Combined Oral Contraceptive Pills for Primary Dysmenorrhea

Study Population: 21 randomized controlled trials (RCTs; N = 3,723) performed in 16 countries between 1966 and 2017; women 15 to 33 years of age with primary dysmenor-rhea (at least moderate pain for at least 1 day of menses) who did not have obvious pelvic pathology on physical examination but did have regular ovulatory menstrual cycles (21- to 35-day cycles)

Harm End Points: Primary: adverse events from treatment (incidence and type of adverse event); secondary: withdrawals from treatment and adverse events

Narrative: Combined oral contraceptive pills (OCPs) are widely accepted as treatment for primary dysmenorrhea, but few trials have assessed effectiveness and any associated adverse events. OCPs are thought to reduce dysmenorrhea by inhibiting ovulation and possibly decreasing menstrual fluid volumes and prostaglandin levels that contribute to painful menstruation. The Cochrane review compared combined OCPs with placebo or no treatment, combined OCPs with each other, and combined OCPs with nonsteroidal anti-inflammatory drugs for the treatment of primary dysmenorrhea.¹

In the review, high-quality evidence demonstrated that patients using combined OCPs had lower pain scores than those receiving placebo or no treatment, as measured by the total dysmenorrhea scale (range = 0 to 6, with lower scores being better; standardized mean pain score = 0.58 points lower; 95% CI, 0.74 to 0.41; six RCTs; n = 588). Low-quality evidence demonstrated that compared with placebo or no treatment, combined OCPs improved pain over 1 to 4 months of follow-up (risk ratio [RR] = 1.65; 95% CI, 1.29 to 2.10; number needed to treat [NNT] = 6; six RCTs; n = 717). For secondary outcomes, low-quality evidence demonstrated that compared with placebo or no treatment, combined OCPs reduced the need for additional medications (RR = 0.63; 95% CI, 0.40 to 0.98; NNT = 8; two RCTs; n = 163) and decreased dysmenorrhea-related absences from work or school (RR = 0.63; 95% CI, 0.41 to 0.97; NNT = 8; two RCTs; n = 148).

Moderate-quality evidence demonstrated that combined OCPs probably increased the risk of any adverse events compared with placebo or no treatment (RR = 1.31; 95% CI, 1.20 to 1.43; number needed to harm [NNH] = 5; seven RCTs; n = 1,025). High-quality evidence demonstrated that compared with placebo or no treatment, combined OCPs increased the risk of irregular bleeding (RR = 2.63; 95% CI, 2.11 to 3.28; NNH = 3; seven RCTs; n = 1,025). Moderate-quality evidence also demonstrated an increase in headaches (RR = 1.51; 95% CI, 1.11 to 2.04; NNH = 11; five RCTs; n = 656) and nausea (RR = 1.64; 95% CI, 1.17 to 2.30; NNH = 16; eight RCTs; n = 948) in patients taking combined OCPs compared with placebo or no treatment. There was no difference between the groups in serious adverse events (e.g., breast cancer, cerebrovascular arterial disease, deep venous thrombosis, depression, myocardial infarction).

When comparing different combined OCP regimens, low-quality evidence demonstrated that continuous low-dose combined OCPs (skipping sugar pills) compared with standard dosing (21 days of low-dose combined OCPs, then 7 days of sugar pills) lowered pain scores over 4 to 6 months of follow-up (standard mean pain score = 0.73 points lower; 95% CI, 1.13 to 0.34; two RCTs; n = 106). Low-quality evidence demonstrated that continuous dosing may increase any adverse events compared with standard dosing (RR = 1.11; 95% CI, 1.01 to 1.22; NNH = 13; three RCTs; n = 602). Moderate-quality evidence demonstrated that continuous dosing also led to more irregular bleeding than standard dosing (RR = 1.38; 95% CI, 1.14 to 1.69; NNH = 8; two RCTs; n = 379). There did not appear to be any difference in serious adverse events between the two groups. Results demonstrated little or no difference in pain improvement when comparing different levels of estrogen replacement or different OCP generations with each other over 6 months of follow-up.

There was insufficient evidence to draw any conclusions when comparing combined OCPs with nonsteroidal anti-inflammatory drugs for primary dysmenorrhea.

Caveats: This meta-analysis is one of the first to review the use of OCPs in primary dysmenorrhea. The inclusion of RCTs from multicenter studies in 16 countries and over multiple decades allows for wide applicability to different populations.

Limitations included significant heterogeneity in each study (i.e., combined OCP regimens differed, length of treatment varied, pain scales were different, most studies were not well powered) and the short-term (up to 6 months) follow-up for all studies. The authors of the review also raised concerns about biased reporting, lack of blinding, and pharmaceutical funding for approximately 50% of the studies.

Conclusions: Given the reported potential benefits, relatively low rate of adverse events, and the noted limitations along with the potential for bias in the findings, we have assigned a color recommendation of yellow (unclear benefits/more data needed) to the use of combined OCPs for primary dysmenorrhea. Longer-term follow-up studies with more standardized comparisons and appropriate reporting of adverse events are needed moving forward.