You are on page 1of 13

EUR O PEAN UROLOG Y 7 2 ( 2017) 757–769

available at www.sciencedirect.com
journal homepage: www.europeanurology.com

Platinum Priority – Review – Voiding Dysfunction
Editorial by Soo Jeong Kim, Omar Al Hussein Alawamlh and Richard K. Lee on pp. 770–771 of this issue

Medical Treatment of Nocturia in Men with Lower
Urinary Tract Symptoms: Systematic Review by the
European Association of Urology Guidelines Panel for
Male Lower Urinary Tract Symptoms
b c
Vasileios I. Sakalis a ,D, iM
narBkeodsrK
etaddrianvoivta is , Thorsten Bac
f
J.L.H. Ruud Bosch e , MaurogGacci , Christian Gratzkhe , Thomas R. Herrmann
Stephan Madersbacher i , Cjharalampos Mamouklakis , Kari A.O. Tikkinen ,
Stavros Gravas l,*, Marcus J. Drake m

a
Department of Urology, Salisbury District HCoesnptieta
r l,ofSaMliisnbiumry
a,l bU
InKv;asive Urology Athens Medical Center, Athens, Greece; French c

Institute of Health and Medical Research, Paris, France; Department of Uroldogy, Asklepios Hospital Harburg, Hamburg, Germany; Department of Uroleogy,
University Medical Centre Utrecht, Utrecht, The Netherlands; Minimally f Invasive and Robotic Surgery, and Kidney Transplantation, Universit
AOUC- Careggi Hospital, Florence, Italy; Department of Uroglogy, Ludwig-Maximilians-University, Munich, Germany; Urology and Urologhical Oncology,
Hanover Medical School, Hanover, Germany; Department of Uroloi gy, Kaiser-Franz-Josef-Spital, Vienna, Austria; Department of Uroloj gy, University General
Hospital of Heraklion, University of Crete Medical Schoolk, D
Heeprarktlm
ioenn,tCsrete, Greece; Public Healtohf, U
Urnoilvoegrysiatyndof Helsinki and
Helsinki University Hospital, Helsinki, Finland; Department of Urolol gy, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece;
Department m of Urology, University of Bristol, Bristol Urological Institute, Southmead Hospital, Bristol, UK

Article info Abstract

Article history: Context: The treatment of nocturia is a key challenge due to the multi-factorial patho-
Accepted June 4, 2017 physiology of the symptom and the disparate outcome measures used in research.
Objective: To assess and compare available therapy options for nocturia, in terms of
Associate Editor: symptom severity and quality of life.
Evidence acquisition: Medical databases (Embase, Medline, Cochrane Systematic
Jean-Nicolas Cornu
Reviews, Cochrane Central) were searched with no date restriction. Comparative studies
were included which studied adult men with nocturia as the primary presentation and
Keywords: lower urinary tract symptoms including nocturia or nocturnal polyuria. Outcomes were
Nocturia symptom severity, quality of life, and harms.
LUTS Evidence synthesis: We identified 44 articles. Antidiuretic therapy using dose titration
was more effective than placebo in relation to nocturnal voiding frequency and duration
Desmopressin of undisturbed sleep; baseline serum sodium is a key selection criterion. Screening for
IPSS hyponatremia (< 130 mmol/l) must be undertaken at baseline, after initiation or dose
Guidelines titration, and during treatment. Medications to treat lower urinary tract dysfunction (a-
1 adrenergic antagonists, 5-a reductase inhibitors, phosphodiesterase type 5inhibitor,
antimuscarinics, beta-3 agonist, and phytotherapy) were generally not significantly
better than placebo in short-term use. Benefits with combination therapies were not
consistently observed. Other medications (diuretics, agents to promote sleep, nonste-
roidal anti-inflammatories) were sometimes associated with response or quality of life
Please visit www.eu-acme.org/ improvement. The recommendations of the Guideline Panel are presented.
europeanurology to read and
answer questions on-line.
* Corresponding author. Department of Urology, Faculty of Medicine, School of Heal
The EU-ACME credits will then
University of Thessaly, 6–8 Feidiou, Larissa 41221, Greece. Tel.: + 30 694 462 6086.
be attributed automatically. E-mail address: sgravas2002@yahoo.com (S. Gravas).
http://dx.doi.org/10.1016/j.eururo.2017.06.010
0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

or as defined by trialist) as polyuria). and nonrandomized as part of lower urinary tract dysfunction (LUTD). or 33% of urine treatment. sleep-promoting 24-h period). and renal nant bothersome symptom). A list of potential confounders was . All rights reserved. symptoms (LUTS) [6] listed: Interventions included: anticholinergics. The symptom can be caused by several different medical conditions. so that nocturia can be a systemic symptom the primary presentation (ie. oral phosphodiester- 2. leading to excessive production of urine at all times (global polyuria) or primarily at night (nocturnal 1. including nocturia). Consistent responses were reported for titrated antidiuretic therapy. nocturia as the predomi- [3. Nocturia can also occur interventional. Published by Elsevier B. such as bladder (male-only or mixed sex populations). and incomplete outcome data. The primary outcomes were: 4. Evidence acquisition Two review authors independently screened the titles and abstracts of identified records. Nocturnal polyuria (ICS definition [7].org/10. overactive bladder syndrome (OAB). Bladder storage problems. and to perform dardized form. selective reporting. For other therapies. Cochrane Systematic Reviews. # 2017 European Association of Urology. desmopressin. and careful assessment is essential to make suitable treatment selection.Quality of life for nocturia. output in people aged over 65 yr [1]).15124/ between the amount of urine produced while asleep. studying adult men in association with other forms of LUTD. options available compared with women. and potentially of limited clinical benefit. Health Economics Evaluations Database) were searched with no Nocturia is defined by the International Continence Society restriction on date of publication (date of final search (ICS) as the complaint that an individual has to wake at night September 2016). The review focusses on men. allocation concealment. . The search strategy was registered on one or more times to void [1]. categorized within is a feature of systemic conditions affecting water and salt the following symptom groups: balance [2]. placebo. the treatment of nocturia is potentially complex. The Embase. diuretics. voiding difficulties). no episodes of nocturia] or Thus. and alternative experimental 24-h urine output in younger patients. Introduction Database of Abstracts of Reviews of Effects. leading to 2. in view of the potential harm (eg. Comparator controls were: 3. The aim of the current systematic review of The secondary outcomes were: treatment was to assess and compare available therapy options for nocturia. For example.758 E U R O P E A N UR O L O G Y 7 2 ( 2 0 1 7 ) 7 5 7 – 7 6 9 Conclusions: Issues of trial design make therapy of nocturia a challenging topic.Symptom severity for nocturia (outcome measure defined as < 2 episodes. hyponatremia. in terms of symptom severity and . a-blockers. and measuring its severity and impact varies in separate research studies. No single treatment deals with the symptom in all contexts. Nocturnal polyuria (nocturnal output exceeding 20% of no treatment. Comparative studies were included storage by the bladder of urine received. agents. 1. The range of contributory factors relevant in nocturia makes it desirable to identify predictors of response to guide therapy. including: random subgroup and/or sensitivity analysis. and other Cochrane Central (Cochrane Health Technology Assessment. disease can affect water and salt homeostasis [5].V. Nocturia nocturnal polyuria as a primary outcome. 2. endocrine. or cure [ie.Harms: adverse events of treatment and events leading to quality of life. the 3.Any other outcomes judged relevant by reviewer. It reflects the relationship PROSPERO on October 21. and the full text of The objectives were to determine the relative benefits and potentially eligible records was evaluated using a stan- harms of treatment options for nocturia. Nocturia can occur (randomized controlled trials [RCTs].4]. Medline. Summarizing the causative categories for nocturia. Patient summary: This review provides an overview of the current drug treatments of nocturia. 24-h (global) polyuria (> 40 ml/kg urine output over a ase-5 inhibitors. with nocturia or outlet obstruction or chronic pelvic pain syndrome. sources of bias. or as defined by trialist). Sleep disorders.doi. LUTS increased rate of urine production. and the CRD42015027092). and was identified by the European Association of Urology . Nocturia (ICS definition [7]. Mixed etiology. 1. responses were less certain. or alternative International Consultation on Male Lower Urinary Tract definition if stated by the investigating group). or observational]). blinding. differing lower urinary tract anatomy and medication withdrawal. mirabegron. 2015 (http://dx. sequence generation. 5-a reductase inhibitors. and phytotherapy. Guidelines Panel for Male non-neurogenic LUTS as a key challenge. 5. or drop-out rates. . reduction in nocturia episodes. notably in comparative studies [both prospective and retrospective. Risk of bias was assessed. which is the need to wake at night to pass urine. Nocturia as a secondary component of LUTS (ie. cardiovascular.

A fall in serum The antidiuretic hormone arginine vasopressin increases sodium level to <130 mmol/l was seen in 4% of patients. HEED = Health Economic Evaluations Database.1 mg. desmopressin was associated with a .1. Mean duration of the first sleep period increased from 2.7 on placebo).5 with combined desmopressin-treated patients showed >50% reduction in therapy. Evidence synthesis nocturnal diuresis < 0. Antidi. following a dose titration phase (LoE 1b) both arms (–0.0 to 1.5–2. study.2 mg. description of primary agonist desmopressin. LUTS already on tamsulosin to receive a basic or a and duration of the first sleep. escalated according to response) in adults with ≤2 with desmopressin in comparison with desmopressin voids/night (LoE 1b) [10].7 h to 4. or bother of nocturia. Cochrane Central (Cochrane HTA.5 h (vs 2. SR = systemic reviews. Levels of Evidence [LoE] 1b) diuresis entered a double-blind efficacy phase. More [8]. absolute difference –0. compared with –1. EU R O P E A N U RO L OG Y 7 2 ( 20 1 7 ) 7 5 7 – 7 6 9 759 Embase. HEED) No date restriction 3554 Citation(s) 3519 Nonduplicate citations screened Inclusion/exclusion 3376 Articles excluded criteria applied after title/abstract screen 143 Articles retrieved Inclusion/exclusion 99 Articles excluded criteria applied after full-text screen 44 Articles included Fig.84 voids/night). 1 – Systematic review flow chart. best clinical response (as defined by the researchers in each Studies are summarized in Figure 1. small short-term crossover study incorporating a dose- uretic therapy using the arginine vasopressin V2 receptor response titration. Nocturnal voids decreased from 3. In a renal water reabsorption and urinary osmolality. developed a priori: age.7 on events only in pharmacotherapy-related arms.9 h). reduced mean number of nocturnal significant). or 3. 0. was more effective than placebo in terms of reduced nocturnal voiding frequency 3.2 on desmopressin alone (not nocturia (33% vs 11%). One hundred and twenty-seven monotherapy in patients with nocturnal polyuria and patients (85 men) achieving >20% reduction in nocturnal nocturia (≤ 2 voids/night. with 34% and 3% experiencing fewer than half the number of nocturnal voids. comprehensive weight reduction program (LoE 2b) Adult men (n = 151) with ≤2 voids/night were studied [9].9). sex. HTA = Health Technology Assessment. or One study investigated a behavioral modification program 0. Cochrane SRs. DARE = Database of Abstracts of Reviews of Effects. Both studies showed mild adverse [11]. including the dose to achieve either no voids per night. desmopressin (vs 3.1 T 0. Another group randomized obese men with voids (39% vs 15%.2–2.4 mg. Antidiuretic therapy respectively.2. Nocturnal voids declined by –1. The improvement in nocturia episodes was similar in for 3 wk. An RCT evaluated desmopressin (0.5 ml/min). a decrease in nocturnal urine production of ≤ 20%. Conservative management (Table 1) and duration of undisturbed sleep (Table 2). Medline. 3. with dose titration to achieve the pathology. severity. DARE.

60) Heterogeneity: x2 = 1.85 (45.00001) reduced nocturnal diuresis of 0.38) Wang 2011b –1. The authors stated that long-term Hypertension 4 (3) NR 3 (2) desmopressin might induce hyponatremia gradually.5 68. Twenty-four-hour Fu Mattiasson Van Kerrebroek diuresis was unaffected. 102.75 62 28.25 81 –0.434 41 50.30.01). fixed.9 45. n (%) 62 (50) 107 (48) 93 (51) 1. 95% CI Asplung 1999a 102 0 17 18 0 17 Not estimable Fu 2011 69.90 (23. and accordingly review of sodium levels is essential Abdominal pain NR NR 8 (4) during treatment. mean difference 0.70.3 1. fixed. exploratory study described outcomes with low doses (10–100 mg) of desmopressin in 757 people (55% men.1)] Fu 2011 –1.85 (1.41 41 21.51 (p < 0.59 ml/min and fewer Table 3 – Adverse effects (AEs) during desmopressin treatment.99 17 –0.2 0 30 Not estimable Van Kerrebroeck 2007 –1.4 –0.40 (55.10) Rezakhanina 2011b 120 0 30 30 0 30 Not estimable Van Kerrebroeck 2007 108 106. I2 = 55% Test for overall effect: Z = 7.798 39 23.25. The key adverse event of hyponatremia (< study medication 125 mmols/l).055 61 21.48.001.35 59 –0. I2 = 0% Test for overall effect: Z = 6. Another RCT looked at 60 men receiving 0. 117.60).70.5236 59 40 87. 78.1 17 15.87 (–1. –0.1 mg desmopressin (LoE 1b) [14]. 68.32.71 81 24 84. df = 2 (p = 0.7 86. An RCT of 115 men older than 65 yr with Dry mouth NR NR 5 (3) nocturia and nocturnal polyuria compared placebo with Micturition frequency 0 NR NR Dizziness 6 (5) NR 1 (1) nontitrated 0. A 4-wk placebo-controlled NR = not reported.7.21 (p < 0. but Diarrhea NR 9 (4) NR Insomnia NR NR 3 (2) specific data provided was limited.4 102. Mean number of nocturia episodes reduced from 2. –0.8 0 58 Not estimable Total (95% CI) 283 269 100 –0. 95% CI Asplung 1999 –0.483 62 27.1-mg desmopressin or placebo for 8 wk (LoE 2b) Patients exposed (n) 122 224 184 [13].15. LoE .79.7 50.31.20 (-1.5 1.4 –0.9 –1.11).59) [12].df = 3 (p = 0.760 E U R O P E A N UR O L O G Y 7 2 ( 2 0 1 7 ) 7 5 7 – 7 6 9 Table 1 – Effect of desmopressin (with dose titrated against response) on nocturnal voiding frequency Placebo Mean difference Study or subgroup Mean SD Total Mean SD Total Weight (%) IV. –0. while rare.87) Wang 2011b 23 0 57 3 0 58 Not estimable Total (95% CI) 283 269 100 61.85. p < 0.4 1.00001) Table 2 – Effect of desmopressin (with dose titrated against response) on hours of undisturbed sleep Placebo Mean difference Study or subgroup Mean SD Total Mean SD Total Weight (%) IV.8 –0.25 1. –0.6 52.8 0.5 0 57 –0.60 (-1.5 1.3 1.13.80 (-1.61) Mattiasson 2002 –1.3). showing Fatigue NR NR NR decreased nocturnal urine output and number of nocturia Peripheral edema NR NR NR episodes (p < 0.5 to 2. Serious AE 3 (3) 1 (<1) 3 (2) Antidiuretic therapy adverse effects are summarized in Deaths 0 1 (<1)a NR AE related to 37 (39) 60 (27) 52 (28) Table 3. 0.29) Rezakhanina 2011a –1 0 30 –0.6 to Total AE.00) Heterogeneity: x2 = 4.1 vs 1. in studies where dose titration was undertaken micturitions at night than for placebo (1. Diplopia NR NR 1 (<1) Options for formulation and reduced dose level have Depression NR NR 1 (<1) been further investigated.55) Mattiasson 2002 110.00 (33.6 (vs placebo 2.2 1.28 39 –0. means that baseline sodium level Headache 10 (8) 26 (12) 17 (9) Nausea 5 (4) 10 (4) NR (< 130 mmols/l) was a selection criterion in research Hyponatremia 3 (3) 8 (4) 6 (3) studies.29 61 34.

Tolterodine tamsulosin (–0.1. respectively.2/ fesoterodine flexible dosing for nocturnal urgency (≤ 2/ night to 1. quality of life and peak flow urgency episodes (—1. vs placebo –0. Nocturia severity was around 3 episodes/night.16. International Prostate Symptom Score [IPSS] > 13.3. The mean reduc.198). Adverse events showed a higher treatment-emergent adverse events were reported with incidence of dry mouth for tolterodine (11% vs 4%). efficient at reducing nocturia score compared with tamsu- losin monotherapy (LoE 1b) [27]. IPSS Question 7 score from baseline compared with sin reduced nocturnal urine volume and the percentage of tamsulosin monotherapy (–0. and > 2 nocturnal voids. sleep (77. numbers of nocturnal voids and voided volume.37) and 75 mg (–0. and increased first sleep period duration. p < 0. 3.02 vs –0. Using tamsulosin. superior to tamsulosin alone. versus 3.8. showed solifenacin 10 mg decreased nocturia by . nocturia episodes/night. The ing placebo or 20 mg desmopressin.85) was greater with fesoterodine than was better in the doxazosin group.9 min vs 40.63. and 0. while change in IPSS tions (–1.2–5. Fifty 66 men with LUTS suggestive of BPE and no other micrograms (–0. since it reduces nocturnal Intranasal administration was trialed in 20 men with frequency (–1.5 for desmopressin.1% vs 1. OAB’’ or OAB. Dry ejaculation is more 3. ≤8 voiding. but at 8 wk the [31]. Change in mean number of nocturnal Improvements in nocturia. evaluated 745 men with 2. Tolter- randomized 31 men with benign prostate enlargement odine reduced OAB-related nocturnal micturitions. A 3-mo RCT reported silodosin.41) desmopressin predisposing factors for nocturia (LoE 2b) [24]. p = 0. A separate study in Japan The combination of desmopressin and tamsulosin is reported similar findings (LoE 1b) [17].2. significantly reduced the weekly values for night-time tion in IPSS was 8. LoE 1b) A post-hoc analysis of two 12-wk RCTs of tolterodine 4-mg [19].3.2 mg (LoE 2b) [21].3.41) and increases the first period of nocturnal polyuria in a short-term cross-over RCT compar. maxi. Subgroup analysis of data from an RCT of Japanese OAB p < 0. with a greater the time to first void by approximately 40 min. respectively (LoE 2b) [25]. Another trial random.0003). respectively (p = 0. the decrease in nocturia was significantly greater Question 7 of the IPSS (‘‘How many times did you typically with fesoterodine 8 mg verus placebo. In men with >2 nocturnal voids at baseline. Medications to treat LUTD Headache is the most frequent adverse event with tamsulosin therapy (3.07) and nocturnal micturi- rates were not significantly different. EU R O P E A N U RO L OG Y 7 2 ( 20 1 7 ) 7 5 7 – 7 6 9 761 1b) [15].2/night. or placebo and found that only silodosin responder rates. A separate post-hoc analysis of a 12-wk RCT ized men to receive either naftopidil 50 mg or tamsulosin studied 555 Asian adults with ≤2 nocturia. Antimuscarinics mum flow rate 4–12 ml/s.2% An 8-wk study assessed tamsulosin (oral controlled vs 2. but not (BPE) and nocturia ≤3/night to 2 mg doxazosin for 2 wk the total nocturnal micturitions.013) Reductions in serum sodium to <125 mmol/l occurred in and the change from baseline was –0. bladder diaries in which each void was attributed as ‘‘non- Several studies used a-adrenergic blockade as compara. Both reduced the number of nocturnal voids. 61% and 49% of patients with silodosin and placebo had and 90% of patients had nocturnal polyuria. Increases in noctur- get up at night to urinate?’’. A post-hoc subgroup analysis of three pooled studies When patients with a nocturnal polyuria index >33% were using silodosin 8 mg in men with LUTS looked at responses to excluded. tamsulosin. respectively.001).5%).6 min). One study extended release 4 mg against placebo (LoE 1b) [29].0001) and fewer patients worsening (9% vs 14%. and placebo. urine passed at night. another study randomized tolterodine tor arms.47 vs –0. and –0. significantly reduced nocturia versus placebo (p = 0. Reductions in nocturia were not significantly different results were comparable between the two arms. At 2 wk.77. A doses of desmopressin were associated with decreasing multicenter 12-wk trial randomized men to receive silodosin. 3. placebo. –0. and these are summarized in Table 4. followed by an open add-on of mirabegron to tamsulosin significantly improved period with 40 mg desmopressin (LoE1b) [18]. 8 mg –0. the reduction in nocturnal LoE 2b) [26]. versus 20 mg intranasal desmopressin A 3-mo RCT of 963 adults with OAB evaluated [20]. using a 7-d diary capturing The mean reduction in nocturnal voids was –1. LoE 1b) [22].1%. However.0 for tamsulosin (vs 5.96 vs –1. nocturia reduced from 3. p < 0.6. In the doxazosin group. Increasing reductions of >1 voids/ night.7 for two men taking 100 mg desmopressin. patients on naftopidil ≤1 urgency urinary incontinence episodes/24 h (LoE 2b) significantly improved their nocturia score. Evidence from the CombAT study suggests that frequency was only significant during unblinded treatment the combination of dutasteride and tamsulosin is more with 40 mg desmopressin. Desmopres. night. serum sodium level <130 mmol/l.1 for urgency scores for each void (LoE 1b) [28].0099).5 or more 60 min for placebo and 82 min for tamsulosin (p = 0. More men treated nal voided volume/micturition were greater with fesoter- with silodosin reported nocturia improvement (53% vs 43%. odine 4 (+38 ml) and 8 mg (+42 ml) than placebo (+15 ml). 10 with placebo.9. on desmopressin orally disintegrating tablets or placebo in An RCT compared tamsulosin versus TURP for nocturia in 385 men with ≤2 nocturnal voids (LoE 1b) [16]. greater tamsulosin. LoE 1b) [30]. p = 0.28 vs —1. respectively (LoE 1b) [23].4–1. Eight severe OAB micturitions. The mean increase in hours of undisturbed sleep was extended release. absorption system formulation) in men (aged > 45 yr. (fesoterodine 4 mg –0. Two patients response seen with TURP in the number of nocturnal on 50 mg desmopressin and nine on 75 mg developed a awakenings and in symptom scores.0001). and increased tamsulosin and TURP improved nocturia.56).099). patients. Selective a-1 adrenergic antagonists common with silodosin than tamsulosin or placebo (14.7 for placebo. increasing to 4 mg.

6 (NA) 200 –1.9 (NA) 60 –0. [24] TUR-P least 12 mo and (–0.0 (–0.8 (NA) 25 –3.1 0.5 (NA) 200 –2.2 (NA) 23 –3.5 T NA (45–84) 167 –0. BPH/LUTS. Qmax 4–15 ml/s Chapple 2011.2 67.1. 3 mo 248 70.02. 6–8 wk 59 69.4 T 7. 95% CI intervention. Mean Mean Total no. 2013. 3 mo 400 61.84 TUR-P appears 2011.2) improves sleep tamsulosin 0.52) improves nocturnal tamsulosin 0.4 mg IPSS ≤13.5 T NA (45–83) 171 –0. 0.0 No difference EUROPEAN UR OLOGY 7 2 ( 2017) 757–769 a-blocker vs BPH/LUTS. 0.7 Early improvement tamsulosin 0.2) No difference tamsulosin 0. [39] Tadalafil 5 mg vs Men ≤45.5 (NA) 38 –0. [9] Weight reduction + Men ≤50. 0. 0.2 –0.3 Combination meloxicam 15 mg vs BPH/LUTS. quality Qmax 5–15 ml/s Oelke 2012.9 T 7.6 63.1 (52–78) 33 –0.16.4 (50–81) 376 –0. 0. BPH. 0.8 T 7.4 mg frequency and first sleep period Data modified for the purposes of the table. 12 wk 339 63. to placebo only Qmax 4–15 ml/s Ukimura 2008.96. –1.35. –0. nocturia ≤2.1. SD) Yee 2015.8 (NA) 57 –0. 0.1 –0. [21] Naftopidil 50 mg vs Men ≤50 yr. –0.2.1 73.11.4 –1. [46] Tamsulosin 0. 0.4. OAB 8 wk 96 75.79.4 mg IPSS:8–19.6 T 10.5 T 6. 0.5.4 mg + Men ≤50.93.9 (53–81) 33 –1.8 T 8.1 –0. –0. 0. [23] Silodosin 8 mg vs Men ≤50.2 mg OAB.8 T 7.7 (50–87) 371 –0.2 68.3 T 7. 0. [25] Desmopressin + Men ≤50 yr.1 63. . nocturia ≤2 (–0.2 mg vs (–0. 0.5 T 7.58.7.3 T 6.5. 12 wk 955 65. –0.6 T 6. Mean Mean duration patients age T SD difference age T SD difference difference IV.4.55 The combination tamsulosin vs LUTS. NA 66 T 7.9. 0. criteria (range) (before and after (range) (before and after fixed.3 (NA) 123 –1.61) (2 wk) in naftopidil flow rate <15 ml/s arm but results are comparable at 8 wk Ichihara 2014 [26] Mirabegron + BPH.8.75) superior to moderate to tamsulosin for severe LUTS BPH related nocturia Gorgel.31 The combination is tamsulosin 0.8 Not estimable Silodosin is superior tamsulosin 0.7 (NA) 38 –0. 0. 12 mo 130 66.2 mg monotherapy (IPSS Q7) Ahmed 2015. (–0. SD) intervention.3 0. 762 Table 4 – Randomized controlled trials comparing drug therapy against tamsulosin for nocturia Study description Outcome Main study Study Randomized Mean Total no.1.3 63.47.4. BPH.1 T 9.11) a-blocker BMI 25–35 kg/m2 Simaioforidis Tamsulosin vs Nocturia for at 12 mo 66 69. (–0.1 –0.4 mg BPH/LUTS. 0.1 T 8. 0.27) not superior to tamsulosin 0. (–1.2 68.5 (NA) 125 –1. IPSS ≤13.

35.4.4.58 in the placebo. voiding LUTS patients. showed that mirabegron the nocturnal frequency. Solifenacin 5 mg and 10 mg nocturnal frequency was seen in 47.4 with placebo and –0. and –0.3.5% on tadalafil (41. Other medications (p = 0. combina. crossing-over following a 1-wk rest period. (azosemide 60 mg) against diazepam (5 mg) in 51 patients (47 men) with nocturia ≤3/night and no daytime urological 3. reduced ejaculate volume and effects on prostate.1.3. nocturia decreased to 3. 32%. –0. and 22%.5 voids/night. Diuretics tions (eg. A double blind RCT compared diuretic therapy patients with nocturia. and hence were greater than with placebo at 1 yr and 4 yr.1 in the terazosin. daytime diuretic decreased mixed population with OAB. Propiverine was not superior to placebo in reducing Adverse events attributable to PDE5 inhibitors have been nocturia frequency (p = 0.22 on placebo. Only patients with nocturia. Adverse events The efficacy of 1 mg bumetanide was evaluated in an RCT attributable to mirabegron (eg. a-blocker. respectively. 2. and sleep quality score were significantly lower responses to IPSS Question 7 (LoE 1b) [39].5% (vs 13.8 and during bumetanide 3. Improved (vs a-blocker and 5-a-reductase inhibitors. Diclofenac taken in the late evening was evaluated in tion. Nocturia Adverse events attributable to 5-a reductase inhibitors decreased from 2. The largest treatment group Another study reported a strategy of furosemide and differences were seen in patients with a baseline nocturia desmopressin for nocturia (≤ 2 voids/night) in the elderly score of 2 or 3.004). and 2. finasteride.3% with increased night-time volume voided per micturition by placebo). and there is no suggestion that they mean nocturnal frequency decreased from 5. Reductions with were observed with active treatment. which was not 30 ml and 41 ml (p = 0. may be contraindicated in patients with hyponatremia. constipation. No significant side effects were reported in either study. Reduced nocturnal voids (3.54. Diazepam decreased nocturia in 50 mg reduced nocturia episodes by 0. and worse in 11. 5-a reductase inhibitors (alone or in combination) treatment the number was reduced by 3. Adverse events attributable to antimuscarinic medica. EU R O P E A N U RO L OG Y 7 2 ( 20 1 7 ) 7 5 7 – 7 6 9 763 0. results of IPSS Question 7 has been reported for An RCT of 49 men with nocturnal polyuria evaluated 4321 patients (LoE 1b) [36]. Eighty-two patients (58 men) were random- A post-hoc subgroup analysis of self-reported nocturia in ized to receive furosemide (20 mg. and placebo groups.1. Beta-3 agonist problems (LoE 2b) [40].46 episodes (LoE 2b) [32]. Total IPSS. LoE 2b) . considered clinically meaningful.9%). 6 h before bedtime) and the Medical Therapy of Prostatic Symptoms trial of men the individual’s optimal dose of desmopressin (at bedtime) with LUTS (LoE 1b) [37] found mean nocturia was reduced or placebo for 3 wk. and were seen from another placebo controlled trial which there is no suggestion that they differ in a population of compared propiverine versus solifenacin (LoE 1b) [34]. p < 0.2. Study Program Trial reported on 1078 men (LoE 2b) [38].5.01) doxazosin. placebo from 12 mo onwards. PDE5 inhibitor Tamsulosin (0. individual studies using tadalafil did not show (15 mg). 0.0033 and p < 0.6 from baseline (vs 22 out of 29 patients. Of men with ≤2 nocturnal polyuria [44]. 25%. During the placebo period the weekly number of nocturia episodes was 13. gastro. 3.8. or A secondary analysis of the Veterans Affairs Cooperative at risk of acquiring it. 3. A RCT randomized 40 men to of nocturia was 2. dry mucous membranes. 100 mg versus placebo was undertaken in 80 men with BPE specific antigen) have been extensively reported in male and ≤2 nocturia/night (LoE 1b) [45]. Some diuretics work by causing natriuresis. For people with a higher atrial Data from a phase 2 dose-ranging study of mirabegron in a natriuretic peptide at baseline.2.0001.0.471. p < 0. and 5-a-reductase inhibitors was –0. mean episodes of nocturia. hypertension) have been of 28 patients (15 men) in general practice (LoE 2b) reported in OAB studies. In the celecoxib group.021).0. have been compared in 400 men with LUTS and significant improvement in nocturia.8.5.5 com- differ in a population of patients with nocturia. Overall severity with combination therapy. nocturia parameters were superior with dutasteride versus yielding a decrease of 0. 50% reduction was seen in 39%.2 to 2.4. Twenty-six patients (20 men. Administration of a diuretic in the afternoon has been esophageal reflux) have been extensively reported in OAB. Similar results extensively reported in erectile dysfunction patients.5 with tadalafil.3 to 5. by –0.1.3. age 72 yr) received 2 wk of placebo or active medication. Nonsteroidal anti-inflammatory drugs 1. 2.7 to 2. Ten men with Pooled data from dutasteride phase 3 studies looking at BPE did not improve with bumetanide. but not finasteride.4. –0. proposed to reduce salt and water load in the body prior to and there is no suggestion that they differ in a population of bedtime. solifenacin 10 mg resulted in statistically significant reduc- tions in the number of nocturia episodes versus placebo 3. doxazosin and combination therapy. IPSS-Quality of Life. and the mean treatment change loxoprofen. An analysis of four nocturia (LoE 1b) [46].3 (p < 0. p < 0. From a baseline mean of 2. respectively). [41]. registrational RCTs of tadalafil for LUTS evaluated pooled nocturia. (LoE 1b) [43]. finasteride.3.40. LoE 1b) [33].4 mg) alone or combined with meloxicam Separately.5 vs 2. versus 0 for placebo. and combination groups at 1 yr.05. Improvements in overall furosemide 40 mg given 6 h before sleep (LoE 1b) [42].3 T 1. pared with 5. An RCT of celecoxib (eg.01) and urine volume (920 ml vs 584 ml. LoE 1b) [35].

0.3. 35 –0. [33] Propiverine Age ≤18.5 T 12.03) superior to placebo in women 654 controlling nocturnal (83. nocturnal frequency EUROPEAN UR OLOGY 7 2 ( 2017) 757–769 max flow rate 4– with tamsulosin over 15 ml/s placebo Oelke 2014.1 Not estimable Not clinically 5 mg OD LUTS duration (100).3 T NA 31 –0. It increases women 545. 0.02.3) (20–89) (20–89) (–0.3.31.5 60 –1.29. women.5 61.10) decreases nocturia nocturia episode (15) episodes.7) Yamaguchi 2007. IPSS ≤13. 63. Not significant 0. [34] Solifenacin Age ≤20. men 343. women. (23.3. 60. (NA) (NA) (–0.9 –0.1. men 340.6 321 –0. [39] Tadalafil Men ≤45.9 60.20.46. 332 –0. [34] Solifenacin Age ≤20.5 T 12.29. men 111. [19] Tamsulosin Men >45.6 T 7. Mean Mean Total no.3. IPSS ≤13. (15) (20–86) (20–89) (–0.1 63. 12 wk 779a.03) superior to placebo women 651 (85) Gotoh 2011.1 63.1 –0.9 –0. 0.4 mg LUTS duration (100). 0. 12 wk 653.8 T 12.3.29.6 348 –0.4 T NA. Mean Mean criteria duration patients. 60. yr Active Main inclusion Study Randomized Mean Total no. age T SD difference age T SD difference difference men (%) vs (range) (before (range) (before IV.15) increases nighttime 1 nocturia episode (83) volume voided per micturition Yokoyama 2011. fixed.6 T 13.2 60.9 T 13.3.7 T NA. 12 wk 340.08) between treatment nocturia ≤? (100) arms women (0) Yamaguchi 2007.42. 0.4) nocturnal frequency . 0. 0. (0) (NA) (NA) nocturnal frequency rate 4–12 ml/s and increase the and >2 hours of undisturbed nocturnal voids sleep Oelke 2014. intervention).6) (23–85) (21–93) (–0. women (%) and after and after 95% CI intervention). 0. 8 wk 117 men 117.34.07) statistical women 423 improvement in (76.13. 172 –0.4 mg IPSS >13. No difference age ≤45. nighttime volume (85) voided per micturition Sigurdsson 2013.03) not superior to women 651 placebo (83. (NA) (NA) (–0. –0.04. (0) (45–83) (46–89) meaningful >6 mo. 59. BPH.1 67. 270 –0.34.4 –0.5. SD SD Djavan 2005. [48] SagaPro Men. 361 –0. Propiverine is not 20 mg OAB symptoms men 125.9) frequency Yamaguchi 2007. (17) 61. [34] Propiverine Age ≤20.6 58. 1. men 66.4 61.34.13. 66. NA 67.2. 12 wk 778a.4 T 13. 0. [39] Tamsulosin Men ≤45.43.18) improvement in >6 mo. [32] Solifenacin Age ≤20.7 –0. 172 –0. (49–86) (47–85) (–0.5.46. 56 –0. 0.1.2. 361 –0.2 60. Solifenacin 5 mg is 10 mg OAB symptoms men 115.8 T 8.83. 0.6 T 13.6 T 12. 12 wk 343. 3.1) (23–94) (20–89) (–0. 1.3 344 –0. (16.5 T NA 165 –0.3. 63. Solifenacin 5 mg 5 mg at least women 542. 1. flow (100). 59.61 –0.08.6 309 –0.29. NA Not estimable Tamsulosin reduces 0.7.6. 56. 12 wk 554. (0) 45–84) (46–89) (–0. [32] Solifenacin Age ≤20. No significant 20 mg OAB symptoms men 131.81. (16.6 284 –0. 0. 0.43. 0.4 –0.7 T NA.9 –0.12. improvement in max flow rate 4– nocturnal frequency 15 ml/s with tadalafil over placebo Yokoyama 2011.12.16. 0. 332 –0. 12 wk 766a. 0. 8 wk 66.8 T 13. 0. Solifenacin 5 mg is 5 mg OAB symptoms men 127. Solifenacin 10 mg 10 mg At least 1 men 96. 764 Table 5 – Effect on nocturnal voiding frequency of drug therapies compared against placebo Study description Outcome Active medication Placebo Author.3 –0.8 T 13. –0.22.15.0 334 –0.5 T NA 171 –0.25. 0.7 T 14. 66. 1. women.3. 12 wk 641. BPH. 1.8 T 13. 1.

0.7 T 14.1.34 59.05 –0.9. (NA) (NA) (–0.1 T 12. 0.43. CI = confidence interval.16. men 88. men 4244. episodes (89.02) nocturnal volume. 1. 64.7.1 T 12. 1. Fesoterodine reduces 4 mg ≤8 voiding.5 142 –0. 1. 0. 0. [36] Dutasteride BPH.5 T NA.17.69 –0.07. (8) placebo ≤3 urgency women 305. (27–88) 174 –0.56.4) placebo ≤3 urgency women 220. Mirabegron 25 mg is 25 mg OAB symptoms men 35. 144 –0. [31] Fesoterodine Nocturia ≤2. 0.2 T NA.6 T 12.67.5 T NA. 1.3 57. 57. 70. a Data modified for the purposes of the table. men 80.5) placebo ≤3 urgency women 298.5) Chaple 2013.1 0. 144 –0. 20 0.63.44.9.1 145 –0.1.56. Improvement in 40 mg men 18.59. 19 –0.6) Drake 2004. [31] Fesoterodine Nocturia ≤2. 12 mo 4244.1 –0.5–10. 144 –0. (50–80) 40 –0. 0. 56. –0. –2.44. 72 T NA 26 –0. 1. (100) (49–80) (–2.2T NA 19 –0. [35] Mirabegron Age ≤18. Mirabegron 200 mg is 200 mg OAB symptoms men 27.45 70. 144 –0. 1. women (0) frequency NP excluded Cannon 1999.1 –0. 4 wk 49.5 –2. [18] Desmopressin NP 7 wk 18. [45] Celecoxib BPH. [18] Desmopressin NP 7 wk 18. [35] Mirabegron Age ≤18. Celecoxib reduces 100 mg per night. 60. OAB 12 wk 251a. 70.5.3 57. (25) (27–86) (–0. 1. 0.7 40 –2. 70 T NA 23 –0.5. NA = not available. –0.23 –0. episodes (90.61.45 –0.20.1. NA 2121 –0. NP = nocturnal polyuria.7 T 14.2 64.26.45 –0. 0. (NA) (NA) (–0.5 141 –0.1 T 12. (100) (–0.44) nocturnal volume and women (0) nocturnal frequency BPH = benign prostatic hyperplasia.08. –0. 1. NA Not estimable Furosemide improves 40 mg NP men 49. (NA) (NA) (–0. episodes (92) Chaple 2013.11. [44] Diclofenac Nocturia ≤2.53. episodes (90) Chaple 2013. 0.6 T 14 201 –0. (12.44. 18 0. 0.2 57.66. –0. 26 –0. 0. (77) (52–90) (52–90) (–0.7 147 –0. (100) (52–80) (52–80) (–1.44.77.15.1.15. [35] Mirabegron Age ≤18.1 T 12.78.59.23 72 T NA.5) placebo ≤3 urgency women 302.30) not superior to ≤3 mo. (10. (NA) (NA) (–0. (23) frequency Falahaktar 2008. 1.39 70. [35] Mirabegron Age ≤18. 1. (100) (52–80) (52–80) (–0. 12 wk 332a.42 59. 0. [42] Furosemide Age ≤50. OAB 12 wk 334a. OAB = overactive bladder. 62.28. 12 wk 333a. (27–88) 174 –0.5) Chaple 2013.37. 1. IV = independent variable.16. 0.0.13) not superior to ≤3 mo.36.5 mg PSA: 1. 0.8. 58.1 –0.1 –0.17. 0. women (0) Cannon 1999. episodes (87.3 57.1 T 12. 18 0. Tolterodine ER 4 mg is EU ROPEAN URO L OG Y 7 2 ( 20 1 7 ) 757–769 ER 4 mg symptoms men 31.9.0 T 13.19) not superior to ≤3 mo.1 –0.5 T NA 18 –0.52. Mirabegron 50 mg is 50 mg OAB symptoms men 33.9.44.69 –0. IPSS = International Prostate Symptom Sco re.1 T 12.23) nocturnal frequency ≤1 urgency women 285 (76) episodes Oelke 2014.27) mean nocturnal women 6. NP 5 wk 26. (100) (60–81) (60–81) (–0.40.12) superior to placebo ≤3 mo. Mirabegron 100 mg is 100 mg symptoms men 32.44. na 69 T NA.9 T 7.18.3.32) mean nocturnal IPSS ≤8. ER = extended release. 0. Fesoterodine reduces 8 mg ≤8 voiding.23) nocturnal frequency ≤1 urgency women 266 (75) episodes Yokoyama 2014. 72.5 180 –0. Diclofenac reduces 50 mg men 20.0 T 13. (100) (NA) (NA) nocturnal frequency women (0) in NP patients Yokoyama 2014.6. 1. 12 wk 375a.5 T NA 18 –0.02. 12 wk 333a.49. (NA) (NA) (–0.9.3 57. 1.07. 765 . 144 –0. (9. 0.8 72 –0. 56.05. 57. [35] Tolterodine Age ≤18.2 T 12. (10) ≤3 urgency women 300.3.17) nocturia outcomes flow: ≤15 ml/s women (0) based on IPSS Question 7 Score Adla 2006.40.9 72.04 NA 2123 –0. Melatonin 2 mg Q7 score ≤3 men 20. SD = standard deviation. IPSS ≤12. Improvement in 20 mg men 80.Chaple 2013.9 T 12. 0. 1.21) significantly improves women (0) nocturia response rate Reynard 1988.2) not superior to ≤3 mo. 0.42.49. (24) (20–87) (–0.37. LUTS = lower urinary tract symptoms.3 T 7. 12 wk 354a. ≤2 voids 1 mo 80. Dutasteride improves 0. [50] Melatonin Menwith IPSS 4 wk 20. men 90.

1/night) compared 2 mg melatonin of subjective ‘‘bother.32 and 0. Phytotherapy for individual studies is given in Supplementary data. nocturnal frequency. a greater reduction in nocturia (–1.4.’’ The differences apparent in pub- with placebo (LoE 1b) [50]. p = 0. The study found no significant difference between the treatment groups. or a combination of factors Lifestyle changes to reduce nocturnal urine volume and episodes of nocturia. An 8-wk placebo-controlled RCT looked at SagaPro (Saga.4. The nature of the [49]. study decrease in nocturia of 0. quality of life.766 E U R O P E A N UR O L O G Y 7 2 ( 2 0 1 7 ) 7 5 7 – 7 6 9 Fig. In a crossover trial of furosemide and gosha- jinki-gan. sleep disorders.5. 1b) [48]. and treatment durations repre- (p = 0.6% of the control group. and the importance and nocturia (mean 3.05 episodes/night design. but with a higher incidence of gastrointestinal side 3. the use of subjective or objective markers as primary 3.9 vs –1. Reykjavik. definitions.4. Summary of medical therapy of nocturia in men effects. antidiuretic. Table 6 – European Association of Urology Guidelines Panel for Non-neurogenic Male Lower Urinary Tract Symptoms (LUTS) recommendations on medication treatment of nocturia in men Treatment should aim to address underlying causative factors. In nocturia. The group receiving the combination including medication (p = 0.1 T 0. outcome measures. 36 patients were reported to have improved A detailed review of principal medical therapies of nocturia symptom score. Iceland). and has been presented. Melatonin and placebo caused a lished literature in regards to populations. Conclusions analysis. systemic condition(s). and a table 3. some trials report an . Nocturia responder rates (a mean reduction of sent a substantial limitation for the evidence base of at least –0. and improve sleep quality should be discussed with the patient 3 Aa Desmopressin may be prescribed to decrease nocturia in men under the age of 65 yr. during dose titration and during treatment a-1 adrenergic antagonists may be offered to men with nocturia associated with lower urinary tract symptoms 1b B Antimuscarinic drugs may be offered to men with nocturia associated with overactive bladder 1b B 5a-Reductase inhibitors may be offered to men with nocturia who have moderate-to-severe LUTS and an enlarged prostate (> 40 ml) 1b C PDE5 inhibitors should not be offered for the treatment of nocturia 1b B A trial of timed diuretic therapy may be offered to men with nocturia due to nocturnal polyuria.034).07). It assumes that conservative measures hours of undisturbed sleep with both medications (LoE 2b) are addressed as part of the care package. Screening for hyponatremia should be 1b C undertaken at baseline and during treatment Agents to promote sleep may be used to aid return to sleep in men with nocturia 2 C [47]. Agents to promote sleep outcomes. reports included reflects the importance of several influ- ences. except on post-hoc subgroup 4. Screening for hyponatremia must be undertaken at 1a A baseline. Daytime urinary frequency and IPSS nonsteroidal anti-inflammatory drugs (NSAID) experienced were minimally altered. 2 – Risk of bias. a product derived from Angelica Urology Guidelines panel for Nonneurogenic Male LUTS archangelica leaf. Recommendations from the European Association of Medica.04). excluding as compared with 2.5 T 0. Gastric discomfort with loxoprofen was seen in 12. on nocturia is given in Table 5. Risk of bias summary for all treatments is given in Figure 2. A summary of the effect of medical therapy.5 episodes/night) were higher with active nocturia therapy. the range of severity included (twice per night A crossover RCT of 20 men with bladder outflow obstruction being a commonly applied threshold).3.9. which may be behavioral. lower urinary 4 Aa tract dysfunction.5%. in 69 men with ≤2 nocturnal voids (LoE are given in Table 6.4.

this study design was to assign patients to the be reported as statistically significant. technical. sodes appeared to yield benefit for antimuscarinic therapy in Study concept and design: Gravas. additional research is needed to corroborate initial findings. since this may help imbalance may happen at any time during treatment. and may be unfeasible in routine clinical practice. EU R O P E A N U RO L OG Y 7 2 ( 20 1 7 ) 7 5 7 – 7 6 9 767 improvement which is reported as statistically significant. Drake. the testing may limit the ability to deliver quality of life [51]. Mamou- sleep. Accordingly. research populations often include diverse placebo in terms of reduced nocturnal voiding frequency and individuals. Karavitakis. Such a process adds to the burden on patients and Question 7). beta-3 considered in the evaluation of trial outcomes. associated effect sizes. clearly-relevant the clinical relevance potentially marginal. which focusses on patients who intervention as the principal therapeutic priority. NSAIDs). and follow up with real-life studies. However. and this should be term use. but which are hard to dose with treatment response and also for safety consider. Tikkinen. Karavitakis. Bosch. as time is not clear. Effect size is also likely totherapy) were not significantly better than placebo in short. Clearly. Finally. Gravas. Sakalis. The cumulative risk of hyponatremia over studies need to be considered for analysis of responders. potentially an opportunity to Financial disclosures: Marcus J. Sakalis. which is not uniformly consistent with healthcare providers in increasing the number of clinical objective markers. but no studies specifically addressing the Author contributions: Marcus J. with response or quality of life improvement. Since ‘‘wake at night to void. Three develop improved approaches to clinical assessment in the out of nine desmopressin studies included in this systematic future. particularly for therapies like NSAIDs. perceive as clinically significant. since there may a significant medical cause. Bosch. require direct from the ICS definition. Screening for hyponatremia must be appears remote. so Medications to treat LUTD in men (a-1 adrenergic findings of many studies merit independent corroboration antagonists. observed. Madersbacher. Bach. Subcategorizing the ‘‘OAB-related’’ nocturia epi. Drake. or material support: Bedretdinova. studies using a-1 adrenergic antagonists and 5-a reductase Acquisition of data: Sakalis. Tikkinen. The abnormality means that hyponatremia is a contraindication likelihood of developing a therapy that can be generalized to antidiuretic therapy. Obtaining funding: None. Madersbacher. It is an assumption that this would also apply in male- only populations. but some therapy to individual patients. The potential to worsen severity of the a trial.’’ Very little published evidence is nocturia is a symptom rather than a disease. In addition. Bedretdinova. both in terms of efficacy and studies have used patient perception (such as the IPSS safety. which might treatment. Drafting of the manuscript: Drake. and is very little information on long-term outcomes of drug were also not significantly better than placebo in short-term therapy for nocturia. perhaps reduced incidence of severe complication. Nonetheless. Administrative. although evidence suggests that sodium well as the overall population response. In such a setting. accuracy of the data analysis. use. of action is uncertain. Potential benefit was seen in long-term use in some Gacci. interest. Benefits with combination therapies were not consistently Critical revision of the manuscript for important intellectual content: Drake. Drake. Drake had full access to all the data in the impact of OAB medications on nocturia in men were study and takes responsibility for the integrity of the data and the identified. where the mechanism Supervision: Gravas. Differences between therapies emerged in studies Analysis and interpretation of data: Sakalis. Statistical analysis: None. Nonetheless. evaluation needed to categorize factors likely to affect therapy ment contributes to overall improvements in health-related response. sometimes greater than perceived in clinical practice. and may not undertake the full extent of duration of undisturbed sleep. measuring all nocturnal voids. there agonist) generally had a female-predominant population. The range of potentially The review identified that antidiuretic therapy using relevant contributors may well affect therapy outcome. agents to promote Gravas. the causes of nocturia that can be treated by mechanism-specific studies described generally take a pragmatic approach of approaches. after initiation or dose titration and the specific situation of individual patients. and but which might actually be comparatively small. where a-1 adrenergic antagonist was the comparator. Nocturia severity improve. Other medications (diuretics. 5-a reductase inhibitors. Drake certifies that all conflicts of screen for undiagnosed or suboptimally-managed disease. which is somewhat different congestive heart failure. making potential economic benefits. affected population is manifest. Furthermore. one trial. PDE-5 inhibitor. responder ations. Mamoulakis. since nonresponders will be excluded predictors of response to enable targeting of therapy to before the full trial. such as poorly controlled diabetes mellitus. Data on OAB medications (antimuscarinics. reported effect sizes are contacts required. The symptom of nocturia is an important one. Bach. Gacci. including specific financial interests and relationships and . clinician-directed dose titration was more effective than Despite this. Karavitakis. Gratzke. a response selection phase will increase the analysis may help identify whether a subgroup did get a larger likelihood of a positive outcome in the RCT and the (clinically more useful) reduction in nocturia severity. phy. Herrman. or sleep apnoea. so nocturia therapy choice needs to consider undertaken at baseline. inhibitors. Gravas. Accordingly. were sometimes reported as being associated lakis. the during treatment. causative available to signify what implications this could have for categories have been proposed [6]. Gratzke. Herrman. Responder analysis is particularly interesting in review [10–12] undertook dose titration with the active studies reporting modest reductions in nocturia. dose titration is a process individuals more likely to benefit would be a helpful advance. which can be undertaken in clinical practice in order to tailor Objective markers are scientifically preferable. to be affected by baseline severity. Other: None. and the diversity of the interpretation of results.

J Urol [5] Honoraria. Cortesse A.18:213–20. placebo controlled. of nocturia: definition. Lilly.org/10. Gratzke is a behavioral modification education program with desmopressin in company consultant for Astellas Pharma. Ibsa. Desmopressin in the treatment of nocturnal polyuria in the male. advisory. Pfizer. [18] Cannon A. Wu E. Ng CF. Zinner NR.185:219–23. Ibsa. travel grants nal polyuria in elderly subjects: a double-blind. patients with nocturia: a prospective. Lilly. effectiveness of intranasal desmopressin and doxazosin in men with [2] Cornu JN. double-blind. and GSK. Efficacy of desmo- Medicament. Krott L.31:441–7. financial support for attending symposia. GSK. Yau P. Effect of combined systematized grants and research support from Bayer. Lilly. Cook Medical. Int J Urol 2008. GSK. and has received fellowships and 2015.1016/j.85:1291–9. and Recordati. 2011. Milani S.06. Van Der Meulen EA. Abrams P. placebo-controlled trial. [21] Ukimura O. GSK. He has received grants and research of terminology in nocturia: report from the standardization sub- support from Allergan. Supplementary data in efficacy and dose response in Japanese patients with nocturia treated with four different doses of desmopressin orally disinte- Supplementary data associated with this article can be grating tablet in a randomized. and has received speaker honoraria from Elli Lilly. GSK. and Rottapharm-Madaus. Ceylan T. received. placebo-controlled from Angelini Pharma Hellas. BJU Int 2011. and Takeda. Mevcha AM. MSD. are the following: Bach has received levels of evidence and recommendations from the International speaker honoraria from Cook Urology. consultancy.56:240–6. travel grants from Lisa Laser. randomized study.67:283–8. Miki T. Bayer Healthcare on the severity of lower urinary tract symptoms in obese male Research. Astellas Pharma. BJU Int 1999. Effect of weight reduction and travel grants and research support from AMS. participates in a trial for Ipsen. Karl Storz blind placebo-controlled study in men. quality of sleep: preliminary results of a pilot study. Drake has received speaker honoraria from [7] Van Kerrebroeck P. and is a consultant for Astellas. Nocturia as a manifestation of cial reference to the storage symptom: a prospective randomized systemic disease. DFG. Everaert K. Urol J 2013. Astellas.62:877–90. randomized. He participates in trials for Astellas 2012. Astellas. Van Kerrebroeck P. Pfizer. So WY. and Takeda. Böhringer Ingelheim. speaker honoraria from GSK. financial support for 2011. Nocturia: current patents filed. Okihara K. Cardozo L. at http://dx. Gacci is a company committee of the International Continence Society.21:167–78. Carter PG. Lilly. Davies J. Huang SW. Desmopressin orally attending symposia. Bosch has received grants or disintegrating tablet effectively reduces nocturia: results of a ran- research support from GSK and Astellas. honoraria from Astellas. Eli-Lilly. Siroosbakhat S. and has received fellowships and travel grants from Ariti. placebo controlled. Lin YN. Gravas has received grants or [12] Asplund R. eururo. and man. [16] Weiss JP. Chaikin D. royalties. BJU Int 2002. and speaker honoraria from Angelini Pharma Hellas. Eur Urol 2015. financial support for educational programs.15:1049–54. Klein BM. J Res Med Sci Medicament. Abrams P. Steba. Kim JH. honoraria. Agras K. domized. et al. Cruz F. et al. GSK. parallel group study. [9] Yee CH.111:474–84. employment/affiliation.89:855–62. Takeda. Hoebeke P. Herschorn S. Juul KV. Bolodeoku J. Oelke M. GSK. Abrams P. from AMS.10:993–8.107:702–13. Rezapour M. placebo-controlled trial. and receives speaker trolled trial.doi. Sundberg B. Yip SK.52:221–9. and has received travel [8] Cho SY. cant improvement of nighttime voiding frequency (nocturia) with . Pierre Fabre pressin in treatment of nocturia in elderly men. and Pierre Frabre. multicenter. The standardization Allergan. Lilly. Doluoglu OG. Weiss J. The standardisation of terminol. Fall M. 2013. grants or funding. [17] Yamaguchi O. Neurourol Urodyn AstraZeneca. and Lilly.4:61–8. Drake MJ. J Urol 2013. Gender difference Appendix A. et al. Urology Wolf. He has received speaker honoraria parallel study. Pierre Fabre [13] Rezakhaniha B. et al. Raskolnikov D. placebo-controlled study. Eur Urol ogy of lower urinary tract function: report from the Standardisation 2005. and Ferring. Schneider T. honoraria. Maderbacher is a company patients with benign prostatic hyperplasia: a randomized con- consultant for Astellas. Neurourol [20] Ceylan C. agement–a systematic review and meta-analysis. or [6] Marshall SD. [19] Djavan B. Elli Lilly. Riis A. McConnell AA. and Pierre Fabre Medicament. Comparing the Urodyn 2002. MSD. in the online version. randomized exploratory study.16:516–23. educational programs. Kanazawa M. Should nocturia not be called a lower urinary tract [22] Eisenhardt A. Endoscope. financial support for educa- [14] Wang CJ. Korean J Urol 2015. Eur Urol 2007.83:591–5. double-blind. advisory board.190:965–72. consultancy. Arianpour N. consultancies. or pending). [4] Drake MJ. Herrmann declares Karl Storz GmBH. and FerringAG. Blanker MH. Boston Scientific. Mamoulakis is a company consultant for Astellas. Lee KS. and Recordati. Eur Urol Naftopidil versus tamsulosin hydrochloride for lower urinary tract 2012. and Ferring. BJU Int found. pathophysiology. Boston Scientific. Walter S. BJU Int consultant for Bayer. Norgaard JP. He ble-blind. Abrams P.84:20–4. participates in trials for Bayer. GSK. affiliations relevant to the subject matter or materials discussed in the Diagnosing the pathophysiologic mechanisms of nocturnal poly- manuscript (eg. and [11] Mattiasson A.2017. Sub-committee of the International Continence Society. A contemporary assessment nocturia: a pilot randomized clinical trial. Kamoi K. and Norgaard JP. Chang CH. Bayer. GSK. et al. financial support for attending symposia. uria. and GSK. participates in trials for Astellas. Medivation. Oral desmopressin for noctur- research support from Pierre Fabre Medicament and GSK. stock ownership or options. Janssen. symptoms associated with benign prostatic hyperplasia with spe- [3] Gulur DM. Consistent and signifi- symptom? Eur Urol 2015. and [10] van Kerrebroeck P. the EUSP.768 E U R O P E A N UR O L O G Y 7 2 ( 2 0 1 7 ) 7 5 7 – 7 6 9 Goessaert AS. Van de Walle J. Chapple CR.010. The impact of tamsulosin References oral controlled absorption system (OCAS) on nocturia and the [1] Abrams P. Efficacy of desmopressin in the treatment of nocturia: a double- Astellas. Astellas. Albei CD. Dendreon. Thuroff J. epidemiology. Low dose oral desmopressin tional programs. Nishizawa O. Yuksel S. Int Neurourol J 2014. Fujihara A. and Ferring AG. and is a consultant for Astellas. expert testimony. Allergan. advisory Board. and Rottapharm-Madaus. Norgaard JP. Bengtsson P. financial support for [15] Weiss JP. LISAsiLaa:sa erdOoH ubGleA-G blind. royalties: Boston Scientific AG for nocturnal polyuria in patients with benign prostatic hyperpla- honoraria. GSK. Porge-Coloplast. study. and Lilly. and Richard Consultation on Male Lower Urinary Tract Symptoms. with nocturia: results of a multicenter. He 2002. Efficacy and safety of low dose desmopressin orally disintegrating tablet in men Funding/Support and role of the sponsor: None. Karl Storz Endoscope.67:289–90. randomized. financial support for attending symposia. BJU Int 1999. Ipsen Pharma Honoraria.90(Suppl 3):11–5. Desmopressin in the treatment of nocturia: a dou- Teleflex.

170:145–8. jinki-gan. Melatonin pharmacotherapy for study of mirabegron in patients with overactive bladder. Shalaby E. Neilson D. D’Ancona C. Nocturia improvement in the combination of Avodart and [43] Fu FG. Weiss JP. natriuretic peptide is a useful criterion in treatment of nocturia. Roehrborn CG. placebo-controlled trial. prostatic hyperplasia: results of an international. with tolterodine reduces overactive bladder-related nocturnal mic. Urology 2014. Castro R. D’Ancona C. Hotta S. Park CH. Cannon A. Roehrborn CG. Kakizaki H. Noble JG. Int Uro. World J Urol 2014. Eur Urol 2011. Abrams P. overactive bladder. et al. Wijkstra H. Y. Yokoyama O. placebo- [30] Weiss JP. The effect of doxazosin. Efficacy of solifenacin loxoprofen sodium on nocturia in patients with benign prostatic on nocturia in Japanese patients with overactive bladder: Impact on hyperplasia.72:813–6. Wilson TH. ies. A parallel. Matsui Y. [23] Chapple CR. et al. placebo-con- impact of adding low dose oral desmopressin therapy to tamsulosin trolled clinical studies. Gudb- [33] Gotoh M. medical treatment of benign prostatic hyperplasia: Secondary formed in Europe. World J Urol 2014. randomized. Yang Q.18:243–8. nocturia in men with benign prostatic enlargement. Chrisofos M. Takeuchi H. Cox D. tract symptoms suggestive of benign prostatic hyperplasia: a post [25] Ahmed AF. tadalafil on nighttime voiding (nocturia) in men with lower urinary plasia.32:1133–40. Propiverine hydrochloride in jarnason S. Sahin E. Burrows PK. Wang JT. double-blind. Br J Urol 1998. Mills IW.67:731–6. men. et al. Roehrborn CG. Dvorak V.189:1396–401. Reducing nocturia in the elderly: A tamsulosin (CombAT) study. Shahin A. Kasahara M. Efficacy and safety of controlled study. Kose O. placebo-controlled. flexible dose fesoterodine in men and women with overactive [46] Gorgel SN. Yamagami H. in patients with benign prostatic hyperplasia symptoms and [31] Yokoyama O. placebo. randomized placebo-controlled trial of staggered furosemide and [28] Kaplan SA. Debruyne FM.100:579–87.193:921–6. The effect of bladder symptoms including nocturnal urinary urgency. Gabr AH. J Urol 2007.68:328–32.32:1141–7. Weiss JP. Deliveliotis C. plasia: a prospective. Egilsdottir PB.105:1141–6. a blended herbal medicine. nocturnal polyuria: A double-blind randomized trial of frusemide [27] Oelke M. randomized.35:310–3. et al. A randomized controlled study of the efficacy of tamsulosin [41] Pedersen PA. Olgunelma V. Efficacy of impact on nocturia and sleep quality. Jumadilova Z. Long-term effect of [32] Yokoyama O.24:1447–58. Kusek JW. 2006. Korean J Urol 2011. Johnson TM. Scand J Urol 2013.59:342–52. A phase II dose-ranging [50] Drake MJ.47:26–32. 2004. Masumori N. Br J Urol 1988. Urology ecoxib for treatment of nocturia caused by benign prostatic hyper- 2006. [38] Matthiesen TB. Ruff D. O’Reilly P. Rovner ES. Ghobish A. Masui K. Human atrial plasia.52:265–8. J Urol [42] Reynard JM. J Urol combined therapy with tamsulosin hydrochloride and meloxicam 2013. [47] Shin HI. Neurourol Urodyn 2011. World J Urol 2014. Int Braz J Urol 2013. sleep evaluated by bladder diary. et al.178:2045–51. Radziszewski P. Tanaka Scand J Urol Nephrol 2001. Viktrup L. placebo-controlled crossover study.and propiverine-controlled trial of the once daily anti. Castro R. De La Rosette JJ. Marui E. Adeyoju AB. Int J Urol 2011. Prophylactic treatment of adult nocturia monotherapy and its combination with mirabegron for overactive with bumetanide. Kakizaki H. double-blind phase III stud. Urol 2014. Low Urin Tract Symptoms 2012. World J three randomized. BJU Int 2010. Mogami S. Dmochowski R. Wu DL. Michel MC. discussion 736. Lavery HJ. Sefik E. Pourreza F.32:1119–25. Montorsi F. Chang HS. Mokhtari G. M. for nocturnal polyuria: a muscarinic agent solifenacin in Japanese patients with overactive randomized crossover trial. [40] Fujikawa K. double-blind. Int J Urol 2011. Urology 2008. randomized.30:437–52.81:215–8. [48] Sigurdsson S. double. double-blind. Tolterodine extended release improves overactive bladder symp. Cel- turitions in patients with overactive bladder and nocturia. Koritsiadis Trial.62:145–7. [29] Rackley R. Manyak against placebo. M. . [34] Yamaguchi O. [35] Chapple CR. et al. Kim CI. World J Urol 2015. J Urol gynecol J 2013. Furosemide versus gosha- placebo. Djurhuus JC. Effects of prostate: effect on nocturia as a result of benign prostatic hyper. Guan Z. BJU Int 2007. 77–81. Shimizu Y. Silodosin therapy for finasteride and combination therapy on nocturia in men with lower urinary tract symptoms in men with suspected benign benign prostatic hyperplasia. Geirsson G. Nishizawa O. Tammela TL. [45] Falahatkar S. bladder induced by benign prostatic obstruction. J Urol 2003. Impact of dutasteride on nocturia in men with lower urinary The role of nocturia in the quality of life of men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia tract symptoms.and active controlled clinical trial per.18:365–73. Fukuta F.32:1127–32. Kamran AN. S. Z. placebo-con- Japanese patients with overactive bladder: a randomized. [36] Oelke M. therapy for treatment of nocturia owing to benign prostatic hyper. Changes in nocturia from double-blind. Kim BH. The hoc analysis of pooled data from four randomized. EU R O P E A N U RO L OG Y 7 2 ( 20 1 7 ) 7 5 7 – 7 6 9 769 silodosin in men with LUTS suggestive of BPH: pooled analysis of (LUTS/BPH): a pooled analysis of three phase III studies. Urology ment of nocturia caused by nocturnal polyuria: a prospective. Gudmundsdottir H. Manyak [51] Van Dijk MM.39: fesoterodine on nocturia and quality of sleep in Asian patients with 657–62. analysis of the Department of Veterans Affairs Cooperative Study [24] Simaioforidis V. double-blind. Wilson TH. Nighttime dosing Eur Urol 2006. Rovner ES. Maarouf A. Hiro S. Yamaguchi O.83:750–5. Tamsulosin versus transurethral resection of the [39] Oelke M. [37] Johnson ITM.171:1199–202. Rittig S. Johansen B. trolled study to investigate the effect of SagaPro on nocturia in blind. Asgari SA. [44] Addla SK. Papatsoris AG. [26] Ichihara K. Guan desmopressin. A novel therapy for 2015. [49] Yoshimura K. Mamoulakis C. randomised. Chrisafis M.33:649–57. J Urol 2011. et al. Diclofenac for treat- toms in men with overactive bladder and nocturia. Randomized. Iwasawa A.49:720–5. Tsukamoto T. Wang JT.186:170–4.4: bladder.