Kampo Medicine for Various Aging-Related Symptoms: A Review of Geriatric Syndrome

With the continued growth of the aging population in Japan, geriatric syndrome (GS), which is associated with aging-related symptoms, has become a social problem. GS is caused by physiological and pathological aging and may manifest various symptoms. Physicians use multidisciplinary approaches to provide treatment for individual GS symptoms. Kampo medicine, a Japanese traditional medicine that uses multiple pharmacologically active substances, is useful for many syndromes, conditions, disorders, and diseases associated with GS. Evidence of the effectiveness of Kampo medicine for GS has accumulated in recent years. The effects of Kampo treatment for symptoms related to functional decline of the cardiovascular, respiratory, and digestive systems, cognitive impairment and related disorders, pain and other sensory issues, among others, support the use of Kampo medicine for the management of GS. The role of Kampo medicine for GS is summarized in this review.


INTRODUCTION
Geriatric syndrome (GS) is a well-known clinical entity characterized by symptoms highly prevalent in old age. It presents with multiple contributing factors, including physiological aging, and requires a multidisciplinary approach. When compared to the "disease" entity, the differences in features are unknown etiology and inclusion of physiological aging as a cause (1). There is no universal definition of GS; there are some variations in the features included in GS definitions. These variations in definition lead to ambiguity regarding the included symptoms. Originally, GS symptoms were expressed as the 3Ms (mentality, micturition, and mobility) or 4Is (immobility, instability, impaired cognition, and incontinence-also named the "geriatric giants") (2). Today, 20 or more symptoms are listed (3). The majority of GS symptoms emerge slowly and are chronic, with a low risk of mortality by themselves. Consequently, they tend to be overlooked as physiological changes, resulting in increased dependency. GS is clinically significant as a warning sign for the risk of increased care dependency. When determining countermeasures for GS, we must exclude the possibility of a single cause before considering multifactorial etiology (3,4) (e.g., endocrine disorders) (5). Then, we must exclude medication-related side effects (6).
Kampo medicine is effective in many cases of GS with multiple causes. Original GS symptoms (such as symptoms related to functional decline of the cardiovascular, respiratory, and digestive systems; cognitive impairment and related disorders; and pain and other sensory issues) are considered treatment targets. Because of the multifactorial nature of GS and specialization in medicine, care for those with GS tends to be fragmented. Kampo medicine could prevent fragmentation of patient care.
On the other hand, medical expenses amounted to more than one third of social security expenses in 2018 (7). With the growing "super-aging" society and the declining birth rate in Japan, medical expenses are only expected to increase. In light of these points, we have herein summarized the efficacy, safety, and social economic advantage associated with the use of Kampo medicine for GS.
In this review, we summarize randomized controlled trials (RCTs) for GS. When no RCT was available for specific conditions or disorders, some observational studies were described. Details of each Kampo medication are listed on the Standards of Reporting Kampo Products (STORK) website (http://mpdb.nibiohn.go.jp/stork/) (8). The names of Kampo medicines were abbreviated according to the Japan Society of Oriental Medicine (9).

KAMPO MEDICINE FOR GS Kampo Medicine for Cardiovascular Disease and Related Symptoms
Generally, cardiovascular disease and related disorders increase with age. The Japanese lifestyle has shifted toward a Western lifestyle; thus, cardiovascular disease has increased in the last half century. Western medications are commonly used to control hypertension and related diseases; furthermore, they have been shown to effectively suppress cardiovascular events. A few clinical trials have been conducted on Kampo medicine for the treatment of cardiovascular disease and related symptoms. Overall, these RCTs were conducted to manage symptoms difficult to control in Western medicine. Soft endpoints were the improvement of accessory symptoms of hypertension, orthopedic hypotension related to diabetes mellitus, and edema according to deep vein thrombosis of the lower limb ( Table 1).

Hypertension
Arakawa et al. conducted a double-blinded (DB) RCT on orengedokuto (OGT) for the treatment of accessory symptoms of hypertension; the study included elderly subjects (10). Efficacy was significantly higher in the OGT group based on the total score for the accessory symptoms of hypertension; sub-analysis showed the efficacy to be higher for hot flashes and facial suffusion in the OGT group. However, there were no significant differences between the OGT and placebo groups regarding the decrease of blood pressure or the antihypertensive effect.
Hypotension Nakamura et al. reported the efficacy of goreisan (GRS) for orthopedic hypotension related with diabetes mellitus in an RCT that included elderly subjects (11). The change in orthopedic systolic and diastolic pressure was significantly lower in the GRS group than in the placebo group. All patients complained of dizziness in the placebo group, but only 10% complained of the symptom in the GRS group.

Disorders Related to Vein Dysfunction
Uchida reported the effect of keishibukuryogan (KBG) for edema according to deep vein thrombosis of the lower limb in an RCT of elderly subjects (12). The improvement rates of circumference difference between the affected and the normal limbs were significantly higher in the KBG group than in the conventional treatment group.

Kampo Medicine for Aspiration Pneumonia and Chronic Obstructive Pulmonary Disease
Respiratory disease is increasing with the aging of society. Kampo medicine has been effective at treating acute respiratory infection, and there are some reports that Kampo medicine has a prophylactic effect in aspiration pneumonia and acute exacerbation of chronic obstructive pulmonary disease (COPD) ( Table 2).

Kampo Medicine for Aspiration Pneumonia
Pneumonia is one of the leading causes of death in the elderly. Therefore, preventing pneumonia, including aspiration pneumonia, is very important. Aspiration pneumonia occurs frequently in patients with cerebrovascular disease, patients with neurodegenerative disease, and bedridden patients with dysphagia and depression of swallowing and cough reflex. Patients with swallowing or coughing impairment have low levels of substance-P in their saliva (13,14). Substance-P is a neuropeptide that plays an important role in swallowing and cough reflexes (13). Table 2A shows studies of Kampo medicine for aspiration pneumonia.
Iwasaki et al. reported that hangekobokuto (HKT) improves swallowing reflex and increases salivary levels of substance-P in patients who had a stroke (15). They also reported that HKT improves swallowing reflex in patients with Parkinson's disease despite no significant changes in their salivary levels of substance-P (16). Iwasaki et al. also showed that HKT improves cough reflex of patients with cerebral atrophy and lacunar infarction (17), reduces the risk of aspiration pneumonia in the elderly, and maintains self-feeding capacity better than the control (18). Additionally, Kawago et al. reported that HKT prevents aspiration pneumonia in patients after cardiovascular surgery (19). HKT is thought to act via regulation of the cerebral levels of 5-hydroxytryptamine, noradrenaline, and dopamine  (20). Impairment of the swallowing reflex correlates strongly with decreased dopamine levels in the basal ganglia (21). Therefore, HKT-induced improvement of swallowing reflex may be associated with HKT-induced increase in brain dopamine levels. Hochuekkito (HET) is another Kampo formula for prevention of aspiration pneumonia. Tamano et al. reported that administration of HET, alone or in combination with rehabilitation, reduces the number of hospitalizations due to aspiration pneumonia (22,23). HET also improves clinical symptoms such as appetite loss and general malaise, increases body weight and serum albumin, and increases temperature in patients with low body temperature. Mantani et al. reported that seihaito (SHT), added to conventional treatment, decreases the mean values of fever, C-reactive protein (CRP) levels, and antibiotics use compared with conventional therapy alone (24). However, SHT does not improve the latency of swallowing reflex. This study indicated that SHT has an anti-inflammatory effect in patients with recurrent aspiration pneumonia but does not improve swallowing reflex. Iwasaki et al. reported that xanthine oxidase activity in lung tissues is elevated in a mouse model of aspiration pneumonia and that SHT is able to reverse this elevation (25). The authors speculated that SHT pretreatment can reduce oxygen radical production in inflamed lungs. Dysphagia is also considered to relate to gastroesophageal reflux disease (GERD).

Kampo Medicine for COPD
COPD does not affect solely the airways; it is considered a systemic inflammation. The treatment guidelines for COPD recommend the use of bronchodilators, inhaled corticosteroids, and rehabilitation. One of the main goals of COPD treatment is to prevent acute exacerbation, which is known to affect patient prognosis. Table 2B shows an RCT of Kampo medicine for COPD. Among Kampo medications, bakumondoto (BAK) and SHT have been shown to improve the symptoms of COPD. Sasaki et al. reported that BAK significantly helps loosen phlegm of patients with chronic respiratory disease (26). Mukaida et al. showed that BAK significantly improves visual analog scale (VAS) scores for cough frequency, but not for cough intensity (27). Kato et al. reported that administration of SHT improves the clinical symptoms of COPD (28). BAK is thought to exert a peripheral antitussive effect by inhibiting the synthesis or release of nitric oxide (29). According to the traditional theory, BAK should be used for patients with dry cough and SHT for patients with productive cough. Shinozuka et al. and Tatsumi et al. reported that HET reduces the number of common cold and acute exacerbation episodes in patients with COPD (30,31). HET decreased serum CRP, tumor necrosis factor (TNF)-α, and interleukin-6 levels and increased serum prealbumin levels. Furthermore, HET resulted in a significant increase in body weight over 6 months and a decrease in St. George's Respiratory Questionnaire score, indicating an improvement in quality of life (QOL). HET has antiviral and anti-inflammatory effects, thus contributing to preventing exacerbation (32). Jo et al. reported that daikenchuto (DKT) reduces exacerbation in patients with COPD (33). Patients treated with DKT had

Kampo Medicine for the Digestive System
Kampo medicine was developed to control and maintain the function of the digestive system. It is used to enhance motility in the gastrointestinal tract and promote digestion. Kampo medicine has recently been used for early recovery from surgical intervention, especially for elderly patients receiving cancer treatment. RCTs have explored the use of Kampo medicine for constipation, perioperative symptoms, and conditions in the gut, functional dyspepsia (FD), GERD, and nonerosive reflux disease (NERD) ( Table 3). After development of a placebo of these Kampo medicines, DB-RCTs using DKT or rikkunshito (RKT) were conducted. RCTs showed that DKT can be used for preventing postoperative ileus, improving bowel movement in the early days, improving QOL, having antiinflammatory effects, improving early oral intake, enhancing total oral/enteral caloric intake and portal venous flow volume, and minimizing weight loss after abdominal surgery in the perioperative stage. RCTs showed that RKT can be used for improving upper gastric symptoms (globus sensation, delayed gastric emptying, abdominal bloating, heavy feeling in the stomach, sick feeling after meals, heartburn after meals, and epigastric pain), psychological symptoms, appetite loss, acyl ghrelin levels, and a low body mass index in FD, GERD, and NERD. Table 3A shows an RCT of Kampo medicine for FD and GERD.

FD and GERD
Tominaga et al. reported the effects of RKT administration on FD and its correlation with anxiety (37). RKT increased the overall treatment efficacy and improved upper gastrointestinal symptoms, especially postprandial fullness/early satiety and bloating. Improvement of the Hospital Anxiety and Depression Scale was correlated with that of the Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index, the Global Overall Symptom scale, and the modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (postprandial fullness/early satiety, dyspepsia, and postprandial distress syndrome). This suggests that RKT may be beneficial for patients with FD to simultaneously treat gastrointestinal and psychological symptoms. Tominaga et al. also studied the use of RKT for patients with NERD refractory to proton-pump inhibitors (PPIs) in a DB-RCT that included elderly subjects (38). The mental component summary scores improved more in the RKT group than in the control group, especially in patients with a low body mass index, and significantly improved the acid-related dysmotility symptoms in female and elderly patients. Sakata et al. reported additional analysis of this study (39).
Especially in the elderly, the degrees of improvement in the total and acid-related dysmotility symptom scores were significantly greater in the RKT group. Combination therapy with RKT led to significant improvement in abdominal bloating, heavy feeling in the stomach, sick feeling after meals, and heartburn after meals. Kato et al. reported that HKT significantly improved respiratory symptoms associated with GERD (40). Suzuki et al. reported the efficacy and safety of RKT for FD in a DB-RCT that included elderly subjects (41). Administration of RKT reduced dyspepsia, particularly the symptoms of epigastric pain and postprandial fullness. Among the patients positive for Helicobacter pylori, RKT improved acyl ghrelin levels. In a DB-RCT, Hayakawa et al.
reported the effects of RKT on enteral feeding and plasma ghrelin levels in critically ill elderly patients (42). The RKT group reached 50% of the target amount of enteral feeding significantly earlier than the metoclopramide group. RKT increased the plasma level of active ghrelin. Tokashiki et al. reported the effects of RKT on the globus sensation in patients with PPI-refractory laryngopharyngeal reflux in an RCT that included elderly subjects (43). RKT or RKT with PPI significantly decreased the globus sensation and improved delayed gastric emptying. A significant positive correlation was found between improvements in the globus sensation and gastric emptying. Tominaga et al. reported the efficacy of RKT for patients with GERD refractory to treatment with PPI in a DB-RCT that included patients from 20 to 90 years of age (44). RKT combined with PPI significantly decreased the frequency scale of the GERD symptoms' score, similar to the decrease seen after treatment with a double dose of PPI. Subgroup analysis showed that the improvement rate of male NERD patients in the RKT group was significantly greater. Subgroup analysis also showed that the patients of male sex or with a low body mass index showed more improvement than other subgroups. Furthermore, no adverse events were observed in this study. Additional RKT therapy for patients with GERD refractory to PPI treatment seemed to be more effective for NERD, male, or low-body mass index patients, and the therapy was shown to be safe. Arai et al. reported a significant improvement in dyspeptic symptoms in patients treated with either RKT or domperidone (45). The improvements of reflux and indigestion symptoms in patients treated with RKT showed good correlations with the increased levels of acylated ghrelin. Harasawa et al. conducted a DB-RCT on RKT for the treatment of dysmotility-like dyspepsia in elderly subjects (46). The regular dose of RKT improved dysmotility-like dyspepsia significantly more than the low dose of RKT. Tatsuta et al. reported the effects of RKT on gastric emptying and gastrointestinal symptoms in dyspeptic patients (47). Gastric emptying was significantly accelerated, and gastrointestinal symptoms were significantly reduced in patients treated with RKT. Miyoshi et al. examined the effects of RKT for complaints related to gastrointestinal function in an RCT that included elderly subjects (48). RKT significantly improved the symptoms of appetite loss, epigastric pain, abdominal discomfort, cold feelings of the limb, and dazzling when compared with cisapride. In a subanalysis, RKT was more effective in patients over 60 years of age, with a thin type body, and with water retention.  (49). Constipation scoring system points, especially the frequency of bowel movements, feeling of incomplete evacuation, and need for an enema/disimpaction, improved significantly with the addition of DKT. The gas volume score also significantly reduced with the addition of DKT. Arita et al. performed a responder analysis of DKT treatment for constipation in poststroke patients (50). The total neurogenic bowel dysfunction score and Gastrointestinal Symptom Rating Scale (GSRS)-constipation subscale score were significantly reduced after DKT administration. The total neurogenic bowel dysfunction score, GSRS-constipation subscale score, and gas volume score at baseline were significantly correlated with the change in these scores, suggesting that higher scores in these categories and a higher gas volume in the gut may be predictors of response to DKT. Horiuchi et al. reported the effect of DKT in patients with chronic constipation in an RCT that included elderly subjects (51). The addition of DKT to sennoside resulted in a significant improvement in bloating and abdominal pain and a significant decrease in the gas volume score comparing a regular dose and a half dose of DKT. Miyoshi et al. reported the effect of daiokanzoto (DKZT) in patients with chronic constipation in an RCT that included elderly subjects (52). DKZT was significantly more effective for constipation than the placebo. A regular dose of DKZT has a strong effect on some patients; as such, the dose should be determined considering the patient's condition.  (57). Bowel movement frequency in the DKT group at postoperative day 8 was significantly lower than that in the placebo group, suggesting that the moderate effects of DKT were observed in the early days after the operation. In a DB-RCT, Yoshikawa reported the effects of DKT after total gastrectomy for gastric cancer in elderly patients (58). DKT administration shortened the median time to the first bowel movement and resulted in fewer gastrointestinal dysfunctions on postoperative day 12. This suggests that DKT administration in the immediate postoperative period after total gastrectomy promotes early recovery of postoperative bowel function. Yaegashi (69). Table 3D shows an RCT of Kampo medicine for other conditions and symptoms related with the digestive system. Bessho et al. reported the effectiveness of saibokuto (SBT) for patients with glossodynia in an RCT that included elderly subjects (70). When compared with diazepam with vitamin B complex, SBT significantly reduced the symptoms of pain, burning sensation, and discomfort.

Other Diseases and Conditions Related to the Digestive System
In an RCT, Okabayashi et al. reported the effects of inchinkoto (ICKT) on the bilirubin reduction rate after biliary drainage in elderly patients with obstructive jaundice (71). ICKT significantly improved jaundice following biliary drainage and also improved subjective symptoms such as loss of appetite and general fatigue. Miyazaki et al. reported the efficacy of ninjinyoeito (NYT) for dry mouth induced by oxybutynin hydrochloride to treat psychogenic frequency or unstable bladder in an RCT that included elderly subjects (72). The addition of NYT reduced the symptom of dry mouth in 75% of patients. Saliva secretion also improved after NYT addition.

Kampo Medicine for Symptoms of Dementia
Dementia has become a global health issue. The number of people living with dementia in the world was estimated to be 46.8 million in 2015 (73). Japan has one of the most rapidly aging societies; the prevalence of dementia was already beyond 3% (five million) in 2015, and it has been increasing, even though the Japanese population has begun to decline (74). This situation might drive doctors to conduct a number of clinical studies using Kampo medicine for the symptoms of dementia. Dementia is a syndrome associated with declines in memory, thinking, behavior, and the ability to perform daily activities. Cognitive disorders and noncognitive symptoms, that is, behavioral and psychological symptoms of dementia (BPSD), are equally important clinical manifestations. Kampo medications are composed of multiple herbal ingredients and have different target symptoms. Therefore, based on the current clinical evidence, we herein introduce some Kampo medications and their target symptoms ( Table 4).

Cognitive Disorders
Chotosan (CTS) was originally used for headache, tinnitus, and dizziness. In 1994, Shimada et al. conducted a multicenter placebo-controlled RCT using CTS (75). After 12 weeks of CTS treatment, patients with vascular dementia had a decrease in the score of cognitive dysfunctions (Hasegawa's Dementia Scale-Revised) when compared to baseline. CTS was superior to the placebo in the global improvement rating, utility rating, global rating for subjective symptoms, subjective symptoms (shoulder stiffness and palpations), global rating for psychiatric symptoms, psychiatric symptoms (decline in interest in television or books and lack of facial expression), and activities of daily living (ADLs). Terasawa et al. conducted another placebo-controlled RCT using CTS for vascular dementia (76). When compared with the placebo, the global improvement rating, global rating for subjective symptoms, psychiatric symptoms (decline in simple arithmetic ability, global intellectual ability, sleep disturbance, hallucination, and delusion), and ADLs significantly improved after a 12-week administration of CTS. In the study, cognitive dysfunctions did not improve. The overall safety rating did not differ significantly between the chitosan treatment group and the placebo group. Suzuki et al. reported that an 8-week treatment of CTS improved cognitive dysfunction [assessed by the Mini-Mental State Examination (MMSE)] and ADL when compared to the baseline in patients with Alzheimer's disease; goshajinkigan (GJG) treatment and the placebo did not improve these symptoms (77). In 2017, Imai et al. conducted a meta-analysis of the three above-mentioned RCTs to assess the effectiveness and acceptability of CTS (78). CTS was more effective than the placebo for short-term improvement of cognitive function. The acceptability, measured in terms of the number of dropouts due to adverse effects, did not differ between the CTS treatment group and the placebo group. However, the results are considered imprecise, partly because of the small number of participants. Iwasaki et al. conducted a placebo-controlled DB-RCT using hachimijiogan (HJG), a pill made with herbs and honey, for the treatment of dementia (79). Administration of HJG for 8 weeks significantly improved cognitive dysfunction (assessed by MMSE) and ADL (assessed by the Barthel index) when compared to baseline, while the placebo did not change those scores. No adverse events were observed. Maruyama et al. reported the effectiveness of a combination of donepezil and kamiuntanto on cognitive function and brain perfusion in patients with Alzheimer's disease (80). A 12-week observer-blinded RCT revealed that combination treatment with a donepezil and kamiuntanto decoction significantly improved cognitive function (MMSE and ADAS-cog) when compared with treatment with donepezil alone. Furthermore, cerebral blood flow in the frontal region (measured by single photon emission computed tomography) significantly increased in the   (81). The MMSE showed significant improvement 3 months after treatment with KHT, but not in the nontreated or GJG-treated groups. The orientation and attention subscale scores of the MMSE improved significantly in the KHT treatment group when compared with those of the nontreatment group. No adverse events were observed in any of the groups.  (86). All three drugs significantly alleviated BPSD, with no significant intergroup differences. The tolerability analysis revealed that adverse effects (constipation, muscle rigidity, and extrapyramidal symptoms) were more frequent in the risperidone treatment group. In 2016, Furukawa et al. conducted a placebo-controlled DB-RCT on patients with Alzheimer's disease (87). Both 4 weeks of YKS treatment and the placebo improved BPSD, with no significant intergroup differences. The subgroup scoring below 20 points on the MMSE at baseline showed a greater improvement in BPSD, especially in agitation/aggregation in the YKS treatment group, when compared to the placebo group. In the subgroup younger than 74 years of age, a significant decrease in the subcategory score for agitation/aggression was shown in the YKS treatment group when compared with the placebo group. In 2016, Matsunaga et al. conducted a meta-analysis of the abovementioned RCTs using YKS for BPSD in dementia patients (88). YKS significantly decreased total BPSD scores when compared with the controls (placebo or usual care), especially the subscale scores for delusions, hallucinations, and agitation/aggression. However, only in the Alzheimer's disease patients, YKS was not superior to the controls for BPSD. YKS treatment significantly improved ADL when compared with the controls. MMSE scores did not improve in the YKS treatment group or in the control group. Incidence of adverse effects did not differ significantly between the YKS treatment and control groups. Various Kampo formulations are clinically effective for the treatment of dementia. A Kampo medicine may be selected according to the patients' symptoms. Adverse events due to Kampo medicine are not frequent. Therefore, Kampo medicine may be a treatment option for both cognitive dysfunction and BPSD.

Kampo Medicine for Pain Control
In elderly individuals, physical, psychological, and social changes cause various types of chronic pain. Western analgesic medications are used as the basic approach for pain relief; however, modulation of organ systems and pharmacokinetics often induce adverse effects in aging patients. Furthermore, chronic pain often accompanies various symptoms such as coldness, fatigue, and depression. These conditions exacerbate pain and hinder the physical exercise needed to control pain. Kampo medicine balances the equilibrium of mind and body disturbed due to external and internal factors. As a result, it is possible to relieve pain as well as multiple coexisting symptoms. In Japan, Kampo medicine is empirically assumed to be effective and widely applied for the treatment of pain. However, the suitable formula often differs depending on the patient's personality. This inhibits the performance of large clinical trials; most studies are case reports or case series ( Table 5). However, animal studies have recently begun to elucidate the mechanisms of Kampo formulae.

Musculoskeletal Pain Back Pain
Back pain has a prevalence of 24.4% in the Japanese population over 70 years of age (89). Degenerative spine conditions (spondylosis, spinal stenosis, interval disc disease, etc.) and osteoporosis (OP) induce skeletal deformities, joint imbalance, and tension in muscular structures (90), which lead to chronic musculoskeletal pain.
GJG is used to alleviate symptoms in the lower part of the body associated with aging. Hamaguchi et al. reported the efficacy of routine GJG administration for low back pain (LBP) (91). In a retrospective observational study, LBP improved within 6 months in 10 out of 28 patients. Patients with spinal stenosis were less likely to respond to GJG than those without spinal disease. GJG is expected to relieve LBP in patients without spinal disease. In a retrospective cohort study, Oohata et al. reported the efficacy of Kampo medicine in patients with lumbar spinal stenosis (92). Patients received routine medication with or without Kampo treatment. The frequently used Kampo medicines were GJG, HJG, and shakuyakukanzoto.  (100). KSTJB and other Kampo formulae diminished the suffering of a bedridden patient. The patient was able to stand 11 months after treatment. Nakae et al. performed an RCT to compare the efficacies of jidabokuippo (JDI) and nonsteroidal anti-inflammatory drugs (NSAIDs) in young and old patients with rib fracture (101). The treatment duration was significantly shorter in the JDI group than in the NSAID group. Furthermore, healthcare expenditure was significantly lower in the JDI group than in the NSAID group.

Osteoarthritis
Osteoarthritis (OA) has a prevalence of 32.5% in the Japanese population over 60 years of age (102). The pain of OA is attributed to unstable joint structure, anatomical degeneration, and inflammation (103). Though standard pharmacotherapy is used for nociceptive pain, it is sometimes ineffective. Boiohito (BOT) is often used for arthritis of the knee. In an RCT, Majima et al. reported the clinical efficacy of BOT on OA of the knee (104). Patients were assigned to the concomitant-use group (both loxoprofen and BOT) and the loxoprofen group (loxoprofen alone). The knee score, based on the Knee Society Rating System and the 36-item short form from the Medical Outcome Study Questionnaire (SF-36), improved in both groups. However, the score for the ability to climb up and down a staircase, based on the Knee Society Rating System functional score and joint fluid, was significantly improved in the concomitant-use group compared to the loxoprofen group.
Bushi is a crude drug with an analgesic effect. In a nonrandomized prospective study, Nakae reported the efficacy and safety of bushimatu (powdered processed aconite root) for the treatment of pain associated with orthopedic disease (105). OA of the knee was the most common orthopedic disease. Patients were administered bushimatu (1.5-8 g/day) with other Kampo formulae without NSAIDs. Patients with ≥50% and ≥25% reductions in VAS accounted 102 and 84 out of 257 patients, respectively, 4 weeks after treatment. Three patients (1.2%) experienced side effects.

Neuropathic Pain
Neuropathic pain develops after difficult-to-treat injury of neurons along nociceptive pathways. YKS has a variety of neuropharmacological actions, such as neuroprotection, anti-stress effect, promotion of neuroplasticity, and antiinflammatory effect (106). Therefore, YKS is sometimes used to treat neuropathic pain. Nakamura et al. reported 11 cases (36-85 years old) of successful treatment of neuropathic pain [postherpetic neuralgia (PHN), central pain, complex regional pain syndrome, and trigeminal neuralgia] using YKS (107). The patients had VAS scores of 17-81 despite Western conventional treatment. The VAS scores decreased to 0-22 after YKS administration for 2 days to 2 months.
PHN is a persisting neuropathic pain syndrome that occurs after resolution of a herpes zoster (HZ) rash. The frequency increases with age, occurring in 20% of people aged 60-65 years and in more than 30% of people aged >80 years who had acute HZ (108). Nakabayashi et al. published a case series on medication combined with KBG and bushimatsu for patients with PHN (2-92 months after HZ onset) (109). The VAS score improvement rate was 76.5 ± 27.7%. However, three of 15 patients could not continue the study due to hot flashes and gastric discomfort. There are some reports of successful PHN treatment with Kampo medicine (110)(111)(112). In these reports, patients had suffered from PHN from 2 months to 2 years. From 8 weeks to 4 months after treatment, their symptoms disappeared with Kampo medicine. However, in some cases, pain worsened again when the Kampo medication was discontinued. Radical treatment of PHN may be difficult, but it may be effective if Kampo medication is started during the acute stage of herpes infection.
In elderly people, the prevalence of diabetes increases due to glucose intolerance. Diabetic neuropathy is the most common chronic complication, with an estimated lifetime prevalence exceeding 50% (113). In an RCT, Watanabe et al. reported the efficacy of GJG on the progression of type 2 diabetes complications in middle-aged and older people (114). GJG significantly decreased glycated hemoglobin and progression of neuropathy (ankle reflex) when compared with the control. GJG is also used to prevent and relieve peripheral neuropathy due to chemotherapy (115).

Peripheral Arterial Disease
Peripheral arterial disease (PAD) represents atherosclerotic disease associated with aging. PAD has a prevalence of 15-20% in the Japanese population over 70 years of age (116). The clinical presentation of a reduction in limb blood flow includes peripheral coldness, atypical leg pain, or intermittent claudication; as it progresses, it may present with ischemic ulcer or critical limb ischemia.
In a prospective study, Kawago et al. reported the efficacy of HJG for improvement of the QOL in patients with PAD (117). The patients were administered HJG for 6 months without any new interventions. The pain score on the Japanese version of the Walking Impairment Questionnaire (WIQ) improved from 25.0 (0.0-50.0) at baseline to 75.0 (68.8-100.0). The absolute change was 37.5 (25.0-75.0). TSGS improved peripheral blood flow and perception of peripheral coldness (118). In a nonrandomized prospective study, Jojima reported the efficacy of TSGS for arteriosclerosis obliterans (ASO) (119). TSGS and cilostazol improved the absolute claudication distance 1 and 3 months after treatment. However, side effects were observed in 4% of patients treated with TSGS, while they were observed in 38% of patients treated without Kampo. One case report has been published regarding Kampo treatment for severe limb pain with ASO (120). A decoction of KBG and daisaikoto relieved pain, coldness, and ischemic ulcers and eliminated the need for limb amputation.

Rehabilitation
Physical exercise is necessary to improve pain and prevent secondary injuries. However, elderly individuals often cannot take exercise sufficiently due to frailty or sarcopenia.
Hozai is one group of Kampo formulations that restore vitality to patients who have lost psychological and physical energy due to various diseases or aging (121). These formulations improve pain in various conditions induced by sarcopenia and frailty, such as fatigue, anorexia, and mental problems. Sakamoto et al. reported their experience of using Kampo, mainly Hozai formulae (RKT, HET, NYT, etc.) for rehabilitation (122). In a prospective non-RCT, Sakisake et al. reported the efficacy of NYT against frailty (123). Administration of NYT for 24 weeks prevented deterioration of muscle mass and muscle quality score when compared to the control group. Furthermore, the NYT group significantly improved grip strength, whereas there was no change in the control group.

DISCUSSION
Here, we reviewed RCTs on the efficacy of Kampo medicine for GS. Figure 1 shows the relationship between Kampo medicines and organs and physiological systems. One of the characteristics of Kampo medicine is the use of multiple crude drugs ( Table 6). Therefore, Kampo medicine can act upon multiple organs and physiological systems. HET is effective for COPD, nutrition, anti-inflammation, and QOL; RKT for GERD, NERD, FD, and appetite; and DKT for constipation and perioperative conditions. As GS symptoms are expressed by the 3Ms or 4Is, Kampo medicine can contribute to GS.
The possible mechanisms of Kampo medicines have been reported in recent years. For example, YKS is composed of seven crude drugs ( Table 6) and has been used to improve irritation, insomnia, muscle twitching, and pain. Several studies reported various neuropharmacological actions of YKS, namely, on serotonergic, glutamatergic, cholinergic, dopaminergic, adrenergic, and gamma-aminobutyric acidergic neural systems (124). These actions maintain neural signal conduction and neuronal function of neurons as well as glial cells (125). GJG is composed of 10 crude drugs and has been used to alleviate various types of age-related conditions, including muscle weakness of the lower limbs, dysuria, foot edema, and cold sensation of the lower limbs. Recently, GJG is used to prevent and relieve various types of peripheral neuropathy. GJG has antinociceptive effects via increasing produced nitric oxide (126), reduces hypersensitivity by suppressing the overexpression of TRPM8 and TRPA1 mRNA (127), and ameliorates allodynia via the suppression of TNF-α expression in the spinal cord (128). Furthermore, GJG has also been reported to suppress sarcopenia via the insulin growth factor-1/insulin pathway, maintains the expression of mitochondrial-related transcription factors, and suppresses the expression of TNF-α (129).
DKT is composed of four crude drugs and has been used to treat abdominal pain and abdominal bloating with abdominal coldness. DKT treats abdominal symptoms by enhancing the secretions of motilin (130), substance-P, calcitonin gene-related peptide, and adrenomedullin (131)(132)(133) and activating the transient receptor potential of the vanilloid receptor complex (134). RKT is composed of eight crude drugs and has been used to treat appetite loss, upper abdominal discomfort, and indigestion. A recent study reported that RKT increases plasma ghrelin levels in humans and mice (135) and restores decreased plasma ghrelin levels induced by serotonin release in rats. HKT is composed of five crude drugs and has been used for pharyngeal discomfort. It has been reported that HKT modulates cerebral levels of 5-hydroxytryptamine, noradrenaline, and dopamine in mice (20).
The efficacy and safety of Kampo medicine were investigated in several clinical studies. Based on these reports, clinical practice guidelines have recommended Kampo medicines for symptoms in geriatrics. Our previous study (136) In recent years, the usefulness of Kampo medicine in the clinical setting has been investigated using the diagnosis procedure combination (DPC) inpatient database in Japan ( Table 7). A propensity score analysis using DPC is a retrospective investigation; however, the groups of patients with or without intervention can be matched, and the subject number is large. Thus, this method can show the intervention's effect and influence on the social economy. Jo et al. reported a reduction in the exacerbation of COPD in patients of advanced age using DKT (33). DKT users had a significantly lower risk of rehospitalization or death after discharge. Subgroup analysis of long-acting muscarinic receptor antagonist users showed a significant difference in rehospitalization or death, while subgroup analysis of long-acting muscarinic receptor antagonist nonusers showed no significant difference. Yasunaga reported the effects of GRS on reoperation rates after burr-hole surgery for chronic subdural hematoma (146). GRS use was significantly associated with a lower reoperation rate when compared with nonuse. These results suggest that GRS use reduced the need for reoperation after burr-hole surgery for chronic subdural hematoma. Yasunaga et al. also reported effects of DKT on postoperative adhesive small bowel obstruction requiring long-tube decompression (LTD) (147). DKT use was associated with a significantly shorter duration of LTD, a shorter duration between long-tube insertion and discharge, and  lower hospital charges when compared with DKT nonuse. This suggests that DKT effectively reduces the duration of LTD and saves costs. Not only the efficacy but also adverse drug reactions (ADRs) were reported in RCTs of Kampo medicine (148). The total incidence of ADRs was 2.47%, and those of pseudoaldosteronism and liver disorders caused by Kampo medicine were 0.02 and 0.16%, respectively. In our previous study, the incidence of ADRs was 0.09% for BAK, 0.44% for DKT, 2.04% for RKT, 1.7% for GJG, 3.45% for HET, 3.34% for CTS, 4.41% for NYT, and 5.17% for YKS. Many of the ADRs were gastrointestinal disorders.
Due to an increase in Japan's "super-aging population" and a decline in the country's birth rate, medical expenses are expected to increase and pose an important problem. Furthermore, medical expenses have grown every year. This review has shown the efficacy, safety, and the social and economic advantages associated with Kampo treatment.