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European Journal of Obstetrics & Gynecology and Reproductive Biology xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

Review

Interstitial cystitis/painful bladder syndrome: epidemiology,

pathophysiology and evidence-based treatment options
N.F. Davis a,b,*, C.M. Brady b, T. Creagh a
a
Department of Urogynaecology, Beaumont Hospital, Dublin, Ireland
b
Department of Urology, Cork University Hospital, Cork, Ireland

A R T I C L E I N F O A B S T R A C T

Article history: Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic debilitating condition that can have a
Received 18 August 2013 severely negative impact on a patient’s quality of life. Its prevalence ranges from 52 to 500/100,000 in
Received in revised form 16 December 2013 females compared to 8–41/100,000 in males, and its incidence is increasing globally. Treatment
Accepted 30 December 2013
algorithms are sub-classified into behavioural, pharmacological, intravesical, interventional and surgical
therapies. Short-term (i.e. <1 year) cure rates range from 50% to 75% for non-/minimally-invasive
Keywords: therapies, but repeat administration of a therapeutic agent is required. Although definitive surgical
Interstitial cystitis
intervention is associated with greater long-term cure rates (80%); significant short- and long-term
Painful bladder syndrome
Interstitial cystitis/painful bladder
adverse effects occur more frequently. Clinicians are likely to experience increasing numbers of patients
syndrome (IC/PBS) with IC/PBS as more is understood about its pathophysiology and evolving epidemiology. Therefore
urogynaecologists should familiarise themselves with appropriate diagnostic criteria and evidence
based therapies to optimise clinical outcomes in this patient cohort.
ß 2014 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
2. Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
3. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4. Pathophysiology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.1. Inflammation and mast cell activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.2. Urothelial dysfunction/GAG layer defects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.3. Nitric oxide metabolism and Tamm–Horsfall protein (THP). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.4. Autoimmune mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
4.5. Genetic predisposition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
5. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6. Treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.1. Conservative . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.2. Pharmacological . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.2.1. Pentosan polysulfate sodium (PPS, ELMIRON1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.2.2. Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.2.3. Immunosuppressant therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.2.4. Antihistamines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.3. Intravesical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.3.1. Dimethyl sulfoxide (DMSO) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.3.2. Chondroitin sulphate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.3.3. Bacillus Calmette–Guerin (BCG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.3.4. Hyaluronon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.3.5. Vaniloid receptor agonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

* Corresponding author at: Department of Urogynaecology, Beaumont Hospital, Co. Dublin, Ireland. Tel.: +353 1 809 3000; fax: +353 1 8093962.
E-mail addresses: nialldavis@rcsi.ie, nialldavis2001@yahoo.com (N.F. Davis).

0301-2115/$ – see front matter ß 2014 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ejogrb.2013.12.041

Please cite this article in press as: Davis NF, et al. Interstitial cystitis/painful bladder syndrome: epidemiology, pathophysiology and
evidence-based treatment options. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2013.12.041
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6.4. Interventional procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

6.4.1. Botulinum toxin A (BoNTA). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.4.2. Cystoscopy and hydrodistension. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.4.3. Neuromodulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.4.4. Hyperbaric oxygen (HBO) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.5. Surgical therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.5.1. Transurethral resection and coagulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
6.5.2. Major surgical procedures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 000

1. Introduction abstract of citations and the full texts of potentially eligible articles
were obtained and analysed in detail. In addition, published
Interstitial cystitis/painful bladder syndrome (IC/PBS) is a guidelines from the European Association of Urology (EAU) and
chronic condition characterised by pelvic pain and urinary storage American Urological Association (AUA) were also included in the
symptoms such as persistent urge to void, nocturia and urinary literature search process [2–4].
frequency. Its aetiology is unknown and a multitude of therapies Two-hundred and eleven studies published between 1938 and
are currently available for its treatment. Although the condition 2013 were retrieved, of which 44 were suitable for this narrative
was previously considered relatively uncommon, with a preva- review, based on clinical relevance and importance of content. The
lence of 0.1%, recent evidence demonstrates that IC/PBS may be epidemiology, pathophysiology, clinical features and diagnostic
present in >2% of females [1]. Early diagnosis is difficult as its criteria for IC/PBS were investigated, with particular emphasis on
clinical presentation is similar to other urogynaecological condi- effective treatment options. The primary data analysed included
tions, and delays in diagnosis can have a severely negative impact study type, sample size, type of treatment, method of administra-
on a patient’s quality of life. Therefore, clinicians should be familiar tion, subjective and objective cure rates, postoperative follow-up
with its natural history, clinical features and diagnostic criteria to period and any associated complications or side-effects.
facilitate appropriate and early therapy for their patients.
In this narrative review we discuss the evolving epidemiology,
3. Epidemiology
clinical presentation and diagnostic investigations for IC/PBS. We
also place particular emphasis on describing the underlying
Epidemiological studies on IC/PBS have demonstrated a variety of
pathophysiology of the condition. As a large number of treatments
results on the prevalence of the condition. This may be due to a lack
have been evaluated over long periods of time for IC/PBS our final
of definitive diagnostic investigations, different definitions for
aim is to objectively investigate recommended treatment options
diagnosing IC/PBS and inaccurate sampling methodologies. Tradi-
and to discuss levels of evidence for oral, intravesical and
tional evidence suggests that females are 9 times more likely to be
interventional therapies (Table 1).
diagnosed with IC/PBS compared to males and female gender is the
only definitive risk factor for developing the condition. In a managed
care population, however, the female to male ratio decreases to 5:1,
2. Materials and methods
which suggests that the condition may be under-diagnosed among
male patients [5]. The prevalence of the condition ranges from 52 to
A literature search was undertaken using the Medline and
500/100,000 in females compared to 8–41/100,000 in males, and its
Embase databases and the Cochrane Central Register of Controlled
incidence has been conservatively estimated at 1.2/100,000 [5].
Trials. The following terms were entered into the search algorithm
Notably, the prevalence of IC/PBS increases to 1431/100,000 among
to identify peer-reviewed articles that investigated the epidemi-
females who have a first-degree relative with the condition and this
ology, clinical presentation, diagnostic investigations or treatment
may suggest a hereditary component for the condition. Although IC/
options for IC/PBS: ‘‘Interstitial Cystitis’’ AND ‘‘Painful Bladder
PBS is more frequently diagnosed in midlife, it may also present in
Syndrome’’ OR ‘‘Interstitial Cystitis/Painful Bladder Syndrome’’.
paediatric patients and infants [6]. The prevalence of IC/PBS in the
Studies on adult patients published in English between January
paediatric population is unknown, as the National Institute of
1957 and August 2013 were included. A manual search of the
Diabetes and Digestive and Kidney Diseases (NIDDK) criteria
bibliographies of retrieved studies was also conducted. If a patient
exclude diagnosing IC/PBS in patients <18 years of age [6]. Anecdotal
group was reported twice, the most recent publication was chosen.
evidence suggests that approximately 25% of adults diagnosed with
Case reports and case series with five or fewer cases were excluded.
IC/PBS report persistence or progression of their symptoms since
The latest search was performed on December 10th 2013. Two
they were children.
authors (N.F.D. and T.C.) independently examined the title and
In the USA, estimates of medical costs plus sick leave for IC/PBS
Table 1 were $428 million in 1987 and the NIDDK has calculated that IC/
Classification of levels of evidence based on type of research study performed. PBS was responsible for at least 4137,000 outpatient visits in 2000
[4]. Furthermore, the recently developed Google Trends demon-
Level of Type of study
evidence
strates a global increase in mean search activity for IC/PBS on an
annual basis since 2004 (Fig. 1). This software is a ‘search-volume’
1a Meta-analysis of randomised trials
tool for providing information on Internet searches that generate a
1b At least one randomised trial
2a One well-designed controlled study without randomisation significant volume of results with data normalised to a reference
2b One other type of well-designed quasi-experimental study population and scaled from 0% to 100% [7,8]. Although an overall
3 Non-experimental study (comparative study, global increase in search engine use may have contributed to this
correlation study, case reports)
significant increase in ‘search-volume’, it is noteworthy that the
4 Expert committee, expert opinion
greatest increase in mean search activity has occurred in the USA,

Please cite this article in press as: Davis NF, et al. Interstitial cystitis/painful bladder syndrome: epidemiology, pathophysiology and
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uropathogens to the urothelium [12]. Notably, GAGs also prohibit

Fig. 1. Scatter plot demonstrating mean search activity on the internet for the term
IC/PBS since 2004. There has been an increase in search activity for the term on an
annual basis sine 2005.
Canada, United Kingdom and Australia, which may suggest an
increasing incidence of patients with symptomatic IC/PBS in these
regions.
4. Pathophysiology
The underlying pathophysiology of PBS/IC is poorly understood
because there is no general consensus on defining and classifying
the condition. Therefore, a number of theories persist on the
pathophysiology of the condition (Table 2).
4.1. Inflammation and mast cell activation
absorption of urine into the lamina propria of the urinary bladder by
releasing mucus which provides an immediate interface between
urine and the bladder’s epithelial surface. Mucus therefore
represents the primary barrier in the bladder for controlling
interactions with urine [12]. Tight junction and adhesion molecular
proteins between GAGs are down-regulated in patients with IC/PBS
and this leads to increased urothelial permeability. Down-regulation
of such proteins also allows potassium to diffuse into the lamina
propria to precipitate urological symptoms consistent with IC/PBS. It
appears that disruption to the GAG layer is strongly associated with
IC/PBS, as demonstrated in one study where the severity of
symptoms was associated with increased levels of urinate and
sulphated GAGs [13].
4.3. Nitric oxide metabolism and Tamm–Horsfall protein (THP)
Regulation of urinary nitric oxide (NO2) synthetase activity has
been proposed to be of importance for immunologic responses in
IC/PBS. Oral administration of L-arginine, the substrate for nitric
oxide, has been shown to increase nitric oxide related enzymes and
metabolites in the urine of patients with PBS [14]. THP is an
abundant urinary protein that is synthesised in the kidney and has
an established role in preventing damage to the urothelium from
cytotoxic agents. A defect in THP may be associated with the
development of IC/PBS, as one study has demonstrated that THP is
quantitatively different in this patient cohort [12].
4.4. Autoimmune mechanisms

Host-derived inflammatory responses disrupt the integrity of
the urinary bladder’s epithelial surface, and this contributes to
sensory nerve upregulation, enhanced activation of mast cells and
upregulation of anti-proliferative factor (APF) [9]. The result of this
process is regional neuropathy with urogynaecological manifesta-
tions such as suprapubic pain and voiding dysfunction. This theory
is substantiated by histological studies that demonstrate increased
numbers of activated mast cells in patients with IC/PBS. Further-
more, activated mast cells promote upregulation of perineural
inflammatory infiltrates of lymphocytes through the release of
substance P. Activated lymphocytes also contain inflammatory
mediators such as histamine and leukotrines, which are associated
with the down-regulation of neurokinin (NK) 1 and NK2 tachykinin
receptors in patients with IC/PBS [10].
4.2. Urothelial dysfunction/GAG layer defects
A significant increase in the prevalence of antinuclear
antibodies (ANA) in patients with IC/PBS has also given rise to
an autoimmune theory of pathophysiology. In the 1970s multi-
tudes of circulating autoantibodies were initially described where
CD8+ and CD4+ lymphocytes, B-lymphocytes, plasma cells and
immunoglobulins such as IgA, IgG and IgM were bound to the
epithelial surface of the bladder in patients with IC/PBS [15].
4.5. Genetic predisposition
A study by Warren et al. reported that adult female first degree
relatives of patients with IC/PBS may have a prevalence of IC/PBS
17 times higher than in the general population [16]. The same
group reported a greater concordance of IC/PBS among monozy-
gotic than among dizygotic twins, which suggests a genetic
predisposition to PBS [16].

Glycosaminoglycans (GAGs) are multifunctional mucopolysac- 5. Diagnosis

charides that bind covalently to a protein core to form a
proteoglycan molecule [11]. GAGs are located on the outer surface The European Society for the Study of IC/PBS proposes that the
of the transitional cell apical membrane and prevent adherence of diagnosis of IC/PBS is based on the following symptoms and signs:

Table 2
Subclassification of pathophysiological mechanisms that may contribute to the development of IC/PBS GAG, glycosaminoglycan; NO2, nitric oxide; THP, Tamm–Horsfall
protein.

Pathophysiology Proposed mechanism

Inflammation and mast cell activation Enhanced activation of mast cells with sensory nerve upregulation leading to regional neuropathy with
urogynaecological manifestations such as suprapubic pain and voiding dysfunction [9,10]
Urothelial dysfunction/GAG layer defects Tight junction and adhesion molecular proteins between GAGs are down-regulated in patients with IC/PBS which
leads to increased urothelial permeability [12]
Severity of symptoms associated with increased levels of urinate and sulphated GAG’s [13]
NO2 and THP Increase nitric oxide related enzymes and metabolites in the urine of patients with IC/PBS
THP has an established role in preventing damage to the urothelium from cytotoxic agents and a defect in its
development is associated with IC/PBS [15]
Autoimmune Significant increase in the prevalence of antinuclear antibodies in patients with IC/PBS
Genetic Prevalence of IC/PBS 17 times higher in first degree relative of adult females with IC/PBS than in the general
population [16]
Greater concordance of IC/PBS among monozygotic than among dizygotic twins [5]

Please cite this article in press as: Davis NF, et al. Interstitial cystitis/painful bladder syndrome: epidemiology, pathophysiology and
evidence-based treatment options. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2013.12.041
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(1) Pelvic pain >6 months duration; (2) pressure/discomfort
accompanied by at least one other urinary symptom such as
urgency or frequency; (3) furthermore, conditions with similar
presenting symptoms should be excluded with appropriate
investigations before a diagnosis is made. A thorough history is
important for patients presenting with pelvic discomfort,
urinary frequency and urgency. Typically, patients with IC/
PBS present with pain on bladder filling that is relieved upon
voiding.
During the initial evaluation a voiding diary can be helpful to
establish frequency and nocturia. Questionnaires such as the
O’Leary–Sant interstitial cystitis symptom and problem indices
reliably identify the most prominent voiding and painful
symptoms in patients with IC/PBS and the extent of the perceived
problem [17]. A thorough physical examination may exclude other
pathologies like vaginitis, vulvar lesions, and urethral diverticulae.
Relevant examination findings for IC/PBS are tenderness of the
urethra and bladder base. Initial investigations should include a
dipstick urinalysis and mid-stream urine (MSU) to exclude
haematuria and active urinary tract infection (UTI). Importantly,
patients presenting with haematuria should also undergo cystour-
ethroscopy with cytology to rule out an underlying bladder
neoplasm.
A diagnostic algorithm proposed by the European Association of
Urology (EAU) emphasises the importance of cystoscopy, hydro-
distension and biopsy (if indicated) for accurately diagnosing IC/
PBS (Fig. 2) [18]. Rigid cystoscopy and hydrodistension also appear
to be the mainstay of diagnosis among paediatric patients. The
classic cystoscopic finding of an inflammatory lesion with
glomerulations and/or haemorrhagic urothelial tissue was initially
described by Hunner in 1914. Notably, a Hunner’s lesion can be
sub-classified into ulcerative and non-ulcerative variants for
prognostic purposes, with the ulcerative lesion correlating with
more severe pelvic pain and urinary urgency.
6. Treatment
A number of treatment and management algorithms have been
described and these are frequently sub-classified into behavioural,
dietary, pharmacological, intravesical and interventional therapies
(Fig. 2; Tables 3–5). Unfortunately, the paucity of randomised
controlled trials comparing different treatment modalities has
precluded the development of evidence-based management
strategies and treatment protocols. In fact, the Interstitial Cystitis
Data Base study noted >180 treatment modalities for IC/PBS, with
poor results in the majority of cases [5].
6.1. Conservative
Behavioural therapy is beneficial for controlling symptoms such
as frequency or urgency and involves times voiding, bladder
training and controlled fluid intake. A reduction in overall stress
levels is associated with decreased levels of pain and urgency in
patients with IC/PBS. Finally, avoidance of caffeine, spicy food and
carbonated drinks may have a role in decreasing the frequency of
symptoms associated with IC/PBS.
6.2. Pharmacological
6.2.1. Pentosan polysulfate sodium (PPS, ELMIRON1)
PPS is a synthetic sulphated polysaccharide that is used to
decrease urothelial permeability by replacing defective GAGs.

Fig. 2. Flow-chart demonstrating the diagnosis and treatment options for IC/PBS [3].

Please cite this article in press as: Davis NF, et al. Interstitial cystitis/painful bladder syndrome: epidemiology, pathophysiology and
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Table 3
Oral medications that have been investigated for the treatment of IC/PBS and their relevant levels of evidence CyA, cyclosporine A.

Agent Level of evidence Data

Pentosan polysulfate sodium (PPS) 1a Double-blind, placebo-controlled trial reported subjective improvement in pain, urgency and frequency in
patients taking PPS compared to the control group [20]
Longer durations of treatment associated with greater response rates with 50% of patients reporting an
improvement after 26 week course
Side effects: Gastrointestinal disturbances, headache, and fatigue; incidence ranges from 1% to 80% [22]
Antidepressants 1b EAU and AUA have recommended amitriptyline as a treatment option for IC/PBS
Prospective randomised, double-blinded study reports greatest symptom improvement in patients that
can tolerate a daily dose 50 mg [21]
High rates of significant side-effects: 79–88% [21]
Immunosuppressants 1b Randomised study reported a significantly superior response rate with CyA compared to PPS (75% versus
19%, P < 0.05) [22]
Recurrence of symptoms shortly after the agent is discontinued
Antihistamines 1b Prospective, randomised controlled trial failed to demonstrate any statistically significant improvement
with hydroxyzine compared to placebo [23,24]

Table 4
Intravesical agents that have been administered for the treatment of IC/PBS and their relevant levels of evidence DMSO, dimethyl sulfoxide; BCG, Bacillus Calmette–Guerin;
RTX, resinferatoxin.

Agent Level of evidence Data

DMSO 1b Response rates: 50–70% for a period of 1–2 months after each instillation [25]
Controlled trial reported a subjective improvement in 53% of patients treated with DMSO compared to 18%
in the placebo group [26]
Chondroitin sulphate 2b Non-randomised trial on 24 patients demonstrated improvement of 73% (range: 50–95%) [30]
1 side effect in 77% of patients [27]
BCG 1b Prospective double-blinded study on 260 patients reported a non-significant improvement (P = 0.062) in
symptoms when BCG was compared to a placebo [29]
Side effects in 50% of patients [29]
Hyaluronon 2b Pilot study demonstrated an immediate response rate of 74% with hyaluronon and hydrodistension
Significant decrease in efficacy after 24 weeks
Vanilloid receptor agonists 1b Randomised double-blind placebo controlled trial of 163 patients demonstrated improvement after
instillation with RTX after a 12 weeks [33,34]

Table 5
Endoscopic, minimally invasive and major surgical procedures that have been investigated for the treatment of IC/PBS and their relevant levels of evidence BoNTA, botulinum
toxin A; HBO, hyperbaric oxygen.

Surgical technique Level of evidence Data

BoNTA 1b Prospective study on 26 patients with IC/PBS reported effective treatment in >50% of patients for 9 months
[35]
Cystoscopy and hydrodistension 3 AUA guidelines recommend that high-pressure, long duration hydrodistension should not be offered as
treatment to patients with IC/PBS due to increased frequency of perioperative adverse events [4]
Neuromodulation 3 Retrospective study reported significant improvement in symptoms in 11/21 (52%) female patients
undergoing sacral nerve stimulation after 5 years [36,37]
HBO 2 Significant decreases in urgency and pain compared to a sham control after 12 months [38]
Transurethral resection N/A Retrospective study describing symptomatic relief in 40% lasting >3 years [39,40]
Reconstructive surgery N/A Supratrigonal cystectomy: Long-term retrospective study on 18 patients. Fourteen (78%) patients were
completely pain free and 12 (67%) patients were able to void spontaneously after 5 years [41,42]
Subtrigonal cystectomy: Indicated for tigonal involvement proven on biopsy and associated with more
complications and poorer bladder rehabilitation
Urinary diversion and ileal conduit: Most common major surgical treatment for IC/PBS

A double-blind, placebo-controlled trial demonstrated a subjective
improvement in pain, urgency and frequency in patients taking PPS
compared to the control group [19]. Another open multicentre trial
demonstrated that PPS is more effective in classic IC/PBS compared
to IC/PBS in patients without bladder lesions. Longer durations of
treatment are associated with greater response rates, with
approximately 50% of patients reporting an improvement in their
symptoms after a 26-week course of therapy [20]. Side effects from
oral PPS are gastrointestinal disturbances, headache, and fatigue,
and their incidence ranges from 1% to 80%.
6.2.2. Antidepressants
EAU guidelines on chronic pelvic pain and AUA Guidelines for
the treatment of IC/PBS have recommended amitriptyline as a
treatment option for IC/PBS [4]. Amitriptyline blocks H1-hista-
minergic receptors and decreases mast cell activity. In addition,
amitriptyline decreases painful nociception by inhibiting synaptic
reuptake of serotonin and norepinephrine. It appears that the
agent is most beneficial with stepwise dose escalation, with one
prospective randomised, double-blinded study demonstrating the
greatest symptom improvement in patients that can tolerate a
daily dose 50 mg. Importantly, amitriptyline is associated with
high rates of significant side-effects, with symptoms such as dry
mouth, dizziness and gastrointestinal problems occurring in 79–
88% of patients compared to 21–72% of patients treated with
placebo [21]. Other potentially useful tricyclic anti-depressants are
doxepin and desipramine, but there is a paucity of available data on
their efficacy.
6.2.3. Immunosuppressant therapy
Cyclosporin A (CyA) has shown potential for the treatment of IC/
PBS, as demonstrated in one randomised study where the agent

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evidence-based treatment options. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2013.12.041
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was compared with PPS in 64 patients [22]. Dose regimens were
1.5 mg/kg for CyA twice daily versus low-dose PPS for 6 months
and results demonstrated a significantly superior response rate
with CyA (75% versus 19%, P < 0.05). Disadvantages of CyA in this
setting are more frequent side-effects (hypertension and increased
serum creatinine) and recurrence of symptoms shortly after the
agent is discontinued. Other possible immunosuppressive agents
for IC/PBS are azathioprine and methotrexate but there is a paucity
of prospective data on their therapeutic potential. Notably,
guidelines from the AUA recommend that oral long-term
glucocorticoid therapy should not be offered as treatment in
patients with IC/PBS [4].
6.2.4. Antihistamines
Hydroxyzine is a histamine receptor antagonist that blocks the
H1-receptor subtypes and inhibits the activation of mast cells.
Hydroxyzine hydrochloride (Atarax1) is administered with the
potential for dose escalation up to 75 mg, and early studies
reported an improvement in >90% of patients on this medication.
Notably, a more recent prospective, randomised controlled trial
failed to demonstrate any statistically significant improvement
with hydroxyzine compared to a placebo [23]. Cimetidine is an H2-
receptor antagonist and perhaps offers greater potential compared
to hydroxyzine. One early pilot study of 31 patients reported
symptomatic relief in 71% of patients with a dosage of 200 mg
three times daily, and these results have been substantiated with a
follow-up randomised controlled trial where the agent signifi-
cantly reduced the incidence of suprapubic pain and nocturia
(P = 0.009 and P = 0.006, respectively) in 34 patients after a 3-
month follow-up period [24].
6.3. Intravesical
Advantages of an intravesical approach for introducing medical
therapy are the potential for high concentrations of therapeutic
agents and decreased potential for systemic side-effects. Dis-
advantages of this approach are its invasiveness, risk of infection
and costly nature. A number of intravesical treatments have been
investigated for the treatment of IC/PBS as described below
(Table 4):
6.3.1. Dimethyl sulfoxide (DMSO)
DMSO is a water-soluble, collagenolytic, anti-inflammatory
chemical solvent with analgesic and muscle relaxant properties.
Although its mechanism of action is poorly understood; its role in
treating IC/PBS is long-standing due to its ability to alleviate pain
and urgency. Response rates range from 50% to 70% for a period of
1–2 months after each instillation [25]. One early controlled trial
compared the effectiveness of intravesical DMSO with a placebo in
33 patients with IC/PBS and reported a subjective improvement in
53% of patients treated with DMSO, compared to 18% in the placebo
group [26].
6.3.2. Chondroitin sulphate
GAG replacement therapy with chondroitin sulphate has shown
promising early results for the treatment of IC/PBS. One non-
randomised trial on 24 patients with refractory IC/PBS demon-
strated an average symptom score improvement of 73% (range 50–
95%) in 20 patients after intravesical treatment with chondroitin
sulphate. Patients underwent instillations with 2% chondroitin
sulphate twice weekly for 2 weeks followed by once weekly with
0.2% for 4 weeks and monthly thereafter for 1 year. Another non-
randomised trial demonstrated an improvement in 92% (n = 12/13)
of patients treated with intravesical chondroitin sulphate for 13
months [27]. In this study, patients underwent weekly instillations
of 40 ml for 4 weeks followed by monthly instillations thereafter.
Please cite this article in press as: Davis NF, et al. Interstitial cystitis/painful bladder syndrome: epidemiology, pathophysiology and
evidence-based treatment options. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2013.12.041
An important limitation with these studies is their relatively small
sample size. In addition, intravesical chondroitin sulphate is
associated with at least one side effect (e.g. dysuria, nausea,
gastrointestinal upset, macular rash and urethritis) in 77% of
patients [28].
6.3.3. Bacillus Calmette–Guerin (BCG)
Although BCG demonstrated response rates of 60% for the
treatment of IC/PBS in the 1990s, its efficacy has recently been
questioned. A subsequent prospective, double blind trial compar-
ing BCG and DMSO failed to demonstrate any benefit with BCG
[29]. Furthermore, significant irritative symptoms occur in
approximately 50% of patients undergoing treatment with BCG
therapy and the AUA recommend that BCG should not be offered as
a treatment option for IC/PBS except in the setting of approved
investigational studies [4].
6.3.4. Hyaluronon
Hyaluronon or hyaluronic acid is a non-sulphated GAG with
short-term efficacy for treating IC/PBS [30]. Response rates are in
the region of 53–56% 4 weeks after intravesical administration
[30]. Interestingly, response rates can increase to 70% after 7
weeks, as demonstrated in one small study of 25 patients
undergoing treatment with intravesical hyaluronon [31]. Another
pilot study demonstrated an immediate response rate of 74% in
patients undergoing treatment with intravesical hyaluronon after
hydrodistension [32]. A limitation with this treatment modality is
a significant decrease in efficacy after 24 weeks, but side-effects
occur infrequently.
6.3.5. Vaniloid receptor agonists
Resinferatoxin (RTX) is a potent analogue of capsaicin that
desensitises C-fibres, which transmit pain. Although efficacy was
demonstrated in small clinical trials, a randomised multicentre
study failed to demonstrate any advantage compared to a placebo
[33]. Another randomised double-blind placebo-controlled trial of
163 patients demonstrated no symptomatic improvement after
intravesical instillation of RTX after a 12 week follow-up period,
and AUA guidelines recommend that RTX should not be offered as
treatment for IC/PBS [4,34].
6.4. Interventional procedures
6.4.1. Botulinum toxin A (BoNTA)
BoNTA has shown recent promise as a minimally invasive
treatment option for IC/PBS. One prospective study recently
evaluated trigonal injection of BoNTA as a treatment option for
refractory IC/PBS in 26 female patients [35]. After 3 months all
patients reported an improvement in their symptoms, and
treatment remained effective in >50% of patients for 9 months
[35]. Although the initial results with BoNTA as a reliable
treatment option for refractory IC/PBS are promising, additional
prospective studies will be required before its true efficacy can be
clearly established.
6.4.2. Cystoscopy and hydrodistension
Although hydrodistension has been used in the treatment of
refractory IC/PBS for a number of years, recent data demonstrate
poor long-term results with regard to symptomatic improvement.
Furthermore, guidelines from the AUA recommend that high-
pressure, long duration hydrodistension should not be offered to
patients with IC/PBS due to its inconsistent nature and increased
frequency of perioperative adverse events [4]. These findings
suggest that hydrodistension represents a useful diagnostic
modality but remains severely limited as a reliable treatment
option for IC/PBS. Diagnosis with hydrodistension includes
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inspection of the bladder with accurate grading of any lesions that
are present:
 Grade 0: Normal mucosa.
 Grade 1: Petechiae in at least two quadrants.
 Grade 2: Large submucosal bleeding.
 Grade 3: Diffuse global mucosal bleeding.
6.4.3. Neuromodulation
There is a paucity of available data on neuromodulation with
sacral nerve stimulation and it still remains an investigational
treatment option. One short-term study on 30 patients undergoing
bilateral caudal epidural sacral neuromodulation for the treatment
of refractory IC/PBS reported a 42% improvement in symptoms 6
months postoperatively [36]. Another more recent retrospective
study demonstrated a significant improvement in suprapubic and
voiding parameters in 11/21 (52%) female patients undergoing
sacral nerve stimulation after 5 years of follow-up [37].
6.4.4. Hyperbaric oxygen (HBO)
HBO therapy has demonstrated significant advantages com-
pared to a sham control for the treatment of IC/PBS after 12 months
[38]. Specifically, HBO is associated with decreases in urgency and
pain, but limited availability and high costs are likely to delay its
progression clinically.
6.5. Surgical therapy
Invasive surgical procedures are usually reserved for patients
who remain refractory to conservative therapies. Pre-operatively,
patients should be counselled thoroughly on the definitive nature
and potential side-effects of the procedure (Table 5)
6.5.1. Transurethral resection and coagulation
Hunner’s lesions can be endoscopically ablated for symptom-
atic relief. One early non-randomised study reported on 77
patients with Hunner’s lesions that were managed conservatively
(n = 42), with fulgaration (n = 7) or with transurethral resection
(n = 28). Although all patients undergoing surgical therapy
experienced short-term symptomatic improvement, efficacy was
not significantly superior to conservative management at 12
months [39]. Encouragingly, a more recent retrospective study
evaluated the long-term outcomes of 259 transurethral resections
on 103 symptomatic patients [40]. Ninety-two patients reported
amelioration of their symptoms, with 40% describing symptomatic
relief lasting >3 years. The authors conclude by suggesting that
transurethral resection should be offered as first-line treatment for
patients with classic features of IC/PBS.
6.5.2. Major surgical procedures
There are three major surgical techniques for the treatment of
refractory IC/PBS and each technique usually necessitates substi-
tution of bladder tissue with a segment of bowel: (1) supratrigonal
cystectomy; (2) subtrigonal cystectomy; and (3) urinary diver-
sion  radical cystectomy and urethrectomy.
Supratrigonal cystectomy and enterocystoplasty represents the
most favourable continence preserving technique. A number of
gastrointestinal segments have been applied for trigonal augmen-
tation, such as ileum, ileocaecum, ascending colon and sigmoid
colon. Gastric tissue, however, appears less effective due to
persistent production of gastric acids with resultant dysuria and
suprapubic pain. Long-term results are encouraging, as described
in one study on 18 patients who were followed up for 5 years [41].
Fourteen (78%) patients were completely pain free and 12 (67%)
patients were able to void spontaneously. Importantly, persistent
Please cite this article in press as: Davis NF, et al. Interstitial cystitis/painful bladder syndrome: epidemiology, pathophysiology and
evidence-based treatment options. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2013.12.041
7
frequency and reduced bladder capacity due to active disease in
the remaining trigone and/or urethra have been reported in up to
30% of patients undergoing supratrigonal cystectomy [42].
Subtrigonal cystectomy is associated with more complications
and poorer bladder rehabilitation, as the procedure typically
requires ureteral reimplantation with associated risks of leakage,
stricture, and reflux [43]. Indications for subtrigonal cystectomy
are patients with refractory IC/PBS and biopsy proven trigonal
involvement. Post-operative self-intermittent catheterisation
(SIC), sexual dysfunction and voiding difficulties are more common
in this patient cohort as demonstrated by Volkmer et al. in one
study on eight female patients where only one patient regained
normal sexual activity after undergoing subtrigonal cystectomy for
IC/PBS [44].
Intuitively, urinary diversion with/without radical cystectomy is
the most invasive surgical treatment option. Indications include
biopsy proven involvement of the trigone (with a highly sensate
urethra) and in patients unwilling or unable to perform intermittent
self-catheterisation post-operatively. Simple urinary diversion with
the formation of an ileal conduit is the most common surgical
treatment for IC/PBS and is particularly recommended for patients
with recurrent pain in the augmented bladder or continent pouch
after enterocystoplasty or continent urinary diversion.
7. Conclusions
Our analysis suggests that IC/PBS is under-diagnosed among the
general population. Clinicians are likely to experience increasing
numbers of patients with the condition as more is understood
about its pathophysiology and evolving epidemiology. Therefore,
urogynaecologists should sufficiently familiarise themselves with
appropriate diagnostic criteria and evidence based therapies for IC/
PBS if clinical outcomes in this complex patient cohort are to
improve in the near future.
Financial disclosures
None.
Condensation
Urogynaecologists should familiarise themselves with appro-
priate diagnostic criteria and evidence-based therapies for
interstitial cystitis/painful bladder syndrome to optimise clinical
outcomes in these patients.
Acknowledgements
None.
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