This activity has been planned and implemented in accordance with the Essential Areas and policies of the
Accreditation Council for Continuing Medical Education through the joint sponsorship of the Dannemiller
Memorial Educational Foundation and SynerMed Communications. The Dannemiller Memorial Educational
Foundation is accredited by the ACCME to provide continuing medical education for physicians.
The Dannemiller Memorial Educational Foundation designates this educational activity for a maximum of
1 category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those
credits that he/she actually spent in the activity.
Vol. 23 No. 26
July 2005
ISSN 0264-6684
Release date: July, 2005
Expiration Date: July 31, 2006
Jointly sponsored by
Dannemiller Memorial Educational Foundation and SynerMed® Communications.
This program is made possible by an educational grant from Ortho Urology
This newsletter provides the most current information on the following:
This activity should take approximately 1 hour to complete. The participant should, in
order, read the objectives and newsletter, answer the 10-question multiple-choice
posttest, placing answers on the Registration/CME Posttest Answer Form/Evaluation on
page 15, and complete the Program Evaluation on page 15. The evaluation form provides each participant with the opportunity to comment on the quality of the instructional
process, the perception of enhanced professional effectiveness, the perception of
commercial bias, and his or her views on future educational needs. To receive credit for
this activity, follow the instructions provided on the posttest.
Chronic pelvic pain syndromes (CPPS) affect an estimated 9 to 15 million women in
the United States, and while the cause of the chronic pelvic pain is often undiagnosed, at least one in seven women is affected by this condition. Studies have
demonstrated that interstitial cystitis (IC) is the source of chronic pelvic pain in a
large number of women. Urogenital syndromes affect an estimated 1 in 10 men in the
United States. In the US, approximately 9% of men aged 40 to 79 years are diagnosed with prostatitis. The overwhelming majority of men with prostatitis have
chronic nonbacterial prostatitis – classified as chronic prostatitis/chronic pelvic pain
syndrome (CP/CPPS). The true epidemiology and pathophysiology of CPPS, and
particularly IC, remain unclear. There is no definitive test to identify IC. Moreover, a
variety of therapeutic options have been employed to treat patients who suffer with
this condition.
Recent advances in both the diagnosis of IC, and available management alternatives,
have enabled health care providers to more easily identify patients with this disease,
and then provide effective treatment to positively impact their quality of life.
Overview and Etiology of IC; Promising Clinical Markers; Challenges in the Diagnosis of
IC in Men; Impact of CPP on Quality of Life; Differential Diagnosis of IC and CP/CPPS;
Challenges in the Diagnosis of IC in Women; Differential Diagnosis of IC and Other
Urologic and Gynecologic Conditions; Current Approach to Diagnosis of IC in Men and
Women; Potassium Sensitivity Test; Symptom Questionnaires; Intravesical Anesthetic
Challenge; Future Directions in the Diagnosis of IC; Patient Stratification for the Diagnosis
and Treatment of IC; Current Approach to Treatment of IC; Conservative/Adjunctive
Therapies; Pharmacologic Treatments Approved by the US Food and Drug
Administration (FDA); Oral Pentosan Polysulfate Sodium; Intravesical Instillation With
Dimethyl Sulfoxide (DMSO); Off-label Treatments for IC; Antihistamines; Antidepressants;
Other Therapies for Pain Relief; Other Intravesical Solutions; Approaches to Multimodal
Treatment of IC; Surgical Intervention.
1. Review the epidemiology/prevalence of IC in men and women.
2. Differentiate between chronic pain of bladder and pelvic origin in men and women.
3. Examine the similarities between chronic nonbacterial prostatitis/chronic pelvic
pain syndrome (CP/CPPS) and IC in clinical presentation, diagnostic evaluation,
purported pathogenesis, and response to therapy.
4. Discuss the clinical presentation of IC and discuss its differential diagnosis in men
and women; discuss the assessment of IC as a diagnosis of exclusion.
5. Explore traditional and emerging pharmacologic and nonpharmacologic treatment
options for the management of IC.
This program is intended for urologists.
J. Curtis Nickel, MD
Professor of Urology
Queen’s University
Kingston General Hospital
Kingston, Ontario, Canada
Jean L. Fourcroy, MD, PhD, MPH
Assistant Professor/Urology
Uniformed Services University Health Sciences
Walter Reed Army Hospital
Bethesda, Maryland
Susan Keay, MD, PhD
Professor of Medicine
University of Maryland School of Medicine
Veterans Affairs Medical Center
Baltimore, Maryland
Robert J. Evans, MD
Chief of Surgery
Moses Cone Health System
Greensboro, North Carolina
David M. Kaufman, MD
Assistant Professor of Clinical Urology
Columbia University College
of Physicians and Surgeons
St. Luke’s – Roosevelt Hospital
New York, New York
Diane K. Newman, RN, MSN
Penn Center for Continence and Pelvic Health
Division of Urology
University of Pennsylvania Medical Center
Philadelphia, Pennsylvania
In accordance with the Accreditation Council for Continuing Medical Education
(ACCME), the Dannemiller Memorial Educational Foundation requires that any person
who is in a position to control the content of a CME activity must disclose all relevant
financial relationships they have with a commercial interest. Accordingly:
• J. Curtis Nickel, MD reports that he has received research support, has been
a consultant and has served on the speakers bureau for Ortho-McNeil
Pharmaceutical, Inc.
• Robert Evans, MD has received research support from Ortho-McNeil
Pharmaceutical, Inc., and has served on the speakers bureau for Medtronic and
• Jean Fourcroy, MD, PhD, MPH has been a consultant and has served on the
advisory board for Ortho-McNeil Pharmaceutical, Inc.
• David Kaufman, MD has received research support from Pfizer Inc., Watson
Pharmaceutical, and Sanofi and has served on the speakers bureau for Ortho-McNeil
Pharmaceutical, Inc.
• Susan Keay, MD, PhD declares no financial interest or other relationship with the
commercial supporter of this activity or any other manufacturer(s) of any commercial
product(s) at this time.
• Diane K. Newman, RN, MSN declares no financial interest or other relationship
with the commercial support of this activity or any other manufacturer(s) of any
commercial product(s) at this time.
• The Dannemiller Memorial Educational Foundation staff that was involved in
the development of this activity has no financial relationships with any
commercial interests.
• The SynerMed staff that was involved in the development of this activity has no
financial relationships with any commercial interests.
• In order to resolve conflict of interest, this activity was reviewed by Bernard Abrams,
MD, Clinical Professor of Medicine, University of Missouri at Kansas City School of
Medicine, who has no financial relationships with commercial interests.
Disclosure of unlabeled/investigational use of drugs/devices will be made in the
instructional text.
Clinical Courier ® is a specialty newsletter reporting on clinical/biomedical issues. The
publishers reserve copyright on all published materials, and such materials may not be
reproduced in any form without the permission of SynerMed Communications.® This
newsletter was developed, produced, and jointly sponsored by the Dannemiller Memorial
Educational Foundation and SynerMed Communications.® The views presented herein are
those of the faculty and not necessarily those of the publisher, grantor, or sponsor. This
material is prepared based upon a review of multiple sources of information, but
it is not exhaustive of the subject matter. Therefore, health care professionals and other
individuals should review and consider other publications and materials on the subject
matter before relying solely upon the information contained within this material.
This educational activity may contain discussion of published and/or investigational
uses of agents that are not indicated by the FDA. The opinions expressed in the
educational activity are those of the faculty. Please refer to the official prescribing
information for each product for discussion of approved indications, contraindications,
and warnings. Further, attendees/participants should appraise the information presented
critically and are encouraged to consult appropriate resources for any product or device
mentioned in this program.
This activity has been planned and implemented in accordance with the Essential Areas and policies of the
Accreditation Council for Continuing Medical Education through the joint sponsorship of the Dannemiller
Memorial Educational Foundation and SynerMed Communications. The Dannemiller Memorial Educational
Foundation is accredited by the ACCME to provide continuing medical education for physicians.
The Dannemiller Memorial Educational Foundation designates this educational activity for a maximum of
1 category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those
credits that he/she actually spent in the activity.
Vol. 23 No. 26
July 2005
ISSN 0264-6684
Release date: July 2005
Expiration Date: July 31, 2006
Interstitial cystitis (IC) is a clinical syndrome characterized by chronic pelvic
pain (CPP) and severe urologic symptoms (urgency and frequency of
urination, both day and night) in the absence of bacterial infection or other
well-defined cause.1 The pathogenesis of IC is largely unknown, the diagnosis
is primarily based on symptoms, and insight into effective treatment is
still evolving.
Prevalence studies have estimated that about 1 million people in the United
States are affected by IC, with most cases being diagnosed in women.2
However, a recent study of patients diagnosed with IC in a managed care
population found a prevalence of 197 cases per 100,000 women and 41 cases
per 100,000 men, which is 10 times the numbers accepted 20 years ago.3
Some researchers believe that the true number of cases of IC could be even up
to 100 times greater than those cited above, if IC is determined by screening
populations for IC symptoms rather than for diagnosed cases.4
IC is a highly prevalent chronic pelvic pain syndrome
whose pathogenesis is largely unknown;
diagnosis is primarily based on symptoms, and insight
into effective treatment is still evolving.
For both men and women, IC is a disorder that exacts a tremendous physical
and psychological toll, including dyspareunia and pelvic pain, depression,
sexual dysfunction, missed work, and overall decrease in quality of life (QOL).5
In one epidemiologic study, 56% of patients with IC reported depression, 94%
said that travel was difficult or impossible, and 70% reported a disruption in
family relationships and responsibilities.6
For the clinician as well as the patient, IC is a frustrating disorder, posing both
diagnostic and treatment challenges. Too often, patients are adequately
identified only after a number of misdiagnoses, with a lost opportunity for early
recognition that could afford the best chance for symptom resolution.7 IC
patients frequently have overlapping symptoms related to the pelvic organs,
which encompass urologic, gastrointestinal, gynecologic, pelvic floor, and
prostate domains. This confusion can translate into a lengthy delay in
diagnosis. One retrospective analysis found an average wait time of 7.8 years
between symptom onset and correct diagnosis. That study found that IC was
frequently misdiagnosed in women as urethral stricture, overactive bladder
(OAB), recurrent cystitis, and endometriosis, and in men as prostatitis, bladder
outlet obstruction, and benign prostatic hyperplasia (BPH).
A presumptive diagnosis of IC may be made by looking for appropriate clinical
criteria and after excluding other disorders such as urinary tract infection (UTI),
bladder cancer, sexually transmitted diseases, neurologic disorders, kidney
diseases, vaginal infections, or prostatitis. In the future, biomarkers may help
identify patients with IC more easily. This will lead to earlier and more accurate
diagnosis and, consequently, more effective treatment. While there is currently
no cure for IC, a multimodal management strategy helps greatly to alleviate
symptoms and improve the QOL for these patients. Available diagnostic tools
and treatment options are described in this report, along with the clinical
experience of and discussion among key opinion leaders in the field of
urology, who recently convened at a roundtable meeting to explore current and
emerging IC diagnostic and treatment issues.
J. Curtis Nickel, MD, FRCS stated that there is no unique known cause of IC
and no specific diagnostic criteria, contributing to the difficulty of determining
a precise definition of IC. The American College of Obstetricians and
Gynecologists (ACOG) defines IC as a “chronic inflammatory condition of the
bladder clinically characterized by irritable voiding symptoms or urgency and
frequency, in the absence of objective evidence of another disease that could
cause the symptoms.”8 In 1987 the National Institute of Diabetes and Digestive
and Kidney Diseases (NIDDK) established criteria to standardize the diagnosis
of IC based on symptoms and cystoscopic findings with the patient under
anesthesia; however, this diagnostic approach is considered more fitting for
research than for clinical purposes.9 (TABLE 1) The National Institutes of
Health IC Database Study found that the strict application of the NIDDK criteria
would probably miss more than 60% of patients likely to have IC.10
ACOG defines IC as a “chronic inflammatory condition of the
bladder clinically characterized by irritable voiding symptoms
or urgency and frequency, in the absence of objective evidence
of another disease that could cause the symptoms.”
• Pelvic/perineal or bladder pain
• Urinary urgency and/or frequency
• Presence of glomerulations or ulcers on cystoscopic examination
(hydrodistention under anesthesia)
• Negative urine culture
• Absence of genitourinary infections
• Absence of prostatitis
• Absence of bladder tumor
• No history of chemical, tuberculosis, or radiation cystitis
The International Continence Society (ICS) prefers the term “painful bladder
syndrome” (PBS) to define “the complaints of suprapubic pain related to
bladder filling, accompanied by other symptoms such as daytime and nighttime frequency, in the absence of proven urinary infection or other previous
pathology.” The ICS reserves the diagnosis of IC for patients with “typical
cystoscopic and histological features,” without further specifying these.11,12
No matter how IC is defined, the essential symptomatology includes chronic
pelvic or bladder pain and urinary symptoms of urgency and frequency. The
pain may be relieved by voiding, usually in small amounts, but soon recurs
when the bladder refills. This is often accompanied by an uncomfortable,
constant urge to void that does not go away even after urination. The average
patient with IC voids 16 times per day, though it is not uncommon for patients
with severe disease to void 20, 40, or even 60 times daily.13,14 Along with
treatment for the CPP, dietary changes and bladder training techniques,
including the use of a bladder diary, are usually helpful in lengthening the time
between voids and in monitoring progress.
Bladder insult
More injury
Epithelial layer damage
Mast cell activation and
histamine release
Potassium leak Into
Activation of C-fibers and
release of substance P
Courtesy of Robert J. Evans, MD.
David M. Kaufman, MD indicated that effective diagnosis and treatment of IC
will be influenced by a deepening understanding of the mechanisms of
pathogenesis, which remain unclear. Most likely, there are multiple causes for
the symptoms of IC in any one patient, including structural, neurologic,
autoimmune, lymphatic, infectious, and psychological factors.5,15 It has been
suggested that susceptible persons may have an underlying genetic defect,
and may develop IC after some initial insult.16
When released, substance P causes an inflammatory cascade that leads
to mast cell degranulation and activation of nearby nerve terminals. Patients
with IC appear to have increased numbers of substance P-containing nerves
(C-fibers) and increased concentration of substance P, which correlates with
pain severity. 19 Increased production of inflammatory mediators such
as leukotrienes and adenosine triphosphate have also been found in
IC patients.20,21
A fundamental finding in IC is marked epithelial dysfunction that results in
increased bladder epithelial permeability. (FIGURE 1) This may occur through
a defect in the glycosaminoglycan (GAG) component of the mucin layer that
covers and protects the bladder urothelium from noxious elements.
Dysfunction of the GAG protective layer allows leakage and transvesical
absorption of urinary solutes that can injure the bladder interstitium.14 Ongoing
exposure to these toxic elements, including potassium, may cause
inflammation, tissue irritation and injury, mast cell degranulation and sensory
nerve depolarization, which may result in the urinary urgency, frequency and
pain of IC (though pain can occur without somatic damage).17,18 (FIGURE 2)
Abnormalities of mast cells (which contain histamine-rich granules) may also
contribute to the development of IC. Patients with IC have increased levels of
histamine and increased numbers of mast cells in the bladder wall, as well as
increased urinary excretion of histamine metabolites. It is believed that
degranulated mast cells abnormally release histamine, which in turn may
cause the initial insult or damage to the GAG layer.14
Jean L. Fourcroy, MD, PhD, MPH commented that neurologic up-regulation
and neurogenic inflammation are also important components in the
pathogenesis of IC. Neuropeptide substance P—an inflammatory mediator
that functions as a nociceptive neurotransmitter—may play a pivotal role.
Referred pain and motor activity to the pelvic floor muscles and the pelvic
organs may be other underlying causes of IC symptoms. Diane K. Newman,
RN, MSN noted that the pelvic floor muscle tenderness and spasm known as
pelvic floor dysfunction often occurs in conjunction with IC and is responsible
for many of the symptoms that she sees in her patients.22
Three proposed contributors to the pathogenesis
of IC are GAG layer abnormalities, mast cell activation,
and neurogenic inflammation.
The presence of glomerulations in the bladder has historically been one of the
requisite criteria for formal diagnosis of IC. Tamaki et al recently concluded
that angiogenic growth factors play a role in the pathogenesis of IC by
promoting the neovascularization that apparently induces these
glomerulations.23 Other researchers have found increased angiogenic factors
in bladder tissue from IC patients, compared to controls, and suggest that
these factors may be involved in the inflammatory process to cause the painful
symptoms of IC.24
Robert J. Evans, MD concluded that he approaches treatment of his IC
patients by targeting the 3 most likely and important contributors to the
pathogenesis of IC: GAG layer abnormalities, mast cell activation, and
neurogenic inflammation.
Promising Clinical Markers
A recent breakthrough in IC research has been the discovery of sensitive and
specific biomarkers for IC, including antiproliferative factor (APF), heparinbinding epidermal growth factor-like growth factor (HB-EGF), epidermal
growth factor (EGF), and urinary glycoprotein (GP)51. Urine levels of all of
these were found to be significantly different between patients with IC and
asymptomatic controls.25-28 In a seminal study by Susan Keay, MD, PhD and
colleagues, antiproliferative activity was found in 9% of urine specimens from
subjects without IC and in 94% of urine specimens from patients with IC.29
APF appears to inhibit the growth of normal bladder epithelial cells. Dr. Keay
commented that the demonstration of a difference in cell replication rates
between IC cells, which produce APF, and normal cells, which do not appear
to, may be evidence that the bladder epithelium is intrinsically abnormal in
IC patients.30
GP51 is a urinary glycoprotein produced and secreted by the transitional
epithelium of the genitourinary tract. Studies on the potential of using GP51 as
a clinical marker for IC have found that low GP51 levels in the urine appear to
be unique to the IC patient, compared to normal controls and to patients with
other urinary tract diseases, supporting the potential usefulness of GP51 as
another clinical marker for IC.28
APF appears to inhibit the normal growth of
bladder cells. Antiproliferative activity was found in
9% of urine specimens from subjects without IC and in
94% of urine specimens from patients with IC.
Data are comparatively scarce regarding the prevalence of IC in men.
Historically, IC has been thought to affect women disproportionately. In most
studies of IC, only about 10% of patient cohorts are male. However, a recent
study found a 1:5 male-to-female ratio of IC patients, accounting for a higher
proportion of men with IC than has previously been recognized.3 (FIGURE 3)
The study was based on a computer search of the Kaiser Permanente
Northwest database of 206,470 (managed care) patients to find those patients
assigned a diagnosis of IC by a clinician. Investigators noted that a significant
No. per (100,000)
ICD-9 Dx
ICD-9 + no excl.
ICD-9 Dx = diagnosis of IC
no excl. = no exclusion (after applying exclusion criteria derived from the NIDDK)
Adapted from J Urol 2005;173(1):98-102, Clemens JQ, Meenan RT, Rosetti MC, et al. Prevalence and
incidence of interstitial cystitis in a managed care population. Copyright © 2005, with permission from
Lippincott Williams & Wilkins.
number of both men and women had bladder-specific symptoms but did not
receive a formal diagnosis of IC. They also found that half the men diagnosed
with IC were additionally coded with a diagnosis of prostatitis. The roundtable
participants concluded that a large number of men with bladder complaints
and/or pelvic pain may have early IC that remains undiagnosed. IC should
be suspected in a man with CPP and urinary symptoms, and he should be
assessed and treated accordingly.
IC should be suspected in a man with CPP
and urinary symptoms, and he should be assessed
and treated accordingly.
Impact of CPP on Quality of Life
IC, nonbacterial chronic prostatitis (CP), and chronic pelvic pain syndrome
(CPPS) all adversely affect a man’s QOL. The QOL of male IC patients was
found to be comparable to that of persons undergoing hemodialysis; the QOL
of men diagnosed with CP/CPPS was found to be on par with severe
congestive heart failure and diabetes and to have a sickness impact
comparable to myocardial infarction, angina, and Crohn’s disease.31,32
For many men, sexual QOL is clearly compromised by IC and CP/CPPS.
Rosen et al demonstrated the impact of lower urinary tract symptoms (LUTS)
on male sexual dysfunction in a multinational survey of men aged 50 to 80
(12,815 men were deemed evaluable).33 The occurrence of sexual disorders,
including ejaculatory loss, painful ejaculation, and erectile dysfunction, and
their degree of “bothersomeness” (assessed by validated symptom scales)
were strongly related to the severity of the urinary symptoms. Although 90%
of the men included in Rosen’s survey had LUTS, only 19% had sought
medical attention.
The constellation of sexual problems with CP/CPPS and IC includes
avoidance of intimacy and sexual dysfunction. Since men are often reluctant to
report genitourinary symptoms to their health care providers, Dr. Fourcroy and
Ms. Newman emphasized the importance of routinely questioning patients,
especially men, about sexual activity and associated symptoms. Discussion
with the patient can aid in early diagnosis and can encourage the patient with
regard to the potential for improvement with treatment.
Differential Diagnosis of IC and CP/CPPS
Urologists should consider CPP of bladder origin (IC) in the differential
diagnosis of men with voiding disorders accompanied by irritative symptoms
(urgency/frequency) and pelvic pain, especially in the absence of bacteria or
following one or more courses of antibiotic therapy.34 The CPP associated with
IC is often attributed to other genitourinary conditions, such as CP/CPPS.
CP/CPPS is defined by the NIDDK of the National Institutes of Health (NIH) as
genitourinary/pelvic pain or discomfort, for at least 3 of the last 6 months, in
the absence of uropathogenic bacteria localized to prostate-specific specimens
on culture.35 CP/CPPS and IC share similar clinical presentations and possibly
similar etiologies.36 The clinical presentation of CP/CPPS includes CPP and
urinary symptoms of urgency, frequency and nocturia. (TABLE 2, page 4)
Ms. Newman suggested that questions about sexual activity should be included
as part of the medical history, because CPP often manifests as testicular or
penile pain, pain in the perineal area, or pain with or following ejaculation.
The clinical presentation of both CP/CPPS and IC includes
pelvic pain and urinary symptoms of urgency, frequency, and
nocturia, with the absence of uropathogenic bacteria.
Both CP/CPPS and IC can be associated with pain upon bladder filling, and
both lack a bacterial etiology. Furthermore, other similarities are seen on
physical examination and cystoscopy, including sensory bladder instability,
• Voiding symptoms
(frequency, urgency, nocturia)
• Voiding symptoms
(frequency, urgency, nocturia)
• Pain with intercourse
• Pain with ejaculation, testicular pain
• Referred pain (lower abdomen,
urethra, lower back, medial thigh,
perineum, postvoid)
• Referred pain (urethral, perineal,
lower abdomen, testicular, scrotal,
rectal, postvoid)
• Pain on bladder filling
• Pain on bladder filling
• Nonrelaxing pelvic floor (70%)
• Nonrelaxing pelvic floor (50%)
• Diet can exacerbate symptoms
• Diet can exacerbate symptoms
Chronic Pelvic Pain
No urinary symptoms
• Antimicrobial therapy
(eg, levofloxacin)
• Anti-inflammatory
(eg, naproxen)
• Alpha-blocker
a non-relaxing pelvic floor muscle, and petechial hemorrhages with
bladder hydrodistention.37
In several recent studies, 58% to 90% of men with CP/CPPS were found to
have cystoscopically confirmed IC.34,38,39 There is emerging evidence that CP
and IC, in fact, may be 2 conditions that are part of the same pathophysiologic
spectrum, namely lower urinary epithelial dysfunction.40
Dr. Kaufman stated that his diagnostic protocol for a male patient who
presents with CPP is to assign him to one of 2 categories: CPP with urinary
symptoms or CPP without urinary symptoms. If results of the physical
examination suggest pelvic floor dysfunction rather than prostatitis, and the
patient does not have urinary symptoms, IC is not immediately indicated
and initial treatment would consist of muscle relaxants and physical therapy.
Dr. Kaufman considers a diagnosis of IC (with or without pelvic floor
dysfunction) when the prostate seems normal to examination and the patient
presents with CPP and urinary symptoms. He confirms that diagnosis with a
potassium sensitivity test (PST, described below). Dr. Kaufman’s approach has
been defined through his clinical experience. (FIGURE 4)
In light of the many similarities in clinical presentation,
IC should be suspected in all men presenting with the
signs and symptoms of CP/CPPS and urinary symptoms.
When IC in a male patient is misdiagnosed as CP/CPPS due to the similarity
of symptoms, it is often managed inappropriately with antibiotics. In light of
the many similarities between the conditions, IC should be suspected in all
men presenting with signs and symptoms of CP/CPPS and urinary symptoms.
When CP/CPPS is the probable diagnosis—based on genitourinary pain,
pain on ejaculation, and substantial perineal discomfort, without irritative
voiding symptoms—one could begin therapy for CP/CPPS and then assess
response at 1 month. Dr. Evans noted that a multimodal treatment approach
would typically involve an antibiotic, alpha-blocker, anti-inflammatory agent,
diet modification and other supportive care. A lack of response at 1 month
would lead to reassessment for IC. Ms. Newman cautioned that differentiation
into 2 groups is not straightforward, especially when the patient has a history
of UTI and occasional urinary frequency/urgency. Dr. Kaufman suggested that,
in those questionable cases, a positive PST might support a diagnosis of IC.
Dr. Evans recommended checking the post-prostatic massage urine specimen
to rule out bacterial prostatitis (a small percentage of patients). His clinical
experience indicates that a large percentage of his patients with CPP have
pelvic floor muscle dysfunction associated with an underlying bladder or
prostate pathology, and his treatment approach targets not just CP or IC, but
also muscle rehabilitation.
No response
Urinary symptoms
IC treatment:
• Amitriptyline
• Hydroxyzine
• Intravesical instillations
• Supportive/adjunctive therapies
Pelvic floor
• Physical therapy
• Muscle relaxant
(eg, lorazepam)
It is estimated that as many as 1 in 3 American women experience pelvic pain
at some point in their lives, and over 9 million have sought treatment for their
pelvic pain.41 For many of these women, an accurate diagnosis of their
complaints may be elusive for years. Clinicians often assume that CPP is
caused by reproductive tract problems, such as unresolved endometriosis,
pelvic adhesions, or vulvodynia. They also frequently diagnose OAB in the
patient with urinary frequency/urgency without ascertaining pelvic discomfort,
and prescribe anticholinergics with variable success. Recurrent UTI is another
common misdiagnosis, and can lead to repeated and often futile courses of
antibiotics.42,43 (TABLE 3)
Of the approximately 9 million women with CPP,
a substantial percentage have a disorder of bladder
origin and may eventually be diagnosed with IC.
Of the approximately 9 million women with CPP, a substantial percentage
have a disorder of bladder origin and may eventually be diagnosed with IC.
While the prevalence of IC is still not definitively established, the consensus is
that IC affects a far greater number of women than the traditional figures have
suggested. Previous estimates have largely been based on diagnosed cases,
excluding women with likely IC who have not been definitively diagnosed.
According to 2 recent studies, as many as 2 in 9 women may have IC.44
A 2004 study screened female medical students for IC symptoms and then
evaluated the suspected cases, identifying probable IC in 30.6% and
Bladder or urinary tract infection
Vulvar dermatoses
Uterovaginal prolapse
Overactive bladder
Renal calculi
Sexually transmitted infection
Chronic pelvic infection
Urethral diverticula
Vaginal infection
Irritable bowel syndrome
Pelvic floor dysfunction
documented IC in 10% of this young, unselected population.45 These data
suggest the estimate of IC prevalence in the United States should be vastly
increased from approximately 1.5 million to perhaps 25 to 30 million women
and that IC is prevalent in young women.45 Earlier diagnosis would increase
the likelihood of prompt and effective resolution of symptoms.
Differential Diagnosis of IC and Other Urologic and
Gynecologic Conditions
All women who present with a history of urinary frequency and urgency along
with pain or discomfort in the pelvis, bladder, or perineum should be
evaluated for the presence of IC. The differential diagnosis can be extensive.
Often, urologic and gynecologic symptoms occur together, further
confounding the diagnosis. Chung et al, in fact, have labeled IC and
endometriosis the “evil twins of chronic pelvic pain.”46 Their retrospective
review of 60 patients with CPP found IC in 97% and endometriosis in 93%.
All women who present with a history of urinary frequency
and urgency along with pain or discomfort in the pelvis, bladder,
or perineum should be evaluated for the presence of IC.
The roundtable participants agreed that pelvic pain is a key presenting
symptom in IC and should raise the suspicion of IC. Similarly, IC should be
suspected in women reporting recurrent symptoms of UTI who have negative
cultures. Because urinary frequency and urgency are also key symptoms of
IC, the need to differentiate IC from OAB is an important goal of diagnosis.
Ms. Newman emphasized that IC should be considered when patients
diagnosed with OAB do not respond to anticholinergics/antimuscarinics and
report pain or discomfort that is relieved by voiding.
The patient with signs and symptoms of IC should undergo a medical history
and physical examination with urinalysis and/or culture, and should complete
a voiding diary. These traditional assessments, however, do not provide
enough information for a definitive diagnosis of IC. Many attempts have been
made to establish objective criteria or a unique diagnostic test. Dr. Nickel
offered the following perspective on currently employed diagnostic methods:
• Testing for presence of Hunner’s ulcers
– Found in fewer than 10% of patients
• Testing for presence of glomerulations via cystoscopy and hydrostatic
bladder dilation
– Invasive, requires general anesthesia, no accepted criteria for identification,
glomerulations may be present in only 50% of IC patients
• Bladder capacity measurement under general anesthesia
– Helpful but does not differentiate IC from other bladder diseases
• Application of NIH/NIDDK criteria
– Fails to diagnose at least 50% of patients
– Simple, inexpensive, generally safe and well-tolerated, provides
objective assessment but fails to diagnose 25% of patients
• Urine biomarkers
– Exciting and promising but currently a research tool; not yet ready for
clinical application
None of the above methods has proved uniformly helpful, but some are more
accurate than others. Two diagnostic approaches have recently become fairly
well established for evaluating and perhaps diagnosing IC—the PST and the
Pelvic Pain and Urgency/Frequency (PUF) Patient Symptom Scale. While
neither is completely reliable alone as a definitive diagnostic tool, together
(and along with a medical history, a physical examination, and appropriate
urine testing) they may be considered sufficient to make a clinical diagnosis of
IC and to initiate appropriate therapy.
The PUF questionnaire and the PST are new
diagnostic tools that allow clinicians to screen patients
suspected of having IC easily and reliably.
Potassium Sensitivity Test
The PST can identify those patients who respond with pain or urgency to the
instillation of an aqueous solution of potassium chloride (KCl) in the bladder,
indicating a dysfunction of the uroepithelium. Because the test involves
catheterization, it may not be readily employed in some primary care
practices. The procedure may be accompanied by immediate pain and
discomfort that quickly subside. Sterile, room temperature water (40 mL) is
first slowly introduced via a thin catheter into the bladder to establish
baseline levels of pain and urgency, using a point scale ranging from 0 to 5
(with 5 representing the most severe pain). The sterile water is generally
retained in the bladder for approximately 5 minutes [Dr. Kaufman allows it to
be retained for 1 minute], and then slowly drained through the catheter. (Dr.
Kaufman mentioned that it may be necessary for men to void out the KCl
solution in order to observe a positive response, which may be induced when
the solution comes in contact with the urothelium of the prostatic urethra.)
Then 40 mL of 0.4M KCl solution is instilled slowly into the bladder, and the
patient is asked to re-evaluate the pain. An increase of 2 or more points is
suggestive of abnormal epithelial function and IC is indicated. Patients who
respond to the introduction of only the initial water solution are considered
likely to have IC, as are those who report discomfort with the KCl solution. A
patient has a clearly negative PST if he or she reports no pain or urgency
response to any part of the procedure (except in certain situations, such as
heavily medicated patients).
80% of IC patients have positive PST results,
compared to 4% of asymptomatic controls.
Eighty percent of IC patients have positive PST results, compared to
4% of asymptomatic controls. Patients with detrusor instability show a 25%
false-positive rate and patients with UTI and radiation cystitis have a
100% false-positive rate.17 A positive PST result is seen in 85% of gynecologic
patients with CPP, endometriosis, or vulvodynia.47 The PST seems to be
appropriately negative in many urologic conditions, but the significant rate of
positive results in others, including OAB and UTI, could confound the
diagnosis of IC.40,44,47,48
While a positive PST does not conclusively diagnose IC, nor a negative PST
rule it out, studies have found a sufficiently significant correlation between a
positive PST result and presence of IC that it remains part of the diagnostic
armamentarium for IC. (FIGURE 5) Positive PST results have been shown to
correlate well with urodynamic findings, helping to confirm a diagnosis of IC.
According to a study in 526 males and 25 females with LUTS, patients with a
positive PST had urgency at significantly lower volumes, lower bladder
capacity, and lower post-void residual than individuals with a negative PST—
urodynamics that are characteristic of IC.49
Dr. Evans and Dr. Kaufman employ the PST in patients who present with CPP
and urinary symptoms, and they consider a positive PST result suggestive of
IC. Dr. Nickel and Ms. Newman generally depend on the medical history, a
physical examination, appropriate urine testing, and other ancillary tests as
indicated for a diagnosis of IC.
Patient’s Name:________________________________________ Today’s date: _________________________
Please circle the answer that best describes how you feel for each question.
1 How many times do you go to the
bathroom during the day?
2 a. How many times do you go to the
bathroom at night?
b. Does your pain bother you?
7 Do you still have urgency after you
go to the bathroom?
b. If you get up at night to go to the
bathroom, does it bother you?
5 Do you have pain associated with
your bladder or in your pelvis (vagina,
labia, lower abdomen, urethra,
perineum, penis, testes, or scrotum)?
8 a. If you have urgency, is it usually
YES _____ NO _____
ACTIVE, do you now or have
you ever had pain or symptoms
during or after sexual activity?
6 a. If you have pain, is it usually
b. Does your urgency bother you?
SYMPTOM SCORE (1, 2a, 4a, 5, 6a, 7, 8a)
BOTHER SCORE (2b, 4b, 6b, 8b)
TOTAL SCORE (Symptom Score + Bother Score) =
Total score ranges are from 1 to 35.
A total score of 10-14 = 74% likelihood of positive PST; 15-19 = 76%; 20+ = 91% Potassium Positive
LUTS Urethral Acute
Acute Radiation
(men) syndrome detrusor bacterial cystitis
instability cystitis
Symptom Questionnaires
The PUF is an 8-question symptom scale that measures the presence and
severity of IC symptoms and the degree to which they are bothersome.44 It
includes questions on the key symptoms of IC (pelvic pain and urinary
frequency and urgency) and questions on symptoms that may manifest during
or after sexual activity. It is easy to administer and score, and the patient can
complete it in about 5 minutes. The maximum score is 35. High symptom,
“bother,” and total scores (>10) can identify patients with a high likelihood of
having IC and can help differentiate IC from other conditions that cause CPP.
Parsons et al showed that patients with a PUF score higher than 10 had a 74%
likelihood of having IC.44 The same study found that high PUF scores strongly
correlated with a positive PST result, supporting the use of the PUF as an
initial screening tool and allowing the more invasive PST to be reserved for
patients with symptoms suggestive of IC but a lower (2-5) PUF score.
© 2000 C. Lowell Parsons, MD. Used with permission.
% PST Positive
3 Are you currently sexually active?
b. If you have pain, does it make you
avoid sexual activity?
Patients With Positive PST Result (%)
PUF Score
High scores on the PUF questionnaire strongly correlate
with a positive PST result.
Other symptom questionnaires can also be of benefit as diagnostic aids. One
symptom scale commonly used is the O’Leary-Sant Interstitial Cystitis
Symptom Index (ICSI), which evaluates IC symptom impact and treatmentrelated change in symptoms. The ICSI comprises a “symptom index” with 4
N = 334 patients urologic/gynecologic; 48 asymptomatic controls.
questions about pain and urgency, and a “problem index” with 4 questions
pertaining to the degree to which the patient experiences each symptom.
Answers are assigned a score of 0 to 5, and a total score can range from 0 to
24 for both indices. Patients with IC typically score a total of 6 or more points
on each index.50,51
Dr. Nickel commented that the PUF is highly sensitive but not specific for IC.
Dr. Evans said he routinely uses the PUF, and finds that patients who score
15 or higher can be reliably diagnosed with IC. A diagnosis of IC indicated by
a high PUF score may then be confirmed by the more invasive PST. Ms.
Newman expressed her preference for the O’Leary-Sant ICSI, particularly for
female patients. Dr. Nickel believes that either the ICSI or the PUF can
be important in the initial assessment of patients because it can quantify their
symptoms. He asks patients to fill out the PUF prior to diagnosis, but
for monitoring patients he prefers the ICSI, which demonstrates treatmentrelated changes.
Intravesical Anesthetic Challenge
An emerging diagnostic procedure that may also give patients temporary
symptomatic relief is the “intravesical anesthetic challenge.” Preliminary
research has found that bladder instillation of an anesthetic lidocainebicarbonate solution leads to significant improvement in pain. Responders are
likely to have pain of bladder origin indicative of IC.52 Although the PST has
proven to be accurate and useful in clinical practice, the anesthetic challenge
approach may be preferred as a diagnostic option because it alleviates rather
than induces pain.53 Dr. Evans mentioned that he always uses a “rescue”
solution that includes either pentosan polysulfate sodium (PPS) [dissolved in
sterile water] or heparin plus lidocaine and bicarbonate after the PST when
assessing a patient whose symptoms suggest a diagnosis of IC, and
sometimes administers it even if he does not give the PST. Dr. Nickel said that
after intravesical instillation of an anesthetic solution, which mutes bladder
pain, pelvic pain associated with the bladder can be better isolated and
defined.52 (FIGURE 7)
Patient with CPP and urinary symptoms
Physical Examination
(Bladder neck tenderness
on bimanual examination;
pelvic floor dysfunction)
(Urgency, frequency, CPP,
dyspareunia, flare-ups)
Treat IC
Urinalysis & Culture
(negative) 24-hour
voiding diary
APF, which is associated with a greatly decreased rate of cell proliferation and
decreased production of HB-EGF, compared to age-, race-, and gendermatched asymptomatic controls, and compared to patients with documented
bacterial cystitis, clinically diagnosed vulvovaginitis, CP/CPPS, or other
urogenital or pelvic organ dysfunction. (TABLE 5)26 In Dr. Keay’s subsequent
study in men, patients with CPP were separated into IC and prostatitis cohorts
based on the presence or absence of irritative voiding symptoms. In both
studies, urinary APF activity was defined by the ability of the urine to inhibit
tritiated thymidine incorporation in normal cells by greater than 2 standard
deviations from controls. Male patients with IC (those with pain and irritative
voiding symptoms) were differentiated from male patients with CPP (those
without irritative voiding symptoms) by the presence of APF activity and
abnormally low HB-EGF levels in their urine.54
Number of Patients
Percent of Patients
Asympt. Controls
Overactive Bladder
Bacterial Cystitis
Micro Hematuria
Stress Incontinence
Neurogenic Bladder
Prostate Cancer
Bladder Cancer
Nonbact Prostatitis
Adapted from Urology. 2001;57:9-14, 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. Copyright © 2001, with permission from Elsevier.
Intravesical anesthetic
Reassess or
modify therapy
Symptoms improve
after 4-6 months?
Continue or
modify therapy
Future Directions in the Diagnosis of IC
The diagnosis of IC is currently dependent on clinical judgment based on
symptoms in the absence of any other clearly defined pelvic disorder.
Noninvasive urine tests for biomarkers specific for IC would greatly improve
diagnostic accuracy. APF was recently shown in a multicenter blinded study to
have the least overlap between IC and control groups of 13 putative
biomarkers tested.27 Dr. Keay explained that the sensitivity and specificity of
APF for identifying IC patients is over 90%, which provides encouragement
that APF activity could become the foundation for an effective screening test.
Dr. Keay and her colleagues discovered that there are inherent differences
between bladder epithelial cells grown from IC patients and those grown from
controls. The main difference seems to be that cells from IC patients produce
The diagnosis of IC is currently dependent on clinical
judgment based on symptoms in the absence of any other
clearly defined pelvic disorder.
Interestingly, the levels of APF significantly diminishes and the level of
HB-EGF increases in the urine of IC patients who undergo cystoscopy and
hydrodistention or percutaneous neurostimulation in a manner that correlates
with symptom relief, thus suggesting a possible benefit in using APF and/or
HB-EGF levels to monitor treatment success.
Slobodov and colleagues evaluated other proteins involved with epithelial
adhesion, cellular differentiation and bladder impermeability in 27 IC patients,
specifically E-cadherin (which has a crucial role in urothelial differentiation),
ZO-1 and uroplakin (which contribute to the impermeability of the bladder
urothelium), and chondroitin sulfate (a component of the GAG layer).55 Normal
marker patterns were found for only 3 of these proteins, upholding the
hypothesis of abnormal cell differentiation in the IC bladder.
The roundtable participants suggested that determination of elevated urinary
levels of APF (and abnormalities of other proteins), in combination with
clinical signs, may allow for a simple, noninvasive, non-cystoscopic diagnosis
of IC in the future.
Patient Stratification for the Diagnosis and Treatment of IC
The patient with severe IC, with unrelenting pain and frequency/urgency, is
relatively easy to identify. Such cases were first recognized over 170 years ago
and the clinical characterization of this disorder has remained essentially
unchanged since that time. 56 The problem comes in recognizing the
mild/intermittent and moderate cases, which appear to be more common.
These patients often have vague, nonspecific urinary and pelvic complaints
that can easily escape detection, escalating over time to a more refractory
disorder. Differences in the presentation of IC indicate that it derives from a
complex etiology, and stratifying patients according to certain characteristics
may help in their diagnosis and treatment.57
Patients with mild/moderate cases of IC often have
vague, nonspecific urinary and pelvic complaints that
can easily escape detection, escalating over time to
a more refractory disorder.
Dr. Evans questioned the clinical relevance of stratifying patients with IC into
subgroups, commenting that regardless of subclassification, treatment options
remain the same. Dr. Nickel suggested that dividing patients into early onset,
newly diagnosed, and chronic IC might be more helpful than some of the other
proposed classifications, such as classic and non-ulcer. Two other possible
means of patient stratification involve whether a patient has a positive or
negative PST, or whether his or her pelvic pain is alleviated by an anesthetic
intravesical cocktail. Urine biomarkers may provide a future means of
identifying and classifying IC patients more simply and definitively. (TABLE 6)
By disease course
• Early onset
• Newly diagnosed
• Chronic
By biomarkers
• KCl +
• KCl -
By anesthetic cocktail
• Pain ↓ with PPS, lidocaine,
and bicarbonate
By hydrostatic bladder dilation
• Classic IC (ulcers)
• Non-ulcer IC
By symptoms
• Urinary urgency/frequency
Because the etiology of IC is unknown, treatment is necessarily symptomdriven and empiric. Dr. Fourcroy stated that evidence-based treatment of IC
remains problematic because of the lack of well-designed, randomized,
placebo-controlled trials. Dr. Evans commented that a scientifically rational
approach supports a multimodal strategy that targets the 3 key elements
associated with IC: the damaged GAG layer of the uroepithelium, associated
allergies, and neural up-regulation.18 (TABLE 7) Ms. Newman added that
non-pharmacologic or conservative approaches, such as diet modification,
physical therapy, and bladder retraining, can be used to enhance the benefits
associated with drug treatment.
Causative Factor
GAG layer dysfunction
Mast cell activation
Hydroxyzine hydrochloride
Neurogenic up-regulation
Pelvic floor dysfunction
Muscle relaxant/analgesic
Because the etiology of IC is unknown, treatment
is necessarily symptom-driven and empiric.
The roundtable participants agreed that the ultimate approach to treatment of
IC is first to understand the mechanisms of pathogenesis and to acknowledge
that they may be interrelated. They concurred that crucial to successful
treatment is diagnosis early in the disease process, when the patient first
complains of urgency or frequency and the pain or discomfort is manageable.
When a patient presents with long-standing IC, the treatment regimen will
need to address not only initiating factors but also the chronic effects on the
patient’s central and local nervous system and the psychological impact the
IC symptoms have had on the patient’s life.
Key to successful treatment of IC is diagnosis early
in the disease process when the patient complains of
a little urgency or frequency and discomfort.
•APF ↑
• GP51 ↓
By PST test (epithelial dysfunction)
Conservative/Adjunctive Therapies
The benefits of pharmacologic agents can be enhanced with various adjunctive
therapies, though they are rarely sufficient as monotherapy. A key component
of multimodal treatment of IC is diet modification, because more than 50% of
IC patients can identify foods that exacerbate symptoms or cause flare-ups.15
Ms. Newman said that foods high in acid (eg, alcohol, carbonated drinks,
caffeine, spicy foods, tomatoes, vinegar) and arylalkylamines (tryptophan,
tyrosine, tyramine, and phenylalanine) are particularly implicated in IC, as are
artificial sweeteners and tobacco. Dr. Evans suggested that because not all
patients are sensitive to the same foods, an elimination/challenge diet will help
identify the offending items that should be avoided.
Bladder training/behavioral modification can improve urinary frequency by
teaching patients to void at designated times and gradually increase the time
between voids. A program of manual physical therapy and pelvic floor
exercises proved beneficial in the treatment of patients diagnosed with IC, with
the greatest improvement seen in the indices of frequency and suprapubic
pain, and less improvement in urgency and nocturia.58 Additionally, patients
should spend adequate time in therapy and complete the recommended
number of sessions in order to achieve maximum benefit. In addition to pelvic
floor exercises, patients with pelvic floor dysfunction can be prescribed a
muscle relaxant, such as lorazepam or baclofen.
Diet modification, physical therapy, and bladder training
are useful adjunctive treatments for IC.
Pharmacologic Treatments Approved by the US Food
and Drug Administration (FDA)
Oral Pentosan Polysulfate Sodium
A defective GAG bladder layer may be a contributing cause of IC. A multimodal
treatment approach, therefore, might include repair of the GAG layer. PPS, a
low molecular weight heparin-like compound, is the only oral drug approved
by the US FDA for the relief of bladder pain or discomfort associated with IC.59
It is believed to act by replenishing the GAG layer, thus controlling cell
permeability and preventing irritating solutes from reaching the
uroepithelium.60 PPS may have a stabilizing effect on mast cells and antiinflammatory properties.61 It has no known drug-drug interactions, and can be
administered together with antihistamines, analgesics, antidepressants and
antispasmodics to provide enhanced pain and symptom relief to the patient
with IC. PPS is well tolerated and is associated with infrequent, mild, and
transient side effects such as minor gastrointestinal discomfort, headache, and
reversible alopecia.59 PPS is a weak anticoagulant (1/15 the activity of heparin)
and as such appears to have no effect on coagulation profiles. Slight liver
function changes have been reported in about 1% of patients receiving PPS,
but these changes resolved spontaneously and have not been associated with
jaundice or other clinical signs or symptoms. Liver function tests are not
routinely required in patients taking PPS.
PPS is the only oral drug approved by the US FDA for relief
of bladder pain or discomfort associated with IC.
The FDA-recommended dose of oral PPS is 300 mg per day taken as one
100-mg capsule 3 times daily; an emerging off-label dose is 200 mg twice
daily, which enhances patient compliance. The slow repair of the uroepithelial
GAG layer facilitated by PPS requires several months of therapy before
significant symptom resolution occurs, although patients diagnosed early in
the disease process may experience pain relief as soon as 4 weeks.60,62 Neither
doubling the dose nor giving PPS more frequently (TID) has been shown to
improve or hasten the onset of efficacy.63 Clinicians have reported that prompt
relief, however, may be achieved through a “jump start” method based on
instillation of a PPS solution into the bladder (this approach is not FDAapproved). Dr. Kaufman uses a mixture of 200 mg PPS (2 tablets dissolved in
saline), 10 mL of 2% lidocaine, and 5 mL of 8.4% sodium bicarbonate,
administered intravesically 2 to 3 times a week, then once every 3 to 4 weeks
until the effect of the oral PPS begins to be evident. In his clinical experience,
patient and physician dedication to this strategy produces impressive results.
Dr. Evans teaches his patients, who come to his office from a great distance, to
do self-instillation of a PPS- or a heparin-lidocaine solution as needed.
Several randomized controlled trials demonstrated that oral PPS produced
significantly greater subjective improvement than did placebo on all 4
parameters of pain, urgency, frequency, and nocturia.60 A recent retrospective
review of the charts of 260 patients with IC diagnosed at cystoscopy revealed a
statistically significant improvement in frequency, urgency, and pain in the
group treated with PPS compared to the IC patients without PPS treatment.64
(TABLE 8) The effect on symptoms is paralleled by a reduction in potassium
sensitivity as measured by the PST, according to the results of a recent study,
which showed that after 32 weeks of PPS therapy, 60% of patients had
a significant improvement on the PST pain and urgency scales and 71%
reported a 50% or greater improvement in symptoms (measured using the
Patient Overall Rating of Improvement in Symptoms [PORIS] scale).63
The results of another study demonstrated that symptomatic improvement
increases with duration of PPS therapy, regardless of study dose (300, 600, or
900 mg/d). The percentage of patients whose responses changed from
“moderately improved” to “symptoms gone” (measured using PORIS-ICSI)
more than doubled from the 4th to the 12th week of PPS therapy.62 (FIGURE 8,
page 10)
Frequency, No. of voids
Nocturia, No. of voids
Urgency, severity*†
Pain, severity*
*Change in parameters over time
† Scale of 1 to 6, from worst to total improvement or complete abatement of symptoms (or both)
Adapted from J Am Osteopath Assoc. 2000;100:S13-S18, Waters MG, Suleskey JF,
Finkelstein LJ, et al. Interstitial cystitis: a retrospective analysis of treatment with pentosan
polysulfate and follow-up patient survey. Copyright © 2000. Reprinted with the consent of
the American Osteopathic Association.
Oral PPS treatment is associated with
significant improvement in pain and urinary symptoms
in patients diagnosed with IC.
A recent study evaluating the efficacy and tolerability of PPS in men with
category III CPPS found that significantly more patients receiving PPS (900
mg/d) experienced “moderate” to “marked” improvement as measured by the
NIH-Chronic Prostatitis Symptom Index (CPSI), the Subjective Global
Assessment, Symptom Severity Index, and Clinical Global Improvement
assessment tools. The PPS was well tolerated even at the 900-mg daily dose,
with diarrhea, nausea, and headache being the most common adverse events.65
demonstrated objective improvement, compared with 35% of the placebo
group; 53% of the DMSO group reported a marked improvement compared
with 18% of the placebo group.70 (TABLE 9) Although DMSO rarely affords
patients complete remissions, it can be combined with heparin and/or
lidocaine to increase benefit.71
Percentage of Patients
Findings for DMSO (RIMSO-50)
IC/2 sessions of
4 treatments each
(every 2 weeks)70
93% of subjects: Objective
53%: Subjective improvement
(n = 376)
(n = 346)
(n = 267)
(n = 137)
Weeks of Treatment
*ICSI scores scale: 0 = no symptoms; 20 = symptoms almost always
Dr. Evans and Dr. Kaufman concurred that PPS, together with pain
management, an antihistamine, diet modification, and a muscle relaxant (with
pelvic muscle relaxation exercises or physical therapy, as required), can
provide optimal benefit for most patients with IC. For the male patient who
presents with CPP with or without urinary symptoms and fails a first round of
antibiotic therapy (with supportive treatments), Dr. Evans will reassess for IC
(usually with the PST) and will recommend PPS as part of a multimodal
therapeutic regimen.
Intravesical Instillation With Dimethyl Sulfoxide (DMSO)
Prior to the approval of oral PPS, the only FDA-approved treatment for IC was
DMSO for bladder instillation, and intravesical treatment is an option for those
patients who do not respond to or cannot tolerate oral therapy. DMSO is an
anti-inflammatory analgesic with muscle-relaxing properties that may prevent
muscle contractions that can cause pain and urinary frequency/urgency. Its
mechanism of action is unknown, but, in addition to its inherent antiinflammatory effects, it appears to inhibit mast cell secretion and to increase
bladder capacity.60 DMSO treatments are administered in the clinician’s office
once a week or once every 2 weeks for 6 to 8 weeks; motivated patients can
self-catheterize at home. DMSO (RIMSO-50) is instilled into the bladder
through a catheter and generally retained for 15 minutes before being expelled.
(Dr. Kaufman instructs his patients to retain the DMSO for 1 hour.) The patient
may experience moderately severe discomfort on administration, but this
diminishes with repeated use. DMSO is generally well tolerated, but it can
leave a garlic-like taste and odor on the breath or skin for up to 72 hours after
treatment. Liver and renal function tests and complete blood count are
recommended every 6 months during DMSO therapy.66
Intravesical treatment with DMSO is an option for those
patients who do not respond to or cannot tolerate oral therapy.
Clinical trials suggest that DMSO affords at least moderate symptom relief for
most patients, with response to therapy reported within 3 to 4 weeks of the first
6- to 8- week cycle.67-69 In a placebo-controlled study of intravesical instillation
of DMSO (every 2 weeks for 2 sessions) 93% of the DMSO recipients
Chronic inflammatory
bladder disease/
3 treatments (every 2 weeks),
then 3 more (every 4 weeks)67
80% of subjects:
Satisfactory symptom relief
No changes on endoscopy/
IC/up to 236 treatments
(every 2 weeks)9.958 pt
75% of subjects had good to
excellent symptomatic relief
~80% had increased
bladder capacity
IC/3-6 treatments
(at varying intervals)69
50%-77% of subjects had
symptomatic relief
Off-label Treatments for IC
More than half of IC patients have reported a history of allergy or asthma.72
Mast cell activation has been shown to occur in patients with IC.73 When
activated, mast cells release histamines and other inflammatory mediators.
Mast cell activation is believed to have a role in the pathogenesis of IC, and
antihistamines have been shown to be beneficial in its treatment, especially in
patients with suspected allergic flares. In a study comparing the effect of
hydroxyzine hydrochloride (75 mg/d for 3 months) on IC patients with or
without a history of allergy, hydroxyzine hydrochloride reduced symptoms in
55% of those with a history of allergy and in 40% of those patients without
allergy.74 In a recent study, the treatment response when hydroxyzine
hydrochloride was administered with PPS was greater than the response for
each agent administered alone.75 Dr. Evans has written that, when taken at
night at a dose of 25 to 75 mg, hydroxyzine hydrochloride’s sedative
properties can help alleviate nocturia and provide the patient a restful night.18
Antidepressants, particularly the tricyclic antidepressants (TCAs), can relieve
pain by inhibiting histamine secretion from mast cells and decreasing
norepinephrine and serotonin reuptake in the central and peripheral nervous
systems. TCAs are useful in IC because, in addition to their antidepressant
effects, they modify pain and have modest antihistamine and anticholinergic
effects. In an early study, amitriptyline (25-75 mg/d taken nightly) provided
mild to moderate central pain modulation in 60% to 90% of patients with IC.76
While few data have established the value of this agent in the treatment of IC,
efficacy and safety were recently demonstrated in a prospective, randomized,
placebo-controlled, double-blind study of 51 patients. Mean symptom score,
pain and urgency intensity were significantly improved in the amitriptyline
group (25-100 mg), along with frequency and functional bladder capacity,
compared with the placebo group.77
Dr. Evans, Dr. Kaufman, and Ms. Newman include amitriptyline in their initial
multimodal treatment regimen for their IC patients, but Dr. Kaufman stated that
it is the first drug that he eliminates from the regimen once the patient begins
to show improvement.
Other Therapies for Pain Relief
Pain symptoms in IC are often suggestive of a neuropathic component for
which the long-acting opioids can be of benefit, especially before PPS therapy
takes effect.78 Dr. Evans’ and Dr. Kaufman’s clinical experience with these
agents in patients with severe IC shows that tolerance can develop over time
but true addiction is rare.
The anticonvulsant gabapentin has proved effective in neuropathic pain
syndromes and has recently demonstrated efficacy in patients with IC and
genitourinary pain.79 In a small study of patients with refractory genitourinary
pain, 10 of 21 patients (including 5 of 8 with IC) reported improvement with
1200 mg per day of gabapentin.80 The current recommendation is to start with
100 mg at bedtime, and titrate to the most effective dose (the usual range is
300 to 2400 mg/d).18
To give immediate relief to patients with severe pain, Dr. Nickel reported
success with short-term epidural anesthetic blockade. This approach may
temporarily down-regulate the pain process, allow for treatment re-initiation,
and provide much-needed sleep. This approach was validated by Sukiennik
and colleagues, who found that urinary substance P levels initially increased,
and then declined, in 5 patients who achieved pain control with a 3-day
epidural infusion.81
Other Intravesical Solutions
Although DMSO is the only FDA-approved intravesical agent indicated for IC,
other agents have promoted pain relief and prolonged remission in some
patients. Intravesical heparin (10,000-40,000 IU/d in 10 mL of water) or PPS
(1 or 2 100-mg capsules dissolved in 10 mL buffered normal saline) can be
administered daily or every other day (this is an off-label use) for more
immediate relief than that afforded by oral PPS treatment.18,82 An early study of
intravesical installation of hyaluronic acid, a GAG present in all connective
tissues, including the GAG layer of the uroepithelium, at a dose of 40 mg
weekly for 4 weeks and then monthly showed it improved symptoms in
patients with IC refractory to other medical therapies. An initial 56% positive
(complete plus partial) response rate at week 4 increased to 71% by week 12
and was maintained until week 20.83 Dr. Evans indicated that 2 recent placebocontrolled trials, however, failed to show any benefit. The unpublished results
of these 2 trials, one of which included Dr. Evans as a principal investigator,
were considered sufficient not to warrant additional studies on the use of
intravesical hyaluronidase for treatment of IC.
Patients with severe disease may derive immediate temporary
relief from urgency and pain with adjunctive anesthetic
intravesical solutions, or “rescue cocktails.”
Patients with severe disease may derive immediate temporary relief from
urgency and pain with adjunctive anesthetic intravesical solutions, or “rescue
cocktails.” A recent study found that 85% of patients treated with rescue
therapy 3 to 7 times weekly for 2 weeks or more experienced not only
immediate but also sustained relief.84 The therapeutic rescue solutions utilize
PPS (100-200 mg) or heparin (10,000-40,000 IU) as the foundation, plus
8.4% sodium bicarbonate (3 mL) and either 1% lidocaine (10 mL) or 2%
lidocaine (16 mL) for a total volume of <25 mL. (The sodium bicarbonate
greatly facilitates the absorption of the lidocaine.) The solution is retained in
the bladder for 30 minutes. In one study, 41 of 55 patients (75%) experienced
significant immediate symptom relief with a rescue solution utilizing PPS.85
Use of the solution 3 to 7 times per week for 2 or more weeks resulted in
sustained pain relief in 85% of patients. Patients can be taught to perform the
rescue instillations at home.
Approaches to Multimodal Treatment of IC
Because long-term multimodal therapy is key to resolution of IC, Dr. Fourcroy
emphasized that prior to beginning a treatment regimen, the clinician should
discuss with the patient the chronic nature of IC and realistic expectations of
treatment outcome. Dr. Evans explains to his patients the 3 principal
components to their disease: GAG layer abnormalities, mast cell dysfunction,
and neurogenic up-regulation. He then recommends treatments to resolve
each of those components: PPS (200 BID, an off-label dose), an
antidepressant or other pain medication (perhaps amitriptyline 25-50 mg), and
an antihistamine (hydroxyzine hydrochloride 25 mg). If pelvic floor
dysfunction is a component of the disease, then rehabilitation (physical
therapy), stress management, and pelvic floor exercises should be added to
the regimen. (FIGURE 9)
Clinician : Confidence
• PPS (for GAG dysfunction)
• Amitriptyline (for pain)
• Hydroxyzine hydrochloride
(for allergic patients; flare-ups)
Narcotics for severe pain
Patient : Empowerment
Adjunctive Therapy
• Diet modification
• Physical therapy
• Stress management
• Bladder retraining
Epidural to break
severe pain cycle
“Jump start” therapy with intravesical instillations
of PPS or heparin with lidocaine and bicarbonate
(every other day for 2 weeks)
Once Dr. Kaufman has made a diagnosis of IC with a medical history, a
physical examination, and a PST, he describes the disease as a manageable
entity and engages the patient in a treatment contract, encouraging him or her
to participate fully in the therapeutic process. He provides patients a brochure
from the Interstitial Cystitis Association (ICA) that deals specifically with diet.
The cornerstone of his treatment plan for his patients with IC is PPS. He
recommends amitriptyline for the neuropathic pain (Elavil at 10 mg for women
and 25 mg for men) and hydroxyzine hydrochloride (Atarax at the lowest dose
of 10 mg) for patients who have a history of allergies. For immediate relief, Dr.
Kaufman “jump starts” his patients on PPS by dissolving 1 or 2 100-mg
tablets in saline and instilling that solution together with 10 mL of 2%
lidocaine and 5 mL of sodium bicarbonate. He administers the jump-start
solution 2 to 3 times per week for 2 weeks and then one instillation every 3-4
weeks, until the oral PPS shows benefit. He has found that intravesical PPS is
more effective for pain relief and less expensive than heparin. He refers his
patients with pelvic floor dysfunction to a physical therapist.
Key to a successful outcome is engaging the patient to
participate fully in the therapeutic process.
Ms. Newman generally adds a pelvic floor muscle rehabilitation program to a
pharmacologic treatment regimen, which can include PPS, amitriptyline,
hydroxyzine hydrochloride, and a muscle relaxant. She offers a handout with
information on adjunctive treatments, including dietary suggestions. She
administers intravesical instillations to patients with severe IC, and teaches
them to self-administer treatment during flare-ups. Dr. Nickel recommends the
short-term addition of muscle relaxants (baclofen or diazepam) for patients
with documented pelvic floor spasm.
When Dr. Nickel asked about the use of DMSO, Dr. Evans and Dr. Kaufman
said they had used it in the past, but no longer included it in their treatment
protocol because their patients generally do not tolerate it as well as PPS. All
of the participants agreed that once patients begin to show improvement, they
continue on the PPS but are slowly weaned off the other medications,
beginning with the amitriptyline.
Surgical Intervention
A primary care clinician has the tools to diagnose and successfully manage
the great majority of patients who present with the signs and symptoms of IC,
but surgical intervention may be a last-resort approach for patients with
severe, intractable disease. Dr. Evans noted that augmentation cystoplasty is
not effective and surgery, such as cystectomy, is rarely indicated. The results
of surgery for IC are variable and significant pain may persist after surgery.86
The current and preferred surgical intervention is that of sacral nerve root
stimulation, a neuromodulation technique that is FDA-approved for the
treatment of urinary frequency and urgency, urge incontinence, and urinary
retention. Treatment with a permanently implanted device (InterStim;
Medtronic) was found to significantly reduce the need for narcotics in 21
patients with refractory IC and to eliminate narcotic use completely in 4 of 18
chronic users.87 Other studies have also demonstrated high rates of clinical
improvement using a similar approach that included percutaneous third sacral
nerve stimulation, with concomitant normalization of the biomarkers APF and
HB-EGF, that could indicate a benefit occurring at the tissue level.88
Although IC can be a challenging disease to diagnose, the PUF questionnaire
and the PST are simple and reliable tools available to the clinician. Because
the CPP associated with IC is often accompanied by depression, anxiety, and
a lowered QOL, it is vital that the clinician take a thorough history and suspect
IC if the pain is accompanied by urinary symptomatology. Misdiagnosis may
occur when clinicians lack adequate knowledge about the etiology of IC and
the availability of treatment options, or when they lack the time that is required
to follow the patient through to a successful outcome. Men and women with IC
should be managed by clinicians who can recognize and differentiate the
symptoms of IC from those of other urogenital disorders, and who are
committed to long-term management approaches and convey encouragement
and optimism to their patients. As Dr. Fourcroy noted, it is crucial to build
confidence in the patient and empower him or her to participate fully in
the treatment process. With commitment from both the patient and the
health care provider, most cases of IC can be accurately diagnosed and
satisfactorily resolved.
IC may be far more prevalent among both men and women than previously
believed. Largely because of the many similarities between IC and other
urologic and gynecologic conditions, identification of IC can be delayed for
many years. Men may be misdiagnosed as having chronic prostatitis. Women
are often thought to have a gynecologic disorder, OAB, or recurrent UTI.
Inappropriate or inadequate treatment may allow IC to progress to a severe and
refractory condition. Delay in diagnosis and treatment adversely affects
prognosis. Patients with long-standing disease are a treatment challenge,
usually requiring longer, more intensive treatment. Those who receive a timely
diagnosis early in their disease course, on the other hand, may improve with
several months of multimodal therapy, and can often taper or withdraw some
of the interventions over time.
New diagnostic measures, such as the PST, the PUF symptom questionnaire,
and the intravesical anesthetic challenge, have enhanced diagnosis and
facilitated earlier treatment. Several biomarkers, particularly APF, have shown
utility in the diagnosis of IC in the research setting. Understanding the reasons
for their altered levels in IC should help to clarify the pathogenesis of this
condition and may provide a dependable tool for diagnosis and a simple
measure of therapeutic efficacy. The mechanisms by which IC develops on a
cellular level may become better elucidated by understanding the gene
regulation that occurs during the neurogenic inflammation of the bladder.
These and other areas of research may lead to novel targeted therapies for IC.
Newer treatments and a multimodal treatment strategy have improved
outcomes and QOL. For many years, bladder instillation with DMSO was the
only FDA-approved treatment for IC. The FDA approval of oral PPS has made
available a safe, effective, and more convenient therapy that now serves as the
foundation for the multimodal treatment strategy that typically includes
antihistamines, antidepressants, and when indicated, physiotherapy. An
intensive “jump start” approach with intravesical instillation of a PPS or
heparin solution may hasten treatment response. In conjunction with oral
PPS, occasional intravesical “rescue treatment” with PPS or heparin plus
lidocaine and sodium bicarbonate can be incorporated as needed for
immediate pain relief.
Nonpharmacologic adjunctive approaches, such as diet modification, although
not sufficient alone, can enhance treatment. Finally, a critical component of
therapy is an empathetic, devoted clinician who will work with the IC patient to
reverse this challenging, but ultimately modifiable, condition.
• IC is far more prevalent in men and women than previously believed
• IC may be misdiagnosed as chronic prostatitis (CP/CPPS) in men and
urogenital infection in women
• Absence of a precise definition and a definitive diagnostic test for
IC complicates its management
• Early diagnosis might be key to “cure” or reversal of IC pathogenesis
• APF is a promising clinical marker for IC
• The PUF questionnaire is a noninvasive diagnostic tool that has been
shown to correlate significantly with a likelihood of a positive PST score
• Multimodal treatment of the 3 principal components of IC (GAG
abnormalities, mast cell activation, and neurogenic up-regulation) is key to
symptomatic improvement
• Research trials and clinical experience have shown that PPS, the only
oral agent approved by the US FDA for the relief of pain and bladder
symptoms associated with IC, has proven safe and effective in men and
women with IC symptoms
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Release Date: July 2005
Expiration Date for Credit: July 31, 2006
This activity should take approximately 1 hour to complete. The participant should, in order,
read the objectives and newsletter, answer the 10-question multiple-choice Posttest below,
and complete the registration/evaluation form. If you wish to receive CME credit and a certificate, please mail/fax a copy of your completed form to:
Dannemiller Memorial Educational Foundation
Attention: 04-762
5711 Northwest Parkway, Suite 100, San Antonio, TX 78249-3360
Phone (210) 641-8311
Fax (210) 697-9318
POSTTEST/SELF-ASSESSMENT (Circle the single most appropriate answer below.)
1. One theory regarding the pathogenesis of IC is based on:
a. The presence of undetectable bacteria/unusual pathogens
b. Immunologic abnormalities
c. Dysfunction of the mucosal glycosaminoglycan (GAG) barrier that allows toxins
to be absorbed
d. Inflammatory processes
2. Which one of the following statements about diagnosis of IC is TRUE?
a. Cystoscopy with hydrodistention is the gold standard diagnostic tool for IC
b. IC currently remains a diagnosis of exclusion
c. A positive PST result correlates well with low PUF scores
d. A positive PST result is seen only in patients with IC, never in patients with other
urogenital disorders
3. Which one of the following biomarkers shows the least overlap between IC patients
and control groups?
a. Glycoprotein (GP)51
b. Vascular endothelial growth factor (VEGF)
c. Antiproliferative factor (APF)
d. Epidermal growth factor (EGF)
4. When used alone, which of the following can conclusively diagnose IC:
a. Cystoscopy with hydrodistention
b. PST
c. PUF questionnaire
d. None of these
5. What is considered by some to be an appropriate first-line management of IC:
a. Antibiotic treatment
b. Antispasmodic treatment
c. Laser therapy
d. Multimodal therapy which includes oral PPS
6. The clinical presentation that is common to chronic prostatitis, chronic pelvic pain
syndrome, and IC is:
a. Genitourinary pelvic pain for 3 of the last 6 months, without uropathic bacteria
b. Genitourinary pelvic pain for 3 of the last 6 months, with uropathic bacteria
c. Pain on ejaculation consistently occurring for at least 3 months, without
uropathic bacteria
d. Irritative voiding, genitourinary pain for at least 6 months, with or without
uropathic bacteria
7. Women with IC are often misdiagnosed as having:
a. Endometriosis
d. Overactive bladder
b. Recurrent UTI
e. Any of the above
c. Vulvodynia
8. Pelvic floor dysfunction often accompanies IC and is best treated by:
a. Oral PPS with intravesical “jump start”
b. Bed rest
c. Physical therapy
d. Epidural blockade
9. Which one of the following statements about the use of PPS in the treatment of
a. Onset of symptom relief is immediate
b. PPS is one of several oral treatments approved by the US FDA for IC
c. Efficacy can be enhanced by increasing the dose and frequency
d. “Jump-starting” with intravesical delivery several times a week for several
weeks may facilitate treatment response
10. For most patients, which one of the following interventions is not part of a longterm rational treatment strategy for IC:
a. PPS
d. Antidepressant
b. Short-acting opioid
e. Diet modification
c. Antihistamine
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