Interstitial Cystitis/Bladder Pain Syndrome

Abstract

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a heterogeneous, chronic, and debilitating condition. It affects 400,000 individuals in the United Kingdom. IC/BPS presents with suprapubic pain or discomfort perceived to be related to the urinary bladder with one or more urinary symptoms (e.g., urgency, frequency or nocturia) for more than 6 weeks. The exact etiology is not clearly understood. It can sometimes co-exist with other chronic pain disorders, complicating the diagnosis and management. IC/BPS can adversely impact the quality of life, impede work, and interfere with the sleep, sexual and social life of the affected individual. The contemporary treatments are palliative and aim for symptom control only. There is no cure available presently. Moreover, treatment effects are highly variable; therefore, personalization of treatment is vital for achieving the desired outcomes. Management includes lifestyle modifications, physical therapy, systemic pharmacotherapy, intravesical therapies and surgery. Conservative treatments are usually used first, followed by invasive and combination therapies if required. Treatment should aim beyond symptom improvement and encompass improvement in quality of life. Further research is needed to understand the etiology and pathophysiology of IC/BPS. It will assist in the development of new biomarkers and drug development.

1. Introduction

Interstitial cystitis or bladder pain syndrome (IC/BPS) is a chronic debilitating condition of uncertain etiology. The American Urology Association (AUA) guidelines define IC/BPS as ‘an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms of more than 6 weeks duration in the absence of infection or other identifiable causes.’ [1].

The exact etiology of IC/BPS is unknown. Most of the affected patients have a poor quality of life. It is a diagnosis of exclusion, meaning that IC/BPS is diagnosed when other conditions causing similar symptoms are excluded. IC/BPS may coexist with other painful conditions, such as irritable bowel syndrome, fibromyalgia etc., which can delay the diagnosis and complicate management. No cure is available yet, and the existing therapies target symptom control and palliation. No treatment has shown a clinically meaningful advantage over the other.

Moreover, the available treatments are not equally effective in all patients. Therefore, it is essential to tailor the management according to the patient’s needs. Management of IC/BPS is best delivered in a multidisciplinary approach and should focus on the quality of life in addition to symptoms.

2. Nomenclature and classification

The term interstitial cystitis is misleading. The symptoms of interstitial cystitis are not reliably associated with the pathology of bladder interstitium. Moreover, bladder inflammation (cystitis) is not observed in all cases of IC/BPS. The term IC was changed to painful bladder syndrome and later replaced by bladder pain syndrome. In the Japanese and East Asian literature, ‘hypersensitive bladder’ is used for IC/BPS, further complicating the nomenclature. The terminology of IC/BPS needs standardization for clarity.

For historical reasons, IC/BPS are reported together. In this chapter, the term IC/BPS will be used.

3. Epidemiology

The exact incidence and prevalence of IC/BPS are unknown due to the lack of formalized diagnostic criteria. It is frequently reported in middle-aged men (55-75 yr) and women (50-60 yr). IC/BPS predominately affects females (female: male ratio 10:1). The prevalence of self-reported disease ranges from 850 per 100,000 in women and 60 per 100,000 in men [2, 3]. Based on this data, approximately 1.2 million women and 83,000 men have IC/BPS in the United States. Medical billing-based prevalence of IC/BPS is slightly lower, 197 per 100,000 in women and 41 per 100,000 in men [3]. The prevalence of IC/BPS in Europe is low (8-16 per 100,000) [4]. IC/BPS prevalence is believed to be very low in children.

4. Etiology and pathophysiology

The etiology of IC/BPS is not fully understood. Some of the proposed theories are mentioned below. However, none of these theories has been proven.

• Good concordance of IC/BPS in monozygotic twins suggests genetic vulnerability [5].

• Urinary tract infection- bacterial or viral infection in the bladder induces an inflammatory process which continues even after clearing the infection.

• Leaky Glycosaminoglycan (GAG) layer- bladder urothelium is covered by glycosaminoglycans (GAG) which act as a protective lining against bacteria and irritants in the urine. It is hypothesized that disruption of the GAG layer results in increased permeability. Irritants in the urine, such as Potassium, depolarize the muscles and nerves in the bladder wall. It, in turn, triggers inflammation and degranulation of mast cells causing lower urinary tract symptoms.

• Autoimmune reaction- autoimmunity may sometimes be responsible for IC/BPS.

• Hypersensitivity reaction- In some cases, mast cell proliferation in the bladder wall biopsies is observed. They release histamines which cause hypersensitivity reactions, thus contributing to the IC/BPS symptoms.

• A functional brain magnetic resonance imaging (MRI) study of patients with IC/BPS revealed an increase in the gray matter volume in brain areas related to pain [6], highlighting the role of the nervous system in the disease.

• Neurologic upregulation- some experts believe that recurrent bladder wall inflammation or irritation results in hyperplasia of the sensory nerves, enhancing pain perception. Repeated painful stimuli also induce changes in the spinal neurons making the signals robust and long-lasting.

• Recreational use of ketamine is associated with severe IC/BPS. Possible explanations include autoimmunity, infection, urothelial damage, and vascular changes due to ketamine or metabolites. Interestingly, ketamine use within the approved doses is not associated with bladder symptoms [7].

5. Clinical features

Pain exacerbated by bladder filling is the trademark of IC/BPS. Bladder pain is accompanied by one or more lower urinary tract symptoms such as urgency, urinary frequency and nocturia. Some patients complain of discomfort, pressure, or spasms in the suprapubic area instead of pain. The emergence of lower urinary tract symptoms may precede pain in some cases. Urgency is a notable symptom of an overactive bladder. However, the quality of urgency differs from IC/BPS. Patients with overactive bladder void to avert incontinence, while those with IC/BPS void to alleviate the pain. Some patients may experience extra bladder pain, e.g., in the lower abdomen, back, urethra, rectum, vulva, and vagina.

Urinary incontinence is uncommon in IC/PBS. In men, the symptoms of chronic prostatitis overlap with IC/BPS and need expert input to differentiate the two.

The disease usually commences with few symptoms, which progress to multiple symptoms. Symptoms typically build gradually; however, some patients may present acutely. The severity of the symptoms varies. Aggravating factors include sexual intercourse, exercise, prolonged sitting, psychosocial stress, menstruation and with certain foods or drinks.

Hypertonic pelvic floor dysfunction is common in IC/BPS. It is likely due to sensitization of thoracolumbar and sacral nerves. Some patients will have allodynia.

Physical examination demonstrates tenderness in the suprapubic area, perineum, lower back, levator muscles, and genitalia.

IC/BPS frequently affects the patient’s social, psychological, and emotional well-being [8]. Depression, anxiety, panic disorder, abnormal work-life balance and sexual dysfunction are more prevalent in IC/BPS than controls. IC/BPS patients complain of moderate to severe sexual dysfunction. Pain is the primary driver of sexual dysfunction.

Moreover, other chronic pain syndromes such as irritable bowel syndrome, fibromyalgia, chronic headaches, Sjogren’s syndrome and vulvodynia may coexist with IC/BPS.

IC/BPS adversely impact on quality of life (QoL). It is associated with decreased work productivity, disturbed sleep, emotional changes, sexual dysfunction, and reduced mobility. The effects on QoL are as severe as reported in maintenance hemodialysis, rheumatoid arthritis, Crohn’s disease, and systemic lupus erythematosus.

The clinical course of the disease is not fully understood. Some patients reported spontaneous resolution of symptoms, while other studies reported a waxing and waning course with a slight improvement over time [9, 10].

6. Diagnosis

IC/BPS is a diagnosis of exclusion. No definitive diagnostic test for IC/BPS exists apart from IC/BPS with Hunner lesion, diagnosed on cystoscopy. The diagnosis is delayed in most cases by 5-6 years [11]. Detailed history taking, examination and laboratory investigations help reach the diagnosis.

According to AUA 2022 guidelines, cystoscopy is not essential for diagnosing IC/BPS. However, cystoscopy is performed to exclude other differential diagnoses. IC/BPS with Hunner lesion is an exception where cystoscopy is diagnostic. Cystoscopy is also indicated in IC/BPS patients who fail to respond to initial treatment to exclude alternative diagnoses.

ICP/BPS with Hunner lesion was first described by Guy Leroy Hunner in 1914. Hunner lesion in the acute phase is a confined, erythematous mucosa with tiny blood vessels radiating toward the center of a pale scar [12] (Figure 1). A Fibrin clot is attached to the lesion. Hunner lesions may bleed after hydrodistension in a waterfall pattern. Chronic lesions are blanched and do not bleed. Microscopy of the Hunner lesion shows chronic infiltrate consisting of neutrophils, eosinophils, lymphocytes, plasma cells, macrophages, and mast cells [12] (Figure 2).

Figure 1.

A Hunner lesion. (a) Hunner lesion is a reddish muscosal lesion lacking the normal capillary structure, frequently covered by fibrin clots. (b) Narrow-band imaging cystoscopy of the Hunner lesion emphaizes the abnormal capillary structure converging toward the lesion (Reproduced with permission).

Figure 2.

Histological features of IC/BPS. (a) IC/BPS with Hunner lesions (lesion area). Dense subepithelial inflammatory infiltrates, epithelial denudation and increased neovascularization are observed, often accompanied by lymph follicles (magnification: x100). (b) IC/BPS with Humner lesion (non-lesion are). Note that similar inflammatory changes observed in a non-lesion area (magnification: x200). (c) IC/BPS without Hunner lesions. Few inflammatory changes with retained urothelium (magnification: x200) (Reproduced with permission).

Hunner lesions are found in only 5-10% of the cases. The multidisciplinary approach to pelvic pain (MAPP) phase II study revealed Hunner lesions in 19.7% between 50 and 70 and 54.5% over the age of 70 yr. [13]. Hunner lesions respond well to treatment. Therefore, it is appropriate to offer early cystoscopy in this age group.

Glomerulations or reactive petechial hemorrhages are observed in some cases. They are non-specific and non-diagnostic. They can be seen in other conditions, e.g., radiation cystitis, bladder cancer and sometimes in healthy individuals. Moreover, glomerulations do not correlate with symptoms of IC/BPS [14].

Urodynamic tests are non-specific and could cause discomfort. Therefore, they are not recommended routinely in diagnosing IC/BPS.

The Potassium sensitivity test (PST) informs about urothelial permeability and dysfunction [15]. It is non-specific and may be positive in urinary tract infection and radiation cystitis. It could be painful and might cause a severe flare-up. Furthermore, PST is not predictive of response to urothelium restoring therapies.

Improvement of symptoms during an anesthetic bladder challenge (which involves the instillation of an anesthetic cocktail) is no longer recommended as a diagnostic test.

Differential diagnoses include bladder/urethral cancer, genital cancers, benign pelvic conditions (e.g., uterine fibroid, pelvic organ prolapse etc.), infections in the pelvic area, chronic pelvic pain syndromes, intravesical pathology (e.g., stone, foreign body etc.), urethral diverticulum, disorders causing bladder outflow obstruction (e.g., enlarged prostate), neurologic disorders, diabetes mellitus, bowel diseases (e.g., inflammatory bowel disease, diverticular disease), trauma, and radiation etc.

7. Assessment tools

Several validated questionnaires are available. Some could assist in diagnosis, while others are used to track changes in the symptoms after an intervention. Some questionnaires assess the impact of IC/BPS on QoL. Table 1 illustrates some of the commonly used validated instruments.

Questionnaire	Domains	Additional information
O’Leary Sant/Interstitial cystitis symptoms and problem indexes [16]	Urinary symptoms, pain, general health, QoL, Sexual health & relationship with menses	Self-administered, monitor changes in symptoms, not a screening test
University of Wisconsin interstitial cystitis inventory (WICI) [17]	Pelvic pain, pelvic discomfort, urine frequency, nocturia, Urgency, dysuria & sleep	Used to monitor changes in the symptoms
Medical outcomes study 36-item short-form health survey (SF-36) [18]	General health, physical function, vitality, body pain, mental health, social function & emotional health	Focused on QoL
Pelvic pain and urinary frequency patient symptom scale (PUF) [19]	Urine frequency, nocturia, pain, QoL & sexual function	Helps in distinguishing bladder pain from reproductive tract pain and is correlated with the Potassium sensitivity test
UPOINT [20]	Urinary, psychosocial, organ specific, infection, neurological/systematic & tenderness	Focused on QoL, Guides in phenotyping the disease
Bladder symptoms impact scale (BSI-6) [21]	Energy level, interest in daily activity, mood, social life, self-worth & ability to perform home activities.	Focused on QoL
King’s Health questionnaire [22]	Sleep, physical limitation, role limitation, symptom bother & emotions	Focused on QoL
Global response assessment (GRA)	Disease symptoms	Monitors change in symptoms before and after treatment, non-specific
Visual analogue score (VAS)	Pain	Monitors change in symptoms before and after treatment, non-specific

Table 1.

Validated questionnaires for IC/BPS.

8. Phenotyping

IC/BPS comes under the umbrella term of chronic pain syndrome (Figure 3). Earlier guidelines did not classify IC/BPS into phenotypes. However, there is growing consensus among experts that IC/BPS is not a single disease but a spectrum. Furthermore, various phenotypes respond to different therapies. The AUA and East Asian Association of Urologists updated guidelines endorses this concept. According to the AUA IC/BPS guidelines 2022, IC/BPS has three distinct phenotypes.

• Bladder-centric phenotype- includes patients with Hunner lesions and small bladder capacity. They improve with intravesical anesthetics. Some experts even propose that IC/BPS with Hunner lesion is an entirely different disease and should not be considered part of BPS.

• Pelvic floor phenotype- exhibits pelvic floor tenderness on physical examination. This subgroup benefits from physical therapy.

• Systemic or widespread pain phenotype- has extra pelvic pain. These patients have chronic overlapping pain conditions (such as fibromyalgia, irritable bowel syndrome etc.), psychosocial issues and widespread somatic symptoms from multiple organs. These patients need a multidisciplinary treatment approach.

Figure 3.

Classification of IC/PBS.

UPOINT (urinary, psychosocial, organ specific, infection, neurologic and or extra pelvic/systemic pain and tenderness of pelvic floor) phenotyping system is a valuable tool to characterize the different domains of the IC/BPS.

A study stratified IC/BPS patients using bladder capacity. Lower bladder capacity was associated with bladder-centric disease [23] with no associated somatic symptoms and affect dysregulation. Large bladder capacity was associated with extra bladder symptoms, e.g., functional somatic syndrome. They also had abnormal psychosocial history, e.g., childhood relationship problems, dissociative pathology etc. [24]. Further validation in extensive studies is warranted before recommending bladder capacity as a biomarker in IC/BPS.

Patients’ stratification and phenotyping could assist in minimizing the variable response to the available treatments.

9. Treatment

Currently, there is no cure available for IC/BPS. The available treatments aim at the palliation of symptoms. Contemporary literature does not support one therapy over the other. It is, therefore, essential to personalize the treatment plans for each patient. Patients should be monitored after treatment; alternative therapies should replace ineffective treatments.

Realistic treatment goals should be outlined right at the inception. Patient-related outcomes should guide treatment goals. Every patient may not achieve the desired symptom control; therefore, the treatment should focus on minimizing the discomfort and improving the quality of life (Figure 4).

Figure 4.

Goals for managing IC/BPS.

The earlier AUA guidelines (2014) recommended a hierarchal approach starting with conservative therapies first and progressing to invasive therapies. The latest AUA guidelines (2022) propose to design treatment plans based on patients’ needs and risk-benefit assessment. Surgical treatments are not effective in every case and are associated with significant morbidity and mortality. Therefore, it should be used as a last resort in refractory disease.

Patients’ education about the disease is vital to bring their expectations close to reality. Complex or resistant cases should be managed by multidisciplinary team approach (Figure 5).

Figure 5.

Multidisciplinary team for managing IC/PBS.

9.1 Lifestyle modifications

Patients should be encouraged to practice lifestyle modification and self-care practices. A symptom diary could help in the identification of triggering or relieving factors.

A moderate fluid restriction could improve bladder discomfort associated with filling. In contrast, those sensitive to concentrated urine may benefit from additional hydration.

More than 80% of patients describe sensitivity to food [25]. Table 2 displays commonly reported culprit foods. Food sensitivity varies from patient to patient. A food diary and elimination diet could assist in spotting the culprit food or drinks.

Food characteristics [26]	Examples
Caffeine-containing food	Coffee, chocolate, tea, soda
Foods which make urine acidic	Citrus fruit, tomatoes, onions, Fava beans
Miscellaneous	Spicy foods, soya, alcoholic drinks, walnuts, pistachios, cashews, nut butter, processed meat or fish, rosemary, thyme, asparagus, broccoli, eggplant, spinach, water

Table 2.

Foods causing exacerbation of IC/BPS.

Pelvic floor relaxation exercises such as squatting, reclining with spread legs, and placing knees against the chest wall can improve symptoms. These exercises increase void volume and interval between urination. Patients should avoid symptom aggravating activities, e.g., some types of physical exercises, recreational activities, and sexual activity. Kegel exercises which strengthen the pelvic floor are better avoided.

Cold or heat application over the bladder or perineum may comfort some patients. Timed voiding, bladder training to increase intervals between voids, and stress management strategies could be effective.

9.2 Physical therapy

Eighty-seven per cent of patients with IC/BPS have hypertonic pelvic floor muscle dysfunction [27]. It is unclear whether it is a primary pathology or a secondary phenomenon. Regardless of its origin, manual physical therapy can mitigate the symptoms.

Manual physical therapy focuses on releasing myofascial trigger points and is effective if palpation of the pelvis triggers the pain. Physical therapy delivered by an expert therapist renders good results.

A study randomly assigned 81 women with IC/BPS and pelvic floor tenderness to either pelvic floor myofascial physical therapy or full-body therapeutic massage. More patients in the physical therapy group experienced moderate to marked improvement in symptoms than in the therapeutic massage group (59 vs. 29%) [28]. The evidence about the role of other forms of massage therapies is scarce. Acupuncture may be effective, but the evidence is limited.

9.3 Pharmacotherapy

9.3.1 Oral pharmacotherapy

Amitriptyline is a tricyclic antidepressant. It blocks the reuptake of serotonin and noradrenaline. In addition, it has anticholinergic, beta3 agonist, sedative, antihistamine, and mast cell stabilization properties. Though not licensed, it is commonly used in IC/BPS. It is commenced at 10 mg and gradually titrated to 75-100 mg once daily. Clinical effects manifest in 4-6 weeks. A small, randomized study (n = 50) of IC/BPS cases compared amitriptyline with a placebo [29]. Sixty-three per cent of patients in the amitriptyline group reported improvement in O′ Leary Sant score compared to 4% in the placebo arm at 16 weeks. Another randomized study showed similar results in favor of amitriptyline (66 vs. 47%) [30]. Symptom control was better in patients who used 50 mg or a higher dose of amitriptyline (66 vs. 45%) at 3 months. Improvement in symptoms was insignificant when all amitriptyline doses were analyzed collectively (55 vs. 45%).

Toxicity (such as such as urinary retention, dry mouth, constipation, hypotension, weight gain, and dysrhythmia) limits the use of amitriptyline.

Amitriptyline is metabolized by cytochrome P450 (CYP450) enzymes. The risk of amitriptyline toxicity increases when co-adminstered with CYP450 inhibitors such as cimetidine, selective serotonin reuptake inhibitors and anticonvulsants. Concomitant use with monoamine oxidase inhibitors could result in Serotonin syndrome- a potentially life-threatening reaction. Amitriptyline can increase the arrhythmogenic effect of Cisapride.

Pentosan polysulphate sodium (PPS) (Elmron®) is a semi-synthetic polymer of xylose hydrogen sulphate. It can be administered orally or intravesical. PPS is the only United States Food and Drug Administration (FDA) approved oral drug for IC/BPS. Orally administered PPS is excreted in the urine restoring the damaged GAG layer over urothelium. The recommended oral dose is 100 mg three times a day. Clinical effects manifest in 3-6 months.

A meta-analysis showed improvement in frequency, urgency and pain with PPS compared to placebo [31]. However, recent RCTs demonstrate conflicting results, probably related to the study design. A RCT of 64 patients compared cyclosporin A (1.5 mg/kg) to PPS (100 mg TID). Cyclosporin A was more effective at all clinical outcomes than PPS (83 vs. 21%) [32]. Another RCT randomly assigned 368 patients either to PPS 100 mg OD, PPS 100 mg TID or placebo. It was terminated earlier due to futility [33]. A meta-analysis of six RCTs reported statistically significant improvement in urinary urgency, frequency, and bladder pain with PPS than placebo (12.4 vs. 9%) [34]. Another controlled trial (n = 41) showed benefits with concomitant use of low-dose heparin and PPS [35].

PPS is associated with diarrhea, nausea, reversible alopecia, and mild transaminitis. Pigmented retinopathy occurs in 16% of patients with long-term (at least 3 yr) use of oral PPS. It manifests as difficulty in reading, blurred vision, and slow adjustment to reduced light. Detailed ophthalmic history and retinal examination are recommended for those with preexisting eye problems. A regular retinal examination is advocated for all patients on PPS. The risk-benefit ratio of continuing PPS should be re-evaluated if pigmentary maculopathy occurs.

Some clinicians have used antihistamines based on the hypothesis that histamine released from mast cells in the bladder is sometimes responsible for IC/BPS. Hydroxyzine is an H1 blocker with anticholinergic activity. Studies have shown contradictory results. A RCT compared hydroxyzine alone or in combination with PPS to a placebo. The effect of hydroxyzine alone was like a placebo (23 vs. 13%). The combination of hydroxyzine + PPS had better efficacy than PPS alone (43 vs. 28%) [36]. Cimetidine is an H2 receptor blocker. It is associated with improvement in suprapubic pain and nocturia [37]. Further work is needed to justify its use in IC/BPS, especially in those with elevated mast cells on bladder biopsy.

Analgesics are usually used as an adjunct to other therapies, e.g., paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs). Opioid analgesics could be considered, but long-term use is associated with dependency. Phenazopyridine and methenamine could be used alone or in conjunction with NSAIDs. Methenamine is contraindicated in patients with hepatic or renal impairment and gout. Phenazopyridine should be used only for 1-3 days due to the risk of methemoglobinemia and renal and hepatic dysfunction.

Neuropathic agents, e.g., gabapentin and pregabalin, sometimes show symptom improvement.

9.3.2 Intravesical pharmacotherapies

Intravesical therapies deliver the drug directly at the site of action, thus increasing bioavailability and reducing the risk of systemic exposure. These therapies could be used in acute flare-ups or as maintenance therapy. A variety of medications, often in combination, are used.

Dimethyl sulfoxide (DMSO) is one of the two intravesical drugs approved by the FDA for IC/BPS. It could be given alone but often used in combination with other drugs. The exact mechanism of action is unknown; however, it relaxes the bladder muscles, has anti-inflammatory properties, and stabilizes mast cells. DMSO is administered intravesical at 50 ml of 50%. The dose is repeated weekly for 6 weeks. If good results are achieved, another 6 weeks course could be prescribed, followed by a monthly dose.

A small RCT (n = 33) compared DMSO to saline placebo. Patients treated with DMSO reported improvement in subjective symptom scores (53 vs. 18%) as well as in urodynamic parameters and voiding diary (93 vs. 35%) [38]. Another study used a cocktail of DMSO, hydrocortisone, bupivacaine, and heparin in 55 women with IC/BPS [39]. At 5 yr. follow-up, 23-47% of patients reported significant improvement in O’Leary Sant symptom index and pain scores. One-third of the cases were in remission without the need for further treatment. Twenty-one per cent of women required oral medication for symptom control. Small bladder capacity (<500 ml), high urine frequency (≥ 15/day) and nocturia were predictors of poor response. Another RCT compared DMSO to intravesical 2% chondroitin sulphate weekly for 6 weeks in 36 patients [40]. More than 50% of patients in the DMSO group withdraw due to instillation associate pain, garlic smell and lack of efficacy. The dropout rate was only 27% in the chondroitin sulphate group. Chondroitin sulphate was more effective in symptom control (72.7 vs. 14%), nocturia (−2.4 vs. −0.7) and pain (−1.2 vs. −0.6). Due to insufficient convincing evidence, DMSO is unlicensed in some countries, e.g., the UK.

Intravesical heparin improves IC/BPS symptoms in some cases. An observational study instilled heparin weekly into the bladder for 3 months and followed patients for 6 months. The responders increased from 33% at week 1 to 90% at week 16; however, the beneficial effect declined to 16.7% at 6 months [41]. A randomized controlled trial showed efficacy in the short term when used with sodium bicarbonate or local anesthetic agents, e.g., lidocaine. A combination of intravesical heparin and alkalinized lidocaine relieved pain and urine urgency (50 vs. 13%) at 12 hours compared to a placebo [42]. Heparin does appear to have beneficial effects, but further research is required.

Intravesical Hyaluronic acid (HA) and Chondroitin sulfate (CS) repair the damaged GAGs layer. Observational studies show a 66-87% efficacy rate of intravesical HA. In a prospective study, 121 women with IC/BPS received 40 mg intravesical HA weekly. All the participants had positive potassium tests suggestive of damaged GAGs layer. Eighty-five per cent of patients reported symptom improvement [43]. Another study randomly assigned 42 patients to intravesical HA or CS. Pain scores improved significantly in both treatment arms at 6 months; however, the CS group showed more remarkable improvement in urinary frequency, nocturia and VAS pain score [44].

A combination of HA and CS was effective in some trials. It is as effective as DMSO but with a better side effect profile. A meta-analysis of 10 studies shows significant improvement in O’Leary-Sant and VAS scores with intravesical HA and a combination of HA + CS [45]. Adequately powered randomized trials are required to assess the role of HA alone and combination HA/CS therapy in IC/BPS.

A meta-analysis of intravesical therapies reported similar response rates for HA, CS and PPS [46].

Local anesthetic agents (1-2% lidocaine) provide immediate symptom relief in acute flare-ups. A RCT compared daily alkalinized lidocaine to placebo for 5 days. A significant proportion of patients in the lidocaine arm showed symptom improvement (30 vs. 24%) [47]. The benefit was substantial on day three but not on day 10.

Intravesical ‘cocktails’ are widely used in clinics, especially for acute flare-ups. Different combinations of steroids, GAGs layer treatments, anesthetic agents, and antibiotics constitute these cocktails. The evidence for their use is limited.

9.4 Vesical procedures

9.4.1 Bladder hydrodistention

Is performed under spinal or general anesthesia. It is assumed to work by disrupting the sensory nerves in the bladder wall [48]. Observational studies report short-term (3-6 months) benefits. Some experts believe repeated distention might result in bladder wall fibrosis and worsening of the symptoms. However, studies have not confirmed this effect.

There is no standard protocol for bladder distention. Distending the bladder with water to a distention pressure of 60-80 cm H₂O for approximately ≤10 min is typical. Side effects include worsening of symptoms in some cases (9%), bladder wall necrosis and rupture. Due to a lack of confirmatory evidence, the European Association of Urology does not recommend bladder hydrodistention.

9.4.2 Treating Hunner lesions

Are treated with fulguration, resection, laser coagulation ± triamcinolone injection. One hundred and three patients who underwent transurethral resection of Hunner lesion reported symptom relief in 89% of cases. Forty per cent of patients did not require further treatment for 3 yrs.; however, the remaining 60% of cases needed repeated treatments (2-4 resections) [49]. The outcomes of resection are like fulguration.

Triamcinolone injection into the lesion improves symptoms in 70-74% of cases. The beneficial effects last for up to 12 months [50]. A systematic review of 13 studies using different procedures reported improvement in symptoms and quality of life; however, recurrence was reported [51].

A study used laser ablation (Neodymium: yttrium aluminum garnet) in 24 patients with Hunner lesions. All study participants reported reduced urgency, pain scores and nocturia [52]. The time between the void increased from 30 minutes to 100 minutes. The disease relapsed in 46% of cases but achieved good results with repeat ablation. Ablation is less invasive than resection or coagulation. Therefore, will cause minmal fibrosis. However, it needs confirmation.

9.5 Miscellaneous therapies

None of the following therapies is approved for IC/BPS; however, benefits are reported in refractory cases. It is essential to inform patients about the side effects. Experienced healthcare providers should administer these therapies.

Botulinum toxin A (BTX-A) injection into detrusor muscles improves IC/BPS symptoms by inhibiting muscle contractions, sensory nerves modulation and anti-inflammatory effects. A randomized controlled trial compared two doses of intra-detrusor BTX-A injection (200 and 100 units) + bladder hydrodistention and hydrodistention alone. BTX-A group reported moderate to a marked improvement in symptoms compared to hydrodistension alone (80 vs. 72 vs. 48% at 3 months). The benefits declined in all the groups at 24 months but more so in the hydrodistention alone group [53]. The 200 units of BTX-A did not add much to the efficacy but was associated with more adverse events. A third of the cases in the 200 units BTX-A group experienced urinary retention. Other studies have reported similar results. The patient should be informed about the possibility of clean intermittent self-catheterization.

Cyclosporine A is a calcineurin inhibitor. It modulates T cells and is an immunosuppressant agent. It is associated with significant toxicity, such as hypertension, nephrotoxicity, increased risk of infections, and malignancy. It is, therefore, reserved for those who failed the less toxic therapeutic options.

Studies show that cyclosporine A is particularly effective in IC/BPS with Hunner lesions compared to non-Hunner lesion phenotypes [54, 55, 56]. A study randomly assigned 64 patients to either cyclosporine A (1.5 mg/Kg BID) or PPS (100 mg TID) for 6 months [32]. Patients in the cyclosporine group showed more remarkable improvement on the symptom scale (75 vs. 19%) and in urinary frequency (−6.7 vs. −2.0 times per day). However, 94% of the patients in the cyclosporine A arm reported side effects.

Sacral neuromodulation (SNM) has shown variable results. SNM targets the sacral or pudendal nerve. Studies have reported preferential improvement in urinary frequency and urgency but not pain. A cross-over RCT prospectively compared sacral to pudendal nerve stimulation in 22 patients with refractory IC/BPS. Each patient used temporary sacral and pudendal nerve modulation separately. More patients opted for pudendal nerve stimulation. At 6 months, 59% of patients with pudendal nerve stimulation reported improved overall symptoms compared to 44% with sacral nerve stimulation [57]. Long-term follow-up data are lacking. It may be helpful in selected patients. Transcutaneous electrical nerve stimulation (TENS) and percutaneous tibial nerve stimulation (PTNS) have shown efficacy in small studies in selected patients.

Long-term use of antibiotics and steroids is not recommended anymore. Furthermore, intravesical instillation of bacillus Calmette-Guerin is no longer advised except in research studies. The efficacy of high-pressure and longer-duration hydrodistention is unpredictable and associated with complications. Therefore, it should not be offered.

9.6 Surgery

Surgery is the last resort option in patients who fail all other therapies but still have significant symptoms. It is associated with considerable morbidity and mortality. Furthermore, every patient may not benefit from surgery. Therefore, patient selection is of utmost importance for achieving the desired outcomes. Limited data suggest that patients with Hunner lesions, small bladder capacity under anesthesia and fibrotic bladder respond to surgery. Those with an extra bladder source of pain are unlikely to benefit from bladder surgery.

The purpose of surgery is to increase bladder capacity or to divert urine from the bladder. The selection of the operative technique depends on the patient and surgeon-specific factors. The options include bladder augmentation cystoplasty, cystoplasty with or without supra-trigone resection, and urinary diversion with or without cystectomy. Each procedure has its unique advantages and complications.

A systematic review of 20 studies reported symptom improvement in 77% of patients after radical surgery. Twenty-three per cent of the patients did not improve. Morbidity and mortality were high (26.5 and 1.3%, respectively) [58].

Figure 6 illustrates treatment algorithm for IC/BPS based on the AUA 2022 guidelines [1].

Figure 6.

Algorithm for managing IC/BPS.

10. Cost of managing IC/BPS

The actual economic burden of IC/BPS on the healthcare system is hard to estimate due to the lack of accurate prevalence. Like other chronic diseases, there are direct and indirect costs. The direct costs include hospital visits, medications, clinical procedures, follow-up, and hospital admission. The average annual cost of managing IC/BPS is higher than the average yearly cost for asthma, depression, diabetes mellitus and hypertension. A study from the United States reported an annual direct cost of $3631 per patient [59].

IC/BPS affects individuals during the most productive period of life. Time away from work and loss of productivity are critical indirect costs that are difficult to calculate but considerable.

The average management cost is higher in women than in men. The extent of indirect costs is proportional to the severity of IC/BPS. The mean annual costs from lost wages in the United States were $4216 per patient. Psychological costs, e.g., emotional distress, social isolation, depression, low QoL, and educational and career unpursued activities, are even more difficult to calculate.

11. Drug development and future perspective

The quest for effective therapeutics is ongoing; however, it is slow due to a poor understanding of the IC/BPS pathophysiology. Cannabinoids have anti-inflammatory and analgesic properties and have a role in chronic pain syndromes. The use of cannabinoids in mice cystitis models demonstrated a reduction in pain. Case reports in humans using cannabinoids showed encouraging data.

Tanezumab is a nerve growth factor blocker. It has shown promising results in a small human trial but was associated with toxicity.

Phosphodiesterase-5 inhibitor is a mast cell stabilizer and smooth muscle relaxant. Sildenafil showed improvement in symptoms and urodynamic studies at 3 months.

Roslptor is an inositol-5-phosphatase 1 (SHIP1) activator which modulates the immune system via phosphoinositide signaling. Patients with moderate to severe IC/BPS experienced an improvement in pain and urinary frequency in phase II trials. Unfortunately, favorable effects were lacking in phase III trials.

Hyperbaric oxygen therapy is used in the management of radiation cystitis. It also showed promising results in IC/BPS.

In preclinical work, extracorporeal shock wave therapy (ESWT) improved pain and inflammation. A small, randomized trial of ESWT in IC/BPS showed improvement in the O’Leary-Sant symptoms index and VAS pain score.

Enhanced drug delivery systems deliver the therapeutics to the target area. Using reverse thermal gelation hydrogel has made it possible to use BTX-A without anesthesia. The drug is instilled into the bladder in liquid form. It solidifies in the bladder and releases BTX-A slowly.

Lidocaine releasing intravesical system releases lidocaine over 2 weeks. A pilot study in IC/BPS population reported encouraging results.

Liposomes are biocompatible drug carriers composed of sphingomyelin and phospholipids. Sphingomyelins are part of the cell membrane. A cohort study using intravesical empty liposomes reported improved pain and overall symptoms with no side effects. Liposomes as BTX-A carrier as an alternative to injection therapy was not advantageous.

The promising results of some of these novel experimental therapeutics and drug delivery technologies warrant examination in larger RCTs.

Future research should consider subgroup analysis as a priori or post hoc analysis to assess treatment responses. A urinary or blood biomarker that could diagnose and monitor the treatment effect will be paramount. A prospective registry of IC/BPS patients will provide an excellent platform for understanding the natural history of the disease, risk factors, and the effect of treatments.

12. Conclusions

IC/BPS is a complex chronic condition. The affected patients have a poor quality of life. No test is available to diagnose IC/BPS. It is, therefore, a diagnosis of exclusion. An exception is IC/BPS with Hunner lesion, where cystoscopy is diagnostic. The diagnosis is delayed due to the diagnostic approach. Sometimes it may co-exist with other chronic pain syndromes, which masks the diagnosis. Our understanding of IC/BPS has increased in the last couple of decades. It is now perceived as a chronic pain syndrome.

The treatment paradigm has shifted from bladder-centric therapies to ameliorating symptoms and enhancing the quality of life. Research shows that some therapies are more effective in specific phenotypes. Treatment effects are variable therefore, should be tailored according to the individual patient’s needs and resposnse. Complex IC/BPS cases may require a multidisciplinary team approach. There is an unmet medical need for new biomarkers and novel therapeutics.

Acknowledgments

I am thankful to my parents, wife, and children, who supported me during the completion of this chapter. I am also grateful to my supervisor Ida Ryland, who encouraged me to continue my academic work despite the busy clinical work.

No funding was received for this work.

Conflict of interest

The authors declare no conflict of interest.

Notes/thanks/other declarations

I would like to thank one of my IC/BPS patients. She consistently and accurately updated me about her symptoms which assisted me in reaching the diagnosis. Her case was a source of inspiration for researching IC/BPS and writing this chapter.

Appendices and nomenclature

AUA

American Urology Association

BTX-A

botulinum toxin A

CS

chondroitin sulfate

DMSO

dimethyl sulfoxide

ESWT

extracorporeal shock wave therapy

FDA

food and drug administration

FM

fibromyalgia

GAGs

glycosaminoglycans

GUPI

genitourinary pain index

HA

hyaluronic acid

IC/BPS

interstitial cystitis/ Bladder pain syndrome

MAPP

multidisciplinary approach to pelvic pain

MRI

magnetic resonance imaging

NSAIDs

non-steroidal anti-inflammatory drugs

PPS

pentosan polysulphate sodium

PST

potassium sensitivity test

PTNS

percutaneous tibial nerve stimulation

QoL

quality of life

RCT

randomized controlled trial

SNM

sacral neuromodulation

TENS

transcutaneous electrical nerve stimulation

UTI

urinary tract infection

VAS

visual analogue scale

WICI

The University of Wisconsin interstitial cystitis inventory