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A Systematic Review of the Efficacy and Safety of Desmopressin for Nocturia in Adults

By M. H. Ebell, T. Radke, and J. Gardner

Journal of Urology, Volume 192, Issue 3, September 2014, Pages 829-835

Associate Editors of the Nocturia Resource Centre, Professor Karl-Erik Andersson and Professor Donald Bliwise give their comment to the same Review article.

Comment by Professor Karl-Erik Andersson:
Even if our knowledge of nocturia, its etiology and its management has substantially improved in recent years, the evidence available on its management remains limited (Cornu et al., 2012, Van Kerrebroeck and Andersson, 2014). Desmopressin remains a first line treatment and it is important that the information on published studies on the drug is collected and analyzed regularly. The study by Ebell and colleagues (2014) contains a systematic review and meta-analysis of publications examining use of desmopressin to treat nocturia in generally healthy adults with a focus on benefits and harms. The authors give a detailed explanation of the search strategy and inclusion criteria utilized to identify studies for the analysis. Ten parallel group design randomized controlled clinical trial (RCTs) including in a total of 2,191 patients, 1,410 in the desmopressin group and 781 in the placebo group, met the study inclusion criteria. The included studies (evaluated based on The Cochrane Collaboration criteria) were generally of high quality, although 4 used an active run-in period to titrate the dose and excluded patients with adverse effects or who were non-responders. The authors confirmed what was found in a previous meta-analysis based on 619 patients (Zong et al., 2012) showing that desmopressin at doses of at least 25 mcg or greater decreased nocturnal voids and increased time to first void. A dose of 100 mcg provided just more than an hour of additional sleep before the first void compared with placebo as well as 0.72 fewer voids per night. Higher doses provided no significant increase in benefit. Hyponatremia and headache were the most common adverse effects, and serious adverse effects were rare. The authors conclude that the initial dose should be between 50 and 100 mcg, and that higher doses should only be used with caution. A lower initial dose of 25 to 50 mcg is appropriate in elderly patients.

Interestingly, the authors found no difference in efficacy and adverse effects between men and women. They mention in the discussion that some studies have shown such differences, but do not discuss in detail, the gender difference in the sensitivity to desmopressin demonstrated by Juul et al. (2011), nor do they mention that a new dose recommendation stratified by gender has been suggested, i.e., for men, 50- to 100-mcg, and for women 25 mcg (Juul et al., 2011). Ebell et al. (2014) underline that all patients should be monitored for hyponatremia, which is in agreement with general recommendations. They also mention that desmopressin should be used with caution in patients with chronic lung disease due to the rare occurrence of respiratory failure. Even if the 3 cases are correctly reported, this adverse effect seems to be a very rare complication, and it may be questioned whether the data really identify a safety signal motivating a caution for use in patients with chronic lung diseases.

It is comforting that this meta-analysis of Ebell et al. (2014) confirms what has been shown in previous meta-analyses and reviews (Cornu et al., 2012Zong et al., 2012Friedman and Weiss, 2013) and that it supports their conclusion: “desmopressin appears to offer a modest benefit for treating nocturia in generally healthy adults with adequate safety”. Their dose recommendations may be based on the presented results, however, meta-analyses are one way of presenting data and are important, but may not be the best basis for an optimized individual treatment.   

References

1. Cornu JN, Abrams P, Chapple CR, Dmochowski RR, Lemack GE, Michel MC, Tubaro A, Madersbacher S. A contemporary assessment of nocturia: definition, epidemiology, pathophysiology, and management--a systematic review and meta-analysis. Eur Urol. 2012 Nov;62(5):877-90.

2. Van Kerrebroeck P, Andersson KE. Terminology, epidemiology, etiology, and pathophysiology of nocturia. Neurourol Urodyn. 2014 Apr;33 Suppl 1:S2-5.

3. Zong H, Yang C, Peng X, Zhang Y. Efficacy and safety of desmopressin for treatment of nocturia: a systematic review and meta-analysis of double-blinded trials. Int Urol Nephrol. 2012 Apr;44(2):377-84.

4. Juul KV, Klein BM, Sandström R, Erichsen L, Nørgaard JP. Gender difference in antidiuretic response to desmopressin. Am J Physiol Renal Physiol. 2011 May;300(5):F1116-22

5. Friedman FM, Weiss JP. Desmopressin in the treatment of nocturia: clinical evidence and experience. Ther Adv Urol. 2013 Dec;5(6):310-7.

Comment by Professor Donald L. Bliwise:
This well-done meta-analysis examined a number of randomized clinical trials examining the efficacy of desmopressin as a treatment for nocturia. Understanding variability across results from randomized clinical trials is considered an important key to understanding the clinical utility of a drug and its mechanisms of action. The analysis focused on several different outcomes (number of voids, duration of first uninterrupted sleep period, overall clinical response) and showed substantial heterogeneity (defined here as higher I2 index) across these studies. There was no obvious evidence of publication bias, as derived from inspection of the figures. The paper attributed most of the heterogeneity of effects to desmopressin dose, although the majority of the studies employing 0.1 mg or higher used the customary oral tablet, whereas the lower dose studies (< 0.1 mg) used a relatively recent oral melt formulation.

Biologically, one might consider two additional other sources of variance in the prediction of desmopressin effects: gender and obesity. Efficacy was seen equally in both men and women, though recent findings suggesting sex differences in V2 receptor expression (females having higher sensitivity) (1,2) might have led to another source of heterogeneity not fully appreciated here, given the small number of studies (only 4 of the trials included both men and women), a limitation fully acknowledged by the authors. Perhaps more provocative is whether obesity (e.g., Body Mass Index) was a significant modifier to desmopressin effects. These studies did not present stratified by BMI, which might be considered relevant, since higher BMI is associated with sleep apnea, itself well-known to be associated with nocturia (3.4), the latter being reduced when sleep apnea is treated successfully (5).

Whether desmopressin effects are maintained in such patients remains to be seen, though one would speculate that, given the high prevalence of this condition in the general population, individuals with sleep apnea were probably included in many of these trials. Effects were therefore seen despite the likely presence of comorbid undiagnosed sleep apnea.

References

1. Juul KV, Bichet DG, Nielsen S et al. The physiological and pathophysiological functions of renal and extrarenal vasopressin V2 receptors. Am J Physiol Renal Physiol 2014; 306: F931-40.

2. Juul KV, Klein BM, Sandstrom R et al. Gender difference in antidiuretic response to desmopressin. Am J Physiol Renal Physiol 2011; 300: F1116-22.

3. Umlauf MG, Chasens ER, Greevy RA, et al. Obstructive sleep apnea, nocturia and polyuria in older adults. Sleep 2004; 27: 139–44.

4. Parthasarathy S, Fitzgerald M, Goodwin JL, et al. Nocturia, sleep-disordered breathing, and cardiovascular morbidity in a community-based cohort. PLoS One 2012; 7: e30969.

5. McMillan A, Bratton DJ, Faria R et al. Continuous positive airway pressure in older people with obstructive sleep apnoea syndrome (PREDICT): a 12-month, multicenter, randomized trial. Lancet Respir Med 2014; 2: 804-12.