Management Strategies for Painful Bladder Syndrome

Abstract

Painful bladder syndrome/interstitial cystitis (PBS/IC) is a condition of chronic pelvic pain associated with irritative voiding symptoms. Management of PBS/IC has been a challenge for generations of physicians, owing to a lack of consensus on its definition, an incompletely understood pathophysiology, and numerous available therapies without high-quality evidence to guide their usage. This article reviews the most current conception of PBS/IC and data on effective treatments to recommend a management strategy.

Painful bladder syndrome/interstitial cystitis (PBS/IC), like many other chronic pelvic pain syndromes, is a perplexing condition that gynecologists often find difficult to manage. Owing to its evolving definition and uncertain pathogenesis, over 180 therapies have been used,¹ but few of these have been proven efficacious when examined systematically. This article reviews the best available evidence and recommends a management strategy.

History

The first description for PBS/IC dates back to a textbook published in 1836. Joseph Parrish, a Philadelphia surgeon, described 3 patients with severe urinary symptoms but no apparent organic cause, such as nephrolithiasis, and labeled them with “tic doloreaux of the bladder.” In 1887, Alex Skene coined the term interstitial cystitis (IC) to describe an inflammation that has “destroyed the mucous membrane [of the bladder] partly or wholly and extended to the muscular parietes.”² In 1915, Hunner presented 8 cases of red, bleeding patches on cystoscopy in women with long-standing pelvic pain and irritative voiding symptoms; Hunner ulcer thus became the classic finding of IC. Several decades later in 1949, Hand reported 223 cases of petechial, submucosal hemorrhages on cystoscopy after hydrodistention; these hemorrhages were later named glomerulations by Walsh. In 1978, Messing and Stamey proposed that glomerulations may be the hallmarks of early IC, whereas Hunner’s ulcers may represent late disease. Today, disease with Hunner’s ulcer is sometimes referred to as classic or ulcerative IC, whereas disease without this finding is referred to as nonclassic or nonulcerative IC.

Definition

For a century after it was first described, there was no clear definition for IC. In 1987, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) finally established a set of consensus criteria for research purposes, which became the de facto diagnostic criteria. These required findings of bladder pain, urgency, glomerulations, or a Hunner’s ulcer, as well as the absence of 18 exclusions (Table 1). The NIDDK criteria were found to be too restrictive in clinical practice, potentially missing 60% of cases.³ In 2002, the International Continence Society (ICS) published new recommendations and, notably, proposed that IC should be renamed painful bladder syndrome (PBS). The ICS diagnosis of PBS is based on suprapubic pain related to bladder filling, day or nighttime frequency, and the absence of other obvious pathology.⁴ The term IC, it was advised, should be reserved for those affected by PBS who also have cystoscopic findings. This new set of criteria recognized that symptoms drive treatment, and it became the most widely accepted definition of PBS/IC.

Table 1.

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Criteria for Interstitial Cystitis

The presence of any 1 of the following excludes a diagnosis of interstitial cystitis:

1. Bladder capacity of greater than 350 mL on awake cystometry using either a gas or liquid-filling medium

2. Absence of an intense urge to void with the bladder filled to 100 mL of gas or 150 mL of liquid-filling medium

3. The demonstration of phasic involuntary bladder contractions on cystometry using the fill rate just described

4. Duration of symptoms less than 9 mo

5. Absence of nocturia

6. Symptoms relieved by antimicrobial agents, urinary antiseptic agents, anticholinergic agents, or antispasmodic agents

7. A frequency of urination while awake of less than 8 times/d

8. A diagnosis of bacterial cystitis or prostatitis within a 3-mo period

9. Bladder or ureteral calculi

10. Active genital herpes

11. Uterine, cervical, vaginal, or urethral cancer

12. Urethral diverticulum

13. Cyclophosphamide or any type of chemical cystitis

14. Tuberculous cystitis

15. Radiation cystitis

16. Benign or malignant bladder tumors

17. Vaginitis

18. Age younger than 18 y

To be diagnosed with interstitial cystitis, patients must have either glomerulations on cystoscopic examination or a classic Hunner ulcer, and they must have either pain associated with the bladder or urinary urgency. An examination for glomerulations should be undertaken after distention of the bladder under anesthesia to 80 to 100 cm H2O for 1 to 2 min. The bladder may be distended up to 2 times before evaluation. The glomerulations must be diffuse—present in at least 3 quadrants of the bladder—and there must be at least 10 glomerulations per quadrant. The glomerulations must not be along the path of the cystoscope (to eliminate artifact from contact instrumentation).

Epidemiology

Epidemiologic studies of PBS/IC have many limitations: the lack of a universally accepted definition, the shortage of a validated diagnostic marker, and uncertainties surrounding its etiology and pathophysiology, to name a few. The available studies have shown that PBS/IC disproportionately affects women by a ratio of 10:1. The mean age of those affected is in the 40s, although rare cases of PBS/IC in children have been reported. The prevalence varies widely across the world, from 1–4/100,000 in Japan and 18/100,000 in Finland. In the United States, data from US Nurses’ Health Study found a prevalence 52–67/100,000,⁵ based on self-reported IC that was confirmed by medical record review. Data from the managed care population showed an even higher prevalence of 158/100,000, based on the use of the IC diagnostic code.⁶ The global variance may be explained in part by familial occurrence or heredity. It has been observed that there is greater concordance of IC between monozygotic twins than dizygotic twins. What does not vary is that patients with PBS/IC uniformly report a lower quality of life than do dialysis patients and are 6 times more likely than the general population to miss work.⁷ The impact of PBS/IC-related suffering and lost productivity is not trivial.

Pathophysiology

Neither the inciting event nor the exact pathogenesis have been determined, but the etiology of PBS/IC is likely multifactorial. Of the numerous theories that have been examined, the factors most likely to play a significant role include infection, autoimmune inflammation, mast cell activation, bladder epithelial permeability, neurogenic inflammation, and antiproliferative factor.² One hypothetical cascade of events is that an initial bladder injury leads to bladder epithelial damage, resulting in leakage of potassium into the interstitium, which then triggers mast cell activation and leads to further bladder damage and neuropathic pain (Figure 1).

Figure 1.

Hypothetic cascade of events in painful bladder syndrome/interstitial cystitis. Reproduced with permission from Hanno PM.²

Presentation

Patients typically present with a constellation of bladder, urethral, or pelvic pain associated with urgency or frequency. Less commonly, nocturia or dysuria may be the driving complaints. It is important to note the similarity between PBS/IC and overactive bladder syndrome-some experts believe these conditions, in fact, lie along the same disease spectrum; the principal differentiation is the persistent pain found in PBS/IC. Patients may also present with a range of associated conditions, including allergy, irritable bowel syndrome (IBS), systemic lupus erythematosus,⁸ endometriosis,⁹ fibromyalgia, vulvodynia, and depression.

Diagnosis

PBS/IC is a clinical diagnosis of exclusion. A thorough history elicits chronic suprapubic pain and frequency (day or night time) but excludes medications that cause cystitis (eg, acetylsalicylic acid, nonsteroidal anti-inflammatory drugs, cyclophosphamides, allopurinol). It is imperative to rule out bladder malignancy based on risk factors (eg, age > 40 years with history of smoking). A focused physical examination should be conducted to reveal no findings to support an alternate diagnosis. The only necessary testing is a urinalysis to look for signs of intrinsic urinary tract disease and a urine culture to exclude infection.

Many other diagnostic adjuncts have been considered for PBS/IC. The most popular are the O’Leary-Sant Symptom Index (OSI), the Pelvic Pain and Urgency/Frequency Questionnaire (PUF), the Potassium Sensitivity Test (PST), and the Anesthetic Challenge Test (ACT). The OSI and PUF are simple questionnaires that consist of 4 and 8 questions, respectively. The OSI has been subjected to test-retest reliability analysis and validated,¹¹ and the PUF (with a score > 20) has been found to correlate 91% with a positive PST.¹² Although their roles in clinical diagnosis have not been established, their use will likely aid in epidemiologic studies and measurement of treatment response. The PST, which uses high doses of intravesical potassium to provoke a pain response, has been found to be insufficiently sensitive or specific to be validated as a diagnostic tool.¹³ The ACT, which employs a mixture of lidocaine and sodium bicarbonate to elicit an improvement in pain, has not been validated for diagnosis either; however, it may be used to localize the source of pelvic pain to the bladder and help differentiate from other etiologies of chronic pelvic pain.¹⁴

Cystoscopy to look for glomerulations, which are nonspecific,¹⁵ or Hunner ulcers is no longer indicated for the diagnosis of PBS. Its main role given the current disease definition is to exclude structural bladder disease in select patients. Urodynamic testing is also unnecessary unless detrusor activity cannot be ruled out clinically. Current and future research will place an emphasis on identifying biomarkers, such as antiproliferative factor,¹⁶ that can support the clinical diagnosis.

Management

Many management options for PBS/IC exist—nonpharmacologic, oral, intravesical, and hydrodistention—but the best approach has yet to be determined. Although studies on the various treatments are abundant, high-quality evidence is scarce. A review of the best available data for each approach follows, with emphasis on outcomes of symptomatic improvement.

Nonpharmacologic Therapy

Nonpharmacologic therapies target diet and behavior modification, physical therapy, management of comorbidities, and patient support and empowerment. Dietary regimens typically restrict caffeine, alcohol, citrus, carbonated beverages, and acidic foods, all believed to trigger histamine release and thereby exacerbate symptoms. Behavioral adaptations emphasize controlled fluid intake, abstention from exacerbating activities, stress reduction through exercise and breathing/relaxation techniques, and bladder training. Bladder training aims to decrease frequency of voiding and is best practiced by those with mild to moderate bladder pain. In a small prospective study where subjects were trained to increase voiding intervals by 15 to 30 minutes every 3 to 4 weeks, 71% of participants reported a 50% decrease in irritative voiding symptoms.¹⁷

Pelvic floor physical therapy, which aims to correct hypertonus of the pelvic floor via external manual realignment of the sacrum and ilium and intravaginal myofascial release (Thiele massage), may be helpful. One small study of 16 PBS/IC patients undergoing manual therapy and Thiele massage for an average of 8 sessions showed a 94% improvement in OSI scores, most notably in the indices of frequency and suprapubic pain.¹⁸ Comorbid conditions such as depression, IBS, or endometriosis should be treated concurrently and optimally. Finally, patients should feel supported and empowered with information; excellent resources are available through the Interstitial Cystitis Association’s website (www.ichelp.com), including a detailed list of foods to avoid.

Oral Pharmacologic Therapy

The best-studied oral agents for treatment of PBS/IC are pentosan polysulfate sodium (PPS), amitriptyline, and hydroxyzine. Notably, PPS—a sulfated polysaccharide thought to decrease the altered permeability of the urothelium—is the only US Food and Drug Administration (FDA)-approved oral medication for the treatment of PBS/IC. In a systematic review of the 6 available randomized, controlled trials of oral PPS versus placebo, the reported overall response rate ranged from 15% to 67% at the FDA-recommended 100-mg tid dosage. The pooled analysis suggested benefit, reporting a relative risk of 1.78 for patients reporting overall symptom improvement.¹

Only one randomized, controlled trial (RCT) of amitriptyline—a tricyclic antidepressant that may modulate pain by decreasing serotonin and norepinephrine reuptake in the central nervous system—was found. Changes in OSI scores from baseline to the 4-month follow-up were compared between the treatment and placebo groups. A statistically significant difference in mean symptom score was found (−8.4 in amitriptyline vs −3.5 in placebo; P = .005).¹⁹ Additionally, 64% in the amitriptyline versus 4% in the placebo group reported “good” or “excellent” satisfaction with their treatment. The average dose in this study was 75 mg qhs; the usual practice is to start at 10 mg qhs and to uptitrate to a maximum dose of 100 mg qhs.

Only one RCT compared hydroxyzine—an ¹H-antagonist that blocks mast cell degranulation—to placebo, and it showed a nonstatistically significant 32% versus 20% global response rate for hydroxyzine versus placebo (P = .26) at the 2-year follow-up.²⁰ The majority of the hydroxyzine treatment group was on the maximum dose of 50 mg qhs. Unfortunately, this pilot study did not meet recruitment goals and was underpowered.

In summary, there is evidence that both oral PPS and amitriptyline improve patient symptoms. As there have been no controlled trials directly comparing the efficacy of these 2 agents, there are no data to guide us as to which is superior. It would be reasonable to choose either agent, taking into account each of their sideeffect profiles. At this time, further research is needed to determine the efficacy of hydroxyzine.

Intravesical Therapy

Nine prospective, randomized trials on 6 intravesical therapies were analyzed by a 2007 Cochrane review, but the authors interpreted that the evidence was inconclusive.²¹ Although dimethyl sulfoxide (DMSO)—an antiinflammatory analgesic with musclerelaxing and mast-cell inhibiting properties—is the only FDA-approved intravesical agent, only one placebocontrolled trial has been conducted. Thirty-three patients were randomized to DMSO versus saline for 4 treatments. Subjectively, 53% in the DMSO versus 18% in the placebo group reported marked improvement; objectively, 93% versus 35% had improvements on urodynamic testing.²² No major adverse events were reported in this study, but DMSO instillation is known anecdotally to be painful and may initially worsen symptoms.

One small RCT was performed on intravesical PPS versus placebo, and symptomatic relief measured by the visual analogue scale and frequency were reported. After twice-weekly treatments for 3 months, more subjects in the treatment arm reported relief and decreased frequency, but the difference was not statistically significant. ²³ The authors did not comment on the power of the study. No major adverse events were reported.

Two studies examined the use of intravesical Bacillus Calmette-Guérin (BCG)—the tuberculosis vaccine that is believed to work immunologically—versus placebo, and both found trends in favor of BCG that were not statistically significant. These studies noted higher rates of hematuria in the BCG-treated groups.²¹ Studies of intravesical resiniferatoxin—a potent capsaicin that desensitizes afferent innervation-versus placebo have found no improvement in patient symptoms; of note, treatment was found to be painful and difficult to tolerate.^24,25 Various additional intravesical agents, from alkalinized lidocaine to botulinum toxin A to chondroitin sulfate, are under investigation. In current practice, many providers elect to use a “cocktail” of 2 to 3 intravesical agents for instillation (recipes are available on www.ichelp.com). There are no data in the literature to support the use of one cocktail over another.

In summary, evidence to support the use of intravesical therapy is scant and highly limited by small, possibly underpowered, studies. In light of the absence of major adverse events associated with DMSO and PPS, it remains reasonable to consider their use in patients who do not respond to initial treatment. Patients should be properly counseled regarding the potential of limited efficacy and variable duration of symptom relief.

Hydrodistention

Hydrodistention has historically been a diagnostic tool for PBS/IC, when cystoscopic findings were still integral to the diagnosis. However, in the past decade, hydrodistention has gained popularity as a treatment. It is performed under anesthesia and consists of filling the bladder with water or saline until 70 mm Hg pressure is reached. Bladder dilatation is maintained for several minutes to half an hour, and then the fluid is released. It is theorized that this aggressive bladder “stretching” leads to disruption of sensory nerves in the bladder wall resulting in pain relief. Only small observational studies of hydrodistention as a treatment are available. One study of 52 patients undergoing hydrodistention with 500 mL of saline for 30 minutes with epidural anesthesia found that 9% were good responders (symptom relief maintained for > 3 years without further treatment) and 58% were moderate responders (symptom relief maintained for 3 to 12 months without further treatment). This appears to be a viable treatment alternative, but the risk of treatment related to anesthesia and the variable duration of symptom relief should be discussed with the patient.

Conclusions

Based on the evidence just reviewed, a multimodal management approach in caring for patients with PBS/IC is recommended (Figure 2). The first step is to initiate comprehensive nonpharmacologic therapies—from patient education and dietary changes to bladder training and, where available, pelvic floor physical therapy-as well as to start an oral medication. The trial of the oral agent, whether PPS or amitriptyline, should be 3 to 6 months in duration. After this trial period, the patient’s response should be assessed. If the response has been adequate, continue the same therapy and reassess symptoms in 6 to 12 months. For poor responders, the next step is to consider adding a second oral agent and intravesical therapy. The choice of intravesical therapy, whether DMSO, PPS, or a “cocktail,” should be guided by patient preference after appropriate counseling of the risks and benefits of each agent is explained. For those who continue to have no symptom improvement, the third step would be to proceed to hydrodistention. Patients whose symptoms are refractory to these initial management steps should be referred to a specialist for consideration of more aggressive therapy, such as neuromodulation via sacral nerve stimulation.

Figure 2.

Management algorithm. DMSO, dimethyl sulfoxide; PPS, pentosan polysulfate sodium.

Main Points.

• Available studies have shown that painful bladder syndrome/interstitial cystitis (PBS/IC) disproportionately affects women by a ratio of 10:1, with the mean age of those affected being in the 40s. Prevalence rates vary worldwide, but patients uniformly report a lower quality of life.

• The factors most likely playing a significant role in the multifactorial etiology of PBS/IC include infection, autoimmune inflammation, mast cell activation, bladder epithelial permeability, neurogenic inflammation, and antiproliferative factors.

• Evidence suggests that both oral pentosan polysulfate sodium (PPS) and amitriptyline improve patient symptoms. No controlled trials have directly compared the efficacy of these 2 agents, so currently there are no data to guide the practitioner on which one is superior. It would be reasonable to choose either agent, taking into account each of their side-effect profiles. Further research is needed to determine the efficacy of hydroxyzine.

• Nonpharmacologic therapies for PBS/IC target diet and behavior modification, physical therapy, management of comorbidities, and patient support and empowerment. The best-studied pharmacologic therapies for treatment are PPS, amitriptyline, and hydroxyzine. Notably, PPS is the only US Food and Drug Administration (FDA)-approved oral medication for the treatment of this condition.

• Evidence to support the use of intravesical therapy is scant. In light of the absence of major adverse events associated with dimethyl sulfoxide (the only FDA-approved intravesical agent) and PPS, it remains a reasonable consideration for patients not responsive to initial treatment. Patients should be counseled on the potential of limited efficacy and variable duration of symptom relief.