Interstitial Cystitis Treatment & Management

The therapy for interstitial cystitis (IC) 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 might include various pharmacological 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, and complementary therapies such as acupuncture and hypnosis.

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. Anti-inflammatory agents, acetaminophen, gabapentin (Neurontin), tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and various other agents are used. 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.

Behavioral therapy

Following each intervention, the patient is reassessed for response. Unfortunately, therapies are often applied in a haphazard "hit-and-miss" fashion, combining numerous different therapies before truly assessing the patient's response to each therapy. 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.

Various dietary measures have been examined as therapy of interstitial cystitis. These dietary measures and the previously mentioned behavioral measures can be effective when used alone, but can also be complementary to virtually all other interventions for interstitial cystitis. Certain foods, including coffee, alcohol, tomatoes, vinegar, spicy foods, chocolate, and particular fruits and vegetables, have been implicated in aggravating symptoms of interstitial cystitis and, in the opinion of some authors, can precipitate symptomatic flares. Avoiding these food items or substituting other food items is often advised. Not uncommonly, patients are 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.

Ultimately, the decision to abandon or augment behavioral therapy and to pursue other therapeutic options is made by both 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.

Oral medication

Oral medications should be considered only after the aforementioned conservative measures have failed. With the exception of Elmiron, the drugs listed in Medications 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 Elmiron 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 National Institutes of Health (NIH)–funded study compared placebo with oral pentosan polysulfate sodium, hydroxyzine, and a combination of both. Using pentosan polysulfate sodium alone or in combination with hydroxyzine was shown to be slightly beneficial, but this was not significant.^[15]

In a randomized, double-blind, placebo-controlled study, amitriptyline has been shown to provide statistically significant improvement in the O'Leary-Sant interstitial cystitis symptom and problem index, pain, and urgency intensity when compared to placebo. Common adverse effects include dry mouth, weight gain, constipation, and sedation.^[16]

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

Cyclosporine A was recently compared to Elmiron in a randomized prospective nonblinded comparative study. In the cyclosporine A arm, micturition frequency was significantly reduced and clinical response rates were superior; however, treatment-related toxicity was increased in this group. While these preliminary studies are promising, continued evaluation and conservative patient selection are necessary.^[17]

The authors' algorithm for treatment is largely based on whether the patient has predominantly a pelvic pain component or an urgency/frequency component. In the authors' experience, patients with pelvic pain and minimal voiding symptoms represent a pharmacological 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 with either 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 Elmiron.

A 6- to 9-month course of Elmiron (100 mg 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 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.

Although interstitial cystitis has been reported in children, the condition is observed almost exclusively in adults; therefore, pediatric dosages are not included.

Instillation therapy

Patients in whom medical therapy fails may benefit from another bladder hydrodistention if the first hydrodistention was therapeutic earlier. When Hunner ulcers are identified, laser fulguration has been shown to be therapeutic. 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, has developed an intravesical formula that they have found to be highly successful in otherwise resistant or difficult cases. They use 50 mL of 1% lidocaine solution, in which they dissolve one tablet of sodium bicarbonate (650 mg), a 100-mg tablet of Elmiron, and a 200-mcg tablet of misoprostol (Cytotec), a synthetic prostaglandin E1 analog. This 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 per day 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; however, resiniferatoxin, a capsaicin analogue, is 100-10,000 times more potent than capsaicin and is not associated with severe burning. 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.^[18]

Hyaluronic acid glycosaminoglycan replenishment therapy has yielded moderate results in non–placebo-controlled studies. Weekly instillation of a 50-mL solution of phosphate-buffered solution containing 40 mg of sodium hyaluronate was performed in patients with an abnormal modified potassium test finding. Eighty-five 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. However, lower response rates are found in patients without evidence of a urine-tissue barrier abnormality.^[19]

Intravesical bacillus Calmette-Guérin (BCG) has been hypothesized to suppress inflammation within the bladder and was evaluated for treatment of refractory interstitial cystitis. A randomized placebo-controlled trial revealed the treatment arm to have 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.^[20] 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.

Medications

Antihistamines inhibit binding to H1 histamine receptor. Hydroxyzine (Atarax, Vistaril) is an H1 histamine receptor blocker that may inhibit mast cell secretion and may suppress histamine activity in subcortical region of CNS. Adult dosing is 25-75 mg/d PO. Hydroxyzine is a pregnancy category C drug.

Tricyclic antidepressants increase the synaptic concentration of serotonin and/or norepinephrine in the CNS. Amitriptyline (Elavil) is an oral tricyclic antidepressant that inhibits reuptake of serotonin and/or norepinephrine at the presynaptic neuronal membrane, which increases concentration in the CNS. It may have anticholinergic and sedative effects. Adult dosing is 25-75 mg PO hs. Amitriptyline is a pregnancy category D drug.

Urinary analgesics relieve pain locally. Pentosan polysulfate sodium (Elmiron) is a negatively charged synthetic sulfated polysaccharide with an affinity for mucosal membranes. It repletes defects in the glycosaminoglycan layer. Adult dosing is 100 mg PO tid. Pentosan polysulfate sodium is a pregnancy category B drug. Other agents used with less success include L -arginine, nalmefene, anticholinergic agents (eg, oxybutynin, oxybutynin XL, tolterodine [Detrol and Detrol LA]), hyoscyamine, corticosteroids, antispasmodics, immunosuppressives, anti-inflammatories, and calcium channel blockers. In addition, a recent report suggests a beneficial role for oral cimetidine. Intravesical agents are described below.

Renal and genitourinary agents are used for the symptomatic relief of interstitial cystitis. Dimethyl sulfoxide, ie, DMSO (Rimso-50) provides anti-inflammatory action, membrane penetration, antifungal activity, cryoprotective effects for living cells and tissues, collagen dissolution action, mast cell stimulation, nerve blockade, diuresis, cholinesterase inhibition, vasodilation, and muscle relaxation. It may be combined with heparin, steroids, or bicarbonate. In adults, instill 50 mL of aqueous 50% solution directly into bladder by catheter or Asepto syringe and allow to remain for 20 min. Dimethyl sulfoxide is a pregnancy category X drug.

Cauterizing agents are used for the removal of granulation tissue. Silver nitrate is used for its caustic, antiseptic, and astringent qualities. In adults, administer concentrations ranging from 1:5000 to 2% intravesically for 2-10 min. Silver nitrate is a pregnancy category C drug.

Dermatological agents are used for their cleansing and disinfection and for the removal of necrotic debris. Sodium oxychlorosene (Clorpactin WCS-90) exerts detergent action on bladder mucosa. It is reserved for patients in whom DMSO or silver nitrate instillations fail. In adults, administer 0.4% solution intravesically for 2-3 min at 60-80 cm water pressure (4-6 treatments qwk). Sodium oxychlorosene is a pregnancy category C drug.

Polysaccharide glycosaminoglycans may exert a protective effect on the bladder. Heparin has been shown to reduce relapses in patients who respond to DMSO. It is an analog to polysaccharide glycosaminoglycan lining of the bladder. Adult dosing is 10,000 U intravesically in 10 mL sterile water monthly. Polysaccharide glycosaminoglycans is a pregnancy category C drug.

Bladder hydraulic distension

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

After draining the bladder from the therapeutic hydrodistention, bladder biopsy may be performed on areas that appear abnormal. Biopsy should be deep enough to sample the detrusor muscle. Unfortunately, no pathognomonic histological findings exist for interstitial cystitis. Biopsies are primarily performed to help rule out other varieties of cystitis or malignant or premalignant (eg, CIS) lesions. In all cases, biopsy should be performed following hydrodistention. In the rare patient in whom a Hunner ulcer is seen on cystoscopy, fulguration or steroid injection is recommended.^[14]

In the authors' opinion, postoperative catheter drainage should be instituted in patients who undergo deep biopsies to reduce the chance of perforation, extravasation, or both. Although some centers advocate limiting the use of cystoscopy and biopsy in the evaluation and workup of patients thought to have interstitial cystitis, the authors believe these are necessary to help exclude other disorders such CIS and bladder calculi.

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

Emerging surgical therapies

Sacral neuromodulation has been approved by the US Food and Drug Administration (FDA) for medically refractory frequency, urgency, and urge incontinence and is showing promising results in patients with interstitial cystitis. Several authors have studied sacral neuromodulation in patients with interstitial cystitis refractory to conservative measures (behavioral modification, diet, medications, hydrodistention). Sacral neuromodulation improved daytime frequency, nocturia, and mean voided volumes and decreased pain and interstitial cystitis symptom and problem index scores. In addition, sacral neuromodulation has been shown to normalize the abnormally high levels of APF and the abnormally low levels of HB-EGF in the urine of patients with interstitial cystitis.

Pudendal nerve stimulation has also been evaluated in patients with interstitial cystitis and compared to sacral nerve stimulation. In a small series, overall reduction in symptoms was 59% for pudendal nerve stimulation and 44% for sacral nerve stimulation.^{[21, 22, 23]}

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 IC. However, higher doses appear to increase the risk of postoperative voiding dysfunction and urinary retention following this procedure. The use of intradetrusor botulinum A toxin for this and other urological conditions remains investigational.^{[11, 10, 12]}

Rarely indicated surgical therapies

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

No established guidelines exist for monitoring patients with interstitial cystitis. This is not surprising given the wide spectrum of severity of patient symptoms.

For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center. Also, see eMedicine's patient education article Urinary Tract Infections.

Although rare, classic interstitial cystitis (IC) may lead to bladder wall scarring that results in a contracted small-capacity bladder. These patients often require augmentation cystoplasty or some form of urinary diversion.

Other long-term sequelae of interstitial cystitis are unknown. However, because of the chronic nature of interstitial cystitis and the significant impact on the patient's quality of life, the psychological impact of the condition can be enormous. Ongoing emotional support is essential.

Interstitial cystitis (IC) is a chronic condition with a variable course, which, unfortunately, responds poorly to treatment in many cases. The most important element in treating these patients is education and emotional support. Patients must understand that interstitial cystitis is characterized by intermittent periods of exacerbations and remissions. Periodic exacerbations are managed as they occur because no long-term therapy has been shown to prevent or delay recurrent episodes. Furthermore, even though only approximately 10% of patients present with classic (ulcerative) interstitial cystitis, no treatment to date has been shown to decrease disease progression; therefore, the purpose of treatment is to palliate and alleviate symptoms.

Diagnosing interstitial cystitis (IC) remains difficult even more than 100 years after it was described by Skene in 1887. No pathognomonic findings exist with regard to patient history, physical examination findings, laboratory findings, or cystoscopy findings. The exclusion of other clinical entities remains the foremost goal of the workup and evaluation of patients thought to have this condition.

A careful, complete, and empathetic history and physical examination are critical. Cystoscopy is an adjunctive, although important, study. The classic Hunner ulcer in the setting of a small-capacity bladder (ie, assessed under anesthesia) rarely confirms the diagnosis with certainty. Until interstitial cystitis is defined completely or a definitive marker becomes universally available, the diagnosis remains one of exclusion.

Studies at several centers are examining various soluble urinary and serum markers in patients with interstitial cystitis. The goals of this research include identifying the causative agent(s) or at least a marker for case identification and diagnosis. Alternatively, certain other soluble factors are being evaluated as potential surrogates of disease activity and response to therapy.