eMedicine Specialties > Urology > Infections and Related Inflammatory Conditions

Cystitis, Nonbacterial: Treatment

Author: Lynda A Frassetto, MD, Associate Clinical Professor, Department of Internal Medicine, University of California at San Francisco School of Medicine
Coauthor(s): Donna Y Deng, MD, Assistant Professor of Urology, Pelvic Reconstruction, Incontinence, and Neurourology, Department of Urology, University of California San Francisco School of Medicine
Contributor Information and Disclosures

Updated: Dec 12, 2008

Treatment

Medical Therapy

Treatment of nonbacterial cystitis depends on the etiology, when it can be determined.

Infectious Etiologies

In recent years, several antiviral agents chemically related to acyclovir have been shown to be effective against HSV-1 and HSV-2. Treatment for immunocompetent adults includes acyclovir 400 mg tid for 10 days or valacyclovir 1000 mg bid for 10 days.

Ganciclovir and vidarabine have been used in some cases of adenoviral-associated hemorrhagic cystitis in patients who have undergone bone marrow transplantation. Cystitis due to BK polyoma virus reportedly resolved without treatment in 9 pediatric patients. However, in adults who have undergone renal transplantation, cidofovir and a decrease in the dose of immunosuppressants is usually recommended because of the concern of renal parenchymal damage from the virus. Mycophenolate mofetil has been associated with more adenoviral infections than azathioprine.

Chlamydia can be treated with doxycycline 100 mg bid for 7 days, azithromycin 1 g orally as a single dose, erythromycin 500 mg qid for 7 days, or one of the fluoroquinolones, such as ofloxacin 300 mg bid for 7 days. Erythromycin, azithromycin, and amoxicillin can also be used in pregnant women.

Mycobacterial treatment begins with 3 or 4 agents, generally starting with isoniazid (INH) and rifampin (RIF) and another 1 or 2 agents, depending on the probable sensitivities of the organism and the underlying state of the immune system. Standard treatment regimens include INH 300 mg/d, RIF 600 mg qd, ethambutol (EMB) 15 mg/kg, and pyrazinamide 2 g/d. Other drugs that can be used include streptomycin 0.75-1 g/d, ethionamide (ETH) 1 g/d, or one of the fluoroquinolones. Treatment regimens are modified when the actual drug sensitivities are determined. Drug toxicities sufficient to require a change in regimen occur in up to 5% of patients.

Treatment is recommended only when the funguria is symptomatic or in cases of fungal colonization when host factors increase the risk of fungemia.21 Fungal cystitis in immunocompetent patients with indwelling catheters may simply respond to removal of the catheter without further treatment of the infection. If removal of the catheter is not an option, treatment with oral azole antifungal agents or bladder irrigations containing amphotericin B 50 mcg/mL for 5 days can be instituted. In immunosuppressed patients, another option may be intravenous amphotericin B, depending on the degree of dissemination of the infection. Susceptibility testing to antifungal agents may be necessary if patients have previously received therapy for fungal infections. Measures to reduce risk factors include removing urinary catheters, limiting antibiotic treatment, and optimizing diabetes management.21

Recently, several new antifungal agents called echinocandins that are active against azole and polyene-resistant pathogens have been developed. One trial that compared one of these newer agents, caspofungin, with amphotericin B for invasive candidiasis demonstrated similar efficacy and markedly fewer side effects for caspofungin. Some infectious disease specialists consider caspofungin to be first-line therapy against invasive non-albicans candidal species.

Noninfectious Etiologies

While minor bleeding episodes due to radiation treatment stops without treatment, severe bleeding may require hospitalization for therapy. Clot evacuation and continuous bladder irrigation are the standard treatment for heavy bleeding.

A small number of patients with severe bleeding require further treatment. Methods that have been tried include hyperbaric oxygen therapy and chemical therapy. The long-term results of hyperbaric oxygen in 11 patients was reported by Del Pizzo—3 had complete resolution of symptoms, 3 had persistent symptoms, and 5 had initial improvement but then relapsed.31 In a more recent review by Chong et al of 60 patients with radiation cystitis, 80% had complete or partial resolution of the hematuria, and 96% (27 of 28) of patients treated within 6 months of the onset of hematuria had complete resolution of symptoms.32

Srisupundit and colleagues reported good short-term results (follow-up, 1-9 mo) in 13 of 20 patients treated with an intravenous infusion of a chemically stabilized chlorite matrix tetrachlorodecaoxygen (TCDO).33 Urinary diversion surgery is presently the surgical treatment of choice in patients whose symptoms fail to resolve.

Chemical cystitis from chemotherapy agents, such as cyclophosphamide, may resolve with hydration or with discontinuation of the drug. Another alternative is mesna, a semisynthetic sulfhydryl compound that reacts chemically with drug metabolites, detoxifying them in a manner similar to the physiologic cysteine-cystine system. Recently, Ballen and colleagues have suggested that extremely aggressive hydration with intravenous fluids and diuretics to maintain a urine output greater than 150 mL/h may be as effective a therapy as mesna, as well as being much less expensive.34

Treatment of autoimmune diseases generally relies on a combination of symptomatic relief, anti-inflammatory, and immunosuppressive agents. In the last several years, monoclonal antibodies to tumor necrosis factor (TNF)–alpha and several of the interleukins have markedly improved symptoms in some of the rheumatic diseases. The greater variety of immunologic targets amenable to treatment modification has allowed rheumatologists to tailor combinations of drugs that yield improved efficacy with fewer symptoms.

At present, no therapy for eosinophilic cystitis is curative. Treatments that have been tried include anti-inflammatory therapies with nonsteroidal anti-inflammatory drugs and steroids and transurethral resection of the bladder lesion.13

Painful Bladder Syndrome/Interstitial Cystitis

Instituting treatment for painful bladder syndrome/interstitial cystitis (PBS/IC) is extremely important. Patients respond differently to the different treatments, and various therapies and approaches may be necessary to optimally control symptoms.

Using a team approach and working with patients and their families to help develop the treatment plan aids in maximizing the benefits of each selected therapy and improving overall symptom relief. Several organizations are dedicated to patients with interstitial cystitis. Finding out that others have the same problems, obtaining support, and accessing up-to-date treatment information can be extremely helpful to patients.

This discussion on the treatment of PBS/IC divides the treatment into 4 broad categories—behavioral therapies, oral medications, cystoscopic and intravesical treatments, and other methods of pain relief.

Behavioral therapies

In many cases, dietary manipulation improves the patient’s symptoms, sometimes dramatically, although controlled studies on this are lacking. Foods to avoid include alcohol, caffeine, canned or processed meats, and high-acid diets (ketogenic, high fat, low carbohydrate). A list of common acidic foods is available on various Web sites. The elevated hydrogen ion content in acidic foods may directly contribute to VR1 activation and pain.

A tasteless dietary supplement, calcium glycerophosphate (Prelief, by AkPharma, Inc), has been suggested as a possible therapy for PBS/IC. Calcium glycerophosphate decreases the effective acidity of many ingested foods. A study by Whitmore et al on the use of calcium glycerophosphate for interstitial cystitis indicated that 70% of these patients reported reduced pain and discomfort, while 61% had improved urinary urgency during therapy. Suggested dosage is usually 2 or 3 tablets with each meal, depending on the acid content of the food ingredients.

High-potassium foods should also be avoided because of the potential irritability of urinary potassium. This is particularly important in patients with a positive potassium leak test result. Other foods that may exacerbate symptoms include chocolate; hot spicy foods, seasonings, and sauces; tea; coffee; cranberry juice; onions; tomatoes; aged cheeses; nuts; carbonated beverages (especially diet colas); strawberries; citrus fruits and juices; beans; sour cream; vinegar; sprouts; avocado; corned beef; fried foods; rye products; and aspartame (Nutrasweet). A clinical trial of abstinence of some or all of these foods may help pinpoint the most important dietary factors in each patient. Diet sodas may cause problems because of their caffeine, carbonation, sugar substitutes, and fruit extracts, all of which can be irritating to a patient with PBS/IC.

Stress is also a significant flare factor in many patients with PBS/IC. A nonstressful work and home environment is important; involving family members in therapeutic regimens and support groups, as well as supportive psychotherapy, are approaches that have been successful.

Voiding diaries, which quantitate the volume, frequency, and pain associated with urination may help provide patients and their doctors an idea of whether a therapy is working. A simple patient symptom score, similar to the American Urological Association (AUA) score for prostate symptoms, can also be used and is very helpful in following progress. Progress may be difficult to measure on a day-to-day basis but is easier to evaluate when assessed on an overall basis over time. While no statistically validated symptom score is currently available for this purpose, the authors prefer use of the Leslie Incontinence Symptom Score (LISS) to monitor patients with interstitial cystitis and patients with incontinence by helping to measure their progress. The LISS scoring system is shown below.

Table 1. Leslie Incontinence Symptom Score (LISS)

Open table in new window

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Table
Circle your score for each below
None1 time2 times3 times4 times5 or more
1. Over the last month or so, how many times each night did you most typically get up to urinate from the time you went to bed to the time you got up in the morning?012345
2. Over the last month or so, how many times have you had to change your underwear, clothes, pants, or pads each day because of wetness or urinary leakage?012345
Not at allLess than 1 time in 5Less than half the timeAbout half the timeMore than half the timeAlmost always
3. Over the past month or so, how often have you had to urinate again less than 2 hours after you finished urinating?012345
4. Over the past month or so, how often have you found it difficult or impossible to postpone urination?012345
5. Over the past month or so, how often would you have the urge to urinate and leak urine before you could reach the bathroom?012345
Few drops or not at allUp to 2 tbs about 1 ozUp to 4 tbs or ¼ cupUp to ½ cup or 4 ozUp to 1 cup or 8 ozMore than 1 cup or drips all the time
6. Over the past month or so, how much urine would you typically lose each time you noticed you were wet or had leaked urine?012345
7. Over the past month or so, how much urine would you typically lose when you coughed, stood up, laughed, strained, lifted, or sneezed?012345
Not at allJust a littleSlightlyModeratelyModerately severeSeverely
8. Over the past month or so, how much has your urinary leakage problem bothered you? (Include any inconvenience, side effects, or discomfort from your current incontinence therapy)012345
Circle your score for each below
None1 time2 times3 times4 times5 or more
1. Over the last month or so, how many times each night did you most typically get up to urinate from the time you went to bed to the time you got up in the morning?012345
2. Over the last month or so, how many times have you had to change your underwear, clothes, pants, or pads each day because of wetness or urinary leakage?012345
Not at allLess than 1 time in 5Less than half the timeAbout half the timeMore than half the timeAlmost always
3. Over the past month or so, how often have you had to urinate again less than 2 hours after you finished urinating?012345
4. Over the past month or so, how often have you found it difficult or impossible to postpone urination?012345
5. Over the past month or so, how often would you have the urge to urinate and leak urine before you could reach the bathroom?012345
Few drops or not at allUp to 2 tbs about 1 ozUp to 4 tbs or ¼ cupUp to ½ cup or 4 ozUp to 1 cup or 8 ozMore than 1 cup or drips all the time
6. Over the past month or so, how much urine would you typically lose each time you noticed you were wet or had leaked urine?012345
7. Over the past month or so, how much urine would you typically lose when you coughed, stood up, laughed, strained, lifted, or sneezed?012345
Not at allJust a littleSlightlyModeratelyModerately severeSeverely
8. Over the past month or so, how much has your urinary leakage problem bothered you? (Include any inconvenience, side effects, or discomfort from your current incontinence therapy)012345

Total symptom score (sum of questions 1-8) = _______________________

Scoring system:

1-12 = Mild

13-25 = Moderate

26-40 = Severe

Other urologists and groups who treat PBS/IC have developed several similar symptomatology questionnaires.

Medications

Many oral medications have been used for the treatment of PBS/IC, with varying success.

Medications often used as first-line therapy include tricyclic antidepressants, such as imipramine (Tofranil) and especially amitriptyline (Elavil), which not only treat the depression often associated with this chronic painful condition but also have some bladder-relaxing and pain-blocking properties.

Hanno and associates reported improvement with amitriptyline (Elavil) therapy in about half of 25 patients in whom hydrodistention and DMSO (RIMSO-50) therapy had failed.35 Starting at 25 mg before bedtime and increasing the dose over a 2-week period to 75 mg, patients reported improvement in voiding intervals with decreased urgency and less pain and dyspareunia. Patients with greater bladder capacity (>450-600 mL) may respond better.

Antihistamines are another commonly used first- or second-line medication. Mast cells, which are often found to be increased in the bladder wall in PBS/IC, contain large amounts of histamine, a vasoactive substance that causes itching and swelling while promoting inflammatory cell infiltration. Hydroxyzine (Atarax) is believed to block mast cell activation and has been shown to be helpful in treating some patients with interstitial cystitis. Doses start at 25 mg qd/tid. The most common adverse effects are drowsiness and dry mouth. Some practitioners use this medication earlier when bladder biopsies confirm high numbers of mast cells in the bladder walls.

Another first- or second-line therapy is pentosan polysulfate (Elmiron, Alza Pharmaceuticals), an oral restorative for the bladder lining's damaged, attenuated, or missing glycosaminoglycans barrier. Pentosan polysulfate was approved by the Food and Drug Administration (FDA) in 1996 for the treatment of interstitial cystitis. The FDA-approved dose is 100 mg orally tid, although many urologists use 200 mg bid to improve efficacy and compliance. Approximately one third of patients experience pain and symptom relief with this medication, although maximum improvement of symptoms may take as long as 6 months.

An open-label, compassionate-use study prior to the official release of pentosan polysulfate in 1996 suggested symptom relief in 62% of patients. However, other studies have not confirmed this very high positive response rate. One suggestion is that this medication should be recommended in patients with a positive potassium leak test who would theoretically be more likely to benefit from this type of treatment with a positive symptomatic response.

Some practitioners add intravesical heparin alone or in combination with DMSO or lidocaine to oral pentosan polysulfate (Elmiron) therapy. Whether this adds much to the therapeutic benefit is not clear, but anecdotal reports suggest that it may be helpful, especially in the short-term for the more severe cases.

Several recent randomized double-blind trials of pentosan polysulfate have been published. In one, 380 adults with cystoscopic evidence of interstitial cystitis were treated with 300, 600, or 900 mg of pentosan polysulfate. After 7 months, symptom scores decreased by similar amounts in about 20% of patients; those classified as responders usually improved within the first 4 weeks. A smaller trial of 136 patients randomized to oral pentosan polysulfate with or without hydroxyzine also demonstrated a low response rate and nonsignificant differences between the groups.

Local anesthetics, such as oral phenazopyridine (Pyridium or Pyridium Plus), can also reduce bladder pain. Pyridium turns the urine orange and may permanently stain fabric. Pyridium Plus also contains hyoscyamine, an atropine derivative and parasympatholytic agent used to treat detrusor muscle spasm, and butabarbital, which is a short-acting anxiolytic sedative.

Opioid narcotics are a common therapy for pain that is resistant to other treatments. Adverse effects include nausea, constipation, and respiratory depression. Tolerance eventually develops to all opioids presently available.

The opiate antagonist nalmefene has also been tried as a possible therapy for PBS/IC because mast cells are known to degranulate and release histamine and other chemical mediators when their endogenous opiate receptors are stimulated; blocking this reaction might prevent the mast cells from releasing the biochemical mediators that may cause many of the symptoms of interstitial cystitis.

In one trial of 37 patients with some prior treatment for PBS/IC, approximately half had improvement in suprapubic pain and dysuria at 6 months and about one fourth had a decrease in daytime and nighttime voiding frequency after 12 months of treatment. Doses were started at 0.5 mg bid and were increased over a period of 6 months to a maximum dose of 60 mg bid. Adverse effects included insomnia and nausea.

Another medication that has been tried is oral L-arginine, 1500 mg daily. L-arginine is a substrate for nitric oxide synthase. In one placebo-controlled trial, L-arginine increased nitric oxide synthase activity. Decreased symptoms of pain, urgency, and frequency were noted in about one third of the 21 patients who took the active drug.

Blockade of the calcium channels has been shown to inhibit detrusor muscle contraction and down-regulate lymphocyte production of the inflammatory mediator interleukin (IL)-2. In a small trial using the calcium channel blocker nifedipine, 8 out of 9 patients reported improvement of symptoms for at least 4 months, but only about half reported longer-term improvement. In many patients, especially those who are normotensive, the drug is better tolerated in the extended-release form. Hypotension is the main adverse effect.

Anticholinergic agents can also be used for treat pain due to smooth-muscle spasms. Common adverse effects of antispasmodics may include dry mouth and drowsiness. Medications such as Cystospaz, Levsin, and Urised contain hyoscyamine, a parasympatholytic agent more peripherally active than atropine and with fewer CNS adverse effects. These medications differ mainly in terms of added ingredients and preservatives used. Some people may find they respond differently to each of the various brands. Other antispasmodics include the acetylcholine inhibitor oxybutynin (Ditropan) and the muscarinic receptor antagonist tolterodine tartrate (Detrol). These agents may be effective as adjuvant symptom therapy in interstitial cystitis.

A recent study on the use of oral gabapentin (Neurontin) for intractable genitourinary pain included 8 patients with interstitial cystitis. Daily dosages ranged from 300-2100 mg with a mean of about 1200 mg per day. Five of the 8 patients noted improvement or relief of symptoms. The medication was well tolerated. Adverse effects included dizziness and drowsiness. While this was a very small study, all other treatments for symptom relief had failed in these patients. Further investigations of the use of gabapentin (Neurontin) for selected cases of interstitial cystitis appear warranted based on this finding. Considering use of this medication in selected cases may be reasonable.

Another small study involved 11 patients with moderate-to-severe PBS/IC who were treated with low-dose cyclosporine (1.5-3 mg/kg) for 3-6 months, with a decrease in pain scores and frequency and an increase in average voided urine volumes, with minimal toxicity (2 patients had elevated blood pressure that resolved following treatment cessation). Long-term studies with cyclosporine for PBS/IC are not available.

Intravesical therapies

Intravesical therapy has the advantages of delivering high concentrations of medications to the relatively impermeable bladder, thereby avoiding the systemic adverse effects of oral medications. The main disadvantages are the costs and patient morbidity associated with the procedure.

Cystoscopy under anesthesia with bladder hydrodistention under pressure to about 80-100 cm water pressure is a recognized treatment for interstitial cystitis. Many patients report significant, but often transient, symptomatic improvement with bladder hydrodistention alone. In about 20% of patients, symptoms improve for several months. Because of the limited response, some practitioners no longer consider hydrodistention an efficacious therapy for interstitial cystitis. Cystoscopy with hydrodistention may be considered for first-line therapy in patients with more severe symptoms.

In addition to cystoscopy, medications administered directly into the bladder (intravesical instillation therapy) are often used. This prevents the unwanted systemic effects of many oral medications.

In 1978, the FDA approved RIMSO-50, a purified form of the industrial solvent DMSO for symptomatic relief of interstitial cystitis. RIMSO-50 is instilled directly into the bladder via a catheter, retained for 15 minutes, and then spontaneously voided. This treatment is administered every 1-2 weeks for 4-8 treatments or until maximum symptomatic relief is obtained.

About half the patients treated with this regimen experience significant pain reduction. However, treatments generally become less effective over time. Adverse effects include transient worsening of bladder symptoms thought to be due to histamine release from mast cells; hematologic, renal, and hepatic dysfunction; and a garliclike odor to the skin and breath.

Interestingly, DMSO has been reported to acutely increase the reflex firing of pelvic efferent axons, decreasing bladder capacity and releasing nitric oxide from both dorsal root ganglia and bladder cells. Nitric oxide release by DMSO may be the initial event in the desensitization of the pain pathways in the urinary tract.

Reports exist that intravesical heparin used in subjects who have responded to RIMSO-50 reduces relapse rates, and intravesical heparin has been suggested as maintenance therapy. Heparin is a polyanionic compound that is thought to mimic the anti-adherence characteristics of the glycosaminoglycans of the bladder mucosal lining.

Intravesical instillation of 20,000 units of heparin in 10-20 mL of sterile water via a small catheter can be used as a temporary therapy while waiting for other treatments to take effect. Intravesical heparin therapy can be performed by the patient with self-catheterization up to 3 times a day and as needed. While this treatment helps some patients immediately, it usually takes 2-3 weeks to create a noticeable effect.

Corticosteroids and/or lidocaine have also been used with RIMSO-50 therapy to improve the anti-inflammatory action of RIMSO-50 and to improve pain relief.

The caustic agent silver nitrate has also been used as intravesical therapy for interstitial cystitis. Various concentrations and dwell times have been used, up to 2% and 10 minutes; higher concentrations require local or general anesthesia at administration. Silver nitrate therapy can also be combined with other therapies such as hydrodistention. Success rates of 50% at 1 year have been reported, but controlled clinical trials are lacking.

Another intravesical therapy is sodium oxychlorosene (Clorpactin WCS-90). A 0.4% solution is commonly used but requires regional or general anesthesia because instillation is quite painful. Repeated instillations are frequently necessary because two thirds of patients report recurring symptoms. Intravesical Clorpactin is usually reserved for patients who do not respond to other therapies, such as DMSO or silver nitrate treatment.

Intravesical therapy with bacillus Calmette-Guérin (BCG) has also been tried, with anecdotal reports of substantial, long-term symptomatic success in some cases. Therapy is thought to work by an immunoregulatory mechanism and possibly through induction of nitric oxide synthase activity or modification of IL-6 response. The beneficial effect of BCG therapy may not become apparent for 6 months, and adverse effects are not uncommon. A recently published multicenter randomized clinical trial of intravesical BCG in 265 patients with moderate-to-severe PBS/IC (based on NIDDK criteria) demonstrated an acceptable safety profile but a low rate of response and only a trend to greater response in the BCG group: 12% for placebo and 21% for BCG.

Capsaicin has been used to produce VR1 blockade or desensitization, which may be a revolutionary treatment for PBS/IC. Intravesical capsaicin was used in small numbers of patients with bladder hyperactivity or hypersensitivity due to various neurologic and nonneurologic lower urinary tract disorders. It significantly decreased the urinary symptoms of frequency and urgency in many of the patients tested.

Another vanilloid receptor antagonist is resiniferatoxin (RTX). In a randomized placebo-controlled trial involving 163 patients, intravesical RTX (given as a single dose of 0.01, 0.05, or 0.1 µmol/L) was compared with placebo. RTX was well tolerated, but the symptom scores did not improve over the 12 weeks of the trial.

A new investigational oral immunoregulatory drug (suplatast tosilate [IPD-1151T]) that is effective in treating various allergic diseases, such as asthma, atopic dermatitis, and rhinitis, by reducing immunoglobulin E (IgE) production and suppressing helper T cell–mediated allergic responses (especially IL-4 and IL-5) has produced promising results when used to treat interstitial cystitis in early studies. In one early pilot study from Japan reported by Ueda et al, 10 of 14 patients (71%) had a complete clinical response or total symptomatic relief after 4 months of treatment that lasted at least a year while on therapy. Two more patients (14%) had moderate or partial relief also lasting a year while on treatment.

If these results are confirmed, an immunological cause for at least some types of PBS/IC, probably the nonulcerative subtypes, is suggested. Although the study was small and had no control or placebo group, almost 86% of patients had complete or moderate symptomatic relief while on treatment, as well as improvement in their overall bladder capacities. Only larger, placebo-controlled, randomized studies will ultimately be able to demonstrate how well this medication or any of the others discussed in this article actually work for symptom relief in PBS/IC.

Shanberg and colleagues reported another type of intravesical therapy to be of use in patients with petechial hemorrhages and Hunner ulcers in whom other therapies had failed.36 This therapy is neodymium:yttrium-aluminum-garnet (Nd:YAG) laser photoirradiation. Treatment requires simultaneous laparoscopy to avoid bowel perforation. Twenty of 28 patients with Hunner ulcers had rapid relief of bladder pain and frequency symptoms, as did 10 of the 20 patients with biopsy evidence of severe inflammation.

Finally, a novel use for botulinum toxin has been developed for patients with overactive bladders. Injection of small amounts of toxin into the detrusor muscles of the bladder has been shown to improve bladder capacity and to decrease the amount of postvoid residual urine. Treatment effects last about 6 months.

Other pain control treatment options

Neuromodulation is a nonspecific term for symptom control through changes in nerve activity and function. Several types of neuromodulation have been tried in the treatment of PBS/IC.

Biofeedback is one therapeutic option. Biofeedback has been used with varying success in other chronic pain conditions, including temporomandibular joint disorders and physiologic conditions, such as urge and fecal incontinence, with reasonably good results and virtually no adverse effects or complications. Treatment generally requires training with biofeedback equipment that monitors pelvic muscle response. A substantial amount of equipment is necessary, as well as a trained technician, to perform this therapy. Some biofeedback exercising and training can be performed at home. Patients keep records of how symptoms are responding.

Another type of treatment is pain relief through nerve stimulation. This has been tried with both acupuncture and transcutaneous nerve stimulation (TENS). In some patients, applying the TENS unit near the affected area (usually to the lower abdominal wall for 0.5-2 hourse twice a day) improves symptoms. In one long-term study by Fall and associates, 54% of 33 patients with classic interstitial cystitis improved with TENS therapy, while only 26% of 27 patients with nonulcer PBS/IC responded to treatment. In one prospective crossover study, though, no improvement was reported in any study endpoint (frequency, urgency, voiding interval, pain control) with either TENS or acupuncture.

A more invasive method for cases refractory to conventional therapy is implantation of neural modulatory electrodes in the sacral roots of the spinal cord (SNS). Worldwide, more than 5000 patients with pelvic floor dysfunction and bladder and bowel problems have been treated with these stimulators. Exactly how this therapy works is unknown. Clinical improvement in symptoms has been noted in about two thirds of patients, with up to 20% remaining dissatisfied with the results. Many patients with PBS/IC notice a reduction in pain, daytime frequency, and urgency and increased urinary voiding volumes.

What to do first: A treatment algorithm

As in many chronic conditions, maintaining a good relationship between the physician and patient seems to improve the patient's ability to control the physical symptoms and pain. The need for supportive interaction with the patient cannot be overestimated in the treatment of interstitial cystitis. Referral to a specialist interested in the diagnosis and treatment of interstitial cystitis and/or pelvic pain syndromes may be useful.

Because no cure for interstitial cystitis exists, the goals of therapy are to make this chronic condition as livable for the patient as possible. Unfortunately, an evidence-based therapeutic algorithm for the treatment of patients with interstitial cystitis, either newly diagnosed or who have failed initial therapy, does not exist.

In the 581 women in the Interstitial Cystitis Data Base (ICDB) Study established by the NIDDK in 1993, cystoscopy and hydrodistention was performed in 33% of the patients at baseline who had been previously diagnosed and in 48% of newly diagnosed patients. Patients with severe symptoms were almost 3 times as likely to undergo cystoscopy as patients with mild symptoms. Intravesical DMSO or heparin was also more likely to be used in patients with more severe symptoms.

Oral amitriptyline was the second most commonly reported therapy (17%), followed by phenazopyridine (Pyridium) in 14%. Approximately 10% of patients were on a special diet at the time of diagnosis, primarily those with less-severe symptoms (P <.01).

The use of other therapies correlated primarily with symptoms. For example, hyoscyamine was used in 10% of patients with severe urgency symptoms compared with 1% of those with mild urgency symptoms, while pain medications were used more often in patients with more severe pain. Documentation of pain (pain diaries), the inciting factors, and the response to various pain treatments may help both the patient and physician develop better control strategies.

One suggestion is that the relative number of mast cells found in bladder biopsy samples of patients with interstitial cystitis can be used to help select those who are most likely to benefit from mast cell inhibitors. When high numbers of mast cells are found, then mast cell inhibitors, such as hydroxyzine, are used. This idea has never been tested rigorously.

Whether switching to another monotherapy or adding therapies is better when symptoms progress or recur has also never been tested; ICDB data suggest that physicians are more likely to add therapies under these circumstances. In all, about 20% of patients were receiving no treatment at baseline, 30% were on one therapy, 20% were on 2 therapies, and 30% were on 3 or more therapies (see Interstitial Cystitis for treatment tables).

Many patients with interstitial cystitis respond to dietary manipulation; a significant proportion of these patients have multiple allergies and/or a concomitant irritable bowel syndrome. Dietary modification is probably the most important conservative treatment available and should be part of the initial therapeutic strategy in every patient with interstitial cystitis.

Pentosan polysulfate (Elmiron) has been studied extensively, but its precise role remains unclear. Initial reports prior to its official release in 1996 suggested that it was well tolerated and very helpful to many patients. Subjective relief has been reported to be as high as 62%, but other studies have not confirmed this high rate of symptomatic improvement. A positive response to the potassium leak test has been suggested to help indicate which patients are likely to respond to the medication, but this has not been confirmed. Pentosan polysulfate has been demonstrated by meta-analysis of all available placebo-controlled studies to be more beneficial than placebo in treating pain, frequency, and urgency, although it was not helpful in alleviating symptoms of nocturia.

This trial and error method is due mainly to the lack of truly adequate therapy, principally because of the lack of understanding of the underlying pathophysiology (pathophysiologies) of this syndrome. This was underscored in another report from the ICDB group, in which the authors concluded, "Although all symptoms fluctuated, there was no evidence of significant long-term change in overall disease severity. Our observations support the clinical observation that interstitial cystitis is a chronic disease and no current treatments have a significant impact on symptoms with time."

Surgical Therapy

Surgical therapy is generally considered only as a treatment of last resort. Perhaps 10% of patients with interstitial cystitis may become candidates for surgical treatment.

One possible procedure for patients with small-capacity bladders (<350-400 mL under general anesthesia) is to increase the bladder size with either large or small bowel without removing the diseased portion of the bladder (augmentation cystoplasty). For a detailed discussion of this operation, see Augmentation Cystoplasty. Concern about leaving a significant portion of diseased bladder intact leads many urologists to perform a more extensive operation, removing the damaged part of the bladder and using a piece of the patient's bowel to make a larger bladder (subtotal cystectomy with substitution cystoplasty). This is often used in patients with small bladder capacity and frequency and urgency related to small bladder capacity. In other cases, the bladder is removed completely and a ureterostomy is performed (cystectomy).

The decision to perform a partial or complete cystectomy may be based on biopsy of the trigone part of the bladder and assessment of urethral sensation. Patients with involvement of the entire bladder and urethra may then undergo removal of both the bladder and the urethra (cystourethrectomy). Unfortunately, some patients in whom medical therapy has failed do not experience improvement in pain even with surgical removal of the bladder and urethra.

Presumably, better understanding of the pathophysiologic processes involved in interstitial cystitis would allow better selection criteria for choosing the appropriate procedure for each patient. Until the pathophysiology is understood, the decision to perform a specific operation on a patient depends on the experience of the surgeon and the wishes of the patient.

Preoperative Details

Patients should have a realistic understanding of the goals and limitations of surgical therapy for interstitial cystitis. This especially is true for patients being considered for cystectomy and urinary diversion, which may require stoma care, use of urinary appliances, and the manual dexterity and motivation to perform self-catheterization. Selection of an appropriate stoma site is important in preventing postoperative stomal complications.

The patient must also be evaluated for other medical problems, such as cardiac, renal, hepatic, or pulmonary dysfunction, that may complicate intraoperative and postoperative care.

Good nutrition helps patients heal faster.

Patients undergoing cystectomy may need blood transfusions; preoperative autologous blood donation or directed blood donations are an alternative to standard blood unit transfusions.

Just before surgery, the patient is administered a skin and bowel preparation, adequate hydration, preoperative anesthetic, and, often, antibiotic medications.

Intraoperative Details

For a partial cystectomy and substitution cystoplasty, after a Foley catheter with a 3-way irrigation system is inserted, the peritoneal cavity is entered and a segment of bowel is divided along the antimesenteric border. The segment of bowel is folded with the posterior surface closed and the anterior surface left partially open. The bladder is opened to expose the trigone, and a supratrigonal cystectomy is performed, leaving a 1- to 2-cm cuff of bladder that includes the trigone and the bladder neck. The bowel segment is anastomosed to the remaining rim of bladder, and a suprapubic catheter is placed. For a detailed discussion of this operation, see Cystectomy, Partial.

A complete cystectomy with urinary diversion is a much more complicated operation. A modified lithotomy position is used to allow exposure to the urethra and vagina. The peritoneal cavity is entered, each ureter is mobilized, and the ureters are divided just above the bladder. The bladder is mobilized free of the anterior wall. In female patients, depending on age, the fallopian tubes, ovaries, and uterus may also be mobilized and removed. The vagina is reconstructed and sutured.

During complete cystectomy, the ureters are either anastomosed to a section of large or small bowel, whereby one end of the small bowel is attached to the abdominal wall (incontinent diversion), or a small reservoir is made out of intestine, to which the ureters are attached and to which nipple valves (also made out of intestine), are attached and then anastomosed to the abdominal wall (continent urinary diversion). Drains are placed in the abdomen, and a catheter is placed through the stoma to fix the anastomotic limb in a straight position while the diversion heals. Before the patient leaves the operating room, ensure that the continence mechanism is effective and that it can be easily catheterized; otherwise, postoperative problems may occur. For a detailed discussion of this operation, see Cystectomy, Radical.

Postoperative Details

  • Postoperatively, the patient needs good pain control to encourage early ambulation. Pain medications can be administered intravenously, via skin patch, and when the patient can tolerate it, orally.
  • Adequate postoperative hydration is important to prevent hypovolemia due to fluid loss and third-spacing. This should be followed carefully, and overhydration should be avoided. Some surgery texts suggest diuretics as needed to prevent excessive fluid retention.
  • Initially, the patients require nasogastric drainage until flatus is passed.
  • Consider intravenous alimentation if some delay in starting oral feedings occurs.
  • In general, antibiotics, often a third-generation cephalosporin, are administered for several days postoperatively.
  • Early mobilization, breathing exercises, and good pulmonary toilet help prevent development of lung infections.
  • If an ileal conduit has been formed, a catheter will need to be kept in place for 6-7 days to keep the conduit compressed and help with wound healing. If a reservoir has been created, the catheter should be left in for about 3 weeks and removed at a follow-up outpatient visit. Initial, frequent irrigation of the catheter may be necessary to prevent mucus plugging.
  • The ureteral stents can be removed after 7-10 days, following some kind of radiologic procedure to show that there are no anastomotic leaks and the conduits are functioning.

Follow-up

For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center, Women's Health Center, and Procedures Center. Also, see eMedicine's patient education articles Bladder Control Problems, Blood in the Urine, Cystoscopy, and Pain During Intercourse.

Complications

Medical Complications

Drug toxicity

Many of the medications mentioned above have adverse effects. Some have been mentioned in the Treatment section. In this section, some other common adverse effects are listed.

  • Hepatic toxicity can be caused by many of the antituberculosis medications, including INH, RIF, pyrazinamide (PZA), and ETH. INH is metabolized primarily by acetylation; approximately 50% of whites and African Americans are slow acetylators, which can lead to higher blood levels and increased toxicity. Hepatocellular dysfunction severe enough to require changing regimens may occur in 3-5% of patients. Alcohol use increases the risk of INH-related hepatitis. The risk of developing fatal hepatitis increases with increasing age, from approximately 0 of 1000 patients younger than 20 years to 23 of 100 patients aged 50-64 years.
  • RIF induces cytochrome P450 metabolizing enzymes. Patients taking other medications (eg, anticonvulsants, antiarrhythmics, azole antifungal agents, calcium channel blockers, some antibiotics, anticoagulants) metabolized by these enzymes may have significant lowering of drug levels because of increased metabolic rates.
  • Cyclophosphamide use is associated with an increased risk for secondary leukemias and bladder cancer and may cause infertility in patients of reproductive age.
  • Intravenous dosing of amphotericin B usually requires pretreatment of the patient with Tylenol and Benadryl to minimize the fevers, chills, or allergic symptoms. Amphotericin B treatment often causes diarrhea (30%), electrolyte abnormalities (15-30%), elevations in liver enzymes (10-20%), and renal disease (20-40%). Intravesical instillation of amphotericin B is much better tolerated than intravenous infusion.

Radiation toxicity

Radiation of living tissues increases the risk of damage to the matrix and the cellular components and to DNA. The effect is dose and tissue dependent. Doses greater than 65 Gy have been associated with late bladder problems. Inability to adequately shield the surrounding tissues can lead to bladder and bowel complications after prostate or cervical radiation, including bleeding, scarring, and pain in 5-20% of patients. In one retrospective review of radiation treatment for prostate cancer, impotence was a common problem.37

Surgical Complications

Complications of the augmentation or subtotal cystectomy during the initial postoperative period include ileus, wound infection, difficulty with catheterization, dehiscence, urinary extravasation, and thromboembolic events. Late complications include persistence of symptoms, ureteral reflux, urolithiasis or stenosis, difficulty with catheterization, and progressive renal failure due to reflux or metabolic abnormalities.

Cystectomies are difficult operations. A 1-3% mortality rate is not unexpected. Twenty to 30% of patients may have a prolonged hospital stay because of postoperative complications. The average hospital stay for a cystectomy is currently about a week and a half.

Postoperative complications for total cystectomy with ureteral diversion are more common. Along with the problems listed above, complications include blood loss sufficient to require transfusion, coagulopathies requiring platelets or fresh frozen plasma, and rectal injury. The most common urology-specific early postoperative complications of the ureteral diversion include leakage at the anastomotic sites, obstruction, and infection. Metabolic changes can occur from loss of bicarbonate through the intestinal mucosal lining, leading to a hyperchloremic metabolic acidosis. This is usually mild, but, occasionally, patients need oral bicarbonate supplementation. These metabolic abnormalities tend to improve with time.

Delayed complications include bacterial colonization of the urine in the reservoir and pyelonephritis from ureteral reflux, renal stones, stomal stenosis or prolapse, parastomal hernias, and ureteral stenosis. All of these chronic problems can lead to the development of progressive renal failure.

More on Cystitis, Nonbacterial

Overview: Cystitis, Nonbacterial
Workup: Cystitis, Nonbacterial
Treatment: Cystitis, Nonbacterial
Follow-up: Cystitis, Nonbacterial
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References
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Further Reading

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Keywords

nonbacterial cystitis, interstitial cystitis, IC, noninfectious cystitis, urgency-frequency syndrome, chemical cystitis, radiation cystitis, autoimmune cystitis, viral cystitis, mycobacterial cystitis, chlamydial cystitis, fungal cystitis, hypersensitivity cystitis, nonbacterial infectious cystitis, potassium leak test, chronic pelvic pain syndrome, painful bladder syndrome, PBS, infectious cystitis, tuberculous cystitis, eosinophilic cystitis

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Contributor Information and Disclosures

Author

Lynda A Frassetto, MD, Associate Clinical Professor, Department of Internal Medicine, University of California at San Francisco School of Medicine
Lynda A Frassetto, MD is a member of the following medical societies: American College of Physicians and American Society of Nephrology
Disclosure: Nothing to disclose.

Coauthor(s)

Donna Y Deng, MD, Assistant Professor of Urology, Pelvic Reconstruction, Incontinence, and Neurourology, Department of Urology, University of California San Francisco School of Medicine
Donna Y Deng, MD is a member of the following medical societies: American College of Surgeons, American Medical Association, American Urological Association, California Medical Association, International Continence Society, Société Internationale d'Urologie (International Society of Urology), and Society of Women in Urology
Disclosure: Nothing to disclose.

Medical Editor

Erik T Goluboff, MD, Professor, Department of Urology, College of Physicians and Surgeons, Columbia University; Director of Urology, Allen Pavilion, New York Presbyterian Hospital
Erik T Goluboff, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Association, American Urological Association, Medical Society of the State of New York, New York Academy of Medicine, Phi Beta Kappa, and Society for Basic Urologic Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

CME Editor

J Stuart Wolf Jr, MD, FACS, David A Bloom Professor of Urology, Director of Division of Minimally Invasive Urology, Department of Urology, University of Michigan
J Stuart Wolf Jr, MD, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Catholic Medical Association, Endourological Society, Society for Urology and Engineering, Society of Laparoendoscopic Surgeons, Society of University Urologists, and Society of Urologic Oncology
Disclosure: Terumo Corporation Consulting fee Consulting; Omeros Corporation Consulting fee Consulting

Chief Editor

Edward David Kim, MD, FACS, Professor of Surgery, Division of Urology, University of Tennessee Graduate School of Medicine; Consulting Staff, University of Tennessee Medical Center
Edward David Kim, MD, FACS is a member of the following medical societies: American College of Surgeons, American Society for Reproductive Medicine, American Society of Andrology, American Urological Association, and Tennessee Medical Association
Disclosure: Lilly Consulting fee Consulting; Astellas Consulting fee Speaking and teaching; Indevus Consulting fee Speaking and teaching

 
 
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