Pharmaceutical Therapy for Enuresis
Desmospressin Contraindications: Hyponatraemia, renal failure, known hypersensitivity Oxybutynin Propiverine hydrochloride Mirabegron (beta-3 adrenoreceptor agonist) Tricyclic antidepressants Desmospressin DDAVP is a synthetic version of the posterior pituitary hormone vasopressin, also known as ADH. DDAVP monotherapy is recommended in cases of NP (with normal bladder capacity). Success rates of
Contraindications: Hyponatraemia, renal failure, known hypersensitivity
Mirabegron (beta-3 adrenoreceptor agonist)
Desmospressin
DDAVP is a synthetic version of the posterior pituitary hormone vasopressin, also known as ADH. DDAVP monotherapy is recommended in cases of NP (with normal bladder capacity). Success rates of 70% can be obtained.[26]
It is recommended to start treatment when the child is ≥6 years old.[27]
Although water intoxication and hyponatraemia are rare, limit fluids to an hour before and 8 hours after medication.[28]
When response to treatment with DDAVP is poor, be aware that poor parental compliance may be a factor.[29]
The starting MELT dosage of 120 µg is recommended. A structured titration increase of up to 240 µg is effective and safe.[30]
DDAVP can be used as monotherapy or in combination with alarm therapy.[26,27]
A recent meta-analysis has shown that structured withdrawal results in better relapse-free rates.[27]
Formulations available:
- Oral tablet. Initial dose 0.2 mg (maximum 0.4 mg) daily 1 hour before bedtime.
- Nasal spray. No longer recommended owing to the increased risk of overdose, nasal discomfort, nasal bleeding and headaches.
- MELT (sublingual desmopressin lyophilisate), dosage 60 µg, 120 µg, 180 µg and 240 µg, daily 1 hour before bedtime. Children preferred the MELT formulation in a randomised study of MELT v. tablet formulation.[31]
Contraindications: Hyponatraemia, renal failure, known hypersensitivity[26]
Anticholinergics
Monotherapy with anticholinergics is not indicated in the management of PMSE.[26,32]
They may be helpful as combination therapy with DDAVP in the management of refractory PMSE or in children with NE and daytime urinary incontinence if there is no post-void residual urine and constipation is excluded or successfully treated. In patients with overactive or small-capacity bladders, the addition of anticholinergic therapy is recommended.
Types of anticholinergics
Oxybutynin and propiverine hydrochloride are the only anticholinergic agents registered for use in children in SA. Tolterodine and solifenacin, newer agents with fewer side-effects, have been combined with DDAVP elsewhere. These drugs can be expected to become available for label prescription soon.
Oxybutynin
Oxybutynin reduces the risk of non-response to treatment by 57% compared with placebo.[33]
A similar response was observed in a randomised controlled trial comparing oxybutynin and tolterodine in patients with primary enuresis.[34]
- Dosage 5 mg 1 hour before bedtime.[3]
The anti-enuretic may not be immediately apparent, so the therapy should be evaluated after 1 - 2 months.[30]
If there is a good response, we recommend that drug withdrawal be attempted regularly, approximately every 3 months.[3]
Daytime incontinence and NE:
- In children aged >5 years, oxybutynin 5 mg twice (or three times) daily, preferably 5 - 10 mg 1 hour before bedtime.
- In children aged >6 years, extended-release oxybutynin, starting at 5 mg daily for a week and increasing to 10 mg daily, can be considered. Tablets should be swallowed and not chewed, crushed or divided.
- Oxybutynin is used as an off-label drug to control OAB in children aged 1 - 5 years, with a dosing regimen of 0.2 mg/kg orally administered two to four times daily.
Propiverine hydrochloride
This drug has recently been registered for use in SA in the paediatric population.
- Dosage 0.8 mg/kg per day in two to three divided doses.
- The coated tablets come in a dose of 5 mg per tablet.
- A minimum body weight of 12 kg is required before use. Children weighing ≥35 kg have the same maximum dose as adults, 15 mg twice daily.
Contraindications to anticholinergic therapy
Anticholinergics are contraindicated in infants aged <6 months, in patients with known hypersensitivity, and in those with myasthenia gravis, closed-angle glaucoma, pyloric stenosis, paralytic ileus or toxic megacolon.
Adverse effects
Anticholinergics are safe, and adverse effects are much less common in children than in adults.[30]
Common clinically relevant side-effects in children are constipation (which may in turn influence lower urinary tract function), increased post-void residual urine (with a risk for urinary tract infections), dry mouth (which may lead to dental caries), and altered behaviour, including night terrors.[35]
The effects on the central nervous system raise greater concern, and symptoms can include hallucinations, sedation, agitation, amnesia and confusion.[35]
Propiverine has a better tolerability profile than oxybutynin.[36]
All these side-effects resolve when the medication is stopped.
Mirabegron (beta-3 adrenoreceptor agonist)
The beta-3 agonist mirabegron was initially developed in 2007 to treat bladder overactivity and its associated symptoms of frequency, incontinence and urgency in adults.[37,38]
Use in the paediatric population has never been evaluated to the same degree. However, in 2016, Blais et al. [39] published the first research demonstrating efficacy and safety in children with OAB, with a median patient age of 10.1 years. Data on the use of mirabegron in the setting of enuresis are scant and primarily based on adult literature describing off-label use. The treatment of enuresis with mirabegron has only been evaluated in a single study, the design of which did not include a control arm.[40]
Data from this study showed complete and partial response in 31.3% and 40.6% of patients, respectively, with about one-third (28.1%) being non-responders after 6 months of treatment. Other limitations of this study included the small number of participants and the concomitant use of anticholinergic agents to improve continence.[40]
The side-effect profile of mirabegron is similar to that of anticholinergic agents, but to a lesser degree, and includes constipation and xerostomia. One specific side-effect is hypertension, and guidelines in the adult literature recommend routine measurement of blood pressure after initiation of treatment.
As no prospective data are currently available, mirabegron should be used with caution and in settings where other pharmacological options have failed, by physicians with experience in managing complicated enuresis.
- Dosage 25 mg per day 1 hour before bedtime in children aged >10 years.
Tricyclic antidepressants
Tricyclic antidepressants (TCAs), mostly imipramine, have been used for >60 years with proven benefits in enuresis.[41]
However, mainly owing to cardiotoxicity, they are used as a third line of therapy initiated by specialists experienced in the use of TCAs. These drugs can be fatal if overdosed or if the patient has long QT syndrome.[30]
The therapeutic-to-toxic ratio can be as low as 1:2. The mechanism of action of TCAs is unclear, but is thought to involve a combination of noradrenergic, serotoninergic and anticholinergic actions on the bladder, urine production, and arousal mechanisms. The most common side-effects are mood swings, nausea, anxiety, dizziness, drowsiness, lethargy, dry mouth, anorexia and vomiting, as well as hepatotoxicity and cardiotoxicity. Teenagers with suicidal ideation have also been described, especially if they have depressive symptoms.[41]
Before treatment with a TCA can commence, other modes of treatment should have been tried and have failed, or be contraindicated. The patient should have an electrocardiogram to exclude long QT syndrome. Parents need to be counselled to keep the medication away from siblings. There has been a rapid increase in the overall growth of antidepressant use in children, especially those aged >6 years, imposing a risk of unintentional ingestion by younger siblings.[42]
Dosage regimen:
- Imipramine is given 1 hour before bedtime.
- The initial dose is 25 - 50 mg daily.
- The lower dose is for children aged 5 - 8 years, and the higher dose is for older children.
- The dose is titrated, watching out for ineffective dose and side-effects.
Therapeutic response is evaluated after 1 month. If treatment is successful, the dose is titrated to the minimum effective dose. Tolerance to imipramine is known to develop, and it is recommended to let the patient have a drug holiday. One suggestion is after 3 months to have at least 2 weeks of a drug-free period.[30,41]
It should be noted and explained to the patient and parents that the dose needs to be decreased gradually when stopping the drug by halving the dose for 1 or 2 weeks. This is to reduce side-effects. On cessation of therapy, the relapse rate is as high as 96%.[41]
The South African Medical Journal_The South African guidelines on enuresis: 2024 update_November 2024; Vol. 114, No. 11