Desmopressin Treats Nocturia in Older Men

Summarized by Robert W. Griffith, MD
November 4, 2002

Introduction

Some circadian rhythms change, as we get older. In man, as well as in other daytime-active mammals, micturition, steered by the glomerular filtration rate, normally occurs during daylight hours. However, with increasing age, this particular rhythm is lost. It may be argued that this is an effect of natural selection at work - after the end of the reproductive life, there is no "evolutionary advantage" for an organism to avoid potential dangers that operate at night. For many mammals, the night danger comes from predators. For man, getting up at night to urinate can be equally perilous - poor night vision, postural hypotension, and the use of medications all contribute to an increased risk of falls, leading to a fractured neck of femur and consequent morbidity and mortality. Restoration of the circadian rhythm of glomerular filtration of youth might represent a real benefit in terms of reduced accidents from falls at night.

Scientists in Scandinavia have been in the forefront establishing a useful role for desmopressin, an oral analog of arginine vasopressin that is devoid of vasoconstrictor properties, in subjects with symptomatic nocturia. Now results from a 3-week study can be added to those from earlier trials, to provide convincing evidence of the effectiveness of the drug.

Method

This was a randomized, double-blind, placebo-controlled study that comprised three phases; screening (1 week), dose-titration (1-3 weeks, followed by a 1-week washout) and a 3-week double-blind treatment period.

Men over 18 years were enrolled if they had two or more voids per night, and a Nocturia Index score of >1 (mean nocturnal urine volume/largest single volume measured at any time). They had to have no well-defined cause for increased urinary frequency.

The dose-titration phase established the optimal individual desmopressin dose (0.1, 0.2, or 0.4 mg) taken orally at bedtime. Those volunteers who obtained a >20% reduction in their nocturnal diuresis with one of the doses of desmopressin were designated 'responders'.

After the 1-week washout period, responders were randomized to receive either desmopressin (at their individual optimal dose) or placebo, for three weeks. During this time they had clinical and laboratory assessments, and kept a diary recording 24 hour fluid intake, and the time and volume of nocturnal voids, among other information.

The primary efficacy endpoint was the proportion of patients who had a reduction by >50% in the mean number of nocturnal voids after treatment, compared with their baseline. There were numerous secondary endpoints.

Results

Of 341 patients screened, 224 entered the dose-titration phase, and 151 were designated responders, and therefore randomized to desmopressin (86) or placebo (65). Of those who withdrew during titration, 22% did so because there was no response to desmopressin, and 19% because of side effects of the drug.

The mean age of the randomized subjects was 65, and their mean number of nocturnal voids was 3.1.

In the desmopressin group, 28 patients (34%) had fewer than half their number of baseline nocturnal voids, compared with 2 (3%) in the placebo group (p<0.001). Other relevant results are given in the table:

	Placebo	Placebo	Desmopressin	Desmopressin
	Baseline	Treatment	Baseline	Treatment
Voids per night	3.2	2.7	3.0	1.7*
Nocturnal diuresis (mL/min)	1.7	1.5	1.5	0.9*
Time to first void (h)	2.5	2.9	2.7	4.5*

* p<0.001 vs. baseline

These results represent the 'intent-to-treat' analyses - i.e. all those patients who were randomized were included.

Similar numbers of patients from each group reported adverse events: 17% in the desmopressin and 25% in the placebo group. The majority of these were mild. Five subjects had serious adverse events, but none was judged to be related to the study medication; one of them was thrombocytopenia that was at first attributed to desmopressin, but re-challenge with the drug after the study failed to reproduce the effect.

Some older patients experienced mild hyponatremia during the titration phase of the study; only 10 of them had sodium levels below 130 mmol/L.

Comment

The results of this study provide further support for the concept that replacement of lost arginine vasopressin secretion in age can partially restore the circadian rhythm of urine formation, and hence lessen the need for nocturnal micturition. The risk of falls in older persons getting out of bed at night has been well documented.¹ To combat this, a pill at bedtime is probably more attune with today's society than our grandparents' way of avoiding perilous trips to the bathroom - the chamber pot under the bed.

It should be noted that nocturia is not confined to men, who are more likely to report it, and in whom prostatism is often incorrectly blamed. Women have nocturia as often as men, but are more likely to endure it without complaint.

Source

• Efficacy of desmopressin in the treatment of nocturia: a double-blind placebo-controlled study in men. A. Mattiasson, P. Abrams, P. Van Kerrebroeck,  et al., Brit J Urol Intern, 2002, vol. 89, pp. 855--862

Footnotes
1. Falls leading to femoral neck fractures in lucid older people. L. Nyberg, Y. Gustafson, D. Berggren,  et al., J Am Geriatr Soc, 1996, vol. 44, pp. 156--160
1. Nocturia: a risk factor for falls in the elderly. RB. Stewart, MT. Moore, FE. May,  et al., J Am Geriatr Soc, 1992, vol. 40, pp. 1217--1220

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