Abstract
Purpose of Review
Bladder pain syndrome (BPS)/interstitial cystitis (IC) can also be classified as either non-ulcerative or ulcerative, corresponding to the characteristic cystoscopic findings under hydrodistention. Promising therapeutic effects, including decreased bladder pain, have been reported from recent clinical trials using botulinum toxin A (BoNTA) for the treatment of BPS/IC. This review summarizes the current state of the literature on the underlying mechanisms of BoNTA therapy in BPS/IC as well as new forms of its application.
Recent Findings
BoNTA has its effect in the central nervous system in the afferent nerves as well as in the bladder wall. Besides the well-known effects of BoNTA in the nervous system, pain control as well as reduction of urinary urgency in BPS patients could be achieved by mast cell stabilization effecting histamine release as well as modulation of TRPV and PGE2 pathways, among other systems. In addition, new forms of BoNTA administration have focused on intravesical instillation of the drug in order to circumvent bladder wall injections. Hyperthermia, intravesical hydrogel, and lysosomes have been studied as new ways of BoNTA application in BPS/IC patients. From the available studies, bladder instillation of BoNTA in combination with EMDA is the most promising and effective novel approach.
Summary
The most promising novel application methods for BoNTA in patient with BPS/IC are bladder instillations. Future research needs to point out if bladder instillations with BoNTA with some form of bladder absorption enhancement such as hyperthermia or EMDA would be able to replace BoNTA injections in patients with BPS/IC
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Introduction
Bladder pain syndrome (BPS) is defined as “bladder filling accompanied by suprapubic pain and intensified daytime and night time frequency in the lack of urinary infection, or other pathologies of the lower urinary tract” [1].
Chronic pelvic pain syndrome (CPPS) is defined by pain in the pelvic area that can have different aetiologies. This can be due to urologic, gynaecologic, musculoskeletal, gastrointestinal, neurologic, and autoimmune or rheumatologic diseases with dramatic psychosocial impacts [2,3,4]. Patients with predominant bladder pain symptoms without any other diagnosis are often referred to as BPS patients. Another often used term is interstitial cystitis (IC) which refers to a subgroup of patients with BPS who have Hunner’s lesion or histological changes in their bladder biopsies.
CPPS, BPS, and IC are linked but are not synonyms. They are often even defined slightly different by different societies or authorities. According to the definition of the International Society for the Study of Interstitial Cystitis/Bladder Pain Syndrome (ESSIC), BPS/IC is defined by the chronic pelvic pain that a patient feels it is related to the bladder, with urgency and/or frequency [5].
BPS/IC is more common in women than men, though it may be confused with chronic prostatitis among men [6].
BPS/IC can also be classified as either non-ulcerative or ulcerative, corresponding to the characteristic cystoscopic findings under hydrodistention [7]. Due to their distinct underlying patho-physiologies and approaches regarding treatment, non-ulcerative BPS/IC and ulcerative are seen as two unique conditions [8]. Those suffering from ulcerative BPS/IC tend to be patients of older age with a smaller bladder capacity and more bladder pain in comparison to those suffering from non-ulcerative BPS/IC. Between 10 and 20% of BPS/IC patients suffer from ulcerative BPS/IC [9].
Subsequently, the majority of treatment methods used are off-label as both the diagnosis and treatment are challenging. A number of invasive treatments have been identified. Among them are intravesical injections of botulinum toxin A [10].
Clinical Efficacy of Botulinum Toxin A BPS/IC
Promising therapeutic effects, including decreased bladder pain, have been reported from recent clinical trials using botulinum toxin A (BoNTA) for the treatment of BPS/IC [10].
Botulinum toxin A selectively regulates sensory function, inflammation, and glandular function, suppresses detrusor overactivity, and disrupts and regulates neurotransmission. Since botulinum toxin A has been known to possess sensory inhibitory effects and anti-inflammatory effects alongside motor effects, it has been used as a treatment method for BPS/IC and overactive bladders (OAB). Consequently, the therapeutic period was observed to be longer with several Botox injections than with a single injection [11].
In another study, it was discovered that ulcerative BPS/IC did not respond well to four recurring injections of 100 U of a BoNTA, once every 6 months [12]. Though this research indicates that BoNTA treatment is perhaps not suitable for ulcerative BPS/IC, a Portuguese group discovered that Botox trigonal injection provided satisfactory results in subjects with ulcerative BPS/IC and that treatment results regarding symptom intensity do not differ among ulcerative and non-ulcerative BPS/IC [13]. A point to be considered is that ulcerative BPS/IC is not properly defined and thus treatment outcomes with regard to Botox injections in ulcerative and non-ulcerative BPS/IC may not be properly compared. Regardless, considering the weak results of conventional treatment methods with ulcerative BPS/IC, ulcerative BPS/IC should be viewed as a different disease from non-ulcerative BPS/IC.
Recent published data support the effectiveness of Botox in relieving bladder pain and inconvenient bladder symptoms in subjects with refractory BPS/IC. Short-term success could be achieved in bladder pain, frequency, and bladder capacity with Botox injections. Long-term therapeutic results are not reached and the application of Botox for BPS/IC has not yet been approved, though repeat Botox injections may have long-term effective outcomes [11].
Systematic reviews and meta-analyses confirm the promising results of BoNTA in reducing pain intensity in BPS/IC patients. However, the number of studies included in the first evidence-based meta-analysis was limited to five randomized clinical trials (RCT) comprising 252 patients (133 subjects in the intervention group vs. 119 cases in the control group), with a varied injection dose between 50 and 200 U. The results showed that VAS score and Interstitial Cystitis Problem Index (ICPI) as well as frequency were improved after the intervention. The other reported outcomes (Interstitial Cystitis Symptom Index (ICSI), nocturia, maximal urinary flow rate (Qmax), and functional bladder capacity (FBC) were not statistically different between the two groups [14]. Another systematic review included only seven RCTs and one retrospective study. The results revealed that despite a slight increase in PVR levels, Botox® injections reduced pelvic pain, ICPI, and ICSI. Except for a significant improvement in daily urinary frequency and maximum cystometric capacity, no difference was observed in Qmax, dysuria, and urinary tract infection (UTI) rate following treatment [15].
In a more recent systematic review by Giannantoni et al., comprising 12 RCTs, the results showed a change in ICSI in ten trials, in ICPI score in nine trials, in pain score based on VAS in seven trials, in the Likert scale in two trials, in urinary frequency in 8 trials, Qmax in 6 trials, in PVR in 7 trials, and FBC in 7 trials. Based on the meta-analysis results, a moderate effect size, considering standardized mean difference, in VAS changes for pain and urinary frequency was observed. Besides, a small to moderate SMD was detected for changes in ICSI and ICPI scores. In terms of nocturia and functional bladder capacity and Qmax, there were no changes in SMD. Larger SMD was detected only for changes in PVR, which, as expected, is a possible complication of neurotoxin injection into the bladder wall and represents a side effect [16].
There is great variation in neurotoxin doses, injection methods, and injection sites in RCTs included in the systematic reviews. In fact, in 11 clinical trials, BoNTA was injected in different doses (50–300 units) and in different locations (Trigone: 3 studies, whole bladder wall: one study, out of Trigone: 3 studies, and bladder neck in one study). Abobotulinum A (Abobot/A or Dysport®, 500 U) was used as the active treatment in a single clinical trial. Recently, the authors reported the outcomes of 300–500 U Dysport® intravesical injection in refractory BPS/IC. The results revealed that most cases had good or intermediate improvement (93%) based on the Bladder Pain/Interstitial Cystitis Symptom Score (BPIC-SS) questionnaire results [17].
In addition, the depth of injections into the bladder wall varied between the included trials. Regarding the injection site, BoNTA was injected into the detrusor or sub-urothelially in four clinical trials. In some cases, BoNTA was administered under general anesthesia (3 trials), spinal anesthesia (1 trial), or local anesthesia (1 trial), and in the remaining studies, the types of anesthesia were not described. There was also a great deal of variation in the factors used in the control groups. In different studies of hydrodistension dilation, normal saline, normal saline plus hydrodistension, Calmette-Guerin bacillus (BCG), lipotoxin, and pentosan polysulfate sodium instillation were reported. In addition, in one study, the control group included patients who received Onabot/A delayed injections compared with patients in the active group who received neurotoxin A immediately [18].
Considering the adverse events including UTI, urinary retention, pain, and haematuria, some researchers attempt to show the role of lipotoxin on the success rate and reduce the side effects. However, to date, lipotoxin has failed to demonstrate a positive proof of concept compared to BoNTA or placebo [19].
To support BoNTA as a standard treatment for patients with BPS/IC, and to know if this method is effective or not, further randomized, placebo-controlled studies (RCTs) with larger patient samples are needed. The studies should aim to clarify how to inject it (injection into the detrusor muscle or in the bladder urothelium), whether or not use other toxin types than Botox® as well as side effects.
Mechanism of Action of Intravesical BoNTA: How Might It Contribute in the Treatment of BPS/IC?
Our understanding of the analgesic mechanism of action of BoNTA in the bladder involves various interactions in nociception pathways, mediated by effects on peripheral sensory nerves and on the central nervous system but, also, by direct histological change [20, 21]. The current notion is largely extrapolated by findings of preclinical studies. On the level of peripheral sensory nerves, BoNTA inhibits the release of urothelial ATP in animal models of chronic bladder inflammation [22], which activates P2X3 receptors, implicated in sensory and pain pathways [23, 24]. BoNTA has also been associated with downregulation of TRPV1 in suburothelial fibers, a tension and pain receptor [25, 26], as well as with a reduction of nerve growth factor (NGF) [27], which has been shown to elicit hyperalgesia and promote neuronal growth and sprouting [28]. In animal models of bladder pain, acute or chronic inflammation, intravesical BOTOX administration reduced not only the release of nociceptive neurotransmitters such as calcitonin gene-related peptide (CGRP) and substance P (SP), but also the histological inflammation [29,30,31]. The anti-inflammatory action of BOTOX is also supported by studies demonstrating a reduction in COX-2 and EP4 expression in animal bladder and spinal cord [32]. Further evidence for the involvement of central pathways in the mechanism of action of Botox was provided by animal models of CYP-induced cystitis: Intravesically administered Botox reduced the c-fos expression in the L6-S1 dorsal root ganglia [33], while the intrathecal administration of BoNTA improved bladder function and pain-associated behavior, possibly via reversal of the effect of CYP on inflammatory markers such as c-Fos, p-ERK, and CGRP [34]. Finally, intravesical administration of BoNTA using low-intensity extracorporeal shock wave treatment was associated with significantly lower expressions of TNF-α and IL-6 and significantly reduced submucosal edema and inflammatory cell infiltration [35]. Further research is warranted to completely unveil the perplexed analgesic action of BoNTA in human urological pain syndromes and BPS/IC.
Novel Approaches to Administer BoNTA into the Bladder Wall
Cystoscopic-guided BoNTA injections into the bladder wall have been used for a variety of bladder dysfunctions. For BPS/IC, bladder wall injections have been well described [14]. Intratrigonal [36] and trigone sparing techniques [37] have been described. Alternative techniques of intravesical administration of botulinum toxin have evolved in recent years, aiming to reduce the adverse effects and improve the acceptability of this agent.
New ideas on BoNTA administration predominantly focus on intravesical instillation of the drug in order to circumvent bladder wall injections [38, 39]. The potential benefits of this application strategy would be a less invasive procedure and a more homogenous spread of the toxin across the bladder wall surface. The main challenge for intravesical BoNTA instillations to work is getting an adequate concentration of the drug across the urothelial barrier.
There is some evidence that BoNTA inhibits COX-2 and EP4 expression in the bladder, interacts with SNARE proteins in the urothelium, and modulates urothelial ATP release [32, 40,41,42]. It is currently unknown if this effect would be clinically relevant in BPS/IC patients, but ATP and purinergic signaling are considered one of the primary afferent signaling pathways within the bladder [40]. If clinically relevant, an inhibitory effect on urothelial afferent pathways would give more rationale for intravesical BoNTA instillation for BPS/IC.
Shatoury et al. explored the use of hyaluronan-phosphatidylethanolamine as a vehicle for BoNTA to improve efficacy of intravesical application of BoNTA and demonstrated a comparable reaction in SNAP25 immunostaining compared to injected BoNTA in a rat model [43].
Another potential route for improving BoNTA incorporation into the bladder wall is to make the urothelium more permeable before BoNTA is applied. To accomplish this, low-energy shockwave treatment combined with BoNTA instillation was investigated in a rat model by Chuang et al. and showed improvement of urodynamic parameters and decreased SNAP and COX-2 expression compared to controls [44]. Shock wave therapy has been found to reduce the inflammation in bladder using another rat model [45]. In a prospective randomized double-blind placebo-controlled trial, low-energy shock wave treatment imparted benefit to the patients with bladder pain syndrome [46].
Hyperthermia could also be an interesting option to explore, since it is being applied for intravesical chemotherapy in bladder cancer [47, 48]. Heated mitomycin C increases the cytotoxic effect by temporarily increasing the permeability of urothelial cell membranes and disruption of cell junctions [47, 49]. This is currently done with radiofrequency (microwave)-heated catheter systems that heat the bladder up to 45–46 °C for 1 h [50]. Applicability for intravesical BoNTA treatments would depend on the stability of the BoNTA compound under hyperthermic conditions and efficacy/burden ratio of a hyperthermia treatment compared to the traditional injection technique.
Electromotive drug administration (EMDA) is a minimally invasive method of intravesical instillation of therapeutic agents using short burst of electromotive force. It involves a combination of iontophoresis, electrophoresis, and electroporation to deliver drugs into deep tissue layers using an electrical current created between two electrodes [51]. This can be done under local anesthesia using lignocaine and epinephrine. It utilizes a system containing a DC current generator and catheter electrodes. This technique has been used to deliver intravesical agents for a variety of clinical conditions such as inflammations of the urinary bladder and the prostate, cancer of the urinary bladder, and overactive bladder [52]. In a systematic review, six studies including 89 patients with bladder pain syndrome, treated with administration of botulinum toxin using EDMA, were identified [53]. These studies report promising results but the limitations of the included studies are the small number of patients, with the non-randomized design.
Several other techniques are being investigated in clinical studies [43, 44, 54]. In the transcellular approach, bladder instillation of drug-containing liposomes is used to cross the urothelial cellular membranes through normally occurring endocytosis processes [54]. Botulinum toxin is a large molecule and cannot penetrate the urothelium to act on the target tissue. Therefore, it has been encapsulated into a liposome to be used as an intravesical instillation [55]. Chuang et al. investigated this with BoNTA in a clinical RCT in 62 OAB patients with a significant effect on symptoms [56]. However, an additional RCT from the same group evaluating 31 BPS/IC patients could not show significant improvement [19]. Intravesical liposomal botulinum toxin has been compared with oral PPS in patients with BPS/IC and found to have equivalent results [57]. In a prospective multicentre double-blind, randomized trial, bladder instillation of liposome encapsulated onabotulinum toxin A was found to improve symptoms in BPS/IC [19].
Intravesical hydrogel is another possible way of drug administration. The complex urothelial layer poses difficulties in intravesical drug administration. Drug delivery systems based on the hydrogel reservoirs have been studied [58]. Hydrogels are three-dimensional network of hygroscopic polymers which act as reservoir of drug [59]. In the urinary bladder, intravesical use of hydrogel for drug delivery can prolong retention time in the bladder giving an opportunity for sustained drug release and maintaining drug concentration resulting in better therapeutic efficacy [39]. A pilot study in patients with overactive bladder concluded that intravesically instilled botulinum toxin embedded in inert hydrogel could be a good alternative to intravesical injections [60]. In a single-arm pilot study, BPS/IC patients were treated with intravesical administration of TC-3 hydrogel embedded BoNTA [61]. Despite lack of a placebo arm, it was concluded that bladder pain and urinary frequency significantly decreased at 12 weeks follow-up. Although preliminary studies revealed promising therapeutic outcomes, only few clinical trials with limited patients have been conducted.
Discussion
Even though repeat injections have shown benefit in cases of refractory BPS/IC [62], there is a subset of patients who may not benefit, especially the ones with ulcerations [12]. Long-term compliance for intravesical botulinum toxin has been poor due to recurrent retention of urine necessitating intermittent catheterizations and voiding LUTS [63]. In Fig. 1, different levels of effect of BoNTA have been summarized. BoNTA has its effect in the central nervous system in the afferent nerves as well as in the bladder wall. Besides the well-known effects of BoNTA in the nervous system, pain control as well as reduction of urinary urgency in BPS patients could be achieved by mast cell stabilization effecting histamine release as well as modulation of TRPV and PGE2 pathways, among other systems.
New forms of BoNTA administration have focused on intravesical instillation of the drug in order to circumvent bladder wall injections. From the available studies, bladder instillation of BoNTA in combination with EMDA is the most promising and effective novel approach although most studies are limited with a small number of included patients and have a non-randomized results. Hence, more high-powered randomized studies are needed to confirm the promising results of BoNTA bladder instillation with EMDA.
Conclusion
The most promising novel application methods for BoNTA in patient with BPS/IC are bladder instillations. Future research needs to point out if bladder instillations with BoNTA with some form of bladder absorption enhancement such as hydrogel, liposomes, hyperthermia, or EMDA would be able to replace BoNTA injections in patients with BPS/IC.
References
Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al. The standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Urology. 2003;61(1):37–49.
Doggweiler R, Whitmore KE, Meijlink JM, Drake MJ, Frawley H, Nordling J, et al. A standard for terminology in chronic pelvic pain syndromes: a report from the chronic pelvic pain working group of the international continence society. Neurourol Urodyn. 2017;36(4):984–1008.
Patnaik SS, Lagana AS, Vitale SG, Buttice S, Noventa M, Gizzo S, et al. Etiology, pathophysiology and biomarkers of interstitial cystitis/painful bladder syndrome. Arch Gynecol Obstet. 2017;295(6):1341–59.
Rahnama’i MS, Javan A, Vyas N, Lovasz S, Singh N, Cervigni M, et al. Bladder pain syndrome and interstitial cystitis beyond horizon: reports from the Global Interstitial Cystitis/Bladder Pain Society (GIBS) Meeting 2019 Mumbai - India. Anesth Pain Med. 2020;10(3):e101848.
van de Merwe JP, Nordling J, Bouchelouche P, Bouchelouche K, Cervigni M, Daha LK, et al. Diagnostic criteria, classification, and nomenclature for painful bladder syndrome/interstitial cystitis: an ESSIC proposal. Eur Urol. 2008;53(1):60–7.
Neuhaus J, Schwalenberg T. Intravesical treatments of bladder pain syndrome/interstitial cystitis. Nat Rev Urol. 2012;9(12):707–20.
Nigro DA, Wein AJ, Foy M, Parsons CL, Williams M, Nyberg LM Jr, et al. Associations among cystoscopic and urodynamic findings for women enrolled in the Interstitial Cystitis Data Base (ICDB) Study. Urology. 1997;49(5A Suppl):86–92.
Peters KM, Killinger KA, Mounayer MH, Boura JA. Are ulcerative and nonulcerative interstitial cystitis/painful bladder syndrome 2 distinct diseases? A study of coexisting conditions. Urology. 2011;78(2):301–8.
Denson MA, Griebling TL, Cohen MB, Kreder KJ. Comparison of cystoscopic and histological findings in patients with suspected interstitial cystitis. J Urol. 2000;164(6):1908–11.
Rahnama’i MS, Marcelissen T, Apostolidis A, Veit-Rubin N, Schurch B, Cardozo L, et al. The efficacy of botulinum toxin A and sacral neuromodulation in the management of interstitial cystitis (IC)/bladder pain syndrome (BPS), what do we know? ICI-RS 2017 think thank, Bristol. Neurourol Urodyn. 2018;37(S4):S99–107.
Chen JL, Kuo HC. Clinical application of intravesical botulinum toxin type A for overactive bladder and interstitial cystitis. Investig Clin Urol. 2020;61(Suppl 1):S33-s42.
Lee CL, Kuo HC. Intravesical botulinum toxin a injections do not benefit patients with ulcer type interstitial cystitis. Pain Physician. 2013;16(2):109–16.
Pinto R, Lopes T, Costa D, Barros S, Silva J, Silva C, et al. Ulcerative and nonulcerative forms of bladder pain syndrome/interstitial cystitis do not differ in symptom intensity or response to onabotulinum toxin A. Urology. 2014;83(5):1030–4.
Shim SR, Cho YJ, Shin IS, Kim JH. Efficacy and safety of botulinum toxin injection for interstitial cystitis/bladder pain syndrome: a systematic review and meta-analysis. Int Urol Nephrol. 2016;48(8):1215–27.
Wang J, Wang Q, Wu Q, Chen Y, Wu P. Intravesical botulinum toxin A injections for bladder pain syndrome/interstitial cystitis: a systematic review and meta-analysis of controlled studies. Med Sci Monit. 2016;22:3257–67.
Giannantoni A, Gubbiotti M, Bini V. Botulinum neurotoxin A intravesical injections in interstitial cystitis/bladder painful syndrome: a systematic review with meta-analysis. Toxins (Basel). 2019;11(9):510. https://doi.org/10.3390/toxins11090510.
Rahnama’i MS, Saar M, Saeedi S, Salehi Pourmehr H, Hajebrahimi S. Intravesical injection with abobotulinumtoxin-A in patients with bladder pain syndrome/interstitial cystitis. Eur Urol. 2022;81(Supplement 1):S1147. https://doi.org/10.1016/s0302-2838(22)00852-1.
Akiyama Y, Nomiya A, Niimi A, Yamada Y, Fujimura T, Nakagawa T, et al. Botulinum toxin type A injection for refractory interstitial cystitis: a randomized comparative study and predictors of treatment response. Int J Urol. 2015;22(9):835–41.
Chuang YC, Kuo HC. A prospective, multicenter, double-blind, randomized trial of bladder instillation of liposome formulation onabotulinumtoxinA for interstitial cystitis/bladder pain syndrome. J Urol. 2017;198(2):376–82.
Matak I, Bölcskei K, Bach-Rojecky L, Helyes Z. Mechanisms of botulinum toxin type A action on pain. Toxins (Basel). 2019;11(8):459. https://doi.org/10.3390/toxins11080459.
Yeh TC, Chen PC, Su YR, Kuo HC. Effect of botulinum toxin A on bladder pain-molecular evidence and animal studies. Toxins (Basel). 2020;12(2):98. https://doi.org/10.3390/toxins12020098.
Smith CP, Vemulakonda VM, Kiss S, Boone TB, Somogyi GT. Enhanced ATP release from rat bladder urothelium during chronic bladder inflammation: effect of botulinum toxin A. Neurochem Int. 2005;47(4):291–7.
Krajewski JL. P2X3-containing receptors as targets for the treatment of chronic pain. Neurotherapeutics. 2020;17(3):826–38.
Ford AP, Gever JR, Nunn PA, Zhong Y, Cefalu JS, Dillon MP, et al. Purinoceptors as therapeutic targets for lower urinary tract dysfunction. Br J Pharmacol. 2006;147(Suppl 2):S132–43.
Apostolidis A, Popat R, Yiangou Y, Cockayne D, Ford AP, Davis JB, et al. Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor injections of botulinum toxin for human detrusor overactivity. J Urol. 2005;174(3):977–82; discussion 82–3.
Avelino A, Charrua A, Frias B, Cruz C, Boudes M, de Ridder D, et al. Transient receptor potential channels in bladder function. Acta Physiol (Oxf). 2013;207(1):110–22.
Liu HT, Kuo HC. Intravesical botulinum toxin A injections plus hydrodistension can reduce nerve growth factor production and control bladder pain in interstitial cystitis. Urology. 2007;70(3):463–8.
Barker PA, Mantyh P, Arendt-Nielsen L, Viktrup L, Tive L. Nerve growth factor signaling and its contribution to pain. J Pain Res. 2020;13:1223–41.
Chuang YC, Yoshimura N, Huang CC, Chiang PH, Chancellor MB. Intravesical botulinum toxin a administration produces analgesia against acetic acid induced bladder pain responses in rats. J Urol. 2004;172(4 Pt 1):1529–32.
Lucioni A, Bales GT, Lotan TL, McGehee DS, Cook SP, Rapp DE. Botulinum toxin type A inhibits sensory neuropeptide release in rat bladder models of acute injury and chronic inflammation. BJU Int. 2008;101(3):366–70.
Rapp DE, Turk KW, Bales GT, Cook SP. Botulinum toxin type a inhibits calcitonin gene-related peptide release from isolated rat bladder. J Urol. 2006;175(3 Pt 1):1138–42.
Chuang YC, Yoshimura N, Huang CC, Wu M, Chiang PH, Chancellor MB. Intravesical botulinum toxin A administration inhibits COX-2 and EP4 expression and suppresses bladder hyperactivity in cyclophosphamide-induced cystitis in rats. Eur Urol. 2009;56(1):159–66.
Vemulakonda VM, Somogyi GT, Kiss S, Salas NA, Boone TB, Smith CP. Inhibitory effect of intravesically applied botulinum toxin A in chronic bladder inflammation. J Urol. 2005;173(2):621–4.
Coelho A, Oliveira R, Rossetto O, Cruz CD, Cruz F, Avelino A. Intrathecal administration of botulinum toxin type A improves urinary bladder function and reduces pain in rats with cystitis. Eur J Pain. 2014;18(10):1480–9.
Nageib M, Zahran MH, El-Hefnawy AS, Barakat N, Awadalla A, Aamer HG, et al. Low energy shock wave-delivered intravesical botulinum neurotoxin-A potentiates antioxidant genes and inhibits proinflammatory cytokines in rat model of overactive bladder. Neurourol Urodyn. 2020;39(8):2447–54.
Pinto RA, Costa D, Morgado A, Pereira P, Charrua A, Silva J, et al. Intratrigonal onabotulinumtoxinA improves bladder symptoms and quality of life in patients with bladder pain syndrome/interstitial cystitis: a pilot, single center, randomized, double-blind, placebo controlled trial. J Urol. 2018;199(4):998–1003.
Apostolidis A, Rahnama’i MS, Fry C, Dmochowski R, Sahai A. Do we understand how botulinum toxin works and have we optimized the way it is administered to the bladder? ICI-RS 2014. Neurourology and urodynamics. 2016;35(2):293–8.
Yunfeng G, Fei L, Junbo L, Dingyuan Y, Chaoyou H. An indirect comparison meta-analysis of noninvasive intravesical instillation and intravesical injection of botulinum toxin-A in bladder disorders. Int Urol Nephrol. 2022;54(3):479–91.
Jhang JF, Kuo HC. Novel applications of non-invasive intravesical botulinum toxin a delivery in the treatment of functional bladder disorders. Toxins. 2021;13(5):359. https://doi.org/10.3390/toxins13050359.
Ibrahim H, Maignel J, Hornby F, Daly D, Beard M. BoNT/A in the urinary bladder-more to the story than silencing of cholinergic nerves. Toxins (Basel). 2022;14(1):53. https://doi.org/10.3390/toxins14010053.
Hanna-Mitchell AT, Wolf-Johnston AS, Barrick SR, Kanai AJ, Chancellor MB, de Groat WC, et al. Effect of botulinum toxin A on urothelial-release of ATP and expression of SNARE targets within the urothelium. Neurourol Urodyn. 2015;34(1):79–84.
Ikeda Y, Zabbarova IV, Birder LA, de Groat WC, McCarthy CJ, Hanna-Mitchell AT, et al. Botulinum neurotoxin serotype A suppresses neurotransmitter release from afferent as well as efferent nerves in the urinary bladder. Eur Urol. 2012;62(6):1157–64.
El Shatoury MG, DeYoung L, Turley E, Yazdani A, Dave S. Early experimental results of using a novel delivery carrier, hyaluronan-phosphatidylethanolamine (HA-PE), which may allow simple bladder instillation of botulinum toxin A as effectively as direct detrusor muscle injection. J Pediatr Urol. 2018;14(2):172.e1-e6.
Chuang YC, Huang TL, Tyagi P, Huang CC. Urodynamic and immunohistochemical evaluation of intravesical botulinum toxin A delivery using low energy shock waves. J Urol. 2016;196(2):599–608.
Wang HJ, Lee WC, Tyagi P, Huang CC, Chuang YC. Effects of low energy shock wave therapy on inflammatory moleculars, bladder pain, and bladder function in a rat cystitis model. Neurourol Urodyn. 2017;36(6):1440–7.
Chuang YC, Meng E, Chancellor M, Kuo HC. Pain reduction realized with extracorporeal shock wave therapy for the treatment of symptoms associated with interstitial cystitis/bladder pain syndrome-a prospective, multicenter, randomized, double-blind, placebo-controlled study. Neurourol Urodyn. 2020;39(5):1505–14.
Jacob J, Hindmarsh JR, Ludgate CM, Chisholm GD. Observations on the ultrastructure of human urothelium: the response of normal bladder of elderly subjects to hyperthermia. Urol Res. 1982;10(5):227–37.
Zhao H, Chan VW, Castellani D, Chan EO, Ong WLK, Peng Q, et al. Intravesical chemohyperthermia vs bacillus Calmette-Guerin instillation for intermediate- and high-risk non-muscle invasive bladder cancer: a systematic review and meta-analysis. Front Surg. 2021;8:775527.
Uçar M, Altok M, Umul M, Bayram D, Armağan İ, Güneş M, et al. The effect of thermochemotherapy with mitomycin C on normal bladder urothelium, an experimental study. Int Urol Nephrol. 2016;48(1):79–84.
Rath-Wolfson L, Moskovitz B, Dekel Y, Kugel V, Koren R. Combined intravesical hyperthermia and mitomycin chemotherapy: a preliminary in vivo study. Int J Exp Pathol. 2003;84(3):145–52.
Giannantoni A, Di Stasi SM, Chancellor MB, Costantini E, Porena M. New frontiers in intravesical therapies and drug delivery. European urology. 2006;50(6):1183–93; discussion 93.
Kajbafzadeh AM, Ahmadi H, Montaser-Kouhsari L, Sharifi-Rad L, Nejat F, Bazargan-Hejazi S. Intravesical electromotive botulinum toxin type A administration–part II: clinical application. Urology. 2011;77(2):439–45.
Hashemi S, Sahai A, Malde S. Applications of electromotive drug administration in urology. Urol Ann. 2020;12(4):301–8.
Chuang YC, Tyagi P, Huang CC, Yoshimura N, Wu M, Kaufman J, et al. Urodynamic and immunohistochemical evaluation of intravesical botulinum toxin A delivery using liposomes. J Urol. 2009;182(2):786–92.
Tyagi P, Chancellor MB, Li Z, De Groat WC, Yoshimura N, Fraser MO, et al. Urodynamic and immunohistochemical evaluation of intravesical capsaicin delivery using thermosensitive hydrogel and liposomes. J Urol. 2004;171(1):483–9.
Chuang YC, Kaufmann JH, Chancellor DD, Chancellor MB, Kuo HC. Bladder instillation of liposome encapsulated onabotulinumtoxina improves overactive bladder symptoms: a prospective, multicenter, double-blind, randomized trial. J Urol. 2014;192(6):1743–9.
Chuang YC, Lee WC, Lee WC, Chiang PH. Intravesical liposome versus oral pentosan polysulfate for interstitial cystitis/painful bladder syndrome. J Urol. 2009;182(4):1393–400.
Qiu H, Guo H, Li D, Hou Y, Kuang T, Ding J. Intravesical hydrogels as drug reservoirs. Trends Biotechnol. 2020;38(6):579–83.
Kopecek J. Hydrogel biomaterials: a smart future? Biomaterials. 2007;28(34):5185–92.
Krhut J, Navratilova M, Sykora R, Jurakova M, Gärtner M, Mika D, et al. Intravesical instillation of onabotulinum toxin A embedded in inert hydrogel in the treatment of idiopathic overactive bladder: a double-blind randomized pilot study. Scand J Urol. 2016;50(3):200–5.
Rappaport YH, Zisman A, Jeshurun-Gutshtat M, Gerassi T, Hakim G, Vinshtok Y, et al. Safety and feasibility of intravesical instillation of botulinum toxin-A in hydrogel-based slow-release delivery system in patients with interstitial cystitis-bladder pain syndrome: a pilot study. Urology. 2018;114:60–5.
Kuo HC. Repeated intravesical onabotulinumtoxinA injections are effective in treatment of refractory interstitial cystitis/bladder pain syndrome. Int J Clin Pract. 2013;67(5):427–34.
Rahnama’i MS, Marcelissen TAT, Brierley B, Schurch B, de Vries P. Long-term compliance and results of intravesical botulinum toxin A injections in male patients. Neurourol Urodyn. 2017;36(7):1855–9.
Funding
Open Access funding enabled and organized by Projekt DEAL.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Competing Interests
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical collection on BPS/Interstitial Cytitis
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 http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Rahnama’i, M.S., Marand, A.J.B., Janssen, D. et al. Botulinum Toxin Therapy for Bladder Pain Syndrome/Interstitial Cystitis. Curr Bladder Dysfunct Rep 18, 147–153 (2023). https://doi.org/10.1007/s11884-023-00695-6
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11884-023-00695-6