Treatment of painful bladder syndrome/interstitial cystitis

Treatment of painful bladder syndrome/interstitial cystitis

Author
Mary P Fitzgerald, MD
Section Editor
Linda Brubaker, MD, FACS, FACOG
Deputy Editor
Sandy J Falk, MD



Last literature review version 16.2: May 2008 | This topic last updated: May 16, 2008 (More)


INTRODUCTION — Although painful bladder syndrome/interstitial cystitis (PBS/IC) can cause major deterioration in quality of life, there is no consensus surrounding the optimal approach to its treatment. This is due, in part, to our lack of a clear understanding of the etiology of the disorder, which precludes development of therapies targeted at the underlying pathophysiology. In addition, there have been few randomized, controlled treatment trials of PBS/IC, instead the great majority of therapeutic studies have been retrospective and/or uncontrolled. Lastly, varying definitions of the condition and outcome have been an impediment to interpretation of results and their application to clinical care [1] .

The symptoms of PBS/IC can be somewhat nonspecific; these patients probably suffer from one or more unrecognized disorders. Therefore, it is not surprising that clinically popular treatment algorithms for PBS/IC usually involve several treatment modalities or cycling through various therapies when initial treatments are unsuccessful. This was illustrated by the Interstitial Cystitis Data Base study, which recorded data on 581 women with a diagnosis of IC [2] . These women underwent 183 different types of therapy over several years follow-up. No one therapy was successful in a majority of patients.

In practice, physicians who treat patients with PBS/IC choose a model of the disease that seems to fit their clinical experience, and treat according to that model. Clinicians tend to favor one theory over others, and initiate treatment(s) in line with their favored theory. Therefore, treatment algorithms are highly empiric and vary considerably from site to site. Since treatments tend to have a low success rate, most patients try more than one therapy before finding relief. In this clinical setting, it cannot be determined whether the relief that patients experience is simply due to the passage of time and natural remission of symptoms, or whether the treatment was responsible for the improvement.

NONSPECIFIC THERAPIES — Common sense dictates that the following components are part of all treatment programs:

Psychosocial support — Psychosocial support is an integral part of treatment of any chronic pain disorder. Patients may benefit from identification of a support person within the clinical practice whom they may contact, as needed. They may wish to be in touch with local pain support groups, or with national support groups, such as the Interstitial Cystitis Society (www.ichelp.org) or the Interstitial Cystitis Network (www.ic-network.com). Some centers may have resources to refer patients for formal counseling by a psychologist with expertise in support of patients with chronic illness.

Depression is common in patients with chronic pain, and may impede treatment success. Referral for mental health evaluation may be useful when there is any suspicion that depression is present. (See "Depression: Clinical manifestations and diagnosis").

Referral to pain management specialists — Referral to specialists in pain management should be considered if the full range of pain management options is not available within the practice.

Treatment of comorbid conditions — Acute genitourinary disorders (eg, urinary tract infection, vulvovaginitis) can exacerbate PBS/IC symptoms, thus they should be addressed promptly. Other disorders associated with visceral pain should also be treated since sensitization of any viscera probably results in increased bladder sensitivity. Therefore, it is critically important to treat concomitant inflammatory bowel disease (Crohn's disease, ulcerative colitis, diverticulitis), irritable bowel syndrome, dysmenorrhea or endometriosis. Since PBS/IC patients often carry more than one of these diagnoses, treatment decisions can be complex, and collaboration with other medical professionals is usually necessary. (See "Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis").

Avoidance of activities associated with flares — Patients frequently note that some exercises or recreational activities, sexual activities, or body positions seem to worsen bladder symptoms. Others note that some foods or beverages are troublesome. Common sense suggests that these factors be avoided until symptoms are resolved, at which time they may be reintroduced. Some practitioners strongly recommend the highly restrictive interstitial cystitis diet [3] , but its benefit has never been studied, and in practice, most patients with food sensitivities are already aware of them and have already excluded them from their diet.

Behavioral therapy — Behavioral therapy forms the cornerstone of all treatment packages. It includes avoidance of exacerbating activities, and also some form of a timed voiding protocol to expand functional bladder capacity. Such protocols are critical because frequent voiding leads to diminished functional bladder capacity (possibly due to shrinkage of smooth muscle, similar to diminished stomach capacity after fasting or after chronic intake of smaller amounts of food).

A typical bladder reeducation protocol involves teaching patients to "void by the clock" rather than voiding when they feel an urge to do so. As an example, a patient who is currently voiding every half an hour is asked to void only on the hour during the daytime (drills are not typically continued through the night), whether they feel the need to void or not, and not to void more frequently than the prescribed interval. This voiding interval is continued for a full week, and if patients are successful at that voiding interval, it is increased by an appropriate amount. This might result in the prescription of a voiding interval of 90 minutes for the second week, of two hours for the third week, 2.5 hours for the fourth week, and three hours for the fifth week. Other similar bladder retraining therapies are widely used since they are cheap, without side effects, and universally available.

The only study of timed voiding in IC patients reported 15 of 21 patients experienced a 50 percent decrease in their IC symptoms [4] .

SPECIFIC THERAPIES

Correction of uroepithelial abnormalities — Proponents of the theory that urothelial abnormalities are responsible for symptoms favor use of therapies directed at the urothelium. These include:

Pentosan polysulfate sodium — Pentosan polysulfate sodium (PPS) is the only oral medication approved by the United States Food and Drug Administration (FDA) for treatment of IC. The approved dose is 100 mg three times daily, although off-label treatment using 200 mg twice daily is clinically common. The medication is a protein that is supposed to be filtered by the kidneys and appear in the urine so that it can reconstitute the deficient glycosaminoglycan (GAG) layer over the urothelium. In fact, only a tiny proportion of the drug is absorbed by the gastrointestinal tract and excreted in the urine. Urinary levels in patients who respond to treatment are not significantly different from the levels in nonresponders [5] .

A systematic review of randomized trials assessing pharmacologic treatments of PBS/IC found that PPS was more effective than placebo in overall improvement of patient-reported symptoms (pain, urgency, frequency) (RR 1.78, 95% CI 1.34-2.35), but the magnitude of effect was modest [6] . There was considerable heterogeneity in the studies that addressed this question.

Intravesical heparin and lidocaine — Some practitioners recommend intravesical instillations of heparin and/or lidocaine, PPS, and sodium bicarbonate in various nonstandardized drug cocktails. No controlled studies of these therapies exist. As an example, use of a solution consisting of 40,000 units of heparin, 8 mL of 2 percent lidocaine, and 3 mL of 8.4 percent of sodium bicarbonate to reach a total fluid volume of 15 mL instilled into the bladder has been described as effective, with over 80 percent of patients experiencing good remissions after two weeks of three treatments per week [7] . Similar solutions have been recommended for use in patients with severe symptoms as a "rescue" intervention. Patients can be taught to perform the instillations themselves at home.

Intravesical dimethyl sulfoxide (DMSO) — Dimethyl sulfoxide (DMSO) was approved by the FDA for use in IC in 1997 on the basis of data from one uncontrolled clinical trial. Its action is thought to be nonspecific, including antiinflammatory, analgesic, smooth muscle relaxing, and mast cell inhibiting effects [8] . Treatment involves bladder catheterization with instillation of 50 mL DMSO weekly for six to eight weeks, followed by 50 mL every two weeks for 3 to 12 months. Small randomized trials initially suggested benefit [9,10] , but adverse effects, including pain and significant exacerbation of symptoms, limited its use. DMSO is currently less commonly used than in the past, as other, less painful treatments have become available.

Hydrodistension — Hydrodistension is usually used as a diagnostic aid for PBS/IC. (See "Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis" section on Hydrodistension). It has also been used as a treatment because some patients report prolonged relief of symptoms after the procedure, possibly due to disruption of sensory nerves within the bladder wall [11] . An uncontrolled study reported a positive effect in 35 of 50 patients who underwent 30 minutes of hydrodistension [8] , but others have reported lower success rates [12] . Even when there is benefit, it is usually short-lived, and many patients experience worsening of their symptoms; thus, many clinicians feel that the risk-benefit ratio of hydrodistension therapy is not appropriate for their patients. It may be appropriate to reserve use of repetitive therapeutic hydrodistension for patients who generally obtain significant and prolonged relief. Risks of hydrodistension include bleeding (from ruptured vessels) and, rarely, rupture of the bladder wall.

Neuromodulating therapies — Proponents of the theory that PBS/IC represents a neurological hypersensitivity disorder tend to favor use of neuromodulating treatments. These include:

Amitriptyline — Medications used to treat other pain syndromes are commonly utilized for IC patients, as well. Amitriptyline is commonly prescribed for relief of PBS/IC symptoms. In Germany, one trial randomly assigned 50 subjects with IC to amitriptyline or placebo (IC was defined according to National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) criteria) (show table 1) [13] . Subjects were treated for four months with a self-titration protocol that allowed them to escalate drug dosage by 25 mg increments weekly to a maximum of 100 mg. Amitriptyline use resulted in greater improvement in symptom scores than placebo. In addition, significantly more subjects prescribed amitriptyline rated their satisfaction with treatment as being "good" or "excellent" than those given placebo, 63 and 4 percent, respectively. However, only 42 percent of patients in the amitriptyline group experienced greater than 30 percent decrease in symptom score, suggesting that benefits are modest.

An open-label study of the long-term use of amitriptyline in 94 patients followed for a mean of 19 months reported similar results [14] . Almost one-half of patients rated satisfaction with treatment as "good" or "excellent" and designated themselves as being "moderately" or "markedly" improved. However, about one-third dropped out of the study after a mean treatment period of six weeks, with nonresponse to treatment being the primary reason for dropout. Side effects of amitriptyline include sedation, dry mouth and weight gain.

A National Institutes of Health-sponsored randomized trial comparing behavioral therapy to amitriptyline-plus-behavioral therapy for treatment of PBS is ongoing [15] .

Side effects of amitriptyline include anticholinergic effects, sedation, weight gain, orthostatic hypotension, and conduction abnormalities. (See "Antidepressant medication in adults: Tricyclics and tetracyclics", section on Heterocyclic antidepressants).

Gabapentin — In an uncontrolled study, 21 patients with refractory genitourinary pain were treated with gabapentin at a dose of 300 to 1200 mg/day [16] . About one-half of the patients reported improvement in pain, including five of eight patients who had a diagnosis of IC. Anecdotal reports also suggest that pregabalin can be effective for pain relief in PBS/IC, but no formal studies support its use. (See "Antiepileptic drugs in the treatment of neuropathic pain").

Electrical stimulation therapy — Several reports support treatment of PBS/IC symptoms with implanted sacral neuromodulation (eg, InterStim device, Medtronic Inc, Minneapolis, MN). This device is FDA approved for treatment of urinary urgency and frequency, but not specifically for treatment of PBS/IC. The device consists of an implanted lead that lies along a sacral nerve root (usually at S3 level) and is attached to an implanted pulse generator. An uncontrolled study from a single center described 17 patients diagnosed with IC according to NIDDK criteria (show table 1) who received InterStim implants and were followed for an average of 14 months [17] . Mean daytime and nighttime voiding frequencies decreased from 17 and 9 to 4 and 1, respectively. Average pain rating decreased from 5.8/10 at baseline to 1.6/10 [17] . Another case series documented "moderate" or "marked" improvement in pain in 20 of 21 IC patients (NIDDK criteria) during one year of follow-up [18] .

InterStim is a costly procedure, and surgical revisions are relatively common. Adverse events include surgical site infections and pain, and reoperation for revisions at the lead or pulse generator site(s) is not uncommon.

Somatic therapy — Proponents of the theory that bladder symptoms are caused or maintained by somatic (body wall) abnormalities favor somatic therapies. At present, physical therapy is the only somatic therapy in routine use.

Physical therapy — Treatment of the somatic abnormalities in PBS/IC patients is not within the scope of training of most physical therapists, even those who are skilled in treatment of urinary incontinence. Resolution of the tender points, trigger points, connective tissue restrictions, and muscular abnormalities of the soft tissues requires specialized training in pelvic soft tissue manual manipulation and rehabilitation. The therapist may also suggest that manual therapy treatments be supplemented by heat or ice treatments.

Several case series have described symptom relief from manual physical therapies. As an example, one study reported that 70 percent of IC patients who were treated with manual physical therapy to the pelvic floor tissues for 12 to 15 visits experienced moderate to marked improvement [19] . Another study of 21 women with IC and associated pelvic floor hypertonicity demonstrated decreased symptom scores after five weeks of pelvic floor massage [20] . A randomized trial of physical therapies for treatment of PBS/IC is currently ongoing [15] .

Therapies directed at mast cells — Proponents of the theory that mast cells play a critical role in the development and/or maintenance of IC symptoms favor therapies directed at mast cells and allergic phenomena. These include:

Hydroxyzine and cimetidine — Until recently, the antihistamine hydroxyzine was a mainstay of IC treatment, with initial dosing of 10 mg in the evening [21] , increasing to 50 to 100 mg daily as needed. However, a randomized controlled trial found hydroxyzine had no benefit over placebo [22] .

Two small studies suggested benefit of treatment with cimetidine, an H2-receptor blocker, but clinical experience has not generally supported these smaller studies and cimetidine is not commonly used [23,24] .

Montelukast — The presence of leukotriene D4 receptors in human detrusor myocytes and increased urinary leukotriene E4 in patients with interstitial cystitis and detrusor mastocytosis suggest cysteinyl containing leukotrienes may have a role as proinflammatory mediators in this disease [25] . One small study of 10 women with interstitial cystitis (NIDDK criteria) and detrusor mastocytosis received a single dose of montelukast daily for three months [25] . After one month of montelukast treatment, there was a statistically significant decrease in 24-hour urinary frequency, nocturia and pain which persisted during the three months of treatment. After three months, 24-hour urinary frequency decreased from 17.4 to 12 voidings, nocturia decreased from 4.5 to 2.8 voidings, and pain decreased from 46.8 to 19.6 mm on a visual analog scale. No side effects were observed during treatment. Further investigation of this modality is required.

Dimethyl sulfoxide — (see "Intravesical dimethyl sulfoxide (DMSO)" above)

Immunomodulatory treatments — There is some current interest in exploration of immunomodulatory treatments for PBS/IC. In one trial, 64 patients were randomized in a 1:1 ratio to 1.5 mg/kg cyclosporine A twice daily or 100 mg PPS three times daily for six months [26] . Cyclosporine A was superior to PPS in all clinical outcome parameters measured: micturition frequency in 24 hours was significantly reduced (-6.7 +/- 4.7 versus -2.0 +/- 5.1 times) and the clinical response rate (according to global response assessment) was significantly higher for cyclosporine than PPS (75 versus 19 percent). Adverse effects of cyclosporine A include hair growth, gingival hyperplasia, paresthesias, abdominal pain, flushing and muscle pain.

Although intravesical instillation of bacillus Calmette-Guerin (BCG) triggers a variety of local immune responses and has an acceptable safety profile, it has not provided significantly greater relief of IC symptoms than placebo in randomized trials [27,28] .

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Painful bladder syndrome and interstitial cystitis" and see "Patient information: Treatment of painful bladder syndrome and interstitial cystitis"). We encourage you to print or e-mail these topics, or to refer patients to our public web site www.uptodate.com/patients, which includes these and other topics.

SUMMARY AND RECOMMENDATIONS — Painful bladder syndrome/Interstitial cystitis (PBS/IC) causes significant deterioration in quality of life, and there is no consensus on the optimal treatment. Several etiologies have been proposed, and clinicians tend to treat according to their belief about the pathophysiology of the disorder. Significant advances in treatment success are likely to depend on major advances in our understanding of the etiology of these disorders, and refinements in diagnosis. (See "Clinical features and diagnosis of painful bladder syndrome/interstitial cystitis").

Pentosan polysulfate sodium is the only oral treatment for IC approved by the FDA. Uncontrolled studies suggest modest benefit, in a minority of patients, but a randomized controlled trial suggested no benefit over placebo. (See "Pentosan polysulfate sodium" above).

Intravesical therapy with dimethyl sulfoxide is approved by the FDA, but is not in common clinical use due to associated pain and uneven clinical benefit. Intravesical therapy with heparin, lidocaine and/or pentosan polysulfate sodium is also used clinically, without strong evidence to support its use. (See "Intravesical heparin and lidocaine" above and see "Intravesical dimethyl sulfoxide (DMSO)" above).
Hydrodistension is primarily a diagnostic test, but may be considered for patients who obtain significant relief of symptoms after the procedure. (See "Hydrodistension" above).

Amitriptyline has clinical utility, probably acting as a nonspecific neuromodulatory agent that decreases the sensitivity of bladder sensory pathways. (See "Amitriptyline" above).

Sacral neuromodulation with implanted electrodes that lie along a sacral nerve root has shown significant benefit in uncontrolled studies, but is expensive and is not approved by the FDA for this indication. (See "Electrical stimulation therapy" above).

Physical therapy is directed at resolution of the tender points, trigger points, connective tissue restrictions, and muscular abnormalities of the soft tissues, but requires specialized training. (See "Physical therapy" above).

There is no good evidence showing that one treatment regimen is clearly superior to another. We suggest physical therapy for initial treatment of patients with PBS/IC (Grade 2C). We also suggest a trial of amitriptyline (Grade 2B). We start with 10 mg nightly and increase to 25 mg nightly as tolerated, in accordance with side effects and symptom relief. In our experience, it is only those women with the most severe symptoms who are willing to tolerate the side effects (eg, sedation and weight gain) that can be associated with amitriptyline use. When symptoms improve on this dual therapy, patients can usually discontinue amitriptyline while maintaining physical therapy, which is continued until their symptoms have resolved. We suggest sacral neuromodulation to patients who do not respond to physical therapy and/or amitriptyline (Grade 2C).