Overactive Bladder in Special Patient Populations

TREATMENT OF OVERACTIVE BLADDER Overactive Bladder in Special Patient Populations Rodney A. Appell, MD, FACS Scott Department of Urology, Baylor College of Medicine, Houston, TX It is now well accepted that overactive bladder (OAB) negatively affects the quality of life of a large number of persons and that the primary mode of therapy is the use of medication—currently antimuscarinic agents. However, it is also important for physicians to understand how the use of these drugs affects specific groups of patients. Most of the concern in this area focuses on the potential for these populations to experience certain adverse events or side effects from the use of antimuscarinic agents; this has prevented these drugs from being prescribed in these populations to the same degree as in the general population of OAB sufferers. The purpose of this article is to review these specific populations of OAB patients, including pediatric, geriatric, and pregnant patients, men with prostate problems, and patients in whom OAB is of neurogenic origin, and to discuss what is currently known about the use of antimuscarinic agents in these groups. [Rev Urol. 2003;5(suppl 8):S37-S41] © 2003 MedReviews, LLC Key words: Overactive bladder • Pediatrics • Geriatrics • Anticholinergic agents he common clinical syndrome of overactive bladder (OAB) can originate from dysfunction of the peripheral or central nervous systems or the urothelium or smooth muscle components of the bladder or can be secondary to inflammatory or malignant changes within the bladder. Interesting developments involving non-neural factors and their contribution to bladder overactivity and the alteration of bladder sensation have been noted. In fact, changes in the T VOL. 5 SUPPL. 8 2003 REVIEWS IN UROLOGY S37 OAB in Special Patient Populations continued urothelium and the altered responsiveness of ischemic or denervated smooth muscle are 2 of the most important factors in the clinical presentation of OAB. Not only can an increase in nervous response be caused by changes in the urothelium or smooth muscle, but the converse may also be true, with changes in urothelium and smooth muscle elicited by altered nerve activity. Under such circumstances, a vicious cycle can develop in which a change in one component influences the other com- augmentation enterocystoplasty, are reserved for severe problems recalcitrant to pharmacologic and behavioral therapeutic endeavors. Pediatric Patients The outcome of pharmacologic therapy for daytime incontinence is unpredictable and inconsistent, and few randomized studies have been performed to evaluate safety and efficacy of this therapy. Oxybutynin remains the most widely used drug for this indication. When oxybutynin A number of processes can cause the same or similar symptoms of OAB. ponents—with the pathophysiologic result being OAB symptomatology. Similar symptoms of OAB can occur in patient populations that are quite different from one another, for example, pediatric and geriatric patients. Several of these groups are reviewed herein. However, the problem with such an undertaking is that no single measure can fully express the outcome of an intervention, whether that intervention is for diagnosis (eg, urodynamics) or treatment (eg, pharmacotherapy). This is complicated by the fact that a number of processes can cause the same or similar symptoms of OAB. For example, neurologic deficits and cellular changes associated with bladder outlet obstruction or aging can all lead to urinary frequency, urinary urgency, nocturia and, in some cases, urge incontinence. For the purpose of this article, treatment of OAB in distinct populations is confined to pharmacologic management, recognizing the importance of concomitant behavioral therapy and pelvic muscle rehabilitation. Surgical techniques, including sacral neuromodulation techniques, injections with botulinum toxin, and S38 VOL. 5 SUPPL. 8 2003 is poorly tolerated because of the usual side effects associated with antimuscarinic agents, intravesical administration may be an option, especially in children with neuropathic bladder who are catheterized at regular intervals.1,2 However, the incidence of side effects with this method of administration seems to be dose-related, as is the case with oral administration.2 Transdermal oxybutynin has been shown to have reduced anticholinergic side effects in adults but has yet to be investigated in children.3 Early results have shown the optimal dosage of tolterodine for children efficacy to the extended-release form of tolterodine for the management of pediatric diurnal urinary incontinence and more effective than both the immediate- and extended-release forms of tolterodine for the management of daytime urinary incontinence and frequency.7 Trospium and propiverine have been studied in children; however, the inclusion and outcome criteria employed were not those designed by the International Continence Society, making comparison with other studies difficult.8-10 Committee 10A of the 2nd International Consultation on Incontinence assessed and reported on the topic of “conservative management of urinary incontinence in childhood.” Of note, after an extensive review of the literature, only 6 of 1013 papers qualified for analysis, which did not allow a reliable assessment of the benefits and risks of treatment of OAB in children.11 Nocturnal enuresis unrelated to OAB is not considered here. Geriatric Patients The prevalence of incontinence increases markedly with advancing age. The contribution of comorbid conditions to this phenomenon should not be overlooked, whether or not the conditions are related to the lower urinary tract. Treatment directed at Transdermal oxybutynin has been shown to have reduced anticholinergic side effects in adults but has yet to be investigated in children. aged 5 to 10 years to be 1 mg twice daily, and no safety concerns have been noted with the use of this drug.4-6 Data from studies examining the once-daily preparations of oxybutynin and tolterodine are beginning to appear. A recently published study found the extended-release form of oxybutynin to be comparable in REVIEWS IN UROLOGY factors unrelated to the lower urinary tract may lead to significant improvement in incontinence and, more importantly, comorbidities that are not addressed can limit the success of interventions aimed at the lower urinary tract. Although aging affects the lower urinary tract, it does not cause incon- OAB in Special Patient Populations tinence. Bladder capacity and the ability to postpone voiding decline in both sexes with advancing age. Functional urethral length and closure pressure decline with age in women; the prostate enlarges in most men, causing urodynamic evidence of obstruction in approximately half of men. Elevated postvoid residual volume appears to reflect an age-related impairment in about the passage of antimuscarinic agents through the blood-brain barrier and the resultant cognitive changes, which could be of particular concern in elderly patients. It has been reported that tolterodine is associated with this problem less often than oxybutynin (although both are tertiary amines) because it is less lipophilic and, therefore, has less Bladder capacity and the ability to postpone voiding decline in both sexes with advancing age. detrusor contractility, and detrusor overactivity becomes more prevalent with age, even among continent persons, and can be documented in more than one third of elderly persons.12 Some reports regarding pharmacologic therapy in frail elderly persons appear contradictory, even those with the same lead author.13,14 In one study, Ouslander and colleagues13 found that the addition of oxybutynin therapy to bladder training had no effect on the frequency of incontinence episodes. However, a subsequent study by Ouslander and colleagues14 found that subjects in whom a prompted-voiding intervention alone had failed had a significantly greater reduction in wetness when given oxybutynin compared with placebo. It would appear, however, that the improvement over placebo (3%) was statistically but not clinically significant. Other studies in frail elderly persons, including an oxybutynin study15 and a propantheline study,16 were too short-lived (8 days and 4 days, respectively) to be meaningful. Appropriately designed studies are sorely needed before any recommendations can be made regarding pharmacologic therapy for OAB in the frail elderly population, let alone any statements regarding cost-effectiveness. A great deal has been written propensity to penetrate into the central nervous system.17,18 If this is the case, trospium and propantheline would have to be considered even safer, because they are quaternary amines and, therefore, cannot cross the blood-brain barrier. Pregnant Women Although pregnant women complain of urinary frequency and some urgency, the major problem in this population is the onset of stress urinary incontinence. The symptoms relating to OAB are due to normal physiologic changes that occur during pregnancy and resolve following outlet obstruction. Approximately 60% of symptomatic older men have bladder storage symptoms,19 which may be of neurogenic origin20,21 or perhaps due to increased -adrenergic responses in the obstructed detrusor secondary to ischemic changes.22 In theory, drugs that primarily reduce bladder outlet obstruction should concurrently improve storage LUTS. It is difficult to compare effects on damaged storage function, and any improvement that occurs is often not sufficient to satisfy the patient. Although most physicians expect the addition of an antimuscarinic agent to treatment to improve LUTS, there is the concern that this may compromise bladder emptying if the outlet obstruction is more severe than anticipated or if weakened detrusor contractility is present. In a recent study by Abrams and colleagues,23 men with bladder outlet obstruction who received tolterodine demonstrated no deterioration of voiding function. On the other hand, in a similar group of men, Dahm and collegues24 found no differences in irritative symptom score and patient evaluation between those receiving flavoxate and those receiving placebo. Chapple and Smith25 have proposed a OAB symptoms in men are usually the result of detrusor overactivity associated with bladder outlet obstruction. delivery. In any event, none of the available agents for OAB has been studied in pregnant women. Men With Prostatic Obstruction Drugs managing lower urinary tract symptoms (LUTS) have been used in both female and male patients, and there is no evidence of differing effects depending on sex. OAB symptoms in men are usually the result of detrusor overactivity associated with bladder combination of an 1-adrenergic antagonist with tolterodine to further reduce LUTS in patients with prostatic obstruction. Additional studies evaluating the extended-release forms of tolterodine and oxybutynin are currently in progress. OAB of Neurogenic Origin Anticholinergic agents are the most useful medications available for OAB of neurogenic etiology. These agents VOL. 5 SUPPL. 8 2003 REVIEWS IN UROLOGY S39 OAB in Special Patient Populations continued are employed to suppress detrusor overactivity of motor origin and to improve bladder compliance by lowering intravesical pressure, reducing ischemic changes to the detrusor muscle, and improving the incontinence caused by detrusor overactivity and reduced bladder compliance. However, these effects of anticholinergic agents reduce the ability of the bladder to completely empty itself, and the subsequent elevation of residual urine level may require intermittent catheterization Because oxybutynin has been available for the longest period (over 30 years), most studies of anticholinergic agents have utilized this agent. Committee 10E of the 2nd International Consultation on Incontinence26 reviewed and reported on the topic of “conservative management of neuropathic urinary incontinence.” The committee identified 178 articles on oxybutynin for review. It assigned an “A” grade of recommendation to oxybutynin, with overall rates of good results (ie, >50% symptom improvement) between 61% and 86% and side effects (primarily dry mouth) between 12.5% and 47.6% at a dosage of 15 mg/d. In clinical practice, one should aim for individual patient titration of drug dosage for a maximum therapeutic effect with minimal side effects; oxybutynin has been approved for use at dosages of 5 mg/d to 30 mg/d.26 The committee reviewed 22 articles on propiverine, a drug with combined antimuscarinic and musculotropic (calcium antagonistic) activity. This agent also received an “A” grade of recommendation at dosages of 10 mg to 15 mg, 2 or 3 with oxybutynin (5 mg 3 times daily) in a randomized, double-blind, urodynamically controlled, multicenter trial involving 95 patients. The investigators concluded that the drugs were equal in their effects (increase in bladder capacity of 30% and reduction in maximum detrusor pressure of 30%), with fewer severe side effects (dry mouth) occurring with trospium. A large number of persons are affected by OAB, and the majority remains untreated or undertreated. times daily. Propiverine has a documented beneficial effect with an acceptable adverse-effect profile. The primary objective finding was an average increase in maximum cystometric capacity of 104 mL.26 Trospium also received an “A” grade of recommendation, despite there being only 6 articles for evaluation.26 Similar to the findings with propiverine, trospium demonstrated significant improvement in maximum cystometric capacity within only 3 weeks of use at a dosage of 20 mg twice daily. Madersbacher and colleagues27 compared the clinical efficacy and tolerability of trospium (20 mg twice daily) The committee could not recommend or grade tolterodine with respect to use in patients with neurogenic bladder based on a lack of studies in this patient population.26 Summary OAB symptomatology is more than an annoyance to those who have this condition; it adversely affects the quality of one’s life. A large number of persons are affected by OAB, and the majority remains untreated or undertreated. Specific populations have certain unique problems with respect to OAB that make it possible to categorize them into groups. These Main Points • Oxybutynin remains the most widely used drug for overactive bladder (OAB) in children. Intravesical administration may be an option when antimuscarinic side effects preclude oral administration; transdermal delivery may also prove useful, but studies of this system in children are needed. • Early studies have shown tolterodine to be safe and effective in children with OAB symptoms. More research is needed to assess the performance of trospium and propiverine in pediatric populations. • Appropriately designed studies are sorely needed before any recommendations can be made for pharmacologic therapy for OAB in the frail elderly. • There is concern that antimuscarinic therapy in men with prostatic obstruction, whose symptoms are primarily associated with bladder outlet obstruction, may compromise bladder emptying; various therapies and drug combinations are under investigation, and more definitive recommendations are anticipated. • A review of studies at the 2nd International Consultation on Incontinence determined that, for OAB of neurogenic origin, oxybutynin, propiverine, and trospium are all effective therapies at appropriate dosages; not enough data were available to make a firm recommendation for tolterodine. S40 VOL. 5 SUPPL. 8 2003 REVIEWS IN UROLOGY OAB in Special Patient Populations groups may best be helped with some combination of behavioral, physical, and pharmacologic therapies. The perfect OAB drug is not yet available, and certain populations may be better helped with some treatments than other populations may be. There is hope that future research will lead to a better understanding of this symptomatic complex. In the meantime, physicians must keep in close contact with patients and effectively communicate to them that a combination of therapies is currently the best way to maximize outcomes. References 1. 2. 3. 4. 5. 6. Aubert D, Cencig P, Royer M. Treatment with oxybutynin hydrochloride of urinary incontinence and hyperactive bladder conditions in children. Ann Pediatr (Paris). 1986;33:629-634. Kaplinsky R, Greenfield S, Wan J, et al. Expanded followup of intravesical oxybutynin chloride use in children with neurogenic bladder. J Urol. 1996;156:753-756. Appell RA, Chancellor MB, Zobrist RH, et al. Pharmacokinetics, metabolism, and saliva output during transdermal and extended-release oral oxybutynin administration in healthy subjects. Mayo Clin Proc. 2003;78:696-702. Hjalmas K, Hellstrom AL, Mogren K, et al. The overactive bladder in children: a potential future indication for tolterodine. BJU Int. 2001;87:1-7. Goessl C, Sauter T, Michael T, et al. Efficacy and tolerability of tolterodine in children with detrusor hyperreflexia. Urology. 2000;55:414-418. Munding M, Wessells H, Thornberry B, et al. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. Use of tolterodine in children with dysfunctional voiding: an initial report. J Urol. 2001; 165:926-928. Reinberg Y, Crocker J, Wolpert J, et al. Therapeutic efficacy of extended release oxybutynin chloride, and immediate release and long acting tolterodine tartrate in children with diurnal urinary incontinence. J Urol. 2003; 169:385-404. Gesch R, Schonberger B. Instabile blase and enuresis im kindesalter. Vortrag 4. Presented at: Deutscher Kongress der GIH; November 6-7, 1992; Berlin. Siegert J, Schubert G, Nentwich H-J. Pharmakotherapie der enuresis mit urge-symptomatik, klinische untersuchungen zur wirksamkeit und vertraglishkeit der kinderform von propiverine-hydrochlorid (Mictonetten®). In: Jonas U, ed. Jahrbuch der Urologie. Zulpich, Germany: Biermann-Verlag; 1994:177-181. Hoashi E, Yokoi S, Akashi S, et al. Safety and efficacy of propiverine hydrochloride (BUP-4® tablets) in children: a study focused on nocturia. Jpn J Paediatr. 1998;51:173-179. Nijman RJM, Butler R, Van Gool J, et al. Conservative management of urinary incontinence in childhood. In: Abrams P, Cardozo L, Khoury S, Wein A, eds. Incontinence. Plymouth, UK: Health Publication Ltd; 2002:513-551. Resnick NM, Elbadawi A, Yalla SV. Age and the lower urinary tract: what is normal? Neurourol Urodyn. 1995;14:577-579. Ouslander JG, Blaustein J, Connor A, et al. Habit training and oxybutynin for incontinence in nursing home patients: a placebo-controlled trial. J Am Geriatr Soc. 1988;36:40-46. Ouslander JG, Schnelle JF, Uman G, et al. Does oxybutynin add to the effectiveness of prompted voiding for urinary incontinence among nursing home residents? A placebo-controlled trial. J Am Geriatr Soc. 1995;43:610-617. Zorzitto ML, Holliday PJ, Jewett MA, et al. Oxybutynin chloride for geriatric urinary dysfunction: a double-blind placebo-controlled study. Age Ageing. 1989;8:195-200. Zorzitto ML, Jewett MA, Fernie GR, et al. Effectiveness of propantheline bromide in the 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. treatment of geriatric patients with detrusor instability. Neurourol Urodyn. 1986;5:133-140. Chapple CR. Muscarinic receptor antagonists in the treatment of overactive bladder. Urology. 2000;55(suppl 5A):33-46. Clemett D, Jarvis B. Tolterodine: a review of its use in the treatment of overactive bladder. Drugs Aging. 2001;18:277-304. Abrams PH, Farrar DJ, Turner-Warwick RT, et al. The results of prostatectomy: a symptomatic and urodynamic analysis of 152 patients. J Urol. 1979;121:640-642. Steers WD, De Groat WC. Effect of bladder outlet obstruction on micturition reflex pathways in the rat. J Urol. 1988;140:864-871. Sibley GN. The physiological response of the detrusor muscle to experimental bladder outflow obstruction in the pig. Br J Urol. 1987;60:332-336. Perlberg S, Caine M. Adrenergic response of bladder muscle in prostatic obstruction: its relation to detrusor instability. Urology. 1982; 20:524-527. Abrams P, Kaplan S, Millard R. Tolterodine treatment is safe in men with bladder outlet obstruction (BOO) and symptomatic detrusor overactivity (DO) [abstract]. Neurourol Urodyn. 2001;20:547. Dahm TL, Ostri P, Kristensen JK, et al. Flavoxate treatment of micturition disorders accompanying benign prostatic hypertrophy: a doubleblind placebo-controlled multicenter investigation. Urol Int. 1995;55:205-208. Chapple CR, Smith D. The pathophysiological changes in the bladder obstructed by benign prostatic hyperplasia. Br J Urol. 1994;73:117-123. Madersbacher H, Wyndaele JJ, Igawa Y, et al. Conservative management in neuropathic urinary incontinence. In: Abrams P, Cardozo L, Khoury S, Wein A, eds. Incontinence. Plymouth, UK: Health Publication Ltd; 2002:697-754. Madersbacher H, Stohrer M, Richter R, et al. Trospium chloride versus oxybutynin: a randomized, double-blind, multicentre trial in the treatment of detrusor hyper-reflexia. Br J Urol. 1995;75:452-456. VOL. 5 SUPPL. 8 2003 REVIEWS IN UROLOGY S41