Refractory overactive bladder

Background

The US Food and Drug Administration (FDA) approved BTX-A for cosmetic use in 1991. It has since been FDA approved for many indications including blepharospasm, cervical neck dystonia, hyperhidrosis, chronic migraine, and upper limb spasticity. In August 2011, BTX-A was approved for the treatment of neurogenic bladder; in January 2013, it was approved for treatment of OAB. BTX-A is a potent neurotoxin derived from the anaerobic bacterium’ Clostridium botulinum. Initially, the proposed method of action was based on data extrapolated from skeletal muscle, where BTX-A acts primarily as a muscle paralytic, inhibiting the presynaptic release of acetylcholine from motor neurons at the neuromuscular junction. As a result, a flaccid paralysis ensues. By cleaving protein receptors within the nerve terminals, BTX-A prevents the normal vesicular transport and release of acetylcholine from the motor nerve terminals into the neuromuscular junction. Since these initial theories were formulated, BTX-A has been found to also affect the afferent side of the nervous system by inducing changes like decreasing the sensory response of C-fibers ( ). It is likely that BTX-A has a complex inhibitory effect on vesicular release of excitatory neurotransmitters and on the axonal expression of other important mediators. Based on histologic evidence, recovery of chemodenervation occurs after 3 to 6 months. This is thought to be the result of turnover of the presynaptic molecules and nerve sprouting from the nerve terminal, forming a new functional synapse.

There are seven immunologically distinct subtypes of botulinum toxin, but only types A and B are available for use in clinical practice. BTX-A, which is approved for OAB treatment, is available as Botox (Allergan Inc., Irvine, CA) in the United States and as Dysport (Medicis Aesthetics) in the United Kingdom. Type B is less potent and is commercially available as MyoBloc in the United States and as NeuroBloc in Europe (Solstice Neurosciences, Louisville, KY). BTX-A is administered by cystoscopic injection of multiple aliquots into the detrusor muscle. The FDA-approved dosage for the treatment of neurogenic bladder is 200 U; the FDA-approved dose for OAB is 100 U.

Efficacy

An extensive Cochrane review’ and AUA systematic review summarize the literature surrounding the use of BTX-A for OAB ( ; ). The results summarized in these reviews and newer, relevant randomized controlled trials (RCTs) are presented here and in Table 32.1 . Four early randomized trials with placebo control groups evaluated intradetrusor injections of 50 to 300 U ( ; ; ; ). Overall, significant reductions in incontinence episodes and in urgency were reported in the active treatment groups. Voiding frequency results are less clear, with studies reporting a large range of reductions (e.g., from a nonsignificant 1.3 episodes per day to up to 14.2 episodes per day). This is likely because of the inclusion of patients with different baseline voiding frequency levels in these studies.

The 2015 AUA literature review retrieved four additional RCTs with placebo control groups ( ; ; ; ) and two with nonplacebo comparator groups ( ; ). In general, most trials reported statistically significant improvements in measured voiding outcomes (UUI, urinary frequency, urgency, nocturia, pad use) and in quality-of-life (QOL) outcomes compared with placebo groups. Not included in these literature reviews was the Anticholinergic versus Botox Comparison (ABC) study, a multicenter RCT that compared the effectiveness of 6 months of daily anticholinergic therapy to a single intradetrusor injection of 100 U of BTX-A in patients with OAB symptoms ( ). This study included women who were either drug-naïve or who had tried two or fewer prior anticholinergic medications. The results demonstrated that anticholinergic medication had similar rates of improvement in daily UUI episodes compared with BTX-A injections (3.4 anticholinergic vs. 3.3 BTX-A; P = .81). However, patients who underwent BTX-A injections had significantly higher cure rates compared with patients who received anticholinergic medication (13% anticholinergic vs. 27% BTX-A; P < .01).

Finally, in the 2016 Refractory Overactive Bladder: Sacral Neuromodulation Versus Botulinum Toxin Assessment (ROSETTA) study, 364 women were randomized to cystoscopic intradetrusor injection of 200 U of BTX-A or to SNM ( ). The women in the BTX-A group had a greater reduction in 6-month mean number of episodes of UUI per day than did those in the SNM group (–3.9 vs. –3.3 episodes per day; P = .01).

Dosing considerations

Although the current FDA-approved dose of BTX-A for idiopathic OAB is 100 U, there is significant variation in reported dose and comparator arms in the literature. RCTs with different doses are reported in Table 32.1 . The studies reporting on active BTX-A (doses from 50–200 U) generally demonstrate improved efficacy of BTX-A compared with placebo, but there is not a clear relationship between dose and efficacy across these trials. One of the largest trials, performed by , randomized patients with idiopathic OAB (≥3 UUI episodes/3 days and ≥8 micturitions per day) to BTX-A at a dose of 100 U ( n = 277) or placebo ( n = 271). They found that, at 12 weeks, BTX-A significantly decreased UUI episodes/day compared with the control group (–2.95 BTX-A vs. –1.03 placebo; P < .001). As previously discussed, noted similar improvement in patients treated with BTX-A 100 U or anticholinergic medications, but an improved cure rate with BTX-A. compared responses across a wide range of BTX-A doses (50–300 U) and reported that doses of 100 U or greater were sufficient to reduce UUI episodes and improve QOL measures, but without clear dose-response effects above 150 U. This study was limited by lack of statistical comparison between groups.

randomized a total of 240 women with refractory OAB to receive either 200 U of BTX-A or placebo injection. The primary outcome was voiding frequency at 6 months. The median voiding frequency was lower after treatment with BTX-A compared with placebo (8.3 vs. 9.67, P < .01). Episodes of UUI also decreased (1.67 vs. 6.0, P < .01). Cure rates were higher in the BTX-A group compared with the placebo group (31% vs. 11%; P = .002). Given the available literature, our expert opinion is that patients should be counseled regarding the option for 100 U versus 200 U for refractory OAB.

Duration of effect and repeat injections

Most studies suffer from lack of long-term follow-up, but longer-term efficacy has been demonstrated in some studies. investigated clinical responders in the ROSETTA trial to determine efficacy up to 2 years. Clinical responders were defined as those experiencing at least a 50% reduction in UUI episodes 1 month after administration of BTX-A. Over the course of 2 years, up to two additional BTX-A injections were allowed after the initial 6-month study. No difference in decreased mean UUI episodes per day was found between the BTX-A and SNM groups over 24 months (–3.88 vs. –3.50, P = .15). The BTX-A group maintained high satisfaction and treatment endorsement throughout the 24-month period. Importantly, of the 115 participants who requested a second BTX-A injection, the median interval between first and second injection was 350 days (interquartile range 242–465 days).

Other prospective and retrospective studies have helped illustrate the duration of efficacy of BTX-A, especially after the first injection.’ reported on 68 women (baseline 5.7 UUI episodes/day) who underwent an intradetrusor injection of 100 U BTX-A and were followed for 12 months. Patients were allowed repeat injection at 12 months if they experienced symptom relapse. On average, patients had sustained improvement in UUI episodes/day up to 9 months (5.7 at baseline vs. 1.9 at 9 months). Twenty-five of the 54 patients with 12-month data requested a second injection, with similar improvements. reported on 125 patients who had two or more 200 U BTX-A injections (667 injections total). The median interval between injections was 14.4 months. There was sustained efficacy after repeat injections, with statistically similar times to repeat injections after the first four injections. Finally, reported similar significant reductions in frequency, urgency, and UUI after BTX-A injections in 100 patients, 63 of whom had two or more injections (mostly of 200 U). Again, the average time between injections ranged between 300 and 450 days.

Rates of BTX-A discontinuation are difficult to estimate because of differences in reporting and poor patient follow-up in many studies. Reasons for BTX-A discontinuation are more consistently reported and include failure of therapy (either subjective or objective) and low tolerability (e.g., having to perform intermittent self-catheterization [ISC], urinary retention, and recurrent urinary tract infections [UTIs]). Given the wide range of times until return of symptoms reported in the literature, it is likely prudent to avoid scheduled repeat injections and to proceed only with return of bothersome symptoms.

Location and depth of botulinum toxin injection

The location and depth of intradetrusor BTX-A injections vary across studies. Two systematic reviews evaluated adverse events and short-term efficacy associated with trigonal and extratrigonal BTX-A ( ; ). Importantly, both included studies that involved patients with neurogenic bladder. The earlier review by evaluated six studies (258 patients) that were carried out between 2006 and 2011. This meta-analysis did not show significant differences between trigonal and extratrigonal BTX-A for acute urinary retention (4.2% vs. 3.7%, P = .93), UTI, or short-term cure rates. In 2018, Jo et al. evaluated eight studies published from 2007 to 2016, only one of which was included in the previous systematic review. They found overall improved outcomes in the trigone inclusion arms based on higher complete dryness rates (odds ratio [OR] = 2.19, 95% confidence interval [CI] 1.32–3.63, P = .002) and fewer incontinence episodes (–0.85 per day, 95% CI –1.55 to –0.16, P = .02). No differences in safety or adverse events, including bladder discomfort, were seen between groups. A limitation of this meta-analysis was an overall small number of patients per study. In terms of depth of injection, the more recent systematic review evaluated an intradetrusor versus suburothelial approach and did not find a difference in reduction in UUI between groups (–1.32 episodes per day, 95% CI –5.69 to –3.06, P = .56; ).

Technique for botulinum toxin injection

The technique of mixing the BTX-A and how to inject it is described on the package insert and is standard ( http://www.allergan.com/assets/pdf/botox_pi.pdf ). The procedure is described here and demonstrated in Video 32.1 .

BTX-A is a vacuum-dried protein available in 50-, 100-, and 200-U vials that must be refrigerated. Before injection, the vials of toxin must be reconstituted with preservative-free saline, and the mixture can be stored at 2° to 8° C for up to 24 hours. This outpatient procedure is easily performed in a clinical setting or, in rare circumstances, in an operating room. One trial reported similar pain scores of approximately 4/10 on a visual analog scale for subjects who had either local or general anesthetic ( ). Experts agree that intravesical premedication can be given in the office, with approximately 30 to 40 mL of 2% lidocaine instilled via catheter into the bladder for about 20 minutes before injection. There is little evidence regarding other management options or the impact of this strategy, and future research would help standardize recommendations.

Cystoscopy may be performed using a 30-degree, 12-degree, or even 0-degree lens with a rigid cystoscope plus working element with channel for injection needle or disposable injection needle. A flexible cystoscope with injection needle may also be used. The bladder is filled with approximately 100 mL of 0.9% normal saline to achieve some tautness to the bladder wall. Injections are spread over different rows to equally cover the bladder dome and posterior base, sparing the ureteral orifices ( Fig. 32.1 ). Some studies included a tiny amount of indigo carmine or methylene blue in the injection solution to facilitate visualization of the injection pattern. Again, depth of injection may not significantly impact efficacy, but visualization of injection may improve the ability to avoid extravasation of the injection through the bladder wall ( ). The concentration of toxin and volume of fluid that is injected are not consistent across studies. Although one study showed that a single BTX-A injection can spread the neurotoxin activity to the opposite side of the bladder ( ), the standard technique uses between 10 and 20 injections. prospectively compared the therapeutic effects and safety of different numbers of BTX-A injections for patients with OAB and found that injection of 1 mL of BTX-A (10 U) at 10 sites was adequate for an optimal therapeutic effect. The BTX-A package insert recommends administering 100 U as 0.5-mL (5 U) injections across 20 sites into the detrusor, for a total volume of 10 cc, but, given the literature, a total of 10 to 20 sites is likely similarly efficacious.

Complications and their management