BJU International (2001), 88, 563571

REVIEW
Treatment of childhood nocturnal enuresis:
an examination of clinically relevant principles
R . B U T L E R and A . S T E N B E R G *
Department of Clinical Psychology, High Royds Hospital, West Yorkshire, UK, and *Uppsala University Children's Hospital,
Section of Urology, Uppsala, Sweden

reviews of studies, using unselected populations of

Introduction
children with NE, report success rates of 6570%, with
Nocturnal enuresis (NE) is a multifactorial condition with a treatment duration of 512 weeks and stated relapse
various aetiologies [1,2]. There are compelling argu- rates of 1530% in the 6 months after treatment
ments in favour of offering treatment for children who [1113]. Furthermore, there appears to be no difference
wet the bed beyond 7 years of age. NE is remarkably between types of enuresis alarm (bed or body-worn) in
prevalent in childhood, with 913% of 9-year-olds and terms of success rates [14].
12% of adolescents and young adults still affected by Controlled studies report that desmopressin is effective
the problem [3]. Children may become socially isolated, in the immediate cessation of wetting [1518], whether
emotionally distressed and have a low self-esteem as administered nasally or orally [19]. Moffatt et al. [20]
a result of enuresis [46]. An improvement in psycho- comprehensively reviewed many published papers on
logical functioning, including self-esteem, has been randomized clinical trials of desmopressin and found,
reported after successful treatment [6,7]. Although compared with placebo, that desmopressin was signi-
most parents are supportive, there is a signicant cantly better in 13 of the 14 studies. With a more selected
number, reportedly up to 30%, who become intoler- population of children with primary NE, Caione et al.
ant towards the NE and their child [8,9]. Finally, the [21] found a 79% success rate after the administra-
cost of enuresis can have a marked effect on the family tion of desmopressin. Devitt et al. [22] showed that the
economy and therefore treatment of this condition response to desmopressin was closely related to the level
cannot be ignored [10]. and variability of AVP. The treatment was successful
in children who had suboptimal levels of AVP and
Understanding of nocturnal enuresis unsuccessful in children with either normal or very low
levels of AVP.
The `three-systems' model, comprising three causes of
Oxybutynin, when used with no bladder training
NE (low arginine vasopressin, AVP, bladder instability
exercises and in unselected populations of children with
and lack of arousal from sleep) has been proposed to offer
NE, has not been effective in randomized controlled
a better understanding of NE and enhance the possibility
studies [23]. However, recent work suggests that
of selecting the most effective treatment for the child or
oxybutynin is effective in reducing unstable bladder
young person [2]. Current treatment modalities gener-
contractions and increasing the urine volume at rst
ated from the three-systems model suggest using desmo-
desire to void [24]. In more selected groups of children
pressin to supplement a lack of AVP release, bladder
with bladder instability as a cause of their NE, Watanabe
training exercises coupled with oxybutynin for bladder
et al. [25] claimed a 67% success rate with oxybutynin;
instability, and the enuresis alarm to encourage the child
Kass et al. [26] reported a 90% success rate and in a study
to wake in response to full bladder sensations. The
of dose escalation, Kosar et al. [24] reported complete
following variables are important when considering the
success after administering 1520 mg oxybutynin in a
most appropriate treatment for any given child.
selected group of 17 children.
Comparisons between pharmacological intervention
Selecting effective treatment interventions
and alarm treatment have been difcult because of dif-
Alarm therapy is proclaimed to be amongst the most ferent philosophical goals [27]. Behavioural interven-
effective interventions for treating childhood NE. Several tions, e.g. alarm treatment, have typically sought to
encourage the cessation of wetting, with the criteria
Accepted for publication 13 June 2001 for success based on consecutive dry nights [28],

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564 R. BUTLER and A. STENBERG

whereas pharmacological treatment has emphasized combined group receiving a more `enhanced' treatment
managing the enuresis and aims to reduce the frequency package than the alarm monotherapy group.
of wetting [1]. Leebeek-Groenewegen et al. [32], in a double-blind
placebo-controlled study, examined 93 children with
monosymptomatic NE. Children were allocated to treat-
Linking treatment to the child's needs
ment with alarm plus desmopressin 40 mg (A+D) or
Some have argued that the type of treatment inter- alarm plus placebo (A+P) for 9 weeks. During the
vention advocated should be based on the cause of the treatment period the desmopressin dose was titrated
child's NE [2]. An appropriate assessment will highlight three times (40, 20 and 0 mg). There were signicant
which of the three systems is affected; thus desmopressin differences between the groups only at 3 weeks, which
is a logical treatment for low AVP release, oxybutynin suggests that the effect was largely the result of desmo-
plus bladder training for bladder instability and the pressin rather than the combination. The response rate
enuresis alarm when the child indicates the potential over 9 weeks suggested that two separate treatment
to wake from sleep [2]. effects could account for the results. In the A+D group
Where children appear to have difculty in more than the immediate reduction in the number of wet nights,
one of the systems, combined therapy (using more than which reached a plateau, is a typical treatment response
one treatment intervention) might reasonably be con- with desmopressin, whereas with A+P the prole showed
sidered. Butler reviewed the methodological issues a gradual reduction in the number of wet nights through
associated with combined treatment [29]. The most to week 9, a response suggestive of alarm treatment.
common combined cause of NE is lack of AVP plus a lack Although the study used unusual success criteria (cure
of arousability. dened as o90% reduction and success as o50%
Three studies reported on combined desmopressin and reduction) the authors concluded that desmopressin
the enuresis alarm on unselected groups of children. does not result in higher cure rates and that combined
Sukhai et al. [30], with a crossover design, randomized treatment is not justied in all enuretic children from
children into two treatment groups, i.e. alarm plus the outset of treatment.
desmopressin (A+D) or alarm with placebo (A+P). The These studies suggest that the success with combined
results suggested that A+D was better (P=0.05) than alarm plus desmopressin is caused by the desmopressin
A+P in treating NE. However, the sample population intervention and not the combination. It might be argued
was both small (28 children) and not homogeneous that when a child is responsive to desmopressin the alarm
(29% of the children having learning difculties). becomes redundant, as it will not be triggered. Using
However, the most problematic methodological issue combined treatment without rst assessing the cause
was the treatment duration. Children were only treated in terms of the three systems [2] may be considered
for 2 weeks before crossover, which is sufcient time to inadvisable, and potentially overloads both child and
assess the effect of desmopressin but clearly insufcient to parents with unnecessary treatment interventions.
test the effectiveness of the alarm, as 512 weeks has A more appropriate combination theoretically might
been suggested as the mean treatment duration with an include anticholinergic medication plus desmopressin,
enuresis alarm [11,12]. Thus treatment success in the where bladder instability and a lack of AVP are indicated
A+D group was arguably caused by a response to [33]. Two studies report the effectiveness of such a com-
desmopressin, whereas insufcient duration of treatment bination [34,35]. An Italian multicentre trial reported
in the A+P group must have contributed to the failure signicantly more success with oxybutynin plus desmo-
rate in this group. pressin (79%) than with oxybutynin monotherapy (54%),
Bradbury [31] randomly allocated 71 children to where children had NE with daytime urgency and
either the alarm plus desmopressin (40 mg) or alarm mono- frequency [35]. The study concluded that the reduced
therapy for 6 weeks; the combined therapy was more urinary output and bladder lling, as a consequence
effective than the alarm alone, particularly where the of desmopressin, decreased the onset of uninhibited
child had severe NE and behavioural problems. How- bladder contractions and thus enhanced the effect of
ever, the samples were not homogenous for severity, as oxybutynin.
before allocation 20% were dry more than four times
per week, which raises questions about treatment eligi-
Understanding the treatment rationale
bility. Furthermore, no information was provided on the
rates of primary/secondary, non-mono or monosympto- The perceived mode of action of desmopressin is in
matic NE, diurnal enuresis, previous alarm therapy mimicking AVP through reducing urine production
or parental intolerance. The absence of a placebo sug- and increasing urine concentration, and as such desmo-
gests a lack of methodological equivalence, with the pressin has been construed as a replacement or

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supplementation. Hansen and Jorgensen [36] conrmed reports and found excess uid intake contributed to six
this by nding reduced night-time urine production cases. They suggested that to prevent hyponatraemia,
during desmopressin treatment. However, some work children should be encouraged not to drink >240 mL
suggests that desmopressin has an additional effect, i.e. on any night that desmopressin is taken.
in increasing arousability. Lackgren et al. [37] found A primary concern with alarm therapy is parental
that >70% of individuals treated with desmopressin intolerance [8,39]. Several parents become angry,
became dry by waking from sleep to void. This raised the annoyed and intolerant of bedwetting, particularly
question as to whether, by reducing urine volume, with an older child and where the family are functioning
desmopressin shifts the point at which the bladder under stress. Parents often seek to blame their child,
becomes full to the early morning, when arousal from believing the bedwetting is somehow under their con-
sleep is easier for the child [38]. trol, and resort to punitive means of coping. Up to a third
Interestingly, the mode of action of the alarm is of parents resort to punitive measures in seeking to cope
ill understood, but several explanations have been with the problem [8,9,52].
suggested: There is ample evidence indicating a close association
between parental (usually maternal) intolerance and
discontinuation or early withdrawal from alarm treat-
' An increased expectation of success [39]. ment [5355]. Enuresis alarms are time-consuming
' Alteration of social reinforcement to a point close to and complicated to set up, notoriously temperamental,
the wetting [40]. tend to disrupt the sleep of everyone in the household
' `Avoidance conditioning', whereby the child seeks to and often take weeks of use before there are positive signs
avoid the unpleasantness of the noise by spontaneous of progress. Alarms therefore potentially increase paren-
waking or by contraction of the pelvic oor muscles tal annoyance and may place the child at greater
[41]. physical and emotional risk [39].
' Increased functional bladder capacity [42].
' Increased production of AVP in response to the stress
Considering pretreatment predictors of outcome
of waking to the alarm, which might explain why
< 80% of children who become dry with the enuresis An understanding of the variables under which a
alarm are able to sleep through the night [43]. treatment is likely to succeed or fail is an important
clinical tool; it improves the choice over available
' A conditioned response whereby waking after urina-
treatment options and enhances the likelihood of suc-
tion serves as an unconditioned stimulus, whilst the
cess [56]. Moffatt and Cheang [57] also argue that
`startle response' of pelvic oor contractions which
research design should incorporate known prognostic
stops urination is the unconditioned response. indicators to ensure comparison groups are matched
With repeated triggering, it is argued, the alarm against variables known to enhance success or increase
produces a conditioned response of inhibition of failure rates across treatment interventions.
urination in the presence of detrusor contractions Pre-treatment predictors of success for desmopressin
during sleep [44]. include:

' The older child [5862].

Acceptability of treatment
' Less severe NE in terms of number of wet nights/week
With oxybutynin the reported side-effects include dry [58,63,64].
mouth, constipation and, in some individuals, ushing ' Normal functional bladder capacity [61,62,6567].
[24]. With desmopressin there are very few side-effects ' Primary as opposed to secondary NE [20].
reported [18,45,46]. Klauber [47] reported no serious ' When enuretic incidents occur during the rst 2 h
adverse reactions in 516 cases. In an exhaustive review
of sleep which may reect an increase in urine
of randomized clinical trials of desmopressin, Moffatt et al.
production due to lack of vasopressin release [66].
[20] found that eight of the 18 studies reported no side-
' Where there is a family history of NE [35,68]. Hogg
effects. Headaches were reported in four children (of a
total of 689) and stomach ache in three. Even during [68] dened a family history broadly, as any family
long-term treatment with desmopressin, side-effects are member (including aunts, uncles and cousins) who
rarely reported [19,48,49]. However, there are rare had persistent enuresis beyond the age of 6 years, and
reported cases of hyponatraemia with desmopressin found a positive family history in all desmopressin
treatment [50]. Robson et al. [51] reviewed 11 case responders, with only 43% of those not responding

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566 R. BUTLER and A. STENBERG

having a positive family history. However, Hogg and ' There is previous lack of success with the enuresis
Husmann [69] found a more striking discrepancy, alarm [82].
with a 91% response to desmopressin in patients with ' If the child voids early in the night when it is more
a family history and only a 7% response in those with difcult to arouse from sleep [38].
no family history. However, other studies have failed ' When maternal education is poor [57].
to nd such a relationship [62,65,7072]. ' With higher socio-economic status [57].
' Increased urine volume at night [73,74]. Rittig et al.
[73] found patients who responded to desmopressin To date, there are no reported pretreatment predictors
were able to reduce urine volume at night to the same with bladder training and anticholinergic medication.
as that of other children.
' Increased urine production during the day [66].
' Less concentrated urine during the day [66]. Offering treatment choice
' Frequent daytime micturition [62]. The importance of inviting children to choose the type
' Increased birth-weight [63]. of enuresis alarm (bed or body-worn), when this is
' Higher dose [16,47,58,75]. considered to be the most appropriate treatment inter-
vention, is being acknowledged clinically [14]. However,
Pre-treatment predictors with the enuresis alarm recent work suggests the importance of choice across
include: the broader spectrum of treatment modalities. Monda
(i) Discontinuation or early withdrawal from treatment and Husmann [71] undertook an intriguing study where
when there is evidence of: children with NE chose the mode of treatment. Using a
very strict success criterion (01 wet night/month) they
found a 68% response with desmopressin, compared
' Parental intolerance and annoyance [5355].
with a 32% response to imipramine and 63% with the
' Children with low self esteem [76].
enuresis alarm.
' Children with behavioural problems [77].
' Family history of bedwetting [78].

(ii) Failure is likely to occur: Using effective treatment adjuncts

Many behaviourally designed interventions have been
' When the bedwetting is severe before treatment used with the enuresis alarm. A fundamental principle
might suggest that for an adjunct to be recommended it
[57].
should add to the effectiveness of the alarm. In their
' There is multiple wetting at night [57].
exhaustive review, Houts et al. [27] failed to nd support
' Children lack motivation or concern about the problem
for the idea that adding behavioural procedures to alarm
[79,80]. treatments improved overall effectiveness, yet later Houts
' Children are perceived to have behavioural problems [44] suggested that the incorporation of selected behav-
[57]. ioural procedures tended to produce better outcomes
' Children have a developmental delay [81]. than alarm monotherapy.
' Children have associated daytime wetting [82]. The most effective behavioural procedures include:
' When the living conditions are unsatisfactory [83], Arousal training which involves reinforcing appropriate
although others, using a similar format for assessing behaviour (waking and toiletting) in response to alarm
housing and living conditions, failed to nd such a triggering. The aim of arousal training is to reinforce the
relationship with alarm failure [80]. child's rapid response to the alarm triggering, not on
`learning to keep the bed dry'. van Londen et al. [84]
' When there are family difculties, disharmony and
reported a 98% success rate within 6 weeks with low
stress [80,83]. This refers to families where both
relapse rates, nding 73% of children remained dry after
natural parents are not present; marital discord with
2.5 years.
threatened or past separation; `other' family dis- Normalized voiding involves encouraging children to
harmony; serious `handicap' with parent or child; increase their uid intake and void regularly during the
parental mental illness; bereavement in the family; and daytime at predetermined times (e.g. 2-hourly or break
serious nancial difculties. times at school). In an attempt to increase cognitive
' Parents adopt punitive reactions to the child's bed- control over voiding, Kruse et al. [85] reported 78%
wetting [57]. success in overcoming bedwetting, and when combined

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with the alarm a success rate of 80%, increasing to 100%

Preventing relapse
when combined with desmopressin.
Dry bed training incorporates the enuresis alarm; The relapse rate with alarm treatment is < 30% and with
positive practice (mass practice of waking); cleanliness medication, immediate and almost total relapse is
training (encouraging the child to take responsibility for inevitable [17,71]. Over-learning has been advocated as
removing wet sheets and re-making the bed); and two a method of preventing relapse with the enuresis alarm.
waking schedules to ease arousability from sleep [40]. It is designed to strengthen the detrusor muscles, and
High success and low discontinuation rates have been increase the bladder's maximum functional capacity,
reported, although relapse rates are no different to alarm through gradually increasing night-time drinking in
treatment [86]. Modications have been advocated the last hour before bed, up to a maximum of 500 mL.
to remove some of the more punitive elements of the Any increased wetting is construed as an opportunity
programme [55]; nonetheless it remains a complex, for additional learning trials. Morgan [90] advocated
time-consuming and demanding procedure. Hirasing over-learning at the point at which the child achieves
et al. [87] reported 80% success with group-administered the dryness criteria, although others begin the process
dry-bed training, with girls responding better than at the start of alarm treatment [88]. Over-learning has
boys. Although most parents were satised with the been found to reduce relapse by 1012% [44,90].
programme the opinions of the children were divided. With desmopressin, a gradual reduction of dose has
An important component analysis by Bollard and been advocated, yet it takes a long time (up to 3 years)
Nettelbeck [86] found the enuresis alarm accounted for and at best only half the children will remain dry [46].
most of the success achieved through dry-bed training. The problem appears to be that in becoming dry the child
They suggested that a large proportion of the components attributes success to the treatment (alarm or medication)
of the procedure could be eliminated without sacric- and in effect externalizes the success. Thus, removing
ing much of its overall effectiveness, and that the wak- the alarm or medication removes what the child believes
ing schedule, coupled with the enuresis alarm, was as to be the reason for success, and relapse consequently
effective as the complete dry-bed training programme. follows. Recently, Butler et al. [91] reported an 8-week
Whelan and Houts [88] failed to substantiate this withdrawal programme specically designed for prevent-
nding; they found that adding the waking schedule to ing relapse on removal of medication. The programme
their full-spectrum home training did not improve focuses on engaging the child in a process of internalizing
effectiveness, either in terms of the number becoming success and highlighting the effective process by which
dry, speed of response or reduction in numbers of patients this is accomplished, whether it be increased arousability
who relapsed after treatment. They cogently argued that or improved AVP release. Results using this programme
this result does not suggest that the waking schedule is suggest that <75% of children remain dry on completing
redundant, but that it may be useful only for certain the programme.
individuals.
Conclusion
Monitoring progress
Nocturnal enuresis is a distressing experience for children
The efcient recording of progress should enable the and young people, and successful treatment invariably
clinician to notice responsiveness to the treatment improves their psychological functioning. A key clinical
method quickly, even if the child is not immediately issue concerns the importance of ensuring that treatment
achieving dry nights. Recording progress should also interventions are effective. This paper reviews a series of
enable the clinician to inform the child as to how he variables as a framework for consideration when clinical
or she is improving. A progress chart, devised around decisions about treatment for NE are made.
the three-systems model, enables this [89]. For each There are few demonstrably effective interventions for
night, irrespective of the treatment modality, the child NE; with unselected samples of children with NE, the
is asked to record one of four events: enuresis alarm has good success rates. In more selected
populations pharmacological therapy is beginning to
' Dry by sleeping through, which indicates vasopressin
reach equivalent success rates. There is good evidence for
release;
differentiating treatment according to the child's needs.
' Dry by waking to toilet, which indicates arousability; The three-systems model [2] is useful in this regard,
' Waking after a wetting episode, which suggests the suggesting desmopressin for low vasopressin release,
child is responding to the alarm (if used); oxybutynin coupled with bladder training for bladder
' Discovery of the wet bed in the morning, which instability, and the enuresis alarm to enhance arous-
indicates both a lack of AVP and arousability. ability from sleep.

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568 R. BUTLER and A. STENBERG

Combined therapy is limited to those individuals who the alarm or desmopressin is discontinued, revolves
have difculties with all three systems. Desmopressin around encouraging the individual to attribute the suc-
coupled with oxybutynin is successful with those who cess to themselves, rather than to the treatment process.
have low AVP release, bladder instability and who are The identication of the principles that inuence the
unable to wake to bladder signals. As yet there are no effectiveness of treatment can assist the clinician in
studies examining the combination of alarm and oxy- developing interventions to suit the individual's par-
butynin. There is no good evidence for combining ticular circumstances and consequently enhance the
desmopressin with the enuresis alarm and there are likelihood of success.
theoretical objections to such an approach.
Many adjuncts to the primary treatment intervention, Acknowledgements
usually the alarm, have been described and two intensive
This work was undertaken with the support of Leeds
programmes (dry-bed training and home-spectrum
Community & Mental Health NHS Trust.
training) incorporating many behavioural procedures,
have been developed. The only effective adjuncts that
enhance the alarm are arousal training and scheduled References
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88 Whelan JP, Houts AC. Effects of a waking schedule on Authors

primary enuretic children treated with full-spectrum home R. Butler, PhD, Consultant Clinical Psychologist.
training. Health Psychol 1990; 9: 16476 A. Stenberg, MD, Associate Professor.
89 Butler RJ. Nocturnal Enuresis Resource Pack 2000. Bristol: Correspondence: R.J. Butler, Department of Clinical Psychology,
Enuresis Resource & Information Centre, 2000 High Royds Hospital, Menston, Nr Ilkley, Leeds LS29 6AQ, UK.
90 Morgan RT. Relapse and therapeutic response in the e-mail: [email protected]
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ndings on intermittent reinforcement, overlearning and
Abbreviations: NE, nocturnal enuresis; AVP, arginine
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