The impact of metronidazole on pain persistence after fertility-sparing endometriosis surgery: METROFERT randomized study

BACKGROUND: Recent studies have shown that a disrupted microbiome is associated with endometriosis. Despite endometriosis affecting 1 in 10 reproductive-aged women, there is a lack of innovative and nonhormonal long-term effective treatments. Studies have reported an approximately 20% to 37.5% persistence of pain after fertility-sparing endometriosis surgery. Metronidazole has been shown to decrease inflammatory markers and the size of endometriosis lesions in animal studies. OBJECTIVE: To determine if modulating the microbiome with oral metronidazole for 14 days after fertility-sparing endometriosis surgery decreases pain persistence postoperatively. STUDY DESIGN: This was a randomized, multicenter, placebo-controlled, double-blind trial. Individuals 18 to 50 years old were prospectively randomized to placebo vs oral metronidazole for 14 days immediately after endometriosis fertility-sparing excision surgery. The primary outcome was binary, subjective pain persistence at 6 weeks postoperatively. Secondary outcomes included quality of life, sexual function, and endometriosis-associated pain scores according to the Endometriosis Health Profile-5, Female Sexual Function Index, and a visual analog scale. RESULTS: One hundred fifty-two participants were approached from October 2020 to October 2023 to enroll in the study. Sixty-four participants were excluded either because they did not meet inclusion or exclusion criteria or because they declined to participate. Eighty-eight participants were randomized in a 1:1 ratio to receive either the oral placebo or metronidazole after endometriosis excision surgery; 18.2% of participants were lost to follow-up or discontinued treatment and this was not significantly different between the 2 arms, yielding a final cohort of 72 participants. Baseline demographics of the 2 study groups were similar. There was no statistically significant improvement in the primary outcome of binary subjective pain persistence between the metronidazole group compared to placebo (84% vs 88%, P=.74) at 6 weeks postoperatively. Further, no significant differences between treatments were detected in the secondary outcomes. CONCLUSION: A postoperative 14-day regimen of oral metronidazole immediately after fertility-sparing endometriosis surgery was not associated with any significant differences between treatment groups in the persistence of endometriosis-related pain symptoms compared to placebo at 6 weeks.