- a Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, Oxfordshire, United Kingdom
- b Phynova Group Plc., Oxford Science Park, Oxford, Oxfordshire, United Kingdom
- c TNO Quality of Life, Zeist, The Netherlands.
- Received 2 May 2005, Revised 10 February 2006, Accepted 10 February 2006, Available online 19 June 2006
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:  mixed-model analysis based on specific covariance structures;  univariate analysis of variance, and  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:  the total number of days of pain or use of rescue medication or  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
Treatment cycle 1
Treatment cycle 2
Treatment cycle 3
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.
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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Copyright © 2006 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.