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National Clinical Guideline Centre (UK). Nocturnal Enuresis: The Management of Bedwetting in Children and Young People. London: Royal College of Physicians (UK); 2010. (NICE Clinical Guidelines, No. 111.)

13Desmopressin and the management of bedwetting

13.1. Introduction

What is it? Desmopressin is a synthetic analogue of the naturally occurring anti diuretic hormone (ADH).

How does it work? In most children levels of ADH rise overnight and prevent as much water being excreted by the kidneys as during the day. This causes urine to become concentrated in a smaller volume overnight which allows the majority of children to sleep through the night without needing to pass urine. In some children this mechanism is late to become established and they continue to produce large volumes of dilute urine overnight, resulting in a full bladder and either needing to get up to pass urine (nocturia – about 10% children at 7 years) or if they fail to wake, they will wet the bed or soak pull ups in large volumes. Desmopressin works by mimicking the action of ADH. It does not prevent the normal development of the childs own ADH excretion.

How is it given? Desmopressin is given as either a melt or a tablet. The nasal spray is no longer licensed for bedwetting owing to an increased incidence of side effects. Younger children often prefer the melt as it avoids needing to swallow tablets. Desmopressin in either form should be taken before bedtime. Children should restrict their fluid intake to sips only from an hour before taking the medicine to 8 hours afterwards to avoid the potential for fluid overload and hyponatraemia (low sodium levels in the blood) which could be a serious side effect.

Side effects and contraindications. Desmopressin is a safe medicine with few side effects. The main concern is the possibility of fluid overload and hyponatraemia but this has not been reported to happen if advice regarding fluid restriction is followed. Other side effects are rare but can include headache, stomach ache and occasional emotional disturbance. These settle quickly on stopping the medicine. Desmopressin has very few interactions with other medicines. There is no evidence for any side effects if desmopressin is taken long term.

Desmopressin should be avoided in children who have fluid control problems such as in heart failure and should be carefully considered if children are likely to find difficulty complying with the fluid restriction requirements.

Desmopressin is pharmacologically active when given by intravenously, subcutaeineously, oral or nasal routes. The duration of action differs little between routes, but absorption does, so different dosages are required for different routes. For nocturnal enuresis the nasal route (either via a rhinyle or by nasal spray) was the only route used for many years until desmopressin tablets were developed. More recently desmopressin lyophilosate (desmomelt R) has been licensed for oral use.

In 2007 nasal desmopressin was withdrawn as a treatment for nocturnal enuresis because of a significantly higher incidence of symptomatic hyponatraemia than oral desmopressin. Although not currently licensed, much of the evidence for use of desmopressin has come from studies using nasal desmopressin. We have therefore included studies using nasal desmopressin as a comparator and as an intervention. Although there have been few comparisons of nasal desmopressin with desmopressin by other routes they do appear to have similar effectiveness.

In the systematic review of the research the evidence of effectiveness for nasal, oral and melt administration are reported separately.

13.2. What is the clinical and cost effectiveness of desmopressin for children and young people under 19 years who have bedwetting?

13.2.1. Evidence review

13.2.1.1. Intranasal desmopressin compared to placebo

Two randomised control trials, compared intranasal desmopressin to placebo, Muller (2001) 120 and Uygur (1997) 121.

Table 13-120 micro grams intranasal desmopressin compared to placebo - Clinical summary of findings

Outcome20 micro grams intranasal desmopressinPlaceboRelative risk (95% CI)Absolute effectQuality
Mean number of wet nights in the last 2 weeks of treatment (no SDs)7375-not pooledVERY LOW

13.2.1.2. Intranasal desmopressin compared to amitriptyline

One randomised control trial Burke (1995) 122 compared 20 micro grams intranasal desmopressin to 25 mg or 50 mg amitriptyline.

Table 13-2Intranasal desmopressin compared to amitriptyline - Clinical summary of findings

OutcomeIntranasal desmopressinAmitriptylineRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 14 consecutive dry nights1/17 (5.9%)3/14 (21.4%)RR 0.27 (0.03 to 2.36)156 fewer per 1000 (from 208 fewer to 291 more)MODERATE
Mean number of wet nights per week at end of treatment1714-MD 1.4 (0.12 to 2.68)MODERATE
Mean number of wet nights per week at follow up1714-MD −0.1 (−1.87 to 1.67)MODERATE
Number of children who dropped out by end of trial3/17 (17.6%)0/14 (0%)RR 5.83 (0.33 to 104.22)0 more per 1000 (from 0 fewer to 0 more)LOW

13.2.1.3. Intranasal desmopressin compared to imipramine

One randomised Vertucci (1997) 123 controlled trial compared 30 mcg intranasal desmopressin to 0.9 mg/kg imipramine.

Table 13-3Intranasal desmopressin compared to imipramine - Clinical summary of findings

OutcomeIntranasal desmopressinImipramineRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 14 consecutive dry nights25/29 (86.2%)19/28 (67.9%)RR 1.27 (0.95 to 1.7)183 more per 1000 (from 34 fewer to 475 more)VERY LOW
Mean number of wet nights per week after treatment (no SD)2928-not pooledVERY LOW

13.2.1.4. Tablet desmopressin compared to imipramine

One randomised control trial Lee (2005) 25 compared 200 micrograms tablet desmopressin to 25 mg imipramine.

Table 13-4Tablet desmopressin compared to imipramine - Clinical summary of findings

OutcomeTablet desmopressinImipramineRelative risk (95% CI)Absolute effectQuality
Number of children who dropped out by end of trial3/49 (6.1%)7/48 (14.6%)RR 0.42 (0.12 to 1.53)85 fewer per 1000 (from 128 fewer to 77 more)VERY LOW

Table 13-5Tablet desmopressin compared to imipramine for children with night and daytime wetting - Clinical summary of findings

OutcomeTablet desmopressinImipramineRelative risk (95% CI)Absolute effectQuality
Number of children who had 0-1 wet nights per month9/26 (34.6%)3/25 (12%)RR 2.88 (0.88 to 9.44)226 more per 1000 (from 14 fewer to 1000 more)VERY LOW
Mean number of wet nights per week at end of treatment2625-MD −1.4 (−2.25 to − 0.55)VERY LOW

13.2.1.5. Intranasal Desmopressin compared to intranasal desmopressin combined with amitriptyline

One randomised control trial Burke (1995) 122 compared 20 micro grams intranasal desmopressin to 20 micro grams intranasal desmopressin and amitriptyline.

Table 13-6Intranasal desmopressin compared to intranasal desmopressin and amitriptyline - Clinical summary of findings

OutcomeIntranasal desmopressinIntranasal desmopressin and amitriptylineRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 14 consecutive dry nights1/17 (5.9%)5/14 (35.7%)RR 0.16 (0.02 to 1.25)300 fewer per 1000 (from 350 fewer to 89 more)MODERATE
Mean number of wet nights per week at end of treatment1714-MD 1.4 (−0.14 to 2.94)MODERATE
Mean number of wet nights per week at end of follow up1714-MD −1.3 (−3.2 to 0.6)MODERATE
Number of children who dropped out by end of trial3/17 (17.6%)3/14 (21.4%)RR 0.82 (0.2 to 3.46)39 fewer per 1000 (from 171 fewer to 526 more)MODERATE

13.2.1.6. Tablet desmopressin compared to tablet desmopressin with oxybutynin

One randomised control trial Lee (2005) 25 compared 200 microgram tablet desmopressin to 100 to 200 microgram tablet desmopressin and 5 mg oxybutynin.

Table 13-7Tablet desmopressin compared to tablet desmopressin and oxybutynin - Clinical summary of findings

OutcomeTablet desmopressinTablet desmopressin and oxybutyninRelative risk (95% CI)Absolute effectQuality
Number of children who dropped out by end of trial3/49 (6.1%)3/48 (6.3%)RR 0.98 (0.21 to 4.62)1 fewer per 1000 (from 50 fewer to 228 more)VERY LOW

Table 13-8Tablet desmopressin compared to tablet desmopressin and oxybutynin for children with night and day wetting - Clinical summary of findings

OutcomeTablet desmopressinTablet desmopressin and oxybutyninRelative risk (95% CI)Absolute effectQuality
Number of children who had 0–1 wet nights per month9/26 (34.6%)9/26 (34.6%)RR 1 (0.47 to 2.11)0 fewer per 1000 (from 183 fewer to 384 more)VERY LOW
Mean number of wet nights per week at end of treatment2626-MD 0.03 (−0.66 to 0.72)VERY LOW

13.2.1.7. Tablet desmopressin compared to placebo for children with bedwetting

Three randomised control trials, Ferrara (2008) 124, Schulman (2001) 26 and Skoog (1997) 27 compared a tablet desmopressin to a placebo. Ferrara (2008) 124 was identified in the update search, all three trials considered children who had only night time wetting.

Table 13-9200 microgram tablet desmopressin compared to placebo - Clinical summary of findings

Outcome200 microgram tablet desmopressinPlaceboRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 14 consecutive dry nights29/127 (22.8%)0/135 (0%)RR 10.96 (1.6 to 75.16)0 more per 1000 (from 0 more to 0 more)LOW
Mean number of wet nights per 2 weeks at end of treatment3336-MD −1 (−1.55 to −0.45)LOW

Table 13-10400 microgram tablet desmopressin compared to placebo - Clinical summary of findings

Outcome400 microgram tablet desmopressinPlaceboRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 14 consecutive dry nights10/81 (12.3%)0/85 (0%)RR 11.42 (1.5 to 86.69)0 more per 1000 (from 0 more to 0 more)MODERATE
Mean number of wet nights per 2 weeks at end of treatment3536-MD −1.5 (−2.12 to − 0.88)MODERATE

Table 13-11600 microgram tablet desmopressin compared to placebo - Clinical summary of findings

Outcome600 mmicrogram tablet desmopressinPlaceboRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 14 consecutive dry nights5/82 (6.1%)0/85 (0%)RR 6.19 (0.76 to 50.48)0 more per 1000 (from 0 fewer to 0 more)LOW
Mean number of wet nights per 2 weeks at end of treatment3336-MD −1.5 (−2.05 to − 0.95)MODERATE

13.2.1.8. Low dose tablet desmopressin compared to high dose tablet desmopressin for children with bedwetting

Two randomised control trials Schulman (2001) 26 and Skoog (1997) 27 compared la ow dose tablet desmopressin to a high dose tablet desmopressin. Both trials considered children who had bedwetting. Skoog (1997) 27 excluded children who were previously non responsive (less than 50% reduction in the number of wet nights) to desmopressin for the study.

Table 13-12200 microgram tablet desmopressin compared to a 400 mirogram tablet desmopressin - Clinical summary of findings

Outcome200 microgram tablet desmopressin400 micrograms tablet desmopressinRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 14 consecutive dry nights3/77 (3.9%)10/81 (12.3%)RR 0.32 (0.09 to 1.12)84 fewer per 1000 (from 112 fewer to 15 more)LOW
Mean number of wet nights in last 2 weeks of treatment2828-MD 0.5 (−0.24 to 1.24)LOW

Table 13-13200 microgram tablet desmopressin compared to 600 microgram tablet desmopressin - Clinical summary of findings

Outcome200 microgram tablet desmopressin600 micrograms tablet desmopressinRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 14 consecutive dry nights3/77 (3.9%)5/82 (6.1%)RR 0.65 (0.16 to 2.62)21 fewer per 1000 (from 51 fewer to 99 more)LOW
Mean number of wet nights in last 2 weeks of treatment2828-MD 0.04 (−0.94 to 1.01)LOW

Table 13-14400 microgram tablet desmopressin compared to 600 microgram tablet desmopressin - Clinical summary of findings

Outcome400 microgram tablet desmopressin600 microgram tablet desmopressinRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 14 consecutive dry nights10/81 (12.3%)5/82 (6.1%)RR 2.02 (0.72 to 5.66)62 more per 1000 (from 17 fewer to 284 more)LOW
Mean number of wet nights in last 2 weeks of treatment2828-MD −0.45 (−1.42 to 0.53)LOW

13.2.1.9. Tablet desmopressin compared to melt desmopressin for children with bedwetting

One randomised control trial Lottmann (2007) 42 compared 200 or 2 × 200 microgram tablet desmopressin to 120 or 240 micro grams melt desmopressin. The trial considered children who had bedwetting. The study was an equivalence study.

Table 13-15Tablet desmopressin compared to melt desmopressin - Clinical summary of findings

OutcomeTablet desmopressinMelt desmopressinRelative risk (95% CI)Absolute effectQuality
Mean number of wet nights per week112112-MD −0.02 (−0.52 to 0.48)VERY LOW

13.2.1.10. Intranasal desmopressin compared to enuresis alarms for children with bedwetting

One randomised control trial Wille (1986) 114 compared 200 micro grams intranasal desmopressin to an enuresis alarms. Children who had only bedwetting were considered.

Table 13-16Intranasal desmopressin compared to enuresis alarm for children with bedwetting - Clinical summary of findings

OutcomeIntranasal desmopressinEnuresis alarmRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 5 wet nights in 28 nights17/24 (70.8%)19/22 (86.4%)RR 0.82 (0.6 to 1.11)156 fewer per 1000 (from 346 fewer to 95 more)VERY LOW
Mean number of wet nights per week at end of treatment2422-MD 1 (−0.11 to 2.11)VERY LOW
Number of children who dropped out by end of trial10/24 (41.7%)1/22 (4.5%)RR 9.17 (1.28 to 65.9)368 more per 1000 (from 13 more to 1000 more)VERY LOW

13.2.1.11. Tablet desmopressin compared to enuresis alarms for children with bedwetting

One randomised control trial Ng (2005) 113 compared 200 microgram tablet desmopressin to enuresis alarms. Children who only had bedwetting were considered.

Table 13-17blet desmopressin compared to enuresis alarm - Clinical summary of findings

OutcomeTablet desmopressinEnuresis alarmRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 14 consecutive dry nights16/38 (42.1%)8/35 (22.9%)RR 1.84 (0.9 to 3.76)192 more per 1000 (from 23 fewer to 632 more)LOW
Mean number of wet nights per week at end of treatment3628-MD −0.1 (−1.23 to 1.03)LOW
Number of children who relapsed at 3 months9/16 (56.3%)0/8 (0%)RR 10.06 (0.66 to 153.71)0 more per 1000 (from 0 fewer to 0 more)VERY LOW
Number of children who dropped out at end of trial2/38 (5.3%)7/35 (20%)RR 0.26 (0.06 to 1.18)148 fewer per 1000 (from 188 fewer to 36 more)LOW

13.2.1.12. Intranasal and tablet desmopressin compared to enuresis alarms for children with bedwetting

Two randomised control trials Ng (2005) 113 and Wille (1986) 114 compared desmopressin (intranasal desmopressin or tablet desmopressin) to an enuresis alarms. Both studies considered children who had only bedwetting. See GRADE table in Evidence review Alarms – Section 12.2.1

13.2.1.13. Tablet desmopressin compared to imipramine for children with bedwetting

One randomised control trial Lee (2005) 25 compared 200 microgram tablet desmopressin to 25 mg imipramine for children with bedwetting.

Table 13-18Tablet desmopressin compared to imipramine for children with bedwetting - Clinical summary of findings

OutcomeTablet desmopressinImipramineRelative risk (95% CI)Absolute effectQuality
Number of children who had 0–1 wet nights per month14/23 (60.9%)3/23 (13%)RR 4.67 (1.55 to 14.09)477 more per 1000 (from 71 more to 1000 more)LOW
Mean number of wet nights per week at end of treatment2323-MD −1.3 (−2.22 to − 0.38)VERY LOW

13.2.1.14. Tablet desmopressin compared to tablet desmopressin combined with enuresis alarms for children with bedwetting

One randomised control trial Ng (2005) 113 compared 200 micro grams tablet desmopressin to 200 micro grams tablet desmopressin with enuresis alarms.

Table 13-19Tablet desmopressin compared to tablet desmopressin and enuresis alarm for children with bedwetting - Clinical summary of findings

OutcomeTablet desmopressinTablet desmopressin and enuresis alarmRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 14 consecutive dry nights16/38 (42.1%)20/32 (62.5%)RR 0.67 (0.43 to 1.07)206 fewer per 1000 (from 356 fewer to 44 more)LOW
Mean number of wet nights per week at end of treatment3629-MD 1.4 (0.35 to 2.45)LOW
Number of children who relapsed at 3 months9/16 (56.3%)7/20 (35%)RR 1.61 (0.77 to 3.36)214 more per 1000 (from 81 fewer to 826 more)LOW
Number of children who dropped out by end of trial2/38 (5.3%)3/32 (9.4%)RR 0.56 (0.1 to 3.15)41 fewer per 1000 (from 85 fewer to 202 more)LOW

13.2.1.15. Tablet desmopressin compared to tablet desmopressin with oxybutynin for children with bedwetting

One randomised control trial Lee (2005) 25 compared 200 microgram tablet desmopressin to 100 to 200 microgram tablet desmopressin and 5 mg oxybutynin for children with bedwetting.

Table 13-20Tablet desmopressin compared to tablet desmopressin and oxybutynin for children with bedwetting - Clinical summary of findings

OutcomeTablet desmopressinTablet desmopressin and oxybutyninRelative risk (95% CI)Absolute effectQuality
Number of children who had 0–1 wet nights per month14/23 (60.9%)14/22 (63.6%)RR 0.96 (0.61 to 1.51)25 fewer per 1000 (from 248 fewer to 324 more)VERY LOW
Mean number of wet nights per week at end of treatment2322-MD −0.23 (−0.91 to 0.45)VERY LOW

13.2.1.16. Intranasal desmopressin compared to placebo for children with monosymptomatic nocturnal enuresis

Two randomised control trials, Longstaffe (2000) 115 and Rushton (1995) 125, compared intranasal desmopressin placebo for children with monosymptomatic nocturnal enuresis.

Table 13-2120 micro grams intranasal desmopressin compared to a placebo for children with monosymptomatic nocturnal enuresis - Clinical summary of findings

Outcome20 micro grams intranasal desmopressinPlaceboRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 14 consecutive dry nights39/109 (35.8%)24/108 (22.2%)RR 2.83 (0.35 to 22.68)406 more per 1000 (from 144 fewer to 1000 more)VERY LOW
Mean number of wet nights in last 2 weeks of treatment4947-MD −1.88 (−3.51 to − 0.25)VERY LOW
Number of children who dropped out by end of trial5/60 (8.3%)4/61 (6.6%)RR 1.27 (0.36 to 4.51)18 more per 1000 (from 42 fewer to 232 more)LOW

Table 13-2240 micro grams intranasal desmopressin compared to placebo for children with monosymptomatic nocturnal enuresis - Clinical summary of findings

Outcome40 micro grams intranasal desmopressinPlaceboRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 14 consecutive dry nights10/49 (20.4%)1/47 (2.1%)RR 9.59 (1.28 to 72.04)180 more per 1000 (from 6 more to 1000 more)LOW
Mean number of wet nights per week at end of treatment4947-MD −2.25 (−4 to −0.5)VERY LOW

13.2.1.17. Tablet desmopressin compared to placebo for children with monosymptomatic nocturnal enuresis

One randomised control trial, Yap (1998) 126 compared a tablet desmopressin to a placebo.

Table 13-23400 microgram tablet desmopressin compared to placebo for children with monosymptomatic nocturnal enuresis - Clinical summary of findings

Outcome400 microgram tablet desmopressinPlaceboRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 14 consecutive dry nights23/34 (67.6%)7/34 (20.6%)RR 3.29 (1.63 to 6.62)472 more per 1000 (from 130 more to 1000 more)MODERATE
Mean number of wet nights per 2 weeks at end of treatment3434-MD −2 (−3.15 to − 0.85)LOW

13.2.1.18. Intranasal desmopressin compared to enuresis alarms for children with monosymptomatic nocturnal enuresis

One randomised control trial Longstaffe (2000) 115 compared 200 micro grams intranasal desmopressin to an enuresis alarms.

Table 13-24Intranasal desmopressin compared to enuresis alarm for children with monosymptomatic nocturnal enuresis - Clinical summary of findings

OutcomeIntranasal desmopressinEnuresis alarmRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 14 consecutive dry nights29/60 (48.3%)35/61 (57.4%)RR 0.84 (0.6 to 1.18)92 fewer per 1000 (from 230 fewer to 103 more)LOW
Number of children who dropped out by end of trial5/60 (8.3%)8/61 (13.1%)RR 0.64 (0.22 to 1.83)47 fewer per 1000 (from 102 fewer to 109 more)LOW

13.2.1.19. Desmopressin compared to enuresis alarms for children with bedwetting

One randomised control trial Tuygun (2007) 116 compared desmopressin (20 to 40 micro grams intranasal desmopressin or 200 to 300 microgram tablet desmopressin) to enuresis alarms.

Table 13-25Desmopressin compared to enuresis alarm - Clinical summary of findings

OutcomeDesmopressinEnuresis alarmRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 14 consecutive dry nights25/49 (51%)20/35 (57.1%)RR 0.89 (0.6 to 1.33)63 fewer per 1000 (from 228 fewer to 188 more)LOW
50–90% reduction in the number of wet nights at end of treatment15/49 (30.6%)9/35 (25.7%)RR 1.19 (0.59 to 2.41)49 more per 1000 (from 105 fewer to 362 more)LOW
Mean number of wet nights per month at end of treatment4919-MD 7.29 (2.67 to 11.91)LOW
Number of children who relapsed at 6 months27/49 (55.1%)10/35 (28.6%)RR 1.93 (1.08 to 3.45)266 more per 1000 (from 23 more to 701 more)LOW

13.2.1.20. Intranasal and tablet desmopressin compared to enuresis alarms for children with monosymptomatic children

Two randomised control trials Longstaffe (2000) 115 and Tuygun (2007) 116 compared desmopressin (intranasal desmopressin or tablet desmopressin) to enuresis alarms.

Table 13-26All desmopressin compared to an enuresis alarm for children with monosymptomatic nocturnal enuresis - Clinical summary of findings

OutcomeDesmopressinEnuresis alarmRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 14 consecutive dry nights54/109 (49.5%)49/96 (51%)RR 0.96 (0.73 to 1.25)20 fewer per 1000 (from 138 fewer to 128 more)LOW
50–90% reduction in the number of wet nights at end of treatment15/49 (30.6%)9/35 (25.7%)RR 1.19 (0.59 to 2.41)49 more per 1000 (from 105 fewer to 362 more)LOW
Mean number of wet nights per month at end of treatment4919-MD 7.29 (2.67 to 11.91)LOW
Number of children who relapsed at 6 months27/49 (55.1%)10/35 (28.6%)RR 1.93 (1.08 to 3.45)266 more per 1000 (from 23 more to 701 more)LOW
Number of children who dropped out5/60 (8.3%)8/61 (13.1%)RR 0.64 (0.22 to 1.83)47 fewer per 1000 (from 102 fewer to 109 more)LOW

13.2.1.21. Intranasal desmopressin compared to placebo for young children

One randomised controlled trial Birkasova (1978) 127, compared intranasal desmopressin to placebo for young children.

Table 13-2710 micro grams intranasal desmopressin compared to placebo - Clinical summary of findings

Outcome10 micro grams intranasal desmopressinPlaceboRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 14 consecutive dry nights0/22 (0%)0/22 (0%)not poolednot pooledLOW
Mean number of wet nights per 2 weeks at end of treatment2222-MD −6.8 (−9.43 to − 4.17)LOW

Table 13-2840 micro grams intranasal desmopressin compared to placebo for young children - Clinical summary of findings

Outcome40 micro grams intranasal desmopressinPlaceboRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 14 consecutive dry nights5/22 (22.7%)0/22 (0%)RR 11 (0.64 to 187.67)0 more per 1000 (from 0 fewer to 0 more)VERY LOW
Mean number of wet nights in the last 2 weeks of treatment2222-MD −6.8 (−9.43 to − 4.17)LOW

13.2.1.22. Low dose intranasal desmopressin compared to high dose intranasal desmopressin for young children

One randomised control trial Birkasova (1978) 127 compared low dose intranasal desmopressin to high dose intranasal desmopressin for young children.

Table 13-2910 micro grams intranasal desmopressin compared to 40 micro grams intranasal desmopressin - Clinical summary of findings

Outcome10 micro grams intranasal desmopressin40 micro grams intranasal desmopressinRelative risk (95% CI)Absolute effectQuality
Number of children who achieved 14 consecutive dry nights0/22 (0%)5/22 (22.7%)RR 0.09 (0.01 to 1.55)207 fewer per 1000 (from 225 fewer to 125 more)VERY LOW

13.2.1.23. Side effects of desmopressin compared to placebo for children with bedwetting

Two randomised controlled trials, Schulman (2001) 26 and Skoog (1997) 27, compared desmopressin to a placebo.

Table 13-30Side effects of tablet desmopressin compared to placebo - Clinical summary of findings

OutcomeDesmopressinPlaceboRelative risk (95% CI)Absolute effectQuality
Number of children with vomiting causing withdrawal2/109 (1.8%)0/38 (0%)RR 1.77 (0.09 to 36.12)0 more per 1000 (from 0 fewer to 0 more)LOW
Number of children with rrhinitis, pharyngitis, infection, headache or fever43/143 (30.1%)13/48 (27.1%)RR 1.11 (0.66 to 1.88)30 more per 1000 (from 92 fewer to 238 more)LOW
Number of children who only required 400 microgram desmopressin3/99 (3%)0/38 (0%)RR 9.75 (0.59 to 160.72)0 more per 1000 (from 0 fewer to 0 more)LOW

13.2.1.24. Desmopressin compared toa placebo for children with monosymptomatic nocturnal enuresis

One randomised controlled trial, Lottmann (2007) 42, considered the side effects of using melt compared to tablet desmopressin for children with monosymptomatic nocturnal enuresis.

Table 13-31Side effects of tablet desmopressin compared to melt desmopressin - Clinical summary of findings

OutcomeMelt desmopressinTablet desmopressinRelative risk (95% CI)Absolute effectQuality
Number of children with headaches6/109 (5.5%)0/109 (0%)RR 13 (0.74 to 227.97)0 more per 1000 (from 0 fewer to 0 more)VERY LOW
Number of children with diarrhoea3/109 (2.8%)0/109 (0%)RR 7 (0.37 to 133.93)0 more per 1000 (from 0 fewer to 0 more)VERY LOW
Number of children with viral gastroenteritis3/109 (2.8%)0/109 (0%)RR 7 (0.37 to 133.93)0 more per 1000 (from 0 fewer to 0 more)VERY LOW

13.2.2. Network Meta-Analysis

Desmopressin was amongst the interventions included in a network meta-analyses of interventions used for nocturnal enuresis. The summary of results of this analysis is presented in chapter 24 and a detailed description of the analysis is presented in appendix F. If studies did not meet the inclusion criteria of the network meta-analysis protocol as stated in appendix F they were not included in the network meta-analysis

13.2.3. Health economic evidence review

Given the lack of published evidence assessing the cost-effectiveness of different interventions, including desmopressin, used in the treatment of bedwetting, the GDG identified this area as high priority for original economic analysis. Therefore, a cost-utility analysis was undertaken where costs and quality-adjusted life-years (QALYs) were considered from a UK National Health Service and Personal Social Services perspective. The time horizon for the analysis was 13 years, modelling patients from the time they entered at age 7 years until they reached age 20.

A summary of the analysis is provided below. The full report is presented in appendix G.

Summary of results

The results of the probabilistic sensitivity analysis are summarised in table 13-32 in terms of mean total costs and mean total QALYs and mean net benefit for each treatment sequence, where each mean is the average of 20,000 simulated estimates. The option with the greatest mean net benefit is the most cost-effective at a specified threshold (for example, £20,000). The percentage of simulations where each strategy was the most cost-effective gives an indication of the strength of evidence in favour of that strategy being cost-effective.

Table 13-32. Basecase probabilistic sensitivity analysis results.

Table 13-32

Basecase probabilistic sensitivity analysis results.

The results of the incremental analysis in the probabilistic analysis, excluding dominated and extendedly dominated strategies, are presented in table 13-33.

Table 13-33. Incremental analysis of basecase probabilistic results with dominated and extendedly dominated sequences removed.

Table 13-33

Incremental analysis of basecase probabilistic results with dominated and extendedly dominated sequences removed.

The GDG considered that the differences between intervention sequences were relatively small and the probabilistic results indicated substantial uncertainty around the mean cost and benefit estimates. Small changes to the model inputs appears to result in substantial changes to the conclusions about modelled sequences’ relative and overall cost-effectiveness.

The GDG was concerned that alarms, despite their cost-effectiveness, may not be an appropriate intervention for all children. For this group of children, a strategy of starting and maintaining desmopressin with or without the addition of an anticholinergic until sustained dryness is achieved is considered cost-effective.

A series of sensitivity analyses were undertaken to test some of the assumptions feeding into the model and none of these affected the cost-effectiveness of the sequence alarm followed by combined alarm and desmopressin and then desmopressin alone compared to no treatment. However, there was some substantial variation in the relative cost-effectiveness of sequences commencing with initial desmopressin.

If the assumption is made that bedwetting is bedwetting and dry is dry, then a partial response to ongoing treatment is no better than no response and a full response to ongoing treatment is the same as a sustained response off treatment. In this scenario, a treatment sequence of desmopressin followed by alarm and then by desmopressin or combined desmopressin and anticholinergic is very likely to be cost-effective. Without real data to inform the utilities of these different health states, it is difficult to know whether this scenario or the basecase scenario is a better reflection of reality.

The basecase analysis included the potential quality of life gain for parents and carers if their child were to achieve temporary or sustained dryness. In a sensitivity analysis, these health benefits were excluded to assess the cost-effectiveness of intervention sequences if there was no health gain accrued to parents and carers. In this scenario, no strategies starting with desmopressin were cost-effective.

In the basecase, treatment only commenced for hypothetical patients at the age of 7 years. In actuality, some children may seek treatment starting at the age of 5 years. When the model is rerun from the age of 5 years, the same treatment sequences as in the base case are included in the incremental analysis. However the ICERs for all strategies except for alarm followed by combined alarm and desmopressin and then desmopressin alone are greater than £20,000 per QALY gained and therefore unlikely to be cost-effective. Treatment sequences starting at age 5 with initial desmopressin are only cost-effective if alarm-based strategies are unsuitable and therefore removed from the list of comparators.

In the basecase it was assumed that 100% of children who experienced a recurrence of bedwetting within 1 week of discontinuing treatment following a full response would resume treatment, either with the same intervention that had worked before or with the next intervention in the sequence. In a sensitivity analysis, this assumption was relaxed to 50% and 75% and results showed that sequences commencing with desmopressin were not cost-effective.

The economic analysis conducted and presented here represents the first undertaken to assess the cost-effectiveness of interventions used in the treatment of children with bedwetting. And although the analysis is directly applicable to decision making in the UK NHS, it has some potentially serious limitations, some of which may significantly impact the overall conclusions that can be drawn. The main limitations of the analysis are related to the fact that assumptions had to be made in the absence of evidence. Some of these key assumptions centre around:

  • treatment effectiveness being independent of age
  • health care resource use having been estimated by GDG
  • utility weights having been estimated by GDG

A full discussion of these can be found in appendix G.

13.2.4. Evidence statements

The evidence statements are presented according to th e population in each study and the method of administration of desmopressin.

Studies included children with bedwetting and possible daytime symptoms

Intranasal desmopressin
Muller (2001) 120, Uygur (1997) 121
  • Two studies showed that children treated with 20 micro grams intranasal desmopressin had 1.63 to 8.6 fewer wet nights in the last 2 weeks of treatment compared to those who were treated with placebo. Children had a mean age of 8.6 to 8.7 in Muller (2001) and an age range of 7 to 17 in Uygur (1997); treatment length was 2 weeks to 6 months. No information on variability was given in the study, therefore calculation of standard deviation was not possible and the mean difference and CI were not estimable.
Burke (1995) 122
  • One study showed there was no statistically significant difference in the number of children who achieved 14 consecutive dry nights between the children treated with intranasal desmopressin and those treated with amitriptyline. Relative risk 0.27, 95% CI 0.03, 2.36. Children had an age range of 8.6 to 8.9 years and treatment was for 16 weeks.
  • Patients treated with amitriptyline had fewer wet nights per week at the end of treatment then those treated with intranasal desmopressin. Mean difference 1.4, 95% CI 0.12, 2.68. Children had an age range of 8.6 to 8.9 years and treatment was for 16 weeks.
  • One study showed there was no statistically significant difference in the number of wet nights per week at follow up between children treated with intranasal desmopressin and those treated with amitriptyline. Mean difference −0.1, 95% CI −1.87, 1.67. Children had an age range of 8.6 to 8.9 years and treatment was for 16 weeks.
  • One study showed there was no statistically significant difference in the number of children who dropped out of the trial between the children treated with intranasal desmopressin and those treated with amitriptyline. Relative risk 5.83, 95% CI 0.33, 104.22. Children had an age range of 8.6 to 8.9 years and treatment was for 16 weeks.
  • One study showed there was no statistically significant difference in the number of children who achieved 14 consecutive dry nights between the children treated with intranasal desmopressin and those treated with intranasal desmopressin and amitriptyline. Relative risk 0.16, 95% CI 0.02, 1.25. Children had an age range of 8.6 to 8.9 years and treatment was for 16 weeks.
  • One study showed there was no statistically significant difference in the number of wet nights per week at the end of treatment between children treated with intranasal desmopressin and those treated with intranasal desmopressin and amitriptyline. Mean difference 1.4, 95% CI −0.14, 2.94. Children had an age range of 8.6 to 8.9 years and treatment was for 16 weeks.
  • One study showed there was no statistically significant difference in the number of wet nights per week at follow up between children treated with intranasal desmopressin and those treated with intranasal desmopressin and amitriptyline. Mean difference −1.3, 95% CI −3.2, 0.6. Children had an age range of 8.6 to 8.9 years and treatment was for 16 weeks.
  • One study showed there was no statistically significant difference in the number of children who dropped out of the trial between the children treated with intranasal desmopressin and those treated with intranasal desmopressin and amitriptyline. Relative risk 0.82, 95% CI 0.2, 3.46. Children had an age range of 8.6 to 8.9 years and treatment was for 16 weeks.
Vertucci (1997) 123
  • One study showed there was no statistically significant difference in the number of children who achieved 14 consecutive dry nights between the children treated with intranasal desmopressin and those treated with imipramine. Relative risk 1.27, 95% CI 0.95, 1.70. Children had an age range of 6 to 15 years and treatment was for 3 weeks.
  • One study showed children treated with intranasal desmopressin had 1.5 fewer wet nights per week at the end of treatment compared to children treated with imipramine. Children had an age range of 6 to 15 years and treatment was for 3 weeks. No information on variability was given in the study, therefore calculation of standard deviation was not possible and the mean difference and CI were not estimable
Tablet desmopressin
Lee (2005) 25
  • One study showed there was no statistically significant difference in the number of children who achieved 0 to 1 wet nights per month between the children treated with tablet desmopressin and those treated with imipramine. Relative risk 2.88, 95% CI 0.88, 9.44. Children had a mean age of 7.8 years and treatment was for 6 months.
  • One study showed children treated with tablet desmopressin had fewer wet nights per week at end of treatment compared to those treated with imipramine. Mean difference −1.4, 95% CI −2.25, −0.55. Children had a mean age of 7.8 years and treatment was for 6 months.
  • One study showed there was no statistically significant difference in the number of children who dropped out between the children treated with tablet desmopressin and those treated with imipramine. Relative risk 0.42, 95% CI 0.12, 1.53. Children had a mean age of 7.8 years and treatment was for 6 months.
  • One study showed children continue to have a decrease in the number of wet nights at 1 month, 3 months and 6 months in treatment with both desmopressin or imipramine treatment. Children had a mean age of 7.8 years and were treated for 6 months.
  • One study showed there was no difference in the number of children who achieved 0 to 1 wet nights per month between the children treated with tablet desmopressin and those treated with tablet desmopressin and oxybutynin. Relative risk 1, 95% CI 0.47, 2.11. Children had a mean age of 7.8 years and treatment was for 6 months.
  • One study showed there was no statistically significant difference in the number of wet nights per week at follow up between children treated with tablet desmopressin and those treated with tablet desmopressin and oxybutynin. Mean difference 0.03, 95% CI −0.66, 0.72. Children had a mean age of 7.8 years and treatment was for 6 months.
  • One study showed there was no statistically significant difference in the number of children who dropped out between the children treated with tablet desmopressin and those treated with tablet desmopressin and oxybutynin. Relative risk 0.98 95% CI 0.21, 4.62. Children had a mean age of 7.8 years and treatment was for 6 months.
  • One study showed children continue to have a decrease in the number of wet nights at 1 month, 3 months and 6 months in treatment with either desmopressin or desmopressin combined with oxybutynin treatment. Children had a mean age of 7.8 years and were treated for 6 months.

Studies include children with bedwetting only

Intranasal desmopressin
Wille (1986) 114
  • Two studies showed there was no statistically significant difference in the number of children who achieved 14 consecutive dry nights between the children treated with intranasal desmopressin and those treated enuresis alarms. Relative risk 0.82, 95% CI 0.6, 1.11. Children were aged over 6 years and treatment was for 3 months.
  • One study showed there was no statistically significant difference in the number of wet nights per week at the end of treatment between children treated with intranasal desmopressin and those treated with enuresis alarms. Mean difference 1, 95% CI −0.11, 2.11. Children were aged over 6 years and treatment length was 3 months.
  • One study showed that children treated with intranasal desmopressin had a faster response compared to children treated with an enuresis alarm. However after treatment children treated with an enuresis alarm had a continued higher response compared to children treated with desmopressin. Wille (1986) considered a response to be the number of dry nights. Children were aged over 6 years and treatment was for 3 months.
  • One study showed children treated with intranasal desmopressin were more likely to drop out of the trial compared to children treated with enuresis alarms. Relative risk 9.17, 95% CI 1.28, 65.9. Children were aged over 6 years and treatment was for 3 months.
Tablet desmopressin
Ferrara (2008) 124, Schulman (2001) 26, Skoog (1997) 27
  • Three studies showed children treated with 200 microgram tablet desmopressin were more likely to achieve 14 consecutive dry nights than those treated with placebo. Relative risk 10.96, 95% CI 1.6, 75.16. Children had a mean age of 8.5 to 11 years and treatment length was 2 weeks to 3 months.
Schulman (2001) 26, Skoog (1997) 27
  • Two studies showed children treated with 400 microgram tablet desmopressin were more likely to achieve 14 consecutive dry nights than those treated with placebo. Relative risk 11.42, 95% CI 1.5, 86.69. Children had an age range of 4 to 18 and treatment length was 2 to 6 weeks.
  • Two studies showed there was no statistically significant difference in the number of children who achieved 14 consecutive dry nights between the children treated with 600 microgram tablet desmopressin and those treated with placebo. Relative risk 6.19, 95% CI 0.76, 50.48. Children had a mean age of 9.1 to 11 and treatment length was 2 to 6 weeks.
Skoog (1997) 27
  • One study showed that children treated with 200 microgram tablet desmopressin had fewer wet nights per 2 weeks at the end of treatment compared to those who were treated with placebo. Mean difference −1, 95% CI −1.55, −0.45. Children had a mean age of 9.1 to 9.5 years and treatment length was 6 weeks.
  • One study showed that children treated with 400 microgram tablet desmopressin had fewer wet nights per 2 weeks at the end of treatment compared to those who were treated with placebo. Mean difference −1.5, 95% CI −2.12, −0.88. Children had a mean age 9.1 to 9.5 years and treatment length was 6 weeks.
  • One study showed that children treated with 600 microgram tablet desmopressin had fewer wet nights per 2 weeks at the end of treatment compared to those who were treated with placebo. Mean difference −1.5, 95% CI −2.05, −0.95. Children had a mean age of 9.1 to 9.5 years and treatment length was 6 weeks.
Ng (2005) 113
  • One study showed there was no statistically significant difference in the number of children who achieved 14 consecutive dry nights between the children treated with tablet desmopressin and those treated with enuresis alarms. Relative risk 1.84, 95% CI 0.9, 3.76. Children had a mean age of 9.5 years and treatment length was 3 months.
  • One study showed there was no statistically significant difference in the number of wet nights per week at the end of treatment between children treated with tablet desmopressin and those treated with enuresis alarms. Mean difference −0.1, 95% CI −1.23, 1.03. Children had a mean age of 9.5 years and treatment length was 3 months.
  • One study showed that children treated with an enuresis alarm had a faster response and continued response compared to children treated with tablet desmopressin. Ng (2005) considered a response to be a reduction in the number of wet nights. Children had a mean age of 9.5 years and treatment was for 3 months.
  • One study showed there was no statistically significant difference in the number of children who relapsed at 3 months between the children treated with tablet desmopressin and those treated with enuresis alarms. Relative risk 10.06 95% CI 0.66, 153.71. Children had a mean age of 9.5 years and treatment length was 3 months.
  • One study showed there was no statistically significant difference in the number of children who dropped out of the trial between the children treated with tablet desmopressin and those treated with enuresis alarms. Relative risk 0.26, 95% CI 0.06, 1.18. Children had a mean age of 9.5 years and treatment length was 3 months.
  • One study showed there was no statistically significant difference in the number of children who achieved 14 consecutive dry nights between the children treated with tablet desmopressin and those treated with tablet desmopressin and enuresis alarms. Relative risk 0.67, 95% CI 0.43, 1.07. Children had a mean age of 9.5 years and treatment was for 12 weeks.
  • Patients treated with tablet desmopressin and enuresis alarms had fewer wet nights per week at the end of treatment then those treated with tablet desmopressin. Mean difference 1.4, 95% CI 0.35, 2.45. Children had a mean age of 9.5 years and treatment was for 12 weeks.
  • One study showed that children treated with tablet desmopressin and enuresis alarm had a faster response and continued response compared to children treated with desmopressin. Ng (2005) considered a response to be a reduction in the number of wet nights. Children had a mean age of 9.5 years and treatment was for 3 months.
  • One study showed there was no statistically significant difference in the number of children who relapsed at 3 months between the children treated with tablet desmopressin and those treated with tablet desmopressin and enuresis alarms. Relative risk 1.61, 95% CI 0.77, 3.36. Children had a mean age of 9.5 years and treatment was for 12 weeks.
  • One study showed there was no statistically significant difference in the number of children who dropped out between the children treated with tablet desmopressin and those treated with tablet desmopressin and enuresis alarms. Relative risk 0.56, 95% CI 0.1, 3.15. Children had a mean age of 9.5 years and treatment was for 12 weeks.
Lee (2005) 25
  • One study showed more children treated with tablet desmopressin achieved 0 to 1 wet nights per month than children treated with imipramine. Relative risk 4.67, 95% CI 1.55, 14.09. Children had a mean age of 7.8 years and treatment was for 6 months.
  • Patients treated with tablet desmopressin had fewer wet nights per week at the end of treatment then those treated with imipramine. Mean difference −1.3, 95% CI −2.22, −0.38. Children had a mean age of 7.8 years and treatment was for 6 months.
  • One study showed there was no statistically significant difference in the number of children who achieved 0 to 1 wet nights a month between children treated with tablet desmopressin and those treated with tablet desmopressin and oxybutynin. Relative risk 0.96, 95% CI 0.61, 1.51. Children had a mean age of 7.8 years and treatment was for 6 months.
  • One study showed there was no statistically significant difference in the number of wet nights per week at the end of treatment between children treated with tablet desmopressin and those treated with tablet desmopressin and oxybutynin. Mean difference −0.23, 95% CI −0.91, 0.45. Children had a mean age of 7.8 years and treatment was for 6 months.
Low dose tablet desmopressin compared high dose tablet desmopressin
Schulman (2001) 26, Skoog (1997) 27
  • Two studies showed there was no statistically significant difference in the number of children who achieved 14 consecutive dry nights between the children treated with 200 microgram tablet desmopressin and those treated with 400 microgram tablet desmopressin. Relative risk 0.32, 95% CI 0.09, 1.12. Children had a mean age of 9.1 to 11 years and treatment length was 2 to 6 weeks.
  • Two studies showed there was no statistically significant difference in the number of wet in the last 2 weeks of treatment between children treated with 200 microgram tablet desmopressin and those treated with 400 microgram tablet desmopressin. Mean difference 0.5, 95% CI −0.24, 1.24. Children had a mean age of 9.1 to 11 years and treatment length was 2 to 6 weeks.
  • Two studies showed there was no statistically significant difference in the number of children who achieved 14 consecutive dry nights between the children treated with 200 microgram tablet desmopressin and those treated with 600 microgram tablet desmopressin. Relative risk 0.65, 95% CI 0.16, 2.62. Children had a mean age of 9.1 to 11 years and treatment length was 2 to 6 weeks.
  • Two studies showed there was no statistically significant difference in the number of wet in the last 2 weeks of treatment between children treated with 200 microgram tablet desmopressin and those treated with 600 microgram tablet desmopressin. Mean difference 0.04, 95% CI −0.94, 1.01. Children had a mean age of 9.1 to 11 years and treatment length was 2 to 6 weeks.
  • Two studies showed there was no statistically significant difference in the number of children who achieved 14 consecutive dry nights between the children treated with 400 microgram tablet desmopressin and those treated with 600 microgram tablet desmopressin. Relative risk 2.02, 95% CI 0.72, 5.66. Children had a mean age of 9.1 to 11 years and treatment length was 2 to 6 weeks.
  • Two studies showed there was no statistically significant difference in the number of wet in the last 2 weeks of treatment between children treated with 400 microgram tablet desmopressin and those treated with 600 microgram tablet desmopressin. Mean difference −0.45, 95% CI −1.42, 0.53. Children had a mean age of 9.1 to 11 years and treatment length was 2 to 6 weeks.
Tablet desmopressin compared to melt desmopressin
Lottmann (2007) 42

One study showed there was no statistically significant difference in the number of wet nights per week at the end of treatment between children treated with tablet desmopressin and those treated with melt desmopressin. Mean difference −0.02, 95% CI −0.52, 0.48. Children had a mean age of 9.6 years and treatment length was 3 weeks.

All types of desmopressin compared to enuresis alarms
Ng (2005) 113, Wille (1986) 114
  • Two studies showed there was no statistically significant difference in the number of children who achieved 14 consecutive dry nights between children treated with desmopressin and those treated with enuresis alarms. Relative risk 1.17, 95% CI 0.46, 2.99. Children were aged over 6 years and treatment was for 3 months.
  • Two studies showed there was no statistically significant difference in the mean number of wet nights per week at the end of treatment between children treated with desmopressin and those treated with enuresis alarms. Mean difference 0.46, 95% CI −0.62, 1.53. Children were aged over 6 years, Wille (1986) and had a mean age of 9.5 years, Ng (2005), and treatment was for 3 months.
  • One study, Wille (1986), showed that children treated with desmopressin had a faster response compared to children treated with an enuresis alarm. Wille (1986) considered a response to be the number of dry nights.
  • One study, Ng (2005), showed that children treated with an enuresis alarm had a faster response compared to children treated with desmopressin. Ng (2005) considered a response to be a reduction in the number of wet nights.
  • Two studies showed after treatment children treated with an enuresis alarm had a continued higher response compared to children treated with desmopressin. Ng (2005) considered a response to be a reduction in the number of wet nights and Wille (1986) considered a response to be the number of dry nights. Children were aged over 6 years and treatment was for 3 months. Ng (2005) considered 200 microgram tablet desmopressin and Wille (1986) considered 200 micro grams intranasal desmopressin.
  • Two studies showed there was no statistically significant difference in the number of children who dropped out of the trial between children treated with desmopressin and those treated with enuresis alarms. Relative risk 1.47, 95% CI 0.04, 51.07. Children were aged over 6 years and treatment was for 3 months.
Ng (2005) 113
  • One study showed there was no statistically significant difference in the mean number of wet nights per week at the end of follow up between children treated with desmopressin and those treated with enuresis alarms. Mean difference 0.9, 95% CI −0.38, 2.18. Children had a mean age of 9.5 years and treatment was for 3 months.
  • One study showed there was no statistically significant difference in the number of children who dropped out between children treated with desmopressin and those treated with enuresis alarms. Relative risk 10.06, 95% CI 0.66, 153.71. Children had a mean age of 9.5 years and treatment was for 3 months.

Studies include children with monosymptomatic nocturnal enuresis

The quality of evidence for outcomes was low or very low except for outcome 14 dry nights for the comparison between 600 micrograms desmopressin and placebo where quality was moderate.

Intranasal desmopressin
Longstaffe (2000) 115
  • One study showed there was no statistically significant difference in the number of children who dropped out of the trial between the children treated with intranasal desmopressin and those treated with enuresis alarms. Relative risk 0.64, 95% CI 0.22, 1.83. Children were aged over 6 years and treatment length was 6 months.
Longstaffe (2000) 115
  • One study showed that giving children treatment for nocturnal enuresis (20 micro grams intranasal desmopressin or enuresis alarm) improved their psychological scores in both treatment groups. Children were aged over 7 years and the length of treatment was 6 months.
Longstaffe (2000) 115
  • One study showed that giving children treatment for nocturnal enuresis (20 micro grams intranasal desmopressin or placebo) improved their psychological scores in both treatment groups. Children were aged over 7 years and the length of treatment was 6 months.
  • One study showed there was no statistically significant difference in the number of children who dropped out of the trial between the children treated with 20 micro grams intranasal desmopressin and those treated with placebo. Relative risk 1.27, 95% CI 0.36, 4.51. Children were aged over 7 years and treatment length was 6 months.
  • One study showed there was no statistically significant difference in the number of children who achieved 14 consecutive dry nights between the children treated with intranasal desmopressin and those treated enuresis alarms. Relative risk 0.84, 95% CI 0.6, 1.18. Children were aged over 6 years and treatment length was 6 months.
Longstaffe (2000) 115, Rushton (1995) 125
  • Two studies showed there was no statistically significant difference in the number of children who achieved 14 consecutive dry nights between children treated with 20 micro grams and children treated with placebo. Relative risk 2.83, 95% CI 0.35, 22.68. Children in Longstaffe (2000) were aged over 7 years and treatment length was 6 months; children in Rushton (1995) had a mean age of 9.7 years and treatment length was 4 weeks
Rushton (1995) (Rushton et al. 749–53)
  • One study showed that children treated with 20 micro grams intranasal desmopressin had fewer wet nights in the last 2 weeks of treatment compared to those who were treated with placebo. Mean difference −1.88, 95% CI −3.51, −0.25. Children had a mean age of 9.7 years and treatment length was 4 weeks.
  • One study showed children treated with 40 micro grams intranasal desmopressin were more likely to achieve 14 consecutive dry nights than those treated with placebo. Relative risk 9.59, 95% CI 1.28, 72.04. Children had a mean age of 9.7 years and treatment length was 4 weeks.
  • One study showed that children treated with 40 micro grams intranasal desmopressin had fewer wet nights in the last 2 weeks of treatment compared to those who were treated with placebo. Mean difference −2.25, 95% CI −4, −0.5. Children had a mean age of 9.7 years and treatment length was 4 weeks.
Tablet desmopressin
Yap (1998) 126
  • One showed children treated with 400 micrograms tablet desmopressin were more likely to achieve 14 consecutive dry nights than those treated with placebo. Relative risk 3.29, 95% CI 1.63, 6.62. Children had an age range of 7 to 18 and treatment length was 5 weeks.
  • One showed that children treated with 400 micrograms tablet desmopressin had fewer wet nights per week at the end of treatment compared to those who were treated with placebo. Mean difference −2, 95% CI −3.15, −0.85. Children had an age range of 7 to 18 years and treatment length was 5 weeks.
Desmopressin (intranasal or tablet)
Tuygun (2007) 116
  • One study showed there was no statistically significant difference in the number of children who achieved a greater than 90% reduction in the number of wet nights between the children treated with desmopressin (intranasal or tablet) and those treated with an enuresis alarm. Relative risk 0.89, 95% CI 0.6, 1.33. Children had a median age of 8.6 to 8 years and treatment was for 3 months.
  • One study showed there was no statistically significant difference in the number of children who achieved a 50 to 90% reduction in the number of wet nights between the children treated with desmopressin (intranasal or tablet) and those treated with an enuresis alarm. Relative risk 1.19, 95% CI 0.59, 2.41. Children had a median age of 8.6 to 8 years and treatment was for 3 months.
  • One study showed children treated with an enuresis alarm had fewer wet nights in the month after treatment compared to those treated with desmopressin (intranasal or tablet). Mean difference 7.29, 95% CI 2.67, 11.91. Children had a median age of 8.6 to 8 years and treatment was for 3 months.
  • One study showed children treated with an enuresis alarm were less likely to relapse at 6 months compared to those treated with desmopressin (intranasal or tablet). Relative risk 1.93, 95% CI 1.08, 3.45. Children had a median age of 8.6 to 8 years and treatment was for 3 months.
All types of desmopressin compared to enuresis alarms
Longstaffe (2000) 115, Tuygun (2007) 116
  • Two studies showed there was no statistically significant difference in the number of children who achieved 14 consecutive dry nights between children treated with desmopressin and those treated with enuresis alarms. Relative risk 0.96, 95% CI 0.73, 1.25. Children were aged over 6 years and treatment was for 3 to 6 months.
Tuygun (2007) 116
  • One study showed there was no statistically significant difference in the number of children who achieved a 50 to 90% reduction in the number of wet nights between the children treated with desmopressin (intranasal or tablet) and those treated with an enuresis alarm. Relative risk 1.19, 95% CI 0.59, 2.41. Children had a median age of 8.6 to 8 years and treatment was for 3 months.
  • One study showed children treated with an enuresis alarm had fewer wet nights in the month after treatment compared to those treated with desmopressin (intranasal or tablet). Mean difference 7.29, 95% CI 2.67, 11.91. Children had a median age of 8.6 to 8 years and treatment was for 3 months.
  • One study showed children treated with an enuresis alarm were less likely to relapse at 6 months compared to those treated with desmopressin (intranasal or tablet). Relative risk 1.93, 95% CI 1.08, 3.45. Children had a median age of 8.6 to 8 years and treatment was for 3 months.
Longstaffe (2000) 115
  • One study showed there was no statistically significant difference in the number of children who dropped out of the trial between children treated with desmopressin and those treated with enuresis alarms. Relative risk 0.64, 95% CI 0.22, 1.83. Children were aged over 6 years and treatment was for 3 to 6 months.

Studies included younger children with bedwetting and possible daytime symptoms

Intranasal desmopressin
Birkasova (1978) 127
  • One study showed there was no difference in the number of children who achieved 14 consecutive dry nights between the children treated with 10 micrograms intranasal desmopressin and those treated with placebo. Both groups had 0 children achieving 14 consecutive dry nights. Children had a mean age of 6.6 and treatment length was 2 weeks.
  • One study showed that children treated with 10 micrograms intranasal desmopressin had fewer wet nights per fortnight at the end of treatment compared to those who were treated with placebo. Mean difference −6.8, 95% CI −9.43, −4.17. Children had a mean age of 6.6 years and treatment length was 2 weeks.
  • One study showed there was no statistically significant difference in the number of children who achieved 14 consecutive dry nights between the children treated with 40 micro grams intranasal desmopressin and those treated with placebo. Relative risk 11, 95% CI 0.64, 187.67. Children had a mean age of 6.6 and treatment length was 2 weeks.
  • One study showed that children treated with 40 micro grams intranasal desmopressin had fewer wet nights during the last 2 weeks of treatment compared to those who were treated with placebo. Mean difference −6.8, 95% CI −9.43, −4.17. Children had a mean age of 6.6 years and treatment length was 2 weeks.
Low dose intranasal desmopressin compared to high dose intranasal desmopressin
Birkasova (1978) 127
  • One study showed there was no statistically significant difference in the number of children who achieved 14 consecutive dry nights between the children treated with 10 micrograms intranasal desmopressin and those treated with 40 micrograms intranasal desmopressin. Relative risk 0.09, 95% CI 0.01, 1.55. Children had a mean age of 6.6 and treatment length was 2 weeks.

Side effects of desmopressin

Desmopressin compared to placebo for children with bedwetting
Schulman (2001) 26
  • One study showed there was no statistically significant difference in the number of children who had vomiting causing withdrawal between children treated with desmopressin and children treated with placebo. Relative risk 1.77, 95% CI 0.09, 36.12. Children had an age range of 5 to 14 years and treatment length was for 8 weeks.
Skoog (1997) 27
Desmopressin compared to melt desmopressin for children with monosymptomatic nocturnal enuresis
Lottmann (2007) 42

NCGC network meta-analysis (see appendix F)

For children with bedwetting and possible daytime symptoms
  • The NCGC NMA showed there was a statistically significant difference in the number of children who achieved a full response between children treated with combined desmopressin and amitriptyline and no treatment/placebo. Relative risk 9.481, 95% CI 6.444, 9.667. Children had an age range of 5 to 17 years and treatment for a minimum of 8 weeks.
  • The NCGC NMA showed there was a statistically significant difference in the number of children who achieved a full response between children treated with combined desmopressin and oxybutynin and no treatment/placebo. Relative risk 8.141, 95% CI 3.539, 9.53. Children had an age range of 5 to 17 years and treatment for a minimum of 8 weeks.
  • The NCGC NMA showed there was a statistically significant difference in the number of children who achieved a full response between children treated with desmopressin and no treatment/placebo. Relative risk 8.641, 95% CI 4.681, 9.569. Children had an age range of 5 to 17 years and treatment for a minimum of 8 weeks.
For children with bedwetting only
  • The NCGC NMA showed there was no statistically significant difference in the number of children who achieved a full response between children treated with nasal desmopressin and no treatment/placebo. Relative risk 2.785, 95% CI 0.387, 7.743. Children had an age range of 5 to 17 years and treatment for a minimum of 8 weeks.
  • The NCGC NMA showed there was a statistically significant difference in the number of children who achieved a full response between children treated with tablet desmopressin and no treatment/placebo. Relative risk 7.281, 95% CI 3.727, 9.109. Children had an age range of 5 to 17 years and treatment for a minimum of 8 weeks.
  • The NCGC NMA showed there was a statistically significant difference in the number of children who achieved a full response between children treated with combined tablet desmopressin and alarm and no treatment/placebo. Relative risk 8.519, 95% CI 3.567, 9.578. Children had an age range of 5 to 17 years and treatment for a minimum of 12 weeks.
  • The NCGC NMA showed there was a statistically significant difference in the number of children who achieved a full response between children treated with combined tablet desmopressin and oxybutynin and no treatment/placebo. Relative risk 7,640, 95% CI 2.012, 9.525. Children had an age range of 5 to 17 years and treatment for a minimum of 8 weeks.

For estimates of treatment effect relative to other active comparators, please see section 24.4 in chapter 24.

13.2.5. Health economic evidence statements

NCGC economic evaluation (see appendix G)

13.2.6. Evidence to recommendations

Relative values of different outcomes

The GDG considered the children, young people and parents or carers starting treatment for bedwetting were seeking an outcome of sustained dryness. A number of different outcomes were used to capture this: the outcome of 14 consecutive dry nights, reduction in wet nights and the mean number of wet nights allow evaluation of the effectiveness of treatment. Follow up rates, where available, can indicate sustained dryness.

Trade off between clinical benefit and harms

Side effect data was collected from RCTs or cohort studies. The consensus of the GDG was that desmopressin was safe as long as the child, young person and family and carers understood and could comply with the need for fluid restriction.

Economic consideration

Desmopressin was evaluated as part of original economic modelling undertaken for this guideline and was shown to be a potentially cost-effective first line treatment option. The analysis showed that there was considerable uncertainty about which intervention was the most cost-effective first line option, and this was likely caused by the uncertainty around estimates of treatment effectiveness observed in the pairwise and network meta-analyses. The GDG considered that given the substantial uncertainty between interventions, it would be reasonable to recommend first line treatment with an alarm as it was consistently shown to be among the less costly and still effective options. Treatment sequences that started with desmopressin were generally more costly than those starting with an alarm, and the incremental benefit was highly uncertain. Therefore, the GDG felt that desmopressin should be reserved as a first line intervention only for children and young people for whom alarms are not suitable. Desmopressin is likely to be the most cost-effective intervention compared to other treatments where short-term improvement is the goal. However, based on original modelling undertaken for this guideline, it is uncertain as to whether using desmopressin as a first line, long term treatment is cost-effective.

Quality of evidence (this includes clinical and economic)

The studies were of varying quality however the clinical evidence was supportive of using desmopressin as an effective treatment for children and young people with bedwetting. There were some well conducted trials with relatively small confidence intervals. In other studies, limitations were identified including; short treatment intervals, small sample size, (therefore under-powered to detect a difference between intervention groups with wide confidence intervals), and incomplete evidence (some studies did not give standard deviations and therefore mean difference and confidence intervals could not be calculated). One study was terminated earlier than planned due to amitriptyline and placebo ceasing to be available. There was no long term follow up data identified for the effectiveness of desmopressin. Six out of sixteen studies were industry funded and nine out of sixteen did not report funding sources.

Other considerations

The GDG used the direct clinical comparisons, the network meta-analysis and the health economic evidence to inform their recommendations.

On study indicated direct equivalence of tablet desmopressin and oral dispersible (melt) desmopressin. The GDG noted the study was designed to assess the impact of patient choice and not to evaluate differences in effectiveness of the two forms of desmopressin. One of the issues for the GDG members was that some of the evidence came from studies of intranasal desmopressin which is no longer recommended in this condition. The GDG, using indirect evidence from the evidence review and from their professional experience and knowledge, considered it appropriate to recommend desmopressin in general rather than to specify a route. When comparing tablet desmopressin to placebo the GDG noted that a lower dosage is effective in a significant number of children. In the absence of effect at a lower dosage there is good evidence that effectiveness is increased by increasing dosage. The evidence for escalating dose is discussed in chapter 13.

Overall comparison of desmopressin to alarm in a bedwetting only and in MNE group shows desmopressin has a faster response; however an alarm is associated with sustained success and lower likelihood of relapse. There is no significant difference between the two for achieving 14 dry nights or mean reduction in the number of wet nights at the end of treatment. The lower likelihood of relapse was considered by the GDG to support an alarm as first line treatment and the use of desmopressin if an alarm is not appropriate. The faster response to desmopressin makes it the choice of treatment if dryness is required to be of rapid onset.

Comparing tablet desmopressin to tablet desmopressin combined with an alarm, the evidence showed no difference in achieving 14 consecutive dry nights at the end of treatment. However, combining the two treatments reduces the mean number of wet nights at the end of treatment compared to each treatment in isolation and combination treatment had a faster and more sustained response compared to desmopressin alone.

The evidence did not support combination of antidepressants with tricyclic antidepressant drugs.

Dose and timing of desmopressin

The GDG included a recommendation about starting desmopressin at a lower dose as some children and young people will achieve a benefit on this. Desmopressin is taken before bedtime but from clinical experience and their knowledge of pharmacokinetics literature the GDG considered it useful to suggest children, youn people and parents and carers take desmopressin 1–2 hours earlier if there has been no response or a partial response. The importance of fluid restriction may need to be re-iterated in these circumstances.

Sustaining treatment for up to 6 months

The GDG considered that one well conducted RCT which compared tablet desmopressin with tablet desmopressin combined with oxybutynin did not show any difference after 6 months treatment but the number of children and young people responding to treatment in both groups continued to increase at 1 month, 3 months and 6 months after treatment.

Use of desmopressin in children between 5 and 7

The GDG were interested in evidence for the use of desmopressin in younger children. One study in a group of children mean age 6.6 years showed that a short course of desmopressin reduces the mean number of wet nights during treatment but does not make a difference with regards to achieving 14 consecutive dry nights. There was no follow-up data. The GDG considered that desmopressin could be used in children between 5 and 7 years, particularly if short term treatment was necessary.

Use of desmopressin in children and young people with bedwetting and daytime symptoms

The evidence review indicated that children and young people with bedwetting and daytime symptoms were likely to respond to desmopressin. The GDG considered from clinical experience that this group might not have as good a response to desmopressin as children with bedwetting alone.

Use of desmopressin in children and young people with sickle cell disease, behavoural, attentional and emotional disorders

Children and young people with sickle cell disease were included as a subgroup as bedwetting is common and the GDG reported that there can be reluctance to use desmopressin in this group because of possible effects of desmopressin. Children and young people with sickle cell disease can lose their concentrating ability of their kidneys resulting in high urine output. One study was identified which considered the side effects of desmopressin in children and young people with sickle cell disease. The study did not identify any side effects different to those seen in children and young people without sickle cell disease. The GDG discussed children and young people with sickle cell disease could be treated with desmopressin if they could comply with the fluid restriction requirements for administration of desmopressin.

There was no specific evidence regarding the use of desmopressin in children and young people with behavioural and attentional disorders and the GDG considered that the important consideration in assessment should be the child or young person’s ability to comply with fluid restrictions.

13.2.7. Recommendations

13.2.7.1.

Offer desmopressin to children and young people over 7 years, if:

  • rapid onset and/or short-term improvement in bedwetting is the priority of treatment or
  • an alarm is inappropriate or undesirable [1.10.1]
13.2.7.2.

Consider desmopressin for children between 5 and 7 years if treatment is required and:

  • rapid onset and/or short-term improvement in bedwetting is the priority of treatment or
  • an alarm is inappropriate or undesirable(see recommendation 1.8.1) [1.10.2]
13.2.7.3.

Do not exclude desmopressin as an option for the management of bedwetting in children and young people who also have daytime symptoms. However, do not use desmopressin in the treatment of children and young people who only have daytime wetting.[1.10.3]

13.2.7.4.

In children and young people who are not completely dry after 1 to 2 weeks on the initial dose of desmopressin (200 micrograms for Desmotabs and 120 micrograms for DesmoMelt), consider increasing the dose (to 400 micrograms of Desmotabs and 240 micrograms of Desmomelt).[1.10.4]

13.2.7.5.

Assess the response to desmopressin at 4 weeks and continue treatment for 3 months if there are signs of a response. Consider stopping if there are no signs of response. Signs of response include

  • smaller wet patches
  • fewer wetting episodes per night
  • fewer wet nights.[1.10.5]
13.2.7.6.

Do not exclude desmopressin as an option for the treatment of bedwetting in children and young people with sickle cell disease if an alarm is inappropriate or undesirable and they can comply with night time fluid restriction. Provide advice about withdrawal of desmopressin at times of sickle cell crisis.[1.10.6]

13.2.7.7.

Do not exclude desmopressin as an option for the treatment of bedwetting in children and young people with emotional, attention or behavioural problems or developmental and learning difficulties if an alarm is inappropriate or undesirable and they can comply with night time fluid restriction.[1.10.7]

13.2.7.8.

Consider advising that desmopressin should be taken 1–2 hours before bedtime in children and young people with bedwetting that have either partially responded or not responded to desmopressin taken at bedtime. Ensure that the child or young person can comply with fluid restriction from 1 hour before the drug is taken.[1.10.10]

13.2.7.9.

Consider continuing treatment with desmopressin for children and young people with bedwetting that has partially responded, as bedwetting may improve for up to 6 months after starting treatment.[1.10.11]

13.2.8. Supporting recommendations - Evidence to recommendations

Relative values of different outcomes

No evidence was identified

Trade off between clinical benefit and harms

No evidence was identified.

Economic considerations

No economic evidence was identified to inform these recommendations. The GDG considered that there was no evidence of need to monitor weight, serum electrolytes, blood pressure and urine osmolality in children with bedwetting being treated with desmopressin. A recommendation to discourage this activity is likely to represent a more cost-effective use of NHS resources.

Quality of evidence (this includes clinical and economic)

No evidence was identified.

Other considerations

The GDG discussed the lack of long term data for the effectiveness of desmopressin. From clinical and patient experience it was discussed that desmopressin may not lead to long term dryness without treatment and therefore this should be discussed with patients when being prescribed desmopressin in the treatment of bedwetting.

The GDG considered that there was no evidence of need to monitor weight, serum electrolytes, blood pressure and urine osmolality in children being treated with desmopressin. They considered that this idea may have arisen because of the other clinical conditions for which desmopressin may be used.

When used as initial treatment, desmopressin can be stopped or gradually withdrawn.

The GDG used their experience as health care professionals treating patients with bedwetting and as patient members to develop recommendations to cover the areas that they considered important when advising children and families.

13.2.9. Supporting recommendations

13.2.9.1.

Do not routinely measure weight, serum electrolytes, blood pressure and urine osmolality in children and young people being treated with desmopressin for bedwetting.[1.10.8]

13.2.9.2.

If offering desmopressin for bedwetting, inform the child and young person and their parents or carers:

  • that many children and young people, but not all, will experience a reduction in wetness
  • that many children and young people, but not all, will relapse when treatment is withdrawn
  • how desmopressin works
  • of the importance of fluid restriction from 1 hour before until 8 hours after taking desmopressin
  • that it should be taken at bedtime
  • if appropriate, how to increase the dose if there is an inadequate response to the starting dose
  • to continue treatment with desmopressin for 3 months
  • that repeated courses of desmopressin can be used.[1.10.9]
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Nocturnal Enuresis: The Management of Bedwetting in Children and Young People.
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