Abstract
Nocturia is a common and bothersome condition experienced by both men and women. Studies have suggested that nocturia contributes a level of morbidity to those who suffer from the condition, both young and old. Desmopressin has historically been utilized to treat conditions such as central diabetes insipidus, certain bleeding disorders and primary nocturnal enuresis. Recently, interest has increased as to the use of desmopressin (a vasopressin analog) in the treatment of adult nocturia, for whom nocturnal polyuria is prevalent. While desmopressin has been traditionally administered in tablet and bioequivalent high dose melt formulations, newer low-dose orally disintegrating sublingual desmopressin has been recently studied to determine safe and efficacious dosing strategies. In this review, nocturia and its associated morbidities are discussed, followed by a contemporary literature review regarding the safety and efficacy of desmopressin for its treatment.
The International Continence Society has defined nocturia as waking at night to void, with each void preceded and followed by sleep [van Kerrebroeck et al. 2002]. Up to 61% of elderly women and up to 59% of elderly men report two or more voids per night; prevalence increases with age [Bosch and Weiss, 2010].
Nocturia is one of the most bothersome of the lower urinary tract symptoms (LUTS). It affects quality of both life and sleep, and is responsible for a significant amount of morbidity secondary to falls in the elderly [Asplund, 2005]. Nocturia has also been associated with increased risk of bone fractures in the elderly [Nakagawa et al. 2010]. Multiple studies have demonstrated an association of increased mortality risk with increasing nocturia severity episodes in the elderly [Asplund, 1999], despite controlling for comorbidities [Kupelian et al. 2005]. Other studies contradict such an association [van Doorn et al. 2012].
Vasopressin, also known as antidiuretic hormone (ADH), is produced by the posterior pituitary gland. Its role is to maintain serum osmolality and volume via free water excretion. Vasopressin, acts at the level of the collecting duct via interaction with the V2 receptor. This relationship results in translocation of aquaporin channels associated with cytosolic vesicles to the apical/luminal membrane of collecting duct cells. Free water then passively reabsorbs from the nephron back into systemic circulation via basolateral membrane channels.
ADH is released from the posterior pituitary in states of hyperosmolality and hypovolemia. Detection of the aforementioned states is facilitated by chemoreceptors and baroreceptors located in the hypothalamus and carotid sinus, respectively. ADH also plays a small role in increasing systemic vascular resistance and increasing urea reabsorption in the medullary collecting tubule; the latter further enhances renal concentrating capacity [Shoskes and McMahon, 2011].
ADH analogs (in the form of DDAVP) have traditionally been used to treat central diabetes insipidus, bleeding disorders such as von Willebrand disease, and primary nocturnal enuresis. However, recent interest in its role for treating nocturia has spawned a growing body of literature examining the role and effect of desmopressin in its treatment.
The utility of desmopressin depends on the pathophysiologic cause of nocturia, which in itself can be deduced by analysis of a 24-hour frequency volume chart. Five major categories exist: global polyuria; nocturnal polyuria; decreased functional bladder capacity; primary sleep disorders; and combinations, often known as ‘mixed’ nocturia etiology [Cornu et al. 2012].
Global polyuria is defined as greater than 40 ml/kg of urine produced over 24 hours [van Kerrebroeck et al. 2002]. Disease states such as diabetes mellitus, diabetes insipidus, hypercalcemia and primary polydipsia can be associated with global polyuria [Gulur et al. 2011]. Diabetes insipidus has many potential causes and is broadly divided between central (neurogenic) due to insufficient ADH synthesis by neurosecretory cells, and nephrogenic, in turn due to renal insensitivity to ADH.
Nocturnal polyuria is defined as excessive volume of urine produced during sleeping hours while 24-hour output remains <40 ml/kg. Nocturnal polyuria is generally defined in accordance with the Standardization Committee of the International Continence Society (ICS) as nocturnal urine volume (NUV) >20–33% (normal NUV increases with age) of total 24-hour urine production [van Kerrebroeck et al. 2002]. Excessive urine production remains a commonly reported cause of nocturia; up to 93% of elderly patients demonstrate nocturnal polyuria [Weiss et al. 2011].
Nocturnal polyuria may be secondary to changes in circadian release of ADH, mobilization of peripheral fluid during sleep hours, or increased nocturnal atrial natriuretic peptide release [Gulur et al. 2011]. Thus, fluid overload states such as congestive heart failure, liver disease with hypoalbuminemia, nephrotic syndrome or lower extremity venous stasis are associated with nocturnal polyuria [Cornu et al. 2012]. Central nervous system lesions contributing to a change in circadian release or action of ADH have also been implicated in causing nocturnal polyuria [Gulur et al. 2011]. Obstructive sleep apnea and excessive evening fluid intake also contribute to nocturnal polyuria.
The frequency volume chart (see Figure 1) is useful in evaluating nocturnal bladder capacity so as to determine whether the bladder can accommodate NUV. Reduced nocturnal bladder capacity can be due to structural or functional abnormalities of the lower urinary tract, namely obstruction, overactive bladder, neurogenic bladder, calculi or cancer [Cornu et al. 2012].
Diary-based differential diagnosis of etiology of nocturia.
Patients with nighttime micturition unassociated with awakening because of the desire to pass urine are categorized as having a primary sleep disorder such as insomnia or arousal disorders, neurologic conditions such as Parkinson’s disease or dementia, psychiatric conditions such as depression, or abuse of drugs or alcohol [Cornu et al. 2012].
A growing body of literature regarding nocturia as a bothersome and potentially morbid condition, often of polyuric origin, has led to consideration of antidiuretic therapy as a mechanistically desirable treatment option. Mattiasson and colleagues performed a short-term, multicenter, international double-blind placebo-controlled trial for adult men who suffered from nocturia, defined as at least two voids per night and a nocturia index (NUV/maximum voided volume) >1 based on voiding diary data [Mattiasson et al. 2002]. An initial dose titration period occurred over 3 weeks, with a 1-week washout period followed by a 3-week randomized, double-blind, placebo-controlled study. Patients who did not report >20% reduction in number of nightly voids despite maximal dosing at 0.4 mg via desmopressin tablet were classified as nonresponders and were not randomized. Those who failed to return to ≥78% of baseline during the washout phase were also excluded. The primary endpoint included a reduction in the number of nightly voids by at least 50% as based on voiding diaries. Secondary endpoints included the number of nightly voids, effect on quality of life and safety (specifically adverse effects and incidence of hyponatremia). Ultimately, 143 patients completed the study after 151 patients were randomized. There was a statistically significant difference in clinical response in the intent-to-treat population between the treatment and placebo arms (34% versus 3%, respectively; p < 0.001), with an odds ratio (OR) of 20 for response (defined as ≥50% reduction in the mean number of nocturnal voids) with desmopressin use [95% confidence interval (CI) 4.0–105.2]. This was confirmed in the population of subjects who were ultimately randomized after the washout period (33% versus 2%, respectively; p < 0.001; OR 22.4; 95% CI 2.5–203.5). Secondary endpoints favored desmopressin as well, with statistically significant differences in change in number of nocturnal voids (43% versus 12% decrease, respectively; p < 0.001) and duration of first sleep period (59% versus 21% increase, respectively; p < 0.001). Regarding safety, while 48% of patients described an adverse effect (15 in the desmopressin group and 16 in the placebo group; a similar number), 94% of adverse events were mild or moderate. The five patients who experienced serious adverse events were not deemed to have experienced those events secondary to the medication, and three were in the placebo arm. Ten (4%) patients experienced hyponatremia, four (40%) of whom were asymptomatic.
Lose and colleagues utilized an identical short-term, double-blind, placebo-controlled study design for women, and included dose titration, washout and a randomization period for responders only [Lose et al. 2003]. Inclusion criteria, dosing, and time frames were the same as that of Mattiasson and colleagues [Mattiasson et al. 2002]. Primary and secondary endpoints were also analogous to the aforementioned study. In total, 141 women completed the short-term study. In the intent-to-treat population, a clinical response (≥50% reduction in the mean number of nocturnal voids) was reached in 33 (46%) of patients in the treatment arm versus 5 (7%) in the placebo arm (p < 0.0001; OR 13.4; 95% CI 4.6–39.2). This statistical significance was confirmed in the randomized population, which consisted only of subjects who clinically responded to desmopressin during the dose-titration period (44% versus 4%; p < 0.0001; OR 33.2; 95% CI 6.0–183.6). All secondary endpoints, specifically first sleep period and number of nightly voids, favored the treatment arm over the placebo arm (78% versus 20% increase, and 46% versus 17% decrease, respectively; p < 0.0001). Regarding safety, despite 71% of patients reporting an adverse event, 90% of the events were reported as mild or moderate. Similar rates were reported between the treatment and placebo arms (36% versus 35%; respectively). Five (2%) patients reported serious adverse events; two deaths were reported as well, one cardiac related and one of unknown cause, which were not thought to be medication-related. A total of 27 (12%) patients recorded serum sodium levels below normal range, half (13) of which were below 130 mmol/l. A total of 11 of these were over the age of 65. All cases of hyponatremia occurred during the dose-titration period.
Lose and colleagues extended the data sets from the aforementioned studies towards 12 months after randomization and examined long-term safety as the primary endpoint [Lose et al. 2004]. Inclusion criteria included at least two voids per night with a nocturia index >1. Dose titration using tablets at 0.1, 0.2 and 0.4 mg was performed, each patient ultimately taking their optimal dose. The authors took specific interest in serum sodium values, having performed periodic assessment of laboratory values, vital signs and weight at each follow-up visit. Secondary endpoints included response to desmopressin in number of nightly voids, time between nightly voids and quality of life. Overall, 95 men and 87 women completed the 11-month followup. Some 25% of men and 68% of women completed 13 months of desmopressin. During long-term treatment, 92 men and 90 women reported adverse effects (70% and 77%, respectively); however, nearly 90% of these were mild or moderate. Adverse effects led to withdrawal in 12% of patients. Four men experienced six serious adverse effects, namely, dizziness in one, cardiac failure, headache and vomiting in two, and chest pain and hypertension in one. One woman experienced four serious adverse effects, namely hyponatremia, headache, vertigo and nausea. Some 14% of patients experienced hyponatremia; however, of the 35 cases, 33 were asymptomatic and borderline (serum sodium not lower than 130 mmol/l but below normal range). The remaining two patients experienced symptomatic class I hyponatremia (serum sodium greater than 125 mmol/l but less than 130 mmol/l). Patients 65 years and older were found to be more susceptible to treatment related adverse events and hyponatremia.
Both men and women experienced a decreased number of nightly voids (3.1–1.6 and 2.9–1.3, respectively), as well as at least a 50% decrease in number of nightly voids from baseline (37–67%, and 46–67%, respectively). In addition, time duration of first sleep period and quality of life improved for both men and women. There were no differences for either adverse effects or efficacy based on medication dose. Lose and colleagues concluded that desmopressin tablets are largely safe and effective for use in adults; however, caution must be used for those beyond the age of 65 [Lose et al. 2004].
Van Kerrebroeck and colleagues described an international, multicenter, double-blind, placebo-controlled trial with 127 patients who reported at least two voids per night [Van Kerrebroeck et al. 2007]. Median age was 65.2 years and 35% of the patient population was female. Tablet doses began at 0.1 mg and were titrated up weekly to a maximum dose of 0.4 mg, with a washout period prior to randomization. The authors reported a statistically significant decrease in the number of nocturnal voids in the desmopressin arm versus placebo (33% versus 11%; p < 0.0014). All secondary endpoints, including time between voids, favored the desmopressin group. Patients in the desmopressin arm gained 108 minutes in the first sleep period compared with 41 minutes in the placebo arm, for a difference of 67 minutes (p < 0.0001). Self-reported quality of sleep in the form of one question, specifically, ‘During the last week, did you often feel fresh in the mornings when you got up?’ favored the desmopressin group as well (OR = 2.71; 95% CI 1.16–6.35; p = 0.02). Desmopressin was generally well tolerated: there was no statistically significant difference between the treatment and placebo arms (15 patients each) in adverse effects and 67% of adverse effects were classified as mild. Six cases of hyponatremia were recorded, five of which (83%) occurred in patients ≥2 years of age. Only one was symptomatic with headache. A total of 20 more patients experienced a postbaseline serum sodium level below normal, while an additional 17 patients experienced borderline hyponatremia (no serum sodium level < 130 mmol/l); 16 of these 17 were asymptomatic. The authors concluded that desmopressin tablets were largely effective and well tolerated.
Weiss and colleagues reported outcomes on a 4-week multicenter, randomized, double-blind placebo-controlled trial aiming to determine the efficacy of orally disintegrating sublingual desmopressin (i.e. ‘melt’ formulation) [Weiss et al. 2012]. The authors randomized patients to various doses, specifically 10, 25, 50 and 100 µg. Approximately 90% of the subject population reported production of at least 33% of their daily voided volume at night, which classified them as nocturnal polyurics. Patients were included if they reported two or more voids at night, and had normal baseline serum sodium and renal function [glomerular filtration rate (GFR) ≥ 60 ml/mm]. Patients with urinary retention, elevated postvoid residual, or evidence of bladder outlet obstruction were excluded. Primary endpoints included change in mean number of nocturnal voids from baseline and proportion of subjects with >33% decrease in mean number of nocturnal voids. Secondary endpoints included duration of first sleep period, nocturnal and total urine volume, and nocturnal quality of life. The ultimate intent to treat population consisted of 757 patients randomized to placebo versus desmopressin at various doses; 710 patients ultimately completed the study.
A statistically significant difference in number of nocturnal voids was seen for all patients with 100 µg (p < 0.0001) and 50 µg (p < 0.02). Women responded to 25 µg as well (p < 0.02); however, for men, there was only a statistically significant difference with 100 µg (p < 0.005). The proportion of patients with at least a 33% reduction in the number of nocturnal voids increased with dosage; however, there was only a significant effect at 100 µg (p < 0.0001) for all patients (i.e. both sexes). A stronger response was seen in women at 25 µg (p = 0.02), 50 µg (p = 0.04) and 100 µg (p < 0.0001). At the conclusion of 4 weeks, NUV had significantly decreased in a dose-dependent manner in all groups for all doses ≥25 µg (p < 0.05). All patients also reported an increase in the time period of initial sleep from 25 µg (p < 0.001) as well as improved quality of life (p < 0.05). Four serious adverse effects were noted amongst the study population; none were thought to be related to the study. A total of 24 patients (3.0%) experienced hyponatremia, nine of whom measured at <125 mmol/l. Patients ≥65 years of age were more likely to develop hyponatremia. The authors concluded that orally disintegrating desmopressin melt is both well tolerated and effective, especially for those under the age of 65.
A significant amount of literature examining the safety and efficacy of oral desmopressin has focused on the elderly, given this group’s predilection towards hyponatremia. Rembratt and colleagues recruited 72 patients with a median age of 75.5 (range 66–90), all of whom experienced two or more voids per night and completed frequency–volume charts for 72 hours while taking 0.2 mg of desmopressin tablets [Rembratt et al. 2003]. Primary endpoint was safety in regard to serum sodium. Despite the fact that 34 patients (47%) reported a total of 49 adverse events, headache being most frequent (16%), only four patients experienced serum sodium <134 mmol/l, and all were at least 79 years of age. There were no serious adverse effects. The authors concluded that desmopressin tablets were well tolerated in the short term; however, clinicians must be prudent in trending serum sodium during the early phase of treatment.
Kuo aimed to examine the efficacy of desmopressin tablets in patients >65 years old, safety and adverse effects being reserved as secondary endpoints [Kuo, 2012]. He recruited patients with more than three episodes of nocturia as well as nocturnal polyuria (>35% of total voided volume at night) according to frequency–volume charts. Those with normal serum electrolytes and complete frequency–volume charts (72 hours of data) were eligible. Desmopressin tablets at a dose of 0.1 mg were administered for 4 weeks; a visit at the 2-week mark was carried out in order to collect another 3-day frequency–volume chart, as well as urine for specific gravity and serum electrolytes. The patients were followed for 4 weeks after stopping desmopressin. Quality of life was also examined. A total of 30 patients ultimately underwent medication administration; 25 men and five women, mean age 75.4 ± 6.6 years, range 65–84. Five patients (16.7%) reported side effects, namely dizziness and headache, generalized erythema, general weakness and increased urinary frequency. Two patients discontinued themselves from the study secondary to side effects. All 28 patients who completed the study reported improved NUV, nocturia frequency and quality of life index (p < 0.0001), with no significant change in serum sodium (139.7 ± 4.06 mEq/l versus 138.9 ± 4.73 mEq/l; p = 0.364). Kuo concluded that desmopressin tablets were safe and effective for administration in the elderly in the short term.
Wang and colleagues expanded the use of desmopressin to elderly men with a clinical diagnosis of BPH, as well as two or more voids per night as well as nocturnal urine production ≥30% of 24-hour urine volume [Wang et al. 2011]. In a randomized, double-blind, placebo-controlled trial using 0.1 mg of desmopressin tablets, 115 men over the age of 65 received placebo or desmopressin daily at bedtime for 12 months. Follow-up visits at 1, 3, 6 and 12 months were performed, at which time the authors collected frequency–volume charts, urine sodium, urine osmolality, serum electrolytes and quality of life questionnaire responses. The primary endpoint was the proportion of patients who had a reduction by two in the mean number of nocturnal voids after long-term treatment as opposed to baseline. Many secondary endpoints were also examined, namely the number of nightly voids, initial sleep duration, nocturnal volume and nocturnal polyuria ratio, quality of life and safety. A total of 35 patients (61.4%) in the desmopressin arm achieved a clinical response (decrease of two or more voids per night) versus eight (13.80%) in the placebo arm (p < 0.001). The desmopressin-treated patients also demonstrated a decrease in total NUV and an increase in the initial sleep period versus placebo (392.1 ± 60.1 ml versus 533.1 ± 93.3 ml, and 120.0 ± 17.7 minutes versus 101.6 ± 19.5 minutes, respectively). Quality of life index increase was significantly greater in the desmopressin arm than in the placebo arm. There was no significant difference in the number of reported adverse effects or rate of asymptomatic hyponatremia between the desmopressin and placebo arms (17 versus 19 and 9 versus 10, respectively). These authors concluded that low-dose desmopressin is safe and well tolerated in the long term in patients with BPH and nocturia.
Weiss and colleagues recently examined the safety and efficacy of orally disintegrating desmopressin in men over the age of 18 in a randomized, double-blind, placebo-controlled, multicenter study [Weiss et al. 2013]. Nocturia included ≥2 voids per night per voiding diary analysis. Patients were randomized to desmopressin 50 µg versus 75 µg versus placebo if they did not meet exclusion criteria (most importantly, evidence of bladder outlet obstruction or incomplete emptying, renal dysfunction, or pre-existing hyponatremia). Randomization was stratified by age <65 versus age ≥65, and subjects were instructed to take the study drug every night 1 hour before bed for the 3-month course of the study. Voiding diaries were collected monthly throughout the study period, as well as at randomization and at week 1. Primary endpoints included change from baseline in mean number of nocturnal voids and proportion of subjects who experienced at least a 33% decrease in the mean number of nocturnal voids at each visit. Secondary endpoints included mean initial sleep period time and mean NUV. Nocturnal quality of life and mean self-rated sleep quality were also assessed. A total of 395 patients were randomized, of whom 327 (83%) completed part I. Both desmopressin 50 and 75 µg significantly decreased the mean number of nocturnal voids from baseline (–0.37, p < 0.0001 and –0.41, p = 0.0003, respectively) and increased the odds of obtaining >33% responder status (OR = 1.98, p = 0.0009 and OR 2.04, p = 0.0004, respectively). There was no significant difference between those younger than 65 years of age and those older than 65. Initial sleep period duration and NUV also improved with both desmopressin 50 and 75 µg versus placebo at 3 months (p ≤ 0.009). There was no difference in the number of patients who reported adverse effects amongst the three groups; however, the incidence of adverse drug reactions, as well as the incidence of patients with hyponatremia, was lower in the desmopressin 50 µg group compared with the 75 µg group. Eleven patients experienced serum sodium <130 mmol/l, of whom nine (82%) were >65 years; five of the six patients (83%) with serum sodium ≤125 mmol/l were >65 years. The authors concluded that desmopressin ‘melt’ 50 µg is the minimum effective and safe dose for use in men with nocturia.
Conclusion
Available data summarized in Table 1 support the use of desmopressin in both tablet and orally disintegrating formulations for patients with nocturia. Mechanistically, nocturnal polyuria as a major substrate of nocturia should respond to antidiuretic therapy using an ADH analog such as desmopressin in order to decrease the amount of urine production and thus alleviate nocturnal voiding. A number of studies have in fact demonstrated its efficacy in decreasing nocturia severity while improving quality of life as compared with placebo. The safety of desmopressin, however, is paramount to its clinical utility. Desmopressin is generally well tolerated, the newer ‘melt’ formulation at lower doses being nearly as effective and better tolerated than tablet (‘high dose’). A minimum dosage of 25 µg orally disintegrating sublingual desmopressin appears to be ideal for women, whereas men may benefit from a minimum of 50 µg. Regardless of formulation or dosing, judicious care should be taken for elderly patients (≥65 years of age) due to the increased risk of hyponatremia in such vulnerable individuals.
Summary of outcomes of clinical trials in nocturia patients treated with desmopressin.
For 100 µg dose only.
Median age.
Odds ratio for achieving >33% decrease in number of nocturnal voids at 75 µg.
Footnotes
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement
J.P.W. is a consultant for Ferring, Pfizer, Allergan, Astellas, Lilly and Drais.