Nocturia is often described as the most bothersome of all urinary symptoms and is also one of the most common. It affects 50 million people in the United States, with 10 million actually diagnosed with nocturia but only 1.5 million receiving specific therapy for it. One in three adults older than age 30 make at least two trips to the bathroom every night, and about 70% of these individuals are bothered by this. Nocturia can be associated with long-term sleep deprivation in addition to the inconvenience that it causes.
Nocturia is defined as the need for a patient to get up at night on a regular basis to urinate. A period of sleep must precede and follow the urinary episode to count as a nocturnal void. This means the first-morning void is not considered when determining nocturia episodes. Nocturnal enuresis is a completely different disorder as patients are generally not aware of a full bladder and typically experience an involuntary void while in bed. Nocturnal frequency is very similar to nocturia except that in nocturia the voiding episodes are each preceded and followed by sleep periods.
Nocturia frequently accompanies an overactive bladder not explainable by urinary tract infections or other identifiable disorders. About half of the patients with daytime urinary urgency will also have nocturia. Those with nocturia of three or more nocturnal voids per night have a significantly higher overall mortality rate than the general population.
Nocturia affects overall health and daytime functioning from loss of sleep, risks falls and injuries at night, reduces the quality of life, lowers productivity, and may even affect the health of the partner whose sleep is often disrupted as well. In particular, older adults with nocturia who make multiple nocturnal trips to the bathroom are at substantially increased risk of potentially serious falls. A quarter of all the falls that occur in older individuals happen overnight. Of these, 25% are directly related to nocturia. Patients who make at least 2 or more nocturnal bathroom visits a night, have more than double the risk of fractures and fall-related traumas. 
Nocturia leads to sleep deprivation, which can cause exhaustion, mood changes, somnolence, impaired productivity, increased risk of falls and accidents, fatigue, lethargy, inattentiveness, and cognitive dysfunction. It has been shown that over 40% of people who have a nighttime awakening will have trouble going back to sleep. It is also associated with decreased physical health, obesity, diabetes, depression, and heart disease.
There is a significant financial aspect associated with nocturia. The disorder costs an estimated $62.5 billion dollars to Americans each year due to lost productivity and sick leave associated with nocturia; primarily as a result of preventable falls, fractures, and associated injuries.
Despite its relative frequency, nocturia is often under-reported, poorly managed, and inadequately treated. Many patients are reluctant or too embarrassed to mention this problem to their physicians, or they mistakenly believe it is a normal part of aging. Compounding the problem, initial treatment of nocturia by physicians is often superficial and somewhat routine regardless of the actual underlying etiology; with men typically receiving alpha blockers and women prescribed overactive bladder medications without any substantial diagnostic investigation. Further evaluation and management of nocturia are often lacking even when these initial measures fail.
For these reasons, it may take one or even two years between the onset of significant symptoms and the beginning of physician-directed, effective nocturia treatment. This creates an obligation of physicians to ask patients about their nocturia, explain that it is an abnormal but treatable condition and offer appropriate help. Treatment should be based on the underlying cause, which requires further evaluation.
The purpose of this review is to facilitate improved diagnosis and treatment of this common and bothersome urinary disorder that often requires additional diagnostic and therapeutic measures beyond simple drug treatment of benign prostatic hyperplasia (BPH) in men or bladder overactivity (OAB) in women. A simple evaluation, based on thorough medical history, diabetes screening, a voiding diary, urinalysis, and post-void residual determination, can identify the underlying etiology (such as diabetes or nocturnal polyuria) leading to better treatment outcomes, improved quality of life scores, and substantial symptom resolution.
Nocturia is multifactorial but generally is caused by one of four 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.
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 defined as a nighttime urinary production that is greater than 20% of the total 24-hour urine volume in younger adults or more than 33% in older individuals. To calculate this, divide the total urinary volume from all nocturia episodes by the total urinary volume for 24 hours and multiply by 100 to get the nocturia episode percentage. To be considered a nocturia episode, the voiding must be preceded and followed by a period of sleep. There is usually a proportional decrease in daytime hourly urine production that results in a normal 24-hour total urinary volume. Another definition would be nocturnal urine production greater than 90 ml per hour or greater than 6.4 ml/kg of body weight. 
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. It is also associated with congestive heart failure, obstructive sleep apnea, evening use of diuretics, and chronic venous insufficiency of the lower extremities. 
Two hormones are involved in the determination of hourly urinary production:
Arginine vasopressin (AVP) is an antidiuretic hormone produced by the hypothalamus that is stored and released from the posterior pituitary gland (the hormone is manufactured by the magnocellular neurosecretory neurons in the paraventricular nucleus of the hypothalamus and the supraoptic nucleus). It is released when plasma osmolality decreases (hyponatremia) and when a patient has low blood pressure. AVP binds to the V2 receptors in the collecting ducts and distal renal tubules which increases water permeability and absorption in these areas, ultimately resulting in decreased urine production. A disruption of nocturnal arginine vasopressin (AVP) levels, where nocturia patients have a reduction in nighttime AVP levels, is a common etiology for nocturnal polyuria. AVP increases 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 is normally increased 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 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 (lithium, diuretics, tetracyclines), and venous insufficiency with peripheral edema of the lower extremities. 
Atrial natriuretic peptide (ANP) is a diuretic hormone made by cardiac muscle cells in the atria. It 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. The goal of atrial ANP secretion is to reduce blood pressure and total blood volume through enhanced renal excretion of sodium and water. ANP has virtually the opposite effect of aldosterone, which increases renal sodium and water retention. ANP excretes sodium and water. Increased secretion of ANP may occur in patients with obstructive sleep apnea, which would then lead to a 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 are mediated by elevated plasma ANP levels. The ANP level can be reduced in patients with obstructive sleep apnea by the use of continuous positive airway pressure (CPAP).
Specific effects on the kidney from ANP are as follows:
Global polyuria is another cause of nocturia. It is defined as continuous urinary overproduction throughout the day and typically results in the urinary output of more than 40 mL/kg per 24 hours (which is typically 2800 mL for a 70 kg individual). It has also been defined as a daily urinary volume of 3000 mL or more. The 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 polydipsia (iatrogenic, psychogenic or dipsogenic), hypercalcemia, drug effects, primary polydipsia, diabetes mellitus or diabetes insipidus. It has also been associated with renal insufficiency and lack of estrogen (in women).
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 made 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. The first-morning urine after such forced dehydration 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 (desmopressin).
Bladder Storage Problems
Patients with nocturia who do not appear to have polyuria are likely to have either a bladder storage problem (reduced bladder capacity, 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. 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 post-menopausal changes that affect urination. Many individuals will have bladder overactivity or other types of bladder storage issues that are aggravated by caffeine and alcohol intake, diuretic medications such as furosemide or lithium, bladder calculi, prostatic enlargement, neurogenic bladder, decompensated detrusor, atrophic vaginitis, vaginal prolapse, peripheral edema in the lower extremities, urinary infections, anxiety, non-infectious cystitis (interstitial or radiation cystitis), reduced bladder capacity from surgery, prolonged Foley catheterization, or radiation. Also, there could be a bladder emptying issue where patients have urinary retention, and the nocturia is overflow.
Insomnia, sleep apnea, and other sleep disturbances can certainly contribute or even cause nocturia. Sleep disorders should be suspected if patients are unable to not 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.
Nocturia will occur in about 50% of patients with obstructive sleep apnea, which causes nocturnal polyuria due to its effect on ANP. This results in increased 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.
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 (severe snoring, apnea, or restless leg syndrome) immediately preceded the awakening 80% of the time, and only 13% of patients with nocturia will have an initial sleep period of more than 2 to 3 hours.
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 then excrete it. This would result in increased 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 going to bed as well as the judicious use and timing of diuretics. Similarly, heart failure, nephrotic syndrome, and venous insufficiency may also cause retention of excess fluid in the lower extremities which are mobilized once the patient assumes recumbency resulting in increased urine production shortly after the patient lies down.
The use of compression stockings during the daytime, especially in the afternoon and evenings, can also help minimize tissue fluid sequestration in the lower extremities before bedtime.
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.
Other causes of nocturnal polyuria and nocturia include diseases such as congestive heart failure, nephrotic syndrome, obesity, hypertension, excessive nighttime fluid ingestion, and liver failure. Depression, use of antidepressants, and a lack of physical activity are also associated with nocturia in both men and women. It is unclear if treatment of depression will reduce the incidence of nocturia in this group of patients.
Parkinson's disease can cause nocturnal polyuria through its effect on reducing sympathetic tone which results in a solute (sodium) based diuresis.
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.
Nocturia becomes more common and more severe with age. More than 50% of men and women over the age of 60 have been diagnosed with nocturia. While the overall rate is about the same between genders, there is a higher prevalence of nocturia in younger women than in younger men. This is reversed in the elderly where older men are more likely to have symptomatic nocturia than older women. The incidence of nocturia in men aged 70 to 79 years with 2 or more nightly voids is almost 50%, and with a rapidly aging population, the incidence of clinically significant nocturia will only increase.
Contributing factors will vary somewhat with gender. Women aged 40 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.
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 but less than the black population.
Obesity appears to be an independent risk factor which increases the incidence of nocturia by 2 to 3-fold.
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, but they are rarely requested by most physicians treating 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, even though such treatments have shown only modest benefits in clinical trials, and the primary cause of nocturia for most patients (nocturnal polyuria) is best treated by other means such as nocturnal supplemental anti-diuretic hormone (desmopressin).
When diagnosing nocturia and counting nocturnal voiding episodes, the last void before going to bed is excluded, but the first-morning urination is counted if the urge to urinate is what wakes the patient. For most patients, nocturia of at least 2 times, but more likely 3 times, per night or more is usually bothersome enough to warrant treatment, but the determination about the degree of bother and the need for treatment is really up to the patient.
The typical question to identify possible nocturia might be "on the average, how many times do you wake up at night to void?" If a positive response is received, the next question would be how much sleep disruption this causes and if it bothers the patient very much. Further questioning would include fluid intake, types of liquids ingested, medications, sleep disturbances, comorbid medical disorders, and the presence of any other urinary tract symptoms.
The type and amount of fluid intake are important in the evaluation of nocturia. Larger fluid intake alone (greater than 40 mL/kg per day) may be responsible for the patient's nocturia without other identifiable causes. This may be voluntary, psychogenic, or a sign of possible diabetes mellitus or diabetes insipidus. Caffeine and alcohol intake should be reduced in the late afternoon and evening. Caffeine usage alone can result in bladder overactivity and polyuria. Ingestion of large amounts of fluids just before bedtime should be discouraged as well as general fluids between dinner and bedtime. Be aware that some elderly patients may already be somewhat dehydrated and might require extra fluid intake earlier in the day before they can safely do any evening fluid restriction before bedtime. Fluid restriction before bed may not cure nocturia but it will not make it worse and may help a little.
Various medications, foods, and supplements can affect bladder storage and diuresis. Loop diuretics should be moved to the early afternoon, so their diuretic effect ends just before bedtime. If prescribed twice a day, the evening dose should optimally be taken 6 to 8 hours before bedtime (in the mid-afternoon) to minimize their effect on nocturia. Beta-blockers, caffeine, alcohol, anticholinergics, cholinesterase inhibitors, diuretics, and medications with diuretic effects, lithium, for example, may all affect the patient's nocturia.
Contributing Co-morbid Medical Conditions
Over 50% of patients with nocturia of at least 2 times per night report at least 3 contributing, comorbid conditions. The most commonly reported include diabetes, use of diuretics, hypertension, and obstructive sleep apnea. Other medical facts to consider include other sleep disorders, vision, and ambulatory issues that might predispose to falls while going to the bathroom at night, prior history of falls, dizziness, and dementia. Obesity doubles or triples the incidence of nocturia in both genders.
Lower Urinary Tract Symptoms (LUTS)
The presence of lower urinary tract symptoms (hesitancy, straining, incomplete emptying, weak stream, frequency, urgency, intermittent stream, incontinence) may suggest the need for further urological evaluation. Irritative bladder symptoms without high post-void residual volumes (less than 200 mL) or obstruction would suggest an overactive bladder and/or neurogenicity which can usually be treated medically. Obstructive symptoms in men would suggest benign prostatic hyperplasia (BPH). These impressions can be investigated more completely with a voiding diary and a post-void residual determination.
Further evaluation including flowmetry, urodynamics, and cystoscopy can be helpful in selected cases. If confirmed, treatment of BPH with alpha-blockers (or other prostatic obstruction modalities) and the use of various bladder relaxing therapies for overactive bladder can be very helpful in alleviating the symptoms and bother of nocturia. However, care needs to be taken in those individuals who are likely to encounter side effects from these therapies, such as in elderly patients prone to dizziness being treated with alpha-blockers.
The following aspects of the physical examination are particularly relevant in the evaluation of a patient with nocturia. They are directed toward diagnosing contributing factors and comorbid health issues that may cause or exacerbate nocturia.
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 identification of the underlying etiology for optimal effectiveness. This cannot be reliably accomplished without a voiding diary.
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 for a full 24 hour day, and this is continued for three consecutive days. The timing and amount of fluid ingested are also helpful and should be recorded as well. This information, together with a post-void residual urine determination, is often sufficient to identify the type of nocturia they may have. Minimal post void residuals together with multiple, small voided amounts suggests bladder overactivity. Large volumes would indicate nocturnal or global polyuria. High, post-void residuals indicate bladder storage or prostate enlargement disorders. Despite the established usefulness of a voiding diary in diagnosing and evaluating nocturia, it has been estimated that only 37% of nocturia patients ever fill one out. 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 helpful if properly done with accurate measurements. The need for accuracy in completing the voiding diary should be carefully explained to the patient as it diagnoses the nocturia type and guides therapy. They also serve to teach patients on the benefits of optimal timing of fluid intake in managing nocturia.
Patients with severe nocturia who void only small amounts and have minimal post-void residual urine volumes are likely to have bladder overactivity. 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.
Attention should also be given to medications and timing, particularly of diuretics. It has become commonplace to see short-acting diuretics like furosemide given in the morning. These medications typically increase urinary excretion for 6 to 8 hours after ingestion. When they wear off, fluid re-accumulates in the tissues from which it originally came. After another 8 hours, these tissue spaces are full, and excess fluid now is removed by the kidneys as urine which corresponds to the overnight period if the patient has taken furosemide in the morning. This will contribute and exacerbate 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.
When Should Nocturia Be Treated?
Traditionally, treatment for nocturia was not deemed necessary unless the patient was sufficiently bothered by the nocturnal voidings to desire it. The general population and many physicians consider nocturia a natural part of aging, and patients are often unaware that it is treatable. Nocturia is generally considered pathological only when it significantly bothers the patient. Most people are not bothered by nocturia until it becomes relatively severe and affects sleep, which is usually when they have 2 or more nocturnal voids per night. However, a recent multicenter study by Park et al. found that nocturia treatment was equally successful regardless of the degree 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 report. The benefits of successful treatment are not apparent until after therapy as patients often underestimate the bother and damage nocturia does to sleep quality, general health, daily activities, and overall quality of life.
The first step in the management of nocturia is to set reasonable goals for treatment. While eliminating all nocturnal voiding episodes would be ideal, for most patients, a goal of a 50% reduction or no more than 1 to 2 voids per night is a reasonably achievable goal. Complete cessation of nocturia may not be possible.
Initial treatments involve simple measures:
Unfortunately, fluid management alone seems to have minimal impact on most cases of nocturia, but it is a reasonable place to start.
Be cautious in overly limiting fluid intake in elderly patients who may otherwise tend to become dehydrated.
Use of 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 reduce fall risk further. Consider using nightlights to help illuminate the passage to the bathroom.
Use mattress covers as necessary to help protect the bed.
Absorbent briefs, pads, and modified underwear can be used to absorb liquids preventing wetness.
Optimizing treatment of known underlying medical conditions, for example, congestive heart failure and diabetes, is recommended but has not been demonstrated to make much of a difference in reducing nocturnal voiding episodes.
Behavioral therapy, which includes pelvic floor muscle training, urge-suppression techniques, delayed voiding, fluid management, sleep hygiene, Kegel exercises, and peripheral edema management, has been shown to be reasonably efficacious both when used alone or together with pharmacological therapy in controlling nocturia.
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.
The standard, recommended, pelvic muscle training protocol is 3 repetitions of a series of eight to twelve slow pelvic contractions or compressions that are held for a duration of 6 to 8 seconds each. This is typically done 3 or 4 times a week and usually continues for at least 3 months.
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: 
Nocturia can be reduced by up to 50% in some patients just by using the simple techniques described above. 
Specific sleep disorders may predispose 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 be very effective in treating nocturia in patients with obstructive sleep apnea and similar problems. In one study, CPAP reduced nocturia from 2.6 to just 0.7 voids per night, which is quite significant.
Pharmacological therapy is most useful in treating nocturia caused by an overactive bladder, nocturnal polyuria, and prostatic obstruction in men.
Diuretic therapy timing adjustments can significantly help reduce nocturia symptoms in patients taking short-acting agents, such as hydrochlorothiazide or furosemide. While it is customary to give these short-acting diuretics in the morning, switching them to the afternoon provides a noticeable benefit to most nocturia patients. The goal is to adjust the timing so that the diuretic is wearing off when the patient goes to bed. During this period, excess fluid tends to re-accumulate in the original tissue spaces rather than pass through the kidneys becoming extra urine. Even if patients are given twice-daily dosages, it's helpful to time the afternoon dose, so it is wearing off at bedtime to take advantage of this period of relatively low urine production.
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. It is thought they may help with the prostatic/urethral angle, but the exact mechanism is unclear. There is also the risk of orthostatic hypotension, especially in the elderly and particularly with older agents such as terazosin and doxazosin which also require dose titration. A single, afternoon dose of hydrochlorothiazide added to alpha-blocker therapy may help improve nocturia, but it should be timed so 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.
A significant nocturia benefit in women from alpha-blocker therapy would be unexpected, but this has not been widely studied. However, there is one intriguing study by Kim et al. involving 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.
About half of the men reporting clinically-significant, benign, prostatic hyperplasia (BPH) will have nocturia of two or more nocturnal voids a night. Treatment of BPH can help alleviate lower urinary tract symptoms, but nocturia is affected less than other urinary symptoms. Thirty-eight percent of patients who underwent transurethral resection of the prostate (TURP) surgery for their BPH symptoms still reported significant nocturia even 3 years after their prostate surgery.
Bladder relaxing drugs such as anticholinergics, will increase bladder capacity and generally reduce urinary frequency and urgency. Their effect on nocturia is less certain, and there is a concern about possibly contributing to slightly higher post void residuals or urinary retention in men. These drugs tend to be more effective in patients with other symptoms of overactive bladder. 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.
Topical vaginal estrogen has demonstrated a significant benefit in reducing nocturia in post-menopausal women. Overall, about 60% of studies reported some benefit from estrogen therapy in this group of female nocturia patients.
Botox (onabotulinum toxin A) 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.
Anti-diuretic 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.
Desmopressin is very similar to natural vasopressin but contains a change in 2 critical amino acids. This leaves the resulting hormone with substantial anti-diuresis effects but eliminates all vasopressor activity which makes it the preferred form of anti-diuretic medical therapy for nocturia due to nocturnal polyuria. Its use 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 the elderly; but men tend to need higher dosages than women. This may be due to the vasopressin V2 receptor gene being located on the X chromosome in an area that is relatively protected from inactivation.) Overall, desmopressin therapy can reduce nocturia episodes by an average of 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.
Desmopressin can be used together with overactive bladder and benign prostatic hyperplasia medications simultaneously and should be considered when there is a failure of alternative medical therapy to reduce nocturia after 30 days.
Since hyponatremia is likely to develop by the first week of therapy, a serum sodium level should be checked after the first week, then at one month and periodically after that in patients at risk for hyponatremia. 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 less than 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 than those who did not develop hyponatremia. Other patients at higher risk of hyponatremia include those taking medications that can contribute to fluid retention (such as selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants, NSAIDs, and opiates). Hyponatremia below 125 mMol/L (with or without symptoms) or less than 130 mMol/L (with symptoms) would require discontinuation of desmopressin.
Due to its tendency to cause hyponatremia, anti-diuretic hormone therapy should not be used in patients with congestive heart failure (CHF), peripheral edema, polydipsia, renal failure (less than 50 mL per minute), uncontrolled hypertension, individuals taking loop diuretics or glucocorticoids, and in patients with low serum sodium levels. It should be used cautiously in patients older than 65 years of age and started at the lowest available therapeutically beneficial dosage which is 25 micrograms for women and 50 micrograms 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 was observed even in high-risk patients. In younger patients with normal serum sodium levels without congestive heart failure (CHF), the anti-diuretic 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.
Use of desmopressin together with staggered, afternoon administration of furosemide has been shown to be safe and effective in treating nocturia in the elderly in a randomized, double-blinded trial, but such combinations need to be monitored carefully for hyponatremia and should be used cautiously.
Desmopressin is available as both an oral tablet and a nasal spray. The two 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, which is specifically FDA-approved for nocturia due to nocturnal polyuria in patients who have 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 the clinical trials. Desmopressin nasal spray has the advantage of more consistent efficacy and increased safety compared with oral desmopressin formulations. The desmopressin in the nasal spray has been modified with cyclopentadecanolide, which increases trans-mucosal absorption. Nasal formulations of desmopressin can cause nasal discomfort or congestion, nasopharyngitis, epistaxis, or bronchitis. 
Two trials of the new nasal spray, including 1,333 patients, were recently published and a pooled analysis performed. The percentage of patients with a 50% or greater reduction in mean nocturia episodes were compared between identical nocturia groups treated with a placebo and two 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 benefit. (p=<0.0001) Importantly, the incidence of significant hyponatremia (defined as <130 mmol/l with symptoms or <125mmol/l regardless of symptoms) was 1% or less 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, resulting in a significant reduction in nocturia episodes, with an acceptable safety profile. In particular, the 0.83 dosage appeared to be the appropriate starting dose for patients at increased risk for hyponatremia such as patients 65 years or older.
Other Remedies of Uncertain Value
While there is a significant relationship between nocturia and depression, it is unclear if treatment of depression with selective serotonin reuptake inhibitors (SSRIs) helps reduce nocturia.
Non-steroidal, 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.
There is no surgical option specifically for nocturia. Prostate surgery can relieve most lower urinary tract symptoms in men, but nocturia is the most persistent remaining urinary problem after prostate surgery suggesting that BPH is not always the etiology of this problem.
In addition to alpha-blockers, 5-alpha-reductase inhibitors (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.
Increased physical activity late in the day appears beneficial but has not been proven by prospective studies.
While not a specific treatment for nocturia, it is recommended that precautions be taken 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.
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 to 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 some modest improvement in nocturia (average reduction of 0.8 nocturnal voiding episodes per night), but it remains unclear what the optimal PTNS-treatment protocol for nocturia might be, how often the therapy should be repeated or how long the benefit will last. 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 non-invasive, non-drug-based therapy, too many questions remained to be resolved before PTNS can become part of the recommended standard treatment regimen for nocturia.
Some studies have shown the advantage of combination therapy in reducing nocturia episodes. Behavioral therapies, managing sleep issues, adjusting the timing of diuretics, elevation of the lower extremities after dinner, and judicious use of medications, particularly anti-diuretic hormone, have produced the best results.
Patient Guide to the Management of Nocturia
The International Continence Society defines nocturia as "the need for an individual to wake up at night one or more times to void." Nocturia is typically found in more than 50% of all men and women older than 60 years of age. The prevalence increases with age such that the vast majority of individuals age 80 years and over will get up at least once every night to void. However, nocturia is not a "normal or inevitable" part of aging and can almost always be improved by utilizing a combination of behavioral therapies, medications, exercises, lifestyle adjustments, dietary modifications, procedures, and other therapeutic techniques.
Nocturia has significant effects on general health, vitality, and quality of life. Sleep disruption can result in daytime sleepiness, fatigue, mood changes, memory problems, cognitive dysfunction with poor concentration and performance. Nocturia is often described as the single most bothersome of all lower urinary tract symptoms, and more than 25% of all falls at home occur at night in relation to toilet visits.
Four basic conditions lead to nocturia. These are:
Patients with nocturia do not necessarily require treatment. Most of the time, evaluation, and treatment of nocturia is recommended only when it is truly bothersome to the patient (usually three or more voids each night) or significantly interferes with the patient’s sleep. An important consideration is whether or not the patient is awakened by the need to void rather than waking up for some other reason.
The patient’s usual total sleep time is also important because the number of voiding sessions per night will vary according to how much time the patient sleeps.
Knowledge of the patient's voiding pattern and the total daily urine volume is helpful. This is determined by measuring each voided urine amount for 24 hours. This is called a voiding diary (a 1 day list of the time and amount in milliliters that is voided) and is very helpful in determining the nature of the underlying problem causing the nocturia.
It turns out that some people naturally make more urine per hour when they are asleep than when they are awake due to a hormonal imbalance; while others produce far more urine all day long than average, which is common in diabetics. The 24-hour voiding diary helps clinicians diagnose these problems without any costly or uncomfortable testing. For the general population, clinicians recommend sufficient fluid intake to maintain a urine output between 1500 and 2000 mL per day, which is slightly higher than the normal average.
Managing Nocturia: The Key Points
When simpler methods fail, consider medications. If a hormone problem is to blame, then medication to correct that specific condition may be useful. A clinical trial of an overactive bladder drug, prostate medication, sleeping pill, or an anti-diuretic hormone supplements can often be helpful when simpler measures are not adequate to control the nocturia.
Care needs to be taken when using anti-diuretic medications in older patients. While effective in most patients with nocturia, they can cause a drop in serum sodium that is potentially dangerous, so most patients taking this type of medication should have their blood sodium levels checked within the first week of starting therapy and then periodically. Also, anti-diuretics are not appropriate for patients with congestive heart failure, those taking diuretics like furosemide or hydrochlorothiazide, or anyone with chronic fluid overload conditions. Your physician will advise you if a trial of an anti-diuretic type of medication is safe and appropriate for you.
If there are still bothersome problems with nocturia even after utilizing all of these remedies, there are still treatment options available, such as botox injections into the bladder, posterior tibial nerve stimulation, or placement of a bladder pacemaker.
Nocturia is not a disease in itself. It is a common but abnormal condition that is caused by a variety of disorders. It can be eliminated or at least significantly improved relatively easily in most people just by using the simple evaluation and treatment measures described.
Guideline and Quick Summary of Nocturia Treatments
Although nocturnal polyuria is the most common etiological finding in patients with bothersome nocturia, mixed causes are very common, usually requiring combination therapy.
Unfortunately, for most cases, there is no specific cure for nocturia. Establishing a reasonable patient expectation for partial resolution is important as complete eradication of significant nocturia is uncommon but most patients will be quite satisfied with a 50% reduction in their nocturnal voids.
Initial evaluation includes a blood test, to rule out diabetes and check serum sodium, a post void residual urine volume and a 24-hour voiding diary. The importance of a properly done voiding diary cannot be overemphasized as it guides diagnostic differentiation (nocturnal polyuria vs. global polyuria versus bladder overactivity) and optimal treatment selection which usually involves a combination of therapies.
Simple behavioral and lifestyle measures should be tried first, for example, limiting fluid intake in the evening, increasing daytime physical activity, minimizing bedroom distractions to enhance sleep, using a bedside commode or urinal, performing regular Kegel and similar pelvic floor exercises, decreasing caffeine ingestion, and elevating the lower extremities for several hours before bed.
Adjusting the timing of administration of short-acting diuretics to mid-afternoon will tend to reduce nocturia as will identifying and treating any sleep-related disorders. In some cases, the addition of a short-acting diuretic is helpful since it will specifically reduce sequestered tissue fluid with the intention that the diuretic effect should have worn off by bedtime and any extra fluid would then return to the tissue spaces overnight rather than be converted into urine.
Identify and treat any specific sleep disorders, such as sleep apnea.
Behavioral and lifestyle measures should be tried first. A 3-month trial is usually suggested before resorting to other treatments.
Alpha-blockers can be useful in male patients with benign prostatic hypertrophy and other lower urinary tract symptoms besides nocturia.
Bladder relaxing medications such as anticholinergics can help patients with detrusor overactivity.
Use estrogen vaginal cream in post-menopausal women with nocturia when safe and appropriate.
Anti-diuretic hormone analogues, such as desmopressin, have been shown to be the single, most effective and recommended medications for the treatment of nocturnal polyuria and nocturia but should be used cautiously, particularly in the elderly, due to their tendency to cause potentially dangerous hyponatremia in patients at risk. Serum sodium levels should be checked after the first week of therapy, at one month and then periodically in patients older than 65. Do not use anti-diuretic hormone agonists in patients on diuretics or in congestive heart failure. Women are more sensitive to desmopressin than men and should be started on a lower dose.
If bothersome symptoms remain despite all of the above treatments, it may be reasonable to consider bladder onabotulinum toxin A injections, posterior tibial nerve stimulation, or bladder pacemaker placement.
Treatment of nocturia should be directed to the underlying cause when possible. There is also a need for new treatments for nocturia that are safer and more effective than what is currently available. Until then, combination therapy, using several of the previously described treatments as needed, is recommended to reduce nocturnal voidings to a more tolerable level.
With minimal effort, using the guidelines above, it is possible for a multidisciplinary team of nurses, physician assistants, and physicians to significantly reduce nocturia episodes in the overwhelming majority of affected patients.
Nocturia is a common and bothersome urinary symptom in many patients. It significantly affects sleep, daily activities, and overall living quality. It frequently remains unrecognized, inadequately treated, and poorly managed. Early identification of the problem combined with proper treatment and closer cooperation between health care providers can significantly improve outcomes and quality of life for patients. [Level V]
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