Journal of Ethnopharmacology 151 (2014) 1209–1217

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The traditional Chinese medicine prescription patterns for migraine patients in Taiwan: A population-based study Yu-Yun Chang a, Yueh-Ting Tsai a, Jung-Nien Lai a,b,n, Chia-Hao Yeh b, Shun-Ku Lin c a

Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei City 112, Taiwan Department of Chinese Medicine, Taipei City Hospital, Yangming Branch, Taipei City 111, Taiwan c Department of Chinese Medicine, Taipei City Hospital, Ren-Ai Chinese Medicine Branch, Taipei, Taipei City 106, Taiwan b

art ic l e i nf o

a b s t r a c t

Article history: Received 14 October 2013 Received in revised form 19 December 2013 Accepted 20 December 2013 Available online 2 January 2014

Ethnopharmacological relevance: Traditional Chinese medicine (TCM), when given for symptom relief, has gained widespread popularity among migraine patients. The aim of this study is to analyze the utilization of TCM among migraine patients in Taiwan. Materials and methods: The usage, frequency of service, and the Chinese herbal products prescribed for migraine were evaluated using a representative sample of one million subjects selected at random from the 22 million beneficiaries of the National Health Insurance scheme of Taiwan. Results: Overall, 89.3% (N¼ 12,827) migraine patients utilized TCM and 24.2% of them sought TCM with the intention of treating their migraine-related symptoms. Migraine patients who are living in urban area and those with an episodic migraine pattern ( o15 days/month) (aOR ¼3.18, 95% CI: 2.75–3.67) were more likely to be TCM users than those living in a rural area and those who suffered from chronic migraine ( Z15 days/month) (aOR ¼1.00). Overall, 81.2% of TCM visits involved the prescription of a Chinese herbal remedy or remedies and Chuan-Xiong-Cha-Tiao-San, Jia-Wei-Xiao-Yao-San, Ge-Gen-Tang, Xue-Fu-Zhu-Yu-Tang, Ban-Xia-Bai-Zhu-Tian-Ma-Tang, Qing-Shang-Juan-Tong-Tang, Xiao-Chai-Hu-Tang, Tian-Ma-Gou-Teng-Yin, Bu-Zhong-Yi-Qi-Tang, and Tian-Wang-Bu-Xin-Dan were the ten most frequently prescribed formula for treating migraine based on syndrome differentiation. Conclusions: Chuan-Xiong-Cha-Tiao-San, which contains sedative and anti-inflammatory agents, is the most commonly prescribed Chinese herbal formula for the treatment of migraine-related phenomena. & 2014 Elsevier Ireland Ltd. All rights reserved.

Keywords: Migraine Chinese Herbal Product Chuan-Xiong-Cha-Tiao-San prescription pattern Traditional Chinese medicine TCM

1. Introduction Migraine is the most frequent neurological disorder in the adult population worldwide and is characterized by recurrent attacks of moderate to severe unilateral headaches that are accompanied by nausea or vomiting as well as sensitivity to light and sound. Migraine affects up to 12% of the general population and is more frequent among women (Raggi et al., 2013) in both its episodic and chronic forms, with the latter imposing more substantial individual and socioeconomic burden (Lipton et al., 2001; Bigal et al., 2008; Munakata et al., 2009). Although several studies have suggested that various symptomatic migraine pharmacotherapies are effective ways of relieving pain and improving the sufferers0 quality of life (Solomon and Santanello, 2000; Evers et al., 2009; Hildreth et al., 2009), migraine remains prevalent and disabling because of the side effects that are associated with the chronic administration of n Corresponding author at: Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, No.155, Sec. 2, Linong Road, Taipei 112, Taiwan . Tel.: 88 662 826 7396. E-mail address: [email protected] (S.-K. Lin).

0378-8741/$ - see front matter & 2014 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jep.2013.12.040

painkillers (Hamel, 2007; Evers and Jensen, 2011) as well as the high recurrence rate, which does not appear to be related to initial clinical efficacy (Geraud et al., 2003). Not surprisingly, complementary and alternative therapies have become increasingly popular as a symptom relief treatment among migraine patients and are quickly approaching conventional therapy in frequency of use (von Peter et al., 2002; Rossi et al., 2005). Previous studies have revealed that some Chinese herbs have sedative and pain-alleviating properties that act via cytokine suppression and COX-2 inhibition (Kang et al., 2007; Wieser et al., 2007; Wang et al., 2011). However, evidence obtained in human studies is limited regarding patterns of use of classical traditional Chinese medicine (TCM) in relation to migraine and is an area in which complementary and alternative medicines have recently grown in popularity. Furthermore, TCMs now seem to be marketed without established efficacy or safety checks in many Western countries (von Peter et al., 2002; Xue et al., 2007). In view of the above and because there is a lack of knowledge about the biochemical profiles of Chinese herbal products (CHPs) prescribed, there is a lack of direction for researchers and doctors trained in conventional medicine when, targeting migraine, they want to explore the

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potential mechanisms of TCM therapy. Such an exploration would help to assess the cost-effectiveness of using TCM therapy, and allow potential interaction between Chinese herbs and conventional therapies to be observed. TCM, which includes acupuncture, traumatology, manipulative therapies and Chinese herbal products, has been an important part of health care in Taiwan for hundreds of years and is fully reimbursed under the current National Health Insurance (NHI) system. CHPs, defined as composed of several herbs (formula) are most widely accepted by TCM users. According to Taiwan0 s laws, to ensure manufacturing quality, all CHPs must comply with good manufacturing practice (GMP) standards, and can only be prescribed by licensed TCM doctors. We downloaded all detailed of reimbursed CHPs, including the proportion of each single herb, the date and period of drug approval, and the name of manufacturer from the Department of Chinese Medicine and Pharmacy website, which is the competent authority of Chinese medicine in Taiwan. Because strict production quality control, only minor differences exist between each CHPs. We classified CHPs with the same components in the same category, regardless of slight variations of pharmaceutical manufacturing company. The unique approach used for TCM diagnosis involves gathering clinical symptoms and signs and then a treatment principle is put forward in accordance with the aforementioned diagnostic process. In this situation, researchers in Taiwan have found that symptoms, signs and ill-defined conditions are one of the most common reasons for TCM visits across various different patient populations (Yang et al., 2009; Fang et al., 2012; Lai et al., 2012). Accordingly, the claims database, part of the Taiwan National Health Insurance Research Database, is able to provide a platform for understanding the utilization of TCM therapies by licensed TCM doctors (Hsieh et al., 2008). The aim of our study is to analyze a random sample from this comprehensive database and to determine the TCM utilization patterns of newly diagnosed migraine patients in Taiwan. The results of this study should provide valuable information that will enable physicians to respond to patient use of the TCM in an informed way. This will, in turn, strengthen further the patient–physician relationship when treating migraine and migraine-related symptoms.

2. Materials and methods 2.1. Data resources This study was designed as a population-based study analyzing a sample of one million subjects selected at random from the 22 million beneficiaries of the National Health Insurance scheme of Taiwan. It was aimed at determining the prevalence of use of prescribed Chinese herbal products among adults with migraine between January 1, 1997, and December 31, 2008. All data were obtained from the National Health Insurance Research Database (NHIRD), which includes all the reimbursement data of the NHI with the identification numbers of all individuals encrypted and transformed; this database is maintained by the National Health Research Institutes of Taiwan (Institutes). The NHIRD database contained patient gender, patient date of birth, all records of clinical visits and hospitalization, drugs prescribed and their dosages (including Chinese herbal products (CHPs)) and three major diagnoses codes which are to effectively depict the whole picture of a patient staying within a typical health service area as included in the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). 2.2. Study subjects The selection of study subjects from the random sample of one million individuals was performed as follows (Fig. 1). Firstly, all

Fig. 1. Flow recruitment chart of subjects from the one million random samples obtained from the National Health Insurance Research Database (NHIRD), 1998 to 2008, in Taiwan.

beneficiaries without migraine (n ¼958,615) as well as those with missing information concerning gender (n¼ 76) were excluded. Secondly, migraine patients (n ¼24,972) that had been diagnosed before the end of 1997 were also excluded to ensure that all the subjects included were newly diagnosed with migraine in the time period 1998–2008. Thirdly, subjects under 20 years of age (n ¼1966) were also excluded to limit the study sample to adults. Finally, 14,371 study subjects remained and these were included in the study cohort. 2.3. Study variables To determine the key independent variables for utilization of TCM among migraine patients, we selected a series of demographic factors based on previous studies (Lipton et al., 2001; Bigal et al., 2008; Chang et al., 2008; Evers et al., 2009; Smitherman et al., 2013). The ages of individuals were categorized into four groups: 21–30, 31–40, 41–50, and 451 years; the geographic areas of Taiwan were classified into seven regions: Taipei city, Kaohsiung city, Northern region, Central region, Eastern region, Southern region, and Outlying islands; and we split the monthly wage levels of the individuals into four levels: New Taiwan Dollars (NT$) 0, 1–19,999, 20,000–39,999 and 440,000. We also searched the NHIRD database for clinical features and treatment records related to migraine as independent variables. The clinical features associated with migraine included episodic migraine, which is defined as those individuals with migraine who have 0 to 14 headache days per month and chronic migraine, which is defined as those individuals with migraine who have 15 or more

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headache days per month for three or more months during the study period (Headache Classification Subcommittee of the International Headache, S. 2004; Olesen et al., 2006; Katsarava et al., 2012). Furthermore, the reimbursement database contains all details related to the prescription of conventional medicines for treating migraine and these were collected. Finally, the types of preparations used for treating acute migraine or preventing the occurrence migraine were categorized according to grading strength of the recommendations and quality of evidence in clinical guidelines (Evers et al., 2009; Headache Classification Subcommittee of the International Headache, S. 2004); these

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were: no use; level A; level B; level C or D; and other preparations, including a combination of the above preparation types. 2.4. Statistical analysis Data analysis consisted of descriptive statistics, including the prescription rates of the TCM users stratified by patient0 s demographic characteristics, indications for the prescription of one or more CHPs and the most frequently prescribed herbal formulae for treating migraine. Primary indications were classified according to their ICD9 code. Diagnoses were coded according to the ICD-9 and grouped into

Table 1 Demographic characteristics and results of multiple logistic regression showing the adjusted odds ratio (aOR) and 95% CI (confidence interval) of patients with migraine from 1998 to 2008 in Taiwan. Characteristics

TCMa nonuser (%)

TCM user (%)

No. of cases Age at diagnosis (years) Mean 7 SD 21–30 31–40 41–50 ≧51

1,544

12,827

52.6(15.8) 123(8.0) 277(17.9) 340(22.0) 804(52.1)

46.7(14.2) 1,638(12.8) 3,177(24.8) 3,374(26.3) 4,638(36.2)

1.22(0.98–1.52) 1.10(0.93–1.30) 1.00 0.69(0.60–0.79)

Gender Male Female

831(53.8) 713(46.2)

4,346(33.9) 8,481(66.1)

1.00 2.20(1.96–2.46)

o0.001

Insured salaries (NT$d/month) 0þ 1–19,999 20,000–39,999 ≧40000

290(18.8) 928(60.1) 194(12.6) 132(8.6)

2,572(20.1) 6,641(51.8) 2,472(19.3) 1,142(8.9)

1.00 0.88(0.76–1.02) 1.40(1.14–1.71) 1.11(0.87–1.40)

o0.001 o0.001 0.764

Insured region Taipei City Kaohsiung City Northern Taiwan Central Taiwan Southern Taiwan East Taiwan Outlying islands

265(17.2) 127(8.2) 380(24.6) 189(12.2) 531(34.4) 32(2.1) 20(1.3)

2,187(17.1) 1,058(8.3) 3,336(26.1) 2,625(20.5) 3,321(25.9) 243(1.9) 56(0.4)

1.00 1.17(0.93–1.48) 1.24(1.04–1.47) 1.95(1.59–2.39) 0.97(0.82–1.15) 1.17(0.78–1.76) 0.37(0.21–0.65)

0.973 0.975 0.992 0.966 0.973 0.931

Classification of migraine Episodic Migrainen Chronic Migrainenn

340(22.0) 1,204(78.0)

6,459(50.4) 6,368(49.7)

3.18(2.75–3.67) 1.00

Medical treatment for Acute Migrainennn Level of recommendation No use Level Ae Level Bf Level C or D Mix–usage

556(36.0) 27(1.8) 850(55.1) 4(0.3) 107(6.9)

6,874(53.6) 151(1.2) 5,133(40.0) 13(0.1) 656(5.1)

1.00 0.84(0.32–2.20) 0.69(0.31–1.58) 0.41(0.11–1.50) 0.65(0.27–1.53)

0.502 0.961 0.372 0.787

10,992(85.7) 1,066(8.3) 454(3.5) 89(0.7) 226(1.8)

1.00 0.99(0.37–2.63) 1.48(1.08–2.02) 1.06(0.56–2.01) 1.11(0.43–2.85)

0.713 0.233 0.877 0.984

Medical treatment for Migraine Prophylaxisnnn Level of recommendation No use 1,299(84.1) Level Ag 139(9.0) h Level B 62(4.0) Level C or D 16(1.0) Mix–usage 28(1.8) a

aORb(95% CI c)

p

o0.001T o0.001 0.047 o0.001

o0.001

TCM refers to traditional Chinese medicine. OR refers to odds ratio. c CI refers to confidence interval. d NT$ refers to new Taiwan dollars. e Level A drugs includes Triptans (Sumatriptan, Zolmitriptan, Naratriptan, Rizatriptan, Almotriptan, Eletriptan and Frovatriptan), Analgesics (Acetylsalicylicacid (ASA), Ibuprofen, Naproxen, Diclofenac, Paracetamol and ASA plus mol plus caffeine). f Level B drugs includes Analgesics (Metamizol, Phenazon and Tolfenamicacid), Antiemetics (Metoclopramide and Domperidon). g Level A drugs includes Betablockers (Metoprolol and Propranolol), Calcium channel blockers (Flunarizine), Antiepileptic drugs (Valproicacid and Topiramate). h Level B drugs includes Amitriptyline, Venlafaxine and Naproxen. T independent t-test. n Criteria of episodic migraine means attack r 44 days per year. nn Criteria of chronic Migraine means attack ≧45days per year (from ICHD-2 criteria). nnn Classification is from “International Classification of Headache Disorders, ICHD-2 criteria”. b

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a series of distinct broad disease categories. The potential effects of Chinese herbs contained in 10 most commonly prescribed CHPs were grouped according to previous in vivo and in vitro studies and the treatment principles of these commonly prescribed CHPs were also demonstrated according to the documentation of ancient Chinese medical texts and these are summarized in Table 4 (Kang et al., 2007; Wieser et al., 2007; Wang et al., 2011). Descriptive statistics with chisquare test results are summarized as shown in Table 1. Multiple logistic regression was conducted to evaluate the factors that correlated with TCM use, by using the odds ratio adjusted for other variables (usually abbreviated “aORs”) as the predicted values of people who is more likely to be a TCM user. Potential predictors (covariates) were medical treatment for acute migraine, medical treatment for migraine prophylaxis, and classification of migraine. The following three models were tested: model 1, adjusted for the demographic factors (age, gender, insured salaries and insured region); model 2, adjusted for the demographic factors, medical treatment for acute migraine, and medical treatment for migraine prophylaxis; model 3, adjusted for the demographic factors, medical treatment for acute migraine, and medical treatment for migraine prophylaxis, and classification of migraine. Migraine patients aged 41–50 was set as a reference category in the variable “age at diagnosis”. “No income” and “Taipei city” were set as reference categories in the other demographic covariates. The reference category for “gender” was male gender. The value of the model was tested with the likelihood ratio test. It can be assessed by comparing the fit of the two models with and without the independent variables. Overall fit of model 3 shows a strong relationship between most of the independent variables, taken together, and dependent variable. A significance level of α¼0.05 was selected. The statistical software SAS 9.13 was used for data management and analysis.

3. Results The database of outpatient claims finally consisted of information on 14,371 adults with migraine from 1998 to 2008. Overall, 1.1% of men and 1.9% of women had experienced migraine each year in Taiwan based on these results and chronic migraine

represents 52.7% of the total migraine population. Among them, 89.3% (N ¼12,827) migraine patients had used TCM outpatient services at least once. Among all TCM users, 24.2% (n ¼3,100) had used TCM for the treatment of migraine. Details on the demographic distribution of TCM users and non-users are provided in Table 1. The mean age of non-TCM users was significantly higher than that of TCM users. There were more TCM users than non-TCM users who had an income level of NT$20,000–39,999 or who were residing in Northern and Central Taiwan. The adjusted odds ratios (aORs) and 95% confidence intervals 95% CIs obtained by multiple logistic regression are summarized in Table 1. Compared with the age group 41–50 years (aOR ¼1.00), those aged 51 years and above were more likely to be non-TCM users. As compared with the low income group (aOR ¼ 1.00), migraine patients with the income group of NT$20,000–39,999 were more likely to be TCM users. After adjusting for other factors, patients with episodic migraine (aOR ¼3.18, 95% CI: 2.75–3.67) were more likely to seek TCM treatment than those with chronic migraine (aOR ¼1.00). As compared with migraine patients without using any medical treatment (aOR ¼1.00), between TCM users and TCM non-users there was no significant difference in the level of evidence-based anti-migraine drugs that were used with the aim of either improving or preventing their headache (monotherapy or combination therapy), except among those who took amitriptyline, venlafaxine, or naproxen (OR¼1.48, 95% CI: 1.08– 2.02) as first-line treatment in migraine prophylaxis. Of the patients visiting TCM doctors, 442,539 (80.0%) visits were treated with a prescription of one or more Chinese herbal remedies, while the rest were prescribed acupuncture, traumatology and manipulative therapy. Analysis of the major disease categories for all TCM visits are summarized in Table 2, which show that “symptoms, signs, and ill-defined conditions” was the most common reason for using CHP (19.9%, n ¼88,254), followed by “diseases of the respiratory system” (13.5%, n ¼59,617) and “diseases of the digestive system” (11.6%, n ¼51,171). A total of 21,029 CHPs (visits) was prescribed by TCM doctors for treating migraine among patients with migraine from 1998 to 2008 in Taiwan. Details of the most frequently prescribed CHPs by TCM doctors for treating migraine are provided in Table 3, which

Table 2 Frequency distribution of traditional Chinese medicine (TCM) visits by major disease categories (according to 9th ICD codes) in patients with migraine from 1998 to 2008 in Taiwan. Major disease category

ICD-9-CM code range

No. of visits (No. of patient) Chinese herbal remedies

Infectious and parasitic diseases Neoplasms Endocrine, nutritional and metabolic diseases, and immunity disorders Mental disorders Diseases of the nervous system and sense organs Migraine Others Diseases of the circulatory system Diseases of the respiratory system Diseases of the digestive system Diseases of the genitourinary system Diseases of the skin and subcutaneous tissue Diseases of the musculoskeletal system and connective tissue Symptoms, signs, and ill-defined conditions Injury and poisoning Supplementary classification Others* Total n

Acupuncture or traumatology

Total of TCM

001–139 140–239 240–279

1,680(447) 1,885(240) 6,319(1,126)

6(4) 32(12) 51(22)

1,686(450) 1,917(248) 6,370(1,135)

290–319 320–389 346

4,252(754) 31,157(4,450) 21,029(3,012) 10,128(2,219) 9,931(1,718) 59,617(6,317) 51,171(5,664) 30,293(3,641) 8,617(1,900) 30,688(4,742)

94(34) 2,333(601) 701(196) 1,632(433) 1,390(128) 270(115) 258(110) 179(49) 62(29) 32,693(5,864)

4,346(773) 33,490(4,742) 21,730(3,100) 11,760(2,498) 11,321(1,770) 59,887(6,333) 51,429(5,692) 30,472(3,653) 8,679(1,911) 63,381(7,913)

88,254(7,872) 2,032(813) 8(5) 0(0) 116,635(8,248)

1,045(391) 37,331(6,479) 0(0) 3(1) 34,672(5,829)

89,299(7,924) 39,363(6,738) 8(5) 3(1) 151,307(9,551)

110,419(9,990)

552,958(12,827)

390–459 460–519 520–579 580–629 680–709 710–739 780–799 800–999 V01–V82, E800–E999

442,539(12,007)

Other include ICD-9-CM code range 280–289, 630–677, 740–759, 760–779 and missing/error data.

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Table 3 Top 10 herbal formulas prescribed by TCM doctors for treating migraine among patients with migraine from 1998 to 2008 in Taiwan Herbal formulae

English name

Number of visits N (%), total N¼ 15,359 (100)

Average daily dose (g)

Average duration for prescription (days)

Chuan-Xiong-Cha-Tiao-San Jia-Wei-Xiao-Yao-San Ge-Gen-Tang Xue-Fu-Zhu-Yu-Tang Ban-Xia-Bai-Zhu-Tian-Ma-Tang Qing-Shang-Juan-Tong-Tang Xiao-Chai-Hu-Tang Tian-Ma-Gou-Teng-Yin Bu-Zhong-Yi-Qi-Tang Tian-Wang-Bu-Xin-Dan

Tea-blended Chuanxiong powder Supplemented free wanderer powder Pueraria Decoction House of Blood Stasis-Expelling Decoction Pinellia, White Atractyodest, and Gastrodia Decoction Upper-body-clearing pain-alleviating decoction Minor bupleurum decoction Gastrodia and uncaria beverage Center-supplementing Qi-boosting decoction Celestial emperor heart-supplementing elixir

4767 2669 1405 1310 1006 998 917 882 723 682

8.7 11.0 13.6 5.2 20.2 4.1 11.5 7.4 9.5 5.7

34.6 44.1 27.3 35.9 32.1 26.4 26.6 45.8 37.8 44.9

shows that Chuan-Xiong-Cha-Tiao-San (Tea-Blended Chuanxiong Powder) was the most frequently prescribed CHP (31.0%), followed by Jia-Wei-Xiao-Yao-San (Augmented Rambling Powder) (17.4%) and Ge-Gen-Tang (Pueraria Decoction) (9.2%). The top 10 prescribed CHPs consist of Chinese herbs that are historically used to relieve migraine-related symptoms. The potential effects of these Chinese herbs when used to treat migraine and its related symptoms are summarized in Table 4 and include antiinflammatory effects, sedation, and pain-alleviating properties (Giner-Larza et al., 2000; Yuan et al., 2004; Chin et al., 2007; Li et al., 2007; Kang et al., 2008; Hwang et al., 2009; Wang et al., 2010; Li et al., 2011; Wang et al., 2011; Yuan et al., 2011; Yue et al., 2012; Zhang et al., 2013; Zhu et al., 2013).

4. Discussion To the best of our knowledge, this study is the first of its kind to use a random national-level sample to document the utilization characteristics of traditional Chinese medicine in migraine patients who have sought to obtain help via TCM therapies. The prevalence of migraine in Taiwan over the 11 years in the study was 1.4%, which appears to be low compared with the estimates given by previous surveys (Lipton et al., 2007; Stovner et al., 2007; Mengistu and Alemayehu, 2013). The present study includes all patients who were newly diagnosed with migraine by qualified conventional doctors between 1998 and 2008 from a random sample of one million subjects among the insured general population. Importantly, the rate of insured individuals has been consistently above 96% since 1997 and therefore we can rule out the possibility of selection bias. Similar to the findings of the American Migraine Study (Stewart et al., 1992), migraine is more prevalent in female and low-income groups compared with their other comparison groups in Taiwan. It is worth noting that the utilization of TCM among adults with migraine in Taiwan during the study period was 89.3%, which appears to be high compared with previous findings (Frass et al., 2012; Lui, 2013). TCM is a unique traditional therapy approach for various ailments that has been used in Taiwan for over hundreds of years and this long period of use may have contributed significantly to the high prevalence of TCM usage among migraine patients. About 4% of all TCM use was intended to treat migraine among the general population in Taiwan which is far below the proportion in the German-speaking countries, where it has been reported that approximately two-thirds of migraine patients use CAM as part of the treatment for relieving their migraine-related phenomena (Frass et al., 2012). The difference in results between the present study and previously reported studies is probably due to disparities in the definition of migraine-related CAM treatment between patients and qualified traditional Chinese medicine (TCM) doctors. Previous studies collected information on migraine

(31.0) (17.4) (9.2) (8.5) (6.6) (6.5) (6.0) (5.7) (4.7) (4.4)

CAM treatment via self-reported questionnaires, which represent the patients0 own perceptions and expectations from any healing practice that does not fall within the realm of conventional medicine. In Taiwan, TCM doctors who are involved in the treatment of migraine must prescribe in line with the requirements of the NHI and code accurately the diagnosis when claiming reimbursement from the NHI bureau. The present study describes only the utilization of TCM, which involves therapies that are also becoming popular in many other counties. Although the present findings cannot be generalized to a comprehensive analysis of the usage of various types of CAM, the present study does use a random national-level sample that reveals the prevalence in use of TCM for the treatment of migraine as prescribed by licensed TCM doctors. The present findings show that, among migraine patients, females and those aged 41–50 years were more likely to be TCM users than males and other age groups as shown in Table 1. The present results also demonstrate that migraine patients who are living in urban areas and who have an episodic pattern (o15 days/month) were more likely to be TCM users than migraine patients who are living in a rural area and who are part of the chronic migraine group (Z15 days/month). Despite prophylactic therapy of migraine being a safe and more or less effective treatment option, only 14.5% of the migraine patients in Taiwan receive this type of conventional treatment. Furthermore, regardless of their experience in receiving different levels of evidence-based anti-migraine drugs with the aim of improving their headache, the choice of any of the major medical options available to migraine patients was not associated with the use of TCM. As shown in Table 2, “symptoms, signs, and ill-defined conditions” was the most common reason for using CHP (26.9%, n¼ 7,872), followed by “diseases of respiratory system” (18.1%, n¼ 6,317), and “diseases of digestive system” (15.6%, n¼5,664). Further analysis found that TCM doctors tended to use Chinese herbal remedies targeting migraine as well as gastrointestinal disorders that might avoid the uncomfortable side effects of painkillers. Although previous studies have demonstrated that acupuncture might be useful as an alternative therapy when treating migrainerelated phenomenon, the present study indicated that acupuncture in Taiwan is used by this study population mainly for injury and diseases of the musculoskeletal system and connective tissue. Chuan-Xiong-Cha-Tiao-San was the most frequently prescribed formula for treating migraine in Taiwan, as is shown in Table 3. Chuan-Xiong-Cha-Tiao-San has a long history of use as part of the traditional Chinese pharmacopoeia and was first documented in the classical Chinese text Tai Ping Fui Min He Ji Ju Fang (Tai-Ping Imperial Grace Pharmacy Formulas) circa A.D. 1136 by the office of “He Ji Ju” of the Song Dynasty. Chuan-Xiong-Cha-Tiao-San is a combination of 8 medicinal Chinese herbs (Glycyrrhiza uralensis Fisch., root and rhizome (Gan Cao), Mentha haplocalyx Briq., aerial part (Bo He), Saposhnikovia divaricata (Turcz.) Schischk., root (Fang Feng), Notopterygium incisum Ting ex H.T. Chang, rhizomes (Qiang Huo), Asarum

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Table 4 Potential effects of the herbs contained in the 10 most common herbal formulae prescribed by TCM doctors based on the Bian zheng lun zhi theory for treating migraine. Lun zhi pattern-matching formulas

Symptom and signs

Treatment principle

TCM prescription

Composition

 Recurrent moderate to severe

To disperse Wind Heat and alleviate headache

Chuan-Xiong-Cha-Tiao-San (Tea-Blended Chuanxiong Powder)

Glycyrrhiza uralensis Fisch., root and rhizome (Gan Cao)ABC,d, Mentha haplocalyx Briq., aerial part (Bo He), Saposhnikovia divaricata (Turcz.) Schischk., root (Fang Feng), Notopterygium incisum Ting ex H.T. Chang, rhizomes (Qiang Huo), Asarum sieboldii Miq., root and rhizome (Xi Xin), Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav., root (Bai Zhi)ACe, Schizonepeta tenuifolia (Benth.) Briq., aerial part (Jing Jie), Ligusticum chuanxiong Hort., rhizome (Chuan Xiong)Cf

To calm and course the Liver Qi and resolve depression or distinguish Wind

Jia-Wei-Xiao-Yao-San (Augmented Rambling Powder)

Angelicae Sinensis (Angelica sinensis (Oliv.) Diels), root (Dang Gui)ABCg, Atractylodes macrocephala Koidz., rhizomes (Bai Zhu), Bupleurum chinense DC., root (Chai Hu)Ch, Poria cocos (Schw.) Wolf, sclerotia (Fu Ling)ACi, Gardenia jasminoides Ellis, fructus (Zhi Zi), Glycyrrhiza uralensis Fisch., root and rhizome (Gan Cao)ABC,d, Mentha haplocalyx Briq., aerial part (Bo He), Paeonia suffruticosa Andr., root bark (Mu Dan Pi), Paeonia lactiflora Pall., root, peeled (Bai Shao)Aj, Zingiber officinale Rosc., rhizome (Jiang) Gastrodia elata Blume, root (Tian Ma), Uncaria rhynchophylla (Miq.) Miq. ex Havil., hook (Gou Teng), Fallopia multiflora (Thunb.) Haraldson, aerial part (Ye Jiao Teng), Haliotis diversicolor Reeve, conch (Shi Jue Ming), Eucommia ulmoides Oliv., cortex (Du Zhong), Scutellaria baicalensis Georgi, root (Huang Qin)Ck, Gardenia jasminoides Ellis, fructus (Zhi Zi), Leonurus japonicus Houtt., aerial parts (Yi Mu Cao), Viscum coloratum (Kom.) Nakai, stem and branch leaf (Sang Ji Sheng), Achyranthes bidentata Blume., root (Huai Niu Xi), Poria cocos (Schw.) Wolf, sclerotia (Fu Ling)ACi Bupleurum chinense DC., root (Chai Hu)Ch, Scutellaria baicalensis Georgi, root (Huang Qin) Ck, Panax ginseng C.A.Mey., root (Ren Shen), Pinellia ternata (Thunb.) Makino, tuber (Ban Xia), Glycyrrhiza uralensis Fisch., root and rhizome (Gan Cao)ABC d, Zingiber officinale Rosc., rhizome (Jiang), Ziziphus jujuba Mill., fructus (Da Zao) Cyathula officinalis K.C.Kuan, root (Chuan Niu Xi), Angelicae Sinensis (Angelica sinensis (Oliv.) Diels), root (Dang Gui)ABCg, Citrus aurantium L., fructus (Zhi Ke), Bupleurum chinense DC., root (Chai Hu)Ch, Carthamus tinctorius L., flos (Hong Hua), Glycyrrhiza uralensis Fisch., root and rhizome (Gan Cao)ABC d, Ligusticum chuanxiong Hort., rhizome (Chuan Xiong)Cf, Paeonia lactiflora Pall., root (Chi Shao)Bl, Prunus persica (L.) Stokes, semem (Tao Ren), Schizonepeta tenuifolia (Benth.) Briq., aerial part (Jie Geng), Rehmannia glutinosa Libosch., root (Sheng Di Huang) Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep, root (Ge Gen), Ephedra sinica Stapf, caulis (Ma Huang), Zingiber officinale Rosc., rhizome (Jiang), Cinnamomum cassia (Nees & T.Nees) J.Presl, ramulus (Gui Zhi)ACm, Paeonia lactiflora Pall., root, peeled (Bai Shao)Aj, Glycyrrhiza uralensis Fisch., root and rhizome, honeyed (Gan Cao)ABC d, Ziziphus jujuba Mill., fructus (Da Zao) Pinellia ternata (Thunb.) Makino, tuber (Ban Xia), Gastrodia elata Blume, root (Tian Ma), Atractylodes macrocephala Koidz., rhizome (Bai Zhu), Citrus maxima (Burm.) Osbeck, Exocarpium (Ju Hong), Poria cocos (Schw.) Wolf, sclerotia (Fu Ling)ACi, Glycyrrhiza uralensis Fisch., root and rhizome (Gan Cao)ABC d, Ziziphus jujuba Mill., fructus (Da Zao), Zingiber officinale Rosc., rhizome (Jiang)



headache that has the quality of throbbing, is fixed and is stabbing in one half of the head Nausea, vomiting, and increased sensitivity to light and sound

 Severe pain on one side of the head caused by upward disturbance of hyperactive Liver Yang

Tian-Ma-Gou-Teng-Yin (Gastrodia and Uncaria Beverage)

Xiao-Chai-Hu-Tang (Minor Bupleurum Decoction)

 Unilateral fixed headache  Usually coexist with menstrual headache or chest discomfort

 Frequently become agitated  More likely to be a poor sleeper

 Headache at the nape of the neck

 Throbbing headache with nausea or dizziness  Short of breath and speech willing  More likely to be a poor sleeper

To invigorate the Blood and expel Blood stasis while regulating Qi and unblocking the Channels

Xue-Fu-Zhu-Yu-Tang (Persica and Carthamus Combination)

To course and dissipate Wind Heat

Ge-Gen-Tang (Pueraria Decoction)

To dry Dampness and transform Phlegm and relieve vomiting feeling

Ban-Xia-Bai-Zhu-Tian-Ma-Tang (Pinellia, White Atractyodest, and Gastrodia Decoction)

Y.-Y. Chang et al. / Journal of Ethnopharmacology 151 (2014) 1209–1217

Bian zheng traditional Chinese medicine diagnoses

 Sensations of oppression

Tian-Wang-Bu-Xin-Dan (Celestial Emperor Heart-Supplementing Elixir)

 Chronic headache and facial pain

To course wind, clear heat and relieve pain

Qing-Shang-Juan-Tong-Tang

 Chronic mild headache

To up bear Yang and supplement center Qi

Bu-Zhong-Yi-Qi-Tang (Center-Supplementing Qi-Boosting Decoction)





which is made worse by activity Short of appetite and speech willing

A

sedative effect. antioxidant effect. C anti-inflammatory effect. d Ref.: Zhang et al., 2013; Chin et al., 2007; Yue et al., 2012. e Ref.: Kang et al., 2008. f Ref.: Wang et al., 2011. g Ref.: Yuan et al., 2004; Li et al., 2007; Yuan et al., 2011. h Ref.: Zhu et al., 2013. i Ref.: Giner-Larza et al., 2000. j Ref.: Zhang et al., 2013. k Ref.: Yue et al., 2012. l Ref.: Li et al., 2011. m Ref.: Hwang et al., 2009. n Ref.: Wang et al., 2010. B

Asparagus cochinchinensis (Lour.) Merr., root (Tian Men Dong), Poria cocos (Schw.) Wolf, sclerotia (Fu Ling)ACi, Scrophularia ningpoensis Hemsl., root (Xuan Shen), Salvia miltiorhiza Bunge, root and rhizome (Dan Shen)ABn, Angelicae Sinensis (Angelica sinensis (Oliv.) Diels), root (Dang Gui)ABCg, Schisandra chinensis (Turcz.) Baill., fructus (Wu Wei Zi), Ophiopogon japonicus (Thunb.) Ker Gawl., root (Mai Men Dong), Ziziphus jujuba var. spinosa (Bunge) Hu ex H.F. Chow, semem (Suan Zao Ren), Rehmannia glutinosa Libosch., root (Sheng Di Huang), Platycladus orientalis (L.) Franco, semem (Bai Zi Ren), Polygala tenuifolia Willd., root (Yuan Zhi) Angelicae Sinensis (Angelica sinensis (Oliv.) Diels), root (Dang Gui)ABCg, Ligusticum chuanxiong Hort.; Ligusticum striatum DC., rhizome (Chuan Xiong)Cf, Notopterygium incisum Ting ex H.T. Chang, rhizome (Qiang Huo), Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav., root (Bai Zhi)ACe, Saposhnikovia divaricata (Turcz.) Schischk., root (Fang Feng), Glycyrrhiza uralensis Fisch, root and rhizome (Gan Cao)ABC d, Angelica biserrata (R.H.Shan & C.Q.Yuan) C.Q.Yuan & R.H.Shan, root (Du Huo), Ophiopogon japonicus (Thunb.) Ker Gawl., root (Mai Men Dong), Scutellaria baicalensis Georgi, root (Huang Qin)Ck, Chrysanthemum morifolium Ramat., flos (Ju Hua), Vitex trifolia L., fructus (Man Jing Zi), Asarum sieboldii Miq., root and rhizome (Xi Xin) Astragalus propinquus Schischkin (Huang Qi), Glycyrrhiza uralensis Fisch., root and rhizome (Gan Cao)ABC d, Panax ginseng C.A.Mey., root (Ren Shen), Angelicae Sinensis (Angelica sinensis (Oliv.) Diels), root (Dang Gui) ABCg, Citrus maxima (Burm.) Osbeck, Pericarpium (Chen Pi), Actaea heracleifolia (Kom.) J.Compton, rhizome (Sheng Ma), Bupleurum chinense DC., root (Chai Hu)Ch, Atractylodes macrocephala Koidz., rhizome (Bai Zhu)

Y.-Y. Chang et al. / Journal of Ethnopharmacology 151 (2014) 1209–1217

To enrich Yin and clear Heat

and distention of the head Fatigue caused by over working

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sieboldii Miq., root and rhizome (Xi Xin), Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav., root (Bai Zhi), Schizonepeta tenuifolia (Benth.) Briq., aerial part (Jing Jie), Ligusticum chuanxiong Hort., rhizome (Chuan Xiong)); this TCM powder is taken with green tea. In the classical literature, Chuan-Xiong-Cha-Tiao-San is said to disperse wind and alleviate headache. A traditional Chinese medical diagnosis of wind heat is arrived at by discerning a characteristic pattern of recurrent moderate to severe headache that has the quality of throbbing, is fixed and is stabbing in one half of the head as well as the presence of nausea, vomiting, and increased sensitivity to light and sound; these are all symptoms that are extremely common in patients with migraine (Table 4). However, no matter how popular the use of Chuan-Xiong-Cha-Tiao-San is in the markets of China, Japan, South Korea, and Taiwan, which are countries having a similar history of traditional Chinese medicine (TCM), no random controlled trial has been conducted yet on Chuan-XiongCha-Tiao-San. We therefore are unable to draw any conclusion about the effectiveness of Chuan-Xiong-Cha-Tiao-San in relieving the migraine-related symptoms for lack of actual clinical data. Among the remaining 10 most frequently prescribed formulas for treating migraine, Jia-Wei-Xiao-Yao-San (Augmented Rambling Powder), Xiao-Chai-Hu-Tang (Minor Bupleurum Combination) and Tian-Ma-Gou-Teng-Yin (Gastrodia and Uncaria Combination) are said to calm the liver, resolve depression and extinguish wind; these TCMs are very often prescribed by TCM doctors when upward disturbance of hyperactive liver yang is diagnosed; this results in severe pain on one side of the head. Other commonly prescribed formulae include one associated with relieving a unilateral fixed headache, namely Xue-Fu-Zhu-Yu-Tang or Persica and Carthamus Combination, one associated with headache at the nape of the neck, namely Ge-Gen-Tang or Pueraria Combination, one associated with chronic headache and facial pain, namely Qing-Shang-Juan-Tong-Tang or Ophiopogon and Cnidium Combination, one associated with throbbing headache with nausea or dizziness, namely Ban-Xia-Bai-Zhu-Tian-Ma-Tang or Pinellia and Gastrodia Combination, one associated with sensations of oppression and distention of the head, namely Tian-Wang-Bu-Xin-Dan or Ginseng and Zizyphus Formula and one associated with chronic mild headache that is made worse by activity, namely Bu-Zhong-YiQi-Tang or Ginseng and Astragalus Combination. It is apparent from this study that TCM doctors in Taiwan prescribed different herbal therapies for reducing different combination of migrainerelated symptoms based on the bian zheng lun zhi theory, which is a unique approach to the diagnosis and treatment involving the essence of a disease pathological process as shown in Table 4; this diagnostic approach differentiates TCM from Western medicine. The essence of bian zheng lun zhi is to gather the clinical symptoms and signs via the four diagnostic methods (inspection; listening and smelling; inquiry; pulse-feeling and palpation) and then differentiate the pattern of the migraine-related symptomatic discomfort in order to reach a specific type of zheng (a pathological summary of the body0 s health condition at a certain stage in the disease process). After the aforementioned diagnostic process, treatment principles are put forward in accordance with the 8 main patterns of migraine; this process is the standard methodology employed when a clinical treatment is arrived by TCM doctors, namely lun zhi. Previous studies have revealed that some Chinese herbs have sedative and pain-alleviating properties that act via cytokine suppression and COX-2 inhibition (Kang et al., 2007; Wieser et al., 2007; Wang et al., 2011). These modes of action are a reasonable explanation for the higher frequency of prescription of formulae containing Chinese herbs that have cytokine suppression and COX-2 inhibition in the present study. However, there is as yet insufficient evidence to allow a conclusion to be reached regarding the cost-effectiveness of the aforementioned formulas in relation to the provision of pain relief

among a population suffering from migraine. Further studies are warranted to assess the formulae with uncertain evidence of costeffectiveness found to be generally used by TCM practitioners in this study and to determine whether they form a potential alternative for migraine patients who have long-term morbidities caused by standard painkiller regimens. A major limitation of our study is that this study does not include Chinese herbal remedies purchased directly from TCM herbal pharmacies nor have we included health foods containing herbs. Thus, the frequency of CHP utilization might have been underestimated. However, because the NHI system has a comprehensive coverage for TCM prescriptions, which is generally less costly than the cost of herbs sold in Taiwan’s markets, the likelihood is that subjects have not purchased large quantities of other herbs outside the NHI database.

5. Conclusions It is apparent that the findings may have implications for physicians treating migraine patients. The results suggest that, under the co-existence of the conventional medical treatments and TCM, most migraine patients consumed herbal therapies with the intention of relieving their migraine-related phenomenon, rather than use acupuncture. Chuan-Xiong-Cha-Tiao-San is the most frequently prescribed formula by TCM doctors in Taiwan for migraine patients.

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