3.2.1. Clinical Efficacy of BoNT-A in Treating IC/BPS

As noted previously, the treatment of patients with IC/BPS remains challenging for urologists. Because the pathogenesis of IC/BPS is not well-understood, it is rare for complete resolution of IC/BPS to occur after a single treatment [1]. Currently, most treatments for IC/BPS mainly target symptomatic relief, rather than resolution of disease; however, even satisfactory improvement of symptoms may not be achieved in all patients [49]. Researchers have used BoNT-A for treatment of patients with IC/BPS in clinical trials since 2004, and the initial results of various studies showed promising outcomes [50,51]. In 2004, Smith et al. first used submucosal injection of BoNT-A in the bladder trigone and floor, combined with cystoscopic hydrodistention. Among the 13 female patients in that study, the Interstitial Cystitis Problem and Symptom Index scores improved by 69% and 71% respectively; the pain, assessed by a visual analog scale, also decreased by 79%. In our pilot study, we used BoNT-A suburothelial injection into 20 sites alone to treat patients with IC/BPS for whom conventional treatments had failed [51]. The bladder visual analog scale pain score, functional bladder capacity, and daytime urinary frequency all showed mild but significant improvement at three months after treatment. More recently, many studies have shown the clinical efficacy of BoNT-A injection in treatment of IC/BPS. New double-blind, randomized controlled studies revealed that BoNT-A intravesical injection could relieve symptoms in patients with IC/BPS; these included reduced bladder pain and increased capacity [52–54]. BoNT-A injection is considered to be standard therapy in the American Urology Association (AUA) guidelines for IC/BPS [2], and is widely used among urologists. There are three types of BoNT-A available for treatment of patients with IC/BPS, including Botox®(onabotulinum toxin A, Allergan, Inc., CA), Dysport®(abobotulinum toxin A, Ipsen, Inc., UK), and LANTOX®(CBTX-A, Lanzhou Institute of

Biological Products, China) [50,51,55]. However, symptom relapse is common after BoNT-A injection in patients with IC/BPS, and most patients require repeated BoNT-A injections [56]. The use of BoNT-A for treatment of IC/BPS has several remaining practical issues that should be addressed.

3.2.2. Two Randomized, Double-Blinded, Placebo-Controlled Studies of the Use of BoNT-A Injection for Treatment of IC/BPS

Although there have been more than 50 clinical studies of the use of intravesical BoNT-A injection for treatment of patients with IC/BPS, clinicians should note that only two of those studies were randomized, double-blinded, and placebo-controlled [53,54,57]. In our first double-blinded study, we enrolled 60 patients with IC/BPS who were refractory to conventional treatments, and used normal saline intravesical injection as the placebo control [53]. At week 8, patients who received BoNT-A 100 U had significantly greater pain reduction than patients who received normal saline (−2.6 ± 2.8 vs. −0.9 ± 2.2, *P* = 0.021) [53]. The overall success rates (global response assessment ≥1) were also higher in the BoNT-A group (26/40, 63%) than in the normal saline group (3/20, 15%, *P* = 0.028). The adverse event rate was similar between the two groups. Pinto et al. published the second double-blinded study in 2018, in which 19 patients with IC/BPS were randomly assigned to intratrigonal injection of BoNT-A 100 U or normal saline [54]. At week 12, a significantly greater reduction of pain was observed in the BoNT-A group than in the normal saline group (−3.8 ± 2.5 vs. −1.6 ± 2.1, *p* < 0.05). O'Leary–Sant score reduction and quality of life improvement were also superior in the BoNT-A injection group. Notably, improvement of bladder symptoms was observed in the placebo group in both studies, which suggested that the placebo effect was strong in clinical treatment of patients with IC/BPS. The patient-inclusion criteria was also different between the two studies. Only a total of 79 patients with IC/BPS had been enrolled in randomized and placebo-controlled studies; [53,54] therefore, additional studies with high levels of evidence are necessary to confirm the therapeutic efficacy of BoNT-A injection. Recruiting more IC/BPS patients is necessary to analyze the therapeutic effect in the subgroup patients (e.g., classification with glomerulation grade).

#### 3.2.3. Dose of BoNT-A Injection in IC/BPS

The dose of BoNT-A injection for treatment of patients with LUTDs is difficult to determine. Although mortality has not been reported following medical use of BoNT-A injection, the estimated lethal dose is 2800 U in humans [58]. Most urologists and studies have established doses based on previous experience, rather than on solid supporting evidence. Previous studies demonstrated a dose-response relationship in the use of BoNT-A to treat patients with detrusor overactivity, and showed that bladder-capacity improvement was also dose-dependent [59]. Moreover, residual bladder volume increased with an increasing BoNT-A dose [59]. For patients with neurogenic detrusor overactivity, the therapeutic effects of BoNT-A 200 U and BoNT-A 300 U were similar [60]. However, dose-comparison studies for patients with IC/BPS have not been reported. Initially, several studies reported satisfactory outcomes of BoNT-A 200 U for treatment of patients with IC/BPS [50,51,61–63], particularly those studies by the Giannantoni group in Italy [61,62]. Our initial experience with a very limited number of patients suggested that BoNT-A 200 U may have a better therapeutic effect than 100 U injection, but this was not found to be statistically significant [64]. However, the rates of dysuria and high residual-urine volume also seemed to be higher in the 200 U group. Most studies have used 100 U BoNT-A for patients with IC/BPS, and this dose is widely used in clinical practice. The American Urology Association guidelines suggest that the use of BoNT-A 100 U is an appropriate treatment and may substantially reduce morbidity compared to BoNT-A 200 U [2]. However, for refractory patients with IC/BPS who do not have satisfactory responses to BoNT-A 100 U, a 200 U injection might be a reasonable second-choice treatment option. The potential therapeutic effect of BoNT-A 200 U injection should be investigated in further dose-comparison studies.
