In children (<18 years), what are the indications, dosing guidelines, contraindications, and safety concerns for using amitriptyline?

Indications of Amitriptyline in Children

Amitriptyline has extremely limited evidence-based indications in pediatric populations, with the strongest support being for migraine prophylaxis in children ≥8 years when combined with cognitive behavioral therapy, though recent high-quality evidence shows it performs no better than placebo. 1, 2

FDA-Approved and Guideline-Supported Indications

Migraine Prevention (Ages 8-17 years)

• Amitriptyline combined with cognitive behavioral therapy is recommended by the American Academy of Neurology as one of three evidence-based preventive options for pediatric migraine, alongside topiramate and propranolol 1, 3
• However, a 2017 multicenter randomized controlled trial (the CHAMP study) demonstrated that amitriptyline at 1 mg/kg/day was no more effective than placebo for reducing headache frequency (52% response vs 61% placebo, P=0.26) 2
• Despite this negative trial, clinicians should discuss with families that placebo was as effective as studied medications in many pediatric migraine trials, making shared decision-making essential 1, 3
• Dosing: 1 mg/kg/day, typically starting low and titrating up 4, 2
• Consider when: ≥2 migraine attacks per month causing disability lasting ≥3 days, or acute medication use >2 times per week, or failed acute treatments 3

Enuresis (Third-Line Only, Tertiary Care)

• Imipramine (not amitriptyline specifically) is the only tricyclic antidepressant with evidence for enuresis, and is relegated to third-line therapy due to cardiotoxicity concerns 1
• Tricyclic antidepressants should only be used at tertiary care facilities due to potentially fatal cardiac toxicity with overdose 1
• This is NOT a primary indication for amitriptyline in children 1

Contraindicated or Not Recommended Uses

Depression in Children

• Antidepressants, including tricyclics, should NOT be used for depression in children 6-12 years in non-specialist settings 1
• Fluoxetine (not tricyclics) is the only antidepressant that may be considered for adolescents with depression, and only with close monitoring for suicidality 1
• WHO guidelines explicitly state that tricyclic antidepressants should not be used for adolescent depression in favor of fluoxetine 1

Anxiety Disorders

• Pharmacological interventions should NOT be considered for anxiety disorders in children and adolescents in non-specialist settings 1

Neuropathic Pain

• While amitriptyline is used for neuropathic pain in adults, there is no high-quality evidence supporting its use in pediatric neuropathic pain conditions 5, 6
• The adult literature shows only third-tier evidence with significant risk of bias 5

Other Behavioral Disorders

• Pharmacological interventions for disruptive behavior disorders, conduct disorder, and oppositional defiant disorder should NOT be offered by non-specialized providers and require specialist referral 1

Critical Safety Concerns and Contraindications

Age Restrictions

• Amitriptyline is contraindicated in children under 6 years of age 7
• Most evidence exists for children ≥8 years for migraine prevention 1, 2

Cardiovascular Risks

• Potentially cardiotoxic with risk of fatal overdose - must be kept locked away from younger siblings 1
• Screen for personal history of palpitations/syncope or family history of sudden cardiac death, long QT syndrome, or unstable arrhythmia before prescribing 1
• Consider ECG monitoring if any cardiac risk factors present 1

Common Adverse Effects

• Fatigue occurs in 30% vs 14% placebo 2
• Dry mouth occurs in 25% vs 12% placebo 2
• Mood changes and sedation are common, even at low doses used for pain 1, 8
• Three patients in the CHAMP trial had serious adverse events of altered mood 2

Monitoring Requirements

• Close monitoring for suicidal ideation/behavior is essential, particularly given one suicide attempt occurred in the CHAMP trial (though in the topiramate group) 2
• Monitor for anticholinergic effects: constipation, urinary retention, sedation 1, 8
• Regular assessment of mood changes, particularly in first weeks of treatment 1

Practical Dosing Algorithm for Migraine Prevention

When amitriptyline is chosen despite limited evidence:

1. Start at low dose: 0.25-0.5 mg/kg at bedtime 4
2. Titrate slowly: Increase by 0.25 mg/kg every 1-2 weeks 4
3. Target dose: 1 mg/kg/day (maximum studied dose) 4, 2
4. Timing: Single daily dose at bedtime to minimize daytime sedation 4
5. Trial duration: Assess response after 8-12 weeks 1, 2
6. Combine with: Cognitive behavioral therapy and lifestyle modifications (regular sleep, meals, hydration, trigger avoidance) 1, 3

Alternative First-Line Options to Consider

• For migraine prevention: Propranolol 2-3 mg/kg/day has stronger evidence with 83% response rate in reducing headache frequency by >50% 3
• For acute migraine treatment: Ibuprofen 10 mg/kg is first-line for all pediatric patients 1, 9
• For adolescent acute migraine: Consider triptans (sumatriptan nasal, zolmitriptan nasal, rizatriptan ODT) if NSAIDs fail 1, 9

Key Clinical Pitfalls

• Do not assume adult neuropathic pain evidence translates to children - no pediatric data exists 5, 6
• Do not use for depression in children - this is explicitly contraindicated 1
• Do not prescribe without discussing the high placebo response rate in pediatric migraine trials 1, 3
• Do not forget to screen for cardiac risk factors before initiating therapy 1
• Do not use doses higher than 1 mg/kg/day - no evidence supports higher doses and adverse effects increase 4, 2