Overactive Bladder: Treatment Options in Primary Care Medicine

CLINICAL PRACTICE

David O. Sussman, DO

Overactive bladder is a highly prevalent condition, affecting overactivity may not be present in up to 25% of patients with approximately 33 million adults in the United States. Despite overactive bladder.4 the considerable impact this condition has on patients’ Patient quality of life (QOL) is substantially impacted by quality of life, overactive bladder remains underrecognized this disorder as social, psychological, occupational, domestic, and undertreated as a result of patient embarrassment and physical, and sexual functioning are all affected.5 As a conse- reluctance to seek medical help, as well as a lack of proac- quence, severe bladder symptoms can have a tremendous tive questioning by physicians. The present article encour- negative impact on patient social interaction, sexual intimacy, ages physicians to initiate a dialogue with patients regarding and even willingness to leave home. In addition, while most urinary control and, specifically, overactive bladder. Treat- people recognize that incontinence, frequency, and nocturia ment options for overactive bladder recommended in the affect patients’ QOL, a 2004 survey6 suggests that urinary current article include both nonpharmacologic and phar- urgency alone also has a significant impact on QOL. macologic therapies. Properties of antimuscarinic agents, In fact, the impact of this disorder extends beyond basic including three new drug therapies, are reviewed and pro- QOL issues and into financial implications and patient comor- vided for physicians to optimize therapy options, particularly bidities. In 2000, for example, the total costs associated with among elderly patients. overactive bladder in the United States were estimated at 7 J Am Osteopath Assoc. 2007;107:379-385 $12 billion. These expenses comprise indirect costs (eg, lost pro- ductivity) and direct costs, including diagnosis, treatment, and routine care. Comorbidities associated with this condi- veractive bladder affects 33 million adults in the United tion include skin infections, urinary tract infections, depression, OStates, which is approximately 16.5% of the popula- and, in older adults, injuries associated with falls that occur as tion.1 The condition affects an equal number of men and a result of hurrying to the toilet. women, though the severity and nature of the condition’s The past 10 years have seen many developments related symptoms may be determined by gender (eg, overactive to overactive bladder, both in terms of physicians’ greater bladder without urge incontinence is more common in men understanding of the implications of this condition and the than in women).2 treatment options available. In 2003 and 2004, the US Food The International Continence Society (ICS) defines over- and Drug Administration (FDA) approved three new agents— active bladder as urgency (with or without urge incontinence), darifenacin, solifenacin succinate, and trospium chloride— usually with frequency and nocturia, in the absence of other for the treatment of patients with overactive bladder. Some of pathologic or metabolic conditions that might explain the these agents differ substantially from earlier compounds and symptoms.3 Urgency is defined as a sudden and compelling may allow for optimization of therapy, particularly among desire to pass urine that is difficult to defer. Nocturia is defined older patients. The present article provides an overview of as waking one or more times per night to void urine. The ICS the pathophysiology of overactive bladder and reviews the cur- definition of overactive bladder describes the condition using rent diagnostic approaches as well as treatment strategies. patient symptoms rather than urodynamic findings. This is an important distinction, as urodynamically detectable detrusor Pathophysiology The two functions of the bladder are to store and void urine. The process of micturition involves neural circuits (afferent and efferent neural pathways and central and peripheral neu- rotransmitters) in the brain and spinal cord that coordinate Address correspondence to David O. Sussman, DO, Urology Associates, PA, 205 the anatomic components of the lower urinary tract. How- E Laurel Rd, Stratford, NJ 08084-1301. E-mail: [email protected] ever, the direct connection and contribution of these elements are not completely understood. Submitted June 20, 2006; revision received October 31, 2006; accepted As bladder volume increases, involuntary contractions November 2, 2006. of the detrusor muscle are often associated with overactive

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volume of urine voided, and experience of each urination (ie, Patient presents with symptoms suggestive of overactive whether or not the urination was associated with urgency). bladder (eg, urgency with or without urge incontinence, Such a diary can be useful at the diagnosis stage to establish usually with frequency and nocturia) the extent and severity of any urinary problems. Achieving a differential diagnosis is a relatively straight- forward process that can be performed in the physician’s office using a simple diagnostic algorithm for overactive bladder Obtain patient history (including past genitourinary (Figure 1). For patients presenting with one or more symp- disorders) toms of this condition (frequency, urgency, urge incontinence, or nocturia), a patient history should be obtained—including information about past genitourinary disorders—to exclude symptoms resulting from comorbid conditions or concomitant Perform physical examination to exclude obvious pathologies medications. (eg, inflammation, prolapse, masses) A physical examination of the abdomen, rectum, pelvis, and genitalia should be performed to exclude obvious pathologies such as inflammation, prolapse, or masses. Urinalysis should be performed to exclude conditions that are some- Obtain urinalysis to exclude conditions sometimes associated times associated with overactive bladder (eg, bacteria in the with overactive bladder (eg, urinary tract infections) urine would suggest an infection, excess glucose in the urine could be a result of diabetes, and blood or protein in the urine may indicate kidney disease). In instances where urinalysis results suggest an associated condition, it may be necessary to In the absence of proven infection or other pathology, the refer the patient for additional diagnostic testing. For example, symptoms of urgency with or without urge incontinence, usually with frequency and nocturia, should be treated as if a patient has unexplained hematuria, a urology referral for overactive bladder cytoscopy is recommended. In the absence of infection or other pathologies, including bladder cancers, a diagnosis of overactive bladder can be made. Figure 1. Algorithm to assist physicians in diagnosing patients with Urodynamic assessment can also be used in the diag- overactive bladder. nosis of overactive bladder, though the value of such assessments for this purpose is controversial. A recent report4 suggests that a positive urodynamic assessment for incontinence bladder—though such urodynamically demonstrable detrusor does not influence treatment success, indicating that these overactivity is not a prerequisite for a diagnosis of the condi- expensive, invasive, and complex tests should be reserved for tion. The mechanisms underlying these involuntary contrac- patients with unusual symptoms or when initial therapy is tions have not yet been fully elucidated, although increasing unsuccessful.4 attention is being focused on the role of sensory afferent nerves in the process.8 Treatment Strategies Treatment of overactive bladder can include nonpharmacologic Recognition and Diagnosis interventions, pharmacologic interventions, or a combination Overactive bladder has sometimes been referred to as the of both.10 Approaching these options in consideration of the “hidden condition”1 because, despite the impact on their lives, whole patient allows physicians to determine the best therapy. patients are often embarrassed by the condition and do not want to discuss it with their physicians.5 Many patients also Nonpharmacologic Treatment consider overactive bladder to be a normal part of aging and Nonpharmacologic interventions in the treatment of patients may assume nothing can be done to alleviate their symptoms.9 with overactive bladder usually involve “bladder retraining,” To manage overactive bladder effectively, physicians which generally consists of patient education, scheduled must first encourage patients to speak openly with them. voiding, and urge-suppression techniques. Educating patients Given the prevalence of this condition, annual physical exam- about bladder function is important in detering patients from inations or medical check-ups may be a good opportunity to using harmful coping behaviors, such as restricting fluid intake. discuss urinary problems with patients. A simple question Patients should also be alerted that consuming certain prod- such as “Are you bothered or worried by your urine control?” ucts (eg, alcohol, caffeine, spicy foods, and tomato-based prod- may be sufficient to initiate discussion. If a patient is con- ucts) may exacerbate their condition. In addition, scheduled cerned about his or her urine control, the physician should voiding can help patients correct the habit of frequent urina- ask the patient to fill out a diary detailing the time, estimated tion and increase bladder capacity. Finally, urge suppression

380 • JAOA • Vol 107 • No 9 • September 2007 Sussman • Clinical Practice CLINICAL PRACTICE techniques such as pelvic floor muscle exercises (Kegel exer- in turn may require physicians to adjust doses individu- cises), which involve tightening and relaxing the muscle around ally to each patient.15,16 the rectum, and biofeedback-assisted training can strengthen Muscarinic receptor subtypes and selectivity—The five and improve voluntary control of muscles. known muscarinic receptor subtypes (M1 through M5) play Within the primary care setting, bladder retraining can be key physiologic roles in the brain as well as in the periph- labor-intensive and time-consuming for both the patient and eral organs. The predominant muscarinic receptors (M2 the physician, and successful implementation requires con- receptors) are present in the bladder wall and urothelium siderable motivation and commitment on the part of the and may be involved with detrusor contraction.17 The patient. Despite these obstacles, bladder retraining should smaller population of M3 receptors mediates direct con- always be considered in the management of overactive bladder, traction of the detrusor muscle.18 Although the presence of as it is a safe treatment option from which many patients can the M1, M4, and M5 receptors are minimal, the M1 receptor benefit.11 Moreover, behavioral modifications that occur as a is thought to play an important role in the central nervous result of bladder retraining may enhance the outcomes system.19,20 Therefore, cognitive changes may be seen with 9 obtained with pharmacologic interventions. drugs that bind to the M1 receptor. Selectivity for muscarinic receptor subtypes has been Pharmacologic Treatment proposed as a mechanism by which antimuscarinic agents While a range of drugs have been used in the past for the man- can provide efficacy for overactive bladder while mini- agement of overactive bladder—from smooth muscle relaxants mizing adverse effects. The clinical impact of subtype selec- to tricyclic antidepressants—antimuscarinic agents now form the tivity on adverse-effect profiles, however, remains to be mainstay in the armamentarium used to control the symptoms proven. associated with this condition. Conventional wisdom12 holds that Metabolism and excretion—The metabolism of antimus- antimuscarinics act by blocking the muscarinic receptors on carinic agents by cytochrome P-450 enzymes in the liver the detrusor muscle (which are normally stimulated by acetyl- may result in interactions with concomitant medications choline released from parasympathetic nerves) thereby dimin- metabolized by the same pathways.21 Antimuscarinic agents ishing the intensity of involuntary detrusor muscle contrac- not metabolized in the liver may therefore be a better treat- tions. Emerging research,12 however, suggests that ment option, particularly for elderly patients with overac- anti-muscarinic agents mainly act during the storage phase, tive bladder in whom polypharmacy is common. Agents decreasing urge and increasing bladder capacity, during which excreted in an active form may provide additional and pro- time there is normally no activity in the parasympathetic nerves. longed clinical efficacy, as they may deliver local effects in Studies12-14 are now focusing on the ability of antimuscarinics to the bladder (eg, to the urothelium). modulate afferent impulses as a means of effectiveness. Antimuscarinic agents differ at the structural and molec- An understanding of these differences—particularly in how ular level, resulting in different metabolism, absorption, they impact the efficacy and safety of the agents—is important potency, and selectivity profiles, as follows: and allows physicians to make informed decisions about the most suitable treatment option for their patients’ needs.15-20 A Tertiary vs quaternary amines—Antimuscarinic agents are summary of these features is provided in Figure 2. either tertiary or quaternary amines, the latter of which are There are currently five antimuscarinic agents available in hydrophilic, resulting in a limited ability to cross the blood- the United States for the treatment of overactive bladder: oxy- brain barrier. (Tertiary amines, on the other hand, are butynin, tolterodine tartrate, darifenacin, solifenacin (all ter- lipophilic.15) Consequently, quaternary amines minimize tiary amines), and trospium (a quaternary amine). The tertiary central nervous system side effects, such as confusion and amines are predominantly metabolized by the cytochrome P-450 blurred vision.15 This feature may be particularly impor- enzymes in the liver with little active compound being excreted tant in elderly patients with overactive bladder. Such patients in the urine. Of administered doses, Ͻ0.1%, Ͻ1%, and Ͻ15% of may be more sensitive to the cholinergic effects of antimus- unchanged oxybutynin, tolterodine, and solifenacin, respec- carinic therapy as a result of reductions in metabolism and tively, is excreted in the urine.22-24 For darfenacin, 3% of the elimination—in addition to increased risk of pharmacoki- dose excreted in urine is unchanged.25 By contrast, trospium netic drug interactions. Elderly patients are also more likely (quaternary amine) is minimally metabolized in the liver, with to be taking prescription and over-the-counter medications the majority (60%) of the absorbed compound being excreted in with anticholinergic properties, which, combined with its active form.26 The different pharmacologic profiles of these antimuscarinics for the treatment of overactive bladder, antimuscarinic agents22-27 may contribute to the differences in may result in a substantial anticholinergic load, putting safety and efficacy seen in clinical practice studies (Table).28-34 them at risk for cognitive side effects. Oxybutynin has been available for the treatment of over- The hydrophilicity of quaternary amines also affects the active bladder for more than 30 years and is effective in a rate of absorption across the gastrointestinal tract, which range of patients. It is available as immediate- and extended-

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Feature Physiologic Effect Clinical Impact Structure ▫ Tertiary amines Allows transfer across the May result in adverse cognitive effects, blood-brain barrier into CNS particularly among elderly patients Allows good absorption across GI tract Does not necessitate dose adjustment ▫ Quaternary amines Limits transfer across the Reduces the potential for blood-brain barrier into CNS cognitive adverse effects Limits absorption across GI tract Necessitates dose adjustment Affinity for Muscarinic Receptor Subtypes

▫ M1 The M1 receptor may play Reduced or absent affinity for M1 is proposed an important role in cognition as beneficial, as this may reduce the incidence of cognitive adverse effects

▫ M2 In the detrusor muscle, 80% of the Reduced or absent affinity for M2 is proposed muscarinic receptors are M2. They may as a mechanism for reducing the incidence be indirectly involved in detrusor smooth of cardiac adverse effects. If M2 receptors are muscle contraction via inhibition of involved in contraction, reduced affinity may muscle relaxation by ␤-adrenoceptors also impact efficacy

▫ M3 In the detrusor muscle, 20% of the Reduced affinity for the M3 receptor subtype muscarinic receptors are M3 receptors. would lower the ability to inhibit unwanted They are believed to be the main detrusor contractions. Overly aggressive M3 receptor subtype responsible for blockade could result in constipation normal micturition contraction

▫ M4 Not present in the bladder in Unknown significant numbers

▫ M5 Not present in the bladder in Unknown significant numbers Metabolism and Excretion ▫ Metabolism by cytochrome Antimuscarinics that are extensively The effects of compounds metabolized P-450 enzymes metabolized via this route may be via the same pathways may be altered involved in drug-drug interactions ▫ Excretion in active form Allows “local” inhibition of bladder May result in prolonged muscarinic receptors and additional efficacy

Figure 2. Differentiating features of antimuscarinic agents and their potential impact on safety, efficacy, and tolerability.15-20 Tertiary amines are not readily soluble in water but are readily soluble in fats, while quaternary amines are readily soluble in water but not in fats. All muscarinic receptor subtypes are found in the central nervous system. In addition, M1 receptors are found in autonomic ganglia and secretory glands; M2 receptors are found in the heart; and M2, M3, and M4 receptors are all found in smooth muscle. Abbreviations: CNS, central nervous system; GI, gastrointestinal. release oral tablets (oxybutynin chloride) and as a transdermal small size, highly lipophilic nature, and its neutral charge, patch.30,35 The most commonly reported adverse event for make it more likely to cross the blood-brain barrier than other extended-release oral oxybutynin is dry mouth, experienced antimuscarinic agents available for the treatment of overactive by up to 68% of patients and causing some patients to dis- bladder. Therefore, central anticholinergic effects, which could continue therapy.36 Transdermal oxybutynin results in a far result in cognitive impairment, are a concern in patients (par- lower incidence of dry mouth (Ͻ10%) but is associated with ticularly elderly patients) taking oxybutynin.37 local skin reactions such as pruritis.30 This lower incidence of Tolterodine, which is orally administered, has been avail- dry mouth is believed to result from the lack of presystemic able in the United States since 1998. Originally launched as an metabolism to form an active metabolite with similar proper- immediate-release formulation, tolterodine is now available as ties to the parent compound (N-desethyl-oxybutynin). an extended-release formulation. Initiated and maintained at Certain attributes of oral oxybutynin, such as its relatively a dose of 4 mg once daily, tolterodine extended-release for-

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Table Efficacy and Tolerability of Antimuscarinic Agents Using Data From Key Clinical Studies

Antimuscarinic Subject Characteristics Adverse Agent Dosage Study Design Age, y Symptoms Efficacy Outcomes Event (%)*

Oxybutynin 5 mg to 30 mg Three placebo- 18-98 Urge or mixed Significant decreases Dry mouth (60.8) chloride every day controlled and one incontinence from baseline in Constipation (13.1) (oral extended- open-label trial of weekly urge Somnolence (11.9) release)22,28 varying duration incontinence, weekly Headache (9.8) total incontinence Diarrhea (9.1) episodes, and Nausea (8.9) micturition frequency Asthenia (6.8) Pain (6.8) Dyspepsia (6.8) Dizziness (6.3) Blurred vision (7.7) Dry eyes (6.1) Rhinitis (5.6) Urinary tract infection (5.1)

Oxybutynin 3.9 mg/d Two 12-week 18-89 Urge and mixed Significant improvements Study 1: (transdermal over 96 hours placebo-controlled incontinence versus placebo in weekly Pruritis† (16.8) patch)29-31 phase 3 trials incontinence episodes, Erythema† (5.6) daily urinary frequency, Dry mouth (9.6) and mean volume Study 2: voided Pruritis† (14.0) Erythema† (8.3) Dry mouth (4.1)

Tolterodine 4 mg every day One 12-week 20-93 Frequency and Significant improvements Dry mouth (23) tartrate placebo-controlled urge incontinence versus placebo in number Headache (6) (oral, extended- phase 3 trial of incontinence episodes Constipation (6) release)23,32 per week, number of micturitions per day, and volume voided per micturition

Darifenacin 7.5 mg/d Pooled analysis 19-93 Frequency and Significant improvements 7.5 mg: (oral)25,33 or 15 mg/d of three 12-week urgency with urge versus placebo in Dry mouth (20.2) placebo-controlled incontinence incontinence episodes Constipation (14.8) phase 3 trials per week, frequency and 15 mg: severity of urgency, Dry mouth (35.3) micturitions per day, and Constipation (21.3) volume voided Dyspepsia (8.4)

Solifenacin 5 mg/d Four 12-week 50-70 Urge or mixed Significant improvements 5 mg: succinate (oral)24 or 10 mg/d placebo-controlled incontinence versus placebo in urinary Dry mouth (10.9) trials frequency, number of Constipation (5.4) incontinence episodes, 10 mg: and volume voided Dry mouth (27.6) per micturition Constipation (13.4)

Trospium 20 mg twice Two 12-week 19-94 Urge or mixed Significant improvements Dry mouth (20.1) chloride a day placebo-controlled incontinence versus placebo in daily Constipation (9.6) (oral)26,34 trials urinary frequency, weekly urge incontinence episodes, and mean volume voided

* Adverse events occurred in more than 5% of the study population. † Adverse effects appearing at application site.

Sussman • Clinical Practice JAOA • Vol 107 • No 9 • September 2007 • 383 CLINICAL PRACTICE mulation is efficacious in the treatment of overactive bladder.38 uals who had ingested a variety of antimuscarinic agents was Tolterodine has comparable efficacy to oxybutynin, but with injected into the bladders of rats. The results of the study14 a reduced incidence of adverse events (eg, dry mouth).37,39,40 showed that, in accordance with its activity in urine, trospium Although preliminary reports41,42 have drawn an association has a local inhibitory effect on detrusor overactivity. between tolterodine and impaired cognitive functioning, tolterodine is less lipophilic than oxybutynin and is therefore Conclusions less likely to cross the blood-brain barrier.43 Overactive bladder is a widespread disorder that is distressing Newer oral antimuscarinic agents darifenacin (7.5 mg and to patients and that is underdiagnosed and undertreated by 15 mg) and solifenacin (5 mg and 10 mg) were approved for the physicians. The detrimental impact of this condition on treatment of overactive bladder and urge incontinence by the patients’ QOL makes it of paramount importance that physi- FDA in 2003 and 2004, respectively. Both agents are well-tol- cians recognize and treat the symptoms associated with this erated and substantially reduce urge incontinence episodes, troublesome condition. By recognizing the symptoms of over- frequency, and urgency, and increase the volume of urine active bladder, it is possible for physicians to diagnose and treat voided.44-47 The most commonly reported adverse events for the condition within the primary care setting and without the both darifenacin and solifenacin are dry mouth and constipation. need for complex urodynamic assessments. Darifenacin has little affinity for the M1 muscarinic subtype Nonpharmacologic treatment options, alone or in com- receptor, a feature that is proposed to minimize cognitive effects bination with drug therapy, are effective in treating patients that might arise if the compound were to cross the blood-brain with overactive bladder. The development of new antimus- barrier. Accordingly, adverse cognitive effects have not been carinic agents and new formulations of more traditional agents reported for darifenacin.48 Solifenacin is a nonselective mus- widens the options available for the treatment of this disorder. carinic antagonist that binds to the M1, M2, and M3 muscarinic The differences in efficacy and tolerability profiles among receptors—though with slightly greater affinity for M1 and M3 available agents provide the opportunity for physicians to 49 27,49 receptors than M2 receptors. Animal studies suggest that choose the form of therapy that best suits the needs of the solifenacin has the highest degree of bladder selectivity compared individual patient. When treating elderly patients, for example, with oxybutynin, tolterodine, and darifenacin. In a recent head- consideration should be given to the use of agents with low to-head trial,50 a flexible dosing regimen with solifenacin was potential to cause cognitive adverse events, and low potential found to be superior to extended-release tolterodine for the for interaction with concomitant medications. majority of efficacy variables investigated. However, because this trial50 was designed to show non-inferiority, these results should References 1. Stewart WF, Van Rooyen JB, Cundiff GW, Abrams P, Herzog AR, Corey R, be viewed with caution. et al. Prevalence and burden of overactive bladder in the United States. Trospium, an antimuscarinic agent approved by the FDA World J Urol. 2003;20:327-336. in 2004 for the treatment of overactive bladder, has been avail- 2. Milsom I, Abrams P, Cardozo L, Roberts RG, Thüroff J, Wein AJ. How able in Europe for more than 20 years. The safety and effi- widespread are the symptoms of an overactive bladder and how are they man- aged? A population-based prevalence study [published correction appears in cacy of trospium have been demonstrated in clinical trials BJU Int. 2001;88:807]. BJU Int. 2001;87:760-766. involving over 3000 patients in the United States and Europe 3. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, et al; Stan- and have been further demonstrated with postmarketing dardisation Sub-Committee of the International Continence Society. The studies involving over 10,000 patients.13 Trospium is unique standardisation of terminology in lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. among the new antimuscarinic agents for several reasons: it has Urology. 2003;61:37-49. the least selectivity and the highest overall affinity for the 4. Malone-Lee J, Henshaw DJ, Cummings K. Urodynamic verification of an muscarinic receptor subtypes; it is a positively charged qua- overactive bladder is not a prerequisite for antimuscarinic treatment response. ternary amine, which prevents transfer across the blood-brain BJU Int. 2003;92:415-417. barrier; and it is minimally metabolized by cytochrome P-450 5. Abrams P, Kelleher CJ, Kerr LA, Rogers RG. Overactive bladder signifi- enzymes, with approximately 60% of the absorbed dose being cantly affects quality of life. Am J Manag Care. 2000;6(suppl 11):S580-S590. excreted in the urine in active form. In addition, this agent 6. Coyne KS, Payne C, Bhattacharyya SK, Revicki DA, Thompson C, Corey R, et al. The impact of urinary urgency and frequency on health-related quality demonstrates a rapid onset of effect, reducing frequency and of life in overactive bladder: results from a national community survey. Value urge incontinence within the first few days of treatment.15,34 Health. 2004;7:455-463. Trospium also has comparable efficacy to oral oxybutynin 7. Hu TW, Wagner TH, Bentkover JD, LeBlanc K, Piancentini A, Stewart WF, and tolterodine, but with fewer adverse events.51 The lack of cog- et al. Estimated economic costs of overactive bladder in the United States. Urology. 2003;61:1123-1128. nitive adverse effects may result from the inability of trospium 8. Kumar V, Cross RL, Chess-Williams R, Chapple CR. Recent advances in to transfer across the blood-brain barrier. The lack of adverse basic science for overactive bladder. Curr Opin Urol. 2005;15:222-226. drug-drug interactions is a result of the lack of metabolism by 9. Burgio KL, Locher JL, Goode PS. Combined behavioral and drug therapy cytochrome P-450 enzymes. Evidence supporting the possible for urge incontinence in older women. J Am Geriatr Soc. 2000;48:370-374. additional benefits of a compound that is active in the urine 10. Burgio KL. Influence of behavior modification on overactive bladder. was provided by a recent study14 in which urine from individ- Urology. 2002;60(5 suppl 1):72-77.

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11. Weinberger MW, Goodman BM, Carnes M. Long-term efficacy of non- 32. Van Kerrebroeck P, Kreder K, Jonas U, Zinner N, Wein A; Tolterodine Study surgical urinary incontinence treatment in elderly women. J Gerontol A Biol Group. Tolterodine once-daily: superior efficacy and tolerability in the treat- Sci Med Sci. 1999;54:M117-M121. ment of the overactive bladder. Urology. 2001;57:414-421. 12. Andersson KE, Yoshida M. Antimuscarinics and the overactive detrusor— 33. Chapple C, Steers W, Norton P, Millard R, Kralidis G, Glavind K, et al. A which is the main mechanism of action? Eur Urol. 2003;43:1-5. pooled analysis of three phase III studies to investigate the efficacy, tolerability 13. Höfner K, Oelke M, Machtens S, Grünewald V. Trospium chloride—an and safety of darifenacin, a muscarinic M3 selective receptor antagonist, in effective drug in the treatment of overactive bladder and detrusor hyper- the treatment of overactive bladder. BJU Int. 2005;95:993-1001. reflexia. World J Urol. 2001;19:336-343. 34. Zinner N, Gittelman M, Harris R, Susset J, Kanelos A, Auerbach S; Trospium 14. Kim YT, Yoshimura N, Masuda H, de Miguel F, Chancellor MB. Intraves- Study Group. Trospium chloride improves overactive bladder symptoms: a mul- ical instillation of human urine concentration of trospium, tolterodine and oxy- ticenter phase III trial. JUrol. 2004;171(pt 1):2311-2315. butynin in a rat model of detrusor overactivity. BJU Int. 2006;97:400-403. 35. Gleason DM, Susset J, White C, Munoz DR, Sand PK. Evaluation of a 15. Pak RW, Petrou SP, Staskin DR. Trospium chloride: a quaternary amine new once-daily formulation of oxybutynin for the treatment of urinary urge with unique pharmacologic properties. Curr Urol Rep. 2003;4:436-440. incontinence. Ditropan XL Study Group. Urology. 1999;54:420-423. 16. Schwantes U, Topfmeier P. Importance of pharmacological and physic- 36. Anderson RU, Mobley D, Blank B, Saltzstein D, Susset J, Brown JS. Once ochemical properties for tolerance of antimuscarinic drugs in the treatment daily controlled versus immediate release oxybutynin chloride for urge urinary of detrusor instability and detrusor hyperreflexia—chances for improvement incontinence. OROS Oxybutynin Study Group. JUrol. 1999;161:1809-1812. of therapy. Int J Clin Pharmacol Ther. 1999;37:209-218. 37. Katz IR, Sands LP, Bilker W, DiFilippo S, Boyce A, D’Angelo K. Identifica- 17. Chapple CR, Yamanishi T, Chess-Williams R. Muscarinic receptor sub- tion of medications that cause cognitive impairment in older people: the types and management of the overactive bladder. Urology. 2002;60(5 suppl case of oxybutynin chloride. J Am Geriatr Soc. 1998;46:8-13. 1):82-88. 38. Zinner NR, Mattiasson A, Stanton SL. Efficacy, safety, and tolerability of extended-release once-daily tolterodine treatment for overactive bladder in 18. Fetscher C, Fleichman M, Schmidt M, Krege S, Michel MC. M3 muscarinic receptors mediate contraction of human urinary bladder. Br J Pharmacol. older versus younger patients. J Am Geriatr Soc. 2002;50:799-807. 2002;136:641-643. Available at: http://www.nature.com/bjp/journal/v136 39. Sussman D, Garely A. Treatment of overactive bladder with once-daily /n5/full/0704781a.html. Accessed August 31, 2007. extended-release tolterodine or oxybutynin: the antimuscarinic clinical effec- 19. Fisher A, Michaelson DM, Brandeis R, Harring R, Chapman S, Pittel Z. M1 tiveness trial (ACET). Curr Med Res Opin. 2002;18:177-184. muscarinic agonists as potential disease-modifying agents in Alzheimer’s dis- 40. Diokno AC, Appell RA, Sand PK, Dmochowski RR, Gburek BM, Klimberg ease. Rationale and perspectives. Ann N Y Acad Sci. 2000;920:315-320. IW, et al; OPERA Study Group. Prospective, randomized, double-blind study 20. Andersson KE. Potential benefits of muscarinic M3 receptor selectivity. of the efficacy and tolerability of the extended-release formulations of oxy- Eur Urol. 2002;1(suppl):23-28. butynin and tolterodine for overactive bladder: results of the OPERA trial. Mayo Clin Proc. 2003;78:687-695. 21. Poslind H, Danielson Å, Lindgren A, Andersson SHG. Tolterodine, a new muscarinic receptor antagonist, is metabolized by the cytochromes P450 2D6 41. Womack KB, Heilman KM. Tolterodine and memory: dry but forgetful. and 3A in human liver microsomes. Drug Metab Dispos. 1998;26:289-293. Arch Neurol. 2003;60:771-773. Available at: http://dmd.aspetjournals.org/cgi/content/full/26/4/289. Accessed 42. Salvatore S, Serati M, Cardozo L, Uccella S, Bolis P. Am J Obstet Gynecol. September 17, 2007. 2007;197:e8. 22. Ditropan XL. Full US prescribing information page. Ditropan XL Web 43. Chapple CR. Muscarinic receptor antagonists in the treatment of overactive site. June 2004. Available at: http://www.ditropanxl.com/html/pdxl/prescribing bladder. Urology. 2000;55(suppl 5A):33-46,50. _consumer.jsp?. Accessed August 31, 2007. 44. Chapple CR, Rechberger T, Al-Shukri S, Meffan P, Everaert K, Huang M, 23. Prescribing information. Detrol LA Web site. 2006. Available at: et al; YM-905 Study Group. Randomized, double-blind, placebo- and toltero- http://www.detrolla.com/cwpb/appmanager/detrolLA/detrolLADesktop?_nfpb dine-controlled trial of the once-daily antimuscarinic agent solifenacin in =true&_pageLabel=detrolLA_prescribingInformation. Accessed August 31, patients with symptomatic overactive bladder. BJU Int. 2004;93:303-310. 2007. 45. Chapple CR. Darifenacin: a novel M3 muscarinic selective receptor antag- 24. Do more about your bladder problems with VESIcare. VESIcare Web onist for the treatment of overactive bladder. Expert Opin Investig Drugs. site. July 2007. Available at: http://www.vesicare.com. Accessed August 31, 2007. 2004;13:1493-1500. 25. Prescribing information. Enablex Web site. December 2004. Available at: 46. Haab F, Stewart L, Dwyer P. Darifenacin, an M3 selective receptor antag- http://www.enablex.com/content/prescribing.jsp. Accessed August 31, 2007. onist, is an effective and well-tolerated once-daily treatment for overactive 26. Sanctura.com. Sanctura Web site. July 2004. Available at: http://www.sanc- bladder. Eur Urol. 2004;45:420-429. tura.com. Accessed August 31, 2007. 47. Gittelman M, Klimberg I, Fincer R, et al. Two randomized, double-blind, 27. Kershen RT, Hsieh M. Preview of new drugs for overactive bladder and placebo-controlled, parallel-group, fixed-dose, multicenter studies assess the incontinence: darifenacin, solifenacin, trospium, and duloxetine. Curr Urol Rep. efficacy and safety of daily oral administration of 10mg YM905 versus placebo 2004;5:359-367. in male and female subjects with overactive bladder [abstract]. JUrol. 2003; 169(suppl):351. DP43. 28. Siddiqui MA, Perry CM, Scott LJ. Oxybutynin extended-release: a review of its use in the management of overactive bladder. Drugs. 2004;64:885-912. 48. Lipton RB, Kolodner K, Wesnes K. Assessment of cognitive function of the elderly population: effects of darifenacin. J Urol. 2005;173:493-498. 29. OXYTROL:HCP - US prescribing information. Information for healthcare professionals page. Oxytrol Web site. June 2005. Available at: http://www. 49. Ikeda K, Kobayashi S, Suzuki M, Miyata K, Takeuchi M, Yamada T, et al. oxytrol.com/hcp/hcp_about_prescribing.asp. Accessed August 31, 2007. M3 receptor antagonism by the novel antimuscarinic agent solifenacin in the urinary bladder and salivary gland. Naunyn Schmiedebergs Arch Pharmacol. 30. Dmochowski RR, Davila GW, Zinner NR, Gittelman MC, Saltzstein DR, 2002;336:97-103. Lyttle, et al, for the Transdermal Oxybutynin Study Group. Efficacy and safety of transdermal oxybutynin in patients with urge and mixed urinary inconti- 50. Chapple CR, Martinez-Garcia R, Selvaggi L, Toozs-Hobson P, Warnack W, nence. JUrol. 2002;168:580-586. Drogendijk T, et al, for the STAR Study Group. A comparison of the efficacy and tolerability of solifenacin succinate and extended release tolterodine at 31. Dmochowski RR, Sand PK, Zinner NR, Gittelman MC, Davila GW, Sanders treating overactive bladder syndrome: results of the STAR trial. Eur Urol SW; the Transdermal Oxybutynin Study Group. Comparative efficacy and 2005;48:464-470. safety of transdermal oxybutynin and oral tolterodine versus placebo in pre- viously treated patients with urge and mixed urinary incontinence. Urology. 51. Rovner ES. Trospium chloride in the management of overactive bladder. 2003;62:237-242. Drugs. 2004;64:2433-2446.

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