Hospital and Tzu Chi University, Hualien, Taiwan

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1 LUTS (2012) 4, ORIGINAL ARTICLE Difficult Urination Does Not Affect the Successful Outcome after 100U OnabotulinumtoxinA Intravesical Injection in Patients with Idiopathic Detrusor Overactivity Yih-Chou CHEN 1 and Hann-Chorng KUO 2 1 Department of Urology, Hualien Hospital, Hualien, Taiwan and 2 Department of Urology, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan Objectives: Intravesical injection of onabotulinumtoxina (i.e. Botox) provides effective treatment for overactive bladder. However, treatment-related adverse events (AEs) remain problems. This study investigated the effect of AEs after onabotulinumtoxina injection on the success rate for idiopathic detrusor overactivity (IDO). Methods: A total of 174 patients who received the first single intravesical onabotulinumtoxina 100U injection for refractory IDO were included. The onabotulinumtoxina related AEs including acute urinary retention (AUR), large postvoid residual (PVR, 150 ml), difficult urination, urinary tract infection, gross hematuria and general weakness were recorded. The success rate was determined based on patient perception of bladder condition improved by two scales. The short-term (3 months) and long-term (up to 24 months) success rates were analyzed according to the occurrence of these AEs. Results: A successful outcome was reported by 138 (79.3%) patients at 3 months. AUR occurred in 12 (6.9%) patients, large PVR developed in 81 (46.6%) and 73 (42%) needed straining to void. Gross hematuria occurred in 17 (9.8%) patients, urinary tract infection developed in 27 (15.5%) and general weakness was noted in 6 (3.4%). The occurrence of AUR did not affect the therapeutic results. Patients having large PVR and difficult urination had a significantly higher success rate at 3 months. Long-term success rates up to 24 months showed no significant difference between patients with and without AEs. Conclusions: AEs after intravesical 100U onabotulinumtoxina for IDO were frequently encountered. However, the occurrence of AUR, large PVR or difficult urination did not affect the final therapeutic outcome. Key words adverse events, detrusor overactivity, onabotulinumtoxina, overactive bladder 1. INTRODUCTION Intravesical injection of onabotulinumtoxina has recently been accepted as an alternative treatment for patients with overactive bladder (OAB) or detrusor overactivity (DO) refractory to antimuscarinic therapy. 1,2 OnabotulinumtoxinA injection provides an alternative for non-surgical augmentation of the dysfunctional bladder. About 50 80% of OAB patients with or without DO regained urinary continence or improved in urinary control. 3 5 Studies which decreased the dose of onabotulinumtoxina from 300 to 100U in the treatment of OAB found similar therapeutic effects. 5 8 Recent studies revealed a dose of 100U of onabotulinumtoxina has acceptable therapeutic effects and adverse events (AEs). 8,9 The reported AEs associated with intravesical onabotulinumtoxina injection are acute urinary retention (AUR), large postvoid residual (PVR), difficult urination and urinary tract infection (UTI). These AEs occurred in about 20 43% of patients in previous studies. 1,2,8 12 UTI is usually associated with the presence of large PVR. 9,12 In a previous study by the author, UTI occurred in 35% of patients, large PVR requiring clean intermittent catheterization (CIC) in about 30% of patients, and difficult urination occurred in 75% of patients after intravesical onabotulinumtoxina injection for OAB. 4 Although there is substantial evidence of the therapeutic efficacy of onabotulinumtoxina on motor and sensory dysfunction in OAB and DO, the incidence of treatment-related AEs remains high and this has limited the wider application of this novel treatment for patients with urinary incontinence The response duration of onabotulinumtoxina injection in patients with DO is closely related to the dose. Detrusor injection of 200U onabotulinumtoxina yielded a response duration of months, 11 whereas the Correspondence: Hann-Chorng Kuo, MD, Department of Urology, Buddhist Tzu Chi General Hospital, 707, Section 3, Chung Yang Road, Hualien 970, Taiwan. Tel: ext. 2117; Fax: hck@tzuchi.com.tw Received 5 May 2011; revised 14 June 2011; accepted 7 August DOI: /j x

2 30 Yih-Chou Chen and Hann-Chorng Kuo therapeutic duration of 100U onabotulinumtoxina was 6 9 months. 13,14 However, the incidence of AEs is also closely related to the dose of onabotulinumtoxina. A randomized trial of different doses of onabotulinumtoxina in patients with DO found the incidence of large PVR was 30, 52 and 72% for the dose of onabotulinumtoxina from 100, 150 and 200U, respectively. 8 Doses greater than 150U of onabotulinumtoxina contributed minor additional, or clinically, relevant improvements in symptoms. Dose dependent changes in PVR were observed and the use of CIC was also dose dependent. 9 A recent study further revealed that onabotulinumtoxina can also reduce the expression of TRPV1 and P2X in the bladder wall, which correlates well with the reduction of urgency in OAB patients. 15 A primary peripheral effect of botulinum toxin A (BoNT-A) in the inhibition of release of, adenosine triphosphate, substance P, and reduction in the axonal expression of the capsaicin and purinergic receptors has been proposed. 16 These mechanisms of action also provide a rapid reduction of urgency in the first week after onabotulinumtoxina injection. 17 In addition to antinociceptive effect, the main mechanism of action of onabotulinumtoxina on IDO is inhibition of the release of acetylcholine that causes paralysis of affected detrusor. 18,19 It is difficult for onabotulinumtoxina to effect on sensory nerves without affecting motor function of the bladder. In order to achieve the reduction of urgency and DO it is rational to develop difficult urination and increased PVR after treatment. Therefore, the onabotulinumtoxina related AEs seem unavoidable and might be essential in the effective treatment. This study analyzed the AEs after intravesical onabotulinumtoxina 100U injection and the effect of these AEs on therapeutic outcome. The results may provide evidence for us to revisit the AEs of onabotulinumtoxina treatment and enable urologists to handle them when intravesical onabotulinumtoxina injection is planning to be used in treatment of patients with idiopathic DO (IDO). 2. METHODS A total of 174 patients who had received clinical trials of intravesical onabotulinumtoxina 100U injection for refractory DO and urinary incontinence were included in this study from 2005 to ,8,13,20 The inclusion criteria were urodynamic DO with or without urinary incontinence refractory to previous antimuscarinics for more than 3 months and free of UTI, stress urinary incontinence, bladder outlet obstruction or neurogenic bladder at enrollment. All patients received 100U of onabotulinumtoxina at different methods of intravesical injections including detrusor or suburothelial injection in the bladder body and/or bladder base including trigone injections. 8,13,20 All studies were approved by the institutional review board and ethics committee. All patients were informed about the advantage and possible AEs and written informed consent was obtained from all patients before onabotulinumtoxina injection. One hundred units of onabotulinumtoxina (BOTOX, Allergan, Inc., Irvine, CA, USA) was reconstituted to ml by normal saline for detrusor and suburothelial injections and to 10 ml with normal saline for bladder base injections. Detrusor injection was performed by injecting onabotulinumtoxina solution to sites about 1 mm in depth in the lateral, posterior wall and thedomeofthebladder,usingausinga23gaugeneedle in a rigid cystoscopic injection instrument (22 Fr, Richard-Wolf, Knittlingen, Germany). The injection sites were equally distributed in the bladder body. Suburothelial injection was performed using a procedure identical to that for detrusor injection except that the needle was inserted just into the suburothelial space and a ballooning formation was noted during injection. Bladder base injection was performed by injecting onabotulinumtoxina solution into 10 sites in the suburothelial space: two injections in the first row near the bladder neck, three injections in the second row anterior and five injections posterior to the interureteric ridge, about 0.5 cm away from the ureteral orifices. All procedures were performed transurethrally under intravenous general anesthesia in the operation room. Anticoagulant was discontinued 1 week before onabotulinumtoxina treatment. The bladder volume was kept at ml and the blood vessels were avoided during injections. An indwelling 14 Fr Foley catheter was placed overnight and the patients were discharged the next morning. Broad spectrum prophylactic antibiotics were given for 3 days. Videourodynamic study was routinely used for the diagnosis of DO and identifying the presence of bladder outlet obstruction or intrinsic sphincter deficiency. Patients with a baseline PVR of more than 150 ml were excluded from the clinical trials. The cystometric bladder capacity, voiding detrusor pressure, maximum flow rate (Q max ), and PVR were recorded. DO was classified as spontaneous or terminal DO depending on whether the uninhibited detrusor contractions occurred at the filling phase or on reaching bladder capacity, respectively. Repeat videourodynamic study was performed at baseline and every 3 months after intravesical BoNT-A injection. During the follow-up period, patients were requested to make follow-up visits regularly until their voiding condition returned to baseline. Uroflowmetry for Q max, voided volume and PVR were performed at each visit. The functional bladder capacity was calculated as the sum of voided volume and PVR. The voiding efficiency (VE) was calculated as the percentage of voided volume of functional bladder capacity. All patients were closely monitored at 1 2 weeks, 1 month, 3 months and every month thereafter until the response to BoNT-A had disappeared. All participants were followed up regularly according to our protocol until the therapeutic effect had disappeared. Patients who failed the treatment were not followed up after 6 months. The occurrence of urgency episodes and urgency incontinence were verified using a 3-day voiding diary. All patients were requested to grade the treatment outcome at 3 months after BoNT-A injection (primary end-point)

3 Adverse Effects of Botox on IDO 31 based on the patient perception of bladder condition (PPBC; scored from 0 to 6) of therapeutic effects and bothersome of AEs. 21 The treatment outcome was assessed using the PPBC. An improvement of PPBC scale by 2 was considered as having a successful outcome. Otherwise, the treatment was considered to have failed. The period between the treatment date and the visit that patients reported disappearance of the therapeutic effect was defined as the therapeutic duration. Any AE considered as possibly related to the BoNT-A treatment was recorded. These AEs included AUR, hematuria and general weakness in the early post-treatment period, and large PVR, straining to void, and UTI during the follow-up period. The success rate at 3 months was analyzed between patients with and without each AE. Kaplan-Meier survival curve was used to analyze the cumulative success rates with time between subgroups with and without each AEs. A P-value <0.05 was considered statistically significant. 3. RESULTS A total of 174 patients were studied including 85 women and 89 men aged from 18 to 94 with a median age of 67 years. Among the 79 male patients aged more than 50 years, 41 had undergone transurethral resection of the prostate and 38 had not. Bladder body injection was given to 129 patients and bladder base/trigonal injection was given to 45. There was no significant difference in the mean age of each demographic subgroup. The demographic distribution of patients and the success rates of each subgroup are listed in Table 1. At 3 months, a successful result was reported by 138 (79.3%) patients and failed treatment by 36 (20.7%) patients. The success rate at 3 months was not significantly different between any of the demographic or urodynamic variable subgroups. During the follow-up period, AUR occurred in 12 (6.9%) patients, large PVR 150 ml developed in 81 (46.6%) patients and 73 (42%) patients needed straining to void. Gross hematuria occurred in 17 (9.8%) patients, UTI developed in 27 (15.5%) patients and general weakness was noted in 6 (3.4%) patients (Table 2). Although AEs were bothersome problems after BoNT-A injection, the occurrence of AUR was not associated with a higher treatment failure rate. On the contrary, patients with large PVR or straining to void after treatment had higher success rate than those without these AEs. However, the development of UTI or hematuria was correlated with a lower success rate at 3 months. Figure 1 shows the changes of bladder capacity, Q max, PVR, voiding detrusor pressure and VE from baseline to 12 months after onabotulinumtoxina injection in subgroups with success or failure outcome assessed at 3 months. PVR and bladder capacity increased to a maximum and VE decreased to a minimum at 1 month, then slowly returned to baseline levels within 12 months. Figure 2 shows the cumulative success rate between AE subgroups. There was no significant difference in the TABLE 1. Comparison of the success rates at 3 months among idiopathic detrusor overactivity subgroups with different demographic and urodynamic variables Inn Success rate P-value Gender Female (80%) Male (79%) Age years (80%) <75 years (79%) Comorbidity Yes (77%) No (81%) Injection site Body (80%) Bladder base and trigone (78%) CBC <250 ml (76%) 250 ml (82%) Q max <10 ml/sec (83%) 10 ml/sec (77%) PVR <100 ml (78%) 100 ml (83%) VE <70% (82%) 70% (79%) DO 0.51 Spontaneous (85%) Terminal (72%) Male Pdet <30 cmh 2 O (76%) 30 cmh 2 O (81%) Female Pdet <20 cmh 2 O (80%) 20 cmh 2 O (80%) The treatment outcome was assessed using the patient perception of bladder condition (PPBC), an improvement of PPBC scale from baseline by 2 was considered as having a successful outcome. CBC, cystometric bladder capacity; DO, detrusor overactivity; Pdet, detrusor pressure; PVR, postvoid residual; Q max, maximum flow rate; VE, voiding efficiency. TABLE 2. Comparison of the success rates at 3 months between patient subgroups with and without adverse events Adverse event (n) Success (n = 138) Failure (n = 36) P-value AUR (12) 9 (75%) 3 (25%) No AUR (162) 129 (79.6%) 33 (20.4%) Large PVR 150 ml (81) 71 (87.7%) 10 (12.3%) Small PVR <150 ml (93) 67 (72%) 26 (28%) Straining to void (73) 67 (91.8%) 6 (8.2%) No straining to void (101) 71 (70.3%) 30 (29.7%) Hematuria (17) 10 (58.8%) 7 (41.2%) No hematuria (157) 128 (81.5%) 29 (18.5%) UTI (27) 17 (63%) 10 (37%) No UTI (147) 121 (82.3%) 26 (17.7%) Weakness (6) 3 (50%) 3 (50%) No weakness (168) 135 (83.3%) 33 (16.7%) AUR, acute urinary retention; PVR, postvoid residual; UTI, urinary tract infection. cumulative success rate between patients with and without AUR (P = 0.95), large PVR (P = 0.43), straining to void (P = 0.19) or UTI (P = 0.48). However, patients with gross hematuria (P = 0.01) and general weakness

4 32 Yih-Chou Chen and Hann-Chorng Kuo Fig. 1 Changes in postvoid residual (PVR), cystometric bladder capacity (capacity), detrusor pressure (Pdet), maximum flow rate (Q max ) and voiding efficiency with time after BoNT-A injection in subgroups with success or failure outcome assessed at 3 months. Data are expressed as mean ± standard error. Fig. 2 The Kaplan-Meier survival curves for the cumulative success rates of different patient subgroups with and without adverse events of acute urinary retention (AUR), large postvoid residual (PVR), difficult urination and urinary tract infection (UTI). The treatment outcome was assessed using the PPBC, an improvement of PPBC scale from baseline by 2 was considered as having a successful outcome.

5 Adverse Effects of Botox on IDO 33 (P = 0.05) had a lower long-term success rate compared with those without these AEs. 4. DISCUSSION This study found that the occurrence of AEs was high after 100U onabotulinumtoxina injection for patients with IDO. More than 40% of patients developed large PVR and needed straining to void, and 6.9% of patients had AUR during the first 3 months after treatment. However, the occurrence of these onabotulinumtoxina related AEs did not affect the likelihood of successful outcome. In the recent decade, intravesical onabotulinumtoxina injection has been shown to be an effective therapeutic alternative for IDO refractory to antimuscarinics. Urinary frequency and episodes of incontinence improved after onabotulinumtoxina injection. 22 Although clinical trials have provided evidence for the efficacy of onabotulinumtoxina in patients with OAB, the incidence of AEs remains high and also seems to have been underreported. Increased dose of onabotulinumtoxina increases the incidence of AE, especially large PVR and AUR needing CIC. 9 There is no agreement on the optimal dose, depth and the sites of onabotulinumtoxina injection in treating IDO. 1,4,8,11,13 In previous studies, the dose of BOTOX for IDO ranged from 300 to 100U, the percentage of patients with large PVR ranged from 0 to 72%. 1 5,11 13 and the percentage of patients needing CIC ranged from 1to43%. 1 5,9 12,23,24 Brubaker et al. used 200U BOTOX injection into the detrusor of women with refractory IDO. They found that approximately 60% of women had a clinical response but 43% developed increased PVR, of whom 75% developed UTI. 12 Dose-dependent AEs were further confirmed in a recently published study. Based on this multicentric placebo control trial, a dose of 100U was recommended as optimal for treating refractory OAB. 9 The incidence of AEs in this study is compatible with previous reports. This study found that the patients with an occurrence of large PVR and straining to void after intravesical 100U onabotulinumtoxina injection had significantly higher success rates at 3 months and no significant at long-term compared with those without these AEs. Our previous study and other reports also showed a decrease of voiding pressure at 1 month but returned thereafter. 8,10 Although voiding pressure returned 1 month after onabotulinumtoxina injection, the VE remained lower than the baseline, indicating the detrusor contractility cannot return in the early period of treatment. However, patients usually could accept the AEs of difficult urination and increased PVR in exchange of the reduction of urgency or urgency urinary incontinence. This result suggests lower detrusor contractility is necessary for the therapeutic effect of onabotulinumtoxina injection. In patients with neurogenic DO, detrusor underactivity is the treatment goal to achieve so that patients can regain continence and CIC is necessary after treatment The major concern is the dose effect of onabotulinumtoxina on detrusor contractility in patients with OAB. If the dose of onabotulinumtoxina is too high the detrusor contractility might be impaired too long and affect the satisfaction perceived by the patients. The mechanism of action of onabotulinumtoxina on OAB might be different from that on neurogenic detrusor overactivity. Reduction of sensory afferent activity might be more important that decrease of detrusor contractility in achieving a successful result in OAB. Although previous studies of decrease of sensory receptors in IDO is based on the trial using 200U onabotulinumtoxina, 15,16 our recent study also revealed a 100U dose is enough for the reduction of urgency and achieve satisfactory longterm effect. 8,13 Dmochowski et al. also demonstrated that dose of onabotulinumtoxina over 150U did not have additional benefits on clinical efficacy but might increase incidence of large PVR and the need for CIC. 9 If 100U of onabotulinumtoxina is adequate for decrease of these sensory receptors, it will not be necessary to use a higher dose so that AEs might be prevented. Although AEs are unavoidable in onabotulinumtoxina treatment for IDO, there are several risk factors that can be used for patient selection. Male gender, baseline PVR >100 ml and presence of comorbidity are independent risk factors for a higher incidence of AUR or large PVR after treatment. 28 Therefore, patients at risk of AEs should be fully counseled on the possibility of urinary retention and trained in CIC before the procedure. 29 After the first month, the AE of difficult urination will resolve and patients may feel improvement in urinary incontinence and urgency symptoms. 4,11 In this study, patients with UTI and gross hematuria had a less favorable success rate at 3 months after onabotulinumtoxina injection. The correlation of UTI and gross hematuria with a lower success rate could be due to increased bladder inflammation and exacerbated storage symptoms associated with UTI. Although over half of patients with UTI also had a successful result, the success rate was far less than in those without UTI. In conclusion, AUR, large PVR and straining to void are AEs after 100U onabotulinumtoxina injection for IDO. The occurrence of large PVR and straining to void did not affect the success rate at 3 months or long-term follow up. Patients with UTI after treatment had a lower success rate, but the long-term success rate was not affected. Disclosure All authors have no financial interest or relationship with any company included in the manuscript. REFERENCES 1. Kuo HC. Urodynamic evidence of effectiveness of botulinum A toxin injection in treatment of detrusor overactivity refractory to anticholinergic agents. Urology 2004; 63: Kessler TM, Danuser H, Schumacher M, Studer VE, Burkhard FC. Botulinum A toxin injections into the detrusor: an effective treatment in idiopathic and neurogenic detrusor overactivity? Neurourol Urodyn 2005; 24: Werner M, Schmid DM, Schussler B. Efficacy of botulinum- A toxin in the treatment of detrusor overactivity incontinence: a prospective nonrandomized study. Am J Obstet Gynecol 2005; 192:

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