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Current Bladder Dysfunction Reports
Published in: Current Bladder Dysfunction Reports 2/2023

Open Access 15-02-2023 | Cystitis | BPS/INTERSTITIAL CYTITIS (D CASTRO-DIAZ AND Y IGAWA, SECTION EDITORS)

Botulinum Toxin Therapy for Bladder Pain Syndrome/Interstitial Cystitis

Authors: Mohammad Sajjad Rahnama’i, Aida Javan Balegh Marand, Dick Janssen, Hadi Mostafaei, Sotirios Gatsos, Sakineh Hajebrahimi, Apostolos Apostolidis, Rajesh Taneja

Published in: Current Bladder Dysfunction Reports | Issue 2/2023

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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
Literature
1.
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.PubMedCrossRef
2.
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.PubMedCrossRef
3.
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.PubMedCrossRef
4.
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.PubMedPubMedCentral
5.
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.PubMedCrossRef
6.
Neuhaus J, Schwalenberg T. Intravesical treatments of bladder pain syndrome/interstitial cystitis. Nat Rev Urol. 2012;9(12):707–20.PubMedCrossRef
7.
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.PubMedCrossRef
8.
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.PubMedCrossRef
9.
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.PubMedCrossRef
10.
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.PubMedCrossRef
11.
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.PubMedCrossRef
12.
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.PubMed
13.
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.PubMedCrossRef
14.
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.PubMedCrossRef
15.
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.PubMedPubMedCentralCrossRef
16.
17.
18.
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.PubMedCrossRef
19.
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.PubMedCrossRef
20.
21.
22.
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.PubMedCrossRef
23.
24.
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.PubMedPubMedCentralCrossRef
25.
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.
26.
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.PubMedCrossRef
27.
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.PubMedCrossRef
28.
29.
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.PubMedCrossRef
30.
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.PubMedCrossRef
31.
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.PubMedCrossRef
32.
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.PubMedCrossRef
33.
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.PubMedCrossRef
34.
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.PubMedCrossRef
35.
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.PubMedCrossRef
36.
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.PubMedCrossRef
37.
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.PubMedCrossRef
38.
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.PubMedCrossRef
39.
40.
41.
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.PubMedCrossRef
42.
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.PubMedPubMedCentralCrossRef
43.
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.PubMedCrossRef
44.
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.PubMedCrossRef
45.
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.PubMedCrossRef
46.
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.PubMedCrossRef
47.
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.PubMedCrossRef
48.
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.PubMedPubMedCentralCrossRef
49.
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.PubMedCrossRef
50.
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.PubMedPubMedCentralCrossRef
51.
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.
52.
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.PubMedCrossRef
53.
54.
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.PubMedCrossRef
55.
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.PubMedCrossRef
56.
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.PubMedCrossRef
57.
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.PubMedCrossRef
58.
Qiu H, Guo H, Li D, Hou Y, Kuang T, Ding J. Intravesical hydrogels as drug reservoirs. Trends Biotechnol. 2020;38(6):579–83.PubMedCrossRef
59.
60.
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.PubMedCrossRef
61.
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.PubMedCrossRef
62.
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.PubMedCrossRef
63.
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.PubMedCrossRef
Metadata
Title
Botulinum Toxin Therapy for Bladder Pain Syndrome/Interstitial Cystitis
Authors
Mohammad Sajjad Rahnama’i
Aida Javan Balegh Marand
Dick Janssen
Hadi Mostafaei
Sotirios Gatsos
Sakineh Hajebrahimi
Apostolos Apostolidis
Rajesh Taneja
Publication date
15-02-2023
Publisher
Springer US
Published in
Current Bladder Dysfunction Reports / Issue 2/2023
Print ISSN: 1931-7212
Electronic ISSN: 1931-7220
DOI
https://doi.org/10.1007/s11884-023-00695-6

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