At the end of the 20th century, textbooks on overactive bladder often stated that antimuscarinic drugs work by inhibiting bladder contractions. We now know that not to be true as, at therapeutic doses, patients do not develop impaired bladder contractility. The drugs inhibit afferent mechanisms resulting in a reduction of urgency and hence urgency incontinence.2 When Brigitte Schurch first used botulinum toxin A (BTA) to treat neurogenic bladder patients with detrusor overactivity and detrusor sphincter dyssynergia, the goal was to inhibit detrusor contractions to prevent incontinence.3 The technique involved cystoscopically injecting the posterior-lateral bladder wall while sparing the trigone as the trigone does not contract during voiding and there was the theoretical risk of ureteric reflux. However, patients had to perform intermittent catheterization to empty their bladder, a perfectly appropriate and useful therapeutic outcome for these patients, as many became continent.
In transitioning the use of BTA to idiopathic OAB, the goal was no longer to block detrusor contraction but rather to maximize the reduction of urgency incontinence and minimize retention of urine. This is difficult to achieve due to its mechanism of action. The goal of BTA in esthetics use is to inhibit synaptic transmission at the neuromuscular junction and cause muscle paralysis. In the bladder, this is its side effect causing impaired bladder contractility resulting in the retention of urine and increased UTI rate.4 The desired effect in the bladder is on afferent innervation possibly by interfering with transportation of the TRPV1 receptor in C-fibers.5
An early placebo RCT run by the NIH on the use of BTA in OAB was halted prematurely as there was an excessive number of patients requiring catheterization in the BTA arm.6 To reduce the retention rate, the definition of retention was loosened, and the dose reduced to 100 units of BTA which allowed the retention rate to drop to 6.5%. However, the technique in the registration Phase III trials used 20 injections sparing the trigone.4
In my view, this was an error. The trigone is thought to be the site of up-regulated Cfibers which need to be chemodenervated to reduce urgency whereas, in the rest of the bladder, parasympathetic fibers should be preserved to allow normal detrusor contraction during voiding. Indeed, our recently published study of radio-frequency ablation of just the trigone did reduce urgency incontinence without causing retention of urine or an increase in UTI rate.7
As it is impossible to separate the afferent (desired) from the efferent (undesired) effects of BTA, this can be achieved by injecting just the trigone with BTA as we did in the reported case series.1 Of course, one injected, BTA does spread from the site of injection but this anatomical targeting should improve the therapeutic ratio and our study suggests that it does.
Given that the vast majority of patients receiving OAB treatment are women, injecting the trigone should be much easier by the vaginal route.8 In this transvaginal trigone treatment (T3), the injection site would be through the anterior vaginal wall just 5cm proximal to the vaginal introitus and therefore easily accessible in an office setting. As the volume of the trigone is only about 3 cubic cm, a single injection to a 5mm depth should suffice. This would obviate the need for cystoscopy and anesthetic and should be quicker and simpler. Dr. Amy Dobberfuhl, in the department of urology at Stanford University, is currently exploring this approach and data should be forthcoming in the near future.
Written by: Eboo Versi, MD, PhD, Clinical Associate Professor, Department of Obstetrics, Gynecology and Reproductive Sciences, Rutgers Robert Wood Johnson Medical School, NJ, United States
References
- Ton J, Downing P, Versi E et al (2021) Outcomes of a Single Trigone-only vs. 20 Trigone-sparing Injections of OnabotulinumtoxinA for Refractory Overactive Bladder (OAB). International Urology and Nephrology https://doi.org/10.1007/s11255-021-02802-0
- Vijaya G, Digesu GA, Derpapas A et al (2012) Antimuscarinic effects on current perception threshold: a prospective placebo control study. Neurourol Urodyn. 31(1):75-79. doi:10.1002/nau.21194
- Schurch B, de Sèze M, Denys P et al (2005) Botox Detrusor Hyperreflexia Study Team. Botulinum toxin type a is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled 6-month study. J Urol.174(1):196-200. doi: 10.1097/01.ju.0000162035.73977.1c. PMID: 15947626.
- FDA. BOTOX® (20190 Full Prescribing Information Including Boxed Warning: https://media.allergan.com/actavis/actavis/media/allergan-pdf-documents/productprescribing/20190620-BOTOX-100-and-200-Units-v3-0USPI1145-v2-0MG1145.pdf
- Pinto RA, Costa D, Morgado A, et al (2018) Intratrigonal OnabotulinumtoxinA Improves Bladder Symptoms and Quality of Life in Patients with Bladder Pain Syndrome/Interstitial Cystitis: A Pilot, Single Center, Randomized, Double-Blind, Placebo Controlled Trial. J Urol 199:998–1003. https://doi.org/10.1016/j.juro.2017.10.018
- Brubaker L, Richter H, Visco A et al (2008) Refractory idiopathic urge urinary incontinence and botulinum A injections. J Urol 180:217-222.
- Rovner E, Versi E, Tu LM et al (2019) One-year results with selective bladder denervation in women with refractory overactive bladder. Neurourology & Urodynamics 38:2178-84 DOI: 10.1002/nau.24110
- Versi E (2011) Method and device for delivering drug to the trigone of the bladder. USPTO, Patent No. 8,029,496.
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