Interstitial Cystitis Part III

Treatment Modalities: Medications

When it comes to treatment options for IC, the list of possibilities is lengthy. However, it is important to note the risks and benefits of the suggested treatments prior to the engagement of any one modality. Treatments range from prescribed and over-the-counter medications to so-called natural interventions, diet and lifestyle modifications.

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen or naproxen sodium are sometimes used for IC patients. The reasoning behind these types of prescriptions is based upon the premise that inflammation plays an integral part in the pathophysiology of IC.²³ With the use of these drugs, prostaglandin production is blocked and reportedly leads to control of inflammatory pain.²³ Challenges may arise, however, due to the increased risk of serious gastrointestinal and cardiovascular adverse effects with NSAID use.²³ Some researchers go so far as to say that IC can be caused by NSAID use, a condition known as drug-induced interstitial cystitis (DIC).²⁴ In a review on DIC and the effects of particular drugs on the development or exacerbation of symptoms, researchers found that NSAIDs may contribute to the initiation or worsening of symptoms.²⁴ Authors were bold enough to state:

“Although there is no clear association between other NSAIDs and cystitis, there is sufficient evidence to suspect strongly that they do occasionally induce cystitis…Unless drugs are essential and cannot be replaced by suitable alternatives, they should be stopped in sequence, starting with obvious candidates such as NSAIDs…New drugs are being introduced all the time and as urologists, we need to raise our level of awareness. It seems that many urologists do not read Current Problems in Pharmacovigilance or The British Medical Journal.”²⁴

Tricyclic antidepressants are another class of drug frequently prescribed for IC. These drugs such as amitriptyline or imipramine work by aiding in the relaxation of the bladder which in turn facilitates blockage of pain.³ The mechanism of action lies in the drug’s ability to inhibit the reuptake of norepinephrine and serotonin from the brainstem to the spinal cord.²⁵ However, though in theory these drugs may suggest benefit, some research has shown that this class of drugs is useless for pain unless the patients taking them are simultaneously suffering from depression.²⁵ Therefore, researchers conclude that in regard to pain, “if the patient is not depressed, the SSRIs are virtually useless”.²⁵

According to Harvard Health, tricyclic antidepressants have the ability to relax the bladder, slow the release of neurochemicals that initiate bladder pain and inflammation and may also enhance sleep.²⁶ With most medications, however, these drugs also carry with them side effect profiles that are less than desirable.²⁶

                    In a study of 94 patients, the long term use of tricyclic antidepressants was examined to determine safety and efficacy.²⁷ Though the researchers concluded that patient satisfaction overall was highly positive (46% of patients), several limitations are of note.²⁷ Not only did 84% of the patients experience negative side effects, but the dropout rate was 31%, a fairly large percentage of the original group.²⁷ Perhaps of even greater significance was the fact that nonresponse to treatment was the leading explanation for dropout with side effects contributing to 86% of those who exited the study.²⁷ With these factors in mind, the so-called “feasible, safe and effective” use of tricyclic antidepressants as a treatment for IC is questionable.²⁷

Antihistamines are another class of frequently prescribed medication in the management of IC. The assumption is that these drugs will reduce issues of urgency and frequency and in turn, relieve additional symptoms.³ In a study of 90 participants, researchers observed the effects of using hydroxyzine as a treatment for IC.²⁸ Results demonstrated a positive and useful effect of the drug for IC patients.²⁸  Side effects such as sedation, increased appetite, urinary retention and nightmares were reported.²⁸ Further, researchers commented that the reasoning as to why hydroxyzine shows positive effect remains unclear, stating that the antihistamine action is not enough to explain positive action.²⁸ Some postulate that since hydroxyzine is a histamine antagonist and inhibits mast cell (found in connective tissue, responsible for releasing histamine and contributing to inflammatory and allergic reactions) degranulation, a reduction in the release of histamine occurs.²⁹ As histamine release is decreased, there may be a benefit for IC patients due to the assumption that increased histamine release appears to be present in the pathophysiology of IC.²⁹

In a prospective, randomized, double-blind placebo-controlled trial, researchers looked at the effectiveness of cimetidine, an oral histamine antagonist, for IC patients.³⁰ Of the 34 patients who completed the study,  significant improvement of symptoms, pain and sleep disturbance due to voiding urgency was observed  in those taking the cimetidine.³⁰ However, researchers also noted that no qualitative change was observed in the bladder mucosa as a result of treatment and further, the mechanism of action for symptom relief was unidentifiable.³⁰

Pentosan polysulfate sodium (PPS), marketed as Elmiron and approved specifically for the amelioration of IC symptoms, is also frequently used in the treatment regimen of IC.³ However, the mechanism of action is unknown.³ Another factor worthy of mention is the reality that pain reduction may take two to four months and improvement in urinary frequency may take up to six months, creating a significant challenge for many patients who have lived with the disorder for extended periods of time.³  In a randomized, double-blind, placebo controlled study, researchers examined the efficacy of using a third of the recommended daily dose of PPS in IC patients.³¹ When compared to a placebo, results demonstrated that there was no statistically significant improvement between the study group and the placebo group.³¹ Further, researchers concluded that despite the broad population of symptomatic patients involved in the study, no treatment effect was revealed.³¹

Retrospectively reviewing the charts of 260 IC patients, authors of another study evaluated the efficacy and safety of PPS.³² Observations demonstrated that symptoms of both groups improved over time but symptom improvement was greater in terms of statistical significance in the treatment group compared to the control group.³² Nocturia was unchanged in the treatment group when compared with the control group.³² Authors concluded that though some areas of symptomatology were unchanged between groups and 15% of patients experienced negative side effects, that PPS remains an efficacious option for symptom reduction in IC patients.³² A systematic review of pharmacologic treatment of IC was performed to determine efficacy of the wide variety of medication options.

Researchers looked at randomized controlled trials in regard to pharmacological options for IC patients with the intention of evaluating the efficacy of medications, examine the effect size of the trials and to begin to develop a clinical consensus in terms of efficacious treatment options.³³ Twenty-one randomized controlled trials were used in the review, including 1470 patients.³³ Though PPS showed modest treatment benefit, researchers concluded that there is an insufficient amount of evidence available for any other pharmacological treatments.³³ Authors stated, “ A consensus on standardized outcome measures is urgently needed”.³³

It is clear that many questions and limitations remain in terms of pharmacological treatment options. Challenges such as unknown mechanisms of action, significant side effects, and lengthy waits for symptom reduction all point to the use of caution prior to the utilization of these medications. It would perhaps be useful to examine what alternatives exist for those suffering from this debilitating issue.

References

23. Gardella B, Porru D, Allegri M, et al. Pharmacokinetic considerations for therapies used to treat interstitial cystitis. Expert Opinion on Drug Metabolism and Toxicology. 2014; 10(5): 673-684.

24. Bramble FJ, Morley R. Drug-induced cystitis: the need for vigilance. British Journal of Urology. 1997; 79: 3-7.

25. Medscape. Symptomatic treatment of neuropathic pain: a focus on the role of anticonvulsants: tricyclic antidepressants (TCAs) for the treatment of neuropathic pain. Available at: https://www.medscape.org/viewarticle/413110_3. Accessibility verified July 17, 2018.

26. Harvard Health Publishing. Diagnosing and treating interstitial cystitis. Available at: https://www.health.harvard.edu/diseases-and-conditions/diagnosing-and-treating-interstitial-cystitis. Accessibility verified July 17, 2018.

27. van Ophoven A, Hertle L. Long-term results of amitriptyline treatment for interstitial cystitis. The Journal of Urology. 2005;174(5): 1837-1840.

28. Theoharides TC, Sant GR. Hydroxyzine for interstitial cystitis. Urology. 1997; 49(5): 108-110.

29. Association of Reproductive Health Professionals. Screening, treatment, and management of IC/PBS. Available at: http://www.arhp.org/Publications-and-Resources/Clinical-Proceedings/Screening-Treatment-and-Management-of-ICPBS/Management. Accessibility verified July 18, 2018.

30. Thilagarajah R, Witherow ON, Walker MM. Oral cimetidine gives effective symptom relief in painful bladder disease: a prospective, randomized, double‐blind placebo‐controlled trial. BJU International. 2001; 87(3): 207-212.

31. Nickel JC, Herschorn S, Whitmore KE, et al. Pentosan polysulfate sodium for treatment of interstitial cystitis/bladder pain syndrome: insights from a randomized, double-blind, placebo-controlled study. The Journal of Urology. 2015; 193(3): 857-62.

32. Waters MG, Suleskey JF, Finkelstein LJ, Van Overbeke ME, Zizza VJ, Stommel M. Interstitial cystitis: a retrospective analysis of treatment with pentosan polysulfate and follow-up patient survey. The Journal of the Osteopathic Association. 2000; 100(3): S13-8.

33. Dimitrakov J, Kroenke K, Steers WD, et al. Pharmacological management of painful bladder syndrome/interstitial cystitis: a systematic review. Archives of Internal Medicine. 2007; 167(18): 1922-1929.