Overactive bladder (OAB) is a chronic, debilitating condition that significantly impacts both individual quality of life and societal health care expenditures. Characterized by urinary urgency, with and without urinary incontinence, urinary frequency and/or nocturia, OAB is complex, with various amalgamations of presenting symptoms that have been described as phenotypes, including OAB-dry and OAB-wet. Published evidence-based guidelines recommend treatments including behavioral therapy, pharmacotherapy and advanced therapies. However, one of the significant challenges in OAB management is the wide range of symptom combinations and patient factors, which often necessitate a tailored approach.

Intradetrusor botulinum toxin A (BTXA) injection is an effective treatment for medication-refractory OAB that received U.S. Food and Drug Association approval in 2013. Advances in our understanding of the mechanism of action (MOA) of BTXA at the cellular level have prompted a resurgence of interest in BTXA injection paradigms in an effort to tailor and improve overall therapy outcomes. During the 2021 SUFU (Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction) Plenary Session on this topic, Dr. Francisco Cruz gave a robust primer on the basic science concepts and the corresponding clinical implications of BTXA MOA. Dr. Michael Kennelly followed with a tailored BTXA injection paradigm based on an assimilation of the literature, over 20 years of clinical experience with BTXA, and attention to individual OAB symptoms and patient factors (see table). These intriguing concepts warrant further study to validate the proposed BTXA injection paradigms.

Table. Proposed botulinum toxin injection paradigm based on patient factors

Data courtesy of Michael Kennelly, MD based on an assimilation of the literature and 21 years of clinical experience with the use of BTXA in the bladder for OAB and neurogenic detrusor overactivity. DHIC, detrusor hyperactivity with impaired contractility. DM, diabetes mellitus. NDO, neurogenic detrusor overactivity.

MOA

OnabotulinumtoxinA exerts its effect at the neuromuscular junction by binding to SV2 (synaptic vesical glycoprotein 2), a high-affinity protein receptor.¹ After entering the neuron, BTXA light chain cleaves the SNAP-25 protein, preventing SNARE complex formation, membrane fusion and release of acetylcholine. This cascade of events occurs in the ganglia and the nerve terminals in the detrusor muscle, reducing bladder contractility. The distribution of SV2 has important implications for BTXA efficacy and its potential adverse events (eg elevated post-void residual). In the human bladder, SV2 is found on over 90% of parasympathetic nerve fibers, which are most abundant in the detrusor muscle.² However, approximately half of human bladder sensory fibers express SV2, identifying potential targets (the sensory nerve fiber-rich suburothelium and bladder trigone) for tailored therapy in OAB-dry patients with sensory urgency and those at high risk for urinary retention.

BTXA also affects the sensory nerves through adenosine triphosphate (ATP), suburothelial neuropeptide release and sensory nerve receptor expression. Mechanical stretch and chemical irritation both stimulate the release of ATP from urothelial umbrella cells, thereby activating purinergic P2X3 receptors on sensory nerves (fig. 1).³ In animal studies, BTXA blocks this release of ATP, thereby reducing activation of P2X3 receptors and diminishing bladder sensory stimulation.² BTXA further minimizes sensory transmission by disrupting transient receptor potential vanilloid-1 channel (TRPV1) and P2X3 receptor transport to the suburothelial sensory nerve membrane,⁴ consequently reducing activation of the micturition reflex. Finally, in rat models, BTXA inhibits the release of calcitonin gene-related peptide (CGRP) and substance P, both neurogenic components of bladder inflammation.⁵

Figure 1. Botulinum toxin A (BoNT/A) blocks ATP, reducing activation of P2X3 receptors and sensory stimulation. Reprinted with permission of Francisco Cruz, MD, PhD, 2021 SUFU Plenary Session.

Clinical Implications of BTXA MOA

In the literature, several factors are thought to impact BTXA therapy outcomes with varying levels of evidence.

Dose. In an onabotulinuntoxinA phase 2 randomized, placebo controlled trial, Dmochowski et al demonstrated a dose-dependent relationship between BTXA and therapy efficacy, quality of life and adverse events.⁶ This dose-response curve identified 100 U as the most effective dose with the lowest risk of side effects. In the phase 3 trials, Nitti et al confirmed therapy efficacy using trigone sparing injections at the 100 U dose, noting a clean intermittent catheterization (CIC) rate of approximately 6%.⁷ Subsequent clinical trials have evaluated various injection techniques to reduce the risk of urinary retention.

Location and injection depth. Given the impact of BTXA on both the motor efferent and sensory afferent nerves, multiple studies have evaluated the impact of trigonal injections versus nontrigonal injections. Early studies avoided trigonal injections due to concern for vesicoureteral reflux. However, subsequent studies failed to demonstrate reflux.⁸ To evaluate the impact of an alternative injection pattern (8 peritrigonal with 2 trigonal injections), Glazier et al conducted a multicenter randomized controlled trial in 120 patients randomized 2:1 to the alternative onabotulinumtoxinA injection pattern (100 U) versus placebo (fig. 2).⁹ Although this trial was not intended to represent a direct comparison to the phase 3 trials, the authors reported 14.3% dry rates (versus 23% in the trigone sparing techniques used in the phase 3 trials⁶) at 12 weeks with a 2.6% CIC rate (versus 6% in the phase 3 trials). In another study, Kuo evaluated the impact of both injection depth and location (suburothelial, lateral wall and trigonal/bladder base) in 45 patients (fig. 3).⁸ The author observed significant subjective improvements in urgency severity in all 3 groups, with a higher proportion and longer duration of clinical success in the detrusor and suburothelial groups. However, there were no urinary retention episodes in the trigonal/bladder base group, while 2 participants in the suburothelial and the detrusor groups experienced urinary retention. In summary, these findings suggest that trigonal injections have less effect on bladder contractility and may be beneficial for patients with OAB-dry with sensory urgency or detrusor hyperactivity with impaired contractility. However, this alternative injection paradigm may negatively impact the duration of therapy.

Figure 2. Alternative onabotulinumtoxinA injection paradigm. Source: International Continence Society 2020.⁹

Figure 3. Injection paradigm. A, suburothelial and detrusor injection template (40 injections). B, suburothelial injection depth. C, detrusor injection depth. D, bladder base and trigone injection template.⁸

Volume and number of injections. In animal studies, higher volume injections increased BTXA distribution and increased expression of cleaved SNAP-25 in the parasympathetic nerves, suggesting a single injection is more effective if diluted in a larger volume of saline.¹⁰ In another study, Liao et al evaluated the therapeutic effect of receiving 10, 20 or 40 injections of BTXA 100 U, and observed similar therapeutic and adverse effects based on validated questionnaires (Urgency Severity Scale, OAB Symptom Score, Patient Perception of Bladder Condition) and objective outcomes (post-void residual, urodynamics, bladder diary).¹¹ These findings suggest that the number of injections are less impactful than the dose and volume of injection.

In summary, identifying opportunities for tailored therapy continues to be a priority in OAB management. The various mechanisms by which BTXA impacts bladder function present opportunities to individualize therapy for our diverse patient populations. However, data are currently lacking to support standard use of these injection paradigms. Further studies are needed to evaluate these concepts and validate these emerging techniques to improve BTXA injection outcomes.