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".)
DEFINITION/DIAGNOSIS — Nocturia is a common symptom rather than a disease and is defined as waking at night to void, where each micturition is preceded and followed by sleep [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 nighttime bed-wetting (enuresis) is distinct from nocturia and likely requires a different approach focusing on sleep problems or urinary obstruction [3,4]. In adults with no daytime symptoms or past history of pediatric bed-wetting enuresis, consideration should be given to causes of nocturnal syncope, including seizures or arrhythmia [5,6]. Urinary incontinence is discussed elsewhere.
EPIDEMIOLOGY AND RISK FACTORS — The prevalence of nocturia increases with increasing age [7]. 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 [8]. 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 estimated as at least twice nightly among men between 70 and 79 [8].
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 [9-13].
Many, but not all women with nocturia also have other urinary tract symptoms (eg, overactive bladder syndrome or polyuria) [7,12,14]. While pregnant women commonly have nocturia, it nearly always resolves by three months postpartum [15]. (See "Maternal adaptations to pregnancy: Renal and urinary tract physiology".)
Most epidemiological 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 (OSA), gastroesophageal reflux [16], benign prostatic hyperplasia (BPH), and congestive heart failure [17-21]. 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 [22,23].
CLINICAL SIGNIFICANCE — Nocturia is a source of significant bother for some patients, especially if there are two or more episodes per night [24,25]. It is one of the most distressing symptoms in older men with benign prostatic hyperplasia (BPH) [26] and is strongly associated with poor quality-of-life ratings [27]. Patients report nocturia as a leading cause of sleep disturbance, affecting both sleep onset and maintenance [28]. Difficulty returning to sleep and morning fatigue contribute to the negative impact [29].
Nocturia is associated with increased rates of depression [17], work absenteeism [30], and lower self-rated physical and mental health [18]. In older patients, it is associated with higher rates of accidental falls [31-33] and subsequent fractures [34,35].
PATHOPHYSIOLOGY AND ASSOCIATED CONDITIONS — Nocturia can be attributed to any disorder or condition (table 1) that causes one of the following [36,37]:
●Low-volume bladder voiding
●Increased volume of nighttime urinary output
●Sleep disturbance
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 hypertrophy (BPH). Reduced bladder volume is common in older patients, likely due to age-related changes in the bladder or detrusor hyperactivity [38,39].
Increased nighttime urinary volume — An increase in urinary volume at night may be due to a higher percentage of the total daily urine output being excreted at night (nocturnal polyuria) or an increase in the total 24-hour urine output (polyuria).
Nocturnal polyuria — The normal physiologic pattern of urination is a decrease in nighttime, relative to daytime, urine output. Overproduction of urine at night, with a normal 24-hour urine output, is called nocturnal polyuria [40]. It is defined as a urine volume during sleep greater than 33 percent of the 24-hour urine volume [41]. Causes include:
●Decrease in arginine vasopressin – There is a normal diurnal periodicity in arginine vasopressin (AVP), with higher AVP plasma levels in the evening leading to decreased nighttime urine output [42]. However, this diurnal variation is absent in many older subjects and likely contributes to age-related increases in nocturia. [43,44]
There are also age-related changes in the action of AVP [45,46]. 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 receptors in the renal distal tubules to increase urine concentration.
●Heart failure or other edematous states (nephrotic syndrome and venous insufficiency) cause interstitial edema. Assumption of the supine position permits mobilization of some of the edema fluid into the vascular space and leads to a solute diuresis.
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. 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 [47]. Causes of polyuria seen in the outpatient setting include uncontrolled diabetes mellitus, diabetes insipidus, and primary polydipsia. (See "Evaluation of patients with polyuria".)
Sleep disorders — Nocturia is the most frequently cited cause of poor sleep quality and insomnia in older adults, and it is a common feature in patients with obstructive sleep apnea (OSA) [48-51].
OSA may cause nocturnal polyuria by release of atrial natriuretic peptide (ANP) due to negative intrathoracic pressure and stretching of the myocardium [52]. ANP release 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 in nocturia episodes in patients with OSA [53-56].
In addition, patients with other primary sleep problems (restless leg syndrome, and periodic limb movements at night) may awaken due to sleep disturbance but recall this as an awakening to void [57]. Some nocturia treatment strategies target sleep disturbance directly. (See 'Sleep disorder medications' below.)
CLINICAL PRESENTATION — 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 gradual in onset and have variable night-to-night occurrence.
Occasionally, nocturia can be an indicator of worsening of an underlying disease, such as chronic kidney disease [58], lithium toxicity [59], diabetes mellitus, or congestive heart failure.
EVALUATION — Patients with nocturia should have a targeted evaluation (table 2) [60]. It is more valuable to quantify and understand how much distress nocturia causes the patient than to focus on obtaining a precise count of nightly episodes [61].
History — Elements of the history include nocturia symptoms, fluid intake patterns, medications, comorbid conditions, dry mouth, and urinary tract symptoms:
●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?
•Are you afraid of falling, do you feel dizzy, or have you fallen when you get up?
●Fluid intake – 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 renal stones, vigorous outdoor exercise, general health belief about fluid intake, attempt at weight loss, diabetes insipidus) are important in developing a meaningful treatment plan.
Some patients may drink large volumes immediately prior to bedtime. Although clinicians should make a recommendation to reduce nighttime fluid intake, patients will often have initiated this on their own prior to seeking help. Intake of diuretic fluids such as caffeine or alcohol should be asked about.
●Sodium intake – Inquire about sodium intake and consider reviewing a dietary history. Counsel on reducing intake of dietary items with high sodium intake [62,63].
●Medications – Certain prescription and over-the-counter medications (eg, diuretics, xanthines, beta blockers, cholinesterase inhibitors) may be related to nocturia onset or worsening.
●Comorbid conditions – Relevant, addressable conditions include congestive heart failure, diabetes mellitus, peripheral edema, depression, and nighttime pain [19,64]. Nocturia may improve with treatment of one of these conditions if it is a direct and principal cause [65].
●Sleep dysfunction – Obstructive sleep apnea (OSA) should be considered as a possible diagnosis in patients with nocturia, and the close association between the conditions has led to a suggestion that nocturia should be a screening question for OSA [66]. Insomnia (difficulty returning to sleep) and daytime sleepiness contribute to increased bother from nocturia [29].
●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 perform the following elements of the physical examination:
●Measure orthostatic vital signs in all patients due to the risk of nocturnal falls, and in men with benign prostatic hyperplasia (BPH) 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 [67].
Frequency-volume chart — Although patients may find it difficult to perform properly, a 24-hour recording of void time and void amount (using a collection device), along with times of going to bed and awakenings, can be helpful in identifying the causes of nocturia. We find this a useful tool in initial diagnosis, but it can also be used in patients who do not respond to initial management [68]. Results can help determine whether nocturia is due to low-volume voiding, increased nocturnal polyuria, or both [69]. For example, documentation of a low functional bladder capacity (the largest bladder volume void in 24 hours) may suggest that low-volume voiding is the problem. By contrast, a normal functional bladder capacity during the day but low volume voids at night may suggest a primary sleep disorder. Results can highlight the presence of high-volume urine output, either just at night (nocturnal polyuria) or over the entire day. A sample log is provided (form 1).
In interpreting the frequency voiding diary, nocturia episodes are voids that occur between going to bed and rising in the morning; the first morning void should not be counted as a nocturia episode (unless the individual was intending to sleep longer but could not return to sleep and remained awake) [70]. A determination of nocturnal polyuria can be made if the nighttime urine volume (including the first morning void) is greater than 35 percent of the 24-hour urine volume [40]. If the voiding record shows that the 24-hour urine output is higher than expected, it is important to confirm fluid intake. A log of the patient's complete fluid intake (including daytime) may be helpful [70].
Clinical testing — Measurement of urinary peak flow rate is not necessary. Post-void residual (PVR) measurement is used selectively.
PVR testing by catheterization or ultrasound can be helpful in diagnosing bladder outlet obstruction or urinary retention. Certain physical examination findings increase the suspicion for urinary retention, including abdominal fullness, suprapubic tenderness, or a patient’s 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. If PVR testing is to be performed, ultrasound testing is preferred to a catheterization because of reduced chance of infection and greater patient comfort.
An elevated PVR (greater than 200 mL) should limit the use of a bladder relaxant medication as these patients are at increased risk of urinary retention (beyond the baseline risk of 1 in 200 treated patients) [71]. In general, a PVR of less than 50 mL is considered adequate emptying, and a PVR greater than 200 mL requires further evaluation, which might include a medication review for discontinuation of any anticholinergic medications, or initial treatment with an alpha-blocker [72].
Laboratory tests — We measure renal function, electrolytes, and serum glucose and obtain a urinalysis in all patients, with urine culture if an infection is suspected.
Urine cytology or cystoscopy are indicated only if hematuria or pelvic pain is present. (See "Etiology and 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 (PSA) testing may be reasonable in the evaluation of men with nocturia and other lower urinary symptoms. (See "Clinical manifestations and diagnostic evaluation of benign prostatic hyperplasia".)
MANAGEMENT — 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 probably unrealistic [73]. Because nocturia can be a manifestation of various conditions, numerous treatments are potentially helpful, and multicomponent interventions are recommended [74-76]. Patients without an underlying medical condition who are not bothered by nocturia do not need treatment. Most treatments show only a small reduction in episodes of nocturia when compared with placebo, ranging from 0 to 0.8 fewer episodes per night.
Treatment of underlying medical conditions — Medical conditions which may cause or contribute to nocturia should be treated as part of initial management. These include:
●Polydipsia – Psychogenic (>10L per day) or other
●Congestive heart failure or peripheral edema
●Poorly controlled diabetes mellitus
●Gastroesophageal reflux disease (GERD) or nighttime cough
●Sleep disorders such as obstructive sleep apnea (OSA), periodic limb movements/restless leg syndrome, and insomnia [77]
●Obesity – Discuss weight optimization as part of healthy lifestyle advice [78]; in morbid obesity treated with surgery, nocturia may diminish [79]
Initial measures — There are several intervention strategies that should be considered in all patients (algorithm 1):
●Decreasing nocturnal urine output
•Reduction of overall fluid intake, especially if it is excessive, and specific reduction of evening intake by taking in this fluid earlier in the afternoon [80]. Care should be taken not to restrict fluid intake in older patients who have borderline or inadequate fluid intake to meet daily needs.
•Reduction of salt intake [81,82], particularly for those with congestive heart failure [63].
•Reduction of evening consumption of diuretic fluids, including caffeine and alcohol.
•Avoiding use of nighttime diuretics. Clinicians may direct patients on twice-daily diuretics to move the nighttime dose to the mid-afternoon.
•Treatment of peripheral edema by use of compression stockings or afternoon elevation of the legs.
•Avoidance of nocturnal hyperglycemia in patients with diabetes.
•Double-voiding prior to bedtime, which can be described as urinating while sitting comfortably on the toilet (men included), leaning slightly forward, and then waiting for 20 to 30 seconds to urinate again, may be helpful in individuals who feel that they have not completely emptied their bladder.
●Decreasing the impact of nocturia – 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. 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 floor way lighting) is also important.
In addition, adopting good sleep hygiene can reduce episodes of nighttime voiding. Elements include sleeping in a quiet room with low lighting and appropriate temperature, avoiding nighttime use of electronic devices, and avoiding daytime naps.
Behavioral treatment, including pelvic floor muscle exercises — Pelvic floor muscle exercises (PFME, or Kegel exercises) and urge-suppression strategies (a combination of remaining still and not running to the bathroom, use of relaxation strategies with three to five rapid contractions of the pelvic floor muscles) are useful in females and males with nocturia [60,83-87]. PFME strengthen the muscular components of the urethral closure mechanism using principles of strength training: small numbers of isometric repetitions at maximal exertion.
The patient’s ability to perform these exercise can be tested on rectal examination and will not usually require the use of computer-assisted biofeedback [87,88]. Primary care providers should refer patients to physical therapists who specialize in this training. 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 [89].
In clinical trials, benefits from this therapy can be seen as early as two to four weeks, with full benefit at 10 to 12 weeks [88]. Reduction in nocturia from these interventions has ranged from 0.5 to 1.4 episodes per night [85,88] and in pilot studies has shown improvements in sleep quality, reduced bother from nocturia, and improvement in nocturia symptom-specific quality-of-life metrics [88]. (See "Patient education: Pelvic floor muscle exercises (Beyond the Basics)".)
Simultaneous behavioral treatment of nocturia and insomnia will likely be effective in reducing nocturia and bother from nocturia [90,91].
Approach to pharmacologic therapy — We offer pharmacologic therapy to patients who continue to have symptoms after initial measures. Initial therapy is based on sex, and, in men, on whether or not benign prostatic hyperplasia (BPH) is present. However, single-agent pharmacologic treatments for nocturia are limited in their effectiveness and are less effective than multicomponent interventions (algorithm 2).
Men with benign prostatic hyperplasia
Initial monotherapy: alpha-1-adrenergic antagonists — We start therapy with alpha-1-adrenergic antagonists. These agents target the dynamic component of bladder outlet obstruction and can reduce several BPH symptoms, including nocturia. The presence of dizziness, low blood pressure, or orthostasis may be contraindications. 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 to other BPH-related symptoms [92]. In one secondary data analysis of a randomized trial, nocturia reduction of 50 percent or greater occurred in 39 percent of men treated with terazosin, compared with 22 percent of men treated with placebo [92]. This relatively small effect in research trials with populations selected to have the best chance for benefit and carefully monitored for compliance [93,94] suggests that nocturia response in the general population will likely be even more minimal.
Terazosin and doxazosin are often associated with dizziness and orthostatic hypotension, which may be of particular concern in patients with nocturia. These side effects can be minimized with gradual dose titration. Tamsulosin and alfuzosin do not require dose titration, and initial starting doses are usually well-tolerated with an incidence of dizziness and orthostasis of 1 to 2 percent [95,96]. Higher doses may result in higher frequency of side effects. (See "Medical treatment of benign prostatic hyperplasia".)
Combination therapy — We suggest combination therapy for patients who continue to have symptoms on an alpha-1-adrenergic antagonist. Most patients can be offered combination therapy with either PFME or with a bladder relaxant [97]. Contraindications to and side effects of bladder relaxant medications limit their usefulness. (See 'Initial monotherapy: bladder relaxant therapies' below.)
For men over age 70 who have continued symptoms on an alpha-1-adrenergic antagonist and who have a prostate larger than 35 g or a prostate-specific antigen (PSA) greater than 1.5, we consider adding a 5-alpha reductase inhibitor. These agents decrease nocturia by reducing the size of the prostate gland. Treatment for four to six months is generally needed before prostate size is sufficiently reduced to improve symptoms. (See "Medical treatment of benign prostatic hyperplasia".)
However, the efficacy of long-term therapy with 5-alpha reductase inhibitors is limited [93]. The Medical Therapy of Prostatic Symptoms (MTOPS) trial demonstrated benefit with 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 [98].
Role of surgery — Prostatectomy for BPH relieves many symptoms, but nocturia is the symptom that persists most frequently following surgery [99]. Some have suggested that BPH is often mistakenly implicated as the cause of nocturia in men [100]. Overall, surgical options are not recommended as first-line treatment for bothersome nocturia. However, for properly selected patients with severe, persistent prostatic symptoms in addition to nocturia, there may be reduction in nocturia that results from prostatic tissue removal when there is bladder outlet obstruction [101]. More details on this topic can be found elsewhere. (See "Surgical treatment of benign prostatic hyperplasia (BPH)".)
Women, and men without benign prostatic hypertrophy
Initial monotherapy: bladder relaxant therapies — We offer bladder relaxant therapies as first-line pharmacologic treatment. Bladder relaxant medications may reduce nocturia by increasing bladder capacity and decreasing urge-associated voids. Agents differ in drug class, efficacy, side effects, costs, and impact on comorbid conditions. However, the demonstrated benefit of bladder relaxants over placebo in nocturia reduction has been small [85,102,103], perhaps owing to the inability of these medications to increase nighttime voided volumes [104].
There are two major drug classes: antimuscarinics and beta-3 agonists. In general, the initial choice of agents is guided by side effects to avoid. Antimuscarinic agents and B-3 agonists can be combined, but there has been no demonstrated improvement in nocturia with combination therapy [105]. Antimuscarinic agents should be avoided in patients with cognitive dysfunction (eg, dementia, delirium, confusion), dry mouth, or severe constipation. Beta-3 agonists should be given with caution in patients with baseline tachycardia or poorly controlled hypertension. These agents are discussed in detail elsewhere. (See "Urgency urinary incontinence/overactive bladder (OAB) in females: Treatment", section on 'Medication prescribing details'.)
There is concern that bladder relaxant therapies may predispose men to urinary retention. Although urodynamic studies have shown a small increase in the post-void residual (PVR) with use of tolterodine this small change has not proven to be clinically meaningful [71,106] and both tolterodine and oxybutynin have been used successfully, with clinical monitoring, in older male patients [86,107].
Antimuscarinic agents — These agents have direct antispasmodic effects and inhibit the action of acetylcholine on smooth muscle. Oxybutynin is the most commonly used; other agents include tolterodine and solifenacin.
All antimuscarinic agents have anticholinergic effects which include dry mouth, constipation, blurred vision for near objects, tachycardia, drowsiness, and decreased cognitive function. These agents are contraindicated in patients with uncontrolled tachyarrhythmias, myasthenia gravis, gastric retention, and narrow angle-closure glaucoma and are discouraged in patients with cognitive impairment.
Additional concerns with antimuscarinic agents include increased risk of gastric ulceration in patients taking slow-release potassium chloride due to delayed gastric emptying [108] and increased risk of urinary retention in patients with severe BPH symptoms [55].
Oxybutynin is available in immediate release (IR), extended release (ER), and transdermal formulations. We recommend the ER formulation as it has fewer side effects (particularly less dry mouth), and a better safety profile.
While most individuals benefit from oxybutynin 10 mg ER, some patients will still have benefit at a lower dose (5 mg ER), and rarely will patients require 20 or 30 mg ER [86,87]. The effect of antimuscarinic agents on nocturia are small with reduction of nocturia by approximately 0.30 episodes per night compared with placebo (no reduction) [85,87,102,109,110].
Beta-3 agonists — Mirabegron and vibegron [111,112], beta 3-adrenoceptor agonists, are an option for patients who have a contraindication to antimuscarinic medications. These agents work by promoting selective beta receptor stimulation of the detrusor muscle to enhance smooth muscle relaxation. Mirabegron has similar efficacy to antimuscarinics [113]. Hypertension is the most common side effect with mirabegron; additional side effects are mostly secondary to elevated blood pressures. Mirabegron and vibegron has been shown to reduce nocturia by a modest degree [114,115]. Patients with severe or uncontrolled hypertension should not be prescribed a drug in this class [113].
Vaginal estrogen therapy (women only) — For postmenopausal women, it is reasonable to use topical vaginal estrogen therapy either alone or in combination with other therapies (table 3).
A systematic review of randomized and observational studies evaluating topical estrogen for the treatment of nocturia in postmenopausal women reported that three of the five studies (60 percent) that reported this outcome reported a reduction in frequency of nocturia compared with placebo [116]. 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'.)
Refractory nocturia — For patients who do not achieve a satisfactory response to therapies described above, there are alternative treatments to be considered based on patient eligibility and clinical indication.
Desmopressin — In 2018, the US Food and Drug Administration (FDA) approved two lower-potency [117] desmopressin analogs, of which one is still available (a sublingual pastille [Nocdurna]), for treatment of nocturia due to nocturnal polyuria [118,119]. However, United States insurance companies have asked for patients to be tried on a higher-potency (generic) formulation(s) of desmopressin acetate prior to receiving approval for the sublingual pastille [120].
While there are data showing the efficacy of desmopressin, there is a substantial risk of hyponatremia, which can be life-threatening if severe, that limits its use. Specifically, it has been demonstrated to cause hyponatremia at a 13-fold higher rate than other medications for lower urinary tract symptoms [121]. In particular, older adults with nocturia have a high prevalence of medical conditions, concomitant medications, and baseline laboratory abnormalities that likely increase the risk of potentially severe adverse side effects from desmopressin [122]. Since roughly three-quarters of those over 80 years of age with nocturia have a contraindication to these agents, a careful evaluation should be performed. Given the potential for harm from treatment of a condition related to quality of life, a shared decision-making process when considering this therapy is appropriate. If used, monitoring of sodium is necessary prior to initiation, once within the first week, once at 30 days, and periodically during therapy due to the potential of severe hyponatremia [117]. (See 'Monitoring' below and 'Safety' below.)
Desmopressin is a neuropeptide similar to endogenous vasopressin; like vasopressin, it has a potent antidiuretic effect, but unlike vasopressin it has no vasopressor activity [123]. desmopressin, taken two hours prior to bedtime, reduces nighttime free-water excretion to provide an opportunity for adequate sleep free from voiding; however, the safety of its use depends on compensatory daytime free-water diuresis, which helps to prevent hyponatremia. Hyponatremia should be considered a dose-related adverse drug reaction likely resulting from reduced drug clearance in certain patients [124]. For some individuals, desmopressin has a narrow therapeutic window and it may be difficult to achieve an effective dose that does not cause hyponatremia. This may be due to either increased bioavailability or reduced excretion.
Daytime polyuria and frequency resulting from desmopressin use may be bothersome to some patients.
Contraindications
●The principal contraindications to desmopressin related to the increased risk of hyponatremia are described in the Nocdurna package insert [118] and include:
•Hyponatremia (<135 mEq/L) at baseline, syndrome of inappropriate antidiuretic hormone secretion (SIADH), or a history of hyponatremia.
•Use of loop diuretics.
•A history of congestive heart failure.
•Use of systemic or inhaled glucocorticoids. However, an expert consensus panel did not feel that inhaled glucocorticoids were an absolute contraindication [117].
•Polydipsia, such as psychogenic polydipsia (a fluid intake of ≥10 liters per day).
•Use during an illnesses that can cause fluid or electrolyte imbalances (eg, gastroenteritis, salt-wasting nephropathies, systemic infection).
•Diminished renal function (estimated glomerular filtration rate [eGFR] of ≤49.9 mL/min/1.73 m2).
•An expert consensus panel felt that use of thiazide diuretics should be considered an absolute contraindication [117].
•An expert consensus panel felt that desmopressin should not be used in frail older adults [117].
The author avoids the use of desmopressin in patients aged ≥65 years due to the high likelihood that older adults with nocturia are highly likely to have contraindications to use and because the manufacturers as well as an expert consensus panel have failed to provide clear instructions for the frequency of needed monitoring [117]. Older adults will have a higher incidence of hyponatremia and higher likelihood of concurrent use of other medications that may depress serum sodium levels in this age group [125-128] (see 'Monitoring' below). Desmopressin is rated as a potentially inappropriate medication according to the Beers criteria for medications for older adults. (See "Drug prescribing for older adults", section on 'Beers criteria'.)
Patients taking certain medications are at increased risk for hyponatremia. Although not an absolute contraindication to use, more frequent monitoring of serum sodium is indicated. (See 'Monitoring' below.)
●Desmopressin should be avoided in patients who have:
•An underlying disease that would be made worse by fluid retention (eg, uncontrolled hypertension, increased intracranial pressure)
•A history of urinary retention
●The nasal preparation should not be given to patients who have nasal conditions that may increase absorption (eg, atrophy of nasal mucosa, acute or chronic rhinitis).
Individuals taking desmopressin who develop a contraindication to therapy should have the medication stopped and a subsequent reevaluation for appropriateness of the drug after resolution of the condition.
Formulations — Desmopressin is available in several formulations: as a sublingual tablet/pastille (Nocdurna), a generic intranasal preparation (desmopressin acetate), and an oral tablet (off-label). There are no comparative trials among these formulations, and the side effect profiles appear to be similar.
All formulations of desmopressin are associated with hyponatremia. Nocdurna was both approved with a boxed warning regarding hyponatremia stating that these medications are recognized to “cause hyponatremia” and that “severe hyponatremia can be life-threatening, leading to seizures, coma, respiratory arrest, or death.” While older, generic formulations of desmopressin carry the same, or higher, risk for hyponatremia, these agents do not have a black box warning [129]. However, sublingual pastilles and nasal spray preparations have the advantage over the oral tablet of not requiring gastric absorption which can be variable, and thus have more predictable drug levels by avoiding first pass metabolism. Some patients cannot use nasal sprays due to nasal congestion or difficulty regulating the number of nasal sprays used.
Formulations include:
●Sublingual tablet – Nocdurna is an orally disintegrating sublingual tablet of desmopressin acetate 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 dosage recommended in women due to their higher risk of hyponatremia. In two studies, the minimal effective dose for women was equivalent to 25 mcg [125,126]. One study showed a minimal effective dose for men equivalent to 100 mcg, whereas the other found 50 mcg to also be efficacious. The dosages recommended by the manufacturer are 27.7 mcg for women and 55.3 mcg for men, in both cases taken without water one hour prior to bedtime. Hyponatremia was more prevalent at higher doses, in older individuals, and in women [126].
●Intranasal – There is a generic formulation desmopressin nasal spray that has not been approved by the FDA for treatment of nocturia. It is available as 10 mcg per spray and a dosage range of 10 to 40 mcg per day.
●Oral tablet – Desmopressin is also available as an oral tablet with a shorter half-life. Previously, it had been the most commonly used formulation for treatment of nocturia, although this use is off-label [130]. Absorption from the gastrointestinal tract can be variable and is limited (about 5 percent); therefore, the oral drug has about one-tenth to one-twentieth the potency of the nasal form. Oral desmopressin is available in 0.1, 0.2, and 0.4 mg doses. The initial oral dose for nocturia is 0.1 mg, although some experts suggest a 0.05 mg starting dose. Oral desmopressin should not be taken with meals, in order to maximize absorption, and should be started at the lowest possible dose [131-133].
Efficacy — These agents have demonstrated efficacy over placebo in trials. However, their effect has not reached the threshold of minimally important clinical difference, which is likely around a 1.5 to 2.2 reduction in voids per night.
In a 2017 systematic review of 14 randomized trials in men with nocturia, desmopressin (oral, sublingual and intranasal formulations) was associated with a reduction in the number of nocturnal voids over 3 to 12 months compared with placebo (mean difference [MD] -0.85, 95% CI -1.17 to -0.53), with one major adverse event [134]. However, there was no benefit of desmopressin 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. Minimal benefit was found in clinical trials of intranasal desmopressin. Among individuals ≥age 50 years with a baseline of 3.3 episodes of nocturia per night, desmopressin nasal spray decreased episodes to 1.9 per night compared with 2.1 episodes on placebo [135].
Oral desmopressin is effective in treating adults with nocturia. A 2014 systematic review of 10 placebo-controlled randomized trials found that desmopressin doses of ≥0.025 mg decreased nocturnal voids and increased time to first void [133]. A dose of 0.1 mg provided one additional hour of sleep before the first void and 0.72 fewer voids per night. The absolute risk increase of hyponatremia was 5.1 percent.
Safety — The risk of hyponatremia in patients on desmopressin is of considerable concern; therefore, patients at increased risk for hyponatremia should not take this medication. (See 'Contraindications' above.)
The mechanism for hyponatremia is that some individuals on desmopressin therapy do not have a free-water daytime excretion. Rather, they continue to excrete a concentrated, hyperosmolar urine well into the day, which induces hyponatremia. While mild hyponatremia may present with a headache [133] or be asymptomatic, severe hyponatremia may result in seizures or be life-threatening [136]. Severe hyponatremia has occurred even within the higher frequency of monitoring performed in clinical trials where structured monitoring and lower-dose initiation of desmopressin has been performed [132].
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) [137]. In patients using intranasal formulations, clinically significant hyponatremia (126 to 129 mEq/L ) was reported in 2.2 percent of those who received desmopressin and none who received placebo, and severe hyponatremia (≤125 mEq/L ) was reported in 0.7 percent of those on desmopressin compared with 0.3 percent on placebo. All of the patients who had severe hyponatremia were older than 65 years [135]. Newer formulations of desmopressin, such as the oral disintegrating tablet, offer lower concentrations of active medication, but their use may still result in clinically significant or severe hyponatremia, particularly when given at higher than the minimally effective dose or when given to women and those over 65 years of age [138]. Symptoms of hyponatremia can be worrisome and myriad (nausea and vomiting, headache, confusion, loss of energy, drowsiness and fatigue, restlessness and irritability, muscle weakness, spasms or cramps, seizures, and coma) [117]. Individuals who develop these symptoms should stop desmopressin pending results of a serum sodium check.
Monitoring — Serum sodium levels should be monitored and the medication discontinued if the sodium falls below 135 mEq/L (equivalent to 135 mmol/L). While the majority of individuals who will develop hyponatremia do so in the first month of treatment, hyponatremia can also occur later [138].
Serum sodium levels should be obtained prior to therapy, within one week of initiating therapy, one month after therapy is initiated, and periodically thereafter during treatment.
There are inadequate data upon which to base the optimum frequency of periodic monitoring. The author suggests monitoring every six months for patients at average risk of hyponatremia and every three months for those at increased risk of hyponatremia (eg, those over the age of 65, or patients taking certain concomitant medications including nonsteroidal antiinflammatory drugs [NSAIDs], selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants [TCAs], thiazide diuretics, opioids, carbamazepine, lamotrigine, or chlorpromazine). Treatment should be discontinued 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.
Patients should also be monitored for the development of contraindications to therapy or a new medication that interacts with desmopressin.
Posterior tibial nerve stimulation — Posterior tibial nerve stimulation (PTNS) treatment involves 12 weekly 30-minute sessions of transcutaneous needle nerve stimulation near the ankle, approximating pudendal nerve stimulation. PTNS has been studied in a sham-controlled randomized trial of 214 patients with overactive bladder [139]. The number of nocturia episodes in the group assigned to weekly PTNS for 12 weeks decreased compared with sham control (a decrease of 0.7 versus 0.3 episodes from a baseline of 2.9 nightly episodes). Improvement in nocturia was sustained over a 12-month period (0.8 episodes less than baseline) when participants had additional treatment on an average of every two to three weeks. It is not known if these gains would be maintained without ongoing treatment [140]. In a treatment trial in 76 women, PTNS and transcutaneous tibial nerve stimulation (TTNS) added to bladder training reduced bother from nocturia versus bladder training alone (1.84, 1.90, and 0.47 episodes reduction for each group, respectively) [141].
Sleep disorder medications — Sleep medications can provide a decrease in nocturia episodes. One randomized study investigated melatonin as a potential treatment for nocturia associated with bladder outlet obstruction in older men [142]. Baseline frequency of nocturia was 3.1 episodes per night. Melatonin showed a nonsignificant reduction in nocturia compared with placebo (-.3 and -0.05 episodes respectively) and significantly reduced reported bother.
Afternoon diuretic therapy — Several small studies have evaluated the effectiveness of an afternoon diuretic dose specific prescribed for nocturia. In two randomized trials, nocturia was reduced by approximately 0.5 episodes per night [143,144]. Combining antidiuretic therapy (at bedtime) with diuretic therapy (six hours prior to bedtime) increased the effect size of reduction of nocturia but was accompanied by hyponatremia in several cases [145].
SUMMARY AND RECOMMENDATIONS
●Definition and goals of management – Nocturia is a symptom, defined as any waking at night to void, most often considered clinically significant if a patient voids two or more times nightly. It is important to try to reduce the bother caused by the nocturia in addition to reducing nocturia episodes. (See 'Definition/Diagnosis' above and 'Management' above.)
●Recognition of underlying causes – Nocturia may be caused by conditions or disorders that result in low bladder volume voids, nocturnal polyuria, or sleep disturbances. Certain medical conditions may contribute to nocturia and should be treated as part of initial management. Many patients have multiple etiologies. (See 'Pathophysiology and associated conditions' above and 'Management' above.)
●Evaluation – Evaluation for nocturia should focus on patterns of fluid intake, other urinary symptoms, symptoms of possible underlying causes, and a focused physical examination. (See 'Evaluation' above.)
•A frequency-volume chart (ie, a voiding diary) will be helpful in determining the contributing causes of nocturia. Nocturnal polyuria is defined as the excretion of ≥35 percent of the 24-hour urine output during the hours of sleep (form 1). (See 'Frequency-volume chart' above.)
●Initial management – Initial measures should include adjustments in timing of fluid intake to earlier in the day, reducing salt intake if excessive, and eliminating nighttime diuretic use if present. A urinal or commode near the bed may be helpful. Fall risk at night should be considered (algorithm 1). (See 'Initial measures' above.)
●Pelvic floor muscle exercises – We suggest pelvic floor exercises for all patients (Grade 2B). Primary care providers should refer patients to physical therapists who specialize in this training. (See 'Behavioral treatment, including pelvic floor muscle exercises' above.)
●Pharmacologic treatment – Suggested initial treatment trials for nocturia include the following (algorithm 2):
•In men with nocturia related to benign prostatic hyperplasia (BPH), we suggest trials of alpha-1-adrenergic antagonists with or without 5-alpha reductase inhibitors (Grade 2B). (See 'Men with benign prostatic hyperplasia' above.)
•In patients without BPH who have low-volume voids, we suggest trials of bladder muscle relaxants (Grade 2C). (See 'Initial monotherapy: bladder relaxant therapies' above.)
•For postmenopausal women with continued nocturia despite a bladder muscle relaxant, we offer topical vaginal estrogen either alone or in combination with other therapies. (See 'Vaginal estrogen therapy (women only)' above.)
Because each of these therapies is associated with only a modest reduction in the number of nighttime voids and also has potential for side effects, many patients may choose no pharmacologic therapy.
●Refractory nocturia – For patients with refractory nocturia and who are <65 years of age, we consider treatment with desmopressin. Studies suggest that desmopressin has a small effect on nighttime voiding frequency that is of uncertain clinical significance. Baseline sodium levels must be normal, and patients must be able to recognize and report subtle fluid status changes and also be willing to undergo frequent monitoring of sodium levels in order to avoid severe hyponatremia. Desmopressin is a potentially inappropriate medication according to Beers criteria for medications for older adults. (See 'Desmopressin' above and "Drug prescribing for older adults", section on 'Beers criteria'.)
