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Tricyclic and related drugs for nocturnal enuresis in children.

BACKGROUND: Enuresis (bedwetting) is a socially unacceptable and stressful condition which affects around 15-20% of five year olds, and up to 2% of young adults. Although there is a high rate of spontaneous remission, the social, emotional and psychological costs to the children can be great. OBJECTIVES: To assess the effects of tricyclic and related drugs on nocturnal enuresis in children, and to compare them with other interventions. SEARCH STRATEGY: The following electronic databases were searched: MEDLINE to June 1997; AMED; ASSIA; BIDS; BIOSIS Previews (1985-1996); CINAHL; DHSS Data; EMBASE (1974 to June 1997); PsycLIT and SIGLE. Organisations, manufacturers, researchers and health professionals concerned with enuresis were contacted for information. The reference sections of obtained studies were also checked for further trials. Date of the most recent search: July 1997. SELECTION CRITERIA: All randomised trials of tricyclic and related drugs for nocturnal enuresis in children were included in the review. Trials were eligible for inclusion if: children were randomised to receive tricyclics compared with placebo, other drugs or other conservative interventions for nocturnal bedwetting; participants with organic causes for their bedwetting were excluded; and baseline assessments of the level of bedwetting were provided. Trials focused solely on daytime wetting were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the quality of the eligible trials, and extracted data. MAIN RESULTS: Twenty two randomised trials, involving 1100 children treated with tricyclic or related drugs, met the inclusion criteria. The quality of many of the trials was poor. Only single trials compared tricyclic or related drugs with each other, other drugs, desmopressin, alarms or other behavioural interventions. Treatment with tricyclic drugs (such as imipramine, amitriptyline, viloxazine, clomipramine and desipramine but not mianserin) were associated with a reduction of about one wet night per week while on treatment (eg using imipramine, WMD -0.99, 95% CI -1.27 to -0.71). Children were almost five times more likely to achieve 14 dry nights with the drugs (eg using imipramine, RR = 4.99, 95% CI 2.4 to 10.40). Desmopressin and tricyclics appeared equally effective while on treatment, but this effect was not sustained after treatment stopped. There was no detectable difference between imipramine and alarms while on treatment, but afterwards those who had used alarms had one fewer wet night per week (WMD 1.03, 95% CI 0. 19 to 1.87). REVIEWER'S CONCLUSIONS: Treatment with tricyclic drugs (imipramine, amitriptyline, viloxazine, clomipramine and desipramine but not mianserin) was associated with a reduction of about one wet night per week while on treatment, but long term effectiveness is unknown. Desmopressin and tricyclics appeared equally effective while on treatment, but this effect was not sustained after treatment stopped. Alarms may be more effective in the long term. Comparisons between drug and behavioural treatments are needed, and should include relapse rates after treatment is finished.

Antidepressive Agents, Tricyclic↗

Desmopressin for nocturnal enuresis in children.

BACKGROUND: Enuresis (bedwetting) is a socially disruptive and stressful condition which affects around 15-20% of five year olds, and up to 2% of young adults. Although there is a high rate of spontaneous remission, the social, emotional and psychological costs to the children can be great. OBJECTIVES: To assess the effects of desmopressin on nocturnal enuresis in children, and to compare desmopressin with other interventions. SEARCH STRATEGY: The following electronic databases were searched: MEDLINE to June 1997; AMED; ASSIA; BIDS; BIOSIS Previews (1985-1996); CINAHL; DHSS Data; EMBASE (1974 to June 1997); PsycLIT and SIGLE. Organisations, manufacturers, researchers and health professionals concerned with enuresis were contacted for information. The reference sections of obtained studies were also checked for further trials. Date of the most recent search: July 1997. SELECTION CRITERIA: All randomised trials of desmopressin for nocturnal enuresis in children were included in the review. Trials were eligible for inclusion if: children were randomised to receive desmopressin compared with placebo, other drugs or other conservative interventions for nocturnal bedwetting; participants with organic causes for their bedwetting were excluded; and baseline assessments of the level of bedwetting were reported. Trials focused solely on daytime wetting were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the quality of the eligible trials, and extracted data. MAIN RESULTS: Twenty one randomised trials involving 948 children treated with desmopressin, met the inclusion criteria. The quality of many of the trials was poor. Desmopressin was compared with a tricyclic drug in two trials, and with alarms in one. Desmopressin was effective in reducing bedwetting in a variety of doses and forms. Each dose of desmopressin reduced bedwetting by at least one night per week during treatment (eg 20microg: 1.56 fewer wet nights per week, 95% CI -1.94 to -1.19). Participants on desmopressin were 4.6 times more likely to achieve 14 consecutive dry nights (95% CI 1.38 to 15.02) compared with placebo. However, there was no difference after treatment was finished. There was no apparent dose-related effect of desmopressin, but the evidence was limited. Data which compared oral and nasal administration were too few to be conclusive. Desmopressin and imipramine (a tricyclic drug) were equally effective in one small trial. Amitriptyline (another tricyclic) was not consistently better than desmopressin either alone or when used as a supplement. In a single trial, desmopressin was initially superior to using an alarm in reducing the number of wet nights per week: WMD -1.7 (95% CI: -2.96 to -0.45), but this result was not sustained; after three months of treatment, patients using the alarm had 1.4 fewer wet nights per week than with desmopressin: (95% CI: 0.14 to 2.65). Participants receiving the alarm intervention were also nine times less likely to relapse than those given desmopressin: RR 9.2 (95% CI: 1.28 to 65.9). Combining alarm and drug therapy was found to be superior to alarm treatment alone. The addition of desmopressin to an alarm schedule resulted in one less wet night per week: (95% CI: -1.55 to -0.45). REVIEWER'S CONCLUSIONS: Desmopressin rapidly reduced the number of wet nights per week, but there was some evidence that this was not sustained after treatment stopped. Comparison with alternative treatments suggested that desmopressin and tricyclics had similar clinical effects, but that alarms produced more sustained benefits. However, based on the available evidence, these conclusions can only be tentative. There was some evidence of minor side effects of desmopressin in the included trials, such as nasal irritation and nose bleeds. However, the risk of water intoxication associated with over-drinking before bedtime has been reported. Patients and their families need to be warned of potential adverse effects and advise

Child↗

Drugs for nocturnal enuresis in children (other than desmopressin and tricyclics).

BACKGROUND: Enuresis (bedwetting) is a socially unacceptable and stressful condition which affects around 15-20% of five year olds, and up to 2% of young adults. Although there is a high rate of spontaneous remission, the social, emotional and psychological costs to the children can be great. OBJECTIVES: To assess the effects of drugs other than desmopressin and tricyclics on nocturnal enuresis in children, and to compare them with other interventions. SEARCH STRATEGY: The following electronic databases were searched: MEDLINE to June 1997; AMED; ASSIA; BIDS; BIOSIS Previews (1985-1996); CINAHL; DHSS Data; EMBASE (1974 to June 1997); PsycLIT and SIGLE. Organisations, manufacturers, researchers and health professionals concerned with enuresis were contacted for information. The reference sections of obtained studies were also checked for further trials. Date of the most recent search: July 1997. SELECTION CRITERIA: All randomised trials of drugs (excluding desmopressin or tricyclics) for nocturnal enuresis in children were included in the review. Trials were eligible for inclusion if: children were randomised to receive drugs compared with placebo, other drugs or other conservative interventions for nocturnal bedwetting; participants with organic causes for their bedwetting were excluded; and baseline assessments of the level of bedwetting were provided. Trials focused solely on daytime wetting were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the quality of the eligible trials, and extracted data. MAIN RESULTS: None of the drugs (phenmetrazine, amphetamine sulphate/ephedrine + atropine, furosemide (sic) or chlorprotixine) were better than placebo during treatment. The numbers were too small to draw reliable conclusions, and none are used in current practice in the UK. Imipramine (a tricyclic) was better than each of the three drugs with which it was compared (meprobamate, ephedrine sulphate and furosemide) even though the numbers were small. Alarm treatment was better than drugs in one small trial. REVIEWER'S CONCLUSIONS: There was not enough evidence to suggest that the included drugs reduced bedwetting. There was limited evidence to suggest that imipramine and alarms were better, and in other reviews, desmopressin, tricyclics and alarm interventions have tentatively been shown to be effective.

Child↗

Alarm interventions for nocturnal enuresis in children.

BACKGROUND: Enuresis (bedwetting) is a socially disruptive and stressful condition which affects around 15-20% of five year olds, and up to 2% of young adults. Although there is a high rate of spontaneous remission, the social, emotional and psychological costs to the children can be great. OBJECTIVES: To assess the effects of alarm interventions on nocturnal enuresis in children, and to compare alarms with other interventions. SEARCH STRATEGY: The following electronic databases were searched: MEDLINE to June 1997; AMED; ASSIA; BIDS; BIOSIS Previews (1985-1996); CINAHL; DHSS Data; EMBASE (1974 to June 1997); PsycLIT and SIGLE. Organisations, manufacturers, researchers and health professionals concerned with enuresis were contacted for information. The reference sections of obtained studies were also checked for further trials. Date of the most recent search: July 1997. SELECTION CRITERIA: All randomised trials of alarm interventions for nocturnal enuresis in children were included in the review. Trials were eligible for inclusion if: children were randomised to alarm treatment compared with controls, other behavioural methods or drugs for nocturnal bedwetting; participants with organic causes for their bedwetting were excluded; and baseline assessments of the level of bedwetting were reported. Trials focused solely on daytime wetting were excluded. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the quality of the eligible trials, and extracted data. MAIN RESULTS: Twenty two randomised trials met the inclusion criteria, involving 1125 children who received treatment with alarms. The quality of many of the trials was poor, and many comparisons were addressed only by single trials. Children treated with alarms were significantly more likely than untreated controls to become dry during treatment (RR for failing to achieve 14 dry nights 0.27, 95% CI 0.19 to 0.39) and failing to remain dry (RR 0.58, 95%CI 0.46 to 0.74). There was insufficient evidence to judge whether one type of alarm is better than another and whether alarms alone were as good as or better than other behavioural interventions alone or as a supplement to alarm treatment. Desmopressin or tricyclics seem as effective as alarms while on treatment. There was limited evidence to suggest that the relapse rate might be lower after stopping alarm treatment than after desmopressin (RR 0.11, 95% CI 0.02 to 0.78). REVIEWER'S CONCLUSIONS: Alarm interventions are an effective treatment for nocturnal bedwetting in children. Desmopressin and tricyclics appeared as effective while on treatment, but this effect was not sustained after treatment stopped, and alarms may be more effective in the long term. Comparisons between drug and behavioural treatments are needed, and should include relapse rates after treatment is finished.

Case-Control Studies↗

Clinical enuresis phenotypes in familial nocturnal enuresis.

The objective of the current study was to identify the associations between phenotype and genotype in children with nocturnal enuresis. Of the total of 167 wetting children, aged 5-10 years, without neurological or structural forms of incontinence, 110 were nocturnal enuretics. The examinations included a full psychiatric and psychological assessment, a paediatric and neurological examination, a family history with pedigree, ultrasonography, uroflowmetery, urinanalysis and bacteriology. Children with secondary nocturnal enuresis (n = 28) had a significantly higher rate of behavioural disorders, life events and continuous psychosocial stress than those with primary nocturnal enuresis (n = 82). Of the latter group, children with primary monosymptomatic nocturnal enuresis (n = 50) had an especially low rate of behavioural problems, when in comparison to primary non-monosymptomatic nocturnal enuretics (n = 32). Formal genetics point to a high genetic predisposition to nocturnal enuresis in all subgroups. Linkage studies to markers on chromosomes 8, 12 and 13 demonstrate both clinical, as well as genetic heterogeneity in nocturnal enuresis.

Chi-Square Distribution↗

Comparison of desmopressin and enuresis alarm for nocturnal enuresis.

Fifty children with primary nocturnal enuresis were randomised for a study comparing desmopressin (DDAVP) and enuresis alarm. Forty six completed the trial, 24 of whom were treated with 20 micrograms intranasal desmopressin nightly and 22 with enuresis alarm for three months. Failures were crossed over and relapses were continued on the same treatment for a further three months. The improvement rate was 70% in the group given desmopressin and 86% in the group treated with alarm; the difference was not significant. During the first week of treatment the group given desmopressin was significantly dryer, and at the end of the study 10 of these patients relapsed compared with one patient in the group given the alarm. No serious side effects were observed. This study confirms the role of conditioning treatment as preferable in long term treatment of nocturnal enuresis. When this fails or when a safe drug with rapid effect is needed, however, desmopressin is a useful alternative.

Behavior Therapy↗

[Nocturnal enuresis in children. II--Diagnosis and treatment of nocturnal enuresis].

The classification of the various types of urination disorders among children as well as the latest theories explaining the causes of nocturnal enuresis were presented in the first part of the article entitled "Nocturnal Enuresis in Children" (in "Medycyna Wieku Rozwojowego" 1998, II, 1 pp. 55-69). The second part of this article concentrates on the differential diagnostics of urination disorders amongst patients seeking help for nocturnal enuresis. The diagnostic model developed by the Urodynamic Unit at the Department of Paediatric Surgery, National Research Institute of Mother and Child can be applied in an outpatient clinic. Hospitalization of the patient is not necessary to carry out the study, meaning that the child is spared any additional stress. Currently applied methods for treating nocturnal enuresis by non-pharmacological methods are also discussed in this text.

Child↗

Long-term treatment with desmopressin in children with primary monosymptomatic nocturnal enuresis: an open multicentre study. Swedish Enuresis Trial (SWEET) Group.

OBJECTIVE: To study the long-term efficacy and safety of desmopressin treatment in children with primary monosymptomatic nocturnal enuresis. PATIENTS AND METHODS: Children (aged 6-12 years) with nocturnal enuresis were recruited into an open multicentre trial. All children underwent an observation period of 4 weeks before starting a 6-week dose-titration period with desmopressin. If the number of wet nights decreased by more than half during medication, they began long-term treatment on 20-40 microg desmopressin. To test for cure and avoid overtreatment, the medication was interrupted for one week every third month. RESULTS: Of the 399 children forming the intention-to-treat cohort, 245 halved their number of wet nights and started long-term treatment. During the periods off medication, 77 children were dry and at the end of the study another 73 (still on medication) reduced the number of wet nights to < or =10% of that during the observation period. A further 51 children halved the number of wet nights compared with the observation period. No serious adverse events occurred. CONCLUSION: Long-term treatment with nasal desmopressin at a main dose of 40 microg is an effective and safe treatment for monosymptomatic nocturnal enuresis.

Administration, Intranasal↗

Oral desmopressin as a new treatment modality for primary nocturnal enuresis in adolescents and adults: a double-blind, randomized, multicenter study. Dutch Enuresis Study Group.

PURPOSE: We evaluated the efficacy and safety of 2 oral doses of desmopressin compared to 20 micrograms. nasal spray and baseline values in the treatment of primary nocturnal enuresis. MATERIALS AND METHODS: A multicenter study was done comparing oral dosages (200 and 400 micrograms.) of desmopressin (4-week, randomized, double-blind phase followed by 12 weeks of open label treatment with 400 micrograms.) to 20 micrograms. nasal spray in 66 adults and adolescents 12 to 45 years old with primary nocturnal enuresis. RESULTS: No significant differences were found between the 2 doses of desmopressin tablets or between the tablets and 20 micrograms. nasal spray during the double-blind phase. However, patients who initially received 200 micrograms. desmopressin tablets experienced fewer wet nights after they completed 12 weeks of open label treatment when the dose was escalated to 400 micrograms. tablets. Those who received 400 micrograms. tablets initially maintained response during this phase. Desmopressin tablets were well tolerated at both dose levels: 96% of patients and 94% of physicians rated the tolerability as excellent. CONCLUSIONS: Desmopressin tablets are an effective and safe alternative for treatment of nocturnal enuresis.

Administration, Intranasal↗

Combined therapy of enuresis alarm and desmopressin in the treatment of nocturnal enuresis.

Twenty-eight children with primary nocturnal enuresis were blindly allocated at random to a combination of enuresis alarm and 20 micrograms intranasal desmopressin or alarm and placebo for 2 weeks. Patients received the other therapy after a 2-week treatment-free period. The combined treatment of desmopressin and alarm showed 5.1 +/- 0.4 (mean +/- SEM) dry nights per week and resulted in significantly more dry nights per week during the 2 weeks of observation than placebo and alarm (4.1 +/- 0.4, P less than 0.05).

Adolescent↗

Efficacy and safety during long-term treatment of primary monosymptomatic nocturnal enuresis with desmopressin. Swedish Enuresis Trial Group.

The Swedish Enuresis Trial (SWEET) was conducted to evaluate the long-term safety and efficacy of intranasal desmopressin treatment in children with primary, monosymptomatic nocturnal enuresis (PMNE). The study had an open, multicentre design and comprised a 4-wk observation period, a 6-wk dose titration period (with 20-40 microg desmopressin) and a 1-y, long-term treatment period. A treatment-free week was introduced every 3 mo to identify dry patients. In total, 399 children aged 6-12 y with PMNE were recruited. Of these, 245 patients (61%) experienced > or = 50% reduction in the number of wet nights during the last 4 wk of dose titration compared with the observation period. These responders entered the long-term phase of the trial. The mean number of wet nights per week decreased from a median of 5.3 (range 1.3-7.0) during the observation period to a median of 0.8 (range 0.0-5.0) during the last 3-mo period. Seventy-seven children became dry, 63 (83%) within 6 mo of treatment initiation. The percentage of children who became dry was similar in all age groups. Significantly fewer children in the lowest age group were defined as responders (52%; 95% CI 45, 59) among the 6-7-y-olds compared to 65% (56, 74) and 81% (72, 90) in the two older age groups. Desmopressin was well tolerated. No serious drug-related adverse events were recorded and no clinical symptoms of hyponatraemia were reported. The SWEET trial has demonstrated that desmopressin is both safe and effective for the long-term treatment of PMNE, with a significant therapeutic effect also in children of 6-7 y of age.

Administration, Intranasal↗

Childhood nocturnal enuresis: factors associated with outcome of treatment with an enuresis alarm.

A study was carried out to assess the factors that may affect the outcome of a single course of treatment for childhood nocturnal enuresis by use of an enuresis alarm. 113 children were treated and followed up; those showing failure of initial arrest of wetting, relapse and longterm successful outcome were analysed separately. Emphasis is placed on the need for the adoption of clear criteria regarding the definition of these three groups, and for an adequate follow-up of treated cases. Unsatisfactory housing conditions and circumstances giving rise to family difficulties were significantly associated with a less favourable rate of initial arrest. In the long term, family difficulties again were found to be significantly related to poor outcome. Behavioural deviance, as revealed by a teacher's behavioural questionnaire also adversely affected long-term success, although less significantly so. Family difficulties emerged as the most important predictor for outcome of treatment and adversely influenced the rate of initial arrest of wetting, the relapse rate and the long-term success rate.

Adolescent↗

Combined treatment with enuresis alarm and desmopressin for nocturnal enuresis.

Seventy-one children with nocturnal enuresis were enrolled in a controlled trial. The children were allocated to two matched groups. Children in both groups used an enuresis alarm until the end of treatment. Children in the first group were treated with 40 micrograms of intranasal desmopressin (Desmospray) for up to 6 weeks at the start of treatment with the alarm. During the observation period treatment there were 2.3 dry nights per week in both groups. At the end of treatment there was a significant difference in the mean number of dry nights per week between the two groups (6.3 in the alarm and desmopressin group and 4.8 in the alarm group) and also in the number of children becoming reliably dry. The combination of desmopressin and alarm was particularly helpful for children with severe wetting and those with family and behavioural problems.

Adolescent↗

Total genome scan analysis in a single extended family for primary nocturnal enuresis: evidence for a new locus (ENUR3) for primary nocturnal enuresis on chromosome 22q11.

OBJECTIVE: In this study we focussed on a single large family to maximize the possibility of recognizing a single locus. This family alone could raise a lod score above 3, i.e. sufficient by tradition for assignment of a locus. METHODS: The family consists of 11 children and 26 grandchildren in whom monosymptomatic primary nocturnal enuresis (PNE) is segregating in three generations. A genome scanning with about 800 polymorphic marker systems was used to localize a chromosome area for the trait and to narrow down the candidate region. RESULTS: Total genome scan and multipoint analysis map PNE to chromosome 22 between the markers D22S446 and D22S343 with a multipoint lod score of 4.51. CONCLUSION: In the candidate area for PNE, the gene GNAZ is mapped. GNAZ has a transducin function in eye and brain and is an obvious candidate gene for PNE.

Chromosome Aberrations↗

[Costs of the treatment of enuresis nocturna. Health economic consequences of alternative methods in the treatment of enuresis nocturna].

The health economic consequences of treating nocturnal enuresis with a buzzer alarm is compared to treatment with Desmopressin. Based on age specific prevalence estimates and reported effects of the two treatments a cost-effectiveness analysis (CEA) was performed. The analysis showed a considerable difference between the costs of the two alternative treatments. A treatment based upon the buzzer alarm could result in a net saving to society of 19.2 million DKK, while a treatment based upon Desmopressin could result in expenses for society of 44.8 million DKK. A treatment based on a combination of the two will be economically neutral to the society. Treatment with a buzzer alarm or a combined treatment is therefore from a health economic point of view preferable. The health economic consequences of the introduction of new treatments are discussed, and it is recommended that health economic analyses are performed before the introduction of new treatments.

Adolescent↗