Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic and debilitating condition that negatively impacts quality of life. Several causes have been postulated in the pathogenesis of this condition; however, the aetiology remains unknown. IC/BPS may go undiagnosed for many years because the condition often co-exists with other chronic pain syndromes. Furthermore, the symptoms of IC/BPS vary considerably across patients, therefore no one treatment has shown to be consistently effective in providing relief. Thus, the goal of management of IC/BPS remains to provide relief of symptoms in order to improve a patient’s quality of life. Intravesical Botulinum toxin A (BoNT-A) is emerging as a potential new pharmacologic treatment for IC/BPS refractory to conventional treatment modalities. However, there is vey few data supporting the efficacy of this treatment. The aim of our short review is to assess the efficacy of intravesical BoNT-A in IC/BPS.

Chronic pain; Interstitial cystitis/bladder pain syndrome; Botulinum toxin A

Saraswat I, Lawrentschuk N (2015) Botulinum Toxin A in the Treatment of Interstitial Cystitis/Bladder Pain Syndrome: A Short Review. J Urol Res 2(1): 1021.

IC/BPS: Interstitial Cystitis/Bladder Pain Syndrome; BoNT-A: Botulinum Toxin A

Interstitial Cystitis/Bladder Pain syndrome (IC/BPS) is a clinical diagnosis primarily based on the symptoms of urinary urgency, frequency, nocturia and pain in the bladder or pelvis related to bladder filling [1,2]. This occurs in the absence of proven urinary tract infection or other obvious pathology. This condition is chronic and can be severely debilitating and has a negative impact on the quality of life of patients [3,4]. Although several causes have been postulated in the pathogenesis of IC/ BPS, including infection, autoimmune reaction, neurogenic inflammation, urothelial dysfunction and inherited susceptibility, the actual aetiology remains unknown [5]. The prevalence of IC/ BPS often tends to be underestimated [6]. IC/BPS occurs five times more commonly in women than men [7]. A comprehensive epidemiology study concluded that between 2.7 and 6.5 percent of United States women have symptoms consistent with IC/BPS [7].

Due to a lack of understanding of the aetiology of IC/BPS and the variability of symptoms among patients, no one treatment has shown to be consistently effective in providing relief. This was illustrated by the Interstitial Cystitis Data Base study, in which women underwent different types of therapy over several years of follow-up, no single therapy was found to be successful in most patients [8]. Consequently management is often directed at pain relief and improving quality of life. Intravesical Botulinum toxin A (BoNT-A) is emerging as a potential new pharmacologic treatment for patients with IC/BPS refractory to conventional treatment modalities. Our aim in this review is to assess the efficacy of intravesical BoNT-A in IC/BPS.

Diagnostic approach of IC/BPS and clinical features

The goal of diagnostic evaluation for IC/BPS is to identify characteristic features and exclude other conditions. The evaluation includes a careful history to elicit the symptoms and associated conditions, physical examination and urine analysis to exclude infection and haematuria. Baseline voiding symptoms and pain levels should be obtained using validated symptom scales such as the IC Symptom and Problem Index and Genitourinary Pain Index to assess symptom severity and measure subsequent treatment [9,10]. Cystoscopy and/or urodynamics are not required to make a diagnosis of IC/BPS. They are typically considered when there is clinical uncertainty about the diagnosis. Cystoscopy can be used to identify conditions such as bladder cancer and foreign bodies, additionally Hunner’s ulcer which is a typical cystoscopic finding in 10-15% of patients with IC/ BPS may be demonstrated [11]. Urodynamics may be indicated if there is suspicion of bladder outlet obstruction or neurogenic dysfunction. These tests are not necessary in uncomplicated presentations. It is also important to note that IC/BPS does not have any characteristic findings on medical imaging.

IC/BPS may go undiagnosed for many years, especially in mild or moderate disease. This is because the condition often coexists with other chronic pain syndromes including fibromyalgia, irritable bowel syndrome and vulvodynia. Additionally, symptoms can overlap with other gynaecological conditions including dysmenorrhoea and endometriosis and urologic conditions like bladder and urethral cancer. As a result this often makes the diagnosis of IC/BPC difficult [2,12].

The symptoms that tend to differentiate IC/BPS from other conditions are pelvic pain usually described as suprapubic or urethral and the most consistent feature being an increase in discomfort with bladder filling and a relief with voiding [13,14]. Urinary incontinence is not a typical feature of IC/BPS [11]. Regarding the onset of symptoms, patients often describe symptoms to be of gradual onset associated with worsening discomfort, urgency, frequency and nocturia over a period of months.

Mechanism of effect of BoNT-A therapy

BoNT-A is a potent neurotoxin derived from the anaerobic bacterium Clostridum botulinum. The mechanism of action of BoNT-A is likely due to its ability to modulate sensory neurotransmission and reduce neurogenic inflammation. This is done by impairing the release of neuropeptides such as such as substance P, calcitonin gene related peptide and glutamate, which are all involved in pain transmission from either dorsal root ganglion neurons, sensory afferents nerves and/or urothelial cells [15,16]. Hence by decreasing noxious input BoNT-A assists in providing analgesic effects, thus improving voiding frequency and nocturia [17,18].

One of the major advantages of intravesical BoNT is that it establishes high concentrations with few systemic side effects [19]. However, a potential disadvantage of BoNT-A administration is that the post void residual may increase and that there is a significant risk of urinary retention [18,19]. This may be especially devastating to a patient with painful bladder. Thus a patient who is considering having intravesical BoNT should be informed for the possibility of urinary retention and must also be willing and able to perform intermittent self catheterisation.

Efficacy of BoNT-A

There is few data regarding the efficacy and safety of BoNT treatment for IC/BPS. The best available data are from a small randomised controlled trial conducted by Kuo and colleagues 2009 [20]. In this study 67 patients were randomised to suburothelial injection of BoNT-A (100 U or 200 U) group combined with hydrodistension or to hydrodistension alone. The BoNT-A groups had a significantly higher proportion of patients with moderate or marked improvements in symptoms at six months (71 versus 48 percent). This difference was maintained at 12 and 24 months follow up (55 versus 26 percent) and (30 versus 17 percent) respectively. The appropriate dose of BoNT-A, however, was not determined. Several patients in the 200 units group had adverse reactions including acute or chronic urinary retention or severe dysuria. For this reason the dose was then decreased to 100 units. With 100 units the number of adverse events reduced but still occurred more frequent with hydrodistension alone.

Another study by Kuo 2013 examined the efficacy and safety of repeated intravesical BoNT-A. In this study thirty-one patients had a combination of 100 U of intravesical BoNT-A injection with cystoscopic hydrodistention under general anaesthesia. Four sessions of BoNT-A intravesical injections were shown to be safe and effective. Long term pain relief was recorded in 61% of the patients with IC/BPS who were refractory to conventional treatment. However, patients with Hunlner’s ulcer were poor candidates for this combined treatment [21]. Similarly, this finding was also concluded in a recent study conducted among 81 patients [22]. The study demonstrated significantly better success rates in patients who received 3 or 4 repeated injections of 100 U intravesical BoNT-A, compared to those who received a single injection. Furthermore, there was no significant difference (p=0.235) in occurrence of adverse events such as urinary tract infection, acute urinary retention and dysuria after repeated BoNT-A injections.

According to a study conducted by Pinto and colleagues 2010, the incidence of voiding dysfunction may be reduced by restraining BoNT-A to the trigone rather than injecting the whole bladder [16]. This is because as a fixed part of the bladder, predominantly innervated by sympathetic nerves the trigone does not contract during voiding [23]. Furthermore, by using only 100 units of BoNT-A the potential risk of complications can be further reduced. In this study and no cases of voiding dysfunction were reported. It is evident that further study is required on a larger cohort of patients in order to determine the optimal dose of BoNT-A and ideal location(s) for application so that patients experience optimal symptomatic relief and without significant complications.

Observational studies suggest that BoNT-A is associated with an improvement in symptoms in a subset of patients with IC/BPS. These symptoms gradually return to base line over six to nine months therefore repeated doses are often needed to maintain effective control of bladder pain and urgency [23-28]. However, if BoNT-A is used in conjunction with other modalities such as hydrodistension, as demonstrated in studies conducted by Kuo and colleagues and Chung and colleagues 2012, rather than BoNT-A alone, patients may experience longer symptomatic relief. The characteristic findings of all the studies are summarised (Table 1).

Table 1: Characteristics of the included studies.

Abbreviations: PVR: Post Void Residual; VAS: Visual Analogue Scale; OSS: O’Leary-Sant Score; FBC: Functional Bladder Capacity; HD: Hydro Distension; QOL: Quality of Life; NGF: Nerve Growth Factor; BDNF: Brain Derived Neurotrophic Factor; ICPI: O’Leary Cystitis Problem Index; ICSI: O’Leary Cystitis Symptom Index

In conclusion IC/BPS is a chronic condition that often exists with other pain syndromes. It also negatively impacts on the quality of life of patients. Its aetiology remains unknown and no one treatment has been shown to be consistently effective in providing relief. BoNT-A appears to provide effective, short term relief for a subset of patients. The beneficial effects, however, progressively decrease within a few months after treatment. Thus repeat injections of the neurotoxin are required. Further studies are warranted in order to determine the ideal dose of BoNT-A and location to apply at so patients receive maximal symptomatic relief without significant complications.

1. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U et al. The standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the international continence society. Neurourol Urodyn. 2002; 2: 167-178.
2. Driscoll A, Teichman JM. How do patients with interstitial cystitis present? J Urol. 2001; 166: 2118-2120.
3. Koziol JA. Epidemiology of interstitial cystitis. Urol Clin North Am. 1994; 21: 7-20.
4. Konkle KS, Berry SH, Elliott MN, Suttorp MJ, Clauw DJ, Clemens JQ. Comparison of an interstitial cystitis/bladder pain syndrome clinical cohort with symptomatic community women from RAND interstitial cystitis epidemiology study. J Urol. 2012; 187: 508-512
5. Diokno AC, Homma Y, Sekiguchi Y, Suzuki Y. Interstitial cystitis, gynecologic pelvic pain, prostatitis, and their epidemiology. Int J Urol. 2003; 10 Suppl: S3-6.
6. Parsons CL, Tatsis V. Prevalence of interstitial cystitis in young women. Urology. 2004; 64: 866-870.
7. Clemens JQ, Joyce GF, Wise M, Payne CK. Interstitial cystitis and painful bladder syndrome. In: Urologic Diseases in America. Litwin MS, Saigal, editors. US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Washington, DC: US Government Publishing Office, 2007; 125–154.
8. Rovner E, Propert KJ, Brensinger C, Wein AJ, Marilou F, Kirkemo A, et al. Treatments used in women with interstitial cystitis: the interstitial database (ICBD) study experience. The Interstitial Cystitis Data Base Study Group. Urology. 2000; 56: 940-945.
9. O'Leary MP, Sant GR, Fowler FJ Jr, Whitmore KE, Spolarich-Kroll J. The interstitial cystitis symptom index and problem index. Urology. 1997; 49: 58-63.
10. Clemens JQ, Calhoun EA, Litwin MS, McNaughton-Collins M, Kusek JW, Crowley EM. Validation of a modified National Institutes of Health chronic prostatitis symptom index to assess genitourinary pain in both men and women. Urology. 2009; 74: 983-987.
11. Dellis A, Papatsoris AG. Intavesical treatment of bladder pain syndrome/interstitial cystitis: from the conventional regimens to the novel botulinum toxin injections. Expert Opin Investig Brugs. 2014; 23: 751-757.
12. Porru D, Politanò R, Gerardini M, Giliberto GL, Stancati S, Pasini L. Different clinical presentation of interstitial cystitis syndrome. Int Urogynecol J Pelvic Floor Dysfunct. 2004; 15: 198-202.
13. Bogart LM, Berry SH, Clemens JQ. Symptoms of interstitial cystitis, painful bladder syndrome and similar diseases in women: a systemic review. J Urol. 2007; 177: 450-456.
14. Teichman JM, Parsons CL. Contemporary clinical presentation of interstitial cystitis. Urology. 2007; 69: S41-S47.
15. 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: 1138-1142.
16. Manning J, Dwyer P, Rosamilia A, Colyvas K, Murray C, Fitzgerald E. A multicentre prospective, randomised, double blinded study to measure the treatment effectiveness of abobotulinum A (AboBTXA) among women with refractory interstitial cystitis/bladder pain syndrome. Int Urogynaecol J. 2014; 25: 593-599.
17. Apostolidis A, Dasgupta P, Denys P, Elneil S, Fowler CJ, Giannantoni A, et al. Recommendations on the use of botulinum toxin in the treatment of lower urinary tract disorders and pelvic floor dysfunctions: a European consensus report. Eur Urol. 2009; 55: 100-119.
18. 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: 1529-1532.
19. Hsu CC, Chuang YC, Chancellor MB. Intravesical drug delivery for dysfunctional bladder. Int J Urol. 2013; 20: 552-562.
20. 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; 104: 657-661.
21. Kuo HC. Repeated intravesical onabotulinumtoxinA injections are effective in treatment of refractory interstitial cystitis/bladder pain syndrome. Int J Clin Pract. 2013; 67: 427-434.
22. Kuo HC. Repeated intravesical onabotulinumtoxin-A injections provide better results than single injection in treatment of painful bladder syndrome. Pain Physician. 2013; 16: E15-E23.
23. Pinto R, Lopes T, Frias B, Silva A, Silva, JA, Silva AM, et al. Trigonal injection of botulinum Toxin A in patients with refractory bladder pain syndrome/interstitial cystitis. Eur Urol. 2010; 58: 360-365.
24. 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: 463-468.
25. 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; 49: 704-709.
26. Giannantoni A, Porena M, Costantini E, Zucchi A, Mearini L, Mearini E. Botulinum A toxin intravesical injection in patients with painful bladder syndrome: 1-year followup. J Urol. 2008; 179: 1031-1034.
27. Kuo HC. Preliminary results of suburothelial injection of botulinum a toxin in the treatment of chronic interstitial cystitis. Urol Int. 2005; 75: 170-174.
28. Chung SD, Kuo YC, Kuo HC. Intravesical onabotulinumtoxinA injections for refractory painful bladder syndrome. Pain Physician. 2012; 15: 197-202.