Efficacy and Safety of Tol Terodine in People With Neurogenic Detrusor Overactivity

Abstract

Objective: To compare tolterodine with oxybutynin and placebo in people with neuragenie detrusor overactivity.

Design: Prospective, randomized, double-blind, crossover trial plus open-label comparative stage.

Participants: Ten participants with neuragenie detrusor overactivity due to spinal cord injury or multiple sclerosis who usedintermittent catheterization.

Methods: Bladder capacity on cystometrogram, a 10-day record of catheterization volumes, number of incontinent episodes perday, and perceived dry mouth using a visual analog scale (VAS) were measured for the following: (a) a blinded comparison:tolterodine, 2 mg twice daily, vs placebo, twice daily; and (b) an unblinded comparison: oxybutynin vs tolterodine, each atself-selected doses (SSDs).

Results: Tolterodine, 2 mg twice daily, was superior to placebo in enhancing catheterization volumes (P<0.0005) and reducingincontinence (P<0.001 ), but was comparable with placebo in cystometric bladder capacity. Efficacy of tolterodine SSD wascomparable with oxybutynin SSD with regard to catheterization volumes, degree of incontinence, and cystometric bladder capacity.The side effect profile (dry mouth) was comparable between tolterodine, 2 mg twice daily, and placebo, but differed significantlywhen comparing tolterodine SSD with oxybutynin SSD (P<0.05).

Conclusion: T olterodine, when used at SSDs, is comparable with oxybutynin at SSDs in enhancing bladder volume and improvingcontinence, but with less dry mouth. T olterodine at the recommended dosage of 2 mg twice daily improves incontinence and bladdervolumes compared with placebo, and without significant dry mouth. Larger doses of tolterodine may be needed to achieve best effectin this population, but further studies are required.     

Six-Year Follow-Up of Botulinum Toxin A Intradetrusorial Injections in Patients with Refractory Neurogenic Detrusor Overactivity: Clinical and Urodynamic Results

Background

Most reports in the literature on botulinum toxin A (BoNTA) therapy for neurogenic detrusor overactivity (NDO) are based on the results of a single injection. Because most patients may require retreatment, the efficacy and safety of multiple injections must be addressed clearly.

Objective

To investigate the effectiveness and safety of BoNTA intradetrusorial injections in a group of spinal cord–injured (SCI) patients with refractory detrusor overactivity (DO).

Design, setting, and participants

Seventeen SCI patients were prospectively included in the study and followed up to 6 yr.

Intervention

All patients received repeat intradetrusorial injections of BoNTA 300 units (Botox, Allergan, Irvine, CA) under cystoscopic control on an inpatient basis.

Measurements

The preliminary assessment included voiding diary, urodynamics, kidney and bladder ultrasound, and cystourethrography. Patients also completed a standardised quality-of-life (QoL) questionnaire. Clinical evaluation, urodynamics, urinary tract imaging, and QoL assessment were repeated every year throughout the follow-up.

Results and limitations

Before treatment, all patients complained of urinary incontinence and had DO. Bilateral and monolateral renal pelvis dilatation were detected in six and five patients, respectively, and a monolateral and third-grade vesicoureteral reflux was observed in three. At 6-yr follow-up, a significant decrease in the frequency of daily incontinence episodes (p < 0.01), a significant increase in first uninhibited detrusor contraction and in maximum bladder capacity (p < 0.001 for both), and a significant decrease in maximum pressure of these contractions (p < 0.01) were observed. Fifteen patients (88.2%) were completely continent. Renal pelvis dilatation and vesicoureteral reflux resolved in all cases, and the QoL index significantly increased. Limitations of the study are related to the small number of included patients.

Conclusions

In SCI patients with refractory NDO who do not want or are unfit for invasive reconstructive surgery, BoNTA intravesical treatment represents a valid alternative to control DO and urinary incontinence and to preserve upper urinary tract function over a long-term follow-up.     

Efficacy and Tolerability of Botulinum Toxin Type A in Patients with Neurogenic Detrusor Overactivity and Without Concomitant Anticholinergic Therapy: Comparison of Two Doses

Background

Botulinum toxin type A (BoNTA) has been reported to be effective for treatment of patients with neurogenic detrusor overactivity (NDO) refractory to anticholinergic agents. However, in most of the studies, the efficacy was associated with concomitant use of anticholinergics.

Objective

To evaluate the efficacy and tolerability of BoNTA and compare two different doses in patients with NDO without concomitant anticholinergics.

Design, setting, and participants

Between 2004 and 2006, adults with NDO refractory to anticholinergics or discontinued anticholinergics due to adverse events or contraindications from four different French clinical centres were included in a prospective, randomised, double-blind, comparative trial. Inclusion criteria were urinary incontinence (UI) resulting from NDO that could not be managed with anticholinergics. Patients with bladder cancer, lithiasis, or urinary infection were excluded.

Intervention

Patients were randomised to receive an intradetrusor injection of 500 U or 750 U of BoNTA.

Measurements

The initial evaluation (ie, clinical and urodynamic variables and quality of life [QoL]) was repeated at days 30, 90, 180, and 360. Primary outcome was complete continence rate at day 30. Secondary outcomes were cumulative incontinence rate, reappearance of leakages, pad usage, urodynamics, and QoL.

Results and limitations

Seventy-seven patients received 500 U (n = 39) or 750 U (n = 38) of BoNTA and were included in the full analysis set for efficacy analysis. Complete continence at day 30 was observed in 22 patients (56.4%) and 28 patients (73.7%) receiving 500 U or 750 U of BoNTA, respectively (p = 0.056; one-sided χ² test to compare to α = 0.025). The median delay in the reappearance of leakages was 168 d. Monotherapy of BoNTA significantly improved UI in patients with NDO. Although there was a trend towards a greater improvement with 750 U of BoNTA, no statistically significant differences in terms of clinical and urodynamic variables and QoL were found between the treatment groups. Tolerability was excellent and equivalent for both doses.

Conclusions

Monotherapy of BoNTA at Dysport (Ipsen, Brisbane, CA, USA) doses of 500 U or 750 U seems to be effective and well tolerated in patients with NDO.     

Long-term neurogenic lower urinary tract dysfunction: A case of cardiovascular nightmares

ContextIndividuals with spinal cord injury (SCI) suffering from autonomic dysreflexia (AD) due to neurogenic detrusor overactivity (NDO) can effectively be treated with intradetrusor onabotulinumtoxinA. We present a complex case to highlight the treatment''s potential limitations to ameliorate AD and improve lower urinary tract (LUT) function in this population.FindingsA 46-year old man, who was relying on an indwelling urethral catheter for bladder emptying due to severely impaired hand function following a SCI (C5, AIS B) sustained 30 years ago, underwent intradetrusor onabotulinumtoxinA injections for treatment of refractory NDO and associated AD. Although LUT function slightly improved (i.e. cystometric capacity increased while detrusor pressure was reduced), severe bladder-related AD persisted post-treatment.ConclusionsThis case raises awareness of serious considerations when treating NDO-related AD in individuals with longstanding neurogenic LUT dysfunction and compromised dexterity following SCI. Given the limited improvement in LUT function and persisting bladder-related AD following treatment, urinary diversion as advocated in the wider literature should be considered to protect an individual''s urinary tract from further deterioration and thus eliminate bladder-related AD consequences long-term. Early treatment and management of NDO and AD is crucial to minimize complications associated with these two major health risks in this population.     

Electrical stimulation of the urethra evokes bladder contractions and emptying in spinal cord injury men: case studies

Objective

Electrical stimulation of the urethra can evoke bladder contractions in persons with spinal cord injury (SCI). The objective of this study was to determine whether electrical stimulation of the urethra could evoke bladder contractions that empty the bladder.

Methods

The first patient was a 45-year-old man with a T6 ASIA A SCI secondary to a gunshot wound 15 years prior. The second patient was a 51-year-old man with a T2 ASIA A SCI secondary to a fall from scaffolding 2 years prior. Both patients demonstrated neurogenic detrusor overactivity on urodynamics and managed their bladder with clean intermittent catheterization and oxybutynin medication. Following informed consent, each patient discontinued oxybutynin 2 days prior to urodynamic testing. Urodynamics were performed with a custom 12 French balloon catheter mounted with ring-shaped electrodes (3 mm) positioned in the prostatic urethra. After filling the bladder to approximately three-fourth of capacity at a rate of 25 ml/minute, the urethra was stimulated with a range of parameters to determine whether electrical stimulation could evoke a bladder contraction and empty the bladder.

Results

Electrical stimulation of the prostatic urethra evoked bladder contractions (peak detrusor pressures of 60–80 cm H₂O) that emptied the bladder in both subjects. In the first subject, stimulation (9–12 mA, 20 Hz) emptied 64–75%, leaving post-void residual volumes (PVRs) of 41–20 ml. In the second subject, stimulation (20 mA, 20 Hz) emptied 68–77%, leaving PVRs of 56–45 ml.

Conclusion

Urethral stimulation evoked bladder emptying in persons with SCI.     

Propiverine vs oxybutynin for treating neurogenic detrusor overactivity in children and adolescents: results of a multicentre observational cohort study

OBJECTIVE

To compare, in a retrospective observational cohort study, the efficacy, tolerability, safety and clinical effectiveness of propiverine and oxybutynin in children and adolescents with neurogenic detrusor overactivity (NDO).

PATIENTS AND METHODS

In all, 255 children and adolescents (aged 1–18 years) with NDO (199 myelomeningocele, 46 spinal cord injury, 10 other diagnoses) were enrolled at 14 study centres. To evaluate the efficacy of propiverine and oxybutynin, urodynamic and clinical variables were assessed before and after at least 12 month of the antimuscarinic agents administered at variable doses.

RESULTS

In all, 127 patients given propiverine and 128 given oxybutynin were enrolled. The primary efficacy outcome, i.e. reductions in urodynamically assessed individual maximum detrusor pressure (P_detmax), was assumed to indicate success in 74.2% of those on propiverine vs 49.6% on oxybutynin. The mean P_detmax was significantly reduced during treatment, from 59.8 to 36.7 cmH₂O in the propiverine and from 65.2 to 54.9 cmH₂O in the oxybutynin groups. The mean maximum cystometric bladder capacity increased from 146 to 242 mL in the propiverine and from 222 to 310 mL in the oxybutynin group. Propiverine was better tolerated than oxybutynin, having fewer adverse drug reactions (9.4% vs 17.2%, odds ratio 2.04), and for its severity grades and premature treatment termination (none vs 11 cases).

CONCLUSION

In this non‐interventional study, reflecting ‘real‐life’ clinical practice, comparing the efficacy, tolerability and safety of propiverine and oxybutynin in children and adolescents with NDO, propiverine was at least as effective as oxybutynin, but better tolerated, resulting in superior clinical effectiveness than for oxybutynin.     

Efficacy and safety of onabotulinumtoxinA in patients with urinary incontinence due to neurogenic detrusor overactivity: a randomised, double-blind, placebo-controlled trial

Background

Neurogenic detrusor overactivity (NDO) frequently results in urinary incontinence (UI) which impairs quality of life (QOL) and puts the upper urinary tract at risk.

Objective

To assess the effects of onabotulinumtoxinA (BOTOX^®, Allergan, Inc.) on UI, urodynamic variables, and QOL in incontinent patients with NDO.

Design, setting, and participants

This multicentre, randomised, double-blind, placebo-controlled study enrolled patients with multiple sclerosis (MS; n = 154) or spinal cord injury (SCI; n = 121) with UI due to NDO (≥14 UI episodes per week).

Intervention

Patients received 30 intradetrusor injections of onabotulinumtoxinA 200 U (n = 92), 300 U (n = 91), or placebo (n = 92), avoiding the trigone.

Measurements

Primary end point was change from baseline in UI episodes per week (week 6). Secondary end points included urodynamics (maximum cystometric capacity [MCC], maximum detrusor pressure during first involuntary detrusor contraction [P_detmaxIDC]), and Incontinence Quality of Life (I-QOL) total score. Adverse events (AEs) were assessed.

Results and limitations

At baseline, mean UI episodes per week (33.5) were similar across groups. At week 6, onabotulinumtoxinA 200 U and 300 U significantly reduced UI episodes per week (−21.8 and −19.4, respectively) compared with placebo (−13.2; p < 0.01); onabotulinumtoxinA benefit was observed by the first posttreatment study visit at week 2. Improvements in MCC, P_detmaxIDC, and I-QOL at week 6 were significantly greater with both onabotulinumtoxinA doses than with placebo (p < 0.001). Benefits were observed in both the MS and SCI populations. The median time to patient request for retreatment was the same for both onabotulinumtoxinA doses (42.1 wk) and greater than placebo (13.1 wk; p < 0.001). Most frequent AEs were localised urologic events (urinary tract infections and urinary retention, which were dose related in patients not using clean intermittent catheterisation [CIC] at baseline). Significant increases in postvoid residual were observed in patients not using CIC prior to treatment, and 12%, 30%, and 42% of patients in the placebo, 200-U, and 300-U groups, respectively, initiated CIC posttreatment.

Conclusions

OnabotulinumtoxinA significantly reduced UI and improved urodynamics and QOL in MS and SCI patients with NDO. Both doses were well tolerated with no clinically relevant differences in efficacy or duration of effect between the two doses (http://www.clinicaltrials.gov; NCT00461292).     

Vardenafil decreases bladder afferent nerve activity in unanesthetized, decerebrate, spinal cord-injured rats

Background

Phosphodiesterase type 5 inhibitors (PDE5-Is) improve storage symptoms in benign prostatic hyperplasia patients, despite a lack of effect on peak urinary flow rate. Moreover, vardenafil improves urodynamic parameters in spinal cord-injured (SCI) patients with neurogenic detrusor overactivity (NDO). SCI rats also display NDO characterized by nonvoiding contractions (NVCs) during bladder filling, resulting in an increased bladder afferent nerve firing (BANF).

Objective

We postulated that vardenafil could improve urodynamic parameters by reducing BANF. The effect of vardenafil has been investigated on intravesical pressure by cystometry experiments while recording BANF in response to bladder filling.

Design, setting, and participants

Complete T7–T8 spinalization was performed in 15 female adult Sprague-Dawley rats (250–275 g).

Measurements

At 21–29 d postspinalization, fine filaments were dissected from the L6 dorsal roots and placed across a bipolar electrode. Bladder afferent nerve fibers were identified by electrical stimulation of the pelvic nerve and bladder distension. SCI rats were decerebrated before cystometry experiments. Bladders were filled to determine the maximal bladder filling volume (BFV) for each rat. Then, after bladder stabilization at 75% of maximal BFV, saline (n = 7) or vardenafil 1 mg/kg (n = 8) was delivered intravenously. NVCs and BANF were recorded for 45 min.

Results and limitations

In all SCI rats, BANF was already present and regular at resting conditions (26.2 ± 4.1 spikes per second). During bladder filling, intravesical pressure (IVP) slowly increased with transient NVCs superimposed. Concomitantly, BANF progressively increased up to 2.4-fold at maximal BFV (2.08 ± 0.24 ml). After stabilization at submaximal BFV, BANF was increased by 186 ± 37%. Vardenafil injection induced an immediate decrease in NVCs compared to saline (p < 0.001) and BANF (52% decrease vs 28% in saline after 45 min; p < 0.001).

Conclusions

Systemic vardenafil reduced both NVCs and BANF in unanesthetized, decerebrate, SCI rats. These findings provide new insights into the mechanism of action by which PDE5-Is improve storage symptoms in SCI patients.     

逼尿肌反射亢进大鼠膀胱ICC细胞数量的变化及意义

目的：观察脊髓损伤后大鼠逼尿肌反射亢进膀胱Cajal间质细胞（ICC）数量的变化,探讨膀胱逼尿肌功能改变和ICC的可能关系。方法：制作大鼠骶髓上损伤模型,膀胱压力测定证实膀胱出现逼尿肌反射亢进后,取膀胱组织行ckit免疫组织化学染色．用激光共聚焦显微镜观察ICC数量的变化。结果：逼尿肌反射亢进大鼠模型制作成功,膀胱ICC数量较正常组和膀胱造瘘组明显增加。结论：脊髓损伤后大鼠膀胱逼尿肌反射亢进可能由ICC数量变化所引起。     

Development of hydronephrosis secondary to poorly managed neurogenic bowel requiring surgical disimpaction in a patient with spinal cord injury: A case report

Context

Case of an adult patient with paraplegia managing neurogenic bladder with intermittent catheterization who was not performing a standard bowel program for management of neurogenic bowel.

Findings

Patient presented with increasing spasticity, fecal incontinence, and abdominal pain and ultimately was hospitalized for management. Imaging revealed massive fecal impaction, resulting in ureteral obstruction and hydronephrosis. Despite repeated aggressive bowel regimens, serial abdominal X-rays showed continued large stool burden. Ultimately surgical intervention was required to evacuate the colon and subsequently the hydronephrosis resolved.

Conclusion/Clinical relevance

This case illustrates the importance of proper management of neurogenic bowel, as significant medical complications, such as hydronephrosis can occur with poorly managed neurogenic bowel.     

Development of hydronephrosis secondary to poorly managed neurogenic bowel requiring surgical disimpaction in a patient with spinal cord injury: A case report

Abstract

Context

Case of an adult patient with paraplegia managing neurogenic bladder with intermittent catheterization who was not performing a standard bowel program for management of neurogenic bowel.

Findings

Patient presented with increasing spasticity, fecal incontinence, and abdominal pain and ultimately was hospitalized for management. Imaging revealed massive fecal impaction, resulting in ureteral obstruction and hydronephrosis. Despite repeated aggressive bowel regimens, serial abdominal X-rays showed continued large stool burden. Ultimately surgical intervention was required to evacuate the colon and subsequently the hydronephrosis resolved.

Conclusion/Clinical relevance

This case illustrates the importance of proper management of neurogenic bowel, as significant medical complications, such as hydronephrosis can occur with poorly managed neurogenic bowel.     

Efficacy and safety of onabotulinumtoxinA therapy are sustained over 4 years of treatment in patients with neurogenic detrusor overactivity: Final results of a long‐term extension study

Aims

To present final efficacy/safety results from a prospective, long‐term extension trial of onabotulinumtoxinA for urinary incontinence (UI) due to neurogenic detrusor overactivity (NDO); patients received treatment for up to 4 years.

Methods

Patients who completed a 52‐week, phase III trial of onabotulinumtoxinA for NDO were eligible to enter a 3‐year, multicenter, open‐label extension study of intradetrusor onabotulinumtoxinA (200U or 300U). Patients were treated “as needed” based on their request and fulfillment of prespecified qualification criteria (≥12 weeks since previous treatment and a UI episode threshold). Assessments included change from study baseline in UI episodes/day (primary efficacy measure), volume/void, and Incontinence Quality of Life (I‐QOL) total score (week 6); duration of effect; adverse events (AEs); and initiation of de novo clean intermittent catheterization (CIC). Data are presented for up to six treatments.

Results

OnabotulinumtoxinA 200U consistently reduced UI episodes/day; reductions from baseline ranged from –3.2 to –4.1 across six treatments. Volume/void consistently increased, nearly doubling after treatment. I‐QOL improvements were consistently greater than twice the minimally important difference (+11 points). Overall median duration of effect was 9.0 months (200U). Results were similar for onabotulinumtoxinA 300U. Most common AEs were urinary tract infections and urinary retention. De novo CIC rates were 29.5, 3.4, and 6.0% (200U), and 43.0, 15.0, and 4.8% (300U) for treatments 1–3, respectively; de novo CIC rates were 0% for treatments 4–6.

Conclusions

OnabotulinumtoxinA treatments consistently improve UI, volume/void, and QOL in patients with UI due to NDO in this 4‐year study, with no new safety signals. Neurourol. Urodynam. 36:368–375, 2017. © 2015 The Authors. Neurourology and Urodynamics Published by Wiley Periodicals, Inc.