Pharmacotherapy of Urinary Incontinence

Pharmacotherapy of Urinary Incontinence Thomas E. Lackner, PharmD, CGP, FASCP

The most effective pharmacotherapy for decreasing the strength of detrusor contractions, improving bladder storage of urine, and improving patient symptoms is the use of anticholinergic/antispasmodic agents.1 From this category, oxybutynin immediate-release (OIR), oxybutynin extended-release (OXL), tolterodine immediate-release (TIR), and tolterodine extended-release (TLA) tablets constitute first-line therapies (Table 1).2 Differences in efficacy, adverse effects, drug interactions, patient tolerability, administration convenience, and drug cost determine drug selection (Table 1). Although OIR is the least expensive (direct cost) pharmacotherapy and is no less effective or expedient in providing symptom relief than any of the first-line urinary incontinence (UI) management options, it is poorly tolerated and inconvenient to administer (Table 1).3–26 These disadvantages largely explain a high short-term patient withdrawal rate of approximately 25%.1,3,9 –13,19,20 Drug discontinuation is predominantly related to xerostomia.3–7,9 –20 Other than the pharmacodynamic effect of worsening anticholinergic effects with multiple drugs having anticholinergic activity, there are no known significant drug-drug interactions with OIR (Table 2).24,27 In addition to untoward anticholinergic effects, histamine1-receptor blockade can cause sedation and alpha1-receptor antagonism can precipitate postural hypotension (Table 1).4,5 These dose-related adverse effects may also indirectly impair efficacy by preventing dose escalation up to an optimal therapeutic level. OIR is best tolerated when started at a dosage of 2.5 mg bid, then escalated in increments of 2.5 mg once daily at 1 to 2-month intervals up to optimal UI control (generally doses no larger than 5 mg tid) or unacceptable adverse effects (Table 1).3 There are no medical conditions (eg, renal or hepatic impairment) that require adjustment of OIR dosage.24 One controlled trial demonstrated that OXL is significantly more effective than placebo, and several others have shown it is as effective as OIR in improving urodynamic and clinical symptoms of urge UI. Specifically, OXL increases the urine volume voided per micturition, increases the number of micturitions, decreases the number of UI episodes, and sometimes Professor and Director of Clinical Services, College of Pharmacy, University of Minnesota and The Institute for the Study of Geriatric Pharmacotherapy, Minneapolis, MN Address correspondence to Thomas E. Lackner, PharmD, CGP, FASCP, Professor and Director of Clinical Services, College of Pharmacy, University of Minnesota and The Institute for the Study of Geriatric Pharmacotherapy, 7-115E Weaver-Densford Hall, 308 Harvard Street SE, Minneapolis, MN 55455. E-mail [email protected]

Copyright ©2002 American Medical Directors Association S16 Lackner

restores continence.11–14,16,25,26 Like OIR, maximum efficacy may not be realized for 4 to 5 weeks after therapy is begun.3 Despite being chemically identical to OIR, OXL is associated with a significantly lower rate of xerostomia and patient withdrawal (approximately 8%), one-third that of the OIR formulation.19,25 A single noncontrolled study found no difference in the rate of xerostomia between OIR and OXL. However, patients receiving OXL had a significantly lower cumulative percentage of xerostomia at all studied dosage levels (5, 10, 15, and 20 mg).28 The lower rate of dry mouth and superior tolerability of the OXL compared with OIR is believed to result from a one-third lower concentration of a toxic metabolite, N-desethyloxybutynin, consequent to diminished first-pass metabolism, as well as a substantially lower maximum plasma concentration that is directly related to anticholinergic toxicity.25,29 –32 The incidence and severity of less common adverse effects appear to be similar to those experienced with OIR (Table 1). There is no difference in the incidence or severity of adverse effects between elderly people and younger adults. The direct drug cost of OXL is greater than that of OIR. However, because medication cost is relatively small compared with the total care costs of UI and because its complications and cost savings can only be realized by continuing therapy, the better-tolerated OXL formulation offers the potential for greater cost savings.33 An additional advantage of OXL over OIR is that unlike the multiple daily doses necessary for OIR, OXL is administered once daily. For these reasons, OXL is preferred as initial therapy in patients intolerant to OIR or individuals at high risk of intolerance, such as those with preexisting xerostomia or its complications of anorexia, taste or vision disturbances, difficulty chewing or swallowing, or other esophageal dysmotility disorders. OXL should be started at the lowest recommended dose of 5 mg once daily and increased by no more than 5-mg increments every 1 to 2 months.25 The elimination, ie, dosage, of OXL is not altered in patients with renal or hepatic insufficiency or in geriatric patients (up to 78 years of age).25 Except for the possible potentiation of untoward anticholinergic effects from multiple anticholinergic medications, there are no known significant drug-drug interactions.25 TIR and TLA are competitive muscarinic receptor antagonists. The urinary bladder is populated by two of five known cholinergic receptor subtypes, M2 and M3, whereas M3 is also located in the parotid glands, where it stimulates salivation. In the urinary bladder, M3 mediates bladder contraction, whereas M2 opposes the effect of beta-receptor-mediated smooth muscle relaxation during urine storage.34 –36 TIR exhibits selectivity for M2 compared with M3 receptors; OIR exhibits the opposite selectivity.37– 41 The clinical significance JAMDA – January/February 2002

SUPPLEMENT

Lackner S17

Oxybutynin IR: 2.5–5 mg bid-tid XL: 5–30 mg qd Tolterodine IR: 1–2 mg bid LA: 2–4 mg qd Tricyclic antidepressants (nortriptyline, desipramine, imipramine) 25–100 mg/day Estrogen (only for urethritis, vaginitis) 0.5 g vaginal cream 3⫻/ week, maintenance of 1–2⫻/week, or 1 (2 mg) estradiol vaginal ring/insert placed for 90 days, or oral conjugated estrogen/progestin 0.625/2.5 mg once daily ␣1-receptor antagonists (only for urge UI symptoms due to benign prostatic hyperplasia) ␣-receptor agonists Ephedrine 25 mg bid Pseudoephedrine 15–45 mg tid Tricyclic antidepressants 25–100 mg qd Estrogen

Urge UI

Bethanechol 10–30 mg bid-qid (short-term use only) (cholinergic)

Overflow with neurogenic bladder

Xerosis, constipation, dyspepsia, tachycardia, abnormal visual accommodation, headache, urinary retention, confusion (especially at high doses and comedication with anticholinergic activity; Table 2)

Anticholinergic as above, postural hypotension, weakness, cardiac arrhythmias, high-risk overdose potential Endometrial/breast cancer, nausea, vaginal bleeding/spotting, edema, bloating, mastodynia, headache

Antagonize muscarinic cholinergic receptors to decrease strength of detrusor contractions, increase bladder volume before contraction, and increase maximal bladder capacity. Oxybutynin is also a direct smooth muscle relaxant Decrease bladder contractility, increase urethral resistance

As above As above

As above As above. Also, increases receptor number and tissue response to ␣-adrenergic stimulation Relax smooth muscle tone in bladder neck and proximal urethra, reducing urethral pressure

Decreases prostate volume by inhibiting conversion of testosterone to dihydrotestosterone (responsible for prostate growth) Acetylcholine agonist increases bladder contractility

Anxiety, agitation, restlessness, insomnia, headache, tachycardia, increased blood pressure, sweating, cardiac arrhythmias

Increase urethral resistance by increasing muscle tone in bladder trigone, base, proximal urethra

Diarrhea, abdominal cramps, bronchoconstriction, bradycardia, hypotension, dizziness, headache, and aggravates peptic ulcers, seizures, Parkinson’s disease, and hyperthyroidism

Decreased libido, erectile impairment, impotence, gynecomastia

Dizziness, asthenia, peripheral edema, fatigue, postural hypotension, first-dose syncope, headache, tachycardia, dyspnea

See Overflow (obstructive)

See Overflow (obstructive)

Improves periurethral vascularity, tone, and coaptation. Decreases bladder contractility, increases urethral closure pressure

Adverse Reactions

Mechanism(s) of Action

UI denotes urinary incontinence; IR, immediate release; XL, extended release; HS, at bedtime; BPH, benign prostatic hyperplasia.

Long-acting selective ␣1-antagonists Doxazosin 1–5 mg q HS Tamsulosin 0.4–0.8 mg pc Terazosin 1–5 mg q HS Finasteride 5 mg q d (antiandrogen)

Obstructive overflow UI (BPH)

Stress UI

Drug/Dosage

Incontinence Type

Table 1. Pharmacotherapy Mechanism and Adverse Drug Reactions

Table 2. Commonly Prescribed Medications With Anticholinergic Activity Antibiotics Anticholinergics (non-anti-incontinence use) Atropine (ophthalmic) Benztropine Trihexphenidyl Antidepressants Amitriptyline Amoxapine Clomipramine Desipramine Doxepin Imipramine Nortriptyline Trazodone Antidiarrheal Diphenoxylate/atropine Antihistamines Brompheniramine Cetirizine Chlorpheniramine Clemastine Cyproheptadine Diphenhydramine Doxylamine Hydroxyzine Meclizine Antiparkinsonian Amantidine Antiplatelets Antipsychotics Chlorpromazine Olanzapine Quetiapine Thioridazine Antispasmodic (gastrointestinal) Belladonna Dicyclomine Hyoscyamine Scopolamine Benzodiazepines Cardiovascular Captopril Digoxin Dipyridamole Furosemide Isosorbide Nifedipine Triamterene/hydrochlorothiazide Histamine2-receptor antagonists Cimetidine Ranitidine Narcotics Codeine Meperidine Oxycodone Theophylline Warfarin Adapted from References 27 and 125.

of the selectivity of tolterodine is uncertain but may explain, at least in part, the lower rate of xerostomia than is seen with OIR. Several controlled studies of TIR demonstrated that it was significantly more effective than placebo and equally S18 Lackner

effective as OIR in relieving symptoms of urgency and frequency, decreasing the number of micturitions per day, and increasing the volume voided per micturition.6 – 8,18,42,43 The maximum efficacy may not be realized for approximately 8 to 10 weeks of therapy.18 However, three of six placebo-controlled studies demonstrated that TIR did not significantly decrease the mean or median number of UI episodes over baseline compared with placebo.6,7,43 Consistent with this finding, the manufacturer’s product information does not claim that TIR significantly decreases UI episodes.19 A significant but modest reduction in incontinence episodes over placebo was reported in the remaining three TIR studies and a single TLA study (two of three studies represent the same data set).18,44 However, the results of one of those studies showing significance are diminished by the highly unusual absolute lack of a placebo response. Conversely, the brief 4-week trial for tolterodine, which requires up to 10 weeks for a maximum response, may have contributed to the modest response that was achieved.42 A review of all published controlled trials indicates both TIR (23%) and TLA (23%) produce a smaller decrease in incontinence episodes than either OIR (33%) or OXL (41%). In the only “head-to-head” comparative trial of OXL 10 mg once daily and TIR 2 mg twice daily, an approximately 30% significantly greater reduction in UI episodes with urge UI or mixed UI was achieved with OXL compared with TIR at the study conclusion after 12 weeks of therapy.45 In the only study that evaluated the effect of TIR on restoring complete continence, an insignificant 9% drug effect rate over placebo was reported.43 Although there are few comparative data and no direct comparisons, this continence rate is lower than rates of 10% to 45% reported for OIR and OXL, respectively.10,13,15 Overall, TIR and TLA are tolerated as well as OXL and better than OIR, with a discontinuation rate of approximately 8%.6,18 –21,44 – 47 Xerosis, xerophthalmia, dyspepsia, headache, and constipation are typical adverse effects of TIR and TLA (Table 1).19,21 Like OIR and OXL, patient withdrawal is predominantly related to xerosis.6 – 8,18,42,43 Xerosis is significantly less common with TIR than with OIR.6,7,18 Although unproven, this difference may be due to the lower selectivity of tolterodine and its only active metabolite, DDO1, for M3 receptors compared with that of OIR. The equivalent rate of xerosis for OXL compared with TIR is attributed to pharmacokinetic characteristics related to its unique delivery system.25 The risk of adverse central nervous system (CNS) effects, including cognitive impairment, posed by anticholinergic therapy, especially in individuals with preexisting cognitive impairment associated with a cholinergic deficiency (eg, Alzheimer’s disease), is unclear.48,49 One small controlled, singledose study of 12 cognitively intact subjects (mean age 69 years) receiving OIR 5 and 10 mg, diphenhydramine 50 mg, and placebo noted similar acute cognitive decrements with OIR (7 of 15 cognitive measures) as with diphenhydramine (5 of 15 measures) but without clinically important adverse reactions reported.50 Although a small number of case reports have implicated OIR in adverse neuropsychiatric effects such as acute mental confusion, with or without hallucinations, a JAMDA – January/February 2002

causal relationship has not been proved.49,51 Some aspects of the pharmacological profile for TIR/TLA and its active metabolite (DD01) raise the possibility of fewer and less severe adverse CNS effects (lower lipophilicity and CNS penetration) than with OIR/OXL.38 – 41,52 However, there is insufficient information to support this hypothesis. The relative potential for adverse CNS effects was estimated indirectly by quantitative electroencephalography (qEEG) in a single study comparing TIR 2 mg bid (n ⫽ 16), trospium chloride 15 mg tid (n ⫽ 16), OIR 5 mg tid (n ⫽ 16), and placebo (n ⫽ 16) in young healthy volunteers (mean age 25 years).53 Compared with placebo (10% confidence interval), TIR and trospium chloride did not induce changes of the qEEG power in five of the six frequency bands (ie, delta, alpha1, alpha2, beta1, and beta2). Conversely, OIR caused significant power reductions in four of the frequency bands (ie, theta, alpha1, alpha2, and beta1). However, the significance of these findings is uncertain because the correlation between the results of qEEG and clinical CNS effects is unproven.53 In the same study, there were no significant differences in the number of adverse effects between OIR and TIR, and no serious adverse effects were reported with either drug. Moreover, several placebocontrolled comparative trials between OIR and TIR demonstrated no significant differences in the incidence or severity of overt CNS toxicity.7,17,18 A direct comparative controlled trial of TIR and OXL demonstrated no significant differences in overt CNS adverse effects (ie, dizziness, somnolence, asthenia, insomnia, or nervousness). However, none of these studies conducted neuropsychiatric testing to evaluate the potential differences in possible subclinical cognitive impairment.45 Controlled direct comparative trials are needed to determine whether there are significant differences in cognitive impairment (acute and chronic) between TIR/TLA and OIR/OXL and to reaffirm the absence of differences in overt CNS toxicity. TIR and TLA are primarily eliminated in extensive metabolizers (most patients) by hepatic metabolism by CYP450 2D6.19,21 Significantly impaired elimination has been demonstrated in patients devoid of CYP2D6 isozymes (7% of the population) taking potent CYP3A4 inhibitors, in which case this alternative pathway for TIR/TLA metabolism becomes the predominant means of elimination (according to the TIR and TLA inserts). Although no clinically significant drug interactions involving CYP2D6 are established, caution is advised when tolterodine is used with drugs metabolized by CYP2D6.54 Conditions that require a reduction in the usual dose of TIR and TLA are renal impairment, hepatic cirrhosis, and individuals receiving potent CYP3A4 inhibitors (eg, macrolide and imidazole-type antimicrobials, fluoxetine, paroxetine, or grapefruit juice); in these cases, the initial dose should be decreased by 50% (Table 1).19,22 No dose adjustment of TIR or TLA is needed for advanced age per se.19,22 Unlike with OIR or OXL, antacids and possibly proton pump inhibitors and histamine2-receptor antagonists significantly increase the maximum plasma concentration of TLA (150% higher than without antacid), which is associated with a rapid and unsteady release of drug that resembles the absorption pharmaSUPPLEMENT

cokinetics of the immediate-release formulation.23,25,55 TLA should be used cautiously in this case because the risk of toxicity may be increased.55 Other pharmacotherapy for urge UI is no more effective than OIR/OXL and/or is associated with a similar or greater incidence of serious adverse reactions and, therefore, is not recommended or considered second-line therapy (Table 1).1,4,5 Because of a lack of superior efficacy over OIR/OXL and a high incidence of bothersome or serious adverse reactions, tricyclic antidepressants are a second-line treatment for urge UI and should be limited to use in individuals with nocturnal incontinence refractory to fluid management and possibly in those with an additional medical indication (eg, depression or painful neuropathy; Table 1).1,4,5,56,57 The only other benefit for UI found with tricyclics (eg, imipramine or doxepin) has been a nonsignificant decrease in incontinence frequency.56,57 Because tricyclics increase urinary bladder outlet resistance and decrease bladder contractility, they may be most useful for individuals with combined urge and stress UI (ie, mixed UI).1 Despite a lack of evidence-based information about their efficacy, but given the lower risk of adverse drug reactions than with imipramine and doxepin, desipramine and nortriptyline are preferred as initial tricyclics.1,2 The results of three small controlled studies demonstrated that the anticholinergic drug propantheline produced a generally small benefit (approximately 13 to 17% decrease in incontinence episodes) over placebo at doses of 30 mg qid and 15 mg tid plus 60 mg at bedtime, which was significantly different from placebo in two of the studies.58 – 60 In two other studies comparing propantheline (15 and 30 mg tid) with OIR (5 mg tid), the urodynamic (maximum cystometric capacity, mean bladder volume at first involuntary cystometric contraction, and maximum detrusor pressure rise on filling) and clinical responses favored OIR, but all differences were not significant.61,62 However, the numerous adverse effects of propantheline together with only modest efficacy discourages its use.1 Four controlled trials of flavoxate, a smooth muscle relaxant with moderate anticholinergic properties, demonstrated no significant difference in various clinical measures, including incontinence episodes, over placebo.1 Therefore, it is not recommended for management of urge UI.1 There is limited evidence supporting the use of dicyclomine hydrochloride, a direct smooth muscle relaxant with anticholinergic effects, for urge UI. In the only controlled study, urge UI was improved in 62% of subjects receiving dicyclomine 10 mg tid (continence restored in 90%) compared with 20% receiving placebo (continence restored in 65%). However, these data were not analyzed statistically.63 The results of a smaller pilot study were similar.64 Lacking sufficient information, the use of the muscle relaxant and anticholinergic agent hyoscyamine is not recommended.1 Anticholinergic adverse reactions, particularly xerosis, common to all of the pharmacotherapies for urge UI can be managed with saliva substitutes and stimulants, dose reduction or drug discontinuation, and avoidance of comedication of anticholinergic activity (ie, anticholinergic burden; Table 2). Lackner S19

Because estrogen improves periurethral vascularity, tone, and coaptation, resulting in decreased urinary bladder contractility and increased urethral resistance, it has been recommended for management of urge UI associated with atrophic vaginitis and urethritis.65 Clinically, estrogen has been shown to relieve vaginal dryness and atrophy.66 However, the results of its efficacy in mitigating urge UI symptoms in randomized trials in urge UI are equivocal.67–70 A small, randomized, short-term study reported subjective improvement in mixed UI with oral estrogen compared with placebo, and another study noted a higher “cure rate” with oral estrogen than with placebo.67,68 However, a large 4-year (mean) controlled study of postmenopausal women (mean age 67 years) with urge UI (n ⫽ 393) or mixed UI (n ⫽ 783) demonstrated a worsening of both UI types with estrogen 0.625 mg plus medroxyprogesterone 2.5 mg once daily compared with placebo.70 It is unknown whether progestin diminishes the anti-incontinence efficacy of estrogen therapy. Although unproven, some women with urethritis or vaginitis and especially individuals with mixed UI may benefit from topical estrogen therapy, with or without an anticholinergic drug. One controlled trial of intravaginal estrogen tablets found a significant improvement in subjective symptoms of urge or stress UI and dysuria (63%) compared with placebo (32%) in women with atrophic vaginitis.71 Maintenance therapy with estrogen cream is sufficient to prevent the recurrence of atrophic vaginitis.66 Alpha1-receptor antagonists such as terazosin and tamsulosin can improve incontinence symptoms in men with urge incontinence related to irritative symptoms of benign prostatic hyperplasia (BPH).72 STRESS UI As determined by a small number of controlled trials and several open trials, alpha1-receptor agonists are modestly effective for relieving symptoms of mild stress UI, with improvement rates up to approximately 30% over placebo.73– 82 However, their use is limited by a high prevalence of cardiovascular contraindications (eg, hypertension, coronary artery disease, myocardial infarction, or tachyarrhythmias) and the recent withdrawal of phenylpropanolamine, the most widely studied and used alpha1-receptor agonist, from the US market because of an unacceptably high rate of strokes in women. Ephedrine was effective in a single open-label study, whereas pseudoephedrine has not been evaluated adequately.77 Although epidemiological studies found an increased prevalence of incontinence in women using estrogen replacement, evidence from several open trials suggested that estrogen may provide symptomatic improvement in patients with stress UI.83– 85 However, five controlled trials of oral estrogen demonstrated no significant urodynamic or clinical benefit compared with placebo (Table 2).67,70,86 – 88 Most recently, a large placebo-controlled trial in 349 postmenopausal women (mean age 67 years) demonstrated no significant benefit from the combination of oral conjugated estrogen 0.625 mg and medroxyprogesterone acetate 2.5 mg administered once daily for a mean of 4 years.70 S20 Lackner

The role of topical estrogen is unclear. One controlled study of vaginal cream demonstrated significant improvement in urgency symptoms in stress UI symptoms and the urine volume lost, with the largest improvement in subjects receiving vaginal estrogen compared with oral estrogen.89 Whereas estrogen increases the receptor number and tissue response to alpha1-receptor agonists, the combination of an alpha1-receptor agonist and estrogen is only somewhat more effective (5-10%) than an alpha1-receptor agonist alone.90 –94 The tricyclic antidepressant imipramine 25 mg tid cured UI in 35% of women (median age 52 years) and improved pad weight ⱖ50% in another 25% of the patients as demonstrated by pad weight measurement.95 Two previous studies, one involving only subjective assessment of patient response, noted cure rates of approximately 70%.93,96 However, no placebo-controlled studies of imipramine or other tricyclics have been conducted, and the threat of serious adverse effects is particularly great in elderly people. Therefore, the use of tricyclics should be considered only after other options have failed to adequately control stress UI (Table 1). MIXED INCONTINENCE Mixed UI is best managed by directing therapy against the predominant UI type (Table 1). In patients for whom other therapies fail, imipramine may be useful because it exhibits both alpha-receptor agonist and anticholinergic effects. In this case, careful monitoring for adverse reactions is imperative. Because tricyclic antidepressants can cause life-threatening QT-interval depression with cardiac arrhythmias, it is recommended that an ECG be performed and the plasma concentration be measured before and approximately 1 week after therapy is begun or the dose is increased (ie, steady-state plasma concentrations). More than one drug is sometimes necessary to control mixed UI. OBSTRUCTIVE OVERFLOW INCONTINENCE The typical causes of anatomic obstruction in women (ie, severe pelvic floor prolapse or anti-incontinence surgery) are managed by nonpharmacological procedures.1 Conversely, there are multiple pharmacological options for managing moderate to severe or bothersome symptoms of BPH, the most common cause of anatomic obstruction in male patients.72 Pharmacotherapy of BPH is less effective than surgical interventions (eg, transurethral resection of the prostate) but is often safer and is useful in patients for whom invasive procedures are unsuitable.72 The most effective and expedient pharmacotherapy for prostatism (obstructive and irritative symptoms) related to BPH is alpha1-receptor antagonists, with significant improvement noted within 2 to 6 weeks of starting therapy (Table 1).97–101 All of the individual alpha1receptor antagonists have generally been found to be similarly effective in ameliorating prostatism, with symptom improvement in up to approximately 25% of patients.102 In 29 women (mean age 61 years), one small controlled study found terazosin ineffective in relieving prostatism-like symptoms. However, urodynamics to categorize the underlyJAMDA – January/February 2002

ing pathophysiology of the irritative voiding symptoms were not conducted.103 A small open, prospective, crossover study of the clinical effects of hyoscyamine 0.375 mg bid (n ⫽ 31), doxazosin 2 mg at bedtime (n ⫽ 25), or the combination (n ⫽ 13) was conducted in 34 women (mean age 62 years) with symptoms of urgency and frequency along with a urodynamic assessment of baseline patient characteristics. Approximately two-thirds of women improved on hyoscyamine or doxazosin, and 77% improved on the combined therapy. Significant mean improvement in the American Urological Association scores over the mean baseline score of 19 were 34%, 30%, and 48% for hyoscyamine, doxazosin, and the combined therapies, respectively. One-half of the subjects unresponsive to hyoscyamine improved with doxazosin or the combination, whereas 38% unresponsive to doxazosin improved with hyoscyamine or the combination. Although not significantly different, a larger proportion of women with elevated voiding pressures (⬎30 cm of water) or decreased compliance responded to doxazosin than hyoscyamine.104 These equivocal results indicate the need for further study to determine whether a subgroup of women with prostatism-like symptoms (eg, dysfunction of the bladder neck or urethra) might benefit from therapy with an alpha1-receptor antagonist. Alpha1-receptor antagonists are generally well tolerated but can cause postural hypotension and dizziness, among other adverse effects (Table 1). However, little decline in blood pressure or postural change has been demonstrated with the only prostate-selective (subtype alpha1A-adrenoreceptor) and lower urinary tract-selective alpha1-receptor antagonist, tamsulosin, even in individuals undergoing concomitant antihypertensive pharmacotherapy.102,105–107 Tamsulosin may also cause less asthenia than the other alpha1-receptor antagonists. Alpha1-receptor antagonists, particularly tamsulosin, are moderately effective in managing hypertension. Therefore, they may not obviate the need for an additional antihypertensive in the patient with hypertension. In addition, a large controlled study (ALLHAT) found a significant 25% higher rate of overall cardiovascular morbidity and twice the incidence of heart failure in hypertensive patients receiving doxazosin compared with those receiving chlorthalidone.108 Until this risk can be evaluated in nonhypertensive patients with BPH, additional caution is advised in monitoring all individuals using alpha1-receptor antagonists. Alpha1-receptor antagonists, particularly doxazosin, should be avoided in persons with heart failure with mild to moderate systolic dysfunction.109 It is unknown whether the same risks are incurred with other alpha1-receptor antagonists or in nonhypertensive patients with BPH. Although unproven, the concurrent use of a diuretic or possibly another antihypertensive agent in the patient with hypertension may lessen this risk.109 Because several controlled trials demonstrated that finasteride was less effective in relieving prostatism, with a considerably slower onset to maximum effect (6 to 12 months), than alpha1-receptor antagonists, it is often reserved for individuals for whom alpha1-receptor antagonists are contraindiSUPPLEMENT

cated or in patients with large prostates ⬎40 mL volume (best responders) who are most responsive to therapy.98,110 Several placebo-controlled trials have demonstrated symptom improvement in up to 30% of patients and a 34 to 50% decrease in the need for operative procedures.111–114 A placebo-controlled trial found that the combination of finasteride and terazosin was no more effective than the alpha1-receptor antagonist alone.98 Finasteride interferes with prostate specific antigen measurement without having any effect on the prostate tumor, which necessitates that the result be multiplied by a factor of two before its interpretation. The results of 18 clinical trials suggest that saw palmetto, the best studied phytotherapy for BPH, is as effective as finasteride in mitigating prostatism and approximately 50% better tolerated, with a similar but lower incidence of adverse effects (3%) than finasteride (3-5%).115 Because saw palmetto is a mild 5-alpha-reductase inhibitor, it is plausible that it could interfere with prostate specific antigen measurement, like finasteride, but this remains uncertain.116 It also acts by reducing smooth muscle tone. A therapeutic effect depends on the presence of either a lipophilic extract or the whole berry. Disadvantages of saw palmetto, resulting from its nonlegend status, are its availability without a prior physical examination (risk of not detecting cancer or determining the specific UI type), potentially significant variability in potency and purity, and a lack of insurance coverage.117 The efficacy of other nontraditional therapies, including soy, zinc, and selenium supplementation, is unsupported by medical evidence. OVERFLOW INCONTINENCE WITH NEUROGENIC BLADDER There is no established effective pharmacotherapy for neurogenic overflow. The efficacy of bethanechol, a cholinergic agonist, is uncertain.118 Preliminary evidence suggests that bethanechol may relieve symptoms in patients with neurogenic overflow of short duration and that related to neurological disease or acute bladder overdistention.119 In summary, alpha1-receptor antagonists are generally the first-line therapy for mild to moderate BPH. In patients at high risk for acute urinary retention, unresponsive or intolerant of alpha1-receptor antagonists, or with a prostate enlarged to 40 mL or greater, finasteride is an option. Bethanechol has a limited role, if any, in managing neurogenic overflow. In the author’s opinion, many elderly people lack the compulsory cognitive and/or physical functioning and motivation to successfully execute many behavioral interventions. Additional barriers to successful behavioral management of UI are inadequate information to identify optimal candidates for the particular intervention and insufficient support staff or insufficient staff knowledge to provide the therapy. Moreover, the delayed response time and diminishing efficacy over time increases patient nonadherence. Finally, behavioral therapy may circumvent possibly superior pharmacotherapy. For these reasons, pharmacotherapy often constitutes a first-line approach to managing UI.121–123 Moreover, pharmacotherapy can be an important adjunct to behavioral therapy.3,124 Lackner S21

REFERENCES 1. Fantl JA, Newman DK, Coiling J, et al. Urinary Incontinence in Adults: Acute and Chronic Management. Rockville, MD: US Dept of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research Clinical Practice Guidelines No. 2, 1996 Update. AHCPR publication 96 – 0682, 1996. 2. Rovner ES, Wyman JF, Lackner TE, et al. Urinary incontinence. In: Dipiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach, 5th ed. Stamford, CT: McGraw-Hill/Appleton & Lange, in press. 3. Burgio KL, Locher JL, Goode PS, et al. Behavioral vs drug treatment for urge urinary incontinence in older women. JAMA 1998;280:1995– 2000. 4. Thuroff JW, Chartier-Kastler E, Corcus J, et al. Medical treatment and medical side effects in urinary incontinence in the elderly. World J Urol 1998;16(suppl 1):S48 –S61. 5. Owens RG, Karram MM. Comparative tolerability of drug therapies used to treat incontinence and enuresis. Drug Saf 1998;19:123–139. 6. Abrams P, Freeman R, Anderstrom C, Mattiasson A. 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. 7. Drutz HP, Appell RA, Gleason D, et al. Clinical efficacy and safety of tolterodine compared to oxybutynin and placebo in patients with overactive bladder. Int Urogynecol 1999;10:283–289. 8. Chancellor M, Freedman S, Mitcheson HD, et al. Tolterodine, an effective and well tolerated treatment for urge incontinence and other overactive bladder symptoms. Clin Drug Invest 2000;19:83–91. 9. Tapp AJS, Cardozo LD, Versi E, Cooper D. The treatment of detrusor instability in postmenopausal women with oxybutynin chloride: A double blind placebo controlled study. Br J Obstet Gynaecol 1990;97: 521–526. 10. Riva D, Casolati E. Oxybutynin chloride in the treatment of female idiopathic bladder instability. Clin Exp Obstet Gynecol 1984;11:37– 42. 11. Nilsson CG, Lukkari E, Haarala M, et al. Comparison of a 10-mg controlled release oxybutynin tablet with a 5-mg oxybutynin tablet in urge incontinent patients. Neurourol Urodyn 1997;16:533–542. 12. Birns J, Malone Lee JG, and the Oxybutynin CR Study Group. Controlled-release oxybutynin maintains efficacy with a 43% reduction in side effects compared with conventional oxybutynin treatment. Neurourol Urodyn 1997;16:429 – 430. 13. Schmidt RA, the Oxybutynin XL Study Group. Efficacy of controlledrelease, once-a-day oxybutynin chloride for urge urinary incontinence. Presented at: International Continence Society; Sept. 14 –17, 1998; Jerusalem. 14. Zinner NR. Patient-oriented outcomes with once-daily oxybutynin for urge incontinence (abstract). Obstet Gynecol 1999;93(suppl):29. 15. Moore KH, Hay DM, Imrie AE, et al. Oxybutynin hydrochloride (3 mg) in the treatment of women with idiopathic detrusor instability. Br J Urol 1990;66:479 – 485. 16. Anderson RU, Mobley D, Blank B, et al, for the OROS® Oxybutynin Study Group. Once daily controlled versus immediate-release oxybutynin chloride for urge urinary incontinence. J Urol 1999;161:1809 –1812. 17. Malone-Lee J, Shaffu B, Anand C, et al. Tolterodine: Superior tolerability than and comparable efficacy to oxybutynin in individuals 50 years old or older with overactive bladder: A randomized controlled trial. J Urol 2001;165:1452–1456. 18. Appell RA. Clinical efficacy and safety of tolterodine in the treatment of overactive bladder: A pooled analysis. Urology 1997;50(suppl 6A): 90 –96. 19. Ditropan: Data on file [ALZA Corporation Web site]. 1998. Available at: http://www.alza.com. Accessed Aug. 25, 2001. 20. Ditropan XL: Data on file [ALZA Corporation Web site]. 1999. Available at: http://www.alza.com. Accessed Aug. 25, 2001. 21. Ditropan® (oxybutynin chloride) extended-release tablets prescribing information [ALZA Corporation Web site]. 1998. Available at: http:// www.alza.com. Accessed Aug. 25, 2001. S22 Lackner

22. Ditropan XL® (oxybutynin chloride) extended-release tablets prescribing information [ALZA Corporation Web site]. 1999. Available at: http://www.alza.com. Accessed Aug. 25, 2001. 23. Detrol: Prescribing information [Pharmacia Web site]. 1998. Available at: http://www.pharmacia.com/Products. Accessed Aug. 25, 2001. 24. Detrol LA: Prescribing information [Pharmacia Web site]. 2001. Available at: http://www:pharmacia.com/Products. Accessed Aug. 25, 2001. 25. Detrol: Data on file [Pharmacia Web site]. 1998. Available at: http:// www.pharmacia.com/Products. Accessed Aug. 25, 2001. 26. Detrol LA: Data on file [Pharmacia Web site]. 2001. Available at: http://www:pharmacia.com/Products. Accessed Aug. 25, 2001. 27. Tune LE, Egeli S. Acetylcholine and delirium. Dement Geriatr Cogn Disord 1999;10:342–344. 28. Versi E, Appell R, Mobley D, et al, for The Ditropan XL Study Group. Dry mouth with conventional and controlled-release oxybutynin in urinary incontinence. Obstet Gynecol 2000;95:718 –721. 29. Madersbacher CA, Knoll M. Intravesical application of oxybutynin: Mode of action in controlling detrusor hyperreflexia: Preliminary report. Eur Urol 1995;28:340 –344. 30. Gupta SK, Sathyan G. Pharmacokinetics of an oral once-a-day controlled-release oxybutynin formulation compared with immediate-release oxybutynin. J Clin Pharmacol 1999;39:289 –296. 31. Buyse G, Waldeck K, Verpoorten C, et al. Intravesical oxybutynin for neurogenic bladder dysfunction: Less systemic side effects due to reduced first pass metabolism. J Urol 1998;160:892– 896. 32. Lukkari E, Tainio H, Lehtoranta K, et al. Absorption and metabolism of oxybutynin after intravesical instillation in patients with detrusor hyperactivity. Neurourol Urodyn 1998;17:320 –322. 33. Arikian SR, Casciano J, Doyle JJ, et al. A pharmacoeconomic evaluation of two new products for the treatment of overactive bladder. Managed Care Interface 2000;Feb:88 –94. 34. Eglen RM, Hedge SS, Watson N. Muscarinic receptor subtypes and smooth muscle function. Pharmacol Rev 1996;48:531–565. 35. Wang P, Luthin GR, Ruggieri MR. Muscarinic receptor subtypes mediating urinary bladder contractility and coupling to GTP binding proteins. J Pharmacol Exp Ther 1995;273:959 –966. 36. Schwantes U, Topfmeier P. Importance of pharmacological and physicochemical properties for tolerance of antimuscarinic drugs in the treatment of detrusor instability and detrusor hyperreflexia: Chances for improvement of therapy. Int J Clin Pharmacol Ther 1999;37:209 –218. 37. Noronha-Blob L, Kachur JF. Enantiomers of oxybutynin: In vitro pharmacological characterization at M1, M2 and M3 muscarinic receptors and in vivo effects on urinary bladder contraction, mydriasis and salivary secretion in guinea pigs. J Pharmacol Exp Ther 1991;256:562–567. 38. Gillberg P-G, Sparf B, Nilvebrant L. Pharmacological in vitro and in vivo profile of DD01, a major metabolite of tolterodine (abstract). Neurourol Urodyn 1996;15:308 –309. 39. Nilvebrant L, Andersson K-E, Gillberg P-G, et al. Tolterodine: A new bladder-selective antimuscarinic agent. Eur J Pharmacol 1997;327:195– 207. 40. Nilvebrant L, Sundquist S, Gillberg P-G. Tolterodine is not subtype (m1-m5) selective but exhibits functional bladder selectivity in vivo (abstract). Neurourol Urodyn 1996;15:310 –311. 41. Gillberg P-G, Modiri A-R, Sparf B. Tolterodine: A new agent with tissue effect selectivity for urinary bladder (abstract). Neurourol Urodyn 1994;13:435– 436. 42. Malone-Lee JG, Walsh JB, Maugourd M-F. Tolterodine: A safe and effective treatment for older patients with overactive bladder. J Am Geriatr Soc 2001;49:700 –705. 43. Millard R, Tuttle J, Moore K, et al. Clinical efficacy and safety of tolterodine compared to placebo in detrusor overactivity. J Urol 1999; 161:1551–1555. 44. Van Kerrebroeck P, Kreder K, Jonas U, et al, for the Tolterodine Study Group. Tolterodine once-daily: Superior efficacy and tolerability in the treatment of the overactive bladder. Urology 2001;57:414 – 421. 45. Appell RA, Sand P, Dmochowski R, et al. 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 2001;76:358 –363. JAMDA – January/February 2002

46. Rentzhog L, Stanton SL, Cardozo L, et al. Efficacy and safety of tolterodine in patients with detrusor instability: A dose-ranging study. 1998;81:42– 48. 47. Jonas U, Hofner K, Madersbacher H. Efficacy and safety of two doses of tolterodine versus placebo in patients with detrusor overactivity and symptoms of frequency, urge incontinence, and urgency: Urodynamic evaluation. World J Urol 1997;15:144 –151. 48. National Institute of Aging. Progress report on Alzheimer’s disease. 1999. Available at: http://www.alzheimers.org/pubs/prog.htm. Accessed September 2000. 49. Movig KLL, Egberts ACG, Lenderink AW, Leufkens HGM. Association between oxybutynin and neuropsychiatric adverse effects not confirmed in daily practice. J Am Geriatr Soc 2001;49:234 –235. 50. Katz IR, Sands LP, Bilker E, et al. Identification of medications that cause cognitive impairment in older people: The case of oxybutynin chloride. J Am Geriatr Soc 1998;46:8 –13. 51. Donnellan CA, Fook L, McDonald P, Playfer JR. Oxybutynin and cognitive dysfunction. BMJ 1997;315:1363–1364. 52. Nilvebrant L, Pahlman I, d’Argy R. Tolterodine and its metabolites show very low penetration into the CNS (abstract). Presented at: 29th Annual Meeting of the International Continence Society; Aug. 23–26, 1999; Denver, CO. 53. Todorova A, Vonderheid-Guth B, Dimpfel W. Effects of tolterodine, trospium chloride, and oxybutynin on the central nervous system. J Clin Pharmacol 2001;41:636 – 644. 54. Colucci VJ, Rivey MP. Tolterodine-warfarin drug interaction. Ann Pharmacother 1999;33:1173–1176. 55. Dmochowski R, Sathyan G, Ye C, et al. The effect of pH on drug release from extended-release formulations of oxybutynin and tolterodine. Presentation at World Health Organization Second International Consultation on Incontinence; July 1–3, 2001; Paris, France. 56. Castleden CM, George CF, Renwick AG, Asher MJ. Imipramine: A possible alternative to current therapy for urinary incontinence in the elderly. J Urol 1981;125:318 –320. 57. Lose G, Jorgenson L, Thuriedborg P. Doxepin in the treatment of female detrusor overactivity: A randomized double-blind crossover study. J Urol 1989;142:1042–1046. 58. Deguecker J. Drug treatment of urinary incontinence in the elderly: Controlled trial with vasopressin and propantheline bromide. Gerontol Clin 1965;7:311–317. 59. Zorzitto ML, Jewett MAS, Fernie GR, et al. Effectiveness of propantheline bromide in the treatment of geriatric patients with detrusor instability. Neurol Urodyn 1986;5:133–140. 60. Blaivas JG, Labib AB, Michalik SJ, Zayed AAH. Cystometric response to propantheline in detrusor hyperreflexia: Therapeutic implications. J Urol 1980;124:259 –262. 61. Thuroff JW, Bunke B, Ebner A, et al. Randomized, double blind, multicentre trial on treatment of frequency, urgency and incontinence related to detrusor hyperactivity: Oxybutynin versus propantheline versus placebo. J Urol 1991;145:813– 817. 62. Holmes DM, Montz FJ, Stanton SL. Oxybutynin versus propantheline in the management of detrusor instability: A patient-regulated variable dose trial. Br J Obstet Gynaecol 1989;96:607– 612. 63. Beck RP, Arnusch D, King C. Results in treating 210 patients with detrusor overactivity incontinence of urine. Am J Obstet Gynecol 1976;125:593–596. 64. Castleden CM, Duffin HM, Millar AW. Dicyclomine hydrochloride in detrusor instability: A controlled clinical pilot study. J Clin Exp Gerontol 1987;9:265–270. 65. Schreiter F, Fuchs P, Stockamp K. Estrogenic sensitivity of ␣-receptors in the urethral musculature. Urol Int 1976;31:13–19. 66. Willhite LA, O’Connell MB. Urogenital atrophy: Prevention and treatment. Pharmacotherapy 2001;21:464 – 480. 67. Samsioe G, Jansson I, Mellstrom D, Svanborg A. Occurrence, nature, and treatment of urinary incontinence in a 70-year-old female population. Maturitas 1985;7:335–342. 68. Walter S, Wolf H, Barlebo H, Jensen H. Urinary incontinence in postmenopausal women treated with estrogens: A double-blind clinical trial. Urol Int 1978;33:135–143. SUPPLEMENT

69. Fantl J, Bump R, Robinson D, et al, and The Continence Program For Women Research. Efficacy of oestrogen supplementation in the treatment of urinary incontinence. Obstet Gynecol 1996;88:745–749. 70. Grady D, Brown JS, Vittinghoff E, et al, for the HERS Research Group. Postmenopausal hormones and incontinence: The Heart and Estrogen/ Progestin Replacement Study. Obstet Gynecol 2001;97:116 –120. 71. Eriksen PS, Rasmussen H. Low-dose 17 beta-estradiol vaginal tablets in the treatment of atrophic vaginitis: A double-blind placebo controlled study. Eur J Obstet Gynecol Reprod Biol 1992;44:137–144. 72. Medina JJ, Parra RO, Moore RG. Benign prostatic hyperplasia (the aging prostate). Med Clin N Am 1999;83:1213–1229. 73. Collste L, Lindskog M. Phenylpropanolamine in treatment of female stress urinary incontinence. Urology 1987;30:398 – 403. 74. Fossberg E, Beisland HO, Lundgren RA. Stress incontinence in females: Treatment with phenylpropanolamine. Urol Int 1983;38:293–299. 75. Lose G, Rix P, Diernaes E, Alexander N. Norfenefrine in the treatment of female stress incontinence. Urol Int 1988;43:11–15. 76. Ek A, Andersson K-E, Gullberg B, Ulmsten U. The effects of long-term treatment with norephedrine on stress incontinence and urethral closure pressure profile. Scand J Urol Nephrol 1978;12:105–110. 77. Diokno AC, Taub M. Ephedrine in treatment of urinary incontinence. J Urol 1975;5:624 – 625. 78. Diernaes E, Rix P, Sorensen T, Alexander N. Norfenefrine in the treatment of female stress incontinence assessed by one-hour pad weighing test. Urol Int 1989;44:28 –31. 79. Lose G, Lindholm P. Clinical and urodynamic effects of norfenefrine in women with stress incontinence. Urol Int 1984;39:298 –302. 80. Awad SA, Downie JW, Kiruluta HG. Alpha-adrenergic agents in urinary disorders of the proximal urethra: Part 1: Sphincteric incontinence. Br J Urol 1978;50:332–335. 81. Stewart BH, Banowsky LHW, Montague DK. Stress incontinence: Conservative therapy with sympathomimetic drugs. J Urol 1976;115: 558 –559. 82. Jonas D. Treatment of female stress incontinence with midodrine: A preliminary report. J Urol 1977;118:980 –982. 83. Brown JS, Seelley DG, Fong J, et al. Urinary incontinence in older women: Who is at risk? Obstet Gynecol 1999;87:715–721. 84. Thom DH, Van Den Eeden SK, Brown JS. Parturition related risk factors for urinary incontinence among women in later life. Obstet Gynecol 1997;90:983–989. 85. Diokno AC, Brock BM, Herzog AR, Bromberg J. Medical correlates of urinary incontinence in the elderly. Urology 1990;36:129 –138. 86. Wilson PD, Faragher B, Butler B, et al. Treatment with oral piperazine oestrone sulphate for genuine stress incontinence in postmenopausal women. Br J Obstet Gynecol 1987;94:568 –574. 87. Jackson S, Sheperd A, Brookes S, Abrams P. The effect of oestrogen supplementation on post-menopausal urinary stress incontinence: A double-blind placebo-controlled trial. Br J Obstet Gynecol 1999;106: 711–718. 88. Jackson S, Shepherd A, Abrams P. Does oestrogen supplementation improve the symptoms of postmenopausal urinary stress incontinence? A double-blind placebo controlled trial (abstract). Neurourol Urodyn 1997;16:350 –351. 89. Hilton P, Tweddell AL, Mayne C. Oral and intravaginal estrogens alone and in combination with alpha-adrenergic stimulation in genuine stress incontinence. Int Urogynecol J 1990;1:80 – 88. 90. Ahlstrom K, Sandahl B, Sjoberg B, et al. Effect of combined treatment with phenylpropanolamine and estriol, compared with estriol treatment alone, in postmenopausal women with stress urinary incontinence. Gynecol Obstet Invest 1990;30:37– 43. 91. Kinn A-C, Lindskog M. Estrogens and phenylpropanolamine in combination for stress urinary incontinence in postmenopausal women. Urology 1988;32:273–280. 92. Ek A, Andersson K-E, Gullberg B, Ulmsten U. Effects of oestradiol and combined norephedrine and oestradiol treatment on female stress incontinence. Zentralbl Gynakol 1980;102:839 – 844. 93. Kiesswetter H, Hennrich F, Englisch M. Clinical and urodynamic assessment of pharmacologic therapy of stress incontinence. Urol Int 1983;38:58 – 63. Lackner S23

94. Beisland HO, Fossberg E, Moer A, Sander S. Urethral sphincter insufficiency in postmenopausal females: Treatment with phenylpropanolamine and estradiol separately and in combination. Urol Int 1984;39: 211–216. 95. Lin H-L, Sheu B-C, Lo M-C, Huang S-C. Comparison of treatment outcomes of imipramine for female genuine stress incontinence. Br J Obstet Gynaecol 1999;106:1089 –1092. 96. Gilja I, Radej M, Kovacic M, Parazajder J. Conservative treatment of female stress incontinence with imipramine. J Urol 1984;132:909 –911. 97. Narayan P, Tewari A. Overview of alpha-blocker therapy for benign prostatic hyperplasia. Urology 1998;51(suppl 4A):38 – 45. 98. Lepor H, Williford WO, Barry MJ, et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Engl J Med 1996;335:533–539. 99. Lepor H, for the Tamsulosin Investigator Group. Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Urology 1998;51:892–900. 100. Fawzy A, Braun K, Lewis GP, et al, for the Multicenter Study Group. Doxazosin in the treatment of benign prostatic hyperplasia in normotensive patients: A multicenter study. J Urol 1995;154:105–109. 101. Roehrborn CG, Oesterling JE, Auerbach S, et al, for the HYCAT Investigator Group. The Hytrin Community Assessment Trial study: A one-year study of terazosin versus placebo in the treatment of men with symptomatic benign prostatic hyperplasia. Urology 1996;47:159 –168. 102. Djavan B, Marberger M. A meta-analysis on the efficacy of alpha1adrenorector antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol 1999;36:1–13. 103. Lepor H, Theune C. Randomized double-blind study comparing the efficacy of terazosin versus placebo in women with prostatism-like symptoms. J Urol 1995;154:116 –118. 104. Serels S, Stein M. Prospective study comparing hyoscyamine, doxazosin, and combination therapy for the treatment of urgency and frequency in women. Neurourol Urodyn 1998;17:31–36. 105. Tsujii T. Comparison of prazosin, terazosin and tamsulosin in the treatment of symptomatic benign prostatic hyperplasia: A short-term open, randomized multicenter study: The BPH Medical Therapy Study Group. Int J Urol 2000;7:199 –205. 106. Wilde MI, McTavish D. Tamsulosin: A review of its pharmacologic properties and therapeutic potential in the management of symptomatic benign prostatic hyperplasia. Drugs 1996;52:883– 898. 107. Lowe FC. Coadministration of tamsulosin and three other antihypertensive agents in patients with BPH: Pharmacodynamic effect. Clin Ther 1997;19:730 –742. 108. The ALLHAT officers and coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT): Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone. JAMA 2000;283:1967–1975.

S24 Lackner

109. Vidt DG. Alpha-blockers and congestive heart failure: Early termination of an arm of the ALLHAT trial. Cleve Clin J Med 2000;67:429–433. 110. Tenover JL, Pagano GA, Morton AS, et al, on behalf of the Primary Care Investigator Study Group. Efficacy and tolerability of finasteride in symptomatic benign prostatic hyperplasia: A primary care study. Clin Ther 1997;19:243–258. 111. Marks LS, Partin AW, Gormley GL, et al. Prostate tissue composition and response to finasteride in men with symptomatic benign prostatic hyperplasia. J Urol 1997;157:2171–2178. 112. Anderson JT, Nickel JC, Marshall VR, et al. Finasteride significantly reduces acute urinary retention and need for surgery in patients with symptomatic benign prostatic hyperplasia. Urology 1997;49:839 – 845. 113. Agency for Health Care Policy and Research. Benign prostatic hyperplasia: Diagnosis and treatment. Clinical practice guideline No. 8. Rockville, MD: AHCPR; 1994. AHCPR publication 94 – 0582. 114. McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338: 557–563. 115. Wilt TJ, Ishani A, Stark G, et al. Saw palmetto extracts for treatment of benign prostatic hyperplasia: A systematic review. JAMA 1998;280: 1604 –1609. 116. Marks LS, Hess DL, Dorey FJ, et al. Tissue effects of saw palmetto and finasteride: Use of biopsy cores for an in situ quantification of prostatic androgens. Urology 2001;57:999 –1005. 117. Anonymous. Saw palmetto for benign prostatic hyperplasia. Med Lett Drugs Ther 1999;41:18. 118. Finkbeiner AE. Is bethanechol chloride clinically effective in promoting bladder emptying? A literature review. J Urol 1985;134:443– 449. 119. Riedl CR, Stephen RL, Daha LK, et al. Electromotive administration of intravesical bethanechol and the clinical impact on acontractile detrusor management: Introduction of a new test. J Urol 2000;164:2108 – 2111. 120. Johnson T. Nonpharmacological treatments for urinary incontinence in long-term care residents. J Am Med Dir Assoc 2002;3(suppl)S25–S30. 121. Schnelle JF, Keeler E, Hays RD, et al. A cost value analysis of two interventions with incontinent nursing home residents. J Am Geriatr Soc 1995;43:1112–1117. 122. Holmes DM, Stone AR, Barry PR. Bladder training 3 years on. Br J Urol 1983;55:660 – 664. 123. Hu TW, Kaltreider DI, Igou RN. The cost-effectiveness of disposable versus reusable diapers. J Gerontol Nurs 1990;16:19 –24. 124. 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. 125. Tune LE, Carr S, Hoag E, et al. Anticholinergic effects of drugs commonly prescribed for the elderly: Potential means for assessing risk of delirium. Am J Psychiatry 1992;149:1393–1394.

JAMDA – January/February 2002