In this discussion, we will talk about the risk factors of migraine, differentiate between types of headaches, red flags of headaches, and treatment plans.

Migraine Facts

Migraine is generally recurring and unilateral. The pain is severe and typically comes with nausea, vomiting, light, and movement. The pain usually occurs in the frontotemporal region. Migraine headaches can be with or without aura.

Migraine headaches affect three times more women than men. Caucasian individuals are the most affected, and Asian Americans are the least affected.

Migraine headaches seem to be heritable, which is a risk factor. Other risk factors are being female and being between 30-39 years.

Headache Types

It is important to know how to differentiate between different types of headaches.

• Migraine:
  • Unilateral
  • Severe, sharp-pulsating pain.
  • Duration is between 4-72 hours
  • May be accompanied by nausea, vomiting, sensitivity to light, and visual change.
• Tension:
  • Bilateral (baseball cap area)
  • Mild to moderate, dull pain
  • Duration is 30 minutes to 7 days
  • This may occur due to stress
• Cluster
  • Unilateral, orbital/supraorbital
  • Sharp, stabbing, very severe pain – generally need ER care
  • The patient may be restless and can have up to 8 attacks per day

Migraine Phases

First phase: prodrome (premonitory symptoms experienced by 20-60% of patients) – yawning, carving, neck stiffness

Second phase: aura (aura is only experienced by 20-30% of patients) – typically occurs 1 hour prior to migraine

• The most common type of aura is visual aura, but patients may also experience sensory and motor aura.

Third phase: headache

Fourth phase: postdrome – the patient is exhausted and drained.

Migraine is the 2nd highest risk factor for stroke. People with migraine with aura are twice as likely to have stroke compared to general population.

Migraine Triggers

• Strenuous physical activity
• Sleeping too much
• Weather
• Stress
• Menses
• Lack of food
• Certain foods, including alcohol and caffeine
• Flashing light

It this helpful to have patients keep a diary, which can help you find a trend.

Diagnostic Criteria for Migraine:

SULTANS – Need at least 2 from “SULTA” and either “N” or “S”.

• S – Severe
• UL – Unilateral
• T – Throbbing
• A – Activity provokes
• N – Nausea
• S – Sensitivity to light/sound/smell

If patients have an increased frequency of migraines, consider medication overuse headache (MOH) or rebound headache – require prophylactic medication.

Medication Overuse Headache (MOH)

Usually, this is when the headache is present more than 15 days per month, and the patient has been using an excessive amount of the treatment drugs for at least 3 months.

Any abortive treatment, including opioids, can cause MOH.

This makes it very difficult to treat because we cannot rely on any abortive treatment. This is why these patients must be put on prophylactic treatment to decrease reliance on acute medication.

Menstrual-Related Migraine (MRM)

Over 60% of women who have migraines experience MRM. This is caused by fluctuating estrogen and can occur starting 2 days prior to the start of menstruation to the end of menstruation. Symptoms are generally similar to migraine without aura.

For this type of migraine, a monophasic low-dose oral contraceptive may be considered and used in a continuous fashion.

Patients with MRM may start triptan 2 days before menses. An agent with level A evidence is frovatriptan (2.5mg QD-BID). Level B are naratriptan (1mg BID) and zolmitriptan (2.5 BID-TID).

Red Flags

These are red flags because they can be a health crisis, potentially.

SNOOPS

• S – Systemic symptoms
• N – Neuro symptoms
• O – Onset (sudden)
• O – Older patient
• P – Previous history of headache
• S – Secondary risk factors like HIV or systemic cancer

Pathophysiology of Migraine

The pathophysiology of migraine is not well understood, but it is thought to be due to neuronal dysfunction that leads to sequential changes in the intra- and extra-cranial processes. This is referred to as the “Depolarization Theory.”

The long-standing hypothesis of migraine, the Vascular Hypothesis, has been disproven.

The depolarization theory (AKA cortical spreading depression) suggests that a wave of neuronal activity leads to an activation of the trigeminovascular system that releases inflammatory mediators, leading to inflammation in the meninges and cortical sensitization.

The cortical sensitization causes neurons to become more responsive to painful stimuli by decreasing the response threshold, increasing the magnitude of response, and increasing spontaneous neuronal activity.

Other hypotheses are the serotonin hypothesis (the trigeminovascular system is activated due to the lack of serotonin), estrogen, and rebound headache (MOH).

Migraine Treatment and Goal

For acute attacks, the goals are:

• Rapid relief of migraine symptoms
• Minimize “rescue” medication use to reduce MOH
• Decrease the frequency, severity, and disability associated with attacks

Treatment should be selected based on patient preference, severity, frequency, and disability.

There are non-pharmacologic options as well, but they are not sufficient treatment for severe symptoms.

• Relaxation
• Ice/cool rag
• Environmental control
• Transcranial magnetic stimulation (approved in 2013)

Abortive Treatment:

Take the medication as soon as possible. Don’t wait to see if it will go away or not. If it’s an aura migraine, administer during the aura.

Abortive treatment can be considered a monotherapy if the patients experience less than 2 episodes per month.

GI symptoms and routes should be taken into consideration when using the agent. Some other considerations are side effects, contraindications, efficacy, and rebound headaches.

Simple Analgesics

First-line for mild to moderate: NSAIDs, acetaminophen, or a combination. These agents work through prostaglandin and help with the inflammatory response. A large one-time dose is better than taking multiple small doses. Make it counts! Side effects of simple analgesics include elevated blood pressure (NSAIDs), renal impact (NSAIDs), hepatic impact (acetaminophen 4g+), dyspepsia (NSAIDs), and tinnitus (aspirin).

Caffeine can help increase GI absorption of analgesics and help augment activity. There is limited evidence for use in moderate to severe. Side effects of caffeine include palpitations, restlessness, insomnia, and tremor.

A combination of NSAIDs and triptan can be used together if simple analgesics have no response.

Remember, the more medications in combination, the higher risk for MOH

Triptans

Triptans work through serotonin receptor (5-HT1B/1D) agonism. Triptans are the first line for moderate to severe migraine. Triptans are referred to as “specific therapy.”

There are a lot of triptan agents and formulations. The use of triptan should be limited to less than 2 times per week. If the patient failed one triptan, another triptan agent may still be effective. When prescribing triptans, it is important to realize that each triptan has its own maximum dose per 24 hours and maximum dose per migraine episode.

Some examples of triptans are sumatriptan (the most flexible dosage forms), rizatriptan (fastest onset), Frovatriptan (long half-life), and naratriptan (the gentle triptan).

Zecuity is a sumatriptan formulation that comes in a battery-powered patch. Treximet is a combination tablet of sumatriptan and naproxen.

Triptans are vasoconstrictors, which means that their side-effect profiles reflect that. Some of these are:

• Dizziness
• Fatigue
• Flushing
• Paresthesia
• Chest discomfort (transient)

There is a serotonin syndrome potential with SSRI.

Triptans are not the best option for patients with ischemic heart disease, especially in postmenopausal females and men older than 40 years. These medications need to be hepatically adjusted.

Do not combine with MAOIs because of the risk of serotonin syndrome. Aside from MOAIs, they also interact with ergot derivatives and CYP3A4 inhibitors (for eletriptan).

Contraindications: cerebrovascular disease (stroke, TIA), cardiovascular disease, use within 24 hours of ergo or other triptans, MAOIs within 2 weeks.

Ergot Alkaloids

These can be considered triptan neighbors. They are nonselective for 5-HT1 receptor agonism. They can be used for moderate to severe migraine.

Ergots come in multiple routes of administration. From the most effective to the least: IV > IM >> inhaled > sublingual > oral.

Usually, if you see it in the pharmacy, it’s probably the nasal spray formulation.

Side effects of ergots are nausea, vomiting, fatigue, muscle cramps, abdominal pain, and sustained generalized vasoconstriction (lead to HTN, MI, etc.)

Ergots interact with CYP3A4 inhibitors as well. It is pregnancy category X.

Watch for persistent numbness and tingling of extremities and ergotism.

Contraindications of ergots include all vascular diseases, renal/liver damage, uncontrolled HTN, Raynaud’s disease, and ischemic bowel disease.

Other agents for abortive treatment:

Butorphanol nasal spray – partial agonist at opioid receptor. It works, but it has a lot of side effects. Only use if the patient is unresponsive to other agents.

Corticosteroids, intranasal lidocaine, and haloperidol.

Antiemetics

Because most migraines are accompanied by nausea, some patients may want to take antiemetics as well.

Some of the agents are metoclopramide, prochlorperazine, and chlorpromazine.

5-HT3 receptor antagonists have poor evidence (ondansetron)

Prophylaxis Treatment

Who should get prophylaxis treatment?

• Headache for more than 2 days per week
• Headache that persists for longer than 2 days
• Severe attacks
• Migraines refractory to abortive treatment
• Cannot tolerate abortive treatment
• Unpredictable migraine
• Migraine with prolonged aura

The starting dose should be low and titrate up slowly every 2-4 weeks

Level A Evidence: Antiepileptic Drugs

These include divalproex/valproic acid and topiramate

Level A Evidence: Beta-Blockers

These include metoprolol, propranolol, and timolol.

Level B Evidence: Antidepressants

These include amitriptyline and venlafaxine.

Level B Evidence: Beta-Blockers

These include atenolol and nadolol.

Level C Evidence Medication:

These are possibly effective: lisinopril, candesartan, guanfacine, carbamazepine, cyproheptadine, nebivolol, and nicardipine.

Botulinum Toxin Type A

This was approved in 2010 by the FDA for chronic migraines. Not to be used for episodic treatment. It is considered “second-line” due to limited reimbursement and high cost.

Health Supplement

There is not a lot of evidence behind these, but they include butterbur, feverfew, riboflavin, magnesium, and coenzyme Q 10.

Prophylaxis Monitoring

A trial of 2-3 months is needed to assess effectiveness. The patient should be tapered off after 1 year, even if effective.

Monitor for efficacy, ADRs, and pregnancy