Managing the patient with “overactive bladder” or “neurogenic bladder” can often pose problems for the treating physician. When dealing with these conditions, it is first important to clarify the terminology. “Overactive bladder” is a complex of symptoms (urinary urgency, frequency, and urge incontinence) resulting from detrusor muscle instability and is idiopathic in origin. The symptoms of overactive bladder tend to adversely affect the patient's quality of life, but typically they do not cause progressive bladder deterioration or subsequent renal failure due to a high intravesical pressure. In contrast, a “neurogenic bladder” results from detrusor hyperreflexia secondary to known neurologic disease. The symptoms of an overactive bladder and neurogenic bladder may be quite similar; however, the neurogenic bladder frequently results in progressive deterioration of the bladder function due to the progressive nature of the underlying neurologic disease process. Subsequently, without aggressive intervention a neurogenic bladder can compromise a patient's renal function. In general, the goal of managing an overactive bladder is to improve a patient's symptoms and thus improve quality of life, whereas the goal of managing a neurogenic bladder is to preserve renal function.
Because the underlying etiology of the neurogenic bladder is complex, and inaccurate or incomplete treatment may result in severe complications, the physician must have good working knowledge of the latest developments to treat patients with neurogenic bladder. Success of therapy can be difficult to quantify because of the frequent irreversibility or progressive nature of the underlying neuropathic disorder causing the bladder dysfunction. Successful treatment, therefore, should be judged not only on improvement or stabilization of the patient's symptoms and complaints but also on control or reduction of the neurogenic bladder's effect on renal function. Specifically, in patients with longstanding, untreated bladder dysfunction, the kidneys may be injured by persistently elevated intravesical pressures that are subsequently transmitted to the renal parenchyma.
Consideration of the overactive bladder and the neurogenic bladder may be divided into 2 basic categories: bladders that fail to successfully empty and those that fail to adequately store urine. Not infrequently, a patient with an overactive bladder may also have impaired bladder contractility resulting in a difficult combination of problems. Not only does the patient have an overactive detrusor muscle, but also the detrusor's contraction may be weak and subsequently the patient cannot empty the bladder sufficiently. Therapy should be based on these categories since a standard treatment prescribed for the wrong bladder condition may lead to “treatment failure.” The diagnosis of the neurologic disorder and the thorough evaluation of the bladder and upper urinary tract function are beyond the scope of this editorial. However, the accuracy of these assessments cannot be underestimated.
Anticholinergic therapy remains a cornerstone for treatment of overactive and neurogenic bladders that fail to store properly. Oral medications such as hyoscyamine, flavoxate, and oxybutynin have been used extensively, with oxybutynin being one of the most widely used. One of the main motivations for developing new products to compete with oxybutynin has been its adverse effects, most notably dry mouth and constipation. Two oral agents have been introduced in the US market: tolterodine tartrate (Detrol) and an extended-release form of oxybutynin chloride (Ditropan XL). Also newly introduced to the market is Detrol LA (once-daily dosing). However, due to its newness, no comparative data are available.
In vitro studies have demonstrated that tolterodine has similar affinity for muscarinic receptors in the bladder as oxybutynin but has 8 times less affinity for the muscarinic receptors in the salivary gland.
1
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Subsequently, in a randomized, double-blind, placebo-controlled study by Abrams et al,4
293 patients with urodynamically confirmed bladder hyperactivity received tolterodine, 2 mg orally twice a day, immediate-release oxybutynin, 5 mg orally 3 times a day, or a placebo. After 12 weeks, both active-drug groups demonstrated statistically significant decreases in mean frequency of micturition-21% for tolterodine and 19% for oxybutynin-vs 10% decrease in the placebo group. Also noted was a similar decrease in mean incontinence episodes in both active-drug groups. Most notably, the incidence of moderate to severe dry mouth was 14% in patients receiving tolterodine vs 51% in patients receiving oxybutynin. The authors concluded that tolterodine, 2 mg twice a day, was as effective as oxybutynin in treating bladder instability and that there was a statistically significant decrease in the incidence of adverse effects with tolterodine. This important decrease in adverse effects theoretically allows more patients to continue to take effective anticholinergic therapy.4
The second newly introduced agent is an extended-release, once-daily form of oxybutynin. It has the same antimuscarinic and smooth muscle relaxant activity as does the immediate-release form; however, the extended-release form has the added benefit of decreased incidence of adverse effects, most notably decreased frequency of moderate to severe dry mouth from 46% with use of the immediate-release form to 25% with use of the extended-release form.
5
The results of the study by Anderson et al5
demonstrated that, with the extended-release form, the adverse effects of oxybutynin could be decreased by delivering a relatively constant concentration of oxybutynin throughout the day, thereby eliminating the peak blood concentrations seen with the immediate-release form (which are believed to be responsible for the adverse effects). Individuals who took the extended-release form had similar reductions in urge incontinence and total incontinence compared with those taking the immediate-release form.5
In a similar study, Gittleman et al6
demonstrated similar results and also noted a decrease in urinary frequency by 14.7% after patients took extended-release oxybutynin.The ever-increasing number of patients with overactive bladder symptoms has stimulated the market for effective treatment options. Prior to the study by Appell et al
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in this issue of Proceedings, no direct comparison of the 2 most commonly prescribed medications, tolterodine and oxybutynin, had been done. Appell and colleagues reported a mean decrease in urge incontinence of 19.5 and 16.3 episodes per week with extended-release oxybutynin and immediate-release tolterodine, respectively, and urinary frequency decreased by means of 24.7 and 20.1 episodes per week, respectively. These results are encouraging and demonstrate progress toward lessening the problem of bladder dysfunction. However, “perfect” treatment options for patients with overactive and neurogenic bladder have yet to be found, as evidenced by the similar dropout rates in both drug groups due to adverse events or intercurrent illness. Among the more exciting alternative treatments under investigation is delivery of the medications not orally but intravesically. Currently, intravesical medications are experimental and reserved for patients with proven neurologic disease processes such as spinal cord injury.8
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However, with time and further study, these medications may become available for the much larger group of patients with idiopathic overactive bladder.Capsaicin and resiniferatoxin are 2 promising intravesical agents used to treat detrusor hyperreflexia of the neurogenic bladder.
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Capsaicin is the primary active ingredient in chili peppers and is a potent neurotoxin that desensitizes the bladder's afferent C fibers when it is instilled intravesically.8
In experimental studies with neurologically intact patients, reflex voiding was initiated normally via myelinated A delta bladder afferent fibers (which are resistant to capsaicin).9
However, in patients with spinal cord injuries, the voiding reflex was initiated via a different short-latency pathway.10
Voiding appears to involve stimulation of the capsaicin-sensitive unmyelinated C fiber afferents.10
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Stimulation of the C fibers appears to be responsible for triggering detrusor hyperreflexia.8
The clinical importance of the capsaicin-sensitive C fibers was first reported by Fowler et al12
in 1994 and subsequently has been validated by multiple other studies.8
, 13
, 14
In a total of 131 patients, these studies demonstrated that intravesical instillation of capsaicin caused symptomatic and urodynamic improvement in 60% to 100% of patients, and the duration of beneficial effect ranged from 1 month to 9 months without systemic toxic effects.13
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Certain limitations of capsaicin use may be responsible for its failure to achieve widespread use to date. With initial capsaicin instillation, the neuronal excitation phase of the primary afferent neurons occurs, which is responsible for temporary acute pain and deterioration of bladder function. These adverse effects are believed to be due to the release of various neuropeptides, and with the depletion of these peptides, the acute pain and hyperactive bladder function resolve.
8
Because of the adverse effects noted with capsaicin, recent interest has been focused on the use of resiniferatoxin, an ultrapotent, capsaicin-like substance, to treat neurogenic bladder.12
Resiniferatoxin is a naturally occurring agent from plants of the species Euphorbia resinifera. The bioactivity level of resiniferatoxin is approximately 1000 times more potent than capsaicin, but the substance has the important benefit of minimal initial excitation, which has been a problem with capsaicin.8
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In a recent multicenter, randomized, double-blind, and placebocontrolled study coordinated by Rivas et al,19
20 neurologically impaired patients with urodynamically proven detrusor hyperreflexia were treated with sequentially increasing intravesical doses of resiniferatoxin and evaluated for changes in bladder capacity and discomfort associated with treatment. The study concluded that with progressive increases in the intravesical dose (0.005, 0.025, and 0.10 μg), the bladder capacity after instillation increased by 42%, 136%, and 150%, respectively. Incontinence was improved in 8 (61.5%) of 13 patients. Most importantly, bladder discomfort was well tolerated and did not appear to be dose related. Based on initial studies, it appears resiniferatoxin has more potential than capsaicin, and with more investigation, it may become a mainstay for the treatment of detrusor hyperreflexia.8
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As the population ages, the problem of management of the overactive bladder is clearly increasing. More physicians are seeing more patients with this condition. Even though an overactive bladder is not life threatening, it nonetheless decreases the quality of life for many patients. The medical dollars spent on this problem are increasing. Therefore, it is imperative for physicians to remain current on the latest advances in this field and to prescribe wisely so that their patients receive the most effective and cost-effective medication with the least adverse effects for this troublesome medical condition.
REFERENCES
- Effect of tolterodine on electrically induced contractions of isolated human detrusor muscle from stable and unstable bladders.Neurourol Urodyn. 1995; 14: 524-526
- Interaction of tolterodine with cholinergic muscarinic receptors in human detrusor.Neurourol Urodyn. 1995; 14: 523-524
- The in vitro pharmacological profile of tolterodine—a new agent for the treatment of urinary urge incontinence [abstract].Neurourol Urodyn. 1994; 13 (Abstract 60A.): 433-435
- Tolterodine, a new antimuscarinic agent: as effective but better tolerated than oxybutynin in patients with an overactive bladder.Br J Urol. 1998; 81: 801-810
- Once daily controlled versus immediate release oxybutynin chloride for urge urinary incontinence.J Urol. 1999; 161: 1809-1812
- Once-daily oxybutynin chloride (Ditropan XL) in patients on other anticholinergic medications [abstract].J Urol. 1999; 161 (Abstract 988.): 256
- Prospective randomized controlled trial of extended-release oxybutynin chloride and tolterodine tartrate in the treatment of overactive bladder: results of the OBJECT study.Mayo Clin Proc. 2000; 76: 358-363
- Intravesical capsaicin and resiniferatoxin therapy: spicing up the ways to treat the overactive bladder.J Urol. 1999; 162: 3-11
- Systemic capsaicin treatment impairs the micturition reflex in the rat.Br J Pharmacol. 1984; 83: 935-941
- Effects of spinal cord injury on neurofilament immunoreactivity and capsaicin sensitivity in rat dorsal root ganglion neurons innervating the urinary bladder.Neuroscience. 1998; 83: 633-643
- Excitatory effect of substance P in parasympathetic ganglia of cat urinary bladder.Am J Physiol. 1989; 257: R1450-R1456
- Intravesical capsaicin for treatment of detrusor hyperreflexia.J Neurol Neurosurg Psychiatry. 1994; 57: 169-173
- Clinical and urodynamic effects of intravesical capsaicin treatment in patients with chronic traumatic spinal detrusor hyperreflexia.J Urol. 1995; 154: 1825-1829
- Intravesical capsaicin in neurologic impaired patients with detrusor hyperreflexia.J Spinal Cord Med. 1996; 19: 190-193
- Intravesical capsaicin for treatment of autonomic dysreflexia in patients with spinal cord injury [abstract].J Urol. 1996; 155 (Abstract 1123.): 591A
- Intravesical capsaicin as a treatment for refractory detrusor hyperreflexia: a dual center study with long-term follow-up.J Urol. 1997; 158: 2087-2092
- Desensitization of bladder sensory fibers by intravesical capsaicin has long lasting clinical and urodynamic effects in patients with hyperactive or hypersensitive bladder dysfunction.J Urol. 1997; 157: 585-589
- Columbus, Capsicum and casaicin: past, present and future.Acta Physiol Hung. 1987; 69: 265-273
- Intravesical resiniferatoxin (RTX) treatment of detrusor hyperreflexia: results of a randomized, double-blind, placebo-controlled, multicenter trial [abstract].J Urol. 1999; 161 (Abstract 1070.): 276
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© 2001 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.
