Overactive Bladder: Pharmacologic Treatments in the Neurogenic Population

Treatment Update

RIU0413_08-13.qxd 8/13/08 5:42 PM Page 182 TREATMENT UPDATE Overactive Bladder: Pharmacologic Treatments in the Neurogenic Population Michael J. Kennelly, MD, William B. DeVoe, BS McKay Department of Urology, Carolinas Medical Center, Charlotte, NC Patients with neurologic disease commonly develop overactive bladder (OAB) symptoms of urgency, frequency, and/or urge incontinence. Although treatment for idiopathic OAB has been extensively studied, therapy for those individuals with neurogenic-mediated OAB has not been thoroughly evaluated. Included in the present article is a description of micturition neurophysiology and a neurourologic evaluation scheme. The pharmacologic treatment options for neurogenic OAB, mainly antimuscarinics and chemical denervation, are reviewed and important studies are discussed. Management of OAB in the neurogenic population is a complex issue with no uniform treatment strategy, and individualized treatment with first-line pharmacologic therapy is often recommended. [Rev Urol. 2008;10(3):182-191] © 2008 MedReviews, LLC Key words: Overactive bladder • Detrusor overactivity • Neurogenic bladder any patients with underlying neurological disease often develop neurovesical voiding dysfunction and present clinically with overactive bladder (OAB) symptoms of urgency, frequency, and/or urge incontinence. These lower urinary tract symptoms in patients with a known neurologic condition are due to disturbances of the neurological control mechanisms and are often referred to as neurogenic overactive bladder. Given the prevalence of OAB and neurologic disease, primary care physicians and urologists frequently encounter patients with neurogenic-mediated OAB. A clinical understanding of micturition physiology and the mechanisms by which neurologic disease cause M 182 VOL. 10 NO. 3 2008 REVIEWS IN UROLOGY RIU0413_08-13.qxd 8/13/08 7:18 PM Page 183 Pharmacologic Treatments for Overactive Bladder OAB is important in the diagnosis and management of neurogenic OAB. In this article, we present an overview of micturition physiology, the evaluation of neurogenic OAB, and various management techniques. Emphasis is placed on the pharmacologic management of neurogenic OAB from currently available effective therapies. Neurophysiology of Micturition Lower urinary tract function involves central (supraspinal and spinal) and peripheral pathways (pelvic parasympathetic, lumbar sympathetic, and somatic pudendal nerve). The pontine micturition center (pons and periaqueductal grey matter of midbrain) is the organizational hub for the micturition executing reflex functions between the higher centers of the brain and the lower urinary tract.1,2 The basal ganglia, cerebellum, cerebral cortex, thalamus, and hypothalamus all have influence on the pontine micturition center. For example, both the basal ganglia and cerebellum have an inhibitory effect on spontaneous reflex bladder contraction, whereas the cortical pathways mediate voluntary control over micturition reflex.1,2 Peripheral innervation for the bladder involves the sympathetic, parasympathetic, and somatic nerves. The bladder receives sympathetic innervation via hypogastric nerves and parasympathetic innervation via pelvic nerves. Activation of sympathetic nerves from thoracolumbar spinal cord T12-L2 segments mediates detrusor muscle relaxation and bladder neck contraction, resulting in storage of urine.1,2 However, activation of the parasympathetic nerves originating from sacral cord S2-S4 segments results in detrusor contraction and promotes voiding. Axons of Onuf’s nucleus in the sacral cord segment (S2-S4) innervate the external urethral sphincter via the pudendal nerve.1,2 Volitional voiding can be achieved only with voluntary relaxation of the external urethral sphincter, allowing release of urine. Neurologic diseases can often damage the central or peripheral pathways that are involved in the central control of the lower urinary tract. To facilitate the discussion, neurologic disease can be categorized as supraspinal, spinal, peripheral, or mixed (Figure 1). Supraspinal refers to those neurologic diseases (Parkinson disease, cerebral palsy, etc) that occur above the pontine micturition center. In general, these diseases cause neurogenic detrusor overactivity with synergic normal voiding (detrusor contraction concurrent with voluntary relaxation of urethral and/or periurethral striated muscle). Spinal refers to those neurologic diseases (spinal cord injury, spinal stenosis, etc) that occur in the spinal cord. Suprasacral injuries often cause neurogenic detrusor overactivity with detrusor sphincter dyssynergia (detrusor contraction concurrent with an involuntary contraction of the urethral Figure 1. The central nervous system, spinal cord, and peripheral nervous system control of bladder function. PNS, parasympathetic nervous system; SNS, sympathetic nervous system. Parietal Lobe of Cerebral Cortex Frontal Lobe of Cerebral Cortex Cingulate Gyrus Hypothalamus Cardiovascular Accident Parkinson Disease Shy-Drager Syndrome Normal Pressure Hydrocephalus Cerebral Palsy Frontal Lobe Lesions Cerebral Trauma Dementia Cerebellum Multiple Sclerosis Cerebellar Ataxia Spinal Cord Injury Spinal Cord Infarction Tabes Dorsalis Pernicious Anemia Cervical Spondylosis Spinal Stenosis Spinal Arachnoiditis Intervertebral Disc Disease Poliomyelitis T10 T11 T12 L1 S2 S3 S4 SNS via Hypogastric Nerve PNS via Pelvic Nerve Diabetes Mellitus Herpes Zoster Pudendal Nerve External Sphincter VOL. 10 NO. 3 2008 REVIEWS IN UROLOGY 183 RIU0413_08-13.qxd 8/13/08 5:42 PM Page 184 Pharmacologic Treatments for Overactive Bladder continued and/or periurethral striated muscle). In addition to neurogenic OAB, patients with detrusor sphincter dyssynergia are at high risk for other urologic complications, including hydronephrosis, vesicourethral reflux, urosepsis, and urolithiasis.3 Consequently, proper neurological evaluation and management of these patients is imperative. Sacral spinal cord lesions (spina bifida, myelodysplasia) and peripheral neurologic diseases (diabetes mellitus, herpes zoster) generally cause an acontractile detrusor. In these lesions, a patient’s perianal sensation, sphincter tone, and bulbocavernous reflex may become diminished in response to a loss of pudendal nerve innervation. It should be noted that many exceptions to the above categorization exist due to either the partial peripheral or combined (peripheral/central) nature of neurologic lesions. Consequently, proper neurourologic evaluation is necessary. Neurourologic Evaluation All patients with neurourologic disease affecting vesicourethral dysfunction require a neurourological evaluation (Table 1). Neurologic disease and lower urinary tract dysfunction are not necessarily causally related. Moreover, urologic abnormalities such as stress urinary incontinence, benign prostatic hyperplasia, or urinary tract infection can commonly coexist with the neurologic disease or may be the underlying cause of OAB and incontinence. Other than the sensory and motor dermatome examinations, the neurologic examination should be focused upon reflex activity present within the S2-S4 spinal cord segments. Anal tone, perianal sensation, bulbocavernous reflex, and voluntary anal control indicate reflex activity in the S2-S4 spinal cord region. Urodynamic evaluation is essential in assessing neurogenic OAB and incontinence because it can determine 184 VOL. 10 NO. 3 2008 Table 1 Evaluation of Overactive Bladder in Patients With Neurologic Disease History and physical examination Neurologic examination Urinalysis with or without urine culture Renal function study (serum creatinine) Table 2 Overactive Bladder Management in Neurologic Disease Neurogenic Detrusor Overactivity Antimuscarinics with/without intermittent catheterization Behavioral therapy and biofeedback Electrical stimulation Endoscopic examination (as indicated) Chemical denervation procedure Capsaicin Resiniferatoxin Botulinum toxin Urodynamic testing Augmentation cystoplasty Computed tomography urogram or renal ultrasound (as indicated) Uroflow External catheter (men) Postvoid residual volume Indwelling Foley catheter Cystometrogram with or without electromyogram Neurogenic Detrusor Overactivity With Detrusor External Sphincter Dyssynergia Treatment of hyperreflexia (first 5 items above) and intermittent catheterization Pressure-flow (micturition) study Videourodynamic study (multichannel with fluoroscopy) External sphincterotomy (men) the underlying neurologic abnormality, categorize the vesicourethral dysfunction, and provide a basis for appropriate therapy (Table 2). The choice of therapy is based on many factors (eg, prognosis of underlying disease, mental status, motivation, age, educability, mobility) and should be tailored to the individual patient. A conservative management scheme begins with simple reversible (medical) therapy before proceeding to irreversible (surgical) therapy. Due to the many complexities of the neurological diseases and individual variability, no single treatment for neurogenic OAB exists. Often several treatments are tested and modified in order to meet the patient’s desired therapeutic goal. Although many goals exist in managing neurovesical dysfunction, the main management goal in treating neurogenic OAB is preservation of upper urinary tract function and improvement of the patient’s troubling urinary symptoms (Table 3). REVIEWS IN UROLOGY Urinary diversion Indwelling Foley catheter Detrusor Areflexia Intermittent catheterization Urinary diversion Credé void (women) Indwelling Foley catheter Table 3 Goals of Overactive Bladder Management Preservation of upper urinary tract Maintain adequate bladder capacity with good compliance Promote low-pressure micturition Avoid bladder overdistension Prevent urinary tract infection Minimize use of Foley catheter Choose therapy that minimizes patient risks while maximizing social, emotional, and vocational acceptability RIU0413_08-13.qxd 8/13/08 5:42 PM Page 185 Pharmacologic Treatments for Overactive Bladder Pharmacotherapy for Neurogenic OAB Antimuscarinics Currently, antimuscarinic agents are the first-line choice for the pharmacologic treatment of OAB. The rationale for treating OAB with antimuscarinic agents is based on the fact that detrusor contractions are primarily mediated via muscarinic receptors, specifically subtype M2 and M3.4 Although the role of M3 receptors in fewer anticholinergic side effects, such as dry mouth.6 More recently, several new once-daily-dosing drugs, trospium chloride (Sanctura XR™, Indevus Pharmaceuticals, Inc., Lexington, MA), darifenacin (Enablex®, Novartis Pharmaceuticals Corporation, East Hanover, NJ), and solifenacin succinate (VESIcare®, Astellas Pharma US, Inc., Deerfield, IL) have also shown impressive clinical improvements in idiopathic OAB symptoms with poten- Oxybutynin is an anticholinergic agent that has antimuscarinic, antispasmodic, and potential local anesthetic effects. normal bladder is well established, evidence suggests there are some pathologic states, such as neurogenic bladder, wherein M2 receptors may become more important in bladder contractility than in healthy individuals.5 The release of acetylcholine from cholinergic nerves stimulates muscarinic receptors on detrusor smooth muscle. By blocking the binding of acetylcholine to detrusor muscarinic receptors, antimuscarinic agents stabilize the detrusor, making it relatively refractory to the stimulation via parasympathetic neural impulses. Through this mechanism, antimuscarinic therapy increases bladder capacity and delays the initial urge to void, thereby reducing the symptoms of OAB. Pharmacotherapy, most often with an antimuscarinic agent, is an established approach to managing neurogenicmediated OAB (Table 4). Oxybutynin chloride (Ditropan®, sanofi-aventis U.S. LLC, Bridgewater, NJ) has seen widespread clinical use since 1975 and has been most extensively studied by clinicians. In 1996, a second anticholinergic, tolterodine tartrate (Detrol®, Pfizer Inc, New York, NY), was introduced as an alternative to oxybutynin. Tolterodine demonstrated equal efficacy as oxybutynin but with tially fewer side effects. Antimuscarinic agents, particularly the older ones, are associated with typical anticholinergic side effects that may limit treatment. These side effects may include dry mouth, gastrointestinal effects such as constipation, and central nervous system effects. The currently available antimuscarinic agents (Table 4) have been extensively investigated in patients presenting with idiopathic OAB; however, the volume of studies examining the agents’ effects on neurogenic OAB is scant. In fact, only 4 antimuscarinic drugs (oxybutynin, trospium chloride, tolterodine, and darifenacin) have documented results on treating OAB in neurogenic populations. The following is a summary of significant studies on pharmacological treatment of neurogenic OAB. Oxybutynin Oxybutynin is an anticholinergic agent that has antimuscarinic, antispasmodic, and potential local anesthetic effects. It is available in immediate-release (Ditropan®), extended-release (Ditropan XL®), and transdermal (Oxytrol®, Watson Pharmaceuticals, Inc., Morristown, NJ) applications. A 2007 study by Stöhrer and colleagues7 found immediaterelease (IR) oxybutynin increased maximum cystometric capacity from 164 to 298 mL and decreased maximum detrusor pressure from 68.6 to 43.1 cm H2O in patients with Table 4 Antimuscarinic Agents Medication Brand Name Dosage Oxybutynin Ditropan® 2.5-5 mg/2-4 times per day Oxybutynin extended release Ditropan XL® 5-30 mg once daily Oxybutynin extended-release transdermal patch Oxytrol® 3.9 mg per day system applied twice weekly (every 3-4 days) Tolterodine Detrol® 1-2 mg twice daily Tolterodine extended release Detrol LA® 2-4 mg once daily Darifenacin Enablex® 7.5-15 mg once daily Solifenacin VESIcare® 5-10 mg once daily Trospium chloride Sanctura® 20 mg twice daily Trospium chloride extended release Sanctura XR® 60 mg once daily VOL. 10 NO. 3 2008 REVIEWS IN UROLOGY 185 RIU0413_08-13.qxd 8/13/08 7:18 PM Page 186 Pharmacologic Treatments for Overactive Bladder continued neurogenic detrusor overactivity. The most common side effect, dry mouth, was reported in 67.2% of patients who were managed with oxybutynin IR. Extended-release oxybutynin (oxybutynin XL) has been shown to alleviate some of the dry mouth seen with immediate-release oxybutynin and is therefore more commonly used in practice. O’Leary and colleagues8 evaluated oxybutynin XL in 10 pa- investigated transdermal delivery of oxybutynin through a multicenter, 8week study. In 22 patients with spinal cord injury and neurogenic OAB, maximum cystometric capacity increased from 247 to 395 mL, reflex volume increased from 190 to 249 mL, and maximum detrusor pressure declined from 61.2 to 37.8 cm H2O after administration of oxybutyninTDS. The maximum dose of 11.7 mg Oxybutynin transdermal system offers several advantages over oral administration, most importantly less frequent dosing (twice weekly) and lower incidence or severity of anticholinergic side effects. tients with OAB secondary to spinal cord injury. Although postvoid residual urine increased in those treated with oxybutynin XL (25 to 51 mL), cystometric bladder capacity increased from 274 to 380 mL and incontinence episodes dropped from 13 to 6 per week.8 There were no adverse effects reported in the trial despite the fact that all patients opted for dosage above 10 mg and 40% chose the maximum 30-mg daily dose of oxybutynin XL. A follow-up study evaluating oxybutynin XL in a mixed neurogenic population (spinal cord injury, multiple sclerosis, and parkinsonism) confirmed the improvement in urodynamic parameters seen previously.9 Of the 39 patients studied, 29 (74.4%) requested higher doses (15-30 mg) than were considered standard dosing. The authors concluded that administration of up to 30 mg per day of oxybutynin XL was both efficacious and safe in neurogenic patients. Oxybutynin can be administered in a patch via the oxybutynin transdermal system (oxybutynin-TDS). Oxybutynin-TDS offers several advantages over oral administration, most importantly less frequent dosing (twice weekly) and lower incidence or severity of anticholinergic side effects. In 2007, Kennelly and coworkers10 186 VOL. 10 NO. 3 2008 per day was found to be well tolerated by patients while improving continence. The most common treatment-related adverse events were application site reactions (3/24 patients; 12.5%) and dry mouth (2/24 patients; 8.3%). The 2 patients who experienced dry mouth were on the lower 3.9 and 7.8 mg per day dose level. All 20 patients on the higher 9.1 and 11.7 mg per day dose level completed the study and did not experience any anticholinergic side effects of dry mouth or constipation. Unlike oral oxybutynin and other titratable an- Oxybutynin may also be delivered via intravesical instillation. The antimuscarinic effect of oxybutynin is comparable to oral administration, but the severity and frequency of side effects is lower. When instilled intravesically, a dose of 5 mg of oxybutynin dissolved in 10 to 30 mL of saline is recommended in adults.14 In adult populations, Lehtoranta and colleagues15 showed a 55% to 90% clinical improvement in symptoms caused by neurogenic detrusor overactivity when treated with intravesical oxybutynin. In particular, voiding episodes decreased from 6.9 to 5.7 episodes per day. Although notable side effects were not observed in adults, treatment of children with oxybutynin intravesical instillations may produce central nervous system– related side effects. In 2001, Ferrara and associates16 noted hallucinations and cognitive changes in 6 of the 34 children with spina bifida who received intravesical oxybutynin therapy at a mean dose of 0.1 to 0.2 mg/kg. Consequently, it is held that oxybutynin should be administered intravesically in those patients who have either failed with other antimuscarinic treatment modalities (such as Both immediate- and extended-release forms of tolterodine are available, but the latter is preferred by both clinicians and patients because of its diminished side-effect profile. timuscarinics, it appears that dose titration of oxybutynin-TDS does not increase the anticholinergic sideeffects profile. All other titratable oral anitmuscarinics (oxybutynin ER, solifenacin, and darifenacin) have higher dry mouth rates and constipation rates at higher doses (dry mouth: 29% oxybutynin ER 10 mg, 61% oxybutynin ER 30 mg; 10.9% solifenacin 5 mg, 27.6% solifenacin 10 mg; and 20.2% darifenacin 7.5 mg, 35.3% darifenacin 15 mg).11-13 REVIEWS IN UROLOGY oral) or who have unbearable side effects from them. Tolterodine Tolterodine is another competitive muscarinic receptor antagonist approved for clinical use in the 1990s. Similar to oxybutynin, the value of tolterodine use in neurogenic detrusor overactivity has been evaluated by a limited number of studies. Both immediate- and extended-release forms of tolterodine are available, but RIU0413_08-14.qxd 8/14/08 9:56 AM Page 187 Pharmacologic Treatments for Overactive Bladder the latter is preferred by both clinicians and patients because of its diminished side-effect profile. In 2004, Ethans and coworkers17 investigated a group of 14 patients with various neurologic diseases associated with neurogenic detrusor overactivity. When administered at 4 mg per day, patients experienced an improvement in incontinent events (2.8 to 1.0 per day) with tolterodine despite an insignificant change in cystometric bladder capacity. Tolterodine, however, was associated with less dry mouth when compared with oxybutynin (4.4 oxybutynin vs 2.6 tolterodine on visual analog scale). The authors recommended investigation into higher doses of tolterodine for neurogenic OAB therapy. A double daily dosage of tolterodine extended release (ER) (8 mg) in a cohort of patients with spinal cord injury, the urodynamic effects of trospium chloride on 61 patients with spinal cord injury and neurogenic detrusor overactivity. When given twice daily at 20 mg, trospium chloride improved maximum cystometric capacity by an average of 138 mL and maximum detrusor pressure by 37.8 cm H2O. Patients treated with trospium chloride reported a comparable side-effect profile to those treated with placebo and both residual urine volume and maximum flow rate were unaffected. A double daily dosage of trospium chloride (90 mg) in a mixed neurogenic patient population was performed in those individuals who had experienced little amelioration from standard trospium chloride dosing.18 Treatment with double-dose trospium chloride yielded improvements in reflex volume (177 to 314 mL), cystometric capacity (271 to 430 mL), and Darifenacin, approved in 2004 for the treatment of OAB, is another enticing option when treating patients with neurogenic OAB. multiple sclerosis, or meningomyelocele was performed in those individuals who had experienced little help from the standard dosing of tolterodine ER.18 Maximum detrusor pressure (54 to 43 cm H2O), reflex volume (225 to 350 mL), and cystometric capacity (308 to 408 mL) all improved after tolterodine ER therapy in the 11 patients evaluated. No patients voluntarily withdrew from the study due to adverse effects, and only 1 patient experienced significant dry mouth. Doubling the recommended daily dose of tolterodine was determined to be effective therapy for neurogenic OAB. Trospium Chloride Trospium chloride, an antimuscarinic agent and smooth muscle relaxant, is also a promising anticholinergeric for neurogenic bladder management. In 1991, Stöhrer and colleagues19 studied detrusor pressure (66 to 51 cm H2O) when normal dosing was compared with double dosing (45 to 90 mg/d). Of the 10 patients included in the study, 1 discontinued trospium chloride use because of intolerable side effects and 2 experienced mild dry mouth. Although larger studies are warranted, Horstmann and colleagues considered 90 mg per day trospium chloride dosing to be safe and effective for managing neurogenic-mediated OAB. The feasibility of increasing trospium chloride dosage even higher above 90 mg per day was investigated by Menarini and associates in 2006.20 Eighty patients were treated over a 3to 5-week interval with a range of trospium chloride concentrations (45-135 mg/d). It was concluded that patients who are generally unresponsive to the standard dosage can be safely treated with up to a triple dose (135 mg) of trospium chloride per day. There was equivalent reported dry mouth rates between those patients treated with increased doses of trospium chloride (35% dry mouth) and standard doses (37% dry mouth) and no person discontinued treatment due to intolerable anticholinergic side effects. Darifenacin Darifenacin, approved in 2004 for the treatment of OAB, is another enticing option when treating patients with neurogenic OAB. The drug has been evaluated in individuals with neurogenic OAB secondary to multiple sclerosis for which a 15-mg dose of darifenacin decreased incontinence episodes (11.1 drug vs 8.0/wk placebo), frequency of micturition (1.2 drug vs 0.8/d placebo), number of episodes of urgency (1.5 drug vs 0.7/d placebo), and bladder capacity (31.6 drug vs 0.8 mL placebo).21 There was no difference in side effects or adverse events for treatment with darifenacin in idiopathic or neurogenic OAB patients. In another study of 38 patients with multiple sclerosis treated daily with 15 mg of darifenacin, urinary continence was achieved in 82% of patients who originally suffered from detrusor overactivity.22 Additionally, bladder compliance improved from 13 to 21 mL/cm H2O and median bladder capacity increased from 225 to 370 mL. Carl and Laschke22 supported the use of darifenacin in patients with multiple sclerosis as it suppressed urgency without complete prevention of bladder emptying or an increase in postvoid residual urine volume. Intravenous administration of darifenacin was conducted in a sample of 8 patients with spinal cord injury.23 Similar to its successful results in patients with detrusor overactivity secondary to multiple sclerosis, detrusor pressure was seen to be diminished at both 30-minute and 90-minute VOL. 10 NO. 3 2008 REVIEWS IN UROLOGY 187 RIU0413_08-14.qxd 8/14/08 9:56 AM Page 188 Pharmacologic Treatments for Overactive Bladder continued intervals after darifenacin therapy (6-mg intravenous dose). Following intravenous darifenacin, detrusor pressure was approximately 50% of that originally in both 30- and 90minute posttreatment intervals. Combination Antimuscarinic Agent Therapy A 2008 study by Amend and colleagues24 probed the question of whether a combination of antimuscarinic agents outperforms monotherapy. Of the 27 patients included, 21 Chemical Denervation Chemical denervation is an experimental alternative approach to the management of neurogenic OAB. Although not currently approved for clinical practice, intravesical application of several neurotoxic agents has returned promising results. These include capsaicin, resiniferatoxin, and botulinum toxin. Capsaicin An early application of chemical denervation for treatment of neurogenic detrusor overactivity was with the Although not currently approved for clinical practice, intravesical application of several neurotoxic agents has returned promising results. had spinal cord injury, 3 had spinal cord dysplasia, 2 had multiple sclerosis, and 1 had viral encephalomyelitis. Patients who had previously been treated with double-dose antimuscarinic monotherapy were divided into 3 combination treatment groups: (1) first tolterodine (8 mg), second oxybutynin (15-30 mg); (2) first trospium chloride (90 mg), second tolterodine (4-8 mg); and (3) first oxybutynin (30 mg), second trospium chloride (45-90 mg). After 4 weeks of combination therapy, incontinence events diminished from 7 to 1 events per day, detrusor compliance improved from 15 to 33 mL/cm H2O, bladder capacity increased from 180 to 393 mL, and reflex volume increased from 125 to 335 mL. Improvements were noted in 85% of patients treated by combination therapy. Five of 27 patients experienced only mild anticholingeric side effects; however, 20 patients discontinued treatment due to dry mouth and blurred vision. A combination of antimuscarinic agents was thus concluded to be an effective treatment strategy in patients who have failed with double-dose anticholinergeric monotherapy. 188 VOL. 10 NO. 3 2008 neurotoxin capsaicin. Intravesical delivery of capsaicin produces a neurotoxic effect on the C-fiber afferents that mediate reflex detrusor muscle contractions.25 The efficacy of capsaicin has been shown in individuals with multiple sclerosis and spinal cord injury. In 1994, Fowler and colleagues26 found that capsaicin instillations produced a decrease in neurogenic OAB symptoms for 3 weeks to 6 months. treatment lasted approximately 3 to 5 years in their series. The experimental results of intravesical capsaicin denervation are promising for treating detrusor overactivity but it still remains experimental. Research into capsaicin and capsaicinoids in general unearthed a more potent toxin, resiniferatoxin, which has emerged as a more impressive denervating treatment alternative. Resiniferatoxin Resiniferatoxin (RTX) is 1000 times more potent than its capsacinoid relative, capsaicin.28 Similar to capsaicin, RTX has a neurotoxic effect on the afferent fibers that, in turn, moderates reflex detrusor contractions. In contrast to capsaicin, RTX is associated with less patient discomfort because it has a diminished effect on neuronal excitation.28 The efficacy of RTX was demonstrated in 2002 by Giannantoni and colleagues29 in patients with neuropathic bladder secondary to spinal cord injury. RTX was shown to improve urodynamic parameters in patients with neurogenic bladder when compared with capsaicin. The detrusor contraction threshold was raised from Research into capsaicin and capsaicinoids in general unearthed a more potent toxin, resiniferatoxin, which has emerged as a more impressive denervating treatment alternative. Peak bladder capacity increased from 106 to 302 mL and maximum detrusor pressure decreased from 54 to 36 cm H2O with intravesical capsaicin delivery. In 1997, De Ridder and colleagues27 corroborated these favorable results with capsaicin while studying a group of patients with neurogenic OAB caused by multiple sclerosis.24 Similar urodynamic benefits were obtained and the effect of treatment was shown to last from 3 to 6 months. Additionally, the effectiveness of capsaicin REVIEWS IN UROLOGY 176 to 275 mL and maximum bladder capacity from 196 to 357 mL 60 days after intravesical RTX injection. RTX therefore exhibited better clinical improvement of symptoms without the side effects seen with capsaicin treatment, such as pain and autonomic dysreflexia. The effect of RTX seemed to be slightly less in patients with spinal cord lesions studied by Kuo in 2003.30 In this cohort of 20 patients treated with 10 µM resiniferatoxin instillations, the maximum cystometric RIU0413_08-13.qxd 8/13/08 5:42 PM Page 189 Pharmacologic Treatments for Overactive Bladder capacity increased from 102.1 to 236.6 mL. Although 67% of those treated with RTX were reported to exhibit a clinical effect, detrusor pressure (55.9 to 47.5 cm H2O) and detrusor sphincter dyssynergy were noticeably unchanged. Botulinum Toxin Botulinum neurotoxin (BTX) is produced anaerobically by a species of bacteria called Clostridium botulinum, (BTX-A and BTX-B) are commercially available; however, the majority of clinical research in neurogenic OAB has been with BTX-A. Evidence for the success of BTX-A (Botox®, Allergan, Inc., Irvine, CA) in the treatment of neurogenic urinary incontinence has been shown by Schurch and colleagues.32,33 Detrusor BTX-A injections of 200 U to 300 U across 20 to 30 injection sites have been effective in restoring continence Detrusor botulinum neurotoxin A injections have been effective in restoring continence and reducing or eliminating antimuscarinic medication usage in neurogenic bladder patients. and is 1 of the most potent neurotoxins known. BTX temporarily inhibits acetylcholine release at the presynaptic cholinergic junction, thereby resulting in decreased muscle contractility where the neurotoxin was injected.31 In skeletal muscle, this effect usually lasts 3 to 4 months due to resprouting of regenerated axons. There are 7 types of BTX (A, B, C, D, E, F, and G), each with different properties and actions. Two BTX subtypes and reducing or eliminating antimuscarinic medication usage in neurogenic bladder patients. In 1 study, 17 of 19 (90%) patients had restored continence within 6 weeks.33 In reviewing the literature, over 900 neurogenic OAB patients have now been treated with BTX-A injections at doses ranging from 200 U to 300 U. Dissimilar to skeletal muscle injections, the treatment benefit from BTX-A in detrusor smooth muscle lasts 6 to 12 months with a minimal side-effect profile.34 A very rare side effect of detrusor BTX injections is transient general muscle weakness lasting 2 to 4 weeks.35,36 Potential risk factors for hyposthenia were speculated to be high drug concentration or higher level of spinal cord injury. In 2005, Schurch and colleagues37 began phase II studies to determine the efficacy and safety of BTX-A injections. A total of 59 patients with neurogenic urinary incontinence received BTX-A injection of 200 or 300 U and were followed over a 24week interval. Urinary incontinence episodes were reduced by an average of 50%, with 49.2% of patients reporting no incontinence episodes during at least 1 1-week posttreatment period. Urodynamic parameters, also indicative of efficacy, supported the effectiveness of BTX-A. At the conclusion of the 24-week study, maximum cystometric bladder capacity was significantly improved with both the 200 and 300 U BTX-A compared with placebo (200 U BTX-A, 398.2 mL; 300 U BTX-A, 440.9 mL; placebo, 301.0 mL), as was maximum detrusor pressure (200 U BTX-A, 55.2 cm H2O; Main Points • Neurologic diseases can often damage the central or peripheral pathways that are involved in the central control of the lower urinary tract. • Urodynamic evaluation is essential in assessing neurogenic overactive bladder (OAB) and incontinence because it can determine the underlying neurologic abnormality, categorize the vesicourethral dysfunction, and provide a basis for appropriate therapy. • The rationale for treating OAB with antimuscarinic agents is based on the fact that detrusor contractions are primarily mediated via muscarinic receptors, specifically subtype M2 and M3. • Evidence suggests there are some pathologic states, such as neurogenic bladder, wherein M2 receptors may become more important in bladder contractility than in healthy individuals. • Only 4 antimuscarinic drugs (oxybutynin, trospium chloride, tolterodine, and darifenacin) have documented results on treating OAB in neurogenic populations. • A combination of antimuscarinic agents was concluded to be an effective treatment strategy in patients who have failed with double-dose anticholinergeric monotherapy. • Chemical denervation is an experimental alternative approach to the management of neurogenic OAB. VOL. 10 NO. 3 2008 REVIEWS IN UROLOGY 189 RIU0413_08-13.qxd 8/13/08 5:42 PM Page 190 Pharmacologic Treatments for Overactive Bladder continued 300 U BTX-A, 48.8 cm H2O; placebo, 80.6 cm H2O). There were no treatment-related adverse events reported in any patients. In 2006, Schurch and colleagues38 evaluated the efficacy and safety of repeated BTX injections in 17 patients with neurogenic detrusor overactivity. An average of 5.4 injections was administered to the participants and an immediate and long-term effect was observed as incontinence episodes dropped from 2.6 per day to 0 per day after the first and last dose. Maximum cystometric capacity increased from 348.8 mL preinjection to 499.1 and 461.5 mL after the first and last BTX injections, respectively. Reflex volume also improved by 145.3 mL after the first injection and 175.5 mL after the final injection. Likewise, detrusor pressure fell from 75.5 cm H2O preinjection to 28.8 and 27.4 cm H2O after the first and final BTX-A injections. Repeated injections of BTX-A in patients with neurogenic OAB were therefore concluded to maintain effectiveness while not augmenting side effects. tools to treat OAB in the neurogenic population. 18. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Conclusions As in the able-bodied population, pharmacotherapy is an established approach to managing OAB in neurogenic populations. Antimuscarinic agents are the first-line choice for pharmacologic treatment of neurogenic OAB. Antimuscarinic therapy increases bladder capacity and delays the initial urge to void. Unlike idiopathic OAB, higher-than-recommended doses of antimuscarinic agents are often needed to achieve the patient’s therapeutic goals. Newer chemical denervation therapy, such as BTX, seems very promising in treating neurogenic OAB. 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