What is the recommended dosing regimen and titration schedule for verapamil in cluster headache, including target dose, maximum dose, ECG monitoring, and contraindications?

Verapamil Dosing in Cluster Headache

Start verapamil at 120-240 mg daily in divided doses (typically 40 mg morning, 80 mg afternoon, 80 mg evening) and titrate upward by 80 mg every 2 weeks with ECG monitoring until attacks are suppressed, side effects occur, or a maximum of 960 mg daily is reached. 1, 2

Initial Dosing Strategy

• Begin with 120-240 mg daily divided into three doses, with the largest dose given before bedtime if nocturnal attacks predominate 1
• Titrate by 80 mg every 2 weeks (or on alternate days for faster control) based on attack timing and response 1, 2
• Time doses strategically: For early morning attacks, set an alarm 2 hours before usual waking time to take medication; for nocturnal episodes, increase the evening dose first 1

Target and Maximum Doses

• Effective range: Most patients (majority) achieve control at 240-480 mg daily 1, 3
• Higher doses often needed: 15-20% of patients require 520-960 mg daily for adequate suppression 1, 4
• Maximum dose: Up to 960 mg daily (occasionally 1200 mg) has been used, though this is off-label and requires intensive monitoring 2, 4, 5

Efficacy by Cluster Type

• Episodic cluster headache: 94% achieve complete relief with individualized dosing 1
• Chronic cluster headache: Only 55% achieve complete relief (69% of men, 20% of women); the remainder require additional prophylactic agents like lithium or sodium valproate 1

Mandatory ECG Monitoring Protocol

ECG monitoring is absolutely essential and non-negotiable due to high cardiac risk:

• Baseline ECG before starting verapamil 2, 4
• Follow-up ECG every 2 weeks during dose escalation 2
• Continue monitoring indefinitely even in stable patients on high doses, as 75% of cardiac adverse events occur after ≥2 years of treatment 4
• Check for: PR interval prolongation (>0.2 seconds indicates first-degree heart block), bradycardia (<60 bpm), second-degree heart block, and junctional rhythm 2, 4

Cardiac Adverse Event Rates

• 19% develop arrhythmias (first-degree heart block most common at 12%, second-degree block rare) 2
• 36% develop bradycardia (<60 bpm), though only symptomatic cases require discontinuation 2
• 38% show ECG changes at very high doses (≥720 mg/day) 4
• Higher doses carry higher risk: Patients with ECG changes average 1,003 mg/day versus 800 mg/day in those without changes 4

Absolute Contraindications

• Second- or third-degree AV block or sick sinus syndrome without a pacemaker 6, 7
• Decompensated heart failure or severe left ventricular systolic dysfunction 6, 8
• Wolff-Parkinson-White syndrome with atrial fibrillation or flutter 6, 7
• Hypotension or cardiogenic shock 6
• Recent β-blocker use (within hours to days) due to additive negative chronotropic effects 6, 7

When to Stop or Reduce Verapamil

• PR interval >0.2 seconds (first-degree heart block): Consider dose reduction or discontinuation; one patient in 108 required permanent pacemaker 2
• Second-degree heart block: Immediate discontinuation required 2, 5
• Symptomatic bradycardia: Stop if patient develops dyspnea, fatigue, or syncope 5
• After cluster period ends: Continue same dose for 2 additional weeks, then systematically reduce 1

Common Pitfalls to Avoid

• Inadequate dosing: Many patients fail because doses are too low; don't stop at 240-360 mg if attacks persist 1
• Skipping ECG monitoring: 41% of patients in one audit had no ECGs—this is dangerous practice given 19% arrhythmia rate 2
• Assuming long-term safety: Cardiac events can occur after years of stable therapy; never discontinue monitoring 4
• Uniform dosing schedules: Individualize timing based on attack patterns rather than using standard three-times-daily dosing 1
• Premature discontinuation: Trial verapamil through at least 2-3 dose escalations before declaring failure 1

Drug Interactions Requiring Dose Adjustment

• Digoxin: Reduce digoxin dose by 30-50% due to increased serum levels 6
• Simvastatin/lovastatin: Increased myopathy risk; consider alternative statin 6
• Dofetilide: Absolute contraindication to co-administration 6
• Grapefruit juice: Avoid completely as it markedly increases verapamil levels 6

Hepatic Impairment Adjustment

• Reduce initial dose by 30-50% in patients with hepatic dysfunction, as verapamil undergoes extensive hepatic metabolism 6
• Titrate more cautiously with closer monitoring 6