First uninterrupted sleep period in children and adolescents with nocturnal enuresis: Added value in diagnosis and follow-up during therapy.

BACKGROUND: The first uninterrupted sleep period (FUSP, time up to the first episode of enuresis/nocturia after falling asleep) is a frequently investigated parameter in adults with nocturia, as it correlates with quality of life. However, it has not been included in pediatric enuresis studies. AIM: Investigate FUSP, circadian renal water and sodium handling, as well as sleep quality before and after desmopressin therapy in enuresis. MATERIALS AND METHODS: We conducted a post hoc analysis of a prospective study in 30 treatment-naïve children with enuresis who underwent a video-polysomnography and a 24-h urine concentration profile before and after 6 months of desmopressin therapy. We analyzed FUSP, periodic limb movements in sleep (PLMS), and arousal indexes and their correlations with the urinary parameters. RESULTS: Sixteen children with a mean age of 10.9 ± 3.1 years had full registrations and were included in this subanalysis. After therapy, FUSP was significantly longer (p < 0.001), and the PLMS index was lower (p = 0.023). Significant differences in the circadian rhythm of diuresis (night/day diuresis, p = 0.041), nocturnal urinary osmolality (p = 0.009), and creatinine (p = 0.001) were found, demonstrating the increase of urinary concentration overnight by desmopressin, as well as a significant antidiuretic effect (diuresis [p = 0.013] and diuresis rate (p = 0.008). There was no correlation between the difference of FUSP, PLMS index, and urinary parameters. Nevertheless, despite this study being underpowered, there are indications of a correlation between nocturnal diuresis and diuresis rate. RESULTS: Our results support the need for further research regarding FUSP in children with enuresis, in accordance with nocturia studies in adults, as this parameter could be valuable in the follow-up and evaluation of therapeutic strategies for enuresis.

Low-dose desmopressin combined with serum sodium monitoring can prevent clinically significant hyponatraemia in patients treated for nocturia.

OBJECTIVE: To explore risk factors for desmopressin-induced hyponatraemia and evaluate the impact of a serum sodium monitoring plan. SUBJECTS AND METHODS: This was a meta-analysis of data from three clinical trials of desmopressin in nocturia. Patients received placebo or desmopressin orally disintegrating tablet (ODT; 10-100 µg). The incidence of serum sodium <130 mmol/L was recorded by age, sex and dose. Potential predictors of clinically significant hyponatraemia were identified using multivariate analysis in a Cox proportional hazards model. RESULTS: Dose, age, baseline serum sodium level and kidney function, according to estimated GFR clearance, were significant risk factors for hyponatraemia in both sexes; similar to the known risk factors associated with hyponatraemia in the general population. In men, arthritis and use of drugs for bone disease were also predictive of hyponatraemia, while in women, raised monocytes and absence of lipid-modifying drugs increased the risk of hyponatraemia. Use of the proposed monitoring scheme and the minimum effective dose would have omitted all patients with clinically significant hyponatraemia from further treatment. CONCLUSIONS: The incidence of hyponatraemia can be reduced by using minimum effective gender-specific dosing with the ODT formulation of desmopressin (25 µg in women, 50 µg in men). A sodium monitoring plan is proposed whereby baseline sodium must be ≥135 mmol/L (especially important in the elderly), with additional monitoring at week 1 and month 1 for those at elevated risk because they are aged ≥65 years or receiving concomitant medication associated with hyponatraemia. This monitoring plan would help to prevent some at-risk patients developing hyponatraemia; retrospective application of the monitoring plan showed that, once at-risk patients were appropriately screened out, only mild, non-clinically significant hyponatraemia was observed, within ranges of other drugs associated with hyponatraemia and similar to the background prevalence in the treatment population.

Desmopressin as an adjuvant to opioids or NSAIDs in treatment of renal colic: a nationwide register-based study.

AIMS: Desmopressin has been reported to be effective as an adjuvant to opioids or NSAIDs in management of pain in renal colic; however real-life data are lacking on the utilisation of desmopressin in this patient segment. METHODS: The Danish National Prescription Registry data-linked with Danish National Patient Registry during a 3-year period from 2009 to 2011 was used to study prescriptions for desmopressin in renal colic. RESULTS: We identified 888 desmopressin prescriptions for renal colic, dispensed to 95 patients. The mean treatment period was 159 days, with a large variation up to a maximum of 924 days. Approximately two thirds of patients received dosing instructions to administer the drug 4 times daily to provide 24-h antidiuretic coverage. Among concomitant opioids and NSAIDs, tramadol and ibuprofen were prescribed most frequently. Antidepressants and diuretics were also widely used. A clear sex difference was seen, with female renal colic patients having three times more prescriptions overall than males, and in particular receiving more antidepressants and psychotropic drugs. A total of 4 (4.2%) of the patients experienced hospital admissions because of hyponatraemia or polydipsia during the 3-year period. We confirmed a previous case report that nephrolithiasis could be at least an occasional complication of successful therapy of Central Diabetes Insipidus (CDI) with desmopressin, identifying 12 CDI patients in total, or 2.4% of all Danish CDI patients in that period, who were also treated for renal colic. CONCLUSION: In summary, these real-life prescription data provide exact epidemiological measures on desmopressin utilisation in renal colic.

The physiological and pathophysiological functions of renal and extrarenal vasopressin V2 receptors.

The arginine vasopressin (AVP) type 2 receptor (V2R) is unique among AVP receptor subtypes in signaling through cAMP. Its key function is in the kidneys, facilitating the urine concentrating mechanism through the AVP/V2 type receptor/aquaporin 2 system in the medullary and cortical collecting ducts. Recent clinical and research observations strongly support the existence of an extrarenal V2R. The clinical importance of the extrarenal V2R spans widely from stimulation of coagulation factor in the endothelium to as yet untested potential therapeutic targets. These include V2R-regulated membranous fluid turnover in the inner ear, V2R-regulated mitogensis and apoptosis in certain tumor tissues, and numerous other cell types where the physiological role of V2Rs still requires further research. Here, we review current evidence on the physiological and pathophysiological functions of renal and extrarenal V2Rs. These functions of V2R are important, not only in rare diseases with loss or gain of function of V2R but also in relation to the recent use of nonpeptide V2R antagonists to treat hyponatremia and possibly retard the growth of cysts and development of renal failure in autosomal dominant polycystic kidney disease. The main functions of V2R in principal cells of the collecting duct are water, salt, and urea transport by modifying the trafficking of aquaporin 2, epithelial Na(+) channels, and urea transporters and vasodilation and stimulation of coagulation factor properties, mainly seen with pharmacological doses of 1-desamino-8-D-AVP. The AVPR2 gene is located on the X chromosome, in a region with high probability of escape from inactivation; this may lead to phenotypic sex differences, with females expressing higher levels of transcript than males.

The Nocturia Impact Diary: a self-reported impact measure to complement the voiding diary.

BACKGROUND: Nocturia is a chronic, fluctuating disease that disrupts sleep and has a wide-ranging impact on quality of life. Valid tools to measure the patient-reported impact of nocturia are essential for evaluating the value of treatment, but the available tools are suboptimal. OBJECTIVES: This study reports the development and validation of the Nocturia Impact Diary-an augmented form of the Nocturia Quality of Life questionnaire designed to be completed in conjunction with the widely used 3-day voiding diary. METHODS: The process comprised three steps: Step 1: Development of a concept pool using the Nocturia Quality of Life questionnaire and data from relevant studies; Step 2: Content validity study; Step 3: Psychometric testing of construct validity, reliability, and sensitivity of the diary in a randomized, placebo-controlled study in patients with nocturia. RESULTS: Step 1: Fourteen items and 4 domains were included in the first draft of the diary. Step 2: Twenty-three patients with nocturia participated in the cognitive debriefing study. Items were adjusted accordingly, and the content validity was high. Step 3: Fifty-six patients were randomized to desmopressin orally disintegrating tablet or placebo. The diary demonstrated high construct validity, with good sensitivity and a good fit to Rasch model, as well as high internal consistency, discriminatory ability, and acceptable sensitivity to change. Results indicated that the diary was unidimensional. CONCLUSIONS: The Nocturia Impact Diary is a convenient, validated patient-reported outcome measure. It should be used in conjunction with a voiding diary to capture the real-life consequences of nocturia and its treatment.

Potential clinical applications of current and future oral forms of desmopressin (Review).

Desmopressin is a synthetic analogue of vasopressin and a selective vasopressin receptor 2 agonist. It was first synthesised in 1967 and utilised for its antidiuretic properties. It is also used in bleeding disorders to enhance clotting. Other potential uses of the drug have been reported. The present review aims to provide a broad overview of the literature on potential further uses of oral forms of desmopressin. Key therapeutic areas of interest were identified based on known physiological activities/targets of desmopressin or reports of an effect of desmopressin in the literature. The feasibility of adequate dosing with oral forms of the drug was also considered. Systematic literature searches were carried out using the silvi.ai software for the identified areas, and summaries of available papers were included in tables and discussed. The results of the searches showed that desmopressin has been investigated for its efficacy in a number of areas, including bleeding control, renal colic, the central nervous system and oncology. Evidence suggests that oral desmopressin may have the potential to be of clinical benefit for renal colic and bleeding control in particular. However, further research is needed to clarify its effect in these areas, including randomised controlled studies and studies specifically of oral formulations (and doses). Further research may also yield findings for cancer, cognition and overactive bladder.

Gender difference in efficacy and dose response in Japanese patients with nocturia treated with four different doses of desmopressin orally disintegrating tablet in a randomized, placebo-controlled trial.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Desmopressin orally disintegrating tablet (ODT) 60-240 µg has proved an effective and well-tolerated antidiuretic treatment in male and female patients with nocturia. The main adverse event is hyponatraemia. Recent studies suggest that female patients are more sensitive to desmopressin ODT, achieving the same efficacy at lower doses than male patients. The study demonstrates the efficacy of desmopressin ODT in male and female Japanese patients with nocturia. It provides further evidence that the optimum desmopressin dose for the treatment of nocturia is lower in females than in males. Tailoring the dose according to gender provides an improved therapeutic window with the benefits of a decreased risk of hyponatraemia without compromising efficacy. OBJECTIVES: To establish the dose-response efficacy of desmopressin in a Japanese patient population for the treatment of nocturia. To explore gender differences in sensitivity to desmopressin in Japanese patients with nocturia. PATIENTS AND METHODS: A phase II multicentre, randomized, placebo-controlled, double-blind, parallel-group, comparative clinical trial was conducted. Subjects aged 55-75 years, with a mean of ≥2 voids per night, were included and randomized to receive placebo or one of four doses of desmopressin orally disintegrating tablet (ODT): 10 µg, 25 µg, 50 µg or 100 µg. The dose-response relationship of pharmacodynamic variables measured after a single dose of desmopressin administered to water-loaded subjects (treatment period 1) was compared with the primary clinical endpoint of change from baseline in mean number of nocturnal voids, after 28 days of desmopressin treatment (treatment period 2). RESULTS: A total of 116 patients were treated in treatment period 1 of whom 113 qualified for treatment period 2, and 111 completed the study. In treatment period 1 a dose-response relationship was observed, both overall and in each gender group. Overall, the duration of antidiuretic action (DOA; time with urine osmolality >200 mOsm/kg) for the 25, 50 and 100 µg doses was 2 h (P = 0.010), 3.45 h (P < 0.001) and 5.74 h (P < 0.001), respectively; all statistically significant compared with placebo. Female patients were found to be more sensitive to desmopressin; DOA in female patients was longer than in male patients after desmopressin 25 and 50 µg. Extrapolation suggests that male patients require ∼58 µg to achieve similar DOA to females receiving 25 µg. A dose-response relationship was also seen in treatment period 2 for the group overall with a greater reduction in mean number of nocturnal voids from baseline to day 28 at higher doses, and with significant reductions in the 25- (P = 0.015) 50- (P < 0.001) and 100-µg (P = 0.001) dose groups compared with placebo. Similar dose-response relationships were also seen when the data were analysed by gender. Desmopressin ODT was well tolerated with no serious or severe adverse events. CONCLUSIONS: A dose-response relationship for desmopressin ODT was shown in a population of Japanese patients with nocturia. The study suggests that the optimum desmopressin dose for the treatment of nocturia is lower in females than in males, indicating a gender-specific therapeutic window with a decreased risk of hyponatraemia without compromising efficacy on reduction of nocturnal voids. Further dose-finding studies are planned to confirm the recommended dose for the treatment of nocturia in a Japanese patient population.

Long-term durability of the response to desmopressin in female and male nocturia patients.

AIMS: To explore the durability of efficacy and gender differences during chronic administration of desmopressin in nocturia. METHODS: This pooled analysis of three short-term efficacy studies, with extensions, of desmopressin administered as orally disintegrating tablet (ODT) or solid tablet in nocturia treatment, comprised 351 patients completing 40-56 weeks' treatment. Efficacy endpoints of change in number of nocturnal voids and duration of initial undisturbed sleep period from baseline were analyzed to determine response durability and gender differences. RESULTS: The mean decrease in number of nocturnal voids during short-term treatment was maintained and further reduced during the long term. At 52 weeks, the mean decrease in number of nocturnal voids from baseline reached 1.4-2.1 voids for desmopressin ODT 25-100 µg. Following 40-week tablet treatment, the decrease in number of nocturnal voids was 0.8-1.5 for desmopressin 100-400 µg. The mean decrease in nocturnal voids (25-50 µg ODT) was greater for females than males. For females, the improvement in initial period of undisturbed sleep was 2.5-3 hr for desmopressin ODT 25-100 µg, compared with 1.3-2.6 hr for males. No gender difference in efficacy was seen in the tablet studies. CONCLUSIONS: The decrease in nocturnal voids and improvement in sleep with short-term desmopressin treatment were maintained throughout long-term treatment. A durable gender difference in efficacy in favor of females was observed with desmopressin ODT 25 µg. Further, large-scale long-term trials are needed to confirm the durability of efficacy with gender-specific doses of desmopressin.

Desmopressin melt improves response and compliance compared with tablet in treatment of primary monosymptomatic nocturnal enuresis.

UNLABELLED: Primary nocturnal enuresis is a prevalent childhood condition that can persist into adulthood. Desmopressin is an antidiuretic available as orally disintegrating lyophilisate (melt) or solid tablet. Recent findings suggesting different food interactions and clinical characteristics, including compliance, between desmopressin melt and tablet motivated a post hoc analysis of a previously reported randomised, crossover study. The efficacy of desmopressin melt compared with tablet was evaluated using the International Children's Continence Society (ICCS) responder definitions. Compliance was further analysed using detailed criteria, and the association between efficacy and compliance was examined. In total, 221 patients aged 5-15 years, already receiving desmopressin tablets were randomised to the treatment sequence melt (120/240 µg)/tablet (0.2/0.4 mg) or tablet/melt in two consecutive 3-week periods. The probability of being a responder (partial or full) during either period was significantly more likely with desmopressin melt compared with tablet (odds ratio, 2.0; confidence intervals, 1.07-3.73; p = 0.03). There was no period effect on compliance in the tablet/melt sequence and no difference in the number of completely compliant patients in each formulation group; however, more patients were >75 % compliant in period 1 compared with period 2 in the melt/tablet sequence. Increased compliance was associated with greater reductions in the number of wet nights for both formulations. CONCLUSIONS: Desmopressin melt, compared with tablet, improves the probability of being a responder. Switching from tablet to melt formulation increased patient compliance. Increased compliance was associated with increased efficacy. Switching to desmopressin melt may benefit patients with suboptimal responses to desmopressin tablet.

Efficacy and safety of desmopressin orally disintegrating tablet in patients with central diabetes insipidus: results of a multicenter open-label dose-titration study.

Central diabetes insipidus (CDI) is associated with arginine vasopressin (AVP) deficiency with resultant polyuria and polydipsia. Intranasal desmopressin provides physiological replacement but oral formulations are preferred for their ease of administration. This study aimed to demonstrate the efficacy and safety of desmopressin orally disintegrating tablet (ODT) in the treatment of Japanese patients with CDI, and confirm that antidiuresis is maintained on switching from intranasal desmopressin to desmopressin ODT. A total of 20 patients aged 6-75 years with CDI were included in this 4-week multicenter, open-label study. Following observation, patients switched from intranasal desmopressin to desmopressin ODT with titration to optimal dose over ≤5 days at the study site. Following three consecutive doses with stable patient fluid balance, patients were discharged with visits at Weeks 2 and 4. Following titration from intranasal desmopressin to ODT, the mean 24-hour urine volume was unchanged, indicating similar antidiuresis with both formulations. The proportion of patients with endpoint measurements (urine osmolality, 24-hour urine volume, hourly diuresis rate and urine-specific gravity) within normal range at Days 1-2 (intranasal desmopressin) and Week 4 (desmopressin ODT) was similar. The mean daily dose ratio of intranasal desmopressin to desmopressin ODT (Week 4) was 1:24 but a wide range was observed across individuals to maintain adequate antidiuretic effect. Hyponatraemia was generally mild and managed by dose titration. Desmopressin ODT achieved sufficient antidiuretic control compared to intranasal therapy and was well tolerated over long-term treatment. The wide range of intranasal:ODT dose ratios underline the importance of individual titration.

Desmopressin orally disintegrating tablet effectively reduces nocturia: results of a randomized, double-blind, placebo-controlled trial.

AIMS: The primary objective was to investigate the efficacy of desmopressin orally disintegrating tablet versus placebo in patients with nocturia. Pharmacodynamics, safety and patient-reported quality of life (QoL) outcomes were also evaluated. One of several benefits of the new formulation is increased bioavailability. Exploring lower doses allows for a better evaluation of therapeutic effect versus tolerability. METHODS: This was a 4-week, randomized, double-blind study comparing 10, 25, 50, or 100 µg desmopressin versus placebo in adults with defined nocturia. RESULTS: The intent to treat population comprised 757 patients experiencing ∼3 voids/night and a high prevalence of nocturnal polyuria (∼90%). Increasing doses of desmopressin were associated with decreasing numbers of nocturnal voids and voided volume, greater proportions of subjects with >33% reduction in nocturnal voids, and increased duration of first sleep period. The lowest dose reaching statistical significance (P < 0.05 vs. placebo) varied by endpoint. Improvements were clinically meaningful, meaning that patients actually had fewer nightly voids. Post hoc analyses by gender suggested a lower minimum effective dose for women. Desmopressin was generally well tolerated. Reductions in serum sodium to <125 mmol/L in six women (taking >25 µg desmopressin) and two men (aged 67 and 82) taking 100 µg, support lower and gender-specific dosing to reduce the small but clinically significant risk of hyponatraemia. Each void reduced/hour of sleep gained was associated with significant improvements in QoL. CONCLUSIONS: Desmopressin orally disintegrating tablet is an effective and well-tolerated treatment for patients with nocturia. Further exploration of the lower dose range is warranted.

Nocturia Think Tank: focus on nocturnal polyuria: ICI-RS 2011.

The following is a report of the proceedings of the Nocturia Think Tank sessions of the annual International Consultation on Incontinence-Research Society, which took place June 13-15, 2011 in Bristol, UK. The report is organized into sections pertaining to the main topics of discussions having occurred at that meeting, centering on the relationship of nocturnal polyuria (NP) and nocturia but also synthesizing more current evidence advancing our knowledge of the diagnosis and management of nocturia. This article is not meant to be a comprehensive review on the subject of nocturia, a number of which are available in the recent literature. All authors were physically present during, or in a preliminary session just prior to, the meeting in Bristol.

Gender difference in antidiuretic response to desmopressin.

Increased age and female gender are well-known risk factors for the development of desmopressin-induced hyponatremia. However, little focus has been on exploring gender differences in the antidiuretic response to desmopressin. Based on an exploratory analysis from three clinical trials, we report a significant gender difference in the effects of desmopressin on nocturnal urine volume that could not be explained by pharmacokinetic differences. Mean desmopressin concentration profiles were tested for covariates, and age and gender were not statistically significant and only weight was significant for log(C(max)) (P = 0.0183) and borderline significant for log(AUC) (P = 0.0571). The decrease in nocturnal urine volume in nocturia patients treated with desmopressin over 28 days was significantly larger for women at the lower desmopressin melt doses of 10 and 25 µg than for men. The ED(50) for men was modeled to be 43.2 µg and 16.1 µg for women, with the ED(50) men/women estimated to be 2.7 (1.3-8.1 95% CI), corresponding to significantly higher sensitivity to desmopressin in women. An increasing incidence of hyponatremia with increasing dose was found, and at the highest dose level of 100 µg decreases in serum sodium were approximately twofold greater in women over 50 yr of age than in men. A new dose recommendation stratified by gender is suggested in the treatment of nocturia: for men, 50- to 100-µg melt is an efficacious and safe dose, while for women a dose of 25 µg melt is recommended as efficacious with no observed incidences of hyponatremia. Areas for further research are proposed to uncover pathophysiological mechanism(s) behind these gender differences.

Excessive nocturnal urine production is a major contributing factor to the etiology of nocturia.

PURPOSE: Nocturnal polyuria is a common but often overlooked cause of nocturia. We investigated the proportion of adults with 2 or greater voids nightly who had nocturnal polyuria in 2 cohorts from the United States and Europe. MATERIALS AND METHODS: Data on nocturnal polyuria were obtained from 3 or 7-day frequency-volume charts completed by patients as part of screening for inclusion in subsequent trials of nocturia therapy. Patients recorded the time and volume of each void. Nocturnal polyuria was defined as nocturnal urine volume greater than 33% of 24-hour volume, including the first morning void. RESULTS: In the first cohort 1,003 patients were screened, of whom 846 provided evaluable diary data, including 641 (76%) with nocturnal polyuria. Of the total screened population of 1,003 patients 641 (64%) had confirmed nocturnal polyuria. The prevalence of nocturnal polyuria increased with age but was high in all age groups. In the second cohort 1,412 patients were screened, of whom 917 provided evaluable diary data, including 806 (88%) with nocturnal polyuria. Of the total screened population of 1,412 patients 806 (57%) had confirmed nocturnal polyuria. The prevalence of nocturnal polyuria increased with age but was high in all age groups. Of 158 patients receiving benign prostatic hyperplasia and/or overactive bladder medication 141 (89%) had nocturnal polyuria. In each cohort the nocturnal polyuria prevalence was high in all ethnic groups (63% or greater). CONCLUSIONS: In this large study nocturnal polyuria was present in most patients with nocturia regardless of gender, age, ethnicity, country and concomitant benign prostatic hyperplasia/overactive bladder therapy.

Association of nocturia and mortality: results from the Third National Health and Nutrition Examination Survey.

PURPOSE: Nocturia, a common problem in men and women, has been associated with chronic illnesses such as heart disease and hypertension. Using data from the Third National Health and Nutrition Examination Survey we investigated the association of nocturia with subsequent mortality risk. MATERIALS AND METHODS: NHANES III is a national probability survey of the United States between 1988 and 1994. Mortality data were obtained by linkage of NHANES III to the National Death Index. Cox proportional hazards regression models were used to assess the association between nocturia and all cause mortality, controlling for potential confounders in a sample of 15,988 men and women 20 years old or older. RESULTS: The prevalence of nocturia, defined as 2 or more voiding episodes nightly, was 15.5% in men and 20.9% in women. Multivariate analyses showed a statistically significant trend of increased mortality risk with increased number of voiding episodes in men and women. The magnitude of the nocturia and mortality association was greater in those younger than 65 years with attenuated associations in the 65 years old or older age group. CONCLUSIONS: Nocturia is a strong predictor of mortality, more so in younger men and women than in the elderly, with a dose-response pattern in increased mortality risk with increasing number of voiding episodes nightly. Potential underlying mechanisms of the observed association of nocturia and increased mortality risk include sleep disruption and subsequent development of related comorbid conditions.

Nocturia research: current status and future perspectives.

This review summarizes the status of nocturia research, highlighting the condition's distinct nature, as well as areas where further studies are needed. Unlike other LUTS, nocturia has a specific and detrimental effect on the sleep period, and when >or=2 voids per night are experienced it is associated with various sequelae including reduced QoL and productivity, and increased morbidity and perhaps mortality. Many sources suggest that nocturia is associated with chronic medical illness, but little evidence demonstrates that successful treatment of these conditions results in normalization of nocturia, or that improvement in nocturia improves QoL and overall health. To date, management algorithms for LUTS have been based upon reasonable supposition and limited evidence, rather than controlled trials. Whilst a working clinical model is useful until conclusive research is available, a healthy scepticism should be maintained. It is likely that more than one contributory factor is responsible for nocturia, and management ought to better reflect this multifactorial pathophysiology. Indeed, traditional perspectives assuming nocturia to be part of the OAB or BPE symptom complex may have helped to propagate the misconception that therapy for these conditions is sufficient to improve nocturia. In reality, improvements in nocturia with anticholinergics, alpha-blockers and/or 5-alpha reductase inhibitors have been consistently disappointing. Antidiuretic therapy may represent a more tailored approach to management for many nocturia patients, given the high rates of nocturnal polyuria reported. Combination therapy may be required. Further high quality research on pathophysiology, management and patient-reported outcomes with treatment is needed to augment existing limited data.

Pediatric Pharmacology of Desmopressin in Children with Enuresis: A Comprehensive Review.

Desmopressin is a synthetic analogue of the natural antidiuretic hormone arginine vasopressin. Over the years, it has been clinically used to manage nocturnal polyuria in children with enuresis. Various pharmaceutical formulations of desmopressin have been commercialized for this indication-nasal spray, nasal drops, oral tablet and oral lyophilizate. Despite the fact that desmopressin is a frequently prescribed drug in children, its use and posology is based on limited pediatric data. This review provides an overview of the current pediatric pharmacological data related to the different desmopressin formulations, including their pharmacokinetics, pharmacodynamics and adverse events. Regarding the pharmacokinetics, a profound food effect on the oral bioavailability was demonstrated as well as different plasma concentration-time profiles (double absorption peak) of the desmopressin lyophilizate between adults and children. Literature about maturational differences in distribution, metabolism and excretion of desmopressin is rather limited. Regarding the pharmacodynamics, formulation/dose/food effect and predictors of response were evaluated. The lyophilizate is the preferred formulation, but the claimed bioequivalence in adults (200 µg tablet and 120 µg lyophilizate), could not be readily extrapolated to children. Prescribing the standard flat-dose regimen to the entire pediatric population might be insufficient to attain response to desmopressin treatment, whereby dosing schemes based on age and weight were proposed. Moreover, response to desmopressin is variable, whereby complete-, partial- and non-responders are reported. Different reasons were enumerated that might explain the difference in response rate to desmopressin observed: different pathophysiological mechanisms, bladder capacity and other predictive factors (i.e. breast feeding, familial history, compliance, sex, etc.). Also, the relapse rate of desmopressin treatment was high, rendering it necessary to use a pragmatic approach for the treatment of enuresis, whereby careful consideration of the position of desmopressin within this treatment is required. Regarding the safety of the different desmopressin formulations, the use of desmopressin was generally considered safe, but additional measures should be taken to prevent severe hyponatremia. To conclude the review, to date, major knowledge gaps in pediatric pharmacological aspects of the different desmopressin formulations still remain. Additional information should be collected about the clinical relevance of the double absorption peak, the food effect, the bioequivalence/therapeutic equivalence, the pediatric adapted dosing regimens, the study endpoints and the difference between performing studies at daytime or at nighttime. To fill in these gaps, additional well designed pharmacokinetic and pharmacodynamic studies in children should be performed.

Poor compliance with primary nocturnal enuresis therapy may contribute to insufficient desmopressin response.

PURPOSE: Studies of desmopressin in children with primary nocturnal enuresis show a greater than 90% decrease in wet nights in 20% to 30%, a 50% to less than 90% decrease in 20% to 40% and less than a 50% decrease in up to 60%. Insufficient response to desmopressin is attributable to various factors, including differences in the primary nocturnal enuresis definition, underlying bladder dysfunction and/or desmopressin pharmacokinetic characteristics. However, little attention has been given to poor compliance with therapy as a possible explanatory factor. For a drug with an effect duration limited to the night after administration a high degree of compliance is essential to ensure consistent therapeutic effects. MATERIALS AND METHODS: This was a substudy of an international investigation of treatment for 6 months or less with desmopressin tablets in children with primary nocturnal enuresis. Medication was dispensed at each visit as required and collected at each subsequent visit. Compliance was determined by pill counts by study staff. RESULTS: Compliance data were available on 723 patients. Of the patients 81% to 91% ingested all medication as instructed during the initial run-in phases. However, this decreased to 77% and 71% during the first and second 3-month treatment periods, respectively. CONCLUSIONS: Patient motivation and compliance are generally stronger in clinical trials than in clinical practice. However, this study shows that some patients were poorly compliant with medication even at study initiation and only 71% were fully compliant with long-term treatment. Decreased compliance was associated with a lower response rate. Patients should be encouraged to comply fully with treatment to achieve an optimal outcome.

A Danish population-based cohort study of desmopressin use in adults with nocturia or nocturnal enuresis.

OBJECTIVE: This study investigated how desmopressin is prescribed to adults in Denmark. METHODS: All adult users of desmopressin over an 8-year period were identified from the Danish National Prescription Registry. Adult patients with nocturia or nocturnal enuresis (NE) were identified by indication codes for "frequent nocturnal voiding" or "involuntary nocturnal voiding", respectively. Patient demographics, desmopressin formulation and dose, and concomitant medication were investigated. RESULTS: In all, 13 871 adults with nocturia and 2872 adults with chronic (i.e. >10 prescriptions) NE were given 102 547 and 43 712 desmopressin prescriptions, respectively. Across the entire patient cohort, 57% were women and mean patient age was 62 years. Over 40% of prescriptions were to elderly patients (≥65 years), and desmopressin use for adult enuresis increased with age. Orally disintegrating tablets were the most frequently used formulation (57%-65% of prescriptions), and a greater proportion of women than men used low-dose desmopressin (60 µg). Concomitant use of painkillers (opioids: 18%-26.7% of prescriptions; non-steroidal anti-inflammatory drugs: 14.2%-16.4% of prescriptions) and antidepressants (14.4%-18.1% of prescriptions) was common in both conditions, and 5.4%-9.2% of concomitant prescriptions were for overactive bladder medications. CONCLUSIONS: This study provides insights into desmopressin use among Danish adults. Nearly half the prescriptions were to patients aged ≥65 years, despite historical manufacturer recommendations that desmopressin be restricted to patients <65 years of age. NE is considered a childhood condition, but desmopressin use for adult NE increased with age. A greater proportion of desmopressin prescriptions to women than men were for the lowest dose, consistent with greater sensitivity to desmopressin in women.