US Pharm. 2012;37(9):Epub.
Interstitial cystitis (IC) is a bladder pain syndrome whose exact
cause remains unknown. About 1.2 million people in the United States
have IC, most of them female (197 women vs. 41 men in 100,000).1-4 Typically, IC onset occurs in an individual’s mid-40s, but one study noted that 25% of patients were younger than 30 years.5
Because the clinical hallmarks of IC (urinary urgency and frequency,
bladder pain, nocturia, dysuria) are not specific, misdiagnosis or
delayed diagnosis of this syndrome is common. Most patients have
symptoms for 2 to 7 years and visit several health care providers before
receiving an accurate diagnosis.6 Outpatient-clinic visits for management of IC incurred about $66 million in health care expenditures in 2000.4,5
The impact of IC on quality of life (QOL) is significant, considering
the associated pain and urinary urgency and frequency, which may
curtail daily activities. Patients may experience interrupted sleep,
leading to fatigue and depression. Additionally, IC may cause pain
during sexual intercourse, thereby affecting sexual intimacy.
Various theories have been developed to explain IC pathophysiology,
but none of them can entirely explain why patients get IC. Most
clinicians agree that IC is caused by multiple factors, such as
defective bladder lining, histamines released by mast cells, autoimmune
conditions, and other situations (e.g., bladder trauma, bladder
overdistention, pelvic-floor dysfunction, spinal cord injury).4-6 The following are descriptions of theories about IC pathophysiology.
Defective Bladder Lining: The most favored
theory holds that a defect in the bladder lining could allow waste in
the urine (e.g., potassium ions) to infiltrate the nerves, causing pain
and stimulating frequent voiding. One study found that the urine of IC
patients had a lower potassium:creatinine ratio, which supports the
theory of permeability resulting in increased potassium diffusion.7
However, this theory cannot explain every case of IC, because only 50%
of IC patients had bladder-lining damage from petechial hemorrhage (glomerulation,
or pinpoint area of bleeding in the bladder wall) and only 10% had
Hunner’s lesion (reddened mucosal area with vessels radiating toward a
central scar on the bladder surface).3,5
Mast Cell Theory: IC patients have an increased number of mast cells in the bladder wall.8 Recent studies have found that mast cells containing histamine are involved in a variety of neural inflammatory diseases.6
The presence of a bladder insult or stimulation by acetylcholine,
stress, and hormone fluctuation activates mast cells, and histamine is
released. This histamine release triggers an inflammation response,
causing smooth-muscle contraction, local tissue damage, and nerve
stimulation. Over time, repetition of these events may further damage
the bladder lining, leading to increased urgency, frequency, and pain.5 Again, this theory cannot explain all cases of IC, and the use of antihistamines to treat IC produces suboptimal results.
Autoimmune Theory: Some clinicians believe that
immune-system dysregulation contributes to IC development because some
clinical features of IC resemble those seen in the dysregulated immune
system. Additionally, IC has unexplained associations with autoimmune
diseases and the pain syndrome involved in vulvar vestibulitis,
fibromyalgia, Hashimoto’s thyroiditis, and irritable bowel syndrome.1,6 A retrospective study revealed that 97% of IC patients and 93% of endometriosis patients had chronic pelvic pain.5
The similarly high percentages of chronic pain among IC patients and
endometriosis patients reinforce the belief that immune-system
dysregulation is a contributing factor to IC.
Signs and Symptoms
IC patients typically experience urinary urgency, urinary frequency, and bladder pain.3-6
With urinary urgency, the patient senses a strong need to void
immediately; pain or spasms may or may not accompany this sensation.3-6
Urinary urgency leads to urinary frequency, with IC patients typically
voiding many times per day. On average, IC patients void up to 16 times
per day, but the urinary volume is less than that of non-IC patients.
Urinary urgency often creates the need to get up at night to urinate
(nocturia), resulting in insomnia and fatigue.3-6
Typically (in about 70% of patients), early-stage IC involves the
presence of only one symptom: either urinary urgency or urinary
frequency.9 Over time, however, bladder pain may develop and
become a dominant symptom. Bladder pain may manifest in different
locations, such as the suprapubic or perineal area, vagina, lower back,
or medial aspect of the thigh.5 It is difficult for the
patient to pinpoint exactly where the pain originates, which could lead
to the mistaken belief that the pain indicates a urinary tract infection
(UTI). One characteristic of IC is that the pain is relieved by
voiding, but often recurs once the bladder fills with urine.5
For initial screening and simple cases of IC, diagnosis is based on
signs and symptoms and the exclusion of other bladder disorders, such as
bladder cancer, overactive bladder (OAB), and UTI. Since IC symptoms
are not specific, it is extremely important for the clinician to
differentiate IC symptoms from those of other bladder disorders (TABLE 1).1,4,5
Bladder cancer shares the typical three IC symptoms, but unlike IC, it
is also associated with hematuria and dysuria. OAB patients have urinary
frequency and urgency, but no bladder pain. UTI involves the three
typical IC symptoms, but bacteriuria, hematuria, and dysuria are also
present. In acute uncomplicated cystitis, patients may experience
urinary frequency and urgency and pain or pressure around the bladder,
but the urine contains bacteria and/or pus.10-13
Basic assessments include a careful review of medical history, a
thorough physical examination, and a laboratory workup to identify IC
symptoms and rule out other bladder-related pathology. The medical
history should include chief complaints; onset, duration,
characteristics, and location of symptoms; and relieving and/or
aggravating factors. In women, the physical examination should include a
pelvic examination, as they may have tenderness at the bladder neck and
anterior vaginal wall; pelvic-floor muscle strength should also be
evaluated because 81% of IC patients have high-tone pelvic-floor muscle
Baseline voiding symptoms and pain levels should be obtained for
future reference and treatment monitoring. The patient should keep a
voiding diary for 3 days to accurately record fluid intake and urine
output; establish severity of frequency and urgency; determine number of
daily voids and voided volumes; and identify which foods may worsen
symptoms. Acidic and potassium-containing foods trigger symptoms in 50%
of IC patients. Some foods that may worsen symptoms are alcohol,
caffeine, carbonated drinks, spicy foods, chocolate, tomatoes, yogurt,
bananas, apples, citrus fruits and juices, dried beans, spinach, and
artificial sweeteners. Patients should test these foods to determine
which ones trigger IC symptoms.6,15
Clinicians typically use symptom and problem questionnaires to screen
for IC. The O’Leary-Sant (OLS) questionnaire includes a symptom index
to measure urgency and pain and a problem index to measure the degree to
which the patient experiences each symptom.16 OLS is also an effective tool for following up and monitoring response to treatment.5,17
The pelvic pain and urgency/frequency (PUF) scale is another tool used
to evaluate the presence and severity of IC symptoms; it focuses on
urinary urgency, urinary frequency, and pelvic pain and quantifies
symptoms related to sexual intercourse.18 For patients in
whom IC is suspected, the intravesical potassium sensitivity test (PST;
discussed below) is used to confirm the diagnosis.19 In one
study, PST was positive in 74% of patients with a PUF score of 10–14,
76% of those with a score of 15–19, and 91% of those with a score ≥20;
if the total score exceeded 5 over 35, then 55% of cases had IC.5,18 One study found that OLS was more efficient than PUF for detecting IC.17
Differential laboratory tests include urinalysis, urine culture to
exclude UTI, urine cytology to rule out carcinoma, and vaginal culture
to exclude Chlamydia, herpes, or other sexually transmitted diseases.1,5,6
For more complicated IC cases in which initial screening cannot
confirm IC, urodynamic testing, PST, and cystoscopy with hydrodistention
should be performed.
Urodynamic Testing: A series of tests is performed to evaluate urinary function during bladder filling, storage, and emptying. Of these tests, the cystometrogram, or filling study, is the most important because it quantifies maximum bladder capacity, sensory urgency, and pain.6 IC patients generally have reduced bladder capacity (<350 mL) compared with non-IC patients, except in the early phase.5,6
PST: This test compares pain and urgency levels
before and after instillation of two solutions into the bladder. First,
40 mL of sterile water is instilled over 2 to 3 minutes; then the water
is drained and replaced with a solution of potassium chloride 0.4 M.19
Patient urgency and pain are graded from 0–5 before and after the
instillations. If the total score is greater than 2 over 5, then the
test is positive for IC. About 81% of IC patients have a positive test,
versus fewer than 3% of non-IC patients.6,14 PST is 100% false-positive in cases of acute bacterial cystitis, radiation cystitis, and UTIs.5
The test is useful in early-phase IC because such patients may not yet
be experiencing pain. PST may reveal urgency in 40% of IC patients and
pain in 28%. A negative PST means that the patient may not have IC; may
have IC, but does not have epithelial permeability problems; or has IC
plus an epithelial permeability problem, but the test is not positive
because of recent intravesical treatment involving dimethyl sulfoxide
Cystoscopy With Hydrodistention: This procedure is
performed only in patients with hematuria and/or abnormal cytology, to
differentiate IC from other bladder-related diseases. Water is instilled
into the bladder to a pressure of 80 to 100 cm H2O. When the
water is drained from the bladder, a patient with IC often shows
glomerulations. For a diagnosis of IC, the glomerulations must be
diffused and located in at least three bladder quadrants.6
To optimize IC treatment, clinicians should adhere to certain
principles. First, the goal is to alleviate or minimize symptoms. The
most conservative treatment should be implemented first. Initial
treatment type and level of treatment should correspond to symptom
severity, clinical judgment, and patient preferences. For multiple
treatments, baseline symptom measurement and regular assessment are
critical to monitor and document the efficacy of combined versus single
treatment. Ineffective treatments should be stopped once a clinically
meaningful interval has elapsed. Pain management and its effect on QOL
should be considered and regularly assessed. Finally, if no improvement
in symptoms is observed after various treatments have been tried, the
diagnosis of IC should be reevaluated.15
Treatment should be initiated with the most conservative regimen
(i.e., least risk of side effects) and progress sequentially to the
least conservative (i.e., greatest risk). Optimally, risks for adverse
drug reactions (ADRs) should be minimized, and benefits maximized. TABLE 2
lists treatment regimens ranked from most conservative to least
conservative based on the 2011 American Urological Association
First-Line: For initial-phase IC, first-line
treatment should be patient education, diet and behavioral modification,
and stress management. As the symptoms worsen over time, oral
medication should be added.4-6
Second-Line: The only FDA-approved medication
for IC treatment is pentosan polysulfate sodium (Elmiron). This drug, a
light-molecular heparinoid, works by adhering to the bladder-wall mucosa
to protect tissues from irritating substances in the urine. The dosage
is 100 mg orally three times daily, taken 2 hours before or after meals.
The most common ADRs are headache, dizziness, alopecia, rash, rectal
hemorrhage, diarrhea, nausea, abdominal pain, and dyspepsia. The drug
typically requires at least 6 months to achieve some symptom relief.
However, early-phase IC patients may experience pain relief in 4 weeks.20 The risks and benefits of use beyond 6 months in unresponsive patients are unknown.
For patients with moderate-to-severe IC, a therapeutic regimen of
Elmiron combined with antihistamines, antidepressants, and analgesics
may be used.21 Hydroxyzine hydrochloride is another drug used
to control IC symptoms, and a combination of pentosan and hydroxyzine
has achieved symptom relief in 40% of IC patients.5
Hydroxyzine acts like an antihistamine, but its use is limited by many
ADRs (e.g., central nervous system depression, pruritus, rash,
urticaria, xerostomia, paresthesia, tremor, blurred vision); therefore,
it may be inappropriate for use in geriatric patients.
Since IC patients are three to four times more likely to have
depression and suicidal thoughts, antidepressants such as amitriptyline
have been used to control depression and pain. Amitriptyline relieves
pain by inhibiting histamine secretion. Its reduction of norepinephrine
and serotonin reuptake in the peripheral nervous system alleviates
frequency and urgency.5 In a randomized, large-scale trial,
amitriptyline at a daily dose of 50 mg orally achieved symptom relief in
more than 50% of IC patients.4,18,20 The most common side effects are sedation, constipation, and dry mouth.
Common pain medications used for short-term pain relief during an IC
symptom flare are phenazopyridine (Pyridium), nonsteroidal
anti-inflammatory drugs, and narcotics.6
Intravesical therapy is used alone or in conjunction with oral
medications in advanced IC or in cases when a patient has an inadequate
response to conservative treatments or oral medications. An
agent—usually DMSO—is instilled into the bladder to reduce urgency,
frequency, and pain through its anti-inflammatory, analgesic, and
antispasmodic activity.1,4,5 At a dosage of 50 mL of 50% DMSO
every 1 to 2 weeks for 4 to 8 weeks, this method provides symptom
relief, but the pain frequently returns.6 In a randomized,
controlled trial, intravesical DMSO had 70% efficacy in reducing
symptoms for several months to 1 year. Heparin, also used off label in
intravesical therapy, works as a mucosal surface protector with
anti-inflammatory and inhibitory effects on bladder scars. One study
found that more than 50% of IC patients who received 25,000 U of heparin
twice a week intravesically for 3 months showed significant improvement
in symptom scores.6
Third-Line: If first- and second-line treatments
do not provide desired symptom control and improve QOL, then cystoscopy
with hydrodistention may be attempted. The stretch stimulus from
hydrodistention increases heparin-binding epidermal growth factor and
reduces antiproliferative-factor activity in the urine. As a result,
this treatment provides short-term benefit of about 6 months in up to
50% of IC patients.4-6 If Hunner’s lesions are present,
fulguration—a procedure using laser or electrocautery—may be performed
to burn the lesions. In one study, 100% of patients achieved complete
pain relief and 70% achieved reduced or normalized frequency for 2 to 42
Fourth-Line: InterStim is a surgically implanted
neuromodulation device used to control urinary frequency and urgency in
IC patients who fail conventional therapy.4,6 InterStim
therapy, approved by the FDA in 1997, has proven effective for up to 5
years. The device sends mild electrical impulses via a thin wire lead to
the sacral nerves that control the bladder, sphincter, and pelvic-floor
muscles. The device may be discontinued at any time, with the condition
reverting to that originally present. Patients receiving InterStim
therapy experienced more significant QOL improvement than those
receiving standard treatments.22,23
Fifth-Line: Cyclosporine A (CyA) may be used orally if
previous treatments fail to provide adequate symptom control. In one
randomized trial, oral CyA dosed at 3 mg/kg/day resulted in significant
clinical improvement after 6 months in 75% of patients versus 19% of
patients taking Elmiron. Serious ADRs include immunosuppression and
Sixth-Line: Cystectomy is a surgical procedure that
removes all or part of the bladder. This procedure is rarely used
because of its complications and unpredictable results; therefore, it is
reserved for severe cases in which all other therapies have failed.6 Supratrigonal cystectomy or urinary diversion may be used.
In supratrigonal cystectomy, a small portion of the bladder is
left intact and bowel tissue is used to form a new bladder. This
procedure increases the size of the bladder, but it can impair the
bladder’s ability to empty properly. Consequently, the patient must
insert a catheter once or twice a day to remove the remaining urine,
which increases the risk of bladder infection. Additionally, bowel
tissue naturally produces mucus, which may block the flow of urine or
make self-catheterization more difficult.24
In urinary diversion, a section of the bowel is used to
redirect the flow of the urine to a stoma (hole in abdominal wall). The
bladder may be left in place or removed entirely, and urine in the stoma
is collected in an external bag. This procedure is associated with a
lower risk of complications, but an external bag may be inconvenient for
the patient. Alternatively, an internal pouch (ileal reservoir) may be
created next to the abdominal wall. The pouch is made of bowel tissue
and has a small stoma where a catheter can be inserted for draining the
pouch. Urinary diversion has a high rate of complications and mucus
Another surgical procedure for IC uses segments of the small
intestine to make a neobladder (storage pouch). The neobladder is
connected to the urethra, allowing urine to pass out of the body
normally. It may take a few weeks to months for the neobladder to
function properly. In a case study, this procedure was performed in 35
female patients with IC for at least 2 years who had failed conservative
treatments. All patients showed significant improvement in QOL, and
only two (5.7%) were placed on intermittent catheterization.25
Treatments to Avoid: According to the recent
guidelines for interstitial cystitis/bladder pain syndrome, the
following treatments should be avoided because of lack of efficacy
and/or unacceptable side effects: long-term oral antibiotics;
intravesical instillation of bacillus Calmette-Guérin outside of
investigational study settings; high-pressure, long-duration
hydrodistention; and long-term systemic oral glucocorticoids.15
IC is caused by multiple factors and occurs mostly in women. Typical
symptoms include urgency, frequency, and bladder pain without signs or
symptoms of infection. IC is diagnosed by a thorough medical history and
physical examination, along with laboratory tests to rule out other
bladder disorders. For optimal treatment, clinicians should implement
the most conservative therapies to prevent unnecessary additional risks
for patients. Multiple simultaneous treatments should be considered.
Additionally, pain management must be applied throughout the course of
therapy. Pharmacists can play an important role in optimizing treatment
by educating patients about IC and available therapies and collaborating
and intervening with the medical team or prescribers to develop the
best treatment regimen for the IC patient.
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