guideline

CUA guideline: Diagnosis and treatment of interstitial cystitis/

bladder pain syndrome

2,5

Consensus panel co-chairs: Ashley Cox, MD, MSc, FRCSC; Nicole Golda, MD, MSc, FRCSC;

Genevieve Nadeau, MD, MSc, FRCSC³

Consensus panel members: J. Curtis Nickel, MD, FRCSC; Lesley Carr, MD, FRCSC;

Jacques Corcos, MD, FRCSC; Joel Teichman, MD, FRCSC

Department of Urology, Dalhousie University, Halifax, NS, Canada; Department of Urology, North

“

The complaint of suprapubic pain, related to bladder ﬁlling

York General Hospital, Toronto, ON, Canada; CHU de Québec, Division of Urology, Quebec, QC,

Canada; Queens University, Kingston, ON, Canada; Department of Surgery, University of Toronto,

Toronto, ON, Canada; McGill University, Montreal, QC, Canada; University of British Columbia,

Vancouver, BC, Canada

accompanied by other symptoms, such as increased daytime

and nighttime frequency, in the absence of proven urinary

infection or other obvious pathology” of the lower urinary

tract. Subsequent to this deﬁnition, some used IC to reﬂect

patients who meet the classic NIDDK criteria and PBS to reﬂect

those with identical symptoms, but who did not undergo formal

hydrodistension or did not meet all of the NIDDK criteria.

Due to similarities with IC/PBS and other chronic pain

syndromes, the European Society for the Study of IC/BPS

Cite as: Can Urol Assoc J 2016;10(5-6):E136-55. http://dx.doi.org/10.5489/cuaj.3786

Published online May 12, 2016.

(

ESSIC) provided a new deﬁnition, which was more descrip-

Methodology

tive of the clinical syndrome and the underlying pathol-

ogy. This expanded term, bladder pain syndrome (BPS),

describes all patients with “chronic pelvic pain, pressure,

or discomfort, perceived to be related to the urinary bladder

accompanied by at least one other urinary symptom: persis-

tent urgency or urinary frequency.” To include all patients

with bladder pain, in 2010, the International Consultation

of Incontinence accepted this revised deﬁnition. In 2009,

the Society for Urodynamics and Female Urology (SUFU)

deﬁned the term IC/BPS as “an unpleasant sensation (pain,

pressure, discomfort) perceived to be related to the urinary

bladder, associated with lower urinary tract symptoms for

more than six weeks duration, in the absence of infection

or other identiﬁable causes.” This is the deﬁnition used by

the American Urological Association (AUA) in the most

recent guidelines on IC/BPS. This is the deﬁnition that will

be referred to for the purpose of this guideline.

The following guidelines were based on MEDLINE and

PUBMED searches of English language literature, in addi-

tion to consensus conference proceedings. Levels of evi-

dence and grades of recommendation were assigned for

each investigation and treatment, as per the modiﬁed Oxford

Centre for Evidence-Based Medicine grading system. Where

the literature was inconsistent or scarce, a consensus expert

opinion was generated to provide treatment guidelines.

Introduction

Terminology

Much confusion regarding the diagnosis of this clinical syn-

drome is due to many changes in deﬁnition and nomencla-

ture since its ﬁrst description in 1887 by Skene. The condi-

The corresponding French terminology is cystite inter-

stitielle, cystalgie à urine claire, or cystalgie abacterienne.

tion classically known as interstitial cystitis (IC) was reserved

for patients with typical cystoscopic ﬁndings, such as glo-

merulations, or the classic bladder wall Hunner’s ulcer.

Epidemiology

Up until 2002, the National Institute for Diabetes and

Digestive and Kidney Diseases (NIDDK) criteria were used

to deﬁne IC. However, it was recognized that the NIDDK

There is wide variation in reported incidence and prevalence

of IC/BPS depending on the criteria used for diagnosis. Current

studiesestimatethatbetween2.7and6.5%ofAmericanwomen

have symptoms consistent with a diagnosis of IC/BPS.⁸The

broad range in incidence depends on whether highly sensitive

or highly speciﬁc deﬁning criteria are used — further highlight-

ing the need for a standardized diagnostic algorithm.

criteria were designed to delineate a homogeneous popula-

tion for research trials and were overly restrictive for use in

routine clinical practice. Therefore, in 2002, the International

Continence Society deﬁned painful bladder syndrome (PBS) as:

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2016 Canadian Urological Association

iC/BPS ꢀꢁꢂꢃꢄꢅꢂꢆꢄ

This translates into approximately 3.3‒7.9 million women

over the age of 18 years in the U.S. affected by symptoms of

IC/BPS. Of these women, however, only 9.7% report being

diagnosed with IC/BPS. In addition, this study found that

women with the diagnosis of IC/BPS were signiﬁcantly more

likely to be uninsured, less likely to be married, and had

more children than controls. Of patients with IC, 94% are

White and the median age is 40 years.

patients with IC/BPS void to relieve pain, whereas OAB

patients void for fear of incontinence. A good response to

antimuscarinics suggests OAB, however, be cautious that this

may confound the diagnosis, as the disorders may coexist.

Despite the absence of urinary infection (UTI) being a

prerequisite at the time of diagnosis, up to 50% of patients

will have a previous history of UTI. It is important to elicit a

comprehensive medical history, including past pelvic surgery

or radiation, medications that can cause cystitis (nonsteroidal

anti-inﬂammatory drugs, cyclophosphamide, and ketamine),

ﬁbromyalgia, depression, sexual dysfunction, autoimmune

diseases, allergies, and other gynecological conditions (vul-

vodynia, endometriosis, dyspareunia). Not only is the past

medical history important for diagnosis, but also because

many of these conditions may co-exist, further stressing the

importance of multidisciplinary management. Table 1 sum-

marizes relevant diseases that may be confused with IC/BPS.

Although the disease can affect both sexes, approximately

0% are female. In addition, the condition is dramatically

under-reported in men. There is signiﬁcant overlap of symp-

toms of IC/BPS to those of chronic prostatitis/chronic pelvic

pain syndrome, with 17% of men found to have symptoms

of both complexes.

Diagnosis of IC/BPS

. History (MANDATORY, all patients, Grade C, Level 4 evidence)

2. Physical examination (MANDATORY, all patients, Grade C, Level

evidence)

A thorough general medical history is of paramount

importance to identify typical diagnostic symptoms of IC/

BPS and other potential mimicking causative conditions.

Unfortunately, delay of diagnosis is common, with an aver-

age time of three to seven years from the time of presentation

The physical exam should include an abdominal and pelvic

exam, with particular focus on looking for masses, blad-

der distension, hernias, and tenderness. A musculoskeletal

and focused neurological exam may also be contributory.

Although there is no physical ﬁnding speciﬁc to patients

with IC/BPS, suprapubic tenderness and bladder neck point

tenderness, in both men and women, is very often noted. In

men, tenderness may be elicited by palpating the perineal

area between the scrotum and anus; in women, palpating

the anterior vaginal wall along the course of the urethra up

to the bladder neck may elicit pain.

2,13

to the general practitioner to diagnosis by a specialist.

The characteristic presentation of IC/BPS includes a

combination of pain, frequency, nocturia, and urgency.

The onset of symptoms may be gradual and/or with only a

single voiding symptom; however, pelvic pain is the main

descriptor of IC/BPS. In early or milder IC/BPS, patients

may not describe frank pain, but rather describe sensations

of “pressure,” “burning,” “sharp,” or “uncomfortable sensa-

tion of having to urinate.” Typically this sensation is felt in

the supra-pubic area, but it can be referred to areas located

in the pelvis, including the urethra, vagina, labia, inguinal

area, perineum, and/or lower abdomen or back.

Peters et al demonstrated an association between IC/

BPS and pelvic ﬂoor dysfunction in a study of 70 women,

Table 1. Summary of differential diagnoses

Disease

How they can be excluded or diagnosed*

The location of pain, relation to bladder ﬁlling/emptying

duration, and a description of the type of pain can all be

useful. Pain that occurs only during voiding is not consistent

with IC/BPS, and vulvar disorders, which cause pain when

urine makes contact with the vulva, should instead be con-

sidered. Symptoms of IC/BPS are generally worse a few days

prior to menses, in contrast to endometriosis, which is worse

during menses. Patients may describe “ﬂares,” or periods

of worsening symptoms, which may be triggered by stress,

intercourse, menses, or diet. Common triggers include cof-

fee, alcohol, citrus fruits, tomatoes, carbonated beverages,

Endometriosis

Pain worse during menses (vs. few days prior)

History of radiation, nonsteroidal anti-

inﬂammatory drugs, cyclophosphamide, and/or

ketamine use

Non-infectious

cystitis

Pain occurs only during voiding, when

urine contacts vulva, and/or painful sexual

intercourse

Vulvar

disorders

Good response to anti-muscarinics, patient

voids to avoid incontinence (vs. to relieve pain);

no signiﬁcant perceived bladder pain

Overactive

bladder

Worse with sitting, positional dependency

suggests a neurogenic or musculoskeletal

process

Pudendal nerve

entrapment

and spicy foods.

The most common presenting symptom, however, is fre-

Prostate-

related pain

Pain during or after ejaculation, pain on

prostate palpation

12,16

quency, estimated to be 92% of one population.

Urgency

Pelvic ﬂoor

disorders

Trigger point, fascial or muscle pain or

tenderness, spasm on palpation

is also prevalent, however, cannot distinguish IC/BPS from

overactive bladder (OAB). Typically, the difference is that

IC/BPS may co-exist.

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Cox ꢄt aꢅ.

with 87% experiencing levator pain during pelvic examina-

5. Laboratory tests: Urinalysis, culture (RECOMMENDED all patients,

Grade C, Level 4 evidence), cytology (OPTIONAL, when indicated,

Grade C, Level 4 evidence)

tion. Palpation of the levator muscles in both sexes, looking

for tenderness, spasm/tight bands, and/or trigger points, is

important for both diagnosis and treatment recommenda-

tions; pelvic ﬂoor or rectal spasms may respond well to

pelvic ﬂoor physiotherapy. Hypo or hypersensitivity of the

perineum, in combination with a weak or absent anal reﬂex,

may suggest pudendal nerve entrapment.

A digital rectal examination (DRE) in men is essential,

noting prostate characteristics along with discrete point ten-

derness of the prostate and pelvic ﬂoor muscles. Prostatic

massage could be considered if pain appears to be more

related to the prostate. Although the diagnosis of IC/BPS

and chronic prostatitis/chronic pelvic pain syndrome in men

may overlap, differentiation between prostate-related and

bladder-related pain generation may help advise treatment

strategies.

A urine dipstick represents the minimum required laboratory

test for IC/BPS. Glucose, leukocytes, hematuria, nitrites, and

osmolality may be simply screened for. Absence of leuko-

cytes does not rule out IC/BPS. If signs of UTI are identi-

ﬁed, a culture and sensitivity is required and possibly test-

ing for Chlamydia trachomatis, Mycoplasma, Ureaplasma,

Corynebacterium species, Candida species, and Mycoplasma

tuberculosis if sterile pyuria persists.

Urine cytology is indicated if microscopic hematuria

is identiﬁed or if there are other risk factors for urothelial

carcinoma present, such as smoking. Hematuria has been

reported in up to 41% of patients with IC/BPS (only 2/60

were gross hematuria) and none were associated with a

life-threatening urological condition.

The female pelvic exam should screen for vulvodynia,

vaginitis, atrophic changes, prolapse, cervical pathology,

and adnexal masses or tenderness. Point tenderness, a mass,

and expression of pus on palpation of the urethra are classic

signs of a urethral diverticulum.

6. Symptom scores (RECOMMENDED, all patients, Grade C, Level 3

evidence)

Symptom scores for IC/BPS are useful to establish base-

line symptom severity and to track response to therapeu-

tic intervention. Five self-administered symptom scores for

IC/BPS have been assessed to variable extents, including:

the Interstitial Cystitis Symptom Index (ICSI); the Interstitial

. Ultrasound/pelvic imaging (OPTIONAL, select patients, Grade C,

Level 4 evidence)

Abdominal or pelvic ultrasonography, or other imaging

modalities, may be useful when alternative clinical condi-

tions are questioned, but are expected to be normal if IC/

BPS is the only diagnosis. The appropriate abdominal/pelvic

imaging should be completed for patients with microscopic

Cystitis Problem Index (ICPI); The Wisconsin Interstitial

Cystitis scale (UW-IC scale); the Pain, Urgency, Frequency

score (PUF score); and the Bladder Pain/IC Symptom Score

(BPIC-SS).

or macroscopic hematuria.

The UW-IC scale, although well-validated and compre-

hensive, has not been adopted in clinical practice. The com-

bined ICSI/ICPI (also known as the O’Leary Sant Symptom

and Problem Index) consist of a four-item symptom and

problem index focusing on urgency, frequency, nocturia,

and pain, over the past month. It met standards for variabil-

ity, test retest reliability, internal consistency, and construct

Level 3 evidence) +/- post-void residual (OPTIONAL, when indicated,

Grade C, Level 4 evidence)

. Frequency volume chart (RECOMMENDED all patients, Grade C,

A frequency volume chart is advocated to differentiate poly-

uria from the classic small voided volumes expected with IC/

BPS. In a study of 47 adult women with IC/BPS, the average

voided volume was less than 100mL. On average, IC/BPS

patients void a volume of urine ranging from 86‒174mL,

compared to an average of 289 mL in an asymptomatic

woman. The average number of daytime voids ranges from

3,27

Further studies have

validity, as well as responsiveness.

re-evaluated the instrument in larger series of IC patients.²⁷^-²⁹

The PUF score has not been subject to as extensive a

validation process, but has additional items related to pelvic

pain and dyspareunia. Kushner et al examined the ability of

the PUF score and the ICSI/ICPI to distinguish IC from other

urinary tract pathologies in a group of 220 clinic patients.

All three scales did distinguish IC, and the PUF score (13 or

0,21

7‒25 compared to six.

A voiding diary also helps to determine the severity of the

storage symptoms and can be used for positive reinforcement

related to behavioural and pharmacological intervention.

When a history of poor emptying is obtained and/or the

bladder is palpable on exam, measurement of a post-void

residual is recommended.

greater) did so more efﬁciently.

The BPIC-SS was developed to address a perceived

need to reliably identify IC/BPS patients with moderate to

severe pain, for inclusion in clinical trials. Through inter-

viewing patients in various countries, the most common

symptoms described include bladder pain, persistent urge

to urinate, and high urinary frequency. After analyzing

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iC/BPS ꢀꢁꢂꢃꢄꢅꢂꢆꢄ

patients’ responses to questionnaires and testing the ques-

tions’ validity, the researchers came up with eight items that

had strong sensitivity and speciﬁcity. The authors concluded

that patients with a BPIC-SS score of 19 or greater should

8. Potassium sensitivity test (NOT RECOMMENDED, Grade C, Level 3

evidence)

A potassium chloride bladder permeability test was based

on the assumption that a “dysfunctional epithelium” (glycos-

be included in clinical trials.

Clinicians must keep in mind that none of the surveys

have sufﬁcient speciﬁcity to serve as a sole diagnostic indica-

tor, but rather can be used as tools to assist with diagnosis.

Based on current literature, the use of the ICSI, ICPI (or its

updated version, the BPIC-SS) and/or the PUF score to grade

severity of symptoms and follow response to therapeutic

intervention in patients with IC/BPS is recommended.

aminoglycan [GAG] layer) allowed potassium ions to cross

the abnormally permeable urothelium, depolarize nerves and

muscles, and result in pain. The technique comparing subjec-

tive pain or urgency responses to intravesically instilled 0.4

M potassium chloride vs. water was described by Parsons et

al, but has been modiﬁed by other authors, including vari-

ants such as the comparative cystometrogram test.³⁸

This test could potentially direct therapy if a positive

potassium sensitivity test correlated well with a favourable

response to agents that attempt to replenish the GAG layer,

. Cystoscopy (RECOMMENDED, all patients, Grade C, Level 3 evidence)

9,40

Cystoscopy performed alone, without hydrodistension, is

expected to be normal (except for discomfort and reduced

as has been suggested in two small series.

However, in

a phase 4 dosing study for pentosan polysulfate (PPS), an

epithelial-directed therapy, no difference in response to PPS

“

functional” bladder capacity) in the majority of patients

41,42

with IC/BPS. Hunner’s ulcers or lesions can be found with

or without hydrodistension under anesthetic in approxi-

mately 16%. Hunner’s lesions are associated with more

severe symptoms and reduced urodynamic and anesthetic

was observed.

The sensitivity and speciﬁcity of the potassium sensitiv-

ity test (69.5% and 50%) were found by Chambers et al to

be poor, adding no additional use over history and cystos-

2,33

capacity.

The classic ﬁndings of terminal hematuria and

copy. Others have found that the potassium sensitivity test

glomerulations are reliably identiﬁed only after a formal

hydrodistension under anesthetic. However, evidence shows

that glomerulations are neither sensitive nor speciﬁc for IC.

As such, the purpose of cystoscopy alone should only

be viewed as a tool to rule out bladder cancer/carcinoma

in situ, to identify Hunner’s lesions that reﬂect severe dis-

ease or even different disease (information that may impact

treatment decisions), to determine effect on pelvic pain dur-

ing bladder ﬁlling and emptying, to objectively evaluate

did not correlate with either cystoscopic ﬁndings or bladder

capacity on urodynamics. Further confounding the diag-

nosis in symptomatic patients, 25% with OAB (almost all

with radiation and IC) and 50‒84% with chronic pelvic pain

7,44

In asymptomatic men, a

syndrome (CPPS) test positive.

36% false-positive rate was found.

At this point, the use of the potassium sensitivity test has

not been widely validated and the ability of this test to pre-

dict efﬁcacy with GAG-replenishing therapies is not reliable.

It is a costly and painful test, with patients experiencing pain

both during and after the procedure. For these reasons, the

potassium sensitivity test is no longer recommended as a

standard evaluation for IC/BPS.

“functional” bladder capacity, to facilitate appropriate pelvic

examination, and to reassure the patient.

The incidence of bladder cancer presenting with symp-

toms compatible with IC/BPS is rare. Tissot et al found

% of 600 patients referred with a diagnosis of IC/BPS had

bladder cancer. Most (5/6) with cancer were older than 60

and all except two had microscopic hematuria or positive

cytology.

9. Intravesical anesthetic bladder challenge (OPTIONAL, select patients,

Grade C, Level 3 evidence)

Cystoscopy may be considered optional in a young

woman with symptoms of IC/BPS and no risk factors for

bladder cancer or other pelvic conditions. This may enable

non-urologist physicians to initiate treatment earlier in the

stage of disease, when it is potentially more effective. It is

reasonable to recommend cystoscopy to assist in making a

diagnosis before initiating therapy, especially if there is any

indication on history, physical examination, urinalysis, or

cytology suggesting that other diseases need to be ruled out.

Identiﬁcation of Hunner’s lesions and pelvic ﬂoor muscle

dysfunction (pelvic ﬂoor examination is easily added to a

cystoscopic examination) will direct treatment strategies.

An anesthetic challenge test, such as an alkalized lidocaine

test, instills 10‒20 mL of an anesthetic mixture (in this case,

200 mg lidocaine mixed with 8.4% sodium bicarbonate)

into an empty bladder. This ﬂuid is held for 10‒15 min-

utes and then drained by catheter. This test can easily be

performed after cystoscopy and can provide both relief to

the patient, as well as provide diagnostic information and

guide future therapy. A patient experiencing relief from

the instillation would provide more certainty that the pain

is originating from the bladder. Resolution of the pain by

intravesical local anesthesia can be both diagnostic and

therapeutic.

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Cox ꢄt aꢅ.

To differentiate between the pain originating from urinary

bladder from that of other pelvic organs, Taneja et al treated

2 women with pelvic pain with 20 mL of 2% intravesical

merulations in 45% of 20 normal women who consented

to undergo HD at the time of tubal ligation.

As the literature is conﬂicting regarding its utility, HD for

diagnostic purposes may be appropriate in certain situations.

These may include: when a patient is unable to tolerate

cystoscopy under local anesthetic and is having a general

anesthetic; when a patient has failed other treatment options

and HD to assess disease severity may contribute informa-

tion to the diagnosis; and when assessing a patient for clini-

cal trial eligibility.

lidocaine solution. Sixty-eight percent experienced a reduc-

tion of pain by 50% or greater. All non-responders were

subsequently diagnosed with non-bladder pathology causing

their pelvic pain.

With no risk of symptom ﬂare, the anesthetic bladder

challenge may be considered when there is uncertainty as

to whether the pain is originating from the bladder.

0. Hydrodistension (OPTIONAL, select patients, Grade C, Level 3

11. Urodynamics (UDS) (NOT RECOMMENDED in the routine evaluation

of IC/BPS, Grade C, Level 3 evidence)

evidence)

Hydrodistension (HD) under general anesthetic allows for

stratiﬁcation of patients into those with more classic disease

associated with ulcers and glomerulations from those with

no obvious mucosal abnormalities. The technique of diag-

nostic HD generally involves gravity ﬁlling of the bladder at

Filling cystometrogram (CMG) has been advocated by some

,52

for the diagnosis of IC/BPS.

Certainly there is overlap

between the conditions of OAB-dry and symptoms of IC/

BPS, and the ﬁnding of detrusor overactivity (DO) on ﬁlling

CMG may lead the clinician to initiate therapy with anti-

cholinergic agents.

0‒100 cmH 0 for a minimum of two minutes, performed

under general or regional anesthetic. Maximum anesthetic

capacity is determined whereby the inﬂow backs up in the

drip chamber or leakage occurs per urethra despite com-

pression against the cystoscope. While severely reduced

anesthetic bladder capacities (<400 mL) do correlate with

According to the NIDDK criteria, the ﬁnding of a capacity

>350 mL, ﬁrst sensation of having to void >150 mL, or the

presence of DO are exclusionary for a diagnosis of classic

IC. However, it is recognized that approximately 15% of

patients diagnosed with IC/BPS will demonstrate DO and,

thus, the coexistence of urge incontinence or DO should not

preclude a diagnosis of IC/BPS. Other ﬁndings on UDS from

the IC database study were a reduced ﬁrst sensation to void

(mean 81 ± 64 mL) and maximum sensory capacity (mean

198 ± 107 mL). While these UDS parameters do correlate

well with frequency, nocturia, and urgency, they have not

been well-correlated to global pain, cystoscopic ﬁndings

at HD (other than the presence of a Hunner’s lesions), or

results of therapeutic intervention.

pain, more than 50% of patients with IC/BPS show capaci-

ties more than 800 mL.

The presence of terminal hematuria upon draining the

infusion ﬂuid and the appearance of petechial submuco-

sal hemorrhages (glomerulations) has been suggested to be

characteristic of IC/BPS and is one of the prerequisite ﬁnd-

ings in the NIDDK criteria. Glomerulation severity has also

been graded.A possible relationship between glomerulations

and angiogenic growth factors has been found, suggesting

that these growth factors may have an important role in the

Bladder capacity may be assessed less invasively and

more cost effectively by means of a frequency volume chart

with self-measurement of voided volumes; this has been

shown to correlate with maximum cystometric capacity and

ﬁrst sensation of having to void in patients with IC/BPS.³³^,⁵³If

a cystoscopy under local anesthetic is planned, a functional

bladder capacity and its relation to the patient’s pain can be

assessed with patient awake.

Pressure ﬂow studies, with or without electromyography,

may be useful in some situations where there are coexistent

voiding symptoms with suspicion of bladder outlet obstruc-

tion or voiding dysfunction due to high-tone pelvic ﬂoor

dysfunction.

pathogenesis of IC/BPS.

Despite the initial adoption of the HD ﬁndings of glo-

merulations as a criteria for the diagnosis of IC/BPS by the

National Institutes of Health (NIH), approximately eight

percent with a diagnosis of IC/BPS do not show glomerula-

tions.¹The severity of glomerulations was found to cor-

relate poorly with symptoms and with histological evidence

9,32

of inﬂammation. In contrast, Lamale et al found a strong

correlation with pain and HD ﬁndings. Their series was

small (12 patients), including perhaps more severe patients,

as evidenced by a mean anesthetic bladder capacity of 604

mL, but represented an untreated cohort where they postu-

lated there were no confounders of treatment allowing a true

correlation to be identiﬁed. In another series of 84 patients,

cystoscopy with HD provided little useful information above

Overall, UDS studies are not recommended in the stan-

dard diagnostic evaluation of a patient suspected of having

IC/BPS.

and beyond the history and physical examination ﬁndings.

Additionally, the speciﬁcity of glomerulations was brought

into question when Waxman et al found characteristic glo-

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iC/BPS ꢀꢁꢂꢃꢄꢅꢂꢆꢄ

2. Bladder biopsy (NOT RECOMMENDED in the routine evaluation of

approach to the treatment of the IC/BPS patient, recognizing

that following a single algorithm is not currently appropriate

for the treatment of IC/BPS.

IC/BPS, Grade C, Level 3 evidence)

There are no speciﬁc features found on bladder biopsy to

conﬁrm a diagnosis of IC/BPS. Findings related to chronic

inﬂammation are not speciﬁc, overlapping with other eti-

ologies, and they correlate poorly to cystoscopic ﬁndings

A. Conservative therapies

1. Patient education (RECOMMENDED in all patients, Grade A) and dietary

modiﬁcations (RECOMMENDED in all patients, Grade B)

observed during hydrodistension. Between 30% and

3%⁵⁴of patients with a clinical diagnosis of IC/BPS may

have normal histology.

Based on best evidence principles, initial management

should focus on conservative strategies. These include

patient education, diet and lifestyle changes, and bladder

training for all patients. Signiﬁcant improvement in 45‒50%

of patients may be expected with only advice and support,

as demonstrated in two well-designed, randomized trials.⁵⁷^,⁵⁸

Bosch et al have developed a practical IC/BPS standard

advice checklist to insure all healthcare topics are discussed

However, correlations have been found with speciﬁc

types of pathological ﬁndings and symptoms. Mucosal denu-

dation (i.e., Hunner’s lesions) and submucosal hemorrhage

was highly associated with pain; mast cell count on tryptase

stain, complete loss of urothelium, granulation tissue in the

lamina propria, and vascular density were associated with

nocturia in a multivariate analysis of patients from the IC

database. The importance of mast cells has been contro-

versial. Dundore et al found no signiﬁcant difference in mast

cell counts in the lamina propria or detrusor on Giemsa-

stained sections between IC/BPS patients compared to con-

with the patient.

Up to 90% of patients have exacerbations of their symp-

5,59

toms after ingesting certain foods or drinks.

Based on

survey studies, common food triggers include coffee, tea,

citrus fruits, carbonated and alcoholic beverages, bananas,

tomatoes, spicy foods, artiﬁcial sweeteners, vitamin C, and

trols. Because an association between speciﬁc pathological

features and symptoms may exist, it is reasonable to include

a bladder biopsy and pathological classiﬁcation in future

research studies.

15,59,60

wheat products.

Only one placebo-controlled, random-

ized, controlled trial (RCT) on the effect of diet in IC/BPS

has been published, which failed to report any signiﬁcant

When a biopsy is indicated for research or to rule out

carcinoma in situ if suspected by a focal lesion or abnormal

cytology, this should be performed from the most abnormal

appearing area and should follow HD to avoid increased

risk of bladder perforation.

Routine bladder biopsies are not recommended for the

diagnosis of IC/BPS, but may be considered in research trials

or to rule out other speciﬁc diagnosis, such as carcinoma in

situ, when clinically indicated.

association. Dietary modiﬁcations, such as a steady intake

of water to dilute urine and reduce constipation, and an

elimination diet trial have been advocated. No standardized

protocol exists, but common practice is to instruct patients

to avoid all foods on the list for a period varying from one

week to three months and then methodically re-introduce

one item at a time, with a waiting period of three days to

0,62

identify potential offenders.

. Bladder training (RECOMMENDED in motivated patients, Grade B)

Treatment of IC/BPS

The purpose of this guideline is to aid clinicians in the treat-

ment of patients diagnosed with IC/BPS. The main goals of

treatment should be maximizing symptomatic control and

quality of life while avoiding adverse events and treatment

complications, recognizing that there is no curative treat-

ment for this condition. Goals of therapy must be realistic

and mutually agreed upon between the physician and the

patient. IC/BPS can progress to include symptoms outside

the bladder, and identiﬁcation and treatment of associated

conditions with early referral to other specialists for multi-

disciplinary management is of paramount importance.

Treatment should be individualized to each patient, with

a focus on the speciﬁc symptom complex or phenotype of

that patient. The application of an algorithmic approach

for the treatment of all patients may lead to unsuccessful

outcomes. Fig. 1 is provided to aid the clinician with an

Bladder training can be initiated with other lifestyle interven-

tions. The goal is to reduce voiding frequency, potentially

increase bladder capacity, and reduce the need to void in

response to urgency or pain. Timed voiding or scheduled

voiding involves urinating at regular set intervals that dis-

regard the normal urge to void. With the urge suppression

strategy, patients are instructed to delay urination by grad-

ually increasing the interval from when the urge is felt to

when they actually void. Distraction (counting backwards)

or relaxation (deep breathing) techniques may be used. The

most appropriate protocol is not clear at this point. These

are quite innocuous, but time-consuming techniques that

require a highly motivated patient. The effectiveness of

such behaviour modiﬁcation program is supported by pro-

spective data showing symptom improvement for 45‒88%

of the cohorts.

CUAJ • May-June 2016 • Volume 10, Issues 5-6

E141

Cox ꢄt aꢅ.

IC/BPS

All patients:

Patient education

Dietary modifications

Sexual counselling

Further treatment options selected based on:

Symptom phenotype

Degree of quality of life impairment

Patient preference

Availability/access

Adverse event profile

)

SYMPTOM PHENOTYPES (adopted from Nickel et al. 2014

Organ-specific*

Urinary*

Infectious

Antimicrobials Gabapentanoids

Hydroxyzine

Neurologic/systemic Tenderness

Psychosocial

Non-Hunner’s Hunner’s

Pelvic floor

physiotherapy,

massage,

Bladder training

Anticholinergics

Intravesical

agents (Heparin,

DMSO, HA, CS,

PPS, oxybutynin)

Hydrodistension

Botulinum toxin A

Stress management

and

psychological support

Amitriptyline

Cimetidine

Hydroxyzine

PPS

CyA

Endoscopic

(Fulguration,

laser, resection,

Cimetidine

Sacral neuromodulation

acupuncture,

trigger point

injections

Quercetin

Intravesical agents Novel therapies

steroid injection)

(DMSO, Hep, HA,

CS, alkalinized

lidocaine, PPS)

Hydrodistension

Botulinum Toxin A

Radical surgery

(hyperbaric oxygen)

Radical surgery

Sacral neuromodulation

Radical surgery

*Almost all patients will have these phenotypes.

Fig. 1. Proposed management paradigm for the treatment of interstitial cystitis/ bladder pain syndrome (IC/BPS); Note: Not intended to be a uniform algorithm,

treatment must be individualized; CS: chondroitin sulfate; DMSO: dimethysulfoxide; HA: hyaluronic acid; PPS: pentosan polysulfate.

. Stress management techniques and psychological support (RECOMMENDED

might include counselling, physiotherapy, complementary

medications, pharmacologic treatments (hormonal and non-

hormonal), or even surgical options. Detailed management

strategies for FSD are beyond the scope of these guidelines.

in patients identiﬁed with suffering from stress or psychological dysfunction,

Grade B)

Because of its chronic nature, the psychological impact of

IC/BPS on the patient’s quality of life should be speciﬁc-

ally addressed as an integral part of treatment. A signiﬁcant

number of patients with IC/BPS have reported experien-

cing depression, anxiety, distress, and various degrees of

Guideline: Based on a large body of literature and the lack of

side effects, conservative therapies, including patient educa-

tion, dietary modiﬁcations, bladder retraining,and stress man-

agement are recommended as ﬁrst-line treatment for IC/BPS.

disability. The physician-patient relationship should be

emotionally supportive. As stress is known to exacerbate

B. Physical therapy techniques

symptoms, stress-reduction strategies, such as exercising,

bathing, reducing working hours, meditation, yoga, and

1. Physiotherapy and massage (RECOMMENDED for patients with pelvic ﬂoor

dysfunction, Grade A)

2,69

can be beneﬁcial.

guided imagery

Sexual dysfunction should be addressed, as it may worsen

IC/BPS symptoms. However, treatment of female sexual

dysfunction (FSD) is challenging. Management strategies

Many IC/BPS patients have high-tone pelvic ﬂoor muscle

dysfunction (PFD). Those patients who have tenderness on

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iC/BPS ꢀꢁꢂꢃꢄꢅꢂꢆꢄ

Table 2. IC/BPS treatments

physical exam might beneﬁt from various physical therapy

techniques, including: physiotherapy (± biofeedback); myo-

fascial tender points release; or intravaginal Thiele massage.

Various techniques have been described that involve skillful,

hands-on maneuvers directed toward relaxation, elongation,

stretching, and massaging of tightened muscles. Physical

therapists with expertise in pelvic ﬂoor muscle relaxation

should be involved. Evidence supporting this management

option in IC/BPS is more robust, with RCTs and prospect-

ive case series reporting moderate or marked improvement

Medication

Amitriptyline

Cimetidine

Dosage

25–75 mg po qhs

400 mg po bid

10–50 mg po qhs

Hydroxyzine

Oral pentosan

polysulfate (PPS)

100 mg po tid

Intravesical pentosan 200 mg PPS mixed with 30 mL sterile

polysulfate

Cyclosporine A

Gabapentin

Quercetin

buffered NS retained for 30–60 minutes

2–3 mg/kg divided bid

300–2100 mg po divided tid

500 mg po bid

2-75

of symptoms in 50‒62% of patients

and an additional

in one study.

1% of patients having complete resolution of symptoms

Intravesical

dimethysulfoxide

50 mL solution of 50% DMSO (Rimso-50)

for 30–60 minutes, once weekly for six

weeks; monthly maintenance prn

(DMSO)

. Acupuncture (OPTION in motivated patients, Grade B)

mL NS for 30–60 minutes, weekly for 4–6

0 000–40 000 IU of heparin diluted in 10

Intravesical heparin

weeks

Insertion of ﬁne needles into speciﬁc points of the body

appears to be an effective treatment to alleviate IC/BPS

symptoms, according to a systematic review of 23 RCTs.

However, it was not possible to determine if efﬁcacy was

beyond placebo effect due to inconsistencies in protocols

across studies. It remains a relatively non-invasive modality

that might be used as an adjunct to allopathic medicine.

40 mg/50 mL vial (Cystistat ), weekly

Intravesical

hyaluronic acid

instillations for 4–12 treatments, then

monthly until symptoms resolve

Intravesical

chondroitin sulfate

20 mL vial of 2.0% CS (Uracyst ), retained

30 minutes, weekly for six weeks, then

monthly until symptoms resolve

(CS)

200 mg lidocaine, alkalinized with a

Intravesical

sequential instillation of 8.4% NaHCO3

alkalinized lidocaine

solution, to a ﬁnal volume of 10 mL

3. Trigger point injections (OPTION for patients with trigger point pain, Grade D)

(Urolieve , PSD597)

0 mg oxybutynin (crushed tablets)

Injections of pelvic ﬂoor trigger points using a 22 or 25

gauge needle with 1‒5 mL of a local anesthetic, with or

without glucocorticoid, has also been described, but only

anecdotal evidence suggests it may be effective in the treat-

Intravesical

oxybutynin

diluted in 500 mL NS instilled until ﬁrst

sensation; weekly for six weeks, then

monthly for three months

Therapeutic HD under spinal or general

anesthesia, where the bladder is ﬁlled

with NS by gravity drainage at a

pressure of 80 cm H2O to its capacity

and distension is maintained for two to

no more than 10 minutes; the bladder

is drained at the end and capacity is

measured

ment of IC/BPS.

Guideline: Based on Level 1 evidence, pelvic ꢀoor physio-

therapy can be recommended for patients identiﬁed with

PFD, while some weak Level 2 evidence suggests that mas-

sage techniques, acupuncture, and trigger point injections

are options for IC/BPS patients with pelvic ꢀoor tenderness.

Hydrodistension (HD)

Triamcinolone

1 mL vial of triamcinolone (40 mg/mL)

steroid) injection for diluted in 9 mL NS (total 10mL), to be

(

Hunner’s lesions

injected in aliquots of 1 mL

C. Medical therapies

Botulinum toxin A

100U suburothelial injection ± trigone

bid: twice daily; IC/BPS: interstitial cystitis/ bladder pain syndrome; NaHCO3: sodium

bicarbonate; NS: normal saline; po: orally; qhs: every night at bedtime; tid: three times daily.

The only two treatments officially approved by Health

Canada for IC/BPS are oral PPS and intravesical dimethy-

sulfoxide (DMSO). All the other treatments discussed are

off-label uses. Table 2 provides a summary of the suggested

dosages for each treatment option discussed.

placebo.⁵⁷^,⁸⁰Van Ophoven et al⁸⁰reported a statistically

signiﬁcant improvement in O’Leary-Sant IC symptom and

problem index scores from baseline in patients treated with

amitriptyline vs. placebo (p=0.05). Overall, 63% vs. 4%

of the treatment group vs. placebo group were considered

signiﬁcantly improved at four months followup. Side effects

were common, with a reported rate of 92% vs. 21% in the

treatment vs. placebo groups, respectively. Most recently,

C1. Oral therapies

. Amitriptyline (OPTION, Grade B)

Observational studies have shown an improvement in

Foster et al reported a statistically signiﬁcant improvement

in global response assessment in treatment-naïve patients

treated with amitriptyline vs. placebo, but only at a dose

8,79

Two

symptoms of IC/BPS with the use of amitriptyline.

RCTs have demonstrated a benefit of amitriptyline over

CUAJ • May-June 2016 • Volume 10, Issues 5-6

E143

Cox ꢄt aꢅ.

of 50 mg or higher (66% vs. 47%, p=0.01). Based on the

intention-to-treat analysis, there was no signiﬁcant differ-

ence between groups (55% vs. 45%, p=0.12). Of note, less

than 50% of patients tolerated a dose of 50 mg and both

groups received standardized education and behavioural

modiﬁcation counselling, which may have contributed to

the high response rate in the placebo group. Side effects

were common, seen in 88% and 72% of the treatment and

placebo groups, respectively.

including data on 448 patients has summarized the ﬁndings

of four of these trials. The primary outcome of success

was deﬁned as a 50% or more improvement in symptoms,

including pain, urgency, frequency, and nocturia. The

overall success rate of PPS was: pain 37%; urgency 28%;

frequency 54%; and nocturia 48%. All were signiﬁcantly

improved over placebo, with the exception of nocturia.

Observational trials have assessed the long-term beneﬁt of

PPS with variable results. At a mean followup of 22 months,

Guideline: Based on Level 1 and 2 evidence, amitriptyline

is an option for the treatment of IC/BPS after conservative

therapies have failed.

Alzharani et al found that 54.2% of patients treated with

PPS reported a >50% improvement in symptoms, whereas

Jepsen et al reported only 6.2‒18.7% of patients main-

tained a beneﬁt after 18 months of treatment.

. Cimetidine (OPTION, Grade B)

Nickel et al studied the effect of dose escalation of PPS

in a RCT that was not placebo-controlled. They compared

300 mg vs. 600 mg vs. 900 mg of PPS per day in 380 sub-

jects. At 32 weeks, 49.6%, 49.6%, and 45.2% of patients

reported a greater than 50% improvement in symptoms,

respectively. There was no signiﬁcant difference between

dosages, but importantly, it was found that success rates

improved with longer duration of therapy. Common side

effects included: diarrhea (25%); headache (18.2%); nau-

sea (15%); pelvic pain (13%); abdominal pain (13%); and

alopecia (5%). Twenty-two percent of patients discontinued

treatment due to side effects.

Most recently, Nickel et al reported the results of 368

patients randomized to placebo vs. PPS 100 mg once daily

vs. PPS 100 mg three time daily for 24 weeks. The primary

endpoint was deﬁned as a 30% or greater reduction in ICSI

total score; 40.7%, 39.8%, and 42.6% of the placebo group,

PPS 100 mg once daily, and PPS 100 mg three time daily,

respectively, met the primary endpoint with no signiﬁcant

difference between groups.

1,82

and one placebo-

Two very small observational trials

controlled RCT have shown an improvement in symptoms

of IC/BPS with cimetidine at various dosages. Thilagarajah

et al randomized 36 patients to cimetidine 400 mg orally

twice daily vs. placebo and reported a signiﬁcant improve-

ment in symptoms in the cimetidine vs. placebo groups,

respectively. Suprapubic pain and nocturia were found to

be the most improved with cimetidine. No side effects were

reported.

Guideline: Based on scarce Level 1, 2, and 3 evidence,

cimetidine 400 mg orally twice daily is an option for the

treatment of IC/BPS after conservative therapies have

failed.

. Hydroxyzine (OPTION for patients with allergic phenotype, Grade C)

One observational study reported a 40% reduction in symp-

toms scores and pain compared to baseline. One RCT

compared placebo vs. hydroxyzine alone vs. PPS alone

vs. a combination of hydroxyzine and PPS. There was no

signiﬁcant difference in symptom improvement between

the hydroxyzine alone and placebo groups (23% vs. 13%).

However, the addition of hydroxyzine to PPS did improve

Guideline: Based on new conꢀicting Level 1 and 2 evidence,

PPS may be offered as an option for the treatment of IC/

BPS; however, expected beneﬁts are predicted to be mar-

ginal in the majority of patients.

the rate of success compared to PPS alone (40% vs. 28%).

5. Cyclosporine A (CyA) (OPTION as a last resort in patients with inꢀammation,

Grade C)

Side effects were common in all groups and primarily con-

sisted of constitutional symptoms, gastrointestinal symptoms,

and pain.

Guideline: There are few studies and conꢀicting results

for the use of hydroxyzine for the treatment of IC/BPS.

Observational studies are encouraging and the medication

appears safe. Based on Level 3 evidence, hydroxazine may

be considered an option (perhaps in patients with an allergy

history) after conservative measures have failed.

Multiple observational trials of small sample sizes suggest

a positive treatment effect of CyA for IC/BPS.⁹⁵^-⁹⁸Patients

with Hunner’s lesions seem to derive a better response than

those without Hunner’s lesions (68% vs. 30%, respective-

ly). A single RCT comparing CyA to PPS showed a signiﬁ-

cant improvement in IC/BPS symptoms with CyA treatment

compared to PPS (59% vs. 13%, p<0.001). This trial was

not placebo-controlled and side effects occurred in 94% of

CyA patients and 56% of PPS patients.

. Pentosan polysulfate (PPS) (OPTION, Grade D)

Following the theory that IC/BPS may be caused by an

autoimmune/inﬂammatory reaction, mycophenolate mofetil

(MMF) has also been studied in a placebo-controlled RCT.

Multiple placebo-controlled RCTs exist comparing PPS to

placebo

5-89

reporting contradictory results. A meta-analysis

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iC/BPS ꢀꢁꢂꢃꢄꢅꢂꢆꢄ

Unfortunately, the study was halted prematurely, but the

interim results on 56 patients showed no difference in

response between treatment and placebo groups (15% vs.

Two RCTs compared DMSO to Bacillus Calmette-Guerin

(BCG), one favouring DMSO (30% response rate compared

to 10% for BCG, p<0.05) and one concluding no beneﬁt

112

6%, p=0.67).

with either regimen. Finally, two other RCTs compared

Guideline: Based on Level 3 evidence, CyA may be consid-

ered a treatment option for IC/BPS. Close patient moni-

toring, including blood pressure, Cr and CyA levels are

necessary. Due to the potential for serious side effects, CyA

should be reserved for severe patients refractory to other

treatment options.

DMSO to chondroitin sulfate (CS), or to CS plus hyaluronic

acid, with signiﬁcantly better performances of CS groups

over DMSO for both objective and subjective outcomes

13,114

(14‒53 % for DMSO against 73% for GAG, p<0.05).

Other observational studies have described use of DMSO in

combination with corticoids, bicarbonate, or heparin.⁵²^,¹¹⁵^-¹¹⁷

Overall, DMSO has a favourable safety proﬁle. Typical

side effects include halitosis (garlic-like breath, as it is elim-

inated through the lungs) and potential ﬂare-up after the ﬁrst

instillation, which usually improves after the second one.¹¹⁸

It is administered as a 50 mL solution of 50% DMSO with

a dwell time of 30‒60 minutes, once weekly for six weeks.

Monthly maintenance doses may be considered.¹¹⁹

Guideline: Based on Level 2 evidence, DMSO is a thera-

peutic option for IC/BPS.

. Gabapentinoids (OPTION in patients with neuropathic pain, Grade C)

Based on success in treating other neuropathic pain condi-

tions, gabapentin has been used for the treatment of IC/BPS.

01,102

Only two case reports

and three small observational

03-105

The only trial that used gabapentin alone

trials exist

found a 48% improvement in pelvic pain.

Guideline: Based on scarce Level 3 evidence, gabapentin

may be an option in the treatment of IC/BPS refractory to

conservative therapies.

2. Heparin (RECOMMENDED in select patients, Grade C)

. Quercetin (OPTION, Grade C)

Heparin, as a GAG analogue, may be instilled intravesically

with virtually no systemic absorption. It may be used alone

by mixing 20 000 to 40 000 IU of heparin diluted in 10 mL

NS on a weekly basis for four to six weeks and retained for

30‒60 minutes. From two prospective, uncontrolled studies,

Quercetin has been used to treat male chronic pelvic pain

118

syndrome with success. One small observational trial has

found a symptomatic improvement in 19/22 patients with

IC/BPS after four weeks of Cysta-Q complex (equivalent to

quercetin 500 mg orally twice daily).

Guideline: Based on scarce Level 3 evidence, quercetin may

be an option in the treatment of IC/BPS.

Table 3. Intravesical cocktails for IC/BPS

Ingredients

References

0 mL 0.5% bupivacaine, 20 mL 2% lidocaine jelly,

0 mg triamcinolone, 10–20 000 IU heparin, 80 mg

Moldwin²¹⁷

C2. Intravesical therapies

gentamicin

heparin

mL 2% lidocaine, 4 mL 8.4% NaHCO3, 20 000 IU

Welk and

Teichman¹²³

Multiple agents have been studied, alone or in combination,

for instillation into the bladder for treatment of IC/BPS. Table

50 mL 0.5% bupivacaine, 50 mL 8.4% NaHCO3

(8.4%), 100 mg hydrocortisone, 10 000 IU heparin,

Lukban et

summarizes various cocktails described in the literature.

218

al.

80 mg gentamicin

Treatments may be administered in the clinic setting or at

home in some cases. Common side effects include tem-

porary discomfort, hematuria, and UTI. The use of an 8 Fr

pediatric feeding tube combined with intraurethral lidocaine

40 mL 0.5% bupivacaine, 10 000 IU heparin, 2 mL

_M_i_s_h_r_a219

dexamethasone, 20 mL NaHCO3

0 mL DMSO, 44 mEq (1 amp) NaHCO3, 10 mg

triamcinolone, 20 000 IU heparin

Hanno²²⁰

may help to improve tolerance to the procedure.

00 mg pentosan polysulfate sodium, 10 mL

% lidocaine, 10 mL 4.2% NaHCO3; add to this

Bade²¹⁹

. Dimethylsulfoxide (DMSO) (RECOMMENDED in select patients, Grade B)

sufﬁcient NaCl 0.9% to reach a total volume of 60

DMSO is an organic solvent with anti-inﬂammatory and

analgesic properties. Theoretically, it may cause dissolution

of collagen that could potentially cause bladder ﬁbrosis if

40 000 IU heparin, 8 mL 1% (80 mg) or 2%

lidocaine (160 mg), 3 mL 8.4% NaHCO3 suspended Parsons¹²⁰

in a volume of 15 mL total ﬂuid

50 mL DMSO, 100 mg hydrocortisone, 10 mL 0.5%

Payne²¹⁹

used on a long-term basis. The strongest data supporting

its use come from ﬁve small RCTs. Perez-Marrero et al com-

pared DMSO to normal saline (NS) and showed a 93%

objective improvement and 53% subjective improvement

bupivacaine, 5 mL NaHCO3 (Optional: add heparin)

Nickel et

mL 4% lidocaine followed by 5 mL 8.4% NaHCO3

150

al.

Adapted from Erickson DR;221 DMSO: dimethysulfoxide; IC/BPS: interstitial cystitis/ bladder

pain syndrome; NaCl: sodium chloride; NaHCO : sodium bicarbonate.

compared to 35% and 18%, respectively, in controls.

CUAJ • May-June 2016 • Volume 10, Issues 5-6

E145

Cox ꢄt aꢅ.

heparin as the sole instillation component provided symp-

small RCT of 15 patients, a low concentration preparation of

CS obtained only 17% treatment satisfaction rate compared

to 63% with HA.

tom improvement for 56‒73% of patients at three months

120,121

147

with few adverse events reported.

Nowadays, it is most

often used within various cocktails (Table 3), mixed with

lidocaine, bicarbonate, or other components, making com-

parisons between studies difﬁcult. Combined with DMSO,

it reduced and deferred relapses compared to DMSO alone,

Guideline: CS should not be used as monotherapy, but may

be considered as part of multimodal therapy for IC/BPS.

5. Lidocaine (RECOMMENDED in select patients, Grade B)

122

for 32% of patients. Combined with lidocaine and sodium

bicarbonate, three observational studies reported success-

ful outcome for 65‒94% of patients at two to four weeks

Intravesical lidocaine is better absorbed from the human

bladder when alkalinized with sodium bicarbonate.¹⁴⁸

Several observational studies have reported therapeutic

potential in treatment of acute ﬂares of IC/BPS.¹²⁰^,¹⁴⁸^,¹⁴⁹In

a phase 2 multicentre RCT of 102 patients, Nickel et al

reported signiﬁcant improvement in symptoms compared

to placebo after a five-day course of buffered lidocaine

three days after last instillation (30% vs. 10%, p=0.012),

which was no longer statistically signiﬁcant at 10 days (24%

20,123,124

Lastly, in a multicentre,

after the last instillation.

double-blind, placebo-controlled, crossover trial, Parsons

et al showed that a combination of alkalinized lidocaine

and heparin provided up to 12 hours of relief from urgency

and pain for 42% of patients.

Guideline: Based on Level 3 evidence, intravesical heparin,

alone or in combination, is a therapeutic option for IC/BPS.

vs. 12%, p=0.102). Electromotive drug administration

(EMDA), a modality used to enhance drug absorption by

the urothelium through active transport, and the lidocaine-

releasing intravesical system (LiRIS), a controlled-release

device that prolongs dwell time, have also been recently

. Hyaluronic acid (HA) (OPTION, Grade C)

HA is thought to help improve or recreate the defective blad-

der GAG layer in IC/BPS. Several observational studies have

9,126-

151,152

reported a wide range of response rates, from 30‒87%.

attempted.

134

Combination therapy with HA and chondroitin sulfate has

also shown encouraging results up to three years in small

Guideline: Instillation on a daily or weekly basis of alka-

linized lidocaine is an option for short-term relief IC/BPS

symptoms, primarily bladder pain, based on Level 2 evi-

dence.

35-137

cohorts of patients.

However, the efﬁcacy of intravesical HA has been ques-

tioned in three reported, but unpublished RCTs, which

found no signiﬁcant symptom improvement compared to

6. Resiniferatoxin (RTX) (NOT RECOMMENDED, Grade B)

38-140

placebo.

Few adverse reactions have been reported

except for mild irritative symptoms.

RTX is a potent analogue of the chili pepper extract capsai-

153

Guideline: Based on published Level 3 evidence, intravesi-

cal HA may be considered part of multimodal therapy for

IC/BPS. However, it should be kept in mind that three nega-

tive trials have been completed without published results.

cin, a neurotoxin that desensitizes C-ﬁber afferent neurons

that transmit pain and, thus, could alleviate pain in IC/BPS.¹⁵⁴

In a systematic review, Mourtzoukou et al concluded that

results from the six studies currently available (three RCTs,

two prospective studies, and one case series) are contra-

. Chondroitin sulfate (CS) (OPTION, Grade D)

dictory regarding the effectiveness of RTX. With import-

ant tolerability issues, primarily pain following instillation,

data are currently insufﬁcient to make a conclusion on its

therapeutic efﬁcacy in IC/BPS.

In theory, treatment with CS may help replenish the GAG

layer of the bladder. A number of small, uncontrolled, sin-

gle-centre studies have suggested that intravesical CS may

ameliorate symptoms in some IC/BPS patients

recent prospective, multicentre “real-life” clinical trial fur-

Guideline: Based on conꢀicting Level 2 evidence and the

adverse side effect proﬁle, RTX is not recommended for

treatment of IC/BPS.

41-143

and a

ther conﬁrmed the potential beneﬁts of this treatment.

Two underpowered RCTs gathering 163 patients have been

recently reported with a tendency for favourable responses

with CS compared to placebo (38‒39% vs. 23‒31%),

7. Bacillus Calmette-Guerin (BCG) (NOT RECOMMENDED, Grade B)

45,146

BCG instilled into the bladder to stimulate an immunologic

response and attenuate symptoms of IC/BPS has been stud-

ied. BCG was tested in a large RCT of 265 patients with a

response rate of 21% (vs. 12% for placebo, p=0.062).¹⁵⁶

Another prospective trial of 30 patients followed for a mean

of eight months showed a success rate of 60% compared

to 27% for placebo, but did not reach statistical signiﬁ-

but the magnitude of beneﬁt observed could not support

its use as a monotherapy of IC/BPS. A higher-power meta-

analysis of all patients treated in these studies showed beneﬁt

over placebo, but like all intravesical therapies, the magni-

tude of beneﬁt suggests it should be used only as part of a

147

planned multimodal treatment strategy. In a head-to-head

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CUAJ • May-June 2016 • Volume 10, Issues 5-6

iC/BPS ꢀꢁꢂꢃꢄꢅꢂꢆꢄ

cance (p=0.06).¹⁵⁷In a prospective study of 21 patients with

a crossover design, the authors failed to demonstrate any

beneﬁt from BCG over DMSO.

Guideline: Based on Level 2 evidence showing no signiﬁ-

cant improvement in symptoms and the adverse side effect

proﬁle, BCG is not recommended for treatment of IC/BPS

rate of 20%.¹⁵³The long-term complication rate of repeated

HD is unknown.

Guideline: Based on Level 3 evidence, short-duration, low-

pressure HD is a treatment option for IC/BPS.

2. Treatment of Hunner’s lesions (RECOMMENDED for patients with identiﬁed

Hunner’s lesions, Grade B)

. Intravesical pentosan polysulfate (PPS) (OPTION, Grade C)

Several case series have reported various endourologic treat-

ments for Hunner’s lesions. Transurethral resection of Hunner’s

lesions with a loop cautery was ﬁrst described in 1971.¹⁶⁸In

the largest series reported by Peeker et al, 90% of 103 patients

had symptomatic relief following resection, which lasted

The rationale for intravesical use of PPS, a weak analogue of

heparin that may replenish the deﬁcient GAG layer, is that only

1‒3% of oral PPS reaches the bladder. It was tested in two

small RCTs. Bade et al observed improvement in symptoms

for 40% of patients compared to placebo, with rare hematuria

169

more than three years for 40% of patients. Fulguration with

a Bugbee electrode is another option that led to symptom-

158

reported as the only adverse event. Davis et al obtained a

2% response rate at Week 18 for patients treated with both

170-173

atic improvement in 76‒90% of 150 cases described.

oral and intravesical PPS compared to oral PPS and intravesical

NS, with no signiﬁcant differences in adverse events between

Transurethral coagulation using neodymium:yttrium-alum-

inum-garnet (Nd:YAG) laser, has been reported in two small

observational series with short-term improvements of 78%

159

treatment groups. Finally, in an open-label, uncontrolled

study, intravesical PPS encapsulated into liposomes showed

74,175

and 100%.

To prevent bladder or bowel perforation,

160

efﬁcacy and safety in eight patients over three months.

low bladder ﬁlling volume and low-power setting (10‒15 W),

Guideline: Based on Level 2 evidence, intravesical PPS,

alone or in combination with oral PPS, is a treatment option

for IC/BPS.

ﬁring during 1‒3 seconds in constant motion until the ulcer

174

is blanched, are recommended. Cox et al described direct

injection of triamcinolone into the ulcers in 30 patients. They

showed a signiﬁcant improvement for 70%, with a lasting

176

. Intravesical oxybutynin (OPTION, Grade C)

response between 7 and 12 months.

Complications of these procedures include bladder per-

175

foration, hemorrhage, bowel injury, and bladder ﬁbro-

169,172

In one small RCT, Barbalias et al showed efﬁcacy of intra-

vesical oxybutynin and bladder training compared to bladder

training alone (with saline bladder instillations) in improving

sis.

necessary over time.

Lesions tend to recur and retreatment will likely be

169,171

bladder capacity, frequency, and quality of life scores.

Guideline: Based on consistent Level 3 evidence, endo-

scopic treatment of Hunner’s lesions is recommended for

IC/BPS patients with Hunner’s lesions.

No adverse events were reported. Intravesical oxybutynin is

well-tolerated and has both anticholinergic and anaesthetic

properties on the bladder wall.

Guideline: Based on scarce Level 2 evidence and a favour-

able side effect proﬁle, intravesical oxybutynin is an option

for treatment of IC/BPS.

3. Botulinum toxin A (BTX-A) (OPTION, Grade C)

Multiple small observational studies have consistently

shown a signiﬁcant improvement in pain, urinary symp-

toms, and quality of life with intravesical BTX-A.¹⁷⁷^-¹⁸¹Two

small, double-blind RCTs have been conducted. Manning et

al found no signiﬁcant overall difference between patients

randomized to HD plus NS injection vs. HD plus 500 U

D. Minimally invasive surgical procedures

. Hydrodistension (HD) (OPTION, Grade C)

182

Despite the lack of randomized data to support the use of

low-pressure, short-duration HD, it remains one of the most

Dysport . However, Kuo et al reported a 72% vs. 48%

success rate in patients randomized to Botox (100 or 200

163

commonly used treatments for IC/BPS. Observational stud-

ies have shown efﬁcacy rates ranging from 30‒54% at one

month; 18‒56% at two to three months; and 0‒37% at ﬁve

U) plus HD vs. HD alone (p=0.032) at three months. 100 U

appear to be as effective as 200 U with fewer side effects.¹⁸³

Unfortunately, it is difﬁcult to comment on the effect of

BTX-A alone, as all groups included HD.

9,164,165

to six months.

There is a lack of standardized protocol throughout stud-

The safety and efﬁcacy of repeat BTX-A injections has

184-187

ies. Complications of HD include ﬂare of symptoms (9%),

been shown in observational studies.

The duration

167

186

bladder rupture, and bladder necrosis. Prolonged HD,

where the bladder is distended with a balloon from minutes

to hours, should be discouraged due to a high complication

(approximately 9‒10 months) and strength of response

seem to be maintained with repeat injections and rate of

adverse events low.

CUAJ • May-June 2016 • Volume 10, Issues 5-6

E147

Cox ꢄt aꢅ.

Side effects associated with BTX-A include UTI, hematu-

ria, elevated post-void residual, and possible need for tem-

porary clean intermittent catheterization.

Guideline: Based on consistent Level 3 evidence, the use of

intravesical BTX-A is an option for the treatment of IC/BPS

in patients refractory to other treatments. Repeat injections

are safe. Therapy is costly and may not be widely available

at all centres. Patients must be counselled on potential side

effects, particularly the possibility of urinary retention and

need to catheterize.

tectomy. A secondary cystectomy was performed in 17%

200

to treat persistent suprapubic pain.

Based on these retrospective series, patients with identiﬁed

bladder disease, such as those with Hunner’s lesions¹⁹⁹^,²⁰⁰

and those with a diminished maximum anesthetic bladder

197,201

capacity,

were more likely to have improvement in pain

and lower urinary tract symptoms postoperatively.

Guideline: Based on Level 3 evidence, major surgery with

substitution cystoplasty or urinary diversion ± cystectomy

are options for treatment of IC/BPS in patients refractory

to all other treatment options with signiﬁcantly impaired

quality of life due to urinary symptoms and pain. Due to the

invasiveness of surgery, the benign nature of IC/BPS, and

multiple other treatment options available, major surgery

should be considered an absolute last resort.

. Sacral neuromodulation (SNM) (OPTION, Grade C)

SNM is not yet approved by Health Canada or the FDA

for the treatment of IC/BPS, but is indicated for urgency

frequency syndrome and urgency urinary incontinence. No

RCTs have been completed to assess the effect of SNM on

symptoms of IC/BPS. However, multiple observational stud-

F. Emerging therapies

88-195

ies have been reported,

including long-term followup

Novel therapies are emerging for treatment of IC/BPS.

Investigational treatments include hyperbaric oxygen, silden-

aﬁl, monoclonal antibodies, cannabinoids, and intravesical

liposomes.

of 86 ± 9.8 months. All studies include patients refractory

to multiple IC/BPS treatment options.

Based on observational studies, 42‒95% of patients experi-

ence at least a 50% improvement in overall urinary symptoms,

89,192,193,195

192

including pain.

Peters et al found a statistically

1. Hyperbaric oxygen (HBO)

signiﬁcant decrease in narcotic use postoperatively (from 81.6

to 52 mg/day injectable morphine equivalents, p=0.015) with

/18 patients stopping narcotic use completely.

HBO has been studied in one case series and two small pilot

RCTs. Tanaka et al reported successful outcomes in 7/11

patients treated with HBO over 2‒4 weeks. Improvements

in pain, urgency, frequency, capacity, and symptom scores

were maintained for up to 12 months (p<0.05 compared to

baseline). Adverse effects included one transient eustachian

tube dysfunction and three cases of otitis media. Gallego-

Potential side effects of SNM include failure to improve

symptoms, painful stimulation, uncomfortable sensations,

battery site pain, seroma, infection, mechanical malfunc-

tion, and lead migration. There is a surgical revision rate

89,191

of 27–50%.

204

Guideline: Based on consistent Level 3 evidence, SNM may

be offered as an option for the treatment of IC/BPS to

patients who have symptoms refractory to multiple other

treatments. Therapy is costly and not widely available at

all centres. Patients must be counselled on potential side

effects, particularly the need for future surgical revisions.

Villar et al and van Ophoven et al both reported small

pilot study RCTs. Van Ophoven et al found 3/14 vs. 0/7

responders in the treatment vs. sham groups respectively

(p<0.05). Gallego-Villar et al reported success in 10/10 vs.

4/10 patients treated with HBO after DMSO instillations

vs. sham treatment after DMSO, respectively. Duration of

response was 9.3 vs. 3.1 months in the treatment vs. sham

groups (p=0.022).

E. Radical surgery (OPTION for severe refractory patients, Grade C)

Guideline: Based on Level 2 and 3 evidence (with small

numbers) HBO may be considered in the treatment of IC/

BPS for informed patients refractory to other options.

Multiple case series exist reporting on the use of invasive

surgical techniques for urinary diversion, with or without

cystectomy, in severe refractory patients. Supratrigonal cys-

tectomy with augmentation cystoplasty (substitution cysto-

plasty) has been reported to be beneﬁcial in many series for

2. Phosphodiesterase-5 (PDE-5) inhibitors

96-201

improving pain, urinary symptoms, and quality of life.

A recent double blind, placebo-controlled RCT compared

sildenaﬁl 25 mg orally once daily (n=24) to placebo (n=24)

in women with non-ulcerative IC/BPS. They found a signiﬁ-

cant improvement in symptoms in the treatment vs. placebo

In a recent series, Anderson et al reported 74% of patients

were pain-free following urinary diversion and 68% were

satisﬁed. Eight of the 36 patients (22%) who did not have a

cystectomy at the original surgery went on to undergo cys-

tectomy for residual symptoms. Rossberger et al reported

on 47 patients undergoing urinary diversion without cys-

arms (P<0.05). Side effects were minimal and included

ﬂushing and headache.

E148

CUAJ • May-June 2016 • Volume 10, Issues 5-6

iC/BPS ꢀꢁꢂꢃꢄꢅꢂꢆꢄ

Guideline: Based on minimal Level 2 evidence, PDE-5

inhibitors may be considered for the treatment of informed

patients with IC/BPS.

such categorization of this heterogenous group of patients

is the UPOINT phenotypic classiﬁcation system, which has

been described to characterize patients with IC/BPS and

6,216

guide potential therapies.

Recently, it has been applied

. Monoclonal antibodies against TNF-alpha

as a treatment approach in a prospective, observational trial

of 100 patients. At 18.3 months mean followup, a major

clinical improvement above baseline was found in 26.9%

and a signiﬁcant improvement in 47.2%; however, it was

noted that almost all patients were satisﬁed with the thera-

Adalimumab, an anti-tumour necrosis factor-alpha, has

been studied for IC/BPS in a Phase 3 RCT. Adalimumab

failed to demonstrate positive proof of concept compared

to placebo due to a signiﬁcant placebo effect. Intravenous

tanezumab, an anti-nerve growth factor, demonstrated a

statistically significant decrease in daily pain score and

improvement in global response assessment in a Phase 2

RCT.²A meta-analysis of all female patients diagnosed with

urologic CPPS showed a signiﬁcant beneﬁt with tanezumab

treatment compared to placebo.

216

peutic approach.

A rationale treatment strategy would be to clinically

characterize individual patients in regard to symptoms and

possible mechanisms and then direct the most appropriate

therapy to each of the phenotypic domains.

Conclusion

Guideline: Monoclonal antibodies are not available or rec-

ommended for IC/BPS at this point, but further studies are

needed.

In conclusion, multiple options exist for the treatment of

IC/BPS, ranging from conservative therapies with few side

effects to major abdominal surgery. Table 4 outlines the

available treatment options based on the data summarized

for the purpose of this guideline. An attempt by the consen-

sus panel to identify (when possible) the optimal therapy for

each patient has been made. It is the panel’s expert opin-

ion that the traditional and structured tiered monotherapy

approach is not the optimal therapeutic strategy. An indi-

vidualized treatment plan, directed towards that patient’s

unique clinical phenotype, based on the recommended

diagnostic algorithm, will lead to the best outcomes.²¹⁶

. Cannabinoids

Cannabinoid analgesia is reported for the management of dif-

ﬁcult-to-treat pain from chronic illnesses.

may reduce pain through various interactions with neuro-

transmitter systems and also have anti-inﬂammatory and

immunomodulatory properties. For IC/BPS, only animal

studies and case reports are available

promising avenue and future studies are needed to assess

its efﬁcacy and safety.

08,209

Cannabinoids

11-213

but it appears a

Guideline: Use of cannabinoid analgesia is not recom-

mended for IC/BPS at this point, but further studies are

needed.

Competing interests: Dr. Cox is has been an Advisory Board member for Asetllas and Ferring; has

received grants/honoraria from Astellas and Pꢀzer; and has participated in clinical trials for Aquinox.

Dr. Golda has received grants/honoraria from Astellas and Pꢀzer. Dr. Nadeau has been an Advisory

Board member for Allergan, AMS, Astellas, Ferring, Pꢀzer, and Red Leaf Medical; a member of the

Speakers’ Bureau for Allergan, Astellas, Ferring, Laborie, and Pꢀzer; and has participated in clinical

trials for Astellas and Ipsen. Dr. Nickel has served as a Consultant for Astellas, Auxillium, Eli Lilly, Farr

Labs, Ferring, Glaxo-Smith-Kline, Pꢀzer, Taris Biomedical, Tribute, and Trillium Therapeutics; has been

a lecturer for Astellas and Eli Lilly; and has participated in clinical trials for Eli Lilly, Glaxo-Smith-Kline,

Johnson & Johnson, Pꢀzer, and Taris Biomedical. Dr. Carr has been an Advisory Board member for

Allergan, Astellas, Gynecare, Janssen, and Pꢀzer; has been a lecturer for Allergan, Janssen, Pꢀzer, and

Triton. Dr. Corcos has been an Advisory Board member for Allergan, Astellas, and Pꢀzer; a member of

the Speakers’ Bureau for Allergan and Astellas; and has received grants/honoraria from Allergan and

Astellas. Dr. Teichman holds investments in Urigen and has participated in clinical trials for Aquinox.

. Intravesical liposomes

Intravesical liposomes, vesicles of phospholipid bilayers,

may serve as a “lotion” for wounded bladder mucosa.

With an approximately 50% response rate in two observa-

tional studies,²¹⁴^,²¹⁵it remains investigational, but appears

promising for symptomatic ﬂare-ups.

Guideline: Use of intravesical liposomes is not recom-

mended for IC/BPS at this point, but further studies are

needed.

References

G. Phenotype-directed multimodal therapy (RECOMMENDED for all

patients, Grade B)

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IC/BPS is a heterogeneous condition challenging to treat

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CUAJ • May-June 2016 • Volume 10, Issues 5-6

E149

Cox ꢄt aꢅ.

Table 4. Summary of guideline for IC/BPS treatment options

Treatment

Grade

Guideline

Conservative therapies

Patient education

Recommended in all patients

Dietary modiﬁcations

Bladder training

Recommended in motivated patients

Stress management and psychological support

Recommended in patients identiﬁed with suffering from stress or psychological

dysfunction

Physiotherapy and massage

Acupuncture

Recommended in patients with pelvic ﬂoor dysfunction

Option in motivated patients

Trigger point injections

Option for patients with trigger point pain

Medical therapies

Amitriptyline

Option

Cimetidine

Option

Hydroxyzine

Option for patients with allergic phenotypes

Oral pentosan polysulfate

Cyclosporine A

Option

Option as a last resort in patients with inﬂammation

Gabapentinoids

Option in patients with neuropathic pain

Quercetin

Option

Intravesical dimethysulfoxide

Intravesical heparin

Recommended in selected patients

Intravesical hyaluronic acid

Intravesical chondroitin sulfate

Intravesical alkalinized lidocaine

Intravesical resiniferatoxin

Intravesical Bacillus Calmette-Guerin

Intravesical pentosan polysulfate

Intravesical oxybutynin

Option

Recommended in selected patients

Not recommended

Option

Minimally invasive surgical procedures

Hydrodistension

Option

Treatment of Hunner’s lesions

Botulinum toxin A

Recommended for patients with identiﬁed Hunner’s lesions

Option

Sacral neuromodulation

Radical surgery

Option

Option in severe, refractory patients as a last resort

Recommended for all patients

Phenotype-directed multimodal therapy

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