What is the best combination of treatments for an adult patient with chronic cephalalgia (headache) and no significant underlying medical conditions?

Best Combination Treatment for Chronic Cephalalgia (Headache)

For chronic migraine (≥15 headache days/month), the optimal combination is onabotulinumtoxinA (Botox) injections every 12 weeks PLUS a daily oral preventive medication (topiramate, propranolol, or amitriptyline), with acute attacks treated using triptan + NSAID combination therapy. 1, 2

Defining Chronic vs. Episodic Headache

First, determine if this is chronic migraine (≥15 headache days per month for at least 3 months, with headaches lasting ≥4 hours) or episodic migraine (<15 headache days/month). 1 This distinction is critical because:

• Botox is only effective for chronic migraine and should NOT be used for episodic migraine 1
• Treatment algorithms differ substantially between these two conditions

For Chronic Migraine: Preventive Combination Strategy

First-Line Preventive Combination

Start with onabotulinumtoxinA 155-195 units to 31-39 sites every 12 weeks (PREEMPT protocol) PLUS one oral preventive medication. 1

The evidence strongly supports combination preventive therapy:

• Recent 2025 real-world data shows combining Botox with atogepant reduced monthly migraine days by 6.5 days, with 45% achieving ≥50% reduction 3
• Combination therapy is appropriate for patients with inadequate response to monotherapy 1
• Botox reduces headache days by 1.9-3.1 days per month compared to placebo 1

Choosing the Oral Preventive Partner

Select based on contraindications and comorbidities:

• Propranolol 80-240 mg/day: First choice unless contraindicated by asthma, low blood pressure, or bradycardia 1, 4
• Topiramate 100-200 mg/day: Alternative first-line option; avoid in pregnancy (teratogenic) 1, 5
• Amitriptyline 30-150 mg/day: Best for mixed migraine and tension-type headache 4
• Valproate: Effective but has weight gain, hair loss, tremor, and is teratogenic 4

Critical timing consideration: Give oral preventives 2-3 months for efficacy assessment before adding Botox, unless contraindications exist. 1 However, Botox can be initiated immediately if oral medications are contraindicated. 1

For Chronic Migraine: Acute Attack Treatment

Use triptan + NSAID combination for each acute attack, limited to ≤2 days per week. 2

Optimal Acute Combination

Sumatriptan 50-100 mg PLUS naproxen sodium 500-825 mg provides the strongest evidence:

• 180 more patients per 1000 achieve sustained pain relief at 48 hours compared to monotherapy 2
• 160 fewer patients per 1000 need rescue medication 2
• High-certainty evidence supports this combination over monotherapy 2

Alternative triptan + NSAID combinations:

• Rizatriptan 10 mg + naproxen 500 mg (rizatriptan is fastest oral triptan, reaching peak in 60-90 minutes) 6
• Any triptan + ibuprofen 400-800 mg 6

Critical Frequency Limitation

Never exceed 2 days per week (10 days per month) of acute medication use to prevent medication-overuse headache, which paradoxically increases headache frequency and can lead to daily headaches. 6 If needing acute treatment more frequently, this signals inadequate preventive therapy requiring escalation. 6

For Episodic Migraine: Different Approach

If the patient has <15 headache days/month:

DO NOT use Botox (ineffective for episodic migraine). 1 Instead:

1. Acute treatment: Triptan + NSAID combination (same as above) 2
2. Preventive therapy (if ≥2 attacks/month causing ≥3 days disability): Start with propranolol, topiramate, or amitriptyline monotherapy 4

Monitoring and Escalation

Timeline for Response Assessment

• Oral preventives: Assess after 2-3 months 1
• Botox: Requires at least 2-3 treatment cycles (6-9 months) before declaring non-response 1
• CGRP monoclonal antibodies: Assess after 3-6 months 1

When to Escalate

Add CGRP monoclonal antibody (erenumab, fremanezumab, galcanezumab) or oral CGRP antagonist (atogepant) to the Botox + oral preventive combination if:

• Inadequate response after appropriate trial periods 1
• Patient continues to have >8 migraine days/month despite dual therapy 3

The 2025 SYNERGY study demonstrates that triple combination (Botox + atogepant + continued acute treatment) is safe and effective, with no novel safety concerns. 3

Critical Pitfalls to Avoid

1. Never use opioids or butalbital-containing compounds for routine headache treatment—they cause dependency, rebound headaches, and loss of efficacy 6, 7

2. Address medication-overuse headache concurrently—limit simple analgesics to <15 days/month and triptans to <10 days/month 1

3. Don't abandon Botox prematurely—requires 6-9 months (2-3 cycles) for full efficacy assessment 1

4. Document headache frequency, intensity, and quality of life impact at each visit to objectively assess treatment response 1

5. Screen for cardiovascular disease before prescribing triptans—they are contraindicated in ischemic vascular disease, vasospastic coronary disease, and uncontrolled hypertension 6