Migraine Medications

Question 1

Migraine Treatment

Overview

Answer 1

• Older agents that abort an attack work primarily by ⊗ release of peptides and neurotransmitters at indicated sites
• Newer agents antagonize actions of peptides such as CGRP
• Prophylactic agents may work by preventing cortical spreading

Question 2

Migraine

Acute Therapy

Answer 2

• NSAIDS ⇒ acetaminophen, naproxen, diclofenac, ibuprofen
• Combination analgesics
  
  • Excedrin–Migraine ⇒ acetaminophen/aspirin/caffeine
• Triptans ⇒ sumatriptan, rizatriptan, zolmitriptan, naratriptan
• Ergots ⇒ ergotamine and dihydroergotamine
• Antipsychotics ⇒ metoclopramide, prochlorperazine

Question 3

Triptans

Mechanism of Action

Answer 3

⊗ release of vasoactive peptides from perivascular trigeminal neurons by acting on presynaptic 5-HT1B/D receptors

• Bind presynaptic receptors in the brain stem ⇒ ⊗ release of neurotransmitters that activate second-order neurons ascending to the thalamus
• Originally thought to provide relief by causing cranial vasoconstriction
  
  • 5-HT1B/D receptors on smooth muscle cells

Question 4

Triptans

Pharmacokinetics

Answer 4

• Most effective when given early in the attack
• Sumatriptan available as tablet, nasal spray, subQ injection
  
  • Peak plasma levels achieved most rapidly w/ SC and least rapidly w/ PO
  • Relieves 85% of attacks and is slightly superior to DHE
• Most other agents are oral
• Zolmitriptan comes in a nasal spray
• Newer agents are more lipophilic ⇒ higher oral bioavailability
  
  • 10-20% greater efficacy than sumatriptan and rates of headache recurrence are lower

Question 5

Triptans

Adverse Effects

Answer 5

• Nausea
• Dizziness
• Paresthesias
• Somnolence
• Chest tightness
• Excessive dosing can cause cerebral vasoconstriction and rebound headache

Question 6

Triptans

Drug Interactions

Answer 6

Should not be used w/ MAO inhibitors ⇒ serotonin syndrome

Should not be used within 24 hours of an ergot ⇒ ↑ vasoconstriction

Question 7

Dihydroergotamine

Mechanism of Action

Answer 7

• Ergots are structurally similar to D-lysergic acid
• 5-HT1D agonist > 5-HT2 A/B/C agonist, dopamine and NE α receptor agonist
• Considered broad spectrum or “dirty” triptan
• MOA in migraine similar to triptans

Question 8

Dihydroergotamine

Pharmacokinetics

Answer 8

• Most effective when given early in the attack
• Available in parental (SC, IM, IV), intranasal preparations, and rectal formulations (ergotamine/caffeine)
  
  • Injections usually more rapid acting
• Rectal formulations for pts w/ nausea, but stimulation of dopamine receptors may cause nausea
• Parental admin w/ metoclopramide (Reglan) to prevent vomiting
• Some oral and rectal preparations contain caffeine ⇒ ± ↑ absorption

Question 9

Dihydroergotamine

Adverse Effects

Answer 9

• Some similarities to the triptans: nausea, dizziness, paresthesias
• Also vomiting, diarrhea, muscle cramps, cold skin
• Cause vasoconstriction through α receptors as well as 5-HT receptors
• Similar contraindications to the triptans ⇒ coronary artery disease and peripheral vascular disease
• Excessive dosing can cause cerebral vasoconstriction and rebound headache

Question 10

Dihydroergotamine

Drug Interactions

Answer 10

• Should not be used w/ β-blockers because α-adrenergic vasoconstriction unopposed by β₂ vasodilation can cause peripheral ischemia
• Cytochrome p450 interaction w/ protease inhibitors and macrolide abx
  
  • Combination may cause excessive vasoconstriction

Question 11

Acute Migraine Treatment

Summary

Answer 11

• Triptans less toxic and slightly more effective than ergots
• Dihydroergotamine w/ longer duration of action (intranasal preparations)
• Use reasonable restrictions on drug use to prevent toxicity and habituation
• First try NSAIDS, then if they are ineffective try triptans or DHE
• Some pts may go straight to the triptans

Question 12

Migraine Prophylaxis

Indications

Answer 12

• Attacks that significantly interfere w/ daily routine despite appropriate acute treatment
• Failure of, contraindication to, or adverse effects from acute medications
• More than two headaches per week
• Patient request
• Hemiplegic migraine

Question 13

Migraine

Prophylactic Therapy

Answer 13

• Antibodies to CGRP receptor (erenumab) or CGRP (coming out soon)
• Cardiac medications ⇒ β-blockers, calcium channel blockers, candesartan
• Antidepressants ⇒ TCAs, SSRIs
• Anti-seizure medications
• Serotonin receptor antagonist ⇒ cyproheptadine (Periactin)
• Botox injections

Question 14

Erenumab

Answer 14

• Ab vs CGRP receptor
• First drug designed specifically for migraine prophylaxis
• Once-a-month subQ injection w/ minimal adverse effects
• Approved for both episodic (less than 15 a month) and chronic headache (more than 15 a month)
• Initial studies indicated it ↓ episodic headaches day by 2-4 a month, and chronic headache days by 6-8 month

Question 15

Beta Blockers

Migraine Prophylaxis

Answer 15

• Only propranolol and timolol are FDA approved for migraine prophylaxis
• MOA in migraine not known
• Indications: migraineurs w/ HTN and/or angina, migraineurs w/ performance anxiety or aggressive behavior
• Contraindications: Asthma or pulmonary disease, significant depression
• Common adverse effects: fatigue, exercise intolerance, cold extremities, diarrhea, constipation, dizziness, worsening of depression

Question 16

Calcium Channel Blockers

Migraine Prophylaxis

Answer 16

• MOA: ⊗ Ca²⁺ influx via slow voltage-dependent channels
  
  • Effect in migraine likely related to effect on neurotransmission
  • Some ⊗ vasospasm such as verapamil
• Indications: Migraineurs w/ HTN; especially effective for hemiplegic migraine
• Common adverse effects: constipation, hypotension, AV block, edema, nausea
• Contraindications: bradycardia, heart block, sick sinus syndrome
• Interactions: Cytochrome p450 interactions

Question 17

Antidepressants

Migraine Prophylaxis

Answer 17

• TCAs particularly amitriptyline and nortriptyline are good second line alternatives for prophylaxis
• SSRIs widely used but no data to support their efficacy ⇒ treat headaches associated w/ PMS or PMDD
• MOA: Effect likely d/t central action via ⊗ of 5-HT and NE reuptake
• Indications: migraineurs w/ depression, anxiety and/or panic, may be effective in migraineurs w/ fibromyalgia
• Caution: may unmask manic behavior in bipolar disorder
• Common adverse effects: antimuscarinic effects include ↑ HR, blurred vision, difficulty urinating, dry mouth, constipation
• Other adverse effects: weight gain or weight loss, orthostatic hypotension
• Contraindications: MAOI, seizures, enlarged prostate, glaucoma, sedation

Question 18

Antiepileptics

Migraine Prophylaxis

Answer 18

• Topiramate (Topamax) and valproic acid (Depakote) are FDA approved for migraine prophylaxis
  
  • Gabapentin also used
• Adverse effects: covered in anti-seizure lecture
• Topiramate is especially helpful in overweight migraineurs or w/ bipolar disorder

Question 19

Topiramate

MOA

Answer 19

Mixed action:

• May antagonize AMPA receptors
• May ⊗ Na⁺ channel
• May potentiate transmission at GABA-A receptors

Question 20

Valproic acid

MOA

Answer 20

• ⊗ low threshold T-type Ca²⁺ channels
• Use dependent block of Na⁺ channels
• ↑ GABA