Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

68. Urinary Incontinence

Eric S. Rovner, Jean Wyman, and Sum Lam


KEY CONCEPTS

 Images In evaluating urinary incontinence (UI), drug-induced or drug-aggravated etiologies must be ruled out.

 Images Accurate diagnosis and classification of UI type are critical to the selection of appropriate pharmacotherapy.

 Images Goals of treatment for UI are reduction of symptoms, minimization of adverse effects, and improvement in quality of life.

 Images Nonpharmacologic, nonsurgical treatment is the first-line therapy for several types of UI, and should be continued even when drug therapy is initiated.

 Images Anticholinergic/antimuscarinic agents are first-line therapies for urge incontinence. Choice of agent should be based on patient characteristics (e.g., age, comorbidities, concurrent medications, and ability to adhere to the prescribed regimen).

 Images Mirabegron, a β3-adrenergic agonist, can be considered as an alternative in patients who failed to achieve optimal efficacy or cannot tolerate adverse effects of anticholinergics.

 Images Duloxetine (approved in Europe only), α-adrenergic receptor agonists, and topical (vaginal) estrogens (alone or together) are the drugs of choice for urethral underactivity (stress incontinence).

 Images Assessment of patient outcomes should include efficacy, adverse effects, adherence, and quality of life.

 Images Management of UI should target individualized goals, which may change over time. If therapeutic goals are not achieved with a given agent at optimal dosage for an adequate duration of trial, consider switching to an alternative agent.


Urinary incontinence (UI) is defined as involuntary leakage of urine.1 It is frequently accompanied by other bothersome lower urinary tract symptoms, such as urgency, increased daytime frequency, and nocturia. It is a common yet underdetected and underreported health problem that can significantly affect quality of life. Patients with UI may have depression as a result of the perceived lack of self-control, loss of independence, and lack of self-esteem, and they often curtail their activities for fear of an “accident.” UI may also have serious medical and economic ramifications for untreated or undertreated patients, including perineal dermatitis, worsening of pressure ulcers, urinary tract infections, and falls.

This chapter highlights the epidemiology, etiology, pathophysiology, and treatment of stress, urge, mixed, and overflow UI in men and women.

EPIDEMIOLOGY

UI is highly prevalent, and the impact of this condition is substantial, crossing all racial, ethnic, and geographic boundaries. In addition, associated lower urinary tract symptoms such as overactive bladder (OAB) are also quite debilitating.2 Several studies have objectively shown that UI is associated with reduced levels of social and personal activities, increased psychological distress, and overall decreased quality of life as measured by numerous indices.3The condition can affect people of all age groups, but the peak incidence of UI, at least in women, appears to occur around the age of menopause, with a slight decrease in the age group 55 to 60 years, and then a steadily increasing prevalence after age 65 years.

Determining the true prevalence of UI is difficult because of problems with definition, reporting bias, and other methodologic issues.4 The Medical, Epidemiologic, and Social Aspects of Aging survey found that the prevalence of UI in noninstitutionalized women 60 years of age and older was approximately 38%. Almost one third of those surveyed noted urine loss at least once weekly, and 16% noted UI daily. A publication from a National Institutes of Health working group conference estimated the median level of UI prevalence to be approximately 20% to 30% during young adult life, with a broad peak around middle age (30% to 40% prevalence) and an increase in the elderly (30% to 50% prevalence).5

In the United States, chronic UI is one of the most common reasons cited for institutionalization of the elderly, and the condition is frequently encountered in the nursing home setting. Little is known about the basic differences in clinical and epidemiologic characteristics of incontinence across racial or ethnic groups. Some studies report a higher incidence of UI overall in white populations as compared with African Americans, but differences in access to healthcare as well as cultural attitudes and mores may contribute to these differences.6,7

Consistent across all studies of unselected, noninstitutionalized populations is that UI is at least half as common in men as in women.8 Overall, the prevalence of UI in men has been estimated to be approximately 9%.10 Unlike in women, the prevalence of UI in men increases steadily with age across most studies, with the highest prevalence recorded in the oldest patient cohorts.9

ETIOLOGY AND PATHOPHYSIOLOGY

Anatomy

The lower urinary tract consists of the bladder, urethra, urinary or urethral sphincter, and surrounding musculofascial structures, including connective tissue, nerves, and blood vessels. The urinary bladder is a hollow organ composed of smooth muscle and connective tissue located deep in the bony pelvis in men and women. The urethra is a hollow tube that acts as a conduit for urine flow out of the bladder. An epithelial cell layer termed the urothelium, which is in constant contact with urine, lines the interior surface of both the bladder and the urethra. Previously considered inert and inactive, the urothelium may play an active role in the pathophysiology of many lower urinary tract disorders, including interstitial cystitis and UI10 and may be a targeted location for future pharmacologic therapeutic interventions for some types of lower urinary tract dysfunction.11 The urinary or urethral sphincter is a combination of smooth and striated muscle within and surrounding the proximal portion of the urethra adjacent to the bladder. In the male, the prostate gland lies just beyond the bladder outlet and is intimately associated with the urethral sphincter. Its location accounts for both the favorable effects of pharmacological manipulation on male lower symptoms as well as the risk of UI in males following some types of prostate surgery.

To understand the principles of pharmacotherapy for UI, an understanding of the neuroanatomy and neurophysiology of the bladder and urethra is needed. The primary motor (efferent) input to the detrusor muscle of the bladder is parasympathetic and travels along the pelvic nerves emanating from spinal cord segments S2 to S4. Acetylcholine appears to be the primary neurotransmitter at the neuromuscular junction in the human lower urinary tract. Both volitional and involuntary detrusor contractions are mediated by activation of postsynaptic muscarinic receptors by acetylcholine. Of the five known subtypes of muscarinic receptors, the majority of bladder smooth muscle cholinergic receptors are of the M2 variety. In humans, the ratio of M2/M3 receptor numbers is approximately 3:1. However, M3 receptors are the subtype responsible for both emptying contractions of normal micturition as well as involuntary bladder contractions that may result in UI.10 Thus, most pharmacologic antimuscarinic therapy is primarily anti-M3 based.

Urinary Continence

To prevent incontinence during the bladder filling and storage phase of the micturition cycle, the urethra, or more accurately the urethral sphincter, must maintain adequate closure in order to resist the flow of urine from the bladder at all times until voluntary voiding is initiated. Urethral closure or resistance to flow is maintained to a large degree by the proximal (under involuntary control) and distal (under both voluntary and involuntary control) urinary sphincters. Variable contributions to urethral closure may also come from the urethral mucosa, submucosal spongy tissue, and the overall length of the urethra. During bladder filling and urinary storage, the bladder accommodates to increasing volumes of urine flowing in from the upper urinary tract without a significant increase in bladder (intravesical) pressure. The maintenance of a low intravesical pressure despite increasing volumes of urine is a unique property of the bladder and is termed compliance. In addition, bladder or detrusor smooth muscle activity is normally suppressed during the filling phase by centrally mediated neural reflexes. Normal bladder emptying occurs with opening of the urethral sphincters concomitant with a volitional bladder contraction. Bladder contraction occurs in a coordinated fashion, resulting in a rise in intravesical pressure. The rise in intravesical pressure is ideally of adequate magnitude and duration to empty the bladder to completion. Opening and funneling of the bladder outlet results in urine flow into the urethra until the bladder is emptied to near completion.

The bladder and urethra normally operate in unison during the bladder filling and storage phase, as well as the bladder emptying phase of the micturition cycle. The smooth and striated muscles of the bladder and urethra are organized during the micturition cycle by a number of reflexes coordinated at the pontine micturition center in the midbrain. Disturbances in the neural regulation of micturition at any level (brain, spinal cord, or pelvic nerves) often lead to characteristic changes in lower urinary tract function that may result in UI.12,13

Mechanisms of Urinary Incontinence

Simply stated, UI may occur as a result of abnormalities of only the urethra (including the bladder outlet and urinary sphincter) or only the bladder or as a combination of abnormalities in both. Abnormalities may result in either overfunction or underfunction of the bladder and/or urethra, with resulting development of UI. Although this simple classification scheme excludes extremely rare causes of UI such as congenital ectopic ureters and urinary fistulas, it is useful for gaining a working understanding of the condition and understanding the basis for therapeutic intervention including pharmacotherapy of various lower urinary tract disorders.

Urethral Underactivity (Stress Urinary Incontinence) This type of incontinence is characterized by brief bursts of UI concomitant with exertional activities such as exercise, running, lifting, coughing, and sneezing. The pathophysiology of stress urinary incontinence (SUI) is related to decreased or inadequate urethral closure forces. In individuals with SUI, the muscular tissues surrounding the urethra that form the urethral sphincter are compromised and thus not able to resist the expulsive forces resulting from transient increases in intraabdominal pressure during physical activity. Such forces are transmitted to the bladder (an intraabdominal organ), compressing it to such an extent as to cause the egress of urine through the urethra. SUI is characterized by episodic, usually low volume urinary leakage but is clearly proportional to the amount of physical exertion or other increases in abdominal pressure such as that related to coughing and sneezing.

Risk factors for SUI in the female include pregnancy, childbirth, menopause, cognitive impairment, obesity, and aging.14,15 In males, SUI is most commonly the result of prior lower urinary tract surgery and injury to the sphincter mechanism within and external to the urethra. Radical prostatectomy for treatment of adenocarcinoma of the prostate and transurethral resection of the prostate (TURP) are probably the most common proximate causes of SUI in the male. Notably, compared with its prevalence in females, SUI in males is actually quite rare.

SUI may be caused or aggravated by some pharmacologic agents such as α-antagonists and angiotensin-converting enzyme (ACE) inhibitors.16 α-Antagonists may relax the smooth muscle at the level of the urethral sphincter, resulting in a weakened closure mechanism and the onset of SUI. An adverse effect of some ACE inhibitors is chronic cough, which can also aggravate existing SUI.

Bladder Overactivity (Urge Urinary Incontinence) Urge incontinence is defined as the leakage of urine associated with urgency, a compelling desire to void.1 This is most often related to detrusor (bladder) overactivity due to involuntary bladder contractions. Bladder overactivity describes the condition in which the detrusor muscle contracts inappropriately during urinary storage that, in the neurologically normal individual, results in a sense of urinary urgency. The terms overactive bladder and detrusor (bladder) overactivity are distinct and should not be used interchangeably.

The International Continence Society defines OAB as a symptom syndrome characterized by urinary urgency, with frequency and nocturia, with/without associated UI in the absence of a known pathologic condition that may result in similar symptoms (e.g., urinary tract infection, bladder cancer).1 Frequency is defined as micturition more than eight times per day. Urgency is described as a sudden compelling desire to urinate that is difficult to delay.1People suffering from OAB typically have to empty their bladder frequently, and, when they experience a sensation of urgency, they may leak urine if they are unable to reach the toilet quickly. Many patients have associated nocturia (>1 micturition per night) and/or nocturnal incontinence (enuresis). Patients with urge urinary incontinence (UUI) often experience high-volume urine leakage when it occurs. Although detrusor overactivity may be related to OAB, the former diagnosis requires urodynamic testing while the latter is symptomatically defined.

Most patients with OAB and UUI have no identifiable underlying etiology and thus are classified as “idiopathic.” Patients with a relevant neurologic condition and with UI related to involuntary bladder contractions demonstrated on urodynamic testing are classified as having neurogenic detrusor overactivity. Clearly identifiable risk factors for UUI include normal aging, neurologic disease (including stroke, Parkinson’s disease, multiple sclerosis, and spinal cord injury), and bladder outlet obstruction (e.g., due to benign prostatic hyperplasia [BPH] or prostate cancer).

The pathophysiology of OAB and UUI is not well understood but is likely related to either neurogenic or myogenic factors or combination of both.17 A full discussion of these differences is complex and beyond the scope of this chapter. However, in practice, although the cause of UUI is difficult to define, the treatment is identical regardless of etiology and pathophysiology.

Some pharmacologic agents may cause or aggravate UUI. Diuretics will cause the rapid accumulation of urine in the bladder with resulting urinary urgency and frequency that can result in UUI. Alcohol will have similar effects. Anticholinesterase inhibitors may also produce urgency and frequency.

Urethral Overactivity and/or Bladder Underactivity (Overflow Incontinence) Overflow incontinence is urinary leakage resulting from an overfilled and distended bladder that is unable to empty. This type of UI occurs when the bladder is filled to capacity at all times but is unable to empty, causing urine to leak from a distended bladder past a normal or even overactive sphincter. Another term related to overflow incontinence is chronic urinary retention.

Overflow incontinence is the result of urethral overactivity, bladder underactivity, or a variable combination of both. Clinically and practically, the most common causes of urethral overactivity in men are anatomic urethral obstruction, including that due to BPH and prostate cancer. In women, urethral overactivity is rare but may result from cystocele formation (with resultant kinking or obstruction of the urethra) or surgical overcorrection following surgery for the repair of SUI (iatrogenic obstruction). In both men and women, overflow UI may be associated with systemic neurologic dysfunction or diseases, such as spinal cord injury or multiple sclerosis.

Bladder underactivity occurs as a result of the detrusor muscle of the bladder becoming progressively weakened and eventually losing the ability to voluntarily contract and expel urine during voiding. In the absence of adequate contractility, the bladder is unable to empty completely, and large volumes of residual urine are left after voiding. Both myogenic and neurogenic factors have been implicated in producing the impaired contractility seen in this condition. Clinically, overflow incontinence is most commonly seen in the setting of long-term chronic bladder outlet obstruction in men, such as that due to BPH or prostate cancer, diabetes mellitus, or denervation due to radical pelvic surgery, such as abdominopelvic resection or radical hysterectomy.

There are numerous pharmacologic agents that can result in urinary retention and overflow incontinence. Agents that increase urethral resistance or closure pressure include α-agonists and tricyclic antidepressants. Over-the-counter cold and cough remedies as well as diet pills may contain agents with α-adrenergic properties and/or antihistaminic properties that can result in voiding dysfunction and urinary retentions. Agents that can decrease bladder contractility include anticholinergics, tricyclic antidepressants, calcium channel blockers, narcotic analgesics, and antipsychotics.

Mixed Incontinence and Other Types of Urinary Incontinence Various types of UI may coexist in the same patient. The combination of bladder overactivity and urethral underactivity is termed mixed incontinence. The diagnosis is often difficult because of the confusing array of presenting symptoms. Bladder overactivity may also coexist with impaired bladder contractility. This occurs most commonly in the elderly and is termed detrusor hyperactivity with impaired contractility.18

Functional incontinence is not caused by bladder- or urethra-specific factors. Rather, in patients with conditions such as dementia or cognitive or mobility deficits, the UI is linked to the primary disease process more than any extrinsic or intrinsic deficit of the lower urinary tract. An example of functional incontinence occurs in the postoperative orthopedic surgery patient. Following extensive orthopedic reconstructions such as total hip arthroplasty, patients are often immobile secondary to pain or traction. Therefore, patients may be unable to access toileting facilities in a reasonable amount of time and may become incontinent as a result. Treatment of this type of UI may involve simple interventions such as placing a urinal or commode at the bedside that allows for uncomplicated access to toileting. Pharmacologically, functional incontinence can be induced by sedative-hypnotics, narcotic analgesics, and other medications with cognitive adverse effects.

Many localized or systemic illnesses may result in UI because of their effects on the lower urinary tract or the surrounding structures:

   1. Dementia/delirium

   2. Depression

   3. Urinary tract infection (cystitis)

   4. Postmenopausal atrophic urethritis or vaginitis

   5. Diabetes mellitus

   6. Neurologic disease (e.g., stroke, Parkinson’s disease, multiple sclerosis, spinal cord injury)

   7. Pelvic malignancy

   8. Constipation

   9. Congenital malformations of the urinary tract

Images As noted above, many commonly used medications may precipitate or aggravate existing voiding dysfunction and UI (Table 68-1).19

TABLE 68-1 Medications That Influence Lower Urinary Tract Function

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CLINICAL PRESENTATION Urinary Incontinence Related to Urethral Underactivity

General

    • The patient usually notes UI during activities such as exercise, running, lifting, coughing, and sneezing. Occurs much more commonly in women (seen only in men with lower urinary tract surgery or injury compromising the sphincter)

Symptoms

    • Urine leakage with physical activity (volume is proportional to activity level). No UI with physical inactivity, especially when supine (no nocturia). May develop urgency and frequency as a compensatory mechanism (or as a separate component of bladder overactivity)

Diagnostic Tests

    • Observation of urethral meatus while patient coughs or strains

Generally, SUI is considered the most common type of UI and probably accounts for at least a portion of UI in more than half of all incontinent women. Some studies have found that mixed UI (SUI plus UUI) is the most common type of UI. However, the proportions of SUI, UUI, and mixed UI vary considerably with age group and gender of patients studied, study methodology, and a variety of other factors.

CLINICAL PRESENTATION

Images UI may present in a number of ways, depending on the underlying pathophysiology. A complete medical and medication history, including an assessment of symptoms and a physical examination, is essential for correctly classifying the type of incontinence and thereby assuring appropriate therapy.

Urine Leakage

UI represents a spectrum of severity in terms of both volume of leakage and degree of bother to the patient. It is important to carefully consider the level of patient discomfort and bother when discussing urine leakage as each individual may or may not desire therapy. A careful and complete history during the patient interview is essential to accurately determine the precise nature of the problem. The onset, nature, timing, and volume of incontinence are recorded as is the use of pads. Use of absorbent products, such as panty liners, pads, or briefs, is an important point of discussion, but the clinician must keep in mind that use of these products varies among patients. The number and type of pads may not relate to the amount or type of incontinence, as their use is a function of personal preference and hygiene. A high number of absorbent pads may be used every day by a patient with severe, high-volume UI or, alternatively, by a fastidiously hygienic patient with low-volume leakage who simply changes pads often to prevent wetness or odor. Nevertheless, a large number of pads that are described by the patient as “soaked” is indicative of high-volume urine loss.

Regardless of the volume of urine loss, the desire to seek evaluation for UI in the majority of patients is most commonly elective and therapy is often contingent on the degree of bother to the individual patient. As with the use of absorbent products, patients differ with regard to the amount of urine loss they will tolerate before considering the condition bothersome enough to seek assistance. However, it is critically important that in some individuals new-onset UI may be the first manifestation of an undiagnosed illness, or may occur as a result of treatment or drug therapy of an unrelated condition. It is these individuals who mandate a full evaluation and treatment.

Symptoms

Under the best of circumstances, UI is difficult to categorize based on symptoms alone (Table 68-2).20 In a study of patients who appeared to have SUI based on symptoms and patient history, urodynamics showed that only 72% of patients had SUI as the sole cause of incontinence.21

TABLE 68-2 Differentiating Bladder Overactivity from Urethral Underactivity-Related UI

Images

Patients with SUI characteristically complain of urinary leakage with physical activity. Volume of leakage is proportional to the level of activity. They will often leak urine during periods of exercise, coughing, sneezing, lifting, or even when rising from a seated to a standing position. Patients with pure SUI will not have leakage when physically inactive, especially when they are supine. Often they will have little or no UI at night, will not awaken to void during the night (nocturia), will not wet the bed, and often do not even wear absorbent products during the night. Urinary urgency and frequency may be associated with SUI, either as a separate component caused by bladder overactivity (mixed incontinence) or as a compensatory mechanism wherein the patient with SUI learns to toilet frequently to prevent large-volume urine loss during physical activity.


CLINICAL PRESENTATION Urinary Incontinence Related to Bladder Overactivity

General

    • Can have bladder overactivity and UI without urgency if sensory input from the lower urinary tract is absent

Symptoms

    • Urinary frequency (>8 micturitions per day), urgency with or without urge incontinence; nocturia (≥1 micturition per night) and enuresis may be present

Diagnostic Tests

    • Urodynamic studies are the gold standard for diagnosis. Urinalysis and urine culture should be negative (rule out urinary tract infection as the cause of frequency)


CLINICAL PRESENTATION Overflow Incontinence (Chronic Urinary Retention)

General

    • Important but rare type of UI in both men and women. Urethral overactivity is usually due to prostatic enlargement (males) or cystocele formation or surgical overcorrection following stress incontinence surgery in women

Symptoms

    • Lower abdominal fullness, hesitancy, straining to void, decreased force of stream, interrupted stream, sense of incomplete bladder emptying. May have urinary frequency and urgency. Abdominal pain if acute urinary retention is present

Signs

    • Increased postvoid residual urine volume

Diagnostic Tests

    • Digital rectal examination or transrectal ultrasound to rule out prostatic enlargement. Renal function tests to rule out renal failure due to acute urinary retention

Typical symptoms of UUI and bladder overactivity include frequency, urgency, and high-volume incontinence. Nocturia and nocturnal incontinence are often present. Urine leakage is unpredictable, and the volume loss may be quite large. Patients often wear protection both day and night. Urinary frequency can be affected by a number of factors unrelated to bladder overactivity, including excessive fluid intake (polydipsia) and bladder hypersensitivity states such as interstitial cystitis and urinary tract infection. In some patients, bladder overactivity manifests as UI without awareness in the absence of a sense of urinary urgency or frequency. Urinary urgency, a sensation of impending micturition, requires intact sensory input from the lower urinary tract. In patients with spinal cord injury, sensory neuropathies, and other neurologic diseases, a diminished ability to perceive or process sensory input from the lower urinary tract may result in bladder overactivity and UI without urgency or urinary frequency. When bladder contraction occurs without warning and sensation is absent, the condition is referred to as reflex incontinence.

Patients with overflow incontinence may present with lower abdominal fullness as well as considerable obstructive urinary symptoms, including hesitancy, straining to void, decreased force of urinary stream, interrupted stream, and a vague sense of incomplete bladder emptying. These patients may also have a significant component of urinary frequency and urgency. In patients with acute urinary retention and overflow incontinence, lower abdominal pain may be present. Although these symptoms are not specific for overflow incontinence, they may warrant further investigation, including an assessment of postvoid residual urine volume.

Signs

A presenting complaint of UI mandates a directed physical examination and a brief neurologic assessment. The workup ideally includes an abdominal examination to exclude a distended bladder, neurologic assessment of the perineum and lower extremities, pelvic examination in women (looking especially for evidence of prolapse or hormonal deficiency), and genital and prostate examination in men. Perineal skin maceration, erythema, breakdown, and ulceration may be indicative of chronic, severe UI. Patients with chronic incontinence may also manifest fungal infections of the skin of the perineum and upper thighs.

SUI can usually be objectively demonstrated by having the patient cough or strain during the examination and observing the urethral meatus for a sudden spurt of urine. In women, SUI may be associated with varying degrees of vaginal prolapse, including cystourethrocele (bladder and urethral prolapse).

In both men and women, digital rectal examination provides an opportunity to check ambient rectal tone and the integrity of the sacral reflex arc (e.g., anal wink) as well as assess the patient’s ability to perform a voluntary pelvic floor muscle contraction (i.e., Kegel exercise), which may be an important factor in deciding on appropriate therapy. In men, a digital examination of the prostate assesses for the presence of prostate cancer, inflammation, and BPH.

A targeted neurologic examination includes assessment of reflexes, rectal tone, and sensory or motor deficits in the lower extremities, which might be indicative of systemic or localized neurologic disease. Neurologic diseases have the potential to affect bladder and sphincter function and thus may have significant implications in the incontinent patient.

Prior Medical or Surgical Illness

UI may present in the setting of concurrent, seemingly unrelated illnesses. New-onset UI may be the initial manifestation of systemic illnesses such as diabetes mellitus, metastatic malignancies, and neurologic diseases such as Parkinson’s disease, brain tumors, and multiple sclerosis. CNS disease, or injury above the level of the pons, generally results in symptoms of bladder overactivity and UUI. Spinal cord injury or disease may manifest as bladder overactivity and UUI or as overflow incontinence, depending on the spinal level and completeness of the injury or disease.

Medications may have wide-ranging effects on lower urinary tract function (see Table 68-1). A thorough inquiry into the use of new medications in the setting of recent-onset UI may show a relationship.

Acute UI manifesting in the immediate postoperative setting may be secondary to a number of factors, including surgical manipulation and immobility, and to a number of medications, especially opioid analgesics and sedative-hypnotics.

Prior surgery may have effects on lower urinary tract function. UI following prostate surgery in men is highly suggestive of injury to the sphincter and resultant SUI. Pelvic surgery for benign and malignant conditions may result in denervation or injury to the lower urinary tract. This includes bowel surgery and gynecologic procedures. For example, new-onset total UI following gynecologic surgery suggests intraoperative bladder injury and subsequent development of a postoperative vesicovaginal fistula. Radiation therapy to the pelvis for malignant disease (e.g., prostate cancer or cervical cancer) may result in injury to the bladder or urethra and subsequent UI.

In women, UI may be related to several gynecologic factors, including childbirth, hormonal status, and prior gynecologic surgery although recently the relationship of some of these factors to UI has come under debate.22Pregnancy and childbirth, particularly vaginal delivery, are associated with SUI and pelvic prolapse. Significant SUI in the nulliparous woman is uncommon. UI that becomes progressive at or around menopause suggests a hormonal component that may be responsive to estrogen or hormone replacement therapy.

UI may present in the setting of other significant pelvic floor disorders, signs, and symptoms. Constipation, diarrhea, fecal incontinence, dyspareunia, sexual dysfunction, and pelvic pain may be related to UI. A history of gross hematuria in the setting of UI mandates further urologic investigation, including radiologic imaging of the upper urinary tract and cystoscopy. Acute dysuria with or without hematuria in the setting of UI suggests cystitis. Urinalysis and urine culture should be performed in these patients.

TREATMENT

Desired Outcomes

Images The efficacy goals for the management of UI include restoration of continence, reduction of the number of UI episodes, and prevention of complications (pressure ulcers, nursing home placement, etc.). Other desired outcomes are minimization of adverse treatment consequences and cost, as well as improvement in patient’s quality of life.

General Approach to Treatment

Nonsurgical, nonpharmacologic intervention is the first-line treatment for UI. Drug therapy may be considered in patients whose UI is not adequately controlled by nonpharmacologic therapies and in those who have no major contraindications to drug treatment. In general, pharmacotherapy provides better response when combined with nonpharmacologic interventions. Selection of agent should be based on the type of UI, and patient characteristics (e.g., age, comorbidities, concurrent drug therapies, ability to maintain medication adherence). Surgery can be considered when the degree of bother or lifestyle compromise is sufficient and other nonsurgical interventions are undesired or ineffective.

Antimuscarinic agents have been the mainstay of pharmacotherapy for OAB and UUI. According to American Urological Association (AUA) guideline, clinicians should avoid antimuscarinic agents in patients with narrow-angle glaucoma unless approved by the treating ophthalmologist. Antimuscarinic agents should be cautiously used in patients with fraility, impaired gastric emptying or a history of urinary retention, or in those who are taking other drugs with anticholinergic properties. When one agent offers inadequate symptom control and/or unacceptable adverse drug events, consider a dose modification or switching to another agent. Before abandoning effective antimuscarinic therapy, clinicians should manage constipation and dry mouth (bowel regimen, fluid management, dose modification or alternative antimuscarinics).23

Nonpharmacologic Therapy

Nonsurgical Treatment

Images Nonpharmacologic, nonsurgical treatment of UI is recommended as the first-line therapy at a primary care level. It is the only option for patients in whom pharmacologic and/or surgical management is inappropriate or undesired. Examples of patients who fulfill these criteria for nonpharmacologic treatment include those who with mild to moderate symptoms who do not want to take medication; those with comorbid conditions that place them at high risk for adverse effects from drug therapy; those who are not medically fit for surgery; those who plan future pregnancies (which may adversely affect long-term surgical outcomes); those with overflow incontinence whose condition is not amenable to surgery or drug therapy; and those who are delaying surgery or do not want to undergo surgery.24,25

Nondrug interventions for UI include behavioral interventions, external neuromodulation, alternative medicine therapy, antiincontinence devices, and supportive interventions (Table 68-3).24,25 Behavioral interventions are generally the first-line of treatment for SUI, UUI, and mixed UI. Interventions include lifestyle modifications, toilet scheduling regimens, and pelvic floor muscle rehabilitation. Because the key to success with any type of behavioral intervention is motivation of patients or caregivers, these individuals must be active participants in developing a treatment plan. Regular follow-up is needed to help motivate patients and caregivers, provide reassurance and support, and monitor treatment outcomes.

TABLE 68-3 Nonpharmacologic Management of Urinary Incontinence

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Images

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External neuromodulation may include nonimplantable electrical stimulation, percutaneous tibial nerve stimulation, or extracorporeal magnetic stimulation. This treatment option is typically prescribed when traditional pelvic floor muscle rehabilitation has failed. Antiincontinence devices such bed alarms, catheters, pessaries, and penile clamps and external collection devices are reserved for special situations depending on patients’ UI symptoms, cognitive and mobility status, and overall health status. Supportive interventions such as physical therapy may be beneficial for patients with muscle weakness and slow gait to reach the toilet in a timelier manner, and absorbent products will provide greater confidence in dealing with unpredictable urine loss.

Surgical Treatment

Only rarely does surgery play a role in the initial management of UI.26 In the absence of secondary complications from UI (e.g., skin breakdown or infection), the decision to surgically treat symptomatic UI should be based on the premise that the degree of bother or lifestyle compromise to the patient is great enough to warrant an elective operation, and that nonsurgical therapy either is undesired or has been ineffective.

Successful application of surgery depends mostly on defining the underlying abnormalities responsible for UI (bladder vs. urethra, underactivity vs. overactivity). Once the underlying factors are determined, other considerations include renal function, sexual function, severity of leakage, history of abdominal or pelvic surgery, presence of concurrent abdominal or pelvic pathology requiring surgical correction, and finally the patient’s suitability for the procedure and willingness to accept the risks of surgery.

If patients with uncomplicated SUI become dissatisfied with the initial management approaches of pelvic floor exercises, medications, and/or behavioral modification, surgical treatment assumes the primary role.26

Surgical correction of female SUI (urethral underactivity) is directed toward either (a) repositioning the urethra and/or creating a backboard of support, or otherwise stabilizing the urethra and bladder neck in a well-supported retropubic (intraabdominal) position that is receptive to changes in intraabdominal pressure; or (b) improving the sealing mechanism and/or creating compression or otherwise augmenting the urethral resistance provided by the intrinsic sphincteric unit, with (i.e., sling) or without (i.e., periurethral injectable bulking agents) urethral and bladder neck support.

Bulking agents are injected into the urethra at the level of the urinary sphincter as an office-based procedure and are generally considered quite safe. However, their durability and efficacy are likely inferior to other options.27

Midurethral synthetic slings have become the most common approach to the treatment of SUI in women in the United States.28 These can be inserted as outpatient procedures that have shorter convalescence periods and allow faster return to usual activities compared with many of the older procedures. These procedures are generally felt to be highly durable and efficacious. However, safety concerns have been recently expressed regarding the implantation of surgical mesh in some patients, the implications of which are yet to be fully clarified.29

SUI in men is very rare in the absence of prior pelvic surgery, injury, or neurologic disease. When it occurs, SUI in men can be treated in a number of ways.30 Bulking agents can be injected periurethrally and submucosally into the region of the external urinary sphincter. This approach is less effective and far less durable than alternative surgical procedures, although it can be performed in the office setting without the need for general anesthesia.

The artificial urinary sphincter is generally considered to be the gold standard for treatment of male SUI.30 Placement of this manually operated silicone device has been associated with very high long-term success and satisfaction rates.31 Male slings placed through a perineal incision are a newer alternative to the artificial urinary sphincter. However, long-term efficacy and safety data are lacking.32

Most patients with UUI are managed nonsurgically with a combination of behavioral modification, pelvic floor exercises, and pharmacologic therapy. However, for patients refractory to such measures, invasive therapy can beneficial. Posterior tibial nerve stimulation is an office-based percutaneous treatment for UUI or OAB. Therapy consists of weekly 30-minute treatments with a needle placed posteriorly to the medial malleolus of the ankle for 3 months. Efficacy appears similar to or slightly better than oral pharmacotherapy.33 However, long-term efficacy and safety data are lacking.34

Surgery for the treatment of UUI generally consists of implantation of a sacral nerve stimulator (neuromodulation) or endoscopic office-based injection of botulinum toxin directly into the detrusor muscle.35,36Neuromodulation is a staged surgical procedure in which a neurostimulator lead is placed transforaminally at the level of sacral spinal cord root S3. Its exact mechanism is unknown, but the device may exert its favorable effects on urination and UUI by rebalancing the afferent and efferent nerve impulses to the lower urinary tract and pelvic floor. The injection of botulinum toxin is performed in the office generally with local anesthesia. The toxin is taken up by the efferent nerve terminals and prevents the release of acetylcholine into the synapse at the neuromuscular junction, thus inducing paralysis of the affected detrusor muscle. The duration of effect of the toxin is about 4 to 8 months, after which repeat injection is necessary to maintain effect. The therapeutic algorithm involving these two choices for treatment of refractory UUI is evolving and is determined largely by patient preference.37

Few surgical treatments for bladder underactivity are effective. After an appropriate evaluation for reversible causes, the most effective management of this condition is intermittent self-catheterization performed by the patient or a caregiver three or four times per day. Sacral nerve stimulation (neuromodulation) has shown some efficacy in this patient population, but success rates for detrusor underactivity (nonobstructive urinary retention) are inferior to those seen with urinary frequency and urgency.38 Proper patient selection for this therapy remains poorly defined. Alternative methods of management that are less satisfactory or more invasive include indwelling urethral or suprapubic catheters and urinary diversion.

Urethral overactivity is most commonly caused by anatomic obstruction. Anatomic obstruction in men is most often caused by benign prostatic enlargement. Treatments may include transurethral surgical resection of the prostate (see Chap. 67).

Rarely, bladder outlet obstruction is caused by a functional obstruction at the level of the bladder neck or external sphincter. Hypertrophy of the smooth muscle fibers at the level of the bladder neck in men and women may result in obstruction to the flow of urine. In patients who do not respond to pharmacologic therapy with α-adrenergic receptor antagonists, endoscopic incision using the cystoscope is highly effective in treating this very uncommon condition.

Pharmacologic Therapy

Urge Urinary Incontinence

Images Anticholinergic/antimuscarinic agents are the first-line drug therapy for relieving UUI symptoms and preventing its complications. Table 68-4 summarizes AUA recommendations for treating OAB in adults.23 Mirabegron, a β3-adrenergic agonist, was approved in 2012 for OAB or UUI. While the guideline does not discuss its role in comparison to other existing drug options, it may be considered as first-line therapy or in patients who do not adequately respond to or cannot tolerate anticholinergic/antimuscarinic drugs. Table 68-5 lists the usual dosage for approved agents for OAB or UUI. Table 68-6 suggests common monitoring parameters for these agents.

TABLE 68-4 AUA Guideline for Treatment of Overactive Bladder in Adults

Images

TABLE 68-5 Dosing of Medications Approved for OAB or UUI

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TABLE 68-6 Monitoring of Medications Approved for OAB or UUI

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Anticholinergic/antimuscarinic agents (oxybutynin, tolterodine, trospium, solifenacin, darifenacin, and fesoterodine) antagonize muscarinic receptors and suppress premature detrusor contractions, thereby enhance bladder storage. They have similar contraindications, precautions, and side effect profiles with incidence/severity varies with each individual agent.39 Choice of therapy should be based on patient characteristics (e.g., age, comorbidities, concurrent medications, and ability to adhere to the prescribed regimen). These agents have been demonstrated to improve quality of life in patients with UUI, and are considered equally effective based on statistical superiority over placebo or active controls. In clinical trials, major efficacy outcomes for these agents in the management of UI are reduction of the mean number of UI episodes, decrease in the number of micturitions per day, and increase of urine volume voided per micturition.40

Oxybutynin IR Oxybutynin IR is the oldest treatment for UUI and the gold standard against which other drugs are compared. It has the disadvantages of giving substantial nonurinary antimuscarinic effects, and these may lead to therapy cessation. Besides antimuscarinic effects, oxybutynin IR also causes orthostatic hypotension, and sedation/weight gain, due to the blockage of α-adrenergic-, and histamine H1-receptors, respectively.41 Overall, significant adverse effects of this agent jeopardize medication adherence and can prevent dose escalation to achieve optimal benefit. Its multiple daily dosing may be too complicated for patients with cognitive impairment or those who are taking multiple medications. It is available in oral solution formulation, which may be easier to administer to patients who have difficulty in swallowing. It is also available generically and thus less costly.

The high incidence of adverse effects, especially dry mouth, with use of oxybutynin IR is largely due to it active metabolite N-desethyloxybutynin (DEO), which is generated during extensive first-pass metabolism in the liver and upper GI tract.41 The lower DEO plasma concentrations seen with long-acting (LA) forms of oxybutynin (due to reduced first-pass metabolism) compared with those of oxybutynin IR may explain the lesser propensity of the LA formulations to cause dry mouth and other anticholinergic adverse effects.42 Another factor associated with the adverse effects of oxybutynin IR, especially in older patients, is the transient high peak serum oxybutynin plasma concentrations.

To optimize tolerability, initiate dose at no more than 2.5 mg twice daily, increase to 2.5 mg three times daily after 1 month, then titrate in increments of 2.5 mg/day every 1 to 2 months until the desired response or the maximum recommended or tolerated dose is attained. The optimal response usually requires no more than 5 mg three times daily. Side effects may be managed by dose reduction. Also, dry mouth may be relieved by use of sugarless hard candy, gum, or a saliva substitute. Constipation can be minimized by increasing the intake of water, dietary fiber, physical activity, or laxative therapy.

Oxybutynin Extended-Release An extended-release (XL) formulation of oxybutynin can be considered an alternative therapy in patients who cannot tolerate IR formulation. These have been shown to be more effective than placebo and are as effective as oxybutynin IR in efficacy outcomes.42

The XL product delivers a controlled amount of oxybutynin over a 24-hour period, reducing first-pass metabolism by cytochrome P450 (CYP) isoenzyme 3A4. This explains the lower dry mouth incidence associated with the XL product. In short-term studies of up to 12 weeks’ duration, oxybutynin XL was better tolerated than oxybutynin IR, with approximately 7% of patients discontinuing treatment because of adverse effects (compared with approximately 27% of those taking oxybutynin IR). The rate and severity of adverse effects did not differ significantly between elderly persons (≥65 years old) and younger adults.42

In a 12-week study, oxybutynin XL was more effective than tolterodine IR in reducing the mean number of weekly incontinence episodes and micturitions. In another study, it was as effective as tolterodine LA in decreasing the mean number of incontinence episodes, but oxybutynin XL was superior in reducing weekly micturition frequency and achieving total dryness. Pooled results of two open-label studies suggested that oxybutynin XL was inferior in patient-perceived improvement in bladder control and adverse effects profile to tolterodine LA. However, both agents provided similar patients’ or physicians’ perception of benefit over baseline and proportions of withdrawals due to lack of efficacy. A major limitation of this study was lack of blinding, which may lead to patient and observer bias.39

Oxybutynin XL should be administered once daily, and should not be crushed or chewed. Elderly patients should start with a dose of 5 mg once daily and titrate gradually to desired effects, which may take at least 4 weeks after dose initiation or escalation. Drug interactions may occur when oxybutynin is used with other anticholinergic drugs, potent CYP3A4 inhibitors (e.g., itraconazole, miconazole, erythromycin, and clarithromycin), and acetylcholinesterase inhibitors via pharmacodynamic antagonism. Elimination of oxybutynin XL is not altered in patients with renal or hepatic impairment or in geriatric patients (up to age 78 years).42

Transdermal Oxybutynin The oxybutynin transdermal system (TDS) is another option for patients who cannot tolerate IR oxybutynin or who prefer topical drug delivery route. The patch allows oxybutynin to bypass first-pass hepatic and gut metabolism, and gives a more tolerable adverse effect profile compare with oral formulations.43 It is superior to placebo in efficacy outcomes, and similar to oxybutynin IR in reducing the frequency of UUI episodes and improving patient-perceived urinary leakage.43,44 Compared with tolterodine LA, oxybutynin TDS provided similar efficacy outcomes, including attaining complete continence and improving quality of life.39 A large multicenter trial (n = 2,878) reported improved quality of life and good tolerability in patients 65 years or older; increase in work productivity was noted among younger patients.45,46

Patients should apply oxybutynin TDS to dry, intact skin on the abdomen, hip, or buttocks every 3 to 4 days (twice weekly). Rotating application site at least weekly may help to minimize local side effects. The most common adverse effects are pruritus (14% to 17%) and erythema (6% to 9%) at the application site, dry mouth (5% to 10%), constipation (3%), and abnormal vision (2.5%), which occur similarly among older and younger populations.43

Oxybutynin Topical Gel Another option for topical application of oxybutynin is gel formulation (available in 10% or in 3%).47,48 It has the same effects on oxybutynin and DEO plasma concentrations as with the patch formulation.49It causes significantly less dry mouth than oxybutynin (6.1% vs. 73.1%).50 In 12-week, randomized, placebo-controlled studies, oxybutynin topical gel has been superior to placebo in efficacy outcomes with common adverse effects being dry mouth and application site reactions.51 Use of this product for 1 week did not cause cognitive impairment in healthy older adults aged 60 to 79 years.52 However, clinicians should monitor for anticholinergic effects during long-term therapy, particularly in frail patients with baseline susceptibility to these adverse effects.

The most common adverse events include dry mouth (8% to 12%), application site reactions (5% to 11%), and dizziness (3%).47,48 Clinicians should counsel patients to avoid applying sunscreen within half an hour before or after application and to avoid showering within 1 hour after application. The transfer of gel between individuals may occur if vigorous skin contact is made at the application site; patients should avoid open fires or exposure to smoking until this alcohol-based gel has dried.47,48

Tolterodine Immediate Release Tolterodine is a competitive muscarinic receptor antagonist that can be considered first-line therapy for UI in patients with symptoms of urinary frequency, urgency, or urge incontinence. It is as effective as oxybutynin IR in efficacy outcomes, and is associated with lower drug discontinuation rates (8% vs. 27% oxybutynin IR).39,53 A retrospective 2-year cohort study suggested that tolterodine was associated with better medication adherence than oxybutynin due to better tolerability among older patients.54

Tolterodine is predominantly eliminated by hepatic metabolism, which is partially under the control of genetic polymorphism.53 The principal metabolic pathway in extensive metabolizers involves oxidation of the parent drug by CYP isoenzyme 2D6 to the active 5-hydroxymethyl metabolite (DD01), followed by further oxidation and dealkylation. In poor metabolizers who lack the CYP2D6 (approximately 7% of the U.S. population), the principal metabolic pathway involves CYP3A4, with dealkylation of the amino group, oxidation to a dealkylated hydroxy metabolite, and further oxidation to a dealkylated acid metabolite that undergoes glucuronidation. Because tolterodine is principally metabolized by CYP3A4 in this case, its elimination may be impaired by inhibitors of this isoenzyme (e.g., fluoxetine, sertraline, fluvoxamine, macrolide antibiotics, azole antifungals, and grapefruit juice). For example, fluoxetine, an inhibitor of CYP2D6 and 3A4, decreases the metabolism of tolterodine to DD01. The result is a mean 4.8-fold increase in the tolterodine area under the plasma concentration-versus-time curve (AUC), mean 52% decrease in peak plasma concentration, and mean 20% decrease in the AUC of DD01.53 Whether tolterodine significantly alters the pharmacokinetics of drugs metabolized by CYP2D6 is unknown, so caution is advised with concurrent use with agents metabolized by CYP2D6.

A pharmacokinetic study demonstrated that tolterodine pharmacokinetics did not differ significantly in healthy elderly volunteers (age 64 to 80 years) and younger healthy volunteers who were below 40 years of age. However, in another phase I study, the mean serum concentrations of tolterodine and DD01 were 20% and 50% greater in elderly volunteers than in young healthy volunteers, respectively. Despite possibly altered pharmacokinetics in elderly individuals, no differences in the incidences and severity of adverse events between these age groups have been noted in clinical trials, so no dosage adjustment is recommended on the basis of age alone.53

Tolterodine IR can be given 1 to 2 mg twice daily with or without food. It is not recommended in patients with creatinine clearance <10 mL/min (<0.17 mL/s) or severe hepatic impairment. The dose should be reduced to 2 mg in patients with mild to moderate hepatic impairment, or creatinine clearance 10 to 30 mL/min (0.17 to 0.5 mL/s), or in those taking potent CYP3A4 inhibitors. The maximum benefit from tolterodine may take up to 8 weeks after therapy initiation or dose escalation.53

The most common adverse effects of tolterodine are dry mouth, dyspepsia, headache, constipation, and dry eyes. Of note, patients who have known hypersensitivity to fesoterodine fumarate should not receive tolterodine because both agents are metabolized to DD01. Monitoring QT prolongation in patients who are also taking Class IA (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications.53

Tolterodine Long Acting Tolterodine LA offers a convenient once-daily dosing, and is a preferred agent in patients who are bothered by dry mouth while taking IR products. It is better than placebo in efficacy outcomes, including ability to complete tasks before voiding and patient perception of benefit.55 It also improves OAB symptoms in men who were taking α-adrenergic blockers.56

Tolterodine LA should be given once daily, and should not be crushed or chewed. The dose should be limited to 2 mg once daily in patients with mild to moderate hepatic impairment (Child-Pugh class A or B), severe renal impairment creatinine clearance 10 to 30 mL/min (0.17 to 0.50 mL/s), or taking drugs that are potent CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, or ritonavir). Patients with creatinine clearance less than <10 mL/min (<0.17 mL/s) or severe hepatic impairment (Child-Pugh Class C) should avoid taking the drug. Patients should be counseled that it takes up to 8 weeks to see maximum benefit after starting therapy or dose escalation. Common adverse effects and monitoring parameters for tolterodine LA are similar to its IR product.55

Fesoterodine Fumarate Fesoterodine fumarate is also indicated for symptoms of urinary frequency, urgency, or urge incontinence. It is a prodrug that is metabolized to its active metabolite, 5-hydroxymethyl tolterodine (also a metabolite of tolterodine), by nonspecific plasma esterases.57

In a large 12-week, randomized, double-blind, placebo-controlled study, fesoterodine was better than tolterodine ER 4 mg and placebo on reducing UUI episodes, micturitions, urgency and improving health-related quality of life. However, fesoterodine caused more dry mouth (28% vs. 13%), and constipation (4% vs. 3%) than tolterodine ER. It has been associated with higher discontinuation rates due to adverse events (5% vs. 3%).58

The usual starting dose is 4 mg daily, increasing to 8 mg daily, as needed and tolerated. The dose of fesoterodine should not exceed 4 mg daily in the presence of severe renal impairment (creatinine clearance <30 mL/min [0.50 mL/s]) or in patients also taking potent CYP3A4 inhibitors. Fesoterodine is not recommended in patients with severe hepatic impairment. It is available in extended-release tablets, which should be swallowed whole; patients should not chew, crush, or divide the product.57

The most common adverse effects of fesoterodine are dry mouth (27%), constipation (5.1%), dyspepsia (2%), and dry eyes (1.6%). Anticholinergic adverse effects associated with fesoterodine are dose related.57

Trospium Chloride Immediate Release Trospium chloride, a quaternary ammonium anticholinergic, is a second-generation antimuscarinic agent for UUI. Trospium chloride is poorly absorbed after oral administration (<10%), and food reduces bioavailability by 70% to 80%. It is principally cleared by the renal route (60%). Metabolites account for approximately 40% of the excreted dose following oral administration. The major metabolic pathway is hypothesized as ester hydrolysis with subsequent conjugation of benzylic acid to form azoniaspironortropanol with glucuronic acid. CYP is not expected to contribute significantly to the elimination of trospium. The plasma half-life is approximately 20 hours, with renal clearance about 30 L/h. Active tubular secretion is a major route of elimination for trospium, which explains its drug interaction profile. Advancing age and mild to moderate hepatic impairment do not affect trospium chloride pharmacokinetics to a clinically significant degree. In contrast, renal impairment does significantly reduce drug clearance. When creatinine clearance is less than 30 mL/min (0.50 mL/s), AUC is increased by a mean of 4.5-fold, peak plasma concentration by a mean of twofold, and terminal disposition half-life by a mean of two- to threefold.59

In a study involving a large proportion of elders (mean age, 63 years), trospium chloride was better than placebo in efficacy outcomes of UUI.60 In a 12-week, controlled study, trospium chloride IR was noninferior to oxybutynin IR in managing UUI, but was associated with less dry mouth.61

The frequency of anticholinergic side effects of trospium was higher in patients 75 years and older than younger subjects. This occurrence is believed to be pharmacodynamic (i.e., increased sensitivity) and not pharmacokinetic in nature. No data at present support the hypothesis that trospium chloride is less neurotoxic than nonquaternary ammonium anticholinergics (based on the hypothesis of reduced transit across the blood–brain barrier of trospium chloride due to its positive electrical charge on the quaternary nitrogen). Trospium may interact with other drugs that are eliminated by active tubular secretion via competition (e.g., procainamide, pancuronium, morphine, vancomycin, and tenofovir).59 Thus, clinicians should monitor the clinical effects of these agents when used concomitantly.

The usual dosage of trospium IR is 20 mg twice daily. The drug should be taken on an empty stomach. Dosage reduction (by 50% of the daily dose) is recommended when creatinine clearance is less than 30 mL/min (0.50 mL/s). In patients age 75 years and older, dose reduction to 20 mg once daily should be considered based upon tolerability.59

Trospium Chloride Extended-Release Trospium chloride ER offers once-daily dosing. Its efficacy and safety have been demonstrated in patients with OAB, including those who are older and taking multiple medications.6264

Trospium is eliminated primarily unchanged in the urine. It is not recommended in patients with severe renal impairment (creatinine clearance <30 mL/min [0.50 mL/s]).

Alcohol should not be consumed within 2 hours of trospium ER administration. Coadministration with antacid may increase or decrease trospium exposure, but the clinical relevance of these findings is unknown. In addition, coadministration of immediate-release (IR) metformin 500 mg twice daily reduced the steady-state systemic exposure of trospium by approximately 29% and peak concentration by 34%.63

The usual dosage of trospium ER is 60 mg daily. Because food decreases the bioavailability by 35% to 60%, extended-release trospium chloride must be taken on an empty stomach (1 hour before or 2 hours after meals).63Common adverse effects with trospium chloride ER have been dry mouth (11%), constipation (9%), dizziness (2%), dry eyes (1.6%), flatulence (1.6%), nausea (1.4%), and abdominal pain (1.4%). Patients should be informed that alcohol may enhance the drowsiness caused by anticholinergic agents.63

Solifenacin Succinate Solifenacin succinate is a second-generation antimuscarinic agent indicated for the treatment of OAB with urge incontinence, urgency, and urinary frequency. Solifenacin was better than tolterodine ER in terms of reducing the number of UUI episodes and pad usage and in improving patients’ perception of their bladder condition.65 An analysis of pooled data from two phase III studies showed that solifenacin recipients had significant improvement in 5 of 10 quality-of-life domains from baseline compared with placebo recipients.66 Compared with oxybutynin IR, solifenacin was associated with fewer episodes (35% vs. 83%) and lower severity of dry mouth.67,68

Solifenacin is well absorbed (mean absolute bioavailability, 88%), and food has no clinically relevant effect on absorption. It is principally eliminated via metabolism and renal excretion of metabolites, with renal excretion of parent compound less than 10% of the dose. With a mean terminal disposition half-life of 50 to 60 hours, the drug can be dosed once daily.64 The primary pathway for elimination of solifenacin is via CYP3A4. Adverse effects, including dry mouth, occurred similarly between younger and older patients.67

The recommended dose of solifenacin is 5 mg once daily. If the drug is well tolerated but the effectiveness is not optimal, the dose can be increased to 10 mg once daily. Little additional benefit is generally achieved with doses exceeding 5 mg daily. Solifenacin can be administered with or without food. For patients with creatinine clearance rates less than 30 mL/min (0.50 mL/s) or with moderate hepatic impairment (Child-Pugh class B), the daily dosage should not exceed 5 mg. Patients who have severe hepatic impairment (Child-Pugh class C) should avoid using this drug. If the patient is receiving concurrent therapy with one or more potent CYP3A4 inhibitors, the daily dose should not exceed 5 mg.

The most common adverse reactions of solifenacin are dry mouth (11% to 28%), constipation (5% to 13%), urinary tract infection (4% to 5%) and blurred vision (3% to 5%). It interacts with CYP3A4 inhibitors and inducers; close patient monitoring is required. Prolonged corrected QT intervals have been reported with high-dose solifenacin, thus its use should be cautioned in at-risk patients.64

Darifenacin Darifenacin is another second-generation antimuscarinics for the management of OAB or UUI. It has demonstrated efficacy outcomes, including improving quality of life.69,70 It may be considered in patients who are dissatisfied with previous antimuscarinic treatments.71

The mean absolute bioavailabilities of the 7.5-, 15-, and 30-mg extended-release (ER) formulations are 15%, 19%, and 25%, respectively. Bioavailability is affected by formulation, CYP2D6 genotype, dose, and race. Bioavailability is enhanced using an ER formulation (70% to 110% higher than IR), in heterozygous CYP2D6 extensive metabolizers and poor metabolizers (40% to 90% higher than homozygous extensive metabolizers), and white race (56% higher than Japanese). Darifenacin is extensively metabolized, with cumulative urinary excretion of the parent compound less than 10%. The 2D6 and 3A4 isoenzymes of CYP are responsible for darifenacin metabolism. With a mean terminal disposition half-life of 3 to 5 hours (depending on CYP2D6 metabolizer status), an ER formulation is needed to allow once-daily dosing.72

Darifenacin ER should be initiated at 7.5 mg once daily, and may be increased to 15 mg once daily after 2 weeks to target clinical response. The dosage should be limited to 7.5 mg daily in patients with moderate hepatic impairment (Child-Pugh B), taking potent CYP3A4 inhibitors. It should be avoided in patients with severe hepatic impairment (Child-Pugh C). It must be swallowed whole without chewing, dividing, or crushing. The most frequently reported adverse reactions are constipation (21%), dry mouth (19%), headache (7%), dyspepsia (5%), and nausea (4%). Darifenacin may interact with substrates of CYP2D6 (flecainide, thioridazine, and tricyclic antidepressants), thus clinical effects of these drugs should be closely monitored.72


Clinical Controversy…

Should antimuscarinic pharmacotherapy be used to treat UUI in patients with mild cognitive impairment or dementia? Antimuscarinic agents may worsen cognitive function, especially in older adults. Caution should be exercise as these agents may antagonize the therapeutic effects of acetylcholine esterase inhibitors indicated for dementia.

Mirabegron Mirabegron is a β3-adrenergic agonist approved by FDA in June 2012 for the treatment of OAB with symptoms of UUI, urgency, and urinary frequency.

Images Mirabegron is an alternative to anticholinergics/antimuscarinic drugs for managing UUI. Similar to other previously approved agents, it is only modestly effective and reduces urinary frequency and incontinence episodes by less than one per day. It increases bladder capacity by relaxing the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by the activation of β3-adrenergic receptors.73

The efficacy and safety of mirabegron have been demonstrated in three 12-week, multicenter, double-blind, randomized, placebo-controlled trials. The majority of patients were female Caucasians with a mean age of 59 years (range, 18 to 95 years). About half the study subjects had prior antimuscarinic pharmacotherapy for OAB. Overall, mirabegron reduced mean number of incontinence episodes per 24 hours, mean number of micturitions per 24 hours, and increased mean volume voided per micturition. The efficacy was seen during 4 to 8 weeks of therapy, and was maintained through the 12-week treatment period.73

Mirabegron reaches its peak plasma concentrations at approximately 3.5 hours, with an oral bioavailability of 29% to 35% with approved doses. It achieves steady state within 7 days of therapy. Coadministration with high-fat meals reduced its peak concentration and drug exposure by 45% and 17%, respectively. In contrast, low-fat meals decreased these parameters by 75% and 51%, respectively. Nevertheless, mirabegron can be taken with or without food.

Mirabegron is extensively distributed in the body, with a volume of distribution of approximately 1,670 L. It has protein binding of approximately 71% to both albumin and α1 acid glycoprotein. Mirabegron is metabolized via multiple pathways involving dealkylation, oxidation, glucuronidation, and amide hydrolysis. It has two inactive metabolites (16% and 11% of total exposure), respectively. Isoenzymes CYP2D6 and 3A4 play a limited role in its elimination. Poor metabolizers of CYP2D6 had an increased mean peak concentration and drug exposure compared to extensive metabolizers of CYP2D6 (16% and 17%, respectively). Other enzymes that are involved in mirabegron metabolism include butylcholinesterase, uridine diphospho-glucuronosyltransferases (UGT) and possibly alcohol dehydrogenase.

Total body clearance of mirabegron is about 57 L/h, with a terminal elimination half-life of 50 hours. Renal clearance equals approximately 13 L/h, primarily through active tubular secretion along with glomerular filtration. The urinary elimination of unchanged mirabegron is dose-dependent and ranges from 6% to 12% after a daily dose of 25 to 100 mg.73

Mirabegron should be initiated at 25 mg once daily, and may titrate upward to 50 mg once daily after 8 weeks, based on individual efficacy and tolerability; limit dose to 25 mg once daily in patients with severe renal impairment or moderate hepatic disease. Mirabegron is available in extended-release tablets, and should be swallowed whole with water without chewing, dividing, or crushing. It should be avoided in patients with end-stage renal disease, severe hepatic impairment, or severe uncontrolled hypertension (≥180/110 mm Hg). Most commonly reported adverse reactions were hypertension (7% to 11%), nasopharyngitis (4%), urinary tract infection (3% to 6%), and headache (3% to 4%). Patient should be monitored for increased blood pressure and urinary retention, particularly in patients with bladder outlet obstruction or those who are taking anticholinergic drugs.73

Mirabegron is a moderate inhibitor of CYP2D6, and may affect the dosage requirement for some 2D6 substrates (e.g., metoprolol and desipramine). Thus, drug level monitoring for certain medications with a narrow therapeutic range, such as thioridazine, flecainide, and propafenone, is advised. When initiating a combination of mirabegron and digoxin, start with the lowest possible dose of digoxin and titrate based drug level and clinical effect.73

Other Anticholinergics and Antimuscarinics Other drugs for treatment of UUI are less effective, are no safer, or have not been adequately studied.24 Thus their use is not recommended. Tricyclic antidepressants are generally no more effective than oxybutynin IR, and they exhibit a high incidence of bothersome and potentially serious adverse effects (e.g., orthostatic hypotension, cardiac conduction abnormalities, dizziness, and confusion). They are also potentially life threatening in overdose. Therefore, their use should be limited to individuals who have one or more additional medical indications for these agents (e.g., depression or neuropathic pain); patients with mixed UI (because of their effect of decreasing bladder contractility and increasing outlet resistance); and possibly those with nocturnal incontinence associated with altered sleep patterns.7476 Because of the lower incidence of adverse effects, desipramine and nortriptyline may be preferred over imipramine and doxepin. However, due to their lower anticholinergic activity, they may not be as effective.

Propantheline, a quaternary ammonium anticholinergic and potential treatment, produces a high incidence of adverse effects and is only modestly effective for UUI. When used, propantheline appears to be best tolerated at a dose no more than 15 mg three times daily plus 60 mg at bedtime.77

Flavoxate is a tertiary amine that relaxes smooth muscle in vitro. Four controlled trials revealed that flavoxate is no more effective than placebo for treatment of UUI; therefore, flavoxate is not recommended.24

Dicyclomine hydrochloride, an anticholinergic agent that relaxes smooth muscle, produced minimal benefit as well as bothersome adverse effects in two small studies.78

Hyoscyamine, an anticholinergic and antispasmodic drug related to atropine, has been suggested for treatment of UUI, but data recommending its use are insufficient.24


Clinical Controversy…

Which approved agent should be used as first-line pharmacotherapy of UUI (oxybutynin, tolterodine, trospium chloride, solifenacin, darifenacin, fesoterodine, or mirabegron)? Financial considerations currently favor generic oxybutynin IR. Choice of an initial agent should be individualized based on tolerability, affordability, and adherence issues. Patient comorbidities may favor the use of more expensive branded agents.

Comparative Data In a meta-analysis, 50 randomized, controlled trials and three pooled analyses were examined for significant difference among anticholinergic agents. Adverse events, particularly dry mouth, were seen less frequently with use of LA products, as compared with IR formulations (oxybutynin and tolterodine). Of interest, the incidence of headache was higher with the use of LA versus IR formulations of tolterodine although LA tolterodine was more effective in the parameters of number of micturitions and volume voided per micturition.79

For tolterodine IR, efficacy was similar for the 2 and 4 mg daily doses, while only dry mouth occurred more frequently with 4 mg daily dose. The IR products of oxybutynin and tolterodine were similar in efficacy. Oxybutynin IR was associated with lower tolerability, particularly dry mouth, than tolterodine IR or LA. Oxybutynin IR, TDS (patch), and tolterodine LA produced similar reductions in the number of incontinence episodes. However, the oral agents were associated with higher frequencies of dry mouth and constipation. In contrast, the patch formulation was associated with higher frequencies of local (application site) reactions.79

Solifenacin 10 mg daily dose achieved better percentage of patients with a 50% or greater reduction in incontinence episode frequency than 5 mg daily dose, but with higher study withdrawal rates due to adverse events, dry mouth, and constipation. Similarly, darifenacin 15 mg daily dose was associated with higher study withdrawal rates due to dry mouth and constipation than 7.5 mg daily dose.79

In a systematic literature review, 94 randomized controlled trials involving drugs for UUI were examined. Overall, drugs for UUI showed similar small benefits.40 Per 1,000 treated women, continence was restored in this decreasing order: fesoterodine, oxybutynin or trospium, solifenacin, and tolterodine. Rates of treatment discontinuation due to adverse effects in this decreasing order: oxybutynin, fesoterodine, trospium, and solifenacin.40Tolterodine was found to be better tolerated than fesoterodine or oxybutynin. More data are needed to assess long-term adherence and drug safety, quality-of-life improvements, and comparative effectiveness among drugs.40

Currently, there is no direct comparison between antimuscarinics and mirabegron. Selection of an initial drug therapy most likely depends on side effect profile, comorbidities, concurrent drug therapy and patient preference in drug delivery methods. Table 68-7 lists the adverse event frequencies for the most common events for oxybutynin, tolterodine, trospium chloride, solifenacin, darifenacin, fesoterodine, and mirabegron based on manufacturers’ product information.

TABLE 68-7 Adverse Event Incidence Rates with Approved Drugs for Bladder Overactivitya

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Botulinum Toxin A Enthusiasm is considerable for the application of botulinum toxin A for treatment of voiding dysfunction. Botulinum toxin is a naturally occurring powerful muscle relaxant produced by Clostridium botulinum.

Injected into smooth or striated muscle, botulinum toxin acts as a neurotoxin by temporarily paralyzing the muscle. The mechanism of action of the paralytic effect is generally ascribed to prevention of the release of the neurotransmitter acetylcholine into the synapse at the neuromuscular junction, although other pathways in neurotransduction may also be affected.

This compound is commercially produced for medical use in a number of conditions such as muscle spasticity, hyperhidrosis, and cosmetic reduction of skin wrinkles. It is currently indicated for the treatment of refractory UUI associated with neurogenic detrusor overactivity. However, outside of this indication in neurogenic bladder patients, botulinum toxin does not carry an FDA-approved indication in any other lower urinary tract disorders. Nevertheless, it has been used for the “off label” treatment of OAB and nonneurogenic (idiopathic) urge incontinence.8082 Despite this lack of a current OAB indication, botulinum toxin is recommended by AUA as the third-line agent in adult patients with idiopathic OAB.23 In the lower urinary tract, it has also been used to treat external urethral sphincter spasticity by direct injection into the external urethral sphincter.

Botulinum toxin is delivered into the detrusor muscle (intravesical injection) using a cystoscope equipped with a needle. The usual dosage is between 100 and 300 units per session. It is injected through the needle directly into the bladder muscle in 10 to 30 injections spaced over 5 to 10 minutes. The procedure is carried out as an outpatient procedure without general anesthesia. The duration of therapeutic effect varies, lasting usually from 4 to 8 months. Repeat injections are necessary to maintain the beneficial effects.82

The adverse effects of botulinum toxin A when used in the urinary tract most frequently include dysuria, hematuria, urinary tract infection, and urinary retention. Urinary retention occurs in up to 20% of treated individuals and persists until the paralytic effects have worn off (up to 6 to 8 months). Therapeutic and adverse effects may not become evident for 3 to 7 days, presumably because this period of time is required for uptake of the toxin following injection.81,82

Intravesical (i.e., bladder) injection of botulinum toxin A in patients with refractory OAB resulted in increased bladder capacity, increased bladder compliance, and improved quality of life.81,82 Adverse effects include urinary tract infection and urinary retention.81 Comparative data with placebo and other interventions, long-term safety and efficacy outcomes, and data regarding the optimal dose of botulinum toxin for idiopathic OAB are needed.

An alternative mechanism of delivery other than intravesical injection would greatly improve the appeal of this agent as needle injection can be painful in some individuals. Results of an open-label trial of intravesical botulinum toxin A in dimethylsulfoxide in 21 women with refractory idiopathic detrusor overactivity demonstrated a significant reduction in the frequency of incontinence episodes without any effect on postvoid residual urine volumes.83Further studies are needed in this regard.

Catheterization Combined with Medications Patients with UUI and an elevated postvoid residual urine volume due to retention may require intermittent self-catheterization along with frequent voiding between catheterizations.

If intermittent catheterization is not possible, surgical placement of a suprapubic catheter may be necessary. Use of a chronic indwelling catheter should be avoided because of the increased occurrence of urinary tract infections and nephrolithiasis.

Regardless of catheterization status, patients may experience symptom relief with oxybutynin (IR, XL, or TDS formulations), tolterodine (IR or LA formulations), trospium chloride, solifenacin, fesoterodine, darifenacin, or mirabegron, as these agents relax the detrusor muscle and enhance bladder storage. Patients with UUI and symptoms of retention may also benefit from an α-adrenergic receptor antagonist that relaxes the internal bladder sphincter (e.g., prazosin, terazosin, doxazosin, tamsulosin, silodosin, and alfuzosin). Although theoretically of benefit, bethanechol, a cholinergic agonist, has not been demonstrated effective in improving bladder emptying in well-done trials. In addition, it causes numerous bothersome (e.g., muscle and abdominal cramping and diarrhea) and potentially life-threatening adverse effects and should not be used in patients with asthma or heart disease.24

Urethral Underactivity

Images Urethral underactivity, or SUI, may be aggravated by agents with α-adrenergic receptor blocking activity, including prazosin, terazosin, doxazosin, tamsulosin, alfuzosin, silodosin, methyldopa, clonidine, guanfacine, guanadrel, and labetalol. The goal of therapy for SUI is to improve the urethral closure mechanism by stimulating α-adrenergic receptors in the smooth muscle of the bladder neck and proximal urethra, enhancing the supportive structures underlying the urethral epithelium, or enhancing the positive effects of serotonin and norepinephrine in the afferent and efferent pathways of the micturition reflex.84

Estrogens Local and systemic estrogens have been used extensively for the pharmacologic management of SUI since the 1940s. Estrogens are believed to work via several mechanisms, including enhancement of the proliferation of urethral epithelium, local circulation, and numbers and/or sensitivity of urogenital α-adrenergic receptors. However, a trial has questioned whether estrogens exert a stimulatory effect on vaginal collagen production, at least over the short term.85

Open trials support the use of a variety of estrogens in the management of SUI: transdermal estradiol, conjugated estrogen vaginal cream, Estring, oral conjugated estrogen, oral quinestradol, oral estriol, intramuscular estrogens, estriol vaginal suppositories, and oral estradiol.86 Variable effects of estrogen treatment on urodynamic parameters, such as maximum urethral closure pressure, functional urethral length, and pressure transmission ratio, have been noted in these studies. Progestogens have an antagonistic effect compared with estrogens, by reducing genitourinary tract muscle tone.

Results of four placebo-controlled comparative trials have not been as favorable, finding no significant clinical or urodynamic effects for oral estrogen compared with placebo.87 In fact, observational studies have documented that oral or systemic estrogen use is associated with an increased risk of UI compared with that in nonusers.88 Systemic estrogen therapy is associated with numerous adverse effects, including mastodynia, uterine bleeding, nausea, thromboembolism, cardiac and cerebrovascular ischemic events, and enhancement of the risk of certain cancers.88 If estrogens are to be used for treatment of SUI, only topical products should be administered. Estrogen use is best justified when SUI exists with urethritis or vaginitis due to estrogen deficiency.

α-Adrenergic Receptor Agonists Numerous open trials have supported the use of a variety of α-adrenergic receptor agonists in SUI, including ephedrine, norfenefrine, phenylpropanolamine, and midodrine.86Phenylpropanolamine was withdrawn from the U.S. market in 2000 because of a risk for stroke in women using the agent.89 Some patients may have left over supplies of this agent or may obtain it from international sources. If so, individuals with the contraindications listed later in the chapter (especially coronary artery disease and/or cardiac arrhythmias) should be warned against self-treatment with this or other α-adrenergic receptor agonists.

Placebo-controlled comparative trials with phenylpropanolamine, norfenefrine, and norephedrine support the modest efficacy of these agents for treatment of mild or moderate SUI.86,89 These agents have been found to variably affect maximum urethral closure pressure and functional urethral length.

Adverse effects include hypertension, headache, dry mouth, nausea, insomnia, and restlessness. Contraindications to the use of these agents include the presence of hypertension, tachyarrhythmias, coronary artery disease, myocardial infarction, cor pulmonale, hyperthyroidism, renal failure, and narrow-angle glaucoma.

Several studies have evaluated whether the clinical and urodynamic effects of a combination of estrogen and an α-adrenergic receptor agonist exceed those of the individual therapies in SUI.90 In general, combination therapy has resulted in somewhat superior clinical and urodynamic responses compared with monotherapy, including severity of complaints, amount of urine lost per episode, number of daily voluntary micturitions, number of leakage episodes per day, patient preference, pad use, maximum urethral closure pressure, functional urethral length, and pressure transmission ratio.

Duloxetine Duloxetine, a dual inhibitor of serotonin and norepinephrine reuptake (SNRI), was approved in 2004 for treatment of depression and painful diabetic neuropathy in the United States.91 It is approved for SUI in Europe only. It is believed to affect central serotoninergic and noradrenergic regions, which are involved in ascending and descending control of urethral smooth muscle and the external urethral sphincter. These mechanisms facilitate the bladder-to-sympathetic reflex pathway, increasing urethral and external urethral sphincter muscle tone during the storage phase.

The mean terminal disposition half-life, clearance, and volume of distribution of duloxetine in healthy volunteers are 10 to 12 hours, 114 to 119 L/h, and 1,787 to 1,943 L, respectively. The drug is extensively metabolized to inactive metabolites via oxidation and eliminated in the urine as conjugated metabolites. Duloxetine is involved with CYP2D6 and 1A2 enzymes. Duloxetine increased the peak plasma concentration, AUC, and terminal disposition half-life of desipramine, a CYP2D6 substrate, by 1.7-, 2.9-, and 1.9-fold, respectively. Paroxetine, a CYP2D6 inhibitor, increased the peak plasma concentration, AUC, and terminal disposition half-life of duloxetine by 1.6-, 1.6-, and 1.3-fold, respectively. Fluvoxamine, a CYP1A2 inhibitor, increased the peak plasma concentration, AUC, and terminal disposition half-life of duloxetine by over fivefold, 2.5-fold, and threefold, respectively. Thus clinicians must be careful when prescribing duloxetine concurrently with CYP2D6 and 1A2 substrates or inhibitors.91

The effect of advancing age on duloxetine pharmacokinetics is not clinically significant. Moderate hepatic dysfunction (Child-Pugh class B) significantly affects duloxetine disposition, increasing mean AUC and terminal disposition half-life by fivefold and threefold, respectively, and reducing clearance 85% compared with controls. Mild or moderate renal impairment (creatinine clearance 30 to 80 mL/min [0.50 to 1.34 mL/s]) does not affect drug disposition. In severe renal impairment (hemodialysis patients), mean peak plasma concentration and AUC are both increased 100%, whereas metabolite concentrations are increased up to 900%.91

Results of six large clinical trials with duloxetine in SUI have been published. All were double-blinded, randomized, placebo-controlled, and parallel group in design. Compared with placebo, duloxetine therapy produced significant reductions in incontinence episode frequency and number of micturitions per day, improvement in incontinence quality-of-life questionnaire scores and patient self-assessment, and increase in mean micturition interval. Results were independent of baseline UI severity (severity based on incontinent episode frequency). Significant intergroup differences were seen by week 4. However, cure rates were generally not improved by duloxetine. When evaluating the absolute differences between treatments, the actual benefit of duloxetine was generally quite modest.91 Duloxetine also reduced incontinence episodes and improved quality of life in men with SUI after radical prostatectomy.92

A randomized, placebo-controlled clinical trial evaluated the effects of duloxetine (80 mg daily), pelvic floor muscle training (PFMT), and the combination of both modalities on incontinent episode frequency, incontinence-related quality of life, pad use, and patient global impression of change. Sham PFMT was used in the placebo group. Results indicated that duloxetine plus PFMT were probably additive in effect and that combination therapy afforded greater improvement than either monotherapy.93

The adverse events associated with duloxetine may make adherence problematic. In the SUI trials, treatment-emergent adverse events occurred in 68% to 93% of duloxetine and 50% to 72% of placebo recipients. Premature study withdrawal rates (due to adverse events) were as high as up to 33%. The most common adverse events reported with duloxetine were nausea (≤46%), headache (≤27%), constipation (≤27%), dry mouth (≤22%), and insomnia (≤14%). Of interest, the drug may be associated with small increases in blood pressure (like venlafaxine, another dual reuptake inhibitor) and withdrawal symptoms (sleep disturbances). Unfortunately, adherence to long-term therapy is quite poor due to a combination of adverse events and lack of efficacy.94

Despite these negatives, duloxetine is the first drug approved by a regulatory agency for treating SUI in Europe. Based on studies conducted to date, a dosage regimen of 40 to 80 mg/day (in one or two doses) appears reasonable. Gradual dose titration (40 mg daily for 2 weeks, then 80 mg daily) helps to reduce the risks of nausea, dizziness, and premature drug discontinuation. If cessation of duloxetine is desired, consider tapering the dosage by 50% for 2 weeks before discontinuation to avoid withdrawal symptoms.

Venlafaxine Venalfaxine is another SNRI. A double-blind, randomized, placebo-controlled clinical trial has demonstrated the benefit of venlafaxine 75 mg once daily for 12 weeks over placebo in terms of incontinence episode frequency, voiding interval, quality of life, and patient global impression of improvement. Nausea occurred in 40% of the venlafaxine group compared with 15% of the placebo group.95

Overflow Incontinence

Overflow incontinence secondary to benign or malignant prostatic hyperplasia may be amenable to pharmacotherapy. For management of malignant prostatic disease, see Chapter 108. The pharmacotherapy of BPH is discussed in Chapter 67.


Clinical Controversy…

The optimal approach to pharmacotherapy of SUI is unclear. Although not supported by evidence-based medicine, many clinicians initiate a trial of topical estrogen, followed by addition of an α-adrenergic receptor agonist in estrogen nonresponders unless contraindicated. No drugs, except duloxetine in Europe, have been approved for the management of SUI. However, long-term tolerability issues may hinder chronic use.

PERSONALIZED PHARMACOTHERAPY

Patient factors (age, comorbidities, concurrent drug therapies, ability to adhere to prescribe regimen, etc.) should be considered when selecting pharmacotherapy for patients with UI.

All anticholinergic/antimuscarinic drugs have similar contraindications and precautions, including urinary retention, gastric retention, uncontrolled narrow-angle glaucoma, CNS effects, angioedema, and myasthenia gravis. IR formulations of older agents (oxybutynin and tolterodine) have been associated with higher rates of anticholinergic adverse effects (dry mouth, constipation, headache, dyspepsia, dry eyes, cognitive impairment, tachycardia, and urinary retention). Older patients are particularly susceptible to these adverse events, thus requires close monitoring of adverse effects. Significant dry mouth may lead to dental caries, ill-fitting dentures, and swallowing difficulty. Orthostatic hypotension and sedation may lead to falls in patients with baseline cognitive or cardiac conditions. Constipation is prevalent among the older patients because of polypharmacy and age-related physiologic changes.

All patients on anticholinergics should be warned about risk of somnolence and advised not to drive or operate heavy machinery until they know how the drugs affect them. Women with mixed UI or UUI plus urethritis or vaginitis may benefit from a topical estrogen (alone or in combination with an anticholinergic drug). Men with irritative symptoms of BPH that are nonresponsive to drug therapy may benefit from anticholinergic therapy while being closely monitored for the risk of precipitating acute urinary retention.

Anticholinergic drugs should be considered for the management of UUI as monotherapy or in combination with nonpharmacologic interventions. None of the currently available anticholinergic agents appears to have a clear advantage in efficacy over others. Selection of an agent should be based on drug tolerability, dosing convenience, cost considerations, and patient preference. In general, LA or ER products given once daily are preferable over IR ones because of better tolerability. Dose escalation of IR formulations may result in improved efficacy, albeit limited, at the cost of an increase in adverse event frequency and severity. Trospium chloride with its quaternary amine structure and reduced penetration of the brain may be a good choice for patients who are intolerable of CNS adverse effects. Topical formulations, such as oxybutynin TDS or gel, may offer favorable systemic adverse effect profiles and convenient dosing. Selection of an agent should also be based on patient factors, such as renal/hepatic function, concomitant diseases, and concurrent drug therapy. It is advisable to review concomitant medications for any possibility of additive, synergistic, antagonistic drug interactions in cholinergic system and liver enzymes (CYP3A4 and 2D6).

EVALUATION OF THERAPEUTIC OUTCOMES

Images Assessment of patient outcomes should include efficacy, side effects, adherence, and quality of life. During long-term management of UI, patient-specific clinical signs and symptoms of most distress (“bother”) to the individual must be monitored. A daily diary may be useful in this regard. Some of the short-form instruments used in incontinence research for measuring symptom impact and condition-specific quality of life can be used in clinical monitoring. In addition, quantitating the use of ancillary supplies, such as pads, may be useful.

Images The main goal of therapy is to minimize the signs and symptoms most bothersome to the patient, as well as the use of pads and other ancillary supplies or devices. Total elimination of UI signs and symptoms may not be possible, and patients and practitioners need to mutually establish realistic goals of therapy. Because the therapies for UI frequently have nuisance adverse effects (e.g., anticholinergic effects such as dry mouth, constipation, sedation, etc.) that may compromise regimen adherence, the presence and severity of adverse effects must be carefully elicited at each visit to the healthcare practitioner. Queries of the patient and caregiver regarding CNS effects are important in elderly or frail patient as these effects can be severe enough to cause loss of independent living skills. Emergence of adverse effects may necessitate drug dosage adjustment or use of alternative strategies (e.g., chewing sugarless gum, sucking on hard sugarless candy, or use of saliva substitutes in xerostomia) or even drug discontinuation. Patient should be encouraged to persist with a particular treatment for 4 to 8 weeks before declaring treatment failure. Nonresponders to an antimuscarinic should be offered at least one other antimuscarinic and/or dose modification attempted to obtain a better balance between efficacy and side effects.

ABBREVIATIONS

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