This chapter should be cited as follows:
Cervigni, M, Glob. libr. women's med.,
(ISSN: 1756-2228) 2014; DOI 10.3843/GLOWM.10485
This chapter was last updated:
September 2014

Bladder Pain Syndrome

Mauro Cervigni, MD
Professor Urogynecology, Catholic University, Rome, Italy

INTRODUCTION

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

DEFINITION

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

 

EPIDEMIOLOGY

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

PATHOPHYSIOLOGY

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

 

DIAGNOSIS

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 centers65, 66, 67 and between the US, Europe, and Asia.19, 68

Table 1 Confusable diseases in BPS/IC 

Disease type

Confusable diseases

Bladder diseases

Overactive bladder

 

Neurogenic bladder

 

Radiation cystitis

 

Bladder calculus

 

Bladder cancer

Genitourinary infections

Bacterial cystitis 

 

Urethritis

 

Prostatitis

Gynecologic diseases

Endometriosis

 

Uterine myoma 

 

Vaginitis

 

Postmenopausal syndrome 

Prostate and urethral diseases

Benign prostatic hypertrophy 

 

Prostate cancer

 

Urethral stenosis 

 

Urethral diverticulum 

Other conditions

Polyuria

 

Hypertonic pelvic floor 

 

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

 

TREATMENT

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*

 Drug
 Randomized controlled trial  Success (%)
 Amitriptyline; tricyclic antidepressant
 Yes
 42
 Antibiotics   Yes
 48
 Cimetidine   Yes 65
 Hydrocortisone   No 80
 Ciclosporin   No 90
 Hydroxyzine   Yes 31
 L-Arginine   Yes Not effective
 Nifedipine
 No 87
 Quercetin  
 No 92
 Sodium pentosanpolysulfate   Yes 33
 Suplatast tosilate  
 No 86

*Adapted from P. Hanno 58

 

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

 Drug
 Randomized controlled trial
 Success (%)
 DMSO Yes 70
 BCG
 Yes Conflicting RCT data as to efficacy 
 Resiniferatoxin Yes No proven efficacy 
 Hyaluronic acid Yes No proven efficacy
 Heparin No 60
 Chondroitin sulfate No 33 
 Lidocaine
 No 65 
 PPS
 Yes Suggestion of possible efficacy 40
*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

 

CONCLUSIONS

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.

 

REFERENCES

1

Hanno P. Interstitial cystitis and related disorders. In: Walsh PC (ed) Campbell’s urology. Elsevier, Philadelphia PA, 2002, pp 631–668.

 

2

Sant GR. Etiology, pathogenesis and diagnosis of interstitial cystitis. Rev Urol 2002;4(suppl 1):S9–S15.

 

3

Paulson JD, Delgado M. Chronic pelvic pain: the occurrence of interstitial cystitis in a gynecological population. J Soc Laparosc Surg 2005;9:426–430.

 

4

Stanford EJ, Koziol J, Fang A. The prevalence of interstitial cystitis, endometriosis, adhesions and vulvar pain in women with chronic pelvic pain. J Minim Invasive Gynecol 2005; 12:43–49.

 

5

Chung MK, Chung RP, Gordon D. Interstitial cystitis and endometriosis in patients with chronic pelvic pain: the “evil twins” syndrome. J Soc Laparosc Surg 2005;9:25–29.

 

6

Sand PK. Chronic pain syndromes of gynecologic origin. J Reprod Med 2004;49:230–234.

 

7

Parsons CL, Dell J, Stanford EJ et al. The prevalence of interstitial cystitis in gynecological patients with pelvic pain, as detected by intravesical potassium sensitivity. Am J Obstet Gynecol 2002;187:1395–1400.

 

8

Yamada T. Significance of complications of allergic diseases in young patients with interstitial cystitis. Int J Urol 2003;10(suppl):S56–S58.

 

9

Peeker R, Atansiu L, Logadottir Y. Intercurrent autoimmune conditions in classic and non-ulcer interstitial cystitis. Scand J Urol Nephrol 2003;137:60–63.

 

10

Novi JM, Jeronis S, Srinivas S et al. Risk of irritable bowel syndrome and depression in women with interstitial cystitis: a case control study. J Urol 2005:174:937–940.

 

11

Alagiri M, Chottiner S, Ratner V et al. Interstitial cystitis: unexplained associations with other chronic disease and pain syndrome. Urology 1997;49:52–57.

 

12

Schaeffer AJ. Clinical practice. Chronic prostatitis and the chronic pelvic pain syndrome. N Engl J Med 2006; 355:1690–1698.

 

13

Hanno PM, Landis JR, Matthews-Cook Y et al. The dia•gnosis of interstitial cystitis revisited: lessons learned from the National Institutes of Health Interstitial Cystitis Database Study. J Urol 1999;161:553–557.

 

14

Sant GR, Hanno PM. Interstitial cystitis: current issues and controversies in diagnosis. Urology 2001;57:82–88.

 

15

Abrams P, Cardozo L, Fall M et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Conti•nence Society. Neurourol Urodyn 2002;21:167–178.

 

16

van de Merwe JP, Nordling J, Bouchelouche P et al. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal. Eur Urol 2008;53:60–67.

 

17

Merskey H, Bogduk N (eds) International Association for the Study of Pain Part III: pain terms: a current list with definitions and notes on usage. In: Classification of Chronic Pain, 2 edn. IASP Task Force on Taxonomy, IASP Press, Seattle, 1994, pp 209–214.

 

18

Warren JW, Meyer WA, Greenberg P et al. Using the International Continence Society’s definition of painful bladder syndrome. Urology 2006;67:1138–1142 ; discussion 1142–1143.

 

19

Homma Y, Ueda T, Tomoe H et al. Clinical guidelines for interstitial cystitis and hypersensitive bladder syndrome. Int J Urol 2009;16:597–615.

 

20

Oravisto KJ. Epidemiology of interstitial cystitis. Ann Chir Gynaecol Fenn 1975;64:75–77.

 

21

Leppilahti M, Tammela TL, Huhtala H, Auvinen A. Prevalence of symptoms related to interstitial cystitis in women: a population based study in Finland. J Urol 2002;168:139–143.

 

22

Leppilahti M, Sairanen J, Tammela TL et al. Prevalence of clinically confirmed interstitial cystitis in women: a population based study in Finland. J Urol 2005;174:581–583.

 

23

Temml C, Wehrberger C, Riedl C et al. Prevalence and correlates for interstitial cystitis symptoms in women participating in a health screening project. Eur Urol 2007;51:803– 808; discussion 809.

 

24

Close CE, Carr MC, Burns MW et al. Interstitial cystitis in children. J Urol 1996;156:860–862.

 

25

Farkas A, Waisman J, Goodwin WE. Interstitial cystitis in adolescent girls. J Urol 1977;118:837–838.

 

26

Mattoks TF. Interstitial cystitis in adolescents and children: a review. J Pediatr Adolesc Gynecol 2004;17:7–11.

 

27

Ito T, Miki M, Yamada T. Interstitial cystitis in Japan. BJU Int 2000;86:634–637.

 

28

Ito T, Ueda T, Homma Y, Takei M. Recent trends in patient characteristics and therapeutic choices for interstitial cystitis: analysis of 282 Japanese patients. Int J Urol 2007;14:1068– 1070.

 

29

Homma Y,Yamaguchi O, Hayashi K. Epidemiologic survey of lower urinary tract symptoms in Japan. Urology 2006;68:560–564.

 

30

Warren JW, Jackson TL, Langenberg P et al. Prevalence of interstitial cystitis in first-degree relatives of patients with interstitial cystitis. Urology 2004;63:17–21.

 

31

AlHadithi HN, Williams H, Hart CA et al. Absence of bacterial and viral DNA in bladder biopsies from patients with interstitial cystitis/chronic pelvic pain syndrome. J Urol 2005;174:151–154.

 

32

Agarwal M, Dixon RA. A study to detect Gardnerella vaginalis DNA in interstitial cystitis. BJU Int 2001;88:868–870.

 

33

Warren JW, Brown V, Jacobs S et al. Urinary tract infection and inflammation at onset of interstitial cystitis/painful bladder syndrome. Urology 2008;71:1085–1090.

 

34

Theoharides TC, Kempuraj D, Sant GR. Mast cell involvement in interstitial cystitis: a review of human and experimental evidence. Urology 2001;57(6 suppl 1):47–55.

 

35

Peeker R, Enerbäck L, Fall M, Aldenborg F. Recruitment, distribution and phenotypes of mast cells in interstitial cystitis. Urology 2000;163:1009–1015.

 

36

Hofmeister MA, He F, Ratliff TL et al. Mast cells and nerve fibers in interstitial cystitis (IC): an algorithm for histologic diagnosis via quantitative image analysis and morphometry (QIAM). Urology 1997;49:41–47.

 

37

Parsons CL, Stauffer C, Schmidt JD. Bladdersurface glycosaminoglycans: an efficient mechanism of environmental adaptation. Science 1980;208:605–607.

 

38

Parsons CL, Lilly JD, Stein P. Epithelial dysfunction in nonbacterial cystitis (interstitial cystitis). J Urol 1991; 145:732–735.

 

39

Metts JF. Interstitial cystitis: urgency and frequency syndrome. Am Fam Physician 2001;64:1199–1206.

 

40

Wel DC, Politano VA, Seizer MG, Lokeshwar VB. The association of elevated urinary total to sulfated glycosaminoglycan ratio and high molecular mass hyaluronic acid with interstitial cystitis. J Urol 2000;163:1577–1583.

 

41

Erickson DR, Sheykhnazan M, Ordille S, Bhavanandan VP. Increased urinary hyaluronic acid and interstitial cystitis. J Urol 1998;160:1282–1284.

 

42

Moskowitz MO, Byrne DS, Callahan HJ et al. Decreased expression of a glycoprotein component of bladder surface mucin (GPI) in interestitial cystitis. J Urol 1994; 151:343–345.

 

43

Keay S, Kleinberg M, Zhang CO et al. Bladder epithelial cells from patients with interstitial cystitis produce an inhibitor of heparin-binding epidermal growth factor-like growth factor production. J Urol 2000;164:2112–2118.

 

44

Keay S, Seillier-Moiseiwitsch F, Zhang CO et al. Changes in human bladder epithelial cell gene expression associated with interstitial cystitis or antiproliferative factor treatment. Physiol Genomics 2003;14:107–115.

 

45

Rosamilia A, Cann L, Scurry J et al. Bladder microvasculature and the effects of hydrodistention in interstitial cystitis. Urology 2001;57:132.

 

46

Pontari MA, Hanno PM, Ruggieri MR. Comparison of bladder blood flow in patients with and without interstitial cystitis. J Urol 1999;162:330–334.

 

47

van Ophoven A, Rossbach G, Pajonk F, Hertle L. Safety and efficacy of hyperbaric oxygen therapy for the treatment of interstitial cystitis: a randomized, sham controlled, double-blind trial. J Urol 2006;176:1442–1446.

 

48

Cervigni M, Zoppetti G, Nasta L et al. Reduced vasculari•zation in the bladder mucosa of bladder pain syndrome/interstitial cystitis patients. In: Proceedings of the ESSIC Annual Meeting, Göteborg, Sweden, 4–6 June 2009.

 

49

Yamada T, Nishimura M, Mita H. Increased number of apoptotic endothelial cells in bladder of interstitial cystitis patients. World J Urol 2007;25:407–413.

 

50

Peters KM, Carrico DJ, Diokno AC. Characterization of a clinical cohort of 87 women with interstitial cystitis/painful bladder syndrome. Urology 2008;71:634–640.

 

51

Hall SA, Link CL, Pulliam SJ et al. The relationship of common medical conditions and medication use with symptoms of painful bladder syndrome: results from the Boston area community health survey. J Urol 2008;180:593–598.

 

52

Weinstock LB, Klutke CG, Lin HC. Small intestinal bacterial overgrowth in patients with interstitial cystitis and gastrointestinal symptoms. Dig Dis Sci 2008;53:1246–1251.

 

53

Fister GM. Similarity of interstitial cystitis (Hunner’s ulcer) to lupus erythematosus. J Urol 1938;40:37–51.

 

54

Silk MR. Bladder antibodies in interstitial cystitis. J Urol 1970;103:307–309.

 

55

Leppilahti M, Tammela TL, Huhtala H et al. Interstitial cystitis-like urinary symptoms among patients with Sjogren’s syndrome: a population-based study in Finland. Am J Med 2003;115:62–65.

 

56

Parsons CL. Interstitial cystitis: epidemiology and clinical presentation. Clin Obstet Gynecol 2002;45:242–249.

 

57

Parsons CL, Bullen M, Kahn BS et al. Gynecologic presentation of interstitial cystitis as detected by intravesical potassium sensitivity. Obstet Gynecol 2001;98:127–132.

 

58

Hanno P, Baranowski A, Fall M et al. Painful bladder syndrome (including interstitial cystitis). In: Abrams P, Cardozo L, Khoury S, Wein A (eds) Incontinence. Health Publication Ltd, Plymouth, 2005, pp 1457–1520.

 

59

Fitzgerald MP, Brensinger C, Brubaker L et al. What is the pain of interstitial cystitis like? Int Urogynecol J Pelvic Floor Dysfunct 2005;17:69–72.

 

60

Parsons CL, Del J, Stanford AJ et al. Increased prevalence of interstitial cystitis: previously un-recognized urologic and gynecologic cases identified using a new symptoms questionnaire and intravesical potassium sensitivity. Urology 2002;60:573–578.

 

61

O’Leary MP, Sant GR, Fowler FJ Jr et al. The interstitial cystitis symptom index and problem index. Urology 1997;49(suppl 5A):58–63.

 

62

Howard FM. Physical examination. In: Howard FM, Perry CP, Carter JA et al (eds) Pelvic pain: diagnosis and management. Lippincott Williams and Wilkins, Philadelphia PA, 2000, pp 26–42.

 

63

Howard FM. Chronic pelvic pain. Obstet Gynecol 2003;101:594–611.

 

64

Kaufman RH, Friedrich EG, Gardner HL. Non-neoplastic epithelial disorders of the vulvar skin and mucosa; miscellaneous vulvar disorders. In: Kaufman RH, Friedrich EG, Gardner HL (eds) Benign diseases of the vulva and vagina. Chicago Yearbook, Chicago, IL, 1989, pp 299–360.

 

65

Hanno PM, Levin RM, Monson FC et al. Diagnosis of interstitial cystitis. J Urol 1990;143:278–281.

 

66

Turner KJ, Stewart LH. How do you stretch a bladder? A survey of UK practice, a literature review, and a recommendation of a standard approach. Neurourol Urodyn 2005;24:74–76.

 

67

Erickson DR, Tornaszewski JE, Kunselman AR et al. Do the National Institute of Diabetes and Digestive and Kidney Diseases cystoscopic criteria associate with other clinical and objective features of interstitial cystitis? J Urol 2005;173:93–97.

 

68

Nordling J, Anjum FH, Bade JJ et al. Primary evaluation of patients suspected of having interstitial cystitis (IC). Eur Urol 2004;45:662–669.

 

69

Frazer MI, Haylen BT, Sissons M. Do women with idiopa•thic sensory urgency have early interstitial cystitis? Br J Urol 1990;66:274–278.

 

70

Awad SA, MacDiarmid S, Gajewski JB, Gupta R. Idiopathic reduced bladder storage versus interstitial cystitis. J Urol 1992;148:1409–1412.

 

71

Al-Hadithi H, Tincello DG, Vince GS et al. Leukocyte populations in interstitial cystitis and idiopathic reduced bladder storage. Urology 2002;59:851–855.

 

72

Braunstein R, Shapiro E, Kaye J, Moldwin R. The role of cystoscopy in the diagnosis of Hunner’s ulcer disease. J Urol 2008;180:1383–1386.

 

73

Moldwin R. How to define the interstitial cystitis patients. lnt Urogynecol J Pelvic Floor Dysfunct 2005;16(suppl 1):S8–S9.

 

74

Nordling J, Anjum FH, Bade JJ et al. Primary evaluation of patients suspected of having interstitial cystitis (IC). Eur Urol 2004;45:662–669.

 

75

Payne CK, Terai A, Komatsu K. Research criteria versus clinical criteria for interstitial cystitis. Int J Urol 2003; 10(suppl):S7–S10.

 

76

Waxman JA, Sulak PJ, Kuehl TJ. Cystoscopic findings consistent with interstitial cystitis in normal women undergoing tubal ligation. J Urol 1998;160:1663–1667.

 

77

Bouchelouche K. Mast cells in PBS/IC. International Symposium: Frontiers in Painful Bladder Syndrome and Interstitial Cystitis. 26–27 October 2006, Bethesda, MD.

 

78

Bomstein J, Gotdschmid N, Sabo E. Hyperinnervation and mast cell activation may be used as histopathologic diagnostic criteria for vulvar vestibulitis. Gynecol Obstet Invest 2004;58:171–178.

 

79

Keay SK, Szekely Z, Conrads TP et al. An antiproliferative factor from interstitial cystitis patients is a frizzled 8 proteinrelated sialoglycopeptide. Proc Natl Acad Sci U S A 2004;101:11803–11808.

 

80

Keay SK, Zhang CO, Shoenfelt J et al. Sensitivity and specificity of antiproliferative factor, heparinbinding epidermal growth factorlike growth factor, and epidermal growth fac•tor as urine markers for interstitial cystitis. Urology 2001; 57:9–14.

 

81

Keay S, Zhang CO, Chai T et al. Antiproliferative factor, heparinbinding epidermal growth factorlike growth factor, and epidermal growth factor in men with interstitial cy•stitis versus chronic pelvic pain syndrome. Urology 2004; 63:22–26.

 

82

Logadottir YR, Ehren I, Fall M et al. Intravesical nitric oxide production discriminates between classic and nonulcer interstitial cystitis. J Urol 2004;171:1148–1150.

 

83

Hosseini A, Ehren I, Wiklund NP. Nitric oxide as an objective marker for evaluation of treatment response in patients with classic interstitial cystitis. J Urol 2004;172:2261–2265.

 

84

Lamale LM, Lutgendorf SK, Zimmerman MB, Kreder KJ. Interleukin-6, histamine, and methylhistamine as diagnostic markers for interstitial cystitis. Urology 2006;68:702–706.

 

85

Canter MP, Graham CA, Heit MH et al. Proteomic techniques identify urine proteins that differentiate patients with interstitial cystitis from asymptomatic control subjects. Am J Obstet Gynecol 2008;198:553 e1–6.

 

86

Kuromitsu S, Yokota H, Hiramoto M et al. Increased concentration of neutrophil elastase in urine from patients with interstitial cystitis. Scand J Urol Nephrol 2008;42:455–461.

 

87

Erickson DR, Tomaszewski JE, Kunselman AR et al. Urine markers do not predict biopsy findings or presence of bladder ulcers in interstitial cystitis/painful bladder syndrome. J Urol 2008;179:1850–1856.

 

88

Hanno P. International Consultation on IC Rome, September 2004/Forging an International Consensus: progress in painful bladder syndrome/interstitial cystitis. lnt Urogynecol J Pelvic Floor Dysfunct 2005;16(suppl 1):S2–S5.

 

89

Lukban JC, Whitmore KE, Sant GR. Current management of interstitial cystitis. Urol Clin North Am 2002; 29:649–660.

 

90

Phatak S, Foster HE Jr. The management of interstitial cystitis: an update. Nat Clin Pract Urol 2006;3:45–53.

 

91

Theoharides TC, Sant GR. New agents for the medical treatment of interstitial cystitis. Expert Opin Investig Drugs 2001;10:521–546.

 

92

Theoharides TC, Sant GR. Immunomodulators for the treatment of interstitial cystitis. Urology 2005;65:633–638.

 

93

Moldwin RM, Sant GR. Interstitial cystitis: a pathophysiology and treatment update. Clin Obstet Gynecol 2002;45:259–272.

 

94

Barbalias GA, Liatsikos EN, Athanasopoulos A, Nikiforidis G. Interstitial cystitis: bladder training with intravesical oxibutinin. J Urol 2000;163:1818–1822.

 

95

Chaiken DC, Blaivas JG, Blaivas ST. Behavioral therapy for the treatment of refractory interstitial cystitis. J Urol 1993;149:1445–1448.

 

96

Mendelowitz F, Moldwin R. Complementary approaches in the management of interstitial cystitis. In: Sant GR (ed) Interstitial cystitis. Lippincott-Raven, Philadelphia PA, 1997, pp 235–239.

 

97

Weiss JM. Pelvic floor myofascial trigger points: manual therapy for interstitial cystitis and the urgency-frequency syndrome. J Urol 2001;166:2226–2231.

 

98

Oyama IA, Rejba A, Lukban JC et al. Modified Thiele massage as therapeutic intervention for female patients with interstitial cystitis and hightone pelvic floor dysfunction. Uro•logy 2004;64:862–865.

 

99

Koziol JA. Epidemiology of interstitial cystitis. Urol Clin North Am 1994;21:7–20.

 

100

Nickel JC, Barkin J, Forrest J et al. Randomized, double blind, dose-ranging study of pentosan polysulfate sodium for interstitial cystitis. Urology 2005;65:654–668.

 

101

van Ophoven A, Heinecke A, Hertle L. Safety and efficacy of concurrent application of oral pentosan polysulfate and subcutaneous lowdose heparin for patients with interstitial cystitis. Urology 2005;66:707–711.

 

102

Minogiannis P, ElMansoury M, Betances JA et al. Hydroxyzine inhibits neurogenic bladder mast cell activation. Int J lmmunopharmacol 1998;20:553–563.

 

103

Theoharides TC. Hydroxyzine for interstitial cystitis. J Allergy Clin Immunol 1993;91:686–687.

 

104

Thilagarajah R, Witherow RO, Walker MM. Oral cimetidine gives effective symptom relief in painful bladder disease: a prospective, randomized, doubleblind placebocontrolled trial. BJU Int 2001;87:207–212.

 

105

Smith SD, Wheeler MA, Foster HE Jr, Weiss RM. Effect of long-term oral l-arginine on the nitric oxide synthase pathway in the urine from patients with interstitial cystitis. J Urol 1997;158:2045–2050.

 

106

Korting GE, Smith SD, Wheeler MA et al. A randomized double-blind trial of oral l-arginine for treatment of interstitial cystitis. J Urol 1999;161:558–565.

 

107

Cartledge JJ, Davies AM, Eardley I. A randomized double blind placebo-controlled crossover trial of the efficacy of L-arginine in the treatment of interstitial cystitis. BJU Int 2000;85:421–426.

 

108

Parson CL, Housley T, Schmidt JD et al. Treatment of interstitial cystitis with intravesical heparin. Br J Urol 1994;73:504–507.

 

109

Loose G, Jespersen J, Frandsen B et al. Subcutaneous heparin in the treatment of interstitial cystitis. Scand J Urol Nephrol 1985;19:27–29.

 

110

Ghoniem GM, McBride D, Sood OR, Lewis V. Clinical experience with multiagent intravesical therapy in interstitial cystitis patients unresponsive to singleagent therapy. World J Urol 1993;11:178–182.

 

111

Sant GR, Larock DR. Standard intravesical therapies for interstitial cystitis. Urol Clin North Am 1994;21:73–83.

 

112

Steinhoff G, Ittah B, Rowan S. The efficacy of condroitin sulfate 0.2% in treating interstitial cystitis. Can J Urol 2002;9:1454–1458.

 

113

Cervigni M, Natale F, Nasta L et al. A combined intravesical therapy with hyaluronic acid and chondroitin for refractory painful bladder syndrome/interstitial cystitis. Int Urogynecol J Pelvic Floor Dysfunct 2008;19:943–947.

 

114

Chuang YC, Yoshimura N, Huang CC et al. Intravesical botulinum toxin a administration produces analgesia against acetic acid induced bladder pain responses in rats. J Urol 2004;172:1529–1532.

 

115

Lucioni A, Bales GT, Lotan TL et al. Botulinum toxin type A inhibits sensory neuropeptide release in rat bladder models of acute injury and chronic inflammation. BJU Int 2008;101:366–370.

 

116

Smith CP, Radziszewski P, Chancellor MB et al. Botulinum toxin a has antinociceptive effects in treating interstitial cystitis. Urology 2004;64:871–875; discussion 875.

 

117

van Ophoven A, Pokupic S, Heineke A et al. A prospective randomized placebo controlled, double blind study of amytriptiline for the treatment of interstitial cystitis. J Urol 2004;172:533–536.

 

118

Peeker R, Haghsheno MA, Holmang S, Fall M. Intravesical bacillus CalmetteGuerin and dimethyl sulfoxide for treatment of classic and nonulcer interstitial cystitis: a prospective, randomized doubleblind study. J Urol 2000;164:1912–1916.

 

119

Mayer R, Propert KJ, Peters KM et al. A randomized controlled trial of intravesical bacillus CalmetteGuerin for treatment refractory interstitial cystitis. J Urol 2005;173:1186– 1191.

 

120

Sairanen J, Forsell T, Ruutu M. Long-term outcome of patients with interstitial cystitis treated with low dose cyclosporine A. J Urol 2004;171:2138–2141.

 

121

Ueda T, Tamaki M, Ogawa O et al. Improvement of interstitial cystitis symptoms and problems that developed during treatment with oral IPD-1151T. J Urol 2000;164:1917– 1920.

 

122

Zhao J, Bai J, Zhou Y et al. Posterior tibial nerve stimulation twice a week in patients with interstitial cystitis. Urology 2008;71:1080–1084.

 

123

Peters KM, Feber KM, Bennett RC. A prospective, single blind, randomized crossover trial of sacral vs pudendal nerve stimulation for interstitial cystitis. BJU Int 2007; 100:835–839.