Download 3 Painful bladder syndrome/interstitial cystitis

Best Practice & Research Clinical Obstetrics and Gynaecology
Vol. 19, No. 6, pp. 843–859, 2005
doi:10.1016/j.bpobgyn.2005.08.004
available online at http://www.sciencedirect.com
3
Painful bladder syndrome/interstitial cystitis
Anna Rosamilia* MBBS, MRCOG, FRANZCOG, CU, PhD
Urogynaecologist, Monash Medical Centre, 13 Brunswick St, Fitzroy, Vic. 3065, Australia
Painful bladder syndrome (PBS) is the term used to refer to a chronic symptom complex of
urinary frequency and bladder ‘pressure’, discomfort or pain in the absence of any other
reasonable cause for these symptoms (such as infection). Interstitial cystitis (IC) is the
established term used by the National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) consensus workshop for which a research definition was formulated in the late
1980s. Opinion varies regarding not only definition but also the usefulness of diagnostic
investigations such as urodynamic assessment and the potassium sensitivity test. There are still
controversies concerning the most basic investigation of cystoscopy in PBS/IC. New
developments in the study of PBS/IC include the identification of a potential urinary
biomarker, antiproliferative factor (APF), which is produced by urothelial cells in IC and
thought to inhibit proliferation. In addition, condition-specific validated questionnaires should
aid evaluation, and a growing number of randomised controlled trials should enable clinicians
to use evidence-based therapeutic options.
Keywords: cystitis; interstitial cystitis; cystoscopy.
DEFINITION: WHAT’S IN A NAME?
The terms ‘painful bladder syndrome’ and ‘interstitial cystitis’ are often used
interchangeably in clinical practice. Historically, interstitial cystitis (IC) was the name
given to the condition, which was associated with severe cystoscopic changes of
‘Hunner’s ulcer’, fissuring and reduced bladder capacity.1 The definition was broadened
in 1978 by Messing and Stamey to include glomerulations at cystoscopy.2 In 1987, the
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) consensus
workshop resulted in a publication in the following year of exclusion and inclusion
criteria for research purposes. These criteria were made more specific, published in a
book, and formed the basis for diagnosis. They were summarized and presented again
by Hanno in 19943:
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844 A. Rosamilia
‘To be diagnosed with interstitial cystitis, patients must have either glomerulations
on cystoscopic examination or a classic Hunner’s ulcer, and they must have either
pain associated with the bladder or urinary urgency. The presence of any one of
the following criteria excludes the diagnosis of interstitial cystitis.
1. Bladder capacity of greater than 350 cm3 on awake cystometry using either a
gas or liquid filling medium.
2. Absence of an intense urge to void with the bladder filled to 100 cm3 of gas or
150 cm3 of water during cystometry, using a fill rate of 30–100 cm3/minute.
3. The demonstration of phasic involuntary bladder contractions on cystometry
using the fill rate described above.
4. Duration of symptoms of less than 9 months.
5. Absence of nocturia.
6. Symptoms relieved by antimicrobials, urinary antiseptics, anticholinergics, or
antispasmodics.
7. A frequency of urination, while awake, of less than eight times per day.
8. A diagnosis of bacterial cystitis or prostatitis within a 3-month period.
9. Bladder or ureteral calculi.
10. Active genital herpes.
11. Uterine, cervical, vaginal, or urethral cancer.
12. Urethral diverticulum.
13. Cyclophosphamide or any type of chemical cystitis.
14. Tuberculous cystitis.
15. Radiation cystitis.
16. Benign or malignant bladder tumours.
17. Vaginitis.
18. Age less than 18 years.
More recently there has been a desire to broaden the definition or change the name.
In any case, the term ‘interstitial cystitis’ is a misnomer, with features of inflammation
not always present, and there is more evidence for epithelial rather than ‘interstitial’
involvement. However, there is a great reluctance to do away with the term IC because
of the public, medical and political awareness of this condition—in no small part due to
the work of the IC associations around the world.
The NIDDK definition was never meant to be a clinical definition but rather a
research definition to allow useful comparison in epidemiological and therapeutic
studies. In support of this argument were early findings that at least 10% or more of
patients with painful bladder symptoms had normal cystoscopic appearance, some had
bladder overactivity as well as pain, and some were arbitrarily excluded by their age.4 In
addition, it was shown that glomerulations were seen after hydrodistention (up to
950 mL) in asymptomatic women.5 The IC database study found that only about 40% of
patients clinically diagnosed with IC by the investigator actually met all NIDDK criteria.4
There are also obvious geographical differences of opinion, with United States experts
favouring a broader definition compared with European experts.
The current consensus terminology is that this condition may be referred to as
PBS/IC. Painful bladder syndrome has been defined by the International Continence
Society (ICS) as ‘the complaint of 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 pathology’. The ICS uses
Painful bladder syndrome/interstitial cystitis 845
the term interstitial cystitis for the symptom syndrome associated with typical
cystoscopic and histological features.6
EPIDEMIOLOGY/BURDEN
The study of the epidemiology of IC/PBS has been confounded by the lack of a uniform
definition for IC/PBS. The difference in prevalence estimates can be explained by
reliance on differing or variable diagnostic criteria in addition to the possibility of
reduced actual incidence or reduced awareness of the condition. As a result, the
population prevalence of IC has been estimated at 18 per 100,000 women in 1975 in
Finland7, 30 per 100,000 in 1987 in the USA8, and 865 per 100,000 women in 1994 in
the USA.9
Curhan et al10 utilized the Nurses Health Study (NHS) I and II—two large
population-based studies of female, mainly white nurses—and found the prevalence of
confirmed IC to be of the order of 60 per 100,000. These studies showed that the delay
between onset of symptoms and diagnosis was 5–7 years, which means that the
prevalence of symptomatic individuals whose disease was not yet confirmed would be
far greater. Leppilahti et al11 administered a symptom questionnaire and calculated the
prevalence of probable IC to be 450/100,000.
A consistent finding is the predominance of women with IC. The male-to-female
ratio varies between 1:4.5 in the Japanese cohort12 and 1:9 in the US population
survey.13 In a series of over 500 IC patients, Koziol14 found the mean age at the time of
first symptoms was 42 years, with 30% younger than 30 years at the onset of symptoms.
Patients with IC were 100 times more likely to have inflammatory bowel disease and 30
times more likely to have systemic lupus erythematosus. Female IC patients were much
more likely to have had a hysterectomy.14
The natural history of the condition was followed by the Interstitial Cystitis
Database (ICDB) and this confirmed no long-term change in overall disease severity
over a period of 48 months in a mainly (92%) female cohort.15 The impact of IC was
also studied by Koziol who found that only 10% of IC patients rated leisure activities,
travel and sleep to be unaffected by their condition.14 Family relationships and
responsibilities were said to be adversely affected in 70%. The quality of life of women
with IC has been said to be worse than women with end-stage renal disease.8
DIAGNOSIS
IC/PBS is a diagnosis of exclusion and requires an assessment of symptoms, physical
examination, urine microscopy and—if indicated—urine cytology, imaging, usually
cystoscopy and sometimes laparoscopy in order to fully differentiate this from other
causes of these symptoms. Helpful to the work-up and management of IC are a urinary
diary and symptom questionnaire. Optional investigations include urodynamics and
bladder biopsy.
Symptoms/diary
Koziol described the main symptoms in a series of IC sufferers; they were frequency
(92%), urgency (92%) and pelvic pain (70%). Over half the women described
846 A. Rosamilia
dyspareunia, daily or constant pain, and described the pain as severe or excruciating.
The pain was described as vaginal in 60% and lower abdominal in 60%. Pain was
exacerbated by spicy foods, alcoholic, acidic, carbonated or caffeinated beverages in
50%, by sexual intercourse (50%), stress (60%) and exercise (40%).14
There is difficulty in describing and quantifying each of the symptoms, which are part
of the painful bladder syndrome. Daytime and night-time frequency can be altered by
reduction of fluid intake, and absolute numbers are therefore not as helpful as volume
voided, which can be obtained from a 24-hour urinary diary. In clinical practice,
consistently small urine volumes associated with pain or discomfort, rather than
incontinence, is a distinguishing feature from bladder overactivity.
Urgency is also a common complaint, by which is meant a constant desire to void,
discomfort or pressure. Recently there has been debate about the definition of urgency,
with the ICS definition being ‘desire to void for fear of leakage’.6 Urgency by this
definition is not usual in IC/PBS; rather it is a painful desire to void or pressure which is
the commonest symptom. Classically, the pain is associated with bladder filling and is
relieved by emptying. However, it is accepted that pain can be felt in the suprapubic
area, vagina, urethra, vulva, perineum or rectum. There are no criteria for the location,
severity or character of the pain.
Urodynamics
The NIDDK criteria referred to urodynamic assessment in a few ways, but it is not
required as part of the work-up of IC/PBS. In the original NIDDK IC patient accrual
form, two of a possible four other positive factors were required for a diagnosis of IC
apart from Hunner’s ulceration at cystoscopy. One of these factors was decreased
bladder compliance.3 Furthermore, the revised exclusion criteria included the presence
of involuntary bladder contractions, bladder capacity O350 mL or the absence of
intense urge to void at 150 mL water. Bladder overactivity was excluded for research
purposes in order to clearly demarcate IC patients. However, in the IC database
project, 14% had bladder overactivity.15 Decreased compliance is quite uncommon and
has an association with more severe disease.
In practice, urodynamic assessment give limited information in IC/PBS. It is not well
tolerated; usually the only finding is that of reduced awake capacity, which could have
been predicted by the urinary diary. It is the overlap with bladder overactivity, which is
of interest; however, it is not known whether there is any role for anticholinergic
medication in this group. In practice, women with IC/PBS frequently complain of
worsening pain and voiding difficulty with anticholinergic agents, unlike overactive
bladder (OAB) patients whose symptoms improve with drug treatment.
Cystoscopy
The cystoscopic findings most often associated with classical descriptions of IC are
Hunner’s ulcer1, described as patches of red mucosa exhibiting small vessels radiating to
a central pale scar or fissure (Figure 1), and glomerulations, which are petechial
hemorrhages—often with cascade bleeding (Figure 2)—which can be seen during
bladder emptying after hydrodistention.2 The cystoscopic capacity may be reduced, in
particular in association with ulceration or fissuring. There are many uncertainties
about these cystoscopic features. The diagnosis of Hunner’s ulcer varies between 6 and
50% in different series of IC patients.16,17 Some of this discrepancy maybe due to a real
Painful bladder syndrome/interstitial cystitis 847
Figure 1. Hunner’s ulcer in interstitial cystitis: patches of red mucosa exhibiting small vessels radiating to a
central pale scar or fissure.
difference in the patient population, but some is due to the subjective nature of the
diagnosis. Glomerulations are most likely a reflection of a chronically underdistended
bladder and not specific to IC; not all patients with symptoms of IC/PBS have
glomerulations5, and not all patients with glomerulations have symptoms of IC/PBS.4
There is no clear correlation between cystoscopic appearance and disease severity;
Figure 2. Glomerulations in interstitial cystitis.
848 A. Rosamilia
however, Nordling and colleagues18 found in a large series that poorer outcome was
most strongly correlated with detrusor mast cell density, anaesthetic bladder capacity
and glomerulations, in that order.
Recently, the cystoscopic findings were compared with other features such as
symptom questionnaires, urinary antiproliferative factor (APF) and biopsy features in a
group of newly diagnosed patients with symptoms of IC. The group who met the
NIDDK cystoscopic criteria had worse frequency and nocturia and lower anaesthetic
bladder capacity than the group who did not have cystoscopic changes, but all other
features were similar.19
Potassium sensitivity test
The potassium sensitivity test (PST) is an office-based examination in which 40 mL
sterile water (control) and 40 mL 0.4N KCl solution (4–10 times physiological urinary
potassium concentration) are sequentially instilled into the bladder and the patient is
asked to rate the degree of urgency and/or pain (0–5 scale) produced by the two
instillations.20 A negative test is when neither water nor potassium provokes any
symptoms. A positive test is a grading R2 for pain/urgency after potassium compared
with water. The proposed mechanism of action is that the potassium ions are
abnormally absorbed through the IC urothelium and stimulate submucosal sensory
nerves to produce pain. It has become popular and used as a diagnostic tool particularly
in the United States; it has the advantage that it is less costly than cystoscopy,
hydrodistension and biopsy.
A review by Payne and colleagues and presented at the NIDDK/IC meeting in
Washington, 2003, summarized that while the PST is negative in many other urological
conditions, there is a significant rate of positive results in potential confounding
conditions such as bladder overactivity and urinary infections. In addition, 85% of
gynaecological patients with pelvic pain and 84% of prostatitis patients were reported
to have a positive PST, which suggests that a positive PST may be a marker for
generalized hyperaesthesia rather than IC. Indeed, PBS may represent only one aspect
of a wider pelvic hyperaesthesia.
Biomarkers
The most thoroughly investigated marker for interstitial cystitis is APF, identified and
characterized by Keay and colleagues.21 They have demonstrated that APF isolated
from urine is a heat-stable, low molecular weight, trypsin-sensitive protein that inhibits
bladder-cell proliferation and has a sensitivity and specificity O94% for women with
documented IC.22 Furthermore, successful treatment of IC by either hydrodistenstion
or neurostimulation normalized APF levels. Further confirmation that APF is a useful
biomarker requires replication in other laboratories.
Histopathology
The case for pathological confirmation of IC is strongest for the classic disease as
defined by either a Hunner’s ulcer or low anaesthetic capacity. The most commonly
reported histological changes in classic IC include epithelial ulceration or denudation,
submucosal inflammation, granulation tissue formation, oedema, congestion, haemorrhage; detrusor fibrosis, increased epithelial, submucosal and detrusor mast cell
Painful bladder syndrome/interstitial cystitis 849
number and activation and increased neuronal staining.16 Early IC is generally
characterized by normal or near-normal bladder capacity under anaesthesia and
glomerulations. Light microscopy findings range from mucosal ruptures, submucosal
haemorrhage and mild inflammation in transurethral resection biopsies16 to normal
histology in forceps biopsies approximately half the time.23 In other words in the clinical
setting of early IC, bladder forceps biopsy pathology may be normal and is not therefore
useful as a confirmatory test.
Biopsy pathology can be useful in confirming IC, but usually in the clinical setting of
severe disease. Urine cytology should be mandatory in the population at risk of
malignancy, but this would not include women less than 40 years of age. There is also
the possibility of false-negative cytology, so that biopsy has an important role if
malignancy is suspected. There are rare occasions when other diagnoses such as
eosinophilic cystitis are made. Biopsy remains an optional test in the diagnostic work-up
of IC.
Questionnaires/quality of life assessment
There are three IC symptom questionnaires: the University of Wisconsin IC Scale, the
O’Leary–Sant IC Symptom Index and IC Problem Index, and the Pelvic Pain and
Urgency/Frequency (PUF) Scale. The University of Wisconsin IC Scale24 has not
published validity yet. It includes some quality-of-life questions and is easy to administer.
The O’Leary–Sant indices are validated25 and are the most commonly published
questionnaire primarily used to follow the course of the condition and response to
therapy. The Pelvic Pain and Urgency/Frequency Patient Symptom Scale or PUF
questionnaire26 was designed to include questions on urgency and especially pelvic pain.
An ‘expert opinion’ level review concluded that further study of all questionnaires is
indicated.27 As yet, none of the questionnaires has been shown to be of value in terms
of diagnosis.
In the context of a randomised prospective trial, the primary endpoint is often
‘global improvement’. A ‘Global Response Assessment’ has been used in recent NIDDK
trials; it is a scale including ‘slightly, moderately and markedly worse, no change, and
slightly, moderately and markedly improved’, which ranges from K3 to C3.28
AETIOLOGY
Neurogenic inflammation and mast cells
Neurogenic inflammation has been proposed to be one of the important
pathophysiological processes occurring in IC, and includes mast cell activation,
sensory nerve fibre proliferation, and altered or increased sensory neuropeptide and
inflammatory mediator expression.29 There is a ten-fold increase in bladder mast cell
count in ulcer IC; however, in non-ulcer IC, the mast cell count is normal or only
slightly increased.30 Other findings include increased sympathetic innervation and
increased submucosal neuronal staining in IC.31 These findings lend support to a
pathogenesis, which includes interaction between the inflammatory, neuronal and
endocrine systems.
850 A. Rosamilia
Urothelial dysfunction
Parsons and colleagues69 have proposed that a defective glycosaminoglycan (GAG)
mucus layer in IC alters bladder permeability.32 Evidence supporting urothelial
dysfunction includes widened tight junctions and increased permeability on scanning
electron microscopy33 and the identification of APF by the urothelial cells in IC.21
Autoimmune mechanisms
There is an association between IC and autoimmune diseases such as systemic lupus
erythematosus34, Sjogren’s syndrome35, and disorders such as asthma, food allergy and
fibromyalgia.36 There are numerous reports on autoantibodies in some patients with
IC.37
Infection
No microorganism has been revealed as the cause of IC. There has been a large number
of studies utilizing special techniques to detect microorganisms—including fastidious
bacteria or viruses—which have been negative.38 There is no evidence of increased
urinary IgA or IgG levels indicating recent or remote Gram-negative or Gram-positive
infection in IC, and no evidence for helicobacter infection.39 It is speculated that a
microbiological cause may be the initial trigger rather than being involved in the chronic
process of IC.
Vascular changes
Vascular changes may play a role in the pathogenesis of IC. Decreased microvascular
density in the suburothelium40 and bladder perfusion have been demonstrated to
decrease with bladder filling in IC patients compared to the opposite in controls.41
MANAGEMENT
General principles
Once a diagnosis of painful bladder disease has been made, patient education—
including an overview of management options—is the next step. Treatment is directed
towards symptom reduction as there is no evidence for disease progression.15 A
percentage of patients will spontaneously improve and ultimately resolve in weeks or
months.4 Patients should be informed that IC/PBS is a non-progressive, non-malignant
condition, and that there are many treatment options including expectant management.
Information regarding the large number of self-help strategies, natural therapies, and
conservative and surgical options available means that patients feel they have greater
control and choice with regard to their own treatment path. The Interstitial Cystitis
Association (http://www.ichelp.org) and its affiliated international organizations are
important resources for patients, researchers and clinicians.
Painful bladder syndrome/interstitial cystitis 851
Behavioural modification
A 1-day voiding chart42 gives both patient and clinician some objective measure of
symptom severity and forms the basis of bladder re-education. Bladder training has
been shown to increase voided volumes and improve frequency; however, the
persistent sense of bladder fullness may still be a problem.43 Patients who experience
pain more than frequency would be unlikely to tolerate bladder training as the sole
intervention.
Physical therapy
Pelvic floor physical therapy is considered to have a place in the management of
functional pelvic and perineal syndromes44, but there are no published randomized,
controlled trials to support this in IC. Biofeedback and soft tissue massage may aid in
muscle relaxation of the pelvic floor.45 Some small uncontrolled series have reported
success rates by varying techniques such as direct myofascial release, joint mobilization
and home exercise program, transvaginal Theile massage and electromyographic
biofeedback. One of the few randomized placebo-controlled studies performed
assessing this type of therapy in IC compared transdermal laser stimulation of the
posterior tibial nerve to sham stimulation and found no difference between active and
sham treatments.46
Dietary manipulation
A significant proportion of interstitial cystitis patients have symptom exacerbation
related to the intake of specific foods and beverages.14 Most often, these are ‘acidic’
beverages, coffee, spicy foods, and alcoholic beverages. However, the list of ‘foods to
avoid’ has never been subjected to controlled clinical trials.
Oral therapy: grade B recommendation
Interstitial cystitis/painful bladder syndrome is an extremely difficult condition in which
to follow the results of any therapy. The disease tends to fluctuate in severity, and up to
50% of patients experience temporary remissions unrelated to therapy for an average
duration of 8 months.8 Most therapies for IC have been associated with very promising
initial results followed by either no or much reduced benefit when analysed in a
randomized placebo-controlled double-blind trial (RCT). This type of trial is important
to minimize the problems of bias and regression to the mean, which occurs as a result
of recruitment of more symptomatic cases to a therapeutic trial. It is crucial to take into
account the placebo effect, which can be of the order of 30%.
A number of both oral treatments (such as L-arginine47 and Nalmefelene48) and
intravesical therapies (such as hyaluronic acid49and resiniferitoxin50) have been shown
not to be efficacious despite promising initial results.
Sodium pentosanpolysulfate/Elmironw
Sodium pentosanpolysulfate (PPS), or Elmiron, is a heparin analogue available in an
oral formulation. The mechanism of action in IC is attributed to correction of a
possible defect in the GAG layer, the ability to inhibit histamine release from mast cells,
852 A. Rosamilia
and a possible binding with inflammatory mediators in the urine. PPS has Food and Drug
Administration (FDA) approval for the treatment of the pain of interstitial cystitis.
The studies for the FDA found ‘more than slight improvement’ in 28% with Elmiron
treatment versus 13% on placebo.51 This was followed by a study, where 50% or more
overall improvement was reported in 32% of the Elmiron compared with 16% of the
placebo group.52 Pain, urgency, and pressure showed significant improvement, but
frequency, nocturia, and volume voided did not. Similar findings were seen as part of the
6-month NIDDK PPS versus hydroxyzine study53, where 28% of the 29 patients on
Elmiron alone had a global response of ‘improved’ compared with 13% on placebo.
Long-term, open-label studies with populations receiving treatment for up to 7 years
or more in the compassionate use program show no further improvement in symptoms
after 1–2 years.54 Elmiron is a well-tolerated medication and is efficacious in improving
the pain of interstitial cystitis in up to one third of patients, often requiring a 3–6-month
treatment duration to show an effect.
Amitriptyline
Amitriptyline has become one of the most commonly used treatments for IC.55 The
only prospective, double-blind, placebo-controlled RCTof 50 patients showed a O30%
decrease in O’Leary–Sant symptom and problem scores at 4 months in 42% of the
amitryptyline (up to 100 mg daily) versus 13% of the placebo group.56 Amitriptyline has
analgesic efficacy related to serotonin or noradrenaline reuptake inhibition and
stabilizes mast cells. One quarter of patients in a trial setting were unable to tolerate
the sedation accompanying 75 mg amitryptline daily.57 The sedation is helpful in the IC
patient with bothersome night-time symptoms. A large multicenter trial to further
investigate the efficacy and adverse effects of amitrypyline in IC is needed.
Oral therapy: grade D recommendation (evidence inadequate or
conflicting)
Hydroxyzine
Hydroxyzine, a H1 receptor antagonist, inhibits bladder mast cell activation, has
anticholinergic, angiolytic, and analgesic effects, and has been reported mainly in openlabel studies.58 The NIDDK trial comparing hydroxyzine, PPS and placebo found a 23%
global response rate of hydroxyzine compared to 13% on placebo53, and this did not
reach statistical significance.
Cimetidine
Cimetidine is a H2 histamine receptor antagonist and has been studied mainly in openlabel series in the United Kingdom.59 A RCT of only 36 patients who received either
oral cimetidine 400 mg twice daily or placebo showed an improvement in median
suprapubic pain and frequency scores.60
IPD-1151T
Suplatast Tosilate (IPD-1151T) is an immunoregulator that suppresses IgE production
and eosinophilia via suppression of helper T cells. It is used in Japan to treat allergic
disorders such as asthma and atopic dermatitis. An initial small open-label study61
Painful bladder syndrome/interstitial cystitis 853
showed significantly increased bladder capacity and decreased urgency, frequency, and
pain in 10 of 14 women.
Quercetin
Quercetin is a flavenoid with a potential anti-inflammatory effect. One open-label study
in 22 patients for a duration of 1 month showed global improvement and amelioration
of the O’Leary–Sant symptom and problem scores. Similar results were reported after
6-month open-label use of a combination of quercetin with chondroitin sulfate and
sodium hyaluronate.62
Antibiotics
Significance was not reached in a RCT comparing a group of 25 patients receiving a total
of 18-week sequence of rifampin, doxycycline, erythromycin, metronidazole,
clindamycin, amoxicillin and ciprofloxacin versus 25 control patients.63 However, 80%
of the antibiotic and 40% of the placebo group had adverse events—mainly nausea and/
or vomiting and diarrhoea. It is common for many patients with IC to have been treated
with empiric antibiotics, especially doxycycline. There is no evidence to support the use
of antibiotics in the management of IC except in the presence of proven concurrent
infection.
Cyclosporine
Eleven patients received cyclosporine for 3–6 months; frequency decreased, and mean
and maximum voided volumes increased significantly. Bladder pain decreased or
disappeared in 10 patients, but symptoms recurred after cessation of treatment in the
majority. A long-term follow-up over 1–10 years in 23 refractory IC patients showed
similar positive results while patients remained on immunosuppressant therapy.64 The
short- and long-term adverse effects need to be carefully considered if cyclosporin
therapy were used.
Analgesics
Medications commonly used for chronic neuropathic pain syndromes can be used for
IC. These include antidepressants, anticonvulsants, non-steroidal anti-inflammatory
drugs (NSAIDS) and antispasmodics. Opiates in this chronic pain state are most safely
incorporated in the patient’s treatment in the setting of a multidisciplinary pain clinic,
which allows for regular reassessment.65 Gabapentin has also been used in this setting,
but no studies have been reported.
Small open-label series (10–25 patients) of drug therapy with methotrexate,
montelukast, nifedipine and misoprostol have been published showing some success,
but no RCTs have been performed.
Intravesical therapy: grade B recommendation
Dimethyl sulfoxide
Until 1996, dimethyl sulfoxide (DMSO) was the only drug approved by the FDA for use
in IC. It is a chemical solvent with anti-inflammatory, analgesic, muscle relaxant, mast
cell inhibition and collagen dissolution properties.66 DMSO can be administered as
854 A. Rosamilia
single therapy or in combination with heparin, steroids and a local anaesthetic as a
cocktail. The treatment regimens vary to suit the convenience of patient and therapist,
but once or twice weekly instillation for 8–12 treatments is commonly used. A
response rate to DMSO of 50–90% has been reported, with a relapse rate of up to 40%;
however, three quarters will respond to further DMSO. Adverse effects include a
garlic-like breath odour and taste, and transient bladder irritability due to a chemical
cystitis in 10%. DMSO is cheap, has relatively few side-effects, and self-instillation can be
taught if required. Perez-Marrero and colleagues67 demonstrated both subjective and
objective improvement over placebo. In a randomized double-blind cross-over study,
DMSO resulted in significant reduction of pain and frequency in classic IC, whereas no
effect could be shown in the non-ulcer group.68
Intravesical therapy: grade C recommendation (beneficial, level 4 trials;
majority opinion)
Heparin
Two clinical uncontrolled studies of intravesical heparin 5000 U twice weekly have been
reported69 that have shown improvement in bladder symptoms.
Lignocaine
Several clinical studies of this drug in patients with interstitial cystitis have been
reported.70,71 All involved electromotive drug administration (EMDA), utilizing an
electric current to facilitate the active transport of the ionised drug. Short-term efficacy
was demonstrated, but randomized controlled studies are needed. Other agents such
as oxychlorosene (chlorpactin) and silver nitrate have been used as instillations in the
past but are rarely used now.
Intravesical therapy: grade A recommendation (not beneficial)
Bacillus Calmette–Guerin (BCG)
Two initial RCTs showed conflicting results. Peters and colleagues72 demonstrated
response to BCG in 60% of cases compared with 27% of controls; of the responders,
eight of nine continued an excellent response at follow-up O2 years. Peeker performed
a cross-over RCT with BCG and DMSO68 and found that BCG was not efficacious. A
large multicenter RCT sponsored by NIDDK compared BCG with placebo (up to six
instillations over 6–10 weeks) in 265 patients with mainly moderate to severe IC found
a response rate of only 21% for BCG versus 12% for placebo at 6 months follow-up
(PZ0.06). Adverse events were similar in both groups, but intravesical BCG cannot be
recommended at this stage due its low response rate.73
Intravesical therapy: grade D recommendation (of no possible
recommendation)
Grade D is applicable to a number of intravesical therapies because the data are either
inadequate or conflicting. These drugs include capsaicin, oxybutynin, PPS and botulinum
toxin type A.
Painful bladder syndrome/interstitial cystitis 855
Surgery for interstitial cystitis/painful bladder syndrome
Surgical options should be considered only when all conservative treatment has failed.
The consequences of surgical intervention—such as voiding dysfunction and the
possibility of persistent pain and repeat surgery—should be discussed.
Sacral neuromodulation consists of a two-stage procedure involving temporary or
percutaneous sacral S3 or S4 root stimulation followed by permanent implantation in
responders. Comiter reported a series of 17–25 patients with refractory IC who went
on to receive a permanent sacral nerve stimulator with sustained effect on pain and
frequency.74 Peters and Konstandt75 reported a series of 21 IC patients with permanent
sacral nerve implant; 20 reported moderate or marked improvement at 15 months
follow-up with a one-third reduction in narcotic use.
Sacral nerve modulation is a promising surgical treatment for IC/PBS; however,
more information is needed on long-term follow-up, adverse events and reoperation rates.
Both cystolysis or peripheral denervation surgery and sympathetic/parasympathetic
denervation have been associated with long-term symptom recurrence in addition to
voiding dysfunction.76,77 These procedures are not indicated for IC/PBS.
Bladder augmentation or cystoplasty has been used for refractory IC/PBS for many
years. First reports of ileocystoplasty were very good, but later publications were
variable with good results varying from 2578 up to 100%.79 Cystoplasty with subtrigonal
cystectomy (trigone removal but preservation of the bladder neck) has no advantage
over supratrigonal cystectomy and is associated with complications related to the need
for ureteric reimplantation such as anastomotic leak, stricture or reflux as well as
voiding dysfunction requiring self-catheterization.80
Total cystectomy and urethrectomy is the ultimate option with simple or continent
urinary diversion.81 Lotenfoe82 described best results (88%) in older patients with
reduced capacity !400 mL compared with 20% in patients with capacity O400 mL.
Unfortunately, pelvic pain can persist even after such major surgery.83
SUMMARY
There are many uncertainties regarding PBS/LC; for the present, diagnosis requires
the exclusion of all other causes of bladder discomfort or pain and urinary
frequency. The work-up includes a urinary diary, urine microscopy and culture, and
usually a cystoscopy. If indicated, urine cytology, urodynamics, imaging, bladder
biopsy or laparoscopy may also be required. A symptom questionnaire can be helpful
to monitor progress. The aetiology is most likely multifactorial, with epithelial
dysfunction and neurogenic inflammation being the most studied and proposed
mechanisms. Prevalence estimates are of the order of 0.5% of the female population
in the United States, and the impact on a person’s life is similar to that of many
other chronic pain states. Management options include information regarding the
condition, direction toward self-help strategies, and oral, intravesical and possibly
surgical treatment. Evidence based on randomized trials to date supports the use of
amitryptyline, Elmironw, and intravesical DMSO. However, many treatments
are available—including analgesics, anti-inflammatories, physical therapies
including electrical stimulation, other oral and intravesical instillations, and even
surgery—which are used widely and require evaluation.
856 A. Rosamilia
New developments include the identification of a urinary biomarker, APF, and it is
hoped that this can be useful in the clinical setting worldwide. There is an expansion in
the possibilities for treatment including the use of sacral neuromodulation and newer
treatments such as intravesical botulinum toxin. Hand in hand with this is the slow
process of evaluating both old and new treatments in a rigorous manner, which will
better inform our decision-making and that of our patients.
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