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Reboxetine in therapy-resistant enuresis: a randomized, placebo-controlled study
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Paediatric Surgery.
Umea Univ, Dept Clin Sci, Div Child & Adolescent Psychiat, Umea, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.ORCID iD: 0000-0002-4590-4957
2016 (English)In: Journal of Pediatric Urology, ISSN 1477-5131, E-ISSN 1873-4898, Vol. 12, no 6Article in journal (Refereed) Published
Abstract [en]

Introduction

A significant minority of children with enuresis do not respond to either desmopressin or the enuresis alarm. Anticholinergics have not proven as successful as expected. The fourth evidence-based treatment, the tricyclic antidepressant imipramine, is cardiotoxic when overdosed, which has led to diminished use.

Aim

The aim was to determine whether there is a role for the noradrenergic antidepressant reboxetine, as monotherapy or combined with desmopressin, in the treatment of enuresis in children who have not responded to standard therapy, and whether there are side effects involved. We also sought prognostic factors in anamnestic data and in the voiding chart.

Patients and methods

The study was a randomized placebo-controlled study with a double-blind cross-over design, in which all patients underwent treatment during three 4-week periods, one with reboxetine 4 mg and placebo, one with reboxetine 4 mg and desmopressin, and one with double placebo treatment. The proportion of wet nights out of 14 was compared before treatment and during the last 2 weeks of each treatment period.

Results

Eighteen patients were included. The reduction of wet nights was much better with either reboxetine in monotherapy or in combination with desmopressin than during the placebo period (p = 0.002) ( Figure). However, only one patient achieved complete dryness, this during monotherapy. There were three intermediate responders to monotherapy and five to combination treatment. With reboxetine in monotherapy, six children experienced negative side effects compared with three with combination therapy, and two with placebo. All of these side effects were mild and reversible. Only one patient chose to cease treatment because of side effects. No prognostic factors were found in either the case history or in voiding chart data.

Discussion

The present study, the first placebo-controlled trial, confirms that reboxetine is an evidence-based alternative to cardiotoxic antidepressant treatment in therapy-resistant enuresis. The fact that few patients achieved complete dryness may be due to the low dosage used. In our clinical practice we increase the dose to 8 mg when dryness is not achieved with the lower dose. Our experience is that this leaves more children with full response, but the evidence of this has yet to be shown.

ConclusionReboxetine seems to be an alternative in the treatment of enuretic children who have not responded to standard treatment.

Place, publisher, year, edition, pages
2016. Vol. 12, no 6
Keywords [en]
Nocturnal enuresis, Reboxetine, Antidepressants, Desmopressin
National Category
Pediatrics
Identifiers
URN: urn:nbn:se:uu:diva-308996DOI: 10.1016/j.jpurol.2016.04.048ISI: 000393060300026OAI: oai:DiVA.org:uu-308996DiVA, id: diva2:1051267
Funder
Sven Jerring FoundationAvailable from: 2016-12-01 Created: 2016-12-01 Last updated: 2019-07-29Bibliographically approved
In thesis
1. Therapy-resistant enuresis: In search of new therapies and prognostic markers
Open this publication in new window or tab >>Therapy-resistant enuresis: In search of new therapies and prognostic markers
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A large minority of children with enuresis do not respond to treatment with either desmopressin or the enuresis alarm. Anticholinergics have not proven as successful as expected. The fourth evidence-based treatment of enuresis, the tricyclic antidepressant imipramine, is cardiotoxic when overdosed, which has led to diminished use. Since the long-term consequences of enuresis are potentially grave it is important that effective treatments of therapy-resistant enuresis are found.

When investigating the enuretic child a full voiding-chart - in addition to the case history - is the method of choice. However, there is no robust evidence that daytime voiding chart data actually do predict nocturnal detrusor function.

The aim of this thesis was to determine whether there is a role for the noradrenergic antidepressant reboxetine in the treatment of therapy-resistant enuresis, and whether anamnestic data and the voiding chart provides prognostic information regarding response to treatment with anticholinergics and antidepressants respectively in therapy-resistant patients.

In a retrospective evaluation of 61 children who for humanitarian purposes had been treated with reboxetine 32(52%) responded to this treatment, 21 of them after desmopressin had been added. We then proceeded with a randomized placebo-controlled study with 18 patients, in which the reduction of wet nights was much better with either reboxetine in monotherapy or in combination with desmopressin than during the placebo period (p=0.002). However, no patient achieved complete dryness. No prognostic markers for therapy-response were found in either of these studies.

In the randomized study we also sought to investigate whether reboxetine had any statistically significant effect on voiding-chart data. No such effect was found, but in respect to this secondary aim the sample size was too small. Nonetheless , this led to the speculation whether reboxetine exerts its antienuretic effect via modulation of arousal mechanisms.

Prognostic markers were sought in a retrospective evaluation of 154 patients treated with anticholinergics or antidepressants, but few and inconsistent differences were found between the groups responding or not responding to the various treatment regimens, and this was true both for anamnestic and voiding chart data.

In conclusion reboxetine seems to be an alternative in the treatment of enuretic children who have not responded to standard treatment, but further trials with higher doses and larger study populations are needed. The internationally recommended assessment of children with therapy-resistant enuresis does not seem to give the prognostic information intended.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 60
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1584
Keywords
Nocturnal enuresis, Reboxetine, Antidepressants, Desmopressin, Voiding chart
National Category
Medical and Health Sciences
Research subject
Pediatrics
Identifiers
urn:nbn:se:uu:diva-389838 (URN)978-91-513-0701-5 (ISBN)
Public defence
2019-10-04, Enghoff-salen, Akademiska Sjukhuset, Ing 50 bv, Uppsala, 13:15 (Swedish)
Opponent
Supervisors
Available from: 2019-09-12 Created: 2019-07-29 Last updated: 2019-10-15

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