This chapter should be cited as follows:
Castellanos, M, Desai, N, et al, Glob. libr. women's med.,
(ISSN: 1756-2228) 2012; DOI 10.3843/GLOWM.10471
This chapter was added to the website: October 2012

Interstitial Cystitis & Bladder Pain Syndrome

Mario E. Castellanos, MD
Faculty Physician, Division of Surgery and Pelvic Pain, Department of Obstetrics and Gynecology, St Joseph’s Hospital and Medical Center, Phoenix, Arizona; Clinical Instructor of Obstetrics and Gynecology, University of Arizona College of Medicine, Phoenix, Arizona; Instructor of Obstetrics and Gynecology, Creighton University School of Medicine-Phoenix Campus, Phoenix, Arizona, USA mario.castellanos@dignityhealth.org
Nita Desai, MD
Faculty Physician, Division of Surgery and Pelvic Pain, Department of Obstetrics and Gynecology, St Joseph’s Hospital and Medical Center, Phoenix, Arizona; Clinical Assistant Professor of Obstetrics and Gynecology, University of Arizona College of Medicine, Phoenix, Arizona; Instructor of Obstetrics and Gynecology, Creighton University School of Medicine-Phoenix Campus, Phoenix, Arizona, USA
Michael Hibner, MD, PhD
Director, Division of Surgery and Pelvic Pain, Department of Obstetrics and Gynecology, St Joseph’s Hospital and Medical Center, Phoenix, Arizona; Clinical Associate Professor of Obstetrics and Gynecology, University of Arizona College of Medicine, Phoenix, Arizona; Professor of Obstetrics and Gynecology, Creighton University School of Medicine Phoenix-Campus, Phoenix, Arizona, USA michael.hibner@dignityhealth.org

INTRODUCTION

Interstitial cystitis or bladder pain syndrome is a common, yet often unrecognized cause of chronic pelvic pain (CPP). CPP is defined as noncyclical pelvic pain for at least 6 months and makes up about 10% of referrals to gynecology practices.1 A study by Parsons et al. found that only 2% of patients with CPP were correctly diagnosed with interstitial cystitis by gynecologists, while the rest of the 98% of patients received gynecological misdiagnosis.2 Indeed, it is well documented that patients with CPP have multiple sources for their pain.1 3 The bladder is one of the most sensitive organs in the pelvis and one of the most common sources of pain in patients with CPP.4 Up to 81% of patients with CPP will have bladder involvement2 and 79% of women with persistent CPP after hysterectomy are diagnosed with interstitial cystitis.5 Therefore, interstitial cystitis may be the most common reason for failure of hysterectomy to alleviate pelvic pain. Recent changes have broadened the definition of interstitial cystitis to recognize early disease states rather than when pathology is present. Thus, the term bladder pain syndrome (BPS) has replaced interstitial cystitis to focus on patient’s clinical presentation and symptoms. The bladder plays an important role in contributing to CPP; thus, early recognition of painful bladders may contribute to better treatment outcomes.6

DEFINITION

The American Urological Association (AUA) defines BPS as “an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms of more than 6 weeks duration, in the absence of infection or other identifiable causes.”7 Thus it is largely a diagnosis of exclusion after a reasonable investigation for infection, malignancy, and other urinary tract problems.

Over the past century, the term “interstitial cystitis” has been replaced with terms such as “painful bladder syndrome” or “bladder pain syndrome”.8 This replacement recognizes the disease has changed from being described as an inflammatory process to a condition described in terms of symptoms. In 1887, Alexander Skene was the first to use the term interstitial cystitis to describe an inflammation that destroys the bladder mucosa.9 Guy Hunner further supported this idea by describing patients with hemorrhagic areas in the bladder later know as Hunner’s ulcers.10 As the disease became more well known, physicians discovered that the majority of patients with BPS symptoms did not have any inflammatory findings on cystoscopy.11 Thus, the idea that the disease existed as a spectrum with early disease not having any physical findings was proposed.

In 1990, the National Institute of Diabetes, Digestive, and Kidney Disorders (NIDDK) established the revised NIDDK Criteria for BPS to guide clinicians and researchers to an accepted definition of BPS. The criteria were listed as follows: pain associated with the bladder or urinary urgency and glomerulation or Hunner’s ulcer in a patient with symptoms for 9 months or more, with at least eight voids per day, one void per night, and cystometric bladder capacity less than 350 ml.12 Nevertheless, 60% of patients with BPS are excluded by this definition.13 Thus, the NIDDK criteria should be used as guidelines to uniform research populations and should not be used to diagnosis or rule out BPS.

EPIDEMIOLOGY

It has been estimated that 15% of women suffer from CPP. Although most patients remain undiagnosed, BPS is the second most commonly diagnosed pelvic pain syndrome.4 Given that BPS likely remains under recognized, population based studies likely underestimate the prevalence of the disease. Studies relying on survey participants’ self-reported disease estimated that 850 per 100,000 women have BPS.14 The RAND Interstitial Cystitis Epidemiology (RICE) study surveyed 150,000 households with validated BPS questionnaires.15 Their results found that 2.7–6.5% of women have symptoms consistent with BPS. BPS is more commonly diagnosed at age 40 and above and five times more likely to occur in women than in men.16

ETIOLOGY

The etiology of BPS is unknown. A common view of BPS is based on repetitive physical bladder insults leading to chronic and progressive injury to the bladder epithelium. Disruption of the glycosaminoglycan (GAG) layer has been proposed to lead to mucosal injury, thereby allowing noxious substances, such as potassium, to gain access to submucosal nerve filaments.17, 18 Indeed, increased permeability has been demonstrated by electron microscopy.19 Subsequently, mast cell activation releasing inflammatory mediators such as histamine, leukotrienes, and cytokines, likely mediate bladder damage.20 Edema, fibrosis, and neogenesis, which are evident in ulcerative BPS, may be a result of mast cell activation. Furthermore, it has been shown that urethelial cells from BPS patients have decreased production of epithelial growth factors and decreased antiproliferative factor.21, 22 Thus, bladder damage may not be adequately repaired, leading to persistent bladder insult.

An alternative view is that BPS results from bladder sensitization by concomitant pelvic pain disorders such as endometriosis, vulvodynia, and hypertonic pelvic floor disorders.23, 24 Prolonged noxious stimuli from CPP leads to biochemical upregulation in the dorsal horn and central sensitization. Pain impulses become amplified which then generate new pain impulses. This physiological “wind-up” leads to expanded areas of perceived pain and decreased sensory thresholds leading to allodynia. Pain is then often localized in the bladder, as it becomes more sensitive to noxious stimuli in the urine, such as potassium, leading to frequency and urgency. Indeed, it has been shown that the bladder has increased nerve density in patients with BPS.25

Neuroinflammatory changes may lead to pelvic organ “cross talk.”26 This “cross talk,” or visceroviceral hyperalgesia, is the reason why BPS is seen with other pelvic pain disorders such as irritable bowel syndrome, vulvodynia, and endometriosis. Indeed, 80% of patients with endometriosis have BPS.27 Visceromuscular hyperalgesia reflex seen in BPS causes pelvic floor muscle spasms. Hypertonic pelvic floor muscles are seen in 80% of patients with BPS28 and are the main factor in voiding dysfunction such as urinary hesitancy and incomplete bladder emptying. Indeed, these patients are often found to have elevated urethral pressures from muscles spasms and not from urethral stricture as previously thought.29 Thus, urethral dilation is a poor treatment option that does not properly recognize the pathophysiology behind the disease. Urethral obstruction from pelvic floor spasms may lead to c-fiber upregulation and neuroinflammatory damage to the bladder. Visceromuscular hyperalgesia is a vicious cycle that self-perpetuates visceral pelvic pain disorders and BPS (Figure 1).

Fig. 1. Visceromuscular hyperalgesia is a vicious cycle that self-perpetuates visceral pelvic pain disorders and BPS





Sparse evidence has implicated other possible underlying causes of BPS. Serum immunoglobulins and depletion of serum complement levels may reflect an autoimmune component to BPS.30 Immunopathological examination has shown immune deposits in the bladder wall.31 This etiology may represent a small subset of patients but does not explain this complex disorder. Indeed, genetic predisposition has been implicated. Reports find a greater concordance among monozygotic twins.32 Also, first-degree relatives are 17 times more likely to have BPS.33

CLINICAL PRESENTATION

Pelvic pain, or suprapubic pain, is the most common presenting complaint of patients with BPS.34 The most common accompanying urological complaints, present in 44–98% of patients are urinary urgency, daytime frequency, and nocturia. At initial presentation, symptoms are usually mild, but progress over time. In fact, 60% of patients report gradual onset of symptoms.35 Although 40% of patients first present with pain, symptoms usually progress from urgency/frequency to nocturia to pain. Patients who were symptomatic for less than 5 years were less likely to experience all of these symptoms compared to patients who were symptomatic for more than 15 years.36

Worsening pain with a full bladder, especially early morning that is relieved by voiding is characteristic of BPS. Certain foods or drinks may aggravate symptoms in up to 50% of patients.34 Most patients may not have identifiable food triggers, but common aggravating foods include caffeine, alcohol, carbonated beverages, and acidic foods and drinks.

Urinary frequency in BPS often overlaps with overactive bladder. About 14% of patients will have urodynamic detrusor instability.37 The differentiating factor is the perception of urinary urgency. Patient with BPS have continuous urgency to pain/discomfort and pressure, while overactive bladder symptoms are intermittent and associated with fear of leakage.38

Although urinary frequency and urgency are usually present, about 15% of patients with BPS do not have any urological complaints.39 These patients often present to their gynecologist with complaints that may be reasonably confused with gynecological pain. Symptoms include vaginal, vulvar, and abdominal pain, dyspareunia, and even dysmenorrhea. Dyspareunia occurs in 70% of patients with BPS and may be more often present in the quadrapedic position. Postcoital dyspareunia, from pelvic floor muscle spasms, is present for several days in 46% of patients.2 Premenstrual flares are common and may be confused with dysmenorrhea of uterine origin.

Hesitancy, or delay in starting a void, is likely pathognomonic for hypertonic pelvic floor disorders. These patients have muscles spasms that prevent the relaxation necessary for voiding.24 Patients may need several minutes to start and finishing voiding, and exhibit postvoid dribbling. Incomplete emptying may then lead to frequency and stress urinary incontinence.

Inciting events are usually not noted, but patients may relate pelvic trauma such as infections, surgery, falls, or vaginal deliveries. These events offer clues to the root of their pain. For instance, BPS after a vaginal delivery may be related to spasm of the pelvic floor muscles or pelvic congestion syndrome. Falls may point to pelvic neuropathies such as pudendal neuralgia.

Quality of life is severely affected. Patients are six times more likely to miss work40 and have a higher incidence of depression, chronic pain, and anxiety.41, 42 Symptoms typically associated with lower quality of life are nocturia and pain intensity.43

On physical examination, patients have variable tenderness of the abdominal wall, especially in the suprapubic region. Pelvic exam may reveal tenderness of the pelvic floor muscles and the anterior vaginal wall. In fact, anterior vaginal wall tenderness, tenderness of the bladder palpated vaginally, is 85% predictive of BPS.44 Cervical motion tenderness seen in 21% of patients34 may be confused with uterine and intraperitoneal pathology such as endometritis and endometriosis. Tenderness from palpation of the cervix is likely referred pain from the bladder, associated with the lower uterine segment and anterior cervix. Vulvodynia is present in 3% of patients with BPS.34

DIAGNOSIS

BPS is difficult to diagnosis secondary to the broad spectrum of presentations and physical exam findings. Efforts to diagnose the disease based on testing and stringent diagnostic criteria, such as the NIDDK criteria, result in significant misdiagnosis and delay in diagnosis. Therefore, diagnosis is largely based on clinical suspicion, after reasonable investigation excludes other treatable conditions.

A thorough medical history should include onset of symptoms and the extent and localization of pain. Pain mapping on a diagram is often useful and may guide clinicians in their assessment. Voiding symptoms such as frequency, urgency, and hesitancy should be meticulously detailed. If the history is unclear, a 24 hour voiding and intake diary can elucidate frequency and urinary retention. Symptoms starting after events such as surgery, vaginal delivery, and falls may point to underlying conditions that may be contributing to BPS. Many patients with hypertonic pelvic floor disorders have childhood elimination disorders.45 Learned dysbehaviors during potty training years can lead to hypervigilance and pelvic floor contractions, with inability to relax to void.

Validated questionnaires have been developed to evaluate BPS using symptom scales. These questionnaires, such as the Pelvic Pain, Urgency, Frequency Scale (PUF) and O’Leary-Sant Symptom and Problem Indexes, are used to assess symptom severity and monitor clinical progress, but are not considered reliable for diagnosis. Nevertheless, the PUF questionnaire is helpful when evaluating patients with CPP to screen for BPS. Indeed, PUF scores correlate with the likelihood of having a positive potassium chloride test which is suggestive of BPS.2

Physical examination should be performed to elicit bladder tenderness and identify trigger points that reproduce the patient’s pain experience. Tenderness of the bladder may be elicited via palpation of its base through the anterior vaginal wall. The pelvic floor muscles may be tender and hypertonic. The physical exam should also be used to exclude other pathology. Common conditions confusable with BPS can be discovered on exam, such as vaginal cuff neuromas, incisional neuromas, illioinguinal and genitofemoral neuralgias, pudendal neuralgia, and pelvic floor tension myalgia. For more information, the International Pelvic Pain Society publishes an update questionnaire and physical exam guidelines for the assessment of CPP. It is available online at: www.pelvicpain.org

Initial laboratory tests should include urine analysis and culture. Hematuria may point to renal pathology or bladder ulcerations and many patients may have persistent urinary tract infections. Although not routinely recommended by the AUA, urine cytology can be easily sent to investigate for occult bladder cancer. If urethral pain is the chief complaint, urethral cultures should be sent separately.

Urodynamics

Urodynamics is a useful tool for patients who present with multiple urological complaints, such as urgency and incontinence. In fact, 14% of patients with PBS will have urodynamic bladder instability.37 High urethral pressure is often associated with hypertonic pelvic floor disorders and is on average equivalent to 131 cm3 of water pressure.29 This high pressure may point to obstructive voiding symptoms. Other urinary problems may be encountered, such as small bladder volume, which is strongly associated with urgency.46 Although not required, urodynamics are useful for initial assessment and to monitor treatment outcomes objectively in patients with urodynamic abnormalities.

Potassium stress test

Potassium stress test (PST) can be used to assist in the diagnosis of BPS, by demonstrating the bladder as the origin of the patient’s symptoms. Infusion of 200 mEq of potassium chloride into the bladder provokes symptoms such as pain and urgency, in patients with BPS. The PST is used to identify dysfunctional epithelium, which allows potassium to penetrate the interstitium and polarize sensory nerves.

Recent AUA guidelines in 2011 do not recommend PST.47 The AUA argues that only 60% of patients who meet the NIDDK criteria test positive, and therefore it is not specific for BPS. Nevertheless, one must remember that the NIDDK criteria can also exclude 60% of patients with BPS. The PST has a sensitivity and specificity of 80% and 97%, respectively.48 False positives, positive tests in truly asymptomatic patients, are seen in only 2%. The PST is an important part of the evaluation of patients with CPP. It can identify the bladder as a significant generator of pain in the pelvis, though should not be used alone for diagnosis.

Analgesic bladder challenge

Anesthetizing the bladder may determine whether the bladder is the origin of pain by proving pain relief. Local anesthetics such as 2% lidocaine or commercially available cocktails are infused into the bladder. This test may be implemented in patients with a high clinical suspicion for BPS, despite having a negative PST, or in a patient where the clinical picture is unclear. About 71% of patients with pelvic pain may respond to a bladder challenge, corresponding to a 50% reduction in visual analogue scale (VAS) score.49 Positive response may guide treatment planning with further bladder instillation.

Cystoscopy with hydrodistension

Cystoscopy with hydrodistension was once considered the gold standard; however, it is no longer a requirement for the diagnosis of BPS. Characteristic findings on cystoscopy include glomerulations (punctate petechial hemorrhages), terminal bleeding, ulcers, scars, and small bladder capacity.49 Ulcerations and small bladder capacity are associated with pain severity and urinary frequency, respectively. Nevertheless, no study has correlated other cystoscopic appearance with disease severity.46 In fact, these findings may be evident in asymptomatic women.50

Biopsies may be taken during cystoscopy from visually abnormal areas to rule out malignancy. Cystoscopy is thus necessary in patients older than 40 years of age who present with risk factors for bladder cancer, such as smoking. Although mast cells may be elevated in patients with BPS,51 no pathological findings are diagnostic of BPS.52 Hydrodistension of the bladder during cystoscopy may result in transient improvement of symptoms in 50% of patients, that may last for a several months.53

DIFFERENTIAL DIAGNOSIS

BPS frequently coexists with other pelvic pain syndromes, thus, it has broad clinical presentations. Recognizing and evaluating associated symptoms may prevent misdiagnosis or over-diagnosis of BPS. It is important to consider more common diseases that may be treatable (Table 1).

 

Table 1. Differential diagnosis of BPS

Confusable Disease

Carcinoma and carcinoma in situ

Infections (bacteria, tuberculosis, herpes, chlamydia)

Recurrent urinary tract infections

Radiation cystitis

Bladder stones or bladder neck obstruction

Urethral diverticulum

Pelvic prolapse

Endometriosis

Vaginal candidiasis

Overactive bladder

Pudendal neuralgia

Vulvodynia

Pelvic floor hypertonic disorders

TREATMENT

Since BPS is frequently associated with other pelvic pain syndromes, study populations are likely to be diverse in their etiology of pain. Thus, studies are difficult to control and no single treatment has been shown to be universally effective. There is a lack of accurate diagnostic testing and no single test has been correlated with treatment response. CPP from BPS arises from multiple organ systems, and it is important to combine multiple treatments to achieve better long-term outcomes.

Conservative treatment

Behavior modification focuses on avoiding stressors and retraining learned behaviors. Therapy includes timed voiding, controlled fluid intake, dietary modification, stress reduction, and physical therapy. Timed voiding can improve urinary frequency in 50% of patients, but there is no effect on urgency or pain.54, 55 Eliminating caustic foods, such as acidic beverages, caffeine, spicy foods, and alcohol has been reported to help patients with pain.56 However, strict avoidance is unnecessary if the patient does not immediately benefit from the food elimination. Food diaries can help patients identify irritating foods.

Hypertonic pelvic floor disorders are an important component of BPS leading to obstructive voiding symptoms and dyspareunia. In addition, visceromuscular hyperalgesia promotes bladder injury by inducing a neuroinflammatory response. Pelvic floor physical therapy has been shown to improve urinary frequency, urgency, and coital pain. Biofeedback and myofascial releases stimulates relaxation of the pelvic floor muscles.57 A recent randomized controlled trial showed that 59% of patients with BPS has moderate to marked improvement.58 Treating the pelvic floor is an important component of BPS and necessary for breaking the vicious cycle of CPP.

Related to pelvic floor muscles spasm, stress is believed to contribute to both muscle spasms and an overall decrease in quality of life. Known mental and physical stressors, such as emotional hardships, long work hours, and physical activity, intensify pain.59Interestingly, many patients with stressors describe improvement in pain after a good nights rest. Patients with associated psychosocial issues should seek treatment and counseling. Support groups are important outlets for patients to cope with their pain and support each other through treatment.

Oral medications

Medications are commonly prescribed for BPS, but only a few have been studied in randomized controlled trials. Given the broad clinical definition of BPS, selection of medical therapy should be tapered to address specific patient symptoms.

Analgesics

When used appropriately, treatment with analgesics is an important aspect of the treatment of chronic pain.60 Nonsteroidal anti-inflammatory drugs (NSAIDS) and acetaminophen may be used initially in patients with mild to moderate pain. Urological analgesics such as Uribel or Phosphasal that are excreted in the urine have been used with good anecdotal results. When these analgesics fail, opioids may be considered. Although there is concern regarding addiction and dependence, treatment of severe pain should not be withheld. Longer acting medications minimize anxiety and pain associated with short acting opioids. Co-management with a pain specialist can be helpful in patients who require chronic narcotic use.

Antidepressants

Tricyclic antidepressants, such as amitriptyline, may have anesthetic effect on the bladder by blocking H1-histaminergic receptors. This blockage inhibits mast cell activation and may improve epithelial damage. Also, it inhibits synaptic reuptake of serotonin and norepinephrine, and inhibits painful stimuli at the level of the central nervous system. Amitriptyline taken at bedtime offers sedation leading to relaxation of the pelvic floor and facilitates urinary storage. A double blind randomized controlled trial of 50 patients taking 100 mg of amitriptyline daily vs. placebo showed a 42% improvement, compared to 13% in the placebo group.61 A follow-up study showed 64% of patients with positive response at 19 months.62

Antihistamine

BPS from mast cell activation suggests that antihistamines may be an effective treatment method. Cimetidine, an H2 inhibitor, has shown promise in a small non-controlled clinical trial. In 31 patients treated with 200 mg TID, 75% improved, with 45% of that cohort being pain free.63 A later report showed 67% of patients with complete relief of symptoms over 4 years.64 Therefore, in patients where mast cell activation is suspected, a trial of antihistamines is a reasonable and safe treatment for BPS.

Immunosuppressants

These medications may also prevent mast cell activation and inflammatory responses that lead to BPS. Cyclosporine is commonly used for organ transplantation and been under investigation for BPS. Doses range from 1.5 to 3 mg/kg daily. In a study of 11 patients, frequency, pain, and bladder capacity all improved. Follow-up for 60 months showed continued improvement of symptoms.65

Sodium pentosan polysulfate

Sodium pentosan polysulfate (Elmiron) is the only FDA approved oral medication for the treatment of BPS. It is excreted into the urine and purportedly replenishes the GAG layer that is damaged in BPS patients. A 3–6 month course is usually required to determine efficacy. Most of its side-effects such as nausea, diarrhea, and headaches are tolerable. Alopecia is the most concerning for patients, occurring in 4%.

Elmiron has been extensively studied with randomized controlled trials.66, 67, 68, 69 Nevertheless, results were conflicting with two trials showing unfavorable results. Trials that showed improvement had a response rate of 1/3. Although statistically significant, response was seen in only a minority of patients. Unfortunately, no study has yet identified in which subset of patients Elmiron may be more beneficial. Therefore, it is reasonable to consider Elmiron as a first-line treatment, but patients should be counseled on its low efficacy rate and long treatment course.

INTRAVESICAL THERAPY

Bladder instillations are an important part of treatment of BPS. It is a technique by which medications are infused directly into the bladder to help with pain and possible repair of the epithelium. Treatment courses may consist of daily to weekly instillations that are slowly tapered to effect. It may also be used as a rescue therapy for unpredictable flares. Although many patients benefit from these treatments, they usually do not offer long-term remission.

Dimethyl sulfoxide

The only FDA approved instillation, dimethyl sulfoxide (DMSO), has been well studied in the literature. It works by reducing inflammation and degranulating mast cells, thereby repairing the bladder layer and eliminating pain. There are no standardized instillation methods, but typically, 50 ml of 50% DMSO is instilled for 10–20 minutes weekly for 6–8 weeks. If improvement is noted, monthly maintenance treatments are recommended. Case series and retrospective studies have shown about an 80% improvement rate.70, 71, 72 Side-effects include garlic-like odor and worsening of symptoms from bladder irritation. Long-term relief is uncommonly achieved, and patients may need continued bladder instillation treatment.

Heparin

Owing to the side-effects of DMSO, heparin has gained an increase in popularity. Theoretically, heparin replenishes the GAG layer in the bladder, thereby decreasing inflammation and increasing bladder capacity. Instillations are generally combined with 1–2% lidocaine for pain and sodium bicarbonate to reduce acidity. Parson et al. reported an 80% success rate.73 Heparin, at 20,000–50,000 units, is used and instilled 3 times a week for 2 weeks. Preprepared solutions are available on the market and may be used at home daily or for rescue therapy. It may be important for patients to have immediate access to this instillation to effectively manage their acute pain.74, 75

Other instillations

Many other medications have been trialed with varying results for patients who do not respond to DMSO or heparin.8 Pentosan polysulfate has recently been given intravesical route as an off-label use. Despite small studies showing possible improvement over oral Elmiron,76 more studies are required to directly compare this treatment with other instillations.

Botox injections into the trigone and lateral bladder walls have been investigated as a neuromodulator to inhibit pain. Small studies have found short-term benefit in the majority of patients with most patients returning to baseline symptoms by 5 months.77, 78 Side-effects include dysuria and incomplete bladder emptying. Patients who benefit from Botox injections usually need repetitive injections every 3–5 months. For patients with pelvic floor tension myalgia associated with BPS, Botox injections into the pelvic floor muscles have been shown to be beneficial in patients with CPP in several small studies.79 In a study by Hibner et al., 30 patients with BPS were treated with Botox injections into the pelvic floor muscles with 73% of patients responding to treatment for 3–4 months.80 Further randomized control trials are necessary to validate the use of Botox.

Neuromodulation

Sacral nerve stimulation has been FDA approved for the treatment of refractory detrusor overactivity. It stimulates the S2–S4 nerve roots and modulates the detrusors and urethral sphincter function. Although well documented for overactive bladder, it is considered investigational for BPS.81, 82 Several small studies have shown improvement. Most notability, Comiter et al. in 2003 showed that 16 of 17 patients with 14 month follow-up showed improvement in frequency, nocturia, bladder capacity, and pain scores.83 Therefore, a trial of neurostimulator may be considered in patients who have been refractory to other treatment modalities.

Surgical treatment

HYDRODISTENTION

Hydrodistention of the bladder has long been a treatment for BPS. Despite published protocols, most physicians practice various methods for distending the bladder.84 The mechanism of action of bladder distention remains obscure. Stretching the bladder wall may increase bladder capacity and induce ischemic necrosis of sensory nerve fibers thereby improving frequency and pain.85 Also, there is some evidence that the GAG layer is replenished postoperatively.86 However, these effects are short lived leading to eventual loss of treatment efficacy.53

Most studies are small and retrospective, using multiple distention protocols and inclusion criteria. Studies involving prolonged hydrodistention (more than 6 minutes) have shown some promise. On average, most positive studies show a 70% efficacy rate lasting for 3–6 months.87, 88, 89 Long-term follow-up shows regression of symptoms, with only a few patients maintaining improvement after 1 year of treatment.88 Complications include bladder perforation and urinary retention. Bladder necrosis has been reported as a very rare complication.90 Unfortunately, distention studies are difficult to blind and randomize given the postoperative pain associated with distention.

RESECTION OF HUNNER’S ULCERS

Hunner first recognized ulcerations during cystoscopy in patients with BPS. Resection of these ulcers would result in symptom resolution. In a retrospective study, 103 patients with Hunner’s ulcers underwent resection of the underlying muscular coat. Ninety-two of the 103 patients showed clinical improvement for an average of 23 months. Recurrence was treated by repeat resection.91 Complications included bladder and bowel perforation. Although there are no randomized control trials, given the high success rate, resection of Hunner’s ulcers is recommended if they are visualized.

DENERVATION PROCEDURES

Peripheral, sympathetic, and parasympathetic denervation of the bladder has been studied. Eliminating innervation would reduced neuroinflammation and prevent nociceptive pain. Nevertheless, outcomes of these small studies are unclear with bladder areflexia found to be a significant complication. Therefore, these treatments are not recommended for the treatment of BPS.8

BLADDER RESECTION

For severe refractory cases of BPS, cystoplasty and urinary diversion, with or without total cystectomy and urethrectomy, has been advocated. The goal of this procedure is to resect bladder affected by end stage BPS. Supratrigonal cystectomy with bowel augmentation has been reported with favorable outcomes. Kontturi et al. reported five cases with sigmoid colon augmentation that were pain free over 4.7 years.92 A recent study showed patients with ulcerative BPS had excellent results following ileocystoplasty as compared to non-ulcerated BPS.93 Subtrigonal cystoplasty does not confer better outcomes, but is associated with more complications and poor return of bladder function.

The most invasive option for the treatment of BPS, and therefore used as a last resort, is urinary diversion with formation of an ileal conduit. Most physicians would perform a urinary diversion, and reserve cystectomy if bladder pain symptoms continue. Continent diversion is also offered for cosmetic results, but pain recurrence may occur at the pouch.94 Good responses to diversion have been reported in small studies.95

SUMMARY

BPS is a complex pelvic pain syndrome, in which multiple organ systems contribute to the patient’s unique pain experience and clinical presentation. It is a devastating and often lifelong disease that affects the patient’s productivity and personal relationships. Although BPS is termed to reflect bladder pathology, the bladder may not be the primary source of pain. A comprehensive evaluation of the patient’s pain may reveal other contributing factors that stimulate bladder pain such as endometriosis, pelvic floor muscle spasms, and pelvic neuralgias. On the other hand, careful examination may reveal the bladder as the sole source of pain in patients who may otherwise not have any urological complaints. Potassium stress testing and anesthetic bladder challenges can add supportive evidence that the bladder is involved in pelvic pain. Indeed, 85% of patients with CPP will have bladder involvement and therefore it is important to address this pain to improve treatment outcomes. There is no universally accepted treatment of BPS, reflecting its the multifactorial etiology. A thorough evaluation with subsequent treatment of pain is vital to offer a comprehensive approach to the treatment of BPS.

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