Pain mechanisms in the transgender individual: a review.

Specific Aim: Provide an overview of the literature addressing major areas pertinent to pain in transgender persons and to identify areas of primary relevance for future research. Methods: A team of scholars that have previously published on different areas of related research met periodically though zoom conferencing between April 2021 and February 2023 to discuss relevant literature with the goal of providing an overview on the incidence, phenotype, and mechanisms of pain in transgender patients. Review sections were written after gathering information from systematic literature searches of published or publicly available electronic literature to be compiled for publication as part of a topical series on gender and pain in the Frontiers in Pain Research. Results: While transgender individuals represent a significant and increasingly visible component of the population, many researchers and clinicians are not well informed about the diversity in gender identity, physiology, hormonal status, and gender-affirming medical procedures utilized by transgender and other gender diverse patients. Transgender and cisgender people present with many of the same medical concerns, but research and treatment of these medical needs must reflect an appreciation of how differences in sex, gender, gender-affirming medical procedures, and minoritized status impact pain. Conclusions: While significant advances have occurred in our appreciation of pain, the review indicates the need to support more targeted research on treatment and prevention of pain in transgender individuals. This is particularly relevant both for gender-affirming medical interventions and related medical care. Of particular importance is the need for large long-term follow-up studies to ascertain best practices for such procedures. A multi-disciplinary approach with personalized interventions is of particular importance to move forward.

Hydration-induced Void-containing Hydrogels for Encapsulation and Sustained Release of Small Hydrophilic Molecules.

Efficient encapsulation and sustained release of small hydrophilic molecules from traditional hydrogel systems have been challenging due to the large mesh size of 3D networks and high water content. Furthermore, the encapsulated molecules are prone to early release from the hydrogel prior to use, resulting in a short shelf life of the formulation. Here, we present a hydration-induced void-containing hydrogel (HVH) based on hyperbranched polyglycerol-poly(propylene oxide)-hyperbranched polyglycerol (HPG-PPG-HPG) as a robust and efficient delivery system for small hydrophilic molecules. Specifically, after the HPG-PPG-HPG is incubated overnight at 4 °C in the drug solution, it is hydrated into a hydrogel containing micron-sized voids, which could encapsulate hydrophilic drugs and achieve 100% drug encapsulation efficiency. In addition, the voids are surrounded by a densely packed polymer matrix, which restricts drug transport to achieve sustained drug release. The hydrogel/drug formulation can be stored for several months without changing the drug encapsulation and release properties. HVH hydrogels are injectable due to shear thinning properties. In rats, a single injection of the HPG-PPG-HPG hydrogel containing 8 µg of tetrodotoxin (TTX) produced sciatic nerve block lasting up to 10 hours without any TTX-related systemic toxicity nor local toxicity to nerves and muscles.

Chronic pain in female breast cancer survivors - prevalence, characteristics and contributing factors: a cross-sectional pilot study.

BACKGROUND: While the global incidence of breast cancer is increasing, there is also an increase in the numbers of breast cancer survivors and in survival duration, as early detection programs are implemented, and treatments are optimized. Breast cancer survivors in several countries commonly struggle with a range of symptoms (fatigue, insomnia, depression) with 25-80% of survivors suffering from chronic pain. There is a paucity of literature reporting on breast cancer survivors in South Africa. In this pilot study we aimed to determine the prevalence of chronic pain in female breast cancer survivors attending the breast oncology clinic. METHODS: A cross-sectional survey was conducted of all breast cancer survivors attending the Groote Schuur Hospital Breast Unit during one month in 2019. 44 female breast cancer survivors (median age 60.5y) completed a sociodemographic questionnaire, the Brief Pain Inventory, Pain Catastrophizing Scale and measures for neuropathic pain (DN4), health related quality of life (HRQoL; EQ-5d-3 L), physical activity (IPAQ), depression and anxiety (PHQ4), and screening questions to evaluate sleep, happiness and perceived discrimination in the language of their choice. RESULTS: The prevalence of chronic pain (pain on most days for more than three months) was 59% (95%CI 44-72), a significantly higher number than the 18,3% prevalence of chronic pain reported by South African adults. 39% of the women were classified as having neuropathic pain. The median pain severity score was 3.75 (IQR = 2.75-5) and the median pain interference with function score was 4 (IQR = 2.9-5.4). The women were experiencing pain in a median of 2 different body sites (IQR = 1-3). The women with pain were more likely to be unemployed or receiving a disability grant, had significantly worse HRQoL, and significantly worse scores for risk of depression and anxiety. CONCLUSION: The results of this pilot study suggest that chronic pain may be a significant burden for South African breast cancer survivors. Routine screening for chronic pain in breast cancer survivors is recommended with a larger study indicated to explore this issue further.

Drug Permeability: From the Blood-Brain Barrier to the Peripheral Nerve Barriers.

Drug delivery into the peripheral nerves and nerve roots has important implications for effective local anesthesia and treatment of peripheral neuropathies and chronic neuropathic pain. Similar to drugs that need to cross the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB) to gain access to the central nervous system (CNS), drugs must cross the peripheral nerve barriers (PNB), formed by the perineurium and blood-nerve barrier (BNB) to modulate peripheral axons. Despite significant progress made to develop effective strategies to enhance BBB permeability in therapeutic drug design, efforts to enhance drug permeability and retention in peripheral nerves and nerve roots are relatively understudied. Guided by knowledge describing structural, molecular and functional similarities between restrictive neural barriers in the CNS and peripheral nervous system (PNS), we hypothesize that certain CNS drug delivery strategies are adaptable for peripheral nerve drug delivery. In this review, we describe the molecular, structural and functional similarities and differences between the BBB and PNB, summarize and compare existing CNS and peripheral nerve drug delivery strategies, and discuss the potential application of selected CNS delivery strategies to improve efficacious drug entry for peripheral nerve disorders.

Emulsion-induced polymersomes taming tetrodotoxin for prolonged duration local anesthesia.

Injectable local anesthetics that can provide a continuous nerve block approximating the duration of a pain state would be a life-changing solution for patients experiencing post-operative pain or chronic pain. Tetrodotoxin (TTX) is a site 1 sodium channel blocker that is extremely potent compared to clinically used local anesthetics. Challengingly, TTX doses are limited by its associated systemic toxicity, thus shortening the achievable duration of nerve blocks. Here, we explore emulsion-induced polymersomes (EIP) as a drug delivery system to safely use TTX for local anesthesia. By emulsifying hyperbranched polyglycerol-poly (propylene glycol)-hyperbranched polyglycerol (HPG-PPG-HPG) in TTX aqueous solution, HPG-PPG-HPG self-assembled into micrometer-sized polymersomes within seconds. The formed polymersomes have microscopically visible internal aqueous pockets that encapsulate TTX with an encapsulation efficiency of up to 94%. Moreover, the polymersomes are structurally stable, enabling sustained TTX release. In vivo, the freshly prepared EIP/TTX formulation can be directly injected and increased the tolerated dose of TTX in Sprague-Dawley rats to 11.5 µg without causing any TTX-related systemic toxicity. In the presence of the chemical penetration enhancer (CPE) sodium octyl sulfate (SOS), a single perineural injection of EIP/TTX/SOS formulation produced a reliable sciatic nerve block for 22 days with minimal local toxicity.

Optimizing and Accelerating the Development of Precision Pain Treatments for Chronic Pain: IMMPACT Review and Recommendations.

Large variability in the individual response to even the most-efficacious pain treatments is observed clinically, which has led to calls for a more personalized, tailored approach to treating patients with pain (ie, "precision pain medicine"). Precision pain medicine, currently an aspirational goal, would consist of empirically based algorithms that determine the optimal treatments, or treatment combinations, for specific patients (ie, targeting the right treatment, in the right dose, to the right patient, at the right time). Answering this question of "what works for whom" will certainly improve the clinical care of patients with pain. It may also support the success of novel drug development in pain, making it easier to identify novel treatments that work for certain patients and more accurately identify the magnitude of the treatment effect for those subgroups. Significant preliminary work has been done in this area, and analgesic trials are beginning to utilize precision pain medicine approaches such as stratified allocation on the basis of prespecified patient phenotypes using assessment methodologies such as quantitative sensory testing. Current major challenges within the field include: 1) identifying optimal measurement approaches to assessing patient characteristics that are most robustly and consistently predictive of inter-patient variation in specific analgesic treatment outcomes, 2) designing clinical trials that can identify treatment-by-phenotype interactions, and 3) selecting the most promising therapeutics to be tested in this way. This review surveys the current state of precision pain medicine, with a focus on drug treatments (which have been most-studied in a precision pain medicine context). It further presents a set of evidence-based recommendations for accelerating the application of precision pain methods in chronic pain research. PERSPECTIVE: Given the considerable variability in treatment outcomes for chronic pain, progress in precision pain treatment is critical for the field. An array of phenotypes and mechanisms contribute to chronic pain; this review summarizes current knowledge regarding which treatments are most effective for patients with specific biopsychosocial characteristics.

Efficacy and Safety of Drug Combinations for Chronic Pelvic Pain: Protocol for a Systematic Review.

BACKGROUND: Chronic pelvic pain with various etiologies and mechanisms affects men and women and is a major challenge. Monotherapy is often unsuccessful for chronic pelvic pain, and combinations of different classes of medications are frequently prescribed, with the expectation of improved outcomes. Although a number of combination trials for chronic pelvic pain have been reported, we are not aware of any systematic reviews of the available evidence on combination drug therapy for chronic pelvic pain. OBJECTIVE: We have developed a protocol for a systematic review to evaluate available evidence of the efficacy and safety of drug combinations for chronic pelvic pain. METHODS: This systematic review will involve a detailed search of randomized controlled trials investigating drug combinations to treat chronic pelvic pain in adults. The databases searched will include the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE from their inception until the date the searches are run to identify relevant studies. The primary outcome will be pain relief measured using validated scoring tools. Secondary outcomes, where reported, will include the following: adverse events, serious adverse events, sexual function, quality of life, and depression and anxiety. Methodological quality of each included study will be assessed using the Cochrane Risk of Bias Tool. RESULTS: The systematic review defined by this protocol is expected to synthesize available good quality evidence on combination drug therapy in chronic pelvic pain, which may help guide future research and treatment choices for patients and their health care providers. CONCLUSIONS: This review will provide a clearer understanding of the efficacy and safety of combination pharmacological therapy for chronic pelvic pain. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42020192231; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=192231. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/21909.

Vulvodynia.

Vulvodynia is a condition that occurs in 8-10% of women of all ages and is characterized by pain at the vulva that is present during sexual and/or non-sexual situations. Diagnosis is established through careful medical history and pelvic examination, including the cotton-swab test. The onset and maintenance of vulvodynia involves a complex interplay of peripheral and central pain mechanisms, pelvic floor muscle and autonomic dysfunction, anxiety, depression and childhood maltreatment as well as cognitive-affective, behavioural and interpersonal factors. Given the absence of empirically supported treatment guidelines, a stepwise approach of pelvic floor physical therapy and cognitive behavioural therapy as well as medical management is suggested, with surgery as the last option. Vulvodynia has a negative effect on the quality of life of women and their partners, and imposes a profound personal and societal economic burden. In addition, women with vulvodynia are more likely to report other chronic pain conditions, which further alters their quality of life. Future efforts should aim to increase girls', women's and healthcare professionals' education and awareness of vulvodynia, phenotype different subgroups of women based on biopsychosocial characteristics among more diverse samples, conduct longitudinal studies and improve clinical trial designs.

The IASP classification of chronic pain for ICD-11: chronic secondary visceral pain.

Chronic visceral pain is a frequent and disabling condition. Despite high prevalence and impact, chronic visceral pain is not represented in ICD-10 in a systematic manner. Chronic secondary visceral pain is chronic pain secondary to an underlying condition originating from internal organs of the head or neck region or of the thoracic, abdominal, or pelvic regions. It can be caused by persistent inflammation, by vascular mechanisms or by mechanical factors. The pain intensity is not necessarily fully correlated with the disease process, and the chronic visceral pain may persist beyond successful treatment of the underlying cause. This article describes how a new classification of chronic secondary visceral pain is intended to facilitate the diagnostic process and to enable the collection of accurate epidemiological data. Furthermore, it is hoped that the new classification will improve the tailoring of patient-centered pain treatment of chronic secondary visceral pain and stimulate research. Chronic secondary visceral pain should be distinguished from chronic primary visceral pain states that are considered diseases in their own right.

Research Design Characteristics of Published Pharmacologic Randomized Clinical Trials for Irritable Bowel Syndrome and Chronic Pelvic Pain Conditions: An ACTTION Systematic Review.

Chronic pain conditions occurring in the lower abdomen and pelvis are common, often challenging to manage, and can negatively affect health-related quality of life. Methodological challenges in designing randomized clinical trials (RCTs) for these conditions likely contributes to the limited number of available treatments. The goal of this systematic review of RCTs of pharmacologic treatments for irritable bowel syndrome and 3 common chronic pelvic pain conditions are to: 1) summarize the primary end points and entry criteria, and 2) evaluate the clarity of reporting of important methodological details. In total, 127 RCTs were included in the analysis. The most common inclusion criteria were a minimum pain duration (81%), fulfilling an established diagnostic criteria (61%), and reporting a minimum pain intensity (42%). Primary end points were identified for only 57% of trials. These end points, summarized in this article, were highly variable. The results of this systematic review can be used to inform future research to optimize the entry criteria and outcome measures for pain conditions occurring in the lower abdomen and pelvis, to increase transparency in reporting to allow for proper interpretation of RCT results for clinical and policy applications, and to facilitate the aggregation of data in meta-analyses. PERSPECTIVE: This article summarizes entry criteria and outcome measures and the clarity of reporting of these important design features in RCTs of irritable bowel syndrome and 3 common chronic pelvic pain conditions. These results can be used to improve design of future trials of these largely unaddressed pain conditions.

AAPT Diagnostic Criteria for Chronic Abdominal, Pelvic, and Urogenital Pain: Irritable Bowel Syndrome.

In conjunction with the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks public-private partnership with the U.S. Food and Drug Administration and the American Pain Society, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks-American Pain Society Pain Taxonomy (AAPT) initiative strove to develop the characteristics of a diagnostic system useful for clinical and research purposes across disciplines and types of chronic pain conditions. After the establishment of these characteristics, a working group of clinicians and clinical and basic scientists with expertise in abdominal, pelvic, and urogenital pain began generating core diagnostic criteria and defining the related extraintestinal somatic pain and other symptoms experienced by patients. Systematic diagnostic criteria for several common abdominal, pelvic, and urogenital pain conditions are in development. In this report, we present the proposed AAPT criteria for irritable bowel syndrome (IBS), the most common chronic, noncancer abdominal pain condition. A systematic review and synthesis was conducted to complement the Rome IV Diagnostic Criteria for IBS. Future efforts will subject these proposed AAPT criteria to systematic empirical evaluation of their feasibility, reliability, and validity. The AAPT IBS criteria are part of an evidence-based classification system that provides a consistent vocabulary regarding diagnostic criteria, common features, comorbidities, consequences, and putative mechanisms of the disorder. A similar approach is being applied to other chronic and often debilitating abdominal, pelvic, and urogenital pain conditions. PERSPECTIVE: The AAPT's goal is to develop an evidence-based taxonomy for chronic pain on the basis of a consistently applied multidimensional framework, and encourage experts to apply this taxonomy to specific chronic pain conditions. In this report, the taxonomy is applied to IBS, a chronic abdominal pain condition.

Visceral pain as a triggering factor for fibromyalgia symptoms in comorbid patients.

Fibromyalgia syndrome (FMS) is a central sensitization syndrome; however, peripheral pain sources potentially exacerbate its symptoms of chronic diffuse musculoskeletal pain and hyperalgesia. This prospective study evaluated visceral pain as a possible triggering factor for FMS pain and hyperalgesia in comorbid patients. Women with (1) FMS + irritable bowel syndrome (IBS); (2) FMS + primary dysmenorrhea (Dys); (3) FMS + Dys secondary to endometriosis (Endo); (4) FMS + colon diverticulosis (Div) were compared with FMS-only women, for fibromyalgia pain (number and intensity of episodes and analgesic consumption) over comparable periods and for somatic hyperalgesia (electrical and pressure pain thresholds) in painful (tender points) and control areas (trapezius, deltoid, quadriceps muscles, and overlying subcutis and skin). In comorbid subgroups, FMS symptoms were also reassessed after treatment of the visceral condition or no treatment. All comorbid groups vs FMS-only had significantly higher FMS pain (number/intensity of episodes and analgesic consumption) and hyperalgesia in deep somatic tissues (subcutis and muscle) at all sites (0.05 < P < 0.0001). Visceral pain (number of IBS days, painful menstrual cycles, and abdominal pain episodes from diverticulitis) correlated directly with all parameters of FMS pain and inversely with muscle pain thresholds at all sites (0.03 < P < 0.0001). Fibromyalgia syndrome pain and hyperalgesia in all tissues and all sites significantly decreased in patients after visceral comorbidity treatment (dietary for 6 months [IBS], hormonal for 6 months [dysmenorrhea], laser [endometriosis], and surgery [diverticulosis]) (0.05 < P < 0.0001) vs no change in untreated patients. Visceral pain enhances FMS symptoms, probably augmenting the level of central sensitization typical of the syndrome. Systematic assessment and treatment of visceral pain comorbidities should be a part of FMS management strategy.

Recommendations for Self-Report Outcome Measures in Vulvodynia Clinical Trials.

OBJECTIVES: Vulvodynia (idiopathic chronic vulvar pain) is a prevalent condition associated with significant and negative impacts in many areas of function. Despite the increased research interest in vulvodynia in recent years, recommendations for outcome measures for use in clinical trials are missing. The purpose of this paper, therefore, was to provide recommendations for outcome measures for vulvodynia clinical trials so that consistent measures are used across trials to facilitate between-study comparisons and the conduct of large multicenter trials, and to improve measurement of the multiple dimensions of vulvodynia. METHODS: Given that provoked vestibulodynia (PVD)-characterized by provoked pain localized to the vaginal opening-is the most common subtype of vulvodynia and the current main focus of clinical trials, this paper focused on recommended outcome measures in PVD clinical trials. The framework used to guide the selection of outcome measures was based on the one proposed by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT). RESULTS: The IMMPACT framework provided a well-suited guideline for outcome measure recommendations in PVD clinical trials. However, given the provoked presentation of PVD and the significant impact it has on sexuality, modifications to some of the IMMPACT recommendations were made and specific additional measures were suggested. DISCUSSION: Measures that are specific to vulvovaginal pain are ideal for adoption in PVD clinical trials, and many such measures currently exist that allow the relevant IMMPACT domains to be captured.

A new paradigm in chronic bladder pain.

The concept of visceral pain has moved from organ-centered disease to a conceptualization based on pathophysiological mechanisms, integrating psychosocial and sexual dimensions. The terms painful bladder syndrome and bladder pain syndrome have been coined to include all patients with bladder pain. There is substantial overlap between IC/BPS and other pelvic/abdominal pain syndromes IC/BPS is likely to be underdiagnosed and undertreated in both men and women IC/BPS requires a multidisciplinary team approach toward management. This report is adapted from paineurope 2014; Issue 2, ©Haymarket Medical Publications Ltd, and is presented with permission. Paineurope is provided as a service to pain management by Mundipharma International, LTD and is distributed free of charge to healthcare professionals in Europe. Archival issues can be accessed via the website: http://www.paineurope.com at which European health professionals can register online to receive copies of the quarterly publication.

Functional somatic syndromes as risk factors for hysterectomy in early bladder pain syndrome/interstitial cystitis.

OBJECTIVE: We tested the hypothesis that functional somatic syndromes (FSSs) are risk factors for hysterectomy in early bladder pain syndrome/interstitial cystitis (BPS/IC). METHODS: In 312 women with incident BPS/IC, we diagnosed seven pre-BPS/IC syndromes: chronic pelvic pain (CPP), fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome (IBS), sicca syndrome, migraine, and panic disorder. Each was defined as present before 12 months (existing syndrome) or onset within 12 months (new syndrome) prior to BPS/IC onset. Retrospectively, we sought associations between prior hysterectomy and existing FSSs. Prospectively, we studied associations of existing and new syndromes with subsequent hysterectomy. Logistic regression analyses adjusted for age, race, menopause and education. RESULTS: The retrospective study showed prior hysterectomy (N=63) to be associated with existing CPP and the presence of multiple existing FSSs. The prospective study revealed that 30/249 women with a uterus at baseline (12%) underwent hysterectomy in early BPS/IC. This procedure was associated with new CPP (OR 6.0; CI 2.0, 18.2), new IBS (OR 5.4; CI 1.3, 22.3), and ≥3 existing FSSs (OR 3.9; CI 1.1, 13.9). CONCLUSION: Accounting for CPP and IBS, the presence of multiple FSSs (most without pelvic pain) was a separate, independent risk factor for hysterectomy in early BPS/IC. This suggests that patient features in addition to abdominopelvic abnormalities led to this procedure. Until other populations are assessed, a prudent approach to patients who are contemplating hysterectomy (and possibly other surgeries) for pain and who have IBS or numerous FSSs is first to try alternative therapies including treatment of the FSSs.

The ACTTION-American Pain Society Pain Taxonomy (AAPT): an evidence-based and multidimensional approach to classifying chronic pain conditions.

UNLABELLED: Current approaches to classification of chronic pain conditions suffer from the absence of a systematically implemented and evidence-based taxonomy. Moreover, existing diagnostic approaches typically fail to incorporate available knowledge regarding the biopsychosocial mechanisms contributing to pain conditions. To address these gaps, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration and the American Pain Society (APS) have joined together to develop an evidence-based chronic pain classification system called the ACTTION-APS Pain Taxonomy. This paper describes the outcome of an ACTTION-APS consensus meeting, at which experts agreed on a structure for this new taxonomy of chronic pain conditions. Several major issues around which discussion revolved are presented and summarized, and the structure of the taxonomy is presented. ACTTION-APS Pain Taxonomy will include the following dimensions: 1) core diagnostic criteria; 2) common features; 3) common medical comorbidities; 4) neurobiological, psychosocial, and functional consequences; and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors. In coming months, expert working groups will apply this taxonomy to clusters of chronic pain conditions, thereby developing a set of diagnostic criteria that have been consistently and systematically implemented across nearly all common chronic pain conditions. It is anticipated that the availability of this evidence-based and mechanistic approach to pain classification will be of substantial benefit to chronic pain research and treatment. PERSPECTIVE: The ACTTION-APS Pain Taxonomy is an evidence-based chronic pain classification system designed to classify chronic pain along the following dimensions: 1) core diagnostic criteria; 2) common features; 3) common medical comorbidities; 4) neurobiological, psychosocial, and functional consequences; and 5) putative neurobiological and psychosocial mechanisms, risk factors, and protective factors.

Urinary symptoms as a prodrome of bladder pain syndrome/interstitial cystitis.

OBJECTIVE: To test the hypothesis that more bladder pain syndrome/interstitial cystitis (BPS/IC) cases than controls report pre-onset urinary symptoms. METHODS: In a risk factor study, the date of BPS/IC onset (index date) was systematically determined in 312 female incident cases; the mean age at onset was 42.3 years. Frequency-matched controls were compared on pre-index date medical history. RESULTS: Three pre-index date symptoms were more common in BPS/IC cases: pelvic pain with urinary features, frequency, and bladder pain; 178 cases (57%) vs 56 controls (18%) had at least 1 symptom (P <.001). Several perspectives suggested that prodromal symptoms were different from BPS/IC symptoms. In prodromal women, the median age of the earliest urinary symptom "more than other people" was 20 years. Women with the prodrome were significantly more likely than those without to have pre-index date nonbladder syndromes (NBSs). The prodrome predicted not only BPS/IC but also a worse prognosis for it. CONCLUSION: Before the onset of BPS/IC, pelvic pain with urinary features, frequency, and/or bladder pain were reported by more than half the cases. Prodromal women recalled abnormal urinary symptoms decades before the onset of BPS/IC. The prodrome was associated with prior NBSs and predicted not only BPS/IC but also its poor prognosis. These data generated 2 hypotheses: that (1) prodromal symptoms are different from BPS/IC symptoms and (2) pain amplification links NBSs, the prodrome, the appearance of BPS/IC, and its poor prognosis. Recognition of the prodrome might provide opportunities for prevention of fully developed BPS/IC.