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Interstitial cystitis/bladder pain syndrome is a complex and chronic medical condition that primarily affects the urinary bladder, leading to a range of distressing symptoms. This disorder is characterized by the inflammation of the bladder's lining, resulting in recurring and often severe discomfort, urgency, and frequency of urination. Interstitial cystitis remains challenging to diagnose and manage, as its precise causes are not fully understood, and it can mimic other urinary tract disorders. Individuals living with interstitial cystitis face a significant impact on their quality of life, as the symptoms can be disruptive and emotionally taxing. Patients' responses to treatment are highly variable. This activity reviews the approach, investigation, and management of interstitial cystitis/bladder pain syndrome and highlights the role of the interprofessional team in evaluating and treating this challenging disorder. Objectives: Identify the multifaceted etiology of interstitial cystitis/bladder pain syndrome. Implement evidence-based treatment plans, integrating the latest therapeutic options and guidelines, tailored to patients' specific needs and severity of interstitial cystitis/bladder pain syndrome. Apply a multidisciplinary approach to assessing the prognosis of interstitial cystitis/bladder pain syndrome. Collaborate with an interprofessional team to create a coordinated and comprehensive care plan for patients with interstitial cystitis/bladder pain syndrome. Access free multiple choice questions on this topic.

Interstitial cystitis/bladder pain syndrome (IC/BPS), formerly called interstitial cystitis, is a chronic (>6 weeks duration) pelvic condition that affects or appears to affect the urinary bladder with symptoms of discomfort, pressure, or pain. The condition is characterized by chronic inflammation and lower urinary tract symptoms, not due to infection or any other clearly identifiable cause.[1][2] As the definition varies somewhat between different societies and organizations, we will use the American Urological Association (AUA) definition. In many cases, because IC/BPS remains a diagnosis of exclusion, the condition is often identified late or misdiagnosed, particularly in men, as chronic prostatitis/chronic pelvic pain syndrome or overactive bladder.[3][4][5][6][7] Patients often describe pain in the bladder or suprapubic region, with an intense sensation of urinary urgency. This sensation is worsened by bladder filling but is temporarily relieved by passing urine, which typically results in severe urinary frequency. This may be during the daytime and/or overnight. The urinary frequency is generally refractory to standard overactive bladder therapy, which should suggest considering a diagnosis of IC/BPS. There may also be other symptoms, such as pain or burning when passing urine (dysuria) and discomfort during sexual intercourse, causing dyspareunia in women and ejaculatory pain in men. These chronic symptoms profoundly impact the patient's emotional, psychological, and social well-being as well as their quality of life.[8] Anatomy The urinary bladder is a hollow viscus organ located in the pelvis, 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 4 layers.[9] The 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. The mucosa also produces glycosaminoglycans (GAGs), making up the superficial coating that protects the mucosa from direct contact with potentially inflammatory urinary irritants. The submucosa is composed of elastic connective tissue and further assists with the stretch of the bladder.

The 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. The mucosa also produces glycosaminoglycans (GAGs), making up the superficial coating that protects the mucosa from direct contact with potentially inflammatory urinary irritants. The submucosa is composed of elastic connective tissue and 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 oriented in multiple directions, which produce a uniform, simultaneous contraction that efficiently empties the bladder when a contraction is triggered. The muscles 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, composed of skeletal muscle and innervated by the somatic nervous system.[10] In women, the external urethral sphincter is distal and inferior to the bladder neck. The clitoris and pubic bone are anterior, while the anterior vaginal roof is immediately posterior. The external sphincter in women is also known as the urogenital sphincter.[10] The fibrous connective tissue layer is the outermost covering of the bladder, except for the superior surface, which is covered by the parietal peritoneum.[11] The bladder floor also contains a fixed, triangular area called the trigone. The openings to each ureter and the outlet to the urethra form the trigone. There are 3 apices, with a ureteral orifice in each lateral wing and the third arm entering the urethra.[11] The trigone is located at the posterior base, also known as the fundus of the urinary bladder.[12] The distal intramural portion of each ureter follows a shallow submucosal course as it travels through the detrusor muscle into the bladder. This anatomy acts as an anti-reflux mechanism or valve to prevent urine reflux into the kidney.

The etiology of IC/BPS is not well understood, and the current thoughts around its pathogenesis remain multifactorial. Current research strongly suggests an underlying inflammatory process, although the precise cause for this is not well-understood.[13] Cystoscopy findings in individuals with normal bladder function are characterized by a pale/pink mucosal appearance, a lack of erythema and swellings, and relatively straight capillaries (see Image. Normal Mucosa of the Bladder Wall). Cystoscopy in IC/BPS patients typically shows submucosal inflammation, which is seen as glomerulations (see Image. Abnormal Mucosa Wall). Large groups of mast cells are frequently found, further stimulating afferent sensory fibers. Increased urothelial permeability due to diminished GAG levels and ultrastructural abnormalities are seen on biopsies with a loss of tight junctions and adhesive junction proteins. This causes a loss of mucosal barrier protection, resulting 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.[13][14][15] 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 lead to further stretching and stimulation of afferent sensory pain fibers.[16] Increased grey matter volume has been found in some IC/BPS patients with the disorder in brain regions responsible for pain perception. This was observed using functional magnetic resonance imaging (fMRI).[17][18] Severe IC-like symptoms can develop after the use of illegally sourced ketamine. The precise etiology of this response remains unknown. The main theories involve urothelial damage, microvascular changes, autoimmunity, and infection either by ketamine or metabolites. The symptoms, cystoscopy, and biopsy findings have a great degree of crossover with IC, 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.[19] Leading concepts regarding the underlying etiology of IC/BPS include the following: [20][21][22][23] Autoimmune or immune-mediated processes Chronic inflammation Chronic stress Fibrosis

Severe IC-like symptoms can develop after the use of illegally sourced ketamine. The precise etiology of this response remains unknown. The main theories involve urothelial damage, microvascular changes, autoimmunity, and infection either by ketamine or metabolites. The symptoms, cystoscopy, and biopsy findings have a great degree of crossover with IC, 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.[19] Leading concepts regarding the underlying etiology of IC/BPS include the following: [20][21][22][23] Autoimmune or immune-mediated processes Chronic inflammation Chronic stress Fibrosis Heightened pain sensitivity due to an increase in grey matter volume Mast cell dysfunction or hyperactivation Neurogenic inflammation/edema Pelvic floor hypertonicity or dysfunction Upregulation and proliferation of sensory afferent fibers Urothelial dysfunction and exposure, especially in the epithelial and glycosaminoglycans (GAGs) layer Vascular malformations that are seen as glomerulations on cystoscopy

Due to the nature of IC/BPS, it is very difficult to formulate a clear early diagnosis, and no accepted screening tool exists. Therefore, the data surrounding its prevalence remains limited. Some studies have specifically looked into the epidemiology of IC/BPS. There are 2 main study designs, one using physician/urologist-based diagnosis and the other using a patient questionnaire involving symptomatology. A lower prevalence is seen when physician-completed questionnaires and histological samples were employed to establish a diagnosis. Based on a large population, questionnaire-based prevalence study in the US, 2.7% of women and 1.9% of men met the specified criteria.[24][25] Other studies have estimated the prevalence at >6% with a higher incidence in women.[26] In terms of age groups, the most common prevalence was in women between 50 to 59 years of age and men between 56 to 74 years of age.[24][25] IC/BPS has an estimated prevalence of 3 million to 8 million women and 1 million to 4 million men in the US.[27] The number of men affected is probably underestimated, as many are misdiagnosed as having chronic prostatitis.[3][4][5][6][7][26] Investigations have noted a female predisposition, with 1 study in the US finding a 5 to 1 ratio.[28] A study in the Netherlands quoted a prevalence as low as 8 to 16 out of 100,000 individuals.[29] It is estimated that IC/BPS affects up to 400,000 patients in the UK, with almost 90% being women between 50 to 69 years of age.[30] The data for children affected by IC/BPS is poor, but the consensus is that the prevalence is very low in the pediatric population.

The underlying pathophysiology of IC/BPS is somewhat uncertain, contributing to the lack of a definitive, curative remedy.[13] Known involved bladder pathological findings include chronic inflammation, afferent sensory hyperactivity, nociceptor upregulation, mast cell overactivity, submucosal microvascular abnormalities, autoimmune disorders, lack of normal bladder epithelial cell growth, and urothelial thinning with a deficient or dysfunctional superficial mucosal GAGs layer.[13][14][22][31][32][33] Other findings associated with chronic bladder inflammation include decreased mucosal protection from GAGs loss or dysfunction, lower adhesive protein E-cadherin, decreased basal cell growth, defective umbrella cell integrity, abnormal apical cell maturation, and increased urothelial cell apoptosis.[31][34] The increased serum levels of C-reactive protein and pro-inflammatory cytokines also point to inflammation as a primary underlying etiology of IC/BPS.[14][15] Tumor necrosis factor-α (TNF-α) and nerve growth factor (NGF) are also increased in IC/BPS patients.[35] IC/BPS can appear as two separate entities: the IC entity clearly demonstrates an inflammatory component that is mostly missing in those with the predominantly BPS entity.[36] IC/BPS patients are much more likely than the general population to have systemic lupus erythematosus.[37] There is also a close association with Hashimoto's thyroiditis, rheumatoid arthritis, ankylosing spondylitis, irritable bowel syndrome, fibromyalgia, chronic fatigue, and especially Sjogren syndrome.[38][39][40] This suggests an autoimmune component, possibly an autoantibody to M3 receptors in the bladder, at least in some patients.[41] Chronic stress is found in >50% of IC/BPS patients, which is a factor in the development and exacerbation of symptoms.[36][42][43][44][45][46] The chronic pain typically associated with IC/BPS is caused by sensory afferent nerve activity and central nervous system sensitization.[47]

Histologically, no specific pathognomonic finding is diagnostic for IC/BPS.[48] However, compared to a similar control group, IC/BPS patients demonstrated a higher frequency and severity of bladder mucosal ulcerations with denuded superficial urothelium, submucosal inflammation of the lamina propria, and lymphocytic inflammatory infiltrate with mast cell accumulations in the lamina propria and detrusor.[49][50] While interesting, these findings are insufficient to be of any diagnostic help except to exclude malignancy and other pathologies.[48][51] Urothelial defects, as seen on electron microscopy, appear to correlate well with symptom severity in patients with IC, which suggests a causal relationship.[13]

Symptoms must last at least 6 weeks with negative urine cultures and no acceptable explanation or alternative diagnosis.[1] Typical symptoms involve urinary frequency, nocturia, and suprapubic pain, which 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 improved but not totally relieved by voiding. Incontinence is not a typical symptom of IC/BPS. A baseline record of the patient's symptoms is useful to compare treatment efficacy. This may be a recommended pain scale index, a visual chart, or a patient-recorded 24-hour voiding diary.[1] Pain can be evaluated and recorded using the IC symptoms index (ICSI), a visual analog chart, or the genitourinary pain index (GUPI).[52][53] Voided volumes and a 24-hour timed voiding diary document the degree and severity of the patient's urinary frequency symptoms.[54][55][56] Symptoms typically have periodic flares or exacerbations and remissions. As a complete remission is uncommon, over the long course of the disorder, patients often become anxious, depressed, and/or have difficulty sleeping.[57] IC/BPS should be considered in all patients originally diagnosed with overactive bladder who do not improve on standard therapy.[1] Unusually high voided volumes or infrequent voiding would suggest an alternative diagnosis. Urinary and related symptoms to record and document include the following: [1] Number of voids per day Urine volume per voiding episode 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 (present or not) 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 24 hours 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. A post-void residual urine volume determination should be completed.[1][54]

Severity (as well as any concomitant dysuria) should be recorded for at least 24 hours 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. A post-void residual urine volume determination should be completed.[1][54] A detailed gynecological history and pelvic examination should be performed on all female patients suspected of having IC/BPS.[1]  Careful attention should be paid to cervical tenderness, masses, prolapse, and abnormalities found on adnexal palpation. An appropriate hematuria evaluation should be performed in patients with unexplained or previously unevaluated urinary blood and those with symptoms of IC/BPS who also have a significant (≥10 pack-years) smoking history.[1][58] A detailed history and careful examination are needed to exclude other causes, as there is considerable overlap between IC/BPS and other conditions.[1][8] 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 IC, which may be the more common disorder even in males.[3][4][5][6][7] The primary differences are the lack of the urinary antiproliferative factor and histological bladder pathology in chronic prostatitis.[59] The 2 conditions have many similarities as both demonstrate the following:[3][4][6][7][60][61] 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 provides relief for the majority of patients Sensitivity to intravesical potassium instillation Symptoms are aggravated by the same foods and dietary irritants Symptoms may last for years Men with IC/BPS or chronic prostatitis/chronic pelvic pain syndrome tend to have a higher incidence of erectile and ejaculatory dysfunction than unaffected males and are more likely to be associated with depression, pain, and stress.[62] Over 70% of men with IC/BPS report sexual dysfunction.[63]

Symptoms may last for years Men with IC/BPS or chronic prostatitis/chronic pelvic pain syndrome tend to have a higher incidence of erectile and ejaculatory dysfunction than unaffected males and are more likely to be associated with depression, pain, and stress.[62] Over 70% of men with IC/BPS report sexual dysfunction.[63] Patients with IC/BPS who have not responded to standard therapy might 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.[64] Patients with pudendal neuralgia tend to describe the pain as more intense and having a "burning" or "electrical shock" feeling. The pain is associated with sitting, bending, or squatting and is generally unrelated to bladder fullness or diet. They also tend not to have the degree of urinary frequency and urgency associated with IC/BPS. 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.[64]

The workup should include laboratory examinations and procedures to identify other disorders that can produce symptoms similar to IC/BPS. This typically includes standard blood tests (CBC, CMP, glucose, HbA1c), urinalyses (microscopic) and urine cultures, and appropriate sexual health screening, including testing for sexually transmitted infections 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 to diagnose IC/BPS according to the AUA guidelines. Neither is diagnostic, but they may be appropriate if the diagnosis is in doubt.[1] IC/BPS patients with Hunner ulcers tend to be older with higher symptom scores, increased urinary frequency, more nocturia episodes, smaller voided volumes, and a reduced bladder capacity with hydrodistension than IC/BPS patients without Hunner lesions.[65] They were also more likely to have an autoimmune disorder comorbidity. A number of urinary inflammatory biomarkers are increased in IC/BPS, such as TNF-α, PGE2, IL-2, IL-6, IL-8, IP10, TAC, and 8-OHdG, although the diagnostic and clinical utility of this finding still needs to be determined.[35][66] A recent study of urinary biomarkers in 191 pateints suggested that TNF-α, IP-10, TAC, 8-OHdG, and IL-2 could be useful in differentiating interstitial cystitis from other urinary disorders.[66] While promising, a definitive, clinically useful urinary cytokine or combination of biomarkers is still to be determined.[20][66] Cystoscopy is appropriate if there is a suspicion of bladder cancer, intravesical foreign bodies, outlet obstruction, strictures, or vesical calculi. Glomerulations are often found but are considered non-specific. 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.[67] 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 and adverse effects.[1]

Cystoscopy is appropriate if there is a suspicion of bladder cancer, intravesical foreign bodies, outlet obstruction, strictures, or vesical calculi. Glomerulations are often found but are considered non-specific. 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.[67] 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 and adverse effects.[1] A Hunner ulcer is characteristic and diagnostic of classic IC. It is described as a central scar in an area of erythematous mucosa.[68] Small blood vessels can be seen radiating toward this scar, which will often have a small adherent blood clot. After hydrodistension, the surrounding mucosa ruptures, resulting in the bleeding typically associated with this pathological lesion.[68] Since many urologists rarely see a Hunner ulcer, reviewing a published atlas of these clinically important diagnostic lesions may be useful.[69] Patients with Hunner ulcers generally respond well to treatment. Standard therapy for a Hunner ulcer includes immediate fulguration of the lesion and/or an injection of triamcinolone.[70] Symptom relief after Hunner ulcer treatment is reportedly as high as 97%.[71] If this fails, oral cyclosporine A is recommended.[72] Since the odds of identifying Hunner lesions are markedly reduced in patients younger than 50 years, routine cystoscopic examinations are not recommended or suggested for patients with IC/BPS symptoms in this age group.[1] Bladder biopsies are not routinely necessary or recommended according to the AUA guidelines unless malignancy is suspected.[1] This is based on the relative rarity of bladder cancer in patients diagnosed with IC/BPS (1:600).[73]

Patients with Hunner ulcers generally respond well to treatment. Standard therapy for a Hunner ulcer includes immediate fulguration of the lesion and/or an injection of triamcinolone.[70] Symptom relief after Hunner ulcer treatment is reportedly as high as 97%.[71] If this fails, oral cyclosporine A is recommended.[72] Since the odds of identifying Hunner lesions are markedly reduced in patients younger than 50 years, routine cystoscopic examinations are not recommended or suggested for patients with IC/BPS symptoms in this age group.[1] Bladder biopsies are not routinely necessary or recommended according to the AUA guidelines unless malignancy is suspected.[1] This is based on the relative rarity of bladder cancer in patients diagnosed with IC/BPS (1:600).[73] However, guidelines from the European Association of Urology (EAU), the International Society for the Study of BPS (ESSIC), the International Continence Society (ICS), and the Canadian Urological Association (CUA) recommend hydrodistension with cystoscopic random biopsies due to the substantial overlap in visual appearance and symptoms between IC/BPS and bladder cancer.[74] In a recent study of 55 IC/BPS patients, 3 (5.5%) were found to have bladder cancer when random biopsies were performed.[74] It is unknown if urine cytology, FISH testing, or bladder washing would be sufficient to identify these cancers without requiring a more invasive biopsy. Cystoscopy primarily rules out malignancy, strictures, Hunner ulcers, and bladder outlet obstruction. The appearance of bladder lesions can be very similar to malignancy, particularly carcinoma-in-situ. The bladder walls may show scarring or petechial hemorrhages, known as glomerulations, which are considered non-specific. During visualization of the distended bladder, there may be Hunner ulcers, often described as pale central scars with or without a fibrin clot and surrounded by erythematous mucosa, with small vessels radiating towards the center (see Image. Abnormal Bladder Mucosa, Showing a Hunner Ulcer). Hunner ulcers are most commonly located at the posterior bladder mucosa (see Image. Illustration of the Bladder Anatomy, with an Illustration of a Classic Hunner's Ulcer). Hunner ulcers are considered diagnostic for IC, but they are uncommon and may only be present in 5% to 10% of cases.[75]

During visualization of the distended bladder, there may be Hunner ulcers, often described as pale central scars with or without a fibrin clot and surrounded by erythematous mucosa, with small vessels radiating towards the center (see Image. Abnormal Bladder Mucosa, Showing a Hunner Ulcer). Hunner ulcers are most commonly located at the posterior bladder mucosa (see Image. Illustration of the Bladder Anatomy, with an Illustration of a Classic Hunner's Ulcer). Hunner ulcers are considered diagnostic for IC, but they are uncommon and may only be present in 5% to 10% of cases.[75] Patients with Hunner ulcers tend to have the most inflammation and require a more aggressive therapeutic approach.[13] Reactive hemorrhages are also a sign of IC. This is when the mucosa appears normal when 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.[76] Further investigations or treatments may also be performed during a cystoscopy, such as hydrodistention, lidocaine or intravesical cocktail instillation, fulguration and/or triamcinolone injections for Hunner ulcers, or random bladder biopsies. 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. There are no specific urodynamic findings that are diagnostic of IC/BPS. However, a small maximum bladder capacity (<300 mL) is frequently found. Urodynamic studies are not recommended in routine cases.[1]

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 IC/BPS is a critical part of the treatment plan.[1] An individualized approach, including shared decision-making for every patient, is suggested. For most 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 managing the symptoms. Treatment should be evaluated periodically, and ineffective therapies 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 the following: [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

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 the following: [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, physiotherapy with relaxation exercises, and pelvic floor trigger point manual therapy provided by a skilled practitioner have shown significant symptom relief in 70% of patients.[77] Standard pelvic floor strengthening treatments, such as Kegel exercises, may cause IC/BPS symptoms to worsen and are not recommended.[1][78] Specific behaviors and activities that can help mitigate symptoms include the following: [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 relatively ineffective 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 (Kegels) Prolonged or untreated constipation Sexual intercourse Tight clothing Pain Management

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 (Kegels) 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 most minimal number of drugs used as possible, in line with the WHO pain ladder. Non-opioid treatments are much preferred over opioid therapy.[79] 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 therapies have been used with moderate success for IC/BPS. Oral overactive bladder (OAB) medications, such as oxybutynin, have limited efficacy in controlling the urinary 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 are amitriptyline, cyclosporine A, and pentosan polysulfate.[80][81] Amitriptyline is a tricyclic antidepressant that has shown activity in reducing chronic pelvic pain, including discomfort from IC/BPS.[82] Adverse effects (drowsiness, nausea, lethargy, sedation) limit usefulness.[83][84][85] Low-dose (10 mg) amitriptyline combined with intravesical instillation therapy is very effective, especially in improving the emotional status of patients with IC/BPS.[86] Standard dosing starts at 10 mg daily and gradually increases to a maximum of 100 mg as tolerated.[1][83]

Amitriptyline is a tricyclic antidepressant that has shown activity in reducing chronic pelvic pain, including discomfort from IC/BPS.[82] Adverse effects (drowsiness, nausea, lethargy, sedation) limit usefulness.[83][84][85] Low-dose (10 mg) amitriptyline combined with intravesical instillation therapy is very effective, especially in improving the emotional status of patients with IC/BPS.[86] Standard dosing starts at 10 mg daily and gradually increases to a maximum of 100 mg as tolerated.[1][83] 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 approximately 60% to 70% of IC/BPS patients.[87][88][89][90] The mechanism for this is unclear and occurs regardless of the presence or absence of increased mast cells in the bladder tissue. No significant adverse effects are reported with its use, and it is very cost-effective as it is not only generic but available without a prescription.[87][88] Cyclosporine A, an immunosuppressive drug 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.[1][72][91][92] A response rate of 84% has been reported in IC/BPS patients with Hunner ulcers treated with cyclosporine A.[81] It has also been suggested that it be considered for use in otherwise intractable cases.[91] 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, higher incidence of malignancies, greater infection risk due to immunosuppression, and decreased renal function.[1][93] It also has a relatively short duration of action. For these reasons, it is suggested to be used only by those familiar with this therapy and in patients with Hunner ulcers who fail other treatments.

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, higher incidence of malignancies, greater infection risk due to immunosuppression, and decreased renal function.[1][93] It also has a relatively short duration of action. For these reasons, it is suggested to be used only by those familiar with this therapy and in patients with Hunner ulcers who fail other treatments. Currently, cyclosporine A is the only immunosuppressive agent recommended by the AUA for clinical use. After a full and frank review of the risks and potential benefits, a mutual decision between the doctor and patient is needed. The patient must be fully aware of systemic immunosuppression risks, such as increased vulnerability to infection and the more rapid development of malignancies. 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 adverse effects. Further studies are necessary until this approach's long-term safety and efficacy have been conclusively determined.[94] Gabapentin has shown some activity in reducing pain and other symptoms of IC/BPS.[95][96][97][98] Gabapentin was originally approved as an antiepileptic 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.[99] Hydroxyzine is an antihistamine and mast cell stabilizer that has shown effectiveness in providing significant symptom relief in some IC/BPS patients. Those IC/BPS patients with allergies may most likely benefit from this treatment.[100]  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. 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.[101] Adverse effects tend to be minor and include mild sedation and weakness. The dosage is usually 50 mg to 100 mg QID.

Hydroxyzine is an antihistamine and mast cell stabilizer that has shown effectiveness in providing significant symptom relief in some IC/BPS patients. Those IC/BPS patients with allergies may most likely benefit from this treatment.[100]  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. 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.[101] Adverse 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 urinary symptoms of IC/BPS. These medications may be beneficial in reducing frequency and urgency, but they generally do not help with pain where a multimodal approach is typically needed.[102][103] Patients with significant OAB symptoms who fail standard treatment 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.[100][104][105][106][107][108] Maximum symptomatic relief may take up to 5 or 6 months or longer.[109][110] A worrisome retinal pigmentary maculopathy has now been clearly associated with the long-term, cumulative use of pentosan polysulfate.[111][112][113][114][115] Symptoms include blurred vision, delayed adjustment to low-light situations, and difficulty reading. 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][110][116]

A worrisome retinal pigmentary maculopathy has now been clearly associated with the long-term, cumulative use of pentosan polysulfate.[111][112][113][114][115] Symptoms include blurred vision, delayed adjustment to low-light situations, and difficulty reading. 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][110][116] For those who choose to use the medication, a retinal examination prior to initiating treatment is recommended, and a recheck at 6 months and periodically thereafter.[1][110] Recent evidence suggests that the retinal macular damage may continue even after cessation of the pentosan polysulfate, and the damage is irreversible.[116] This new data is very worrisome and makes pentosan polysulfate a far less attractive therapy as an oral agent.[117] For these reasons, pentosan polysulfate is now used infrequently for IC/BPS. Sacral neuromodulation has been shown in most studies to be a reasonably effective treatment for controlling intractable bladder overactivity and chronic pelvic pain in some IC/BPS patients.[118][119] It is FDA-approved only for severe bladder overactivity and frequency, for which it seems more effective than its effect on pain control in IC/BPS.[1][120] Tibial nerve stimulation has also shown a benefit in treating IC/BPS.[121][122] A clinical trial of sacral neuromodulation or tibial nerve stimulation can be reasonably considered in selected IC/BPS patients who have failed other treatment modalities.[1][118][120][123] Intravesical Instillations Various medications are effective when used as intravesical instillation therapy in IC/BPS when oral pharmaceuticals and dietary measures alone are insufficient.[124] No optimal or ideal cocktail has yet been agreed upon. The most commonly used medications include the following:

Sacral neuromodulation has been shown in most studies to be a reasonably effective treatment for controlling intractable bladder overactivity and chronic pelvic pain in some IC/BPS patients.[118][119] It is FDA-approved only for severe bladder overactivity and frequency, for which it seems more effective than its effect on pain control in IC/BPS.[1][120] Tibial nerve stimulation has also shown a benefit in treating IC/BPS.[121][122] A clinical trial of sacral neuromodulation or tibial nerve stimulation can be reasonably considered in selected IC/BPS patients who have failed other treatment modalities.[1][118][120][123] Intravesical Instillations Various medications are effective when used as intravesical instillation therapy in IC/BPS when oral pharmaceuticals and dietary measures alone are insufficient.[124] No optimal or ideal cocktail has yet been agreed upon. The most commonly used medications include the following: Dimethylsulfoxide (DMSO) is an effective agent for symptom control when used as an intravesical instillation in patients with IC/BPS.[125][126][127][128] It acts as an anti-inflammatory and a topical anesthetic, rapidly absorbed into the bladder mucosa and detrusor. It is a carrier, meaning it greatly enhances the absorption of other agents with which it may be combined. This should be considered when putting together a cocktail "recipe" to avoid potential toxicity. It is often mixed with bupivacaine or lidocaine, heparin, sodium bicarbonate, and hydrocortisone or triamcinolone.[1] DMSO by itself is odorless, but when used in patients, it causes an extremely strong garlic odor that can last up to 72 hours following intravesical administration. This makes it unacceptable for some patients. The results were similar when instillations of DMSO alone were compared to applications of a standard intravesical cocktail of bupivacaine, heparin, and triamcinolone.[129] However, bladder instillations of DMSO plus triamcinolone were found to be significantly (50%) superior in symptom relief compared to the same standard intravesical cocktail of bupivacaine, heparin, and triamcinolone in newly diagnosed women with IC/BPS.[126] There is also evidence that DMSO may be more effective in patients with Hunner ulcers.[130]

The results were similar when instillations of DMSO alone were compared to applications of a standard intravesical cocktail of bupivacaine, heparin, and triamcinolone.[129] However, bladder instillations of DMSO plus triamcinolone were found to be significantly (50%) superior in symptom relief compared to the same standard intravesical cocktail of bupivacaine, heparin, and triamcinolone in newly diagnosed women with IC/BPS.[126] There is also evidence that DMSO may be more effective in patients with Hunner ulcers.[130] DMSO becomes painful if held in the bladder longer than about 20 minutes. The typical dose is 50 mL of a 50% DMSO solution. Intravesical instillation of DMSO is FDA-approved and recommended by the AUA guidelines.[1] Some experts have added gentamicin, an aminoglycoside antibiotic, into intravesical cocktail formulas in certain situations. Antibiotics are not routinely recommended for intravesical IC/BPS therapy, but adding gentamicin may be a reasonable precaution for patients who have had recent infections or where there is evidence of bacteriuria or pyuria. Patients with an active infection should not have IC/BPS intravesical instillations until the infection is cleared. There is no evidence that gentamicin alone has any significant efficacy in treating IC/BPS directly. The typical dose is 80 mg. Heparin acts as a synthetic GAG layer to help protect the bladder mucosa from urinary irritants when used for intravesical therapy in IC/BPS patients. Initial studies with heparin used only 10,000 IU 3 times a week for 3 months and reported significant improvement in 56% of patients.[131] Heparin is more effective than lidocaine alone for relieving IC/BPS symptoms.[132][133] Most intravesical instillation cocktails include heparin, which the AUA guidelines recommend.[1][134] 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.[134]

Heparin acts as a synthetic GAG layer to help protect the bladder mucosa from urinary irritants when used for intravesical therapy in IC/BPS patients. Initial studies with heparin used only 10,000 IU 3 times a week for 3 months and reported significant improvement in 56% of patients.[131] Heparin is more effective than lidocaine alone for relieving IC/BPS symptoms.[132][133] Most intravesical instillation cocktails include heparin, which the AUA guidelines recommend.[1][134] 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.[134] Hyaluronic acid alone or with chondroitin sulfate has shown some efficacy in treating patients with IC/BPS.[135][136][137][138] Both of these chemicals are decreased in chronically inflamed bladders. Hyaluronic acid is a mucopolysaccharide non-sulfated component of the normal bladder GAG layer. 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 Spanish Association of Urology conducted the review through the Functional, Female, and Urodynamic Urology Group, which found that dosage and schedule to be safe and effective.[135] A study from Taiwan used a schedule of 4 weekly intravesical treatments followed by monthly therapy for 5 months. They reported improved urinary symptoms in 73% of patients.[139] Another study of intravesical hyaluronic acid found it to be more effective for relieving bladder pain than alleviating urinary storage symptoms.[140] Lidocaine is a local anesthetic that has demonstrated usefulness in reducing short-term (<2 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.[141] Alkalinization with sodium bicarbonate improves bladder tissue penetration, potentially leading to toxicity.[132][133]

Lidocaine is a local anesthetic that has demonstrated usefulness in reducing short-term (<2 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.[141] Alkalinization with sodium bicarbonate improves bladder tissue penetration, potentially leading to toxicity.[132][133] The AUA guidelines recommend lidocaine as an effective agent for IC/BPS when used in an intravesical cocktail.[1] A typical intravesical dose is 25 mL to 50 mL of a 2% lidocaine solution or viscous gel. Bupivacaine (a longer-acting lidocaine analog) 0.5% is usually dosed at 10 mL to 20 mL for intravesical use. Sodium bicarbonate (alkalinizer) is typically given as an 8.4% solution in 5 mL to 50 mL volumes. Misoprostol is a prostaglandin E1 analog used orally to help prevent gastric ulcers from heavy NSAID use by interfering with nuclear factor kappa B (NF-kappa B) signaling activity. This interference affects cytokine production, DNA transcription, immune response, and cell survival.[142] This same pathway is activated in patients with IC/BPS bladders.[143] Additionally, misoprostol acts synergistically when used with cyclosporine and enhances GAG synthesis.[144] It was theorized by Dr. Ray Rackley at the Cleveland Clinic that misoprostol might be helpful when used intravesically for IC/BPS. It is typically added to intravesical cocktails when they are ineffective before advancing to more invasive therapeutic options.[145] There are isolated anecdotal reports and small studies of misoprostol helping IC/BPS patients both as an oral agent (200 mcg TID) and as a supplement to an intravesical cocktail (200 mcg to 400 mcg).[146][147]

It was theorized by Dr. Ray Rackley at the Cleveland Clinic that misoprostol might be helpful when used intravesically for IC/BPS. It is typically added to intravesical cocktails when they are ineffective before advancing to more invasive therapeutic options.[145] There are isolated anecdotal reports and small studies of misoprostol helping IC/BPS patients both as an oral agent (200 mcg TID) and as a supplement to an intravesical cocktail (200 mcg to 400 mcg).[146][147] Triamcinolone is a frequent ingredient in IC/BPS intravesical cocktails as an anti-inflammatory agent, but its effectiveness is unclear. A randomized trial of 2 identical cocktails, except for adding triamcinolone to one, demonstrated no detectable difference in efficacy as both groups improved similarly.[148] The studied cocktails did not include DMSO, which has proven efficacy when combined with triamcinolone.[126] Taken together, this suggests some efficacy, particularly when combined with DMSO. Triamcinolone is a frequent ingredient in many intravesical cocktails used for IC/BPS. The typical dosage used is 40 mg or 80 mg. Intravesical triamcinolone injections for patients with Hunner ulcers have clearly shown effectiveness in IC/BPS and are recommended by the AUA guidelines when these pathognomonic lesions are found.[1][149] Electromotive Drug Administration (EMDA) EMDA is a method of improving bladder tissue penetration of intravesical drug instillations. A low-voltage gradient is created using electrical probes in the bladder and abdomen, creating a voltage differential that enhances drug delivery and improves tissue penetration. A small randomized prospective trial demonstrated improved short-term efficacy.[150] The main issue with the study is the small sample size (n=31). Additional extensive, randomized, long-term studies are needed to compare EMDA to current passive diffusion to determine its ultimate efficacy, cost-effectiveness, safety, and utility.[151] Botulinum Toxin Type A Detrusor Injections

A small randomized prospective trial demonstrated improved short-term efficacy.[150] The main issue with the study is the small sample size (n=31). Additional extensive, randomized, long-term studies are needed to compare EMDA to current passive diffusion to determine its ultimate efficacy, cost-effectiveness, safety, and utility.[151] Botulinum Toxin Type A Detrusor Injections Botulinum toxin A has been widely used for neurogenic detrusor overactivity, overactive bladder, and detrusor-sphincter dyssynergia to help control urinary symptoms in patients with IC/BPS. Botulinum toxin A can inhibit the release of sensory nerve terminal vesicles, which can help reduce inflammation in addition to its effect on bladder motor activity.[31] It is effective for individuals with IC/BPS when used alone or with hydrodistension and can also reduce pain.[152][153][154][155][156][157][158] The overall success rate with botulinum toxin type A bladder injections is reported to be over 60%.[159] Retreatments with botulinum toxin A remained effective when the initial therapeutic benefit faded.[160] The European Association of Urology recommends hydrodistension followed by botulinum toxin detrusor injections for intravesical instillation therapy failures. Postvoid residual volumes tend to increase, and even successfully treated patients may notice some dysuria or difficulty in voiding. The therapy will eventually wear off after some months, so retreatments are to be expected. There is also a risk of urinary retention after botulinum toxin A bladder injections, which is why it is most useful in patients who can do intermittent self-catheterization if necessary. A 2020 meta-analysis reviewed treatment efficacy in IC/BPS symptom control from all available treatments as reported in 81 randomized, controlled trials. The review focused on antidepressants, neuromuscular blockade (botulinum toxin A), and pentosan polysulfate therapies. Intravesical instillations were not included due to inadequate numbers meeting reporting and statistical criteria. The study found improved outcomes only from botulinum toxin A therapy.[161]

A 2020 meta-analysis reviewed treatment efficacy in IC/BPS symptom control from all available treatments as reported in 81 randomized, controlled trials. The review focused on antidepressants, neuromuscular blockade (botulinum toxin A), and pentosan polysulfate therapies. Intravesical instillations were not included due to inadequate numbers meeting reporting and statistical criteria. The study found improved outcomes only from botulinum toxin A therapy.[161] Intravesical detrusor injections of botulinum toxin A are recommended in the AUA guidelines for use when other oral and intravesical options have failed, but only for patients willing and able to perform intermittent self-catheterization after treatment if necessary.[1] Alternate delivery systems that do not require detrusor injections are being studied. Cystoscopy Guided Treatment Cystoscopy is performed 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. Oral cyclosporine A is recommended if this fails. If no Hunner ulcers are found at cystoscopy, short-duration, low-pressure hydrodistension under anesthesia can be performed. Low-pressure, short-duration hydrodistension under anesthesia offers substantial pain relief to some patients but risks a temporary symptom flair.[162] High-pressure hydrodistension under anesthesia is not recommended due to inconsistent symptom improvement and an increased risk of sepsis and bladder rupture.[163] Neuromodulation Neuromodulation has been shown in most studies to be a reasonably effective treatment for controlling intractable bladder overactivity and chronic pelvic pain in some patients who have not achieved adequate symptom control with other modalities.[119] Neuromodulation therapy is FDA-approved only for intractable bladder overactivity and frequency, which seems more effective than its effect on pain control in IC/BPS.[1][118][120][164][165][166] Sacral neuromodulation has been shown in most studies to be a reasonably effective treatment for controlling intractable bladder overactivity and chronic pelvic pain in some IC/BPS patients.[118][119] It is FDA-approved only for severe bladder overactivity and frequency, for which it seems more effective than its effect on pain control in IC/BPS.[1][120]

Sacral neuromodulation has been shown in most studies to be a reasonably effective treatment for controlling intractable bladder overactivity and chronic pelvic pain in some IC/BPS patients.[118][119] It is FDA-approved only for severe bladder overactivity and frequency, for which it seems more effective than its effect on pain control in IC/BPS.[1][120] The treatment is relatively invasive, expensive, frequently requires reprogramming, may need a reoperation, and lacks long-term data on efficacy. Complications include infection or pain at the implantation site, lead migration, and loss of efficacy over time. Tibial nerve stimulation has also been beneficial in treating patients with IC/BPS.[121][122] A clinical trial of sacral neuromodulation or tibial nerve stimulation can be reasonably considered in selected IC/BPS patients who have failed other treatments.[1][118][120][121][122][123] Treatments Specifically Not Recommended Treatments that are specifically not recommended by multiple sources (the American Urological Association, the National Institute for Clinical Excellence, and the European Association of Urology) include the following: Intravesical BCG Intravesical clorpactin (oxychlorosene) Long-term oral antibiotics Prolonged high-pressure bladder hydrodistention Prolonged oral steroids Surgical Treatment Surgery 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. About 75% of patients can expect pain relief with open surgery. A urethrectomy is usually not necessary and adds considerable time and morbidity to the procedure.[167] A supra-trigonal bladder resection with augmentation ileocystoplasty has been suggested as it appears to be a successful surgical therapy for most of these patients and avoids the need for a urostomy.[167][168][169][170] Good results have been reported with over 14 years of follow-up using this procedure.[170][171] Concern about inadequate symptom control, if the trigone is not removed appears unfounded.[170][171] A combined robot-assisted laparoscopic and mini-laparotomy approach for this procedure has been described and used successfully.[167][170] A summary of possible last-resort surgical options includes the following: [172] Cystoplasty only

A supra-trigonal bladder resection with augmentation ileocystoplasty has been suggested as it appears to be a successful surgical therapy for most of these patients and avoids the need for a urostomy.[167][168][169][170] Good results have been reported with over 14 years of follow-up using this procedure.[170][171] Concern about inadequate symptom control, if the trigone is not removed appears unfounded.[170][171] A combined robot-assisted laparoscopic and mini-laparotomy approach for this procedure has been described and used successfully.[167][170] A summary of possible last-resort surgical options includes the following: [172] Cystoplasty only Cystoplasty with supra-trigonal resection Cystoplasty with sub-trigonal resection Urinary diversion, with or without cystectomy, usually with an ileal conduit Investigational Therapies Monoclonal antibody therapy has shown some promise, but additional research needs to be done to find the ideal antibody mix.[173] Certolizumab pegol is an investigational pharmacologic therapy under development for treating IC/BPS.[82] Chondroitin sulfate (2% solution) is approved for intravesical use in Europe and Canada. Chondroitin appears to repair, restore, or replace the mucosal GAG layer and is often used with hyaluronic acid.[174][175][176][177] Hyperbaric oxygen therapy appears beneficial in treating IC/BPS patients, but it requires a special chamber, is not very cost-effective, and is quite time-consuming.[178][179] There is limited data on long-term results. Intravesical liposomes have shown activity in reducing symptoms of IC/BPS.[180][181] Liposomes can be used as biocompatible lipid-based drug carriers for intravesical therapy. They tend to stick to the bladder walls, and their lipid-based walls reduce mucosal inflammation while promoting and facilitating drug penetration (such as Botulinum toxin type A) into bladder tissue.[181] While promising, only limited data is currently available, and long-term, randomized prospective trials are needed.

Intravesical liposomes have shown activity in reducing symptoms of IC/BPS.[180][181] Liposomes can be used as biocompatible lipid-based drug carriers for intravesical therapy. They tend to stick to the bladder walls, and their lipid-based walls reduce mucosal inflammation while promoting and facilitating drug penetration (such as Botulinum toxin type A) into bladder tissue.[181] While promising, only limited data is currently available, and long-term, randomized prospective trials are needed. Mesenchymal stem cells may be valuable in treating patients with IC/BPS as they have been shown to minimize bladder tissue injury and inflammation. After migrating into the detrusor tissue, they differentiate into bladder cells, inhibit mast cell buildup, decrease cellular apoptosis, reduce inflammation, mitigate oxidative stress, diminish collagen deposition, and promote normal regenerative functions. Mesenchymal stem cells also secrete exosomes and other factors that protect against tissue injury.[182] Platelet-rich plasma is widely used to promote wound healing.[183] It contains abundant cytokines and growth factors that affect the inflammatory process to promote healing and reduce neuropathic pain.[13][184][185] Direct platelet-rich plasma detrusor injections have been shown to increase urothelial cell growth, decrease inflammation, improve mucosal lining barrier function, repair ultrastructural damage, and relieve symptoms.[13][178][186][187][188][189][190] Low-energy shock wave therapy has experimentally shown a benefit in reducing bladder pain, decreasing tumor necrosis factor-α (TNF-α), and lowering nerve growth factor (NGF) in IC/BPS patients.[191] It suppresses bladder overactivity, reduces the inflammatory response, and increases urothelial permeability, making it potentially valuable for enhancing the penetration of therapeutic drug instillations of bladder tissue.[192]

Low-energy shock wave therapy has experimentally shown a benefit in reducing bladder pain, decreasing tumor necrosis factor-α (TNF-α), and lowering nerve growth factor (NGF) in IC/BPS patients.[191] It suppresses bladder overactivity, reduces the inflammatory response, and increases urothelial permeability, making it potentially valuable for enhancing the penetration of therapeutic drug instillations of bladder tissue.[192] A preliminary study has shown that low-energy shock wave therapy can allow for bladder muscle absorption of intravesical instillation of botulinum toxin A with a corresponding improvement in IC/BPS symptoms.[192] The benefit of this approach is that it does not require invasive detrusor injections or anesthesia, appears to be safe and effective with no reported adverse effects, and combines the benefits of 2 different therapeutic modalities. These results are very preliminary, and substantial study is needed before such treatments can be recommended for clinical use. The chronic inflammatory bladder changes and negative bacterial cultures associated with IC/BPS could be explained by a viral infection such as Epstein-Barr virus (EBV), found in up to 87.5% of patients.[193] This suggests the possible use of valacyclovir as an antiviral treatment in infected individuals. Early unpublished data suggest this may be a promising treatment, particularly for patients unresponsive to other therapies who are shown to have EBV exposure.[13] Treatment Summary Conservative treatment of IC/BPS involves dietary adjustments, pelvic floor relaxation therapies, myofascial release and trigger point therapy, and stress reduction. Initial oral pharmacotherapy includes amitriptyline, cimetidine, and hydroxyzine. Oral pentosan polysulfate may be effective in some patients but is associated with potentially significant and permanent retinal damage. OAB medications can help with urinary symptoms but are generally insufficient when used alone. Gabapentin may be useful for pain control. Cyclosporine A can be used in patients with Hunner ulcers who have failed fulguration and/or triamcinolone injection therapy. Intravesical instillations are very effective non-surgical therapies. Recommended drug cocktail options include DMSO, lidocaine (or bupivacaine) with sodium bicarbonate, and heparin. Additional intravesical drugs include chondroitin sulfate, hyaluronic acid, misoprostol, and triamcinolone.

Cyclosporine A can be used in patients with Hunner ulcers who have failed fulguration and/or triamcinolone injection therapy. Intravesical instillations are very effective non-surgical therapies. Recommended drug cocktail options include DMSO, lidocaine (or bupivacaine) with sodium bicarbonate, and heparin. Additional intravesical drugs include chondroitin sulfate, hyaluronic acid, misoprostol, and triamcinolone. Cystoscopy with low-pressure, short-duration hydrodistension and possible direct Hunner ulcer therapy should be considered for patients who continue to have symptoms. Patients who do not respond adequately to the above treatments may be candidates for the following: Botulinum toxin A detrusor injections Cyclosporine A Neuromodulation Misoprostol (oral or intravesical) Tibial nerve stimulation Definitive surgical therapy is reserved for patients who continue to have significant symptoms that have not been adequately controlled with any of the listed alternative treatments.

The possible list of differential diagnoses is extensive, and this list is not exhaustive, but the causes can be broken down into categories as follows: [194] Infections Sexually transmitted infections such as chlamydia and gonorrhoea Tuberculous infections of the bladder Urinary tract infections Urological and Urogynecological Conditions Bladder stones Chronic urethral syndrome Distal ureteral calculi Pelvic organ prolapse 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

The majority of patients suffer from chronic symptoms with periodic exacerbations and remissions of varying intervals, but there is a wide variation in prognosis, course, and resolution. Patterns of the disease have been observed and described. These include the following: Complete resolution Relapsing-remitting Intermittent disease flares Chronic progression The patient may also experience spontaneous resolution and unexpected recurrences regardless of treatment.[195] IC/BPS appears to be an extremely stable condition, as urinary symptoms and discomfort tend to remain unchanged in severity for up to 9 years.[196]

If left untreated and without spontaneous resolution, the bladder may undergo more fibrosis, further reducing the bladder volume and further compounding the symptoms experienced. The patient would experience psychological and social health deterioration through sleep disturbance, sexual dysfunction, anxiety, depression, and social embarrassment. Treatment complications depend on various factors, such as the pharmacological agent, cystoscopy, or surgical complications. Proper counseling and consent before treatment are paramount.[197] Complications can be broadly categorized as: Bleeding COVID-19 [198] Death (from procedure or anesthesia) Infection (introduced through intravesical routes or surgery) Perforation of the bladder during high-pressure hydrodistention Trauma Anesthetic complications are predominantly due to human factors and have an estimated mortality of 0.4 per 100,000 patients.[199] Anesthetic complications include the following: [200] Anaphylaxis Aspiration Cardiovascular collapse Medication errors Nausea and vomiting Respiratory depression 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, bladder damage, and symptoms. A short course of therapeutic antibiotics could be started in selected cases like these, but prolonged treatment is not recommended for therapy or prophylaxis.

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 local support groups, such as those offered by the Interstitial Cystitis Association (https://www.ichelp.org/) in the United States and Bladder Health UK or PainUK in the United Kingdom. Some patients who have used self-help resources found it a very effective treatment option.[201] 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. Patients must understand that the condition may not be cured, and symptoms may return anytime. However, with proper treatment, there can be significant improvements in symptoms and quality of life.

Recent evidence suggests that many men diagnosed with chronic prostatitis/chronic pelvic pain syndrome may have IC/BPS as the symptoms are very similar, and each is a diagnosis of exclusion.[3][4][5][6][7] Men diagnosed with chronic prostatitis/chronic pelvic pain syndrome 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.[3][4][5][6][7] Pudendal neuralgia and nerve compression should also be considered when dealing with patients with IC/BPS symptoms, especially those unresponsive to conservative, oral, and intravesical therapies.[202] Pain management should be involved in the care of patients with IC/BPS who have ongoing chronic pain. Before progressing to invasive therapies when oral and intravesical instillations have failed, consider a trial of cyclosporine A, misoprostol (oral or intravesical), botulinum toxin A, or neuromodulation therapy. Failure of all non-invasive therapies should suggest a reconsideration of the underlying diagnosis. There is no need to wait for oral therapies to fail before starting intravesical instillations in appropriate cases. A number of urinary inflammatory biomarkers are increased in IC/BPS, such as TNF-α, PGE2, IL-6, and IL-8, although the diagnostic and clinical utility of this finding still needs to be determined.[35] A clinically useful biomarker for IC/BPS is still awaiting discovery.[20] Supplements For most dietary supplements used for pelvic pain or IC/BPS, there is only very limited scientific data or proof of efficacy, but there is some interesting, if limited, favorable evidence: L-arginine at a dose of 1,500 mg/day has been shown to improve symptoms of IC/BPS by increasing urinary nitric oxide synthase activity in a preliminary randomized, double-blinded, placebo-controlled trial. About half of the patients treated noted symptomatic improvement.[203] Omega-3 fatty acids and alpha lipoic acid are effective anti-oxidants and have shown some anti-inflammatory effects and pelvic pain relief.[204][205] Quercetin is a bioflavonoid that may also help reduce inflammation by scavenging free radicals. It has shown some clinical activity in improving symptoms in IC/BPS in a limited study that was not placebo-controlled or randomized.[206]

Omega-3 fatty acids and alpha lipoic acid are effective anti-oxidants and have shown some anti-inflammatory effects and pelvic pain relief.[204][205] Quercetin is a bioflavonoid that may also help reduce inflammation by scavenging free radicals. It has shown some clinical activity in improving symptoms in IC/BPS in a limited study that was not placebo-controlled or randomized.[206] Calcium glycerophosphate should be taken before meals, especially before eating foods known to trigger an IC reaction. A survey by the Interstitial Cystitis Association reported that 75% of patients who tried the supplement thought it provided some symptomatic benefit. A 2001 prospective nonrandomized study of over 200 IC patients reported a benefit in >40% of participants.[207] There are some anecdotal reports of a benefit from oral hyaluronic acid therapy, but no formal published studies exist. Bladder Cocktails for Intravesical Instillation Home bladder cocktail instillations done by the patient are preferred over office/clinic administration whenever possible. A typical schedule might be weekly instillations until symptom control is reached. Then, the interval between instillations is slowly extended as tolerated. Some experts recommend having 2 intravesical cocktail formulas available: one with DMSO and the other without. If the original cocktail selected appears to be losing effectiveness or is unacceptable for some reason, the second formula can be substituted. In this way, intravesical therapy is maintained as it remains the single most effective overall non-surgical treatment. While there is no accepted standard intravesical cocktail, several noted experts have published their own personal recipes: 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 mL–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. Dimethylsulfoxide (DMSO) Cocktail Gentamicin 80 mg in 5 mL Heparin 10,000 IU–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

Dimethylsulfoxide (DMSO) Cocktail Gentamicin 80 mg in 5 mL Heparin 10,000 IU–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 mL–40 mL Heparin 10,000 IU–20,000 IU Gentamicin 80 mg Triamcinolone 40 mg (Increase to 80 mg in patients with documented Hunner ulcer) Schedule: Weekly instillations in the office/clinic May also be self-administered by patients at home up to 3 times weekly. Increase the interval between instillations as symptoms improve. Maximum symptom improvement is expected by 12 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 6 to 8 weeks. Increase the interval between instillations as symptoms improve. Use B&O suppositories if patients cannot 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 3 months) Heparin 10,000 IU in 10 mL Hydrocortisone 100 mg: 5 mL of normal saline Sodium Bicarbonate 8.4%: 40 mL–50 mL Schedule: Six weekly instillations. Should be administered during a premenstrual flare when possible. Appropriate for patients who can self-catheterize and administer at home.

IC/BPS is a long-term, chronic condition that can significantly negatively affect the patient's quality of life and physical, psychological, and social health. The condition is often not easily managed by 1 intervention alone, and many physical and psychological comorbidities often exist. Therefore, an interprofessional team approach involving different specialties is best suited to offer optimal care to the patient. Urologists, pain management specialists, gynecologists, urogynecologists, primary care physicians, specialist nurses, mental health professionals, pharmacists, dieticians, social workers, physical therapists, and other healthcare professionals all play crucial roles in delivering comprehensive care.[161][208] Healthcare professionals must possess specialized skills in recognizing, diagnosing, and managing IC/BPS. This includes proficiency in conducting cystoscopy and urodynamics to confirm the diagnosis and a deep understanding of the latest treatment modalities and therapeutic options. Developing evidence-based treatment plans tailored to each patient's specific needs is vital. Strategies should encompass dietary modifications, physical therapy, and pharmacological interventions. Furthermore, clinicians must be well-versed in monitoring patient progress and adjusting treatment regimens accordingly. Effective communication among team members is paramount. Clinicians should exchange information about patient progress, potential complications, and treatment adjustments to ensure cohesive and comprehensive care. Collaboration fosters a holistic approach to addressing the physical and emotional aspects of IC/BPS. IC/BPS care is most effective when healthcare professionals collaborate to provide patient-centered, evidence-based care. The combined efforts of an interprofessional team are critical for enhancing the quality of life and overall well-being of individuals living with IC/BPS.