September 2006Volume 86, Issue
3, Pages 762–764
Stephen Kennedy, M.D., M.R.C.O.G.
Correspondence information about the author M.D., M.R.C.O.G. Stephen Kennedy
Email the author M.D., M.R.C.O.G. Stephen Kennedy
, Correspondence information about the author M.D., M.R.C.O.G. Stephen KennedyEmail the author M.D., M.R.C.O.G. Stephen Kennedy
Xu Jin, Ph.D.
,
Hongwen Yu, M.Sc.
,
Shouming Zhong, Ph.D.
,
Patrick Magill, M.D.
,
Trinette van Vliet, Ph.D.
,
Cor Kistemaker, B.Sc.
,
Christine Voors, M.D.
,
Wilrike Pasman, Ph.D.
Article Info
A
proof-of-concept study to assess the safety and efficacy of a
traditional Chinese medicine formula as treatment for primary
dysmenorrhea showed no statistically significant benefit over placebo.
However, some efficacy parameters suggested possible superiority of the
active treatment and so a larger study needs to be performed to
determine whether this remedy has a role in the treatment of
dysmenorrhea.
In
the Western world, the drugs most commonly prescribed for dysmenorrhea
are nonsteroidal antiinflammatory drugs (NSAIDs), analgesics, and
combined oral contraceptives (COCs), despite some reluctance to use the
COC from a young age because of possible long-term health risks.
Nonsteroidal antiinflammatory drugs are beneficial, and aspirin is
likely to be beneficial, but the efficacy of COCs when taken
conventionally is uncertain (1).
Various herbal medicines have been used for centuries, and in the
Chinese literature we have accessed, 83%–97% efficacy is reported for a
range of traditional Chinese medicine (TCM) remedies. However, such
studies do not generally conform to Western standards, and detailed data
often are inaccessible, which makes it difficult to evaluate TCM
properly (2).
In the Western literature, no randomized controlled trials (RCTs) of
TCM remedies have been published for the treatment of dysmenorrhea (3),
although in a controlled clinical trial, a Japanese herbal remedy,
toki-shakuyaku-san, has been shown to relieve pain and reduce the need
for rescue medication compared with placebo (4). We evaluated, as a potential treatment for dysmenorrhea, a TCM formula consisting of three ingredients: root of Angelica sinensis, root of Paeonia lactiflora, and rhizome of Corydalis yanhusuo. These were chosen on the basis of their previously reported safety and efficacy in the Chinese literature.
We
performed a randomized, parallel-group, placebo-controlled,
double-blind trial with blinded evaluation and statistical analysis of
results. It was conducted in The Netherlands (Zeist) by TNO Quality of
Life, a contract organization in the field of life sciences, in
collaboration with the University of Oxford. The study received ethics
approval in Oxford and The Netherlands. The participants were recruited
from a pool of subjects at TNO Quality of Life by using the following
key inclusion criteria: women aged 18–45 years, with menstrual cycles
occurring every 21–42 days and with dysmenorrhea who usually required
and obtained relief from analgesia and/or whose daily functioning was
significantly impaired. If the menstrual cycle was not regular, women
had to be aware in advance that menstruation was likely to commence.
During the study, they had to be willing to refrain from taking other
drugs, stimulants, or tranquilizers; they also were asked to maintain
their normal diet, mealtimes, and drinking and smoking habits. Key
exclusion criteria were the following: known to have pathology
associated with dysmenorrhea, such as endometriosis and/or adenomyosis;
concurrent use of an intrauterine contraceptive device; concurrent use
of any other TCM, alternative therapy, or herbal remedy for
dysmenorrhea; likely to take analgesics, sedatives, or muscle relaxants
in the 48 hours before menstruation; use of mood-altering medication;
and not willing to use reliable contraception if sexually active.
Before
starting treatment, all subjects were observed over one menstrual
cycle. They then were divided into two groups, an intervention group
treated with the TCM remedy and a control group given placebo tablets
that were indistinguishable in appearance. A computer-generated
randomization list, prepared by an independent statistician, was used to
allocate the participants randomly to one or the other group. The
randomization list was drawn up for 44 entry numbers to provide for
dropouts. Block length was such that at each stage, approximately equal
numbers were allocated to each group, and of the first 40 numbers, 20
were allocated to each group. The investigator was supplied with sealed
envelopes containing the treatment allocation; the sealed code was kept
at the pharmacy. Treatment continued for three consecutive menstrual
cycles, after which the women were observed over one menstrual cycle
without treatment.
The women in both groups took three
tablets twice per day for 7 days, commencing 2 days before the
anticipated start of menstruation. The active tablets contained a
concentrated formulation of A. sinensis, P. lactiflora, and C. yanhusuo (in a ratio of approximately 1:1.5:1). The doses were in the middle range of those recommended in the Pharmacopoeia of the People’s Republic of China (5).
They also were consistent with the doses contained in products that are
commercially available in China; for example, Yuan Hu Zhi Tong Pian and
Dang Gui Jing Gao Pian contain concentrated extracts of C. yanhusuo and A. sinensis,
respectively, at equivalent dry-herb doses of 6.6 and 6.0 g/d. The
Institute for Medicinal Plant Development (Beijing, China) sourced the
herbs and extracted the concentrated ingredients in ethanol. The tablets
were manufactured in the United Kingdom with strict quality controls to
ensure dose consistency. The placebo tablets, which also were
manufactured in the United Kingdom, contained sugar beet fiber and
maltodextrin. Tablets were swallowed whole without chewing, with water,
at breakfast and dinner. Within 7 days of the end of each menstrual
period, the women were seen and compliance was evaluated by counting the
number of unused tablets. Ibuprofen tablets (200 mg) were provided as
rescue medication; ≤6/d could be taken to relieve dysmenorrhea if
necessary.
Efficacy was measured by assessing the effect on dysmenorrhea intensity by using a 100-mm visual analog scale (VAS) (6),
scored in a daily diary from 2 days before the anticipated start of
menstruation until the end of menstruation. Other endpoints included the
duration of dysmenorrhea, the amount of rescue medication used, and a
global assessment of treatment; safety was assessed by using standard
hematological and biochemical tests. The RCT was designed as a pilot
study, and therefore no formal statistical sample size estimation was
performed, although it was hoped that the sample size of 40, as used in a
previous study (4),
would give sufficient discrimination to allow a definitive phase II
study to be powered. The data were analyzed using three different
statistical approaches, given that the analysis of repeated measurements
depends on different assumptions: [1] mixed-model analysis based on
specific covariance structures; [2] univariate analysis of variance, and
[3] multivariate and univariate analysis after linear transformations.
All analyses were performed using SAS/STAT V8.2 software, according to a
repeated-measurement analysis of a parallel design. The procedure
compares mutually supplementary tests on quality, model fit, and
statistical significance to give a complete insight into possible
treatment effects. The null hypothesis (no treatment effect) was
rejected at the .05 level of probability in all statistical tests
performed.
Forty-one women who were drawn from the
general population participated in the observation cycle. Three withdrew
before randomization, and the remaining 38 were randomized and started
treatment. One woman dropped out in the first treatment cycle because of
irregular menstruation, and another withdrew for personal reasons in
the second treatment cycle. Their data were not analyzed; both had been
allocated to the TCM remedy. All the remaining 36 women completed the
study. The mean ± SD ages of those in the TCM (n = 17) and placebo (n =
19) groups were 30 ± 7 and 30 ± 9 years, respectively; their mean body
mass indices were 22.6 ± 2.5 and 23.8 ± 4.1 kg/m2. Compliance was 99.9%; only 4 of 4,536 tablets allocated were not used.
To
determine whether the worst pain experienced during menstruation
changed, the maximal pain scores (Cmax) and total pain (area under the
curve [AUC]) were examined over time and between treatments. The values
were highest during the initial observation cycle, but there was no
difference between the treatment groups in terms of any effect on the
worst pain experienced during each period (Table 1).
Over time, neither Cmax nor the AUC within each cycle were reduced at
the time of taking rescue medication. Similarly, there was no evidence
within each cycle of any reduction in the following: [1] the total
number of days of pain or use of rescue medication or [2] the amount of
rescue medication used on the day of maximum pain (data not shown).
Although not statistically significant, the amount of ibuprofen used as
rescue medication was lower in the TCM group in treatment cycle 2 but
not in cycle 3. However, after cycle 3, 5 (26%) of 19 women in the
placebo group reported less pain than normal, compared with 9 (53%) of
17 in the TCM group (P=.10). Headache was the most frequently
reported side effect, with equal frequency in both groups. There were no
serious adverse events and no clinically relevant changes in laboratory
values; the global assessment data were similar in both groups.
| Treatment | Obs | Study period | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Observation cycle | Treatment cycle 1 | Treatment cycle 2 | Treatment cycle 3 | Follow-up cycle | |||||||
| Mean | SD | Mean | SD | Mean | SD | Mean | SD | Mean | SD | ||
| Cmax dysmenorrhoea intensity | |||||||||||
| Placebo | 95 | 76 | 14 | 67 | 27 | 57 | 28 | 61 | 31 | 60 | 30 |
| ONP-21 | 85 | 77 | 19 | 59 | 28 | 58 | 36 | 51 | 36 | 61 | 28 |
| AUCt dysmenorrhoea intensity (area) | |||||||||||
| Placebo | 95 | 186 | 73 | 123 | 69 | 115 | 84 | 134 | 102 | 138 | 119 |
| ONP-21 | 85 | 207 | 84 | 128 | 83 | 130 | 97 | 112 | 88 | 150 | 84 |
ONP-21 = TCM formula; obs = number of observations
Kennedy. TCM RCT in primary dysmenorrhea. Fertil Steril 2006.
Kennedy. TCM RCT in primary dysmenorrhea. Fertil Steril 2006.
To
the best of our knowledge, this is the first properly conducted RCT to
evaluate the efficacy of the three TCM ingredients that are commonly
used in China for dysmenorrhea: A. sinensis, P. lactiflora and C. yanhusuo, albeit in combination with a large number of other ingredients (5).
The choice of these herbs and their dosages depended on a number of
factors, principally their use in commercially available formulae in
China and reported effectiveness in the Chinese literature; other
factors included the authors’ personal experience of TCM practice and a
need to avoid herbs with known side effects or possible toxicity. The
root of A. sinensis is the source of a TCM product that is known as Dang Gui, Danggui, Dang Quai or Dong Quai.
Ligustilide and ferulic acid are considered to be the important active
compounds. A wide range of pharmacological effects has been claimed,
including antispasmodic, analgesic, sedative and antiinflammatory
actions; the recommended oral dose range is equivalent to 4.5–9.0 g of
root per day (5). The root of P. lactiflora is the source of a TCM product that is known as Baishao, Bai Shao, Chishao, Chi Shao, Shaoyao, and Shao Yao.
Paeoniflorin and albiflorin are considered to be the important active
compounds. It has been reported to have immunoregulatory, analgesic,
sedative and antiinflammatory properties; the recommended oral dose
range is equivalent to 6.0–12.0 g of root per day (5). The C. yanhusuo tuber is the source of a TCM product that is known as Yanhusuo, Yan Hu Suo, Yuanhu, and Yuan Hu. The most important active compound is believed to be dl-tetrahydropalmatine,
which has analgesic, sedative, tranquilizing, and mild hypnotic
effects; the recommended oral dose range is equivalent to 3.0–9.0 g of
root per day (5).
We
found no significant differences in any measure of efficacy between the
TCM formula and placebo. The worst pain (Cmax) and the total pain (AUC)
in each cycle were reduced over time, but there were no differences
between the two groups and the effects arose mainly because of the
overall fall in VAS scores after the observation cycle. However, after
cycle 3, 53% of women in the TCM group reported less pain than usual
compared with only 26% in the placebo group. Although not statistically
significant, the finding is nevertheless interesting in the light of the
commonly held TCM belief that these ingredients have a cumulative
effect over time. We conclude that there might be an effect that
accumulates over time but that the present study was inadequately
powered to reject the possibility completely. We calculate that 260
subjects would be required in each group to detect a >60% difference
in pain intensity (measured by the AUC) with 80% power at the .05
confidence level. If the results of such a placebo-controlled trial were
encouraging, it then would be reasonable to consider evaluating the TCM
formula against an NSAID in an adequately powered, double-blind RCT.
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Supported by the Oxford Natural Products and Phynova Ltd., Oxford, United Kingdom.
© 2006 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved
