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7 Articles in Volume 5, Issue #1
Diagnosing and Managing Interstitial Cystitis
Intractable Pain Centers’ Treatment Approach
Musculo-Skeletal Diagnostic Ultrasound Imaging
Pain Management Pitfalls
Selection Criteria for Intrathecal Opioid Therapy: A Re-examination of the "Science"
‘High Dosage’ Opioid Management
‘Opiophobia’ Past and Present

Diagnosing and Managing Interstitial Cystitis

Long believed to be a rare condition with difficult diagnostic criteria and scarce treatment options, new research suggests interstitial cystitis (IC), a painful bladder disorder, is quite prevalent in the general population.

Chronic pelvic pain (CPP) is commonly encountered in the primary care office, affecting nearly 1 in 7 women in the United States.1 Interstitial cystitis is one of the causes of chronic pelvic pain and may be more common than previously thought. In the past, IC has been labeled a diagnosis of exclusion: urinary urgency/frequency and/or pelvic pain in the absence of any other definable cause. In fact, IC can be readily identified from its symptom complex and therefore, should be diagnosed without numerous tests or procedures. The characteristic symptoms and patterns of IC presentation are listed in Table 1.

This article has been written from a dual-specialty prespective as the authors include a primary care physician and a gynecologist. Collaboration on this article resulted from the mutual belief that early intervention by a primary care clinician can significantly impact patient outcomes. Referral to a specialist may be avoided if primary care clinicians understand that a large number of patients in the primary care population may have IC, and that these patients can be diagnosed and treated successfully. The goal of managing IC is finding and treating the disease in its early stages, thereby reducing the number of advanced cases, which tend to be resistant to current therapies.

An Overview of the Pathogenesis of CPP

Pain serves as an important alarm that warns us of threatened or ongoing tissue damage. However, chronic pain can become the true pathology — the “disease” that can be disabling. The neuropathology of chronic pelvic pain has been nicely reviewed by others and is beyond the scope of this article.2,3

Key points include the fact that a prolonged barrage of noxious stimuli can result in changes in the sensory processing of all stimuli entering the dorsal horn and this results in allodynia (when a non painful stimulus is perceived as painful).4 This is an example of the neuroplasticity of the dorsal horn and is a key component in the pathogenesis of visceral pain syndromes such as endometriosis, irritable bowel syndrome and interstitial cystitis.

This up-regulated state within the dorsal horn also results in neurogenic inflammation in neighboring organ systems (this “cross-talk” is referred to as viscero-visceral hyperalgesia) and in the pelvic floor musculature becoming hypertonic and tender (this is referred to as pelvic floor tension myalgia).5

Chronic pelvic pain syndromes and especially visceral pain syndromes involve neurogenic inflammation, afferent overactivity and central sensitization, which interact to perpetuate pain. This model of chronic pain explains why therapeutic approaches must involve the treatment of all pain generators because all of these new pain generators project their noxious stimuli into the same dorsal horn segments. It has been shown that approximately 75% of women seen by a gynecologist for complaints of a variety of chronic pain syndromes also have symptoms of urgency, frequency or irritative voiding symptoms.6 Therefore there is an obvious overlap of IC and CPP syndromes that the clinician must be aware of and be prepared to identify and treat.

The Suspected Pathogenesis of IC

The basic role of the bladder is to hold and void urine.7 The bladder is not intended to be an absorptive organ, nor should it possess any sensory component of its contents beyond pressure. Normally, urothelium is shielded from the urine by a glycosaminoglycan (GAG)-containing mucous layer.8 IC is thought to occur when the protective GAG layer becomes defective, therein allowing irritative substances from the urine to aggravate the urothelium and cause inflammation and neurgenic upregulation in the bladder wall.9 The resultant disease process is marked by symptoms of urinary urgency, frequency, pelvic pain, and occasional urinary hesitancy.

Studies suggest potassium may be the urinary constituent primarily responsible for evoking the symptoms of IC.9 Various other factors have also been investigated for their potential roles in the pathogenesis of IC including lymphatic, infectious, neurologic, psychologic, autoimmune, and vasculitic. These factors have not yet been proven to be pertinent to this disease process.

Presentation

Familiarity with disease presentation facilitates easy recognition of IC by the primary care clinician. The general pattern of IC symptoms is quite unique, though an affected patient may report some variance from day to day.

Table 1. IC: Symptoms and Patterns of Presentation


Symptoms

  • Urinary frequency: Voiding eight or more times per day. This symptom is not always present.· Urinary urgency: Having a need to void urine, particularly to relieve pain.
  • Pelvic pain: Perceived in one or more locations anywhere in the pelvis. This symptom is not always present.
  • Pain with sexual activity: Present in three out of four patients with IC.

Patterns

  • In mild to moderate IC: Symptoms occur in patterns of flares and remissions.
  • Symptom flares can be provoked by seasonal allergies, physical or emotional stress, or hormonal fluctuations (in women).
  • Symptoms may be worsened by certain foods, including citrus fruits, foods high in potassium, caffeinated beverages, and alcoholic beverages.
  • History of diagnosis of recurrent UTIs, nighttime urination, urethral syndrome, urethritis, frequent vaginitis (in women), or prostatitis (in men).
Table 2. Practice Trends in the Management of IC
Therapeutic Approach % of
Use
Dietary restrictions 93%
Oral agents* 93%
Behavioral Modification 83%
Intravesical therapy 83%
Biofeedback (relaxation phase) 63%
Physical therapy 57%
*Oral agents including Amitriptyline: 59%, PPS: 54%, NSAID: 54%

As previously mentioned, a patient with IC generally suffers from urinary urgency/frequency and pelvic pain. However, the disease should not be dismissed in the absence of one or two of these symptoms. A study by Parsons et al of 466 women and men with IC found that 9% had pain alone, and 8% only had urgency.10

Urinary frequency, typically the first symptom to develop in IC, is often unrecognized or disregarded as significant by the patient and therefore goes unreported. It is not uncommon to find patients who believed it is normal to void 12 or 15 times a day. Urgency tends to present somewhat later in the supposed disease progression. Not to be confused with urgency due to overactive bladder (OAB) in which patients have small-volume voids primarily due to fear of urine leakage, patients with IC urgency void to relieve pain. The intensity and duration of the pain component of IC fluctuates from patient to patient. In addition, dyspareunia is a common complaint among IC patients.10

While most cases of IC develop gradually and insidiously, some patients know exactly when and where their symptoms began. Patients tend to experience symptoms in patterns of flares and remissions during early stages of IC. Seasonal allergies, physical or emotional stress, sexual activity,10 and/or hormone fluctuations are all that are needed to provoke such flares.11 As IC progresses, the severity and constancy of associated symptoms increases. The etiology and possible risk factors of IC are unknown.

Patients with a diagnosis of recurrent urinary tract infection (UTI) should be evaluated for IC, especially when this diagnosis is made in spite of negative urine cultures. Recurrent UTIs are not common and it is important to confirm the presence of a true infection with a urine culture.12

Historically, IC was not often diagnosed in its early stages because little was known about the disease. Lack of understanding of the disease progression led to inappropriate ideals of IC as only the most advanced cases, in which symptoms were commonly severe and constant, were considered representative. In reality, the majority of patients experience symptoms in patterns of flares and remissions, which is more indicative of mild to moderate IC. The potential to control disease symptoms, decrease related costs, and even halt disease progression may be contingent upon early recognition and treatment of this disease.

Prevalence

The prevalence of interstitial cystitis appears to be much greater than previously thought. Past studies, which only counted diagnosed individuals, may have missed a substantial number of patients with unrecognized IC.13 More recent studies have sought to accommodate the oversight of their predecessors by surveying populations for IC symptoms and then testing only symptomatic individuals for the disease.

A study of nearly 4,000 primary care patients, presented at the 2004 American Urological Association Annual Meeting, identified significant symptoms of urgency, frequency, and/or pelvic pain in more than 20% of patients.14 These patients were further interviewed regarding the problematic nature of their symptoms and it was found that approximately one third desired treatment. The potassium sensitivity test (discussed later in this text) was administered to patients who desired treatment. IC was diagnosed in patients with a positive PST, constituting 88% of those tested. Overall the PST results indicated the presence of IC in more than 4% of the total patient population.14

Other studies have presented data suggesting that nearly 1 in 4 women in the general population,15 25.7% of 1,066 patients from eight different gynecologic practices,16 and 90% of 141 gynecologic patients with CPP have IC.17 According to a recent bulletin from the American College Of Obstetricians and Gynecologists, 38-85% of women presenting to a gynecologist for CPP may have IC.18

Diagnosing IC

Once considered a diagnosis of exclusion, IC can actually be diagnosed simply via identifying the symptom complex and, when necessary, implementing simple office-based tests. IC should be given primary consideration when a patient presents with symptoms of urinary urgency, frequency, and/or pelvic pain. Unfortunately, the typical IC patient has been symptomatic for 4-7 years prior to diagnosis.19-21 As with other disease states, it is expected that early recognition of IC increases the probability of effective treatment. In a study by Forrest and Vo, a simple multiple drug oral therapeutic approach produced greater that a 75% improvement in symptoms in greater than 80% of the patients.22 These patients were diagnosed within 2.5 years of the onset of their symptoms.22 It is reasonable to conclude that early identification is the foundation of successful therapy.

History and Physical Examination

Evaluating a patient who has IC symptoms begins with a comprehensive history and physical examination. A query of symptoms such as urgency/frequency and pelvic pain should be included as part of a general genitourinary review. It is also important to attain a patients’ sexual history as most women with IC (63%) report dyspareunia.6,10 A careful physical examination should be conducted with the key points kept in mind: where does the patient indicate tenderness, and does this reproduce the same pain of which the patient complains.

Symptom Surveys

Patient’s complaints can be easily quantified by a good symptom survey. Further, a survey may also uncover symptoms that might otherwise go unreported. This attribute is quite valuable in identifying key IC symptoms, such as pelvic pain and dyspareunia, which patients may inadvertently omit because they do not appear to come from the bladder.

Table 3. Multimodal Oral Treatment of Interstitial Cystitis
Compound Dosage Purpose Most Common Adverse Events
Pentosan
polysulfate sodium
300mg/day in 2 or 3 divided doses, 600mg/day* in 3 divided doses for males in some cases† Possibly aids in repairing or restoring the mucous layer of the bladder Diarrhea, nausea, localized alopecia (reversible upon discont.), headache, rash, dyspepsia, abdominal pain, liver function abnormalities, and dizziness
Hydroxyzine 25mg daily at bedtime; increase to 50 to 100mg/d during allergy season Controls allergies that can provoke symptom flares Drowsiness, dry mouth, and twitches
Amitriptyline or imipramine‡ 25mg daily at bedtime; increase to 50mg after one to two months Aids in control of severe pain or depression Dizziness; drowsiness; dry mouth; headache; increased appetite; nausea; fatigue; unpleasant taste; weight gain
Phenazopyridine HCl
 
200mg 3 times/day after meals Relieves pain and other discomforts from irritation of the lower urinary tract Headache, rash, pruritus, and gastrointestinal disturbances
Oxybutynin
chloride
10mg qd Treatment of OAB with symptoms of urge, urinary incontinence, urgency, and frequency Mild to moderate dry mouth
* Off-label use.
† See Nickel JC, et al. Urology. 2001;57(suppl 6A):122-123.
‡Alternatively, a selective serotonin reuptake inhibitor such as fluoxetine 10 to 20 mg/d or sertraline 50 to 100 mg/d can be given.

Two of the most commonly used surveys, the Pelvic Pain and Urgency/Frequency (PUF) patient symptom scale and the O’Leary-Sant (OLS) Symptom and Problem Index (See Figures 1 and 2) have been validated for screening a general population for IC symptoms and following disease progression, respectively.23,24 A direct correlation between PUF scores and a patient’s likelihood of having IC, as indicated by the presence of bladder mucosal defects, has been demonstrated in a number of studies.25,26

Tests

A prudent clinician begins testing for IC after ruling out obvious causes of CPP, such as abnormal physical findings or UTIs. The finding of hematuria and/or bacteriuria upon urinalysis is not a sign of IC and should initiate appropriate work-up and treatment. To exclude conditions such as carcinoma in situ of the bladder, a urine cytology examination is often used. Evaluation for sexually transmitted diseases, pelvic ultrasound, and computed tomography scan are other tests to consider, depending on the clinical circumstances.

Perhaps the most convenient way to identify IC is to use an office-based test, such as the PST or anesthetic bladder challenge (ABC). Rooted in the theory that IC arises from a dysfunctional GAG-layer and urothelial insult, the PST (Figure 3) uses a potassium chloride solution in attempts to reproduce the symptoms of an IC flare.9,10 A number of studies have acknowledged its ability to detect IC.26-28 When performed properly, the PST is very well tolerated despite the fact that its’ result is gauged by the pain that it may provoke. The potassium solution should be withdrawn and an anesthetic immediately instilled if IC symptoms are reproduced by the test (ie. pain is elicited). A recent study surveyed 111 patients who underwent a PST and found the discomfort during the procedure to be reportedly the same as, or less than, that of other standard medical procedures, such as the Pap smear, digital rectal examination, sigmoidoscopy, or mammography.27 Any clinician comfortable with performing bladder catheterization should be able to administer the PST.

If a patient presents with pain having a suspected bladder origin, the PST should be withheld. Instead, the anesthetic bladder challenge (ABC), an investigative test that uses the resolution of pain as an indicator of IC, can be employed. Significant amelioration of the patient’s pain upon anesthetic instillation into the bladder provides empirical evidence that the bladder is the organ of origin. This gives the clinician a good place to start when further evaluating CPP (Figure 4).29 Patients receiving the ABC should be informed that they might experience “rebound” pain once the solution has worn off (within three to five hours).

Cystoscopy with hydrodistention under general anesthesia, or cystoscopy alone under local anesthesia, is used to visualize bladder wall idiosyncrasies that may be indicative of IC, glomerulations or Hunner’s ulcers. Though commonly applied by specialists to diagnose IC, the usefulness of these procedures is not supported by data reported in the literature.30 These tests are unnecessary in patients with a normal urinalysis.

Laparoscopy is often one of the first “tests” recommended for the evaluation of patients with chronic pelvic pain. Certainly pathologies such as endometriosis and adhesions are often found, but recent evidence has brought into question the success of the laparoscope in the treatment of chronic pelvic pain.31 One point that can be made is that the high prevalence of IC in patients with chronic pelvic pain mandates that cystoscopy should be considered at the same time as the laparoscopic procedure.

Treating the Chronic Pelvic Pain of Interstitial Cystitis

The goal in treating any complex pain syndrome is to identify all sources of pain and then to treat all sources of pain. The hope is that by reducing the “volume” of noxious stimuli presenting to the dorsal horn that the dorsal horn will then down-regulate. A multimodal approach is therefore the key to successful therapy. The myofascial component (pelvic floor tension myalgia), the bladder component (IC), the GI component (irritable bowel syndrome) and the neuropathic up-regulation must all be targeted. At the Interstitial Cystitis Association’s research symposium in 2000 this concept of multimodal therapy was demonstrated in an abstract concerning practice trends in the management of IC (Table 2).32

Behavioral Therapy

The treatment of IC should begin with altering behavior that may contribute to disease progression. For instance, certain foods (Table 1) are known to exacerbate IC flares and therefore should be avoided.33 Although the role stress plays in IC is still unclear, stress reduction may help the patient control or deal with the symptoms of IC.34

Oral Therapy

Restoring the bladder’s protective mucous layer, reducing any co-existing inflammation, and blocking neuropathic up-regulation are the goals of current pharmacologic therapy for IC. Pentosan polysulfate sodium (PPS) is the only FDA-approved oral therapy for IC at this time. It is believed to help restore the epithelial mucous layer of the bladder.35 Inflammation associated with IC is thought to be spurred by the degranulation of mast cells in the lamina propria. Hydroxyzine, a primary antihistamine, is advocated due to its unique ability to stabilize mast cells, therein suppressing such degranulation.36 Regarding the neurologic component of IC, amitriptyline can be given to regulate sensations of pain and urgency in the bladder. As an added benefit, amitriptyline might also have antihistamine properties that can heighten a patient’s pain threshold.37,38 Clinicians should be careful not to underestimate the level of pain a patient with IC may be enduring. In some cases the shrewd employment of analgesics, including narcotics, may be warranted. A summary of the multimodal approach to treating IC is provided in Table 3.

Since rapid improvement may not ensue treatment initiation, it is important for clinicians to manage expectations and encourage compliance in their IC patients. Treatment combination and duration should both be individually tailored to maximize patient benefits in light of disease variability.

Intravesical Therapy

To directly target the source of pelvic pain in IC, the bladder can be instilled with pharmacologic agents. Dimethyl sulfoxide (DMSO) is one FDA approved intravesical agent intended to relieve pain in patients with IC. Patients with severe symptoms may benefit from long-term intravesical heparin therapy at a dose of 10,000 to 40,000 IU/day in 10 mL water; instillations can be reduced to three times a week for maintenance. Another agent with suspected potential to help restore the GAG-layer is hyaluronic acid. Though currently marketed in Canada, this agent has not yet been approved for use in the U.S.39

Other intravesical therapies being investigated for IC are anesthetic cocktails, which contain lidocaine, sodium bicarbonate, and heparin or PPS.39 The sodium bicarbonate is included to increase the absorption of lidocaine. Although not yet approved by the FDA, clinicians implementing these cocktails anecdotally report successful interruption of the patient’s pain cycle and restoration of the protective GAG-layer.39

Hydrodistention

Hydrodistention may have a role in relieving pain in the refractory patient. However, its effectiveness has yet to be demonstrated in controlled studies.30

Surgery: The Last Resort

In the most severe cases of IC, in which patients are unresponsive to behavioral and pharmacologic therapy, surgical intervention may be necessary. Implanted neurostimulators to regulate pain are also currently being investigated for IC therapy.40

Summary

Presenting symptoms for this lower urinary tract disorder include urinary urgency/frequency, and/or pelvic pain. Diagnostic questionnaires can be employed to unveil the unique symptoms consistent with IC in a general population. Advanced tests and/or specialist referral can often be avoided when the potassium sensitivity test, a simple office-based intravesical instillation of potassium, is used to confirm/refute suspicions of IC. Dietary changes, behavior modifications, and oral and/or intravesical medications yield good therapeutic results in the majority of cases. Early identification and treatment of IC patients is an important strategy for successful pain management.

IC is a disease in which close patient follow-up is crucial to successful therapy. Clinicians must be proactively involved in ensuring patient compliance and adapting treatment regimen to a dynamic symptom presentation. Understanding that IC patients have frequently been symptomatic for a long time and have been subjected to multiple misdiagnoses and failed treatment attempts is crucial to successful management. Acknowledging positive strides and reassuring patients that they are not unique in requiring adjustments to the therapeutic plan helps motivate compliance with therapy and maintain confidence in the way they are being treated for the disease. Further evaluation by a gynecologist or urologist is required if patiients with IC do not respond to therapy.

 

Last updated on: December 5, 2012
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