Skip to main content

Efficacy and safety of oral pharmacological and supplementary therapies in bladder pain syndrome: a systematic review


Treatment goals in bladder pain syndrome (BPS) or interstitial cystitis (IC) focusing on relieving symptoms to improve quality of life and avoiding adverse events (AEs) since curative treatment for BPS/IC is not available. The readily available pharmacologic options for BPS/IC including oral, intravesical, and transdermal therapy. The purpose of this study is to review randomized trial studies over the last 15 years examining the efficacy and safety of oral pharmacological and supplementary therapies for BPS/IC. A systematic search was conducted in PubMed and Medline Library. Only randomized-controlled trials and randomized comparative trials published between 2005 and 2020 on the efficacy and safety of oral therapies for BPS/IC were included. The keywords used were “bladder pain syndrome”, or “interstitial cystitis”, and “random” or “trial”. From 629 articles, nine were included in this review. Oral therapies included consist of cyclosporine A (CyA), amitriptyline, amitriptyline plus alpha lipoic acid (ALA) and omega-3 fatty acids (n-3 PUFA), PD-0299685, sildenafil, pentosan polysulfate sodium (PPS), AQX-1125, and hydrogen-rich water. Among retrieved trials, amitriptyline in combination with ALA and n-3 PUFA, sildenafil, and cyclosporine A proved their efficacy for BPS/IC. Sildenafil was generally well tolerated, while amitriptyline and CyA must be used with caution, the supplementation of ALA/n-3 PUFAs possibly lower dosage of amitriptyline, subsequently reduce its AEs. CyA was superior to PPS but possessed greater AEs. Further studies focusing on etiopathology and phenotype differentiation of this syndrome will greatly contribute to the development of effective therapy.


Bladder pain syndrome (BPS) can be described as a chronic bladder pain condition without any identifiable etiology. The Society for Urodynamics and Female Urology (SUFU) explained this syndrome as an unpleasant sensation (pain, discomfort, or pressure) considered to be related to the lower urology system for more than 6 weeks, without identifiable causes [1]. NHANES III survey from the USA recorded a prevalence of 470 per 100,000 population, which was 850 per 100,000 women and 60 per 100,000 men [2].

BPS/IC has various clinical presentations includes discomfort feeling, increased bladder pressure, pain, and increase sensitivity in the bladder and pelvic areas, increased voiding frequency and urgency, or a combination of several symptoms. The pain often aggravates during menstruation, intercourse, or bladder filling with symptoms improvement after bladder emptying [1, 3].

Genitourinary pain in general can be neuropathic, nociceptive, or have elements of both. BPS/IC is one of the quite challenging conditions in chronic urologic pain. Various theories exist on the potential etiology of chronic urologic pain. These include infection, voiding dysfunction, anatomic abnormalities, immune disorders, endocrine, neurological, musculoskeletal, and psychological associations [4]. The development of urologic pain chronicity as in BPS is still unclear.

Nerves regeneration following injury may have abnormal connections, leading to inappropriate propagation of pain signals proximally, further mediating cross-talk, and the perception of non-painful stimuli as painful. There are suggestions of visceral and dorsal root ganglion neuron cross-sensitization as the underlying mechanism. Besides, phenotypic progression has also been reported [4].

Initial management in BPS should include prompted education, managing the comorbid condition, and psychosocial therapy. The step ladder of treatment should start from the most feasible conservative approach and step further to the less conservative option if control of symptoms is still inadequate. There is no single specific therapy consistently effective for all cases. Treatment should be tailored for each individual and the goal should focus on optimizing patients’ quality of life [1, 5].

The readily available pharmacologic options for BPS/IC include oral, intravesical, and transdermal therapy. Several categories of oral medication that commonly been used for BPS include analgesics, antidepressants, antihistamines, glycosaminoglycans, immunosuppressants, and also pentosan polysulfate sodium which readily approved by the Food and Drug Administration (FDA). Many of these therapies are used empirically, while only a few of them have been studied in randomized controlled trials over recent decades [6].

Current research approaches on BPS systemic therapy, including anti-nerve growth factor treatment, activation of SHIP1 (AQX-1125), anti-tumor necrosis factor-α treatment, α1 adrenoceptor antagonists, and P2X3 receptor antagonists are potential systemic treatments [2, 7]. Alongside its systemic effect, the safety profile from oral therapies should carefully be measured. The interest in complementary therapies for BPS is increasing which encompasses physical and systemic therapy yet their evidence of effectiveness is still lacking [8, 9].

In this review, we aimed to analyze the efficacy and safety profile of oral pharmacological and supplementary therapies for BPS/IC from RCT and randomized comparative trial over the last 15 years.

Materials and methods

A systematic literature search for articles regarding oral therapies for BPS/IC that were published between 2005 and 2020 was conducted on scientific databases, namely, PubMed and Medline, following the PRISMA reporting guidelines for systematic reviews [10]. The keywords used were (bladder pain syndrome), or (interstitial cystitis), and (random or trial). 629 studies were found (Fig. 1).

Fig. 1
figure 1

Preferred reporting items for systematic reviews and meta-analyses (PRISMA) diagram of included studies

The inclusion criteria for this systematic review comprise of:

  1. 1.

    Randomized studies either RCT or randomized comparative study whose results were published as a full article.

  2. 2.

    English publications only.

  3. 3.

    Trials on BPS oral therapies (including oral pharmacological and oral supplementary therapy).

  4. 4.

    Outcomes of the trials include efficacy and safety aspects.

The exclusion criteria for this systematic review comprise of:

  1. 1.

    Studies involving non-oral therapies for BPS.

  2. 2.

    Pre-clinical trials.

  3. 3.

    Case–control, cohort, cross-sectional, case report, literature review.

  4. 4.

    Trials with non-available data on the safety issue.

After applying the PRISMA protocol, a total of nine articles were retrieved (seven of them were randomized-placebo controlled trial studies, and two of them were randomized-comparative studies). Our main goal in this systematic review is to explore the characteristics of each study and equally analyze the efficacy and safety of oral therapies on these trials. Data were collated on study characteristics (Table 1), including patient characteristics, details of oral therapy, outcome parameters, results, and adverse events.

Table 1 JADAD Scale


Out of the 629 citations identified by electronic literature searches, nine studies that fulfilled the inclusion and exclusion criteria were included in the systematic review (Fig. 1).

Quality assessment

The overall quality of the studies was good. We used JADAD Scale to assess the quality of our studies. The nine studies are randomized, blinded, and described the subject withdrawal. The quality assessment can be seen in Table 1 (JADAD Scale).

The characteristics of the included studies were assessed in several dimensions: types of oral therapy, sample size, study methods, intervention, and control or comparison groups, outcomes, and AEs (Table 2). In the design category, seven of the nine studies were randomized placebo-controlled trial study, while the rest were randomized comparative trials. The randomized comparative trials included in this review are a comparison study of cyclosporine A to PPS by Sairanen et al. [11] and a comparison between amitriptyline to amitriptyline combined with ALA and n-3 PUFA by Murina et al. [12].

Table 2 Characteristics of studies included in the systematic review of oral pharmacological and supplementary therapies in BPS/IC

Types of oral therapy included in this review comprise amitriptyline, amitriptyline plus ALA and n-3 PUFA, sildenafil, pentosan polysulfate sodium (PPS), cyclosporine A, PD-0299685, SHIP1 activator (AQX-1125), and hydrogen-rich water. Interstitial Cystitis Symptom Index (ICSI) was the most commonly used parameter for the outcome. Four from nine studies used Visual Analogue Scale (VAS) for their quantification of pain severity, the rest of the studies used Numeric Rating Scale (NRS).

Some of the randomized trials in this systematic review include drugs not mentioned in American Urological Association (AUA) guidelines [1], those include PD-0299685, sildenafil, SHIP1 activator, and supplementary therapies with ALA plus n-3 PUFA and hydrogen-rich water. The absence of a universal treatment for BPS triggers the existence of new drugs being studied to treat this syndrome.



Foster et al. conducted a randomized-controlled trial study comparing amitriptyline with placebo of 271 BPS patients. Both study groups were combined with the Educational and Behavioral Modification Program (EBMP). The results showed that from 231 subjects who were randomized, the response rate was higher in the amitriptyline group but not significant statistically (p = 0.12). However, there was a significantly higher response rate in patients who achieved a minimum of 50 mg dose of amitriptyline (p = 0.01) [13].


Most of the participants reported at least one AE, classified primarily as mild or moderate. The rate of AE on the amitriptyline group was 88% and 72% on the placebo group (p = 0.0013). General malaise, dizziness, gastrointestinal and genitourinary problems were significantly more frequent in the amitriptyline group. From drug titration over 6 weeks, subjects who achieved 50 mg dose daily and continued it for 12 weeks were 46% on the amitriptyline group and 72% on placebo group. 20% of subjects from the amitriptyline group with 50 mg dose daily by 6 weeks reduced their dose for the rest of follow-up [13].

Amitriptyline in combination with alpha lipoic acid and omega-3 fatty acids


Murina et al. in 2017 published their randomized trial to study the effectiveness of amitriptyline combined with ALA and n-3 PUFA in patients with vestibulodynia/BPS. The VAS and the short-form McGill Pain Questionnaire (SF-MPQ) points significantly decrease after treatment in both amitriptyline and amitriptyline plus ALA and n-3 PUFA groups. Pain in the latter group improved with greater significance. The average dose of amitriptyline on this combined therapy to achieve efficacy was 22 mg, which was smaller than the average dose in general. The overall incidence of side effects was (9.5%) and there was no subject dropout [12].


The overall incidence of AEs was low from this drug combination without any treatment discontinuation. Eight patients (9.5%) experienced drug AEs: three from the amitriptyline group and five from the amitriptyline plus ALA and n-3 PUFAs group. Sedation, constipation, and dry mouth were the most common AEs [12].

Cyclosporine A


Sairanen et al. in 2005 published their comparative study and concluded that CyA was superior to PPS in all clinical outcome parameters at 6 months [11]. They chose to compare CyA with PPS since PPS has been tested several times against placebo and accepted for BPS/IC therapy [14]. The number of responders from the study was significantly improved after 6 months compared to after 1 month of CyA therapy (p = 0.006) [11].


There were more AEs in the CyA group compared to the PPS group. They consisted of increased blood pressure and serum creatinine with mild to moderate AEs, such as induced hair growth, gingival pain and hyperplasia, paresthesias in extremities, abdominal pain, muscle pain, flushing, and shaking. Despite that condition, 19 patients from the study decided to continue the CyA treatment after 6 months of study, while 4 patients continued on PPS treatment [11].



Nickel et al. conducted a phase II a, randomized, double-blind, placebo-controlled study for PD-0299685. From the 161 subjects admitted in their study, PD-0299685 in 30 or 60 mg dose daily did not succeed to prove a positive impact for pain treatment and urinary parameters related to BPS/IC. Nickel et al. included a cohort with prolonged symptoms so they might represent a subgroup of cases that were refractory to treatment and subsequently it was difficult to demonstrate unequivocal efficacy [15].


The most common AEs from PD-0299685 were somnolence, dizziness, and nausea. They were reported at a greater proportion in the treatment group compared to placebo. A higher dose of 60 mg compared to 30 mg resulted in greater AEs incidences. Serious treatment-related AEs (deep vein thrombosis and suicide attempt) were reported in 2 of 54 participants in the 30 mg dose group [15].



A randomized, double-blind, placebo-controlled trial published in 2014 by Chen et al. evaluate the efficacy of daily low dose (25 mg) sildenafil for BPS/IC. The study conducted on 48 women and resulted in a significantly improved ICSI, ICPI, and urodynamic index starting from the 4th week until 3 months after treatment. The efficiency of treatment reached 62.5%. However, the VAS score had significant changes only at the 12th week in the sildenafil group [16].


Chen et al. concluded that the daily low-dose of sildenafil was well-tolerated. All 48 patients completed the study. There was only mild to moderate AEs such as mild headache and flushing at the beginning of treatment but they only last temporary (2–4 days) [16].

Pentosan polysulfate sodium


Nickel et al. in 2014 reported their study on the efficacy and safety of the currently recommended dose of PPS (300 mg per day) with one-third of daily dose and with placebo. There was no statistically significant difference between either the PPS dose group and placebo or between the PPS dose groups for the primary endpoint [17].


They concluded that PPS was well tolerated with similar discontinue percentages between treatment and control group because of an adverse event. The majority of AEs were moderate in intensity. The most common treatment-emergent AEs were bladder pain, nausea, headache, and exacerbation of BPS symptoms [17].

SHIP1 activator (AQX-1125)


In 2016, Nickel et al. published their initial phase II pilot study to evaluate the efficacy of AQX-1125. The oral SHIP1 activator AQX-1125 administered once 200 mg daily for 6-week reduced pain, voiding frequency, and BPS symptoms [18]. The promising result of this phase II RCT prompted the initiation of the much larger and longer phase III dose-ranging RCT to evaluate the therapeutic benefit of this regimen. Nickel et al. in 2019 published their 12-week, RCT, phase 3 trial on SHIP1 activator. 298 female subjects with moderate to severe symptoms of BPS/IC were treated with 100 or 200 mg SHIP1 activator once daily for 12 weeks. Treatment demonstrated no difference in maximum daily bladder pain compared to the placebo. There was no treatment benefit over that of placebo in the secondary endpoints [19].


Nickel et al. concluded that AQX-1125 was generally well tolerated at the 100 and 200 mg doses. Overall adverse event rates between the placebo group and the two AQX-1125 treatment groups were similar [19].

Hydrogen-rich water


Matsumoto et al. in 2013 published their study on the first RCT of hydrogen-rich water for the treatment of patients with BPS/IC. 30 participants were randomized in a 2:1 ratio to receive hydrogen-rich water or placebo water for 8 weeks. The results from their study do not support the use of hydrogen-rich water as supplementation for BPS/IC therapy. The score of bladder pain was significantly improved in both groups but did not differ significantly per statistic [20].


All patients reported no adverse events.


Based on our systematic review, we obtained nine randomized studies on oral therapy for BPS. Amitriptyline plus ALA and n-3 PUFA, sildenafil, and cyclosporine A have proved their efficacy. Amitriptyline is considered the second-line treatment for BPS according to AUA guidelines. Amitriptyline as tricyclic antidepressants has analgetic effect and capability to improve depression. It blocks acetylcholine receptors, inhibits the reuptake of released serotonin and norepinephrine, and blocks histamine H1 receptors [6, 21]. Its pharmacologic action in BPS/IC is presumed by blocking H1-histamine receptors, helping to stabilize mast cells, so that mast cell degranulation within the bladder wall decreased [22]. Urinary storage improvement may be facilitated through the stimulation of beta-adrenergic receptor. The primary side effect of amitriptyline is sedation but this effect may alleviate BPS nocturnal symptoms when administered at night [6, 23].

van Ophoven et al. conducted a prospective RCT study of amitriptyline in 48 subjects with BPS/IC. Oral amitriptyline (25 mg titrated until 100 mg daily if tolerated) over 4 months was effective compared to placebo (63% versus 4%) [24]. A newer RCT study conducted by Foster et al. suggested that amitriptyline was effective at a minimum dose of 50 mg, but adherence to higher doses was poor. The most common side effects of amitriptyline are sedation, nausea, and drowsiness (found in up to 79% of cases) [1]. AEs experienced by some patients might influence patients’ compliance and decrease their willingness to continue the treatment.

It is expected that combined therapy with ALA and n-3 PUFA can reduce the amitriptyline dose needed and reduce potential AEs [12]. Several studies regarding alpha-lipoic acid (ALA) reveal its antioxidant and anti-inflammatory effects. ALA may reduce pain and paresthesia, and has been used in several chronic neuropathic conditions as in diabetic neuropathy and carpal tunnel syndrome. Intake of Docosahexaenoic acid which belongs to predominant Omega-3 polyunsaturated fatty acid can increase the neuropathic and thermal pain threshold, it also provides anti-nociceptive effects [12, 25].

ALA can cross the blood–brain barrier and exert anti-inflammatory effects. Meanwhile, n-3 PUFAs also has several physiological roles in the nervous and cardiovascular systems. n-3 PUFAs are precursor of eicosanoids [26]. Multiple mechanisms with synergistic interactions of this drug combination might provide better pain relief compared to monotherapy [27].

The superiority of cyclosporine A compared to PPS was found in all clinical outcome parameters measured at 6 months but AEs were greater in the CyA arm [11]. The safety aspect of this drug must be cautiously considered. CyA acts as a calcineurin inhibitor which inhibits T cell activation by blocking cytokines genes transcription process and also stabilizing mast cells [28]. Before the comparative trial between CyA and PPS published in 2005, there was already a previous retrospective analysis on CyA which resulted in its highly efficient effect for BPS/IC [14]. The clinical efficacy of CyA improved with a longer treatment period which might be described by the inhibition of chronic inflammation that comes slowly as seen with relief from symptoms [11].

Sildenafil on a small daily dose improves BPS outcome and was well-tolerated [16]. BPS/IC encompasses a variety of symptoms, such as increased frequency voiding frequency and urgency. Phosphodiesterase type 5 inhibitors (PDE5I) may relax the contraction of smooth muscle caused by adrenergic activity or elevating potassium. Several studies reported that sildenafil was effective in treating an overactive bladder by the cyclic guanosine monophosphate (cGMP)-dependent protein kinase GRhoA/Rho-kinase signaling pathway Result from previous studies revealed the beneficial effect of PDE5I on various lower urinary tract symptoms (LUTS) benign prostatic hyperplasia and overactive bladder [29], those results suggested PDE5I can be a potential treatment for BPS/IC. Future studies with a larger population and longer follow-up are needed to confirm this promising result.

Regarding other therapies included in this review, SHIP-1 activator in phase II study showed satisfactory results, but in the phase III trial, there was no significant benefit over placebo [18, 19]. AQX-1125, being one of SHIP-1 activator is new pharmaceutical compounds that appears to be a potentially effective therapy in women with BPS/IC. AQX-1125 is a modulator of phosphoinositide signaling for diverse processes including cell growth, activation, and immune/inflammatory regulation [30]. There were discrepancies between the efficacy observed in the phase II and III trials of this drug [18, 19].

PPS that has been recognized for BPS did not succeed to show significant effect compared to placebo according to RCT by Nickel et al. [17]. Oral PPS was approved by AUA guideline as a treatment option in BPS. The proposed pharmacologic mechanism of PPS is that it rejuvenates the deficiency of glycosaminoglycan layer to protect the urothelium [31, 32]. Nonetheless, there is only a small amount of PPS absorbed by the alimentary system [33, 34]. Nickel et al. emphasized that early termination, study design, inclusion criteria, and high dropout rates might limit the study [17].

PD-0299685 study published by Nickel et al. concluded that the risk and benefit profile appeared to be unfavorable [15]. Drug tolerability was concluded as poor. PD-0299685 belongs to Calcium channel α2δ ligand. The α2δ subunit of ligand-gated Ca2+ ion channels give an impact on chronic pain conditions since it mediates afferent nerve pain fibers. It has been studied in inflammatory pain with a nonclinical model and demonstrated efficacy, it may indicate benefit for conditions with chronic inflammatory pain [35]. There was also a small number of non-controlled trial reports indicating that α2δ ligand may be efficacious in BPS/IC.

The interest in complementary and alternative therapies for BPS is high, while the effectiveness is still questionable. Oxidative stress is hypothesized as one of the BPS causes. Several investigations have shown that hydrogen acts as an antioxidant for preventive and therapeutic purposes [36,37,38]. Ohsawa et al. reported that hydrogen selectively reduces cytotoxic oxygen radicals so that it may act as a therapeutic antioxidant [39]. From the first RCT on hydrogen-rich water, Matsumoto et al. did not support the use of hydrogen-rich water for BPS/IC [20].


From this systematic review, we delineate that as there are many options of oral therapies for BPS/IC, amitriptyline in combination with ALA and n-3 PUFA, sildenafil, and cyclosporine A provide good efficacy for BPS/IC. From the safety aspect, ALA and n-3 PUFA supplementation is expected to reduce the minimum dose of amitriptyline needed and reduce its adverse events. Sildenafil was generally well tolerated, while CyA should be administered with caution as its superiority over PPS possessed greater incidence of adverse events.

BPS/IC cases are heterogeneous with varying clinical phenotypes. Future studies focusing on etiopathology and phenotype differentiation of this syndrome will greatly contribute to the development of effective therapy.

Availability of data and materials

Not applicable.



Bladder pain syndrome


Interstitial cystitis


Adverse events


Randomized-controlled trials


Cyclosporine A


Alpha lipoic acid

n-3 PUFA:

Omega-3 fatty acids


Pentosan polysulfate sodium


The Society for Urodynamics and Female Urology


Food and Drug Administration


Preferred Reporting Items for Systematic Reviews and Meta-Analysis


Interstitial Cystitis Symptom Index


Interstitial Cystitis Problem Index


Visual Analog Scale


Global Response Assessment


Education and Behavioral Modification Program


Numeric Rating Scale


Maximum Voided Volume


Mean Micturition Frequency


Urgency Episode Frequency


Patient’s Overall Rating of Improvement of Symptoms


Bladder Pain/Interstitial Cystitis Symptom Score

SF 12V2:

Short form 12 item (version 2)


Short-form McGill Pain Questionnaire


Phosphodiesterase type 5 inhibitors


Cyclic guanosine monophosphate


Lower urinary tract symptoms


  1. Calik G, Rosette J. Bladder pain syndrome: a review. EMJ Urol. 2020;8(1):38–45.

    Google Scholar 

  2. Payne CK, Joyce GF, Wise M, Clemens JQ. Interstitial cystitis and painful bladder syndrome. J Urol. 2007;177(6):2042–9.

    Article  Google Scholar 

  3. Pazin C, de Souza Mitidieri AM, Silva AP, Gurian MB, Poli-Neto OB, Rosa-E-Silva JC. Treatment of bladder pain syndrome and interstitial cystitis: a systematic review. Int Urogynecol J. 2016;27(5):697–708.

    Article  PubMed  Google Scholar 

  4. Wu C, Jarvi K. Mechanisms of chronis urologic pain. Can Urol Assoc J. 2018;12(6Suppl3):S147–8.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Rovner E, Propert KJ, Brensinger C, Wein AJ, Foy M, Kirkemo A, et al. Treatments used in women with interstitial cystitis: the interstitial cystitis data base (ICDB) study experience. Urology. 2000;56(6):940–5.

    Article  CAS  Google Scholar 

  6. Greiman A, Cox L. Pharmacotherapy for interstitial cystitis/bladder pain syndrome. Curr Bladder Dysfunct Rep. 2019;14:365–76.

    Article  Google Scholar 

  7. Andersson KE, Birder L. Current pharmacologic approaches in painful bladder research: an update. Int Neurourol J. 2017;21:235–42.

    Article  Google Scholar 

  8. Verghese TS, Riordain RN, Champaneria R, Latthe PM. Complementary therapies for bladder pain syndrome: a systematic review. Int Urogynecol J. 2016;27:1127–36.

    Article  Google Scholar 

  9. O’Hare PG 3rd, Hoffmann AR, Allen P, Gordon B, Salin L, Whitmore K. Interstitial cystitis patients’ use and rating of complementary and alternative medicine therapies. Int Urogynecol J. 2013;24(6):977–82.

    Article  Google Scholar 

  10. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339: b2535.

    Article  Google Scholar 

  11. Sairanen J, Tammela TL, Leppilahti M, Multanen M, Paananen I, Lehtoranta K, et al. Cyclosporine A and pentosan polysulfate sodium for the treatment of interstitial cystitis: a randomized comparative study. J Urol. 2005;174:2235–8.

    Article  CAS  Google Scholar 

  12. Murina F, Graziottin A, Felice R, Gambini D. Alpha lipoic acid plus omega-3 fatty acids for vestibulodynia associated with painful bladder syndrome. J Obstet Gynaecol Can. 2017;39(3):131–7.

    Article  Google Scholar 

  13. Foster HE Jr, Hanno PM, Nickel JC, Payne CK, Mayer RD, Burks DA, et al. Effect of amitriptyline on symptoms in treatment naïve patients with interstitial cystitis/painful bladder syndrome. J Urol. 2010;183(5):1853–8.

    Article  Google Scholar 

  14. Sairanen J, Forsell T, Ruutu M. Long-term outcome of patients with interstitial cystitis treated with low dose cyclosporine A. J Urol. 2004;171:2138.

    Article  CAS  Google Scholar 

  15. Nickel JC, Crossland A, Davis E, Haab F, Mills IW, Rovner E, et al. Investigation of a Ca2+ channel α2δ ligand for the treatment of interstitial cystitis: results of a randomized, double-blind, placebo controlled phase II trial. J Urol. 2012;188(3):817–23.

    Article  CAS  Google Scholar 

  16. Chen H, Wang F, Chen W, Ye Xt, Zhou Q, Shao F, et al. Efficacy of daily low-dose sildenafil for treating interstitial cystitis: results of a randomized, double-blind, placebo-controlled trial—treatment of interstitial cystitis/painful bladder syndrome with low-dose sildenafil. Urology. 2014.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Nickel JC, Herschorn S, Whitmore KE, Forrest JB, Hu P, Friedman AJ, et al. Pentosan polysulfate sodium for treatment of interstitial cystitis/bladder pain syndrome: insights from a randomized, double-blind, placebo-controlled study. J Urol. 2014.

    Article  PubMed  Google Scholar 

  18. Nickel JC, Egerdie B, Davis E, Evans R, Mackenzie L, Shrewsbury SB. A phase II study of efficacy and safety of a novel, oral SHIP1 activator, AQX-1125, in subjects with moderate to severe interstitial cystitis/bladder pain syndrome (IC/BPS). J Urol. 2016;196:747.

    Article  CAS  Google Scholar 

  19. Nickel JC, Moldwin R, Hanno P, Dmochowski R, Peters KM, Payne C, et al. Targeting the SHIP1 pathway fails to show treatment benefit in interstitial cystitis/bladder pain syndrome: lessons learned from evaluating potentially effective therapies in this enigmatic syndrome. J Urol. 2019;202(2):301–8.

    Article  Google Scholar 

  20. Matsumoto S, Ueda T, Kakizaki H. Effect of supplementation with hydrogen-rich water in patients with interstitial cystitis/painful bladder syndrome. Urology. 2013;81(2):226–23.

    Article  Google Scholar 

  21. Fall M, Oberpenning F, Peeker R. Treatment of bladder pain syndrome/interstitial cystitis 2008: can we make evidence-based decisions? Eur Urol. 2008;54(1):65–75.

    Article  Google Scholar 

  22. Vij M, Srikrishna S, Cardozo L. Interstitial cystitis: diagnosis and management. Eur J Obstet Gynecol Reprod Biol. 2012;161(1):1–7.

    Article  Google Scholar 

  23. Hanno PM, Buehler J, Wein AJ. Use of amitriptyline in the treatment of interstitial cystitis. J Urol. 1989;141(4):846–8.

    Article  CAS  Google Scholar 

  24. van Ophoven A, Pokupic S, Heinecke A, Hertle L. A prospective, randomized, placebo controlled, double-blind study of amitriptyline for the treatment of interstitial cystitis. J Urol. 2004;172(2):533–6.

    Article  Google Scholar 

  25. Nakamoto K, Nishinaka T, Mankura M, Fujita-Hamabe W, Tokuyama S. Antinociceptive effects of docosahexaenoic acid against various pain stimuli in mice. Biol Pharm Bull. 2010;33:1070–2.

    Article  CAS  Google Scholar 

  26. Salinthone S, Yadav V, Bourdette DN, Carr DW. Lipoic acid: a novel therapeutic approach for multiple sclerosis and other chronic inflammatory diseases of the CNS. Endocr Metab Immune Disord Drug Targets. 2008;8:132–42.

    Article  CAS  Google Scholar 

  27. Lee FH, Raja SN. Complementary and alternative medicine in chronic pain. Pain. 2011;152:28–30.

    Article  Google Scholar 

  28. Matsuda S, Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology. 2000;47:119.

    Article  CAS  Google Scholar 

  29. Porst H, McVary KT, Montorsi F, Sutherland P, Elion-Mboussa A, Wolka AM, et al. Effects of once-daily tadalafil on erectile function in men with erectile dysfunction and signs and symptoms of benign prostatic hyperplasia. Eur Urol. 2009;56:727–35.

    Article  CAS  Google Scholar 

  30. Stenton GR, Mackenzie LF, Tam P, Cross JL, Harwig C, Raymond J, et al. Characterization of AQX-1125, a small-molecule SHIP1 activator: part 1. Effects on inflammatory cell activation and chemotaxis in vitro and pharmacokinetic characterization in vivo. Br J Pharmacol. 2013;168:1506.

    Article  CAS  Google Scholar 

  31. Nickel JC, Forrest JB, Tomera K, Hernandez-Graulau J, Moon TD, Schaeffer AJ, et al. Pentosan polysulfate sodium therapy for men with chronic pelvic pain syndrome: a multicenter, randomized, placebo-controlled study. J Urol. 2005;173(4):1252–5.

    Article  Google Scholar 

  32. Fritjofsson A, Fall M, Juhlin R, Persson BE, Ruutu M. Treatment of ulcer and nonnuclear interstitial cystitis with sodium pentosanpolysulfate: a multicenter trial. J Urol. 1987;138(3):508–12.

    Article  CAS  Google Scholar 

  33. Mulholland SG, Hanno P, Parsons CL, Sant GR, Staskin DR. Pentosan polysulfate sodium for therapy of interstitial cystitis. Urology. 1990;35(6):552–8.

    Article  CAS  Google Scholar 

  34. Erickson DR, Sheykhnazari MS, Bhavanandan VP. Molecular size affects urine excretion of pentosan polysulfate. J Urol. 2006;175(3):1143–7.

    Article  CAS  Google Scholar 

  35. Zin CS, Nissen LM, Smith MT, O’Callaghan JP, Moore BJ. An update on the pharmacological management of post-herpetic neuralgia and painful diabetic neuropathy. CNS Drugs. 2008;22:417.

    Article  CAS  Google Scholar 

  36. Bratslavsky G, Kogan BA, Matsumoto S, Aslan AR, Levin RM. Reperfusion injury of the rat bladder is worse than ischemia. J Urol. 2003;170:2086–90.

    Article  Google Scholar 

  37. Cetinel S, Ercan F, Sirvanci S, Sehirli AO, Ersoy Y, San T, et al. The ameliorating effect of melatonin on protamine sulfate induced bladder injury and its relationship to interstitial cystitis. J Urol. 2003;169:1564–8.

    Article  CAS  Google Scholar 

  38. Kobayashi M, Nomura M, Nishii H, Matsumoto S, Fujimoto N, Matsumoto T. Effect of eviprostat on bladder overactivity in an experimental cystitis rat model. Int J Urol. 2008;15:356–60.

    Article  Google Scholar 

  39. Ohsawa I, Ishikawa M, Takahashi K, Watanabe M, Nishimaki K, Yamagata K, et al. Hydrogen acts as a therapeutic antioxidant by selectively reducing cytotoxic oxygen radicals. Nat Med. 2007;13:688–94.

    Article  CAS  Google Scholar 

Download references


Not applicable.



Author information

Authors and Affiliations



IPEW was the first one to come up with the idea for this systematic review and was a major contributor in writing the manuscript. VTD collect and analyze the data for the available publication and previous researches regarding this topic also contribute in writing the manuscript. IASW and KBU contributed to review the data analyzed. All authors read and approved the final manuscript.

Corresponding author

Correspondence to I Putu Eka Widyadharma.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Widyadharma, I.P.E., Dewi, V.T., Wijayanti, I.A.S. et al. Efficacy and safety of oral pharmacological and supplementary therapies in bladder pain syndrome: a systematic review. Egypt J Neurol Psychiatry Neurosurg 58, 61 (2022).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: