Adjuvant use of melatonin for pain management in dysmenorrhea - a randomized double-blinded, placebo-controlled trial

Lisa Söderman, Måns Edlund, Ylva Böttiger, Lena Marions, Lisa Söderman, Måns Edlund, Ylva Böttiger, Lena Marions

Abstract

Purpose: Dysmenorrhea is a common, recurring, painful condition with a global prevalence of 71%. The treatment regime for dysmenorrhea includes hormonal therapies and NSAID, both of which are associated with side effects. A dose of 10 mg melatonin daily has previously been shown to reduce the level of pelvic pain in women with endometriosis. We chose to investigate how this regime, administered during the week of menstruation, would affect women with dysmenorrhea but without any signs of endometriosis, as adjuvant analgesic treatment.

Methods: Forty participants with severe dysmenorrhea were randomized to either melatonin or placebo, 20 in each group. Our primary outcome was pain measured with numeric rating scale (NRS); a difference of at least 1.3 units between the groups was considered clinically significant. Secondary outcomes were use of analgesics, as well as absenteeism and amount of bleeding. Mixed model was used for statistical analysis.

Results: Eighteen participants completed the study in the placebo group and 19 in the melatonin group. Mean NRS in the placebo group was 2.45 and 3.18 in the melatonin group, which proved to be statistically, although not clinically significant.

Conclusion: This randomized, double-blinded, placebo-controlled trial could not show that 10 mg of melatonin given orally at bedtime during the menstrual week had better analgesic effect on dysmenorrhea as compared with placebo. However, no adverse effects were observed.

Clinical trials: NCT03782740 registered on 17 December 2018.

Keywords: Adjuvant analgesics; Dysmenorrhea; Melatonin; Menstruation; Pelvic pain; RCT.

Conflict of interest statement

LS, YB, and LM report no conflict of interest. ME holds a full-time position as Medical Director for SOBI AB.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Flowchart showing recruitment and progress through the study. Intent-to-treat (ITT) analyses included 19 participants in the melatonin group and 18 in the placebo group. Per-protocol (PP) analyses were made on 16 participants in each group
Fig. 2
Fig. 2
Dysmenorrhea day by day. Mean level of dysmenorrhea reflected by numeric rating scale (NRS) days 2–7 for the two study groups during the two treatment cycles, respectively

References

    1. Armour M et al (2019) Self-care strategies and sources of knowledge on menstruation in 12,526 young women with dysmenorrhea: a systematic review and meta-analysis. PLoS One 14(7):e0220103
    1. Keogh E, et al. The effects of menstrual-related pain on attentional interference. Pain. 2014;155(4):821–827. doi: 10.1016/j.pain.2014.01.021.
    1. ACOG Committee Opinion No 760: Dysmenorrhea and endometriosis in the adolescent. Obstet Gynecol. 2018;132(6):e249–e258. doi: 10.1097/AOG.0000000000002978.
    1. Dawood MY. Primary dysmenorrhea: advances in pathogenesis and management. Obstet Gynecol. 2006;108(2):428–441. doi: 10.1097/01.AOG.0000230214.26638.0c.
    1. Chan WY, Dawood MY, Fuchs F (1981) Prostaglandins in primary dysmenorrhea. Comparison of prophylactic and nonprophylactic treatment with ibuprofen and use of oral contraceptives. Am J Med 70(3):535–41
    1. Iacovides S, et al. Women with dysmenorrhea are hypersensitive to experimental deep muscle pain across the menstrual cycle. J Pain. 2013;14(10):1066–1076. doi: 10.1016/j.jpain.2013.04.010.
    1. Han F, et al. Correlation between thalamus-related functional connectivity and serum BDNF levels during the periovulatory phase of primary dysmenorrhea. Front Hum Neurosci. 2019;13:333. doi: 10.3389/fnhum.2019.00333.
    1. Cipolla-Neto J, Amaral FGD. Melatonin as a hormone: new physiological and clinical insights. Endocr Rev. 2018;39(6):990–1028. doi: 10.1210/er.2018-00084.
    1. Andersen LP (2016) The analgesic effects of exogenous melatonin in humans. Dan Med J 63:10
    1. Chen WW, Zhang X, Huang WJ. Pain control by melatonin: physiological and pharmacological effects. Exp Ther Med. 2016;12(4):1963–1968. doi: 10.3892/etm.2016.3565.
    1. Szmidt MK et al (2020) Primary dysmenorrhea in relation to oxidative stress and antioxidant status: a systematic review of case-control studies. Antioxidants (Basel) 9:10
    1. Reiter RJ, et al. Melatonin as an antioxidant: under promises but over delivers. J Pineal Res. 2016;61(3):253–278. doi: 10.1111/jpi.12360.
    1. Ayar A, et al. Melatonin inhibits spontaneous and oxytocin-induced contractions of rat myometrium in vitro. Neuro Endocrinol Lett. 2001;22(3):199–207.
    1. Stefani LC et al (2013) A phase II, randomized, double-blind, placebo controlled, dose-response trial of the melatonin effect on the pain threshold of healthy subjects. PLoS One 8(10):e74107
    1. Caumo W, et al. The clinical impact of preoperative melatonin on postoperative outcomes in patients undergoing abdominal hysterectomy. Anesth Analg. 2007;105(5):1263–1271. doi: 10.1213/01.ane.0000282834.78456.90.
    1. de Zanette SA, et al. Melatonin analgesia is associated with improvement of the descending endogenous pain-modulating system in fibromyalgia: a phase II, randomized, double-dummy, controlled trial. BMC Pharmacol Toxicol. 2014;15(1):40–40. doi: 10.1186/2050-6511-15-40.
    1. Lu WZ, et al. Melatonin improves bowel symptoms in female patients with irritable bowel syndrome: a double-blind placebo-controlled study. Aliment Pharmacol Ther. 2005;22(10):927–934. doi: 10.1111/j.1365-2036.2005.02673.x.
    1. Leone M, et al. Melatonin versus placebo in the prophylaxis of cluster headache. Cephalalgia. 2016;16(7):494–496. doi: 10.1046/j.1468-2982.1996.1607494.x.
    1. Schwertner A, et al. Efficacy of melatonin in the treatment of endometriosis: a phase II, randomized, double-blind, placebo-controlled trial. Pain. 2013;154(6):874–881. doi: 10.1016/j.pain.2013.02.025.
    1. Todd KH, et al. Clinical significance of reported changes in pain severity. Ann Emerg Med. 1996;27(4):485–489. doi: 10.1016/S0196-0644(96)70238-X.
    1. Hilli J et al (2008) The effect of oral contraceptives on the pharmacokinetics of melatonin in healthy subjects with CYP1A2 g.-163C>A polymorphism. J Clin Pharmacol 48(8):986–94
    1. Harpsøe NG, et al. Clinical pharmacokinetics of melatonin: a systematic review. Eur J Clin Pharmacol. 2015;71(8):901–909. doi: 10.1007/s00228-015-1873-4.
    1. Nelson FA, Farr LA, Ebadi M. Salivary melatonin response to acute pain stimuli. J Pineal Res. 2001;30(4):206–212. doi: 10.1034/j.1600-079X.2001.300403.x.
    1. Almay BG, von Knorring L, Wetterberg L. Melatonin in serum and urine in patients with idiopathic pain syndromes. Psychiatry Res. 1987;22(3):179–191. doi: 10.1016/0165-1781(87)90033-3.
    1. Brzezinski A, et al. The circadian rhythm of plasma melatonin during the normal menstrual cycle and in amenorrheic women. J Clin Endocrinol Metab. 1988;66(5):891–895. doi: 10.1210/jcem-66-5-891.
    1. Kostoglou-Athanassiou I, et al. Neurohypophysial hormone and melatonin secretion over the natural and suppressed menstrual cycle in premenopausal women. Clin Endocrinol (Oxf) 1998;49(2):209–216. doi: 10.1046/j.1365-2265.1998.00504.x.
    1. Shechter A, Varin F, Boivin DB. Circadian variation of sleep during the follicular and luteal phases of the menstrual cycle. Sleep. 2010;33(5):647–656. doi: 10.1093/sleep/33.5.647.
    1. Schulz KF, Altman DG, Moher D (2010) CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMJ 340:c332

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