Bladder Instillations Versus Onabotulinumtoxin A for Treatment of Interstitial Cystitis/Bladder Pain Syndrome
Summary
Recognition of interstitial cystitis (IC)/bladder pain syndrome (BPS) is increasing. There is a dire need to develop effective treatment options for these patients as it manifests as more than a physical disease, affecting general and psychological health as well. Existing trials comparing varying bladder instillation formulations have not identified an optimal bladder instillation therapy, however existing studies support combined heparin and alkalinized lidocaine bladder instillation as an affordable and effective treatment for IC/BPS. Additionally, intradetrusor onabotulinumtoxinA injection has been well established for the treatment of overactive bladder (OAB), a constellation of symptoms similar to that of IC/BPS. OnabotulinumtoxinA has now come into the forefront for treatment of OAB due to its efficacy, safety profile, and absence of cognitive effects related to the previous mainstay anticholinergic treatment. While both bladder instillation and onabotulinumtoxinA therapy have been shown to be effective for treatment of IC/BPS, a direct comparison of these treatments has not been performed. We therefore designed a randomized controlled trial to compare the efficacy of heparin with alkalized local anesthetic bladder instillation versus intradetrusor onabotulinumtoxinA injection in treating IC/BPS symptoms.
Timeline
- Start
- 2020-09-15
- Primary completion
- 2023-06-01
- Completion
- 2023-06-01
Publications
- Background Hanno P, Dmochowski R. Status of international consensus on interstitial cystitis/bladder pain syndrome/painful bladder syndrome: 2008 snapshot. Neurourol Urodyn. 2009;28(4):274-86. doi: 10.1002/nau.20687.
- Background Berry SH, Elliott MN, Suttorp M, Bogart LM, Stoto MA, Eggers P, Nyberg L, Clemens JQ. Prevalence of symptoms of bladder pain syndrome/interstitial cystitis among adult females in the United States. J Urol. 2011 Aug;186(2):540-4. doi: 10.1016/j.juro.2011.03.132. Epub 2011 Jun 16.
- Background Clemens JQ, Link CL, Eggers PW, Kusek JW, Nyberg LM Jr, McKinlay JB; BACH Survey Investigators. Prevalence of painful bladder symptoms and effect on quality of life in black, Hispanic and white men and women. J Urol. 2007 Apr;177(4):1390-4. doi: 10.1016/j.juro.2006.11.084.
- Background Rothrock NE, Lutgendorf SK, Hoffman A, Kreder KJ. Depressive symptoms and quality of life in patients with interstitial cystitis. J Urol. 2002 Apr;167(4):1763-7.
- Background Rothrock N, Lutgendorf SK, Kreder KJ. Coping strategies in patients with interstitial cystitis: relationships with quality of life and depression. J Urol. 2003 Jan;169(1):233-6. doi: 10.1016/S0022-5347(05)64075-X.
- Background Nickel JC, Payne CK, Forrest J, Parsons CL, Wan GJ, Xiao X. The relationship among symptoms, sleep disturbances and quality of life in patients with interstitial cystitis. J Urol. 2009 Jun;181(6):2555-61. doi: 10.1016/j.juro.2009.02.030. Epub 2009 Apr 16.
- Background Nickel JC, Tripp DA, Pontari M, Moldwin R, Mayer R, Carr LK, Doggweiler R, Yang CC, Mishra N, Nordling J. Psychosocial phenotyping in women with interstitial cystitis/painful bladder syndrome: a case control study. J Urol. 2010 Jan;183(1):167-72. doi: 10.1016/j.juro.2009.08.133.
- Background Payne CK, Joyce GF, Wise M, Clemens JQ; Urologic Diseases in America Project. Interstitial cystitis and painful bladder syndrome. J Urol. 2007 Jun;177(6):2042-9. doi: 10.1016/j.juro.2007.01.124.
- Background Hurst RE. Structure, function, and pathology of proteoglycans and glycosaminoglycans in the urinary tract. World J Urol. 1994;12(1):3-10. doi: 10.1007/BF00182044.
- Background Parsons CL. The role of the urinary epithelium in the pathogenesis of interstitial cystitis/prostatitis/urethritis. Urology. 2007 Apr;69(4 Suppl):9-16. doi: 10.1016/j.urology.2006.03.084.
- Background Cvach K, Rosamilia A. Review of intravesical therapies for bladder pain syndrome/interstitial cystitis. Transl Androl Urol. 2015 Dec;4(6):629-37. doi: 10.3978/j.issn.2223-4683.2015.10.07.
- Background Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain. Cell. 2009 Oct 16;139(2):267-84. doi: 10.1016/j.cell.2009.09.028.
- Background Henry RA, Morales A, Cahill CM. Beyond a Simple Anesthetic Effect: Lidocaine in the Diagnosis and Treatment of Interstitial Cystitis/bladder Pain Syndrome. Urology. 2015 May;85(5):1025-1033. doi: 10.1016/j.urology.2015.01.021.
- Background Nickel JC, Stephens A, Landis JR, Mullins C, van Bokhoven A, Lucia MS, Ehrlich GD; MAPP Research Network. Assessment of the Lower Urinary Tract Microbiota during Symptom Flare in Women with Urologic Chronic Pelvic Pain Syndrome: A MAPP Network Study. J Urol. 2016 Feb;195(2):356-62. doi: 10.1016/j.juro.2015.09.075. Epub 2015 Sep 26.
- Background Pearce MM, Zilliox MJ, Rosenfeld AB, Thomas-White KJ, Richter HE, Nager CW, Visco AG, Nygaard IE, Barber MD, Schaffer J, Moalli P, Sung VW, Smith AL, Rogers R, Nolen TL, Wallace D, Meikle SF, Gai X, Wolfe AJ, Brubaker L; Pelvic Floor Disorders Network. The female urinary microbiome in urgency urinary incontinence. Am J Obstet Gynecol. 2015 Sep;213(3):347.e1-11. doi: 10.1016/j.ajog.2015.07.009. Epub 2015 Jul 23.
- Background Abernethy MG, Rosenfeld A, White JR, Mueller MG, Lewicky-Gaupp C, Kenton K. Urinary Microbiome and Cytokine Levels in Women With Interstitial Cystitis. Obstet Gynecol. 2017 Mar;129(3):500-506. doi: 10.1097/AOG.0000000000001892.
- Background Nickel JC, Stephens-Shields AJ, Landis JR, Mullins C, van Bokhoven A, Lucia MS, Henderson JP, Sen B, Krol JE, Ehrlich GD; MAPP Research Network. A Culture-Independent Analysis of the Microbiota of Female Interstitial Cystitis/Bladder Pain Syndrome Participants in the MAPP Research Network. J Clin Med. 2019 Mar 26;8(3):415. doi: 10.3390/jcm8030415.
- Background Meriwether KV, Lei Z, Singh R, Gaskins J, Hobson DTG, Jala V. The Vaginal and Urinary Microbiomes in Premenopausal Women With Interstitial Cystitis/Bladder Pain Syndrome as Compared to Unaffected Controls: A Pilot Cross-Sectional Study. Front Cell Infect Microbiol. 2019 Apr 8;9:92. doi: 10.3389/fcimb.2019.00092. eCollection 2019.
- Background Wolfe AJ, Toh E, Shibata N, Rong R, Kenton K, Fitzgerald M, Mueller ER, Schreckenberger P, Dong Q, Nelson DE, Brubaker L. Evidence of uncultivated bacteria in the adult female bladder. J Clin Microbiol. 2012 Apr;50(4):1376-83. doi: 10.1128/JCM.05852-11. Epub 2012 Jan 25.
- Background Weiss JM. Pelvic floor myofascial trigger points: manual therapy for interstitial cystitis and the urgency-frequency syndrome. J Urol. 2001 Dec;166(6):2226-31. doi: 10.1016/s0022-5347(05)65539-5.
- Background Bedaiwy MA, Patterson B, Mahajan S. Prevalence of myofascial chronic pelvic pain and the effectiveness of pelvic floor physical therapy. J Reprod Med. 2013 Nov-Dec;58(11-12):504-10.
- Background Sant GR, Propert KJ, Hanno PM, Burks D, Culkin D, Diokno AC, Hardy C, Landis JR, Mayer R, Madigan R, Messing EM, Peters K, Theoharides TC, Warren J, Wein AJ, Steers W, Kusek JW, Nyberg LM; Interstitial Cystitis Clinical Trials Group. A pilot clinical trial of oral pentosan polysulfate and oral hydroxyzine in patients with interstitial cystitis. J Urol. 2003 Sep;170(3):810-5. doi: 10.1097/01.ju.0000083020.06212.3d.
- Background Foster HE Jr, Hanno PM, Nickel JC, Payne CK, Mayer RD, Burks DA, Yang CC, Chai TC, Kreder KJ, Peters KM, Lukacz ES, FitzGerald MP, Cen L, Landis JR, Propert KJ, Yang W, Kusek JW, Nyberg LM; Interstitial Cystitis Collaborative Research Network. Effect of amitriptyline on symptoms in treatment naive patients with interstitial cystitis/painful bladder syndrome. J Urol. 2010 May;183(5):1853-8. doi: 10.1016/j.juro.2009.12.106. Epub 2010 Mar 29.
- Background Cassinelli G, Naggi A. Old and new applications of non-anticoagulant heparin. Int J Cardiol. 2016 Jun;212 Suppl 1:S14-21. doi: 10.1016/S0167-5273(16)12004-2.
- Background Nickel JC, Moldwin R, Lee S, Davis EL, Henry RA, Wyllie MG. Intravesical alkalinized lidocaine (PSD597) offers sustained relief from symptoms of interstitial cystitis and painful bladder syndrome. BJU Int. 2009 Apr;103(7):910-8. doi: 10.1111/j.1464-410X.2008.08162.x. Epub 2008 Nov 13.
- Background Kuo HC. Urodynamic results of intravesical heparin therapy for women with frequency urgency syndrome and interstitial cystitis. J Formos Med Assoc. 2001 May;100(5):309-14.
- Background Henry R, Patterson L, Avery N, Tanzola R, Tod D, Hunter D, Nickel JC, Morales A. Absorption of alkalized intravesical lidocaine in normal and inflamed bladders: a simple method for improving bladder anesthesia. J Urol. 2001 Jun;165(6 Pt 1):1900-3. doi: 10.1097/00005392-200106000-00014.
- Background Birch BR, Miller RA. Absorption characteristics of lignocaine following intravesical instillation. Scand J Urol Nephrol. 1994 Dec;28(4):359-64. doi: 10.3109/00365599409180513.
- Background Parsons CL, Zupkas P, Proctor J, Koziol J, Franklin A, Giesing D, Davis E, Lakin CM, Kahn BS, Garner WJ. Alkalinized lidocaine and heparin provide immediate relief of pain and urgency in patients with interstitial cystitis. J Sex Med. 2012 Jan;9(1):207-12. doi: 10.1111/j.1743-6109.2011.02542.x. Epub 2011 Nov 14.
- Background Nomiya A, Naruse T, Niimi A, Nishimatsu H, Kume H, Igawa Y, Homma Y. On- and post-treatment symptom relief by repeated instillations of heparin and alkalized lidocaine in interstitial cystitis. Int J Urol. 2013 Nov;20(11):1118-22. doi: 10.1111/iju.12120. Epub 2013 Feb 22.
- Background Davis EL, El Khoudary SR, Talbott EO, Davis J, Regan LJ. Safety and efficacy of the use of intravesical and oral pentosan polysulfate sodium for interstitial cystitis: a randomized double-blind clinical trial. J Urol. 2008 Jan;179(1):177-85. doi: 10.1016/j.juro.2007.08.170. Epub 2007 Nov 14.
- Background Sun Y, Chai TC. Effects of dimethyl sulphoxide and heparin on stretch-activated ATP release by bladder urothelial cells from patients with interstitial cystitis. BJU Int. 2002 Sep;90(4):381-5. doi: 10.1046/j.1464-410x.2002.02912.x.
- Background Shiga KI, Hirano K, Nishimura J, Niiro N, Naito S, Kanaide H. Dimethyl sulphoxide relaxes rabbit detrusor muscle by decreasing the Ca2+ sensitivity of the contractile apparatus. Br J Pharmacol. 2007 Aug;151(7):1014-24. doi: 10.1038/sj.bjp.0707317. Epub 2007 Jun 4.
- Background Perez-Marrero R, Emerson LE, Feltis JT. A controlled study of dimethyl sulfoxide in interstitial cystitis. J Urol. 1988 Jul;140(1):36-9. doi: 10.1016/s0022-5347(17)41478-9.
- Background Rawls WF, Cox L, Rovner ES. Dimethyl sulfoxide (DMSO) as intravesical therapy for interstitial cystitis/bladder pain syndrome: A review. Neurourol Urodyn. 2017 Sep;36(7):1677-1684. doi: 10.1002/nau.23204. Epub 2017 Feb 21.
- Background Erickson DR, Kunselman AR, Bentley CM, Peters KM, Rovner ES, Demers LM, Wheeler MA, Keay SK. Changes in urine markers and symptoms after bladder distention for interstitial cystitis. J Urol. 2007 Feb;177(2):556-60. doi: 10.1016/j.juro.2006.09.029.
- Background Hanno PM, Wein AJ. Conservative therapy of interstitial cystitis. Semin Urol. 1991 May;9(2):143-7. No abstract available.
- Background Kuo HC, Chancellor MB. Comparison of intravesical botulinum toxin type A injections plus hydrodistention with hydrodistention alone for the treatment of refractory interstitial cystitis/painful bladder syndrome. BJU Int. 2009 Sep;104(5):657-61. doi: 10.1111/j.1464-410X.2009.08495.x. Epub 2009 Mar 30.
- Background Welch MJ, Purkiss JR, Foster KA. Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins. Toxicon. 2000 Feb;38(2):245-58. doi: 10.1016/s0041-0101(99)00153-1.
- Background Durham PL, Cady R, Cady R. Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy. Headache. 2004 Jan;44(1):35-42; discussion 42-3. doi: 10.1111/j.1526-4610.2004.04007.x.
- Background 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 Sep;70(3):463-8. doi: 10.1016/j.urology.2007.04.038.
- Background Smith CP, Radziszewski P, Borkowski A, Somogyi GT, Boone TB, Chancellor MB. Botulinum toxin a has antinociceptive effects in treating interstitial cystitis. Urology. 2004 Nov;64(5):871-5; discussion 875. doi: 10.1016/j.urology.2004.06.073.
- Background Giannantoni A, Costantini E, Di Stasi SM, Tascini MC, Bini V, Porena M. Botulinum A toxin intravesical injections in the treatment of painful bladder syndrome: a pilot study. Eur Urol. 2006 Apr;49(4):704-9. doi: 10.1016/j.eururo.2005.12.002. Epub 2006 Jan 4.
- Background Apostolidis A, Dasgupta P, Fowler CJ. Proposed mechanism for the efficacy of injected botulinum toxin in the treatment of human detrusor overactivity. Eur Urol. 2006 Apr;49(4):644-50. doi: 10.1016/j.eururo.2005.12.010. Epub 2006 Jan 4.
- Background Coupland CAC, Hill T, Dening T, Morriss R, Moore M, Hippisley-Cox J. Anticholinergic Drug Exposure and the Risk of Dementia: A Nested Case-Control Study. JAMA Intern Med. 2019 Aug 1;179(8):1084-1093. doi: 10.1001/jamainternmed.2019.0677.
- Welch EK, Dengler KL, DiCarlo-Meacham AM, Wheat JE, Pekny CJ, Aden JK, Vaccaro CM. Bladder instillations vs onabotulinumtoxinA injection for interstitial cystitis/bladder pain syndrome: a randomized clinical trial. Am J Obstet Gynecol. 2024 Nov;231(5):528.e1-528.e11. doi: 10.1016/j.ajog.2024.05.027. Epub 2024 May 18.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Comparator | Botulinum toxin type A | Protein / enzyme biologic | 100 unknown | Other |
| Comparator | Heparin | Other / unclassified | 40000 iu | Other |
| Comparator | Lidocaine | Other / unclassified | 200 mg | Other |
| Comparator | sodium bicarbonate | Diagnostic / imaging agent | 2 ml | Other |