Nocturia

Etiology

Nocturia is multifactorial but generally is caused by 1 of 4 main problems: nocturnal polyuria, global polyuria, bladder functional storage issues, and sleep disorders. A combination of these can also lead to nocturia. Primarily, hormonal issues cause nocturnal and global polyuria.[3]

Nocturnal Polyuria

The most common cause of nocturia, reportedly found in up to 88% of patients, is nocturnal polyuria, although there are many causes and contributing factors. According to the International Continence Society, nocturnal polyuria is a nighttime urinary production greater than 20% of the total 24-hour urine volume in younger adults or more than 33% in older individuals.[3][4] To calculate this, divide the total urinary volume from all nocturia episodes by the total urinary volume for 24 hours and multiply by 100 for the nocturia episode percentage. The voiding must be preceded and followed by a sleep period to be considered a nocturia episode. Nocturnal polyuria is usually accompanied by a proportional decrease in daytime hourly urine production, resulting in a normal 24-hour total urinary volume. Another definition would be nocturnal urine production of more than 90 mL per hour or more than 6.4 mL per kg of body weight.[3][4]

Nocturnal polyuria as a cause of nocturia is more prevalent in older patients, while in younger patients, a decreased nocturnal bladder capacity is the more common etiology. Caffeine and excessive oral fluid intake in the evenings, as well as alcoholism, can contribute significantly to this disorder. Nocturia is also associated with congestive heart failure, obstructive sleep apnea, evening use of diuretics, peripheral edema, high dietary salt intake, and chronic venous insufficiency of the lower extremities.[3][4]

Arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) are the hormones involved in determining hourly urinary production. AVP is manufactured by the magnocellular neurosecretory neurons in the paraventricular nucleus of the hypothalamus and the supraoptic nucleus. AVP, an antidiuretic hormone, is then stored and released from the posterior pituitary gland. This hormone is released when plasma osmolality increases (ie, hypernatremia) and a patient has low blood pressure. AVP binds to the V2 receptors in the collecting ducts and distal renal tubules, increasing water permeability and absorption in these areas, ultimately decreasing urine production. A disruption of nocturnal AVP levels, where nocturia patients have a reduction in nighttime AVP levels, is a common etiology for nocturnal polyuria. AVP increases the reabsorption of free water returned to the circulation from the filtrate in the renal collecting tubules, which results in reduced urine volume but higher urinary concentration.

AVP also constricts arterioles, which increases peripheral vascular resistance and raises systolic blood pressure. AVP production normally increases during sleep as part of the normal circadian rhythm cycle. When this surge is diminished or missing, increased nocturnal polyuria and nocturia will result. This normal diurnal variation tends to diminish or disappear in older individuals. Parkinson's disease can also cause nocturnal polyuria through its effect on AVP. Other causes of decreased nocturnal AVP secretion include AVP receptor mutations, intrinsic renal disease, electrolyte abnormalities, congestive heart failure, sleep apnea, drug usage (eg, lithium, diuretics, tetracyclines), and venous insufficiency with peripheral edema of the lower extremities.[5][6][7]

Atrial natriuretic peptide (ANP) is a diuretic hormone made by cardiac muscle cells in the atria. ANP increases renal sodium excretion, which acts as a diuretic because extra water is also excreted. The muscle cells in the atria have volume receptors that respond to increased fluid and stretching of the atrial walls by releasing ANP, which happens in congestive heart failure and uncontrolled hypertension. Atrial ANP secretion reduces blood pressure and total blood volume through enhanced renal excretion of sodium and water. ANP has the opposite effect of aldosterone, which increases renal sodium and water retention. ANP excretes sodium and water.

Increased secretion of ANP also occurs in patients with hypoxia (eg, obstructive sleep apnea), which would then lead to nocturnal natriuresis and increased nocturia. This effect occurs from increased airway resistance and negative intrathoracic pressure, resulting in myocardial stretching and ANP production. Obstructive sleep apnea sufferers have been shown to have increased renal sodium and water excretion that is induced by elevated plasma ANP levels. The ANP level can be reduced in patients with obstructive sleep apnea by using continuous positive airway pressure (CPAP).[8][9][10] Specific effects on the kidney from ANP include:

• Relaxation of the glomerular afferent arterioles while constricting the efferent raises glomerular filtration fluid pressure and the glomerular filtration rate, contributing to increased diuresis.
• Increased blood flow through the vasa recta reduces the reabsorption of tubular fluid.
• ANP decreases sodium reabsorption in the collecting duct and distal convoluted tubules.
• Inhibition of renin secretion reduces aldosterone production and decreases renal sympathetic tone.
• ANP is increased during congestive heart failure, uncontrolled hypertension, and sleep apnea.

Global Polyuria

Global polyuria is defined as continuous urinary overproduction throughout the day and is another cause of nocturia. Global polyuria typically results in a urinary output of >40 mL/kg per 24 hours, typically 2,800 mL for a 70 kg individual. This etiology has also been defined as a daily urinary volume of ≥3000 mL. Urinary overproduction is not just confined to sleeping periods like nocturnal polyuria. Global polyuria is always associated with an increased fluid intake, which may be caused by iatrogenic, psychogenic, or dipsogenic polydipsia; hypercalcemia; drug effects; primary polydipsia; diabetes mellitus; or diabetes insipidus. Global polyuria has also been associated with renal insufficiency and a lack of estrogen in women.[3][4]

Low levels of AVP cause central diabetes insipidus, while in nephrogenic diabetes insipidus, the etiology is a failure of the kidneys to respond to appropriate levels of AVP. Diagnosing diabetes insipidus can be done by the overnight water deprivation test, during which patients are asked to stop fluid intake for a defined period, usually 8 to 12 hours, before bed. After such forced dehydration, the first morning urine would normally result in highly concentrated urine. If this is not found, then diabetes insipidus can be diagnosed. Central diabetes insipidus can be treated with synthetic AVP (eg, desmopressin).[3][4][5][6][7]

Bladder Storage Problems

Patients with nocturia who do not appear to have polyuria are likely to have either a bladder storage problem (eg, reduced bladder capacity and detrusor overactivity) or a sleep disorder. Bladder storage problems contributing to nocturia are most often associated with multiple, frequent voidings with small urinary volumes. About 50% of patients who have daytime urinary urgency will also have clinically significant nocturia.[3][4] There may also be a variety of other lower urinary tract symptoms, particularly frequency and urgency. In men, prostate problems increase with age, while in women, there may be issues related to postmenopausal changes that affect urination. Many individuals will have bladder overactivity or other types of bladder storage issues that are aggravated by many factors, including:

• Abnormal bladder emptying
• Alcohol
• Anxiety
• Atrophic vaginitis
• Bladder calculi
• Caffeine
• Decompensated detrusor function
• Diuretic medications (eg, thiazides, furosemide or lithium)
• High potassium foods
• Hypotonic bladder
• Neurogenic bladder
• Noninfectious cystitis (interstitial or radiation cystitis)
• Overactive bladder 
• Overflow incontinence
• Peripheral edema in the lower extremities
• Prolonged Foley catheterization
• Prostatic enlargement
• Prostatitis
• Radiation effect
• Reduced bladder capacity from surgery
• Urethral strictures
• Urinary retention
• Urinary tract infections
• Vaginal prolapse [3][4]

Sleep Disorders

Insomnia, sleep apnea, and other sleep disturbances can certainly contribute to or even cause nocturia. Sleep disorders should be suspected if patients cannot return to sleep quickly after an episode of nocturia or complain of morning fatigue. In patients with insomnia, their nocturia is usually a manifestation of their sleep disturbance, and nocturnal urinary frequency is an incidental side effect rather than a cause.[3][4]

Nocturia will occur in about 50% of patients with obstructive sleep apnea, which causes nocturnal polyuria due to its effect on ANP. Sleep apnea causes hypoxemia, which increases pulmonary artery vasoconstriction. The elevated pulmonary vascular resistance from this vasoconstriction increases right atrial pressure, which induces ANP production and increases nocturnal urine production or nocturnal polyuria. This occurs so commonly that it has been suggested that obstructive sleep apnea should be considered a possible diagnosis in all patients with nocturia, especially younger male patients younger than 50 years of age.[3][4] In a sleep clinic retrospective review of over 1,000 consecutive patients, snoring and significant nocturia were strong predictive factors of obstructive sleep apnea, with a sensitivity of 97.4%.[11]

Often, patients with a primary sleep disorder will fail to recognize the true reason for their awakening as being a sleep disturbance. They will identify only the need to void as the reason for their waking when studies have proven that sleep-related disorders (eg, severe snoring, apnea, or restless leg syndrome) immediately preceded the awakening 80% of the time. Only 13% of patients with nocturia will have an initial sleep period of more than 2 to 3 hours.[3][4] All patients with significant nocturia and fatigue should be screened for obstructive sleep apnea.[4] This is most easily accomplished with a simple questionnaire, including the STOP-Bang questionnaire, which consists of only 8 simple questions that can easily be performed in an office or clinic setting.[4][12] If the results suggest obstructive sleep apnea, patients can be referred to a sleep center for polysomnography for confirmation and further treatment. There is also evidence that treatment of obstructive sleep apnea, if present, will improve the patient's nocturia.[13][14][15]

Other Causes and Contributing Factors

Peripheral edema can contribute to nocturnal polyuria. When a patient with significant lower extremity edema lies down, much of the extra fluid is returned to the vascular system, where the kidneys can excrete it. This would increase urine production shortly after the patient assumes a recumbent or supine position. This effect can be minimized by having the patient elevate their lower extremities sometime before bed, as well as the judicious use and timing of diuretics. Similarly, heart failure, nephrotic syndrome, venous insufficiency, high sodium intake, and even just long-term standing still may also cause excess fluid retention in the lower extremities, which are mobilized once the patient assumes recumbency, resulting in increased urine production shortly after the patient lies down.[3] Compression stockings during the daytime, especially in the afternoon and evenings, can also help minimize tissue fluid sequestration in the lower extremities before bedtime.[3][4] Drinking large amounts of fluids shortly before going to bed and ingesting caffeine or alcohol late in the day and before bed is likely to contribute to nocturia as well.[3][4]

Other causes of nocturnal polyuria and nocturia include congestive heart failure, nephrotic syndrome, obesity, hypertension, excessive nighttime fluid ingestion, and liver failure. Depression, the use of antidepressants, and a lack of physical activity are also associated with nocturia in both men and women. Whether treatment of depression will reduce the incidence of nocturia in this group of patients is unclear.[3][4] Parkinson's disease can cause nocturnal polyuria through its effect on reducing sympathetic tone, which results in a solute (eg, sodium) based diuresis.[3][4] Nocturia is associated with a normal pregnancy. No specific medical treatment is required as the nocturia will resolve once the pregnancy is over. Only behavioral and lifestyle therapies are recommended during pregnancy.[16][17][18]

Epidemiology

Nocturia becomes more common and more severe with age. More than 50% of men and women older than 60 years have been diagnosed with nocturia. Although the overall rate is about the same between genders, younger women have a higher prevalence of nocturia than younger men. This is reversed in older patients; older men are more likely to have symptomatic nocturia than older women. The incidence of nocturia is approximately 50% in men aged 70 to 79 years with ≥2 nightly voids, and with a rapidly aging population, the incidence of clinically significant nocturia will only increase.[19]

Contributing factors will vary somewhat with gender. Women aged 40 years or older have a 40% incidence of at least minimal nocturia, and pregnant women frequently have nocturia, which almost always resolves spontaneously approximately 3 months after delivery.[3][4] The incidence of nocturia is highest in blacks and does not appear to be related to socioeconomic factors. Hispanics tend to have a somewhat higher incidence of nocturia than whites, though less than the black population.[3][4] Obesity appears to be an independent risk factor that increases the incidence of nocturia by 2- to 3-fold.[3][4]

Patients with nocturia and other lower urinary tract symptoms will often delay seeking help for these conditions. Voiding diaries are extremely useful and essential tools to evaluate nocturia and diagnose nocturnal polyuria. However, clinicians rarely request them from patients with nocturia despite universal recommendations in the literature to obtain them. Initial treatment is often arbitrary, with 59% of men receiving alpha-blockers and 76% of women getting anticholinergics. Such treatments have shown only modest benefits in clinical trials. Moreover, nocturnal polyuria, the primary cause of nocturia for most patients, is best treated by other means (eg, desmopressin).[3][4]

History and Physical

Clinical Symptoms

Nocturia has multiple potential causes. The initial evaluation should start with a good history and physical examination, including drinking habits, caffeine and alcohol consumption, and sleeping habits. Additionally, a high sodium intake, hypertension, use of diuretics, and diabetes all influence nocturia. Clinicians should also note the presence of any peripheral or dependent edema.

The cornerstone of nocturia diagnosis and management is the 24-hour voiding diary because correctly identifying polyuria and bladder overactivity is essential for diagnosis and tracking posttreatment progress. Therefore, all patients with nocturia desiring treatment should be asked to do a 24-hour voiding diary. Clinicians should also initiate a discussion of nocturia symptoms and their nature and severity if present. A typical question to identify possible nocturia might be, "On average, how often do you wake up at night to void?" If nocturia is present, clinicians should inquire about how much sleep disruption this causes and if the patient finds the nocturia bothersome. Further questioning would include the amount of fluid intake, the types of liquids ingested, medications taken (eg, diuretics), sleep disturbances, comorbid medical conditions, and any urinary tract symptoms.

• Fluid intake: The type and amount of fluid intake are important in evaluating nocturia. Large quantities of fluid consumption alone (ie, >40 mL/kg/d) can cause nocturia without other identifiable etiologies. Increased fluid intake may be voluntary, psychogenic, or a sign of diabetes mellitus or diabetes insipidus. Caffeine and alcohol intake should be reduced in the late afternoon and evening, as caffeine usage alone can result in bladder overactivity and polyuria. Consuming large quantities of fluid before bedtime should be discouraged. Fluids, in general, between dinner and bedtime should be avoided as well. Clinicians should be aware that some elderly patients may already be mildly dehydrated and require extra fluid intake earlier in the day before these individuals can do evening fluid restriction safely. Although fluid restriction before bed may not cure nocturia, symptoms will not worsen and may be improved.[3][4]

• Medications: Various medications, foods, and supplements can affect bladder storage and diuresis. Patients should take loop diuretics early in the afternoon so the diuretic effect ends before bedtime. If a loop diuretic is prescribed twice daily, the evening dose should optimally be taken 6 to 8 hours before bedtime, in the mid-afternoon, to minimize nocturia. Other medications can contribute to nocturia, including beta-blockers, caffeine, alcohol, anticholinergics, cholinesterase inhibitors, diuretics, and medications with diuretic effects (eg, lithium).[3][4] Clinicians should also ask patients how much fluid they consume when taking their medications. Patients should be advised to drink a sip rather than a whole glass of water in the evenings.

• Contributing comorbid medical conditions: Over half of patients with nocturia ≥2 times per night also have a minimum of 3 contributing comorbid conditions. The most commonly reported comorbid conditions include diabetes, the use of diuretics, hypertension, and obstructive sleep apnea. Clinicians should also consider other medical factors, including other sleep disorders and issues that may increase a patient's fall risk when going to the bathroom at night (eg, vision impairment, ambulatory difficulties, prior history of falls, dizziness, and dementia). Obesity doubles or triples the incidence of nocturia in both genders.[3][4]

• Lower urinary tract symptoms: Further urological evaluation may be indicated for lower urinary tract symptoms (LUTS), including hesitancy, straining, incomplete emptying, weak stream, frequency, urgency, intermittent stream, and incontinence. Irritative bladder symptoms, especially urgency, without high postvoid residual volumes (<200 mL) or other evidence of obstruction suggest an overactive or neurogenic bladder, usually treated medically. The use of overactive bladder medications to treat nocturia in patients without urgency symptoms is not likely to be successful. The presence of daytime irritative symptoms (eg, urgency) indicates overactive bladder medications may reduce nocturnal voids. However, clinicians often overutilize such drugs when treating nocturia. Obstructive symptoms in men can indicate benign prostatic hyperplasia (BPH). Clinicians should investigate these kinds of impressions more completely with a voiding diary and a postvoid residual volume.[3][4] Further evaluation, including flowmetry, urodynamics, and cystoscopy, can be helpful in selected cases. Confirmed BPH can be treated with alpha-blockers or other prostatic obstruction modalities, while overactive bladder can be treated with various bladder relaxing therapies to alleviate bothersome nocturia symptoms. However, clinicians should use caution when treating individuals likely to encounter adverse effects (eg, older patients prone to dizziness being treated with alpha-blockers).[3][4]

Physical Examination

The following clinical findings during a physical examination are relevant in evaluating nocturia because these findings help diagnose contributing factors and comorbid health conditions causing or exacerbating nocturia.[3][4]

• Orthostasis and dizziness: These findings may suggest orthostatic hypotension, an adverse effect of alpha-blockers.
• Fluid overload or congestive heart failure signs: Findings on examination can include auscultation of crackles, tachypnea, tachycardia, and dyspnea
• Suprapubic distension or tenderness: On abdominal examination, these findings may indicate bladder over-distension or high postvoid residual volumes, although such signs are unreliable. 
• Abnormal rectal examination: A digital rectal examination should be performed, especially in men, to evaluate for decreased rectal muscle tone, rectal masses, and fecal impactions, which can contribute to nocturia. Estimating prostatic size in men by digital rectal examinations is useful, though imprecise.
• Abnormal neurological evaluation: Abnormal findings, including an absent anal wink which is a quick contraction of the anus visualized after lightly scratching the skin lateral to the rectum, and decreased perineal sensation can indicate an impaired sacral plexus nerve (ie, S2 to S4).
• Lower extremity edema: This finding suggests fluid overload or congestive heart failure.

Evaluation

Nocturia is a complicated, multifactorial disorder that is often resistant to initial therapy with overactive bladder or BPH medications. Successful treatment of nocturia will require correct identification of the underlying etiology for optimal effectiveness. This cannot be reliably accomplished without a voiding diary.[2][3][4]

The Voiding Diary

The key to the evaluation of nocturia is the 24-hour voiding diary. Ideally, the patient accurately records the time and amount of urine they void within 24 hours for 3 consecutive days. When diagnosing nocturia and counting nocturnal voiding episodes, the last void before going to bed is excluded. However, the first-morning urination is counted if the urge to urinate wakes the patient. For most patients, nocturia of 2 or more times, but more likely more than 3 times per night, is usually bothersome enough to warrant treatment. Nevertheless, the patient determines the severity of symptoms and the need for treatment.

The timing, amount, and type of fluid ingested should also be documented. Alcoholic drinks tend to act as diuretics, and caffeinated beverages can increase bladder activity. However, recording this degree of detail may be too complex or cumbersome for some patients. The most critical information in the voiding diary is the time of urination and voided urinary volume. A postvoid residual urine volume and the voiding diary information are often sufficient to diagnose the type of nocturia present. For example, high, postvoid residuals indicate bladder storage or prostate enlargement disorders. Patients with severe nocturia, who void only small amounts and have minimal postvoid residual urine volumes, are likely to have bladder overactivity, especially if associated with daytime urinary urgency. Those who void large volumes are likely to have global or nocturnal polyuria, depending on whether the increased diuresis is only overnight or involves the entire day.[3][4]

Despite the well-established usefulness of a voiding diary in diagnosing and evaluating nocturia, studies have estimated that only 37% of nocturia patients provide a diary. For any serious evaluation of a patient with nocturia, a 24-hour voiding diary is critical and required. While a 3-day voiding diary is optimal, even a single 24-hour diary is extremely helpful if properly done with accurate measurements. The need for accuracy in completing the voiding diary should be carefully explained to the patient as this information diagnoses the nocturia type, identifies the underlying etiology, and guides management. Voiding diaries also demonstrate to patients the benefits of optimal timing of fluid intake in managing their nocturia problem.[3][4]

Attention should also be given to medication timing, particularly diuretics. A patient taking short-acting diuretics like furosemide in the morning has become commonplace. These medications typically increase urinary excretion for 6 to 8 hours after ingestion. When the medication effects diminish, fluid reaccumulates in the tissues from which it originates. In patients taking furosemide in the morning, after 8 hours, these tissue spaces are again full, and excess fluid is excreted as urine overnight. This contributes to and exacerbates nocturnal polyuria and nocturia. The optimal time to take furosemide to minimize its effect on nocturia would be 6 to 8 hours before bedtime, so the nocturnal hours would correspond to the period of expected tissue space fluid sequestration and rehydration but not to either the period of increased diuresis.[3][4]

Additional Diagnostic Studies

Nocturia is diagnosed based on clinical history; however, additional diagnostic studies are performed to assess for the underlying etiology and comorbid conditions. Serum glucose hemoglobin A1C, renal function, urinary osmolality, and serum electrolytes should be evaluated. A urinalysis should also be done. Patients with poorly controlled diabetes, renal disease, or nephrogenic diabetes insipidus often report nocturia. A formal postvoid residual volume with a straight catheterization or bladder scan should be performed. A postvoid residual of more than 200 mL is considered pathological and may require further evaluation. Patients with urinary retention and overflow can present with frequency and nocturia.[4][20][21][22][23] Cystoscopy and urodynamics are not generally necessary or recommended for most patients with nocturia.[4]

Treatment / Management

Nocturia Treatment Indications

Traditionally, treatment for nocturia was not deemed necessary unless the patient was sufficiently bothered by the nocturnal voidings to desire therapy. The general population and many clinicians consider nocturia a natural part of aging; patients are often unaware that the condition is treatable. Nocturia is generally considered pathological only when a patient is bothered significantly. Most individuals are not bothered by nocturia until sleep is severely affected, usually when they have ≥2 nocturnal voids per night. However, a recent multicenter study by Park et al found that nocturia treatment was equally successful regardless of patient bother. This suggests that treatment should be offered to all patients with significant nocturia, at least on a trial basis, regardless of how little discomfort they initially reported. The benefits of successful treatment are not apparent until after therapy, as patients often underestimate the severity of nocturia symptoms and the impairment of sleep quality, general health, daily activities, and overall quality of life.[24][25]

The first step in the management of nocturia is setting reasonable treatment goals. While eliminating all nocturnal voiding episodes would be ideal, a 50% reduction or no more than 1 to 2 voids per night is a reasonably achievable goal for most patients. Complete cessation of nocturia may not be possible.[3][4]

Initial Management Strategies

Nocturia management initially involves the implementation of the following lifestyle modifications:

• Prepare for bed 20 to 30 minutes before bedtime with a relaxing protocol, including meditation, listening to soft music, yoga, breathing exercises, reading, and a warm bath.
• Limit fluid intake in the late afternoon and evening, especially between dinner and bedtime.
• Avoid fluid intake 2 hours before going to bed.
• Limit total daily fluid intake to 2 L per day or reduce fluid intake by 25% from the initial baseline.
• Reduce dietary salt and protein intake, especially late in the day.
• Adjust the timing of short-acting diuretics to the afternoon.
• Elevate lower extremities and use support hose starting just after dinner until bedtime.
• Use compression stockings to lower peripheral edema as needed.
• Perform pelvic floor muscle exercises.
• Increase regular physical activity (eg, afternoon walks) but not too close to bedtime.
• Limit nocturnal oral fluids, alcohol, and caffeinated beverages.
• Use the bed only for sleeping or sexual activity.
• Get up and perform a relaxing activity (eg, reading) if unable to sleep before returning to bed.
• Establish regular sleep routines such as timing, minimizing electronic usage, and optimizing the bedroom environment (eg, acoustics, light, and temperature)
• Avoid long periods of standing still, which promotes dependent edema.
• Avoid afternoon naps, especially after 3 PM, or going to bed too early.
• Avoid smoking after dinner, as nicotine from tobacco tends to interfere with sleep.
• Avoid exercise late in the day, although daytime exercise is encouraged.
• Avoid thinking of serious life issues, problem-solving, or rehashing daytime events while going to bed.[3][4][26]

Although fluid management alone has minimal impact on most cases of nocturia, the strategy is reasonable initially. However, clinicians should be cautious in overly restricting fluid intake in elderly patients who may otherwise become dehydrated easily. 

Using a bedside commode or urinal can minimize the bother, if not the frequency, of nocturia and may reduce the risk of falls. Remove any obstacles, loose rugs, or furniture between the bed and the nearest commode to minimize fall risk further. Consider using nightlights to help illuminate the passage to the bathroom. Patients can also use mattress covers as necessary to help protect the bed. Furthermore, absorbent briefs, pads, and modified underwear can absorb liquids, preventing wetness. Optimizing treatment of known underlying medical conditions (eg, congestive heart failure and diabetes) is recommended but has not been demonstrated to reduce nocturnal voiding episodes significantly.

Nocturia Behavioral Therapy

Behavioral therapy, which includes pelvic floor muscle training, urge-suppression techniques, delayed voiding, fluid management, sleep hygiene, Kegel exercises, and peripheral edema management, is reasonably efficacious when used alone or with pharmacological therapy in controlling nocturia.[27] Behavioral therapy in men, alone or combined with an alpha-blocker therapy, has consistently shown large and statistically significant reductions in nocturia episodes and favorable effects on sleep and quality of life. Based on these findings, behavioral therapy may provide a meaningful treatment option for men with nocturia.[28](A1)

The standard recommended pelvic muscle training protocol is 3 repetitions of 8 to 12 slow pelvic contractions or compressions, each held for 6 to 8 seconds. This is typically done 3 or 4 times a week and continues for at least 3 months.[3][4]

Sleep issues can significantly affect nocturia, particularly when the first nocturnal void is within the first 3 to 4 hours after falling asleep since this is typically a period of deep sleep. Following are some simple steps patients can take to improve their sleeping experience, which may also help their nocturia:[3][4]

• Reduce the time they spend in bed. Excess hours in bed will make sleep shallower, worsening their nocturia. Also, the longer patients stay in bed, the more likely they are going to need to urinate.
• Make the bedroom as comfortable as possible for sleeping by eliminating as much noise and light as possible. Consider using earplugs or blindfolds if noise or light keeps one awake. Opaque curtains reduce light and tend to keep the room quieter.
• Go to bed at the same time each day. 
• Maintain a comfortable room temperature, which is around 69 °F (20.6 °C) for most people.
• Make the bed a little warmer (eg, using a hot water bottle, adding an extra-light bed covering, or using an electric blanket).
• Avoid watching television, using a smartphone, or operating a computer shortly before bedtime. The light from these devices sends a "wake-up" signal to the brain, which makes falling asleep more difficult.
• Consider using 1 to 2 mg of melatonin, a natural sleep aid available without a prescription, which some evidence shows can help reduce nocturia when taken at bedtime.

These techniques can reduce nocturia by 50% in some patients.[3][4] Specific sleep disorders may predispose patients to nocturia, so consider a formal sleep study evaluation if initial treatment strategies for nocturia do not result in adequate improvement. Continuous airway positive airway pressure (CPAP) can effectively treat nocturia in patients with obstructive sleep apnea and similar problems. In a study, CPAP significantly reduced nocturia from 2.6 to 0.7 voids per night.[3][4]

Pharmacological Therapy

Medications are most helpful in treating nocturia caused by an overactive bladder, nocturnal polyuria, and prostatic obstruction in men.[29]

Diuretic therapy

Diuretic therapy timing adjustments can significantly help reduce nocturia symptoms in patients taking short-acting agents (eg, hydrochlorothiazide or furosemide). While clinicians customarily prescribe these short-acting diuretics to be taken in the morning, taking these medications in the afternoon instead provides a noticeable benefit to most nocturia patients. The goal is to adjust the timing so the diuretic wears off when the patient goes to bed. Excess fluid tends to reaccumulate during this period in the original tissue spaces rather than pass through the kidneys, becoming extra urine. Even if patients are given twice-daily dosages, timing the afternoon dose so it wears off at bedtime is helpful to take advantage of this relatively low urine production period.[3][4][30](A1)

Alpha-blockers

Alpha-blockers are the most effective single pharmacological agents to treat male prostatic obstruction, but they offer only relatively modest reductions in nocturia in most men. They tend to work relatively quickly, usually within 30 days. However, they are less successful overall in reducing nocturia than in relieving other symptoms of prostatic hyperplasia. Alpha-blockers may help with the prostatic and urethral angle, but the exact mechanism is unclear. The risk for orthostatic hypotension is also present, especially in older adults and with older agents (eg, terazosin and doxazosin), which require dose titration. A single afternoon dose of hydrochlorothiazide added to alpha-blocker therapy may help improve nocturia but should be timed so that the diuretic has worn off by the patient's bedtime. The exact mechanism by which alpha-blockers relieve nocturia is not well understood, but theoretically, they may tend to reduce detrusor instability and overactivity indirectly by lowering urinary outflow resistance.[3][4]

A significant nocturia benefit in women from alpha-blocker therapy would be unexpected, but this has not been widely studied. However, one intriguing study by Kim et al involved 296 women with nocturia who were treated with low-dose tamsulosin and showed a significant reduction in nocturnal voiding episodes. This suggests that it might be worth trying alpha-blocker therapy in women.[31](B2)

About half of the men reporting clinically significant, benign prostatic hyperplasia (BPH) will have nocturia of ≥2 nocturnal voids a night. Treatment of BPH can help alleviate lower urinary tract symptoms, but nocturia is affected less than other urinary symptoms. Approximately 38% of patients who underwent transurethral resection of the prostate (TURP) procedures for their BPH symptoms still reported significant nocturia even 3 years after their surgery.[3][4]

Bladder-relaxing drugs

Bladder-relaxing drugs (eg, anticholinergics) will increase bladder capacity and reduce urinary frequency and urgency. Their effect on nocturia is less certain, and possibly contributing to slightly higher postvoid residuals or urinary retention in men is a concern. These drugs tend to be more effective in patients with other symptoms of overactive bladder (OAB), such as daytime frequency and urgency. In older patients or those with dementia, OAB medications that minimize CNS side effects are generally preferred, such as darifenacin, mirabegron, trospium, and vibegron. Of these, trospium is the most cost-effective as it is now generic. One reasonably effective strategy is to use a short-acting anticholinergic, such as immediate-release oxybutynin 5 mg, just before bed with the expectation that it will have worn off by morning.[3][4]

Topical vaginal estrogen

Topical vaginal estrogen has demonstrated a significant benefit in reducing nocturia in postmenopausal women. Overall, about 60% of studies reported some benefit from estrogen therapy in this group of female nocturia patients.[3][4]

Onabotulinum toxin A

Onabotulinum toxin A (ie, Botox) bladder injections have been shown to reduce nocturia episodes in patients with significant overactive bladder without nocturnal polyuria who do not respond to alternative medications or treatments.[3][4]

Antidiuretic hormone therapy

Antidiuretic hormone therapy is the recommended medical treatment for patients with nocturia due to nocturnal polyuria. Importantly, it appears to be most effective in patients with the most severe nocturia.[3][4]

Desmopressin is very similar to natural vasopressin but contains a change in 2 critical amino acids. This leaves the resulting hormone with substantial antidiuretic effects but eliminates all vasopressor activity, making it the preferred form of antidiuretic medical therapy for nocturia due to nocturnal polyuria. The use of desmopressin is usually associated with a slight increase in daytime diuresis but may lead to hyponatremia in high-risk groups. The lowest effective dose of the medication should be used, especially in older patients, but men tend to need higher dosages than women. This may be because the vasopressin V2 receptor gene is located on the X chromosome in an area relatively protected from inactivation. Overall, desmopressin therapy can reduce nocturia episodes by about 50%, as shown in 2 recent studies of 1045 patients. This effect typically takes 7 days to become clinically evident. When effective, the benefits of desmopressin therapy appear to be long-lasting.[32] Different recommended dosages exist for men and women, as females tend to be more sensitive to desmopressin. 

Desmopressin can be used together with overactive bladder and benign prostatic hyperplasia medications simultaneously and should be considered when alternative medical therapy fails to reduce nocturia after 30 days.[3][4][33] Since hyponatremia is likely to develop by the first week of therapy, a serum sodium level should be assessed after the first week, then at 1 month, and approximately every 6 months after that in patients at risk for hyponatremia.[4] Severe hyponatremia can be dangerous if left untreated, causing seizures, coma, respiratory depression, or even death. About 5% of all patients taking high-dose desmopressin were found to develop some degree of hyponatremia, defined as <130 mmol/L. Patients at risk tended to be older than 65 years, with lower body weight, higher urinary output, lower hemoglobin, reduced baseline serum sodium levels, and lower GFR compared to those who did not develop hyponatremia.(A1)

Other patients at higher risk of hyponatremia include those taking medications that can contribute to fluid retention (eg, selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants, NSAIDs, and opiates). Hyponatremia <125 mmol/L with or without symptoms or <130 mmol/L with symptoms require discontinuation of desmopressin.[3][4] Due to the tendency to cause hyponatremia, antidiuretic hormone therapy should not be used in patients with congestive heart failure (CHF), peripheral edema, polydipsia, renal failure, uncontrolled hypertension, individuals taking loop diuretics or glucocorticoids, and hyponatremia. Antidiuretic hormone therapy should also be used cautiously in patients older than 65 years and started at the lowest available therapeutically beneficial dosage, which is 25 mcg for women and 50 mcg for men.

Older patients with low baseline or chronically low serum sodium levels have a 75% risk of developing some degree of hyponatremia with prolonged desmopressin therapy, and cardiac patients have 10 times the risk. However, when lower doses are used along with a careful serum sodium monitoring plan, only mild, clinically insignificant hyponatremia is observed, even in high-risk patients. In younger patients with normal serum sodium levels without congestive heart failure (CHF), antidiuretic hormone is probably the medical treatment of choice for most nocturia patients. Other reported side effects of desmopressin include dry mouth, headaches, nausea, and edema.[3][4] 

In a randomized, double-blinded trial, desmopressin and staggered afternoon administration of furosemide is safe and effective in treating nocturia in older adults. Still, such combinations need to be monitored carefully for hyponatremia and should be used cautiously.[34] Desmopressin is available as both an oral tablet and a nasal spray. The 2 formulations are essentially equivalent in efficacy, but the oral tablets contain much larger doses of the medication, as gastrointestinal (GI) absorption of desmopressin tablets is only about 5%. The newest therapy is a desmopressin nasal spray, specifically FDA-approved for nocturia due to nocturnal polyuria in patients with at least 2 episodes of nocturia every night. This medication has shown efficacy in reducing nocturnal voidings by 50% or more in about half of all patients in clinical trials. Desmopressin nasal spray has the advantage of more consistent effectiveness and increased safety compared with oral desmopressin formulations. The desmopressin in the nasal spray has been modified with cyclopentadecanolide, which increases transmucosal absorption. Nasal formulations of desmopressin can cause nasal discomfort or congestion, nasopharyngitis, epistaxis, or bronchitis.[35](A1)

Two trials of the new nasal spray, including 1,333 patients, were recently published, and a pooled analysis was performed. The percentage of patients with a ≥50% reduction in mean nocturia episodes was compared between identical nocturia groups treated with a placebo and 2 different nasal spray dosages. The placebo group had a 30.3% response rate, the 0.83 mcg nasal spray patients had 37.9%, and the 1.66 mcg nasal spray group had 48.7% reporting significant benefits (P ≤ .0001). Notably, the incidence of significant hyponatremia, defined as less than 130 mmol/L with symptoms or less than 125 mmol/L regardless of symptoms, was ≤1%, and all were in the 1.66 mcg mmol/L treatment group, indicating a high degree of safety. Overall, the desmopressin nasal spray treatment was effective at all dosages, significantly reducing nocturia episodes, with an acceptable safety profile. In particular, the 0.83 mcg doses appeared to be the appropriate starting dose for patients at increased risk for hyponatremia (eg, patients 65 years or older).[36](A1)

Alternative Therapies

Nocturia is occasionally treated with alternative therapies that have unclear value. While there is a significant relationship between nocturia and depression, whether the treatment of depression with selective serotonin reuptake inhibitors (SSRIs) helps reduce nocturia is uncertain.[37] Nonsteroidal anti-inflammatory drugs (NSAIDs) have been proposed as a remedy for nocturia by decreasing the glomerular filtration rate. Results from several studies are conflicting and inconclusive.[38] Additionally, melatonin, a sleep aid, has shown conflicting results in formal studies but is reasonable to add in selected cases.[39][40](B2)

There is no surgical option specifically for nocturia. Prostate surgery can relieve most lower urinary tract symptoms in men. Still, nocturia is the most persistent remaining postoperative urinary symptom, suggesting that BPH is not always the etiology of this problem.[41][42] In addition to alpha-blockers, 5-alpha-reductase inhibitors (eg, finasteride, dutasteride) are also used to treat BPH in men, but studies regarding their effect on nocturia are somewhat conflicting. In the largest pooled study of 4,722 patients done by Oelke et al, greater improvements in nocturia were noted in patients on 5-alpha-reductase inhibitors than in similar groups without the medication. However, this effect generally took at least 1 year to become clinically apparent.[43](A1)

Increased physical activity late in the day appears beneficial but has not been proven by prospective studies. While not a specific treatment for nocturia, taking precautions to minimize the risk of falls by clearing obstacles, rugs, and furniture from the passageways between the bed and the nearest bathroom, adding nightlights, and using a bedside commode, bedpan, or urinal may be helpful.

Posterior tibial nerve stimulation (PTNS) uses a small transcutaneous needle to electrically stimulate the end of the tibial nerve near the ankle. A tiny amount of this electrical stimulation passes through the pudendal and pelvic sympathetic nerves to the bladder, where it improves bladder storage and reduces voidings through neuromodulation. There is also stimulation of the large somatic afferent fibers of the sacral plexus, which causes central inhibition of the micturition reflexes. Studies of posterior tibial nerve stimulation have shown modest improvement in nocturia, with an average reduction of 0.8 nocturnal voiding episodes per night. However, what the optimal PTNS treatment protocol for nocturia is, how often the therapy should be repeated, or how long the benefit will last remains unclear. Additionally, patients with pacemakers, implanted defibrillators, pelvic nerve injuries, and those who have not failed a trial of voluntary behavioral therapies should not try posterior tibial nerve stimulation therapy. While promising as a noninvasive, non-drug-based therapy, too many questions remain to be resolved before PTNS can become part of the recommended standard treatment regimen for nocturia.[44][45](B3)

Combination Therapy

Some studies have shown the advantage of combination therapy in reducing nocturia episodes. Behavioral therapies, managing sleep issues, adjusting the timing of diuretics, the elevation of the lower extremities after dinner, and judicious use of medications, particularly antidiuretic hormone, have produced the best results.[33](A1)

Differential Diagnosis

Differential diagnoses that should be considered when evaluating nocturia include:

• Benign prostatic hyperplasia (BPH)
• Bladder cancer
• Chronic bacterial prostatitis
• Prostate cancer
• Prostatitis
• Simple prostatectomy
• Urinary tract infection in males
• Urinary tract infection in pregnancy
• Urinary tract obstruction
• Uterine prolapse
• Vesicovaginal fistula

Prognosis

The prognosis of nocturia is relatively good as the disorder is bothersome, affects the quality of life, and can cause sleep deprivation. However, nocturia is rarely dangerous in itself. Still, precautions should be taken to avoid accidental falls when going to the bathroom at night. With proper evaluation and management, nocturia patients can expect to improve their quality of life and overall health significantly.[46] A careful and individualized selection of treatments to minimize adverse effects is recommended, particularly in older adults and those with memory issues.

Complications

There are no direct complications of isolated nocturia, but complications associated with the underlying etiology or treatment (eg, hyponatremia or dehydration) may arise.