Chronic Pelvic Pain of Bladder Origin: Interstitial Cystitis

Transcription

1 OBSTETRICS AND GYNECOLOGY BOARD REVIEW MANUAL STATEMENT OF EDITORIAL PURPOSE The Hospital Physician Obstetrics and Gynecology Board Review Manual is a peer-reviewed study guide for residents and practicing physicians preparing for board examinations in obstetrics and gynecology. Each quarterly manual reviews a topic essential to the current practice of obstetrics and gynecology. PUBLISHING STAFF PRESIDENT, GROUP PUBLISHER Bruce M. White EDITORIAL DIRECTOR Debra Dreger ASSISTANT EDITOR Rita E. Gould EXECUTIVE VICE PRESIDENT Barbara T. White EXECUTIVE DIRECTOR OF OPERATIONS Jean M. Gaul Chronic Pelvic Pain of Bladder Origin: Interstitial Cystitis Editor: Paul B. Marshburn, MD, FACOG Director, Reproductive Endocrinology, Department of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Carolinas Medical Center, Charlotte, NC Contributors: Daniel R. Mishell, Jr., MD The Lyle G. McNeile Professor and Chairman, Department of Obstetrics and Gynecology, Keck School of Medicine, University of Southern California, Los Angeles, CA Jeffrey R. Dell, MD, FACOG, FACS Director, Institute for Female Pelvic Medicine, Urogynecology and Reconstructive Pelvic Surgery, Generations Ob/Gyn, PC, Knoxville, TN PRODUCTION DIRECTOR Suzanne S. Banish PRODUCTION ASSISTANT Kathryn K. Johnson ADVERTISING/PROJECT MANAGER Patricia Payne Castle SALES & MARKETING MANAGER Deborah D. Chavis NOTE FROM THE PUBLISHER: This publication has been developed without involvement of or review by the American Board of Obstetrics and Gynecology. Endorsed by the Association for Hospital Medical Education Table of Contents Introduction Pathophysiology of IC Evaluation and Diagnosis of Suspected IC Treatment for IC References Cover Illustration by Carole R. Owens Copyright 2004, Turner White Communications, Inc., 125 Strafford Avenue, Suite 220, Wayne, PA , All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications, Inc. The editors are solely responsible for selecting content. Although the editors take great care to ensure accuracy, Turner White Communications, Inc., will not be liable for any errors of omission or inaccuracies in this publication. Opinions expressed are those of the authors and do not necessarily reflect those of Turner White Communications, Inc. Obstetrics and Gynecology Volume 9, Part 4 1

2 OBSTETRICS AND GYNECOLOGY BOARD REVIEW MANUAL Chronic Pelvic Pain of Bladder Origin: Interstitial Cystitis Daniel R. Mishell, Jr., MD, and Jeffrey R. Dell, MD, FACOG, FACS INTRODUCTION Chronic pelvic pain (CPP) is a common condition that affects an estimated 9 million women of reproductive age in the United States, or approximately 15% of the adult female population. 1 The American College of Obstetricians and Gynecologists (ACOG) defines CPP as noncyclic pain of 6 or more months duration that localizes to the anatomic pelvis, anterior abdominal wall at or below the umbilicus, lumbosacral back, or the buttocks and is of sufficient severity to cause functional disability or lead to medical care. 2 Women with CPP typically complain of pain in the lower abdomen, vulva, urethra, vagina, medial thighs, and/or perineum; pain during or after sexual intercourse; and pain associated with hormonal changes. Additionally, the pain is typically accompanied by urinary or irritative voiding symptoms. Evaluation of CPP accounts for 12% of gynecologic outpatient referrals 3 and 40% of gynecologic laparoscopies; 4 however, in the majority of laparoscopies performed for evaluation of CPP, no evidence of pathology is found. 5 At least 10% of hysterectomies are performed for the evaluation of CPP. 6 Multiple disorders are associated with pelvic pain, including recurrent urinary tract infections (UTIs), endometriosis, vulvodynia, irritable bowel syndrome, and disorders of bladder origin, specifically interstitial cystitis (IC). The cause of CPP frequently is not diagnosed, as demonstrated by a prevalence study of CPP in which 61% of women who reported having pelvic pain in the previous 3 months also reported that the etiology of the pain was unknown. 1 Up to 85% of women with undiagnosed CPP may have pain of bladder origin. 7 The most common cause of CPP of bladder origin in women is interstitial cystitis (IC), a chronic inflammation of the bladder characterized by urinary frequency/urgency and pelvic discomfort or pain in the absence of other obvious bladder pathology. An estimated 700,000 individuals in the United States currently have IC, 90% of whom are women. 8 Previous prevalence estimates of IC varied from 67 in 100,000 women 9 to 510 in 100,000 women; 10 however, recent studies indicate that as many as 1 in 4 or 5 women may have IC. 11 Most women diagnosed with IC are white. Women typically first notice the pain and urinary symptoms characteristic of IC during their twenties or early thirties but are usually not accurately diagnosed for 5 to 7 years, 9 resulting in an average age at diagnosis of 42 to 46 years. 12 The psychological and physical effects of IC on quality of life (QOL) are considerable: up to 50% of women with IC are unable to work full time, and more than 60% have dyspareunia. 13 The chronicity and pain of this disorder can lead to emotional problems; in fact, patients with IC score worse on QOL inventories than patients on dialysis. 13 This manual describes the pathophysiology of IC and methods to diagnose the presence of this disorder. Effective therapies for treating IC are reviewed. PATHOPHYSIOLOGY OF IC The pathophysiology of IC remains unknown but is believed to be multifactorial. The prevailing theory is based upon specific alterations in permeability of the epithelial layer of the bladder. In the healthy bladder, a mucopolysaccharide lining, or glycosaminoglycan (GAG) layer, overlays the bladder epithelium. This lining secretes bladder surface mucin that prevents the absorption of caustic urinary components. Mucin also prevents bacteria from adhering to urothelial surfaces, thereby inhibiting bladder infections. Damage to the GAG-mucus-mucin layer allows urinary solutes such as urea and potassium to permeate the bladder wall. 14 Leakage of potassium into the bladder depolarizes nerves and muscles, eventually causing tissue damage and pain (Figure 1). 15 It should be noted that pain can occur in the absence of histologic evidence of tissue damage; most patients with mild IC will have an entirely normal bladder appearance on cystoscopy. Women with IC also have more C fibers (pain-carrying nerves that carry and release substance P) and mast cells 2 Hospital Physician Board Review Manual

3 Irritating solutes GAG layer Urothelium Irritated nerve Inflammation Figure 1. The pathophysiology of interstitial cystitis is believed to involve damage to the glycosaminoglycan (GAG) layer overlying the bladder epithelium. within their bladder walls. 16 Activation of C fibers causes the release of substance P, triggering activation of mast cells and the release of histamines as well as other inflammation-producing substances (including leukotrienes and prostaglandins). This release causes the activation of nerve fibers, which eventually leads to a hyperalgesic response to many stimuli, with considerable pain and nerve cell injury. Mast cells have been observed histologically in the submucosa and detrusor muscles of some patients with IC 17 as well as in the lamina propria and bladder epithelium, but their absence does not rule out the presence of IC. Substance P can also be transmitted along C fibers and has been associated with other painful inflammatory syndromes. 16 Women with IC have significantly lower levels of the urinary glycoprotein GP51 than do women with other inflammatory conditions. 18 Similarly, antiproliferative factor (AFP) is found in an overwhelming majority of women with IC (94%) versus only 9% of asymptomatic control patients. 19 Despite excitement regarding the possibility that these substances might become urinary markers for IC, AFP and GP51 are still entirely investigational and are not currently available outside of a research setting. Although GP51 is a GAG marker, it may not be exclusive to it. A potential genetic susceptibility was recently supported by a pilot study that found that first-degree relatives of women previously diagnosed with IC have a risk for IC 17 times greater than that in women in the general population. 20 Other theories that have not been substantiated include the presence of as yet unidentifiable microbes or bacteria and autoimmune processes. The pathogenesis of IC, therefore, most likely is due to damage and depletion of the GAG layer, neural upregulation, and mast cell activation that, over time, leads to the destruction of muscle and blood vessels in the bladder wall. Activation of C fibers causes the release of substance P, which along with the release of other inflammation-producing substances (eg, leukotrienes and prostaglandins) leads to a hyperalgesic response with considerable pain and nerve cell injury. 16 As such, IC is not an end organ disease but rather a visceral pain syndrome in which neuropathic up-regulation is a key component. EVALUATION AND DIAGNOSIS OF SUSPECTED IC CASE PRESENTATION Initial Presentation and History A 36-year-old white woman (gravida 1 para 1) presents for evaluation of ongoing pelvic pain and dyspareunia. The patient reports a 5-year history of constant symptoms Obstetrics and Gynecology Volume 9, Part 4 3

4 Table 1. Differential Diagnosis of Interstitial Cystitis Bladder or recurrent urinary tract infection Sexually transmitted infection Vaginal infection Neurologic disorders Uterovaginal prolapse Cystoceles/rectoceles Urethral diverticula Bladder cancer Pelvic inflammatory disease Endometriosis Untreated chlamydial infection Primary and secondary dysmenorrhea Vulvodynia/vaginitis Renal calculi Low-count bacteria in urine culture Pelvic floor dysfunction Adenomyosis Intra-abdominal adhesions of CPP, dyspareunia, and recurring UTI-type symptoms. She has undergone 2 laparoscopies for suspected endometriosis, which revealed no pathologic changes in the pelvic cavity. The patient has been seen by a urologist for her recurrent UTI symptoms and has undergone 2 urethral dilatation procedures. The patient reports taking 5 courses of antibiotic therapy over the past year, including ciprofloxacin, levofloxacin, nitrofurantoin monohydrate/macrocrystals, and cotrimoxazole. What is the clinical presentation of IC? CLINICAL PRESENTATION IC is characterized by urinary urgency and frequency along with pelvic pain that may worsen with bladder filling and lessen with bladder emptying. These symptoms can range from mild to severe in intensity and are not associated with any overt bladder pathology or defined bacterial etiology. Most patients with early IC suffer from only urgency or frequency. 21 Some patients have pain only, some have urgency/frequency only, and many have both. 22 Women with IC typically report nocturia, which may be mild (voiding twice per night) to severe (voiding 12 times per night), dyspareunia, and premenstrual and/or postcoital flares. IC should be suspected in all women with CPP symptoms or urinary urgency and frequency, particularly in women with refractory UTI or overactive bladder (OAB) who have failed to respond to antibiotics or anticholinergic treatments, respectively, and women with persistent symptoms of endometriosis who have failed to respond to standard therapies, including variabledose oral contraceptives or leuprolide. However, anatomic, metabolic, or functional abnormalities should be ruled out in women with suspected UTI who fail to respond to antibiotic therapy. 23 Studies have found that up to 26% of women who underwent hysterectomy for CPP continued to have pelvic pain after the procedure, and 80% of women with persistent or recurrent pelvic pain post-hysterectomy were found to have IC. 27 Any woman who presents with CPP and urinary urgency and frequency in the absence of definable pathology should be evaluated for IC, and diagnostic tests to identify IC should be performed prior to laparoscopy or hysterectomy for CPP. What is the differential diagnosis of IC? DIFFERENTIAL DIAGNOSIS IC is a diagnosis of exclusion. Other possible causes of urinary urgency and frequency and pelvic pain must be ruled out, including recurrent UTI, sexually transmitted disease (particularly chlamydial or mycoplasmal infection and gonorrhea), vaginal infection, and vaginitis (Table 1). In addition, several abdominopelvic and urogenital causes of CPP should be considered in the differential diagnosis of IC. Both IC and gynecologic conditions can present with generalized pelvic pain (eg, lower abdomen, urethra, perineum, medial thighs), dyspareunia, pain on bladder filling, voiding symptoms (frequency, urgency, nocturia), premenstrual exacerbations, and exacerbations after sexual intercourse. The etiology of CPP is frequently assumed to be endometriosis, chronic pelvic inflammatory disease (PID), or vulvodynia. However, in a recent study at least one third of women with CPP were found to have cystoscopically confirmed IC, 28 defined as glomerulations ( 10/quadrant in at least 3 quadrants) and/or a Hunner s ulcer. In addition, endometriosis and vulvodynia can coexist with IC. A prospective study found a high incidence (81%) of comorbidity between IC and endometriosis, suggesting that IC should be considered even when endometriosis is present. 29 Finally, PID, untreated chlamydial infection, 30 intra-abdominal adhesions, 31,32 secondary dysmenorrhea, and adenomyosis can cause CPP. Vulvodynia is characterized by acute-onset vulvar pain, soreness, rawness, burning, or stinging that can become chronic without appropriate treatment. 33 As 4 Hospital Physician Board Review Manual

5 with IC, vulvodynia is almost exclusively present in premenopausal white women 33 and is a common cause of dyspareunia. 34 Vulvar vestibulitis syndrome (VVS) is the only subclass of vulvodynia related to IC. VVS is characterized by introital erythema and chronic and severe tenderness or pain with intercourse or vestibular touch. Acute VVS can be caused by human papillomavirus (HPV), an allergic reaction, or an autoimmune process; in contrast, there is no known cause of chronic VVS. The 4 other subclasses of vulvodynia include vulvar dermatoses, vestibular papillomatosis, dysesthetic (or essential) vulvodynia, and cyclic candidiasis/vulvovaginitis. Vulvar dermatoses, and particularly vulvar dermatitis, are painful infections or diseases of the vulvar skin characterized by thick or scaly vulvar lesions, itching, and erythema. Treatment typically involves topical corticosteroids, testosterone, or imidazole. Vestibular papillomatosis may be a normal anatomic variation or a result of HPV. Dysesthetic vulvodynia is characterized by diffuse, constant (versus cyclic) vulvar pain or burning, with no apparent point tenderness upon physical examination or intercourse. Subclinical doses of tricyclic antidepressants (TCAs) appear to provide the necessary relief from pain for women with this classification of vulvodynia. Vulvovaginitis and cyclic candidiasis are common causes of vulvodynia in women of reproductive age and are characterized by vulvar discomfort and burning, predominantly caused by Candida albicans. Women with cyclic candidiasis/vulvovaginitis may report that these symptoms are exacerbated prior to or during menses. Cyclic vulvovaginitis can be treated with fluconazole and dietary changes. Bladder-related conditions that present with CPP symptoms include OAB and recurrent UTI. These are characterized by urinary urgency and frequency, with or without urge incontinence, and with or without pain. Unlike UTI, neither IC nor OAB has a bacterial etiology. How is the diagnosis of IC made? DIAGNOSIS The approach to diagnosing IC is currently evolving. In its 1987 workshop on IC, the National Institute of Arthritis, Diabetes, Digestive, and Kidney Diseases developed a research definition for IC, 35 which has since been called into question as being too restrictive to be used as a clinical diagnosis for IC. 36 Revised criteria have recently been developed but await formal publication. These criteria reflect a clinical diagnosis emphasizing a history of urinary frequency and urgency with pelvic pain in the absence of other overt bladder pathology combined with urinalysis and urine culture to rule out Table 2. Diagnosing Interstitial Cystitis Pertinent symptom history Urinary urgency and frequency Pelvic pain (3 months) Premenstrual flares Flares with diet, allergies, coitus High symptom/bother and total scores on PUF scale Pertinent physical examination findings Suprapubic tenderness Anterior vaginal wall/bladder base tenderness Levator muscle spasm Rectal spasm Laboratory analyses Urinalysis and urine culture Urine cytology Voiding log Other tests Potassium sensitivity test Cystoscopy with or without hydrodistention PUF scale = Pelvic Pain Urgency and Frequency Symptom Scale. infection and cytology to rule out bladder cancer in women with microscopic hematuria (Table 2). Some women with IC may require an intravenous pyelogram to rule out the presence of calculi in the lower ureter and/or a cystometrogram with uroflow examination to identify any blockages in the passage of urine or the presence of a voiding dysfunction. Two additional tools useful for facilitating a diagnosis when IC is suspected are the Pelvic Pain Urgency and Frequency (PUF) Symptom Scale and the intravesical potassium sensitivity test (PST). Pelvic Pain Urgency and Frequency Scale The PUF symptom scale is a self-administered questionnaire that measures both the presence and severity of symptoms characteristic of IC and the degree to which women are bothered by the symptoms (Figure 2). 11 The questions address the frequency and urgency of voiding during waking and sleeping hours, the presence of pelvic pain, and the presence of pain or urinary urgency during or after sexual intercourse. The questionnaire requires approximately 5 minutes to complete and is easy to score. The PUF symptom scale can differentiate IC from other bladder conditions causing CPP, including recurrent UTI or OAB, and can reliably identify women with Obstetrics and Gynecology Volume 9, Part 4 5

6 Circle the answer that best describes how you feel for each question. Symptom Bother Score Score 1. How many times do you go to the bathroom during waking hours? a. How many times do you go to the bathroom at night? b. If you get up at night to go to the bathroom, to what extent None Mild Moderate Severe does it usually bother you? 3. Are you currently sexually active: Yes No 4. a. If you are sexually active, do you now have or have you ever Never Occasionally Usually Always had pain or urgency to urinate during or after sexual intercourse? b. Has pain or urgency ever made you avoid sexual intercourse? Never Occasionally Usually Always 5. Do you have pain associated with your bladder or in your pelvis, Never Occasionally Usually Always vagina, lower abdomen, urethra, perineum, testes, or scrotum? 6. Do you still have urgency shortly after urinating? Never Occasionally Usually Always 7. a. When you have pain, is it usually... Mild Moderate Severe b. How often does your pain bother you? Never Occasionally Usually Always 8. a. When you have urgency, is it usually... Mild Moderate Severe b. How often does your urgency bother you? Never Occasionally Usually Always Symptom score (1, 2a, 4a, 5, 6, 7a, 8a) = Bother score (2b, 4b, 7b, 8b = Total score (symptom score + bother score) = Figure 2. The Pelvic Pain Urgency and Frequency (PUF) Symptom Scale for diagnosis of interstitial cystitis (IC). PUF is a constellation of symptoms identified by IC experts as characteristic of IC. The more symptoms a patient experiences, the more likely the diagnosis of IC. Note that IC also may occur in men. (Adapted with permission from Parsons CL, Dell J, Stanford EJ, et al. Increased prevalence of interstitial cystitis: previously unrecognized urologic and gynecologic cases identified using a new symptom questionnaire and intravesical potassium sensitivity. Urology 2002;60:575.) a high likelihood of having IC. The maximum score is 35 points; high symptom/bother and total scores (considered to be 10 points) indicate a high probability of IC. Women who score 5 or more points on the PUF questionnaire have at least a 55% likelihood of having IC. 11 In contrast, nearly all healthy women have low PUF scores (< 2 points), indicating the test is highly specific. Potassium Sensitivity Test The PST is based upon the premise that women with IC have an abnormality of the GAG layer, and the introduction of a potassium solution into the bladder will cause symptoms of pain and urgency. The test is performed on an outpatient basis and can identify those patients who have a bladder etiology for their pelvic pain. The PST involves the very slow introduction (over 2 to 3 minutes) of 40 ml of room temperature sterile water into the bladder through a thin catheter, such as a LoFric (Astra Tech Inc., Waltham, MA) catheter or a #8 French pediatric feeding tube used as a catheter (Figure 3). Women with IC are quite volume sensitive and can respond with symptoms of sensory urgency upon the rapid introduction of any solution into the bladder. The woman establishes her baseline of pain and urgency upon bladder filling by rating the symptoms following the initial instillation on a scale of 0 to 5 points, with 5 representing the most severe pain. The water is left in the bladder for up to 5 minutes before being emptied through the catheter, after which potassium chloride (KCl) solution is instilled. The solution mixes 20 meq of KCl with enough sterile water to bring the volume to 50 ml; 40 ml of the mixture is used. 7 The woman then reevaluates her level of pain and/or urgency. An increase of 2 points or greater with KCl compared with water indicates abnormal epithelial dysfunction and should be considered a positive reaction, which is highly diagnostic of the presence of IC. 7 Women who respond with pain and urgency to only the instillation of water 6 Hospital Physician Board Review Manual

7 Drain bladder Insert small urethral catheter Solution 1 Solution 2 Solution 3 40 ml water 40 ml 0.4 M KCl Immediate pain: drain bladder and wash with 60 ml water Slowly instill over 2 3 min No immediate reaction: allow to remain 5 min Positive test Rank urgency (0 5) Rank pain (0 5) Rank urgency (0 5) Rank pain (0 5) Instill rescue therapy Drain bladder Void bladder Figure 3. The potassium sensitivity test for interstitial cystitis. KCl = potassium chloride. (Adapted with permission from Parsons CL, Greenberger M, Gabal L, et al. The role of urinary potassium in the pathogenesis and diagnosis of interstitial cystitis. J Urol 1998; 159: ) also are considered likely to have IC. Some women with IC do not respond immediately to the KCI solution; as such, it can be retained in the bladder for up to 5 minutes before evaluating the pain/urgency response. Women without IC rarely respond with pain following instillation of the KCI solution, even after retaining it for an extended period of time. A significant proportion of patients with IC (> 70%) have a positive PST result, in contrast to 9% or fewer of healthy patients. 15,37,38 Two recent studies reported that 80% 11 to 85% 7 of gynecologic patients with CPP who were initially diagnosed with other causes of CPP (eg, endometriosis or vulvodynia) had a positive PST result, confirming a bladder component as the cause of CPP. The PST is not considered sufficient evidence to conclusively diagnose IC, 39 as other bladder diseases (most notably acute bacterial cystitis and radiation cystitis) can also cause a positive test result. Negative results can occur in patients with IC who have recently undergone hydrodistention or intravesical dimethyl sulfoxide (DMSO) or heparin therapy, women taking pain medications, or women whose sensory nerves are already maximally stimulated. 15 It is important to note that patients may experience mild symptom exacerbation following potassium sensitivity testing. What is the value of cystoscopy with hydrodistention in the diagnosis of IC? Historically, cystoscopy with or without hydrodistention was considered necessary to diagnose IC. Approximately 11% of patients with severe IC demonstrate the presence of classic erythematous patches (Hunner s ulcers) during cystoscopy; 40 however, it is currently believed that fewer than 2% of all patients with IC have a Hunner s patch. In addition, petechial hemorrhages have been reported in normal patients. 41 There is a risk of small ureteral tears and a very rare risk of significant bladder perforations associated with cystoscopy with hydrodistention. This procedure is therefore of limited benefit for diagnosing IC and should be performed only in women with microscopic or gross hematuria to rule out the presence of bladder carcinoma in situ. Cystoscopy with hydrodistention can be used in the diagnosis of bladder cancer, with follow-up biopsy. Finally, cystoscopy with hydrodistention often results in a significant increase in symptoms for 2 to 4 weeks post-procedure. CASE CONTINUED Physical Examination On physical examination, the patient exhibits suprapubic tenderness, tenderness of the anterior vaginal wall and bladder base, and rectal spasm. The physical Obstetrics and Gynecology Volume 9, Part 4 7

8 examination rules out vaginitis, vulvodynia, urethral diverticula, uterovaginal prolapse, and pelvic floor dysfunction. Initial Evaluation Urinalysis with urine culture and sexually transmitted disease testing are performed, and all results are negative. The physician administers the PUF symptom scale questionnaire, which is scored as Given the highly positive score, the physician does not administer the PST. Based on the patient s history, physical examination, urine assessment, and PUF score, the physician makes a presumptive diagnosis of IC. Is it appropriate to forgo the PST when there is a positive result on the PUF scale? The approach demonstrated in this case is supported by earlier studies that demonstrated that 91% of women with a PUF score greater than 20 have a positive result on potassium sensitivity testing. 11 Similarly, 76% of women who score between 15 and 19 and 74% of women who score between 10 and 14 points have a positive PST result, whereas patients with a PUF score below 4 have only a 2% or less likelihood of a positive test. 11 The high correlation between the PUF symptom scale and the PST enables clinicians to administer the PUF questionnaire as the initial diagnostic technique, reserving the PST for those women whose symptoms and history are highly suggestive of IC but who have a PUF score of 5 to 9 points. TREATMENT FOR IC CASE CONTINUED The patient expresses relief at having a diagnosis for her symptoms. However, she is concerned about how IC is treated and asks her physician what therapies are available. What treatment options are available for patients with IC? PHARMACOLOGIC TREATMENTS Only 2 pharmacologic treatments have been approved by the Food and Drug Administration (FDA) for the management of IC: intravesical instillations with DMSO 42 and oral pentosan polysulfate sodium (PPS). 43 Dimethyl Sulfoxide DMSO is an anti-inflammatory analgesic with musclerelaxing properties. The exact mechanism of action underlying the efficacy of DMSO for the management of IC remains unknown. Intravesical administration of DMSO has been shown to acutely increase reflex firing of pelvic nerve afferent axons and to decrease bladder capacity as well as induce release of nitric oxide from afferent neurons. 44 It has also been hypothesized that DMSO stimulates mast cell degranulation, but a study to confirm this found no immediate or delayed histamine release after intravesical administration of DMSO. 45 DMSO treatments can be administered at home or in the office for 6 to 8 weeks on a weekly or biweekly schedule. The procedure involves instilling 50 ml of DMSO into the bladder through a catheter, where it is retained for approximately 15 minutes before being voided. DMSO can produce a garlic-like taste and/or odor on the breath and skin for up to 72 hours posttreatment. DMSO has a good safety profile but, as per product prescribing information, patients receiving chronic DMSO treatments are advised to undergo kidney and liver function tests, as well as full eye examinations (including slitlamp eye evaluations) every 6 months. 42 Clinical trials have demonstrated moderate efficacy with DMSO treatment, with subjective improvements reported in 50% to 80% of patients with IC Symptomatic relief is reported within 3 to 4 weeks after the first 6- to 8-week cycle; however, DMSO rarely provides complete remissions, and many patients require additional treatment courses that can reduce the duration of remissions. Pentosan Polysulfate Sodium PPS is a heparinoid-like compound similar in chemistry and structure to the GAGs that are produced in the urinary epithelium. 43 PPS is believed to replenish the defective GAG (mucus) layer and inhibit inflammatory processes, 48 thereby acting as a buffer to control cell permeability and prevent irritating solutes from reaching epithelial cells; it may also have a stabilizing effect on mast cells. 49 PPS is the only FDA-approved oral therapy for management of IC. The recommended dosage of oral PPS is 300 mg/day taken as one 100-mg capsule 3 times daily. PPS has a good safety profile, with no drugdrug interactions and infrequent, mild and transient side effects (including minor gastrointestinal discomfort, headache, and reversible alopecia). Slight liver function changes have been reported in approximately 1% of patients receiving PPS; these changes, which spontaneously resolve, have not been associated with clinical signs or symptoms, and do not necessitate routine liver function testing in patients using this agent. Women whose IC symptoms are not debilitating 8 Hospital Physician Board Review Manual

9 usually experience pain relief with oral PPS within 3 months after treatment initiation; women with moderate-to-severe disease usually require therapy for at least 4 to 6 months before improvement occurs. 50 Clinical trials have shown that, compared with placebo, oral PPS (300 mg/day) affords women greater subjective improvement in pain, urgency, frequency, and nocturia, as well as significant objective improvement in average voided volumes. 51,52 Ongoing treatment with PPS (> 3 months) leads to greater symptomatic relief of the pain and urgency of IC as well as longer remissions that persist for 3 or more years. 53 In general, it is recommended that women remain on oral PPS therapy for a minimum of 6 months, with longer treatment durations (6 to 12 months) suggested for women with severe or long-standing disease. Patients who are taking PPS are typically scheduled for follow-up visits at 3 months and 6 months, and then on an annual basis thereafter. Some women will require ongoing therapy with oral PPS, particularly if they have severe and/or long-standing disease. ADJUNCTIVE THERAPIES FOR PAIN RELIEF Anesthetic intravesical solutions containing lidocaine (either 10 ml 1% lidocaine or 16 ml 2% lidocaine) and heparin (10,000 40,000 U) as the active agents are currently used as adjunctive therapy for women with severe disease in order to provide immediate relief of urinary urgency and pain. Sodium bicarbonate (8.4%) dramatically increases the intravesical absorption of lidocaine. 54 Because the benefits of the solution are temporary, lasting for several days at most, case series recommend using a total of 9 instillations, with 3 during the first week and 1 per week for 6 weeks. The procedure involves the instillation of the anesthetic solution into an empty bladder with either a LoFric catheter or a #8 French pediatric feeding tube while the patient is placed in the dorsal lithotomy position. The patient retains the solution for approximately 30 minutes or until she needs to void. The procedure can be performed in the office or by the patient herself at home. Women with moderate-to-severe IC may require other adjunctive therapy to facilitate greater relief from their pain and bladder symptoms (Table 3). Analgesics, including aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), inhibit prostaglandin synthesis and alleviate mild discomfort. However, NSAIDs can exacerbate symptoms by releasing histamines, so they should only be recommended with caution. Women with severe disease may require opioid analgesics, including acetaminophen with codeine, during the initial treatment phase. Table 3. Supportive Therapies in the Management of Interstitial Cystitis Pharmacologic approaches Oral analgesics Oral antihistamines Oral amitriptyline Oral antispasmodic agents Intravesical heparin sulfate Nonpharmacologic approaches Diet modification Bladder re-training techniques Women with considerable nocturia or difficulty sleeping may benefit from antihistamines, particularly hydroxyzine hydrochloride (25 75 mg/day), which has been shown to reduce IC symptoms in at least 40% of patients with IC. 55 The analgesic and soporific properties of the TCA amitriptyline (10 75 mg for every hour of sleep) provide mild-to-moderate central pain modulation in a majority of patients and can also reduce the symptoms of nocturia and urinary frequency. 56 TCAs facilitate pain relief by inhibiting histamine secretion from mast cells and decreasing norepinephrine and serotonin reuptake in the central and peripheral nervous system. However, TCAs can cause cardiac irregularities and constipation. Adjunctive treatment with amitriptyline should be initiated at the lowest dosage and gradually titrated up to the dosage that provides maximal symptomatic relief without unnecessary adverse effects. Antispasmodic agents (eg, hyoscyamine sulfate), hormone therapies (eg, gonadotropin analogues and oral contraceptives), 57 and the antiepileptic agent gabapentin 58 have also been used to help manage IC in women. These therapies reduce symptom severity and pain. Intravesical heparin sulfate has been used as both monotherapy and combination therapy with DMSO for the treatment of IC, although it is not approved by the FDA for the treatment of IC. Heparin is a natural component of the bladder epithelium, which is believed to help protect the bladder mucosa against bacterial invasion. 59 When instilled intravesically, heparin has led to clinical remissions 60 and significant improvement of symptoms 61 in more than half of the women treated. The addition of intravesical heparin to DMSO therapy reduces the relapse rate, 62 extends remissions, 63 and may provide greater symptom relief than DMSO alone. 64 Obstetrics and Gynecology Volume 9, Part 4 9

10 NONPHARMACOLOGIC APPROACHES Behavioral approaches, specifically diet modification and bladder re-training techniques, can enhance the benefits of pharmacologic treatments for IC and are occasionally sufficient as monotherapy. Case series suggest that women with IC benefit from eliminating foods high in potassium, acidity, caffeine, spices, or artificial sweeteners. Cigarette smoking is a major known cause of bladder cancer and may also exacerbate IC symptoms; smoking cessation should be strongly recommended. Because women with IC void an average of 16.5 times per day, versus 6.5 times per day for healthy women, 65 bladder re-training techniques, including scheduled or timed voiding, can help women with IC gradually increase the time between voids until they can be spaced every 3 to 4 hours. Relaxation, distraction, and biofeedback techniques can augment these behavioral therapies. Physical therapy to teach gentle stretching and pelvic floor relaxation exercises may also be indicated. Warm sitz baths may provide short-term symptom relief; heating pads on the perineal area prior to intercourse and/or ice packs after intercourse can help minimize IC-related dyspareunia. When is surgery indicated? SURGICAL MANAGEMENT Surgery is used only as a last resort, and success is not ensured. Hunner s ulcers can be cauterized through fulguration or a laser passed through the urethra under general anesthesia. Surgical resection, also through the urethra under general anesthesia, can excise Hunner s ulcers. The bladder can be enlarged through augmentation by attaching part of the large intestine, which will allow for less frequent voiding but will not necessarily cure the pain. In fact, IC can recur in the segment of bowel used for the bladder augmentation, and the symptoms of pain, frequency, and urgency can remain or return after the surgery. Bladder augmentation can also lead to incontinence. Finally, cystectomy (removal of the bladder) is performed only under extreme circumstances. CASE CONCLUSION The physician initiates treatment with oral PPS therapy 100 mg 3 times daily for 6 months. The patient also is treated with bladder instillation therapy using a solution containing 10,000 U of heparin, 16 ml of 2% lidocaine, and 3 ml of sodium bicarbonate buffer. The patient is scheduled for follow-up visits at 3 months. At 3 months, the patient s PUF symptom score is reduced to 8. The Patient Overall Rating of Improvement in Symptoms (PORIS) scale reveals 75% overall improvement with regard to urgency and pain. At 6 months, the patient reports significant reduction in her discomfort with intercourse and says she has not experienced symptoms of bladder or vaginal infection in several months. The physician recommends that the patient continue PPS therapy, noting that some patients may experience a return of symptoms if the drug is discontinued too early. REFERENCES 1. Mathias SD, Kuppermann M, Liberman RF, et al. Chronic pelvic pain: prevalence, health-related quality of life, and economic correlates. Obstet Gynecol 1996;87: Chronic pelvic pain. Washington (DC): American College of Obstetricians and Gynecologists; ACOG practice bulletin, No Walker EA, Katon WJ, Jemelka R, et al. The prevalence of chronic pelvic pain and irritable bowel syndrome in two university clinics. J Psychosom Obstet Gynaecol 1991;12: Howard FM. The role of laparoscopy in chronic pelvic pain: promise and pitfalls. Obstet Gynecol Surv 1993;48: Levitan Z, Eibschitz I, de Vries K, et al. The value of laparoscopy in women with chronic pelvic pain and a normal pelvis. Int J Gynaecol Obstet 1985;23: Lee NC, Dicker RC, Rubin GL, Ory HW. Confirmation of the preoperative diagnoses for hysterectomy. Am J Obstet Gynecol 1984;150: Parsons CL, Bullen M, Kahn BS, et al. Gynecologic presentation of interstitial cystitis as detected by intravesical potassium sensitivity. Obstet Gynecol 2001;98: National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC). Interstitial cystitis. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; NIH Publication No Curhan GC, Speizer FE, Hunter DJ, et al. Epidemiology of interstitial cystitis: a population based study. J Urol 1999;161: Jones CA, Nyberg L. Epidemiology of interstitial cystitis. Urology 1997;49(5A Suppl): Parsons CL, Dell J, Stanford EJ, et al. Increased prevalence of interstitial cystitis: previously unrecognized urologic and gynecologic cases identified using a new symptom questionnaire and intravesical potassium sensitivity. Urology 2002;60: Propert KJ, Schaeffer AJ, Brensinger CM, et al. A prospective study of interstitial cystitis: results of longitudinal follow-up of the interstitial cystitis data base cohort. The 10 Hospital Physician Board Review Manual

11 Interstitial Cystitis Data Base Study Group. J Urol 2000; 163: Ratner V, Slade D, Greene G. Interstitial cystitis. A patient s perspective. Urol Clin North Am 1994;21: Moldwin RM, Sant GR. Interstitial cystitis: a pathophysiology and treatment update. Clin Obstet Gynecol 2002; 45: Parsons CL, Greenberger M, Gabal L, et al. The role of urinary potassium in the pathogenesis and diagnosis of interstitial cystitis. J Urol 1998;159: Pang X, Marchand J, Sant GR, et al. Increased number of substance P positive nerve fibres in interstitial cystitis. Br J Urol 1995;75: Theoharides TC, Sant GR. Bladder mast cell activation in interstitial cystitis. Semin Urol 1991;9: Byrne DS, Sedor JF, Estojak J, et al. The urinary glycoprotein GP51 as a clinical marker for interstitial cystitis. J Urol 1999;161: Keay SK, Zhang CO, Shoenfelt J, et al. Sensitivity and specificity of antiproliferative factor, heparin-binding epidermal growth factor-like growth factor, and epidermal growth factor as urine markers for interstitial cystitis. Urology 2001;57(6 Suppl 1): Warren JW, Jackson TL, Langenberg P, et al. Prevalence of interstitial cystitis in first-degree relatives of patients with interstitial cystitis. Urology 2004;63: Parsons CL. Interstitial cystitis: epidemiology and clinical presentation. Clin Obstet Gynecol 2002;45: Driscoll A, Teichman JM. How do patients with interstitial cystitis present? J Urol 2001;166: MacDiarmid SA, Whitmore KE. Framework for understanding overactive bladder, interstitial cystitis, urinary tract infection. Female Patient 2003;Suppl: Kjerulff KH, Langenberg PW, Rhodes JC, et al. Effectiveness of hysterectomy. Obstet Gynecol 2000;95: Stovall TG, Ling FW, Crawford DA. Hysterectomy for chronic pelvic pain of presumed uterine etiology. Obstet Gynecol 1990;75: Hillis SD, Marchbanks PA, Peterson HB. The effectiveness of hysterectomy for chronic pelvic pain. Obstet Gynecol 1995;86: Chung MK. Posthysterectomy pelvic pain (do not forget the bladder!) [abstract]. JSLS 2003;7:S Clemons JL, Arya LA, Myers DL. Diagnosing interstitial cystitis in women with chronic pelvic pain. Obstet Gynecol 2002;100: Chung MK, Chung RR, Gordon D, Jennings C. The evil twins of chronic pelvic pain syndrome: endometriosis and interstitial cystitis. JSLS 2002;6: Alexander LL, Treiman K, Clarke P. A national survey of nurse practitioner chlamydia knowledge and treatment practices of female patients. Nurse Pract 1996;21:48, Gowri V, Krolikowski A. Chronic pelvic pain. Laparoscopic and cystoscopic findings. Saudi Med J 2001;22: Almeida EC, Nogueira AA, Candido dos Reis FJ, Rosa e Silva JC. Cesarean section as a cause of chronic pelvic pain. Int J Gynaecol Obstet 2002;79: Metts JF. Vulvodynia and vulvar vestibulitis: challenges in diagnosis and management. Am Fam Physician 1999;59: , Bergeron S, Binik YM, Khalife S, Pagidas K. Vulvar vestibulitis syndrome: a critical review. Clin J Pain 1997;13: Gillenwater JY, Wein AJ. Summary of the National Institute of Arthritis, Diabetes, Digestive, and Kidney Diseases workshop on interstitial cystitis. National Institutes of Health, Bethesda, MD, August 28 29, J Urol 1988; 140: Hanno PM, Landis JR, Mathews-Cook Y, et al. The diagnosis of interstitial cystitis: lessons learned from the National Institutes of Health Interstitial Cystitis Database study. J Urol 1999;161: Parsons CL, Zupkas P, Parsons JK. Intravesical potassium sensitivity in patients with interstitial cystitis and urethral syndrome. Urology 2001;57: Parsons CL. Prostatitis, interstitial cystitis, chronic pelvic pain, and urethral syndrome share a common pathophysiology: lower urinary dysfunctional epithelium and potassium recycling. Urology 2003;62: Chambers GK, Fenster HN, Cripps S, et al. An assessment of the use of intravesical potassium in the diagnosis of interstitial cystitis. J Urol 1999;162(3 Pt 1): Nigro DA, Wein AJ, Foy M, et al. Associations among cystoscopic and urodynamic findings for women enrolled in the Interstitial Cystitis Data Base (ICDB) Study. Urology 1997;49(5A Suppl): Waxman JA, Sulak PJ, Kuehl TJ. Cystoscopic findings consistent with interstitial cystitis in normal women undergoing tubal ligation. J Urol 1998;160: RIMSO-50. In: 2004 physicians desk reference. 58th ed. Montvale (NJ): Thomson Healthcare; 2003: Elmiron. In: 2005 physicians desk reference. 59th ed. Montvale (NJ): Thomson Healthcare; 2004: Birder LA, Kanai AJ, de Groat WC. DMSO: effect on bladder afferent neurons and nitric oxide release. J Urol 1997;158: Stout L, Gerspach JM, Levy SM, et al. Dimethyl sulfoxide does not trigger urine histamine release in interstitial cystitis. Urology 1995;46: Barker SB, Matthews PN, Philip PF, Williams G. Prospective study of intravesical dimethyl sulphoxide in the treatment of chronic inflammatory bladder disease. Br J Urol 1987;59: Obstetrics and Gynecology Volume 9, Part 4 11

12 47. Perez-Marrero R, Emerson LE, Feltis JT. A controlled study of dimethyl sulfoxide in interstitial cystitis. J Urol 1988;140: Parsons CL, Boychuk D, Jones S, et al. Bladder surface glycosaminoglycans: an epithelial permeability barrier. J Urol 1990;143: Chiang G, Patra P, Letourneau R, et al. Pentosan polysulfate inhibits mast cell histamine secretion and intracellular calcium ion levels: an alternative explanation of its beneficial effect in interstitial cystitis. J Urol 2000; 164: Parsons CL, Benson G, Childs SJ, et al. A quantitatively controlled method to study prospectively interstitial cystitis and demonstrate the efficacy of pentosan polysulfate. J Urol 1993;150: Parsons CL, Mulholland SG. Successful therapy of interstitial cystitis with pentosan polysulfate. J Urol 1987;138: Mulholland SG, Hanno P, Parsons CL, et al. Pentosan polysulfate sodium for therapy of interstitial cystitis. A double-blind placebo-controlled clinical study. Urology 1990;35: Parsons CL, Forrest J, Nickel JC, et al. Effect of pentosan polysulfate therapy on intravesical potassium sensitivity. Elmiron Study Group. Urology 2002;59: Henry R, Patterson L, Avery N, et al. Absorption of alkalized intravesical lidocaine in normal and inflamed bladders: a simple method for improving bladder anesthesia. J Urol 2001;165(6 Pt 1): Theoharides TC, Sant GR. Hydroxyzine therapy for interstitial cystitis. Urology 1997;49(5A Suppl): Hanno PM. Amitriptyline in the treatment of interstitial cystitis. Urol Clin North Am 1994;21: Lentz GM, Bavendam T, Stenchever MA, et al. Hormonal manipulation in women with chronic, cyclic irritable bladder symptoms and pelvic pain. Am J Obstet Gynecol 2002;186: Hansen HC. Interstitial cystitis and the potential role of gabapentin. South Med J 2000;93: Chin JL, Sharpe JR. The anti-adherence effect of heparin: a visual analysis. Urol Res 1983;11: Parsons CL, Housley T, Schmidt JD, Lebow D. Treatment of interstitial cystitis with intravesical heparin. Br J Urol 1994;73: Kuo HC. Urodynamic results of intravesical heparin therapy for women with frequency urgency syndrome and interstitial cystitis. J Formos Med Assoc 2001;100: Perez-Marrero R, Emerson LE, Maharajh DO, Juma S. Prolongation of response to DMSO by heparin maintenance. Urology 1993;41(1 Suppl): Ghoniem GM, McBride D, Sood OP, Lewis V. Clinical experience with multiagent intravesical therapy in interstitial cystitis patients unresponsive to single-agent therapy. World J Urol 1993;11: Sun Y, Chai TC. Effects of dimethyl sulphoxide and heparin on stretch-activated ATP release by bladder urothelial cells from patients with interstitial cystitis. BJU Int 2002;90: Parsons CL, Koprowski PF. Interstitial cystitis: successful management by increasing urinary voiding intervals. Urology 1991;37: Copyright 2005 by Turner White Communications Inc., Wayne, PA. All rights reserved. 12 Hospital Physician Board Review Manual