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Migraine Headache

Author: Marco A. Pescador Ruschel Editor: Orlando De Jesus Updated: 7/5/2024 3:31:32 AM

Introduction

Migraine is a genetically influenced complex neurological disorder characterized by episodes of moderate-to-severe headaches, typically unilateral and frequently accompanied by nausea and heightened sensitivity to light and sound. The word "migraine" is derived from the Greek word hemikrania, which was later converted into Latin as hemigranea. The French translation of the term is migraine.[1] 

Migraine is a common cause of disability and loss of work. Migraine attacks are complex and recurrent neurological events that can unfold for hours to days and significantly impact daily activities and the quality of life of individuals. The most prevalent type of migraine, accounting for 75% of cases, is migraine without aura.

Subtypes of Migraine

Migraines can be classified into the following subtypes according to the Headache Classification Committee of the International Headache Society.[2] 

  • A migraine without aura: This subtype involves recurrent headache attacks lasting 4 to 72 hours. The pain is typically unilateral, pulsating in quality, moderate-to-severe in intensity, aggravated by physical activity, and associated with nausea, light (photophobia), and sound sensitivity (phonophobia).
  • Migraine with aura: This subtype features recurrent, fully reversible attacks lasting minutes, typically presenting with 1 or more unilateral symptoms such as visual, sensory, speech and language, motor, brainstem, or retinal disturbances, usually followed by headache and other migraine symptoms.
  • Chronic migraine: This is defined as a headache that occurs on 15 or more days in a month for more than 3 months, with migraine features present on at least 8 or more days in a month.
  • Probable migraine: This is a symptomatic migraine attack that lacks 1 of the features required to fulfill the criteria for 1 of the above and does not meet the criteria for another type of headache.
  • Episodic syndromes that may be associated with migraine are mentioned below.
    • Recurrent gastrointestinal disturbances involve recurrent attacks of abdominal pain, discomfort, nausea, and vomiting that may be associated with migraines.
    • Benign paroxysmal vertigo involves brief, recurrent attacks of vertigo.
    • Benign paroxysmal torticollis is characterized by recurrent episodes of head tilt to 1 side.

Complications of Migraine

Migraines can lead to various complications, including the following:                                                 

  • Status migrainosus: This is a debilitating migraine attack that lasts more than 72 hours.
  • Persistent aura without infarction: This refers to an aura that persists for more than 1 week without evidence of infarction on neuroimaging.
  • Migrainous infarction: This refers to 1 or more aura symptoms associated with brain ischemia on neuroimaging during a typical migraine attack.
  • Migraine aura-triggered seizure: This occurs during an attack of migraine with aura, where a seizure is triggered. 

Etiology

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Etiology

Understanding the etiology of migraine headaches is crucial for effective diagnosis and treatment. Migraines are believed to result from a combination of genetic, environmental, and neurological factors. Research indicates that these headaches are linked to abnormal brain activity that affects nerve signals, chemicals, and blood vessels within the brain.

Genetics and Inheritance

Migraine has a strong genetic component, with the risk of migraines in affected relatives being 3 times greater than in relatives of unaffected individuals, although no specific inheritance pattern has been identified.[3][4] The genetic basis of migraine is complex, involving multiple loci and genes whose specific roles in pathogenesis remain uncertain. This is likely influenced by more than one genetic source at various genomic locations acting in tandem with environmental factors to influence susceptibility and disease characteristics in affected individuals.[5] Identifying these genes in individuals with migraines holds potential for predicting targeted prophylactic treatments.

Familial Hemiplegic Migraine

  • Hemiplegic migraine can occur in families or sporadically (where an individual is the first in the family to experience a hemiplegic migraine).[6] Channelopathies are responsible for the primary 3 types:
    • Type 1 is caused by mutations in the CACNA1A gene (voltage-gated calcium channel α1A-subunit) on chromosome 19p13.[7] 
    • Type 2 is caused by mutations in the ATP1A2 gene (ATPase, Na+/K+ transporting α2-subunit) on chromosome 1q23.[8]
    • Type 3 is caused by mutations in the SCN1A gene (voltage-gated sodium channel type 1α-subunit).
  • Mutations in the PRRT2 gene (proline-rich transmembrane 2) are recognized as a possible cause.[9] The PRRT2 gene encodes a protein that interacts with the SNAP25 (synaptosomal nerve-associated protein 25), which may pose a role in voltage-gated calcium channel regulation.[10] 
  • Mutations in the SLC4A4 gene (solute carrier family 4 member 4) have also been associated with familial forms of migraine.[11]

Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes

MELAS is a syndrome characterized by mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. This multisystemic disorder, caused by maternal inheritance, can present as recurrent migraine headaches.[12]

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

CADASIL is an angiopathy with autosomal dominant inheritance caused by mutations in the NOTCH3 gene (notch receptor 3) on chromosome 19. CADASIL can present with migraine with aura (prodrome in 80%) in nearly 50% of carriers.[13]

Retinal Vasculopathy with Cerebral Leukodystrophy

RVCL is an angiopathy primarily caused by C-terminal frame-shift mutations in the TREX1 (3-prime repair exonuclease 1) gene, accounting for nearly 60% of cases.[14]

Hereditary infantile hemiparesis, retinal arteriolar tortuosity, and leukoencephalopathy

HIHRATL is a novel hereditary autosomal dominant condition that affects retinal and cerebral vessels.

Hereditary endotheliopathy with retinopathy, nephropathy, and stroke

HERNS is a cerebroretinal vasculopathy linked to a locus on chromosome 3p21.

Migraine Triggers

Withdrawal or exposure to several factors contributes to the development of migraine headaches.[15] A retrospective study found that 76% of the patients reported triggers.[16] Some factors are probable contributors, while others are possible or unproven. These factors include:

  • Stress affecting 80% of cases (probable factor)
  • Hormonal changes in 65% of cases during menstruation, ovulation, and pregnancy (probable factor)
  • Skipped meals, 57% of patients (probable factor)
  • Weather changes affecting 53% of individuals (probable factor)
  • Excessive or insufficient sleep affecting 50% of patients (possible factor)
  • Odors, such as perfumes, colognes, and petroleum distillates, affecting 40% of cases
  • Neck pain in 38% of cases
  • Exposure to lights in 38% of cases (probable factor)
  • Alcohol ingestion in 38% of individuals (wine as a probable factor)
  • Smoking in 36% of patients (unproven factor)
  • Late sleeping in 32% of cases
  • Heat affecting 30% of cases
  • Food in 27% of cases (aspartame as a possible factor and tyramine and chocolate as unproven factors)
  • Exercise in 22% of cases
  • Sexual activity in 5% of cases

Epidemiology

Migraine is highly prevalent, affecting approximately 12% of the population, with annual rates reaching up to 17% among women and 6% among men.[17][18][19] Among children, it is more prevalent in girls than boys.[20] The prevalence of migraine increases during puberty, peaks between ages 35 and 39, and tends to decrease later in life, particularly after menopause.[18]

The adjusted prevalence of migraine is highest in North America, followed by South America, Central America, Europe, Asia, and Africa. Globally, it ranks as the second leading cause of disability.[21] 

Migraine tends to run in families,[17] with a reported risk of 40% if 1 parent has a history of migraine, which increases to 75% when both parents have a migraine history and are affected. This condition ranks consistently as the fourth or fifth most common reason for emergency room visits, accounting for approximately 3% of all annual emergency room visits.[22] Moreover, migraine is considered the second major cause of disability after back pain in terms of years lived with disability.[20]

Pathophysiology

Although not fully understood, the pathogenesis of migraine headaches involves multiple components of both the peripheral and central (CNS) nervous systems. This section describes some of the most well-understood concepts. According to the older vascular theory of migraine, headaches were thought to be produced by vasodilation and auras by vasoconstriction; however, this theory is no longer considered viable.[23] Current theories suggest that multiple primary neuronal impairments lead to a series of intracranial and extracranial changes that cause migraines.[24]

The activation of trigeminal afferents occurs through neuronal pannexin-1 mega channel opening and subsequent activation of caspase-1. This is followed by the release of proinflammatory mediators, activation of nuclear factor kappa-B (NF-kB), and the spreading of this inflammatory signal to trigeminal nerve fibers around the vessels of the pia mater.[25] This process triggers a series of cortical, meningeal, and brainstem events, provoking inflammation in the pain-sensitive meninges and resulting in headaches through central and peripheral mechanisms.[26][27] This pathway can explain the cortical depression (which establishes the aura) and the latter prolonged activation of trigeminal nociception (which leads to headache).

The cortical spreading depression of Leão—a propagating wave of neuronal and glial depolarization that initiates a cascade—is hypothesized to cause the aura, activate trigeminal afferents, and alter the hematoencephalic barrier permeability by activating brain matrix metalloproteinases.[28] In migraine without aura, it is suggested that cortical spreading depression may occur in areas where depolarization is not consciously perceived, such as the cerebellum.[29]

The anterior structures are primarily innervated by the ophthalmic division of the trigeminal nerve, which may account for pain in the anterior region of the head. A convergence of fibers from the upper cervical roots exists, originating from neurons of the trigeminal nerve and ganglion at the trigeminal nucleus caudalis. This convergence may explain the distribution of pain from anterior to posterior, as these fibers ascend to the thalamus and sensory cortex.[30] 

Based on vasodilation, edema, and plasma protein extravasation, neurogenic inflammation results from the activation of nociceptors, particularly within the trigeminal system. This process is associated with the release of substance P, calcitonin gene–related peptide (CGRP), and neurokinin A—vasoactive neuropeptides liberated by stimulation of the trigeminal ganglion.[31] Elevated levels of these neuropeptides have been observed in the spinal fluid of patients with chronic migraines.[32][33] Neurogenic inflammation can lead to sensitization—a process where neurons become more responsive to stimulation. This may explain clinical symptoms of pain and the transition from episodic migraine to chronic migraines.[34]

Neuropeptides believed to play a role in migraine pathogenesis include the following:

Serotonin: Serotonin is released from the brainstem serotonergic nuclei and is thought to be involved in migraine; however, the exact mechanisms are still debated. Between migraine attacks, serotonin levels are likely to decrease, potentially resulting in a deficiency in the serotonin pain inhibition system. This decrease could contribute to trigeminal system activation, thereby exacerbating migraine symptoms. Serotonin may exert its effects by directly influencing cranial vessels, central pain control pathways, or cortical projections from brainstem serotonergic nuclei.[35][36] 

Calcitonin gene-related peptide: CGRP is abundant in trigeminal ganglion neurons and released from the peripheral and central nerve terminals. CGRP is secreted within the trigeminal ganglion. Upon release from peripheral terminals, CGRP stimulates increased synthesis of nitric oxide and subsequent sensitization of trigeminal nerves.[37][38] CGRP acts as a potent vasodilator of cerebral and dural vessels, contributing to neurogenic inflammation, and it mediates pain transmission from trigeminal vessels to the CNS.

Pituitary adenylate cyclase-activating polypeptide: PACAP may also have a significant role in mediating migraine attacks, as its concentration is elevated during the attacks, and infusion of PACAP may trigger migraines in susceptible patients.

History and Physical

Migraine headaches typically progress through distinct phases that characterize the course of an attack, each with unique symptoms. Understanding these stages is crucial for effective management and patient education.

The 4 phases identified in migraine attacks are as follows: [39]

Prodrome: Premonitory symptoms associated with hypothalamic activation (dopamine).[40][41]

  • Approximately 77% of patients experience prodromal symptoms for up to 24 to 48 hours before headache onset. This phase is more common in females than males (81% versus 64%).
  • Common symptoms include yawning (34%), mood changes, lethargy, neck stiffness, sensitivity to light and sound, restlessness, difficulty focusing vision, feeling cold, cravings, sweating, increased energy, thirst, and edema.

Aura: Changes in cortical function, blood circulation, and neurovascular integration occur in approximately 25% of cases.[2][13][42][43]

  • Auras can precede the headache or present it simultaneously.
  • Auras are typically gradual, lasting less than 60 minutes, predominantly visual, and encompass positive and negative symptoms.
    • Positive symptoms result from active release by neurons in the CNS (such as bright lines or shapes, tinnitus, noises, paresthesias, allodynia, or rhythmic movements).
    • Negative symptoms indicate a lack or loss of function (such as reduced or lost vision, hearing, sensation, or movement).
  • Auras must be fully reversible by definition. 
  • Tingling sensations, usually present on 1 side of the face or a limb, are considered paresthesias. 
  • The most common positive visual symptom is scintillating scotoma (an area of absent vision with a shimmering or glittering zigzag border). 
  • The most common negative visual symptom is visual field defects. 
  • Visual auras are the most frequent.
  • Sensory auras are also common and can follow visual symptoms or occur independently.
  • Language auras, which consist of transient dysphasia, are infrequent.
  • Motor auras are rare and involve complete or partial hemiplegia of the limbs and face.

Headache: Additional changes in blood circulation and function of the brainstem, thalamus, hypothalamus, and cortex can occur.

  • The headache is often unilateral, generally with a pulsatile or throbbing feature, and increases in intensity within the first hours. 
  • The intensity can correlate with nausea, vomiting, photophobia, phonophobia, rhinorrhea, lachrymation, allodynia, and osmophobia.
  • The headache can last from hours to days.
  • Patients may seek relief in dark places, and the pain usually resolves with sleep.

Postdrome: Persistent blood changes with symptoms after headache termination.

  • This phase consists of movement-vulnerable pain in the exact location of the previous headache. 
  • Common symptoms include exhaustion, dizziness, difficulty concentrating, and euphoria.

Evaluation

The diagnosis of migraine is based on patient history, physical examination, and fulfillment of diagnostic criteria. Demographic features of the patient, including age, gender, race, and profession, should also be noted. Additional necessary information that must be gathered from the patient consists of answers to relatively simple questions, including:

  • When did the headache start?
  • Where does it hurt? (specific location and irradiation)
  • What is the intensity of the pain?
  • How is the pain? What are the qualitative characteristics of pain?
  • How long does the pain last?
  • At which moment of the day does the pain appear?
  • How has it evolved since it started?
  • What is the frequency of appearance?
  • What are the triggering situations?
  • Are there simultaneous symptoms?
  • Is it related to sleep?
  • How does it get better or worse?
  • Which medications do you take to make it better? What is the frequency of this medication?

Patients should also be queried about somatosensory disturbances, such as spreading unilateral numbness or tingling in the face and arm, as well as about disturbances in speech or thinking. Some aura symptoms may indicate uncommon types of migraine and include:

  • Motor weakness
  • Dysarthria
  • Hypacusis
  • Diplopia
  • Ataxia
  • Vertigo
  • Tinnitus
  • Decreased level of consciousness

Diagnostic Criteria for Migraine as per the International Classification of Headache Disorders

The International Classification of Headache Disorders (ICHD-3) describes the below-mentioned diagnostic criteria for migraine.[2]

Criterion B1. Migraine without aura

  • B1a: Headache attacks lasting 4 to 72 hours (untreated or unsuccessfully treated) 
  • B1b: Headache has at least 2 of the following characteristics:
    • Unilateral location 
    • Pulsating quality 
    • Moderate-to-severe pain intensity
    • Aggravation by or causing avoidance of routine physical activity (walking or climbing stairs)                                            
  • B1c: During a headache, at least 1 of the following:
    • Nausea and/or vomiting
    • Photophobia and phonophobia

Criterion B2. Migraine with aura

  • B2a: 1 or more of the fully reversible aura symptoms mentioned below.
    • Visual
    • Sensory
    • Speech and language
    • Motor
    • Brainstem 
    • Retinal                                                                                                                                                  
  • B2b: At least 2 of the characteristics mentioned below.                                                                               
    • At least 1 aura symptom spreads gradually over 5 or more minutes
    • 2 or more aura symptoms occur in succession
    • Each aura symptom lasts 5 to 60 minutes 
    • At least 1 aura symptom is unilateral
    • At least 1 aura symptom is positive 
    • The aura is accompanied, or followed within 60 minutes, by the headache

Criterion C. On 8 days or more per month for more than 3 months, fulfilling any of the below-mentioned criteria.

  • Criteria B1b and B1c: For migraine without aura 
  • Criteria B2a and B2b: For migraine with aura 
  • Believed by the patient to be migraine headaches at onset and relieved by a triptan or ergot derivative

Criterion D. Not better accounted for by another ICHD-3 diagnosis.

The International Classification of Headache Disorders Criteria for Migraine Without Aura

The criteria of ICHD-3 for migraine without aura are listed below.

  • At least 5 attacks fulfilling criteria B to D 
  • Headache attacks that last 4 to 72 hours, untreated or unsuccessfully treated 
  • Headache that has at least 2 of the following criteria:
    • Unilateral location
    • Pulsating quality
    • Moderate-to-severe pain intensity
    • Aggravation by or causing avoidance of routine physical activity (such as walking or climbing stairs)
  • During headaches, at least 1 of the following:
    • Nausea, vomiting, or both
    • Photophobia and phonophobia
  • Not better accounted for by another ICHD-3 diagnosis

The International Classification of Headache Disorders Criteria for Migraine With Aura

The criteria of ICHD-3 for migraine with aura are listed below.

  • At least 2 attacks fulfilling the criteria from B to D.
  • At least 1 or more of these fully reversible aura symptoms, including visual, sensory, speech and language, motor, brainstem, and retinal.
  • At least 3 of the following 6 characteristics:
    • At least 1 aura symptom spreads gradually over 5 minutes or more.
    • Two or more symptoms occur in succession.
    • Each aura symptom lasts 5 to 60 minutes.
    • At least 1 aura symptom is unilateral.
    • At least 1 aura symptom is positive.
    • The aura is accompanied, or followed within 60 minutes, by the headache.
  • Not better accounted for by another ICHD-3 diagnosis.
  • Hemiplegic migraine is diagnosed when the aura consists of motor weakness.
  • Migraine with brainstem aura (previously known as basilar artery migraine or basilar migraine) is diagnosed if the aura symptoms emerge from the brainstem (bilateral hemianopic visual disturbance, diplopia, vertigo, ataxia, dysarthria, tinnitus, hyperacusis, bilateral paresthesia, or numbness).
  • Retinal migraine is diagnosed when the aura involves a monocular visual field defect.

The International Classification of Headache Disorders Criteria for Chronic Migraine

The criteria of ICHD-3 for chronic migraine are listed below.

  • Headache (tension-type-like or migraine-like) on 15 or more days per month for more than 3 months and fulfilling criteria B and C.
  • A patient who has had at least 5 attacks fulfilling the criteria for migraine without aura (B1) or migraine with aura (B2).

Neuroimaging, such as computed tomography (CT) scan, magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), or magnetic resonance venography (MRV), is indicated in the following cases:[44][45]

  • Acute severe headache, especially if it is the first or worst episode (to exclude subarachnoid hemorrhage).
  • Abnormal neurological examination, especially if there are unexplained symptoms or signs (such as confusion, stiff neck, papilledema, or epilepsy).
  • Atypical headache characteristics
  • Changes in the patient's typical headache features or patterns
  • New episodes in patients aged 50 or older or those who are immunosuppressed
  • Systemic or meningeal signs or symptoms (such as fever, weight loss, or fatigue)
  • New neurological symptoms or signs on examination
  • Headache not responding to treatment
  • Headache lasting longer than 72 hours
  • Significant change in the frequency, pattern, or severity of headaches
  • Severe headache pain (or "worst headache of life") or headache causing awakening from sleep
  • New-onset headache in patients with HIV infection or cancer
  • Associated symptoms or signs suggestive of meningitis or stroke

The commonly used acronym "SNOOP" can be used to aid in the determination of neuroimaging indications as follows:

  • "S" for systemic signs or symptoms and secondary risk factors
  • "N" for neurological signs or symptoms
  • "O" for onset
  • "O" for older
  • "P" for position-dependent intensity changes, the prior pattern changes, papilledema, and precipitated by Valsalva maneuvers

Cerebrospinal fluid analysis and electroencephalogram are not typically performed unless seizure activity of an infectious etiology must be excluded.

Treatment / Management

The treatment of migraine headaches involves a multifaceted approach aimed at alleviating symptoms, preventing attacks, and improving patients' overall quality of life. Effective management typically combines acute treatments for immediate relief during attacks, preventive strategies to reduce frequency and severity, and personalized lifestyle modifications addressing individual triggers and patient needs. 

Acute or Abortive Treatments

Acute treatment aims to stop the progression of a migraine headache, which must be treated quickly and with a large single medication dose. Oral medications may be ineffective in patients with migraine-induced gastric stasis. Therefore, parenteral medication may be the rule for some patients, especially those with nausea or vomiting.[46][47][48] Therapy consists of stratified options as mentioned below and also in the Treatment Planning section (see Table 1. Acute Therapy Options for Migraine).(A1)

Nonsteroidal anti-inflammatory drugs (NSAIDs): Ibuprofen (400-600 mg), naproxen (275-825 mg), diclofenac (65 mg), aspirin (900-1000 mg), or acetaminophen (1000 mg).[49] This drug class is usually prescribed for patients with mild-to-moderate attacks without nausea or vomiting. If an NSAID is ineffective, switching to another class of drug is recommended.

Triptans: Triptans are first-line treatments, especially effective in patients with allodynia. Options include:

  • Sumatriptan: This is administered as a subcutaneous (SQ) injection of 6 mg, nasal spray of 20 to 40 mg over 24 hours, nasal powder of 10 to 30 mg over 24 hours, or oral dose of 50 to 100 mg once.
  • Zolmitriptan: This is administered as nasal 2.5 to 5 mg in a single dose or oral 2.5 mg in a single dose, not exceeding 10 mg in 24 hours.
  • Eletriptan, rizatriptan, or almotriptan.

Triptans may be used with or without naproxen for moderate-to-severe attacks. Unlike NSAIDs, patients who do not respond well to a triptan may respond to another, necessitating individualized therapy.

Here are important considerations for the use of triptans in migraine management:

  • Triptans should be limited to less than 10 days of use per month to avoid medication overuse. 
  • Due to their activation of 5-HT(1B) and 5-HT(1D) receptors on coronary and cerebral vessels, triptans are contraindicated in patients with ischemic stroke, ischemic heart disease, poorly-controlled hypertension, angina, pregnancy, and hemiplegic or basilar migraine. In patients with cardiovascular risks, lasmiditan, a selective serotonin 1F receptor agonist that does not induce vasoconstriction, is the preferred medication.
  • Patients concurrently taking selective serotonin reuptake inhibitors or serotonin-noradrenaline reuptake inhibitors should be monitored for serotonin syndrome risk.
  • Combining NSAIDs with triptans is often more effective than using either drug class alone. Initial therapy may include sumatriptan succinate 85 mg and naproxen sodium 500 mg in a single tablet.[50] 
    • (A1)

Antiemetics: Anti-nausea medications such as metoclopramide, chlorpromazine, or prochlorperazine are commonly used adjunctively with NSAIDs or triptans to reduce nausea and vomiting, particularly in emergency settings. Diphenhydramine may also be added to prevent dystonic reactions, primarily associated with metoclopramide.

Calcitonin gene–related peptide antagonists: CGRP, such as rimegepant (75 mg as a single dose) or ubrogepant, may be considered for patients who do not respond to conventional treatments or those with coronary artery disease.[51] 

Selective serotonin 1F receptor agonist: The US Food and Drug Administration (FDA) approved oral lasmiditan tablets in October 2019 for acute migraine treatment in adults. Initial doses of lasmiditan include 50 or 100 mg, and this is particularly effective for patients who cannot use triptans due to cardiovascular risks. Although doses can escalate to 100 or 200 mg as needed, but no more than 1 dose should be administered within 24 hours. The significant adverse effect is dizziness. Therefore, patients should refrain from engaging in potentially hazardous activities or driving a motor vehicle for at least 8 hours after each dose of lasmiditan.[52] (A1)

Ergots: Ergots such as ergotamine and dihydroergotamine (intravenous [IV], intramuscular [IM], SQ, and intranasal use) are recommended for acute attacks via parenteral administration. They serve as effective bridge therapy for medication overuse headaches and status migrainosus. However, the effectiveness of ergotamine is not well-established, and it carries significant adverse effects such as cerebrovascular, cardiovascular, and peripheral ischemic complications.

Dexamethasone: This can reduce the recurrence of early headaches but does not provide immediate relief.[53][54] (B3)

Transcutaneous supraorbital nerve stimulation: This can reduce intensity.[55] (A1)

Transcranial magnetic stimulation: This has proved effective as a second-line treatment with no severe adverse effects. This can also be considered an option to treat chronic migraines but is contraindicated in patients with epilepsy.[56][57][58] (A1)

Nonpainful remote electric neurostimulation: This may be considered a first-line treatment in some patients.[59][60] (A1)

Peripheral nerve blocking: This (occipital plexus and sphenopalatine ganglion) may also be considered.[61][62](B3)

Prophylactic or Preventive Treatments

Preventive treatment aims to reduce migraine frequency, improve responsiveness to the severity and duration of acute attacks, and reduce disability.[63][64] Patients should document their migraine triggers to effectively reduce their impact in the future.(A1)

  • Indications for preventive treatment include:  
    • Frequent or long-lasting headaches
    • Attacks causing significant disability and reduced quality of life
    • Contraindications or failure with acute therapies
    • Significant adverse effects from abortive therapies
    • Risk of medication overuse headache
    • Menstrual migraine (with short-term premenstrual prophylaxis)
    • Hemiplegic migraine
    • Brainstem aura migraine
    • Persistent aura without infarction
    • Migrainous infarction
  • Preventive treatment agents include (see Table 2. Preventive Therapy Options for Migraine):
    • β-Blockers: Metoprolol and propranolol, especially in hypertensive and nonsmoking patients.
    • Antidepressants: Amitriptyline and venlafaxine, especially beneficial for patients with depression, anxiety disorders, and insomnia.
    • Anticonvulsants: Valproate acid and topiramate, especially recommended for patients with epilepsy.
    • Calcium channel blockers: Verapamil and flunarizine, especially recommended for women of childbearing age and patients with Raynaud phenomenon.
    • CGRP antagonists: Erenumab, fremanezumab, and galcanezumab.
    • Botulin toxin (onabotulinumtoxinA): Recommended for adult patients experiencing headaches 15 or more days per month and lasting 4 or more hours a day.

Alternative Treatments

Incorporating lifestyle changes requires patient commitment, with social support playing a vital role in enhancing mental health and encouraging active patient participation. The following therapies can also be included to improve the quality of life in patients suffering from migraine headaches:

  • Regular exercise
  • Yoga
  • Relaxation training
  • Cognitive-behavioral therapy
  • Biofeedback
  • Reduction of triggers
  • Detoxification
  • Butterbur
  • Melatonin

Differential Diagnosis

Accurately diagnosing migraine headaches involves distinguishing them from other types of headaches and neurological conditions. The differential diagnosis entails carefully considering various factors and symptoms that may overlap with other disorders. This meticulous process ensures patients receive the most suitable and effective treatment for their condition.

Diagnostic considerations in a patient with a migraine include:

  • Tension-type headache
  • Cluster headache
  • Cerebral aneurysms
  • Chronic paroxysmal hemicrania
  • Dissection syndromes
  • Encephalitis
  • Subarachnoid/intracranial hemorrhage
  • Meningitis
  • Temporal/giant cell arteritis

Tension-type headaches typically present as bilateral pain lasting from 30 minutes to 7 days. Patients often describe a sensation of pressure or tightness but typically remain active without associated symptoms.

Cluster headaches typically manifest as unilateral pain that abruptly begins around the eye or temple. These headaches rapidly escalate in intensity over minutes to become excruciating and continuous, lasting between 15 minutes to 3 hours. Associated symptoms include lacrimation (tearing) and redness of the eye, nasal congestion (rhinorrhea), pallor, sweating, Horner syndrome (drooping eyelid and constricted pupil on the affected side), agitation, and focal neurological symptoms. Cluster headaches are often triggered by alcohol consumption.

Treatment Planning

 Table 1. Acute Therapy Options for Migraine 

Drug Class/Drug Drug Dosage Range Notes/Contraindications
NSAIDs
  • Aspirin [49]
  • Ibuprofen
  • Naproxen
  • Diclofenac
  • Diclofenac epolamine
  • Tolfemanic acid
  • Celecoxib [65]
  • Dexletoprofen
  • 900-1000 mg
  • 400-600 mg
  • 275-825 mg
  • 50-100 mg
  • 65 mg
  • 200 mg
  • 120 mg
  • 50 mg
  • All NSAIDs have similar efficacy 
Nonopioid analgesic
  • Acetaminophen [66]
  • 1000-3000 g
  • Acute life-threatening hepatotoxicity at doses >4 g/d.

Serotonin 1b/1d agonists (triptans)

(Sumatriptan)* [67]
  • Sumatriptan (oral)                                                                                                                                                                                                                                                                                          
  • Sumatriptan (intranasal solution) [68]                                                                                                                                                                                                                                                                                                
  • Sumatriptan (intranasal powder)                                                                                                                                                                                                                                                               
  • Sumatriptan (spray)                                                                                                                                                                                                                                                                                                                                                                                                                     
  • Sumatriptan (SQ)
  • 50-100 mg as a single dose, with a maximum dosage of 200 mg/d.

 

  • 20 mg as a single dose in 1 nostril; if symptoms persist, may repeat dose after ≥2 hours. The maximum dosage is 40 mg/d.

 

  • 22 mg as a single dose; may repeat dose after ≥2 hours if symptoms persist or return. The maximum dosage is 44 mg/d.

 

 

  • 10 mg as a single dose in 1 nostril; may repeat dose after ≥1 hour if symptoms persist or return. The maximum dosage is 30 mg/d.

 

  • 6 mg as a single dose; may repeat dose (usually same as the first dose) after ≥1 hour if symptoms persist or return, or a lesser dosage if 6 mg was not tolerated. The maximum dosage is 6 mg/dose and 12 mg/d.
  • All formulations of triptans are contraindicated in patients with severe hepatic impairment.
  • Contraindicated in patients with cardiovascular illness due to the risk of prolonged QT interval on electrocardiogram (ECG) and subsequent ventricular arrhythmias, including torsades de pointes (TdP) and ventricular fibrillation.
  • This formulation may also cause dizziness, lethargy, tremors, vertigo, akathisia, dystonia, and pathological laughter.
  • Other vasospasm-related events include peripheral ischemia, ischemic colitis, splenic infarction, and Raynaud disease.
  • This formulation should be avoided in patients with uncontrolled hypertension and pregnancy.
  • Ocular adverse effects include transient and permanent blindness and significant partial vision loss.
  • The use of concomitant serotonergic drugs may cause serotonin syndrome.
  • Unpleasant taste is less common with intranasal zolmitriptan compared to intranasal sumatriptan.
  • Patients who do not respond to a triptan may respond to another.
  • Naratriptan and frovatriptan have a slower onset and lower efficacy.

Serotonin 1b/1d agonists (triptans)

(Naratriptan) [69]

  
  • Naratriptan
  • 2.5 mg as a single dose; may repeat dose after ≥4 hours. The maximum dosage is 2.5 mg/dose and 5 mg/d.
  • Using within 24 hours of an ergotamine preparation or a different triptan is not advised.
  • Contraindicated with severe renal impairment (CrCl <15 mL/min).

Serotonin 1b/1d agonists (triptans)

(Zolmitriptan)
  • Zolmitriptan (oral)

 

 

  • Zolmitriptan (intranasal)
  •  2.5 mg as a single dose; may repeat dose after ≥2 hours. The maximum dosage is 5 mg/dose and 10 mg/d.[70]
  • 2.5 to 5 mg as a single dose; may repeat dose after ≥2 hours. The maximum dosage is 5 mg/dose and 10 mg/d.
  • Refer to the section on sumatriptan for the adverse effects of triptans.

Serotonin 1b/1d agonists (triptans)

(Frovatriptan)
  • Frovatriptan
  • 2.5 mg as a single dose; may repeat dose after ≥2 hours if needed. The maximum dosage is 2.5 mg/dose and 5 mg/d.
  • Slower onset 

Serotonin 1b/1d agonists (triptans)

(Almotriptan) 
  • Almotriptan 
  • 12.5 mg as a single dose; may repeat dose after ≥2 hours when needed. The maximum dosage is 12.5 mg/dose and 25 mg/d.[71]
  • Reduce dose to half in patients with hepatic impairment 

Serotonin 1b/1d agonists (triptans)

(Rizatriptan)
  • Rizatriptan

 

  • 5-10 mg as a single dose; may repeat dose after ≥2 hours if needed. The maximum dosage is 20-30 mg/d.
  • Propranolol increases rizatriptan levels by 70%, necessitating a downward adjustment in the dose of rizatriptan in these patients.

Serotonin 1b/1d agonists (triptans)

(Eletriptan)
  • 40 mg as a single dose; may repeat dose after ≥2 hours if needed. The maximum dosage is 40 mg/dose and 80 mg/d.
  • Primarily metabolized by cytochrome P450 enzyme CYP3A4, this medication should not be administered within at least 72 hours of treatment with other drugs that are potent CYP3A4 inhibitors, such as itraconazole, ketoconazole, clarithromycin, nefazodone, troleandomycin, ritonavir, and nelfinavir.

Antiemetics
  • Metoclopramide (IV, IM, oral) [73]

 

  • Prochlorperazine (IV, IM)
  • 10-20 mg as a single dose.
  • 10 mg as a single dose.
  • IV route is preferred for metoclopramide. Pretreatment with diphenhydramine is recommended to prevent akathisia and other acute dystonic reactions.
CGRP antagonists

 
  • 75 mg every other day, with a maximum dosage of 75 mg/d.
  • 50-100 mg as a single dose; may repeat dose after ≥2 hours if needed. The maximum dosage is 200 mg/d.
  • Administration at the onset of a migraine attack may improve treatment response.
  • This is used as second-line therapy when triptans are contraindicated, poorly tolerated, or ineffective.
  • Further studies are required to establish efficacy and safety.
Serotonin 5-HT1F receptor agonist
  • 50-100 mg as a single dose; may increase to 100 or 200 mg as a single dose if needed. Repeat doses have not established efficacy.
  • Administration early in the course of a migraine attack may improve treatment response.
  • Used as second-line therapy when triptans are contraindicated, poorly tolerated, or ineffective.
  • A major adverse effect is dizziness (9%-17%). Wait for at least 8 hours between dosing and driving or operating heavy machinery.
  • This formulation may enhance the CNS depressant effects of alcohol.
Ergot derivative
  •  Dihydroergotamine [77]
  • IM: 1 mg as a single dose; may repeat hourly as required. The maximum dosage is 3 mg/d and 6 mg/week.
  • IV: 1 mg as a single dose; may repeat hourly as required. The maximum dosage is 2 mg/d and 6 mg/week.
  • SQ: 1 mg as a single dose; may repeat every 2 hours as required. The maximum dosage is 3 mg/d and 6 mg/week.
  • Intranasal: 0.5 mg per spray: 1 spray (0.5 mg) into each nostril. Repeat after 15 min (total of 4 sprays per dose). The maximum dosage is 4 sprays (1 dose)/d.
  • Use is contraindicated in severe hepatic or renal impairment, pregnancy, and breastfeeding.
  • Also contraindicated in patients with hypertension or ischemic heart disease.
  • Avoid use within 24 hours of triptans or ergot-like agents.
  • Use with potent inhibitors of CYP3A4 (including azole antifungals, protease inhibitors, and some macrolide antibiotics) should be avoided.

 *Adverse effects in this section pertain to all triptans unless specified.

Table 2. Preventive Therapy Options for Migraine

Drug Class Drug Dosage Range Adverse Effects/Contraindications
β-Adrenoceptor blockers [78]
  • Propranolol
  • Metoprolol
  • Timolol
  • 80-240 mg
  • 50-150 mg
  • 10-20 mg
  • Contraindicated in patients with asthma, syncope, or heart blockage.
Antidepressants
  • Amitriptyline
  • Nortriptyline
  • Venlafaxine
  • 10-150 mg
  • 25-100 mg
  • 37.5-150 mg
  • Somnolence
  • Insomnia and hypertension
Calcium-channel blockers
  • 180-480 mg
  • Constipation, hypotension, and edema
Antiepileptic drugs [78]
  • Divalproex sodium
  • Topiramate
  • Gabapentin
  • 200-1500 mg
  • 25-150 mg
  • 300-1800 mg
  • Weight gain, thrombocytopenia, and tremors
  • Renal calculi, amnesia, glaucoma, disequilibrium, and weight loss
CGRP monoclonal antibodies
  • Erenumab
  • Galcanezumab
  • 70-140 mg every 4 weeks, SQ
  • 120 mg monthly, SQ
  • Injection site reactions, muscle spasms, and hypersensitivity reactions
  • Injection site reactions, vertigo, pruritus, and constipation
Botulinum toxin
  • 31 individual injections per session of 0.1 mL (5 Units) each, divided and administered across specific head and neck muscle areas, totaling 155 total Units
  • Neck pain and headache
  • Irritation at the injection site
  • Drooping eyelids

Reference for Table 2.[83]

Prognosis

The prognosis of migraine headaches varies widely among individuals, but with appropriate management, many patients can achieve significant relief and an improved quality of life. While migraines are a chronic condition with no definitive cure, advancements in treatment options, including preventive medications and lifestyle modifications, can substantially reduce the frequency and severity of attacks.

Early diagnosis and intervention are critical, as they help tailor personalized treatment plans that can prevent the progression of chronic migraines. Chronic migraines can revert to episodic migraines in 26% to 70% of patients. Prolonged remissions are common; however, some patients experience a pattern of alternating between episodic and chronic states.

The severity and frequency of migraines can diminish with age.[84] Episodes increase during puberty and continue to climb until 35 to 39 years of age, decreasing later in life, particularly after menopause.[18] Although some individuals may experience a decrease in migraine frequency with age, others may continue to have persistent symptoms. Overall, ongoing medical care and patient education are key to managing migraines effectively and enhancing long-term outcomes.

Complications

Migraine headaches can lead to numerous complications that significantly affect patients' lives. Understanding these potential issues is essential for healthcare professionals to manage and mitigate long-term impacts on patients' health.

Complications of migraine headaches include the following:

  • Status migrainosus, which is a debilitating migraine attack lasting over 72 hours
  • Migrainous infarction
  • Migraine aura-triggered seizure
  • Persistent aura without infarction
  • Work disability and loss of productivity

Consultations

Patients with migraine headaches often require consultations with various healthcare professionals to manage their condition effectively. Neurologists conduct detailed evaluations and develop comprehensive treatment plans. Psychologists or psychiatrists may address accompanying mental health issues, such as anxiety or depression, which are common in migraine sufferers.

In addition, nutritionists offer guidance on dietary triggers, and physical therapists provide strategies to alleviate migraine-associated muscle tension. In some cases, pain management specialists explore advanced treatment options. This multidisciplinary approach ensures holistic care, addressing all aspects of the patient's well-being.

Deterrence and Patient Education

Timely diagnosis and management of migraine headaches are crucial, given their potential to be debilitating and impact quality of life significantly. Effective patient education is key to empowering individuals to manage their condition better. Patients should be informed about the different phases of migraine headaches and the benefits of abortive and preventive therapies. Patients should also be educated about lifestyle changes, including regular exercise, adequate hydration, and relaxation techniques, which are also important in reducing the frequency and severity of migraine attacks. Encouraging patients to maintain a headache diary can help identify patterns and triggers effectively. Additionally, patients should be instructed to seek medical attention if symptoms worsen or new neurological symptoms occur, which may warrant neuroimaging.

Pearls and Other Issues

Understanding migraine headaches involves recognizing several critical facts that highlight their impact and management challenges. These salient points include the following:

  • Cortical spreading depression is the probable cause of the aura, which can activate trigeminal nerve afferents and alter hematoencephalic barrier permeability. Trigeminovascular system activation can initiate neurogenic inflammation related to migraine headaches.
  • Migraine attacks are recurrent and unfold over hours to days through a cascade of events.
  • Typical migraines progress through phases—a prodrome, an aura, a headache, and a postdrome. 
  • There is no one-size-fits-all approach to treating migraines. Each case requires individualized treatment tailored to its specific comorbidities.

Enhancing Healthcare Team Outcomes

Treating migraine patients requires the efforts and collaboration of an interprofessional healthcare team. The integrated care pathway provided by the healthcare team to patients must be combined with an evidence-based approach to planning and evaluating all joint activities. Primary care clinicians, including physicians and advanced practitioners, may seek the expertise of an internist, neurologist, or headache specialist if there is any doubt regarding the diagnosis.

Nurses and psychologists contribute to team management by educating patients on lifestyle adjustments, providing mental health support, guiding medication detoxification for overuse, and offering recommendations on medication use. Pharmacists are critical in the team by verifying proper dosing and identifying potential drug interactions, particularly in chronic migraine treatments. 

All interprofessional healthcare team members must document observed changes in patient status and promptly communicate with other team members. This ensures timely adjustments in diagnostic or therapeutic strategies as needed. Open communication among healthcare team members is essential for providing optimal care to patients and achieving the best possible outcomes. Collaboration, shared decision-making, and effective communication are necessary for achieving optimal results.

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