10.1517/14656560802519845 © 2008 Informa UK Ltd ISSN 1465-6566
All rights reserved: reproduction in whole or in part not permitted
Theoharis C Theoharides†, Kristine Whitmore, Edward Stanford,
Robert Moldwin & Michael P O’Leary
†Tufts University School of Medicine, Department of Pharmacology and Experimental Therapeutics,
Experimental Therapeutics and Tufts University School of Medicine, 136 Harrison Avenue, Boston,
MA 02111, USA
Background: Interstitial cystitis is characterized by over 6 months of chronic
pain, pressure and discomfort felt in the lower pelvis or bladder. It is often
relieved with voiding, along with daytime frequency and nocturia in the
absence of a urinary tract infection. Interstitial cystitis occurs primarily in
females including adolescents and its diagnosis is still one of exclusion. It is
now recognized as a serious medical condition associated with significant
disability. Objective: The aim of this paper was to review the pathogenesis
and treatment of interstitial cystitis with emphasis on new pathogenetic
trends and therapeutic modalities. Methods: About 713 mostly original
papers were reviewed in Medline from 1990 to August. 2008. All authors
independently reviewed the literature. Large, double-blind, placebo-controlled,
clinical trials were few and the medical histories of the patients used varied
considerably making conclusions difficult. Promising pilot trials turned out
mostly negative on follow-up. Results: Increasing evidence of co-morbid
diseases, neurogenic inflammation and the effect of stress are promising as
new targets for pathophysiology. No new effective treatments have
emerged. Oral pentosanpolysulfate, amitriptyline, hydroxyzine and quercetin,
as well as intravesical heparin/bicarbonate/lidocaine solutions, are still used
with variable success. Some pilot open-label trials presented encouraging
findings. Conclusion: Interstitial cystitis contributes substantially to chronic
pelvic pain and to poor quality of life. Oral or intravesical administration of
solutions containing sodium hyaluronate, chondroitin sulfate and quercetin
to both reduce bladder inflammation and ‘replenish’ the glycosaminoglycan
layer should be tried. There is a clear need for therapeutic modalities. New
potential translational research areas are suggested.
Keywords: amitriptyline, bladder, hydroxyzine, inflammation, mast cells, pain, pentosan polysulfate,
Expert Opin. Pharmacother. (2008) 9(17):2979-2994
Interstitial cystitis is a disorder with urinary bladder pain and irritative symptoms
being the main manifestation . Interstitial cystitis occurs mostly in young and
middle-aged women (median age 40 years) , with no known etiology or
cure [2-5]. Interstitial cystitis is an important disorder that can contribute to
chronic pelvic pain (CPP) and poor quality of life . The constellation of inter-
stitial cystitis symptoms has been given different names. The International
Continence Society named the disease interstitial cystitis/painful bladder syndrome
(IC/PBS) , while the Multinational Interstitial Cystitis Association called it
painful bladder syndrome/interstitial cystitis (PBS/IC) . The European Society
for the Study of Interstitial Cystitis proposed it be named ‘bladder pain syndrome’,
in keeping with ‘pelvic pain syndrome’ and to avoid the confusion generated by
4. Other invasive approaches
6. Expert opinion
the fact that interstitial cystitis may have different meanings
for different urologists, centers or countries . It was further
decided that the term ‘bladder pain syndrome (BPS)/interstitial
cystitis’ be used in the interim. Here, the term interstitial
cystitis was used alone since it appeared in all but five of the
publications surveyed and because of the added confusion
between the terms ‘interstitial cystitis/PBS’, PBS/interstitial
cystitis and ‘BPS/interstitial cystitis’.
The study reviewed the pathophysiology and treatment of
interstitial cystitis by searching English-language publications
in Medline and references from relevant articles published
between 1990 and 2008. About 713 publications were reviewed.
Most of the clinical studies were small (< 20 patients), open
label and used different ways of evaluating symptoms.
Articles were selected on the basis of their quality, relevance
to the illness and importance in illustrating a proposed
pathophysiology or on the basis of whether clinical trials
were randomized and placebo controlled or whether they
were multicenter; only open-label studies that included at
least 20 patients were included. Case reports were excluded
unless they made a unique point that contributed to our
understanding of the disease. All the authors independently
reviewed the selected publications and contributed comments
as necessary. A group consensus had to be reached for any
study to be included in this review.
The main search terms were allergy, amitriptyline, animal
models, antidepressants, antiproliferative factor (APF), anxiety,
biopsy, bladder, bladder pain, botulinum toxin, capsaicin,
chronic cystitis, chronic fatigue syndrome, CPP, co-morbid
diseases, corticotropin-releasing hormone, cure, cystoscopy,
detrusor instability, dimethyl sulfoxide (DMSO), eosinophilic
cystitis, epidemiology, cytokines, endometriosis, etiology,
flavonoids, fibromyalgia, glomerulations, glycosaminoglycans,
growth factors, Hunner’s ulcers, hydroxyzine, infection,
inflammation, interstitial cystitis, irritable bowel syndrome
(IBS), mast cells, mechanisms, neuromodulation, neuropathic
pain, neuropeptides, overactive bladder, pain threshold,
pathogenesis, pathophysiology, pelvic floor muscles, pentosan
polysulfate (PPS), phantom pain, reflex sympathetic dystrophy,
sensory nerves, sensory urgency, stress, treatment, therapies,
trigger points, twins, urgency, urodynamics, urothelial damage
Interstitial cystitis is a symptomatic diagnosis by exclusion
based on 3 – 6 months of pain, pressure or discomfort felt
over the lower pelvic area or the bladder along with
frequency of urination in the absence of a urinary tract
infection or other identifiable causes for the symptoms [1,4].
Interstitial cystitis pain is regional, chronic and diffuse over
the lower pelvic/suprapubic area and in many aspects mimics
neuropathic pain as in ‘chronic regional pain syndrome’ .
Even though the pain presentation is consistent with bladder
pain, it does not prove the bladder is the origin of the pain
as patients with vulvodynia or urethral syndrome often present
similarly . In fact, interstitial cystitis patients may experience
pain differently than controls, possibly through a lower pain
threshold as is often reported for fibromyalgia and IBS
patients . The pain most often worsens on bladder filling
and may be relieved by voiding. Of the 629 interstitial cystitis
patients (mean age 45 years) in the Interstitial Cystitis
Database (ICDB), 94% reported pain or discomfort, in
whom 80% was abdominal, 74% urethral and 65% low
back pain . In another retrospective study of 68 interstitial
cystitis patients (mean age 41 years), of those 47 who had
undergone hydrodistention, 61% reported bladder pain,
62% vaginal pain and 67% dyspareunia .
The National Institutes of Health (NIH)/National Institute
of Diabetes and Digestive and Kidney Disorders (NIDDK)
has established stringent clinical research criteria for interstitial
cystitis (see  for a list of the criteria and a discussion), but
over 60% of patients diagnosed with interstitial cystitis failed
these criteria, thereby prompting an expansion of the interstitial
cystitis definition [14,15]. Frequency of urination is less common
in men, who comprise ∼ 10 – 15% of interstitial cystitis
patients and who may also be diagnosed as having chronic
prostatitis . The urgency felt by interstitial cystitis patients
tends to be excluded for definition purposes because it is more
due to pain, rather than the impeding loss of control typical
of an overactive bladder . Moreover, there was no association
between urgency and any histological findings . Never-
theless, a study of 138 female patients with a recent (12 months)
diagnosis of interstitial cystitis concluded that the severity of the
persistent need to void may be more appropriate for evaluation
in interstitial cystitis patients than its sudden nature .
One study showed that interstitial cystitis symptoms can
worsen with stress . Spicy or ‘acid’ foods and smoking
may also exacerbate the symptoms . However, a prospective,
double-blind, randomized, crossover study raising the urine
pH of interstitial cystitis patients had no effect on their
pain . The results from the Events Preceding IC Study
reported recently that the pain in 151 out of 156 patients
(97%) worsened with certain foods and drinks: this value
was compared to 262 out of 270 (97%) in the ICDB .
Interstitial cystitis symptoms are often confused with or
may overlap those of sensory urgency and an overactive
bladder. One study suggested that the prevalence of interstitial
cystitis may be higher in women with detrusor instability
who do not respond to anticholinergics . Interstitial cystitis
patients also have a higher incidence of other co-morbid
diseases (Table 1) [24-29] including allergies (40 – 60% of
interstitial cystitis patients), with allergic complications
reported in 86% of young patients [1,30,31], fibromyalgia ,
IBS (35% of interstitial cystitis patients) , vulvodynia
(20% to as high as 51.4% )  and inflammatory bowel
disease (IBD) (over 30 times higher in those patients with
Hummer’s ulcers) [25,27]. Investigation of 127 twin pairs showed
that interstitial cystitis was more common in the twin who
had chronic fatigue syndrome . One study reported that
there was an increased incidence of interstitial cystitis, endo-
metriosis and vulvar pain in women with CPP . Results
from a database of ∼ 2 million beneficiaries also indicated that
patients with symptoms consistent with interstitial cystitis often
had a higher diagnostic prevalence of endometriosis, vulvodynia
and CPP . A case – control study of mental health diagnoses
in patients with interstitial cystitis and CPP concluded that
depression and panic disorder were present in 23% more
interstitial cystitis patients than female controls (p < 0.0001) .
Moreover, a family linkage study identified a high correlation
of interstitial cystitis with panic disorder .
The prevalence of interstitial cystitis was originally estimated
to be between 18 and 67 in every 100 000 women. However,
95% of those participants were White professionals, suggesting
that patients with limited access to healthcare may have
been missed . Recent studies have reported higher rates ,
with a population-based study in Finland estimating an inter-
stitial cystitis prevalence of 230 in every 100 000 women .
A study of urban females in Vienna gave an estimate of 464
in every 100 000 women , an office survey in the USA
indicated 575 in every 100 000 women  and a study
Allergies/Asthma47 – 60
Vulvodynia and VVS20 – 50
*Approximate percentage of PBS/interstitial cystitis patients with the disease
shown on the left.
‡Many patients describe ‘sensitive’ skin in the absence of any allergic diathesis.
§This prevalence of IBD in PBS/interstitial cystitis patients with ‘classic’ interstitial
cystitis with Hunner’s ulcers was 33 times higher than that seen in the general
¶PBS/interstitial cystitis patients were reported to be 100 times more likely to have
IBD and 30 times more likely to have SLE than the general population .
IBD: Inflammatory bowel disease; IBS: Irritable bowel syndrome; SLE: Systemic
lupus erythematosus; VVS: Vulvar vestibulitis syndrome.
of self-reported adult interstitial cystitis cases in an urban
community estimated a prevalence of 4% .
Children and adolescents can also have interstitial cystitis :
in fact, interstitial cystitis patients appear to have had
10 times more bladder problems as children than the
general population .
Interstitial cystitis remains a diagnosis of exclusion [1,44,45].
The most common presumed initial ‘diagnosis’ in interstitial
cystitis patients is urinary tract infection, in spite of negative
urine cultures or repeated courses of antibiotics. A medical
history should include suprapubic pain/pressure/discomfort
related to bladder filling and an increased daytime and
night-time frequency and any pelvic surgery or spinal cord
trauma, as well as allergic, gastrointestinal, gynecological and
musculoskeletal diseases . Questions on possible abuse
should be included as it is more common in females, especially
with CPP . Moreover, it was recently reported that 49%
of 76 interstitial cystitis women evaluated had a history of
abuse, with more than 50% of them mentioning sexual
abuse , often in more than one life stage .
Interstitial cystitis symptoms can be evaluated using a
number of validated questionnaires, which are not designed for
diagnosing interstitial cystitis but measuring the extent of
symptom severity. These include the one-page O’Leary – Sant
Symptom and Problem Index , which correlates well with
the University of Wisconsin Symptom Instrument  and
with the Global Response Assessment (GRA). A change of
1.2 points on the O’Leary – Sant Symptom and Problem
Index correlated with a 3.1 point change on the University
of Wisconsin Symptom Instrument and a one-category
change in the GRA: all changes were responsive over time .
The Pelvic Pain, Urgency and Frequency Index  is often
used for screening purposes but has not been sufficiently
validated yet, especially since urgency is excluded for an
interstitial cystitis diagnosis as mentioned above.
There are no specific blood or urine markers available for
interstitial cystitis diagnosis [53,54]. However, combination of
specific urine markers may prove helpful, possibly for subsets
of patients. The histamine metabolite methylhistamine 
and the unique mast cell protease tryptase  were increased
in the 24-h urine of interstitial cystitis patients who met
NIDDK criteria, but the sample was too small for calculating
the specificity or sensitivity. A small number of newly diagnosed
interstitial cystitis patients have elevated levels of IL-6 [53,57,58],
which appears to be associated with their age at symptom
onset and the severity of bladder inflammation . The
urine histamine metabolite 1,4-methyl imidazole acetic acid
and eosinophil cationic protein have been shown to be
increased and correlated with bladder mast cell density in
interstitial cystitis . Antiproliferative factor, as determined
by its ability to decrease in vitro proliferation of bladder
2982? Expert?Opin.?Pharmacother.?(2008) 9(17)
epithelial cells, is increased in interstitial cystitis urine [53,60]
and was identified as a frizzled-8 surface sialoglycopeptide .
Antiproliferative factor and heparin-binding epidermal growth
factor (HB-EGF) and insulin-like growth factor binding
protein-3 were also increased in 24 h urine . Urine APF
and glycoprotein-51 levels clearly separate interstitial cystitis
patients from controls [53,62]. Antiproliferative factor could
distinguish interstitial cystitis from other urologic disorders ,
but still needs to be validated and reproduced independently.
A recent study comparing 40 women with interstitial cystitis
to 29 healthy controls showed that 24-h urine IL-6 and
histamine, normalized to urine creatinine, were significantly
elevated: there was 70% sensitivity and 72.4% specificity,
with a positive predictive value of 77.8% and a negative
value of 63.6% . Increased urinary levels of chondroitin
sulfate and hyaluronic acid have been reported in some
PBS/interstitial cystitis patients [64,65], along with decreased
mucosal glycoprotein GP1 . In another study, urine urate
and sulfated glycosaminoglycans normalized to creatinine
were compared between 37 interstitial cystitis patients who
fulfilled the NIDDK criteria (except for glomerulations) and
14 normal controls: there was 80 and 88% sensitivity and
92.3 and 69.2% specificity, respectively, for detecting the
severity of interstitial cystitis symptoms . The key regulator
of inflammatory genes, NF-kB, was also activated in the bladder
of interstitial cystitis patients . Interestingly, urine markers
taken before and 1 month after bladder hydrodistention in
33 newly diagnosed interstitial cystitis patients with no prior
treatment showed some statistical improvement for APF and
HB-EGF, but these changes were not associated with the
mild decrease in symptom scores . A recent study of
72 interstitial cystitis patients showed that the only statistically
significant correlation was between spot urine IL-8 levels
and the number of mast cells in the lamina propria, irrespec-
tive of the presence of Hunner’s ulcers . Classic interstitial
cystitis may be differentiated from non-ulcer interstitial cystitis
by decreased urine nitric oxide levels in patients with classic
interstitial cystitis who responded to treatment .
A reduced urine level of nitric oxide synthase activity was
also found in common interstitial cystitis , but higher
nitric oxide synthase activity was reported in interstitial
cystitis bladder biopsies .
Intravesical administration of concentrated (0.4 M) KCl,
known as the potassium sensitivity test, is used by some
physicians to help determine whether the bladder is the
source of pain in women with CPP and whose histories and
physical examination results are unclear . However, even
though the use of the potassium sensitivity test may be helpful
for eliciting bladder pain of unknown origin, it is not appro-
priate for diagnosis because of its low prognostic value
(75% sensitivity and specificity) .
Cystoscopy and ‘hydrodistension’ under general or spinal
anesthesia is mandated by the NIDDK criteria and commonly
performed in interstitial cystitis patients, especially in
Europe [1,7,44]. This procedure should be performed (preferably
with isotonic saline or glycine) in order to avoid hypotonic
urothelial cell damage due to water (hydro) that may also result
in non-specific histological and urine marker findings. This
procedure can identify bladder ulcers (‘Hunner’s ulcers’) :
this is often referred to as ‘classic’ interstitial cystitis and
could vary considerably (still < 10%) among urologists .
Classic interstitial cystitis might be differentiated from non-
ulcer disease by elevated urine nitric oxide . In a recent
study of 38 Chinese interstitial cystitis patients with Hunner’s
ulcers (26 without, 10 normal controls, 10 with bacterial
cystitis and 10 with bladder cancer) APF was higher and
HB-EGF was lower (p < 0.0001) in interstitial cystitis, but the
classic form could not be distinguished from the common
type . Cystoscopy with bladder distension could also
document urothelial petechiae (glomerulations) . However,
glomerulations may be noted even in non-interstitial cystitis
bladders and are not diagnostic by themselves . For
instance, in a retrospective study of 68 women and 16 men
with interstitial cystitis (mean age 41 years), cystoscopy with
hydrodistension did not provide useful information over
that of their history and physical examination . Moreover,
when interstitial cystitis patients were compared using cysto-
scopic appearance, bladder biopsy, urine markers and the
University of Wisconsin Symptom Instrument 1 month after
bladder hydrodistension under anesthesia, the only positive
correlation was between those interstitial cystitis patients meet-
ing the cystoscopic NIDDK criteria and worse frequency .
Another study of 12 newly diagnosed and untreated interstitial
cystitis patients did show a positive correlation between pain
on bladder filling and inflammation (p = 0.011), as well as
nocturia (p = 0.001) but not daytime frequency . Uro-
dynamic studies remain controversial in interstitial cystitis,
but may be useful for identifying those patients with sensory
urgency and detrusor overactivity, as well as patients with
atypical symptoms, especially voiding difficulty.
Bladder biopsies may be necessary for excluding other
pathologies. An analysis of bladder biopsies in the ICDB
identified subgroups, the bladder histopathology of which
correlated with an increased 24-h frequency (p < 0.001) .
When the biopsy features were analyzed individually instead
of in clusters, multivariant analysis revealed several associations
between biopsy features and symptom severity. Nocturia was
associated with an increased number of mast cells in the
lamina propria (p = 0.048), complete loss of urothelium
and granulation tissue and vascular density in the lamina
propria [79,80]. In fact, a count of > 28 mast cells/mm2
tryptase-positive bladder mast cells in the detrusor was
recommended by the European Society for defining a subtype
of interstitial cystitis .
There is no known pathogenesis. However, increasing evidence,
including the existence of co-morbid diseases discussed
earlier and the effect of stress, suggests that interstitial cystitis
may actually be a systemic disorder with bladder symptoms
being the main manifestation [81,82].
There may be some genetic predisposition, since the
interstitial cystitis prevalence was reported to be 17 times
more common in first-degree relatives than the general
population . Moreover, five out of eight monozygotic
twins had either probable or confirmed interstitial cystitis, as
compared with none out of eight in dizygotic twins .
No infectious etiology has been identified to date,
including Helicobacter pylori, Gardnerella vaginalis and
Chlamydia trachomatis, as well as adenovirus, cytomegalovirus,
herpes simplex I and II and all types of papillomavirus . One
report of a 16S rRNA fragment from some unknown Gram-
negative bacteria in the bladder of 29% of interstitial cystitis
patients is considered a sampling artefact. However, frequent
clinical or subclinical infections could lead to neuroimmune
activation through activation of toll-like receptors .
There are a number of non-mutually exclusive theories
that may help explain some of the objective findings and
symptoms in interstitial cystitis (Table 2). Neurogenic inflam-
mation could explain the pain and some histological aspects
of interstitial cystitis, even though bladder inflammation is
variable . In one study of 12 newly diagnosed, untreated
female patients with interstitial cystitis, bladder inflammation
only correlated positively (p = 0.011) with pain . Interstitial
cystitis bladder nerve endings are increased and correlate
positively with the number of mast cells . In particular,
there was an increased number of nerve endings positive for
the pro-inflammatory neuropeptide substance P and these
were associated with mast cells, which are also increased in
interstitial cystitis bladders . An increased number of
activated bladder mast cells in interstitial cystitis has been
repeatedly reported . There are two times more urothelial
and 10 times more detrusor mast cells in ulcerative interstitial
cystitis than controls , but only 50% of patients in the
ICDB had high lamina propria mast cell counts . One
paper reported similar lamina propria mast cell counts
between non-ulcer interstitial cystitis patients and controls ,
but this study did not use either appropriate staining methods
or controls (cancer) . The most critical point generally
missed is the high degree of activation and not simply the
number of mast cells in interstitial cystitis . These mast
cells may be recruited by stem cell factor or monocyte
chemoattractant protein-1, which is produced by human
detrusor muscle cells  and is chemotactic for mast cells .
Bladder biopsies from interstitial cystitis patients have shown
stem cell factor to be increased [90,94]. Mast cells have been
implicated in immunity and inflammatory disorders  by
secreting many vasoactive, inflammatory and nociceptive
mediators : histamine, kinins and proteases, such as tryptase,
as well as cytokines, leukotrienes, prostaglandins and nitric
oxide, including vascular endothelial growth factor , which
is over-expressed in 58% of interstitial cystitis bladders .
In addition to histamine, IL-6 and IL-8 are also secreted,
as discussed earlier. Tryptase could cause microvascular
leakage  and stimulate protease-activated receptors, leading
to widespread inflammation and neuronal hyperexcitability.
Mast cell-derived tumor necrosis factor-α (TNF-α) could
also mediate urothelial inflammation .
There may also be some bladder lining damage in interstitial
cystitis. A layer made primarily of the glycosaminoglycans
chondroitin sulfate and hyaluronate sodium, as well as other
glycoproteins and mucins, protects the bladder . Some studies
have shown that there was increased epithelial permeability,
as determined by urea absorption in interstitial cystitis ,
but a subsequent permeability study using 99mtechnetium
failed to confirm this . Nevertheless, the apparent ability
of concentrated KCl to elicit pain in suspected interstitial
cystitis cases  may indicate glycosaminoglycan/urothelial
damage. Increased urinary hyaluronic acid levels normalized
to creatinine were significantly higher in untreated interstitial
cystitis patients (n = 17) who met the NIDDK criteria ,
regardless of the presence of glomerulations as compared to
interstitial cystitis patients with mild symptoms (n = 12)
and normal controls (n = 14) (p < 0.001) . One study
(n = 32) reported no change in interstitial cystitis urine
chondroitin sulfates and total sulfated glycosaminoglycans
normalized to creatinine when compared to 16 controls ,
but a more recent prospective study showed that total sulfated
glycosaminoglycans normalized to urine creatinine were elevated
(n = 25) in moderate-to-severe cases . However, it is
difficult to determine whether this was due to elevated
production rather than glycosaminoglycan damage. Moreover,
the discrepancies among studies could be due to symptom
severity, with mild cases showing no difference.
Functional neuroimmune networks in the bladder may explain
the sensory neuronal hyper-reactivity leading to neuropathic
pain in interstitial cystitis . Antidromic stimulation of
the lumbosacral dorsal roots induced vascular permeability
in the rat urinary bladder, an effect reduced after capsaicin
administration, thereby implicating sensory neuropeptides .
Moreover, rat CNS-induced neurogenic cystitis was associated
with bladder mast cell degranulation .
Mast cells are located peri-vascularly close to nerve
endings, especially those containing substance P : they
communicate with neuronal processes  and are involved
in antigen-induced cystitis .
Restraint stress in rodents induced bladder mast cell
activation, increased urine histamine and IL-6  and
also resulted in loosening of urothelial tight junctions .
Corticotropin-releasing hormone (CRH) released under
stress from sacral spinal cord projections  could have
pro-inflammatory actions , apparently through activation
of mast cells . Interestingly, the vasodilatory effect of
CRH on human skin was greater in female subjects .
Intravesical administration of CRH led to increased vascular
endothelial growth factor release from mouse bladder
2984? Expert?Opin.?Pharmacother.?(2008) 9(17)
explants . Corticotropin-releasing hormone was also
reported to lower the micturition threshold in vitro .
Finally, cats with feline interstitial cystitis also had elevated
plasma CRH, which may characterize a subset of interstitial
cystitis patients with other co-morbid conditions .
There is no curative therapy for interstitial cystitis [2,3,5].
Behavioral, physical, dietary, oral and intravesical interventions
are used, often together, based on the symptoms [5,116]. The
most common interventions for interstitial cystitis compiled
by the ICDB were bladder hydrodistention, intravesical heparin
and oral amitriptyline .
Frequently prescribed oral products include PPS, amitrip-
tyline, hydroxyzine and quercetin-containing formulations
(Table 3). A major problem of the clinical studies reported
to date has been the inclusion of patients with a widely
varied duration and severity of symptoms, making both
comparisons and the likelihood of significant findings difficult.
Moreover, most of the studies used different methods for
evaluating any ‘efficacy’ (e.g., questionnaires, visual scales,
global assessment, response rates, percentages of patients with
symptom reduction at particular stages, i.e., 25% response,
etc.), thereby precluding any reasonable analysis. Consequently,
any ‘evidence-based’ single treatment for all interstitial cystitis
patients cannot be recommended.
A recent systematic review of randomized controlled clinical
trials reported that only PPS was ‘modestly beneficial’ .
Pentosan polysulfate is a polysaccharide originally synthesized
as a ‘small molecular weight heparin substitute’. It is promoted
as ‘replenishing’ the glycosaminoglycan layer and is the only
oral drug approved for interstitial cystitis (under the Orphan
Disease Act) in the USA (Table 2) . Two early randomized,
double-blind, placebo-controlled, multicenter studies of 110
and I48 interstitial cystitis patients each on PPS (300 mg/day
for 3 months) showed 25% (p = 0.03)  and 32%
(p = 0.04)  symptom reductions, but the control group’s
response rate was unusually low at 18%. A meta-analysis of
four studies showed that there was only a 16% benefit in pain
and frequency . A more recent randomized, double-blind,
placebo-controlled multicenter clinical trial funded by the
NIH of 121 interstitial cystitis refractory interstitial cystitis
patients meeting the NIDDK criteria showed that PPS
(300 mg/day for 3 month) had no significant effect (p < 0.064)
(Table 2) over that of placebo . Another randomized,
double-blind, multicenter dose-ranging study of 380 interstitial
cystitis patients showed no significant difference among the
three doses (300, 600 or 900 mg/day for 32 months) using the
Patients’ Overall Rating of Symptoms Index, but was not
designed for evaluating efficacy . A more recent randomized
study of 64 interstitial cystitis patients using 300 mg
PPS for 6 months produced a 19% response that was
indistinguishable from placebo .
Due to the increased incidence of allergies and high
number of bladder mast cells in interstitial cystitis , the
histamine-1 receptor antagonist hydroxyzine was used because
it also exhibits anticholinergic, sedative and anxiolytic as
well as bladder mast cell inhibitory properties , which
are not shared by the hydroxyzine metabolite cetirizine. In
two open-label studies [126,127] hydroxyzine (75 mg four
times a day titrated over 1 month for 4 months) reduced
symptoms by 55% (n = 140). When hydroxyzine (25 – 50 mg)
was compared to PPS neither was found to be effective,
even though the two together had the best response rate,
although this was still not significant . However, that
study was underpowered and most patients did not reach
the recommended dose of 50 – 75 mg of hydroxyzine per
day (Table 3) because of worries over sedation. However, when
hydroxyzine is given at night, it reduces nocturia, while
morning sedation is minimized.
The histamine-2 receptor antagonist cimetidine was reported
to decrease the median symptom score in 34 patients studied,
Bladder lining abnormalities Damage to the bladder protective glycosaminoglycan (glycosaminoglycan) layer
Abnormalities of descending
inhibitory pain pathways
Dysfunction in brain centers (or the pathways from these centers) that
normally downregulate pain signaling in the spinal cord
Neurogenic inflammationIncreased bladder neuropeptide containing nerve endings juxtaposed to
increased and activated mast cells, increased urine IL-6
Neurohormonal dysregulationDysfunction in the hypothalamic-pituitary-adrenal axis, including higher
bladder expression of corticotropin-releasing hormone (CRH)
Decreased urothelial repair Increased secretion of antiproliferative factor (APF) shown to inhibit urothelial
cell growth in?vitro
Comorbid conditions Increased rate of psychiatric comorbid conditions, including depression,
anxiety, post-traumatic stress, and somatization, as well as allergies,
chronic fatigue syndrome, endometriosis, fibromyalgia, IBS, and IBD
*These could vary for individual patients.
Randomized, double-blind, placebo-controlled
p = 0.005
p < 0.001
p < 0.05
p < 0.05
25 – 50 mg/day
Randomized, double-blind, placebo-controlled,
Randomized, double-blind, placebo-controlled
21/27 ex 25/26 pl
48% ↓ vs 24%
p = 0.04
Randomized double-blind, placebo-controlled,
↓ 2.2 overall
p > 0.05
p < 0.05
Double-blind, placebo-controlled, multicenter
p = 0.03
Randomized, double-blind, placebo-controlled,
p = 0.04
Randomized, double-blind, placebo-controlled,
p = 0.064
300 mg tid
p < 0.05
Quercetin (+Rutin# G+GS+SH)
300 mg bid
p < 0.0001
*no difference in voided volume, frequency or nocturia.
‡Symptom reduction using different evaluation techniques.
§Increased to 75 mg over 3 weeks.
¶Controlled patient rate was unusually low at 16%.
#55% for patients with history of allergies.
ex = Experimental; G = Glucosamine; GS = Chondroitin sulfate; m = Months; NS = Not significant; pl = Placebo; PPS = Pentosanpolysulfate; SH = Sodium hyaluronate.
2986? Expert?Opin.?Pharmacother.?(2008) 9(17)
but with no apparent histological changes in the bladder
mucosa . The leukotriene D4 receptor antagonist
montelukast (single dose for 3 months) was used in 10 women
with interstitial cystitis and detrusor mastocytosis was
documented: there was a statistically significant improvement
for urinary frequency, nocturia and pain within 1 month of
treatment using a visual analog scale . An open-label
study also tested the oral prostaglandin agonist misoprostol
(600 mg daily for 3 months) in 25 patients with refractory
interstitial cystitis: 14 out of 25 (56%) of patients reported
a significant improvement .
In view of the fact that tricyclic antidepressants have often
been used in chronic pain, amitriptyline was used (75 mg
four times a day over 3 weeks) in one open-label study
with interstitial cystitis patients who had failed hydro-
distention and intravesical DMSO: it led to a 50% reduction
in pain and daytime frequency but not nocturia in 20
out of 25 patients [1,130]. A randomized, double-blind,
placebo-controlled clinical trial (Table 2) of 50 patients with
interstitial cystitis (using self-titration of up to 100 mg/day
four times a day for 4 months) reported a 64% response
rate using the GRA: however, during follow-up for
19 ± 12.5 months (mean dose of 55 mg/day), there was a
31% drop-out rate after 6 weeks (mean dose of 70 mg/day)
due to non-response . Even though no comparative
studies have been conducted, it is the authors’ opinion that
non-tricyclic antidepressants do not appear to have the same
benefit on interstitial cystitis symptoms, even though they
may be useful in treating any depression experienced by
such patients. In an open-label study of 48 women with
interstitial cystitis, the non-tricyclic antidepressant duloxetine
(titrated to 40 mg twice daily for 5 weeks) showed no
significant improvement of symptoms using either the GRA
or the O’Leary – Sant Symptom and Problem Index .
Many interstitial cystitis women of reproductive age often
complain that their symptoms worsen during their menstrual
cycle [48,133]. This finding and the prevalence of interstitial
cystitis in women may be at least partially related to the fact
that estradiol increases interstitial cystitis bladder biopsy
mast cell pro-inflammatory molecule secretion , possibly
through activation of the high-affinity estrogen receptors
expressed on bladder mast cells . Leuprolide acetate may
be useful in such cases, as it could co-manage other CPP
conditions, such as endometriosis .
No study has evaluated non-steroidal anti-inflammatory
drugs, but they may actually be detrimental . The
authors’ opinion is that they are not useful. However, there
may be reason to consider some immunomodulators in
patients with documented bladder inflammation .
One open-label study of 14 interstitial cystitis patients
with Hunner’s ulcers using 25 mg of prednisone daily
for 2 months reduced (p < 0.02) the O’Leary – Sant Symptom
and Problem Index by 22% and pain by 69% (p < 0.001) .
A randomized study of 64 patients with interstitial cystitis
(meeting the NIDDK criteria) compared cyclosporin (100 mg
three times daily) to PPS (1.5 mg/kg) for 6 months (Table 2):
using the GRA, cyclosporin produced a 75% response rate
as compared to 19% for PPS (p < 0.001) .
The natural flavonoid quercetin has anti-allergic, anti-
inflammatory and mast cell-blocking actions . In one
open-label study, 37 female interstitial cystitis patients refractory
to other treatments were administered quercetin (300 mg
three times daily, together with 300 mg each of chondroitin
sulfate and glucosamine) for 4 months, which resulted in a
52% (p < 0.05) reduction in their symptoms (Table 2) using
the O’Leary – Sant Symptom and Problem Index and GRA
scales . A more recent open-label study (Table 2) of 127
interstitial cystitis patients used 300 mg quercetin twice
daily (together with chondroitin sulfate, glucosamine and
sodium hyaluronate at 300, 280 and 40 mg, respectively)
and reported similar results (51% reduction) (p < 0.0001)
whether taken for 6, 12 or 18 months . These formulations
can be given alone or together with any other treatment. In
fact, they are increasingly added to or substitute for PPS
when the latter has no apparent effect or results in adverse
effects, such as alopecia.
In view of the fact that urine nitric oxide synthase was
found to be decreased in common interstitial cystitis  and
urine nitric oxide levels were decreased in classic interstitial
cystitis that responded to treatment , oral L-arginine was
used since it is the precursor for nitric oxide synthesis.
In one randomized, double-blind, placebo-controlled study,
21 out of 27 interstitial cystitis patients received 1500 mg
of L-arginine for 3 months and were compared to 25 out of
26 patients on placebo: only pain was reduced in 48% of
the patients on L-arginine as compared to 24% for placebo
(p = 0.07) . Another smaller randomized, double-blind,
crossover study using 2.4 g of L-arginine in 16 interstitial
cystitis patients for 1 month led to a reduction of 2.2 overall
symptom score, but there was no significant difference in
voided volume, frequency or nocturia .
A recent paper reported that a virus-induced neurogenic
inflammation in mice led to an ∼ 20-fold increase in
degranulated mast cells in the lamina propria that was primarily
dependent on TNF-α. These findings, along with the fact that
TNF-α can promote mast cell trafficking , and can induce
urothelial inflammation , prompted the suggestion of
possible use of anti-TNF therapy.
Most interstitial cystitis patients experience pain, chronically,
to various extents. However, few clinical trials have been
conducted in interstitial cystitis with oral agents. Opioids
(Table 4) could be given alone or together with hydroxyzine
to increase the analgesic response and decrease adverse
effects . Tramadol, an opioid with weaker addiction
potential and fewer adverse effects than those of morphine,
is also available as an extended release preparation and,
together with acetaminophen (37.5/325 mg twice daily),
may be helpful. Pregabalin, a drug similar to gabapentin,
has been approved for fibromyalgia pain and may also be
useful in interstitial cystitis.
Intravesical approaches include cystoscopic ‘hydrodistention’,
as well as the instillation of DMSO, hyaluronate sodium or
‘cocktails’ containing heparin with lidocaine, bicarbonate,
gentamicin and/or glucocorticoids. Bladder ‘hydrodistension’
under anesthesia is commonly used in interstitial cystitis patients,
but is often associated with immediate pain and its effect in
decreasing the symptoms of interstitial cystitis is unclear [1,2].
In a retrospective study comparing 47 patients with ‘hydro-
distension’ to those without, 56% reported an improvement
that lasted 2 months . However, a recent study showed
that, out of 33 previously untreated interstitial cystitis patients
who underwent bladder hydrodistension, only 36% had at
least a 30% decrease in their University of Wisconsin Symptom
Instrument symptom score 1 month later and this benefit
did not correlate with any reduction of urine ‘markers’ .
Dimethyl sulfoxide is the only intravesical agent approved
in the USA. In a prospective randomized, double-blind
study DMSO was compared to BCG in 6-weekly instillations
in 11 patients with classic interstitial cystitis and 10 patients
with non-classic interstitial cystitis diagnosed with the
NIDDK criteria: there was a reduction in urinary frequency
and pain but only in classic interstitial cystitis and there was
no effect with Bacillus Calmette-Guérin (BCG) . In
another study of 28 interstitial cystitis patients, a series of
six instillations of DMSO reduced the symptoms in 13 classic
interstitial cystitis patients . However, such studies are
hard to control since there is a strong odor due to DMSO.
Intravesical administration of resiniferatoxin, a more potent
analog of the hot pepper ingredient capsaicin, was used in some
studies with variable results. A double-blind, placebo-controlled
multicenter study (n = 163) using a single intravesical dose
of 50 ml of resiniferatoxin (0.01, 0.05 or 0.1 μM) for
12 weeks failed to show any benefit . Botulinum toxin
injections in the trigone, external sphincter or bladder base
B + O
1 – 3 qdAnticholinergic¶
Fentanyl patch50 – 100 μg/h Opioid Dizziness,
200 – 400 mg qid AntiepilepticSedation,
75 – 100 mg qdOpioid§
*Belladonna + opium.
‡Together with morphine shown to have superior benefit.
§Weak addiction potential and fewer adverse effects compared to morphine.
¶Also available with acetaminophen (50 mg tramadol/250 mg acetaminophen).
N/V = Nausea/vomiting; qd = Once per day; qid = 4 times per day.
may decrease interstitial cystitis symptoms. However, all
studies were uncontrolled using very few patients, which are
reported here in spite of the stated intent not to include
studies with such few patients. One open-label study using
suburothelial botulinum toxin (100 units) in 10 patients
with refractory interstitial cystitis resulted in a limited
improvement in the frequency and pain in only two out of
10 patients . A recent open-label study of three men and
12 women with interstitial cystitis used 200 units of botulinum
toxin submucosally in the bladder trigone and lateral walls:
13 out of 15 (86.6%) had a significant urinary frequency
decrease (p < 0.05) using a visual analog scale.
Intravesical hyaluronate sodium (0.04%) is approved for
interstitial cystitis in Canada (but not the USA) based on
two open-label studies using weekly instillations for 4 weeks
that reported some pain reduction . A recent study of
intravesical sodium hyaluronate (40 mg/50 ml) administered
weekly in 126 women with interstitial cystitis reported an
improvement in 103 out of 126 patients (85%) with a
visual analog scale mean score reduction from 8.5 to 3.5
(p < 0.0001) . However, two randomized, double-blind,
placebo-controlled multicenter studies using 10 times
more concentrated sodium hyaluronate (0.4%) failed to
show any benefit and were terminated by the sponsor
(personal communication, ). A recent open-label study of
23 women with refractory interstitial cystitis used intravesical
administration of both hyaluronic acid (1.6%) and chondroitin
sulfate (2.0%) weekly for 20 weeks and then monthly for
3 months. Even though the daily voids did not decrease,
pain was reduced from 5.4 to 3.6 (p = 0.001) .
Intravesical ‘cocktails’ using heparin, lidocaine and bicar-
bonate with or without gentamicin and/or glucocorticoids
are widely used . In one uncontrolled study, heparin
(40 000 IU) together with either 1 or 2% lidocaine and
8.4% sodium bicarbonate three times weekly for 2 weeks
resulted in an over 50% improvement in ∼ 75% of newly
diagnosed interstitial cystitis patients . One study reported
an improved dyspareunia response following intravesical
lidocaine, bicarbonate and heparin . Another study argued
for combined use of intravesical and systemic treatments .
In one prospective study of 25 patients, 17 qualified for
permanent sacral nerve stimulator implantation and 16 out
of 17 sustained significant improvement . In another
retrospective study, the mean intramuscular morphine dose
equivalents of interstitial cystitis patients refractory to other
forms of therapy decreased from 81.6 to 52 mg/day (35%)
(p = 0.015) following sacral neuromodulation and four
out of 18 patients stopped narcotics . In contrast, a
double-blind study of daily 30-s transdermal laser stimulation
of the posterior tibial nerve for 12 weeks in 29 patients with
interstitial cystitis compared to 27 placebo-sham-stimulated
patients showed no significant difference between groups .
2988? Expert?Opin.?Pharmacother.?(2008) 9(17)
When such treatments have failed, laser therapy and surgical
approaches such as cystoplasty, bladder wall resection or bladder
division with or without cystectomy may be indicated.
The pathogenesis and diagnosis of interstitial cystitis remains
unknown. Interstitial cystitis appears to be much more
prevalent than previously suspected and may contribute signifi-
cantly to CPP, in addition to IBS and endometriosis.
Treatment is still challenging and no new effective curative
therapies are available. However, the symptoms in some
patients could be contained with some fairly well-tolerated
agents. Subgroups of interstitial cystitis patients with either
distinct bladder pathology (e.g. increased mast cells) or
co-morbid diseases (e.g., fibromyalgia) may respond differently
to specific treatments. Nevertheless, some patients fail all
treatments and are debilitated and disabled.
As was also concluded elsewhere recently, many clinical
studies have a poor description of interstitial cystitis patients,
with variable inclusion and exclusion criteria . In general,
it was felt that small, well-controlled studies using newly
diagnosed patients with a recent onset of symptoms and
no co-morbidities may yield better information than larger
studies using chronic patients who have already been
on numerous treatments and have many co-morbid
diseases, making any conclusion difficult to reach. The
possibility of using CRH receptor antagonists  certainly
In spite of considerable funding from the US NIH,
the pathogenesis, diagnosis and treatment of interstitial
cystitis remains elusive. There are a number of key areas
that appear to have escaped serious research. These include
The reason(s) why interstitial cystitis occurs primarily in
females and the role of female sex hormones.
Common pathogenetic mechanism(s) explaining why
interstitial cystitis is co-morbid with other diseases, also
occurring more often in females.
The relationship between bladder mastocytosis and many
interstitial cystitis symptoms.
The molecular mechanisms involved in the worsening of
interstitial cystitis symptoms associated with emotional or
A comprehensive plasma and urine cytokine/chemokine/
growth factor profile of interstitial cystitis patients
The use of oral or intravesical solutions that address
inflammation or mastocytosis, such as combinations of
select flavonoids and glycosaminoglycan components that
could both reduce bladder inflammation and correct any
glycosaminoglycan layer defects.
The use of newly diagnosed untreated patients with a short
history of symptoms (< 12 months) in clinical trials and
powered sufficiently to allow cohort analysis of interstitial
Appropriate funding should be directed at the establishment
of research alliances to address such topics, in addition
to funding general themes such as ‘epidemiology’ or
The Interstitial Cystitis Association and NIH grants
DK42409, DK44816, DK62861, NS38326 and AR47652
(PI: T.C.T.), as well as DK63652 and DK30102 (Co-I:
M.P.O.) funded aspects of this research. Some authors
also participated in the Interstitial Cystitis Clinical Trials
Group/Clinical Research Network funded by NIH grants
DK54133 and DK65244 (T.C.T.) and in the Chronic
Prostatitis Collaborative Research Network by NIDDK grant
UO1 DK065187 (Co-PI, M.P.O.). Theoharis C. Theoharides
also helped develop a dietary supplement licensed to
Alavenpharm (Marietta, GA).
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Theoharis C Theoharides†1 MS MPhil PhD MD,
Kristine Whitmore2 MD,
Edward Stanford3 MD MS,
Robert Moldwin4 MD &
Michael P O’Leary5 MD MPH
†Author for correspondence
1Professor of Pharmacology, Biochemistry and
Internal Medicine and Director
Molecular Immunopharmacology and
Drug Discovery Laboratory,
Experimental Therapeutics and Tufts University
School of Medicine,
Tufts Medical Center,
Department of Pharmacology,
136 Harrison Avenue,
Boston, MA 02111, USA
Tel: +1 617 636 6866; Fax: +1 617 636 2456;
2Chief of Urology
Female Pelvic Medicine and Reconstructive Surgery
Professor of Urology and OB/GYN
Drexel University College of Medicine,
Hahnemann University Hospital,
230 North Broad Street,
Philadelphia, PA 19102, USA
3Division Head, Gynecologic Specialties
Chief, Urogynecology and Female Pelvic Medicine
Professor of Obstetrics and Gynecology
956 Court Avenue, Memphis, TN 38163, USA
4Associate Professor of Clinical Urology
Pelvic Pain Center
The Arthur Smith Institute for Urology,
North Shore-Long Island Jewish Healthcare System,
450 Lakeville Road,
Suite M41 New Hyde Park, NY 11040, USA
5Senior Urologic Surgeon
Professor of Surgery
Harvard Medical School,
Division of Urology,
Brigham and Women’s Hospital,
75 Francis Street, Boston,
MA 02115, USA