Accepted Manuscript

Title: Pharmacopuncture for asthma: A systematic review and

a meta-analysis of randomized controlled trials

Authors: Miran Bang, Seju Chang, Jang Hyun Kim, Sang

Yeon Min

PII: S1876-3820(17)30062-8
DOI: http://dx.doi.org/doi:10.1016/j.eujim.2017.03.006
Reference: EUJIM 659

To appear in:

Received date: 18-1-2017

Revised date: 16-3-2017
Accepted date: 16-3-2017

Please cite this article as: Bang Miran, Chang Seju, Kim Jang Hyun, Min
Sang Yeon.Pharmacopuncture for asthma: A systematic review and a meta-
analysis of randomized controlled trials.European Journal of Integrative Medicine
http://dx.doi.org/10.1016/j.eujim.2017.03.006

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Pharmacopuncture for asthma: A systematic review and a meta-analysis of randomized
controlled trials.

Miran Bang,1 Seju Chang,2 Jang Hyun Kim3 Sang Yeon Min1,4*

1
Department of Pediatrics of Korean Medicine, Graduate School of Dongguk University, 30, Pildong-ro 1-gil,
Jung-gu, Seoul, 04620, Republic of Korea

2
Department of Rehabilitation Medicine of Korean Medicine, Graduate School of Dongguk University, 30,
Pildong-ro 1-gil, Jung-gu, Seoul, 04620, Republic of Korea

3
Department of Pediatrics of Korean Medicine, Dongguk University Bundang Korean Hospital, 268, Buljeong-
ro, Bun-dang-gu, Seongnam-si, Gyeonggi-do, 13601, Republic of Korea

4
Department of Pediatrics of Korean Medicine, Korean Medicine Hospital, Dongguk University Medical Center,
27, Dongguk-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10326, Republic of Korea

Mi Ran Bang

E-mail: godorhoi@gmail.com

Seju Chang

E-mail: seju2094@gmail.com

Jang Hyun Kim

E-mail address: kjh@dongguk.ac.kr

*Correspondence author at Department of Pediatrics of Korean Medicine, Korean Medicine Hospital, Dongguk
University Medical Center, 27, Dongguk-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10326, Republic of Korea.
Tel: +82-31-961-9072 / Fax: +82-31-961-9009

e-mail address: bubbblem@dongguk.edu (S. Y. Min)

1
Abstract

Introduction. Pharmacopuncture, a new type of acupuncture treatment in traditional East Asian medicine
combining acupuncture and the injection of herbal medicine, is widely used for asthma in China and Korea.
However, the evidence is equivocal. This systematic review aims to summarize and evaluate the efficacy of
pharmacopuncture for asthma.

Methods. Eleven electronic databases and five journals were searched. Randomized controlled trials (RCTs)
assessing the efficacy of pharmacopuncture for asthma were included. The risk of bias was assessed using the
Cochrane risk of bias assessment tool. Data analysis was conducted using RevMan Rsoftware (version 5.3).

Results. Eighteen RCTs involving 1624 patients with asthma were included for qualitative synthesis. Data from
12 RCTs were used for meta-analysis. There were various types of pharmacopuncture used. Use of Chuankezhi
pharmacopuncture (CKZ PA) and Huangqi pharmacopuncture (HQ PA) usually overlapped among included
studies. Subgroup analysis was conducted after dividing experimental groups into two groups: CKZ PA and HQ
PA. When added to conventional therapy, pharmacopuncture significantly improved the response rate (RR =
1.18, 95% CI: 1.12–1.24, I2 = 0%), forced expiratory volume in 1 second (FEV1) (SMD = 1.31, 95% CI: 0.59–
2.03, P = 0.0004, I2 = 94%) and peak expiratory flow (PEF) (SMD = 0.62, 95% CI: 0.22-1.01, P = 0.002, I2 =
76%).

Conclusions. Evidence of pharmacopuncture efficacy for asthma is encouraging, but not conclusive, because of
the low methodological qualities, substantial heterogeneity, and small sample sizes of the examined studies.
Further research using large-scale, rigorous study designs should be conducted.

Keywords: asthma; pharmacopuncture; acupoint injection; systematic review; meta-analysis

1. Introduction

Asthma is a chronic inflammatory disease of lung airways that results in episodic airflow obstruction [1]. The
disease is characterized by coughing, wheezing, shortness of breath, and chest congestion. Asthma is a common
childhood chronic disease, causing significant morbidity [2]. Many studies have reported an increase in the
asthma prevalence rate of approximately 50% per decade [1].

Current therapeutic strategies for asthma include long-term control medications and quick-relief medications,
each of which is based on controlling asthma severity and symptoms. As a long-term control therapy, inhaled
corticosteroids (ICS) are the most effective anti-inflammatory medications for persistent asthma [3]. However,
poorly controlled ICS use can lead to reduced growth velocity [4, 5]. Asthma patients or their families may
worry about potential adverse drug reactions and are increasingly seeking treatments that are more secure.
2
Therefore, many asthma sufferers have turned to complementary and alternative treatments with fewer adverse
effects, typically as adjunctive therapies in addition to conventional therapy [6].

Pharmacopuncture, or herbal acupuncture, is a new type of acupuncture treatment in traditional East Asian
medicine that combines acupuncture and the injection of herbal medicine. Pharmacopuncture treatment is
applied by injecting sterilized herbal extracts into acupoints via syringe [7]. Owing to its ease for dosage control,
as well as its rapid and synergistic effects, pharmacopuncture is widely used to treat various diseases including
musculoskeletal diseases, obesity, and asthma in China and Korea [7-9]. Although a systematic review of the
effectiveness of pharmacopuncture for asthma was published in 2011 [9], it did not include subgroup analysis
based on the type of pharmacopuncture. Moreover, because, many randomized controlled trials (RCT) have
been conducted from 2011 to 2017, additional analysis is thought necessary. This systematic review aims to
evaluate the effectiveness of pharmacopuncture for treating asthma.

2. Methods

2.1. Data Source and search strategy

The following electronic databases were searched to identify relevant studies that were uploaded by 15th
March 2017: MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL),
Cochrane Library, along with five Korean Databases (KoreaMed, KMBASE, KISS, NDSL, KSITI), one
Chinese Medical Database (CNKI), and one Japanese Database (J-STAGE). We also manually searched the
following Korean journals from inception to 15th March 2017: Korean J. Acupunct, J. Pharmacopuncture
Institute, The Acupuncture, Korean J. Intern Med, J. Korean Med.

The study used “asthma”, “pharmacopuncture”, “herbal acupuncture”, “acupoint”, “acupuncture point”, “aqua
acupuncture”, “acupuncture”, and “acupoint injection” as search terms. A representative search strategy in
Embase is shown in Table 1. This review’s protocol was registered in PROSPERO (an international prospective
register of systematic reviews) with registration number CRD42016046607.

2.2 Inclusion criteria

2.2.1. Study design. The RCTs designed to assess the efficacy of pharmacopuncture for asthma were included.
Other study designs such as in vivo, in vitro, case reports, and retrospective studies were excluded.

2.2.2. Participants. Participants were patients with asthma. There were no restrictions on race, age, or sex.

2.2.3. Intervention and Comparisions. Pharmacopuncture and herbal acupoint injection for treating asthma were
included. Trials using other injections, such as steroids, local anesthetics, oxygen, self-blood, and allergens were
excluded. Combination therapy with acupuncture, traditional Chinese herbal medicine, and moxibustion was
also excluded. Studies comparing pharmacopuncture as an adjunct or sole intervention to conventional
treatments or a placebo were included.

3
2.2.4. Outcome measures. The studies’ primary outcome measures were response rate as determined by clinical
symptoms. Secondary outcome measures included pulmonary function test results; forced expiratory volume in
1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and peak expiratory flow (PEF).

2.3. Study selection and data extraction

2.3.1. Selection of literature articles. After excluding duplicate articles, two authors (M. Bang and S. Chang)
reviewed titles and abstracts for the first round of exclusion. Full texts of the selected articles that potentially
met the eligibility criteria were then subjected to another review before the final article selection. For excluded
articles, the reason for exclusion was recorded. Differences were resolved by discussion with the third author (J.
H. Kim) in order to reach consensus.

2.3.2. Data extraction. One author (M. Bang) conducted data extraction, and a different author (S. Chang)
reviewed the data. Items extracted from each study included author, publication year, sample size, patient age,
duration of disease, period of treatment, experimental and control intervention, outcomes, ingredients of the
injection, and acupoint.

2.4. Assessment with Risk of Bias

Two authors (M. Bang and S. Chang) assessed methodological quality by using the Risk of Bias (RoB) tool,
which was developed by Cochrane. Each study was assessed for selection bias (random sequence generation and
allocation concealment), performance bias (blinding of participants and personnel), detection bias (blinding of
outcome assessment), attrition bias (incomplete outcome data reporting), and reporting bias (selective outcome
reporting). Each item of all included RCTs was given a “high risk,” “unclear,” or “low risk” rating.
Disagreements were resolved by discussion with other reviewers.

2.5. Data analysis

The meta-analysis and statistical analysis were performed by using RevMan 5.3 software of the Cochrane
Collaboration. The effect of pharmacopuncture on dichotomous outcomes was expressed as a risk ratio (RR)
with 95% confidence interval (CI). For continuous outcomes, the standardized mean difference (SMD) or mean
difference (MD) with 95% confidential interval (CI) was used. To update a previous systematic review of the
effectiveness of pharmacopuncture for asthma [9], which lacked subgroup analysis based on the type of
pharmacopuncture, the analyses in the present review were divided into two pharmacopuncture-type subgroups:
Chuankezhi pharmacopuncture (CKZ PA) and Huangqi pharmacopuncture (HQ PA). Chi-squared and Higgins I2
tests were used to assess the heterogeneity of the data. A random effect model was used to estimate the efficacy
of pharmacopuncture for asthma because high variability in pharmacopuncture efficacy was expected.

3. Results.

3.1. Study selection and description

4
 A total of 2810 studies were initially retrieved; 100 in MEDLINE, 1007 in EMBASE, 298 in the Cochrane
Library, 169 in CINAHL, 1195 in CNKI, 110 in J-STAGE, 11 in KISS, 12 in KMBASE, 5 in KoreaMed, 19 in
KSITI, 41 in NDSL, and 21 in other sources that were manually searched. Among them, 2713 studies remained
after eliminating duplications, and 919 studies were excluded after screening of titles and abstracts. After
reviewing full texts of 131 studies, 18 RCTs [10-27] were included in this systematic review.

Among the 18 RCTs [10-27], 16 studies [10-20, 22-25, 27] compared pharmacopuncture plus medication in
an experimental group with medication alone in a control group, one study [21] compared pharmacopuncture
plus medication in an experimental group with medication and Bricalin inhalation in a control group, and the
remaining study [26] compared pharmacopuncture as a sole treatment with conventional therapy. Two studies
[21, 26] were excluded from the meta-analysis because those studies did not compare pharmacopuncture plus
medication with medication alone. Among the 16 studies [10-20, 22-25, 27] comparing pharmacopuncture plus
medication with medication alone, ten [10-13, 16, 17, 19, 22, 24, 25] used CKZ PA, three [15, 23, 27] used HQ
PA, and the remaining three [14, 18, 20] used different types of pharmacopuncture. Because the ingredients of
the three pharmacopunctures used in three studies [14, 18, 20] were different, data from those three studies
could not be included in the meta-analysis. One study [15] of the 12 CKZ and HQ PA studies was excluded from
the meta-analysis because the treatment period of that study was up to 2 years, while those of the remaining
studies varied from 7 days to one month. Finally, considering clinical heterogeneity such as duration of
treatment and type of pharmacopuncture, 12 studies [10-13, 16, 17, 19, 22-25, 27] were used for the meta-
analysis, and all 18 RCTs [10-27] were included in the qualitative synthesis. The entire process was displayed
by generating a flow diagram in PRISMA (Preferred Reporting Items for Systematic reviews and Meta-
Analyses) (Figure 1).

The characteristics of the 18 studies [10-27] are summarized in Table 2. Five studies [11, 12, 20, 23, 25] had
sample sizes greater than 100, while 13 studies [10, 13-19, 21, 22, 24, 26, 27] had smaller sample sizes between
40 and 98. Among the 18 studies, four [11, 13, 14, 19] consisted of children only. The duration of treatment in
one study [15] was over one year, while those of the remaining studies varied from 7 days to one month. Twelve
studies [10, 12, 13, 15, 16, 18, 21, 23-27] stated the stage of asthma. Of those 12 studies, one study [15]
analyzed patients during catabasis, and the remaining 11 studies [10, 12, 13, 16, 18, 21, 23-27] included patients
during the acute stage. Conventional therapy used in the studies included oxygen, antibiotics, antispasmodic,
cough and phlegm medicine, anti-allergic treatment, ICS, corticosteroid, and bronchodilator. Ingredients of the
pharmacopuncture and acupoints used in the included RCTs are summarized in Table 3. There were three trials
[15, 23, 27] that used single herb pharmacopuncture, while the others [10-14, 16-22, 24-26] used herbal formula
compounds. The acupoints used in the studies were those commonly applied for respiratory diseases including
asthma and are based on traditional Chinese medicine (TCM) theory The following five acupoints overlapped
among the studies: BL13 in 12 studies [11, 12, 14-16, 19-21, 23, 24, 26, 27], BL23 in five studies [12, 14, 20,
23, 26], ST36 in seven studies [10-12, 16, 17, 19, 23], EX10 in four studies [12, 19, 24, 27], and CV22 in four
studies [11, 18, 20, 21].

5
3.2. Assessment with Risk of Bias

Among 18 studies [10-27], five studies [11, 15, 17, 21, 23] that reported the method of randomization were
given a low risk of bias, but the other 13 studies [10, 12-14, 16, 18-20, 22, 24-27] did not state the method of
random sequence generation and, thus, were given an unclear risk of bias. All of the included studies had a high
risk of bias for participant and personnel blinding due to the absence of a placebo alternative for
pharmacopuncture in the control groups, and all studies were assessed as unclear for concealing allocation and
outcome assessment blinding. All of the included studies had a low risk for incomplete outcome data and
selective outcome reporting. Details pertaining to the risk of bias are provided in Figure 2 (a) and (b).

3.3. Outcomes of the included studies

3.3.1. Response rate. Eleven RCTs [10, 11, 13, 16, 17, 19, 22-25, 27] were analyzed in the meta-analysis, and
they included 994 patients (500 in the experimental groups and 494 in the control groups). Following subgroup
meta-analysis, the combined effects of nine of the trial results [10, 11, 13, 16, 17, 19, 22, 24, 25] indicated that
CKZ PA plus medication improved the response rate over that in control groups accepting medication alone
(nine studies, n = 776 patients, RR = 1.18, 95% CI: 1.11–1.26, I2 = 18%) (Figure 3), and the combined effects of
two of the trial results [23, 27] showed that HQ PA plus medication improved the response rate over that in the
control groups (two studies, n = 218 patients, RR = 1.18, 95% CI: 1.05–1.34, I2 = 0%) (Figure 3). The pooled
data of these eleven studies [10, 11, 13, 16, 17, 19, 22-25, 27] yielded encouraging effects on response rates in
favor of pharmacopuncture plus medication, with no obvious heterogeneity (RR = 1.18, 95% CI: 1.12–1.24, I2 =
0%) (Figure 3). In addition, Li [14] used acupoint injection plus medication in an experimental group and
reported that acupoint injection plus medication improved the response rate over that in a control group
accepting medication alone (n = 80 patients, RR = 1.23, 95% CI: 1.02–1.47, P = 0.03). Liang et al. [15] used
HQ PA plus medication in an experimental group and reported that HQ PA plus medication showed no
significant effects on response rate when compared with the control group (n = 70 patients, RR = 1.10, 95% CI:
0.96–1.25, P = 0.17). Lu and Tang [18] used Haqing compound acupoint injection plus medication in an
experimental group and reported that the experimental group significantly improved response rate when
compared with the control group (n = 68 patients, RR = 1.27 95% CI:1.04–1.54, P = 0.02). Sheng [20] used
acupoint injection plus medication in an experimental group and reported that acupoint injection plus
medication had no significant effect on response rate when compared with a control group (n = 146 patients, RR
= 1.13, 95% CI: 1.00–1.28, P = 0.05). Tong [21] used acupoint injection plus conventional therapy in an
experimental group and reported that the experimental group showed no significant effect on response rate when
compared with a control group that accepted conventional therapy plus Bricalin inhalation (n = 90 patients, RR
= 1.06, 95% CI: 0.92–1.21, P = 0.42). Zhang and Zhang [26] compared the effects of water acupuncture with
conventional therapy on response rate and reported that water acupuncture had no significant effect on response
rate (n = 60 patients, RR = 1.07, 95% CI: 0.94–1.23, P = 0.31)

3.3.2. Lung function.

6
3.3.2.1. FVC. Of the 18 RCTs [10-27] included, two studies of HQ PA [15, 23] and one study of CKZ PA [11]
reported on FVC. Hu et al. [11] used CKZ PA plus conventional therapy in a CKZ PA group for 7 days and
reported that the CKZ PA group showed significant improvements in FVC relative to a control group accepting
conventional therapy alone (n = 206 patients, MD = 0.54 L, 95% CI: 0.31–0.77, P < 0.00001). Liang et al. [15]
used HQ PA plus conventional therapy in a HQ PA group for 2 years and reported that the HQ PA group had
improved FVC compared to that in a control group accepting conventional therapy alone (n = 70 patients, MD =
0.94 L, 95% CI: 0.68–1.20, P < 0.00001). Wang and Fu [23] used HQ PA plus conventional treatment in a HQ
PA group for 2 weeks and reported that the HQ PA group showed significant improvements in FVC relative to a
control group accepting conventional treatment alone (n = 158 patients, MD = 0.48 L, 95% CI: 0.22–0.74, P =
0.0002).

3.3.2.2. FEV1/FVC. Of the 18 RCTs [10-27] included, only one study [25] reported the FEV1/FVC ratio. Zhang
[25] included CKZ PA plus conventional therapy in a CKZ PA group for 7 days and reported that the CKZ PA
group showed significant improvements in FEV1/FVC when compared with a control group accepting
conventional therapy alone (n = 110 patients, MD = 8.09%, 95% CI: 6.70–9.48, P < 0.00001).

3.3.2.3. FEV1. Five RCTs [11, 12, 19, 23, 25] were analyzed for FEV1 meta-analysis, and they included 650
patients (328 in the experimental groups and 322 in the control groups). On subgroup meta-analysis, four RCTs
[11, 12, 19, 25] that compared CKZ PA plus medication with medication alone showed encouraging effects in
favor of CKZ PA plus medication on FEV1 (four studies, n = 492 patients, SMD = 1.56, 95% CI: 0.65–2.46, I2 =
95%) (Figure 4), while the RCT of HQ PA with medication [23] showed significant improvements in FEV1 (one
study, n = 158 patients, SMD = 0.40, 95% CI: 0.08–0.72) (Figure 4). Combining the results for these five studies
[11, 12, 19, 23, 25] indicated that pharmacopuncture plus medication improved FEV1 over that in the control
groups accepting medication alone (SMD = 1.31, 95% CI: 0.59–2.03, P = 0.0004). Heterogeneity between
studies existed (P < 0.00001, I2 = 94%) (Figure 4). In addition, Li [14] used acupoint injection plus medication
in an experimental group and reported that acupoint injection plus medication showed significant improvements
in FEV1 compared to that in a control group accepting medication alone (n = 80 patients, MD = 6.68%, 95% CI:
2.66–10.70, P = 0.001). Liang et al. [15] used HQ PA plus conventional therapy in a HQ PA group for 2 years
and reported that the HQ PA group had improved FEV1 when compared to that in a control group accepting
conventional therapy alone (n = 70 patients, MD = 1.65 L, 95% CI: 1.39–1.91, P < 0.00001).

3.3.2.4. PEF. Five RCTs [10, 11, 17, 19, 23] were analyzed for meta-analysis of PEF, and they included 514
patients (260 in the experimental groups and 254 in the control groups). After subgroup meta-analysis, four
studies [10, 11, 17, 19] that compared CKZ PA plus medication with medication alone yielded encouraging
effects in favor of CKZ PA plus medication on PEF (four studies, n = 356 patients, SMD = 0.68, 95% CI: 0.15–
1.20, I2 = 78%) (Figure 5). The HQ PA plus medication study [23] showed significant improvements in PEF
(one study, n = 158 patients, SMD = 0.42, 95% CI: 0.10–0.73) (Figure 5). Combining the results of these five
studies [10, 11, 17, 19, 23] showed that pharmacopuncture plus medication improved PEF over that in control
groups accepting medication alone (SMD = 0.62, 95% CI: 0.22–1.01, P = 0.002). Heterogeneity between studies

7
existed (P = 0.002, I2 = 76%) (Figure 5). In addition, Tong [21] used acupoint injection plus conventional
therapy in an experimental group and reported that the experimental group showed no significant improvement
in PEF when compared with a control group accepting conventional therapy plus Bricalin inhalation (n = 90
patients, MD = 14.02 L/min, 95% CI: -17.25–45.29, P = 0.38)

3.4. Adverse events

Among the 18 RCTs [10-27], 16 studies [10-16, 18, 20-27] did not describe the adverse events, while two [17,
19] reported that none of the participants had experienced adverse events.

4. Discussion

4.1. Summary of evidence

The present study analyzed data from 18 RCTs [10-27] involving 1624 individuals to assess the efficacy of
pharmacopuncture to treat asthma. Based on the findings of this meta-analysis, pharmacopuncture can
significantly improve response rate, FEV1, and PEF when used in combination with conventional medication.
However, substantial heterogeneity was observed in the meta-analysis evaluating the effects on FEV1 and PEF
of pharmacopuncture plus medication versus medication alone. In addition, pharmacopuncture showed
significant effects on FVC in three studies [11, 15, 23] and on FEV1/FVC in one study [25] when added to
conventional medication. However, these results should be interpreted carefully because of the low
methodological qualities of the included trials. Conclusions regarding the safety of pharmacopuncture could not
be drawn because of insufficient evidence provided by the included studies.

4.2. Mechanism of pharmacopuncture

Positive therapeutic effects of pharmacopuncture for asthma may be associated with the anti-inflammatory
effects of the ingredients used in pharmacopuncture. CKZ PA is mainly composed of Ba Ji Tian (Morindae
Radix) and Yin Yang Huo (Epimedii Herba). The herbal medicine used in HQ PA is Huang Qi (Radix
Astragali). Monotropein isolated from Ba Ji Tian (Morindae Radix) has shown anti-inflammatory action [28,
29]. Icariin, the major active ingredient of Yin Yang Huo (Epimedii Herba), was reported to inhibit the
activation of NF/κB in pulmonary tissue and to attenuate lung inflammation [30, 31]. Yang et al. [32] reported
that extracts of Huang Qi (Radix Astragali) reduced eosinophils, cytokines, airway hyper-responsiveness, and
mucus secretion by attenuating goblet cell hyperplasia in asthmatic mouse models. Moreover, Huang et al. [33]
reported that Astragaloside IV, the main extract of Huang Qi (Radix Astragali), regulates Th1/Th2 cytokine and
enhances CD4+CD25+Foxp3 T cells in asthmatic mouse models. These findings suggest that Ba Ji Tian
(Morindae Radix), Yin Yang Huo (Epimedii Herba), and Huang Qi (Radix Astragali), via their anti-
inflammatory actions, can be useful in the treatment of patients with asthma.

4.3. Comparison with other systematic reviews

8
 In 2011, a systematic review reported that pharmacopuncture had potential benefits for patients with asthma,
both in acute and convalescent stages [9]. The results of that meta-analysis reported that pharmacopuncture, as
an adjunct to conventional treatments, significantly improved the response rate and showed favorable effects on
PEF. However, because only four trials were included in that systematic review, and because numerous
additional RCTs have been published since 2011, herein, we provide an updated systematic review that includes
further subgroup analysis based on the types of pharmacopuncture used in the published RCTs. In our
systematic review, 18 studies [10-27] were included in the qualitative synthesis and 12 studies [10-13, 16, 17,
19, 22-25, 27] were used in the meta-analysis. The results of our meta-analysis suggest that pharmacopuncture
as an adjunct therapy can significantly improve the response rate, with no obvious heterogeneity, when
compared with that obtained by using conventional treatment alone. With regard to FEV1 and PEF,
pharmacopuncture as an adjunct therapy showed favorable effects, but substantial heterogeneities were observed
among the included studies. Despite our efforts to perform subgroup analysis based on the type of
pharmacopuncture, heterogeneities were still observed in our meta-analysis, as were observed in the 2011
systematic review [9].

4.4. Limitations

The present systematic review has several limitations. First, the trials included in this systematic review had
poor methodological qualities, which might make it difficult to form firm conclusions regarding the clinical
efficacy of pharmacopuncture for treating asthma. All of the included studies had unclear or high risk of bias for
more than one item. Blinding procedures were not conducted or were not described in the included RCTs.
Moreover, all of the included studies were conducted in China, and thus this systematic review may have
publication or location biases. Second, the median sample size of the 12 trials [10-13, 16, 17, 19, 22-25, 27]
included in the meta-analysis was 76 patients. Owing to these small sample sizes, we cannot guarantee that
statistically significant improvements in response rate and lung function measures in the included RCTs are true
effects. Third, all of the included studies determined the response rate based on changes in symptoms. However,
details regarding the criteria that determined the response rate were not unified among the included studies, and
those criteria can be considered subjective outcomes rather than objective ones. Fourth, heterogeneities were
observed among studies and the review included studies that recruited children or adults. Moreover, different
doses and numbers of injections for pharmacopuncture were used in the included studies, and the control
interventions varied (i.e., bronchodilator alone, ICS and short-acting beta-agonist, or added oral corticosteroids).
These factors may affect the results of studies to an undetermined extent and may partly explain the appearance
of heterogeneity in pulmonary outcomes. Fifth, subgroup analysis according to the severity of asthma was not
performed in this review. In most of the included studies which mention the level of severity in asthmatic
patients, the level of severity has not been divided, but rather it covered all levels from mild to severe or two
levels from mild to moderate. In addition, there was no study that recruited only severe level asthmatic patients.
Therefore, we could not perform subgroup analysis related to the severity of asthma. Due to this lack of detail
about asthma severity levels, previous systematic reviews about treating asthma [9, 34] are also thought to have
been unable to perform subgroup analysis according to the severity of asthma. Finally, conventional therapies

9
were concurrently used in both the experimental and control groups in the RCTs included in our meta-analysis.
Therefore, the positive effects cannot be solely attributed to the efficacy of pharmacopuncture.

4.5. Suggestions for Future Research

To improve the methodological quality of the studies, future RCTs should employ rigorous randomization
methods and blinding procedures, and they should describe the details of the methods used. In addition, future
large-scale RCTs are needed and should be conducted both inside and outside of China. To improve the
applicability and generalizability of pharmacopuncture treatment, independent researchers should employ
consistent response rate criteria to assess the efficacy of pharmacopuncture for asthma and should standardize
protocols related to treatment, dose, and number of injections of pharmacopuncture. Finally, to evaluate the
safety of pharmacopuncture, adverse events associated with pharmacopuncture need to be reported and assessed.

5. Conclusions

The results indicate that pharmacopuncture had a positive therapeutic effect in the treatment of asthma when
added to conventional medication. Considering the low methodological quality, small sample sizes, and
substantial heterogeneity among the studies included in this review, definitive conclusions cannot be drawn, and
the results of our meta-analysis have to be interpreted cautiously. To substantiate these results, further research
with large-scale, rigorous study designs should be conducted.

Conflicts of Interest

All authors declare that there are no conflicts of interest regarding the publication of this paper.

Author’s Contribution

Miran Bang developed the protocol, performed literature searches, extracted data, participated in data
analysis, and drafted the manuscript. Seju Chang participated in literature searches, extracted data, and
conducted data analysis. Jang Hyun Kim participated in study selection and critically reviewed the manuscript.
Sang Yeon Min supervised the study design and concept, and critically reviewed the manuscript. All authors
participated in the analysis and interpretation of data and approved the final paper.

Acknowledgments

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-
profit sectors.

10
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on IFN-γ and IL-4, J. TCM Univ. Hunan 33 (2013) 78-80.
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390-395.
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Figure 1. PRISMA flow diagram of study selection.

Figure 2. (a) Risk of bias graph: review authors' judgements about each risk of bias item presented as
percentages across all included studies.

Figure 2. (b) Risk of bias summary: review authors' judgements about each risk of bias item for each
included study. “+”: low risk, “?”: unclear risk, and “-”: high risk.

Figure 3. Effects of pharmacopuncture with medication versus medication alone on response rate.
CKZ: Chuankezhi; PA: pharmacopuncture; HQ: Huangqi

Figure 4. Effects of pharmacopuncture with medication versus medication alone on forced expiratory
volume in 1 second (FEV1).
CKZ: Chuankezhi; PA: pharmacopuncture; HQ: Huangqi

Figure 5. Effects of pharmacopuncture with medication versus medication alone on peak expiratory
flow (PEF).
CKZ: Chuankezhi; PA: pharmacopuncture; HQ: Huangqi

14
Table 1. Search strategy (Embase)

Asthma
#1 'asthma'/exp OR asthma
#2 antiasthma* OR anti AND asthma*
#3 wheez*
#4 bronchospas*
#5 bronch* NEAR/3 spasm*
#6 bronchoconstrict*
#7 bronch* NEAR/3 constrict*
#8 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7
Pharmacopuncture
#9 pharma* NEAR/2 puncture
#10 acup* NEAR/2 inject*
#11 herb* AND acu* AND inject*
#12 aqua* AND puncture
#13 acup*
#14 #9 OR #10 OR #11 OR #12 OR #13
#15 #8 AND #14

15
Table 2. Characteristic of the included studies.

Type of
Author, Sample size Age (mean or Stage, Levels Experimental Resu
Control Intervention Period pharmaco Outcomes
year (E/C) range) of severity Intervention (Resp
puncture
Lung
Response rate
Conventional therapy
1) PA (2 (change of 1.00
E: 57.70 ± Acute, all (oxygen, antibiotics,
Gan and mL/point, q.d. for symptom score)
12.6 years levels (mild, antispasmodic, cough
Huang, 40 (20/20) 7 days) 7 days CKZ PA
C: 59.85 ± moderate, and phlegm medicine,
2011 [10] 2) Conventional
8.82 years severe) correcting fluid and PEF% 7.26
therapy
electrolyte imbalance)

Response rate
(change of
Conventional therapy symptom, 1.30
1) PA (2 (budesonide 200–400 change of PEF
E: 6.8 ± 2.1
mL/point, q.d. for μg, salbuterol or FEV1)
Hu et al., 206 years
n.r., all levels 7 days) inhalation 100–200 7 days CKZ PA
2013 [11] (103/103) C: 6.8 ± 2.1 FVC (L) 0.54
2) Conventional μg), correcting fluid
years
therapy and electrolyte
FEV1 (L) 0.36
imbalance)

PEF (L/s) 0.41

Conventional therapy
E: 51.12 ± 1) PA (1
(only take anti-
10.24 (18–69) mL/point, once
inflammatory,
Hui et al., years every 2 days for
116 (58/58) Acute, n.r. expectorant, 10 days CKZ PA FEV1% 5.76
2013 [12] C: 49.35 ± 10 days)
antispasmodic and
9.75 (19–68) 2) Conventional
other conventional
years therapy
Western medicines)
Conventional therapy
E: 3.4 ± 2.6 (anti-inflammation,
years (8 spasmolysis, dyspnea
1) PA (0.5
months–9 relief and sputum Response rate
mL/point for 7
Huo, years) elimination, Pulmicort (change of
90 (45/45) Acute, n.r. days) 7 days CKZ PA 1.22
2015 [13] C: 3.5 ± 2.1 Respules (budesonide symptoms and
2) Conventional
years (7 inhalation suspension) signs)
therapy
months–8 atomization inhalation
years) (1 mg/d, 2 times/d for
7 days))
1) PA (dosage, Response rate
Conventional therapy
number of (change of 1.23
5.22 ± 0.25 (oxygen, anti-
Li, 2012 injections not 1 Acupoint symptom score)
80 (40/40) (1–18 n.r., n.r. infection, diuretics and
[14] provided) month injection
months) symptomatic
2) Conventional FEV1% 6.68%
treatment)
therapy

16
 1) PA (1 Response rate
mL/point, 2 (degree of
times/week, 3 asthmatic attack,
Beclomethasone
months/session, 3 change in PEF%
E: 36.87±8.85 dipropionate + 1.10
months break or FEV1%,
Liang et (15–58) years ventolin inhalation
Catabasis, all between 2 steroids and
al., 2004 70 (35/35) C: 37.58 ± (q.d. for 2 years, 2 years HQ PA
levels sessions, 2 bronchodilators
[15] 6.21 (16–60) dosage modulated
sessions/year) required or not)
years according to
2)
symptoms) FVC (L) 0.94
Beclomethasone
dipropionate +
FEV1 (L) 1.65
ventolin inhalation
1) PA (2 Conventional therapy
E: 59.3 ± 4.1
mL/point, b.i.d. (cough medication, Response rate
Li et al. (45–72) years 1
98 (49/49) Acute, n.r. for 1 month) sputum elimination, CKZ PA (change of 1.21
2016 [16] C: 58.8 ± 4.5 month
2) Conventional anti-inflammatory, symptom)
(46–70) years
therapy anti-allergy treatment)
Conventional therapy Response rate
(oxygen, antibiotics, (change of
1) PA (2 1.10
hormones, symptoms,
mL/point, q.d. for
Liu, 2011 n.r., mild or antispasmodic drugs, FEV1 or PEF)
50 (25/25) 18–75 years 7 days) 7 days CKZ PA
[17] moderate cough and phlegm
2) Conventional
medicine, correcting
therapy PEF (L/s) -0.08
fluid and electrolyte
imbalance)
1) PA (1 Conventional therapy Haqing
E: 49 (32–63) Response rate
Lu and mL/point, q.d. for (glucocorticoid, compoun
years 10–15 (degree of the
Tang, 68 (34/34) Acute, n.r. 10–15days) aminophylline, acidity d 1.27
C: 47 (35–61) days asthmatic
2005 [18] 2) Conventional modulation, oxygen acupoint
years attack)
therapy uptake) injection
Response rate
(degree of
daytime
symptoms,
Conventional therapy degree of
1) PA (2 (oxygen, limited mobility,
6 ± 2.54 years mL/point, q.d. for aminophylline, degree of
Luo et al.,
60 (30/30) (3 months–11 n.r., n.r. 7 days) terbutaline, inhalation 7 days CKZ PA nocturnal 1.33
2013 [19]
years) 2) Conventional pulmicort 1 mg, 2 symptoms and
therapy times/day for 3 to 6 awakening,
days) demand for drug
treatment, PEF
or FEV1, degree
of asthmatic
attack)

17
 FEV1% 8.96

PEF (L/s) 0.30

1) PA (1
mL/point, every Response rate
Conventional therapy
E: 43.8 ± 4.2 other day, 5 10 (change of
(anti-inflammatory,
Sheng, (17–60) years times/course) days/co Acupoint symptom, lung
146 (73/73) n.r., n.r. cough medication, 1.13
2016 [20] C: 44.4 ± 4.7 2) Conventional urse, 3 injection function test,
sputum elimination,
(18–60) years therapy * courses serum
antispasmodic)
exception-CV22: indicators)
2 mL/point
Response rate
(frequency of
Bricalin inhalation (0.5
asthma attack,
1) PA (1.5–2 mL t.i.d. for 10 days) +
E: 45.74 (18– breathing rate, 1.06
mL/point, q.d. for Conventional therapy
Tong, 65) years Acute, mild or Acupoint pulse rate,
90 (60/30) 10 days) (anti-inflammtion, 10 days
2007 [21] C: 41.9 (18– moderate injection wheezing
2) Conventional spasmolysis, dyspnea
65) years sound)
therapy relief and sputum
elimination)
PEF (L/min) 14.02

Response rate
(change of
1) PA (2
E: 41.5 ± 4.1 symptom,
mL/point, q.d. for Theophylline tablet
Wang, (18–60) years degree of
62 (31/31) n.r., n.r. 10 days) (0.1 g, 2 times/day for 10 days CKZ PA 1.21
2010 [22] C: 42.7 ± 4.2 asthmatic attack,
2) Theophylline 10 days)
(18–60) years steroids and
tablet
bronchodilators
required or not)
Response rate
(degree of
asthmatic attack,
1) PA (1 change in PEF% 1.20
E: 32 ± 18.6
Wang mL/point, q.d. for Bricalin inhalation or FEV1%, need
(14–62) years 2
and Fu, 158 (82/76) Acute, n.r. 2 weeks) (0.25–0.5mL, t.i.d. for HQ PA for steroids and
C: 35 ± 20.3 weeks
2008 [23] 2) Bricalin 2 weeks) bronchodilators)
(13–63) years
inhalation
FVC (L) 0.48

FEV1 (L) 0.31

PEF (L/s) 0.36

Conventional therapy Response rate
Yang, E: 53.3 ± 4.4 1) PA (2mL/point 1
60 (30/30) Acute, n.r. (anti-inflammatory, CKZ PA (change of 1.22
2016 [24] (35–70) years for 1 month) month
antispasmodic symptom)

18
 C: 52.6 ± 4.7 2) Conventional medication, oxygen
(40–68) years therapy therapy)
Response rate
(change of
Conventional therapy
E: 42.3 ± 16.3 1) PA (4 mL, b.i.d. symptom, 1.16
(anti-inflammation,
Zhang, (15–59) years for 7 days) change of PEF
110 (55/55) Acute, n.r. spasmolysis, dyspnea 7 days CKZ PA
2014 [25] C: 40.1 ± 19.9 2) Conventional or FEV1%)
relief and sputum
(16–60) years therapy FEV1% 6.98
elimination)

FEV1/FVC ratio 8.09

5% glucose 250 mL,

Zhang E: 61 (49–78) Response rate
PA (dosage not aminophylline 0.25 g, Water
and years (change of
60 (30/30) Acute, n.r. provided, q.d. for methylprednisone 40 5 days acupunct 1.07,
Zhang, C: 62 (52–71) symptoms and
5 days) mg, 2 times/d I.V. ure
2012 [26] years signs)
injection
Drug inhalation (q.d.
for 10 days)
E: 45.27 ±
- mild: fluticasone
12.55 (28–71) 1) PA (1 Response rate
Zheng et inhaler 125 μg, 2
years Acute, mild to mL/point, q.d. for (change of
al., 2014 60 (30/30) times/day for 10 days 10 days HQ PA 1.14
C: 46.10 ± moderate 10days) symptom and
[27] - moderate: salmeterol
4.26 (21–74) 2) Drug inhalation signs)
50 μg and fluticasone
years
propionate 100 μg, 2
times/day for 10 days

Notes: E: experimental group; C: control group; PA: pharmacopuncture; q.d.: once a day; RR: risk ratio; MD:
mean difference; CI: confidence interval; PEF: peak expiratory flow; CKZ: Chuankezhi; n.r.: not reported;
FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; HQ: Huangqi; b.i.d.: twice a day

a
include FEV1, FVC, FEV1/FVC ratio, and PEF

19
Table 3. Pharmacopuncture ingredients and acupoint injection point used in included studies.

Author, Pharmacopuncture
Pharmacopuncture ingredients Injection point
year type
Gan and
Huang, CKZ PA Morindae Radix, Epimedii Herba ST36 (both side)
2011 [10]
Hu et al.,
CKZ PA Morindae Radix, Epimedii Herba BL13, ST36 (one side at a time)
2013 [11]
CV22
Hui et al.,
CKZ PA Morindae Radix, Epimedii Herba EX10 BL13, BL23, ST36 (both
2013 [12]
side)
Huo, 2015
CKZ PA Morindae Radix, Epimedii Herba n.r.
[13]

Li, 2012 Piper nigrum, Sinapsis Semen, Asia Radix, Angelicae GV14, BL23, BL13, BL20 (both
Acupoint injection
[14] Dahuricae Radix, Semiliquidambar cathayensis side)
Liang et al.,
HQ PA Radix Astragali BL13 (one side at a time), GV14
2004 [15]

Li et al. ST36, LI11, BL13, GV14 (select

CKZ PA Morindae Radix, Epimedii Herba
2016 [16] 2 points)
Liu, 2011
CKZ PA Morindae Radix, Epimedii Herba ST36 (both side)
[17]
Bufo, Radix Astragali, Semen Ginkgo, Semen
Lu and
Haqing compound Armeniacae Amarum, Radix et Rhizoma Asteris, Radix
Tang, 2005 CV22
acupoint injection Peucedani, Fructus Schisandrae Chinensis, Radix
[18]
Aconiti lateralis Praeparata, Fructus Piperis, etc.
Luo et al.,
CKZ PA Morindae Radix, Epimedii Herba BL13 (both side)
2013 [19]
1st course: BL13, EX10, BL12,
ST36, LI11
2nd course: BL13, EX10, BL11,
Sheng, ST40, CV22
Acupoint injection Cnidii Rhizoma, Salviae Miltiorrhizae Radix
2016 [20] 3rd course: BL13, EX10, LI11,
ST36, BL23
(both sides)
* exception - CV22 (single side)
Tong, 2007 Radix Angelicae Sinensis, Rhizoma Chuanxiong, Flos EX-B1, BL13, CV22, SJ6, ST40
Acupoint injection
[21] Carthami (one side at a time)
Wang,
CKZ PA Morindae Radix, Epimedii Herba ST40
2010 [22]
Wang and
ST36, BL13, BL23 (one side at a
Fu, 2008 HQ PA Radix Astragali
time)
[23]

20
 Yang, 2016
CKZ PA Morindae Radix, Epimedii Herba BL13, EX10
[24]
Zhang,
CKZ PA Morindae Radix, Epimedii Herba n.r.
2014 [25]
Zhang and
Zhang, Water acupuncture Semen Cassiae, Manitis Squama, Datura stramonium BL13, BL23
2012 [26]
Zheng et
al., 2014 HQ PA Radix Astragali BL13, BL17, ST40, EX10
[27]

Notes: CKZ: Chuankezhi; PA: pharmacopuncture; HQ: Huangqi; n.r.: not reported

21