UROLOGY

Urological Applications of BoNT Therapy

Advisory Editor
Michael B. Chancellor, MD
Director, Neurourology and Female Urology Programs
University of Pittsburgh Medical Center
Professor, Departments of Urology and Obstetrics and Gynecology
McGowan Institute for Regenerative Medicine
University of Pittsburgh School of Medicine
Pittsburgh, Pennsylvania

Botulinum neurotoxin (BoNT) therapy has been studied most widely in two urological disorders: detrusor-sphincter dyssynergia (DSD) and overactive bladder (OAB). DSD, a spastic condition commonly seen in spinal cord injury and multiple sclerosis patients, affects the nerves that control the skeletal and smooth muscles of the urinary system, causing a lack of coordination between the bladder and the external sphincter. The external sphincter remains in a contracted state, leading to outlet obstruction as the bladder attempts to expel the urine. This dyssynergy results in excessive bladder pressures and inability to empty the bladder completely, and increased pressure can result in detrusor damage, renal damage, or urethral reflux (Jost and Naumann, 2004). Clinical utility of BoNT is suggested by animal studies that demonstrated that BoNT injected into rat bladder and urethra markedly inhibited the release of labeled norepinephrine and acetylcholine (McNeil et al, 2001; Franks et al, 2000; Smith et al, 2002a; Smith et al, 2002b). Blocking norepinephrine release may inhibit sympathetic transmission and smooth muscle dyssynergia (Smith et al, 2002a; Smith et al, 2002b).

OAB is a disorder characterized by urinary frequency and urgency, with or without urge incontinence (Sahai et al, 2005). The underlying cause of OAB is detrusor overactivity, which is subdivided into neurogenic or idiopathic (non-neurogenic) detrusor overactivity. Medical therapy for this condition most commonly entails systemic anticholinergic agents that suppress muscarinic receptors in bladder smooth muscles and thereby inhibit bladder contractions, but these agents have unpleasant side effects such as dry mouth, constipation, blurred vision, tachycardia, and sedation, leading many patients to discontinue treatment (Sahai et al, 2005; Yoshimura and Chancellor, 2002). OAB can have a significant impact on the patient’s quality of life, affecting interpersonal and sexual relationships and causing the patient to feel shame, embarrassment, and loss of self-confidence. Figure 1 shows current and potential targets for BoNT within the lower urinary tract.

Figure 1. Current and potential future targets for BoNT within the lower urinary tract. IC = interstitial cystitis; DH = detrusor hyperreflexia; DISD = detrusor internal sphincter dyssynergia; BNO = bladder neck obstruction; BPH = benign prostatic hyperplasia; DESD = detrusor external sphincter dyssynergia. Sensory urgency/IC and BPH are potential future targets for BoNT therapy; the others are current targets of BoNT therapy. Reproduced with permission from Smith CP, Somogyi GT, Chancellor MB. Emerging role of botulinum toxin in the treatment of neurogenic and non-neurogenic voiding dysfunction. Curr Urol Rep. 2002b;3:382-387.

Clinical studies of BoNT therapy in urological disorders

Detrusor-sphincter dyssynergia

BoNT therapy has been used to treat spinal cord injured and multiple sclerosis patients with detrusor-sphincter dyssynergia. BoNT injections into the external urethral sphincter produce a reversible chemical sphincterotomy, thereby eliminating the need for surgical treatment (Schurch, 2004). Chemical denervation of the external sphincter by BoNT typically produces clinical improvement in the symptoms of DSD within 5 to 7 days after injection (Schurch, 2004). The first demonstrations that BoNT type A injections by percutaneous or cystoscopic injection of the sphincter in spinal cord patients with DSD reduced urethral pressure and postvoid residual urine volume were reported in the late 1980s and early 1990s (Dykstra et al, 1988; Dykstra and Sidi, 1990). Electromyography confirmed that these changes were associated with denervation of the spastic rhabdosphincter. The average duration of effect in these two studies was 50 to 60 days.

In another early investigation of the effect of BoNT type A in patients with spinal cord injury and DSD, treatment efficacy was reported in 21 of 24 patients (Schurch et al, 1996). Concomitant reductions in postvoid residual volume were noted in most patients. Also notable was the finding that transurethral injections, as compared with transperineal injections, had a greater effect on maximum urethral pressure during DSD and a longer duration of efficacy. Schurch et al subsequently reported successful treatment of spinal cord injured patients (n = 21) with detrusor hyperreflexia with intravesical BoNT type A injections (200 to 300 U), with an increase in maximum bladder capacity (296 to 480 mL; P = .016) and a reduction in maximum detrusor voiding pressure (65.6 to 35 cm H 2O) at 6 weeks postinjection (Schurch et al, 2000b). Improved urodynamic function and continence were sustained in the subset of 11 patients that were reassessed at 16 and 36 weeks (Schurch et al, 2000b). These results were supported by other open-label investigations in spinal cord injured patients (Gallien et al, 1998; Petit et al, 1998).

One randomized controlled trial compared the efficacy and tolerability of BoNT type A (100 U) and lidocaine (4 mL of 0.5%) applied in the external urethral sphincter with a single transperineal injection in patients with spinal cord injury, DSD, and chronic urinary retention (de S èze et al, 2002). The primary efficacy variable was postvoiding residual urine volume, assessed three times daily on days 1, 7, and 30 after each injection. Postvoiding residual volume decreased significantly more in the patients treated with BoNT type A compared with lidocaine. Clinical symptoms also improved significantly more with BoNT type A injection than with lidocaine.

A study by Kuo examined 103 patients with various types of lower urinary tract dysfunction (including 29 with DSD) who received urethral injection of BoNT type A (Kuo, 2003). Therapeutic results were largely based on patient subjective interpretation of improvement. Among 29 patients with DSD, 28% had an excellent result and 52% had significant improvement.

Smith et al recently reviewed the 6-year experience of 110 patients with voiding dysfunction resulting from a variety of lower urinary tract disorders, including DSD. Patients received BoNT type A injections into the bladder or urethra (Smith et al, 2005). These investigators reported that maximal efficacy of BoNT type A occurred between 7 and 30 days postinjection, with neither systemic nor local complications observed. Analysis of the 110 patients showed that over 67% reported a decrease or absence of incontinence, with a decrease in both daytime and nighttime voiding symptoms, and improved quality of life symptom scores.

Although the results of studies of BoNT in DSD are encouraging, they are difficult to interpret because of the small numbers of patients, wide range of doses, and variable outcome measures employed in these studies. Controlled studies with well-defined patient populations and validated and reproducible outcome measures are needed.

Overactive bladder

Data are accumulating on the use of BoNT injections for the treatment of neurogenic and idiopathic OAB symptoms (Table), but only recently has a well-controlled study been published (Schurch et al, 2005). 

Table. Clinical Trials of BoNT Therapy in Neurogenic and Idiopathic OAB Symptoms

Currently, there is much more published data on the use of BoNT type A than BoNT type B in the treatment of OAB. Rapp et al recently evaluated the role of BoNT type A intradetrusor injections in 35 patients with OAB in whom anticholinergic therapy failed (Rapp et al, 2004). At 3 weeks after treatment, significant decreases in Incontinence Impact Questionnaire and Urogenital Distress Inventory scores were observed. Overall, 60% of patients reported slight to complete improvement of voiding symptoms after 3 weeks. Improvement was seen for up to 6 months after treatment. In the only double-blind, controlled study of patients with neurogenic detrusor overactivity, Schurch et al injected 200 or 300 units of BoNT type A or placebo into the detrusor, sparing the trigone (Schurch et al, 2005). In this 6-month study, involuntary urine loss episodes decreased significantly with both doses compared with placebo and there was an approximate 50% decrease in losses in both treatment groups compared with baseline at the majority of timepoints. Furthermore, all urodynamic changes were desirable and significantly improved at most timepoints. Quality of life assessments also showed significant improvements at all timepoints in both treatment groups but not in the placebo group. Remarkably, there were no adverse events attributable to the drug and no patients withdrew due to an adverse event.

A recent open-label, dose-escalation pilot study by Dykstra et al examined the efficacy and safety of BoNT type B (Myobloc®; Solstice Neurosciences, Malvern, PA) in the treatment of 15 patients with OAB (Dykstra et al, 2003). All but one patient had relief of OAB symptoms, responding with decreased frequency and urgency and no incontinence.

In a 200-patient open-label neurogenic detrusor overactivity study (Reitz et al, 2004), investigators at 10 European sites injected 300 units of BoNT type A (Botox®) cystoscopically into the detrusor muscle at 30 different locations, sparing the trigone. By the time of the initial follow-up (mean, 12 weeks after injection) as well as at the second urodynamic follow-up examination (mean, 36 weeks after injection), the mean cystometric bladder capacity (P < .0001) and the mean reflex volume (P < .01) had increased significantly, while the mean voiding pressure (P < .0001) had decreased significantly. No injection- related complications or toxin-related side effects were reported. Patients considerably reduced or stopped taking concomitant anticholinergics without recurrence of reflex incontinence and were satisfied with the treatment.

The growth in experience of BoNT use for the management of neurogenic bladder has been reflected in the latest guidelines from the 3rd International Consultation on Incontinence in Monaco, June 26-29, 2004. In the reports from both the Pharmacological Treatment of Urinary Incontinence Committee (Committee 10) and the Neurologic Urinary & Faecal Incontinence Committee (Committee 12), the potential value of BoNT type A in managing a range of urologic conditions is discussed. The International Consultation on Incontinence considered the level of evidence for BoNT type A in neurogenic detrusor overactivity to be 2B, ie, there is fair, research-based evidence to support the recommendation (individual cohort studies, including randomised controlled studies). International Consultation on Incontinence recommendations for practice stated that BoNT bladder injections may be an alternative for detrusor overactivity if conventional therapy fails and that sphincteric injections may be an alternative to sphincterotomy in case of DSD.

Double-blind, placebo-controlled studies are underway to determine the safety and efficacy of BoNT in idiopathic OAB.

Future studies

Early small open-label investigations and clinical experience with BoNT therapy for urological disorders demonstrated clinical improvement in bladder symptoms firmly supported by urodynamic and electromyographic measurements. For neurogenic bladder, results from early experience have been confirmed by one large open-label trial and a placebo-controlled study. There is much less evidence in the idiopathic OAB literature. BoNT therapy holds promise in the management of bladder disorders and DSD, but further double-blind controlled trials are needed to determine the safety and efficacy of this therapeutic approach to DSD and OAB.

Clinical considerations and injection technique for BoNT therapy in bladder disorder

Dr. Chancellor discusses dosing and injection technique for BoNT therapy in bladder disorders. (Windows Media)

Urological applications of non-botulinum neurotoxins

Non-botulinum neurotoxins have received considerable investigative attention in the field of urology. Specifically, they have been applied clinically in the treatment of disorders involving bladder overactivity, detrusor hyperreflexia, and bladder pain. The majority of this research involves two plant-derived neurotoxins, capsaicin and resiniferatoxin (RTX), although the use of other non-botulinum neurotoxins has been explored. Both of these toxins activate nociceptive sensory nerve fibers by binding the vanilloid receptor subtype 1, a nonselective cation channel, on the peripheral terminals of nociceptive neurons (Andersson, 2004; Yoshimura and Chancellor, 2002).

Capsaicin

Capsaicin is a neurotoxin derived from hot peppers which belong to the genus Capsicum (de Sèze et al, 1999; Kim and Chancellor, 2000). Capsaicin has been studied in a variety of pain conditions because after an initial irritation, it produces analgesic effects in a number of different painful disorders. The effect of capsaicin on pain is thought to be mediated through its effects on sensory neurons with unmyelinated C-fibers, which participate in the transmission of nociceptive information to the central nervous system and release a number of proinflammatory mediators involved in pain pathways. It is likely that the same or similar mechanisms are relevant to the effects of capsaicin on the bladder.

Intravesicular capsaicin desensitizes afferent C-fibers in the bladder that transmit nociceptive signals to the central nervous system and are thought to play a role in the transmission of signals that trigger detrusor overactivity (Kim and Chancellor, 2000; Chancellor and de Groat, 1999).

Capsaicin activates sensory nerve fibers through an ion channel known as vanilloid receptor subtype 1 (Caterina et al, 1997). After activation of the vanilloid receptor subtype 1, capsaicin and other vanilloids desensitize sensory neurons, making them refractory to subsequent noxious stimuli (Szallasi, 1996).  However, the initial irritation due to excitation of sensory neurons by capsaicin causes uncomfortable side effects during the period immediately following intravesical instillation (de S èze et al, 1999). In addition to desensitizing C-fiber afferent neurons, capsaicin also alters the release from peripheral terminals of substance P, neurokinin A, calcitonin gene-related peptides, and other neurotransmitters/neuropeptides involved in inflammatory responses. The desensitization of C-fibers produced by capsaicin is caused by the depletion of these neuropeptides (Chancellor and de Groat, 1999; Cruz, 1998) (Figure 2).

Figure 2. Mechanism of action of capsaicin.Used with permission from Chancellor MB, de Groat WC. Intravesical capsaicin and resiniferatoxin therapy: spicing up the ways to treat the overactive bladder. J Urol. 1999;162:3-11.

The clinical efficacy of capsaicin has been evaluated in several different lower urinary tract disorders such as detrusor instability, hypersensitive bladder disorders, and pelvic pain (de S èze et al, 1999). Two double-blind, placebo-controlled, randomized trials investigated the efficacy and tolerability of capsaicin intravesically in the treatment of detrusor hyperreflexia in spinal cord patients. de S èze et al conducted a double-blind, placebo-controlled study in 20 patients with spinal cord lesions with detrusor hyperreflexia and urge incontinence (de S èze et al, 1998). Patients received one intravesical instillation of either capsaicin or ethanol. Thirty days after the instillation, patients who had received capsaicin showed capsaicin significantly reduced 24-hour voiding frequency and urinary incontinence episodes and increased maximum cystometric capacity and decreased maximum detrusor pressure compared with no changes in the placebo group. Thus, intravesical capsaicin significantly improved clinical and urodynamic parameters of detrusor hyperreflexia. Wiart et al reported that all paraplegic or tetraplegic subjects with neurogenic hyperreflexic detrusor treated with intravesical capsaicin experienced clinical improvement with significant regression of urinary leakage and sensory urgency compared with improvement in only one patient in the placebo-treated group (Wiart et al, 1998). Instillation immediately produced side effects lasting for roughly 7 days (including suprapubic burning sensation, sensory urgency, hot flushes, autonomic hyperreflexia, exacerbation of incontinence, and hematuria).

In a review of 10 clinical trials (2 randomized, placebo-controlled and 8 open noncontrolled studies) of intravesical administration of capsaicin in 200 patients with a variety of lower urinary tract disorders, de S èze et al concluded that capsaicin effectively reduces bladder spasticity from a variety of etiologies (de S èze et al, 1999). Among all patients in these trials, clinical or urodynamic symptoms improved in 84.3% of the patients who received intravesical capsaicin for neurogenic hyperreflexic bladder. Capsaicin was less effective, however, in patients with detrusor instability, hypersensitive bladder disorders, or pelvic pain.

More recently, Soontrapa et al evaluated the efficacy of capsaicin in 25 patients with overactive or hypersensitive bladder and primary detrusor instability (Soontrapa et al, 2003). Overall, capsaicin treatment produced a reduction in voiding frequency, leakage, bladder capacity, and detrusor contraction. These researchers rated the efficacy of capsaicin very high for overactive and hypersensitive bladder and primary detrusor instability.

Most studies have not found any serious or long-term complications of capsaicin therapy. However, the initial discomfort (suprapubic burning sensation or pain), associated with the instillation of capsaicin is a significant deterrent to the wider use of capsaicin therapy (Chancellor and de Groat, 1999).

Resiniferatoxin

Resiniferatoxin, an analog of capsaicin derived from the Euphorbia resinifera, a cactus-like plant, has been explored as an alternative therapy to capsaicin with a more favorable side effect profile (Cruz, 1998; Kim and Chancellor, 2000; Giannantoni et al, 2002). RTX is approximately 1000 times more potent than capsaicin and may induce neuronal desensitization more rapidly and with less irritation than capsaicin (Kim and Chancellor, 2000; Giannantoni et al, 2002).

Preliminary studies suggest that RTX produces clinical improvement in patients with detrusor hyperreflexia and overactive bladder. Data from a double-blind, placebo-controlled, multicenter phase 2 trial of RTX in 26 patients with refractory, stable, neurologic disease showed improvements compared with baseline in cystometric capacity, the number of incontinence episodes, and  patients' subjective ratings (Chancellor, 2000).

Lazzeri et al conducted a randomized, placebo-controlled study of intravesical RTX to treat hypersensitive disorder of the lower urinary tract and bladder pain in 18 patients (Lazzeri et al, 2000). Intravesical RTX significantly reduced voiding frequency at both the 30-day and 90-day follow-up evaluations. Pain was significantly reduced by RTX at the 30-day follow-up but not at the 90-day endpoint. No reduction in pain or in voiding frequency was observed in the placebo-treated group at either endpoint. RTX treatment did not produce a significant burning sensation at the suprapubic or urethral levels.

Another randomized controlled trial compared RTX with capsaicin administered intravesically in 24 spinal cord injured patients with refractory detrusor hyperreflexia (Giannantoni et al, 2002). There was no significant urodynamic or clinical improvement in the capsaicin-treated patients at 30 and 60 days of follow-up. In contrast, the RTX-treated group showed an increase in the mean uninhibited detrusor contraction from 176 to 250 mL at 30 days (P < .05) and to 275 mL at 60 days (P < .01). Mean maximum bladder capacity increased and daily catheterizations and incontinent episodes were significantly reduced at 30-day and 60-day follow-up in the RTX-treated group. Side effects including autonomic dysreflexia, limb spasms, suprapubic discomfort, and hematuria were reported by most patients who received capsaicin but in none who received RTX. This study demonstrated that intravesical administration of RTX produced superior urodynamic results and clinical improvement compared with capsaicin without the inflammatory side effects associated with capsaicin (Giannantoni et al, 2002).

Silva et al evaluated the effect of a 50 nM solution of RTX instilled in the bladder for 30 minutes in patients with idiopathic detrusor instability to determine the role of bladder C-fiber input in involuntary detrusor activity (Silva et al, 2002). RTX instillation delayed or suppressed involuntary detrusor contractions during filling cystometry, reduced mean micturition frequency, and increased mean maximal cystometric capacity. These results suggest that C-fiber input plays a role in the involuntary detrusor contractions and lower urinary tract symptoms in patients with idiopathic detrusor instability. Accordingly, neurotoxin-induced inhibition of C-fiber input is a reasonable therapeutic option in lower urinary tract disorders. The investigators speculate that the prolonged clinical effect of RTX may involve long-lasting down-regulation of C-fiber receptors and neuropeptides such as substance P or calcitonin gene-related peptide.

Future studies

Further randomized placebo-controlled trials of the safety and efficacy of RTX in the management of bladder dysfunction are needed. Currently, resiniferatoxin is not in development; a phase II trial investigating resiniferatoxin for treatment of interstitial cystitis failed and appropriate formulations have not been derived. However, large-scale trials will confirm the role of RTX therapy for overactive bladder and related disorders. RTX therapy could represent a substantial advance in the therapeutic management of these disorders: simple instillation for 30 minutes may control symptoms for 3 to 6 months without the systemic side effects of pharmacologic approaches currently in use.

Although almost all of this research has made use of plant-derived neurotoxins, future studies may consider a variety of other neurotoxins. For example, preclinical research in an animal model of spinal cord injury demonstrated that alpha-bungarotoxin, a toxin extracted from the venom of the Formosan Banded Krait snake, improved voiding function by reducing urethral outlet resistance (Yoshiyama et al, 2000). This toxin selectively blocks nicotinic receptors without affecting the transmission in autonomic ganglia, thereby inducing striated muscle relaxation. 0These findings support the idea that therapeutic actions of neurotoxins, such as suppression of striated muscle activity, may also be useful in the treatment of bladder dysfunction. In summary, non-botulinum neurotoxins have been investigated and appear promising in the treatment of smooth muscle disorders affecting the lower urinary tract.

References and Further Reading

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Chancellor MB, de Groat WC. Intravesical capsaicin and resiniferatoxin therapy: spicing up the ways to treat the overactive bladder. J Urol. 1999;162:3-11.

Chancellor MB. Discussion: Resiniferatoxin—preliminary data. Urology. 2000;55(5A suppl):65.

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