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Pharmacologic therapies for neurogenic bladder


A variety of pharmacologic agents are available for the treatment of neurogenic bladder ( NGB ) as part of a patient’s comprehensive bladder management program.

The most commonly used class of medications to treat neurogenic bladder are antimuscarinics. These medications are orally administered in the majority of patients, with intravesical instillation rarely used. Combination therapy using two or three different oral agents ( antimuscarinics, alpha-blockers, and tricyclic antidepressants ) has been found to be effective in patients with neurogenic bladder and poor bladder compliance.

Mirabegron ( Betmiga, Myrbetriq ), a beta-agonist, is an oral therapy that has been studied to treat overactive bladder ( OAB ). Although this does not include an indication for neurogenic bladder, it is potentially likely this medication will be used either in combination with antimuscarinics or alone in antimuscarinic-refractory patients.

Lastly, Onabotulinumtoxin A ( BoNT/A; Botox ) was approved by the FDA ( Food and Drug Administration ) following phase 3 clinical trials that demonstrated the agent’s efficacy in decreasing urinary incontinence episodes in patients with neurogenic detrusor overactivity ( NDO ). This treatment is FDA approved for the treatment of neurogenic bladder ( indicated for urinary incontinence due to detrusor overactivity associated with a neurologic condition in adults who have an inadequate response to or are intolerant of an antimuscarinic medication ).

Antimuscarinics

Antimuscarinic drugs comprise the foundation of first-line treatments for patients with neurogenic bladder / neurogenic detrusor overactivity. The physiologic basis for treating bladder overactivity with these agents is that detrusor contractions are primarily mediated by muscarinic receptors.
Acetylcholine release from cholinergic nerves stimulates muscarinic receptors on the smooth muscle within the detrusor. Antimuscarinics competitively inhibit acetylcholine at the muscarinic receptors, leading to relaxation of the detrusor and improved bladder storage. By blocking the action of acetylcholine, these agents stabilize the detrusor, rendering it refractory to parasympathetic nerve impulses.
This results in increased bladder capacity and a delay in the urge to void.

Oxybutynin ( Ditropan; Kentera ) has been in widespread clinical use for this purpose since 1975, with Tolterodine tartrate introduced in 1996 as an alternative to Oxybutynin. Oxybutynin is available in both immediate- and sustained-release oral formulations as well as transdermal and topical gels.
In addition, intravesical administration of oxybutynin has been described in the past.

Tolterodine tartrate ( Detrol; Detrusitol ) and Trospium chloride ( Sanctura; Uraplex ) are also available in immediate- and sustained-release oral formulations.
It appears that most extended-release preparations of antimuscarinics may produce less cognitive side effects and dry mouth than immediate-release Oxybutynin.

It is thought that Trospium, owing to its size and charge as a quaternary amine, does not cross the blood-brain barrier and thus produces fewer cognitive side effects.

Blood-brain barrier permeability can be an important factor when treating neurogenic bladder because blood-brain barrier integrity can be disrupted in patients with stroke, multiple sclerosis, Parkinson’s disease, trauma, and older age.

Multiple antimuscarinic agents are available in different dosages and may be administered orally, or in some cases, through intravesical or topical administration. Overall, antimuscarinic therapy can provide substantial benefits to patients with neurogenic bladder and neurogenic detrusor overactivity.

A recent meta-analysis that included a total of 960 patients with neurogenic detrusor overactivity in 16 randomized clinical trials found that antimuscarinics were associated with statistically significantly better patient-reported cure or improvement, higher maximum cystometric capacity, higher volume at first detrusor contraction, and lower maximum detrusor pressure when compared with placebo.
A multitude of agents were studied, and no one drug was found to demonstrate superiority over another. While the drugs were all found to be highly effective, a greater incidence of adverse events, including dry mouth, constipation, nausea, and visual disturbances, was noted in the treatment cohorts versus those receiving placebo in these randomized controlled trials. Although the authors urged caution, as the data referred to limited follow-up, they concluded that the findings overall supported the use of antimuscarinic drugs in patients with neurogenic detrusor overactivity to reduce the risk of long-term deterioration of renal function associated with neurogenic detrusor overactivity.

Combining antimuscarinic agents is sometimes considered for patients with neurogenic bladder; one study found that whereas 63% of patients diagnosed with neurogenic bladder were using 1 antimuscarinic agent, another 9% of patients were taking more than 1.
Combining antimuscarinics may be an effective strategy in patients in whom monotherapy has failed, including double-dose antimuscarinic therapy. One study demonstrated that when combined high-dosage antimuscarinics were used, 85% of the patients who previously experienced failed treatment with dosage-escalated monotherapy were treated successfully, including improvements in bladder capacity, detrusor compliance, and reflex volume without a significant increase in adverse events.
In addition, Bennett and colleagues found that patients with neurogenic bladder were more likely to request higher doses of Oxybutynin-XL compared with patients with overactive bladder.

Therapy combining an antimuscarinic with the tricyclic antidepressant Imipramine ( Tofranil ) and/or an alpha-blocker has been found to be effective in patients with neurogenic bladder and poor bladder compliance.

Combination therapy using either two or three drugs improved bladder compliance, decreased pressures at capacity, and improved clinical outcomes. Combination therapy is a potential pathway to consider in patients in whom antimuscarinic monotherapy proves inadequate.

The use of intravesical Oxybutynin has been used as well, more so in the past. The theory is that with intravesical administration the efficacy can be maintained with minimization of side effects such as dry mouth and constipation.
Oxybutynin has been shown to be both safe and effective when administered in this manner, and other drugs have been tested for this type of use.
However, the drug can still be absorbed through the detrusor, and side effects related to the blocking of muscarinic receptors such as dry mouth do not appear to eliminated.
Lastly, the administration of Oxybutynin intravesically, multiple times daily, can be challenging for patients and their families and is a primary reason why patients discontinue the treatment.

Although antimuscarinics have obvious benefits, some of these agents have been associated with poor patient compliance, and patients with neurogenic bladder can be intolerant of some adverse events associated with treatment, such as bowel dysfunction. One epidemiologic study found that during a 1-year period, 38% of patients with neurogenic bladder taking antimuscarinics discontinued use of these agents and did not restart, more than 80% of patients interrupted antimuscarinic therapy, and approximately 34% stopped and restarted therapy. Patient compliance and persistence with therapy can be suboptimal and may vary depending on the drug prescribed. Compliance / adherence / persistence surrounding therapy is an area that clinicians must pay special attention to initially and throughout follow-up when using antimuscarinics for management of neurogenic bladder / neurogenic detrusor overactivity.

OnabotulinumtoxinA

Botulinum toxin is one of the most potent naturally occurring neurotoxins in existence. It is derived from the gram-positive coccus bacterium Clostridium botulinum and leads to a flaccid paralysis of striated muscle through a mechanism that involves blocking acetylcholine release at the presynaptic level.

Botulinum toxin was first approved by the FDA in 1989 for treatment of strabisumus, blepharospasm, and hemifacial spasm, and it has further been developed and approved for a variety of other applications.

There are 7 immunologically distinct types of Botulinum toxin. Types A and B are available commercially, and OnabotulinumtoxinA ( BoNT/A ) is the FDA-approved form for use in urologic indications.
The toxin blocks neuromuscular junction presynaptic vesicle fusion, preventing acetylcholine release and blocking signal transmission across the neuromuscular junction. This effect clearly impacts the efferent muscle contraction, and there is evidence to support possible afferent effects on bladder function ( and for other applications ) as well.

Injection of BoNT/A into the detrusor muscle leads to dose-dependent muscle relaxation due to reduced neural signal transmission. Interestingly, BoNT/A’s duration of effect in the bladder, which is composed of smooth muscle, is significantly longer than that seen in skeletal muscle. Long-lasting improvement in neurogenic detrusor overactivity, urinary incontinence, and quality of life in individuals with spinal cord injury and multiple sclerosis, the patients in whom it has been most extensively studied, has been noted in multiple studies evaluating its use for neurogenic bladder.

At present, this agent is approved for use for treatment of urinary incontinence due to detrusor overactivity associated with neurologic conditions ( eg, spinal cord injury, multiple sclerosis ) in adult patients who have an inadequate response to or are intolerant of antimuscarinic medications.

The two primary trials that ultimately led to the approval of BoNT/A for the treatment of neurogenic bladder studied 691 patients with either spinal cord injury or multiple sclerosis. The studies enrolled 275 and 416 patients, respectively, with urinary incontinence due to neurogenic detrusor overactivity ( greater than 14 episodes per week ) who received 30 intradetrusor injections of BoNT/A 200 U, 300 U, or placebo.
The primary end point was the change in baseline in urinary incontinence episodes per week at week 6. Secondary end points included urodynamic end points ( maximum cystometric capacity, maximum detrusor pressure during first involuntary detrusor contraction ) and quality of life using the Incontinence Quality of Life questionnaire ( I-QoL ) score.
The studies found that both BoNT/A doses significantly reduced UI and improved urodynamic outcomes and quality of life in the patients studied. Both doses of BoNT/A were well tolerated with no clinically relevant differences in effect or duration between the two doses tested.
The most common adverse events were urinary tract infections and urinary retention. Increased risk of urinary retention and elevated postvoid residual ( PVR ) were seen in patients who did not perform intermittent catheterization at baseline.

Although many initial studies evaluated the higher dosage of 300 U of BoNT/A, these clinical trials trial demonstrated that the 200-U and 300-U doses had similar efficacy, with patients on the 300-U dose experiencing a greater risk of certain adverse events.
Thus, the 200-U dose was approved by the FDA due to similar efficacy and an improved risk-benefit ratio compared with the 300-U dose.
The average duration of effect of BoNT/A in patients studied was approximately 9 months.

Another retrospective trial of 200 patients with neurogenic bladder receiving BoNT/A found a greater than 50% increase in mean bladder volume to first reflex detrusor contraction and maximum cystometric capacity accompanied by a proportional decrease in maximum detrusor pressure.
The benefits of BoNT/A administration persisted over more than 6 months and could potentially prove most cost-effective over this duration of therapy ( ie, continuous use of BoNT/A for 5.1 months of therapy or more ).

Studies assessing HRQoL following BoNT/A administration in patients with neurogenic detrusor overactivity have also been performed, and results in general have demonstrated improvements in QOL as assessed by I-QOL scores or Urinary Dress Inventory ( UDI-6 ) assessment. ( Xagena )

Ginsberg D, Am J Manag Care 2013; 19(10 Suppl):s197-204

XagenaMedicine_2013



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