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Evaluating use of higher dose oxybutynin in combination with desmopressin for refractory nocturnal enuresis
Aaron Berkenwald, Jacqueline Pires, Pamela Ellsworth
Commented by Konstantinos Kamperis:
This study explores the efficacy of a combination treatment with desmopressin and oxybutynin in children who prove refractory to monotherapy with desmopressin.
Abnormal bladder function especially filling phase issues such as low capacity and overactivity represent at least part of the pathophysiology of nocturnal enuresis. The incidence of children with bladder dysfunction is higher among children who no not respond to desmopressin treatment or treatment with the enuresis alarm. Although results from studies of anticholinergics in children with monosymptomatic nocturnal enuresis are still scarce, it seems rational to attempt treatment of these children with anticholinergics.
The authors perform a retrospective analysis of 62 enuresis patients seen in their clinics. Among those 25 were refractory to treatment and were subsequently treated with a combination of desmopressin and incremental doses of oxybutynin, up to 10 mg, thus converting the majority of the patients to responders. The medication was well tolerated by the patients.
The authors describe an overall success rate of 97%. Daytime symptoms and neuropsychological comorbidities were associated with unfavorable outcome of desmopressin monotherapy.
Although the majority of children with enuresis can be successfully treated with desmopressin of the enuresis alarm, further treatment options exist for the refractory cases. Anticholinergics either as monotherapy or in combination with desmopressin seem a rational treatment option for the refractory cases.
Nocturnal enuresis is a common pediatric condition with limited treatment options. In older children, pharmacologic therapy is often the preferred treatment. Pharmacologic therapies including desmopressin (DDAVP) or imipramine are effective in 40-50% of children. However, imipramine has serious safety concerns. Desmopressin in combination with a fixed dose anticholinergic has been shown to be useful in individuals who fail desmopressin monotherapy, but still fails to achieve success rates greater than 60%.
The goal was to explore the efficacy and safety of using combination therapy desmopressin plus oxybutynin with increasing dose of oxybutynin in patients refractory to standard combination therapy.
This was a single institution, IRB-approved, retrospective chart review of 61 patients (ages 7-18 years) including those with monosymptomatic primary nocturnal enuresis and non-monosymptomatic enuresis with controlled daytime voiding symptoms (CDVS) treated initially with desmopressin. All patients who failed initial therapy with desmopressin were started on combination therapy desmopressin (0.6 mg) plus standard dose (5 mg) oxybutynin. In patients who failed standard combination therapy, the dose of oxybutynin was titrated upwards until a response or the maximum dose of 10 mg was achieved. Demographic and medical history data were evaluated to determine predictive factors associated with response/failure to different therapy groups.
The use of escalating doses of oxybutynin in combination with desmopressin achieved an overall response rate of 96.7% defined as a 2-week period without any enuretic events following initiation of treatment. Low-dose combination therapy (LDCT) (0.6 mg of desmopressin+5 mg of oxybutynin) had a response rate of 68% (Table). Advanced dose combination therapy (ADCT) (0.6 mg of desmopressin+7.5-10 mg of oxybutynin) had a response rate of 75.0%. A statistically significant relationship was found correlating both attention deficit disorder/attention-deficit hyperactivity disorder(ADD/ADHD) and CDVS with failure on monotherapy. No patients in the study reported any adverse events or side effects from the medications.
The overall success rate of 96.7% with titrated doses of oxybutynin in combination with desmopressin is considerably higher than the response rates on fixed dose combination therapy quoted in the literature and supports the need for further evaluation in larger studies. Additionally, we found a statistically significant association between monotherapy failure and children with either ADD/ADHD or controlled daytime voiding symptoms. Our study is limited by small numbers and larger studies are needed to confirm these results.
Our results suggest that ADCT is a safe and effective treatment option for primary nocturnal enuresis refractory to standard and low-dose combination therapy.