Adding piroxicam improves the efficacy of levonorgestrel emergency contraception

A single dose of levonorgestrel 1.5 mg, taken within 72 hours of unprotected sexual intercourse, is the most widely used method of emergency contraception. However, levonorgestrel is only effective as an emergency contraceptive when given before (not after) ovulation. It prevents pregnancy by blocking or postponing the luteinizing hormone surge, which disrupts the ovulatory process. Levonorgestrel is not effective when taken after the luteinizing hormone surge has started, a time when intercourse is most likely to result in pregnancy. The later in the follicular phase that levonorgestrel is taken, the lower its ability to block ovulation (and prevent fertilization) will be.1 Prostaglandins facilitate several reproductive processes, including ovulation, fertilization, tubal function and embryo implantation. Inhibiting the cyclo-oxygenase (COX) enzyme, the key enzyme involved in prostaglandin production, might result in a synergistic effect with oral emergency contraceptives and improve their efficacy in regulating both ovulatory and post-ovulatory processes.1 To examine this issue, researchers investigated whether a single 40 mg oral dose of piroxicam as co-treatment with levonorgestrel improved emergency contraceptive efficacy. The researchers chose piroxicam as the study drug because it has a long half-life (~50 h) compared to meloxicam (~20 h) or celecoxib (11–16 h).1 The randomized double-blind placebo-controlled trial recruited women who required levonorgestrel emergency contraception within 72 hours of unprotected sexual intercourse. They were randomized to receive a single supervised dose of levonorgestrel 1.5 mg plus either piroxicam 40 mg or placebo orally. At follow-up (one to two weeks after the next expected menstrual period), pregnancy status was noted by history or pregnancy test. The primary efficacy outcome was the proportion of pregnancies prevented out of those expected based on an established model.1 Results showed the following: The study included 860 women (430 in each group). At follow-up, one (0.2%) of 418 efficacy-eligible women in the piroxicam group was pregnant, compared with seven (1.7%) of 418 in the placebo group (odds ratio 0.20 [95% CI 0.02–0.91]; p=0.036). Levonorgestrel–piroxicam prevented 94.7% of expected pregnancies compared with 63.4% for levonorgestrel–placebo. No significant difference was seen between the two groups in the proportion of women with advancement or delay of their next period, or in the adverse event profile.1 The investigators conclude that oral piroxicam 40 mg co-administered with levonorgestrel improves the efficacy of emergency contraception and should be considered clinically when levonorgestrel is the emergency contraceptive of choice. Piroxicam–levonorgestrel co-treatment results in a significantly higher efficacy in preventing pregnancy, as well as a significantly lower failure rate, than levonorgestrel alone. Piroxicam co-treatment does not seem to be associated with an increase in menstrual pattern disturbances or adverse events compared with levonorgestrel alone. The findings of this study, if confirmed by other studies, have the potential to change practice and emergency contraception clinical guidelines.1 The authors note that their study excluded women with current or recent use of hormonal contraception, as well as those with more than one episode of unprotected sexual intercourse before emergency contraception. Therefore, it is uncertain whether the piroxicam–levonorgestrel regimen will be equally effective when applied to women who seek emergency contraception because of missed hormonal contraceptive doses or those with multiple episodes of unprotected sexual intercourse. In addition, as the study involved women of Asian ethnicity in Hong Kong, the body weight of participants was low, with only 9% of the piroxicam group and 11% of the placebo group having a body mass index (BMI) > 26 kg/m² or weighing > 70 kg. Since the efficacy of levonorgestrel emergency contraception is lower in women with obesity, the efficacy shown with piroxicam–levonorgestrel in this study might not be generalizable to patients with higher body weight.1,2 References 1. Li RHW, Lo SST, Gemzell-Danielsson K, et al. Oral emergency contraception with levonorgestrel plus piroxicam: a randomised double-blind placebo-controlled trial. Lancet 2023;402:851-8. (accessed September 14, 2023). 2. Cahill EP. Adding a COX-2 inhibitor improves efficacy of emergency contraception. Lancet 2023;402:826-7. (accessed September 14, 2023).

Adding piroxicam improves the efficacy of levonorgestrel emergency contraception

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