Continuing Education Activity

Interstitial cystitis/bladder pain syndrome is a chronic, non-infectious, inflammatory condition of poorly understood etiology that affects the urinary bladder. It is often a difficult condition to manage, with a variable response. It has a profound impact on the psychological and social well-being of the patient if symptoms are inadequately treated. This activity explains the approach, investigation, and management of interstitial cystitis and highlights the role of the interprofessional team in evaluating and treating interstitial cystitis.

Objectives:

• Describe the etiology of interstitial cystitis.
• Outline the management of patients with interstitial cystitis.
• Explain the prognosis of interstitial cystitis.
• Summarize how an interprofessional team can coordinate the care of interstitial cystitis to provide the best outcomes.

Introduction

Interstitial cystitis/bladder pain syndrome (IC/BPS), formerly called interstitial cystitis, is a chronic (>six weeks duration) pelvic condition that affects or appears to affect the urinary bladder, characterized by chronic inflammation and lower urinary tract symptoms not due to infection or any other identifiable cause.[1] Incontinence is not a typical symptom of the disorder. In many cases, because it remains a diagnosis of exclusion, the condition is often diagnosed late or misdiagnosed, particularly in men, as chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).

Patients often describe pain in the bladder region (suprapubic), with a strong sensation to want to urinate (urgency). This sensation is worsened by filling the bladder and is often relieved by passing urine more often (frequency). This may be during the daytime and/or during the night (nocturia). There may also be other symptoms such as pain or burning when passing urine (dysuria) and discomfort during sexual intercourse, known as dyspareunia. These chronic symptoms have a profound impact on the emotional, psychological, and social well-being of the patient as well as their quality of life.[2]

Anatomy

The urinary bladder is a hollow viscus located in the pelvis which is anterior to the rectum in both sexes and the uterus in females. It is partially covered by the peritoneum on the superior surface. It is composed of four layers.[3]

• Mucosa, which contains the transitional epithelium, is the bladder lining and allows for the stretch of the urinary bladder. When stretched, the surface is smooth, but when relaxed, folds form in the mucosa, known as rugae. It also produces the glycosaminoglycans superficial coating that protects the mucosa from direct contact with potentially inflammatory urinary irritants.
• Submucosa, which is composed of elastic connective tissue, further assists with the stretch of the bladder.
• The muscularis layer (detrusor muscle) is composed of several layers  (inner longitudinal, middle circular, and outer longitudinal) of smooth muscle in multiple directions, which assists with the voiding of the bladder when contraction occurs. They also form a small band that encircles the area between the opening of the bladder and the urethra. This is known as the internal urinary sphincter and is controlled by the autonomic nervous system. Another distal band around the urethra controls conscious voiding, called the external sphincter, which is composed of skeletal muscle and innervated by the somatic nervous system.
• The fibrous connective tissue layer is the outermost covering of the bladder except for the superior surface, with is covered by the parietal peritoneum.

The bladder floor also contains a fixed, triangular area called the trigone. This is formed by the openings to each ureter and the outlet to the urethra. This forms three apices with a ureteral orifice in each lateral wing and the third arm entering the urethra.[4] The trigone is located at the posterior base, also known as the fundus of the urinary bladder.[5]

The distal intramural portion of each ureter follows a shallow course as they travel through the detrusor muscle into the bladder. This anatomy acts as an anti-reflux valve to prevent reflux of urine into the kidney. 

Etiology

The etiology of interstitial cystitis is not well understood, and the current thoughts around its pathogenesis remain multifactorial. Leading concepts include: [6][7][8][9]

• Autoimmune or immune-mediated processes
• Fibrosis
• Increase in grey matter volume leading to heightened pain sensitivity
• Mast cell dysfunction or hyperactivation
• Neurogenic inflammation/edema
• Pelvic floor hypertonicity or dysfunction
• Upregulation and proliferation of sensory afferent fibers
• Urothelial dysfunction, especially in the epithelial and glycosaminoglycans (GAG) layer
• Vascular malformations that are seen as glomerulations on cystoscopy.

Current research strongly suggests an underlying inflammatory process, although the precise cause for this is not well understood.[10] 

In a recent study, they describe an organic process behind interstitial cystitis. Through cystoscopy, they observed submucosal inflammation, which is seen as glomerulations, with large groups of mast cells, which further stimulates afferent sensory fibers. They also describe increased urothelial permeability due to diminished glycosaminoglycans (GAG) levels and ultrastructural abnormalities seen on biopsies that show loss of tight junctions and adhesive junction proteins. This results in a loss of mucosal barrier protection and results in a "leaky urothelium." This is also thought to be the reason why immunoglobulin and immune mediators are detected at higher levels in the urine of affected individuals.[10][11][12]

Fibrosis also results from the chronic inflammatory process, evident by the upregulation of extracellular matrix proteins, increased myofibroblasts, and decreased capillary density, which reduce bladder capacity and leads to further stretching and stimulation of afferent sensory pain fibers.[13]

Another multi-center study has demonstrated a non-organic process behind interstitial cystitis, demonstrating increased grey matter volume in some patients with interstitial cystitis in brain regions that are responsible for pain perception. This was observed using functional magnetic resonance imaging (fMRI).[14][15]

An interesting relationship to discuss is between severe interstitial cystitis-like symptoms to the use of illegally sourced ketamine. With this, the etiology remains unknown as well. The main theories behind this are urothelial damage, microvascular changes, autoimmunity, and infection either by ketamine or through metabolites. The symptoms, cystoscopy, and biopsy findings have a great degree of crossover with interstitial cystitis, and the main difference would be the recreational abuse of ketamine. The risk of developing ketamine cystitis does not appear to be increased with the proper medical use of the drug.[16]

Epidemiology

Due to the nature of interstitial cystitis, it is very difficult to formulate a clear diagnosis easily, and there exists no screening tool for it. Hence, the data surrounding its prevalence remains limited. However, some studies have looked into the epidemiology of interstitial cystitis. There are two main study designs, one based on physician/urologist-based diagnosis and the other by a questionnaire around symptomatology. Based on a large population, questionnaire-based prevalence study in the US, 2.7% of women meet the specified criteria, with 1.9% of men meeting the criteria.[17][18] In terms of age groups, women between 50-59 and men between 56 to 74 years of age.

However, a lower prevalence is seen when physician-completed questionnaires and histological samples were employed to establish a diagnosis. A study in the Netherlands quoted as low as between 8-16 out of 100,000 individuals.[19] Investigations have noted a female predisposition, with one study in the US quoting a 5 to 1 ratio.[20]

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic bladder disorder with an estimated US prevalence of 3–8 million women and 1–4 million men.[21] The number of men affected is probably underestimated as many men are probably misdiagnosed as having chronic prostatitis.[22][23][24][25][26]

It is estimated that it affects up to 400,000 patients in the UK, with almost 90% of the patients being women between 50 and 69 years of age.[27]

The data for children affected by interstitial cystitis is poor, but the consensus opinion is that the prevalence is very low in the pediatric population.

Pathophysiology

IC pathophysiology [10]

Biomarkers [6][10]

Interstitial cystitis/bladder pain syndrome can appear as two different entities. The interstitial cystitis aspect clearly demonstrates an inflammatory component that is mostly missing in those with bladder pain syndrome. [28] 

The underlying pathophysiology of IC/BPS is somewhat uncertain, contributing to the lack of a definitive, curative remedy.[10] Known involved bladder pathological findings include chronic inflammation, which causes afferent sensory hyperactivity, nociceptor upregulation, mast cell overactivity, and urothelial thinning with a deficient or dysfunctional superficial mucosal glycosaminoglycans layer.[8][10][11][29]

Other findings associated with chronic bladder inflammation include decreased mucosal protection from glycosaminoglycans dysfunction, lower adhesive protein E-cadherin, decreased basal cell growth, defective umbrella cell integrity, abnormal apical cell maturation, and increased urothelial cell apoptosis.[11][29][30] The increased serum levels of C-reactive protein and pro-inflammatory cytokines also point to inflammation as a primary underlying etiology of IC/BPS.[11][12] Tumor necrosis factor-α (TNF-α) and nerve growth factor (NGF) are also increased in IC/BPS patients.[31]

Interstitial cystitis/bladder pain syndrome patients are much more likely than the general population to have systemic lupus erythematosus.[32][33] There is also a close association with Hashimoto's thyroiditis, rheumatoid arthritis, ankylosing spondylitis, and especially Sjogren syndrome.[33][34][35] This suggests an autoimmune component, possibly an auto-antibody to M3 receptors in the bladder, may be a factor.[33]

Chronic stress is found more than 50% of IC/BPS patients and is a factor in the development and exacerbation of symptoms.[28][36][37][38][39]

Pathophysiology of Interstitial cystitis Birder   [28] 

Broader Horizons in Interstitial Cystitis   [40]

Histopathology

Bladder Pain Syndrome [41]

AUA Guidelines [1]

 [42]  Efficacy of botox

[43] Hunner ulcer in women

Pathophysiology of Interstitial cystitis Birder   [28] 

Broader Horizons in Interstitial Cystitis   [40]

Toxicokinetics

Tibial nerve stimulation has also shown a benefit in treating IC/BPS and should be considered for a clinical trial of therapy before going on to more invasive treatments.[44][45][44]

History and Physical

Symptoms need to be at least six weeks with negative urine cultures with no acceptable explanation or alternative diagnosis.[1] Typical symptoms involve urinary frequency, nocturia, and suprapubic pain, which tends to persist even after voiding. There may be urgency, nocturia, or dysuria but usually no incontinence.[1] IC/BPS pain is usually suprapubic but may also be perineal. The discomfort is typically not relieved by voiding.

A baseline record of the patient's symptoms is useful to compare the efficacy of treatment. This may be in the form of a recommended pain scale index, a visual chart, or a patient-recorded 24-hour voiding diary.[1]

Pain can be evaluated and recorded by using the interstitial cystitis symptoms index (ICSI), a visual analog chart, or the genitourinary pain index (GUPI).[46][47]

Voided volumes and a 24-hour timed voiding diary document the degree and severity of the patient's urinary frequency symptoms.[48][49][50]

IC/BPS should be considered in patients originally diagnosed with overactive bladder who do not improve on standard therapy.

Unusually high voided volumes or infrequent voiding would suggest an alternative diagnosis.[1]

Urinary and related symptoms to record and document would include: [1] 

• Number of voids per day
• Episodes of incontinence
• Episodes of urgency
• Hematuria
• Details and characteristics of pain:
  • Character
  • Duration
  • Dyspareunia (present or not) in women
  • Dysuria present or not
  • Ejaculatory dysfunction or pain (present or not) in men
  • Location
  • Pain relieved by voiding (yes or no)
  • Presence of pressure or urge to void
  • Relationship of pain to menstruation, food, or any other activity
  • Severity (as well as any concomitant dysuria) should be recorded for at least a 24-hour period
  • Time
  • Unexplained fevers
  • Vulvar pain

All patients suspected of having IC/BPS should have a neurological examination performed, including tone, reflexes, power, sensation, and cranial nerve testing.[1] A post-void residual urine volume determination should be done.[1][48]

A detailed gynecological history with a pelvic examination should be performed in all female patients suspected of IC/BPS.[1]  Careful attention should be paid to cervical tenderness, masses, prolapse, and any abnormalities found on adnexal palpation.

An appropriate hematuria evaluation should be performed in patients with unexplained or previously unevaluated urinary blood, and considered in patients with symptoms of IC/BPS who also have a significant (10 pack-years or more) smoking history.[1][51]

A detailed history and careful examination are needed to exclude other causes, as there is considerable overlap between IC/BPS and other conditions.[1][2]

Interstitial Cystitis/Bladder Pain Syndrome and Chronic Prostatitis/Chronic Pelvic Pain Syndrome 

Many experts believe that chronic prostatitis in men may often be misdiagnosed as interstitial cystitis, which may actually be the more common disorder even in males.[22][23][24][25][26] The primary differences are the lack of the urinary antiproliferative factor and no histological bladder pathology in chronic prostatitis.[23][52] The two conditions have many similarities as both demonstrate the following:[22][23][25][26][53][54]

• Associated with psychosocial depression.
• Characterized by chronic pelvic pain and urinary symptoms, usually urgency and frequency but not incontinence.
• Diagnosis is primarily by exclusion.
• Dietary changes often have a significant impact on the disorder.
• Negative urine cultures.
• Oral medications can offer symptomatic relief.
• Pelvic floor dysfunction.
• Physical therapy offers relief to the majority of patients.
• Sensitivity to intravesical potassium instillation.
• Symptoms are aggravated by the same foods.
• Symptoms may last for years.

Men with interstitial cystitis/bladder pain syndrome or chronic prostatitis/chronic pelvic pain syndrome tend to have a higher incidence of erectile and ejaculatory dysfunction than normal males and were more likely to be associated with depression, pain, and stress.[55] Over seventy percent of men with interstitial cystitis/bladder pain syndrome report sexual dysfunction.[56]

Patients with IC/BPS who have not responded to standard therapy might actually have chronic prostatitis/chronic pelvic pain syndrome, and consideration should be given to a change in therapy. Likewise, patients with chronic prostatitis who have not responded to conservative treatment should be evaluated for possible IC/BPS.

Pudendal neuralgia can mimic IC/BPS in many ways. Common symptoms include chronic pelvic pain, sexual dysfunction, discomfort with sexual activity, and urinary dysfunction. Pudendal neuralgia patients often have very tight, dysfunctional pelvic floor musculature, but so can patients with IC/BPS.[57]

Patients with pudendal neuralgia tend to describe the pain as more intense and having a "burning" or "electrical shock" feeling to it.[57] The pain is very much associated with sitting, bending, or squatting and is generally unrelated to bladder fullness or diet.[57] They also tend not to have the degree of urinary frequency and urgency associated with IC/BPS.[57] If in doubt, pudendal nerve blocks can be both diagnostic and potentially therapeutic, particularly in patients unresponsive to standard therapies for IC/BPS where pudendal neuralgia might be possible.[57]

Evaluation

The workup should include laboratory examinations and procedures to identify any other disorders that can produce symptoms similar to interstitial cystitis. This typically includes standard blood tests (CBC, CMP, glucose, HbA1c), urinalyses (microscopic) and urine cultures, and appropriate sexual health screening, including testing for STIs as appropriate. 

Urine cultures in patients with negative urinalysis are suggested to identify low or borderline bacteria levels that may still be clinically significant but escape detection on standard examinations.[1]

Neither cystoscopy nor urodynamics is required for a diagnosis of IC/BPS. Neither is diagnostic, but they may be appropriate if the diagnosis is in doubt.[1]

Cystoscopy is appropriate if there is a suspicion of bladder cancer, intravesical foreign bodies, outlet obstruction, strictures, or vesical calculi. There are no specific cystoscopic findings diagnostic of IC/BPS other than a Hunner ulcer which is more commonly found in patients over age 50 in whom a cystoscopy may therefore be justified.[1][58] Patients who fail conventional therapy may also be candidates for a cystoscopy, especially if they have not previously had the procedure, but the examination is generally discouraged in younger patients where Hunner ulcers are far less common, and it is likely to cause more complications as well as unwanted side effects.[1] 

Patients with Hunner ulcers generally respond well to treatment. Standard therapy of a Hunner ulcer includes immediate fulguration of the lesion and/or an injection of triamcinolone.[1] If this fails, oral cyclosporine A is recommended.[1][59] Since the odds of identifying Hunner lesions are markedly reduced in patients younger than 50, routine cystoscopic examinations are not recommended or suggested for patients with IC/BPS symptoms in this age group.[1] 

Cystoscopy primarily rules out malignancy, strictures, and bladder outlet obstruction.

• The appearance of lesions is very similar to malignancy, particularly carcinoma-in-situ.

• The bladder walls may show scarring or petechial hemorrhages known as glomerulations, but these are considered non-specific.

• During visualization of the distended bladder, there may be Hunner's ulcers, which are often described as a pale central scar with or without a fibrin clot and surrounded by erythematous mucosa, with small vessels radiating towards the center.

• Hunner's ulcers are considered diagnostic for interstitial cystitis, but they are uncommon and may only be present in 5% to 10% of cases.[60]

• Reactive hemorrhages are also a sign of interstitial cystitis. (This is when the mucosa appears normal (distended) on an initial examination under cystoscopy, but when deflated and re-inspected, points of capillary bleeding are noted on a background of normal mucosa.[61]

• Further investigations may also be performed during a cystoscopy, such as hydrodistention, lidocaine or intravesical cocktail instillation, or a biopsy.

Urodynamics can be helpful when patients are refractory to standard medical treatments, or there is evidence of bladder outlet obstruction, detrusor hypotonicity, neurogenic bladder, or other conditions that might otherwise explain the patient's symptoms.[1] There are no specific urodynamic findings that are diagnostic of IC/BPS, although a small maximum bladder capacity (<300 mL) is frequently found, and therefore urodynamic studies are not recommended in routine cases.[1] 

Treatment / Management

Before commencing treatment, the American Urological Association (AUA)Guidelines recommend educating the patient about the disease's complex nature and the need for multimodal therapy, as patient education about interstitial cystitis/bladder pain syndrome is a critical part of the treatment plan.[1] An individualized approach, including shared decision-making for every patient, is suggested.[1]

For the majority of patients, no single treatment exists to cure the condition or permanently relieve the symptoms. Patients should also be aware that multiple treatment options in combination may be needed for optimal symptom control and that the condition is chronic, often with periodic exacerbations and remissions.[1]

As the underlying pathophysiology is still largely unknown, treatment is based on the management of the symptoms.

Treatment should be evaluated periodically, and therapies that are ineffective should be discarded. If simple pain management techniques are not adequate, additional therapy should be used, and consideration given to a pain management consultation as a multidisciplinary approach is recommended. Failure of multiple modalities of therapy suggests a possible misdiagnosis.

Conservative Measures

Initial treatment for IC/BPS should be based on dietary and lifestyle modifications. The determination of specific dietary adjustments is based on known common irritants. Elimination diets are used to identify additional exacerbating dietary factors. The final recommended diet should be individualized, with a diary to record which foods, beverages, additives, or substances cause symptoms to flare.

Generally, a number of common foods are known to irritate sensitive bladders, cause pain, and exacerbate urinary symptoms. A complete list can be found at the website for the Interstitial Cystitis Association at  www.ichelp.org.The prevailing theory is many foods contain substances or chemicals that are inherently irritating to the bladder, such as a high acid content, potassium, or capsaicin. Indian, Mexican, and Thai food is not recommended. Specific foods known to cause bladder irritation include: [1]

• Alcohol
• Benzyl alcohol
• Caffeine
• Carbonated beverages
• Coffee
• Chili
• Chocolate
• Citric acid
• Citrus
• Cranberry juice
• Horseradish
• Hot peppers
• "Hot" sauces such as Tabasco
• Ketchup
• Pickles
• Pizza
• MSG
• Sauerkraut
• Spices
• Sweeteners (particularly artificial sweeteners such as saccharin)
• Tea
• Tomato juice
• Tomato sauce
• Tomatoes
• Vinegar
• Worcester sauce

Myofascial release and pelvic floor trigger point manual therapy provided by a skilled practitioner has shown significant symptom relief in 70% of patients.[62][63] Standard pelvic floor strengthening treatments, such as Kegel exercises, may cause IC/BPS symptoms to worsen and are not recommended.[62] 

Specific behaviors and activities that can help mitigate symptoms include: [1]

• Avoidance of known dietary irritants (see list above).
• Bladder training with urge suppression.
• Cognitive-behavioral therapy.
• Dietary aids for bladder discomfort (calcium glycerophosphates, nutraceuticals, phenazopyridine).
• Increasing fluid intake to minimize urinary concentration.
• Manual physical therapy for pelvic floor tenderness to relieve tender muscle points, contracture lengthening, and/or scars.
• Meditation and imagery techniques for pain management.
• Neuromodulation (can help urinary frequency/urgency but is not effective for pain control).
• Pelvic floor muscle relaxation training.
• Stress management and reduction techniques.
• Support groups.
• Transcutaneous electrical nerve stimulation (TENS).
• Use of elimination diets to help determine which additional specific foods should be avoided.
• Use of heat or cold to bladder and/or perineum for symptomatic relief.
• Avoidance of behaviors and activities that are known to exacerbate bladder irritability, such as:
  • Pelvic floor muscle strengthening exercises (Kegel's)
  • Prolonged or untreated constipation
  • Sexual intercourse
  • Tight clothing

Pain Management

Most patients do not respond to a single agent, and a complex multidisciplinary option with expert guidance under a pain specialist or clinic should be sought. Treatment should be introduced slowly, with the lowest possible dose and a minimal number of drugs used as possible, in line with the WHO pain ladder. Non-opioid treatments are much preferred over opioid therapy.[64]

• Acetaminophen
• Amitriptyline
• Gabapentin
• Hot sitz baths
• Intravesical "cocktail" therapy
• Meditation and imagery
• NSAIDs (ibuprofen, naproxen)
• Opioids
• Pregabalin
• Stress reduction
• Transcutaneous electrical nerve stimulation (TENS)
• Trigger point manual therapy

Pharmacological Therapy

Oral therapy has been used with moderate success for IC/BPS. Oral overactive bladder (OAB) medications, such as oxybutynin, have minimal efficacy in controlling the symptoms from IC/BPS, except possibly for some decrease in urinary frequency. Overactive bladder patients who fail to improve on OAB medications should be evaluated for possible IC/BPS.

The most effective oral agents for treating IC/BPS appear to be amitriptyline, cyclosporine A, and pentosan polysulfate.[65][66]

Amitriptyline is a tricyclic antidepressant that has shown activity in reducing chronic pelvic pain, including discomfort from IC/BPS.[67][68] Side effects (drowsiness, nausea, sedation) tend to limit its usefulness.[68][69] Low-dose (10 mg) amitriptyline in combination with intravesical instillation therapy has been shown to be very effective, especially in improving the emotional status of patients with IC/BPS.[70] Standard dosing starts at 10 mg daily and gradually increases to a maximum of 100 mg as tolerated.[1][68]

Cimetidine is an H2 blocker normally used for reducing gastric acid secretion, but it has also shown activity in reducing pain, frequency, and nocturia in about 60% to 70% of IC/BPS patients.[71][72][73][74] The mechanism for this is unclear and occurs regardless of the presence or absence of increased mast cells in the bladder tissue.[71][72][73][74] No significant side effects are reported with its use, and it is very cost-effective as it is not only generic but available without a prescription.[71][72]

Cyclosporine A, an immunosuppressive that blocks cell-mediated immune reactions, has shown superior efficacy compared to pentosan polysulfate, particularly in patients with Hunner ulcers who do not respond to triamcinolone injections or electrofulguration.[59][75][76] A response rate of 84% has been reported in IC/BPS patients with Hunner ulcers treated with cyclosporine A.[66] For this reason, it's been suggested that it be considered for use in otherwise intractable cases.[75]

While cyclosporine A has shown good efficacy in controlling pelvic and bladder symptoms, it has only been used in relatively small numbers of IC/BPS patients. There are serious potential complications with regard to increased blood pressure, neurotoxicity, immunosuppression, and decreased renal function.[1][77] For this reason, it's been suggested that it be used only by those familiar with this therapy and in patients with Hunner ulcers who fail more conservative treatment.

Experimentally, low-dose (1.5 mg/kg or less) cyclosporine A daily therapy has shown efficacy in providing long-term symptom relief when used immediately after Hunner ulcer fulguration. The lower dose limits side effects. Further studies are necessary until this approach's long-term safety and efficacy have been conclusively determined.[78]

Gabapentin has shown some activity in reducing pain and other symptoms of IC/BPS.[79][80][81][82] Gabapentin was originally approved as an anti-epileptic but has since found a role in managing various types of neuropathic pain. Dosage starts at 300 mg TID, which is then slowly titrated up to a maximum of 1,200 mg TID.[83]

Hydroxyzine is an antihistamine and mast cell stabilizer that has shown effectiveness in providing significant symptom relief in some IC/BPS patients.[84] Those IC/BPS patients with allergies may be the most likely to benefit from this treatment.[84]  Hydroxyzine prevents the degranulation of mast cells, reducing the release of toxic agents that would otherwise cause inflammation and IC/BPS symptoms in some patients.[85] The degranulation of mast cells causes the release of neuroactive and vasoactive agents and is believed to be responsible for the symptoms of IC/BPS, at least in some patients.[85] Side effects tend to be minor and include mild sedation and weakness. The dosage is usually 50 mg to 100 mg QID.

Overactive bladder (OAB) medications (oxybutynin, mirabegron, etc.) are usually insufficient when used alone in managing the symptoms of IC/BPS. These medications may be of some benefit in reducing symptoms of bladder overactivity, but they do not help with pain where a multimodal approach is usually needed.[86][87] Patients with overactive bladder symptoms who fail standard medications should be considered for possible IC/BPS.

Pentosan polysulfate is the only FDA-approved oral medication approved for IC/BPS.[1] It acts by restoring a protective layer over the bladder mucosal lining. Studies on its efficacy are conflicting; some show a benefit while others do not.[84][88][89][90][91][92] It may take up to five or six months or longer for maximum symptomatic relief.[93][94]

A worrisome retinal pigmentary maculopathy has now been clearly associated with the long-term, cumulative use of pentosan polysulfate.[95][96][97][98][99] Symptoms include blurred vision, delays in adjusting to low-light situations, and difficulty reading.[94][95][96][97][100] Patients should be warned about these effects, that they are related to the total cumulative amount of therapy, and that the visual damage does not appear to be reversible.[1][94][100] 

For those who choose to use the medication, a retinal examination prior to initiating treatment is recommended, as well as a recheck at 6 months and periodically thereafter.[1][94] Recent evidence suggests that the retinal macular damage may continue even after cessation of the pentosan polysulfate, and the damage is irreversible.[100][101] This new data is very worrisome and makes pentosan polysulfate a far less attractive therapy as an oral agent.[101] For these reasons, pentosan polysulfate is now being used very infrequently for IC/BPS.

Sacral neuromodulation has been shown in the majority of studies to be a reasonably effective treatment for control of intractable bladder overactivity and chronic pelvic pain.[102][103] It is FDA-approved only for bladder overactivity and frequency, where it seems to be more effective compared to pain control in IC/BPS.[1][102][104] Tibial nerve stimulation has also shown a benefit in treating IC/BPS.[44][45] A clinical trial of sacral neuromodulation or tibial nerve stimulation can be reasonably considered in selected patients who have failed other treatments.[1][44][45][102][104][105]

• Analgesics, e.g.: paracetamol and ibuprofen.
• Antihistamines (cimetidine)
• Antidepressants (amitriptyline)
• Pentosan-polysulfate
• Oxybutynin and gabapentin

Intravesical Instillations

A variety of medications have been found to be effective in IC/BPS when oral medications and dietary measures alone are insufficient.[106] No optimal or ideal cocktail has yet been agreed upon. The most commonly used ingredients include the following:

Dimethylsulfoxide (DMSO) is an effective agent for symptom control when used as an intravesical instillation in patients with IC/BPS.[107][108][109][110] It acts as an anti-inflammatory and a topical anesthetic which is rapidly absorbed into the bladder mucosa and detrusor. It is a carrier meaning that it enhances the absorption of other agents with which it may be combined. This should be taken into account when putting together a cocktail "recipe" to avoid potential toxicity. It is often mixed with bupivacaine, heparin, hydrocortisone, lidocaine, sodium bicarbonate, and/or triamcinolone.[1] 

Bladder instillations of dimethylsulfoxide plus triamcinolone were found to be superior in symptom relief by about 50% to a cocktail of bupivacaine, heparin, and triamcinolone in newly diagnosed women with IC/BPS.[108] DMSO becomes painful if held in the bladder longer than about twenty minutes. The typical dose is 50 mL of a 50% DMSO solution.

Heparin acts as a synthetic glycosaminoglycans layer to help protect the bladder mucosa from urinary irritants when used for intravesical therapy in IC/BPS patients.[111] Initial studies with heparin used only 10,000 IU three times a week for three months and reported significant improvement in 56% of patients.[111] Heparin has been shown to be more effective than lidocaine alone for relieving symptoms when mixed with lidocaine.[112][113] The typical dose is 10,000 IU to 20,000 IU, but dosages up to 50,000 IU have been used as the optimal dose has not been determined.[114] Most intravesical instillation cocktails include heparin.[114]

Lidocaine is a local anesthetic that has demonstrated usefulness in reducing short-term (< two weeks) bladder pain and symptoms when used for intravesical therapy.  Lidocaine reduces histamine release from mast cells, exerts an anti-inflammatory effect on eosinophils, decreases leukocyte adherence, and is bactericidal.[115] Alkalinization with sodium bicarbonate improves bladder tissue penetration, but this can also potentially lead to toxicity.[112][113] A typical intravesical dose would be 25 mL to 50 mL of a lidocaine 2% solution. Bupivacaine (a longer-acting lidocaine analog) 0.5% is usually dosed at 10 mL to 20 mL. Sodium bicarbonate (alkalinizer) is usually given as an 8.4% solution in volumes of 5 to 10 mL up to 50 mL.

Hyaluronic acid alone or with chondroitin sulfate has shown efficacy in treating IC/BPS.[116][117] Both of these chemicals are decreased in bladders that are chronically inflamed. There is no standard dosing schedule or good data on this medication, but the most recent review used 40 mg starting at several treatments a week and then extending the time interval based on the response. The review was conducted by the Spanish Association of Urology, through the Functional, Female, and Urodynamic Urology Group, which found the dosage and schedule to be safe and effective.[116]  A study from Taiwan used a schedule of four weekly intravesical treatments followed by monthly therapy for five months. They reported improved urinary symptoms in 73% of patients.[118]

Bladder Cocktail Formulas for Intravesical Instillation

Alkalinized Lidocaine Cocktail

• Gentamicin 80 mg in 5 mL
• Heparin 10,000 IU in 10 mL
• Lidocaine 2% solution: 25 mL
• Sodium Bicarbonate 8.4%: 5 to 10 mL
• Schedule: 
  • Weekly as needed in office/clinic.
  • Should be mixed immediately before intravesical instillation to avoid precipitation.
  • Increase the interval between instillations as symptoms improve.

DMSO (Dimethylsulfoxide) Cocktail

• Gentamicin 80 mg in 5 mL
• Heparin 10,000 to 20,000 IU
• Rimso-50 (DMSO) 50 mL
• Sodium Bicarbonate 8.4%: 10 mL
• Triamcinolone 40 mg
• Schedule:
  • Weekly as needed in the office/clinic.
  • Increase the interval between instillations as symptoms improve.

Robert Moldwin, MD—Smith Institute for Urology & Long Island Jewish Medical Center

• Bupivacaine (Marcaine) 0.5% and Lidocaine jelly 2% in a 1:1 mixture: Total of 30 to 40 mL.
• Heparin 10,000 to 20,000 IU
• Gentamicin 80 mg
• Triamcinolone 40 mg (Increase to 80 mg in patients with documented Hunner’s ulcer.)
• Schedule:
  • Weekly instillations in the office/clinic.
  • May also be self-administered by patients at home up to three times weekly.
  • Increase the interval between instillations as symptoms improve.
  • Maximum symptom improvement is expected by twelve weeks.
  • If no longer effective, switch to “DMSO Cocktail.” May resume the above bupivacaine combination cocktail later if symptoms return.

Christopher Payne, MD “Payne Cocktail 1”

• Bupivacaine (Marcaine) 0.5%: 10 mL
• Heparin 10,000 IU
• Schedule:
  • Weekly instillations in the office/clinic.
  • May also be self-administered by patients at home as often as daily.
  • Increase the interval between instillations as symptoms improve.

Christopher Payne, MD “Payne Cocktail 2”

• Bupivacaine (Marcaine) 0.5%: 10 mL
• Heparin 10,000 IU (Optional. May be reserved as separate instillation treatment.)
• Hydrocortisone (Solu-Cortef) 100 mg
• Rimso-50 (DMSO): 50 mL
• Sodium Bicarbonate 8.4%: 5 mL
• Schedule:
  • Weekly instillations of 30 to 50 mL for six to eight weeks.
  • Increase the interval between instillations as symptoms improve.
  • Use B&O suppositories if patients are unable to hold the solution for at least 30 minutes.

Kristene Whitmore, MD—Drexel University College of Medicine

• Bupivacaine (Marcaine) 0.5%: 20 mL
• Gentamicin 80 mg: 5 mL of Normal Saline. (Add for patients with a documented UTI within three months.)
• Heparin 10,000 IU in 10 mL
• Hydrocortisone 100 mg: 5 mL of Normal Saline
• Sodium Bicarbonate 8.4%: 40 to 50 mL
• Schedule:
  • Six weekly instillations. Should be administered during a premenstrual flare when possible.
  • Appropriate for patients who are able to self-catheterize and administer at home.

Trials are looking at improved efficacy of intravesical preparations when a low voltage is applied to drive the preparations into the bladder tissue. This is achieved by using probes in the bladder and abdomen to create a voltage gradient known as electromotive drug administration (EMDA). A randomized prospective trial demonstrated improved short-term efficacy. The main issue with the study is the low sample size (n=31).[119]

Cystoscopy Guided Treatment

• Cystoscopy is done to rule out other diagnoses and to look for Hunner ulcers.
• If Hunner lesions are present, they can be treated using direct fulguration with electrocautery or laser, and/or injection of triamcinolone.
• If no Hunner ulcers are found at cystoscopy, short-duration, low-pressure hydrodistension under anesthesia distension can be performed. This offers substantial pain relief to some patients but risks a temporary symptom flair.[120]
• High-pressure hydrodistension under anesthesia is not recommended due to inconsistent symptom improvement and an increased risk of sepsis and bladder rupture.[121]

Intra-detrusor Injection (with Botulinum toxin type A)

• This is quoted as a 4th line treatment option by the AUA, and current recommendations are that the patient should be warned that there may be a need for intermittent self-catheterization in the future.

Systemic Immunosuppression

Currently, only cyclosporine A is recommended for clinical use. A mutual decision between the doctor and patient is needed after a full and frank review of the risks and benefits. The patient needs to be made fully aware of the risks of systemic immunosuppression, such as vulnerability to infection and the development of malignancies. This is the last non-surgical option available currently.

A recent meta-analysis done in July 2020 looked at 81 randomized, controlled trials and compared the effectiveness of treatment of all the options, but focused on three main groups, namely antidepressants, pentosan polysulfate, and neuromuscular blockade, which is achieved by Botulinum injections. They found improved outcomes compared to control for antidepressants and neuromuscular blockade. However, the former is of very low certainty. There was no difference in pain relief, daytime frequency, or nocturia. Pentosan polysulfate did not show any improvement compared to control in all domains. However, the authors did not have a separate analysis for the mode of delivery.[122]

Surgical Treatment

This has recently seen a fall in popularity, especially after the introduction of intra-detrusor injections of Botulinum toxin A. However, surgery remains the last resort option for patients with intractable disease as a final resolution of symptoms. A summary of possible options are: [123]

• Cystoplasty only
• Cystoplasty with supra-trigonal resection
• Cystoplasty with sub-trigonal resection
• Urinary diversion, with or without cystectomy and urethral resection. This may be in the form of a urostomy.

Furthermore, multiple sources in addition to the American Urological Association, such as the National Institute for Clinical Excellence (NICE) and the European Association of Urology (EAU), do not currently recommend prolonged oral antibiotics, prolonged oral steroids, intravesical BCG, intravesical chlorpactin, or prolonged high-pressure hydrodistention as treatment options.

Hyaluronic acid instillations [116]

Investigational Therapies

Monoclonal antibody therapy has shown some promise, but much additional research needs to be done to find the ideal antibody mix.[124]

Certolizumab pegol is an investigational pharmacologic therapy under development for the treatment of IC/BPS.[67]

Mesenchymal stem cells may potentially be of some value in the treatment of IC/BPS as they have been shown to minimize bladder tissue injury and inflammation.[125] After migrating into the detrusor tissue, these cells differentiate into bladder cells and inhibit mast cell buildup, decrease cell apoptosis, reduce inflammation, mitigate oxidative stress, reduce collagen deposition, and promote normal regenerative functions.[125] These mesenchymal stem cells secrete exosomes and other factors that protect against injury.[125]

Platelet-rich plasma (PRP) is widely used to promote wound healing.[126] It contains abundant cytokines and growth factors that affect the inflammatory process to promote healing and reduce neuropathic pain.[127][128] 

IC/BPS symptoms correspond to the severity of bladder wall inflammation, which causes poor basal cell proliferation, defective umbrella cell integrity, and decreased barrier function [1,18,45]. The defective urothelium in IC/BPS is similar to an unhealed wound in the bladder mucosa. Therefore, the use of PRP to promote mucosal wound healing and eradicate residual inflammation in the bladder is rational [44]. Urothelial cell proliferation, cytoskeleton markers, and barrier function protein expression increase after PRP treatment in IC/BPS bladders [46].e conducted a study to determine the therapeutic efficacy of intravesical PRP injections in IC/BPS patients [47]. Forty patients received four monthly PRP injections and follow-up visits. Global response assessment scores improved after the first PRP injection, and the therapeutic effect persisted up to three months after the fourth PRP injection; the success rate was 67.5%. IC symptom scores and bladder pain scores decreased. Bladder capacity increased, but PVR did not change after PRP treatment, and no UTIs or dysuria occurred. Thus, repeated autologous PRP injections may be effective in patients with IC/BPS refractory to conventional therapy.

After four PRP injections in patients with IC/BPS, urinary levels of NGF, MMP-13, and VEGF decreased, and PDGF-AB levels significantly increased in responders, suggesting that PRP injections decrease inflammation, resulting in improvements in bladder pain and frequency episodes [48]. In addition, the expression of the urothelial barrier function protein and the urothelial cell proliferation protein increased after repeated PRP injections [49]. Thus, intravesical PRP injections may improve urothelial regeneration and differentiation to recreate a healthy urothelial barrier in IC/BPS bladders [50]. Repeated PRP intravesical injections improve IC/BPS symptoms by promoting the recovery of urothelial ultrastructural defects [51].  

Botulinum toxin A (BoNT-A) has been widely used in several urological functional disorders including neurogenic detrusor overactivity (NDO), overactive bladder (OAB), lower urinary tract dysfunction, and interstitial cystitis/bladder pain syndrome (IC/BPS). Chronic inflammation is found in a large proportion of patients with OAB and IC/BPS. The chronic inflammation activates sensory afferents which resulting in central sensitization and bladder storage symptoms. Because BoNT-A can inhibit the sensory peptides released from the vesicles in sensory nerve terminals, the inflammation can be reduced and symptom subsided. Previous studies have demonstrated that the quality of life improved after BoNT-A injections, both in neurogenic and non-NDO. Although the use of BoNT-A in treatment of IC/BPS has not been approved by FDA, intravesical BoNT-A injection has been included in the AUA guideline as the fourth line therapy. Generally, intravesical injections of BoNT-A are well tolerated, though transient hematuria and urinary tract infection can occur after the procedure. In order to prevent these adverse events, experimental trials have been conducted to test if BoNT-A can be delivered into the bladder wall without intravesical injection under anesthesia such as using liposomes encapsulated BoNT-A or application of low energy shock wave on the bladder to facilitate BoNT-A penetrating across the urothelium and treat OAB or IC/BPS. This article reviews current clinical and basic researches of BoNT-A on OAB and IC/BPS.

Experimentally, low-energy shock wave therapy has shown a benefit in reducing bladder pain, tumor necrosis factor-α (TNF-α), and nerve growth factor (NGF) in IC/BPS patients.[129] These results are very preliminary, and substantially more study is needed before such treatment can be recommended clinically.

Differential Diagnosis

The possible list of differential diagnoses is extensive, and this list is not exhaustive, but the causes can be broken down into:[130]

Infections

• Sexually transmitted infections such as Chlamydia and Gonorrhoea
• Tuberculous infections of the bladder
• Urinary tract infection

Urological and Urogynecological Conditions

• Bladder stone
• Chronic urethral syndrome
• Distal ureteral calculi
• Pelvic organ prolapses
• Prior pelvic surgery, especially involving mesh
• Prostate pathology, including but not limited to benign prostatic hyperplasia, prostate cancer, and chronic prostatitis.
• Neoplasms of the urinary bladder
• Neurogenic bladder 
• Overactive bladder
• Stress incontinence
• Urge incontinence/detrusor instability

Gynecological Conditions

• Endometriosis
• Pelvic inflammatory disease
• Pregnancy
• Vulvodynia

Neurological

• Cauda equina/cord compression
• Demyelinating diseases
• Diabetic neuropathy
• Pudendal neuralgia
• Stroke

Other Causes

• Congenital bladder malformations
• Diabetes
• Diverticular disease
• Inflammatory bowel disease
• Radiation-induced effects
• Rheumatoid arthritis
• Trauma
• Urinary diverticula

Prognosis

The majority of patients suffer from chronic symptoms, but there is a wide variation in prognosis and resolution. Patterns of the disease have been observed and described. These are

• Complete resolution
• Relapsing-remitting
• Intermittent disease flares
• Chronic progression.

The patient may also experience spontaneous resolution and unexpected recurrences regardless of treatment.[131]

IC/BPS appears to be an extremely stable condition as urinary symptoms and discomfort tend to remain unchanged in severity for up to nine years.[132]

Complications

If left untreated and without spontaneous resolution, the bladder may undergo further fibrosis, further reducing the bladder volume and further compounding the symptoms experienced. The patient would experience deterioration in their psychological and social health through sleep disturbance, sexual dysfunction, anxiety, depression, and social embarrassment.

Complications of treatment depend on various factors, such as the pharmacological agent used, cystoscopy or surgical complications, and proper counseling and consent before treatment are paramount.[133] It can be broadly categorized as:

• Infection (introduced through intra-vesical routes or surgery)
• Bleeding
• Trauma 
• Perforation of the bladder during high-pressure hydrodistention
• Death (from procedure or anesthesia)
• Anesthetic complications include respiratory depression, pulmonary aspiration, cardiovascular collapse, postoperative nausea and vomiting, anaphylaxis, medication error, and death.[134] The majority of these are due to human factors and patient status, which in the healthiest group has an estimated mortality of 0.4 per 100,000 patients.[135]
• At the time of writing this article, the risk of potentially contracting COVID-19.[136]

There is also a theoretical risk of urinary tract infections. The symptoms may change and worsen during this time, and tests for infection should always be checked in those circumstances. This is due to the damage and breach of the urothelium, which increases the probability of bacterial invasion, harm, and symptoms. In selected cases like these, a short course of antibiotics could be started. However, prolonged courses for prophylaxis or treatment are not recommended.

Deterrence and Patient Education

Once the diagnosis is made, the patient should be counseled on what that means, why they experience the symptoms, and that the etiology is not well-understood at present.

The patient should be directed and encouraged to engage with self-help and the local support groups, such as those offered by the Interstitial Cystitis Association (https://www.ichelp.org/) in the United States, as well as Bladder Health UK, or PainUK in the United Kingdom. Some patients that have used self-help found that it is a very effective treatment option.[137]

There are many treatments for the condition, with variable results. It can take up to months before the patient notices an improvement, and the effects may be only marginal. They need to be explained that the condition may not be cured, and symptoms may return at any time. However, with the right treatment, there can be significant improvements in their symptoms and quality of life for the right patient.

Pearls and Other Issues

Recent evidence suggests that many men diagnosed with chronic prostatitis/chronic pelvic pain syndrome may actually have interstitial cystitis/bladder pain syndrome as the symptoms are very similar, and each is a diagnosis of exclusion. Men diagnosed with CP/CPPS who fail to respond to the standard therapy for prostatitis and continue to have symptoms, including frequency, painful bladder filling, suprapubic discomfort, dysuria, urgency, or pelvic discomfort, should be considered for treatment of IC/BPS.[22][23][24][25][26]

Pudendal neuralgia and nerve compression should also be considered when dealing with patients with IC/BPS symptoms, especially for those who are unresponsive to conservative, oral, and intravesical therapies.[138]

While there is no standard intravesical cocktail, several noted experts have published their own personal recipes. 

Bladder Cocktail Formulas for Intravesical Instillation

Alkalinized Lidocaine Cocktail

• Gentamicin 80 mg in 5 mL
• Heparin 10,000 IU in 10 mL
• Lidocaine 2% solution: 25 mL
• Sodium Bicarbonate 8.4%: 5 to 10 mL
• Schedule: 
  • Weekly as needed in office/clinic.
  • Should be mixed immediately before intravesical instillation to avoid precipitation.
  • Increase the interval between instillations as symptoms improve.

DMSO (Dimethylsulfoxide) Cocktail

• Gentamicin 80 mg in 5 mL
• Heparin 10,000 to 20,000 IU
• Rimso-50 (DMSO) 50 mL
• Sodium Bicarbonate 8.4%: 10 mL
• Triamcinolone 40 mg
• Schedule:
  • Weekly as needed in the office/clinic.
  • Increase the interval between instillations as symptoms improve.

Robert Moldwin, MD—Smith Institute for Urology & Long Island Jewish Medical Center

• Bupivacaine (Marcaine) 0.5% and Lidocaine jelly 2% in a 1:1 mixture: Total of 30 to 40 mL.
• Heparin 10,000 to 20,000 IU
• Gentamicin 80 mg
• Triamcinolone 40 mg (Increase to 80 mg in patients with documented Hunner’s ulcer.)
• Schedule:
  • Weekly instillations in the office/clinic.
  • May also be self-administered by patients at home up to three times weekly.
  • Increase the interval between instillations as symptoms improve.
  • Maximum symptom improvement is expected by twelve weeks.
  • If no longer effective, switch to “DMSO Cocktail.” May resume the above bupivacaine combination cocktail later if symptoms return.

Christopher Payne, MD “Payne Cocktail 1”

• Bupivacaine (Marcaine) 0.5%: 10 mL
• Heparin 10,000 IU
• Schedule:
  • Weekly instillations in the office/clinic.
  • May also be self-administered by patients at home as often as daily.
  • Increase the interval between instillations as symptoms improve.

Christopher Payne, MD “Payne Cocktail 2”

• Bupivacaine (Marcaine) 0.5%: 10 mL
• Heparin 10,000 IU (Optional. May be reserved as separate instillation treatment.)
• Hydrocortisone (Solu-Cortef) 100 mg
• Rimso-50 (DMSO): 50 mL
• Sodium Bicarbonate 8.4%: 5 mL
• Schedule:
  • Weekly instillations of 30 to 50 mL for six to eight weeks.
  • Increase the interval between instillations as symptoms improve.
  • Use B&O suppositories if patients are unable to hold the solution for at least 30 minutes.

Kristene Whitmore, MD—Drexel University College of Medicine

• Bupivacaine (Marcaine) 0.5%: 20 mL
• Gentamicin 80 mg: 5 mL of Normal Saline. (Add for patients with a documented UTI within three months.)
• Heparin 10,000 IU in 10 mL
• Hydrocortisone 100 mg: 5 mL of Normal Saline
• Sodium Bicarbonate 8.4%: 40 to 50 mL
• Schedule:
  • Six weekly instillations. Should be administered during a premenstrual flare when possible.
  • Appropriate for patients who are able to self-catheterize and administer at home.

Enhancing Healthcare Team Outcomes

Due to the nature of interstitial cystitis to follow a chronic path, it can lead to significant disturbance in a patient's quality of life and therefore have a profound negative impact on their psychological and social health. The condition is often not easily managed by one intervention alone, and there are often many physical and psychological co-morbidities. Therefore, an interprofessional approach involving different specialties is best suited to offer the best care to the patient. This would likely include a urologist, pain specialist/team, specialist nurses, mental health specialists, and their family doctor.[122][139]