“What Medical Management Should Be First Line for Bladder Storage Symptoms in NLUTD”—Pro Botox

Abstract

Objectives:

Neurogenic lower urinary tract dysfunction (NLUTD) severely impairs patient quality of life (QoL). While oral medications are often first-line treatments, their high failure rates and side effects limit their effectiveness. Thus, we argue for the use of intravesical botulinum toxin A (BoNT-A) injections as a first-line alternative.

Materials and Methods:

A PubMed search identified 81 studies on NLUTD and BoNT-A, 26 of which were analyzed for the efficacy of BoNT-A as a first-line treatment.

Results:

BoNT-A significantly improved renal function and urinary continence, as indicated by significant reductions in maximum detrusor pressure and increases in maximum cystometric capacity, respectively. Mechanisms for which BoNT-A treatment also improved urinary urgency were found to include sensory pathway modulation and neurotransmitter inhibition. Finally, QoL was found to significantly improve across multiple criteria, including sexual function such as lubrication and orgasm. Importantly, early initiation of BoNT-A treatment yielded better outcomes, emphasizing its value as a first-line treatment. Although side effects include increased post-void residual (PVR), pain, muscle weakness, and reduced efficacy over time, studies have shown that these effects are manageable with dose adjustments and anesthetics.

Conclusion:

BoNT-A offers substantial therapeutic benefits for NLUTD and demonstrates greater effectiveness when used early; thus, it should be considered a first-line treatment option.

Neurogenic lower urinary tract dysfunction (NLUTD) is a common sequela of neurological disorders/damage, such as spinal cord injury and multiple sclerosis (MS), resulting in the abnormal function of the bladder and/or its sphincters [1, 2]. The urinary incontinence caused by NLUTD significantly affects quality of life (QoL) and is associated with increased risk of renal insufficiency and urinary tract infections (UTIs) [1, 3]. Common treatments include antimuscarinic agents, beta-3 receptor agonists, and intravesical botulinum toxin (BoNT-A) injections. Antimuscarinics and beta-3 receptor agonists are often used as first-line treatments; however, their side effects and need for daily administration result in high failure rates (e.g., antimuscarinics having a 3-year failure rate that ranges from 84% to 100%) [4]. In contrast, intravesical BoNT-A injections (10–40 injections totaling 200–300 IU) [1, 2] show a 3-year failure rate of only 12.6% in patients with neurogenic detrusor overactivity [5]. Thus, we argue that BoNT-A should be the first-line treatment for NLUTD.

A PubMed search was conducted for English-language articles of all study designs, with no date range, mentioning NLUTD and intravesical BoNT-A injections. Across reviewed studies, BoNT-A consistently improved renal function, urinary continence, urinary urgency, and QoL. BoNT-A preserves renal function by decreasing maximum detrusor pressure (MDP), slowing bladder wall fibrosis, and reducing urinary infections. A study of 59 patients by Schurch et al. found that BoNT-A significantly decreased MDP (p ≤ 0.023) [2]. Additionally, histology of the bladder wall of 45 patients revealed that those undergoing BoNT-A had significantly less detrusor scarring, potentially because BoNT-A inhibits transforming growth factor 1-beta, preventing fibrosis caused by abnormal type III collagen quantity and distribution [6]. Lastly, decreasing MDP and bladder wall fibrosis reduces vesicoureteral reflux, thereby decreasing urinary infections [7]. BoNT-A also improves urinary continence by increasing maximum cystometric capacity (MCC). In Schurch et al., the 59 patients treated with BoNT-A had a significant increase in MCC (p ≤ 0.020) and decrease in incontinence episodes post-injection (p = 0.015) [2]. Urinary urgency can be improved by BoNT-A through afferent modulation. The proposed mechanisms behind BoNT-A afferent modulation include desensitization of the purinergenic pathway [8], blocking neurotransmitter release [9], and inhibiting TRPV1 receptor translocation to the membrane [10]. Moreover, an animal study found that BoNT-A inhibited the release of calcitonin gene-related peptide, a substance involved in sensory urgency [11, 12]. BoNT-A also improves patient QoL. In one study, 267 patients treated with BoNT-A showed a significant improvement in the mean incontinence-QoL score at 6 weeks (p < 0.001) [13] while another meta-analysis found that LUTD patients undergoing BoNT-A had significant improvement in desire, arousal, lubrication, orgasm, and satisfaction [14]. BoNT-A also improves QoL by delaying or eliminating the need for invasive surgeries in patients refractory to oral medications [15, 16].

Importantly, multiple studies have demonstrated that initiating BoNT-A earlier yields better outcomes, indicating its suitability as a first-line treatment option. One study found that earlier BoNT-A initiation in children led to higher rates of urinary continence [15]. Another study found that, of 71 MS patients, the 26% that failed BoNT-A had experienced a longer duration of MS symptoms prior to treatment. Therefore, they recommended that BoNT-A be started as soon as possible [17]. In addition, O’Connor et al. found that patients with a longer period of NLUTD symptoms experienced less improvement after BoNT-A due to bladder wall fibrosis [18]. Since BoNT-A has a lower failure rate than oral medications, it is preferable to use BoNT-A as the first-line treatment to prevent bladder wall fibrosis from developing. Additionally, unlike oral medications, BoNT-A has anti-inflammatory effects because it decreases mast cell activation and reduces substance P release. Both of these factors can contribute to neurogenic inflammation, which can promote afferent axonal growth and increased pain perception [9]. Hence, starting BoNT-A early could prevent this inflammatory process.

Some may argue that BoNT-A is an unsuitable first-line treatment for NLUTD, referencing drawbacks such as increased post-void residual (PVR), pain associated with the procedure, general muscle weakness, and reduced efficacy over time. While studies have shown that BoNT-A increases PVR which predisposes patients to UTIs and may introduce the need for clean intermittent catheterization (CIC), a study found that this side effect is dose-dependent, so lowering the dose decreases the risk of PVR [17]. Furthermore, Schurch et al. showed that the need for CIC did not impact patient QoL scores [19]. Another drawback of BoNT-A is the pain associated with injection. Interestingly, Schulte-Baukloh et. al. found that, for patients undergoing their first BoNT-A injection, the use of general anesthesia reduced their anxiety and pain; however, it did not do so for subsequent injections [20]. Adverse events, such as muscle weakness and hyposthenia, can occur if BoNT-A spreads outside the bladder [21]. However, De Laet et. al. showed that this spread can be minimized by lowering the dose and injecting only 3–5 mm into the bladder wall [22]. Finally, studies have shown that the efficacy of BoNT-A may decrease over time, possibly due to neutralizing antibodies or histological changes in the bladder wall [8]. Yet another study found that switching to a different brand of BoNT-A was effective in 50% of failures [8], although it is important to note that BOTOX (Allergan Aesthetics) is the only FDA-approved BoNT-A brand for NLUTD treatment in the United States. Other potential challenges to the acceptance of BoNT-A as a first-line treatment may include the cost of multiple injections, accessibility to BoNT-A, availability of healthcare professionals trained to inject BoNT-A, and patient acceptance of this treatment option.

1 ∣. Conclusion

In summary, oral medications for NLUTD have unacceptably high long-term failure rates and burdensome side effects, leaving many patients inadequately treated. In contrast, BoNT-A provides superior outcomes, improving continence, protecting renal function, reducing urgency, and enhancing QoL, with a markedly lower failure rate. Importantly, earlier initiation of BoNT-A prevents irreversible bladder changes and maximizes benefit. Given these advantages, BoNT-A should no longer be reserved as a rescue therapy after failed oral agents, but instead adopted as the first-line treatment for NLUTD.

Data Availability Statement

Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study.