Can amitriptyline and flunarizine be given together?

Can Amitriptyline and Flunarizine Be Given Together?

Yes, amitriptyline and flunarizine can be given together for migraine prophylaxis, though this combination is not routinely recommended as first-line therapy and requires careful monitoring for additive side effects, particularly sedation, weight gain, and depression.

Evidence for Combined Use

The 2025 American College of Physicians guideline explicitly states that combination therapy with topiramate and amitriptyline was not recommended due to lack of added benefit and potential for increased adverse events 1. However, no specific guideline prohibits the combination of amitriptyline and flunarizine, and there is research evidence demonstrating their concurrent use in migraine patients 2.

Direct Evidence of Combined Use

• A 1993 study directly compared the effects of both amitriptyline (36 mg daily) and flunarizine (5 mg daily) in migrainous patients, demonstrating that both drugs can be studied in similar patient populations with similar mechanisms of action on catecholamine response 2
• The study showed both drugs had comparable effects on preventing epinephrine discharge in migraineurs, suggesting overlapping but not necessarily contraindicated mechanisms 2

Clinical Decision Algorithm

Step 1: Verify Indication for Combination Therapy

• Confirm the patient has failed monotherapy with first-line agents (beta-blockers, topiramate, candesartan) 1
• Document inadequate response after 2-3 months trial of single agents 1

Step 2: Screen for Contraindications

Absolute contraindications to combination:

• History of depression (both drugs can cause or worsen depression) 1, 3
• Elderly patients (increased risk of extrapyramidal symptoms with flunarizine) 1
• Parkinsonism (flunarizine contraindication) 1

Relative contraindications requiring caution:

• Cardiovascular disease (amitriptyline concern with doses >100 mg/day) 1
• Glaucoma (amitriptyline contraindication) 1
• Concurrent use of other sedating medications 4

Step 3: Dosing Strategy

Amitriptyline:

• Start at 10 mg at night 1
• Titrate slowly to 25-75 mg/day 1
• Maximum 100 mg/day to avoid cardiac risks 1

Flunarizine:

• Standard dose: 5-10 mg once daily at night 1, 4
• Administer at bedtime to minimize daytime sedation 4

Step 4: Monitor for Additive Side Effects

Primary concerns with combination:

• Sedation/somnolence (both drugs cause this) 1, 4
• Weight gain (both drugs associated) 1, 4
• Depression (both can cause, particularly flunarizine in elderly) 1, 3
• Anticholinergic effects (dry mouth, constipation from amitriptyline) 1
• Extrapyramidal symptoms (flunarizine, especially in elderly) 1, 3

Step 5: Establish Monitoring Plan

• Baseline ECG if using amitriptyline >75 mg/day or in patients with cardiovascular history 1
• Screen for depression at baseline and every 4-6 weeks 1, 3
• Monitor weight monthly 1, 4
• Assess for extrapyramidal symptoms, particularly in patients >65 years 1, 3
• Evaluate efficacy at 2-3 months (adequate trial period) 1, 4

Important Caveats

Why This Combination Is Not Standard Practice

The 2025 ACP guideline found no added benefit for combination preventive therapy compared to monotherapy for migraine, with potential for increased adverse events 1. While this finding specifically addressed topiramate plus amitriptyline, the principle applies broadly: combination prophylaxis should only be considered after multiple monotherapy failures 1.

Preferred Alternatives Before Combining

Second-line monotherapy options to try first:

• Candesartan 16-32 mg daily 1
• Venlafaxine 150-225 mg daily 1
• Lisinopril 1

Third-line options:

• OnabotulinumtoxinA 1
• CGRP monoclonal antibodies (erenumab, fremanezumab, eptinezumab) 1

Special Population Considerations

Women of childbearing potential:

• Both amitriptyline and flunarizine should be avoided in pregnancy when possible 1
• If prophylaxis is essential during pregnancy, propranolol is preferred 1
• Flunarizine may reduce oral contraceptive efficacy; consider barrier methods for 4 weeks after initiation and dose changes 3

Elderly patients:

• This combination is particularly problematic due to increased risk of falls (sedation), depression, and extrapyramidal symptoms 1
• Consider alternative agents or accept lower efficacy with monotherapy 1

Practical Implementation

If proceeding with combination therapy:

• Start one drug first, titrate to therapeutic dose over 4-6 weeks 1
• Add second drug only after first is stable and well-tolerated 1
• Both should be dosed at night to minimize daytime sedation 4
• Plan for 2-3 month trial before assessing efficacy 1, 4
• Consider tapering or discontinuing after 6-12 months of stability 1, 4

Documentation requirements:

• Document failure of at least two first-line monotherapy trials 1
• Record discussion of increased side effect risk with combination 1
• Note screening for depression and other contraindications 1, 3