Nocturia in adults: Clinical presentation, evaluation, and management

INTRODUCTION — 

This topic will discuss the clinical presentation, evaluation, and treatment of nocturia in adults. Detailed discussions of some conditions that cause or are associated with nocturia are presented separately. (See "Evaluation of patients with polyuria" and "Clinical manifestations and diagnostic evaluation of benign prostatic hyperplasia" and "Female urinary incontinence: Evaluation".)

In this topic, when discussing study results, we will use the terms "men" and "women" as they are used in the studies presented. Depending on the underlying etiology, nocturia may be experienced differently by people assigned male and female at birth. We encourage the reader to consider the specific counseling and treatment needs of transgender and gender-expansive patients as they relate to the information presented in this topic.

DEFINITION — 

Nocturia is a common symptom related to a variety of clinical conditions. It is defined as waking to pass urine during the main sleep period [1]. Nocturia is likely clinically meaningful if a patient voids two or more times nightly [2]. The diagnosis is based on patient history.

New-onset adult nocturnal urinary incontinence or bed-wetting (enuresis, any unintended voiding during nighttime sleep) is distinct from nocturia. Nocturnal urinary incontinence requires a different approach focusing on sleep arousal disorders, sedating medications, or bladder outlet dysfunction [3,4]. In adults with no daytime urinary symptoms or past history of pediatric bed-wetting enuresis [5], consideration should be given to causes of nocturnal syncope, including seizures or arrhythmia [6,7]. Urinary incontinence is discussed separately. (See "Female urinary incontinence: Evaluation" and "Urinary incontinence in males".)

EPIDEMIOLOGY AND RISK FACTORS — 

At the population level, nocturia is one of the most bothersome of the lower urinary tract symptoms [8]. The prevalence of nocturia increases with increasing age [9]. Among 18- to 49-year-olds, more women than men have nocturia; the sex ratio reverses after 60 years of age, with greater prevalence in men than women [10]. Approximately 50 percent of adults between the ages of 50 to 79 have nocturia. Symptoms are occasional among those aged 50 to 59 years and often at least twice nightly among men between 70 and 79 [10].

Most studies indicate that the prevalence of nocturia is higher among Black and Hispanic adults and that these differences are likely due to socioeconomic factors [11-15].

Most women with nocturia also have other urinary tract symptoms (eg, overactive bladder syndrome or polyuria) [9,14,16]. While pregnant women nearly always develop urinary frequency and nocturia [17,18], both symptoms reduce significantly following delivery [18,19]. (See "Maternal adaptations to pregnancy: Kidney and urinary tract physiology".)

Most epidemiologic studies of nocturia are cross-sectional, which makes separating causes, effects, and markers for risk of nocturia difficult. Potentially modifiable conditions that likely cause nocturia include obesity, uncontrolled hypertension, poorly controlled diabetes, restless leg syndrome and periodic limb movements, obstructive sleep apnea, gastroesophageal reflux [20], benign prostatic hyperplasia, and congestive heart failure [21-25]. Longitudinal studies have shown that the temporal relationship between depression and nocturia appears to be bidirectional, with prevalent nocturia associated with a higher risk of incident depression and vice versa [26,27].

While most individuals with nocturia have no bother or only mild distress from the symptom [8], some patients may have moderate or high bother, particularly if there are two or more episodes per night [2,28]. Older men with nocturia have associated poor quality-of-life ratings [29,30]. Patients report nocturia as a leading cause of sleep disturbance, affecting sleep onset and maintenance and sleep quality [31,32]. Difficulty returning to sleep and morning fatigue contribute to the negative impact of nocturia [33].

Nocturia is associated with increased rates of depression [21], work absenteeism [34], and lower self-rated physical and mental health [22]. In older patients, it is associated with higher rates of accidental falls [35-37] and subsequent fractures [38,39].

PATHOPHYSIOLOGY — 

Nocturia results from one of three mechanisms: low-volume bladder voiding, increased nighttime urine production, and sleep-related disorders [40,41]. Associated conditions are discussed below and in the table (table 1).

Low-volume bladder voids — Low-volume voids may be due to either reduced bladder capacity or impaired bladder function. The two most common causes of low-volume bladder voids are an overactive bladder and bladder outlet obstruction, often related to benign prostatic hyperplasia (table 1). Reduced bladder capacity is also common in older patients, likely due to age-related changes in the bladder or detrusor hyperactivity [42,43].

Increased nighttime urine production — An increase in urinary volume at night may be due to either nocturnal polyuria or global polyuria.

Nocturnal polyuria — With nocturnal polyuria, a higher percentage of the total daily urine output is excreted at night during the individual's main sleep period (table 1) [44]. It is defined in an age-dependent fashion as nocturnal output greater than 20 percent of the daily total in young adults, between 20 to 33 percent in middle age, and greater than 33 percent of the daily total in older adults [45]. Mechanisms include:

●Decreased arginine vasopressin (AVP) – AVP, a peptide hormone secreted by the neurohypophyseal system, is released when plasma osmolality is increased or blood pressure has decreased (as seen with orthostasis, vasodilation, or significant blood loss). AVP targets vasopressin 2 receptors in the renal distal tubules to mobilize aquaporins that facilitate increased urine concentration.

AVP exhibits a normal diurnal periodicity with higher AVP plasma levels in the evening leading to decreased nighttime urine output [46]. Nocturnal polyuria results from disruptions to the diurnal secretion pattern, including changes in sleep or acute sleep deprivation [47]. The kidneys also exhibit a decreased response to AVP with age [48,49].

●General volume overload – Heart failure or other edematous states (nephrotic syndrome, venous insufficiency) cause interstitial edema. Assumption of the supine position permits fluid mobilization into the vascular space and an associated solute diuresis. This association is sufficiently strong that nocturia independently predicts left ventricular hypertrophy and left atrial enlargement among patients with cardiac symptoms [50].

Global polyuria — Global polyuria is defined as a 24-hour urine volume that exceeds 3 liters per day (or 40 mL per kg) and is mainly caused by a water diuresis. Causes of polyuria seen in the outpatient setting include primary polydipsia, uncontrolled diabetes mellitus, AVP disorders, and intake of diuretic substances (table 1). (See "Evaluation of patients with polyuria".)

Other types — Solute-induced polyuria is rare and mainly seen in the inpatient setting following a high-solute load (eg, enteral or parental feedings) or following relief of urinary obstruction [51].

Sleep-related disorders — Nocturia is present in nearly a third of all patients with obstructive sleep apnea (OSA) [52-57]. OSA may cause nocturnal polyuria by release of atrial natriuretic peptide (ANP) due to negative intrathoracic pressure and stretching of the myocardium [58]. ANP causes vasodilation and inhibits aldosterone, resulting in increased sodium and water excretion. Continuous positive airway pressure can result in significant reductions in ANP levels, nighttime urine volume, and nocturia episodes in patients with OSA [59-61].

Patients with other primary sleep problems (eg, restless leg syndrome, periodic limb movements at night) may awaken due to sleep disturbance but recall this as an awakening to void [62].

CLINICAL PRESENTATION — 

Nocturia typically comes to clinical attention when it is causes some amount of distress or bother to the patient. Patients may initiate a discussion of their sleep being interrupted by nighttime voiding, or the clinician might learn of nocturia during a review of symptoms. Symptoms are usually insidious and gradual in onset and vary from night to night. Rarely, nocturia can indicate worsening of an underlying disease, such as chronic kidney disease [63], lithium toxicity [64], diabetes mellitus, obstructive sleep apnea, or heart failure [50]. In such patients, the onset of nocturia is typically more acute.

EVALUATION

History and physical examination

●History – Key historical elements include the following (table 2):

•Nocturia symptoms – Examples of informative questions include:

-How often do you get up at night to void?

-How much does waking at night to void bother you?

-When you get up at night to void, do you feel dizzy, or do you have concerns about falling in getting to the bathroom?

While an estimation of nightly episodes is important, an estimation of the degree of distress the nocturia causes is more valuable in determining a treatment plan and improving patient-important outcomes [65].

•Fluid intake

-Volume – Very large fluid intake (>40 mL/kg per day) may be responsible for nocturia. Follow-up questions about the reason for the large fluid intake (psychogenic, history of kidney stones, vigorous outdoor exercise, general health belief about fluid intake, attempt at weight loss, arginine vasopressin disorders) are important in developing a meaningful treatment plan.

Some patients may drink large volumes immediately prior to bedtime. Although clinicians should recommend reduced nighttime fluid intake, patients will often have initiated this on their own prior to seeking help.

-Fluid type – Caffeine and alcohol have a diuretic effect.

•Sodium intake – Inquire about sodium intake and review a dietary history. Counsel on reducing intake of dietary items with high sodium intake [66,67].

•Medications – Certain prescription and over-the-counter medications (eg, diuretics, xanthines, calcium channel blockers, beta blockers, cholinesterase inhibitors) may be related to nocturia onset or worsening.

•Comorbid conditions – Relevant, addressable conditions include heart failure, diabetes mellitus, peripheral edema, depression, obstructive sleep apnea (OSA), and nighttime pain [23,68,69].

•Sleep dysfunction – Nocturia is closely associated with OSA [70]. Insomnia (difficulty returning to sleep) and daytime sleepiness contribute to increased bother from nocturia [33].

•Urinary tract symptoms – These include obstructive symptoms (hesitancy, weak stream, incomplete emptying, or intermittency), irritative symptoms (urinary frequency, urgency), and urinary incontinence.

●Physical examination – We focus on the following elements of the physical examination (table 2):

•Measure orthostatic vital signs in all patients due to the risk of nocturnal falls and in men with benign prostatic hyperplasia due to the consideration of prescribing alpha-1 adrenergic antagonists.

•Evaluate for volume overload suggestive of congestive heart failure or nephrotic syndrome.

•Palpate the lower abdomen to evaluate for bladder distention.

•Perform a rectal examination to detect fecal impaction, evaluate resting and volitional rectal tone (which may be important for teaching pelvic floor muscle exercise-based strategies), and estimate gross prostate size in men.

•Inspect for peripheral edema [71].

Voiding diary — We use a voiding diary for initial diagnosis as well as for patients who do not respond to initial management [72]. A sample log is provided (form 1); key components include a 24-hour recording of void time and void amount using a collection device, timing of going to bed and awakenings, and complete fluid intake. Results help determine whether nocturia is due to low-volume voiding, increased nocturnal polyuria, or both [73]. For example, documentation of low-volume voids over 24 hours suggests reduced bladder capacity due to overactive bladder or bladder outlet obstruction. By contrast, a normal functional bladder capacity during the day (eg, normal-volume voids) but low-volume voids at night may suggest a primary sleep disorder. Results can also highlight the presence of high-volume urine output, either just at night (nocturnal polyuria) or over the entire day.

Information from the voiding diary also assists with:

●Measuring the total number of nocturia episodes, eg, the number of voids that occur between going to bed and rising for the morning, not including the next day's first morning void [74]

●Measuring the total nighttime urine volume, eg, the sum of every nighttime voided volume plus the volume of the first morning void

●Diagnosing nocturnal polyuria if the nighttime urine volume, including the volume of the first morning void, is greater than 35 percent of the total 24-hour urine volume [44]

The patient's complete fluid intake assists with the evaluation of polyuria, especially if the 24-hour urine output is higher than expected [74]. Fluid intake recordings also assist with schedule planning to minimize nocturia. (See 'Implement nonpharmacologic strategies' below.)

Clinical testing — Postvoid residual (PVR) testing by catheterization or bladder ultrasound can be helpful in diagnosing bladder outlet obstruction or urinary retention (table 2). We perform PVR testing in patients with signs or symptoms of urinary retention, including abdominal fullness, suprapubic tenderness, or a strong urge to void during suprapubic palpation or percussion. Urinary retention may also be suspected in patients with neurologic conditions affecting the bladder, such as diabetic neuropathy, older men with prominent symptoms of intermittent or low flow with voiding, and those with a history of genitourinary surgery. When available, ultrasound PVR testing is preferred to catheterization because of the reduced chance of infection and greater patient comfort.

While the precise cutoff values are often debated [75], in general, a PVR of less than 50 mL is considered normal emptying. An elevated PVR of 200 mL or greater warrants additional evaluation and treatment, as below. (See 'Management' below.)

Urodynamic studies, including measurement of urinary peak flow rate, are usually not needed to treat nocturia. However, they can be useful in determining whether a large PVR is due to bladder outlet obstruction or a poorly contractile bladder (such as in diabetic neuropathy). Traditional urodynamics usually require catheterization, whereas newer UroCuff devices allow the noninvasive measurement of urine flow rate and bladder pressure in male patients.

Laboratory tests — We measure kidney function, electrolytes, and serum glucose and obtain a urinalysis in all patients, with urine culture if an infection is suspected (table 2).

Urine cytology or cystoscopy are indicated only if hematuria or pelvic pain is present. (See "Evaluation of hematuria in adults" and "Chronic pelvic pain in adult females: Evaluation" and "Chronic prostatitis and chronic pelvic pain syndrome".)

Patients with undiagnosed prostate cancer are usually asymptomatic. Nonetheless, prostate-specific antigen testing is reasonable in the evaluation of men with nocturia and other lower urinary symptoms. (See "Clinical manifestations and diagnostic evaluation of benign prostatic hyperplasia".)

MANAGEMENT

Establish treatment goals — The goals of nocturia treatment are to decrease the bother of symptoms and to reduce the number of nocturia episodes as complete resolution of nocturia is usually unrealistic [76]. Patients who are not bothered by nocturia do not need treatment.

Because nocturia may be related to several conditions, numerous treatments are potentially helpful, and multicomponent interventions are recommended [77-79]. Most individual treatments show only a small reduction in episodes of nocturia compared with placebo, ranging from 0 to 0.8 fewer episodes per night.

Address underlying medical conditions — Medical conditions that may cause or contribute to nocturia should be evaluated and optimized as part of initial management (algorithm 1). In our experience, addressing these conditions results in meaningful improvement in nocturia and reduced bother. These include:

●Polydipsia – Psychogenic (>10 L per day) or other.

●Heart failure or peripheral edema.

●Poorly controlled diabetes mellitus.

●Gastroesophageal reflux disease or nighttime cough.

●Sleep disorders such as obstructive sleep apnea, periodic limb movements/restless leg syndrome, and insomnia [80,81].

●Obesity – Discuss weight optimization as part of healthy lifestyle advice [82]; in severe obesity treated with surgery, nocturia may diminish [83].

●Urologic conditions, including overactive bladder (OAB) and benign prostatic hyperplasia (BPH) – Addressing related symptoms, including urinary urgency or weak urinary stream, can improve nocturia.

Implement nonpharmacologic strategies

Lifestyle modifications — We discuss these strategies with all patients with bothersome nocturia (algorithm 1):

●Decrease nocturnal urine output

•Reduce overall fluid intake, particularly if it is an excessive volume, and reallocation of evening intake by moving this fluid to earlier in the afternoon [84]. Care should be taken not to restrict fluid intake in older patients who have impaired thirst sensation and borderline or inadequate fluid intake to meet daily needs.

•Reduce salt intake [85,86], particularly for those with heart failure [67] and chronic kidney disease [63].

•Reduce evening consumption of diuretic fluids, including caffeine and alcohol.

•Avoid evening administration of diuretics – Clinicians may direct patients on twice-daily diuretics to move the nighttime dose to the midafternoon.

•Use compression stockings and frequent elevation of legs in patients with edema.

•Avoid nocturnal hyperglycemia in patients with diabetes.

•Double-voiding prior to bedtime, (eg, urinating while sitting comfortably on the toilet [all genders], leaning slightly forward, and then waiting for 20 to 30 seconds to urinate again).

●Decrease the impact of nocturia

•Address sleep hygiene – Good sleep hygiene (table 3) can reduce the impact of episodes of nighttime voiding, including improving the ability to fall asleep after nighttime voids. Elements include sleeping in a quiet room with low lighting and appropriate temperature, avoiding nighttime use of electronic devices, and avoiding daytime naps.

•Improve safety on trips to the bathroom

-Reduce concerns about falling – Nighttime ambulation may be particularly worrisome or hazardous in older adult patients or others at high risk of falling, so attention to environmental safety (eg, clear pathway, motion-activated nightlights) is also important [87].

-Limit trips for those at highest fall risk – The use of a handheld urinal or a bedside commode may be helpful for patients bothered by trips to and from the bathroom at night.

Pelvic floor muscle exercises — Pelvic floor muscle exercises (PFME or Kegel exercises) can reduce nocturia and nocturia-related bother in patients of all genders [88-93]. PFME strengthens the muscular components of the urethral closure mechanism through isometric repetitions at maximal exertion. PFME requires a referral to a physical therapist who specializes in this method; access and availability may vary by practice location. The basic recommended regimen is three sets of 8 to 12 slow-velocity contractions sustained for six to eight seconds each, performed three or four times a week, and continued for at least 15 to 20 weeks [94]. When available, computer-assisted biofeedback may be added to help the patient identify the target muscles [93,95].

In clinical trials, benefits from PFME can be seen as early as two to four weeks, with full benefit at 10 to 12 weeks [95]. Reduction in nocturia from these interventions ranged from 0.5 to 1.4 episodes per night [91,95]. In one randomized trial, PFME also improved sleep quality, reduced bother from nocturia, and improved nocturia symptom-specific quality-of-life metrics [95]. (See "Patient education: Pelvic floor muscle exercises (Beyond the Basics)".)

Other behavioral treatments

●Urge-suppression strategies – Urge-suppression and bladder-training strategies (table 4) assist with retraining patient behaviors to manage urges to urinate. These entail a combination of remaining still and not running to the bathroom, visualization or other mental distraction techniques, and pelvic floor contractions during urges (eg, three to five rapid contractions of the pelvic floor muscles). These strategies send a message to the bladder to relax and hold urine.

●Behavioral treatment for insomnia – Nocturia and concomitant insomnia are common. Behavioral treatment for insomnia, including sleep hygiene measures (table 3), reduces the number of nocturia episodes and bother from nocturia [81,96,97].

Pharmacologic therapy for persistent symptoms

Patient selection — We offer pharmacologic therapy to patients who continue to have symptoms after initial lifestyle and behavioral measures. Because pharmacotherapy is associated with only a modest reduction in the number of nighttime voids and has the potential for serious side effects, many patients may choose no pharmacologic therapy after an informed discussion using shared decision-making.

Initial pharmacotherapy is based on sex and the presence of symptomatic BPH in patients with a prostate (algorithm 2). For most patients, single-agent pharmacologic treatments for nocturia are less effective than multicomponent interventions. We also continue all effective nonpharmacologic strategies alongside pharmacotherapy (algorithm 2). (See 'Implement nonpharmacologic strategies' above.)

Males with BPH-related symptoms — Benign prostatic hyperplasia (BPH) may be asymptomatic; however, when it leads to enlargement of the prostate and obstruction at the bladder neck, it can cause nocturia and other lower urinary tract symptoms, including urinary frequency, urgency, incontinence, straining to void, and urinary intermittency or slow urinary stream. In patients with nocturia and other BPH-related symptoms, we initiate pharmacotherapy for BPH as first-line treatment. Pharmacotherapy for nocturia with BPH is discussed below and in further detail in a separate topic review. (See "Medical treatment of benign prostatic hyperplasia".)

Pharmacotherapy of nocturia for male patients without BPH-related symptoms is discussed below. (See 'Bladder relaxants for all other patients' below.)

Initial therapy with alpha-1 adrenergic antagonists — We use alpha-1 adrenergic antagonists as initial therapy for nocturia in patients with BPH symptoms (table 5). These agents target the dynamic component of bladder outlet obstruction and can reduce both storage symptoms (nocturia, urgency, and frequency) and voiding symptoms (hesitancy, weak or intermittent stream) [93]. Symptom reduction, if it occurs, can be expected within a month.

Reductions in nocturia with alpha-1 adrenergic antagonists are modest (on average, net 0.2 to 0.4 fewer episodes versus placebo) and less than the response for other BPH-related symptoms [98]. In one secondary analysis of a randomized trial, nocturia reduction of 50 percent or greater occurred in 39 percent of patients treated with terazosin, compared with 22 percent of patients treated with placebo. This relatively small effect in trials with populations selected to have the best chance for benefit and carefully monitored for compliance suggests that nocturia response in the general population is likely even more minimal [99].

Contraindications to alpha-1 adrenergic antagonists include dizziness, low blood pressure, or documented orthostasis. We avoid nonselective alpha blockers such as terazosin or doxazosin (table 5) as they are associated with higher rates of dizziness and orthostatic hypotension, which may be of particular concern in older patients. Side effects can be minimized with gradual dose titration and avoidance of higher doses. Selective alpha-1 antagonists such as tamsulosin and alfuzosin do not require dose titration, and initial starting doses are usually well tolerated, with an incidence of dizziness and orthostasis of 0.3 to 5 percent [100,101]. (See "Medical treatment of benign prostatic hyperplasia".)

We dose alpha-1 adrenergic antagonists at bedtime. Nocturia and coincident erectile dysfunction are common; we advise patients taking both an alpha blocker for nocturia and a phosphodiesterase 5 (PDE-5) inhibitor for erectile dysfunction (eg, sildenafil, tadalafil) to dose their alpha blocker at bedtime but skip it on evenings when they take a PDE-5 inhibitor for sexual activity. This practice helps to avoid an additive hypotensive effect if both medications are taken at the same time.

Additional pharmacotherapy — We offer additional pharmacotherapy for patients with BPH who do not respond adequately to alpha-1 blockers. Nocturia in such patients may be a symptom of either BPH, OAB, or both. We review the patient's additional symptoms to identify the more likely etiology, recognizing that symptoms often overlap. With OAB, storage symptoms predominate (eg, frequency, urgency, and incontinence), whereas with BPH, voiding symptoms predominate (eg, urgency, straining, weak urine stream, and dribbling). A referral to urology is appropriate for additional evaluation and diagnostic testing if the underlying etiology remains unclear.

●Bladder relaxants for OAB symptoms – For patients with persistent nocturia despite treatment with alpha-1 adrenergic antagonists, we add bladder relaxants (eg, beta-3 agonists [preferred] or antimuscarinic agents) as a next step. These are discussed in further detail below. (See 'Bladder relaxants for all other patients' below.)

●5-ARIs for BPH symptoms with enlarged prostate – We offer a 5-alpha reductase inhibitor (5-ARI) for patients with persistent nocturia and other BPH symptoms who have evidence of an enlarged prostate (table 6). However, while these agents are effective in reducing prostate size and improving overall lower urinary tract symptoms, studies suggest their impact on nocturia is much more limited [99]. Therefore, although 5-ARIs are routinely used for symptomatic BPH with an enlarged prostate, we do not prescribe them specifically for the treatment of nocturia in the absence of other BPH symptoms (eg, daytime frequency, straining, urinary hesitancy, etc).

The Medical Therapy of Prostatic Symptoms (MTOPS) trial demonstrated the benefit of finasteride on a combined endpoint of reduction of BPH symptoms, need for intervention for urinary retention, and reduction of urinary symptoms. Combination therapy (finasteride plus doxazosin) was superior to therapy with either single agent. However, the net benefit of combination therapy compared with placebo, with respect to nocturia, was small, with a difference of less than 0.2 fewer nightly episodes at one- and four-year follow-up [102].

The use of 5-ARIs in the treatment of BPH is discussed in further detail separately. (See "Medical treatment of benign prostatic hyperplasia".)

Limited role of surgery — Prostatectomy for BPH relieves severe lower urinary tract symptoms; however, nocturia is the symptom most likely to persist following surgery [103]. Some have interpreted this finding to indicate that BPH is often mistakenly implicated as the cause of nocturia [104]. While surgical options are not usually recommended as first-line treatment for bothersome nocturia, properly selected patients with bladder outlet obstruction can have positive results [105,106]. This is discussed in further detail separately. (See "Surgical treatment of benign prostatic hyperplasia (BPH)".)

Postmenopausal females — For postmenopausal individuals, we offer topical vaginal estrogen therapy (table 7). In a systematic review of randomized and observational studies evaluating topical estrogen for the treatment of nocturia in postmenopausal women, three of the five studies (60 percent) reported a reduction in frequency of nocturia compared with placebo [107]. There did not appear to be a difference in efficacy or safety among the different preparations (vaginal tablets, ovules, creams, gels, or rings). (See "Female urinary incontinence: Treatment", section on 'Topical vaginal estrogen'.)

Vaginal estrogen therapy may be combined with other therapies if nocturia symptoms persist. (See 'Bladder relaxants for all other patients' below.)

Bladder relaxants for all other patients — We offer bladder relaxant therapies as a first-line pharmacologic treatment for nocturia for premenopausal female patients and male patients without BPH. We also use it as add-on therapy for male patients with BPH with persistent symptoms after alpha blocker therapy and for postmenopausal individuals with persistent symptoms after vaginal estrogen therapy (algorithm 2). (See 'Initial therapy with alpha-1 adrenergic antagonists' above and 'Postmenopausal females' above.)

Bladder relaxant medications reduce nocturia by increasing bladder capacity and decreasing urge-associated voids. Published data suggest the benefit of bladder relaxants over placebo in nocturia reduction is small [91,108,109], perhaps owing to the inability of these medications to increase nighttime voided volumes [110].

There are two major classes of bladder relaxants: beta-3 agonists and antimuscarinics (table 8). The choice of agent is guided by availability and side effect profiles:

●Beta-3 agonists are preferred – Mirabegron and vibegron are our preferred bladder relaxant agents (table 8). These agents work by promoting selective beta receptor stimulation of the detrusor muscle to enhance smooth muscle relaxation. Mirabegron and vibegron have been shown to reduce nocturia by a modest degree, and are well tolerated, without the anticholinergic side effects of antimuscarinic medications [111,112].

Hypertension is the most common side effect of mirabegron; additional side effects are mostly secondary to elevated blood pressures. Therefore, we avoid the use of beta-3 agonists in patients with severe or uncontrolled hypertension or baseline tachycardia [113]. These agents are discussed in further detail separately. (See "Urgency urinary incontinence/overactive bladder (OAB) in females: Treatment", section on 'Medication prescribing details' and "Lower urinary tract symptoms in males", section on 'Beta-3 adrenergic agonists'.)

●Antimuscarinic agents – Although beta-3 agonists are our preferred bladder relaxant agents, as above, antimuscarinic agents may be more widely available or affordable and are an acceptable alternative (table 8). These agents have direct antispasmodic effects and inhibit the action of acetylcholine on smooth muscle. Oxybutynin is the most used; other agents include tolterodine and solifenacin. Oxybutynin is available in immediate-release, extended-release (ER), and transdermal formulations. We use the ER formulation as it has fewer side effects (particularly less dry mouth) and a better safety profile.

The usual dose is oxybutynin 10 mg ER, though the therapeutic range varies; some patients achieve adequate relief at 5 mg ER, while, rarely, patients may require up to 20 or 30 mg ER [92,93]. The effect of antimuscarinic agents on nocturia is small, with a reduction of nocturia by 0.3 episodes per night compared with placebo [91,93,108,114,115].

Antimuscarinic agents should be avoided in patients with cognitive dysfunction (eg, dementia, delirium, confusion), dry mouth, or severe constipation [116,117]. For individuals without known memory impairment, epidemiologic studies have shown an increased risk of future cognitive decline. A more detailed discussion of the association between anticholinergics and dementia is presented separately. (See "Epidemiology, pathology, and pathogenesis of Alzheimer disease", section on 'Medications'.)

Additional concerns with antimuscarinic agents include an increased risk of gastric ulceration in patients taking slow-release potassium chloride due to delayed gastric emptying [118] and an increased risk of urinary retention in patients with severe BPH symptoms or a postvoid residual (PVR) volume of ≥200 mL [119,120]. Although urodynamic studies have shown a small increase in the PVR with tolterodine, this change has not been clinically meaningful [120,121], and both tolterodine and oxybutynin have been used successfully in older male patients [92,122]. Antimuscarinics for OAB are discussed in further detail separately. (See "Urgency urinary incontinence/overactive bladder (OAB) in females: Treatment", section on 'Adverse drug effects' and "Lower urinary tract symptoms in males", section on 'Antimuscarinic agents'.)

Antimuscarinic agents and beta-3 agonists can be prescribed together; however, this treatment regimen has not demonstrated additive improvement in nocturia [123].

REFRACTORY SYMPTOMS

Treatment approach — Patients with nocturia often experience relapsing or refractory symptoms. In such patients, we repeat the evaluation, including a voiding diary (form 1) to confirm the mechanism of nocturia and ensure underlying medical conditions are addressed (see 'Evaluation' above and 'Address underlying medical conditions' above). We also revisit lifestyle modifications and behavioral treatments, including referral or repeat referral for pelvic floor muscle exercises, if available. (See 'Implement nonpharmacologic strategies' above.)

For patients who do not achieve a satisfactory response to the therapies described above, we offer the following additional treatments using a shared decision-making approach, including a detailed discussion of adverse effects and potential benefits.

Desmopressin — Desmopressin is a neuropeptide similar to endogenous vasopressin; like vasopressin, it has a potent antidiuretic effect, but unlike vasopressin, it has no vasopressor activity [124]. Desmopressin reduces nighttime free-water excretion to provide an opportunity for adequate sleep free from voiding; however, this benefit must be weighed against the potential for hyponatremia.

●Options and dosing

•Sublingual tablet – The sublingual tablet/pastille (Nocdurna) is the only desmopressin formulation with an approved indication for nocturia from the US Food and Drug Administration (FDA). It is available as 27.7 mcg tablets (equivalent to 25 mcg of desmopressin) and 55.3 mcg tablets (equivalent to 50 mcg of desmopressin), with the 27.7 mcg dose recommended in females due to their higher risk of hyponatremia. In two studies, the minimal effective dose for females was 25 mcg, and the minimal effective dose for males was 50 to 100 mcg [125,126]. The sublingual tablet is dosed at bedtime.

•Oral tablet – Desmopressin is also available as a generic oral tablet with a shorter half-life compared with other formulations. Previously, it had been the most commonly used formulation for the treatment of nocturia, although this use is off label and not FDA approved [127,128]. Oral desmopressin is available in 0.1, 0.2, and 0.4 mg doses. The initial oral dose for nocturia is 0.05 to 0.1 mg every evening one hour before bedtime, taken on an empty stomach to maximize absorption and minimize variation in bioavailability [129-131].

•Intranasal – A generic desmopressin nasal spray is available that delivers 10 mcg per spray, with a dose range of 10 to 40 mcg per evening. While a commercial desmopressin nasal spray was approved by the FDA for the treatment of nocturia, the manufacturer has since discontinued it due to low sales. Generic desmopressin nasal sprays remain available, though some patients may prefer other formulations due to nasal congestion or difficulty regulating the number of nasal sprays used. We avoid the nasal preparation in patients with atrophy of the nasal mucosa, acute or chronic rhinitis, or other conditions that may increase intranasal absorption.

●Efficacy – All desmopressin formulations have demonstrated some efficacy over placebo in trials. There are no comparative trials among these formulations.

In a systematic review of 14 randomized trials in men with nocturia, desmopressin (oral, sublingual, and intranasal formulations) reduced the number of nocturnal voids over 3 to 12 months compared with placebo (mean difference -0.85, 95% CI -1.17 to -0.53), with no increase in major adverse events [132]. However, there was no benefit of any desmopressin formulation in short-term evaluation (up to three months) and no benefit in the combined use of desmopressin with an alpha-1 adrenergic antagonist or anticholinergic drug.

Oral desmopressin is effective in treating adults with nocturia. In a systematic review of 10 randomized trials, desmopressin doses of ≥0.025 mg decreased nocturnal voids and increased time to first void [131]. A dose of 0.1 mg provided one additional hour of sleep before the first void and 0.72 fewer voids per night.

●Adverse effects and contraindications – Hyponatremia is the primary dose-related adverse effect for all formulations, which can be severe and life-threatening [133]. Because comorbidities, age, and polypharmacy increase the risk of severe adverse effects, we avoid desmopressin in patients aged ≥65 years and in patients with any of the following conditions [125,126,134-137]:

•Baseline hyponatremia (<135 mEq/L)

•Syndrome of inappropriate antidiuretic hormone secretion

•Diminished kidney function (estimated glomerular filtration rate of ≤49.9 mL/min/1.73 m²)

•Urinary retention

•Any condition or treatment associated with fluid or electrolyte imbalances or increased intracranial pressure

Given the potential for significant harm from treating a condition related to quality of life, we use a shared decision-making process when offering this therapy. According to the Beers criteria for medications for older adults, desmopressin is rated as a potentially inappropriate medication. (See "Drug prescribing for older adults", section on 'Beers criteria'.)

The frequency of reported hyponatremia with desmopressin ranges from 3 to 30 percent, with a pooled estimate of 7.6 percent (95% CI 3.7-15.1) [138]. Older, generic formulations have been demonstrated to cause hyponatremia at a 13-fold higher rate than other medications for lower urinary tract symptoms [139].

●Monitoring – We check a baseline serum sodium prior to starting desmopressin then recheck sodium once within the first week, once at 30 days, and at least once every six months thereafter [140]. Patients with an increased risk of hyponatremia (eg, age ≥65 years or concomitant use of medications known to depress serum sodium) should have sodium monitoring once every three to four months. The optimum sodium monitoring frequency has not been established, as severe hyponatremia has been reported even with the higher frequency of monitoring performed in clinical trials of desmopressin [130]. While many individuals develop hyponatremia within the first month of treatment, hyponatremia can also occur later on in the treatment course [141].

Desmopressin should be discontinued if the sodium falls below 135 mEq/L (equivalent to 135 mmol/L) and in patients who cannot comply with monitoring. In addition, all patients should have serum sodium monitored within three to seven days after each dose change and with any change in patient status, such as fluid retention, headaches, confusion, and/or disorientation.

Other treatments

●Melatonin – Limited evidence suggests melatonin may decrease nocturia episodes [142-144]. In one randomized trial of 20 older men with bladder outlet obstruction, treatment with melatonin reduced reported bother from nocturia; while nocturia frequency was also reduced compared with placebo (-0.3 and -0.05 episodes, respectively), this finding was not statistically significant [142]. Many studies of melatonin and melatonin receptor agonists for nocturia are limited by methodologic issues [143].

●Afternoon diuretic therapy – Several small studies have evaluated the effectiveness of an afternoon diuretic dose specifically prescribed for nocturia. In two randomized trials, nocturia was reduced by approximately 0.5 episodes per night [145,146]. Combining bedtime antidiuretic therapy with diuretic therapy six hours prior to bedtime increased the effect size of reduction of nocturia but was accompanied by hyponatremia in several cases [147].

●Tibial nerve stimulation or modulation – Tibial nerve stimulation addresses overactive bladder (OAB) by modulating the nerve signals responsible for bladder control. With percutaneous tibial nerve stimulation (PTNS), a needle is inserted near the tibial nerve at the ankle, while with transcutaneous tibial nerve stimulation (TTNS), surface electrodes are placed on the skin. Both treatment approaches involve a series of weekly 30-minute sessions of nerve stimulation for 6 to 12 weeks.

In one randomized trial of 214 patients with OAB, 12 weekly sessions of PTNS reduced the number of nocturia episodes compared with sham control (0.7 versus 0.3 fewer episodes from a baseline of 2.9 nightly episodes) [148]. Improvement in nocturia was sustained over a 12-month period (0.8 fewer episodes than baseline) when participants had additional treatment every two to three weeks. It is not known if these gains would be maintained without ongoing treatment [149]. In a smaller study of 76 women, PTNS or TTNS with bladder training reduced bother from nocturia compared with bladder training alone (1.84, 1.90, and 0.47 episode reduction for each group, respectively) [150].

PTNS and TTNS procedures are discussed in further detail separately. (See "Urgency urinary incontinence/overactive bladder (OAB) in females: Treatment", section on 'Tibial nerve stimulation'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Benign prostatic hyperplasia" and "Society guideline links: Urinary incontinence in adults".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Bladder training (The Basics)" and "Patient education: Benign prostatic hyperplasia (enlarged prostate) (The Basics)")

●Beyond the Basics topic (see "Patient education: Benign prostatic hyperplasia (BPH) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition – Nocturia is defined as waking to pass urine during the main sleep period. It is distinct from nocturnal urinary incontinence, or unintended voiding during sleep. Nocturia is a common symptom of several clinical conditions that result in low-volume bladder voids or increased urine output at night (table 1). Several medical conditions contribute to nocturia, including heart failure and other edematous states, sleep disorders, bladder and prostate conditions, and medication effects. (See 'Definition' above and 'Clinical presentation' above.)

●Evaluation – Evaluation for nocturia should focus on patterns of fluid intake, other urinary symptoms, and signs and symptoms of possible underlying causes. (See 'History and physical examination' above.)

A voiding diary (form 1) assists with determining if nocturia is secondary to reduced bladder capacity, nocturnal polyuria, or other mechanisms. Measurement of postvoid residual (PVR) assists with diagnosing bladder outlet obstruction or urinary retention. When available, ultrasound PVR testing is preferred to catheterization because of the reduced chance of infection and greater patient comfort. (See 'Voiding diary' above and 'Clinical testing' above.)

We measure a basic chemistry and urinalysis in all patients. We perform a urine culture if an infection is suspected. (See 'Laboratory tests' above.)

●Initial management – The goals of nocturia treatment are to decrease the bother of symptoms and to reduce the number of nocturia episodes. Patients who are not bothered by nocturia do not need treatment.

Initial measures include treating underlying medical conditions and lifestyle modifications (eg, adjusting fluid intake to earlier in the day, reducing salt intake if excessive, sleep hygiene, and eliminating nighttime diuretic use) (algorithm 1). (See 'Implement nonpharmacologic strategies' above.)

For all patients with bothersome nocturia, we also suggest pelvic floor muscle exercises (PFME) as part of the initial management plan (Grade 2B). PFME programs reduce nocturia and improve symptom-specific quality of life. If access to PFME is limited due to cost or availability, urge-suppression strategies (table 4) are a reasonable alternative that patients may complete on their own. (See 'Pelvic floor muscle exercises' above.)

●Pharmacologic treatment – We offer pharmacologic therapy to patients with continued symptoms after initial lifestyle and behavioral measures (algorithm 2). Because pharmacotherapy is associated with only a modest reduction in the number of nighttime voids and carries the potential for serious side effects, many patients may choose no pharmacologic therapy.

•Male patients with benign prostatic hyperplasia (BPH)-related symptoms – In males with nocturia and additional symptoms of BPH, we treat with alpha-1 adrenergic antagonists (table 5). Alpha-1 adrenergic antagonists are effective for lower urinary tract symptoms due to BPH, though their effect on nocturia is modest. (See 'Initial therapy with alpha-1 adrenergic antagonists' above and "Medical treatment of benign prostatic hyperplasia".)

If nocturia persists despite treatment with an alpha-1 adrenergic antagonist, we add bladder relaxants (eg, beta-3 agonists [preferred] or antimuscarinic agents) as a next step. If there is also evidence of an enlarged prostate (table 6), we add a 5-alpha reductase inhibitor (5-ARI). Combination therapy with 5-ARIs and alpha-1 antagonists improves lower urinary tract symptoms due to BPH; the combined effect on nocturia is modest. (See 'Additional pharmacotherapy' above and "Medical treatment of benign prostatic hyperplasia".)

•Postmenopausal female patients – For postmenopausal individuals, we suggest topical vaginal estrogen therapy (table 7) either alone or in combination with other therapies (Grade 2C). Though the evidence of efficacy is modest, it is safe and well tolerated, with minimal adverse effects. (See 'Postmenopausal females' above.)

•All other patients – In premenopausal female patients and male patients without BPH-related symptoms, we offer a trial of antimuscarinics or beta-3 agonists (table 8). While both are effective options, we prefer beta-3 agonists, when available, as they do not carry the risk of anticholinergic side effects or dementia associated with antimuscarinics. (See 'Bladder relaxants for all other patients' above.)

•Desmopressin for refractory nocturia – For patients who are <65 years of age with continued nocturia despite trials of other medications, we suggest a trial of desmopressin (Grade 2C). Desmopressin produces a small reduction in nighttime voiding frequency in randomized trials; however, there are a number of contraindications to this therapy due to the risk of severe hyponatremia. (See 'Desmopressin' above.)