(Published May 2008)
Management of Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS)
Note that the majority of agents used in the treatment of interstitial cystitis/painful bladder syndrome (IC/PBS) are not approved by the Food and Drug Administration (FDA) for this indication. Pentosan polysulfate sodium and dimethylsulfoxide and are the only FDA-approved agents. The majority of medications mentioned in this Clinical Proceedings either have shown efficacy in non-FDA-based clinical trials or are used in clinical practice by advisory committee members.
The management of IC/PBS consists of three basic components:
- Diet and behavior modification
- Oral therapy
- Intravesical therapy
Clinicians vary somewhat in their preferred approach to first-line therapy. For this reason, it is difficult to construct treatment algorithms for IC/PBS. Surgery is an option of last resort, for patients whose symptoms are unresponsive to primary forms of treatment, and is rarely performed.
Diet and Behavior Modification
|Figure 7: Substances That May Trigger IC/PBS Symptom Flares3|
• Alcoholic beverages
• Caffeinated beverages
• Citrus fruits and juices
• Artificial sweeteners
• Spicy foods (eg, hot pepper)
• Food additives and preservativesThis list was compiled from responses to a questionnaire by patients with IC/PBS published by Shorter and colleagues, supplemented with Committee members’ anecdotal reports from patients. A full list is available at www.ichelp.org/diet.
Many patients with IC/PBS have noticed that avoiding certain foods, beverages, vitamins, and additives can help control symptoms and avoid flare-ups.1 At the same time, not every patient is affected by these substances (see list in Figure 7). Experts have postulated that metabolites from these substances traverse the bladder epithelium, stimulating hypersensitive nerves or triggering an immune response.2
Patients may find it helpful to work with a knowledgeable registered dietitian on an elimination diet, removing potential trigger substances and then reintroducing them one at a time. In general, patients who are sensitive to a particular substance will notice symptoms 30 minutes to six hours after ingesting it.2
In addition to dietary changes, many patients with IC/PBS find that the use of behavioral modification can help them better manage the symptoms associated with the condition. Self-help strategies also encourage patients to take an active role in managing IC/PBS.
Although there are no randomized controlled trials evaluating these interventions, the expert committee believes that patients may find the following strategies helpful:
- Gentle exercise, such as low-impact aerobics, walking, yoga, and Tai Chi
- Stress reduction techniques, such as relaxation techniques, meditation, visualization, self-hypnosis, massage, and psychotherapy
- Pain relief strategies, such as a warm sitz bath or use of a cold pack or hot water bottle on the perineum
- Wearing comfortable and nonrestrictive clothing
- Alternative therapies, such as acupressure, acupuncture, and biofeedback
- Physical therapy—transvaginal massage using the Thiele technique (shown to improve IC/PBS symptoms and decrease tone of pelvic floor muscles)4
- Bladder retraining programs that include suppression of urgency—a protocol of progressive, small increases in the intervals between voiding with the goal of reducing urinary frequency (appropriate only for patients who are free of pain)
- Experimenting with different positions during sexual intercourse or using lubricants, if dyspareunia is an issue
- Controlled fluid intake, but not fluid restriction (if symptoms increase when urine is concentrated, it is suggested that patients increase fluid intake, but not more than about 2 liters per 24 hours; some clinicians suggest that patients “drink to thirst”)
Oral therapy is a mainstay of IC/PBS management. The most commonly used oral agents (with the exception of use in clinical trials) are:5
- Pentosan polysulfate sodium
Pentosan polysulfate sodium
Pentosan polysulfate sodium (PPS; Elmiron®) is the only oral therapy that is FDA-approved for IC/PBS (approved in 1996). PPS is a heparin analogue that has 1/15th the anticoagulation activity of heparin.2 It is purported to repair the normal lining of the bladder, counteracting the increased permeability seen in IC/PBS.2
In the trials that formed the basis of FDA approval, PPS was found to be beneficial in a minority of patients (overall improvement of greater than 25 percent in 32 percent of PPS-treated patients compared with 16 percent for placebo).6,7 More recent open-label studies have found greater efficacy, although the data for subjects who did not complete the study were not analyzed as treatment failures in many of these open-label trials. A long-term, open-label study found that 42 percent to 62 percent of patients treated with PPS experienced moderate or better improvement in overall symptoms, when the data are analyzed without the subjects who withdrew due to lack of efficacy.8 PPS therapy can take up to two or three months to be effective. The drug is generally well tolerated. Side effects include dyspepsia and reversible alopecia.
Amitriptyline is a tricyclic antidepressant that is often used to treat IC/PBS. The agent may be helpful in IC/PBS for a number of reasons. Amitriptyline modulates pain by decreasing reuptake of serotonin and norepinephrine in the central nervous system.2 In addition, it may help stabilize mast cells, which are cells in the connective tissue that release pro-inflammatory substances during allergic reactions.2 Finally, amitriptyline may increase bladder capacity, possibly through effects on beta-adrenergic receptors located on the bladder.9 Amitriptyline seems to be most effective for IC/PBS patients for whom pain is a significant component of their symptom complex.
A randomized, placebo-controlled trial (n=50) evaluating amitriptyline efficacy in IC/PBS found that treatment with the drug significantly reduced mean symptom score compared with placebo (p = 0.005).10 However, 92 percent of patients in the treatment group reported anticholinergic side effects including dry mouth and constipation.
Sedation can be a limiting side effect, although if taken in the early evening, the drug can promote sleep. The dose of amitriptyline used for IC/PBS is much lower than that used for depression. Amitriptyline should be prescribed for treatment of IC/PBS only by health care providers familiar with its side effect profile and use in IC/PBS.
Hydroxyzine (Atarax®, Vistaril®) is a histamine H1 antagonist. It inhibits mast cell degranulation, thus reducing histamine release.5 This action may explain its effectiveness in IC/PBS management, because excessive histamine release has been implicated in the pathophysiology of IC/PBS.2
An open-label study found that hydroxyzine reduced symptom scores by 55 percent on average in patients with a history of allergies.11 However, in a subsequent randomized controlled trial, the drug did not reduce global assessment scores significantly more than placebo.12 Hydroxyzine may promote sleep and may act as a skeletal muscle relaxant, two actions that may help modify IC/PBS symptoms.
In addition to these commonly used oral agents, specialists occasionally use a number of other oral agents (see Table 2) to treat IC/PBS symptoms. Clinical trial data are not available for these agents in treatment of IC/PBS.
|Table 2: Other Oral Agents Used in IC/PBS Management2,5,13-15|
|Tricyclics other than amitriptyline||Examples: imipramine, nortriptyline, doxepin|
|Antihistamines other than hydroxyzine||Anecdotal reports exist of symptom improvement in some patients with loratadine or diphenhydramine|
|Anticonvulsants||Examples: gabapentin, pregabalin, carbamazepine. These agents are used by some clinicians to treat IC/PBS; like many agents used for IC/PBS, they are not FDA-approved for this use.|
|Muscle relaxants||Can be an effective therapy for muscle spasticity syndromes like pelvic floor dysfunction|
|Opioids||Chronic narcotic therapy is sometimes used in patients with poor response to other therapies; referral for pain management can be helpful for some patients|
|Selective serotonin reuptake inhibitors (SSRIs)||Examples: venlafaxine, paroxetine|
|H2 antagonists||Example: cimetidine|
|Leukotriene inhibitors||Example: montelukast|
|Urinary anesthetics||Example: phenazopyridine|
|Alpha blockers||Examples: doxazosin, terazosin|
Intravesical therapy involves the instillation of an agent or a “cocktail” of agents into the bladder. It is normally used as second-line treatment or in conjunction with oral therapy or other types of conservative therapies.
Dimethylsulfoxide (DMSO; RIMSO®-50) is the only intravesical therapy that has received FDA approval for use in IC/PBS (approved in 1978). Dimethylsulfoxide is a byproduct of the wood pulp industry. It appears to have anti-inflammatory, analgesic, and some muscle relaxant effects.
Generally, DMSO is instilled in the bladder via catheter and allowed to remain for 15 minutes. It also can be administered in the form of a cocktail containing heparin or other agents, such as a corticosteroid and sodium bicarbonate.16 The treatment is repeated weekly for six to eight weeks.
In randomized controlled trials, intravesical DMSO has been shown to have a 70 percent efficacy rate in reducing the symptoms of IC/PBS.17,18 Patients who respond often experience symptom improvement for several months, perhaps up to a year. Side effects associated with DMSO therapy include a garlic taste in the mouth and discomfort related to catheterization.
Other Intravesical Agents
Other intravesical therapies are occasionally used to treat IC/PBS, including lidocaine, which is sometimes also used in diagnosis, and heparin alone or in combination with other agents.19,20 Oxychlorosene (Clorpactin®), which is a derivative of bleach originally used to treat bladder tuberculosis, and silver nitrate are painful intravesical treatments that require anesthesia for administration. These agents have been used in the past but are not commonly used today for management of IC/PBS.
Hydrodistention under general anesthesia is often used during diagnosis, but it also can have short-term therapeutic benefit in up to 50 percent of patients.9 With the patient under anesthesia, the urologist performs a cystoscopic examination, obtains urine for cytology, and distends the bladder with sterile water for one to two minutes. The bladder is emptied and refilled to allow the urologist to look for lesions or ulceration. The urologist then distends the bladder again for eight minutes. The bladder is emptied again, at which time the urologist may take a biopsy specimen. Figure 8 shows typical IC/PBS lesions in a patient during hydrodistention.
As previously mentioned, about half of patients experience some relief of symptoms after distention, but relief rarely lasts longer than six months. Experts believe that the procedure causes increased bladder capacity and interference with pain signals transmitted via nerves in the bladder.
Surgery should be considered for the management of IC/PBS only in patients with severe disease that is unresponsive to conservative therapy. The purpose of surgery is to increase the functional capacity of the bladder or to divert the urine stream.5 Surgical options include cystoscopic treatment, implantable nerve stimulators, and radical surgery. Cystoscopic treatment involves either bladder wall resection or laser therapy ablation of Hunner’s ulcers, the characteristic lesions of IC/PBS.
The FDA has approved an implantable nerve stimulator (called InterStim®) for urinary frequency and urgency; it is less helpful for IC/PBS patients who have severe pain. Although clinical trial data for this approach are limited, two open, noncomparative studies found that a majority of IC/PBS patients whose condition was refractory to other treatment experienced at least 50 percent improvement in symptoms with implantation of the device.21,22
Radical surgery generally involves urinary diversion with or without cystectomy or augmentation cystoplasty, in which a portion of bowel is added to the bladder to increase bladder capacity.
Surgical procedures—with the exception of fulguration (tissue destruction using high-frequency electric current) of a Hunner’s ulcer—should be considered a treatment of last resort, reserved for patients with severe symptoms. Unfortunately, even with removal of the bladder, some patients may continue to experience pelvic pain, possibly due to pelvic floor spasm or central nervous system-mediated pain.
Referral to a Specialist for Management of IC/PBS
The timing of referral depends on comfort level and experience of the individual provider in the management of IC/PBS. Some providers refer patients to specialists when IC/PBS is first suspected; others complete an initial evaluation, begin therapy, and refer for care by a specialist only if conservative treatment fails. Referral to a specialist is recommended, however, if:
- Symptoms do not respond to oral therapies
- The diagnosis is in doubt
- The provider is uncomfortable treating IC/PBS or lacks the time to do so
It’s best to refer patients needing a specialist’s care to a urologist, gynecologist, or urogynecologist who has experience diagnosing and treating IC/PBS. Inquiring about comfort and experience with IC/PBS before referring is recommended. In addition, clinicians should consider referral to a pain management clinic if appropriate urologic and gynecologic evaluations have been performed and interventions have not been sufficiently effective in relieving the pain associated with IC/PBS.
- Interstitial Cystitis and Diet. [brochure] Rockville, MD: Interstitial Cystitis Association; 2006.
- Moldwin RM, Sant GR. Interstitial cystitis: a pathophysiology and treatment update. Clin Obstet Gynecol. 2002;45:259-72.
- Shorter B, Lesser M, Moldwin RM, Kushner L. Effect of comestibles on symptoms of interstitial cystitis. J Urol. 2007;178:145-52.
- Oyama IA, Rejba A, Lukban JC, Fletcher E, Kellogg-Spadt S, Holzberg AS, et al. Modified Thiele massage as therapeutic intervention for female patients with interstitial cystitis and high-tone pelvic floor dysfunction. Urology. 2004; 64(5):862-5.
- Hanno PM. Painful bladder syndrome (interstitial cystitis). In: Hanno PM, Wein AJ, Malkowicz SB, editors. Penn Clinical Manual of Urology. Philadelphia: Saunders; 2007. pp. 217-34.
- Parsons CL, Benson Parsons CL, Benson G, Childs SJ, Hanno PM, Sant GR, et al. A quantitatively controlled method to study prospectively interstitial cystitis and demonstrate the efficacy of pentosanpolysulfate. J Urol. 1993;150(3):845-8.
- Mulholland SG, Hanno PM, Parsons CL, Sant GR, Staskin DR. Pentosan polysulfate sodium for therapy of interstitial cystitis. Urology. 1990;35(6):552-8.
- Hanno PM. Analysis of long-term Elmiron therapy for interstitial cystitis. Urology. 1997;49(Suppl 5A):93-9.
- Hanno PM. Painful bladder syndrome/interstitial cystitis and related disorders. In: Wein AJ, editor. Campbell-Walsh Urology. 9th ed. Philadelphia: Saunders; 2007. pp. 330-70.
- van Ophoven A, Pokupic S, Heinecke A, Hertle L. A prospective, randomized, placebo controlled, double-blind study of amitriptyline for the treatment of interstitial cystitis. J Urol. 2004;172:533-6.
- Theoharides TC, Sant GC. Hydroxyzine therapy for interstitial cystitis. Urology. 1997;49:108-10.
- Sant GR, Propert KJ, Hanno PM. A pilot clinical trial of oral pentosan polysulfate and oral hydroxyzine in patients with interstitial cystitis. J Urol. 2003;170(3):810-15.
- Chancellor M, Yoshimura N. Treatment of interstitial cystitis. Urology. 2004;63 (Suppl A):85-92.
- Moldwin RM, Evans RJ, Stanford EJ, Rosenberg MT. Rational approaches to the treatment of patients with interstitial cystitis. Urology. 2007;69(Suppl 4A):73-81.
- Nickel JC, Berger R, Pontari M. Changing paradigms for chronic pelvic pain: a report from the Chronic Pelvic Pain/Chronic Prostatitis Scientific Workshop, October 19–21, 2005, Baltimore, MD. Rev Urol. 2006;8(1):28-35.
- Ghoniem GM, McBride D, Sood OP, Lewis V. Clinical experience with multiagent intravesical therapy in interstitial cystitis patients unresponsive to single-agent therapy. World J Urol. 1993;11(3):178-82.
- Perez-Merrero R. A controlled study of dimethylsulfoxide in interstitial cystitis. J Urol. 1988;140:36-9.
- Peeker R. Intravesical BCG and DMSO for treatment of classic ulcer and non-ulcer interstitial cystitis: a prospective, double blind, randomized study. J Urol. 2000;164:1912-15.
- Parsons CL. Successful downregulation of bladder sensory nerves with combination of heparin and alkalinized lidocaine in patients with interstitial cystitis. Urology. 2005;65(1):45-8.
- Taneja R, Jawade KK. A rational combination of intravesical and systemic agents for the treatment of interstitial cystitis. Scand J Urol Nephrol. 2007:1-5
- Peters KM. Neuromodulation for the treatment of refractory interstitial cystitis. Rev Urol. 2002;4(Suppl.1):S36-S43.
- Comiter CV. Sacral neuromodulation for the symptomatic treatment of refractory interstitial cystitis: a prospective study. J Urol. 2003;169:1369-73.