1.Introduction

Chronic bladder pain is one of the most recognized causes of chronic pelvic pain syndrome. It can be caused by a spectrum of conditions with different etiologies. These include bladder pain syndrome (BPS) and chronic cystitis secondary to radiation or chemicals such as ketamine and Bacillus Calmette–Guérin (BCG).¹

The definition of BPS varies between different societies and organizations. The European Association of Urology definition is very comprehensive and detailed. It is defined as the occurrence of persistent or recurrent pain perceived in the urinary bladder region, accompanied by at least one other symptom, such as pain worsening with bladder filling and daytime and/or nighttime urinary frequency in the absence of proven infection or other obvious local pathology. It is often associated with negative cognitive, behavioral, sexual, or emotional consequences, as well as with symptoms suggestive of lower urinary tract and sexual dysfunction. Other terms that have been used include "interstitial cystitis," "painful bladder syndrome," and "PBS/IC" or "BPS/IC." These terms are no longer recommended.²

The prevalence of the disease is generally underestimated. This is likely due to a lack of specific diagnostic criteria among different studies. According to the Third National Health and Nutrition Examination Survey of the United States of America (USA), the prevalence was 470/100,000 people, with a higher prevalence in women than men.³ In 2019, the United Kingdom (UK) National Institute for Health and Care Excellence (NICE) projected that BPS impacted roughly 400,000 individuals in the UK.⁴

Although thoroughly investigated, the pathophysiology of BPS is still heterogeneous and incompletely understood. Proposed mechanisms include chronic inflammation, urothelial dysfunction (such as a deficit in the glycosaminoglycan [GAG] layer), autoimmune processes, neurogenic inflammation, and activation by neuropeptides, mast cell activation, and central sensitization. The literature suggests that an initial bladder insult (such as trauma, stress, allergies, toxin exposure, or acute bacterial infection) induces an inflammatory cascade that results in localized and systemic inflammation, leading to the emergence of clinical signs.⁵,⁶

Despite increasing awareness, the diagnosis and management of BPS remain challenging for clinicians. The overlap in symptomatology with other lower urinary tract and gynecological disorders often results in diagnostic delay, misclassification, and fragmented care. Furthermore, the unpredictable clinical course, fluctuating symptom severity, and psychosocial burden contribute to significant impairment in quality of life (QoL) and high healthcare utilization.

Like all other chronic pain conditions, chronic bladder pain requires a holistic, multimodal approach along with shared decision-making and active involvement of the patient.² A realistic discussion of the condition, management options, and the tendency for symptoms to remit is essential before starting any treatment, which aims primarily to improve QoL.⁷

It is generally agreed by all guidelines that management should begin with conservative options, such as dietary modifications, pelvic floor relaxation, biofeedback, and bladder retraining. If these are insufficient, oral pharmacologic therapy is considered, ranging from simple analgesics to oral neuromodulator agents. In cases where oral treatments fail to provide adequate symptom relief, second-line treatments such as oral pentosan polysulfate sodium (PPS) or intravesical instillations of local anesthetics, heparin, dimethyl sulfoxide, mixtures of lidocaine/sodium bicarbonate, or GAG replacement therapy can be offered.²,⁷,⁸

Cystoscopy with hydrodistension can provide both diagnostic and symptomatic benefit. In selected patients, intra-detrusor Botox, spinal cord stimulation, or fulguration/resection of Hunner's lesions can be offered before considering more invasive options such as urinary diversion (ileal conduit) with or without total cystectomy or substitution cystoplasty.²

In recent years, increasing attention has been directed toward the role of bladder surface repair and urothelial barrier restoration in the treatment of BPS. PPS, a synthetic heparin-like macromolecule, is thought to replenish the defective GAG layer of the bladder epithelium and exert anti-inflammatory effects. Although it remains the only oral therapy licensed for BPS in the UK, clinical evidence regarding its real-world effectiveness and safety remains limited and at times inconsistent. Moreover, there is growing interest in its off-label use for related conditions such as ketamine-associated and radiation-induced cystitis, where mucosal injury and inflammation share similar pathophysiological mechanisms.

The efficacy of oral PPS in patients with BPS has been shown in several randomized controlled trials when compared to a placebo. Our study aims to assess the safety and efficacy of this treatment in the management of chronic bladder pain conditions.

2.Materials and methods

2.1. Methods

A retrospective review was conducted in a tertiary care center to evaluate the use of PPS in patients with chronic bladder pain. The study included all urology patients prescribed PPS from the initiation of PPS prescribing at our institution, from January 2020 to December 2024. We included all living patients who were prescribed oral PPS after being diagnosed with chronic bladder pain conditions, including BPS, ketamine-induced cystitis (KIC), and radiation cystitis. None of our patients received the treatment for BCG cystitis. Patients were identified through hospital pharmacy dispensing records. Two patients were excluded due to loss to follow-up. Three of the patients who were started on PPS in our Trust passed away during the study period and were therefore excluded from our cohort. By including all consecutive patients treated at the institution, the study aimed to minimize selection bias and reflect pragmatic prescribing practices.

Data were extracted by two independent reviewers to enhance accuracy, and discrepancies were resolved by consensus. Where documentation was incomplete, patients were contacted through telephone to clarify follow-up status and symptom progression. The study population was intentionally broad to encompass not only classic BPS but also off-label indications such as KIC and radiation-induced cystitis, enabling subgroup comparison and exploratory evaluation of differential responses across etiologies.

The study was registered with the Trust's clinical audit department and did not require ethical approval due to its retrospective nature.

The dosing protocol for PPS followed institutional standards based on NICE guidance, typically 100 mg administered orally three times daily. Treatment duration varied according to clinical response, tolerability, and patient preference, with follow-up assessments conducted every 3–6 months. Adherence was assessed through pharmacy refill data and patient-reported continuation.

Data collection was performed through a detailed review of electronic medical records and outpatient clinic correspondence. The following variables were extracted: age, gender, past medical history, indication for PPS use, results of prior investigations, previous treatments, prior use of intravesical GAG therapy, whether PPS was used concurrently with GAG therapy, documentation of counseling regarding the risk of macular degeneration, ophthalmology referral status, treatment discontinuation, and any reported side effects.

The diagnosis of BPS was based on the European Society for the Study of Interstitial Cystitis criteria. Specifically, inclusion required chronic bladder-related pain with associated urinary symptoms persisting for more than 6 months, after exclusion of infection and other identifiable causes. All patients with BPS underwent cystoscopy to evaluate for Hunner lesions and rule out other pathologies. Urodynamics was not part of the routine diagnostic pathway and was selectively performed to assess detrusor overactivity or poor compliance. The QoL was assessed based on patient-reported outcome measures, including the Interstitial Cystitis Symptom Index (ICSI) and Interstitial Cystitis Problem Index (ICPI) questionnaires before and after treatment. A routine ophthalmology referral at 6 months was offered if the patient decided to continue treatment.

2.2. Statistical analysis

Descriptive statistics were used to summarize demographic and clinical data. Frequencies, means, medians, and ranges were reported where appropriate. Changes in patient-reported QoL were analyzed using the Wilcoxon signed-rank test for paired non-parametric data. Differences in symptom scores (ICSI and ICPI) across indications were assessed using one-way analysis of variance (ANOVA). Effect sizes were reported using eta squared (η²). Statistical analyses were conducted using SPSS (IBM SPSS Statistics, USA), and significance was set at p<0.05. The primary outcome measures were patient-reported improvement in QoL and treatment continuation rates. Secondary outcomes included the incidence and nature of reported side effects.

3.Results

3.1. Patient demographics and baseline characteristics

The baseline characteristics are given in Table 1. The cohort was predominantly female (81%, n=34), with a mean age of 49.7 years (SD=19.0). The primary indication for treatment was BPS in 69% (n = 29) of patients, KIC in 21.4% (n = 9) of patients, and radiation-induced cystitis in 9.5% (n = 4) of patients (Table 2). Relevant comorbidities included a history of pelvic surgery in 31% (n = 13), mental health conditions in 26.2% (n = 11), endometriosis in 12% (n = 5), and fibromyalgia in 4.8% (n = 2). The median follow-up period was 15.3 months (range: 4.5–117.5).

All patients had previously trialed conservative measures and oral analgesics. These included paracetamol in 100% (n = 42), oral opioid-based analgesics (co-codamol and codeine) in 95% (n = 40), non-steroidal anti-inflammatory drugs in 90% (n = 38), neuromodulatory pain killers (amitriptyline/pregabalin) in 38% (n = 16), and antimuscarinic solifenacin in 78% (n = 33). Intravesical GAG therapy was used in 40.5% (n = 17) of cases, and 26.2% (n = 11) underwent bladder hydrodistension. Intra-detrusor botulinum toxin injections were administered in 14.3% (n = 6). Radiological investigations were performed in 97.6% (n = 41) of patients, with ultrasound (81%) and computed tomography (42.9%) being the most common modalities. Magnetic resonance imaging was utilized in 19.0% of cases. Cystoscopic evaluation was performed in 100% (n = 42). In 5 out of the 27 patients (18.5%) with BPS who underwent cystoscopy, Hunner's ulcers were seen. Urodynamic studies were performed for 23.8% (n = 10) of patients due to predominant storage lower urinary tract symptoms. The previous investigations and treatments are listed in Table 2.

The median duration of treatment among responders was 10.5 months (inter-quartile range: 7–18), whereas non-responders discontinued therapy earlier (median: 4 months), usually due to perceived lack of benefit. Patients who continued treatment for at least 6 months had a higher likelihood of meaningful QoL improvement, suggesting a time-dependent therapeutic effect.

3.2. Subjective QoL

At baseline, all 42 patients reported themselves as being "severely symptomatic." Following treatment with PPS, 42.5% (n = 17) reported being "not symptomatic," 25% (n = 10) reported being "mildly symptomatic," and 32.5% (n = 13) remained "severely symptomatic." Two patients were lost to follow-up. A Wilcoxon signed-rank test showed a statistically significant improvement in QoL post-treatment (Z = −4.71, p<0.001), indicating that the treatment had a meaningful effect.

3.3. ICSI/ICPI scores

Symptom severity, as assessed by ICSI and ICPI scores, also demonstrated clinical improvement. Out of the 38 who responded, patients treated for BPS experienced the greatest mean reductions (ICSI: 6.04 ± 7.01; ICPI: 5.26 ± 6.42). Patients with KIC exhibited relatively more improvement (ICSI: 3.25 ± 2.32; ICPI: 2.13 ± 2.30) than those with radiation-induced cystitis (ICSI: 3.00 ± 3.00; ICPI: 1.33 ± 2.31). Two patients did not provide completed post-treatment questionnaires as they stopped the medication due to perceived side effects early in the course of treatment. Figure 1 shows the patients available for analysis. One-way ANOVA did not reveal statistically significant differences in symptom improvement between indication groups; however, the effect sizes (η² = 0.046 for ICSI and 0.074 for ICPI) suggest a small-to-moderate association between underlying diagnosis and treatment response (Table 3).