Migraine headache in adults

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

The main goal of treatment for migraine is to find a reliable, rapidly effective treatment for acute attacks that restores the person’s ability to function.[34] Treatment should be matched to the severity of the patient's headache and disability.

Acute treatment early in the migraine attack often results in better response, and treatment during the prodrome phase may be reasonable.[81]

Preventive treatment is recommended for patients who have frequent attacks or for whom acute treatments are ineffective or cannot be tolerated.

Treatment plans should be individualized to take account of factors such as the medical needs, treatment history, preferences, and goals of the patient, evidence of efficacy, tolerability, potential adverse effects, contraindications, comorbidities, drug interactions, and the effects of a treatment on the patient’s functional capacity, disability, and quality of life.[34] The Migraine Disability Assessment (MIDAS) Questionnaire is a validated 5-question tool giving the clinician an objective evaluation of headache-related impact on a patient’s daily life.[82]

In older adults, comorbid conditions, drug-drug interactions, and adverse effects affecting patients' cognition and functional status are increasingly important.[34][39][83][84] Treatment of migraine in pregnant women requires special considerations.[85][86]

Symptom relief

Treatment should be started as soon as the patient recognizes that a typical migraine attack is beginning, even if symptoms are mild. It may need to be repeated later in the attack.[34][39][87]

If nausea and vomiting are prominent symptoms, therapy with an antiemetic can be of benefit.[87]

Dehydration is a trigger for migraine attacks, and the nausea and vomiting of migraine may lead to significant dehydration. Therefore hydration with oral or intravenous fluids should be considered for any patient with prolonged migraine headache associated with nausea and vomiting.[88] Hydration improves comfort and may speed resolution of a migraine.

Mild symptoms

Treatment of migraine is often initiated by patients themselves without any consultation with their physicians. Clinicians should be familiar with the pharmacology, clinical benefits, and potential safety issues of nonprescription drugs used in the self-management of migraine.

Nonprescription drugs with proven efficacy for migraine include nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, or diclofenac. Acetaminophen is less effective.[39][89] The proprietary combination of aspirin/acetaminophen/caffeine is more effective than placebo and nonprescription analgesics alone for mild to moderate symptoms.[34][90][91]

Prescription-strength NSAIDs such as aspirin, diclofenac, ibuprofen, and naproxen have been shown to be effective initial treatments.[34][39][92][93][94][95][96][97] [ ] [ ]

If NSAIDs are contraindicated or not tolerated, or if a patient is pregnant, acetaminophen may be used.[39][87][95] It is more effective than placebo in treating migraine, but may be less effective than other simple analgesics. The combination of acetaminophen and metoclopramide has equivalent short-term efficacy to oral sumatriptan, with fewer adverse effects.[98] [ ]

Evidence for the efficacy of opioids in acute migraine is limited and their use should be avoided.[97]

Moderate to severe symptoms

Initial therapy is with a migraine-specific drug.[34]

Triptans

Triptans (5HT1 receptor agonists) are the first-line treatment for patients with moderate to severe migraine.[34][87][89][99] They are effective and generally well tolerated, although they are associated with a greater risk of any adverse event, or a treatment-related adverse event, compared with placebo and nontriptans.[100] Triptans are contraindicated in patients with coronary artery disease, and should be used with caution in patients with cardiovascular risk factors.[34][101]

Early treatment with triptans, while the headache is still mild, improves the likelihood of complete pain relief, lowers the chance of recurrent headache, and decreases the amount of medication needed to treat the entire attack.[34][39][87][96]

All oral triptans have been shown to be effective for the acute treatment of migraine, and choice depends on factors such as availability and patient preference.[34][39][97][99][102]

Alternative routes of administration (e.g., subcutaneous or intranasal sumatriptan, intranasal zolmitriptan) have been shown to be effective for acute migraine attacks. These formulations are particularly useful for patients with severe nausea or vomiting or who have trouble swallowing.[34][39][102]

The individual patient response to any particular triptan cannot be predicted, so if one triptan is ineffective a second one should be trialed.[34][39][87]

If treatment with a triptan alone is insufficiently effective, an NSAID, acetaminophen, or acetaminophen/aspirin/caffeine may be used as adjunctive therapy. This improves the efficacy of acute treatment, with a minimal increase in adverse effects.[87][96][103][104]

Lasmiditan and calcitonin gene-related peptide (CGRP) antagonists

Lasmiditan and oral/intranasal CGRP antagonists (also known as gepants) are effective for the acute treatment of migraine with or without aura in adults, and are recommended second-line options if triptans are ineffective or contraindicated.[34][39][83][89][105] These drugs do not constrict blood vessels, and appear to be safe for patients with cardiovascular disease.[34][97] If treatment with either of these therapies alone is insufficiently effective, an NSAID, acetaminophen, or acetaminophen/aspirin/caffeine may be used as adjunctive therapy.

Lasmiditan, a first-in-class serotonin 5-HT1F receptor agonist, was associated in trials with significant improvements in pain freedom, pain relief, and relief from the most bothersome symptom at 2 hours after dosing, as well as pain freedom at 1 day and 1 week (compared with placebo).[97][106] Reported adverse effects were mostly mild (e.g., dizziness, paresthesia, somnolence, fatigue), although clinically meaningful impairment in driving performance has been observed. Patients are advised not to drive for at least 8 hours after using lasmiditan.[34][97][106]
Oral CGRP antagonists include rimegepant and ubrogepant. Rimegepant and ubrogepant were associated with significant improvements in pain freedom, pain relief, and the most bothersome (non-pain) symptom at 2 hours, as well as sustained pain freedom at 1 day and at 1 week in trials versus placebo.[34][97] They have shown good safety and tolerability in trials and are associated with fewer adverse effects than lasmiditan.[34][107] In one study, ubrogepant was significantly more effective than placebo in eliminating headache when given during the prodrome phase.[81]
Zavegepant is an intranasal CGRP antagonist. Zavegepant was associated in trials with significant improvements in pain and symptom relief compared with placebo, and has fewer adverse effects than other intranasal-specific therapies for treating acute migraine.[108][109]

Ergot derivatives

Ergot derivatives are approved for the acute treatment of migraine, although triptans, lasmiditan, or CGRP antagonists are the preferred drug options compared to ergot derivatives for most patients requiring migraine-specific treatment, because of both superior efficacy and fewer adverse effects.[34][39][87][110][111] Dihydroergotamine is the only drug in the class that is commonly used in the US to treat migraine. Ergot derivatives should not be used with triptans. If treatment with an ergot derivative alone is insufficiently effective, an NSAID, acetaminophen, or acetaminophen/aspirin/caffeine may be used as adjunctive therapy.

Noninvasive neuromodulation

Neuromodulatory devices may be considered as an option for treating acute migraine if triptans are ineffective or contraindicated, and/or if a non-oral treatment is required because of severe nausea or vomiting. Furthermore, adjunctive neuromodulation may reduce acute medication and so reduce the risk of medication-overuse headache. Approaches shown to be effective and approved for acute migraine treatment are electrical trigeminal nerve stimulation (eTNS), noninvasive vagus nerve stimulation (nVNS), single-pulse transcranial magnetic stimulation (sTMS), and remote electrical neuromodulation (REN).[34][83][97][112][113]

Rescue medication for severe migraine

First-line treatment of adults with acute migraine in the emergency department should include an intravenous antiemetic (e.g., metoclopramide or prochlorperazine) with or without diphenhydramine.[114][115][116][117] Promethazine can also be used for the symptomatic relief of nausea. Evidence suggests it may help other migraine symptoms. Prochlorperazine appears to work faster than promethazine but has similar outcomes at 60 minutes.[118]

American Headache Society (AHS) guidelines recommend offering subcutaneous sumatriptan. They also support the use of intravenous administration of ketorolac, valproic acid, haloperidol, or acetaminophen.[114]

The use of opioids should be avoided because there is a risk of dependence, misuse, or overdose, and other treatments appear more effective.[97][114]

Hydration with oral or intravenous fluids should be considered for any patient with prolonged migraine headache associated with nausea and vomiting.[88] High-flow oxygen may provide effective acute treatment for migraine.[119]

Intravenous corticosteroid

An intravenous corticosteroid such as dexamethasone should be offered to prevent migraine recurrence.[114] Although frequent use can result in adrenal suppression, osteoporosis, osteonecrosis, or elevated serum glucose levels, the risk of irreversible adverse effects such as osteonecrosis is extremely low after one dose of dexamethasone.[114]

Intravenous magnesium

Intravenous magnesium may be considered for selected patients

Low brain and serum levels of ionized magnesium have been demonstrated in some people with migraine.[120] One systematic review suggested potential benefits in pain control beyond 1 hour, aura duration, and need for rescue analgesia, but noted that evidence was conflicting.[121]

AHS guidelines state that no recommendation can be made regarding use of intravenous magnesium for adults who present to an emergency department with acute migraine, but that it may be of benefit for patients with migraine with aura.[114]

Peripheral intravascular catheter: animated demonstration

How to insert a peripheral intravascular catheter into the dorsum of the hand.

Acute treatment of migraine in pregnancy

Women with migraine should be offered preconception counseling.[85][86]

Noninvasive neuromodulation is a potential nonpharmacologic treatment for acute migraine during pregnancy, although efficacy in pregnant women has not been assessed and evidence for its use in pregnancy is limited.[85]

If pharmacologic treatment of migraine is needed during pregnancy, the safest medication should be recommended at the lowest dose for the shortest duration possible to achieve effective symptom control.[86]

Acetaminophen is recommended as the initial therapy for treatment of acute migraine.[85]

For persistent migraine, metoclopramide alone or combined with diphenhydramine is recommended by the American College of Obstetricians and Gynecologists (ACOG).[85] Diphenhydramine may also be used with prochlorperazine.

NSAIDs for intractable migraine may be considered in the second trimester only. Sumatriptan may be considered with caution, but is not suitable for patients with cardiac disease or hypertension.[85] One systematic review concluded that triptans do not appear to increase the risk of adverse pregnancy outcomes.[123]

Intravenous magnesium may be considered for patients with migraine that has not responded to other therapies, but only as a short-term treatment, as it may cause bone thinning in the developing fetus when used for longer than 5-7 days in a row.[85][124]

Oral prednisone is the preferred corticosteroid for use in pregnancy due to its safety profile, although effectiveness may be lower than that of dexamethasone. Dexamethasone may be considered with caution for pregnant patients with severe recalcitrant migraine.[85]

Little information is available about the safety of lasmiditan or CGRP antagonists in pregnancy, and they are not currently recommended for pregnant women.[85]

Ergot derivatives, aspirin at analgesic doses, and opioids are not recommended for treating migraine in pregnancy.[85][86]

Valproic acid and its derivatives are contraindicated during pregnancy.

Preventive treatment: principles

Consideration of preventive treatment is recommended if any of the following apply: migraine attacks interfere significantly with patient’s daily activities despite acute treatment; frequent attacks; contraindication to, adverse effects with, failure of, or overuse of acute treatments.[34]

Prevention comprises trigger avoidance and the use of specific nonpharmacologic and pharmacologic therapies.[34][39][83]

The choice of preventive treatment should be individualized, based on proven efficacy, patient preference and headache profile, drug adverse effects, and the presence or absence of coexisting or comorbid conditions, including pregnancy.[34][39][83][125][126][127]

Trigger avoidance

Various factors may act as migraine triggers in some patients. However, in most cases data are from patient surveys, and evidence from randomized controlled trials is lacking.

Reported triggers include:

High caffeine intake. Caffeine increases the risk of migraine and chronic migraine, especially in younger women and in people with chronic headaches of recent onset. Sudden caffeine withdrawal may also trigger migraine attacks.[128][129][130]
Specific foods and alcohol. Patient survey studies have suggested dietary triggers for migraine. Preliminary evidence suggests that changes in diet may improve headache frequency or severity, but evidence is weak and this needs to be investigated in randomized controlled trials.[128][129]
Weather changes. Changes in temperature, humidity and/or atmospheric pressure may trigger migraine in some patients.[129][131]
High altitude. There is some evidence that high altitude increases migraine prevalence and severity.[129][131][132]
Specific odors. Perfume or odor has been reported as a migraine trigger.[131]

Patients should be educated about trigger avoidance, and encouraged to keep a headache diary so that triggers can be identified and avoided if possible. However, in some cases avoiding triggers may not be realistic.[39][129]

Preventive treatment: nonpharmacologic therapies

Nonpharmacologic therapies are especially appropriate for women who are pregnant or attempting pregnancy, and for others who wish to avoid or do not tolerate drug therapy.[34][39][83]

Inadequate sleep, stress, depression, anxiety, and medication overuse are risk factors for poor outcome in prospective studies; nonpharmacologic treatments or specialist consultation to address these problems may improve outcomes.[126][129]

Biobehavioral therapies

Several forms of biobehavioral therapy are recommended for migraine prevention, including cognitive behavioral therapy, biofeedback, and relaxation training.[34][83][126][133] Mindfulness-based therapies also have some evidence of effectiveness.[34][126] However, one 2019 Cochrane review concluded that evidence on psychological therapies for the prevention of migraine in adults is of low quality, making it difficult to reach conclusions on effectiveness.[134]

Noninvasive neuromodulation

eTNS, nVNS, and sTMS have evidence of effectiveness and are approved for the preventive treatment of migraine.[34][126][135] Guidelines recommend considering a trial of a neuromodulatory device for prevention as an adjunct to the existing treatment plan for all patients with migraine. Neuromodulation may also be beneficial as monotherapy for patients who have to or prefer to limit or avoid drugs due to contraindications or low tolerability.[34]

Physical activity

There is some evidence that aerobic exercise, yoga, and strength training may decrease migraine frequency and the number of migraine days.[126][136][137][138][139]

Evidence for the effectiveness of physical therapies (e.g., massage, physical therapy, chiropractic treatment) is very limited, and more research is needed.[83][126][140]

Acupuncture

One Cochrane review reported that adding acupuncture to the symptomatic treatment of attacks reduced the frequency of headaches, although when compared with prophylactic drug treatment this effect was not maintained at follow-up (3 months).[141] Other systematic reviews have suggested that acupuncture may be an effective and safe prophylactic treatment for migraine, but the quality of the evidence is low.[142][143]

Acupuncture may be useful for patients who do not want to use prophylactic drugs or in whom prophylactic drugs are ineffective.[39][83]

Preventive treatment: pharmacologic therapies

CGRP antagonists are recommended as a first-line pharmacologic therapy for migraine prevention by the American Headache Society (AHS); there is substantial evidence for their efficacy, safety, and tolerability, compared with other first-line therapies.[34][83][125][126][127][144][145][146][147] CGRP antagonists for migraine prophylaxis include oral CGRP antagonists (also known as gepants) and CGRP antagonist monoclonal antibodies.[125]

Other drug treatments used for prevention of migraine include anticonvulsants (e.g., divalproex sodium, topiramate), beta-blockers, candesartan (an angiotensin-II receptor antagonist), tricyclic antidepressants (e.g., amitriptyline), and serotonin-norepinephrine reuptake inhibitors (SNRIs; e.g., venlafaxine, duloxetine).[34][83][89][125][127][147] [ ]

Treatment should be started at a low dose and reevaluated after an adequate trial period (at least 8 weeks).[34][126] The optimal duration of preventive treatment is unknown. Once an effective treatment is found, most experts recommend continuing it for at least 4 to 6 months. At that time, the dose can be slowly lowered over weeks or months, while monitoring any change in headache frequency and resuming full treatment if necessary.[34] Some patients whose headaches are extremely disabling or troublesome may prefer to stay on preventive treatment indefinitely.[34] However, tolerance to preventive therapies may limit their effectiveness.[148]

CGRP antagonists

CGRP antagonists are a first-line option for migraine prevention.[125]

Oral CGRP antagonists for migraine prophylaxis include atogepant and rimegepant.[125] Both drugs have been shown to reduce the mean number of migraine days per month in trials.[145][149][150][151][152][153] They are generally safe and well tolerated for migraine prevention.[154]

CGRP antagonist monoclonal antibodies (e.g., erenumab, fremanezumab, galcanezumab, eptinezumab) are another option. They are administered subcutaneously or intravenously depending on the drug. All four drugs have been demonstrated in randomized controlled trials to reduce monthly migraine days in patients with episodic or chronic migraine, and are safe and well tolerated.[34][144][145][154][155][156][157] Real-world data support trial results, although evidence is limited.[158] There is preliminary evidence that switching to an alternative CGRP antagonist monoclonal antibody after a lack of response to a first may be effective for some patients.[159][160][161]

Anticonvulsants

Topiramate is recommended for migraine prevention.[34][127][147][162]Silberstein SD, Holland S, Freitag F, et al; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012 Apr 24;78(17):1337-45.[163] [ ] It is effective in reducing migraine headache days and generally well tolerated, although adverse events may result in treatment discontinuation.[164] Topiramate did not prevent the development of chronic daily headache at 6 months in one study.[165] It is associated with weight loss, and is especially useful in patients who are overweight or unwilling to take drugs that might cause weight gain.

Topiramate exposure during pregnancy is associated with child neurodevelopmental disorders and congenital malformations.[166][167]

In some countries, topiramate is contraindicated in pregnancy and in women of childbearing age unless the conditions of a pregnancy prevention program are fulfilled to ensure that women of childbearing potential: are using highly effective contraception; have a pregnancy test to exclude pregnancy before starting topiramate; and are aware of the risks associated with use of the drug.[168][169]

Divalproex sodium (a valproic acid derivative) is also recommended for migraine prevention.[34][127][147][162]Silberstein SD, Holland S, Freitag F, et al; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012 Apr 24;78(17):1337-45.[170]

Valproic acid and its derivatives may cause major congenital malformations, including neurodevelopmental disorders and neural tube defects, after in utero exposure.

These agents must not be used in female patients of childbearing potential unless other options are unsuitable, there is a pregnancy prevention program in place, and certain conditions are met.
Precautionary measures may also be required in male patients owing to a potential risk that use in the 3 months leading up to conception may increase the likelihood of neurodevelopmental disorders in their children.
Regulations and precautionary measures for female and male patients may vary between countries, with some countries taking a more heightened precautionary stance, and you should consult your local guidance for more information.

Beta-blockers

Propranolol, timolol, metoprolol, nadolol, and atenolol have shown evidence of benefit.[28][34][127][147][162]Silberstein SD, Holland S, Freitag F, et al; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012 Apr 24;78(17):1337-45.[163][171]

Candesartan

Randomized controlled trials have demonstrated that candesartan (an angiotensin-II receptor antagonist) is effective for the prevention of migraine.[172][173][174]

Tricyclic antidepressants

Tricyclic antidepressants are thought to prevent migraine by inhibiting serotonin and norepinephrine reuptake. No tricyclic antidepressant is approved in the US for migraine prevention. Amitriptyline has been reported to be effective in migraine prevention, but trials have been low quality.[34][127][175]

SNRIs

Data suggest that venlafaxine is as effective as amitriptyline for migraine prevention.[176] There is also some evidence that duloxetine is effective for migraine prevention.[127][177][178] These drugs may be especially useful for patients with comorbid depression.

OnabotulinumtoxinA

OnabotulinumtoxinA has been shown to reduce migraine attacks compared with placebo, to be well tolerated, and to improve quality of life.[34][126][146][179][180] [ ] It is recommended as a treatment option for migraine prevention in US guidelines.[34] It is also recommended for treatment of chronic migraine (headache occurring on ≥15 days per month for > 3 months) in European and Canadian guidelines.[163][181] Response to treatment should be evaluated regularly, taking into account that any effect will wear off over time, and treatment should be stopped if the patient does not respond to the first two to three treatment cycles.[181] Combination treatment with a CGRP antagonist monoclonal antibody may be more effective than botulinum toxin treatment alone.[34][126][182]

Preventive medication for women with menstrual migraine

Women with menstrual migraine should be considered for hormonal therapy to suppress menses if medically appropriate.[27][183] A thorough history should be obtained, and Medical Eligibility Criteria for contraceptive use applied, to determine safe use of contraception for menstrual suppression.[184]

Combined hormonal contraceptives are contraindicated in women who have migraine with aura due to an increased risk of cerebrovascular events.[185] Women with migraine with aura should be offered pharmacologic treatments other than cycle control.

Evidence shows that frovatriptan is effective, and zolmitriptan and naratriptan are probably effective, for the short-term prevention of menstrual migraine.[27][34][39][162]Silberstein SD, Holland S, Freitag F, et al; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012 Apr 24;78(17):1337-45.[186]

Oral magnesium may be used as a preventive treatment for migraine headache in women with menstrual-related headaches.[187]

Preventive treatment for pregnant women

Trigger avoidance and nonpharmacologic therapies (e.g., noninvasive neuromodulation, biobehavioral therapies) are suggested as first-line preventive treatment for pregnant women and women planning pregnancy.[39][85]

Specialist advice should be sought if pharmacologic preventive treatment for migraine is needed during pregnancy. No medication is completely free of risk, and decisions should be made on an individual basis, balancing the risk of the untreated headache disorder as a threat to the health of the mother and unborn child against the risk of the treatment, and taking into account the patient's values and priorities.[34][85][86]

Topiramate, divalproex sodium, and candesartan are contraindicated in pregnancy.

There is limited evidence on the efficacy and safety of the use of medications for headache prevention in pregnancy. ACOG guidelines note that beta-blockers have evidence of relative safety in pregnancy for other indications.[85] One review concluded that, of medication commonly used for migraine prevention, propranolol has the best evidence for safety during pregnancy.[188] One systematic review noted that anticonvulsants, venlafaxine, tricyclic antidepressants, and beta-blockers may all be associated with fetal/child adverse effects.[189]

CGRP antagonists have not been studied in pregnant women with migraine. Some CGRP antagonists have been shown to cross the placenta in animal studies, but their effects on the developing human fetus are unknown. CGRP antagonist monoclonal antibodies may have a very long half-life (28 days or more), resulting in a prolonged elimination time after discontinuing treatments. Future plans for pregnancy should be discussed prior to initiating therapy.

Magnesium is no longer recommended as a daily preventive medication in pregnant women with migraine.[190] This is because parenteral magnesium may cause bone thinning in the developing fetus when used for longer than 5-7 days in a row.[124]

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