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You have accessJournal of UrologyReview Science1 Mar 2024

Urologic Chronic Pelvic Pain Syndrome Flares: A Comprehensive, Systematic Review and Meta-Analysis of the Peer-Reviewed Flare Literature

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    Abstract

    Purpose:

    We sought to systematically review and summarize the peer-reviewed literature on urologic chronic pelvic pain syndrome flares, including their terminology, manifestation, perceived triggers, management and prevention strategies, impact on quality of life, and insights into pathophysiologic mechanisms, as a foundation for future empirical research.

    Materials and Methods:

    We searched 6 medical databases for articles related to any aspect of symptom exacerbations for interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome. A total of 1486 abstracts and 398 full-text articles were reviewed, and data were extracted by at least 2 individuals.

    Results:

    Overall, we identified 59 articles, including 36 qualitative, cross-sectional, or case-control; 15 cohort-based; and 8 experimental articles. The majority of studies described North American patients with confirmed diagnoses. “Flare” was a commonly used term, but additional terminology (eg, exacerbation) was also used. Most flares involved significant increases in pain intensity, but less data were available on flare frequency and duration. Painful, frequent, long-lasting, and unpredictable flares were highly impactful, even over and above participants’ nonflare symptoms. A large number of perceived triggers (eg, diet, stress) and management/prevention strategies (eg, analgesics, thermal therapy, rest) were proposed by participants, but few had empirical support. In addition, few studies explored underlying biologic mechanisms.

    Conclusions:

    Overall, we found that flares are painful and impactful, but otherwise poorly understood in terms of manifestation (frequency and duration), triggers, treatment, prevention, and pathophysiology. These summary findings provide a foundation for future flare-related research and highlight gaps that warrant additional empirical studies.

    Urologic chronic pelvic pain syndrome (UCPPS) is an umbrella term that encompasses interstitial cystitis/bladder pain syndrome (IC/BPS) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). Both of these syndromes are characterized by chronic pelvic, bladder, or prostate pain; and urinary symptoms, such as urinary urgency and frequency. The etiology and pathophysiology of UCPPS are poorly understood, and its symptoms are difficult to diagnose and treat.1 UCPPS affects an estimated 1.8% to 6.5%2,3 of the US population and contributes to considerable health care expenditures,4 as well as significant reductions in physical and mental quality of life (QOL).2,5

    Similar to many other chronic pain conditions, UCPPS symptoms are widely known to fluctuate, including periods of symptom exacerbation (or “flares”) and remission. Although flares are well recognized by patients and providers, and have been discussed extensively in the lay literature (eg, self-help books and patient websites), they are much less well represented in the scientific literature. Most of the extant literature is limited to descriptions of patients’ beliefs about flare triggers and their treatment and management strategies. Therefore, to support future empirical research, we systematically reviewed and summarized the existing, peer-reviewed literature on numerous aspects of flares to serve as a foundation for future flare-related research. Aspects included in our comprehensive systematic review and meta-analysis were terminology; manifestation; perceived and tested triggers, therapies, and prevention strategies; impact on QOL; and insight into pathophysiologic mechanisms.

    MATERIALS AND METHODS

    Literature Search

    We searched the literature for records including the concepts of UCPPS and exacerbation using a combination of key words and controlled vocabulary in Embase.com 1947-, Ovid Medline 1946-, Scopus 1823-, The Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Clinicaltrials.gov 1997- (PROSPERO ID: 288603). Initial searches were performed on November 3, 2021, and again on February 28, 2023, with no added limits. In April 2023, we discovered that several qualitative articles that included flare-related quotes were not captured with the initial search terms. Therefore, we created a supplemental search to capture the concepts of UCPPS and qualitative research (performed on April 14, 2023). The Supplementary Appendix (https://www.jurology.com) contains fully reproducible search strategies. We also hand-searched the references of all identified articles and contacted select study authors for additional data.

    Eligibility Criteria

    We included English-language, full-text articles that addressed IC/BPS and/or CP/CPPS in humans. Articles were excluded if they (1) focused exclusively on chronic bacterial prostatitis; lupus, radiation-induced, or other forms of cystitis; endometriosis; gynecological chronic pelvic pain; or sequelae of other conditions (eg, Crohn’s disease); or (2) did not include separate analyses of UCPPS participants in studies of multiple conditions. UCPPS-specific articles were further excluded if they (1) did not address flares; (2) focused exclusively on iatrogenic flares following organ-specific procedures (eg, prostate biopsy, bladder instillation); or (3) focused exclusively on pain with or following sexual activity, ejaculation, or urination; or pain relieved by urination, as these are well-known characteristics of UCPPS that have already been incorporated into patient-reported outcome measures.6

    As no well-accepted definition of flares exists, we included all studies that reported any form of symptom exacerbation that was transient in nature (ie, observed to resolve) or that participants described as a symptom exacerbation (Supplementary Appendix Figure 1A, https://www.jurology.com). We did not include studies that described sustained symptom worsening (ie, worsening that was not observed or described to resolve; Supplementary Appendix Figure 1B, https://www.jurology.com), or symptom recurrence or worsening following a transiently successful therapy (eg, “wearing off” of the effects of a therapy; Supplementary Appendix Figure 1C, https://www.jurology.com). In addition, given the general sparsity of the flare literature, we included studies of any design, methodology, or size, as long as they addressed at least 1 of the following aspects of flares: patient terminology, manifestation, triggers, treatments and prevention strategies (including studies that described/tested interventions to reduce flare triggers even if they did not evaluate flares as their outcome), QOL impact, or pathophysiologic mechanisms.

    Study Selection

    We identified 1486 unique abstracts: 1149 from the initial, 87 from the updated, and 250 from the supplemental search (Figure 1). These were reviewed for relevance by 2 authors each. A total of 1088 citations did not meet eligibility criteria and were removed, leaving 398 for full-text review (303 from the original, 18 from the updated, and 77 from the supplemental search). Full-text articles of all original UCPPS research studies were reviewed, even if they did not mention flares in the abstract, to ensure identification of flare-related data found only in the body of the manuscript. Full-text articles were reviewed by 2 authors each and discrepancies were resolved by team consensus. A total of 352 full-text articles were excluded at this stage, leaving 47 eligible articles (32 from the original, 3 from the updated, and 12 from the supplemental search). Hand-searches identified an additional 12 articles, bringing the total number of eligible articles to 59.

    Figure 1.PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram for the systemic review of urologic pelvic pain syndrome symptom flares.

    Figure 1. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram for the systemic review of urologic pelvic pain syndrome symptom flares.

    Data Extraction and Synthesis

    Data extraction was performed by at least 2 authors. When articles included overlapping information, data from the largest analysis and/or the one dedicated to addressing flare-related questions were selected. Given the wide range of study designs/methodologies included, data were summarized in several different ways as (1) the number of studies that mentioned a concept for qualitative studies; (2) a summary prevalence estimate for cross-sectional and descriptive case-control studies; (3) individual results for cohort-based studies, case reports, and single-arm trials because of the small number of studies with similar information; and (4) a summary difference in mean change across arms in pilot randomized controlled trials. Summary estimates were calculated by generalized linear mixed (“random effects”) models. Models for prevalence estimates included a logit link and robust variance estimation7 to account for inclusion of multiple estimates per study (eg, multiple individual citrus fruit values in the citrus fruit category). Results were presented for all participants combined, as well as separately by sex to approximate clinical diagnosis (IC/BPS or CP/CPPS).

    With respect to methodologic quality, we did not use a formal instrument, as few are designed to evaluate data from the wide range of study designs and methodologies included in our review (ie, from qualitative to experimental studies). Instead, we presented aspects of study design and conduct that we considered important for interpreting study findings (eg, clinical confirmation of diagnoses, sampling frame, study design, etc). Finally, we did not present data for known aspects of UCPPS, including procedure-based iatrogenic flares; symptom worsening with/after bladder filling, urination, ejaculation, and sexual activity; and symptom improvement following urination.

    RESULTS

    Overall, 59 articles provided data related to UCPPS flares (Table). Most included data from North America (75%), followed by Asia (12%), Northern Europe (including the United Kingdom [10%]), Russia (1.7%), and 1 international study (1.7%). Approximately half were descriptive in nature (including qualitative and cross-sectional articles [59%]) and recruited participants from only 1 or a few specialty clinics (eg, urology [49%]). Fifteen articles included participants from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network (25%). Over half studied female IC/BPS participants only (or predominantly female [61%]), 22% studied male CP/CPPS participants only, and 19% studied both female and male participants. Most articles included participants with confirmed diagnoses (90%). Participants’ mean age ranged from 36 to 64 years (median 32-51 years), and the majority self-identified as White (57%-100%), followed by Asian in studies conducted in Asia. Participants’ mean condition duration ranged from > 0.6 to 17 years (median 0.1-12 years) and their typical pelvic pain intensity ranged from a mean of 2.9 to 9.1 out of 10 (median 4-6).

    Table. Characteristics of Studies Related to Urologic Chronic Pelvic Pain Syndrome Symptom Flares

    First author, y Countrya Study (or analysis) design Characteristics of IC and/or CP participants Flare characteristics
    Sampling framea Sample sizeb Female No. (%) Diagnosis Condition duration (mean), y Typical pelvic pain intensity (0-10, mean)c Terminology used by authors Aspects studied
    Gillespie, 199339 US Single-arm trial 1 specialty clinic 10 (95d) ICe NS NS Attack D
    Koziol, 199450 US Cross-sectional Multiple specialty clinics and ICA members 565 503 (89) ICe 5.4 6.6f Increased pain C, D
    Webster, 19958 US Mixed qualitative/cross-sectional ICA members and internet 138 138 (100) ICe 9 3.4f Attack A, B, C, D
    Alexander, 199617 Mainly US Cross-sectional Internet newsgroups 163 0 (0.00) CP 6.5 9.1f Flareup B, C
    Moon, 199751 US Cross-sectional National Guard unit 8 0 (0.00) CP NS NS Worse symptoms C
    Venäläinen, 199752 Finland Case-control 1 hospital 50 0 (0.00) CPe Onset or relapse in the past 2 y NS Relapse C
    Mehik, 200018 Finland Cross-sectional General population 261 0 (0.00) CP NS NS Worst symptoms B, C
    Lutgendorf, 200036 US Experimental 1 specialty clinic 14 14 (100) ICe NS 3.6f Symptom exacerbation C
    Rothrock, 200135 US Cohort 1 specialty clinic 45 45 (100) ICe NS 3.6f Symptom exacerbation C
    Lentz, 200238 US Cohort 1 specialty clinic 15 15 (100) ICe 9.5d 5.5d Flare, exacerbation, relapse C, D
    Powell-Boone, 200553 US Cohort Multiple specialty clinics 7 7 (100) ICe NS 5.4-6.1 Pain flare C
    Turner, 200654 US Cross-sectional HMO primary care and specialty clinics 286 0 (0.00) CPe 0.1f,g 3.1f Symptom worsening C, D
    Hedelin, 200719 Sweden Interviews 1 specialty clinic 10 0 (0.00) CPe 10g Range 0.7-6.5f Symptom relapse, aggravation B, C, D
    Hedelin, 200755 Sweden Cross-sectional Community 48 0 (0.00) CP 12g 4.3f Symptom relapse, exacerbation C, D
    Shorter, 200756 US Cross-sectional 1 specialty clinic 104 104 (100) ICe NS 5.5f Worsened symptoms C, D
    Stanford, 200721 US Cohort 1 specialty clinic 106 106 (100) ICe NS 5.4f Urinary tract infection symptoms, flare B, C
    Warren, 200820 and 201057 US Case-control ICA, ICN, internet, and other 158 158 (100) ICe 0.84d,g 6.4d,f Worse/worst pain B, C
    Cross-sectional Multiple specialty clinics 270 270 (100) ICe 7.7d,g 8.1d,f C
    Nickel, 201058 Canada Cohort 1 specialty clinic 100 100 (100) ICe 11.3f 5.2f Flare C
    Bassaly, 201159 US Cross-sectional ICA members 598 (91d) IC 7.1f NS Flare C, D
    Hedelin, 201260 Sweden Cross-sectional 1 specialty clinic 31 0 (0.00) CPe 17 4.7f Symptom relapse, aggravation, period of intense pain C
    Jeong, 201222 South Korea Single-arm trial 1 specialty clinic 7 7 (100) ICe 5.5f 8.3 Flare-up symptoms B, D
    Herati, 201361 US Cross-sectional 1 specialty clinic 62 0 (0.00) CPe NS 4.4d,f Worsened symptoms C, D
    O’Hare, 201362 US Cross-sectional ICA members 1982 NSh ICe NS NS Flare D
    Anderson, 201363 US Mixed qualitative/cross-sectional Multiple specialty clinics 53 53 (100) ICe NS NS Flare C, D
    Shin, 201423 South Korea Cohort 1 specialty clinic 77 0 (0.00) CPe NS 2.9f Breakthrough pain, severe pain attack, flare-up B, C
    Lee, 201443 Taiwan Randomized controlled trial 1 specialty clinic 65 65 (100) ICe NS 5.0f Flare D
    Sutcliffe, 201424 US Cross-sectional 2 specialty clinicsi 76 46 (61) ICe, CPe 13.3 4.2 Flare B, E
    Sutcliffe, 201525 US Cohort 1 specialty clinici 56 27 (48) ICe, CPe 9.8d,f 4.0-5.0d,g Flare B
    Sutcliffe, 20159 US Focus groups Multiple specialty clinicsi 57 57 (100) ICe 11.8 4.0 Flare A, B, C, D, E
    Parsons, 201526 US Cross-sectional 1 specialty clinic 100 100 (100) ICe NS NS Flare B, C
    Schrepf, 201646 US Cohort 1 specialty clinici 24 24 (100) ICe 7.2 4.9f Flare F
    Nickel, 201664 US Cross-sectional Multiple specialty clinicsi 213 213 (100) ICe NS 5.3f Flare C
    Kanter, 201710 US Focus groups 1 specialty clinic 15 15 (100) ICe 12.0 NS Flare A, E
    Wood, 201765 UK Interviews/written narratives BPSA and Prostate Cancer UK 12 0 (0.00) CP 12.1f NS Symptom exacerbation C
    Oh-oka, 201741 Japan Randomized controlled trial 1 hospital 40 40 (100) ICe 5.3f 6.8f Symptom exacerbation D
    Lee, 201844 Taiwan Randomized controlled trial 1 specialty clinic 56 56 (100) ICe NS 3.6f Flare D
    Nickel, 201827 Canada Cross-sectional 2 specialty clinics 32 32 (100) ICe NS 5.5 Flare B, D, E
    Sutcliffe, 201834 US Case-crossover Multiple specialty clinicsi 292 176 (60) ICe, CPe 8.4 5.1 Flare C
    Sutcliffe, 201928 US Cohort Multiple specialty clinicsi 385 215 (56) ICe, CPe 8.8 5.1 Flare B
    Xu, 201929 US Cohort 1 specialty clinici 27 18 (67) ICe, CPe 4.9g 4.0g Flare B, F
    Lai, 201930 US Cross-sectional 1 specialty clinici 53 29 (55) ICe 10.3 5.1 Flare B, C, D
    Harte, 201947 US Cohort Multiple specialty clinicsi 22 (50d) ICe, CPe 5.5d 5.0d,f Flare F
    Nickel, 202066 US Nested design within a cohort Multiple specialty clinicsi 202 202 (100) ICe 7.5-10.2 NS Flare C
    Li, 202067 US Case-crossover/cohort Multiple specialty clinicsi 409 227 (56) ICe, CPe 3.9g 5.0g Flare C
    Britzhatyuk, 202031 Russia Cross-sectional NS 105 0 (0.00) CPe NS 6.1f Relapse B, C
    Abdurrohim, 202042 Indonesia Case report 1 specialty clinic 1 1 (100) ICe >0.6f 3j Pain attack D
    Chen, 202068 Taiwan Mixed qualitative/cross-sectional 1 specialty clinic 22 22 (100) ICe 4d NS Symptom worsening D
    McKernan, 202011 US Mixed qualitative/cross-sectional Academic medical center and ResearchMatch 27 27 (100) ICe 15f 6.2f Symptom exacerbation, flare period A, C, D, E
    Javed, 202137 US Case-crossover/cohort Multiple specialty clinicsi 409 227 (56) ICe, CPe 3.9g 5.0g Flare C
    Volpe, 202112 US Mixed qualitative/cross-sectional ICA and ICN members 673 660 (98) ICe NS 5.5f,g Flare A, B, C, D, E
    Quallich, 202213 US Focus groups 2 specialty clinicsi 16 0 (0.00) CPe 10 3.7 Flare A, B, C, D, E
    Jarman, 202269 US Cross-sectional VA patients across US 266 106 (40) ICe NS NS Worsened symptoms C
    Gordon, 202240 US Cross-sectional/randomized case-crossover trial 1 specialty clinic 10 10 (100) ICe NS 8.3f Period of severe pain and lower urinary tract symptoms, flare C, D
    Hassani, 202232 US Focus groups Multiple specialty clinics 21 21 (100) ICe 2.5g 6f,g Acute worsening of symptoms, flare B, C, D, E
    Kirkham, 202215 UK, US Written narratives Specialist IC online messaging forums 20 20 (100) ICe NS NS Flare-up, episode A, D, E
    Meriwether, 202214 US Mixed qualitative/cross-sectional 1 specialty clinic 45 45 (100) ICe NS NS NS A, D, E
    Sutcliffe, 202333 US Cross-sectional Multiple specialty clinicsi 613 405 (66) ICe, CPe 8.0 5.0g Flare B, E
    Kim, 202345 US Interviews Multiple specialty clinics 30 30 (100) ICe 2g 5f,g NS D, E
    Gonzalez, 202316 Global Digital ethnography Online discussions 3902 3902 (100) IC NS NS Periodic/symptom exacerbation, flare A, C, D, E

    Abbreviations: A, terminology; B, manifestation; BPSA, British Prostatitis Support Association; C, triggers; CP, chronic prostatitis/chronic pelvic pain syndrome; D, therapy; E, impact on quality of life; F, insight into pathophysiologic mechanisms; HMO, Health Maintenance Organization; IC, interstitial cystitis/bladder pain syndrome; ICA, Interstitial Cystitis Association; ICN, Interstitial Cystitis Network; NS, not stated; VA, Veterans Affairs.

    Either extracted from the manuscript or assumed based on the authors’ affiliation or other details provided in the manuscript.

    Sample size based on the largest analysis relevant to flares.

    Based on data from pelvic pain scales when available, followed by the Genitourinary Pain Index pain scale, Genitourinary Pain Index total index, and the Pelvic Pain and Urgency/Frequency Symptom Scale, Interstitial Cystitis Symptom Index, or Interstitial Cystitis Problem Index.

    Based on data from a larger or smaller sample size of participants than stated in the sample size column.

    Clinician-confirmed diagnosis.

    Calculated from the data provided and/or converted to an 11-point scale from 0 to 10 (no pain to worst pain).

    Median.

    Assumed to be predominantly female based on the demographic distribution of ICA members.

    Participants include subsets of those in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Epidemiology and Phenotyping Study.

    Assumed to be on a scale from 0 to 10.

    Terminology

    The most commonly used term for symptom exacerbations by article authors was “flare” or derivations thereof, followed by “exacerbation,” “relapse,” “aggravation,” and “attack” (Table). Additional terms used by investigators were “increased,” “intense,” or “breakthrough” pain, and “worse,” “worst,” or “acute worsening” symptoms. Nine articles assessed participants’ own terminology for exacerbations or incorporated their exacerbation-related quotes into the manuscript (not including studies that used exacerbation-related language in their study instructions or moderator/interviewer guide, or that did not provide their guide). These studies included an older mixed-methods study of IC/BPS participants,8 as well as several more recent qualitative and mixed-methods studies of mainly IC/BPS participants.9-16 The most commonly used term by participants in the older study was “attack,”8 whereas the most commonly used term in more recent studies was “flare” or derivations thereof.9-16 Additional terms mentioned were “bad,” “bad bladder,” or “stay-in-bed” days; “episodes,” “pelvic floor episodes,” “incidents,” “exacerbation,” and “inflammation.”9,11-13 Participants also subdivided their flares into “minor” or “moderate” flares vs “major” flares and other similar terms.9,13,15

    Manifestation

    Twenty-one articles provided information on flare manifestation,8,9,12,13,17-33 although only 6 documented participants’ experiences prospectively over time.21-23,25,28,29 Most participants reported at least 1 flare during their lifetime and/or symptom fluctuations (57%-100%; Supplementary Appendix Tables 1 and 2, https://www.jurology.com). However, typical or recent flare frequency varied considerably across studies, driven largely by the stringency of the flare definition and inclusion criteria of the study. The highest flare frequency was observed for flares of very short duration (<1 hour) defined as “urologic or pelvic pain symptoms that are much worse than usual” in a study of UCPPS participants not following any specific therapy (25%),24 whereas the lowest frequency was observed for flares of longer duration defined as a 50% increase in “breakthrough pain” lasting ≥ 2 weeks in another study of IC/BPS participants on triple gabapentin, amitriptyline, and nonsteroidal anti-inflammatory drug therapy (6.7% every 2-6 months or less).22

    With respect to flare duration, 8 articles provided data,8,9,12,13,24,25,28,33 including 6 from the MAPP Research Network9,13,24,25,28,33 and only 1 that documented flare duration prospectively (limited to days-long flares).25 Three studies assessed participants’ lifetime history of flares of any duration, all of which were performed in the MAPP Network (Supplementary Appendix Table 1, https://www.jurology.com).9,13,24 In 1 of these studies, 37% of participants reported ever experiencing flares lasting only minutes or < 1 hour, 61% reported flares lasting several hours but less than 1 day, and 76% reported flares lasting ≥ 1 day.24 A small, but unknown, percentage of participants also reported flares with extreme durations (eg, only during urination or up to months or years) in 2 qualitative studies.9,13 These values were skewed toward longer flares in studies that assessed participants’ typical flare experiences: 16% reported flares lasting < 1 day in 1 study,33 and 38% to 84% reported flares lasting ≥ 1 day (including 16% lasting ≥1 week33) in 2 studies.8,33 Variability in flare duration was also observed within the same participant in 3 studies (28%-51% variable duration8,24; 94% intraindividual variability28).

    With respect to symptom intensity, 14 articles provided data,8,9,12,13,19,20,22,24,25,27-29,32,33 half of which were conducted in the MAPP Network9,13,24,25,28,29,33 and only 4 of which documented participants’ symptoms prospectively.22,25,28,29 These articles indicated that pelvic pain and urologic symptom intensity were elevated during flares (mean = 5.2-8.8 [median = 8.0] for pain8,20,22,24,25,27-29,33 and mean = 3.5-5.6 for urologic symptoms out of 1024,25,28,29) and greater than nonflare or baseline symptoms by a mean of 2.6 to 5.8 points (median = 4.0) for pain22,25,28,29,33 and a mean of 1.7 to 2.2 points for urologic symptoms (Supplementary Appendix Table 1, https://www.jurology.com).25,28,29 Data from a small number of studies also indicated that (1) symptom intensity could vary across flares from the same participant (intraindividual variability = 38% for pain and 26% for urologic symptoms28),9,13 (2) symptom intensity was significantly greater for flares of longer duration,24 (3) most flares involved increases in both pain and urologic symptoms (61%), and only a small percentage involved increases in pain (20%) or urologic symptoms only (5.8%),28 and (4) flares could also be accompanied by non-UCPPS symptoms such as diarrhea and extrapelvic pain (Supplementary Appendix Table 3, https://www.jurology.com).9,13,24,28,29 One small study attempted to identify symptoms independently associated with flare onset and found that only pelvic/genital pain (≥ 2-point increase) and urination-related pain (≥ 1-point increase) were independently predictive.29 With respect to other flare characteristics, a small number of studies observed variability in flare onset (sudden [54%17] to gradual [45%17]9,13), remission (rapid to gradual9,13), and diurnal timing (no typical time of day or night [91%]30).

    Triggers

    Thirty-nine articles investigated flare triggers, including 13 that examined potential triggers empirically and 1 that tested potential triggers experimentally. A wide variety of potential triggers were investigated and reported in these studies. The most commonly investigated trigger was diet and the most commonly reported dietary triggers were fruits and fruit juices (particularly citrus fruits and tomatoes), spicy food and chili/hot peppers, caffeinated (eg, tea, coffee) and alcoholic beverages, and chocolate (Figure 2, and Supplementary Appendix Figure 2 and Appendix Tables 4-6, https://www.jurology.com). Female participants tended to be more likely to report food triggers than male participants. Only 1 study investigated individual dietary triggers empirically, observing positive associations for greater recalled intake of tomatoes, yogurt, spicy foods, caffeinated or carbonated beverages, and alcohol with flare onset, but only among participants who believed that diet had triggered their flare.34

    Figure 2. Urologic chronic pelvic pain syndrome dietary flare triggers.

    Other commonly reported triggers were stress; physical activity, sedentary behavior, and jostling forms of transportation; various infections and infection-like symptoms; menstrual cycle variation; cold weather and other cold experiences (eg, sitting on a cold surface); and additional exposures, such as tight clothing (Supplementary Appendix Tables 7-10, https://www.jurology.com). In the small number of studies that investigated these factors empirically, some evidence of association was observed for stress, particularly in the 1 small cohort35 and trial36 on this topic; abdominal muscle exercises34; vaginal and urinary tract infection‒like symptoms,34 which likely reflects the similarity in symptoms between these infections and flares; spring, autumn, and winter season23; and increases in pollen.37

    Therapy and Prevention

    Thirty articles investigated flare treatment and prevention strategies, including 9 small studies that tested these empirically (Figure 3, and Supplementary Appendix Tables 11 and 12, https://www.jurology.com). Common medical strategies included contacting health care providers for general medical care, hydrodistension, and bladder instillations, and taking various prescription, over-the-counter, and complementary medications and products. Only 2 of these strategies were tested empirically. Hormonal therapy was associated with symptom improvement in IC/BPS patients with menstrual cycle‒related flares in 1 small retrospective cohort study,38 and prednisolone improved symptoms in female IC/BPS patients when added to triple gabapentin, amitriptyline, and nonsteroidal anti-inflammatory drug therapy in 1 small single-arm trial.22

    Figure 3.Urologic chronic pelvic pain syndrome symptom flare therapy.

    Figure 3. Urologic chronic pelvic pain syndrome symptom flare therapy.

    Common nonmedical or behavioral strategies for flare treatment and prevention included thermal therapy (heat and cold), increasing water or fluid intake, resting or relaxation techniques such as meditation, light exercise, consuming baking soda, and dietary changes such as avoiding perceived trigger foods and adopting a bland diet (eg, rice, bread). This last strategy was tested in 1 small single-arm trial39 and 2 small randomized controlled trials with40 and without41 an anti-inflammatory diet; each of these studies observed symptom improvement. Combinations of medical and behavioral strategies were also tested in 1 case report and 2 pilot randomized controlled trials, observing symptom improvement for acupuncture, gabapentin, ibuprofen, and ranitidine combined,42 and for over 10 behavioral strategies combined.43,44

    Finally, in studies that assessed participants’ preferences for flare treatment, many mentioned the importance of a structured flare plan, particularly one including self-management.9,11,32,45 Participants in 1 study also mentioned being more open to taking UCPPS medications during flares than at other times.32

    QOL Impact

    Thirteen articles presented data on the impact of flares on participants’ QOL, including 10 qualitative/mixed-methods and 3 cross-sectional analyses.9-16,24,27,32,33,45 During flares, participants reported a wide range of impact—from difficulty concentrating, irritability, anxiety, drowsiness from pain medications, difficulty sleeping, and cancelling social plans to leaving/staying home from work or school, staying in bed or close to a toilet, going to the emergency room, and feeling depressed and occasionally suicidal.9-15,27,45 The degree of impact tended to be related to the intensity, duration, frequency, and unpredictability of symptoms, particularly pain.9,13,24,33 Findings for flare frequency persisted in 1 study after adjustment for average pain intensity, suggesting that flares negatively impact participants’ lives over and above typical pain intensity. Other flare characteristics were not tested in this analysis.33

    In addition to an immediate impact, participants also reported a longer-term impact of flares. This included small adjustments to participants’ lives, such as changes to their diet, clothing, and level of travel, spontaneity, and sexual activity to much larger changes, such as social isolation from avoiding social events with food, educational and career changes, employment loss, disability leave, marital strain, and depression. Participants also reported a constant vigilance for flare triggers, attempt to control these factors, and worry about future flares.9-11,13,16,32

    Pathophysiology

    Only 3 small cohort analyses investigated additional aspects of flares that might inform flare pathophysiology, all of which were conducted in the MAPP Research Network. Schrepf and colleagues observed no association for toll-like receptor-2 inflammation, toll-like receptor-4 inflammation, and diurnal cortisol slope with flare frequency in IC/BPS participants.46 Xu and colleagues observed that participants with chronic overlapping pain conditions reported increased extrapelvic pain intensity and widespreadness during flares than at nonflare times, possibly suggesting increased central sensitization or global hypersensitivity during flares,29 and Harte and colleagues observed that participants had greater pressure pain sensitivity during flares,47 again possibly suggesting increased global hypersensitivity during flares.

    DISCUSSION

    Overall, our review identified a large number of flare-related articles (N = 59), although most were limited to 1 aspect of flares and/or participant self-report (ie, qualitative or cross-sectional studies). Only a small number of studies documented flare manifestation prospectively or tested proposed flare triggers and treatments empirically. In addition, almost one-quarter was derived from 1 main study population, the US-based, multisite MAPP Epidemiology and Phenotyping Study. Nevertheless, accumulated articles still provide useful, foundational data for future flare research. The term “flare” or derivations thereof were used commonly and well understood by participants, although additional terms, such as exacerbation or relapse, were also used. Flares tended to involve significant increases in pelvic pain, but less data were available on flare frequency and duration. Painful, frequent, long, and/or unpredictable flares were highly impactful, even over and above participants’ nonflare symptoms. A large number of triggers were proposed to cause flares and many therapeutic strategies were reported by participants, providing numerous hypotheses for empirical research; however, few studies investigated flare triggers or treatments empirically, or attempted to understand the biologic mechanisms underlying flare occurrence.

    Despite their frequent mention in the lay literature and growing number of studies in the peer-reviewed literature, no standard definition of flares exists. In our review, patient-reported flare experiences tended to be painful and transient, but were otherwise variable in frequency, duration, presence and intensity of additional symptoms, and predictability. Reported flares occurred infrequently (eg, less than once/y) to multiple times per day, lasted a few seconds (only during urination) or minutes to multiple years, involved small increases in pelvic pain as well as other UCPPS and extrapelvic symptoms to large increases in symptoms, and occurred predictably for some participants and unpredictably for others. This wide variability makes it difficult to define and study flares. It also raises the possibility of varying pathophysiology and triggers across flare experiences. For instance, patient-reported flares that occur only during urination could potentially reflect the bladder hypersensitivity feature of UCPPS itself or possibly acute pelvic floor muscle spasms. Minutes-long painful flares could also potentially reflect these spasms. In contrast, longer hours- to days-long painful flares may be more likely to reflect a pathophysiologic process that includes interactions between a trigger (eg, diet) and proposed biologic flare mediators (eg, bladder mast cell‒/histamine-mediated mechanisms, increased central sensitization, or global hypersensitivity).29,47-49 Finally, flares that extend months to years may potentially reflect an overall worsening of patients’ conditions rather than a transient experience.

    Although complex, this issue is not unlike the hypothesized heterogeneity of UCPPS itself. UCPPS is often classified and studied as 1 or 2 conditions (ie, IC/BPS and CP/CPPS), but may potentially represent several more pathophysiologically distinct conditions. Therefore, future research should explore the potential for pathophysiologically distinct flares to facilitate preventive and therapeutic flare research. In the meantime, however, strategies such as collecting information to characterize flares by frequency, duration, intensity, and other characteristics, and performing analyses stratified by or limited to certain flare manifestations should facilitate future flare research. The development of a validated flare outcome measure would also aid future research.

    Additional flare research is needed because, despite data to suggest that flares impact patients’ QOL and health care‒seeking behavior, few scientific data exist on flare triggers and treatments. Although many triggers have been proposed and many therapies have been used by patients, few studies have investigated these triggers and treatments empirically to inform the efficacy of prevention and treatment strategies. Data from the small body of empirical research provide preliminary support for diet, stress, abdominal muscle exercises, and pollen as potential flare triggers, and for steroids, hormones, dietary modification, and various other medical and behavioral strategies combined as potential prevention and treatment strategies, but additional empirical research that tests these strategies is still clearly needed. Although this type of research would be facilitated by a better understanding of flare pathophysiology and potential flare heterogeneity, much could still be learned even in the absence of such data simply by using an empirical approach.

    Strengths of our review include its systematic nature, rigorous execution (including double data extraction and review), and comprehensive evaluation of multiple aspects of flares. Similar to most reviews, limitations include those of the existing literature, most notably the dearth of empirical studies.

    CONCLUSIONS

    Our comprehensive review demonstrated that flares are painful and impactful, but otherwise poorly understood in terms of manifestation, triggers, treatment, and underlying pathophysiology. Development of a validated flare outcome measure and collection of detailed flare manifestation data would facilitate much-needed new prospective and empirical research on UCPPS flares to reduce their high patient burden.

    Acknowledgments

    We thank members of the MAPP Research Network for thoughtful flare-related discussions.

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    Support: This review was funded by NIH research grants R01DK129226, U01DK082315, and T32DK120497.

    Conflict of Interest Disclosures: R.M.: Abbvie Pharmaceuticals: PI and consultant, Ironwood Pharmaceuticals: PI and consultant, Kuste Pharmaceuticals: PI and consultant, Trigone Pharmaceuticals: Consultant, Vaneltix Pharmaceuticals: PI; J.L.L.: Expert witness; H.L.: Medtronic: Consultant, Astella: Consultant, IronWood: Consultant, BioHaven: Consultant, Aquinox: Consultant, Teva: Consultant, MicroGenDx: Consultant, Neuspera: Data and safety monitoring board. All other authors have nothing to disclose.

    Ethics Statement: As this systematic review and meta-analysis did not include human subjects research—only a review and synthesis of published, aggregated data from the literature and select de-identified primary data—we did not seek Institutional Review Board approval.

    Author Contributions: Conception and design: L.H.Y., J.L.L., E.S.B., K.C., H.H.L., S.S.; Data analysis and interpretation: V.L.B., R.P., R.M., B.S., J.L.L., E.S.B., K.C., H.H.L., S.S.; Data acquisition: H.M., L.H.Y., E.S.B., K.C., A.C., S.S.; Critical revision of the manuscript for scientific and factual content: V.L.B., H.M., L.H.Y., R.P., J.L.L., E.S.B., K.C., A.C., H.H.L.; Drafting the manuscript: L.H.Y., R.M., B.S., J.L.L., E.S.B., K.C., S.S.; Statistical analysis: R.P., E.S.B., K.C., S.S.; Supervision: R.M., A.C., H.H.L., S.S.

    Data Availability: All extracted aggregate data were presented in the main and supplementary tables of the manuscript. Primary data from individual studies can be requested from the authors of the original studies.

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