Management and treatment

Chapter 6

Management and treatment 6.1

Introduction

A number of therapies are available for nocturia, as described in subsequent sections. After implementing a therapy, safety, efficacy, and effect on patients should be assessed regularly. Consideration should be given to combining therapies/interventions in case of inadequate response (Oelke et al., 2017). Patients with nocturia of undetermined cause who are not responding to lifestyle and behavioral modifications, or not responding to drug therapies, should be considered for assessment by specialists.

6.2

Phototherapy

Circadian disorder can be an etiology of nocturia (see Chapter 2: Etiology, pathophysiology, and risk factors). Phototherapy may be helpful to reset the normal circadian rhythm in some patients whose circadian rhythm is disrupted (Kujubu, 2009).

6.3 6.3.1

Interventional approaches and surgery Overview

Interventional approaches and surgery are available for severe functional abnormalities in patients with refractory low global bladder capacity (“endstage bladder”). They include intravesical injection of toxin A, nerve stimulation, and surgery.

6.3.2

Botulinum toxin A

The use of botulinum toxin A in the treatment of nocturia is limited. American Urological Association (AUA) and European Association of Urology (EAU) guidelines recommend that intravesical injection of botulinum toxin A should be offered to patients with urgency urinary incontinence refractory to antimuscarinic therapy. The mechanism of botulinum toxin A includes inhibition of vesicular release of neurotransmitters and the axonal expression of capsaicin and purinergic receptors in the suburothelium, as Nocturia. DOI: https://doi.org/10.1016/B978-0-12-820097-1.00006-8 © 2020 Elsevier Inc. All rights reserved.

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well as attenuation of central sensitization. Multiple randomized, placebocontrolled trials have demonstrated that botulinum toxin A is an effective treatment for patients with refractory idiopathic or neurogenic detrusor overactivity (Hsieh et al., 2016). The urinary incontinence episodes, nocturia, maximum cystometric capacity, and maximum detrusor pressure were improved when compared to placebo. The adverse effects of botulinum toxin A, such as urinary retention and urinary tract infection, were primarily localized to the lower urinary tract. Botulinum (onabotulinum) toxin A injections may also be used in pediatric patients with nonneurogenic detrusor overactivity (NNDO) (Bayrak et al., 2017). This is based on a study investigating the effectiveness and reliability of botulinum toxin A injections in 39 pediatric patients with NNDO (Bayrak et al., 2017). The results of this study showed that botulinum (onabotulinum) toxin A injections were effective in decreasing voiding frequency, incontinence episodes, and increasing bladder capacity, with negligible side effects and complications.

6.3.3

Nerve stimulation

There are three types of nerve stimulation: sacral nerve stimulation (SNS), percutaneous or posterior tibial nerve stimulation (PTNS), and transcutaneous electrical nerve stimulation (TENS). SNS, PTNS, and TENS are used in the context of overactive bladder (OAB), with nocturia as a secondary outcome. Several clinical studies have been conducted to provide promising evidence for the efficacy and safety of this approach in patients with OAB symptoms (Sherif and Abdelwahab, 2013; Slovak et al., 2015; Staskin et al., 2012). Adequate standardization of stimulation criteria and outcome measures is necessary to define the best way to administer this therapy and document its efficacy (Slovak et al., 2015).

6.3.4

Surgery

Bladder augmentation and bladder replacement are potentially useful albeit rarely employed in such patients. Bladder outlet obstruction surgery is performed in the context of lower urinary tract symptoms (LUTS) and benign prostatic obstruction. For some men suffering from benign prostatic hyperplasia (BPH), surgery has proven successful. Also, men who had part or all of their prostate removed have reported improved sleep and quality of life (Zhou et al., 2010). Despite some success, surgery should remain a last resort and only after all less invasive methods have been exhausted, especially those that focus on nutrition or lifestyle changes. Also, surgery should be avoided in monosymptomatic nocturia.

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6.4 6.4.1

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Lifestyle and behavioral modification Used as first-line therapy for nocturia

The physiological basis and evidence for the effectiveness of lifestyle and behavioral modifications in the treatment of nocturia, OAB, and urgency urinary incontinence are well established. Lifestyle and behavioral modification should be the first intervention before instigating other treatments (Oelke et al., 2017; van Kerrebroeck et al., 2010), because they are of low cost, effective, and safe. A reasonable time period over which to assess treatment response from lifestyle and behavioral modifications is 3 months, unless the symptoms are increasing or patients find the symptoms intolerable (Oelke et al., 2017; van Kerrebroeck et al., 2010). Lifestyle and behavioral modifications have been known to improve the symptoms of nocturia (Cornu et al., 2012; Rees et al., 2018; Weiss et al., 2011; Wyman et al., 2009), and lifestyle modifications are especially applicable in patients with global and nocturnal polyuria (Soda et al., 2009, 2010) in the absence of glycosuria or diabetes insipidus.

6.4.2

Types and personalized treatment

Lifestyle and behavioral modifications include the following items. The choice of specific lifestyle and behavioral modifications should be individualized, based on the condition and situation of the patients.

6.4.2.1 Dietary and fluid management A common type of lifestyle and behavioral modification is dietary and fluid restriction, together with management of fluid and food intake and timing of their consumption. Examples are: G

G G G

G

Managing fluid intake and the type of fluid, as well as the timing and amount of fluid intake, such as avoiding the following fluid in the evening: 2 alcoholic beverages, 2 caffeinated beverages, 2 carbonated beverages, and 2 sweetened beverages. Nocturnal dehydration. Reduce or eliminate fluid intake 4 hours before bedtime. Identifying bladder irritants (see Table 6.1) to which patients are sensitive, and eliminating the bladder irritants from the diet. Note that most people are not sensitive to ALL potential bladder irritants listed in Table 6.1 (Yamanishi et al., 2014). The goal is to identify and avoid the foods that worsen nocturia. Reduce salt consumption (Matsuo et al., 2019; Matsuo et al., 2015).

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TABLE 6.1 List of potential bladder irritantsa,b. Fruits (including juice, foods and beverages containing these fruits) G Apple G Grape G Cranberry G Guava G Cantaloupe G Peaches G Pineapple G Plums G Strawberries G Citrus fruits Sweets G Sugar G Artificial sweeteners G Saccharin G Aspartame G Corn sweeteners G Honey G Fructose G Sucrose G Lactose

Beverages Alcoholic G Carbonated beverages (e.g., soda, and carbonated water) G Coffee (including decaffeinated) G Tea G

Foods Chili and spicy foods G Chocolate G Tomatoes, tomato juice, and tomatocontaining foods and beverages G Vitamin B complex G Vinegar and vinegar-containing foods and beverages G

Dairy products Milk G Cheese G Cottage cheese G Yogurt G Ice cream G

a

Information is based on those described by Hanno et al. (2011), Gormley et al. (2015), and Wyman et al. (2009). b Most people are not sensitive to ALL potential bladder irritants listed in this table. The goal is to identify and avoid the foods that worsen nocturia.

6.4.2.2 Voiding patterns As a part of behavioral intervention, patients should establish appropriate voiding patterns. They should include: G

G G

Establishing normal voiding intervals and continence. Note that this involves bladder training techniques associated with a progressive voiding schedule together with relaxation and distraction for urgency suppression and multicomponent behavioral training. Preemptive voiding immediately before going to bed. Double voiding, which tends to be helpful for those with significant postvoid residual (PVR) issues. This means voiding once and then doing it again about 5 10 minutes later.

6.4.2.3 Bowel regularity Establishing bowel regularity can be beneficial in managing nocturia. Management of bowel regularity includes: G

bowel movement training to establish consistency in the time of each day in using the toilet;

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regular pelvic floor exercises (PFE); and moderate physical exercise.

6.4.2.4 Healthy habits Establishing healthy habits and eliminating unhealthy ones can be beneficial in managing nocturia. Examples are: G G G

regular exercise and avoid immobility; smoking cessation; and regular fiber diet, which can be helpful to establish bowel regularity.

6.4.2.5 Others Other lifestyle and behavioral modifications in managing nocturia include: G

G G

G G

evening leg elevation to help drain fluids that may be causing swelling of the legs; using leg compression stockings to help prevent swelling of the legs; Try to go to bed at midnight, as the circadian effects of prostaglandin decline at that time. It also extends the time between dinner and going to bed; use of protective undergarments; and use of sleep medications/aides.

6.4.3

Pelvic flood exercise

One of the lifestyle and behavioral modifications listed above is PFE. PFE should include contraction to control urgency and increasing interval between voids. Biofeedback technique is also frequently used. PFE can strengthen the muscles around the bladder, vagina or penis, and back passage. Strengthening of pelvic floor muscles can help stop incontinence, may be beneficial to prolapse, and improve sex. They are beneficial to both men and women. These exercises have also been found to have moderate success against urgency at night in cases of OAB (Johnson et al., 2005). Examples of videos of PFE can be found in youtube.com, such as those listed below: G G G

G

https://www.youtube.com/watch?v 5 QHwVglPQR_w https://www.youtube.com/watch?v 5 S7d1z_jJ5wo https://video.search.yahoo.com/yhs/search?fr 5 yhs-adk-adk_sbnt&hsimp 5 yhs-adk_sbnt&hspart 5 adk&p 5 what 1 is 1 Pelvic 1 floor 1 exercises# id 5 1&vid 5 a4eab82eed28f3bf402d7dae9ea7b4b2&action 5 click https://video.search.yahoo.com/yhs/search?fr 5 yhs-adk-adk_sbnt& hsimp 5 yhs-adk_sbnt&hspart 5 adk&p 5 what 1 is 1 Pelvic 1 floor 1 exercises#id 5 3&vid 5 8ee3e9499aaa9518c4f37d99505b249b&action 5 view

6.4.4

Practicality of lifestyle and behavioral modification

A significant number of patients have had improvement with the drug-free treatment approach. However, many primary care clinicians may have a limited awareness of the evidence supporting the often straightforward treatment

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recommendations and guidance for incorporating lifestyle and behavioral interventions. One reason is due to the busy schedule of primary care practices. Another reason is that most of the information associated with lifestyle and behavioral modification has appeared in specialty literature (Weiss and Blaivas, 2000). Furthermore, lifestyle and behavioral modifications are cumbersome, and they require dedication and commitment. Not all patients are willing to practice these therapies for extended periods of time. As a result, few patients adhere to them long term. In spite of these problems, it is important to take steps in lifestyle modifications and behavioral therapy prior to initiating medical therapy, as they are of low cost, effective if applied appropriately, lack side effects, and are generally beneficial to the general health of patients. Drug therapy should be considered only if necessary, due to its potential side effects and costs (Chughtai et al., 2008).

6.5 6.5.1

Drug treatments Overview

Pharmacological therapies should be introduced after lifestyle and behavioral modifications have failed or as adjuncts, and should be introduced in patients with sustained bother from nocturia (Oelke et al., 2017). The choice of drugs for nocturia depends on the primary etiology (Friedman and Weiss, 2013; Khan et al., 2011; Weiss et al., 2011). Table 6.2 lists the drugs used in the clinic to treat nocturia in the United States and other countries. Subsequent sections describe evidence supporting the use of drugs for treatment of nocturia. Among all the drugs used to treat nocturia, desmopressin is the only drug approved by the FDA for this particular indication, and it is used as monotherapy. The approval was supported by a number of large well-designed (including placebo-control and double-blinded) clinical trials including Phase 1, 2, and 3 trials during clinical development, prior to FDA approval. These clinical trials include those reported by Asplund et al. (1999), Hoverd and Fowler (1998), Johnson et al. (2007a), Kuo (2002), Lose et al. (2003, 2004), Mattiasson et al. (2002), Rezakhaniha et al. (2011), and Weiss et al. (2012). The other drugs currently used to treat nocturia are not specifically approved by the FDA for such an indication. These drugs are supported by limited clinical studies assessing nocturia parameters as the primary endpoint. Despite achieving statistical significance, these clinical trials were associated with small sample size, not always well-designed, short-term, involved subjective assessment, and/or were designed for assessment of lower urinary tract disorders other than nocturia as the primary endpoint (Smith and Wein, 2011). Well defined objective assessment (instead of subjective assessment) in drug assessment for the treatment of nocturia is of paramount importance, as clinical trials on treatment of nocturia are known to

TABLE 6.2 Drugs investigated and/or used for treatment of nocturia in the United States and other countries. Types

Specific drugs

Tradename

Indication approved in the United States

Nocturia condition under which drug is used

Antidiuretics

Desmopressin

Noctiva, nasal spray

Nocturia

G G

Nocdurna, sublingual tablet Diureticsb

Furosemide

Lasix

Edema and hypertension

G G

Azosemidec

Antimuscarinics (anticholinergics)

Bumetanide

Bumex, Burinex

Edema associated with CHF, hepatic and renal diseases

Oxybutynin

Oxytrol

OAB

Fesoterodine

Toviaz

OAB

Darifenacin

Enablex

OAB

Tolterodine

Detrol LA

OAB

Tolterodine

Detrol

OAB

Solifenacin

Vesicare

OAB

Trospium

Sanctura

G G

Nocturia polyuria of all sources For nocturia in men ,65 year old (screen for hyponatremia at baseline, during dose titration and during treatment)a High baseline atrial natriuretic factor Timed diuretic therapy for men with nocturia due to nocturnal polyuria (screen for hyponatremia at baseline and during treatment)a

Nocturia associated with OAB Men with nocturia associated with OABa

(Continued )

TABLE 6.2 (Continued) Types

Specific drugs

Tradename

Indication approved in the United States

Nocturia condition under which drug is used

Alpha-1 blockers

Terazosin

Hytrin

BPH

G

Agents to promote Sleep NSAID

d

Alfuzosin

Uroxatral

BPH

Doxazosin

Cardura

BPH

Silodosin

Rapaflo

BPH

Tamsulosin

Flomax

BPH

Melatonin

Sleep aid

Celecoxib

Celebrex

Diclofenac Loxoprofen

Voltaren c

Loxonin, Oxeno, Loxomac, etc.c

Indomethacin

Indocin, Tivorbex, etc.

Aspirin

Ascriptin; Aspergum; Bayer Aspirin; Norwich Aspirin, etc.

Various types of inflammation and/or pain

G

Nocturia associated with BPH Men with nocturia associated with LUTSa

G

Nocturia associated with bladder outlet obstruction Aid return to sleep in men with nocturiaa

G

Nocturia polyuria

G

5ARIs

Finasteride

Proscar

BPH

Dutasteride

Avodart

BPH

Tadalafil

Cialis

BPH and erectile dysfunction

Sildenafil

Viagra

Erectile dysfunction and hypertension

Avanafil

Stendra

Erectile dysfunction

Vardenafil

Staxyn, Levitra

Erectile dysfunction

β3-Agonists

Mirabegron

Myrbetriq

OAB

Plant Extracts

Permixon from Serenoa repens

PDE5i’se

G

Nocturia associated with BPH Men with nocturia who have moderate-to-severe LUTS and an enlarged prostate ( . 40 mL)a

G

Nocturia associated with BPH

G

Nocturia associated with decreased functional bladder capacity

G

Nocturia associated with BPH

G

ADH, Antidiuretic hormone; AVP, arginine vasopressin; 5ARI, 5α-reductase inhibitors; BPH, benign prostate hyperplasia; CHF, congestive heart failure; ICI, International Consultation on Incontinence; LUTS, lower urinary tract symptoms; NSAID, nonsteroidal anti-inflammatory drugs; OAB, overactive bladder; PDE5i, phosphodiesterase type 5 inhibitor; SR, sustained release. a Per recommendations from European Association of Urology Guidelines Panel for Non-Neurogenic Male LUTS for treatment of nocturia in men (Sakalis et al., 2017). b The ICI committee does not recommend diuretics for the management of nocturia (Khan et al., 2011). c Not approved or marketed in the United States. d The National Institute for Health and Clinical Excellence guidelines do not recommend NSAIDs for nocturia, due to the toxicity risks with chronic use of NSAIDs. e European Association of Urology Guidelines Panel for Non-Neurogenic Male LUTS does not recommend treatment of nocturia in men with LUTS (Sakalis et al., 2017).

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have great placebo effect, such as those observed in clinical studies of desmopressin Phase 3 trial and other clinical trials (Lee et al., 2019). Some investigators express doubt on the clinical significance of some of these drugs [such as alpha-1 blockers, 5α-reductase inhibitors (5ARI), and antimuscarinics] in treating nocturia (Cornu et al., 2012; Khan, et al., 2011; Schneider, et al., 2009; Smith and Wein, 2011; Rao et al., 2016). The use of off-label drugs for the treatment of nocturia, in spite of not being supported by substantial clinical data, is a reflection of a lack of options in FDA-approved drugs. Better drug therapies with good efficacy and safety profiles for nocturia treatment are of great medical need. Nocturia is frequently associated with BPH, OAB, and other lower urinary tract disorders. One would expect that successful drug treatment of these disorders would attenuate nocturia; however, this is often not the case. Nocturia has been shown to respond poorly to traditional drug therapies for BPH, including alpha-1 blockers, 5ARI, and phosphodiesterase type 5 inhibitor (PDE5i) (Oelke et al., 2014c; Smith and Wein, 2011). For example, a retrospective analysis of men who received terazosin, finasteride, combination, or placebo for BPH showed that drug therapies did not have clinically significant effect on nocturia when compared to placebo (Johnson et al., 2003). Specifically, in 788 (75.8%) out of 1,040 men with 2 or more nocturia episodes, nocturia was changed from a baseline mean of 2.5 episodes to 1.8 episodes with terazosin, 2.1 episodes with finasteride, 2.0 episodes with combination, and 2.1 episodes with placebo. Of men with 2 or more episodes of nocturia, 50% reduction in nocturia was seen in 39% of those treated with terazosin, 25% with finasteride, 32% with combination, and 22% with placebo. The PDE5i tadalafil significantly improves overall LUTS suggestive of BPH, yet improvements in nocturia were not significant in several clinical trials (Oelke et al., 2014c). Nocturia has also been shown to respond poorly to traditional drug therapies for OAB, including antimuscarinics (Smith and Wein, 2011). For example, tolterodine (an antimuscarinic agent) has been shown in a clinical trial in patients with nocturia associated with OAB that, when compared to placebo, tolterodine improved OAB-specific symptoms, but not nocturia (Rackley et al., 2006). A lack of significant attenuation in nocturia with successful drug treatment of these BPH and OAB suggests that nocturia is a complicated pathologic condition, rather than simply a symptom of these disorders. Subsequent sections described each category of drugs for treatment of nocturia.

6.5.2

Antidiuretics

6.5.2.1 Desmopressin as monotherapy The only FDA-approved nocturia drug is desmopressin, which has two dosage forms: nasal spray (Noctiva) and sublingual tablet (Nocdurna). Desmopressin is approved to be used as a single agent for the treatment of nocturia due to nocturnal polyuria (Friedman and Weiss, 2013; Oelke et al., 2017;

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Song et al., 2014). Desmopressin is a synthetic analog of the peptide hormone vasopressin, also called antidiuretic hormone, arginine vasopressin (AVP), or argipressin (Anderson, 2012). Desmopressin increases water resorption in the distal and collecting tubules of the kidney, thus decreases urine production and reduces voiding episodes. The efficacy of desmopressin for the treatment of nocturia has been established in both short- and longterm studies in various populations, including men, women, and the elderly, as well as in patients with detrusor instability and cystometic capacity of # 250 mL (Ahmed et al., 2015; Cho et al., 2014; Kuo, 2002; Lose et al., 2003, 2004; Mattiasson et al., 2002; Slawson, 2014; Weiss et al., 2012). Desmopressin was shown to decrease the severity of nocturia and improve quality of life. Although the efficacy in reducing nightly voids is great when compared to baseline ($50% improvement), its efficacy is limited when compared to placebo (0.2 and 0.3 0.4 nightly void reduction beyond those from placebo for the nasal spray and sublingual tablet, respectively). Nevertheless, low-dose, gender-specific desmopressin is effective in treating nocturia due to idiopathic nocturnal polyuria (Oelke et al., 2017). The safety profiles of both formulations of desmopressin are good, with the exception of the risk of a serious and potentially fatal adverse event—hyponatremia. For a higher desmopressin dosage form for a different indication, there were 61 cases of hyponatremia-related seizures reported, two of which resulted in death (Lee et al., 2019). In nocturia treatment, although the lower dose versions had lower hyponatremia incidence, it remains the most frequent adverse event and leads to treatment discontinuation in some cases. The FDA requires a black-box warning on the product label for potentially life-threatening hyponatremia. In the use of either formulation of desmopressin, care should be taken when prescribing desmopressin, especially to elderly patients ($65 years), as the risk of hyponatremia is higher in this population (Song et al., 2014). It is also advisable to check serum sodium levels before starting treatment or changing the dose of desmopressin in elderly patients. Important instructions and precautions with the use of desmopressin are summarized in Table 6.3. These instructions and precautions are mainly based on Package Inserts of the two formulations of desmopressin, as well as 2019 International Continence Society (ICS) guidelines (Everaert et al., 2019). Critical to the appropriate and safe use of desmopressin is a follow-up schema during desmopressin therapy, for monitoring of sodium homeostasis in the acute and chronic phase of therapy. An informed and engaged patient is also critical to desmopressin safety. Changes in fluid ingestion or alterations in concomitant comorbidities may potentiate the risk of hyponatremia. Before starting therapy, baseline sodium levels must be obtained in patients at risk for hyponatremia. Bioavailability and formulation delivery appear to have an impact on desmopressin half-life and the area under the curve (indicative of drug exposure), both of which impact the risk of hyponatremia (Olesen et al., 2018). A serum sodium monitoring plan should begin with a

TABLE 6.3 Summary of instructions and precautions with the use of desmopressin. Do’s G G

G

G G

Monitor sodium levels regularly Monitor volume status regularly in patients with NYHA Class I congestive heart failure Discontinue the nasal spray form in patients with concurrent nasal conditions that may increase absorption, until resolved Regular use of Voiding Diary Advise patients to: 2 Restrict fluid intake 2 Report to the doctor any nausea, vomiting, headache, loss of energy and fatigue, restlessness and irritability, muscle weakness, spasms or cramps, decreased serum sodium, weight gain, seizures, coma 2 Regular follow-up with the doctor 2 Consult the doctor in case of any untoward symptom. 2 Follow the instructions given by doctor in the use of desmopressin 2 Inform the doctor that you are taking desmopressin when you have any hospitalization

Don’ts G

G

G

G

G

Use in patients with one of the following disorders or conditions is not safe: 2 Hyponatremia or a history of hyponatremia 2 Polydipsia 2 Uncontrolled hypertension 2 Primary nocturnal enuresis 2 SIADH 2 Illnesses that can cause fluid or electrolyte imbalance 2 NYHA Class II IV congestive heart failure 2 Loose motions, fever, infection 2 Heart ailments and other conditions requiring treatment with diuretic drugs. 2 Moderate-to-severe renal disease (eGFR ,50 mL/min/1.73 m2) 2 At risk of increased intracranial pressure or history of urinary retention 2 Peripheral edema 2 Uncontrolled hypertension 2 Diabetes 2 Children under the age of 5 years Use in patients taking the following medications: 2 Loop diuretics 2 Systemic or inhaled glucocorticoids, or oral steroids 2 Medications that have a high risk for hyponatremia or a low risk for hyponatremia Patient should not drink: 2 Excess fluids 2 Beverages such as tea or coffee at night 2 Alcoholic beverages when on desmopressin Nonbothersome nocturia, or convenient voids Demopressin therapy should stop, if monitoring of therapy on days 3 to 7 and at 1 month shows serum Na is ,130 mmol/L regardless of symptoms, and if serum Na is 130 135 mmol/L with symptoms of hyponatremia

eGFR, Estimated glomerular filtration rate; NYHA, New York Heart Association; SIADH, syndrome of inappropriate antidiuretic hormone secretion.

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baseline sodium $ 135 mmol/L and with additional serum sodium assessment at week 1, month 1, and year 1 after initiation of desmopressin in patients who are at increased risk (e.g., due to older age, or concomitant medications) (Olesen et al., 2018), as most clinically significant cases of hyponatremia occur within 2 3 weeks of treatment initiation. Time to return to normal serum sodium after cessation of treatment is a median of 17 days (range 8 28). In young healthy patients, serum sodium checks may not be necessary if there are no underlying medical conditions. Fluid restriction should be advised for all patients. If the response to desmopressin is insufficient at a low dose, the dose can be up-titrated, depending upon the frailty of the patient. A serum sodium check should be carried out before up-titration. If the dose is up-titrated then further sodium checks should be carried out within 7 days. If hyponatremia is found after initiating desmopressin therapy, treatment should be discontinued when serum sodium concentration is below 130 regardless of the presence of symptoms. If sodium check is 130 135 and the patient is asymptomatic, treatment need not be discontinued, but further serum sodium checks, drug-free intervals, or lowering the dose is needed (Everaert et al., 2019).

6.5.2.2 Desmopressin combination therapy Desmopressin, both nasal spray (Noctiva) and sublingual tablet (Nocdurna) dosage forms, is the only drug approved by the FDA to treat nocturia. It was developed and approved by FDA as monotherapy for those with the nocturnal polyuria. Given that desmopressin has limited efficacy (0.2 and 0.3 0.4 nightly void reduction beyond those from placebo for the nasal spray and sublingual tablet, respectively) and since nocturia is a multifactorial medical condition in most cases, a combination of treatment options may be required to provide improved efficacy in broad patient population (Rao et al., 2016; Yazici and Kurt, 2015). Subsequent sections describe clinical trials on combination therapy associated with desmopressin. A number of investigations on the combination use of desmopressin with another agent in the treatment of nocturia have been completed. Although results from some of these investigations are interesting and promising, none of them were designed as Phase 3 trials with the intention of obtaining FDA supplemental approval in using desmopressin as a combination product. As such, there is no formal FDA-approved use of desmopressin in combination with another product in the treatment of nocturia. 6.5.2.3 Desmopressin and tamsulosin (an alpha-1 blocker) combination A clinical study was conducted to evaluate the desmopressin/tamsulosin combination in the treatment of nocturia in patients with benign prostate hyperplasia (BPH) (Ahmed et al., 2015). In this clinical study, 248 patients

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with nocturia associated with BPH were enrolled and randomized into two groups. Group 1 patients received tamsulosin (0.4 mg/day) and the sublingual formulation of desmopressin (60 mcg/day) (the D/T group), whereas Group 2 patients received tamsulosin 0.4 mg only (the T group). The duration of treatment was 3 months. The results showed that, when compared to tamsulosin alone, the combination improved nocturia (44.6% vs 64.3%) and prolonged the first sleep period (from 83.2 to 123.8 minutes vs from 82 to 160 minutes, P , .001). International Prostate Symptom Score (IPSS), quality of life, PVR volume, and maximum urinary flow rate (Qmax) at night were significantly improved compared with baseline, but without statistical differences between the two groups. No serious adverse effects were reported in both groups. Therefore these results suggested that desmopressin/tamsulosin combination is a viable and more effective treatment of nocturia. A clinical study involving the use of desmopressin as an add-on therapy was conducted to evaluate the desmopressin/tamsulosin combination in the treatment of nocturia (Bae et al., 2013). This clinical study enrolled 216 patients, of whom 158 (76%) had nocturnal polyuria, 15 (7.2%) had decreased nocturnal bladder capacity, and 35 (16.8%) had nocturia due to both causes, despite alpha-1 blocker treatment for a minimum of 4 weeks. The optimum dose of oral desmopressin was determined during a 4-week dose titration period, and this dose was maintained for the subsequent 24 weeks. The results showed that the number of nocturnal voids significantly decreased from baseline (from 7 to 5.7 voids/night, P , .01). The average IPSS and subscores significantly decreased by week 4 and were maintained at week 24. IPSS voiding subscores were significantly improved at week 24 in patients younger than 65 years old compared with those in patients aged 65 years or older. Hence, desmopressin add-on therapy for refractory nocturia has been found effective and well tolerated.

6.5.2.4 Desmopressin and solifenacin (an antimuscarinic) combination A clinical study investigating the effect of desmopressin combined with the anticholinergic drug, solifenacin, has been conducted in 68 female patients with OAB (Han et al., 2011). In this study, patients were treated with either 5 mg of solifenacin or 5 mg of solifenacin plus 0.2 mg of desmopressin for 2 weeks. The results showed that there was no statistical difference in the time to first void between the two groups (105 vs 117 minutes), but time to the second and third voids were improved by the combination therapy when compared to solifenacin alone (255 vs 203 minutes for second voids, and 368 vs 312 minutes for the third voids). The combination therapy also improved the first urgency episode when compared to solifenacin alone (255 vs 212 minutes). Quality of life scores also improved with combination therapy. Although OAB symptoms were improved, nocturia was not specifically

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assessed. Therefore whether desmopressin and solifenacin combination can be beneficial in patients with nocturia associated with OAB is unknown.

6.5.2.5 Desmopressin and furosemide (a diuretic) combination A randomized control trial reported a strategy of furosemide and desmopressin for nocturia in the elderly, by comparing a furosemide 1 desmopressin combination with furosemide alone (Fu et al., 2011). In this study, 58 elderly men and 24 elderly women with nocturia $ 2 voids/night were randomized to receive furosemide at 20 mg given 6 hours before bedtime, and either individually optimized dose of desmopressin or placebo given at bedtime for 3 weeks. The results showed that the furosemide 1 desmopressin combination induced greater reduction in nocturnal voids when compared to furosemide 1 placebo (2.0 vs 3.5 voids/night, respectively, P , .01) and greater reduction in nocturnal urine volume (584 vs 920 mL, respectively, P , .01). 6.5.2.6 Desmopressin and behavioral modification combination Combining desmopressin with a Systematized Behavioral Modification Program (SBMP) is another potentially useful approach in the management of nocturnal polyuria. A prospective, multicenter, randomized, parallel study comparing desmopressin alone with a combination of desmopressin and the SBMP has been conducted (Cho et al., 2014). In this study, 124 male and female patients aged 20 years or older who had nocturia and nocturnal polyuria were randomized to receive desmopressin alone or desmopressin plus SBMP combination. The results showed that nocturnal voids were reduced slightly (not statistically significantly) more with the combination than desmopressin alone (21.5 vs 21.2 nightly voids). The combination was better than desmopressin alone in nocturnal polyuria index (0.29 vs 0.37, P 5 .028), with improvement in the maximal bladder capacity (13.3 vs 241.3 mL, P , .001), and the rate of patients lost to follow up (0% vs 10.3%, P 5 .016). Self-perception for nocturia significantly improved in both groups. Therefore although not adding benefit to reducing nocturnal voids, desmopressin in combination with SBMP may be a preferable therapy than desmopressin alone in treating patients with nocturia due to improving other aspects of nocturia. 6.5.3

Diuretics

If antidiuretics, such as desmopressin, can alleviate nocturia (see previous section), one would expect that diuretics would worsen nocturia. Ironically, diuretics may actually be effective in relieving nocturia, by preventing water and salt accumulation via forcing water out of the body when taken during daytime. Randomized controlled clinical trials of diuretics evaluating behavioral measures which focus on nocturia as a primary outcome are not

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available. However, there were small clinical trials suggesting the benefits of some diuretics in patients with nocturia. Examples are described below. A randomized controlled trial involving 49 men with nocturnal polyuria was conducted to evaluate the benefit of furosemide (40 mg) given 6 hours before bedtime when compared to placebo (Reynard et al., 1998). The results showed that furosemide decreased 0.5 voids/night from baseline, versus 0 void/night with placebo. There were no differences in nocturnal voided volume between treatment with furosemide and placebo. A double-blind randomized control trial was conducted to compare azosemide at 60 mg versus diazepam at 5 mg in 47 men and 4 women with nocturia $ 3 voids/night and no daytime urological problems (Fujikawa et al., 2001). The results showed that administration of azosemide at daytime decreased nocturnal void frequency in study subjects with a higher atrial natriuretic peptide at baseline. Diazepam decreased nocturia in 22 out of 29 patients, probably due to better sleep hours. A randomized control trial was conducted in 15 men and 13 women to evaluate the efficacy of 1 mg bumetanide compared to placebo (Pedersen and Johansen, 1988). The results showed that, during the placebo period, the weekly number of nocturia episodes was 13.8. It was reduced by 3.8 during bumetanide treatment. The nocturia episodes were not improved by bumetanide in 10 men with benign prostate enlargement. Note that the diuretics investigated work by causing natriuresis, and hence may be contraindicated in patients with hyponatremia, or at risk for hyponatremia. The International Consultation on Incontinence (ICI) committee does not recommend diuretics for the management of nocturia (Khan et al., 2011). However, some physicians found diuretics effective if the timing of administration is appropriate. Specifically, they should be administered during the mid-late afternoon, taking into consideration the plasma half-life of the specific diuretics (Oelke et al., 2017).

6.5.4

Antimuscarinics (anticholinergics)

Antimuscarinic agents are used in the treatment of nocturia caused by detrusor overactivity and OAB. The mechanism of action in the treatment of nocturia is related to reducing the muscarinic effect of acetylcholine on relaxing bladder smooth muscle. Early publications speculated that antimuscarinic agents should be able to provide relief from the symptoms of OAB along with nocturia in the majority of patients, including the elderly, with a minimal side effect profile (Chughtai et al., 2008; Rackley, 2006). Subsequent publications indicate that there is limited evidence in support of the broad use of antimuscarinics for the management of nocturia in the context of OAB (Cornu et al., 2012; Rao et al., 2016). A number of antimuscarinic agents (such as trospium, darifenacin, and solifenacin) have been used for the treatment of OAB, but they have not been evaluated for nocturia

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(Rao et al., 2016). The dermal patch form of oxybutynin (a nonselective muscarinic receptor antagonist with high affinity for muscarinic receptors in human bladder tissue) has been shown to decrease the number of nocturia episodes compared to placebo (Rackley, 2006; Yokoyama et al., 2015b). Tolterodine has been shown in a large clinical trial in patients with nocturia associated with OAB that, when compared to placebo, tolterodine improved OAB-specific symptoms, but not nocturia (Rackley et al., 2006). A thorough review of clinical studies on antimuscarinics as a potential drug treatment of nocturia by Cornu et al. (2012) showed that the vast majority of the studies on antimuscarinics were conducted in the context of OAB management, with a few focusing on nocturia. One of the few studies focusing on nocturia as the endpoint was a randomized control trial that compared tolterodine with placebo (Rackley et al., 2006), as briefly described above. In this study, 850 men and women with nocturia associated with OAB received placebo or tolterodine for 12 weeks after a placebo run-in period. Patients were evaluated by a Voiding Diary, and the main outcome criterion was the change in the mean number of nighttime micturitions from baseline. While tolterodine was associated with an improvement in other OABspecific symptoms, the difference between the two groups for nocturnal frequency was not statistically significant (decrease of 19% and 23% for placebo and tolterodine, respectively, P 5 .145). A meta-analysis in the use of solifenacin (5 or 10 mg) compared to placebo to treat nocturia in patients with OAB and nocturia has been conducted (Brubaker and FitzGerald, 2007). This analysis pooled data from four Phase 3 trials for evaluation of reductions in nocturia episodes after treatment with solifenacin versus placebo. A second analysis was performed in patients with and without nocturnal polyuria. The results showed that patients treated with solifenacin experienced statistically significant reductions in nocturia episodes, with median reductions of 235.5% for 5 mg of solifenacin and 236.4% for 10 mg of solifenacin, compared to only 225.0% for placebo. There were significantly more patients treated with solifenacin than placebo who achieved a mean nocturia frequency of # 1 episode/night. Additionally, solifenacin significantly reduced nocturia episodes only in patients without nocturnal polyuria, with mean reduction of 20.61 episodes/night for both doses of solifenacin compared to 20.43 episodes/night for placebo. Solifenacin also significantly improved nocturia symptoms, but only in OAB patients without nocturnal polyuria. Other studies that primarily focused on nocturia as the endpoint were either pooled analyses or post hoc analyses of previous randomized control trials (Chapple et al., 2006; Fitzgerald et al., 2008; Johnson et al., 2005; Yokoyama et al., 2011). Two of these studies reported statistically significant reductions of nocturnal voids per night, but the effect size was low and the clinical significance doubtful. A meta-analysis on the use of antimuscarinics for OAB did not evaluate nocturia (Chapple et al., 2006). Another meta-analysis

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on the use of antimuscarinics to treat nocturia in men with LUTS revealed that these drugs were generally not significantly better than placebo in short-term use (Sakalis et al., 2017). In conclusion, some antimuscarinic agents (e.g., oxybutynin and solifenacin) may be effective in improving nocturia in OAB patients. There is limited evidence that other antimuscarinics are efficient for the specific management of nocturia in the context of OAB. Unless proven with randomized placebocontrolled large clinical trials, antimuscarinic agents should not be assumed effective in treating nocturia (Cornu et al., 2012; Rao et al., 2016).

6.5.5

Alpha-1 blockers

The mechanism of action for the effectiveness of alpha-1 blockers is inhibition of prostate smooth muscle contraction by blocking the alpha-1 receptor, thus relaxing the dynamic component of blockade decreasing resistance to urinary flow. Since the bladder body only has a negligible density of alpha-1 receptors, while the bladder neck contains a substantial amount of alpha-1 receptors, alpha-1 blockers reduce bladder outlet resistance without impairing bladder emptying. Alpha-1 blockers may also regulate prostate growth by inducing apoptosis in both the epithelial and stromal smooth muscle cells, without affecting the rate of cell proliferation. According to a thorough review of clinical studies on alpha-1 blocker as a potential drug treatment of nocturia by Cornu et al. (2012), all studies on alpha-1 blockers have been conducted in the context of LUTS/BPH management. Only five randomized controlled trials studies used nocturia parameters as endpoints (Djavan et al., 2005; Johnson et al., 2007b, 2003; Simaioforidis et al., 2011; Zhang et al., 2011), with only one using nocturia parameters as the primary endpoint (Djavan et al., 2005). The randomized controlled trial using nocturia parameters as the primary endpoint (Djavan et al., 2005) enrolled 117 patients .45 years old with LUTS/BPH with a total IPSS $ 13 and $ 2 nightly voids, according to a sleep diary. The primary endpoint was the mean variation of hours of undisturbed sleep compared with baseline after 8 weeks of treatment by tamsulosin oral controlled absorption system at 0.4 mg/day versus placebo. The results showed that the mean decrease in nightly voids was no different between the two groups [0.7 for placebo vs 1.1 for tamsulosin (P 5 .099)]. Thus although secondary endpoints such as nocturia subscore drawn from Question 7 of IPSS were statistically significant, this superiority study failed to demonstrate the superiority of tamsulosin in improving nocturia. In another one of these five randomized control studies (Simaioforidis et al., 2011), transurethral resection of the prostate was compared to tamsulosin at 0.4 mg/day in 66 patients, followed for 1 year. Patients were evaluated by 72-hour Voiding Diary (essentially a Frequency-Volume Charts with

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additional descriptive information pertaining to voiding), Nocturia Quality of Life (NQoL) scores, and hours of uninterrupted sleep. The primary endpoint was the change in the number of nocturnal awakenings compared with baseline. At 1 year, the reduction in number of nocturnal awakenings was not significantly different in the two groups. In yet another of these five randomized control studies (Zhang et al., 2011), doxazosin at 4 mg/day was compared to tamsulosin at 0.2 mg/day given for 8 weeks to patients with LUTS/BPH presenting with nocturia. The primary endpoints were self-reported nocturia rate based on a Voiding Diary and self-reported Quality of life. According to a cutoff of 25% reduction in nocturnal episodes on Voiding Diary, doxazosin was presented as superior to tamsulosin. Note that this study compared nonequivalent therapeutic doses of drugs (4 mg doxazosin vs 0.4 mg tamsulosin), thus potentially favoring the outcome of the drug at a higher dose level. The two other randomized control studies specifically addressed the effect of alpha-1 blockers on nocturia (Johnson et al., 2003, 2007b), but they are post hoc analyses from the Medical Therapy of Prostatic Symptoms and Veterans Affairs cooperative studies. The studies compared alpha-1 blockers, placebo, finasteride (Proscar, a 5ARI used mainly to treat symptoms of BPH), and combination therapy. Both studies present significant results for alpha-1 blockers and combination over placebo, but with mild efficacy and was based on Question 7 of IPSS. There are newer alpha-1 blockers that are more selective for alpha-1 receptors in the prostate than the older alpha-1 blockers. For example, silodosin (Rapaflo) has been shown to provided clinical benefit in patients with nocturia associated with BPH, based on results from three randomized, placebo-controlled, double-blind Phase 3 trials (Eisenhardt et al., 2014; Koch, 2015; Montorsi, 2010). In summary, based on thorough review of clinical studies on older alpha1 blockers as a potential drug treatment of nocturia by Cornu et al. (2012), the evidence for the efficacy of alpha-1 blockers to treat nocturia in the majority of studies on LUTS/BPH is based on Question 7 of the IPSS, hence failing to recognize and exclude patients with coexisting nocturnal polyuria and failing to take into account associated OAB in these patients. This is consistent with the view of other investigators that studies of alpha-1 blockers in patients with nocturia have provided only inconsistent evidence that at best accounted for only minor improvements in nocturia (Khan et al., 2011; Rao et al., 2016; Schneider et al., 2009). However, newer alpha-1 blockers (e.g., silodosin) are more selective for alpha-1 receptors in the prostate than the older alpha-1 blockers. One such drug, silodosin, has been shown to provide clinical benefit in patients with nocturia associated with BPH, based on results from three randomized, placebo-controlled, double-blinded Phase 3 trials (Eisenhardt et al., 2014; Koch, 2015; Montorsi, 2010).

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6.5.6

Agents to promote sleep

Melatonin (N-acetyl-5-methoxytryptamine) maintains the circadian rhythm and thus affects urine production at night. In the elderly, melatonin secretion is decreased, which leads to a disturbed circadian rhythm of micturition, and consequently, nocturia (Khan et al., 2011). A study has been conducted in elderly patients with nocturia associated with BPH (Drake et al., 2004a). In this study, patients who were given 2 mg melatonin at night reported decreased bother score related to nocturia when compared to placebo. However, there was no statistically significant improvement in the number of nocturia episodes and there was no effect on urine product when compared to placebo. Another randomized double-blinded crossover trial was conducted in 20 men with bladder outlet obstruction who reported nocturia ($3 voids per night) (Drake et al., 2004b). In this study, patients took 2 mg of melatonin or placebo for 4 weeks, and crossover followed a 7-day washout. Patients were assessed by Voiding Diary at baseline, 4 weeks, and 8 weeks. The primary endpoint was the mean change from baseline on nocturia episodes per night. The mean frequency of nocturia per night changed from 3.1 at baseline to 2.8 with melatonin and 3.0 with placebo (P 5 .07). No effect was noted on urine production. Since the improvement in nightly void was not observed in one trial and was very mild in the other, data from these trials do not support the use of melatonin for nocturia.

6.5.7

Nonsteroidal anti-inflammatory drugs

The utility of nonsteroidal anti-inflammatory drugs (NSAIDs), at antiinflammatory dosages, in the treatment of nocturia has been investigated in several clinical trials. For example, a clinical study evaluating the efficacy of celecoxib (Celebrex) in treating nocturia has been conducted (Falahatkar et al., 2008; Sengottayan et al., 2009). In this study, 80 men with nocturia related BPH with an IPSS .8 and $ 2 voids per night, whose nocturia had not responded to alpha-1 blockers and 5ARIs, were randomized to receive a month treatment of either daily administration of celecoxib at 9 pm of 100 mg (the anti-inflammatory dosage) or placebo. The primary outcome was focused on nocturia and based on self-assessment, and it was classified as excellent, improved, or unchanged. The results showed that 70% of celecoxib-treated patients, when compared to 7.5% of placebo patients, preferred drug treatment. The actual changes in nocturia frequency were not reported. Another randomized placebo-controlled trial investigating the efficacy of diclofenac at anti-inflammatory dosages in the treatment of nocturnal polyuria has also been conducted (Addla et al., 2006). In this study, 20 male and 6 female patients with nocturnal polyuria [night-to-24-hour urine volumes ratio being .33%, and Nocturia Index (Ni) .1] and .2 voids per night were treated for 2 weeks with either diclofenac at 50 mg (the anti-inflammatory dose)

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given at 2100 hours, or placebo. Following a 1-week rest period, patients were crossed over to the other medication for a further 2 weeks. The main outcome was the change in nocturnal frequency. The results showed that diclofenac significantly decreased nocturia frequency when compared to control (2.7 to 2.3 vs 2.7 to 2.6 nightly voids). Diclofenac also improved the night-to-24-hour urine volumes ratio from 44% to 39%. Note that although statistically significant, the reduction in nightly voids was small (mean decrease of 0.3 void per night for the diclofenac group compared with a means decrease of 0.1 void per night for the placebo group). The clinical significance of the small improvement in nightly voids remains doubtful. Furthermore, the sample size of this trial is small (26 patients), and reliability of the results is to be repeated in large clinical trials. The nocturia efficacy for the treatment of nocturia of another NSAID, loxoprofen, at anti-inflammatory dosage, has also been demonstrated (Araki et al., 2004, 2008; Saito et al., 2005). Loxoprofen is not used in the United States, but is marketed in Brazil, Mexico and Japan (tradename Loxonin), Argentina (tradename Oxeno), and India (tradename Loxomac), and Thailand (tradename Japrolox). Once again, these clinical trials were conducted using an anti-inflammatory dosage of 60 mg per day. There are other clinical studies using NSAIDs at anti-inflammatory dosages for the treatment of nocturia. For example, indomethacin has been shown to reduce void frequency and volume in enuresis (Al-Waili, 2002) and relieve symptoms of BPH (Presti, 1995). Aspirin and diclofenac relieve nocturnal polyuria symptoms (Le Fanu, 2001; Presti, 1995), and celecoxib reduces nocturnal voids and IPSS (Falahatkar et al., 2008). Tamsulosin and meloxicam combination has been shown to improve symptoms and NQoL scores greater than tamsulosin alone (Gorgel et al., 2013). In spite of the efficacy from these clinical trials of NSAIDs in the treatment of nocturia, the National Institute for Health and Clinical Excellence guidelines do not recommend NSAIDs for nocturia. The toxicity risks with chronic use of NSAIDs are a major reason. NSAIDs are packaged at doses suitable for analgesia and anti-inflammation. Long-term exposure to NSAIDs at analgesia and anti-inflammation dosages increase the risk of cardiovascular and gastrointestinal toxicities, and risk of hepatotoxicity secondary to inadvertent overdose with acetaminophen. In addition to toxicity risks with chronic use, NSAIDs are mostly formulated as immediate release formulations. Due to the short half-life of approximately 2 hours, they do not provide benefit for 6 8 hours of normal sleep duration.

6.5.8

5α-Reductase inhibitor

5ARIs inhibit 5-alpha-reductase, an isoenzyme that metabolizes testosterone to dihydrotestosterone (DHT) in the prostate gland, liver, and skin. They block conversion of testosterone to DHT and reducing serum and tissue

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DHT. Blocking the production of DHT in the prostate may help prevent pathological growth of prostate in BPH and may prevent prostate cancer. Various clinical studies have shown the effectiveness of 5ARIs, including dutasteride and finasteride. Examples of these studies are described below. Pooled data from Phase 3 studies of dutasteride using data from 4,321 patients on answers to Question 7 of IPSS have been evaluated (Oelke et al., 2014b). The results showed that improvements in overall nocturia parameters were superior with dutasteride compared to placebo from 12 months onward. The largest treatment group differences were seen in patients with a baseline nocturia score of 2 or 3.

6.5.9

Phosphodiesterase type 5 inhibitors

The mechanism of action is selective inhibition of PDE5 and increased cyclic guanosine monophosphate (cGMP). Since the smooth muscle cells of the prostate, bladder, and surrounding vasculature contain PDE5, inhibition and elevation of cGMP levels in these tissues cause smooth muscle relaxation. Prospective randomized clinical trials of PDE5i using appropriate nocturia parameters (such as the use of Voiding Diaries) as primary endpoints with large sample size would provide strong evidence for the treatment of nocturia. Unfortunately, these clinical trials were not conducted. Therefore evidence for the efficacy of PDE5i for the treatment of nocturia is based on other less well-designed clinical trials or post hoc analysis. A post hoc meta-analysis of pooled data from four randomized, placebocontrolled clinical studies investigating the PDE5i, tadalafil, at 5 mg once daily on LUTS/BPH which included nighttime voiding as one of the parameters has been conducted (Oelke et al., 2014c). These four clinical studies used Question 7 of IPSS scores as a means to assess nighttime voiding. The results from this analysis showed that the sample size for the tadalafil group was 752 and placebo was 748. The baseline characteristics were well balanced, and the overall severity of nocturia per mean scores from Question 7 of IPSS was 2.3 6 1.2. The improved nocturnal frequency was 41.3% for the placebo group and 47.5% for the tadalafil group, whereas the proportion with no change was 44.8% and 41.0%, and with worsening was 13.9% and 11.5%, respectively. In summary, a statistically significant improvement in nocturia frequency was seen with tadalafil over placebo; however, the treatment difference was small and not considered clinically meaningful. According to another meta-analysis of 44 articles (Sakalis et al., 2017), the use of PDE5i’s to treat nocturia in men with lower urinary tract dysfunction was generally not significantly better than placebo with short-term use. In conclusion, based on the results of meta-analyses by different investigators, the clinical benefit in the use of PDE5i’s for treatment of nocturia is not obvious.

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6.5.10 β3-Agonists The mechanism of action is related to increasing bladder capacity by relaxing the bladder smooth muscle during the storage phase of the urinary bladder fill-void cycle. There is currently only one β3-agonist (mirabegron) that has been used to treat nocturia, although the clinical impact of such a treatment appears to be limited (Oelke et al., 2017). Prospective randomized clinical trials of mirabegron using appropriate nocturia parameters (such as the use of Voiding Diaries) as primary endpoints with large sample size, which would provide strong evidence for the treatment of nocturia, were not conducted. This is because mirabegron was developed for the treatment of OAB. Evidence for the efficacy of mirabegron for the treatment of nocturia is based on other less well-designed clinical trials or post hoc analysis. Data from a Phase 2 dose-ranging study of mirabegron in a mixed population with OAB showed that mirabegron at 50 mg reduced nocturia episodes by 0.6 from baseline versus 0.22 from baseline for those on placebo (P , .05) (Chapple et al., 2013). During the course of developing mirabegron for the treatment of OAB, four large Phase 3 randomized control trials (three versus placebo, and one versus tolterodine) were conducted (Nitti et al., 2014). These studies assessed symptoms of OAB, not specifically nocturia. The results from these clinical trials showed that mirabegron largely lacks the side effect of dry mouth and is generally considered to be safe. These Phase 3 studies did not identify a risk for blood pressure or heart rate increase (Michel and Gravas, 2016). However, emerging pharmacovigilance data have identified a rare risk for excessive blood pressure elevation, which has led to a contraindication in patients with severe hypertension (systolic blood pressure of .180 mm Hg, diastolic blood pressure of .110 mm Hg) (Medicines and Healthcare Regulatory Agency, 2015). This finding was surprising because the human heart lacks functional β3-adrenoceptors (Michel et al., 2011). However, mirabegron can induce positive inotropic effects in isolated human atrium mediated by β1-adrenoceptors, which may be the mechanism of action (Mo et al., 2017). Although β3-adrenoceptor agonists had been suggested as a promising treatment of OAB for over a decade, mirabegron was the first and only drug of this new therapeutic class to be approved by the FDA and European Medicine Agency for treatment of OAB. Other β3-adrenoceptor agonists are still in clinical development. For example, Solabegron (GW427353) is a β3agonist originally developed by GlaxoSmithKline and acquired by Velicept in 2015. A randomized, placebo-controlled Phase 2 trial demonstrated reduction of OAB symptoms and a good safety profile (Ohlstein et al., 2012). Another β3-agonist under clinical development is Ritobegron (KUC-7483), discovered and developed by Kissei Pharmaceuticals. Phase 1 trial data on Ritobegron have been reported (Abe et al., 2016). A Phase 3 trial had been started, but was withdrawn in 2010. Another Phase 3 trial has been completed,

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but no data have been presented or published. The second Phase 3 trial had failed to reach its primary endpoint and the program has been put on hold. Yet another β3-agonist under clinical development is Vibegron (MK4618/KRP 114 V). Vibegron is a successor compound to another investigational product MK-0634. MK-0634 had exhibited efficacy in a Phase 2 study in patients with OAB, but it was discontinued due to unacceptable toxicity according to preclinical studies (Edmondson et al., 2016). Vibegron was discovered and developed by Merck (or MSD in non-US countries). Following a completed Phase 2 trial with promising findings, the program had been put on hold, but has recently been out-licensed to Kissei for development for the Japanese market. Positive results from a Phase 3 study conducted in Japan by Kissei have recently been reported (Yoshida et al., 2018). Another company, Urovant, is about to initiate an international Phase 3 registration program for Vibegron.

6.5.11 Plant extracts As in the case with most drugs currently used in the clinic, prospective randomized clinical trials of plant extract using appropriate nocturia parameters (such as the use of the Voiding Diaries) as primary endpoints with large sample size were not conducted. Therefore, evidence for the efficacy of plant extracts has relied on less well-designed clinical trials or post hoc analysis. According to meta-analysis of 44 articles (Sakalis et al., 2017), the use of phytotherapy to treat nocturia in men with lower urinary tract dysfunction was not significantly better than placebo in short-term use. Examples of some of the studies on different plant extracts are described below. Permixon is for the treatment of men with BPH. It is the n-hexane lipidosterolic extract of the dwarf American palm (also known as Serenoa repens) and is a complex mixture of various compounds. A post hoc metaanalysis of pooled data from 11 randomized and 2 open-label clinical trials investigating the efficacy of Permixon for the treatment of nocturia has been performed (Boyle et al., 2000). These clinical trials were disparate in size (22 592 patients) and duration (21 180 days), with a total of 2,859 patients. Peak urinary flow rate and nocturia were the common endpoints. The results showed that the average 6 standard of error (SE) of peak urinary flow rate was an increase of 0.51 6 0.51 mL/s from baseline in the placebo group. The estimated effect of Permixon was a further increase of 2.20 6 0.51 mL/s from baseline (P , .001). Placebo was associated with a reduction in the mean number 6 SE of nocturnal urinations of 0.69 6 0.15 compared to baseline. A further reduction of 0.50 6 0.01 episodes of urination compared to control occurred that was attributable to Permixon (P , .001). In summary, this meta-analysis on the published results from the 13 clinical trials showed that Permixon provided a significant improvement in peak flow rate and nocturia when compared to placebo in men with BPH.

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An 8-week randomized control trial investigating SagaPro, a product derived from Angelica archangelica leaf, in 69 men with $ 2 nocturnal voids (Sigurdsson et al., 2013) showed no significant difference between the treatment and placebo groups, except on post hoc subgroup analysis. In a crossover trial of furosemide and goshajinkigan (a traditional Japanese medicine consisting of 10 crude drugs traditionally used for improvement of symptoms like numbness), 36 patients were reported to have improved symptom score, quality of life, nocturnal frequency, and hours of undisturbed sleep with both agents (Yoshimura et al., 2012). In conclusion, not all plant extracts can be used for treatment of nocturia. Unless proven with randomized placebo-controlled large clinical trials, plant extracts should not be assumed effective in treating nocturia.

6.5.12 Drug combination A significant number of drugs have been approved and are available for the treatment of LUTS in men and women. However, their use to treat nocturia is off-label, as none of them were approved for treatment of nocturia (see Table 6.2). The one exception is the use of desmopressin, which is approved by the FDA to treat nocturia as monotherapy. Regardless of their original indications, regulatory approval and recommendations stated in various guidelines are based mostly on clinical trials involving monotherapies. Most of these drugs have not been thoroughly evaluated for use as combination therapies. The possible added efficacy and potential increased adverse events as combination therapies are mostly unknown. As a result, the risk-to-benefit assessment for using drug combination in the treatment of nocturia is not available to physicians. Furthermore, not all drug combinations provide better efficacy when compared to monotherapy or placebo. An example is that terazosin (an alpha-1 blocker) induced modest improvement in nocturia, whereas finasteride (a 5ARI) and the combination of terazosin and finasteride did not provide clear benefit when compared to placebo (Matthiesen et al., 2003). There are a number of drug combination studies that evaluate efficacy and safety in male and female LUTS patients (Serati et al., 2019). Only a limited number of these studies assessed nocturia, and none except those related to desmopressin used nocturia as the primary endpoint. Drug combination studies involving desmopressin and using nocturia as the primary endpoint are described in Section 5.2. The drug combination studies of other drugs that included assessment of nocturia, though not as a primary endpoint, are described in subsequent sections.

6.5.12.1 5α-Reductase inhibitors/alpha-1 blocker combination A post hoc 4-year analysis was performed to examine various LUTS parameters in patients treated with either tamsulosin (an alpha-1 blocker) or

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dutasteride (a 5ARI) alone, or in combination, as part of the Combination of Avodart and Tamsulosin (CombAT) study (Roehrborn et al., 2010, 2014). The effects of dutasteride/tamsulosin combination therapy, compared with dutasteride or tamsulosin monotherapy, on nocturia (assessed using question 7 of the IPSS) using data from the CombAT study have been reported (Oelke et al., 2014a). The results showed that mean nocturia improvements were significantly superior with combination therapy than with either monotherapy. Reductions in nocturia scores with combination therapy were significantly better than tamsulosin monotherapy across all baseline subgroups tested, except for men with previous 5ARI use. Furthermore, among those with a baseline IPSS Question 7 of $ 2 voids/night, more patients with combination therapy had a score of ,2 voids/night at month 48 (34%) compared with dutasteride (30%, P 5 .018) or tamsulosin (26%, P , .0001). The results from this clinical trial suggested that dutasteride 1 tamsulosin combination therapy may be a more effective treatment for nocturia than monotherapy. A post hoc subgroup analysis of self-reported nocturia in the Medical Therapy of Prostatic Symptoms trial of men with LUTS (Johnson et al., 2007b) showed that, compared to baselines, placebo reduced mean nocturia by 20.35 void/night, finasteride (a 5ARI) by 20.40 void/night, doxazosin (an alpha-1 blocker) by 20.54 void/night, and combination of finasteride and doxazosin by 20.58 void/night, after treatment for 1 year. Reductions with doxazosin and combination therapy, but not finasteride, were statistically greater than placebo after treatment for 1 and 4 years. Also, the reductions in nocturia were similar between the combination and doxazosin. Also, according to a secondary analysis of the Veterans Affairs Cooperative Study Program Trial which reported on 1,078 men (Matthiesen et al., 2003), nocturia was decreased from a baseline mean of 2.5 voids/night to 1.8 voids/night by terazosin (an alpha-1 blocker), 2.1 voids/night by finasteride (an 5ARI), and 2.0 voids/night by terazosin and finasteride combination, and 2.1 voids/night by placebo. Of men with $ 2 episodes of nocturia, 50% reduction in nightly void was seen in 39% of terazosin-treated subjects, 25% of finasteride-treated subjects, 32% of terazosin and finasteride-treated subjects, and 22% of placebo-treated subjects. Thus the results from this analysis suggest that terazosin might have modest improvement in nocturia, whereas finasteride and the combination of these two drugs did not provide clear benefit when compared to placebo.

6.5.12.2 Antimuscarinic/β3 agonist combination A clinical trial (the BESIDE trial) was conducted to evaluate and compare the efficacy, safety, and tolerability of the combination of solifenacin (an antimuscarinic) 5 mg and mirabegron (a β3-agonist) 50 mg versus solifenacin 5 or 10 mg in OAB patients remaining incontinent after 4 weeks of solifenacin 5 mg (Drake et al., 2016; Gibson et al., 2017). The results showed that

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the combination was superior to solifenacin 5 and 10 mg with significant improvements in daily incontinence (21.80 vs 21.53 vs 21.63, P 5 .003 and P 5 .01, respectively). The combination was also superior to solifenacin at 5 and 10 mg with regard to urgency episodes/24 hours (22.95 vs 22.41 vs 22.54, P , .001 and P 5 .007, respectively) and mean voided volume (MVV)/micturition (28.0 vs 16.5 vs 20.3 mL, P , .001 and P 5 .005, respectively). However, there was no significant improvement in nocturia with the combination versus solifenacin 5 and 10 mg. There was also no acute urinary retention (AUR) observed. Only the results from the OAB-5D questionnaire (which was derived from the OAB-q questionnaire, and both are for assessing the severity of OAB symptoms) showed a statistically significant benefit for combination versus solifenacin alone (Herdman et al., 2017). All treatments were well tolerated. The incidence of adverse events was lowest with solifenacin 5 mg (33.1%), highest with solifenacin 10 mg (39.4%), and 35.9% with combination. There was no synergistic effect on cardiovascular safety (Drake et al., 2017). In conclusion, although the solifenacin/mirabegron combination was effective in improving most OAB symptoms and this combination is safe and well tolerated, it did not improve nocturia.

6.5.12.3 Double antimuscarinic combination A clinical trial was conducted to assess the effectiveness of combined standard-dosed solifenacin and trospium (both are antimuscarinics) for the management of symptoms of OAB in male patients after initial treatment with tamsulosin, an alpha-1 blocker (Kosilov et al., 2015). A total of 417 men with diagnosed prostatic obstruction received 2-month treatment with tamsulosin at 0.4 mg/day. One hundred and nine patients (45.8%) continued to exhibit OAB symptoms at the end of the 2-month period and were prescribed solifenacin 5 mg 1 trospium 5 mg, or placebo, as an add-on therapy for another 2 months. The results showed that nighttime frequency, urgency, urgent urinary incontinence (UUI), and Qmax were significantly improved by the combination therapy. These results suggested that the alpha-l-blocker/ antimuscarinic combination may be promising. However, the use of three different medications could be limiting in terms of costs and adherence, especially for elderly patients in polytherapy regimens (Serati et al., 2019). 6.5.12.4 Alph-1 blocker and antimuscarinic combination A clinical study (the ADDITION study) involving an add-on therapy was conducted to evaluate the combination of imidafenacin (an antimuscarinic) and tamsulosin (an alpha-1 blocker) (Takeda et al., 2013). In this study, imidafenacin was given to BPH patients with OAB symptoms despite tamsulosin treatment. Patients (n 5 308) with urinary urgency at least once per week and with total OAB symptom scores (OABSS) of $ 3 points after $ 8 weeks of treatment with tamsulosin were randomized to receive tamsulosin

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0.2 mg/day alone or tamsulosin 0.2 mg/day 1 imidafenacin 0.1 mg twice per day. The results showed significant improvements in the following parameters from 4 weeks through 12 weeks in the imidafenacin 1 tamsulosin group when compared to the tamsulosin group: frequencies of daytime urination (21.4 vs 20.3); nighttime urination (20.4 vs 20.1); urinary urgency (21.7 vs 20.7); UUI (21.1 vs 20.5); IPSS (25.4 vs 23.4); IPSS-Qualityof-Life (IPSS-QoL, 21.6 vs 20.8); and BPH Impact Index (BII, 23 vs 21.3). No events of urinary retention were reported. In conclusion, this combination may be beneficial to patients with nocturia, in addition to other OAB symptoms. Another clinical study was conducted to evaluate the efficacy and safety of imidafenacin as add-on therapy for male LUTS with nocturia and nocturnal polyuria despite receiving a stable dose of an alpha-1 blocker (Yokoyama et al., 2015a). In this study, patients were randomized to the control group (i.e., an alpha-1 blocker alone), imidafenacin twice per day group (i.e., an alpha-1 blocker 1 0.1 mg imidafenacin twice daily), or imidafenacin nightly group (i.e., an alpha-1 blocker plus 0.1 mg imidafenacin nightly), treated for 8 weeks. The results showed that compared to the control group, patients treated with imidafenacin twice per day and imidafenacin nightly had a significantly lower nighttime frequency (changes from baseline: 0.1 6 0.8 in control, 20.6 6 0.9 in imidafenacin twice per day, and 20.4 6 1.0 in imidafenacin nightly). The time of undisturbed sleep (40.9 6 12 vs 14.9 6 11 minutes) and NQoL score (8.99 6 2.13 vs 11.22 6 2.00) were significantly improved in the imidafenacin twice per day group, although not in the imidafenacin nightly group. Nocturnal urine volume was significantly reduced in the nightly group, but the total urine volume remained unchanged. There were no reports of urinary retention. In conclusion, although this randomized control trial was open label and not double blinded, imidafenacin may be a viable add-on therapy in male LUTS with nocturia and nocturnal polyuria despite receiving a stable dose of an alpha-1 blocker.

6.5.12.5 Estrogen and progestin combination Low estrogen and menopause are recognized as a cause of nocturia (van Kerrebroeck et al., 2002). Androgen deprivation is also associated with LUTS and nocturia (van Kerrebroeck et al., 2002). However, hormone replacement therapy (HRT) is not currently considered a treatment option for nocturia. A clinical study was conducted to investigate the role of combined HRT in women with micturition complaints in which nocturia was assessed (Kok et al., 1999). This study enrolled 95 postmenopausal women with micturition complaints. They were treated with 2 mg 17β-estradiol in combination with 2.5, 5, 10, or 15 mg dydrogesterone, both given orally once a day. The results showed that postmenopausal women reported an improvement after

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6 months of continuous combined HRT. Nocturia disappeared in 65.4% of the women after treatment, and 23.3% reported to be cured of their urinary incontinence. There was also a trend of improvement in diurnal frequency (P 5 .01). The results from this study were encouraging, although the study was not a randomized control trial and with small sample size.

6.6 2019 ICS guidelines on diagnosis and treatment of nocturia ICS guidelines on the diagnosis and treatment of nocturia for different disciplines published in 2019 (Everaert et al., 2019) are summarized in Table 5.6. The diagnostic aspects of these guidelines are also described in Chapter 5, Diagnosis, assessment, and examination. Subsequent section describes the treatment aspects of these guidelines. For the treatment of nocturia, lifestyle modifications are recommended in all disciplines. However, the type of lifestyle modifications differs among varying disciplines. For example, bladder training and pelvic floor training are recommended for the LUT discipline, whereas restriction of salt, protein, and calorie are recommended for the kidney discipline (see Table 5.6). The use of desmopressin is recommended in five of six disciplines, but with specific recommendations for each discipline. In all cases, the use of desmopressin tends to be prescribed (and is approved in most countries) when nocturia is due to nocturnal polyuria. For the kidney discipline, desmopressin should not be used if estimated glomerular filtration rate (eGFR) is ,50 and is to be used with caution if desmopressin is used in patients with low/moderate renal failure. In the hormone discipline, desmopressin can be used in patients with blunted AVP secretion at night. For the sleep discipline, desmopressin can be used in patients with insomnia, nocturia, and nocturnal polyuria. For the cardiovascular and edema discipline, desmopressin can be used in patients with Class I congestive heart failure and with no severe leg edema and should be used with caution. In the intake discipline, the use of desmopressin is not recommended. Other than the use of desmopressin in most disciplines, additional drugs and interventions are also recommended. As in the case with lifestyle modifications, the recommendations for pharmacological and other interventions are different among varying disciplines. For example, OAB and bladder outlet obstruction medications, botulinium toxin, sacral neuromodulation, and surgery such as prostatic, urethral, and prolapse correction surgeries are recommended for the LUT discipline, whereas antihypertensive medication, dialysis, kidney transplantation, and nephrectomy are recommended by 2019 ICS guidelines for the kidney discipline (see Table 5.6). Obviously, the drastic measures such as dialysis, kidney transplantation, and nephrectomy are not for treating nocturia alone, but for managing serious or life-threatening comorbidities leading to or concurrent with nocturia.

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Sherif, H., Abdelwahab, O., 2013. Posterior tibial nerve stimulation as treatment for the overactive bladder. Arab J. Urol. 11 (2), 131 135. Sigurdsson, S., Geirsson, G., Gudmundsdottir, H., Egilsdottir, P.B., Gudbjarnason, S.A., 2013. Parallel, randomized, double-blind, placebo-controlled study to investigate the effect of SagaPro on nocturia in men. Scand. J. Urol. 47, 26 32. Simaioforidis, V., Papatsoris, A.G., Chrisofos, M., Chrisafis, M., Koritsiadis, S., Deliveliotis, C., 2011. Tamsulosin versus transurethral resection of the prostate: effect on nocturia as a result of benign prostatic hyperplasia. Int. J. Urol. 18, 243 248. Slawson, D., 2014. Desmopressin effective for treating nocturia in adults. Am. Fam. Physician 90, 796 797. Slovak, M., Chapple, C.R., Barker, A.T., 2015. Non-invasive transcutaneous electrical stimulation in the treatment of overactive bladder. Asian J. Urol. 2 (2), 92 101. Smith, A.L., Wein, A.J., 2011. Outcomes of pharmacological management of nocturia with nonantidiuretic agents: does statistically significant equal clinically significant? BJU Int. 107, 1550 1554. Soda, T., Masui, K., Okuno, H., Terai, A., Ogawa, O., Yoshimura, K., 2009. Predictors of the efficacy of non-drug lifestyle modifications for the management of nocturia. Abstract 44 ICS. Soda, T., Masui, K., Okuno, H., Terai, A., Ogawa, O., Yoshimura, K., 2010. Efficacy of nondrug lifestyle measures for treatment of nocturia. J. Urol. 183 (3), 1000 1004. Song, M., Hong, B.S., Chun, J.Y., Han, J.Y., Choo, M.S., 2014. Safety and efficacy of desmopressin for the treatment of nocturia in elderly patients: a cohort study. Int. Urol. Nephrol. 46, 1495 1499. Staskin, D.R., Peters, K.M., MacDiarmid, S., Shore, N., de Groat, W.C., 2012. Percutaneous tibial nerve stimulation: a clinically and cost effective addition to the overactive bladder algorithm of care. Curr. Urol. Rep. 13 (5), 327 334. Takeda, M., Nishizawa, O., Gotoh, M., Yoshida, M., Takahashi, S., Masumori, N., 2013. Clinical efficacy and safety of imidafenacin as add-on treatment for persistent overactive bladder symptoms despite alpha-1 blocker treatment in patients with BPH: the ADDITION study. Urology 82, 887 893. Weiss, J.P., Blaivas, J.G., 2000. Nocturia. J. Urol. 163 (1), 5 12. Weiss, J.P., Blaivas, J.G., Bliwise, D.L., Dmochowski, R.R., Dubeau, C.E., Lowe, F.C., et al., 2011. The evaluation and treatment of nocturia: a consensus statement. BJU Int 108, 6 21. Weiss, J.P., Zinner, N.R., Klein, B.M., Nørgaard, J.P., 2012. Desmopressin orally disintegrating tablet effectively reduces nocturia: results of a randomized, double-blind, placebo-controlled trial. Neurourol. Urodyn. 31, 441 447. Wyman, J.F., Burgio, K.L., Newman, D.K., 2009. Practical aspects of lifestyle modifications and behavioural interventions in the treatment of overactive bladder and urgency urinary incontinence. Int. J. Clin. Pract. 63 (8), 1177 1191. Yamanishi, T., Fuse, M., Yamaguchi, C., Uchiyama, T., Kamai, T., Kurokawa, S., et al., 2014. Nocturia Quality-of-Life questionnaire is a useful tool to predict nocturia and a risk of falling in Japanese outpatients: a cross-sectional survey. Int. J. Urol. 21, 289 293. Yazici, C.M., Kurt, O., 2015. Combination therapies for the management of nocturia and its comorbidities. Res. Rep. Urol. 7, 57 63. Yokoyama, O., Yamaguchi, O., Kakizaki, H., Itoh, N., Yokota, T., Okada, H., et al., 2011. Efficacy of solifenacin on nocturia in Japanese patients with overactive bladder: impact on sleep evaluated by bladder diary. J. Urol. 186, 170 174. Yokoyama, O., Tsujimura, A., Akino, H., Segawa, N., Tamada, S., Oguchi, N., et al., 2015a. Add-on anticholinergic therapy for residual nocturia in patients with lower urinary tract

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symptoms receiving alpha-1 blocker treatment: a multi-centre, prospective, randomised study. World J. Urol. 33, 659 667. Yokoyama, O., Yamaguchi, A., Yoshida, M., Yamanishi, T., Ishizuka, O., Seki, N., et al., 2015b. Once-daily oxybutynin patch improves nocturia and sleep quality in Japanese patients with overactive bladder: post-hoc analysis of a phase III randomized clinical trial. Int. J. Urol. 22 (7), 684 688. Yoshida, M., Takeda, M., Gotoh, M., Nagai, S., Kurose, T., 2018. Vibegron, a novel potent and selective b3-adrenoreceptor agonist, for the treatment of patients with overactive bladder: a randomized, double-blind, placebo-controlled phase 3 study. Eur. Urol. 73 (5), 783 790. Yoshimura, K., Shimizu, Y., Masui, K., Okuno, H., Ueda, T., Soda, T., et al., 2012. Furosemide versus goshajinkigan, a blended herbal medicine, for nocturnal polyuria: a randomized crossover trial. Low. Urin. Tract Symptoms 4, 77 81. Zhang, K., Yu, W., Jin, J., Ye, H., Wang, X., Zhang, N., et al., 2011. Effect of doxazosin gastrointestinal therapeutic system 4 mg vs tamsulosin 0.2 mg on nocturia in Chinese men with lower urinary tract symptoms: a prospective, multicenter, randomized, open, parallel study. Urology 78, 636 640. Zhou, L.L., Li, H.X., Wang, B., You, M., Wu, S.S., Tang, P., et al., 2010. The effect of prostatectomy on nocturia in patients with benign prostatic hyperplasia. Zhonghua Wai Ke Za Zhi 48 (23), 1778 1780.

Further reading Wu, Y., Davidian, M.H., DeSimone, E.M.I., 2016. Guidelines for the treatment of benign prostatic hyperplasia. US Pharm. 41 (8), 36 41. Yap, T.L., Cromwell, D.A., Brown, C., van der Meulen, J., Emberton, M., 2007. The relationship between objective frequency-volume chart data and the I-PSS in men with lower urinary tract symptoms. Eur. Urol. 52, 811 818.