The American Journal of Chinese Medicine, Vol. 41, No.

5, 1011–1025
© 2013 World Scientific Publishing Company
Institute for Advanced Research in Asian Science and Medicine
DOI: 10.1142/S0192415X13500687

Systematic Review and Meta-Analysis

of Traditional Chinese Medicine
in the Treatment of Migraines
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Liang Zhou,*,a Pinyi Chen,*,a Ling Liu,* Yanqi Zhang,* Xiaoyu Liu,* Yazhou Wu,*
by UNIVERSITY OF TORONTO on 02/12/15. For personal use only.

Lei Jiang,† Dixiang Cheng,‡ Wenquan Huang,† Julia Christine Pettigrew§ and Dong Yi*
*Department of Health Statistics, College of Preventive Medicine
Third Military Medical University
Chongqing 400038, China
†
Department of Rehabilitation and Physiotherapy
Xinqiao Hospital, Third Military Medical University
Chongqing 400038, China
‡Soft College, Chongqing University of Posts and Telecommunications
Chongqing 400065, China
§Department of Biological Sciences and Department of Asian Language and Literature
University of Washington, School of Arts and Sciences
Snohomish, WA 98290, USA

Abstract: Migraine is a chronic disorder characterized by recurrent moderate to severe

headaches often in association with a number of autonomic nervous system symptoms. It is a
common disease and incidence has increased yearly. Chinese medical treatments are
popularly used in Asian countries, although they vary in effectiveness. In this study, we
applied a systematic review method and combined meta-regression with meta-subgroup
analysis to explore heterogeneity of clinical therapeutic efficacy upon meta-analysis of
randomized controlled Chinese medical treatments for migraine. We also aimed to provide a
more effective Chinese prescription and to advance the knowledge in evaluating validity of
preventing or alleviating migraine symptoms with Chinese medical treatments. Twenty
randomized migraine control trails, including 2246 patients, were collected from online
databases: PubMed, MEDLINE, EMBASE, CENTRAL of Cochrane Library, CBM, inte-
grated version of CMCI/CMCC, TCM online, CDFD, and CMFD from January 2000 to
December 2011. The results showed that the major factors influencing therapeutic efficacy
were either the specific medicine form of or its prescription type (p < 0:05). The use of TCM
decoctions, especially those that condition the viscera, treat from the perspective of “wind”,

Correspondence to: Dr. Dong Yi, Department of Public Health, College of Preventive Medicine, Third Military
Medical University, PO Box 400038, 30 Gao Tanyan street, Sha Pingba district, Chongqing, China. Tel/Fax:
(þ86) 23-6875-2344, E-mail: yd house@hotmail.com
a
These authors contributed equally to this work.

1011
 1012 L. ZHOU et al.

and target the Shaoyang gateway, could be the best migraine treatment in clinical TCM
practice (RR > 1:30).

Keywords: Migraine; Traditional Chinese Medicine; Systemic Review; Meta-Regression

Analysis; Meta-Subgroup Analysis.

Introduction

A migraine is a common primary headache manifested as a repeated unilateral or bilateral

pulsating headache. The attack is often accompanied by autonomic nervous system
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symptoms, such as nausea, vomiting, pallor, tachycardia, tachypnea, and gastrointestinal

dysfunction. Frequent migraines seriously affect patient’s life and work (Lipton et al.,
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2004). Epidemiological investigation has shown that the incidence of migraine in the US is
18% for females and 6% for males. Additionally, approximately 23% of American families
were living with at least one migraine patient (Lipton et al., 2001). In Asia (besides South
Korea and Hong Kong), the incidence in females was 11.3–14.4% and in males, 3.6–6.7%
(Wang, 2003a). Incidence in China was about 1% in the 1980s (Guo, 1993). Western
doctors believe that three mechanisms contribute to migraine pathogenesis: the dilation of
the intracranial and extracranial blood vessels that supply blood to the meninges, neuro-
genic inflammation caused by vasoactive peptides released from the perivascular nerves,
and a decrease in the inhibition of pain transmission from the central nervous system
(Hargreaves and Shepheard, 1999). Most patients take non-steroidal anti-inflammatory
drugs as analgesics, and a fraction of patients take selective calcium channel blockers
(nimodipine, 5-hydroxytryptamine receptor agonist) and triptans (sumatriptan, ergotamine
preparations) (Evers et al., 2010). However, these drugs only have a temporary analgesic
effect, and the symptoms return promptly after drug withdrawal (Geraud et al., 2003; Tfelt-
Hansen, 2009).
In traditional Chinese medicine (TCM), it is believed that the etiology and pathogenesis
of migraines are relatively complex. There are two types of etiologies: external and
internal. Pathogenesis includes the pathological changes caused by “liver fire”, “liver
wind”, “liver coldness”, “liver stasis”, and “liver deficiency”, which lead to (1) organ
dysfunction, (2) synergy of internal and external factors, or (3) the “Shaoyang” gateway
dysfunction followed by illnesses. In other words, the combined effects of the internal and
external factors cause a yin-yang imbalance in Qi and the blood in addition to organ
dysfunction, resulting in the obstruction of channels, poor circulation of Qi and the blood,
and pain (Zhao et al., 2009).
Randomized controlled trials (RCTs) have been used increasingly to compare TCM and
Western medicine in the treatment of migraines and have indicated significant differences
in the efficacies of the two types of medicine. However, the TCM treatment protocols were
complex, exhibiting a high degree of heterogeneity between RCTs (Huedo-Medina et al.,
2006). Thus, this study analyzed and evaluated the heterogeneity of the RCTs that com-
pared TCM and Western medicine in the treatment of migraines using heterogeneity
 META-ANALYSIS OF TCM TREATMENT FOR MIGRAINES 1013

analysis, meta-regression, and meta-subgroup analysis to provide a more solid basis for the
evaluation of TCM efficacy in the clinical treatment of migraines.

Materials and Methods

Study Design

The relevant literature published between January 2000 and December 2011 was searched
to retrieve the relevant randomized controlled trials (RCTs) that compared TCM and
Western medicine in the treatment of migraines.
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Methodological Quality Appraisal

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(1) The literature used in the study was written in either Chinese or English, and included
RCTs that compared TCM and Western medicine in the treatment of migraines, regardless
of the blinding method used. (2) The RCT interventions adhered to the following treatment
strategies: the experimental group received TCM treatment alone, and the control group
received Western medicine treatment alone without any Chinese patent medicine. (3) The
analysis of balance between the groups showed that the baseline data were comparable. (4)
Clinical efficacy (cured, markedly effective, and effective) and invalid evaluation results
were used as the end-point.

Exclusion Criteria

The exclusion criteria included the following: (1) non-RCTs or duplicate publications;
(2) animal studies; (3) case reports and review articles; (4) clinical research studies that
compared different TCM methods; and (5) literature in which methods other than TCM,
such as acupuncture, massage, qigong and therapeutic diet were used, or both TCM and
Western medicine were used.

Search Strategy

The Chinese Biomedical Literature Database (CBM), the Chinese Medical Citation
Database (CMCI/CMCC integrated version), the online database of Chinese medicine, the
full-text database of Chinese doctoral dissertations, the database of excellent Chinese
Master’s degree theses, the CENTRAL database of the Cochrane Library, PubMed,
MEDLINE, and EMBASE were searched. The relevant database of the Third Military
Medical University Library was also manually searched.
The search strategy used migraine, headache, head wind, and brain wind as subjects and
“traditional Chinese medical practice and medicine”, “traditional Chinese medical prac-
tice”, and “traditional Chinese medicine” as keywords to retrieve all of the studies pub-
lished between January 2000 and December 2011. If the full study text could not be
 1014 L. ZHOU et al.

retrieved, the journal database of the Third Military Medical University Library was
manually searched. The literature retrieval was carried out on January 7, 2012.

Data Extraction and Criteria of Therapeutic Effects

All of the patients enrolled in the RCTs were diagnosed in accordance with the 2002
“Guiding Principles of Clinical Research on New Traditional Chinese Medicine” diag-
nostic criteria (Ministry of Public Health of China, 1995). Specific diagnostic criteria: all
inclusive cases were fit with diagnostic criteria under “Clinic Research Principle of Tra-
ditional Chinese Medicine New Drugs” (the criteria include safety observation, e.g.
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physical examination, routine blood examination and urinalysis, liver and renal function
tests, and therapeutic observation, e.g. migraines attack duration per week and, signs and
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physiological indicators). Headache degree was scaled to four sections by Bussone

(Bussone et al., 1987). Clinically cured, which means headache and its associated symp-
toms have disappeared. Significant, headache intensity has alleviated two levels and its
associated symptoms have lightened, or either headache attacks or their duration have
reduced at least 2/3. Effective, headache intensity has alleviated a level, or interval of
headache attacks has extended, or its duration has reduced, but by less than 2/3. Ineffective,
headache intensity has alleviated lower than a level, or headache attack duration was one
third shortened or less, or aches and pains were aggravated and extended.

Assessment Methodology

The first author, year of publication, total number of patients enrolled in the experimental
and control groups, and end-point evaluation indicators were extracted from all of the
studies. One researcher (L.Z.) first extracted the data, while another researcher (P.C.) read
the studies again to double-check the data. Any differences were resolved through con-
sultation with a third researcher (X.L.), and agreement was reached through discussion.
The literature was assessed for quality in accordance with the Cochrane Systematic
Review Manual and the Jadad scale (Jadad et al., 1996) using a scale of 1–7 (1–3 for low
quality and 4–7 for high quality). RCTs with a Jadad score
2 were included in this study.

Statistical Methods

The relative risk (RR) and 95% confidence interval (CI) were used as efficacy indicators in
this study. p values < 0:05 were considered statistically significant. The Cochrane
Handbook was used to divide the heterogeneity derived from the meta-analysis into clinical
heterogeneity, methodological heterogeneity, and statistical heterogeneity (Green et al.,
2009). Clinical heterogeneity is the main source of heterogeneity in the systematic reviews
of TCM (Hu et al., 2010). This study first utilized the overall heterogeneity analysis to
evaluate whether there was clinical heterogeneity among the RCTs. If clinical hetero-
geneity was present, influential factors such as TCM ingredients, formulations, doses,
and drug classifications were used as the sources of heterogeneity (Hu et al., 2010).
 META-ANALYSIS OF TCM TREATMENT FOR MIGRAINES 1015

A meta-regression analysis was subsequently utilized to search for the influential factors
that caused clinical heterogeneity. The meta-subgroup analysis was also based on these
factors. In the absence of clinical heterogeneity, a statistical heterogeneity analysis was
conducted to select either the fixed effects model or the random effects model to merge the
meta-analyses. Stata 11.0 software was used for the meta-analysis.

Results

Results of the Literature Search

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A total of 289 studies, including 40 studies in English and 249 studies in Chinese, were
retrieved. At the beginning, eight duplicate papers were removed, and then 147 papers
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were excluded after reading the titles and abstracts. After 134 papers went through to the
next round of secondary screening, the full text of the included studies was the obtained,
and the methodology was read and evaluated carefully to extract the relevant data. Studies
were excluded as a result of duplicate publications (8), inappropriate TCM treatment
principles (20), physical therapies, such as acupuncture, or the external use of TCM (38),
inability to obtain the full texts (3), issues with the systematic review scheme or quality
evaluation alone (4), integrative treatment with both TCM and Western medicine (29), and
comparison of different TCMs (10). Thirty-seven publications were included in this study
after the second round of screening. The Cochrane Systematic Review Manual and Jadad
scale were subsequently used to evaluate the quality of the 37 studies, with those studies
receiving a score < 2 being excluded. Finally, 20 RCTs that met the inclusion criteria were
included in this study, all of which compared TCM and Western medicine in the treatment
of migraines (Table 1 and Fig. 1).

Analysis of the Overall Heterogeneity

The overall heterogeneity analysis was first conducted to evaluate the heterogeneity of the
20 RCTs. The results showed that Q ¼ 36:95, df ¼ 19, p ¼ 0:008, and I 2 ¼ 48:6%,
suggesting heterogeneity among the 20 RCTs.

Determination of the Influential Heterogeneity Factors and Meta-Regression Analysis

The complexity and diversity of the disease diagnosis and TCM treatment resulted in
different symptoms for the same disease and the same symptoms for different diseases
(Zeng et al., 2011; Wang et al., 2012b). Moreover, there were significant differences in the
TCM ingredients, formulations, classifications, and doses of single or multiple TCM
treatments (Wu et al., 2012; Xutian et al., 2012). All of these factors became the main
sources of heterogeneity in the systematic reviews. Meanwhile, these factors also affected
the quality of the systematic TCM reviews (Green et al., 2009; Wang et al., 2009). Thus,
this study analyzed the TCM ingredients, formulations, classifications, and doses as the
main factors that may lead to clinical heterogeneity using a meta-regression analysis.
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1016

Table 1. Basic Characteristics of the Included RCTs and Evaluation of the Methodology Quality

Number Intervention Used in the Intervention Used Duration of TCM Jadad

No. Included RCTs of Patients Experimental Group in the Control Group Treatment (Days) Score

1 (Chu et al., 2000) 88/30 Qingshangjuantong granule Aminopyrine, caffeine 10 4

2 (Zhou, 2002) 64/60 Yupian decoction Nimodipine 28 3
3 (Hu et al., 2002) 30/30 Shutianning granule Flunarizine hydrochloride 28 5
4 (Niu et al., 2003) 35/35 Yangxueqingnao granule Flunarizine hydrochloride 30 3
5 (Li and Xu, 2004) 71/43 Tianle capsule Ibuprofen 30 2
6 (Wang, 2003b) 172/159 Tongmian decoction Nimodipine 28 2
7 (Lv and Feng, 2004) 30/30 Tongfengyudian decoction Flunarizine hydrochloride 28 3
8 (Shang and Wang, 2004) 50/50 Chuanjuzhitong Capsule Nimodipine 10 3
9 (Liu, 2005) 88/86 Tongluoxifeng decoction Flunarizine hydrochloride 28 3
10 (Tang et al., 2005) 50/50 Xuefuzhuyu decoction Flunarizine hydrochloride 30 3
11 (Su, 2005) 45/35 Qufengyangxuehuoxue decoction Flunarizine hydrochloride 28 3
12 (Dai, 2005) 95/92 Qufengsanre mixture Flunarizine hydrochloride 30 3
L. ZHOU et al.

13 (Lin, 2005) 30/30 Toufeng decoction Flunarizine hydrochloride 28 3

14 (Qian, 2006) 57/60 Tongluohuoxue decoction Flunarizine hydrochloride 28 3
15 (Xiong and Zhang, 2008) 36/33 Tongluohuoxue decoction Ibuprofen, nimodipine 30 3
16 (Zhang, 2009) 36/31 Gastrodia Chuanxiong decoction Aspirin 15 2
17 (Zhang, 2010) 60/60 Toutongning capsule Flunarizine hydrochloride 28 4
18 (Gao, 2011) 100/60 Qufengtongluo decoction Nimodipine 30 2
19 (Dong, 2011) 40/32 Self-made TCM decoction Flunarizine hydrochloride 30 2
20 (Lu, 2011) 32/31 Self-made folk prescription Nimodipine 14 2
 META-ANALYSIS OF TCM TREATMENT FOR MIGRAINES 1017

289 records were identified through 0 additional records were identified

database searching through other sources

8 duplicates removed 281 records were duplicates and were removed 147 irrelevant topics

Studies were excluded

as a result of treatment
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principles (20), physical 134 records screened

therapies, such as
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acupuncture, or the
external use of TCM
(38), not being able to
obtain the full texts (3),
30 full-text articles Studies excluded due to low
issues with the
assessed for eligibility quality (n = 17)
systematic review
scheme or quality
evaluation alone (4),
integrative treatment
with both TCM and 20 studies included in
Western medicine (29), qualitative synthesis
and comparison of
different TCMs (10).

0 studies were included in

the quantitative synthesis

Figure 1. Flowchart illustrating the literature inclusion process.

(1) TCM ingredients: due to the complexity of compound TCMs, the comprehensive
efficacy of treatments and TCM treatment routes were divided into four types (from
the perspective of “liver”, conditioning of viscera, from the perspective of “wind”, and the
Shaoyang gateway), and the sub-variables were set for the meta-regression analysis. The
results of this analysis were statistically significant (p < 0:05).
(2) TCM formulations: the TCM formulations were grouped into granule, decoction,
and capsule according to the processing of modern medicine and conventional TCM
formulations, and the sub-variables were set for the meta-regression analysis. The results of
this analysis were statistically significant (p < 0:05).
(3) TCM classifications: the original TCM or TCM prescription was retrospectively
traced. The analysis, which was guided by the TCM experts in the project, showed that all
of the TCMs used in the included studies belonged to the blood-conditioning class (pre-
scription of “blood-circulation promoting and stasis-reducing”). Thus, this heterogeneity
factor was excluded after discussion.
(4) TCM doses: due to a lack of clarity in the data provided in the included studies and
the inability to obtain these data from the original authors, this factor was not evaluated in
this study.
 1018 L. ZHOU et al.

Table 2. Results of the Meta-Regression Analysis

Heterogeneity Factors Coefficient Standard Deviation t-Value p-Value

Year of publication 0.0092866 0.0110185 0.84 0.414

Sample size 0.0000631 0.0004813 0.13 0.898
TCM ingredients 0.1314412 0.0581035  2.26 0.038
TCM formulations 0.1479617 0.0639671  2.31 0.033
Western medicine ingredients 0.2188617 0.1842819  1.19 0.255
Western medicine formulations 0.0243507 0.0969244  0.25 0.805
Western medicine classifications 0.0681821 0.1465891  0.47 0.648
Western medicine doses 0.0235333 0.0823894 0.29 0.779
Duration of TCM and Western 0.003266 0.0052907 0.62 0.547
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medicine treatment
Jadad Score 0.024339 0.0511053  0.48 0.641
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The Western medicine that was used in the control groups may also have caused clinical
heterogeneity. Thus, the ingredients, formulations, classifications, and doses of Western
medicine were also evaluated for sources of heterogeneity. All of the factors, except drug
dose, were classified according to the active chemical ingredients, traits, and efficacy, after
which the sub-variables were set for the meta-regression analysis. The results of this
analysis were not statistically significant (p > 0:05). However, the dosing was included in
the baseline data for the analysis.
The clinical epidemiology, time of publication, sample size, duration of TCM and
Western medicine treatment, and literature quality were all evaluated as sources of het-
erogeneity. The meta-regression analysis showed that there were no significant differences
in these factors (p > 0:05).
The results of the meta-regression analysis showed that the TCM ingredients and for-
mulations were the main factors that led to heterogeneity (Table 2).

Single-Factor Meta-Subgroup Analysis

The included studies were divided into four subgroups based on their TCM ingredients: A.
from the perspective of “liver”, B. conditioning of viscera, C. from the perspective of
“wind”, and D. targeting of the Shaoyang gateway. The results of the single-factor meta-
analysis of the subgroups are shown in Fig. 2. There were six, four, five, and five studies in
subgroups A, B, C, and D, respectively. The I2 values of the heterogeneity analysis were
16.1% (p ¼ 0:310), 0.0% (p ¼ 0:799), 25.5% (p ¼ 0:251), and 0.0% (p ¼ 0:974) in
subgroups A, B, C, and D, respectively, suggesting no significant difference in hetero-
geneity among the subgroups. The RR values were 1.13 (95% CI: 1.07–1.20), 1.36 (95%
CI: 1.22–1.52), 1.37 (95% CI: 1.27–1.47), and 1.28 (95% CI: 1.16–1.42) in subgroups A,
B, C, and D, respectively. The overall aggregated RR value was 1.27 (95% CI: 1.22–1.32),
suggesting that the effect of TCM in the treatment of migraine was superior to that of
Western medicine in all of the subgroups (Fig. 2).
The included studies were divided into three subgroups based on the TCM formula-
tions used: A. granule, B. decoction, and C. capsule. The results of the single-factor
 META-ANALYSIS OF TCM TREATMENT FOR MIGRAINES 1019

Study
ID RR (95% CI)

A
Zhaohu Zhu (2000) 1.02 (0.82, 1.28)
Jinggang Zhou (2002) 1.21 (1.06, 1.38)
Zhengping Niu (2003) 1.03 (0.88, 1.21)
Zhongliang Dai (2005) 1.09 (1.00, 1.18)
xiuling Zhang (2010) 1.27 (1.08, 1.50)
Zhengchang Dong (2011) 1.14 (0.94, 1.37)
Subtotal (I-squared = 16.1%, p = 0.310) 1.13 (1.07, 1.20)
.
B
Zhiqiang Hu (2002) 1.35 (1.02, 1.79)
Xiangjiang Tang (2005) 1.31 (1.08, 1.60)
Xi Su (2005) 1.52 (1.17, 1.98)
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liangyu Qian (2006) 1.30 (1.08, 1.57)

Subtotal (I-squared = 0.0%, p = 0.799) 1.36 (1.22, 1.52)
.
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C
Fuyu Li (2004) 1.47 (1.18, 1.84)
Shiyang Wang (2004) 1.36 (1.20, 1.54)
Sixin Liu (2005) 1.20 (1.05, 1.38)
Ping Gao (2011) 1.55 (1.27, 1.88)
Yu Lu (2011) 1.32 (1.04, 1.68)
Subtotal (I-squared = 25.5%, p = 0.251) 1.37 (1.27, 1.47)
.
D
Chongshan Lv (2004) 1.30 (0.97, 1.74)
Yanjie Shang (2004) 1.23 (1.05, 1.44)
Zaigang Lin (2005) 1.30 (0.97, 1.74)
Weihong Xiong (2008) 1.36 (1.07, 1.72)
Menglie Zhang (2009) 1.27 (1.02, 1.59)
Subtotal (I-squared = 0.0%, p = 0.974) 1.28 (1.16, 1.42)
.
Overall (I-squared = 48.6%, p = 0.008) 1.27 (1.22, 1.32)

.5 1 5

Figure 2. Results of the meta-analysis of TCM ingredients. (Notes: A. from the perspective of “liver”, B.
conditioning of viscera, C. from the perspective of “wind”, and D. targeting of the Shaoyang gateway; I-squared
and P is the criterion of heterogeneity test; RR, relative risk; ^, pooled relative risk; ——, relative risk and 95
confidence interval; ¥, weight.)

meta-analysis of the subgroups are shown in Fig. 3. There were four, thirteen, and three
studies in subgroups A, B, and C, respectively. The I2 values of the heterogeneity analysis
were 2.7% (p ¼ 0:379), 0.0% (p ¼ 0:637), and 0.0% (p ¼ 0:974) for subgroups A, B, and
C, respectively, suggesting no significant difference in heterogeneity among the subgroups.
The RR values were 1.13 (95% CI: 1.07–1.20), 1.36 (95% CI: 1.22–1.52), and 1.37 (95%
CI: 1.27–1.47) for subgroups A, B, and C, respectively. The overall aggregated RR value
was 1.27 (95% CI: 1.22–1.32), suggesting that the effect of TCM in the treatment of
migraines was superior to that of Western medicine in all of the subgroups (Fig. 3).

Meta-Subgroup Analysis of Interacting Factors

Because two factors affected the systematic reviews of heterogeneity, the subgroups were
divided based on the two interacting factors and subsequently analyzed. Meanwhile, the
subgroups included in less than two studies were excluded; thus, 16 studies spanning five
 1020 L. ZHOU et al.

Study
ID RR (95% CI)

A
Zhaohu Zhu (2000) 1.02 (0.82, 1.28)
Zhiqiang Hu (2002) 1.35 (1.02, 1.79)
Zhengping Niu (2003) 1.03 (0.88, 1.21)
Zhongliang Dai (2005) 1.09 (1.00, 1.18)
Subtotal (I-squared = 2.7%, p = 0.379) 1.09 (1.02, 1.18)
.
B
Jinggang Zhou (2002) 1.21 (1.06, 1.38)
Shiyang Wang (2004) 1.36 (1.20, 1.54)
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Chongshan Lv (2004) 1.30 (0.97, 1.74)

Sixin Liu (2005) 1.20 (1.05, 1.38)
Xiangjiang Tang (2005) 1.31 (1.08, 1.60)
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Xi Su (2005) 1.52 (1.17, 1.98)

Zaigang Lin (2005) 1.30 (0.97, 1.74)
liangyu Qian (2006) 1.30 (1.08, 1.57)
Weihong Xiong (2008) 1.36 (1.07, 1.72)
Menglie Zhang (2009) 1.27 (1.02, 1.59)
Ping Gao (2011) 1.55 (1.27, 1.88)
Zhengchang Dong (2011) 1.14 (0.94, 1.37)
Yu Lu (2011) 1.32 (1.04, 1.68)
Subtotal (I-squared = 0.0%, p = 0.637) 1.32 (1.25, 1.39)
.
C
Fuyu Li (2004) 1.47 (1.18, 1.84)
Yanjie Shang (2004) 1.23 (1.05, 1.44)
xiuling Zhang (2010) 1.27 (1.08, 1.50)
Subtotal (I-squared = 0.0%, p = 0.405) 1.32 (1.19, 1.46)
.
Overall (I-squared = 48.6%, p = 0.008) 1.27 (1.22, 1.32)

.5 1 5

Figure 3. Results of the meta-analysis of the TCM formulations. (Notes: A. granule, B. decoction, and C. capsule;
I-squared and P is the criterion of heterogeneity test; I-squared and P is the criterion of heterogeneity test; RR,
relative risk; ^, pooled relative risk; ——, relative risk and 95 confidence interval; ¥, weight.)

subgroups were included in the analysis. The subgroups were A. granule that treated from
the perspective of “liver”, B. decoction that treated from the perspective of “liver”, C.
decoction that targeted the Shaoyang gateway, D. decoction that treated from the per-
spective of “wind”, and E. decoction that conditioned viscera.
There were three, two, four, four, and three studies in subgroups A, B, C, D, and E,
respectively. The I2 values of the heterogeneity analysis were 0.0% (p ¼ 0:754), 0.0%
(p ¼ 0:600), 0.0% (p ¼ 0:986), 35.6% (p ¼ 0:199), and 0.0% (p ¼ 0:603) in subgroups A,
B, C, D, and E, respectively, suggesting that there were no significant differences in the
heterogeneity of the subgroups. The RR values were 1.06 (95% CI: 0.98–1.14), 1.18 (95%
CI: 1.06–1.32), 1.31 (95% CI: 1.15–1.49), 1.35 (95% CI: 1.25–1.49), and 1.36 (95% CI:
1.21–1.54) in subgroups A, B, C, D, and E, respectively. The overall aggregated RR value
was 1.26 (95% CI: 1.21–1.32), suggesting that with the exception of group A (granule that
 META-ANALYSIS OF TCM TREATMENT FOR MIGRAINES 1021

treated from the perspective of “liver”), the TCM treatments for migraines were superior to
those of Western medicine, with groups C (decoction that targeted the Shaoyang gateway),
D (decoction that treated from the perspective of “wind”), and E (decoction that con-
ditioned viscera) being particularly effective.
The meta-analysis of interacting factors showed no significant difference in the het-
erogeneity of the subgroups ( p > 0:05). The above mentioned analysis shows that the
TCM decoctions were all superior to Western medicine in the treatment of migraine.
However, the effects of the TCM granules that treated from the perspective of “liver” could
not be viewed as superior to Western medicine ( p > 0:05).
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Analysis of Publication Bias and Sensitivity

by UNIVERSITY OF TORONTO on 02/12/15. For personal use only.

The begg diagram suggests that there was a publication bias in the included studies
(t ¼ 2:68, p < 0:05), while the sensitivity analysis suggests that the results of systematic
reviews were reliable.

Discussion

TCM migraine treatments primarily prescribe “blood-circulation promoting and stasis-

reducing” medicines, which increase cerebral blood flow, improve cerebral vasomotor
function, and inhibit vascular smooth muscle spasms (Ma et al., 2003). These effects
coincide with the migraine etiology accepted in Western medicine, suggesting that a dis-
order in the intracellular calcium environment of platelets and the slowing of blood flow in
migraine patients enable microvascular blood stasis and changes in microcirculation
(Gelmers, 1983). Thus, TCM achieves the goal of symptomatic treatment.
Almost all prescriptions have mentioned Rhizoma Ligustici Chuanxiong; Chu et al.,
(2000) and Zhou (2002) believed the extract of Rhizoma Ligustici Chuanxiong and its
active ingredient Ligustrazine are able to protect vascular endothelial cell, relieve smooth
muscle spasm, inhibit platelet aggregation, prevent 5-HT and Bradykinin release, reduce
blood viscosity, and improve cerebral blood flow and nervous system dysfunction (Ohta
et al., 1997; Paragh et al., 1997; Wang et al., 2012a). However, each prescription has its
own synergy, e.g. Group A. Niu et al. (2003) have described that Rhizoma Ligustici
Chuanxiong combined with Radix Angelicae Sinensis, Radix Rehmanniae Preparata,
Concha Margaritifera, Semen Cassiae, Spica Prunella and Radix Paeoniae Alba, etc. can
possibly improve microcirculation of leptomeninges, and alleviate vasospasm and head-
ache are accordingly (Wang et al., 2001).
In Group B, the prescriptions have not only focused on microcirculation, but also have
pointed out tissue recovering and internal organs comprehensive coordinating, e.g. Qian
and Yan (2006) have mentioned by given the circumstance, while blood viscosities have
been reduced distinctly, the addition of Semen Persicae and Flos Carthami etc., could lower
cholesterol, inhibit platelet adhesion, aggregation, so as to improve the peripheral tissues
and organs of the blood circulation (Zhang et al., 1996; Rong and Zhong, 2000), but Su
believed the addition of Radix Polygoni Multiflori could enhance immunity, lower blood
 1022 L. ZHOU et al.

lipids, and aid in nervous system recovery via its contained Lecithin (Huang et al., 1991;
Qin, 1991).
In Group C, all prescriptions are more concerned with the analgesic effect from TCM,
e.g. Lu (2011), has added Radix Paeoniae Alba. Pharmacological experiments have proved
that total the glucosides of paeonia, an element of Radix Paeoniae Alba, have a very similar
function as an analgesic and tranquillizer towards the central nervous system. Moreover,
smooth muscle spasm relief effect was considered (Zhou and Li, 2003; Yang et al., 2006).
Additionally, Li and Xu (2004) have pointed out that Rhizoma Gastrodiae is efficient in
reducing cerebrovascular resistance and peripheral vascular resistance and promoting
cerebral blood circulation. It showed significant analgesic, sedative, anti-convulsive and
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anti-aging effects on the central nervous system (Huang, 1994).

D grouped prescriptions have displayed the idea of long-term coordination, in order to
by UNIVERSITY OF TORONTO on 02/12/15. For personal use only.

reduce complications, e.g. Xiong and Zhang (2008) have added Radix Angelicae Sinensis
to alleviate cerebral anoxia by its function as an antioxidant and inhibitior of free radicals.
Additionally, it can prevent platelet aggregation and thrombosis development, which has
lowered blood lipids and has reduced the risk of the complication of atherosclerosis (Wu
et al., 2001).
Through a statistical exploration of different causes and classifications according to
those causes, this study found that TCM ingredients and formulations were the two main
factors that led to clinical heterogeneity in the systematic reviews of TCM or Western
medicine migraine treatments. The results of the single-factor meta-subgroup analysis
showed that TCM ingredients and formulations were superior to Western medicine in all of
the subgroups. However, the results of the meta-subgroup analysis of interacting factors
showed that there were no significant differences in the treatment efficacies of TCM
granules that treated from the perspective of “liver” and Western medicine. The efficacies
of TCM decoctions in the remaining subgroups were superior to those of Western medi-
cine. Moreover, the decoctions that conditioned viscera, treated from the perspective
of “wind”, and targeted the Shaoyang gateway, were particularly effective. Thus, TCM
decoctions may be the best medicine for treating migraines in clinical practice, and
decoctions that condition viscera, treat from the perspective of “wind”, and target the
Shaoyang gateway can be used as preferred medications.
The number of heterogeneity factors considered and the number of studies included in
this systematic review were limited. Additional factors also need to be evaluated in
combination with clinical practice. In addition, more multi-center, large-scale, double-blind
RCTs are needed to provide a higher level of evidence for systematic TCM reviews.
Although there are many domestic reviews of TCMs, the overall quality is not high.
High-quality systematic reviews of TCMs are rare, and the lack of sensible evaluation
systems leads to a scarcity of reliable evidence for the clinical use of TCMs (Zhang et al.,
2007). These issues arise because TCM treatment protocols are complex, and the protocol
heterogeneity is difficult to unravel, leading to low evaluation reliability (Liu and Xia,
2007; Wang et al., 2011). This systematic review searched relevant studies under the
guidance of TCM experts and evaluated the factors that may cause heterogeneity to provide
a sensible, reliable basis for evidence-based medicine. Moreover, significant factors were
 META-ANALYSIS OF TCM TREATMENT FOR MIGRAINES 1023

identified using meta-regression analysis, and a meta-subgroup analysis based on those

factors was performed. The results obtained using this method reduced the interference
caused by heterogeneity, identified the results that were the most reliable and provided
evidence for the clinical selection of TCMs in the treatment of migraine. Meanwhile, the
results also provided more sensible ideas for the systematic review of TCM.
However, one limitation of our study that there is to some extent is publication bias
(p < 0:05). Overall inclusion trials were low in quality, only 15% (3/20) of RCTs were
superior. All RCTs in the paper have mentioned randomization, about 25% (5/20) did not
demonstrate this specifically. 5% (1/20) has talked about randomization concealment and
10% (2/20) has referred blinding, however, up to 65% (13/20) has referred to follow-ups.
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Side effects have been cited in 15% of the papers (3/20), the commonly used examination
indexes included blood tests, urine tests, stool tests, and, liver and kidney function tests, all
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results showed Chinese prescription has relatively lower side effects. In conclusion, more
multi-center, large-scale, double-blind RCTs are needed to provide a higher level of
evidence for systematic TCM reviews.

Acknowledgments

The study was supported by three grants from the Natural Science Foundation of China
(Nos. 81172773, 30872184 and 30901242).

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