Interstitial cystitis: Bladder pain and beyond

Article (PDF Available)inExpert Opinion on Pharmacotherapy 9(17):2979-94 · January 2009with75 Reads
DOI: 10.1517/14656560802519845 · Source: PubMed
Abstract
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. The aim of this paper was to review the pathogenesis and treatment of interstitial cystitis with emphasis on new pathogenetic trends and therapeutic modalities. 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. 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. 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.
Review
10.1517/14656560802519845 © 2008 Informa UK Ltd ISSN 1465-6566 2979
All rights reserved: reproduction in whole or in part not permitted
Interstitialcystitis:bladderpain
andbeyond
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,
quercetin, treatment
Expert Opin. Pharmacother. (2008) 9(17):2979-2994
1. Introduction
Interstitial cystitis is a disorder with urinary bladder pain and irritative symptoms
being the main manifestation [1]. Interstitial cystitis occurs mostly in young and
middle-aged women (median age 40 years) [1], 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 [6]. 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) [7], while the Multinational Interstitial Cystitis Association called it
painful bladder syndrome/interstitial cystitis (PBS/IC) [8]. 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
1. Introduction
2. Methods
3. Presentation
4. Other invasive approaches
5. Conclusion
6. Expert opinion
Interstitialcystitis:bladderpainandbeyond
2980 ExpertOpin.Pharmacother.(2008) 9(17)
the fact that interstitial cystitis may have different meanings
for different urologists, centers or countries [9]. 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’.
2. Methods
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, Hunners 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
and vulvodynia.
3. Presentation
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’ [10].
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 [11]. 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 [12]. 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 [10]. 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 [13].
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 [1] 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 [16]. 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 [1]. Moreover, there was no association
between urgency and any histological findings [17]. 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 [18].
One study showed that interstitial cystitis symptoms can
worsen with stress [19]. Spicy or ‘acid’ foods and smoking
may also exacerbate the symptoms [20]. However, a prospective,
double-blind, randomized, crossover study raising the urine
pH of interstitial cystitis patients had no effect on their
pain [21]. 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 [22].
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 [23]. 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 [29],
IBS (35% of interstitial cystitis patients) [32], vulvodynia
(20% to as high as 51.4% [33]) [31] and inflammatory bowel
disease (IBD) (over 30 times higher in those patients with
Theoharides,Whitmore,Stanford,Moldwin&O’Leary
ExpertOpin.Pharmacother.(2008) 9(17) 2981
Hummers ulcers) [25,27]. Investigation of 127 twin pairs showed
that interstitial cystitis was more common in the twin who
had chronic fatigue syndrome [34]. One study reported that
there was an increased incidence of interstitial cystitis, endo-
metriosis and vulvar pain in women with CPP [31]. 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 [35]. 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) [36].
Moreover, a family linkage study identified a high correlation
of interstitial cystitis with panic disorder [37].
3.1 Epidemiology
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 [1]. Recent studies have reported higher rates [38],
with a population-based study in Finland estimating an inter-
stitial cystitis prevalence of 230 in every 100 000 women [39].
A study of urban females in Vienna gave an estimate of 464
in every 100 000 women [40], an office survey in the USA
indicated 575 in every 100 000 women [41] and a study
Table1.Co-morbidconditions.
Diseases %* Ref.
Allergies/Asthma 47 – 60 [24,27,30]
Atopic dermatitis
40 [24]
Endometriosis 30 [26,31]
Fibromyalgia 25 [26,29]
IBD
§
2.3 [25,27]
IBS 40 [25,32]
Migraines 20 [81]
Panic disorder 30 [37,48]
Rheumatoid arthritis 13 [27]
SLE
2 [25,27]
Vulvodynia and VVS 20 – 50 [26,48]
*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
population [27].
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 [25].
IBD: Inammatory 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% [42].
Children and adolescents can also have interstitial cystitis [43]:
in fact, interstitial cystitis patients appear to have had
10 times more bladder problems as children than the
general population [1].
3.2 Diagnosis
Interstitial cystitis remains a diagnosis of exclusion [1,44,45].
The most common presumed initial diagnosisin 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 [1]. Questions on possible abuse
should be included as it is more common in females, especially
with CPP [46]. 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 [47], often in more than one life stage [48].
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 [49], which correlates well with
the University of Wisconsin Symptom Instrument [50] 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 [51].
The Pelvic Pain, Urgency and Frequency Index [52] 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.
3.2.1 Non-invasive
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 [55]
and the unique mast cell protease tryptase [56] 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 [59]. 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 [53]. Antiproliferative factor, as determined
by its ability to decrease in vitro proliferation of bladder
Interstitialcystitis:bladderpainandbeyond
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 [61].
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 [53]. 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 [60],
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% [63]. 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 [66]. 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 [67]. The key regulator
of inflammatory genes, NF-kB, was also activated in the bladder
of interstitial cystitis patients [68]. 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 [69]. 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 Hunners ulcers [70]. 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 [71].
A reduced urine level of nitric oxide synthase activity was
also found in common interstitial cystitis [72], but higher
nitric oxide synthase activity was reported in interstitial
cystitis bladder biopsies [73].
3.2.2 Invasive
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 [52]. 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) [74].
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’) [75]:
this is often referred to as ‘classic’ interstitial cystitis and
could vary considerably (still < 10%) among urologists [76].
Classic interstitial cystitis might be differentiated from non-
ulcer disease by elevated urine nitric oxide [71]. In a recent
study of 38 Chinese interstitial cystitis patients with Hunners
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 [62]. Cystoscopy with bladder distension could also
document urothelial petechiae (glomerulations) [1]. However,
glomerulations may be noted even in non-interstitial cystitis
bladders and are not diagnostic by themselves [77]. 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 [13]. 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 [45].
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 [17]. 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) [78].
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/mm
2
tryptase-positive bladder mast cells in the detrusor was
recommended by the European Society for defining a subtype
of interstitial cystitis [9].
3.3 Pathogenesis
There is no known pathogenesis. However, increasing evidence,
including the existence of co-morbid diseases discussed
Theoharides,Whitmore,Stanford,Moldwin&O’Leary
ExpertOpin.Pharmacother.(2008) 9(17) 2983
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 [83]. Moreover, five out of eight monozygotic
twins had either probable or confirmed interstitial cystitis, as
compared with none out of eight in dizygotic twins [84].
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 [85]. 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 [86].
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 [59]. In one study of 12 newly diagnosed, untreated
female patients with interstitial cystitis, bladder inflammation
only correlated positively (p = 0.011) with pain [63]. Interstitial
cystitis bladder nerve endings are increased and correlate
positively with the number of mast cells [87]. 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 [88]. An increased number of
activated bladder mast cells in interstitial cystitis has been
repeatedly reported [89]. There are two times more urothelial
and 10 times more detrusor mast cells in ulcerative interstitial
cystitis than controls [90], but only 50% of patients in the
ICDB had high lamina propria mast cell counts [79]. One
paper reported similar lamina propria mast cell counts
between non-ulcer interstitial cystitis patients and controls [90],
but this study did not use either appropriate staining methods
or controls (cancer) [91]. The most critical point generally
missed is the high degree of activation and not simply the
number of mast cells in interstitial cystitis [91]. These mast
cells may be recruited by stem cell factor or monocyte
chemoattractant protein-1, which is produced by human
detrusor muscle cells [92] and is chemotactic for mast cells [93].
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 [82] by
secreting many vasoactive, inflammatory and nociceptive
mediators [82]: histamine, kinins and proteases, such as tryptase,
as well as cytokines, leukotrienes, prostaglandins and nitric
oxide, including vascular endothelial growth factor [95], which
is over-expressed in 58% of interstitial cystitis bladders [96].
In addition to histamine, IL-6 and IL-8 are also secreted,
as discussed earlier. Tryptase could cause microvascular
leakage [97] 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 [98].
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 [1]. Some studies
have shown that there was increased epithelial permeability,
as determined by urea absorption in interstitial cystitis [99],
but a subsequent permeability study using
99m
technetium
failed to confirm this [100]. Nevertheless, the apparent ability
of concentrated KCl to elicit pain in suspected interstitial
cystitis cases [101] 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 [65],
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) [67]. 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 [102],
but a more recent prospective study showed that total sulfated
glycosaminoglycans normalized to urine creatinine were elevated
(n = 25) in moderate-to-severe cases [67]. 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.
3.4 Newtrends
Functional neuroimmune networks in the bladder may explain
the sensory neuronal hyper-reactivity leading to neuropathic
pain in interstitial cystitis [103]. 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 [104].
Moreover, rat CNS-induced neurogenic cystitis was associated
with bladder mast cell degranulation [105].
Mast cells are located peri-vascularly close to nerve
endings, especially those containing substance P [88]: they
communicate with neuronal processes [106] and are involved
in antigen-induced cystitis [107].
Restraint stress in rodents induced bladder mast cell
activation, increased urine histamine and IL-6 [108] and
also resulted in loosening of urothelial tight junctions [109].
Corticotropin-releasing hormone (CRH) released under
stress from sacral spinal cord projections [110] could have
pro-inflammatory actions [82], apparently through activation
of mast cells [111]. Interestingly, the vasodilatory effect of
CRH on human skin was greater in female subjects [112].
Intravesical administration of CRH led to increased vascular
endothelial growth factor release from mouse bladder
Interstitialcystitis:bladderpainandbeyond
2984 ExpertOpin.Pharmacother.(2008) 9(17)
explants [113]. Corticotropin-releasing hormone was also
reported to lower the micturition threshold in vitro [114].
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 [115].
3.5 Oraltreatment
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 [117].
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’ [118].
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) [119]. 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) [119] and 32%
(p = 0.04) [120] symptom reductions, but the control groups
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 [121]. 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 [122]. 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 [123]. 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 [124].
Due to the increased incidence of allergies and high
number of bladder mast cells in interstitial cystitis [89], the
histamine-1 receptor antagonist hydroxyzine was used because
it also exhibits anticholinergic, sedative and anxiolytic as
well as bladder mast cell inhibitory properties [125], 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 [122]. 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,
Table2.Potentialmechanismsinvolvedinthepathogenesisofinterstitialcystitis*.
Mechanism Pathophysiologiceffect Ref.
Bladder lining abnormalities Damage to the bladder protective glycosaminoglycan (glycosaminoglycan) layer [99,102]
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
[67,103,104]
Neurogenic inammation Increased bladder neuropeptide containing nerve endings juxtaposed to
increased and activated mast cells, increased urine IL-6
[88,107]
Neurohormonal dysregulation Dysfunction in the hypothalamic-pituitary-adrenal axis, including higher
bladder expression of corticotropin-releasing hormone (CRH)
[19,108-110,114]
Decreased urothelial repair Increased secretion of antiproliferative factor (APF) shown to inhibit urothelial
cell growth invitro
[60,61]
Comorbid conditions Increased rate of psychiatric comorbid conditions, including depression,
anxiety, post-traumatic stress, and somatization, as well as allergies,
chronic fatigue syndrome, endometriosis, bromyalgia, IBS, and IBD
See Table1
*These could vary for individual patients.
Theoharides,Whitmore,Stanford,Moldwin&O’Leary
ExpertOpin.Pharmacother.(2008) 9(17) 2985
Table3.Somekeyclinicaltrialsoforalagentsininterstitialcystitis.
Agent Dose Typeofstudy #Patients Duration Results
#
Signicance Date Ref.
Amitriptyline 75 mg/ml
#
Open-label 75
3 weeks 50% NA 1989 [130]
Amitriptyline
§
100 mg/day Randomized, double-blind, placebo-controlled 50 4 m 31.2% p = 0.005 2004 [131]
Cyclosporin 1.5 mg/kg Randomized 64 6 m 75% p < 0.001 2006 [139]
Hydroxyzine 75 mg/qhs Open-label, prospective 13 3 m 40%
§
p < 0.05 1993 [126]
Hydroxyzine
§
75 mg/qhs
#
Open-label, prospective 140 3 m 40%
§
p < 0.05 1997 [127]
Hydroxyzine 25 50 mg/day Randomized, double-blind, placebo-controlled,
multicenter
121 3 m 31% 0.26 2003 [122]
L-arginine 1500 mg Randomized, double-blind, placebo-controlled 21/27 ex
25/26 pl
3 m Only pain
48% vs 24%
p = 0.04 1999 [144]
L-arginine 2.4 g Randomized double-blind, placebo-controlled,
crossover
16 1 m 2.2 overall
symptom score*
p > 0.05 2000 [145]
Misoprostol 600 mg/day Open-label, prospective 25 6 m 56% p < 0.05 [129]
PPS 300 mg/day Double-blind, placebo-controlled, multicenter 110 3 m 25
p = 0.03 1990 [119]
PPS 300 mg/day Randomized, double-blind, placebo-controlled,
multicenter
148 12 m 32
p = 0.04 1993 [120]
PPS 300 mg/day Randomized, double-blind, placebo-controlled,
multicenter
121 3 m 34% p = 0.064 2003 [122]
PPS 300 mg/day Randomized 64 6 m 19% NS 2006 [124]
Quercetin (+G+GS) 300 mg tid Open-label, prospective 37 4 m 52.2% p < 0.05 2003 [141]
Quercetin (+Rutin
#
G+GS+SH) 300 mg bid Open-label, prospective 127 6 m 51% p < 0.0001 2008 [142]
*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 signicant; pl = Placebo; PPS = Pentosanpolysulfate; SH = Sodium hyaluronate.
Interstitialcystitis:bladderpainandbeyond
2986 ExpertOpin.Pharmacother.(2008) 9(17)
but with no apparent histological changes in the bladder
mucosa [128]. 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 [116]. 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 [129].
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 [131]. Even though no comparative
studies have been conducted, it is the authorsopinion 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 [132].
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 [134], possibly
through activation of the high-affinity estrogen receptors
expressed on bladder mast cells [135]. Leuprolide acetate may
be useful in such cases, as it could co-manage other CPP
conditions, such as endometriosis [3].
No study has evaluated non-steroidal anti-inflammatory
drugs, but they may actually be detrimental [136]. The
authors opinion is that they are not useful. However, there
may be reason to consider some immunomodulators in
patients with documented bladder inflammation [137].
One open-label study of 14 interstitial cystitis patients
with Hunners 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) [138].
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) [139].
The natural flavonoid quercetin has anti-allergic, anti-
inflammatory and mast cell-blocking actions [140]. 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 [141]. 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 [142]. 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 [72] and
urine nitric oxide levels were decreased in classic interstitial
cystitis that responded to treatment [143], 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) [144]. 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 [145].
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 [146], and can induce
urothelial inflammation [98], 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 [147]. 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.
Theoharides,Whitmore,Stanford,Moldwin&O’Leary
ExpertOpin.Pharmacother.(2008) 9(17) 2987
3.6 Intravesicaltreatment
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-
distensionto those without, 56% reported an improvement
that lasted 2 months [13]. 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’ [69].
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) [148]. In
another study of 28 interstitial cystitis patients, a series of
six instillations of DMSO reduced the symptoms in 13 classic
interstitial cystitis patients [149]. 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 [150]. Botulinum toxin
injections in the trigone, external sphincter or bladder base
Table4.Paintreatmentsusefulinterstitialcystitis.
Agent Doseregiment Class Adverse
effects
Systemic
B + O
Suppositories*
1 3 qd Anticholinergic
Retention
Fentanyl patch 50 100 μg/h Opioid Dizziness,
N/V
Gabapentin
200 400 mg qid Antiepileptic Sedation,
N/V
Pregabalin Antiepileptic
Tramadol
75 100 mg qd Opioid
§
Nausea
*Belladonna + opium.
Together with morphine shown to have superior benet.
§
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 [151]. 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 [1]. 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) [152]. 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, [153]). 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) [152].
Intravesical cocktails using heparin, lidocaine and bicar-
bonate with or without gentamicin and/or glucocorticoids
are widely used [5]. 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 [154]. One study reported
an improved dyspareunia response following intravesical
lidocaine, bicarbonate and heparin [155]. Another study argued
for combined use of intravesical and systemic treatments [156].
4. Otherinvasiveapproaches
In one prospective study of 25 patients, 17 qualified for
permanent sacral nerve stimulator implantation and 16 out
of 17 sustained significant improvement [157]. 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 [158]. 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 [159].
Interstitialcystitis:bladderpainandbeyond
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.
5. Conclusion
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 [160]. 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 [161] certainly
warrants consideration.
6. Expertopinion
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 following.
The reason(s) why interstitial cystitis occurs primarily in 1.
females and the role of female sex hormones.
Common pathogenetic mechanism(s) explaining why 2.
interstitial cystitis is co-morbid with other diseases, also
occurring more often in females.
The relationship between bladder mastocytosis and many 3.
interstitial cystitis symptoms.
The molecular mechanisms involved in the worsening of 4.
interstitial cystitis symptoms associated with emotional or
physical stress.
A comprehensive plasma and urine cytokine/chemokine/5.
growth factor profile of interstitial cystitis patients
and subgroups.
The use of oral or intravesical solutions that address 6.
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 7.
history of symptoms (< 12 months) in clinical trials and
powered sufficiently to allow cohort analysis of interstitial
cystitis subgroups.
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
‘basic science’.
Declarationofinterest
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).
Theoharides,Whitmore,Stanford,Moldwin&O’Leary
ExpertOpin.Pharmacother.(2008) 9(17) 2989
Bibliography
Papers of special note have been highlighted
as either of interest (•) or of considerable
interest (••) to readers.
1. Hanno PM. Painful bladder syndrome.
In: Wein AJ, Kavossi LR, Novick AC, Partin
AW, Peters CA ,editors,. Campbell’s
Urology, 9th edition. Philadelphia: Elsevier,
2007. p. 330-70
•• Themostcomprehensivereviewon
interstitialcystitisavailable.
2. Phatak S, Foster HE Jr. The management
of interstitial cystitis: an update. Nat Clin
Pract Urol 2006;3(1):45-53
3. Theoharides TC. Treatment approaches for
painful bladder syndrome/interstitial
cystitis. Drugs 2007;67(2):215-35
•• Agooddetailedreviewofpossible
therapeuticoptionsforinterstitialcystitis.
4. Nickel JC. Interstitial cystitis: a chronic
pelvic pain syndrome. Med Clin N Am
2004;88:467-81
5. Lukban JC, Whitmore KE, Sant GR.
Current management of interstitial cystitis.
Urol Clin N Am 2002;29:649-60
6. Hanno P, Nordling J, Van OA. What is new
in bladder pain syndrome/interstitial
cystitis? Curr Opin Urol 2008;18(4):353-8
•• Arecentattempttoreviewthediagnosis
andmanagementofinterstitialcystitis.
7. Abrams P, Cardozo L, Fall M, et al. The
standardisation of terminology of lower
urinary tract function: report from the
Standardisation Sub-committee of the
International Continence Society. Am J
Obstet Gynecol 2002;187(1):116-26
8. Hanno P, Keay S, Moldwin R, Van OA.
International consultation on IC – Rome,
September 2004/Forging an international
consensus: progress in painful bladder
syndrome/interstitial cystitis. Report and
abstracts. Int Urogynecol J Pelvic Floor
Dysfunct 2005; 16(Suppl 1):S2-34
•• Animportantefforttotrytoreacha
consensusonhowtodiagnoseandcall
interstitialcystitis.
9. Van De Merwe JP, Nordling J,
Bouchelouche P, et al. Diagnostic criteria,
classification, and nomenclature for painful
bladder syndrome/interstitial cystitis: an
ESSIC proposal. Eur Urol 2008;53(1):60-7
•• Anewproposalfordiagnosticcriteria
andanameforinterstitialcystitisand
possiblesubclasses.
10. Fitzgerald MP, Brensinger C, Brubaker L,
Propert K. What is the pain of interstitial
cystitis like? Int Urogynecol J
Pelvic Floor Dysfunct 2006;17(1):69-72
• Agoodpaperdiscussingthepainfeltby
interstitialcystitispatients,especiallysince
itisoftendoubted.
11. Warren JW, Langenberg P, Greenberg P,
et al. Sites of pain from interstitial
cystitis/painful bladder syndrome. J Urol
2008;180(4):1373-7
12. Ness TJ, Powell-Boone T, Cannon R, et al.
Psychophysical evidence of hypersensitivity
in subjects with interstitial cystitis. J Urol
2005;173:1983-7
• Therstdocumentedevidencethat
interstitialcystitispatientsmaybe
hypersensitivetopainsensation.
13. Ottem DP, Teichman JM. What is the value
of cystoscopy with hydrodistension for
interstitial cystitis? Urology 2005;66(3):494-9
14. Abrams P, Baranowski A, Berger RE, et al.
A new classification is needed for pelvic
pain syndromes – are existing terminologies
of spurious diagnostic authority bad for
patients? J Urol 2006;175(6):1989-90
15. Kusek JW, Nyberg LM. The epidemiology
of interstitial cystitis: is it time to expand
our definition? Urology 2001;57:95-9
16. Forrest JB, Schmidt S. Interstitial cystitis,
chronic nonbacterial prostatitis and chronic
pelvic pain syndrome in men: a common
and frequently identical clinical entity.
J Urol 2004;172:2561-2
• Aconvincingpresentationoftheoverlapof
interstitialcystitisandchronicprostatitis
inmen.
17. Lamale LM, Lutgendrof SK, Hoffman AN,
Kreder KJ. Symptoms and cystoscopic
findings in patients with untreated
interstitial cystitis. Urology 2006;67:242-5
• Thesendingscastdoubtonthe
specicityofglomerulationforinterstitial
cystitisdiagnostics.
18. Diggs C, Meyer WA, Langenberg P, et al.
Assessing urgency in interstitial
cystitis/painful bladder syndrome.
Urology 2007;69(2):210-4
19. Lutgendorf SK, Kreder KJ, Rothrock NE,
et al. Stress and symptomatology in patients
with interstitial cystitis: a laboratory stress
model. J Urol 2000;164:1265-9
•• Evidenceinacontrolledsettingthatstress
canworseninterstitialcystitissymptoms.
20. Kennedy CM, Bradley CS, Galask RP,
Nygaard IE. Risk factors for painful bladder
syndrome in women seeking gynecologic
care. Int Urogynecol J Pelvic Floor Dysfunct
2006;17(1):73-8
21. Nguan C, Franciosi LG, Butterfield NN,
et al. A prospective, double-blind,
randomized cross-over study evaluating
changes in urinary pH for relieving the
symptoms of interstitial cystitis. BJU Int
2005;95:91-4
•• Agoodstudydispellingthelongheldview
thatacidicurinecontributestointerstitial
cystitissymptoms.
22. Warren JW, Brown J, Tracy JK,
et al. Evidence-based criteria for
pain of interstitial cystitis/painful
bladder syndrome in women.
Urology 2008;71(3):444-8
23. Minaglia S, Ozel B, Bizhang R, Mishell DR
Jr. Increased prevalence of interstitial cystitis
in women with detrusor overactivity
refractory to anticholinergic therapy.
Urology 2005;66(4):702-6
•• Thisarticleprovidesadditionalevidence
ofthepossibleexistenceofinterstitial
cystitissubgroups.
24. Koziol JA, Clark DC, Gittes RF, Tan EM.
The natural history of interstitial cystitis: a
survey of 374 patients. J Urol
1993;149:465-9
• Oneoftherstpublicationsindicatingthe
presenceofco-morbiddiseasesin
interstitialcystitispatients.
25. Alagiri M, Chottiner S, Ratner V, et al.
Interstitial cystitis: unexplained associations
with other chronic disease and pain
syndromes. Urology 1997;49:52-7
26. Erickson DR, Morgan KC, Ordille S,
et al. Nonbladder related symptoms
in patients with interstitial cystitis.
J Urol 2001;166:557-62
27. Peeker R, Atansiu L, Logadottir Y.
Intercurrent autoimmune conditions in
classic and non-ulcer interstitial cystitis.
Scand J Urol Nephrol 2003;137:60-3
28. Aaron LA, Buchwald D. A review of the
evidence for overlap among unexplained
clinical conditions. Ann Intern Med
2001;134(Part 2):868-81
29. Clauw DJ, Schmidt M, Radulovic D, et al.
The relationship between fibromyalgia and
interstitial cystitis. J Psychiatr Res
1997;31:125-31
30. Yamada T. Significance of complications of
allergic diseases in young patients with
interstitial cystitis. Int J Urol
2003;10(Suppl):S56-8
31. Stanford EJ, Koziol J, Feng A. The
prevalence of interstitial cystitis,
endometriosis, adhesions, and vulvar pain in
Interstitialcystitis:bladderpainandbeyond
2990 ExpertOpin.Pharmacother.(2008) 9(17)
women with chronic pelvic pain. J Minim
Invasive Gynecol 2005;12:43-9
•• Therstpapershowingtheco-morbidity
ofinterstitialcystitisandendometriosisin
womenwithchronicpelvicpain.
32. Novi JM, Jeronis S, Srinivas S, et al.
Risk of irritable bowel syndrome and
depression in women with interstitial
cystitis: a case–control study. J Urol
2005;174(3):937-40
33. Peters K, Girdler B, Carrico D, et al.
Painful bladder syndrome/interstitial
cystitis and vulvodynia: a clinical correlation.
Int Urogynecol J Pelvic Floor Dysfunct
2008;19(5):665-9
34. Aaron LA, Herrell R, Ashton S, et al.
Comorbid clinical conditions in chronic
fatigue: a co-twin control study. J Gen
Intern Med 2001;16:24-31
•• Agoodstudyshowingtheco-morbidity
ofinterstitialcystitisandchronic
fatiguesyndrome.
35. Wu EQ, Birnbaum H, Mareva M,
et al. Interstitial cystitis: cost, treatment
and co-morbidities in an employed
population. Pharmacoeconomics
2006;24(1):55-65
36. Clemens JQ, Brown SO, Calhoun EA.
Mental health diagnoses in patients with
interstitial cystitis/painful bladder
syndrome and chronic prostatitis/chronic
pelvic pain syndrome: a case/control study.
J Urol 2008;180(4):1378-82
• Themostrecentstudyofthepresenceof
anxietyininterstitialcystitispatients.
37. Weissman MM, Gross R, Fyer A, et al.
Interstitial cystitis and panic disorder:
a potential genetic syndrome.
Arch Gen Psychiatry 2004;61:273-9
•• Awellexecutedfamilylinkagestudy
showingtheassociationofinterstitial
cystitiswithpanicsyndrome.
38. Clemens JQ, Meenan RT, Rosetti MC,
et al. Prevalence and incidence of interstitial
cystitis in a managed care population.
J Urol 2005;173:98-102
39. Leppilahti M, Sairanen J, Tammela TL,
et al. Prevalence of clinically confirmed
interstitial cystitis in women: a population
based study in Finland. J Urol
2005;174(2):581-3
40. Temml C, Wehrberger C, Riedl C, et al.
Prevalence and correlates for interstitial
cystitis symptoms in women participating
in a health screening project. Eur Urol
2006;51(803):809
41. Rosenberg MT, Hazzard M. Prevalence of
interstitial cystitis symptoms in women: a
population based study in the primary care
office. J Urol 2005;174(6):2231-4
42. Ibrahim IA, Diokno AC, Killinger KA,
et al. Prevalence of self-reported interstitial
cystitis (IC) and interstitial-cystitis-like
symptoms among adult women in the
community. Int Urol Nephrol
2007;39(2):489-95
• Oneofanumberofrecentstudies
showingthatinterstitialcystitismaybe
moreprevalentthanpreviouslysuspected.
43. Shear S, Mayer R. Development of
glomerulations in younger women with
interstitial cystitis. Urology 2006;68(2):253-6
•• Aninterestingreportshowingthat
glomerulationsmaynotbeadiagnostic
featureofinterstitialcystitisespeciallyin
youngwomen.
44. Nordling J, Anjum FH, Bade JJ, et al.
Primary evaluation of patients suspected of
having interstitial cystitis (IC). Eur Urol
2004;45(5):662-9
45. Erickson DR, Tomaszewski JE,
Kunselman AR, et al. Do the National
Institute of Diabetes and Digestive and
Kidney Diseases cystoscopic criteria
associate with other clinical and objective
features of interstitial cystitis? J Urol
2005;173:93-7
46. Latthe P, Mignini L, Gray R, et al.
Factors predisposing women to
chronic pelvic pain: systematic review.
BMJ 2006;332(7544):749-55
• Oneofthefewstudiesdocumentingthe
riskfactorsforinterstitialcystitis.
47. Peters KM, Kalinowski SE, Carrico DJ,
et al. Fact or fiction – is abuse prevalent in
patients with interstitial cystitis? Results
from a community survey and clinic
population. J Urol 2007;178(3 Part 1):891-5
•• Anexcellentstudyreportingontherisk
factors,includingabuse,ininterstitial
cystitispatients.
48. Peters KM, Carrico DJ, Ibrahim IA,
Diokno AC. Characterization of a clinical
cohort of 87 women with interstitial
cystitis/painful bladder syndrome.
Urology 2008;71:634-40
•• Averygoodstudyoffurther
characterizingfactorsthatmay
contributetothepathophysiologyof
interstitialcystitis.
49. O’leary MP, Sant GR, Fowler FJ, JR,
et al. The interstitial cystitis symptom
index and problem index.
Urology 1997;49(Suppl 5A):58-63
•• Themostreliableandwidelyused
instrumentforevaluatingsymptoms
andthequalityoflifeininterstitial
cystitispatients.
50. Sirinian E, Azevedo K, Payne CK.
Correlation between 2 interstitial cystitis
symptom instruments. J Urol
2005;173:835-40
51. Propert KJ, Mayer RD, Wang Y, et al.
Responsiveness of symptom scales for
interstitial cystitis. Urology 2006;67(1):55-9
52. Parsons CL, Dell J, Stanford EJ,
et al. Increased prevalence of interstitial
cystitis: previously unrecognized urologic
and gynecologic cases identified using a
new symptom questionnaire and
intravesical potassium sensitivity.
Urology 2002;60:573-8
•• Aninterestingstudyshowingthehigh
incidenceofinterstitialcystitis.
53. Erickson DR, Xie SX, Bhavanandan VP,
et al. A comparison of multiple urine
markers for interstitial cystitis.
J Urol 2002;167:2461-9
54. Wilkinson DR, Erickson AD. Urinary and
serologic markers for interstitial cystitis: an
update. Curr Urol Rep 2006;7(5):414-22
•• Agoodreviewofvariousurinemarkers
measuredininterstitialcystitisand
theirsignicance.
55. El-Mansoury M, Boucher W, Sant GR,
Theoharides TC. Increased urine histamine
and methylhistamine in interstitial cystitis.
J Urol 1994;152:350-3
56. Boucher W, El-Mansoury M, Pang X, et al.
Elevated mast cell tryptase in urine of
interstitial cystitis patients. Br J Urol
1995;76:94-100
• Therststudyshowingtheuniquemast
cellenzymetryptaseintheurineof
interstitialcystitispatients.
57. Felsen D, Frye S, Trimble LA, et al.
Inflammatory mediator profile in urine and
bladder wash fluid of patients with
interstitial cystitis. Urology 1994;152:355-61
58. Lotz M, Villiger P, Hugli T, et al.
Interleukin-6 and interstitial cystitis.
J Urol 1994;152:869-73
59. Erickson DR, Belchis DA, Dabbs DJ.
Inflammatory cell types and clinical
features of interstitial cystitis.
Urology 1997;158:790-3
60. Keay SK, Zhang CO, Shoenfelt J,
et al. Sensitivity and specificity of
antiproliferative factor, heparin-binding
Theoharides,Whitmore,Stanford,Moldwin&O’Leary
ExpertOpin.Pharmacother.(2008) 9(17) 2991
epidermal growth factor-like growth factor,
and epidermal growth factor as urine
markers for interstitial cystitis.
Urology 2001;57:9-14
•• Apromisingpaperonthepossibilityof
APFbeingusedforinterstitialcystitis
diagnosis,butrequiresindependent
vericationandcommercialavailability.
61. Keay SK, Szekely Z, Conrads TP,
et al. An antiproliferative factor
from interstitial cystitis patients is a
frizzled 8 protein-related sialoglycopeptide.
Proc Natl Acad Sci USA 2004;101:11803-8
•• AgoodpaperontheidentityofAPFthat
shouldhaveallowedthedevelopmentofa
commercialELISAassay.
62. Zhang CO, Li ZL, Kong CZ. APF,
HB-EGF, and EGF biomarkers in patients
with ulcerative vs. non-ulcerative interstitial
cystitis. BMC Urol 2005;5(1):7
• Agoodattempttodistinguishbetween
thetwotypesofinterstitialcystitisusing
urinemarkers.
63. Lamale LM, Lutgendorf SK, Hoffman AN,
Kreder KJ. Symptoms and cystoscopic
findings in patients with untreated interstitial
cystitis. Urology 2006;67(2):242-5
64. Wei DC, Politano VA, Selzer MG,
Lokeshwar VB. The association
of elevated urinary total to sulfated
glycosaminoglycan ratio and high
molecular mass hyaluronic acid with
interstitial cystitis. J Urol
2000;163:1577-83
65. Erickson DR, Sheykhnazari M, Ordille S,
Bhavanandan VP. Increased urinary
hyaluronic acid and interstitial cystitis.
J Urol 1998;160:1282-4
66. Moskowitz MO, Byrne DS, Callahan HJ,
et al. Decreased expression of a
glycoprotein component of bladder
surface mucin (GP1) in interestitial cystitis.
J Urol 1994;151:343-5
67. Lokeshwar VB, Selzer MG, Cerwinka WH,
et al. Urinary uronate and sulfated
glycosaminoglycan levels: markers for
interstitial cystitis severity. J Urol
2005;174(1):344-9
68. Abdel-Mageed AB, Ghoniem GM.
Potential role of rel/nuclear
factor-kappaB in the pathogenesis
of interstitial cystitis. J Urol
1998;160(6 Part 1):2000-3
69. Erickson DR, Kunselman AR, Bentley CM,
et al. Changes in urine markers and
symptoms after bladder distension for
interstitial cystitis. J Urol
2007;117(2):556-60
•• Agoodreportofthedifferential
expressionofurinemarkersafterbladder
distensionininterstitialcystitispatients.
70. Erickson DR, Tomaszewski JE,
Kunselman AR, et al. Urine markers
do not predict biopsy findings or
presence of bladder ulcers in interstitial
cystitis/painful bladder syndrome.
J Urol 2008;179(5):1850-6
•• Agoodpaperindicatingthaturine
markersdonotreectbladderpathology
ininterstitialcystitis.
71. Logadottir YR, Ehren I, Fall M, et al.
Intravesical nitric oxide production
discriminates between classic and nonulcer
interstitial cystitis. J Urol 2004;171:1148-50
72. Smith SD, Wheeler MA, Foster HE, JR,
Weiss RM. Urinary nitric oxide synthase
activity and cyclic GMP levels are decreased
with interstitial cystitis and increased with
urinary tract infections. J Urol
1996;155:1432-5
73. Koskela LR, Thiel T, Ehren I, et al.
Localization and expression of inducible
nitric oxide synthase in biopsies from
patients with interstitial cystitis.
J Urol 2008;180(2):737-41
74. Hanno P. Is the potassium sensitivity test a
valid and useful test for the diagnosis of
interstitial cystitis? Against Int Urogynecol J
Pelvic Floor Dysfunct 2005;16(6):428-9
75. Braunstein R, Shapiro E, Kaye J, Moldwin R.
The role of cystoscopy in the diagnosis of
Hunners ulcer disease. J Urol
2008;180(4):1383-6
76. Bade J, Ishizuka O, Yoshida M. Future
research needs for the definition/diagnosis
of interstitial cystitis. Int J Urol
2003;10(Suppl):S31-4
77. Waxman JA, Sulak PJ, Kuehl TJ.
Cystoscopic findings consistent with
interstitial cystitis in normal women
undergoing tubal ligation. J Urol
1998;160:1663-7
• Anotherpaperdispellingtheusefulness
ofglomerulationsforinterstitial
cystitisdiagnosis.
78. Leiby BE, Landis JR, Propert KJ,
Tomaszewski JE. Discovery of
morphological subgroups that correlate
with severity of symptoms in interstitial
cystitis: a proposed biopsy classification
system. J Urol 2007;177(1):142-8
•• Agoodpaperconrmingtheexistenceof
recognizableinterstitialcystitissubgroups.
79. Tomaszewski JE, Landis JR, Russack V,
et al. Biopsy features are associated with
primary symptoms in interstitial cystitis:
results from the interstitial cystitis database
study. Urology 2001;57(Suppl. 6A):67-81
80. Larsen MS, Mortensen S, Nordling J, Horn T.
Quantifying mast cells in bladder pain
syndrome by immunohistochemical
analysis. BJU Int 2008;102(2):204-7
•• Arecentpaperspecifyinghowbladder
mastcellsshouldbeidentiedforaossible
diagnosisofinterstitialcystitissubgroups.
81. Theoharides TC, Pang X, Letourneau R,
Sant GR. Interstitial cystitis: a
neuroimmunoendocrine disorder. Ann NY
Acad Sci 1998;840:619-34
• Oneoftherstsuggestionsthat
interstitialcystitismaybeasystemic
diseasewithprimaryexpressionin
thebladder.
82. Theoharides TC, Cochrane DE.
Critical role of mast cells in inflammatory
diseases and the effect of acute stress.
J Neuroimmunol 2004;146:1-12
•• Aninformativereviewoftheroleofmast
cellactivationinco-morbidinammatory
diseasesthatworsenbystress.
83. Warren JW, Jackson TL, Langenberg P,
et al. Prevalence of interstitial cystitis in
first-degree relatives of patients with
interstitial cystitis. Urology 2004;63:17-21
•• Therstreportthatinterstitialcystitisis
frequentlydiagnosedinfamilies.
84. Warren JW, Keay SK, Meyers D, Xu J.
Concordance of interstitial cystitis in
monozygotic and dizygotic twin pairs.
Urology 2001;57:22-5
•• Therstevidenceofapossiblegenetic
involvementininterstitialcystitis.
85. Al-Hadithi HN, Williams H, Hart CA,
et al. Absence of bacterial and viral DNA in
bladder biopsies from patients with
interstitial cystitis/chronic pelvic pain
syndrome. J Urol 2005;174(1):151-4
• Akeypaperreportingonlackof
evidenceofaninfectiouscauseof
interstitialcystitis.
86. Mayerhofer M, Aichberger KJ, Florian S,
Valent P. Recognition sites for microbes
and components of the immune system on
human mast cells: relationship to CD
antigens and implications for host defense.
Int J Immunopathol Pharmacol
2007;20(3):421-34
• Arecentreviewoftheevidencethat
bacteriaandvirusescanactivatemastcells
eveninsubclinicalinfections.
Interstitialcystitis:bladderpainandbeyond
2992 ExpertOpin.Pharmacother.(2008) 9(17)
87. Lundeberg T, Liedberg H, Nordling L,
et al. Interstitial cystitis: correlation with
nerve fibres, mast cells and histamine.
Br J Urol 1993;71:427-9
•• Oneoftherstpaperstoindicatean
increasedpresenceofnerveendingsand
associatedmastcellsinthebladderof
interstitialcystitispatients.
88. Pang X, Marchand J, Sant GR, et al.
Increased number of substance P positive
nerve fibers in interstitial cystitis. Br J Urol
1995;75:744-50
89. Sant GR, Kempuraj D, Marchand JE,
Theoharides TC. The mast cell in
interstitial cystitis: role in pathophysiology
and pathogenesis. Urology
2007;69(Suppl 4A):34-40
•• Agoodreviewoftheavailableevidenceof
thepresenceandactivationofbladder
mastcellsininterstitialcystitis.
90. Peeker R, Enerbäck L, Fall M, Aldenborg F.
Recruitment, distribution and phenotypes
of mast cells in interstitial cystitis.
Urology 2000;163:1009-15
91. Theoharides TC, Sant GR, El-Mansoury M,
et al. Activation of bladder mast
cells in interstitial cystitis: a light
and electron microscopic study.
J Urol 1995;153:629-36
•• Therstevidencethatbladdermast
cellactivationismoreimportantthan
simplynumbers.
92. Bouchelouche K, Alvarez S, Andersen L,
et al. Monocyte chemoattractant protein-1
production by human detrusor smooth
muscle cells. J Urol 2004;171(1):462-6
•• Aninterestingpapershowingthat
detrusorcellsproducemonocyte
chemoattractantprotein-1,whichisalso
chemotacticformastcells.
93. Conti P, Pang X, Boucher W, et al. Impact
of Rantes and MCP-1 chemokines on
in vivo basophilic mast cell recruitment in
rat skin injection model and their role
in modifying the protein and mRNA
levels for histidine decarboxylase.
Blood 1997;89:4120-7
94. Pang X, Sant GR, Theoharides TC. Altered
expression of bladder mast cell growth
factor receptor (c-kit) expression in
interstitial cystitis. Urology 1998;51:939-44
• Therstreportthatbladdermastcellsin
interstitialcystitisover-expresssurface
receptorsforagrowthfactorthatmay
explainbladdermastocytosis.
95. Cao J, Papadopoulou N, Kempuraj D,
et al. Human mast cells express
corticotropin-releasing hormone (CRH)
receptors and CRH leads to selective
secretion of vascular endothelial growth
factor. J Immunol 2005;174:7665-75
•• Therstindicationthathumanmastcells
canexpressfunctionallyactivereceptors
forastresshormoneleadingtoreleaseofa
pro-inammatoryangiogenicfactor.
96. Tamaki M, Saito R, Ogawa O, et al.
Possible mechanisms inducing
glomerulations in interstitial cystitis:
relationship between endoscopic findings
and expression of angiogenic growth
factors. J Urol 2004;172:945-8
97. He S, Walls AF. Human mast cell tryptase:
a stimulus of microvascular leakage and
mast cell activation. Eur J Pharmacol
1997;328:89-97
98. Batler RA, Sengupta S, Forrestal SG, et al.
Mast cell activation triggers a urothelial
inflammatory response mediated by tumor
necrosis factor-alpha. J Urol
2002;168:819-25
99. Parsons CL, Lilly JD, Stein P.
Epithelial dysfunction in nonbacterial
cystitis (interstitial cystitis). J Urol
1991;145:732-5
•• Therstindirectindicationof
possiblebladderliningdysfunctionin
interstitialcystitis.
100. Chelsky MJ, Rosen SI, Knight LC,
et al. Bladder permeability in
interstitial cystitis is similar to that of
normal volunteers: direct measurement by
transvesical absorption of 99mtechnetium-
diethylenetriaminepentaacetic acid. J Urol
1994;151:346-9
•• Agoodstudydisputingbladderlining
dysfunctionininterstitialcystitis.
101. Parsons CL, Greene RA, Chung M,
et al. Abnormal urinary potassium
metabolism in patients with interstitial
cystitis. J Urol 2005;173:1182-5
•• Therstindicationthattheremaybe
abnormalurinepotassiumhandlingby
interstitialcystitispatientsthatmay
explainbladdersensorynerveexcitability.
102. Erickson DR, Ordille S, Martin A,
Bhavanandan VP. Urinary chondroitin
sulfates, heparan sulfate and total sulfated
glycosaminoglycans in interstitial cystitis.
J Urol 1997;157:61-4
103. Theoharides TC, Sant GR. Neuroimmune
connections and regulation of function in
the urinary bladder In: Bienenstock J,
Goetzl E, Blennerhassett M, editors.
Lausanne: Hardwood Academic Publishers,
Auton Neuroimmunol 2003; p. 345-69
•• Areviewsettingthestagefortheinterplay
betweentheCNSandbladderinthe
pathogenesisofinterstitialcystitis.
104. Pinter E, Szolcsanyi J. Plasma extravasation
in the skin and pelvic organs evoked
by antidromic stimulation of the
lumbosacral dorsal roots of the rat.
Neuroscience 1995;68:603-14
105. Jasmin L, Janni G, Ohara PT, Rabkin SD.
CNS induced neurogenic cystitis is
associated with bladder mast cell
degranulation in the rat. J Urol
2000;164:852-5
• AgoodstudysuggestingthatCNSinsults
couldleadtobladderpathology.
106. Saban R, Saban MR, Nguyen NB, et al.
Neurokinin-1 (NK-1) receptor is required
in antigen-induced cystitis. Am J Pathol
2000;156:775-80
•• AgoodstudyshowingthatsubstanceP
anditsreceptorisinvolvedin
experimentalcystitis.
107. Suzuki R, Furuno T, Mckay DM, et al.
Direct neurite-mast cell communication
in vitro occurs via the neuropeptide
substance P. J Immunol 1999;163:2410-5
108. Spanos C, Pang X, Ligris K, et al.
Stress-induced bladder mast cell activation:
implications for interstitial cystitis. J Urol
1997;157:669-72
•• Therstevidencethatacutestresscan
activatebladdermastcellsandleadto
bladderinammation.
109. Ercan F, San T, Cavdar S. The effects of
cold-restraint stress on urinary bladder wall
compared with interstitial cystitis
morphology. Urol Res 1999;27:454-61
110. Kawatani M, Suzuki T, De Groat WC.
Corticotropin releasing factor-like
immunoreactivity in afferent projections to
the sacral spinal cord of the cat. J Auton
Nerv Syst 1996;61(3):218-26
111. Theoharides TC, Singh LK, Boucher W,
et al. Corticotropin-releasing hormone
induces skin mast cell degranulation and
increased vascular permeability, a possible
explanation for its pro-inflammatory
effects. Endocrinology 1998;139:403-13
•• Therstreportthatcorticotropin-releasing
hormonereleasedunderstresscanactivate
mastcells.
112. Clifton VL, Crompton R, Smith R,
Wright IM. Microvascular effects of CRH
in human skin vary in relation to gender.
J Clin Endocrinol Metab 2002;87:267-70
Theoharides,Whitmore,Stanford,Moldwin&O’Leary
ExpertOpin.Pharmacother.(2008) 9(17) 2993
113. Cao J, Boucher W, Donelan JM,
Theoharides TC. Acute stress and
intravesical corticotropin-releasing
hormone induces mast cell-dependent
vascular endothelial growth factor release
from mouse bladder explants. J Urol
2006;176:1208-13
•• Therstindicationthatacute
psychologicalstressandastresshormone
caninducereleaseofavascularfactor
thatmightleadtobladderglomerulations
andinammation.
114. Klausner AP, Steers WD. Corticotropin
releasing factor: a mediator of emotional
influences on bladder function. J Urol
2004;172:2570-3
115. Buffington CA. Comorbidity of interstitial
cystitis with other unexplained conditions.
J Urol 2004;172:1242-8
•• AgoodpapershowingthatCRHmaybe
increasedininterstitialcystitis.
116. Theoharides TC, Sant GR. New agents for
the medical treatment of interstitial cystitis.
Exp Opin Invest Drugs 2001;10:521-46
117. Rovner E, Propert KJ, Brensinger C,
et al. Treatments used in women with
interstitial cystitis: the Interstitial Cystitis
Data Base (ICDB) Study experience.
Urology 2000;56:940-5
118. Dimitrakov J, Kroenke K, Steers WD, et al.
Pharmacologic management of painful
bladder syndrome/interstitial cystitis:
a systematic review. Arch Intern Med
2007;167(18):1922-9
•• Agooddetailedreviewofpublished
clinicaltrialsininterstitialcystitis,but
withoutemphasisonlackofanycommon
assessmentsorsuggestionsfortreatment.
119. Mulholland SG, Hanno PM, Parsons CL,
et al. Pentosan polysulfate sodium
for therapy of interstitial cystitis. A
double-blind placebo-controlled clinical
study. Urology 1990;35:552-8
120. Parsons CL, Benson G, Childs SJ,
et al. A quantitatively controlled method
to study prospectively interstitial cystitis
and demonstrate the efficacy of
pentosanpolysulfate. J Urol
1993;150:845-8
121. Hwang P, Auclair B, Beechinor D, et al.
Efficacy of pentosan polysulfate in the
treatment of interstitial cystitis: a
meta-analysis. Urology 1997;50:39-43
122. Sant GR, Propert KJ, Hanno PM, et al.
A pilot clinical trial of oral pentosan
polysulfate and oral hydroxyzine in patients
with interstitial cystitis. J Urol
2003;170:810-5
•• Arstattemptatstudyingtwoofthe
mostpopulartreatmentsforinterstitial
cystitisaloneandtogether,but
underpoweredforpropercohortanalysis
andlackofspecicdirectionsforthebest
hydroxyzineleveltouse.
123. Nickel JC, Barkin J, Forrest J, et al.
Randomized, double-blind, dose-ranging
study of pentosan polysulfate sodium for
interstitial cystitis. Urology 2005;65:654-68
• Astudyshowingnodifferenceofincreased
dosesinanapparentsmallbenetof
PPS(300,600or900mg)on
interstitialcystitis.
124. Sairanen J, Tammela TL, Leppilahti M,
et al. Cyclosporin A and pentosan polysulfate
sodium for the treatment of interstitial
cystitis: a randomized comparative study.
J Urol 2005;174(6):2235-8
125. Minogiannis P, El-Mansoury M,
Betances JA, et al. Hydroxyzine inhibits
neurogenic bladder mast cell activation.
Int J Immunopharmacol 1998;20:553-63
126. Theoharides TC. Hydroxyzine for
interstitial cystitis. J Allergy Clin Immunol
1993;91:686-7
•• Therstopen-labelstudyontheuseof
oralhydroxyzineininterstitialcystitis.
127. Theoharides TC, Sant GR. Hydroxyzine
therapy for interstitial cystitis.
Urology 1997;49(Suppl):108-10
128. Thilagarajah R, Witherow RO, Walker MM.
Oral cimetidine gives effective symptom
relief in painful bladder disease:
a prospective, randomized, double-blind
placebo-controlled trial. BJU Int
2001;87:207-12
129. Kelly JD, Young MR, Johnston SR, Keane PF.
Clinical response to an oral prostaglandin
analogue in patients with interstitial
cystitis. Eur Urol 1998;34:53-6
130. Hanno PM, Buehler J, Wein AJ. Use of
amitriptyline in the treatment of interstitial
cystitis. J Urol 1989;141:846-8
• Therstopen-labelstudysuggesting
thatamitriptylinemaybeusefulin
interstitialcystitis.
131. Van Ophoven A, Pokupic S, Heinecke A,
Hertle L. A prospective, randomized,
placebo controlled, double-blind study of
amitriptyline for the treatment of
interstitial cystitis. J Urol 2004;172:533-6
132. Van Ophoven A, Hertle L. The dual
serotonin and noradrenaline reuptake
inhibitor duloxetine for the treatment of
interstitial cystitis: results of an
observational study. J Urol
2007;177(2):552-5
133. Powell-Boone T, Ness TJ, Cannon R, et al.
Menstrual cycle affects bladder pain
sensation in subjects with interstitial
cystitis. J Urol 2005;174(5):1832-6
• Agoodpapersuggestingthatthe
menstrualcyclecanworseninterstitial
cystitissymptoms.
134. Spanos C, El-Mansoury M, Letourneau RJ,
et al. Carbachol-induced activation of
bladder mast cells is augmented by estradiol
– implications for interstitial cystitis.
Urology 1996;48:809-16
•• Therstpapershowingthatmastcells
frominterstitialcystitisbladderbiopsies
canbestimulatedbythebladder
neurotransmitteracetylcholineandthat
thiseffectisaugmentedbyestradiol.
135. Pang X, Cotreau-Bibbo MM, Sant GR,
Theoharides TC. Bladder mast cell
expression of high affinity estrogen
receptors in patients with interstitial
cystitis. Br J Urol 1995;75:154-61
•• Therstreportthathumanbladdermast
cellsexpresshigh-afnityestrogen
receptorsandthatthereisahigher
numberofsuchcellsinthebladdersof
interstitialcystitispatients.
136. Ghose K. Cystitis and nonsteroidal
antiinflammatory drugs: an incidental
association or an adverse effect? NZ Med J
1993;106(968):501-3
•• Agoodpapersuggestingthat
anti-inammatorydrugsarenot
necessarilyhelpfulininterstitialcystitis.
137. Theoharides TC, Sant GR.
Immunomodulators for the treatment of
interstitial cystitis. Urology 2005;65:633-8
138. Soucy F, Gregoire M. Efficacy of
prednisone for severe refractory ulcerative
interstitial cystitis. J Urol 2005;173:841-3
139. Buffington CA. Re: cyclosporine A and
pentosan polysulfate sodium for the
treatment of interstitial cystitis: a
randomized comparative study. J Urol
2006;176(2):838
140. Kempuraj D, Madhappan B,
Christodoulou S, et al. Flavonols inhibit
proinflammatory mediator release,
intracellular calcium ion levels and protein
kinase C theta phosphorylation in human
mast cells. Br J Pharmacol
2005;145:934-44
• Agoodstudyshowingthatselect
avonoidscaninhibitthereleaseof
Interstitialcystitis:bladderpainandbeyond
2994 ExpertOpin.Pharmacother.(2008) 9(17)
pro-inammatorymoleculesfromhuman
mastcells.
141. Theoharides TC, Sant GR. A pilot open
label of CystoProtek
®
in interstitial cystitis.
Int J Immunopathol Pharmacol
2005;18:183-8
•• Therstopen-labelstudyshowingthat
oraladministrationofchondroitinsulfate,
sodiumhyaluronateandquercetincould
beusefulininterstitialcystitis.
142. Theoharides TC, Kempuraj D, Vakali S,
Sant GR. Treatment of refractory interstitial
cystitis/painful bladder syndrome with
CystoProtek
®
- an oral multi-agent natural
supplement. Can J Urol 2008; In press
143. Hosseini A, Ehren I, Wiklund NP. Nitric
oxide as an objective marker for evaluation
of treatment response in patients with
classic interstitial cystitis. J Urol
2004;172:2261-5
144. Korting GE, Smith SD, Wheeler MA, et al.
A randomized double-blind trial of oral
L-arginine for treatment of interstitial
cystitis. J Urol 1999;161:558-65
145. Cartledge JJ, Davies AM, Eardley I.
A randomized double-blind
placebo-controlled crossover trial of the
efficacy of L-arginine in the treatment of
interstitial cystitis. BJU Int 2000;85:421-6
146. Chen MC, Blunt LW, Pins MR, Klumpp DJ.
Tumor necrosis factor promotes differential
trafficking of bladder mast cells in neurogenic
cystitis. J Urol 2006;175(2):754-9
147. Hupert C, Yacoub M, Turgeon LR. Effect
of hydroxyzine on morphine analgesia
for the treatment of postoperative pain.
Anesth Analg 1980;59:690-6
•• Agoodclinicalstudyshowingthat
administrationofhydroxyzinewith
morphineincreasesanalgesiaandreduces
adverseeffects.
148. Peeker R, Haghsheno MA, Holmang S,
Fall M. Intravesical bacillus
Calmette – Guerin and dimethyl
sulfoxide for treatment of classic and
nonulcer interstitial cystitis: a prospective,
randomized double-blind study. J Urol
2000;164:1912-6
149. Rossberger J, Fall M, Peeker R. Critical
appraisal of dimethyl sulfoxide treatment
for interstitial cystitis discomfort,
side-effects and treatment outcome.
Scand J Urol Nephrol 2005;39:73-7
150. Payne CK, Mosbaugh PG, Forrest JB, et al.
Intravesical resiniferatoxin for the treatment
of interstitial cystitis: a randomized,
double-blind, placebo controlled trial.
J Urol 2005;173:1590-4
151. Kuo HC. Preliminary results of
suburothelial injection of botulinum a
toxin in the treatment of chronic interstitial
cystitis. Urol Int 2005;75(2):170-4
152. Cervigni M, Natale F, Nasta L,
et al. A combined intravesical
therapy with hyaluronic acid and
chondroitin for refractory painful
bladder syndrome/interstitial cystitis.
Int Urogynecol J Pelvic Floor Dysfunct
2008;19(7):943-7
153. Available from: www.icahelp.org
154. Parsons CL. Successful downregulation of
bladder sensory nerves with combination
of heparin and alkalinized lidocaine in
patients with interstitial cystitis.
Urology 2005;65:45-8
•• Therststudyshowingthatadministering
twoglycosaminoglycancomponentsmay
bebenecialininterstitialcystitis.
155. Welk BK, Teichman JM. Dyspareunia
response in patients with interstitial cystitis
treated with intravesical lidocaine,
bicarbonate, and heparin. Urology
2008;71(1):67-70
156. Taneja R, Jawade KK. A rational
combination of intravesical and systemic
agents for the treatment of interstitial
cystitis. Scand J Urol Nephrol
2007;41(6):511-5
•• Agoodpapersuggestingcombinationof
oralandintravesicaltherapiesin
interstitialcystitis.
157. Comiter CV. Sacral neuromodulation for
the symptomatic treatment of refractory
interstitial cystitis: a prospective study.
J Urol 2003;169(4):1369-73
158. Peters KM, Konstandt D. Sacral
neuromodulation decreases narcotic
requirements in refractory interstitial
cystitis. BJU Int 2004;93(6):777-9
159. O’reilly BA, Dwyer PL, Hawthorne G,
et al. Transdermal posterior tibial nerve
laser therapy is not effective in women with
interstitial cystitis. J Urol 2004;172:1880-3
160. Fall M, Oberpenning F, Peeker R. Treatment
of bladder pain syndrome/interstitial
cystitis 2008: can we make evidence-based
decisions? Eur Urol 2008;541:65-75
161. Theoharides TC, Donelan JM,
Papadopoulou N, et al. Mast cells as targets
of corticotropin-releasing factor and related
peptides. Trends Pharmacol Sci
2004;25:563-8
•• AreviewsuggestingtheuseofCRH
receptorantagonistsfordiseases
implicatingmastcells.
Afliation
Theoharis C Theoharides
†1
MS MPhil PhD MD,
Kristine Whitmore
2
MD,
Edward Stanford
3
MD MS,
Robert Moldwin
4
MD &
Michael P O’Leary
5
MD MPH
Author for correspondence
1
Professor 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;
E-mail: theoharis.theoharides@tufts.edu
2
Chief 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
3
Division Head, Gynecologic Specialties
Chief, Urogynecology and Female Pelvic Medicine
Professor of Obstetrics and Gynecology
956 Court Avenue, Memphis, TN 38163, USA
4
Associate Professor of Clinical Urology
and Director
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
5
Senior Urologic Surgeon
Professor of Surgery
Harvard Medical School,
Division of Urology,
Brigham and Womens Hospital,
75 Francis Street, Boston,
MA 02115, USA
    • "Interstitial cystitis (IC) is a chronic disease caused by inflammation of the bladder wall (Theoharides et al., 2008). The clinical features of interstitial cystitis are often associated with a constant condition of pelvic pain, recurrent urinary frequency and nocturia (Hanno, 2002; Hanno et al., 2009). "
    [Show abstract] [Hide abstract] ABSTRACT: Interstitial cystitis is a debilitating bladder inflammation disorder. To date, the understanding of the causes of interstitial cystitis remains largely fragmentary and there is no effective treatment available. Recent experimental results have shown a functional role of the endocannabinoid system in urinary bladder. In this study, we evaluated the anti-inflammatory effect of selective cannabinoid CB1 and CB2 receptor agonists in a mouse model of interstitial cystitis. Bladder inflammation was induced in mice by lipopolysaccharide (LPS) and whole bladders were removed 24h later. LPS induced a significant increase of the contractile amplitude in spontaneous activity and a hypersensitivity to exogenous acetylcholine-induced contraction of whole-isolated bladder. Next, we evaluated the anti-inflammatory activity of cannabinoidergic compounds by pretreating mice with CB1 or CB2 selective agonist compounds, respectively ACEA and JWH015. Interestingly, JWH015, but not ACEA, antagonized LPS-induced bladder inflammation. Additionally, anti-inflammatory activity was studied by evaluation, leukocytes mucosa infiltration, myeloperoxidase activity, and mRNA expression of pro-inflammatory interleukin (IL-1α and IL-1β), tumor necrosis factor-alpha (TNF-α) and cannabinoid CB1 and CB2 receptors. JWH015 significantly decreased leukocytes infiltration in both submucosa and mucosa, as well as the myeloperoxydase activity, in LPS treated mice. JWH015 reduced mRNA expression of IL-1α, IL-1β, and TNF-α. LPS treatment increased expression of bladder CB2 but not CB1 mRNA. Taken together, these findings strongly suggest that modulation of the cannabinoid CB2 receptors might be a promising therapeutic strategy for the treatment of bladder diseases and conditions characterized by inflammation, such as interstitial cystitis.
    Full-text · Article · Feb 2014
    • "This convergence, along with different MRF neuronal responses to urinary and sexual inputs, also creates the potential for cross-organ sensitization centrally . Cross talk between organs is an area of research that has been receiving increasing attention, as it likely explains why some individuals with irritation in one pelvic/visceral organ experience referred pain or altered sensations in unaffected viscera (Alagiri et al. 1997; Dmitrieva and Berkley 2002; Malykhina et al. 2006; Pezzone et al. 2005; Qin et al. 2005; Theoharides et al. 2008; Winnard et al. 2006). MRF neurons are well placed to be a potential site for central cross-organ sensitization. "
    [Show abstract] [Hide abstract] ABSTRACT: Despite common co-morbidity of sexual and urinary dysfunctions, the interrelationship between the neural control of these functions are poorly understood. The medullary reticular formation (MRF) contributes to both mating/arousal functions and micturition, making it a good site to test circuitry interactions. Urethane-anesthetized adult Wistar rats were used to examine the impact of electrically stimulating different nerve targets (dorsal nerve of the penis or clitoris - DNP / DNC; L6/S1 trunk) on responses of individual, extracellular-recorded MRF neurons. The effect of bladder filling on MRF neurons was also examined as was stimulation of DNP on bladder reflexes via cystometry. In total, 236 MRF neurons responded to neurostimulation: 102 to DNP stimulation (12 males), 64 to DNC stimulation (12 females), and 70 to L6/S1 trunk stimulation (12 males). Amplitude thresholds were significantly different at DNP (15.0 ± 0.6 µA), DNC (10.5 ± 0.7 µA) and L6/S1 trunk (54.2 ± 4.6 µA), whereas similar frequency responses were found (max responses near 30-40 Hz). In 5 males, filling/voiding cycles were lengthened with DNP stimulation (11.0 ± 0.9 µA), with a maximal effective frequency plateau beginning at 30 Hz. Bladder effects lasted around two minutes after DNP stimulus offset. Many MRF neurons receiving DNP/DNC input responded to bladder filling (35.0% and 68.3%, respectively), either just before (43%) or simultaneously with (57%) the voiding reflex. Taken together, MRF-evoked responses with neurostimulation of multiple nerve targets along with different responses to bladder infusion has implications for the role of MRF in multiple aspects of urogenital functions.
    Full-text · Article · Aug 2013
    • "Interstitial cystitis (IC), currently referred to as IC/bladder pain syndrome (BPS), is a bladder disease complex that the Society for Urodynamics and Female Urology (SUFU) defines as: " an unpleasant sensation (pain, pressure, discomfort ) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms of more than 6 weeks duration, in the absence of infection or other identifiable causes " [1] With few effective treatments available for IC [2], patients are often willing to try treatments that traditional medicine does not offer. Their interest in complementary and alternative medicine (CAM) therapies, especially diet, has been apparent since the earliest support group meetings [3]. "
    [Show abstract] [Hide abstract] ABSTRACT: Introduction and hypothesis: The purpose of this study was to describe the use of complementary and alternative medicine (CAM) therapies among interstitial cystitis (IC) patients, patients' perception of CAM therapies' effectiveness, and the association of time since diagnosis with perceived effectiveness of these therapies. Methods: In April 2009, the Interstitial Cystitis Association (ICA) initiated an Internet-based survey on CAM. Respondents indicated whether they received an IC diagnosis and how long ago, whether they tried CAM, and who recommended it. On a 5-point scale, respondents rated 49 therapies. For respondents confirming a diagnosis, we used a chi-square goodness-of-fit test to assess which therapies were rated positively or negatively by a majority of patients who tried them. Using separate one-way analyses of variance, we assessed differences in mean perceived effectiveness among groups based on time since diagnosis and conducted post hoc tests, if necessary. Using chi-square tests, we explored the association of time since diagnosis with the use of CAM and the number of therapies tried. Results: A total of 2,101 subjects responded to the survey; 1,982 confirmed an IC diagnosis. Most (84.2 %) had tried CAM, and 55 % said physicians had recommended CAM. Of those trying CAM, 82.8 % had tried diet or physical therapy and 69.2 % other therapies. Of the therapies, 22 were rated positively and 20 negatively; 7 were inconclusive. Therapies patients perceived to be helpful included dietary management and pain management adjuncts such as physical therapy, heat and cold, meditation and relaxation, acupuncture, stress reduction, exercise, and sleep hygiene. Many therapies worked better for those diagnosed recently than for those diagnosed long before. Conclusions: Randomized, placebo-controlled studies are needed to demonstrate which therapies may indeed control IC symptoms and help send research in new and productive directions.
    Full-text · Article · Nov 2012
Show more