Pediatr Nephrol

DOI 10.1007/s00467-016-3536-9

ORIGINAL ARTICLE

Combination treatment of nocturnal enuresis

with desmopressin and indomethacin
Konstantinos Kamperis 1,2 & Soren Hagstroem 3 & Mia Faerch 2 & Birgitte Mahler 2 &
Soren Rittig 2 & Jens C Djurhuus 1

Received: 9 August 2016 / Revised: 3 October 2016 / Accepted: 3 October 2016

# IPNA 2016

Abstract
Background We investigated the effect of combining indomethacin and desmopressin in treating children with
monosymptomatic nocturnal enuresis (MNE) and
desmopressin-resistant nocturnal polyuria.
Methods Twenty-three children with MNE, nocturnal polyuria, and partial or no response to desmopressin were recruited
from incontinence clinics of our tertiary referral center. We
used a randomized single-arm crossover placebo-controlled
study design consisting of two 3-week treatment periods with
a combination of desmopressin (0.4 mg) and indomethacin
(50 mg) or desmopressin and placebo at bedtime. Home recordings at baseline and for the final 2 weeks of each treatment
period were performed and included nocturnal urine output
measurements. The number of dry nights achieved and reduction in the nocturnal urine output were the main effect parameters. Students t test and Pearsons correlation coefficient
were used for statistical analysis.
Results The addition of indomethacin to desmopressin significantly reduced nocturnal urine output (from 324 14 ml to
258 13 ml, p < 0.001). This did not lead to more dry nights
in all children, and we found no statistically significant reduction in enuresis frequency (from 68 % 0.1 to 56 % 0.1,
p = 0.24).

* Konstantinos Kamperis
konskamp@rm.dk

Institute of Clinical Medicine, University of Aarhus,

Aarhus, Denmark

Department of Pediatrics, Aarhus University Hospital,

Aarhus, Denmark

Department of Pediatrics, Aalborg University Hospital,

Aalborg, Denmark

Conclusions Addition of indomethacin to desmopressin can

further reduce nocturnal urine output in children with MNE
and desmopressin-resistant nocturnal polyuria. The combination treatment does not, however, improve outcome in terms
of frequency of nights with enuresis. The dissociation of
antidiuretic and antienuretic effect may reflect nocturnal bladder reservoir dysfunction in children who present with normal
daytime bladder function.
Keywords Nocturnal polyuria . Natriuresis . Prostaglandins .
Osmotic diuresis . Children

Introduction
Nocturnal enuresis is a common and distressful childhood condition with a multifactorial background. The production of abnormally large quantities of urine at night, termed nocturnal
polyuria; the impairment of bladder reservoir function; and
inability to awake to the stimuli of a full bladder are all causal
factors of an enuresis episode. A blunted diurnal rhythm of
arginine vasopressin (AVP) secretion demonstrated in enuretic
individuals [1, 2] seems in some cases responsible for the observed polyuria. Treatment with desmopressin restores the normal circadian variations in urine production [3]. However, not
all children with enuresis and nocturnal polyuria show an adequate response to the agent. Bladder reservoir dysfunction can
in some cases explain the nonoptimal response [4], but there are
children in whom the antidiuretic effect of desmopressin is
suboptimal [5]. Mechanisms hypothesized to account for
desmopressin-resistant nocturnal polyuria include excess urinary excretion of sodium and potassium [6, 7], hypercalciuria
[8], abnormal urea and prostaglandin excretion [9], changes in
diurnal rhythms of angiotensin and aldosterone production
[10], abnormal circadian rhythm in glomerular filtration rate

Pediatr Nephrol

[11], and also sleep-disordered breathing [12]. Recently, abnormal sleep architecture was described in children with refractory
nocturnal enuresis [13], showing an overrepresentation of children with periodic limb movements. To what extent this is part
of the pathophysiology of nocturnal enuresis is still unclear.
Cyclooxygenase inhibitors demonstrate antidiuretic properties and are used in clinical settings of excess polyuria, such
as nephrogenic diabetes insipidus, Bartters syndrome, and
other tubulopathies [14]. In recent years, these agents have
been evaluated in patients with enuresis and show promising
results [1518]. There is now evidence suggesting that certain
populations of children with enuresis produce excessive
amounts of prostaglandin E2 during the night [9, 19].
Cyclooxygenase inhibition may represent a therapeutic alternative in such children who fail to improve on first-line treatment strategies.
With this study, we evaluate the antidiuretic and
antienuretic effect of adding indomethacin to desmopressin
treatment in a highly selected population of children with
desmopressin-resistant monosymptomatic nocturnal enuresis
(MNE) and nocturnal polyuria. Our hypothesis was that the
combination treatment is superior to desmopressin monotherapy in terms of nocturnal diuresis reduction and reduction in
enuresis frequency.

Materials and methods

Study participants
The study protocol was approved by the local Ethics
Committee, and informed consent was acquired from all participants and their parents. The protocol conformed to the
recommendations for good clinical practice (CPMP/ICH/
135/95) and was registered with clinicaltrials.gov
(NCT00226122).
Twenty-three children (aged 614 years) with MNE and
nocturnal polyuria were enrolled in the study. All were recruited from the clinics of the Center for Child Incontinence,
Aarhus University Hospital, Denmark. Inclusion criteria were
MNE, normal maximal voided volume (MVV, defined as
>65 % of the expected for age), nocturnal polyuria [nocturnal
urine production (NUP) on wet nights >130 % of the expected
MVV (MVVe)], lack of clinical or laboratory signs suggestive
of an underlying disease other than MNE, normal
uroflowmetry, and residual urine measurement (<20 ml, or
10 % of voided volume), unremarkable clinical examination,
and normal urine dipstick analysis. To be considered for the
study, participants had to be desmopressin nonresponders,
demonstrating <50 % reduction in the number of wet nights
on maximal recommended dose of desmopressin. All children
were previous nonresponders to the enuresis alarm. For clinical characterization, 2-week frequency volume charts were

obtained. A 2-week titration period with incremental doses

of either desmopressin spray (2040 g) or tablets (0.2
0.4 mg) served the definition of response rates at home before
entering the study protocol.
Study design
A randomized double blind single-arm crossover placebocontrolled design was used. Prior to entering the study protocol, biochemical determinations were performed for serum
creatinine and electrolytes. Participants completed two treatment periods each covering 3 weeks, with a week of washout
for both drugs in between. Treatment period succession was
randomized using computer-generated randomization codes
and facilitated by a person unrelated to the study, ensuring
allocation concealment. During treatment, a combination of
desmopressin tablets (0.4 mg) and indomethacin tablets
(50 mg) or desmopressin and placebo was administered, and
this was blinded to investigators and participants. Patients
were advised to take the medication at bedtime. For
desmopressin, we chose the maximal dose commonly used
in our incontinence clinics and that we expected to have adequate effect on urine concentrating capacity. As pharmacodynamic data for indomethacin in children with enuresis are not
available, we used the maximal single doses suggested.
There were no restrictions regarding diet and fluid intake
with the exception of the advice included in standard
urotherapy (toilet posture improvement when needed, fluid intake of 1.5 L/day, of which 1 L before 16.00 h, fluid restriction
for 2 h before bedtime, bladder emptying at bedtime).
Participants were advised to avoid fluid intake following
desmopressin and indomethacin administration until breakfast
the following day. Two-week home recordings were used to
register enuresis episodes and nocturnal urine volumes using
diaper weights and registrations of the first-morning voiding
volumes [20]. Children were requested to empty their bladders
as soon as they were awake in the morning. Home recordings
were requested for the last 2 weeks of each treatment period.
Primary endpoints were number of dry nights and NUP during
treatment. Participants were asked to report any adverse effects.
Compliance with therapy was measured by counting the
number of tablets returned by the participants at the end of the
study. Compliance with medication administration of <80 %
was considered an exclusion criterion. Sample size was calculated considering a further reduction in the number of wet nights
of 30 % when adding indomethacin to desmopressin as clinically significant and with = 0.05 and = 0.2.
Statistical analysis
Results were tested for normal distribution and presented as
mean standard deviation (SD). Comparisons were made
using paired Students t tests. Multivariate regression was used

Pediatr Nephrol

to detect correlations between demographic and clinical parameters and for treatment effect, and Pearsons test was used
for bivariate correlation testing. P < 0.05 was considered statistically significant. SPSS 23 (IBM Corp.) was used for all
statistical analysis.

Results
Two children were excluded from the study: one due to difficulties in swallowing the tablets and one due to reported adverse effects of aggressive behavior while on indomethacin.
Table 1 shows participant demographics and clinical
characteristics.
Antidiuretic effect of combination treatment
The addition of indomethacin to desmopressin further reduced
NUP from 324 60 ml to 258 62 ml (p < 0.001). Mean difference was 66 53 ml with a range of 5144 ml. All but two
children experienced reductions in NUP, as shown in Fig. 1.
We found a significant difference in NUP between wet and
dry nights in patients in both the desmopressin and the combination arm.
A multiple regression was used to predict the reduction in
NUP on combination treatment compared with monotherapy
with desmopressin with gender (p = 0.61), age (p = 0.84),
body weight (0.70), and MVV/MVVe ratio. (p = 0.92) as
predictors.
Antienuretic effect of combination treatment
Despite the observed reduction in NUP compared with monotherapy, the indomethacindesmopressin combination did not
significantly change enuresis frequency (68 29 % dry on
desmopressin compared with 56 32 % dry on combination
treatment, p = 0.24, Fig. 1). One child experienced full effect,
and five reduced their number of wet nights by >50 %. When
Table 1 Participant (n =
21) demographic data
and clinical
characterization

Variables

Results

Age (years)
Gender
Body weight (kg)
Height (cm)
MVV (ml)
MVV/MVVe (%)

9.1 2.3
19 males
37 18
142 12
320 110
103 26

Values are means standard deviation

(SD). Maximal voided volume (MVV)
yielded from frequency volume charts at
home and ratio to the expected MVV
(MVVe) for age (MVV/MVVe)

further evaluating NUP on wet nights during combination

treatment, we identified 12 (57 %) children who experienced
wet nights with average nocturnal urine volumes well below
their daytime MVVs.
By using multiple regression we assessed age, sex, body
weight, and MVV/MVVe ratio as predictors of response in
terms of enuresis episode frequency, but none of the parameters reached statistical significance (sex p = 0.21, age p = 0.94,
body weight p = 0.92). We found no significant correlation
between reduction in NUP during indomethacin
desmopressin combination therapy and reduction in enuresis
frequency (Pearsons correlation coefficient p = 0.54, Fig. 2).
Figure 3 shows intraindividual variability of enuresis volumes
(as registered by pad weight) and NUP during wet nights.
When looking for signs of increased nocturnal bladder capacity, we compared the NUP on dry nights from monotherapy
to combination treatment. We found no significant differences
(desmopressin 257 76 ml, combination 240 65, p = 0.31).
Side effects
One child experienced aggressive behavior on indomethacin
desmopressin combination. No other adverse effects were
reported.

Discussion
We present evidence that addition of indomethacin to
desmopressin treatment further reduces nocturnal urine output
in children with MNE and desmopressin-resistant nocturnal
polyuria. This, however, does not seem to lead to more dry
nights. We found a variable antienuretic effect of combination
treatment, indicating that further reduction in nocturnal urine
output does not necessarily secure dry nights in this highly
selected population of children with refractory MNE. This is
the first study to evaluate indomethacindesmopressin combination treatment in children with MNE in a randomized
placebo-controlled fashion.
This study involved a highly selected population of children with MNE refractory to standard treatment with
desmopressin and the enuresis alarm. Children with
desmopressin-resistant nocturnal enuresis and nocturnal polyuria are to be encountered in all clinical settings and represent
a difficult-to-treat subpopulation [21]. Several mechanisms
may account for the inadequate desmopressin response in
terms of reduction in nocturnal urine output, comprising variability in pharmacokinetics and pharmacodynamics, compliance, the effect of timing of desmopressin administration, and
dietary factors and hydration status at the time of administration [5, 21]. Pathophysiological mechanisms beyond the vasopressinaquaporin 2 axis have also been hypothesized to be
responsible for the nocturnal polyuria in this subgroup of

Fig. 1 Differences in enuresis

frequency (diff ENU) and
nocturnal urine production (diff
NUP) on indomethacin
desmopressin combination
treatment compared with
treatment with desmopressin +
placebo. Further reduction in
NUP did not lead to more dry
nights in all participants

Subjects

Pediatr Nephrol

-1.0

-0.5

0.0

diff ENU

0.5

-200

-150

-100

-50

50

diff NUP (ml)

children unresponsive to desmopressin [10, 22, 23], including

a role for prostaglandins [9].
Nonsteroidal anti-inflammatory drugs (NSAID) share
antinatriuretic and antidiuretic properties. Indomethacin, a cyclooxygenase 1 and 2 inhibitor, is commonly used in renal
tubulopathies characterized by excess urine production unresponsive to desmopressin. NSAIDs have previously been
evaluated in clinical studies of children with enuresis [15,
16, 18, 24, 25]. However, they were performed in unselected
and often poorly characterized populations of enuretic children, which is a major limitation. NSAIDs are not considered
first-line treatment for enuresis but, rather, a last resort in children in whom common therapeutic strategies fail and reduction of NUP remains an objective. For this study, we recruited
children who may be considered for treatment with NSAIDs
in a tertiary clinical setting, in whom desmopressin failed to
control nocturnal urine output, and who present with normal
MVV during daytime. However, as the enuresis episode can
be the result of both excess urine production and reduced

nocturnal bladder capacity, one must dissociate antidiuretic

and antienuretic effects of any treatment targeting nocturnal
urine output. This may also be the explanation as to why
previous studies of NSAIDs in children with enuresis have
yielded variable results in terms of efficacy. Natochin et al.
reported response to diclofenac as high as 33 % [15] in an
unselected population of children with enuresis; Varan et al.
did not find indomethacin to be effective [17]; and Sener et al.
[16] and Waili et al. [18] found it superior to placebo in unselected populations. A more recent study enrolling a large number of children with enuresis demonstrates ibuprofen to be
superior to placebo [26]. The inconsistent antienuretic effect
of prostaglandin inhibition may reflect the complex pathophysiology of MNE.
Subpopulations of enuretic children share distinct clinical
characteristics that necessitate individualized treatment. The
population recruited in this study was homogenous in terms
of clinical presentation; regardless, outcomes were variable.
Not all participants responded to combination treatment with

Fig. 2 Left panel: Relationship between maximum voided volumes/

expected MVV (MVV/MVVe) ratio and change in enuresis frequency
on desmopressinindomethacin combination compared with
desmopressinplacebo combination. Right panel: Relationship between
reduction in NUP (diff NUP) and change in enuresis frequency on

d e s m o p r e ss i n i nd o m e t h a c i n c o m b i n at io n c om pa r e d wi th
desmopressinplacebo combination. Neither correlation was statistically
significant. ENU enuresis frequency, MVV maximal voided volume, NUP
nocturnal urine output

Pediatr Nephrol
Fig. 3 Enuresis (ENU) volumes
as yielded by pad weight and
nocturnal urine output (NUP) on
combination treatment during wet
nights plotted against maximal
voided volumes (MVV) during
daytime. There is a large
intraindividual variability in the
antidiuretic effect of combination
treatment and a considerable
number of wet nights with NUP
well below the MVV

reductions in diuresis to levels below their daytime bladder

capacities, as was our aim. The antienuretic effect of this combination treatment still seems inadequate, despite its
antidiuretic effect. These observations question the pharmacodynamics of the dosage used in the study, although efficacy in
terms of reduction in urine production does not seem to correlate to patient weight. Further studies are needed to establish
the optimal indomethacin dose and timing in children with
enuresis.
In children in whom the combination of indomethacin and
desmopressin fails to ensure dry nights, urine production during wet night seems well below their daytime MVV, thus
revealing an element of nocturnal bladder reservoir dysfunction. Bladder overactivity and instability have previously been
demonstrated in children with treatment-refractory MNE [4].
However, the reasons for this variability in bladder reservoir
function during sleep need further elucidation.
Our findings stress the importance of home recordings when
assessing the effect of any antidiuretic treatment in children
with enuresis. Although demanding, nighttime registrations
during treatment can easily differentiate children with inadequate antidiuretic response from those with reduced nocturnal
bladder capacities, thus enabling treatment tailoring. Children
with nocturnal reservoir function issues may benefit from a
combination of antidiuretic agents and anticholinergics.
Interestingly, prostaglandins may participate in the pathophysiology of overactive bladder, and indomethacin has
been suggested to influence bladder function [27]. Studies
in rats indicate that cyclooxygenase inhibitors influence the
micturition reflex, thus improving bladder capacity [28]. It is
therefore hypothesized that indomethacin may improve nocturnal bladder capacity. When comparing the volumes of
morning voidings following dry nights before and after the
addition of indomethacin, we found no significant changes.
We have therefore no indication that indomethacin in the
dose used in this study influences the nocturnal bladder capacity. To what extent indomethacin influences bladder
function in children with nocturnal enuresis needs further
investigation.

The effect of indomethacin on NUP can be attributed to

indomethacins potent antinatriuretic properties [29, 30], considerable reductions in urea excretion, and overall osmotic
clearance [31]; it has also been shown to correlate with the
effect on urinary nitric oxide excretion [24]. Excess sodium
and urea excretion have both been implicated in the pathophysiology of MNE, thus providing a rationale for treatment
with NSAIDs. As excess natriuresis is an element of enuresis
pathophysiology, a combination of desmopressin and NSAID
is attractive when maximal antidiuresis needs to be achieved.
Limitations of the study
This study was designed to investigate whether the addition of
indomethacin to desmopressin improves outcomes in children
with MNE and nocturnal polyuria refractory to standard treatment. According to our power calculations, the number of
participants enrolled would suffice to show what we consider
a clinically significant improvement. The variability in the
effect parameters was high, and the small study population
may have limited the power to detect significant differences
in terms of reduction in the number of wet nights.
Regarding the dose of indomethacin used in the study, only
tablets of 25 mg are available, making an exact dosing according to body weight difficult. We therefore chose the same dose
for all children, which may have limited the effect in the children with the highest body weight.

Conclusions
The combination of indomethacin and desmopressin is superior to desmopressin as monotherapy in regard to reduction in
NUP. Regardless, combination treatment does not seem to
improve outcomes in terms of reduction in number of wet
nights in a highly selected population of children with MNE
resistant to standard treatment. Nocturnal bladder dysfunction
may account for this dissociation between antidiuretic and
antienuretic effects.

Pediatr Nephrol

A combination of desmopressin and indomethacin can represent a useful treatment strategy in children with
desmopressin-resistant nocturnal polyuria and normal bladder
reservoir function. Home recordings of nocturnal urine output
on desmopressin can help clinicians identify patients in whom
desmopressin fails to control NUP and who could benefit
from such a treatment approach.

11.

12.

13.
Compliance with ethical standards
Financial statement The study was financially supported by Karen
Elise Jensen Foundation.
Conflict of interest All authors declare that they have no conflicting
interests involving this work.
Ethics statement The study protocol was approved by the local Ethics
Committee and informed consent was acquired from all participants and
their parents. The protocol conformed to the recommendations for good
clinical practice (CPMP/ICH/135/95) and was registered with
clinicaltrials.gov (NCT00226122).

14.
15.

16.

17.

18.
19.

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