Age-Related Differences in Corticospinal Function and Muscle Strength: A Systematic Review and Meta-Analysis.

Dysmenorrhea, or menstrual pain, is extremely common, affecting 16%–91% of reproductive-aged girls and women (), and severely affecting approximately 10%–20% of girls and women to the extent of regularly missing school or work (, ). Although dysmenorrhea sometimes (∼20%) appears to be caused by anatomical issues like endometriosis and fibroids, most often (∼80%) there are no clearly identifiable problems other than uterine contractions (). Although it is believed that excess levels of prostaglandins cause increased uterine contractions, inflammation, and pain, other mechanisms, including alterations in the central nervous system, also seem to be involved, suggesting multiple pathways that may be responsible for the experience of menstrual pain (–). Notably, the inhibition of prostaglandin synthesis by nonsteroidal anti-inflammatory drugs (NSAIDs) is considered the first-line treatment for dysmenorrhea. A review of 35 randomized controlled trials estimated an odds ratio of 4.37 for pain relief when comparing NSAIDs to placebo (), suggesting that those who take NSAIDs were approximately four times more likely to experience moderate or excellent pain relief. However, pain relief is most often incomplete (, ). A review of 51 papers estimated that 18% of women with dysmenorrhea experience minimal or no relief from NSAIDs (). Reasons for non-responsiveness to NSAIDs for menstrual pain are unclear and may differ based on underlying pathophysiology (). One study in dysmenorrhea found that women with minimal pain relief had significantly lower serum naproxen levels, implicating suboptimal NSAID bioavailability as one potential mechanism (). Also, anatomical problems (e.g., endometriosis) could render prostaglandin-focused therapies less effective. Studies suggest that NSAIDs are less effective for menstrual pain in those with endometriosis or fibroids (). It is also plausible that central nervous system sensitization contributes to NSAID non-response (). Sensory testing in endometriosis and some dysmenorrhea patients reveals signs of altered central sensitization compared to pain-free participants (, ). As NSAIDs primarily target peripheral rather than central pain processes (), we may expect markers of central sensitization (e.g., pain sensitivity, comorbid chronic pain conditions) to be associated with poorer response to NSAIDs to the extent that central processes are important drivers of menstrual pain.