This randomized, double-blind, 2-group parallel, clinical trial conducted in Brazil compared the effects of melatonin compared with a placebo on endometriosis-associated pelvic pain, brain derived neurotrophic factor level and sleep quality. Forty women were randomized into melatonin 10 mg/day (n=20) or placebo (n=20) groups for 8 weeks.
Forty women with chronic pelvic pain, who were between 18 and 45 y.o. were recruited from gynecology outpatient clinics. Chronic pelvic pain was defined as a moderate-to-severe pain lasting for more than 6 months and eliciting pain scores of at least 4 or greater on a 10 point pain scale that required regular analgesic use. All patients had a diagnosis of endometriosis as confirmed on laparoscopy and included patients with any stage from stage 1 to stage 4. Three patients in the melatonin group and one in the placebo group withdrew due to treatment inefficacy.
The primary outcome of the trial was pain, as assessed by pain score diaries within the last 24 hours, painful menstrual periods or dyspareunia, as well as the amount of analgesics used each week throughout the treatment period and the level of brain derived neurotrophic factor (BDNF). Secondary outcomes were pain during urination or defecation and sleep quality.
The melatonin group had significantly lower pain visual analogue scale (VAS) scores than the placebo-treated group with a mean pain reduction of 39.3% in the melatonin group vs the placebo group. The melatonin group also had significantly lower pain score during menstruation with mean reduction in analgesic use of 42.2% in the placebo group and 22.9% of patients in the melatonin group. The placebo group was 80% more likely to require additional analgesics than the melatonin group. In the placebo group, acetaminophen was used by 66.7%, NSAIDS by 60% and codeine or tramadol by 60%. In the melatonin group, 33.3% used acetaminophen, 40% used tramadol or codeine and 35% used NSAIDS.
The reduction in BDNF, greater with melatonin than placebo, suggests that melatonin has a direct effect on pain pathways or on the levels of chemicals that are signals for pain. Patients in the melatonin group also had better sleep quality than the placebo group and melatonin produced a mean improvement of 42% in how patients felt upon waking in the morning.
Commentary: This study demonstrated that melatonin at 10 mg/day reduces endometriosis associated chronic pelvic pain, including a reduction in pelvic pain, pelvic pain during menses, pain during vaginal penetration, pain during urination and pain during defecation that is statistically and clinically significant. This reduction in pelvic pain due to melatonin was of a magnitude > 35% overall, as well as an 80% reduction in analgesic use.
This study is consistent with evidence from animal studies in which melatonin caused regression and atrophy of endometriotic lesions. The current study also corroborates other randomized clinical trials on melatonin and pain in particular, in treating fibromyalgia and acute postoperative pain.
Melatonin is well tolerated by most patients and appears to represent an effective option for pain symptoms related to endometriosis. A 2013 observational study on N acetyl cysteine also resulted in significant pain reduction and ovarian cyst size reduction associated with endometriosis. I consider these two nutrients as mainstays in our treatment strategies for endometriosis.
Schwertner A, Conceicao dos Santos C, Costa G, et al. Efficacy of melatonin in the treatment of placebo endometriosis: A phase II, randomized, double-blind, placebo controlled trial. PAIN 2013;154(6):874-881.