nterstitial cystitis (IC)/bladder pain syndrome (BPS) is a frustrating disease of chronic bladder pain associated with lower urinary tract symptoms. Although there are many proposed treatment algorithms, the uncertainty as to their etiology has a negative impact on the therapeutic outcome. Oftentimes combination therapy of drugs with different mechanisms of action will be utilized to relieve the symptoms. With the various treatment options available to patients and providers, there is an ever-growing need to implement drug efficacy as well as safety to promote best practice in use of the approved drug

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Comparative safety review of current
pharmacological treatments for interstitial
cystitis/ bladder pain syndrome
Po-Yen Chen, Wei-Chia Lee & Yao-Chi Chuang
To cite this article: Po-Yen Chen, Wei-Chia Lee & Yao-Chi Chuang (2021): Comparative safety
review of current pharmacological treatments for interstitial cystitis/ bladder pain syndrome, Expert
Opinion on Drug Safety, DOI: 10.1080/14740338.2021.1921733
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2. REVIEW
Comparative safety review of current pharmacological treatments for interstitial
cystitis/ bladder pain syndrome
Po-Yen Chena,b
, Wei-Chia Leea,b
and Yao-Chi Chuang a,b
a
Department of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; b
Center for
Shock Wave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung,
Taiwan
ABSTRACT
Introduction: Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a frustrating disease of chronic
bladder pain associated with lower urinary tract symptoms. Although there are many proposed
treatment algorithms, the uncertainty as to their etiology has a negative impact on the therapeutic
outcome. Oftentimes combination therapy of drugs with different mechanisms of action will be utilized
to relieve the symptoms. With the various treatment options available to patients and providers, there is
an ever-growing need to implement drug efficacy as well as safety to promote best practice in use of
the approved drug.
Areas covered: This review will focus on guideline-based pharmacotherapies as described by the AUA
and EAU, specifically oral, and intravesical therapies with the most up-to-date published literature.
Pharmacotherapies targeting bladder, and/or systemic factors in the overall treatment of IC/BPS are
discussed with a particular focus on efficacy and drug safety evaluation.
Expert opinion: IC/BPS is a syndrome that requires bladder targeting agents to restore the urothelium
barrier function and inhibit bladder hypersensitivity as well as various drugs with anti-inflammatory
effects, and immune modulation effects. Current pharmacotherapies for IC/BPS have various therapeu­
tic effects and adverse effects depending on the dose and individual response.
ARTICLE HISTORY
Received 14 January 2021
Accepted 21 April 2021
KEYWORDS
Interstitial cystitis; bladder
pain syndrome; intravesical
therapies; oral medications;
safety
1. Introduction
1.1. Prevalence of IC/BPS
Interstitial cystitis/bladder pain syndrome (IC/BPS) is
a debilitating disease associated with persistent or recurrent
chronic bladder pain accompanied with other lower urinary
tract symptoms (LUTS) such as urgency, frequency or nocturia
[1]. The American Urological Association (AUA) defined IC/BPS
as ‘an unpleasant sensation (pain, pressure, or discomfort)
perceived to be related to the urinary bladder, associated
with LUTS of more than six weeks duration, in the absence
of infection or other identifiable causes [2]. Many IC/BPS
patients also suffer a variety of comorbid disorders, including
endometriosis, irritable bowel syndrome, fibromyalgia, rheu­
matoid arthritis, systemic lupus erythematosus, Sjögren’s syn­
drome, and depression, and impair quality of life [3,4].
The prevalence of IC/BPS was estimated to be 2.7% to 6.5%
and 1.9% to 4.2% for US women and men, respectively [5,6]. In
Japan, 1.0% of the general population experienced bladder pain
every day [7]. The prevalence was 21.8 out of 100,000 in 2002,
and 40.2 out of 100,000 in 2013, for Taiwan people [8]. The
estimated prevalence among women in Finland was 300 per
100,000 [9]. In a cross-sectional study in 5 European countries,
759 out of 62,000 (1.22%) of bladder pain and 0.44% of study
population were diagnosed BPS [10]. It appears that the
prevalence of IC/BPS varies widely because of ambiguity in the
definition, differences in the populations studied, and inconsis­
tencies in diagnostic methods. After ICS changed the name from
‘interstitial cystitis’ to ‘painful bladder syndrome’ in 2002, the
definition and prevalence became much ambiguous. The studies
relied on earlier outdated concepts of IC are lot lower that what
one sees in more contemporary surveys like the RICE study.
2. Diagnosis of IC/BPS
IC/BPS is currently diagnosed by urinary symptoms and pain
levels after excluding cancer, infection, bladder stone and certain
other diseases [2,7]. Patients complain of bladder or suprapubic
pain, which is often related to bladder filling and relieved by
voiding. The O’Leary-Sant Problem and Symptom Index, are
validated patient-reported symptom-based survey instruments
that were used to identify IC/BPS patients for inclusion into
clinical trials as well as for outcome measures [11]. Although
routine cystoscopy is not currently recommended for diagnosis
of IC, most experts use cystoscopic findings to categorize IC/BPS
patients into two general subtypes: with Hunner’s lesions (HIC)
and without Hunner’s lesions (NHIC) [12,13]. 10–20% of IC/BPS
patients have the ulcerative subtype (HIC) based on the presence
of one or more distinct, recurring inflammatory lesions in the
bladder [14].
CONTACT Yao-Chi Chuang chuang82@ms26.hinet.net Department of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College
of Medicine, Kaohsiung, Taiwan
EXPERT OPINION ON DRUG SAFETY
https://doi.org/10.1080/14740338.2021.1921733
© 2021 Informa UK Limited, trading as Taylor & Francis Group

3. 3. Pathophysiology of IC/BPS
3.1. Urothelial defects
Urothelial cells, classified as transitional epithelium, cover
the inner lining of the urinary bladder [15], and provide
a robust permeability barrier, which function is dependent
on a protective layer of dense glycosaminoglycans (GAG)
and tight-junction complexes that limit the transfer of ions
and solutes across the urothelium. Compromised urothe­
lium was detected on cystoscopic findings of denudation or
thinning, glomerulations, and ulcer lesion in IC/BPS
patients [16]. Furthermore, the abnormal expression of
urothelial barrier proteins such as zonula occludens-1, uro­
plakin, E-cadherin, and chondroitin sulfate was attributed
to IC/BPS symptoms [17]. Increased apoptotic activity and
decreased proliferative activity were noted in IC bladder
[18], and the mechanism of apoptosis was mediated by
tumor necrosis factor alpha (TNF-α) and p38 MAPK [19].
The identification of urotheilal defects forms the basis for
GAG replenishment therapy.
3.2. Mast cell activation
In patients with IC/BPS, the bladder has been found to
have an increased number of mast cells, which play
a pivotal role in this local inflammation through release
of histamine and synthesis of pro-inflammatory cytokines,
recruitment of leukocytes and vascular remodeling [20].
A recent mouse bladder model studies indicate that hista­
mine enhances the sensitivity of bladder afferents to dis­
tension via interactions with histamine H1 receptor and
TRPV1, and increased sensory input and activation in the
spinal cord, all of which may underlie the symptoms of IC/
BPS [21]. The cascade of mast cell activation was sug­
gested to induce IC/BPS symptoms, therefore, antihista­
mines was often used for the treatment of IC/BPS.
3.3. Inflammation
Chronic inflammation is always observed in the bladder
mucosa of HIC. The inflammatory cells, including lymphocytes
and plasma cells are most densely distributed in the sube­
pithelial region [7]. In addition, a small number of eosinophils
and neutrophils can be identified. The bladder of NHIC
patients shows little, if any, inflammatory changes [7].
A previous study reported that elevated levels of TLR-
mediated inflammation detected from peripheral blood
mononuclear cells and dysregulated diurnal cortisol slope
were associated with less improvement in genitourinary pain
in a sample of women suffering from IC/BPS[22]. Bladder
inflammation, regardless of etiologies, might induce afferent
nerve overactivity and IC/BPS symptoms. Anti-inflammatory
drugs were used for the treatment of IC/BPS.
3.4. Central sensitization
Central sensitization is a phenomenon of the nervous system that
is associated with the development and maintenance of chronic
pain[23]. When central sensitization occurs, the nervous system
gets regulated in a persistent activation of dorsal horn neurons in
the spinal cord, which can induce pain long after inflammation or
other problems of the pelvis are cured [24]. This persistent, or
regulated, state of reactivity explains why some patients with IC/
BPS still have significant pain after undergoing cystectomy.
3.5. Miscellaneous factors
In addition, urothelial-sensory fiber dysfunction, infection,
stress, autonomic nervous system dysfunction, nitric oxide
metabolism, toxic agents or hypoxia have been attributed to
IC/BPS with various degree of evidence [3,4,7,18,25].
4. Current pharmacotherapy OF IC/BPS
The pharmacotherapy includes oral medical treatment and sub­
sequent intravesical instillation or bladder wall injection after the
failure of oral medication [2,7]. The principles of pharmacother­
apy for the treatment of IC/BPS are based on (1) replenishment
of the glycosaminoglycan (GAG) layer for controlling the dys­
functional epithelium; (2) antihistamines for mast cell deactiva­
tion and suppression of allergies; (3) antidepressants; (4)
painkillers and nonsteroidal anti-inflammatory drugs; and (5)
intravesical therapy with botulinum toxin injection, and dimethyl
sulfoxide, hyaluronic acid or chondroitin sulfate instillation.
The purpose of the review for Drug Safety Evaluation is to
promote best practice in use of the approved drug. This
review will focus on guideline-based pharmacotherapies as
described by the AUA and EAU, specifically oral, and intrave­
sical therapies with the most up-to-date published literature.
4.1. Oral medication for interstitial cystitis
4.1.1. Pentosan polysulfate sodium
Pentosan polysulfate (PPS), consists of synthetic sulfated poly­
saccharide GAG-like molecule, which can bind to the GAG
layer for replenishment and anti-inflammation for the injured
Article highlights
● Lack of consistent biomarkers for diagnosis and follow up of patients
is a big challenge in understanding the real role of each drug for the
treatment of IC/PBS.
● The current medications for IC/BPS are aimed to diminish the bladder
pain and irritative symptoms of bladder, however, durability of ther­
apeutic effects remained to be achieved.
● Of the guideline-based oral therapies, PPS is an oral GAG replenishing
therapy with balanced safety profile. While commonly prescribed,
evidence supporting efficacy and safety of using amitriptyline, anti­
histamine, and NSAIDs for daily practice is still demanding.
● Guideline-based intravesical therapy is often used as monotherapy
rather than in a cocktail with other oral medication used in real world
practice.
● Novel agents with better efficacy and favorable safety profiles are
needed to improve the therapeutic outcome for IC/BPS.
● This box summarizes key points contained in the article.
2 P.-Y. CHEN ET AL.

4. bladder wall. It is the only FDA approved oral treatment agent
and it is one of the most studied drugs for the treatment of IC/
BPS. In a recent systematic review and meta-analysis, six ran­
domized placebo-controlled studies were included and it was
proven to diminish symptom scores, bladder pain, urinary
frequency, and urgency. Furthermore, a 12.4% difference treat­
ment response rate between PPS and placebo treatment was
also mentioned [26]. As for dose efficacy, the recommended
doses are 100 mg three times daily. In a previous study, similar
clinical response increased over time was demonstrated in
patients received 300 mg, 600 mg, 900 mg daily, which indi­
cated the treatment duration is more important than the
treatment dosage [27].
The common adverse effects of PPS were diarrhea, head­
ache, nausea, and abdominal pain. Although most of them
were typically mild and self-limited, the patients received
900 mg daily were reported high incidence of GI symptoms
(40% of diarrhea, 13.2% of abdominal pain, 14% of rectal
bleeding). The study also described dose-related events of
diarrhea, abdominal pain, rectal bleeding and treatment drop­
out rate [27].
In a recent study, Pearce et al. reported six adult patients
under long term PPS therapy for IC/BPS with median duration
186 months had a problem of difficulty reading [28]. Clinical
examination revealed subtle paracentral hyperpigmentation at
retinal pigment epithelium with vitelliform-like deposits. The
following multicenter study echoed the PPS associated macu­
lopathy as a vision-threatening condition. [29,30] FDA released
information regarding an Elmiron label change in 2020 which
recommended an eye exam including retina evaluation when
prescribing Elmiron. Further comprehensive studies for certain
risk factors and clinical management are warranted.
4.1.2. Amitriptyline
Amitriptyline is the widely used tricyclic antidepressants which
acts as an antagonist of serotonin, muscarinic, and histamine
receptors for IC/BPC treatment and was granted as second line
therapy for IC/BPS after behavior therapy from AUA and sig­
nificant value treatment in EAU. The initial therapy dosing
starts from 10 mg at bedtime, and titrate to 50–100 mg as
tolerated [2,31]. Amitriptyline blocks the release of histamine
and relieves pain intensity accompanied with bladder relaxing
effect, thereby reducing the irritated symptoms such as urin­
ary frequency and urgency. A prospective, randomized rando­
mized controlled trial (RCT) showed less pain and urgency
intensity in 4 months. On the contrary, Foster et al. failed to
meet primary endpoint for diminished symptom score.
However, in the sub-group analysis, the dose above 50 mg
showed a greater response rate and better clinical efficacy.
[32,33]
As for adverse effects, mouth dryness was the most fre­
quent adverse reaction, followed by urinary retention, consti­
pation, blurred vision, acute angle glaucoma and other
anticholinergic effects. Other side effects including highly
sedating, weight gain, dizziness, fatigue, orthostatic hypoten­
sion, QTc prolongation and sexual dysfunction [34]. It should
take caution with co-administration of cytochrome P450 inhi­
bitor (eg, cimetidine, anticonvulsants, selective serotonin inhi­
bitors) for increasing serum levels and toxicity. It can
exacerbate preexisting conduction delay, and even cause car­
diac arrest. Patients using high doses amitriptyline (300 mg)
have been reported to increase sudden death even without
underlying heart disease [35,36].
There were drug-drug interactions between amitriptyline
and other agents: The patient under monoamine oxidase
inhibitor such as Isocarboxazid or phenelzine treatment in
14 days should be avoided since this may cause serotonin
syndrome; patients under medications(eg, astemizole, cisa­
pride, indapamide, quinidine) can induce significant QTc pro­
longation [37]. Further clinical monitoring and
electrocardiogram should be arranged for the patients with
cardiac condition.
4.1.3. Antihistamines
Hydroxyzine and cimetidine are the commonly used antihista­
mines for IC/BPS and suggested as second line therapy in AUA
and significant value treatment in EAU guideline. Hydroxyzine
bases on the mechanism of histamine H1-receptor antagonist
and cimetidine acts as H2-receptor antagonist, inhibiting mast
cells activation and stabilizing hypersensitive bladder. The
typical dose of hydroxyzine is 25 to 75 mg. Although the
clinical efficacy was described in the case series which showed
improvement in symptom scores, the RCT in 121 patients
compared hydroxyzine to oral PPS showed nonsignificant effi­
cacy and low response rate as low as 31%. [38,39] The typical
dose of cimetidine is 300–400 mg twice daily. Of the 36
patients recruited RCT, cimetidine decreased symptom scores
and nocturia without histological change of bladder wall [40].
Adverse reactions, such as headache, dizziness and drowsi­
ness, should be concerned for patients under cimetidine ther­
apy and some of the post-marketing data reported about
hematologic and central nervous system problems [41].
Transient increased serum creatinine and vitamin B12 defi­
ciency after cimetidine therapy was also mentioned [42,43].
There are some rare but severe side effects for hydroxyzine.
Prolongation of QTc and torsade de pointes were mentioned
in elderly and females patients taking concomitant drugs
known to lead QTc prolongation [44]. The other uncommon
side effect is acute generalized exanthematous pustulosis,
which may completely subsided within 3 days after drug
discontinued [45].
4.1.4. Immunosuppressants
Azathioprine, cyclosporin A, and methotrexate (MTX) were
immunosuppressant agents aimed to reduce inflammation
process and tissue injury to minimize the irritative symptoms.
It showed clinical efficacy on pain score in some studies and
cyclosporin A is the fifth line therapy in AUA and significant
value treatment in EAU [46,47]. A randomized comparative
study demonstrated that cyclosporine A was superior to PPS
at 6 months with better response rate and both of the agents
improved micturition frequency, nocturia, and symptom
scores [48].Oral methotrexate were also reported significantly
improved bladder pain but not in urinary frequency [49].
The clinical trial compared CyA and PPS demonstrated that
the CyA group had greater clinical dropout rate and reported
more overall and severe adverse events [48]. CyA toxicity is
related with concentration levels, and it is commonly used for
EXPERT OPINION ON DRUG SAFETY 3

5. patients receiving organ transplantation. The adverse events
including increased blood pressure, serum creatinine, hair
growth, gingival pain and hyperplasia, and paresthesia.
Sairanen et al. reported long term CyA treatment outcome
and side effects with median follow up 60.8 months. The initial
usage dose was 3 mg/kg divided into 2 daily dosages. In total
23 patients, there were 3 hypertension, 3 gingival hyperplasia
and 2 induced hair growth. There were no clinical nephrotoxi­
city was noted [50]. However, one should regular monitor
renal function after immunosuppressants prescribed.
4.1.5. Adjuvant and analgesic therapy
Some analgesics and adjuvant medication were used for mini­
mizing pain and for symptomatic relief which were described
in the sixth line therapy in AUA. Acetaminophen and nonster­
oidal antiinflammatory drugs (NSAIDs; e.g. ibuprofen, diclofe­
nac) are necessary in patients combined with pelvic pain and
refractory conditions. The safety issues of NSAIDs including
risk of serious cardiovascular thrombotic events, gastrointest­
inal inflammation, ulceration, bleeding, and contraindication
following coronary artery bypass graft (CABG) surgery.
Additionally, phenazopyridine, narcotics, oxybutynin, and
anticonvulsants (gabapentin, pregabalin) are not effective as
primary therapy, whereas they are often used for short-term
pain relief when symptom flared up [51]. The patients under
these agents should monitor the problems of central nervous
system such as ataxia, dizziness and drowsiness.
We summarized the Oral medication suggestions for IC/BPC
in current guidelines in Table 1 and Miscellaneous agents and
analgesic therapy for IC/BPS in Table 2.
4.2. Intravesical pharmacotherapies
The GAG replenishment therapy by using intravesical instilla­
tion is the mainstream of IC/BPS treatment [59–61] to restore
the disrupted GAG layer of urothelium and to prevent further
penetration of urinary toxins and pathogens into the bladder.
Various GAG-like molecules have been explored, including
hyaluronic acid (HA), chondroitin sulfate (CS), heparan sulfate,
dermatan sulfate, and keratin sulfate listing in guidelines. The
commercial products of HA, CS, pentosan polysulfate (PPS),
DMSO were commonly used in clinic [60]. Among these
agents, HA and Chondroitin instillations are not available in
the US. We summarized the intravesical treatment for IC/BPC
in current guidelines in Table 3.
4.2.1. Hyaluronic acid
HA, the only non-sulfated GAG, consists of large polymers
and can reach a molecular weight between 500,000 and
4 million Daltons and a chain length of 10,000 nm.
Table 1. Oral medication suggestions for the treatment of IC/BPC based on current guidelines.
Medication Mechanism of action Clinical efficacy Guideline Dose
Adverse effects and safety
considerations
Pentosan
polysulfate
sodium
Synthetic poly-sulfated GAG-like
molecule binding to the GAG
layer for replenishment and anti-
inflammation
Overall response, pain,
urgency and frequency
in SRMA of RCTs[26]
AUA: second-line
therapy
EAU: LE 1a,
Strong
recommendation
100 mg, 3 doses
daily
Diarrhea, headache, nausea
dizziness, skin rash
peripheral edema, hair loss
abdominal pain27
*Maculopathy in chronic usage[28–30]
Amitriptyline Acetylcholine/histamine (H1)
receptors inhibition
Serotonin/noradrenaline
reuptake inhibition
Pain and urgency intensity
improved in 4 months
[32]
No efficacy in treatment
naïve patients. Dose
>50 mg increase
response rate[33]
AUA: second-line
therapy,
evidence Grade
B
EAU: LE 1b,
Strong
recommendation
10 mg daily and
titrate to
50–100 mg
as tolerated
92% vs 21% compared to placebo
79% dry mouth32
Drowsiness, weight gain, dizziness,
fatigue, constipation, orthostatic
hypotension, QTc prolongation,
sexual dysfunction
*Avoid MAOi
*Caution QTc and CYP450
interaction
Hydroxyzine Histamine H1-receptor antagonist No significant trend in RCT
[39]
AUA: second-line
therapy,
evidence Grade
C
25 mg to
50–75 mg as
tolerated
Sedation, weakness
*Acute generalized exanthematous
pustulosis
*Prolongation of QT interval and
torsade de pointes
Cimetidine Histamine H2-receptor antagonist Improve median symptom
scores, suprapubic pain
and nocturia decreased
in RCT[40]
AUA: second-line
therapy,
evidence Grade
B
300–400 mg
BID
Dizziness, headache, increased serum
creatinine
*Use caution in elders for confusion/
CNS effects
*May cause Vitamin B12 deficiency
in long term uses43
Cyclosporine
A
Calcineurin inhibitor, T cell
suppression
Greater response than PPS
in RCT[48]
Improve pain, nocturia,
frequency[47]
AUA: fifth-line
therapy,
evidence Grade
C
1.5–3 mg daily Hypertension, dyslipidemia, edema,
headache, paresthesia, hirsutism,
hypertrichosis, renal toxicity,
susceptibility to infection
Methotrexate Immunosuppressant Improve pain but not in
urgency/frequency[49]
EAU: treatment of
significant value
7.5–12.5 mg
weekly
Dizziness, alopecia, diarrhea, nausea
and vomiting, thrombocytopenia,
hepatotoxicity
*Unexpectedly severe bone marrow
suppression and aplastic anemia
with concomitant NSAIDs
Azathioprine Immunosuppressant Improve pain and urinary
frequency[46]
EAU: treatment of
significant value
50–100 mg
daily
Malaise, nausea and vomiting,
hepatotoxicity, susceptibility to
infection
4 P.-Y. CHEN ET AL.

6. Hyaluronic acid has a high capacity to bind water: 1 g of
hyaluronic acid binds 6 L of water. HA may have two major
effects on urothelium: restoring barrier effect and facilitating
cell proliferation at the basal cell membrane. It is thought
that higher molecular weight (HMW) HA is associated with
increased viscosity and may restore the GAG layer and
enhance barrier function [60]. In contrast, the lower molecu­
lar weight (LMW) HA may be associated with better penetra­
tion into tissues and receptor activation, which theoretically
leading to a reduction of immunologic effects within the
bladder wall and restoring a good environment for cell pro­
liferation in urothelium. Commercial products include,
Cystistat® containing HMW HA (0.08%) 40 mg/50 ml and
Uromac® containing LMW HA (0.2%) in 100 mg/50 ml. In
a meta-analysis, Barua et al reported that HMW HA seems
to have some advantage over other instillation agents com­
pard with LMW HA [60].
Previous publications showed a wide range of symptom
improvement from 30% to 85% of IC patients by using intra­
vesical instillation of 40 mg HA [59].In 2011, Engelhardt et al
[70]reported their long-term results of intravesical HA therapy;
they observed a 50% complete symptom remission at the
5-year follow-up without any additional therapy, while 41.7%
with symptom recurrence improved with HA maintenance
therapy. Lai et al [71]reported that different regimen of intra­
vesical HA instillation may reach similar therapeutic effects
(e.g. a decrease in urgency and pain) in IC/PBS patients.
Mild adverse events were reported such as urinary tract
infection (0–17.4%), temporary worsening of storage symp­
toms (0–11.3%), and events related to catheterization [72–
75]. Riedl et al. reported that there were no adverse reactions
over the whole treatment period with a total of 1,521 instilla­
tions [76]. Thus, we consider that intravesical HA instillation is
well tolerated and can be performed with careful
catheterization.
4.2.2. Chondroitin sulfate
CS is the most abundant GAG, principally associated with
a protein core to form proteoglycans [61]. There are four differ­
ent types of CS, depending on the position of the sulfate com­
plex. CS has a molecular weight of approximately 20,000 Dalton
and a chain length of 50 nm. In the bladder, chondroitin sulfate
is localized on the urothelial surface. The mechanisms of intra­
vesical CS instillation may involve in reducing the recruitment of
inflammatory cells (neutrophils and mast cells) to the sub-
urothelial space, without altering the recruitment of CD45-
Table 2. Miscellaneous agents and analgesic therapy.
Medication Mechanism of action Possibility of efficacy Dose Adverse effects and safety considerations
Sildenafil PDE5 inhibitors, increased
nitric oxide synthase
Improve symptom scores in 3 months
in a single RCT[52]
25 mg daily Flushing, headache, dyspepsia, visual
disturbance, epistaxis
Certolizumab
pegol
PEGylated anti-TNFα
agents
Improve pain, overall symptoms and
urgency in RCT[53]
Subcutaneous 400 mg at
weeks 0, 2, 4, and 8
GI disturbance, antibody development,
infection
L-arginine natural amino acid,
increased urinary nitric
oxide synthase
Decrease pain and urgency in RCT[54] 1,500 mg daily Headache, nausea, vomiting
Duloxetine Serotonin/Norepinephrine
Reuptake Inhibitor
No clinical effect in observational trial
[55]
40 mg twice daily Induce mania or hypomania, gingival
hemorrhage, gastrointestinal hemorrhage
Montelukast leukotriene D4 receptor
antagonist
Decrease urinary frequency, nocturia
and pain in a small cohort[56]
10 mg/day Headache, dizziness, dermatitis, otalgia,
increased serum aspartate
aminotransferase
Adalimumab Antirheumatic monoclonal
Antibody
Improve symptoms but failed to reach
difference compared to placebo in
RCT[57]
80 mg subcutaneous then
40 mg every 2 weeks
Headache, skin rash, positive ANA titer,
infection, increased creatine
phosphokinase
Suplatast
tosilate
Th2 cytokine inhibitor not statistically significant compared
to placebo in RCT[58]
600 mg daily Stomach discomfort, nausea, sleepiness,
rash
Acetaminophen Analgesics Pain relief 325–650 mg every
4–6 hours, maximum
dose: 4 g/day
Erythema of skin, hypoalbuminemia,
increased serum aspartate
aminotransferase
*Overdose may cause acute liver failure
and hepatotoxicity
Ibuprofen Nonsteroidal Anti-
inflammatory Drugs
Pain relief 200–800 mg 3 to 4 times
daily, maximum:
3,200 mg/day
Decreased hemoglobin, epigastric pain,
abdominal distress, renal function
abnormality
* Increased risk of serious cardiovascular
thrombotic events
*Increased risk of serious gastrointestinal
inflammation, ulceration, bleeding, and
perforation
* Use is contraindicated following
coronary artery bypass graft (CABG)
surgery
Pregabalin GABA Analog, decrease
neurogenic
inflammation
Neurologic pain relief 75 mg once daily, up to
300 mg in 3 divided
doses
Peripheral edema, weight gain, dizziness,
drowsiness
Gabapentin GABA Analog, decrease
neurogenic
inflammation
Neurologic pain relief 300 mg to 1200 mg daily Viral infection, ataxia, dizziness, drowsiness
Phenazopyridine Urinary analgesics Urinary pain relief 200 mg 3 times daily Methemoglobinemia, renal or liver
dysfunction, headache, dizziness
EXPERT OPINION ON DRUG SAFETY 5

7. positive lymphocytes, demonstrating an anti-inflammatory
effect in animals. CS is prepared in 2 different products, 0.2%
(Gepan instill®) and 2% (Uracyst®) in clinical use [60,61].
In a double-blind RCT, Nickel et al suggested that intrave­
sical 2% CS therapy (Uracyst®) have no significant safety issue
for IC/BPS patients. Although these studies cannot reach the
primary outcome, some responders can benefit from the
improvement of IC/BPS-related symptoms. We suggested
that CS instillation could not serve as a monotherapy for IC/
BPS patients [77–80]. Steinhoff et al [81]. reported that instilla­
tion of 40 ml CS 0.2% (Gepan instill®) may benefit the IC
patients who have positive potassium stimulation results,
and a 45% response rate after initial 3 months was observed.
There was no significant safety issue during these studies.
Table 3. Intravesical therapies for the treatment of IC/BPC.
Medication Mechanism of action Clinical efficacy Guideline Dose
Adverse effects and
safety considerations
Hyaluronic acid Restore barrier and basal cell
membrane cell proliferation.
Reduction of immunologic
effects of the bladder
Decrease in urgency
and pain[84]
EAU
Grade:
Weak
40 mg/50 ml
Or 120 mg instillation
Urinary tract infection,
temporary worsening
of storage symptoms
Chondroitin sulfate Reducing the recruitment of
neutrophils and mast cells
No significant Improves
Global Response
Assessment, ICSI[79]
EAU:
LOE:2b,
Grade:
Weak
2% in 20 mL instillation No significant safety issue
Dimethyl sulfoxide
(DMSO)
Anti-inflammation, antispasmodic
effect, depleting substance P,
increasing capacity
Relief urgency, reduce
pain, increase
maximum bladder
capacity
Higher response rate
to DMSO than BCG in
RCT[62]
AUA:
Second-
line
Grade C
27 g DMSO (5.4%) in 50 ml flushing-related
symptoms, bladder
irritation or pain,
cystitis,dysuria,
strangury
Combination
lidocaine plus
sodium
bicarbonate
Local anesthetics, penetrate
urothelium and sensory nerves
downregulation
Improve Global
Response
Assessment[63]
EAU:
LOE:1b,
Grade:
Weak
AUA:
Second-
line
Grade C
200 mg lidocaine + 8.4% sodium
bicarbonate total 10 ml
Renal and urinary
disorders: Bladder pain,
micturition urgency,
dysuria, pollakiuria
Combination oral and
intravesical
Pentosane
polysulphate
Synthetic poly-sulfated GAG-like
molecule binding to the GAG
layer for replenishment and anti-
inflammation
Greater relief frequency,
urgency, and return
to normal protective
coating[64]
EAU:
LOE:1b
200 mg 2 capsules in 30 ml saline Headache, hair loss
Heparin May restore bladder surface barrier
function
Improve symptom
score, nocturia, first
sensation, bladder
capacity[[65],[66]]
AUA:
Second-
line
Grade C
EAU:
Grade:
Weak
25,000 units twice a week/
10,000 units in 10 ml sterile
water, 3 times per week,
3 months
Not mention
Oral pentosane
polysulphate plus
subcutaneous
heparin
GAG replenishment Significant improve
pain in RCT[67]
EAU:
LOE:1b,
Grade:
Weak
3 x 5000 IU/day heparin for
2 days, followed by 2 × 5000
IU/day for 12 days, 5000 IU/day
maintenance
No catheterization
needed
Stronger menstrual
bleeding, gum
hemorrhage
OnabotulinumtoxinA
(onaBoNTA)
injection
Paralysis of the detrusor muscle
Modulates sensory transmission
and blocks neurotransmitters
release
Reduce pain score in
RCT better than
hydrodistension
alone[96]
(EAU)
LOE:2b,
Grade:
Strong
AUA:
Fourth-
line
Grade C
100 U/200 U intravesical injection Cystoscopy under
anesthesia needed
Large amount post-
voiding residual urine,
infection, hematuria,
dysuria
Combination
Hyaluronic acid/
Chondroitin sulfate
As above Reduction in pain
intensity effective as
DMSO at 6 months in
RCT[90]
- HA (800 mg//50 ml) + CS (1 g/
50 ml)
Bladder pain, urinary tract
infections
Combination
lidocaine, sodium
bicarbonate,
heparin
As above Relief symptoms and
pain[68]
Reduce dyspareunia
[69]
- 50,000 units heparin + 200 mg
lidocaine + 420 mg sodium
bicarbonate in 15 mL water
8 mL of 2% lidocaine, 4 mL of
8.4% sodium bicarbonate, and
2 mL heparin (10,000 U/mL)
Not mention
6 P.-Y. CHEN ET AL.

8. 4.2.3. Combination of hyaluronic acid and chondroitin
sulfate
Since GAG replacement therapy is the cornerstone of IC/BPS
instillation therapy, a combination of two GAGs (CS and HA)
has been used to treat IC/BPS patients. In a 3-D bladder
epithelium model, Stellavato [82] suggested that the HA/CS
product (Ialuril®) with more calcium ions could provide more
anti-inflammatory activity and superior mucoadhesivity than
other regimens.
Giberti et al [72] used Ialuril® (800 mg LMW-HA, 1.6%/CS,
2% in 50 ml) to treat IC/BPS patients weekly in the first month,
biweekly for the second month, and monthly instillation for at
least 3 months. In 20 female IC/BPS patients, CS/HA therapy
can improve IC/BPS symptoms significantly. Cervigni et al [83]
reported the long-term results of intravesical HA/CS therapy in
12 IC/BPS patients refractory to other treatments. Ialuril® was
applied on the IC/BPS patients over a period of 3 years and the
improvements in bladder function were observed for 3 years
(mean number of daily voids decreased from 17.8 at baseline
to 15.5 at 9 months and 11.9 at 3 years, and mean volume per
void from 136.8 mL at baseline to 143.9 mL at 9 months and
180.9 mL at 3 years).
In a meta-analysis of HA and HA/CS, Pyo and Cho [84]
further confirmed the significant therapeutic effects of intra­
vesical HA, alone or in combination with CS. Mild adverse
events were reported such as urinary tract infections (0–­
17.4%) and temporary worsening of storage (11.3%). Hence,
Literature supports the beneficial effects of intravesical GAG
replenishment therapy by using HA or HA/CS to provide
symptomatic relief for patients with IC/BPS.
4.2.4. Dimethyl sulfoxide (DMSO)
Dimethyl sulfoxide (DMSO), Rimso-50® containing 27 g DMSO
(5.4%) in 50 ml, was the first FDA-approved intravesical instil­
lation specifically for IC/PBS in 1978 [85]. The exact mechanism
of action is still unclear. Several therapeutic effects had been
reported, including anti-inflammation to reduce bladder irrita­
tion, antispasmodic effect to relax bladder and pelvic muscles,
depleting substance P from bladder nerves, and increasing
bladder capacity by breaking down scar tissue. Some health­
care providers combined DMSO with other intravesical instilla­
tions containing lidocaine and sodium bicarbonate as cocktail
therapy, but no increased efficacy was found to exceed DMSO
alone.
According to AUA guidelines, intravesical DMSO adminis­
tration was designated as a second-line therapy for reliving
symptoms of IC/BPS patients. Intravesical DMSO instillation is
listed as an option with only grade C evidence. Perez-Marrero
et al [86] published the first placebo controlled trail to prove
better effects of DMSO in reliving urgency, increasing max­
imum bladder capacity and reducing pain at maximum capa­
city than 50 ml of normal saline, albeit a significant placebo
effect was found. Recently, in a multicenter randomized dou­
ble-blind placebo-controlled clinical trial, Yoshimura et al [87]
used KRP-116D (50% DMS) to treat IC/BPS patients. After a 12-
week treatment course, the KRP-116D can improve the urinary
frequency, voiding volume, and bladder pain of IC/BPS
patients. By using bacillus calmette guerin (BCG) as
a treatment control, Sairanen el al [88] reported
a significantly higher response rate to DMSO than BCG (30%
versus 11%). Furthermore, Peeker et al [89] reported that
DMSO treatment can improve urinary frequency and pain.
Recently, Cervigni et al. [90] reported a randomized, open
label, multicenter study for comparisons of efficacy and safety
between intravesical HA/CS and dimethyl sulfoxide in women
with IC/BPS. After a 3-month treatment and followed up at
a period of 6 months, they suggested treatment with HA/CS
resulted in a greater reduction in pain intensity at 6 months
compared to DMSO-used patients. Also, the HA/CS users had
the advantage of fewer treatment-related adverse effects
(1.35% versus 22.22%) and a better cost-effectiveness, com­
pared to DMSO-users. Only one HA/CS user (1.35%) reported
bladder pain. However, DMSO-users experienced bladder irri­
tation (2.78%) or pain (2.78%), cystitis (5.56%), dysuria
(11.11%), and strangury (2.78%).
Taken together, the DMSO intravesical instillation showed
the efficacy in reliving bladder pain and urinary frequency in
IC/BPS patients. No standard physiological biomarkers or spe­
cific phenotype of IC/BPS (e.g. ulcerative and non-ulcerative
disease) have been set to monitor efficacy of DMSO or select
patients for this therapy. Garlic odor, bladder pain, and dysuria
are the common adverse effects of DMSO treatment. In
a head-to-head study to compare CS and DMSO therapies in
IC patients, Tutolo et al reports that more withdrawers in
DMSO arm than in the chondroitin sulfate arm due to adverse
events of DMSO instillation [91].
4.2.5. OnabotulinumtoxinA (onaBoNTA)
OnaBoNTA has been widely used in the treatment for lower
urinary tract dysfunction since 1988 and the mechanisms of
action were well investigated. The neurotoxic protein can bind
its heavy chain to synaptic vesicle protein 2 and translocate its
light chain into the cytosol. After synaptosomal-associated
protein (SNAP) 25 were cleaved, the soluble
N-ethylmaleimide-sensitive factor attachment protein receptor
(SNARE) proteins were following blocked, leading interference
of synaptic acetylcholine vesicle fusion to the cell membrane
and induce chemo denervation [92]. OnaBoNTA effect is not
only limited to the motor function, it could also modulate
sensory transmission and blocks the neurotransmitters release
including substance P, adenosine triphosphate, calcitonin
gene-related peptide, and nerve growth factor (NGF) to
reach anti-inflammation and antinociceptive effects.
OnaBoNTA has proven to be efficient for IC/BPS. Kuo et al.
reported a RCT including 60 patients received 100 units
OnaBoNTA suburothelial bladder injection compared to
hydrodistension alone. The pain score reported a greater
reduction in the OnaBoNTA group with successful treatment
rates of 63% [93].The following systematic review with meta-
analysis also reported significant improvement for post-void
residual volume, pain and symptom scores [94]. Pinto et al.
reported a double-blind RCT of intratrigonal
OnabotulinumtoxinA injection which significantly reduced
VAS pain score and voiding frequency [95].
The most concerned adverse effect of OnaBoNTA treatment
is urinary retention and it was found more often in patients
receiving 200 U than in patients receiving 100 U injection.
EXPERT OPINION ON DRUG SAFETY 7

9. Besides, large amount post-voiding residual urine, infection,
hematuria, and dysuria, were also reported dose related
adverse effects and it might be greater UTI and retention
risks in patients receiving intratrigonal OnabotulinumtoxinA
injection according pathophysiology and clinical report
[95,96]. In a comparative study, some adverse effects were
less mentioned in patients with IC/BPS than in patients with
overactive bladder, acute urinary retention event was no sig­
nificant difference in both groups [97].
In recent years, various approaches for OnaBoNTA combi­
nation injection-free procedures for intravesical delivery were
investigated [98]. The only RCT for IC/BPS treatment with
liposomes showed clinical efficacy but failed to reach signifi­
cant difference compared to placebo, whereas it demon­
strated little adverse effects [99].
5. Conclusions
We have reviewed the efficacy and common AEs associated
with guideline-based oral medication or intravesical therapies
used in the treatment of IC/BPS reported by clinical trials and
real-world data. Combination regimens based on different
mechanisms of action seemed to make sense to cover the
bladder center symptoms as well as systemic symptoms with­
out evidence of increased toxicity. Research on new com­
pounds for providing more therapeutic effects and more
safety is mandatory.
6. Expert opinion
Diagnosing interstitial cystitis/bladder pain syndrome (IC/BPS)
is still challenging as there is no definitive test or disease
marker for IC/BPS [14]. Furthermore, IC/BPS symptoms overlap
with symptoms of bladder cancer, urinary tract infection or
overactive bladder, and are often influenced by comorbidities,
such as depression, irritable bowel syndrome, and some
immune diseases. Taken together, many patients may go
years without a correct diagnosis, which makes proper disease
management difficulty.
IC/BPS remains a prevalent, but intractable disease. The
pathophysiologies are not fully delineated. Researchers suggest
that (I) disruption of the bladder GAG layer, (II) upregulated
immune/inflammatory response, (III) neurogenic inflammation
and central sensitization, and (IV) pelvic floor dysfunction may all
play a role in the pathophysiology of the disease.
A number of treatments and management algorithms,
including behavioral, dietary, pharmacologic and surgical
therapies, have been developed for the treatment of patients
with IC/BPS, and all of these methods attempt to control the
disease and to offer substantial benefits to the affected
patients. Nevertheless, the complexity of IC/BPS in terms of
pathogenesis and etiology still has made it difficult to induce
significant and long-lasting therapeutic effects, even with
balanced safety profile.
Who will benefit from certain medical treatment is still
uncertainty. Most medication may relieve IC/BPS symptoms
for a subset of patients that is not readily identifiable before
treatment and that therapeutic try with all kind of available
agents fits most or all patients. Therefore, uncertainty existing
for most treatments regarding the balance between benefits
and risks/burdens is still challenging.
Albeit several convincible treatments could relieve urinary fre­
quency, urgency, and bladder pain for IC/BPS patients, further
large scale randomized controlled studies along with a longer
follow-up period are needed to collaborate the efficacy and safety
of these treatments. Most clinical trials of IC/BPS may involve in
different phenotypes of this disease. This situation causes certain
difficulty to obtain a conclusion from meta-analyses studies.
Precision medicine bases on the phenotypes, biomarkers and
gene identification may improve the current therapeutic
outcome.
Oral medication with or without intravesical treatment aimed
at the different pathophysiologies to support the therapeutic
strategies. PPS is the only FDA-approved oral drug and it is
substantially proven to have benefits for pain, urgency and fre­
quency in several high-quality studies. For the patients with
maculopathy, gastrointestinal problems or peripheral edema,
PPS should be used cautiously or avoided. The elders or patients
with cardiovascular disease are at the risk of QTc prolongation
and central nerve system problems, therefore, amitriptyline and
hydroxyzine used should be carefully monitored the safety profile.
To date, clinical guideline varies in the following regimens
such as serotonin/norepinephrine reuptake inhibitors, PDE5
inhibitors, GABA Analogs, L-arginine, and adalimumab. There
were some single-arm cohort studies trying to prove the clinical
efficacy but the inclusion criteria were not well described. Due
to the placebo effects were prominent in patients with IC/BPS,
well-designed randomized controlled trials to rule out the pla­
cebo effects are the keys for developing new drugs.
IC/BPS is a complex disease, hence, a single medication
might not achieve an enough outcome. It is rational to use
cocktail therapy to advance the therapeutic benefits for IC/BPS
patients. It is still an unmet medical need to have a try on
combination of oral and intravesical treatments to reach
a good efficacy and safety. Self-instillation in an on-demand
schedule may be optimal for good responder to GAG replen­
ishment treatment. We are still expecting more clinical data or
other newly developing drugs for the treatment of IC/BPS.
Funding
This paper was not funded.
Author contributions
Conceptualization: YCC
Data curation: PYC, WCL
Writing - original draft: PYC, WCL
Writing - review & editing: YCC
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
8 P.-Y. CHEN ET AL.

10. Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
ORCID
Yao-Chi Chuang http://orcid.org/0000-0002-1468-3792
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