US Pharm. 2016;41(9):22-26.
ABSTRACT: Urinary incontinence (UI) is a common problem, especially in women, and it can significantly impact quality of life. UI involves involuntary urine leakage, which can result in a number of symptoms, including urgency, frequency, and nocturia. UI may be classified as stress, urge, overflow, functional, or mixed, depending on the underlying etiology. First-line treatment involves nonpharmacologic measures regardless of UI type. When nonpharmacologic measures are insufficient, pharmacologic options may be considered for some types of UI. Many of the pharmacologic options for UI are associated with undesirable, yet manageable, adverse effects; therefore, counseling is important in fostering patient adherence to medications used to treat UI.
Urinary incontinence (UI), which is defined as an involuntary leakage of urine, is a common problem in the United States.1,2 Symptoms of UI include urgency (a sudden need to urinate that is difficult to suppress), increased daytime frequency (urination >8 times per day), and nighttime urination. Although UI seems to occur most frequently in women of menopausal age, anyone can be affected.1 It is difficult to determine the exact prevalence of this condition; however, it is estimated that UI affects 20% to 30% of young females, 30% to 40% of middle-aged females, and 30% to 50% of elderly females. The overall estimated prevalence in men is much lower (3% to 11%).3
IMPACT OF UI
UI significantly and negatively impacts one’s quality of life.1 The condition may cause patients to feel uncomfortable in social situations and to avoid certain activities.2 Over time, the individual may feel a loss of control, a loss of independence, or poor self-esteem, which can result in psychological conditions such as depression.1 If a patient does not seek treatment for UI symptoms, there can be potential medical consequences, such as urinary tract infections, perineal irritation, and worsening pressure ulcers.1
NORMAL URINARY FUNCTION
In normal urinary function, the sphincters remain closed, causing the urine to remain in the bladder until a person voluntarily urinates.1 The unique structure of the bladder allows for an increase in urine volume without significant increases in bladder pressure. The central nervous system also prevents smooth-muscle activity in the bladder as it fills. With normal voiding, the urinary sphincters relax and the bladder muscles contract simultaneously, enabling appropriate urine flow. UI occurs when there are abnormalities in the function of the bladder, the sphincters, or both.1
TYPES OF UI
There are multiple classifications of UI, including stress, urge, overflow, functional, and mixed UI.1
Stress UI (SUI): SUI involves an involuntary loss of urine caused by inadequate urethral-sphincter closure under increased intra-abdominal pressure. Activities such as exercise, coughing, sneezing, and lifting frequently trigger it. SUI occurs more often in females than in males and is associated with pregnancy, childbirth, menopause, and obesity. Certain medications, such as alpha-antagonists and ACE inhibitors, can exacerbate existing SUI.1,4,5
Urge UI (UUI): In UUI, urine leakage is due to involuntary contractions of the bladder. The cause is typically an overactive bladder, which presents with feelings of urgency and frequency. Large amounts of leakage tend to occur in patients with UUI. Most cases have no identifiable cause and are considered to be idiopathic. Risk factors include aging, certain diseases (e.g., stroke, Parkinson’s disease, benign prostatic hyperplasia [BPH]), and certain medications (e.g., diuretics, alcohol, acetylcholinesterase inhibitors).1,4,5
Overflow UI (OUI): In OUI, the bladder cannot fully empty because an obstructed urine flow or weakened bladder muscles result in overfilling and subsequent leakage. OUI, which is sometimes referred to as chronic urinary retention, is more common in older men. Certain conditions, such as BPH, prostate cancer, diabetes, and denervation (from surgery), can result in OUI. Medications with alpha-adrenergic or antihistaminic properties also can cause overflow incontinence.1,5
Functional UI: Functional urinary incontinence is not typically associated with a lower urinary tract–related cause, but rather is associated with conditions that affect cognitive function or mobility (e.g., dementia, post surgery). The individual may not recognize the need to urinate or may be unable to get to the bathroom in a timely manner. Functional incontinence may be exacerbated by certain medications with cognitive adverse effects, such as sedatives and narcotics.1,5
Mixed UI: In many instances, a patient may have more than one type of incontinence. For example, SUI and UUI often occur simultaneously in women. This can sometimes make diagnosis difficult. As mentioned, certain conditions and medications can aggravate incontinence symptoms, further complicating the situation.1,5
Diagnosis is primarily based on clinical presentation. UI presentation is influenced by the underlying pathophysiology. It is important to get a complete history from the patient, including conditions, surgeries, and medications. The healthcare provider should evaluate the timing and frequency of symptoms, and a physical examination should be performed. Diagnostic tests can help rule out conditions such as urinary tract infection and renal failure. Proper classification is vital since it will influence subsequent treatment.1,4,5
The treatment approach depends on the classification of UI, as well as on patient-specific parameters (e.g., age, comorbid conditions, other medications). Generally, nonpharmacologic management is considered first-line treatment for UI regardless of the type of UI. Pharmacologic therapy may be added if nonpharmacologic approaches alone are insufficient. Surgery is typically reserved for patients with an inadequate response to other therapies. Overall goals of therapy include a reduction in episodes of incontinence and the prevention of complications (e.g., pressure ulcers).1,4,5
In most patients, nonpharmacologic measures are initiated first, especially if symptoms are mild-to-moderate. A variety of nonpharmacologic measures exist. Traditional lifestyle modifications, such as smoking cessation, weight reduction, caffeine restriction, and fluid restriction, can be helpful in managing symptoms. Other behavior modifications include toilet-scheduling regimens and pelvic-floor muscle rehabilitation. Toileting can be scheduled at fixed intervals or at progressive intervals while the patient is awake. The selected regimen depends on the patient’s cognitive and functional status, as well as on his or her living environment. Fixed schedules tend to be more appropriate for patients with cognitive or functional impairments. Bladder training that uses progressive intervals is more appropriate for patients without impairments. Pelvic-floor muscle rehabilitation, such as Kegel exercises and vaginal weight training, requires intact cognition. If pelvic-floor muscle rehabilitation fails, external neuromodulation, which involves the stimulation of nerves with some type of electrical or magnetic device, may be considered. Acupuncture and anti-incontinence devices (e.g., bed alarm, urethral insert [for women], penile clamp, catheter) are other potential nonpharmacologic options.1,4,5
Appropriate pharmacologic treatment is determined by the type of UI, along with patient-specific parameters. Some agents have an approved indication for UI, and there are several medications that are used off-label. In some instances, combination therapy may be appropriate, depending on the type of incontinence and patient response.
SUI Treatment: Because of insufficient and/or low-quality evidence, pharmacologic treatment of SUI is not recommended on a routine basis, according to the American College of Physicians’ clinical practice guidelines for nonsurgical management of UI in women.4 First-line treatment of SUI continues to be pelvic-floor muscle training exercises. In some cases in which nonpharmacologic measures are insufficient, pharmacologic options may be considered.4
Pharmacologic options that have been examined for use in SUI include estrogens, alpha-adrenergic receptor agonists, and serotonin-norepinephrine reuptake inhibitors (SNRIs). Estrogens may be administered locally or systemically, and many dosage forms can be used in the treatment of SUI, including transdermal patches, vaginal creams, vaginal rings/suppositories, IM injection, and multiple oral formulations. Mixed evidence is available regarding the use of estrogens for SUI. Estrogen therapy should be reserved for cases of estrogen deficiency, and topical products should be used when possible. Some observational studies suggest an increased risk of UI with systemic estrogen use. Additionally, healthcare providers should carefully consider the adverse effects associated with systemic therapy, including breast pain, uterine bleeding, thromboembolism, and an increased risk of vascular events and certain cancers.1,2,4
Midodrine is the only alpha-adrenergic receptor agonist available in the U.S. Studies with other medications in this class (not currently available in the U.S.) may support use in mild-to-moderate SUI. Potential adverse effects of this class include hypertension, dry mouth, nausea, and insomnia. Patients with certain cardiovascular conditions, such as coronary artery disease and arrhythmias, should avoid using these medications.1,6 Combination treatment with estrogens and alpha-adrenergic receptor agonists may show increased efficacy compared with monotherapy with regard to symptom relief.1
SNRIs, including duloxetine and venlafaxine, have been used off-label for SUI, and duloxetine has received approval for SUI treatment in Europe. Studies have examined duloxetine 40 to 80 mg daily and venlafaxine 75 mg daily. Compared with placebo, SNRIs showed some improvements with regard to symptom manifestations, especially when used in combination with pelvic-floor muscle training. Common adverse effects of these medications include nausea, headache, constipation, dry mouth, and insomnia. Although these agents do not have an indication for UI, they may be a more appropriate option for patients with concomitant depression.1,4,7,8
UUI Treatment: First-line pharmacologic treatment for UUI, according to the American Urological Association, includes anticholinergic/antimuscarinic agents such as oxybutynin, tolterodine, trospium, solifenacin, darifenacin, and fesoterodine.9 An alternative agent, mirabegron (a beta-3 adrenergic agonist), was introduced in 2012.1,2 All agents are considered to be equally efficacious. Selection is patient-specific and depends on a variety of factors, such as cost, dosing, adverse effects, and potential drug/disease state interactions. Generally, extended-release formulations are preferred over immediate-release formulations because their side effects are less bothersome. Transdermal formulations may be considered, if available, since they also may be associated with fewer side effects.1,9
Adverse effects of anticholinergic/antimuscarinic agents include dry mouth, constipation, headache, dry eyes, blurred vision, tachycardia, and sedation. Transdermal applications may also cause redness and itching. The use of anticholinergic/antimuscarinic agents should generally be avoided in patients with narrow-angle glaucoma, impaired gastric emptying, or urinary retention. Additionally, caution should be exercised in elderly patients because of the potential risks of cognitive impairment and falls, especially when these agents are combined with other agents that have anticholinergic effects. Adverse effects of mirabegron include hypertension, urinary tract infections, headaches, and nasopharyngitis. Mirabegron should be avoided in patients with severe or uncontrolled hypertension and urinary retention. Mirabegron has been studied in combination with solifenacin and demonstrated improved efficacy with no additional safety concerns.10
Certain medications should be started at the initial recommended dosage and titrated accordingly.1,9,11-17 Specific dosing information is found in TABLE 1, which provides a comparison of available agents for treatment of UUI. Patients with hepatic or renal dysfunction may require dosage adjustment depending on the specific agent and any drug interactions, as outlined in TABLE 1.
If a patient experiences poor response in terms of efficacy, an alternative agent may be selected. However, in cases in which the patient experiences effective urinary symptom control along with minor anticholinergic side effects (e.g., dry mouth or constipation), adverse effects should be managed before the effective UI medication is discontinued. In some cases, reduction to the minimally effective dosage may be helpful in relieving minor adverse effects. Nonpharmacologic measures may also be used to help manage these effects; for example, sugar-free candies and gum or a saliva substitute can be helpful in reducing dry mouth. Increasing the patient’s water consumption, fiber intake, and physical activity may help relieve constipation. If necessary, the patient also could consider using a laxative. It is important to discuss potential side effects and subsequent management strategies with patients to avoid the discontinuation of an effective agent.1,9
Patients should be given additional product-specific counseling information: Extended-release formulations should not be crushed or chewed. Transdermal formulations should be applied to clean, dry, intact skin in the appropriate location, as per product labeling. The site of patch placement among applications should be rotated at least weekly. Gel formulations contain alcohol. The application of sunscreen should be avoided for 30 minutes before or after gel application, and showering should be avoided for 1 hour after use.1
Overflow, Functional, and Mixed UI Treatment: The majority of available pharmacologic options for incontinence target SUI and UUI. Pharmacologic treatment for overflow incontinence aims to manage the underlying condition, which is usually BPH. Agents such as tamsulosin may be appropriate in these cases, with or without other pharmacologic agents.18 Functional incontinence involves managing the underlying cognitive dysfunction or mobility impairment when possible. Nonpharmacologic measures (e.g., bedside commode) are the mainstay of treatment. Mixed incontinence may require a combination of pharmacologic treatments, depending on the etiology (e.g., stress and urge), if nonpharmacologic measures alone are inadequate. Certain medications for other concomitant disease states can aggravate UI symptoms. If possible, the offending agent should be discontinued and an alternative agent selected. If discontinuation is not appropriate, nonpharmacologic and/or pharmacologic treatment may be initiated to manage symptoms. Regardless of the type of UI diagnosed, nonpharmacologic measures remain the first-line treatment.1
UI is a condition that can affect anyone, especially older women. It can significantly impact an individual’s quality of life. There are many opportunities for pharmacists to improve the care of patients with UI. Pharmacists can play an important role in patient education on nonpharmacologic measures, which are recommended as first-line treatment for UI. If pharmacologic measures are warranted, the pharmacist should counsel the patient regarding the appropriate use of medications and potential side effects. Additionally, the pharmacist can make recommendations to help manage minor adverse effects in order to improve patient adherence to UI medications.
1. Rovner ES, Wyman J, Lam S. Urinary incontinence. In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York, NY: McGraw-Hill; 2014.
2. Agency for Healthcare Research and Quality. Nonsurgical treatments for urinary incontinence in adult women: diagnosis and comparative effectiveness. http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productid=1021. Accessed June 9, 2016.
3. Nitti VW. The prevalence of urinary incontinence. Rev Urol. 2012;3(suppl 1):S2-S6.
4. Qaseem A, Dallas P, Forciea MA, et al. Nonsurgical management of urinary incontinence in women: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2014;161:429-440.
5. Canales AE, Nixon-Lewis BD. Urinary incontinence. In: Linn WD, Wofford MR, O’Keefe M, Posey L, eds. Pharmacotherapy in Primary Care. New York, NY: McGraw-Hill; 2009.
6. Midodrine. Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc; 2016. https://online.lexi.com. Accessed May 17, 2016.
7. Venlafaxine. Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc; 2016. https://online.lexi.com. Accessed May 17, 2016.
8. Duloxetine. Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc; 2016. https://online.lexi.com. Accessed May 17, 2016.
9. Gormley EA, Lightner DJ, Burgio KL, et al. Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline. www.auanet.org/common/pdf/education/clinical-guidance/Overactive-Bladder.pdf. Accessed May 17, 2016.
10. Abrams P, Kelleher C, Staskin D, et al. Combination treatment with mirabegron and solifenacin in patients with overactive bladder: efficacy and safety results from a randomised, double-blind, dose-ranging, phase 2 study (Symphony). Eur Urol. 2015;67:577-588.
11. Mirabegron. Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc; 2016. https://online.lexi.com. Accessed May 17, 2016.
12. Tolterodine. Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc; 2016. https://online.lexi.com. Accessed May 17, 2016.
13. Trospium. Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc; 2016. https://online.lexi.com. Accessed May 17, 2016.
14. Solifenacin. Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc; 2016. https://online.lexi.com. Accessed May 17, 2016.
15. Darifenacin. Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc; 2016. https://online.lexi.com. Accessed May 17, 2016.
16. Oxybutynin. Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc; 2016. https://online.lexi.com. Accessed May 17, 2016.
17. Fesoterodine. Lexi-Drugs Online. Hudson, OH: Lexi-Comp, Inc; 2016. https://online.lexi.com. Accessed May 17, 2016.
18. DeMaagd GA, Davenport TC. Management of urinary incontinence. P T. 2012;37:345-361H.
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