Interstitial Cystitis Treatment & Management

Therapy for interstitial cystitis begins with extensive patient education regarding the chronic nature of the disease and realistic assessments of the condition, prognosis, and potential responses to therapy. Ongoing reassurance and physical and emotional support are important as the diagnostic evaluation progresses and therapies are applied.

Only rarely will patients with interstitial cystitis have an immediate, complete, and durable response to any particular therapy. They must be counseled at length regarding the lack of universally effective therapies. Often, referral to one of the local interstitial cystitis support groups, especially a local chapter of the Interstitial Cystitis Association, can be helpful in providing a continuing network of support for the patient.

Ideally, in clinical practice, the treatment of interstitial cystitis should be initiated with the least invasive, least expensive, and most reversible therapy. In general, this consists of a program of dietary and fluid management, time and stress management, and behavioral modification. Thereafter, treatments are applied in a progressively more invasive step-wise fashion until some degree of symptomatic relief is obtained.

The level of initial treatment may also be influenced by clinical judgment, taking into account the severity of presenting symptoms and patient-specific factors. At times, multiple simultaneous treatments may be used in select patients. In patients who have shown no response to multiple treatment modalities, reassessment for any underlying patient condition should be undertaken.^[14]

Interventions may include the following:

• Oral pharmacologic agents (eg, pentosan polysulfate sodium [Elmiron], antihistamines, tricyclic antidepressants, analgesics, anti-inflammatory agents)
• Intravesical therapy (ie, medications intermittently instilled directly into the bladder via a catheter)
• Electrical stimulation
• Complementary therapies (eg, acupuncture, hypnosis)

Following each intervention, the patient is reassessed for response. Unfortunately, therapies are often applied in a haphazard, "hit-or-miss" fashion, combining numerous different therapies before the patient's response to each therapy is truly assessed. This approach is sometimes partly driven by unrealistic patient demands and expectations regarding the success of various therapeutic interventions.

Again, patients must receive extensive counseling regarding the nature and prognosis of their condition and its response to therapy. This is critically important, and such counseling must be initiated prior to embarking on invasive interventions for which no proven overwhelming benefit may be achieved.

Biofeedback and pelvic floor rehabilitation, bladder training programs (ie, progressively increasing the voiding interval over the course of weeks to months), and other behavioral measures are excellent initial interventions and have been used by some authors with some success. The urinary frequency and urgency components seem to respond better to these interventions than the pelvic pain component.

Treatment decisions

Ultimately, the decision to abandon or augment behavioral therapy and to pursue other therapeutic options is made by the patient and physician when a general lack of progress occurs or when symptoms progress. Very few, if any, studies have looked at the minimal duration of time necessary to assess response to behavioral therapy in patients with interstitial cystitis. Furthermore, an optimal behavioral program has also not been defined.

Given the chronic nature of the condition and the possibility of spontaneous improvement or remission, progressively more invasive and expensive treatment should be initiated with caution. Generally, if tolerated by the patient, a trial of 3-6 months of behavioral therapy is warranted prior to proceeding to more invasive or expensive therapies.

Various dietary measures have been examined as therapy for interstitial cystitis. These dietary measures and the previously mentioned behavioral measures can be effective when used alone, but they can also be complementary to virtually all other interventions for interstitial cystitis.

Foods that have been implicated in aggravating symptoms of interstitial cystitis and, in the opinion of some authors, can precipitate symptomatic flares, include the following:

• Coffee
• Alcohol
• Tomatoes
• Vinegar
• Spicy foods
• Chocolate
• Particular fruits and vegetables

Avoiding these food items or substituting other food items is often advised. Patients may be instructed to fill out a food diary, recording the relationship between the consumption of various food and drink items and their interstitial cystitis symptoms. In this manner, items that provoke or exacerbate the interstitial cystitis symptom complex can be eliminated from the diet in a methodical fashion.

Oral medications should be considered only after the aforementioned conservative measures have failed. With the exception of pentosan polysulfate sodium, the drugs listed in the Medication section are not specific for the treatment of interstitial cystitis; however, all of them have demonstrated some degree of efficacy in controlled or uncontrolled studies.

The duration of individual pharmacotherapy is variable. The clinical studies on pentosan polysulfate sodium seem to suggest that maximal effects are not observed until the patient has been on drug therapy for 5-6 months. Other medications are dispensed and their effects are reevaluated as per the expected pharmacokinetics. For example, steady-state serum levels of many tricyclic antidepressants are not attained until 6-8 weeks of stable dosing. Only at this time can the drug dose be safely and reasonably adjusted.

A study funded by the National Institutes of Health found that using pentosan polysulfate sodium alone or in combination with hydroxyzine was slightly beneficial, but this was not significant. The study compared placebo with oral pentosan polysulfate sodium, hydroxyzine, and a combination of both.^[16]

In a randomized, double-blind, placebo-controlled study, amitriptyline was shown to provide statistically significant improvement in the O'Leary-Sant interstitial cystitis symptom index and problem index, pain, and urgency intensity. Common adverse effects of amitriptyline include dry mouth, weight gain, constipation, and sedation.^[17]

Anticholinergic agents such as oxybutynin and tolterodine can be used to treat the urinary frequency component of interstitial cystitis; however, these agents can impair bladder emptying and thus may exacerbate pelvic pain. They should be used with caution in patients with interstitial cystitis.

In a randomized, prospective, nonblinded study, cyclosporine significantly reduced micturition frequency and demonstrated superior clinical response rates when compared with pentosan polysulfate sodium; however, treatment-related toxicity was higher in the cyclosporine arm.^[18]

Treatment algorithm

The authors' algorithm for treatment is largely based on whether the patient has predominantly pelvic pain or urgency/frequency. In the authors' experience, patients with pelvic pain and minimal voiding symptoms represent a pharmacologic challenge, making an early pain-clinic referral a useful adjunct.

In patients with significant voiding symptoms, the authors suggest an algorithm proposed by Hanno. Conservative treatment may include patient education, dietary manipulation, nonprescription analgesics, and pelvic floor relaxation. If an improvement in symptoms is inadequate, begin oral therapy either with antispasmodics and nonnarcotic analgesics or with amitriptyline for 8 weeks. If amitriptyline fails, a trial of hydroxyzine for 8 weeks is suggested. If no response is observed, follow hydroxyzine with pentosan polysulfate sodium.

A 6- to 9-month course of pentosan polysulfate sodium (100mg tid) is followed by a reassessment of interstitial cystitis symptoms. The authors have found that lower doses of this compound are not as effective, but we have not used the higher doses advocated by some authors. In the authors' experience, the better plan is to try single-agent therapy first, moving down the ladder of medications, rather than treating patients with multiple agents from the outset. If conservative measures and medical therapy fail to provide adequate relief, surgical therapy should be considered.

Managing the pain component can be difficult in patients with interstitial cystitis. The etiology of the pain remains unclear, but various authors have postulated the etiology to be mediated centrally, peripherally, or locally via a neurogenic or inflammatory mechanism. Some patients require long-term pain medications, while others rely on these only during periods of symptomatic flares.

Agents used for pain relief include the following:

• Anti-inflammatory drugs
• Acetaminophen
• Gabapentin (Neurontin)
• Tricyclic antidepressants
• Selective serotonin reuptake inhibitors (SSRIs)
• Various other agents

Most clinicians tend to avoid the extensive use of narcotics in patients with interstitial cystitis. When the pain component becomes unresponsive to nonnarcotic agents, referral to a chronic pain management facility may be helpful.

Transcutaneous electrical nerve stimulation (TENS) units, electrical stimulation (intravaginal), acupuncture, and intrathecal and intraspinal infusions have all been used. Topical anesthetics such as lidocaine have been applied directly to the bladder intravesically and have yielded some success.

Patients in whom medical therapy fails may benefit from another bladder hydrodistention if the first hydrodistention was therapeutic. In the rare patient in whom a Hunner ulcer is seen on cystoscopy, laser fulguration or steroid injection is recommended.^[14]

If patients still do not respond, intravesical therapy may be initiated, beginning with weekly dimethyl sulfoxide (DMSO) therapy for 6 courses. Monthly maintenance DMSO instillations have been advocated by some clinicians in order to prevent flares, although data supporting this approach are lacking.

DMSO may be combined with steroids, bicarbonate, and heparin. Intravesical lidocaine may also be added. Some patients with refractory interstitial cystitis symptoms self-catheterize at home and instill a variety of these medications intravesically on an as-needed basis for symptom flares or simply for long-term therapy. In patients who respond poorly to DMSO, intravesical heparin or sodium oxychlorosene (Clorpactin) may be tried.

Raymond Rackley, MD, from the Cleveland Clinic, developed an intravesical formula that has been highly successful in otherwise resistant or difficult cases. The formula uses 50mL of 1% lidocaine solution, in which the following is dissolved:

• A tablet of sodium bicarbonate (650mg)
• A 100mg tablet of pentosan polysulfate sodium
• A 200mcg tablet of misoprostol (Cytotec), a synthetic prostaglandin-E1 analogue

This solution is allowed to sit for 1 hour and is then instilled into the bladder through a catheter; the patient is asked to retain it for as long as possible. The procedure is repeated as often as necessary to achieve relief, typically starting at 3-4 times daily in severe cases.

Long-term application of capsaicin, a component of hot pepper, has been associated with the desensitization of C fibers, the unmyelinated nerve fibers known for transmitting pain. Intravesical instillation of capsaicin has been limited in its use in interstitial cystitis because of the sensation of severe burning.

Resiniferatoxin, a capsaicin analogue, is 100-10,000 times more potent than capsaicin and is not associated with severe burning. However, resiniferatoxin has shown poor effectiveness after single administration, with no significant improvement in symptoms of interstitial cystitis, and side effects of dose-dependent pain and urgency symptoms.^[19]

Hyaluronic acid glycosaminoglycan replenishment therapy has yielded moderate results in non–placebo-controlled studies. In a study of weekly instillation of a 50mL solution of phosphate-buffered solution containing 40mg of sodium hyaluronate, 85% and 84% of patients reported symptomatic and quality-of-life improvement, respectively, with 50% of patients reporting a lasting effect at 5-year follow-up.^[20]

Patients in this study had demonstrated abnormal results on a modified potassium sensitivity test. Lower response rates are seen in patients without evidence of a urine-tissue barrier abnormality.^[20]

Intravesical bacillus Calmette-Guérin (BCG) has been hypothesized to suppress inflammation within the bladder. A randomized, placebo-controlled trial in patients with refractory interstitial cystitis revealed borderline statistical significance for global response assessment questioning, as well as most secondary outcome measures, including capacity, pain scores, urgency/frequency symptoms, and interstitial cystitis inventories.^[21]

However, given the potential for serious adverse effects from BCG, coupled with the paucity of data demonstrating efficacy, this treatment should not be offered outside of investigational studies.^[14] Patients in whom all forms of noninvasive therapy fail, including a referral to a pain clinic, should be considered candidates for sacral neuromodulation or other investigational protocols.

Following diagnostic hydrodistention, a therapeutic hydrodistention may be performed. This is usually performed at 80-100cm water for 8-10 minutes. Hydrodistention at pressures greater than 100cm water or for a duration exceeding 10 minutes is associated with adverse outcomes, including bladder rupture.^[14]

The mechanism of action of bladder hydraulic distention is unknown. Hypotheses include neurapraxias by mechanical trauma and epithelial damage from mechanical trauma.

Surgical placement of an electrode into the S-3 foramen to provide direct sacral nerve root stimulation, or sacral neuromodulation, has been approved by the US Food and Drug Administration (FDA) for medically refractory frequency, urgency, and urge incontinence. This technique is showing promising results in patients with interstitial cystitis.

Studies in patients with interstitial cystitis refractory to conservative measures (ie, behavioral modification, diet, medications, hydrodistention) have found that sacral neuromodulation improved daytime frequency, nocturia, and mean voided volumes and decreased pain and interstitial cystitis symptom and problem index scores. In patients taking chronic narcotics for refractory pain associated with interstitial cystitis, sacral neuromodulation has been shown to decrease (but not eliminate) narcotic requirements.

In addition, sacral neuromodulation has been shown to normalize the abnormally high levels of antiproliferative factor and the abnormally low levels of heparin-binding epidermal growth factor in the urine of patients with interstitial cystitis.

Pudendal nerve stimulation has also been evaluated in patients with interstitial cystitis and has been compared with sacral nerve stimulation. In a small series, overall reduction in symptoms was 59% for pudendal nerve stimulation and 44% for sacral nerve stimulation.^{[22, 23, 24]}

Transurethral intradetrusor injection of botulinum toxin type A coupled with therapeutic hydrodistention has been shown to be superior to hydrodistention alone in improving symptoms and bladder capacity in patients with interstitial cystitis. However, higher doses appear to increase the risk of postoperative voiding dysfunction and urinary retention. The use of intradetrusor botulinum A toxin for this and other urologic conditions remains investigational.^{[25, 26, 27]}

Rarely indicated surgical therapies include the following:

• Laser photoradiation (poor results)
• Electrical stimulation
• TENS (more marked effect on bladder pain than on urinary frequency)
• Peripheral denervation (rarely indicated)
• Bladder augmentation (controversial because pain usually does not improve)
• Urinary diversion (most invasive; usually reserved as last resort)

Indications for urinary tract reconstruction or urinary diversion are very limited in patients with interstitial cystitis. Candidates for these procedures should have exhausted all reasonable and available medical, pharmacologic, and behavioral therapies for their condition. They should also understand that even technically successful urinary tract reconstruction or urinary diversion still may not relieve the underlying symptoms of pain and urinary urgency.

These procedures are large surgical undertakings and, for the most part, are irreversible. Only limited success has been reported; thus, patients should be extensively counseled prior to undergoing this type of surgical therapy for interstitial cystitis.