Publications by authors named "Kevin M Hellman"

27 Publications

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Cortical mechanisms of visual hypersensitivity in women at risk for chronic pelvic pain.

Pain 2021 Aug 27. Epub 2021 Aug 27.

Department of Ob/Gyn, NorthShore University HealthSystem, Evanston, IL, United States Department of Ob/Gyn, Pritzker School of Medicine, University of Chicago, Chicago, IL, United States Department of Psychology, Loyola University Chicago, Chicago, IL, United States Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, MI.

Abstract: Increased sensory sensitivity across non-nociceptive modalities is a common symptom of chronic pain conditions and is associated with chronic pain development. Providing a better understanding of the brain-behavior relationships that underlie multimodal hypersensitivity (MMH) may clarify the role of MMH in the development of chronic pain. We studied sensory hypersensitivity in a cohort of women (n=147) that had diary confirmation of menstrual status and were enriched with risk factors for chronic pelvic pain, such as dysmenorrhea and increased bladder sensitivity. We administered two experimental tasks to evaluate the cross-modal relationship between visual and visceral sensitivity. Visual sensitivity was probed by presenting participants with a periodic pattern-reversal checkerboard stimulus presented across five brightness intensities during EEG recording. Self-reported visual unpleasantness ratings for each brightness intensity were simultaneously assessed. Visceral sensitivity was evaluated with an experimental bladder-filling task associated with early clinical symptoms of chronic pelvic pain. Visually evoked cortical activity increased with brightness intensity across the entire scalp, especially at occipital electrode sites. Visual stimulation-induced unpleasantness was associated with provoked bladder pain and evoked primary visual cortex activity. However, the relationship between unpleasantness and cortical activity was moderated by provoked bladder pain. These results demonstrate that activity in primary visual cortex is not greater in individuals with greater visceral sensitivity. We hypothesize that downstream interpretation or integration of this signal is amplified in individuals with visceral hypersensitivity. Future studies aimed at reducing MMH in chronic pain conditions should prioritize targeting of cortical mechanisms responsible for aberrant downstream sensory integration.
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http://dx.doi.org/10.1097/j.pain.0000000000002469DOI Listing
August 2021

Noninvasive bladder testing of adolescent females to assess visceral hypersensitivity.

Pain 2021 Apr 12. Epub 2021 Apr 12.

Department of Ob/Gyn, NorthShore University HealthSystem Evanston, IL, United States, Department of Ob/Gyn, University of Chicago, Pritzker School of Medicine, Chicago, IL, United States, Department of Psychology, Loyola University of Chicago, Chicago, IL, United States, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, United States.

Abstract: Excess pain after visceral provocation has been suggested as a marker for chronic pelvic pain risk in women. However, few noninvasive tests have been validated that could be performed readily on youth in early risk windows. Therefore, we evaluated the validity and reliability of a noninvasive bladder pain test in 124 healthy premenarchal females (median age 11, [interquartile range 11-12]), as previously studied in adult women. We explored whether psychosocial, sensory factors, and quantitative sensory test results were associated with provoked bladder pain and assessed the relation of bladder pain with abdominal pain history. Compared with findings in young adult females (age 21 [20-28]), results were similar except that adolescents had more pain at first sensation to void (P = 0.005) and lower maximum tolerance volume (P < 0.001). Anxiety, depression, somatic symptoms, and pain catastrophizing predicted provoked bladder pain (P's < 0.05). Bladder pain inversely correlated with pressure pain thresholds (r = -0.25, P < 0.05), but not with cold pressor pain or conditioned pain modulation effectiveness. Bladder pain was also associated with frequency of abdominal pain symptoms (r = 0.25, P = 0.039). We found strong retest reliability for bladder pain at standard levels of sensory urgency in 21 adolescents who attended repeat visits at 6 to 12 months (intraclass correlations = 0.88-0.90). Noninvasive bladder pain testing seems reproducible in adolescent females and may predict abdominal pain symptomatology. Confirmation of our findings and further investigation of the bladder test across menarche will help establish how visceral sensitivity contributes to the early trajectory of pelvic pain risk.
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http://dx.doi.org/10.1097/j.pain.0000000000002311DOI Listing
April 2021

Mechanisms, diagnosis, prevention and management of perioperative opioid-induced hyperalgesia.

Pain Manag 2021 Apr 29;11(4):405-417. Epub 2021 Mar 29.

Department of Anesthesiology & Perioperative Pain Medicine, Texas Children's Hospital, Houston, TX 77030, USA.

Opioid-induced hyperalgesia (OIH) occurs when opioids paradoxically enhance the pain they are prescribed to ameliorate. To address a lack of perioperative awareness, we present an educational review of clinically relevant aspects of the disorder. Although the mechanisms of OIH are thought to primarily involve medullary descending pathways, it is likely multifactorial with several relevant therapeutic targets. We provide a suggested clinical definition and directions for clinical differentiation of OIH from other diagnoses, as this may be confusing but is germane to appropriate management. Finally, we discuss prevention including patient education and analgesic management choices. As prevention may serve as the best treatment, patient risk factors, opioid mitigation, and both pharmacologic and non-pharmacologic strategies are discussed.
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http://dx.doi.org/10.2217/pmt-2020-0105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023328PMC
April 2021

Racial Distribution and Characterization of Pelvic Organ Prolapse in a Hospital-Based Subspecialty Clinic.

Female Pelvic Med Reconstr Surg 2021 03;27(3):147-150

Department of Obstetrics and Gynecology, University of Chicago.

Objectives: Prior literature has suggested a decreased prevalence of pelvic organ prolapse (POP) in Black women. We sought to describe POP rates by race, investigate whether specific types of prolapse differ based on race, and investigate the role of uterine weight and fibroids on POP.

Methods: We conducted a retrospective cohort study of new patients seen between April 2017 and April 2019 at a tertiary urogynecology clinic. Variables collected included POP quantification, race, age, smoking history, medical history, gravity, parity, vaginal delivery, hysterectomy, fibroids, and uterine weight. χ2 tests were used to compare the proportions of types of POP between Black and non-Black women. Binary and ordinal logistic regression tested the association between types of prolapse and race, adjusting for covariates.

Results: Nine hundred thirty-six patients were identified by ICD codes, 768 met inclusion criteria. There were 85.3% of the women identified as non-Black and 14.7% identified as Black. There were 39.8% of the Black women that had a fibroid diagnosis compared with 20.8% of non-Black women (P < 0.001). Black women had a higher median uterine weight, 112.2 g versus 56 g (P = 0.002), and median fibroid size, 3.4 cm versus 1.92 cm (P = 0.0001). 56.9% of women presented with anterior prolapse. No difference was found in POP type between Black and non-Black women after adjusting for age, body mass index, parity, and delivery route (P = 0.45).

Conclusions: Black women had increased body mass index, rates of comorbidities (diabetes and hypertension), higher uterine weight and fibroid size than non-Black women in our study. However, there was no significant difference in POP type based on race.
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http://dx.doi.org/10.1097/SPV.0000000000001016DOI Listing
March 2021

Development and validation of a real-time method characterizing spontaneous pain in women with dysmenorrhea.

J Obstet Gynaecol Res 2021 Apr 15;47(4):1472-1480. Epub 2021 Feb 15.

Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, Illinois, USA.

Aim: Prior research has primarily focused on static pain assessment, largely ignoring the dynamic nature of pain over time. We used a novel assessment tool for characterizing pain duration, frequency, and amplitude in women with dysmenorrhea and evaluated how these metrics were affected by naproxen treatment.

Methods: Dysmenorrheic women (n = 25) rated their menstrual pain by squeezing a pressure bulb proportional to the magnitude of their pain. To evaluate whether bulb squeezing was affected by naproxen, we compared parameters before and after naproxen. We also analyzed the correlation between pain relief on a numerical rating scale to changes in bulb squeezing parameters. Random bulb-squeezing activity in pain-free participants (n = 14) was used as a control for nonspecific effects or bias.

Results: In dysmenorrheic women, naproxen reduced the duration of the squeezing during a painful bout, the number of painful bouts and bout intensity. Before naproxen, the correlation between these bulb squeeze parameters and self-reported pain on numeric rating scale was not significant (R = 0.12, p = 0.304); however, there was a significant correlation between changes in bulb squeeze activity and self-reported pain relief after naproxen (R = 0.55, p < 0.001).

Conclusion: Our study demonstrates a convenient technique for continuous pain assessment, capturing three different dimensions: duration, frequency, and magnitude. Naproxen may act by reducing the duration and frequency of episodic pain in addition to reducing the severity. After further validation, these methods could be used for other pain conditions for deeper phenotyping and assessing novel treatments.
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http://dx.doi.org/10.1111/jog.14663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8317258PMC
April 2021

Cortical Mechanisms of Visual Hypersensitivity in Women at Risk for Chronic Pelvic Pain.

medRxiv 2021 Jan 18. Epub 2021 Jan 18.

Multisensory hypersensitivity (MSH), which refers to persistent discomfort across sensory modalities, is a risk factor for chronic pain. Developing a better understanding of the neural contributions of disparate sensory systems to MSH may clarify its role in the development of chronic pain. We recruited a cohort of women ( =147) enriched with participants with menstrual pain at risk for developing chronic pain. Visual sensitivity was measured using a periodic pattern-reversal stimulus during EEG. Self-reported visual unpleasantness ratings were also recorded. Bladder pain sensitivity was evaluated with an experimental bladder-filling task associated with early clinical symptoms of chronic pelvic pain. Visual stimulation induced unpleasantness was associated with bladder pain and evoked primary visual cortex excitation; however, the relationship between unpleasantness and cortical excitation was moderated by bladder pain. Thus, future studies aimed at reversing the progression of MSH into chronic pain should prioritize targeting of cortical mechanisms responsible for maladaptive sensory input integration.
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http://dx.doi.org/10.1101/2020.12.03.20242032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836135PMC
January 2021

Wikipedia: A Medical Student Educational Project to Edit Wikipedia in Preparation for Practicing Evidence-Based Pain Medicine.

J Med Educ Curric Dev 2020 Jan-Dec;7:2382120520959691. Epub 2020 Sep 22.

University of Chicago Pritzker School of Medicine, Chicago, IL, USA.

Objective: Wikipedia is commonly used to acquire information about various medical conditions such as chronic pain. Ideally, better online pain management content could reduce the burden of opioid use disorders. Our goal was to improve the quality of the content available on Wikipedia to make it more accurate and applicable to medical students and the general public while training medical students to practice evidence-based medicine and critically assess their sources of information.

Methods: An elective class in Neuroscience, Pain, and Opioids composed of 10 medical students met biweekly to discuss landmark and practice-changing research articles in the fields of acute pain, chronic pain, and opioid management. The professor chose Wikipedia articles relevant to this course. Three independent viewers analyzed the quality of citations, anecdotal medical content, and content value for both patients and medical professionals. As part of their coursework, students then edited the Wikipedia articles.

Results: Although some of the Wikipedia pain topic content (6.7% ± 2.0) was anecdotal, financially biased, or inconsistent with Western Medical Practice content, overall articles included primarily high-quality citations (85.6% ± 3.1). On a 0-5 Likert scale, students felt content would be moderately helpful for both medical students/professionals (3.4 ± 0.2) and laypersons (3.5 ± 0.2). Editing and adding citations was feasible, but novel material was often reverted.

Conclusion: A significant amount of pain medicine content was relevant and amenable to student editing. Therefore, future use of this tactic could provide a unique opportunity to integrate evidence-based medicine into the medical curriculum and have a direct impact on the widely available medical information. Future refinement in the editorial process may also further improve online information.
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http://dx.doi.org/10.1177/2382120520959691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513391PMC
September 2020

Low Serum Naproxen Concentrations Are Associated with Minimal Pain Relief: A Preliminary Study in Women with Dysmenorrhea.

Pain Med 2020 11;21(11):3102-3108

Department of Obstetrics and Gynecology, NorthShore University HealthSystem & Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA.

Objective: Incomplete pain relief after administration of nonsteroidal anti-inflammatory drugs (NSAIDs) is common, but it is unknown whether malabsorption or heightened metabolism contributes to NSAID resistance. To explain the etiology of NSAID resistance, we evaluated naproxen absorption and metabolism in relation to pain relief in a pilot study of women with dysmenorrhea.

Methods: During menses, participants completed before and after naproxen ingestion pain assessments. Analgesic effectiveness was calculated as a percent change in pain rating before and after naproxen administration. To evaluate the impact of malabsorption, the correlation between analgesic effectiveness and serum naproxen was analyzed. To identify whether hypermetabolism contributes to NSAID resistance, we also analyzed the metabolite O-desmethylnaproxen.

Results: Serum naproxen and O-desmethylnaproxen concentrations of the dysmenorrheic cohort (N = 23, 126 ± 10 µg/mL, 381 ± 56 ng/mL) and healthy controls (N = 12, 135 ± 8 µg/mL, 355 ± 58 ng/mL) were not significantly different (P > 0.05), suggesting that menstrual pain does not affect drug absorption and metabolism. However, nine dysmenorrhea participants had levels of analgesic effectiveness <30%. Among dysmenorrheic women, analgesic effectiveness was correlated with serum naproxen (r = 0.49, P = 0.019) and O-desmethylnaproxen (r = 0.45, P = 0.032) concentrations. After controlling for other gynecological diagnoses, a multivariate model analysis confirmed that lower serum naproxen concentrations were associated with reduced pain relief (P  = 0.038).

Conclusions: Our preliminary findings suggest that poor drug absorption contributes to ineffective pain relief in dysmenorrheic women. Future studies should explore whether malabsorption contributes to NSAID resistance for other pain conditions.
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http://dx.doi.org/10.1093/pm/pnaa133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784249PMC
November 2020

Dysmenorrhea subtypes exhibit differential quantitative sensory assessment profiles.

Pain 2020 06;161(6):1227-1236

Department of Ob/Gyn, Northshore University HealthSystem, Evanston, IL, United States.

Women who develop bladder pain syndrome (BPS), irritable bowel syndrome, or dyspareunia frequently have an antecedent history of dysmenorrhea. Despite the high prevalence of menstrual pain, its role in chronic pelvic pain emergence remains understudied. We systematically characterized bladder, body, and vaginal mechanical sensitivity with quantitative sensory testing in women with dysmenorrhea (DYS, n = 147), healthy controls (HCs) (n = 37), and women with BPS (n = 25). Previously, we have shown that a noninvasive, bladder-filling task identified a subset of women with both dysmenorrhea and silent bladder pain hypersensitivity, and we repeated this to subtype dysmenorrhea sufferers in this study (DYSB; n = 49). DYS, DYSB, and BPS participants had lower vaginal mechanical thresholds and reported more pain to a cold stimulus during a conditioned pain modulation task and greater pelvic examination after-pain than HCs (P's < 0.05). DYSB participants also had reduced body mechanical thresholds and less conditioned pain modulation compared to HCs and DYS participants (P's < 0.05). Comparing quantitative sensory testing results among the DYS and HC groups only, provoked bladder pain was the only significant predictor of self-reported menstrual pain (r = 0.26), bladder pain (r = 0.57), dyspareunia (r = 0.39), and bowel pain (r = 0.45). Our findings of widespread sensory sensitivity in women with dysmenorrhea and provoked bladder pain, much like that observed in chronic pain, suggest a need to study the trajectory of altered mechanisms of pain processing in preclinical silent visceral pain phenotypes to understand which features convey inexorable vs modifiable risk.
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http://dx.doi.org/10.1097/j.pain.0000000000001826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230023PMC
June 2020

Low Serum Oxytocin Concentrations Are Associated with Painful Menstruation.

Reprod Sci 2020 02 6;27(2):668-674. Epub 2020 Jan 6.

Department of Obstetrics and Gynecology, NorthShore University HealthSystem and The University of Chicago Pritzker School of Medicine, Evanston, IL, USA.

Oxytocin-dependent mechanisms are hypothesized to contribute to painful menses, but clinical trials of oxytocin antagonists for dysmenorrhea have had divergent outcomes. In contrast, broader studies have shown that increased systemic oxytocin concentrations are associated with increased pain tolerance and improved psychosocial function. We sought to confirm whether increased serum oxytocin concentrations are associated with menstrual pain and other psychosocial factors. Women with a history of primary dysmenorrhea (n = 19), secondary dysmenorrhea (n = 12), and healthy controls (n = 15) completed pain and psychosocial questionnaires, provided a medical history, and rated their pain during the first 48 h of menses. Serum samples were collected during menses to measure oxytocin concentrations. Oxytocin was significantly lower in participants with a history of primary (704 ± 33 pg/mL; p < 0.001) or secondary (711 ± 66 pg/mL; p < 0.01) dysmenorrhea compared to healthy controls (967 ± 53 pg/mL). Menstrual pain over the past 3 months (r = -0.58; p < 0.001) and during the study visit (r = -0.45; p = 0.002) was negatively correlated with oxytocin concentrations. Pain catastrophizing (r = -0.39), pain behavior (r = -0.32), and pain interference (r = -0.31) were also negatively correlated with oxytocin levels (p's < 0.05). Oxytocin was not significantly correlated with psychosocial factors. Contrary to our hypothesis, women with a history of primary or secondary dysmenorrhea had lower oxytocin concentrations during menses when compared to healthy controls. Lower circulating oxytocin concentrations were also associated with worse menstrual pain and pain-related behavior. When considering the existing literature, low circulating oxytocin may be a sign of dysfunctional endogenous pain modulation.
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http://dx.doi.org/10.1007/s43032-019-00071-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044072PMC
February 2020

Clinical profile of comorbid dysmenorrhea and bladder sensitivity: a cross-sectional analysis.

Am J Obstet Gynecol 2020 06 20;222(6):594.e1-594.e11. Epub 2019 Dec 20.

Department of Obstetrics and Gynecology, Northshore University HealthSystem, Evanston, IL; Pritzker School of Medicine, University of Chicago, Chicago, IL.

Background: Antecedents of chronic pelvic pain are not well characterized, but pelvic organ visceral sensitivity is a hallmark of these disorders. Recent studies have identified that some dysmenorrhea sufferers are much more likely to exhibit comorbid bladder hypersensitivity. Presumably, these otherwise healthy women may be at higher risk of developing full-blown chronic bladder pain later in life. To encourage early identification of patients harboring potential future risk of chronic pain, we describe the clinical profile of women matching this putative pain-risk phenotype.

Objective(s): The objectives of the study were to characterize demographic, menstrual, pelvic examination, and psychosocial profiles of young women with comorbid dysmenorrhea and bladder hypersensitivity, defined using a standardized experimental visceral provocation test, contrasted with healthy controls, pure dysmenorrhea sufferers, and women with existing bladder pain syndrome.

Study Design: This prospective cohort study acquired data on participants with moderate to severe dysmenorrhea (n = 212), healthy controls (n = 44), and bladder pain syndrome (n = 27). A subgroup of dysmenorrhea patients was found on screening with noninvasive oral water challenge to report significantly higher bladder pain during experimentally monitored spontaneous bladder filling (>15 out of 100 on visual analogue scale, based on prior validation studies) and separately defined as a group with dysmenorrhea plus bladder pain. Medical/menstrual history and pain history were evaluated with questionnaires. Psychosocial profile and impact were measured with validated self-reported health status Patient Reported Outcomes Measurement Information System short forms and a Brief Symptom Inventory for somatic sensitivity. Pelvic anatomy and sensory sensitivity were examined via a standardized physical examination and a tampon provocation test.

Results: In our largely young, single, nulliparous cohort (24 ± 1 years old), approximately a quarter (46 out of 212) of dysmenorrhea sufferers tested positive for the dysmenorrhea plus bladder pain phenotype. Dysmenorrhea-only sufferers were more likely to be African American (24%) than healthy controls (5%, post hoc χ, P = .007). Pelvic examination findings did not differ in the nonchronic pain groups, except for tampon test sensitivity, which was worse in dysmenorrhea plus bladder pain and dysmenorrhea sufferers vs healthy controls (2.6 ± 0.3 and 1.7 ± 0.2 vs 0.7 ± 0.2, P < .05). Consistent with heightened pelvic sensitivity, participants with dysmenorrhea plus bladder pain also had more nonmenstrual pain, dysuria, dyschezia, and dyspareunia (P's < .05). Participants with dysmenorrhea plus bladder pain had Patient Reported Outcomes Measurement Information System Global Physical T-scores of 47.7 ± 0.9, lower than in women with dysmenorrhea only (52.3 ± 0.5), and healthy controls 56.1 ± 0.7 (P < .001). Similarly, they had lower Patient Reported Outcomes Measurement Information System Global Mental T-score than healthy controls (47.8 ± 1.1 vs 52.8 ± 1.2, P = .017). Similar specific impairments were observed on Patient Reported Outcomes Measurement Information System scales for anxiety, depression, and sleep in participants with dysmenorrhea plus bladder pain vs healthy controls.

Conclusion: Women with dysmenorrhea who are unaware they also have bladder sensitivity exhibit broad somatic sensitivity and elevated psychological distress, suggesting combined preclinical visceral sensitivity may be a precursor to chronic pelvic pain. Defining such precursor states is essential to conceptualize and test preventative interventions for chronic pelvic pain emergence. Dysmenorrhea plus bladder pain is also associated with higher self-reported pelvic pain unrelated to menses, suggesting central nervous system changes are present in this potential precursor state.
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http://dx.doi.org/10.1016/j.ajog.2019.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263950PMC
June 2020

Persistent autonomic dysfunction and bladder sensitivity in primary dysmenorrhea.

Sci Rep 2019 02 18;9(1):2194. Epub 2019 Feb 18.

Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston IL, 60201, USA.

Menstrual pain, also known as dysmenorrhea, is a leading risk factor for bladder pain syndrome (BPS). A better understanding of the mechanisms that predispose dysmenorrheic women to BPS is needed to develop prophylactic strategies. Abnormal autonomic regulation, a key factor implicated in BPS and chronic pain, has not been adequately characterized in women with dysmenorrhea. Thus, we examined heart rate variability (HRV) in healthy (n = 34), dysmenorrheic (n = 103), and BPS participants (n = 23) in their luteal phase across a bladder-filling task. Both dysmenorrheic and BPS participants reported increased bladder pain sensitivity when compared to controls (p's < 0.001). Similarly, dysmenorrheic and BPS participants had increased heart rate (p's < 0.01), increased diastolic blood pressure (p's < 0.01), and reduced HRV (p's < 0.05) when compared to controls. Dysmenorrheic participants also exhibited little change in heart rate between maximum bladder capacity and after micturition when compared to controls (p = 0.013). Our findings demonstrate menstrual pain's association with abnormal autonomic activity and bladder sensitivity, even two weeks after menses. Our findings of autonomic dysfunction in both early episodic and chronic visceral pain states points to an urgent need to elucidate the development of such imbalance, perhaps beginning in adolescence.
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http://dx.doi.org/10.1038/s41598-019-38545-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379479PMC
February 2019

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

Am J Obstet Gynecol 2018 07 5;219(1):91.e1-91.e7. Epub 2018 May 5.

Department of Obstetrics and Gynecology, NorthShore University HealthSystem and Pritzker School of Medicine, University of Chicago, Evanston IL. Electronic address:

Background: Dysmenorrhea is a pervasive pain condition that affects 20-50% of reproductive-aged women. Distension of a visceral organ, such as the uterus, could elicit a visceromotor reflex, resulting in involuntary skeletal muscle activity and referred pain. Although referred abdominal pain mechanisms can contribute to visceral pain, the role of abdominal muscle activity has not yet been investigated within the context of menstrual pain.

Objective: The goal of this study was to determine whether involuntary abdominal muscle activity precedes spontaneous episodes of menstrual cramping pain in dysmenorrheic women and whether naproxen administration affects abdominal muscle activity.

Study Design: Abdominal electromyography activity was recorded from women with severe dysmenorrhea (n = 38) and healthy controls (n = 10) during menses. Simultaneously, pain was measured in real time using a squeeze bulb or visual analog rheostat. Ninety minutes after naproxen administration, abdominal electromyography activity and menstrual pain were reassessed. As an additional control, women were also recorded off menses, and data were analyzed in relation to random bulb squeezes. Because it is unknown whether mechanisms of menstrual cramps are different in primary or secondary dysmenorrhea/chronic pelvic pain, the relationship between medical history and abdominal muscle activity was examined. To further examine differences in nociceptive mechanisms, pressure pain thresholds were also measured to evaluate changes in widespread pain sensitivity.

Results: Abdominal muscle activity related to random-bulb squeezing was rarely observed in healthy controls on menses (0.9 ± 0.6 episodes/hour) and in dysmenorrhea participants off menses (2.3 ± 0.6 episodes/hour). In dysmenorrheic participants during menses, abdominal muscle activity frequently preceded bulb squeezing indicative of menstrual cramping pain (10.8 ± 3.0 episodes/hour; P < .004). Whereas 45% of the women with dysmenorrhea (17 of 38) had episodes of abdominal muscle activity associated pain, only 13% (5 of 38) had episodes after naproxen (P = .011). Women with the abdominal muscle activity-associated pain were less likely to have a diagnosis for secondary dysmenorrhea or chronic pelvic pain (2 of 17) than women without this pain phenotype (10 of 21; P = .034). Similarly, women with the abdominal muscle activity-associated pain phenotype had less nonmenstrual pain days per month (0.6 ± 0.5) than women without the phenotype (12.4 ± 0.3; P = .002). Women with abdominal muscle activity-associated pain had pressure pain thresholds (22.4 ± 3.0 N) comparable with healthy controls (22.2 ± 3.0 N; P = .967). In contrast, women without abdominal muscle activity-associated pain had lower pressure pain thresholds (16.1 ± 1.9 N; P = .039).

Conclusion: Abdominal muscle activity may contribute to cramping pain in primary dysmenorrhea but is resolvable with naproxen. Dysmenorrheic patients without cramp-associated abdominal muscle activity exhibit widespread pain sensitivity (lower pressure pain thresholds) and are more likely to also have a chronic pain diagnosis, suggesting their cramps are linked to changes in central pain processes. This preliminary study suggests new tools to phenotype menstrual pain and supports the hypothesis that multiple distinct mechanisms may contribute to dysmenorrhea.
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http://dx.doi.org/10.1016/j.ajog.2018.04.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6741772PMC
July 2018

Identification of experimental bladder sensitivity among dysmenorrhea sufferers.

Am J Obstet Gynecol 2018 07 25;219(1):84.e1-84.e8. Epub 2018 Apr 25.

Department of Obstetrics/Gynecology, NorthShore University HealthSystem, Evanston, IL; Pritzker School of Medicine, University of Chicago, Chicago, IL. Electronic address: https://www.thegyrl.org.

Background: Dysmenorrhea is a common risk factor for chronic pain conditions including bladder pain syndrome. Few studies have formally evaluated asymptomatic bladder pain sensitivity in dysmenorrhea, and whether this largely reflects excess pelvic symptom reporting due to comorbid psychological dysfunction.

Objective: We sought to determine whether bladder hypersensitivity is more common among women reporting moderate or greater dysmenorrhea, without chronic pain elsewhere, after accounting for anxiety and depression. Demonstrating this would suggest that dysmenorrhea might be an early clue for visceral or widespread pain hypersensitivity and improve understanding of potential precursors to bladder pain syndrome.

Study Design: We compared cohorts of regularly menstruating women, without symptoms of chronic pain elsewhere, reporting (1) moderate-to-severe dysmenorrhea (n = 98) and (2) low levels or no menstrual pain (n = 35). Participants underwent rapid bladder filling following a standard water ingestion protocol, serially rating bladder pain and relative urgency during subsequent distension. Potential differences in bladder volumes were controlled for by sonographic measurement at standard cystometric thresholds. Bladder sensitivity was also measured with complementary measures at other times separately including a simplified rapid filling test, palpation of the bladder wall, and through ambulatory self-report. Anxiety and depression were evaluated with the National Institutes of Health Patient-Reported Outcomes Measurement Information System measures.

Results: Women with moderate-to-severe dysmenorrhea reported more urinary symptoms than controls and had a lower maximum capacity (498 ± 18 mL vs 619 ± 34 mL, P < .001) and more evoked bladder filling pain (0-100 visual analog scale: 25 ± 3 vs 12 ± 3, P < .001). The dysmenorrhea-bladder capacity relationship remained significant irrespective of menstrual pain severity, anxiety, depression, or bladder pain (R = 0.13, P = .006). Severity of menstrual pain predicted evoked bladder pain (R = 0.10, P = .008) independent of anxiety (P = .21) and depression (P = .21). Women with moderate-to-severe dysmenorrhea exhibiting provoked bladder pain (24/98, 24%) also reported higher pain during the screening rapid bladder test (P < .001), in response to transvaginal bladder palpation (P < .015), and on prospective daily diaries (P < .001) than women with dysmenorrhea without provoked bladder pain.

Conclusion: Women experiencing moderate-to-severe dysmenorrhea also harbor a higher pain response to naturally evoked bladder distension. Noninvasive bladder provocation needs to be tested further longitudinally in those with dysmenorrhea to characterize the course of visceral sensitivity and determine if it may help predict individuals at risk for developing subsequent pain in the bladder or elsewhere.
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http://dx.doi.org/10.1016/j.ajog.2018.04.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054462PMC
July 2018

Somatic symptoms in women with dysmenorrhea and noncyclic pelvic pain.

Arch Womens Ment Health 2018 10 10;21(5):533-541. Epub 2018 Mar 10.

Pritzker School of Medicine, University of Chicago, Chicago, IL, USA.

Somatic symptoms are a robust, transdiagnostic risk factor for pain conditions. However, the extent to which somatic symptoms contribute to the manifestation of the women's pain syndromes, such as dysmenorrhea and noncyclic pelvic pain (NCPP), is unclear due to high rates of co-occurrence. Therefore, the present study investigated the primary hypothesis that somatic symptoms would be elevated in NCPP and distinctly influence the relationship between dysmenorrhea and co-occurring NCPP. A secondary analysis was performed on cross-sectional questionnaire data from 1012 nonpregnant reproductive-aged women. Eligible analyzed participants (n = 834) were categorized into four groups: healthy, dysmenorrhea, NCPP, and NCPP with co-occurring dysmenorrhea (NCPP+dysmenorrhea). A parallel mediation analysis was run to evaluate the primary hypothesis that somatic symptoms are the primary factor associated with increased NCPP accounting for dysmenorrhea. The NCPP+dysmenorrhea group had higher somatic, anxiety, and depression symptom T-scores (respectively 61, 61, 60) compared to the healthy controls (46, 51, 51; p's < .001) and the dysmenorrhea group (50, 53, 54; p's < .001). The pain and psychological symptoms were significantly correlated across the entire sample (r's = .29, - .64, p's < .01). Results from parallel mediation analysis showed that somatic symptoms were distinctly associated with NCPP+dysmenorrhea. Women with NCPP+dysmenorrhea have increased psychological and somatic symptoms compared to women with dysmenorrhea alone. Given that NCPP often co-occurs with dysmenorrhea, failure to account for comorbidity in previous studies has likely led to an overestimation of psychological symptoms in dysmenorrhea. Future studies should evaluate whether somatic sensitivity is a modifiable risk factor for NCPP.
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http://dx.doi.org/10.1007/s00737-018-0823-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126970PMC
October 2018

Cine MRI during spontaneous cramps in women with menstrual pain.

Am J Obstet Gynecol 2018 05 2;218(5):506.e1-506.e8. Epub 2018 Feb 2.

Department of Radiology, Northshore University HealthSystem, Evanston, IL; Department of Radiology, Pritzker School of Medicine, University of Chicago, Chicago, IL.

Background: The lack of noninvasive methods to study dysmenorrhea has resulted in poor understanding of the mechanisms underlying pain, insufficient diagnostic tests, and limited treatment options. To address this knowledge gap, we have developed a magnetic resonance imaging-based strategy for continuously monitoring the uterus in relationship to participants' spontaneous pain perception.

Objective: The study objective was to evaluate whether magnetic resonance imaging can detect real-time changes in myometrial activity during cramping episodes in women with dysmenorrhea, with a handheld squeeze bulb for pain reporting.

Study Design: Sixteen women with dysmenorrhea and 10 healthy control women both on and off their menses were evaluated with magnetic resonance imaging while not taking analgesic medication. Continuous magnetic resonance imaging was acquired using half-Fourier acquisition single-shot turbo spin echo sequence along with simultaneous reporting of pain severity with a squeeze bulb. Pearson's coefficient was used to compare results between reviewers. Proportional differences between women with dysmenorrhea and controls on/off menses were evaluated with a Fisher exact test. The temporal relationships between signal changes were evaluated with Monte Carlo simulations.

Results: Spontaneous progressive decreases in myometrial signal intensity were more frequently observed in women on their menses than in the absence of pain in the same women off their menses or participants without dysmenorrhea (P < .01). Women without reductions in myometrial signal intensity on their menses either had a history of endometriosis or were not in pain. Observations of myometrial events were consistently reported between 2 raters blinded to menstrual pain or day status (r = 0.97, P < .001). Episodes of cramping occurred either immediately before or 32-70 seconds after myometrial signal change onset (P < .05).

Conclusion: Transient decreases in myometrial uterine T2-weighted signal intensity can be reliably measured in women with menstrual pain. The directionality of signal change and temporal relationship to pain onset suggest that cramping pain may be caused by a combination of uterine pressure and hemodynamic dysfunction.
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http://dx.doi.org/10.1016/j.ajog.2018.01.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916049PMC
May 2018

Nonsteroidal antiinflammatory drug resistance in dysmenorrhea: epidemiology, causes, and treatment.

Am J Obstet Gynecol 2018 04 6;218(4):390-400. Epub 2017 Sep 6.

Department of Obstetrics and Gynecology, NorthShore University HealthSystem and Pritzker School of Medicine University of Chicago, Evanston, IL. Electronic address:

Although nonsteroidal antiinflammatory drugs can alleviate menstrual pain, about 18% of women with dysmenorrhea are unresponsive, leaving them and their physicians to pursue less well-studied strategies. The goal of this review is to provide a background for treating menstrual pain when first-line options fail. Research on menstrual pain and failure of similar drugs in the antiplatelet category suggested potential mechanisms underlying nonsteroidal antiinflammatory drug resistance. Based on these mechanisms, alternative options may be helpful for refractory cases. This review also identifies key pathways in need of further study to optimize menstrual pain treatment.
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http://dx.doi.org/10.1016/j.ajog.2017.08.108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839921PMC
April 2018

The Effects of Platelet-Activating Factor on Uterine Contractility, Perfusion, Hypoxia, and Pain in Mice.

Reprod Sci 2018 03 20;25(3):384-394. Epub 2017 Jun 20.

1 Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, IL, USA.

It is widely hypothesized that menstrual pain is triggered by prostaglandin synthesis that evokes high-pressure uterine contractions and ischemia. However, the effects of molecules implicated in menstrual pain on uterine contractility, perfusion, and oxygenation in vivo have been rarely demonstrated. Studies in women that do not respond to nonsteroidal anti-inflammatory drugs (NSAIDs) have reported elevated levels of platelet-activating factor (PAF). To establish in vivo evidence of PAF's capability to impair uterine homeostasis and to elicit visceral pain, we examined the effects of the PAF receptor agonist (carbamyl PAF [CPAF]) in comparison to other molecules hypothesized to play a role in uterine pain in mice. Uterine pressure was increased by oxytocin, prostaglandin F2α (PGF2α), and CPAF. Even in the absence of inflammatory molecules, uterine contractions reduced uterine oxygenation by 38%. CPAF reduced uterine perfusion by 40% ± 8% and elicited further oxygen desaturation approaching hypoxia (9.4 ± 3.4 mm Hg Pao). Intraperitoneal injections of CPAF and PGF2α evoked visceral pain and pelvic hyperalgesia in awake wild-type mice. However, pain was not observed in identically injected PAF-receptor knockout mice. Thus, our model provides a demonstration that a molecule implicated in NSAID-resistant dysmenorrhea has a detrimental effect on uterine homeostasis and is capable of causing visceral pain. Our results support the general hypothesis that menstrual cramps are caused by uterine contractions, impaired perfusion, and reduced oxygenation. Since this study was limited to mice, confirmation of these results in humans would be valuable for development of novel therapeutics targeted at inflammatory precursors, contractility, perfusion, and tissue oxygenation.
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http://dx.doi.org/10.1177/1933719117715122DOI Listing
March 2018

Reply.

Am J Obstet Gynecol 2016 07 2;215(1):132-3. Epub 2016 Mar 2.

Department of Obstetrics and Gynecology, Division of Gynecological Pain and Minimally Invasive Surgery, NorthShore University HealthSystem, 2650 Ridge Avenue, Suite 1530, Evanston, IL 60201. Electronic address:

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http://dx.doi.org/10.1016/j.ajog.2016.02.051DOI Listing
July 2016

Multimodal nociceptive mechanisms underlying chronic pelvic pain.

Am J Obstet Gynecol 2015 Dec 20;213(6):827.e1-9. Epub 2015 Aug 20.

Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, IL; Department of Obstetrics and Gynecology, Pritzker School of Medicine, University of Chicago, Chicago, IL. Electronic address:

Objective: We sought to evaluate candidate mechanisms underlying the pelvic floor dysfunction in women with chronic pelvic pain (CPP) and/or painful bladder syndrome (PBS)/interstitial cystitis. Notably, prior studies have not consistently controlled for potential confounding by psychological or anatomical factors.

Study Design: As part of a larger study on pelvic floor pain dysfunction and bladder pain sensitivity, we compared a measure of mechanical pain sensitivity, pressure pain thresholds (PPTs), between women with pelvic pain and pain-free controls. We also assessed a novel pain measure using degree and duration of postexam pain aftersensation, and conducted structural and functional assessments of the pelvic floor to account for any potential confounding. Phenotypic specificity of pelvic floor measures was assessed with receiver operator characteristic curves adjusted for prevalence.

Results: A total of 23 women with CPP, 23 women with PBS, and 42 pain-free controls completed the study. Women with CPP or PBS exhibited enhanced pain sensitivity with lower PPTs (1.18 [interquartile range, 0.87-1.41] kg/cm(2)) than pain-free participants (1.48 [1.11-1.76] kg/cm(2); P < .001) and prolonged pain aftersensation (3.5 [0-9] vs 0 [0-1] minutes; P < .001). Although genital hiatus (P < .01) was wider in women with CPP there were no consistently observed group differences in pelvic floor anatomy, muscle tone, or strength. The combination of PPTs and aftersensation duration correlated with severity of pelvic floor tenderness (R(2), 41-51; P < .01). Even after adjustment for prevalence, the combined metrics discriminated pain-free controls from women with CPP or PBS (area under the curve, 0.87).

Conclusion: Both experimental assessment of pelvic floor pain thresholds and measurement of sustained pain are independently associated with pelvic pain phenotypes. These findings suggest systematic clinical assessment of the time course of provoked pain symptoms, which occurs over seconds for mechanical pain thresholds vs minutes for aftersensation pain, would be helpful in identifying the fundamental mechanisms of pelvic floor pain. Longitudinal studies of therapies differentially targeting these discrete mechanisms are needed to confirm their clinical significance.
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http://dx.doi.org/10.1016/j.ajog.2015.08.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711364PMC
December 2015

The association of dysmenorrhea with noncyclic pelvic pain accounting for psychological factors.

Am J Obstet Gynecol 2013 Nov 22;209(5):422.e1-422.e10. Epub 2013 Aug 22.

Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, IL.

Objective: The factors that underlie pelvic pain are poorly understood. Specifically, the relative influence of dysmenorrhea and psychological factors in the etiology of noncyclic pelvic pain conditions, such as interstitial cystitis and irritable bowel syndrome, is unknown. To further characterize pelvic pain, we compared the frequency of menstrual, somatosensory, and psychological risk factors between women with and without severe noncyclic pelvic pain symptoms.

Study Design: A total of 1012 reproductive-aged women completed a 112-item questionnaire with domains including mood, fatigue, physical activity, somatic complaint, and pain. Questionnaire items included existing items for menstrual distress and newly written items derived from qualitative interviews. The relationship of dysmenorrhea and noncyclic pelvic pain complaints (dyspareunia, dyschezia, or dysuria) was modeled using quantile regression.

Results: Among women who menstruate regularly, those with dysmenorrhea had disproportionally more severe noncyclic pelvic pain (54/402, 13%) than women without dysmenorrhea (5/432, 1%; odds ratio, 13; 95% confidence interval, 5-33). In a multivariate-adjusted model, dysmenorrhea (β = .17), activity capability (β = .17), somatic complaint (β = .17), and bodily pain (β = .12) were the primary predictors of noncyclic pelvic pain. Depression (β = .03) and anxiety (β = .01) were not significantly predictive. The presence of dysmenorrhea, somatic complaint, and low activity capability predicted 90% of the cases of women with noncyclic pelvic pain.

Conclusion: The association between dysmenorrhea and noncyclic pelvic pain suggests that menstrual pain is an etiological factor in noncyclic pelvic pain, whereas depression and anxiety may be secondary effects. Longitudinal studies are needed to determine whether dysmenorrhea causally influences development of noncyclic pelvic pain or shares common underlying neural mechanisms.
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http://dx.doi.org/10.1016/j.ajog.2013.08.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4191839PMC
November 2013

A noninvasive bladder sensory test supports a role for dysmenorrhea increasing bladder noxious mechanosensitivity.

Clin J Pain 2013 Oct;29(10):883-90

*Department of Obstetrics and Gynecology, NorthShore University HealthSystem †Department of Obstetrics and Gynecology, Pritzker School of Medicine, University of Chicago, Chicago, IL.

Objective: Catheterization to measure bladder sensitivity is aversive and hinders human participation in visceral sensory research. Therefore, we sought to characterize the reliability of sonographically estimated female bladder sensory thresholds. To demonstrate this technique's usefulness, we examined the effects of self-reported dysmenorrhea on bladder pain thresholds.

Methods: Bladder sensory threshold volumes were determined during provoked natural diuresis in 49 healthy women (mean age, 24±8 y) using 3-dimensional ultrasound. Cystometric thresholds (Vfs, first sensation; Vfu, first urge; Vmt, maximum tolerance) were quantified and related to bladder urgency and pain. We estimated the reliability (1-wk retest and interrater). Self-reported menstrual pain was examined in relationship to bladder pain, urgency, and volume thresholds.

Results: Average bladder sensory thresholds (mL) were Vfs (160±100), Vfu (310±130), and Vmt (500±180). Interrater reliability ranged from 0.97 to 0.99. One-week retest reliability was Vmt=0.76 (95% CI, 0.64-0.88), Vfs=0.62 (95% CI, 0.44-0.80), and Vfu=0.63 (95% CI, 0.47-0.80). Bladder filling rate correlated with all thresholds (r=0.53 to 0.64, P<0.0001). Women with moderate to severe dysmenorrhea pain had increased bladder pain and urgency at Vfs and increased pain at Vfu (P's<0.05). In contrast, dysmenorrhea pain was unrelated to bladder capacity.

Discussion: Sonographic estimates of bladder sensory thresholds were reproducible and reliable. In these healthy volunteers, dysmenorrhea was associated with increased bladder pain and urgency during filling but unrelated to capacity. Plausibly, women with dysmenorrhea may exhibit enhanced visceral mechanosensitivity, increasing their risk to develop chronic bladder pain syndromes.
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http://dx.doi.org/10.1097/AJP.0b013e31827a71a3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644544PMC
October 2013

Opioids disrupt pro-nociceptive modulation mediated by raphe magnus.

J Neurosci 2012 Oct;32(40):13668-78

Department of Neurobiology, University of Chicago, Chicago, Illinois 60637, USA.

In anesthetized rats, opioid analgesia is accompanied by a specific pattern of tonic activity in two neuronal populations within the medullary raphe magnus (RM): opioids silence pain-facilitatory ON cells and produce sustained discharge in pain-inhibitory OFF cells. These tonic activity patterns, hypothesized to generate a tonic analgesic state, have not been observed in recordings made without anesthesia. Therefore, we recorded ON and OFF cell activity before and after an analgesic dose of morphine in unanesthetized mice. The tonic activity of ON and OFF cells was unchanged by morphine. Rather, morphine suppressed the phasic ON cell excitation and OFF cell inhibition evoked by noxious stimulation. Before morphine, the magnitude of the noxious stimulus-evoked burst in ON cells correlated with motor withdrawal magnitude, suggesting that ON cells facilitate nocifensive motor reactions. Contrary to model prediction, OFF cell activity was greater before stimulus trials that evoked withdrawals than those without withdrawals. Since withdrawals only occurred when OFF cell activity was suppressed, a decrease in OFF cell activity appears to serve as a pro-nociceptive signal that synchronizes and therefore strengthens the ensuing motor reaction. We further propose that morphine acts in RM to suppress ON and OFF cell phasic responses and thereby disable RM's pro-nociceptive output. Thus, RM cells produce antinociception by failing to exert the pro-nociceptive effects normally engaged by noxious stimulation. These findings revise the conventional understanding of supraspinal opioid analgesia and demonstrate that RM produces on demand rather than state modulation, allowing RM cells to serve other functions during pain-free periods.
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http://dx.doi.org/10.1523/JNEUROSCI.1551-12.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3752126PMC
October 2012

Gynecologic management of neuropathic pain.

Am J Obstet Gynecol 2011 Nov 12;205(5):435-43. Epub 2011 May 12.

Department of Obstetrics and Gynecology, NorthShore University HealthSystem, Evanston, IL, USA.

Obstetrician/gynecologists often are the initial management clinicians for pelvic neuropathic pain. Although treatment may require comprehensive team management and consultation with other specialists, there are a few critical and basic steps that can be performed during an office visit that offer the opportunity to improve quality of life significantly in this patient population. A key first step is a thorough clinical examination to map the pain site physically and to identify potentially involved nerves. Only limited evidence exists about how best to manage neuropathic pain; generally, a combination of surgical, manipulative, or pharmacologic methods should be considered. Experimental methods to characterize more precisely the nature of the nerve dysfunction exist to diagnose and treat neuropathic pain; however, additional scientific evidence is needed to recommend these options unanimously. In the meantime, an approach that was adopted from guidelines of the International Association for the Study of Pain has been tailored for gynecologic pain.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205239PMC
http://dx.doi.org/10.1016/j.ajog.2011.05.011DOI Listing
November 2011

Opioid microinjection into raphe magnus modulates cardiorespiratory function in mice and rats.

Am J Physiol Regul Integr Comp Physiol 2009 Nov 26;297(5):R1400-8. Epub 2009 Aug 26.

Department of Neurobiology and 2Committee on Neurobiology, University of Chicago, Chicago, Illinois 60637, USA.

The raphe magnus (RM) participates in opioid analgesia and contains pain-modulatory neurons with respiration-related discharge. Here, we asked whether RM contributes to respiratory depression, the most prevalent lethal effect of opioids. To investigate whether opioidergic transmission in RM produces respiratory depression, we microinjected a mu-opioid receptor agonist, DAMGO, or morphine into the RM of awake rodents. In mice, opioid microinjection produced sustained decreases in respiratory rate (170 to 120 breaths/min), as well as heart rate (520 to 400 beats/min). Respiratory sinus arrhythmia, indicative of enhanced parasympathetic activity, was prevalent in mice receiving DAMGO microinjection. We performed similar experiments in rats but observed no changes in breathing rate or heart rate. Both rats and mice experienced significantly more episodes of bradypnea, indicative of impaired respiratory drive, after opioid microinjection. During spontaneous arousals, rats showed less tachycardia after opioid microinjection than before microinjection, suggestive of an attenuated sympathetic tone. Thus, activation of opioidergic signaling within RM produces effects beyond analgesia, including the unwanted destabilization of cardiorespiratory function. These adverse effects on homeostasis consequent to opioid microinjection imply a role for RM in regulating the balance of sympathetic and parasympathetic tone.
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http://dx.doi.org/10.1152/ajpregu.00140.2009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2777768PMC
November 2009

Activity of murine raphe magnus cells predicts tachypnea and on-going nociceptive responsiveness.

J Neurophysiol 2007 Dec 3;98(6):3121-33. Epub 2007 Oct 3.

Department of Neurobiology, University of Chicago, Chicago, IL 60637, USA.

In rats, opioids produce analgesia in large part by their effects on two cell populations in the medullary raphe magnus (RM). To extend our mechanistic understanding of opioid analgesia to the genetically tractable mouse, we characterized behavioral reactions and RM neural responses to opioid administration. d-Ala(2), N-Me-Phe(4)-Gly(5)ol-enkephalin, a mu-opioid receptor agonist, microinjected into the murine RM produced cardiorespiratory depression and reduced slow wave electroencephalographic activity as well as increased the noxious heat-evoked withdrawal latencies. As in rat, RM cell types that were excited and inhibited by noxious stimuli, termed on and off cells, respectively, were observed in mice. However, in contrast to findings in rat, opioid doses that suppressed withdrawals did not alter the background discharge rate of murine on and off cells, suggesting that the cellular mechanisms by which the murine RM generates opioid analgesia are substantially different from those in rats. Murine on cell discharge did not predict the latency or magnitude of an ensuing withdrawal but did correlate to the magnitude and latency of concurrent withdrawals. Although opioids failed to alter the background discharge of on and off cells, they reduced the responses of RM neurons to noxious stimulation, further evidence that RM modulates on-going withdrawals. In characterizing the role of RM in respiratory modulation, we found that on cells burst and off cells paused during tachypneic events. The effects of opioids in the murine RM on homeostasis and the association of on and off cell discharge with tachypnea corroborate roles for opioid signaling in RM beyond analgesia.
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http://dx.doi.org/10.1152/jn.00904.2007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759357PMC
December 2007

Raphe magnus neurons help protect reactions to visceral pain from interruption by cutaneous pain.

J Neurophysiol 2006 Dec 23;96(6):3423-32. Epub 2006 Aug 23.

Department of Neurobiology, Pharmacology, and Physiology, University of Chicago, MC 0926, 947 East 58th St., Chicago, IL 60637, USA.

Suppression of reactions to one noxious stimulus by a spatially distant noxious stimulus is termed heterotopic antinociception. In lightly anesthetized rats, a noxious visceral stimulus, colorectal distension (CRD), suppressed motor withdrawals but not blood pressure or heart rate changes evoked by noxious hindpaw heat. Microinjection of muscimol, a GABA(A) receptor agonist, into raphe magnus (RM) reduced CRD-evoked suppression of withdrawals, evidence that RM neurons contribute to this heterotopic antinociception. To understand how brain stem neurons contribute to heterotopic antinociception, RM neurons were recorded during CRD-elicited suppression of hindpaw withdrawals. Although subsets of RM neurons that were excited (on cells) or inhibited (off cells) by noxious cutaneous stimulation were either excited or inhibited by CRD, on cells were inhibited and off cells excited by an intracerebroventricularly administered opioid, evidence that the nociception-facilitating and -inhibiting functions of on and off cells, respectively, are predicted by the cellular response to noxious cutaneous stimulation alone and not by the response to CRD. When recorded during CRD-elicited antinociception, RM cell discharge resembled the pattern observed in response to CRD stimulation alone. However, when hindpaw withdrawal suppression was incomplete, RM cell discharge resembled the pattern observed in response to heat alone. We propose that on cells excited by CRD facilitate responses to CRD itself, which in turn augments excitation of off cells that then act to suppress cutaneous nociception. RM cells may thereby contribute to the dominance of quiet recuperative reactions evoked by potentially life-threatening visceral stimuli over transient somatomotor activity elicited by less-injurious noxious cutaneous stimuli.
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http://dx.doi.org/10.1152/jn.00793.2006DOI Listing
December 2006
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