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
Introduction
Nocturnal enuresis (NE) is a multifactorial condition with
various aetiologies [1,2]. There are compelling argu-
ments in favour of offering treatment for children who
wet the bed beyond 7 years of age. NE is remarkably
prevalent in childhood, with 913% of 9-year-olds and
12% of adolescents and young adults still affected by
the problem [3]. Children may become socially isolated,
emotionally distressed and have a low self-esteem as
a result of enuresis [46]. An improvement in psycho-
logical functioning, including self-esteem, has been
reported after successful treatment [6,7]. Although
most parents are supportive, there is a signicant
number, reportedly up to 30%, who become intoler-
ant towards the NE and their child [8,9]. Finally, the
cost of enuresis can have a marked effect on the family
economy and therefore treatment of this condition
cannot be ignored [10].
Understanding of nocturnal enuresis
The `three-systems' model, comprising three causes of
NE (low arginine vasopressin, AVP, bladder instability
and lack of arousal from sleep) has been proposed to offer
a better understanding of NE and enhance the possibility
of selecting the most effective treatment for the child or
young person [2]. Current treatment modalities gener-
ated from the three-systems model suggest using desmo-
pressin to supplement a lack of AVP release, bladder
training exercises coupled with oxybutynin for bladder
instability, and the enuresis alarm to encourage the child
to wake in response to full bladder sensations. The
following variables are important when considering the
most appropriate treatment for any given child.
Selecting effective treatment interventions
Alarm therapy is proclaimed to be amongst the most
effective interventions for treating childhood NE. Several
Accepted for publication 13 June 2001
# 2001 BJU International
reviews of studies, using unselected populations of
children with NE, report success rates of 6570%, with
a treatment duration of 512 weeks and stated relapse
rates of 1530% in the 6 months after treatment
[1113]. Furthermore, there appears to be no difference
between types of enuresis alarm (bed or body-worn) in
terms of success rates [14].
Controlled studies report that desmopressin is effective
in the immediate cessation of wetting [1518], whether
administered nasally or orally [19]. Moffatt et al. [20]
comprehensively reviewed many published papers on
randomized clinical trials of desmopressin and found,
compared with placebo, that desmopressin was signi-
cantly better in 13 of the 14 studies. With a more selected
population of children with primary NE, Caione et al.
[21] found a 79% success rate after the administra-
tion of desmopressin. Devitt et al. [22] showed that the
response to desmopressin was closely related to the level
and variability of AVP. The treatment was successful
in children who had suboptimal levels of AVP and
unsuccessful in children with either normal or very low
levels of AVP.
Oxybutynin, when used with no bladder training
exercises and in unselected populations of children with
NE, has not been effective in randomized controlled
studies [23]. However, recent work suggests that
oxybutynin is effective in reducing unstable bladder
contractions and increasing the urine volume at rst
desire to void [24]. In more selected groups of children
with bladder instability as a cause of their NE, Watanabe
et al. [25] claimed a 67% success rate with oxybutynin;
Kass et al. [26] reported a 90% success rate and in a study
of dose escalation, Kosar et al. [24] reported complete
success after administering 1520 mg oxybutynin in a
selected group of 17 children.
Comparisons between pharmacological intervention
and alarm treatment have been difcult because of dif-
ferent philosophical goals [27]. Behavioural interven-
tions, e.g. alarm treatment, have typically sought to
encourage the cessation of wetting, with the criteria
for success based on consecutive dry nights [28],
563
564 R. BUTLER and A. STENBERG
whereas pharmacological treatment has emphasized
managing the enuresis and aims to reduce the frequency
of wetting [1].
Linking treatment to the child's needs
Some have argued that the type of treatment inter-
vention advocated should be based on the cause of the
child's NE [2]. An appropriate assessment will highlight
which of the three systems is affected; thus desmopressin
is a logical treatment for low AVP release, oxybutynin
plus bladder training for bladder instability and the
enuresis alarm when the child indicates the potential
to wake from sleep [2].
Where children appear to have difculty in more than
one of the systems, combined therapy (using more than
one treatment intervention) might reasonably be con-
sidered. Butler reviewed the methodological issues
associated with combined treatment [29]. The most
common combined cause of NE is lack of AVP plus a lack
of arousability.
Three studies reported on combined desmopressin and
the enuresis alarm on unselected groups of children.
Sukhai et al. [30], with a crossover design, randomized
children into two treatment groups, i.e. alarm plus
desmopressin (A+D) or alarm with placebo (A+P). The
results suggested that A+D was better (P=0.05) than
A+P in treating NE. However, the sample population
was both small (28 children) and not homogeneous
(29% of the children having learning difculties).
However, the most problematic methodological issue
was the treatment duration. Children were only treated
for 2 weeks before crossover, which is sufcient time to
assess the effect of desmopressin but clearly insufcient to
test the effectiveness of the alarm, as 512 weeks has
been suggested as the mean treatment duration with an
enuresis alarm [11,12]. Thus treatment success in the
A+D group was arguably caused by a response to
desmopressin, whereas insufcient duration of treatment
in the A+P group must have contributed to the failure
rate in this group.
Bradbury [31] randomly allocated 71 children to
either the alarm plus desmopressin (40 mg) or alarm mono-
therapy for 6 weeks; the combined therapy was more
effective than the alarm alone, particularly where the
child had severe NE and behavioural problems. How-
ever, the samples were not homogenous for severity, as
before allocation 20% were dry more than four times
per week, which raises questions about treatment eligi-
bility. Furthermore, no information was provided on the
rates of primary/secondary, non-mono or monosympto-
matic NE, diurnal enuresis, previous alarm therapy
or parental intolerance. The absence of a placebo sug-
gests a lack of methodological equivalence, with the
combined group receiving a more `enhanced' treatment
package than the alarm monotherapy group.
Leebeek-Groenewegen et al. [32], in a double-blind
placebo-controlled study, examined 93 children with
monosymptomatic NE. Children were allocated to treat-
ment with alarm plus desmopressin 40 mg (A+D) or
alarm plus placebo (A+P) for 9 weeks. During the
treatment period the desmopressin dose was titrated
three times (40, 20 and 0 mg). There were signicant
differences between the groups only at 3 weeks, which
suggests that the effect was largely the result of desmo-
pressin rather than the combination. The response rate
over 9 weeks suggested that two separate treatment
effects could account for the results. In the A+D group
the immediate reduction in the number of wet nights,
which reached a plateau, is a typical treatment response
with desmopressin, whereas with A+P the prole showed
a gradual reduction in the number of wet nights through
to week 9, a response suggestive of alarm treatment.
Although the study used unusual success criteria (cure
dened as o90% reduction and success as o50%
reduction) the authors concluded that desmopressin
does not result in higher cure rates and that combined
treatment is not justied in all enuretic children from
the outset of treatment.
These studies suggest that the success with combined
alarm plus desmopressin is caused by the desmopressin
intervention and not the combination. It might be argued
that when a child is responsive to desmopressin the alarm
becomes redundant, as it will not be triggered. Using
combined treatment without rst assessing the cause
in terms of the three systems [2] may be considered
inadvisable, and potentially overloads both child and
parents with unnecessary treatment interventions.
A more appropriate combination theoretically might
include anticholinergic medication plus desmopressin,
where bladder instability and a lack of AVP are indicated
[33]. Two studies report the effectiveness of such a com-
bination [34,35]. An Italian multicentre trial reported
signicantly more success with oxybutynin plus desmo-
pressin (79%) than with oxybutynin monotherapy (54%),
where children had NE with daytime urgency and
frequency [35]. The study concluded that the reduced
urinary output and bladder lling, as a consequence
of desmopressin, decreased the onset of uninhibited
bladder contractions and thus enhanced the effect of
oxybutynin.
Understanding the treatment rationale
The perceived mode of action of desmopressin is in
mimicking AVP through reducing urine production
and increasing urine concentration, and as such desmo-
pressin has been construed as a replacement or
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supplementation. Hansen and Jorgensen [36] conrmed
this by nding reduced night-time urine production
during desmopressin treatment. However, some work
suggests that desmopressin has an additional effect, i.e.
in increasing arousability. Lackgren et al. [37] found
that >70% of individuals treated with desmopressin
became dry by waking from sleep to void. This raised the
question as to whether, by reducing urine volume,
desmopressin shifts the point at which the bladder
becomes full to the early morning, when arousal from
sleep is easier for the child [38].
Interestingly, the mode of action of the alarm is
ill understood, but several explanations have been
suggested:
' An increased expectation of success [39].
' Alteration of social reinforcement to a point close to
the wetting [40].
' `Avoidance conditioning', whereby the child seeks to
avoid the unpleasantness of the noise by spontaneous
waking or by contraction of the pelvic oor muscles
[41].
' Increased functional bladder capacity [42].
' Increased production of AVP in response to the stress
of waking to the alarm, which might explain why
< 80% of children who become dry with the enuresis
alarm are able to sleep through the night [43].
' A conditioned response whereby waking after urina-
tion serves as an unconditioned stimulus, whilst the
`startle response' of pelvic oor contractions which
stops urination is the unconditioned response.
With repeated triggering, it is argued, the alarm
produces a conditioned response of inhibition of
urination in the presence of detrusor contractions
during sleep [44].
Acceptability of treatment
With oxybutynin the reported side-effects include dry
mouth, constipation and, in some individuals, ushing
[24]. With desmopressin there are very few side-effects
reported [18,45,46]. Klauber [47] reported no serious
adverse reactions in 516 cases. In an exhaustive review
of randomized clinical trials of desmopressin, Moffatt et al.
[20] found that eight of the 18 studies reported no side-
effects. Headaches were reported in four children (of a
total of 689) and stomach ache in three. Even during
long-term treatment with desmopressin, side-effects are
rarely reported [19,48,49]. However, there are rare
reported cases of hyponatraemia with desmopressin
treatment [50]. Robson et al. [51] reviewed 11 case
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565
reports and found excess uid intake contributed to six
cases. They suggested that to prevent hyponatraemia,
children should be encouraged not to drink >240 mL
on any night that desmopressin is taken.
A primary concern with alarm therapy is parental
intolerance [8,39]. Several parents become angry,
annoyed and intolerant of bedwetting, particularly
with an older child and where the family are functioning
under stress. Parents often seek to blame their child,
believing the bedwetting is somehow under their con-
trol, and resort to punitive means of coping. Up to a third
of parents resort to punitive measures in seeking to cope
with the problem [8,9,52].
There is ample evidence indicating a close association
between parental (usually maternal) intolerance and
discontinuation or early withdrawal from alarm treat-
ment [5355]. Enuresis alarms are time-consuming
and complicated to set up, notoriously temperamental,
tend to disrupt the sleep of everyone in the household
and often take weeks of use before there are positive signs
of progress. Alarms therefore potentially increase paren-
tal annoyance and may place the child at greater
physical and emotional risk [39].
Considering pretreatment predictors of outcome
An understanding of the variables under which a
treatment is likely to succeed or fail is an important
clinical tool; it improves the choice over available
treatment options and enhances the likelihood of suc-
cess [56]. Moffatt and Cheang [57] also argue that
research design should incorporate known prognostic
indicators to ensure comparison groups are matched
against variables known to enhance success or increase
failure rates across treatment interventions.
Pre-treatment predictors of success for desmopressin
include:
' The older child [5862].
' Less severe NE in terms of number of wet nights/week
[58,63,64].
' Normal functional bladder capacity [61,62,6567].
' Primary as opposed to secondary NE [20].
' When enuretic incidents occur during the rst 2 h
of sleep which may reect an increase in urine
production due to lack of vasopressin release [66].
' Where there is a family history of NE [35,68]. Hogg
[68] dened a family history broadly, as any family
member (including aunts, uncles and cousins) who
had persistent enuresis beyond the age of 6 years, and
found a positive family history in all desmopressin
responders, with only 43% of those not responding
566 R. BUTLER and A. STENBERG
having a positive family history. However, Hogg and
Husmann [69] found a more striking discrepancy,
with a 91% response to desmopressin in patients with
a family history and only a 7% response in those with
no family history. However, other studies have failed
to nd such a relationship [62,65,7072].
' Increased urine volume at night [73,74]. Rittig et al.
[73] found patients who responded to desmopressin
were able to reduce urine volume at night to the same
as that of other children.
' Increased urine production during the day [66].
' Less concentrated urine during the day [66].
' Frequent daytime micturition [62].
' Increased birth-weight [63].
' Higher dose [16,47,58,75].
Pre-treatment predictors with the enuresis alarm
include:
(i) Discontinuation or early withdrawal from treatment
when there is evidence of:
' Parental intolerance and annoyance [5355].
' Children with low self esteem [76].
' Children with behavioural problems [77].
' Family history of bedwetting [78].
(ii) Failure is likely to occur:
' When the bedwetting is severe before treatment
[57].
' There is multiple wetting at night [57].
' Children lack motivation or concern about the problem
[79,80].
' Children are perceived to have behavioural problems
[57].
' Children have a developmental delay [81].
' Children have associated daytime wetting [82].
' When the living conditions are unsatisfactory [83],
although others, using a similar format for assessing
housing and living conditions, failed to nd such a
relationship with alarm failure [80].
' When there are family difculties, disharmony and
stress [80,83]. This refers to families where both
natural parents are not present; marital discord with
threatened or past separation; `other' family dis-
harmony; serious `handicap' with parent or child;
parental mental illness; bereavement in the family; and
serious nancial difculties.
' Parents adopt punitive reactions to the child's bed-
wetting [57].
' There is previous lack of success with the enuresis
alarm [82].
' If the child voids early in the night when it is more
difcult to arouse from sleep [38].
' When maternal education is poor [57].
' With higher socio-economic status [57].
To date, there are no reported pretreatment predictors
with bladder training and anticholinergic medication.
Offering treatment choice
The importance of inviting children to choose the type
of enuresis alarm (bed or body-worn), when this is
considered to be the most appropriate treatment inter-
vention, is being acknowledged clinically [14]. However,
recent work suggests the importance of choice across
the broader spectrum of treatment modalities. Monda
and Husmann [71] undertook an intriguing study where
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
with a 32% response to imipramine and 63% with the
enuresis alarm.
Using effective treatment adjuncts
Many behaviourally designed interventions have been
used with the enuresis alarm. A fundamental principle
might suggest that for an adjunct to be recommended it
should add to the effectiveness of the alarm. In their
exhaustive review, Houts et al. [27] failed to nd support
for the idea that adding behavioural procedures to alarm
treatments improved overall effectiveness, yet later Houts
[44] suggested that the incorporation of selected behav-
ioural procedures tended to produce better outcomes
than alarm monotherapy.
The most effective behavioural procedures include:
Arousal training which involves reinforcing appropriate
behaviour (waking and toiletting) in response to alarm
triggering. The aim of arousal training is to reinforce the
child's rapid response to the alarm triggering, not on
`learning to keep the bed dry'. van Londen et al. [84]
reported a 98% success rate within 6 weeks with low
relapse rates, nding 73% of children remained dry after
2.5 years.
Normalized voiding involves encouraging children to
increase their uid intake and void regularly during the
daytime at predetermined times (e.g. 2-hourly or break
times at school). In an attempt to increase cognitive
control over voiding, Kruse et al. [85] reported 78%
success in overcoming bedwetting, and when combined
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with the alarm a success rate of 80%, increasing to 100%
when combined with desmopressin.
Dry bed training incorporates the enuresis alarm;
positive practice (mass practice of waking); cleanliness
training (encouraging the child to take responsibility for
removing wet sheets and re-making the bed); and two
waking schedules to ease arousability from sleep [40].
High success and low discontinuation rates have been
reported, although relapse rates are no different to alarm
treatment [86]. Modications have been advocated
to remove some of the more punitive elements of the
programme [55]; nonetheless it remains a complex,
time-consuming and demanding procedure. Hirasing
et al. [87] reported 80% success with group-administered
dry-bed training, with girls responding better than
boys. Although most parents were satised with the
programme the opinions of the children were divided.
An important component analysis by Bollard and
Nettelbeck [86] found the enuresis alarm accounted for
most of the success achieved through dry-bed training.
They suggested that a large proportion of the components
of the procedure could be eliminated without sacric-
ing much of its overall effectiveness, and that the wak-
ing schedule, coupled with the enuresis alarm, was as
effective as the complete dry-bed training programme.
Whelan and Houts [88] failed to substantiate this
nding; they found that adding the waking schedule to
their full-spectrum home training did not improve
effectiveness, either in terms of the number becoming
dry, speed of response or reduction in numbers of patients
who relapsed after treatment. They cogently argued that
this result does not suggest that the waking schedule is
redundant, but that it may be useful only for certain
individuals.
Monitoring progress
The efcient recording of progress should enable the
clinician to notice responsiveness to the treatment
method quickly, even if the child is not immediately
achieving dry nights. Recording progress should also
enable the clinician to inform the child as to how he
or she is improving. A progress chart, devised around
the three-systems model, enables this [89]. For each
night, irrespective of the treatment modality, the child
is asked to record one of four events:
' Dry by sleeping through, which indicates vasopressin
release;
' Dry by waking to toilet, which indicates arousability;
' Waking after a wetting episode, which suggests the
child is responding to the alarm (if used);
' Discovery of the wet bed in the morning, which
indicates both a lack of AVP and arousability.
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567
Preventing relapse
The relapse rate with alarm treatment is < 30% and with
medication, immediate and almost total relapse is
inevitable [17,71]. Over-learning has been advocated as
a method of preventing relapse with the enuresis alarm.
It is designed to strengthen the detrusor muscles, and
increase the bladder's maximum functional capacity,
through gradually increasing night-time drinking in
the last hour before bed, up to a maximum of 500 mL.
Any increased wetting is construed as an opportunity
for additional learning trials. Morgan [90] advocated
over-learning at the point at which the child achieves
the dryness criteria, although others begin the process
at the start of alarm treatment [88]. Over-learning has
been found to reduce relapse by 1012% [44,90].
With desmopressin, a gradual reduction of dose has
been advocated, yet it takes a long time (up to 3 years)
and at best only half the children will remain dry [46].
The problem appears to be that in becoming dry the child
attributes success to the treatment (alarm or medication)
and in effect externalizes the success. Thus, removing
the alarm or medication removes what the child believes
to be the reason for success, and relapse consequently
follows. Recently, Butler et al. [91] reported an 8-week
withdrawal programme specically designed for prevent-
ing relapse on removal of medication. The programme
focuses on engaging the child in a process of internalizing
success and highlighting the effective process by which
this is accomplished, whether it be increased arousability
or improved AVP release. Results using this programme
suggest that <75% of children remain dry on completing
the programme.
Conclusion
Nocturnal enuresis is a distressing experience for children
and young people, and successful treatment invariably
improves their psychological functioning. A key clinical
issue concerns the importance of ensuring that treatment
interventions are effective. This paper reviews a series of
variables as a framework for consideration when clinical
decisions about treatment for NE are made.
There are few demonstrably effective interventions for
NE; with unselected samples of children with NE, the
enuresis alarm has good success rates. In more selected
populations pharmacological therapy is beginning to
reach equivalent success rates. There is good evidence for
differentiating treatment according to the child's needs.
The three-systems model [2] is useful in this regard,
suggesting desmopressin for low vasopressin release,
oxybutynin coupled with bladder training for bladder
instability, and the enuresis alarm to enhance arous-
ability from sleep.
568 R. BUTLER and A. STENBERG
Combined therapy is limited to those individuals who
have difculties with all three systems. Desmopressin
coupled with oxybutynin is successful with those who
have low AVP release, bladder instability and who are
unable to wake to bladder signals. As yet there are no
studies examining the combination of alarm and oxy-
butynin. There is no good evidence for combining
desmopressin with the enuresis alarm and there are
theoretical objections to such an approach.
Many adjuncts to the primary treatment intervention,
usually the alarm, have been described and two intensive
programmes (dry-bed training and home-spectrum
training) incorporating many behavioural procedures,
have been developed. The only effective adjuncts that
enhance the alarm are arousal training and scheduled
waking, both of which seek to improve waking to
full bladder sensations, and both need replication.
Normalized voiding, which aims to improve bladder
instability, has enhanced desmopressin treatment in
a small sample and again requires replication before
its potential can be accurately assessed.
There are several ndings about pretreatment factors
and their effect on outcome. Many need replication but
those links which consistently emerge include early dis-
continuation from alarm treatment when the parents
react intolerantly to the child's wetting, and enhanced
success with desmopressin in older children, those with
less severe enuresis and those with a normal functional
bladder capacity. There are as yet no investigations of
pretreatment factors with oxybutynin. Awareness of
such factors can lead to improved decision making over
treatment for any particular child or young person.
A full explanation of the treatment process, including
possible side-effects and sleep disruption, will enable
both parents and children to determine acceptability.
Informed choice has been shown to be important in
inuencing treatment compliance and success rates
[71]. During treatment some method of monitoring
progress has anecdotally and generally been regarded as
important. An understanding of spontaneous waking,
time of alarm triggering, functional bladder capacity
and dry nights by sleeping through the night, enables
the clinician to both feed back to the child which of the
three systems are developing, and help to unravel the
mode of action of each treatment intervention.
Finally, relapse is a problem with both desmopressin
and alarm treatment. Arguably the most crucial
measure of treatment effectiveness concerns how many
children remain dry once the treatment is discontinued.
Over-learning has reportedly been effective in reducing
relapse with the alarm, although this requires replica-
tion. A structured withdrawal programme is showing
promise in reducing relapse rates with desmopressin.
The important issue in maintaining dryness, once either
the alarm or desmopressin is discontinued, revolves
around encouraging the individual to attribute the suc-
cess to themselves, rather than to the treatment process.
The identication of the principles that inuence the
effectiveness of treatment can assist the clinician in
developing interventions to suit the individual's par-
ticular circumstances and consequently enhance the
likelihood of success.
Acknowledgements
This work was undertaken with the support of Leeds
Community & Mental Health NHS Trust.
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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,
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90 Morgan RT. Relapse and therapeutic response in the e-mail: drbutler-lcmh@cwcom.net
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