What is the appropriate initial evaluation and management for a patient with a three‑month history of unilateral headache refractory to over‑the‑counter analgesics and without vomiting?

Evaluation and Management of Chronic Unilateral Headache Refractory to Over-the-Counter Analgesics

Immediate Diagnostic Priority: Rule Out Secondary Causes

This patient requires urgent neuroimaging (MRI brain with and without contrast preferred) because a three-month unilateral headache unresponsive to analgesics raises concern for secondary headache disorders including mass lesion, vascular malformation, or trigeminal neuralgia. 1, 2, 3

Red-Flag Assessment

• Unilateral location persisting for three months without side-switching is atypical for migraine and warrants imaging to exclude structural pathology 4, 5
• Failure of over-the-counter analgesics after three months suggests either inadequate acute therapy, wrong diagnosis, or secondary headache 6, 3
• Absence of vomiting does not exclude serious pathology—many secondary headaches present without nausea or vomiting 3, 7

Critical History Elements to Obtain

• Attack frequency and duration: If ≥15 days/month for >3 months with migraine features on ≥8 days, this meets chronic migraine criteria 1
• Presence of cranial autonomic symptoms (tearing, nasal congestion, eyelid swelling, facial sweating): Ipsilateral autonomic features with strictly unilateral pain suggest cluster headache or other trigeminal autonomic cephalalgia 2, 4
• Attack duration: Cluster headache attacks last 15–180 minutes and occur 1–8 times daily; migraine lasts 4–72 hours 2, 7
• Temporal pattern: Circadian or seasonal clustering of attacks points toward cluster headache 2
• Exact acute medication use: Document frequency (days per month) of all analgesics, NSAIDs, and any triptans to assess for medication-overuse headache 6, 1

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Differential Diagnosis Algorithm

If Imaging Is Normal and History Reveals:

Scenario A: Chronic Migraine (≥15 headache days/month for >3 months)

• Confirm diagnosis: Headache on ≥15 days/month with migraine features (unilateral, pulsating, moderate-to-severe, aggravated by activity, plus nausea or photophobia/phonophobia) on ≥8 days 1
• Screen for medication-overuse headache (MOH): If patient uses simple analgesics ≥15 days/month or triptans/combination analgesics ≥10 days/month for ≥3 months, MOH is present and must be addressed first 6, 1

Management:

• Withdraw overused medications immediately (no taper required); warn patient of 2–10 days of worsening headache during withdrawal 6
• Initiate CGRP monoclonal antibody (erenumab, fremanezumab, galcanezumab) as first-line preventive for chronic migraine—reduces migraine days by 2–4.8 days/month 1
• Alternative if CGRP unavailable: Topiramate 25 mg daily, titrate to 100–200 mg daily over 4–6 weeks 1
• Limit acute therapy to ≤2 days/week once MOH resolves to prevent recurrence 6, 1

Scenario B: Cluster Headache (Strictly Unilateral with Autonomic Features)

• Diagnostic features: Severe unilateral orbital/supraorbital/temporal pain lasting 15–180 minutes, occurring 1–8 times daily, with ipsilateral tearing, nasal congestion, eyelid edema, or facial sweating 2
• Absence of photophobia/phonophobia makes cluster headache more likely than migraine 2

Acute Treatment:

• 100% oxygen at 12–15 L/min via non-rebreather mask for 15–20 minutes—most effective and safe, relieves 70–80% of attacks within 15 minutes 2
• Subcutaneous sumatriptan 6 mg—provides relief in 70–82% within 15 minutes 2

Preventive Treatment:

• Verapamil is first-line preventive for cluster headache 2
• Refer to neurology immediately for cluster headache diagnosis confirmation and verapamil initiation with EKG monitoring 2, 3

Scenario C: Episodic Migraine with Inadequate Acute Therapy

• If <15 headache days/month, this is episodic migraine, not chronic 1, 7

Optimized Acute Treatment Algorithm:

1. First-line for mild-to-moderate attacks: Naproxen 500–825 mg or ibuprofen 400–800 mg at headache onset 6, 7
2. First-line for moderate-to-severe attacks or NSAID failure: Sumatriptan 50–100 mg PLUS naproxen 500 mg—superior to either alone, with 130 additional patients per 1,000 achieving sustained 48-hour relief 6
3. If oral therapy fails: Subcutaneous sumatriptan 6 mg provides highest efficacy (59% pain-free at 2 hours) with 15-minute onset 6
4. Critical frequency limit: Restrict all acute medications to ≤2 days/week (≤10 days/month) to prevent MOH 6, 1

When to Initiate Preventive Therapy:

• ≥2 migraine attacks per month causing disability ≥3 days 6, 1
• Acute medication use >2 days/week 6, 1
• Contraindication to or failure of acute therapies 6

First-line preventive options:

• Propranolol 80–240 mg/day (avoid in asthma, heart block) 6
• Topiramate 25 mg daily, titrate to 100–200 mg (warn about cognitive side effects, teratogenicity) 6, 1
• Amitriptyline 30–150 mg/day if comorbid depression or tension-type headache 6

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Medications to Absolutely Avoid

• Opioids (codeine, hydromorphone, tramadol) are contraindicated—they provide questionable efficacy, cause dependency, trigger rebound headaches, and worsen long-term outcomes 6
• Butalbital-containing compounds carry high risk of MOH and should be avoided 6

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Critical Pitfalls to Avoid

1. Do not delay imaging in a patient with three months of strictly unilateral headache unresponsive to analgesics—secondary causes must be excluded 3, 4, 5
2. Do not allow continued daily analgesic use while "waiting to see if it improves"—this perpetuates MOH and guarantees treatment failure 6, 1
3. Do not diagnose migraine based solely on unilateral location—cluster headache and trigeminal neuralgia also present unilaterally and require different management 2, 4, 5
4. Do not prescribe preventive therapy without first withdrawing overused acute medications if MOH is present—preventives will not work until overuse is stopped 1

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Referral Indications

• Immediate neurology referral if cluster headache is suspected (for verapamil initiation and EKG monitoring) 2, 3
• Neurology referral if diagnosis remains uncertain after imaging, if all preventive strategies fail, or if patient requires onabotulinumtoxinA for chronic migraine 6, 1, 3