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Nocturia: Clinical presentation & its treatment in patients with lower urinary tract symptoms

Nocturia is defined by the American Urological Association (AUA) as “the need to urinate at least twice during the night.” According to International Continence Society (ICS), nocturia is a complaint that the individual has to wake at night one or more times to void.1

Epidemiology of nocturia

Nocturia, or voiding at night, is a bothersome symptom which affects patient’s quality of life negatively. Although nocturia increases with age, a substantial proportion of younger adults are also affected. Nocturia is generally found to be equally common in men and women. However, some studies show that younger women are more likely to be affected than men. The prevalence of nocturia (≥1 and ≥2 nocturnal voids) is summarized by age and gender below (Table 1).2

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Another study reported that the prevalence of nocturia in middle aged (40-60 years) women ranged from 15-18% and in men 13-25%.3

Nocturia is a complex and highly multifactorial condition. According to the ICS report, nocturia can be related to one or a combination of three primary underlying causes, all of which increase with age.

Primary causes of nocturia:

  • Bladder storage problems
  • 24 hour polyuria
  • Nocturnal polyuria

Nocturia has been observed to be associated with congestive cardiac failure, coronary artery disease, hypertension, bronchial asthma, pulmonary emphysema, insomnia, etc.4

Impact of nocturia

Nocturia is often considered as the most bothersome lower urinary tract symptom, and there is an association between the extent of impact and frequency of nocturnal voiding. At least 7-8 hours of uninterrupted sleep is necessary for most adults to maintain physical, mental and emotional well-being. Increased frequency of voiding during night interrupts sleep, which may result in decreased cognitive performance during daytime, decreased working performance and depression. Nocturia has also been associated with increased frequency of falls resulting in bone fracture, excessive daytime somnolence and nocturnal enuresis. Disturbed sleep due to nocturia may even lead to increased long-term morbidity and mortality. According to a study conducted on 284 patients with lower urinary tract symptoms (LUTS), nocturia appeared to be associated with further negative effects on sleep quality, health-related quality of life, and symptom bother.5  Not only does increased frequency of nocturnal voids negatively impact on the quality of sleep, it also results in decreased perceived daytime vitality/energy and general feeling of well-being (Figure.1).6

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Causes of nocturia

Nocturia is a condition with many possible causes. These causes can be categorized into four types as follows (Figure 2):

  • Global polyuria: It is characterised by continuously raised urine output defined as >40 mL/kg/24 hours. Primary polydipsia is the most common cause. Polydipsia can also be a compensatory mechanism for fluid loss, such as the osmotic diuresis of uncontrolled diabetes mellitus. Global polyuria can also result from diabetes insipidus.
  • Nocturnal polyuria : This refers to increased urine production only during night time, but the total daily urine output is within normal limits. Nocturnal polyuria exists when the nocturnal urine volume represents >20% of the 24 hour voided volume in younger adults and >33% in patients aged 65 years and over. This can be caused by low ADH secretion during night in the elderly population and also in patients who have had cerebrovascular accidents. Peripheral edema can also result in nocturnal polyuria as the accumulated fluid is redistributed to the intravascular compartment once recumbent in bed. This excess fluid is then excreted by kidneys. This has also been associated with obstructive sleep apnea.8  
  • Bladder storage problems: Patients with sleep disorders and reduced voided volume also present with nocturia and these patients do not have either polyuria or nocturnal polyuria according to the above criteria. In these patients, nocturnal bladder capacity is reduced, which may be related to age related changes, prostatic obstruction, nocturnal detrusor overactivity, neurogenic bladder, primary bladder pathology such as cancer (bladder, prostate, or urethra), learned voiding dysfunction, anxiety disorders, certain pharmacological agents, or bladder and ureteral calculi.9  
  • Mixed nocturia: Various cases of nocturia have more than one etiology. Mixed nocturia is a combination of nocturnal polyuria and decreased voided volume.

Clinical assessment of nocturia

Although a careful history is the best indicator of nocturia, but this is dependent on the patient’s ease at discussing these conditions. Some may not raise the issue as they feel embarrassed, do not realize that treatment is available, or may perceive it as a normal part of ageing. Hence, an initial screen should include a detailed history, including questions relevant to voiding behavior, medical and neurological abnormalities, and sleep disturbance, as well as information on relevant surgery or previous urinary infections. During physical examination, patients should be screened for edema, age-related changes of the genitalia, and prolapse. Neurologic examination should include evaluation of anal sphincter tone, the bulbocavernous reflex, and sensation in the sacral dermatomes. Given the wide range of possible etiologies, the key diagnostic tool is the frequency-volume chart (FVC)/voiding bladder diary. Information that should be collected and recorded in the voiding bladder diary includes timing of voids, number of voids, and volume of urine voided. Fluid intake volume and time of fluid intake should also be recorded. On the basis of voiding dairy patient is classified as having polyuria, nocturnal polyuria, low nocturnal bladder capacity, or a mixed disorder (Table 2).

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Management of nocturia

Management should be directed at correctly identifying the underlying etiology. A successful treatment of nocturia should result in a clinically, and not just statistically, significant reduction in nocturnal voiding frequency. The management approach for nocturia is divided into non-pharmacological, pharmacological and surgical therapies.

Non-pharmacological therapy– Lifestyle factors

Smoking, obesity and alcohol have been considered among the causes for nocturia; modulation of these unhealthy factors may play a significant role. Restricting fluid intake before bed time is also an important factor. Regular exercise can lead to deeper sleep and increases the bladder volume arousals threshold. In patients with peripheral edema, lower limb elevation before going to bed is useful. Dosage times for diuretics should be moved from evening to mid afternoon.11   Other techniques reported to be effective include a daytime nap of 30 min or less with the feet elevated, and the use of compression stockings.12

Surgical management

In patients with obstruction related to the prostate, which is a primary cause of nocturia, transurethral prostatectomy/transurethral incision of the prostate can be considered. In patients with intractable nocturia associated with overactive bladder (OAB), surgical correction of pelvic organ prolapse, sacral nerve neuromodulation, detrusor myectomy, and clam cystoplasty are options for treatment.

Pharmacological treatment

Medications in the treatment of nocturia depend on the etiology of nocturia. Drug therapies for nocturia include desmopressin, antimuscarinic agents, alpha-blockers, and 5-alpha reductase inhibitors.

Drug therapy for bladder storage disorder – Nocturia accompanying OAB

OAB is a typical bladder storage disorder, and drug therapy is the fundamental treatment for OAB, which includes drugs like flavoxate, propiverine, oxybutynin, and botulinum toxin.12

Anticholinergic drugs: In patients with detrussor overactivity, a component of OAB syndrome and the common symptom of urinary incontinence, anticholinergic drugs can be used to reduce the voiding frequency.13

Drugs like oxybutynin, tolterodine, solifenacin etc. are used. But all these drugs, although effective, were commonly associated with adverse effects like dry mouth, constipation, GI problems (pain, nausea, dyspepsia), UTI, vertigo, dry eyes, drowsiness, etc.

Flavoxate

Flavoxate is an antispasmodic agent, widely used to treat urgency and incontinence. Its muscle relaxant properties may be due to a direct action on the smooth muscle rather than by antagonizing muscarinic receptors. Flavoxate is the antispasmodic agent approved by the Food and Drug Administration (FDA) to treat symptoms of OAB.

A study was conducted on 361 patients with urgency/incontinence of various types. These patients were administered 200 mg flavoxate three times daily, orally, for two weeks; and were assessed for frequency, urgency, dysuria, nocturia and incontinence. Results from 336 evaluable patients indicated that 228 (67%) were completely cured of urgency/incontinence symptoms, 66 (20%) were improved and 42 (13%) patients were unchanged (Figure 3). Flavoxate was also effective in 77.4% of patients refractory to previous anticholinergic treatment. The 1200 mg dose produced a complete cure in 82% of patients and improvement in the remaining 18%, with no side-effects. In conclusion, flavoxate is an effective and well tolerated treatment for urgency/incontinence of various causes.15

One more study examined the effectiveness of supplemental administration of flavoxate hydrochloride in patients with benign prostatic hyperplasia (BPH) whose nocturia was not adequately relieved by an alpha1-adrenoceptor blocker. With supplemental administration of flavoxate hydrochloride, significant improvement was observed in the number of nocturnal micturition, total International Prostate Symptom Score (IPSS), quality of life (QOL) score and BPH impact index. This study therefore demonstrated that supplemental administration of flavoxate hydrochloride is effective for the improvement of nocturia and QOL in BPH patients resistant to an alpha1-adrenoceptor blocker.16   When compared to other antimuscarinic/anticholinergic agents, flavoxate exhibits minimum adverse effects (Table 3).17

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A study which compared 600 mg and 1200 mg of flavoxate in the treatment of unstable bladder showed the superior efficacy of 1200 mg/day of flavoxate compared to 600 mg /day. But, both the dosages resulted in marked improvement in clinical symtpoms. In urodynamic terms, particularly with respect to uninhibited detrusor contractions, 1200 mg/day was significantly superior to 600 mg/day.18

Superior efficacy of flavoxate in comparison to other drugs like imipramine, oxybutynin was observed in a study conducted on children. In this study greater tolerability and lesser side effects were observed with flavoxate use.19

A review analysis was conducted to compare anticholinergic drugs with other drugs for treating OAB. In this, a comparison of efficacy and adverse effects of anticholinergics with flavoxate was also conducted. This study reported flavoxate as the drug of preference by patients, and the symptomatic relief provided by flavoxate was either superior or equal to that of anticholinergic drugs. Increased number of adverse effects were reported with anticholinergic use. Reported adverse events included dryness of mouth, dizziness, nausea, blurred vision, swelling of lips, diarrhea and constipation. Hence, flavoxate may be preferred to anticholinergics in the management of OAB due to its efficacy and minimum adverse effects (Figure 4).21

Alpha-blockers: Tamsulosin

In patients with BPH, administration of α1-blockers relaxes both the bladder neck and prostatic smooth muscle, thus decreasing pressure in the bladder and urethra and improving urinary flow. Unlike other agents of the class, tamsulosin, alfuzosin, and silodosin have higher affinity and selectivity for α1a-adrenergic receptors, which are located in nonvascular smooth muscle as is found in the prostate, than for α1b-adrenergic receptors located in vascular smooth muscle. This selectivity may result in a decreased incidence of adverse cardiovascular effects with tamsulosin, alfuzosin, and silodosin.22,23

Tamsulosin, a superselective alpha 1 adrenoceptor blocker, has been extensively studied for treatment of BPH. Large clinical trials have provided the evidence that tamsulosin is effective in relieving urinary symptoms and improving peak urinary flow rate, and that it has rapid onset of action.24   Tamsulosin has the clinical advantage that, in addition to being relatively long-acting with a rapid onset of action, it has been demonstrated not to affect steady blood pressure levels in either normotensive or hypertensive patients.25   These patients can therefore be started and maintained on the therapeutic dosage.

A study was conducted on 51 patients with complaint of LUTS associated with BPH; and they were administered tamsulosin 0.4 mg and were followed up for 2,4, and 8
weeks post-treatment. The IPSS-QoL and N-QoL (nocturia related quality of life) scores significantly improved at visit 3 through end of study, and also significant improvement in nocturia and hours of undisturbed sleep was observed in their last clinic visit.26   A recently conducted study demonstrated that tamsulosin effectively reduced nighttime urine production in BPH patients with nocturnal polyuria.27   In patients with double-J stent, tamsulosin effectively reduced nocturia, pain, and also improved quality of life (Figure 5).28

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Tamsulosin with ADS technology – an innovative advantage – Unlike conventional tamsulosin formulations that depend on the presence of water in the gastrointestinal tract (GIT) to release the active ingredient, the innovative Advanced Delivery System (ADS) ensures continuous and consistent tamsulosin release throughout the entire length of the GIT, including the colon where water is poorly available. This results in a more constant exposure to tamsulosin over 24 hours with a smaller peak-to-trough fluctuation (PTF) than the conventional formulations; and also reduces/eliminates the dependency on food. In fact, the innovation appears superior to conventional MR formulation of tamsulosin that has a variable absorption profile dependent on when it is taken in relation to food and gastrointestinal transit time. Furthermore, as not all patients comply with the dosing recommendations in the patient leaflet, the independence of food intake might considerably improve the tolerability of Tamsulosin.29   Consequently, the ADS advantage equates with less adverse effects on physiologic parameters.

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Drug therapy for nocturnal polyuria

In treating nocturnal polyuria, along with lifestyle modifications, desmopressin, diuretics and tricyclic antidepressants are recommended.12

Desmopressin: In patients with nocturia due to ADH disorder, desmopressin can be used. In these patients, the increased urine output can be treated with desmopressin orally at bedtime, generally giving low doses.12   However, its use in elderly requires special caution as hyponatremia has been reported to be common adverse effect associated with its use.

Diuretics: Day time administration of diuretics such as furosemide, can be considered for the treatment of nocturnal polyuria.12

Tricyclic antidepressants: Drugs like imipramine exhibit antidiuretic property along with their antidepressant property.

Conclusion

Nocturia, a bothersome symptom with increasing prevalence in the older age group, has a profound impact on quality of life and has been shown to be a predictor of morbidity. Hence, early diagnosis and treatment plays an important role, as its effective management improves patients’ quality of life. Overactive bladder and benign prostatic hyperplasia are the commonest reasons for nocturia. The voiding diary is the cornerstone to the evaluation of a patient presenting with nocturia, and history and physical examination allow for further evaluation of treatable causes of nocturia. Classifying nocturia into one of four categories (diurnal polyuria, nocturnal polyuria, bladder storage problem, and mixed nocturia) allows for a tailored treatment regimen. Use of a diagnostic and treatment algorithm can help direct decision making in clinical practice. Although behavioral and lifestyle changes may help the overall population suffering from nocturia, an individualistic approach for identifying and treating medical conditions that cause nocturia with appropriate pharmacologic therapies may have a significant impact on nocturia.

Desmopressin has been demonstrated to be effective in those individuals suffering from nocturnal polyuria, but has to be used cautiously in elderly patients. Various drug therapies are recommended for the management of nocturia in OAB and BPH patients. Improvement in nocturnal voids and nocturnal OAB-related voids has been demonstrated with Flavoxate and other antimuscarinic agents. In males suffering from bladder outlet obstruction secondary to BPH, reduction in nocturnal voids has been demonstrated in clinical trials with both alpha-adrenergic receptor blockers as well as 5-alpha-reductase inhibitors. Tamsulosin and flavoxate, used singly or in combination have shown to be effective in the management of nocturia. Tamsulosin, a super-selective alpha 1 adrenoceptor blocking agent, has rapid onset of action, and effectively reduces the nighttime urine in patients with BPH.

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