Migraine Headache Medication

Pharmacologic agents used for the treatment of migraine can be classified as abortive (ie, for alleviating the acute phase) or prophylactic (ie, preventive).

Abortive medications include the following:

• Selective serotonin receptor (5-HT1) agonists (triptans)
• Ergot alkaloids
• Analgesics
• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Combination products
• Antiemetics

Prophylactic medications include the following:

• Antiepileptic drugs
• Beta-blockers
• Tricyclic antidepressants
• Calcium channel blockers
• Selective serotonin reuptake inhibitors (SSRIs)
• NSAIDs
• Serotonin antagonists
• Botulinum toxin

Class Summary

Triptans are selective serotonin agonists, specifically acting at 5-hydroxytryptamine 1B/1D/1F (5-HT_1B/1D/1F) receptors on intracranial blood vessels and sensory nerve endings. Triptans are used as abortive medications for moderately severe to severe migraine headaches.

The most common side effects are asthenia; nausea/vomiting; dizziness; somnolence; chest, throat, or jaw tightness/discomfort; and worsening of head pain (often transient).

Drug interactions include potent CYP450 3A4 inhibitors (eg, ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir), which may increase toxicity, and concurrent administration with ergot-containing drugs, which may increase vasospastic reactions. Zolmitriptan, eletriptan, and naratriptan are primarily metabolized by CYP450 3A4.

Sumatriptan (Imitrex, Sumavel DosePro)

The efficacy of sumatriptan is 82% at 20 min when administered by injection, 52-62% at 2 h when administered intranasally, and 67-79% at 4 h when administered orally.^{[89, 90, 91]}

Naratriptan (Amerge)

A selective agonist for serotonin 5-HT1 receptors, naratriptan has higher bioavailability and longer half-life than sumatriptan, which may contribute to lower rate of headache recurrences. It has a duration of action of up to 24 hours with low headache recurrence rate. It is useful for patients with slow onset, prolonged migraine, such as menstrual migraine. Pain relief is experienced by 60-68% of patients within 4 h of treatment and maintained up to 24 h in 49-67% of patients.

Zolmitriptan (Zomig, Zomig-ZMT)

A selective agonist for serotonin 5-HT1 receptors in cranial arteries, zolmitriptan suppresses the inflammation associated with migraine headaches. It has efficacy of 62% at 2 h and 75-78% within 4 h.

Rizatriptan (Maxalt, Maxalt-MLT)

A selective agonist for serotonin 5-HT1 receptors in cranial arteries, rizatriptan suppresses the inflammation associated with migraine headaches. It has reported early onset of action (30 min) and efficacy of 71% at 2 h.

Almotriptan (Axert)

A selective 5-HT1B/1D receptor agonist, almotriptan results in cranial vessel constriction, inhibition of neuropeptide release, and reduced pain transmission in trigeminal pathways. It induces cranial vessel constriction, inhibition of neuropeptide release, and reduces pain transmission in trigeminal pathways.

Frovatriptan (Frova)

Frovatriptan is a selective 5-HT1B/1D receptor agonist with a long half-life (ie, 26-30 h) and low headache recurrence rate within 24 hour of taking the drug. It constricts cranial vessels, inhibits neuropeptide release, and reduces pain transmission in trigeminal pathways.

Eletriptan (Relpax)

A selective serotonin agonist, eletriptan specifically acts at 5-hydroxytryptamine 1B/1D/1F (5-HT1B/1D/1F) receptors on intracranial blood vessels and sensory nerve endings to relieve pain associated with acute migraine.

Class Summary

Ergot alkaloids are nonselective 5-HT1 agonists that have a wider spectrum of receptor affinities outside of the 5-HT1 system, including dopamine receptors. They can be used for the abortive treatment of moderately severe to severe migraine headache.

Ergotamine tartrate (Ergomar)

Ergotamine counteracts episodic dilation of extracranial arteries and arterioles.

Dihydroergotamine (DHE-45, Migranal)

Dihydroergotamine is an alpha-adrenergic blocking agent with a direct stimulating effect on smooth muscle of peripheral and cranial blood vessels. It depresses central vasomotor centers. Its mechanism of action is similar to that of ergotamine; it is a nonselective 5HT1 agonist with a wide spectrum of receptor affinities outside 5HT1 system; it also binds to dopamine. Thus, it has an alpha-adrenergic antagonist and serotonin antagonist effect.

Dihydroergotamine is indicated to abort or prevent vascular headache when rapid control is needed or when other routes of administration are not feasible. It tends to cause less arterial vasoconstriction than ergotamine tartrate. It is usually administered in conjunction with antiemetics such as metoclopramide, which is a 5HT3-receptor antagonist and a dopamine antagonist, to treat migraine-associated nausea.

Dihydroergotamine is available in IV or intranasal preparations. The IV route is used when more rapid results are desired. A dose of 1 mg intravenously every 8 hours with or without metoclopramide is safe and effective for treatment of status migrainosus.

Class Summary

These agents are used as initial abortive therapy for patients with infrequent migraines.

Acetaminophen (Tylenol)

These agents are used as initial abortive therapy for patients with infrequent migraines.

Oxycodone (OxyContin, Roxicodone)

Oxycodone is an analgesic with multiple actions similar to those of morphine. However, it may produce less constipation, smooth muscle spasm, and depression of cough reflex than similar analgesic doses of morphine.

Morphine sulfate (Duramorph, MS Contin, Astramorph)

Morphine is the drug of choice for narcotic analgesia because of its reliable and predictable effects, safety profile, and ease of reversibility with naloxone. Morphine sulfate administered IV may be dosed in a number of ways and is commonly titrated until the desired effect is obtained.

Meperidine (Demerol)

Meperidine is an analgesic with multiple actions similar to those of morphine. However, it may produce less constipation, smooth muscle spasm, and depression of cough reflex than similar analgesic doses of morphine.

Hydromorphone (Dilaudid)

Hydromorphone is a potent semisynthetic opiate agonist similar in structure to morphine. It is approximately 7-8 times as potent as morphine on mg-to-mg basis, with a shorter or similar duration of action.

Butorphanol (Stadol)

A mixed agonist-antagonist narcotic with central analgesic effects for moderate to severe pain, butorphanol causes less smooth muscle spasm and respiratory depression than morphine or meperidine. Weigh these advantages against the higher cost of butorphanol.

Class Summary

NSAIDs inhibit cyclo-oxygenase (COX), an early component of the arachidonic acid cascade, resulting in reduced synthesis of prostaglandins, thromboxanes, and prostacyclin. They elicit anti-inflammatory, analgesic, and antipyretic effects. NSAIDs are generally used as abortive therapy in mild to moderately severe migraine headaches. However, these agents, especially ketorolac, may also be effective for severe headaches.

NSAIDs are also used as prophylactic agents, but they are associated with a higher risk of adverse effects, particularly gastropathy or nephropathy, than when used as abortive medications.

Aspirin (Bayer Aspirin, Anacin)

Aspirin is a mild analgesic that can be used to treat infrequent migraine episodes.

Ketorolac (Sprix [intranasal])

Ketorolac is indicated for short-term (up to 5 d) management of moderate to moderately severe pain. The bioavailability of a 31.5-mg intranasal dose (2 sprays) is approximately 60% of 30-mg IM dose. Intranasal spray delivers 15.75 mg per 100-µL spray; each 1.7-g bottle contains 8 sprays.

Ibuprofen (Motrin, Advil)

Ibuprofen is used for treatment of mild to moderate pain if no contraindications are present. It inhibits inflammatory reactions and pain, probably by decreasing the activity of the enzyme cyclo-oxygenase, resulting in prostaglandin synthesis.

Naproxen (Naprosyn, Naprelan, Anaprox)

Naproxen is used for relief of mild to moderate pain, as an abortive agent, and for prophylaxis. It inhibits inflammatory reactions and pain by decreasing the activity of the enzyme cyclo-oxygenase, resulting in prostaglandin synthesis.

Ketoprofen

Ketoprofen is used for relief of mild to moderately severe headaches and inflammation. Administer small dosages initially to patients with small body size, elderly patients, and patients with renal or liver disease. Doses >75 mg do not have increased therapeutic effects. Administer high doses with caution, and closely observe the patient for response.

Class Summary

The first combination product of a 5HT receptor agonist and an NSAID was approved by the US Food and Drug Administration in April 2008. Other combination products that contain ergots, sedatives, and analgesics may be used when simple analgesics are not effective and the patient is not a candidate for treatment with 5-HT1 agonists or when the patient needs an alternative drug.

Some agents are used in combination with aspirin and acetaminophen for pain relief and to induce sleep. Caffeine is also used to increase GI absorption. Analgesics like butalbital and narcotics are associated with rebound headaches. Increasing the use of combination preparations may fail to provide pain relief and worsen headache symptoms.

Sumatriptan and naproxen (Treximet)

This is a combination product containing sumatriptan, a selective 5-hydroxytryptamine (5-HT1) receptor agonist, and naproxen sodium, an arylacetic acid NSAID in a fixed combination of sumatriptan 85 mg and naproxen sodium 500 mg. It is indicated for acute migraine. Sumatriptan mediates vasoconstriction of the basilar artery and vasculature of dura mater, which correlates with migraine relief. Naproxen provides analgesic, anti-inflammatory, and antipyretic properties. It decreases activity of cyclooxygenase, thereby interrupting prostaglandin synthesis.

Butalbital, aspirin, and caffeine (Fiorinal)

This combination drug is effective for mild to moderately severe migraine headache. . The barbiturate component has generalized depressant effect on CNS. Caffeine is used to increase GI absorption. However, butalbital and narcotics are associated with rebound headaches. Increasing the use of combination preparations may fail to provide pain relief and worsen headache symptoms.

Isometheptene, dichloralphenazone, and acetaminophen (Midrin, Epidrin)

This combination drug has sympathomimetic properties. It dilates cranial and cerebral arterioles, causing a reduction in the stimuli that lead to vascular headaches.

Butalbital, acetaminophen, and caffeine (Fioricet)

This combination drug is effective for mild to moderately severe migraine headache. . The barbiturate component has a generalized depressant effect on CNS. Caffeine is used to increase GI absorption. However, butalbital and narcotics are associated with rebound headaches. Increasing the use of combination preparations may fail to provide pain relief and worsen headache symptoms.

Acetaminophen and codeine (Tylenol No. 3)

This drug combination is indicated for treatment of mild to moderately severe headache. Note that some patients may respond to maximal acetaminophen alone, without codeine.

Class Summary

As dopamine antagonists, these agents are effective if nausea and vomiting are prominent features. They also may act as prokinetics to increase gastric motility and enhance absorption.

These agents are used to treat migraine and the emesis associated with acute attacks. Drugs in this category are commonly combined with diphenhydramine to minimize the risk of akathisia. This combination of drugs has been found to be superior to subcutaneous sumatriptan when given intravenously in emergency patients.^[73]

Chlorpromazine (Thorazine)

The mechanisms of chlorpromazine include blocking postsynaptic mesolimbic dopamine receptors, anticholinergic effects, and depression of reticular activating system. Blocks alpha-adrenergic receptors and depresses release of hypophyseal and hypothalamic hormones. As a rule, dopamine antagonists are avoided in patients with traumatic brain injury.

Droperidol (Inapsine)

Used alone or in combination with other analgesics as adjuncts, especially if migraine attack associated with significant nausea and vomiting. Its role in migraine based on findings that increased dopamine concentration is associated with prominent migraine symptomatology.

Prochlorperazine (Compro)

An antidopaminergic drug that blocks postsynaptic mesolimbic dopamine receptors, prochlorperazine has an anticholinergic effect. It can also depress the reticular activating system, a possible mechanism for relieving nausea and vomiting.

Promethazine (Phenergan, Phenadoz)

Promethazine is a phenothiazine derivative that possesses antihistaminic, sedative, antimotion sickness, antiemetic, and anticholinergic effects.

Droperidol

Droperidol is used alone or in combination with other analgesics as adjuncts, especially in migraine attacks associated with significant nausea and vomiting. Its role in migraine is based on findings that increased dopamine concentration is associated with prominent migraine symptoms.

Class Summary

These drugs are effective in prophylaxis of migraine headache.

Divalproex sodium/valproate (Depakote, Depacon, Depakene)

Divalproex is now considered first-line preventive medication for migraine. This agent is believed to enhance GABA neurotransmission, which may suppress events related to migraine that occur in cortex, perivascular sympathetics, or trigeminal nucleus caudalis. Divalproex has been shown to reduce migraine frequency by 50%.

Gabapentin (Neurontin)

Gabapentin is used for migraine headache prophylaxis. It has shown efficacy in migraine and transformed migraine.

Topiramate (Topamax)

Topiramate is indicated for migraine headache prophylaxis. Its precise mechanism of action is unknown, but the following properties may contribute to its efficacy: 1) blockage of voltage-dependent sodium channels, 2) augmentation of activity of the neurotransmitter GABA at some GABA-A receptor subtypes, 3) antagonization of the AMPA/kainate subtype of the glutamate receptor, and 4) inhibition of the carbonic anhydrase enzyme, particularly isozymes II and IV.

Class Summary

Beta-blockers may prevent migraines by blocking vasodilators, decreasing platelet adhesiveness and aggregation, stabilizing the membrane, and increasing the release of oxygen to tissues. Significant to their activity as migraine prophylactic agents is the lack of partial agonistic activity. Latency from initial treatment to therapeutic results may be as long as 2 months.

Metoprolol (Lopressor, Toprol XL)

Metoprolol is not FDA approved for migraine prevention. Efficacy in prophylactic therapy is presumably by the same mechanism as with other beta-blockers.

Propranolol (Inderal)

Beta-blockers may prevent migraines by blocking vasodilators, decreasing platelet adhesiveness and aggregation, stabilizing the membrane, and increasing the release of oxygen to tissues. Significant to their activity as migraine prophylactic agents is the lack of partial agonistic activity. Latency from initial treatment to therapeutic results may be as long as 2 months.

Timolol

Timolol is FDA approved for migraine prophylaxis, although there is less scientific evidence of efficacy for timolol than for propranolol.

Nadolol (Corgard)

Nadolol is not FDA approved for migraine prevention. Efficacy in prophylactic therapy is presumably by the same mechanism as with other beta-blockers.

Atenolol (Tenormin)

Atenolol is not FDA approved for migraine prevention. Efficacy in prophylactic therapy is presumably by the same mechanism as with other beta-blockers.

Class Summary

Amitriptyline, nortriptyline, doxepin, and protriptyline have been used for migraine prophylaxis, but only amitriptyline has proven efficacy and appears to exert its antimigraine effect independent of its effect on depression.

Amitriptyline

Amitriptyline has efficacy for migraine prophylaxis that is independent of its antidepressant effect. Its mechanism of action is unknown, but it inhibits activity of such diverse agents as histamine, 5-HT, and acetylcholine.

Doxepin (Adapin)

Doxepin has efficacy for migraine prophylaxis that is independent of its antidepressant effect. Its mechanism of action is unknown, but it increases concentration of serotonin and norepinephrine in the CNS by inhibiting their reuptake by presynaptic neuronal membrane. It also inhibits histamine and acetylcholine activity.

Nortriptyline (Pamelor)

Nortriptyline has efficacy for migraine prophylaxis that is independent of its antidepressant effect. Its mechanism of action is unknown, but it inhibits activity of such diverse agents as histamine, 5-HT, and acetylcholine.

Protriptyline (Vivactil)

Protriptyline has efficacy for migraine prophylaxis that is independent of its antidepressant effect. It inhibits activity of such diverse agents as histamine, 5-HT, and acetylcholine.

Class Summary

This group is commonly used as prophylactic medication, although studies of their effectiveness have shown mixed results. Flunarizine has the best-documented efficacy but is not available in the United States. The efficacy of verapamil is supported by studies.

This group is particularly useful in patients with comorbid hypertension and in those with contraindications to beta-blockers such as asthma and Raynaud disease. This group may have particular advantage in patients with prolonged aura, vertebrobasilar migraine, or hemiplegic migraine.

Verapamil (Calan, Covera, Verelan)

During depolarization, verapamil inhibits calcium ion from entering slow channels or voltage-sensitive areas of vascular smooth muscle.

Class Summary

These may be considered first-line drugs, but they have low efficacy.

Paroxetine (Paxil, Pexeva)

Paroxetine is an atypical non-tricyclic antidepressant with potent specific 5HT-uptake inhibition and fewer anticholinergic and cardiovascular adverse effects than tricyclic antidepressants.

Fluoxetine (Prozac)

Fluoxetine has been shown to be of benefit in migraine prophylaxis. It is an atypical, nontricyclic antidepressant with potent specific 5-HT-uptake inhibition with fewer anticholinergic and cardiovascular side effects than tricyclic antidepressants.

Sertraline (Zoloft)

Sertraline is an atypical nontricyclic antidepressant with potent specific 5-HT uptake inhibition and fewer anticholinergic and cardiovascular adverse effects than tricyclic antidepressants.

Class Summary

Agents in this class with potent serotonin antagonist activity have been reported to be effective in the treatment of migraine.

Cyproheptadine (Periactin)

Cyproheptadine acts primarily as antagonist of cerebral vascular 5-HT2 receptors and has been used traditionally for pediatric migraine prevention despite minimal objective evidence of its efficacy.

Class Summary

Botulinum toxin A may be beneficial in patients with intractable migraine headaches that fail to respond to at least 3 conventional preventive medications.

Onabotulinumtoxin A (BOTOX)

This is one of several toxins produced by Clostridium botulinum. It blocks neuromuscular transmission through a 3-step process, as follows: (1) blockade of neuromuscular transmission; botulinum toxin type A (BTA) binds to the motor nerve terminal. The binding domain of the type A molecule appears to be the heavy chain, which is selective for cholinergic nerve terminals. (2) BTA is internalized via receptor-mediated endocytosis, a process in which the plasma membrane of the nerve cell invaginates around the toxin-receptor complex, forming a toxin-containing vesicle inside the nerve terminal. After internalization, the light chain of the toxin molecule, which has been demonstrated to contain the transmission-blocking domain, is released into the cytoplasm of the nerve terminal. (3) BTA blocks acetylcholine release by cleaving SNAP-25, a cytoplasmic protein that is located on the cell membrane and that is required for the release of this transmitter. The affected terminals are inhibited from stimulating muscle contraction.

The injections are administered to the scalp and temple. They may reduce the frequency and severity of migraine attacks after 2-3 months of injections.