Desmopressin for nocturnal enuresis in children

Cathryn MA Glazener; Jonathan HC Evans

doi:10.1002/14651858.CD002112

. 2002 Jul 22;2002(3):CD002112. doi: 10.1002/14651858.CD002112

Desmopressin for nocturnal enuresis in children

Cathryn MA Glazener ^1,^✉, Jonathan HC Evans ²

Editor: Cochrane Incontinence Group

PMCID: PMC8984681 PMID: 10796860

Abstract

Background

Enuresis (bed‐wetting) is a socially disruptive and stressful condition which affects from 15% to 20% of five year olds, and up to 2% of young adults.

Objectives

To assess the effects of desmopressin on nocturnal enuresis in children, and to compare desmopressin with other interventions.

Search methods

We searched the Cochrane Incontinence Group Specialised Trials Register (searched 10 May 2006). The reference list of the original version of this review was also searched.

Selection criteria

All randomised controlled trials of desmopressin for nocturnal enuresis in children were included in the review. Trials focused solely on daytime wetting were excluded.

Data collection and analysis

Two reviewers independently assessed the quality of the eligible trials and extracted data.

Main results

Forty seven randomised controlled trials involving 3448 children (of whom 2210 received desmopressin) met the inclusion criteria. The quality of many of the trials was poor.

Desmopressin was effective in reducing bed‐wetting during treatment, compared with placebo (e.g. 20 µg: 1.34 fewer wet nights per week; 95% confidence interval (CI) 1.11 to 1.57), and children were more likely to become dry (e.g. 118/146, 81% versus 140/142, 98% still wet; relative risk (RR) for failure to achieve 14 dry nights with 20 µg was 0.84; 95% CI 0.79 to 0.91). However, there was no difference between the two patient groups after treatment was finished. There was no clear dose‐related effect of desmopressin, but the evidence was limited. Data which compared oral and nasal administration were too few to be conclusive.

In four small trials, there were no significant differences between desmopressin and alarms during treatment when these were used separately, but the chance of failure or relapse after treatment stopped was lower after an alarm in two small trials (40/62, 65% versus 26/57, 46%; RR 1.42, 95% CI 1.05 to 1.91).

Although children had fewer wet nights during treatment when they used desmopressin combined with alarm treatment compared with alarms alone (WMD ‐0.83, 95% CI ‐1.11 to ‐0.55), there were no significant differences either in failure rates during treatment (RR 0.88; 95% CI 0.73 to 1.05) or for relapse after treatment stopped (105/213, 49% versus 118/214, 55%: RR 0.91, 95% CI 0.76 to 1.08).

Comparison with some tricyclic drugs (e.g. amitriptyline) suggested that they might be as effective as desmopressin, although in two trials children were less likely to achieve 14 dry nights with imipramine than desmopressin (RR 0.44, 95% CI 0.27 to 0.73) but there was not enough information about subsequent relapse. There were more side effects with the tricyclics. Desmopressin may be better than diclofenac or indomethacin.

There was not enough information to evaluate the relative effects of behavioural or complementary treatments against desmopressin.

Authors' conclusions

Desmopressin rapidly reduced the number of wet nights per week experienced by children, but the limited evidence available suggested that this was not sustained after treatment stopped. Comparison with alternative treatments suggested that desmopressin and tricyclics had similar clinical effects during treatment, but that alarms may produce more sustained benefits. However, based on the available limited evidence, these conclusions are only tentative. Children should be advised not to drink more than 240 ml (8 ounces) of fluid during the evening before desmopressin treatment in order to avoid the possible risk of water intoxication.

Plain language summary

Desmopressin for bedwetting in children

Bedwetting is a distressing and stressful condition for children and their families. Some children take longer than others to stop bedwetting. Up to 20% still wet at the age of five years, but by the age of 16 only 2% or less do so. Desmopressin is a drug which reduces bedwetting by reducing the amount of urine produced at night. It is taken before bedtime, and the children are also advised not to drink more than 240 ml (8 ounces) of fluid in the evening. However, it only works on the nights when it is used, so does not cure the problem in the long term.

When desmopressin is used, most of the children have fewer wet nights (one night less on average per week) and more become dry (19% compared with only 2% using dummy treatment in five trials involving 288 children). However, many children start wetting again when treatment stops. On the other hand, more children remain dry when alarm treatment is finished (54% after alarm compared with 35% after desmopressin in two trials involving 119 children). Adding desmopressin to alarm treatment did not result in better cure rates after the end of treatment (51% remained dry after combination treatment compared with 45% after alarm alone).

Those using desmopressin (or their parents) should be warned that over‐drinking before bedtime should be avoided as this may lead to serious, but rare, adverse effects. Drugs called tricyclic antidepressants have a similar effect to desmopressin and are cheaper, but have more adverse effects. There are few adverse effects with alarms, other than short‐term disruption for the family. In summary, alarms take longer to reduce bed‐wetting, but their effect may persist longer than desmopressin.

Background

This is one of seven reviews of interventions for bed‐wetting, or non‐organic nocturnal enuresis. The others focus on: tricyclics and related drugs (Glazener 2004e); other drugs (Glazener 2004c); alarms (Glazener 2004a); simple behavioural interventions (Glazener 2004d); complex behavioural interventions (Glazener 2004b); and miscellaneous and complementary therapy (in preparation). All seven reviews were based on the work of Lister‐Sharp and her colleagues at the Centre for Reviews and Dissemination at the University of York, United Kingdom (Lister‐Sharp 1997).

Nocturnal enuresis is the involuntary loss of urine at night, in the absence of organic disease, at an age when a child could reasonably be expected to be dry (by consensus, at a developmental age of five years) (APA 1980; WHO 1992). Although bed‐wetting is pathologically benign and has a high rate of spontaneous remission, it may bring social and emotional stigma, stress and inconvenience to both the children with enuresis and their families (Fitzwater 1992). Children who wet the bed may experience parental disapproval, sibling teasing and repeated treatment failure, which may lower self‐esteem (Warzak 1993). The children may also be at increased risk of emotional and physical abuse (Warzak 1993). Consequently, it is important that enuresis is properly managed on 'humane grounds' (Moffatt 1994).

Although daytime wetting is a significant problem, and is often associated with bed‐wetting, it is usually considered separately. It has been suggested that there are different aetiologies underlying the two conditions (Jarvelin 1989). If daytime symptoms are present, investigations to identify physical causes such as urinary tract dysfunction, congenital malformation and neurogenic disorders are usually necessary (Djurhuus 1992). An organic cause is more often found in children with daytime wetting: more structural abnormalities and functional disorders of the urinary tract were found in daytime wetters than controls (Jarvelin 1990).

Prevalence and causes

Nocturnal enuresis is a complaint that affects many families. Estimating the prevalence of nocturnal enuresis is difficult, however, because there is variation in methods of diagnosis and definitions (de Jonge 1973; Krantz 1994). In the United Kingdom, the generally quoted prevalence rates are that 15% to 20% of five year olds, 7% of seven year olds, 5% of ten year olds, 2% to 3% of 12 to 14 year olds and 1% to 2% of those aged 15 and over wet the bed twice a week on average (Blackwell 1989; Rutter 1973). The incidence of nocturnal enuresis is particularly high amongst children in residential care (Morgan 1970). About 1% of adults remain enuretic. Without treatment, about 15% of bed‐wetting children become dry each year (Forsythe 1974).

The causes of nocturnal enuresis are unclear (Lister‐Sharp 1997). Genetic (APA 1980 1980; Bakwin 1971; Bakwin 1973; Eiberg 1995), physiological (Djurhuus 1992; Norgaard 1993) and psychological (Devlin 1991; Moffatt 1989; Rutter 1973; Shaffer 1977) factors, as well as delay in maturation of the mechanism for bladder control (Jarvelin 1989; Koff 1995), have been suggested. Other factors which may contribute to bed‐wetting include: constipation, sleep apnoea, upper airway obstructive symptoms (Maizels 1993), diet and intake of mild caffeine drinks with diuretic effects (e.g. cola) (Blackwell 1989).

Interventions

Pharmacological, psychological/behavioural and a variety of 'unconventional' interventions are commonly used for people who wet the bed.

Pharmacological interventions include desmopressin, tricyclic drugs (amitriptyline, dothiepin, doxepin, trimipramine, clomipramine, desipramine, imipramine, lofepramine, nortriptyline and protriptyline) (Glazener 2004e); drugs related to the tricyclics (viloxazine, desipramine, mianserin and maprotiline) (Glazener 2004e); and amphetamine, diazepam and oxybutynin (Glazener 2004c). However, some of these drugs are now contraindicated. Simple behavioural interventions include reward systems (such as star charts), lifting, scheduled wakening (Glazener 2004d), and alarms and over‐learning (after successful alarm treatment) (Glazener 2004a). Complex behavioural interventions include multidimensional behavioural treatment such as dry bed training or full spectrum home training (Glazener 2004b). Less common interventions include: psychotherapy, retention control training, surgery, fluid deprivation and complementary therapies.

This review is restricted to pharmacological treatment with desmopressin, or to any other intervention that is compared with, or used in combination with, desmopressin.

Desmopressin

Desmopressin is an analogue of the human pituitary hormone arginine vasopressin. Its antidiuretic effect results from increased reabsorption of water from the kidney, leading to a reduced volume of more concentrated urine entering the bladder (Djurhuus 1992). In 1972, desmopressin was introduced in a dropper bottle allowing drops to be placed into the nose. It has also become available as a measured dose spray giving doses in multiples of 10 µg; a single dose pipette giving doses in multiples of 20 µg; and 0.2 mg oral tablets. Generally, 20 µg to 40 µg is given intranasally at bedtime irrespective of age and body weight (Harris 1989). Although initially prescribed for short‐term treatment, longer‐term treatment may be considered appropriate for some children. It has been recommended that after three months, treatment should be withdrawn for at least one week pending reassessment (BNF 2002).

About 10% of intranasal desmopressin is absorbed from the nasal mucosa. The maximum plasma concentration of desmopressin is reached within an hour, and the biological effect lasts for 10 to 12 hours (Harris 1989).

A review of the adverse effects of desmopressin for nocturnal enuresis noted that 22 adverse experiences, most commonly nasal irritation and nose bleeds, were reported in seven published studies (Hjalmas 1993). Twelve additional published studies reported no adverse effects. Although 21 cases of water intoxication were spontaneously reported by physicians and patients prior to 1993, the authors of the review concluded that desmopressin produces few, mostly mild, adverse effects in children treated for nocturnal enuresis (Hjalmas 1993).

Water intoxication is potentially the most serious complication. It is associated with over‐drinking at bedtime, and its symptoms include headache, nausea, hyponatraemia, cerebral oedema and convulsions. Current guidelines recommend that not more than 240 ml (8 ounces) of fluid should be consumed on any night when desmopressin is used (Bernstein 1997; Robson 1994; Robson 1996).

Objectives

To determine the effects of desmopressin for the treatment of children with nocturnal enuresis.

The following comparisons were made:   (1) desmopressin versus no active treatment / placebo;   (2) lower versus higher doses of desmopressin;   (3) oral versus nasal administration of desmopressin;   (4) desmopressin versus other drugs, alone or in combination;   (5) desmopressin alone versus alarm treatment alone;   (6) desmopressin alone versus desmopressin supplemented by alarm treatment;   (7) desmopressin supplemented by alarm treatment versus alarm treatment alone;   (8) desmopressin versus behavioural methods, alone or in combination;   (9) desmopressin versus complementary treatment .

Methods

Criteria for considering studies for this review

Types of studies

Randomised or quasi‐randomised controlled trials of desmopressin with any comparable control groups for the treatment of nocturnal enuresis.

Types of participants

Children (as defined by trialists, usually as less than 16 years of age) suffering from nocturnal enuresis.

Types of interventions

Any trial that used desmopressin in at least one arm of the study.

Comparisons were made with no active treatment, other types of drugs, and alarm or behavioural interventions, either alone or in combination with desmopressin.

Types of outcome measures

The outcomes considered in this review were:

mean number of wet nights per week during treatment;
number of children failing to attain 14 consecutive dry nights during treatment;
mean number of wet nights per week when children were followed up after treatment ends;
number of children failing during treatment and/or relapsing after treatment ends;
adverse effects.

Search methods for identification of studies

This review has drawn on the search strategy developed for the Incontinence Review Group. Relevant trials were identified from the Group's Specialised Register of controlled trials which is described, along with the group search strategy, under the Incontinence Group's details in The Cochrane Library (For more details please see the ‘Specialized Register’ section of the Group’s module in The Cochrane Library). The register contains trials identified from MEDLINE, CINAHL, the Cochrane Central Register of Controlled Trials (CENTRAL) and hand searching of journals and conference proceedings. The Incontinence Group Specialised Trials Register was searched using the Group's own keyword system. The search terms used were:

({design.cct*} OR {design.rct*})   AND   {topic.enuresis*}   (All searches were of the keyword field of Reference Manager 9.5N, ISI ResearchSoft.)     Date of the most recent search of the register for this review: 10 May 2006.

The trials in the Incontinence Group's trials register are also contained in CENTRAL.

The reference list of a previous systematic review of enuresis treatments was also searched (Lister‐Sharp 1997).

No language restriction or other limits were imposed on the searches.

Data collection and analysis

Identification of primary studies

The titles, and where possible, abstracts of all studies located by the searches were checked to identify any potentially relevant studies. Full papers were then obtained and assessed to identify those which met the inclusion criteria.

Quality assessment

A range of both general and more specific quality issues were noted, including:

level of concealment of random allocation in the trials;
whether data to assess the comparability of groups at baseline were given, including baseline levels of wetting;
use of a 'washout' period if a crossover design was employed;
intention‐to‐treat analysis;
whether outcomes were clearly defined;
blinding;
a follow up of at least three months;
the use of appropriate statistical techniques;
whether useful data (e.g. means and standard deviations) were presented;
whether children with daytime wetting were specifically excluded;
whether children who had physical (organic) causes for their enuresis were specifically excluded.

Data extraction

The data were extracted using a standard form. Included data were processed as described in the Cochrane Reviewers' Handbook (Clarke 2003). Where appropriate, the results were converted to the mean and standard deviation of the number of wet nights per week; the number of children failing to achieve cure during treatment, defined as 14 consecutive dry nights; or the number of children who were not cured during treatment plus those who relapsed after stopping active treatment (to allow for possible differences in initial 'success' rates). When a mean value was reported with no standard deviation, we entered the data into 'Other Data Tables'.

Data analysis

We calculated, where possible, weighted mean differences (WMD) and relative risks (RR) plus 95% confidence intervals (CI). A fixed effect model was used to calculate the pooled estimates and the 95% CIs (Berlin 1989). The WMDs were weighted by the inverse of the variance and reported as differences in the number of wet nights per week. Negative values indicated fewer wet nights in the intervention group at the left‐hand side of the tables. Differences between trials were further investigated when statistically significant heterogeneity was apparent either at the 10% probability level, using the chi squared test or assessment of the I‐squared statistic (Higgins 2003), or from visual inspection of the results. If there was no obvious reason for the heterogeneity, or it persisted despite the removal of outlying trials, a random effects model could have been used.

Crossover trials were indicated by the symbol # after the trial ID. These were analysed as if they were parallel groups, but a sensitivity analysis was carried out by excluding these trials to determine if their inclusion biased the findings.

Results

Description of studies

Of 75 studies identified as potentially relevant, 28 were excluded: 21 were not randomised controlled trials (RCTs); five included some adults with detrusor overactivity or daytime wetting, or both; one did not use desmopressin therapeutically (Bogaert 2005); and one switched children between treatment groups. In this minor update (Issue 3 2006), 2 of the 28 were new excluded studies (see Characteristics of Excluded Studies). Of the remaining included trials, 18 (Bradbury 1995; Faraj 1999; Folwell 1997#; Hamano 2000; Kahan 1998; Leebeek 2001; Longstaffe 2000; Muller 2001#; Natochin 2000; Neveus 1999#; Radmayr 2001; Rodriguez 2001; Schulman 2001a; Schulman 2001b; Sener 1998; Skoog 1997; Vertucci 1997; Yap 1998#) were RCTs added in the previous update (Glazener 2002). Two others (Dimson 1986#; Stenberg 1994#) had been excluded in the first published version of this review (Glazener 2000), and one more was added in the second update (Gibb 2004). In the third update (Issue 3 2006), a further five RCTs have been added (Fera 2004; Hoashi 1995; Lee 2005; Ng 2005; Uygur 1997#).

The 47 included trials were described in 44 reports (three reports described two separate trials each). Seventeen trials used a crossover design (indicated by symbol #). All the trials, bar two (Rodriguez 2001; Hoashi 1995), gave measures of baseline wetting, and all but three specifically excluded children with organic causes of enuresis (Fera 2004; Radmayr 2001; Yap 1998#). However, all three of these trials included only children with monosymptomatic nocturnal enuresis, and excluded children with daytime wetting (Fera 2004; Radmayr 2001; Yap 1998#). In general, sample sizes were small, ranging from 10 to 182 with an average of about 73 children. Out of a total of 3448 children, 2210 received treatment with desmopressin.

Participants

Two studies included some older children or adults (Janknegt 1997; Rittig 1988#), while another focused on adolescents who had failed previous treatment (Stenberg 1994#). Only seven of the trials excluded children who had previously received treatment for their enuresis (Faraj 1999; Fera 2004; Kahan 1998; Muller 2001#; Ng 2005; Radmayr 2001; Sener 1998). The remainder either failed to report this factor (9 trials) or included some children who had failed previous drug or behavioural treatments (31 trials). Of the latter, all the children in one trial had previously failed to improve with desmopressin (Gibb 2004). In another trial, a baseline trial of desmopressin was used to select out those children who failed to respond to desmopressin: only responders were enrolled in the crossover RCT (Uygur 1997#).

Dosage of desmopressin

Some trials used dose titration until dry nights were achieved (Birkasova 1978#; Faraj 1999; Fera 2004; Hamano 2000; Lee 2005; Radmayr 2001; Rittig 1988#; Rodriguez 2001; Rushton 1995; Schulman 2001b; Stenberg 1994#; Terho 1991#; Uygur 1997#), or compared a variety of doses of active drug (Kjoller 1984; Janknegt 1990#; Janknegt 1997; Miller 1990a; Miller 1990b; Neveus 1999#; Schulman 2001a; Skoog 1997). One reduced the dose from 40 µg to 20 µg for the second three weeks of the trial (Leebeek 2001).

Route of administration and comparators

Intranasal administration was used in all but ten of the trials: oral tablets were specified in ten (Fera 2004; Janknegt 1997; Lee 2005;Neveus 1999#; Ng 2005; Schulman 2001a; Schulman 2001b; Skoog 1997; Stenberg 1994#; Yap 1998#), and two different routes of administration were compared in one (Fjellestad 1987#). Twenty trials included other interventions:

other drugs (Burke 1995; Hoashi 1995; Holt 1986; Lee 2005; Natochin 2000; Sener 1998; Vertucci 1997);
alarms (Bradbury 1995; Faraj 1999; Gibb 2004; Leebeek 2001; Longstaffe 2000; Ng 2005; Rodriguez 2001; Sukhai 1989#; Wille 1986);
other behavioural treatment (Fera 2004; Hamano 2000; Kahan 1998); and
complementary treatment (laser acupuncture) (Radmayr 2001).

One ongoing trial has yet to be completed (Hjalmas 2001).

Risk of bias in included studies

Of the 47 identified RCTs which included desmopressin in at least one arm, only 15 described a secure randomised method of allocation (e.g. by computer allocation or use of sealed opaque envelopes) (Birkasova 1978#; Bradbury 1995; Burke 1995; Dimson 1986#; Folwell 1997#; Leebeek 2001; Longstaffe 2000; Neveus 1999#; Ng 2005; Schulman 2001a; Schulman 2001b; Stenberg 1994#; Sukhai 1989#; Uygur 1997#; Yap 1998#). A further 31 trials did not provide adequate details for this to be assessed (although some used double‐blind placebo controls and others were crossover trials), and one trial used a quasi‐randomised method (Natochin 2000).

There were 17 crossover trials, identified by the symbol # (Birkasova 1978#; Dimson 1986#; Fjellestad 1987#; Folwell 1997#; Janknegt 1990#; Muller 2001#; Neveus 1999#; Post 1983a#; Post 1983b#; Rittig 1988#; Stenberg 1994#; Sukhai 1989#; Terho 1984#; Terho 1991#; Tuvemo 1978#; Uygur 1997#; Yap 1998#). One other crossover trial compared desmopressin with imipramine, but only results from the first arm of the trial were used, which in effect formed parallel groups (Vertucci 1997). Because of their crossover design, none of the crossover trials could address longer‐term post‐treatment effects. A further 21 trials used double‐blind placebos to ensure blinding to treatment (Aladjem 1982; Burke 1995; Gibb 2004; Hoashi 1995; Holt 1986; Janknegt 1997; Kahan 1998; Kjoller 1984; Leebeek 2001; Longstaffe 2000; Martin 1993; Miller 1990a; Miller 1990b; Natochin 2000; Rushton 1995; Schulman 2001a; Schulman 2001b; Segni 1982; Sener 1998; Skoog 1997; Uygur 1997#). In the remainder of the studies, blinding to treatment allocation was not possible because the treatments were too dissimilar.

Two trials failed to report systematic baseline measures of wetting (Hoashi 1995; Rodriguez 2001), and three failed to exclude children with organic (physical) causes for their bed‐wetting (Fera 2004; Radmayr 2001; Yap 1998#), but all these trials excluded children with daytime wetting. Three trials included some children with daytime wetting but excluded children with organic (physical) causes (Bradbury 1995; Gibb 2004; Martin 1993). Daytime wetting was specifically excluded or reported separately in 27 trials, and not mentioned in another 17.

Only three trials reported using a washout period between the two arms of a crossover trial (Fjellestad 1987#; Sukhai 1989#; Yap 1998#), while another interposed a 'placebo' arm between the first and second active arms (Janknegt 1990#). Children who did not respond in one trial (Schulman 2001a) received placebo treatment during a two‐week washout phase before being randomly assigned again in a second trial (Schulman 2001b).

Ten trials reported continuous data without a measure of dispersion such as a standard deviation (Dimson 1986#; Fjellestad 1987#; Leebeek 2001; Miller 1990a; Miller 1990b; Muller 2001#; Rittig 1988#; Terho 1991#; Uygur 1997#; Vertucci 1997). Further data are being sought from the authors of some trials. Only two of the included trials provided a power calculation of the sample size, which helps to define the minimum sample size required to detect a true difference between the treatment groups (Janknegt 1990#; Leebeek 2001).

Effects of interventions

(1) Twenty nine trials compared desmopressin with placebo treatment (Aladjem 1982; Birkasova 1978#; Dimson 1986#; Fjellestad 1987#; Folwell 1997#; Janknegt 1990#; Kjoller 1984; Longstaffe 2000; Martin 1993; Miller 1990a; Miller 1990b; Muller 2001#; Natochin 2000; Neveus 1999#; Post 1983a#; Post 1983b#; Rittig 1988#; Rushton 1995; Schulman 2001a; Schulman 2001b; Segni 1982; Sener 1998; Skoog 1997; Stenberg 1994#; Terho 1984#; Terho 1991#; Tuvemo 1978#; Uygur 1997#; Yap 1998#);   (2) Two trials compared oral with nasal administration (Fjellestad 1987#; Faraj 1999);   (3) Seven trials compared desmopressin with tricyclic or other drugs (Burke 1995; Hoashi 1995; Holt 1986; Lee 2005; Natochin 2000; Sener 1998; Vertucci 1997);   (4) Nine trials compared desmopressin with alarms (Bradbury 1995; Faraj 1999; Gibb 2004; Leebeek 2001; Longstaffe 2000; Ng 2005; Rodriguez 2001; Sukhai 1989#; Wille 1986);   (5) Three trials compared desmopressin with behavioural interventions (Fera 2004; Hamano 2000; Kahan 1998);   (6) One trial compared desmopressin with laser acupuncture (Radmayr 2001).

1. Desmopressin versus no active treatment / placebo (see Comparisons 01 and 02, Other Data Tables 01)

Desmopressin was better than placebo treatment in achieving fewer wet nights per week during treatment and more children cured during treatment. Desmopressin was better (fewer wet nights per week) at doses of 10 µg in two trials (WMD ‐2.30; 95% CI ‐3.42 to ‐1.18); 20 µg in 12 trials (WMD ‐1.34; 95% CI ‐1.57 to ‐1.11); 40 µg in six trials (WMD ‐1.33; 95% CI ‐1.67 to ‐0.99); and 60 µg in two trials (WMD ‐1.50; 95% CI ‐1.92 to ‐1.08, Comparison 01.01). This held true in a sensitivity analysis when the crossover trials were excluded (e.g. WMD for 20 µg in seven trials ‐1.21; 95% CI ‐1.49 to ‐0.95, Comparison 08.01). Thus, desmopressin significantly reduced bed‐wetting by about one to two nights a week, irrespective of whether the crossover studies were included. There were also fewer wet nights during desmopressin treatment in trials which used variable doses of the drug (Birkasova 1978#; Rushton 1995), or in trials which failed to provide standard deviations (Other Data Tables 01.02).

Ten trials reported the number of children cured (defined as achieving 14 consecutive dry nights) while taking either desmopressin or placebo. Despite differences in desmopressin dose, the trials were consistent, suggesting that desmopressin increased the chances of cure (RR for failure with 20 µg in five trials was 0.84; 95% CI 0.79 to 0.91: RR for 40 µg in six trials was 0.81; 95% CI 0.74 to 0.88: RR for 60 µg in two trials was 0.94; 95% CI 0.89 to 0.99, Comparison 01.03). A sensitivity analysis excluding the crossover trials supported these findings (Comparison 08.03).

However, the data suggest that this effect was not sustained after treatment had finished. In four trials (Aladjem 1982; Kjoller 1984; Miller 1990a; Miller 1990b), there was little difference between the groups in terms of wet nights per week, but the trials were small, the confidence intervals were wide, and two trials did not report standard deviations (Comparison 01.04, Other Data Tables 01.05). Only one small trial reported relapse rates: all the children either failed to respond to treatment or relapsed afterwards (Comparison 01.06) (Dimson 1986#).

2. Lower versus higher doses of desmopressin (see Comparison 03, Other Data Tables 03)

Eight small trials compared different doses of desmopressin with each other (Janknegt 1990#; Janknegt 1997; Kjoller 1984; Miller 1990a; Miller 1990b; Neveus 1999#; Schulman 2001a; Skoog 1997). Two of these trials were crossovers and two did not report standard deviations. There was some evidence that a higher dose was more likely to reduce the numbers of wet nights than a lower dose (e.g. for 20 µg versus 40 µg the WMD for wet nights during treatment was 0.42; 95% CI ‐0.01 to 0.84: for 20 µg versus 60 µg the WMD was 0.72; 95% CI 0.3 to 0.14, Comparison 02.01, Other Data Tables 02). However, there was no difference in cure rates (Comparison 02.03). One trial reported no difference between two oral doses, but it did not provide any useable data (Janknegt 1997).

3. Oral versus nasal administration of desmopressin (see Comparison 04, Other Data Tables 04)

Only one study compared oral (200 µg) and nasal (20 µg) administration of desmopressin (Fjellestad 1987#). This was a crossover trial which did not provide standard deviations and involved only 20 children. There were insufficient data to judge whether the two routes were equally effective. Nasal discomfort (two children) and epistaxis (three children) were reported with nasal administration. This did not appear to be specifically linked to desmopressin because it was reported equally by patients from both the other groups who received placebo nose drops (Fjellestad 1987#).

4. Desmopressin versus other drugs (see Comparison 05, Other Data Tables 05)

Seven trials compared desmopressin with other drugs: amitriptyline (Burke 1995); imipramine (Hoashi 1995; Holt 1986; Lee 2005; Vertucci 1997); indomethacin (Natochin 2000); and diclofenac (Sener 1998). One trial included an arm which combined amitriptyline with desmopressin (Burke 1995) and another combined desmopressin with oxybutynin (Lee 2005). In two small separate studies, desmopressin performed better than indomethacin (WMD for wet nights per week ‐1.45; 95% CI ‐2.37 to ‐0.53, Comparison 04.01.05) (Sener 1998) and diclofenac (RR for failure to achieve 14 dry nights was 0.52; 95% CI 0.30 to 0.89, Comparison 04.02.03) (Natochin 2000) during treatment, but there was no information about relapse rates after treatment ended. There was not enough evidence to clarify whether desmopressin was better than amitriptyline or oxybutynin added to desmopressin: the sample sizes were too small to address the issue reliably, the follow‐up information was scant, and the confidence intervals were wide. However, more children achieved dry nights with desmopressin than imipramine during treatment (RR for failure to achieve 14 dry nights 0.44, 95%CI 0.27 to 0.73, Comparison 05.02.04) (Lee 2005) but there was no information about subsequent relapse.

5, 6, 7. Desmopressin and alarms

Nine trials compared desmopressin with alarm interventions (Bradbury 1995; Faraj 1999; Gibb 2004; Leebeek 2001; Longstaffe 2000; Ng 2005; Rodriguez 2001; Sukhai 1989#; Wille 1986). In four trials, desmopressin was compared with an alarm alone (Faraj 1999; Longstaffe 2000; Ng 2005; Wille 1986). In three other studies, the children used alarms in both arms of the trials supplemented with either desmopressin or placebo (Gibb 2004; Leebeek 2001; Sukhai 1989#), the latter in a double‐blind crossover design with a two‐week washout period. In a further three trials, children used alarms in both arms of the trial, supplemented by desmopressin in one arm (Bradbury 1995; Ng 2005; Rodriguez 2001).

5. Desmopressin alone versus alarm treatment alone (see Comparison 06)

In four trials, desmopressin was compared with an alarm alone (Faraj 1999; Longstaffe 2000; Ng 2005; Wille 1986). One small trial reported that at the end of the first week of treatment, there were 1.7 fewer wet nights per week with desmopressin treatment than with alarm treatment (WMD ‐1.7; 95% CI ‐2.95 to ‐0.45, Comparison 06.01.01) (Wille 1986). In the final week (after three months) there was no significant difference between desmopressin and alarm groups in terms of wet nights per week (WMD 0.52, 95% CI ‐0.32 to 1.36, Comparison 06.01.02) (Ng 2005; Wille 1986) or in numbers remaining wet (RR 1.07, 95%CI 0.83 to 1.36, Comparison 06.02.01) (Faraj 1999; Longstaffe 2000; Ng 2005). However, the relapse rate was significantly less after the end of alarm treatment (40/62, 65% after desmopressin versus 26/57, 46% after alarm, RR 1.42, 95% CI 1.05 to 1.91, Comparison 06.03.01) (Wille 1986; Ng 2005). Where combination of data was possible, the heterogeneity was high.

6. Desmopressin alone versus desmopressin supplemented by alarm treatment (see Comparison 07)

One small trial tested the effect of adding alarm treatment to desmopressin (Ng 2005). The data were too few to draw reliable conclusions.

7. Desmopressin supplemented by alarm treatment versus alarm treatment alone (see Comparison 08)

Six trials addressed this comparison (Bradbury 1995; Gibb 2004; Leebeek 2001; Ng 2005; Rodriguez 2001; Sukhai 1989#). Desmopressin combined with alarm treatment was associated with fewer wet nights than alarms alone in four trials (WMD ‐0.83, 95% CI ‐1.11 to ‐0.55, Comparison 08.01.01), whether a placebo was used (Gibb 2004; Sukhai 1989#) or not (Bradbury 1995; Ng 2005). However, this was not reflected in failure rates during treatment: RR for the number of children failing to achieve 14 dry nights was 0.88; 95% CI 0.73 to 1.05, Comparison 08.02.01) with placebo (Gibb 2004; Leebeek 2001) or without placebo (Bradbury 1995; Ng 2005; Rodriguez 2001): the heterogeneity was high.

After treatment stopped, there were no statistically significant differences in the combined failure and relapse rate: RR 0.91, 95% CI 0.76 to 1.08, Comparison 08.03.01) with placebo (Gibb 2004; Leebeek 2001) or without (Bradbury 1995; Ng 2005). However, the trials were small; one was a crossover with a short duration of treatment (Sukhai 1989#); the confidence intervals were wide; and follow‐up results were not available for two trials (Rodriguez 2001; Sukhai 1989#).

8. Desmopressin versus behavioural methods, alone or in combination (see Comparison 09)

Three small trials compared desmopressin alone or in combination with other behavioural methods of managing enuresis (Fera 2004; Hamano 2000; Kahan 1998). The interventions were so dissimilar (retention control training alone in one (Hamano 2000), a complex package of psychological therapy with retention control training in another (Kahan 1998) and a mix of toileting, waking with alarm clock, pelvic floor training and diet and fluid changes in the third (Fera 2004) that data could not be combined. Thus each comparison was addressed by single arms of the trials only.

There was insufficient evidence to compare desmopressin with retention control training alone (Comparisons 09.01.01, 09.02.01, 09.04.01) (Hamano 2000) or with a complex intervention (Comparisons 09.01.04, 09.02.04) (Fera 2004). There was conflicting evidence about the effects of the complex package during treatment (Comparisons 09.01.02 and 03, and 09.02.02 and 03) and afterwards: children recorded fewer wet nights after desmopressin supplemented by the complex package of psychological and behavioural methods, compared to desmopressin alone (WMD ‐2.10; 95% CI ‐2.67 to ‐1.53, Comparison 09.03.02) but this did not reflect in lower failure/relapse rates (RR 0.98; 95% CI 0.91 to 1.06, Comparison 09.04.02) (Kahan 1998).

9. Desmopressin versus complementary treatment (see Comparison 10)

One small trial compared desmopressin with laser acupuncture (Radmayr 2001). However, results were only reported at six months after completing the trial. There was no difference between the groups at follow up, but the numbers were too small to draw reliable conclusions.

Adverse effects

Adverse effects of desmopressin reported amongst 1057 children in 14 trials included (number of events in brackets): anorexia (5), bad taste (2), headache (12), nasal discomfort (20), nosebleeds (6), rash/dermatitis/oedema (6), sight disturbance (1), vomiting (3) and other minor problems (44). Some trials reported that side effects (headaches, stomach ache and nasal symptoms) were equally common with active and placebo treatment (Fjellestad 1987#; Folwell 1997#; Janknegt 1990#), or with desmopressin and tricyclics (Hoashi 1995) or were not due to treatment (Schulman 2001a; Schulman 2001b). Four trials reported that most minor side effects resolved as the trials continued (Schulman 2001a; Schulman 2001b; Skoog 1997; Stenberg 1994#). Side effects were not mentioned in nine trials (Faraj 1999; Fera 2004; Janknegt 1997; Longstaffe 2000; Muller 2001#; Neveus 1999#; Post 1983a#; Post 1983b#; Rodriguez 2001). The remaining 17 trials reported that there were no adverse effects in a further 865 children (Aladjem 1982; Birkasova 1978#; Burke 1995; Kjoller 1984; Leebeek 2001; Natochin 2000; Ng 2005; Radmayr 2001; Rushton 1995; Segni 1982; Sener 1998; Sukhai 1989#; Terho 1984#; Terho 1991#; Tuvemo 1978#; Uygur 1997#; Yap 1998#). One of these trials involved another drug, amitriptyline, with and without desmopressin (Burke 1995). When reported, more adverse effects were associated with tricyclics (83/480, 17.3 per 100 patients (Glazener 2004e)) than with desmopressin (70/1319, 5.3 per 100 patients).

Discussion

This is the third update of the desmopressin review, including 25 new trials identified since the original review was published in 1997 (Lister‐Sharp 1997). The quality of the trials was often poor: small numbers of children were assessed; reporting of data and the method of randomisation were inadequate; and follow up was short or non‐existent. In the crossover trials there was a lack of washout phases and, by their design, no follow up was possible. In particular, little information was available about comparisons with non‐drug interventions. However, all trials focused on children who did not have an organic cause for their enuresis: in the trials which did not specifically exclude organic causes, any children who had daytime wetting were excluded. Only two trials failed to objectively assess baseline wetting. Seven trials selected children who had not had previous enuresis treatment. The majority of the trials (30/46) included at least some children who had failed with previous treatment, and therefore had been referred to specialist clinics; the remainder did not specify past treatment.

Desmopressin compared with placebo

There was clear evidence that desmopressin reduced bed‐wetting by approximately one to two wet nights per week, compared to placebo. In addition, people receiving desmopressin were almost twice as likely as those receiving placebo to achieve at least 14 consecutive dry nights. However, after treatment stopped, the limited evidence available suggested that this improvement was not sustained. Ten crossover trials were analysed as if they were parallel groups. However, a sensitivity analysis showed that their exclusion did not affect the conclusion that desmopressin significantly reduced bed‐wetting by one to two nights a week while on treatment. Crossover trials were unable to contribute follow‐up data after the end of the treatments because the children had received both trial treatments by then.

Dose of desmopressin and route of administration

There were insufficient data to reliably assess whether a higher dose of desmopressin was more effective than a lower dose. To minimise side effects and costs, the lowest dose should be used. In practice, clinicians would increase the dose until the lowest effective dose is achieved. If a higher dose is used with no incremental improvement, the dose should be returned to the lowest effective level. There was not enough evidence to judge whether oral and nasal administration were equally effective, but eight trials used the oral route with no apparent difference in effectiveness. This suggests that equivalent doses may be comparable, irrespective of the route of administration.

Desmopressin compared with other drugs (see also review of tricyclics for enuresis, Glazener 2004e)

The four trials comparing desmopressin with amitriptyline or imipramine were too small to provide definitive results. Desmopressin is more expensive than imipramine, but imipramine has more side‐effects, some of them potentially serious. In two other small trials, desmopressin was better than either indomethacin or diclofenac during treatment, but there was no follow‐up information (Natochin 2000; Sener 1998).

Desmopressin compared with alarms (see also review of alarms for enuresis Glazener 2004a)

Although nine trials including desmopressin and alarm treatments were identified, the findings were difficult to interpret because of the poor quality (small size and dissimilar outcome measures) and variation in interventions (with or without desmopressin or placebo supplementation) of the trials.

In direct comparisons of desmopressin with alarm treatment, the initial advantage of desmopressin (fewer wet nights) was not sustained: children using alarms had fewer wet nights by the end of the trial, and the subsequent relapse rate was lower after alarm treatment (Wille 1986, Ng 2005). While another two small trials demonstrated no significant difference in the failure rate during treatment, follow‐up information was not available (Bradbury 1995; Rodriguez 2001).

There is a move towards combining behavioural and drug interventions (Howe 1992). The rationale is that the rapid onset of action of drugs will augment the more gradual treatment effect of alarms (Sukhai 1989#). Using low doses of desmopressin as an adjunct to alarm treatment might also be used to ensure that the child only wets the bed once each night, which minimises changes of bedding (Djurhuus 1992). The alternative argument, however, is that by using a drug to reduce the wetting, the child has fewer chances to learn behavioural control with the alarm (Gibb 2004). Although there were indeed fewer wet nights during combination treatment compared with desmopressin alone (Comparison 07.01.01, Ng 2005) and alarm alone (Comparison 08.01.01, Bradbury 1995; Gibb 2004; Ng 2005; Sukhai 1989#), it was not possible to judge whether this was reflected in lower failure or relapse rates (Comparison 07.03.01, Ng 2005; and Comparison 08.03.01, Bradbury 1995; Gibb 2004; Leebeek 2001; Ng 2005). This evidence was limited by small numbers and disparate interventions. The use of desmopressin as an adjunct to alarm treatment may be a good way of easing the initial weeks of alarm treatment or for giving families a break, but it is uncertain whether this helps in the long term. This needs to be evaluated by further research.

Desmopressin compared with other behavioural methods

There was no clear evidence to support the use of a complex package of behavioural methods, delivered either with or without desmopressin, in terms of numbers of children cured. Although desmopressin may have contributed to a reduction in the number of wet nights per week during treatment and afterwards, there was no difference in cure rates. This finding needs to be verified with further research. There was not enough evidence to compare desmopressin with retention control training alone.

Desmopressin compared with complementary treatments

In one small trial (comparing desmopressin with laser acupuncture), there was no difference in the failure rate six months after the end of the trial, but the numbers were too small to reliably compare the groups (Radmayr 2001). However, in view of the lack of effect of desmopressin after treatment stops (see comparison of desmopressin with placebo above, Comparisons 01.04 and 01.06, Other Data Tables 01.05), it was not possible to determine if the apparent cure of three quarters of the children in both groups was an effect of both treatments or due to spontaneous cure with time.

Other considerations

Relevant outcome measures

Most trials reported outcome criteria in terms of number of wet nights per week. The number achieving 14 dry nights was reported less often, and few trials provided follow‐up data or relapse rates. It is likely that parents would prefer a treatment that cured the problem in the long term, rather than simply decreasing the frequency of wet nights during treatment. However, reported outcome measures may reflect different aims of treatment: drugs could be used as a way to reduce the frequency of wetting for a specific purpose such as nights away from home (e.g. on a 'dry for camp' basis, for holidays or staying with friends (Meadow 1989)). Some families may find desmopressin useful over winter to overcome laundry problems.

Daytime wetting / organic causes

Only including trials that definitely excluded all children with daytime wetting would have severely limited the review. Only 26 of the 46 trials specifically excluded children with diurnal wetting; the remainder either failed to mention it (17 trials) or failed to exclude it (3 trials). All but one of the trials specifically excluded children with known organic causes for their enuresis. It is likely that the underlying pathologies of monosymptomatic bed‐wetting and mixed night and day wetting differ. The former group might be expected to respond better to treatment aimed at the symptom of bed‐wetting, whereas the latter might respond better to treatment aimed at the underlying pathology (e.g. urinary tract infection, unstable bladder). Alternative managements for these conditions need to be reviewed.

Settings and previous treatment

It should not be assumed that the interventions that are most effective in the trial situation are always the treatments of choice in the clinical situation. Most of the included trials have recruited children from enuresis clinics or are hospital based. Twenty of the trials included at least some children who had already failed previous treatments and were being referred for further advice. These participating families may be especially motivated to tackle bed‐wetting. In addition, strict inclusion or exclusion criteria were imposed in many of the trials. Consequently, the children involved were not necessarily representative of the wider population of bed‐wetters. Factors that made treatment more likely to be successful included: older age, fewer initial wet nights and larger functional bladder capacity (Rushton 1996).

Adverse effects

The reporting of adverse effects varied. In some trials they were not mentioned, while in others they were reported just as often in placebo groups. Some trials reported no adverse effects in any treatment group. All trials reported that the adverse effects of desmopressin were minor and did not require the treatment to cease. Although there appear to be fewer adverse reactions associated with desmopressin than tricyclic drugs, these are rare but can be serious. The risk of water intoxication should be minimised by restricting evening fluid intake on the nights that desmopressin is used (Bernstein 1997; Robson 1994; Robson 1996). Tricyclics are the most common cause of fatal poisoning in children (Parkin 1972). Overdose with tricyclics may occur accidentally or when children believe that a greater dosage gives a better effect (Wille 1986).

Costs

In the United Kingdom, 16 weeks of drug treatment (the usual time allowed for fourteen consecutive dry nights to be attained using an alarm (Butler 1991)) costs (BNF 2002):

UK£78 for desmopressin nasal spray (20 µg per night) or UK£116 for desmopressin tablets (200 µg);
UK£4 for imipramine hydrochloride (25 mg tablet per night) or UK£14 for imipramine syrup (25 mg);
enuresis alarms (including batteries and sensor) typically cost UK£33.60, although alarms but not sensors (UK£12) may be reused several times.

Although treatment with tricyclic or related drugs is considerably less expensive than alarms or desmopressin, this does not take into account the administrative or human costs involved in using alarms. Alarm systems may not be returned to clinics and have to be followed up. Alarm treatment is accompanied by broken nights for various family members until success is attained. The Guidelines on Minimum Standards of Practice (Morgan 1993) suggest that follow‐up supervisory contacts should occur at least every three weeks, with medication reviewed at least monthly. However, this must be considered in light of the lower likelihood of relapse after completing alarm treatment, compared with after desmopressin, tricyclics or related drugs, and the potential for adverse effects with tricyclics.

Authors' conclusions

Implications for practice.

Desmopressin rapidly reduced the number of wet nights per week, compared with placebo in children with monosymptomatic nocturnal enuresis, but this effect was not sustained after treatment stopped. Only two small RCTs followed up children treated with desmopressin or an enuresis alarm; those treated with the alarm were more likely to achieve long‐term success, but this needs to be confirmed in further research. Children who used alarms supplemented with desmopressin initially had fewer wet nights compared to after alarms alone, but this was not reflected in better cure rates or reduced relapse rates after stopping treatment. Potential difficulties, such as the commitment and time needed to attain success, need to be discussed with families before embarking on alarm treatment.

Treatment with desmopressin is considerably more expensive than with tricyclic drugs, but is associated with fewer adverse effects and less risk of fatal overdose. Although alarm interventions are intermediate in cost and are more disruptive in the short term, they do not have the same risk of side effects.

Patients and their families need to be warned about potential adverse effects associated with desmopressin. In particular, children should be advised not to drink more than 240 ml (8 ounces) of fluid on any night that desmopressin is given in order to avoid the possible risk of water intoxication.

Implications for research.

More trials comparing desmopressin with other methods of management are required, especially with alarms, tricyclic drugs, and other behavioural interventions such as lifting, star charts, reward systems and fluid deprivation. Further trials of desmopressin versus placebo should address the issue of whether the benefits are sustained after stopping treatment. Such trials should focus on children who do not have organic causes of bed‐wetting, and should include adequate assessment of baseline levels of wetting.

The trials should use uniform outcome measures such as: the number of wet nights during treatment and after the end of treatment; the number of children achieving 14 consecutive dry nights (cure rate); adverse effects; acceptability of treatment; compliance; and especially relapse rates.

The trials should include children from a variety of backgrounds and populations, particularly those children who have not already failed previous treatment, in order to increase the generalisability of the results. Important demographic factors that should be considered include previous treatment, age, presence of other organic pathology or daytime wetting and family circumstances, as well as co‐existing psychological, emotional or behavioural problems. It has been suggested that not all interventions are suitable for all children. Therefore, further research is needed to determine which interventions are appropriate for which patient groups and under what circumstances (for example, as a short‐term measure to cover nights away from home), in order to guide choice of treatment.

Children with daytime enuresis are more likely to have specific pathology, such as bladder dysfunction or urinary tract infections. Alternative managements for this condition need to be reviewed.

What's new

Date	Event	Description
16 September 2008	Amended	Converted to new review format.

Date	Event	Description
4 October 2006	New search has been performed	Minor update Issue 3 2006. Includes 5 new trials, and the previous tentative conclusions regarding alarms were strengthened: there is now firmer evidence that alarms are more effective (lower relapse rates) than desmopressin after treatment stops. There is no statistically significant evidence to suggest that combining desmopressin and alarm treatment is more effective than alarm treatment alone. Desmopressin appeared to be better than imipramine during treatment.
20 May 2004	New search has been performed	Minor update Issue 3, 2004. Six new studies were excluded and one new trial (Gibb 2004) was included. The conclusions were, however, unchanged.
21 May 2002	New citation required and conclusions have changed	Substantive amendment. The review was updated for Issue 3, 2002. 18 new trials were added, and the data from some old trials recalculated to include relapse rates and failure rates together.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of wet nights per week during treatment	17		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.1 10 mcg vs placebo	2	57	Mean Difference (IV, Fixed, 95% CI)	‐2.30 [‐3.42, ‐1.18]
1.2 20 mcg vs placebo	12	813	Mean Difference (IV, Fixed, 95% CI)	‐1.34 [‐1.57, ‐1.11]
1.3 40 mcg vs placebo	6	424	Mean Difference (IV, Fixed, 95% CI)	‐1.33 [‐1.67, ‐0.99]
1.4 60 mcg vs placebo	2	164	Mean Difference (IV, Fixed, 95% CI)	‐1.5 [‐1.92, ‐1.08]
1.5 combined dose vs placebo	1	44	Mean Difference (IV, Fixed, 95% CI)	‐3.4 [‐4.71, ‐2.09]
1.6 dose titration vs placebo	2	231	Mean Difference (IV, Fixed, 95% CI)	‐1.58 [‐2.08, ‐1.09]
2 Number of wet nights per week during treatment (no SDs)			Other data	No numeric data
2.1 20 mcg vs placebo			Other data	No numeric data
2.2 dose titration vs placebo			Other data	No numeric data
3 Number failing to achieve 14 consecutive dry nights during treatment	10		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
3.1 10 mcg vs placebo	1	32	Risk Ratio (M‐H, Fixed, 95% CI)	0.64 [0.41, 0.98]
3.2 20 mcg vs placebo	5	288	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.78, 0.91]
3.3 40 mcg vs placebo	6	463	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.74, 0.89]
3.4 60 mcg vs placebo	2	165	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.88, 1.00]
3.5 80 mcg vs placebo	1	66	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.71, 1.00]
4 Number of wet nights per week at follow‐up	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only
4.1 10 mcg vs placebo	2	54	Mean Difference (IV, Fixed, 95% CI)	0.09 [‐1.10, 1.27]
4.2 20 mcg vs placebo	1	22	Mean Difference (IV, Fixed, 95% CI)	0.54 [‐1.15, 2.23]
5 Number of wet nights per week at followup (no SDs)			Other data	No numeric data
5.1 20 mcg vs placebo			Other data	No numeric data
5.2 40 mcg vs placebo			Other data	No numeric data
6 Number failing to achieve 14 consecutive dry nights or relapsing after cure	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
6.2 20 mcg vs placebo	1	34	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Number of wet nights per week during treatment (no SDs)
Study	Desmopressin	Placebo
20 mcg vs placebo
Dimson 1986#	3.4 wet nights, n=17	5.0 wet nights, n=17
Fjellestad 1987#	2.9 wet nights, n=19	4.5 wet nights, n=19
Miller 1990a	4.4 wet nights, n=19	5.4 wet nights, n=31
Miller 1990b	5 wet nights, n=27	5.3 wet nights, n=26
Muller 2001#	3.27 wet nights, n=19	4.9 wet nights, n=21
dose titration vs placebo
Rittig 1988#	0 wet nights, n=34	3 wet nights, n=34
Terho 1991#	2.3 wet nights, n=52	4.7 wet nights, n=52
Uygur 1997#	0.5 wet nights, n=54	4.8 wet nights, n=54

Number of wet nights per week during treatment (no SDs)
Study	lower dose	higher dose
20 mcg vs 40 mcg
Miller 1990a	4.4 wet nights, n=19	3.5 wet nights, n=26
Miller 1990b	5 wet nights, n=27	4 wet nights, n=24

Number of wet nights per week during treatment (no SDs)
Study	oral	nose drops
Fjellestad 1987#	3 wet nights, n=19	2.9 wet nights, n=19

Number of wet nights per week during treatment (no SDs)
Study	Desmopressin	Alarm
desmopressin vs imipramine (first arm)
Vertucci 1997	1 wet night, n=29	2.5 wet nights, n=28

Number of wet nights per week during treatment (no SDs)
Study	Desmopressin + Alarm	Alarm alone
desmopressin + alarm vs alarm (+/‐ placebo)
Leebeek 2001	2.93 wet nights, n=47	3.86 wet nights, n=45

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2 Number failing to achieve 14 consecutive dry nights during treatment	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
2.1 desmopressin vs laser acupuncture	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.22, 2.01]
4 Number failing to achieve 14 consecutive dry nights or relapsing after cure	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
4.1 desmopressin vs laser acupuncture	1	40	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.27, 1.88]

Methods	RCT (double blind, method not specified)   Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: Not mentioned   Follow up after 30 days
Participants	Number of children: 32 (boys: A:7, B:8)   Previous treatment: 5/23 responded to chlorimipramine hydrochloride   Mean age (years): A:10.5, B:10.0 (range 7‐15)   Baseline wetting: mean (SD) number of wet nights in 30: A:18.7 (6.5), B:21.3 (8.5)   No significant difference between groups in urine osmolalities
Interventions	A (15): 10 µg DDAVP intranasally   B (17): placebo as above
Outcomes	Mean (SD) number of wet nights out of 30: A:6.5 (9.2), B:18.8 (8.3)   Number totally dry: A:6, B:1   Number of wet nights at follow up: A:15.7 (8.9), B:16.9 (9.4)   Significant difference in response of children according to age Only those over 10 years became completely dry The only failures (n=3) were less than 10 years old   Side effects: none reported   Prompt response to DDAVP ‐ as early as 1‐3 days
Notes	Unclear about dropouts   Short follow up   Age effect suggested   Inclusion criteria: not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	RCT (double blind crossover)   Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: Not mentioned   Follow up after 4‐6 weeks
Participants	Number of children: 22 (14 boys)   Previous treatment: all had failed to respond to psychotherapy and a regimen that included fluid deprivation after 5 pm   Some had previously been unsuccessfully treated with imipramine   Exclusion criteria: organic causes of enuresis   Mean age (years): 6.6 (range 4‐12)   Baseline wetting: mean (SD) wet beds per fortnight: 10.6 (4.9)
Interventions	A: 10 µg DDAVP drops intranasally at bedtime   B: 40 µg DDAVP drops intranasally at bedtime   C: placebo   Duration of treatment: 2 weeks in each arm
Outcomes	Mean (SD) number of wet nights per fortnight   A+B:4.2 (4.5) C:11 (4.4)   Side effects: none reported   5 patients receiving a higher dosage were totally dry   9 continued DDAVP single blind for 4 to 6 weeks then given placebo   7 remained dry without drug   1 wet once monthly and 1 returned to daily wetting   4 who had wet nightly continued on DDAVP for 3 more months by which time they were dry   1 had 1 wet night per fortnight and 1 had 1 wet night in 3   2 patients who were indifferent to wetting showed no response to DDAVP or placebo
Notes	No measure of comparability at baseline   No washout period   Not clear if intention to treat because no details of dropouts   Subjects were very young   High and low doses combined in analysis
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Methods	RCT (quota allocation system based on age, baseline wetting, family or housing problems, gender, previous alarm use, daytime wetting and previous dry periods)   Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: No   6 month follow up
Participants	Number of children: 71 (boys 48)   Dropouts A: 3, B: 8   Inclusion criteria: nocturnal enuresis at least 1 night per week (40/71 = severe, >4 times per week)   Exclusion criteria: neuropathic bladder, urinary tract abnormalities, cystic fibrosis, allergic rhinitis, deafness/ learning difficulties, UTI   Previous treatment: 29 had used alarms
Interventions	A (36): desmopressin 40 µg intranasally and alarm (bell‐and‐pad or Mini Drinite)   B (35): alarm alone   Duration 6 weeks or until dry
Outcomes	Mean DRY nights per week: A: n=33, mean = 6.1, 95% CI 5.6‐6.7; B: 27, 4.8, 4.0‐5.6   Number not achieving 4 dry nights: A: 6/33; B: 11/27   Number failing or relapsing: A: 10/33; B: 14/27   Side effects: none reported   Subgroup analysis in more severe group: A still better than B
Notes	Mini Drinite = body‐worn alarm   Relapsing = 2 wet nights in 2 weeks after 4 weeks dry   Authors recommended using combined desmopressin and alarm only for children with severe wetting problems
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Methods	RCT (multi‐centre, double blind)   Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: Not mentioned
Participants	Number of children: 45 (boys: A:11, B:10, C:9)   Dropouts: A:0, B:3, C:3   Inclusion criteria: age 6‐17 years; at least 3 wet nights per week for preceding 3 month period and not dry for more than 6 months   Exclusion criteria: enuresis treatment in preceding 6 months; nocturnal enuresis of neurogenic origin; urinary tract infection; abnormal urinalysis haematology or blood biochemistry; concomitant medication known to interfere with study medication   Age, mean years (SD): A:8.6 (2.4), B:8.9 (2.5), C:8.9 (2.4) (range 6‐14)   Baseline wetting: mean (SD) number of wet nights per week: A:5.8 (0.9), B:6.0 (0.9), C:6.3 (0.9)
Interventions	A (14): amitriptyline hydrochloride (25 mg or 50 mg)   B (17): desmopressin (20 µg) intranasally   C (14): DDAVP and amitriptyline   Duration of treatment: 16 weeks   Follow up 12 weeks
Outcomes	Mean (SD) number of wet nights per week: A:3.3 (1.9), B:4.7 (1.7), C:3.3 (2.5)   Number attaining cure: A:3, B:1, C:5   7 out of 8 children who were cured relapsed. The exception was treated with amitriptyline and DDAVP   Follow up: mean (SD) number of wet nights per week: A:(n=10) 3.9 (2.9), B:(n=5) 3.8 (1.9), C:(n=8) 5.1 (3.2)   Side effects: none reported   Most parents said all the drugs were easy to use
Notes	No significant difference between groups in terms of number, age, height and weight   Trial prematurely halted due to one drug ceasing to be available   Not stated if intention to treat   Not full quota of subjects
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Methods	RCT (random number tables, details not given)   Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: Yes
Participants	Number of children: 135   Dropouts: 23 excluded for non‐compliance, and 39 lost to follow up including 12 failed with alarms   Inclusion criteria: monosymptomatic nocturnal enuresis, age >5 years   Exclusion criteria: previous treatment with DDAVP or alarm, urological pathology, diurnal enuresis, UTI   Age, mean years: 11.2   Baseline wetting: A 21% dry nights, B 14% dry nights
Interventions	A (62): desmopressin 20 µg intranasally increasing to 40 µg if response partial   B (73): alarm (pad‐and‐bell)   Duration of treatment 3 months. If failed at that time, changed to alternative arm
Outcomes	DRY nights at 3 months: A 85%; B: 90%   Number not achieving 14 dry nights: A 12/39; B: 6/37   Side effects: not mentioned
Notes	No follow up   No mention of adverse events
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	RCT (randomized in 2 groups)   Systematic baseline measure of wetting: Yes   Organic causes excluded: No   Daytime wetting excluded: Yes   Setting: Federal University of Sao Paulo
Participants	No. of children (boys): 30 (21)   Dropouts: None   Inclusion: monosymptomatic nocturnal enuresis, age over 5 years, no daytime wetting   Exclusion: none mentioned   Previous treatment: none   Age, mean years (SD): 9.23 (1.85)   Baseline wetting, mean (SD) wet nights in 2 weeks: 9.40 (3.40)
Interventions	A (15): DDAVP (desmopressin), titrated to maximum 0.4 mg at bedtime   B (15): behavioural modification (dietary and fluid adjustment, voiding schedules, double voiding, bedtime toileting, alarm clock once at night, pelvic floor training, environmental modifications, changes in parents' attitudes, improvement of self‐esteem, self care)   Duration of treatment: 30 days   Follow up: none
Outcomes	Wet nights during last 2 weeks of treatment N, mean (SD): A: 15, 7.27 (4), B: 15, 3.93 (3.32)   50% improvement: A: 7/15, B: 8/15   Complete failure: A: 5/15, B: 1/15   Adverse effects: not mentioned
Notes	Groups comparable at baseline on age, gender and baseline wetting   No data for children 'cured' (14 consecutive dry nights)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	RCT (double blind, double dummy, cross over)   Periods of treatment preceded and followed by one week of observation   Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: Yes   Follow up after 1 week
Participants	Number of children: 30 (20 boys), 1 dropout   Exclusion criteria: urinary tract infections; diurnal wetting; faecal soiling; neurological or urological abnormalities; 3+ wet nights a week during baseline   Previous treatment: 69% tried one or more other treatment   Age, mean (SD): 9.8 (2.5) (range 6‐15)   Baseline wetting: mean number of dry nights in week: 2.2 (SD 0.2)
Interventions	A: 200 µg oral desmopressin   B: 20 µg intranasal desmopressin   C: placebo tablets   D: placebo nasal pipette   Duration of treatment: 2 weeks placebo then 2 weeks each condition
Outcomes	During treatments mean number of dry nights: A:4, B:4.1, C:2.5   2 patients totally dry while taking tablets; 1 patient totally dry while using intranasal   9 children (31%) remained totally dry   Side effects: no significant adverse effects but 2 patients complained of occasional nasal discomfort and 3 of epistaxis but no difference between placebo and active arms
Notes	Not reported if comparable groups   Washout one week between each arm   Not intention to treat   Many results only given graphically   Short follow up   No SDs
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	RCT (double‐blind crossover)   Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: Yes
Participants	Number of children: 31 (22 boys), small number of adults   Dropouts/not included: 6   Inclusion criteria: primary monosymptomatic enuresis, age over 6 years   Exclusion criteria: diabetes, neurological or renal disease, steroids, diuretics, daytime wetting   Previous treatment: failed on alarms, anticholinergics   Age, mean years: 11.2 (SD 5.4)
Interventions	A: desmopressin 20 µg intranasal   B: placebo   21 days each, then crossed over
Outcomes	Mean wet nights/week during trial: A: 3.24 (SE 0.45); B: 4.86 (0.35)   Side effects: A: 1 nausea; B: 1 drowsy and vomiting
Notes	No washout period   No follow up   Groups reported to be comparable but data not given
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Methods	RCT (drug dispensed randomly by pharmacist) Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: No Setting: Paediatric outpatients, Children's Hospital, Melbourne, Australia
Participants	Number of children (boys): 207/210 (A:64, B:78)   Dropouts: 10 eligible children declined, incomplete data on A:9/101, B:17/106 but dropouts counted as failures for analysis   Inclusion criteria: Non‐responders to desmopressin treatment (<50% reduction in wet nights), age 6‐16 years, wetting at least twice per week, some daytime wetting (A:11, B:8)   Exclusion criteria: Neuropathic bladder, urinary tract abnormality, cystic fibrosis, allergic rhinitis, UTI in previous 2 weeks, imipramine or diuretics   Previous treatment: some had alarm (A:37, B:32) or desmopressin (A:31, B:28)   Age: mean 9.4 years (SD 2.08)   Baseline wet nights in 28 days: A: 23.9 (SD 5.05), B: 23.7 (5.83)
Interventions	A (84/101): desmopressin (40 µg nasal spray) + alarm (pad and bell)   B (85/106): placebo (nasal spray) + alarm (pad and bell) Duration of treatment: 8 weeks Follow up: 2 months
Outcomes	Cure = 28 dry nights, relapse = 2 wet nights in 2 weeks   Wet nights during treatment (number, mean (SD)): A: 101, 1.8 (1.13), B: 106, 2.4 (1.53)   Cure during treatment: A: 52/101, B: 51/106 P=0.63 (failed: A: 49/101, B: 55/106)   Relapse after treatment stopped: A: 7, B: 3   Failed or relapsed: A: 56/101, B: 58/106   Adverse effects: A: 1 (headache), B: 1 (nose bleed)   Other: compliance same in both groups   Cure in daytime wetting: A: 6/11, B: 3/8
Notes	Intention to treat analysis   Groups comparable at baseline on age, wetting, gender, family history, secondary enuresis, daytime wetting and previous treatment
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	RCT (method not given)   Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: Yes   Follow up 2 weeks
Participants	Number of children: 114 (88 boys)   Dropouts: 18 (not wet or poor compliance)   Inclusion criteria: primary monosymptomatic nocturnal enuresis, at least 4 times per week   Exclusion criteria: neurological or physical abnormalities, UTI   Age: 5‐15 years, A: 9.2; B: 9.4   Baseline wetting (SD): A: 6.8 (0.7); B: 6.7 (0.9)
Interventions	A (54): DDAVP intranasally, 5 µg increasing to 20 if no response, decreasing when strongly responding   B (60): retention control training; holding voiding once a day to increase bladder capacity   Duration of treatment: 12 weeks
Outcomes	Wet nights per week (N, mean, SD): A: 54, 6.8 (SD 0.76); B: 60, 6.7 (0.87)   Number not achieving 14 dry nights A: 33/54; B: 46/60   Relapsing after cure: A 17; B: 5   Failed or relapsing after trial: A: 50/54; B: 51/60   Side effects: adverse events infrequent: A: 2/54 (nasal discomfort); B: 0/60
Notes	Results presented according to functional bladder capacity but merged here Short follow up   Groups comparable at baseline
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	RCT (randomly allocated in blocks of 4)   Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: Yes   Setting: Day clinics at drug company
Participants	No. of children (boys): 231 (167)   Dropouts: 7 not wet at baseline, 1 moved, 2 daytime wetting, 4 delayed treatment, 2 non‐compliance   Inclusion: wet 10/14 nights   Exclusion: daytime wetting, organic causes, family disruption   Previous treatment: no information   Age: at least 6 years   Baseline wetting: mean 12.8 wet nights in 2 weeks
Interventions	A (112): desmopressin 10 µg nasal drops + placebo tablet   B (112): imipramine tablet (25 mg) + placebo nasal drops Duration of treatment: 4 weeks   Follow up: none
Outcomes	Wet nights during treatment (N, mean, SE)   At 2 weeks: A: 111, 9.5 (SE 0.5), B: 111, 9 (0.5)   At 4 weeks: A: 109, 8.7 (SE 0.5), B: 109, 8 (0.5)   Adverse effects causing stopping: A: 0, B: 1   Other adverse effects: Oedema, headache, sleepyness, insomnia, sleep disorder, dizziness, appetite loss, nausea, vomiting, diarrhoea, abdominal pain, eyelid swelling, rash, red eyelid, nose symptoms (itchy nose, bleeding nose, blocked nose, runny nose), fever, tiredness, shaking head, thirsty, dry lips   Total number of side effects: A: 29/120, B: 29/118   Total number of children with side effects: A: 16/120, B: 16/118   Other outcomes: wetting score, side effect score, satisfaction score, overall score
Notes	Japanese language   Data measured from graphs   No follow up
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	RCT (method not given, double‐blind)   Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: Yes
Participants	Number of children: 36   Inclusion criteria: 2 or more wet nights per week; age 8‐12;   Exclusion criteria: day time wetting; diabetes, insipidus or other chronic illness where need daily medication; other treatment for bed wetting   Mean age (years): A:9.8, B:9.5 (range 8‐12)   Baseline wetting: wet bed 2 or more times per week
Interventions	A (19): imipramine 50 mg and placebo nasal spray   B (17): intranasal desmopressin 20 µg and placebo tablets   Duration of treatment: 4 weeks   Follow up: 6 weeks
Outcomes	Results first 2 weeks of treatment: % reduction in wet nights: A:48%, B:45%   Results final 2 weeks of treatment: A:54%, B:32%   Mean (SD) number of wet nights per first 14 days: A:4.9 (4.3), B:4.8 (4.0)   Mean (SD) number of wet nights per last 14 days: A:4.5 (3.7), B:6.0 (4.4)   Mean (SD) number of wet nights per 14 days at follow up: A:7.7 (3.9), B:7.3 (4.5)   Side effects: B: rash (1)
Notes	Norwegian translation   Direct comparison of imipramine and DDAVP   Children comparable in terms of sex, age and weight   No details of previous treatment
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

PERMALINK

Desmopressin for nocturnal enuresis in children

Cathryn MA Glazener

Jonathan HC Evans

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Prevalence and causes

Interventions

Desmopressin

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Search methods for identification of studies

Data collection and analysis

Identification of primary studies

Quality assessment

Data extraction

Data analysis

Results

Description of studies

Participants

Dosage of desmopressin

Route of administration and comparators

Risk of bias in included studies

Effects of interventions

1. Desmopressin versus no active treatment / placebo (see Comparisons 01 and 02, Other Data Tables 01)

2. Lower versus higher doses of desmopressin (see Comparison 03, Other Data Tables 03)

3. Oral versus nasal administration of desmopressin (see Comparison 04, Other Data Tables 04)

4. Desmopressin versus other drugs (see Comparison 05, Other Data Tables 05)

5, 6, 7. Desmopressin and alarms

5. Desmopressin alone versus alarm treatment alone (see Comparison 06)

6. Desmopressin alone versus desmopressin supplemented by alarm treatment (see Comparison 07)

7. Desmopressin supplemented by alarm treatment versus alarm treatment alone (see Comparison 08)

8. Desmopressin versus behavioural methods, alone or in combination (see Comparison 09)

9. Desmopressin versus complementary treatment (see Comparison 10)

Adverse effects

Discussion

Desmopressin compared with placebo

Dose of desmopressin and route of administration

Desmopressin compared with other drugs (see also review of tricyclics for enuresis, Glazener 2004e)

Desmopressin compared with alarms (see also review of alarms for enuresis Glazener 2004a)

Desmopressin compared with other behavioural methods

Desmopressin compared with complementary treatments

Other considerations

Relevant outcome measures

Daytime wetting / organic causes

Settings and previous treatment

Adverse effects

Costs

Authors' conclusions

Implications for practice.

Implications for research.

What's new

History

Acknowledgements

Data and analyses

Comparison 1. DESMOPRESSIN VS PLACEBO.

1.1. Analysis.

1.2. Analysis.

1.3. Analysis.

1.4. Analysis.

1.5. Analysis.

1.6. Analysis.

Comparison 2. DESMOPRESSIN VS PLACEBO excluding crossover trials.

2.1. Analysis.

2.2. Analysis.

2.3. Analysis.

2.4. Analysis.

Methods	RCT (double‐blind randomised crossover of dosages with placebo between)   Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: Not mentioned   Follow up after 4 weeks
Participants	Number of children: 22 (18 boys)   No dropouts   Inclusion criteria: maximum of 4 dry nights a week during baseline   Mean age: 10 years (range 6‐16)   Previous treatment: all used imipramine or other medications, or enuresis alarm (8), acupuncture (1), and psychotherapy (1)   More than one method used with many patients   Baseline wetting: mean (SD) number of dry nights per week: 1.3 (1.3)
Interventions	A: Placebo nasal pipette   B: 20 µg desmopressin intranasally   C: 40 µg desmopressin intranasally   Duration of treatment: 1 month each condition
Outcomes	Mean (SD) number of dry nights per week: A:1.7 (1.8), B:3.6 (2.5), C:3.2 (2.2)   At follow up mean (SD) number of dry nights per week: 2.2 (1.8)   Morning urine osmolality not significantly different in pre‐treatment or treatment periods   Significant increase in body weight   No significant changes in blood pressure, haematology or blood chemistry   Side effects: most common adverse reactions were headaches (3) and stomach ache (3) (though no different from placebo)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	RCT (double blind multi‐centre trial, method not given)   Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: Yes   12 week open label follow up
Participants	Number of children: 65 (boys: A:18, B:19)   3 dropouts   Exclusion criteria: diurnal wetting; other medical conditions; urological causes of wetting   Mean age: 19.4 years (range 12‐45)   At least 6 wet nights in 2 weeks at baseline
Interventions	A (34): desmopressin tablets 200 µg   B (31): desmopressin tablets 400 µg   Duration of treatment: 4 weeks
Outcomes	Mean change from baseline wetting (wet nights per week 95% CI) A:‐3.2 (‐2.4, ‐4.1), B:‐3.4 (‐2.7, ‐4.1)   Side effects: not mentioned
Notes	Only DDAVP responders   Mixed age group (some adults)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	RCT (double‐blind, method not specified)   Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: Not mentioned   Follow up for 2 months
Participants	Number of children: 228   Dropouts: A 6, B 1; due to difficulty complying with schedule of behavioural therapy   Inclusion criteria: primary nocturnal enuresis at least 2 times per week, age >7 years   Exclusion criteria: previous treatment, other physical disorders, previous traumatic life events, psychiatric disorders, abnormal laboratory findings   Baseline differences in wetting between groups: A 5.1 (SD 2.1); B 5.5 (1.8); C 5.8 (1.6): P=0.044
Interventions	A (70): desmopressin and behaviour therapy   B (75): placebo and behaviour therapy   C (76): desmopressin alone (20 µg intranasal)   Duration 8 weeks
Outcomes	Wet nights at end of trial (N, mean, SD): A: 70, 3.0 (2.0); B: 75, 3.3 (2.2); C: 76, 4.5 (2.0)   Number not achieving 14 dry nights: A: 48/70; B: 63/75; C: 45/76   Number failing or relapsing: A: 66/70; B: 69/75; 73/76   Wet nights after end of trial (N, mean, SD): A: 70, 2.6 (1.7); B: 74, 3.0 (2.0); C: 76, 4.7 (1.8)   Side effects: nasal itch: A 5, B 1, C 4   7 dropouts due to problems with behavioural treatment schedule
Notes	Power calculation given   Behaviour treatment = psychological (teaching self control, taking responsibility), bladder continence exercises, giving information about the mechanisms of wetting   Blinding of treatment not possible due to differences in interventions (but placebo and DDAVP blinded)   Group A had less wetting at baseline
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	RCT (double‐blind)   Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: Not mentioned   Follow up after 3 months
Participants	Number of children: 37   Dropouts from follow up: A:3, B:2   Inclusion criteria: normal, healthy children who had failed with previous treatment, informed consent, more than 25% wet nights during baseline   Previous treatment: all failed treatment with tricyclic antidepressants and/or enuresis alarm   Mean age: 11.0 years (range 9‐15)   Baseline wetting: mean (SD) number of wet nights per 100: A:56.6 (8.0), B:65.9 (7.5), C:64.7 (7.3)
Interventions	A (13): 10 µg DDAVP intranasally before bedtime   B (12): 20 µg DDAVP intranasally before bedtime   C (12): placebo   Duration of treatment: 1 month
Outcomes	Number of wet nights per 100 (mean, SD): A:35.5 (10), B:35.0 (7.6), C:54.8 (8.8)   Follow up: mean (SD) number of wet nights per 100: A:60.9 (11.4), B:60.0 (8.5), C:52.3 (8.9)   Side effects: none reported   DDAVP ineffective when participants had respiratory tract infections
Notes	Not reported if the groups were comparable
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	RCT (randomly assigned to 1 of 3 groups)   Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: 53% also had daytime wetting but results available separately   Setting: 2 hospitals, 2003 to 2004
Participants	Number of children (boys): 145 (100)   Monosymptomatic enuresis (Trial 1): 68   Polysymptomatic (+ daytime wetting, Trial 2): 77   Dropouts: 13 (drug side effects or outcome unknown: A: 3, B: 3, C: 7)   Inclusion criteria: at least 3 wet nights/week   Exclusion criteria: drug treatment in 14 days prior to start of study   Age: 7.8 years (SD 2.5) (range 5 to 15)   Baseline wetting: 6.36x/week (SD 1.5)
Interventions	Trial 1 (monosymptomatic enuresis)   A (22): desmopressin 0.1 or 0.2 mg, oxybutynin 5 mg   B (23): desmopressin0.2 mg increased to 0.4 mg if no response   C (23): imipramine 25 mg   Given orally before bedtime   Duration of treatment: 6 months   Follow up: none
Outcomes	Trial 1   Wet nights at 6 months, N mean (SD): A: 22, 0.93 (1.35), B: 23, 0.7 (0.95), C: 23, 2.0 (2.05)   No. children cured (excellent response = 0‐1 wet night per month): A: 14/22, B: 14/23, C: 3/23   No. children failed (not excellent): A: 8/22, B: 9/23, C: 20/23   Trial 2   Wet nights at 6 months, N mean (SD): A: 26, 1.2 (1.55), B: 26, 1.23 (0.88), C: 25, 2.63 (2)   No. children cured (excellent response = 0‐1 wet night per month): A: 9/26, B: 7/26, C: 3/25   No. children failed (not excellent): A: 17/26, B: 19/26, C: 22/25   Adverse effects (both trials, including dropouts): A: 0/51, B: 2/52, C: 22/55
Notes	Data obtained from author enabling results to be given separately for nocturia and daytime wetting groups   Groups comparable at baseline on age, sex, disease type, baseline wetting   Higher side effect and drop out rate in imipramine group
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	RCT (double blind parallel group study)   Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: Yes   Follow up at 2 weeks and 6 months after end of trial
Participants	Number of children (boys): 93 (62)   Inclusion criteria: at least 6 wet nights per week   Exclusion criteria: treatment in previous 2 weeks; daytime wetting/ pollakisuria; urological or psychological disease; poor motivation to use alarm   Previous treatment: none in previous 2 weeks   Age: 6‐14 years   Baseline wetting: mean number of wet nights: A: 6.14, B: 6.12 (NS)
Interventions	A (47): alarm and desmopressin 40 µg intranasal for 3 weeks, then alarm and desmopressin 20 µg for 3 weeks, then alarm alone for 3 weeks   B (46): alarm and placebo for 6 weeks, then alarm alone for 3 weeks
Outcomes	Wet nights (number, mean):   First 3 weeks: A: 47, 2.93, B: 45, 3.86 (P=0.014)   Last 3 weeks, alarm only: A: 43, 2.77, B: 39, 2.21   Number cured 2 weeks after end of trial: A: 15/47, B: 17/46   Number cured 6 months after end of trial: A: 17/47, B: 17/46   i.e. failed at 6 months: A: 20/47, B: 21/46   Wet nights at 6 months (number, mean): A: 41, 2.72, B: 37, 1.90   Adverse events: none in either group
Notes	Power calculation provided   Groups comparable for sex and age   SDs not given (authors contacted for more information)   Study supported by drug company (Ferring Pharmaceuticals A/S Ferring)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Methods	RCT (computer generated randomisation)   Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: Yes   Setting: Recruited from hospital clinic and advertising
Participants	Number of children: 182   At 6 months 17 withdrew due to failure (A 8; B 5; C 4)   Inclusion criteria: primary monosymptomatic nocturnal enuresis, age >7 years, wet >3 times per week, normal bladder capacity   Exclusion criteria: daytime wetting, CNS disorder, developmental delay, current alarm or DDAVP treatment, encopresis, other medical problems
Interventions	A (61): alarm   B (60): desmopressin intranasally   C (61): placebo   Duration 6 months, then failures crossed over to alternative arm for 6 months (not randomised)
Outcomes	Number not achieving 14 dry nights after 6 months: A: 26/61; B: 31/60; C: 38/61   All children improved psychologically, e.g. behaviour and self concept, regardless of outcome or treatment assignment   Side effects: not mentioned
Notes	Dose of DDAVP not given   No follow up as failures assigned to alternative treatment   Blinding to method not possible for alarm group
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate

Methods	RCT (double‐blind randomised placebo controlled)   Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: No   Only 7 DDAVP successes followed up
Participants	Number of children: 44   Boys: A:54%, B:41%   Mean age (year): A:8.9, B:9.13   Previous treatment: all children had failed to improve during 1 month treatment with motivational therapy and bladder training   Baseline wetting: mean (SD) % of dry nights per month: A:24.45 (18.8), B:19.9 (20)
Interventions	A (22): placebo   B (22): 40 µg desmopressin drops 15 minutes before retiring   Duration of treatment: 2 months
Outcomes	Mean (SD) % of dry nights per month after 2 months: A:47.4 (32.1), B:69.2 (33.5)   Number (%) of children becoming totally dry: A:1 (5), B:5 (27)   Side effects: anorexia (1)
Notes	Groups similar at baseline   No follow up   Very small sample   Unclear about dropouts   Inclusion/ exclusion criteria not stated
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	RCT (multi‐centre, double‐blind) Trial A = Centre 1   Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: Not mentioned   No significant differences between groups except that more older children in group (A) in one centre   4 weeks open label phase then 2 week no treatment   Number at 2 week follow up: 1A:19, 1B:26, 1C:16
Participants	Number of children: 99 (70% boys)   4 dropouts   Inclusion criteria: children aged 7‐14 with nocturnal enuresis; informed consent from parents; 10 or more wet nights per fortnight; no organic urologic disorders; no urinary tract infection; no abnormal urine osmolality   Previous treatment: 58% taken other drugs; 87% imipramine; 40% tried other measures of these, 76% tried enuresis alarm   Age range 7‐14 (46% aged 7‐8)   Baseline wetting: mean number of wet nights in 14: 1A:12.3, 1B:11.8, 1C:12.3
Interventions	1A (32): 20 µg desmopressin acetate intranasally at bedtime   1B (36): 40 µg desmopressin acetate intranasally at bedtime   1C (31): placebo   Duration of treatment: 4 weeks
Outcomes	Mean number of wet nights in final 14 days: 1A:8.7, 1B:7.0, 1C:10.7   Active treatment significantly different to placebo   2 week follow up: mean number of wet nights per 14: 1A:11.1, 1B:11.0, 1C:9.9   Side effects: no serious adverse events (6 minor)
Notes	No intention to treat   Short follow up   Statistics suggest sample size too small for conclusive findings   No SDs
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear

Methods	RCT (multi‐centre, double‐blind) Trial B = Centre 2   Systematic baseline measure of wetting: Yes   Organic causes excluded: Yes   Daytime wetting excluded: Not mentioned   No significant differences between groups except that more older children in group (A) in one centre   4 weeks open label phase then 2 week no treatment   Number at 2 week follow up: 2A:19, 2B:20, 2C:20
Participants	Number of children: 77 (70% boys)   4 dropouts   Inclusion criteria: children aged 7‐14 with nocturnal enuresis; informed consent from parents; 10 or more wet nights per fortnight; no organic urologic disorders; no urinary tract infection; no abnormal urine osmolality   Previous treatment: 58% taken other drugs; 87% imipramine; 40% tried other measures of these, 76% tried enuresis alarm   Age range 7‐14 (46% aged 7‐8)   Baseline wetting: mean number of wet nights in 14: 2A:12.6, 2B:12.3, 2C:12.4
Interventions	2A (27): 20 µg desmopressin acetate intranasally at bedtime   2B (24): 40 µg desmopressin acetate intranasally at bedtime   2C (26): placebo   Duration of treatment: 4 weeks
Outcomes	Mean number of wet nights in final 14 days: 2A:10.0, 2B:8.1, 2C:10.5   Active treatment significantly better than placebo except A versus C not significant   2 week follow up: mean number of wet nights per 14: 2A:10.8, 2B:11.4, 2C:11.3   Side effects: no serious adverse events (11 minor)
Notes	No intention to treat   Short follow up   Statistics suggest sample size too small for conclusive findings   No SDs
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Unclear risk	B ‐ Unclear