**3. Discussion**

In the present paper, we describe our single-center experience with OnaBotA intratrigonal injection in the treatment of BPS/IC patients. To the best of our knowledge, this is the first long-term evaluation of a BPS/IC cohort with this treatment in real-life conditions. Previously, short and mid-term evaluations done in our and other departments had contributed to the validation of OnaBotA treatment in this disease [14,21].

The grea<sup>t</sup> majority, 37 patients, corresponding to 78% of the total cohort, requested more than one treatment. In recent years, we changed our approach and started to re-treat the patients that presented an unsatisfactory duration response to the first treatment at least one more time. This change was based on the perception that even patients with a poor response duration after the first injection could have a good response to posterior treatments. Such subjective opinion was now undoubtedly confirmed by the analysis of the present cohort.

There were no significant differences in age, the time to reinjection request, and pain intensity before the first intervention between responders and non-responders. Caution should be taken when interpreting the variables of time length for treatment requests after the first treatment and overall treatments, since group B includes nine patients that only underwent one treatment and, consequently, fewer patients contributed to this variable.

Contrariwise, patients that maintain a positive response to the OnaBotA treatment and longer time in treatment (5.4 ± 3.1 vs. 2.6 ± 2.1, *p* = 0.03), showed a longer period of follow-up in the urologic clinic (9.3 years vs. 3.4 years, *p* < 0.001). The reason is probably a selection bias because those that are more satisfied with the treatment results are more prone to continue in the program.

Interestingly, the intervals between injections were longer than expected, compared to the duration reported in well-controlled cohorts or randomized clinical trials, in which only OnabotA treatment was allowed [5,21]. On average, the duration of each injection among the responders exceeded one year. This may indicate that OnabotA injections eventually combined with simple conservative measures and eventually oral medication with which patients had previous experience and could be used at their own decision (essentially non-opioid analgesic drugs, amitriptyline, the leukotriene receptor antagonist montelukast and antihistaminics [2,24]) may eventually substantially reduce the necessity of toxin injections, decreasing the burden that repeated injections cause to patients and health facilities. The median time between injection and a new request seems independent of the number of total injections and independent of the duration of the previous treatment, with the possible exception of the interval between the first injection and the request for a second treatment.

The sustained duration of the effect, despite the increase in the number of procedures, suggests that intratrigonal sensory neurons do not develop tolerance to OnaBotA, even during long periods of administration. The use of botulinum toxin in other areas of bladder pathologies has shown the rare possibility of the development of antibodies as a cause of the appearance of resistance to the toxin [25,26]. It may be recalled that in a systematic review evaluating long-term treatment with intravesical OnaBotA in another urinary condition, overactive bladder, the data regarding the time between reinjections was heterogeneous among the analysed studies [27]. In some, the interval between injections was stable, while in others it could become either longer or shorter.

As presented, seven of nine patients with a shorter time of effect after their first injection (lower than percentile 25) become good responders in subsequent treatments. As a matter of fact, they presented, in the following interventions, a time between injections and requests for retreatment similar to that found in the rest of the cohort. This could be justified by a cumulative therapeutic effect of the toxin, an adjustment on the parallel oral therapy, or by the stabilization of the disease. This finding could also be related to the inter-surgeon variation of the surgical technique and the process of reconstitution of OnaBotA. However, these two possibilities seem less probable, as if present they only occurred in the first treatment cycle.

Despite the significant number of patients with positive results that maintained the treatment in our cohort, approximately 53%, as seen in Figure 2, a large number of patients abandoned the long-term OnabotA program. One should remember that despite being effective in the long run, OnabotA injections can be rather unpleasant for BPS/IC patients. This had already been observed in overactive bladder and neurogenic detrusor overactivity cohorts, and reflects the low adherence to long-term reinjection programs [28]. Nevertheless, in our series almost half of the patients remained in the long-term program, exceeding the long-term adherence in OAB which may be as low as 10% [28]. Eventually, as the treatment for BPS/IC should be tailored-made for each patient, and since flares and remissions occur frequently, these different circumstances may introduce large variations in the time for patients to request another injection. [29].

The adverse effects observed in this group of patients are in line with other studies, with the risk of UTI and straining being the main concerns. This point should be fully discussed with the patients, since a UTI may markedly aggravate their symptomatology and the need for CIC will surely demand urethral manipulation.
