FEMALE UROLOGY Evaluation of Therapeutic Effect of Intratrigonal Injection of AbobotulinumtoxinA(Dysport) and Hydrodistention in Refractory Interstitial Cystitis /Bladder Pain Syndrome Mahtab Zargham1*, Mahdieh Mahmoodi1, Hamid Mazdak1, Farhad Tadayon2, Mansooreh Mansori3, Maryam Kazemi4, Mohamad Hatef Khorami1, Narjes Saberi1 Purpose: There are two brands of BotulinumtoxinA(BTXA) that are commonly used in the treatment of Lower Urinary Tract Disease: OnabotolinumtoxinA(Ona-BTXA) and AbobotulinumtoxinA (Abo-BTXA). The present study was conducted to assess the potential therapeutic and adverse effects of Abo-BTXA or Dysport for interstitial cystitis/bladder pain syndrome (IC/BPS). Materials and Methods: Twenty-two out of 52 women diagnosed with IC/BPS who were refractory or had a low response to oral treatments of IC/BPS after 6 months, were included in the study. The end-point was O'Leary-Sant Score (OSS) including “symptoms” and “problem” indexes (ICSI and ICPI respectively) assessment after 1,3and 6 months after Abo-BTXA injection. Each patient underwent cystoscopy and immediately after hydrodistention received intratrigonal injections of 300 IU of Abo-BTXA (Dysport®) in 30 sites. The effect and side effects of this treatment over time have been investigated. Complications including high post void residual urine (PVR), bladder rupture, and urinary tract infections (UTI) were also assessed. Results: The mean age of patients was 46.2 ± 13.7 years and the median OSS was 27.8 ± 5.8.: After a single injec- tion ICSI, ICPI, and total OSS significantly reduced in 1, 3, and 6 months follow up; rate of decreased total OSS was 39.5%, 36%, 18%, respectively. Its effect lasted up to six months and started to decrease after 1 month (p-value < 0.05). Complications included urinary retention (PVR > 200ml), bladder rupture, and UTI in 13.5%, 4.3%, and 18% of the patients, respectively. Conclusion: Intravesical injection of 300IU Abo-BTX(Dysport) could be a useful approach for the treatment of patients with refractory IC/BPS in a period of six months. Keywords: AbobotilinumtoxinA; bladder pain syndrome; Botulinum toxin ; Dysport; refractory interstitial cystitis; intravesicle injection INTRODUCTION Interstitial cystitis/bladder pain syndrome (IC/BPS) is characterized by symptoms like urinary urgency, urinary frequency, and nocturia in middle-aged wom- en. Due to the lack of a universal concurrence of the diagnostic criteria, it is not possible to estimate the prevalence of IC/BPS precisely; however, it has been reported that between 2.7% and 6.5% of the women in the United States suffer from IC.(1) In addition, based on the O'Leary-Sant Score (OSS) questionnaire prevalence of IC/BPS among women has been reported to be 265 in 100,000 in Japan, 450 in 100,000 in Finland, and 306 in 100,00 in Austria(2-4) Although patients usually suffer from dysuria and have urinary urgency in the absence of UTI, their conditions rarely (14%) related to urodynamic detrusor overactiv- ity.(5) The exact pathophysiology of IC/BPS is unclear; 1Isfahan Kidney Transplantation Research center, Department of urology, AL-Zahra Research Institute, Isfahan University of Medical Science, Isfahan, Iran 2Isfahan Kidney Transplantation Research center, Department of urology, Noor Hospital, Isfahan University of Medical Science, Isfa- han, Iran 3Urology Department, Treata Hospital, Iran university of medicine science 4Pelvic Floor Research Center Department of Physical Therapy Faculty of Rehabilitation Sciences Isfahan University of Medical Sciences Isfahan, School of Public Health, Isfahan University of Medical Sciences. *Correspondence: Urology Department, Al-Zahra Hospital, Shohadaye Soffeh Blvd., Isfahan, Iran. E mail: mah_zargham@yahoo.com. Received December 2019 & Accepted November 2020 however, some possible underlying factors are pro- posed to explain the etiology of the disease including changes in urothelial permeability, mast cell activation, and abnormal sensory nerve stimulation especially in bladder afferent pathways. The interesting point in the last hypothesis is that it includes all other mechanisms and provides a comprehensive explanation; i.e., neu- ritis.(6) According to this hypothesis, some of the sug- gested treatments focused on intravesical therapy; e.g., hydraulic distension of the bladder, intravesical instilla- tion of DMSO, or chondroitin sulfate.(1) Considering the probable neuritis origin of IC/BPS, a neuromodulation procedure that directly manipulates the vesical nerves can be a reasonable treatment(7) Intravesical injection of Botulinum toxin type A (BTXA) was suggested as an overactive bladder (OAB) and IC/BPS treatment for the first time 15 years ago.(8) Many studies approved its positive effect in, improv- Urology Journal/Vol 18 No. 2/ March-April 2021/ pp. 203-208. [DOI: 10.22037/uj.v16i7.5879] ing bladder sensory symptom and pain in association with reduction of the level of urinary NGF levels.(9-11), and interestingly some other studies reported that the response in patients with IC/PBS depends on the pheno- type of the disease, i.e., ulcerative or non-ulcerative.(12) To assess the effects of Abo-BTXA on IC/BPS symp- toms according to OSS questionnaire including urinary urgency, urinary frequency, nocturia, and suprapubic pain, patient’s quality of life, and potential complica- tions of this method, we designed the present study to compare the symptoms and complications related to IC/ BPS in female patients before and after intravesical in- jection of Abo-BTXA. To our knowledge, there is little evidence about intravesical injection effects of Abo- BTXA versus Ona-BTXA (BOTOX). MATERIALS AND METHODS Patients The study was designed as a single-center prospective interventional quasi-experimental study and was con- ducted between November 2013 and October 2017 in our center. Ethical and technical approval was obtained from the Urology and Transplantation Research Center of Isfahan University of Medical Sciences. The partici- pants of the present study included women 18- 80 years old examined at the outpatient clinics affiliated to Isfa- han University of Medical Sciences. The participants were diagnosed with IC/BPS based on ICDB criteria and their symptoms lasted at least 4 months.(13) All these patients received different medical treatments approved in the AUA guideline of interstitial cystitis for 1 year.(14) Other inclusion criteria were a lack of response to the medical treatment or recurrence of symptoms after at least 6 months. All participants were informed about the therapeutic effects and complications of the treatment including generalized muscle weakness, difficulties in urination, transient urinary retention, clean intermittent catheterization (CIC), and UTI. Informed consent was obtained from all participants. Exclusion criteria included any gross pathology in uri- nary tract, active UTI (as documented by urine culture), pregnancy, pelvic radiation, endometriosis, bladder cancer, pelvic reconstructive surgery, anti-incontinence surgery, and any contraindications of BTXA injection including a known allergy to Dysport, a history of my- asthenia gravis, amyotrophic lateral sclerosis or injec- tion of the toxin for any reason in previous 6 months. Procedures and technique Among 52 women diagnosed with IC/BPS, 22 patients who did not respond to conventional medication treat- ments of IC/BPS according to 2017 EUA guidelines, developed side effects, or who refused the treatment were enrolled in the study. All patients were admitted to the hospital on the day of the procedure. IC/BPS symptom and problem indexes were evaluated before the treatment by the OSS questionnaire. The internal consistency of the indices is precisely enhanced by Cronbach's alpha, which exceeded 0.85 for the symp- tom index, and 0.90 for the problem index.(15) All patients received 1g ceftriaxone before the proce- dure and underwent regional or general anesthesia de- pending on the choice of the anesthesiologist. injection technique and type of toxin are still controversial issues. We used Dysport because it is the only type of BTXA approved by the Ministry of Health in Iran. In addition, there are few studies about the intravesical injection of Abo-BTXA for the treatment of IC/PBS; therefore, the result of evaluating this type of botulinum in this group of women would be interesting. All patients received 300UI of Dysport (Abobotulinum toxin A, Ipsen Biop- harmaceuticals, Pharma, Germany, DYS-US-001865). After cystoscopy and bladder hydrodistention, each 300U Dysport vial was diluted with 3 ml of normal sa- line (the concentration was 100IU/ml). The amount of toxin is controversial and depends on the type of BTXA and indications. We used the lowest doses of Abo- BTXA (300 IU) which has been utilized intravesical successfully in adult patients. Dysport 300U in 3 cc saline was injected as 30 trigonal and bladder base of 0.1 ml (every lateral side of trigon triangle 6-8 injections and inside and outside of base or inter orifice ridge of trigon at suburothelium 14-18 injections) using 21GA needle (10 IU/site). We chose intratrigonal injection because trigon contains a prom- inent parasympathetic plexus, the most concentrated site of sensory and peripheral afferent nerve ending in the bladder. Foley catheter was removed after 24 hours. Patients were discharged during the first postoperative day if PVR was less than 200 ml. Patients had been recommended and taught timed voiding. Ciprofloxacin 500mg for 5 days was also prescribed for them. Pa- tients were in a stable condition regarding their LUTS before intervention; therefore, the change of their OSS was considered to result from intravesical treatment. Patients were examined at 1, 3, and 6 months after the injection. The primary goal of the study was assessing the changes of OSS, the voiding diary, brief symptoms inventory, the occurrence of UTI, CIC, and urethra or bladder perforation. Finally, the results of the OSS and voiding diary were compared between pre and post in- travesical injection. The therapeutic outcome was assessed using the OSS Demographic variable Details Age(year),mean ±SD 46.24 ± 13.791 Duration of symptoms(m),mean ± SD 111.73 ± 113.653 Marriage, N (%) Married 20(90.9) Single 2(9.1) Pelvic surgery N (%) C/S 5(22.72) Hysterectomy 4(18.18) Tube ligation 3(13.63) Cystocele repair 2(9.09) Perianal abscess drainage 1 (4.54) None 9(40.9) NVD N (%) None 9(40.9) 2 5(22.72) 4 4(18.18) 3 2(9.09) 5 1(4.54) 1 1(4.54) Comorbidity N (%) None 12(54.54) IBS 4(18.18) Anemia 2(9.09) Discopathy 2(9.09) PUD 1(4.54) HTN 1(4.54) IBD 1(4.54) Nephrolithiasis 1(4.54) Hypothyroidism 1(4.54) UTI, N (%) 10(45.5) Nervosas 18(81.8) Table 1. Demographic information and medical records. Dysport) in Refractory IC/BPS-Zargham et al. Vol 18 No 2 March-April 2021 204 changes, every patient's OSS was compared with base- line: women with more than 10% improved total OSS after treatment were considered to have recovery re- sponse, otherwise, patients were considered “non-re- sponder”. Statistical analysis was performed using SPSS version 25.0 and the level of significance was considered 0.05. Investigation of changes in OSS and symptom indices mean over time were performed by repeated measures analysis of variance (ANOVA) to examine the impact of the intervention over time. The post-hoc test is then performed to find a significant dif- ference at times. In addition, tests of within-subject's contrasts were performed to examine the shape of the mean changes over time. RESULTS Twenty-two out of 52 women diagnosed with BPS en- rolled in the interventional phase of the study. The steps are shown in Figure 1. The patients aged from 24 to 74 years with a mean of 46.24 ± 13. 71 years. The duration of symptoms was from 6 to 396 months and its mean was 111.73±113.653 months. The majority of patients (90.9%) were married. The most common pelvic surgery was a cesarean sec- tion (5 patients, 22.7%), which may be a predispos- ing factor for PBS. More than half of the patients did not have any comorbidities but the most common one among those who had was IBS (4 patients, 18.18%). Positive urine culture in a patient’s medical records was considered as UTI. According to this index, 12 patients (54.5%) did not have any infection and 10 (45.5%) had at least one episode of UTI. Demographic information and medical records of patients are detailed in Table 1. The results (Table 2) show a total mean of 27.86 ± 5.808 for total OSS score before the treatment, the mean rate of its was reduced to 38.99% after 1 month, 36.72% after 3 months, and 18.78% after 6 months (p-value< 0.001). We obtained a mean of 14.82 ± 3.800 for the ICSI before the treatment. As presented in Table 2, the mean symptom index reduced to 45.38%, 40.18%, and 18.1% after 1, 3, and 6 months, respectively (p-value< 0.001). Each of the symptoms evaluated by OSS ques- tionnaire including urgency, frequency, nocturia, and suprapubic pain/dysuria had a significant reduction (all p values: < 0.001). The ICPI mean was 13.04 ± 2.192 before the treatment that reduced to 36.28%, 33.44%, and 18.49% after 1, 3, and 6 months, respectively(all p values: < 0.001). Willing to retreatment was taken into account when the patient asked for the re-injection again. Seven patients (31.8%) were willing to receive the treatment again while 15 were not, which of these 15, one patient was completely cured and two experienced a major decrease in their symptoms. Only 4 patients did not have a record of nervosis, such as depression, anxiety, chronic tension headache. Complications were classified into two major cate- gories: the systemic adverse effects of Dysport and Vesicle formation after surgery. The systemic adverse effects of Dysport (including weakness in all of the muscles in the body, double vision, difficulty breathing, or swallowing) did not happen in any of the patients. The bladder complication happened in 4 patients. In one of them, “bladder rupture” was developed due to neglected urinary retention, which was completely re- stored. The patient administered an indwelling catheter for 7 days and was advised to take CIC for 5 days. This patient finally had completely normal urination and was one of the patients who returned after 1 year for retreat- Dysport) in Refractory IC/BPS-Zargham et al. Table 2. The changes of Parameters at baseline, 3 and 6 months after single BoNT-A injection Parametrs Baseline 1 Months 3 Months 6 Months p-value OSS 27.863 ± 5.808 17.0 ± 9.304 17.636 ± 9.348 22.636 ± 8.742 < 0/001 Symptom 14.818 ± 3.800 8.090 ± 5.681 8.863±5.453 12.136 ± 5.148 < 0/001 Problem index 13.045 ± 2.192 8.318 ± 4.156 8.681±4.133 10.636 ± 3.885 < 0/001 Urgency (s1) 4.22 ± 1.06 2.40 ± 1.62 2.50 ± 1.50 3.27 ± 1.57 < 0/001 Frequency (s2) 3.90 ± 1.37 2.04 ± 1.49 2.22 ± 1.44 3.04 ± 1.52 < 0/001 Nocturia(s3) 3.00 ± 1.57 2.04 ± 1.98 2.09 ± 1.94 2.68 ± 1.75 < 0/001 Suprapubic pain/dysuria (s4) 3.68 ± 1.24 2.04 ± 1.13 2.18 ± 1.29 2.86 ± 1.32 < 0/001 Figure 1. Flow diagram of enrollment of patients to the study. Female Urology 205 ment. Voiding dysfunction and overflow incontinence due to impaired detrusor contractility happened in 3 pa- tients who needed CIC for 1-2 weeks after the interven- tion. UTI developed in 5 of the patients during the first 6-month follow-up. DISCUSSION Our results suggest that a dose of 300 IU Abo-BTXA results in the improvement of QOL and a decrease in irritative symptoms in IC/BPS patients similar to the ef- fect of 100 IU of Botox.(16,17) OSS and QOL improved significantly: The peak effect of the treatment was about 1 month (40% reduction rate in OSS) but it could last for six months (20% reduction rate in OSS). Tests of contrasts showed the decline over the six-month was non-linear. The sharpest decline was observed in the first month, followed by a trend of up to three months and rising in six months. Although various botulinum toxin preparations and serotypes have a similar mech- anism, which is blocking neurotransmitter release(18), a comparison of Ona-BTXA (Botox) and Abo-BTXA (Dysport) showed that Botox tends to have higher effi- cacy, longer duration, and higher frequency of adverse effects in the treatment of detrusor overactivity.(19) Our results show that urine urgency has the highest frequency among patients but the one that makes the biggest effect on the quality of life is suprapubic pain or dysuria. Based on the literature, Abo-BTXA is a chemical neuromodulator affecting the sensory and pain nerves by inhibition of neurotransmitter release in neuromuscular junctions, especially in cholinergic terminals(20) and reduction of some sensory receptors like P2X3 and TRPV1(21), and capsaicin expression in axons. In addition, it has central desensitization effects by a decrease in uptake of substance P in CNS.(22) The efficacy of Abo-BTXA in our groups of patients was less than expected compared to Botox used in another similar study.(22) Our results were different from the results obtained by Kuo HC et al.(23) One possible explanation is the use of different questionnaires - OSS in our study versus VAS in Kuo’s study. Another explanation is that BOTOX is more effective than Dysport in blocking of sensory nerve endings. It is expected that patients referred for LUTS treatment who have a high urinary score on UPOINT show a bet- ter response to intravesical injection. Therefore, esti- mation of the patient’s UPOINT score before treatment helps in the identification and selection of those who have a high score on urinary or organ-specific domain, which leads to a better rate of successful treatment. BTXA has been reported to have an antinociceptive ef- fect on IC/BPS.(8) In addition, other studies approved the positive effect of BTXA on decreasing the IC/BPS symptoms(9,23,24) and increasing the bladder capacity and urodynamic parameters.(10,25,26) Some studies reported that the injection of Abo-BTXA followed by hydro- distention can reduce bladder pain.(27,28) In contrast, oth- er studies that used the injection of BTXA without hy- drodistention supported the efficacy of injecting BTXA without hydrodistention.(11) We decided to use hydrodistention before Dysport in- jection according to the theory that sensory nerve end- ing necrosis due to hydrodistention may increase toxin absorption and efficacy. It has been reported that this treatment can reduce the irritative symptoms and in- crease the bladder capacity only in the non-ulcer type of IC/BPS, and there is no improvement in symptoms or urodynamic in ulcer type of the disease.(12) In a cohort study by Pinto et al. (2014), it was suggested that there is no connection between the presence and absence of “Hunner’s ulcer” and response to Ona-BTXA.(29) Stud- ies that injected Botox multiple times reported that the therapeutic effects of multiple injections are persistent. (30) In addition in another study, it was suggested that multiple injections provide better outcomes compared to a single injection.(31) There are other studies including a multi-center randomized double-blind study that did not obtain any positive effects - reducing or curing the symptoms - after treatment.(32,33) There is no study about the therapeutic and adverse effects of Abo-BTXA or Dysport on IC/BPS in Iran; therefore, this study can be a guide for more sophisticated researches in the future. The follow-up period was 6 months in this study and we observed that the therapeutic effects reduced over time, however, the effects remained after the 6-month follow-up. In one study, the authors reported that the therapeutic effects can persist more than 50% after 9 months.(26) Since we excluded any patient with contrain- dications to BTXA including patients with Gillen Barre, patients using aminoglycoside, or those with any histo- ry of Dysport hypersensitivity, we did not observe any significant systemic adverse effects related to Dysport. It is noteworthy that no other study reported such ad- verse effects.(20) We had two major bladder-related complications, one was bladder rupture and the other was prolonged urinary retention ( > 4 weeks) which was reported in other studies (10,30,34) and could be related to the dosage of the toxin. In a study that used 100 IU Bot- ox, no adverse effects were reported.(26) Extraperitoneal bladder rupture was observed in one of the patients 24 hours after injection due to the neglected urinary reten- tion. Although the rupture was successfully restored and the patient did not experience any difficulties and returned for retreatment the next year, it is a serious issue that should be investigated further. Certainly, it should be kept in mind that the rupture of the bladder is a limitation on the scientific basis of hydrodistention(34) and urinary retention, especially in thin bladder wall of BPS patients. We advised routine control of PVR in all the patients because bladder sensation after Abo-BTXA (Dysport) injection is not reliable. Post-surgery UTI is one of the complications reported in some studies.(10,35) We also observed acute cystitis in 4 (18%) patients dur- ing the 6-month follow-up. It may be due to impaired contractility and high PVR after Dysport injection. The response rate to intravesical injection of Dysport was less than 40%, the matter is why it fails in some of patients and how we must improve patient selection for intravesical treatment? Because of heterogeneous nature of PBS, detailed clinical phenotype using UP- OINT (urinary, psychosocial, organ specific, infection, neurological/systemic / tenderness) system may guide therapy for this organ specific and urinary treatment.(36) IC/BPS women with less domains of UPOINT may be have a better response to treatment.(37) Due to finan- cial limitations we designed the study without a control group. In addition, we did not include urodynamic test and only asked if patients suffered from voiding dys- function or urge incontinence. Therefore, further in- vestigations using UPOINT, applying other assessment methods and having a control group provide additional Dysport) in Refractory IC/BPS-Zargham et al. Vol 18 No 2 March-April 2021 206 Female Urology 207 information about the treatment options of the patients. CONCLUSIONS Injection of 300 IU Abo-BTX A has shown to improve symptoms and QOL in half of the women with refracto- ry IC/ PBS. In addition, there was a low risk of retention and morbid complications in the patients. CONFLICT OF INTEREST None declared. APPENDIX: https://journals.sbmu.ac.ir/urolj/index.php/uj/libraryFiles/downloadPublic/19 REFERENCES 1. Berry SH, Elliott MN, Suttorp M, et al. Prevalence of symptoms of bladder pain syndrome/interstitial cystitis among adult females in the United States. J Urol. 2011;186:540-4. 2. Inoue Y, Mita K, Kakehashi M, Kato M, Usui T. Prevalence of painful bladder syndrome (PBS) symptoms in adult women in the general population in Japan. Neurourol Urodyn. 2009;28:214-8. 3. Leppilahti M, Tammela TL, Huhtala H, Auvinen A. Prevalence of symptoms related to interstitial cystitis in women: a population based study in Finland. J Urol. 2002;168:139- 43. 4. Temml C, Wehrberger C, Riedl C, Ponholzer A, Marszalek M, Madersbacher S. Prevalence and Correlates for Interstitial Cystitis Symptoms in Women Participating in a Health Screening Project. European Urology. 2007;51:803-9. 5. Hanno PM, Landis JR, Matthews-Cook Y, Kusek J, Nyberg L, Jr. The diagnosis of interstitial cystitis revisited: lessons learned from the National Institutes of Health Interstitial Cystitis Database study. J Urol. 1999;161:553-7. 6. Elbadawi AE, Light JK. Distinctive ultrastructural pathology of nonulcerative interstitial cystitis: new observations and their potential significance in pathogenesis. Urol Int. 1996;56:137-62. 7. Karsenty G, AlTaweel W, Hajebrahimi S, Corcos J. Efficacy of Interstitial Cystitis Treatments: A Review. EAU-EBU Update Series. 2006;4:47-61. 8. Smith CP, Radziszewski P, Borkowski A, Somogyi GT, Boone TB, Chancellor MB. Botulinum toxin a has antinociceptive effects in treating interstitial cystitis. Urology. 2004;64:871-5; discussion 5. 9. Gao Y, Liao L. Intravesical injection of botulinum toxin A for treatment of interstitial cystitis/bladder pain syndrome: 10 years of experience at a single center in China. Int Urogynecol J. 2015;26:1021-6. 10. Emami M, Shadpour P, Kashi AH, Choopani M, Zeighami M. Abobotulinum - a toxin injection in patients with refractory idiopathic detrusor overactivity: injections in detrusor, trigone and bladder neck or prostatic urethra, versus detrusor - only injections. International braz j urol : official journal of the Brazilian Society of Urology. 2017;43:1122-8. 11. Akiyama Y, Nomiya A, Niimi A, et al. Botulinum toxin type A injection for refractory interstitial cystitis: A randomized comparative study and predictors of treatment response. Int J Urol. 2015;22:835-41. 12. Lee CL, Kuo HC. Intravesical botulinum toxin a injections do not benefit patients with ulcer type interstitial cystitis. Pain Physician. 2013;16:109-16. 13. Simon LJ, Landis JR, Erickson DR, Nyberg LM. The Interstitial Cystitis Data Base Study: concepts and preliminary baseline descriptive statistics. Urology. 1997;49:64-75. 14. Hanno PM, Burks DA, Clemens JQ, et al. AUA guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. J Urol. 2011;185:2162-70. 15. 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. 16. Grosse J, Kramer G, Stöhrer M. Success of repeat detrusor injections of botulinum a toxin in patients with severe neurogenic detrusor overactivity and incontinence. Eur Urol. 2005;47:653-9. 17. Ruffion A, Capelle O, Paparel P, Leriche B, Leriche A, Grise P. What is the optimum dose of type A botulinum toxin for treating neurogenic bladder overactivity? BJU Int. 2006;97:1030-4. 18. Aoki KR. Pharmacology and immunology of botulinum toxin serotypes. Journal of Neurology. 2001;248:I3-I10. 19. Rosales RL, Bigalke H, Dressler D. Pharmacology of botulinum toxin: differences between type A preparations. European Journal of Neurology. 2006;13:2-10. 20. Jhang JF, Jiang YH, Kuo HC. Potential therapeutic effect of intravesical botulinum toxin type A on bladder pain syndrome/ interstitial cystitis. Int J Urol. 2014;21 Suppl 1:49-55. 21. Apostolidis A, Popat R, Yiangou Y, 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;174:977-82; discussion 82-3. 22. Apostolidis A, Dasgupta P, Fowler CJ. Proposed Mechanism for the Efficacy of Injected Botulinum Toxin in the Treatment of Human Detrusor Overactivity. European urology. 2006;49:644-50. 23. Kuo HC, Jiang YH, Tsai YC, Kuo YC. Intravesical botulinum toxin-A injections reduce bladder pain of interstitial cystitis/ bladder pain syndrome refractory to conventional treatment - A prospective, multicenter, randomized, double-blind, placebo-controlled clinical trial. Neurourol Urodyn. 2016;35:609-14. 24. Smith CP, Nishiguchi J, O'Leary M, Dysport) in Refractory IC/BPS-Zargham et al. Yoshimura N, Chancellor MB. Single- institution experience in 110 patients with botulinum toxin A injection into bladder or urethra. Urology. 2005;65:37-41. 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;49:704-9. 26. Pinto R, Lopes T, Frias B, et al. Trigonal injection of botulinum toxin A in patients with refractory bladder pain syndrome/interstitial cystitis. Eur Urol. 2010;58:360-5. 27. Zargham M, Abedi S, Alizadeh F, et al. Is there any Relationship Between Bladder Trabeculation and Efficacy and Safety of Intravesical Botulinum Toxin A Injection in Refractory Idiopathic Overactive Bladder Women? Advanced biomedical research. 2017;6:113-. 28. 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;104:657-61. 29. Pinto R, Lopes T, Costa D, 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;83:1030-4. 30. Pinto R, Lopes T, Silva J, Silva C, Dinis P, Cruz F. Persistent therapeutic effect of repeated injections of onabotulinum toxin a in refractory bladder pain syndrome/interstitial cystitis. J Urol. 2013;189:548-53. 31. Kuo HC. Repeated onabotulinumtoxin-a injections provide better results than single injection in treatment of painful bladder syndrome. Pain Physician. 2013;16:E15-23. 32. Kuo HC. Preliminary results of suburothelial injection of botulinum a toxin in the treatment of chronic interstitial cystitis. Urol Int. 2005;75:170-4. 33. Manning J, Dwyer P, Rosamilia A, Colyvas K, Murray C, Fitzgerald E. A multicentre, prospective, randomised, double-blind study to measure the treatment effectiveness of abobotulinum A (AboBTXA) among women with refractory interstitial cystitis/bladder pain syndrome. International urogynecology journal. 2014;25:593-9. 34. Ham BK, Kim JH, Oh MM, Lee JG, Bae JH. Effects of combination treatment of intravesical resiniferatoxin instillation and hydrodistention in patients with refractory painful bladder syndrome/interstitial cystitis: a pilot study. International neurourology journal. 2012;16:41-6. 35. Kuo H-C. Repeated intravesical onabotulinumtoxinA injections are effective in treatment of refractory interstitial cystitis/ bladder pain syndrome. International Journal of Clinical Practice. 2013;67:427-34. 36. Guan X, Zhao C, Ou Z-Y, et al. Use of the UPOINT phenotype system in treating Chinese patients with chronic prostatitis/chronic pelvic pain syndrome: a prospective study. Asian journal of andrology. 2015;17:120-3. 37. Giannantoni A, Gubbiotti M, Bini V. Botulinum Neurotoxin A Intravesical Injections in Interstitial Cystitis/Bladder Painful Syndrome: A Systematic Review with Meta-Analysis. Toxins. 2019;11:510. Dysport) in Refractory IC/BPS-Zargham et al. Vol 18 No 2 March-April 2021 208