Materials and methods
endometriosis, bleeding, Endometriosis, Pain, blood loss, dyspareunia, amenorrhea, pain, dysmenorrhea, dysuria, amenorrhoeic, Insomnia, liver or kidney disease, NRS
ENDOMETRIOSIS, BLEEDING, ENDOMETRIOSIS, BLOOD LOSS, DYSPAREUNIA, ADVERSE EVENTS, RECRUITMENT, DYSMENORRHEA, SECONDARY, CHRONIC PAIN
We conducted this randomized, double-blinded, parallel placebo-controlled trial at Södersjukhuset, a hospital in Stockholm, Sweden. Participants were recruited between August 2019 and March 2021. Prior to enrolment, a written informed consent was obtained from the participants. The principles expressed in the Declaration of Helsinki were respected in conducting the trial. The trial was approved by The Regional Ethical Review Board at Karolinska Institutet (2017/1177-21/2). Registration number at Clincaltrials.gov NCT03782740. The first participant was enrolled 21August 2019, last patient last visit was 27 June 2021.Call for participation was advertised on posters in the hospital, in gynecological outpatient clinics, in maternity care outpatient clinics, and on social media. We recruited women who rated their dysmenorrhea 7 or higher on a numeric rating scale (NRS) during the most painful day or a mean NRS of 3 or more for seven days with endometriosis diagnosed through laparoscopy, ultrasound or MRI. All participants were aged 18–50, in good general health and speaking and understanding Swedish. Initial recruitment included only women without any hormonal treatment with regular menstrual bleedings. The inclusion criteria was expanded to women with hormonal treatment, with or without amenorrhea, due to recruitment difficulties. Screening was made by phone followed by one observational menstrual cycle or 30-day period, during this period of time pain was recorded daily, and evaluated prior to inclusion. The first patients enrolled came for a visit with one of the doctors in charge of the trial, at the clinics Research Center for Womens’ Health for inclusion. The visit included medical history and a pregnancy test. Due to Covid-19 the study was converted entirely to remote visits. The inclusion visit was substituted with a video call for identification with id-card, after randomization the study drugs were sent by registered mail or delivered personally to participants living in Stockholm, a pregnancy test and a consent form were included in the consignment. A picture of the taken pregnancy test was returned prior to commencing with the study drug and the signed form of consent was returned by mail. Exclusion criteria were smoking, pregnancy, prior or current liver or kidney disease, ongoing use of melatonin, alteration of any medication during the last three months, regular use of opioids.After inclusion, participants were randomized to 20 mg melatonin or placebo, each dose identical and dispersed in four capsules of 5 mg melatonin or placebo (both manufactured for the trial by APL, Stockholm, Sweden). The study drug was taken at bedtime daily for two consecutive menstrual cycles with start on the first day of menstrual bleeding or 60 consecutive days for amenorrhoeic participants. If needed, the participants continued with their usual pain medication regime, for the three menstrual cycles/ months of the study. The study period was one observational cycle/month followed by two interventional cycles/months, i.e. three menstrual cycles/months in total.The primary outcome was EAPP recorded daily. The secondary outcomes were use of analgesics, dysuria, dyschezia, dyspareunia, days of pain, absenteeism, quality of life, pain catastrophization and sleep.Daily assessments of pain (using NRS), use of analgesics (with specified dosage and number of tabelts), absenteeism and bleeding using a pictorial blood loss assessment chart (PBAC) were made at bedtime using an online questionnaire sent by email every day. Recording of potential adverse events was included in the questionnaire. General experience of the study drug was evaluated at completion of the study.Quality of life was assessed with Endometriosis Health Profile-30 (EHP-30), chronic pain was assessed with the Pain Catastrophizing Scale and sleep was assessed with Insomnia sleep index (ISI) all done with online questionnaires during the first and last cycle/month respectively.The study data was collected and then managed using REDCap electronic data capture tools (9.5.9 Vanderbuilt University, Nashville TN, USA) hosted at Karolinska Institutet.Participants were randomized consecutively in order of inclusion. The manufacturer of the study drug provided consecutively numbered drug containers and made the randomization in blocks of 4. The randomization key was retrieved and opened after the last participant had completed the study asserting double blinding.