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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: Roger Dmochowski, MD, MMHC, FACS, Professor of Urology, and Director Pelvic Medicine and Reconstruction Fellowship, Vanderbilt University, Nashville, TN, USA)

The role of antidiuretic therapy for nocturia continues to be an area of active investigation.  Manipulation of arginine vasopressin receptors remains the primary pharmacological target currently for therapy of nocturia. The primary mode for manipulation of these receptors is with the use of synthetic vasopressin receptor analogues. In general, these analogues have shown reasonable therapeutic indices, with adequate efficacy but with concern related to hyponatremia. The management of nocturia is dependent upon adequate diagnosis and identification of modifiable comorbidities. As is noted in this paper, lifestyle factors do play a role in management of this condition and should be optimized in addition to any initiated pharmacologic therapy.  Also, the identification of the true nocturnal polyuric patient (using nocturnal urine volume diary assessment) may optimize affect related to vasopressin analogues. Other types of pharmacologic agent classes (alpha antagonists in males and antimuscarinics in both genders) have been shown to produce minimal benefit in this condition but for unique individuals may play a role in therapeutic management and may be explored for therapeutic benefit.

Recently, new formulations of vasopressin analogues have been investigated in clinical trials. Desmopressin and remains the most extensively investigated analog. Dye to compound bioavailability concerns, new formulations of this analog have been recently investigated in clinical trials in an effort to maintain efficacy and reduce hyponatremia exposure risk. One of the recent sentinel findings of research related to vasopressin analogues has been the relative sensitivity of elderly (arbitrarily defined as greater than 65) and women to vasopressin analogue dosing magnitudes. The explanation for this sensitivity is, as of yet undefined, but may reflect differences in vasopressin (V2) receptor sensitivity and/or numeric quantity in these subpopulations. A direct outgrowth of this experience is the clear message that dosing magnitude reductions are necessary in these populations and also that these populations should be started on lower initial dosing levels during therapy inception.

The newest analog formulation does appear to improve bioavailability and does appear to reduce hyponatremia. The absolute magnitude of this reduction continues to be assessed from a safety standpoint for regulatory approval. As the authors rightly point out, an assessment of quality-of-life disruption and specifically sleep disturbance is critical in the assessment of these patients  and the use of a standardized quality-of-life tool is very useful to establish baseline bother in any potential symptomatic improvement after the rendering of therapy. As has been found with other forms of lower urinary tract symptoms, effective therapy is founded on the several factors.  These factors include specific diagnosis, optimization of lifestyle and comorbidity modification, and appropriate instruction, education and motivation of the affected individual undergoing therapy.

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.