1. Migraine Headache Ibrahim Sales, Pharm.D. Associate Professor of Clinical Pharmacy King Saud University isales@ksu.edu.sa

2. Epidemiology & Etiology Migraines – 10-15% of adults in the US, 34 million worldwide Tension-Type Headache – 30 – 90% of population per year 5% have them chronically (> 15 attacks /month) – Females > Males

3. Tension-type vs Migraine Headaches Tension-type headacheMigraine Occurs without warningOccurs after warning signs or aura Pain more likely to be all overPain more likely to be one-sided No throbbingThrobbing No nauseaNausea and/or vomiting No light or noise sensitivityLight and/or noise sensitivity No visual disturbancesVisual disturbances Rare to start during sleepNot uncommon to start during sleep

4. Clinical Presentation

5. International Headache Society Diagnostic Criteria Migraine without auraMigraine with aura Diagnostic criteria: Headache lasts 4-72 hours (untreated or unsuccessfully treated) Headache has at least two of the following: Aggravation by or causing avoidance of routine physical activity (e.g. walking) Moderate or severe pain intensity Pulsating quality Unilateral location During headache, at least one of the following: Nausea and/or vomiting Photophobia and phonophobia Not attributed to another disorder History of at least five attacks fulfilling above criteria Recurrent disorder manifesting in headaches of reversible focal neurologic symptoms that usually develop gradually over 5-20 minutes and last for less than 60 minutes Headache with the features of migraine without aura usually follows the aura symptoms Less commonly, headache lacks migrainous features or is completely absent Diagnostic criteria: Aura consisting of at least one of the following, but no motor weakness: Fully reversible dysphasic speech disturbance Sensory symptoms that are fully reversible, including positive features (pins and needles) and/or negative features (numbness) Visual symptoms that are fully reversible, including positive features (flickering lights, spots) and/or negative features (loss of vision) At least two of the following: Homogeneous visual symptoms and/or unilateral sensory symptoms At least one aura symptom develops gradually over 5 minutes or different aura symptoms occur in succession over 5 minutes Each symptom lasts at least 5 minutes, but no longer than 60 minutes Headache fulfilling criteria for migraine without aura begins during the aura or follows aura within 60 minutes Not attributed to another disorder History of at least two attacks fulfilling above criteria

6. Diagnosis POUND – Pulsatile quality of headache – One-day duration (four to 72 hours) – Unilateral location – Nausea or vomiting – Disabling intensity In a primary care setting, the probability of migraine is 92% in patients who report at least four of the five symptoms The probability decreases to 64% in patients with three of the symptoms and 17 % in patients with two or less symptoms

7. Treatment Evaluation Migraine Disability Assessment Test (MIDAS) – Validated, seven-item questionnaire to determine the severity of migraine headaches – Addresses limitations in activities at work and home as well as social and leisure activities – The score is a sum of missed days of activities at work/home and reduced productivity over 3 months – Final two questions assess frequency and pain MIDAS Questionnaire

8. Classification MIDAS questionnaire cont. Grade I (sum of 0 – 5): Minimal or infrequent disability Grade II (sum of 6 – 10): Mild or infrequent disability Grade III (sum of 11 – 20): Moderate disability Grade IV (sum of 21 or greater): Severe disability

9. Seek Urgent Medical Evaluation New onset of sudden and/or severe pain Onset after 40 years of age Usual pattern gets worse Systemic signs (fever, weight loss) Papilledema Cough, exertion Pregnancy or post partum Cancer, HIV or other immunodeficiency/infection Seizures

10. Treatment Goals Identify abortive and prophylactic treatments Reduced migraine attack frequency Reduced number of migraine days Reduced attack severity Relieve associated adverse effects Enhance quality of life

11. Drug Therapy Treatment: – Analgesics APAP, ASA, NSAIDs; Opiods; Caffeine & Metoclopramide – Serotonin (5-HT1) Receptor Agonists – Ergot Alkaloids Prevention – Beta-blockers, CCB – AED, TCA, et al.

12. Analgesics First-line for mild to moderate migraines – Aspirin – NSAIDs – Acetaminophen – OTC combinations acetaminophen, aspirin & caffeine (Excedrin Migraine) acetaminophen, isometheptene & dichloralphenazone (Midrin) aspirin, caffeine and butalbital* (Fiorinal) acetaminophen, caffeine and butalbital* (Fioricet)

13. Aspirin MOA: Inhibits prostaglandin synthesis by inhibiting COX-1 and COX-2 enzymes thereby reducing sensitivity of pain receptors to the initiation of pain impulses at the source of inflammation Immediate-release, buffered, enteric coated, effervescent and chewable tablets 650 – 1000 mg every 4 – 6 hours up to 4000 mg Adverse effects: GI bleeding, dyspepsia, epigastric discomfort, nausea, and vomiting; Reye’s syndrome Should be taken with food

14. NSAIDS MOA: Inhibition of prostaglandin synthesis through peripheral inhibition of COX enzymes Ibuprofen: Immediate release and chewable tablets; capsules – 200 – 400 mg every 4 – 6 hours up to 1200 mg Naproxen: Tablets – 220 mg every 8 – 12 hours up to 660 mg – Longer t 1/2 Adverse effects: GI bleeding, dyspepsia, heartburn, nausea, epigastric pain Should be taken with food

15. Acetaminophen MOA: Inhibition of prostaglandin synthesis by inhibiting COX enzymes in the CNS Immediate-release, extended-release, effervescent, chewable tablets, capsules, suppositories 325 mg – 1000 mg every 4 – 6 hours – Maximum previously was 4000 mg

16. Combination Products Acetaminophen, 250 mg/aspirin, 250 mg/caffeine, 65 mg (Excedrin Migraine) – 1 or 2 tablets (or capsules) every 6 hours, not to exceed 8 tablets per day Acetaminophen, 325 mg/dichloralphenazone, 100 mg/isometheptene, 65 mg (Midrin) – 1 to 2 capsules orally every 4 hours; not to exceed 8 capsules per day Potential to cause medication-overuse headache with frequent use

17. Analgesics Opioids – Studies have demonstrated effectiveness in pain relief – Guidelines for use: Infrequent use in the treatment of moderate-to-severe headaches not responsive to standard medications For acute headache when nonopioid medication has failed or is contraindicated, or in the presence of a coexistent disease or lack of diagnosis As rescue medication for severe, middle-of-the-night headache In patients with no history of abuse Limit use to 1 or 2 treatment days per week. Set strict limits and prescribe small amounts to avoid overuse. Relax restrictions with menstrual migraine Barbiturates – Butalbital; butorphanol – Issues: overuse, drug-induced headache, and withdrawal – Withdrawal symptoms Minor (e.g., restlessness, anxiety, sleep disturbances, tremulousness, and gastric distress) Major ≥400mg/day (e.g., agitation, delirium, psychosis, hypotension, hyperthermia, and seizures)

18. Serotonin (5-HT1) Receptor Agonists “Triptans” First-line therapy in moderate to severe migraine or mild to moderate migraine unresponsive to analgesics 5-Hydroxytryptamine (5-HT): 5-HT 1B, 5-HT 1D Agonists – MOA: Block release of vasoactive peptides Take early in attack for best effect Most patients prefer oral form (if no N/V) 20-40% will have recurrence within 24 hours – Give second dose of same triptan up to maximal daily dose

19. Serotonin (5-HT1) Receptor Agonists “Triptans” Sumatriptan (SC, NS, PO) – SC & NS good if associated N/V – Relief at 2 hours depends on dosage form SC = 80%, NS = 60%, PO 50 – 60% Almotriptan (Axert), Eletriptan (Relpax), Rizatriptan (Maxalt), Zolmitriptan (Zomig), Frovatriptan (Frova) – All are similar in effectiveness and tolerability

20. Triptan Clinical Pearls A 100mg dose of sumatriptan may be more effective than lower doses It is sometimes necessary to increase the dose of an individual agent before judging response Nonresponders to one triptan may respond to another Zolmitriptan tastes “better” Rizatriptan has a quicker onset of action than sumatriptan Frovatriptan, naratriptan, and eletriptan have longer t 1/2 than sumatriptan Matching the pharmacokinetics to the temporal pattern of the migraine – Rapid onset medication for short course migraine vs. long-acting medication for slower onset, long lasting symptoms

21. Triptans Almotriptan (Axert) – 6.25 to 12.5 mg orally, can be repeated in 2 hours, not to exceed 25 mg per day Eletriptan (Relpax) – 20 to 40 mg orally, can be repeated in > 2 hours, not to exceed 80 mg per day Frovatriptan (Frova) – 2.5 mg orally, can be repeated in 2 hours, not to exceed 7.5 mg per day Naratriptan (Amerge) – 1 to 2.5 mg orally, can be repeated in 2 hours, not to exceed 5 mg per day Rizatriptan (Maxalt) – 5 to 10 mg orally, can be repeated in 2 hours, not to exceed 30 mg per day Sumatriptan (Imitrex) – Intranasal: 5 to 20 mg, can be repeated in 2 hours, not to exceed 40 mg per day – Oral: 25 to 100 mg, can be repeated in 2 hours, not to exceed 200 mg per day – Subcutaneous: 4 to 6 mg, may repeat in 1 hour, not to exceed 12 mg per day Zolmitriptan (Zomig, Zomig-ZMT) – Intranasal: 5 mg, may repeat in 2 hours, not to exceed 10 mg per day – Oral disintegrating tablets: 2.5 mg, can be repeated in 2 hours, not to exceed 10 mg per day – Oral: 1.25 to 2.5 mg, can be repeated in 2 hours, not to exceed 10 mg per day Sumatriptan, 85 mg/naproxen, 500 mg (Trexima) – 1 tablet at onset, may repeat in 2 hours, not to exceed 2 tablets per day

22. Triptan Adverse Effects Tingling, flushing, dizziness, drowsiness, fatigue & feeling of heaviness, tightness or pressure in chest with all – Uncomfortable but not life threatening… – Highest with Sumatriptan Injection* * Also causes injection reaction Cardiovascular vasoconstriction – Rare: angina, MI, arrhythmia, stroke & death – Contraindications: Coronary, CV or other arterial disease, uncontrolled HTN – Caution with other vascular disease

23. Triptan Drug Interactions & Issues Avoid giving within 24 h of Ergot, another triptan (additive vasoconstriction) Risk of Serotonin syndrome with SSRI, SNRI’s Need 2 week washout from Monoamine oxidase inhibitors (MAO-I) for some – Rizatriptan, sumatriptan, zolmitriptan CYP-3A4 with Almotriptan, Eletriptan Pregnancy Category C

24. Ergot Alkaloids Serotonin agonist – vasoconstrictor Less effective than triptans in general, may work in triptan-refractory patients Ergotamine tartrate – Combination with caffeine may have fewer adverse effects than pure ergotamines Dihydroergotamine mesylate – SC, IM, IV or sprayed intranasally – Relief in 2 hours for 50% of patients

25. Ergot Alkaloids Ergotamine tartrate + Caffeine – 2 tablets at onset of attack, then 1 tablet every ½ hour if needed; max 6 tabs/attack, 10 tabs/week. Dihydroergotamine (DHE; Migranal) – Intranasal: 1 spray in each nostril, repeat once after 15 minutes; not to exceed 4 sprays per attack, 6 sprays per day, 8 sprays per week – IV: 0.5 to 1 mg repeated every 8 hours, or continuous IV infusion totaling 3 mg per 24 hours; not to exceed 3 mg per attack – Subcutaneous: 1 mg every hour; not to exceed 3 mg per day

26. Ergot Adverse Effects Dihydroergotamine < Ergotamine Nausea / vomiting common Vascular occlusion (MI, gangrene) rare except in overdose Contraindicated in pregnancy Potentiated by beta-blockers, nicotine, triptans – Don’t give triptans/ergot within 24 hrs of each other CYP-3A4 inhibitors – contraindicated with clarithromycin, itraconazole

27. Prevention Frequent or severe migraine, or those that can’t take / don’t respond to acute treatment Beta-blockers (usual ADE’s, contraindications) – Propranolol, Timolol FDA approved Metoprolol, Nadolol, atenolol work Tricyclic antidepressants (sedation, dry mouth) – Amitriptyline has best data, others used too

28. Prevention Calcium Channel Blockers – Verapamil shown better than placebo – Interacts with ergots via CYP-3A4 – Don’t use with beta blockers (heart block) Antiepileptic drugs – Valproate, topiramate = best data – Half of patients will have > 50% reduction in frequency of migraines – VPA: Nausea, fatigue, tremor, weight gain & hair loss Liver failure, pancreatitis, hyper-ammonemia et al Others: ACE-I, NSAIDs…

29. Preventative Evidence

30. Summary Mild to moderate: non-opioid analgesic – Acetaminophen (esp. if pregnant), ASA, NSAID Moderate to severe: triptan – Sumatriptan SC is fastest, most effective – May try different one if inadequate response – Ergots are not as effective, more toxic Prevention – Beta-blockers, AEDs 1 st line VPA, topiramate work but ADE’s…