Migraine in adults

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13 Interesting Facts of Migraine in adults

Migraines are recurrent, episodic headache attacks that may or may not be preceded by a focal neurologic symptom (aura)
History and physical examination, including neurologic examination, are the primary diagnostic methods
Neuroimaging and laboratory tests are generally only necessary to help explore differential diagnoses for patients with headache and unexplained abnormal findings on neurologic examination
Therapy involves either treatment of acute headache or prevention of subsequent migraine. No medication is curative; encourage lifestyle modification and nondrug therapy to reduce the recurrence of migraine
Acute (abortive) therapy can be accomplished with analgesics, triptans, or ergotamine plus antiemetics as needed; emerging agents with novel mechanisms include small molecule calcitonin gene‐related peptide receptor antagonists and a selective serotonin receptor agonist
Preventive therapy includes antiepileptics and β-blockers; tricyclic antidepressants, angiotensin receptor blockers, and injectable preventive therapies are also options
Comorbidities frequently associated with migraine include depression, anxiety, obesity, epilepsy, myocardial infarction, patent foramen ovale, Raynaud syndrome, irritable bowel syndrome, seasonal affective disorder, and fibromyalgia
Complications include chronic migraine, status migrainosus, medication overuse headache, serotonin syndrome, migrainous infarction, and persistent aura without infarction
Prognosis varies; migraine is a leading cause of disability
Primary headache disorder characterized by recurrent, moderate to severe headaches
Similar features include multifocal intermittent neurologic symptoms
Differentiating symptoms include temporal relationship with severe head pain
Diagnosed typically by history and physical examination; if MRI is obtained, there may be smaller and more subtle T2 hyperintensities

Pitfalls

Long-term use of analgesics may lead to medication overuse headache and should be avoided
No medication is curative; encourage lifestyle modification and nondrug therapy to reduce the recurrence of migraine
Oral contraceptives containing estrogen are contraindicated in patients with migraine with aura

Migraines are recurrent, episodic headache attacks that may or may not be preceded by a focal neurologic symptom (aura)

Classification

Migraine with aura (classic migraine)
Migraine without aura (common migraine)
Chronic migraine: occurs 15 or more days per month for 3 or more months
Status migrainosus: debilitating migraine attack lasting 72 hours or longer

Clinical Presentation

Symptoms of Migraine in Adults

Family history of migraine is common
May be worsened by routine physical activity
Prodromal phase may last for hours or days and may involve fatigue or difficulty concentrating before headache begins
Migraine without aura
- 5 attacks fulfilling the following criteria:
  - Headache lasting 4 to 72 hours
  - Headache has at least 2 of the following characteristics:
    - Unilateral location
    - Pulsating quality
    - Moderate or severe pain intensity
    - Aggravated by or causes avoidance of routine physical activity
- At least 1 of the following occurs during headache:
  - Nausea and/or vomiting
  - Photophobia and phonophobia
- Not attributed to another disorder
Migraine with aura
- At least 2 attacks fulfilling the following criteria:
  - Aura consisting of at least 1 of the following fully reversible symptoms:
    - Visual effects, including positive features (eg, flickering lights, spots, lines) and/or negative features (eg, loss of vision)
    - Sensory symptoms, including positive features (eg, pins and needles) and/or negative features (eg, numbness)
    - Speech and/or language symptoms (usually aphasic but often hard to categorize)
    - Motor weakness
    - Brainstem (eg, dysarthria, vertigo, tinnitus, diplopia)
    - Retinal (eg, scintillations, scotomata, blindness)
  - At least 3 of the following occur:
    - At least 1 aura symptom spreads gradually over 5 or more minutes
    - 2 or more aura symptoms occur in succession
    - Each aura symptom lasts between 5 and 60 minutes
    - At least 1 aura symptom is unilateral
    - At least 1 aura symptom is positive
    - Aura is accompanied or followed within 60 minutes by headache
- Not attributed to another disorder
Other symptoms of migraine may include:
- Neck pain/cervicalgia
- Paresthesia
- Asthenia
- Fatigue
- Irritability

Physical examination

Perform complete neurologic and otolaryngologic examinations
Findings will be typical between episodes and in those who have migraine without aura
May observe focal motor or sensory abnormalities in patients who have migraine with aura or variants

Causes

Pathophysiology is not well understood
May involve neurogenic inflammation
Cortical spreading depression, a slowly propagating wave of neuronal and glial depolarization, may be responsible for the aura

Risk factors and/or associations

Age

Peak prevalence is in people aged 25 to 55 years

Sex

Female to male ratio is 3:1

Genetics

Familial predisposition
Autosomal dominant transmission for some variants

Ethnicity/race

More prevalent in white population

Other risk factors/associations

Possible triggers include:
- Stress
- Fatigue
- Sleep disorders or variations in sleep schedule
- Increased physical activity
- Weather changes
- High altitude
- Missing a meal or change in meal schedule
- Environmental factors (eg, odors, noise, flickering lights)
- Alcohol
- Caffeine
- Foods and food additives (eg, monosodium glutamate, chocolate, cheese, artificial sweeteners, nuts, citrus fruits, nitrite preservatives in meats, garlic, raw onions, vinegar, pickled products)
- Menstruation
- Medications (eg, oral contraceptives, vasodilators)

Diagnostic Procedures

Primary diagnostic tools

Base diagnosis on history and physical examination, including neurologic examination
Neuroimaging and laboratory tests are generally only necessary to help explore differential diagnoses for patients with headache and unexplained abnormal findings upon neurologic examination

Differential Diagnosis

Most common

Tension type headache
Cluster headache
Medication overuse headache
Rhinosinusitis
Hemicrania continua
Subarachnoid hemorrhage
Giant cell arteritis
Bacterial Meningitis in Adults
Idiopathic intracranial hypertension
Encephalitis
Brain tumor
Brain Abscess

Treatment Goals

Reduce severity and duration of migraine and decrease functional impairment

Admission criteria

In patients with intractable vomiting, inpatient treatment with IV fluids and IV antiemetics may be necessary
In rare cases, status migrainosus may require hospitalization for hydration and nonopioid IV medications

Recommendations for specialist referral

Consider referral to neurologist for evaluation and treatment recommendations

Treatment Options

Therapy involves treatment of acute headache and/or prevention of subsequent migraine

Acute (abortive) therapy

Analgesics
- First line therapy for mild to moderate acute migraine
  - NSAIDs
  - Acetaminophen-aspirin-caffeine combination
Triptans
- For moderate to severe acute migraine and for mild migraine that does not respond to analgesics
- Use NSAID plus triptan for prolonged or recurring migraine
Ergotamine preparations
- For moderate to severe acute migraine and for mild migraine that does not respond to analgesics
Antiemetics
- For nausea and vomiting during acute migraine
Emerging agents with novel mechanisms include small molecule calcitonin gene‐related peptide receptor antagonists (ubrogepant and rimegepant) and a selective serotonin receptor agonist (lasmiditan)

Preventive therapy

Typically indicated when headache occurs more than once per week or if symptomatic treatments are ineffective or contraindicated
Continue preventive medication for at least 3 months before it is considered a failure
- American Headache Society recommends a trial of 2 to 3 months for each treatment
Specific therapy depends on individual patient; antiepileptics and β-blockers have strongest supporting evidence
Tricyclic antidepressants and angiotensin receptor blockers are options
Injectable preventive therapies are also available
- OnabotulinumtoxinA
- Monoclonal antibodies targeting calcitonin gene‐related peptide (CGRP) (fremanezumab, galcanezumab) or the CGRP receptor (erenumab)
  - Indications for initiating treatment are discussed in the 2019 American Headache Society Position Statement

Other therapies

Lifestyle modifications to prevent subsequent migraine
Behavior therapy

Treatment of status migrainosus (emergency department or inpatient setting) focuses on hydration and nonopioid IV medications; no specific medication protocol has proved to be most efficacious

1 L 5% dextrose in half-normal saline (to rehydrate)
IV antiemetic
IV dihydroergotamine
IV ketorolac

Drug therapy

Acute (Abortive) therapy
- Analgesics
  - NSAIDs
    - For mild to moderate migraine
    - NSAIDs are first line therapy for patients with moderate to severe migraine for whom triptans are contraindicated, who are intolerant of triptans, or who respond poorly to triptans
    - Naproxen
      - Naproxen Oral tablet; Adults: 500—750 mg PO at onset, then 500 mg PO 2 or 3 times daily has been recommended.
    - Ibuprofen
      - Ibuprofen Oral tablet; Adults: 200 to 400 mg PO at migraine onset.
    - Ketorolac
      - For treatment of status migrainosus
        Ketorolac Tromethamine Solution for injection; Adults younger than 65 years: 60 mg IM or 30 mg IV.
  - Acetaminophen-aspirin-caffeine combination
    - Acetaminophen, Aspirin, Caffeine Oral tablet; Adults: For self-treatment, 2 tablets or caplets/24 hours PO. Prescriber may instruct, 2 tablets/caplets PO every 6 hours; Max: 4 doses/24 hours.
- Triptans
  - For moderate to severe acute migraine and for mild migraine that does not respond to analgesics
  - Use NSAIDs plus triptans for prolonged or recurring migraine
  - Sumatriptan
    - Oral
      - Sumatriptan Succinate Oral tablet; Adults: 25, 50, or 100 mg PO once. May repeat a dose 2 hours after first dose if headache has not resolved or returns after transient improvement. Max: 200 mg/day. If headache returns after initial treatment with sumatriptan injection, may give up to 100 mg/day PO with intervals of at least 2 hours between oral doses.
    - Nasal spray
      - Sumatriptan Nasal spray, solution; Adults: 5, 10, or 20 mg into 1 nostril as single dose. May repeat dose once after 2 hours if headache returns. Max: 40 mg/day.
    - Subcutaneous injection
      - Sumatriptan Succinate Solution for injection; Adults: 6 mg subcutaneously. May repeat dose once with a minimum 1-hour interval between doses if migraine symptoms return. Max: 12 mg/24 to 48 hours.
  - Zolmitriptan
    - Oral
      - Zolmitriptan Oral tablet; Adults: Initially, 1.25 mg or 2.5 mg PO as a single dose. Max single dose is 5 mg PO. If the headache returns, the dose may be repeated after 2 hours. Max: 10 mg PO within a 24 hour period.
    - Nasal spray
      - Zolmitriptan Nasal spray, solution; Adults, Adolescents, and Children >= 12 years: 2.5 mg into 1 nostril as a single dose initially; may titrate to individual response. Max: 5 mg/dose. If headache returns within 2 hours, the dose may be repeated once. Max: 10 mg per 24 hour period.
- Ergotamine preparations
  - For moderate to severe acute migraine and for mild migraine that does not respond to analgesics
  - Ergotamine-caffeine combination
    - Ergotamine Tartrate, Caffeine Oral tablet; Adults: 1 to 2 tablets PO at the first sign of an attack. Then, 1 to 2 tablets PO after 30 minutes if needed. If the additional dose is well tolerated, the initial dose may be increased at the next attack, up to a max initial dose of 3 mg ergotamine. Max: 6 tablets for 1 attack or per 24 hours or 10 tablets/week.
  - Dihydroergotamine
    - IV for treatment of status migrainosus
    - Dihydroergotamine Mesylate Solution for injection; Adults: 1 mg IM, subcutaneously, or IV at the first sign of headache, repeat every 1 hour until symptoms resolve. Maximum total dose per 24 hours: 3 mg IM or subcutaneously, or 2 mg IV. Maximum weekly total dose: 6 mg. Do not exceed recommended dose limits.
- Antiemetics
  - For nausea and vomiting during acute migraine
  - Administer via IV for treatment of status migrainosus
  - Chlorpromazine
    - IV
      - Chlorpromazine Hydrochloride Solution for injection; Adults and Adolescents: 0.1 mg/kg IV every 15 minutes, up to 3 doses, has been recommended.
    - Oral
      - Chlorpromazine Hydrochloride Oral tablet; Adults and Adolescents: Single dose of 10 to 50 mg PO.
  - Prochlorperazine
    - Prochlorperazine Edisylate Solution for injection; Adults: 10 mg via IM or via slow IV injection over 2 minutes.
  - Metoclopramide
    - Metoclopramide Hydrochloride Solution for injection; Adults: 10 mg IM or IV as a single dose.
- Small molecule calcitonin gene‐related peptide receptor antagonists
  - Ubrogepant
    - Ubrogepant Oral tablet; Adults: 50 or 100 mg PO as a single dose. Second dose may be taken at least 2 hours after initial dose if needed. Max: 200 mg/day. Coadministration of certain other drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
- Selective serotonin receptor agonist
  - Lasmiditan
    - Lasmiditan Oral tablet; Adults: 50, 100, or 200 mg PO as a single dose. Do not exceed more than 1 dose in 24 hours. A second dose has not been shown to be effective for the same migraine attack. The safety of treating an average of more than 4 migraine attacks within 30 days has not been established.
Preventive therapy
- Specific therapy depends on each individual patient; antiepileptics and β-blockers have the strongest supporting evidence for efficacy
- Antiepileptics
  - Topiramate
    - Topiramate Oral tablet; Adults: 25 mg PO every evening for 1 week, then 25 mg PO twice daily for 1 week, then 25 mg PO every morning and 50 mg PO every evening for 1 week, and then 50 mg PO twice daily. Adjust dose and titration according to clinical outcome; use longer intervals between dose adjustments if needed.
  - Divalproex sodium
    - Divalproex Sodium Gastro-resistant tablet; Adults 65 years of age and younger: Initially, 250 mg PO twice daily. Titrate as needed up to Max: 500 mg PO twice daily.
- β-blockers
  - Metoprolol
    - Metoprolol Tartrate Oral tablet; Adults: Initially, 25 mg PO twice daily. Titrate to response; up to 200 mg/day PO in divided doses used.
  - Propranolol
    - Propranolol Hydrochloride Oral tablet; Adults: Initially, 80 mg/day PO given in divided doses. May gradually increase dosage if needed to 160 to 240 mg/day. Doses of 40 to 320 mg/day PO also recommended.
  - Timolol
    - Timolol Maleate Oral tablet; Adults: Initially, 10 mg PO twice daily. May give maintenance dose of 20 mg PO once daily. Dose range: 10 to 30 mg/day PO.
- Tricyclic antidepressants
  - Amitriptyline
    - Amitriptyline Hydrochloride Oral tablet; Adults: 25 mg PO once daily at bedtime, initially; titrate as tolerated to efficacy. Usual effective target dose range: 75 to 100 mg PO once daily.
- Angiotensin receptor blockers
  - Candesartan
    - Candesartan Cilexetil Oral tablet; Adults: 16 mg PO daily.
- Triptans (for menstruation associated migraine)
  - Frovatriptan
    - Prevention
      - Frovatriptan Oral tablet; Adults: 5 mg PO twice daily on day 1, then 2.5 mg PO twice daily on days 2 through 6. Begin 2 days before anticipated onset of menstrual migraine.
    - Treatment
      - Frovatriptan Oral tablet; Adults: 2.5 mg PO as single dose at migraine onset. May repeat dose in 2 hours if needed. Max: 7.5 mg/24 hours.
- OnabotulinumtoxinA
  - OnabotulinumtoxinA Solution for injection; Adults: 155 units IM as 5 units/injection divided across 7 specific head and neck muscle areas. Recommended muscle injection sites: frontalis (2 injections each side), corrugator (1 injection each side), procerus (1 injection midline), occipitalis (3 injections each side), temporalis (4 injections each side), trapezius (3 injections each side), and cervical paraspinal (2 injections each side); total of 31 injections. Repeat every 12 weeks.
- Monoclonal antibodies targeting CGRP receptor
  - Fremanezumab
    - Fremanezumab Solution for injection; Adults: 225 mg subcutaneously once monthly or 675 mg subcutaneously every 3 months.
  - Galcanezumab
    - Galcanezumab Solution for injection; Adults: 240 mg subcutaneously once as loading dose, followed by 120 mg subcutaneously once monthly.
  - Erenumab
    - Erenumab Solution for injection; Adults: 70 mg subcutaneously once monthly. Some patients may benefit from 140 mg subcutaneously once monthly.

Nondrug and supportive care

No medication is curative; encourage lifestyle modification and nondrug therapy to reduce the recurrence of migraine
Lifestyle modifications to prevent subsequent migraine
- Stress management
- Adequate rest
- Exercise
Behavior therapy
- Biofeedback
- Relaxation training
- Cognitive behavioral therapy
Acupuncture
- Evidence suggests adding acupuncture to symptomatic treatment of attacks decreases headache frequency

Comorbidities

Conditions more frequently associated with migraine
- Depression
- Anxiety
- Obesity
- Epilepsy
- Stroke
- Myocardial infarction
- Patent foramen ovale
- Raynaud syndrome
- Irritable bowel syndrome
- Seasonal affective disorder
- Fibromyalgia
Oral contraceptives containing estrogen are contraindicated in patients with migraine with aura

Monitoring

It is suggested that patient complete headache diary over 1 month and include the following:
- Characteristics of headaches (ie, frequency, severity, duration)
- Details of functional impairment
- Details of drug therapy
  - Type used
  - Dosage
  - Patient response
  - Adverse effects, if any
Information from headache diary will help guide management plan at next evaluation
Reevaluate patients periodically to monitor effectiveness of therapy and adverse events

Complications

Chronic migraine
- Migraine occurring 15 or more days per month for 3 or more months
Medication overuse headache
- Subset of chronic daily headache, occurring 15 or more days per month but with the added criterion of medication overuse, particularly analgesics
- Involves regular overuse of at least 1 acute treatment drug for 3 or more months
- Headache worsens in some way, usually frequency, as the use of acute medications becomes more frequent
Status migrainosus
- Debilitating migraine attack lasting 72 hours or longer
Serotonin syndrome
- Potentially life-threatening condition associated with increased serotonergic activity in the central nervous system; may occur with therapeutic medication use and inadvertent interactions between drugs
- Involves a spectrum of clinical findings, including mental status changes, autonomic hyperactivity, and neuromuscular abnormalities
- Evidence does not support limiting use of triptans with selective serotonin reuptake inhibitors or selective serotonin-norepinephrine reuptake inhibitors owing to concerns for serotonin syndrome
Migrainous infarction (or stroke)
- 1 or more migrainous aura symptoms associated with an ischemic brain lesion in appropriate region demonstrated by neuroimaging; rare
- Risk factors include migraine with aura, female sex, and cigarette smoking
Persistent aura without infarction
- Aura symptoms persist for 1 or more weeks without radiographic evidence of infarction

Prognosis

Prognosis varies
Migraine is a leading cause of disability
Many patients experience sustained reduction of migraine headache with advancing age; however, migraine aura without headache becomes more frequent with advancing age
Some patients with episodic migraine will develop chronic migraine

Prevention

Avoid migraine triggers, including:
- Stress
- Fatigue
- Alcohol
- Caffeine
- Foods that cause migraine in patient

Sources

American Headache Society: The American Headache Society position statement on integrating new migraine treatments into clinical practice [published correction appears in Headache. 59(4):650-1, 2019]. Headache. 59(1):1-18, 2019 Reference