There are limited treatment options for management of dysmenorrhea, and the physiological processes they affect are not completely understood. For example, NSAIDs are effective in reducing menstrual pain in some women by inhibition of prostaglandin synthesis, but whether those effects are mediated by affecting contractility, perfusion, or hypoxemia is unknown. Understanding how these drugs relieve menstrual pain (and why they fail) would be of substantial clinical significance. Given the foregoing, Two Specific Aims are proposed: Aim #1: Characterize menstrual pain phenotypes associated with impairments in myometrial activity, perfusion, and/or oxygenation. Continuous MRI scans of the uterus will be performed with simultaneous measurement of self-reported pain in healthy women and those experiencing menstrual pain. The investigators will include cohorts of women with imaging diagnosed leiomyoma and surgically-confirmed endometriosis to evaluate the contribution of structurally identifiable factors. Based on preliminary data, the investigators anticipate finding four phenotypes with menstrual pain related to: 1) myometrial activity, 2) inadequate perfusion and/or oxygenation, 3) a combination of phenotypes 1 \& 2, and 4) a non-uterine source. Aim #2: Evaluate the effects of naproxen on myometrial activity, perfusion, and/or oxygenation with respect to pain relief. In women with primary dysmenorrhea, the investigators will acquire pelvic MRI scans and evaluate self-reported menstrual cramping pain before and after administration of randomized naproxen or placebo. Naproxen could principally affect one or more potential sources of uterine pain such as myometrial activity, perfusion, and/or oxygenation. The investigators will corroborate preliminary data findings, which suggest menstrual phenotypes with myometrial activity will be more likely to respond. Conversely, Aim 2 will also elucidate the mechanisms responsible for inadequate pain relief from naproxen. Bioavailability of naproxen levels and other molecules associated with NSAID-resistance will be evaluated from the serum of participants after taking naproxen using HPLC-MS.
Due to a lack of noninvasive tools to study uterine physiology, the root causes of menstrual cramping pain within primary dysmenorrhea and secondary dysmenorrhea (leiomyoma, endometriosis, adenomyosis) remain unknown. This pain does not respond to typical over-the-counter anti-inflammatories in 15% of women and is a leading risk factor for developing challenging chronic pelvic pain disorders. In order to guide drug discoveries and create personalized treatment approaches, it is essential to unveil the underlying mechanisms of dysmenorrhea. Our research program has focused on key gaps in our knowledge of uterine physiology, such as the contributions of uterine contractions, perfusion, and oxygenation to menstrual pain. Although these factors are strongly implicated in this debilitating pain disorder, confirmatory human data is still needed. Such research would be quite timely, as numerous drug candidates targeting these potential mechanisms already exist. Our collaborative team has developed MRI-based tools to noninvasively and dynamically measure uterine contractions, perfusion, relative tissue oxygenation, and metabolites indicative of anaerobic respiration. The investigators have also pioneered methods that link spontaneous pain report to simultaneous uterine events. Together, these methods will allow us to evaluate the contribution of contractility, perfusion, or hypoxemia to menstrual pain. Notably, our preliminary data supports our central hypothesis that menstrual pain is associated with different phenotypes involving myometrial hypercontractility, impaired uterine perfusion, uterine hypoxemia, or a non-uterine source. Since understanding how current anti-inflammatory medications relieve or prevent pain (and why they fail) is valuable for the development of improved treatment strategies, the investigators will also investigate the effects of naproxen on uterine physiology in women with menstrual pain. To test our hypothesized contributions of altered uterine muscle activity, perfusion, and oxygenation on pain, The investigators propose: Aim 1: Characterize menstrual pain phenotypes associated with impairments in myometrial activity, perfusion, and/or oxygenation. Continuous MRI sequences of the uterus will be performed with simultaneous measurement of self-reported pain in healthy women and those experiencing menstrual pain. A cohort of women with leiomyoma and endometriosis will also be analyzed to evaluate the contribution of myometrial activity, perfusion, and oxygenation in women with structurally identifiable conditions. Aim 2: Evaluate the effects of naproxen on myometrial activity, perfusion, and/or oxygenation with respect to pain relief. Preliminary data suggests unresolved myometrial activity and inadequate naproxen absorption are associated with insufficient pain relief. Evaluating the naproxen-dependent effects of uterine physiology will provide a foundation for diagnostic tests to indicate relevant personalized treatment for patients that have failed conventional treatments. Further translation of these studies could advance mechanisms for discovery in other chronic pelvic pain conditions and uterine disorders such as idiopathic preterm labor and unexplained infertility.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
QUADRUPLE
Enrollment
183
Single oral dose of 550 mg naproxen sodium (equivalent to 500 mg naproxen base), given as one tablet identical in size, shape, and appearance to the matching placebo. Administered once during a menstrual MRI visit (within 48 hours of menses onset), immediately after the pre-treatment scan and approximately 90 minutes before the post-treatment scan. Each participant receives naproxen at only one of the two MRI visits; the alternate visit (1-2 months later) uses placebo, per the randomized, quadruple-masked crossover. 550 mg naproxen sodium is the highest FDA-approved starting dose; the sodium salt formulation is used to speed absorption.
Single oral placebo pill containing no active drug, matched in size, shape, and appearance to the 550 mg naproxen sodium tablet and supplied in coded containers by the clinical research pharmacy. Administered once during a menstrual MRI visit on the same schedule as naproxen (immediately after the pre-treatment scan, approximately 90 minutes before the post-treatment scan). Each participant receives placebo at only one of the two MRI visits; the alternate visit uses naproxen, per the randomized, quadruple-masked crossover.
NorthShore University HealthSystem
Evanston, Illinois, United States
Number of Participants With Concordant Phenotype Assignment at Both MRI Visits
Menstrual pain phenotypes were derived post hoc rather than assigned. Eleven quantitative signal variables extracted from HASTE and BOLD sequences of the pre-dose menstrual MRI scan were reduced by principal component analysis (6 components retained), and scans were grouped by Ward hierarchical clustering, which yielded three reproducible phenotypes. Each participant's two menstrual MRI scans were independently assigned to one of these phenotypes. A participant was counted as concordant if both scans were assigned to the same phenotype. Reported as the number and percentage of participants with concordant assignment.
Time frame: Two menstrual MRI visits separated by 1 to 2 menstrual cycles (approximately 4 to 8 weeks).
Frequency of Uterine Contractions and BOLD Oxygenation-desaturation Events by Menstrual Pain Phenotype
Menstrual pain phenotypes were derived post hoc rather than assigned. Eleven quantitative signal variables extracted from HASTE and BOLD sequences of the pre-dose menstrual MRI scan were reduced by principal component analysis (6 components retained), and scans were grouped by Ward hierarchical clustering, which yielded three reproducible phenotypes. Clustering was performed at the scan level; each participant contributed up to two scans (84 participants, 119 scans). This measure reports the mean number of uterine contractions and BOLD oxygenation-desaturation events detected per 10-minute scan within each phenotype. R2\* and arterial spin labeling sequences were not acquired in this round and were not included in phenotyping.
Time frame: Pre-dose menstrual MRI scan at each MRI visit; each scan approximately 1 hour.
Mean Duration of Individual Uterine Contractions by Menstrual Pain Phenotype
Menstrual pain phenotypes were derived post hoc rather than assigned. Eleven quantitative signal variables extracted from HASTE and BOLD sequences of the pre-dose menstrual MRI scan were reduced by principal component analysis (6 components retained), and scans were grouped by Ward hierarchical clustering, which yielded three reproducible phenotypes. Clustering was performed at the scan level; each participant contributed up to two scans (84 participants, 119 scans). This measure reports the mean duration of an individual uterine contraction within each phenotype. Duration was quantified as the number of HASTE frames spanning each contraction, acquired at 2 frames per second, and is reported here in seconds. Longer values indicate contractions of greater individual duration.
Time frame: Pre-dose menstrual MRI scan at each MRI visit; each scan approximately 1 hour.
Myometrial and Junctional Zone Thickness by Menstrual Pain Phenotype
Menstrual pain phenotypes were derived post hoc rather than assigned. Eleven quantitative signal variables extracted from HASTE and BOLD sequences of the pre-dose menstrual MRI scan were reduced by principal component analysis (6 components retained), and scans were grouped by Ward hierarchical clustering, which yielded three reproducible phenotypes. Clustering was performed at the scan level; each participant contributed up to two scans (84 participants, 119 scans). This measure reports mean myometrial and junctional zone thickness, measured in millimetres at the anterior and posterior uterine wall, within each phenotype.
Time frame: Pre-dose menstrual MRI scan at each MRI visit; each scan approximately 1 hour.
BOLD Signal Intensity and Desaturation Dip Magnitude by Menstrual Pain Phenotype
Phenotypes were derived post hoc by principal component analysis and Ward hierarchical clustering of eleven HASTE and BOLD signal variables from the pre-dose menstrual MRI scan, at the scan level; each participant contributed up to two scans (84 participants, 119 scans). A desaturation event is a transient drop in BOLD signal. Baseline signal intensity is the mean BOLD signal preceding a desaturation event; minimum signal intensity is the mean signal at the nadir of the event; range of signal change is the difference between them. Higher baseline and minimum values indicate greater BOLD signal, and a larger range indicates a deeper desaturation, i.e. a greater transient drop in oxygenation. Scans with no desaturation event were assigned a nadir equal to baseline and a range of zero. Values are in arbitrary scanner signal intensity units and are not comparable across studies.
Time frame: Pre-dose menstrual MRI scan at each MRI visit; each scan approximately 1 hour.
Percentage Change in BOLD Signal From Baseline by Menstrual Pain Phenotype
Menstrual pain phenotypes were derived post hoc rather than assigned. Eleven quantitative signal variables extracted from HASTE and BOLD sequences of the pre-dose menstrual MRI scan were reduced by principal component analysis (6 components retained), and scans were grouped by Ward hierarchical clustering, which yielded three reproducible phenotypes. Clustering was performed at the scan level; each participant contributed up to two scans (84 participants, 119 scans). Percentage signal change expresses the magnitude of the BOLD desaturation as a proportion of baseline signal intensity, so larger values indicate a deeper transient drop in oxygenation. It is defined only where a desaturation event was detected; scans without a detected event were assigned a value of zero. Phenotype P2 was characterized by near-absent BOLD activity, so its distribution consists predominantly of these structural zeros.
Time frame: Pre-dose menstrual MRI scan at each MRI visit; each scan approximately 1 hour.
Change in Junctional Zone Thickness From Pre-dose to Post-dose Scan, Naproxen Versus Placebo
Within-subject change in junctional zone thickness, measured in millimetres, from the pre-dose to the post-dose scan, compared between the naproxen and placebo conditions in participants with primary dysmenorrhea. Change is calculated as post-dose minus pre-dose, so positive values indicate greater thickness after dosing. Each participant contributed a change score under both conditions. Row numbers analyzed differ because not every participant had both scans measurable at both wall locations. Post-dose BOLD sequences were successfully acquired at only 5 of 39 crossover visit pairs, and R2\* and arterial spin labeling sequences were not acquired in this round, so no naproxen-versus-placebo comparison is reported for those signal families.
Time frame: Pre-dose scan to post-dose scan at each of two menstrual MRI visits; the post-dose scan began approximately 90 minutes after dosing (each scan approximately 1 hour).
Change in Uterine Contraction Frequency From Pre-dose to Post-dose Scan, Naproxen Versus Placebo
Within-subject change in the number of uterine contractions detected per 10-minute scan, from the pre-dose to the post-dose scan, compared between the naproxen and placebo conditions in participants with primary dysmenorrhea. Change is calculated as post-dose minus pre-dose, so positive values indicate more contractions after dosing. Each participant contributed a change score under both conditions. Post-dose BOLD sequences were successfully acquired at only 5 of 39 crossover visit pairs, and R2\* and arterial spin labeling sequences were not acquired in this round, so no naproxen-versus-placebo comparison is reported for those signal families.
Time frame: Pre-dose scan to post-dose scan at each of two menstrual MRI visits; the post-dose scan began approximately 90 minutes after dosing (each scan approximately 1 hour).
Agreement Between Primary and Sensitivity Phenotype Clustering Solutions (Adjusted Rand Index)
Sensitivity analysis testing the stability of the three-phenotype clustering solution. Clustering was re-run after excluding participants reclassified on independent anatomical review, and the resulting partition was compared with the primary solution across the retained pre-dose MRI scans using the adjusted Rand index. The adjusted Rand index measures agreement between two partitions of the same data, corrected for chance: 1.0 indicates identical partitions, 0 indicates agreement no better than chance, and negative values indicate agreement worse than chance. The index is a single value describing agreement across the entire retained set of scans rather than a per-participant measurement, so one number is reported for the group as a whole and no comparison between arms is possible.
Time frame: Two menstrual MRI visits separated by 1 to 2 menstrual cycles (approximately 4 to 8 weeks). Pre-dose scan at each visit assessed.
Correlation of NSAID Resistance With Clinical/Psychosocial Covariates
NSAID resistance was defined as pain intensity at 6 hours after naproxen dosing minus peak pre-dose pain intensity, each rated on a 0 to 10 Numerical Rating Scale, so that higher values indicate less pain relief. This measure reports the Spearman rank correlation between NSAID resistance and six covariates: age in years; parity, the number of prior deliveries; the Sexual and Physical Abuse Questionnaire total score, scored only where all seven items were completed; PROMIS Anxiety and PROMIS Depression short-form scores, reported as raw summed scores rather than standardized T-scores; and pressure-pain threshold, the mean force at which applied abdominal pressure was first reported as painful. A positive correlation indicates that higher covariate values are associated with less pain relief.
Time frame: Peak pre-dose pain to 6 hours after naproxen dosing at the naproxen menstrual MRI visit.
Correlation of NSAID Resistance With Serum Naproxen (90 Min)
NSAID resistance was defined as pain intensity at 6 hours after naproxen dosing minus peak pre-dose pain intensity, each rated on a 0 to 10 Numerical Rating Scale, so that higher values indicate less pain relief. Serum naproxen concentration was measured from a blood sample drawn 90 minutes after dosing, at approximately the time of the post-dose scan. This measure reports the Spearman rank correlation between serum naproxen concentration and NSAID resistance, testing whether variation in drug absorption accounts for variation in pain relief. A negative correlation would indicate that higher serum concentrations are associated with greater pain relief.
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Time frame: Peak pre-dose pain to 6 hours after naproxen dosing at the naproxen menstrual MRI visit; serum was sampled 90 minutes after dosing.