What is the role of imipramine (tricyclic antidepressant) in treating bladder dysfunction, specifically nocturnal enuresis, in pediatric patients?

Imipramine in Pediatric Bladder Dysfunction (Nocturnal Enuresis)

Imipramine should be reserved as third-line therapy for nocturnal enuresis in children, used only after failure of both enuresis alarm and desmopressin, and only at tertiary care facilities due to significant cardiac safety concerns. 1, 2

Treatment Algorithm

First-Line Therapies (Try These First)

• Enuresis alarm: Best for well-motivated families and children without polyuria but with low voided volumes 1
• Desmopressin: Best for children with nocturnal polyuria and normal bladder reservoir function 1
• If one first-line therapy fails, offer the other before proceeding 1

Second-Line Therapy (Before Imipramine)

• Anticholinergics should be the next therapeutic attempt in therapy-resistant children, provided constipation is excluded or treated 1
• May be combined with desmopressin 1

Third-Line: When to Consider Imipramine

Only consider imipramine if: 1, 2

• Both enuresis alarm and desmopressin have failed
• Anticholinergics have been unsuccessful
• Treatment is at a tertiary care facility with appropriate monitoring capabilities
• All safety requirements can be met

Dosing Protocol

Initial Dosing

• Children aged 6-9 years: 25 mg orally at bedtime 2, 3
• Children older than 9 years: 50 mg orally at bedtime 2, 3
• Give medication 1 hour before bedtime 3

Dose Titration

• Evaluate response after 1 month 2, 4
• If inadequate response after 1 week, increase to 50 mg nightly in children under 12 years 3
• Children over 12 may receive up to 75 mg nightly 3
• Do not exceed 2.5 mg/kg/day - ECG changes of unknown significance reported at twice this dose 3
• Doses greater than 75 mg do not enhance efficacy and increase side effects 3

For Early Night Bedwetters

• Consider divided dosing: 25 mg in mid-afternoon, repeated at bedtime 3

Maintenance and Discontinuation

• If successful, taper gradually to the lowest effective dose 2, 4
• Institute regular drug holidays of at least 2 weeks every third month to decrease tolerance risk 2, 4
• Never stop abruptly - taper gradually to reduce 50% relapse rate 4, 5
• Consider drug-free period after adequate therapeutic trial with favorable response 3

Critical Safety Requirements

Mandatory Pre-Treatment Screening

Obtain ECG before starting imipramine if ANY of the following: 1, 2, 5

• History of palpitations or syncope in the child
• Any sudden cardiac death in the family
• Any unstable arrhythmia in the family
• This screens for long QT syndrome

Medication Storage

• Keep medication securely locked and completely out of reach of the patient and younger siblings 1, 2, 5
• Overdose may prove fatal due to cardiotoxicity 2

Cardiac Risks

• Potentially cardiotoxic even at therapeutic doses 2
• Can cause conduction defects, arrhythmias, and tachycardia 2
• Fatal in overdose 2

Expected Efficacy and Side Effects

Response Rates

• Approximately 50% of unselected children with enuresis respond to imipramine 2, 6
• In therapy-resistant cases (after desmopressin, alarm, and anticholinergics failed), 64.6% achieved at least 50% reduction in enuresis frequency 6
• Relapse rate as high as 50% after discontinuation 4, 5

Favorable Prognostic Indicators

• Older age (mean 11.4 years in responders vs 8.7 years in non-responders) 6
• Low spontaneous bladder capacity 6

Poor Prognostic Indicators

• Constipation 6
• History of daytime incontinence 6

Common Side Effects

• Mood changes 1, 2
• Nausea 1, 2
• Insomnia 1, 2
• These often appear earlier than beneficial effects but may gradually disappear even if treatment continues 1

Combination Therapy Options

With Desmopressin

• If partial response to imipramine, add desmopressin at standard dose 2, 5
• Critical requirement: Restrict fluid intake during evening and night to prevent water intoxication 2, 5

Low-Dose Combination Strategy

• Recent evidence suggests low-dose imipramine (5-25 mg) combined with solifenacin (anticholinergic) may be effective and safer in desmopressin-refractory cases 7, 8
• This approach uses lower imipramine doses to minimize cardiac risks while maintaining efficacy through synergistic anticholinergic action 7

Important Clinical Pearls

When Children Relapse

• Children who relapse when imipramine is discontinued do not always respond to subsequent courses 3
• Consider transitioning to enuresis alarm, which has 66% success rate 4
• Therapy-resistant children benefit from regular new attempts with enuresis alarm, even if it failed previously 1
• Adding desmopressin to alarm therapy may be beneficial, especially if child has nocturnal polyuria 1

Drug Interactions

• Avoid sympathomimetic amines (decongestants, local anesthetics with epinephrine) - imipramine potentiates catecholamine effects 3
• Hepatic enzyme inhibitors (cimetidine, fluoxetine) increase imipramine levels 3
• Hepatic enzyme inducers (barbiturates, phenytoin) decrease imipramine levels 3

Contraindication

• Do not use imipramine for depression in adolescents - lack of proven efficacy, high lethality in overdose, safer alternatives available 5