Heliyon 9 (2023) e14996

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Heliyon
journal homepage: www.cell.com/heliyon

Research article

Data mining-based analysis on medication rules of Chinese herbal

medicine treating headache with blood stasis syndrome
Guang-hui Liu a, b, 1, Hui-ting Yang a, 1, Li Bai b, Yang Wang c, En-long Wang b,
Xiu-ye Sun d, Hong-yuan Zhang b, Li Zhou e, f, g, Zhe Zhang h, *
a
Graduate College, Liaoning University of Traditional Chinese Medicine, No.79, Chongshan East Road, Huanggu District, 110847, Shenyang,
Liaoning, China
b
Department of Neurology, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, No.33, Beiling Street, Huanggu District,
110032, Shenyang, Liaoning, China
c
Office of Academic Research, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine, No.33, Beiling Street, Huanggu District,
110032, Shenyang, Liaoning, China
d
Department of Rehabilitation, Second Hospital Affiliated to Liaoning University Traditional Chinese Medicine, No.60, Huanghe North Street,
110034, Shenyang, Liaoning, China
e
Second Clinical Medical College, Guangzhou University of Chinese Medicine, No.111, Dade Road, Yuexiu District, 510120, Guangzhou,
Guangdong, China
f
Second Affiliated Hospital of Guangzhou University of Chinese Medicine, No.111, Dade Road, Yuexiu District, 510120, Guangzhou, Guangdong,
China
g
Key Unit of Methodology in Clinical Research, Guangdong Provincial Hospital of Chinese Medicine, No.111, Dade Road, Yuexiu District, 510120,
Guangzhou, Guangdong, China
h
Traditional Chinese Medicine Innovation Engineering Technology Centre, Liaoning University of Traditional Chinese Medicine, No.79, Chongshan
East Road, Huanggu District, 110847, Shenyang, Liaoning, China

A R T I C L E I N F O A B S T R A C T

Keywords: Objective: The incidence of headaches with blood stasis syndrome has increased. Herein, we used
Headache scientific, statistical methods to explore the medication rules of Chinese herbal medicines (CHMs)
Blood stasis syndrome to treat headaches with blood stasis syndrome and provide a scientific and reliable theoretical
Chinese herbal medicine
basis for clinical treatment.
Medication rule
Data mining
Methods: First, we retrieved studies related to CHMs used to treat headaches with blood stasis
syndrome from the VIP, CNKI, Wanfang, and PubMed databases. We used Excel 2013 to establish
a database and SPSS Modeler 18.0 and SPSS 25.0 to conduct frequency, association rule, and
cluster analyses.
Results: Based on the screening criteria, we retrieved 126 CHM prescriptions for headaches with
blood stasis syndrome involving 149 herbs. The top three high-frequency herbs were Chuanxiong
Rhizoma (Chuanxiong), Angelica Sinensis Radix (Danggui), and Carthami Flos (Honghua). Blood-
activating and stasis-eliminating herbs were the most frequently used herb efficacy categories.
The liver meridian represented the most frequently used herb meridian tropism. The properties
and taste of herbs were mainly warm and bitter, respectively. We obtained 21 association rules
and five new clusters. The Chuanxiong Rhizoma (Chuanxiong) and Angelica Sinensis Radix
(Danggui) herb pair had the strongest correlation.

* Corresponding author. Liaoning University of Traditional Chinese Medicine, No.79, Chongshan East Road, Huanggu District, 110847, Shenyang,
Liaoning, China. .
E-mail address: pedtrainzhzh7676@163.com (Z. Zhang).
1
Guang-hui Liu and Hui-ting Yang contributed equally to this work and should be regarded as co-first authors.

https://doi.org/10.1016/j.heliyon.2023.e14996
Received 2 September 2022; Received in revised form 16 March 2023; Accepted 23 March 2023
Available online 30 March 2023
2405-8440/© 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
G.-h. Liu et al. Heliyon 9 (2023) e14996

Conclusion: We analyzed published CHM prescriptions for headaches with blood stasis syndrome
and eliminated factors that did not reach an agreement, such as herb dosage. We used different
data mining and analysis methods to ensure that the method and process were scientific and the
conclusion was reliable, comprising a valuable reference for selecting herbs for the clinical
treatment of headaches with blood stasis syndrome. The Xuefu Zhuyu Decoction (XFZYD) was the
primary CHM prescription for headaches with blood stasis syndrome. Xiaoyao San (XYS) and
Buyang Huanwu Decoction (BYHWD) might also be clinical references for treatment selection.
Meridian-inducing and insect herbs might be used according to syndromes.

1. Introduction

Headache is a common clinical and spontaneous symptom that manifests as overall or localized swelling and pain of the head. Often
it may also be accompanied by nausea, vomiting, dizziness, and visual disturbances [1]. Headache occurs predominantly in patients
aged 20–40 years [2]. The Global Burden of Disease 2017 showed that headache is the second most common disease and one of the top
four major causes of chronic disease [3]. However, the pathogenesis of headaches from a Western medical perspective is unclear. In the
International Classification of Headache Disorders 3rd edition (ICHD-3) [4], the International Headache Society (IHS) divides primary
headache into four categories: migraine, tension-type headache, trigeminal autonomic cephalalgias, and other primary headache
disorders. Tension-type is the most common headache. Recently, the trigeminal vascular theory has received extensive attention in
describing the pathogenesis of migraine. Typically, neurotransmitters at the ends of trigeminal afferent fibers, such as calcitonin
gene-related peptide (CGRP), substance P, and neurokinin A (NKA), act on intracranial and extracranial vessels, causing vascular
dilation and leading to headaches [5,6]. Tension-type headaches are associated with peripheral sensitization, cranial muscle
tenderness, abnormal muscle activity, abnormal pain modulation of the central nervous system, and disturbances in the metabolism of
cytokines and inflammatory mediators [7]. However, due to the unclear pathogenesis, pain relief is usually the primary goal of
Western medicine in the treatment of headaches. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as Aspirin and Ibuprofen, are
the first nonspecific choice, while Triptans are the first specific choice [8]. Although these drugs are effective for pain relief, they have
common side effects, such as neurological and gastrointestinal adverse effects, stroke, and risk of bleeding [9,10]. In addition, the lack
of headache treatment management may lead to the overuse of pain medications [11].
Blood stasis (Xueyu in Chinese) is defined as poor circulation or stagnation of blood flow and the formation of bruises [12]. This
concept does not refer to a specific disease but a symptom diagnosed in the traditional Chinese medicine (TCM). The main clinical
features of blood stasis are fixed pain (worse at night), subcutaneous hematoma or purpura, and cyanosis of the face and lips [13]. The
concept of headaches with blood stasis syndrome was first proposed by Qingren Wang from the Qing Dynasty in the Corrections on the
Errors of Medical Works [14]. In this definition, abnormal blood flow can lead to headaches with blood stasis syndrome because of
problems such as Qi and blood deficiency, Qi stagnation, cold coagulation, turbid phlegm, and toxic heat [15]. From modern medical
and clinical studies, the pathological basis of headaches with blood stasis syndrome comprises dysfunctional micro-circulation related
to irregular hemorheology, hemodynamics, and scar tissue formation [13,16,17]. Hence, the main treatment principle should be to
activate the blood and remove blood stasis.
Nowadays, TCM doctors have different views on how to treat headaches with blood stasis syndrome. For example, some experts
believe that wind herbs should be used more frequently based on blood-activating and stasis-eliminating properties [18,19]. In
contrast, others believe that the therapeutic principles of clearing heat, external drainage, and regulating Qi are equally important as
activating blood circulation and resolving blood stasis [20]. Therefore, statistical methods are essential to explore the rules of CHMs for
headaches with blood stasis syndrome.
Data mining is an information processing technique widely used to obtain rules from big data, including frequency statistics, cluster
analysis, and association rules, which reflect mapping relationships between multidimensional data [21]. Data mining for clinical
prevention and treatment in TCM could help explore previous findings, discover potential rules, and guide future clinical practice.
After reviewing various studies, we found that the current research on headaches with blood stasis syndrome only comprises

Table 1
Search strategy for literature on CHM in headaches with blood stasis syndrome.
Search Strategy Keywords Content

A.Search strategy to locate “headache” 1 headache

2 headache disorders
3 primary headache
4 migraine
5 tension-type headache
6 trigeminal autonomic cephalalgias
7 cephalalgias
B.Search strategy to locate “blood stasis” 8 blood stasis
9 stasis of blood

* This search strategy was used in all databases.

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clinical observations and case reports, lacking systematic analysis and rule summaries. Therefore, it is crucial to explore and sum­
marize the appropriate medication rules through scientific and rigorous statistical methods, which is the main goal and strength of our
current study. In this study, we used data mining from the relevant literature over the past 20 years to explore the success of CHM in the
treatment of blood stasis headache and to provide a practical and effective theoretical basis for clinical treatment.

2. Materials and methods

2.1. Data collection

We searched three Chinese databases (VIP, China National Knowledge Infrastructure, and Wanfang data) and one English database
(PubMed) from January 1st, 2000, to May 1st, 2021. We restricted the language to English or Chinese. The search strategy and
keywords are shown in Table 1.

2.2. Selection criteria

2.2.1. Inclusion criteria

We included randomized controlled trials (RCTs) using CHM prescription for the treatment of blood stasis type headache. Par­
ticipants should be diagnosed with primary headaches according to the ICHD-3 [4] and blood stasis syndrome symptoms following the

Fig. 1. Screening process.

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diagnosis and therapeutic effect criteria for internal diseases and syndromes of TCM [22]. Studies should contain at least one of the four
outcomes: pain intensity, duration, frequency, and recurrence of headaches, with clear and good results.

2.2.2. Exclusion criteria

We excluded case reports, animal experiments, retrospective studies, literature reviews, and systematic reviews. Additionally, we
excluded studies without specific CHM compositions or that used CHM treatment only as a control group, as well as studies without
better outcomes with CHM treatment.

2.3. Screening process

After reading the titles and abstracts, H. Yang identified the non-repetitive literature and excluded irrelated studies, such as case
reports, animal experiments, retrospective studies, literature reviews, and systematic reviews. Then, G. Liu read the full text of the
remaining studies and conducted the secondary screening. In this section, 27 non-RCTs, 17 studies with sample sizes <40, 2 studies
without full prescriptions, and 2 studies without TCM treatment superiority were excluded. Finally, Z. Zhang, G. Liu, and H. Yang
checked the documents that met the above screening criteria. Differences in the literature selection process were resolved through joint
discussion. Finally, we selected 126 herbal prescriptions. The screening process is shown in Fig. 1.

2.4. Data processing

2.4.1. Data normalization

Since many synonyms were available for TCM herbs, we unified and normalized them before statistical analyses. The standards for
TCM herb name normalization were verified in the 2020 edition of The Pharmacopoeia of the People’s Republic of China [23] and The
Dictionary of Chinese Herbal Medicine [24]. We analyzed CHM prescriptions without considering different herbal doses because of the
difficulty of unifying and standardizing herbal doses.

2.4.2. Statistical analyses

We used Microsoft Excel 2017 (Microsoft Excel, RRID: SCR_016137) to establish a database to record literature names and sources,
interventions, and CHM prescriptions with herb compositions and efficacy results. Then, we analyzed the frequency, properties, tastes,
meridian tropisms, and drugs.
Association rule analysis is a data mining approach commonly used in clinical medicine. It inferred the probability of related
diseases and random events by using frequent associations between combinations of variables [25]. Here, we used support, confidence,
and lift as indicators to measure the strength of associations. Support comprised the probability of the simultaneous occurrence of two
items. Confidence comprehended the probability of occurrence of the last item under the former item. The lift reflected the correlation

Table 2
High-frequency herbs used to treat headaches with blood stasis syndrome.
a
No. Herb Properties Tastes Meridian Tropisms Frequency Proportion/
%

1 Chuanxiong Rhizoma (Chuanxiong) Warm Pungent Liver/Gallbladder/ 111 88.10

Pericardium
2 Angelicae Sinensis Radix (Danggui) Warm Pungent/Sweet Liver/Heart/Spleen 73 57.94
3 Carthami Flos (Honghua) Warm Pungent Heart/Liver 69 54.76
4 Paeoniae Radix Rubra (Chishao) Cold Bitter Liver 66 52.38
5 Persicae Semen (Taoren) Mild Bitter/Sweet Heart/Liver/Large intestine 63 50.00
6 Bupleuri Radix (Chaihu) Cold Pungent/Bitter Liver/Gallbladder/Lung 52 41.27
7 Angelicae Dahuricae Radix (Baizhi) Warm Pungent Stomach/Large intestine/Lung 51 40.48
8 Glycyrrhizae Radix Et Rhizoma (Gancao) Mild Sweet Heart/Lung/Spleen/Stomach 50 39.68
9 Scorpio (Quanxie) Mild Pungent Liver 49 38.89
10 Scolopendra (Wugong) Warm Pungent Liver 41 32.54
11 Astragali Radix (Huangqi) Warm Sweet Lung/Spleen 39 30.95
12 Puerariae Lobatae Radix (Gegen) Cool Pungent/Sweet Spleen/Stomach/Lung 36 28.57
13 Gastrodiae Rhizoma (Tianma) Mild Sweet Liver 33 26.19
14 Paeoniae Radix Alba (Baishao) Cold Bitter/Sour Liver/Spleen 32 25.40
15 Asari Radix Et Rhizoma (Xixin) Warm Pungent Heart/Lung/Kidney 32 25.40
16 Notopterygii Rhizoma Et Radix (Qianghuo) Warm Pungent/Bitter Bladder/Kidney 31 24.60
17 Pheretima (Dilong) Cold Salty Liver/Spleen/Bladder 28 22.22
18 Viticis Fructus (Manjingzi) Cold Pungent/Bitter Bladder/Liver/Stomach 28 22.22
19 Corydalis Rhizoma (Yanhusuo) Warm Pungent/Bitter Liver/Spleen 27 21.43
20 Salviae Miltiorrhizae Radix Et Rhizoma (Danshen) Cold Bitter Heart/Liver 26 20.63
21 Ligustici Rhizoma Et Radix (Gaoben) Warm Pungent Bladder 22 17.46
22 Achyranthis Bidentatae Radix (Niuxi) Mild Bitter/Sweet/ Liver/Kidney 21 16.67
Sour
23 Uncariae Ramulus Cum Uncis (Gouteng) Cool Sweet Liver/Pericardium 20 15.87
a
The proportion refers to the percentage of a herb’s frequency in the total frequency of all herbs.

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G.-h. Liu et al. Heliyon 9 (2023) e14996

Fig. 2. a. Herb properties of CHMs for headaches with blood.

b. Herb tastes of CHMs for headaches with blood.
c. Herb meridian tropisms of CHMs for headaches with blood stasis syndrome.

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between A and B. For lift >1, the higher the value, the stronger the positive correlation. In contrast, for lift <1, the lower the value, the
stronger the negative correlation. A lift = 1 indicates no association. We used SPSS Modeler 18.0 (IBM SPSS Statistics, RRID: SCR_
019096) to analyze the association rules of herbs.
Systematic cluster analysis is an exploratory approach without established standards during classification. It automatically clas­
sifies the sample data and provides new data clusters. Specific cluster sets are further analyzed by observing the characteristics of each
kind of data. Cluster analysis has been previously used for data mining in TCM, mainly to determine the compatibility law between
drugs and identify the combination rules of different CHM prescriptions [26]. Here, we conducted a systematic cluster analysis of herbs
using SPSS 25.0 (IBM SPSS Statistics, RRID: SCR_019096).

3. Results

3.1. Frequency analysis

After literature search and collection, we obtained 1680 studies and included 126 after screening according to the above criteria.
Among the included studies, 11,511 cases and 126 prescriptions, including 149 herbs, were reported. The cumulative herb frequency
was 1610. Among the 149 herbs, 23 (15.44%) herbs presented a frequency ≥20, classified as high-frequency, comprising 62.11% of the
cumulative frequency (Table 2). Chuanxiong Rhizoma (Chuanxiong) was the most frequent herb (111 times - 88.1%) for headaches
with blood stasis syndrome. Angelicae Sinensis Radix (Danggui), Carthami Flos (Honghua), Persicae Semen (Taoren), and Paeoniae
Radix Rubra (Chishao) were also frequently used (frequency >50%).

3.2. Properties, tastes, and meridian tropisms

The total frequency of herb properties was 149. Warm herbs were used 61 times (40.94%), followed by cold [44 times (29.53%)]
and mild [34 times (22.82%)] herbs. Cool and hot herbs were rarely used (Fig. 2a). The total frequency of herb tastes was 239. Bitter
herbs were used 74 times (30.96%), comprising the highest frequency, followed by pungent [71 times (29.71%)] and sweet [62 times
(25.94%)] herbs (Fig. 2b). The total frequency of herb meridian tropisms was 363, with the liver meridian as the most frequent [82
times (22.59%)]. Herbs were also frequently used in the lung, spleen, stomach, heart, and kidney meridians (Fig. 2c).

3.3. Herb categories analysis

CHMs have different curative effects when used in diverse combinations. Accordingly, they can be divided based on their char­
acteristic curative effects [27]. The total frequency and proportions of each herbal category are presented in Fig. 3. Blood-activating
and stasis-eliminating herbs were the most frequently used [372 times - 23.11% of the total (1610 times)], followed by
exterior-relieving (344 times; 21.37%), deficiency-tonifying (290 times; 18.01%), and liver-wind calming (218 times; 13.54%) herbs.

3.4. Association rule analysis and network display

We applied the Apriori algorithm to conduct the association rule analysis on the 149 herbs. We obtained 21 herb association rules
with support ≥30%, confidence ≥90%, and lift >1. The support ≥30% means that the occurrence probability of the former and the last

Fig. 3. Categories frequency for CHMs for headaches with blood stasis syndrome.

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item at the same time must be ≥ 30%. The confidence ≥90% indicates that the occurrence probability of the last item under the former
item must be ≥ 90%. The lift >1 means that the association rules are positively correlated. Chuanxiong Rhizoma (Chuanxiong) and
Angelicae Sinensis Radix (Danggui) had the strongest association (Table 3).
Furthermore, we used SPSS Modeler 18.0 to generate a network diagram of association rules. In the network diagram, the thicker
the lines, the stronger the correlation between herbs, whereas the thinner the lines, the weaker the correlation. We detected strong
correlations for Chuanxiong Rhizoma (Chuanxiong) and Angelicae Sinensis Radix (Danggui); Chuanxiong Rhizoma (Chuanxiong) and
Carthami Flos (Honghua); Paeoniae Radix Rubra (Chishao) and Chuanxiong Rhizoma (Chuanxiong); Chuanxiong Rhizoma (Chuan­
xiong) and Persicae Semen (Taoren); Carthami Flos (Honghua) and Persicae Semen (Taoren). These results suggested that Chuanxiong
Rhizoma (Chuanxiong), Angelicae Sinensis Radix (Danggui), Carthami Flos (Honghua), Persicae Semen (Taoren), and Paeoniae Radix
Rubra (Chishao) were the most important CHMs to treat headaches with blood stasis syndrome (Fig. 4).

3.5. Cluster analysis

Furthermore, we selected the 23 herbs used more than 20 times and conducted systematic cluster analysis with SPSS 25.0. This
approach can indicate the compatibility and combination rules of different CHMs [26]. Herein, five new clusters were referenced for
treatment (Fig. 5). Cluster 1 included Carthami Flos (Honghua), Persicae Semen (Taoren), Paeoniae Radix Rubra (Chishao), Achyr­
anthis Bidentatae Radix (Niuxi), Angelicae Sinensis Radix (Danggui), Astragali Radix (Huangqi), and Pheretima (Dilong). Cluster 2
comprised Scorpio (Quanxie), Scolopendra (Wugong), Angelicae Dahuricae Radix (Baizhi), Viticis Fructus (Manjingzi), and Corydalis
Rhizoma (Yanhusuo). Cluster 3 contained Notopterygii Rhizoma Et Radix (Qianghuo), Ligustici Rhizoma Et Radix (Gaoben), Puerariae
Lobatae Radix (Gegen), and Asari Radix Et Rhizoma (Xixin). Cluster 4 included Gastrodiae Rhizoma (Tianma), Uncariae Ramulus Cum
Uncis (Gouteng), and Salviae Miltiorrhizae Radix Et Rhizoma (Danshen). Cluster 5 comprised Bupleuri Radix (Chaihu), Glycyrrhizae
Radix Et Rhizoma (Gancao), Paeoniae Radix Alba (Baishao), and Chuanxiong Rhizoma (Chuanxiong).
The herbs in cluster 1 represent the Buyang Huanwu Decoction (BYHWD) and the Xuefu Zhuyu Decoction (XFZYD). Herbs in
clusters 2 and 4 are related to wind and pain-relieving effects. Meanwhile, cluster 3 included pungent exterior-relieving herbs with
meridian-inducing effects. Finally, herbs in cluster 5 represent Xiaoyao San (XYS).

4. Discussion

Various studies have confirmed that herbs have been widely used in the treatment of cardiovascular and cerebrovascular diseases,
and they have the effects of promoting blood circulation and anti-thrombotic, Qi-regulating, pain-relieving, blood-tonifying, and Qi-
tonifying. The effective effects of the first eight HF herbs in the article also validate the results of previous studies. Why are they
effective? Their active ingredients and related mechanisms are shown in Appendix A (Online Supplementary Appendix). We found that
warm and cold herbs were the most frequently used with a predominantly bitter, spicy, and sweet taste. In TCM theory, herbs are
summarized by four properties and five tastes, and ancient TCM books put forward the idea of selecting herbs based on their properties
[28]. Additionally, molecular network-level studies have shown that bitter herbs can affect the cell cycle, blood circulation, and other
processes. In contrast, cold herbs promote vasoconstriction and coagulation, while warm herbs regulate platelet activation, improve
blood circulation and relieve pain [29]. Among high-frequency herbs, pungent, such as Chuanxiong Rhizoma (Chuanxiong), and

Table 3
Association rules of CHMs for headaches with blood stasis syndrome.
No. Former item Latter item Support/ Confidence/ Lift
% %

1 Chuanxiong Rhizoma (Chuanxiong) Angelicae Sinensis Radix (Danggui) 57.94 94.52 1.07
2 Chuanxiong Rhizoma (Chuanxiong) Carthami Flos (Honghua) 53.17 97.01 1.10
3 Chuanxiong Rhizoma (Chuanxiong) Paeoniae Radix Rubra (Chishao) 52.38 90.91 1.03
4 Carthami Flos (Honghua) Persicae Semen (Taoren) 50.00 92.06 1.73
5 Chuanxiong Rhizoma (Chuanxiong) Persicae Semen (Taoren) 50.00 93.65 1.06
6 Carthami Flos (Honghua) Persicae Semen (Taoren) and Chuanxiong Rhizoma (Chuanxiong) 46.83 94.92 1.78
7 Chuanxiong Rhizoma (Chuanxiong) Persicae Semen (Taoren) and Carthami Flos (Honghua) 46.03 96.55 1.10
8 Persicae Semen (Taoren) Carthami Flos (Honghua) and Angelicae Sinensis Radix (Danggui) 41.27 92.31 1.85
9 Chuanxiong Rhizoma (Chuanxiong) Carthami Flos (Honghua) and Angelicae Sinensis Radix (Danggui) 41.27 96.15 1.09
10 Chuanxiong Rhizoma (Chuanxiong) Bupleuri Radix (Chaihu) 40.48 94.12 1.07
11 Persicae Semen (Taoren) Paeoniae Radix Rubra (Chishao) and Carthami Flos (Honghua) 40.48 92.16 1.84
12 Chuanxiong Rhizoma (Chuanxiong) Paeoniae Radix Rubra (Chishao) and Carthami Flos (Honghua) 40.48 98.04 1.11
13 Chuanxiong Rhizoma (Chuanxiong) Glycyrrhizae Radix Et Rhizoma (Gancao) 39.68 98.00 1.11
14 Chuanxiong Rhizoma (Chuanxiong) Angelicae Dahuricae Radix (Baizhi) 39.68 98.00 1.11
15 Carthami Flos (Honghua) Persicae Semen (Taoren) and Paeoniae Radix Rubra (Chishao) 38.89 95.92 1.80
16 Chuanxiong Rhizoma (Chuanxiong) Persicae Semen (Taoren) and Paeoniae Radix Rubra (Chishao) 38.89 95.92 1.09
17 Carthami Flos (Honghua) Persicae Semen (Taoren) and Angelicae Sinensis Radix (Danggui) 38.89 97.96 1.84
18 Chuanxiong Rhizoma (Chuanxiong) Persicae Semen (Taoren) and Angelicae Sinensis Radix (Danggui) 38.89 95.92 1.09
19 Chuanxiong Rhizoma (Chuanxiong) Paeoniae Radix Rubra (Chishao) and Angelicae Sinensis Radix (Danggui) 36.51 95.65 1.09
20 Chuanxiong Rhizoma (Chuanxiong) Scolopendra (Wugong) 32.54 90.24 1.02
21 Chuanxiong Rhizoma (Chuanxiong) Astragali Radix (Huangqi) 30.95 92.31 1.05

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Fig. 4. Network diagram of CHMs for headaches with blood stasis syndrome.

sweet, such as Angelicae Sinensis Radix (Danggui), herbs might be used to treat headaches with blood stasis syndrome through the
above effects.
In the frequency analysis of meridian tropisms, we found that the liver meridian herbs were the most frequently used. Many modern
physicians treat headaches using the liver meridian [30,31]. In Chinese medicine, liver meridian herbs can treat blood stasis and are
effective in treating pathological factors such as qi stagnation, blood deficiency, and liver depression. Our study found that the first six
high-frequency herbs belong to the liver meridian, which is consistent with the meridian tropical frequency analysis. Category fre­
quency analysis shows that blood-activating herbs are most commonly used to treat blood stasis type headaches. In addition, there are
various herbs that assist blood stasis evidence headaches. Exterior-relieving herbs have analgesic effects [32] and can be used as
specific headache-guiding medical herbs [33]. Deficiency-tonifying herbs play a tonic role without damaging health. Liver-wind
calming herbs can treat insomnia, dreaminess, and anxiousness caused by recurrent headaches. Additionally, the insects in this
category have strong analgesic effects [34] and are commonly used for intractable headaches [35]. The cooperation of these four herb
categories was evident and complementary, leading to better therapeutic effects.
The association rule analysis showed that Chuanxiong Rhizoma (Chuanxiong) and Angelicae Sinensis Radix (Danggui) (Table 3 -
NO.1) had the highest support degree. We found a strong correlation between Chuanxiong Rhizoma (Chuanxiong) and Carthami Flos
(Honghua) (Table 3 - NO.2); Chuanxiong Rhizoma (Chuanxiong) and Paeoniae Radix Rubra (Chishao) (Table 3 - NO.3); Carthami Flos
(Honghua) and Persicae Semen (Taoren) (Table 3 - NO.4); and Chuanxiong Rhizoma (Chuanxiong) and Persicae Semen (Taoren)
(Table 3 - NO.5). Chuanxiong Rhizoma (Chuanxiong) and Angelicae Sinensis Radix (Danggui) (Table 3 - NO.1) are a common clinical
herb pair. Their combination, Xiongzhi San, first appeared in the Song Dynasty and has been developed into various Chinese medicine
patents [36]. Additionally, their extract can significantly improve the rheology and coagulation function of acute blood stasis rats [37].
The combination of Chuanxiong Rhizoma (Chuanxiong) and Paeoniae Radix Rubra (Chishao) is significantly more efficient than each
herb alone [38], improving hemorheology and myocardial ischemia and protecting the brain and nerves (Table 3-NO.3), which
demonstrates their complementarity [39]. Carthami Flos (Honghua) and Persicae Semen (Taoren) (Table 3-NO.4) can promote blood
circulation and treat blood stasis [40]. Hence, combining these two herbs can eliminate blood stasis while benefiting blood circulation,
amplifying the removal of blood stasis [41]. Besides, since these herbs can be foods or medicines, they are widely used and highly
accepted [42].
In the cluster analysis, Cluster 1 includes BYHWD, which is commonly used in the treatment of post-stroke conditions, such as Qi
deficiency and blood stasis syndrome. Modern pharmacological studies have shown that BYHWD can improve hemorheology and

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Fig. 5. Tree diagram from cluster analysis of CHMs for headaches with blood stasis syndrome.

reperfusion injury and has anti-thrombosis, anti-atherosclerosis, and anti-cerebral ischemia effects [43]. Also, BYHWD has therapeutic
effects on cerebrovascular diseases through multiple pathways and targets [44] and can treat headaches [45]. For example, Zhang
showed that BYHWD could relieve headache symptoms by regulating endothelin (ET) and CGRP [46]. However, Astragali Radix
(Huangqi) has the largest dose in BYHWD, while the dose of blood-activating herbs is smaller. According to the association rule
analysis, the correlation between Astragali Radix (Huangqi) and other high-frequency herbs and herb couples was not strong.
Moreover, the combination of Carthami Flos (Honghua), Persicae Semen (Taoren), Paeoniae Radix Rubra (Chishao), and Angelicae
Sinensis Radix (Danggui), all from XFZYD, indicated that Astragali Radix (Huangqi) compatibility was not preferred. Additionally,
BYHWD takes a long time to take effect [47]. Since headache is a recurrent disease, patients generally comply poorly with long-term
medications. Thus, it is challenging to achieve the best therapeutic effects using BYHWD. In summary, BYHWD can be used as a
reference for the clinical treatment of headaches with blood stasis syndrome or long-term intractable headaches, but it might not be the
best choice for common headaches with blood stasis syndrome.
Cluster 2 herbs reflect the TCM view of treating symptoms and underlying causes. Given the etiology and pathogenesis of headaches
with blood stasis syndrome, wind herbs, and analgesics can timely relieve pain symptoms. For example, Scorpio (Quanxie) and
Scolopendra (Wugong) are liver-wind calming herbs and have good efficacy in treating headaches [48]. Ngelicae Dahuricae Radix
(Baizhi) and Viticis Fructus (Manjingzi) have exterior-relieving effects, suitable for head and face diseases, with evident pain-relieving
effects [49]. Corydalis Rhizoma (Yanhusuo) can promote blood circulation, regulate the Qi, and have other analgesic effects. The
composition of cluster 3 suggested that specific herbs for headaches can be selected for different pain locations. Herbs with a pungent
taste have better effects and might be preferred in clinical practice. In addition, modern physicians emphasize applying specific herbs
to treat headaches [50,51].
Herbs in cluster 5 composed the XYS prescription. They mainly belong to the liver meridian and can smooth the liver and resolve
depression. This prescription has soothing effects on irritability, anxiety, depression [52,53], and other harmful emotions caused by
liver Qi-stagnation. Thus, XYS is also often used in gynecological menstruation. Moreover, XYS has good effects on clinical headache
treatments [54–56]. Modern pharmacology studies have shown that XYS and similar prescriptions play an antidepressant role by
regulating the hypothalamic-pituitary-adrenal axis, intervening in the inflammatory reaction process, affecting autophagy, and

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alleviating neuronal apoptosis [57]. These results suggest that more XYS prescriptions can be used to treat patients with a bad mood
due to recurrent headaches.
Based on the frequency, association rule, and cluster analyses, Angelicae Sinensis Radix (Danggui), Chuanxiong Rhizoma
(Chuanxiong), Carthami Flos (Honghua), Paeoniae Radix Rubra (Chishao), and Persicae Semen (Taoren) were frequently used to treat
headaches with blood stasis syndrome. Cluster 1 and the association rules in Table 3-NO.1 to NO.9 were strongly correlated to these
five herbs. Their combination is the base of XFZYD, playing an important role in treating headaches with blood stasis syndrome. XFZYD
originated from the Qing Dynasty and is mainly used to treat symptoms such as headaches with blood stasis syndrome and angina
pectoris. XFZYD has presented good efficacy in headaches with blood stasis syndrome [58,59] and provides significant relief from
vascular headaches caused by blood stasis and associated symptoms, such as irritability, insomnia, dreaminess, tiredness, and
palpitation [60]. XFZYD is also widely used in the cardiovascular, blood, and cerebrovascular systems [61]. It inhibits the proliferation
of cardiac interstitial fibroblasts, the necrosis, and apoptosis of myocardial cells, have anti-atherosclerosis effects and induce endo­
thelial cell proliferation and angiogenesis. The use of XFZYD is consistent with the TCM viewpoint.
Herein, we analyzed published CHMs for headaches with blood stasis syndrome and excluded conflicting factors, such as herb
dosage. We combined data mining and analysis methods to provide scientifically reliable results and a reference for selecting herbs to
treat headaches with blood stasis syndrome. However, our current study also has some limitations. First, most studies were from
Chinese databases, and diagnoses relied on subjective factors. Hence, it is difficult to verify the valid authenticity of the selected
literature. Meanwhile, we included only RCTs on CHMs with definite curative effects. We excluded studies on CHMs without definite
efficacy or statistical significance between the CHM treatment and control groups. Besides, there was a certain degree of bias in the
prescription screening. We did not systematically evaluate the medication rules for safety and effectiveness, and more RCTs are needed
to verify them in the future.

5. Conclusion

In summary, we provided a reasonable reference for selecting CHMs for headaches with blood stasis syndrome. The preferred
prescription comprised the combination of Angelica Sinensis Radix (Danggui), Chuanxiong Rhizoma (Chuanxiong), Carthami Flos
(Honghua), Persicae Semen (Taoren), Paeoniae Radix Rubra (Chishao), Bupleuri Radix (Chaihu), Achyranthis Bidentatae Radix
(Niuxi), and Glycyrrhizae Radix Et Rhizoma (Gancao). This prescription is based on XFZYD, which might be used as the first reference
in the clinic. XYS and BYHWD herbs might also be used, and meridian-inducing and insect herbs can enhance the efficacy or treat the
concomitant syndrome. However, the effectiveness and safety of these prescriptions or herbs should be rigorously verified by RCTs or
systematic reviews in the future.

Author contribution statement

Guanghui Liu; Huiting Yang: Conceived and designed the experiments; Performed the experiments; Analyzed and interpreted the
data; Wrote the paper.
Li Bai; Yang Wang; Enlong Wang; Xiuye Sun; Hongyuan Zhang; Li Zhou; Zhe Zhang: Contributed reagents, materials, analysis tools
or data.

Funding statement

This work was supported by Key Technologies Research and Development Program [2018YFC1707407].

Data availability statement

Data will be made available on request.

Conlifict of interest

The authors declare no competing interests.

Acknowledgments

The authors thank Ran An, Qian Li, Ting-ting Li, Wen-jun Zhang, Liang Mao, Juan Liu, Xing-an Liu, Guang-yi Luan, Shi Zhang, and
Yang Li (Department of Neurology, Affiliated Hospital of Liaoning University of Traditional Chinese Medicine) for contributions in the
experimental design.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.heliyon.2023.e14996.

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