CE/CME

Interstitial Cystitis: A Painful Syndrome

Clinician Reviews. 2013 July;23(7):30-37

References

1. Dasgupta J, Tincello DG. Interstitial cystitis/bladder pain syndrome: an update. Maturitas. 2009;64:212-217.

2. Hanno PM, Burks DA, Clemens JQ, et al. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: American Urological Association (AUA) Guideline (2011). www.auanet.org/education/guidelines/ic-bladder-pain-syndrome.cfm. Accessed June 5, 2013.

3. Evans RJ; University of Tennessee Advanced Studies in Pharmacy. Pathophysiology and clinical presentation of interstitial cystitis (2005). www.utasip.com/files/articlefiles/pdf/XASIP_Issue_Mar_p8_14.pdf. Accessed June 5, 2013.

4. Sant GR. Etiology, pathogenesis, and diagnosis of interstitial cystitis. Rev Urol. 2002;(4 suppl 1):S9-S15.

5. Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn. 2002;21:167-178.

6. van de Merwe JP, Nordling J, Bouchelouche P, et al. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal. Eur Urol. 2008;53:60-67.

7. Bogart LM, Berry SH, Clemens JQ. Symptoms of interstitial cystitis, painful bladder syndrome and similar diseases in women: a systematic review.  J Urol. 2007;177:450-456.

8. Kusek JW, Nyberg LM. The epidemiology of interstitial cystitis: is it time to expand our definition? Urology. 2001;57(6 suppl 1):95-99.

9. Clemens JQ, Meenan RT, Rosetti MC, et al. Prevalence and incidence of interstitial cystitis in a managed care population. J Urol. 2005;173:98-102.

10. Berry SH, Elliott MN, Suttorp M, et al. Prevalence of symptoms of bladder pain syndrome/interstitial cystitis among adult females in the United States. J Urol. 2011;186:540-544.

11. Rosamilia A, Dwyer PL. Pathophysiology of interstitial cystitis. Curr Opin Obstet Gynecol. 2000;12:405-410.

12. Grover S, Srivastava A, Lee R, et al. Role of inflammation in bladder function and interstitial cystitis. Ther Adv Urol. 2011;3:19-33.

13. Rosenberg MT, Page S, Hazzard MA. Prevalence of interstitial cystitis in a primary care setting. Urology. 2007;69(4 suppl):S48-S52.

14. Evans RJ. Treatment approaches for interstitial cystitis: multimodality therapy. Rev Urol. 2002;(4 suppl 1):S16-S20.

15. Wesselmann U. Interstitial cystitis: a chronic visceral pain syndrome. Urology. 2001;57(6 suppl 1):102.

16. Hosseini A, Ehrén I, Wiklund NP. Nitric oxide as an objective marker for evaluation of treatment response in patients with classic interstitial cystitis.  J Urol. 2004;172(6 pt 1):2261-2265.

17. Ho MH, Bhatia NN, Khorram O. Physiologic role of nitric oxide and nitric oxide synthase in female lower urinary tract. Curr Opin Obstet Gynecol. 2004;16:423-429.

18. Rosenberg MT, Newman DK, Page SA. Interstitial cystitis/painful bladder syndrome: symptom recognition is key to early identification, treatment. Cleve Clin J Med. 2007;74:854-862.

19. Driscoll A, Teichman JM. How do patients with interstitial cystitis present?  J Urol. 2001;166:2118-2120.

20. Parsons CL. Interstitial cystitis: epidemiology and clinical presentation. Clin Obstet Gynecol. 2002;45:242-249.

21. Hanno PM, Landis JR, Matthews-Cook Y, et al. The diagnosis of interstitial cystitis revisited: lessons learned from the National Institutes of Health Interstitial Cystitis Database study. J Urol. 1999;161:553-557.

22. Whitmore KE, Theoharides TC. When to suspect interstitial cystitis. J Fam Pract. 2011;60:340-348.

23. Butrick CW, Howard FM, Sand PK. Diagnosis and treatment of interstitial cystitis/painful bladder syndrome: a review. J Womens Health (Larchmt). 2010;19:1185-1193.

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30. Davis EL, El Khoudary SR, Talbott EO, et al. Safety and efficacy of the use of intravesical and oral pentosan polysulfate sodium for interstitial cystitis: a randomized double-blind clinical trial. J Urol. 2008;179:177-185.

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TREATMENT
Management of IC/BPS can be challenging, because it is such a multifaceted disorder. Patient education beginning shortly after diagnosis is crucial, as treatment regimens may involve complex multimodal therapy over long periods of time, oftentimes with a very gradual response (see “For Your Patient”).

Lifestyle changes for patients with IC/BPS are considered an important component of treatment. Dietary changes—specifically, reducing intake of foods with high acidic content (citrus fruits, tomatoes), alcoholic beverages, spices, and potassium—have been found helpful.⁵ Reducing stress and anxiety, whenever possible, has also been noted to alleviate symptoms.²⁴

Another nonpharmacologic option is physical therapy, including biofeedback and bladder retraining.^12,13 Biofeedback is particularly useful in patients who experience pelvic pain attributed to spasms of the pelvic floor.¹² Bladder retraining can be used to reduce urinary frequency through techniques that include scheduled voiding. Physical therapy strategies should be revisited regularly to maintain their therapeutic benefits.^5,12

Oral Medications
The mainstay of pharmacologic treatment, and the one most thoroughly studied, is oral pentosan polysulfate (PPS), which belongs to the class of heparins or heparinoids.^2,26 PPS is thought to attach to the mucosa of the bladder, reestablishing its glycosaminoglycan layer and restoring normal function of this permeable barrier.¹⁴ Overall, this drug is well tolerated and relieves the symptoms of pain, urgency, and frequency. Patients may start to experience improvement in symptoms after four weeks of treatment; however, it can take six months or longer to achieve the full benefit of this therapy.^13,25

Other pharmacologic agents used in the treatment of IC/BPS include antihistamines, tricyclic antidepressants, and some antiepileptic medications. Some patients with IC/BPS experience symptoms attributable to bladder mastocytosis and mast cell activation, explaining the efficacy of antihistamines for these particular patients.²⁷ Among the antihistamines, hydroxyzine, an H₁-receptor antagonist, is a common pharmacologic option. Similarly, cetirizine can be used in patients for whom the sedating effects of hydroxyzine may prove hazardous.²⁸

Antidepressants, especially tricyclic antidepressants (TCAs, eg, amitriptyline), can also provide some relief for patients, including alleviation of pain, possible antihistamine effects, and mild anticholinergic action, leading to decreased urinary urgency and frequency.^2,26,29 Of note, the TCA imipramine should be avoided in patients with IC/BPS, as it has a sympathomimetic effect that can worsen symptoms of dysfunctional voiding in this patient population.¹⁴

Gabapentin, an antiepileptic, is used for improvement of severe, persistent pain. Alternatives to gabapentin include, but are not limited to, phenytoin, carbamazepine, and valproic acid.¹⁴ The effectiveness of these medications in the treatment of IC/BPS lend credence to the theory that, in addition to bladder mucosa dysfunction, symptoms are also mediated through an inflammatory neurogenic pathway.

Patients should be encouraged to continue use of PPS or other prescribed pharmacologic treatments even if there is no immediate relief of symptoms.²⁵ According to a treatment algorithm from the American Urological Association,² however, ineffective treatments should be stopped and diagnosis should be reconsidered if there is no improvement within a “clinically meaningful time frame.”

Additional Pharmacologic Options
Intravesical therapy is another mode of pharmacologic treatment.^2,29 This treatment is usually reserved for IC/BPS flares and management of cases lacking the desired response to oral medications. Dimethyl sulfoxide (DMSO) is a commonly used intravesical agent. DMSO acts to provide pain relief and reduce inflammation, in addition to effecting histamine release from mast cells.²⁷ Intravesical heparinoids essentially employ the same mechanism of action as oral PPS to maintain and enhance the bladder’s mucosal lining. This treatment is also commonly used in patients who need to discontinue use of oral PPS due to side effects.^27,30

Treatment options for refractory IC/BPS include immunosuppression (and surgical therapy, below). Prednisone and cyclosporine have been shown to be effective immunosuppressive agents.²³ Side effects make the use of these medications less desirable; also, symptoms have been shown to return in many patients after treatment is stopped.²³

The FDA has recently approved the use of onabotulinum toxin A (Botox) injections into the bladder for treatment of urinary urgency and frequency that are not responsive to standard medical therapy. Since patients with IC often experience such symptoms with no relief from standard therapy, intratrigonal and periurethral injections of Botox are being administered for treatment of IC in some patients with moderate success.^31-33 Although intradetrusor Botox use is recommended as a fifth-line treatment in the AUA guidelines,² it is important to note that this agent is not FDA-approved specifically for IC, but rather for any refractory condition presenting with urinary frequency and urgency.

Surgical Therapy
Surgical intervention (a sixth-line treatment option, according to the AUA guidelines²) is rarely indicated except in cases of severe IC/BPS that have been refractory to all other treatment options and in which spontaneous remission of symptoms seems unlikely. Supravesical urinary diversion, usually through the creation of an ileal conduit, is the procedure of choice and is often performed in conjunction with a cystectomy. Unfortunately in some cases, pelvic pain has been noted to continue postcystectomy, a finding that also supports a neurogenic etiology for IC/BPS.¹⁴

On the Horizon
Although IC/PBS is difficult to treat, new data suggest that use of extended diagnostics, including molecular markers to detect the disease early and guide effective treatment, may greatly improve current therapeutic options.³⁴

Prescribing selective anticholinergic and antihistamine pharmacotherapy based on the patient’s specific muscarinic and histamine receptor profile, respectively, may provide greater symptom relief.³⁴ Maintaining the appropriate, individualized therapy could represent a significant advance in treatment for IC/BPS. However, further research on the topic is needed.

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