Taking the oral cyclo-oxygenase (COX)-2 inhibitor piroxicam in combination with levonorgestrel improved emergency contraception efficacy versus levonorgestrel alone, with no additional adverse events, a randomized controlled trial showed.

Piroxicam 40 mg combined with levonorgestrel 1.5 mg prevented 94.7% of expected pregnancies compared with 63.4% with levonorgestrel plus placebo (P

Only one woman in the piroxicam group was pregnant after emergency contraception versus seven in the placebo group (OR 0.20, 95% CI 0.02-0.91, P=0.036), they noted in The Lancet.

“To our knowledge, this is the first randomized trial to assess the contraceptive action of a COX inhibitor in humans,” Li and team wrote. “[The] findings of this study could potentially change practice and clinical guidelines.”

The researchers said they chose to study piroxicam over other COX-2 inhibitors because “it is one of the longest-acting COX inhibitors commercially available.”

There were no significant differences between the two groups in the proportion of women with advancement or delay of their next period, and rates of adverse events were also comparable. Fatigue or weakness, nausea, lower abdominal pain, dizziness, breast tenderness, and headache were the most frequently reported adverse events (at least 5%) in both groups.

In an accompanying comment, Erica Cahill, MD, of Stanford University in California, noted that the study “adds to the potential options for pericoital oral contraception.”

“There remains a global unmet need for contraception as people who want to avoid pregnancy have barriers to access, or no method exists with an acceptable route and side-effects,” she wrote, noting that the best available options for an on-demand contraceptive method are emergency contraceptive pills, including levonorgestrel and ulipristal acetate.

“Yet both medications have timing limitations in terms of approved indication — use after unprotected intercourse — and efficacy, with studies showing that levonorgestrel becomes ineffective after luteinizing hormone surge, and ulipristal acetate becomes ineffective after luteinizing hormone peak,” she added.

In an email, Cahill told MedPage Today that “this study showed that it helped prevent pregnancy for a one-time emergency contraception progestin-only pill. More studies are needed to see if it would be helpful to add to other oral contraceptive methods.”

For this study, the researchers recruited patients requesting emergency contraception at the Family Planning Association of Hong Kong — a community sexual and reproductive health clinic — from August 2018 through August 2022. Women were counseled on both ulipristal acetate and levonorgestrel, and those who chose levonorgestrel were eligible for the study.

Participants had to be 18 or older, requesting emergency contraception within 72 hours of unprotected sexual intercourse, have menstrual cycles between 24 and 42 days in length, agree not to have unprotected sex during the study period, and be available for follow-up over 6 weeks.

In total, 860 women were eligible and were block-randomized 1:1 to either piroxicam or placebo plus levonorgestrel. Median age was 31 in the piroxicam group and 30 in the placebo group, and 97% of patients in each group were Chinese.

Twelve women were lost to follow-up in each group; the remaining 418 participants in each group were included in the analysis.

One limitation to the study was that women who recently used hormonal contraception were excluded and therefore the researchers were unable to ascertain whether the regimen was equally effective for people seeking emergency contraception after missing a dose of hormonal contraception.

Since levonorgestrel is less effective among patients with obesity, the results may not be applicable to populations with higher body mass indexes, the authors added.

Future studies should look at using piroxicam in combination with ulipristal acetate versus ulipristal acetate alone, Li and team said.