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Journal of the American Academy of Physician Assistants:
doi: 10.1097/01.JAA.0000442703.33717.85
Review Article

Evaluation and management of patients with nocturia

Easterling, S. Adair PA-C; Master, Viraj MD; Carney, K. Jeff MD, PharmD

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Author Information

S. Adair Easterling practices at Grady Memorial Hospital in Atlanta, Ga. Viraj Master is an associate professor of urology and director of clinical research in the Department of Urology at Emory University School of Medicine in Atlanta, Ga., and assistant chief of service at Grady Memorial Hospital. K. Jeff Carney is an assistant professor of urology in the Department of Urology at Emory University School of Medicine and chief of urology at Grady Memorial Hospital. The authors have indicated no relationships to disclose relating to the content of this article.

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Abstract

ABSTRACT: Nocturia, or awakening one or more times to void at night, becomes clinically significant with two or more voids a night. In the past, nocturia has typically been viewed as a symptom of benign prostatic hyperplasia and/or overactive bladder syndrome. However, newer evidence supports that this is no longer just a symptom but a medical condition that warrants further workup and treatment given its effect on quality of life. The negative effects of nocturia include sleep fragmentation, decreased productivity at work, and increased risk of falls and fractures. A workup to find the underlying cause of nocturia will help guide treatment, which may include pharmacologic agents.

Nocturia is defined by the International Continence Society as the complaint of awakening one or more times to void at night. Each void is preceded and followed by sleep.1 However, retrospective and population-based survey research have found that the relationship between quality of life and nocturia becomes clinically significant with two or more voids per night.2,3 This article focuses on clinically relevant nocturia. Nocturia is one of the most bothersome lower urinary tract symptoms reported by men and women.3

Nocturia has traditionally been regarded as a symptom of benign prostatic hyperplasia (BPH) or overactive bladder syndrome, which are both associated with urinary frequency. However, nocturia is multifactorial and can also be caused by upper urinary tract dysfunction such as excessive urine production at night, also called nocturnal polyuria.4 Nearly 83% of patients with nocturia have a component of nocturnal polyuria as contributing factor.5 Patients may have nocturnal polyuria only, or in combination with BPH, overactive bladder, or obstructive sleep apnea (OSA). Evaluating the underlying cause of nocturia is an essential part of determining whether nocturia is a result of excessive urine production at night, small voided volumes due to bladder storage problems, or a combination of these factors.4

Common across populations, nocturia affects men and women.6 Among patients ages 18 to 49 years, more women than men have nocturia. About half of men and women ages 50 to 59 years have nocturia, and after age 60 years, more men than women are affected.6 The prevalence increases with age, although nocturia affects a significant number of younger patients: up to 1 in 5 or 6 younger patients (ages 20 to 40 years) consistently wake up to void at least twice each night. Up to 60% of people age 70 and older void twice per night.7 The loss of sleep is associated with daytime fatigue and subsequently decreased quality of life. These symptoms worsen as the number of nighttime voids increases.8

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THE EFFECT OF NOCTURIA

Negative effects of nocturia include sleep fragmentation, reduced productivity at work, mood disturbance, and poorer overall health. Older adults who wake up during the night to void are at increased risk of falls and fractures, with subsequent immobility and debility.9 The estimated annual medical cost of nocturia-associated falls is $1.5 billion.9

Nocturia clearly carries an economic burden. Patients who had more than two voids per night had significant lost productivity, estimated at 127 hours per person per year.9 The total economic value of productivity lost in 2008 was estimated at $61 billion, according to an analysis based on 2008 wages.9 The estimate is based on a study that showed 28 million people in the United States over age 30 years regularly experience nocturia (more than two voids per night).

Compared to patients without nocturia, adults ages 70 to 97 years with nocturia have a significantly increased mortality risk, even when controlling for diabetes, smoking status, coronary disease, renal disease, stroke tranquilizers, hypnotics, and diuretics.10 Kupelian and colleagues reported that adults over age 20 years had a significantly increased mortality risk with two or more voids per night. The magnitude of the nocturia and mortality association was greater in patients younger than 65 years and in those without baseline comorbidities, and may be related to sleep disruption and subsequent development of comorbid conditions.11 Lightner and colleagues reported that men under age 60 years with nocturia are at increased risk for coronary heart disease.12 Men over age 60 years with nocturia were at increased risk of mortality even after adjusting for age, BMI, urologic medications, and coronary heart disease.12

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EVALUATING PATIENTS WITH NOCTURIA

The cause of nocturia can be multifactorial, including behavioral and environmental factors and other pathologic causes. A thorough history and physical examination is necessary to help diagnose underlying causes of nocturia, such as diabetes mellitus, diabetes insipidus, overactive bladder, OSA, benign prostatic hyperplasia, urinary tract infection, or heart failure (Figure 1).13,14 The physical examination may include an abdominal, rectal, vaginal, neurological, or cardiovascular examination (Table 1).

Figure 1
Figure 1
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Table 1
Table 1
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Obtain a list of the patient's medications because some medications can increase urine production. Patients on lithium may develop 24-hour polyuria, and the concurrent use of lithium and serotonergic antidepressants increases this risk.15 Diuretics, selective serotonin reuptake inhibitors, calcium channel blockers, and tetracyclines also can increase urine output.16 Keep in mind that nocturia can be caused by mixed etiologic factors.

Further evaluations that should be considered, based on the patient's history and physical examination, include:

* retroperitoneal ultrasound to evaluate for pelvic or bladder masses and stones in the urinary tract. Increased urinary frequency can be a symptom of these serious underlying conditions.

* urinalysis to evaluate for signs and symptoms of infection, abnormal bleeding, electrolyte dysfunction, or renal dysfunction

* urine flow rate and postvoid residual volume to evaluate for significant voiding dysfunction that can lead to impaired bladder storage capacity. Patients may need to perform self-catheterization at bedtime to reduce nocturia.16

The next step is a frequency voiding chart, also known as a voiding diary, that the patient should keep for 3 days (Table 2). This is an invaluable tool in assessing a patient's urologic symptoms, including nocturia. The patient records episodes of incontinence, time of voids, volume voided, and frequency and volume of fluid intake. These data can help determine the potential factors underlying nocturia (Table 3).13 Common urologic causes are classified into broad categories, including:

Table 2
Table 2
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Table 3
Table 3
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TREATMENT OPTIONS

The first step in managing nocturia is to address underlying conditions. If these issues are not addressed first, treating nocturia is much more difficult. For example, a patient with OSA should be referred to a pulmonologist. Patients at increased risk for nocturia caused by OSA include patients who are morbidly obese, those who snore, and patients with acromegaly, asthma, hypertension, type 2 diabetes, or craniofacial abnormalities. These patients have a 30% to 40% risk of OSA.17 Patients with OSA have a greater number of nocturia episodes.

Moriyama and colleagues found that OSA may be the underlying cause in men under age 50 years whose only complaint is nocturia.18 In one study, patients with OSA who used continuous positive airway pressure had a statistically significant decrease in the number of reported nocturia events, with 73 of the 97 patients reporting improvement ranging from good to total elimination of nocturia.19

Other examples include tight glycemic control in patients with diabetes, treatment for diabetes insipidus, and referral for patients with primary polydipsia. Patients referred to urologists for frequent daytime and nighttime urination may have high A1C levels that have not been addressed.

Many clinicians mistakenly attribute nocturia in men to prostatic problems that obstruct the bladder. Patients with symptomatic BPH are typically treated with alpha-1 blockers and/or 5-alpha reductase inhibitors, which are only 25% to 39% effective, perhaps because nocturia is multifactorial.20 A study of men with nocturia found that 83% had nocturnal polyuria—20% had nocturnal polyuria alone and 63% had nocturnal polyuria in combination with another factor such as small bladder capacity, bladder outlet obstruction, or OSA.21 Yoong and colleagues found that 85% of men with nocturia that was resistant to alpha-blocker therapy had nocturnal polyuria. Because alpha-1 blockers and 5-alpha reductase inhibitors do not treat nocturnal polyuria, nocturia persists for many patients treated with these medications.22

Patients whose nocturia is related to medication should discuss alternate medications with their prescriber.

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NONPHARMACOLOGIC TREATMENTS

Behavioral therapy can be initiated, and is individualized based on the patient's history and physical examination. For patients with heart failure and a history of lower extremity edema, wearing compression stockings and elevating the legs in the afternoon decreases the retention of fluid that otherwise would return to circulation at night.22 Patients can elevate their legs for 30 to 60 minutes or until edema decreases; this may help patients whose nocturnal polyuria is caused by venous insufficiency.

Avoiding nighttime alcohol and caffeine may help reduce nocturia episodes.23 Patients whose nocturia is related to drinking large volumes of fluid before bedtime should be advised to avoid fluid intake 1 to 2 hours before bedtime, except for fluids needed to take medicine.23 Some patients have found that just decreasing their nighttime fluid intake improves nocturia.

A study that found urinary frequency, nocturia, urgency, incontinence, and incomplete emptying more common in patients with constipation suggests that the constipation process may directly contribute to lower urinary tract symptoms.24 Constipation reduces bladder capacity, which can make symptoms worse.25 Treating underlying constipation may help improve lower urinary tract symptoms including nocturia. In a study of 52 patients ages 65 to 89 years, Charach and colleagues demonstrated that medical relief of constipation significantly improved lower urinary tract symptoms in older adults, which, in turn, improved patients' mood, sexual activity, and quality of life.26 Treatment of constipation increased the number of weekly defecations from 1.5 (±0.9) to 4.7 (±1.2).26 Fewer patients reported urinary urgency (16 versus 34), frequency (25 versus 47), and burning sensation (6 versus 17). Urinary stream disturbances improved in 32 of the 52 patients. Residual urine volume decreased from 85 mL (±39.5 mL) to 30 mL (±22.6 mL).26 Two options for bowel regimens are shown in Table 4.

Table 4
Table 4
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PHARMACOTHERAPY

Desmopressin is used in Europe to treat nocturia in adults under age 65 years. The International Consultation on Incontinence recommends desmopressin as the pharmacologic therapy of choice for nocturia when nocturnal polyuria is present, given the drug's specific antidiuretic action.27 Desmopressin is not FDA-approved for nocturia in adults in the United States, but frequently is prescribed off-label.

Due to its prolonged duration of action, desmopressin can cause free-water excess and hyponatremia. Most patients with nocturia tolerate desmopressin treatment without clinically significant hyponatremia; however, the risk increases with increasing age and decreasing baseline serum sodium concentration.28

Desmopressin can be an effective treatment in patients with nocturnal polyuria. Van Kerrebroeck and colleagues concluded that desmopressin has a significant beneficial effect on nocturnal voiding, frequency, sleep, quality of life, and productivity.13 Patients with disorders of the vasopressin system are more sensitive to this therapy.29

Compared with vasopressin, desmopressin has a longer-lasting and more potent antidiuretic effect without vasopressor activity. Desmopressin increases water reabsorption in the distal and collecting tubules of the kidneys and concentrates the urine, decreasing urine production and postponing the need to void.30

In a double-blind, placebo-controlled trial of oral desmopressin in 127 patients, desmopressin resulted in a significant reduction in the mean number of nocturnal voids (39% reduction with desmopressin versus 15% with placebo; absolute difference -0.84, P < 0.0001) and duration of the first sleep period (prolonged by 108 minutes with desmopressin versus 41 minutes with placebo; P < 0.0001). Quality of sleep was also improved with desmopressin versus placebo.28

More recent studies have also shown the benefit of desmopressin in older adults. An analysis of the short-term effect of desmopressin therapy found the therapy well-tolerated and effective after 2 weeks in two groups of patients with nocturnal polyuria: 20 adults under age 64 years and 14 adults age 65 years and older. Only two patients (from the group of 14 older adults) developed hyponatremia, which resolved after discontinuation of therapy.31

A randomized, single-blind, placebo-controlled trial found that low-dose oral desmopressin (0.1 mg) was effective and well tolerated for men with nocturnal polyuria. The study followed 136 men over age 65 years with BPH, nocturia, nocturnal polyuria, and International Prostate Symptom scores of 14 or higher. A clinical response (decrease of two or more voids per night) was achieved in 35 patients (61.4%) receiving desmopressin and in 8 placebo-treated patients (13.8%) (P < 0.001).32

Lee and colleagues investigated the efficacy and safety of desmopressin in 103 patients age 18 years and older with mixed nocturia. The dose-titration study was followed by a treatment period of 4 weeks with the individual optimum oral dose. Ninety-four patients completed the dose-titration study, and 90 patients completed the treatment period. The optimum doses were: 0.1 mg in 44% of patients (n = 41), 0.2 mg in 33% (n = 31), and 0.4 mg in 23% (n = 22). In 72% of patients (n = 68) (95% CI: 0.63–0.81) (P < 0.001), the mean number of nocturnal voids decreased significantly, from 3.20 to 1.34 after the 4-week treatment with desmopressin. The number of patients who reported a good night's sleep increased significantly, from 19.8% to 78.7% after 4 weeks of desmopressin treatment (P = 0.001).33

Patients' sodium levels should be monitored within 3 days of starting desmopressin therapy; the dosage can be titrated higher if no hyponatremia is seen. Monitor older adults' sodium levels closely. Patients with a baseline serum sodium concentration below normal range should not be treated with desmopressin.34 Avoid using desmopressin in patients with cirrhosis, renal failure, or heart failure.35

To maximize absorption, patients should take desmopressin on an empty stomach.28 A newer melt formulation (an orally disintegrating tablet) has a higher bioavailability than the oral tablets, but is not available in the United States.36 Post-hoc analysis of a randomized double-blind placebo-controlled trial of this formulation suggested a lower minimum effective dose for women.

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ANTIMUSCARINIC (ANTICHOLINERGIC) AGENTS

Nocturia has shown a poor clinical response to traditional therapies for overactive bladder such as antimuscarinics (including oxybutynin, tolterodine, solifenacin, and darifenacin). The actual clinical effect of these drugs is negligible—often a reduction of a half a void, or less, per night.37 Antimuscarinics decrease voluntary and involuntary bladder contractions by blocking muscarinic receptors on the detrusor muscle. This reduces the bladder's ability to contract and therefore reduces the urge to urinate, increasing bladder capacity. Antimuscarinic drugs are most effective in patients with lower urinary tract symptoms and a diminished ability to store urine.38 Nocturia is commonly attributed to overactive bladder and bladder storage problems. However, 62% of patients with overactive bladder (and 86% of patients ages 65 to 74 years with overactive bladder) also have nocturnal polyuria.13 Antimuscarinic drugs are most effective in patients with a large number of small-volume voids due to urgency, not nocturnal polyuria.38–40 Because of the bothersome adverse reactions to antimuscarinic drugs, including dry mouth, constipation, dry skin and eyes, and upset stomach, patient adherence rates for these drugs are low. As mentioned earlier, constipation reduces bladder capacity, which can worsen nocturia symptoms.25

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BETA-3 ADRENERGIC AGONIST

Mirabegron was approved by the FDA in 2012 for treatment of overactive bladder. Through agonist action at beta-3 receptors, mirabegron causes relaxation of detrusor smooth muscle, leading to increased bladder-storage capacity, increased mean voided volume per micturition, decreased frequency of nonvoiding contractions, reduced micturition frequency, reduced episodes of urgency, and reduced nocturia in patients with overactive bladder. The drug is well-tolerated overall, with a lower incidence of the well-known adverse reactions to antimuscarinics, such as dry mouth and constipation. The long-term safety data, including cardiac and vascular events caused by mirabegron, are under investigation.41

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DIURETICS

Diuretics such as hydrochlorothiazide and furosemide can be used as second-line treatments for patients who cannot tolerate desmopressin. These drugs may be helpful in patients with lower limb venous insufficiency or heart failure. Patients can take hydrochlorothiazide 8 hours before bedtime to prevent water accumulation before the early stage sleeping hours.4 In men with lower urinary tract symptoms whose most prominent symptom is nocturia, 40 mg of furosemide daily, taken 6 hours before bedtime, resulted in a significant reduction in nighttime frequency and percentage of volume voided.16

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CYCLOOXYGENASE-2 INHIBITOR

A recent study evaluated the effectiveness of the cyclooxygenase-2 inhibitor celecoxib for refractory nocturia. In the study, nocturia either improved or disappeared in 82.5% of patients after treatment with celecoxib, compared with 22.5% in the placebo group. The treatment was generally well-tolerated, none of the patients discontinued treatment, and only 10% of patients in the celecoxib group experienced mild gastric discomfort. No serious adverse reactions were reported.42

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CONCLUSION

Nocturia is becoming recognized as an important clinical entity of its own that generally is not well treated. Nocturia can impair patient quality of life and overall health. Providers need to ask patients about nighttime urination, as many patients think it is just something that is part of aging and others are too embarrassed to discuss it. A thorough history and physical examination should be done to evaluate the underlying cause. A frequency voiding chart is an essential tool for evaluating nocturia. Recent research shows that nocturia is not just a symptom of overactive bladder and BPH, but is caused by nocturnal polyuria in most cases. Treatments that are traditionally used for overactive bladder and BPH may not significantly improve a patient's nocturia. Desmopressin may decrease voids per night and improve quality of life. Nocturia can be challenging to treat because the cause may be multifactorial and require combination therapy. Studies that evaluate combination therapies for nocturia will help guide future treatment.

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REFERENCES

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37. Smith AL, Wein AJ. Outcomes of pharmacological management of nocturia with non-antidiuretic agents: does statistically significant equal clinically significant. BJU Int. 2011;107(10):1550–1554.

38. Yamaguchi O, Marui E, Kakizaki H, et al. Randomized, double-blind, placebo- and propiverine-controlled trial of the once-daily antimuscarinic agent solifenacin in Japanese patients with overactive bladder. BJU Int. 2007;100(3):579–587.

39. Brubaker L, FitzGerald MP. Nocturnal polyuria and nocturia relief in patients treated with solifenacin for overactive bladder symptoms. Int Urogynecol Pelvic Floor Dysfunct. 2007;18(7):737–741.

40. Nitti VW, Dmochowski R, Appell RA, et al. Efficacy and tolerability of tolterodine extended-release in continent patients with overactive bladder and nocturia. BJU Int. 2006;97(6):1262–1266.

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42. Falahatkar S, Mokhtari G, Pourreza F, et al. Celecoxib for treatment of nocturia caused by benign prostatic hyperplasia: a prospective, randomized, double-blind, placebo-controlled study. Urology. 2008;72(4):813–816.

Keywords:

nocturia; obstructive sleep apnea; nocturnal polyuria; benign prostatic hypertrophy; desmopressin; antimuscarinic agents

© 2014 American Academy of Physician Assistants.

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