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. 2018 Mar 27;14:1744806918770320. doi: 10.1177/1744806918770320

Comparison of the efficacy and safety of non-steroidal anti-inflammatory drugs for patients with primary dysmenorrhea: A network meta-analysis

Xuan Feng 1,2, Xiaoyun Wang 3,✉
PMCID: PMC5987898  PMID: 29587566

Short abstract

Objective

Non-steroidal anti-inflammatory drugs are used as first-line treatment of primary dysmenorrhea, but there has been no optimal clinical choice among non-steroidal anti-inflammatory drugs yet. The present study was to assess the relative benefits of different common non-steroidal anti-inflammatory drugs for primary dysmenorrhea patients with a network meta-analysis.

Methods

Randomized controlled trials were screened by our criteria and included in the network meta-analysis. Pain relief was considered as primary outcomes and adverse effect was supplied as a safety outcome, while additional rescue, assessment score, and pain intensity difference were secondary outcomes. All the indexes were evaluated with odds ratio or standardized mean difference. Surface under cumulative ranking curve result was used to calculate the ranking of each treatment.

Results

Totally, 72 randomized controlled trials of 5723 patients and 13 drugs were included in our study after screening. As for pain relief, all drugs except nimesulide, rofecoxib, and waldecoxib were superior to aspirin (odds ratio with 95% credible intervals, diclofenac: 0.28 (0.08, 0.86), flurbiprofen: 0.10 (0.03, 0.29), ibuprofen: 0.32 (0.14, 0.73), indomethacin: 0.21 (0.07, 0.58), ketoprofen: 0.25 (0.10, 0.64), mefenamic acid: 0.28 (0.09, 0.87), naproxen: 0.31 (0.15, 0.64), piroxicam: 0.15 (0.03, 0.59), and tiaprofenic acid: 0.17 (0.04, 0.63)). Aspirin also required additional rescue when compared with the majority of other drugs (flurbiprofen: 3.46 (1.15, 11.25), ibuprofen: 6.30 (2.08, 20.09), mefenamic acid: 7.32 (1.51, 37.71), naproxen: 2.66 (1.17, 6.55), and tiaprofenic acid: 9.58 (1.43, 94.63)). As for assessment of the whole treatment, ketoprofen, naproxen, rofecoxib, and ibuprofen got higher score significantly than placebo. In addition, ibuprofen performed better than placebo in pain intensity difference. Considering the safety, tiaprofenic acid and mefenamic acid were noticeable in low risk, and indomethacin revealed higher risk than any other drugs. According to the results of network analysis and surface under cumulative ranking curve, flurbiprofen was considered to be the best one among all the treatments in efficacy, and aspirin was worse than most of others. On the other hand, tiaprofenic acid and mefenamic acid were indicated as the safest drugs.

Conclusion

Considering the efficacy and safety, we recommended flurbiprofen and tiaprofenic acid as the optimal treatments for primary dysmenorrhea.

Keywords: Primary dysmenorrhea, non-steroidal anti-inflammatory drugs, efficacy, safety, network meta-analysis

Introduction

Dysmenorrhea is commonly divided into two types: primary dysmenorrhea (PD) and secondary dysmenorrhea. PD is defined as the hypogastric pain originated from uterine without pathology during menstrual period which often occurs with the menarche or after the establishment of the ovulatory cycles of reproductive women and usually lasts two or three days during each period.1 About 43%–91% adolescent females (under 20 years) are reported with PD and show a decreasing tendency as the age grows older.2 Women experiencing severe PD will be debilitated to accomplish daily works, even absent from school or job. According to the previous studies, PD is often considered to be the result of abnormal prostaglandin release which leads to strong contracts of uterus and reduced oxygen supply to the uterus muscles.3 Besides, unhealthy lifestyle (such as smoking, intemperance, and stressfulness) and family history may also have some negative influence on the symptoms of PD.4

There are several treatments for PD like non-steroidal anti-inflammatory drugs (NSAIDs), oral contraceptive drugs, physical therapy interventions, Chinese traditional herbology, and so on.5 Among them, NSAIDs are the first-line treatment.6 There are many types of NSAIDs which are widely used as analgesics and anti-inflammatory agent through inhibiting cyclooxygenase (COX) enzymes including COX-1 and COX-2. The pain relieve ability of NSAIDs is mainly attributed to COX-2 enzymes inhibition—an important pathway related to hormone release and the process of inflammation, while their adverse effects (such as indigestion, headaches, and lethargy, which are considered to be the most concerning adverse effects in PD patients) are thought to be involved with the COX-1 enzymes inhibition.7,8 Recently, selective COX-2 inhibitors have been established to mitigate the adverse effects in gastrointestinal tract and extend the drug effects with lower dose.9 However, this kind of drug has been discovered to be related to increase the risk of heart complications if taken regularly and thus should be used more prudently.10 Therefore, the requirement to evaluate efficacy and safety of NSAIDs is imminent for patients with PD.

To date, a large number of randomized controlled trials (RCTs) assessing the efficacy and safety of NSAIDs have been conducted,11,12 and several published meta-analysis studies also compared the mainly used NSAIDs in the PD treatment.13 However, the traditional meta-analysis only evaluates the direct comparison of pair-wised drugs, and there also exists conflict between different studies. Therefore, the purpose of this network meta-analysis is to indicate the relative efficacy and safety among most of the NSAIDs through not only direct but also indirect comparisons. We expect to draw a conclusion about the optimal treatment of PD by analyzing all published RCTs data of 13 individual NSAIDs.

Materials and methods

Literature search and selection criteria

We searched through China National Knowledge Internet, MEDLINE, and Embase to obtain the relevant RCTs comparing the efficacy and safety of NSAIDs for patients with PD using the key words “primary dysmenorrhea,” “randomized controlled trial,” “non-steroidal anti-inflammatory agents,” “aspirin,” “diclofenac,” “flurbiprofen,” “ibuprofen,” “indomethacin,” “ketoprofen,” “mefenamic acid,” “nimesulide,” “piroxicam,” “rofecoxib,” “tiaprofenic acid,” and “valdecoxib” in searching process (Supplemental Material). As for ketorolac and celecoxib, they were not been included in this network meta-analysis due to their serious adverse effects and main function which are often in the treatment in arthritis.

One RCT would be included in this network meta-analysis if it fulfilled each of the following criteria: (1) trials evaluating the efficacy or safety of NSAIDs in patients with PD, (2) trials that were designed as single-/double-/triple-blind, (3) trials covering at least one of the outcomes of interest, and (4) trials that using the same or close evaluation index (the way to describe the pain intensity difference and other outcomes). Two investigators independently reviewed abstracts and studies to evaluate the trial eligibility, and all conflicts were solved through discussion. There was no language restriction.

Outcome measures and data extraction

The primary efficacy outcome was pain relief (the proportion of patients who received effective or at least moderate pain relief), and the incidence of total treatment-related adverse effects like insomnia and gastrointestinal disease was added as a complementally safety outcome. As for secondary outcomes, we also assessed the requirements for additional rescue and pain intensity difference from baseline to end point. Using rescue medication or other medical assistance beyond the trials during specified time periods would be regarded as additional rescue. Pain intensity difference was defined as change scores of pain intensity rated by patients from baseline to end point. Assessment of the whole treatment from patients in each trail was also included in the secondary outcome; a higher score represents a better global assessment of patients.11 However, since all these outcomes contained more than one score scale, we standardized each continuous data during analysis.

After excluding the studies that failed to fulfill the criteria, two independent reviewers screened each study and extracted relevant data concerning of the outcomes of this network meta-analysis. The main information was extracted including basic study background, enrollment numbers, detailed interventions, and outcome measures.

Statistical analysis

We used a Bayesian framework with STATA software (13.0) and R software (V3.3.1) for this network meta-analysis. One advantage of using the Bayesian framework was its ability to produce ranking probabilities which could be used to evaluate medications with respect to each end point. The forest plots showed the result of the meta-analysis included in this research. Furthermore, odds ratio (OR) and standardized mean difference were calculated for dichotomous outcomes and continuous outcomes, respectively, with 95% credible intervals (CrIs) between the two treatments on each outcome. Moreover, the surface under the cumulative ranking curve (SUCRA) was computed based on the outcomes above to estimate the performance of different interventions, and higher SUCRA represented better efficacy and safety. The inconsistency of each outcome between direct and indirect evidence was evaluated by node-splitting results and the heat plots.

Results

Study selection and characteristics of included trials

A total of 1476 potentially relevant publications were identified by literature research. Then, 316 publications were removed as duplicates and 1039 publications were excluded due to the weak relevance to the subject. As a result, we retrieved 121 publications with full length into systematic review and included 70 studies with 72 RCTs of 5723 patients into our network meta-analysis due to the selection criteria as shown earlier.11,12,14–81 The flowchart of the whole process is shown in Figure 1. Among the 70 studies, 18 trials were three-arm studies, 48 trials were conducted between one intervention and placebo, and 6 trials were between two different interventions. All trials included 13 drugs as follows: aspirin, diclofenac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, mefenamic acid, mefenamic, nimesulide, piroxicam, rofecoxib, tiaprofenic acid, and valdecoxib. The network structure is shown in Figure 1 and Figure S1, the circle area represented the enrollment of each treatment, and lines width showed the number of compared trials. Main characteristics of the included publications and trials are presented in Table 1.

Figure 1.

Figure 1.

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Flowchart and network structure for pain relief. The network plots show direct comparison of different drugs, with node size corresponding to the sample size. The number of included studies for specific direct comparison decides the thickness of solid lines.

Table 1.

Main characteristics of included studies.

Trial Country Type Blinding No. Study period Intervention 1
 Intervention 2
 Intervention 3
Drug Size Dosage Drug Size Dosage Drug Size
Three-arm trials
 Daniels et al.72 USA RCT, crossover Double-blind 120 4 cycles Valdecoxib 183 20 mg/40 mg Naproxen 93 550 mg Placebo 94
 Daniels et al.67 USA RCT, crossover Double-blind 118 4 cycles Valdecoxib 192 20 mg/40 mg Naproxen 96 550 mg Placebo 96
 Morrison et al.66 USA RCT, parallel Double-blind 127 – Rofecoxib 233 25 mg + 25 mg/50 mg +25 mg Naproxen 122 550 mg Placebo 118
 Marchini et al.62 Italy RCT, crossover Double-blind 60 3 cycles Ibuprofen 56 400 mg Diclofenac 56 50 mg Placebo 57
 Tilyard and Dovey61 New Zealand RCT, crossover Double-blind 50 8 cycles Mefenamic acid 40 250 mg Tiaprofenic acid 40 200 mg Placebo 40
 Mehlisch60 USA RCT, crossover Double-blind 70 3 cycles Ketoprofen 180 25-mg LD/50 mg/75 mg Naproxen 60 500-mg LD +250 mg Placebo 60
 Pasquale et al.56 USA RCT, parallel Double-blind 74 1 cycle Piroxicam 39 20 mg/40-mg 1d +20 mg/40 mg Ibuprofen 15 400 mg Placebo 11
 Palmisano and Lamb55 USA RCT, crossover Double-blind 36 3 cycles Ketoprofen 36 150 mg Ibuprofen 36 800 mg Placebo 36
 Mehlisch54 USA RCT, crossover Double-blind 43 3 cycles Ketoprofen 26 150 mg Ibuprofen 26 800 mg Placebo 26
 Shapiro50 USA RCT, crossover Double-blind 43 4 cycles Flurbiprofen 43 50 mg Aspirin 43 650 mg Placebo 43
 Kauppila et al.49 Finland RCT, crossover Double-blind 42 6 cycles Tiaprofenic acid 31 200 mg Naproxen 31 250 mg Placebo 31
 Roy43 USA RCT, crossover Double-blind 48 2 cycles Mefenamic acid 48 – Ibuprofen 48 Placebo 48
 Gookin et al.40 USA RCT, crossover Double-blind 42 3 cycles Ibuprofen 31 400 mg Indomethacin 31 25 mg Placebo 31
 Delia et al.37 USA RCT, crossover Double-blind 59 3 cycles Flurbiprofen 59 50 mg Aspirin 59 650 mg Placebo 59
 Rosenwaks et al.36 USA RCT, crossover Double-blind 32 2 cycles Naproxen 23 275 mg Aspirin 23 325 mg Placebo 16
 Pogmore and Filshie33 UK RCT, crossover Double-blind 80 3 months Flurbiprofen 39 50 mg Aspirin 39 500 mg Placebo 39
 Pulkkinen and Csapo29 USA RCT, crossover Single-blind 15 2 cycles Naproxen 15 1100 mg Ibuprofen 15 800 mg Placebo 30
 Kajanoja17 Finland RCT, crossover Double-blind 47 6 cycles Indomethacin 90 25 mg Aspirin 89 500 mg Placebo 90
Two-arm trials
 Salmalian et al.81 Iran RCT, parallel Triple-blind 56 2 cycles Ibuprofen 24 200 mg Placebo 28
 Iacovides et al.12 South Africa RCT, crossover Double-blind 24 2 cycles Diclofenac 24 50 mg Placebo 24
 Heidarifar et al.80 Iran RCT, parallel Double-blind 50 2 cycles Mefenamic acid 24 250 mg Placebo 23
 Nahid et al.79 Iran RCT, parallel Double-blind 120 3 cycles Mefenamic acid 55 250 mg Placebo 51
 Daniels et al.77 USA RCT, crossover Double-blind 149 3 cycles Naproxen 123 550 mg Placebo 122
RCT, crossover Double-blind 154 3 cycles Naproxen 120 550 mg Placebo 121
 Iacovides et al.78 USA RCT, crossover Double-blind 10 – Diclofenac 10 150 mg Placebo 10
 Chantler et al.76 South Africa RCT, crossover Double-blind 12 3 cycles Diclofenac 12 100 mg Placebo 12
 Daniels et al.11 USA RCT, crossover Double-blind 135 3 cycles Naproxen 124 500 mg Placebo 125
 Doubova et al.75 Mexico RCT, parallel Double-blind 88 – Ibuprofen 46 1200 mg Placebo 42
 Dawood and  Khan-Dawood74 USA RCT, crossover Double-blind 12 3 cycles Ibuprofen 10 400 mg Placebo 10
 Letzel et al.73 Germany RCT, crossover Double-blind 127 3 cycles Naproxen 92 500 mg Placebo 93
 De Mello et al.71 Brazil RCT, parallel Double-blind 337 3 cycles Meloxicam 190 7.5 mg/15 mg Mefenamic acid 97 500 mg
 Bitner et al.70 USA RCT, crossover Double-blind 109 3 cycles Naproxen 89 500 mg Placebo 88
 Malmstrom et al.69 USA RCT, crossover Double-blind 73 3 cycles Naproxen 60 550 mg Placebo 60
 Milsom et al.68 UK RCT, crossover Double-blind 1242 3 cycles Naproxen 412 400 mg/200 mg Placebo 206
 Di Girolamo et al.65 Argentina RCT, crossover Double-blind 24 3 cycles Ibuprofen 24 400 mg Placebo 24
 Ezcurdia et al.64 Spain RCT, crossover Double-blind 52 – Ketoprofen 44 50 mg Placebo 44
 Mehlisch and  Fulmer63 USA RCT, crossover Double-blind 54 4 cycles Naproxen 53 550 mg Placebo 51
 Fedele et al.59 Italy RCT, parallel Double-blind 55 4 cycles Naproxen 14 250 mg Placebo 31
 Andersch and  Milsom58 Sweden RCT, crossover Double-blind 60 4 cycles Flurbiprofen 57 50 mg Naproxen 57 250 mg
 Akerlund and  Stromberg57 Sweden RCT, crossover Double-blind 42 2 cycles Ketoprofen 39 100 mg Naproxen 39 500 mg
 Pulkkinen53 Finland RCT, crossover Double-blind 14 4 cycles Nimesulide 28 100 mg Placebo 18
 Kapadia52 UK RCT, parallel Single-blind 56 3 cycles Naproxen 28 550 mg Ibuprofen 23 400 mg
 Fraser and McCarron51 Australia RCT, crossover Double-blind 38 6 cycles Ibuprofen 38 400 mg Placebo 38
 Wilhelmsson et al.48 Sweden RCT, crossover Double-blind 83 – Piroxicam 83 40 mg + 20 mg Naproxen 83 1000 mg
 Saltveit47 Norway RCT, crossover Double-blind 92 4 months Piroxicam 92 20 mg Placebo 92
 Osathanondh et al.46 USA RCT, parallel Double-blind 85 6 months Aspirin 24 650 mg Placebo 24
 Milsom and Andersch45 Sweden RCT, crossover Double-blind 60 4 cycles Ibuprofen 57 6a200 mg Naproxen 57 4a125 mg
 Rondel et al.44 Germany RCT, crossover Double-blind 12 4 cycles Nimesulide 12 200 mg Placebo 12
 Lalos and Nilsson42 Sweden RCT, crossover Double-blind 21 4 periods Naproxen 20 250 mg Placebo 20
 Jacobson et al.41 Sweden RCT, crossover Double-blind 39 4 cycles Naproxen 39 500 mg + 250 mg Placebo 39
 Gleeson and Sorbie39 Canada RCT, crossover Double-blind 27 6 cycles Ketoprofen 27 – Placebo 27
 Chan et al.38 USA RCT, cross-over Double-blind 12 3 cycles Naproxen 12 275 mg Placebo 12
 Riihiluoma et al.35 Finland RCT, crossover Double-blind 35 4 cycles Diclofenac 58 25 mg Placebo 57
 Chan et al.34 USA RCT, crossover Double-blind 14 – Naproxen 20 550 mg + 275 mg Placebo 20
 Morrison et al.32 USA RCT, crossover Triple-blind 55 3 cycles Ibuprofen 51 400 mg Placebo 51
 Hamann30 Denmark RCT, crossover Double-blind 30 4 cycles Naproxen 26 250 mg Placebo 26
 Henzl et al.31 – RCT, parallel Double-blind 431 – Naproxen 212 – Placebo 219
 Elder and Kapadia24 – RCT, crossover Double-blind 32 6 cycles Indomethacin 32 25 mg Placebo 32
 Pulkkinen 1979 USA RCT, crossover Single-blind 15 2 cycles Ibuprofen 15 400 mg Placebo 15
 Morrison and  Jennings27 USA RCT, crossover Double-blind 32 4 cycles Indomethacin 16 25 mg Placebo 16
 Larkin et al.26 USA RCT, crossover Double-blind 22 – Ibuprofen 22 400 mg Placebo 22
 Jacobson et al.25 Sweden RCT, parallel Double-blind 34 2 cycles Naproxen 16 250–500 mg Placebo 18
 Dandenell et al.23 Sweden RCT, parallel Double-blind 97 2 cycles Naproxen 48 250 mg Placebo 49
 Budoff22 USA RCT, crossover Double-blind 46 6 cycles Mefenamic acid 23 250 mg Placebo 21
 Sande et al.21 Norway, USA RCT, parallel Double-blind 32 3 cycles Naproxen 15 275 mg Placebo 17
 Pulkkinen and  Csapo20 Finland, USA RCT, crossover Single-blind 12 – Ibuprofen 12 800 mg Placebo 12
 Pauls19 Canada RCT, parallel Double-blind 17 3 cycles Naproxen 9 275 mg Placebo 8
 Lundstrom18 – RCT, crossover Double-blind 52 6 cycles Naproxen 26 550 mg + 275 mg +275 mg Placebo 26
 Janbu et al.16 Norway RCT, crossover Double-blind 30 3 cycles Aspirin 30 500 mg Placebo 30
 Hanson et al.15 USA RCT, parallel Double-blind 64 3 cycles Naproxen 29 275 mg Placebo 35
 Henzl et al.14 USA RCT, parallel Double-blind 20 4 cycles Naproxen 10 550 mg + 275 mg Placebo 10
RCT, parallel Double-blind 23 4 cycles Naproxen 12 550 mg + 275 mg Placebo 12
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Note: RCT: randomized controlled trials.

aThe article does not mention the type of dysmenorrhea. 1d: Day 1.

Overall outcomes

All the data of this network meta-analysis results for five outcomes are presented in Tables 2 to 4 and the forest plots in Figure 2 and Figures S2 to S5. For the primary outcomes shown in Table 2, the comparison between each pair of drugs was evaluated. As for pain relief, all drugs except aspirin were superior to placebo. When aspirin was compared with other drugs, the results showed that it was worse than most of the drugs such as diclofenac (OR = 0.28, 95% CrI = 0.08–0.86), indomethacin (OR = 0.21, 95% CrIs = 0.07–0.58), and flurbiprofen (OR = 0.10, 95% CrI = 0.03–0.29), and so on. On the other hand, considering the safety, tiaprofenic acid and mefenamic acid were noticeable in low incidence of adverse effects, and indomethacin revealed higher adverse effects than any other drugs.

Table 2.

Network meta-analysis results for pain relief (lower left) and adverse effects (upper right).

Placebo 0.99 (0.59, 1.65) 3.22 (0.97, 12.55) 1.82 (1.04, 3.29) 0.90 (0.56, 1.45) 3.60 (1.68, 7.46) 0.73 (0.36, 1.46) 0.66 (0.31, 1.39) 1.08 (0.87, 1.38) – 1.14 (0.56, 2.20) 1.17 (0.64, 2.23) 0.45 (0.08, 1.68) 1.22 (0.75, 2.05)
0.57 (0.29, 1.11) Aspirin 3.25 (0.84, 14.15) 1.86 (1.00, 3.46) 0.91 (0.42, 1.82) 3.60 (1.60, 8.08) 0.74 (0.32, 1.75) 0.65 (0.27, 1.68) 1.09 (0.64, 1.90) – 1.14 (0.48, 2.69) 1.19 (0.54, 2.66) 0.46 (0.07, 1.93) 1.23 (0.61, 2.53)
0.16 (0.06, 0.39) 0.28 (0.08, 0.86) Diclofenac 0.57 (0.13, 2.27) 0.28 (0.07, 0.91) 1.13 (0.22, 4.57) 0.23 (0.05, 0.93) 0.20 (0.05, 0.83) 0.34 (0.09, 1.15) – 0.35 (0.08, 1.40) 0.36 (0.08, 1.48) 0.14 (0.02, 0.83) 0.38 (0.09, 1.42)
0.06 (0.02, 0.17) 0.10 (0.03, 0.29) 0.35 (0.09, 1.55) Flurbiprofen 0.49 (0.21, 1.05) 1.93 (0.77, 4.85) 0.39 (0.17, 1.00) 0.35 (0.14, 0.91) 0.59 (0.33, 1.07) – 0.61 (0.25, 1.48) 0.64 (0.28, 1.49) 0.25 (0.04, 1.05) 0.66 (0.32, 1.42)
0.18 (0.11, 0.30) 0.32 (0.14, 0.73) 1.14 (0.42, 3.22) 3.19 (0.95, 10.70) Ibuprofen 4.06 (1.63, 9.30) 0.82 (0.35, 1.84) 0.73 (0.32, 1.67) 1.21 (0.76, 2.05) – 1.28 (0.55, 2.83) 1.32 (0.61, 2.86) 0.51 (0.09, 1.95) 1.36 (0.70, 2.69)
0.12 (0.05, 0.29) 0.21 (0.07, 0.58) 0.73 (0.20, 2.75) 2.05 (0.50, 8.25) 0.64 (0.23, 1.77) Indomethacin 0.20 (0.08, 0.57) 0.18 (0.07, 0.55) 0.30 (0.14, 0.67) – 0.32 (0.11, 0.85) 0.33 (0.12, 0.90) 0.13 (0.02, 0.57) 0.34 (0.14, 0.85)
0.15 (0.07, 0.28) 0.25 (0.10, 0.64) 0.90 (0.30, 2.94) 2.56 (0.71, 9.03) 0.79 (0.37, 1.75) 1.23 (0.41, 3.86) Ketoprofen 0.90 (0.32, 2.59) 1.48 (0.73, 3.06) – 1.57 (0.57, 4.06) 1.60 (0.64, 4.10) 0.63 (0.10, 2.89) 1.67 (0.72, 3.94)
0.16 (0.06, 0.40) 0.28 (0.09, 0.87) 0.97 (0.27, 3.78) 2.77 (0.66, 11.59) 0.86 (0.31, 2.39) 1.34 (0.36, 5.10) 1.07 (0.35, 3.35) Mefenamic acid 1.67 (0.76, 3.56) – 1.73 (0.63, 4.53) 1.79 (0.70, 4.71) 0.70 (0.11, 2.89) 1.86 (0.77, 4.66)
0.18 (0.12, 0.25) 0.31 (0.15, 0.64) 1.09 (0.41, 3.03) 3.10 (0.98, 9.49) 0.97 (0.53, 1.77) 1.51 (0.56, 4.06) 1.21 (0.59, 2.41) 1.13 (0.41, 3.00) Naproxen – 1.05 (0.51, 2.01) 1.08 (0.58, 2.03) 0.41 (0.07, 1.57) 1.13 (0.68, 1.88)
0.21 (0.05, 0.92) 0.37 (0.07, 1.88) 1.30 (0.23, 7.77) 3.67 (0.56, 23.34) 1.15 (0.23, 5.64) 1.79 (0.30, 10.38) 1.43 (0.27, 7.39) 1.34 (0.22, 7.85) 1.19 (0.25, 5.47) Nimesulide – – – –
0.08 (0.02, 0.28) 0.15 (0.03, 0.59) 0.53 (0.11, 2.51) 1.49 (0.28, 7.46) 0.46 (0.12, 1.73) 0.72 (0.15, 3.35) 0.58 (0.14, 2.29) 0.54 (0.11, 2.51) 0.48 (0.14, 1.60) 0.41 (0.06, 2.83) Piroxicam 1.03 (0.43, 2.66) 0.40 (0.06, 1.84) 1.07 (0.48, 2.53)
0.21 (0.05, 0.99) 0.37 (0.07, 2.01) 1.31 (0.23, 8.41) 3.71 (0.57, 24.53) 1.16 (0.23, 5.99) 1.80 (0.30, 11.36) 1.46 (0.27, 7.85) 1.35 (0.22, 8.33) 1.20 (0.25, 5.99) 1.02 (0.12, 8.94) 2.48 (0.36, 19.11) Rofecoxib 0.38 (0.07, 1.65) 1.04 (0.47, 2.27)
0.10 (0.03, 0.30) 0.17 (0.04, 0.63) 0.59 (0.13, 2.69) 1.67 (0.33, 8.17) 0.52 (0.14, 1.84) 0.81 (0.18, 3.67) 0.65 (0.17, 2.46) 0.61 (0.15, 2.39) 0.54 (0.16, 1.77) 0.45 (0.07, 3.06) 1.13 (0.21, 6.17) 0.45 (0.06, 3.06) Tiaprofenic acid 2.72 (0.66, 14.59)
0.23 (0.09, 0.58) 0.41 (0.13, 1.26) 1.46 (0.41, 5.64) 4.10 (0.98, 16.78) 1.28 (0.45, 3.67) 1.99 (0.54, 7.46) 1.62 (0.53, 4.90) 1.49 (0.40, 5.53) 1.34 (0.54, 3.35) 1.13 (0.20, 6.62) 2.77 (0.63, 12.94) 1.11 (0.18, 6.62) 2.46 (0.57, 10.91) Valdecoxib
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Note: The column treatments are compared against row treatments.

Table 3.

Network meta-analysis results for additional rescue (lower left) and assessment (upper right).

Placebo −0.12 (−0.93, 0.68) – −0.69 (−1.29, −0.10) −0.65 (−1.42, 0.12) −0.91 (−1.73, −0.10) – −0.71 (−1.11, −0.30) −1.05 (−2.33, 0.23) – −0.86 (−1.62, −0.11) – −0.60 (−1.60, 0.40)
1.19 (0.52, 2.64) Aspirin – −0.57 (−1.55, 0.40) −0.53 (−1.47, 0.41) −0.79 (−1.93, 0.35) – −0.58 (−1.48, 0.31) −0.93 (−2.44, 0.58) – −0.74 (−1.84, 0.36) – −0.48 (−1.76, 0.81)
4.10 (1.49, 11.59) 3.46 (1.15, 11.25) Flurbiprofen – – – – – – – – – –
7.46 (3.42, 17.12) 6.30 (2.08, 20.09) 1.80 (0.50, 6.69) Ibuprofen 0.04 (−0.83, 0.92) −0.22 (−1.12, 0.69) – −0.01 (−0.73, 0.71) −0.36 (−1.77, 1.05) – −0.17 (−1.13, 0.79) – 0.09 (−1.07, 1.26)
– – – – Indomethacin −0.26 (−1.36, 0.84) – −0.05 (−0.92, 0.81) −0.40 (−1.89, 1.09) – −0.21 (−1.29, 0.87) – 0.05 (−1.21, 1.31)
2.27 (0.55, 9.78) 1.92 (0.38, 10.38) 0.55 (0.10, 3.22) 0.31 (0.06, 1.58) – Ketoprofen – 0.21 (−0.70, 1.11) −0.14 (−1.66, 1.38) – 0.05 (−1.06, 1.16) – 0.31 (−0.98, 1.60)
8.67 (2.2, 34.81) 7.32 (1.51, 37.71) 2.10 (0.38, 11.70) 1.16 (0.23, 5.75) – 3.82 (0.5, 27.66) Mefenamic acid – – – – – –
3.16 (2.29, 4.66) 2.66 (1.17, 6.55) 0.77 (0.28, 2.20) 0.42 (0.19, 0.98) – 1.39 (0.35, 5.58) 0.36 (0.09, 1.55) Naproxen −0.35 (−1.69, 1.00) – −0.16 (−0.96, 0.64) – 0.11 (−0.9, 1.11)
– – – – – – – – Nimesulide – 0.19 (−1.30, 1.67) – 0.45 (−1.17, 2.08)
3.67 (1.19, 11.70) 3.10 (0.79, 12.81) 0.90 (0.19, 4.14) 0.49 (0.13, 1.79) – 1.62 (0.25, 10.18) 0.43 (0.07, 2.53) 1.16 (0.35, 3.82) – Piroxicam – – –
1.22 (0.45, 3.46) 1.03 (0.29, 3.90) 0.30 (0.07, 1.25) 0.17 (0.05, 0.59) – 0.54 (0.09, 3.00) 0.14 (0.03, 0.79) 0.39 (0.14, 1.05) – 0.33 (0.07, 1.54) Rofecoxib – 0.26 (−0.97, 1.50)
11.25 (2.01, 95.58) 9.58 (1.43, 94.63) 2.75 (0.37, 28.79) 1.52 (0.23, 14.44) – 5.00 (0.52, 62.18) 1.32 (0.14, 15.96) 3.56 (0.62, 29.96) – 3.10 (0.39, 33.78) 9.30 (1.25, 95.58) Tiaprofenic acid –
2.69 (1.30, 5.87) 2.27 (0.79, 7.10) 0.65 (0.19, 2.32) 0.36 (0.12, 1.06) – 1.19 (0.24, 5.81) 0.31 (0.07, 1.52) 0.85 (0.39, 1.79) – 0.73 (0.19, 2.89) 2.20 (0.63, 7.61) 0.24 (0.03, 1.58) Valdecoxib
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Note: The column treatments are compared against row treatments.

Table 4.

Network meta-analysis results for secondary pain intensity difference.

Placebo
−0.02 (−1.94, 1.91) Aspirin
−1.86 (−3.89, 0.17) −1.84 (−4.64, 0.95) Diclofenac
−1.99 (−5.00, 1.03) −1.97 (−5.55, 1.60) −0.13 (−3.76, 3.51) Flurbiprofen
−1.56 (−2.92, −0.20) −1.54 (−3.90, 0.81) 0.30 (−2.14, 2.75) 0.43 (−2.64, 3.50) Ibuprofen
– – – – – Indomethacin
−1.62 (−4.33, 1.09) −1.61 (−4.93, 1.72) 0.24 (−3.15, 3.62) 0.37 (−3.69, 4.42) −0.06 (−3.10, 2.97) – Ketoprofen
−0.95 (−2.52, 0.62) −0.94 (−3.42, 1.55) 0.91 (−1.66, 3.47) 1.04 (−2.36, 4.43) 0.60 (−1.47, 2.68) – 0.67 (−2.46, 3.80) Mefenamic acid
−1.00 (−2.36, 0.35) −0.98 (−3.34, 1.37) 0.86 (−1.58, 3.30) 0.99 (−1.71, 3.68) 0.56 (−0.91, 2.03) – 0.62 (−2.41, 3.65) −0.05 (−2.12, 2.02) Naproxen
−0.88 (−3.34, 1.59) −0.86 (−3.99, 2.27) 0.98 (−2.21, 4.18) 1.11 (−2.78, 5.01) 0.68 (−2.14, 3.50) – 0.75 (−2.92, 4.41) 0.08 (−2.39, 2.54) 0.12 (−2.69, 2.94) Tiaprofenic acid
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Note: The column treatments are compared against row treatments.

Figure 2.

Figure 2.

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Forest plots for pain relief using ORs and 95% CrIs. OR: odds ratios; Crls: credible intervals.

The secondary outcomes of this network meta-analysis are listed in Tables 3 and 4. According to the outcomes, most of the drugs needed less additional rescue after assigned interventions compared with placebo. Nevertheless, aspirin still required additional rescue when compared with the majority of other drugs. As for assessment of the whole treatment, ketoprofen, naproxen, rofecoxib, and ibuprofen got higher score significantly than placebo. In addition, ibuprofen performed better than placebo in pain intensity difference.

Ranking conclusion

The results of SUCRA under five outcomes are shown in Table 5. According to the standing list of the primary outcomes, flurbiprofen (SUCRA: 0.904) ranked first in pain relief, successively followed by piroxicam (SUCRA: 0.787), tiaprofenic acid (SUCRA: 0.751), and indomethacin (SUCRA: 0.678). Besides, aspirin was indicated to be the worst among all of the NSAIDs in pain relief. In terms of adverse effects, the lower SUCRA suggested the higher incidence of adverse effects. Tiaprofenic acid (SUCRA: 0.872) performed best with mefenamic acid (SUCRA: 0.824) and ketoprofen (SUCRA: 0.781) followed. Combining these two primary outcomes, flurbiprofen was the most efficacious treatment in our result, and tiaprofenic acid was also a good treatment when took efficacy and safety into consideration. The ranking in secondary outcomes also revealed the excellent performance of these drugs. In addition, aspirin was considered to be the worst intervention because it ranked last among all the interventions except for placebo in most outcomes.

Table 5.

Surface under the cumulative ranking curve (SUCRA) results of six outcomes.

graphic file with name 10.1177_1744806918770320-table5.jpg

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Note: The warm color represents a high SUCRA value, which also suggests a relatively high ranking.

Inconsistency test

Node-splitting analysis of five outcomes for all the drugs is shown in Tables 6 and 7. A value of P less than 0.05 indicated that there was a significant inconsistency. As the results of the analysis show that there was no significant difference in the outcome of pain relief, additional rescue, pain intensity difference, and assessment. As for the outcome of adverse effects, inconsistency between flurbiprofen and aspirin (P = 0.012), as well as naproxen and flurbiprofen (P = 0.036), was found. The net heat plot results of consistency test are also shown in Figure 3 and Figures S6 to S9, which revealed the same result.

Table 6.

Node-splitting results of the network meta-analysis for three dichotomous outcomes.

Outcomes Comparison OR (95% CrI)
 P
Direct Indirect Network (Direct vs. indirect)
Pain relief Ibuprofen vs. placebo 5.30 (3.00, 9.80) 2.80 (0.41, 19.00) 5.50 (3.30, 9.20) 0.5200
Ketoprofen vs. placebo 6.60 (2.90, 15.00) 4.30 (0.75, 26.00) 6.90 (3.70, 13.00) 0.6550
Naproxen vs. placebo 5.10 (3.50, 7.70) 14.00 (4.10, 51.00) 5.70 (4.10, 8.50) 0.1150
Piroxicam vs. placebo 29.00 (3.80, 260.00) 7.20 (1.50, 34.00) 11.00 (3.70, 42.00) 0.2663
Indomethacin vs. aspirin 3.80 (0.65, 17.00) 5.90 (1.30, 28.00) 4.80 (1.70, 14.00) 0.6425
Naproxen vs. aspirin 5.80 (0.89, 35.00) 3.00 (1.30, 6.70) 3.20 (1.50, 7.00) 0.5188
Ibuprofen vs. diclofenac 0.76 (0.16, 3.30) 0.65 (0.14, 2.50) 0.87 (0.31, 2.30) 0.9000
Indomethacin vs. ibuprofen 0.87 (0.14, 4.70) 2.70 (0.69, 9.40) 1.60 (0.60, 4.60) 0.2913
Ketoprofen vs. ibuprofen 2.00 (0.58, 7.50) 0.94 (0.33, 2.70) 1.30 (0.58, 2.70) 0.3688
Mefenamic acid vs. ibuprofen 1.10 (0.22, 5.00) 1.80 (0.41, 7.00) 1.20 (0.43, 3.20) 0.6338
Naproxen vs. ibuprofen 2.00 (0.28, 12.00) 0.95 (0.51, 1.80) 1.00 (0.59, 1.90) 0.4413
Naproxen vs. ketoprofen 1.10 (0.35, 3.40) 0.60 (0.25, 1.60) 0.82 (0.41, 1.70) 0.4513
Tiaprofenic acid vs. mefenamic acid 1.80 (0.22, 17.00) 1.30 (0.18, 10.00) 1.60 (0.47, 6.00) 0.8063
Piroxicam vs. naproxen 1.30 (0.29, 5.80) 5.40 (0.62, 53.00) 2.00 (0.65, 7.30) 0.2850
Tiaprofenic acid vs. naproxen 1.70 (0.28, 10.00) 3.20 (0.49, 28.00) 1.80 (0.59, 5.80) 0.6088
Adverse effects Flurbiprofen vs. placebo 2.20 (1.00, 4.50) 0.75 (0.26, 2.00) 1.80 (1.00, 3.20) 0.0888
Ibuprofen vs. placebo 0.99 (0.53, 1.90) 0.67 (0.30, 1.50) 0.91 (0.57, 1.50) 0.4925
Ketoprofen vs. placebo 0.67 (0.30, 1.50) 1.80 (0.24, 14.00) 0.74 (0.36, 1.40) 0.3750
Naproxen vs. placebo 1.10 (0.83, 1.40) 1.50 (0.75, 3.00) 1.10 (0.87, 1.30) 0.3500
Piroxicam vs. placebo 0.90 (0.38, 2.10) 1.60 (0.53, 5.10) 1.10 (0.55, 2.20) 0.4275
Flurbiprofen vs. aspirin 3.10 (1.40, 6.70) 0.53 (0.15, 1.80) 1.90 (0.99, 3.50) 0.0125
Indomethacin vs. aspirin 2.50 (0.91, 6.80) 5.20 (1.20, 25.00) 3.70 (1.60, 8.30) 0.3913
Naproxen vs. aspirin 0.61 (0.06, 4.40) 1.20 (0.66, 2.10) 1.10 (0.63, 2.00) 0.5225
Naproxen vs. flurbiprofen 1.40 (0.49, 4.00) 0.39 (0.20, 0.80) 0.60 (0.34, 1.10) 0.0363
Indomethacin vs. ibuprofen 6.30 (0.70, 180.00) 3.70 (1.40, 8.80) 4.00 (1.70, 9.40) 0.6863
Ketoprofen vs. ibuprofen 0.52 (0.09, 2.70) 0.95 (0.37, 2.50) 0.81 (0.35, 1.70) 0.5288
Mefenamic acid vs. ibuprofen 0.38 (0.10, 1.20) 1.20 (0.36, 4.00) 0.72 (0.31, 1.80) 0.1713
Naproxen vs. ibuprofen 1.60 (0.75, 3.40) 0.97 (0.52, 1.90) 1.20 (0.74, 1.90) 0.3150
Naproxen vs. ketoprofen 0.64 (0.06, 4.30) 1.70 (0.85, 3.80) 1.50 (0.72, 3.10) 0.3413
Tiaprofenic acid vs. mefenamic acid 0.63 (0.06, 4.30) 0.48 (0.02, 5.00) 0.69 (0.13, 3.00) 0.8838
Piroxicam vs. naproxen 1.50 (0.52, 4.20) 0.81 (0.31, 1.90) 1.00 (0.49, 2.10) 0.4000
Rofecoxib vs. naproxen 0.96 (0.41, 2.50) 0.83 (0.31, 2.20) 1.10 (0.57, 2.10) 0.8150
Tiaprofenic acid vs. naproxen 0.18 (0.01, 2.40) 0.55 (0.07, 3.30) 0.42 (0.08, 1.70) 0.5313
Additional rescue Flurbiprofen vs. placebo 0.12 (0.03, 0.49) 0.57 (0.10, 3.10) 0.25 (0.09, 0.71) 0.1638
Ibuprofen vs. placebo 0.10 (0.04, 0.26) 0.23 (0.05, 0.90) 0.14 (0.06, 0.29) 0.3200
Naproxen vs. placebo 0.35 (0.23, 0.48) 0.11 (0.03, 0.44) 0.32 (0.21, 0.43) 0.1088
Flurbiprofen vs. aspirin 0.20 (0.05, 0.89) 0.62 (0.09, 4.40) 0.30 (0.09, 0.93) 0.3650
Naproxen vs. aspirin 0.13 (0.01, 0.88) 0.45 (0.15, 1.20) 0.38 (0.14, 0.82) 0.2663
Naproxen vs. flurbiprofen 0.59 (0.12, 2.80) 2.40 (0.60, 9.60) 1.30 (0.42, 3.50) 0.1738
Naproxen vs. ibuprofen 1.30 (0.31, 5.70) 3.10 (1.10, 8.80) 2.30 (0.99, 5.40) 0.2875
Piroxicam vs. ibuprofen 1.70 (0.26, 18.00) 2.70 (0.39, 19.00) 2.00 (0.53, 7.30) 0.7175
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Note: Three dichotomous end points include pain relief, adverse effects, and additional rescue. Direct, indirect, or network odds ratios (ORs) and 95% credible intervals (CrIs) indicate the relative efficacy or safety. Bold values means P-value is smaller than 0.05, which indicated that there was significant inconsistency.

Table 7.

Node-splitting results of the network meta-analysis for two continuous outcomes.

Outcomes Mean difference
Comparison Direct
 Indirect
 Difference
 P
Coef. Standard error Coef. Standard error Coef. Standard error
Pain intensity difference Ibuprofen vs. placebo −1.2558 1.0796 −2.4998 1.6782 1.2440 1.9946 0.533
Naproxen vs. Placebo −1.4379 1.0737 −0.1431 1.6798 −1.2948 1.9926 0.516
Tiaprofenic acid vs. placebo −0.3432 1.8128 −3.5687 4.0633 3.2254 4.4491 0.468
Naproxen vs. flurbiprofen 0.9860 1.7619 −16.6152 63.4955 17.6012 63.5210 0.782
Naproxen vs. ibuprofen 1.0838 1.2938 −0.1717 1.5209 1.2556 1.9967 0.529
Tiaprofenic acid vs. mefenamic acid −0.4577 1.8129 2.7677 4.0631 −3.2254 4.4491 0.468
Assessment Aspirin vs. placebo 0.2518 0.6091 −1.5296 2.1541 1.7814 2.2388 0.426
Ibuprofen vs. placebo 0.6275 0.4445 1.5780 1.6097 −0.9505 1.6704 0.569
Indomethacin vs. placebo 0.6747 0.6239 0.4538 1.4531 0.2210 1.5815 0.889
Ketoprofen vs. placebo 0.9528 0.6320 0.5631 1.8575 0.3897 1.9633 0.843
Naproxen vs. placebo 0.6854 0.3055 1.8207 2.2829 −1.1353 2.3033 0.622
Rofecoxib vs. placebo 0.8675 0.6165 0.8525 1.6429 0.0150 1.7561 0.993
Valdecoxib vs. placebo 0.6082 0.8688 0.5697 1.6436 0.0384 1.8622 0.984
Indomethacin vs. aspirin 0.8192 0.8590 −0.0481 1.1864 0.8673 1.4648 0.554
Indomethacin vs. ibuprofen −0.4408 0.8810 0.3675 0.9207 −0.8083 1.2745 0.526
Ketoprofen vs. ibuprofen 0.1405 0.9008 0.3077 0.9797 −0.1672 1.3307 0.900
Rofecoxib vs. naproxen −0.0010 0.8642 0.3188 0.8571 −0.3198 1.2178 0.793
Valdecoxib vs. naproxen −0.1140 0.8685 −0.0756 1.6440 −0.0384 1.8622 0.984
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Note: Three continuous outcomes include pain intensity difference and assessment. Direct, indirect, or network results of standardized mean difference and standard error indicate the relative efficacy or safety.

Figure 3.

Figure 3.

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Heat plots for pain relief. The size of the gray squares indicates the contribution of the direct evidence (shown in the column) to the network evidence (shown in the row). The colors are associated with the change in inconsistency between direct and indirect evidence. Blue colors indicate an increase in inconsistency, and warm colors indicate a decrease in inconsistency.

Discussion

PD is a high-frequency female disease which will disturb the quality of normal lives of women.82 NSAIDs are considered to be the first-line treatment for patients with PD; they are certain to be effective in relieving pain, but there is still no conclusion about the optimal choice in clinic.13 Therefore, the objective of this network meta-analysis is to draw a conclusion about the optimal treatment within several types of NSAIDs through direct and indirect statistical analysis. Although only a small amount of studies in our database performed in the recent years, the results of our research were still meaningful since NSAIDs system has been developed a long time ago and maintained its crucial role in relieving PD in the last 30 years.

The results of our network meta-analysis suggested that all the drugs except aspirin were significantly more efficacious than placebo. However, there is no significant difference between each pair of NSAIDs concerning pain relief through direct evidence, which is consistent with the research by Marjoribanks et al.3 In their research, they pointed out that NSAIDs were effective in relieving dysmenorrhea, whereas the sample size was too small to conduct a suitable meta-analysis for the comparison between two NSAIDs. Complementary to their results, the SUCRA ranking in our research provided the information of more efficacious treatments: flurbiprofen, piroxicam, and tiaprofenic acid. Naproxen was an analgesic that has been applied widely in many disease and showed significant relief of pain in PD in early time.38 However, with the development of NSAIDs drugs, several other drugs have been illustrated as similar efficacy to naproxen.11,73 In our result, naproxen was not significant efficacious compared to other NSAIDs drugs and showed an average efficacy in ranking.

As for the safety outcome, tiaprofenic acid and mefenamic acid were indicated as the safest NSAIDs drugs, while indomethacin was the worst one which was more likely to cause mild gastrointestinal discomfort. Naproxen, different from the research by Marjoribanks et al., was not reported with higher incidence of gastrointestinal side effects according to our network meta-analysis. Importantly, it is generally believed that selective COX-2 inhibitors, for example, rofecoxib and valdecoxib, are related with higher risk of serious cardiovascular disease with long-term usage.9 Accordingly, our research demonstrated that the inferior performance of both rofecoxib and valdecoxib which were already announced withdrawal from the U.S. market in 2004 and 2005, respectively. Furthermore, it should be noted that flurbiprofen and tiaprofenic acid revealed good efficacy and were recommended to be the suitable choices for the patients with severe adverse effects. The safety ranking of flurbiprofen was not ideal in our results; however, the inconsistency of direct and indirect evidence was significant between flurbiprofen and naproxen as well as flurbiprofen and aspirin. Besides, there was only one trial having direct comparison of each pair. Thus, the relevant safety of flurbiprofen lacked enough credibility, and more researches are needed in the future.

Although the result of our network meta-analysis was relatively comprehensive, there were still several limitations which may affect the strength of each result. Firstly, even though the trials included in the research were various, the population employed was small scale (many trials included less than 100 people), and the reliability of the data was lightly weakened, especially in recommended NSAIDs like tiaprofenic acid (assessed in only 71 patients). Moreover, the availability and cost of these drugs have not been taken into consideration when they are regarded as recommended therapies. Secondly, we only evaluated the difference of efficacy and safety among NSAIDs but overlooked the dosage and frequency factor related to one drug. Also, we did not provide the optimal intake way of one single drug. Furthermore, previous studies have mentioned that the symptoms of PD were similar to the adverse effects of drug treatments which may also reduce the credibility of the results.63 Thirdly, some included studies are pharmaceutically funded and may have risks of bias, though it can be adjusted with network meta-analysis method in some degree.

In conclusion, according to our network meta-analysis, we advocate flurbiprofen and tiaprofenic acid as the recommended NSAIDs therapies for patients with PD. Naproxen, as a well-established drug, did not show superior in efficacy or safety in our result. More efforts need to be made to further explore the characteristic of NSAIDs for PD patients.

Supplemental Material

Supplemental material for Comparison of the efficacy and safety of non-steroidal anti-inflammatory drugs for patients with primary dysmenorrhea: A network meta-analysis
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Supplemental material for Comparison of the efficacy and safety of non-steroidal anti-inflammatory drugs for patients with primary dysmenorrhea: A network meta-analysis by Xuan Feng and Xiaoyun Wang in Molecular Pain

Author Contributions

XF contributed to research conception and design, data analysis, interpretation, and drafting of the manuscript. XW contributed to data analysis, interpretation, and statistical analysis. XW and XF are involved in critical revision of the manuscript, approval of final manuscript, and taking public responsibility for appropriate portions of the content.

Supplemental Material

Supplementary material is available for this article online.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Lingnan traditional Chinese medicine gynecology treatment of menstruation and clinical study (No. 2013B032500013) and State Administration of Traditional Chinese Medicine (16MLZY02), 2016 National Famous Traditional Chinese Medicine Expert Inheritance Studio Construction Project-Wang Xiaoyun Chinese Medicine Office.

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