Unraveling Prostaglandin and NLRP3 Inflammasomemediated Pathways of Primary Dysmenorrhea and the Role of Mefenamic Acid and Its Combinations

Abstract

Painful menstrual cramps during or around the time of the monthly cycle are known as dysmenorrhea. The estimated global prevalence in women of reproductive age ranges from 45% to 95%. It has a significant negative impact on regular activities and productivity at work. However, despite the severe consequences on quality of life, primary dysmenorrhea (PD) is underdiagnosed. Dysmenorrhea has complex pathogenesis. It involves the release of prostaglandins and activation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome and also includes the involvement of other mediators such as bradykinin, histamine and acetylcholine. Even though nonsteroidal anti-inflammatory drugs (NSAIDs) remain the most common type of pain medication, the question of which one should be the most preferred is still open to debate. The current review examines the existing evidence for the pathogenesis of PD and makes evidence based and clinical experience based recommendations for the use of mefenamic acid and its combination in the treatment of dysmenorrhea. Mefenamic acid alleviates PD by inhibiting endometrial prostaglandin formation, restoring normal uterine activity, and reducing the inflammatory response by inhibiting the NLRP3 inflammasome and reducing the release of cytokines such as interleukin (IL)-1β. It is also known to have bradykinin antagonist activity. Dicyclomine has a dual action of blocking the muscarinic action of acetylcholine in postganglionic parasympathetic effect or regions and acting directly on uterine smooth muscle by blocking bradykinin and histamine receptors to relieve spasms. According to the experts, mefenamic acid and dicyclomine act synergistically by acting on the different pathways of dysmenorrhea by blocking multifactorial agents attributed to the cause of dysmenorrhea. Hence, the combination of mefenamic acid and dicyclomine should be the preferred treatment option for dysmenorrhea.