Review of treatments for interstitial cystitis

Transcription

1 The University of Toledo The University of Toledo Digital Repository Master s and Doctoral Projects Review of treatments for interstitial cystitis Lindsey Ann Miller The University of Toledo Follow this and additional works at: This Scholarly Project is brought to you for free and open access by The University of Toledo Digital Repository. It has been accepted for inclusion in Master s and Doctoral Projects by an authorized administrator of The University of Toledo Digital Repository. For more information, please see the repository's About page.

2 Review of Treatments for Interstitial Cystitis Lindsey Ann Miller The University of Toledo 2011

3 ii Dedication I would like to dedicate this paper to my husband, Steve, my family, and all my friends. Your encouragement and support throughout the past two and a half years has meant so much to me. I know I would not have been able to make it this far without all of you and your love!

4 iii Acknowledgements I would like to acknowledge and thank my advisor, April Gardner, for all of her assistance and encouragement throughout this scholarly project. Thank you for taking all the time to read through my drafts and help me reach the end of this paper. I could not have asked for a better mentor and friend, and I truly appreciate your support more than you could know!

5 iv Table of Contents Introduction...1 Methods...12 Literature Review...13 Treatment Recommendations...62 Conclusion...65 References...67 Figures...80 Abstract...86

6 v List of Figures Figure Figure Figure Figure

7 1 Introduction Definition: Interstitial cystitis (IC) is a chronic, debilitating condition from which approximately 1.5 to 25 to 30 million women in the United States currently suffers (Myers, 2009). It is a condition that most commonly afflicts women and is characterized by bladder pain. Estimates of its prevalence vary widely because there are no diagnostic criteria for IC. Its current name is even debatable, often used interchangeably with Painful Bladder Syndrome (PBS) and Bladder Pain Syndrome (BPS). Historically, IC has been defined using the National Institute for Diabetes and Disease of the Kidney (NIDDK) criteria. However, this definition was actually created with the intent of defining IC for research purposes, not for clinical diagnosis, but since the disease has remained so difficult to define, many clinicians have resorted to utilizing the NIDDK criteria to diagnose patients with IC. In order to meet NIDDK criteria, the following criteria must be satisfied: diffusely present Hunner s ulcerations or glomerulations upon bladder hydrodistention with cystoscopy in addition to symptoms of bladder pain or urinary urgency. Furthermore, the presence of any of the following exclude the diagnosis of IC: symptoms present less than nine months; bladder capacity greater than 350 cubic centimeters (cc) on awake cystometry using either a gas or liquid filling medium; absence of an intense urge to void with the bladder filled to 11 cc gas or 150 cc water during cystometry using a fill rate of 30 to 100 cc per minute; the demonstration of phasic involuntary bladder contractions on cystometry using the fill rate described previously; absence of nocturia; symptoms relieved by antimicrobials, urinary antiseptics, anticholinergics, or antispasmodics; a frequency of urination, while awake, of less

8 2 than eight times a day; a diagnosis of bacterial cystitis or prostatitis within a three month period (Hanno, Landis, Matthews-Cook, Kusek, & Nyberg, 1999). A study involving 379 women was conducted to determine the practicality of the NIDDK definition in diagnosing IC clinically. All participants had not been diagnosed with any certain disease or etiology but did present with at least six months of urinary frequency, urgency, or pain. The researchers found that when utilizing strict NIDDK criteria, more than 60% (227) of participants who were considered by experienced study physicians to definitely or likely have IC would have been misdiagnosed. This shows that using such a restrictive definition is not suitable to use clinically as a large proportion of IC patients will be missed and likely suffer from delays in treatment (Hanno et al., 1999). Since the NIDDK criteria were widely considered too restrictive, a new definition for IC was developed in 2002 by the International Continence Society (ICS). They proposed using PBS instead of IC for suprapubic pain during bladder filling with associated symptoms like daytime and night-time frequency without infection or pathology. Patients who demonstrated the symptoms of PBS but were additionally found to have cystoscopic and histologic features on bladder cystoscopy examination could be described using the term IC. PBS was considered a clinical syndrome while IC was utilized as an exact diagnosis (Abrams et al., 2003). However, the ICS definition has been shown to fail in identifying all patients with IC. In a case-controlled study of 138 women diagnosed with IC within the last 12 months, only 91 (68%) were identified as having IC using the ICS definition. The researchers were confident that the 47 (34%) women who were excluded using the ICS definition truly did suffer from IC, and additionally, they had even been diagnosed with IC before enrolling in the study. Furthermore, it was shown that these women did not significantly differ from those who successfully met the

9 3 ICS definition when the groups were compared using 97 different variables (p<0.01) (Warren et al., 2006). The results of this study suggest that the ICS definition of IC must be broadened in order to adequately recognize all patients with IC. One way to accomplish this is to include bladder pain that is not only suprapubic or retropubic as defined by the ICS but to incorporate a broader definition using pelvic pain that additionally includes pain in the genital, rectal, and urethral regions. When incorporating all these types of pain, all 138 (100%) women in the study fulfilled these criteria. Therefore, when even minor adjustments were made in the ICS definition, it seemed to become increasingly sensitive and inclusive of more women with diagnosed IC (Warren et al., 2006). Yet another proposed definition was published and brought forth by the European Society for the Study of Interstitial Cystitis (ESSIC) in 2008, attempting to re-define the disorder in a way that is more consistent internationally. The ESSIC suggested the name IC be changed to BPS, diagnosed by chronic pelvic pain, greater than six months, pressure, or discomfort perceived to be related to the urinary bladder accompanied by at least one other urinary symptom such as persistent urge to void or frequency (van de Merwe et al., 2008). Furthermore, it is necessary to exclude any other diseases or conditions with similar symptoms that may be confused with BPS, and cystoscopy with hydrodistension should be performed on all patients, with biopsies when situationally indicated. Patients are then classified according to the severity of the cystoscopy and histologic findings, if performed (van de Merwe et al.). The definition of IC is constantly evolving. It is important to recognize these various definitions and be aware of their connotations. Further modifications will likely continue to develop in the future as research persists to determine the exact etiology and pathophysiology of

10 4 this disorder. Until one universally accepted definition is agreed upon, it is likely that all the different definitions will continue to be used in the literature and in clinical practice to identify patients with IC. Prevalence: Classically, IC is most commonly found in middle-aged women between 42 and 45 years old, although it may present at any age. Additionally, it is thought that IC is commonly underdiagnosed. A large, population based study of 184,583 women demonstrated that the prevalence of IC in the United States is more than 50% greater than previously reported in the literature. IC was diagnosed in approximately 60 per 100,000 cases. Women who took part in this Nurses Health Study completed questionnaires that contained self-reports of IC diagnosis which were then confirmed with medical record review. It is important for practitioners to recognize and diagnose IC because the average time the participants waited to be diagnosed was five to seven years. Delays in treatment can lead to a decreased quality of life since symptoms of IC can be very debilitating (Curhan, Speizer, Hunter, Curhan, & Stampfer, 1999). Another study done in Canada supports the fact that IC is much more prevalent than previously believed and is found in women more frequently than in men. When the medical records of 8,712 urology patients were examined, IC was found to be diagnosed eight times more often in females than in males (211 of 2,675 and 26 of 6,037, respectively). The prevalence of IC in the women who were studied was shown to be 7.9% (211 of 2,675), which was much higher than initially predicted by the researchers (Nickel, Teichman, Gregoire, Clark, & Downey, 2005). Other reports suggest that IC may be so common that one in every four to five women and one in every twenty men may have IC (Parsons, Kurth, & Sant, 2007). All these results support the idea that IC remains commonly underdiagnosed and therefore, should be

11 5 considered in the differential diagnosis of all patients, especially women, who present with IC symptomatology. Pathophysiology: Prevalence values for IC are often variable among different studies, and the main reason for this diversity is the lack of solid diagnostic criteria for the disease. Clinically, IC is typically diagnosed empirically and based upon each individual practitioner. It has been difficult to reach definitive criteria because the etiology and pathogenesis of IC remain unknown. It is likely that the population of patients who are diagnosed with IC are actually suffering from several separate conditions with different etiologies, making IC more of a syndrome. Various pathogenic mechanisms have been proposed which are believed to contribute to the development of IC symptomatology (Figure 1), which also remains highly variable as IC patients may have anywhere from mild to severe clinical manifestations. It is thought that any of these insults, whether discovered alone or in combination with others, have the ability to cause the symptoms of IC. One common pathology that is found in most patients with IC is an abnormal bladder urothelium, but it is not yet known whether these changes occur as a result or a cause of IC. Regardless, the urothelium is normally impermeable in unaffected individuals and does not allow irritative substances in the urine, such as potassium and ammonia, to leak outside of the bladder cavity. However, in patients with IC, bladder biopsies have shown an increased permeability of the urothelium. It is believed that leakage of these irritants may lead to underlying nerve and muscle tissue injury which contribute to the development of the irritative, painful voiding symptoms of IC (Slobodov et al., 2004).

12 6 Particularly, the glycosaminoglycan (GAG) layer is thought to be a very important and protective component of the urothelium. It is commonly damaged or defective in IC patients and exhibits lower levels of the chondroitin sulfate protein. A deficit in the GAG layer greatly impacts and impedes the differentiation and growth of the urothelium, preventing the tissue from repairing itself and regenerating after sustaining injury from toxic urinary solutes. This can lead to chronic inflammation from continual insults to the underlying nerve and muscle tissue, causing further activation and attraction of inflammatory cells (Hurst et al., 1996). These events involving chronic injury and inflammation can lead to an increase in the number of mast cells, which is a very common finding in patients with IC. The exact mechanism of mast cell activation and proliferation in IC is unknown, yet it is hypothesized that cytokines and other signaling proteins are released from the damaged urothelial cells, subsequently attracting the mast cells. Once mast cells are activated, they secrete proinflammatory and nociceptive substances like histamine, prostaglandins, and substance P (SP). These can cause vasodilatation of blood vessels, contributing to the painful symptoms of IC while activating more mast cells and maintaining this destructive cycle (Myers, 2009). Additionally, neuropathic pain is thought to be related to mast cell involvement and may lead to an upregulation of sensory innervation in the bladder (Theoharides, Kempuraj, & Sant, 2001). Another key component thought to be involved in the pathophysiology of IC is neurogenic inflammation which can be attributed to the release of acetylcholine (Ach) and SP mediated by mast cells. With these changes, the bladder becomes hypersensitive and upregulates its innervation, causing symptoms of pain and voiding dysfunction (Nazif, Teichman, & Gebhart, 2007). Also, the increased permeability of the bladder is thought to allow potassium to leak through. This causes depolarization of nerves and muscle, leading to more tissue injury

13 7 (Parsons, 2007). Eventually, neurons in the spinal cord and the central nervous system become excessively activated and lead to increased pain in other areas of the pelvis outside of the bladder, such as gynecologic and gastrointestinal organs and tissues. This helps accounts for other common symptoms and problems found in IC patients like dyspareunia, pelvic floor dysfunction, vulvodynia, and irritable bowel syndrome (Sant, Kempuraj, Marchand, & Theoharides, 2007). With all of the inflammatory changes that occur within the bladder as IC develops and progresses, fibrosis can occur and cause a decreased functional capacity, hindering the bladder s ability to hold normal amounts of urine. The bladder mucosa becomes thinned and denuded with small cracks and ulcerations in the urothelium. Fibrotic changes occur to the musculature as well, impeding the bladder s ability to properly fill and thereby contributing to the symptoms of IC (Hurst, Moldwin, & Mulholland, 2007). Along with the inflammatory events, urine leukocytosis has been observed in patients with ulcerative IC. A specific type of lymphocyte has been found in these IC patients but not in healthy subjects (Keay, Takeda, Tamaki, & Hanno, 2003). It is believed that this increase in leukocytes can lead to the obstruction of vascular or lymphatic vessels, contributing to fibrosis of the bladder wall (Hurst et al., 1996). Recently, a specific protein that is separate from the GAG layer was discovered that experts believe could be a major causative factor in the development of IC. Defective Tamm- Horsfall proteins (THP) have been found in patients with IC. This protein is thought to normally play a protective role in the urine, but in IC, the protein has a much less cytoprotective effect due to structural aberrations (Parsons, Stein, et al., 2007). More research will likely be done in the future to determine whether this protein could become a diagnostic marker for IC.

14 8 Another recent finding in the search to determine the etiology of IC has been the antiproliferative factor (APF) protein. Research has shown APF is expressed by urothelial cells in patients with IC but not in healthy patients. This protein promotes urothelial permeability and bladder hypersensitivity which can lead to symptoms of IC. Future research will likely continue to explore whether this protein could be used as a urinary diagnostic marker for IC. Its role in the pathogenesis of IC will also continue to be studied as it suggests the etiology to be an alteration in IC urothelial cells (Graham & Chai, 2006). The true etiology and pathophysiology of IC are believed to be multifactorial in nature, involving varying components of urothelial injury, mast cell activation, chronic inflammatory changes, leukocytosis, fibrosis, and hypersensitivity, with the most important central finding in IC patients being an altered bladder urothelium (Parsons, 2007). These events often occur cyclically in IC patients, leading to very debilitating symptoms. Research has yet to show an exact trigger responsible for the development of these changes and whether all these events occur in every patient with IC. Some inciting agents that have been proposed as possible triggers for IC are infections, toxic urine, or surgeries that block adequate blood flow to the bladder (Hurst et al., 1996). As research continues, it is believed that treatment for IC will shift from being empiric in nature to more targeted toward specific deficits and abnormalities found in patients with IC. Symptoms: The symptoms of IC are highly variable among individual patients, but the majority will complain of bladder pain with filling and emptying, urinary urgency, frequency, and usually nocturia. Most patients have mild to moderate forms of the disease while some suffer from severe symptomatology. The pain experienced by IC patients is not only found in the suprapubic

15 9 location of the bladder but can be anywhere in the pelvis and/or perineum including the urethra, lower abdomen, and lower back. Other symptoms commonly experienced with IC are vaginal burning and dyspareunia. Symptoms of IC tend to occur cyclically with alternating periods of flares and remissions. Sexual activity, the onset of the menstrual cycle, seasonal allergies, physical or emotional stress, and certain food and drinks are all common flares for bladder symptoms (Evans & Sant, 2007). Frequently, patients with IC suffer from comorbid conditions. Some of these comorbidities include irritable bowel syndrome, fibromyalgia, endometriosis, headache, and backache (Clemens, Meenan, O'Keeffe Rosetti, Kimes, & Calhoun, 2008). IBS is one of the most common disorders found concomitantly with IC, and it is estimated that 38-50% of patients with IC also fulfill diagnostic criteria for IBS (Ustinova, Fraser, & Pezzone, 2006). Other studies have shown an association with allergies and urinary incontinence. Problems with depression are also frequently seen in IC patients with some studies reporting 55-67% of IC patients suffering from depression. This is likely due to the fact that patients with IC wait an average of five years before being properly diagnosed (Teichman & Parsons, 2007). Additionally, it is believed that many men and women diagnosed with chronic pelvic pain are actually suffering from IC, which is the cause of their pain. IC is a diagnosis of exclusion that can commonly be suspected with a comprehensive history and physical examination. The medical interview should include questions aimed at discerning whether the patient has consistent symptomatology of IC, such as painful intercourse or triggers to their symptoms. The practitioner should ask about the existence of comorbid conditions that are commonly seen in IC patients. The physical examination should include examining for pelvic floor dysfunction (PFD) and pain upon bimanual examination in women or

16 10 digital rectal examination in men. If PFD or pain with either examination is found, a practitioner s suspicion should increase for IC. Laboratory blood tests and urine analysis with culture should show an absence of infection. A complete hematuria work-up is warranted in any patient that presents with hematuria (Evans & Sant, 2007). Diagnosis: There are several symptom questionnaires that exist which can be very helpful to a practitioner when diagnosing IC. The most widely utilized and recognized one is the O Leary- Sant Interstitial Cystitis Symptom Index and Problem Index (ICSI and ICPI, respectively). This questionnaire is useful in eliciting many pain and voiding symptoms and finding out how much of an impact these problems have on each patient s daily life (Evans & Sant, 2007). They are not meant to serve as screening tests for IC but rather as tools for clinicians to use as adjuncts in evaluation and management (O'Leary, Sant, Fowler, Whitmore, & Spolarich-Kroll, 1997). The Pelvic Pain and Urgency/Frequency Questionnaire (PUF) is a newer item which has been shown to be beneficial as it includes more symptoms related to IC than the O Leary-Sant indexes. It is typically considered a good screening questionnaire for IC. In practice, either questionnaire can be used as an aid in monitoring a patient s disease progression and response to IC treatment (Evans & Sant). Although it is not mandatory for diagnosis, bladder cystoscopy with hydrodistention is frequently performed in patients with suspected IC. This is especially important to perform in any patient with suspected bladder cancer as the procedure allows for tissue biopsy, if necessary. It also enables a clinician to determine what type of IC each patient actually possesses. In about ten percent of IC patients, this procedure will show Hunner s patches of the bladder mucosa, which is referred to as classic or ulcerative IC. In the vast majority of patients, glomerulations

17 11 will be found in the bladder wall, making this non-ulcerative IC type most common. (Lau & Bengtson, 2010) Regardless of the type, patients with IC will usually experience pain or discomfort upon filling of their bladders with hydrodistention and will demonstrate reduced bladder capacities (Evans & Sant, 2007). In summary, IC is a chronic, debilitating condition that appears to be increasing in prevalence. This is why it is so important for clinicians, including physician assistants, to be aware of this disease. IC should always be in a practitioner s differential diagnosis when any of the symptoms, such as irritative voiding problems, are reported by a patient. This paper will serve to provide physician assistants with an understanding of IC and to be familiarized with the various treatment modalities currently available to offer IC patients.

18 12 Methods PubMed was used to search the following terms combined with interstitial cystitis: etiology, pathophysiology, epidemiology, diagnosis, comorbidities, clinical presentation, treatment, pentosan polysulfate, amitryptyline, hydroxyzine, gabapentin, cyclosporine, montelukast, hydrodistention, physical therapy, dimethyl sulfoxide, intravesical therapies, intravesical pentosan polysulfate, intravesical resiniferatoxin, intravesical heparin, bacillus Calmette-Guerin, botox, increasing urinary voiding intervals, behavioral therapy, exercise, tibial nerve stimulation, sacral neuromodulation, acupuncture, endoscopic ablation, reconstructive surgery, hyperbaric oxygen, clinical phenotyping, suplatast tosilate, amphetamine, misoprostol, guided imagery, hyaluronic acid, intravesical alkalinized lidocaine, heparin and alkalinized lidocaine, chondroitin sulfate, intravesical liposome, and hypnosis. The Interstitial Cystitis Association s website was searched for interstitial cystitis diet and behavioral therapies. The American Urological Association s website was searched for treatment guidelines. Articles not available in English were excluded from this paper.

19 13 Literature Review Treatment Many different therapeutic modalities have been used to treat the symptomatology of IC. A true curative treatment is still unknown since definite etiologic agents and pathogenesis have yet to be identified. The definition of IC is even currently debatable. The major predicament concerning IC treatment modalities is the lack of concrete, high-quality, scientific evidence to support their use (Lau & Bengtson, 2010). A combination of nonpharmacologic and pharmacologic therapies is usually needed to target the various IC problems. Nonpharmacologic therapies involve diet and behavioral modifications, physical therapy, psychosocial support for patients and families, and controlling comorbidities. The classic pharmacologic treatments include oral medications and intravesical therapies. Surgery is typically considered a last resort. Classic treatment options will be discussed initially with the intent to develop an understanding of the therapies that are most supported by current evidence. Newer therapies will be presented subsequently, including possible new medications still in clinical trials. Using this information, a suggested approach to IC therapy for practitioners to consider utilizing when treating IC patients will be discussed last. What is the most favorable therapeutic regimen for clinicians to utilize when treating IC based on current literature, guidelines, and recommendations? Classic Treatments: Oral Medications Pentosanpolysulfate sodium (PPS), or Elmiron, is the only oral medication, approved in September 1996, by the United States Food and Drug Administration (FDA) for treatment of IC (Jepsen et al., 1998). It is one of the most studied IC therapies although it is still relatively new,

20 14 with the earliest published studies dating back to the 1980s. The mechanism by which PPS is believed to work is to restore the antibacterial and protective glycosaminoglyan (GAG) layer of the bladder that is thought to be damaged in IC patients (Parsons & Mulholland, 1987). When re-establishment of the GAG layer takes place, the symptoms of IC seem to alleviate as suggested by the majority of clinical studies involving PPS. One of the earliest double-blind, randomized, placebo-controlled PPS studies was conducted by Parsons and Mulholland (1987). When a total of 62 IC patients were assessed, a significant improvement in subjective symptomatology of pain, urgency, frequency, and nocturia was found in the PPS group compared to placebo (p=0.02, p=0.03, p=0.005, and p=0.04, respectively). The PPS group also demonstrated significantly higher average voided volumes than placebo (p=0.009), but there was no statistically significant difference found in the average number of daily voids between the two groups. Only one patient out of the 25 who took PPS for longer than 18 months did not experience symptom remission, showing that this therapy is effective long-term. This study helped to show the benefits that could come from utilizing PPS in treating IC. Another randomized, double-blind, placebo-controlled study showed similar results yet was slightly larger in size and multicentered. A total of 110 patients with IC were investigated for three months, and statistically significant improvements were found in the PPS group. When subjective assessment of overall improvement in symptomatology was evaluated, 28% (15) of patients taking PPS reported improvement compared to 11% (6) of placebo (p=0.04). Examination by blinded investigators assessing improvement in physical examination, voiding profiles, and pain and urgency scales produced similar significant results with 26% (14) of PPS patients showing overall improvement versus 11% (6) of placebo patients (p=0.03). The

21 15 researchers of this study concluded that PPS was an effective and safe therapy for IC as there were few side effects observed, and a significant proportion of PPS patients showed improvement in symptoms (Mulholland, Hanno, Parsons, Sant, & Staskin, 1990). Some of the most promising evidence that oral PPS is effective in ameliorating symptoms of IC was shown by a multicentered, randomized, double-blind, placebo-controlled prospective clinical study in which 148 IC patients were evaluated after three months of treatment. Statistically significant improvements were shown in various areas of symptomatology. Primarily, 32% (24) of patients on PPS reported significant overall improvement using a global assessment method versus 16% (12) of placebo patients (p=0.01). Significant improvements were also found in both pain and urgency (p=0.005 and p=0.04, respectively). Interestingly, this study also reported positive changes in sexual functioning and found that while on PPS, patients who were sexually active experienced and enjoyed a higher occurrence of sexual intercourse than placebo (31% versus 18%, respectively). Although these results only approached statistical significance (p=0.06), this part of an IC patient s quality of life is important to consider and is not always examined by researchers (Parsons et al., 1993). The previous study also showed that voiding profile changes, related to functional bladder capacity, are not substantially improved by PPS treatment alone, especially in the first few months of therapy, and this data has been confirmed by other studies (Holm-Bentzen et al., 1987; Mulholland et al., 1990; Parsons & Mulholland, 1987). A voiding profile is made by each individual patient by keeping a log of the time and quantity of all voids during waking hours, as well as the number of voids during sleeping hours (Parsons et al., 1993). PPS therapy alone cannot improve the often dysfunctional pelvic floor musculature found in IC patients, and

22 16 correcting PFD probably takes a long time. This may be explained by the fact that IC is both an insidious and slow-developing condition (Parsons et al., 1993). Nevertheless, PPS has been shown to be effective and safe in relieving symptoms in some IC patients. A few studies have attempted to evaluate the long-term effectiveness of PPS. These studies followed IC patients for a longer length of time compared to most previously short-term, three month studies. The studies ranged from 32 weeks (Nickel, Barkin, et al., 2005) to 35 months (Hanno, 1997) and 96 months (Jepsen et al., 1998). Two of the three studies were successful in demonstrating that a longer duration of PPS treatment correlated with various symptom improvement in regards to pain, urgency, frequency, and nocturia (Hanno, 1997; Nickel, Barkin, et al., 2005). The study by Jepsen et al. (1998) was unable to demonstrate significant efficacy of long-term PPS therapy. The multicentered, randomized, double-blind, parallel-group study of 380 IC patients by Nickel et al. (2005) was conducted over 32 weeks to determine if symptoms of IC would be alleviated more effectively by 600 and 900 mg of PPS, daily doses two to three times higher than the current recommended dose, 300 mg per day. Patients were assessed using the ICSI at baseline in addition to the Patient s Overall Rating of Symptoms Index (PORIS) questionnaire throughout the study. The PORIS assesses the patient s subjective overall change in their IC condition, pain, and urgency after treatment. No statistically significant differences were observed in the patients responses to the three different dosages, showing that there was not a dose dependent response to treatment. Mean ICSI scores improved significantly for all three dosages throughout the study (p<0.001). The greatest improvements in symptomatology were reported at the end of 32 weeks with 49.6% (182), 49.6% (182), and 45.2% (166) of patients being positive responders according to their PORIS scores at a dose of 300, 600, and 900 mg,

23 17 respectively. This is compared to 21.1% (71), 17.0% (57), and 15.8% (53) being responders after four weeks of treatment at a dose of 300, 600, and 900 mg, respectively. This study showed that greater improvements in symptomatology were observed in patients after a duration of 32 weeks of therapy that was not dependent upon the dose of PPS. Another study that demonstrated the benefits of long-term PPS therapy was conducted by Hanno (1997) and was open-labeled. Over the course of ten years, IC patients purchased three month supplies of PPS and could electively continue treatment as long as every three months, they completed symptom questionnaires, laboratory assessments, medical examinations, and reported any adverse events. The maximum duration of reported therapy was 35 months, and patients were required to undergo treatment for at least three months to be included in the study. Participants were enrolled continuously throughout the length of the study so the length of treatment varied with each patient. A total of 2,809 IC patients initiated PPS therapy throughout the study. The results showed that 42% (1,179) to 62% (1,741) of patients reported a moderate improvement or better change in both their overall IC condition and their overall pain as the duration of therapy increased. The greatest number of participants experienced pain relief after 29 months of therapy. Additionally, the greatest number of patients who reported a decline in urgency was 56% (1,573) after 29 months of treatment, showing that improvements in urgency also occurred in a duration-dependent fashion. More patients, 58% (1,629), expressed an improvement in the severity of their pain after at least 17 months of treatment compared to 50% (1,404) in the first five months. Improvements in nocturia were also demonstrated in a duration-dependent manner with 83% (2,331) reporting at least one less void per night after 17 months of therapy. This

24 18 study was successful in demonstrating that many symptoms of IC can be controlled more effectively with long-term PPS therapy. Another study by Jepsen et al. (1998) involved the long-term use of PPS therapy and was similar in design to the study by Hanno (1997) in that it was a compassionate use study. However, the study s main objective was not necessarily to determine the effectiveness of longterm PPS treatment but to analyze baseline parameters in an attempt to characterize long-term responders (Jepsen et. al, 1998). The researchers wanted to see if certain baseline characteristics of IC patients would predict long-term response to PPS therapy. The 97 IC participants were required to complete baseline questionnaires, and they were followed for as long as they elected to continue the treatment during the eight year study. The results showed that patients used oral PPS an average of 12.3 months. Only one statistically significant correlation of less constant pain at baseline could be associated with a favorable response to long-term PPS therapy (p=0.04). This was the only baseline characteristic that could be used to predict favorable outcomes with long-term PPS use. The researchers also concluded that between 6.2% (6) and 18.7% (14) of patients benefited from long-term therapy although it is important to note that this study did not specifically seek to measure the effectiveness of long-term PPS use. Nevertheless, this study was not successful in demonstrating a significant benefit from long-term PPS treatment. While the majority of research indicates that PPS is effective for IC patients, a study by (Holm-Bentzen et al., 1987) reached the conclusion that oral PPS was not more clinically significant than placebo. Following a total of 115 IC patients, this four month study was doubleblinded, multicentered, and placebo-controlled. This study evaluated the patients by IC symptoms, urodynamics and cystoscopy with hydrodistension, and bladder biopsies before and

25 19 after the trial. The only statistically significant improvement that was shown in the PPS group was increased bladder capacity as demonstrated by cystoscopy (p<0.05). No statistically significant improvements were shown in any of the measured IC symptoms, including pain, dysuria, frequency, and nocturia when PPS was compared to placebo. The bladder biopsies were also not significantly different between the treatment and placebo groups. As with many IC treatments, current clinical studies are usually small and often produce conflicting conclusions. This is true of research regarding oral PPS despite that it is FDAapproved to treat symptoms of IC. However, the majority of studies show PPS to be both safe and effective for most IC patients making it a sensible therapeutic modality to try. Current studies suggest beneficial effects, especially with long-term oral PPS use. The tricyclic antidepressant, amitriptyline, is one of the most frequently used oral medications to alleviate symptoms of IC (van Ophoven, Pokupic, Heinecke, & Hertle, 2004). Its pharmacology is complex but can generally be described by three mechanisms. First, it is an anticholinergic both centrally and peripherally which causes bladder relaxation. Next, it selectively blocks reuptake of serotonin and noradrenaline at the presynaptic membrane of the nerve leading to increased levels of both substances. Lastly, amitriptyline is believed to have a sedative effect due to central actions or possibly antihistamine properties, which would also help explain its usefulness in treating IC. Even though it is very commonly prescribed for IC patients, the literature regarding the use of this medication for this condition is slightly conflicting. In most studies, some researchers have found it to be effective at statistically significant levels in treating irritative bladder symptoms while one study did not find substantiated beneficial effects (Foster et al., 2010).

26 20 A multicenter, randomized, double-blind, placebo controlled clinical trial conducted by Foster et al. (2010) from February 2005 to October 2007 studied the effects of amitriptyline when used by IC patients who were naïve to treatment. The median age of participants was 38 years with the majority being Caucasian women. A total of 271 patients were randomized, and 231 (85%) completed twelve week follow-up with completion of a 7-point global response assessment (GRA) to determine the overall impact of symptoms. The GRA asks patients how their overall symptoms currently rate compared to how they were at the beginning of the study. According to the GRA, responders would be considered those who reported marked or moderate improvement. Subjects were randomized in a 1:1 ratio to either the amitriptyline or placebo group. Each group was instructed to comply with an educational and behavioral modification program (EBMP) throughout the study targeted at bladder training plus diet, symptom, and fluid management. This ensured that a minimal level of care was received by the placebo group. Over six weeks, the daily dose of oral amitriptyline or placebo was increased weekly until tolerable then maintained until 12 weeks after beginning the study (Foster et al., 2010). Results after 12 weeks of treatment failed to show a significant difference in symptom improvement according to the GRA between the amitriptyline and placebo groups. In the subset of patients who tolerated a daily dose of at least 50 mg of amitriptyline, there was a significantly higher response rate when compared to placebo (p=0.01) although higher response rates were reported for both groups as doses increased. According to the researchers, this significant finding may not be directly due to the actual efficacy of amitriptyline and could be attributed to bias. Therefore, despite the relatively large size and strong design of this clinical trial, alone it

27 21 does not demonstrate that amitriptyline is a significantly effective treatment for IC (Foster et al., 2010). Although the study above did not find high-quality evidence proving amitriptyline is useful in treating IC, several other studies have reached different conclusions. One of these was a well-designed clinical study by (van Ophoven, Pokupic, et al., 2004) in Germany which produced results in favor of amitriptyline. This prospective, double-blind study followed 48 patients, the majority being women, who met NIDDK criteria for IC. After being randomized in a 1:1 ratio into the amitriptyline or placebo group, all participants began a once daily dose of 25 mg at bedtime. They were permitted to increase dosage in defined intervals up to 100 mg as tolerated. After four months, the patients symptoms and improvement were evaluated. Supporting amitriptyline, a statistically significant decrease in mean symptom score was found in its group compared to placebo (p=0.005) in addition to a statistically significant improvement in pain and urgency (p<0.001) versus placebo. These results support using amitriptyline for symptoms of IC (van Ophoven, Pokupic, et al., 2004). Similarly, a long-term prospective observational study completed by (Hertle & van Ophoven, 2010) between October 2001 and September 2004 produced results in favor of amitriptyline. A total of 94 participants were divided into two groups: 59 who met NIDDK symptom criteria for IC and 35 who had a purely clinical diagnosis of IC and met at least one NIDDK exclusion criteria (non-niddk). These patients were permitted to remain on their current baseline IC therapy but were discouraged from beginning any new treatment regimen while in the study.

28 22 Participants were instructed to take amitriptyline each night at bedtime and were free to increase the dosage if tolerable. The average follow-up was 19.0+/-12.5 months, and 60 patients (64%) responded at this time. Forty-six percent (43 patients) reported either excellent (15%) or good (31%) overall satisfaction with the drug s therapeutic effect, and the average dose taken by participants was 55mg. The following symptoms improved significantly from baseline: pain intensity (p=0.002), urgency (p=0.004), daily frequency (p=0.021), and functional bladder volume (p=0.039). There was no statistically significant difference in the response rate or clinical response to symptoms between the two groups thereby suggesting that amitriptyline treatment is appropriate for either set of patients (Hertle & van Ophoven, 2010). The most common side effects of amitriptyline are anticholinergic and antimuscarinic in nature. Dry mouth (79%) and weight gain (59%) were reported by 84% of patients. The authors suggest beginning with a low dose and only taking at bedtime to help cope with these nearly inevitable drawbacks. Additionally, the drug is metabolized by the liver so it is crucial to monitor liver enzymes at least once per year when used long-term to avoid adverse events. Despite these side effects of amitriptyline, this study shows that it is a safe, reasonable, and useful medication to relieve irritative bladder symptoms such as pain, urgency, frequency, and functional bladder volume in patients with IC (Hertle & van Ophoven, 2010). While the results of various trials for using amitriptyline do not all corroborate perfectly with one another, the majority have shown it to be an effective oral medication to treat symptoms of IC. However, there is no study to compare the effects of PPS and amitriptyline to show which is more efficacious. This should be conducted in the future to help guide practitioners in choosing between these two frequently prescribed oral medications for IC (Lau & Bengtson, 2010).

29 23 Another oral therapy that has been used for treating IC symptomatology, but is not as well studied as PPS or amitriptyline, is hydroxyzine. This is an H1-receptor antagonist that blocks mast cell degranulation to prevent histamine release. Excessive mast cells are thought to play a role in IC pathogenesis making hydroxyzine a rational therapy. However, only one randomized clinical trial has been performed to test its effectiveness, in addition to a single case study. The only randomized clinical trial by (Sant et al., 2003) was a 2x2 factorial study design that tested the effectiveness of oral PPS alone, hydroxyzine alone, and the combination of the two against placebo. Out of the total 121 participants who were randomized for the study, only 79% (96 patients) completed follow-up at 18 months. No statistically significant improvement in symptomatology was reported for hydroxyzine or PPS therapy although a nonsignificant trend of benefit was found in the PPS only group. A higher percentage of patients responded in a positive manner to combination therapy, but it was also not statistically significant. The case study that did show positive results of hydroxyzine was open-label study compiled by (Theoharides & Sant, 1997). In it, 140 patients were prescribed hydroxyzine by their doctor and given a visual analog scale to rate their overall response and severity of the following symptoms: frequency, nocturia, burning/pain, pressure, and painful intercourse. Only 90 (65%) patients returned the standardized form, and 75 patients were found to have an allergic medical history. Overall, the patients reported a 40% reduction in symptoms when hydroxyzine was taken for at least three months, but when only the subgroup of patients with an allergic history were measured, a 55% symptom reduction was found. Results of this case study suggest hydroxyzine may be a useful oral drug in treating symptoms of IC. It appears to work best in

30 24 patients with a history of allergies including allergic rhinitis, food or drug allergies, asthma, contact dermatitis, and eczema. Larger placebo-controlled clinical studies are needed in order to gain high-quality evidence regarding hydroxyzine s ability to treat IC. The only randomized placebo-controlled clinical trial failed to show statistically significant results to support its use while a small case study did reveal statistically significant results. It is too early to conclude that hydroxyzine is an effective drug for treating symptoms of IC because there is not enough scientific evidence to encourage its use. Pentosan polysulfate sodium, amitriptyline, and hydroxyzine are considered to be the most studied treatments for IC, however, there are other oral agents that are utilized by prescribers in an effort to relieve IC symptoms (Lau & Bengtson, 2010). Since an exact etiologic agent and the pathophysiology of IC have yet to be defined, it seems reasonable to attempt different agents. The medications discussed below have been shown to help some patients with IC improve, but the literature and clinical trials surrounding each one is still substandard. The antiepileptic, gabapentin, is one such agent. No clinical trial has been conducted to determine its efficacy in treatment of IC, but a few case studies have reported its ability to improve IC symptomatology, specifically, associated perineal and bladder pain. (Hansen, 2000) reported two cases in which women who suffered from IC-related pain had considerable improvement in both their pain and ability to function in daily life once they began a regimen of oral gabapentin. (Takatani, Takeshima, Okuda, Miyakawa, & Noguchi, 2009) also reported a case in which a long-suffering woman with IC had failed multiple other therapies but found extraordinary pain relief with gabapentin. Her visual analogue scale (VAS) score for pain went from 100 down to 20. Any type of symptom can be evaluated using a visual analogue scale. It is

31 25 continuous, ten centimeter horizontal line that extends between two endpoints. A common example is the pain scale that asks patients to rate their pain on a one to ten scale, with ten being the highest amount of pain possible and one describing the least amount of pain. The patient marks the severity of their symptom on the scale, and a value for the VAS score is made by measuring, in millimeters, how far their mark is from the left-hand side of the scale. The most appealing features of gabapentin are its high efficacy yet low side effect profile with drowsiness and nausea being most common. It has been shown to be a very safe and effective drug in pain treatment which makes it an alluring choice to help IC patients who typically suffer from bladder-associated pain (Hansen, 2000). Further research into this medication is warranted and should be conducted as it appears to be a promising therapy that could potentially help many suffering IC patients. An autoimmune component has been implicated in IC etiology which has prompted the investigation of immunosuppressant therapy as treatment. Cyclosporine A (CyA) is one of these recognized agents, and recent studies have shown it to be a very promising drug for IC. For example, a retrospective analysis done from 1993 to 2001 that followed 23 IC patients who used CyA for at least one year found exceptional results in favor of CyA. Twenty patients reported no pain at all, daily voidings were decreased significantly (p<0.001), and the maximal bladder volume and mean voided volume both increased at statistically significant levels (p<0.001 and p<0.001, respectively). Symptoms seemed to be cured but returned in most patients within a few months once CyA was discontinued (Sairanen, Forsell, & Ruutu, 2004). Another randomized clinical study with 64 patients compared the efficacy of CyA and PPS over a duration of six months. Participants were naïve to previous CyA use but refractory to other IC therapies. Researchers discovered that CyA had superior efficacy at statistically

32 26 significant levels in all measured outcomes including voiding frequency (p<0.001), maximum bladder capacity (p=0.003), mean voiding volume (p<0.001), nocturia (p<0.001), O Leary-Sant symptom score (p<0.001), IC symptom and problem index (p<0.001), and VAS (p<0.001). At the six month follow-up, there was a significantly higher GRA clinical response rate in the CyA arm (75%, 22 patients) compared to PPS (19%, six patients) (p<0.001) (Sairanen et al., 2005). The above mentioned studies indicate that CyA has the potential to be a very efficacious drug in treating IC. The fact that CyA was shown to be superior to PPS in one study should prompt future researchers and pharmaceutical companies to explore the rationale supporting its use. One major pitfall of CyA is that it can raise blood pressure and serum creatinine, so vigilant surveillance is crucial (Sairanen et al., 2005). Nevertheless, CyA should continue to be researched and considered a possible therapy option, especially for severe IC, due to the promising results it has shown thus far. Montelukast, a leukotriene receptor antagonist, is another oral medication that has been found useful to treat IC. Leukotrienes are thought to be involved in inflammation and are released by mast cells and eosinophils, all of which have been linked to IC symptoms and pain. However, though this drug seems to be a rational therapy, only one clinical study has been conducted to test its effectiveness. Lasting three months, this trial involved ten women who were diagnosed with IC and showed statistically significant improvement in daily urinary frequency (p=0.009) and VAS measured pain (p=0.006). No control group was utilized, and all ten women completed daily therapy with montelukast (Bouchelouche, Nordling, Hald, & Bouchelouche, 2001). Although quite small, this study suggests that montelukast may be a successful agent and should be studied more thoroughly in the future. Hydrodistention

33 27 Cystoscopy with hydrodistention has classically been used not only to treat IC, but to help diagnose the condition as well. Bladder tissue can be biopsied during the procedure, and this is important in excluding the presence of bladder cancer since IC is primarily a diagnosis of exclusion (Ottem & Teichman, 2005). Some researchers even regard hydrodistention as first line IC therapy (Yamada, Murayama, & Andoh, 2003). As was the case with IC oral medications, clinical studies on hydrodistention are few in number and possess some conflicting results. Exactly why hydrodistention helps alleviate IC symptomatology remains unclear, but a proposed theory suggests that expansion of the bladder wall decreases pain by disrupting sensory innervation. Other theories propose that the procedure may stimulate the GAG layer to grow again (Yamada et al., 2003). As with other treatment modalities for IC, a drug or therapy s precise mechanism of action is difficult to determine as etiology remains unknown. Regardless of how it works, hydrodistention has been shown by a number of studies to alleviate symptoms. Recent reports will be presented below to reveal the efficacy of this very common IC intervention. A study of 52 IC patients treated with adjuvant hydrodistention under epidural anesthesia carried out by Yamada et al. (2003) showed five participants (about 10%) to be good responders, defined as greater than or equal to three years without requiring additional treatment, and 30 to be moderate responders, defined as three months to 1 year without symptoms. Overall, about 70% (36) of participants reported effective therapy via hydrodistention, and close to 60% (31) had no symptoms for 3-12 months. Although researchers were expecting a higher number of good responders, this study did show that hydrodistention is an effective therapy to alleviate IC symptoms.

34 28 Another clinical study that produced similar results involved evaluation of 30 patients with IC. A local anesthetic introduced into the bladder was used versus an epidural which was used in the previously mentioned study. This method was shown to be both safe and effective with 71% (21 patients) reporting positive therapeutic outcomes one month after hydrodistention. These results were statistically significant for the following symptoms: improved O Leary-Sant ICSI and IPSI scores (both p<0.0001), increased minimum, maximum, and average voided volumes (p<0.0001, p<0.0005, and p<0.0001, respectively), and decreased daily frequency (p<0.0001). This study continues to support the use of hydrodistention as an effective IC treatment (Aihara et al., 2009). Another study examined the improvement in symptoms of 33 IC patients who were naïve to other treatments and underwent cystoscopy with hydrodistention under general or regional anesthesia. One month later, the median University of Wisconsin (UW) symptom score was found to be decreased significantly (p<0.001). The UW score asks patients to rate the extent to which they are experiencing symptoms that day and includes seven bladder items, each scored from zero, none or not at all, to six, a lot (Erickson et al., 2007). The seven symptoms of IC that the UW scale includes are burning sensation in the bladder, urgency to urinate, going to the bathroom frequently during the day, bladder discomfort, bladder pain, getting up at night to go to the bathroom, and difficulty sleeping because of bladder problems (Keller, McCarthy, & Neider, 1994). The total UW score ranges from zero to 42 and is the sum of the scores for each of the seven symptoms. In addition, at least 30% improvement in UW score was reported by 12 patients (36%), at least 50% improvement by eight patients (24%), and only two patients (6%) reported at least 80% improvement in overall UW symptom score. These results suggest that

35 29 although hydrodistention appears to help some patients gain symptom alleviation, only a few benefit substantially with at least 80% improvement (Erickson et al., 2007). A study that demonstrated only mild efficacy with utilizing hydrodistention involved 47 participants who underwent cystoscopy with hydrodistention. Follow-up was completed by 43 patients, and it was found that a 56% improvement in symptomatology resulted, lasting an average of two months. This was not considered to be substantially long-lasting therapy, and only a little over half of the patients experienced any symptom relief. Therefore, this study does little to support the idea that hydrodistention should be regarded as first-line treatment in IC patients (Ottem & Teichman, 2005). It can be concluded that, as with most other IC therapies, cystoscopy with hydrodistention should be further researched in order to determine its therapeutic efficacy. However, cystoscopy should always be performed to rule out bladder cancer when suspected (Ottem & Teichman, 2005). The majority of studies thus far show that hydrodistention does relieve many symptoms of IC. It will likely become more common to utilize hydrodistention in the future as scientists gain a better understanding of the mechanism behind its therapeutic actions. Physical Therapy Some estimate that up to 80% of IC patients have associated high-tone pelvic floor dysfunction (PFD) which can lead to dyspareunia, pelvic pain aggravated by extended sitting or vigorous physical activity, and impaired emptying of the bladder and rectum. It is therefore feasible to predict that a transvaginal approach to manually relax the pelvic floor musculature by utilizing the Thiele massage may help alleviate some of these IC symptoms. The Thiele technique involves the practitioner applying a tolerable amount of pressure from the muscle s

36 30 origin to insertion 10 to 15 times during a session, and if deemed necessary, 10 to 15 seconds of ischemic compression to trigger points. Muscles are massaged in the following order: coccygeus, iliococcygeus, pubococcygeus, and obturator internus (Oyama et al., 2004). Using this rationale, a prospective clinical pilot study conducted by Oyama et al. (2004) set out to determine the effectiveness of Thiele massage in 21 women who were diagnosed with IC using Interstitial Cystitis Database criteria. All subjects possessed high-tone PFD found initially on vaginal examination with documented tender pelvic floor musculature, or hypertonus, of the coccygeus, iliococcygeus, pubococcygeus, and obturator internus muscles. Subjective tenderness was measured using a 5-point, 0-to-4 scale. The women were then assessed for appropriate sacroiliac alignment by a physical therapist, and the following questionnaires were completed by each participant: O Leary-Sant Interstitial Cystitis Symptom and Problem Indexes (ICSI and ICPI) (Figure 3); Likert Visual Analogue Scales for urgency and pain; and Short-Form 12-item (SF-12) Quality-of-Life Scale. Therapy using the intravaginal Thiele technique was performed twice each week for five weeks with at least two days between each session so discomfort or inflammation could subside. All ten massages were completed by one of three qualified women s health nurse practitioners with each session lasting about five minutes. Within two weeks of the final treatment, the women completed the same questionnaires and underwent vaginal examinations to record pelvic floor tenderness. A statistically significant improvement was seen in the average ICSI and ICPI scores (p=0.015 and p=0.039, respectively), the average Likert Visual Analogue Scales for urgency and pain (p=0.001 and p=0.005, respectively), the average Physical and Mental Component Summary of the SF-12 Quality-of-Life Scale (p=0.049 and p=0.042, respectively), and the average modified Oxford Scale which showed statistically significant pelvic floor tone

37 31 improvement in all of the four muscles (p<0.05). These results were maintained five months later in a follow-up study with the exception of the coccygeus musculature (Oyama et al., 2004). Although rather small, this study demonstrates that Thiele massage in IC patients with high-tone PFD is a promising therapy. It is highly effective in decreasing irritative bladder symptoms and reducing pelvic musculature tone. Future studies should be larger in size with longer follow-up to gain a better understanding of optimal Thiele massage use and technique (Oyama et al., 2004). A smaller clinical study of only ten women with IC showed similarly positive results. Subjects were treated with six intravaginal massage sessions using a deep vaginal Thiele massage approach referred to as the stripping technique. Both this technique and a myofascial release, applying pressure for eight to twelve seconds over a trigger point, were performed over the obturator internus, levator ani, and piriformis muscles. An improvement in urgency, pain, and frequency and/or nocturia was reported by 90% (9) of participants. Furthermore, substantial improvement in the ability to contract and relax pelvic floor muscles was demonstrated by physical examination. Statistical significance was not reported. These findings help to further support the use of an easy and noninvasive internal Thiele massage technique to help relieve symptoms of IC (Holzberg, Kellog-Spadt, Lukban, & Whitmore, 2001). Another study shows comparable results when manual physical therapy is used to treat symptoms of IC related to PFD. Sixteen females with a mean age of 42.5 years with IC, hightone PFD, and sacroiliac dysfunction were treated with manual therapy an average of 8.72 times. However, this trial also took into account sexual dysfunction unlike previously mentioned studies. Researchers observed a 94% improvement in dyspareunia, and nine of sixteen patients were able to have pain-free intercourse. Additionally, a 94% improvement in symptoms,

38 32 especially of frequency and suprapubic pain, was demonstrated. Statistical significance was not reported. These are more results that help show how useful manual physical therapy can be to patients with IC, especially when symptomatology consists of dyspareunia, frequency, and suprapubic pain (Lukban et al., 2001). While manual physical therapy, particularly use of the Thiele massage, seems to ameliorate IC symptoms, there are some drawbacks to its use. The main issue is that experienced physical therapists or practitioners are necessary in order for the massage to be performed correctly, and these professionals may be difficult to find in certain communities. Without proper technique, patients may not experience an adequate amount of symptom relief. However, in circumstances where qualified individuals can successfully apply the Thiele massage to IC patients, this approach should be considered as current studies have shown promising results and improvement in IC symptomatology. Biofeedback therapy can be a useful adjunct to physical therapy in relaxing high-tone pelvic floor musculature (Dell & Parsons, 2004). Although there are no reports in the literature of biofeedback therapy and its impact on IC symptomatology, it is a tool that physical therapists may use to enhance the treatment of PFD. Using biofeedback may improve the effectiveness of the muscle relaxation efforts while strengthening weak pelvic muscles, thus reducing pain (Newman, 2000). The Interstitial Cystitis Association (ICA) also suggests the use of biofeedback to help patients learn how to relax their pelvic floor musculature. Intravesical Therapies Since IC is primarily a disease of the bladder, many different intravesical treatments have been used in an attempt to alleviate symptoms. The only FDA-approved agent is dimethyl sulfoxide (DMSO) whose mechanism of action is still unclear (Lau & Bengtson, 2010) although

39 33 hypothesized to be anti inflammatory, analgesic, and neuromodulatory in nature (Perez-Marrero, Emerson, & Feltis, 1988). Although DMSO has been evaluated in multiple studies, only one placebo-controlled clinical study has been performed to test its effectiveness (Lau & Bengtson, 2010). This study was conducted on 33 individuals with IC and had a crossover design in order to better compare the efficacy of DMSO to placebo of normal saline and to determine if any improvements obtained by DMSO administration would continue with time. Patients underwent four intravesical treatments every two weeks in phase one and then rested for a month before undergoing crossover in phase two. At the end of phase one, 93% (14) of the patients who were treated with DMSO showed objective improvement compared to 35% (6) of placebo. Statistical significance was not reported. Subjective improvements were found in the DMSO group and were statistically significant (no p values given). After phase one, 40% (6) of the treatment group reported marked improvement versus 18% (3) of the placebo group. Additionally, at the end of phase two, 53% (8) of the patients who originally were treated with DMSO reported maintenance of marked symptom improvement, and 47% (7) of patients initially treated with placebo had marked improvement while undergoing DMSO instillations (Perez-Marrero et al., 1988). Although small, this study shows that with DMSO intravesical therapy, symptom alleviation occurs in a significant number of IC patients. One unavoidable side effect of DMSO is strong garlic halitosis which one could argue would make placebo-control of a DMSO study difficult. Even though patients in the study are not supposed to know whether they are treated with DMSO or placebo, it is likely that they would know if they were treated with DMSO because of this obvious side effect. The previously described study reported that control was

40 34 exerted by blinding the individuals who assessed objective response. This means that the researchers collected all urodynamic data of the patients, including two-day voiding charts, and had evaluators who were otherwise completely uninvolved in the study assess the data for improvements. Nevertheless, the improvement in symptomatology cannot be denied, and DMSO therapy seems to be a reasonable option for some IC patients (Perez-Marrero et al., 1988). A more recent study helped to support the use of DMSO as IC treatment. It involved a retrospective review of medical charts belonging to 28 IC patients who had been treated with at least one DMSO instillation. These patients were then interviewed over the telephone to evaluate whether or not they were still experiencing relief from their DMSO therapy. The researchers found that in some patients, the residual effects of DMSO therapy were experienced up to months later. However, side effects were also commonly observed, and the most frequent one was transient urethral irritation or pain after initial DMSO instillation reported by 48% (13) of patients. Other side effects were transient and short-lived, including nausea, fever, chills, and hematuria. While not pleasant, the majority of DMSO side effects are mild, and the benefit patients experience in symptom relief likely outweigh these minor drawbacks. Therefore, DMSO should be considered as therapy in IC patients (Rossberger, Fall, & Peeker, 2005). Another commonly utilized intravesical agent is PPS, a heparin analogue structurally identical to the previously mentioned FDA-approved oral medication for IC treatment. The proposed mechanism of action is the same as the oral formulation, and it is believed to replace the protective GAG layer in the bladder urothelium that is damaged in IC patients. Although not as convenient as an oral medication, direct instillation of PPS into the bladder is proposed to be

41 35 faster in alleviating the symptoms of IC, making it an appealing treatment modality (Davis, El Khoudary, Talbott, Davis, & Regan, 2008). There is currently only one study that has tested the effectiveness of intravesical PPS by comparing it to placebo. Conducted in the Netherlands, a total of twenty female IC patients were randomized into two groups and received either PPS or placebo intravesically twice a week for three months. The results only showed a statistically significant improvement in urodynamic bladder capacity in patients treated with PPS (p=0.047). All other measured outcomes did not reach statistical significance although 18 months after the beginning of the study, eight patients who were still being treated with PPS reported an overall improvement in symptom relief compared to four patients without treatment. Though this small study was not able to show much evidence of symptom relief that was statistically significant with use of intravesical PPS, it should be noted that a few patients did experience successful symptom amelioration with its use (Bade, Laseur, Nieuwenburg, van der Weele, & Mensink, 1997). Another small, open-labeled, uncontrolled study looked at the results of PPS intravesical administration twice a week for ten weeks in 29 female IC patients. Responses were measured using VAS scales and O Leary-Sant Symptom and Problem Index (OSPI) throughout the duration of the study and up to 12 months after its completion. An overall improvement in VAS and OPSI scores were found at statistically significant levels. The baseline mean VAS of eight point eight dropped to four after 10 weeks of treatment and continued to decline after 12 months of completion to three point four (p=0.00). A similar trend was shown in the patients OSPI with an average baseline value of 26.4 continually being reduced to 12.1 at one year after the study ended (p=0.00). Recurrence of symptomatology occurred in the vast majority of patients once intravesical PPS therapy was stopped, but symptom alleviation again took place once treatment

42 36 resumed. From this study, it is reasonable to consider intravesical PPS as maintenance therapy in IC treatment although larger, placebo-controlled studies should be conducted in the future (Daha, Lazar, Simak, & Pfluger, 2008). The two previously mentioned studies help to demonstrate that intravesical PPS can be an effective treatment modality for symptoms of IC. However, one recent randomized, doubleblind study of 41 female IC patients by Davis et al. (2008) sought to investigate the effectiveness of combination therapy with both oral and intravesical PPS against symptoms. Subjects were randomly selected to receive either intravesical and oral PPS or intravesical normal saline placebo with oral PPS for six weeks. In addition, both groups continued taking oral PPS for another 12 weeks, making the study a total of 18 weeks in duration. At week 12, a significant 46% reduction in the combination treatment group s O Leary-Sant IC Symptoms and Problem Index was found versus a 24% reduction in the placebo group (p=0.04). More statistically significant results were observed at 18 weeks with an improvement in all eight Health Related Quality of Life (HRQL) domains in the group receiving combination therapy compared to an improvement in only three HRQL domains in the placebo group (p<0.05). According to these results, it appears that combination therapy with intravesical PPS and oral PPS medications may enhance the therapeutic efficacy of each other and help alleviate symptoms of IC better than either modality alone. Future research into PPS use should reference this pilot study because it suggests that combination therapy is more effective than monotherapy when it comes to utilizing PPS. As with the rest of IC treatment options, this specific combination therapy should be evaluated with larger studies in order to gain an understanding of its long-term efficacy and ability to treat all degrees of IC symptom severity (Davis et al., 2008).

43 37 Heparin, like intravesical PPS, is thought to help restore the damaged GAG layer in IC patients and is another commonly used intravesical agent. In a study of 40 women with IC, Kuo (2001) found that 72.5% (29) reported significant improvement in symptoms after treatment with intravesical heparin twice a week for three months (p<0.05). This meant they reported a greater than 50% improvement in overall IC symptomatology. Statistically significant improvements were found in nocturia (p<0.001), the first sensation of bladder filling (p=0.001), urge sensation with bladder filling (p=0.009), and bladder capacity as demonstrated by cystometric filling (p=0.002). This study helped show the benefits of intravesical heparin therapy in alleviating irritative voiding symptoms commonly suffered by IC patients. Another study that examined the effects of heparin therapy was conducted by C. Parsons, Housley, Schmidt, & Lebow (1994) on 48 IC patients who were treated with intravesical heparin therapy three times a week for three months. After completing therapy, 56% (27) reported a significant improvement in symptoms and at least a 50% improvement in overall IC symptoms. Statistically significant improvements were found in pain, urgency, and nocturia (p<0.001 for all). Once the patients completed three months of therapy, they were offered the chance to electively continue intravesical heparin treatments. Twenty patients were still undergoing therapy at six months and were in remission of their IC symptoms. Sixteen patients continued therapy for another six months, and fifteen (31%) reported continued remission at one year follow-up. It is a safe option for IC patients because the heparin stayed within the bladder and did not affect their blood clotting times. This study helps show the benefits of intravesical heparin and demonstrates that long-term improvements can be experienced by patients who continue undergoing therapy for up to one year.

44 38 Yet another intravesical agent that has gained popularity in IC treatment is resiniferatoxin (RTX) which is an extremely potent capsaicin analogue believed to desensitize afferent sensory nerve fibers involved in the bladder pain experienced by IC patients (Payne et al., 2005). While possibly able to yield pain-relieving results, a very common side effect of RTX instillation is urethral and bladder pain upon administration (Chen, Corcos, Camel, Ponsot, & Tu le, 2005; Lazzeri et al., 2000; Payne et al., 2005; Peng & Kuo, 2007). Furthermore, the literature regarding the efficacy of this treatment modality has produced rather conflicting results. One of the clinical studies that has shown the most favorable results with RTX use was conducted by Lazzeri et al. (2000). It was a randomized, placebo-controlled study involving 18 patients who were not primarily diagnosed with IC but rather were described by possessing hypersensitive and bladder pain disorders. After undergoing either one intravesical RTX or placebo instillation, the researchers found statistically significant improvements in multiple symptoms at one month and three month follow-up visits. The treatment group reported decreases in frequency and urgency at the one month follow-up (p<0.01 for both), and at the three month follow-up. The same patients had decreased frequency, just to a lesser extent (p<0.05). Statistically significant improvements were also noted in the treatment group s pain score at one month follow-up (p<0.01). This study shows that RTX may be a very effective treatment in relieving symptoms that are consistent with IC symptomatology (Lazzeri et al., 2000). An open-labeled clinical trial of 13 IC patients studied the efficacy of using multiple intravesical instillations of RTX once per week for four weeks. This was the first time researchers evaluated the outcomes with multiple instillations versus a single instillation of RTX. Overall, after three months of treatment initiation, patients reported a 58.3% satisfaction rate

45 39 with improvements in the International Prostate Symptoms Score (IPSS), 5-Point Pain Scale, and Quality of Life Index. Although very small, this study showed that some patients were able to benefit from multiple instillations of RTX and experience symptom alleviation (Peng & Kuo, 2007). While the two studies mentioned above showed some benefits with RTX use, another well-designed, multicentered, randomized, double-blind, placebo-controlled trial reached the conclusion that no significant results were produced by RTX intravesical instillation when compared to placebo. This study was large in comparison to the two previously mentioned, with 163 IC patients undergoing a single RTX or placebo instillation after randomization. Participants were evaluated over a course of 12 weeks after treatment, and researchers found no statistically significant results indicating that RTX treatment was beneficial in ameliorating IC symptoms (Payne et al., 2005). The current literature regarding RTX instillation as treatment for IC lacks any strong evidence to support its use. The trial by Lazzeri et al. (2000) that claimed beneficial effects from RTX was not conducted solely upon IC patients making the results arguably questionable in applying to IC patients. The trial by Peng and Kuo (2007) was extremely small and lacked a control. A place for RTX in IC treatment has yet to be established but should be researched more extensively in the future to gain a better understanding of its potential benefits to IC patients. In addition to DMSO, PPS, and RTX, bacillus calmette-guerin (BCG) has also been utilized as an intravesical agent to alleviate IC symptomatology. Its exact mechanism in IC remains unknown yet a main proposed theory exists. It has been hypothesized that BCG may

46 40 down-regulate sensory nerves which transmit pain or alter autoimmune pathways leading to IC symptoms (Peters et al., 1997). Some studies have shown it to be effective in IC treatment. The pilot study that helped demonstrate its efficacy was a double-blind, placebocontrolled phase II clinical trial in which 30 female IC patients were randomly selected to undergo six weekly instillations of either BCG or placebo. Participants were followed-up periodically over an average of eight months. Statistically significant improvements were found in the BCG group when compared to placebo for the following symptoms: increased minimum voiding volume (p=0.004), better social functioning (p=0.036), and less fatigue (p=0.007). Although not statistically significant, improvements were also noted by the BCG group in vaginal/urethral pain, pelvic pain, urgency, overall well-being, and pain with intercourse (Peters et al., 1997). The same patients who received intravesical BCG in the previously mentioned study were followed up an average of 27 months later in a separate long-term analysis of BCG efficacy. Although only nine patients were questioned, eight of them (89%) reported maintaining excellent results, and six out of seven responders (86%) reported resolution of dyspareunia. Additionally, six out of eight patients who experienced improvement with BCG were able to stop using narcotics they previously used for pain. These results show intravesical BCG is a promising therapy that seems to be both safe and effective in treating IC on a long-term basis since no adverse events were reported (Peters, Diokno, Steinert, & Gonzalez, 1998). Despite the rather promising results of the studies mentioned above, a large, multicentered, randomized, double-blind, placebo-controlled trial evaluating 248 patients with refractory IC failed to demonstrate any significant benefits of BCG use compared to placebo (Mayer et al., 2005). In most studies, patients experienced symptom relief with BCG, but a

47 41 substantial number still have not shown improvement. These conclusions suggest that more studies are needed to test the effectiveness of BCG in relieving IC symptoms. An interesting and relatively new intravesical agent that has gained recent popularity with the results of a few promising studies is botulinum A toxin (BTX-A or botox). This neurotoxin must be injected into the bladder suburothelium under general anesthesia, making it obviously less convenient than previously mentioned oral and intravesical therapies. Nevertheless, in the majority of studies that have been conducted, it has been found to be of some benefit to IC patients, especially those with refractory disease. Its mechanism of action in IC patients remains unknown, but it has been hypothesized that BTX-A may modulate visceral sensory pathways with an antinociceptive effect (Ramsay, Small, & Conn, 2007). A pilot study evaluated the response of 14 patients with IC and found that after undergoing a session of multiple BTX-A injections to the bladder floor and trigone area, at one month and three month follow-ups, 85.7% (12 patients) achieved subjective improvement. Statistically significant improvements at one and three month follow-ups were also reported in mean VAS scores (p<0.05), daytime and nighttime frequency (p<0.01 and p<0.05, respectively), and functional bladder capacity (p<0.01). These results showed that BTX-A injections could be effective on a short-term basis for IC patients (Giannantoni et al., 2006). Another study that helped to confirm the findings above was conducted on 15 IC patients who were followed-up for evaluation at one month, three months, five months, and one year after a therapy of BTX-A injections to the bladder s lateral wall and trigone region. Significant improvements were noted at the one and three month follow-ups, but by five months, eleven patients (73%) experienced a recurrence of bladder pain and symptomatology. At one year, all the patients reported bladder pain and the re-emergence of original symptoms. It appears that

48 42 while BTX-A can be beneficial at relieving IC symptoms, its therapeutic effects begin to decline after approximately three months and repeat injections are likely required to maintain symptom alleviation. Furthermore, both studies on BTX-A demonstrated impaired detrusor contractility in some patients causing incomplete bladder emptying. These patients required intermittent selfcatheterization. Future studies on BTX-A use as an intravesical agent are warranted based upon the promising results shown thus far, but it will be necessary to determine the lowest effective BTX-A dose to decrease the incidence of side effects (Giannantoni et al., 2008). Behavioral Therapies One of the most basic yet essential things that all IC patients can do is to modify parts of their lifestyle to help manage their symptoms. These are nonpharmacologic approaches that are widely promoted and accepted by the ICA (2011), a valuable resource for any patient with IC. One major aspect of this modification is to eliminate dietary items that irritate the bladder. A complete, user-friendly list of various food and beverages that are considered either irritative or bladder-friendly is available at the ICA website ( (Figure 2). The most common items that are associated with bladder irritation that IC patients are encouraged to avoid include citrus, acidic, and spicy foods, caffeine, alcohol, and carbonated beverages. There are few clinical trials in the literature that specifically address dietary modifications for IC patients. However, a large web-based questionnaire was recently orchestrated by Bassaly, Downes, & Hart (2011) in which 598 responses were recorded by IC patients. The survey was accessed through the ICA s website, and it was done in an attempt to discover the most irritative food and beverage items according to IC patients. The findings correlate well with previously mentioned irritative dietary items. Patients reported the most bothersome things to be citrus

49 43 fruits, tomatoes, spicy foods, caffeinated items like coffee and tea, carbonated beverages, and alcohol. The ICA encourages patients to keep a detailed food and symptom diary to help identify which items irritate their bladder. It is also useful to try an elimination diet in which patients strictly adhere to consuming only items considered to be non-irritating then slowly adding in other items one at a time. This allows the patient to identify which food and beverages to avoid due to any triggering of symptoms on an individual basis. Another important part of behavioral therapy for IC patients is to learn and apply bladder retraining methods. One study specifically evaluated the response of 21 IC patients who were instructed to gradually increase voiding intervals over a course of three months. Every three to four weeks, patients increased the time between voids by 15 to 30 minutes until reaching a goal of three to four hour voiding intervals. At the end of the study, 71% (15 patients) reported an overall improvement in their general well-being and symptomatology. Statistically significant improvements were found in the average voided volume (p=0.01), average number of daily voids (p=0.005), bladder capacities (p<0.01), and feelings of urgency (p=0.001). Although additional clinical studies specifically aimed at evaluating the effectiveness of increased voiding intervals are unavailable, the results from this trial show that patients can benefit therapeutically when able to successfully retrain their bladders. It is an approach that most patients should attempt to see if it provides any benefit to them (Parsons & Koprowski, 1991). Exercise is another activity that is both advocated by the ICA and practitioners as it provides a way to attain overall health and wellness. One article containing two case reports also provided a link between exercise and an improvement in IC symptoms. A three day per week exercise regimen was completed by two women with IC for six months. The program consisted

50 44 of walking, light strength training, balance exercises, range of motion exercises, calisthenics, and core strengthening. Both patients reported improvements in their IC symptoms at the end of the study. These included less bladder pressure and urgency, better global IC symptom ratings, and improved depression and quality of life ratings (Karper, 2004). According to the ICA, it is important for IC patients to start any exercise program slowly and to ease into a regimen. It may even be beneficial for patients to consult with an experienced physical therapist who can help the patient avoid exercises that are known to irritate the bladder and trigger symptoms. It is recommended that a well-rounded program should address each of the following aspects of exercise: flexibility, strengthening, and low-impact/gentle aerobic conditioning. While each IC patient s ability to complete an exercise regimen will vary, it is recommended that all IC patients attempt to make it a part of their daily lifestyle. Since IC can be a debilitating condition, it is important that patients become involved with support groups or psychotherapy for professional counseling, if necessary, to help promote emotional well-being. The ICA is the only nonprofit IC organization dedicated to serving IC patients, and it has many resources patients can use to locate local support groups. Additionally, IC can be diagnosed comorbidly with depression in some patients, and if present, it is very crucial for practitioners to address and treat both conditions adequately or refer to a psychiatrist. An important part of any practitioner s responsibility is to take sufficient time at each visit with IC patients, educating them about their condition and helping them to apply the behavioral modifications. Electrical Nerve Stimulation Patients with IC that do not respond to traditional therapies often have few therapeutic options prior to radical surgery. The use of sacral neuromodulation in this subset of patients has

51 45 recently been studied and has shown promising results. Although its exact mechanism of action remains unknown, sacral neuromodulation is thought to somehow disrupt faulty nerve signals that contribute to IC symptomatology (Peters, Carey, & Konstandt, 2003). Two approaches used to stimulate the sacral nerve are percutaneous methods or permanent stimulator implant devices (InterStim). The majority of studies show a higher degree of efficacy with the implant device. One study that supports this idea was done to compare the efficacy of these techniques. The researchers concluded that permanent placement produced more beneficial results to patients with refractory IC. They also found that InterStim placement in 26 IC patients produced statistically significant improvements in various symptoms including decreased daily voids, nocturia, and 24-hour voids (p<0.001 for all). Additionally, more than two-thirds of patients subjectively reported either moderate or marked improvements in frequency, urgency, pelvic pain, pelvic pressure, quality of life, incontinence, and vaginal pain (Peters et al., 2003). Another study that further supports the use of a permanent sacral stimulator evaluated 17 patients with refractory IC an average of 14 months after undergoing permanent implantation. Impressive results were found with 94% (16 patients) showing sustained improvement in all measured outcomes at their last postoperative evaluation. Furthermore, statistically significant improvements were demonstrated in all measured outcomes which were the average number of daily voids, nocturia, average voided volumes, average pain, ICSI, and ICPI scores (p<0.01 for all) (Comiter, 2003). The results from these two studies show that placement of a permanent sacral nerve stimulator, such as the InterStim device, appears to provide symptom relief to patients with IC that did not respond to any other therapies. Although these devices must be surgically

52 46 implanted, it is a much less radical procedure than a cystectomy with reconstructive surgery which is often associated with poor clinical outcomes (Whitmore, Payne, Diokno, & Lukban, 2003). Additional large, long-term studies should be carried out in the future to continue studying the effects and mechanism of this promising therapy for patients with refractory IC. Since stimulation of the sacral nerve has been shown to provide some benefit to IC patients, a less expensive and less invasive approach using percutaneous posterior tibial nerve stimulation (PTNS) has gained recent interest. Because the tibial nerve shares common nerve roots with the sacral nerve, it has been hypothesized that this method may be both effective in treating symptoms of IC and more convenient to the patient. However, studies thus far have not been very successful in demonstrating its usefulness and efficacy (Zhao, Bai, Zhou, Qi, & Du, 2008). In a prospective open-label trial, 18 women with IC were treated with 30 minutes of intermittent PTNS twice a week for a total of ten therapy sessions. The researchers found statistically significant improvements in the following areas: nighttime bladder volume (p<0.05), ICPI and ICSI scores (p=0.001 and p=0.01, respectively), and the health status score (p=0.041). However, these results were not thought to be clinically substantial since no patient subjectively reported the trial as being significantly effective. Ten patients stated the treatment had no effect at all, and only eight reported some effect from the treatment. These results suggest that PTNS may be beneficial in alleviating a few symptoms in some IC patients, but it does not provide high-quality evidence in favor of the treatment (Zhao et al., 2008). Another study conducted on women with refractory IC to test the effectiveness of PTNS was a double-blind, randomized trial. Patients were randomly assigned to either a treatment group (29 women) or a placebo group (27 women). Instead of the percutaneous method used in

53 47 the previously mentioned study, patients in this trial underwent transdermal laser activation of the tibial nerve. The treatment group utilized an active device while the placebo group s device was programmed to be inactive. Patients performed the laser therapy once per day for 30 seconds over a total of 12 weeks. The results of this study were similar to the other PTNS trial discussed above. No statistically significant improvements were found when the active group was compared to the placebo group (O'Reilly et al., 2004). Therefore, it seems that the use of PTNS therapy in refractory IC patients must be researched further in order to validate its usefulness. Sacral modulation is effective in alleviating symptoms of IC, particularly in patients who fail to benefit from traditional therapies. Additional research is warranted to confirm the promising results produced thus far. Acupuncture The use of complementary and alternative medicine (CAM) in treating IC has not been presented to a large extent in the literature. However, it is important to recognize that many patients, especially those who do not respond well to traditional therapies, may turn to CAM approaches for symptom relief. Acupuncture is one of these treatment approaches that is often used by patients with chronic pain and is thought to be effective through neuromodulation (Whitmore, 2002). One case study has been presented in the literature in which a man with refractory IC pain and also low back pain reported substantial pain relief after undergoing auricular acupuncture. The procedure is a percutaneous auricular nerve stimulation device which can provide stimulation up to 96 hours. This particular IC patient experienced pain relief for two months from just one session (Horrigan, 2008).

54 48 A small prospective study comprised of 12 women with IC failed to show any significant improvement in symptoms with acupuncture use. Only one patient subjectively and objectively reported an improvement in symptomatology, lasting for three months (Geirsson, Wang, Lindstrom, & Fall, 1993). It is evident that further research must be performed in order for highquality evidence to be established in favor of acupuncture use for IC patients. The information available in the current literature does not support wide-spread advocacy of this treatment modality. Surgery When patients with IC cannot find symptom relief with any other treatments, laser or traditional surgery can be used as a last resort. Most therapeutic effects with these modalities have been reportedly better in the rarer Hunner s type IC when compared to non-ulcer IC. A study that demonstrated the success of laser therapy in endoscopically ablating Hunner s lesions involved 14 IC patients. After undergoing this treatment, statistically significant improvements were found in the number of daily voids (p=0.014) and average pain score (p=0.0002). Additionally, 86% (12 patients) reported feeling >50% improved in regard to their symptoms, and, at a follow-up an average of 27.8 months after treatment, eight patients reported complete resolution of symptoms. Laser treatment appears to be a beneficial treatment option mainly for patients with Hunner s ulcers that do not respond to other therapies (Payne, O'Connor, Kressin, & Guralnick, 2009). Another option for patients with refractory IC that suffer from Hunner s type disease is reconstructive surgery of the bladder. Studies have shown this option to be more beneficial in those with Hunner s type IC when compared with classic non-ulcer type IC. A study that helped confirm these findings was conducted on a total of 47 refractory IC patients: 34 patients with

55 49 Hunner s type disease and 13 patients with non-ulcer IC. After all patients underwent major reconstructive surgery, they were followed-up and prospectively evaluated an average of 89 months later. The results showed favorable outcomes in the Hunner s type patients, with 28 reporting complete resolution of symptoms. Only three patients with non-ulcer disease reported the same symptom alleviation, and ten patients still had residual pain after surgery. Reconstructive surgery is only a last resort treatment option for patients with Hunner s ulcers. It remains to be shown that this type of major, irreversible surgery is beneficial for those with classic IC disease (Rossberger, Fall, Jonsson, & Peeker, 2007). New Treatments: Hyperbaric Oxygen Since current treatment options are often suboptimal for many IC patients, new therapies are commonly researched. One of these treatment modalities currently being studied is the use of hyperbaric oxygen (HBO), which basically hypersaturates hemoglobin and drives more oxygen into damaged tissues, allowing faster granulation and healing to occur. This therapy has shown success in treating patients with radiation cystitis, a condition which shares many of the same symptoms as IC. Therefore, its effectiveness in treating IC symptomatology has piqued the interest of a few groups of researchers (van Ophoven, Rossbach, Oberpenning, & Hertle, 2004). A small clinical study comprising five women and one man with IC that had failed to respond to conventional therapies was conducted to test the effectiveness of HBO. Treatments involved inhaling 100% oxygen through facial masks while lying in a hyperbaric chamber. Sessions lasted about 90 minutes each day, and were performed six days a week for five weeks. This made a total of 30 treatment sessions per patient. During follow-up over a period of 15 months, four of the patients successfully reported an improvement in overall well-being according to the Patient Global Assessment Form and rated their therapeutic outcome as either

56 50 good or excellent. An improvement in urinary frequency, nocturia, urgency, and pain symptoms were all reported. Before treatment, two women had reportedly suffered from dyspareunia, but both experienced complete resolution of pain with intercourse even at 12 months post-treatment. The promising results from this pilot study show that HBO treatment may be an option for IC patients that do not respond to other therapies (van Ophoven, Rossbach, et al., 2004). Another small case series report shows similar results with HBO use. In this article, two women with refractory IC disease were treated with a total of 20 sessions of HBO therapy. At follow-up, both women experienced improvement in frequency and pelvic pain and demonstrated increased functional bladder capacity. One woman had glomerulations and a Hunner s ulcer on cystoscopic examination before treatment, but after HBO therapy, there was a substantial healing of these pathologies. These results support the conclusions from the previous study and show HBO therapy to be effective in some IC patients (Tanaka et al., 2007). Refractory IC has typically been treated with major, irreversible bladder surgeries, but new ideas like HBO may provide patients with a less invasive approach to symptom alleviation. The major drawbacks to this therapy are its high cost and the inconvenience of daily treatment regimens that are required for its therapeutic effects. The estimated cost of one HBO session is $212 to $354. The resulting total cost of 30 treatment sessions can range from $6,377 to $10,628. Nevertheless, it remains a possible option for patients who wish to retain their bladders and find amelioration of their symptoms without surgery. More studies should be conducted in the future to provide more evidence that can support the use of HBO in patients with refractory disease (van Ophoven, Rossbach, et al., 2004). Clinical Phenotyping

57 51 A new concept in the management of IC has recently been introduced in the literature. It is based upon the idea that IC is compromised of heterogeneous etiologies and symptoms, unique to each individual with the disease, and so it has been suggested that treatment should be aimed at each patient s clinical phenotype. A six-point classification system using the mnemonic UPOINT has been recommended that breaks down IC symptomatology into its six domains: urinary symptoms (frequency, urgency, nocturia, incontinence, and/or dysuria), psychosocial dysfunction (depression, anxiety, maladaptive coping mechanisms, and/or history of abuse), organ-specific findings (bladder glomerulations or ulcerations), infection, neurologic dysfunction (comorbid irritable bowel syndrome, fibromyalgia, vulvodynia, and/or chronic fatigue syndrome), and tenderness of muscles (pelvic floor trigger points). A thorough history, physical examination, and appropriate diagnostic test(s) guide the clinician to specifically target multimodal therapies at each particular phenotype domain for which the patient qualifies. For example, if muscle tenderness is present, it could be treated with manual physical therapy of the pelvic floor musculature. This approach allows clinicians to treat IC patients on an individual basis according to their specific symptoms and complaints (Shoskes, Nickel, Rackley, & Pontari, 2009). While this novel idea may help guide management strategies in treating IC, it does not change the fact that specific treatments to target each domain remain elusive. For example, amitriptyline has multiple mechanisms of action making it possible that its therapeutic effects likely target symptoms from more than one domain. As previously discussed, research must continue to be conducted on the various treatment modalities for IC to help determine which are truly more efficacious. In the meantime, using the UPOINT classification system to target

58 52 treatments at patient-specific clinical phenotypes may be useful in guiding multimodal therapy regimens (Nickel, Shoskes, & Irvine-Bird, 2009). Suplatast Tosilate A new oral medication that has just begun to be studied in IC patients is suplatast tosilate (IPD-1151T). This drug has a unique mechanism of action compared to traditional IC therapies. It is an immunoregulator that acts to suppress cytokine-producing T cells, ultimately causing decreased levels of IgE and eosinophils. The rationale for IPD-1151T use lies in the hypothesis that an autoimmune component involving increased IgE and eosinophils may be part of the disease s etiology (Ueda, Tamaki, Ogawa, Yamauchi, & Yoshimura, 2000). The recent pilot study that showed IPD-1151T to be effective in some IC patients was conducted with 14 women diagnosed with IC. The participants took the oral medication each day for a duration of one year. Overall, 85.7% (12 patients) demonstrated a good response to IPD-1151T. Statistically significant improvements were found in average bladder capacity, ICSI scores, and ICPI scores (p<0.05 for all), which indicate decreased symptoms of urgency, frequency, and pain. It is also interesting to note that blood eosinophils and IgE levels both decreased after treatment (Ueda et al., 2000). The results from this preliminary clinical study provide some evidence that IPD-1151T may be an alternative treatment option for IC patients, particularly those with non-ulcerative disease. All of the patients who responded well to the medication were classified with nonulcerative disease before treatment, while one of the patients who failed to respond positively had ulcerative IC. Additionally, no adverse side effects were reported during treatment, showing that IPD-1151T currently appears to be a safe drug. Although larger, placebo-controlled, randomized trials are necessary to truly define the efficacy of IPD-1151T in IC patients, this

59 53 novel therapy has shown promising results thus far in relieving voiding symptoms and bladder pain (Ueda et al., 2000). Amphetamines Another intriguing oral medication that was recently shown to dramatically improve two women with refractory IC disease is the sympathomimetic agent, dextroamphetamine. Both women failed water overload tests and were consequently diagnosed with idiopathic orthostatic edema, which researchers suggest is associated with IC. An abnormal water load test occurs when a patient fails to excrete more than 75% of an ingested water load of 1500 cc in 30 minutes over a four-hour period (Check, Katsoff, Citerone, & Bonnes, 2005). The two pathologies may be related by defects in vascular or epithelial permeability. Nevertheless, these patients were treated with oral dextroamphetamine sulfate based on the diagnosis of idiopathic orthostatic edema, and a substantial improvement in IC symptomatology was observed. The first patient experienced complete resolution of pelvic pain and bladder symptoms within two days of treatment and has remained in remission of her IC symptoms for one and a half years while continuing 20 milligrams per day of extended release dextroamphetamine sulfate. The second woman had complete resolution of pelvic pain and bladder symptoms by one week of therapy and has remained free of symptoms for one year on 10 milligrams of dextroamphetamine sulfate twice daily (Check et al., 2005). One woman experienced a return of symptoms when she failed to take the medication for just five days, but she went back into remission quickly after resuming dextroamphetamine sulfate. The researchers suggest that IC may be caused in part by idiopathic orthostatic edema based upon these results and how quickly the two women responded to this medication after failing conventional therapies. There is a great need for more studies to determine the

60 54 effectiveness of sympathomimetics in larger populations of patients with IC, but these two case reports show that dextroamphetamine sulfate may be a very effective treatment option for refractory IC disease (Check et al., 2005). Prostaglandins Since oral prostaglandins are known to be cytoprotective in the gastric mucosa, it has been suggested that these agents may have similar protective roles in the bladder. In an openlabel phase II clinical trial, 25 refractory IC patients were administered daily doses of misoprostol, an oral prostaglandin analogue, for three months. If patients reported improvement, they were offered the option of continuing the drug for another six months. After three months of treatment, the overall response rate in patients who reported >50% improvement in symptoms was 56% (14 patients), while the response rate measured at nine months was 48% (12 patients). Two patients experienced a relapse of their symptoms between three months and nine months of therapy. Participants who responded positively to misoprostol were found to improve significantly in all symptoms at three and nine month evaluations, including nocturia, frequency, urgency, and pain (p<0.01 for all) (Kelly, Young, Johnston, & Keane, 1998). It is important to note that a substantial amount of participants experienced adverse side effects while on misoprostol therapy. The most common complaints were abdominal cramping and diarrhea which were reported by 64% (16 patients). Nevertheless, the results that were produced by this preliminary trial show that misoprostol may be an effective oral drug in alleviating symptoms of IC, especially in those who are refractory to conventional treatments and can tolerate the side effects. More experimental and clinical studies should be performed to accurately define this drug s action upon the bladder.

61 55 Antiproliferative Factor Antagonists Since the presence of APF is thought to play a role in the pathogenesis of IC, recent research has been conducted to study the effects of blocking this protein. One study was successful in developing two novel APF antagonists that were able to block the detrimental effects of APF in samples of bladder urothelial tissue from IC patients. These compounds led to increased bladder cell proliferation and decreased permeability suggesting that APF antagonists may be an effective treatment modality for IC. Future research is needed, but the results of this study help provide a template for which future treatments may be derived (Keay et al., 2011). Guided Imagery The role of CAM was previously discussed in regard to using acupuncture as a therapy for IC patients. A recent prospective pilot study examined another type of CAM, guided imagery, to see if it would be effective in relieving symptoms in IC patients. The researchers suggest that since up to 85% of IC patients experience pelvic floor dysfunction, it may be effective to use guided imagery in relaxing these muscles and improving corresponding irritative bladder pain and symptoms. In this study, thirty women with IC were randomized into either the treatment group or the control group. The fifteen women in the treatment group listened to a compact disc (CD) that contained guided imagery specifically aimed at symptoms of IC while the control group was instructed to sit or lie down, resting quietly. Both groups underwent their protocols for 25 minutes, twice per day, for a total duration of eight weeks (Carrico, Peters, & Diokno, 2008). The study showed that after treatment, statistically significant improvements were found in the group who listened to guided imagery in VAS pain scores (p=0.027) and feelings of urgency (p=0.02). Overall, 45% (five patients) of the treatment group reported an improvement

62 56 in IC symptoms that was moderate or marked according to the GRA. Another characteristic of guided imagery that makes it an appealing option is that there are no adverse effects for treatment. These preliminary findings suggest that guided imagery may be an alternative therapy for IC patients, but larger studies are needed to support this small trial (Carrico et al., 2008). Intravesical Agents Intravesical agents are commonly used in IC patients as they are directly instilled into the bladder. Some of the most common agents used were previously discussed, but there are some newer options that have gained recent interest. One of these instillation products is hyaluronic acid (HA), which is thought to function in part by restoring the damaged GAG layer of the bladder in IC patients. A study that succeeded in demonstrating the effectiveness of HA instillations evaluated 20 female IC patients. Participants were treated with a total of six HA instillations without anesthesia. They were followed-up after three months, at which point all women were given the option to continue treatment if desired. Thirteen patients (65%) decided to continue monthly instillations of HA therapy due to pain relief. After three years, all original patients were evaluated for final follow-up (Kallestrup, Jorgensen, Nordling, & Hald, 2005). The researchers found that seven patients (35%) continued to receive monthly instillations of HA up until the three year follow-up, while four (30%) had stopped treatment due to a complete response to therapy with decreased daily voids, nocturia, and pain. Out of the original 20 patients, 15 (about 55%) reported an improvement in pain according to the VAS, and correspondingly, analgesic use was found to be decreased. No adverse events occurred during the study in regards to HA use. This small pilot trial showed that intravesical instillations of HA may be safe and effective in treating symptoms of IC.

63 57 A different pilot study that also examined effects of HA instillations studied the use of sequential hydrodistention with HA administration under general anesthesia for patients with refractory IC disease. This method was suggested as particularly useful for patients who would be unable to sustain hydrodistention without general anesthesia. A total of 23 refractory IC patients underwent two sessions of hydrodistention with HA intravesical instillation under general anesthesia. These initial sessions were conducted one month apart from each other, and additional treatments were given subsequently per each patient s individual request. An immediate improvement in at least one of the following symptoms was reported by 17 patients (74%): frequency, urgency, pain, and/or nocturia. Their average functional bladder capacity was also found to be increased significantly (p<0.05). Although this small trial was not controlled or randomized in design, it demonstrated that the majority of IC patients found some beneficial symptom amelioration with sequential hydrodistention and intravesical HA therapy while under general anesthesia. Additionally, no side effects were observed from using HA. This may suggest an alternative treatment for patients who are unable to tolerate these procedures under local anesthesia (Ahmad, Sarath Krishna, & Meddings, 2008). Another intravesical agent that has been recently researched is intravesical alkalinized lidocaine (PSD597), which is thought to provide symptom relief in IC patients by downregulating bladder sensory innervation. In a multicentered, randomized, double-blind, placebocontrolled phase II clinical trial, a total of 102 IC patients were allocated to receive either daily intravesical instillations of PSD597, lidocaine with sodium bicarbonate, or placebo, normal saline, for five consecutive days. Fifty patients were treated with PSD597 while 52 received placebo instillations (Nickel, Moldwin, et al., 2009).

64 58 The first follow-up was done three days after the last treatment, and significantly more patients in the PSD597 group reported moderate or marked improvement using a GRA than the placebo group (p=0.012). The ICSI and ICPI scores were significantly lower in the PSD597 group compared to placebo (p=0.041 and p<0.001, respectively). Although not statistically significant when compared with placebo, a trend toward reduction in pain was noted in the PSD597 group at this follow-up as well (Nickel, Moldwin, et al., 2009). After five days of therapy in the double-blind phase, patients in both groups were given the opportunity to undergo open-label PSD597 instillation treatment for 5 consecutive days on day 15. Eighty-two (86%) of the 95 patients who had successfully completed the double-blind placebo-controlled phase chose to undergo PSD597 treatment, and 78% (64) reported an improved GRA score on day 22. A sustained improvement in GRA score was also found on day 29 by 72% (59) of participants. Overall, the most common adverse side effect that was attributed to PSD597 was short-term bladder pain primarily upon instillation. From this preliminary study, it seems that PSD597 is more effective in alleviating symptoms of IC than placebo and may prove to be a safe intravesical treatment option. More studies are required to determine its longterm efficacy. Building upon these results, a new intravesical agent has recently emerged that consists of a combination of heparin and alkalinized lidocaine. A pilot study conducted on 82 newly diagnosed IC patients was effective in showing this novel solution to be beneficial. To begin, 47 patients, group one, were treated with the above combination that included 1% lidocaine, and when no side effects occurred and patients tolerated it well, the remaining 35 patients, group two, were given the same combination but with 2% lidocaine. The researchers were hoping to

65 59 accomplish an immediate effect of pain relief and urgency as very few options, short of narcotics, currently allow for this type of symptom relief (Parsons, 2005). The results showed that directly following instillation, 94% (33) in group two reported immediate significant pain and urgency relief compared to 75% (35) of group one. This demonstrated a significantly higher response rate in group two, which received the higher concentration of lidocaine (p<0.01). A few days after treatment, 28 patients from group two were interviewed, and it was found that over half had symptom relief for at least four hours after instillation. Additionally, 20 of these patients agreed to have three more weekly instillations of the combination solution for two weeks, and 80% (16) reportedly had significant reductions in both pain and urgency that lasted at least two days after treatment. These findings show that an intravesical combination of heparin and alkalinized lidocaine, especially 2% lidocaine, may be beneficial in relieving irritative bladder and pain symptoms in IC patients. Also, since symptoms were relieved in most patients for a much longer duration than lidocaine s known anesthetic effect, the mechanism by which it works in IC patients may be due to down-regulation of sensory nerves in the bladder. The mechanism and long-term efficacy of intravesical heparin and alkalinized lidocaine should be researched further in the future (Parsons, 2005). Another intravesical agent that has recently been studied is chondroitin sulfate, which is thought to be an important part of the GAG layer in the bladder urothelium. Intravesical instillation of this material is believed to help restore any damaged or dysfunctional parts of the GAG layer in IC patients. A multicentered, open-label study in which 53 IC patients were treated with chondroitin sulfate instillations was recently conducted to test its safety and efficacy. Participants underwent a total of 10 treatments: weekly sessions for six weeks and then once monthly sessions for an additional 16 weeks. After the initial six treatments, 47.2% (25)

66 60 reported a moderate or marked improvement according to a GRA, and statistically significant improvements were found in symptom and bother scores plus pain, urgency, and frequency symptoms (p<0.001 for all). At the conclusion of the study, 60% (32) maintained significant improvements seen in all the symptoms noted at initial follow-up (p<0.001). From this study, it appears that chondroitin sulfate is an effective intravesical agent in alleviating symptoms of IC (Nickel, Egerdie, et al., 2009). Building upon the Nickel et al. (2009) study results, a more structured trial took place that was multicentered, randomized, and double-blind in design. Once a week for six weeks, 33 IC patients received intravesical instillations of chondroitin sulfate while another 32 IC patients were given instillations with a vehicle control of saline. At follow-up, the researchers found that there was no statistically significant difference in the number of patients who reported a moderately or markedly improved condition when comparing the two groups. However, the number of responders in the treatment group (39.4%) was almost double the responders in the vehicle control group (22.6%). The researchers suggest that this pilot study was underpowered and would require a much larger number of participants to demonstrate significant differences between the groups. Although this study does not show convincing, high-quality evidence in favor of intravesical chondroitin sulfate use in IC patients, it should be investigated more extensively in the future in larger studies as it has shown to be somewhat promising so far (Nickel, Egerdie, Steinhoff, Palmer, & Hanno, 2010). A new intravesical instillation agent which has only recently begun to be studied is liposome (LP) therapy. It is believed that intravesical LPs act to heal or improve areas of damaged bladder urothelium in IC patients, leading to less inflammation and corresponding bladder symptoms. Only one study has been conducted in which the efficacy of intravesical LP

67 61 therapy has been tested on IC patients. This small trial studied intravesical LP therapy and oral PPS treatment separately and did not seek to compare the two therapies to one another due to significant differences found between the two groups at baseline (Chuang, Lee, & Chiang, 2009). A total of 24 IC patients were divided equally into two groups, and each was treated for a total of four weeks. A group of 12 patients received once weekly bladder instillations of LPs while the other group was administered oral PPS therapy each day. While both treatment modalities were shown to be beneficial, the LP group demonstrated statistically significant decreases in frequency, nocturia, pain, urgency, and O Leary-Sant symptom scores at the end of therapy (p<0.05 for all). Follow-up at 8 weeks showed that the symptom improvements had been maintained, indicating that LP instillation may be effective for up to eight weeks. While larger, placebo-controlled studies are needed to determine its true efficacy, intravesical LPs appear to be a promising new instillation treatment for patients with IC (Chuang et al., 2009). In summary, it is evident that further research is necessary to delineate a precise treatment regimen aimed at not only alleviating IC symptoms but curing the disease itself. This will require further studies on patients with IC to evaluate which medications and therapies are more effective and will probably require studies on animal models, too, to help explore the etiology and pathogenesis of IC. Many of these newer IC treatments require further studies before widespread advocacy of their use can confidently be done.

68 62 Treatment Recommendations Even though the treatment modalities presented are considered to be classic regimens for IC, the scientific literature regarding them remains weak. One explanation for this is that IC is a relatively rare disease, and researchers may have difficulty recruiting patients for clinical studies. Also, since the etiology and pathophysiology remain unknown, treatments are symptomatic instead of curative in nature. There is much variability among IC patients as well, with some suffering from more severe, debilitating disease while others experience only mild symptomatology. Because of all these factors, high-quality scientific evidence to support one IC treatment modality over another is lacking. Few studies have been performed that compare the efficacies of different types of treatment. More comparative studies, along with larger, wellcontrolled studies, are needed to help guide practitioners who are treating IC patients. A multimodal therapy approach should be utilized when treating patients with IC. Most treatment options by themselves do not manage the full extent of symptomatology that IC patients experience. A combination of nonpharmacologic and pharmacologic options should be attempted. All IC patients should first begin a noninvasive, behavioral treatment regimen when they are diagnosed. This involves eliminating bladder-irritating foods and beverages from the diet, participating in low-impact, gentle exercises, learning and applying bladder retraining techniques, and to consider joining an IC support group. If possible, patients can also undergo manual physical therapy, particularly using the Thiele massage approach, if qualified therapists are available. These are all nonpharmacologic therapies that have been shown in the literature to help IC patients manage their symptoms, and practitioners should encourage all IC patients to try adapting these behaviors into their lifestyles.

69 63 Amitriptyline and PPS are the most studied oral medications for IC. Both have been shown to be beneficial in some populations of IC patients and can be tried along with the behavioral modifications previously mentioned. Hydroxyzine, gabapentin, cyclosporine, and montelukast are other oral medications that have not been studied to the extent of PPS and amitriptyline. However, promising results for these drugs have been shown, especially with cyclosporine. Very recently, the American Urological Association (AUA) brought forth a set of IC treatment guidelines (Figure 4) for the first time in history (Hanno et al., 2011). Their recommendations support the initial use of conservative measures in treating IC symptomatology which include lifestyle changes, behavioral modifications, stress management, and pain management. Pain that is not alleviated by other treatment modalities is to be controlled with either non-steroidal anti-inflammatory drugs (NSAIDs), non-narcotics, or narcotic agents. Second-line treatments are oral PPS, amitryptyline, and hydroxyzine which can be tried along with physical therapy techniques to relax the pelvic floor musculature when trained therapists are available. The AUA recommends the use of DMSO, heparin, or lidocaine for second-line intravesical treatments. They note that bladder cocktails using DMSO, heparin, sodium bicarbonate, a local steroid, and/or lidocaine can be used by clinicians for possible synergenistic effects; however, no clinical trials comparing a DMSO instillation and a DMSO bladder cocktail have been performed. The third-line therapeutic choice is cystoscopy with hydrodistention under anesthesia. Using cystoscopy with hydrodistention can be helpful in diagnosing IC and excluding bladder cancer while also helping to alleviate symptoms (Ottem & Techman, 2005). If this does not remedy symptoms, then neuromodulation of the sacral or pudendal nerve may be utilized. Fifth-line agents are CyA and botox injections to the bladder. These agents have been

70 64 useful in alleviating symptoms in some IC patients but have adverse effects. For example, CyA can cause increased blood pressure, nephrotoxicity, and immunosuppression (Sairanen et al., 2005). Symptom relief from botox therapy is typically short-lived, and a common side effect is impaired detrusor contractility which may require intermittent self-catheterization (Giannantoni et al., 2006). Reconstructive bladder surgery is a last resort for IC patients refractory to all other therapies. Montelukast and gabapentin were not included in the AUA guidelines. There are not enough clinical studies to support their widespread use at this time. Additionally, the use of RTX is discouraged as instillation of this drug causes pain. The use of neuromodulation, CyA, and botox do not yet have enough evidence to support and encourage their widespread use in IC patients. This is why they are considered fourth and fifth-line agents, respectively. The AUA recommends that only practitioners who are experienced in utilizing these agents should prescribe them as treatment options.

71 65 Conclusion Interstitial cystitis is a chronic, debilitating condition that can be very difficult to treat. Patients suffer from variable stages of disease, and not every patient responds to therapies in the same way. The most difficult aspect of treatment is that it still remains empiric, not curative, which will continue to be the case until the etiology and pathophysiology of IC can be determined. There are currently few randomized, placebo-controlled clinical studies that have been performed to study the effects of most IC treatments. Additionally, few studies have been done that compare different treatment regimens. Future research is needed to fully evaluate current therapies and to gain a better understanding of their role in treating IC. The recent release of the AUA s IC treatment guidelines has been an encouragement to the IC community. Now practitioners can follow this algorithm which is based upon the currently available scientific literature. It provides evidence-based recommendations for practitioners to follow when treating IC patients, even though more research should be conducted on many of these therapeutic options. One of the newer scientific discoveries, the APF antagonist, may provide clinicians with an effective treatment option for IC. This therapy aims at curing the damaged bladder mucosa because the APF protein has been implicated in the pathogenesis of IC. Future treatment may also evolve to treat each patient s individual clinical phenotype. Other promising therapies, such as HBO, suplatast tosilate, intravesical HA, intravesical LPs, and intravesical chondroitin sulfate, can be tried when treatment recommendations from the AUA guidelines fail to effectively help IC patients. All of these newer options have not been studied enough to encourage their widespread use. Clinicians must use their own individual clinical judgment and

72 66 experience when offering these choices to their IC patients. More research and clinical studies are needed in order to gain a clearer understanding of their benefits, long-term efficacy, and possible side effects.

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86 80 Figures Figure 1. Hypothetical cascade of events involved in pathophysiology of interstitial cystitis From Management strategies for painful bladder syndrome, by Lau, T. C., & Bengtson, J. M., 2010, Reviews in Obstetrics and Gynecology, 3, p Copyright 2007 by Elsevier Health Sciences. Reprinted with permission.

87 81 IC/PBS Food List Bladder Friendly Try It Caution Note: Foods labeled with a plus sign (+) can be especially soothing during an IC flare. Beverages water test to find one that works for you juice blueberry, pear milk + milk substitutes almond +,rice,lactaid+ milkshake vanilla + tea chamomile +, peppermint + non-dairy creamers check label eggnog non alcoholic +, without problem ingredients Juice low-acid orange, grape, some apple, baby coffee herbal,low-aciddecaf,roastedcarob tea alfalfa, roasted carob soda root beer with ice (decaffeinated, not diet) sports drinks test to find one that works for you (e.g., blue Gatorade) alcohol not only irritating to the bladder but also contraindicated with many IC medications water carbonated, vitamin, flavored juice cranberry, orange,acai milk chocolate, soy coffee regular & decaf teas regular, green, herbal, iced sodas colas, citrus, orange, diet drink powders such as Kool-aid, lemonade, orange, or powdered ice tea drinks sports drinks energy drinks guarana, mate Grains breads corn bread +,oatbread +,pita, potato bread +,whitebread +,Italiansweet bread, whole wheat bread (i.e. Ezekiel) cereals most cereals without problem ingredients, oat cereal, rice cereal (hot or cold) crackers matzo grains couscous,grits,millet,quinoa+,spelt flours buckwheat, wheat pasta rice + breads rye, sourdough cereals instant packaged hot cereal crackers without problem ingredients grain amaranth breads made with unsafe ingredients and/or heavily processed and fortified cereals heavily preserved, sweetened, heavily fortified, flavored, flour soy pasta prepared or boxed pasta dishes rice boxed dishes Fats and Nuts nuts almonds, cashews, peanuts butters almond, peanut oils canola, coconut, corn, olive, peanut, safflower, sesame, soy margarine lard shortening salad dressing homemade without problem ingredients nuts macadamia, pecans, walnuts mayonnaise tahini seeds sunflower seeds shortening butter-flavored nuts filberts, hazelnuts, pecans, pistachios oils check label salad dressings most If you have nut or other food allergies, talk with your healthcare provider about your special diet needs. Bladder Friendly Try It Caution Eggs, Meat, Fish and Poultry eggs + poultry chicken+, turkey fish + beef + seafood clams, crabmeat (not canned), lobster, shrimp lamb + pork protein powder whey, egg whites veal liver beef or chicken garden/veggie burgers without soy products beef corned beef sandwich meats liverwurst, ham (fresh or boiled, without heavy preservatives or flavorings.) bacon anchovies caviar prosciutto sausages without problem ingredients cured meats bologna, pepperoni, salami cannedcrabmeat hot dogs sausage most smoked fish soy products soy veggie patties, protein powder, tofu Dairy, Cheeses, Frozen Desserts cheeses American, mozzarella, cheddar cheese (mild), feta, ricotta+, string cheeses + cream cheese cottage cheese + ice cream + most milk + milk substitutes Lactaid sherbet no citrus or chocolate flavors Rice Dream dessert vanilla whipped cream Cool Whip cheeses blue cheese, brie, brick parmesan, camembert, cheddar cheese (sharp), edam, emmenthaler, gruyere hard jack, Monterey Jack, parmesan (fresh & canned), Roquefort, stilton, Swiss buttermilk sour cream -accentonabakedpotatoorsoup pizza - plain, chicken & garlic, veggie or made with white sauce - no pepperoni sorbet yogurt - blueberry, vanilla, plain cheeses processed, Cheez Whiz ice cream caution with citrus or chocolate flavors soy products soy milk, soy cheeses Fruits apples Gala, Fuji, Pink Lady applesauce homemade with Gala, Fuji or Pink Lady apples blueberries + coconut without preservatives dates without preservatives pears + watermelon applesauce commercial or baby apricots bananas berries blackberries, raspberries, olallieberries cherimoya cherries fresh, maraschino citrus peels currants figs mango melon Crenshaw, honeydew peaches plums raisins brown rhubarb berries cranberries, most citrus lemons, limes, oranges, grapefruit dried fruit with preservatives grapes guava kiwi fruit melons cantaloupe nectarines passion fruit papaya persimmon pineapple starfruit strawberries raisins golden

88 82 Bladder Friendly Try It Caution Snacks almonds carrots celery chips (plain) corn, potato crackers soda or soup fruit bars blueberry, pear milkshake vanilla oatmeal bars peanuts peanut butter popcorn pretzels plain donuts glazed, old fashioned chips potato (seasoned, barbequed) graham crackers dessert cakes fast food restaurants fruit & nut bars with safe ingredients licorice pizza plain, chicken & garlic, veggie or made with white sauce - no pepperoni Desserts and Sweets berries blueberries cake homemade pound cake +, angel food +, homemade white/yellow cakes +,carrot frostings - homemade vanilla frosting, homemade caramel frosting, carob, whipped cream carob cookies oatmeal +,shortbread,sugar + muffins carrot cheesecake creme brûlée custards + pie custard,creampie,homemadeapplepie (with safe apples), pumpkin pie divinity sweet breads homemade zucchini bread + candy licorice maple syrup pastries plain, almond, pear ice cream peppermint, vanilla + pudding tapioca, vanilla +,rice + milkshake vanilla + sweeteners brown sugar, honey +,sugar artificial sweeteners Splenda (sucralose) candy caramel chocolate white ice cream caramel, coconut, mango, peppermint, butter pecan sorbet coconut pastries blueberry, cinnamon popsicles some sweet bread banana yogurt frozen artificial sweeteners acesulfame K aspartame, Nutrasweet, saccharine, Sweet- N-Low, stevia candy red hot-type cinnamon chocolate cocoa, milk, bittersweet, dark ice cream chocolate, coffee, rocky road sorbets with problem fruits pastries with problem fruits pie pecan, mincemeat desserts with problem nuts fruitcakes Bladder Friendly Try It Caution Vegetables and Dried Beans asparagus avocado beans black eyed peas, garbanzo, lentils, pinto, white, most dried beans beets broccoli brussels sprouts cabbage carrots + cauliflower celery chives corn + cucumber eggplant green beans greens collard greens, kale, mustard greens, okra, swiss chard, spinach, bok choy lettuce & most salad greens mushrooms + olives black parsley + peas green +, snow peas, split peas bell peppers yellow, orange, red potatoes + white, yams pumpkin radishes rhubarb rutabaga squash + summer, winter, zucchini turnips beans fava, kidney beans, lima beans, black beans bell peppers green olives green greens chicory, dandelion greens, purslane, turnip greens leeks (cooked) onions white, red, cooked bulb onion, raw green tomatoes homegrown, low acid watercress chili peppers onions raw bulb onions pickles sauerkraut soy beans edamame, roasted tomato tomato sauces, tomato juice tofu homemade soup & stock from okay meats and vegetables soups canned, low sodium, organic soups (without problem ingredients) bouillon cubes, powder canned most packaged soups most Soups

89 83 Bladder Friendly Try It Caution Condiments, Seasonings, and Flavor Enhancers allspice almond extract anise basil + caraway seed coriander dill fennel garlic + mace marjoram + oregano + poppy seed rosemary + sage + salt in small quantities thyme tarragon vanilla extract black pepper celery seed cilantro cinnamon powdered citric acid in small quantities cumin (small amt) dried parsley dried chervil ginger lemon extract mayonnaise malt powder nutmeg onion powder orange extract turmeric ascorbic acid autolyzed yeast BHA and BHT benzoates catsup (ketchup) cayenne cloves chili powder horseradish hot curry powder hydrolyzed protein meat tenderizers miso mustard oleoresin paprika paprika pickles red pepper soy sauce tamari vinegar worcestershire sauce MSG monosodium glutamate metabisulfites sulfites acacia fiber Benefiber Metamucil plain psyllium bulk psyllium fiber not sugar free Colace Metamucil -cinnamonwafers Metamucil orange, berry burst psyllium fiber sugar-free due to the presence of artificial sweeteners senna Fiber Supplements Figure 2. Interstitial cystitis diet From Understanding the interstitial cystitis/painful bladder syndrome diet, by Beyer, J., Interstitial Cystitis Association, Laumann, B., Osborne, J., & Shorter, B, Copyright 2009 by Interstitial Cystitis Association. Reprinted with permission.