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The investigation and management of

interstitial cystitis
Matthew Parsons and Philip Toozs-Hobson
Department of Urogynaecology, Birmingham Womens Hospital, Birmingham, UK


Interstitial cystitis (IC) is a chronic inflammatory disorder

of the bladder that is notoriously difficult to manage and
can result in considerable morbidity. It very likely overlaps
with painful bladder syndrome, but they are different
conditions. The aetiology remains obscure, and the definition
and diagnostic criteria are debated. The diagnosis of IC
is one of exclusion, frequently based on symptoms and
cystoscopy findings. Typical symptoms include frequency,
urgency, dysuria and lower abdominal, bladder, vaginal,
urethral or perineal pain, in the absence of bacterial cystitis.
Voiding often relieves the suprapubic discomfort, and
drinking alcohol- and caffeine-containing drinks frequently
exacerbates it. Many treatments have been tried, with little
sustained success. Proposed systemic treatments include antihistamines, heparin, amitriptyline and pentosan polysulfate
(a synthetic analogue of glycosaminoglycan which augments
the mucous protective layer of the bladder). In many patients
symptoms are improved following cysto-distension but the
benefits are short-lived. Instillations of dimethyl sulfoxide,
hyaluronic acid or chondroitin also show promise. Where
treatments have failed and symptom severity is such that the
patients quality of life is poor, a urological opinion should
be sought and reconstructive surgery considered. Available
options include partial cystectomy, augmentation cystoplasty,
and urinary diversion with or without cystectomy.
Keywords: Bladder, chronic pelvic pain syndrome, inflammation, interstitial cystitis, painful bladder syndrome

Interstitial cystitis (IC) is a chronic inflammatory disorder
of the bladder that is notoriously difficult to manage
and can result in considerable morbidity. It can cause
symptoms of frequency and urgency, with pain as a
predominant feature in one or more regions of the pelvis
typically in the bladder, vagina or perineum leading to a
poor quality of life.
Correspondence: Matthew Parsons, Consultant,
Department of Urogynaecology, Birmingham Womens
Hospital, Metchley Park Road, Edgbaston, Birmingham
B15 2TG, UK. Email:


Painful bladder syndrome (PBS) was defined only in

2002 and thus most of the literature in the area of bladder
pain refers to IC specifically, as will this article.1 There is
undoubtedly some overlap between the two, but at present
they remain distinct.
IC is a disease of extremes extremes of severe symptoms, of underdiagnosis and overdiagnosis, of aetiologic
theories that vary from the abstruse to the fashionable, of
treatment that varies from the alpha of vitamin prescriptions to the omega of radical bladder substitution surgery,
and sadly often, of confusion in medical thinking. 2 The
aim of this article is to summarize the presentation, investigation and treatment of women with IC.

Women between the ages of 40 and 60 years are most
commonly affected. The condition occurs more frequently
in Caucasians and there is a 9:1 female predominance. 3
Reported prevalence rates for this condition vary widely
as there is no universally accepted definition.
In the Nurses Health Study I and II (n = 184,583) the
prevalence of IC was 5267/100,000, with no substantial
age variation.4 Although the results must be interpreted
in the light of the higher proportion of Caucasians in
this study than the background population, this is 50%
higher than was previously reported in the United States,
and three times greater than in European studies. In a
Finnish study of 2000 participants randomly selected
from the population register, the prevalence of symptoms
corresponding to probable IC was 450/100,000 (95% CI
100800), which is an order of magnitude higher again. 5

A brief summary is presented of some hypotheses relating
to the management and investigation of IC.6

Bladder wall dysfunction and GAG layer

Dysfunctional epithelium in the lower urinary tract
is characterized by damage to the glycosaminoglycan

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M Parsons & P Toozs-Hobson

(GAG) layer, which leads to increased permeability to

potassium. Potassium can then permeate the bladder
musculature, triggering urgency and bladder contractions.
Mast cell activation is considered to be a result of GAG
layer deficiency, which induces neurogenic inflammation,
with over-expression of neurotransmitters. This proposal
remains controversial and as yet unconfirmed by electron

An infective cause for IC has been postulated repeatedly
since 1915 (see under Cystoscopy, below). However,
according to the criteria of the National Institute of
Diabetes and Digestive and Kidney Diseases (NIDDK), 3
infection is a cause for the exclusion of a diagnosis of IC,
and an infective agent has not been consistently identified.

Interstitial cystitis

chronic in the absence of urinary tract infection. It may

be experienced as sharp pain or as a pressure, or as a
burning. It may also be related to sexual intercourse. The
relationship of pain to voiding is important pain related
to filling, relieved by voiding, is a classic symptom of IC.
Pain during voiding is more suggestive of urinary tract
infection, vulval or vaginal disorders, or urethral diverticulum.9
Urinary frequency depends on many environmental
factors, and so a normal frequency does not preclude a
diagnosis of IC if urgency is present. In a study of women
with IC, none reported simultaneous onset of urgency, frequency, pain and nocturia. Sixty per cent presented with
urinary tract infection, 27% with urgencyfrequency and
13% with pain.11 All symptoms were present at a mean of
11 months after the onset of the first.

Autoimmune system disorder

Investigation and assessment

Disorders of the immune system are suspected as

being causative because of the association with certain
groups of human leukocyte antigen (HLA), allergies
and autoimmune processes, and sporadic successes with
immune suppressants.

Pelvic examination

Urinary toxins and allergens have been postulated to be
involved in the deficiency of the GAG layer.

Vascular, hormonal or toxic factors leading to hypoxia
of the bladder wall could affect the integrity of the GAG
layer. A reduced blood flow in the sub-urothelial layers
(but not deeper layers) has been seen in women with IC.

Clinical features
The symptom complex that should define IC is controversial. Typical symptoms include frequency, urgency, dysuria,
and lower abdominal, bladder, vaginal, urethral or perineal
pain, in the absence of bacterial cystitis. Voiding often
relieves the suprapubic discomfort, and drinking alcoholand caffeine-containing drinks frequently exacerbates the
pain. In a UK-based postal questionnaire survey, 64% of
respondents described daily pain when symptoms were at
their worst, and 37% described daily pain at the time of
survey. Most reported frequency, urgency and nocturia.7
Sixty-seven per cent reported a considerable impact
or more on their lifestyle and 46% reported moderate
depression or worse. Forty-nine per cent reported at least
considerable difficulties with sexual intercourse.
Incontinence tends not to be a major feature of IC,
although 14% of IC patients have evidence of detrusor
overactivity on subtracted cystometry.8 What is not clear
is whether the presenting complaint affects the likely
outcome of treatment.9 At a consensus workshop in Kyoto,
attendees were of the opinion that pelvic pain, urgency
and urinary frequency are necessary for IC to be a differential diagnosis.10
Pain typically occurs in the pelvic area in the bladder,
vagina, urethra, rectum or perineum and must be

Pelvic examination is often unhelpful. The bladder may

be tender on palpation, but examination is rather more
helpful in excluding other conditions that can cause
similar symptoms.

Urine studies
Urinalysis is usually normal but haematuria may be
present. Urine culture is essential to exclude simple
urinary tract infection, as well as atypical infections,
such as Ureaplasma urealyticum, Mycoplasma hominis or
Chlamydia trachomatis.
Urine cytology is recommended if haematuria is
present, or if there are risk factors for bladder cancer
(smoking, age, family history, occupational exposure to
certain industrial chemicals such as aromatic amines). In
a study of 128 women with irritative bladder symptoms,
and a total of 202 urine specimens, no positive cytology
nor transitional cell carcinomas were found in women
without haematuria.12 The cost-effectiveness of urinary
cytology in women without haematuria or risk factors is
therefore questionable.

Questionnaires and symptom scales

There are three published questionnaires for use in IC:
the University of Wisconsin IC Scale, the OLearySant
IC Symptom Index and IC Problem Index, and the Pelvic
Pain and Urgency/Frequency (PUF) Scale.1317
The University of Wisconsin IC Scale has not yet been
validated or published in a format for general use.14,15
However, it addresses quality of life and could therefore
be very useful.
The OLearySant indices were developed using a
focus group and validated using IC patients and asymptomatic controls.16,17 They are useful because they focus
on symptoms of urgency and bladder-related pain, but
they do little to assess the relationship of pain to more
general issues, or sexual activity, on the grounds that these
are not needed to distinguish IC.13
The PUF Scale is the most recently published and
widely studied in a urological and a gynaecological
pain setting. A large study utilizing the PUF Scale has

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Interstitial cystitis

concluded that up to 23% of US females have IC, and this

had made many experts wary of its use.18
The general consensus of the expert panel in Kyoto,
and in the opinion of the authors of an expert review
of the literature, is that none of the scales can be used
for diagnosis, although they may be more valuable in
monitoring the progress of treatment outcomes.13,19

Urine markers
Certain markers are significantly increased in IC,
including anti-proliferative factor, epidermal growth factor,
insulin-like growth factor (IGF) binding protein-3 and
interleukin (IL)-6. Anti-proliferative factor is the most
likely candidate to become a diagnostic test, as it gives the
least overlap between the IC and control groups.20
Luminal nitric oxide (NO) can be used as a marker
to differentiate inflammation, which defines IC, from
urgency, frequency, nocturia and pain due to noninflammatory disorders, such as outflow obstruction
and neurogenic dysfunction.21 There is a nearly 20-fold
increase in mean bladder NO concentration in patients
with IC compared with those with detrusor overactivity,
outflow obstruction or sensory urgency, and compared
with asymptomatic controls. Further study has shown a
statistically significant correlation between changes in
symptom/problem scores and changes in luminal bladder
NO in individual patients, which suggests that NO could
be used not only to measure inflammation but also as an
objective evaluation of treatment response.22

Voiding diary
The voiding diary is an important tool in the investigation of lower urinary tract symptoms.23 It may range in
complexity from simple records of intake and output to
more complex diaries that include symptoms and incontinence episodes, and pad use, to facilitate history taking
about the degree of frequency, nocturia and volumes
voided at each episode. They are useful in the identification of polydipsia and polyuria as a cause of urinary
In order for a voiding diary to have value, it must be
completed correctly. If the diary is too long then compliance is likely to be poor. Day-to-day variability may
compromise diaries that cover only one or two days,
and so a three-day diary has been suggested as optimal,
although others advocate a single-day diary. 24,25
Patients with IC have lower volumes at first sensation
to void and lower functional capacity than those without
the condition.26 Maximum voided volume is usually taken
to represent functional capacity. A significant positive
correlation has been found between cystometric bladder
capacity and maximum voided volume as recorded in a
home diary (rr = 0.4938, P < 0.01), which establishes the
validity of the latter.27 It is therefore usual to see women
with IC having frequent voids of small volume.

The role of urodynamics is to rule out alternative
pathology, such as obstructed voiding or detrusor overactivity, rather than to provide a positive diagnosis of IC.
The relationship of uninhibited bladder contractions
with IC or painful bladder syndrome is not clear. In a


study correlating cystometric findings with presenting

symptoms, uninhibited detrusor contractions (UDCs)
were seen in 56 of 384 patients (14.6%).26
In practice, the diagnosis of IC is as much a clinical,
symptom-based one as one based on any particular test,
and many believe that urodynamics should be reserved
for selected cases. However, the inclusion of patients in
research studies requires some degree of standardization
and studies using the NIDDK criteria therefore require

Potassium sensitivity testing (PST)

PST involves a comparison of pain and urgency sensation
after a 5 min instillation of 40 ml water and 5 min instillation of 40 ml 40 mEq/100 ml potassium chloride (KCl)
in the bladder. A positive test result is an increase in
pain with KCl and this occurs in a large majority of IC
sufferers.28 Intravesical PST is thought to be able to
detect abnormal epithelial permeability, and to discriminate patients with IC and normal subjects.29 No specific
urodynamic parameter or specific symptoms can predict
a positive KCl test in patients with frequencyurgency
syndrome or IC. 30
The role of PST is uncertain and is not part of routine
assessment in the UK. It may be useful in the assessment
of pain of uncertain origin but an empirical instillation
of 10 ml 1% lidocaine and 10 ml 8.4% bicarbonate has
been proposed as an alternative. Lidocaine alone is not
absorbed from the bladder and so needs to be alkalinized.
It is a very effective, but short-lasting, treatment for
bladder pain in a rescue scenario; if the pain persists
despite this, the patient is unlikely to get relief from
bladder treatments for IC. 31

The pursuit of a definition and diagnosis of IC began in
1887, when Skene described the disease as an inflammation of the bladder that destroyed the mucosa and
extended to the muscular parietes. In 1915 Hunner
described an ulcer. Glomerulations small, discrete,
purple haemorrhages of the bladder mucosa that are often
found in IC patients were first described in 1949.2
The purpose of cystoscopy is the exclusion of local,
intravesical abnormalities. The majority of patients with
IC have a urothelium that appears normal. In a study
of 196 women suffering from frequency, urgency and/or
bladder pain, patients with bladder pain at full bladder
and a positive KCl test had only a 45.2% chance of having
the characteristic appearances of the urothelium at
cystoscopy (see Figure 1). 30
The decision for cystoscopy, then, is frequently based
on the presence or absence of risk factors for conditions
such as bladder cancer. Since 1% of IC patients in a tertiary unit in the United States were eventually diagnosed
with transitional cell carcinoma of the bladder, some
authorities advocate cystoscopy as a mandatory investigation. 32,33
Rigid cystoscopy, under general or regional anaesthesia, is preferred to facilitate biopsy glycine should
be used as a filling medium if diathermy is to be used
for coagulation, although saline is adequate where
Versapoint (Bipolar Electrosurgery System) is available.
Infusion height should be approximately 80 cm above the

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Box 1 An experts view of the debate31

Mandatory investigations
History and physical examination
Urinalysis, urine culture, urine cytology
Optional investigations
Symptom questionnaires
Further investigations for specific patients, where
Bladder biopsy

Figure 1 Typical appearances of the bladder at cystoscopy in a

patient with IC.

symphysis pubis, using a dripping chamber until the flow

stops, observing for blood vessels, deposits, white spots,
hyperaemia, scars, cracks or mucosal changes.
When maximum capacity is reached, distension is
maintained for three minutes; the bladder is then emptied
and refilled to around a third of the maximum for visualization of haemorrhage and for possible biopsy, which
should include detrusor muscle.
The commonest pathological findings are epithelial
denudation or ulceration, mononuclear inflammation,
oedema, congestion, haemorrhage and mast cell activation. The mast cell count is calculated. If it is over 28/mm 2
it is thought significant, although no histological features
are considered pathognomonic for IC, and the prognostic
features of many inflammatory markers are not known. 33
Mast cell activity, however, is thought to relate to disease
activity, and long term to result in fibrosis. 34
Cystoscopic appearances do not appear to identify
a distinct pathophysiological subset of patients with IC
symptoms. Patients who have typical cystoscopic findings
for IC have worse daytime frequency and nocturia, and a
lower bladder capacity under anaesthesia than those who
do not. However, the groups have similar urine markers
and bladder biopsy findings. 35

There have been three major conferences in recent years
to try to establish a consensus on the diagnosis of IC:

International Consultation on Interstitial Cystitis Japan

(ICICJ) Kyoto, Japan, 2830 March 2003;36
European Copenhagen Workshop on Interstitial
Cystitis (IC) Copenhagen, Denmark, 2224 May
National Institute of Diabetes and Digestive and
Kidney Diseases (NIDDK)/Interstitial Cystitis
Association (ICA) International Scientific
Symposium Virginia, USA, 30 October 1 November
2003. 38

Box 1 provides an experts view of the debate, which is

summarized below.

History and examination

At all three conferences it was agreed that a history of
urgency, frequency and pain associated with bladder
filling is typical of IC, and that systemic and pelvic
examination is necessary to exclude other major

Questionnaires and symptom scales

The proceedings of the Kyoto conference record
discussion of the use of Wisconsin IC Scale, the OLeary
Sant IC Symptom Index and IC Problem Index and the
PUF Scale (see above). They were not advocated for
diagnosis but rather as markers of disease progression.1317
At the Copenhagen conference it was decided to use the
OLearySant indices, supplemented by a sexual score
to be defined. The use of voiding diaries and of a visual
analogue scale for grading of pain was agreed. At the
Virginia conference the PUF Scale was advocated as
a screening tool for epidemiological studies, with the
addition of some exclusion criteria.

Urine tests and urodynamics

At both the Kyoto and the Virginia conferences there was
support for the use of urine cytology in the diagnostic
workup, as well as exclusion of infection by culture and
microanalysis of the urine. The need for urodynamics was
discussed at all three conferences at Kyoto and Virginia
it was agreed that urodynamics are not essential. The
proceedings of the Kyoto conference go so far as to state:
not practised, no value, unnecessary, and painful for IC
patients. And, in addition: bladder hyperactivity should not
exclude IC. Yet the majority of attendees voted to include
urodynamic investigation in a future research protocol.
At Virginia, however, it was agreed that a voiding diary
is less expensive and provides more useful information.
At Copenhagen filling cystometry was strongly advocated
for both sexes, with pressureflow studies in men whose
maximum flow rate is less than 20 ml/s.
The Kyoto conference discussed the PST but it was felt
that, in view of the potential bias in some patients, the

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difficulty in interpreting the result and the extreme pain

for severely affected patients, it should not be undertaken.

inhibiting neurological activity;

suppression of allergies.

Cystoscopy and biopsy

Single-drug therapy is sufficient for most patients, but

multi-modal therapy may be appropriate for those with
severe or long-standing disease.

No consensus, nor even a majority decision, was reached

in Kyoto with regard to the need for cystoscopy. There was
agreement, however, that bladder biopsy is not required.
Attendees in Virginia disagreed as to whether cystoscopy
is required and over whether it should not be needed in
epidemiological studies, owing to the difficulty of standardization. The group agreed, however, that cystoscopy
is useful in determining treatment strategies and is
necessary when a patient has a high risk of bladder cancer.
At Copenhagen there was a consensus that bladder biopsy,
including muscle for mast cell analysis, is mandatory.

All three conferences debated their dissatisfaction with
the term interstitial cystitis. In Kyoto the suggestion
was that the term chronic pelvic pain syndrome
should be used, but this was countered by the argument
that some women respond to anticholinergics while
others do not, and that this therefore distinguishes an
overactive bladder from IC. The compromise IC as
part of a chronic pelvic pain syndrome (IC/CPPS) was
unanimously agreed. In Virginia there was disagreement
as to whether the term IC detracts from the diagnosis,
but it was felt that, as IC is prevalent in the medical
literature, dropping it would be too confusing. Rather,
it should be coupled with chronic pelvic pain (IC/
CPPB) and eventually IC dropped. In Copenhagen, the
definition provided by the International Continence
Society was adhered to more closely: of painful bladder
syndrome (PBS) as suprapubic pain related to bladder
filling, accompanied by other symptoms, such as
increased daytime and night-time frequency, in the
absence of proven urinary infection or other obvious

Management options can seem as bewildering as the
aetiology to those clinicians trying to manage patients
with IC. Management begins with the first visit and
assessment, by acknowledging and validating the pain,
and setting patient expectations. 39 A wide range of
treatments are frequently offered, but in the UK drugs
of proven efficacy are typically offered to only a third or
less of patients. These include cimetidine (offered to 36%
of patients in one survey); antihistamines (5%); pentosan
polysulfate (12%); dimethyl sulfoxide (DMSO) (33%);
and anticonvulsants (2%).7 The five most commonly used
therapies in the United States have been reported to be
cystoscopy and hydrodistension, amitriptyline, phenazopyridine (a urinary tract analgesic not available in the
UK), special diet and intravesical heparin.40 A total of 183
different types of therapy were recorded!
Pharmacotherapy in IC is based on three principles:

controlling a dysfunctional urothelium by restoring the

mucous/GAG layer with GAG or GAG-like drugs;


Behavioural treatments
A major part of the management of patients with IC is
behavioural and non-pharmacological: physical therapy,
avoidance of flare-inducing foods, bladder training,
and stress management techniques can supplement
pharmacological treatment and improve clinical
Patients need to become involved in their management
and should be offered advice about accurate educational
resources. The Internet provides an easy way to access
a support group42,43 and gain valuable information, for
example regarding diet (dietary modification is usually
recommended, although there is little evidence from
randomized trials as to which foods are best avoided).
Avoiding foods with a high acidity or high potassium
content is desirable (see Table 1).

Cystoscopy with hydrodistension is the most commonly
performed diagnostic test and procedure and is thought
to work by disrupting bladder neuronal pathways and thus
pain transmission. The benefits are short-lived: in one
casecontrol series the benefits of hydrodistension lasted
a mean of only two months.44 It is therefore no longer

Pharmacological treatments
Dimethyl sulfoxide (DMSO) and intravesical heparin
DMSO, a by-product of the wood industry, has been in
use as a commercial solvent since 1953. DMSO reduces
inflammation by several mechanisms. It is an antioxidant
and a scavenger of the free radicals that gather at the site
of injury; DMSO also stabilizes membranes and slows or
stops leakage from injured cells, and so may be useful in
restoring the GAG layer.
In a study evaluating the effectiveness of DMSO in the
treatment of cystoscopy-positive IC, patients were randomly allocated to receive either 50% DMSO or placebo
(saline) intravesically every two weeks for two sessions of
four treatments each. Subjectively, 53% of DMSO-treated
patients were markedly improved, compared with 18% in
the placebo group. Objectively, 93% of the DMSO group
were improved versus 35% in the placebo group.45 While
there were no significant side-effects, many patients complained of garlic halitus. In 25 patients followed for 12
months the relapse rate was 59%.
Heparin is a GAG that may afford protection to
the urothelium and reduce the relapse rate. It is better
tolerated than DMSO and does not produce garlic
halitus. It is not associated with coagulation anomalies
when administered intravesically, and may be useful in
up to 56% of patients.46 It also produces a significant
reduction in the relapse rate among patients who respond
to DMSO.47

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Table 1 Dietary advice for IC sufferers 42,43

Food group


Best avoided


Bottled water, red bush tea, pear juice


White bread, rice bread/cakes, millet, buck wheat,

matzo, plain pita bread
Refined rice, plain pasta
Butter, margarine, vegetable oils
Soups made with allowed vegetables
Beef, chicken, lamb, veal, flounder, halibut, salmon,
snapper, scallops, sole, mackerel, tuna, crab, shrimp

Alcoholic beverages (e.g. beer and wine), carbonated

drinks such as sodas, coffee, tea, and fruit juices,
especially citrus or cranberry juice
Rye and sourdough bread

Meat, fish,


herbs and

Breakfast cereals

Aged, canned, cured, processed or smoked meats and

fish, anchovies, caviar, chicken livers, corned beef, and
meats which contain nitrates or nitrites
Cream cheese, cottage cheese, ricotta
Aged cheeses, sour cream, yogurt
Alfalfa, beets, broccoli, Brussels sprouts, chicory, carrots, Fava beans, lima beans, onions, tofu, soy beans and
celery, cucumber, cauliflower, okra (ladies fingers),
courgette, squash, turnips, kale, leeks
Aduki, navy, chick peas, split peas, kidney, peas
Melons other than cantaloupes, blueberries and pears
Apples, apricots, avocados, bananas, cantaloupes,
citrus fruits, cranberries, grapes, nectarines, peaches,
pineapples, plums, pomegranates, rhubarb, strawberries
and juices made from these fruits
White chocolate, frozen yogurt and milk
Other chocolate, sugars, artificial sweeteners
Rosemary, thyme, oregano, basil, marjoram, fennel,
Mayonnaise, ketchup, mustard, salsa, spicy foods
sage, dill, mixed herbs
(especially such ethnic foods as Chinese, Indian, Mexican
and Thai), soy sauce, salad dressing and vinegar,
including balsamic and flavoured vinegars
Pine, cashews, almonds
Most other nuts

Sodium pentosanpolysulfate
Sodium pentosanpolysulfate is chemically and structurally
similar to naturally occurring GAGs that are produced
by, and form a protective layer covering, the epithelium
of the urinary tract. It inhibits complement reactions in
inflammatory processes.48 It is the only oral agent used to
treat IC that has been rigorously investigated in doubleblind trials.
In a randomized, prospective, double-blind, placebocontrolled study conducted in 148 patients, 32% of the
group on sodium pentosanpolysulfate (100 mg three times
daily) showed significant improvement, compared with
16% on placebo ((P
P = 0.01). They also experienced a significant decrease in pain and urgency ((P
P = 0.04 and 0.01,
Further, in a randomized, double-blind, doubledummy, parallel-group, multicentre, 32-week study of
380 adults examining 300 mg, 600 mg and 900 mg doses
of sodium pentosanpolysulfate, improvement was not
dose dependent. The duration of therapy appeared more
important. 50
Hyaluronic acid and chondroitin sulfate
Hyaluronic acid is an important GAG that is present
throughout the body in connective tissues. In 25 patients
with the characteristic picture of IC and refractory
to other medical treatments, intravesical hyaluronic
acid produced a positive response rate of 56% at week
4, increasing to 71% by week 12. This response was
maintained until week 20; beyond week 24 there appeared
to be a moderate decrease in the effectiveness of the
medication. 51 There was no significant toxicity attributable to the presence of hyaluronic acid in the bladder. In
a small Danish follow-up study, monthly instillation of
sodium hyaluronate solution over three years gave benefit

in approximately two-thirds of patients, and apparent

recovery in 20%. 52
Chondroitin sulfate is a major component of the GAG
layer. An open-label study of chondroitin sulfate was
undertaken to determine the response of patients with IC
and positive PST, of whom 67% responded favourably. 53
Bacilli CalmetteGuerin (BCG)
Case reports suggested that BCG might be effective in the
treatment of IC, by affecting the GAG layer. Non-specific
inflammation of the urothelium is stimulated, which is
thought to promote its regeneration.
In 265 patients with treatment-refractory IC comparing
intravesical BCG to placebo instillations, the response
rate was not significant: 12% for placebo and 21% for
P = 0.062). 54 A much smaller study (n = 30) found
a 60% BCG response rate, compared with a 27% placebo
response rate. 55 However, in the light of the larger study
this must be interpreted with caution.
Intravesical instillation of capsaicin, a neurotoxin
extracted from red chilli peppers, has significant effect
over placebo in the treatment of neurogenic detrusor
overactivity. 56 It exerts a biphasic effect on sensory nerves,
with initial excitation followed by a long-lasting block of
C-fibres, which are rendered resistant to natural stimuli. 57
Resiniferatoxin (RTX) is an analogue of capsaicin
extracted from euphorbia, a cactus-like plant. When given
intravesically, it is 1000 times more potent than capsaicin
in stimulating bladder activity; it is hypothesized that
such drugs will be effective in the treatment of IC by
decreasing the pain that leads to urinary frequency and
urgency. However, a randomized controlled trial found no
evidence of efficacy in IC. 58

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Box 2 Key clinical messages

There is a 9:1 female-to-male preponderance.
Typical features are of bladder pain related to filling,
urgency and frequency.
Urine cytology is needed only if haematuria is present,
or where risk factors for bladder cancer are identified.
Urinary tract infection must be excluded.
The role of urodynamics is to rule out alternative
The purpose of cystoscopy in the investigation of
bladder pain is the exclusion of local, intravesical abnormalities.
The majority of patients with IC have a normal
appearance to the urothelium.
Non-pharmacological strategies can improve clinical
Sodium pentosanpolysulfate is the only oral agent used
to treat IC that has been rigorously investigated in large
double-blind trials.
Bladder instillations of DMSO may be very effective and
should be considered for use in patients with IC.
Other bladder instillations need further investigation
but show promise.

combination of bladder or pelvic pain, urinary urgency

and frequency.
The investigation is based very heavily on history and
examination clinical investigation is used to exclude
other pathology rather than to make a positive diagnosis.
The management is as varied as the list of possible
aetiologies, as one might expect. It is essential that the
patient be involved with the diagnosis and treatment, as
non-pharmacological dietary and behavioural treatment is
very important. Multiple modes of therapy are frequently
employed, although many of the newer agents have yet to
be subjected to large randomized studies. This reflects the
difficulty of identifying and standardizing a study population for such a heterogeneous condition.

Competing interests: MP has acted as an adviser for and

received support to attend scientific meetings from UCB,
Astellas and BioControl. PTH has received support from
Pfizer, AstraZeneca, UCB, Astellas, Eli Lilly, Molliston,
Gynecare and Galen.

Amitriptyline is frequently used in pain management. 59
Anecdotal experiences with the tricyclic class of antidepressants suggest that amitriptyline may be an effective
treatment modality in non-ulcerative IC.60 It was shown to
be effective in a small placebo-controlled study.61
Increased numbers of activated mast cells have been
documented close to nerve endings containing substance
P in the bladders of patients with IC. Bladder mast cells
can be activated by carbachol, while hydroxyzine reduces
carbachol-induced serotonin release from rat bladder.62 In
an open-label case series of patients treated by their local
doctor, a 40% reduction in symptom scores was reported.
This rose to 55% in patients with a history of allergies,
suggesting that hydroxyzine is a useful drug for the
symptomatic treatment of IC, especially in patients with
documented allergies or evidence of bladder mast cell
activation.63 However, larger randomized studies would be
required to support a strong recommendation.

Where other treatments fail and symptom severity is such
that the patients quality of life is very poor, a urological
opinion should be sought and reconstructive surgery
considered. Available options include partial cystectomy,
augmentation cystoplasty, and urinary diversion with or
without cystectomy.

IC is a chronic, disabling condition affecting predominantly women (Box 2). The aetiology is uncertain,
but almost certainly multi-modal. It presents with a


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