Examining the Role of Improved NSAID Management in Treating Dysmenorrhea and Bladder Pain
Phase: PHASE4
Conditions: Dysmenorrhea, Pain
Sponsor: Endeavor Health

IRB PROTOCOL 
EH18-128: Examining the role of improved NSAID 
management in treating dysmenorrhea NCT03697720, May 31 
2018 
PI: FRANK F. TU, MD MPH 
EH18-128
Version 
1.1 

 
 
I R B  P R O T O C O L  
Examining the role of improved NSAID 
management in treating dysmenorrhea  
 The Gyrl Lab 2018 
 
 

N S A I D  P R O T O C O L  E H 1 8 - 1 2 8  
 
1 
Table of Contents 
Protocol: Revision 1 dated 5/4/18 .................................................................... 2 
Overview: .................................................................................................... 2 
Study participants ....................................................................................... 3 
Inclusion Criteria: ............................................................................. 3 
Exclusion criteria: ............................................................................ 3 
Recruitment: .................................................................................... 3 
Phone Screen .................................................................................. 4 
Study Visits ................................................................................................. 4 
Consent ........................................................................................... 4 
Questionnaires ................................................................................ 4 
Rapid Bladder Test .......................................................................... 5 
Assessments ................................... Error! Bookmark not defined. 
Naproxen: ........................................................................................ 9 
Between visit measurements: .......................................................... 9 
Repeat Assessment: ....................................................................... 9 
Power Analysis/Data Analysis: .................................................................. 10 
Bibliography .............................................................................................. 10 
 
 
 
Chapter 
1 

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2 
 
Protocol Version: 1.1  
Overview:  
Many of the women experience severe menstrual pain, yet undermanage their pain level by 
not taking a sufficient amount of NSAIDs. Notably, biochemical analyses demonstrate that the 
administration of naproxen prior to the initiation of the COX-2 cascade results in nearly complete 
suppression of prostaglandin synthesis; attempting to block synthesis afterwards only leads to a 
gradual and incomplete suppression.1 The single, but underpowered trial, comparing menstrual pain 
relief between prophylactic versus response use to pain with ibuprofen did not find a difference.2 It 
is possible that differences in prophylactic use of naproxen and ibuprofen could be due to different 
preferential binding to COX-1 and COX-2 receptors. Aside from this trial, clinical investigators have 
not sufficiently investigated prophylactic use of NSAIDs prior to the onset of menses. Although an 
educational trial regarding prophylaxis did demonstrate increased patient knowledge, reduction of 
menstrual pain was not evaluated.3 Therefore, in the present study we will establish whether 
prophylactic and adequate dosages of Naproxen are capable of reducing menstrual pain more than 
response use. Secondly, we will establish whether reduction of menstrual pain with optimized 
naproxen use can reduce bladder pain via cross-organ sensitization or central sensitization. We 
hypothesize that cross-organ sensitization (COS) is the mechanism by which dysmenorrhea may 
lead to some forms of chronic pelvic pain. Uterine inflammation during menstruation likely 
contributes to chronic pelvic pain (CPP) by triggering neurogenic inflammation in adjacent organs.4 
This COS has been demonstrated with experimental injury and infection in animal models.5,6 Our 
prior findings discussed above7,8 motivate our present central hypothesis: dysmenorrhea produces CPP 
via repetitive COS episodes. 
In our ongoing study looking at the relationship between dysmenorrhea, COS and CPP 
(EH13-094), we planned to determine whether oral contraceptive pills (OCPs), by alleviating 
menstrual pain could reverse the development of COS. However, our interim analyses of 
participants in this study identify that many are unwilling to initiate OCPs due to the perceived side 
effects and fear of hormones. Other interventions to reduce the development of COS also plausibly 
exist, notably NSAIDs. Therefore, we propose to re-enroll many of the participants from EH13-094 
who gave permission for future contact.  We will utilize their baseline assessment visit data in order 
to establish whether naproxen can improve menstrual and bladder outcomes. After consent, prior 
data will be linked with the current study. We will also open this study to new participants who will 
be asked to perform a baseline visit (bladder test, pressure tests, EEG, questionnaires and blood 
draw). Participants will be invited to an open label (non-randomized) prospective trial of naproxen. 
After six to eight months of diary data, urine monitoring, and blood samples, a repeat visit (bladder 
test, pressure tests, EEG, questionnaires, and blood draw) will be conducted. The majority of the 
testing details below have been previously approved for the ongoing study EH13-094.  
Additionally, we will investigate whether mechanisms involved in pain sensitivity predict 
responses to effectiveness of NSAID treatment for menstrual or bladder pain.  Several studies 
identify that women with menstrual pain have central sensory processing abnormalities akin to what 
is observed in women with chronic pelvic pain states.9–11  Focused investigation into gynecological 
risk factors for bladder pain syndrome is of particularly high value, as it more commonly affects 
women 12, and current treatments, such as pentosan polysulfate,13 amitriptyline, 14 or cystoscopic 
hydrodistension15 are only modestly effective. The limited efficacy of these treatments reflects the 
multifactorial mechanisms underlying BPS, particularly in later stages, which may include cross-
organ sensitization, central nervous system sensitization, mucosal inflammation, and 
neuropsychological factors.16 One underlying hypothesis for this finding is that repetitive episodes of 

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3 
dysmenorrhea promote cross-organ or central sensitization. This is supported by clinical 
observations17 and experimentally in animal models of provoked uterine inflammation.6 Mechanisms 
involved in central pain modulation can be evaluated with conditioned pain modulation and pressure 
pain testing10,18 and both will be used in this proposal. Additionally, we will look at neural 
mechanisms using audio and visual tasks19 with EEG. We will determine whether baseline 
mechanisms are correlated with menstrual and bladder outcomes. The within subject design also 
allows us to determine if changes in mechanisms (baseline vs repeat visit) are associated with better 
outcomes.  
 
Study participants 
Inclusion Criteria:  
Reproductive-age women (age 18-45) with dysmenorrhea will be recruited. Cases will have: 
a) average menstrual pain ≥ 5/10 (0=no pain and 10=the worst imaginable pain) on at least one day 
during menses or during withdrawal uterine bleeding from cyclic OCs without painkillers, b) 
menstrual pain in the region between the umbilicus and the perineum, above the level of the inguinal 
ligament, and c) indication the participant has attempted to resolve pain by medical means (including 
NSAIDs and/or OCPs). In the circumstance that a participant originally assigned to the 
dysmenorrhea group does not reach a pain of 5 on any days on the daily diary, this will be handled 
on a case-by-case basis particularly if they used a continuous around-the-clock, effective pain 
treatment regimen. Participants who endorse bladder symptoms (subclinical urgency, frequency, 
bladder pain) on the phone screen or bladder symptoms as reported in EH13-094 will be 
preferentially recruited (at least 50% of enrolled participants); those who do not endorse bladder 
symptoms may be determined ineligible. They must not have a formal urological diagnosis such as 
overactive bladder or painful bladder syndrome.  
 
Exclusion criteria:  
Includes: a) presence of active pelvic or abdominal malignancies (primary or metastatic), b) 
absence of regular menses (including current pregnancy, recent pregnancy, or active breast feeding), 
c) active genitourinary infection in the last four weeks, d) unable to read or comprehend the 
informed consent in English, e) unwilling to complete study procedures, and f) presence of 
hypertension or risk for developing hypertension, g) unwillingness to take naproxen and/or placebo, 
h) or contradictions to taking naproxen (allergies, kidney disease, anemia, alcoholism, cardiovascular 
disease, stomach or intestinal ulcer or abnormal liver function). Participants with a history of 
epilepsy will not complete the visual unpleasantness task.  
 
Recruitment: 
Participants will primarily be recruited based on prior participation in the parent study 
(EH13-094), which has currently more than 100 potential participants. Additional recruitment may 
occur from NorthShore’s clinical sites in the Chicago-area and from the community through 
advertising in: NorthShore University HealthSystem’s outpatient clinics; web-based advertising; 
posters and flyers in local businesses (coffee shops, athletic clubs) and on college campuses; referrals 

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from local gynecologists; and the Illinois Women’s Health Registry based at Northwestern 
University’s Feinberg School of Medicine. All flyers and ads will be IRB approved. We will use IRB 
approved ads from our Recruitment Registry (EH16-117) that informs participants about any of our 
open studies in our lab. Participants may call our research hotline directly, respond to our online 
pre-screen, or after they indicate interest and give permission, their doctor will send us their contact 
information and a research coordinator will call the patient to formally assess eligibility using a 
phone screen. At the end of the phone screen, participants will be asked if we have permission to 
put their phone screen and contact information into our recruitment registry (EH16-117).  
 
Phone Screen 
All callers will complete a phone screen to assess eligibility before being scheduled for a 
screen visit. At the end of the phone screen, all callers will be asked if we have their permission to 
keep their phone screen information and contact them for future studies. Participants who indicate 
yes will be added to our recruitment registry (EH16-117) study upon study closeout. Eligible callers 
will be scheduled for a screen visit. We may attempt to match groups for age and demographics. 
Thus, in some cases, eligibility on the phone screen may vary based on the study’s current need for 
individuals with certain demographics for each group. We may also require dysmenorrhea 
participants to endorse bladder symptoms on the phone screen in order for them to be eligible to 
come in for a screen visit. During the phone screen, we will discuss when their last period occurred 
and when they anticipate their next period to schedule the study visits. Participants will be instructed 
not to donate blood before the study visit to avoid excessive blood draw. Participants will receive 
directions from well-known medical educational web sites (such as 
https://www.mayoclinic.org/diseases-conditions/menstrual-cramps/ , 
https://www.webmd.com/women/menstrual-cramps ). Our trial is in consensus with expert 
recommended medical guidelines that are suggested on these web sites.    
Study Visits 
We will perform 3-4 study visits: a screen visit, a baseline study visit, a blood draw study visit, and a 
follow-up study visit. Participants that have participated in EH13-094 in the last 12 months will not 
need to participate in the baseline study visit as the data was collected during the EH13-094 
assessment visit.  
 
Consent  
Informed consent will be obtained by a trained research assistant at the screen visit before 
any questionnaires or study procedures are completed.  
 
Questionnaires 
At the screen, baseline and follow-up visit (either in person or over the web using a 
REDCAP, secure interface) participants will complete the following questionnaires: a) complete 
medical, surgical, and gynecological history, and b) a psychosocial assessment using short-form 
PROMIS instruments (pain behavior, pain interference, fatigue, sleep, anxiety, depression, physical 
function, satisfaction with participation in social roles, and 10 item global health scale).20 Participants 
will also complete the following pain rating questionnaires (the Interstitial Cystitis Problem and 
Symptom Indices, the Pain Catastrophizing Scale, Revised Short-form McGill Pain Inventory72 and 
MIDAS headache questionnaire.)67 These scales have been linked to pain intensity and quality of life 

N S A I D  P R O T O C O L  E H 1 8 - 1 2 8  
 
5 
in CPP sufferers, and catastrophizing (rumination, magnification, and feelings of helplessness about 
pain) is a well-validated intervention target for many cognitive-behavioral approaches for chronic 
pain.21–24 Validated, CPP-specific assessment tools will be used to characterize IBS (Rome III 
criteria)25 and bladder pain symptoms (Genitourinary Pain Index).26 Subjects will also complete the 
Female Sexual Function Index (FSFI)68 and Brief Symptom Inventory (BSI)- based questionnaire 
containing 6 somatization questions selected from the BSI-1869 plus a vision question, and the 
Complex Medical Symptoms Inventory (CMSI)-General, Fibromyalgia Symptoms, Fatigue, and 
Vulvodynia sections.70,71  
 
Rapid Bladder Test 
 
At the screen visit, all participants will be asked to undergo a “rapid bladder test.” Participants will 
be asked to rate their bladder pain on a 0-100 VAS scale when they reach “first urge.” If a participant 
arrives to the visit already at first urge, we will have them rate their pain and if not ≥ 10 we will wait 15 
minutes past first urge and have them rate their pain again. This is because the participant may not have 
been focusing on the feeling of their bladder. Participants not already at first urge will be encouraged to 
drink water (at least 20 oz) during the screening visit until they reach first urge at which point a pain rating 
will be attained. After they reach first urge, they can go to the bathroom and leave their urine sample. 
Pelvic Floor Exam: 
The baseline and follow-up visit includes internal vaginal pressure-pain threshold testing, which is 
similar in nature to the pelvic floor portion of a gynecological exam. Thus, for participants who have 
never had a gynecological exam, a study nurse or study doctor may complete a simple exam of the 
pelvic floor at the screen to promote understanding of the internal vaginal pressure-pain threshold 
testing that will be completed at the baseline and follow-up visit. This ensures that the integrity of 
our data is not biased by unfamiliar experience. Participants will be asked whether they have ever 
had a gynecological exam on the phone screen and a simple exam of the pelvic floor for those that 
say they have never had an exam will be scheduled into their screen.  
 
Creatinine Test:  
A creatinine test will be conducted to check for kidney function for all participants. This will be 
done via blood draw at the screen visit.  
 
  
Menstrual Diaries: 
All participants will be asked to complete daily diaries for a full menstrual cycle to assess their 
baseline scores.  
 
Baseline Visit: 
A baseline visit will be performed for all participants that have not conducted an assessment 
visit for EH13-094 in the last 12 months: [Note all of these assessments are the same as the 
assessments approved in EH13-094].  The baseline visit will be scheduled to occur during the 
luteal phase (15 to 25 days after the start of the prior menstrual cycle). Participants will be asked to 
confirm that menstrual pain or bleeding has not started during the baseline visit. 
Food: Baseline Visits are very long so we will offer snacks to the participants (e.g., teddy grahams 
and fruit roll-ups).  

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Instrumentation: During the baseline visit, EMG and EKG electrodes, and respiratory rate monitors 
will be applied and information will be recorded throughout the visit.  EMG leads will be placed on 
the lower abdomen during the bladder testing to measure muscular recruitment. The abdominal 
EMG leads will be moved to the knees once the bladder pain test is completed.  The EKG leads and 
respiratory belt are placed to measure autonomic activity. The autonomic activity will be recorded to 
verify nociceptive experience.  During each testing session, participants will also have their blood 
pressure and pulse taken.  
Bladder pain test: All participants will first undergo bladder pain testing described in our validation 
study7. Subjects will be provided directions for the bladder study. The bladder study involves voiding 
and obtaining baseline measurements of bladder volume with a 3D ultrasound abdominal transducer 
(GE Voluson 750, Wauwatosa, WI). After hydration with 20 oz of water, participants are instructed 
to report when they reach standard levels of bladder urgency: first sensation, first urge, and 
maximum tolerance and volumetric measurements of the bladder will be made. At each of these 
time points and every 15 minutes, 0-100 VAS measurements of pain and urgency are recorded. After 
scanning at maximum tolerance, subjects will urinate in a graded toilet hat to allow for measurement 
and saving a urinary specimen.  Samples will be banked for analyses. If the participant gives 
permission in the consent form, urine samples will continue to be stored after the study is completed 
for possible future analyses by our lab on women’s health conditions. If the participant does not give 
permission in the consent form for analyses beyond the current study, their sample will be destroyed 
upon study completion.  
 
Pressure Pain Threshold Test:  Participants will undergo body and pelvic floor pressure pain 
threshold testing following the same validated protocols in our published studies27,28 using digital 
external and internal vaginal pressure algometers. The body algometer (for example models see 
www.paintest.com) is a commonly used hand-held device in pain research that measures the 
4 
1 
3 
2 
View of introitus in lithotomy position with relative 
position of pelvic floor exam points (exam finger 
inserts into introitus at these sites) (Lewis, 1918) 
Diagram 3: 
All points are examined 3 cm proximal to the vaginal introitus 
#1: right iliococcygeus - located medial to the length of the tendinous arch 
#2: left iliococcygeus  
#3: 12 o’clock position, anterior vaginal wall (adjacent to the bladder) 
#4: 6 o’clock position, posterior vaginal wall (adjacent to the rectum) 
Cutaway of pelvis showing index finger 
examining left iliococcygeus site (#5) 
(adapted from (Peters, et al., 2007)) 
2 
Vaginal introitus 

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7 
amount of pressure applied to a 1 cm2 circular rubber tip. The vaginal algometer consists of 2.5 cm2 
circular force sensitive resistor, which fits over the pad of the examiner’s index finger under an exam 
glove (Detailed documentation was provided in a separate earlier supplement to the IRB). Prior to 
evaluation, subjects will report their baseline pain on a NRS 0-10 scale and will be asked to identify 
any painful body sites.  
To evaluate bodily pain pressure thresholds, we will assess three external measurement sites 
corresponding to American College of Rheumatology fibromyalgia tender point sites: the right 
trapezius, the right medial knee fat pad, and the right greater trochanter.29 One additional site will be 
a sham tender point, the middle of the forehead. A digital algometer (described above) will be used 
to conduct the external site measurements using a ramp rate of 0.5 kg/cm2/s. Trials of the shoulder, 
hip, and knee may be terminated by examiner at 7.0 kg/cm2 and trials of the forehead may be 
terminated at 4.0 kg/cm2 in the case that the subject does not reach pressure pain threshold before 
then. Subjects will report level of pain at the time they pressed the button on a NRS 0-10 scale 
immediately after testing each individual site. After a two minute break, the sites will be retested 
again. 
Next, we will use the vaginal algometer (described above), The four pelvic sites will be 
accessed by intravaginal exam, with all measurements conducted using the right index finger 
(Diagram 3) and a ramp rate of 0.5 kg/cm2/s. Internal trials may be terminated by examiner at 3.0 
kg/cm2.  A trained clinician will perform all pressure-pain tests.  Subjects will report the pain at the 
time they pressed the button on a NRS scale immediately after testing each individual site. After a 
two minute break, the sites will be retested again. In order to compare within-subject results from 
the baseline and follow-up visits and in order to standardize timing of post-testing time scores 
(collected every 5 minutes as described below), the order of testing sites will not be counterbalanced.   
Subjects will be allowed to rest for another 5 minutes, and subject will be queried on the level of 
NRS pain at each site again (shoulder, hip, knee, forehead, global vagina). Subjects will be queried 
every 5 minutes until pain returns to baseline levels or up to 30 minutes (the time of resolution in 
minutes will also be recorded).  
Conditioned Pain Modulation (CPM) : CPM testing involves repeating pressure pain threshold 
testing in the presence of a heterotopic stimulus (in this case cold water). The testing stimulus will be 
a mechanical pressure on the left medial knee fat pad. As in the first task, pressure will be applied 
(0.5 kg/cm2/s ramp) until the participant achieves pressure pain threshold. Baseline pressure pain 
thresholds of the testing stimulus on the left knee and left shoulder will be determined. After waiting 
approximately 2 minutes, the conditioning stimulus will be applied by instructing the subject to 
insert their right hand up to their wrist into a bucket of water maintained between 0-6° C. After 10 s 
of immersion, subjects will be asked to rate their level of hand pain on a NRS 0-10 scale. After 20s 
of immersion, the pressure pain threshold will be re-applied using a 0.5 kg/cm2/s ramp rate at the 
knee and the participant will be asked to rate their knee pain at the time they reached threshold (i.e. 
pressed the button) on a NRS 0-10 scale. After testing (~20s of immersion), subjects will 
immediately remove their hand and the pressure pain threshold will be determined at the shoulder. 
After waiting 5- and 10-minutes after water immersion, the testing stimuli will be re-applied. This 
paradigm combines a method for measuring CPM used by Dr. Clauw30 and methods for accurately 
measuring participation of descending inhibition by Dr. Hellman.31 CPM will be measured by the 
standardized differences in pain threshold, EMG activity and autonomic responses before and after 
heterotopic stimulation. This strategy will provide the most reliable measurement of descending 
inhibition.31,32  
Temporal Summation (TS): Participants will be instrumented to undergo tests of spinal pain 
modulation. Temporal summation will be tested using an algometer on the right medial knee fat pad.  

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We will repeatedly apply an amount of pressure (0.5 kg/cm2/s ramp rate; ITI = 5-15 seconds) equal 
to the average of the participant’s two pressure pain thresholds assessed during the first task. After 
each press, the participant will be asked to rate their pain on a NRS 0-10 scale. The pressure will be 
applied ten times or until the participant rates their pain as a 6, whichever comes first.   
EEG Testing: Subjects will be instrumented with a standard EEG cap.  Encephalography (EEG) 
recordings will be obtained using a standard montage and equipment. A trained research assistant or 
nurse will place the EEG cap and electrodes. All participants will undergo a resting state EEG task 
in order to analyze brain activity patterns associated with pain behavior. Participants will be asked to 
focus on a fixation cross on a computer monitor with their eyes open and sitting with their eyes 
closed for one minute each. In total, the task is expected to take 10 minutes. All participants will 
complete a handedness questionnaire,33 consisting of a series of questions asking which hand they 
use for different activities, in REDCap, which will help us interpret our EEG results.  
Sensory Amplification Tests: To evaluate whether sensitivity extends to other modalities we will use 
a software application that measures self-reported unpleasantness to increasingly loud and bright 
stimuli (safe and well below thresholds that could cause auditory or visual damage).  
Auditory stimuli will be provided by waveforms generated by a PC and transmitted through 
headphones calibrated by an audio monitor34 . Each stimulus will be a two-tone combination of 
1200 and 1350 Hz. Sounds will ranged in 5 dB steps from 35 to 90 dB SPL (A-weighted). After 
receiving instructions, the subject will be presented with a series of sounds, in random order of 
intensity. After each 2 s stimulus, the participant will be asked to rate its unpleasantness from 0 (“not 
at all unpleasant”) to 20 (“the most unpleasant sound imaginable”). 
Visual stimuli will be displayed on a computer monitor capable of providing up to 300 lux. In this 3 
min task, two visual stimuli will be presented in an alternating block design.  The control stimulus is 
a fixed crosshair centered in the middle of a solid background; the experimental stimulus will be a 
flashing (12.5 Hz) blue/yellow checkerboard presented at varying levels of brightness (luminance) in 
both an ascending and random manner.  Each subject will be presented with 6 test patterns 
alternated with 6 blanks patterns. Subjects will use a 0 (“not at all unpleasant”) to 20 (“the most 
unpleasant pattern imaginable”) numerical descriptor scale to rate the unpleasantness of each visual 
stimulus and the entire task. 
The visual task may be annoying or elicit a headache or nausea in sensitive individuals. Participants 
may stop at any time.  The sensory testing will take in total about 20 minutes and will be performed 
while the participant is connected to EEG. 
Additional quality controls: We may need to repeat a task, modify electrode positions, reconfigure 
equipment, or adjust features in the environment to evaluate the quality of our data acquisition 
scheme. For example, if a PPT measurement was not obtained or an electrode does not stay put, we 
may ask the subject to allow us to repeat additional measurements.  All embedded quality controls 
with permission from the subject will be documented in the subject record. 
Hormone Measurements: We will ascertain that subjects have not had more than 100 ml of blood 
drawn over the past 24 hours or 200 ml over the past 30 days. After completion of the 
pressure/pain testing, a trained nurse, physician, or phlebotomist will draw up to 60 mL of blood 
into vacutainers. Separation of serum and plasma will be performed using centrifugation and 
samples will be aliquoted and banked appropriately to allow for hormone measurements and 
analyses.  To control for the potential influence of reproductive hormones on pain sensitivity, and 
test our hypothesis about the role of hormonal influences on neurophysiological pain assessments, 
we will measure serum samples for E2, P4 and testosterone using methods that do not cross-react to 
contraceptives (some participants may be taking contraceptives) from the UVA or Emory Assay 
core.35  If the participant gives permission in the consent form, blood samples may also be analyzed 
for genetics. If the participant gives permission in the consent form, blood samples will continue to 

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9 
be stored after the study is completed for possible future analyses by our lab on women’s health 
conditions. If the participant does not give permission in the consent form for analyses beyond the 
current study, their sample will be destroyed upon study completion. 
 
Naproxen:  
Participants will be instructed on usage of prophylactic and recommended dosage of naproxen. 
Participants will be instructed to take one Naproxen (500 mg) pill in the morning and one again 12 
hours later the first day before their anticipated first day of menses. The research coordinators will 
help interpret the menstrual pain calendars for the participants to predict their next menstrual cycle. 
Participants will continue to take a pill twice daily for the first 3 days of their menstrual period. If 
participants still have menstrual pain the following day, they will be instructed to continue taking 2 
pills a day until their pain stops. Any unrelieved pain can be treated with acetaminophen (according 
to directions listed on the package). Participants will continue taking pills before and during their 
period for 6-8 months until the follow up visit is performed. In the event that a participant has been 
taking Naproxen for 3 consecutive days and has been asymptomatic (i.e., not started their menses) 
we will have them stop taking the study medication. The research staff will instruct them to start 
taking it again as soon as they start their period. 
 
The dosage does not exceed the maximal daily recommended over the counter dose for Naproxen (1500 
mg first day, 1000 mg subsequent days).   
Between visit measurements: 
Diaries: On each day of menstrual bleeding and/or pain, participants will complete a daily diary. The 
daily diary will be completed using REDCap and asks them to rate their menstrual, bladder, and 
bowel pain (using a numeric rating scale where 0-no pain, 10-worst pain imaginable), describe any 
bleeding, and what time the study medication wastaken. They will be asked to record any other pain 
reliever/medication they tried that day (heat pads, muscle relaxers, herbal teas, etc) in the notes 
section. They will be instructed to not take any additional painkillers except acetaminophen during 
their menses or while taking the study medication. Outside of their menses, they can treat their pain 
however they normally would (flu, headache). To protect confidentiality, subjects will not enter 
identifying information and only use their assigned subject ID #.  
Urine:  Participants will be told that urine samples will allow us to verify they are taking the study 
medication as directed. Participants will be asked to freeze urine collected from the evening of day 2 
of their menses for each cycle. 6 storage vials will be provided. The urine samples will allow us to 
verify if participants are taking the provided pills.   
Blood: Participants will be instructed to arrive at Evanston Hospital for a scheduled blood draw1.5-3 
hours after ingesting naproxen pills. This will allow us to verify naproxen is sufficiently absorbed to 
provide therapeutic effects. Only one naproxen absorption blood draw will be performed per 
participant. Participants will be allowed to choose the most convenient period day for testing, but 
cannot come on the first day. 
 
Follow up visit:  
Six to eight months later, participants will be invited to return for a follow-up visit. Participants will 
perform the same measurements obtained in the original baseline visit.  In the event participants are 
unable to return for a complete baseline visit, participants will receive a prorated stipend for partial 

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completion of items (including questionnaires). Participants will bring in any unused study 
medication to this visit. 
 
Power Analysis/Data Analysis: 
The primary outcomes are menstrual pain and bladder pain. Menstrual pain will be evaluated by 
comparing diary data and questionnaire data from baseline to 6-8 months after treatment.  We 
estimated the needed sample size with a power analysis. Historically, the effects of NSAIDS are 
known to have a large effect size (dz>.7).  A power analysis (α=.05,1-β=.80) suggests that to detect a 
more moderate effect of dz=.7 sample size of 20 would be needed. To account for a ~20-30% drop 
out rate, we will recruit 30 participants.    
 
 
An additional primary outcome is bladder pain as measured by the experimental bladder pain test 
and the GUPI questionnaire.  We estimated the needed sample size with a power analysis. The 
effects of oral contraceptives on bladder pain had enormous effect size (dz=2.9). Unfortunately, too 
few participants were willing to take oral contraceptives. A power analysis (α=.05,1-β=.80) suggests 
that to detect a more moderate effect of dz=1 sample size of 10 would be needed. We will attempt 
to attain a sample size of n=20 to allow detection of and even lower effect size dz=0.7 (per the 
primary outcome for menstrual pain).  
 
Secondary outcomes include predicting NSAID effectiveness via the investigated mechanisms. We 
predict impaired conditioned pain modulation and reduced pain pressure thresholds will predict 
NSAID effectiveness for dysmenorrhea. With n=20, we can detect relationships between treatment 
response and conditioned pain modulation or pain pressure threshold testing with a correlation 
coefficient (Pearson’s r) exceeding 0.38.     
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