Migraine abortives

Page last modified: November 25, 2011

Triptans

Triptans are the prototype migraine abortive drug. At this writing, this category includes sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, frovatriptan and eletriptan. These drugs are all group-1 agents. These drugs are 5HT-1B and 1D (serotonin) receptor agonists. Some also affect 5HT-1F. Serotonin does a lot of things in the body and there are many receptors, presently ranging from 5HT1-7. The table below contains an overview of the timing of these drugs. Tmax is the time when the effect peaks. T 1/2 tells you (approximately) how long the effect lasts. As a general rule, it takes 5 half-lives for a drug to be completely eliminated -- thus this varies from about 10 hours to 5 days.

Compound	Dose	Tmax	T 1/2
Rizatriptan (Maxalt)	10	1	2-2.5
Eletriptan (Relpax)	40	1-1.25	4-7
Sumatriptan (Imitrex)	100	2.5	2-2.5
Zolmitriptan (zomig)	2.5	2.5	3
Almotriptan (Axert)	12.5	2.5	3.6
Naratriptan (Amerge)	2.5	2-3	5-6
Frovatriptan (Frova)	2.5	2-4	25
(modified from Matthew and Loder, 2005)

Chemical name: Almotriptan

Proprietary names: Axert®.
Data: Randomized, double-blind, placebo-controlled trials demonstrated the efficacy of this drug (Dahlof et al. 2006; Diener 2005; Dowson et al. 2002; Pascual et al. 2000).
Class: Triptan.
Mechanism of action: Serotonin receptor agonist with strong affinity for 5-HT_1B/1D/1F receptors; weak affinity for 5-HT_1A/7 receptors.
Pharmacokinetics: Bioavailability 70%; peak concentration at 1-3 hrs.; half-life 3-4 hrs.
Metabolism: Monoamine oxidase and CYP-450. Excreted in urine (40%) and feces (13%).
Precautions: Contraindicated in patients with cardiovascular disease, uncontrolled hypertension, basilar migraine, hemiplegic migraine.
Dosing: 6.25, 12.5 mg
Adverse effects: Nausea, somnolence, paresthesias, dry mouth, palpitations.
Comments: A medium strength triptan

Chemical name: Eletriptan

Proprietary names: Relpax®.
Data: Randomized, double-blind, placebo-controlled trials demonstrated efficacy of this drug (Sandrini et al. 2002; Sheftell et al. 2003; Stark et al. 2002). Several trials demonstrated superiority of eletriptan over sumatriptan (Deleu and Hanssens 2003; Goadsby et al. 2000).
Class: Triptan.
Mechanism of action: Serotonin receptor agonist with strong affinity for 5-HT_1B/1D/1F receptors; weak affinity for 5-HT_1A/1E/2B/7 receptors.
Pharmacokinetics: Bioavailability 50%; peak concentration achieved at 1.5 hrs, though during an attack can be reached at 2 hrs.; half-life 4 hrs.
Metabolism: N‑demethylated by CYP-3A4. Excreted in urine (10%).
Precautions: Contraindicated in patients with cerebrovascular, cardiovascular or peripheral vascular disease, uncontrolled hypertension, hemiplegic or basilar migraine, severe hepatic impairment. Avoid within 24 hrs. of using other 5‑HT₁ agonists or ergot-type drugs.
Dosing: 20 mg, 40 mg.
Advantages: Powerful and rapidly acting triptan.
Adverse effects: Weakness, chest discomfort, dry mouth, paresthesias, fatigue.
Comments: We prescribe eletriptan often.

Chemical name: Frovatriptan

Proprietary names: Frova®.
Data: A review of randomized trials found this drug to be more efficacious than placebo (Poolsup et al. 2005). Dose-finding studies found 2.5 mg to be the optimal balance between efficacy and tolerability (Goldstein and Keywood 2002; Rapoport et al. 2002). As with other triptans, taking frovatriptan earlier in a migraine attack is more likely to be efficacious (Cady et al. 2004). Several randomized, double-blind, placebo-controlled trials found efficacy of this drug in the unusual use as a prophylactic for menstrual migraine (Adelman and Calhoun 2005; Silberstein et al. 2004).
Class: Triptan.
Mechanism of action: Serotonin receptor agonist with strong affinity for 5-HT_1B/1D receptors
Pharmacokinetics: Bioavailability 20% (males), 30% (females); peak concentration achieved at 2-4 hrs.; half-life 26 hrs.
Metabolism: Feces (62%), urine (32%).
Precautions: Contraindicated in cerebrovascular, cardiovascular and peripheral vascular disease, uncontrolled hypertension, hemiplegic or basilar migraines. Avoid within 24 hrs. of using 5‑HT₁ agonists or ergot-type drugs.
Dosing: 2.5 mg.
Advantages: Long half-life.
Adverse effects: Paresthesias, dry mouth, gastric upset, fatigue, flushing.
Comments: Due to its long half-life, this drug has been marketed as effective for menstrual migraines. We find this property to be useful in other migraines as well.

Chemical name: Naratriptan

Proprietary names: Amerge®.
Data: Randomized, double-blind, placebo-controlled trials (Klassen et al. 1997; Mathew et al. 1997) and dose-ranging trials (Havanka et al. 2000) showed efficacy of naratriptan. A meta-analysis of randomized trials showed that naratriptan is better tolerated than rizatriptan, sumatriptan or zolmitriptan. Its efficacy is poorer than rizatriptan and sumatriptan, but comparable to zolmitriptan. It is also less efficacious than eletriptan (Garcia-Ramos et al. 2003). Several randomized, double-blind, placebo-controlled trials found efficacy of this drug in the unusual use as a prophylactic for menstrual migraine (Mannix et al. 2007b; Newman et al. 2001).
Class: Triptan.
Mechanism of action: Serotonin receptor agonist, with strong affinity for 5-HT_1B/1D receptors.
Pharmacokinetics: Bioavailability 70%; peak concentration reached at 2-3 hrs., though during an attack can be reached at 3-4 hrs; elimination half-life 6 hrs.
Metabolism: Excreted in urine (50%).
Precautions: Contraindicated in patients with uncontrolled hypertension, cerebrovascular, cardiovascular, or peripheral vascular disease, basilar and hemiplegic migraines. Use with caution in renal or hepatic impairment. Avoid within 24 hrs. of using another 5‑HT₁ agonist or ergot-type drugs.
Dosing: Although a 1 mg dose exists, the 2.5 mg dose is usually used.
Advantages: —
Adverse effects: Paresthesias, drowsiness, fatigue.
Comments: We use this dose for patients who need a weak triptan.

Chemical name: Rizatriptan

Proprietary names: Maxalt® (tablet), Maxalt-MLT® (orally disintegrating wafer)
Data: Randomized, double-blind, placebo-controlled studies have shown efficacy of this drug in migrines associated with nausea (Freitag et al. 2008), menstrual migraines (Mannix et al. 2007a), and migraines in adolescents (Winner et al. 2002).
Class: Triptan.
Mechanism of action: Serotonin receptor agonist with strong affinity for 5-HT_1B/1D receptors; weak affinity for 5-HT_1A/1E/1F receptors.
Pharmacokinetics: Bioavailability 45%; peak concentration 1-1.5 hrs. (tablet) or 1.6-2.5 hrs. (orally disintegrating wafer); half-life 2-3 hrs.
Metabolism: Oxidative deamination via monoamine oxidase A. Excreted in urine (82%) and feces (12%).
Precautions: Contraindicated in patients with uncontrolled hypertension, cardiovascular disease, hemiplegic or basilar migraines. Avoid within two weeks of using a monoamine oxidase inhibitor or within 24 hrs. of ergot-type drugs or serotonergic drugs.
Dosing: 5 mg, 10 mg (tablet or orally disintegrating wafer).
Advantages: Has an orally disintegrating wafer formulation.
Adverse effects: Paresthesias, dry mouth, nausea, fatigue.
Comments: Powerful triptan.

Chemical name: Sumatriptan

Proprietary names: Imitrex®.
Data: Randomized, double-blind, placebo-controlled trials have demonstrated the efficacy of oral sumatriptan (Sheftell et al. 2005; Winner et al. 2003), nasal sumatriptan (Winner et al. 2000), and subcutaneous sumatriptan (Russell et al. 1995; Wendt et al. 2006).
Class: Triptan.
Mechanism of action: Serotonin receptor agonist with strong affinity for 5-HT_1D receptors; weak affinity for 5-HT_1A/5A/7 receptors.
Pharmacokinetics: Oral: bioavailability 15%; peak concentration reached in 2 hrs.; elimination half-life 2.5 hrs. Intranasal: bioavailability 17%; elimination half-life 2 hrs. Subcutaneous: bioavailability 97%; peak concentration reached in 12 min; half-life 115 min. Excreted in urine.
Metabolism: Monoamine oxidase.
Precautions: Contraindicated in patients with a history of uncontrolled hypertension, cardiovascular, cerebrovascular, or peripheral vascular disease, severe hepatic impairment, hemiplegic or basilar migraines. Avoid within two weeks of using a monoamine oxidase inhibitor or within 24 hrs. of ergotamine-containing agents or other 5‑HT₁ drugs.
Dosing: 50 or 100 mg (oral). 5 or 20 mg (intranasal), 6 mg (subcutaneous).
Advantages: Has intranasal and intramuscular formulations.
Adverse effects: Palpitations, anxiety, paresthesias, flushing.
Comments: We prescribe sumatriptan fairly often, more so now that it has achieved generic status. In 2008 a combination drug of sumatriptan (85 mg) plus naproxen (500 mg) was marketed as a migraine abortive, though we do not yet have sufficient experience with it. Efficacy was shown in several randomized, double-blind, placebo-controlled trials (Landy et al. 2007). Another such study was funded by the drug’s manufacturer, GlaxoSmithKline and Pozen (Brandes et al. 2007).

Chemical name: Zolmitriptan

Proprietary names: Zomig® (tablet), Zomig-ZMT® (orally disintegrating wafer), Zomig® intranasal.
Data: Randomized, double-blind, placebo-controlled trials demonstrated efficacy similar to sumatriptan (Gruffyd-Jones et al. 2001) and efficacy in menstrual migraine (Loder et al. 2004).
Class: Triptan.
Mechanism of action: Serotonin receptor agonist with strong affinity for 5-HT_1B/1D receptors; weak affinity for 5-HT_1A receptors.
Pharmacokinetics: Bioavailability 40%; peak concentration reached at 1.5 hr (tablet) or 3 hr (orally disintegrating tablet, nasal). Half-life of the nasal formulation is 3 hrs.
Metabolism: Excreted in the urine (65%) and feces (30%).
Precautions: Contraindicated in patients with cardiovascular disease, hemiplegic or basilar migraine. Use with caution in patients with hypertension, hepatic or renal impairment.
Dosing: 2.5 mg, 5 mg (tablet and orally disintegrating wafer), 5 mg (intranasal).
Advantages: Has orally disintegrating wafer and intranasal formulations.
Adverse effects: Parethesias, weakness, dry mouth, nausea. The nasal spray has an unusual taste.
Comments: The sublingual form has a pleasant taste (so keep away from small children). We would use this drug in persons in need of a medium strength triptan.

Ergot derivatives

Chemical name: Dihydroergotamine (DHE)

Proprietary names: D.H.E. 45
Data: Parenteral dihydroergotamine has been used in acute treatment of migraines since 1925 (Tfelt-Hansen and Koehler 2008) and has been used quite consistently since then (Becker et al. 1996; Callaham and Raskin 1986; Scott 1992; Winner et al. 1993). One randomized, double-blind study found similar efficacy of subcutaneous dihydroergotamine and subcutaneous sumatriptan found that migraines were less likely to recur in patients treated with dihydroergotamine than with sumatriptan (Winner et al. 1996).
Class: Ergot derivative.
Mechanism of action: Vasoconstrictor.
Pharmacokinetics: Half-life 9 hrs. Plasma protein binding 93%.
Metabolism: Hepatic. Eliminated mostly in feces, only slightly (6-7%) in urine.
Precautions: Often needs to be administered intravenously in a hospital setting due to adverse effects of nausea and because of the need for cardiac monitoring. Contraindicated in patients with hypertension, cardiovascular or peripheral vascular disease, hemiplegic or basilar migraines, severe renal or hepatic dysfunction. Avoid within 24 hrs. of using 5‑HT₁ agonists or other ergot-type medications.
Dosing: 1 mg intravenous, intramuscular, subcutaneous.
Advantages: —
Adverse effects: Nausea, palpitations, hypertension, anxiety, shortness of breath, flushing, sweating.
Comments: We seldom prescribe dihydroergotamine because it requires injection, because of the nausea, and because there are good alternatives. Headache clinics use this drug for intractable migraine.

Chemical name: Dihydroergotamine (DHE) nasal

Proprietary names: Migranal®.
Data: Several randomized, double-blind, placebo-controlled studies demonstrated the efficacy of dihydroergotamine nasal (Dihydroergotamine Nasal Spray Multicenter Investigators 1995; Ziegler et al. 1994), though one randomized, double-blind, placebo-controlled study found dihydroergotamine nasal to be little better than placebo (Tulunay et al. 1987). A randomized, double-blind, crossover study found dihydroergotamine nasal to be inferior to sumatriptan nasal (Boureau et al. 2000). A crossover study found dihydroergotamine nasal to have slower onset of effect than subcutaneous sumatriptan (Touchon et al. 1996).
Class: Ergot derivative.
Mechanism of action: Vasoconstrictor.
Pharmacokinetics: Bioavailability 32%.
Metabolism: Excreted primarily in bile, less (2%) in urine.
Precautions: Contraindicated in patients with cardiovascular or peripheral vascular disease, uncontrolled hypertension, hemiplegic or basilar migraine. Avoid within 24 hrs. of using 5‑HT₁ agonists or other ergot-type drugs.
Children -- according to Valeant, safety in persons under the age of 18 has not been established.
Dosing: 0.5 mg per spray.
Advantages: Nasal formulation.
Adverse effects: Rhinitis, altered taste, fatigue.
Comments: We occasionally prescribe dihydroergotamine nasal.

Chemical name: Ergotamine / caffeine

Proprietary names: Cafergot®.
Data: Randomized, double-blind, placebo-controlled and crossover trials found ergotamine + caffeine to be less efficacious than almotriptan (Lainez et al. 2007), eletriptan (Diener et al. 2002), and rizatriptan (Christie et al. 2003).
Class: Ergot derivative and caffeine.
Mechanism of action: Ergotamine is an alpha adrenergic blocker that directly stimulates the smooth muscle of cranial blood vessels and produces depression of the central vasomotor center. Caffeine is a cranial vasodilator.
Precautions: Contraindicated in patients with hypertension, peripheral vascular disease, hepatic or renal dysfunction.
Dosing: 1 mg ergotamine, 100 mg caffeine.
Advantages: —
Adverse effects: Chest discomfort, tachycardia or bradycardia, itching, paresthesias, muscle pain, leg weakness. Retroperitoneal and pleuropulmonary fibrosis may result from frequent use.
Comments: We occasionally prescribe ergotamine for migraine. It is less expensive than triptans.

Dopamine antagonists

Chemical name: Chlorpromazine

Proprietary names: Thorazine®.
Data: A randomized, double-blind, placebo-controlled trial found some efficacy (McEwen et al. 1987). A randomized, double-blind study with no placebo arm found intravenous chlorpromazine and intravenous metoclopramide to have similar efficacy (Cameron et al. 1995). A randomized, double-blind study with no placebo arm found intravenous chlorpromazine and intravenous ketorolac to have similar efficacy (Shrestha et al. 1996). A randomized, unblinded study with no placebo arm premedicated patients with metoclopramide and then compared intravenous chlorpromazine versus intramuscular sumatriptan, and found similar efficacy (Kelly et al. 1997).
Class: Phenothiazine (typical antipsychotic).
Mechanism of action: Dopamine D2 receptor antagonist. Also has strong anti-adrenergic and weakner peripheral anti-cholinergic activity and ganglionic blocking action (PDR 2009).
Pharmacokinetics: Half-life 23-27 hrs.
Metabolism: CYP-450. Excreted in urine (37%), bile and feces.
Precautions: Caution with respiratory disorders, glaucoma, cardiovascular disease, hepatic or renal impairment.
Dosing: 1 mg/kg oral or intravenous.
Advantages: —
Adverse effects: Tardive dyskinesia, akathesia, neuroleptic malignant syndrome, drowsiness, jaundice, agranulocytosis, hypotension, EKG changes, anticholinergic effects.
Comments: We seldom prescribe chlorpromazine for migraine.

Chemical name: Droperidol

Proprietary names: Inapsine®.
Data: One randomized, double-blind, placebo-controlled, dose-ranging trial found droperidol to be efficacious (Silberstein et al. 2003). A randomized, single-blind study with no placebo arm compared intramuscular droperidol with intramuscular meperidine and found similar efficacy (Richman et al. 2002).
Class: Butyrophenone (neuroleptic).
Mechanism of action: Dopamine D2 receptor antagonist. Also antagonizes alpha-adrenergic receptors.
Pharmacokinetics: Half-life 134 min.
Metabolism: CYP-450. Excreted in urine (75%), feces (22%).
Precautions: Contraindicated in known or suspected QT prolongation. Caution with renal or hepatic impairment, hypertension, pheochromocytoma, electrolyte imbalances, alcohol abuse.
Dosing: 2.5 mg intramuscular or intravenous. It can also be used sublingually.
Advantages: Poweful drug for nausea.
Adverse effects: Hypotension, tachycardia, dysphoria, drowsiness, restlessness, hyperactivity, anxiety, irregular cardiac rhythm.
Comments: We seldom prescribe droperidol for migraine, primarily due to its risk.

Chemical name: Haloperidol

Proprietary names: Haldol®.
Data: A randomized, double-blind, placebo-controlled trial found intravenous haloperidol to be efficacious (Honkaniemi et al. 2006).
Class: Butyrophenone (neuroleptic).
Mechanism of action: Antagonizes dopamine D2 receptors.
Pharmacokinetics: Half-life 21-24 hrs.
Metabolism: CYP-450. Excreted in urine (40%), feces (15%).
Precautions: Contraindicated in Parkinson’s disease and depressed states of consciousness. Caution in patients with cardiovascular disease, seizures or EEG abnormalities, QT-prolonging conditions, and in the elderly.
Dosing: 5 mg oral.
Advantages: extremely powerful dopamine blocker
Adverse effects: Tardive dyskinesia and dystonia, neuroleptic malignant syndrome, hypertension, tachycardia, dry mouth, blurred vision, urinary retention.
Comments: We seldom prescribe haloperidol for migraine, primarily due to its adverse effects.

Chemical name: Metoclopramide (+ diphenhydramine)

Proprietary names: Reglan® (+ Benadryl®).
Data: A meta-analysis of randomized, placebo-controlled trials concluded that metoclopramide is efficacious as a migraine abortive (Colman et al. 2004). An interesting randomized, double-blind trial with no placebo arm compared subcutaneous sumatriptan with repeated doses (up to four) of intravenous metoclopramide (20 mg) in which alternate doses of metoclopramide were given with intravenous diphenhydramine 25 mg (Benadryl®). The study found similar efficacy of the two approaches (Friedman et al. 2005).
Class: Anti-emetic.
Mechanism of action: Metoclopramide is a dopamine receptor antagonist. Diphenhydramine is a histamine H₁ receptor antagonist.
Pharmacokinetics: Bioavailability 80%; peak concentration achieved in 1-2 hrs.; plasma protein binding 30%; half-life 5-6 hrs.
Metabolism: Excreted in the urine (80%), bile and feces (5%).
Precautions: Caution in patients with hypertension, Parkinson’s disease or other extrapyramidal disorders.
Dosing: 5 mg, 10 mg (oral metoclopramide), 20 mg (intravenous metoclopramide).
Adverse effects: Tardive dyskinesia, neuroleptic malignant syndrome.
Comments: We seldom prescribe metoclopramide alone. We sometimes use the combination of metoclopramide and diphenhydramine in the emergency room setting.

Chemical name: Prochlorperazine

Proprietary names: Compazine®.
Data: A randomized, double-blind, placebo-controlled trial demonstrated the efficacy of intravenous prochlorperazine as a migraine abortive (Coppola et al. 1995). A randomized, double-blind, placebo-controlled trial showed intramuscular prochlorperazine to be more efficacious than intramuscular metoclopramide (Jones et al. 1996). A randomized, double-blind, placebo-controlled trial of rectal prochlorperazine demonstrated efficacy (Jones et al. 1994).
Class: Anti-emetic.
Mechanism of action: Dopamine receptor antagonist.
Pharmacokinetics: Half-life 3-5 hrs.
Metabolism: CYP-450. Excreted in urine, bile and feces.
Precautions: Caution in patients with glaucoma, dehydration.
Dosing: 5 mg, 10 mg (oral), 25 mg (rectal). Intravenous formulations are also available.
Advantages: Has suppository formulation.
Adverse effects: Tardive dyskinesia and other extrapyramidal symptoms, neuroleptic malignant syndrome.
Comments: We seldom prescribe prochlorperazine for migraine.

Other Medications for Migraine (non-triptan, non ergot, non anti-emetic)

Chemical name: Magnesium sulphate

Data: A randomized, single-blind, placebo-controlled study found magnesium sulphate 1 g IV over 15 minutes to be efficacious (Demirkaya et al. 2001). A randomized, double-blind, placebo-controlled study found magnesium sulphate to be efficacious for migraine with aura (Bigal et al. 2002). One randomized, double-blind, placebo-controlled trial found intravenous magnesium sulphate to be no more efficacious than placebo as a migraine abortive (Cete et al. 2005).
Class: Mineral.
Precautions: Intravenous magnesium should be administered in a monitored setting due to the risk of cardiac arrhythmias and respiratory depression.
Dosing: 1 g intravenous over 15 minutes.
Advantages: Can be used in pregnancy.
Adverse effects: Cardiac arrhythmias, depression of muscle reflexes, hypocalcemia.

Chemical name: Meperidine + promethazine

Proprietary names: Demerol® + Phenergan®
Data: One randomized, double-blind study with no placebo arm compared meperidine + promethazine versus dihydroergotamine + metoclopramide and found both similarly efficacious, but the meperidine + promethazine arm was better tolerated (Scherl and Wilson 1995). One randomized, double-blind study with no placebo arm compared ketorolac to meperidine + promethazine and found no statistically significant difference (Davis et al. 1995).
Class: Meperidine is an opioid analgesic. Promethazine is a phenothiazine derivative with antiemetic and sedative properties.
Mechanism of action: Meperidine is an opinoid receptor agonist. Promethazine antagonizes histamine H₁ receptors.
Pharmacokinetics: —
Metabolism: —
Precautions: Contraindicated in patients with head injury, increased intracranial pressure, intracranial lesions, asthma or other respiratory impairment, hypotension, cardiac arrhythmias. Avoid within 14 days of using monoamine oxidase inhibitors.
Dosing: One tablet contains meperidine 50 mg + promethazine 25 mg.
Advantages: —
Adverse effects: Lightheadedness, sedation, sweating. Meperidine is potentially addictive.
Comments: We almost never prescribe this combination.

Chemical name: Methylprednisolone

Proprietary names: Medrol Dose Pack
Data: There are no convincing data from randomized, double-blind, placebo-controlled trials showing any corticosteroid is an effective migraine abortive. Nevertheless, it continues to be used, largely based on anecdotal experience. A randomized, double-blind, placebo-controlled trial of dexamethasone (a different steroid) showed no efficacy (Rowe et al. 2008).
Class: Glucocorticoid.
Mechanism of action: Anti-inflammatory effects.
Pharmacokinetics: —
Metabolism: —
Precautions: Avoid in patients with active systemic fungal infections.
Dosing: Down-tapering dose from 32 mg to 4 mg.
Advantages: —
Adverse effects: Agitation, insomnia, hypertension, hyperglycemia.
Comments: This drug is reasonable to try in pregnancy when other medications cannot be used.

Caffeine, aspirin, acetaminophen. Efficacy of each drug individually shown in randomized, double-blind, placebo-controlled trials (Smith 1998).

The combination of indomethacin, prochlorperazine and caffeine suppositories was shown to be comparable to sumatriptan in a randomized, double-blind, parallel group trial (Sandrini et al. 2007), and was shown to be more efficacious than sumatriptan in a randomized, double-blind, crossover trial (Di Monda et al. 2003).

Naproxen was studied in randomized, double-blind, placebo-controlled trials (Andersson et al. 1989). The trial showed that naproxen diminished headache severity at 2 hrs., though it did not improve the attack overall. A double-blind, parallel group study found naproxen and ergotamine to have similar efficacy (Treves et al. 1992).

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