## 2 Results
### Evidence Synthesis  
#### 2.1.1 Bladder Pain Syndrome/Interstitial Cystitis  
We included eight studies investigating the role of BTX-A in the context of IC/BPS, 5 RCT and three comparative studies [10; 11; 12; 13; 14; 15; 16; 17] (Supplementary Table S2). Overall participants included 319 patients. The type and dose of BTX-A administered were variable, with three studies using onabotulinum toxin A (onaBTX-A), one using abobotulinum toxin A (aboBTX-A) and the others not specifying this data, as well as the number and the location of injections, which ranged from 10 to 40, and were carried out in the entire bladder, only in the trigome, or in the bladder body. All manuscripts except one reported that patients before to study participation failed previous conservative treatment and had symptoms of IC/BPS lasting more than six months. The intervention and control groups differed greatly among the studies included. One study compared intradetrusorial BTX-A injections and hydrodistension (HD) with placebo (normal saline injections) and HD [10], one compared BTX-A immediate versus delayed (after one month) injections [11], and two evaluated the differences between sub-urothelial BTX-A injections using a 'trigonal template' against a 'bladder-body/trigone sparing template' [12; 13]. Another RCT compared intradetrusorial BTX-A injections with intravesical instillation of Bacille Calmette-Guerin (BCG) [14]. Finally, two comparative studies investigated the differences in response of BTX-A injections in ulcerative and non-ulcerative IC phenotype [15; 16], while one assessed the differences  
Figure 1: PRISMA flow diagram for systematic review assessing the efficacy of BTX-A in the treatment of CPPS. between different doses of BTX-A (100 vs. 200 IU) administered [17]. Five studies used the visual analogical scale (VAS) for pain evaluation ranged from 0 up to 10, two reported the pain experience of patients using the O'Leary Sant questionnaire (OLS), while one used the Likert scale ranged from 0 up to 9. All studies analyzed changes in lower urinary tract symptoms, as the reduction in frequency and noturia episodes. Results hugely differs among studies evaluated. [PERSON] et al. reported that BTX-A injections were associated with no overall improvement in total OLS score, although a benefit was noted in BTX-A patients who showed an improvement of the OLS-PI (problem index) questionnaire at three months [10]. Other two studies showed a significant benefit in favor of BTX-A as compared to the control arm. Specifically, [PERSON] et al. reported an improvement in the domains of daytime frequency, noturia and pelvic pain among women randomized to treatment with BTX-A [14]. [PERSON] et al. showed that although IC/BPS symptoms score significantly decreased in all the three arms of the study (BTX-A 200 IU plus HD vs. BTX-A 100 IU vs. HD), VAS score reduction was significant only in the BTX-A group after three or in some cases after six months of follow up [17]. Two manuscripts analyzed differences in response among BTX-A administration only in the trigone or outside of trigone or in the entire bladder, showing that there was no location dependent improvement in IC/BPS symptom scores. Specifically, [PERSON] et al. reported that patients in both groups experienced significant improvement in OLS and pain/urgency/frequency (PUF) questionnaire, both at 30 and 90 days, regardless of which injection template was used [12]. Similarly, [PERSON] et al. demonstrated an improvement in VAS and OLS after treatment, even though no changes was noted among urinary frequency and urodynamic parameters from baseline to eight weeks between two groups [13]. Finally, two studied experienced opposite results among the response of BTX-A in ulcerative and non-ulcarcative IC. [PERSON] et al. showed that repeated intradetrusorial BTX-A injections provide effective outcomes in 50% of patients with non-ulcer IC/BPS but did not benefit any patient with ulcer type [15].