Research Article

Hindawi
Evidence-Based Complementary and Alternative Medicine

Volume 2020, Article ID 5181587, 20 pages
https://doi.org/10.1155/2020/5181587
Research Article
Oral Chinese Herbal Medicine as Prophylactic Treatment for
Episodic Migraine in Adults: A Systematic Review and
Meta-Analysis of Randomized Controlled Trials
Shaohua Lyu ,1,2 Claire Shuiqing Zhang ,2 Xinfeng Guo ,1 Anthony Lin Zhang ,2
Jingbo Sun ,1 Chuanjian Lu,1 Charlie Changli Xue ,1,2 and Xiaodong Luo 1
1
The Second Affiliated Hospital of Guangzhou University of Chinese Medicine,
Guangdong Provincial Hospital of Chinese Medicine and Guangdong Provincial Academy of Chinese Medical Sciences,
Guangzhou 510120, China
2
The China-Australia International Research Centre for Chinese Medicine, School of Health and Biomedical Sciences,
Royal Melbourne Institute of Technology, Melbourne 3083, Australia
Correspondence should be addressed to Charlie Changli Xue; [email protected] and Xiaodong Luo; [email protected]
Received 15 May 2020; Revised 7 December 2020; Accepted 13 December 2020; Published 28 December 2020
Academic Editor: Mohieddin Jafari
Copyright © 2020 Shaohua Lyu et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Background. The prophylactic effects of Chinese herbal medicine (CHM) for migraine were examined in numerous clinical trials.
This review aimed to analyze the effectiveness and safety of CHM as prophylactic treatment of migraine compared to flunarizine.
Methods. Nine databases were searched for randomized controlled trials (RCTs) that evaluated effects of CHM for episodic
migraine prophylaxis compared to flunarizine, published before March 2019. Results. Thirty-five RCTs with 2,840 participants met
the inclusion criteria, and 31 of them were included in meta-analyses. The overall meta-analysis indicated that, when compared to
flunarizine, CHM reduced the frequency of migraine attacks at the end of treatment (EoT) (21 studies, mean difference (MD)
−1.23, 95% confidence interval (CI) (−1.69, −0.76)) and at the end of follow-up (EoFU) (five studies, MD −0.96, 95% CI (−1.70,
−0.21)). Subgroup analyses based on the treatment duration, follow-up duration, and the dosage of flunarizine showed that CHM
was superior to or comparable with flunarizine in reducing migraine frequency. Similar results were also found for secondary
outcomes such as the pain visual analogue scale, migraine duration, responder rate, and acute medication usage. In particular, the
studies that used CHM containing herb pairs (Chuan Xiong plus Bai Zhi and Chuan Xiong plus Tian Ma) showed promising
results. However, the certainty of this evidence was evaluated as “low” or “very low” using the Grading of Recommendations,
Assessment, Development and Evaluations approach. Conclusion. CHM appeared to be comparable with flunarizine in reducing
the frequency of episodic migraine attacks in adults at EoT and EoFU and well-tolerated by participants, regardless of the
treatment duration, follow-up duration, and dosage of flunarizine. Due to the low certainty of the evidence, the suggested
promising prophylactic outcomes require higher quality evidence from further rigorous RCTs.
1. Introduction Migraine has an estimated global prevalence of 14.7%

[2]. According to the Global Burden of Disease published in
Migraine is a primary headache disorder, manifesting in 2018, migraine was ranked as the seventh most disabling
episodic headache attacks which usually lasts for 4–72 hours. disease and the third leading cause of disability of people
The typical characteristics of a migraine headache include aged 15–49 years [3]. Furthermore, the total financial burden
unilateral, pulsating pain with moderate to severe intensity, of the disease on individuals and society, as reported in 2010,
aggravation by routine physical activity, and association with equated to over three billion pounds a year in the United
nausea and/or photophobia and phonophobia [1]. Kingdom [4].
2 Evidence-Based Complementary and Alternative Medicine
Migraine can be subdivided into episodic and chronic Cumulative Index of Nursing and Allied Health Literature
migraine. The former refers to headache attacks occurring (CINAHL), Cochrane Central Register of Controlled Trials
less than 15 days per month, while the latter refers to 15 or (including the Cochrane Library), and the Allied and
more headache days per month. Episodic migraine accounts Complementary Medicine Database (AMED), and four
for the majority of migraineurs [1], but the condition can Chinese databases—Biomedical Literature, China National
progress to chronic migraine, if not properly managed [5]. It Knowledge Infrastructure (CNKI), Chongqing VIP
was estimated that approximately 2.5% of episodic migraine (CQVIP), and Wanfang database, from their inceptions to
cases develop into chronic migraine annually [6]. November 2018. An updated search was conducted in March
The clinical management of migraine involves pain 2019. The search strategy was designed according to three
rescue and prophylactic treatment. Generally, migraineurs groups of search terms: participant condition (migraine),
are advised to be on continuous prophylactic treatment to intervention (Chinese medicine, CHM, and related terms),
reduce the frequency and severity of attacks. However, it was and control (flunarizine). Reference lists of previously
estimated that more than half of the migraineurs were published reviews were screened for eligibility.
unsatisfied with prophylactic pharmacotherapy due to in-
sufficient improvements and unbearable side effects [7–9].
Flunarizine is a first-line medication recommended by 2.2. Study Selection. The inclusion criteria for this review
clinical guidelines for migraine prophylaxis [10–13]. Its were as follows: (1) participants aged between 18 and 75
effects of preventing migraine attacks in adults have been years; (2) diagnosis of episodic migraine, with or without
confirmed by recently published systematic reviews [14, 15], aura, according to clinical guidelines [1, 39, 40, 42]; (3)
clinical trials [16–18], and experimental studies [19–23]. treatment intervention of orally administered CHM; (4)
However, unwanted adverse effects such as tiredness, mood utilized only flunarizine as the control intervention; studies
swings, weight gain, and depression limit its use in clinical which allowed acute pain medications were included if the
practice [16, 24]. same medications were used in both the intervention and
Chinese herbal medicine (CHM) has been widely used in control groups; and (5) evaluated at least one of the fol-
clinical practice for thousands of years in China, usually in the lowing outcomes: migraine frequency, number of migraine
form of herbal formulas consisting of a group of individual days per month, responder rate, headache pain severity,
herbs and often involves herb pairs [25]. CHM has been average duration of attack, acute medication usage, and
gradually gaining acceptance worldwide [26–29]. There have health-related quality of life.
been a number of laboratory experiments [30–32], clinical The exclusion criteria were as follows: (1) studies which
trials [33], and systematic reviews with meta-analyses [34–37] focused on acute migraine attack management; (2) com-
evidence supporting CHM as a potential alternative therapy bination of CHM with other types of Chinese medicine
for migraine. therapy or pharmacotherapy; (3) treatment duration of less
Four systematic reviews showed that oral CHM was than four weeks; and (4) different acute pain rescue med-
more effective than placebo or conventional pharmaco- ications applied in the intervention and control groups.
therapies for migraine management [35–38]. However, none
of these reviews provided evidence of prolonged treatment 2.3. Data Extraction. After screening titles and abstracts, full
effects, which is important for migraine prophylaxis. In texts were obtained and checked for eligibility by two au-
addition, the reviews accepted a range of medication used in thors (SL and CSZ). Data from eligible studies were extracted
the control groups [35–37]. Furthermore, most of the studies and cross-checked by two research assistants (YX and LL)
included in these reviews did not fulfil requirement that an using the EpiData software (EpiData Association, Odense,
effective migraine prophylaxis should be taken for no less Denmark). Information of authors, publication year, title,
than four weeks [10–12, 39, 40]. journal, setting, study design, diagnostic criteria, sample
To provide more precise evidence to support the use of size, dropout, age, gender, duration of migraine, CHM
oral CHM for preventing episodic migraine in adults, this formula names and ingredients, dosage of flunarizine,
systematic review evaluates the clinical effectiveness and treatment duration, follow-up duration, outcome measures,
safety of CHM comparing with a first-line medication and adverse events (AEs) were extracted. Disagreements
(flunarizine) in randomized controlled trials (RCTs). were discussed and resolved by the reviewers (SL and CSZ).
Where there were missing, conflicting, or unclear data, we
2. Methods contacted the authors of the respective studies for
clarification.
This review applies the methods recommended by the
Cochrane Handbook of Systematic Reviews of Interventions
5.1.0 [41]. The review protocol was registered in PROSPERO 2.4. Risk of Bias Assessment. The methodological quality of
(CRD42019123039). included studies was assessed by two authors (SL and CSZ)
using the Cochrane Risk of Bias Tool [41]. Trials were judged
as “low,” “unclear,” or “high” risk of bias for the domains of
2.1. Database Search and Study Screening. A rigorous elec- sequence generation, allocation concealment, blinding of
tronic search was initially conducted in five English data- participants, blinding of personnel and outcome assessors,
bases—PubMed, Excerpta Medica Database (EMBASE), incomplete outcome data, selective reporting, and other
Evidence-Based Complementary and Alternative Medicine 3
forms of bias such as conflicts of interest. Discrepancies were control groups and allowed acute pain rescue medicine as
discussed with a third reviewer (XG). needed. According to the available information on gender,
there were more female than male (1,750 vs. 1,060), but none
of the studies reported gender-based treatment effects data.
2.5. Publication Bias Assessment. Publication bias was
The treatment duration ranged from 28 days to 90 days.
assessed by funnel plots and Egger’s test using the Stata 12
Eight studies involved a follow-up phase [46, 50, 53–58],
software (StataCorp LLC, Texas, USA), where more than 10
where six provided detailed outcome data [46, 50, 53–56]
RCTs were included in the meta-analysis.
(Table 1).
The outcome measures reported by the included studies
2.6. Certainty of Evidence Assessment. The certainty of evi- were migraine frequency, migraine attack duration, mi-
dence, referring to the strength or reliability of study graine days, pain VAS, responder rate, usages of pain
findings, was evaluated using the Grading of Recommen- medication, and quality of life using the 6-item Headache
dations, Assessment, Development and Evaluations Impact Test (HIT-6). With regard to AEs, nine studies
(GRADE) approach [43, 44]. The GRADE approach clas- [49, 52, 54, 56, 59–63] provided a general statement that
sifies the certainty of evidence in four levels (high, moderate, there were no severe AEs, 15 studies reported details of AEs
low, and very low) based on five factors: risk of bias, im- [47, 48, 50, 55, 57, 58, 71–79], and the remaining eleven
precision, inconsistency, indirectness, and publication bias. studies did not report information on AEs
[45, 46, 51, 53, 64–70].
2.7. Data Analyses. Available data were merged for meta-
analyses in RevMan 5.3.0 to evaluate the effects of CHM. The 3.2. CHM Treatments Used in the Included Studies.
primary outcome measure was the frequency of migraine, CHM was administered in the forms of decoctions (28
and the secondary outcomes included days of migraine, pain studies), capsules (five studies) [47, 53, 55, 57, 72], granules
visual analogue scale (VAS), duration of migraine attack, (one study) [78], and pills (one study) [71] (Table 1). Twenty-
responder rate, acute medication usage, quality of life scores, seven CHM formulas involving 104 individual herbs were
and AEs. Treatment effects were evaluated at two time used in the included studies. Two formulas were evaluated
points: at the end of treatment (EoT) and at the end of by multiple studies, namely, San Pian Tang [50, 74] and
follow-up (EoFU), where possible. Frequency analyses were Zheng Tian granules [55] or pills [71]. The most frequent
conducted on CHM formulas and individual herbs. Mean herbs used by all studies were Chuan Xiong (31 studies), Bai
difference (MD) and 95% confidence intervals (CI) were Zhi (18 studies), Bai Shao (16 studies), Gan Cao (13 studies),
used for continuous data, while risk ratios (RR) with 95% CIs Tian Ma (13 studies), Dang Gui (12 studies), and Chai Hu (11
were for dichotomous data. Statistical heterogeneity was studies) (Table 2). It should be noted that, two herb pairs
assessed using the I2 statistic. The random-effects model was were frequently used by the included studies, specifically
selected for the meta-analyses presenting high heterogeneity Chuan Xiong plus Bai Zhi (18 studies) and Chuan Xiong plus
with unknown reason; otherwise, the fixed-effects model was Tian Ma (10 studies). These two herb pairs had been de-
employed [41]. Where possible, subgroup analyses were veloped into commercialized CHM products for migraine
performed to explore heterogeneity based on variables in- and documented in the Pharmacopoeia of China [80].
cluding the treatment duration, follow-up duration, and the
dosage of flunarizine. Subgroup analyses were also con- 3.3. Risk of Bias. All studies mentioned randomization,
ducted based on RCTs which applied the same CHM for- however, only 13 RCTs (37.1%)
mulas and common herb pairs. AEs were summarized, and [46, 48, 49, 51, 55, 59, 60, 62, 67, 69, 76, 78, 79] were assessed
the frequencies were compared between groups. to have “low risk” of bias in terms of sequence generation;
four studies (11.4%) [45, 50, 54, 74] were considered as “high
3. Results risk” in this domain as participants were allocated based on
the order of enrollment. All included studies were assessed as
The original comprehensive electronic database search (until
“unclear risk” of bias for allocation concealment due to lack of
November 2018) identified 4,958 citations, and the updated
adequate information. In terms of blinding of participants,
search conducted in March 2019 yielded another 50 cita-
research personnel, and outcome assessors, all studies were
tions. In total, 35 RCTs met the inclusion criteria, with 31
judged as “high risk” of bias because no adequate blinding
RCTs included in the meta-analyses (Figure 1).
methods were employed despite the different types of in-
tervention between groups. Most of the studies were at “low
3.1. Characteristics of Included Studies. All included studies risk” of bias for incomplete outcome data; only one [48] was
were open-label studies conducted in China and published assessed as “high risk” in this domain due to a high and
in the Chinese language from 2003 to 2019. The RCTs en- unbalanced dropout rate. Thirty-one studies (88.6%) were
rolled 2,840 participants, with sample size ranging from 32 assessed as “unclear risk” of bias regarding selective outcome
[45] to 240 [46] people. Dropouts were reported in seven reporting due to the lack of registered protocols, while four
studies [46–52]. The age of participants ranged from 18 to 75 RCTs were assessed as “high risk” because they did not report
years old, with disease durations between one month and 38 AEs [53] or outcome data of the follow-up phase [56–58]
years. All studies used either 5 mg or 10 mg flunarizine in (Figure 2).
Records identified through the initial Records identified through the updated
database searching (n = 4,958) searching (n = 50)
Records after duplicates removed

(n = 4,286)
Records screened (n = 4,286) Records excluded (n = 3,234)
Full-text articles excluded,

with reasons (n = 1,017):
Full-text articles assessed for eligibility (i) Duplicate literature (n = 9)
(n = 1,052) (ii) Diagnosis of migraine not
defined (n = 7)
(iii) Not clinical study (n = 16)
(iv) Not RCT (n = 493)
(v) Acute stage of migraine
Studies included in qualitative (n = 9)
synthesis (n = 35) (vi) Age under 18 (n = 8)
(vii) CHM combined with other
therapies (n = 351)
(viii) Inappropriate control
(n = 108)
Studies included in meta-analysis (viii) Did not report predefined
(n = 31) outcomes (n = 16)
Figure 1: PRISMA flowchart of the study selection process.
Table 1: Characteristics of included studies.

Treatment
No. of Dosage (mg)
Duration of Age of Gender duration,
Author participants and Formula Ingredients of
migraine participants (male/ follow-up
(year) randomized frequency of names (form) formulas
(years) (years) female) duration
(I: C) flunarizine
(days)
I: Bai Shao, Gui Zhi,
Cai Dang Gui Si
36.95 ± 7.140 Dang Gui, Tong Cao,
(2018) 49: 49 NS 38/60 30, NF 10, qn Ni Tang
C: Gan Cao, Xi Xin, and
[69] (decoction)
37.08 ± 6.82 Da Zao
Huang Qi, Ge Gen,
Dan Shen, Chuan
Cai et al. I: 6.50 ± 5.36 I: 33.6 ± 7.62 Li Xu Qu Feng
Xiong, Bai Zhi, Man
(2017) 32: 28 C: C: 24/36 28, NF 10, qn Tongluo Fang
Jing Zi, Xi Xin, Tu Bie
[61] 6.30 ± 5.24 34.20 ± 7.21 (decoction)
Chong, and Jiang
Chan
Chuan Xiong, Dang
Chen Shao Zhi Zhen
I: 0.5-30 I: 20-65 Gui, Jiang Chan,
(2010) 40: 30 21/47 28, NF 5, qn Tong Fang
C: 0.83-28 C: 19-62 Quan Xie, Di Long,
[52] (decoction)
Bai Zhi, and Gan Cao
Dai
I: 5.70 I: 35.6 Xue Sai Tong
(2005) 36: 34 22/48 90, 60 10, qn San Qi
C: 5.40 C: 37.2 soft capsule
[53]
Chuan Xiong, Bai
Zhi, Bai Shao, Ge
I:
Du I: 6.18 ± 5.06 Xiong Zhi Jian Gen, Xi Xin, Man
44.93 ± 13.49
(2014) 44: 44 C: 22/64 90, NF 5, qn Fang Jing Zi, Xia Ku Cao,
C:
[73] 6.30 ± 5.24 (decoction) Bo He, Gao Ben, Chai
48.27 ± 11.22
Hu, Ju Hua, and Fang
Feng
Table 1: Continued.
Treatment
No. of Dosage (mg)
(I: C) flunarizine
(days)
Ren Shen, Shui Zhi,
Du et al. I: 3.80 ± 2.30 Quan Xie, Tu Bie,
I: 40.5 ± 10.6 Tong Xin Luo
(2011) 50: 50 C: 22/78 28, NF 10, qn Chong, Wu Gong,
C: 39.4 ± 10.3 capsule
[47] 3.90 ± 2.40 Chan Lian, Suan Zao
Ren, and Bing Pian
Chuan Xiong, Niu
I: 3.40 ± 2.10 Qu Feng Huo Xi, Bai Ji Li, Gan Cao,
Fu (2015) I: 43.4 ± 2.7
40: 40 C: 42/38 90, NF 5, qn Xue Fang Gao Ben, Tian Ma,
[64] C: 42.6 ± 2.5
4.10 ± 2.30 (decoction) Bai Zhi, Gou Teng,
Ge Gen, and Chai Hu
Gao et al. I: 3.20 ± 1.30
I: 35.4 ± 4.6 Tian Shu Chuan Xiong and
(2006) 40: 42 C: 32/50 60, 365 5, qd
C: 36.1 ± 6.8 capsule Tian Ma
[57] 3.00 ± 1.40
Sha Ren, Chi Shao,
Bai Shao, Shi Jue
Gao et al. I: 9.75 ± 5.53 I: 41.4 ± 19.56 Ming, Mai Dong, Ju
NS
(2009) 29: 27 C: C: 0/56 30, 60 5∼10, qn Hua, Tao Ren, Ji Xue
(decoction)
[58] 8.96 ± 6.56 42.5 ± 18.42 Teng, Ye Jiao Teng,
Quan Xie, and Wu
Gong
Chuan Xiong, Bai
Gou and
Zhi, Bai Shao, Bai Jie
Miao San Pian Tang
30: 30 NS 26∼65 37/23 90, NF 10, qn Zi, Xiang Fu, Chai
(2014) (decoction)
Hu, Yu Li Ren, and
[74]
Gan Cao
Huang I: Quan Xie, Di Long,
et al. 10.50 ± 4.60 I: 35.3 ± 3.6 NS Tian Ma, Chuan
30: 30 22/38 30, NF 5, qn
(2006) C: C: 37.1 ± 3.5 (decoction) Xiong, Wu Gong,
[65] 9.80 ± 3.70 and Jiang Chan
Chai Hu, Chuan
Xiong, Huang Qin,
I:
Liang I: 6.01 ± 3.75 He Jie Zhi Ban Xia, Dang Shen,
35.35 ± 10.87
(2015) 120: 120 C: 53/170 56, 28 10, qn Tong Fang Bai Zhu, Gan Cao,
C:
[46] 6.16 ± 3.20 (decoction) Long Gu, yuan zhi,
34.01 ± 9.06
Quan Xie, and Wu
Gong
Huang Lian, zhi Ban
Xia. Chen Pi, Zhi Shi,
I: Dan Nan Xing, Zhu
Liu Tou Tong
44.47 ± 11.21 Ru, Shi Chang Pu,
(2009) 40: 40 NS 22/51 30, NF 10, qn Fang
C: Mo Han Lian, Quan
[48] (decoction)
42.77 ± 9.53 Xie, Man Jing Zi, Bai
Zhi, and Chuan
Xiong
Tian Ma, Gou Teng,
Luo and Shi Jue Ming, Ju Hua,
Tzu Tong
Shu I: 4.50 I: 25–60 Chuan Xiong, Bai
32: 32 25/39 28, NF 5, bid Tang
(2013) C: 4.80 C: 24–59 Zhi, Man Jing Zi,
(decoction)
[79] Quan Xie, and Di
Long
Chai Hu, Gui Zhi,
I: Chai Hu Gui
Ma Gan Jiang, Ban Xia,
42.90 ± 11.74 Zhi Gan Jiang
(2014) 30: 30 NS 31/29 28, NF 10, qn Huang Qin, Dang
C: Tang
[59] Shen, Fu Ling, and
46.97 ± 12.29 (decoction)
Gan Cao
Table 1: Continued.
Treatment
No. of Dosage (mg)
(I: C) flunarizine
(days)
Chai Hu, Bai Shao,
Mao
Chai Shao Zhi Bai Zhu, Dang Gui,
et al. I: 11.05 I: 39
20: 20 6/32 30, NF 5, qn Tong Fang Chuan Xiong, Qing
(2011) C: 9.19 C: 42.6
(decoction) Feng Teng, Zhi Ke,
[49]
and Gan Cao
Dang Gui, Chuan
Niu et al. Yang Xue Xiong, Shu Di, Zhen
(2003) 35: 35 NS NS NS 30, NF 5, qn Qing Nao Ke Zhu Mu, Jue Ming Zi,
[56] Li (granule) Xia Ku Cao, and Bai
Shao
Yan Hu Suo, Chuan
Pan et al. Xiong Long Xiong, Ge Gen, Bai
I: 7.10 I: 47.52
(2015) 30: 30 27/33 90, 90 5∼10, qn Tang Zhi, Tao Ren, Di
C: 6.50 C: 51.38
[54] (decoction) Long, Niu Xi, Hong
Hua, and Xi Xin
1. San Qi, Chuan
Xiong, Fu Shen, Chi
Shao, Dan Shen, Tao
Ren, Bai Zhi, Yu Jin,
and Chen Pi
1. Tong Qiao 2. Yi Mu Cao, Tian
Huo Xue Tang Ma, Zhi Zi, Niu Xi,
(decoction) Di Long, Gou Teng,
2. Tian Ma Huang Qin, Shi Jue
Gou Teng Yin Ming, Sang Ji Sheng,
Peng I: 5.40 ± 1.80 (decoction) and Du Zhong
I: 36.2 ± 4.2
(2017) 38: 38 C: 48/28 30, NF 10, qn 3. Qi Ju Di 3. Gou Qi, Mo Han
C: 35.5 ± 4.1
[75] 5.00 ± 1.50 Huang Tang Lian, Nv Zhen Zi, Ju
(decoction) Hua, Shan Zhu Yu,
4. Ren Shen Shan Yao, Shu Di, Fu
Yang Rong Ling, Ze Xie, and Mu
Tang Dan Pi
(decoction) 4. Chen Pi, Huang
Qi, Bai Shao, Ren
Shen, Shu Di, Bai
Zhu, Chuan Xiong,
Dang Gui, and Gan
Cao
Chi Shao, Chuan
Xiong, Tao Ren,
Qian and
Tong Qiao Hong Hua, Bai Zhi,
Yan, I: 5.30 I: 42.5 ± 6.12
57: 60 47/70 28, NF 10, qn Huo Xue Tang Cong, Sheng Jiang,
(2006) C: 5.10 C: 41.5 ± 7.36
(decoction) Da Zao, Huang Jiu,
[60]
Dan Shen, and
Huang Qi
Ba Ji Tian, Zhen Zhu
Mu, Rou Gui, Huang
Qu et al. Yi Li Tian Kan
I: 41.52 ± 8.6 Lian, Gui Zhi, Bai
(2010) 31: 32 NS 20/43 30, NF 5, qn Tang
C: 42.31 ± 7.3 Shao, Fu Ling, Chai
[67] (decoction)
Hu, Zhi Zi, and Wu
Mei
Chuan Xiong, Bai
Shen Shao, Chai Hu, Yu Li
I: 4.62 ± 2.48 I: 26.98 ± 4.6
et al. San Pian Tang Ren, Xiang Fu, Bai
60: 60 C: C: 40/75 28, 28 5, qn
(2016) (decoction) Zhi, Gan Cao, Bai Jie
5.05 ± 3.05 25.54 ± 4.35
[50] Zi, Chi Shao, and
Jiang Chan
Table 1: Continued.
Treatment
No. of Dosage (mg)
(I: C) flunarizine
(days)
1. Gan Cao, Ju Hong,
Man Jing Zi, Chuan
Xiong, Fa Ban Xia,
Tian Ma, Fu Ling, Ci
Ji Li, and Bai Zhu
2. Tao Ren, Chuan
1. Ban Xia Bai
Xiong, Hong Hua,
Zhu Tang
Bai Zhi, Chi Shao,
(decoction)
Yan Hu Suo, Chai
2. Tong Qiao
Hu, Shi Chang Pu,
Huo Xue Tang
Song Yu Jin, and Dan Shen
I: 0.01 ± 0.01 I: 38.9 ± 2.5 (decoction)
(2017) 32: 32 9/55 60, NF 10, bid 3. Dang Gui, Gou Qi
C: 0.01 ± 0.01 C: 39.1 ± 2.4 3. Da Bu Yuan
[68] Zi, Du Zhong, Shan
Jian
Zhu Yu, Shan Yao,
(decoction)
Shu Di, Dang Shen,
4. Tian Ma
and He Shou Wu
Gou Teng Yin
4. Chuan Xiong,
(decoction)
Huang Qin, Tian Ma,
Chong Wei Zi, Sang
Ji Sheng, Niu Xi, Gou
Teng, Ye Jiao Teng,
Zhi Zi, and Shi Jue
Ming
Sun and Chuan Xiong, Jin Jie,
I: 0.17 ± 0.02 Chuan Xiong
Xu I: 56.26 ± 5.1 Fang Feng, Xi Xin,
60: 60 C: 65/55 56, NF 10, qd Cha Tiao San
(2016) C: 55.60 ± 4.6 Qiang Huo, Bai Zhi,
2.03 ± 0.20 (decoction)
[76] Bo He, and Gan Cao
Chuan Xiong, Sha
Wang San Han Huo Shen, Tu Fu Ling,
I: 5.40 ± 2.60
et al. I: 38.5 ± 12.9 Yu Zhi Tong Bahi Zhi, Bai Jie Zi,
60: 60 C: 36/84 60, NF 10, qn
(2012) C: 39.2 ± 13.4 Fang Quan Xie, Jin Jie,
6.30 ± 2.20
[77] (decoction) Man Jing Zi, Gan
Cao, and Xi Xin
Bai Shao, Gou Qi Zi,
He Shou Wu, Xiang
Wang I: 36.30 ± 9.66 Rou Gan Xi
Fu, Chai Hu, Tian
(2016) 60: 60 NS C: 31/89 56, NF 10, qn Feng Tang
Ma, Chuan Xiong,
[62] 34.33 ± 10.5 (decoction)
Huang Qin, and Gan
Cao
Chuan Xiong, Bai
Shao, He Shou Wu,
I:
Wang Shi Jue Ming, Man
I: 7.64 ± 2.34 39.30 ± 12.97 NS
(2013) 58: 52 60/50 30, NF 5, qn Jing Zi, Dang Gui,
C: 6.18 ± 2.7 C: (decoction)
[51] Tian Ma, Tao Ren,
41.37 ± 12.03
Bai Zhi, and Quan
Xie
Bai Shao, Bai Zhi,
Chuan Xiong, Dang
Gui, Di Huang, Du
Xie I: 35.05 ± 8.54 Zheng Tian
Huo, Fang Feng, Fu
(2015) 24: 24 NS C: 15/33 84, 28 5, qn Jiao Nang
Zi, Gou Teng, Hong
[55] 33.55 ± 8.79 (capsule)
Hua, Ji Xue Teng, Ma
Huang, and Qiang
Huo
Table 1: Continued.
Treatment
No. of Dosage (mg)
(I: C) flunarizine
(days)
Huang Qi, Ren Shen,
Dang Gui, Bai Shao,
Xin Tou Tong
I: 18–65 Chuan Xiong, Yan
(2016) 30: 30 NS 31/29 28, 28 10, qn Fang
C: 18–65 Hu Suo, Xi Xin, Bai
[56] (decoction)
Zhi, and Shui Niu
Jiao
Chai Hu, Huang Qin,
Xiao Chai Hu Huang Lian, Ban Xia,
I:
Yuan I: 3.90 ± 4.63 Tang plus Ge Gen, Dan Nan
42.53 ± 12.19
(2017) 30: 30 C: 16/44 28, NF 10, qn Qing Kong Xing, Chuan Xiong,
C:
[63] 4.30 ± 4.24 Gao Hou Po, Chen Pi,
41.87 ± 12.33
(decoction) Qiang Huo, Fang
Feng, and Dang Shen
Chuan Xiong, Dang
Gui, Bai Shao, Di
I: Huang, Gou Teng,
Zhang
39.30 ± 12.97 Zheng Tian Tao Ren, Hong Hua,
(2013) 30: 30 NS 27/33 56, NF 10, qn
C: Wan (pill) Fu Zi, Du Huo, Fang
[71]
41.37 ± 12.03 Feng, Ma Huang, Ji
Xue Teng, and Bai
Zhi
Xuan Fu Hua, Zhe
Shi, Shi Gao, Dang
Zhang I:
I: 8.57 ± 3.65 Yang Xue Gui, Chuan Xiong,
and Sun 49.86 ± 11.37
32: 32 C: 17/47 28, F 10, qn Ping Gan Tang sheng di, Bai Shao,
(2019) C:
6.29 ± 4.68 (decoction) Shou Wu Teng,
[78] 50.23 ± 9.16
Xiang Fu, and Gan
Cao
Tian Ma, Chuan
Xiong, Dang Gui, Zhi
Zi, Niu Xi, Bai Shao,
Zhang Tian Ma Gou
I: 40.4 ± 9.5 Sang Ji Sheng, Gou
(2014) 42: 42 NS 34/50 28, NF 5, qn Teng Yin
C: 41.2 ± 7.9 Teng, Shi Jue Ming,
[70] (decoction)
Ye Jiao Teng, Zhen
Zhu Mu, and Tao
Ren
Zhong Ping Gan
I: 2.10 ± 0.60 Tian Ma, Gou Teng,
et al. I: 34.7 ± 6.2 Qian Yang
16: 16 C: 11/21 20, NF 5, qn Shi Jue Ming, Mu Li,
(2009) C: 33.8 ± 7.1 Fang
2.20 ± 0.50 and Chuan Xiong
[45] (decoction)
Zhu
Tian Ma Su
(2006) 42: 42 NS 33.4 ± 8.5 32/52 30, NF 10, qn Tian Ma
capsule
[72]
Note: bid, bis in die; C, control group; I, intervention group; mg, milligram; NF, no follow-up; No., number; NS, not stated; qd, quaque die; qn, quaque nocte;
SD, standard deviation.
3.4. Treatment Effects effective than flunarizine in terms of reducing migraine attack
frequency (MD: −1.23, 95% CI (−1.69, −0.76), I2 � 97%).
3.4.1. Primary Outcomes Measures The subgroup analysis based on treatment duration in-
dicated that CHM was superior to flunarizine when applied for
(1) Frequency of Migraine at EoT. Twenty-one studies with a treatment period of 28 or 30 days (14 studies, MD: −1.16, 95%
1,567 participants reported the frequency of migraine attacks at CI (−1.55, −0.76), I2 � 88%) [45, 47, 48, 50, 56,
EoT. Overall meta-analysis showed that oral CHM was more 58–61, 66, 67, 69, 70, 78] and 84 or 90 days (five studies, MD:
Table 2: Most frequently used herbs in the included studies.

Most commonly used herbs Number. of studies Scientific names
Chuan Xiong 31 (1) Ligusticum chuangxiong Hort.
(1) Angelica dahurica (Fisch. ex Hoffm.) Benth. et Hook. f.
Bai Zhi 18 (2) Angelica dahurica (Fisch. ex Hoffm.) Benth. et Hook. f. var.
formosana (Boiss) Shan et Yuan
(1) Paeonia lactiflora Pall.
Bai Shao 16
(2) Paeonia veitchii Lynch
(1) Glycyrrhiza uralensis Fisch.
Gan Cao 13 (2) Glycyrrhiza inflata Bat.
(3) Glycyrrhiza glabra L.
Tian Ma 13 (1) Gastrodia elata Bl.
Dang Gui 12 (1) Angelica sinensis (Oliv.) Diels
(1) Bupleurum chinense DC.
Chai Hu 11
(2) Bupleurum scorzonerifolium Willd.
(1) Asarum heterotropoides Fr. Schmidt var. mandshuricum (Maxim) Kitag.
Xi Xin 9 (2) Asarum sieboldii Miq. var. seoulense Nakai
(3) Asarum sieboldii Miq.
(1) Prunus persica (L.) Batsch
Tao Ren 9
(2) Prunus davidiana (Carr.) Franch.
Quan Xie 8 (1) Buthus martensii Karsch
Gou Teng 8 (1) Uncaria rhynchophylla (Miq.) Miq. ex Havil.
Random sequence generation (selection bias)

Allocation concealment (selection bias)
Blinding of participants and personnel (performance bias)
Blinding of outcome assessment (detection bias)
Incomplete outcome data (attrition bias)
Selective reporting (reporting bias)
Other bias
0 25 50 75 100
%
Low risk of bias

Unclear risk of bias
High risk of bias
Figure 2: Risk of bias assessment of the included RCTs. RCT, randomized control trial.
−0.87, 95% CI (−1.15, −0.60), I2 � 75%) [53–55, 64, 74]. (−1.70, −0.21), I2 � 96%). Subgroup analyses showed CHM
However, such effects were not seen in the subgroup of RCTs being more effective than flunarizine at the end of a 28-day
conducting 56 or 60 days treatments (two studies, MD: −1.92, follow-up phase (three studies, MD: −1.33, 95% CI (−2.45,
95% CI (−4.43, 0.60), I2 � 100%) [57, 77] (Figure 3). −0.20), I2 � 92%) [50, 55, 56], but not at the end of a 60-day
The subgroup analysis based on dosage of flunarizine follow-up phase (two studies, MD: −0.45, 95% CI (−1.20,
showed that oral CHM was more effective than flunarizine 0.30), I2 � 89%) [53, 54] (Figure 5).
on both 5 mg daily (eight studies, MD: -1.64, 95% CI (−2.65, Two RCTs which conducted a 28-day treatment showed
−0.64), I2 � 99%) [45, 50, 55, 57, 64, 66, 67, 70] and 10 mg that at EoFU, CHM was more effective than flunarizine
daily (11 studies, MD: −0.99, 95% CI (−1.25, −0.74), (MD: −1.84, 95% CI (−2.62, −1.05), I2 � 78%) [50, 56]. While
I2 � 75%) [47, 48, 53, 56, 59–61, 69, 74, 77, 78] (Figure 4). studies which conducted a 90-day treatment showed no
difference between groups at EoFU (three studies, MD:
(2) Frequency of Migraine at EoFU. Five studies reported the −0.43, 95% CI (−0.98, 0.12), I2 � 81%) [53–55] (Figure 6).
frequency of migraine attacks at EoFU. The follow-up du- Based on the dosage of flunarizine, it was found that
ration was either 28 days [50, 55, 56] or 60 days [53, 54]. The CHM showed equivalent effects when compared to a dose
overall meta-analysis favored CHM (MD: −0.96, 95% CI of 5 mg flunarizine at EoFU (two studies, MD: −1.29, 95%
Chinese herbal medicine Flunarizine Weight Mean difference Mean difference

Study or subgroup (%)
Mean SD Total Mean SD Total IV, random, 95% CI IV, random, 95% CI
1.1.1 treatment duration ≈ 1 month
Qu M, 2010 2.64 3.28 31 8.56 6.4 32 2.0 –5.92 (–8.42, –3.42)
Cai ZX, 2017 5.33 2.19 32 8.77 5.3 28 2.6 –3.44 (–5.54, –1.34)
Shen B, 2016 0.97 0.84 58 3.05 0.85 57 9.0 –2.08 (–2.39, –1.77)
Ma JD, 2014 2.06 1.15 30 4.07 1.94 30 6.8 –2.01 (–2.82, –1.20)
Qian YL, 2006 1.58 1.32 57 2.98 1.71 60 8.0 –1.40 (–1.95, –0.85)
Cai MK, 2018 1.71 0.63 49 2.88 1.81 49 8.1 –1.17 (–1.71, –0.63)
Niu CP, 2003 0.86 0.66 35 1.89 0.83 35 8.8 –1.03 (–1.38, –0.68)
Zhang YD, 2014 2.68 1.22 42 3.7 2.72 42 6.3 –1.02 (–1.92, –0.12)
Zhang QX, 2019 1.74 1.46 32 2.56 1.5 32 7.2 –0.82 (–1.55, –0.09)
Zhang GW, 2009 1.2 0.37 16 1.8 0.34 16 9.2 –0.60 (–0.85, –0.35)
Du YX, 2011 1.6 1.5 48 2.2 1.6 47 7.7 –0.60 (–1.22, –0.02)
Gao JY, 2009 0.35 0.31 29 0.82 0.6 27 9.2 –0.47 (–0.72, –0.22)
Xin LN, 2016 1.73 1.48 30 2.17 1.74 30 6.7 –0.44 (–1.26, –0.38)
Liu TT, 2009 2.16 0.99 38 2.57 0.95 35 8.5 –0.41 (–0.86, –0.04)
Subtotal (95% CI) 527 520 100.0 –1.16 (–1.55, –0.76)
Heterogeniety: tau2 = 0.42, chi2 = 112.09, df = 13 (P < 0.00001); I2 = 88%
Test for overall effect: Z = 5.77 (P < 0.00001)
1.1.2 treatment duration ≈ 2 months

Gao HM, 2006 1.8 0.35 40 5 0.39 42 50.0 –3.20 (–3.36, –3.04)
Wang GF, 2012 0.49 0.51 60 1.12 0.49 60 50.0 –0.63 (–0.81, –0.45)
Subtotal (95% CI) 100 102 100.0 –1.92 (–4.43, 0.60)
Test for overall effect: Z = 1.49 (P = 0.14)
1.1.3 treatment duration ≈ 3 months

Gou CG, 2014 1.03 0.32 30 2.37 0.97 30 19.1 –1.34 (–1.71, –0.97)
Dai BH, 2005 3.8 0.32 36 4.8 0.31 34 26.5 –1.00 (–1.15, –0.85)
Pan Pk, 2015 1.23 0.67 30 2.06 0.89 30 18.0 –0.83 (–1.23, –0.43)
Xie YL, 2015 0.95 1.08 24 1.58 0.78 24 13.9 –0.63 (–1.16, –0.10)
Fu GY, 2015 0.92 0.81 40 1.43 0.34 40 22.4 –0.51 (–0.78, –0.24)
Subtotal (95% CI) 160 158 100.0 –0.87 (–1.15, –0.60)
–4 –2 0 2 4
Test for subgroup differences: chi2 = 1.88, df = 2 (P = 0.39); I2 = 0% Chinese herbal medicine Flunarizine
Figure 3: Subgroup meta-analysis results of migraine frequency at the end of treatment based on treatment duration.
CI (−3.09, 0.52), I2 � 96%) [50, 55], but was more effective flunarizine in shortening the duration of migraine attacks
when compared with 10 mg daily flunarizine (two studies, at EoT (MD: −2.24 (−3.18, −1.30), I2 � 92%) but not at
MD: −0.98, 95% CI (−1.50, −0.46), I2 � 61%) [53, 56] EoFU (three studies, MD: −3.60 (−8.85, 1.66), I2 � 97%)
(Figure 7). [53–55] (Table 3).
(4) Responder Rate. Five studies [46, 55, 56, 65, 75] involving
3.4.2. Secondary Outcomes Measures 547 participants reported responder rate at EoT and meta-
analysis showed superior effects of CHM (RR: 1.37 (1.23,
(1) Days of Migraine. Four studies with 446 participants 1.52), I2 � 0%) (Table 3).
[46, 50, 55, 56] reported data on the days of migraine attack,
and the meta-analysis showed no difference between CHM and (5) Acute Medication Usage. In terms of the acute medication
flunarizine, both at EoT (MD: −1.65 (−3.85, 0.54), I2 � 96%) usage, participants in the CHM group used less pain
and EoFU (MD: −2.18 (−5.08, 0.72), I2 � 97%) (Table 3). medication than those in the flunarizine group at both EoT
(five studies, MD: −0.58 (−1.03, −0.13), I2 � 94%)
(2) Pain VAS. Fourteen studies with 1,036 participants [46, 50, 54, 55, 59] and EoFU (four studies, MD: −0.69
[48–50, 52, 55, 64, 68, 71–76, 78] reported pain VAS at EoT, (−1.22, −0.15), I2 � 96%) [46, 50, 54, 55] (Table 3).
showing a greater pain reduction achieved by CHM than
flunarizine (MD: −1.04 (−1.67, −0.40), I2 � 96%). However, (6) Quality of Life. One study [62] involving 120 participants
there was no difference at EoFU of 28 days (two studies, MD: reported data on quality of life using HIT-6 at EoT, with the
−1.56 (−3.73, 0.61), I2 � 96%) [50, 55] (Table 3). results favoring the CHM group (Table 3).
(3) Duration of Migraine Attack. Twenty studies with 1,495

participants reported the average duration of migraine 3.4.3. Meta-Analyses for Individual Formula. Two RCTs
attacks [45, 47, 48, 51, 53–55, 57, 58, 60, 64, 66, 69, 70, [50, 74] evaluated the effectiveness of the oral CHM formula
72, 74, 75, 77–79]. Oral CHM was more effective than San Pian Tang on 175 participants. Meta-analysis of pain

Study or subgroup
Mean SD Total Mean SD Total (%) IV, random, 95% CI IV, random, 95% CI
1.2.1 10mg
Cai ZX, 2017 5.33 2.19 32 8.77 5.3 28 1.3 –3.44 (–5.54, –1.34)
Ma JD, 2014 2.06 1.15 30 4.07 1.94 30 6.1 –2.01 (–2.82, –1.20)
Qian YL, 2006 1.58 1.32 57 2.98 1.71 60 9.1 –1.40 (–1.95, –0.85)
Gou CG, 2014 1.03 0.32 30 2.37 0.97 30 12.0 –1.34 (–1.71, –0.97)
Cai MK, 2018 1.71 0.63 49 2.88 0.81 49 9.4 –1.17 (–1.171, –0.63)
Dai BH, 2005 3.8 0.32 36 4.8 0.31 34 15.2 –1.00 (–1.15, –0.85)
Zhang QX, 2019 1.74 1.46 32 2.56 1.5 32 7.0 –0.82 (–1.55, –0.09)
Wang GF, 2012 0.49 0.51 60 1.12 0.49 60 14.8 –0.63 (–0.81, –0.45)
Du YX, 2011 1.6 1.5 48 2.2 1.6 47 8.2 –0.60 (–1.22, 0.02)
Xin LN, 20196 1.73 1.48 30 2.17 1.74 30 6.1 –0.44 (–1.26, 0.38)
Liu TT, 2009 2.16 0.99 38 2.57 0.95 35 10.8 –0.41 (–0.86, –0.04)
Subtotal (95% CI) 442 435 100.0 –0.99 (–1.25, –0.74)
Heterogeneity: tau2 = 0.11; chi2 = 39.87, df = 10 (P < 0.0001); I2 = 75%
1.2.2 5 mg
Qu M, 2010 2.64 3.28 31 8.56 6.4 32 7.4 –5.92 (–8.42, –3.42)
Gao HM, 2006 1.8 0.35 40 5 0.39 42 13.5 –3.20 (–3.36, –3.04)
Shen B, 2016 0.97 0.84 58 3.05 0.85 57 13.4 –2.08 (–2.39, –1.77)
Niu ZP, 2003 0.86 0.66 35 1.89 0.83 35 13.4 –1.03 (–1.38, –0.68)
Zhang YD, 2014 2.68 1.22 42 3.7 2.72 42 12.3 –1.02 (–1.92, –0.12)
Xie YL, 2015 0.95 1.08 24 1.58 0.78 24 13.1 –0.63 (–1.16, –0.10)
Zhong GW, 2009 1.2 0.37 16 1.8 .34 16 13.5 –0.60 (–0.85, –0.35)
Fu GY, 2015 0.92 0.81 40 1.43 0.34 40 13.5 –0.51 (–0.78, –0.24)
Subtotal (95% CI) 286 288 100.0 –1.64 (–2.65, –0.64)
–4 –2 0 2 4
Test for subgroup differences: chi2 = 1.53, df = 1 (P = 0.22); I2 = 34.4% Chinese herbal medicine Flunarizine
Figure 4: Subgroup meta-analysis results of migraine frequency at the end of treatment based on flunarizine dosage.

Study or subgroup
1.3.1 Follow-up period, 60 days
Dai BH, 2005 2.3 0.26 36 3.1 0.24 34 54.8 –0.80 (–0.92, –0.68)
Pan PK, 2015 1.3 0.98 30 1.33 0.92 30 45.2 –0.03 (–0.51, –0.45)
Subtotal (95% CI) 66 64 100.0 –0.45 (–1.20, –0.30)
Heterogeneity: tau2 = 0.26; chi2 = 9.29, df = 1 (P = 0.002); I2 = 89%
1.3.2 Follow-up period, 28 days
Shen B, 2016 1 0.87 58 3.18 0.75 57 35.6 –2.18 (–2.48, –1.88)
Xie YL, 2015 1.87 1.19 24 2.21 1.18 24 32.3 –0.34 (–1.01, –0.69)
Xin LN, 2016 1.6 1.16 30 2.97 1.52 30 32.1 –1.37 (–2.05, –0.69)
Subtotal (95% CI) 112 111 100.0 –1.33 (–2.45, –0.20)
–2 –1 0 1 2
Test for subgroup differences: chi2 = 1.60, df = 1 (P = 0.21); I2 = 37.5%
Chinese herbal medicine Flunarizine
Figure 5: Subgroup meta-analysis results of migraine frequency at the end of follow-up based on follow-up duration.
VAS showed that San Pian Tang was more effective than frequency. Ten RCTs [48, 50, 54–56, 60, 61, 64, 74, 77] with
flunarizine at EoT (MD: −1.88, 95% CI (−3.14, −0.62), 793 participants used CHM containing the herb pair Chuan
I2 � 92%). Another two studies with 108 participants [55, 71] Xiong plus Bai Zhi. These studies achieved superior effects
evaluated the effectiveness of Zheng Tian pills/granules in of CHM in reducing migraine attack frequency at EoT
reducing pain VAS at EoT, showing that Zheng Tian pill/ (MD: −1.00, 95% CI (−1.41, −0.60), I2 � 90%). However,
granule achieved lower pain VAS than flunarizine at EoT such effects were not observed at EoFU (four studies, MD:
(MD: −0.64, 95% CI (−1.08, −0.20), I2 � 0%) (Table 3). −0.99, 95% CI (−2.17, 0.19), I2 � 96%) [50, 54–56] (Table 3).
Four studies used the herb pair Chuan Xiong plus Tian
3.4.4. Frequency of Migraine Based on Herb Pairs. Ma [45, 57, 64, 70] and showed no difference between two
Common herb pairs identified from the CHM formulas of groups at EoT (MD: −1.34, 95% CI (−3.00, 0.32), I2 � 99%)
the RCTs were pooled for subgroup analyses for migraine (Table 3).

Study or subgroup (%)
Mean SD Total Mean SD Total IV, random, 95% CI IV, random, 95% CI
1.4.1 treatment duration, 90 days
Dai BH, 2005 2.3 0.26 36 3.1 0.24 34 41.8 –0.80 (–0.92, –0.68)
Pan PK, 2015 1.3 0.98 30 1.33 0.92 30 32.1 –0.03 (–0.51, –0.45)
Xin YL, 2015 1.87 1.19 24 2.21 1.18 24 26.1 –0.34 (–1.01, –0.33)
Subtotal (95% CI) 90 88 100.0 –0.43 (–0.98, –0.12)
Heterogeneity: tau = 0.19; chi = 10.74, df = 2 (P = 0.005); I2 = 81%
2 2

1.4.2 treatment duration, 28 days
Shen B, 2016 1 0.87 58 3.18 0.75 57 57.5 –2.18 (–2.48, –1.88)
Xie YL, 2015 1.6 1.16 30 2.97 1.52 30 42.5 –1.37 (–2.05, –0.69)
Subtotal (95% CI) 88 87 100.0 –1.84 (–2.62, –1.05)
Heterogeneity: tau = 0.26; chi = 4.53, df = 1 (P = 0.03); I = 78%
2 2 2
–2 –1 0 1 2
Test for subgroup differences: chi2 = 8.23, df = 1 (P = 0.004); I2 = 87.9%
Chinese herbal medicine Flunarizine
Figure 6: Subgroup meta-analysis results of migraine frequency at the end of follow-up based on treatment duration.

Study or subgroup
1.5.1 10 mg
Dai BH, 2005 2.3 0.26 36 3.1 0.24 34 68.2 –0.80 (–0.92, –0.68)
Xin LN, 2016 1.6 1.16 30 2.97 1.52 30 31.8 –1.37 (–2.05, –0.69)
Subtotal (95% CI) 66 64 100.0 –0.98 (–1.50, –0.46)
Heterogeneity: tau2 = 0.10; chi2 = 2.59, df = 1 (P = 0.11); I2 = 61%
1.5.4 5mg
Shen B, 2016 1 0.87 58 3.18 0.75 57 51.4 –2.18 (–2.48, –1.88)
Xie YL, 2015 1.87 1.19 24 2.21 1.18 24 48.6 –0.34 (–1.01, 0.33)
Subtotal (95% CI) 82 81 100.0 –1.29 (–3.09, 0.52)
Heterogeneity: tau = 1.62; chi = 24.19, df = 1 (P < 0.00001); I2 = 61%
2 2
–2 –1 0 1 2
Test for subgroup differences: chi2 = 0.10, df = 1 (P = 0.75); I2 = 0% Chinese herbal medicine Flunarizine
Figure 7: Subgroup meta-analysis results of migraine frequency at the end of follow-up based on flunarizine dosage.
3.5. Publications Bias. The funnel plots of migraine fre- in the flunarizine group (34 vs 50). As shown in Table 5, most
quency, migraine attack duration, and pain VAS at EoT were AEs were mild and did not require additional medical
conducted as the meta-analyses of these outcomes involved management. None of the participants dropped out due to
more than ten studies. All funnel plots (Figure 8) were AEs. Gastrointestinal symptoms (i.e., nausea, stomach dis-
symmetrical and seemed unlikely to have publication bias. comfort, diarrheal, and abdominal distension) and other
Egger’s test was further conducted, and publication bias was symptoms (including drowsiness, dizziness, fatigue, and
not detected (P > 0.05) (Figure 9). Funnel plots and Egger’s insomnia) were commonly seen in both CHM and flunar-
test could not be conducted for the other outcome measures izine groups. Other AEs reported in the CHM group were
due to the limited number of included studies. three cases of irregular menstruation [57], one acne [48], and
one slight decrease in platelet count [55], while the flu-
narizine group had common reports of weight gain [57, 76],
3.6. Assessment Using GRADE. The certainty of evidence
some extrapyramidal symptoms such as ataxic [57, 72] and
obtained from meta-analyses on the primary outcome
involuntary movements [47], as well as one case of moderate
measures is presented in Table 4. Oral CHM was more
liver function impairment [76].
effective than flunarizine for reducing migraine frequency at
EoT and EoFU, but the certainty of this evidence was “low”
and “very low,” respectively. 4. Discussion
4.1. Summary of Results. This systematic review provides
3.7. Adverse Events. AEs were categorized and calculated to evidence showing that oral CHM is more effective than
assess the safety of the treatments. Based on the available flunarizine for episodic migraine prophylaxis based on
data from 15 studies that reported detailed information of these outcome measures: migraine frequency, pain VAS,
AEs, the number of AEs in the CHM group was less than that migraine attack duration, responder rate, and acute
Table 3: Treatment effects of all outcome measures.

Number of Number of Estimated effects (RR or I2
Outcome Overall analysis or subgroup analysis
studies (n�) participants (I/C) MD with 95% CI) (%)
Overall analysis 21 1567 (787/780) MD: −1.23 (−1.69, −0.76) 97
Subgroup analysis (treatment
5 318 (160/158) MD: −0.87 (−1.15, −1.15) 75
duration >60 days)
2 202 (100/102) MD: −1.92 (−4.43, 0.60) 100
duration � 56 or 60 days)
14 1047 (527/520) MD: −1.16 (−1.55, −0.76) 88
duration � 28 or 30 days)
Frequency at EoT Subgroup analysis (flunarizine
8 574 (286/288) MD: −1.64 (−2.65, −0.64) 99
dosage at 5 mg daily)
Subgroup analysis (flunarizine
11 877 (442/435) MD: −0.99 (−1.25, −0.74) 75
Subgroup analysis (studies used
10 793 (399/394) MD: −1.00 (−1.41, −0.60) 90
Chuan Xiong plus Bai Zhi)
4 278 (138/140) MD: −1.34 (−3.00, 0.32) 99
Chuan Xiong with Tian Ma)
3 178 (90/88) MD: −0.43 (−0.98, 0.12) 81
duration > 60 days)
2 175 (88/87) MD: −1.84 (−2.62, −1.05) 78
duration � 28 days)
Subgroup analysis (follow-up
2 130 (66/64) MD: −0.45 (−1.20, 0.30) 89
period � 56 or 60 days)
Frequency at EoFU Subgroup analysis (follow-up
3 223 (112/111) MD: −1.33 (−2.45, −0.20) 92
period � 28 days)
2 163 (82/81) MD: −1.29 (−3.09, 0.52) 96
2 130 (66/64) MD: −0.98 (−1.50, −0.46) 61
4 253 (142/141) MD: −0.99 (−2.17, 0.19) 96
Chuan Xiong with Bai Zhi)
Migraine days at EoT Overall analysis 4 446 (225/221) MD: −1.65 (−3.85, 0.54) 96
Migraine days at
Overall analysis 3 386 (195/191) MD: −2.18 (−5.08, 0.72) 97
EoFU
Subgroup analysis (San Pian Tang) 2 175 (87/88) MD: −1.88, (−3.14, −0.62) 92
Pain VAS/NRS at EoT
Subgroup analysis (Zheng Tian pill/
2 108 (54/54) MD: −0.64, (−1.08, −0.20) 0
granule)
Pain VAS/NRS at
EoFU
Attack duration at
EoT
Attack duration at
EoFU
Responder rate at EoT Overall analysis 5 467 (235/232) RR: 1.37 (1.23, 1.52) 0
Acute medication at
EoT
Acute medication
usage at EoFU
HIT-6 at EoT Overall analysis 1 120 (60/60) MD: −3.29 (−5.51, −1.07) —
Note: C, control group; CI, confidence intervals; EoFU, end of follow-up; EoT, end of treatment; HIT-6, Headache Impact Test-6; I, intervention group; MD,
mean difference; n, number; NRS, numerical rating scale; RR, risk ratio; VAS, visual analogue scale.
medication usage at EoT. Oral CHM also showed better evidence was “low” or “very low” based on GRADE
effects than flunarizine for migraine frequency and acute assessment.
medication usage at EoFU. In addition, there was no As substantial heterogeneity existed in most meta-analyses,
difference between CHM and flunarizine in migraine days subgroup meta-analyses were conducted on the primary
(at both EoT and EoFU) and pain VAS and migraine attack outcome measures, based on the treatment duration, follow-up
duration at EoFU. Nevertheless, the overall methodological duration, and dosage of flunarizine. These subgroup analyses
quality of the included studies was low, and the certainty of showed that CHM produced superior or equivalent effects as
Funnel plot with pseudo 95% confidence limits Funnel plot with pseudo 95% confidence limits
0 0
0.5
2
_seES
_seES
1 3
4
1.5
−6 −4 −2 0 2 −10 −5 0 5 10
_ES _ES
(a) (b)
Funnel plot with pseudo 95% confidence limits
0
0.2
_seES
0.4
0.6
0.8
−3 −2 −1 0 1 2
_ES
(c)
Figure 8: Funnel plot. (a) Migraine frequency at the end of treatment. (b) Migraine attack duration at the end of treatment. (c) Pain VAS at
the end of treatment; VAS, visual analogue scale.
flunarizine. However, heterogeneity remained considerable for its side effects, CHM could be an alternative for el-
within the subgroup analyses. The possible causes of hetero- derly patients and those who suffer from common side
geneity are the uses of different CHM formulas, disease se- effects of flunarizine.
verity, and duration across trials. It should be noted that two As shown in the meta-analyses, CHM has an advantage
studies reported migraine frequency at EoT with exceptional in reducing acute pain medication usage, indicating its
results [51, 75]; therefore, they were excluded from the meta- potential of preventing medication overuse, which is
analysis of this outcome. a common concern in headache [10] and chronic migraine
This study shows that CHM is well-tolerated when [88] treatment.
compared to flunarizine. Fifteen studies provided de- Previous research suggested that CHM is an effective
tailed information on AEs; all of them were mild or add-on therapy for migraine [36]. It is known that flunar-
moderate and did not require specific management. Most izine should be taken for several weeks to show its full effects
of the common complaints in both CHM and flunarizine in migraine prevention [11, 40, 83, 84]; during this period,
groups such as fatigue, insomnia, and digestive problems patients may be unsatisfied with its treatment effects. The
could be the associated symptoms of migraine [1] rather subgroup analysis in our review demonstrated that oral
than side effects caused by treatments. One case of de- CHM was superior to flunarizine when they were used for
creased platelet count was reported, but there was not four weeks and equivalent to flunarizine when they were
a confirmed association between this event and CHM used for eight weeks. Hence, our results support the use of
[55]. Weight gain and ataxia were only reported in the CHM as a potential adjuvant therapy to increase the ef-
flunarizine group, which agrees with previous research fectiveness of flunarizine. However, the drug interactions
results on flunarizine [15, 16, 18, 24, 81, 82]. Considering between flunarizine and Chinese medicine herbs or formulas
that aging [81, 83–85] and increased dosage have not been well investigated, and this is an area which
[11, 40, 86, 87] of flunarizine and the predisposing factors requires further research.
Egger’s publication bias plot Egger’s publication bias plot

20 5
Standardized effect
0
0
−5
−20
−10
−40 −15
0 5 10 15 0 2 4 6
Precision Precision
(a) (b)
Egger’s publication bias plot
10
−10
−20
0 2 4 6 8
Precision
(c)
Figure 9: Egger’s test. (a) Migraine frequency at the end of treatment. (b) Migraine attack duration at the end of treatment. (c) Pain VAS at
the end of treatment; VAS, visual analogue scale.
Table 4: Summary of GRADE assessment.

Number of participants Number of studies Estimated effects Certainty of the
Outcome
(n�) (n�) (MD with 95% CI) evidence
Migraine frequency at the end of MD: −1.23 (−1.69, ⊕⊕○○
1567 21
treatment −0.76) Lowa,b
Migraine frequency at the end of MD: −0.96 (−1.70, ⊕○○○
345 5
follow-up −0.21) Very lowa,b,c
GRADE working group grades of evidence
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect
Moderate certainty: we are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but
there is a possibility that it is substantially different
Low certainty: our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect
Very low certainty: we have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate
of the effect
Explanation:
a
High risk of bias in blinding may limit the certainty of the results; bhigh heterogeneity may limit the certainty of the results; csmall sample
size may limit the certainty of results
Note: CI, confidence interval; MD, mean difference; n, number.
4.2. Mechanisms of Herbs. There has been increasing ex- turnover rates of monoamine neurotransmitters and de-
perimental research on the active compounds of CHM in crease nitric oxide (NO) levels in the blood and brain [32].
attempts to elucidate their potential mechanisms for mi- Bai Zhi (Angelicae Dahuricae Radix) was reported to have
graine. For example, one of the main compounds found in antimigraine actions by modulating the levels of vasoactive
Chuan Xiong (Ligusticum chuanxiong), senkyunolide I, was substances such as NO, calcitonin gene-related peptides, and
proved to reduce migraine pain by adjusting the levels and endothelin [89, 90]. Tian Ma (Gastrodia elata) contains the
Table 5: Summary of adverse events.

Number and severity reported by
Number and severity reported by the CHM
Adverse events the
group
flunarizine group
Gastrointestinal symptoms 11 mild 12 mild
Drowsiness 5 mild 7 mild
Fatigue 6 mild 11 mild
Dizziness 5 mild 2 mild
Insomnia 3 mild 3 mild
Irregular menstruation 3 mild 0
Decrease of platelet 1 mild 0
Acne 1 mild 0
Extrapyramidal symptoms 0 5 mild
Weight gain 0 9 mild
Liver dysfunction 0 1 moderate
Dry mouth 0 1 mild
All adverse events reported in treatment and follow-up
35 mild 50 mild and 1 moderate
phases
Note: CHM, Chinese herbal medicine.
active ingredient, gastrodin, which has been found to This review also conducted subgroup analyses based on
demonstrate antimigraine, antihyperalgesic, and anti- the treatment duration, follow-up duration, and dosage
nociceptive effects, possibly by inhibiting trigeminal nerve of flunarizine.
activation at central sites and also inhibiting the peripheral The major limitations of this systematic review include
release of calcitonin gene-related peptides following the NO the low methodological quality of included studies and high
scavenging effect [91, 92]. heterogeneity across most meta-analyses and subgroup
This review has also provided meta-analysis evidence analyses, reducing the certainty of evidence. Future studies
supporting the use of two herb pairs in migraine, namely, need to adopt more rigorous designs to ensure appropriate
Chuan Xiong plus Bai Zhi and Chuan Xiong plus Tian sequence generation, allocation concealment, and blinding
Ma. Herb pairs form the basis of CHM formulation and procedures. It was noted that the CHM formulas were
are believed to result in synergistic effects or reduced side administered with different forms including decoction, pills,
effects/toxicity [93]. It has been suggested that herb pairs and granule. However, this systematic review failed to
are potential research entry-point for research on CHM conduct subgroup meta-analysis based on CHM forms due
mechanisms [93]. The two herb pairs evidenced in this to the small number of studies which applied same CHM
review are also CHM formulas that have been tradi- formulation and reported same outcome measures. Differ-
tionally used for the treatment of headaches/migraines ences of effectiveness among diverse CHM forms with the
[80]. The combination of Chuan Xiong and Bai Zhi is same formulation could be explored in future studies. Safety
a formula known as Du Liang Wan with experimental evaluation of treatments should also be given more attention
studies showing the function of adjusting the level of in future clinical studies so that clinicians and patients will
neurotransmitters and vasoactive substances to relieve be able to make more informed decisions.
neurogenic inflammation [94, 95]. The other herb pair
(Chuan Xiong plus Tian Ma) is known as Da Chuan 5. Conclusion
Xiong Wan, which has been proved to reduce in-
flammatory mediators through inhibition of the NF- Cautiously, the oral CHM has the potential to act as an
kappaB pathway [31]. alternative prophylactic treatment of migraine. The results
from this review show that the effects of oral CHM are, at
least, equivalent to flunarizine in preventing migraine at-
4.3. Strengths and Limitations of This Study. One strength of tacks in adults at EoT and EoFU, well-tolerated by partic-
this review is that the prolonged effects of oral CHM has ipants, regardless of the treatment duration, follow-up
been evaluated, which has been highlighted by clinical duration, and dosage of flunarizine. However, these results
guidelines as an important outcome assessment of pro- need to be interpreted with caution due to the low certainty
phylactic treatments of migraine [10, 11, 96, 97]. Fur- of evidence. Future studies with more rigorous designs are
thermore, the active comparator in this review was needed to provide more concrete evidence for stronger
restricted to flunarizine with a treatment duration of at conclusions. This review also provides evidence for two herb
least four weeks; this is consistent with the recommen- pairs, Chuan Xiong plus Bai Zhi and Chuan Xiong plus Tian
dations of clinical guidelines for migraine prophylaxis Ma for migraine prophylaxis. In addition, this review draws
[10–12, 39, 40]. This allows for more targeted evaluations attention to the potential and need to evaluate oral CHM as
and reduces variables regarding the different types and an adjunct treatment to flunarizine in the prophylactic
doses of conventional migraine prophylaxis treatment. treatment of migraines.
Data Availability Headache: The Journal of Head and Face Pain, vol. 57, no. 10,
pp. 1532–1544, 2017.
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migraine,” Acta Neurologica Taiwanica, vol. 26, no. 1,
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Hindawi

Evidence-Based Complementary and Alternative Medicine

Academic Editor: Mohieddin Jafari

1. Introduction Migraine has an estimated global prevalence of 14.7%

Records after duplicates removed

Records screened (n = 4,286) Records excluded (n = 3,234)

Full-text articles excluded,

Figure 1: PRISMA ﬂowchart of the study selection process.

Table 1: Characteristics of included studies.

Table 2: Most frequently used herbs in the included studies.

Random sequence generation (selection bias)

Low risk of bias

Chinese herbal medicine Flunarizine Weight Mean diﬀerence Mean diﬀerence

1.1.2 treatment duration ≈ 2 months

1.1.3 treatment duration ≈ 3 months

(3) Duration of Migraine Attack. Twenty studies with 1,495

Chinese herbal medicine Flunarizine Weight Mean diﬀerence Mean diﬀerence

Chinese herbal medicine Flunarizine Weight Mean diﬀerence Mean diﬀerence

Chinese herbal medicine Flunarizine Weight Mean diﬀerence Mean diﬀerence

Test for overall eﬀect: Z = 1.54 (P = 0.12)

Test for overall eﬀect: Z = 4.59 (P < 0.00001)

Chinese herbal medicine Flunarizine Weight Mean diﬀerence Mean diﬀerence

Test for overall eﬀect: Z = 1.40 (P = 0.16)

Table 3: Treatment eﬀects of all outcome measures.

Egger’s publication bias plot Egger’s publication bias plot

Table 4: Summary of GRADE assessment.

Table 5: Summary of adverse events.

tumor necrosis factor-α via mitogen-activated protein kinases

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