Drugs used in migraine prophylaxis

Marcello Cherchi M.D. Ph.D., Chicago IL. Page last modified: June 9, 2010

Other links on this site:

• Migraine prevention (similar information, with different authorship)
• Migraine in general
• Migraine and vertigo
• Migraine in Women (link)
• Alternative Therapies (link)
• Migraine and Foods (link)

The following incomplete list includes various medications, all of which have been discussed in the medical literature, and each of which has been asked about by patients at some point.  The list contains some comments regarding our prescribing practices, but we do not endorse any particular drugs.

Alpha-adrenergic agonists

Chemical name:                 Clonidine

• Proprietary names:            Catapres®
• Data:                                    Several studies show clonidine is better than placebo for migraine prophylaxis, though the effect is minimal (Bigal et al. 2004; Buchanan and Ramadan 2006; Ramadan 2004; Ramadan et al. 2000).
• Class:                                  Adrenergic agent.
• Mechanism of action:       Alpha-2 adrenergic agonist.
• Pharmacokinetics:            Plasma level peaks at 3-5 hrs.  Plasma half-life is 12-16 hrs. (PDR 2009)
• Metabolism:                       Liver 50%.  About 50% is excreted unchanged in the urine (PDR 2009).
• Precautions:                       Clonidine should be used with caution in patients with cardiovascular disease.  Avoid abrupt discontinuation due to risk of rebound hypertension.
• Dosing:                               Start at 0.1 mg/day.
• Advantages:                       Reasonable choice in selected patients with comorbid hypertension.
• Adverse effects:                Dry mouth, dry eyes, constipation, fatigue, low blood pressure, erectile dysfunction.
• Comments:                         We rarely prescribe clonidine.

Chemical name:                 Guanfacine

• Proprietary names:            Tenex®
• Data:                                    Reported to be efficacious in a single double-blind trial, but magnitude of effect is unclear (Elkind et al. 1989).
• Class:                                  Adrenergic agent.
• Mechanism of action:       Alpha-2 adrenergic agonist.
• Pharmacokinetics:            About 80% is absorbed after oral ingestion.  Reaches peak plasma concentration at 2.6 hrs.  Half-life 17 hrs.
• Metabolism:                       Excreted in urine (50% unchanged).
• Precautions:                       Guanfacine should be used with caution in patients with severe coronary insufficiency, recent myocardial infarction, cerebrovascular disease, chronic renal or hepatic failure.  Avoid abrupt discontinuation due to risk of rebound hypertension.
• Dosing:                               Start at 1 mg/day.  Maximum 3 mg/day.
• Advantages:                       —
• Adverse effects:                Dry mouth, somnolence, asthenia, dizziness, constipation, impotence, headache.
• Comments:                         We do not prescribe guanfacine.

Chemical name:                 Tizanidine

• Proprietary names:            Zanaflex®
• Data:                                    One randomized, double-blind, placebo-controlled trial showed efficacy (Saper et al. 2002).
• Class:                                  Adrenergic agent.
• Mechanism of action:       Alpha-2 adrenergic agonist.
• Pharmacokinetics:            Complete absorption after ingestion, though absolute bioavailability is 40%.  Reaches peak plasma concentration in 1 hr (if fasting) to 1 hr 15 min (if fed).  Half-life 2.5 hrs.
• Metabolism:                       Hepatically metabolized by CYP1A2.  Excreted in urine (60%) and feces (20%).
• Precautions:                       Avoid concomitant use with fluvoxamine, ciprofloxacin, or potent inhibitors of CYP1A2.  Use with extreme caution in hepatic impairment.  Avoid abrupt discontinuation due to risk of rebound hypertension (PDR 2009).
• Dosing:                               Start at 4 mg/day.
• Advantages:                       —
• Adverse effects:                Sedation, dry mouth, urinary frequency.
• Comments:                         We do not prescribe tizanidine.

Beta-adrenergic antagonists

Chemical name:                 Metoprolol

Proprietary names:            Lopressor®, Toprol®

Data:                                    One double-blind, placebo-controlled crossover study showed metoprolol to be better than placebo (Kangasniemi et al. 1987).  Several double-blind studies showed metoprolol to be comparable to propranolol as a migraine prophylactic (Kangasniemi and Hedman 1984; Olsson et al. 1984).

Class:                                  Adrenergic agent.

Mechanism of action:       Selective beta-1 adrenergic blocker.

Pharmacokinetics:            Non-extended-release preparation: Complete absorption.  Half-life 2.8-7.5 hrs.  Albumin-bound (12%).

Metabolism:                       Hepatically metabolized (CYP2D6).  Excreted in urine (5-10%).

Precautions:                       Use with caution in patients with hypotension, sinus bradycardia, 2^nd or 3^rd degree heart block, cardiac failure, sick sinus syndrome, pheochromocytoma.

Dosing:                               Start at 50 mg/day.

Advantages:                       Reasonable choice in selected patients with concomitant hypertension.

Adverse effects:                Slow heartbeat, low blood pressure, shortness of breath, fatigue, depression.

Comments:                         We prescribe metoprolol occasionally.

Chemical name:                 Nebivolol

Proprietary names:            Bystolic®

Data:                                    A single double-blind, randomized comparison of nebivolol and metoprolol found nebivolol to have equivalent efficacy and to be better tolerated than metoprolol (Schellenberg et al. 2008).

Class:                                  Adrenergic agent.

Mechanism of action:       Selective beta-1 adrenergic blocker.

Pharmacokinetics:            Peak plasma concentration achieved at 1-4 hrs.

Metabolism:                       Hepatically metabolized (P450 2D6).  Excreted in urine (38%) and feces (44%).

Precautions:                       Use with caution in patients with bradycardia, 2^nd or 3^rd degree heart block, decompensated cardiac failure, sick sinus syndrome, bronchospasm, severe hepatic impairment, pheochromocytoma.  Avoid abrupt discontinuation due to risk of rebound hypertension.

Dosing:                               Start at 5 mg/day.

Advantages:                       Reasonable in selected patients with comorbid hypertension.

Adverse effects:                Fatigue, nausea, diarrhea.

Comments:                         This is a relatively new agent and we have only used it in a few patients.

Chemical name:                 Propranolol

Proprietary names:            Inderal®, Inderal LA®, Inderide®, InnoPran®

Data:                                    Numerous randomized, double-blind, placebo-controlled trials support the efficacy of beta-adrenergic blockers in migraine prophylaxis (Bigal et al. 2004; Buchanan and Ramadan 2006; Linde and Rossnagel 2004; Ramadan 2004; Ramadan et al. 2000).  Meta-analyses also support its efficacy (Holroyd et al. 1991).  For a review of beta-blockers in general, see (Limmroth and Michel 2001).

Class:                                  Adrenergic agent.

Mechanism of action:       Nonselective beta adrenergic blocker.

Pharmacokinetics:            Non-extended-release preparation: Reaches peak plasma concentrations in 1-4 hrs.  Half-life 3-6 hrs.  Plasma protein binding 90%.

Metabolism:                       Hepatically metabolized (CYP2D6, CYP1A2).

Precautions:                       Use with caution in paients with sinus bradycardia, 2^nd or 3^rd degree heart block, congestive heart failure, asthma, chronic obstructive pulmonary disease, bronchospasm.  Avoid abrupt discontinuation due to risk of rebound hypertension.

Dosing:                               Start at 80 mg/day.  Maximum 240 mg/day.

Advantages:                       Reasonable choice in selected patients with comorbid hypertension.

Adverse effects:                Slow heart beat, low blood pressure, depression.

Comments:                         We prescribe propranolol frequently.  It is an old, well-understood medication.

Calcium channel blockers

Chemical name:                 Verapamil

Proprietary names:            Calan®, Covera®, Isoptin®, Verelan®

Data:                                    A small randomized, double-blind, placebo-controlled trial showed efficacy of verapamil in migraine prophylaxis (Solomon et al. 1983).  A subsequent paper also reviews several other randomized, double-blind, placebo-controlled trials (Solomon 1989).

Class:                                  Antihypertensive.

Mechanism of action:       Calcium channel blocker.

Pharmacokinetics:            Non-extended-release preparation: Bioavailability of 20-35%.  Peak plasma concentrations achieved in 1-2 hrs.  Half-life 4.5-12 hrs.  Plasma protein binding 90%.

Metabolism:                       Biotransformation.  Excreted primarily in the feces, much less (3-4%) in the urine.

Precautions:                       Use with caution in patients with severe ventricular dysfunction, hypertrophic cardiomyopathy, hypotension, sick sinus syndrome, 2^nd or 3^rd degree atrioventricular block, atrial fibrillation/flutter with accessory bypass tract.  Verapamil interacts with simvistatin and the simvistatin dose should be reduced to 10 mg/day when both are used.

Dosing:                               Start at 80 to 120 mg/day.

Advantages:                       Reasonable choice in selected patients with comorbid hypertension.

Adverse effects:                Constpiation, nausea, hypotension, atrioventricular block, transient bradycardia, PR interval prolongation.

Comments:                         We prescribe verapamil fairly commonly for migraine prophylaxis.

Angiotensin modulators

Chemical name:                 Candesartan

Proprietary names:            Atacand®

Data:                                    One randomized, double-blind, placebo-controlled crossover study found that candesartan decreased migraine frequency (Tronvik et al. 2003).

Class:                                  Angiotensin modulator.

Mechanism of action:       Angiotensin receptor blocker.

Pharmacokinetics:            Absolute bioavailability of 14%.  Peak plasma levels achieved at 3-4 hrs.  Plasma protein bound >99%.  Elimination half-life 9 hrs.

Metabolism:                       Small degree of hepatic metabolism (CYP2C9), though excreted mostly unchanged in feces (56%) and urine (26%).

Precautions:                       Use with caution in patients with renal artery stenosis, congestive heart failure, or hyperkalemia.

Dosing:                               Start at 16 mg/day.

Advantages:                       Reasonable choice in selected patients with comorbid hypertension.

Adverse effects:                Hyperkalemia, back pain, upper respiratory tract infection.

Comments:                         We do not prescribe candesartan for migraine prophylaxis.

Chemical name:                 Lisinopril

Proprietary names:            Prinivil®, Prinzide®, Zestoretic®, Zestril®

Data:                                    One double-blind, placebo-controlled crossover study found that lisinopril reduced migraine frequency (Schrader et al. 2001).

Class:                                  Angiotensin modulating agent.

Mechanism of action:       Type 1 angiotensin II converting enzyme inhibitor.

Pharmacokinetics:            Absorption 25%.  Peak plasma concentration levels achieved in 7 hrs.  Half-life 12 hrs.

Metabolism:                       Excreted unchanged in the urine.

Precautions:                       Avoid in patients with a history of ACE-inhibitor angioedema or idiopathic angioedema.  Caution in patients with diabetes, renal insufficiency, renal artery stenosis, congestive heart failure, left ventricular outflow obstruction, neutropenia, hypoglycemia.

Dosing:                               Start at 5 mg/day.

Advantages:                       Reasonable choice in selected patients with comorbid hypertension without renal disease.

Adverse effects:                Cough, chest pain, low blood pressure, fatigue.

Comments:                         We do not prescribe lisinopril for migraine prophylaxis.

Antidepressants

Chemical name:                 Amitriptyline

Proprietary names:            Elavil®

Data:                                    An early double-blind study, although small, suggested efficacy of amitriptyline in migraine prophylaxis (Gomersall and Stuart 1973).  A subsequent randomized, double-blind, placebo-controlled trial found amitriptyline to be superior to placebo as a migraine prophylactic (Couch and Hassanein 1979).  Eventually a double-blind, placebo-controlled crossover study found amitriptyline’s efficacy comparable to that of propranolol (Ziegler et al. 1987).

Class:                                  Tricyclic antidepressant.

Mechanism of action:       Serotonin and noradrenaline reuptake inhibitor.

Pharmacokinetics:            Rapid absorption.

Metabolism:                       Metabolized by N‑demethylation and hydroxylation.

Precautions:                       Avoid concomitant use with monoamine oxidase inhibitors.  Caution in patients with a history of cardiac arrhythmias, myocardial infarction, seizures, urinary retention, angle-closure glaucoma, hyperthyroidism or hepatic dysfunction.  Avoid alcohol.

Dosing:                               Start at 10 mg/day.

Advantages:                       Reasonable choice in selected patients with comorbid depression.

Adverse effects:                Urinary retention, constipation, blurred vision, dry mouth, fever, edema.

Comments:                         We prescribe amitriptyline occasionally for migraine prophylaxis.

Chemical name:                 Fluoxetine

Proprietary names:            Prozac®

Data:                                    One randomized, double-blind, placebo-controlled trial showed a reduction in migraine severity (d'Amato et al. 1999).  One randomized, double-blind, placebo-controlled study showed reduction in migraine frequency (Steiner et al. 1998).

Class:                                  Antidepressant.

Mechanism of action:       Serotonin reuptake inhibitor.

Pharmacokinetics:            Achieves peak plasma concentration at 6-8 hrs.  Half-life is 1-3 days (fluoxetine) and 4-16 days (for the catabolite norfluoxetine).  Plasma protein bound 94.5%.

Metabolism:                       Hepatically metabolized.  Renally excreted.

Precautions:                       Avoid concomitant use with monoamine oxidase inhibitors, thioridazine, or pimozide.  Use with other serotonergic agents increases the risk of serotonin syndrome.  Avoid alcohol.

Dosing:                               Start at 10-20 mg/day.

Advantages:                       Reasonable choice in selected patients with comorbid depression.

Adverse effects:                Nausea, diarrhea, insomnia, fatigue, tremor, sweating, anorexia, dry mouth, dyspepsia.

Comments:                         We do not prescribe fluoxetine for migraine prophylaxis.

Chemical name:                 Venlafaxine

Proprietary names:            Effexor®

Class:                                  Antidepressant.

Data:                                    One randomized, double-blind, placebo-controlled trial showed safety and efficacy of venlafaxine in migraine prophylaxis (Ozyalcin et al. 2005).

Mechanism of action:       Inhibits reuptake of serotonin and norepinephrine.

Pharmacokinetics:            Non-extended-release preparation: Absorption of 92% after ingestion.  Relative bioavailability of 45%.  Half-life 5 hrs.  Plasma protein binding of 27%. According to manufacturor (Wyeth), metabolism varies from patient to patient. There are "extensive metabolizers", "poor metabolizers", and heterozygous extensive metabolizers (HEM) based on the genotype for the CYP2D6 liver enzyme. Extensive metabolizers convert 72% of venlafaxine to the active metabolite, while poor metabolizers, only 21%. This may explain observations that some patients need more drug than others. (updated 7/31/08)

Metabolism:                       Hepatic metabolism (CYP2D6).  Excreted in urine.

Precautions:                       Avoid concomitant use with monoamine oxidase inhibitors.  Risk of serotonin syndrome.

Dosing:                               Start at 12.5 mg/day, escalate to 25 mg/day after one week.

Advantages:                       Reasonable choice in selected patients with comorbid depression.

Adverse effects:                Higher doses may increase blood pressure, though at the low doses used in migraine prophylaxis there is usually not much of an effect in this respect.  Other adverse effects may include palpitations, agitation, nervousness, anxiety, pupillary dilation, slight appetite suppression, slight weight loss.

Comments:                         We prescribe venlafaxine fairly frequently as a migraine prophylactic.  Overall it appears well tolerated and patients are generally pleased with its efficacy.  We find it is especially effective in patients whose migraines involve sensory amplification.  Because of its mild stimulant effect, we generally recommend that patients take this medication in the morning.  A similar drug, desvenlafaxine (Pristique®) was released in 2008 (Deecher et al. 2006).  No trials have yet examined this medication as a migraine prophylactic.

Antiepileptic drugs

Chemical name:                 Divalproex sodium

Proprietary names:            Depakote®, Depakote ER®

Data:                                    A randomized, double-blind, placebo-controlled trial demonstrated efficacy of divalproex sodium in migraine prophylaxis (Freitag et al. 2002).  For reviews see (Freitag 2003; Silberstein 1996).  A randomized, triple-blind, placebo- and dose-controlled study of valproate showed efficacy in prophylaxis of migraine without aura (Jensen et al. 1994).

Class:                                  Antiepileptic.

Mechanism of action:       Increases GABA concentrations in the brain .(PDR 2009)

Pharmacokinetics:            Non-extended-release preparation: Achieves peak plasma concentrations in 4-8 hrs.  Half-life 9-16 hrs.  Plasma protein binding 10-18.5%.

Metabolism:                       Hepatic  (glucuronidation, mitochondrial beta-oxidation).  Excreted in the urine.

Precautions:                       Avoid in patients with hepatic dysfunction.  Potential for interaction with multiple other medications.  Monitor liver enzymes and drug levels during therapy.

Dosing:                               Start at 250 – 500 mg BID (Depakote) or 500 – 1000 mg mg QD (Depakote ER).

Advantages:                       Reasonable choice for migraine prophylaxis in selected patients with comorbid bipolar disorder or certain subtypes of epilepsy.

Adverse effects:                Weight gain, alopecia, hepatic dysfunction.

Comments:                         We seldom prescribe divalproex due to its hepatotoxicity and the necessity of checking drug levels.

Chemical name:                 Gabapentin

Proprietary names:            Neurontin®

Data:                                    Two randomized, double-blind, placebo-controlled trial showed efficacy of gabapentin in migraine prophylaxis (Di Trapani et al. 2000; Mathew et al. 2001).

Class:                                  Antiepileptic.

Mechanism of action:       GABA analog, though the exact mechanism of action is not established.

Pharmacokinetics:            Minimal plasma protein binding (<3%).

Metabolism:                       Half-life 5-7 hrs.  Not appreciably metabolized.

Precautions:                       Excreted in urine unchanged.

Dosing:                               Titrate up to an initial total daily dose of 1200 mg/day.

Advantages:                       Does not significantly interact with other medications.

Adverse effects:                Fatigue, tremor, dysarthria, double vision.

Comments:                         We prescribe gabapentin occasionally for migraine prophylaxis.

Chemical name:                 Topiramate

Proprietary names:            Topamax®

Data:                                    Two large, randomized, double-blind, placebo-controlled trial demonstrated efficacy of topiramate in migraine prophylaxis (Brandes et al. 2004; Silberstein et al. 2004).

Class:                                  Antiepileptic.

Mechanism of action:       Blocks voltage-dependent sodium channels, potentiates GABA activity, inhibits AMPA/kainate subtype of glutamate receptors, blocks L‑ and N‑calcium channels (Buchanan and Ramadan 2006), and inhibits carbonic anhydrase isoenzymes II and IV (PDR 2009).

Pharmacokinetics:            Rapid absorption.  Achieves peak plasma concentration at 2 hrs.  Half-life 21 hrs.  Plasma protein binding 15-41%.

Metabolism:                       About 30% is metabolized by hydroxylation, hydrolysis, and glucoronidation.  Excreted 70% unchanged in urine.

Precautions:                       Use with caution in patients with a history of kidney stones or hepatic dysfunction.  Avoid concomitant use with carbonic anhydrase inhibitors.

Dosing:                               Start at 25 mg/day.  After two weeks escalate to 50 mg/day.

Advantages:                       —

Adverse effects:                Fatigue.  Most patients experience numbness or tingling in the fingers and toes, but this disappears in almost everybody.  Rarely, patients experience word-finding difficulties.

Comments:                         We prescribe topiramate fairly commonly as a migraine prophylactic.  In some patients it causes mild sedation, so we usually recommend that it be taken in the evening.

Chemical name:                 Levetiracetam

Proprietary names:            Keppra®

Data:                                    Two small prospective open-label studies suggested efficacy of levetiracetam in migraine prophylaxis (Brighina et al. 2006; Pakalnis et al. 2007).

Class:                                  Anticonvulsant.

Mechanism of action:       Uncertain.  Appears to inhibit burst firing and hypersynchronization of neurons.

Pharmacokinetics:            Rapid and complete absorption.  Half-life 6-8 hrs.  Plasma protein binding <10%.

Metabolism:                       Enzymatic hydrolysis, though not extensively.  Excreted in urine.

Precautions:                       Caution in patients with renal dysfunction.  Avoid abrupt discontinuation.

Dosing:                               Start at 500 mg BID.

Advantages:                       Does not interact significantly with other medications.

Adverse effects:                Fatigue.  A small number of patients experience incoordination or behavioral abnormalities.

Comments:                         We occasionally prescribe levetiracetam in migraine prophylaxis.  The data supporting its use are emerging.

Nutritional supplements

Chemical name:                 Coenzyme Q10

Proprietary names:            —

Data:                                    One open-label study of adolescents with migraine who had low levels of coenzyme Q10, and who were given supplements of coenzyme Q10, found improvement in migraine frequency and in disability resulting from migraines (Hershey et al. 2007).

Class:                                  Vitamin.

Mechanism of action:       Thought to influence mitochondrial metabolism.

Pharmacokinetics:            —

Metabolism:                       —

Precautions:                       —

Dosing:                               Start at 1-3 mg/kg/day.

Advantages:                       —

Adverse effects:                —

Comments:                         We sometimes recommend coenzyme Q10 for patients who cannot take other medications, such as during pregnancy.

Chemical name:                 Magnesium oxide

Proprietary names:            —

Data:                                    One randomized, double-blind, placebo-controlled, parallel-group study suggested a trend towards reduced frequency and severity of migraine headaches in children (Wang et al. 2003).  Another randomized, double-blind, placebo-controlled study showed a significant decrease in frequency of migraines, but no change in intensity or duration of attacks (Peikert et al. 1996).  Another trial showed no difference from placebo (Pfaffenrath et al. 1996).

Class:                                  Mineral.

Mechanism of action:       Unknown.

Pharmacokinetics:            —

Metabolism:                       —

Precautions:                       —

Dosing:                               Start at 300-600 mg/day.

Advantages:                       Low side-effect profile.

Adverse effects:                Diarrhea.  Usually this is easily counteracted by taking calcium supplementation (which would normally cause mild constipation).

Comments:                         Although the data are conflicting, we sometimes recommend magnesium for patients who cannot take other medications, such as during pregnancy.

Chemical name:                 Riboflavin (vitamin B2)

Proprietary names:            —

Data:                                    One randomized, placebo-controlled trial found efficacy of riboflavin (Schoenen et al. 1998).  One trial found an effect “greater than would be expected for placebo” (although there was no pure placebo arm in the study) of riboflavin for migraine prophylaxis (Maizels et al. 2004).

Class:                                  Vitamin.

Mechanism of action:       —

Pharmacokinetics:            —

Metabolism:                       —

Precautions:                       —

Dosing:                               Start at 400 mg/day.

Advantages:                       Low side-effect profile.

Adverse effects:                There is no known toxicity of riboflavin.

Comments:                         We sometimes recommend riboflavin for patients who cannot take other medications, such as during pregnancy.

Others

Chemical name:                 Botulinum toxin

Proprietary names:            Botox®, Myobloc®

Data:                                    Some randomized, double-blind, placebo-controlled studies find botulinum toxin to be efficacious (Blumenfeld et al. 2008; Cady and Schreiber 2007; Freitag et al. 2008; Vo et al. 2007), while others do not (Saper et al. 2007).   Review studies reach very different results, with some concluding botulinum toxin is effective (Ashkenazi and Silberstein 2008), others concluding it is similar to pharmacotherapy or to placebo (Schulte-Mattler and Leinisch 2008), and others concluding it is ineffective (Pakalnis and Couch 2008; Roach 2008; Schurks et al. 2008).

Class:                                  Paralytic.

Mechanism of action:       Inhibits release of acetylcholine from presynaptic nerve terminals.  It is unclear why this should be effective in migraine, but it may inhibit synaptobrevin I mediated exocytosis of CGRP from sensory neurons (Meng et al. 2007).

Pharmacokinetics:            —

Metabolism:                       —

Precautions:                       —

Dosing:                               —

Advantages:                       —

Adverse effects:                Hoarseness, facial weakness.

Comments:                         In view of the mixed data, we do not yet prescribe botulinum toxin injections for migraine prophylaxis.

Chemical name:                 Butterbur (Petasites hybridus)

Proprietary names:            —

Data:                                    A relatively large (n=245) randomized, placebo-controlled, dose-controlled study found that butterbur significantly reduced migraine frequency (Lipton et al. 2004).

Class:                                  —

Mechanism of action:       Antagonizes L-type calcium channels in vascular smooth muscle (resulting in vasodilation), and inhibits leukotrienes (resulting in anti-inflammatory effects) (Buchanan and Ramadan 2006).

Pharmacokinetics:            —

Metabolism:                       —

Precautions:                       —

Dosing:                               Start at 75 mg BID (Lipton et al. 2004).

Advantages:                       —

Adverse effects:                —

Comments:                         We do not usually recommend butterbur for migraine prophylaxis.

Chemical name:                 Feverfew (Tanacetum parthenium)

Proprietary names:            —

Data:                                    A randomized, double-blind, placebo-controlled trial found that feverfew was comparable to placebo in migraine efficacy (Pfaffenrath et al. 2002).  A Cochrane review of the available trials found insufficient evidence for efficacy of feverfew in migraine prophylaxis (Pittler and Ernst 2004).  A subsequent randomized, double-blind, placebo-controlled, parallel group study found a statistically significant reduction in migraine frequency (Buchanan and Ramadan 2006).

Class:                                  —

Mechanism of action:       Perhaps related to blocking of activation of nuclear factor kappa B, resulting in attenuation of inducible nitric oxide synthase (Buchanan and Ramadan 2006).

Pharmacokinetics:            —

Metabolism:                       —

Precautions:                       —

Dosing:                               —

Advantages:                       —

Adverse effects:                —

Comments:                         We do not usually prescribe feverfew for migraine prophylaxis.

Chemical name:                 Memantine

Proprietary names:            Namenda®

Data:                                    Data from animal models suggests that memantine prevents cortical spreading depression, a phenomenon believed to underlie some types of migraines (Peeters et al. 2007).  Subsequently a case report described resolution of chronic migraines in a patient treated with memantine (Spengos et al. 2008), and a retrospective case series of 60 patients reported decreased headache frequency and improved level of function (Charles et al. 2007).

Class:                                  NMDA receptor antagonist.

Mechanism of action:       Binds to, and blocks, NMDA receptor-operated cation channels.

Pharmacokinetics:            Peak plasma concentrations achieved in 3-7 hrs.  Half-life 60-80 hrs.  Plasma protein binding 45%.

Metabolism:                       Excreted in urine (48%).

Precautions:                       Use with caution in patients with renal or hepatic dysfunction.

Dosing:                               Start at 5 mg/day.  Increase by 5 mg/day/week.  Maximum 10 mg BID (Charles et al. 2007).

Advantages:                       —

Adverse effects:                Confusion, constipation, cough, hypertension, nausea, somnolence, hallucinations.

Comments:                         We have prescribed memantine as a migraine prophylactic in very few patients.  The data supporting its use are nascent.

 

References

• Ashkenazi A, and Silberstein S. Botulinum toxin type A for the treatment of headache: why we say yes. Arch Neurol 65: 146-149, 2008.
• Bigal ME, Krymchantowski AV, and Rapoport AM. Prophylactic migraine therapy: emerging treatment options. Curr Pain Headache Rep 8: 178-184, 2004.
• Blumenfeld AM, Schim JD, and Chippendale TJ. Botulinum toxin type A and divalproex sodium for prophylactic treatment of episodic or chronic migraine. Headache 48: 210-220, 2008.
• Brandes JL, Saper JR, Diamond M, Couch JR, Lewis DW, Schmitt J, Neto W, Schwabe S, and Jacobs D. Topiramate for migraine prevention: a randomized controlled trial. Jama 291: 965-973, 2004.
• Brighina F, Palermo A, Aloisio A, Francolini M, Giglia G, and Fierro B. Levetiracetam in the prophylaxis of migraine with aura: a 6-month open-label study. Clin Neuropharmacol 29: 338-342, 2006.
• Buchanan TM, and Ramadan NM. Prophylactic pharmacotherapy for migraine headaches. Semin Neurol 26: 188-198, 2006.
• Cady R, and Schreiber C. Botulinum Toxin Type A as Migraine Preventive Treatment in Patients Previously Failing Oral Prophylactic Treatment Due To Compliance Issues. Headache 2007.
• Charles A, Flippen C, Romero Reyes M, and Brennan KC. Memantine for prevention of migraine: a retrospective study of 60 cases. J Headache Pain 8: 248-250, 2007.
• Couch JR, and Hassanein RS. Amitriptyline in migraine prophylaxis. Arch Neurol 36: 695-699, 1979.
• d'Amato CC, Pizza V, Marmolo T, Giordano E, Alfano V, and Nasta A. Fluoxetine for migraine prophylaxis: a double-blind trial. Headache 39: 716-719, 1999.
• Deecher DC, Beyer CE, Johnston G, Bray J, Shah S, Abou-Gharbia M, and Andree TH. Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor. J Pharmacol Exp Ther 318: 657-665, 2006.
• Di Trapani G, Mei D, Marra C, Mazza S, and Capuano A. Gabapentin in the prophylaxis of migraine: a double-blind randomized placebo-controlled study. Clin Ter 151: 145-148, 2000.
• Elkind AH, Webster C, and Herbertson RK. Efficacy of guanfacine in a double-blind parallel study for migraine prophylaxis. Cephalalgia 9: 369-370, 1989.
• Freitag FG. Divalproex in the treatment of migraine. Psychopharmacol Bull 37 Suppl 2: 98-115, 2003.
• Freitag FG, Collins SD, Carlson HA, Goldstein J, Saper J, Silberstein S, Mathew N, Winner PK, Deaton R, and Sommerville K. A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. Neurology 58: 1652-1659, 2002.
• Freitag FG, Diamond S, Diamond M, and Urban G. Botulinum Toxin Type A in the treatment of chronic migraine without medication overuse. Headache 48: 201-209, 2008.
• Gomersall JD, and Stuart A. Amitriptyline in migraine prophylaxis. Changes in pattern of attacks during a controlled clinical trial. J Neurol Neurosurg Psychiatry 36: 684-690, 1973.
• Hershey AD, Powers SW, Vockell AL, Lecates SL, Ellinor PL, Segers A, Burdine D, Manning P, and Kabbouche MA. Coenzyme Q10 deficiency and response to supplementation in pediatric and adolescent migraine. Headache 47: 73-80, 2007.
• Holroyd KA, Penzien DB, and Cordingley GE. Propranolol in the management of recurrent migraine: a meta-analytic review. Headache 31: 333-340, 1991.
• Jensen R, Brinck T, and Olesen J. Sodium valproate has a prophylactic effect in migraine without aura: a triple-blind, placebo-controlled crossover study. Neurology 44: 647-651, 1994.
• Kangasniemi P, Andersen AR, Andersson PG, Gilhus NE, Hedman C, Hultgren M, Vilming S, and Olesen J. Classic migraine: effective prophylaxis with metoprolol. Cephalalgia 7: 231-238, 1987.
• Kangasniemi P, and Hedman C. Metoprolol and propranolol in the prophylactic treatment of classical and common migraine. A double-blind study. Cephalalgia 4: 91-96, 1984.
• Limmroth V, and Michel MC. The prevention of migraine: a critical review with special emphasis on beta-adrenoceptor blockers. Br J Clin Pharmacol 52: 237-243, 2001.
• Linde K, and Rossnagel K. Propranolol for migraine prophylaxis. Cochrane Database Syst Rev CD003225, 2004.
• Lipton RB, Gobel H, Einhaupl KM, Wilks K, and Mauskop A. Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. Neurology 63: 2240-2244, 2004.
• Maizels M, Blumenfeld A, and Burchette R. A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: a randomized trial. Headache 44: 885-890, 2004.
• Mathew NT, Rapoport A, Saper J, Magnus L, Klapper J, Ramadan N, Stacey B, and Tepper S. Efficacy of gabapentin in migraine prophylaxis. Headache 41: 119-128, 2001.
• Meng J, Wang J, Lawrence G, and Dolly JO. Synaptobrevin I mediates exocytosis of CGRP from sensory neurons and inhibition by botulinum toxins reflects their anti-nociceptive potential. J Cell Sci 120: 2864-2874, 2007.
• Olsson JE, Behring HC, Forssman B, Hedman C, Hedman G, Johansson F, Kinnman J, Palhagen SE, Samuelsson M, and Strandman E. Metoprolol and propranolol in migraine prophylaxis: a double-blind multicentre study. Acta Neurol Scand 70: 160-168, 1984.
• Ozyalcin SN, Talu GK, Kiziltan E, Yucel B, Ertas M, and Disci R. The efficacy and safety of venlafaxine in the prophylaxis of migraine. Headache 45: 144-152, 2005.
• Pakalnis A, and Couch J. Headache therapy with botulinum toxin: form over substance. Arch Neurol 65: 149-151, 2008.
• Pakalnis A, Kring D, and Meier L. Levetiracetam prophylaxis in pediatric migraine--an open-label study. Headache 47: 427-430, 2007.
• PDR. Physicians Desk Reference Online. 2009.
• Peeters M, Gunthorpe MJ, Strijbos PJ, Goldsmith P, Upton N, and James MF. Effects of pan- and subtype-selective N-methyl-D-aspartate receptor antagonists on cortical spreading depression in the rat: therapeutic potential for migraine. J Pharmacol Exp Ther 321: 564-572, 2007.
• Peikert A, Wilimzig C, and Kohne-Volland R. Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia 16: 257-263, 1996.
• Pfaffenrath V, Diener HC, Fischer M, Friede M, and Henneicke-von Zepelin HH. The efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis--a double-blind, multicentre, randomized placebo-controlled dose-response study. Cephalalgia 22: 523-532, 2002.
• Pfaffenrath V, Wessely P, Meyer C, Isler HR, Evers S, Grotemeyer KH, Taneri Z, Soyka D, Gobel H, and Fischer M. Magnesium in the prophylaxis of migraine--a double-blind placebo-controlled study. Cephalalgia 16: 436-440, 1996.
• Pittler MH, and Ernst E. Feverfew for preventing migraine. Cochrane Database Syst Rev CD002286, 2004.
• Ramadan NM. Prophylactic migraine therapy: mechanisms and evidence. Curr Pain Headache Rep 8: 91-95, 2004.
• Ramadan NM, Silberstein SD, Freitag FG, Gilbert TT, and Frishberg BM. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management for prevention of migraine. US Headache Consortium 2000.
• Roach ES. Questioning botulinum toxin for headache: reality or illusion. Arch Neurol 65: 151-152, 2008.
• Saper JR, Lake AE, 3rd, Cantrell DT, Winner PK, and White JR. Chronic daily headache prophylaxis with tizanidine: a double-blind, placebo-controlled, multicenter outcome study. Headache 42: 470-482, 2002.
• Saper JR, Mathew NT, Loder EW, DeGryse R, and VanDenburgh AM. A double-blind, randomized, placebo-controlled comparison of botulinum toxin type a injection sites and doses in the prevention of episodic migraine. Pain Med 8: 478-485, 2007.
• Schellenberg R, Lichtenthal A, Wohling H, Graf C, and Brixius K. Nebivolol and metoprolol for treating migraine: an advance on beta-blocker treatment? Headache 48: 118-125, 2008.
• Schoenen J, Jacquy J, and Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology 50: 466-470, 1998.
• Schrader H, Stovner LJ, Helde G, Sand T, and Bovim G. Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomised, placebo controlled, crossover study. Bmj 322: 19-22, 2001.
• Schulte-Mattler WJ, and Leinisch E. Evidence based medicine on the use of botulinum toxin for headache disorders. J Neural Transm 115: 647-651, 2008.
• Schurks M, Diener HC, and Goadsby P. Update on the prophylaxis of migraine. Curr Treat Options Neurol 10: 20-29, 2008.
• Silberstein SD. Divalproex sodium in headache: literature review and clinical guidelines. Headache 36: 547-555, 1996.
• Silberstein SD, Neto W, Schmitt J, and Jacobs D. Topiramate in migraine prevention: results of a large controlled trial. Arch Neurol 61: 490-495, 2004.
• Solomon GD. Verapamil in migraine prophylaxis--a five-year review. Headache 29: 425-427, 1989.
• Solomon GD, Steel JG, and Spaccavento LJ. Verapamil prophylaxis of migraine. A double-blind, placebo-controlled study. Jama 250: 2500-2502, 1983.
• Spengos K, Theleritis C, and Paparrigopoulos T. Memantine and NMDA antagonism for chronic migraine: a potentially novel therapeutic approach? Headache 48: 284-286, 2008.
• Steiner TJ, Ahmed F, Findley LJ, MacGregor EA, and Wilkinson M. S-fluoxetine in the prophylaxis of migraine: a phase II double-blind randomized placebo-controlled study. Cephalalgia 18: 283-286, 1998.
• Tronvik E, Stovner LJ, Helde G, Sand T, and Bovim G. Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. Jama 289: 65-69, 2003.
• Vo AH, Satori R, Jabbari B, Green J, Killgore WD, Labutta R, and Campbell WW. Botulinum toxin type-a in the prevention of migraine: a double-blind controlled trial. Aviat Space Environ Med 78: B113-118, 2007.
• Wang F, Van Den Eeden SK, Ackerson LM, Salk SE, Reince RH, and Elin RJ. Oral magnesium oxide prophylaxis of frequent migrainous headache in children: a randomized, double-blind, placebo-controlled trial. Headache 43: 601-610, 2003.
• Ziegler DK, Hurwitz A, Hassanein RS, Kodanaz HA, Preskorn SH, and Mason J. Migraine prophylaxis. A comparison of propranolol and amitriptyline. Arch Neurol 44: 486-489, 1987.