In the present study, we performed a systematic review, direct meta-analysis, and indirect network meta-analysis to evaluate the difference in efficacy between drugs for dysmenorrhea approved in Japan. This is the first such study to include the progestin DNG 1 mg/day in a comparison of the efficacy of LEPs, a combined oral contraceptive commonly used overseas. In this study, the efficacy of the drugs was evaluated by two evaluation indexes for dysmenorrhea as follows: First, total dysmenorrhea score that defined pain according to limited ability to work and need for analgesics [11]. Second, VAS that visualized the current degree of pain.

In the direct meta-analysis, we found significant differences between all drugs and placebo in both types of dysmenorrhea and both outcomes except NET/EE ULD-cyclic in primary dysmenorrhea. In the indirect network meta-analysis, which included eight RCTs, we found a significant difference in VAS between DNG and NET/EE LD-cyclic in secondary dysmenorrhea but no other differences between drugs. Endometriosis is one of the causes of secondary dysmenorrhea. In a network meta-analysis in 2127 patients that compared drugs for endometriosis-related pain, Samy et al. reported that the probability ranking p-score of DNG was the highest among five interventions (DNG 2 mg/day, oral contraceptives, elagolix 150 mg, elagolix 250 mg, placebo) for improvement in pelvic pain as measured by a VAS in the third month after initiation of the drugs [29].

We suggest two possible reasons for the significant difference in improvement of VAS between NET/EE LD-cyclic and DNG in secondary dysmenorrhea. First, NET/EE LD-cyclic involves withdrawal bleeding and pelvic pain (due to the hormone-free interval), whereas DNG causes amenorrhea by suppressing ovulation and thus prevents pain [30]. Furthermore, in endometriosis—a typical cause of secondary dysmenorrhea—DNG is expected to have anti-inflammatory effects and antiproliferation effects on the endometrium because of its high progestin activity [30,31,32]. Although DNG was shown to be effective in improving VAS in endometriosis, the dose of DNG included in this study was half of the dose generally used for the treatment of endometriosis, so the estrogen-suppressing effect was relatively weak [14]. The pain suppression by DNG in secondary dysmenorrhea shown in our study was thought to be due to both maintenance of amenorrhea symptoms and a direct effect on organic diseases, as mentioned above.

We also evaluated the differences between administration regimens. Extended and cyclic regimens of LEP have been investigated in many systematic reviews and clinical trials [17,18,19,20,21, 33], and international guidelines recommend the extended regimen. However, VAS was not significantly different between the extended and cyclic groups in this study. A meta-analysis by Damm et al. showed that LEP extended regimens reduced the duration of pain by 4 days compared with LEP cyclic regimens [19], although the difference in efficacy in reducing the severity of dysmenorrhea was unclear. Our study likely underestimated efficacy in the extended group because the included studies assessed the efficacy of DRSP/EE-extended at the end of a cycle, i.e., the time of painful withdrawal bleeding. To precisely evaluate the difference in efficacy in reducing the severity of dysmenorrhea between drugs with different administration regimens, appropriate evaluation methods should be used.

Zorbas et al. considered that, compared with a LEP cyclic regimen, a LEP extended regimen relieves pain by achieving amenorrhea [20]. Consequently, the progestin continuous group without a hormone-free interval could be expected to be more effective than the cyclic group. Therefore, in the present study, we also compared administration regimens by dividing the studies into continuous (progestin), extended (LEP-extended), and cyclic (LEP-cyclic) groups. As a result, we found slightly better improvement of the total dysmenorrhea score in the continuous and extended groups, but the continuous group showed greater improvement in VAS than the cyclic group did, regardless of the type of dysmenorrhea. One of the reasons for the higher efficacy in continuous (progestin) groups than in cyclic (LEP cyclic) groups was considered to be the contribution of amenorrhea occurring in continuous (progestin) groups. On the other hand, differences in the presence or absence of estrogen inclusion and progestin activity should also be considered. The degree to which differences in regimens between both drugs contributed to efficacy is unknown.

We observed a difference in heterogeneity between comparisons evaluating the total dysmenorrhea score and those evaluating the VAS in both dysmenorrhea types and considered the measurement methodology of each score as a major cause of the difference [34]. The total dysmenorrhea score is a verbal rating scale that assesses the impact on daily life and the frequency of analgesic intake, and the degree of impact on daily life depends on health literacy [35] and social position and tends to show high variance among responders. In contrast, the VAS assesses the intensity of one’s own pain. As regards clinical heterogeneity, we concluded that it has limited impact on our conclusions because we performed separate analyses of different disease types, i.e., primary and secondary dysmenorrhea, and found similar clinical characteristics according to the distribution of basic demographics and baseline total dysmenorrhea scores that could cause clinical heterogeneity among the eligible studies.

We included only RCTs in our analyses to guarantee the quality of the studies; nevertheless, our study has some limitations. First, the assessment time point of each score was not always the same. In the present analysis, we mainly used the values reported in each trial, but the duration of a treatment course differed even within the LEP drugs with an extended regimen (LNG/EE-extended, 84-day cycle; DRSP/EE-extended, 124-day cycle). In addition, the pain-suppressing effect in a LEP extended regimen has been reported to appear soon after the initiation of treatment, whereas in a LEP cyclic regimen, it increases throughout the continued administration and consequently decreases the frequency of analgesic use over time [26, 36]. Consequently, the efficacy of the LEP cyclic regimen was likely underestimated. Second, all of the eligible studies were performed by pharmaceutical companies to confirm the efficacy of their compounds. The risk of bias in each study was evaluated (Fig. S1 in the supplementary material), and no serious bias was identified in any of the studies. Although we did not investigate other elements of study design that are not evaluated by the risk of bias assessment, we considered their impact to be limited because all eligible studies were sponsored by companies. Third, the publication bias could not be statistically evaluated because of the limited number of eligible studies, although we did find asymmetry in the funnel plots (Fig. S4 in the supplementary material). Fourth, the 95% CrIs were wide for the total dysmenorrhea score, which is considered to be due to the insufficient number of studies and patients in our analysis. If more studies are conducted in future, analyses will be able to evaluate whether the drugs with higher mean differences in our study actually are more effective than others. Fifth, our meta-analyses synthesized only efficacy and did not consider the safety of each drug. Thus, additional investigations are required to evaluate the overall usefulness of the drugs in real-world clinical settings.