Bladder Pain Syndrome

Bladder pain syndrome/interstitial cystitis (BPS/IC) is a syndrome primarily based on symptoms of urgency, frequency, and pain in the bladder and/or pelvis. These collective terms describe debilitating, chronic bladder disorders of unknown causes with an exclusion of confusable diseases. Current data show that the condition is much more prevalent than previously thought. BPS/IC is also a disorder of the pelvic floor occurring mostly (>90%) in women.^{1, 2} A number of studies have identified the bladder as one of major causes of chronic pelvic pain (CPP).^{3, 4, 5, 6, 7}

Misdiagnosis and ineffective treatments are common, leaving patients with persistent pain and the potential for neuropathic upregulation and allodynia. Currently BPS/IC is considered a diagnosis of exclusion because its etiology is not known and clinical characteristics vary among patients. Voiding often relieves the typical symptoms of pain, pressure, or discomfort involving the lower pelvic area including gastrointestinal organs. The symptoms have to be present for no less than 6 months, obviously in the absence of urinary tract infection (UTI).¹ Early recognition of BPS/IC is very important because symptoms are quite disabling, affecting quality of life and leading to patients being seen by a variety of specialists (usually between five and seven times in a period of 3–5 years). The syndrome is also exacerbated by the high incidence of other comorbid diseases including: allergies, asthma, atopic dermatitis, inflammatory bowel syndrome (IBS), systemic lupus erythematosus (SLE), Sjögren’s syndrome, chronic fatigue syndrome, and fibromyalgia.^{8, 9, 10, 11} Vulvodynia may also be present in 20% of cases,⁴ as well as endometriosis in 45–65% of women with pelvic pain of bladder origin.⁵ Even though BPS/IC is considered a gender disease, it may be present also in men.¹²

The National Institute of Diabetes and Digestive Kidney Diseases (NIDDK) established a set of consensus criteria, which were developed to ensure the comparability of patients enrolled in clinical studies.¹³ These included:

• Hunner’s ulcers

• any two of:

 – pain on bladder filling, relieved by emptying

 – suprapubic, pelvic, urethral, vaginal, or perineal pain for 9 months

 – glomerulations on endoscopy or upon hydrodistension under spinal or general anesthesia.

However, over 60% of patients with possible BPS/IC appear to fail these criteria expanding the definition.¹⁴

The International Continence Society (ICS) in 2002 defined the term painful bladder syndrome as “The complaint of suprapubic pain related to bladder filling, accompanied by other symptoms such as frequency and nocturia in the absence of proven pathologies”.¹⁵

Most recently, the European Society for the Study of Interstitial Cystitis (ESSIC) named this disease Bladder Pain Syndrome¹⁶ according to the definition of the International Association for the Study of Pain (IASP).¹⁷

Sometimes a significant proportion of BPS/IC patients do not complain of pain but relate their feelings to pressure and discomfort.¹⁸ In this situation, patients not complaining of pain would remain undiagnosed for IC if only pain syndromes are applicable to a diagnosis of BPS/IC; therefore in May 2009, the Asian Society published clinical guidelines for IC, proposing a new definition of the syndrome as “hypersensitive bladder syndrome” (HBS) – bladder hypersensitivity, usually associated with urinary frequency, with or without bladder pain.¹⁹

The prevalence of BPS/IC was estimated in the past at 18.1/100,000 women.²⁰ Subsequent studies in 2002 indicated it was 450 per 100,000 (0.45%), and more recently it was 680 per 100,000 (0.68%) for a probable IC and 300 per 100,000 (0.3%) for a definite diagnosis of IC.^{21, 22}

A recent study of 981 urban females in Vienna showed an overall prevalence of 306 per 100,000 (0.3%), with the highest number in the 40–59 years age group.²³ BPS/IC has also been reported in children and adolescents.^{24, 25, 26} In Japan the prevalence reported from a questionnaire survey of 300 major hospitals was only 2 per 100,000 patients.²⁷ The patients were older (52.9 years on average) than those in Europe and the United States.²⁸ This may indicate that patients have had symptoms for a long time before diagnosis. However, a recent epidemiological investigation in Japan found that 1.0% of the general population experienced bladder pain every day.²⁹ There is some evidence of genetic predisposition; the prevalence of BPS/IC in first-degree relatives has been shown to be 17 times higher than in the general population.³⁰

Several etiologic theories have been proposed in recent years, although they remain somewhat speculative and controversial, and the precise causes of BPS/IC are still unknown. One aspect has been emphasized: the multifactorial etiology of the disease. Interaction between nervous, immune, and endocrine factors creates a vicious cycle, provoking and maintaining the inflammatory effect in the bladder.

Infection

To date, no infectious etiology has been identified using reverse transcriptase polymerase chain reaction (RT-PCR) for Chlamydia trachomatis, adenovirus, cytomegalovirus, herpes simplex virus, papillomavirus, or Gardnerella vaginalis.^{31, 32} It is well known that antibiotic treatment is ineffective for BPS/IC. Flare-up of symptoms can occasionally be elicited by an infection, as an associated factor that initiates or exacerbates IC.³³

Mastocytosis

An increased number of activated bladder mast cells has been reported repeatedly in BPS/IC.³⁴ There are twice as many mast cells in the urothelium of BPS/IC patients and ten times more in the detrusor as compared to controls.³⁵ In addition, more than 70% of bladder mast cells were activated in BPS/IC as compared to less than 10% in controls.³⁴ In fact the mast cells play a pivotal role in the inflammatory process: they release potent inflammatory mediators such as histamine, leukotriene, and serotonin, and also interact with immunoglobulin E (IgE) antibodies, other inflammatory cells, and the nervous system.^{35, 36}

Dysfunctional bladder epithelium

The protective inner layer of the bladder is made up of glycosaminoglycans (GAGs), chondroitin sulphate (CS), and sodium hyaluronate (SH). This GAG component is hydrophilic and binds a layer of water molecules that is thought to protect the urothelium from potentially harmful agents, including bacteria, proteins, and ions. Proponents of the leaky endothelium theory suggest that the GAG layer may be damaged in BPS/IC;^{37, 38} this deficiency allows irritants in the urine to leak through the urothelium and causes inflammation, irritation, and numerous, other reactions.³⁹

Increased urinary levels of CS and SH have been reported in some BPS/IC patients,^{40, 41} with concomitant decrease of mucosal glycoprotein GP1.⁴²

The etiology of the defect in the GAG layer is currently unknown. Antiproliferative factors (APFs), detected in the urine of IC patients, downregulate expression of genes that stimulate proliferation of bladder epithelial cells, and upregulate genes that inhibit proliferation, leading to urothelial undermaturation and dysfunction.^{43, 44}

Neurogenic inflammation

BPS/IC is not an end-organ condition; it should be considered a condition of the peripheral and central nervous systems as they relate to acute or chronic pain. The initiating event is a noxious stimulus such as trauma, infection, or inflammation. Acute pain is associated with nociception, which results in pain perception modulated in the peripheral and central nervous systems. Conversion of acute to chronic pain begins with activation of visceral silent unmyelinated C-fibers by prolonged noxious stimulation and inflammation. The neurotransmitter glutamate is released, which activates N-methyl-d-aspartate receptors. A chronic pain cycle begins as dorsal horn neurons are activated (wind-up), which causes exaggerated responses to less noxious stimuli (hyperalgesia), or a painful response to normally innocuous stimuli (allodynia), as small volumes of urine in the bladder are perceived as a full bladder. The neuro-transmitter substance P stimulates the release of histamine and nitric oxide, which causes neurogenic inflammation. Once the dorsal horn becomes hypersensitive, the pain syndrome becomes a chronic pain syndrome. Prolonged noxious stimuli can cause dorsal horn cells to transmit efferent signals to peripheral nerve terminals (antidromic transmission). Thus a self-perpetuating signal is established as a visceral chronic pelvic pain syndrome (CPPS), causing expression of genes such as c-Fos in the spinal cord and loss of inhibitory neurons, resulting in a decreased threshold for activation.

Reduced vascularization

A decrease in the microvascular density has been observed in the suburothelium in patients with BPS/IC.⁴⁵ Bladder vascular perfusion is reduced by bladder filling in BPS/IC, while it is slightly increased in controls.⁴⁶

A recent paper showed that hyperbaric therapy seems to relieve the symptoms of BPS/IC⁴⁷ confirming indirectly that a reduced blood supply may cause a decrease in epithelial function as well as epithelial thinning and denudation.⁴⁸ It is reasonable that the impaired blood circulation in the bladder is related to BPS/IC and the apoptotic activity of microvascular endothelial cells is increased.⁴⁹

Pelvic floor dysfunction

Women with BPS/IC have often a history of hysterectomy, cesarean section, miscarriage, stillbirth, or abortion.^{50, 51} Pelvic surgery can be the trigger for symptom development. The symptoms are likely to be affected by the menstrual cycle.⁵⁰ Another frequent association of BPS/IC is with irritable bowel syndrome (IBS); both are improved by treating small intestinal bacterial overgrowth, which probably potentiates visceral hypersensitivity.⁵² On the other hand, vulvodynia, dyspareunia, scrotal and perineal pain are one of the expressions of the exaggerated muscle tone activity, contributing to the maintenance of the noxious stimuli.

Autoimmunity

Many of the clinical features of BPS/IC reflect an autoimmune component of the disease process. Investigators have also reported concomitant association of BPS/IC and other autoimmune diseases, such as SLE, rheumatoid arthritis, and Sjögren’s syndrome.^{53, 54, 55}

It is important to keep in mind that BPS/IC patients may present with only one of the symptoms, particularly early in the course of the disease. Up to 30% with BPS/IC present without pelvic pain⁵⁶ and approximately 15% present with pain as the only symptom.⁵⁷

The diagnosis of BPS/IC is symptom driven by exclusion, but should not necessarily be organ oriented, considering the large number of confusable diseases (Table 1). A comprehensive medical history should include suprapubic pain, pressure, and discomfort related to bladder filling, as well as frequency and urgency in the absence of UTI or other pathology.⁵⁸

A retrospective analysis from the IC Database (ICDB) pointed out the most common baseline pain site was lower abdominal (80%), urethral (74%), and low back (65%), with the majority of patients describing their pain as intermittent.⁵⁹

Questionnaires can be helpful in screening for BPS/IC. The most commonly used screening tools are the Pelvic Pain, Urgency, Frequency symptom scale (PUF) and O’Leary–Sant Symptom and Problem Index.^{60, 61} Both surveys include questions regarding pain, urgency, frequency, and nocturia and how these symptoms impact on quality of life.

Physical evaluation is a critical component of diagnosing BPS/IC. Since the bladder is a pain generator, tenderness with single-digit examination of the trigonal area can help establish a diagnosis of BPS/IC⁶² as pelvic floor tenderness at the trigger point in the levator muscles.⁶³ Physical examination should also address high tone of the pelvic floor muscles, and hypersensitivity of the perineal area using the Kaufman Q-tip touch sensitivity test that might screen for the presence of vulvar vestibulodynia (VVS).⁶⁴ Urine analysis can rule out hematuria, urine culture is required to identify bladder infection and cytology can help rule out bladder cancer. Several optional diagnostic tests are also used but diagnostic evaluation varies among urologists/urogynecologists, in different centers^{65, 66, 67} and between the US, Europe, and Asia.^{19, 68}

Table 1 Confusable diseases in BPS/IC 

Urodynamic studies can highlight detrusor overactivity or reduced bladder capacity without detrusor overactivity (bladder hypersensitivity) suggestive of BPS/IC.^{69, 70, 71} A mild impaired voiding phase with detrusor–sphincter discoordination is probably related to the dysfunctional pelvic floor behavior.

Local cystoscopy is not mandatory but is a good preliminary investigation to rule out other conditions (e.g. bladder stone, hematuria, or cancer). Cystoscopy is also needed to identify Hunner’s ulcer⁷² the positive specific finding of BPS/IC. Typically, an ulcer is recognized as a well-demarcated reddish mucosal lesion lacking the normal capillary structure. In addition, some scars or fissures with a rich hypervascularization or a pale mucosal aspect may be found, and are an indirect index of hypovascularization.

Cystoscopy with hydrodistension under anesthesia is proposed by the NIDDK research criteria, but is now considered too restrictive;⁶⁷ however, it remains the most common procedure performed in patients with BPS/IC especially in Europe.⁷³ Hydrodistension is also done using different methodologies, making comparison between studies difficult.^{64, 74, 75} It may be necessary to exclude other pathologies and to identify the presence of “classic” BPS/IC with “Hunner’s ulcers”, and document urothelial bleeding (glomerulations), even though these have also been noted in the bladders of normal women undergoing tubal ligation.⁷⁶

Bladder biopsy has to be performed after hydrodistension to avoid the risk of bladder rupture, to prove the presence of mast cell infiltration, and to orientate toward a more specic therapy. Biopsy with histopathology may be necessary to exclude neoplasm and eosinophilic or tuberculosis cystitis. A count of tryptase-positive bladder mast cells is recommended by the European Society, with >28 mast cells/mm constituting detrusor mastocytosis, which is considered diagnostic for BPS/IC.^{67, 74, 77} An increased number of mast cells was also proposed as a diagnostic criterion for vulvar vestibulitis.⁷⁸

There are no specific blood or urine markers available for diagnosis. An APF, recently identified as a frizzled-8 surface sialoglycopeptide⁷⁹ was increased in BPS/IC urine as determined by its ability to decrease in vitro proliferation of bladder epithelial cells, and could distinguish BPS/IC from other urologic disorders.⁸⁰ Urine APF levels also apparently distinguished BPS/IC from CPPS in men.⁸¹

However, antiproliferative factor (APF) still needs to be validated and independently reproduced. Classic BPS/IC might be differentiated from nonulcer disease by elevated urine nitric oxide (NO).⁸²

Other urinary markers include heparin-binding epidermal growth factor-like growth factor (HB-EGF), histamine, methylhistamine, and interleukin-6 (IL-6).^{83, 84} Four proteins that differed signicantly between IC and controls have been identified, with uromodulin and two kininogens found to be higher for controls and inter-alphatrypsin inhibitor heavy chain H4 higher for IC.⁸⁵ Urinary concentration of neutrophile elastase is increased in patients with pain and small bladder capacity.⁸⁶ These markers are not necessarily precise predictors of ulcer and/or symptom severity.⁸⁷

Intravesical administration of 40 mL of a solution of 40 mEq of potassium chloride in 100 mL of water (potassium sensitivity test – PST), with pain and urgency scored by the patient as compared to administration of sterile water has been proposed for BPS/IC diagnosis.⁶⁰ However, this test’s sensitivity and specificity is only about 75% and the participants at the International IC Consultation in Rome recommended that it should not be used for diagnostic purposes because of its low prognostic value.⁸⁸

There is no curative therapy for BPS/IC.^{89, 90, 91, 92} This is consistent with the fact that the causes of BPS/IC are yet not understood and the pathophysiology remains uncertain. Therefore, the therapeutic strategy is to reduce or eliminate the symptoms of BPS/IC, thereby interfering with the potential disease mechanism and improving quality of life. Because IC is a chronic disease, patients should be counselled regarding realistic expectations of treatment. Remission may be attained but should not be expected, and even when it is attainable, months of medical treatment may be required.⁹³ Exacerbations during periods of remission are common and patients need to be encouraged that therapy is not failing.

Conservative therapy

Behavioral modication may have modest benefit for IC patients (grade of recommendation B). Barbalias et al. looked at a type of bladder training as an adjunct to treatment with intravesical oxybutynin in patients with IC; there was a modest improvement in O’Leary–Sant questionnaire at 6 months.⁹⁴ Chaiken et al. reported similar results with diary-timed voiding and pelvic floor muscle training.⁹⁵ There are no randomized controlled trials attesting the efficacy of pelvic floor physical therapy. Biofeedback and soft tissue massage may aid in muscle relaxation of the pelvic floor.⁹⁶

Manual physical therapy (grade of recommendation C) to the pelvic floor myofascial trigger points twice per week for 8–12 weeks also resulted in moderate to marked improvement in 7/10 BPS/IC patients.⁹⁷

Modified Thiele intravaginal massage of high-tone pelvic floor muscle trigger points twice per week for 5 weeks, has been shown to improve the O’Leary–Sant Index.⁹⁸

Common-sense dietary changes, especially avoidance of potential bladder irritancy as identified by individual patients may be beneficial (grade of recommendation B). A majority of BPS/IC patients seem to have symptom exacerbation related to the intake of specific foods and beverages: coffee, spicy foods, and alcoholic beverages.⁹⁹ However, different patients seem to be affected to different degrees by specific foods and beverages and patients should avoid only those foods and beverages that they find worsen their symptoms.

Medical therapy

Medical therapies for BPS/IC include oral, subcutaneous, and intravesical agents. These drugs are categorized according to their intended point of action within the disease process.

Protection of the mucosal surface

One of the theories in the pathogenesis of IC is that deficiency of the GAG layer causes symptoms related to the increased permeability of the urothelium. Therefore, a number of agents have been used to improve the integrity of the mucosal surface. Pentosan polysulfate (PPS), a branched polysaccharide presumably acting to “replenish” the GAG layer, is the only oral drug approved in the US for BPS/IC (grade of recommendation B, level of evidence 2). One study of PPS (300 mg/day) used for 3 years showed it was twice as potent as placebo (18%) in reducing pain but the placebo response was unusually low.^{1, 90} A randomized double-blind multicenter study, with a range of doses (300, 600 or 900 mg per day) for 32 months, of 380 BPS/IC patients with >6 months’ symptoms and positive cystoscopic examination but no placebo control, reported that 45–50% of all patients were classified as responders (50% or greater improvement on the Patients’ Overall Rating of Symptoms Index – PORIS), irrespective of the dose.¹⁰⁰ In a more recent prospective study, 41 patients with BPS/IC were divided into three groups according to their response to PPS (major, intermediate, minor); they were administered 3 x 5000 IU subcutaneous heparin per day for 2 days, followed by 2 x 5000 IU per day for 12 days plus 300 mg PPS per day, compared to 17 nonmatched patients taking PPS alone; 32% of the patients in the minor response group reported a significant improvement in “overall well-being” over that of PPS alone.¹⁰¹          

Hydroxyzine is a histamine 1 receptor antagonist, with additional anxiolytic, sedative, anticholinergic, and mast cell inhibitory properties (grade of recommendation D, level of evidence 1). It has been shown to reduce neurogenic bladder inflammation.¹⁰² Hydroxyzine has shown mixed results in treating BPS/IC symptoms. One open label study showed a 55% reduction in symptoms, particularly in patients who suffered from allergies.¹⁰³ Cimetidine is a histamine-2 receptor antagonist (grade of recommendation D, level of evidence 4). It was reported to decrease the median symptom score in 34 BPS/IC patients studied, but with no apparent histological changes in the bladder mucosa.¹⁰⁴ L-Arginine is a natural substrate of nitric oxide synthase (NOS) (grade of recommendation D). It may re-activate NOS activity, which is suppressed in IC, and relieve symptoms.¹⁰⁵ No significant effect was observed in double-blind studies.^{106, 107} More detailed results of the use of oral drugs in BPS/IC patients are reported in Table 2.

Intravesical instillation or bladder wall injection

Intravesical and subcutaneous heparin has been used for the treatment of IC since early 1960. It is either instilled or administered subcutaneously. When instilled, heparin does not have systemic anticoagulant effects. In one study, 48 patients with IC self-administered intravesical heparin (10,000 IU in 10 mL sterile water 3 times weekly for 3 months). Fifty-six per cent of the patients attained clinical remission after 3 months.¹⁰⁸ Subcutaneous heparin has been demonstrated to produce rapid relief of symptoms in eight patients, who reported long-term benefit over 1 year.¹⁰⁹ Intravesical dimethylsulfoxide (DMSO) remains the basis of intravesical therapy for IC (grade of recommendation B, level of evidence 2). It has been shown to reduce symptoms for up to 3 months.¹¹⁰ Its multiple effects include an anti-inflammatory and analgesic effect, muscle relaxation, mast cell inhibition, and collagen dissolution.¹¹¹ Patients treated with DMSO have experienced a 50–70% reduction of symptoms, although the relapse rate is 35–40%. Administration in combination with various other agents including hydrocortisone, heparin, and sodium bicarbonate has been recommended to improve the response to DMSO.¹ Intravesical hyaluronic acid (grade of recommendation C, level of evidence 4), has been used with a long-lasting moderate efficacy with no side effects, but a recent multicenter study found no significant efficacy (Interstitial Cystitis Association – Physician perspectives, unpublished data). Chondroitin sulfate (grade of recommendation C, level of evidence 3) demonstrated a 33% response rate.¹¹² Combined instillation of hyaluronic acid and chondroitin sulfate in refractory interstitial cystitis resulted in significant symptomatic improvement.¹¹³ Botulinum toxin (grade of recommendation C, level of evidence 4) inhibits the release of calcitonin gene-related peptide and substance P from afferent nerves, and weakens pain.^{114, 115} Small studies of intravesical Botox into the bladder wall indicated symptom relief in IC patients, without significant adverse events.¹¹⁶ Table 3 shows the results of drugs administered intravesically for the treatment of BPS/IC.

Pain modulation

Tricyclic antidepressants (TCAs), especially amitriptyline, are known to have pain-reducing effects (grade of recommendation B, level of evidence 2). One randomized controlled trial of amitriptyline evaluated 50 patients with IC. Improvement in overall symptom scores was significantly greater in the treatment group, as well reduction in pain and urgency (P <0.001).¹¹⁷

Table 2 Oral medications for treatment of BPS/IC: results*

*Adapted from P. Hanno ⁵⁸

Table 3 Intravesical medications for treatment of BPS/IC: results*

*Adapted from Hanno⁵⁸

Pain modulation

Tricyclic antidepressants (TCAs), especially amitriptyline, are known to have pain-reducing effects (grade of recommendation B, level of evidence 2). One randomized controlled trial of amitriptyline evaluated 50 patients with IC. Improvement in overall symptom scores was significantly greater in the treatment group, as well reduction in pain and urgency (P <0.001).¹¹⁷

Immunologic modulation

Immune stimulants and suppressants have been used in BPS/IC. Intravesical Bacillus Calmette–Guérin (BCG) (grade of recommendation D, level of evidence – no efficacy) was initially reported to have some benefit in BPS/IC;¹¹⁸ however, a subsequent randomized placebo-controlled trial of BPS/IC patients, who met the NIDDK research criteria, showed that there was no statistical difference at 34 weeks.¹¹⁹ Ciclosporin is an immunosuppressant used in organ transplantation (grade of recommendation C, level of evidence 2). It was tested in a small, open-label study of 11 patients. The results were largely positive and bladder pain decreased or stopped completely in 10 patients.¹²⁰ Suplataste tosilate (IPD-1151T) is a new immunoregulator that selectively suppresses IgE, IL-4 and IL-5 (grade of recommendation C, level of evidence 4). Treatment for one year in 14 women resulted in a significantly increased bladder capacity and decreased urgency, frequency, and pain.¹²¹

Multimodal medical therapy

To manage the multiple pathological features of IC, a multimodal approach, combining agents from different classes, is suggested to improve the therapeutic response by attacking the disease at several points. One common multimodal approach is:

1. To restore epithelial funtion with heparinoid;
2. To treat neural activation and pain with TCA;
3. To control allergies with an anthistamine.

In advanced form, intravesical treatment may be required. Combination intravesical therapy is also indicated for patients who experience significant flare of symptoms after remission.

Procedural intervention

BPS/IC is a chronic and debilitating disease with an impairment of quality of life due to disabling symptoms. Surgical options should be considered only when all conservative treatment has failed.

Laser resection, augmentation cystoplasty, cystolysis, cystectomy, and urinary diversion may be the ultimate option for refractory BPS/IC patients.⁹³ Continent diversion may have better cosmetic and lifestyle outcome, but recurrence is a real possibility.

Posterior tibial nerve stimulation somewhat improved less than half of patients.¹²²

Sacral nerve neuromodulation as a treatment for BPS/IC in initial studies seems to relieve the symptoms of IC. Further studies are needed.¹²³

BPS/IC is a chronic, multifactorial disorder with symptoms of urinary frequency, urgency, and pelvic pain, often associated with other painful diseases, which profoundly affects patients’ quality of life due to its disabling aspects. Pelvic pain in BPS/IC is a visceral pain syndrome with multiple pain generators, which can make the diagnosis difficult. Patients with a history of recurrent UTIs that are culture negative, those with endometriosis and significant bladder symptoms, with overactive bladder syndrome who have responded poorly to therapy, or with vulvodynia or chronic pelvic pain are all likely to have untreated BPS/IC. The primary providers of care for women with pelvic pain must consider the bladder as a very important source of pain. The earlier the diagnosis is made and therapy begun, the sooner patients with BPS/IC will experience improvement of their symptoms.