as a treatment for FD?
Statement:
Rikkunshito is effective as therapeutic agent, and it is recommended to use.
(1) Strong recommendation, (A) High quality evidence
Kampo medicines other than Rikkunshito may be useful, and it is proposed to use.
(2) Week recommendation, (B) Moderate quality evidence
Comment:
Rikkunshito has been elucidated in various pharmacological actions centered on improving gastric motor function, and isa widely used drug for epigastric symptoms.1) As for the effectiveness of Rikkunshito for FD, a lot of evidences have beenshown since 1993, mainly in Japan, based on the relationship between gastric motor function improving effect and epigastric
symptoms.2-5) In recent years, RCTs using placebo have also been performed, and a report in 2014 on Rome III-based FD
patients did not show significance in the subjective symptom improvement rate after 8 weeks, which is the primary endpoint,whereas it showed significance in improvement of epigastric pain as a secondary endpoint.6) On the other hand, in a RCT
in 2018, patients who had a placebo effect during the single-blind period were excluded and then Rikkunshito (7.5 g/day)
was administered for 8 weeks in the main study, a general therapeutic improvement effect, which was the primary endpoint,
was reported to be significant compared to placebo. In addition, an improving effect on anxiety symptoms was also observed,
and a positive correlation was shown between the degree of improvement of gastrointestinal symptoms and anxiety
symptoms.7)
There is still little evidence of FD treatment with Kampo medicines other than Rikkunshito. There is a report from Japanthat Hangekobokuto is effective for upper abdominal pain and dyspepsia.8)
1) Tominaga K, et al. Kampo medicines for gastrointestinal tract disorders: a review of basic science and clinical evidence and their futureapplication. J Gastroenterol 48: 452-462, 2013.
2) Tatsuta M, et al. Effect of treatment with liu-jun-zi-tang (TJ-43) on gastric emptying and gastrointestinal symptoms in dyspeptic patients.
Aliment Pharmacol Ther 7: 459-462, 1993.
3) Harasawa S, et al. Multicenter post-marketing clinical trial of TJ-43 rikkunshito for dysmotility-like dyspepsia: a double-blind comparativestudy. Igakunoayumi 187: 207-229, 1998. (in Japanese)4) Shiratori M, et al. Effect of rikkunshito on gastric sensorimotor function under distention. Neurogastroenterol Motil 23: 323-329, 2011.
5) Kusunoki H, et al. Efficacy of Rikkunshito, a traditional Japanese medicine (Kampo), in treating functional dyspepsia. Intern Med 49:2195-2202, 2010.
6) Suzuki H, et al. Randomized clinical trial: rikkunshito in the treatment of functional dyspepsia – a multicenter, double-blind, randomized,placebo-controlled study. Neuro-gastroenterol Motil 26: 950-961, 2014.
7) Tominaga K, et al. Rikkunshito simultaneously improves dyspepsia correlated with anxiety in patients with functional dyspepsia: arandomized clinical trial (the DREAM study) Neuro-gastroenterol Motil 30: e13319, 2018.
8) Oikawa T, et al. Hangekobokuto (Banxia-houpo-tang), a Kampo medicine that treats functional dyspepsia. Evid Based Complement
Alternat Med 6: 375-378, 2009.

Department of Japanese Oriental Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama

April 1, 2021

Evidence-based Clinical Practice Guidelines for Functional Dyspepsia (FD) 2014
The Japanese Society of Gastroenterology
Grading Scale of Strength of Evidence
A: High quality evidence (High)
B: Moderate quality evidence (Moderate)
C: Low quality evidence (Low)
D: Very low quality evidence (Very Low)
Grading Scale of Strength of Recommendation
1: Strong recommendation
Recommend to "implement"
2: Weak recommendation
Propose to "implement"

Recommend to “do not implement"
Propose to “do not implement”

CQ 4-10: Are Kampo medicines effective as a treatment for FD?
Statement:
Some Kampo medicines are effective as therapeutic agents for FD, and it is proposed to use them.
Strength of recommendation: (2) Weak recommendation
Grading Scale of Strength of Evidence: (A) High quality evidence
Comment:
Kampo medicine has a long-standing concept of the Kampo diagnosis "sho", and based on that concept, it has been
empirically shown to be effective for various indefinite clinical complaints. Symptoms of functional dyspepsia (FD) are often
included in the category of indefinite complaints in daily clinical practice, as they are sometimes referred to as "physicalsymptoms that are medically difficult to explain." Under such circumstances, in a comparative study with placebo in 1993,
symptoms such as epigastric bloating, belching, and nausea were improved in non-ulcer dyspepsia (the current FD) patients
after 7-day administration of rikkunshito.1) At the same time, it was also shown to improve gastric motility, which is involved
as part of pathophysiology. After that, a large-scale comparative study, which is not a strict placebo, was conducted in Japan,
and it is worth noting that the effect of improving epigastric complaints was shown in FD patients with motor dysfunction
symptoms.2) Regarding the effect of improving motor function related to upper abdominal symptoms, since then somestudies focusing on the improvement of gastric retention capacity have been reported.3,4) Furthermore, because it wasreported that rikkunshito has an effect of increasing the plasma level of ghrelin, a peptide that controls gastrointestinal
motility function, a comparative study with a gastrointestinal motility improving drug (domperidone) was conducted andrikkunshito was effective in improving the dyspepsia symptoms.5) In addition, a case-control study was reported that
hangekobokuto was effective in improving the symptoms of epigastric pain and dyspepsia.6) Thus, there are evidencessuggesting that some Kampo medicines may have effects of improving dyspepsia symptoms, corresponding to theimprovement of pathophysiology in FD patients. There is also review article showing a part of the above contents.7) However,
it is a fact that there is still little high-quality evidence such as randomized controlled trials using placebo, so further studies
are awaited in the future.
1) Tatsuta M, et al. Effect of treatment with liu-jun-zi-tang (TJ-43) on gastric emptying and gastrointestinal symptoms in dyspeptic patients.
Aliment Pharmacol Ther 7: 459-462, 1993.
2) Harasawa S, et al. Multicenter post-marketing clinical trial of TJ-43 rikkunshito for dysmotiiity-like dyspepsia: a double-blind comparative
study. Igakunoayumi 187: 207-229, 1998. (in Japanese)3) Shiratori M, et al. Effect of rikkunshito on gastric sensorimotor function under distention. Neurogastroenterol Motil 23: 323-329, 2011.
4) Kusunoki H, et al. Efficacy of Rikkunshito, a traditional Japanese medicine (Kampo), in treating functional dyspepsia. Intern Med 49:2195-2202, 2010.
5) Arai M, et al. Rikkunshito improves the symptoms in patients with functional dyspepsia, accompanied by an increase in the level ofplasma ghrelin. Hepato-Gastroenterology 59: 62-66, 2012.
6) Oikawa T, et al. Hangekobokuto (Banxia-houpo-tang), a Kampo medicine that treats functional dyspepsia. Evid Based Complement
Alternat Med 6: 375-378, 2009.
7) Suzuki H, et al. Japanese herbal medicine in functional gastrointestinal disorders. Neuro-gastroenterol Motil 21: 688-696, 2009.
Department of Japanese Oriental Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama

April 1, 2021

Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease(GERD) 2015 (2nd Edition)
The Japanese Society of Gastroenterology
Grading Scale of Strength of Evidence
A: High quality evidence (High)
B: Moderate quality evidence (Moderate)
C: Low quality evidence (Low)
D: Very low quality evidence (Very Low)
Grading Scale of Strength of Recommendation
1: Strong recommendation
Recommend to "implement"
2: Weak recommendation
Propose to "implement"

Recommend to “do not implement"
Propose to “do not implement”

CQ 4-6: Are there any drugs that can be expected to have an additional effectwhen used in combination with PPI,such as gastrointestinal motility improving drugs and Kampo medicines?
Statement:
Although there is no evidence to indicate the usefulness of monotherapy with gastrointestinal motility
improving drugs, Kampo medicines, etc., it is proposed to use them because they may have symptom
improving effect when used in combination with proton pump inhibitor (PPI).
Strength of recommendation: (2) Weak recommendation
Grading Scale of Strength of Evidence: (C) Low quality evidence
Comment:
In recent years, in clinical trial for non-erosive GERD conducted in Japan, it was shown that mosapride (gastrointestinal
motility improving drug) had an additional effect when used in combination with PPI, although without statisticalsignificance.1) In a study of PPI-resistant GERD, the combined use of rikkunshito and PPI was shown to have the same
additional effect as PPI double dose administration, therefore, if PPI monotherapy is insufficiently effective, it is meaningfulto use these drugs in combination.2)
1) Miwa H., et al. Randomised clinical trial: efficacy of the addition of a prokinetic, mosapride citrate, to omeprazole in thetreatment of patients with non-erosive reflux disease: a double-blind, placebo-controlled study. Aliment Pharmacol Ther33: 323-332, 2011.
2) Tominaga K, et al. Rikkunshito improves symptoms in PPI-refractory GERD patients: a prospective, randomized,multicenter trial in Japan. J Gastroenterol 47: 284-292, 2012.

Department of Japanese Oriental Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama

April 1, 2021

Evidence-based Clinical Practice Guidelines for Irritable Bowel Syndrome (IBS) 2020
(2nd Edition)
The Japanese Society of Gastroenterology
Grading Scale of Strength of Evidence
A: High quality evidence (High)
B: Moderate quality evidence (Moderate)
C: Low quality evidence (Low)
D: Very low quality evidence (Very Low)
Grading Scale of Strength of Recommendation
1: Strong recommendation
Recommend to "implement"
2: Weak recommendation
Propose to "implement"

Recommend to “do not implement"
Propose to “do not implement”

CQ 3-17: Are Kampo medicines effective as a treatment for IBS?
Statement:
Some Kampo medicines are effective as therapeutic agents for IBS, and it is proposed to use them.
Strength of recommendation: (2) Weak recommendation
Grading Scale of Strength of Evidence: (C) Low quality evidence
Comment:
The effectiveness of keishikashakuyakuto for IBS patients has been shown. Sasaki et al., conducted a 4-week multicenter
RCT of IBS with keishikashakuyakuto.1) As a result of evaluating 232 IBS patients (including 108 in the placebo group), there
was no significant difference between two groups in the final overall improvement (moderate or higher improvement: 50.9%
in the active group vs. 47.9% in the placebo group), and also in the improvement of all of stool shape, number of defecations
and feeling of residual stool. In the abdominal pain improvement, the active group showed a tendency to improve comparedto the placebo group (p = 0.051). When evaluated in each stool subtype, in the diarrhea type, the active group showed asignificant improvement in the abdominal pain improvement compared to the placebo group (p = 0.037), but significant
improvement was not shown in other types (constipation type and combined type). Almost no serious side effects wereobserved by keishikashakuyakuto.
The effect of hangeshashinto on diarrhea type IBS has been reported. Bizen conducted a case-accumulation study inwhich 6 patients with diarrhea type IBS were treated with hangeshashinto for 7-28 days.2) As a result, the degree ofimprovement in general symptoms was marked improvement in 2 cases, improvement in 3 cases, and mild improvement in
1 case, and the abdominal pain score and stool shape score after treatment were significantly decreased than those beforetreatment.
The effectiveness of daikenchuto on constipation type IBS is suggested. As a result of a case accumulation study by
Takeda et al., in which daikenchuto 7.5-15 g/day was administered to 26 IBS patients with abdominal distension for 4-8weeks, abdominal distension, flatus, borborygmus and feeling of residual stool were improved significantly along with
reduction of the intestinal gas area in abdominal plain X-ray.3) Manabe et al., evaluated the gastrointestinal transit time inhealthy subjects in the period of 5-days administration of placebo (21 cases), daikenchuto 7.5 g/day (19 cases) ordaikenchuto 15 g/day (20 cases) by RCT.4) As a result, it was shown that the transit time in the ascending colon in thedaikenchuto 7.5 g/day group significantly shortened compared to the placebo group.
Based on the above, keishikashakuyakuto, hangeshashinto, and daikenchuto are considered to be useful for IBS, and it
is proposed to administer them. However, it is necessary to select an appropriate Kampo medicine in consideration of thepredominant symptoms. In recent years, the results of clinical trials of Kampo medicines on IBS patients have not beenreported so much, therefore further accumulation of evidence is expected.
1) Sasaki D., et al. Clinical effect of keishikashakuyakuto on irritable bowel syndrome: multicenter, randomized, comparative clinical trial.
Rinshotokenkyu 75: 1136-1152, 1998. (in Japanese)2) Bizen A.: Examination of hangeshashinto (tablet) on diarrhea type irritable bowel syndrome accompanied by psychological stress.
Igakutoyakugaku 68: 127-133, 2012. (in Japanese)3) Takeda H., et al.: Kampo medicines in the field of gastroenterology. Nihontoyoshinshin-igakukenkyu 25: 37-41, 2010. (in Japanese)
4) Manabe N, et al. Effect of daikenchuto (TU-100) on gastrointestinal and colonic transit in humans. Am J Physiol Gastrointest Liver Physiol
298: G970-G975, 2010.
Department of Japanese Oriental Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama