Urge Urinary Incontinence
O The anticholinergic/antispasmodic drugs are the first-line pharmacologic treatment for UUI. They are the most effective agents in suppressing premature detrusor contractions, enhancing bladder storage, and relieving symptoms. It must be emphasized that the improvements in clinical and urodynamic parameters are modest at best, although still considered by experts in the field to be positive.10 In the recent systematic review/meta-analysis of 50 clinical trials in UUI by Novava et al., there were no clinically important or relevant differences found among different anticholinergics.10
The major problem with existing agents is their lack of selectivity to bladder mus-carinic receptors, thus leading to dose-limiting side effects outside ofthe urinary tract. These include dry mouth, constipation, blurred vision, confusion, cognitive dysfunction, and tachycardia. With oxybutynin, orthostasis due to a-receptor blockade and sedation and weight gain due to histamine-1 receptor blockade may also occur. Dry mouth is the most problematic of the anticholinergic side effects and is frequently dose limiting. In the systematic review and meta-analysis cited previously, in terms of tolerability, only the difference between tolterodine immediate-release (IR) and oxy-butynin IR (wherein the former was better and tolerable than the latter) was statistically and clinically significant. With regard to IR formulations, dose escalation might yield some limited improvements in efficacy, but at the cost of significant increases in the rates of adverse events. Comparing extended-release (ER) and IR formulations, the former demonstrated advantages in terms of efficacy and safety. Lastly, with regard to route of administration, the dermal route of administration did not provide a significant advantage over the oral route. Thus, oral ER formulations should probably be preferred over IR and/or dermal (i.e., transdermal or gel) ones. More clinical trials are necessary to identify first-, second-, and third-line agents.11 In terms of urinary retention, relative safety of at least one anticholinergic has been suggested. In a preliminary open-label trial in males with UUI and presumed nonobstructive BPH (where maximum urine flow rates were at least 15 mL/s), tolterodine LA (as monotherapy or combined with prior unsuccessful a-adrenoceptor antagonist therapy) produced significant objective and subjective benefits versus UUI and BPH. Mean postvoid residual urine volume did not increase and urinary retention occurred at a rate of only 0.3%.12
Details regarding the pharmacokinetics, contraindications/precautions, and dosing of the six recommended agents (oxybutynin, tolterodine, trospium chloride, solifen-acin, darifenacin, and fesoterodine) are illustrated in Table 53-3.13-21 A current clinical controversy is which of these agents should be considered first line in UUI, and in the case of oxybutynin, tolterodine, and trospium chloride which formulations should be recommended. There are few head-to-head clinical trials to assist in decision making and those few that exist have demonstrated either broad equivalence or clinically unimportant differences in efficacy. In the recent systematic review of Shamliyan et al., data for analysis were adequate only for oxybutynin IR (5-10 mg/day) and tolterodine LA (4 mg/day). Both of these agents restored continence with an effect size of 0.18 (95% CI, 0.13-0.22). The authors could not claim one as being superior to the other.9 Patient characteristics (e.g., age, comorbidities, concurrent drug therapies, and ability to adhere to the prescribed regimen) can also influence drug therapy selection. Drug selection frequently will be based on differences in tolerability (wherein the ER oral, or gel TD formulations are better tolerated than the IR formulations) and cost. Careful dose titration is necessary to maximize efficacy and tolerability. The selected agent should be titrated to the maximum tolerated dose and maintained there for at least 4 weeks in order to assure an adequate therapeutic trial. If therapeutic goals are not achieved, a switch to an alternative agent should be made. There is no rationale for use of two or more anticholinergics concurrently at low doses. Another clinical controversy is the relevance of the pharmacologic antagonism between anticholinergics and cholinesterase inhibitors when used concurrently.22
Other drugs, such as propantheline, flavoxate, tricyclic antidepressants (TCA; especially imipramine), dicyclomine, and scopolamine, are less effective, no safer, and/ or have not been adequately studied; therefore, their use is not recommended.6
Women with mixed UI (UUI plus SUI) or UUI plus atrophic vaginitis and/or urethritis may also benefit from the addition of a locally administered (per vagina [PV]) estrogen to anticholinergic therapy. Preliminary data suggest that desmopressin (DDAVP) may reduce daytime UUI symptoms (i.e., for up to approximately 8 hours after morning dosing) when used on both regular and "as needed" bases. 3 An intriguing pilot placebo-controlled trial ofduloxetine in UUI in individuals with bladder
capacities below 400 mL suggests at least short-term (12 weeks) benefit. Stress Urinary Incontinence
The goal of pharmacologic therapy of urethral underactivity is to improve the urethral closure mechanism by one or more of the following:
• Stimulating a-adrenoceptors in the smooth muscle of the proximal urethra and bladder neck
• Enhancing the supportive structures underlying the urethral mucosa
• Enhancing the positive effects of serotonin and norepinephrine in the afferent and efferent pathways of the micturition reflex
Table 53-3 Anticholinergic/Antispasmodic Drugs Recommended for UUI
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It is generally felt that there is no role for pharmacologic therapy in SUI in males resulting from surgery or trauma. Initial data, however, suggest a possible role for duloxetine added to nonpharmacologic treatment (PFMR), rather than PFMR alone, in males postradical prostatectomy, at least over the first 4 to 6 months.26 It should be kept in mind that SUI (in contrast to UUI) is frequently curable by surgery, thus obviating years of drug therapy that may be incompletely effective in symptom relief.
O Vaginally administered estrogen plays only a modest role in managing SUI (urethral underactivity), unless it is accompanied by local signs of estrogen deficiency (e.g., atrophic urethritis or vaginitis).
Although not supported by rigorous clinical trial evidence, local (PV) and systemic estrogens have been considered mainstays of pharmacologic management since the 1940s. They are believed to work by a trophic effect on uroepithelial cells and underlying collagenous subcutaneous tissue, enhancement of local microcirculation by increasing the number of periurethral blood vessels, and enhancement of the number and/or sensitivity of a-adrenoceptors. Open trials have supported the use of estrogens administered by the oral, TD, and local routes of administration. However, randomized controlled trials have found no significant clinical or urodynamic effects of oral estrogen compared to placebo in SUI. In fact, most trials have found that oral estrogen/hormone replacement therapy actually increases the risk of new-onset UI (SUI, UUI, mixed UI).9 Systemic estrogen therapy also carries numerous short- and long-term side effect risks (mastodynia, uterine bleeding, nausea, thromboembolism, cardiac and cerebrovascular ischemic events, and enhanced breast and endometrial cancer risks). If estrogens are to be used in SUI management, only locally administered products should be used (Table 53-4). Even with locally administered products, improvement of continence has been inconsistent between trials.9
Open and randomized controlled trials utilizing clinical and urodynamic endpoints have supported the use of a variety of a-adrenoceptor agonists, including phenylpro-panolamine, ephedrine, and pseudoephedrine, in the therapy of mild and moderate SUI. In addition, several studies have demonstrated clinical and urodynamic benefits for combination estrogen-a-adrenoceptor agonist use over those of the individual agents. However, in the recent systematic review of Shamliyan et al., monotherapy with this class failed to restore continence or improve incontinence compared with placebo or PFMR.9 Phenylpropanolamine was removed from the U.S. market in late
2000 due to the risk of ischemic stroke in women taking this drug. However, this drug is still available via the Internet, so clinicians need to monitor and discourage its use. Although still available by prescription, ephedrine is considerably more toxic than other a-adrenoceptor agonists and its use is not recommended. Although phenylephrine is now available in oral formulations, the lack of data regarding its use in SUI and the reported lack of efficacy in maximum recommended doses for rhinitis suggest that this agent should be avoided at present.
This leaves the clinician with only one practical agent to use pseudoephedrine: (Table 53-4). Side effects include hypertension, headache, dry mouth, nausea, insomnia, and restlessness.28 The major impediment to using the a-adrenoceptor agonist class is the extensive list of contraindications (Table 53-4). In the past, a-adreno-ceptor agonist therapy was generally added to estrogen therapy in those insufficiently improved with estrogen alone and in whom its use was not contraindicated. With the recent availability of duloxetine, treatment is now available for estrogen non or hypo-responders whether they can or cannot take a-adrenoceptor agonists.
Duloxetine is a selective serotonin-norepinephrine reuptake inhibitor similar pharmacologically to venlafaxine. Approved for the treatment of major depression, painful diabetic peripheral neuropathy, fibromyalgia, and generalized anxiety disorder,, its use in SUI is off-label in the United States. Duloxetine enhances central serotonergic and adrenergic tone which is involved in ascending and descending control of urethral smooth muscle and the internal urinary sphincter. Urethral and urinary sphincter smooth muscle tone during the filling phase are thus enhanced.30,31 The pharmacokin-
etics, contraindications/precautions, and dosing of duloxetine are illustrated in Table
53-4. ' Clearly, duloxetine has demonstrated modest efficacy in SUI and a major question is its role in SUI compared to estrogen and a-adrenoceptor agonists as well as potentially curative surgery. In the absence ofhead-to-head clinical trial data, this is a difficult question to answer, at least for the comparison ofduloxetine to a-adrenocept-or agonists. In the recent systematic review of Shamliyan et al., duloxetine improved incontinence with an effect size of 0.11 (95% CI, 0.07-0.14) but failed to restore continence.9 One controlled trial has demonstrated modest, although significant, benefit from duloxetine in the treatment of SUI in males after radical prostatectomy33 The use of duloxetine in stress UI is complicated by (a) the potential for multiple clinically relevant drug drug interactions with cytochrome P450 (CYP450) 2D6 and 1A2 inhibitors, (b) withdrawal reactions if abruptly discontinued, (c) high rates of nausea and other side effects, (d) hepatotoxicity contraindicating its use in patients with any degree of hepatic impairment, and (e) its mild hypertensive effect. Another disconcerting finding is the high discontinuation rate when duloxetine is used in a "usual use" clinic environment (68%, two-thirds due to adverse events and one-third due to lack of efficacy)34
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