Patients with bladder pain syndrome/interstitial cystitis Long-term use of intratrigonal onabotulinum toxin A
Dr. Pedro Abreu- Mendes Dept. of Urology, Centro Hospitalar
Universitário de São João and Faculty of Medicine of Porto (PT)
Assoc. Prof. Rui Almeida Pinto Dept. of Urology, Centro Hospitalar
Universitário de São João and Faculty of Medicine of Porto (PT)
Fig. 1: The median duration of effect between injections (y-axis in days of effect duration counting the time between an injection and the patient request for a new treatment).
may further contribute to an increase in the intervals between retreatments. This data may indicate that OnabotA, combined with simple conservative measures and eventually oral medication should be used by patients at their own discretion. The comparison of the baseline characteristics of patients considered responders and non-responders did not identify predictive parameters for success or failure. Interestingly, the lack of response after the first injection should not be a reason to negate a second injection to BPS/IC patients starting an OnaBotA treatment. In fact, 7 out of 9 patients in this situation had excellent results in posterior treatments. It should be stressed that more than half of the patients in our cohort remained in treatment, a proportion that compares positively with that observed in overactive bladder cohorts . A limitation of this real-life study is the confoundable effect caused by the possible use of other drugs during each treatment cycle with OnabotA. As already mentioned patients had free access, at their discretion, to non-opioid analgesic drugs, amitriptyline, leukotriene receptor antagonists and antihistaminics to better control the symptomatology. The additional medication would probably be taken more often when the OnaBotA effect started to decline. However, in a real-life setting, BPS/IC patients rarely achieve symptom control with monotherapy, in particular, the patients represented in this cohort were refractory to oral and intravesical instillation treatments. Combination therapy to control systemic pain and to control urological symptoms is often necessary to increase the quality of life of BPS/IC patients.
References 1. Engeler D, Baranowski AP, Berghmans B, Borovicka J, Cottrell AM, Dinis-Oliveira P, et al., EAU guidelines on chronic pelvic pain 2022. Eur Urol. 2022 2. Cruz F., Targets for botulinum toxin in the lower urinary tract. Neurourol Urodyn [Internet]. 2014 Jan 1;33(1):31–8. Available from: www.doi. org/10.1002/nau.22445 3. Pinto R, Lopes T, Frias B, Silva A, Silva JA, Silva CM, et al. Trigonal injection of botulinum toxin A in patients with refractory bladder pain syndrome/ interstitial cystitis. Eur Urol. 2010;58(3):360–5 4. Giannantoni A, Di Stasi SM, Nardicchi V, Zucchi A, Macchioni L, Bini V, et al. Botulinum-A toxin injections into the detrusor muscle decrease nerve growth factor bladder tissue levels in patients with neurogenic detrusor overactivity. J Urol. 2006 Jun;175(6):2341–4 5. Pinto RA, Costa D, Morgado A, Pereira P, Charrua A, Silva J, et al. Intratrigonal onabotulinumtoxinA improves bladder symptoms and quality of life in patients with bladder pain syndrome/interstitial cystitis: A pilot, single centre, randomised, double-blind, placebo controlled trial. J Urol [Internet]. 2018;199(4):998–1003. Available from: www.doi.org/10.1016/j.juro.2017.10.018 6. 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-centre study in real-life conditions. Toxins (Basel). 2022;14(11). 7. Marcelissen TAT, Rahnama’i MS, Snijkers A, Schurch B, De Vries P., Long-term follow-up of intravesical botulinum toxin-A injections in women with idiopathic overactive bladder symptoms. World J Urol [Internet]. 2017 Feb 7;35(2):307–11. Available from: www.link.springer.com/10.1007/ s00345-016-1862-y
was 50.7 (±14.5) years, the mean baseline VAS score on a scale of 1-10 was 5.7 (±1.7), and the mean follow-up was 8.8 (± 4.2) years. The global treatment maintenance ratio was 53%, meaning that approximately half of the patients accepted the necessity of a long-term treatment programme with the toxin. Results The intervals between treatment requests were surprisingly long. The median time between the 1st injection and the request for the 2nd injection was the shortest, with a median duration of 390 days (P25: 287; P75: 590). Afterwards, the duration of the effect of each treatment increased and remained very stable (see Fig. 1 above). The median intervals for requesting another treatment ranged between 414 and 669 days. The overall median interval between one injection and the following patient's request for reinjection was of 500.5 days (P25: 350; P75: 581). Age, time to request the reinjection and pain intensity before the first intervention was not different between responders and non-responders. The majority of patients had a short response to the first trigonal injection, with 9 patients being responders (7 patients), while only 2 patients abandoned the OnabotA programme because of lack of efficacy. This suggests that the duration of the effect after the first injection should not be used as a predictor of long-term treatment efficacy. Concerning safety, and urinary tract infection (UTI), straining to void and acute urinary retention with the need to initiate clean intermittent catheterisation (CIC) were reported. Of the 193 procedures carried out 71 procedures had no information about adverse events. In the remaining 122 procedures, 58 had no adverse events, simple UTIs were recorded in 36 cases, and straining was reported in 13 patients. The need for CIC occurred in only one procedure. "The long efficacy is a relevant finding for clinical practice as it decreases the burden that repeated injections cause to patients and health facilities." The most interesting finding from the analysis of our cohort was the long interval between the patient request for retreatment. The duration of effect of each treatment, exceeding one year on average, was longer than the duration reported in clinical trials, in which only OnabotA was allowed. The on-demand use of non-opioid analgesic drugs, amitriptyline, leukotriene receptor antagonists and antihistaminics were allowed in the cohort and may have substantially reduced the necessity of toxin reinjections. The long efficacy is a relevant finding for clinical practice as it decreases the burden that repeated injections cause to patients and health facilities. As the treatment for BPS/IC is tailored to each patient, and flares and remissions occur at various times and frequencies, these factors may increase the time between patients requests for a reinjection. In addition, the invasiveness and potential complications associated with OnabotA injections
Prof. Francisco Cruz Dept. of Urology, Centro Hospitalar Universitário de São Joãoand Faculty of Medicine of Porto (PT)
Bladder pain syndrome /interstitial cystitis (BPS/IC) remains a difficult condition to manage, and has no curative treatment so far. Thus, a key part of BPS/IC management is on symptom control, with a particular focus on pain. The first line of treatment involves patient education and stress control . The second line involves oral analgesic therapies and pharmacological agents, intended to replenish the glycosaminoglycan layer. In the later line of treatment, surgical therapies may be introduced, including intratrigonal injection of onabotulinum toxin type A (OnaBotA) . Once the OnaBotA is inward, the neurons cleave proteins that are essential for the docking of the neuronal vesicles to the membrane . In sensory neurons, the release of neuro peptides, ATP and the trafficking of pain receptors from neuronal vesicles to the membrane is impaired . The application of OnabotA in the trigone was previously justified by the fact that this bladder region has the highest density of nociceptors . Since 2004, multiple studies showed that 100 units of OnaBotA are effective and safe in pain control, decreasing LUTS and improving life quality, in BPS/IC patients. OnabotA action rarely extends for more than 12 months, after which symptoms recur and patients request new injections. Previous prospective studies were mainly short- or medium-term with only a few injection cycles [4, 5]. Information regarding long-term efficacy and safety in real-life conditions were lacking, until 2022 . Real-life study In the retrospective study of our cohort of BPS/IC patients treated with intratrigonal OnaBotA, the duration of treatment cycles was analysed and possible predictors of response and persistence on therapy were investigated. Patient characteristics were compared: age, the initial pain intensity, the overall treatment duration, and the duration of the first treatment cycle. For this purpose, three groups of patients were defined. The responders group comprised of 25 patients currently in treatment (patients with disease control achieved after an injection and patients that requested a reinjection). The group of non-responders to OnaBotA included 17 patients. The third group included 5 patients lost to follow-up due to non-therapeutic causes. A total of 193 procedures were performed. Treatment per patient varied between 1 (10 patients) and 14 treatments (1 patient). Approximately 50% of patients received 4 or more treatments. The mean age of the patients at the time of the first injection
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