Menstrual pain (dysmenorrhea) is a major cause of distress, disability, and development of chronic pelvic pain (CPP). Very little is known about how local uterine inflammation and central neural dysregulation interact to cause painful periods. Understanding their interaction and how it might worsen central neural hypersensitivity is essential to prevent dysmenorrhea from progressing into CPP conditions like bladder pain syndrome, irritable bowel syndrome, or endometriosis. There are two factors in dysmenorrhea we have studied that hold promise as targets to reduce future risk of CPP – the presence of co-occurring bladder hypersensitivity and the individual response to common anti-inflammatory treatments. The expansion of pain from one pelvic organ to nearby ones suggests sensory processing dysregulation in the spinal cord or brain. Our preliminary data shows that effective NSAID therapy for dysmenorrhea may reduce future CPP risk by normalizing local nerve activation, inflammatory molecules in the uterine lining, and painful hypersensitivity in adjacent pelvic organs. To distinguish the role of different sensory mechanisms in CPP progression, our interdisciplinary team will use a collection of validated sensory tasks involving mechanical, thermal, electrical stimulation and bladder filling. Our proposal also pairs high-density electroencephalography with sensory testing to identify brain differences related to abnormal pain interpretation. We plan to administer these tasks along with symptom questionnaires to understand why some women with menstrual pain respond better to NSAIDs, and which factors predict diminished CPP risk following an optimized program to reduce menstrual pain. In Aim 1 we will conduct a one- year, randomized controlled trial (n=300) of optimized NSAID vs. placebo treatment for period pain in moderate-plus dysmenorrhea sufferers. We will determine whether active treatment, menstrual pain relief, and lower levels of uterine inflammatory molecules predict lower nonmenstrual pelvic pain (NMPP, a marker for future CPP risk) at one year post-treatment. Aim 2, conducted within the Aim 1 study structure, will establish which specific sensory tests predict reductions in NMPP following treatment. EEG will be used to pinpoint precise mechanisms for differences in these sensory responses. Collectively, this study of higher-risk women is designed to characterize how menstrual pain and bladder hypersensitivity interact to promote CPP, and if these factors predict who benefits from early preventative treatment. The approach is novel for using a sample of women enriched for future pain risk (women with dysmenorrhea and bladder pain) and for conducting future pain-risk prediction with recognized factors: sensory testing profiles, adjacent organ pain involvement, and observed response to a targeted treatment. Structural equation modeling will be used to formally define how these interact to cause CPP while controlling for other key pain risk factors, such as relative local inflammation and psychosocial profiles. These study results obtained by a diverse team of interdisciplinary collaborators are expected to markedly improve our understanding of pain risk heterogeneity for chronic pain prevention

This proposal aligns with the objectives of RFA-NS-24-021 by developing an innovative model of inter-individual differences of lived comorbid menstrual and pelvic pain, incorporating the interplay of inflammatory and neurobiological mechanisms, as well as psychosocial factors with a multidisciplinary team that will lead to evidenced based precision medicine. Focusing on mechanistic insights into uterine pain associated with prevalent gynecological conditions in women, this project aligns NICHD mission that women suffer no harmful effects from reproductive processes and that all children have the chance to achieve their full potential for healthy and productive lives, free from disease or disability, and to ensure the health, productivity, independence and wellbeing of all people.