Migraine Labs and Next Steps: What to Do After Your First or Recurring Attack

What Causes Migraine?

Migraine arises from a genetically influenced dysfunction of brainstem pain-modulation pathways combined with abnormal sensitization of the trigeminovascular system. It is not simply "a bad headache." Cortical spreading depression, a wave of neuronal and glial depolarization moving across the cortex at 3 to 5 mm per minute, is now the best-supported mechanism behind migraine aura and the subsequent pain phase. Hadjikhani et al., PNAS 2001.

Neurochemical Drivers

Calcitonin gene-related peptide (CGRP) is released from trigeminal nerve endings during an attack and causes vasodilation, neurogenic inflammation, and central sensitization. Plasma CGRP rises measurably during spontaneous migraine and returns to baseline after successful triptan treatment. Goadsby et al., Ann Neurol 1990. Serotonin (5-HT) receptors on trigeminal afferents are the target of the triptan drug class, which is why selective 5-HT1B/1D agonists abort attacks in 60 to 70 percent of patients.

Genetic Architecture

First-degree relatives of a person with migraine have a two- to fourfold elevated risk. Familial hemiplegic migraine subtypes (FHM1, FHM2, FHM3) are caused by single-gene mutations in CACNA1A, ATP1A2, and SCN1A respectively, but these are rare. Pietrobon and Striessnig, Nat Rev Neurosci 2003. Common migraine is polygenic, with genome-wide association studies identifying 44 independent susceptibility loci as of 2016. Gormley et al., Nat Genet 2016.

Triggers vs. Root Cause

Triggers (sleep disruption, hormonal fluctuation, caffeine withdrawal, stress, skipped meals) lower the threshold for an attack. They do not cause migraine on their own. Estrogen withdrawal is the dominant trigger in women, which explains the high prevalence of perimenstrual migraine and the frequent worsening in perimenopause. MacGregor, J Fam Plann Reprod Health Care 2009.

How Is Migraine Diagnosed?

Migraine is a clinical diagnosis. The International Classification of Headache Disorders, 3rd edition (ICHD-3), published by the International Headache Society, defines the criteria used worldwide.

ICHD-3 Criteria for Migraine Without Aura

A diagnosis requires at least 5 attacks lasting 4 to 72 hours (untreated or unsuccessfully treated), with the headache having at least 2 of these 4 features:

• Unilateral location
• Pulsating quality
• Moderate or severe pain intensity
• Aggravation by or causing avoidance of routine physical activity

The attack must also include at least 1 of: nausea or vomiting, or photophobia and phonophobia. ICHD-3, Cephalalgia 2018.

Migraine With Aura

Aura affects about 30 percent of people with migraine. Aura symptoms are fully reversible and typically develop over 5 to 20 minutes, lasting under 60 minutes. Visual aura (scintillating scotoma, fortification spectra) is the most common. Sensory or speech aura occurs in fewer than 10 percent of cases. Aura itself does not require imaging unless features are atypical (prolonged, motor, or lacking a history of prior aura).

Validated Screening Tools

The ID Migraine screener (3 yes/no questions: nausea, disability, photosensitivity) has a sensitivity of 81 percent and specificity of 75 percent in primary care. Lipton et al., Neurology 2003. The MIDAS (Migraine Disability Assessment) questionnaire quantifies functional impairment over 90 days and is widely used to match treatment intensity to disability level.

What Labs and Imaging Should Be Ordered?

No blood test diagnoses migraine. Workup is ordered to exclude secondary causes when red-flag features are present or when the clinical picture is atypical.

Blood Tests to Consider

Routine testing in a classic presentation is low-yield. When secondary headache is on the differential, consider:

• CBC and ESR/CRP: ESR above 50 mm/hr in a patient over 50 raises concern for giant cell arteritis, a medical emergency. Hunder et al., Arthritis Rheum 1990.
• Thyroid-stimulating hormone (TSH): Both hypothyroidism and hyperthyroidism may cause or worsen headache.
• Fasting glucose and HbA1c: Hypoglycemia is a recognized migraine trigger; metabolic screening is appropriate in high-risk patients.
• Antinuclear antibody (ANA) and antiphospholipid antibodies: Relevant when lupus or antiphospholipid syndrome is considered (e.g., young woman with migraine with aura plus prior pregnancy loss or livedo reticularis).
• Coagulation studies: For migraine with aura in patients under 45 who have had stroke-like symptoms, a thrombophilia screen may be ordered per neurology guidance.

Imaging Criteria

The American College of Radiology (ACR) Appropriateness Criteria and the U.S. Headache Consortium guidelines agree that neuroimaging is not required for patients with a stable, typical migraine pattern. Evans et al., Neurology 2000.

MRI brain with and without gadolinium contrast is preferred over CT when imaging is indicated. Indications include:

• First or worst headache of life (thunderclap)
• Progressive worsening over weeks
• New neurological deficit
• Age over 50 with new headache type
• Headache triggered by exertion, Valsalva, or sexual activity
• Known immunosuppression or malignancy
• Papilledema on fundoscopy

CT without contrast remains the fastest rule-out for acute subarachnoid hemorrhage in an emergency setting. If CT is negative and clinical suspicion remains high, lumbar puncture to detect xanthochromia is the next step.

Lumbar Puncture

LP is not routine for migraine but is indicated when thunderclap headache is present and CT is negative, when infectious meningitis is suspected, or when idiopathic intracranial hypertension is being evaluated. Opening pressure above 25 cm H2O supports the latter diagnosis.

Red-Flag Features That Change Management

Certain headache features are termed "SNOOP4" red flags and require urgent evaluation. Missing them risks delayed diagnosis of hemorrhage, tumor, or infection.

The SNOOP4 acronym covers:

• S: Systemic symptoms or secondary risk factors (fever, weight loss, cancer, HIV)
• N: Neurological symptoms or signs
• O: Onset sudden (thunderclap)
• O: Onset after age 50
• P: Pattern change (progressive worsening)
• P: Postural component (worsens lying flat, suggests raised ICP)
• P: Precipitated by Valsalva (cough, exertion, sex)
• P: Papilledema

As the American Headache Society states in its 2019 position statement: "The presence of any red-flag feature should prompt neuroimaging before attributing the headache to a primary disorder." American Headache Society, Headache 2019.

Acute Treatment Options

Acute ("abortive") treatment aims to stop an attack in progress. Treatment within 2 hours of onset produces better outcomes than waiting.

Step 1: Non-Prescription Options

For mild to moderate attacks, ibuprofen 400 to 600 mg or naproxen sodium 500 to 550 mg is first-line. Aspirin 900 mg plus metoclopramide 10 mg was superior to placebo in a Cochrane review of 13 trials (NNT approximately 6 for headache relief at 2 hours). Derry et al., Cochrane Database Syst Rev 2013.

Step 2: Triptans

Sumatriptan was the first triptan approved and remains the most studied. A 2010 Cochrane review of sumatriptan 100 mg oral in 19,604 patients found 2-hour pain freedom in 29 percent versus 8 percent for placebo. Derry et al., Cochrane Database Syst Rev 2012. Seven triptans are available (sumatriptan, rizatriptan, eletriptan, almotriptan, frovatriptan, naratriptan, zolmitriptan). Eletriptan 40 mg has the highest NNT for 2-hour pain relief among oral options.

Triptans are contraindicated in hemiplegic migraine, basilar-type migraine, uncontrolled hypertension, and established cardiovascular or cerebrovascular disease.

Step 3: Newer Acute Agents

Two mechanistically distinct drug classes were approved between 2018 and 2020.

Gepants (ubrogepant, rimegepant) are oral CGRP receptor antagonists. They carry no triptan-class cardiovascular contraindications. In the ACHIEVE-I trial (N=1,327), ubrogepant 100 mg achieved 2-hour pain freedom in 21.2 percent versus 11.8 percent for placebo (P<0.001). Dodick et al., JAMA 2019.

Ditans (lasmiditan) act on 5-HT1F receptors without vasoconstriction. In SAMURAI (N=1,856), lasmiditan 200 mg produced 2-hour pain freedom in 38.8 percent versus 21.3 percent for placebo. Kuca et al., Lancet 2018. Lasmiditan is a Schedule V controlled substance because of dizziness and CNS effects.

Preventive Treatment: Who Needs It and What Works

Prevention is indicated when attacks occur on 4 or more days per month, when acute medications are failing or overused, or when the migraine subtype carries elevated stroke risk (migraine with aura in a smoker on combined oral contraceptives).

Oral Preventives

The American Headache Society and the American Academy of Neurology give Level A evidence (established efficacy) to four oral agents:

• Topiramate 50 to 100 mg/day: Reduces monthly migraine days by a mean of 2.4 versus 1.4 for placebo in controlled trials. Brandes et al., JAMA 2004.
• Valproate/divalproex 500 to 1500 mg/day: Avoid in women of childbearing age due to teratogenicity.
• Propranolol 80 to 240 mg/day and metoprolol 100 to 200 mg/day: First-line in patients with comorbid hypertension or anxiety.
• Amitriptyline 10 to 75 mg nightly: Preferred when insomnia or depression co-exists.

Anti-CGRP Monoclonal Antibodies

Four anti-CGRP or anti-CGRP-receptor monoclonal antibodies are FDA-approved for migraine prevention: erenumab (Aimovig), fremanezumab (Ajovy), galcanezumab (Emgality), and eptinezumab (Vyepti, IV infusion).

In the STRIVE trial (N=955), erenumab 140 mg monthly reduced monthly migraine days by 3.7 versus 1.8 for placebo at 6 months (P<0.001). Goadsby et al., NEJM 2017. These agents have a favorable tolerability profile and show onset of effect within 4 weeks, faster than older oral agents.

OnabotulinumtoxinA (Botox)

FDA-approved for chronic migraine (15 or more headache days per month, 8 of which meet migraine criteria). The PREEMPT protocol delivers 155 to 195 units across 31 to 39 injection sites every 12 weeks. PREEMPT 2 (N=705) showed a 2.3-day reduction in headache days versus placebo at 24 weeks. Diener et al., J Headache Pain 2010.

Non-Pharmacological Prevention

Aerobic exercise (3 sessions per week, 40 minutes, moderate intensity) reduced monthly migraine frequency by 0.6 days in a 2023 meta-analysis of 10 RCTs (N=508). Carvalho et al., Neurology 2023. Cognitive behavioral therapy and biofeedback show Level B evidence. Magnesium glycinate 400 mg daily has modest evidence; serum magnesium below 0.85 mmol/L predicts better response.

Migraine in Women: Hormonal Considerations

Women are three times more likely than men to have migraine, and hormonal fluctuation is central to that disparity. Perimenstrual migraine (attacks beginning 2 days before to 3 days after menses) occurs in 50 to 60 percent of women who have migraine. MacGregor et al., Neurology 2006.

Oral Contraceptives and Risk

Combined oral contraceptives (estrogen plus progestin) may worsen migraine with aura and carry a small but real additive stroke risk in this subgroup. The World Health Organization rates combined hormonal contraceptives as Category 4 (unacceptable risk) in women with migraine with aura. Progestin-only methods are Category 2 (benefits likely outweigh risks). WHO Medical Eligibility Criteria, 2015.

Perimenopause and HRT

Migraine frequency often spikes during perimenopause as estrogen levels fluctuate widely. Transdermal estradiol at stable low doses (0.05 to 0.1 mg/day patch) is less likely to trigger attacks than oral estrogen because it avoids peak-and-trough serum fluctuations. Women with migraine with aura who are also on HRT should use the lowest effective estradiol dose and avoid progestins that lower the migraine threshold.

Medication-Overuse Headache: A Common Complication

Using acute headache medications on 10 or more days per month for 3 or more months causes medication-overuse headache (MOH). Triptans and opioids carry higher risk than NSAIDs. Prevalence in chronic headache clinics reaches 30 to 40 percent. Diener et al., Lancet Neurol 2019.

Withdrawal is the definitive treatment. Abrupt cessation is preferred over tapering for triptans and analgesics (though opioid and barbiturate overuse requires gradual taper). Expect a withdrawal headache lasting 2 to 10 days. Bridge therapy with naproxen or corticosteroids reduces withdrawal severity.

The HealthRX clinical team uses the following 3-tier framework to guide next steps after a new migraine diagnosis:

Tier 1 (Episodic, <4 days/month, no red flags): ICHD-3 confirmation, lifestyle trigger audit, ibuprofen or triptan prescription, MIDAS score at 3 months.

Tier 2 (Episodic, 4 to 14 days/month, or Tier 1 failure): Add preventive oral agent, assess for MOH, order TSH and CBC if not done, consider neurology referral if 2 oral preventives have failed.

Tier 3 (Chronic, 15+ days/month, or complex features): MRI brain with contrast, neurology referral, OnabotulinumtoxinA or anti-CGRP monoclonal antibody, multidisciplinary team including behavioral health.

When to Refer to a Neurologist

Most uncomplicated episodic migraine can be managed in primary care. Referral is appropriate in several situations:

• First or worst headache of life, or any SNOOP4 red flag
• Diagnostic uncertainty after initial workup
• Hemiplegic or brainstem aura
• Failure of 3 or more preventive medication trials
• Chronic migraine (15+ headache days per month)
• Consideration of OnabotulinumtoxinA or anti-CGRP biologics
• Suspected MOH requiring supervised withdrawal

The American Headache Society's 2021 model of care notes that neurologists and headache specialists manage roughly 30 percent of all migraine cases in the U.S. Despite migraine affecting 39 million Americans. Burch et al., Headache 2015.

Tracking and Monitoring Outcomes

A headache diary is the single most useful tool for diagnosis and treatment monitoring. Patients should record:

• Date and time of onset, duration
• Pain intensity (0 to 10)
• Associated symptoms (aura, nausea, photophobia)
• Acute medications used and response
• Probable triggers (sleep, food, hormonal timing, stress)
• Menstrual cycle phase (for women)

After starting any preventive therapy, reassess at 8 to 12 weeks with a repeat MIDAS score. A 50 percent reduction in monthly migraine days is the standard benchmark for treatment success used in clinical trials. Response below that threshold at 12 weeks warrants dose adjustment or agent change.