Chapter 7 Ana Charrua1,2,3,*; Francisco Cruz1,2,3,4 1 IBMC—Instituto de Biologia Molecular e Celular da Universidade do Porto, Porto, Portugal Vanilloids, such as capsaicin and resiniferatoxin (RTX), have gained clinical interest, as they modulate urinary bladder primary afferents that control micturition under pathological conditions. In fact, the intravesical use of vanilloid solutions, in particular the intravesical use of RTX solutions, was shown to ameliorate low urinary tract symptoms, such as urinary incontinence and frequency associated with overactive bladder and neurogenic detrusor overactivity. In addition, vanilloids may be useful to treat pain associated with bladder pain syndrome/interstitial cystitis. Nevertheless, the lack of a correct formulation and dosage of intravesical RTX solutions made the results obtained inconsistent and not replicable. However, the rational for the intravesical use of RTX is still strong, which may still justify the undertaking of well-designed clinical studies. Neurogenic detrusor overactivity Idiopathic detrusor overactivity Bladder pain syndrome/interstitial cystitis Capsaicin and resiniferatoxin (RTX) are clinically useful drugs because they specifically bind to, excite, and then desensitize the transient receptor potential vanilloid type 1 (TRPV1) [1,2]. TRPV1 is expressed in peptidergic primary afferents that course the mucosa and muscular layers of the urinary bladder [3–7] and in urothelial cells [6–8]. TRPV1 is known to be involved in the development of bladder pain associated with cystitis [9–11] and bladder hyperactivity of neurogenic and idiopathic origin [10–13]. Micturition is under the control of two distinct neuronal circuits [13]. In normal conditions, the circuit that prevails is the long, supraspinal pathway, initiated in Aδ bladder afferents and passing through the periaqueductal gray matter (PAG) and the pontine micturition center (PMC) [13]. Under certain abnormal conditions, another circuit, which is shorter and is entirely located in the lumbosacral spinal segments, may take over bladder control [13]. This circuit is initiated in C-type bladder afferents. The emergence of a micturition reflex commanded by the sacral micturition pathway was first observed in felines with chronic spinal cord transection between PMC and sacral spinal cord [13]. Posteriorly, this same reflex was shown to prevail in nonneurological conditions like chronic bladder obstruction [14] and inflammation [15]. The sacral micturition reflex, being entirely located in the lumbar-sacral spinal cord segments, escapes the control of supraspinal centers that regulate micturition, including PAG, PMC, and cortical areas that modulate those two centers [13]. The consequence is that the parasympathetic outflow generated by the sacral micturition reflex can generate detrusor contractions totally independent of voluntary control [13]. This can generate sudden, imminent desire to void (usually known as urgency to void). If the impulse is strong enough to overcome sphincteric resistance, it may cause urinary leakage (urgency urinary incontinence) [16,17]. Being initiated by C fibers, desensitization of these primary afferents by capsaicin or RTX can decrease or suppress the abnormal sacral micturition reflex [13]. This possibility was first shown in chronic spinal cord transected cats. These animals, once treated with systemic capsaicin, lose the reflex micturition [13]. In contrast, capsaicin administration to the spinal cord of intact cats does not alter reflex micturition [13]. Likewise, capsaicin and RTX were shown to suppress bladder hyperactivity induced by cyclophosphamide-induced cystitis [10] and to decreased noxious input induced by bladder inflammation [10,18]. These experiments clearly suggested that the desensitization of bladder C fibers by capsaicin or RTX could have relevant clinical application. Two pertinent studies tested the application of capsaicin and RTX by intravesical route, taking advantage of the fact that capsaicin is part of the human diet, and RTX was used as a pain killer for centuries in the Roman Empire. The first clinical study used capsaicin [19] and the second study used RTX [15]; both studies involved patients with bladder overactivity of neurogenic origin. Importantly, neither intravesical capsaicin nor RTX induces persistent morphological changes in the bladder. After 5 years of capsaicin instillation, there were no morphological changes in the bladder urothelium [20]. Bladder biopsies taken from patients with detrusor overactivity treated for 2 years with intravesical RTX showed no evidence of inflammatory reaction, hyperplastic response, or tumor formation in the bladder mucosa, or any damage in the urothelium and its basal membrane [21]. Furthermore, electron microscopic (ultrastructural) observations showed that RTX did not alter the structure of unmyelinated nerve fibers in the lamina propria of the aforementioned bladder samples [21]. As RTX was shown to desensitize bladder afferents without the intense initial excitation perceived by patients treated with capsaicin [22], most of the studies that are reviewed in this chapter have used RTX rather than capsaicin as the desensitizing agent. Initial studies with capsaicin to ameliorate hyperreflexia were promising, with patients showing an increase in cystometric capacity and a decrease in maximum detrusor pressure up to 7 months posttreatment [19,23–31]. However, acutely capsaicin produces a strong abdominal burning pain after intravesical instillation. This adverse effect and the possibility of autonomic dysreflexia during capsaicin instillation discouraged the wider use of intravesical capsaicin [31–35]. The advantage of RTX over capsaicin to manage bladder hyperreflexia in neurogenic detrusor overactivity (NDO) patients was confirmed by de Sèze and coworkers in a double-blinded randomized clinical trial [36]. In this study, 21 patients were included in the RTX group, and 18 patients were included in the capsaicin group. One month after instillation, both groups (80% of patients for RTX and 78% of patients for capsaicin) had improvement in continence (5.5—0.5 leakage episodes/day in the capsaicin arm, and 4—0 leakage episodes/day in the RTX arm), frequency (10—6 voids/day in the capsaicin arm and 8—6 voids/day in the RTX arm), and urgency, with increased maximum cystometric capacity (175–282 ml in the capsaicin arm and 221–263 ml in the RTX arm). The follow-up of these patients demonstrated that the duration of RTX and capsaicin desensitization was similar: 66.8 days in the capsaicin arm and 91.1 days in the RTX arm [36]. However, the comparison of the tolerability of these two compounds showed that suprapubic pain complaints were significantly more frequent in the capsaicin group [36]. Other side effects such as urethral pain, autonomic dysreflexia, or hematuria were rarely observed in either group. Also, no bladder changes were observed on cystoscopy [36]. In a placebo-controlled, randomized clinical trial involving 28 patients with NDO, Silva and coworkers [37] have demonstrated that intravesical instillation of 50 nM RTX (dissolved in 10% ethanol in saline) increased bladder volume to first involuntary detrusor contraction from 143 ± 95 to 184 ± 93 ml in NDO patients, whereas placebo instillation (10% ethanol) did not change that volume (from 115 ± 58 to 115 ± 61 ml). Similarly, maximal cystometric capacity increased from 189 ± 99 to 314 ± 135 ml in the RTX group, whereas the increase in the placebo group was minimal (from 198 ± 111 to 204 ± 92 ml). Also, the mean frequency and daily incontinence improved 20% (from 9.5 ± 2.5 to 7.6 ± 2.1 voids/day, p = 0.01) and 60% (from 4.5 ± 4.5 to 1.6 ± 1.4 incontinence episodes/day, p = 0.03), respectively, in the RTX-treated group and were unaltered in the placebo group (from 10 ± 2 to 9.6 ± 2.6 voids/day, p = 0.6; 1.8 ± 2.5 to 1.0 ± 1.4 incontinence episodes/day). Because the etiology underlying NDO was diverse (each one represented by only a few cases), the authors did not analyze the effect of RTX and placebo per etiology [37]. The follow-up of these patients showed that RTX-induced improvement in urodynamic characteristic was maintained up to 3 months [37]. Furthermore, using a visual analog scale, the authors concluded that the intensity of the discomfort during the vehicle or the RTX solution instillation were similar [37]. Importantly, intravesical instillation of RTX did not cause autonomic dysreflexia, hematuria, or persistent infection [37]. These results were replicated by Kim and coworkers in 32 patients with NDO [38]. RTX (500-1000 nM) instilled into the bladder induced minimal pain, similar to that observed in the placebo arm [38]. Also, these authors observed a superior effect of RTX in mean cystometric capacity and in the mean number of incontinence episodes when compared to the placebo solution. RTX instillation was not associated with any significant complication. In another study, Kuo and coworkers treated 15 patients with NDO, 20 patients with bladder outlet obstruction, and 19 patients with idiopathic detrusor overactivity (IDO) with four intravesical RTX instillations (10 nM each), compared to placebo [39]. During the follow-up of these patients, the success rate of treatment was analyzed at 1, 3, 6, and 12 months follow-up [39]. Using the Kaplan-Meier analysis, the authors concluded that the success rate was higher in the RTX group than in placebo group (results were: 73% versus 29% (p < 0.001) at 1 month, 62% versus 21% (p < 0.001) at 3 months, 50% versus 11% (p < 0.001) at 6 months, and 12% versus 0.4% (p > 0.05) at 12 months after treatment, respectively). As in the previous studies, no adverse effects due to RTX intravesical installations were observed [39]. Silva and coworkers enrolled 23 overactive bladder (OAB) patients with refractory urgency into a clinical trial; these patients had their anticholinergic medication for bladder dysfunction interrupted for a month, after which they had filled out a 7-day voiding chart to score bladder sensations before each voiding [40]. On average, patients experienced 71 ± 12 episodes of severe urgency per week. Thereafter, patients received intravesical ethanol (10%), and 1 month later they were asked to fill out a second 7-day voiding chart. This time, the mean number of urgency episodes was 56 ± 11, with 17% of patients considering they had improved their urinary symptoms. In the last step of the study, the bladder of the OAB patients was treated with 50 nM RTX dissolved in ethanol (10%). One and 3 months later, patients filled in a third and fourth 7-day voiding chart. After RTX administration, the episodes of urgency decreased to 39 ± 9 and 37 ± 6, respectively, with 69% of patients reporting an improvement of urinary symptoms [40]. Of note, intravesical RTX is not the only therapeutic tool available to overcome bladder hyperreflexia in OAB patients. Botulinum toxin has become another option. Giannantoni and coworkers have performed a randomized clinical trial to compare the efficacy of these two treatments [41]. A total of 25 patients were randomly assigned to receive intravesically RTX (0.6 M) in saline or detrusor muscle injection with 300 units of botulinum toxin type-A (OnabotA). In both arms, there was a significant decrease in catheterization need and incontinent episodes and a significant increase in first detrusor contraction and maximum bladder capacity at 6-, 12-, and 18-month follow-up. There were no local side effects with either treatment. However, OnabotA induced significantly greater improvements than RTX. At 6 months, compared to RTX, OnabotA decreased the number of daily incontinence episodes (from 5.4 ± 1.3 to 2.2 ± 1.2 in the RTX arm, and from 4.8 ± 1.1 to 1.4 ± 1.7 in the OnabotA arm, p < 0.001 in both arms), significantly increased the volume for involuntary detrusor contraction (from 200.5 ± 69.7 to 288.7 ± 83.7 ml in the RTX arm and from 190 ± 48.6 to 326.3 ± 80.9 ml in the OnabotA arm, p < 0.01 in the RTX arm versus OnabotA arm) and in maximum bladder capacity (from 223.3 ± 68.1 to 329.0 ± 72.3 ml in the RTX arm and from 211.9 ± 49.7 to 370.0 ± 79.6 ml in the OnabotA arm, p < 0.01 in the RTX arm versus OnabotA arm), and significantly decreased maximum detrusor pressure (from 70.2 ± 26.0 cm H2O to 63.1 ± 26.2 cm H2O in the RTX arm and from 78.5 ± 21.5 cm H2O to 47.0 ± 18.3 cm H2O in the OnabotA arm, p < 0.01 in the RTX arm versus OnabotA arm). The efficacy of RTX and botulinum toxin was also compared in patients with IDO [42]. Santos-Silva and coworkers enrolled 34 female patients into this study: 17 patients were treated with 100 nM RTX (in 10% ethanol), and another 17 patients were injected with 100 U OnabotA. As endpoints, the number of incontinence episodes in a 3-day bladder diary, the quality-of-life questionnaires, and urodynamic studies were used. These parameters were analyzed at baseline and at 3 months after treatment. OnabotA was more effective in abolishing urinary incontinence (from 3 to 0 incontinence episodes/day in the OnabotA arm and from 3.5 to 2.5 incontinence episodes/day in the RTX arm), in reducing frequency (from 11 to 6 episodes/day in the OnabotA arm and from 9.5 to 8.5 episodes/day in the RTX arm), in increasing quality of life (score increase from 29.2% to 45.9% in the OnabotA arm and from 12.4% to 15.7% in the RTX arm), and improving bladder capacity (from 363 to 490 ml in the OnabotA arm and from 450.5 to 558.5 ml in the RTX arm) [42]. Due to their ability to relieve pain by desensitizing nociceptive capsaicin-sensitive fibers, intravesical instillation of vanilloids was investigated as a tool to treat pain in patients with bladder pain syndrome/interstitial cystitis (BPS/IC) [43]. A pilot study was performed to assess the effect of multiple intravesical capsaicin instillations in increasing doses on the treatment of pain [43]. Most of the patients reported an improvement of symptoms (bladder capacity, frequency, nocturia) and pain, without any observed side effects. These results suggested intravesical capsaicin as a promising treatment for BPS/IC. In a randomized, placebo-controlled study, Lazzeri and coworkers evaluated the clinical benefit of intravesical application of 0.3 μM capsaicin (twice a week for a month) for severe bladder pain [44]. Before the study, all of the 36 patients had severe pelvic pain and all had undergone prior pain therapy such as nonsteroidal anti-inflammatory drugs, antihistamines, intravesical lidocaine hydrochloride, or transvaginal electrostimulation [44]. All patients complained about the warm and burning sensation in the pelvic region that accompanied the capsaicin intravesical instillation and was long-lasting but progressively less intense in the capsaicin group on successive instillations. In the placebo group, this discomfort had a shorter duration but was sustained on successive instillation of vehicle. An improvement in frequency (41.2-11.8% of patients that presented more than 10 voiding episodes after 6 months) and in nocturia (29.4-5.9% of patients that presented more than 10 episodes after 6 months) was noted in the capsaicin-treated group only [44]. The authors have also observed a significant decrease in the pain score after capsaicin intravesical instillation (3.22 ± 0.42, p < 0.01 after treatment; 3.83 ± 0.47, p < 0.01 6 months after treatment) compared to before capsaicin treatment (5.61 ± 0.40). In fact, 71% of capsaicin-treated patients reported an improvement in quality of life, which lasted for 6 months without need for another medication for 22% of those patients. In the placebo group, pain score after treatment was 4.47 ± 0.36 after instillation and 4.48 ± 0.34 at 6 months after treatment. No histopathology changes or side effects were observed in either group after treatment [44]. Lazzeri and coworkers also evaluated the efficacy of prolonged intravesical infusion of 10 nM of RTX in the treatment of pain and lower urinary tract symptoms associated with BPS/IC [45]. One month after RTX infusion, the five patients enrolled in this study had statistically significant reduction of pain (from 6.7 ± 0.83 to 2.4 ± 0.54, p < 0.01 1 month after treatment, and to 3.2 ± 0.44, p < 0.05 3 months after treatment), frequency (from 11.3 ± 1.39 to 7.4 ± 1.51, p < 0.01 1 month after treatment, and to 8.7 ± 1.76, 3 months after treatment), and nocturia (from 3.6 ± 0.54 to 1.2 ± 0.44, p < 0.01 1 month after treatment, and to 1.9 ± 0.74, 3 months after treatment). Again, no significant side effects were noticed during or after RTX infusion, which made RTX intravesical treatment preferred over the painful capsaicin intravesical instillation. These data prompted Payne and coworkers to perform a large randomized, double-blinded, multicenter, placebo-controlled study to evaluate the efficacy of intravesical RTX treatment (10, 50, and 100 nM) in 163 BPS/IC patients [46]. Three months after treatment neither placebo nor RTX-treated group presented significant changes at global response assessment score (p = 0.827), pain, nocturia, urgency, frequency, average voided volume, nor to responses to the O’Leary-Sant and Pelvic Pain and Urgency/Frequency Symptom Scale questionnaires [46]. These authors have observed that RTX instillation presented a dose-dependent increase in instillation pain (52% of patients from placebo arm and 72-80% of patients from RTX arm) and urgency. In fact, there was an increase in the percentage of patients who did not tolerate the 30 min required for RTX instillation. One of the patients treated with 10 nM RTX presented severe lower abdominal pain requiring hospitalization [46]. Intravesical capsaicin instillation was initially promoted as a promising tool to overcome bladder hyperactivity. The pungency of capsaicin solutions was, however, not tolerated by many patients, and this compound was quickly replaced by RTX. Unfortunately, there are several problems with RTX treatment that need to be solved to render this compound clinically appealing. First and foremost, the optimal formulation of RTX is still unknown. RTX is unstable in aqueous solutions, which is thought to have contributed to some of the differences between the results of the studies where this molecule was used. Furthermore, RTX adheres to plastics, and if prepared in advance for instillation, a marked decay of active molecule rapidly occurs [47]. Therefore, studies to determine the adequate vehicle, the doses to be used, the number of applications, and the material used during administrations are still needed. In fact, botulinum toxin type-A (which has a stable formulation) has largely replaced intravesical RTX. That said, RTX may present important advantages over botulinum toxin-A, such as that it does not exacerbate poor bladder emptying. In a recent large randomized clinical trial with OAB patients, botulinum toxin type-A induced almost 16% of urinary retention, which lasted for several weeks [48]. Furthermore, RTX instillation is easier and cheaper to administer than botulinum toxin type-A injection, which requires cystoscopy. In summary, if the adequate formulation and dosage are determined, the use of intravesical RTX solution may regain a therapeutic position in the treatment of some lower urinary tract symptoms, most probably placed between oral drugs and botulinum toxin injections.
Intravesical Capsaicin and Resiniferatoxin for Bladder Disorders
2 Departamento de Urologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
3 Departamento de Doenças Renais, Urológicas e Infecciosas, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
4 Departamento de Urologia, Hospital São João, Porto, Portugal
* Corresponding author: anacharr@gmail.com
Abstract
Capsaicin and Resiniferatoxin Targets and Effects in the Urinary Bladder
The Rationale for Using Vanilloids to Overcome Lower Urinary Tract Symptoms
Intravesical Application of Vanilloids
Intravesical Application of Vanilloids in Patients with Neurogenic Detrusor Overactivity and Idiopathic Detrusor Overactivity
Intravesical Application of Vanilloids in Patients with Bladder Pain Syndrome/Interstitial Cystitis
Is There a Future for Intravesical Instillation of Vanilloids in the Urinary Bladder?
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