European Urology Supplements 3:6 (2005) 1 7. Nocturia" the effect on sleep and related health consequences

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1 %0% Supplements European Urology Supplements 3:6 (2005) 1 7 Nocturia" the effect on sleep and related health consequences Paul Abrams* Southmead Hospital, Bristol Urological lr~stitute, Bristol, United Kingdom Abstract Nocturia is one of the most bothersome complaints in men with lower urinary tract symptoms suggestive of benign prostatic obstruction (LUTS/BPO). Storage symptoms such as nocturia interfere considerably with the patient's performance of daily activities and quality of life. So far little attention has been paid as to why nocturia is such a trouble for men with LUTS/BPO and their partners. It is increasingly believed that disturbed sleep due to frequent awakenings at night resulting in reduced daytime energy and alertness is the underlying cause of the interference with daily-life activities and the reduced quality of life. It seems that in particular awakening during deep sleep, i.e. during the first third of the night, results in increased sleep inertia (i.e. performance impairment immediately after awakening) and reduced daytime performance. It has been shown that the prevalence of frequent night-time voiding interfering with sleep and leading to poor sleep, feeling tired during the day and poor health increases with the number of nocturnal voids. Disturbed sleep not only leads to reduced productivity and increase in the number of sick days, but nocturia and disturbed sleep can also have serious health consequences with a dramatic impact on patients, their family and society. Sleep deprivation has a detrimental effect on somatic and mental health, and is implicated in accidents and even increased mortality. Therefore, it is important to know how LUTS/BPO treatment improves nocturia, reduces disturbed sleep and improves the overall quality of life of patients. Preliminary data suggest that LUTS/BPO therapy reduces nocturia and that a reduction in the number of nocturnal voids during treatment for nocturnal polyuria improves the hours of undisturbed sleep in the first third of the night, when deep sleep predominates. However, further research is required to more precisely assess the impact of LUTS/BPO treatment on nocturia, disturbed sleep and quality of life. The Nocturia Quality of Life (N-QOL) questionnaire which is adopted in the International Consultation on Incontinence modular questionnaire may be a useful tool for this Elsevier B.V. All rights reserved. Keywords: Lower urinary tract symptoms; Benign prostatic obstruction; Nocturia; Bothersomeness; Sleep; Quality of life; Drug therapy; Surgery 1. Introduction Nocturia has been defined by the International Continence Society (ICS) as "the complaint that the individual has to wake at night one or more times to void" [1]. Although one nocturnal void is often considered as within normal limits (in particular in the elderly), it may be bothersome to individuals. However, at least two nocturnal voids are in general * Corresponding authon Pro R Abrams. Southmead Hospital, Bristol Urological Institute, Departmerlt of Urology, Westbury-on-Trym, Bristol BS10 5NB, United Kingdom. Tel.: ; fax: address." panl_abrams@bn.ac.nk (g Abrams). regarded as bothersome. Nine to fourteen percent of the adult male population has to void at least twice a night [2] with the prevalence increasing from 3.4% in men under 30 years to a prevalence of 32.4% in those aged 60 years and over [3]. Nocturia can be due to excessive fluid intake (in particular alcohol and caffeinated drinks), nocturnal polyuria, decreased bladder capacity [e.g. due to detrusor overactivity in men with lower urinary tract symptoms suggestive of benign prostatic obstruction (LUTS/BPO) resulting in reduced voided volume with increased micturition frequency] or a combination of these [2]. It has been recognised for a long time by urologists /.:~ /$ - see front matter 2005 Elsevier B.M All rights reserved. EL~LVI LR

2 2 t? Abrams~European Urology Supplements 3 No. 6 (2005) 1 7 Table 1 Consequences of sleep fragmentation and deprivation associated with nocmria Short-term Increased daytime sleepiness/reduced daytime alertness Longer reaction time Reduced daytime energy Reduced psychomotor performance Reduced concentration/memory/cognitive function Poor mood Longer-term Depression Increased susceptibility to somatic disease Increased risk of cardiovascular disease Increased risk of car accidents and/or falls with fractures Insfimtionali sation Death that nocturia is one of the most bothersome symptoms in patients with LUTS/BPO [4], not only for the patient but also for his partner [5]. Therefore, it is not surprising that nocturia also substantially affects the patient's daily life activities and his quality of life [2]. Recently, more attention is being paid to the fact that nocturia is not only a urological problem. The considerably negative effect on daily life activities and quality of life is probably due to the fact that nocturia induces sleep fragmentation and may therefore lead to lack of sleep; nocturia is cited as the most frequent cause of disturbed sleep continuity in older men [6]. Impaired sleep in turn can induce excessive daytime fatigue [7,8]. In addition, sleep deprivation has a negative impact on daytime energy and psychomotor performance, cognitive function/concentration and mood[9] (Table 1). Nocturia and/or impaired sleep can even have serious health consequences such as depression, immunosuppression and increased susceptibility to cardiovascular disease, can cause car accidents and falls with fractures, and can potentially even lead to death [9 11]. It is also clear that the instruments currently available for urologists to measure nocturia are very limited, and more attention should be paid more specifically to measure nocturia, its impact on the hours of undisturbed sleep and ultimately the patient's quality of life. Therefore, a group of European expert urologists gathered on 8 November 2004 to be updated on and discuss with each other and with a sleep expert and general practitioner, nocturia as a urological problem in LUTS/BPO patients and the impact of existing treatment, the physiology of sleep, the impact of ageing and nocturia as a sleep and quality-of-life problem. This paper summarises the main outcomes of this meeting. Full reports of the presentations and reviews on the discussed topics are also included in this supplement [2,12,13]. 2. The importance of sleep for human living In order to understand how nocturia affects sleep and what consequences this has for performance the next day and the long-term well-being of a patient with LUTS/BPO, it is important to have more insight into the function of sleep for human living, the normal physiology of sleep in adults and how this is affected by ageing [12]. Although there are considerable inter-individual variations in the amount of sleep required, we usually need approximately 8 hours of sleep. This indicates that we spend around one third of our life sleeping. However, sleep is not a passive state of unconsciousness. It is a dynamic brain process that is the result of two largely independent mechanisms: the circadian rhythm and the homeostatic drive to sleep. It is of vital importance for human functioning, as it is needed for recuperation and restoration of physical and, in particular, mental functioning, not only in the short term (i.e. daytime energy and performance and mood the next day) but also in the long term (chronic lack of sleep can result in the development of, e.g., depression and changes in endocrine and immune systems) [ 12]. 3. Normal sleep pattern/architecture in adults Sleep patterns are studied by means of electroencephalography, electrooculography and electromyography. During sleep, rapid-eye-movement sleep can be differentiated from non-rapid-eye-movement sleep. During rapid-eye-movement sleep normal homeostatic processes such as respiratory and temperature control are disrupted, resulting in high brain activity, very low muscle tone, irregular breathing and increased heart rate, and vivid dreams with erections. It is believed that rapid-eye-movement sleep contributes to psychological rest and long-term emotional wellbeing, and that it may also bolster memory. During normal sleep, rapid-eye-movement sleep represents approximately 20 25% of total sleep time. The other 75 80% of sleep time is referred to as non-rapid-eye-movement sleep which is thought to contribute to physical rest and to bolstering of the immune system. During non-rapid-eye-movement

3 t? Abrams~European Urology Supplements 3 No. 6 (2005) 1 7 sleep, four different stages can be differentiated with increasing sleep depth and decreasing muscle tone, respiratory and heart rate and eye movement. Stage 1 represents the shift from being awake to sleeping, i.e. light or drowsy sleep, only takes 3-5 minutes, and therefore represents 1-5% of total sleep time. Its recuperative value seems negligible [10]. Stage 2 concerns a deeper stage of sleep and is often referred to as true sleep because we spend half of the total sleep time in this stage[10]. Although we spend almost 50% of the night in stage-2 non-rapid-eyemovement sleep, it does not seem to be of vital importance. Stages 3 and 4 are the deepest stages of sleep with the highest arousal threshold. Therefore, they are also referred to as deep sleep. Deep sleep represents approximately 25% of total sleep time. Deep sleep is considered to be the most important part of the night and to represent the daily process of restitution [10,12,14,15]. During a normal night, there are 3-6 non-rapideye-movement/rapid-eye-movement cycles which each last between 90 and 120 minutes. During the night, the proportion of non-rapid-eye-movement stages 3 and 4 (deep sleep) decreases and that of rapid-eye-movement sleep increases (Fig. 1). Therefore, non-rapid-eyemovement stages 3 and 4 predominate during the first third (3 4 hours) of the night while rapid-eyemovement sleep predominates during the last half of the night. The rhythm of deep sleep predominating during the first part of the night and rapid-eyemovement sleep during the last part of the night should be preserved as well as possible. Waking during rapid-eye-movement sleep is the optimum time to wake spontaneously, and is associated with a feeling of restfulness. In contrast, non-rapid-eyemovement stages 3 and 4 (deep sleep) is associated with the highest arousal threshold, and provoked wakening during these stages (e.g. due to the need to go to the toilet) results in increased sleep inertia Minutes of Decreasing Stage 4 25 Stage 4 and ~ ='~ REM 20 r.- --'j I i I I Hours of sleep Increasing Fig. 1. Non-rapid-eye-movement (stage 4) deep sleep predominates during the first part of the night and rapid-eye-movement (REM) sleep during the second hal f [ 12]. (i.e. performance impairment immediately after awakening), may even lead to a state of confusion, and results in reduced daytime energy and performance. When woken during deep sleep, the non-rapideye-movement/rapid-eye-movement cycle has to be started again, and deep sleep is lost as the cycles in the last part of the night are associated with less deep sleep. Therefore, interference with deep sleep during the first part of the night, which is the most protective part of sleep, should be avoided as much as possible [12,14-16]. 4. Impact of ageing on sleep As LUTS/BPO patients are in general older men, it is also important to understand how ageing affects sleep. With ageing, there is a gradual decline in overall sleep time. Although older people spend more time in bed, the total sleep time decreases: this is called decreased sleep efficiency. Often this is associated with daytime napping. Older people also have more frequent awakenings during the night and furthermore have difficulties falling asleep again[12,16]. In addition, they do not preferentially awake during rapid-eye-movement sleep (as in younger people). In older people, there is in particular a decrease in nonrapid-eye-movement stages 3 and 4 (deep sleep), and it may even become completely absent. 5. Impact of nocturia on sleep Nocturia is the most important cause of disturbed sleep in older men (Fig. 2) [6]. Furthermore, increased sleep disturbance such as frequent awakenings and poor sleep is related to the severity of nocturia u "o O. 0= =_ "6 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% [ l~worries DAnxiety [] Other Unknown Nocturia Fig. 2. Nocturia is the most frequent cause of disturbed sleep continuity in men aged years [6].

4 t? Abrams~European Urology Supplements 3 No. 6 (2005) % ] 70% = 60% J 50% 40% "6 30% 20% 10% 0% [] Nocturnal voids: 0 [~Nocturnal voids: 1 []Nocturna voids: 2 IINocturna vo de: 3 Frequent Frequent Poor sleep Feel often Do not feel awakenings voiding tired during well preventing the day sleep Fig. 3. Association between tile number of nocturnal voiding episodes, sleep quality, daytime vitality and general feeling of health in older men []71. (Fig. 3)[2,13,17]. Figure 3 also shows that one has to wake at least twice a night to experience problems with frequent awakenings and overall quality of the sleep [ 17]. 6. Impact of nocturia and/or disturbed sleep on daytime energy, concentration and performance and overall feeling of health Not only is the quality of sleep related to the number of nocturnal voids, the perceived daytime vitality/energy and general feeling of health also inversely correlates with the number of nocturnal voids (Fig. 3)[13,17]. This is probably due to the fact that disturbed sleep with reduced daytime energy interferes with concentration, mood and performance of daily-life activities[2,13]. This has not only personal (and family) consequences but also impacts on society as it leads to reduced productivity at work in otherwise healthy subjects, with the number of sick days being linearly related to the number of nocturnal voids [2,13,18,19]. 7. Serious (longer-term) consequences of nocturia/disturbed sleep Society is also impacted by nocturia and/or disturbed sleep leading to increased daytime fatigue and concentration loss, which in turn leads to an increased risk of accidents at work and/or on the road, and falls and fractures [13], the treatment of which increases healthcare costs. In addition, these misadventures may result in elderly people becoming disabled and losing physical independence and/or the caregiver not being able to cope anymore with the nocturnal awakenings, and this may make institutionalisation inevitable. It is needless to say that institutionalisation is strongly resisted by most patients and very expensive for society. Nocturia and sleep deprivation can also lead to depression. There is also emerging evidence that undisturbed sleep is essential for optimal functioning of the endocrine, metabolic and the immune system. Impaired glucose tolerance and increased activity of the sympathetic nervous system with increased levels of catecholamines, following sleep deprivation, seem to increase the susceptibility for the development of type-2 diabetes and cardiovascular diseases (cardiac arrhythmia, angina pectoris and myocardial infarction). Finally, mortality may be increased in elderly patients with disturbed sleep. 8. Impact of treatment for lower urinary tract symptoms/benign prostatic obstruction on nocturia, sleep and health/quality of life In the field of LUTS/BPO, the most important efficacy variable included in clinical trials has been the International Prostate Symptom Score (I-PSS) questionnaire [20,21]. This questionnaire was specifically developed by the American Urological Association in the early 1990s [20] to investigate the frequency of LUTS and the impact of treatment; it was adopted by the International Consultation on Benign Prostatic Hyperplasia (BPH) as the I-PSS [21]. Since the 1990s, the I-PSS has been included in numerous clinical trials with medical therapy and (minimally) invasive interventions. So far, little research has been devoted to the impact of LUTS/BPO treatment on the reduction of nocturia in particular. The only data available today relate to the nocturia question included in the I-PSS questionnaire. For this question the patient has to indicate how many times (over the past month) he most typically had to get up to urinate from the time he went to bed at night until the time he got up in the morning. This can range from none (score 0) to 5 or more times (score 5) per night. Sub-analysis of the 1-year Veterans Affairs Cooperative Study in patients with LUTS/BPO evaluating the impact of the (~l-adrenoceptor antagonist terazosin, the 5(~-reductase inhibitor finasteride and their combination on the I-PSS nocturia score suggests that the (yq-adrenoceptor antagonist reduces not only the total I-PSS but also the nocturia score to a greater extent than

5 t? Abrams~European Urology Supplements 3 No. 6 (2005) == 04 III Baseline DAfter treatment I Jr7 before treatment [] placebo desmopressin ] =02 O) ~O _=,1 placebo finasteride terazosin combin a~ion (n=254) (n=252) (n=262) (n=272) medical therapy (n=93) surgery (n=126) Fig. 4. Reduction in I-PSS nocturia score in LUTS/BPO patients following medical and surgical therapy. Results were derived from two separate studies: left [22] and right [23]. both placebo and the 5(y~-reductase inhibitor [22]. In 1040 patients with at least 1 nocturnal void, the mean I-PSS nocturia score at baseline was 2,5 points, This was reduced by 0,3 points (13%) with placebo, 0.4 points (16%) with the 5~-reductase inhibitor, 0.7 points (28%) with the c~]-adrenoceptor antagonist and 0.4 points (17%) with the combination (Fig. 4), Japanese researchers showed that in 93 LUTS/BPO patients, medical therapy (mainly (~-adrenoceptor antagonists) reduced the I-PSS nocturia score from 2.5 points at baseline to 2,1 points (Fig, 4)[23]. In their study, another group of 126 patients received surgery. Not surprisingly, the mean I-PSS nocturia score at baseline was higher (3.3 points) in these patients. After surgery, the mean score was reduced by 1.4 points (42%) (Fig. 4). Similar findings were reported by another Japanese research group [24]. This shows that the reduction in I-PSS nocturia score is dependent on baseline severity but that after both medical and surgical LUTS/BPO treatment, the mean I-PSS nocturia score is reduced to approximately 2. It also seems that treatment, depending on baseline nocturia severity, reduces the I-PSS nocturia score by (points) nocturnal voids, This reduction is often regarded as small. However, it should be noted that the I-PSS questionnaire was not specifically developed for measuring storage symptoms and, in particular, nocturia, In addition, these studies did not exclude patients with nocturnal polyuria, i,e. a nocturnal urine output of 33% or greater. If these patients would have been excluded, e,g, by the use of simple frequency/volume charts, the reduction in nocturnal voids might have been more pronounced, Moreover, if the reduction of 1 nocturnal void takes place during the first part of the night and deep sleep is not interrupted, this may considerably improve the patient's quality of sleep and daytime performance. Unfortunately, there is currently no information as to whether or not a reduction in the number of Number of nocturnal Time from bedtime to Longest period of voids first void (h) sleep (h) Fig. 5. Rednction in nocturnal voi& is associated with improvement in the hours of nndisturbed sleep [25]. nocturnal voids by approximately 1 with treatment for LUTS/BPO is clinically relevant for the patient in terms of improved quality of sleep and overall quality of life, However, in this regard information is available for desmopressin, a treatment that reduces nocturia caused by nocturnal polyuria (another frequent cause of nocturia). In a double-blind, placebo-controlled, cross-over study, desmopressin reduced the nocturnal voids from 1.9 at baseline to 1.1 following 2 weeks of treatment, whereas no such reduction was noticed following placebo treatment (Fig. 5)[25]. It appeared that this reduction of nocturia by almost 1 void was associated with a considerable improvement in sleep duration. The time from bedtime to first void was improved from 3.2 to 4,7 hours and the longest sleep period was improved from 3.7 to 5.4 hours. The increase in the time from bedtime to first void implies that the patients had 1.5 hours more of sleep in the deep-sleep period which if disrupted leads to reduced daytime performance and confusion, These data have been confirmed by other investigators [26,27]. It therefore seems very likely that a reduction in the number of nocturnal voids by around 1 void after LUTS/BPO treatment will improve the hours of undisturbed sleep and that this will positively affect daytime energy and performance and the patient's overall quality of life. It is however clear that more research is urgently required in this area. In other words, how does a reduction in nocturnal voids after treatment for LUTS/BPO affect the hours of undisturbed sleep and during which period of sleep and how does this translate, in turn, in improved quality of life? The recently developed nocturia quality of life questionnaire, the N-QOL, seems to be a promising tool in this regard [28]. This is a 13-item self-report questionnaire which consists of 2 domains/sub-scales related to nocturia: the sleep/energy domain consisting of 7 questions and the bother/concern domain consisting of 5 questions.

6 t? Abrams~European Urolsgy Supplements 3 Ns. 6 (2005) J 7 In addition, there is one global quality of life question to be completed. The N-QOL questionnaire is also included in the modular questionnaire developed by the International Consultation on Incontinence (ICI- Q) [29]. Each of the 12 questions in the 2 domains has 5 possible answers (scored from 0 to 4) with the total score for the sleep/energy domain ranging from 0 to 28 and for the bother/concern domain ranging from 0 to 24. The additional use of devices which measure sleep and activity during the night (for both the patient and his partner) will objectively provide information on the time of awakening and may overcome potential patient-report problems. The clinical research data obtained through nocturia-specific sleep/quality of life questionnaires and advanced sleep-assessment tools will provide further insight into the relationships between nocturia and sleep, effects on daytime energy and quality of life, and how this is affected by treatment. However, it is unlikely that these tools will be used in primary care practice. Therefore, attention should also be paid to the development of simple tools which are easily used by general practitioners and support their day-to-day management of men with LUTS/BPO who mainly complain of nocturia. Also, as the origin of nocturia is often multifactorial, future research may be devoted to the effect of combination therapy (e.g. an (q-adrenoceptor antagonist with an antimuscarinic) on the relief of storage symptoms such as nocturia in patients with LUTS/BPO. 9. Conclusions Nocturia is the most frequent cause of disturbed sleep in older men. The prevalence of frequent night-time voiding preventing sleep and leading to poor sleep, feeling tired during the day and reduced general health, is related to the number of nocturnal voids/nocturia. The origin of nocturia is often multifactorial, but LUTS/BPO is a major cause of nocturnal micturition in older men. Treatment of LUTS/BPO seems to reduce nocturia, although there are currently no data available as to how this improves disturbed sleep. However, as treatment of nocturnal polyuria, which also reduces the number of nocturnal voids, also increases the hours of undisturbed sleep, it seems very likely that LUTS/BPO treatment will also improve the quality of sleep. This should be further investigated, and in this regard, it should be established how an increase in the hours of undisturbed sleep translates into improved daytime energy and quality of life of the patient. 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7 t? Abrams~European Urology Supplements 3 No. 6 (2005) Resnick M, Reehrborn C and tile Members of the Committees. 5th International Consultation on BPH. Recommendations of tile International Scientific Committee: evaluation and treatment of lower urinary tract symptoms (LUTS) in older men. In: Chatelain C, Denis L, Fen KT, Khoury S, McConnell J (editors). Benign Prostatic Hyperplasia. Plymouth: Plymbridge Distributors Ltd; 2001, pp [22] Johnson TM, Jones K, Williford WO, Kutner MH, Issa MM, Leper H. Changes in nocturia from medical treatment of benign prostatic hyperplasia: secondary analysis of the Department of Veterans Affairs Cooperative Study Trial. J Urol 2003;170: [23] Homma Y, Yamaguchi T, Kondo Y, Horie S, Takahashi S, Kitamura T. Significance of nocturia in the International Prostate Symptom S core for benign prostatic hypeeplasia. J Urol 2002;167: [24] Yoshimura K, Ohara H, Ichioka K, Terada N, Matsui Y, Terai A, ArM Y. Nocturia and benign prostatic hyperplasia. Urology 2003;61: [25] Asplund R, Sundberg B, Bengtsson R Oral desmepressin fur nocturnal polyuria in elderly subjects: a double-blind placebocontrolledrandomized exploratory study. BJU Int 1999;83: [26] Abrams P, Weiss J, Matiasson A, et al. The efficacy and safety of oral desmopressin in the treatment of nocturia in men. Neurourol Urodyn 2001;20: [27] Jennum E Sleep and nocturia. BJU Int 2002;90(Suppl 3): [28] Abraham L, Hareendran A, Mills IW, Martin ML, Abrams R Drake MJ, MacDonagh RE NoNe JG. Development and validation of a quality-of-life measure for men with nocturia. Urology 2004 ;63: [29] Avery K, Hashim H, Gardener N, Abrams R Donovan J, Abraham L. Development and psychometric evaluation of tile ICIQ nocturia module: the ICIQ-N. Neurourol Urodyn 2004;23: Abstract 595.