Can flunarizine and duloxetine be prescribed together?

Can Flunarizine and Duloxetine Be Given Together?

Yes, flunarizine and duloxetine can be prescribed together safely, and this combination has demonstrated clinical efficacy for chronic migraine with comorbid depression and anxiety. 1

Evidence Supporting Combined Use

Direct Clinical Evidence

• A 2022 randomized controlled trial specifically evaluated flunarizine combined with duloxetine in 59 patients with chronic migraine and comorbid depression/anxiety disorders 1
• This combination significantly reduced inflammatory markers (TNF-α, IL-6, hs-CRP) compared to flunarizine with loxoprofen 1
• Depression scores (HAMD) and anxiety scores (HAMA) improved more with the flunarizine-duloxetine combination than alternative regimens 1
• The study reported effective improvement in neuroelectrophysiological parameters without significant safety concerns 1

Pharmacokinetic Compatibility

Flunarizine and duloxetine do not have clinically significant metabolic interactions:

• Duloxetine is metabolized primarily by CYP1A2 and CYP2D6 enzymes 2, 3
• Flunarizine does not significantly inhibit or induce these cytochrome P450 pathways
• Duloxetine inhibits CYP2D6 but not CYP1A2, CYP3A, CYP2C9, or CYP2C19 to clinically relevant degrees 2
• The only clinically significant drug interactions with duloxetine occur with strong CYP1A2 inhibitors (like fluvoxamine, which increases duloxetine exposure by 460%) or MAO inhibitors 3

Clinical Application Algorithm

When to use this combination:

• Chronic migraine patients with comorbid depression or anxiety 1
• Neuropathic pain conditions where both migraine prophylaxis and mood/pain management are needed 4
• Fibromyalgia with migraine headaches, as duloxetine is FDA-approved for fibromyalgia 4

Dosing considerations:

• Start duloxetine at standard doses of 40-60 mg daily 5
• Flunarizine typically dosed at 5-10 mg daily for migraine prophylaxis
• No dose adjustments needed for the combination based on pharmacokinetic data 1, 3

Safety Monitoring

Monitor for duloxetine-specific adverse effects:

• Nausea, dry mouth, headache, constipation, and dizziness (most common) 6, 2
• Blood pressure increases (check periodically) 6
• Rare but serious: hepatic failure, severe skin reactions, suicidal thinking 6

Monitor for flunarizine-specific effects:

• Weight gain, sedation, extrapyramidal symptoms (with prolonged use)
• Depression (paradoxically, though the combination with duloxetine may mitigate this)

Critical Contraindications

Avoid this combination if:

• Patient is taking MAO inhibitors (absolute contraindication with duloxetine) 2, 3
• Patient is on strong CYP1A2 inhibitors like fluvoxamine or ciprofloxacin 3
• Severe hepatic impairment (duloxetine contraindication) 3
• Severely impaired renal function (duloxetine requires caution) 3

Common Pitfalls to Avoid

Do not confuse this safe combination with problematic duloxetine interactions:

• The flunarizine-duloxetine combination is NOT comparable to combining duloxetine with fluoxetine, which has significant CYP2D6 interaction concerns requiring 5-week washout periods 5
• Unlike combining two SNRIs (venlafaxine + duloxetine), which can be fatal due to serotonin syndrome 7, flunarizine is a calcium channel blocker without serotonergic activity
• Flunarizine does not enhance serotonin syndrome risk, unlike other serotonergic agents 2