Chronic Pelvic Pain: When to Suspect Interstitial Cystitis

ABSTRACT: Consider interstitial cystitis (IC) when a patient presents with urinary frequency and urgency and/or pelvic pain and no other cause of the symptoms can be identified. Symptom surveys, such as the Pelvic Pain and Urgency/Frequency scale and the O’Leary-Sant symptom and problem indices, can facilitate diagnosis. Rule out diseases that have similar symptoms, such as urinary tract infection, and order a urinalysis to screen for hematuria and bacteriuria. The potassium sensitivity test and the anesthetic bladder challenge may also help with the diagnosis. Avoidance of potassium-rich foods and stress reduction may ameliorate symptoms. Oral pentosan polysulfate sodium and intravesical dimethyl sulfoxide have been approved by the FDA for the treatment of IC. Symptoms may be slow to respond to therapy; thus, close follow-up (every month for the first 3 months of treatment and every 3 months thereafter) is recommended. Referral to a gynecologist or urologist may be necessary if symptoms do not respond to behavioral or pharmacologic approaches within 6 months.  _______________________________________________________________________________________ Long believed to be a relatively obscure disease, interstitial cystitis (IC) is more prevalent than previously thought. Include this disorder in your differential when a patient presents with urinary urgency and frequency and/or pelvic pain.  In this article, we provide a symptom-based approach to the diagnosis of IC, which can help you identify the condition sooner and distinguish it from other causes of pelvic pain, such as urinary tract infection (UTI) and endometriosis. We also describe office-based diagnostic tests and outline the latest treatment options. OVERVIEW About 1 woman in 7 in the United States experiences chronic pelvic pain.1  Often, it is accompanied by urinary urgency and frequency.1-3  IC is a far more common cause of this symptom complex than was once thought.4  IC can be debilitating. Among patients with severe IC who do not receive treatment, 25% are unable to work full-time. In addition, they are 5 times more likely to be treated for emotional disorders than are persons who do not have the disease.5  One study showed that patients with IC scored significantly worse on quality-of-life evaluations than renal dialysis patients.5 PREVALENCE Historically, the prevalence of IC has been thought to be low. A US population-based study gives prevalence rates of 52 per 100,000 in Nurses Health Study I (IC diagnosed via cystoscopy) and 67 per 100,000 in Nurses Health Study II (prior IC diagnosis).6  These figures are consistent with those in similar diagnosisbased prevalence studies.5,7,8 If these findings were accurate, then it would be rare for clinicians even in large primary care practices to see many patients with this disease. However, in these studies, the diagnosis of IC was based on the classic criteria proposed by Messing and Stamey9  in 1978 and adopted by the National Institute of Diabetes and Digestive and Kidney Diseases in 1988.5 According to these criteria, a diagnosis of IC requires the following: • Pelvic pain. • Urinary urgency and frequency. • Absence of identifiable causes. • Cystoscopic findings of abnormalities (ulcers and/or patchy vascular areas ([glomerulations] produced by hydrodistention of the bladder).9 These highly restrictive criteria were not intended for clinical use (although they have often been used in this way). When they are applied in an office setting, mild or moderate IC may be overlooked.10,11  Moreover, no study has demonstrated the value of cystoscopic findings in the identification of IC, nor have pathologic findings— including glomerulations—been correlated clinically with a diagnosis of IC.12-14 When IC is defined as a symptom complex of urinary urgency and frequency and/or pain in the absence of other definable causes, prevalence rates are much higher. Two surveys are commonly used to assess the symptoms associated with IC: the Pelvic Pain and Urgency/Frequency (PUF) Patient Symptom Scale (Table 1) and the O’Leary-Sant (OLS) symptom and problem indices (Table 2).4,15  Although both are useful, the PUF scale was designed primarily for screening, whereas the OLS indices were created for follow-up.4,15 The ability of the PUF scale to identify the IC symptom complex has been shown through the correlation of PUF scores with results on the potassium sensitivity test (PST), which is thought to be capable of identifying IC. Results of the PST were positive and IC was likely in 1.8% of patients who reported PUF scores of 0 to 4, in 55% of those with scores from 5 to 9, in 74% of those with scores from 10 to 14, in 76% of those with scores from 15 to 19, and in 91% of those with scores of 20 or more.16,17  As part of an exploratory prevalence study, investigators administered the PUF questionnaire to 3883 patients older than 18 years who presented for an office visit for any reason over a 12-month period. When the PUF score and positive PST result were correlated, the prevalence of IC symptoms in the total study population was 13.1%.18 This percentage is notably higher than earlier prevalence figures. The “increase” may be attributable to the study’s reliance on a symptombased evaluation to predict the prevalence of IC in a random population. Other investigators who have looked for IC symptoms in various populations have reported prevalence rates as high as 25%.4,19,20  According to a recent bulletin from the American College of Obstetricians and Gynecologists, 38% to 85% of women who see a gynecologist for chronic pelvic pain may have IC.21 In this article, we define IC as a chronic condition of the lower urinary tract associated with a symptom complex of urinary urgency and frequency and/or pain with no other identifiable cause. PATHOPHYSIOLOGY The exact cause of IC is not fully understood; however, there is mounting evidence that IC is associated with abnormal permeability of the epithelium in the lower urinary tract.10 Normally, the bladder epithelium is coated with a protective mucin layer that contains glycosaminoglycan (GAG).22  Disruption of this protective layer would allow irritative substances from the urine to penetrate the urothelium and affect nerves and muscles in the bladder wall.23-27  This process would result in symptoms such as urinary urgency, frequency, and pain. In their recent study, Keay and colleagues28  identified a glycosylated frizzled-related peptide inhibitor of cell proliferation that is secreted by bladder epithelial cells from IC patients. This substance, known as antiproliferative factor, profoundly inhibits bladder cell production. This important finding strongly supports the theory that a dysfunctional and irritated GAG layer is instrumental in the pathogenesis of IC. An abnormal GAG layer may be only one factor in the development of IC. Evans29  has suggested that irritation of the GAG layer initiates an inflammatory response, which in turn leads to further disruption of the GAG layer (Figure). Current treatment of IC, which includes both repair of the disrupted GAG layer and stabilization of the inflammatory response, targets various aspects of this cycle. Figure – This diagram illustrates one theory of how interstitial cystitis develops. It also indicates the aspects of the disease cycle that are targeted by various therapeutic interventions. To identify the agent or agents that provoke the initial irritation associated with IC, researchers have tested various solutes normally found in the urine for causticity in both healthy and damaged bladders. Parsons and colleagues16  have found convincing evidence that potassium plays a major role in the provocation of symptoms in patients with IC. The concentration of potassium is greater in the urine than in the interstitium, thereby creating an osmotic gradient. This gradient is normally blocked by the protective GAG layer. In the Parsons study, potassium did not provoke symptoms of urgency and pain in healthy patients unless the bladder mucosa had been injured with protamine. Lymphatic, infectious, neurogenic, autoimmune, hormonal, and vasculitic factors have been investigated, but no studies have determined a role for any of these in the pathogenesis of IC.30  Although IC has been observed concomitantly with other diseases, such as irritable bowel syndrome, endometriosis, overactive bladder, allergic/autoimmune phenomena, and vestibulitis, no substantial link has yet been proved. DIAGNOSIS The symptoms of IC overlap those associated with many other chronic pelvic disorders, including UTI, prostatitis, overactive bladder, vulvodynia, vaginitis, and endometriosis.31-34  Often, the cause of a patient’s pelvic pain is never identified.1 Several conditions are commonly misdiagnosed in patients who present with pelvic pain and urinary frequency and urgency. These include: • UTI. • Endometriosis. • Prostatitis. UTI is often diagnosed when a female patient presents with pain, urgency, and frequency; each year, nearly 12 million primary care office visits result in this diagnosis. However, urine culture results are negative in nearly half the patients in whom UTI is diagnosed.35,36  Many patients with recurrent UTI symptoms do not seem to respond to antibiotic treatment, and their specimens do not grow positive cultures.37 Gynecologists frequently diagnose endometriosis in patients with pelvic pain. However, it is not uncommon for patients who have received a diagnosis of endometriosis to return to their primary care provider with persistent bothersome symptoms after numerous tests and failed treatment attempts.31,38-42 When men present with pelvic pain, urgency, and frequency, urologists often provisionally diagnose prostatitis. However, few of these patients have an identifiable bacterial cause of their symptoms, and most do not seem to be helped by a prolonged course of antibiotics.43-47 Clinical clues. An awareness of the typical history of IC symptoms may help you distinguish IC from other disorders. Patients with IC typically have had symptoms for many years before they seek care.5,9,10,48  Because it is fairly common for patients with IC to have 1 or more comorbid conditions, it is also important to ask about other health problems. Frequency is a common initial symptom; some affected patients void 14 or 15 times per day. Urgency and pain generally develop next.3  As the bladder fills, the unprotected portions of the urothelium are exposed to caustic solutes in the urine; this exposure initiates neurogenic up-regulation and provokes a pain response.49  Patients often experience urgency and void frequently to relieve this pain. Frequent voiding to relieve pain can help differentiate patients with IC from those with overactive bladder syndrome; the latter tend to void for fear of urine leakage. In the early stages of the disease, symptoms generally occur in patterns of flares and remissions. A flare, which can often last several days, may lead to the misdiagnosis of a UTI even when urine culture results are negative. Flares can be provoked by seasonal allergies, physical or emotional stress, sexual activity, or hormonal fluctuations.50,51  As the disease progresses, flares become more frequent and severe and can eventually render the patient a “pelvic cripple.” The sexual history is a pertinent component of the history taking. Most women with IC (63%) report dyspareunia.3 The symptom surveys mentioned earlier (PUF scale and OLS indices) are useful for quantifying patients’ complaints (see Tables 1 and 2). They can also uncover symptoms that a patient might not have mentioned. An advantage of the PUF scale is that the patient’s score correlates with the probability of having IC. Although the findings of a symptom survey are helpful, use them only as a supplement to the patient interview. At this time, the risk factors for IC are unknown. Because affected patients often have relatives with IC, the disease is speculated to have a genetic component; however, this speculation has not yet been validated. Stress can provoke flares and is thought by some to be a risk factor.50,52 The physical examination of patients with IC reveals no major structural abnormalities. We have found that a vaginal examination in women may elicit pain at or around the bladder neck and that men may exhibit prostatic discomfort on rectal palpation. Laboratory evaluation. Laboratory testing for IC starts with the exclusion of diseases that have similar symptoms, such as diabetes and UTI. Measurement of blood glucose levels is a reasonable way to rule out diabetes; also, unlike patients with IC, those with diabetes typically display polyuria. Although the likelihood of confusing IC and diabetes is quite small, it is important not to miss any potentially confounding factor. Order a urinalysis to screen for hematuria and bacteriuria. Hematuria is not infrequent in patients with IC; however, such a finding must be worked up appropriately. Urine cytology can be considered in high-risk patients (eg, smokers) to rule out carcinoma; however, the literature does not conclusively support the use of this study. Depending on the clinical circumstances, an evaluation for sexually transmitted diseases may be warranted. Urinary markers, such as the antiproliferative factor mentioned earlier, have shown promise in research, but no such marker is currently available for office use. Diagnostic tests. Parsons and colleagues16,17  developed the PST based on the theory that a dysfunctional GAG layer plays a central role in the pathogenesis of IC. The concept behind this test is quite simple: patients with an intact GAG layer should not feel pain when a potassium solution is instilled in their bladder, whereas patients with a dysfunctional GAG layer should. The correlation between PST results and symptom-defined IC has been documented in a number of studies. In one study, the PST was used to evaluate 188 patients in whom IC was suspected. Of these patients, 166 had a positive response, whereas the responses of 26 controls (score of 0 on the PUF scale) were all negative.18  The use of the PST is well documented in the literature, but its effectiveness has yet to be established in a controlled study. A significant concern about the PST is that results are based on whether the test provokes pain. However, when performed properly, the PST is often very well tolerated, even by patients with IC. Patients to whom the PST was administered, both those in whom IC was suspected and controls, described the discomfort of the test as similar to or less than that experienced during such procedures as a Papanicolaou test, digital rectal examination, venipuncture, sigmoidoscopy, or mammography.53 An alternative to the PST is the anesthetic bladder challenge (ABC). In this test, patients whose pelvic pain is thought to originate in the bladder are catheterized and an intravesical anesthetic cocktail is administered. The cocktail consists of lidocaine and bicarbonate (the latter promotes absorption of the lidocaine). If a patient’s pain dissipates on instillation, the pain probably originated in the bladder. This test has been used by several investigators.54 Historically, cystoscopy with bladder distention under anesthesia has been used to detect bladder abnormalities and visualize glomerulations (the pinpoint petechial hemorrhages that develop after distention). Because this procedure can result in suspicious findings in women without voiding symptoms, the literature does not support its use to detect IC.9,13,14  However, anecdotal evidence suggests that some patients experience temporary relief from symptoms (for 3 to 6 months) after their bladder is stretched. TREATMENT Nondrug approaches. Diet plays a noteworthy role in the treatment of IC. Certain foods, especially potassium-rich foods, can cause flares.52  A list of potentially aggravating foods can be found on the Web site of the Interstitial Cystitis Association (www.ichelp.com) under “treatment options.”55 Anxiety and related syndromes are commonly seen in patients with IC. Although it remains unclear whether stress is a precipitant or consequence of the disease, alleviation of stress may help control symptoms or help patients cope with them.56  If patients are unable to reduce stress on their own, suggest counseling or a support group. Oral pharmacologic therapy. Currently available oral medications target specific points in the postulated cycle of IC (see Figure). The goals of therapy are to restore bladder surface integrity, modulate neuronal dysfunction, and reduce any coexisting inflammation. A heparinoid compound, pentosan polysulfate sodium (PPS), is the only oral medication currently approved by the FDA for the treatment of IC. Heparin is similar in structure to GAG, the key component of the bladder’s protective mucin layer. Providing the bladder with a structurally analogous compound is believed to facilitate restoration of the GAG layer, thereby preventing further urothelial insult.57 Studies have shown the value of PPS in treating IC patients.58-64  We use PPS at an off-label dosage of 200 mg bid. This seems to result in better compliance than the approved 100-mg tid dosing schedule. Data presented at the 2004 annual meeting of the American Urological Association18 seem to indicate that initiation of PPS therapy earlier in the disease process is associated with better outcomes. This has yet to be demonstrated in a large randomized controlled trial; however, preliminary work by the authors suggests that recognition of IC early in its natural history—with subsequent initiation of treatment—yields more rapid and more significant improvement. An inflammatory response is part of the postulated IC cycle; thus, we advocate the addition of a primary antihistamine (hydroxyzine) to suppress mast cell degranulation in the lamina propria. Hydroxyzine is unique among antihistamines in its ability to effect this specific suppression.65 Amitriptyline is occasionally used in patients with IC to regulate pain and urgency by modulating neuronal dysfunction. An additional benefit of amitriptyline is that, like other tricyclic antidepressants, it may have antihistaminic properties.57,66,67  A recent German study showed amitriptyline to be safe and effective in patients with IC for up to 4 months.67 Other medications may be appropriate, depending on a patient’s symptoms and response to therapy. Anticholinergics (eg, oxybutynin, trospium chloride, tolterodine) may alleviate urgency, frequency, and urge urinary incontinence. Phenazopyridine helps subdue irritation and pain in the lower urinary tract. Finally, do not ignore the pain experienced by patients with IC. Frequently, patients have had the disease for some time and are debilitated by their discomfort. The responsible use of analgesics, including narcotics, may be appropriate in some patients. Intravesical pharmacologic therapy.  The instillation of pharmacologic agents into the bladder can directly target the source of pelvic pain in IC. Intravesical dimethyl sulfoxide (DMSO) has been approved by the FDA for the relief of IC symptoms.68  Although DMSO seems to reduce pain and produce objective and subjective improvement in other symptoms (such as urgency and frequency) superior to that seen with placebo,69  it does not address the cause of IC—a deficient GAG layer. Patients with severe symptoms may benefit from long-term intravesical heparin therapy at a daily dose of 10,000 to 40,000 IV in 10 mL of sterile water.70  Much like oral PPS, intravesical heparin is thought to play a role in the restoration of the dysfunctional mucin layer, thereby preventing further urothelial insult and neurogenic up-regulation.71 Intravesical hyaluronic acid—already available in Canada71—is currently being studied in the United States for its potential to restore the GAG layer in patients with IC.72  Intravesical anesthetic cocktails—heparin or PPS solution that contains lidocaine and sodium bicarbonate—are also being investigated as IC therapy.71  We have found that such cocktails can interrupt the patient’s pain cycle and help repair the bladder’s epithelial mucin layer. We start with 3 instillations per week for 3 weeks while oral therapy is begun. Surgery. Surgical interventions have limited value in patients with IC. Cystoscopy with hydrodistention appears to have a role in the treatment of refractory IC, but this has not been demonstrated in controlled studies.13  There is ongoing investigation of the use of implanted neurostimulators to reduce the pain associated with the disease.73  Cystectomy with urinary diversion should be considered as a last resort. FOLLOW-UP Patients with IC have frequently had symptoms for a long time, received multiple misdiagnoses, and undergone numerous failed treatments. As a result, they are often disillusioned with the health care system and wary of new treatments. Thus, it is essential to offer continuing support. For patients in whom this “learned skepticism” is evident, we recommend the PST or ABC (depending on clinical presentation). If a patient perceives that you have identified the source of the pain (in this case, the bladder), he or she is more likely to accept the diagnosis of IC and to be amenable to a potentially prolonged treatment plan. We recommend close follow-up of patients with IC every month for the first 3 months and every 3 months thereafter. This provides opportunities to monitor the patient’s progress, inquire about relapses, and modify the regimen as needed. Symptoms may be slow to respond to therapy. Thus, is it vital to encourage compliance and discuss the patient’s expectations. If the symptoms of IC do not respond to therapy within 3 to 6 months, further evaluation (ie, urologic and/or gynecologic consultation) is required. 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;87:321-327. 2. Gelbaya TA, El-Halwagy HE. Focus on primary care: chronic pelvic pain in women. 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