Introduction to full text of Urology magazine article

The publisher of the medical journal UROLOGY, Elsevier, has given us permission to put the abstract of our article in UROLOGY on our website, in the Elsevier format.  That link is:  http://dx.doi.org/10.1016/j.urology.2007.09.011

We also have permission to publish the full text of the article, but not in the Elsevier format; instead, we will publish it here in the format in which Dr. Hill submitted our article in the January, 2008 UROLOGY.   This will give you a cost-free copy of the full article (see below).

If you wish to see a lay version, or a version in plain English, you will find that at the end of the article that we wrote for the National Women’s Health Network, and which appears in their March 2009 Newsletter, and on their site:  Click here:  http://www.nwhn.org/newsletter/article1.cfm?newsletterarticles_id=332

For your consideration:  It is my impression that the 25% success rate reported by patients for some of the treatments should not necessarily be considered an indication that the treatment is successful or safe to do.   The Interstitial Cystitis Data Base study, which followed almost 600 patients for up to 4 years concluded that “No current (prescribed, urological) treatments have a significant impact on symptoms with time.” My parentheses.  Propert, KJ, Schaeffer, AJ, Brensinger, CM, Kusek, JW, Nyberg, JRL and the Interstiticial Cystitis Data Base Study Group, “A Prospective Study of Interstitial Cystitis: Results of Longitudinal Followup of the Interstitial Cystitis Data Base Cohort,” The Journal of Urology, Vol. 163, 1434-1439, May, 2000, p. 1434.  And the treatments listed in the survey – hydrodistention, dilation, instillations, implants of neuromodulators, etc., are primarily surgeries, with the exception of medications.  K. Zakariasen

PATIENT PERCEIVED OUTCOMES OF TREATMENTS USED FOR INTERSTITIAL CYSTITIS

Jennifer R. Hill, MD,
Ginger Isom-Batz, MD,
Kay Zakariasen, MA,
Georgia Panagopoulos, PhD,
Elizabeth Kavaler, MD

Department of Urology
Lenox Hill Hospital , New York , NY

Corresponding author contact information:

Jennifer R. Hill, MD
Department of Urology
Lenox Hill Hospital
100 East 77 th Street
NY , NY 10021 USA

Acknowledgements:
Yelena Aronson and Mikhail Markov for design and programming of the website
Steve Davis for data exportation.
Financial disclosures: None

INTRODUCTION:

Interstitial Cystitis (IC) remains a challenging disease complex for doctors and patients. A universally accepted definition does not exist for IC; it is a diagnosis of exclusion. The data suggest that IC can be a chronic unremitting disease and no current treatments have a significant impact on symptoms over time. 1 As a result, patients are subject to many different treatment modalities. The treatments that have been reported for IC range from invasive therapy to holistic medications.

After years of debate, it is now agreed that IC is a multi-factorial syndrome. Different theories have been explored to understand the etiology of this elusive disease. Such theories have included neurological, immunological, hormonal, toxic, allergic, and infectious causes for the disease complex. With such a difficult disease to define, the ability to effectively treat the patient’s symptoms comes into question. The outcomes of our interventions, either invasive or medical, are marginal at best when dealing with IC. For lack of objective measures, the patients’ perceptions of the outcomes may be the best determinant of therapeutic efficacy. These perceptions may aid in guiding therapy for this very challenging disease.

Our study focused on a large group of women with a diagnosis of IC who self-reported on perceived outcomes after undergoing various treatments. Our purpose was to elicit patient perceptions of invasive procedures and medical therapy on the symptoms of IC. All data received were based on patient perspective.

MATERIALS AND METHODS:

750 patients with a diagnosis of IC completed a computerized, internet-based survey. The survey was listed at the web address of www.cystitispatientsurvey.com . The survey was a direct link from three separate websites including the Interstitial Cystitis Network, National Women’s Health Network, and Our Bodies Ourselves. Consisting of 37 questions, the questionnaire queried each patient about her demographics, symptoms, concomitant diagnoses, number of physicians consulted, treatments, and their perceived treatment outcomes. Informed consent was obtained via the internet. The patients were fully informed they were being surveyed for the purpose of a scientific study and that the results would be published. No written form was used. Specific information was obtained on the different procedures and medications used to treat IC and whether they perceived their condition as improved, not affected, or deteriorated. Data were collected over a 12 month period from December 2004 through December 2005 with a mean follow up of six months. Descriptive statistics were calculated. Person chi-squared tests were used to compare the percentage of patients who fell into each of the three groups based on their perceptions of each treatment; these were improved, no effect and made worse. SPSS statistical software (version 14.0, Chicago, IL) was utilized for the analyses.

RESULTS:

750 women with IC responded to our survey. Mean age: 39.7 years (SD+/- 12.5 yrs.). 94.2% were Caucasian, 3.0% Hispanic, 2.0% African-American and 0.8% Asian-American. 28.7% had seen <3 physicians, 53.2% had seen 4-10 doctors, and 12.1% had sought the opinion of more than 10 physicians. The number of doctors consulted directly affected the number of concomitant diagnoses; the most common diagnoses were urinary tract infection (55.2%), overactive bladder (27.6%), pelvic pain syndrome (15.3%), painful bladder syndrome and urethritis (13.5%), urethral syndrome (9.1%), and lower urinary tract syndrome (8.4%).

Invasive procedures and medical therapy were both surveyed. The most commonly performed invasive procedures for the 750 respondents in our survey were hydrodistention (61.9%), intravesical therapy (40.1%), and urethral dilatation (26.5%). The various procedures and their outcomes are listed in Table 1. The statistical comparison of the procedures revealed a significant difference among the three groups for all procedures except for urethrotomy (p=0.9). Equal numbers of patients were improved and made worse by the invasive procedures in all categories with the exception of cauterization which showed that patients were improved by this procedure, p=0.02. The percentage of patients reporting no effect as a result of all procedures ranged from 12.5-49.8%.

The survey also queried the types of the intravesical therapy agents utilized. The most commonly used intravesical treatments were DMSO, Cystistat (hyaluronic acid product) and heparin sodium. The perceived efficacy of the various intravesical agents is summarized in Table 2.

The most commonly used pharmaceuticals and their perceived efficacy are listed in Table 3. A comparison of the number of patients who improved to those who deteriorated was found to be significant for all drugs (p<.001). The majority of patients reported that medications improved their condition, perceptively. More patients reported improvement than no effect when pentosan polysulfate sodium, phenazopyridine, calcium glycerophosphate (Prelief; AK Pharma Inc., Pleasantville, NJ), amitriptyline and codeine were administered. The reverse was true when patients were given vistaril, tolterodine, oxybutynin, oxybutyninXL and diphenhydramine.

The percentage of patients discontinuing their IC medications due to intolerable side effects is also listed in Table 3. Overall, calicum glycerophosphate (Prelief), a food acid reducer, and phenazopyridine were the best tolerated.

Other medications that were used to treat IC included, narcotic and non-narcotic pain relievers, muscle relaxants, alpha blockers, histamine receptor 2 blockers, selective serotonin reuptake inhibitors, and antihistamines; all with negligible efficacy.

COMMENT:

Without a clinical or pathological definition, IC continues to challenge the field of Urology. Reports suggest the disease may affect as many as 9 million Americans with 90% of cases being female. 2 It is clear that the number of patients with IC continues to grow as awareness of the disease increases.

Our goals as physicians are to find therapies that are helpful to our patients. While many patients are being helped by our current treatments, we found that an equal number of patients perceive their condition to have deteriorated due to treatment. By surveying this cohort of patients, we attempted to gain insight into the various treatments and their perceived efficacies. Our study group suggests that traditionally recognized procedures for IC are perceived to be beneficial only 25-45% of the time.

Hydrodistention, intravesical instillation and urethral dilation have been the mainstay of treatment for IC. However, we found that less than half of patients improved with these traditional invasive therapies. Patients reported that their illness was made worse by these treatments 25-30% of the time. Glemain et al. found that prolonged hydrodistension (3 hours) performed on patients with initial bladder capacities of >150ml had a treatment efficacy of 37.7% at 6 months and 21.9% at one year. 3 This is consistent with our findings of 24.4% improvement with hydrodistension. Others have found no therapeutic value in the use of hydrodistention for IC. 4

Although urethral dilation had been used on 26.5% of our respondents, little had been written as to the efficacy of this procedure for IC. No prospective or retrospective studies were found in a review of the literature. Our survey found, of the 199/750 women that had undergone urethral dilation, 43.2% of them felt the procedure had no effect on their symptoms. Also, more patients were made worse with this procedure (30.7%) as compared to improved (26.5%). This leads us to the conclusion that urethral dilation is of no perceived therapeutic value in IC patients and leads to a deterioration in many patients.

Of the invasive procedures studied, intravesical therapy had the best perceived outcome. Bladder instillations were found to be beneficial 45.3% of the time; however 27.7% of patients were made worse by the treatment and 27.0% felt no effect. A Scandinavian study by Kallestrup et al. found that after three months of weekly instillations for one month and monthly instillations for two months with hyaluronic acid (Cystistat), 13/20 patients or 65% were found to be responders to the therapy. 5 However, only 20% were complete responders.

Other innovations in the treatment of IC include sacral neuromodulation. This procedure has shown improvement in patient symptoms in the literature, especially in refractory cases of IC. Our study showed that 56.3% of respondents that had sacral neurostimulation were improved. Comiter found, in a prospective study, that neuromodulation is a safe and effective means of treating refractory IC. In his study 25 patients were given a trial of sacral neurostimulation. 17 patients, (68%), showed a 50% improvement in frequency, nocturia, voided volume and average pain. 6 This result was also shared by Peters et al. who found that two-thirds of their patients undergoing the implant had moderate to marked improvement in their symptoms. 7

Less utilized procedures for the treatment of IC were evaluated in our study; cauterization (5.1%), urethrotomy/meatotomy(5.1%), and cryotherapy(2.0%). Cauterization for the treatment of IC has been used in the patients with Hunner’s ulcers. Greenberg et al. reported 61% of patients that underwent fulguration or resection of the bladder mucosa and submucosa were subjectively improved. Patients undergoing this procedure were symptom free for more than one year, n=28. 8 Our study correlated to this finding showing 55.3% of patients undergoing cauterization perceived improvement. Netto et al. postulated from his small series that internal urethrotomy was not effective in treating patients with recurrent cystitis. 9 However, Krietzer and Allen reported on 800 patients undergoing extensive urethrotomy (cold knife at 12,9,6 and 3 o’clock positions) for chronic cystitis and found 73% of their patients to be asymptomatic with a mean follow up of 22.4 months. 10 Unfortunately, no quantitative or subjective data were offered in this study to corroborate the findings. Although 2.0% of our patients had undergone cryotherapy, no case reports, reviews or scientific papers were found in the literature search for cryotherapy as a treatment for IC.

The superiority of medical therapy was not a surprising outcome of this study. Of all of the therapies surveyed, pentosan polysulfate sodium (PPS), had one of the best outcomes overall. 52.7% of the patients reported an improvement of their symptoms using PPS. Nickel et al. of the Elmiron study group found that the duration of PPS therapy, not the dosage, was the most important parameter in ameliorating symptoms of IC. Their trial tested PPS dosages of 300, 600 and 900 mg per day and found after 32 weeks that 49.6%, 49.6%, and 45.2% of patients were responders. 11 These results are similar to the result of our survey showing that 53.4% of patients reported an improvement in symptoms while taking PPS for their disease.

A mainstay in the medical arsenal of IC is amitriptyline. In 2004, van Ophoven et al. published data studying the safety and efficacy of amitriptyline in the treatment of IC. 48 patients were evaluated using the O’Leary-Sant IC symptom and problem index and was the primary parameter of the study outcome. The mean symptom score in the amitriptyline group decreased from 26.9 to 18.5 as compared to the placebo group with 27.6 to 24.1 (p=.005). 40% of the amitriptyline patients experienced a reduction in their symptom score. 12 In a 2005 follow-up study, van Ophoven et al. found a favorable overall therapeutic outcome in 46% of patients. 13 Our survey found similar numbers with 47.4% of responders stating that amitriptyline helped their symptoms.

A surprising finding in the survey was the number of women (40.1%) that had taken the over the counter medication, calcium glycerophosphate (Prelief). Calcium glycerophosphate neutralizes food acids. 60.7% of patients that had taken calcium glycerophosphate felt their symptoms were much improved. The side effect profile was superior to all medications surveyed. This unexpected finding lends credence to the theories of IC being caused by environmental irritants and allergy. However, on a review of the literature, no studies or anecdotal case reports have been published studying the efficacy of this food acid reducer. Calcium glycerophosphate may be a strong candidate for a new study designed to test the true efficacy in IC patients and its mechanism of action.

Phenazopyridine also had a large percentage of patients with improved symptoms, 57.3%. Phenazopyridine is commonly used for bladder analgesia and for 60% of patients, appears to offer relief from the symptoms of IC, again lending credence to the local irritant theory of the disease.

Our study had a large number of responders. However, due to the computerized nature of this English language survey, a socio-economic as well as language bias may be seen. Because the study was an internet based survey, the patients were self-selected and may have possibly been self-diagnosed. Our study did not survey the responders as to the length of time they had their disease or the severity of their disease. These parameters were not quantified. Our outcomes for the procedures and medical therapies were not qualified with symptom scores and pain indices. Also, our study did not look at the dosages or length of time that the drugs were taken by our responders. Although our study is limited by the nature of our self-reported data, the overall outcome is apparent. Future studies will have a standardized approach in the evaluation of the respondants.

Long term studies of the treatment options must be performed if any consensus is to come in the treatment of IC. 14 To treat these patients, a more sound mechanism of pathology must be elucidated and more aggressive treatment regimens delineated.

The invasive procedures looked at in our study appear to be perceived as less efficacious when compared to medical therapy. The invasive procedures also have a higher likelihood of causing a perceived deterioration as compared to medical therapy. Therefore, invasive therapies must be used with caution in IC patients.

CONCLUSION:

Medical therapy is perceived to be superior to invasive therapy in the treatment of IC. Medication should be considered the first line therapy for IC. A greater percentage of patients reported a perceived benefit from medical therapy versus invasive therapy. Calcium glycerophosphate (Prelief), an over the counter food acid reducing agent, has shown the greatest number of patients with improvement in symptoms and best tolerability from our survey.

Table 1

Table 2

Table 3

References

1. Hanno, PM: Interstitial Cystitis and Related Disorders,In Walsh, Retik, Vaughn, Wein (eds.) Campbell’s Urology 8 th EditionUSA, Saunders, vol 1, pp 631-670, 2002.

2. Curhan GC, Speizer FE, Hunter DJ, Curhan SG, Stampfer MJ: Epidemiology of Interstitial Cystitis: A population based study. J Urol 161:549-52, 2002.

3. Glemain P, Riviere C, Lenormand, Karam G, Bouchot O, Buzelin JM: Prolonged hydrodistension of the bladder for symtomatice treatment of Interstitial cystitis: efficacy at 6months and 1 year. Eur Urol 41(1):79-84, 2002.

4. Cole EE, Scarpero HM, Dmochowski RR: Are patient symptoms predictive of the diagnostic and/or therapeutic value of hydrodistension? Neurourology and Urodynamics 24 (7) 638-42, 2005.

5. Kallestrup EB, Jorgenssen SS, Nordling J, HaldT: Treatment of interstitial cystitis with Cystistat: a hyaluronic acid product. Scand J Urol Nephrol 39(2):143-7, 2005.

6. Comiter, CV: Sacral neuromodulation for the symtompatic treatment of refractory interstitial cystitis: A prospective study. J Urol 169(4):1369-73, 2003.

7. Peters KM, Carey JM, Konstandt DB: Sacral neuromodulation for the treatment of refractory interstitial cystitis: Outcomes based on Technique. Int Urogynecol J pelvic Floor Dysfunct 14(4):223-8, 2003.

8. Greenberg E, Barnes R, Stewart S, Furnish T: Transurethral resection of Hunner’s ulcer.J Urol 111:764-66, 1974.

9. Netto NR, Pimenta DaSilva R: Treatment of Recurrent Cystitis in women by internal urethrotmy or antimicrobial agents. Int Urol and Neph 12(3):211-15, 1980.

10. Keitzer WA, Allen JS: Operative treatment of chronic cystitis by urethrotomy: 10 years of experience.J Urol 103:429-31, 1970.

11. Nickel JC, Barkin J, Forrest J, Mosbaugh PG, Hernandez-Graulau J, Kaufman D, Lloyd K, Evans RJ, Parsons CL, Atkinson LE, Elmiron Study Group: Randomized, double-blind, dose-ranging study of pentosan polysulfate sodium for interstitial cystitis.

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12. 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 172(2):533-6, 2004.

13. van Ophoven A, Hertle L: Long-term result of amitriptyline treatment for interstitial cystitis. J Urol 174(5):1837-40, 2005.

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