This article is a review of the current and past literature on medical management of the neurogenic bladder, with a particular focus on spinal cord injury and multiple sclerosis. The use of antimuscarinics, αα-blocker, and tricyclic antidepressants and their combined use are discussed along with new therapies in human and animal trials.
Neurogenic bladder (NGB) is a heterogeneous diagnosis broadly describing bladder dysfunction because of neurologic insult. The symptoms range from urgency, frequency, and/or urgency incontinence to complete urinary retention, and the presentation is often different for the various causes. Diseases that are almost always associated with NGB include those with more severe neurologic dysfunction: spinal cord injury (SCI), multiple sclerosis (MS), and spina bifida; hence, these are the focus of this review. The goals of bladder management in NGB are the same, regardless of the cause. These goals are preservation of renal function, social continence, and efficient bladder emptying, which are achieved by treating most individuals in a targeted fashion based on urodynamic findings. The exception to this is MS, in which elevated bladder pressures or upper tract damage are rare; therefore, symptoms and postvoid residuals (PVRs) are often sufficient to guide management. NGB for other causes, such as diabetes, Parkinson disease, and rare neurologic disorders, has been less well studied; however, the general principles of bladder management in NGB would also apply to these disorders.
Bladder storage pressures ideally must be kept below 40 cm H 2 O, because higher pressures carry a high risk of renal dysfunction and vesicoureteric reflux (VUR). Bladder compliance must be maximized, because it is known that compliance less than or equal to 12.5 cm H20/ml often results in upper tract deterioration on radiological examination, VUR, and pyelonephritis. Detrusor overactivity must also be treated, because it results in incontinence or increased pressure on the upper tract if there is detrusor sphincter dyssynergia (DSD).
Several oral and intravesical pharmacotherapeutic agents have been evaluated for treating detrusor overactivity and diminished bladder compliance in the NGB. These agents are the focus of this review, with surgical therapy and botulinum toxin injections being the subject of other articles in this series.
Anticholinergics
Antimuscarinic (aka anticholinergic) medications have been the mainstay of pharmacologic therapy for neurogenic detrusor overactivity (NDO) for more than 30 years. They decrease detrusor overactivity and significantly increase bladder capacity, reduce bladder filling pressure, improve compliance, reduce urge urinary incontinence events, and help to protect the upper urinary tract from deterioration. Muscarinic receptor antagonists have traditionally been seen to act by binding to receptors on the detrusor muscle and thereby preventing acetylcholine release from parasympathetic nerves. These receptors are now known to be located on the detrusor and the mucosa, and the newer pharmacotherapeutic agents have been shown to bind to both these receptor sites.
Antimuscarinic use is recommended in NGB by the European Association of Urology and a UK consensus group on the treatment of MS patients. Furthermore, in a survey of the membership of the Society for Urodynamics and Female Urology, 84% thought that antimuscarinics and clean intermittent catheterization (CIC) were the best option for bladder management in SCI with detrusor overactivity. However, a Cochrane review on anticholinergics for urinary symptoms in MS could not find sufficient evidence to support their use given the lack of randomized controlled trials, but there exists level 1b evidence of their effectiveness in MS and they are widely used.
The side effects of the antimuscarinic drugs include dry mouth, constipation, blurred vision, drowsiness, and dry skin and mucosa. Dry mouth is the most common side effect, but many individuals with neurologic disorders are already using medications that cause dry mouth; hence, they often are unaware of the change. Also, bowel constipation seems to be less problematic, because most individuals have concomitant neurogenic bowel and already use laxatives, suppositories, and manual defecation. Urinary retention is possible in those who void spontaneously; hence, upward dose titration in those individuals should be done carefully and PVRs monitored. Retention is obviously not problematic in those who use CIC, and higher doses can be used. Even in studies in which the doses of antimuscarinics are doubled, the side-effect profile remains minimal, with significant increases in effectiveness. Efficacy may be further increased by using 2 different antimuscarinics to take advantage of their slightly different receptor profiles while keeping side effects low. It has also been observed that in the NGB population, higher doses are required to be effective compared with the non-neurogenic population.
There is ample basic science evidence to support antimuscarinic therapy in NGB. In the human, there exist 5 muscarinic receptor subtypes M1 to M5, however only M2 and M3 subtypes exist in the bladder. The density of muscarinic receptors and the bladder’s sensitivity to muscarinic agents is greatest in the dome and decreases toward the base of the bladder, which allows for efficient emptying of the bladder. Muscarinic receptor density is also increased along with an increase in the sensitivity to muscarinic agonists after denervation of the bladder. M2 receptors outnumber M3 receptors 3:1, but it is the M3 receptors that mediate bladder contractions, at least in vitro, in normal bladders. M3 knockout mice have significantly diminished bladder contractions, but only male animals develop significant bladder distention. Because these animals continue to have bladder contractions, there are other muscarinic acetylcholine receptor subtypes or other mediators that rescue these contractions.
The contribution of the M2 receptors is controversial. In muscarinic receptor knockout mouse models, including M2 knockout, M3 knockout, and double M2/M3 knockout animals, there is evidence to support the M2 receptor contributing to bladder contraction by rescuing the muscarinic contractile response after inactivation of the M3 receptors and enhancing the M3 receptor-mediated contractions. Detection of M2 receptor function is difficult when M3 and M2 receptors are activated, possibly explaining the difficulty in determining the true function of the M2 receptor.
In the NGB, there is significant bladder remodeling with new expression of many proteins, raising the possibility that the M2 receptors change in their density, increase in responsiveness, or both. In the denervated rat bladder, there is a 60% increase in M2 receptor density, and these M2 receptors provide a contractile function that is normally mediated by only M3 in normal bladder. In the human bladder with NGB, M2 receptors were found to mediate contractions in one study but were found to play no part in bladder contractions in another.
There are currently several antimuscarinics available, but there are few head-to-head comparison studies. The vast majority of publications have been related to the idiopathic overactive bladder population. However, the receptor mechanism behind NDO and idiopathic detrusor overactivity are believed to be similar.
In a meta-analysis of antimuscarinic therapy for overactive bladder (OAB), the longer-acting formulations were found to be more effective and to have decreased side effects, but little evidence supports the use of one long-acting agent over another. However, there seems to be a difference in the cognitive impact of these drugs, especially on memory. The pathophysiology behind this side effect is believed to be related to the drug penetrating the blood-brain barrier. In a review of the current literature, oxybutynin was consistently associated with cognitive deficits, and darifenacin caused no detectable impairment in cognition. There was insufficient evidence to draw conclusions about the other antimuscarinics. The drug-related decrease in cognition was unnoticed by the patients in these studies. Most studies were performed on healthy individuals, but the NGB population may be more susceptible to the effects of drugs that cross the blood-brain barrier, because individuals with MS, stroke, and Parkinson diseases actually have an increase in permeability.
Oxybutynin has long been used in the treatment of NGB. It is a commonly used drug in children with NGB and has been shown to be safe and effective regardless of the preparation (syrup, tablet, extended-release tablets, transdermal) in this population. Oxybutynin is a tertiary amine metabolized by the liver that has antimuscarinic, spasmolytic, and local anesthetic properties, but the spasmolytic and local anesthetic effects on detrusor smooth muscle are 500-fold weaker than the muscarinic receptor blocking.
Extended-release (ER) oxybutynin has significantly fewer side effects that the immediate release and should be used if possible. In individuals with NGB, when the dosage of oxybutynin ER is titrated upwards based on symptoms, side effects, and urodynamics, even including individuals who void spontaneously, the dose most often chosen is 30 mg/d. The side effects do not increase linearly with dosage as is the case with immediate release oxybutinin. Recently, transdermal oxybutynin systems have been evaluated in individuals with SCI, with the expected improvements in the number of CICs per day, urinary leakage, maximum cystometric capacity (MCC), and detrusor pressures seen in other studies of the oral preparation. The incidence of dry mouth was low at 8.3%, but skin reactions to the patch were high at 12.5%.
A common misconception is that individuals with NGB managed with indwelling catheters do not benefit from antimuscarinic therapy. In a retrospective review of individuals with SCI who had indwelling catheters with or without oxybutynin for a mean of 11.9 years, bladder compliance was significantly better in those using oxybutynin. Complications, including hydronephrosis and febrile urinary tract infections, were much less frequent in those taking the medication as well.
Intravesical administration of oxybutynin is only easily accomplished in individuals who already catheterize, which is why the neurogenic population are ideal candidates. Intravesical oxybutynin is absorbed systemically from the bladder but has fewer metabolites generated because of the reduced first-pass metabolism. These metabolites result in dry mouth and other side effects. Also, mucosal muscarinic receptors in the bladder are blocked by oxybutynin, which are probably responsible for the effectiveness of intravesical administration as well as afferent C-fibers that are inactivated by its local anesthetic effects. Intravesical oxybutynin has been shown to significantly improve continence and quality of life in NGB. Increasing doses of oxybutynin instilled intravesically increases effectiveness without a significant increase in side effects and can be safely combined with oral antimuscarinics with better effectiveness. Intravesical oxybutynin is prepared by breaking up standard oral tablets and dissolving them in water or saline with additives as needed. If larger batches are prepared for convenience, saline or water with gentamicin as an additive are better than tap water, because these are stable at room temperature for 4 weeks. Although effective, intravesical administration is time-consuming and with the increased tolerability of ER oral preparations, remains an infrequent route of administration.
Tolterodine is an antimuscarinic that is equipotent with oxybutynin in the bladder but has an 8-fold lower affinity for the muscarinic receptors of the salivary glands. Tolterodine is available in immediate release (IR) and ER formats. In clinical trials in individuals with NGB, it is as effective as oxybutynin at improving symptoms but has less incidence of dry mouth. Tolterodine does reduce the QT interval on electrocardiogram, hence the maximum daily dose is 8 mg. In randomized double-blind placebo controlled trials, tolterodine has been shown to improve urodynamic variables as well as continence and voided volumes, with increased effectiveness at 4 mg compared with 2 mg in NGB. Increasing the dosage from 4 mg/d to 8 mg/d if incontinence persists is safe and effective in most patients with NGB. In patients with MS, compared with oxybutynin, in an interim analysis of the cognitive safety of this drug, tolterodine showed a trend toward fewer cognitive side effects. Recently, tolterodine has been expanded in its use to the pediatric NGB population, with the IR, ER, and oral solution showing improvements in bladder symptoms with a good safety profile.
Trospium chloride is a quaternary amine with atropinelike effects that has been studied in the NGB population. Compared with oxybutynin, it has an equivalent increase in MCC and bladder compliance and decrease in bladder storage pressures, but with considerably less dry mouth. Dose escalation in individuals with insufficient clinical response is warranted, with improvements in all parameters with minimal increase in side effects even at doses up to 135 mg/d.
The newer antimuscarinics, darifenacin, solifenacin, and fesoteridine, have not been evaluated in the NGB population. However, given their favorable side-effect profiles and similarity to other antimuscarinics, they are probably effective in NGB, but further data in this population are needed.
Propiverine is an antimuscarinic with additional calcium channel modulating properties, and it is available in Europe for the treatment of OAB and NDO but is not currently Food and Drug Administration-approved. It is only available in an IR formulation. Propiverine is well tolerated in children and adolescents with NGB, and when compared with oxybutynin, it has similar improvements in urodynamic MCC. However, propiverine was associated with fewer adverse events, especially dry mouth, fewer dropouts, and more children achieving normal detrusor pressures of 40 cm H 2 O or less. In a randomized double-blind study comparing IR propiverine and IR oxybutynin in adults with NGB, there were equivalent improvements in capacity, compliance, and detrusor pressure but improved side-effect profile with propiverine.
α-Blockers
α-Blockers are widely used for the treatment of benign prostatic hyperplasia (BPH), and they relieve the voiding symptoms and associated bladder storage symptoms of urgency, frequency, and nocturia. Their utility in NGB is often overlooked, despite their favorable side-effect profile, and there is evidence to support their use in the treatment of poor compliance, emptying difficulty, and autonomic dysreflexia (AD). α-Blockers are recommended as a possible treatment for NGB by the Clinical Practice Guidelines for the Paralyzed Veterans of America.
α 1 -adrenergic blockers that are currently used include alfuzosin, terazosin, doxazosin, and tamsulosin. The more commonly reported side effects of these medications are nasal congestion, abnormal ejaculation (especially with tamsulosin), and dizziness or postural hypotension that are more common with doxazosin and terazosin, which is why these 2 drugs require dose escalation.
There are significant basic science data to support α-blockers as a therapeutic option in NGB. There are three α 1 -adrenergic receptor (AR) subtypes in the human: α 1 a, α 1 b, and α 1 d. Based on human histochemical studies, it is well known that the prostate and trigone contain predominantly α 1 a-AR messenger (m)RNA and protein and that α 1 -AR–mediated smooth muscle contractions from sympathetic nervous system stimulation is the dynamic component of obstruction in BPH.
However, α 1 -ARs are not just present in the prostate. The human bladder dome and bladder base contain α 1 a receptors, but the urothelium only contains the mRNA encoding the receptor, not the expressed protein. In contrast to rats, a commonly used animal model of the bladder, only 2 types of α 1 -AR are present in the human detrusor muscle: α 1 a and α 1 d in a 2:1 proportion, whereas the rat has a 1:1:1 proportion of a, b, and d. Hence, one must interpret animal studies with caution, and human tissue studies need to be performed before any conclusions about receptor distribution or function can be drawn.
α 1 a-ARs are present in human arteries, and all 3 receptors are present in the spinal cord, with a predominance of α 1 d. It is plausible that these spinal receptors impact the bladder. In the bladder, the AR number increases significantly in the NGB when compared with the normal bladder.
Doxazosin has also been shown to play a sensory role in the bladder. Adenosine triphosphate (ATP) is released by the bladder urothelium when stretched, which in turn acts as a sensory neurotransmitter and binds to the suburothelial sensory nerve endings via P2X3 receptors. This action sends an afferent signal to the brain indicating fullness of the bladder. Bladders of those with interstitial cystitis and of those with BPH released significantly more ATP compared with normal controls. This increase in ATP release was eliminated with doxazosin, which may explain how it relieves irritative symptoms in these patients.
There are many articles on the study of phenoxybenzamine and prazosin, nonselective adrenergic blockers, with successful results in the treatment of NGB to facilitate bladder storage function. In none of these trials, however, was there improvement in the ability to empty the bladder. The high side-effect profile of both drugs and the theoretical risk of malignancy with long-term usage of phenoxybenzamine has limited their use. Newer, more selective α 1- blockers are safer choices, even in this population.
Voiding is not possible in many individuals with NGB, and treatment with α-blockers does not appear to change this state. However, in several studies of individuals with NGB who can spontaneously void with a residual volume, the newer α-blockers have been shown to be effective. In a study of 28 patients with DSD, American Urological Association symptom index, PVRs, and urodynamic urine flow all improved with 2 months of treatment with tamsulosin. In a study of 24 patients with NGB examined with urodynamics before and after 1 month of 0.4 mg tamsulosin, there were no changes in residual volume, but the maximum flow rate on free uroflow and the maximum detrusor pressure on urodynamics were improved after treatment.
In a 4-week randomized controlled trial (RCT) of 263 patients with suprasacral SCI followed by a 1-year open label study of placebo compared with tamsulosin, maximum urethral pressure (MUP), the primary outcome of the study, was not significantly different between groups at the 4-week mark. However, in the 186 patients who completed the 1-year open label study, there were significant improvements in MUP (−18 cm H2O) as well as improved MCC, PVR, and voiding time. There were also improvements seen in incontinence and other lower urinary tract symptoms in the treated group. On a global assessment by the investigators, 71% of treated patients were improved on the 1-year follow-up study.
Other investigators have also successfully demonstrated a dose-dependent reduction in MUP with intravenous alfuzosin in 163 patients with NGB. Upper tract stasis on renal scan, presumably because of poor voiding in men with SCI of T6 and above who reflex-voided improved in 8 of 10 men started on α-blockers.
There is evidence that α-blockers are also effective in MS for help in bladder emptying. In a placebo-controlled RCT of 18 men with MS younger than 50 years with elevated PVR, indoramin, an α 1 -adrenergic blocker, improved flow by 41%. Seven-ninths of patients on the indoramin reported improvement in their symptoms and 4 had enough objective and subjective improvement to elect to continue the medication long-term.
α-Blocker therapy has also been shown to improve AD symptoms in SCI individuals. Prazosin was shown to be effective in a group of 16 symptomatic patients compared with placebo, but this drug is not currently used because of high systemic side effects. In prospective trials, terazosin, which is well tolerated in the SCI population, has been shown to reduce the frequency of AD episodes and the severity of the symptoms, with only minor side effects of fatigue and dizziness, and it did not cause changes in resting blood pressure or impact erectile function. In the aforementioned RCT of tamsulosin, Alzheimer disease symptoms were improved in those individuals with injuries above T6, with 44% becoming symptom-free.
The impact of α-blockers on bladder storage symptoms, including capacity, compliance, and detrusor pressure, has been less well evaluated. Some authors have reported no change in capacity or compliance with urapidil, an α-blocker available in Europe, but maximum detrusor pressures and bladder capacity have been improved in other studies on tamsulosin.
α-Blockers
α-Blockers are widely used for the treatment of benign prostatic hyperplasia (BPH), and they relieve the voiding symptoms and associated bladder storage symptoms of urgency, frequency, and nocturia. Their utility in NGB is often overlooked, despite their favorable side-effect profile, and there is evidence to support their use in the treatment of poor compliance, emptying difficulty, and autonomic dysreflexia (AD). α-Blockers are recommended as a possible treatment for NGB by the Clinical Practice Guidelines for the Paralyzed Veterans of America.
α 1 -adrenergic blockers that are currently used include alfuzosin, terazosin, doxazosin, and tamsulosin. The more commonly reported side effects of these medications are nasal congestion, abnormal ejaculation (especially with tamsulosin), and dizziness or postural hypotension that are more common with doxazosin and terazosin, which is why these 2 drugs require dose escalation.
There are significant basic science data to support α-blockers as a therapeutic option in NGB. There are three α 1 -adrenergic receptor (AR) subtypes in the human: α 1 a, α 1 b, and α 1 d. Based on human histochemical studies, it is well known that the prostate and trigone contain predominantly α 1 a-AR messenger (m)RNA and protein and that α 1 -AR–mediated smooth muscle contractions from sympathetic nervous system stimulation is the dynamic component of obstruction in BPH.
However, α 1 -ARs are not just present in the prostate. The human bladder dome and bladder base contain α 1 a receptors, but the urothelium only contains the mRNA encoding the receptor, not the expressed protein. In contrast to rats, a commonly used animal model of the bladder, only 2 types of α 1 -AR are present in the human detrusor muscle: α 1 a and α 1 d in a 2:1 proportion, whereas the rat has a 1:1:1 proportion of a, b, and d. Hence, one must interpret animal studies with caution, and human tissue studies need to be performed before any conclusions about receptor distribution or function can be drawn.
α 1 a-ARs are present in human arteries, and all 3 receptors are present in the spinal cord, with a predominance of α 1 d. It is plausible that these spinal receptors impact the bladder. In the bladder, the AR number increases significantly in the NGB when compared with the normal bladder.
Doxazosin has also been shown to play a sensory role in the bladder. Adenosine triphosphate (ATP) is released by the bladder urothelium when stretched, which in turn acts as a sensory neurotransmitter and binds to the suburothelial sensory nerve endings via P2X3 receptors. This action sends an afferent signal to the brain indicating fullness of the bladder. Bladders of those with interstitial cystitis and of those with BPH released significantly more ATP compared with normal controls. This increase in ATP release was eliminated with doxazosin, which may explain how it relieves irritative symptoms in these patients.
There are many articles on the study of phenoxybenzamine and prazosin, nonselective adrenergic blockers, with successful results in the treatment of NGB to facilitate bladder storage function. In none of these trials, however, was there improvement in the ability to empty the bladder. The high side-effect profile of both drugs and the theoretical risk of malignancy with long-term usage of phenoxybenzamine has limited their use. Newer, more selective α 1- blockers are safer choices, even in this population.
Voiding is not possible in many individuals with NGB, and treatment with α-blockers does not appear to change this state. However, in several studies of individuals with NGB who can spontaneously void with a residual volume, the newer α-blockers have been shown to be effective. In a study of 28 patients with DSD, American Urological Association symptom index, PVRs, and urodynamic urine flow all improved with 2 months of treatment with tamsulosin. In a study of 24 patients with NGB examined with urodynamics before and after 1 month of 0.4 mg tamsulosin, there were no changes in residual volume, but the maximum flow rate on free uroflow and the maximum detrusor pressure on urodynamics were improved after treatment.
In a 4-week randomized controlled trial (RCT) of 263 patients with suprasacral SCI followed by a 1-year open label study of placebo compared with tamsulosin, maximum urethral pressure (MUP), the primary outcome of the study, was not significantly different between groups at the 4-week mark. However, in the 186 patients who completed the 1-year open label study, there were significant improvements in MUP (−18 cm H2O) as well as improved MCC, PVR, and voiding time. There were also improvements seen in incontinence and other lower urinary tract symptoms in the treated group. On a global assessment by the investigators, 71% of treated patients were improved on the 1-year follow-up study.
Other investigators have also successfully demonstrated a dose-dependent reduction in MUP with intravenous alfuzosin in 163 patients with NGB. Upper tract stasis on renal scan, presumably because of poor voiding in men with SCI of T6 and above who reflex-voided improved in 8 of 10 men started on α-blockers.
There is evidence that α-blockers are also effective in MS for help in bladder emptying. In a placebo-controlled RCT of 18 men with MS younger than 50 years with elevated PVR, indoramin, an α 1 -adrenergic blocker, improved flow by 41%. Seven-ninths of patients on the indoramin reported improvement in their symptoms and 4 had enough objective and subjective improvement to elect to continue the medication long-term.
α-Blocker therapy has also been shown to improve AD symptoms in SCI individuals. Prazosin was shown to be effective in a group of 16 symptomatic patients compared with placebo, but this drug is not currently used because of high systemic side effects. In prospective trials, terazosin, which is well tolerated in the SCI population, has been shown to reduce the frequency of AD episodes and the severity of the symptoms, with only minor side effects of fatigue and dizziness, and it did not cause changes in resting blood pressure or impact erectile function. In the aforementioned RCT of tamsulosin, Alzheimer disease symptoms were improved in those individuals with injuries above T6, with 44% becoming symptom-free.
The impact of α-blockers on bladder storage symptoms, including capacity, compliance, and detrusor pressure, has been less well evaluated. Some authors have reported no change in capacity or compliance with urapidil, an α-blocker available in Europe, but maximum detrusor pressures and bladder capacity have been improved in other studies on tamsulosin.
Related posts:
Management Goals for the Spina Bifida Neurogenic Bladder: A Review from Infancy to Adulthood
Review of Neurologic Diseases for the Urologist
Spinal Cord/Brain Injury and the Neurogenic Bladder
The Neurogenic Bladder and Incontinent Urinary Diversion
Botulinum Toxin Therapy for Neurogenic Detrusor Overactivity
Urologic Complications of the Neurogenic Bladder
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