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Herbal medicine (Hyeolbuchukeo-tang or Xuefu
Zhuyu decoction) for treating primary
dysmenorrhea
A systematic review and meta-analysis of randomized
controlled trials
Jungtae Leem, MD, (DKM), PhD
a,b
, Junyoung Jo, MD, (DKM), PhD
c,d
, Chan-Young Kwon, MD, (DKM), MSc
b,e
,
Hojung Lee, MD, MSc
f
, Kyoung Sun Park, MD, (DKM), PhD
g,∗
, Jin Moo Lee, MD, (DKM), PhD
g,∗
Abstract
Background: Primary dysmenorrhea is a condition characterized by painful menstrual cramps that usually occurs in the absence
of any identifiable pathological condition among menstruating women, with the prevalence estimates varying between 45% and 95%.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered as a standard treatment for primary dysmenorrhea; however, the
failure rate of NSAIDs is often 20% to 25% and these drugs commonly cause adverse effects. In this review, we investigated the
current evidence related to the effectiveness of Xuefu Zhuyu decoction (XZD) or Hyeolbuchukeo-tang, a traditional herbal formula, as
a treatment for primary dysmenorrhea.
Methods: Literature search was conducted about randomized controlled trials (RCTs) for XZD on primary dysmenorrhea. PubMed,
Cochrane Library, Embase, China National Knowledge Infrastructure Database, Oriental Medicine Advanced Searching Integrated
System, and other Chinese, Korean, Japanese databases were searched up to December 20, 2017. Two independent reviewers
extracted and assessed the data. The main outcome domains were visual analogue scale (VAS) score and response rate.
Results: Among 475 publications, 8 RCTs involving 1048 patients were finally included. Methodological quality of included RCTs
was relatively low. In 4 add-on design studies, XZD plus western medication (WM) group showed better response rate as compared
to the WM sole therapy (relative risk 1.18, 95% confidence interval [1.11, 1.25], P<.01). VAS score after the 3rd month of treatment in
the XZD plus WM group was also lower than that in the WM group (mean difference –0.45, 95% confidence interval [–0.79, –0.12],
P<.01). In 4 XZD versus WM design studies, XZD sole therapy showed better response rate than did WM sole therapy (relative risk
1.26, 95% confidence interval [1.06, 1.49], P<.01).
Conclusion: The existing trials showed a favorable effect of XZD for the management of primary dysmenorrhea. However, the
efficacy of XZD on primary dysmenorrhea is not conclusive owing to the small number of studies and the high risk of bias. Large-scale,
long-term RCTs with rigorous methodological input are needed to clarify the role of XZD for the management of primary
dysmenorrhea.
Trial registration number: CRD42016050447 in PROSPERO 2016
Editor: In-Hyuk Ha.
JL and JJ contributed equally to this study (co-first authors).
This study is supported by the Traditional Korean Medicine R&D program that is funded by the Ministry of Health & Welfare through the Korea Health Industry
Development Institute (KHIDI, grant HB16C0018).
Our manuscript is a unique submission and is not being considered for publication by any other source in any medium. Further , the manuscript has not been
published, in part or in full, in any form.
The authors declare that they have no conflicts of interest.
Supplemental Digital Content is available for this article.
a
Department of Internal Medicine of Korean Medicine, Dongshin Korean Medicine Hospital, Seoul,
b
Chung-Yeon Medical Institute, Gwangju,
c
Department of Korean
Medicine Obstetrics & Gynecology, Conmaul Hospital of Korean Medicine, Seoul,
d
Research Institute of Korean Medicine, College of Korean Medicine, Dongguk
University, Gyeongsangbuk-do,
e
Department of Clinical Korean Medicine, Graduate School, Kyung Hee University, Seoul,
f
Dongguk University in Los Angeles, Los
Angeles, CA,
g
Department of Korean Medicine Obstetrics & Gynecology, College of Korean Medicine, Kyung Hee University, Seoul, South Korea.
∗
Correspondence: Kyoung Sun Park and Jin Moo Lee, Department of Korean Medicine Obstetrics & Gynecology, College of Korean Medicine, Kyung Hee University,
26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, South Korea (e-mails: goodsmile8119@gmail.com, lovepks0116@ gmail.com, goodsmile8119@gmail.com,
hanbang9597@hanmail.net).
Copyright ©2019 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is
permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the
journal.
Medicine (2019) 98:5(e14170)
Received: 26 May 2018 / Received in final form: 17 December 2018 / Accepted: 27 December 2018
http://dx.doi.org/10.1097/MD.0000000000014170
Systematic Review and Meta-Analysis Medicine®
OPEN
1
Abbreviations: AE =adverse event, CHM =Chinese herbal medicine, CI =confidence interval, MD =mean difference, NSAIDs =
nonsteroidal anti-inflammatory drugs, PI =pattern identification, RCT =randomized controlled clinical trial, RR =risk ratio, TCM =
traditional Chinese medicine, VAS =visual analogue scale, VIP =Chinese Scientific Journals Database, WM =western medication,
XZD =Xuefu Zhuyu decoction.
Keywords: herbal medicine, Hyeolbuchukeo-tang, primary dysmenorrhea, systematic review, Xuefu Zhuyu decoction
1. Introduction
Primary dysmenorrhea is a menstrual disorder characterized by
painful cramps that usually occurs in the absence of any
identifiable pathological condition among menstruating women,
with the prevalence estimates varying between 45% and
95%.
[1,2]
Despite the high prevalence, dysmenorrhea is often
poorly understood, treated, and even disregarded by health
professionals and the women themselves, who may accept it as a
normal characteristic of their menstrual cycle.
[3]
However,
dysmenorrheic pain is not only the primary cause of recurrent
short-term school or work absenteeism among young women,
but also the cause of a significantly reduced quality of life, low
mood, and poor sleep quality during menstruation as compared
to the women without primary dysmenorrhea.
[3]
Nonsteroidal anti-inflammatory drugs (NSAIDs) are consid-
ered as a standard as well as an effective treatment for primary
dysmenorrhea.
[4]
However, the failure rate of NSAIDs is often
20% to 25%, and these drugs may be contraindicated or may not
be tolerated by some women.
[4]
In addition, NSAIDs commonly
cause adverse effects, including indigestion, headaches, and
drowsiness.
[4]
Therefore, many women also seek alternative
therapies to manage their menstrual discomfort including
Chinese herbal medicine (CHM).
[5]
Traditional Chinese medicine (TCM) or Korean medicine
identified blood stagnation as the main factor causing abdominal
pain during menstruation.
[6]
Blood stasis is one of the important
pathological concepts in TCM since its concept was first
documented in Huangdi Inner Classic. Additionally, it is one
of the currently active and vibrant research domains in TCM.
[7,8]
Generally, blood stasis is a significant pathological product due to
stagnant blood.
[7,8]
If blood stasis occurs within the body,
characteristic symptoms such as pain in a fixed position,
nyctalgia, dark-purple coloring of the tongue or face, infraorbital
darkness, sublingual varicosis, blood spots under the skin or
tongue, or an astringent pulse can manifest.
[9]
In clinical practice,
many diseases such as ischemic heart disease, cerebral vascular
accident, chronic gastritis, trauma, and dysmenorrhea can be
related to blood stasis.
[10]
Hyeolbuchukeo-tang also known as Xuefu Zhuyu decoction
(XZD) was the most frequently used formula in research focused
on blood stasis in Korea.
[11]
XZD is recorded in the book
“Correction on Errors in Medical Classics”in 1830. The
components of XZD include the followings: Angelicae Sinensis
Radix, Rehmanniae Radix, Persicae Semen, Carthami Flos,
Aurantii Fructus, Paeniae Radix Rubra, Bupleuri Radix,
Glycyrrhizae Radix et Rhizoma, Chuanxiong Rhizoma, Achyr-
anthis Bidentatae Radix, and Platycodonis Radix. There have
been substantial randomized controlled clinical trials (RCTs)
using XZD for primary dysmenorrhea, but no review focused on
the use of XZD in the treatment of primary dysmenorrhea has
been published yet. Therefore, in this review, we investigated the
current evidence related to the effectiveness of XZD or
Hyeolbuchukeo-tang, a traditional herbal formula, as a
treatment for primary dysmenorrhea.
2. Materials and methods/design
We have followed a previously published systematic review
protocol.
[12]
A detailed explanation of the methodology has
been described in the protocol. We have also registered the
systematic review protocol. The trial registration number is
CRD42016050447 in PROSPERO 2016.
2.1. Data sources and search strategy
Two independent reviewers (J L, H L) searched for the following
databases from inception to December 20, 2017: The Cochrane
Central Register of Controlled Trials, EMBASE (via OVID),
Medline (via PubMed), Cumulative Index to Nursing and Allied
Health Literature, and Allied and Complementary Medicine
Database. Three Chinese databases Wanfang, Chinese Scientific
Journals Database (VIP), and China National Knowledge
Infrastructure Database were also searched. Six Korean medical
databases (KoreaMed, DBPia, Oriental Medicine Advanced
Searching Integrated System, Research Information Service
System, Korean Traditional Knowledge Portal, Korean studies
Information Service System) and 1 Japanese medical database
(CiNii) were also searched. Clinical trial registries, conference
proceedings, and relevant journals were manually searched. The
search terminologies comprised of:
(1) the disease or its symptoms (eg, pelvic pain, menstrual
disorder, cramps, painful period, period pain, painful
menstruation, menstrual pain, and dysmenorrhea)
(2) intervention term (eg, Xuefu Zhuyu granule/decoction/
formula/tang/capsule/pill/ tablet or Hyeolbuchukeo-tang).
The search strategy for each database was modified according
to the database. The details of the search strategies are explained
in supplementary 1, http://links.lww.com/MD/C771.
2.2. Eligibility criteria
We included the prospective, RCTs only. In Chinese articles, the
randomization process was not described in detail, although the
word “randomization”was used; we included such studies.
Patients with primary dysmenorrhea were included in our review.
Patients with secondary dysmenorrhea due to a specific
pathological condition such as infection or endometriosis were
excluded. In the intervention group, both XZD sole therapy or
XZD adjunctive therapy (XZD plus other agent used for
intervention) were included in our review. In addition, the
control group intervention included no treatment or usual care or
western medication (WM) sole therapy. Studies involving
combined therapies such as XZD with acupuncture versus
WM were excluded. “Head to head design”that compared XZD
versus other traditional medicine interventions such as herbal
medicine, moxibustion, or acupuncture were also excluded. The
XZD is composed of 11 medicinal herbs. We also included
modified XZD which contains less than 6 modified (50%)
medicinal herbs. There was no restriction of language for
Leem et al. Medicine (2019) 98:5 Medicine
2
including the study in our review. Disagreement between the 2
reviewers was finally judged by a third independent reviewer (J J).
2.3. Data extraction
According to our previous protocol,
[12]
data extraction form was
prepared that included the information related to the study
design, first author, country where the study was conducted,
published year, language, clinical setting, age, number of patients
as well as the dropout rate in the control group and the
intervention group, diagnostic criteria, disease duration, disease
severity, number of arms, type of XZD formulation, number of
adverse events (AEs), composition and dosage of XZD, pattern
identification (PI), treatment duration, follow up duration,
control group intervention, and types of outcome variables. If
the outcome variables were measured several times, we extracted
the data at every time point. Two authors performed data
extraction independently (H L, C K). Disagreement between the
reviewers (H L, C K) was resolved by discussion among all
authors. In case of ambiguous or insufficient data, we contacted
the author of the article for further clarity.
2.4. Outcome measurement
In our previous systematic review protocol,
[12]
visual analogue
scale (VAS) score and response rate were the primary outcomes of
our research. In Chinese articles, treatment response was usually
divided into 4 categories viz. “Cured”(C), “Markedly improved”
(M), “Improved”(I), and “No effect”(N). In our previous
protocol, we defined 3 types of response rates viz. type I, type II,
and type III. In type I category, “No effect”group was defined as
a nonresponder group and the other group (C, M, and I groups)
was defined as a responder group. In type II category, the
responders were defined as those with more than 50%
improvement in the symptoms while the nonresponders were
defined as those with less than 50% improvement in the
symptoms. The proportion of responders between the treatment
and the control group in each type were compared. In our
previous protocol,
[12]
we also defined the response rate (type III),
according to which any patient whose symptoms showed no
change or showed worsening were classified into nonresponder
group regardless of the treatment response category; while the
others were classified into responders. However, in our review,
type I and type III have the same meaning; therefore, we
conducted the analysis with type I and type II categories only. In
our previous protocol, quality of life and AEs were included as
secondary outcomes. In addition to the predefined secondary
outcomes, we also extracted the recurrence rate and the symptom
score.
2.5. Assessment of risk of bias
A risk of bias about the included studies was conducted using the
risk of bias assessment tool from the Cochrane handbook.
[13,14]
Two independent reviewers (J L, C K) assessed the risk of bias
into low, unclear, or high grade. If the disagreement was not
resolved by a mutual discussion among the 2 reviewers, a final
decision was made by the third reviewer (J J). We assessed the
selection bias (random sequence generation and allocation
concealment), the performance bias (blinding of participants
and personnel), the detection bias (blinding of outcome
assessment), the attrition bias (incomplete outcome data), the
reporting bias (selective reporting), and other bias. A “high”risk
of bias was graded in case of random sequence generation
assessment, where only the word “randomization”was used
without any further explanation.
2.6. Statistical analysis and data synthesis for meta-
analysis
To assist researchers, the effect size of every outcome variable was
presented for related clinical trial protocol development. Review
manager (V.5.3 Copenhagen: The Nordic Cochrane Centre, The
Cochrane Collaboration, 2014) was used for data synthesis and
meta-analysis. Outcome variables were combined according to
the study design (add-on design or head to head design) and the
type of outcome measure. Continuous outcome data were pooled
and expressed as mean difference (MD) with a 95% confidence
interval (CI). Binary outcome data were also pooled and
expressed as risk ratio (RR) with a 95% CI. Heterogeneity
among studies was evaluated by I
2
statistic and tested with a
significance level of P<.1. The I
2
statistic indicates the
proportion of variability among the included studies that cannot
be explained by chance alone.
[15]
Random effect model was used
if the I
2
statistic value was >50%, which indicates a substantial
heterogeneity. If I
2
statistic value was <50%, the fixed model was
used. We also explored the source of heterogeneity. Subgroup
analysis was performed separately depending on whether the PI
was applied or not while prescribing XZD to the patient.
3. Results
3.1. Description of the included studies
A total of 475 studies were screened by electronic and manual
searching. These studies were assessed for duplication and after
removing the duplication, 175 articles were assessed by title and
abstract after which 141 articles were excluded. The remaining
34 articles were assessed with full-text and 26 articles were
identified as having an inappropriate design, disease, or
intervention (Supplementary 2, http://links.lww.com/MD/
C771). Eight articles were finally included for qualitative and
quantitative analysis (Fig. 1). Thus, among 475 publications, 8
RCTs involving 1048 patients were finally included 4 studies
were “add-on study design”that compared XZD and WM
combination therapy group versus WM sole therapy group.
[16–19]
In add-on study, the control group receives conventional
treatment, while the experimental group receives XZD along
with conventional treatment.
[20]
Other 4 studies were “head to
head study design”that compared XZD sole therapy versus WM
sole therapy.
[21–24]
We did not find any placebo-controlled trial.
A summary of the included studies is shown in Table 1. The
details of XZD treatment are described in Table 2.
3.2. Summary of the included studies and detailed
information of XZD treatment
All studies were conducted in China and published in Chinese
language. Four of these studies were outpatient studies and the
others could not be identified. The number of participants was
524 in each group (treatment as well as the control group). The
mean age of included patients ranged from 16.8 to 26.5 years.
The average disease duration ranged from 1.6 to 7 years. One of
the included studies used XZD Koufuye (oral liquid)
[22]
and the
other 7 studies used XZD decoction. The number of patients in
each group ranged from 30 to 128. WM used by the patients in
Leem et al. Medicine (2019) 98:5 www.md-journal.com
3
the studies were Fenbid, Oryzanol, Thiamine, Indometacin,
Naproxen, Ibuprofen, or Diclofenac Sodium (Table 1).
Primary dysmenorrhea was diagnosed by pelvic sonography in
1 RCT.
[21]
Four RCTs reported that they excluded secondary
dysmenorrhea due to pelvic inflammatory diseases, endometri-
osis, or uterine fibroids, but they did not describe specific methods
in detail.
[16,19,22,24]
The other 3 RCTs did not mention how they
diagnosed primary dysmenorrhea.
[17,18,23]
In 5 studies, XZD was prescribed only to the patients who were
diagnosed with blood stasis due to qi stagnation according to the
TCM PI.
[16,18,19,21,23]
Modification of XZD according to PI or
symptom was allowed in 6 studies.
[16,17,19,21,23,24]
The total
number of treatment cycles comprised of 3 cycles except for 1
study in which it was 6 cycles.
[22]
However, the definition of 1
treatment cycle was somewhat different between the studies. The
outcome assessment timing was 3 months from the start of the
treatment except for 1 study for which it was 6 months.
[22]
Furthermore, excluding 2 studies, an additional follow up
assessment was conducted in all other studies.
[16,18,19,22–24]
XZD
is composed of 11 medicinal herbs. In our review, some studies
allowed modification of the medicinal herbs based on the PI or
related symptoms. Therefore, the daily dose of the included
medicinal herbs was slightly different from each other. The details
of the XZD and its daily dose are presented in Table 2.
3.3. Risk of bias in the included studies
The overall risk of bias of the included studies was high or
unclear. A graphical illustration about the risk of bias is shown in
Figure 2. In random sequence generation, only 2 studies were
graded as low as they mentioned about using random number
table.
[16,19]
Other studies that did not mention about random
sequence generation were graded as high. Allocation conceal-
ment was not mentioned in any of the included studies and hence
it was graded as unclear in all the studies. Placebo-controlled
design trial was not included in any of the studies and hence the
risk of bias accounting from the blinding of participants was
graded as high in all the studies. The risk of bias accounting from
the “blinding of outcome assessment”and “incomplete outcome
data”were graded as unclear in all studies because none of the
Figure 1. PRISMA flow diagram. PRISMA =preferred reporting items for systematic reviews and meta-analyses.
Leem et al. Medicine (2019) 98:5 Medicine
4
Table 1
Summary of the included studies.
First author, yr
Country/
setting
Disease duration yrs; mean ±
SD (range)/disease severity;
[(n) mild /moderate/ severe]
Age, yrs;
mean ±SD
(range)
Treatment
group (n)
Control group
intervention
(n) Outcome Effect size
∗
Adverse
events
(AEs)
Xuefu Zhuyu decoction (XZD) + western medication (WM) versus western medication (WM)
Chou (2015)
[16]
China/OPD TG) 4.1 ±2.2 (2–9)
[17/28/19]
CG) 3.6 ±2.1 (1–8)
[19/29/16]
TG) 26.5 ±5.2
(16–41)
CG) 25.8 ±5.7
(16–39)
XZD decoction
+ WM (64)
Fenbid (64) ①Symptom score
②VAS
③TRR
[C/M/I/N]
①3.78 (MD, 95% CI [4.62, 2.94])
②1st, 2nd, 3rd mo
1mo)0.52 (MD, 95% CI [0.73, 0.31])
2mo)0.51 (MD, 95% CI [0.67, 0.37])
3mo)0.28 (MD, 95% CI [0.43, 0.13])
③1.15 (RR, 95% CI [1.02, 1.29])
[(TG) 28/24/10/2 (CG) 19/20/15/10]
TG) 7
‡
CG) 10
‡
Wang (2013)
[17]
China/ND TG) 1.7 (0.3–4)
[ND]
CG) 1.6 (0.2–4)
[ND]
TG) 18.6
(16–27)
CG) 17.9
(15–26)
XZD decoction + WM
(60)
Oryzanol, Thiamine,
(if severe)
Indometacin, Fenbid,
Naproxen
(60)
‡
①TRR
[M/I/N]
①1.19 (RR, 95% CI [1.03, 1.36])
[(TG) 45/12/3 (CG) 24/24/12]
ND
Wu (2014)
[18]
China/OPD TG) 2.1 ±0.3 (0.5–8)
[21/23/7]
CG) 2.3 ±0.2 (0.8–7)
[18/27/6]
TG) 22.5 ±3.2
(16–31)
CG) 23.1 ±4.3
(18–33)
XZD decoction + WM
(51)
Ibuprofen (51) ①TRR [C/M/I/N] ①1.37 (RR, 95% CI [1.07, 1.59])
[(TG) 24/15/8/4 (CG) 9/15/12/15]
No AEs
Zhang (2015)
[19]
China/ND TG) 4.2 ±2.4 (2–9)
[34/56/38]
CG) 3.5 ±2.0 (1–9)
[38/58/32]
TG) 25.4 ±4.8
(17–40)
CG) 25.3 ±4.6
(17–41)
XZD decoction + WM
(128)
Fenbid (128) ①Symptom score
②VAS
③TRR
[C/M/I/N]
①3.83 (MD, 95% CI [4.43, 3.23])
②1st, 2nd, 3rd mo
1mo)0.52 (MD, 95% CI [0.67, 0.37])
2mo)0.51 (MD, 95% CI [0.61, 0.41])
3mo)0.45 (MD, 95% CI [-0.79, 0.12])
{0.17, 95% CI (–0.71, 1.05)}
†
③1.15 (RR, 95% CI [1.06, 1.24])
[(TG) 57/47/21/3 (CG) 39/39/31/19]
TG) 7
‡
CG) 10
‡
Xuefu Zhuyu decoction (XZD) versus western medication (WM)
Huang (2014)
[21]
China/OPD TG) 2 (0.5–9)
[21/27/8]
CG) 4 (0.75–7)
[19/30/7]
TG) 22 (16–31)
CG) 24 (18–33)
XZD decoction
(56)
Diclofenac Sodium
(56)
①TRR [C/M/I/N] ①1.26 (RR, 95% CI [1.03, 1.53])
[(TG) 25/16/8/7 (CG) 12/18/9/17]
ND
Li (2014)
[22]
China/ND TG) 1.9 ±3.2 (ND)
[9/12/9]
CG) 1.9 ±3.5 (ND)
[10/13/7]
TG)23.9 ±9.1 (ND)
CG)24.7 ±8.9 (ND)
XZD Koufuye (30) Indometacin
(30)
①TRR [C/M/I/N]
②6 mo recurrence rate
①1.07 (RR, 95% CI [0.96, 1.20])
[(TG) 12/10/8/0 (CG) 1/14/13/2]
②0.08 (RR, 95% CI [0.01, 0.60])
[(TG) 1 case (CG) 12 cases]
ND
Wang (2015)
[23]
China/ND TG) 7 ±1.2 (0.4–6)
[33/40/27]
CG) 4.1 ±1.4 (0.6–8)
[38/42/20]
TG) 25.2 ±1.1
(16–34)
CG) 24.8 ±1.3
(15–32)
XZD decoction (100) Diclofenac Sodium
(100)
①TRR [C/M/I/N] ①1.34 (RR, 95% CI [1.14, 1.57])
[(TG) 31/29/27/13 (CG) 24/21/20/35]
TG) 1
CG) 9
Zhao (2016)
[24]
China/OPD All) 5.1 ±3.2 (0.4–11)
[14/32/24]
All) 16.8 ±3.5
(13–28)
XZD decoction (35) Symptomatic treatment
of pain (35)
①TRR [C/M/I/N] ①1.48 (RR, 95% CI [1.16, 1.89])
[(TG) 20/9/5/1 (CG) 1/8/14/12]
ND
Unit of disease duration: years. Treatment response is categorized as C (cured), M (markedly improved), I (improved), N (no effect). In this Table, total response rate (TRR) follows the definition of response rate type I in the manuscript. TRR is calculated as (C + M + I) ∗100/(C+M+I+N)
which means proportion of patients showing any positive change. Dropout rate is not described in any trial.
AE =adverse event, C =cured, CG =control group, CI =confidence interval, I=improved, M =markedly improved, MD =mean difference, N=no effect, ND=not described, OPD=out patient department, RR =risk ratio, TG =treatment group, TRR=total response rate, VAS =visual
analogue scale, WM =western medication, XZD =Xuefu Zhuyu decoction.
∗
Effect size was presented with mean difference (MD, 95% confidence interval [lower limit, upper limit]) in continuous variables or risk ratio (RR, 95% confidence interval [lower limit, upper limit]) in dichotomous variables.
†
Zhang (2015) reported that visual analogue scale (VAS) of 3 month after treatment completion was significantly better in the treatment group. However, in the table of the article, VAS score was 0.07±0.4 in the control group, and 0.69 ±0.44 in the treatment group. We tried to contact the
author, however, we could not find the means of contact. Therefore, according to the conclusion of the article, we exchanged the values (control with treatment) and conducted a meta-analysis. The results based original data are also presented in {}.
‡
In case of psychiatric symptom, sedative medication was prescribed.
‡
All the reported adverse events (AEs) were mild stomach discomfort.
Leem et al. Medicine (2019) 98:5 www.md-journal.com
5
studies mentioned about these issues. In selective reporting, there
were no previously published study protocols. However, 3 trials
in which the outcome variables previously intended to analyze
were reported in the article, were graded as low.
[16,19,23]
Other
articles were graded as unclear due to the lack of information. We
could not assess any other bias, so they were graded as unclear in
all the studies.
3.4. Outcome
There were 2 types of study designs:
(1) “add-on design study”that compared XZD plus WM
combined therapy versus WM sole therapy.
[16–19]
(2) “head to head design study”that compared XZD sole
therapy versus WM sole therapy.
[21–24]
In “add-on design studies,”VAS)
[16,19]
symptom score,
[16,19]
and response rate
[16–19]
were used to examine the effect of XZD,
while in “head to head design studies,”response rate
[21–24]
and
recurrence rate
[22]
were used. We conducted a qualitative as well
as quantitative analysis in each design (Table 1).
3.4.1. XZD plus WM combined therapy versus WM sole
therapy (add-on design study)
3.4.1.1. Response rate (type I). Pooling the data from 4 add-on
study design,
[16–19]
the XZD and WM combined group showed
significantly better response rate (type I) than the WM sole
Table 2
Details of Xuefu Zhuyu decoction (XZD) treatment.
XZD + WM treatment group XZD sole treatment group
First author, yr Chou (2015) Wang (2013) Wu (2014) Zhang (2015) Huang (2014) Li (2014) Wang (2015) Zhao (2016)
Prescribed XZD only to
patients diagnosed with
blood stasis due to qi
stagnation by pattern
identification (PI)
YNYY YNYN
Modification by PI or
symptoms
YYNY YNYY
Treatment cycle 3 3 3 3 3 6 3 3
Definition of treatment
cycle (when to take
XZD)
3to0 3to10d
∗
3to0 3to0 5to0 3to+1 5to0 7to+3
Outcome assessment
timing, mo
3mo 3mo 3mo 3mo 3mo 6mo 3mo 3mo
Additional follow up
duration, mo
3mo N 3mo 3mo N 6mo 3mo 3mo
Daily dose of included medicinal herbs (unit) g
Angelicae Sinensis
Radix
†
912151515ND1512
Rehmanniae Radix
†
12 –10 20 10 ND 10 15
Persicae Semen
†
12 15 10 12 10 ND 10 10
Carthami Flos
†
9 9 10 10 10 ND 10 8
Aurantii Fructus
†
9 9 10 10 10 –10 10
Paeniae Radix Rubra
†
12 12 10 10 10 ND 10 15
Bupleuri Radix
†
910151015ND1510
Glycyrrhizae Radix et
Rhizoma
†
6686 8–810
Chuanxiong Rhizoma
†
8151010 10ND1010
Achyranthis Bidentatae
Radix
†
9101215 12ND1215
Platycodonis Radix
†
9 10 10 9 10 ND 10 10
Medicinal herbs that are not included in the original XZD
Corydalis Rhizoma 12 12 12
Paeoniae Radix Alba 20
Salviae Miltiorrhizae
Radix et Rhizoma
15
Poria 15
Atractylodis
Macrocephalae Rhizoma
15
Zingiberis Rhizoma
Praeparatum
12
Definition of treatment cycle is as follows: For example, Zhao (2016) is expressed as 7 to +3. It means XZD treatment was started 7 days before menstruation. XZD medication was finished 3 days after
menstruation. XZD was consumed twice a day.
d=day, mo =month, N =no, NA =not applicable, ND=not described. Used in the prescription but dosage was not known, PI =pattern identification, WM =western medication, XZD=Xuefu Zhuyu decoction,
Y=yes.
∗
XZD decoction was started 3 days before menstruation and maintained for 10 days.
†
11 Medicinal herbs included in the original XZD prescription.
Leem et al. Medicine (2019) 98:5 Medicine
6
therapy group (RR 1.18, 95% CI [1.11, 1.25], P<.01; Fig. 3).
We also conducted a subgroup analysis to check whether
adopting PI affected the results. Three studies prescribed XZD
only to those patients who were diagnosed with blood stasis due
to qi stagnation by PI.
[16,18,19]
In the“‘adopting PI
group,”
[16,18,19]
RR was 1.18 995% CI [1.10, 1.25], P<.01).
In the “not adopting PI group,”
[17]
RR was 1.19 (95% CI [1.03,
1.36, P=.02). As both the groups showed statistical significance
with 95% CI (overlapping), we could not find any difference
between adopting PI versus nonadopting PI group in response
rate (type I) by subgroup analysis.
3.4.1.2. Response rate (type II). Only 2 studies reported the
proportion of patients who showed more than 50% of symptom
improvement.
[16,19]
the XZD and WM combined group showed
significantly better response rate (type II, symptom improved
more than 50%) as compared to the WM sole therapy group (RR
1.33, 95% CI [1.17, 1.52], P<.01; Fig. 4).
3.4.1.3. VAS. Two studies that prescribed XZD for 3 months
reported VAS score every month.
[16,19]
The XZD and WM
combined group showed significantly lower VAS score as
compared to the WM sole therapy group after the 1st month
(MD 0.52, 95% CI [–0.64, 0.40], P<.01) and after the 2nd
month (MD 0.51, 95% CI [–0.59, 0.43], P<.01). At the end
of the 3rd month also, Zhang
[19]
described that the treatment
group showed significantly lower VAS score. However, as
depicted in the table of the article, the VAS score was 0.69±0.44
in the treatment group and 0.07 ±0.40 in the control group. We
predicted that the table may contain a writing error and hence we
tried to contact the author. However, we could not find the e-mail
on the homepage. Therefore, we concluded that the authors must
have made a mistake. We exchanged the values of the treatment
group with that of the control group and conducted a meta-
analysis. Consequently, the VAS score at the end of the 3rd
month in the treatment group was also significantly lower than
that in the WM sole therapy group (MD 0.45, 95% CI [–0.79,
0.12], P<.01; Fig. 5).
3.4.1.4. Symptom score. Two studies reported the symptom
score.
[16,19]
The XZD and WM combined group showed
significantly lower symptom score as compared to the WM sole
therapy group (MD 3.81, 95% CI [–4.30, 3.32], P<.01;
Fig. 6).
3.4.2. XZD versus WM (head to head design study)
3.4.2.1. Response rate (type I). Pooling the data from 4 head to
head study design,
[21–24]
the XZD group showed significantly
better response rate (type I) as compared to the WM group (RR
1.26, 95% CI [1.06, 1.49], P<.01; Fig. 7). I
2
statistic was partially
high (75%). Li
[22]
used Koufuye form of XZD for 6 months.
However, other studies used decoction form and prescribed it for 3
months only. To identify the origin of heterogeneity we excluded
Li
[22]
and conducted a meta-analysis again. The I
2
statistic
decreased to 0%; however, the XZD effect persisted (RR 1.34,
95% CI [1.20, 1.50], P<.01; data not shown). We also conducted
a subgroup analysis to assess whether adopting PI affects the
results. There were 2 studies that adopted PI when prescribing
XZD only to the patients who were diagnosed with blood stasis
due to qi stagnation syndrome. In the “adopting PI group,”
[21,23]
RR was 1.31 (95% CI [1.15, 1.48], P<.01) whereas in the “not
adopting PI group,”
[22,24]
RR was 1.24 (95% CI [0.83, 1.87],
P=.30). “However, due to Li’s (2014) study, the heterogeneity in
the “not adopting PI group”was high (I
2
=89%).
3.4.3. AEs. In “add-on design group,”1 study reported no
AEs,
[18]
another study did not describe about AEs
[17]
while 2
other studies reported AEs
[16,19]
(Table 1). Fourteen AEs were
reported in XZD + WM group and 20 AEs were reported in WM
sole therapy group. In the meta-analysis, RR of AEs between the
2 groups were not significantly different (RR 0.70, 95% CI [0.37,
1.34], P=.28; Fig. 8). All the 34 AEs were mild stomach
discomfort. In “head to head design group,”only one study
mentioned about AEs.
[23]
Only 1 AE occurred in the treatment
group and 9 AEs occurred in the control group. RR of AEs was
0.11 (95% CI [0.01, 0.86]) in the XZD group.
4. Discussion
4.1. Main findings
Our systematic review and meta-analysis revealed that XZD sole
or combined with WM appears to be more effective for pain relief
Figure 2. Summary of the risk of bias. +, low risk of bias; ?, unclear risk of bias;
, high risk of bias.
Leem et al. Medicine (2019) 98:5 www.md-journal.com
7
Figure 3. Forest plot of comparison: XZD plus WM versus WM, outcome: 1.1 Response rate type I. WM =western medication, XZD =Xuefu Zhuyu decoction.
Figure 4. Forest plot of comparison: XZD plus WM versus WM, outcome: 1.2 Response rate type II. WM =western medication, XZD =Xuefu Zhuyu decoction.
Figure 5. Forest plot of comparison: XZD plus WM versus WM, outcome: 1.3 VAS. VAS =visual analogue scale, WM =western medication, XZD =Xuefu Zhuyu
decoction.
Leem et al. Medicine (2019) 98:5 Medicine
8
over WM alone. However, the evidence was limited because of
the generally high risk of bias of the included trials and poor
reporting or validity of the herbal interventions. Furthermore, the
total number of RCTs and the total sample size included in our
analysis were not sufficient to draw a firm conclusion. Although
reports on AEs were insufficient, there were few AEs associated
with XZD as compared to WM.
4.2. The mechanism of XZD on dysmenorrhea
Our previous review has shown that the underlying molecular
mechanisms of herbal medicines for dysmenorrhea are associated
with prostaglandin level reduction, suppression of cyclooxygen-
ase-2 expression, superoxide dismutase activation and malon-
dialdehyde reduction, nitric oxide, inducible nitric oxide
synthase, and nuclear factor-kappa B reduction, stimulation of
somatostatin receptor, intracellular Ca
2+
reduction, and recovery
of phospholipid metabolism.
[25]
Especially, XZD is known to be
associated with enhanced angiogenesis on vascular endothelial
cells
[26]
or reduced inflammatory substances,
[27]
which are
considered to be related with pathology or symptoms of
dysmenorrhea.
[28,29]
These results also suggest the beneficial potentials of XZD on
blood stasis, which is recognized as the main factor causing
Figure 6. Forest plot of comparison: XZD plus WM versus WM, outcome: 1.4 TCM symptom score. TCM =traditional Chinese medicine, WM =western
medication, XZD =Xuefu Zhuyu decoction.
Figure 7. Forest plot of comparison: XZD versus WM, outcome: 2.1 Response rate type I. WM =western medication, XZD =Xuefu Zhuyu decoction.
Figure 8. Forest plot of comparison: XZD plus WM versus WM, outcome: 3 AE rate. AE =adverse event, WM =western medication, XZD =Xuefu Zhuyu
decoction.
Leem et al. Medicine (2019) 98:5 www.md-journal.com
9
dysmenorrhea in traditional East Asian medicine theory.
[30]
Especially in Chinese, Zhuyu has the meaning of removing blood
stasis, and some decoctions having this on its name have been
used for the treatment of various blood stasis-related diseases
including dysmenorrhoea. In this regard, several herbal medi-
cines including other “Zhuyu decoction,”Shaofu Zhuyu
decoction, have been shown to be effective in treating
dysmenorrhea.
[31–33]
XZD has been consider to be one of those
herbal medicines, which perform the function of promoting qi
and activating blood to relieve the symptoms of blood stasis due
to qi stagnation. And this decoction has been investigated in
many pathological conditions related to blood stasis.
[34–37]
In our study, XZD has shown some beneficial potentials in
treating dysmenorrhea and, considering previous studies, it may
be associated with, at least partially, its anti-inflammatory
activity, improving blood circulation, and antinociceptive effect
as well as removing blood stasis.
4.3. Strengths and limitations
This systematic review had a predefined and explicit methodolo-
gy. Also, the protocol for this systematic review was registered in
PROSPERO for transparency. A comprehensive search was
conducted in a variety of databases without language restrictions.
Independent study selection, data extraction, and the risk of bias
assessment by independent reviewers’minimized errors. None-
theless, this systematic review had several limitations. Consistent
with other systematic reviews on CHM, a major limitation of this
report lies in the methodological flaws of the included studies.
First, most of the included trials used the response rate as an
outcome variable, which lacks reliability and validity and poses a
risk of possible bias from the practitioner.
[32]
Second, all of the
RCTs were conducted in China and hence the generalization of
these results may be limited. Third, the risk of bias in the present
findings is generally considered high because most of the included
studies were graded as having high risk and unclear risk of bias
for the key methodological elements such as randomization,
allocation concealment, and patient/outcome assessment. An-
other issue is the lack of standardization of herbal ingredients
used in each study. The herbal medicine interventions are usually
complex and highly variable, and hence a detailed report on the
quality and preparation of the herbal medicine that follows the
relevant reporting guidelines is important.
[38,39]
In our previous protocol, we have suggested several additional
analyses. We conducted a subgroup analysis only for PI because
the analyses for other factors were not applicable in our review.
We planned to conduct the sensitivity analysis according to the
quality of trials assessed by consolidated standards of reporting
trials extension for herbal interventions.
[40]
However, as the
quality of included trials were low; we did not conduct the
sensitivity analysis. Furthermore, as the number of included trials
were less than 10, we did not assess a publication bias using either
funnel plot or Egger method.
[14]
4.4. Comparison with existing literature
This systematic review showed that XZD alone or combined
with conventional WM is effective for pain relief in women
with primary dysmenorrhea. This is consistent with the findings
of most other systematic reviews on CHM for primary
dysmenorrhea.
[32,33,41]
We tried to conduct subgroup analysis
to assess whether adopting PI affects the results, so as to help
physicians in their everyday practice. There is a tendency that PI
is effective when prescribing XZD to the patients who were
diagnosed with blood stasis due to qi stagnation syndrome;
however, no such conclusion can be drawn due to high
heterogeneity observed in the “not adopting PI group”in head
to head design.
4.5. Implications for research
To be used widely for pain relief in clinical practice, XZD should
show superiority or safety over NSAIDs, which are considered as
a standard treatment for primary dysmenorrhea. Future trials
should use international standards and validated scales for pain
such as VAS for evaluating the treatment effects because the
response rate cannot represent the precise degree of improve-
ment. We suggest evaluating VAS during the first 5 days of each
menstrual cycle using a horizontal unmarked VAS of 0 to 10 cm
(0 cm representing no pain; 10 cm, severe pain). Pain scores of
painful days over the first 5 days of menstruation can be averaged
at the screening and end of treatment cycles as overall-pain
intensity.
[42,43]
The average scores of the first 2 menstruation
days can also be calculated to assess the most intensive menstrual
pain. Data regarding the type and frequency of the intake of all
drugs and the use of other remedies, as possible confounders,
need to be collected along with the VAS pain intensity in the
diary.
[42]
Moreover, the outcome assessment in a majority of the trials
occurred immediately following the intervention period, and thus
the information on the persistence of the effect of XZD could not
be gathered. More studies focusing on a long-term follow-up are
needed to examine the effectiveness of XZD for pain relief as well
as to assess the sustainability of the effect. Further studies are also
required not only to determine whether XZD effectively blocks
the dysmenorrheic pain, but also, to assess the possibility of
preventing and ameliorating the risk of the development of
chronic pain disorders in adolescent girls.
[3]
5. Conclusions
The existing trials showed a favorable effect of XZD for the
management of primary dysmenorrhea. However, the efficacy of
XZD on primary dysmenorrhea is not conclusive owing to the
small number of studies and the high risk of bias. Given the poor
reporting and methodological flaws of existing studies, large-
scale, long-term RCTs with rigorous methodological input are
desirable to clarify the role of XZD for the management of
primary dysmenorrhea.
Author contributions
Conceptualization: Jungtae Leem, Junyoung Jo.
Formal analysis: Jungtae Leem, Chan-Young Kwon.
Funding acquisition: Jin Moo Lee.
Investigation: Hojung Lee, Kyoung Sun Park.
Methodology: Junyoung Jo.
Project administration: Kyoung Sun Park.
Resources: Jin Moo Lee, Kyoung Sun Park.
Software: Chan-Young Kwon.
Supervision: Kyoung Sun Park.
Visualization: Junyoung Jo, Chan-Young Kwon.
Writing –original draft: Jungtae Leem, Junyoung Jo.
Writing –review and editing: Jin Moo Lee, Kyoung Sun Park.
Leem et al. Medicine (2019) 98:5 Medicine
10
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