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Nocturia: A Nonspecific but Bothersome Symptom in Urology
Urol Sci 2011;22(1):1−6
CME Credits
MINI REVIEW
Nocturia: A Nonspecific but Bothersome Symptom in Urology Sung-Lang Chen1,2* 1
Department of Urology, Chung Shan Medical University Hospital, Taichung, Taiwan School of Medicine, Chung Shan Medical University, Taichung, Taiwan
2
Nocturia is a common symptom in both men and women. It can be troublesome by itself by disturbing sleep and can have a significant impact on the quality of sleep and the quality of life. In men, nocturia is often ascribed to prostatic disease without due consideration of other causes. However, other factors or a combination of factors are just as likely to be the cause. The cause of nocturia can usually be determined by a simple assessment of a patient’s history, an examination, and a voiding diary, plus a urodynamic study if necessary. Lifestyle and behavioral changes may benefit some individuals, but for many people, the only treatment option is pharmacology. Antimuscarinic agents are the most common therapies for an overactive bladder and are often used to manage nocturia. The vasopressin analog desmopressin consistently leads to improvement in nocturnal episodes of patients with proven polyuria. The risk of adverse events associated with most available medications requires careful monitoring to optimize better safety and tolerability.
Accepted: October 9, 2009
KEY WORDS: desmopressin; muscarinic receptor; nocturia
*Corresponding author. Department of Urology, Chung-Shan Medical University Hospital, 110 Chang-Kuo North Road, Section 1, Taichung 402, Taiwan. E-mail: [email protected]
There are 2 CME questions based on this article
1. Introduction Voiding at night, or nocturia, is not a recent problem. However, an aging population and recent innovations in treatment have brought more attention to this disorder. The International Continence Society (ICS) defines nocturia as, “the complaint that the individual has to wake at night one or more times to void”.1,2 This definition excludes nocturnal convenience voids, i.e., when the subject voids after having woken up for a different reason. Most related studies published prior to that nomenclature report, and even many studies reported afterwards, did not strictly adhere to this definition when reporting the prevalence, consequence, and treatment of nocturia. The ICS defines the nocturnal urine volume as, “the total volume of urine passed between the time the individual goes to bed with the intention of sleeping and the time of waking with the intention of rising.” Therefore, nocturnal ©2011 Taiwan Urological Association. Published by Elsevier Taiwan LLC.
urine volume does not include the last void before going to bed, but it does include the first morning void. There is no known reason why a healthy, elderly person should suffer from nocturia. Nocturia can result from a broad range of urological and non-urological conditions, and in any given individual, multiple conditions may coexist. Nocturia can also result from a number of pathological conditions, including cardiovascular disease, fluid redistribution, diabetes mellitus or insipidus (DI), lower urinary tract obstruction, and obstructive sleep apnea. Pathological changes in blood pressure, plasma urine electrolyte gradients, osmolarity gradients, plasma calcium, and glucose are strongly related to nocturia. In the elderly, the condition is often multifactorial. This article reviews the prevalence of nocturia, its medical impacts, its urological and non-urological causes, and possible strategies for its management by urologists. 1
S.L. Chen
2. Prevalence It is difficult to determine the exact prevalence of nocturia because epidemiological studies vary in their definition of the condition. Prevalence increases with age, and therefore, most men and women over 80 years old will rise at least once at night to empty their bladder.3–5 The amount of data available on the frequency of voiding and the volume voided nocturnally across all age groups are also limited. The prevalence of nocturia in community-dwelling populations is typically present in > 50% of both men and women older than 60 years. One survey, based on the definition by the ICS, yielded nocturia prevalence rates of 9–14% in the general adult male population, and considerably higher rates were found in the elderly and men with lower urinary tract symptoms suggestive of benign prostate hyperplasia.6 No large differences have been observed in the prevalence of nocturia between men and women; however, there is a tendency for young women to have this symptom more often than young men, and for very old men to have it more often than very old women.7
3. Impact of Nocturia Nocturia is relatively common among the elderly and becomes increasingly prevalent with age with profound influences on the quality of life (QoL), quality of sleep, daytime function, morbidity, and even mortality. Interestingly, nocturia is regarded as the most bothersome urological symptom, not only by the afflicted but also by their partners.8,9 It is generally accepted that adults require 7–8 hours of sleep per night to refresh and restore the body. Nocturia is a major cause of sleep disturbance in people over 50 years of age.10 More than 60% of men and women have reported that nocturia has a negative effect on their QoL and quality of sleep.7 In addition to an increase in daytime fatigue and impaired performance, sleep disruption may also result in more-serious consequences, such as immunosuppression, depression, and endocrine and metabolic alterations, which can affect motivation and job performance. There is also an increased likelihood of traumatic fractures from falling when making trips to the toilet. A study of 1500 older ambulatory patients (with a mean age of 80 years) found that individuals voiding two or more times per night were significantly more likely to fall than those who did not void at night (odds ratio [OR], 1.84; p = 0.03). Another study found that the likelihood of falling increased among patients who voided three or more times a night (OR, 2.15; p = 0.04).11 Taken together, those data show that the presence of nocturia, particularly when involving two or more episodes per night, has a major impact on the well-being of 2
patients and may be associated with considerable morbidity and even mortality.12 A recently developed nocturia QoL questionnaire measurement tool consists of 13 items assessing the productivity, level of activity impairment, energy, fatigue, and level of concern. The score is able to discriminate between men suffering from one, two, or more episodes of nocturia, but it is has not been validated for use in women.13
4. Pathophysiology of Nocturia The causes of nocturia fall into four categories: diurnal polyuria, nocturnal polyuria, decreased bladder capacity, and mixed nocturia.
4.1. Diurnal polyuria Diurnal polyuria is defined as an output of more than 40 mL of urine per kg of body weight over a 24-hour period.14 As a result, polyuria is usually associated with increased urinary frequency during both daytime and nighttime. The common causes of diurnal polyuria are diabetes mellitus and DI of both central and nephrogenic origins. Central DI is caused by the deficient synthesis of the antidiuretic hormone, arginine vasopressin (AVP), secondary to the loss of neurosecretory neurons in the hypothalamus or posterior hypophysis. Central DI can usually be treated with desmopressin.16 Nephrogenic DI occurs when the kidneys fail to respond to antidiuretic hormones, which could be a result of renal AVP resistance. Renal AVP resistance can be due to multiple mutations of the AVP receptor, which cause various degrees of receptor dysfunction.15 Nephrogenic DI can be treated with appropriate regulation of fluid intake. In addition, polydipsia, which may be either disogenic or psychogenic, can increase the total daily urine volume.
4.2. Nocturnal polyuria Two key hormones regulating fluid homeostasis are AVP17 and atrial natriuretic peptide (ANP).18 AVP is secreted from the pituitary gland and acts on distal tubules and collecting ducts to promote water reabsorption. ANP is typically secreted from the atria of the heart in response to fluid overload and promotes water and sodium excretion by the kidneys. Pathophysiological changes due to these two hormones may lead to nocturnal polyuria. Nocturnal polyuria is defined as an increase in nighttime urine production with a corresponding decrease in daytime urine production, resulting in a normal 24-hour urine volume. Although its precise definition remains somewhat flexible, an approximate description of nocturnal polyuria from the ICS is a nocturnal urine volume at least one third that of the total daily urine production.14 Vol. 22, 1–6, March 2011
Nocturia in urology The formula for calculating the nocturnal polyuria index is simply the nocturnal urine volume divided by the 24-hour urine volume. If 24-hour urine production is within normal limits, a nocturnal polyuria index of > 35% indicates nocturnal polyuria.18 Nocturnal polyuria was found to be the sole etiology for nocturia in 33% of patients and it was a combined etiology in 54.2% of patients.19 Nocturnal polyuria results from a disordered diurnal rhythm of sodium recreation and other unknown factors causing nocturnal urinary dilution.20 Compared with normal controls, nocturia patients have no diurnal variations in urine output and greater nocturnal urine production, which are associated with a lack of a nocturnal increase in AVP levels. Other causes of nocturnal polyuria include congestive heart failure, diabetes mellitus, peripheral edema due to venous stasis or lymphostasis, nephritic syndrome, hepatic failure, and hypoalbuminemia, or lifestyle patterns such as excessive nighttime drinking and a high intake of salt. Respiratory conditions, such as sleep apnea, may also cause nocturnal polyuria. Hypoxia in the lungs can lead to pulmonary vasoconstriction and a higher concentration of ANP, which is responsible for the elimination of sodium in the urine. This can result in nocturnal polyuria while the patient is sleeping.21
4.3. Decreased nocturnal bladder capacity (NBC) A decreased NBC was found to be the sole etiology for nocturia in 16.2% of patients and it was a combined etiology in 37.4% of patients.19 NBC is defined as the largest voided volume during the hours of sleep. A lower NBC is related to a decreased maximum voided volume.21 Storage problems may also arise through bladder irritation as a result of infection, interstitial cystitis, calculi, and bladder hypersensitivity.22 The NBC index is a complicated formula that addresses voiding at night in patients with a decreased NBC. The NBC index is the actual number of nightly voids minus the predicted number of nightly voids. An NBC index of > 2 may result from prostatic obstruction, nocturnal detrusor overactivity, a neurogenic bladder, a primary bladder pathology such as cancer (bladder, prostate, or urethra), learned voiding dysfunction, anxiety disorders, certain pharmacological agents, or bladder and ureteral calculi.23
4.4. Mixed nocturia Many patients with nocturia have a combination of nocturnal polyuria and a lower NBC. The relative roles of these factors may differ between sexes. It has been reported that male nocturia is more often related to nocturnal polyuria, whereas female nocturia is more often related to a small bladder capacity.24 The relative roles of the various factors may also differ between ethnic groups.25 Vol. 22, 1–6, March 2011
Mixed nocturia should be diagnosed through the maintenance and analysis of bladder diaries.
5. Treatment The large range of causes of nocturia suggests that the same treatment strategy is unlikely to work in all patients. The logical first step to approach nocturia treatment should be to eliminate underlying causes. If nocturia appears to be due to a non-urological disease such as congestive heart failure, poorly controlled diabetes, or obstructive sleep apnea, these underlying conditions should be treated as a priority. Obese individuals may have increased nocturnal production of urine as a result of increased fluid intake before bedtime, and AVP sensitivity is also impaired in obese individuals. Abdominal obesity can increase intraabdominal pressure and cause nocturia. These findings suggest that the relationship between obesity and nocturia is unidirectional; obesity increases the risk of nocturia.26 Changes in lifestyle and behavior might also be effective in selective patients with nocturia. If a patient history indicates that nocturia is due to excessive fluid intake, particularly caffeinated or alcoholic beverages, then restrictions on caffeine, alcohol, and fluid consumption may help alleviate the disorder.2 One recent study demonstrated the effect of modification of fluid intake on nocturia.27 In contrast, Shiri et al.26 found no significant association between coffee consumption and nocturia. However some data suggest that this method alone might not be ideal for improving nocturia in the elderly. Asplund and Aberg28 found that nearly half of elderly patients who woke more than three times a night to urinate had already restricted their fluid intake in the evening. Fluid restriction only before bedtime is rarely effective if nocturia is the result of gravity-induced third spacing of fluid in the lower extremities. Diuretics given during the late afternoon or early evening may help decrease the third spacing of fluid. Compression stockings and afternoon leg elevation may combat fluid retention in the legs and help diminish nocturnal urinary output. Any factors that adversely influence nighttime sleep should be addressed and eliminated. However, lifestyle and behavioral changes are rarely effective alone, necessitating pharmacotherapy in most nocturia patients.
6. Pharmacology 6.1. Desmopressin acetate If nocturia is due to nocturnal polyuria but is not explained by underlying diseases, lifestyle factors, or medications, inadequate AVP secretion or disturbed AVP function can 3
S.L. Chen be assumed. Treatment with AVP analogs appears justified under such conditions. Desmopressin acetate is a synthetic analog of AVP that has been used for several decades to treat DI and nocturnal enuresis and is available in nasal, oral, and parenteral formulations. Early studies mostly used a desmopressin dose of 20 μg given either orally or intranasally.29–31 The populations in those studies tended to be very small (fewer than 25 patients), but in later studies they were considerably larger with higher applied oral doses (0.1–0.4 mg) with 3 weeks of doubleblind treatment.32,33 The efficacy of desmopressin in treating nocturia has been examined in various populations, including men, women, and the elderly, in both short- and long-term studies.32,34,35 QoL analyses have also indicated greater improvement in terms of prevalence, annoyance, and problems caused by nocturia, in patients treated with desmopressin compared with placebos.35 Desmopressin increases the length of time until the first nocturnal void, lowers the number of nocturnal voids, and decreases the percentage of urine voided at night.35 Treatment of nocturia in elderly patients with desmopressin should only be undertaken together with careful monitoring of serum sodium concentrations. A significant fall in serum sodium concentration can occur within 72 hours, and the risk rises with increasing age (over 65-year-old group being most at risk).36 In patients at risk of hyponatremia, the sodium concentration should be checked within 1 week, and the dose should be titrated. For long-term desmopressin administration, the serum sodium concentration should be carefully assessed for at least 6 months.37
study showed that a combination of a muscarinic antagonist (tolterodine) and an alpha blocker (tamsulosin) caused a greater, although still only moderate, improvement in nocturia than either agent alone.49 The available antimuscarinic agents have different physicochemical and pharmacokinetic properties that may impact their safety and tolerability in certain populations. Oxybutynin, solifenacin, tolterodine, and darifenacin are tertiary amines, which have the potential to cross the blood-brain barrier.50 The blockade of central muscarinic receptors may cause adverse central nervous system effects, including cognitive dysfunction, hallucinations, and confusion. A new quaternary amine antimuscarinic agent, trospium, is hydrophilic and lipophobic, resulting in a low possibility of crossing the blood-brain barrier and causing adverse effects.51 Because nocturnal production of hormones is impaired in some nocturia adults, administration of melatonin can restore a normal circadian rhythm of micturition and improve sleep. It was reported that men treated with 2 mg of melatonin generally experienced a 10% reduction in episodes of nocturia.52 Alpha1-adrenoceptor antagonists and 5α-reductase inhibitors are also used in men with symptoms indicative of benign prostate hyperplasia, and one of their effects is a reduction in nocturia. On the other hand, in women, estrogen deficiency, a common consequence of the menopausal transition, causes atrophic changes within the urogenital tract. Consequently, such women are more disposed to having urogenital symptoms, among which is nocturia.53
6.2. Antimuscarinic agents
7. Surgery
Muscarinic receptor antagonists are the mainstay of medical treatment for an overactive bladder. These agents are believed to exert their effects by directly inhibiting the muscarinic receptors within the detrusor muscle, which leads to bladder contraction and voiding.38 Recent reviews have suggested that in addition to this mechanism, antimuscarinics also function via afferent pathways, alleviating the sensation of urgency.39,40 Their effect on nocturia was also evaluated in a series of 12-week double-blind studies including darifenacin,41,42 solifenacin,43,44 tolterodine,45,46 and trospium.47 In a double-blind trial comparing solifenacin with tolterodine in patients with an overactive bladder, both were observed to be effective in reducing nocturia episodes (a reduction of 0.71 and 0.63 episodes, respectively).48 However, this study lacked a placebo arm, which limits its validity because the extent of improvement attributable to the placebo effect could not be determined. Improvements in nocturia have typically been only moderate and do not consistently reach statistical significance across all studies of a given drug. A recent
Transurethral resection or incision of the prostate may be appropriate when obstruction related to the prostate is the main causative factor of nocturia. Treatment options for selective nocturia patients include pelvic reconstructive surgery for organ prolapse, detrusor myomectomy and cystoplasty for decreased bladder capacity, and botulinum toxin detrusor injection for neurogenic and idiopathic detrusor overactivity.54 A mini-invasive surgical technique for urgency, urge incontinence, and nocturia is sacral neuromodulation. Although evidence of its efficacy is preliminary, the procedure has been successfully used for reducing the degree of urgency and total number of voids.55
4
8. Conclusions The pathophysiology of nocturia is multifactorial and can be complex. Its cause remains unclear in a significant number of patients. The ICS defines nocturia as, “the complaint that the individual has to wake at night one or more times to void”.2 Vol. 22, 1–6, March 2011
Nocturia in urology In general, the inconvenience associated with nocturia occurring once is limited, whereas nocturia occurring twice or more is highly disruptive. Bladder diaries are necessary to make a differential diagnosis of the etiology of a subject’s nocturia. Treatment should be tailored to the condition causing the nocturia. If nocturia appears to be due to non-urological diseases, such as congestive heart failure, poorly controlled diabetes, or obstructive sleep apnea, the underlying condition should be treated as a priority. Changes in lifestyle and behavior can be effective in selective patients with nocturia, but pharmacological treatment is often required. Desmopressin, antimuscarinic agents, and α1-blockers are modestly effective compared with placebos. Correctly diagnosing and treating nocturia, especially in elderly patients, will improve the patients’ sleep and, in turn, reduce their risk of fall injuries and the associated detrimental consequences, thereby improving the patients’ health and QoL.
References 1.
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13. Abraham L, Hareendran A, Mills IW, et al. Development and validation of a quality-of-life measure for men with nocturia. Urology 2004;63:481–6. 14. Van Kerrebroeck P, Abrams P, Chaikin D, et al. The standardization of terminology in nocturia: report from the standardization subcommittee of the International Continence Society. BJU Int 2002; 90(Suppl 3):11–5. 15. Insel PA, Tang CM, Hahntow I, Michel MC. Impact of GPCRs in clinical medicine: monogenic diseases, genetic variants and drug targets. Biochim Biophys Acta 2007;1768:994–1005. 16. Rivkees SA. Should off-label drug use be off-the-table? J Pediatr Endocrinol Metab 2007;20:171–2. 17. Ishikawa S. Cellular actions of arginine vasopressin in the kidney. Endocr J 1993;40:373–86. 18. Matthiesen TB, Rittig S, Nørgaard JP, Pedersen EB, Djurhuus JC. Nocturnal polyuria and natriuresis in male patients with nocturia and lower urinary tract symptoms. J Urol 1996;156:1292–9. 19. Klingler HC, Heidler H, Madersbacher H, Primus G. Nocturia: an Austrian study on the multifactorial etiology of this symptom. Neurourol Urodyn 2009;28:427–31. 20. Chang SC, Lin AT, Chen KK, Chang LS. Multifactorial nature of male nocturia. Urology 2006;67:541–4. 21. Krieger J, Petiau C, Sforza E, Delanoë C, Hecht MT, Chamouard V. Nocturnal pollakiuria is a symptom of obstructive sleep apnea. Urol Int 1993;50:93–7. 22. Weiss JP, Blaivas JG. Nocturia. Curr Urol Rep 2003;4:362–6. 23. Weiss JP, Blaivas JG. Nocturia. Adv Exp Med Biol 2003;539:751–72. 24. Paick JS, Kim SW, Oh SJ, Ku JH. Voiding patterns in men and women with lower urinary tract symptoms combined with nocturia. Int J Urol 2007;14:699–703. 25. Mariappan P, Turner KJ, Sothilingam S, Rajan P, Sundram M, Stewart LH. Nocturia, nocturia indices and variables from frequency-volume charts are significantly different in Asian and Caucasian men with lower urinary tract symptoms: a prospective comparison study. BJU Int 2007;100:332–6. 26. Shiri R, Hakama M, Hakkinen J, et al. The effects of lifestyle factors on the incidence of nocturia. J Urol 2008;180:2059–62. 27. Hashim H, Abrams P. How should patients with an overactive bladder manipulate their fluid intake? BJU Int 2008;102:62–6. 28. Asplund R, Aberg H. Health of the elderly with regard to sleep and nocturnal micturition. Scand J Prim Health Care 1992;10:98–104. 29. Asplund R, Sundberg B, Bengtsson P. Oral desmopressin for nocturnal polyuria in elderly subjects: a double-blind, placebocontrolled randomized exploratory study. BJU Int 1999;83:591–5. 30. Hilton P, Stanton SL. The use of desmopressin (DDAVP) in nocturnal urinary frequency in the female. Br J Urol 1982;54:252–5. 31. Cannon A, Carter PG, McConnell AA, Abrams P. Desmopressin in the treatment of nocturnal polyuria in the male. BJU Int 1999; 84:20–4. 32. Mattiasson A, Abrams P, Van Kerrebroeck P, Walter S, Weiss J. Efficacy of desmopressin in the treatment of nocturia: a doubleblind placebo-controlled study in men. BJU Int 2002;89:855–62. 33. van Kerrebroeck P, Rezapour M, Cortesse A, Thuroff J, Riis A, Norgaard JP. Desmopressin in the treatment of nocturia: a doubleblind, placebo-controlled study. Eur Urol 2007;52:221–9. 34. Rembratt A, Norgaard JP, Andersson KE. Desmopressin in elderly patients with nocturia: short-term safety and effects on urine output, sleep and voiding patterns. BJU Int 2003;91:642–6. 35. Lose G, Mattiasson A, Walter S, et al. Clinical experiences with desmopressin for long-term treatment of nocturia. J Urol 2004; 172:1021–5. 36. Rembratt A, Riis A, Norgaard JP. Desmopressin treatment in nocturia; an analysis of risk factors for hyponatremia. Neurourol Urodyn 2006;25:105–9. 37. Bae JH, Oh MM, Shim KS, et al. The effects of long-term administration of oral desmopressin on the baseline secretion of antidiuretic hormone and serum sodium concentration for the treatment of nocturia: a circadian study. J Urol 2007;178:200–3.
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S.L. Chen 38. Andersson KE, Yoshida M. Antimuscarinics and the overactive detrusor—which is the main mechanism of action? Eur Urol 2003; 43:1–5. 39. Andersson KE. Bladder activation: afferent mechanisms. Urology 2002;59:43–50. 40. Hegde SS. Muscarinic receptors in the bladder: from basic research to therapeutics. Br J Pharmacol 2006;147(Suppl 2):S80–7. 41. Haab F, Stewart L, Dwyer P. Darifenacin, an M3 selective receptor antagonist, is an effective and well-tolerated once-daily treatment for overactive bladder. Eur Urol 2004;45:420–9. 42. Steers W, Corcos J, Foote J, Kralidis G. An investigation of dose titration with darifenacin, an M3-selective receptor antagonist. BJU Int 2005;95:580–6. 43. Chapple CR, Rechberger T, Al-Shukri S, et al. Randomized, doubleblind placebo- and tolterodine-controlled trial of the once-daily antimuscarinic agent solifenacin in patients with symptomatic overactive bladder. BJU Int 2004;93:303–10. 44. Cardozo L, Lisec M, Millard R, et al. Randomized, double-blind placebo controlled trial of the once daily antimuscarinic agent solifenacin succinate in patients with overactive bladder. J Urol 2004;172:1919–24. 45. Nitti VW, Sanders S, Staskin DR, et al. Transdermal delivery of drugs for urologic applications: basic principles and applications. Urology 2006;67:657–64. 46. Kaplan SA, Roehrborn CG, Dmochowski R, Rovner ES, Wang JT, Guan Z. Tolterodine extended release improves overactive bladder symptoms in men with overactive bladder and nocturia. Urology 2006;68:328–32.
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47. Zinner N, Gittelman M, Harris R, Susset J, Kanelos A, Auerbach S. Trospium chloride improves overactive bladder symptoms: a multicenter phase III trial. J Urol 2004;171:2311–5. 48. Chapple CR, Abrams P. Comparison of darifenacin and oxybutynin in patients with overactive bladder: assessment of ambulatory urodynamics and impact on salivary flow. Eur Urol 2005;48: 102–9. 49. Rovner ES, Kreder K, Sussman DO, et al. Effect of tolterodine extended release with or without tamsulosin on measures of urgency and patient reported outcomes in men with lower urinary tract symptoms. J Urol 2008;180:1034–41. 50. Pak RW, Petrou SP, Staskin DR. Trospium chloride: a quaternary amine with unique pharmacologic properties. Curr Urol Rep 2003; 4:436–40. 51. Doroshyenko O, Jetter A, Odenthal KP, Fuhr U. Clinical pharmacokinetics of trospium chloride. Clin Pharmacokinet 2005;44:701–20. 52. Drake MJ, Mills IW, Noble JG. Melatonin pharmacotherapy for nocturia in men with benign prostatic enlargement. J Urol 2004; 171:1199–202. 53. Asplund R. Pharmacotherapy for nocturia in the elderly patient. Drugs Aging 2007;24:325–43. 54. Kessler TM, Danuser H, Schumacher M, Studer UE, Burkhard FC. Botulinum A toxin injections into the detrusor: an effective treatment in idiopathic and neurogenic detrusor overactivity? Neurourol Urodyn 2005;24:231–6. 55. Hassouna MM, Siegel SW, Nyeholt AA, et al. Sacral neuromodulation in the treatment of urgency-frequency symptoms: a multicenter study on efficacy and safety. J Urol 2000;163:1849–54.
Vol. 22, 1–6, March 2011
CME Credits
MINI REVIEW
Nocturia: A Nonspecific but Bothersome Symptom in Urology Sung-Lang Chen1,2* 1
Department of Urology, Chung Shan Medical University Hospital, Taichung, Taiwan School of Medicine, Chung Shan Medical University, Taichung, Taiwan
2
Nocturia is a common symptom in both men and women. It can be troublesome by itself by disturbing sleep and can have a significant impact on the quality of sleep and the quality of life. In men, nocturia is often ascribed to prostatic disease without due consideration of other causes. However, other factors or a combination of factors are just as likely to be the cause. The cause of nocturia can usually be determined by a simple assessment of a patient’s history, an examination, and a voiding diary, plus a urodynamic study if necessary. Lifestyle and behavioral changes may benefit some individuals, but for many people, the only treatment option is pharmacology. Antimuscarinic agents are the most common therapies for an overactive bladder and are often used to manage nocturia. The vasopressin analog desmopressin consistently leads to improvement in nocturnal episodes of patients with proven polyuria. The risk of adverse events associated with most available medications requires careful monitoring to optimize better safety and tolerability.
Accepted: October 9, 2009
KEY WORDS: desmopressin; muscarinic receptor; nocturia
*Corresponding author. Department of Urology, Chung-Shan Medical University Hospital, 110 Chang-Kuo North Road, Section 1, Taichung 402, Taiwan. E-mail: [email protected]
There are 2 CME questions based on this article
1. Introduction Voiding at night, or nocturia, is not a recent problem. However, an aging population and recent innovations in treatment have brought more attention to this disorder. The International Continence Society (ICS) defines nocturia as, “the complaint that the individual has to wake at night one or more times to void”.1,2 This definition excludes nocturnal convenience voids, i.e., when the subject voids after having woken up for a different reason. Most related studies published prior to that nomenclature report, and even many studies reported afterwards, did not strictly adhere to this definition when reporting the prevalence, consequence, and treatment of nocturia. The ICS defines the nocturnal urine volume as, “the total volume of urine passed between the time the individual goes to bed with the intention of sleeping and the time of waking with the intention of rising.” Therefore, nocturnal ©2011 Taiwan Urological Association. Published by Elsevier Taiwan LLC.
urine volume does not include the last void before going to bed, but it does include the first morning void. There is no known reason why a healthy, elderly person should suffer from nocturia. Nocturia can result from a broad range of urological and non-urological conditions, and in any given individual, multiple conditions may coexist. Nocturia can also result from a number of pathological conditions, including cardiovascular disease, fluid redistribution, diabetes mellitus or insipidus (DI), lower urinary tract obstruction, and obstructive sleep apnea. Pathological changes in blood pressure, plasma urine electrolyte gradients, osmolarity gradients, plasma calcium, and glucose are strongly related to nocturia. In the elderly, the condition is often multifactorial. This article reviews the prevalence of nocturia, its medical impacts, its urological and non-urological causes, and possible strategies for its management by urologists. 1
S.L. Chen
2. Prevalence It is difficult to determine the exact prevalence of nocturia because epidemiological studies vary in their definition of the condition. Prevalence increases with age, and therefore, most men and women over 80 years old will rise at least once at night to empty their bladder.3–5 The amount of data available on the frequency of voiding and the volume voided nocturnally across all age groups are also limited. The prevalence of nocturia in community-dwelling populations is typically present in > 50% of both men and women older than 60 years. One survey, based on the definition by the ICS, yielded nocturia prevalence rates of 9–14% in the general adult male population, and considerably higher rates were found in the elderly and men with lower urinary tract symptoms suggestive of benign prostate hyperplasia.6 No large differences have been observed in the prevalence of nocturia between men and women; however, there is a tendency for young women to have this symptom more often than young men, and for very old men to have it more often than very old women.7
3. Impact of Nocturia Nocturia is relatively common among the elderly and becomes increasingly prevalent with age with profound influences on the quality of life (QoL), quality of sleep, daytime function, morbidity, and even mortality. Interestingly, nocturia is regarded as the most bothersome urological symptom, not only by the afflicted but also by their partners.8,9 It is generally accepted that adults require 7–8 hours of sleep per night to refresh and restore the body. Nocturia is a major cause of sleep disturbance in people over 50 years of age.10 More than 60% of men and women have reported that nocturia has a negative effect on their QoL and quality of sleep.7 In addition to an increase in daytime fatigue and impaired performance, sleep disruption may also result in more-serious consequences, such as immunosuppression, depression, and endocrine and metabolic alterations, which can affect motivation and job performance. There is also an increased likelihood of traumatic fractures from falling when making trips to the toilet. A study of 1500 older ambulatory patients (with a mean age of 80 years) found that individuals voiding two or more times per night were significantly more likely to fall than those who did not void at night (odds ratio [OR], 1.84; p = 0.03). Another study found that the likelihood of falling increased among patients who voided three or more times a night (OR, 2.15; p = 0.04).11 Taken together, those data show that the presence of nocturia, particularly when involving two or more episodes per night, has a major impact on the well-being of 2
patients and may be associated with considerable morbidity and even mortality.12 A recently developed nocturia QoL questionnaire measurement tool consists of 13 items assessing the productivity, level of activity impairment, energy, fatigue, and level of concern. The score is able to discriminate between men suffering from one, two, or more episodes of nocturia, but it is has not been validated for use in women.13
4. Pathophysiology of Nocturia The causes of nocturia fall into four categories: diurnal polyuria, nocturnal polyuria, decreased bladder capacity, and mixed nocturia.
4.1. Diurnal polyuria Diurnal polyuria is defined as an output of more than 40 mL of urine per kg of body weight over a 24-hour period.14 As a result, polyuria is usually associated with increased urinary frequency during both daytime and nighttime. The common causes of diurnal polyuria are diabetes mellitus and DI of both central and nephrogenic origins. Central DI is caused by the deficient synthesis of the antidiuretic hormone, arginine vasopressin (AVP), secondary to the loss of neurosecretory neurons in the hypothalamus or posterior hypophysis. Central DI can usually be treated with desmopressin.16 Nephrogenic DI occurs when the kidneys fail to respond to antidiuretic hormones, which could be a result of renal AVP resistance. Renal AVP resistance can be due to multiple mutations of the AVP receptor, which cause various degrees of receptor dysfunction.15 Nephrogenic DI can be treated with appropriate regulation of fluid intake. In addition, polydipsia, which may be either disogenic or psychogenic, can increase the total daily urine volume.
4.2. Nocturnal polyuria Two key hormones regulating fluid homeostasis are AVP17 and atrial natriuretic peptide (ANP).18 AVP is secreted from the pituitary gland and acts on distal tubules and collecting ducts to promote water reabsorption. ANP is typically secreted from the atria of the heart in response to fluid overload and promotes water and sodium excretion by the kidneys. Pathophysiological changes due to these two hormones may lead to nocturnal polyuria. Nocturnal polyuria is defined as an increase in nighttime urine production with a corresponding decrease in daytime urine production, resulting in a normal 24-hour urine volume. Although its precise definition remains somewhat flexible, an approximate description of nocturnal polyuria from the ICS is a nocturnal urine volume at least one third that of the total daily urine production.14 Vol. 22, 1–6, March 2011
Nocturia in urology The formula for calculating the nocturnal polyuria index is simply the nocturnal urine volume divided by the 24-hour urine volume. If 24-hour urine production is within normal limits, a nocturnal polyuria index of > 35% indicates nocturnal polyuria.18 Nocturnal polyuria was found to be the sole etiology for nocturia in 33% of patients and it was a combined etiology in 54.2% of patients.19 Nocturnal polyuria results from a disordered diurnal rhythm of sodium recreation and other unknown factors causing nocturnal urinary dilution.20 Compared with normal controls, nocturia patients have no diurnal variations in urine output and greater nocturnal urine production, which are associated with a lack of a nocturnal increase in AVP levels. Other causes of nocturnal polyuria include congestive heart failure, diabetes mellitus, peripheral edema due to venous stasis or lymphostasis, nephritic syndrome, hepatic failure, and hypoalbuminemia, or lifestyle patterns such as excessive nighttime drinking and a high intake of salt. Respiratory conditions, such as sleep apnea, may also cause nocturnal polyuria. Hypoxia in the lungs can lead to pulmonary vasoconstriction and a higher concentration of ANP, which is responsible for the elimination of sodium in the urine. This can result in nocturnal polyuria while the patient is sleeping.21
4.3. Decreased nocturnal bladder capacity (NBC) A decreased NBC was found to be the sole etiology for nocturia in 16.2% of patients and it was a combined etiology in 37.4% of patients.19 NBC is defined as the largest voided volume during the hours of sleep. A lower NBC is related to a decreased maximum voided volume.21 Storage problems may also arise through bladder irritation as a result of infection, interstitial cystitis, calculi, and bladder hypersensitivity.22 The NBC index is a complicated formula that addresses voiding at night in patients with a decreased NBC. The NBC index is the actual number of nightly voids minus the predicted number of nightly voids. An NBC index of > 2 may result from prostatic obstruction, nocturnal detrusor overactivity, a neurogenic bladder, a primary bladder pathology such as cancer (bladder, prostate, or urethra), learned voiding dysfunction, anxiety disorders, certain pharmacological agents, or bladder and ureteral calculi.23
4.4. Mixed nocturia Many patients with nocturia have a combination of nocturnal polyuria and a lower NBC. The relative roles of these factors may differ between sexes. It has been reported that male nocturia is more often related to nocturnal polyuria, whereas female nocturia is more often related to a small bladder capacity.24 The relative roles of the various factors may also differ between ethnic groups.25 Vol. 22, 1–6, March 2011
Mixed nocturia should be diagnosed through the maintenance and analysis of bladder diaries.
5. Treatment The large range of causes of nocturia suggests that the same treatment strategy is unlikely to work in all patients. The logical first step to approach nocturia treatment should be to eliminate underlying causes. If nocturia appears to be due to a non-urological disease such as congestive heart failure, poorly controlled diabetes, or obstructive sleep apnea, these underlying conditions should be treated as a priority. Obese individuals may have increased nocturnal production of urine as a result of increased fluid intake before bedtime, and AVP sensitivity is also impaired in obese individuals. Abdominal obesity can increase intraabdominal pressure and cause nocturia. These findings suggest that the relationship between obesity and nocturia is unidirectional; obesity increases the risk of nocturia.26 Changes in lifestyle and behavior might also be effective in selective patients with nocturia. If a patient history indicates that nocturia is due to excessive fluid intake, particularly caffeinated or alcoholic beverages, then restrictions on caffeine, alcohol, and fluid consumption may help alleviate the disorder.2 One recent study demonstrated the effect of modification of fluid intake on nocturia.27 In contrast, Shiri et al.26 found no significant association between coffee consumption and nocturia. However some data suggest that this method alone might not be ideal for improving nocturia in the elderly. Asplund and Aberg28 found that nearly half of elderly patients who woke more than three times a night to urinate had already restricted their fluid intake in the evening. Fluid restriction only before bedtime is rarely effective if nocturia is the result of gravity-induced third spacing of fluid in the lower extremities. Diuretics given during the late afternoon or early evening may help decrease the third spacing of fluid. Compression stockings and afternoon leg elevation may combat fluid retention in the legs and help diminish nocturnal urinary output. Any factors that adversely influence nighttime sleep should be addressed and eliminated. However, lifestyle and behavioral changes are rarely effective alone, necessitating pharmacotherapy in most nocturia patients.
6. Pharmacology 6.1. Desmopressin acetate If nocturia is due to nocturnal polyuria but is not explained by underlying diseases, lifestyle factors, or medications, inadequate AVP secretion or disturbed AVP function can 3
S.L. Chen be assumed. Treatment with AVP analogs appears justified under such conditions. Desmopressin acetate is a synthetic analog of AVP that has been used for several decades to treat DI and nocturnal enuresis and is available in nasal, oral, and parenteral formulations. Early studies mostly used a desmopressin dose of 20 μg given either orally or intranasally.29–31 The populations in those studies tended to be very small (fewer than 25 patients), but in later studies they were considerably larger with higher applied oral doses (0.1–0.4 mg) with 3 weeks of doubleblind treatment.32,33 The efficacy of desmopressin in treating nocturia has been examined in various populations, including men, women, and the elderly, in both short- and long-term studies.32,34,35 QoL analyses have also indicated greater improvement in terms of prevalence, annoyance, and problems caused by nocturia, in patients treated with desmopressin compared with placebos.35 Desmopressin increases the length of time until the first nocturnal void, lowers the number of nocturnal voids, and decreases the percentage of urine voided at night.35 Treatment of nocturia in elderly patients with desmopressin should only be undertaken together with careful monitoring of serum sodium concentrations. A significant fall in serum sodium concentration can occur within 72 hours, and the risk rises with increasing age (over 65-year-old group being most at risk).36 In patients at risk of hyponatremia, the sodium concentration should be checked within 1 week, and the dose should be titrated. For long-term desmopressin administration, the serum sodium concentration should be carefully assessed for at least 6 months.37
study showed that a combination of a muscarinic antagonist (tolterodine) and an alpha blocker (tamsulosin) caused a greater, although still only moderate, improvement in nocturia than either agent alone.49 The available antimuscarinic agents have different physicochemical and pharmacokinetic properties that may impact their safety and tolerability in certain populations. Oxybutynin, solifenacin, tolterodine, and darifenacin are tertiary amines, which have the potential to cross the blood-brain barrier.50 The blockade of central muscarinic receptors may cause adverse central nervous system effects, including cognitive dysfunction, hallucinations, and confusion. A new quaternary amine antimuscarinic agent, trospium, is hydrophilic and lipophobic, resulting in a low possibility of crossing the blood-brain barrier and causing adverse effects.51 Because nocturnal production of hormones is impaired in some nocturia adults, administration of melatonin can restore a normal circadian rhythm of micturition and improve sleep. It was reported that men treated with 2 mg of melatonin generally experienced a 10% reduction in episodes of nocturia.52 Alpha1-adrenoceptor antagonists and 5α-reductase inhibitors are also used in men with symptoms indicative of benign prostate hyperplasia, and one of their effects is a reduction in nocturia. On the other hand, in women, estrogen deficiency, a common consequence of the menopausal transition, causes atrophic changes within the urogenital tract. Consequently, such women are more disposed to having urogenital symptoms, among which is nocturia.53
6.2. Antimuscarinic agents
7. Surgery
Muscarinic receptor antagonists are the mainstay of medical treatment for an overactive bladder. These agents are believed to exert their effects by directly inhibiting the muscarinic receptors within the detrusor muscle, which leads to bladder contraction and voiding.38 Recent reviews have suggested that in addition to this mechanism, antimuscarinics also function via afferent pathways, alleviating the sensation of urgency.39,40 Their effect on nocturia was also evaluated in a series of 12-week double-blind studies including darifenacin,41,42 solifenacin,43,44 tolterodine,45,46 and trospium.47 In a double-blind trial comparing solifenacin with tolterodine in patients with an overactive bladder, both were observed to be effective in reducing nocturia episodes (a reduction of 0.71 and 0.63 episodes, respectively).48 However, this study lacked a placebo arm, which limits its validity because the extent of improvement attributable to the placebo effect could not be determined. Improvements in nocturia have typically been only moderate and do not consistently reach statistical significance across all studies of a given drug. A recent
Transurethral resection or incision of the prostate may be appropriate when obstruction related to the prostate is the main causative factor of nocturia. Treatment options for selective nocturia patients include pelvic reconstructive surgery for organ prolapse, detrusor myomectomy and cystoplasty for decreased bladder capacity, and botulinum toxin detrusor injection for neurogenic and idiopathic detrusor overactivity.54 A mini-invasive surgical technique for urgency, urge incontinence, and nocturia is sacral neuromodulation. Although evidence of its efficacy is preliminary, the procedure has been successfully used for reducing the degree of urgency and total number of voids.55
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8. Conclusions The pathophysiology of nocturia is multifactorial and can be complex. Its cause remains unclear in a significant number of patients. The ICS defines nocturia as, “the complaint that the individual has to wake at night one or more times to void”.2 Vol. 22, 1–6, March 2011
Nocturia in urology In general, the inconvenience associated with nocturia occurring once is limited, whereas nocturia occurring twice or more is highly disruptive. Bladder diaries are necessary to make a differential diagnosis of the etiology of a subject’s nocturia. Treatment should be tailored to the condition causing the nocturia. If nocturia appears to be due to non-urological diseases, such as congestive heart failure, poorly controlled diabetes, or obstructive sleep apnea, the underlying condition should be treated as a priority. Changes in lifestyle and behavior can be effective in selective patients with nocturia, but pharmacological treatment is often required. Desmopressin, antimuscarinic agents, and α1-blockers are modestly effective compared with placebos. Correctly diagnosing and treating nocturia, especially in elderly patients, will improve the patients’ sleep and, in turn, reduce their risk of fall injuries and the associated detrimental consequences, thereby improving the patients’ health and QoL.
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