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Management of Nocturia: The role of Antidiuretic therapy

J.P. Weiss, K.V. Juul and A.J. Wein.

Neurourology and Urodynamics, Volume 33, Issue S1, Pages S19-S24, April 2014

Editor's comments: 
 (Guest Expert: Andrea Tubaro, DM, PhD, Chairman Sant´Andrea Hospital, Professor of Urology at "La Sapienza” University of Rome, Italy)

The diagnosis and management of nocturia is one of the most disappointing issues in urology as most (if not all) of the randomized trials targeting this condition failed to separate nocturia from nocturnal polyuria. Overall we know that the outcome of surgery, alpha-blockers and antimuscarinics may reach statistical significance but results looks quite disappointing. Antimuscarinics are entitled of a mean difference in the number of nocturnal voids that ranges from -0.46 to -0.72 episodes/night with a difference from placebo of 0.2 episodes/night or lower. Alphablockers produced a maximum of -1 episode of nocturia/night with a maximum difference of -0.3 episodes/night versus placebo. Evaluation of patients suffering nocturia using bladder diaries suggests that about 50% of them actually suffer nocturnal polyuria. Pathophysiology of nocturnal polyuria is know to be multifactorial and associated with cardiac failure, sleep apnea, increased secretion of atrial natriurectic peptide and other common conditions of an aging population. Although there is no consensus as to the definition of nocturnal polyuria one may speculates that these patients have an excess urine production during sleep time with a nocturnal voided volume that clearly exceeds the patient bladder functional capacity (some Authors define polyuria as the production of more than 1/3 of the daily urine volume during the 8 hours of nocturnal sleep) so that the only way to address the problem is to reduce nocturnal urine output. Desmopressin, a selective vasopressin receptor 2 agonist, has been developed for the treatment of polyuria and enuresis and proved to be effective in reducing nocturnal urine volume. The drug is associated with an increased risk of hyponatremia particularly in patients older than 65 years but the recent availability of a new sublingual oral formulation allows to reduce the drug dosage thus decreasing the risk of hyponatremia. Studies have shown a dose-dependent decrease of nocturnal urine volume with a mean reduction of up to 1.43 nocturia episodes/night.

Clinical research into the management of nocturia/nocturnal polyuria finally starts to make sense, the clinical issues are far from being resolved but at least another therapeutic approach is now available in our armamentarium.

Abstract
Strategies to manage nocturia include lifestyle modifications and treatment with alpha-blockers, antimuscarinic therapies, and antidiuretics. The concept of achieving success should not be limited to reduction of nighttime voids; it should ideally include proof of improvement of conditions generally associated with nocturia, such as falls, quality of life, and overall health. Few studies have looked specifically at parameters other than nocturnal voids, such as sleep latency, first undisturbed sleep period (FUSP), and total sleep time, including their clinical relevance to patient well-being. Lifestyle modifications, such as voiding before bedtime, limiting caffeine and alcohol, and adjusting medication timing, may be initially effective in mild cases of nocturia. Statistically significant reductions in voiding have been reported with antimuscarinic agents and alpha-blockers as initial therapy, but these reductions generally are not clinically relevant. The antidiuretic therapy desmopressin acetate, a selective vasopressin receptor 2 agonist, is effective in adults with nocturia associated with nocturnal polyuria; however, hyponatremia can occur. The newest formulation—desmopressin orally disintegrating sublingual tablet (ODST)—has greater bioavailability; thus, lower doses can be used, potentially reducing hyponatremia risk. A phase 3 study demonstrated statistically significant reductions in nocturnal voids for desmopressin ODST 50 and 100 µg versus placebo (−1.18 and −1.43 vs. −0.86; P = 0.02 and P < 0.0001, respectively) in patients with nocturia. Treatment was well-tolerated, and low-dose desmopressin ODST was associated with statistically significant increases in duration of FUSP. Development of a validated composite endpoint may help clinicians identify and compare strategies for treating nocturia. 
Neurourol. Urodynam. 33:S19–S24, 2014. © 2014 Wiley Periodicals, Inc.