Investigation on Chinese herbal medicine for primary dysmenorrhea: Implication from a nationwide prescription database in Taiwan

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Complementary Therapies in Medicine (2013) xxx, xxx—xxx

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Investigation on Chinese herbal medicine for primary dysmenorrhea: Implication from a nationwide prescription database in Taiwan Hsing-Yu Chen a,b, Yi-Hsuan Lin a,b, Irene H. Su c, Yu-Chun Chen d,e,∗, Sien-hung Yang a,f, Jiun-liang Chen a,f,g a

Division of Chinese Internal Medicine, Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan b Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung, University, Taoyuan, Taiwan c University of California, San Diego, Department of Reproductive Medicine, La Jolla, CA, United States d Department of Medical Research and Education, National Yang-Ming University Hospital, I-Lan, Taiwan e Institute of Hospital and Health Care Administration, School of Medicine, National, Yang-Ming University, Taipei, Taiwan f School of Traditional Chinese Medicine, College of Medicine, Chang Gung, University, Taoyuan, Taiwan g Institute of Traditional Medicine, School of Medicine, National Yang-Ming, University, Taipei, Taiwan

KEYWORDS Primary dysmenorrhea; Chinese herbal medicine; The National Health Insurance Research Database; Association rule mining

Summary Objective: Primary dysmenorrhea is a common gynecological condition, for which Chinese herbal medicine (CHM) has been widely used in addition to western medicine. The aim of this study is to explore CHM commonly used to treat dysmenorrhea in young Chinese women. Design: Observational retrospective study. Setting: The National Health Insurance Research Database in Taiwan. Population: Women aged from 13 to 25 years with single diagnosis of primary dysmenorrhea. Methods: CHM prescriptions made for primary dysmenorrhea women during 1998—2008 were extracted to build up CHM prescription database. Association rule mining was used to explore the prevalent CHM combination patterns in treating primary dysmenorrhea. Main outcome measures: Prevalence and mechanisms of CHM combinations. Results: Totally 57,315 prescriptions were analyzed and, on average, 5.3 CHM was used in one prescription. Dang-Gui-Shao-Yao-San (DGSYS) was the most commonly used herbal formula (27.2%), followed by Jia-Wei-Xiao-Yao-San (JWXYS) (20.7%) and Wen-Jing-Tang (WJT) (20.5%).

∗ Corresponding author at: Department of Medical Research and Education, National Yang-Ming University Hospital, No. 152, Xin Min Rd, 26042 I-Lan, Taiwan. Tel.: +886 3 932 5192x1750. E-mail address: [email protected] (Y.-C. Chen).

0965-2299/$ — see front matter. Crown Copyright © 2013 Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ctim.2013.11.012

Please cite this article in press as: Chen H-Y, et al. Investigation on Chinese herbal medicine for primary dysmenorrhea: Implication from a nationwide prescription database in Taiwan. Complement Ther Med (2013), http://dx.doi.org/10.1016/j.ctim.2013.11.012

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H.-Y. Chen et al. Corydalis yanhusuo and Cyperus rotundus were the most commonly used single herb, found in 33.1% and 29.2% of all prescriptions. Additionally, C. yanhusuo with C. rotundus is the most commonly used two CHM in combination, accounting for 14.24% of all prescriptions, followed by DGSYS with C. yanhusuo (10.47%). Multi-target effects on primary dysmenorrhea, such as analgesia, mood modifying and hormone adjustment, were found among commonly prescribed CHM in this study. Conclusions: This study discovered the potential importance of C. yanhusuo, C. rotundus and DGSYS in treating primary dysmenorrhea. Further clinical trials or bench studies are warranted based on the results. Crown Copyright © 2013 Published by Elsevier Ltd. All rights reserved.

Introduction Dysmenorrhea is the most prevalent gynecological discomfort among women during reproductive age and it is also the main reason for sick leave or short-term absenteeism among school-aged girls.1,2 Six-hundred million hours lost from work and two billion US dollar economic cost was reported in the mid 1980s in the United States and the cost is believed to be much higher today.3,4 Primary dysmenorrhea is characterized by cramping, colicky, or dull suprapubic pain associated with menses in the absence of other gynecologic pathology such as endometriosis, uterine myoma, or malformation of genital organs; additionally, this pain usually happens few hours before or after onset of menstrual bleeding; the duration of pain may last 2—3 days.5 The onset of primary dysmenorrhea is usually during mid and late adolescence after normal ovulatory patterns are established.1 The mechanisms of primary dysmenorrhea have been attributed to the high serum level of prostaglandin E2 (PGE2), prostaglandin F2-␣ (PGF2-␣), and leukotriene among primary dysmenorrhea women. Severe myometrial contraction, vasoconstriction, uterine ischemia, and subsequent dysmenorrheic pain are resulted from the release of these cytokines. Moreover, progesterone withdrawn before the beginning of menstrual cycle initiates the arachidonic acid release and further cytokine from degradation of arachidonic acid. Higher cytokine level contributes to higher intensity of dysmenorrhea pain and the associated symptoms.6—8 Non-steroid anti-inflammatory drugs (NSAID), therefore, are the primary treatment for this condition, but are limited by inadequate pain control, gastrointestinal discomfort and impact on renal function. Combined oral contraceptives are also frequently used, but are not universally accepted perhaps due to its potential side effects on inducing endometriosis.2,9 For the above reason, alternative therapies are in high demand in many countries.10 Chinese herbal medicine (CHM) is well-accepted and commonly used in Taiwan to treat various conditions, such as menopausal symptoms, gastrointestinal dysfunction and allergic diseases.11,12 For primary dysmenorrhea, CHM has been shown to be more effective than other TCM interventions, such as acupuncture in previous metaanalysis, although the quality of clinical trials were generally poor.4 In addition to diagnosis of a particular disease, TCM doctors focus on the sub-categories of disease, namely ‘‘syndrome’’, or ‘‘zheng’’ in Chinese; for example, colddampness stagnation, and blood-qi stagnation syndrome of dysmenorrhea.13,14 Each TCM syndrome is judged by TCM doctor on the basis of patient’s physical condition, disease

status, and constitution,15 after which CHM prescriptions for treatment are given. The combinations of CHM used to treat dysmenorrhea are heterogeneous and not wellcharacterized. Identifying these common combinations of CHM will enhance understanding of diseases and focus intervention trials. Therefore, the aim of this study is to determine the pattern of use of CHM to treat primary dysmenorrhea in young Chinese women by using a nationwide prescription database.

Methods Chinese herbal medicine (CHM) in Taiwan The National Health Insurance (NHI), which provides coverage for more than 98% of the population of Taiwan, includes prescription coverage for CHM. Prescriptions for CHM and western medicine (WM) are equally covered by national health insurance in Taiwan, and therefore patients are free to choose treatments. There are two types of CHM reimbursed by the NHI in Taiwan, herbal formulas (HF) and single herbs (SH). SH are single Chinese medical substances recorded in the ancient classics, and they are obtained and processed from individual plants, animals, insects or even minerals. In contrast, HF are mixtures of several SH with fixed proportions according to ancient TCM classics and have specific indications to TCM syndrome and purported therapeutic effectiveness. HF and SH are all processed into concentrated powders. Additionally, CHM in Taiwan is provided by pharmaceutical manufacturers with certificates of Good Manufacturing Practice and is closely monitored by the government.

Chinese herbal medicine (CHM) prescription database The national insurance claim database captures contents of every ambulatory visits, including reasons for visits, facilities visited, examinations ordered by doctors, and prescriptions. Additionally, patients’ characteristics are recorded in detail, such as gender, birth date, critical illness and identification number. All these claim data are recompiled by the National Health Research Institutes (NHRI) to build up the National Health Insurance Research Database (NHIRD). The NHIRD becomes a nationwide database since the coverage of the national health insurance (NHI) is as high as 98.3% and keeps increasing. From the entire database, a total of two million patients were sampled randomly by the

Please cite this article in press as: Chen H-Y, et al. Investigation on Chinese herbal medicine for primary dysmenorrhea: Implication from a nationwide prescription database in Taiwan. Complement Ther Med (2013), http://dx.doi.org/10.1016/j.ctim.2013.11.012

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managers of the NHIRD to build up the CHM prescription database. This CHM prescription database well represented the content of whole NHIRD since no differences in patient’s age or gender between these two databases were reported by the NHRI.

Inclusion and exclusion criteria Subjects within the NHIRD were eligible if they were female, between ages 13 and 25, and incurred a primary diagnosis of dysmenorrhea (ICD-9 625.3) at an ambulatory visit between 1998 and 2008. Clinically, primary dysmenorrhea was diagnosed by exclusion of other uterine or anatomyrelated disorders, such as endometriosis, uterine myoma or congenital deformities.16 To obtain cases of primary dysmenorrhea, we excluded subjects with other ICD-9 code in second or third diagnosis. Ambulatory visits within the NHIRD can be coded for up to 3 diagnoses using the 9th version of International Classification of Diseases, Clinical Modification (ICD-9-CM). Importantly, the first code is required to be the main reason for each visit. The reliability of ICD-9 coding as reasons for visits has been demonstrated in prior studies.17,18 Moreover, the age range was selected because primary dysmenorrhea occurred in adolescent much more than adult.16 However, there was yet definite range for primary dysmenorrhea so far. Primary dysmenorrhea usually occurred about 1—3 years after menarche and might persist during entire adulthood. While the onset of symptoms was later, the possibility of primary dysmenorrhea was much lower.16 In Taiwan, menarche was usually found at 9—14 years old (mean age is 11.67 years), and endometriosis, the most prevalent etiology of secondary dysmenorrhea, was much more prevalent in patients older than 30 years.19,20 As a consequence, the age limitation was set between 13 years and 25 years for the most precise population selection for primary dysmenorrhea in this study.

Ethical considerations This study was approved by the Institutional Review Board (IRB) of Chang Gung Medical Foundation, Taipei, Taiwan (IRB 101-3604b). Patient’s privacy is well protected, since patient’s identification number is well encrypted in the NHIRD and thus it is impossible to trace for the patient’s true identity.

Statistical analysis Association rule mining (ARM) was used in this study to explore the combination patterns of CHM frequently used for primary dysmenorrhea. As a datamining technique, ARM aimed to discover relationships among variables in large-scale databases and has been extensively applied in several subjects, such as CHM combination patterns, WM co-prescription medications, TCM syndrome differentiation, and co-morbidities.11,15,21—23 By using two factors, support and confidence, ARM was efficient in discovering important CHM combinations in large scale prescription databases. For example, if there were two CHM, namely CHM A and CHM B, support factor, similar to prevalence of CHM or

Figure 1 Distribution of Chinese herbal medicine (CHM) counts per prescription.

combinations, was defined as the percentage of CHM A or CHM B among all possible combinations. Additionally, confidence factor was the conditional probability of CHM A and CHM B under the existence of CHM A, which could be expressed as probability (CHM A ∩ CHM B)/probability (CHM A), and higher value of confidence factor meant closer connections between CHM A and CHM B. Decision of thresholds of support and confidence factors was an iterative process and thus expert opinion was still necessary. In this study, the support and confidence factors were set to 1% and 30%, respectively. Results from these setting were quite meaningful and compatible with clinical experience.11 The software R (version 2.15.1) with ‘‘arules’’ statistical package was used to manage and analyze the dataset. Most frequently coprescribed CHM for primary dysmenorrhea were presented as a network graph using an open-sourced software NodeXL (http://nodexl.codeplex.com/).

Results 57,315 CHM prescriptions made for 20,141 TCM users during 1998—2008 were included in this study. A total of 647 different CHM were used and each prescription contained 5.32 CHM on average. Fig. 1 demonstrates that TCM doctors commonly made up a prescription by 5 CHM and more than 90 percent prescriptions contained more than two CHM. Among all HF, Dang-Gui-Shao-Yao-San (DGSYS) was used most commonly (27.2%), followed by Jia-Wei-Xiao-Yao-San (JWXYS, 20.7%), and Wen-Jing-Tang (WJT, 20.5%) (Table 1). The minor difference in prevalence between HF implied that each HF might have its own unique role in treating primary dysmenorrhea. Corydalis yanhusuo was the most commonly prescribed SH, and one-third prescriptions contained C. yanhusuo (Table 2). Cyperus rotundus was the second commonly used SH for dysmenorrhea, with a rather high prevalence similar to C. yanhusuo (29.2% of all prescriptions). Additionally, the TCM syndromes, as specific references for prescribing CHM, were also listed and summarized. Qi stagnation and blood stasis was the main syndrome for prescribing CHM (Tables 1 and 2). As the important indications for prescribing CHM, TCM syndromes were implications from

Please cite this article in press as: Chen H-Y, et al. Investigation on Chinese herbal medicine for primary dysmenorrhea: Implication from a nationwide prescription database in Taiwan. Complement Ther Med (2013), http://dx.doi.org/10.1016/j.ctim.2013.11.012

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H.-Y. Chen et al. Table 1

The top five most frequently used herbal formula (HF) for primary dysmenorrhea among 57,315 prescriptions.

Name

Constituents

TCM syndrome

Prevalence (%)

Dang-Gui-Shao-Yao San (DGSYS)

Angelicae sinensis, Ligustici chuanxiong, Paeoniae alba, Atractylodis macrocephalae, Poriae cocos, and Alisma plantago-aquatica

15,615 (27.2)

Jia-Wei-Xiao-Yao-San

Paeoniae alba, Bupleurum chinense, Atractylodis macrocephalae, Poriae cocos, Angelicae sinensis, Mentha haplocalyx, Glycyrrhizae uralensis, Zingiberis officinalis recens, Paeonia suffruticosa radicis, and Gardeniae jasminoidis Evodia rutaecarpa, Cinnamomum cassia, Angelica sinensis, Paeoniae alba, Ligustici chuanxiong, Panax ginseng, Glycyrrhizae uralensis, Equus asinus, Ophiopogon japonicus, Pinellia ternata, and Zingiberis recens Cinnamomum cassia, Poriae cocos, Paeoniae alba, Paeonia suffruticosa, and Prunus persica Foeniculum vulgare, Zingiberis recens, Cinnamomum cassia, Angelicae sinensis, Ligustici chuanxiong, Peoniae rubra, Trogopterus xanthipes, Typha angustifolia, Myrrha, Corydalis yanhusuo

Liver blood deficiency and disharmony of Liver and Spleen Liver qi stagnation and spleen deficiency

Wen-Jing-Tang

Gui-Zhi-Fu-Ling-Wan Shao-Fu-Zhu-Yu-Tang

comprehensive analysis on patients’ symptoms and signs. Therefore, Qi stagnation and blood stasis may be the most important syndrome for primary dysmenorrhea on TCM’s viewpoint. C. yanhusuo combined with C. rotundus were the central part of two or three CHM commonly used in combination (Tables 3 and 4). Among all two CHM in combination, C. yanhusuo with C. rotundus had the highest prevalence, 14.24% of all prescriptions, followed by DGSYS with C. yanhusuo (10.47%) and Herba Leonuri with C. rotundus (8.86%). Moreover, among all three CHM in combination, DGSYS plus C. rotundus with C. yanhusuo was the most prevalent combination (4.67%), followed by Leonurus heterophyllus plus C. rotundus with C. yanhusuo (3.98%). Clearly, the combination of C. yanhusuo and C. rotundus had a crucial role in

Table 2

11,846 (20.7)

Deficient cold and blood stasis

11,750 (20.5)

Blood stasis in uterus Qi stagnation, and blood stasis

10,437 (18.2) 9025 (15.7)

treating primary dysmenorrhea, and the importance may be higher than any of HF due to the high prevalence among all CHM whether used alone or in combination. Moreover, combing with C. yanhusuo and C. rotundus, DGSYS was the most commonly used HF, account about 5% of all prescriptions, followed by JWXYS (3%) and WJT (2.94%) (Table 4). The relations between commonly used CHM can be presented as a pharmacological network to find the role of single CHM among all available options (Fig. 2). The higher prevalence of significant combinations, defined as confidence higher than preset threshold, was presented with thicker connection lines; while the more connections to a CHM meant that the more crucial role among all CHM. The central role of C. yanhusuo and C. rotundus in treating primary dysmenorrhea can be reasonably assumed in Fig. 2.

The top ten most frequently used single herb (SH) for primary dysmenorrhea among 57,315 prescriptions.

Latin scientific name

TCM syndrome

Prevalence (%)

Corydalis yanhusuo Cyperus rotundus Leonurus heterophyllus Trogopterus xanthipes Salviae miltiorrhizae Meliae toosendan Typha angustifolia Lindera aggregata Eucommiae ulmoidis Lycopus lucidus

Qi stagnation and blood stasis Liver Qi stagnation Blood stasis Blood stasis Blood stasis Qi stagnation Blood stasis Qi stagnation and Kidney cold deficiency Liver and Kidney deficiency Blood stasis

18,992 (33.1) 16,733 (29.2) 11,244 (19.6) 5475 (9.5) 5133 (9.0) 4976 (8.7) 4880 (8.5) 4104 (7.1) 2666 (4.6) 2506 (4.4)

Please cite this article in press as: Chen H-Y, et al. Investigation on Chinese herbal medicine for primary dysmenorrhea: Implication from a nationwide prescription database in Taiwan. Complement Ther Med (2013), http://dx.doi.org/10.1016/j.ctim.2013.11.012

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Table 3 The top ten most frequently used two Chinese herbal medicine (CHM) in combination for primary dysmenorrhea (number of total prescriptions, n = 57,315). Combination of two CHM

Prescription counts

Prevalence (%)

Cyperus rotundus with Corydalis yanhusuo Dang-Gui-Shao-Yao-San with Corydalis yanhusuo Leonurus heterophyllus with Cyperus rotundus Dang-Gui-Shao-Yao-San with Cyperus rotundus Leonurus heterophyllus with Corydalis yanhusuo Meliae toosendan with Corydalis yanhusuo Jia-Wei-Xiao-Yao-San with Cyperus rotundus Wen-Jing-Tang with Corydalis yanhusuo Trogopterus xanthipes with Typha angustifolia Wen-Jing-Tang with Cyperus rotundus

8159 6001 5079 5000 4156 3878 3802 3784 3696 3540

14.24 10.47 8.86 8.72 7.25 6.77 6.63 6.60 6.45 6.18

Table 4 The top five most frequently used three Chinese herbal medicine (CHM) in combination for primary dysmenorrhea. (number of total prescriptions, n = 57,315). Combination of three CHM

Prescription counts

Prevalence (%)

Dang-Gui-Shao-Yao-San plus Cyperus rotundus with Corydalis yanhusuo Leonurus heterophyllus plus Cyperus rotundus with Corydalis yanhusuo Typha angustifolia plus Trogopterus xanthipes with Corydalis yanhusuo Jia-Wei-Xiao-Yao-San plus Cyperus rotundus with Corydalis yanhusuo Wen-Jing-Tang plus Cyperus rotundus with Corydalis yanhusuo

2679 2278 1832 1719 1686

4.67 3.98 3.20 3.00 2.94

Discussion This is the first large-scale pharmaco-epidemiological report about CHM commonly used for primary dysmenorrhea. To treat primary dysmenorrhea, TCM doctors usually prescribe

Figure 2 Visualization of frequently co-prescribed Chinese herbal medicine (CHM) for primary dysmenorrhea. Gray straight lines represent connections between CHM, thicker connection lines means higher prevalence of combinations. Abbreviations: SFZYT, Shao-Fu-Zhu-Yu-Tang; GZFLW, Gui-Zhi-Fu-Ling-Wan; DGSYS, Dang-Gui-Shao-Yao-San; JWXYS, Jia-Wei-Xiao-Yao-San; WJT, Wen-Jing-Tang; CHM, Chinese herbal medicine

multiple CHM at the same time and the nature of therapeutic effects on multi-organ achieved by CHM makes it possible to relieve pain and adjust constitution such as mood disorder and hormone imbalance, in one prescription. In average, 5.32 CHM was used in one prescription to achieve the therapeutic goal, and more than 90% prescriptions contain more than 3 CHM in this study (Fig. 1). This result is similar to our previous work for menopausal syndrome (5.46 CHM per prescription in average) and it may be attributed to the complexity of menstrual disorder.11 Among commonly used CHM, C. yanhusuo and C. rotundus were central components of treating primary dysmenorrhea. This fact is not only supported by TCM viewpoints but also the potential pharmacological mechanisms provided from bench and clinical studies. As an external validation, Pubmed was searched for the possible mechanisms and effectiveness of CHM on primary dysmenorrhea (accessed 05.11.12) in accordance with the Latin scientific names of SH and all possible naming of HF, such as Kampo names and English names. Nearly all CHM commonly used for primary dysmenorrhea has analgesic effects (Table 5). The mechanisms of analgesia among CHM include anti-inflammation, reducing prostaglandin, vasorelaxation, and anti-oxidation. These mechanisms are comparable to NSAID used for primary dysmenorrhea. However, more than the NSAID-like cyclooxygenase inhibitor, C. yanhusuo and C. rotundus also have anxiolytic effect and ability to inhibit 5-lipoxygenase respectively, and these plausible effects may be the reason for the high prevalence of C. yanhusuo and C. rotundus among all CHM.24,25 In this study, C. yanhusuo and C. rotundus were tightly linked to several CHM, which were regularly used to

Please cite this article in press as: Chen H-Y, et al. Investigation on Chinese herbal medicine for primary dysmenorrhea: Implication from a nationwide prescription database in Taiwan. Complement Ther Med (2013), http://dx.doi.org/10.1016/j.ctim.2013.11.012

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H.-Y. Chen et al. Table 5

The possible mechanisms of Chinese herbal medicine (CHM) in treating primary dysmenorrhea.

CHM

Active ingredients

Possible mechanisms

Single herb (SH) Corydalis yanhusuo

Corydalis alkaloid

Cyperus rotundus

Hydroalcoholic extract

Leonurus heterophyllus

Leonurine Methanol extract Water extract Salvianolic acid B Tanshinone IIA

Analgesia via increasing serum DL-tetrahydropalmatine in mice model43 Analgesia by oral intake of tetrahydropalmatine in rat model44 Anxiolytic effects in rat model24 Antioxidation and free radical scavenger in vitro45 5-Lipoxygenase inhibitor in vitro and in mice model25 Anti-inflammation via suppressing overproduction of NO in vitro46 Endothelium-independent vasorelaxation in vitro41 Anti-inflammation in vitro and in rat model47,48 Anti-oxidative stress in rat model49 Analgesia in vivo50 Analgesia by inhibiting ERKs pathway and decreasing pro-inflammatory response in rat model51 Anti-inflammation and analgesia in mice model52 Anti-oxidation in vitro53 Endothelium-dependent vasorelaxation in vitro54

Salviae miltiorrhizae

Meliae toosendan Eucommiae ulmoidis Herbal formula (HF) Dang-Gui-Shao-Yao-San

Jia-Wei-Xiao-Yao-San

Wen-Jing-Tang

Gui-Zhi-Fu-Ling-Wan

Shao-Fu-Zhu-Yu-Tang

Ethanol extract Water extract

Anti-oxidation in vitro32 Analgesic effects on dysmenorrhea for women with TCM syndrome ‘‘Yin deficiency, cold, and stagnated blood’’ in a double-blinded clinical trial29 Suppress contraction of uterus smooth muscle in vitro55 Correct luteal phase insufficiency in women31 Anti-depression effect from suppressing central arginine vasopressin in mice and rat model33 Anti-depression effect in rat model26 Anxiolytic effect via stimulation of gamma-amino-butyric acid A/benzodiazepine receptor and synthesis of neurosteroid in mice model27,56 Suppress uterus contraction via antagonism of prostaglandin F2␣ and acetylcholine in vitro57 Endocrine adjustment for women with luteal phase insufficiency58 Anti-inflammation via suppressing cyclo-oxygenase-2 in vitro59 Increase progesterone secretion and decrease estradiol level in vitro60 Gonadotropin-releasing hormone antagonist and anti-estrogen effect in rat model61 Analgesia via decreasing prostaglandin E2 in vitro62

treat mood disorders, such as JWXYS and DGSYS (Fig. 2). Though no analgesic effects has been reported, Chen et al. believed, JWXYS is effective in treating mood disorder, such as depression26 and anxiety,27 and it is also the most commonly prescribed HF for menopausal syndrome for the same reason.11 Gamma-amino-butyric acid A/benzodiazepine receptor stimulation and hippocampal neurogenesis enhancement have been reported to and thus effective in both anxiety and depression disorders.26,27 The bi-directional mood adjustment effect may explain the second high prevalence of JWXYS in menstrual disorders since anxiety and depression are both common complaints of patients with menopause or primary dysmenorrhea.2,28

DGSYS was the most commonly used HF for primary dysmenorrhea. In addition to anti-depression effect, the analgesic effect on primary dysmenorrhea was proven in one clinical trial, in which dose of diclofenac was able to be reduced after treating for 2 months.29 Based on this evidence, the use of DGSYS for primary dysmenorrhea was thought to be helpful and thus suggested in a consensus guideline.5 Dang gui (Angelica sinesis), one of the most important component of DGSYS, was reported to have anti-inflammation effect via suppression pro-inflammatory mediators, such as prostaglandin E2.30 Additionally, antioxidation, suppression of uterus contraction, and correction of luteal insufficiency are all possible mechanisms for relieving symptoms by using DGSYS.31—33

Please cite this article in press as: Chen H-Y, et al. Investigation on Chinese herbal medicine for primary dysmenorrhea: Implication from a nationwide prescription database in Taiwan. Complement Ther Med (2013), http://dx.doi.org/10.1016/j.ctim.2013.11.012

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Chinese herbal medicine for primary dysmenorrhea Furthermore, various effects in addition to analgesia or anti-inflammation were extensively found in CHM, such as anti-depression, correction of luteal insufficiency and antioxidation (Table 5). The effects on multi-organ or multiple patho-physiological pathways were the characteristics of CHM, and combinations of CHM with different effects may produce a synergistic effect. The efficacy is believed to be better than CHM use alone with fewer unwanted side effects.34,35 Depression, one of the most common symptoms associated with dysmenorrhea, is reported to be highly related to severity of dysmenorrhea and also the main cause for sick leave and activity limitation.36,37 From TCM’s viewpoint, depression and anxiety may directly contribute to dysmenorrhea, and vice versa. Therefore, pain relief and mood adjustment should be considered at the same time to interrupt the vicious cycle. Consequently, the highly prevalent concept ‘‘analgesia combined with mood modifier’’ in TCM may be an important reference for WM doctor if patients have inadequate relief of symptoms. More interestingly, the combination of NSAID and JWXYS or DGSYS may be worthy of further studies for the possible maximal synergistic effects in treating primary dysmenorrhea. Hormone adjustment is another pharmacological mechanism of CHM commonly associated with analgesia effect achieved by C. yanhusuo or C. rotundus combined with DGSYS, WJT, or GZFLW. DGSYS and WJT are able to correct luteal insufficiency and GZFLW has anti-estrogen effect (Table 5). It is hypothesized that luteal insufficiency with earlier progesterone withdrawal or low progesterone itself causes higher prostaglandin secretion and more severe dysmenorrhea. In TCM teaching, WJT is usually used to treat dysmenorrhea patients with ‘‘Cold deficiency syndrome’’, characterized by aversion to cold or incapable of body temperature maintenance. These symptoms are similar to luteal phase defect and use of WJT was proven to lengthen luteal phase and correct luteal phase defect. This combination pattern commonly and long-term used by TCM doctors may suggest the importance of treating luteal insufficiency on primary dysmenorrhea. CHM has been reported to be superior to WM in treatment of dysmenorrhea in some aspects; for example, lowering the recurrence rate.4 Constitution adjustment, including modifying mood or correcting luteal insufficiency, combined with analgesia may be the potential mechanism to relieve pain and reduce recurrence. To adjust one’s constitution and relieve symptoms by administering a single prescription, such as mood modifying and analgesia in primary dysmenorrhea, TCM doctors use a special diagnosis system, syndrome differentiation and treatment (bian-zheng-lungzhi in Chinese). Different from diagnosing a disease in western medicine, ‘‘diagnosing pattern’’ is defined as a summary of nature, current status and progress of diseases and patient’s constitution.15,38 By collecting information from inspection, listening, inquiry and pulse diagnosis, TCM doctors are able to summarize one’s physical condition as one pattern, and prescription can be made up according to this pattern. Precise TCM syndrome recognition in addition to disease diagnosis is the key to treat disease successfully and the treatment effect can be maximized.15 However, due to the heterogeneity in agreement on syndrome differentiation in clinical practice,39 the large-scale epidemiological studies about patterns of certain diseases are still lacking.

7 Performing an epidemiological survey of TCM syndrome status by using the NHIRD is not possible since only disease diagnoses are recorded in this database by using ICD-9 codes, not TCM syndromes. However, from the characteristics of prescriptions for primary dysmenorrhea, the TCM syndrome ‘‘Qi stagnation and Blood stasis’’ is found extensively, and it may be the most common TCM syndrome for primary dysmenorrhea in this population. Surprisingly, the presentation and pathogenesis of the TCM syndrome and current opinion about primary dysmenorrhea are remarkably similar. In TCM teaching, the stabbing and distension pain is caused by impeding blood flow, which may be caused by constitution, emotional stress, and even environment factors, such as Qi stagnation, Cold, Dampness, and Blood deficiency in TCM’s categories. The unsmooth blood flow in TCM resembles uterine ischemia due to vasoconstriction in western medicine, and uterine vascular relaxation can be found when trying to resolve blood stasis.40,41 Nevertheless, the commonest TCM syndrome of primary dysmenorrhea is quite different from other studies in Beijing, China, where Cold and Dampness syndrome is the most common syndrome for primary dysmenorrhea, followed by Qi stagnation and Blood stasis.13 Beijing is in higher latitude than Taiwan and therefore the average temperature is much lower. This difference reflects that people’s physical condition is not only related to disease and constitution, geographic difference is also a decisive factor for syndrome recognition. By analyzing the nationwide prescription database, CHM and its combinations can be easily explored and the results are important references for both clinicians and researchers. Currently, evidences of efficacy are still insufficient as a guide to daily practice and the cause may be the choice of TCM regimens. The effectiveness of commonest CHM and combinations are yet carefully evaluated. Among the top 15 CHM (5 HF and 10 SH), only one CHM, DGSYS, has been proven to be effective in relieving pain caused by primary dysmenorrhea.29 Even the most commonly used SH, C. yanhusuo, existed in nearly one-third (33.1%) prescriptions; the clinical efficacy has yet been thoroughly studied. In contrast, a clinical trial about Si-Wu-Tang showed no advantages in treating primary dysmenorrhea compared to placebo,42 which may be because Si-Wu-Tang is only the 7th HF used for dysmenorrhea and existed only in 5% prescription. More emphases should be put on the frequently prescribed CHM to provide adequate proof for clinical practice. There are several limitations of this study. First, a systematic bias on prescription number may occur since only visits with single diagnosis were included in this study. Some subjects with diagnosis of dysmenorrhea may be excluded if other diagnoses co-existed. For example, mood disorders, such as depression and anxiety, were known to highly associate with primary dysmenorrhea,36 and therefore the number of prescriptions may be underestimated. However, since TCM doctors make up prescriptions on the basis of whole body’s condition, severe co-morbidities may influence the prescription content and contribute to unnecessary confounding bias subsequently. From this point of view, use of single diagnosis is important to ensure that the results were obtained from primary dysmenorrhea precisely as much as possible. Second, folk medicine in Taiwan was not reimbursed by the NHI and thus was not included in this study. Since certificate of safety was not well issued and quality

Please cite this article in press as: Chen H-Y, et al. Investigation on Chinese herbal medicine for primary dysmenorrhea: Implication from a nationwide prescription database in Taiwan. Complement Ther Med (2013), http://dx.doi.org/10.1016/j.ctim.2013.11.012

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control was questionable, the reliability of folk medicine was not ensured. Therefore, to provide repeatable and reliable result of CHM as reference for further studies, only CHM manufactured by GMP pharmacy was included in this study. Third, no therapeutic effectiveness was provided in this study. Currently, no subject symptoms, laboratory or image study results are recorded in the NHIRD, and therefore effectiveness analysis is not feasible by using this database as well as safety evaluation. Further well-designed, randomized, double-blinded and placebo-controlled clinical trials are still needed to elucidate this problem.

Conclusion This is the first study about large-scale pharmacoepidemiological analysis on TCM prescriptions for primary dysmenorrhea. Multiple CHM were combined to relieve manifestations of dysmenorrhea. Among all CHM, C. yanhusuo and C. rotundus were used most frequently, and thus became the central component for treating primary dysmenorrhea. Additionally, several potential pharmacological mechanisms have been achieved in a synergistic manner when CHM were used in combination, such as analgesic, mood modifying and luteal correction. These observed combination patterns provide valuable information for clinicians in treating primary dysmenorrhea. Further well-designed clinical trials and bench studies, both in vivo and in vitro, are warranted on the basis of these results to clarify the efficacy and mechanisms of action of commonly used CHM.

Conflict of interest All authors declare no conflicts of interests.

Ethical approval The protocol of this study was approved by the Institutional Review Board (IRB) of Chang Gung Medical Foundation, Taipei, Taiwan (IRB 101-3604b).

Role of the funding source This work was supported by intramural grant of the National Yang Ming University hospital, Taipei, Taiwan (RD2012-025). The sponsor was not involved in data collection, analysis of data, interpretation of results, and manuscript submission.

Acknowledgements The data set used in this study was a portion of the NHIRD, which was provided by the BNHI, and was maintained by the NHRI in Taiwan.

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Please cite this article in press as: Chen H-Y, et al. Investigation on Chinese herbal medicine for primary dysmenorrhea: Implication from a nationwide prescription database in Taiwan. Complement Ther Med (2013), http://dx.doi.org/10.1016/j.ctim.2013.11.012