Neuro-urologyEffect of Intravesical Resiniferatoxin (RTX) on Lower Urinary Tract Symptoms, Urodynamic Parameters, and Quality of Life of Patients with Urodynamic Increased Bladder Sensation
Introduction
Intravesical resiniferatoxin (RTX) has been used with variable efficacy to treat intractable lower urinary tract symptoms (LUTS), particularly those associated with neurogenic detrusor overactivity (NDO) [1], [2], [3], [4], [5] or idiopathic DO (IDO) [4], [6], [7]. In these patients, RTX increased bladder capacity and reduced frequency and urgency incontinence, with responses lasting 3–12 mo. However, trials of RTX in patients with IDO, though uncontrolled, have not evaluated patients beyond 3 mo and conflicting results have been reported in placebo-controlled trials of patients with NDO, attributable to methodological problems regarding patient numbers and RTX preparation limitations [8], [9].
The clinical features of bladder dysfunction in patients with DO are fundamentally different from those of patients with urgency and frequency due to increased bladder sensation (previously “sensory urgency”). The former have an overactive detrusor with little or no pain, whereas the latter have no evidence of DO on urodynamic investigation, but still experience urgency at low volumes, often associated with discomfort or pain on filling. Abnormal afferent nerve activity has been suggested as the cause of human spinal NDO and the successful use of intravesical vanilloids in such patients provides indirect evidence that an aberrant segmental sacral spinal reflex, mediated by capsaicin-sensitive, C-fibre afferents, contributes to DO [5], [10], [11]. Afferently mediated intrinsic bladder wall reflexes have been implicated in the pathophysiology of IDO [12], [13].
Despite evidence that the sensation of bladder fullness is mediated by complex interactions between the urothelium and suburothelial afferent nerves [14], [15], [16], [17], the pathophysiology of the sensation of urgency is not clearly understood. Levels of suburothelial mechanosensory receptors have been correlated with degree of urgency [18]. Peripheral afferent neuromodulation has been used successfully to suppress the sensation of urge in patients with lower urinary tract dysfunction [19], [20]. Further, a small placebo-controlled study has reported that RTX is effective in patients with urgency-frequency due to increased bladder sensation [21], suggesting a causative role for capsaicin-sensitive C-fibres in this condition. Interestingly, although all participants in this study also suffered from bladder pain, a large multicentre placebo-controlled trial of various doses of a single intravesical instillation of RTX in patients with interstitial cystitis (now “painful bladder syndrome” [PBS/IC]) [22] showed no response to treatment [23].
As such, the treatment of the urgency-frequency syndrome due to increased bladder sensation, with or without accompanying bladder pain, remains problematic. In a placebo-controlled study in such patients a low RTX dose (10 nM) significantly reduced frequency, nocturia, and pain up to 1 mo after treatment, but produced little improvement at 3 mo or in urodynamic parameters [21].
We conducted an open-label study to evaluate the safety and efficacy of a single administration of a higher dose of intravesical RTX in patients with urgency and frequency due to increased bladder sensation and for a longer, more clinically significant period of time (6 mo).
Section snippets
Study design
A history of >1 yr of intractable urgency and frequency, with or without urgency incontinence, and presence of increased bladder sensation [22] but no evidence of DO during standard voiding cystometry were the clinical and urodynamic criteria for study recruitment. Patients with additional bladder pain/discomfort were also enrolled. The definition of urgency agreed on by the International Continence Society—a sudden, compelling desire to void which is difficult to defer [22]—applied to all
Demographics
Fifteen patients (13 women, 2 men; mean age, 52.5 yr; range, 31–82 yr) were treated. Increased bladder sensation was of idiopathic aetiology in 10 patients, 4 had a clinical and histopathological diagnosis of PBS/IC based on the European Society for the Study of IC (ESSIC) criteria [25], whereas in one patient bladder dysfunction was due to cerebrovascular accident. LUTS were accompanied by bladder/urethral pain in 46% (7 of 15) of patients. Six patients were considered incontinent according to
Discussion
In this small, uncontrolled study, a single intravesical instillation of RTX produced significant improvements in 24-h frequency, daytime frequency, MMV, MCC, and urodynamic FD vol in a group of patients with urodynamic increased bladder sensation. Clinical and urodynamic improvements were sustained for at least 6 mo after treatment and were accompanied by a significant amelioration in patients’ QOL. Urgency incontinence episodes, nocturia, and micturition episodes associated with urgency were
Conclusions
In our small, uncontrolled study, a single intravesical administration of RTX resulted in improvement in LUTS, urodynamic parameters, and QOL in a group of patients with frequency and urgency due to increased bladder sensation, for periods as long as 6 mo. Should RTX become available in a licensed form, it could be considered an alternative treatment option to oral pharmacotherapy in these patients.
Acknowledgement
We thank Ms Trish Dyson, Principal Pharmacist at the National Hospital for Neurology and Neurosurgery, for her contribution in the organisation and completion of this study. Funding: Pfizer Inc (C.J.F. and A.A.).
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