Journal of Pediatric Urology (2011) 7, 10e20
REVIEW ARTICLE
Desmopressin treatment regimens in monosymptomatic and nonmonosymptomatic enuresis: A review from a clinical perspective ¨rtz c, C. Lang b, H. Madersbacher d, G. Strugala c, S.H. Alloussi a,b,*, G. Mu J. Seibold a, C. Schwentner a, A. Stenzl a, S. Alloussib a
Eberhard-Karls-University, Department of Urology, University of Tu¨bingen, Germany Sta¨dtisches Klinikum Neunkirchen, Department of Urology, University of Saarland, Germany c Apogepha Arzneimittel GmbH, Dresden, Germany d Neuro-Urological Unit, Medical University Innsbruck, Innsbruck, Austria b
Received 9 January 2010; accepted 13 April 2010 Available online 25 June 2010
KEYWORDS Desmopressin; Review; Enuresis; Monosymptomatic enuresis; Nonmonosymptomatic enuresis; Antimuscarinics; Enuresis alarm
Abstract Objective: To evaluate outcomes of desmopressin treatment in monosymptomatic enuresis (ME) and nonmonosymptomatic enuresis (NME). Materials and methods: PubMed was searched for all studies investigating enuresis, up to July 2009, in which desmopressin was administered alone or combined with other treatments. Each study was graded according to its respective level of evidence. Results: Altogether, 99 studies enrolling 7422 patients were identified as fulfilling the inclusion criteria. In 76 studies, desmopressin was administered as monotherapy; in 29 it was combined with other treatments such as antimuscarinics and enuresis alarm. Conclusion: Studies incorporating a minor invasive versus a non-invasive diagnostic approach seem to achieve superior long-term success rates. Primary efficacy outcomes following desmopressin treatment are more favourable in ME than NME. Desmopressin administered with adjunct measures achieves superior outcomes compared to monotherapy, especially in NME. Compared to sudden withdrawal, the structured withdrawal programs show better long-term success and lower relapse rates. So far, no superiority has been shown for either time- or dose-dependent structured withdrawal programs. Most studies incorporated only small case series; only 25 studies with level of evidence 1 or 2 have been conducted. The broad range of mono- and adjunct treatments were evaluated according to the evidence based criteria recommended by the European Association of Urology. ª 2010 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Eberhard-Karls-University, Department of Urology, University of Tu ¨bingen, Germany. E-mail address:
[email protected] (S.H. Alloussi). 1477-5131/$36 ª 2010 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.jpurol.2010.04.014
Desmopressin treatment for enuresis: a review
Introduction The International Children’s Continence Society (ICCS) 2006 update on terminology defines enuresis as ‘any type of wetting episode that occurs in discrete amounts during sleep’, further subdividing enuresis into two groups. 1. Monosymptomatic enuresis (ME): ‘enuresis in children without any other LUT symptoms (nocturia excluded) and without a history of bladder dysfunction is defined as monosymptomatic enuresis’. 2. Nonmonosymptomatic enuresis (NME): ‘other children with enuresis and any other LUT symptoms are classified as nonmonosymptomatic enuresis’. This differentiation is crucial, because there is ample evidence that children with enuresis who have concomitant symptoms of LUT (lower urinary tract) malfunction differ pathogenetically, clinically and therapeutically from children without such symptoms. Various interventions have been advocated as treatment options: besides enuresis alarm, hormonal substitution (desmopressin), antimuscarinics (e.g. oxybutynin, propiverine, tolterodine), behavioural interventions, alternative medicine and urotherapy have been used so far, all of them resulting in more or less acceptable success rates [1]. The analyses of the Cochrane Collaboration were updated in 2006 and reported the evidence for efficacy of desmopressin (DDAVP) in the treatment of non-organic nocturnal enuresis in children [2], based on a previous systematic review published in 2000 [3]. Although more than 100 trials were included, direct comparisons between different types of interventions, especially combined interventions, were performed only to a limited extent. The difficulty in comparing different interventions is exacerbated by the lack of uniform definitions of success rates and the failure in some studies to report on key parameters, e.g. baseline of bedwetting, diagnostic assessment and success rates. Many of the included randomized trials have methodological flaws such as small sample size and high rate of dropouts, introducing potential bias and leading to low statistical power. Cochrane showed this lack of statistical significance caused by wrongly designed studies, in particular insufficient details reported about the method of randomization or inadequate followup data. From the perspective of evidence based medicine, the Cochrane review focussed only on studies that fulfilled the requirements of evidence based medicine to a certain standard. The Cochrane review did identify 47 studies from 1974 to 2006 [2], randomized to a varying extent. These studies were therefore not in accordance with the recent ICCS terminology, resulting in discrepancies in definitions, e.g. diagnosis or success rate. The review also lacked evaluation of more clinically relevant parameters, such as relapse rates or comparisons of structured withdrawal programs versus sudden termination. Furthermore, clinically relevant comparisons between different treatment regimens, such as monotherapy versus different combination treatments, were not conducted. The Cochrane analyses showed no attempt to develop a basic ‘language’, which could
11 interlink all relevant studies for practical comparisons. This suggests low general office compatibility, despite the urgent need for an easy understandable overview of treatment options and their respective therapeutic relevance. In conclusion, the Cochrane review is no more up to date, despite being updated in 2009, and therefore has only limited clinical applicability. Contrary to Cochrane, our review aimed at a more clinical perspective: DDAVP was analyzed both as monotherapy and in combination with other treatment options, such as enuresis alarm and antimuscarinics, further differentiating into ME and NME. Diagnosis-related efficacy and the impact of structured withdrawal programs compared to sudden withdrawal were analyzed as well.
Materials and methods This review adheres to the recent ICCS terminology [1], and aims at a more qualitative assessment of desmopressin treatment from a clinical perspective, including also quasiand non-randomized studies. PubMed was searched up to July 2009 for studies administering desmopressin in ME and NME, either applied as monotherapy or combined with enuresis alarm or antimuscarinics. Studies available as abstracts only were not incorporated, so as not to increment further the potential bias with respect to subtyping of enuresis, success definition, etc. Studies involving oral or intranasal application, administered either as tablets or as sublingual lyophilisate, were included. The search was convened using the terms enuresis and desmopressin. Studies published in English, German, French, Italian, Norwegian, Swedish, Danish, Czech and Spanish were incorporated. The selected studies had to meet the following inclusion criteria: - ME or NME, - children above 5 years of age and adolescents, - treatment applied for at least 2 weeks. Supplementary inclusion criteria represented topics of additional interest: - degree of (non-)invasiveness of the diagnostic assessment, - route of desmopressin application (intranasal, oral, sublingual), - desmopresssin dosages, - short-term success rates, - long-term success rates (according to the ICCS [1], long term was assumed if treatment periods beyond 6 months were reported), - relapse rates, - application of structured withdrawal programs or sudden termination of medication, - adverse events, - combination treatment regimens comprising enuresis alarm or antimuscarinics. There were two key issues to address in this review: terminology and outcome measures. We used the ICCS
12
S.H. Alloussi et al.
terminology [1], although it was applied in a few papers only. Most studies were published prior to the ICCS standardization; however, to achieve common ground, we adapted to the internationally acknowledged terminology. In cases of ambiguity concerning the issue of ME or NME, those studies clearly defining the non-occurrence of daytime symptoms were classified as ME, while those studies not clearly reporting on this issue were classified as NME. The other key issue was the necessity to transform the terms of outcome measures into recent ICCS terminology, although few papers used the new terminology. In cases of ambiguity concerning the issue of short- and long-term success rates according to the ICCS, success was defined as 50% improvement (partial responder). According to the ICCS, non-response was assumed in the case of