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Therapy-resistant enuresis: In search of new therapies and prognostic markers
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. (Pediatrisk inflammations- och metabolismforskning samt barnhälsa)
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 [en]
Nocturnal enuresis, Reboxetine, Antidepressants, Desmopressin, Voiding chart
National Category
Medical and Health Sciences
Research subject
Pediatrics
Identifiers
URN: urn:nbn:se:uu:diva-389838ISBN: 978-91-513-0701-5 (print)OAI: oai:DiVA.org:uu-389838DiVA, id: diva2:1339472
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
List of papers
1. Reboxetine in therapy-resistant enuresis: a retrospective evaluation
Open this publication in new window or tab >>Reboxetine in therapy-resistant enuresis: a retrospective evaluation
2009 (English)In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 43, no 5, p. 365-368Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Imipramine is the only evidence-based treatment available for enuretic children resistant to standard therapy. The drug's antienuretic effect is probably due to noradrenergic facilitation. The drug is, however, potentially cardiotoxic. In this study, the non-cardiotoxic noradrenergic antidepressant reboxetine was tested as an alternative to imipramine. PATIENTS AND METHODS: 61 patients, aged 7-19 years, with enuresis-resistant to desmopressin, the alarm, urotherapy and anticholinergics, were given 4-8 mg reboxetine at bedtime, if necessary combined with desmopressin. RESULTS: 32 patients became dry on reboxetine treatment, although 21 of them required combination treatment with desmopressin to achieve this. Eighteen children did not respond and eight children discontinued because of side-effects before treatment could be evaluated. No serious adverse events occurred. CONCLUSIONS: These results need to be confirmed with randomized controlled studies, but indicate that reboxetine will become a safe and efficient treatment alternative for enuretic children resistant to standard therapy.

Keywords
Antidepressants, enuresis, reboxetine
National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-113343 (URN)10.3109/00365590903099959 (DOI)000272144300004 ()19921980 (PubMedID)
Available from: 2010-01-27 Created: 2010-01-27 Last updated: 2019-07-29
2. Reboxetine in therapy-resistant enuresis: a randomized, placebo-controlled study
Open this publication in new window or tab >>Reboxetine in therapy-resistant enuresis: a randomized, placebo-controlled study
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.

Keywords
Nocturnal enuresis, Reboxetine, Antidepressants, Desmopressin
National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-308996 (URN)10.1016/j.jpurol.2016.04.048 (DOI)000393060300026 ()
Funder
Sven Jerring Foundation
Available from: 2016-12-01 Created: 2016-12-01 Last updated: 2019-07-29Bibliographically approved
3. Effects of antidepressant therapy on voiding chart data andnocturnal urine production in children with enuresis – a randomized controlled study
Open this publication in new window or tab >>Effects of antidepressant therapy on voiding chart data andnocturnal urine production in children with enuresis – a randomized controlled study
(English)Manuscript (preprint) (Other academic)
Abstract [en]

 

Introduction:

Since a substantial minority of enuretic children does not respond to either first- or second-line treatment, there is still need for antidepressants in therapy-resistant enuresis. We recently published the results of a placebo-controlled study of the noradrenergic antidepressant reboxetine in this patient group. The drug was found to have a modest but statistically significant antienuretic effect.

 

Aim:To determine whether reboxetine exerts its antienuretic effect via modulation of either bladder function or nocturnal urine production, as reflected by the voiding chart.

Patients and Methods:The study had a randomized, double-blind cross-over design, with three treatment periods of four weeks each. The therapies given were 1) placebo, 2) reboxetine 4 mg + placebo and 3) reboxetine 4 mg + desmopressin 0.4 mg, all drugs given orally in the evening. During the last two weeks of each treatment period, the families were asked to complete a voiding chart in which day-time voiding frequency and voided volumes were documented during 48 hours. Nocturnal urine production was assessed via weighing of diapers.

 

Results:No clear and consistent reboxetine effects were seen on either voiding parameters or nocturnal urine production. Neither did we find any significant difference in the voiding chart data of responders to active treatment, compared to that of non-responders.

Discussion:This observation may have several different, non-exclusive explanations, one of which is that the anti-enuretic action of reboxetine is explained by the drug’s noradrenergic effects on arousal. It may also be the case that the voiding chart is too blunt an instrument to detect nocturnal, or indeed daytime, detrusor overactivity. It is thus not ascertained that the lack of reboxetine influence on the bladder variables actually precludes that the drug can affect detrusor function. The lack of difference in nocturnal urine production between treatment  periods with and without desmopressin may indicate that nocturnal polyuria is of minor importance in therapy-resistant enuresis.

Finally, it may obviously be the case that the number of patients was too small, since the power calculations underlying the determination of sample size in this study were made based on treatment response, not voiding chart variables.

Conclusion:In this randomized, placebo-controlled study we found no effect on daytime voiding parameters or nocturnal urine production that can explain the antienuretic effect of reboxetine. This may indicate that the drug exerts its beneficial effects via noradrenergic modulation of arousal.

Keywords
Nocturnal enuresis, voiding chart, reboxetine, antidepressants, desmopressin
National Category
Medical and Health Sciences
Research subject
Pediatrics
Identifiers
urn:nbn:se:uu:diva-389833 (URN)
Available from: 2019-07-29 Created: 2019-07-29 Last updated: 2019-08-15Bibliographically approved
4. The prognostic value of voiding chart data in therapy-resistant enuresis
Open this publication in new window or tab >>The prognostic value of voiding chart data in therapy-resistant enuresis
(English)Manuscript (preprint) (Other academic)
Abstract [en]

 

Introduction: The case history is the primary tool when investigating the enuretic child. To further determine whether nocturnal polyuria or detrusor overactivity is present, a full voiding chart, as defined by the ICCS, is the method of choice. However, there is no robust evidence that daytime voiding chart data actually do predict nocturnal detrusor function.

Aim: The aim of this study was to assess the predictive value of anamnestic data and the voiding chart in the treatment of children with therapy-resistant enuresis.

Patients and Methods: The patients all suffered from therapy-resistant nocturnal enuresis. In accordance with international recommendations, the children were first treated with anticholinergics. If the therapeutic effect was not satisfactory dosage was adjusted and desmopressin was added. If sufficient treatment effect was not achieved, antidepressant therapy was tried next, combined with desmopressin if needed. Since this was an evaluation of clinical practice, not a randomized trial, treatment success was graded according to family satisfaction, not the actual frequency of wet nights. Thus, only children who reported that they were completely dry were regarded as full responders and those who stated that there was a substantial and useful reduction of wet nights were labeled intermediate responders.

Results: 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. The only statistically significant findings were that responders to antidepressant therapy were older (p=0.013) than non-responders, and patients who benefited from addition of desmopressin had a higher micturition frequency than those who did not (p= 0.027). Surprisingly, the children who needed desmopressin as part of combination treatment to become dry did not have significantly higher nocturnal urine production than those who had no such benefit (p=0.619). Equally surprisingly, neither the presence of urgency nor a history of previous daytime incontinence was significantly  more common in children responding to anticholinergics (p = 0.375 and 0.072, respectively).

Discussion: No clear and consistent differences in either anamnestic factors or voiding chart data were found between the patients responding or not responding to the various treatment regimens. Not even urgency could predict anticholinergic efficacy. Somewhat surprisingly, no association between nocturnal polyuria and desmopressin benefit was found.

Conclusion: In this study no prognostic value was found in anamnestic or voiding chart data in children with therapy resistant enuresis.

Keywords
Nocturnal enuresis, voiding chart, anticholinergics, antidepressants, desmopressin
National Category
Medical and Health Sciences
Research subject
Pediatrics; Pediatrics; Pediatrics
Identifiers
urn:nbn:se:uu:diva-389835 (URN)
Available from: 2019-07-29 Created: 2019-07-29 Last updated: 2019-08-15Bibliographically approved

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