Urodynamic Effect of Intravesical Resiniferatoxin in Patients with Neurogenic Detrusor Overactivity of Spinal Origin: Results of a Double-Blind Randomized Placebo-Controlled Trial

Abstract

Objectives:

To access by a placebo-controlled randomized clinical trial the effect of intravesical resiniferatoxin on the urodynamic parameters of patients with neurogenic detrusor overactivity (NDO) of spinal origin.

Methods:

Twenty eight patients with spinal NDO were randomised to receive intravesically 50 nM resiniferatoxin dissolved in 10% ethanol in saline (RTX group) or only the vehicle solution (placebo group). Filling cystometries were obtained in each patient at 1 month and 1 week before and at 1 and 3 months after treatment. In a visual analog scale patients were asked to estimate the discomfort induced by treatment. Patients were also persuaded to fill a micturition chart during the 3 days preceding each cystometry.

Results:

The RTX and placebo groups were homogeneous in what respects the volume to first involuntary detrusor contraction (FDC, 143 ± 95 ml and 115 ± 58 ml, respectively, p = 0.3) and maximal cystometric capacity (MCC, 189 ± 99 ml and 198 ± 111 ml, respectively, p = 0.8). At the end of the study, mean FDC and MCC in the RTX group, 184 ± 93 ml and 314 ± 135 ml, respectively were significantly higher than in the placebo group, 115 ± 61 ml (p = 0.03) and 204 ± 92 ml (p = 0.02). In the visual analogue scale discomfort caused by treatment was similar. Only 10 patients in the RTX group and 6 patients in the placebo group completed adequately the micturition chart. Mean frequency and urinary incontinence decreased significantly only in the RTX group.

Conclusions:

Intravesical RTX is effective in increasing bladder capacity in spinal NDO patients. Such increment might contribute to decrease urinary frequency and incontinence of these patients.

Introduction

Resiniferatoxin (RTX) and capsaicin, two natural occurring vanilloid compounds, share a unique property, the capacity to excite and then to desensitize type C primary afferent fibers [1]. Both actions require the activation of a non-selective calcium channel abundantly expressed in those sensory fibers, the so called transient receptor potential vanilloid 1 (TRPV1), previously known as vanilloid receptor type 1 (VR1) [2]. Excitation is the consequence of TRPV1 opening which generates spike-like calcium currents [1]. The transient high intracellular calcium causes desensitization, a still imprecise phenomenon that includes neuropeptide release, block of sensory transmission and eventually neuronal degeneration [1], [3]. Regardless of the evident similarities between the two molecules, as shown by the occurrence of an identical homovanillyl ring in both [1], [3], RTX is several thousands times more potent in desensitization than capsaicin but only a few hundreds more in excitation [1]. As a result, in studies conducted in the rat bladder, complete C-fiber desensitization could be obtained with RTX in concentrations so low that preliminary excitation was negligible [4].

As predicted by experimental studies [4], pilot, non-placebo controlled trials carried out with spinal NDO patients [5], [6], [7], [8], [9], [10] showed that intravesical RTX in concentrations ranging from 10 nM up to 1000 nM caused a very modest bladder C-fiber excitation. Abdominal pain was minimal and episodes of autonomic dysreflexia were not reported [5], [6], [7], [8], [9], [10]. Nevertheless, RTX in concentration of 50 nM or higher induced a long-lasting desensitization that, likewise observed with capsaicin, delayed involuntary detrusor contractions, increased bladder capacity and improved urinary symptoms in NDO patients [5], [7], [8], [9], [10]. A recent prospective double-blinded, dose escalating clinical trial conducted in spinal NDO patients confirmed the low exciting effect of RTX on bladder C-fibers [11]. Surprisingly, however, this study could not demonstrate a clear superiority of RTX, whatever the concentration used, 5 to 1000 nM, to increase bladder capacity in NDO patients [11]. Unfortunately, the discrepancy between this and previous open labelled studies were never solved by a new placebo controlled randomised clinical trial. The reported difficulties in the preparation of RTX solutions might have contributed to the lack of new studies. In fact, this compound is unstable and adheres to plastics [12]. At this moment, these inconveniences can only be overtaken by preparing RTX solutions immediately before intravesical administration [13], a contingency that many centres might not be prepared to face.

To decide whether or not bladder desensitization by intravesical RTX delays involuntary detrusor contractions and increases bladder capacity in NDO patients we conducted a double blind placebo controlled study in which 50 nM RTX was compared against the vehicle solution, 10% ethanol in saline. As primary endpoints we investigated the effect of RTX on the volume to first involuntary detrusor contraction (FDC) and on maximal cystometric capacity (MCC). As secondary endpoints we investigated the discomfort brought about by RTX instillation and the effect of this compound on urinary frequency and daily number of episodes of urinary incontinence.