Discussion
endometrial lesions, endometriosis, pelvic pain, pain
OXIDATIVE STRESS, ENDOMETRIOSIS
This randomized double-blinded placebo-controlled study could not show that 20 mg melatonin ingested at bedtime reduced endometriosis-associated pain, in contrast to a previous study [Studies have shown that melatonin inhibits the estrogen-driven epithelial cell migration, invasion and epithelial-mesenchymal transition (EMT) [A significantly higher level of protein oxidative stress markers has been shown in the peritoneal fluid of women with endometriosis compared to controls, with a positive correlation between the level of advanced oxygen protein products and the pelvic pain symptom scores [The analgesic effects of melatonin are not fully understood and have been attributed to its anti-oxidative properties, but it is now evident that naloxone inhibits the antinociceptive effect of melatonin concluding the involvement of the opioid system, perhaps via melatonin receptors present in the spinal cord and in the brain [Our regime was fixed to taking the study drug at bedtime to mimic the endogenous production of melatonin, considering the short half-life of melatonin in humans (20–40 minutes) [The given dose and/or mode of administration might not have been sufficient to render any anti-inflammatory effect, to reduce the size of endometrial lesions and to reduce inflammatory pain. A mode of administration with longer duration such as transdermal application, assessed with serum levels of melatonin as well as measuring its clinical effect on pain, could provide information on how to treat endometriosis with melatonin. We could not show any differences between the groups in quality of life or pain catastrophization which were included to assess the more chronic effect of pain.Plasma concentrations of melatonin were not evaluated, which would have provided valuable information, since bioavailability is low at 15% and is associated with high inter-subject variability [The strengths of the study include the comparison of melatonin and placebo in a double blinded, parallel placebo-controlled trial, the low level of dropouts and missing data and the low risk for recollection bias with a daily questionnaire. There was a high rate of adherence to the study drug, no participant had lower than 82% adherence. The study design offers high internal validity. The trial was conducted according to the CONSORT guidelines [The study limitations involve study design as well as method. By including only self-selected non-smoking, Swedish-speaking women in good health our study population is lacking in diversity with a possibly low external validity due to selection bias. By underestimating the standard deviation of the primary outcome the study might be underpowered, as the effect of 1.3 units is included in the confidence interval, a type II error cannot be excluded and the result could be inconclusive [