Chronic Bladder Pain Research Articles

The Pathomechanism and Current Treatments for Chronic Interstitial Cystitis and Bladder Pain Syndrome.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic and debilitating condition characterized by symptoms such as bladder pain, frequent urination, and nocturia. Pain is typically perceived in the lower abdomen, pelvic floor, or urethra, causing significant discomfort and impacting quality of life. Due to the similarity of its symptoms with those of overactive bladder and acute bacterial cystitis, patients often face misdiagnosis and delayed appropriate treatment. Hunner's (HIC) and non-Hunner's IC (NHIC), each with distinct clinical presentations, urothelial dysfunction, chronic inflammation, and central sensitization and thus multimodal symptomatic treatment approaches, may be the most common pathogeneses of IC/BPS. Treatment of IC/BPS should involve identifying the different clinical phenotypes and underlying pathophysiology causing clinical symptoms and developing strategies tailored to the patient's needs. This review discusses the roles of urine biomarkers, bladder inflammation, and glycosaminoglycans in the pathogenesis of IC/BPS. Various bladder treatment modalities are explored, including glycosaminoglycan replenishment, botulinum toxin A injection, platelet-rich plasma injection, low-energy shock waves, immunosuppression, and low-dose oral prednisolone. Pelvic floor muscle physiotherapy and bladder therapy combined with psychiatric consultation can help alleviate psychological stress and enhance the quality of life of patients with IC/BPS. Elucidating the pathological mechanisms and exploring diverse treatment options would help advance the care of individuals suffering from this challenging bladder condition.

Adult zymosan re-exposure exacerbates the molecular alterations in the brainstem rostral ventromedial medulla of rats with early life zymosan-induced cystitis

Recent evidence suggests that the descending modulatory pathways from the brainstem rostral ventromedial medulla (RVM) are important for bladder inflammatory pain. This study aimed to identify the long-term molecular changes in RVM neurons due to early life cystitis during neuronal development and the effect of reexposure later in adulthood. RVM tissues from two treatment protocols were used: (1) neonatal zymosan exposures with acute adult rechallenge (RC) and (2) only neonatal zymosan exposures (NRC). RNAseq analysis showed upregulation of several genes associated with synaptic plasticity (Grin1, Grip2, Notch1, Arc, and Scn2b) in the cystitis groups compared to controls in both protocols. The RC protocol exhibited a stronger treatment effect with significantly higher fold differences between the groups compared to the NRC protocol (p < 0.001, fold differences RC vs NRC). In microarrays, miR-34a-5p showed cystitis-induced downregulation in both protocols. Bioinformatics analysis identified multiple 3′UTRs complementary binding sites for miR-34a-5p on Grin2b, Notch1, Grip2, Scn2b, and Arc genes. The enhanced response in the RC protocol indicates a possible priming effect of early life cystitis on rechallenge in adulthood. These long-term molecular alterations may play a critical role in the development of chronic bladder pain conditions as seen in patients with Interstitial Cystitis/Bladder pain syndrome.

Acute Autonomic Nervous System Response to Direct Sacral Nerve Root Stimulation in Lower Urinary Tract Dysfunction: A New Approach to Understand the Mechanism of Action of Sacral Nerve Modulation.

Our goal was to assess acute autonomic nervous system (ANS) response to direct sacral nerve root (SNR) stimulation in the context of lower urinary tract dysfunction. In this retrospective monocentric study, patients undergoing 2-stage sacral nerve modulation for overactive bladder, nonobstructive urinary retention, or chronic bladder pain syndrome between March 2022 and June 2023 were analyzed. A standardized stimulation protocol was applied during the lead implantation, each of the 4 contact points being sequentially stimulated at the amplitude required to elicit anal motor response. Stimulations were labeled as StimA, StimB, StimC, and StimD, ordered by ascending order of minimum amplitude required for anal motor response. Heart rate variability parameters were collected using PhysioDoloris Monitor, and computed through the time-domain (standard deviation of normal-to-normal intervals [SDNN], root mean square of successive differences), the frequency-domain (low frequency, high frequency) and the graphical (Analgesia Nociception Index [ANI]) methods. Fifty patients were analyzed, including 35 females. Twelve patients had an underlying neurological disease. Efficacy was deemed achieved in 54% of patients. SDNN variability significantly increased during StimA to StimC, while maximum SDNN significantly increased only during StimA. ANI variability significantly increased during all 4 stimulations, while maximum ANI significantly increased only during StimA. Direct stimulation of SNR is responsible for a significant increase in ANS and relative parasympathetic nervous system activity, with a greater effect observed when the stimulation was delivered closer to the SNR. These results shed light on potential mechanisms underlying sacral nerve modulation, particularly regarding the treatment of ANS dysregulation in lower urinary tract dysfunction.

Efficacy of Pudendal Nerve Blocks and Ultrasound-Guided Superior Hypogastric Plexus Blocks for the Management of Refractory Interstitial Cystitis: A Case Series

Interstitial cystitis/bladder pain syndrome (IC/BPS) is characterized by chronic pelvic, perineal, or bladder pain in addition to lower urinary tract symptoms. The etiology of this condition is not fully understood, which presents a challenge for effective therapeutic intervention. Current treatment guidelines recommend the use of multimodal pain management strategies including behavioral/non-pharmacologic, oral medications, bladder instillations, procedures, and major surgery. However, the safety and efficacy of these modalities vary, and there is currently no optimal treatment for the management of IC/BPS. The pudendal nerves and superior hypogastric plexus, which together mediate visceral pelvic pain and bladder control, are not addressed in the current guidelines but may serve as a therapeutic target. Here, we report improvements in pain, urinary symptoms, and functionality following bilateral pudendal nerve blocks and/or ultrasound-guided superior hypogastric plexus blocks in three patients with refractory IC/BPS. Our findings provide support for the use of these interventions in patients with IC/BPS unresponsive to prior conservative management.

Pelvic pain after laparoscopic lateral suspension for pelvic organ prolapse: an unrecognized problem?

The laparoscopic lateral suspension (LLS) represents an alternative mesh procedure to avoid the dissection at the promontory. However, mesh-related complications such as chronic pelvic pain, dyspareunia, and bladder pain are emerging. The present study is aimed to present a video case report and describe a small case series of patients referred to our center for chronic pelvic pain after LLS. A surgical video of the management of a 50-year-old woman with chronic abdominal and pelvic pain, dyspareunia, and recurrent urinary tract infection (UTIs) after uterus sparing LLS is provided. Moreover, we performed a retrospective chart review of similar cases in our institution. The featured procedure was completed without complications and was successful in obtaining symptom relief. Between 2018 and 2022 five patients underwent total or subtotal mesh removal for pain-related symptoms after LLS. At the median follow-up of 24 months, all patients were free from pain, but two (40%) required reoperation for prolapse recurrence CONCLUSIONS: Our experience suggests that LLS involves a certain risk of chronic pelvic pain, which may be challenging to manage and require surgical treatment.

Persistent need to urinate: A common sensory symptom leading to urinary discomfort. A study of 79 cases

An unpleasant, inappropriate, and persistent need to urinate (PNU) is a sensory symptom reported by some patients with lower urinary tract symptoms (LUTS). However, no detailed definition of this symptom exists. This study aimed to describe the characteristics of patients reporting PNU and to discuss the pathophysiology and therapeutic approach. The clinical and urodynamic findings of patients presenting with PNU without chronic bladder pain syndrome or neurological or urological conditions between October 2019 and December 2020 were retrospectively reviewed. The treatment efficacy was self-reported at follow-up as “total cure”, “significant improvement” or “no modification”. Seventy-nine patients were included (51 women (65%), mean age 49 years (Standard Deviation (SD) 18)). The mean duration of symptoms was 7 years (SD 11). Frequency was commonly associated with PNU (mean interval between voids 103 min (SD 69)) and 50 patients (63%) reported nocturia. Voiding difficulties were described in 33 cases (40%). The mean first desire to void was 112mL (SD 93) with normal maximum cystometric capacity of 397mL (SD 135), and 5 patients had detrusor overactivity. Proposed treatments were tibial nerve stimulation (n=25) with a total cure or significant improvement in 17 cases, alpha-blockers (n=8) with an improvement in 4 patients, antimuscarinics (n=29) with an improvement in only 3 patients, and antidepressant or antiepileptic (n=8) with an improvement in 5 patients. PNU is poorly described but could be responsible for LUTS. Further studies to understand the underlying mechanisms and to assess the therapeutic efficacy of the different options are required.

Pulsed Electromagnetic Field Therapy for Pain Management in Interstitial Cystitis/Bladder Pain Syndrome: A Proof-of-Concept Case Series

ObjectiveTo evaluate the efficacy of pulsed electromagnetic field (PEMF) therapy for symptom and pain management in women with non-bladder centric interstitial cystitis/bladder pain syndrome (IC/BPS). MethodsWomen with non-bladder centric IC/BPS and a numeric rating scale score for pelvic pain ≥6 underwent twice-daily 8-minute full body PEMF therapy sessions for 4 weeks. The primary outcome metric was a reduction in pelvic pain score ≥2 points. A 7-day voiding diary (collected at baseline and conclusion), 3 validated symptom scores, and the Short Form-36 Quality of Life questionnaire (completed at baseline, conclusion of treatment, and 8-week follow-up), were used to assess secondary outcomes. Treatment effects were analyzed via Wilcoxon-signed rank test; P < .05 was considered significant. ResultsThe 4-week treatment protocol was completed by 8 of 10 enrolled patients, and 7:8 (87.5%) had a significant reduction in pelvic pain (-3.0 points, P = .011) after 4 weeks. There was also a significant decrease in scores on all validated IC/BPS questionnaires, daily number of voids, and nocturia symptom score (P < .05). Significant increases in several quality-of-life questionnaire sub-scores were also identified at 4 weeks (P < .05). At 8-week post-therapy, the positive effects were somewhat attenuated, yet 4:8 patients (50%) continued to have significant pain reduction (P = .047). No adverse events or side effects were reported. ConclusionWhole body pulsed electromagnetic field therapy is an alternative treatment option for women with chronic bladder pain syndrome that warrants investigation through comparative trials.

The Role of Amygdala Calcitonin Gene-related Peptide (CGRP) Receptors in the Development of Persistent Bladder Pain

The underlying mechanisms of visceral pain (e.g. bladder pain) are poorly understood, making it difficult to treat. The central amygdala (CeA) is known as a significant contributor to the pathology of chronic pain. While the CeA in the right hemisphere has been shown to increase bladder pain, the left CeA has been shown to reduce bladder pain. Recent evidence has shown that CeA activity is not only asymmetric, but also changes with time once somatic pain is induced. However, it is unknown whether time-dependent activation of the CeA contributes to the development of chronic bladder pain. We seek to study the hemispherical and temporal changes of the CeA in the context of bladder pain and identify cell-types that might be responsible for contributing to these changes. One interesting target that has been shown to produce asymmetric functions within the brain is calcitonin gene-related peptide (CGRP). In this study, we used a CGRP antagonist – CGRP8-37, to study the role of CeA CGRP receptors (CGRP-Rs) on bladder pain-related changes over time. The effects of CGRP8-37 were examined using a mouse model of bladder pain (100 mg/kg cyclophosphamide, 3 days). Two pain assays, abdominal von Frey and the voiding spot assay were conducted (2-14 days post-injury) in mice that received direct CeA injections (right CeA) of CGRP8-37 (1 uL of 100uM) or saline. Preliminary data indicate that animals that received saline displayed a decrease in 50% withdrawal threshold (bladder nociception) in the abdominal von Frey assay once treated with cyclophosphamide. Animals that received a direct injection of CGRP8-37 displayed an increase in 50% withdrawal threshold (less nociception) compared to saline treated animals. In the voiding assay, CGRP8-37 led to changes in voiding frequency. Collectively, these data support the study of cell-specific manipulation of the right CeA to produce pain relief. Grant support from 7R01DK115478-04 and 1F32DK128969.

Step-wise Treatment of Bladder Pain Syndrome: Case Report

Bladder pain syndrome/interstitial cystitis is a condition characterized by chronic pelvic and bladder pain (lasting longer than 6 months) accompanied by urinary symptoms (urinary frequency, urgency and nocturia). It can have a highly negative effect on the quality of life. The treatment of this disease is impeded by lack of understanding of its etiology. Therefore, treatment recommendations and information about their efficacy are scarce. The American Urological Association recommends a step-wise therapeutic approach starting from mere patients’ lifestyle modification to pharmacological therapy or to even more complex methods, such as intravesical botulinum toxin-A injections. We present here a case of a 60-year old woman, who presented in 2020 with tiresome symptoms characteristic to bladder pain syndrome lasting for two years. Previous treatments with antibiotics, anti-inflammatory, analgesic and anticholinergic medications were unsuccessful; urine culture was negative. During the cystoscopy in our center small bladder capacity and minute glomerulations were observed. Urodynamic tests (cystometry) were performed showing hypersensitive bladder with small capacity. Bladder hydrodistention procedure was performed twice; however the positive effects only lasted up to one month each time. Therefore, it was decided to perform an intravesical botulinum toxin-A injection into bladder trigonal area after which the patient experienced a significant relief in bladder pain, reduced urinary frequency during the day and night and improved quality of life.

Icariin attenuates cyclophosphamide-induced cystitis via down-regulation of NF-кB and up-regulation of Nrf-2/HO-1 signaling pathways in mice model

Cystitis is a chronic bladder pain associated with frequency and nocturia. In the present study, Icariin a prenylated flavonoid extracted from Epimedium koreanum, was investigated against cyclophosphamide (CYP)-induced cystitis pain in mice model. Preliminarily in an acute model, single dose of CYP (150 mg/kg; i.p) was administered followed by Icariin (5, 25 and 50 mg/kg, i.p.). The visceral sensitivity and nociceptive behaviors were significantly ameliorated by pretreatment with Icariin (25, 50 mg/kg) that were assessed by spontaneous pain scoring, von Frey test and clinical scoring. Further, in chronic model Icariin (25 mg/kg, i.p.) was administered for 10 consecutive days prior to CYP (75 mg/kg; i.p) challenged every 3rd day for the duration of 10 days. Icariin not only had a protective effect on edema including bladder wet weight and hemorrhage but also had a potential to reduce vascular permeability, mast cells infiltration and tissue fibrosis. Evidently, Icariin prevented the neutrophilia/lymphopenia caused by CYP, and markedly improved the antioxidant enzymes level including superoxide dismutase, glutathione sulfo-transferase, catalase, glutathione level and reduced Malondialdehyde level, myeloperoxidase activity and nitric oxide, and also decreased the production of tumor necrosis factor-α (TNF-α) and interleukin-1 beta (IL-1β) in bladder. Icariin markedly enhanced the Nrf-2, heme oxygenase (HO-1) and IкB-α expression, while attenuated the expression level of Keap1, TLR-4, NF-кB, i-NOS, COX-2 and TRPV1 as compared to negative group. This research illustrated the anti-inflammatory properties of Icariin and effectively improved CYP-induced cystitis pain.

Interstitial cystitis/bladder pain syndrome patient is associated with subsequent increased risks of outpatient visits and hospitalizations: A population-based study.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is not only a chronic urinary bladder pain syndrome but is also associated with multifactorial etiology. Our study aimed to test the hypothesis that IC/BPS is associated with subsequent increased risks of outpatient visits and hospitalizations. Using nationwide database, the diagnoses were based on the International Classification Codes (ICD-9-CM) (595.1) of at least three outpatient services during 2002-2008, (n = 27,990) and cystoscopic finding Hunner type and/or glomerulation with pre-audit criteria. All recruited cases monitored for subsequent outpatient visits and hospitalizations for 2 years, including all-cause and specialty-specific departments, were classified according to medical specialty and age group (<40, 40-60, ≥60 years of age). IC/BPS patients have more overall outpatient department (OPD) visits and an overall adjusted incidence rate ratio (IRR) of 1.64. As for specialty, IRRs were higher in psychiatry (2.75), Chinese medicine (2.01), and emergency medicine (2.00), besides urology and gynecology. The IRRs decreased as age advanced (2.01, 1.71, and 1.44, respectively), except for gynecology (2.42, 2.52, and 2.81). A similar phenomenon happens in hospitalization with IRR of 1.69. Due to claim data characteristics, whether ulcer type IC/BPS findings can be deductive to non-ulcer type remains inclusive. Current results indicate the impacts of healthcare burden in broad spectrum about IC/PBS patients. IC/BPS has been suggested to be associated with lower threshold of healthcare visits and some coexisting disease and is comprised of systemic dysregulation, and is beyond the scope of local bladder-urethra disease. Adequate recognition of associated or comorbid factors and possible recommendation or referral for IC/BPS patients can help provide better healthcare quality.

MP02-05 SYMPTOMS OF CENTRAL SENSITIZATION ARE ASSOCIATED WITH WORSE LOWER URINARY TRACT SYMPTOMS IN MEN

You have accessJournal of UrologyUrodynamics/Lower Urinary Tract Dysfunction/Female Pelvic Medicine: Non-neurogenic Voiding Dysfunction I (MP02)1 Sep 2021MP02-05 SYMPTOMS OF CENTRAL SENSITIZATION ARE ASSOCIATED WITH WORSE LOWER URINARY TRACT SYMPTOMS IN MEN Angela Senders, Kamran Sajadi, Scott Bauer, Thu Le, Ryan Wexler, Yiyi Chen, Barry Oken, and Lynn Marshall Angela SendersAngela Senders More articles by this author , Kamran SajadiKamran Sajadi More articles by this author , Scott BauerScott Bauer More articles by this author , Thu LeThu Le More articles by this author , Ryan WexlerRyan Wexler More articles by this author , Yiyi ChenYiyi Chen More articles by this author , Barry OkenBarry Oken More articles by this author , and Lynn MarshallLynn Marshall More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001963.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Central sensitization (CS) is an impairment in the processing of sensory information that results in ongoing hypersensitivity to nociceptive and other somatic signals. CS has been examined as a possible mechanism of overactive bladder among women, but studies of CS and urinary symptoms among men are lacking. Our objective was to determine the association between CS symptoms and lower urinary tract symptoms (LUTS) among men. METHODS: We conducted a cross-sectional study using an electronic survey. From June-August 2020, we contacted 209 men, age 18 years or older, who had received urodynamic testing for LUTS in the past 3 years at our institution’s adult urology clinic. Of these, 75 did not respond, 43 declined, and 91 (44%) consented. We obtained demographics, history of diagnosed neurological conditions, chronic pain syndromes, current bladder or genital pain, the American Urological Association Symptom Index (AUASI) and the Central Sensitization Inventory (CSI). The CSI is a 25-item questionnaire quantifying symptoms commonly reported by people with CS, with the sum of items resulting in a total score of 0-100 points. A CSI score of ≥40 indicates moderate-to-severe CS-related symptoms. We used multivariable linear regression to model the association between moderate-to-severe CS and AUASI score. We estimated regression coefficients (β) and 95% confidence intervals (CI) adjusted first for age. The final model was adjusted for age, existing neurologic conditions (multiple sclerosis, Parkinson’s disease), chronic prostatitis (CP), chronic bladder or pelvic pain, and pain with urination or ejaculation in the past week. RESULTS: Among 90 men with complete data, the mean (standard deviation, sd) age was 66 (14) years, 76 (84%) were non-Hispanic white, 27 (30%) had CSI scores ≥ 40, and the mean (sd) AUASI score was 15 (9) points. Controlled for age, the AUASI score averaged 8 points greater among men with CS compared to men without CS (β=8.1, 95% CI: 4.3, 11.9). The positive association remained in the final model (β=7.6, 95% CI: 3.4, 11.7). When restricted to 53 men without neurologic conditions, CP, pain syndromes, or urination or ejaculation pain, the association remained (age-adjusted β=8.7, 95% CI: 2.5, 14.9). CONCLUSIONS: Symptoms suggestive of moderate-to-severe CS were common among men with a recent history of urodynamic testing for LUTS and associated with significantly greater AUASI scores. The association was independent of existing neurologic and chronic pain conditions including CP. Objective assessment for the presence of CS among men with LUTS is warranted. Source of Funding: Unfunded © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e13-e13 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Angela Senders More articles by this author Kamran Sajadi More articles by this author Scott Bauer More articles by this author Thu Le More articles by this author Ryan Wexler More articles by this author Yiyi Chen More articles by this author Barry Oken More articles by this author Lynn Marshall More articles by this author Expand All Advertisement Loading ...

Immunomodulation—A Molecular Solution to Treating Patients with Severe Bladder Pain Syndrome?

BackgroundPatients with bladder pain syndrome experience debilitating pain and extreme frequency of urination. Numerous therapeutic approaches have been tested, but as the molecular basis of disease has remained unclear, specific therapies are not available. ObjectiveRecently, a systematic gene deletion strategy identified interleukin-1 (IL-1) hyperactivation as a cause of severe cystitis in a murine model. Treatment with an IL-1 receptor antagonist (IL-1RA) restored health in genetically susceptible mice, linking IL-1–dependent inflammation to pain and pathology in the bladder mucosa. The study objective was to investigate whether IL-1RA treatment might be beneficial in patients with bladder pain syndrome. Design, setting, and participantsPatients diagnosed with bladder pain syndrome were invited to participate and subjected to daily IL-1RA injections for 1 wk, followed by a treatment break. Patients with other urological disorders accompanied by pain were included as controls. Outcome measurements and statistical analysisWhen symptoms returned, treatment was resumed and responding patients were maintained on treatment long term, with individualized dosing regimens. Symptom scores were recorded and molecular effects were quantified by neuropeptide and gene expression analysis. DNA samples were subjected to exome genotyping. Results and limitationsIL-1RA treatment reduced bladder pain and the frequency of urination in 13/17 patients (p < 0.001). Substance P levels in urine were lowered, and responders returned to a more normal lifestyle. Neuroinflammatory-dependent and IL-1–dependent gene networks were inhibited, as well as regulators of innate immunity. Genotyping revealed disease-associated IL1R1, NLRP3, and IL1RN DNA sequence variants in the responders. Controls did not benefit from IL-1RA treatment, except for one patent with cystitis cystica. ConclusionsIn this clinical study, IL-1RA treatment is proposed to reduce chronic bladder pain, immediately and in the long term. Despite the limited number of study patients, the potent acute effect and lasting symptom relief indicate that this therapeutic approach may be worth exploring in controlled clinical trials. Patient summaryTreatment with an interleukin-1 (IL-1) receptor antagonist is proposed for treating bladder pain syndrome, as it can result in symptom relief and increase quality of life. Reduced neuroinflammation and IL-1 signaling provided molecular evidence of the treatment effects.

Mechanistic Rationale and Clinical Efficacy of Hyperbaric Oxygen Therapy in Chronic Neuropathic Pain: An Evidence-Based Narrative Review.

Background Chronic neuropathic pain is a condition affecting an increasing proportion of the general population and its management requires a comprehensive, multidisciplinary program. A growing body of evidence supports the use of hyperbaric oxygen therapy (HBOT) in several chronic neuropathic pain conditions; however, its role and efficacy remain unclear. Purpose To summarize current evidence for the mechanistic rationale of HBOT in chronic neuropathic pain conditions and to evaluate its clinical efficacy. Methods This narrative review was conducted after searching the following databases (Medline, Embase, Cochrane, PsycINFO, the Web of Science, Scopus, ClinicalTrials. gov, WHO ICTRP, and ProQuest Digital Dissertation) from January 1946 to March 2020. Articles published in English that involved either animal or human studies with acute or chronic neuropathic pain evaluating any HBOT-related intervention were included. Results A total of 2971 citations were identified. A total of 29 studies were included in this review. The mechanisms of action for HBOT use in neuropathic conditions included the primary effects of hyperoxia and edema resolution, as well as the secondary effects pertinent to the production of oxygen and nitrogen reactive species (serving as pain signaling molecules), nitric oxide-dependent release of opioid peptides, and reduction of inflammatory mediators. A robust evidence for HBOT use in the clinical setting was associated with chronic regional pain syndrome and chronic primary bladder pain syndrome. Some evidence supported its use for chronic secondary (peripheral) neuropathic pain including radiation-induced plexus neuropathies, postherpetic neuralgia, and trigeminal neuralgia. Conclusions HBOT has been shown to have antinociceptive and analgesic effects in animal models of inflammatory, neuropathic, and chronic pain. Human studies demonstrated beneficial effects of HBOT in improving clinical outcomes such as pain scores, pain-related symptoms, and quality of life. A systematic methodology of HBOT application is necessary to confirm its safety and efficacy.

МАНУАЛЬНА ТЕРАПІЯ В ЛІКУВАННІ СИНДРОМУ ХРОНІЧНОГО ТАЗОВОГО БОЛЮ

Синдром хронічного тазового болю поєднує в собі численні синдроми хронічного сечостатевого болю. Дана публікація присвячена лише кільком із них: простатичному, сечоміхуровому і вагінальному та можливості їх лікування методами мануальної терапії у разі неінфекційного виникнення цих синдромів. Дослідження доводить, що метод мануальної терапії в поєднанні з ударно-хвильовою терапією дозволяє успішно надавати допомогу хворим із стійкими до лікування проявами СХТБ, зокрема, простатичного, сечоміхурового та вагінального больових синдромів, які не отримали бажаного результату при використанні традиційних методів лікування.

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

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. 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. 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. 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 χ2, 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. Women with dysmenorrhea who are unaware they alsohave 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 statesis 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.

Neuromodulatory effects of pudendal nerve stimulation on bladder hypersensitivity are present in opioid-pretreated rats

Background and objectivesBilateral electrical pudendal nerve stimulation (bPNS) reduces bladder hypersensitivity in rat models and anecdotally reduces pain in humans with pelvic pain of urologic origin. Concomitant opioids are known...

Spinal macrophage migration inhibitory factor and high mobility group box 1 mediate persistent bladder pain

Repeated intravesical PAR4 (protease activated receptor 4) activation elicits persistent bladder pain lasting 5 days after the last treatment. Persistent bladder pain was fully reversed by a systemic HMGB1 (high mobility group box 1) inhibitor while a MIF (macrophage migration inhibitory factor) antagonist partly reversed it. Since there is growing evidence that spinal MIF and HMGB1 mediate inflammatory and neuropathic pain we examined whether there were spinal changes occurring during persistent bladder pain that may be responsible for maintaining bladder pain. In addition, we tested whether we could modulate persistent bladder pain with spinal MIF or HMGB1 antagonists. Persistent bladder pain was elicited in female C57 mice by repeated (3x) intravesical instillation of PAR4-activating peptide while control animals received scramble peptide treatment. On day 4, spinal cord (L6-S1) changes in c-fos (non-specific marker of spinal activation) was assessed with immunofluorescence while MIF and HMGB1 were assessed with immunofluorescence, western blotting and real-time PCR. On day 7, mice received an intrathecal injection of a neutralizing MIF monoclonal antibody (15 μg in 5 μl PBS) or a HMGB1 inhibitor glycyrrhizin (25 μg in 5 μl of 5% alcohol in PBS) and abdominal mechanical threshold was tested. On day 9, mice were treated with vehicle or control and abdominal mechanical threshold was tested. Immunofluorescence showed that c-fos and MIF in the dorsal horn, dorsal grey commissure and intermediolateral areas significantly increased in PAR4-treated mice while HMGB1 was decreased. In addition, intrathecal treatment with MIF neutralizing mAb or glycyrrhizin significantly alleviated abdominal mechanical hypersensitivity at 1 and 2 h and the analgesic effect diminished at 6 h. Vehicle or control treatment had no effect. Persistent bladder pain is associated with spinal changes in MIF and HMGB1 levels. Furthermore, spinal treatment with MIF monoclonal antibody and HMGB1 inhibitor temporarily reversed bladder pain. Our findings suggest that spinal MIF and HMGB1 participate in persistent bladder pain induced by repeated intravesical PAR4 and may be potential therapeutic targets in chronic bladder pain conditions.

Molecular pathogenesis of interstitial cystitis/bladder pain syndrome based on gene expression.

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic bladder inflammation that leads to chronic bladder pain and urinary urgency and frequency. The presentation of IC/PBS is heterogeneous, and it is classified as ulcerative IC/PBS and nonulcerative IC/PBS. The main cause of IC/PBS is thought to be a persistent inflammatory condition in the bladder, though the actual pathophysiology has not been identified yet. Although the underlying pathophysiology of IC/PBS is not completely understood, several theories for the etiology of this syndrome have been suggested, including deficiency of the glycosaminoglycan covering urothelium surface that results in leaky urothelium infection, immunological etiology, activated mast cells, neural changes, and inflammation. In addition, there are no gold standards for the detection of this disorder to date. So, determination of gene expression and its role in different signaling pathways in the pathogenesis of this heterogeneous disorder contribute to the more efficient cognition of the pathophysiology of this disease and to the design of effective treatments and molecular diagnostic methods for IC/PBS.

Modeling Neural Behavior and Pain During Bladder Distention using an Agent-based Model of the Central Nucleus of the Amygdala

Chronic bladder pain evokes asymmetric behavior in neurons across the left and right hemispheres of the amygdala. An agent-based computational model was created to simulate the firing of neurons over time and in response to painful bladder stimulation. Each agent represents one neuron and is characterized by its location in the amygdala and response type (excited or inhibited). At each time step, the firing rates (Hz) of all neurons are stochastically updated from probability distributions estimated from data collected in laboratory experiments. A damage accumulation model tracks the damage accrued by neurons during long-term, painful bladder stimulation. Emergent model output uses neural activity to measure temporal changes in pain attributed to bladder stimulation. Simulations demonstrate the model's ability to capture acute and chronic pain and its potential to predict changes in pain similar to those observed in the lab. Asymmetric neural activity during the progression of chronic pain is examined using model output and a sensitivity analysis.