Effect of Shakuyaku‐kanzo‐to in patients with muscle cramps: A systematic literature review

Abstract Background Previous clinical studies have reported that Shakuyaku‐kanzo‐to (SKT) has a therapeutic effect on muscle cramps, but few studies have clarified how SKT acts to treat muscle cramps. The aim of this study was to perform an updated systematic review of clinical trials for SKT in patients with muscle cramps. Methods The literature was systematically reviewed to assess the effects of SKT in patients with muscle cramps. PubMed, Web of Science, Cochrane Library, Google Scholar, and Ichushi‐Web were searched using the terms “Shakuyaku‐kanzo‐to” (“shakuyakukanzoto”, etc), “clinical trials” and “muscle cramps”. Two quality assessments were conducted independently by three authors. Data were extracted using a standardized extraction tool, and a qualitative synthesis of evidence was performed. Results Three randomized controlled articles were identified and enrolled in this study. A systematic review, but not a meta‐analysis, was performed because of the high heterogeneity and limited number of studies. In patients with liver cirrhosis, the odds ratio (OR) for improvement with SKT compared to placebo was 1.27 (95% confidence interval [CI], 0.445‐2.086) and compared to Goshajinkigan was 0.81 (95%CI, −1.734‐0.114). The OR for improvement with SKT compared with eperisone hydrochloride in patients with lumbar spinal stenosis was 2.86 (95%CI, 0.980‐4.744). Conclusions Current evidence appears insufficient to allow a meta‐analysis of the effects of SKT, but SKT might show efficacy in treating muscle cramps in patients with cirrhosis or lumbar spinal stenosis.


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OTA eT Al. structural disorders or leg positioning; neurologic disorders; metabolic disorders, including extracellular fluid volume depletion and electrolyte disturbances; and medications. The latest scientific research suggests the primary cause of muscle cramps involves spinal pathways rather than peripheral excitation of the motor neurons, although the etiology remains unclear. 1,2 The Japanese traditional herbal medicine Shakuyaku-kanzo-to (SKT) represents an equal combination of the roots of Radix paeoniae (peony) and R glycyrrhizae (licorice), and has long been used for the treatment of muscle cramps in Kampo medicine (Japanese traditional medicine). Two components of SKT can promote an efflux of potassium ions and inhibit the intracellular influx of calcium ions by inhibiting Ca 2+activated K + channels. [3][4][5] Although the mechanisms underlying the actions of SKT in the inhibition of muscular contraction remain unclear, SKT can act on receptors at neuromuscular synapses with an antispasmodic effect and may act on spinal pathways with antinociceptive effects. While several animal studies and case reports have investigated the effectiveness of SKT, clinical evidence is needed to clarify how SKT is effective against muscle cramps. We therefore aimed to prepare an updated systematic review of SKT in the treatment of muscle cramps.

| Search strategy
A search strategy was developed using PubMed, Web of Science, Cochrane Library, Ichushi-Web, and Google Scholar without language limitations in January 2019. Searches were made with filtering for the following keywords: "Shakuyaku-kanzo-to", "Shakuyakukanzoto", "Shakuyakukanzo-to", "Shakuyakukanzo to", "Shakuyaku kanzo to"; "muscle cramps"; and "Clinical trial". AND and NOT "animal study" were applied to a database to create subsets of search results. Citations of studies obtained in the search were also comprehensively reviewed.

| Inclusion criteria
All studies investigating the efficacy of SKT in the treatment of muscle cramps were included, because the number of studies into SKT use was small.

| Exclusion criteria
Studies meeting any of the following criteria were excluded: (a) studies for which the full text was not available in English or Japanese; (b) studies focusing on topics other than use of SKT; (c) studies focusing on topics other than muscle cramps; (d) animal studies; and (e) reviews, letters, or editorials.

| Data extraction and quality assessment
The PRISMA guideline and Cochrane Handbook for Systematic Reviews of Interventions were used when searching articles. 6 We published the protocol for this systematic review in the PROSPERO database (identifier: CRD 42019123160). The following data were extracted from eligible studies: (a) study characteristics (authors, year of publication, institution and country of the study, study period, number of patients, and study design [randomized vs nonran-

| Data synthesis and statistical analysis
The primary outcome examined in this study was the efficacy of SKT against muscle cramps. The incidence of adverse events associated with SKT was evaluated as an additional outcome. Calculation of these outcomes was attempted using a  All three studies were conducted in Japan. Blinded and nonblinded randomized controlled trials of SKT in patients with muscle cramps were included.

| Study characteristics
Age distributions were similar in the three studies, but patient background characteristics differed (Table 1). Patients with cirrhosis were the target population in the studies of Kumada et al 8

and
Nishizawa et al, 9 whereas patients with lumbar spinal stenosis were the target in the study by Takao et al. 10 Meta-analysis was not feasible because of the high heterogeneities and limited number of studies, so only a systematic review was performed.

| Outcomes
Kumada et al 8 reported that the improvement rate ("markedly improved" or "improved") in terms of the frequency of muscle cramps was significantly superior with SKT than with placebo (Wilcoxon rank-sum test, P = .011) in patients with liver cirrhosis. The OR for improvement comparing the SKT group to the placebo was 1.27 (95% confidence interval [CI]: 0.445-2.086; Figure 2A). Nishizawa   Figure 2C). The ORs of all three studies did not show statistical significance.

| Quality assessment
The quality of the studies included in this review varied considerably. We evaluated the methodological quality of the three studies using the Cochrane risk-of-bias criteria and a modified version of the assessment checklist developed by Downs and Black (Tables 2 and   3

| D ISCUSS I ON
The present systematic review included only three clinical trials that investigated the efficacy of SKT against muscle cramps. These three studies had insufficient methodological quality, and we were thus unable to reach statistically valid conclusions. Although meta-analysis could not be conducted because of the heterogeneity of the data and the small number of studies, SKT showed some clinical efficacy and safety in treating muscle cramps.
Shakuyaku-kanzo-to has significantly mitigated muscle symptoms in patients with a wide variety of underlying diseases. SKT has been found to show immediate efficacy against painful muscle cramps induced by liver cirrhosis, hemodialysis, 11,12 and diabetic neuropathy. 13 SKT has been reported to inhibit acetylcholine-induced and neurogenic contractions of the gastrointestinal tract and to decrease unfavorable smooth muscle contractions during upper and lower gastrointestinal endoscopy. 14-16 SKT also inhibits oxytocin-induced myometrial contractions of uterine tissue in pregnant women in a dose-dependent manner. 17,18 In addition to ameliorating muscle symptoms, SKT has been found to improve extrapyramidal symptoms while exerting no significant effect on psychiatric symptoms. 19 SKT has also been reported to ameliorate the myalgia and arthralgia induced by chemotherapy, using combination of paclitaxel and carboplatin in patients with non-small-cell lung cancer 20  because it can act quickly and the prolonged usage can potentially cause pseudoaldosteronism.
In conclusion, current evidence appears insufficient to allow adequate meta-analysis of the effects of SKT, but SKT showed efficacy in the treatment of muscle cramps in patients with cirrhosis or lumbar spinal stenosis. Further randomized controlled trials with larger sample sizes are needed to assess the efficacy of SKT for muscle cramps.

ACK N OWLED G EM ENTS
We wish to thank Tsumura & Co. (Tokyo, Japan) for providing the information on SKT and its adverse effects.

CO N FLI C T O F I NTE R E S T S
The authors have stated explicitly that there are no conflicts of interest in connection with this article.

AUTH O R S CO NTR I B UTI O N S
KO designed the study and wrote the initial draft of the manuscript. KF contributed to analysis and interpretation of data, and assisted in the preparation of the manuscript. All other authors have contributed to data collection and interpretation, and critically reviewed the manuscript. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

E TH I C S A PPROVA L A N D CO N S E NT TO PA RTI CI PATE
Not applicable.

CO N S E NT TO PU B LI S H
Not applicable.

DATA AVA I L A B I L I T Y S TAT E M E N T
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.