Here is a long screed on nocturia.
Please read the article before doing the poll.
Anyone who has managed to read all this, and understand it, is entitled to 5 Continuing Education Credits from the CpapTalk University of Texas. Lesser understandings will receive lesser credits. We are grateful to the CpapTalk University of Texas for making available the Continuing Education Credits.Pamela Ellsworth, MD, FACS, FAAP, is an Associate Professor of Surgery (Urology), Warren Alpert School of Medicine, Brown University, Providence, RI.
From Urologic Nursing
Demystifying Nocturia: Identifying the Cause and Tailoring the Treatment
by Paula Laureanno, RN; Pamela Ellsworth, MD, FACS, FAAP
Abstract and Introduction
Abstract
Nocturia is a common problem with a significant impact on quality of life. The etiology of nocturia is multifactorial. Recent standardized terminology with respect to nocturia has been developed to promote more efficient communication among providers/specialists. A careful history, physical examination, and use of a voiding diary are important steps in identifying the etiology of nocturia and assist in tailoring the treatment regimen.
Objectives
1. Define nocturia.
2. Explain the impact of nocturia on sleep.
3. Discuss the evaluation of nocturia.
4. Explain the treatment options currently being used for patients with nocturia.
Introduction
Nocturia is a highly prevalent and bothersome condition with significant healthre lated consequences. Patients with nocturia may present to multiple practitioners, including a urologist, gynecologist, geriatrician, neurologist, sleep expert, endocrinologist, and primary care provider. Each practitioner/specialty may approach patients from a different perspective. Therefore, it is important that some of the basic terms surrounding nocturia have specific definitions so each individual provider refers to the same condition in his or her clinical evaluation and management.
Despite its impact, nocturia has been poorly described and managed. In 2002, the International Continence Society (ICS) defined nocturia as the complaint the individual has to wake at night one or more times to void (Abrams et al., 2003). The standardization subcommittee of the ICS further defined the terminology related to nocturia so that colleagues in different specialties could communicate effectively with respect to nocturia. Developments in the characterization of nocturia have allowed for simplified and concise approaches to the evaluation of patients presenting with nocturia. A greater understanding of the etiologies of nocturia has promoted the development of more focused treatment strategies.
Prevalence of Nocturia
Historically, the definition of nocturia has varied, making it difficult to arrive at a precise prevalence figure. Furthermore, few epidemiologic studies have been performed in the United States. Nocturia prevalence has been reported to be between 58% and 66% in women and men ages 50 to 59 years, and 72% and 91% in women and men over 80 years, respectively (Middelkoop, Smilde-van den Doel, Neven, Kamphuisen, & Springer, 1996). In a more recent national survey conducted by telephone of 5204 community-based adults with an average age of 45.8 years, 31% reported at least one void per night, and 14.2% reported at least two voids per night (Coyne et al., 2003). Studies in Japan and Austria, in which nocturia was defined as two voids or more per night, found rates of 28.5% and 11.3%, respectively (Schatzl et al., 2000; Yoshimura et al., 2004).
Impact of Nocturia
The impact of nocturia is significant. A number of studies has demonstrated that a high proportion (63% to 75%) of individuals with nocturia perceive it to be troublesome (Jolleys, Donovan, Nanchahal, Peters, & Abrams, 1994; Scarpa, 2001; Swithinbank et al., 1999). Nocturia has a significant impact on sleep, and according to Marschall-Kehrel (2004), uninterrupted sleep is necessary for the maintenance of physical, mental, and emotional well-being. In a Dutch cross-sectional epidemiologic study, nocturia was found to be one of the two most important causes of sleep disturbance in adults over 50 years of age (Middelkoop et al., 1996).
In an elderly population in Sweden, nocturia was found to be associated with an increased prevalence of sleep disorders, poorer quality sleep, and increased day time fatigue (Asplund & Aberg 1992). This population experienced frequent awakenings and a general feeling of insufficient and nonrestorative sleep. In addition, normal somatic symptoms, such as muscle cramps in the calves, leg tingling, and nocturnal sweating, are also increased in parallel with increasing number of voids (Asplund & Aberg 1992). The changes in sleep associated with nocturnal voiding result in day time sleepiness and impaired perception and balance, which can also increase the risk of fall injuries (Van Balen et al., 2001). In a study of night time falls in the elderly, it was found that the occurrence of two or more nocturnal voids was associated with a two-fold increase in falls compared with fewer than two voids (Stewart, Moore, May, Marks, & Hale, 1992).
Nocturia is associated with an increased mortality. In an epidemiologic study of over 6000 men and women 65 years of age and older in northern Sweden, 190 men and 287 women reported having three or more nocturnal voids. Fifty-four deaths were noted among the men with three or more nocturnal voids and 34 deaths among the women. The death rate was twice as high for males and females, with three or more voids per night as all men and women in the study (Asplund, 1999). Finally, there is some evidence to suggest that sleep deprivation may have an effect on the function of the immune system (Benca & Quintas, 1997) and that sleep is important in maintaining host defenses (Irwin et al., 1996).
Terminology Related to Nocturia
ICS has developed several definitions for terms that apply to the evaluation and identification of the cause of an individual's nocturia (van Kerrebroeck et al., 2002). Weiss and colleagues have also identified several parameters pertinent to the evaluation of nocturia (Weiss, Blaivas, & Stember, 1998). Table 1 lists terms and definitions with respect to nocturia. Adoption of these terms by health care professionals evaluating and managing nocturia will allow for a more efficient communication among providers/specialties.
Table 1. Nocturia Terminology and Definitions
Term...................................... Definition
Night time................................ The period of time between going to bed with the intention of sleeping and waking with the intention of rising.
Nocturia................................... The number of voids recorded during a night's sleep. Each void is preceded and followed by sleep.
Nocturnal urine volume................. Total volume of urine passed during the night including the first morning void.
Rate of nocturnal urine production..... The nocturnal volume/time asleep (for example, night), measured in ml/minutes.
Nocturnal polyuria....................... The production of an abnormally large volume of urine during sleep – Should include all urine produced after going to bed and the first void after arising, nocturnal volume greater than 20% to 30% of total 24-hour urine volume (age dependent).
24-hour voided volume. ................. Total volume of urine voided during a 24-hour period (first void to be discarded; 24 hours begins at the time of the next void).
Polyuria................................... 24-hour voided volume in excess of 2800 ml in a 70 kg person or more than 40 ml/kg.
Night time frequency.................... The number of voids recorded from the time the individual goes to bed with the intention of going to sleep, to the time the individual wakes with the intention of rising.
First morning void....................... The first void after waking with the intention of rising.
Maximum voided volume (MVV)........ The largest single voided volume measured in a 24-hour period.
Nocturia index (Ni)...................... Mean-measured nocturnal urine volume (NUV) divided by the functional bladder capacity (deduced from the frequency volume chart). An Ni greater than 1 means that nocturnal urine production is greater than the functional bladder capacity.
Nocturnal polyuria index (NPi).......... Mean-measured nocturnal volume/24-hour voided volume. NPi greater than 33% implies nocturnal polyuria as opposed to diurnal polyuria.
Nocturia bladder capacity index (NBCi) The difference between the actual number of nocturnal voids (ANV) and the predicted number of nocturnal voids (PNV). The greater the NBCi, the more often nocturia is occasioned by nocturnal voided volumes smaller than the MVV.
Predicted number of nocturnal voids.. Ni minus 1.
Source: Abrams et al., 2003.
Types of Nocturia
Nocturia may be related to a variety of causes. These causes can be divided into four categories:
polyuria,
nocturnal polyuria,
bladder storage problems,
and mixed nocturia.
Polyuria
Polyuria is defined as a total 24-hour urine volume greater than 40 ml/kg.
Causes of Polyuria
Diabetes Mellitus Type 1 (IDDM) and Type 2 (NIDDM)
Diabetes insipidus
Pituitary
Renal
Secondary nephrogenic due to:
Lithium
Electrolyte disturbances – Hypercalcemia, hypokalemia
Primary polydipsia
Psychogenic
Dipsogenic
Iatrogenic
Nocturnal Polyuria
Urine output normally decreases during the night. This appears to be related to a corresponding increase in secretion of antidiuretic hormone (ADH). As ADH secretion increases, there is increased resorption of water from the renal tubule, resulting in lower volumes of concentrated urine. The urine output during sleep can be expressed as a percentage of the total urine output over 24 hours if the 24-hour urine output is normal. This value can vary considerably from person to person and normally increases with age. Healthy, young adults from 21 to 35 years of age produce 14% ± 4% of their total urine output between the hours of 11:00 p.m. and 7:00 a.m. (95% confidence interval [CI] 10% to 19%) (Robertson et al., 1999), whereas older adults produce an average of 34% ± 15% (95% CI 30% to 36%) (Rembratt, Robertson, Norgaard, & Andersson, 2000).
Nocturnal polyuria is defined as a night time urine output greater than 20% of the daily total in young adults and 33% in older adults, with the value for middle age somewhere in the middle of these two age extremes (Carter, 1992). Exceptions to this stratification are individuals with diabetes insipidus and those whose sleeping patterns vary greatly from the normal eight-hour night time sleep pattern. Causes of nocturnal polyuria can be divided into those that cause a water diuresis or a solute/water diuresis (see Table 3 ).
Congestive heart failure, low blood volume, venous stasis disease, and high intake of salt may result in third spacing of fluid in the lower extremities, which can contribute to fluid retention associated with nocturnal polyuria, as can renal insufficiency (Weiss & Blaivas, 2000, 2002). With certain respiratory conditions such as sleep apnea, hypoxia in the lungs can lead to pulmonary vasoconstriction and increased concentrations of peptides responsible for the elimination of sodium in the urine. This can result in increased secretion of water while the patient is sleeping (Krieger et al., 1993).
Table 3. Causes of Nocturnal Polyuria
Secondary to Water Diuresis
Circadian defect in secretion or action of antidiuretic hormone
• Primary (idiopathic)
• Secondary
→ Excessive intake of fluid, caffeine, alcohol
→ CNS lesion from CVA which affects hypothalamic-pituitary axis
Solute/Water Diuresis
Congestive heart failure
Autonomic dysfunction
Sleep apnea syndrome
Renal insufficiency
Estrogen deficiency
Bladder Storage Problems – Reduced Voided Volumes
In both men and women, the mean voided volumes at night are on average one-third larger than those in the day time, irrespective of the number of nocturnal micturition episodes (Asplund, 1992). If the individual's actual number of night time voids (ANV) is greater than the predicted number of night time voids (PNV), then the night time voids are occurring at volumes less than the individual's actual bladder capacity. The greater the difference between the predicted and actual numbers of nocturnal voids, the more the nocturia may be attributed to reduced voided volumes secondary to an underlying urologic disorder as opposed to a medical disorder (Stember, Weiss, Lee, & Blaivas, 2007). Problems with bladder storage may be related to decreased bladder capacity, decreased nocturnal bladder capacity, detrusor overactivity, and conditions that can cause bladder irritations (Weiss & Blaivas, 2002).
Bladder Storage Problems
Decreased functional bladder capacity
Bladder outlet obstruction with increased post-void residual
Cancer of the bladder, prostate, or urethra
Decreased bladder contractility with increased post-void residual
Decreased nocturnal bladder capacity
Detrusor over-activity
Idiopathic (overactive bladder)
Secondary to neurogenic causes (multiple sclerosis)
Bladder irritation
Urinary tract infection
Interstitial cystitis/painful bladder syndrome
Bladder calculi
Source: Weiss & Blaivas, 2002.
Mixed Nocturia
Patients with nocturia may have more than one etiology, such as both nocturnal polyuria (NP) and reduced voided volumes. In a study of 94 nocturic patients, nocturia was due to NP in 7%, reduced voided volumes in 57%, diurnal polyuria in 23%, and a mixture of NP and reduced voided volumes in 36% (Weiss et al, 1998).
Evaluation of Nocturia
An important first step in the evaluation of nocturia is establishing whether the individual has awakened at night to void or voids because the individual is already awake. Health care providers need to be aware that there may be discrepancies between the actual causes of the patient's awakening and the reason given. In a sleep study performed by Pressman, Figueroa, Kendrick-Mohamed, Greenspon, and Peterson (1996), explanations provided by patients as to the cause of their awakenings rarely matched the "objective" findings from polysomnograms.
An accurate history is crucial to determine if there is a treatable underlying medical condition present as listed in Tables 2, 3, and 4. If the patient has risk factors for obstructive sleep apnea, further evaluation with a specialist may be warranted (see Table 5). Eliciting any prior history of urinary complaints, treatments and the patient's medication usage, the pattern of fluid intake is also an important component.
The voiding diary is the cornerstone of the evaluation of nocturia. It provides important information regarding patterns of micturition, mean and total voided volume, and maximum voided volume. The physical examination is useful to rule out a possible underlying neurologic condition, a distended bladder secondary to increased post-void residual, and benign or malignant enlargement of the prostate, and to assess for lower extremity edema and venous stasis disease.
Risk Factors for Obstructive Sleep Apnea
Excessive weight
Family history of sleep apnea
Neck circumference greater than 17.5 inches
Use of alcohol, sedatives, or tranquilizers
Hypertension
Smoking
Narrowed airway – Naturally or secondary to enlarged tonsils or adenoids
Ethnicity – African Americans have highest risk than any other ethnic group
Male sex
Diabetes mellitus
Postmenopausal
GERD
Older age – 3 times more likely in adults older than 65 years of age
Polycystic ovary syndrome – 3 times more likely
In patients with diurnal polyuria, an overnight water deprivation test (WDT) can distinguish between diabetes insipidus and primary polydipsia (Adam, 1997). If the osmolality of the first morning void is greater than 800 mOsm/kg H2O, one can conclude there is both normal secretion of ADH and renal response to ADH. Polyuria with a normal WDT is indicative of primary polydipsia If the WDT is abnormal, then the patient either has deficient production of ADH (central diabetes insipidus) or an inappropriate renal response to ADH (nephrogenic diabetes insipidus).
A renal concentrating capacity test (RCCT) can distinguish between central and nephrogenic diabetes insipidus. This is accomplished by administering demopressin (Minirin®, Ferring®, DDAVP®) orally (0.4 mg) or intranasally (40 mcg or 0.4 ml) after restricting water. The bladder is emptied, and a urine sample is collected three to five hours later. A urine osmolality greater than 800 mOsm/kg demonstrates normal renal concentrating ability indicating the patient has central diabetes insipidus. If the RCCT yields low urinary osmolality (< 500 mOsm/kg), polyuria is due to nephrogenic diabetes insipidus (Weiss, Weinberg, & Blaivas, 2008).
Treatment of Nocturia
Once a patient has undergone an evaluation of nocturia and the etiology has been defined, treatment will then be tailored to the specific etiology. A formalized diagnostic and treatment algorithm may be useful in directing clinical care. An algorithm developed and used in the authors' clinical practice is presented in Figure 1 (not posted).
In most individuals, the first steps in treatment are lifestyle and behavioral changes. Fluid intake in the evening should be discontinued, if possible, and alcohol and caffeine consumption reduced. For individuals with lower extremity edema and venous stasis, the use of compression stockings and afternoon leg elevation may combat fluid retention before retiring at night. The use of nasal continuous positive airway pressure can be used to treat sleep apnea, therefore reducing associated nocturia (Appell & Sand, 2008).
Diuretic use is associated with a two-fold increase in nocturia (Asplund, 2003). Diuretics are generally taken in the morning, which can lead to increased thirst and increased fluid intake later in the day, thereby increasing nocturnal urine output (Asplund, 2007). If furosemide (Lasix®) is taken six hours before going to bed, nocturnal diuresis may be reduced (Reynard, Cannon, Yang, & Abrams, 1998). In a randomized, placebo-controlled trial comparing night time doses of placebo and bumetamide (Bumex®) 1 mg, bumetamide treatment decreased nocturia episodes by 25% compared with placebo (Pedersen & Johansen, 1988).
Pharmacologic Therapy in the Management of Nocturia
There are no FDA-approved agents for the treatment of nocturia. However, depending on the etiology of the nocturia, desmopressin and antimuscarinic agents have been used to treat the nocturia. An oral desmopressin "melt" (Minirin, Ferring, DDAVP), an intranasal formulation of desmopressin (SER-120®) (Serenity Pharmaceuticals and licensed by Allergan), is currently being evaluated for nocturia in clinical trials.
Desmopressin (DDAVP)
Desmopressin is a synthetic analog of the antidiuretic hormone arginine vasopressin. Vasopressin is secreted from the pituitary gland in response to changes in plasma osmotic pressure and increases water reabsorption from the kidney. As an analog of arginine vasopressin, desmopressin increases urine osmolality and decreases total urinary volume (Lose, Lalos, Freeman, van Kerrebroeck, & the Nocturia Study Group, 2003).
The molecular structural differences between desmopressin and arginine vasopressin give desmopressin a longer duration of action, an increase in antidiuretic activity, and a decrease in vasopressor activity (Cvetkovic & Plosker, 2005). In healthy men aged 55 to 70 years, oral desmopressin has a half-life of about three hours, with only minor differences between day time and night time values. The median time required to reach the maximum serum concentration is one-and-a-half hours regardless of administration time.
The bio availability of desmopressin is low (8%) (Rembratt, Graugaard-Jensen, Senderovitz, Norgaard, & Djurhuus, 2004). The gastrointestinal absorption of desmopressin is decreased and delayed if it is administered within one-and-a-half hours after a meal. However, there is no observed effect of food on the pharmacodynamics of oral desmopressin. Urine volume is decreased, and urine osmolality is increased to similar extents, regardless of the timing of ingestion of food and intake of desmopressin (Rittig, Jensen, Jensen, & Pederson, 1998).
Desmopressin has been used since the 1960s for the treatment of diabetes insipidus and from the early 1980s for the treatment of nocturnal enuresis in children (Asplund, 2007). The first reports of the use of desmopressin for nocturia were published in 1993 (Asplund & Aberg, 1993a, b). The recommended dose of desmopressin for nocturia is 0.1 mg to 0.4 mg orally at bedtime (Asplund, Sundberg, & Bengtsson, 1998). It is recommended to start at the lowest dose and assess the patient's response.
Responders to treatment will in most cases note a reduction in nocturnal urine output and nocturnal voids after the first dose or at least after a few days (Asplund, 1992, 1995; Asplund et al., 1998). A good response from treatment is a nocturnal urine output of 350 to 450 ml, including the volume of the void in the morning and one, possibly two, nocturnal micturition episodes. If this goal is not achieved, then the dose of desmopressin can be increased within one week. Serum sodium concentration should be assessed before and three to four days after starting desmopressin, as well as three to four days after each increase in dose.
Efficacy of Desmopressin
The efficacy of desmopressin in treating nocturia has been evaluated in different populations, including men, women, and older adults, in both short-term and long-term studies (Cannon, Carter, & McConnell, 1999; Lose et al., 2003; Mattiasson, Abrams, van Kerrebroeck, Walter, & Weiss, 2002; Rembratt, Norgaard, & Andersson, 2003). The greater the severity of a disorder of the vasopressin system, the higher the sensitivity to desmopressin, and substantial reductions in nocturia and nocturnal polyuria have been noted with the lowest dose of desmopressin (0.1 mg) in individuals with pronounced symptoms (Asplund et al., 1998; Kuo, 2002).
In a study of 30 older adults (both men and women) (mean age 75.4 ± 6.6 years) with three or more micturition episodes per night and nocturnal polyuria treated with oral desmopressin 0.1 mg at bedtime for four weeks, nocturnal urine output decreased from a mean of 955 ± 255 ml to 522 ± 210 ml (p < 0.0001). The mean number of nocturnal voiding episodes was also decreased from 5.20 ± 1.16 to 2.24 ± 1.12 per night (p < 0.0001) (Kuo, 2002).
Desmopressin use in nocturia has been shown to improve sleep. In a three-week study by Mattiasson and colleagues (2002), the mean duration of the first sleep period increased by 59% (from 2.7 to 4.5 hours) in the desmopressin group, compared with an increase of 21% (from 2.5 to 2.9 hours) in the placebo group (p < 0.001). Another study evaluated the effects of 12 months of treatment in adult men and women with the optimal dose of desmopressin (0.1 mg, 0.2 mg or 0.4 mg) or placebo (Lose et al., 2004). The mean duration of the first sleep period gradually increased in both men (from 157 minutes to 288 minutes) and women (from 142 minutes to 310 minutes) from baseline to 12 months.
The feeling of being well rested in the morning and better day time performance improved in parallel with the sleep improvement. At follow up one month after treatment had been discontinued, the mean duration of the first sleep period had decreased, confirming that the increase was a treatment-related effect (Lose et al., 2004).
Safety and Tolerability of Desmopressin
When treating nocturics with desmopressin, it is important that excess fluid intake be avoided after the medication has been taken. Desmopressin should be discontinued if edema in the legs or other signs of fluid retention occurs. If the antidiuretic effect of desmopressin persists into the day time, the dose may need to be reduced or the desmopressin discontinued (Asplund, 2007).
Adverse events associated with desmopressin treatment include headache, nausea, dizziness, and hyponatremia. The risk of hyponatremia with desmopressin use appears to increase with age and decreasing baseline serum sodium concentration (Rembratt, Riis, & Norgaard, 2006). A systematic review of older adults treated with oral or nasal desmopressin showed an incidence of 7.6% for hyponatremia (Weatherall, 2004). Desmo pressin should be avoided in patients with primary polydipsia and related polyuria, cirrhosis of the liver, renal failure, and congestive heart failure (Abrams, Mattiasson, Lose, & Robertson, 2002).
Treatment of Nocturia Related to Low Bladder Capacity
Pharmacologic Treatment
Few clinical trials have specifically evaluated the use of medications for treating nocturia by improving bladder capacity. While the evidence base for use of antimuscarinic agents to treat nocturia has not been established, these drugs have been investigated in studies of over-active bladder (OAB) syndrome, of which nocturia is a common symptom.
Darifenacin (Enablex®). The effects of darifenacin on nocturia are variable. Improvements in weekly nocturia episodes were observed in one 12-week, placebocontrolled trial (Hill, Khullar, Wyndaele, Lheritier, & the Darifenacin Study Group, 2006), while no improvement was seen in another trial of similar duration (Haab, Stewart, & Dwyer, 2004). In a pooled analysis of three phase III studies to evaluate the efficacy, tolerability, and safety of darifenacin, the decrease in number of nocturnal awakenings per week caused by OAB was greater with darifenacin than placebo, although the between-group difference was not statistically significant.
The median change from baseline for darifenacin 7.5 mg was -1.7 vs. -0.8 for placebo and -1.9 for darifencacin 15 mg versus -1.1 for placebo (Chapple et al., 2005). In a two-year, non-comparative, open-label extension study with darifenacin 7.5 mg and 15 mg, the median change in nocturnal awakenings at 24 months was -1.5 (14.3% change) (Haab et al., 2006).
Fesoterodine (Toviaz®). In a randomized, placebo-controlled, double-blind multi-center trial performed in the United States comparing fesoterodine 4 mg or 8 mg to placebo, fesoterodine 4 mg showed significant improvement in mean change from baseline compared to placebo for the number of nocturnal micturitions (p < 0.05). The mean percent change from baseline for placebo was -25.5%, for fesoterodine (4 mg) it was -33.3%, and for fesoterodine (8 mg) it was -25% (Nitti et al, 2007). Several other clinical trials with fesoterodine have demonstrated a decrease in nocturnal voids/24 hours. However, when compared to placebo, the difference was not statistically significant (Chapple et al., 2007; Dmochowski et al., 2010; Hesrchorn et al., 2009).
Oxybutynin (Ditropan®). Published data are limited regarding the efficacy of oxybutynin for nocturia. In a placebo-controlled trial investigating the effects of behavioral and drug therapy on nocturia in older incontinent women, oxybutynin decreased nocturia episodes significantly more than placebo, though these effects were less than those observed with behavioral modification (Johnson, Burgio, Redden, Wright, & Goode, 2005).
Solifenacin (Vesicare®). An analysis of whether patients with OAB and nocturia achieved relief of night time voiding symptoms when treated with solifenacin and if having nocturnal polyuria affected the response was performed using pooled data from four phase III clinical trials. The first analysis looked at reductions in nocturia episodes after treatment with solifenacin (5 mg or 10 mg), and a second analysis was performed in patients with and without nocturnal polyuria. Patients were considered to have nocturnal polyuria if their nocturnal urinary volume was greater than the percentage of hours in the day asleep multiplied by the 24-hour urine volume (Weiss & Blaivas, 2000). Statistically significant reductions in nocturia episodes were noted in patients treated with solifenacin.
Median reductions were -35.5% for 5 mg solifenacin and -36.4% for 10 mg solifenacin compared to -15% for placebo (p = 0.021 and p < 0.001, respectively). In addition, significantly more patients treated with solifenacin versus placebo achieved a median nocturic frequency of one episode/night or fewer. Solifenacin reduced nocturia episodes only in patients without nocturnal polyuria. In those patients treated with solifenacin without nocturnal polyuria, more than 60% achieved an average of one nocturic episode nightly or fewer by the end of the study (Brubaker & Fitzgerald, 2007).
Tolterodine (Detrol®). The efficacy and tolerability of night time tolterodine dosing on urgency-related micturitions in patients with OAB and nocturia were assessed. In this study, changes in the number of night time and 24-hour micturitions were analyzed using a 5-point urgency rating scale for each micturtition, ranging from no urgency to severe urgency and urgency urinary incontinence. Tolterodine ER was noted to decrease the total number of nocturnal micturitions, compared to placebo, though the difference was not statistically significant. Tolterodine ER did, however, significantly reduce OAB-related and severe OABrelated nocturnal micturitions compared to placebo. No effect was reported on non-OAB micturitions (Rackley et al., 2006).
A six-month, open-label trial in 43 men with BPH-related symptoms who failed alphablocker therapy was conducted. These men were treated with tolterodine ER 4 mg and demonstrated a reduction in nocturnal voids from 4.1 episodes per night to 2.9 episodes per night (Kaplan, Walmsley, & Te, 2005).
Trospium chloride IR and XR (Sanctura®). A multi-center, placebo-controlled trial involving 134 men and 389 women with OAB and urge incontinence was conducted. The sample was randomized to receive either trospium chloride 20 mg twice a day (BID) or placebo for 12 weeks. The trospium chloride-treated pa tients showed a statistically significant decrease in the average number of nocturnal voids after week four (p < 0.001) and week 12 (p < 0.05), but not at week one (Zinner et al., 2004).
An analysis using pooled data from two identically designed phase III trials involving males and females compared trospium chloride extended release to placebo. A significantly greater mean reduction from baseline in nocturnal voids (0.8 vs. -0.6, p = 0.006) was noted. Reductions in nocturnal voids were accompanied by significant improvements in sleep-related quality-of-life domains (Ginsberg, Oefelein, & Ellsworth, 2009).
A subgroup analysis of male patients from two large, phase III, double-blind, randomized, placebo-controlled studies evaluated tropsium chloride extended release versus placebo. A greater decrease from baseline with trospium chloride extended release compared to placebo was noted for nocturnal voids (-0.9 vs. -0.5, p < 0.05) (MacDiarmid, Ellsworth, Ginsberg, Oefelein, & Sussman, 2009).
Nocturia and Benign Prostatic Hyperplasia (BPH)
Variable results have been demonstrated for the effects of alpha blockers and 5-alphareductase inhibitors on nocturia in men with benign prostatic hyperplasia (BPH). In the VA cooperative study program trial, 1978 men with BPH had baseline nocturia of 2.5 episodes per night. They were randomized to receive terazosin (Hytrin®), finasteride (Proscar®), terazosin plus finasteride, or placebo. Nocturia episodes decreased to around two per night for all groups, including placebo. No significant difference was found among any treatment arms, including placebo (Johnson et al., 2003).
In an observational study evaluating an extended release formulation of alfuzosin (Uroxatral®) 10 mg/day, 144 of the males had more than two nightly voids at the start of the study, and 51.4% improved to two nightly voids or fewer after nine days of treatment. At three months on treatment, 60.4% had two nightly voids or fewer (Roehrborn, van Kerrebroeck, & Nordling, 2003). A pooled analysis of three double-blind studies noted alfuzosin improved nocturia in patients with BPH (Saad et al., 2005). In a long-term study, the occurrence of three or more nocturnal voiding episodes was decreased by two-thirds after three months of therapy with alfuzosin, with these results being maintained at two years (Elhilali et al., 2006).
The effectiveness of single or combination drug therapy on nocturia in men with lower urinary tract symptoms suggestive of BPH was analyzed. The analysis included 2583 men with at least one nocturnal void per night who were randomized to receive doxazosin (Cardura®) alone, finasteride alone, combination therapy, or placebo, and were followed for at least 12 months of the four-year study period. Doxazosin alone and combination therapy led to a statistically significant reduction in nocturnal voids. Mean nocturia was reduced at one year by 0.35, 0.40, 0.54, and 0.58 for placebo, finasteride, doxazosin, and combination groups, respectively. Similar results were seen at one year and four years (Johnson et al., 2007). The clinical impact of this change on quality of life was not assessed.
5-Alpha-Reductase Inhibitors
Little data are available regarding the effect of 5-alphareductase inhibitors on nocturia. Two studies have demonstrated no effect of finasteride monotherapy on nocturia (Johnson et al., 2003, 2007). In a prospective, multi-center, open-label study evaluating the effect of dutasteride 0.5 mg/day on the symptoms of BPH, a decrease from baseline at 12 weeks and 24 weeks with respect to Q7 of the International Prostate Symptom Score (IPPS) was noted. Q7 of the IPPS refers to how many times a person most typically gets up to urinate from bedtime until getting up in the morning. Significant reductions of -0.5 and -0.6 nocturnal voids were also noted at 12 weeks (p < 0.001 for each) (Desgrandchamps, Droupy, Irani, Saussine, & Comenducci, 2006).
Summary
Nocturia is a prevalent and bothersome symptom that has significant impact on health and quality of life. Terminology has now been adopted that allows health care providers across all specialties to "speak the same language" as it pertains to nocturia. This will greatly facilitate the evaluation and subsequent management of nocturia. The voiding diary is the cornerstone to the evaluation of a patient presenting with nocturia, and the history and physical examination allow for further evaluation of treatable causes of nocturia. Classifying nocturia into one of four categories (diurnal polyuria, nocturnal polyuria, bladder storage problem, and mixed nocturia) allows for a tailored treatment regimen. Use of a diagnostic and treatment algorithm can help direct clinical decision making in nursing practice.
Although behavioral and lifestyle changes may help the overall population suffering from nocturia, an individualistic approach identifying and treating medical conditions that cause nocturia with appropriate pharmacologic therapies may have a significant impact on nocturia.
Desmopressin has been demonstrated to be effective in those individuals suffering from nocturnal polyuria. Some improvement in nocturnal voids and nocturnal OAB-related voids has been demonstrated with various antimuscarinic agents. In males suffering from bladder outlet obstruction secondary to BPH, reduction in nocturnal voids has been demonstrated in clinical trials with both alpha-adrenergic receptor blockers as well as 5-alpha-reductase inhibitors. Currently, there are no pharmacologic therapies approved by the Food and Drug Administration for the treatment of nocturia; however, two formulations of desmopressin are currently in clinical trials.
References
* Abrams, P., Cardozo, L., Fall, M., Griffiths, D., Rosier, P., Ulmsten, U., … Wein, A. (2003). The standardization of terminology in lower urinary tract function: Report from the standardization sub-committee of the International Continence Society. Urology, 61, 37.
* Abrams, P., Mattiasson, A., Lose, G.R., & Robertson, G.L. (2002). The role of desmopressin treatment in adult nocturia. British Journal of UrologyInternational, 90, 32–36.
* Adam, P. (1997). Evaluation and management of diabetes insipidus. AmericanFamily Physician, 55, 2146–2153.
* Appell, R.A., & Sand, P.K. (2008). Nocturia: Etiology, diagnosis and treatment. Neurourology andUrodynamics, 27, 34–39.
* Asplund, R. (1992). Micturition habits anddiuresis in relation to sleep and wellbeingin elderly subjects with emphasison antidiuretic hormone (thesis). Stockholm: Karolinksa Institute.
* Asplund, R. (1995). The nocturnal polyuria syndrome (NPS). GeneralPharmacology, 26, 1203–1209.
* Asplund, R. (1999). Mortality in the elderly in relation to nocturnal micturition. British Journal of UrologyInternational, 84(3), 297–301.
* Asplund, R. (2003). Nocturia in relation to sleep, somatic diseases and medical treatment in the elderly. BritishJournal of Urology International, 91, 302–303.
* Asplund, R. (2007). Pharmacotherapy for nocturia in the elderly patient. DrugsAging, 24(4), 325–343.
* Asplund, R., & Aberg, H. (1992). Health of the elderly with regard to sleep and nocturnal micturition. ScandinavianJournal of Primary Health Care, 10, 98–104.
* Asplund, R., & Aberg, H. (1993a). Desmopressin in elderly women with increased nocturnal diuresis: A shortterm study. British Journal of Urology,72, 42–45.
* Asplund, R., & Aberg, H. (1993b). Desmopressin in elderly subjects with increased nocturnal diuresis: A two-month study. ScandinavianJournal of Urology Nephrology, 27, 77–82.
* Asplund, R., Sundberg, B., & Bengtsson, P. (1998). Desmopressin for the treatment of nocturnal polyuria in elderly subjects: A dose titration study. British Journal of Urology, 82, 642–646.
* Benca, R.M., & Quintas, J. (1997). Sleep and host defenses: A review. Sleep,20, 1027–1037.
* Brubaker, L., & Fitzgerald, M.P. (2007). Nocturnal polyuria and nocturia relief in patients treated with solifenacin for overactive bladder symptoms. International Urogynecology,18, 737–741.
* Cannon, A., Carter, P.G., & McConnell, A.A. (1999). Desmopressin in the treatment of nocturnal polyuria in the male. British Journal of UrologyInternational, 84, 20–24.
* Carter, P.G. (1992). The role of nocturnalpolyuria in nocturnal urinary symptomsin healthy elderly males. MDthesis. Bristol, United Kingdom.
* Chapple, C., Steers, W., Norton, P., Millard, R., Kralidis, G., Glavind, K., & Abrams, P. (2005). A pooled analysis of 3 phase III studies to evaluate the efficacy, tolerability and safety of darifenacin, a muscarinic M3 selective receptor antagonist, in the treatment of overactive bladder. British Journalof Urology International, 95(7), 993–1001.
* Chapple, C., Van Kerrebroeck, P., Tubaro, A., Haag-Molkenteller, C., Forst, HT., Massow, U., … Brodsky, M. (2007). Clinical efficacy, safety and tolerability of once-daily fesoterodine in subjects with overactive bladder. European Urology, 52, 1204–1212.
* Coyne, K.S., Zhou, Z., Bhattacharyya, S.K., Thompson, C.L., Dhawan, R., & Versi, E. (2003). The prevalence of nocturia and its effect on health-related quality of life and sleep in a community sample in the USA. British Journal ofUrology International, 92(9), 948–954.
* Cvetkovic, R.S., & Plosker, G.L. (2005). Desmopressin: in adults with nocturia. Drugs, 65, 99–109.
* Desgrandchamps, F., Droupy, S., Irani, J., Saussine, C., & Comenducci, A. (2006). Effect of dutasteride on the symptoms of benign prostatic hyperplasia, and patient quality of life and discomfort, in clinical practice. BritishJournal of Urology International, 98, 83–88.
* Dmochowski, R.R., Peters, K.M., Morrow, J.D., Guan, Z., Gong, J., Sun, F., … Staskin, D.R. (2010). Randomized, double-blind placebo-controlled trial of flexible-dose fesoterodine in subjects with overactive bladder. Urology, 75(1), 62–68.
* Elhilali, M., Emberton, M., Matzkin, H., van Moorselaar, R.J., Hartung, R., Harving, N., … the ALF-ONE Study Group. (2006). Long-term efficacy and safety of alfuzosin 10 mg once daily: A 2-year experience in "reallife" practice. British Journal ofUrology International, 97, 513–519.
* Ginsberg, D.A., Oefelein, M., & Ellsworth, P.I. (2009). Once-daily trospium chlorideextended release provides 24-hour coverage of daytime and nocturnalsymptoms of overactive bladder:An integrated analysis of two phaseIII trials. Oral presentation at the Western Section Meeting of the AUA, Las Vegas, 2009.
* Haab, F., Corcos, J., Siami, P., Glavind, K., Dwyer, P., Steel, M., … Steers, W.D. (2006). Long-term results with darifenacin for overactive bladder: Results of a 2-year open label extension study. British Journal of UrologyInternational, 98, 1025–1032.
* Haab, F., Stewart, L., & Dwyer, P. (2004). Darifenacin, an M3 selective receptor antagonist, is an effective and well-tolerated once-daily treatment for overactive bladder. European Urology, 45, 420–429.
* Herschorn, S., Swift, S., Guan, Z., Carlsson, M., Morrow, J.D., Brodsky, M., Gong, J. (2009). Comparison of fesoterodine and tolterodine extended release for the treatment of overactive bladder: a head-to-head placebo controlled trial. British Journal ofUrology International, 105, 58–66.
* Hill, S., Khullar, V., Wyndaele, J.J., Lheritier, K., & the Darifenacin Study Group. (2006). Dose response with darifenacin, a novel once-daily M3 selective receptor antagonist for the treatment of overactive bladder: Results of a fixed dose study. International Urogynecology Journalof Pelvic Floor Dysfunction, 17, 239–247.
* Irwin, M., McClintick, H., Costlow, C., Fortner, M., White, J., & Gillin, J.C. (1996). Partial night sleep deprivation reduces natural killer and cellular immune responses in humans. TheFederation of American Societies forExperimental Biology, 10, 643–653.
* Johnson, T.M., 2nd, Burgio, K.L., Redden, D.T., Wright, K.C., & Goode, P.S. (2005). Effects of behavioral and drug therapy on nocturia in older incontinent women. Journal of the AmericanGeriatric Society, 53, 846–850.
* Johnson, T.M., 2nd, Burrows, P.K., Kusek, J.W., Nyberg, L.M., Tenover, J.L., Lepor, H., … Weiss, J.P. (2007). The effect of doxazosin, finasteride and combination therapy on nocturia in men with benign prostatic hyperplasia. Journal of Urology, 178, 2045–2051.
* Johnson, T.M., 2nd, Jones, K., Williford, W.O., Kutner, M.H., Issa, M.M., & Lepor, H. (2003). Changes in nocturia from medical treatment of benign prostatic hyperplasia: Secondary analysis of the Department of Veterans Cooperative Study Trial. Journal of Urology, 170, 145–148.
* Jolleys, J.V., Donovan, J.L., Nanchahal, K., Peters, T.J., & Abrams, P. (1994). Urinary symptoms in the community: How bothersome are they? BritishJournal of Urology, 74, 551–555.
* Kaplan, S.A., Walmsley, K. & Te, A.E. (2005). Tolterodine extended release attenuates lower urinary tract symptoms in men with benign prostatic hyperplasia. Journal of Urology, 174, 2273–2275.
* Krieger, J.N., Petiau, C., Sforza, E., Delanoe, C., Hecht, M.T., & Chamouard, V. (1993). Nocturnal pollakiuria is a symptom of obstructive sleep apnea. Urology International, 50, 93–97.
* Kuo, H.C. (2002). Efficacy of desmopressin in treatment of refractory nocturia in patients older than 65 years. Urology,59, 485–489.
* Lose, G., Lalos, O., Freeman, R.M., van Kerrebroeck, P., & the Nocturia Study Group. (2003). Efficacy of desmopressin (Minirin) in the treatment of nocturia: A double-blind placebocontrolled study in women. American Journal of Obstetrics andGynecology, 189, 1106–1113.
* Lose, G., Mattiasson, A., Walter, S., Lalos, O., van Kerrebroeck, P., Abrams, P., & Freeman, R. (2004). Clinical experiences with desmopressin for longterm treatment of nocturia. Journal ofUrology, 172, 1021–1025.
* MacDiarmid, S., Ellsworth, P., Ginsberg, D., Oefelein, M., & Sussman, D. (2009). The safety and efficacy of once-dailytrospium chloride extended release inmale patients with overactive bladder. Oral presentation at the Western Section Meeting of the AUA, Las Vegas, 2009.
* Marschall-Kehrel, D. (2004). Update on nocturia: The best of rest is sleep. Urology,64, 21–24.
* Mattiasson, A., Abrams, P., van Kerrebroeck, P., Walter, S., & Weiss, J. (2002). Efficacy of desmopressin in the treatment of nocturia: A double-blind placebo-controlled study in men. British Journal of Urology International, 89, 855–862.
* Middelkoop, H.A., Smilde-van den Doel, D.A., Neven, A.K., Kamphuisen, H.A., & Springer, C.P. (1996). Subjective sleep characteristics of 1485 males and females aged 50–93: Effects of sex and age, and factors related to self-evaluated quality of sleep. The Journals ofGerontology Biological Sciences andMedical Sciences, 51, 108–115.
* Nitti, V.W., Dmochowski, R., Sand, P.K., Forst, H.T., Haag-Molkenteller, C., Massow, U., … Bavendam, T. (2007). Efficacy, safety and tolerability of fesoterodine for overactive bladder syndrome. Journal of Urology, 178, 2488–2494.
* Pedersen, P.A., & Johansen, P.B. (1988). Prophylactic treatment of adult nocturia with bumetanide. British Journalof Urology, 62, 145–147.
* Pressman, M.R., Figueroa, W.G., Kendrick-Mohamed, J., Greenspon, L.W., & Peterson, D.D. (1996). Nocturia: A rarely recognized symptom of sleep apnea and other occult sleep disorders. Archives Internal Medicine, 156, 545–550.
* Rackley, R., Weiss, J.P., Rovner, E.S., Wang, J.T., Guan, Z., & the 037 Study Group. (2006). Nighttime dosing with tolterodine reduces overactive bladder-related nocturnal micturitions in patients with overactive bladder and nocturia. Urology, 67(4), 731–736.
* Rembratt, A., Graugaard-Jensen, C. Senderovitz, T., Norgaard, J.P., & Djurhuus, J.C. (2004). Pharmaco-kinetics and pharmacodynamics of desmopressin administered orally versus intravenously at daytime versus nighttime in healthy men aged 55–70 years. European Journal of ClinicalPharmacology, 60, 397–402.
* Rembratt, A., Norgaard, J.P., & Andersson, K.E. (2003). Desmopressin in elderly patients with nocturia: Short-term safety and effects on urine output, sleep and voiding patterns. British Journal ofUrology International, 91, 642–646.
* Rembratt, A., Riis, A., & Norgaard, J.P. (2006). Desmopressin treatment in nocturia: An analysis of risk factors for hyponatremia. Neurourology andUrodynamics, 25, 105–109.
* Rembratt, A., Robertson, G.L., Norgaard, J.P., & Andersson, K.E. (2000). Pathogenicaspects of nocturia in the elderly:Differences between nocturics andnonnocturics. Presentation at the 30th International Continence Society Meeting, Finland, August 2000.
* Reynard, J.M., Cannon, A., Yang, Q., & Abrams, P. (1998). A novel therapy for nocturnal polyuria: A double-blind randomized trial of frusemide against placebo. British Journal of Urology, 81, 215–218.
* Rittig, S., Jensen, A.R., Jensen, K.T., & Pederson, E.B. (1998). Effect of food intake on the pharmacokinetics and antidiuretic activity of oral desmopressin (DDAVP) in hydrated normal subjects. Clinical Endocrinology (Oxf),48, 235–241.
* Robertson, G., Rittig, S., Kovacs, L., Gaskill, M.B., Zee, P., & Nanninga, J. (1999). Pathophysiology and treatment of enuresis in adults. ScandinavianJournal of Urology and Nephrology, 202 (Suppl.), 36–39.
* Roehrborn, C.G., van Kerrebroeck, P., & Nordling, J. (2003). Safety and efficacy of alfuzosin 10 mg once-daily in the treatment of lower urinary tract symptoms and clinical benign prostatic hyperplasia: A pooled analysis of three double-blind, placebo-controlled studies. British Journal of UrologyInternational, 92, 257–261.
* Saad, F., Nickel, J.C., Valiquette, L., Casey, R., Kuzmarov, I., Elhilali, M., & the ALF-X Study Group. (2005). Early symptom improvement of benign prostatic hyperplasia (BPH) treated with once daily alfuzosin. Canadian Journal of Urology, 12, 2745–2754.
* Scarpa, R.M. (2001). Lower urinary tract symptoms: What are the implications for patients? European Urology, 40, 12–20.
* Schatzl, G., Temml, C., Schmidbauer, J., Dolezal, B., Haidinger, G., & Madersbacher, S. (2000). Cross-sectional study of nocturia in both sexes: Analysis of a voluntary health screening project. Urology, 56, 71–75.
* Stember, D.S., Weiss, J.P., Lee, C.L., & Blaivas, J.G. (2007). Nocturia in men. International Journal of ClinicalPractice, 61(Suppl., 155), 17–22.
* Stewart, R.B., Moore, M.T., May, F.E., Marks, R.G., & Hale, W.E. (1992). Nocturia: A risk factor for falls in the elderly. Journal of the American GeriatricSociety, 40, 1217–1220.
* Swithinbank L.V., Donovan J.L., duHeaume J.C., Rogers C.A., James M.C., Yang Q., & Abrams, P. (1999). Urinary symptoms and incontinence in women: Relationships between occurrence, age, and perceived impact. British JournalGeneral Practice, 49(448), 897–900.
* van Balen, R., Steyerberg, E.W., Polder, J.J., Ribbers, T.L., Habbema, J.D., & Cools, H.J. (2001). Hip fracture in elderly patients: Outcomes for function, quality of life, and type of residence. Clinical Orthopedics, 390, 232–243.
* Van Kerrebroeck, P., Abrams, P., Chaikin, D., Donovan, J., Fonda, D., Jackson, S.,… Weiss, J. (2002). The standardization of terminology in nocturia: Report from the Standardization Sub-Committee of the International Continence Society. Neurourology and Urodynamics, 21, 179–183.
* Weatherall, M. (2004). The risk of hyponatremia in older adults using desmopressin for nocturia: A systematic review and meta-analysis. Neurourology and Urodynamics, 23, 302–305.
* Weiss, J.P., & Blaivas, J.G. (2000). Nocturia. Journal of Urology, 163, 5–12.
* Weiss, J.P., & Blaivas, J.G. (2002). Nocturnal polyuria versus overactive bladder in nocturia. Urology, 60, 28–32.
* Weiss, J.P., Blaivas, J.G., & Stember, D.S. (1998). Nocturia in adults: Classification and etiology. Neurourologyand Urodynamics, 17(4), 467–472.
* Weiss, J.P., Weinberg, A.C., & Blaivas, J.G. (2008). New aspects of the classification of nocturia. Current UrologyReports, 9, 362–367.
* Yoshimura, K., Terada, M., Matsui, Y., Terai, A., Kinukawa, N., & Arai, Y. (2004). Prevalence of and risk factors for nocturia: Analysis of a health screening program. International Journal of Urology, 11, 282–287.
* Zinner, N., Gittelman, M., Harris, R., Susset, J., Kanelos, A., Auerbach, S., & the Trospium Study Group. (2004). Trospium chloride improves overactive bladder symptoms: A multicenter phase III trial. Journal of Urology, 171, 2311–2315.
Additional Reading
Weiss, J.P., Blaivas, J.G., Stember, D.S., & Chaikin, D.C. (1999). Evaluation of nocturia in men: The nocturia and nocturnal bladder capacity indices. Neurourology and Urodynamics, 18, 559–565.
Posted: 11/21/2010; Urol Nurs. 2010;30(5):276-287. © 2010 Society of Urologic Nurses and Associates
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