Abdominal skeletal muscle activity precedes spontaneous menstrual cramping pain in primary dysmenorrhea.

In this preliminary study, we sought to examine the relationship between abdominal muscle activity and menstrual pain. Women with primary dysmenorrhea often had abdominal muscle activity preceding cramping pain, more than expected by chance as demonstrated during control conditions. In contrast, women with CPP or secondary dysmenorrhea diagnoses were less likely to have abdominal muscle activity preceding cramping pain and responded poorly to naproxen. Overall, these findings suggest abdominal muscle activity contributes to certain forms of menstrual pain, which in part are characterized by the presence of a putative VMR. This is the first report that provides evidence linking distinct abdominal muscle activity to reported spontaneous cramps in dysmenorrhea. Key strengths include the use of a novel method to record spontaneous pain, the evaluation of the experimental effects of naproxen, the implementation of control measurements (in healthy controls and on non-menses days), and blinded analyses by two independent reviewers. The inter-rater agreement (81%) was limited due to difficulties in consistently establishing whether abdominal muscle activity was electrical artifact due to movement. However, the agreement was sufficiently high to imply that the results should be reproducible by future reviewers. A potential bias is our choice of time interval (0–3 seconds) for temporal precedence of abdominal muscle activity before pain onset. However, this preselected time interval could reflect a 2-second delay for C-fiber mediated conduction of pain and 1-second delay for reaction time. 24 Additionally, the cross-sectional design of this study lacks reliability analyses and prospective surgical confirmation of secondary dysmenorrhea. Although significant differences were observed between participants with dysmenorrhea on and off-menses or healthy controls, findings still should be corroborated in larger studies. We hypothesize that abdominal muscle activity preceding cramping pain is evidence of viscero-motor reflexes (VMRs). As first described by MacKenzie, 15 VMRs are skeletal muscle reflexes triggered by visceral stimulation that can be sources of referred pain. VMRs have been recorded in response to colorectal, 25 bladder, 26 and uterine cervical distention, 27 but not in response to uterine distension. During dysmenorrhea, high pressure uterine contractions occur 14 and could elicit VMRs. Although VMRs are often considered a metric for evaluating nociceptive reflexes, 28 the consistent observation of abdominal EMG activity preceding cramping pain suggests that VMRs could also be a source of referred pain during dysmenorrhea. We labeled these EMG events as “putative” VMRs because we did not simultaneously record uterine contractility; simultaneous uterine recordings could have interfered with electrical recordings. However, we have shown that myometrial events often precede spontaneous pain report with MRI. 18 Although direct evidence that abdominal muscle activity causes pain is lacking, an observational study evaluating the effects of lidocaine injections into abdominal muscle trigger points in dysmenorrhea supports this role. 10 Although prior studies have not specifically been designed to identify VMRs in humans, their results are supportive of our presented findings. The noxious perception of human colorectal distension has been associated with alterations in abdominal tension (as studied with a bellows device), along with reflexive changes in sympathetic drive. 16 Although abdominal EMG activity occurs after episodes of uterine activity during labor, 29 it is difficult to resolve which episodes of EMG activity are due to voluntary contraction. Abdominal EMG activity may also be due to muscle guarding in anticipation of an upcoming uterine cramp. 30 Other studies investigating patients with bloating pain 31 , 32 identified alterations in EMG activity. A key difference between prior studies and ours is we studied the temporal association of spontaneous episodes of pain and EMG activity. Thus, in regards to our findings, studies of spontaneous pain should be performed in other pain conditions and in treatment studies to confirm whether abdominal muscle activity contributes to referred pain. Our results also suggest different mechanisms contribute to dysmenorrhea. Symptomatic women without putative VMRs had lower PPTs and more pain throughout the menstrual cycle. The 25% reduction of PPTs in women without putative VMRs is comparable to the reduction in pain thresholds reported with chronic widespread pain in fibromyalgia. 22 Since fibromyalgia pain is associated with central sensitization and impaired descending modulation 33 , we hypothesize that alterations in central nervous system sensory processing contribute similarly to menstrual pain lacking the VMR phenotype. Notably, treating dysmenorrhea via hormonal methods or ablating endometriotic lesions has been shown to reduce symptoms of chronic widespread pain indicative of central sensitization. 21 The phenotyping methods described here provide a novel strategy for characterizing nociceptive mechanisms in cyclical uterine pain and may ultimately predict treatment responsiveness. Our results support the idea that different sub-phenotypes of dysmenorrhea exist, besides the typical differentiation of primary/secondary dysmenorrhea. Further clarification of the central nervous mechanisms contributing to menstrual pain possibly using functional MRI of the spinal cord, 34 particularly in treatment-refractory women, would be valuable for the development of targeted therapeutics.

Enrolled participants with dysmenorrhea and healthy controls were of comparable age and race/ethnicity ( Table 1 ). According to daily diary entries, average menstrual pain in the dysmenorrhea cohort was 5.3 ± 0.4 on 0–10 NRS. Participants with dysmenorrhea missed 2.2 ± 0.4 days of school or work over the past 3 months. Thirty-two percent (12/38) of the dysmenorrhea cohort had been previously or currently diagnosed with a CPP condition (i.e. bladder pain syndrome, irritable bowel syndrome) or a secondary cause of dysmenorrhea (endometriosis, leiomyoma). To examine whether putative VMRs are related to cramping pain, we examined the relationship between abdominal EMG activity and bulb-squeezing in healthy controls and dysmenorrhea participants ( Table 2 ). An example of abdominal muscle activity preceding cramping pain is shown in Figure 1 . Abdominal EMG activity related to random-bulb squeezing in healthy controls on menses was rarely observed (0.9 ±0.6 episodes / hour). Similarly, during non-menses visits, EMG activity was rarely associated with random-bulb squeezing in participants with dysmenorrhea (2.3 ± 0.6 episodes / hour). In contrast, EMG activity preceded episodes of cramping pain on average 10.8 ± 3.0 times per hour in dysmenorrhea participants on their menses. Thus, the frequency of EMG activity preceding bulb-squeezing in dysmenorrhea participants on their menses was significantly higher than that observed on their non-menses visit ( p =0.004) or among healthy controls on their menses visit ( p =0.001). Putative VMRs preceding pain were detected in women with dysmenorrhea in similar proportions with use of the rheostat (50%; 7/14) and squeeze bulb (42%; 10/24; p =0.740). Before naproxen administration, dysmenorrheic women rated their menstrual pain 5.8±0.4 on an NRS. After naproxen administration, pain was reduced to 3.4±0.4 ( p <0.001). The frequency of putative VMRs was also reduced after naproxen (2.5 ± 1.1 episodes / hour) compared to before naproxen (10.8 ± 3.0 episodes / hour; p =0.001). Whereas 45% (17/38) of women with dysmenorrhea had putative VMRs, only 13% (5/38) had associated activity after naproxen ( p =0.011) Because only a subset of women with dysmenorrhea had putative VMRs associated with cramping pain (45%; 17/38), we performed additional subgroup analyses to identify differences in nociceptive mechanisms ( Table 3 ). There were no differences in age or pregnancy history between phenotypic groups ( p ’s>0.4). Menstrual pain in both groups was similar on the testing day before and naproxen ( p ’s>0.3). However, participants with the putative VMR phenotype reported greater average menstrual pain without NSAIDs during a typical cycle (82 ± 2) than participants without VMR phenotype (68 ± 5; p = 0.039) on a 0–100 VAS. Also, VMR phenotype participants reported more effective analgesia with NSAIDs (-50 ± 5) than those without (-22 ± 5; p =0.01). VMR phenotype participants were less likely to have a secondary dysmenorrhea or chronic pain diagnosis [12% (2/17) vs. 48% (10/21); p =0.034]. The VMR phenotype cohort also had fewer days per month of non-menstrual pelvic pain (0.6 ± 0.5 vs. 12.4 ± 0.5; p =0.002). To establish whether widespread pain sensitivity differed between the groups, we examined pressure pain thresholds (PPTs). Women with putative VMRs had PPTs (22.4 ±3.0 N) comparable to healthy controls (22.2 ± 3.0 N; p =0.967). In contrast, women without putative VMRs had lower PPTs (16.1 ± 1.9 N) compared to women with VMRs and healthy controls ( p =0.039). There was no significant effect of day ( p =0.917) or PPT location ( p =0.293), suggesting a generalized mechanism of widespread pain sensitivity is engaged in dysmenorrheic women without VMRs. As a final posthoc analysis, we examined the differential effects associated with CPP/secondary dysmenorrhea in women without the VMR phenotype on pain pressure thresholds. Both women with (17.1 ± 3.7 N) or without CPP/secondary dysmenorrhea (15.4 ± 1.5 N) within the no VMR phenotype had comparably low PPTs (p=0.694).

This study was approved by the NorthShore University HealthSystem Institutional Review Board. Following written informed consent, participants with severe dysmenorrhea and healthy controls (ages 18–45) were prospectively recruited from physician referral or from participation in separate studies 18 between January 2012 and February 2017. Dysmenorrhea participants were allowed to have chronic pelvic pain diagnoses, given the substantial co-morbidity. These separate studies utilized magnetic resonance imaging (MRI) and/or ultrasonography alongside EMG recordings to investigate the mechanisms underlying dysmenorrhea. Participants with dysmenorrhea were required to have menstrual pain greater than 6 on the worst day of their cycle on a numeric rating scale ( NRS ; 0: “no pain at all” to 10: “worst pain imaginable”) 19 when not taking analgesic medication. The magnitude of menstrual pain was confirmed with a daily diary as described below. Healthy controls were required to have menstrual pain less than 3 on a NRS without analgesic medication during menses. Exclusion criteria for the study included history of pelvic or abdominal malignancies, irregular menses (> 45 days between menses), pregnancy within prior 6 months, breastfeeding, active genitourinary infection in the previous 4 weeks, body mass index > 40, unwillingness to stop taking NSAIDs on the day of the study visit, unwillingness to have a withdrawal bleed on continuous oral contraceptives, inability to read/comprehend a consent form in English, or standard MRI contraindications (because of a companion MRI study). Between study visits, participants were asked to report their daily menstrual pain (0–10 NRS) using an online version of menstrual diaries 20 over a 1-month cycle. Participants were required to record their pain during menses for confirmation. Participants were scheduled for a visit during the first 48 hours following menstrual bleeding onset or during the peri-ovulatory phase of their menstrual cycle. Participants were instructed to abstain from taking short-acting analgesic medications at least 8 hours before the visit, or 12 hours for long-acting analgesics. Upon arrival, participants were asked to rate their menstrual pain using the NRS. This reported pain served as a baseline pain that participants experienced between cramps. Dysmenorrheic participants used a 10-cm linear rheostat attached to a visual analog scale ( VAS ; 0: “no pain at all” to 10: “worst pain imaginable”) to continuously indicate their pain. After the first 14 participants, we opted to switch our pain recording apparatus to allow for a more rapid indication of cramping pain with a squeeze-bulb validated previously. 18 Dysmenorrheic participants were instructed to proportionally squeeze the bulb to indicate their increased pain during a menstrual cramp. Participants were instructed to squeeze the bulb only when they experienced pain above their baseline. Statistically similar results were obtained with the linear rheostat and bulb-squeeze paradigm. Therefore, we combined the linear rheostat and bulb-squeeze data for the proposed analyses. To control for spontaneous abdominal activity, we implemented two control conditions. In the first control condition, dysmenorrheic participants were instructed to squeeze the bulb randomly for approximately 30 seconds every 2 to 5 minutes during their luteal phase. Similarly, in the second control condition, healthy controls, who do not report painful menstrual cramps, were also instructed to randomly squeeze the bulb at both visits. To measure abdominal muscle activity, an array of 3 standard EMG electrodes was placed between the umbilicus and pubic bone of each participant. Two electrodes were placed approximately 4–6 cm laterally and 2 cm above the umbilicus. The third electrode was placed 4 cm below one of the above electrodes. EMG activity was amplified by 10,000 with an AC BIOPAC amplifier (Biopac Systems, Aero Camino Goleta, CA) and filtered between 100–250 Hz to isolate abdominal muscle activity. We obtained approximately 15 minutes of abdominal EMG activity from each participant. Following baseline assessment, participants ingested two tablets of naproxen sodium (440 mg) and water. During a subsequent 90-minute wait time, participants filled out questionnaires to obtain complete medical, surgical, psychological, gynecological, and obstetrical history. We verified that participants reporting a history of endometriosis had reported prior surgical confirmation in their medical records. Among these questionnaires, participants were asked to rate their typical level of menstrual pain with and without painkillers on a 100 mm VAS using an iPad. After 90 minutes, abdominal EMG recordings were repeated again for 15 minutes with bulb squeezes proportional to their new current baseline pain. At the end of the visit, participants rated their menstrual pain with a NRS. In the last 30 participants (dysmenorrhea: n = 21, healthy control: n = 9), pressure pain thresholds were obtained to establish whether deep muscle sensitivity, a potential marker of central sensitization, 21 differentiated VMR phenotypes. Pressure pain thresholds in a subset of sites historically used to evaluate chronic widespread pain/fibromyalgia 22 were obtained by a research nurse on both the menses and non-menses visit at the right trapezius (shoulder), the right medial knee fat pad (knee), the right greater trochanter (hip), and the forehead. A digital algometer with a 1-cm 2 rubber tip was used to measure pressure pain thresholds at a rate of between 4 and 10 Newtons/cm 2 /s. Participants pressed a button to terminate the trial when the stimulus first became painful. For safety, if the participant had not yet pressed the button by the time the examiner reached 70 Newtons, the test was terminated. A lower threshold of 40 Newtons was used for the forehead. Averaged thresholds from two trials with a two-minute inter-trial interval were calculated for the final analysis. Participant BIOPAC files containing bulb-squeeze and EMG data were coded to blind two independent reviewers to both the participant group and experiment. Because abdominal muscle activity during a bulb-squeeze could reflect movement artifact due to pain, we primarily examined EMG activity immediately prior to pain report via the squeeze bulb. Abdominal EMG activity preceded pain report by about 2 seconds in our initial participants. Therefore, a window of 3 seconds was used to allow for a variable short delay in reaction time. In this study, a VMR was defined as abdominal EMG activity preceding pain report by 3 seconds. There was an 81% agreement rate on abdominal muscle activity scores between the two blinded reviewers for the baseline data. Because similar results were obtained with both reviewers, only results from the reviewer that analyzed both the menses and non-menses data are presented. In a pilot study with participants with dysmenorrhea (n=12), we observed VMR activity in 50% of the participants with an average frequency of 10 events per hour. A power analysis using G-Power 23 for a within-subject ANOVA (α=0.05, 1-β=0.8) indicated that a sample size of 34 would be needed to detect a medium effect size (dz = 0.5) reduction in VMR activity either after naproxen or on a non-menstrual visit. Also, we predicted VMR activity would be observed less frequently (<15%) after naproxen or off-menses. A power analysis for a Fisher’s exact test suggested a sample size of 32 would be required to identify proportional group differences after naproxen or off-menses (α=0.05, 1-β=0.8). Additional dysmenorrhea participants were enrolled to accommodate technical problems or drop-outs and 10 healthy controls were enrolled for reference comparisons. Out of 86 participants screened by phone, 36 were ineligible, 1 was disqualified, and 1 was lost to follow up. Complete EMG data were obtained from all 48 participants on menses. Non-menses data was obtained on 17 women with dysmenorrhea and 8 healthy controls. The remainder was unavailable due to scheduling limitations or lost to follow-up. Data were analyzed in Microsoft Excel (version 2016, Redmond, VA) or Stata (version 13.1, College Station, Texas) and p <0.05 was considered the threshold for significance. Fisher’s exact test was used to compare differences in proportions across the groups. Student’s T-test was used to compare continuous variables such as age, self-reported NRS scores, and abdominal muscle activity frequency across the groups.

Menstrual pain, also known as dysmenorrhea, affects the well-being and productivity of nearly half of reproductive-age women, 1 – 3 and is the leading risk factor for chronic pelvic pain ( CPP ). 1 – 3 Although the hallmark symptom associated with dysmenorrhea is severe menstrual cramping, the underlying nociceptive mechanisms are not understood. Because dysmenorrhea can be resistant to available treatments, a better understanding of its mechanisms is needed to improve therapeutic strategies. 4 Several treatments proposed to treat dysmenorrhea (including hot water bottles, 5 heat wraps, 6 microwave diathermy, 7 massage, 8 transcutaneous electrical nerve stimulation, 9 and trigger point anesthesia 10 ) might plausibly target referred or primary abdominal muscle dysfunction. Despite this implied role, most prior research in dysmenorrhea has focused on prostaglandin-mediated increases in uterine contractility. 11 – 13 Evidence that abdominal transcutaneous electrical nerve stimulation reduces menstrual pain, but has no effect on uterine contractility 14 suggests that abdominal muscle activity may be a distinct and key contributor to menstrual pain. Such abdominal muscle activity may be due to muscle guarding or may be elicited as part of a viscero-motor reflex 15 caused by visceral distension 16 due to high pressure uterine contractions. 13 Repetitive episodes of involuntary abdominal muscle activity lasting for several days could potentially elicit muscle fatigue and soreness. Despite its plausibility, there are few studies formally establishing associations between abdominal muscle activity and dysmenorrhea. We sought to determine whether abdominal muscle activity is related to cramping pain in dysmenorrhea. To establish whether episodes of spontaneous abdominal muscle activity precede a reported cramping pain, we developed a novel method to characterize spontaneous cramping pain in real-time in relation to viscero-motor reflexes ( VMR ). We recorded abdominal muscle activity with electromyography ( EMG ) simultaneously with continuous patient self-report of abdominal cramp intensity. As a control, we evaluated the relationship between abdominal EMG activity and random event reporting in healthy controls during menses and in both groups during non-menses. To assess mechanistic contributions, we evaluated the effects of naproxen on EMG activity and menstrual pain across a range of dysmenorrhea phenotypes. Differences between women with EMG activity related to pain (henceforth known as the VMR phenotype ) and women without EMG activity related to pain (the no VMR phenotype ) were also evaluated. Since it is unknown whether mechanisms of menstrual cramps are different in primary or secondary dysmenorrhea, the relationship between medical history and EMG activity was also examined. Finally, a common method of examining nociceptive pain mechanisms, quantitative sensory testing of pressure pain sensitivity, 17 was evaluated in women with and without the VMR phenotype. The analyses described above provide a framework for identifying specific physiological phenotypes associated with dysmenorrhea.