guideline  
CUA guideline: Diagnosis and treatment of interstitial cystitis/  
bladder pain syndrome  
1
2,5  
Consensus panel co-chairs: Ashley Cox, MD, MSc, FRCSC; Nicole Golda, MD, MSc, FRCSC;  
Genevieve Nadeau, MD, MSc, FRCSC3  
4
5
Consensus panel members: J. Curtis Nickel, MD, FRCSC; Lesley Carr, MD, FRCSC;  
6
7
Jacques Corcos, MD, FRCSC; Joel Teichman, MD, FRCSC  
1
2
Department of Urology, Dalhousie University, Halifax, NS, Canada; Department of Urology, North  
The complaint of suprapubic pain, related to bladder filling  
3
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  
4
5
6
7
5
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.  
6
7
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.  
1
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  
2
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.8 The  
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.  
3
,9  
criteria were designed to delineate a homogeneous popula-  
tion for research trials and were overly restrictive for use in  
4
routine clinical practice. Therefore, in 2002, the International  
Continence Society defined painful bladder syndrome (PBS) as:  
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©
iC/BPS ꢀꢁꢂꢃꢄꢅꢂꢆꢄ  
This translates into approximately 3.37.9 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.  
1
0
Although the disease can affect both sexes, approximately  
9
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  
1
1
of both complexes.  
Diagnosis of IC/BPS  
. History (MANDATORY, all patients, Grade C, Level 4 evidence)  
1
2. Physical examination (MANDATORY, all patients, Grade C, Level  
4
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.  
1
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  
1
4
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  
1
5
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  
17  
overactive bladder (OAB). Typically, the difference is that  
*
IC/BPS may co-exist.  
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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)  
18  
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  
22  
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  
3
. 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  
2
3
Cystitis Problem Index (ICPI); The Wisconsin Interstitial  
24  
Cystitis scale (UW-IC scale); the Pain, Urgency, Frequency  
25  
score (PUF score); and the Bladder Pain/IC Symptom Score  
2
6
(BPIC-SS).  
4
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  
4
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 86174mL,  
compared to an average of 289 mL in an asymptomatic  
woman. The average number of daytime voids ranges from  
2
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  
1
9
25  
2
0,21  
1
725 compared to six.  
A voiding diary also helps to determine the severity of the  
30  
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-  
2
6
be included in clinical trials.  
37  
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  
37  
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,  
7
. Cystoscopy (RECOMMENDED, all patients, Grade C, Level 3 evidence)  
3
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-  
3
1
3
2,33  
43  
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  
4
3
capacity on urodynamics. Further confounding the diag-  
nosis in symptomatic patients, 25% with OAB (almost all  
with radiation and IC) and 5084% with chronic pelvic pain  
34  
3
7,44  
In asymptomatic men, a  
syndrome (CPPS) test positive.  
36% false-positive rate was found.  
4
5
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-  
3
5
toms compatible with IC/BPS is rare. Tissot et al found  
% of 600 patients referred with a diagnosis of IC/BPS had  
1
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 1020 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 1015 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  
3
6
4
6
therapeutic.  
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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  
51  
to undergo HD at the time of tubal ligation.  
2
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  
4
7
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.  
1
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  
3
,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.  
3
7
0100 cmH 0 for a minimum of two minutes, performed  
2
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  
3
IC. However, it is recognized that approximately 15% of  
5
3
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.  
33  
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-  
3
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.33,53 If  
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.  
4
8
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.1 The severity of glomerulations was found to cor-  
relate poorly with symptoms and with histological evidence  
9,32  
4
9
of inflammation. In contrast, Lamale et al found a strong  
5
0
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.  
19  
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  
1
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)  
4
9
49  
observed during hydrodistension. Between 30% and  
4
3%54 of 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 4550%  
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  
5
5
58  
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-  
1
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  
56  
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.  
6
1
association. Dietary modifications, such as a steady intake  
6
2
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  
6
0,62  
identify potential offenders.  
2
. 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-  
6
3
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  
6
4
most appropriate protocol is not clear at this point. These  
are quite innocuous, but time-consuming techniques that  
6
5
require a highly motivated patient. The effectiveness of  
such behaviour modification program is supported by pro-  
spective data showing symptom improvement for 4588%  
6
6
of the cohorts.  
CUAJ • May-June 2016 • Volume 10, Issues 5-6  
E141  
Cox ꢄt aꢅ.  
IC/BPS  
All patients:  
1
2
3
.
.
.
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  
2
16  
)
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.  
3
. 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)  
70  
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.  
6
7
disability. The physician-patient relationship should be  
6
2
emotionally supportive. As stress is known to exacerbate  
B. Physical therapy techniques  
6
8
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)  
6
2,69  
can be beneficial.  
guided imagery  
Sexual dysfunction should be addressed, as it may worsen  
7
0
IC/BPS symptoms. However, treatment of female sexual  
dysfunction (FSD) is challenging. Management strategies  
Many IC/BPS patients have high-tone pelvic floor muscle  
71  
dysfunction (PFD). Those patients who have tenderness on  
E142  
CUAJ • May-June 2016 • Volume 10, Issues 5-6  
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  
7
2-75  
of symptoms in 5062% of patients  
and an additional  
2
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  
7
5
(DMSO)  
2
. Acupuncture (OPTION in motivated patients, Grade B)  
2
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  
7
6
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)  
1
0 mg oxybutynin (crushed tablets)  
Injections of pelvic floor trigger points using a 22 or 25  
gauge needle with 15 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  
7
7
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.57,80 Van Ophoven et al80 reported 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  
1
. Amitriptyline (OPTION, Grade B)  
5
7
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  
7
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  
90  
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,  
9
1
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  
9
2
Jepsen et al reported only 6.218.7% of patients main-  
tained a benefit after 18 months of treatment.  
9
3
2
. 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.  
8
1,82  
and one placebo-  
Two very small observational trials  
8
3
controlled RCT have shown an improvement in symptoms  
of IC/BPS with cimetidine at various dosages. Thilagarajah  
8
3
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.  
9
4
3
. Hydroxyzine (OPTION for patients with allergic phenotype, Grade C)  
One observational study reported a 40% reduction in symp-  
8
4
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.  
8
5
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.95-98 Patients  
with Hunner’s lesions seem to derive a better response than  
those without Hunner’s lesions (68% vs. 30%, respective-  
9
6
ly). A single RCT comparing CyA to PPS showed a signifi-  
cant improvement in IC/BPS symptoms with CyA treatment  
9
9
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.  
4
. 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  
8
5-89  
reporting contradictory results. A meta-analysis  
E144  
CUAJ • May-June 2016 • Volume 10, Issues 5-6  
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  
1
11  
to 10% for BCG, p<0.05) and one concluding no benefit  
1
00  
112  
1
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  
1
13,114  
(1453 % 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 3060 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.  
6
. 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.  
1
01,102  
Only two case reports  
and three small observational  
03-105  
The only trial that used gabapentin alone  
1
trials exist  
found a 48% improvement in pelvic pain.  
1
05  
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)  
7
. 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  
3060 minutes. From two prospective, uncontrolled studies,  
Quercetin has been used to treat male chronic pelvic pain  
1
06  
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.  
1
07  
Table 3. Intravesical cocktails for IC/BPS  
Ingredients  
References  
2
4
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  
8
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  
3
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  
Mishra219  
dexamethasone, 20 mL NaHCO3  
0 mL DMSO, 44 mEq (1 amp) NaHCO3, 10 mg  
triamcinolone, 20 000 IU heparin  
5
Hanno220  
1
08  
may help to improve tolerance to the procedure.  
3
2
00 mg pentosan polysulfate sodium, 10 mL  
% lidocaine, 10 mL 4.2% NaHCO3; add to this  
Bade219  
1
. Dimethylsulfoxide (DMSO) (RECOMMENDED in select patients, Grade B)  
sufficient NaCl 0.9% to reach a total volume of 60  
mL  
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%  
1
09  
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  
5
mL 4% lidocaine followed by 5 mL 8.4% NaHCO3  
150  
al.  
Adapted from Erickson DR;221 DMSO: dimethysulfoxide; IC/BPS: interstitial cystitis/ bladder  
1
10  
pain syndrome; NaCl: sodium chloride; NaHCO : sodium bicarbonate.  
compared to 35% and 18%, respectively, in controls.  
3
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 5673% 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 6594% 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.120,148,149 In  
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%  
1
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  
1
25  
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.  
1
50  
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  
3
. 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  
3
9,126-  
151,152  
reported a wide range of response rates, from 3087%.  
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.  
1
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)  
1
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-  
1
55  
4
. 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.  
1
41-143  
and a  
1
44  
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 (3839% vs. 2331%),  
7. Bacillus Calmette-Guerin (BCG) (NOT RECOMMENDED, Grade B)  
1
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  
E146  
CUAJ • May-June 2016 • Volume 10, Issues 5-6  
iC/BPS ꢀꢁꢂꢃꢄꢅꢂꢆꢄ  
cance (p=0.06).157 In 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%.153 The 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.  
1
12  
2. Treatment of Hunner’s lesions (RECOMMENDED for patients with identified  
Hunner’s lesions, Grade B)  
8
. 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 1971.168 In  
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  
13% 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  
6
atic improvement in 7690% 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  
1
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 (1015 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 13 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  
9
. 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  
1
61  
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  
1
62  
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.177-181 Two  
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  
1
. 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 3054% at one  
month; 1856% at two to three months; and 037% 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.  
1
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  
1
9
184-187  
ies. Complications of HD include flare of symptoms (9%),  
been shown in observational studies.  
The duration  
1
66  
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 910 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.  
4
. 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  
1
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.  
1
91  
of 86 ± 9.8 months. All studies include patients refractory  
to multiple IC/BPS treatment options.  
Based on observational studies, 4295% of patients experi-  
ence at least a 50% improvement in overall urinary symptoms,  
1
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  
2
02  
4
RCTs. Tanaka et al reported successful outcomes in 7/11  
patients treated with HBO over 24 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  
1
89,191  
of 27–50%.  
2
03  
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/