Therapeutic Approaches for Urologic Chronic Pelvic Pain Syndrome; Management: Research Advances, Experimental Targets, and Future Directions

Abstract

Urologic chronic pelvic pain syndrome (UCPPS) is a painful chronic condition with persistent pain originating from the pelvis that often leads to detrimental lifestyle changes in the affected patients. The syndrome develops in both sexes, with an estimated prevalence of 5.7% to 26.6% worldwide. This narrative review summarizes currently recommended therapies for UCPPS, followed by the latest animal model findings and clinical research advances in the field. The diagnosis of UCPPS by clinicians has room for improvement despite the changes in the past decade aiming to decrease the time to treatment. Therapeutic approaches targeting growth factors (i.e., nerve growth factor, vascular endothelial growth factor), amniotic bladder therapy, and stem cell treatments gain more attention as experimental treatment options for UCPPS. The development of novel diagnostic tests based on the latest advances in urinary biomarkers would be beneficial to assist with the clinical diagnosis of UCPPS. Future research directions should address the role of chronic psychologic stress and the mechanisms of pain refractory to conventional management strategies in UCPPS etiology. Testing the applicability of cognitive behavioral therapy in this cohort of UCPPS patients might be promising to increase their quality of life. The search for novel lead compounds and innovative drug delivery systems requires clinically relevant translational animal models. The role of autoimmune responses triggered by environmental factors is another promising research direction to clarify the impact of the immune system in UCPPS pathophysiology.

SIGNIFICANCE STATEMENT

This minireview provides an up-to-date summary of the therapeutic approaches for UCPPS with a focus on recent advancements in the clinical diagnosis and treatments of the disease, pathophysiological mechanisms of UCPPS, signaling pathways, and molecular targets involved in pelvic nociception.

Introduction

Urologic chronic pelvic pain syndrome (UCPPS) is a complex and multifactorial disorder characterized by voiding dysfunction, visceral hyperalgesia, and chronic pelvic pain (CPP) (Clemens et al., 2014). It includes interstitial cystitis/bladder pain syndrome (IC/BPS) and nonbacterial chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). In addition to pain, UCPPS patients often complain of lower urinary tract symptoms (LUTS), including urinary frequency, urgency, and nocturia (Bogart et al., 2007). The impacts of UCPPS are substantial, with patients experiencing a poor quality of life (QoL). The variability in UCPPS symptoms suggests complex and diverse underlying etiologies. The biologic mechanisms driving the development of this syndrome are not fully understood. The pathophysiology of UCPPS may involve covert inflammation, neural hypersensitivity, central sensitization, urothelial dysfunction, and environmental factors. Recent research studies also suggest the involvement of biopsychosocial factors that may contribute to the development of UCPPS symptoms (Bogart et al., 2007). Current guidelines from the American Urological Association (AUA) categorize the treatments into nonpharmacologic, oral medicines, bladder instillations, interventional procedures, and surgical approaches (Clemens et al., 2022). They also recommend shared decision-making between physicians and patients and recording baseline voiding dysfunction and pain levels in UCPPS patients to provide a longitudinal assessment of the treatment outcomes. While the common approaches are adequate in improving symptoms and overall QoL, most of the treatments for UCPPS have limited effectiveness, as they are unable to target the underlying pathophysiology of this disorder. The recommended AUA guidelines target specific disease symptoms and phenotypes, providing specialized care for treating urinary, psychosocial, organ-specific, infection, neurologic, and tenderness disease presentations to improve the overall QoL (Clemens et al., 2022).

In this review, we summarize current knowledge about the latest treatment options for UCPPS, their mechanisms of action, and the limitations of the prior work. Clinical and translational studies on treatment approaches provide a rationale for multimodal, patient-individualized therapeutic strategies to achieve more beneficial patient outcomes. Comprehensive clinical “endophenotyping” seems to be the way to identify and group patients based on trigger points, pain profiles, and potential responses to specific treatments.

Clinical Features of UCPPS and Patient Presentation

Historically, CP/CPP and IC/BPS were considered separate conditions until 2007, when the National Institute of Diabetes and Digestive and Kidney Diseases suggested grouping them under the umbrella term “UCPPS.” Subsequent findings from the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network have confirmed that CP/CPP and IC/BPS are related syndromes (https://www.mappnetwork.org/). UCPPS affects both men and women, with women having a higher overall prevalence (up to 27%) when compared with men (up to 12%) (Dybowski et al., 2018; Anger et al., 2022). A significant population of men with UCPPS (17%) have CP/CPP and IC/BPS concurrently (Suskind et al., 2013). Older people also tend to have a higher occurrence and more significant disease morbidity (Lee et al., 2018). These estimates vary wildly due to difficulties with diagnosing the conditions and nonuniform disease definitions. Additionally, studies may underestimate the true prevalence of UCPPS due to inadequate sample sizes, misclassification biases, or incorrect diagnoses.

UCPPS patients typically present with pain in the pelvic region and urinary symptoms, often accompanied by sexual dysfunction. The presentation of symptoms varies and is often complicated by other chronic overlapping pain conditions (Krieger et al., 2015). Approximately 75% of patients experience pain outside of the pelvis, suggesting the presence of a centralized pain phenotype (Lai et al., 2017; Clemens et al., 2019). Patients of both genders experience high rates of painful bladder filling and urinary urgency, and up to 20% report sporadic symptom flares (Clemens et al., 2007; Lai et al., 2015; Bradley et al., 2022). The symptom flares usually increase pain and impact QoL (Sutcliffe et al., 2015, 2023). Epidemiologic evidence on the causes of flares was inconclusive, as frequency, duration, symptomology, and reported triggers were highly variable between individuals (Sutcliffe et al., 2018, 2019; Quallich et al., 2022). These findings suggest that flares should be clinically addressed on a patient-to-patient basis, with tailored management of unique symptoms and triggers. In addition, widespread psychosocial comorbidities are common in men and women with UCPPS, and these conditions may predict pain intensity and urinary symptoms (Naliboff et al., 2015; Dybowski et al., 2018). It remains unclear what the actual risk factors for developing UCPPS are, how significantly they may differ between men and women, and what mechanisms drive disease progression in each gender group.

Clinical studies of the MAPP Research Network determined that many UCPPS patients felt disconnected between what physicians perceive as necessary for treatment and the patients’ lived experiences (Nickel et al., 2018). A recent study provided evidence that a reduction in symptoms of 30% to 50% was considered by patients as adequate to improve their QoL (Stephens-Shields et al., 2023). Furthermore, a recent study by Naliboff et al. showed that a positive feedback loop exists between LUTS, pelvic pain, mood, and QoL, suggesting that multimodal treatments may interrupt the downward spiral of symptom worsening (Naliboff et al., 2021).

Diagnostic Procedures for UCPPS Patients

The diagnosis of UCPPS continues to be a challenge for healthcare providers, also leading to frustration among patients who often must visit multiple providers prior to being accurately diagnosed with UCPPS. Due to many overlapping symptoms, clinicians may incorrectly diagnose patients with another disease or falsely diagnose UCPPS instead of nonurologic, chronic overlapping pain conditions (Gross et al., 2021). Diagnosis typically includes obtaining a detailed patient history, physical examinations, and laboratory testing. Initial workup often utilizes questionnaires such as the Chronic Prostatitis Symptom Index and International Prostate Symptom Score. Due to the number of patients experiencing comorbidities and complicated presentations, questionnaires are supplemented with other diagnostic tools, such as cystoscopy, to rule out anatomic abnormalities. Therefore, UCPPS is often “a diagnosis of exclusion” after other disorders have been ruled out (Clemens et al., 2022).

Initial evaluation of patients with CPP often begins with the healthcare provider assessing for alarm symptoms to rule out emergent conditions such as acute appendicitis or a ruptured ovarian cyst in females. Once these conditions are ruled out, a different approach is used to help diagnose the source of CPP. For male patients, if chronic bacterial prostatitis is suspected, physicians may test for bacterial infection or serum prostate-specific antigen or order a complete blood count, which is often not helpful for confirming UCPPS (Nadler et al., 2006). Therefore, after obtaining a medical history and performing a physical exam, providers often use the latest AUA guidelines to help direct their diagnostic approach. They include basic laboratory studies such as urinalysis and culture to rule out a urinary tract infection, as well as imaging, cystoscopy, and, if necessary, a laparoscopy (Clemens et al., 2022).

Conventional Therapies for UCPPS

UCPPS treatments focus on reducing symptom severity and improving patient QoL (Fig. 1). Many aim to target the underlying mechanisms thought to be responsible for the condition to varying degrees of success. Currently, there is no definitive treatment of UCPPS due to the heterogeneous etiology of the syndrome and the widely diverse range of symptoms. While most conventional treatments focus on symptom reduction, new and experimental approaches follow specific pathways known to be involved in the condition. New research indicates that urothelial dysfunction, inflammation, mast cell activation, and central sensitization are some of the critical mechanisms contributing to the development of UCPPS.

Fig. 1.

Clinical framework for UCPPS treatment management. Copyright license to use Fig. 1 from Clemens et al., 2022 [Clemens, J. Q., Erikson, D.R., Varela, N.P., Lai, H.H. (2022). Diagnosis and Treatment of Interstitial Cystitis/Bladder Pain Syndrome. Journal of Urology, 208(1), 34-42] was obtained from RightsLink/Wolters Kluwer Health, Inc.

Urothelial Treatments.

Urothelial and mucosal dysfunction in the urinary bladder is a possible factor contributing to UCPPS pathology. Leaky urothelium may allow toxic substances from the urine to pass into the detrusor muscle layer, activate afferent bladder nerves, and increase pain and urinary symptoms (Parsons, 2011; Hurst et al., 2015). The urothelial barrier contains glycosaminoglycans (GAGs) that help maintain urothelial impermeability. Pentosan polysulfate sodium is the only U.S. Food and Drug Administration (FDA) approved oral drug to treat IC/BPS and is the most well-studied oral UCPPS medication (Clemens et al., 2022). The drug has shown the most success of any oral treatment used as a monotherapy (Davis et al., 2008; Santos et al., 2018), but effects still vary significantly among patients and symptom presentation. Additional GAG-replenishing treatments have also been investigated. Chondroitin sulfate treatment has improved damaged urothelial function in vitro through GAG replenishment (Rozenberg et al., 2020). Multiple clinical studies have tested its treatment potential in patients, with wildly varying results (Nickel et al., 2009, 2012; Steinhoff et al., 2002). Hyaluronic acid is another recommended alternative treatment of UCPPS that repairs the urothelial barrier and reduces local inflammation (Rooney et al., 2015; Lin et al., 2022). Studies on hyaluronic acid treatment efficacy varied from nonsignificant findings to up to 85% symptom improvement (Cervigni, 2015).

Anti-Inflammatory Therapies.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are historically used therapeutics that target pain and inflammation in patients and function through the inhibition of cyclooxygenase (COX) enzymes (Vane, 2003). Prostaglandins involved in proinflammatory pathways and pain sensation are produced via the COX pathway, which can be triggered by mast cell activation through the H1-receptor (Krystel-Whittemore et al., 2016). While NSAIDs may have short-term benefits in attenuating the COX signaling pathways, clinical studies in men with CP/CPPS revealed that pain relief in this cohort of patients may last only for a few weeks, thus, limiting the effectiveness of NSAIDs as a monotherapy (Nickel et al., 2003, 2004b; Zhao et al., 2009). AUA guidelines recommend the use of NSAIDs alongside paracetamol as the initial analgesic treatment of IC/BPS patients but acknowledge that symptom relief varies from patient to patient (Clemens et al., 2022).

Clinical studies determined that mast cells accumulate in the mucosa, lamina propria, and detrusor layers of the urinary bladder in IC/BPS patients, as well as in the prostate of CP/CPPS patients (Rudick et al., 2008; Done et al., 2012; Skaper et al., 2018). These immune cells, when activated, release proinflammatory cytokines, causing local inflammatory reaction, vascular remodeling, and the development of neurologic pain (Anand et al., 2012). Histamine release from activated mast cells and subsequent local inflammatory reaction was suggested to be one of the potential mechanisms contributing to pain symptoms in UCPPS (Rudick et al., 2008). Histamine induces expression of toll-like receptors (TLR) TLR2 and TLR4 in endothelial cells via H1 receptor stimulation, as well as increasing proinflammatory molecule release, such as interleukin-1, interleukin-6, and tumor necrosis factor-α (Tan et al., 2007; Krystel-Whittemore et al., 2016). In both human UCPPS patients and animal models of IC/BPS, elevated serum levels of TLR4 were linked to increased nonspecific pain severity and pain frequency and were associated with urinary dysfunction (Schrepf et al., 2014; Cui et al., 2019). Antihistamines, such as the H1 receptor blocker hydroxyzine, have been assessed in patients with UCPPS, with mixed results. Sant et al. found no significant improvements in pain, urgency, or frequency symptoms in a clinical trial of oral pentosan polysulfate and hydroxyzine in IC/BPS patients (Sant et al., 2003). A previous clinical trial by the same group determined that hydroxyzine significantly improved pain in patients with chronic allergies (Theoharides and Sant, 1997). However, neither of these studies showed any marked improvements in LUTS.

Dimethyl sulfoxide (DMSO) is known to have local anesthetic and anti-inflammatory effects, and research data gathered over the last three decades suggest that it may work to reduce urinary, inflammatory, and pelvic pain symptoms of UCPPS when instilled directly into the urinary bladder (Clemens et al., 2022). The instillation may also be administered along with lidocaine and heparin to reduce pain and urinary urgency further (Parsons et al., 2015). A recent randomized control trial established that DMSO provided the most symptom relief when combined with triamcinolone rather than heparin, and this drug combination was also the least painful to instill (Moss et al., 2023). Despite being the only FDA-approved instillation treatment of IC/BPS, many of the studies purporting DMSO as a UCPPS treatment lack appropriate controls and long-term follow-up observations, raising questions about the drug’s efficacy. Due to these facts, the European Association of Urology removed DMSO from their UCPPS treatment guidelines in 2014 (http://uroweb.org/guideline/chronic-pelvic-pain/).

5α-Reductase Inhibitors and α1-Adrenergic Antagonists.

5α-reductase inhibitors are medications often used with NSAIDs and antihistamines for the treatment of CPP. 5α-reductase is an enzyme that converts testosterone to dihydrotestosterone, a potent androgen implicated in prostatic growth (Azzouni et al., 2012). 5α-reductase inhibitors directly target this pathway and lead to decreased production of dihydrotestosterone (Azzouni et al., 2012). For male patients with UCPPS secondary to benign prostatic hyperplasia (BPH), finasteride helps reduce prostatic volume and subsequently leads to decreased LUTS (Roehrborn et al., 2004; https://www.mappnetwork.org/). Finasteride was found to have some benefit in patients with CPP but was not recommended as monotherapy unless patients also had coinciding BPH (Nickel et al., 2004a). Tadalafil, a phosphodiesterase-5 inhibitor that is used to treat erectile dysfunction, was tested in a placebo-controlled clinical trial as a CP/CPPS treatment and resulted in a significant, however limited, reduction in LUTS severity and QoL improvement over six weeks (Tawfik et al., 2022).

Alpha-1 adrenergic antagonists such as tamsulosin, silodosin, and alfuzosin are commonly used in patients with UCPPS secondary to BPH (Table 1). Alpha-1 adrenergic receptors are present throughout the genitourinary tract and regulate smooth muscle tone. Symptom relief from tamsulosin treatment is likely due to relaxation of the prostatic smooth muscle via the blockade of Alpha-1 adrenergic receptors (Lepor, 2007). In past clinical trials, α1 blockers, such as alfuzosin, were not shown to improve LUTS (Nickel et al., 2008). However, using α1 blockers as part of a multimodal approach, which included antibiotics, massage, and neuromuscular agents, significantly improved symptoms compared with single therapies (Shoskes et al., 2003). In addition, recent studies on silodosin provided evidence that the drug was efficacious in improving sexual function, urinary symptoms, and pain in CP/CPPS patients (Jindan et al., 2022). Although α1 blockers have demonstrated their use in reducing LUTS in men (Kim et al., 2019) and in animal studies replicating various aspects of IC/BPS (Markiewicz et al., 2014; Liu et al., 2016), these drugs only recently started to be studied in women with UCPPS diagnosis. A pilot clinical trial conducted on 20 IC/BPS female patients demonstrated that silodosin effectively reduced urinary frequency, nocturia, voiding volume, and pain (Abreu-Mendes et al., 2022).

TABLE 1.

Therapeutic options for UCPPS patients

Medication Class	Indications	Examples	Mechanism	References
GAG replenishment	Bladder pain, urinary dysfunction	Pentosan polysulfate sodium Chondroitin sulfate Hyaluronic acid	Reduces bladder mucosa permeability Improves urothelial layer Anti-inflammatory	Steinhoff et al., 2002; Davis et al., 2008; Nickel et al., 2009, 2012; Cervigni, 2015; Rooney et al., 2015; Santos et al., 2018; Clemens et al., 2022; Lin et al., 2022
NSAIDs	Inflammation, pain	Ibuprofen	COX inhibitors	Vane, 2003; Krystel-Whittemore et al., 2016
Antihistamines	Nonspecific pain, local pain	Hydroxyzine	Histamine H1-receptor antagonist Decreased mast cell activation	Theoharides and Sant, 1997; Cui et al., 2019; Kalava et al., 2023
DMSO	Bladder pain, urinary dysfunction	DMSO	Anti-inflammatory Local anesthetic	Parsons et al., 2015; Clemens et al., 2022; Moss et al., 2023
5-alpha-reductase inhibitors	Urinary dysfunction, benign prostatic hyperplasia	Finasteride Dutasteride	Decrease amount of dihydrotestosterone in the body	Nickel et al., 2004b; Roehrborn et al., 2004; Azzouni et al., 2012; Tawfik et al., 2022
Alpha-1 adrenergic receptor antagonists	Urinary dysfunction, sexual dysfunction	Tamsulosin Alfuzosin Silodosin	Alpha-1 adrenergic receptor antagonists Regulate bladder muscle tone	Nickel et al., 2008; Markiewicz et al., 2014; Liu et al., 2016; Kim et al., 2019; Lander et al., 2019; Abreu-Mendes et al., 2022; Jindan et al., 2022
Anti-cholinergics	Urinary dysfunction, sexual dysfunction	Oxybutynin Tolterodine	Block the action of acetylcholine	Barbalias et al., 2000; Gerretsen and Pollock, 2011; Kim et al., 2011; Narter et al., 2019; Raisin et al., 2023; https://www.ncbi.nlm.nih.gov/pubmed/32310353
Modulation of neuronal exitability	Inflammation, urinary dysfunction	BoTN-A	Blockade of nerve fiber excitability	Apostolidis et al., 2005; Schulte-Baukloh, 2012; Papagiannopoulou et al., 2016; Jhang, 2019; Taidi et al., 2019; Maignel et al., 2022
Antidepressants	Psychogenic comorbidities, urinary incontinence	Sertraline Duloxetine Amitryptyline Nortriptyline	Serotonin-norepinephrine reuptake inhibitors SSRIs Treat underlying psychosocial conditions	Engel et al., 1998; van Ophoven et al., 2004; Lee et al., 2005; van Ophoven and Hertle, 2005; Hertle and van Ophoven, 2010; Giannantoni et al., 2014; M. Zhang et al., 2017; Bi et al., 2018; Cakici et al., 2018
Phytotherapy	Nonspecific pain, urinary symptoms	Pollen extracts Eviprostat Terpene Pumpkin seed oil	Anti-inflammatory Antioxidants	Morán et al., 2013; Pang and Ali, 2015; K. Zhang et al., 2017; Cui et al., 2020; Dashdondov et al., 2021; Wazir et al., 2021; Tokita et al., 2023
Amniotic membrane therapy	Bladder pain, urinary dysfunction	Micronized amniotic membrane (Clarix Flo)	Heals urothelial barrier May promote GAG expression and nerve regeneration	Madan et al., 2023
Stem cell therapy	Urinary dysfunction, inflammation, pain	Embryonic stem cells Induced pluripotent stem cells Multipotent stem cells	Replaces damaged tissues Anti-inflammatory properties	Kim et al., 2016; Furuta et al., 2018; Xie et al., 2018; Chung et al., 2019; Lander et al., 2019; Dayem et al., 2020; Tabata et al., 2021; Dayem et al., 2022; Furuta et al., 2022; Gao et al., 2023
NGF inhibitors	Urinary dysfunction, pain	Tanezumab LM11A-31	Inhibit tropomyosin-related kinase A or B or pan-neurotrophin receptor Humanized monoclonal antibodies prevent NGF from interacting with receptors	Nickel et al., 2016; Lai et al., 2017; Abreu-Mendes et al., 2022; Hsiang et al., 2022, 2023

Nonpharmacological Interventions

Voiding dysfunction complicated by visceral hyperalgesia in UCPPS may involve alterations in the processing of sensory information by the nervous system (Malykhina et al., 2006; Pan et al., 2010; Jhang et al., 2023). Human research as well as studies of UCPPS-like symptoms in animals suggest that visceral neurogenic inflammation and central sensitization may play an important role in the generation and maintenance of UCPPS symptoms, especially urinary pain and urgency (Malykhina, 2007; Rudick et al., 2008; Harte et al., 2019; Sanford et al., 2020; Schrepf et al., 2022). Several treatment options have been explored to combat the role of neuroinflammation and hypersensitization in UCPPS patients (Fig. 1). Nonpharmacological interventions, such as cognitive behavioral therapy, physical exercise, pelvic floor strengthening, and myofascial physical therapy, are considered to be the first line of treatment and have shown promise in reducing CPP symptoms in UCPPS patients, especially in the cohorts with additional comorbidities (Fitzgerald et al., 2013; Eccleston et al., 2014; Meissner et al., 2016; Williams et al., 2020).

Cognitive Behavioral Therapy.

While the physical symptoms are often the focus of UCPPS, many patients suffer from social isolation, which predisposes these patients to anxiety, depression, and economic distress; a reduction in QoL further exacerbates these psychosocial problems. However, through cognitive behavioral therapy interventions and identification of what UCPPS patients have in common (e.g., pain, depression, socioeconomic difficulties), a more comprehensive approach may be developed to help treat UCPPS patients (Lackner et al., 2022). Psychologic trauma continues to be prevalent in this cohort of patients. The associations between UCPPS and CPP with psychologic trauma range from 62.3% to 83.3%, respectively (van Knippenberg et al., 2022). In a feasibility trial, cognitive behavioral therapy reduced symptom burden in patients with CPP as measured by the Pain Disability Index (Brünahl et al., 2021). Additionally, patients receiving both physical therapy and cognitive behavioral therapy had an 8.8-point decrease in their Chronic Prostatitis Symptom Index score, which is well above the 6-point reduction threshold, proven to be clinically meaningful (Anderson et al., 2018).

Pelvic floor and myofascial physical exercises are used alongside other nonpharmaceutical interventions such as cognitive behavioral therapy (Fig. 1). A consistent pelvic floor exercise and yoga regimen were positively correlated with improved incontinence symptoms and QoL related to LUTS (Kim et al., 2015). Pelvic floor exercises are often combined with transcutaneous electrical nerve stimulation to achieve better results. A statistically significant improvement in pain symptoms was observed in patients treated with pelvic floor exercises combined with electrotherapy (Ghaderi et al., 2019). Thiele’s massage is another nonpharmaceutical intervention for UCPPS. It targets the levator ani, a broad muscle group on either side of the pelvis comprising the pubococcygeus, iliococcygeus, and puborectalis muscles (Montenegro et al., 2010). In men with CP/CPP who reported symptoms of pain in the pelvic region, manual muscle stimulation (for muscles such as the ischiococcygeus) when combined with myofascial release (for muscles such as the levator ani and internal obturator) resulted in reduced pain scores, with pain intensity having a mean decrease of 38.6% immediately after completion of the treatment protocol (Rabal Conesa et al., 2022). Thus, given the importance of multimodal treatment of UCPPS symptoms, incorporating pelvic floor and myofascial physical exercises may provide additional symptom reduction in UCPPS patients.

Additional Therapeutic Considerations

Urinary Microbiome.

Numerous studies have examined microorganisms and their role in UCPPS, but few have found correlations between current urinary infections and UCPPS. New evidence has been provided that there is an association between polyomavirus loads in the urine and increased symptoms (Robles et al., 2020), and an additional study found that papillomavirus infection may be a risk factor for CPP (Jain et al., 2020). Research into the role of the urinary microbiome in UCPPS is ongoing, but initial results are unclear (Bhide et al., 2020; Nickel et al., 2020; Jacobs et al., 2021; Wolfe et al., 2023). A recently published study suggests that men with CP/CPP have distinct microbiome differences that may be useful as a diagnostic tool (C. Wang et al., 2023).

Anticholinergic drugs block the action of the neurotransmitter acetylcholine and are used to treat many urological conditions (https://www.ncbi.nlm.nih.gov/pubmed/32310353). The FDA approved oxybutynin and tolterodine to treat urinary incontinence and detrusor overactivity (Gerretsen and Pollock, 2011). While there is sufficient evidence of the efficacy of anticholinergic drugs in treating LUTS in general, there is mixed data about their effectiveness in UCPPS patients. While some studies reported little to no improvement in symptom severity or QoL measures in CP/CPPS patients (Kim et al., 2011), others determined that anticholinergic drugs significantly decreased CP/CPPS symptoms in patients with the urinary-centric phenotype when combined with alpha-blockers or antimuscarinic drugs (Narter et al., 2019). Additional clinical trials on women with IC/BPS have demonstrated that intravesical instillations of anticholinergic drugs can reduce LUTS and pain in combination with other therapies (Barbalias et al., 2000; Raisin et al., 2023).

Botulinum toxin A (BoTN-A) injections in the urinary bladder have local anti-inflammatory effects and modulate sensory processing by reducing the excitability of nerve fibers in the tissue (Apostolidis et al., 2005; Schulte-Baukloh, 2012; Taidi et al., 2019). A recent animal study showed that after intradetrusor injections of BoTN-A, there was a retrograde transport of BoTN-A to the lumbosacral sensory ganglia, followed by further transmission to the spinal cord (Papagiannopoulou et al., 2016). However, evidence of therapeutic efficacy in epidemiologic clinical studies has been inconsistent, raising concerns about BoTN-A’s long-term effectiveness (Jhang, 2019). Due to the risk of therapeutic escape (Maignel et al., 2022), inconsistent outcomes, and practical concerns regarding BoTN-A injections, this is currently a fourth-line treatment option for UCPPS patients (Fig. 1).

Electrical nerve stimulation is also a fourth-line treatment recommended for patients for whom other conventional therapies have failed (Clemens et al., 2022). The most common types include pudendal neuromodulation, sacral neuromodulation, and tibial nerve stimulation (TNS). In a clinical trial, pudendal neuromodulation provided greater pain relief than intravesical instillations of heparin and lidocaine (Li et al., 2021). A recent case series highlighted the application of pudendal nerve block as a potential intervention for CPP and LUTS (Kalava et al., 2023). Results from multiple studies have shown that sacral neuromodulation may improve the symptoms of bladder overactivity, CPP, and sexual dysfunction in both men and women (Ghazwani et al., 2011; Yih et al., 2013; Moon et al., 2014; Siegel et al., 2016; de Oliveira et al., 2019). Multiple studies reported improvements in pain, QoL, and bladder dysfunction following TNS treatment (Gokyildiz et al., 2012; Ugurlucan et al., 2013; Andersen et al., 2021; Alkis et al., 2022). In contrast, a recent long-term study determined nonsignificant improvements in pain and void frequency but did see reductions in urinary urgency and nocturia (Abdalla et al., 2023). Another pilot study found that only a minority of subjects responded to TNS, although this could be due to the small sample size (Sudol et al., 2021). In general, much of the evidence supporting any form of electrical nerve stimulation as a therapeutic approach for UCPPS is limited by poor study designs in human subjects and high heterogeneity of outcomes in preclinical animal models (Padilla-Fernández et al., 2022; Kendall et al., 2024).

Antidepressants have a potential role in improving symptoms and QoL for patients living with UCPPS. Since many UCPPS patients suffer from psychogenic comorbidities, including major depressive disorder and generalized anxiety disorder, the use of antidepressants may improve some of the symptoms and allow patients to manage pain more effectively. In addition, antidepressant drugs have indirect effects on opioid, histamine, 5-serotonin, and other receptors that produce an analgesic effect (Sawynok et al., 2001). Duloxetine is a serotonin-norepinephrine reuptake inhibitor that was shown to improve UCCPS symptoms when used alone or in combination with other treatments (Giannantoni et al., 2014; M. Zhang et al., 2017; Bi et al., 2018). Amitriptyline is a selective serotonin reuptake inhibitor (SSRI) that may significantly reduce symptoms of UCPPS and improve QoL (van Ophoven et al., 2004; van Ophoven and Hertle, 2005; Hertle and van Ophoven, 2010). Another SSRI, sertraline, has been tested as a UCPPS treatment but produced mixed results (Engel et al., 1998; Lee et al., 2005; Cakici et al., 2018). The small sample sizes of the studies raise questions about validity and reproducibility, and further research into the SSRI class of drugs is warranted. Additionally, almost all of the aforementioned studies reported a high frequency of adverse events associated with antidepressant use, which are likely to impact patient treatment adherence in the long term.

Herbal therapies for UCPPS have also been assessed with mixed outcomes (Dashdondov et al., 2021). These therapies have proven efficacies in treating urological disorders (Pang and Ali, 2015; Moran et al., 2013), but the outcomes in UCPPS patients are variable. While there are several animal studies suggesting the potential benefits of herbal therapies for IC/BPS treatment (K. Zhang et al., 2017; Cui et al., 2020; Wazir et al., 2021; Tokita et al., 2023), there were only a few well-designed clinical trials with appropriate controls and sample sizes to provide definitive conclusions about their therapeutic effects. Therefore, future translational and clinical research on the mechanisms of the herbal substances’ action and their efficacy for UCPPS patients is warranted (Dashdondov et al., 2021).

The Latest Therapeutic Advances and Experimental Targets

The more recent studies published within the last five years have highlighted the need to better understand the individual characteristics of UCPPS patients to guide their treatment. There were differences in treatment effectiveness depending on the symptoms experienced, such as the range of pain, the presence of lesions in the bladder, and the existence of psychogenic or chronic comorbidities (Clemens et al., 2019). Widespread versus local neurologic pain is important to acknowledge when assigning treatments and designing clinical trials, as treatment efficacy may differ substantially between patients with different pain profiles (J. Farrar et al., preprint, DOI: https://doi.org/10.21203/rs.3.rs-2441086/v1). The use of a molecular-guided magnetic resonance imaging to detect biomarkers of bladder wall permeability has been recently proposed as a potential diagnostic tool to help guide treatment and tailor it to the cohort of patients with urothelial dysfunction (Towner et al., 2020, 2021).

Amniotic Bladder Therapy.

Amniotic bladder therapy is a new treatment option under exploration with the goal of healing the urothelial barrier in IC/BPS patients. An ongoing clinical trial has provided an update that, three months following intradetrusor injections of 100 mg micronized amniotic membranes, patients reported improved voiding symptoms and reduced bladder pain (Madan et al., 2023). While research into this therapy is limited due to its novelty, the proposed mechanism of action is that amniotic membranes help promote glycoprotein and hyaluronic acid expression, reduce inflammation, and promote nerve regeneration (Madan et al., 2023).

Stem Cell Therapy.

The injection, instillation, or intravenous delivery of stem cells into the urinary bladder has shown a detectable therapeutic potential (Dayem et al., 2020). Animal studies using various UCPPS models have demonstrated that stem cell treatments result in anti-inflammatory benefits (Chung et al., 2019; Tabata et al., 2021; Gao et al., 2023). In addition, stem cell injections may help repair the urothelial barrier and reduce bladder lesions and fibrosis (Kim et al., 2016; Xie et al., 2018; Furuta et al., 2022), as well as reduce nociceptive signaling (Furuta et al., 2018, 2019, 2022). Because mesenchymal stem cells have a known cancerogenic potential, mesenchymal stem cells-derived extracellular vesicles have been suggested as a potential treatment that requires further investigation (Dayem et al., 2022). To date, only one clinical trial has assessed the efficacy of stem cell therapy to manage UCPPS, but the lack of a control group and inconsistent methods limited its conclusions (Lander et al., 2019). There is a clear need for more extensive, well-designed, randomized clinical trials to investigate the therapeutic potential of stem cell treatments.

Transcranial magnetic stimulation (TMS) is a noninvasive form of brain stimulation and has shown some promise in reversing central sensitization and reducing chronic pain (Giannoni-Luza et al., 2020). TMS of the supplementary motor area of the brain was shown to improve pelvic floor muscle tone and reduce urinary dysfunction (Yani et al., 2019). A small pilot study reported initial positive results of TMS in 11 CP/CPPS patients, with patients experiencing an overall reduction in pain and LUTS (Nikkola et al., 2020). A randomized, blinded crossover study of 15 patients with IC/BPS showed similar results (Cervigni et al., 2018). Another trial assessed the efficacy of TMS in combination with muscle vibration to treat pelvic pain in women and reported an overall reduction in pain but did not assess urinary symptoms (Calabrò et al., 2022). The existing studies of TMS efficacy on UCPPS patients are few and have low sample sizes or lack controls, which makes interpreting results difficult. An ongoing randomized controlled trial of 63 female patients may offer additional insight into the therapeutic potential of TMS (M. Wang et al., 2023).

Antibody Therapy.

Several growth factor-related antibodies approved by the FDA to treat different pathologies have been tested as a UCPPS treatment. Tanezumab, a humanized monoclonal antibody against nerve growth factor (NGF), has been purported to lessen pain symptoms in UCPPS patients by inhibiting NGF from interacting with its receptors, tropomyosin-related kinase A and pan-neurotrophin receptor p75 ^NTR (Nickel et al., 2016). This treatment was most effective in women with IC/BPS. Animal models of UCPPS have confirmed that therapeutics targeting NGF and brain-derived neurotrophic factor signaling through pharmacological inhibition of tropomyosin-related kinase A and tropomyosin-related kinase B pathways, respectively, improved bladder capacity and urinary frequency symptoms (Hsiang et al., 2022, 2023). However, these studies in animals did not assess changes in pain symptoms, and urinary symptom relief through TrkB inhibition was only significant in the acute IC/BPS model; no improvements were observed in the chronic model.

A study from the MAPP Research Network provided evidence that vascular endothelial growth factor (VEGF) could be considered one of the urinary biomarkers of UCPPS (Dagher et al., 2017). The study assessed protein composition of urine samples in male and female patients with UCPPS, a positive control group (patients with chronic pain without pelvic pain), and healthy controls. At the initial (baseline) clinical visit, males with UCPPS had significantly higher urinary levels of VEGF without any correlation with pain severity or urinary symptoms. In contrast, elevated urinary VEGF levels were significantly associated with pain severity in women (Dagher et al., 2017). Despite the clinical findings (Lee and Lee, 2011), the sites, mechanisms of VEGF action in the central nervous system centers controlling micturition and pelvic pain, and effects on the excitability of peripheral and central neurons innervating the LUT are poorly understood. Preclinical animal models determined that activation of VEGF signaling in the urinary bladder enhanced innervation of the bladder wall (Cheppudira et al., 2008; Malykhina et al., 2012; de Rijk et al., 2022) and that intravesical instillations of VEGF in mice promoted sensory and motor nerve density, triggered detrusor overactivity, and worsened pelvic sensitivity (Malykhina et al., 2012; Xie et al., 2022). In animal studies, silencing of lumbosacral sensory neurons with intrathecal delivery of designer receptors exclusively activated by designer drugs reversed VEGF-induced visceral hypersensitivity (Xie et al., 2022), and the use of anti-VEGF antibodies effectively reduced pelvic nociception, suggesting potential benefits of anti-VEGF therapy in UCPPS patients (Lai et al., 2017). A transcriptome study of bladder biopsy samples from IC/BPS patients with Hunner’s lesions found overexpression of VEGF and B-cell activating factor in the urinary bladder. It proposed that VEGF expression should be considered unique to IC/BPS with Hunner’s lesions, to be followed by further investigations for subtype-specific treatment options (Akiyama et al., 2020; Akiyama, 2021). Further proof of the mechanistic involvement of VEGF in bladder pain and voiding dysfunction would provide scientific justification and “proof-of-concept” data for designing clinical trials with anti-VEGF treatments to alleviate bladder pain in UCCPS.

Calcitonin gene-related peptide (CGRP) is another potential therapeutic target for UCPPS. In animal studies, inhibition of CGRP expression with respective antibody has been shown to lessen LUTS and pain resulted from urinary tract infection and also reduced the development of cross-sensitization between the urinary bladder and distal gut (Mohammadi et al., 2018, 2021, 2023; Montalbetti et al., 2023). CGRP is expressed in the peripheral and central nervous systems and is involved in the regulation of vasodilation, immune modulation, and development of pelvic organ cross sensitization (Pan et al., 2010; Russell et al., 2014). Antibodies targeting CGRP have been effective in treating acute migraine pain (Do et al., 2019; Bhakta et al., 2021), suggesting their potential effectiveness in other chronic pain conditions. Currently, there are no studies assessing anti-CGRP treatments in animal models of UCPPS pathology or in UCPPS patients, thereby warranting future research in this direction.

Concluding Remarks

The heterogeneous etiology of UCPPS provides challenges in diagnosis, pathophysiology, and treatment of the affected patients. Knowledge gaps exist around comorbid conditions such as major depressive disorder and generalized anxiety disorder that complicate the effectiveness of the chosen therapeutic options. Therefore, future research directions should address the role of chronic psychological stress and the occurrence of pain refractory to conventional management strategies. Testing the applicability of cognitive behavioral therapy in this cohort of patients might be promising to increase their QoL. Prior research also highlighted sex differences in immune responses, microbiome composition, pain processing, and psychosocial status (Zagni et al., 2016), indicating the need to conduct sex-specific research. The role of autoimmune responses triggered by environmental factors is another potential research direction to address the impact of the immune system in UCPPS pathophysiology. While existing therapeutics have shown moderate efficacy, several experimental treatments including humanized monoclonal antibodies against NGF (Tanezumab), stem cell delivery into the bladder tissue, and amniotic bladder therapy start to gain more interest in the field. The search for novel lead compounds and innovative drug delivery systems requires preclinical testing on appropriate animal models. Integrative and interactive research should be a top priority, with a tighter integration of clinical investigations and research on human subjects with appropriate animal models to facilitate the development of novel therapies for UCPPS patients.

Abbreviations

AUA

American Urological Association

BoTN-A

botulinum toxin A

BPH

benign prostatic hyperplasia

CGRP

Calcitonin gene-related peptide

COX

cyclooxygenase

CP/CPPS

chronic prostatitis/chronic pelvic pain syndrome

CPP

chronic pelvic pain

DMSO

dimethyl sulfoxide

FDA

Food and Drug Administration

GAG

glycosaminoglycan

IC/BPS

interstitial cystitis/bladder pain syndrome

LUTS

lower urinary tract symptoms

MAPP

Multidisciplinary Approach to the Study of Chronic Pelvic Pain

NGF

nerve growth factor

NSAID

nonsteroidal anti-inflammatory drug

QoL

quality of life

SSRI

selective serotonin reuptake inhibitor

TLR

toll-like receptor

TMS

transcranial magnetic stimulation

TNS

tibial nerve stimulation

UCPPS

urologic chronic pelvic pain syndrome

VEGF

vascular endothelial growth factor

Authorship Contributions

Participated in research design: Ashraf, Clarkson, Malykhina.

Preformed data analysis: Ashraf, Clarkson, Malykhina.

Wrote or contributed to the writing of the manuscript: Ashraf, Clarkson, Malykhina.