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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

Authors:
  • Conmaul Hospital of Korean Medicine

Abstract and Figures

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.
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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 identiable pathological condition among menstruating women, with the prevalence estimates varying between 45% and 95%.
Nonsteroidal anti-inammatory 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 nally 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% condence 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% condence 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% condence 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
efcacy 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-rst 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 conicts 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 nal 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 =condence interval, MD =mean difference, NSAIDs =
nonsteroidal anti-inammatory drugs, PI =pattern identication, RCT =randomized controlled clinical trial, RR =risk ratio, TCM =
traditional Chinese medicine, VAS =visual analogue scale, VIP =Chinese Scientic 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
identiable 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 signicantly reduced quality of life, low
mood, and poor sleep quality during menstruation as compared
to the women without primary dysmenorrhea.
[3]
Nonsteroidal anti-inammatory 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
identied 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 rst
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 signicant pathological product due to
stagnant blood.
[7,8]
If blood stasis occurs within the body,
characteristic symptoms such as pain in a xed 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 Classicsin 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 Scientic
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 modied 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 randomizationwas used; we included such studies.
Patients with primary dysmenorrhea were included in our review.
Patients with secondary dysmenorrhea due to a specic
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 designthat 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
modied XZD which contains less than 6 modied (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 nally 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, rst 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
identication (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 insufcient 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 dened 3 types of response rates viz. type I, type II,
and type III. In type I category, No effectgroup was dened as
a nonresponder group and the other group (C, M, and I groups)
was dened as a responder group. In type II category, the
responders were dened as those with more than 50%
improvement in the symptoms while the nonresponders were
dened 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 dened the response rate (type III),
according to which any patient whose symptoms showed no
change or showed worsening were classied into nonresponder
group regardless of the treatment response category; while the
others were classied 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 predened 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 nal
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 highrisk
of bias was graded in case of random sequence generation
assessment, where only the word randomizationwas 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% condence
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
signicance 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 xed 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
identied as having an inappropriate design, disease, or
intervention (Supplementary 2, http://links.lww.com/MD/
C771). Eight articles were nally included for qualitative and
quantitative analysis (Fig. 1). Thus, among 475 publications, 8
RCTs involving 1048 patients were nally included 4 studies
were add-on study designthat compared XZD and WM
combination therapy group versus WM sole therapy group.
[1619]
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 designthat compared XZD sole therapy versus WM
sole therapy.
[2124]
We did not nd 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 identied. 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 inammatory diseases, endometri-
osis, or uterine broids, but they did not describe specic 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]
Modication 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 denition 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.
[16,18,19,2224]
XZD
is composed of 11 medicinal herbs. In our review, some studies
allowed modication 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 assessmentand incomplete outcome
datawere graded as unclear in all studies because none of the
Figure 1. PRISMA ow 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 (29)
[17/28/19]
CG) 3.6 ±2.1 (18)
[19/29/16]
TG) 26.5 ±5.2
(1641)
CG) 25.8 ±5.7
(1639)
XZD decoction
+ WM (64)
Fenbid (64) Symptom score
VAS
TRR
[C/M/I/N]
3.78 (MD, 95% CI [4.62, 2.94])
1st, 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])
1.15 (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 (0.34)
[ND]
CG) 1.6 (0.24)
[ND]
TG) 18.6
(1627)
CG) 17.9
(1526)
XZD decoction + WM
(60)
Oryzanol, Thiamine,
(if severe)
Indometacin, Fenbid,
Naproxen
(60)
TRR
[M/I/N]
1.19 (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 (0.58)
[21/23/7]
CG) 2.3 ±0.2 (0.87)
[18/27/6]
TG) 22.5 ±3.2
(1631)
CG) 23.1 ±4.3
(1833)
XZD decoction + WM
(51)
Ibuprofen (51) TRR [C/M/I/N] 1.37 (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 (29)
[34/56/38]
CG) 3.5 ±2.0 (19)
[38/58/32]
TG) 25.4 ±4.8
(1740)
CG) 25.3 ±4.6
(1741)
XZD decoction + WM
(128)
Fenbid (128) Symptom score
VAS
TRR
[C/M/I/N]
3.83 (MD, 95% CI [4.43, 3.23])
1st, 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)}
1.15 (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 (0.59)
[21/27/8]
CG) 4 (0.757)
[19/30/7]
TG) 22 (1631)
CG) 24 (1833)
XZD decoction
(56)
Diclofenac Sodium
(56)
TRR [C/M/I/N] 1.26 (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)
TRR [C/M/I/N]
6 mo recurrence rate
1.07 (RR, 95% CI [0.96, 1.20])
[(TG) 12/10/8/0 (CG) 1/14/13/2]
0.08 (RR, 95% CI [0.01, 0.60])
[(TG) 1 case (CG) 12 cases]
ND
Wang (2015)
[23]
China/ND TG) 7 ±1.2 (0.46)
[33/40/27]
CG) 4.1 ±1.4 (0.68)
[38/42/20]
TG) 25.2 ±1.1
(1634)
CG) 24.8 ±1.3
(1532)
XZD decoction (100) Diclofenac Sodium
(100)
TRR [C/M/I/N] 1.34 (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 (0.411)
[14/32/24]
All) 16.8 ±3.5
(1328)
XZD decoction (35) Symptomatic treatment
of pain (35)
TRR [C/M/I/N] 1.48 (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 denition 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 =condence 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% condence interval [lower limit, upper limit]) in continuous variables or risk ratio (RR, 95% condence interval [lower limit, upper limit]) in dichotomous variables.
Zhang (2015) reported that visual analogue scale (VAS) of 3 month after treatment completion was signicantly 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 nd 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 studythat compared XZD plus WM
combined therapy versus WM sole therapy.
[1619]
(2) head to head design studythat compared XZD sole
therapy versus WM sole therapy.
[2124]
In add-on design studies,VAS)
[16,19]
symptom score,
[16,19]
and response rate
[1619]
were used to examine the effect of XZD,
while in head to head design studies,response rate
[2124]
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,
[1619]
the XZD and WM combined group showed
signicantly 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
identication (PI)
YNYY YNYN
Modication by PI or
symptoms
YYNY YNYY
Treatment cycle 3 3 3 3 3 6 3 3
Denition 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 8810
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
Denition 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 nished 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 identication, 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 signicance
with 95% CI (overlapping), we could not nd 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
signicantly 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 signicantly 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 signicantly 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 nd 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 signicantly 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
signicantly 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,
[2124]
the XZD group showed signicantly
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 Lis (2014) study, the heterogeneity in
the not adopting PI groupwas 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 signicantly 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 ndings
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 sufcient to draw a rm conclusion. Although
reports on AEs were insufcient, 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 inammatory substances,
[27]
which are
considered to be related with pathology or symptoms of
dysmenorrhea.
[28,29]
These results also suggest the benecial 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.
[3133]
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.
[3437]
In our study, XZD has shown some benecial potentials in
treating dysmenorrhea and, considering previous studies, it may
be associated with, at least partially, its anti-inammatory
activity, improving blood circulation, and antinociceptive effect
as well as removing blood stasis.
4.3. Strengths and limitations
This systematic review had a predened 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 reviewersminimized 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 aws 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
ndings 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 ndings
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 groupin 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 rst 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 rst 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 rst 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 efcacy 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 aws 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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Supplementary resource (1)

... A recent systematic review [21] revealed that XFZY has a promising effect on PD management. Some trials also found the efficacy of XFZF on PD. ...
... Another randomized trial found that compared with fenbid solely, XFZY decoction plus fenbid had a better pain intensity relief [28]. But in the review [21], none of the included trials used a placebo as a control or with blinding of participants and personnel. Moreover, most of the previous trials appeared to be of low methodological quality. ...
... This study may be limited in that 3 months of treatment duration may be insufficient for complete PD pain relief. However, a systematic review of XFZY for PD [21] found that the treatment duration was 3 months (menstrual cycles) for all of the included trials, with only one exception [39]. Therefore, we believe that 3 months is a sufficient duration for observing the preliminary clinical effects of XFZY on PD and that an RCT is needed to evaluate the long-term effects. ...
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Background Epidemiological studies have shown that young women often suffer from primary dysmenorrhea (PD) which is a common cause that affects their routine work and quality of life. Chinese herbal medicine has been widely used for PD in China. A systematic review found that Xuefu Zhuyu (XFZY) has a promising effect on PD management, yet there is a dearth of high-quality evidence in support of this claim. We want to conduct a randomized controlled trial to evaluate the efficacy and safety of XFZY for PD patients. Methods This is a protocol for a multicenter, randomized, placebo-controlled trial. A total of 248 participants with PD will be recruited at 6 centers and randomized into two groups—a herbal treatment group and a placebo group. The participants will receive either XFZY or placebo, three times per day, for 3 menstrual cycles, with a 12-week follow-up. The primary outcome will be the mean change in pain intensity as measured by VAS, while the change in menstrual pain duration, the change in peak pain intensity as measured by VAS, the Cox Menstrual Symptom Scale (CMSS), quality of life EQ-5D-5L, cumulative painkiller consumption, and health economics will be included as secondary outcomes. Adverse events will also be reported. Discussion This protocol describes a multicenter, double-blind, randomized, placebo-controlled trial that investigates the efficacy and safety of XFZY for primary dysmenorrhea. Validated evaluation tools will assess dysmenorrhea severity. We believe that this research will provide important evidence regarding the use of XFZY to treat dysmenorrhea. Trial registration Chinese Clinical Trial Registry ChiCTR1900026819 . Registered on 23 October 2019
... Xuefu Zhuyu decoction (XFZYD) has been widely researched and applied clinically for the treatment of blood stasis syndrome (Leem et al., 2019;Tao et al., 2019), which has been described in 'Yi Lin Gai Cuo' (Corrections of Errors Among Physicians) by Wang Qingren in 1830s (Zhou et al., 2014). Blood stasis, characterised by blood flow retardation and stagnation (Goto, 2014;He et al., 2016), is an essential factor for tumourigenesis in TCM theory (Liu et al., 2007;Qian and Wang, 2009). ...
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Background: Tumours are among the most lethal diseases that heavily endanger human health globally. Xuefu Zhuyu Decoction (XFZYD) is a prescription used to treat blood-activating stasis. Although XFZYD has been shown to suppress migration and invasion of tumour cells, the active ingredients, potential targets, and underlying mechanism remain largely elusive. Purpose: To identify the prospective ingredients and major targets of XFZYD against tumours, and evaluate the efficacy and potential molecular mechanisms of XFZYD extract on tumour growth and invasion. Methods: We predicted that XFZYD might act on 80 targets through 128 active components using the network pharmacology analysis method. In addition, we prepared an XFZYD aqueous extract and employed the Ras V12 / lgl −/− -induced Drosophila tumour model to carry out experimental verification. Results: XFZYD did not exhibit any side effects on development, viability, and fertility. Furthermore, XFZYD significantly impeded tumour size and invasion at moderate concentrations and suppressed the increased phosphorylation of JNK but strongly enhanced the expression of Caspase 3 in the Ras V12 / lgl −/− model. Finally, the mRNA level of the transcription complex AP-1 component c-FOS was remarkably reduced. In contrast, the transcription of three pro-apoptotic genes was significantly increased when XFZYD was used to treat the tumour model. Conclusion: The study findings suggest that XFZYD may promote tumour cell apoptosis by activating caspase signalling to control primary growth and hinder tumour cell invasion by suppressing JNK/AP-1 signalling activity, thus providing a potential therapeutic strategy for XFZYD in the clinical treatment of cancer and other related diseases.
... 12 Herbal products are one of the most basic methods of combating diseases, which have a significant advantage over chemical medicines due to more acceptability and fewer side effects. 13,14 Thyme, Fennel, Calendula, Dill extract, Saffron, Teucriumpolium, Bromelain, Fenugreek, Rosemary, and Yarrow have been reported to be effective on dysmenorrhea and menstrual disorders. 15 Due to inadequate number of studies and poor methodology, it is not possible to draw definite conclusions about the effect of these plants. ...
Article
Background: Primary dysmenorrhea is characterized by pain during menstruation without any pelvic pathology. It is a common problem among females in their reproductive age which is caused by increased production of prostaglandin in the endometrium as one of leading causes. Chamomile extract ceases the production of prostaglandins and leukotrienes. The aim of this study was to systematically review the clinical trials to determine the effect of Chamomile on pain and menstural bleeding in primary dysmenorrhea. Methods: Search process to find relevant articles was conducted on electronic Iranian (MagIran, SID) and international databases (Google Scholar, Science Direct, PubMed, ProQuest, Cochrane library, Scopus, Web of Science and EBSCO), using English keywords and Persian equivalents such a "Dysmenorrhea", "Pain", "Menstrual bleeding" and "Chamomil" without a time limit until March 2020. Irrelevant, duplicate, descriptive, or qualitative studies were excluded. To evaluate the quality of articles, we used the Cochran's Risk of Bias tool. Results: Among124 articles found in the initial search, finally 7 clinical trials (with a sample size of 1033) were systematically examined. Two out of 7 studies examined the effect of Chamomile on the pain of primary dysmenorrhea, 2 studies on the effect of Chamomile on menstrual bleeding volume, and 3 on the effect of Chamomileon pain and menstural bleeding in primary dysmenorrhea. Conclusion: Based on results of the most reviewed studies, Chamomile can be considered as an effective treatment for primary dysmenorrhea and reducing menstrual bleeding.
... Herbal medicine has been used in China for many years to treat PD [6][7][8][9][10]. Ge-Gen decoction (GGD, Kakkon-to in Japanese) is a traditional Chinese prescription that is widely applied in the clinical treatment of PD [11,12]. ...
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Ge-Gen decoction (GGD) is widely used for the treatment of primary dysmenorrhea (PD) in China. However, the mechanisms that underlie this effect are unclear. We investigated the protective mechanism of GGD in a rat model of PD using label-free quantitative proteomics. The model was established by the administration of estradiol benzoate and oxytocin. Thirty rats were divided into three groups (ten rats/group): a control group (normal rats), a model group (PD rats), and a treatment group (PD rats treated with GGD). The serum levels of prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) were measured by ELISA. Nanohigh-performance liquid chromatography-tandem mass spectrometry (nano-HPLC-MS/MS) was used to identify differentially expressed proteins (DEPs), and bioinformatics was used to investigate the protein function. Proteomic data were validated by western blot analysis. Oxytocin-induced writhing responses and abnormal serum levels of PGE2 and PGF2α were reversed following the administration of GGD. A total of 379 DEPs were identified; 276 were identified between the control group and the model group, 144 were identified between the model group and the treatment group, and 41 were identified as DEPs that were common to all groups. Bioinformatics revealed that the DEPs between the control group and the model group were mainly associated with cellular component biogenesis and binding processes. The DEPs between the model group and the treatment group were mainly involved in the protein binding and metabolic process. The expression levels of HSP90AB1 and the phosphorylation levels of ERK, JNK, and P-p38 in the uteri of rats in the three groups were consistent with the proteomic findings; MAP kinases (ERK, JNK, and p38) are known to be involved in the production of inflammatory cytokines and oxytocin signaling while HSP90AB1 is known to be associated with estrogen signaling. Collectively, these data indicate that GGD may exert its protective function on PD by regulating the inflammatory response and signaling pathways associated with oxytocin and estrogen. 1. Introduction Primary dysmenorrhea (PD) refers to recurrent menstrual cramps caused by uterine contractions [1, 2]. This condition affects 40%–50% of adolescent women and can have a disruptive effect on a patient’s quality of life [1–3]. The most common medications for treating PD are oral contraceptives, analgesics, and nonsteroidal anti-inflammatory drugs (NSAIDs) [4, 5]. However, these drugs may induce a range of side effects and are associated with a failure rate of up to 25% [4, 5]. Thus, there is an urgent need to develop new, safe, and effective, therapeutic options for the treatment of PD. Herbal medicine has been used in China for many years to treat PD [6–10]. Ge-Gen decoction (GGD, Kakkon-to in Japanese) is a traditional Chinese prescription that is widely applied in the clinical treatment of PD [11, 12]. GGD is developed from Shang Han Za Bing Lun and is composed of Pueraria lobata (Ge Gen), Ephedrae (Ma Huang), cinnamon twig (Gui Zhi), Paeonia lactiflora (Shao Yao), ginger (Sheng Jiang), Glycyrrhizae radix et rhizome (Zhi Gan Cao), and red dates (Hong Zao) in a specific ratio (4 : 1 : 3 : 3 : 2 : 2 : 4) [13, 14]. Previous studies revealed that Paeonia lactiflora, Glycyrrhizae Radix et Rhizoma, and ginger could exert antidysmenorrhea effects [12]. Cinnamic acid and cinnamaldehyde, the two major constituents of cinnamon twig, have also been reported to inhibit uterine contractions induced by oxytocin [10, 15]. Furthermore, ephedrine, a major constituent of Ephedrae, has been shown to relax smooth muscle and activate β-adrenoceptors [12, 14]. However, the molecular mechanisms that underlie the protective effect of GGD in patients with PD have yet to be elucidated. In this study, we used label-free quantitative proteomics to investigate the effects of the GGD administration in a rat model of PD. 2. Materials and Methods 2.1. GGD Preparation GGD was obtained by the Jiangsu Province Hospital of Chinese Medicine (Jiangsu, China) and consisted of seven components (Table 1). The principal components of GGD were prepared and systematically identified using methodology described previously [14]. Component Part Weight (g) Pueraria lobata (Ge Gen) Root 20 Ephedra (Ma Huang) Twigs 5 Cinnamon twig (Gui Zhi) Twigs 15 Paeonia lactiflora (Shao Yao) Root 15 Glycyrrhizae radix et rhizome (ZhiGanCao) Rhizome and root 10 Ginger (Sheng Jiang) Root 10 Red dates (Hong Zao) Fruit 20
... [14][15][16][17] It consists of herbal medicine, acupuncture, moxibustion, Tui-na, and any others. [14][15][16][17][18][19][20][21][22] Studies suggested that TCM can manage PD in UK. [23,24] However, there is still insufficient evidence to support the clinical efficacy and safety of TCM for PD in UK. Thus, this study will explore the clinical efficacy and safety of TCM for the treatment of PD in UK systematically and comprehensively. ...
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Background: This study aims to appraise the clinical efficacy of traditional Chinese medicine (TCM) for the management of patients with primary dysmenorrhea (PD) in the UK. Methods: We will comprehensively search electronic databases (Cochrane Library, PUBMED/MEDLINE, EMBASE, PsycINFO, AMED, Web of Science, and CNKI) and additional resources for original articles on randomized controlled trials published in English, Chinese, German, Spanish, Korean and Japanese. Outcomes will be the pain intensity, pain duration, menstrual cramps, amount of bleeding, and severity of dysmenorrhea symptoms, quality of life, and adverse events. Two authors will independently check all citations, extract data, and assess study quality. All potential conflicts will be solved through discussion by consulting another experienced author. A narrative synthesis will summarize the characteristics and findings of eligible trials. If it is possible, we will also pool the data and carry out meta-analysis. Results: The available evidence of the clinical efficacy of TCM for the treatment of PD in UK will be assessed through outcome measurements. Conclusion: The findings of this study will determine whether or not TCM is effective and safe for the treatment of PD in UK. OSF REGISTRATION NUMBER:: osf.io/jyc95.
... Pain, self-rating anxiety scale, self-rating depression scale and Quality of Life Scale are listed as secondary outcomes along with an ambitious monitoring of gene expression and biochemical parameters. Notably, XFZY has been used in CHM as a treatment of primary dysmenorrhea, indicating a possible link to endometriosis (Leem et al., 2019). ...
Article
Background: Given the disadvantages and limitations of current endometriosis therapy, there is a progressive increase in studies focusing on plant-derived agents as a natural treatment option with the intention of achieving high efficiency, avoiding adverse effects and preserving the chance for successful pregnancy. The heterogeneity of these studies in terms of evaluated agents, applied approaches and outcomes illustrates the need for an up-to-date summary and critical view on this rapidly growing field in endometriosis research. Objective and rationale: This review provides a comprehensive overview of plant-derived agents and natural treatment strategies that are under preclinical or clinical investigation and critically evaluates their potential for future endometriosis therapy. Search methods: An English language PubMed literature search was performed using variations of the terms 'endometriosis', 'natural therapy', 'herb/herbal', 'plant', 'flavonoid', 'polyphenol', 'phytochemical', 'bioactive', 'Kampo' and 'Chinese medicine'. It included both animal and human studies. Moreover, the Clinicaltrials.gov database was searched with the term 'endometriosis' for clinical trials on plant-derived agents. No restriction was set for the publication date. Outcomes: Natural therapies can be assigned to three categories: (i) herbal extracts, (ii) specific plant-derived bioactive compounds and (iii) Chinese herbal medicine (CHM). Agents of the first category have been shown to exert anti-proliferative, anti-inflammatory, anti-angiogenic and anti-oxidant effects on endometrial cells and endometriotic lesions. However, the existing evidence supporting their use in endometriosis therapy is quite limited. The most studied specific plant-derived bioactive compounds are resveratrol, epigallocatechin-3-gallate, curcumin, puerarin, ginsenosides, xanthohumol, 4-hydroxybenzyl alcohol, quercetin, apigenin, carnosic acid, rosmarinic acid, wogonin, baicalein, parthenolide, andrographolide and cannabinoids, with solid evidence about their inhibitory activity in experimental endometriosis models. Their mechanisms of action include pleiotropic effects on known signalling effectors: oestrogen receptor-α, cyclooxygenase-2, interleukin-1 and -6, tumour necrosis factor-α, intercellular adhesion molecule-1, vascular endothelial growth factor, nuclear factor-kappa B, matrix metalloproteinases as well as reactive oxygen species (ROS) and apoptosis-related proteins. Numerous studies suggest that treatment with CHM is a good choice for endometriosis management. Even under clinical conditions, this approach has already been shown to decrease the size of endometriotic lesions, alleviate chronic pelvic pain and reduce postoperative recurrence rates. Wider implications: The necessity to manage endometriosis as a chronic disease highlights the importance of identifying novel and affordable long-term safety therapeutics. For this purpose, natural plant-derived agents represent promising candidates. Many of these agents exhibit a pleiotropic action profile, which simultaneously inhibits fundamental processes in the pathogenesis of endometriosis, such as proliferation, inflammation, ROS formation and angiogenesis. Hence, their inclusion into multimodal treatment concepts may essentially contribute to increase the therapeutic efficiency and reduce the side effects of future endometriosis therapy.
... Mefenamic acid is a common NSAID but cause a range of adverse effects such as diarrhea, stomachache, and nausea to serious illness such as chronic renal disease and osteoporosis (20). Nowadays, complications of chemical drugs have shifted the attention of people and researchers to complementary therapies (21,22). ...
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Background Dysmenorrhea is one of the most common pelvic pains in women, impairing their quality of life.This study investigated the effects of chamomile sachet and mefenamic acid on primary dysmenorrhea, associated symptoms and bleeding. Methods In this randomized clinical trial, 200 female students with primary dysmenorrhea from Arak universities were randomly assigned to two groups. The group (A) received mefenamic acid (250 mg) and group (B) received chamomile (5000 mg) plus one teaspoonful of honey )as a flavoring( for two days before up to the first three days of menstruation, three times a day in two consecutive cycles. Pain severity, associated symptoms and bleeding were assessed using visual analog scale, Andersch-Milsom Verbal Scale and Higham chart, respectively. Data were analyzed by descriptive and inferential statistical tests by SPSS 21. Results Severe pain during two months after intervention was in 6 (6.3%) of group (B) and 6 (6.3%) in group (A) (p = 0.351, p = 0.332). Mean severity of associated symptoms two months after the treatment was( 4.93 ± 3.54) in group (B) and (5.62 ± 3.54 ) in group (A), indicating further reduction in group (B) but not significant (p = 0.278). Mean of bleeding was (88.71 ± 66.4 vs. 70.54 ± 53. 34) in group (B) and (A) respectively, in two months later. therefore decrease in the two groups but was not significant between groups(p = 0.567). Conclusions It seems chamomile sachet can reduce the severity of pain and bleeding similar to mefenamic acid and even further mitigate the symptoms associated with dysmenorrhea. Trial registration This study was performed with the proposal approval code of 2611, ethics code of (ARAKMU.REC.1395.164) at Arak University of medical sciences and code of IRCT 2016100825031N5 on 2016.11.08.
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Dysmenorrhea disorder is a significant concern of this era in young girls at the stage of the menarche or near menstrual period. Primary dysmenorrhea is prevailing all around the world. Objectives: To evaluate reducing effects of Cinnamon, vitamin D and starch capsules in patients suffering from dysmenorrhea. Methods: The 30 candidates for each group were selected following the minimum sample size rule. The questionnaire and numeric pain rating scale were the main tools for assessing dysmenorrhea severity, reduction in dysmenorrhea, quality of life and other variables in patients. Results: The demographic data showed that the maximum participants belonged to middle-class families, well-educated and living in their own homes. The results depicted that Cinnamon reduced pain severity, bleeding and physical pain and improved physical activity, leisure activities, life satisfaction, health services, meaningful life and body appearance among most participants. Likewise, vitamin D also exhibited a significant reduction in dysmenorrhea symptoms and increased the quality of life among most patients. However, the effects of starch capsules were observed to be less effective than the cinnamon tea and vitamin D. Conclusions: The study concluded that cinnamon tea and vitamin D were the best therapy for reducing dysmenorrhea symptoms.
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A high occurrence of primary dysmenorrhea denotes a considerable female health concern. The objective of this study has been to evaluate the efficacy of topical application of a synergistic blend of plant-extracts oil in relieving the symptoms of primary dysmenorrhea (menstrual pain, pain duration, and menstrual flow). The study design was randomized, double-blind, multi-phasic and was a placebo-controlled cross-over study. Participants were females, 18-20 years old with regular cycles and suffering from symptoms of primary dysmenorrhea. Sixty-four participants were randomly allocated to apply either the test oil or the placebo for first phase of the study. For the second phase, the interventions were switched. It was assessed that topical application of the oil significantly and efficiently reduced 1) menstrual pain within 30 minutes during the first three days of menstruation, 2) duration of menstrual pain during the first three days of menstruation, and 3) amount of menstrual flow as compared to the placebo.
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Ethnopharmacological relevance The species Lippia origanoides Kunth, popularly known as “salva-de-marajó”, is used in Brazilian traditional “quilombola” communities to treat menstrual cramps and uterine inflammation. Aim of the study Evaluate the spasmolytic activity of Lippia origanoides essential oil (LOO) on experimental models of uterine conditions related to menstrual cramps and investigate its mechanism of action. Materials and methods Virgin rat-isolated uterus was mounted in the organ bath apparatus to evaluate the spasmolytic effect of LOO on basal tonus and contractions induced by carbachol, KCl, or oxytocin. We used pharmacological agents to verify the relaxation mechanism of LOO. The evaluation of uterine contractility in virgin rats, after treatment with LOO for three consecutive days, was carried out by the construction of a concentration-response curve with oxytocin or carbachol. The primary dysmenorrhea animal model was replicated with an injection of estradiol cypionate in female mice for three consecutive days, followed by intraperitoneal application of oxytocin. Results LOO relaxed the rat uterus precontracted with 10⁻² IU/mL oxytocin (logEC50 = 1.98 ± 0.07), 1 μM carbachol (logEC50 = 1.42 ± 0.07) or 60 mM KCl (logEC50 = 1.53 ± 0.05). It was also able relax uterus on spontaneous contractions (logEC50 = 0.41 ± 0.05). Preincubation with glibenclamide, propranolol, phentolamine or L-NAME in contractions induced by carbachol did not alter significantly the relaxing effect of LOO. However, in the presence of 4-aminopyridine, CsCl or tetraethylammonium there was a reduction of LOO potency, whereas the blockers methylene blue, ODQ, aminophylline and heparin potentiated the LOO relaxing effect. Preincubation with LOO in a Ca²⁺ free medium at concentrations of 27 μg/mL or 81 μg/mL reduced the contraction induced by carbachol. The administration of LOO for 3 days did not alter uterus contractility. The treatment with LOO at 30 or 100 mg/kg intraperitoneally, or 100 mg/kg orally, inhibited writhing in female mice. The association of LOO at 10 mg/kg with nifedipine or mefenamic acid potentiated writhing inhibition in mice. Conclusions The essential oil of L. origanoides has tocolytic activity in rat isolated uterus pre-contracted with KCl, oxytocin, or carbachol. This effect is possibly related to the opening of potassium channels (Kir, KV, and KCa), cAMP increase, and diminution of intracellular Ca²⁺. This relaxant effect, probably, contributed to reduce the number of writhings in an animal model of dysmenorrhea being potentiated by nifedipine or mefenamic acid. Taken together, the results here presented indicate that this species has a pharmacological potential for the treatment of primary dysmenorrhea, supporting its use in folk medicine.
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Purpose: Wenjing decoction is a well-accepted traditional Chinese medicine for the treatment of primary dysmenorrhea in East Asia, but its clinical effectiveness and risk have not been adequately assessed. In this paper, we conducted a systematic review and meta-analysis to evaluate the efficacy of Wenjing decoction for the treatment of primary dysmenorrhea. Methods: Eight databases were used in our research: the Cochrane Library, the Web of Science, PubMed, EMBASE, the Chinese Biomedical Literature Database (CBM), the Chinese National Knowledge Infrastructure (CNKI), the Chinese Scientific Journal Database, and the Wan-fang Database. The following search terms were used: (Wenjing decoction OR Wenjing formula OR Wenjing tang) AND (primary dysmenorrhea OR dysmenorrhea OR painful menstruation) AND (randomized controlled trial). No language limitation was used. Results: A total of 18 studies, including 1736 patients, were included in the meta-analysis. Wenjing decoction was shown to be significantly better than nonsteroidal anti-inflammatory drugs for the improvement of primary dysmenorrhea according to the clinical effective rate (RR 1.41, 95% CI 1.24-1.61), the visual analogue scale (MD -1.77, 95% CI -2.69 to -0.84), and the pain scale for dysmenorrhea (MD -1.81, 95% CI -2.41 to -1.22). Conclusions: The results supported the clinical use of Wenjing decoction for the treatment of primary dysmenorrhea. However, the quality of the evidence for this finding was low due to a high risk of bias in the included studies. Therefore, well-designed randomized controlled trials are still needed to further evaluate the efficacy of Wenjing decoction for the treatment of primary dysmenorrhea.
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Introduction Primary dysmenorrhoea is menstrual pain without pelvic pathology and is the most common gynaecological condition in women. Xuefu Zhuyudecoction (XZD) or Hyeolbuchukeo-tang, a traditional herbal formula, has been used as a treatment for primary dysmenorrhoea. The purpose of this study is to assess the current published evidence regarding XZD as treatment for primary dysmenorrhoea. Materials and methods The following databases will be searched from their inception until April 2017: MEDLINE (via PubMed), Allied and Complementary Medicine Database (AMED), EMBASE, The Cochrane Library, six Korean medical databases (Korean Studies Information Service System, DBPia, Oriental Medicine Advanced Searching Integrated System, Research Information Service System, Korea Med and the Korean Traditional Knowledge Portal), three Chinese medical databases (China National Knowledge Infrastructure (CNKI), Wan Fang Database and Chinese Scientific Journals Database (VIP)) and one Japanese medical database (CiNii). Randomised clinical trials (RCTs) that will be included in this systematic review comprise those that used XZD or modified XZD. The control groups in the RCTs include no treatment, placebo, conventional medication or other treatments. Trials testing XZD as an adjunct to other treatments and studies where the control group received the same treatment as the intervention group will be also included. Data extraction and risk of bias assessments will be performed by two independent reviewers. The risk of bias will be assessed with the Cochrane risk of bias tool. All statistical analyses will be conducted using Review Manager software (RevMan V.5.3.0). Ethics and dissemination This systematic review will be published in a peer-reviewed journal. The review will also be disseminated electronically and in print. The review will benefit patients and practitioners in the fields of traditional and conventional medicine. PROSPERO registration number CRD42016050447.
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Neuroinflammation is central to the pathology of traumatic brain injury (TBI). Xuefu Zhuyu decoction (XFZY) is an effective traditional Chinese medicine to treat TBI. To elucidate its potential molecular mechanism, this study aimed to demonstrate that XFZY functions as an anti-inflammatory agent by inhibiting the PI3K-AKT-mTOR pathway. Sprague-Dawley rats were exposed to controlled cortical impact to produce a neuroinflammatory response. The treatment groups received XFZY (9 g/kg and 18 g/kg), Vehicle group and Sham group were gavaged with equal volumes of saline. The modified neurologic severity score (mNSS) and the Morris water maze test were used to assess neurological deficits. Arachidonic acid (AA) levels in brain tissue were measured using tandem gas chromatography-mass spectrometry. TNF-α and IL-1β levels in injured ipsilateral brain tissue were detected by ELISA. AKT and mTOR expression were measured by western blot analysis. The results indicated that XFZY significantly enhanced spatial memory acquisition. XFZY (especially at a dose of 9 g/kg) markedly reduced the mNSS and levels of AA, TNF-α and IL-1β. Significant downregulation of AKT/mTOR/p70S6K proteins in brain tissues was observed after the administration of XFZY (especially at a dose of 9 g/kg). XFZY may be a promising therapeutic strategy for reducing inflammation in TBI.
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Background: Dysmenorrhoea refers to painful menstrual cramps and is a common gynaecological complaint. Conventional treatments include non-steroidal anti-inflammatory drugs (NSAIDs) and oral contraceptive pills (OCPs), which both reduce myometrial activity (contractions of the uterus). A suggested alternative approach is dietary supplements. We used the term 'dietary supplement' to include herbs or other botanical, vitamins, minerals, enzymes, and amino acids. We excluded traditional Chinese medicines. Objectives: To determine the efficacy and safety of dietary supplements for treating dysmenorrhoea. Search methods: We searched sources including the Cochrane Gynaecology and Fertility Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, AMED, PsycINFO (all from inception to 23 March 2015), trial registries, and the reference lists of relevant articles. Selection criteria: We included randomised controlled trials (RCTs) of dietary supplements for moderate or severe primary or secondary dysmenorrhoea. We excluded studies of women with an intrauterine device. Eligible comparators were other dietary supplements, placebo, no treatment, or conventional analgesia. Data collection and analysis: Two review authors independently performed study selection, performed data extraction and assessed the risk of bias in the included trials. The primary outcomes were pain intensity and adverse effects. We used a fixed-effect model to calculate odds ratios (ORs) for dichotomous data, and mean differences (MDs) or standardised mean differences (SMDs) for continuous data, with 95% confidence intervals (CIs). We presented data that were unsuitable for analysis either descriptively or in additional tables. We assessed the quality of the evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods. Main results: We included 27 RCTs (3101 women). Most included studies were conducted amongst cohorts of students with primary dysmenorrhoea in their late teens or early twenties. Twenty-two studies were conducted in Iran and the rest were performed in other middle-income countries. Only one study addressed secondary dysmenorrhoea. Interventions included 12 different herbal medicines (German chamomile (Matricaria chamomilla, M recutita, Chamomilla recutita), cinnamon (Cinnamomum zeylanicum, C. verum), Damask rose (Rosa damascena), dill (Anethum graveolens), fennel (Foeniculum vulgare), fenugreek (Trigonella foenum-graecum), ginger (Zingiber officinale), guava (Psidium guajava), rhubarb (Rheum emodi), uzara (Xysmalobium undulatum), valerian (Valeriana officinalis), and zataria (Zataria multiflora)) and five non-herbal supplements (fish oil, melatonin, vitamins B1 and E, and zinc sulphate) in a variety of formulations and doses. Comparators included other supplements, placebo, no treatment, and NSAIDs.We judged all the evidence to be of low or very low quality. The main limitations were imprecision due to very small sample sizes, failure to report study methods, and inconsistency. For most comparisons there was only one included study, and very few studies reported adverse effects. Effectiveness of supplements for primary dysmenorrhoea We have presented pain scores (all on a visual analogue scale (VAS) 0 to 10 point scale) or rates of pain relief, or both, at the first post-treatment follow-up. Supplements versus placebo or no treatmentThere was no evidence of effectiveness for vitamin E (MD 0.00 points, 95% CI -0.34 to 0.34; two RCTs, 135 women).There was no consistent evidence of effectiveness for dill (MD -1.15 points, 95% CI -2.22 to -0.08, one RCT, 46 women), guava (MD 0.59, 95% CI -0.13 to 1.31; one RCT, 151 women); one RCT, 73 women), or fennel (MD -0.34 points, 95% CI -0.74 to 0.06; one RCT, 43 women).There was very limited evidence of effectiveness for fenugreek (MD -1.71 points, 95% CI -2.35 to -1.07; one RCT, 101 women), fish oil (MD 1.11 points, 95% CI 0.45 to 1.77; one RCT, 120 women), fish oil plus vitamin B1 (MD -1.21 points, 95% CI -1.79 to -0.63; one RCT, 120 women), ginger (MD -1.55 points, 95% CI -2.43 to -0.68; three RCTs, 266 women; OR 5.44, 95% CI 1.80 to 16.46; one RCT, 69 women), valerian (MD -0.76 points, 95% CI -1.44 to -0.08; one RCT, 100 women), vitamin B1 alone (MD -2.70 points, 95% CI -3.32 to -2.08; one RCT, 120 women), zataria (OR 6.66, 95% CI 2.66 to 16.72; one RCT, 99 women), and zinc sulphate (MD -0.95 points, 95% CI -1.54 to -0.36; one RCT, 99 women).Data on chamomile and cinnamon versus placebo were unsuitable for analysis. Supplements versus NSAIDSThere was no evidence of any difference between NSAIDs and dill (MD 0.13 points, 95% CI -1.01 to 1.27; one RCT, 47 women), fennel (MD -0.70 points, 95% CI -1.81 to 0.41; one RCT, 59 women), guava (MD 1.19, 95% CI 0.42 to 1.96; one RCT, 155 women), rhubarb (MD -0.20 points, 95% CI -0.44 to 0.04; one RCT, 45 women), or valerian (MD points 0.62 , 95% CI 0.03 to 1.21; one RCT, 99 women),There was no consistent evidence of a difference between Damask rose and NSAIDs (MD -0.15 points, 95% CI -0.55 to 0.25; one RCT, 92 women).There was very limited evidence that chamomile was more effective than NSAIDs (MD -1.42 points, 95% CI -1.69 to -1.15; one RCT, 160 women). Supplements versus other supplementsThere was no evidence of a difference in effectiveness between ginger and zinc sulphate (MD 0.02 points, 95% CI -0.58 to 0.62; one RCT, 101 women). Vitamin B1 may be more effective than fish oil (MD -1.59 points, 95% CI -2.25 to -0.93; one RCT, 120 women). Effectiveness of supplements for secondary dysmenorrhoea There was no strong evidence of benefit for melatonin compared to placebo for dysmenorrhoea secondary to endometriosis (data were unsuitable for analysis). Safety of supplements Only four of the 27 included studies reported adverse effects in both treatment groups. There was no evidence of a difference between the groups but data were too scanty to reach any conclusions about safety. Authors' conclusions: There is no high quality evidence to support the effectiveness of any dietary supplement for dysmenorrhoea, and evidence of safety is lacking. However for several supplements there was some low quality evidence of effectiveness and more research is justified.
Article
Shaofu Zhuyu decoction (SFZY), a traditional herbal formula, is used as a treatment for primary dysmenorrhea. We searched four English, seven Korean, three Chinese, and one Japanese database from inception through January 2016 without a language restriction. All randomized controlled trials (RCTs) of SFZY or modified SFZY (MSFZY) were included. Data extraction and risk of bias assessments were performed by two independent reviewers. A total of 51 potentially relevant studies were identified, and 9 RCTs met our inclusion criteria. Seven RCTs tested the effects of SFZY or modified SFZY in treating dysmenorrhea. Three RCTs showed superior effects of (M)SFZY on the response rate, while the other three RCTs failed to do so (n = 531, RR: 1.17, 95% CI: 1.09 to 1.26, P < 0.0001, I2 = 0%). Three RCTs showed favourable effects of MSFZY for pain reduction compared with conventional drugs (n = 340, SMD: −1.39, 95% CI: −2.23 to −0.55, P = 0.01). Two RCTs examined the effects of modified SFZY plus conventional drugs and conventional drugs alone. The meta-analysis showed favourable effects of MSFZY (n = 206; RR, 1.12; 95% CI 1.08 to 1.36; P = 0.0009, I2 = 0%). Our systemic review and meta-analysis provide suggestive evidence of the superiority of SFZY over conventional drugs for treating primary dysmenorrhea. However, the level of evidence is low because of a high risk of bias.
Article
Danggui Shaoyao San (DSS), a traditional herbal prescription, has long been used to treat menopause-related symptoms, including dysmenorrhea. We conducted a systematic review of randomized controlled trials to evaluate the efficacy of DSS for dysmenorrhea. We searched the following electronic databases through October 2015: PubMed; EMBASE; the Cochrane Library; AMED; five Korean databases (KoreaMed, DBPIA, OASIS, RISS, and KISS); three Chinese databases (CNKI, Wan Fang Database, and VIP), and one Japanese database (CiNii). The Cochrane criteria were used to assess the risk of bias for the individual studies. All randomized clinical trials (RCTs) of DSS or modified DSS were included. Data from all articles were extracted by two independent reviewers. Meta-analysis was used to pool the data. A total of 746 potentially relevant studies were identified, and four RCTs met our inclusion criteria. All of the included RCTs had a high risk of bias across their domains. Three RCTs showed favourable effects of DSS on response rate compared with conventional medicine, and a meta-analysis showed that DSS had superior effects compared to analgesics (RR: 1.31, 95%CI, 1.06–1.63, I2 = 73%). One RCT showed a beneficial effect of DSS on pain compared with placebo control. Our systematic review and meta-analysis provided suggestive evidence of the superiority of DSS over analgesics or placebo for dysmenorrhea. The quality of evidence for this finding was low to moderate because of a high risk of bias.