Route
Treatment
Proposed mechanism of action
Observation
Spontaneous voiding
–
Oral
Antimuscarinics
Suppresses detrusor muscle contractions
Tricyclic antidepressant
Central and peripheral anticholinergic
Catheterization
Intermittent
Drainage of bladder/urinary tract
Condom (male)
Suprapubic tube
Indwelling urethral
Urinary diversion
Ileovesicostomy (continent or incontinent)
Ileal conduit
Intravesical
Intradetrusor on a botulinum toxin A injection
Paralyzes detrusor muscle
Antimuscarinics
Suppresses detrusor muscle contractions
Pharmacologic intervention is often necessary to ameliorate involuntary bladder contractions secondary to NDO when intermittent catheterization is the preferred method of management in those with NGB. This is typically accomplished with the use of antimuscarinic agents of which a myriad are available commercially (i.e., oxybutynin, tolterodine, solifenacin, etc.). Antimuscarinic drugs are thought to suppress bladder contractions by the blockade of muscarinic receptors on the detrusor muscle, however, effects on the urothelium and central nervous system may also play a role. Use of these agents in combination or in conjunction with other drugs with anticholinergic effects such as the tricyclic antidepressant class may be of benefit when monotherapy is insufficient at achieving the clinical goal. In the case when oral therapies are unable to suppress the bladder effectively, options include various intravesical treatments, augmentation ileocystoplasty, or a change to another form of bladder management. Direct instillation or injection of different substances into the bladder have the advantage of obviating the need for oral administration and avoiding many of the associated side effects of antimuscarinic agents such as dry mouth, constipation, and less commonly, mental status changes. Currently, the only Food and Drug Administration (FDA)-approved drug for intravesical administration for NGB is botulinum toxin A which has performed well in multiple clinical trials with an acceptable side effect profile (Linsenmeyer 2013). The mechanism of action behind its efficacy is a selective blockade of acetylcholine-mediated detrusor muscle contractions (Schurch et al. 2000). Intravesical instillations of oxybutynin and lidocaine have also been described but are not used commonly for the management of NGB. It is in this clinical situation and administration route that vanilloids have shown some clinical efficacy in patients with NGB.
There have been numerous studies investigating the therapeutic benefit of intravesical vanilloids (capsaicin and RTX) in patients with NGB secondary to SCI and MS that are refractory to oral antimuscarinic therapy. A thorough review of the published randomized trials was performed by MacDonald et al. in 2007 (MacDonald et al. 2008). They compiled data from nine clinical trials (288 patients) comparing capsaicin and RTX to each other, placebo, or, in 1 trial, to botulinum toxin A (BTX-A). The majority of patients had either SCI or MS and nearly three quarters (71 %) were male. The main outcome measure was improvement in urinary incontinence as measured by the number of daily episodes. Doses of capsaicin ranged from 1 mM, 30 mg, and 2 mM and that of RTX was 0.005–1.0 μM, and 100 nM. Duration of treatment was 4 weeks to 18 months with the majority being at least 90 days duration. Many of the trials were placebo controlled and double blinded. Capsaicin reduced the number of daily urinary incontinence episodes by 3.8 episodes when compared to placebo. There was also a significant reduction in the numbers of pads used per day from 10 to 4. In the two trials comparing capsaicin to RTX, one showed no difference between treatment arms with both agents decreasing the urinary incontinence episodes at 30 days. As expected, the RTX groups had more durable responses at 90 days with the median number of daily incontinence episodes being 1 and 4 in the RTX and capsaicin groups, respectively. The side effect profile of capsaicin demonstrated greater incidences of pelvic pain/burning and flushing with the former occurring in 50–60 % of those treated with this agent. Although it was thought that the ethanol solvent may be responsible for this result, the effect was unchanged when glucidic acid was used as the solvent. Other side effects were similar to that of the placebo group. When capsaicin and RTX were compared to each other, capsaicin had a significantly higher incidence of pelvic pain (50 vs. 12 %).
Lazzeri et al. reported on their 10-year experience using intravesical vanilloids in 54 patients with neurogenic incontinence (Lazzeri et al. 2004). Doses of capsaicin and RTX were 10 mM and 10 nM–10 μM, respectively. A number of treatment outcomes were investigated including improvement in clinical status (dry on intermittent catheterization and bladder capacity 50 % higher at 3 months), number who continued therapy, number of instillations received, interval length between instillations, and alternative therapies when vanilloids failed. Over half (53.7 %) of those who received capsaicin had an improvement in their clinical symptoms and urodynamic parameters at 3 months. A higher response rate (73.33 %) was noted in those who received RTX at the 10 μM dose.
In summary, capsaicin and RTX do appear to provide acceptable treatment results in patient with neurogenic bladder, primarily due to SCI and MS. Randomized studies, however, are few and involve relatively small numbers of patients. The side effect profile generally favors RTX and durability of response is longer as would be expected. Although promising, at this point, use of these agents cannot be recommended as a standard treatment for NGB based on available data.
13.3 Overactive Bladder
OAB comprises a constellation of symptoms including urinary frequency, urgency with or without urinary incontinence in the absence of definable pathology such as urinary tract infection, bladder outlet obstruction, bladder cancer, or disorder of the neurologic system (i.e., SCI, MS, cerebrovascular accident, spina bifida, Parkinson’s disease, etc.) which can result in a similar clinical presentation. The prevalence of OAB in the United States ranges from 7–27 % in men and 9–43 % in women (Gormley et al. 2012). It also disproportionately affects the elderly population and can heighten the risks of falls potentially resulting in hip fractures and skull injuries with their concomitant comorbidities (deep vein thrombosis, pulmonary embolus, intracranial hemorrhage etc.). Despite not having direct impact on duration of life, OAB can have tremendous negative effects on the quality of life. Many find that their ability to perform and/or enjoy daily activities and ability to obtain satisfactory sleep is encumbered by the frequent and urgent need to void. Furthermore, management of the often associated urinary (urgency type) incontinence can often be a costly venture requiring the use of various types of protective devices such as sanitary pads and diapers. In severe cases, chronic urethral catheterization may be chosen as the most pragmatic method of management, exposing the patient to some of the long-term consequences previously mentioned when used in the neurogenic population.
Evaluation of the patient with OAB revolves around diagnostic tests able to detect causative and potentially treatable etiologies. Simple urinalysis can detect evidence of urinary tract infection, glucosuria which may be causing an osmotic diuresis, and hematuria (microscopic or gross), a potential indicator of urinary tract pathology such as neoplasia or urolithiasis. Urine cytology while not highly sensitive does have good specificity (low false positives) and can be utilized when social data (tobacco use or exposure to chemicals) suggest predisposition to urothelial malignancy. Measurement of post-void residual urine can assist in the detection of bladder outlet obstruction and neurogenic vesicourethral dysfunction when elevated. Direct inspection of the bladder and urethra with cystourethroscopy may be indicated when there are reasons to suspect bladder neoplasm (primarily hematuria or suspicious urine cytology). Urodynamics, although not required for diagnosis, can be helpful in determining if bladder outlet obstruction or neurogenic bladder is the underlying pathophysiological process. Typical findings in patients with OAB are the presence of involuntary detrusor contractions of varying magnitudes during the filling phase, sometimes accompanied by the loss of urine. The absence of this pattern, however, is not sufficient to eliminate the diagnosis of OAB as the study can be normal in up to 50 % of affected patients.
Management and treatment of OAB is dictated primarily by the severity of the symptoms and the level of impact it has on the patient’s quality of life (Table 13.2). Oftentimes behavioral modification by the moderation in fluid intake, reduction in the use of caffeinated products and others with diuretic properties (i.e. alcohol), and elimination of food stuffs with high spice content can be sufficient at satisfactorily ameliorating the symptoms of OAB. In most instances, however, this is not adequate and pharmacological or surgical options must be considered. The goal of these therapies is either reduction in the frequency or amplitude of the associated involuntary detrusor contraction or their elimination altogether. As with NGB, pharmacotherapy for OAB generally involves the use of agents with antimuscarinic properties that interfere with detrusor contractions. Many are commercially available with no significant differences in their efficacy. Oral preparations are most commonly used; however, agents that can be topically administered (transdermal patch, gel) exist. Recently, another agent with beta-3 agonist properties (mirabegron) has become commercially available that has similar efficacy to the antimuscarinics but without the typical side effects of dry mouth and constipation (Herschorn et al. 2013). Studies to investigate the potential benefit of combination therapy with the antimuscarinics and beta-3 agonists are currently in development and may provide an additional option for treatment. When pharmacotherapy fails to achieve significant clinical benefit, surgical options include intravesical injections of botulinum toxin or sacral neuromodulation utilizing the Interstim device made by Medtronic. Both have demonstrated acceptable results in patients in whom medical therapy is inadequate or side effects are intolerable. The advantages of botulinum toxin are its simplicity of administration and low side effect profile. Repeat injections (every 6–9 months), however, are necessary to maintain efficacy and there is the potential for transient urinary retention requiring catheterization (indwelling or intermittent) until resolution. Sacral neuromodulation typically requires two phases, one of which is a testing period with a stimulating lead in place to establish efficacy followed by surgical implantation of the generator when successful. Complications can include infection, pain, and lead displacement.
Table 13.2
Treatment options for OAB
Route | Treatment | Proposed mechanism of action |
---|---|---|
Behavioral
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