Painful Conditions of the Lower Urinary Tract Including Painful Bladder Syndrome

Steven E. Swift

Toby C. Chai

Alfred E. Bent

INTRODUCTION

Chronic pelvic pain is one of the most difficult and frustrating conditions to manage in gynecology. It can result from a multitude of pathologic entities and various pelvic organs can be involved such that there is overlap between pathologic entities and organ systems involved, and the initiating insult is often only distantly related to the patient’s current symptom complex. The diagnostic criteria for specific diagnoses are usually vague and response to therapy is disappointing. Painful conditions of the lower urinary tract are no different and make up a subset of these complaints. Similar to their counterparts elsewhere in the pelvis they represent a very difficult and frustrating series of disease entities. Another complicating factor involves the role of external pathology affecting symptoms and function of the lower urinary tract so as to further confuse the clinical picture. Diseases such as endometriosis and pelvic inflammatory disease can present within the context of lower urinary tract symptoms. For clarity this chapter will limit its focus on those pathologic entities that are intrinsic to the bladder and urethra. Chapters 9 and 10 will cover pelvic floor myalgia and urinary tract infections, respectively.

PAINFUL BLADDER SYNDROME/INTERSTITIAL CYSTITIS

Currently there is a great deal of debate centered around the diagnosis of interstitial cystitis (IC), making it difficult to comment on its definition. The standard definition that has been recommended for years (for research protocols) comes from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) branch of the National Institutes of Health (NIH). This definition involves both bladder pain and evidence of bladder abnormalities (glomerulations or Hunner’s ulcers) upon cystoscopic examination (1). The original intent of this criteria list was to ensure maximal objective standardization of patients enrolled into NIH-sponsored IC studies. These criteria were not designed as a diagnostic tool (Table 8.1). Painful bladder syndrome (PBS), on the other hand, was first defined by the International Continence Society (ICS) in 2002 and is defined as the complaint of suprapubic pain related to bladder filling, accompanied by other symptoms such as increased daytime and nighttime frequency, in the absence of proven urinary infection or other obvious pathology (2). The ICS further defined the “symptom” of bladder pain as pain felt suprapubically or retropubically that usually increases with bladder filling, though it may persist after voiding. This is slightly different from the definition of IC as defined by the NIDDK guidelines. The ICS definition defines the location of the pain as suprapubic (and/or retropubic if you use the ICS symptom definition) and also ties in the pain to bladder filling. It specifically does not require evidence of bladder abnormalities (glomerulations) upon cystoscopic examination. The ICS, in their document defining PBS, acknowledged that it would be used as an alternative to IC in a footnote:

The ICS believes this to be a preferable term to “interstitial cystitis.” Interstitial cystitis is a specific
diagnosis and requires confirmation by typical cystoscopic and histological features. In the investigation of bladder pain it may be necessary to exclude conditions such as carcinoma in situ and endometriosis.

So while the two terms PBS and IC may not be identical, readers should recognize that in the literature the two will often be used interchangeably. In a recent study of IC patients, only 105 of 138 of those defined as having IC reported suprapubic pain with a relationship to bladder filling status, which led these investigators to question the sensitivity of the ICS definition of PBS in identifying IC patients (3). In order to lessen the confusion for the reader, for the remainder of this chapter we will use the term “interstitial cystitis.” This section of the chapter will focus on IC, as this terminology and definition have been in use longer and the literature to date conforms predominantly to this standard.

TABLE 8.1 NIDDK Definition of Interstitial Cystitis

Inclusion Criteria

Cystoscopy—glomerulations and/or classic Hunner’s ulcer
Symptoms—bladder pain and/or bladder urgency

Exclusion Criteria

Bladder capacity greater than 350 cc on awake cystometry
Absence of an intense urge to void with the bladder filled to 100 cc during cystometry using a fill rate of 30 to 100 cc/min
Demonstration of phasic involuntary bladder contractions on cystometry using the fill rate described in number 2
Duration of symptoms less than 9 months
Absence of nocturia
Symptoms relieved by antimicrobials, urinary antiseptics, anticholinergics, or antispasmodics
Frequency of urination while awake of less than eight times a day
Diagnosis of bacterial cystitis or prostatitis within a 3-month period
Bladder or ureteral calculi
Active genital herpes
Uterine, cervical, vaginal, or urethral cancer
Urethral diverticulum
Cyclophosphamide or any type of chemical cystitis
Tuberculous cystitis
Radiation cystitis
Benign or malignant bladder tumors
Vaginitis
Age less than 18 years

Epidemiology

IC is best described as a chronic hypersensory bladder condition manifested by urinary frequency, urgency, and bladder pain without an identifiable etiology. This disease mainly afflicts women in their 30s and 40s (4). However, it is being more frequently recognized in males, and the female-to-male ratio is 5:1 (5). This remains a disease more common in females, and because females commonly have acute bacterial cystitis, the diagnosis of IC is often delayed. The primary care physician often treats IC with oral antibiotics because IC symptoms mimic acute bacterial cystitis and urine cultures are not typically sent before treatment of acute bacterial cystitis. The current estimated prevalence of IC in the United States is between 66 and 197 per 100,000 (5,6). The estimation of the number of females afflicted with IC in the United States is between 450,000 and 700,000. Recently, investigators mailed a validated IC symptoms questionnaire (O’Leary-Sant questionnaire; see later section for description) to be completed by 5,000 females in a health maintenance organization (7). This study found that prevalence of IC symptoms is 30- to 50-fold higher in women than the prevalence of a coded physician diagnosis of IC in the same population. The authors concluded that IC may be significantly underdiagnosed.

The etiology of IC remains unclear; however, several causes, such as mast cell activation, neurogenic inflammation, and transitional epithelial dysfunction, have been proposed (8). The most frequently discussed pathologic abnormality used to explain IC is a defect of the transitional epithelium, and specifically the glycosaminoglycan (GAG) layer that separates and protects the transitional epithelium from urine. The rationale that the bladder urothelium is “leaky” in IC patients because of a proposed deficiency in the GAG layer (a proteoglycan or glycoprotein) was derived from several observations. First, in animal models, application of protamine sulfate, which purportedly
“strips” the GAG layer, increased bladder permeability in rabbit bladder urothelium (9). Furthermore, the protamine-induced increased permeability was reversed by the addition of sodium pentosan polysulfate, a GAG. Second, protamine placed into normal human volunteers induced pain, urinary frequency, urinary urgency, and increased bladder permeability to urea similar to IC (10). Third was the finding of increased urea uptake by the IC bladders (when exogenous urea was introduced intravesically) compared with control bladders, suggesting increased bladder permeability with IC (11). Finally, there was clinical evidence that sodium pentosan polysulfate (a GAG) alleviates some of the symptoms of IC (12,13). While this theory may explain some cases of IC, the disease is probably multifactorial, which may explain why its etiology remains elusive.

It is also thought that IC may be genetically inherited. This is based on twin studies demonstrating a greater rate of concordance of IC among monozygotic twins than dizygotic twins (14). In addition, there is a 17-fold increase, over the general population, in the incidence of IC in first-degree relatives of patients with IC (15). Future epidemiologic and genetic studies may help pinpoint etiologic mechanisms and also determine the natural history of this puzzling disease.

Clinical Diagnosis

Currently there are no proven etiologies for IC, and defining the disease clinically remains a challenge. The diagnosis is most often made on the grounds of symptoms in the absence of other pathologic entities. There are no classic physical findings, blood tests, histopathology, or radiologic tests for IC. The presentation of symptoms in IC is highly variable, and some have proposed that IC is a complex of diseases with multiple etiologies rather than just a single entity. Because bladder pain is a prominent symptom component of IC, some have included IC in the disease complex of chronic pelvic pain. When IC is better understood from the pathophysiologic standpoint, a more specific terminology may be developed.

Patients who with IC have the prototypical symptom complex of urinary frequency, urinary urgency, and bladder pain without a definable etiology and have had these chronic symptoms for longer than 9 months. The intensity of these symptoms typically waxes and wanes during the course of the disease. Because of the imprecise nature of these symptoms, IC patients are frequently thought to have recurrent urinary tract infection, urethritis, urethrotrigonitis, trigonitis, urethral pain syndrome, urethral stenosis, endometriosis, vulvodynia, vulvar vestibulitis, or pelvic congestion syndrome. A few studies have also found an association between IC, vulvodynia, and chronic pelvic pain, further suggesting that there may be overlap in both symptoms and organs affected (16,17).

Recently, it has been speculated that IC may be a systemic disease because of its association with other conditions, such as irritable bowel disease, allergies, sensitive skin, inflammatory bowel disease, fibromyalgia, chronic fatigue syndrome, and systemic lupus erythematosus (18, 19, 20, 21). Whether these associations represent common pathophysiologic mechanisms or spurious associations may relate to the relatively nonspecific diagnostic criteria for all of these conditions and the potential for selection bias of cases and controls in these studies. Recently, a validated questionnaire for non-bladder-related symptoms was given to 35 IC patients and 35 age-matched controls, and it was found that the IC patients did not have more non-bladder symptoms than the controls (22).

Therefore, the diagnosis of IC remains primarily a process of exclusion and clinical suspicion. A list of exclusionary conditions has been set forth by the NIH and the NIDDK (see Table 8.1).

The pain component of IC can be difficult for patients to describe. Because the bladder is autonomically innervated, it is classified as a visceral organ. From a neuroanatomic perspective, this simply means that there is an intervening synapse (ganglia) between the autonomic motor (preganglionic) neuron and the end effector organ (the bladder). However, from a sensory standpoint, patients often have difficulty localizing or describing visceral sensations. The pain may be referred to other areas of the pelvis. Besides the typical pain over the suprapubic (bladder) area, which may be relieved by voiding, IC patients may complain of referred urethra-based pain, such as dysuria, stranguria, or constant burning. They may also complain of low back pain, vulvar pain, rectal pain, and dyspareunia. Quantitation of the severity of pain is quite difficult because of the waxing-waning presentation of symptoms, and there are no formal quantitative objective measures of bladder or pelvic pain.

Urinary urgency is another symptomatic component of IC that can be difficult to separate from pain in some patients. IC patients may describe a constant strong urge to void, despite low bladder volumes, that when severe is described as pain. Urinary frequency is a manifestation of the actual act of voiding, but IC patients have been known
not to void because they realize that frequent voiding does not necessarily lead to relief of pain and urge sensations. From the standpoint of quantification of IC symptoms, measurement of voiding frequency may be the best objective parameter.

In summary, the clinical presentation of IC is characterized by chronic urinary frequency, urgency, and pelvic pain in the absence of precise identifiable etiologic features. These symptoms do not necessarily follow a set pattern and may be quite different from one patient to another. IC patients may have one symptomatic component that predominates over the others. Finally, IC symptoms typically wax and wane, which further complicates the evaluation and treatment of this condition. The key is to rule out identifiable and potentially reversible causes of the bladder symptoms.

Symptom Quantitation

Because IC symptoms are variable, it becomes important to quantitate these symptoms as objectively as possible. This is especially important for clinical researchers examining treatment options for IC. Two sets of validated instruments have been described in the literature. One questionnaire instrument was developed by O’Leary et al in 1997 specifically to assess IC patients (23). The questionnaire had two subscales to quantify symptoms and their impact on quality of life: the Interstitial Cystitis Symptom Index (ICSI) and Interstitial Cystitis Problem Index (ICPI) (Table 8.2). These questionnaires were administered to a group of women with chronic pelvic pain before undergoing laparoscopy and cystoscopy with hydrodistention to determine whether these instruments can detect IC in this patient population. Using positive findings from cystoscopy and hydrodistention as objective criteria for IC, these investigators determined that the sensitivity, specificity, positive predictive value, and negative predictive value of these indices were 94%, 50%, 53%, and 93%, respectively (24). Furthermore, they found that 38% of these patients with chronic pelvic pain had IC.

A second symptom measurement instrument, the University of Wisconsin IC Scale (UW-ICS), has also been developed and validated (25). The UW-ICS is a 7-point, 0-to-6 rating scale with each item anchored between the extremes of 0 (not at all) and 6 (a lot) (Fig. 8.1). The scale is completed by the patient within the context of reporting the symptoms as, “How much have you experienced the following symptoms today?” Seven items are defined to characterize the IC patient, with a summary score being the sum of the seven individual items. This summated UW-ICS score will have a value ranging from 0 to 42.

Any of these validated instruments should be administered to the patient with IC to quantitate her symptoms during the course of evaluation and treatment. It is important to use these standardized instruments so that changes in a patient’s symptoms and quality of life can be followed as objectively as possible.

Diagnosis

Cystoscopy with Hydrodistention

Cystoscopy with hydrodistention of the bladder under anesthesia is the standard method for the objective diagnosis of IC according to the NIDDK recommendations. The conventional wisdom is that IC bladders have the appearance of glomerulations (or petechiae) after bladder hydrodistention (nonulcerative form of IC). However, glomerulations are often not found in subjects with symptomatic IC and are noted in up to 45% of normal subjects without symptoms of IC (26,27). The appearance of classic Hunner’s ulcers is uncommon in IC, although it has been suggested that the appearance of Hunner’s ulcers is a more specific sign for IC (ulcerative form of IC). Anesthetic bladder capacity of IC patients may also be reduced, although typically IC patients have normal anesthetic capacity. The presumed diagnostic specificity of appearance of postdistention bladder glomerulations or Hunner’s ulcers resulted in the NIDDK using this as the only objective criterion in classifying a patient as having IC. Although this single criterion is not uniformly accepted by all clinicians, its main purpose is to standardize IC patients enrolled in NIH-sponsored studies.

Description of Hydrodistention

Hydrodistention is performed with the patient under general or regional anesthesia. A full cystoscopic examination of the bladder is performed first. Patients with IC can have a completely normal-appearing bladder without evidence of uroepithelial lesions. Cystoscopic irrigant, water or saline, is then infused at a pressure of 80 to 100 cmH₂O into the bladder until filling stops (pressure cut-off). The bladder is distended for 2 to 5 minutes before all the irrigant is released from the bladder. Terminal bloody efflux of irrigant suggests the diagnosis of IC. The bladder epithelium is re-examined with the cystoscope during repeat filling. Glomerulations (petechiae) or Hunner’s
ulcers, appearing as fissures or cracks in the epithelium, are consistent with IC (Fig. 8.2).

TABLE 8.2 Interstitial Cystitis Symptoms Quantitation

IC Symptom Index (ICSI)

IC Problem Index (ICPI)

1. During the past month, how often have you felt the strong urge to urinate with little or no warning?
0_____not at all
1_____less than 1 time in 5
2_____less than half the time
3_____about half the time
4_____more than half the time
5_____almost always
2. During the past month, have you had to urinate less than 2 hours after you finished urinating?
0_____not at all
1_____less than 1 time in 5
2_____less than half the time
3_____about half the time
4_____more than half the time
5_____almost always
3. During the past month, how often did you most typically get up at night to urinate?
0_____not at all
1_____less than 1 time in 5
2_____less than half the time
3_____about half the time
4_____more than half the time
5_____almost always
4. During the past month, have you experienced pain or burning in your bladder?
0_____not at all
1_____less than 1 time in 5
2_____less than half the time
3_____about half the time
4_____more than half the time
5_____almost always

During the past month, how much has each of the following been a problem for you?
1. Frequent urination during the day
0_____no problem
1_____very small problem
2_____small problem
3_____medium problem
4_____big problem
2. Getting up at night to urinate
0_____no problem
1_____very small problem
2_____small problem
3_____medium problem
4_____big problem
3. Need to urinate with little warning
0_____no problem
1_____very small problem
2_____small problem
3_____medium problem
4_____big problem
4. Burning pain, discomfort, or pressure in your bladder
0_____no problem
1_____very small problem
2_____small problem
3_____medium problem
4_____big problem

Potassium Sensitivity Test

The potassium sensitivity test (PST) was developed as a method to diagnose IC in a relatively noninvasive manner (as compared with cystoscopy and hydrodistention under anesthesia) (28). The rationale for this test is based on the assertion that the bladder urothelium is “leaky” in IC patients because of a proposed deficiency in the GAG layer (a proteoglycan or glycoprotein) on the luminal surface of the bladder uroepithelium. If urothelial leak were the pathophysiologic mechanism in IC, urinary potassium in the urine would cross the leaky IC urothelial barrier to activate (depolarize) the sensory nerve endings in the suburothelium.

FIGURE 8.1 ● The University of Wisconsin Interstitial Cystitis scale.

The patient is awake and without anesthesia for the PST. The test is performed by infusing 40 mL of solution 1 (sterile water) into the bladder over 2 to 3 minutes. After 5 minutes, the patient rates her pain and urgency using a visual scale from 0 to 5, with 5 being worst. She voids the contents of her bladder. Next, 40 mL of solution 2 (0.4 molar potassium chloride [KCl]) is instilled into the bladder and left for 5 minutes. The patient rates her pain and urgency and voids the solution. A score of at least 2 in either pain or urgency is considered a positive PST, provided the patient does not respond to solution 1. It was shown in this same study that 75% of patients with IC have a positive PST, as compared with 4% of controls. Neither IC nor control subjects had a positive test with 40 mL of water infusion. Parsons observed that there was an 85% positive test when the KCl was administered to gynecologic patients with chronic pelvic pain, leading him to conclude that most gynecologic patients with chronic pelvic pain have IC (29). This is compared with a rate of 38% as determined by cystoscopy and hydrodistention in patients with chronic pelvic pain (9).

FIGURE 8.2 ● (A) IC before hydrodistention. The initial filling of the bladder appears normal. (continued)

However, the ability of the PST to diagnose IC has been questioned. Other investigators have
noted that up to 25% of women with strict NIDDK criteria-positive IC had a negative PST and 36% of men without symptoms of IC had a positive PST (30,31). Finally, when the PST was compared with cystoscopy and hydrodistention as a diagnostic test, it fared no better in terms of positive predictive value (59% and 66%, respectively) in a population who had symptoms suggestive of IC (32). These investigators concluded that the general use of the PST is not validated and that we must continue to depend on cystoscopy and hydrodistention for the diagnosis of IC.

FIGURE 8.2 ● (continued) (B) IC after hydrodistention in same patient. Numerous petechiae and-glomerulations appear after the bladder has been distended and emptied, then refilled, indicating a diagnosis of IC. Eventually, enough blood accumulates to cloud the picture in the bottom right of figure.

Finally, the PST does not discriminate between patients with IC and other forms of cystitis (bacterial, radiation, etc.), further limiting its role in diagnosis.

The PST has also been evaluated as a prognostic tool. Teichman found that a positive PST predicted better response to oral sodium pentosan polysulfate than occurs in patients with a negative PST (33). In this study, the complete NIDDK criteria were not used for the diagnosis of IC. Specifically, not all patients received cystoscopy and hydrodistention to look for glomerulations or Hunner’s ulcers. Therefore, most patients had an IC diagnosis based solely on symptoms and exclusionary criteria. Interestingly, the IC patient population in this study had a 34% negative PST rate. The investigators gave sodium pentosan polysulfate to all patients regardless of whether their PST was positive or negative. Those who had a positive PST fared better than those who had a negative PST. However, the predictive value of a positive PST was not consistent across all improvement categories (i.e., greater than 25% improvement, greater than 50% improvement).

In conclusion, both “objective” diagnostic tests, hydrodistention under anesthesia and PST, have advantages and disadvantages. Hydrodistention has been traditionally used to categorize patients in NIH-funded studies. The anesthetic capacity of the bladder can be measured, and other potential anatomic abnormalities of the bladder can be cystoscopically assessed. Some patients may symptomatically benefit from hydrodistention, although some also have a temporary worsening of symptoms. PST is a noninvasive test meant to induce temporary pain in IC patients. It might also help to predict those who will respond to sodium pentosan polysulfate.

Taken in whole, the utility of these two tests requires further investigation. It also shows that until the pathophysiology of IC can be proved, a better diagnostic test (such as urine markers, discussed subsequently) awaits.

Role of Urinary Markers

Because of the dilemma that exists in the diagnosis of IC, many investigators have sought urine markers that might serve as noninvasive diagnostic surrogates. Finding a highly sensitive and specific urine marker will also serve to provide insights into the pathophysiologic mechanisms, which may eventually lead to specific targeted treatments. Many urinary substances have been described as increased or decreased in patients with IC compared with controls. These substances, such as histamine, interleukins, GAGs, hyaluronic acid, epithelial growth factors, nerve growth factor, and others, were selected based on theorized etiologies for IC. One of the major problems in using many of these substances as a diagnostic marker is that although the levels may be statistically significantly higher or lower in the IC population when averaged, there is significant overlap of values among control and IC subjects. The reasons for this may be that IC is multifactorial in etiology and that subgroups of IC patients exist depending on the cause. A more extensive review of urine markers has been recently published.

Two markers that have shown particular potential in diagnostic capability are glycoprotein-51 (GP-51) and antiproliferative factor (APF) (34,35). GP-51 levels in urine were examined in controls and those who met NIDDK criteria for IC (36). There was no overlap in urinary GP-51 concentration between those control and IC individuals. APF is a low-molecular-weight protein present in IC urine that is able to inhibit the ability of cultured normal bladder urothelial cells to incorporate ³H-thymidine (37). Recently, both the molecular structure of APF and the receptor for APF have been identified (38,39). Therefore, the development of a clinical diagnostic kit and/or treatment aimed at APF-APF receptor interaction may be possible. The levels of APF activity in patients who meet NIDDK criteria for IC and in control urine specimens do not overlap (40). Both of these markers were based on the gold standard NIDDK objective criteria of presence of glomerulations on cystoscopy or hydrodistention, which may not be a specific finding. It is unknown how these urinary markers are altered in patients with painful bladder symptoms who do not fulfill the NIDDK criteria for IC. Nevertheless, these two markers provide the foundation for elucidation of the pathophysiologic mechanisms involved in IC and may ultimately serve to be a diagnostic marker for IC.

Urodynamics

The use of urodynamics in the management of IC is also debated. The IC Database Study Group analyzed urodynamic data and compared them to data collected from voiding diaries (41). It was not surprising that urodynamic data closely correlated with the findings of the voiding diaries. Patients with low-volume, high-frequency voiding as recorded in a voiding diary had decreased cystometric capacity and decreased volume of first sensation. Therefore, it has been suggested that urodynamics are unnecessary in the evaluation of IC because the voiding diary, which is noninvasive, would capture the necessary information. However, some believe that urodynamics will allow discrimination between those patients with IC who have bladder symptoms and those with non-bladder symptoms (42). Patients who show motor instability on urodynamics are considered not to have IC and are treated with antimuscarinics.

Summary of Diagnostics

The diagnosis of IC remains a clinical one, and therefore the diagnosis of PBS carries a lot of credibility. The presence of small, frequent, painful voids in the absence of other potential pathologic etiologies is all that is required by most clinicians to render the diagnosis of IC. This criterion can be met employing a voiding diary, urine cultures, and clinical acumen. Cystoscopy, the PST, and urinary markers may eventually find a role in routine clinical practice, but currently they remain research tools for confirming the diagnosis of IC that is clinically suspected.

Treatment of Symptoms

After the diagnosis of IC has been made, a cornucopia of therapies exists. Unfortunately, many of these therapies have not been tested in a rigorous, randomized, blinded fashion using standardized data collection techniques and standardized questionnaire instruments. Part of the difficulty with treatment studies relates to the subjective nature of this condition. Additionally, the typical waxing-waning course of IC makes assessment of treatment modalities more difficult. Finally, because of the lack of understanding of the precise etiology of IC, there does not exist a highly effective treatment,
and currently there is no cure for this disease. These reasons make it imperative to assess the outcomes of the available treatments scientifically so that clinicians can counsel patients on the best form of therapy. To date there are only a few prospective randomized clinical trials, with relatively small numbers (Table 8.3).

The NIH, in its commitment to understanding the pathophysiology and treatment of IC, is currently conducting multicenter clinical trials examining outcomes of different IC treatments in a prospective, randomized manner that addresses all these problematic issues. These clinical centers compose the NIH Interstitial Cystitis Clinical Trials Group (ICCTG). The ICCTG recently completed a four-arm blinded, prospective, randomized study comparing sodium pentosan polysulfate plus placebo, hydroxyzine plus placebo, sodium pentosan polysulfate plus hydroxyzine, and placebo plus placebo. Results from this study suggest that there was no benefit of sodium pentosan polysulfate or hydroxyzine over placebo, and therefore a larger trial was abandoned (43). There were many difficulties with this trial, including low patient recruitment, that led to smaller-than-anticipated patient numbers. Nevertheless, the results were not promising. A second clinical trial studying the effectiveness of intravesical bacille Calmette-Guérin (BCG) was recently completed by the same group, with similar findings of no significant efficacy of BCG over placebo (44). Currently, the ICCTG (renamed ICCRN [Interstitial Cystitis Clinical Research Network]) is conducting several other clinical trials in PBS/IC. However, until precise pathophysiologic mechanisms are identified, IC treatments will continue to be empiric (Table 8.4).

TABLE 8.3 Randomized Controlled Clinical Trials of IC Therapies

Drug	#RCTs	% improved with drug	% improved with placebo	p value
Amitriptyline (47) (n = 50)	1	63%	4%	<0.001
Pentosanpolysulphate (PPS) (40,42, 43, 44, 45) (n = 62-248)	5	˜30%	˜15%	NS; 0.01
Hydroxyzine (49) (n = 121)	1	31%	20%	NS
Cyclosporine A (49) (n = 64)	1	40%	19% (comparator was PPS)	0.001
Intravesical DMSO (50) (n = 33)	1	40%	18%	Significant
Intravesical BCG (41) (n = 265)	1	21%	12%	0.062

Oral-Based Therapies

Oral pharmacologic treatments remain a mainstay of therapy. Each of the following agents has been used with a specific targeted pathway in mind, and most are used in other diagnoses besides IC.

Sodium pentosan polysulfate (Elmiron): This medication was developed as a specific treatment for IC based on the theory that IC is due to a leaky urothelium because of the deficiency of the GAG layer in the bladder. Sodium pentosan polysulfate, a weak heparinoid, supposedly replenishes the GAG layer and thus makes the urothelium less leaky. This is the first oral medication for IC that has undergone randomized, placebo-controlled clinical trials (45, 46, 47, 48). These studies have shown that sodium pentosan polysulfate can significantly decrease certain IC symptoms. Several caveats should be discussed. First, there seemed to be a period of time (3 to 6 months) before maximal beneficial effect was seen, and this was found in an open-label continuation of the initial clinical trials. Second, differences between control and treated patients in the early trials, although statistically significant, were not dramatically different from a clinical standpoint (28% of sodium pentosan polysulfate treated patients had more than 25% improvement versus 13% of placebo-treated patients). If IC is truly due to only a GAG deficiency that is readily reversible with sodium pentosan polysulfate, a high concentration of sodium pentosan polysulfate introduced intravesically should ameliorate all the symptoms of IC (because only
3% of the oral dose is excreted into the urinary tract). Empirically, this is not the case. There are some preliminary reports of combining pentosan polysulfate or heparin with lidocaine and sodium bicarbonate and administering it intravesically to provide acute relief (49).

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