Diagnostic Evaluation of Chronic Pelvic Pain of Bladder Origin
Robert Greene, MD; Lee P. Shulman, MD

Chronic pelvic pain (CPP) is a common and potentially debilitating problem for reproductive-aged and menopausal women. The pain associated with CPP is localized to the pelvis, persisting for more than 6 months and severe enough to cause functional disability requiring medical or surgical intervention.^1,2 However, CPP is characterized by a lack of distinct and unique presentations and characteristics, thus making it difficult to accurately diagnose and effectively treat the cause of the pain. Women with CPP commonly undergo unnecessary evaluation and ineffective therapy, leaving many frustrated and seeking alternative remedies for relief from their pain.¹

Prevalence and Impact of CPP

Based on statistical extrapolation from a study of 5,263 women, it is estimated that more than 9 million women in the United States suffer from CPP.³ Chronic pelvic pain accounts for up to 10% of outpatient gynecologic referrals, 10% to 12% of hysterectomies,⁴ and 20% of laparoscopic procedures⁵ performed in the United States. Notably, these statistics represent only the segment of the patient population that has discussed the problem with a gynecologist. These estimates should therefore be considered conservative in their scope.

Reported estimates of the prevalence of interstitial cystitis (IC) have varied considerably, with estimates from the Nurses Health Studies I and II of 52 to 67 women per 100,000,⁶ and other estimates of 450 women per 100,000.⁷ Inconsistencies in early estimates may have been due to differences in the definition and diagnostic criteria. Indeed, criteria published by the National Institutes of Health (NIH) and National Institute of Diabetes and Digestive and Kidney Diseases⁸ (NIDDK) may identify only the most advanced and severe cases of IC.⁸ Hanno et al⁶ reported that more than 36% of patients with documented IC failed to meet the NIH research definition for IC, suggesting that these criteria may be too limiting for the clinical setting.

Interstitial cystitis is one of the most common bladder conditions associated with CPP. Clemons and colleagues⁹ in 2002 showed that 38% (17/42) of women with CPP had IC.⁸ In another study by Chung et al,¹⁰ IC was found to be present in 96.4% (54/56) of women with CPP who had a diagnosis of endometriosis (active or inactive) and 97.7% (47/48) with biopsy-confirmed endometriosis. Parsons et al11 reported positive results for IC in 85% of gynecologic patients with a suspected diagnosis of CPP, thus supporting IC as a widespread and underdiagnosed etiology for CPP. It is also noteworthy that in a study by Parsons et al, 80% of women with CPP and a clinical diagnosis of endometriosis had a positive potassium sensitivity test (PST). The PST is an effective diagnostic protocol for confirming IC beyond the traditional category of diagnosis by exclusion.¹²

Why the Gynecologist?

More than 9 million women in the United States suffer from CPP, for which they consult gynecologists more often than any other specialty.³ When a woman feels pain in her pelvic region, she seeks out her gynecologist, her health care provider with historical and physical findings associated with pelvic pathology. As a result of the extensive clinical experience, the gynecologist, therefore, is positioned to play a key role in the performance of screening and diagnostic testing, and initiation of effective therapeutic modalities for CPP.^3,13 However, the extensive experience may, at times, fail to properly serve women who present with pain as the main symptom. Indeed, many experienced providers may fail to recognize that the bladder is a common source of pain with CPP syndrome as well as an etiology for the pain associated with urinary tract infections (UTIs). This failure, in combination with a tendency of some women to underreport, downplay, or overlook the presence and significance of genitourinary symptoms, may lead to medical or surgical courses of action for CPP that fail to provide symptom relief and may prolong and exacerbate the existing problems.^10,14

Traditional Diagnostic Evaluation of CPP

Several factors contribute to the challenge of diagnosing CPP in women. The close proximity of various organs within the pelvis serves as a major obstacle to differentiate and identify sources of pain. For example, an anterior fibroid impinging on the bladder may present initially with only bladder-related symptoms that may be exacerbated at the time of menses. Confusion can be increased by the presence of nonpelvic pathologic states such as psychological disturbances and disorders of the musculoskeletal, nervous, and immune systems that can all be associated with CPP, either as a source of the condition or as a contributing or exacerbating factor. A differential diagnosis for CPP must include a detailed review of several organ systems, which are listed in Table 1.⁸

Commonly Misdiagnosed Conditions

Many diagnostic approaches have been used to identify the cause of CPP with varying degrees of success.^1,4 Initial evaluation of women with CPP should include a detailed history (a pain diary is ideal) and complete pelvic examination. Following the initial assessment, laboratory testing should include appropriate assessment for gonorrhea, chlamydia, and vaginal or urinary tract infection, as well as a complete blood count. Additional diagnostic procedures based on initial findings may include imaging studies such as pelvic ultrasound and/or magnetic resonance imaging. Finally, invasive procedures, such as laparoscopy, sigmoidoscopy/colonoscopy, and cystoscopy may be performed and are vital tools in the detection of pelvic organ pathology. However, if the gynecologist does not believe that the bladder is a likely origin for CPP, cystoscopy is usually not performed. As such, the remaining tests do not address IC as a possible cause and thus may prevent the gynecologist from correctly diagnosing CPP.¹ There are multiple etiologies that may result in CPP, and more than one may be present in an individual patient. Frequently, no distinct etiology can be identified.⁷

Recurrent urinary tract infections.—Early stage IC may closely resemble the symptoms of recurrent UTIs and therefore may be initially misdiagnosed. Patients are often prescribed an antibiotic based upon the presence of irritative voiding symptoms, dysuria and (possibly) a questionable urinalysis. Their response to antibiotics is variable but generally is less than satisfactory. In many cases these patients’ urinary symptoms are due to other common bladder conditions such as overactive bladder or IC, both of which can flare-up for a number of reasons. It is important to perform urine cultures during exacerbations to help differentiate recurrent UTIs from other bladder conditions. Patients’ responses to antibiotics is also important in finding the correct diagnosis. Patients who have a low response to antibiotics should undergo a thorough evaluation to rule out functional, metabolic, and anatomic abnormalities.¹⁵

Endometriosis.—This is a common identifiable cause of CPP. It is estimated that between 70% and 90% of women with CPP also have endometriosis.⁵ The overlapping clinical symptoms of endometriosis and bladder causes of CPP—in particular IC—may prove challenging. Unfortunately, IC has not historically been considered a major etiology of CPP by women’s health care providers. More recent studies suggest that IC may be a major source of CPP even in women with proven endometriosis.

Considering the Bladder

Clinical Profile of Interstitial Cystitis

Interstitial cystitis is characterized by a constellation of nondistinct signs and symptoms including frequent or urgent urination, pelvic pain in the absence of any other pathology and dyspareunia.¹⁰ Pain may range from a mild burning to excruciating and debilitating pain. Interstitial cystitis is not characterized by a single signature feature, but rather is represented in many women by a variety of symptoms that generally persist and become more severe over the years as the disease progresses. In the early stage, IC may look like dyspareunia, overactive bladder or recurrent UTIs; other gynecologic disorders (eg, endometriosis, pelvic inflammatory disorder, vulvodynia, recurrent candidiasis) may also be suspected. A diagnosis of IC is often not determined until the disease is in an advanced stage with persistent, severe symptoms, causing destructive changes to the bladder tissue. These causes are ultimately detectable by cystoscopy and biopsy.⁵ The average patient may have symptoms for three or more years prior to diagnosis and may have seen multiple specialists before the diagnosis is made. The continuum of increasingly severe symptoms parallels the probability of diagnosis—the further the patient advances, the more likely she is to be diagnosed (Figure 1).

The hallmark symptoms of IC, urinary urgency/frequency and pain, tend to be cyclic in reproductive-aged women and thus influenced by hormonal surges.^8,11 It is well established that pain intensity varies with the menstrual cycle, increasing between ovulation and the onset of menses.¹⁶ Women with IC often report symptom flares the week before the start of menses. In one study, 78% of women reported that pelvic pain intensified during the premenstrual period.¹⁶ Premenstrual increases in urgency and frequency without pain have also been reported.¹⁶ In these cases, the premenstrual decrease in estrogen and progesterone may have a stabilizing effect that raises the pain threshold, giving women a brief respite between painful episodes that tend to last through the menstrual cycle. Discontinuation of hormone therapy (HT) has also been associated with IC flares. Therefore, a diagnosis of IC should also be considered in women who present with symptoms following HT discontinuation. In addition, pain during sexual intercourse and pain and/or symptom flares after sexual intercourse, although not unique to IC, are a fairly consistent finding and a common complaint of women with IC suggesting a role of prostaglandins in CPP.¹³

Voiding symptoms are frequently associated with early IC and tend to be relatively mild and intermittent. They may include frequency, urgency, and nocturia. However, pelvic pain becomes the dominant symptom as the disease progresses. Pain may be associated with the bladder or may be referred to the urethra, vagina, suprapubic area, lower abdomen, lower back, medial aspect of the thigh, inguinal region, vulva, perineum, or a combination of these areas.¹¹ Although the majority of patients present with pelvic pain or bladder pain, 30% of women who are found to have IC do not report pain.¹¹ A small percentage (15%) of women report only pain without frequency or urgency.^11,12 Many women with IC actually present with a history of recurrent UTIs that consistently yield negative urine cultures and shortened temporal relief with continued antibiotic therapy. Other factors that can exacerbate IC symptoms include physical and emotional stress, seasonal allergies (suggesting a role for histamine in pain associated with IC), and certain foods, particularly those high in potassium.^11,12

Diagnosis of Interstitial Cystitis

Interstitial cystitis is a diagnosis of exclusion as its hallmark symptoms of pain and urinary urgency/frequency are common to other urologic, gynecologic, and gastrointestinal disorders. Endometriosis, for example, is often characterized by cyclic premenstrual pain and urinary frequency. Frequency and urgency are also characteristic of recurrent UTIs. Innervation of both the bladder and pelvic floor originate from common sacral nerve roots; accordingly, completely different pathologic processes may present with similar pain complaints.⁸

Cystoscopy.—Cystoscopy with hydrodistension performed under general anesthesia is considered the gold standard for making the diagnosis of IC and should be considered especially when patients with irritative bladder symptoms fail to respond to conservative treatment options. Cystoscopic findings that may be present in patients with IC include submucosal hemorrhage, glomerulations, Hunner’s ulcerations, and blood-tinged terminal effluent after the bladder has been filled to and kept at a pressure of 80 cm of water for 1 to 2 minutes. Originally the criteria from the NIDDK were not intended to define the disease, but to establish that patients selected for clinical research studies would be relatively comparable. Although designed as a research tool, this research definition and criteria became the de facto definition of the disease. The specificity of demonstrating glomerulations in the bladder has been questioned, and the sensitivity of these glomerulations is not fully understood since IC patients can present with no glomerulations seen on cystoscopy under anesthesia. Also bladder ulcerations (Hunner’s ulcer) are rarely visualized. The NIDDK criterion omits specific pathologic findings from the criteria because there is no consensus which pathologic findings, if any, should be required to make a diagnosis.¹⁷

 


The Pelvic Pain and Urgency/Frequency Patient Symptom Scale (PUF).—The PUF questionnaire was developed to assess both IC-related voiding symptoms (urgency and frequency) and pain, including pain associated with sexual intercourse. As a prelude to an invasive procedure, the questionnaire evaluates how severe and bothersome symptoms are to the patient, based on a total score of 0 to 35. It is a self-administered tool that takes about 5 minutes to complete.¹³ High PUF scores (≥10) correlate directly with positive potassium sensitivity test (PST) results.¹⁸ A PUF score of 15 or higher was found to be associated with an 84% chance of having a positive PST, which strongly suggests the presence of IC.¹³ Using a combination of screening and diagnostic tools (PUF questionnaire and PST), Parsons et al¹³ estimated that among 130 million American women, 1 in 4.5 may have IC.

In addition to the PUF being an excellent screening tool for IC, the information obtained can be of great importance for gynecologists seeking information not necessarily related to bladder pathology. (The PUF questionnaire can be found at www.femalepatient.com, in the Special Editions section and may be downloaded for use with patients.)

The potassium sensitivity test.—The PST is frequently used in the diagnostic evaluation of IC. The basis for the PST is the hypothesis that the permeability of the bladder epithelium is altered by a defect in the protective glycosaminoglycan (GAG) layer of the bladder mucosa.¹² In most IC patients, the uroepithelium is abnormally permeable, allowing irritating substances in the urine to penetrate into the bladder wall.¹¹ The PST is performed by instilling a solution of potassium chloride directly into the bladder to trigger a response from the patient. Women with an increase in bladder epithelium permeability experience pain and/or urgency as a result of potassium penetration into the bladder muscularis. (Information about how to perform a PST is provided at www.femalepatient.com, in the Special Editions section and may be downloaded for use with patients.) A positive PST occurs in more than 80% of patients diagnosed with IC; less than 2% of healthy women experience pain or urgency symptoms during a PST.^11,14 Figure 2 represents a simplified algorithm for establishing a differential diagnosis of CPP of bladder origin or IC.¹²

Treatment of Interstitial Cystitis

Successful treatment for IC usually consists of a multimodal approach,¹² including bladder training and diet modification (Figure 3).¹² Currently, there are two medications approved by the FDA for the treatment of IC: oral pentosan polysulfate sodium (PPS; Elmiron), a compound that is structurally similar to mucosal GAGs¹¹; intravesical dimethyl sulfoxide (DMSO, RIMSO-50), an anti-inflammatory analagesic with muscle-relaxing properties. It is thought that PPS decreases the abnormal permeability of the uroepithelium, which eventually reduces the pain associated with IC.

Study data indicate that PPS is effective, safe, and well tolerated in patients with IC.¹¹ A 12-week course of PPS (300 mg/day) provided significant pain relief in 27% to 42% of patients compared to placebo in four clinical trials.¹¹ Efficacy improves as the length of treatment increases, and full effect is usually achieved with long-term (approximately 6 months) therapy. In a long-term study of continued PPS treatment, improvement in symptom relief was maintained for 3 years.¹⁸ PPS also has an excellent tolerability profile. Dyspepsia is the most commonly reported adverse event (AE), with overall rates of AEs ranging from 1% to 4%.¹⁹ Hair loss, which can induce stress, has proved to be rare and reversible with drug discontinuation. If it does occur, the patient may experience spotty hair loss rather than diffuse or total hair loss.

A multimodal approach is often needed as PPS usually requires several weeks to reduce the pain associated with IC. Aside from PPS, there are other methods of management for IC, including hydrodistension procedures and the use of DMSO and other compounds that are instilled into the bladder to provide relief of symptoms at least for the short-term. Accordingly, antihistamines, anticholinergics and selective serotonin reuptake inhibitors may provide short-term relief, although such regimens are associated with considerable AE profiles. Life-style modifications and conventional calcium supplementation may also help relieve pain prior to the onset of clinical effectiveness of PPS.

Empiric Therapy

Empiric therapy is used to treat gynecologic patients when signs and symptoms strongly support the diagnosis, and the risk of an inaccurate diagnosis is minimal. For example, in the case of presumed endometriosis, antiestrogen agents (eg, danazol) and gonadotropin-releasing hormone (GnRH) agonists have been used empirically.⁵ Empiric therapy gives patients with endometriosis an initial treatment option that is noninvasive and is not associated with the risks of surgery. However, it remains very costly and has many side effects. Additionally, there is typically a worsening of endometriosis-related symptoms prior to improvement.

Such adverse considerations are not associated with the empiric use of PPS for IC. The strong clinical correlation of PUF scores and PST results allows for the consideration of PPS without cystoscopic directed biopsies. PPS has been shown to be effective and safe, with a minimal rate (1% to 4%) of AEs.²⁰ Treatment-related side effects are minor and reversible, unlike those associated with other empiric therapies such as GnRH; no undesirable effects persist after the drug is discontinued. Finally, PPS therapy may cost less when compared to other medical or surgical therapies following more additional and more invasive diagnostic protocols.

Economic Considerations

Using conservative cost estimates including only office visits to physicians and mental health professionals and out-of-pocket expenses, direct annual costs of CPP are likely to be more than $2.8 billion; when the costs of laparoscopies and hysterectomies performed for CPP are added, actual costs escalate substantially.¹¹

The negative impact of IC on the health and quality of life of women who suffer from CPP is considerable. Women with CPP report interference with their household, professional, physical, and sexual activities. The indirect costs of time lost from work and reduced productivity due to CPP in women adds to the overall financial burden. In a 1995 study,³ indirect costs were estimated at $555 million among US women aged 18 to 50 years.

The components of evaluation and treatment of IC are covered through many insurance and managed care organizations. Table 3 shows the CPT codes for the testing and treatment commonly associated with IC. As with any medical condition, the level and extent of insurance coverage will vary based on plan and medical condition.

Conclusion

Chronic pelvic pain is a debilitating yet readily treatable condition common among all racial and ethnic groups in the United States. The diagnosis and treatment of CPP is complicated by common symptoms representing different pathophysiological states. In addition, the training of clinicians who care for women has not, until recently, encompassed all possible etiologies for CPP. The message is essentially simple: the bladder is part of the pelvis. Specifically, the bladder must be considered as a potential (and common) etiology for CPP by all clinicians who attempt to diagnose and treat the condition. This epiphany does not alter the diagnostic and surgical procedures needed to make the correct diagnosis; rather, it allows for gynecologists to be more successful in their treatment of affected women. Increased awareness of IC, even in cases of documented endometriosis, will make for more accurate diagnoses and more effective therapeutic outcomes.

The screening (PUF) and diagnostic (PST) paradigms for IC are easy to implement and interpret with outcomes strongly associated with the presence or absence of IC. Dimethyl sulfoxide provides at least moderate symptomatic relief for the majority of patients, including an increase in bladder capacity and at least initial sustained remissions.^21-25 Pentosan polysulfate sodium has been shown to be an effective therapy; however, recognition of the relatively prolonged time (3 to 6 months) to clinical benefit must be integrated into a multimodal therapeutic plan that will provide short- and long-term benefit and help women avoid the frustration and unnecessary referrals that have long been associated with CPP.

Robert Greene, MD, is assistant clinical professor at the University of California, Davis. Lee P. Shulman, MD, is professor of obstetrics and gynecology; head, section of reproductive genetics; The Feinberg School of Medicine, Northwestern University, Chicago, Ill.

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