**1. Introduction**

The European Society for the Study of Interstitial Cystitis (ESSIC) defines bladder pain syndrome/interstitial cystitis (BPS/IC) as a persistent or recurrent chronic pelvic pain, pressure or discomfort perceived to be related to the urinary bladder in the absence of any identifiable pathology which could explain this symptom [1]. It must be accompanied by at least one other urinary symptom, such as an urgen<sup>t</sup> need to void or urinary frequency [1]. Therefore, BPS/IC diagnosis is still largely one of exclusion.

BPS/IC has no curative treatment as of ye<sup>t</sup> [2]. Thus, symptom control, with the main focus on pain, represents a key part of BPS/IC management. The first line of treatment is centered on patient education and stress control to inform the patient about the uncertain

**Citation:** Abreu-Mendes, P.; Ferrão-Mendes, A.; Botelho, F.; Cruz, F.; Pinto, R. Effect of Intratrigonal Botulinum Toxin in Patients with Bladder Pain Syndrome/Interstitial Cystitis: A Long-Term, Single-Center Study in Real-Life Conditions. *Toxins* **2022**, *14*,775. https://doi.org/10.3390/ toxins14110775

Received: 18 October 2022 Accepted: 5 November 2022 Published: 10 November 2022

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<sup>4710-057</sup> Braga, Portugal

evolution of the disease and to explain the importance of self-management by avoiding situations that may aggravate the symptoms [2]. When necessary, oral analgesic therapies and pharmacological agents intended to replenish the glycosaminoglycan layer and decrease urothelial permeability are used as the second-line treatment. When these measures are insufficient, surgical therapies may be introduced [3–5]. One option is the intratrigonal injection of onabotulinum toxin type A (OnaBotA) [6,7].

OnaBotA is a potent biological neurotoxin that accesses the neurons after binding the synaptic vesicle protein type 2C, a ubiquitous neuronal protein [6,8,9]. Once inside the neurons, the light chain of the toxin cleaves the proteins that are essential for the docking of the neuronal vesicles to the membrane in all types of neurons [9]. In sensory neurons, the trafficking of pain receptors from neuronal vesicles to the membrane of sensory neurons will be impaired and the release of CGRP and SP, two neuropeptides involved in neurogenic inflammation, will be substantially decreased [6,7,10]. In addition, a decrease of ATP release from urothelial cells occurs which may further impair bladder sensation [7,11,12]. The OnabotA-induced inhibition of the acetylcholine release from preand post-ganglionic parasympathetic neurons [13] is expected to have a limited role in BPS/IC, as this neurotransmitter is not involved in peripheral pain pathways and detrusor overactivity is a rare event associated with BPS/IC [9,14].

The application of OnabotA in the trigone is justified by the fact that this bladder region has the highest density of nociceptors [11,15,16]. Since 2004, multiple cohort studies and randomized placebo-controlled trials showed that OnaBotA was effective and safe in pain control in BPS/IC patients refractory to conservative treatment, in the dosage of 100 Units (U) [14,17–20]. In addition, trigonal injections of OnabotA also improve day and nighttime frequency, maximum functional bladder capacity, and overall quality of life, which are believed to result from less pain felt by patients during bladder filling [21].

One of the characteristics of OnabotA action is the limited duration of the effect, which, although variable, rarely extends for more than 12 months [7]. After this period of effect, BPS/IC symptoms tend to return, and repeated bladder injections are commonly requested by patients [21]. In previous prospective studies, overall, a statistically significant improvement in the pain as well as in other urinary symptoms has been reported, ye<sup>t</sup> these results were mainly at short-term or after a few injection cycles [13,21–23]. Thus, information regarding the long-term effects and safety in real-life conditions is lacking.

We aim to report the results and safety of this intra-trigonal treatment in a real-life cohort of patients with a long-term follow-up. Differences between patients maintained in long-term therapy with intratrigonal OnaBotA treatment and those who stopped treatment, mainly for lack of response, were evaluated, looking for possible predictors of response. The rate of therapy maintenance was also assessed.
