The effects of melatonin on endometriosis-associated pain and regression of endometrioma; a triple blind randomized controlled trial

<h2>Abstract</h2><h3>Background</h3> Current treatment options for endometriosis-associated symptoms are limited, prompting the exploration of alternative therapeutic approaches. Melatonin has been recognized as a significant analgesic, antioxidant, and anti-inflammatory agent. We aimed to investigate the effect of melatonin, on endometriosis-associated pain and regression of endometrioma. <h3>Methods</h3> Ninety-eight women with confirmed endometriosis and moderate-to-severe pain were randomized to receive 10 mg melatonin or placebo for 8 weeks. Primary outcomes included dysmenorrhea, with secondary endpoints such as chronic pelvic pain, analgesic use, and endometrioma size. A multivariable mixed-effects linear regression model was employed to evaluate the adjusted mean difference (aMD) in the primary outcomes, from baseline to week 8 across the two intervention groups. <h3>Results</h3> Dysmenorrhea, significantly improved in the melatonin group compared to placebo (aMD: 1.15, −1.74, −0.55; p < 0.001). The ‘moderate' and ‘severe' categories of Biberoglu and Behrman (B&B) pelvic pain symptoms (melatonin vs placebo: p = 0.216 at baseline, p = 0.406 at 8 weeks), dysmenorrhea (p = 0.702 at baseline, p = 0.562 at 8 weeks), and dyspareunia (p = 0.694 at baseline, p = 0.395 at 8 weeks) redistributed toward ‘mild' or ‘none' categories in both groups. Analgesic intake decreased significantly in the melatonin group (−1.04 ± 1.32 tablets/56 days) compared to the placebo group (−0.04 ± 0.45 tablets/56 days), with a statistically greater reduction in the melatonin group (aMD: 0.56, 95 % CI: 0.86, −0.26; p < 0.001). There was no significant difference between the groups in the size of right (aMD: 3.49, 95 % CI: 9.28, 2.28; p = 0.226) and left (aMD: 0.91, 95 % CI: 4.19, 2.36; p = 0.584) endometriomas. <h3>Conclusion</h3> Melatonin supplementation is an acceptable complementary option for pain control in endometriosis, showing benefits in the reduction of endometriosis-related pain, including dysmenorrhea, and reduced analgesic intake compared to placebo, without impacting endometrioma size.