3. No disclosures. Some medications discussed may be used off label.

4. Goals and Objectives Review migraine pathophysiologyReview migraine pathophysiology Discuss optimal selection and timing of acute migraine treatmentsDiscuss optimal selection and timing of acute migraine treatments Learn to individualize triptans for maximum efficacyLearn to individualize triptans for maximum efficacy Briefly review preventive strategies and optionsBriefly review preventive strategies and options

5. Migraine Diagnostic Criteria: A) At least 5 attacks fulfilling criteria B–D B) Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated) C) Headache has at least 2 of the following 4 characteristics: 1. unilateral location 2. pulsating quality 3. moderate or severe pain intensity 4. aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs) D) During headache at least 1 of the following: 1. nausea and/or vomiting 2. photophobia and phonophobia E) Not better accounted for by another ICHD-3 diagnosis

7. Migraine Epidemiology 18% of adult females18% of adult females 6% of adult males6% of adult males 35-45 million migraineurs in the US35-45 million migraineurs in the US 12% of US population12% of US population 50% of all neurologic disability50% of all neurologic disability 2.1 million ED visits/year2.1 million ED visits/year Economic burden > $20 billion/yearEconomic burden > $20 billion/year Lipton RB, et al. Headache. 2001. Goldstein JN. Cephalalgia. 2006.

8. http://www.az-tmj.com/treatment-headaches.php

9. Migraine Pathophysiology 1. Activation of neuronal “central generator” (cortical spreading depression vs. brainstem origin?) → 2. Disrupted cortical ion homeostasis, neuronal dysfunction, release of neurochemicals → 3. Meningeal blood vessel dilation + activation of trigeminovascular system →

10. Migraine Pathophysiology 4. Release of vasoactive neuropeptides (Calcitonin Gene Related Peptide (CGRP), Neurokinins, Prostaglandins, Substance P) from activated trigeminal sensory nerves leads to s terile neurogenic inflammation → 5. Worsening vasodilation, increasing firing of trigeminal afferents causing pain intensification →

11. Migraine Pathophysiology 6. Trigeminal nociceptive afferents carry pain signals to trigeminal nucleus caudalis (TNC) for processing and ascent through thalamus to cortex → 7. Continuous ascending pain signals activate more neurons leading to associated symptoms such as photo/phonophobia, N/V → 8. Continued TNC firing can become autonomous, leading to central sensitization if activated pathways are not stopped →

14. Standard of Care Goals of Acute Migraine Treatment 1. Treat attacks effectively, rapidly, consistently 2. Restore ability to function 3. Minimize need for back-up and rescue meds 4. Optimize self-care and reduce subsequent use of resources 5. Provide cost-effective management 6. Cause minimal or no adverse events American Academy of Neurology / US Headache Consortium Guidelines (Sept 2000; update in progress): http://www.aan.com/professionals/practice/pdfs/gl0087.pdf

15. How many days in the last 3 months were you at least 50% disabled by your migraines at work, home, school, or recreational activities? Migraine Disability Assessment Scale MIDAS: Migraine Disability Assessment Scale Courtesy of Dr. Stewart Tepper, MD

16. MIDAS: Migraine Disability Assessment MIDAS Grade I Little to no disability Score 0-5MIDAS Grade I Little to no disability Score 0-5 ---> Low or no treatment needs ---> Low or no treatment needs MIDAS Grade II Mild disability Score 6-10MIDAS Grade II Mild disability Score 6-10 ---> Moderate treatment needs ---> Moderate treatment needs MIDAS Grade III Moderate disability Score 11-20MIDAS Grade III Moderate disability Score 11-20 ---> High treatment needs ---> High treatment needs MIDAS Grade IV Severe disability Score 21+MIDAS Grade IV Severe disability Score 21+ ---> Urgent treatment needs ---> Urgent treatment needs Useful on initial screening and follow-up visits to assess level of function and determine if med change is neededUseful on initial screening and follow-up visits to assess level of function and determine if med change is needed MIDAS Questionnaire; Version 3.0, 1997. Innovative Medical Research. Courtesy of Dr. Stewart Tepper, MD

17. Treatment Strategy Stratified vs. Step Care?

18. Stratified Care Treatment selection based on severity of migraine and associated disabilityTreatment selection based on severity of migraine and associated disability Supported by Class I evidenceSupported by Class I evidence Stratified care more cost effectiveStratified care more cost effective - May lead to initial use of more costly meds, but… - Migraine specific meds lead to significant decrease in ED/office visits and in medical procedures Williams, et al. Pharmacoeconomics. 2001 Sculpher, et al. Pharmacoeconomics. 2002

19. Step Care Treatment escalated within or across attacksTreatment escalated within or across attacks If simple analgesics are ineffective, other combinations are given later in the same attack or for future attacksIf simple analgesics are ineffective, other combinations are given later in the same attack or for future attacks Triptans or DHE considered after other “steps” have failedTriptans or DHE considered after other “steps” have failed Step care causes a delay in necessary migraine- specific administrationStep care causes a delay in necessary migraine- specific administration Long process of trial and error; many patients lapse from care untreated = unnecessary pain and impairmentLong process of trial and error; many patients lapse from care untreated = unnecessary pain and impairment

20. Disabilities in Strategies of Care (DISC) Study Compared 3 strategies of migraine management over 6 attacksCompared 3 strategies of migraine management over 6 attacks Stratification based on disability (stratified care) -MIDAS Grade II: aspirin (ASA) + metoclopramide -MIDAS Grade III, IV: triptan (zolmitriptan)Stratification based on disability (stratified care) -MIDAS Grade II: aspirin (ASA) + metoclopramide -MIDAS Grade III, IV: triptan (zolmitriptan) Step care within attacks -ASA + metoclopramide: Assess response at 2 hours -Rescue with triptan prnStep care within attacks -ASA + metoclopramide: Assess response at 2 hours -Rescue with triptan prn Step care across attacks -ASA + metoclopramide -Assess response after 3 attacks -Escalate treatment to triptan if ASA + metoclopramide fails 2/3 or 3/3Step care across attacks -ASA + metoclopramide -Assess response after 3 attacks -Escalate treatment to triptan if ASA + metoclopramide fails 2/3 or 3/3 Lipton RB, et al. JAMA. 2000;284(20):2599-2605. Courtesy of Dr. Stewart Tepper, MD

21. * 28 69 55 20* Stratified Care vs Step Care across 6 attacks: Headache Resolution 53 41 0 20 40 60 80 100 1 hour2 hours4 hours Stratified care Stepped care across attacks Attacks (%) * *p<0.001 vs stepped care across attacks Time post-dose Lipton RB, et al. JAMA. 2000;284(20):2599-2605. Courtesy of Dr. Stewart Tepper, MD

22. Delay in use of migraine specific meds wastes time as migraine pathways become stronger and more refractory…

23. Unhindered escalating migraine power and increasing central sensitization Acetaminophen

24. Treatment Strategy: Individualize Treatment Mild-moderate attacks (MIDAS I-II):Mild-moderate attacks (MIDAS I-II): 1) NSAIDS 2) Combination analgesics Moderate-severe attacks (MIDAS III-IV) or poor response to NSAIDS or combo analgesics in previous attacks:Moderate-severe attacks (MIDAS III-IV) or poor response to NSAIDS or combo analgesics in previous attacks: 1) Triptans 2) Dihydroergotamine (DHE)

25. NSAIDSNSAIDS Inhibit arachidonic acid cascade and trigeminovascular inflammationInhibit arachidonic acid cascade and trigeminovascular inflammation Inhibit dural plasma extravasationInhibit dural plasma extravasation Help prevent central sensitizationHelp prevent central sensitization Contraindications: significant renal or GI disease, bleeding disorders, allergiesContraindications: significant renal or GI disease, bleeding disorders, allergies Use maximum dose possible for most efficacyUse maximum dose possible for most efficacy Evidence based support as a 1st line option for mild-moderate disabilityEvidence based support as a 1st line option for mild-moderate disability

26. NSAIDs, Combination Analgesics, and Non-opiate Analgesics Drug http://www.aan.com/professionals /practice/pdfs/gl0087.pdf Quality of Evidence Adverse effects CommentsRole Ibuprofen (400-2400 mg) A Gastric irritation/ discomfort, N/V common. NSAIDs should not be used in patients with ulcer or renal dz. First-line for patients with migraine. Naproxen (750-1250 mg) B Naproxen sodium (750-1750 mg) A Piroxicam SL (40 mg) B Pirprofen (400 mg) B Tolfenamic acid (200- 400 mg) A Acetaminophen + ASA + caffeine (500 mg + 500 mg + 130 mg [2 tablets]) AInfrequent Common adverse events described above and include insomnia. First-line for patients with migraine. Isometheptene (130- 780 mg) Isometheptene + Acetaminophen + Dichloralphenazone (65mg + 325mg + 100mg) (2-5caps) Isometheptene + Paracetamol(2-6 caps) BInfrequent Drowsiness, dizziness, and nausea. Consider for patients w/ mild-to-moderate HA.

27. NSAIDs, Combination Analgesics, and Non-opiate Analgesics Drug http://www.aan.com/professionals /practice/pdfs/gl0087.pdf Quality of Evidence Adverse effects CommentsRole Acetaminophen (650- 4000 mg)BInfrequent Well tolerated May be considered for use in either pediatric or pregnant patients. Diclofenac sodium IM (75 mg) B Ketoprofen PR (100mg) B Ketorolac IM (30-60 mg) BInfrequent Drowsiness and nausea common adverse events. Should not be used w/ renal and GI diseases. Consider for use in emergency department. Oral Aspirin (500-1000 mg)AOccasional Gastric irritation/ discomfort, N/V common. NSAIDs should not be used in patients with ulcer or renal dz. First-line for patients with migraine. Diclofenac K* (50-100 mg) B Flurbiprofen (100-300 mg) B

28. TriptansTriptans 8 Triptans:8 Triptans: - Sumatriptan: PO (25, 50, 100 mg), SC (4, 6 mg), Needle-less SC (6 mg), NS (5, 20 mg) - Zolmitriptan: NS (5 mg), PO (2.5, 5 mg), ODT (2.5, 5 mg) - Naratriptan: PO (1, 2.5 mg) - Rizatriptan: PO (5, 10 mg), ODT (5, 10 mg) - Almotriptan: PO (6.25, 12.5 mg) - Frovatriptan: PO (2.5 mg) - Eletriptan: PO (20, 40 mg) - Sumatriptan/Naproxen: PO (85/500 mg)

29. TriptansTriptans Group 1:Group 1: - Faster onset, higher potency, higher recurrence -Sumatriptan -Sumatriptan/Naproxen -Zolmitriptan -Rizatriptan -Almotriptan -Eletriptan Rapoport AM, Tepper SJ, et al. CNS Drugs. 2003. Group 2:Group 2: - Slower onset, lower potency, lower recurrence -Naratriptan -Frovatriptan

30. TriptansTriptans 5-HT1B agonists:5-HT1B agonists: -constrict pain-producing meningeal blood vessels -also present in brainstem, significance uncertain -preferentially expressed in intracranial extracerebral arteries > periphery (coronary arteries); coronary vasoconstriction up to 10- 20% may still occur MaassenVanDenBrink A, et al. Circulation. 1998. MacIntyre PD, et al. Circulation. 1993

31. TriptansTriptans 5-HT1D agonists:5-HT1D agonists: -presynaptically inhibit trigeminal peptide release -inhibit central trigeminal nucleus caudalis nociceptive transduction and processing -inhibit nausea/vomiting in nucleus tractus solitariuus Tepper SJ, Millson D. Expert Opin Drug Saf. 2003. Tepper SJ. Med Clin North Am. 2001.

32. TriptansTriptans End result:End result: 1) Reversal of vasodilation 2) Decrease in neurogenic inflammation 3) Reduction of central nociceptive signal transmission to the thalamus and cortex 4) Cessation of ascending cortical pathways which lead to photo/phonophobia, N/V, central sensitization

34. TriptansTriptans Contraindications:Contraindications: - Coronary artery disease - Cerebrovascular disease - Peripheral arterial disease - Uncontrolled HTN - Pregnancy (Category C) - Breastfeeding - Renal or hepatic failure - Sepsis - Prinz-Metal angina - Hemiplegic or basilar-type migraine

35. TriptansTriptans Risk factors for arterial diseaseRisk factors for arterial disease - HTN, obesity, HLP, DM, smoking, premature CAD family hx (men < 55, women < 65), postmenopausal women - 1 risk factor: ECG and administration of 1st dose in office suggested in prescribing info. >1 Framingham risk factor: further work-up may be warranted, similar to a preoperative evaluation

36. Triptans (Serotonin 1B/1D Receptor Agonists ) Drug http://www.aan.com/professionals /practice/pdfs/gl0087.pdf Quality of Evidence Adverse effects CommentsRole Sumatriptan nasal spray (tested: 1-40 mg) (approved: 5, 10, 20 mg)AOccasional Adverse events with nasal spray: unpleasant taste, and flushing. Chest symptoms common but true ischemic events rare. Contraindicated w/ risk of CAD, basilar or hemiplegic migraine, or uncontrolled HTN. Based on post-marketing information, rare incidences of MI and stroke have been reported. Naratriptan is associated with a slower onset of action and lower recurrence rate. Sumatriptan SC is associated with a very rapid onset of action. Moderate-to-severe migraine. Especially useful when nonoral route is needed. Oral Naratriptan (tested: 1-2.5 mg) (approved: 1, 2.5 mg) AInfrequentModerate-to-severemigraine. Oral Rizatriptan (tested: 5-40 mg) (approved: 5, 10 mg) AOccasional Oral Sumatriptan* (tested: 25-100 mg) (approved: 25, 50 mg) AOccasional Oral Zolmitriptan (tested: 1-25 mg) (approved: 2.5, 5 mg) AOccasional Sumatriptan SC (tested: 1-8 mg) (approved: 6 mg) AFrequentModerate-to-severe migraine. Especially useful when nonoral route is needed.

37. TriptansTriptans Vary in: Vary in: - lipophilicity - bioavailability - time to maximum plasma concentration (Tmax) - peak plasma concentrations (Cmax) - half-life (t1/2) - AUC - metabolism - elimination routes - formulations - drug-drug interaction profiles - side effects Rapoport AM, Tepper SJ, et al. CNS Drugs. 2003.

38. Rapoport AM, Tepper SJ, Bigal ME, Sheftell FD. 2003 RouteTmaxT(1/2)Metabolism SumatriptanSC0.17-0.22 Hepatic (MAO-A), renal NS12 PO2.52 PR2.52 Sumatriptan / Naproxen PO S: 1 N: 5 S: 2 N: 19 Hepatic (MAO-A), renal ZolmitriptanPO22.7 Hepatic(MAO- A/CYP) ODT32.5-3 NS43 RizatriptanPO1.22 Hepatic(MAO-A), renal ODT1.6-2.52 AlmotriptanPO1.4-3.83.2-3.7 Hepatic(MAO- A/CYP), renal EletriptanPO1-23.6-5.5Hepatic(CYP3A4) NaratriptanPO2-35-6* Hepatic(CYP), renal FrovatriptanPO2-426

39. Does it matter which triptan I pick??

40. Choose based on patient and migraine characteristics Choose based on patient and migraine characteristics C omorbidities O nset to peak migraine pain R ecurrence of migraine after treatment (within 24 hours?) N ausea and vomiting severity

41. Which Triptan Do I Pick? CORN

42. C omorbidities - Coronary artery disease - Cerebrovascular disease - Peripheral arterial disease - Uncontrolled HTN - Pregnancy (Category C) - Breastfeeding - Renal or hepatic failure - Sepsis - Prinz-Metal angina - Hemiplegic or basilar-type migraine

43. O nset to migraine peak pain Group 1 (quicker onset) vs. Group 2 (slower onset)Group 1 (quicker onset) vs. Group 2 (slower onset) -In general, response rates for group 2 triptans at 4 hrs are similar to response rates for group 1 triptans at 2 hrs Tepper SJ, Spears RC. Neurol Clin. 2009. Subcutaneous injection or nasal spray form of triptan needed if:Subcutaneous injection or nasal spray form of triptan needed if: - Patient wakes with migraine - Peak pain within 30 minutes

44. R eturn of migraine after treatment If migraine recurrence occurs within 24 hours:If migraine recurrence occurs within 24 hours: - Combine triptan with NSAID -Try a group 2 triptan (Naratriptan vs. Frovatriptan)

45. N ausea and vomiting severity If N/V occur early in the attack or are severe:If N/V occur early in the attack or are severe: - A subcutaneous injection or nasal spray form of triptan should be used - *Remember: dissolvable tablets are still absorbed via GI tract, not sublingually

46. Triptan Pearls Sumatriptan:Sumatriptan: - Highest potency (SC) and quickest onset (SC+NS) of all triptans - Greatest flexibility Rizatriptan:Rizatriptan: - Fastest onset of an oral triptan - Greatest likelihood of 2h pain-free and sustained pain-free response - Propranolol increases its serum concentration so Rizatriptan should be no more than 5mg per dose if used together Rapoport AM, Tepper SJ, et al. CNS Drugs. 2003. Rapoport AM, Tepper SJ. Arch Neurol. 2001.

47. Triptan Pearls Zolmitriptan:Zolmitriptan: - Most likely to treat persistent HA when 1st dose fails Almotriptan:Almotriptan: - Group 1 triptan w/ least side effects Eletriptan:Eletriptan: - Highest potential for drug interactions. Decrease dosage w/ CyP3A4 drugs such as macrolides, fungal, HIV, etc. Rapoport AM, Tepper SJ, et al. CNS Drugs. 2003. Rapoport AM, Tepper SJ. Arch Neurol. 2001.

48. Triptan Pearls Naratriptan:Naratriptan: - The "gentle triptan", least side effects - Slower onset of action, but lowest recurrence rate - Does not have monoamine oxidase metabolism, so can be given w/ MAOI (as can Eletriptan and Frovatriptan) Rapoport AM, Tepper SJ, et al. CNS Drugs. 2003. Rapoport AM, Tepper SJ. Arch Neurol. 2001.

49. Triptan Pearls FrovatriptanFrovatriptan - Slower onset of action, longest half life, and lowest range of 24h HA recurrence compared with placebo - Good choice to give night prior to expected migraine and known trigger (menstruation, travel, etc.) Rapoport AM, Tepper SJ, et al. CNS Drugs. 2003. Rapoport AM, Tepper SJ. Arch Neurol. 2001.

50. Triptan Pearls Triptan + NSAID Combination Studies show increased efficacy and reduced recurrence for sumatriptan and rizatriptan + NSAID and rizatriptan + COX-2 inhibitorsStudies show increased efficacy and reduced recurrence for sumatriptan and rizatriptan + NSAID and rizatriptan + COX-2 inhibitors Krymchantowski A. Cephalalalgia 2001;21:425-426. Krymchantowski AV, Barbosa JS. Cephalalgia 2002; 22:309–312. Krymchantowski AV, Bigal ME. BMC Neurol 2004; 28; 4(1):10. Sumatriptan/Naproxen combination pill:Sumatriptan/Naproxen combination pill: - Faster Sumatriptan Tmax for combination pill vs. Sumatriptan 100 mg alone (1h vs. 1.5 hrs) - Cmax for Naproxen is 36% lower with combination pill vs. Naproxen 550 mg alone - Tmax for Naproxen occurs 4 hrs later with combination pill vs. Naproxen 550 mg alone (5h vs. 1-2h) http://us.gsk.com/products/assets/us_treximet.pdf

51. Sumatriptan + Naproxen Sodium Combination Tablet: Pain Relief at 2 and 4 hours 75 64 54 37 0 20 40 60 80 2 Hours4 Hours Combo (n=726) Sumatriptan 85 mg (n=724) Naproxen Sodium (n=720) Placebo (N=742) *P<0.05 Combination vs placebo, sumatriptan, and naproxen sodium Pooled results from two head-to-head, randomized, double-blind, placebo-controlled trials, MT-301 and MT-302 of a single moderate or severe migraine attack. Individual study results were similar. % of Patients Experiencing Pain Relief Brandes et al. JAMA 2007;297:1443-1454 Courtesy of Dr. Stewart Tepper, MD * *

52. ErgotsErgots Dihydroergotamine (DHE), ErgotamineDihydroergotamine (DHE), Ergotamine Broader spectrum of receptors than triptans:Broader spectrum of receptors than triptans: - additional side effects, but… additional efficacy in some patients (1/3rd of patients respond poorly to triptans) Interact with adrenergic and dopaminergic receptors, 5-HT 1A, 1B*, 1D*, 1F*, 2A, 2C, 3, 4 subtypesInteract with adrenergic and dopaminergic receptors, 5-HT 1A, 1B*, 1D*, 1F*, 2A, 2C, 3, 4 subtypes (*RED = Triptan receptors) Side effect profiles reflect agonist activity at:Side effect profiles reflect agonist activity at: - 5-HT1A receptors: nausea, dysphoria - 5-HT2A and adrenergic receptors: peripheral vasoconstriction - Dopamine D2 receptors: nausea, vomiting Bigal ME, Tepper SJ. Curr Pain Headache Rep. 2003 Silberstein SD, McRory DC. Headache. 2003

53. Dihydroergotamine (DHE) Intravenous (IV), Subcutaneous (SC), Intramuscular (IM), Intranasal (IN) forms; (Inhaled DHE coming soon)Intravenous (IV), Subcutaneous (SC), Intramuscular (IM), Intranasal (IN) forms; (Inhaled DHE coming soon) IV DHE is very useful to break status migrainosusIV DHE is very useful to break status migrainosus No triptan use in pre or post 24 hours of DHENo triptan use in pre or post 24 hours of DHE Contraindications same as triptans except pregnancy is Category XContraindications same as triptans except pregnancy is Category X

54. IV DHE 1. +/- EKG if concern for CAD risk 2. IV Antiemetic +/- IV Diphenhydramine 30 mins prior to IV DHE (1 mg/1 mL) 3. 0.25 mg IV (virgin) vs. 0.50 mg IV. Then, 0.25 mg q15 mins until 1 of the following: a) HA resolves b) Severe nausea or other intolerable side effects occur c) Cumulative dose of 1 mg reached 4. Repeat max tolerated dose (up to 1 mg) q8h with IV Antiemetic +/- IV Diphenhydramine 30 mins prior to IV DHE 5. AAN Practice Parameter Guidelines suggest IV DHE is safe and effective up to 3 mg/day and 20 mg/week (packaging says 6 mg/week)

55. IM / SC DHE 1 mg (1 ml) at onset of migraine1 mg (1 ml) at onset of migraine Then, q1h x 2 for a max dose of 3 mg/attack, ORThen, q1h x 2 for a max dose of 3 mg/attack, OR Once every 8 hours x 3-5 days or until HA free x 24 hrsOnce every 8 hours x 3-5 days or until HA free x 24 hrs IM and SC DHE are limited to 3 mg/day and 20 mg/week (packaging says 6 mg/week)IM and SC DHE are limited to 3 mg/day and 20 mg/week (packaging says 6 mg/week)

56. IN DHE Insert in nostril, aim away from face, don't sniffInsert in nostril, aim away from face, don't sniff 1 spray in each nostril (0.5 mg each nostril = 1 mg total dose)1 spray in each nostril (0.5 mg each nostril = 1 mg total dose) In 15 minutes, repeat 1 spray in each nostril (0.5 mg each nostril = 1 mg total dose)In 15 minutes, repeat 1 spray in each nostril (0.5 mg each nostril = 1 mg total dose) Total treatment dose: 4 sprays = 2 mg; May repeat this cycle q8h x 72h or until HA is resolved (whichever comes first)Total treatment dose: 4 sprays = 2 mg; May repeat this cycle q8h x 72h or until HA is resolved (whichever comes first) Per packaging, max dose: 4 mg/attack, 6 sprays/day and 8 sprays/week. (As above, we often use higher doses)Per packaging, max dose: 4 mg/attack, 6 sprays/day and 8 sprays/week. (As above, we often use higher doses)

57. When do I consider DHE? Long migraines with multiple recurrences, including menstrually-related migrainesLong migraines with multiple recurrences, including menstrually-related migraines Migraine upon awakening, as its central effects may reverse central sensitization less responsive to triptansMigraine upon awakening, as its central effects may reverse central sensitization less responsive to triptans Can be used at moderate to severe levels of pain, in the presence of allodynia, when triptans are less effectiveCan be used at moderate to severe levels of pain, in the presence of allodynia, when triptans are less effective Baron EP, Tepper SJ. Headache. 2010.

58. When do I consider DHE? Can be used repetitively to break status migrainosis (migraine lasting > 72 hours)Can be used repetitively to break status migrainosis (migraine lasting > 72 hours) Repetitively for rescueRepetitively for rescue Repetitively as a bridge to wean a patient out of medication overuse headacheRepetitively as a bridge to wean a patient out of medication overuse headache With nausea and vomiting, when a non-oral alternative is necessaryWith nausea and vomiting, when a non-oral alternative is necessary Baron EP, Tepper SJ. Headache. 2010.

59. Ergot Alkaloids and Derivatives Drug http://www.aan.com/professionals /practice/pdfs/gl0087.pdf Quality of Evidence Adverse effects CommentsRole DHE SC (tested: 1mg) (approved: 1 mg)BOccasional Most common adverse events with DHE include nausea, vomiting, dysphoria, flushing, restlessness, and anxiety. Should not be used in patients at risk for ischemic heart disease. Treatment associated with low recurrence rates. DHE SC/IM has considerable less adverse events than IV. Use in patients with moderate-to-severemigraine. DHE IM (tested: 1 mg)BOccasional DHE IV (tested: 1-2 mg)BFrequent DHE IV plus antiemetics (0.5-1 mg DHE)BFrequent Useful in patients w/ long-standing HA. May be used as therapy of choice in ED. DHE nasal spray (tested: 0.5-4 mg) (approved: 2 mg)AOccasional Common adverse events: nasal congestion, N/V. Should not be used in patients with risk of CAD. Associated with low incidence of recurrence. Moderate-to-severe HA. Treatment option for patients w/ nausea and/or vomiting.

60. Ergot Alkaloids and Derivatives Drug http://www.aan.com/professionals /practice/pdfs/gl0087.pdf Quality of Evidence Adverse effects CommentsRole Oral Ergotamine (tested: 1-5 mg) (approved: 2 mg)BFrequent Nausea and vomiting common adverse events. Treatment may be associated with ischemia, ergotism, and rebound. Consider for selected patients with moderate to severe migraine. Ergotamine plus caffeine (tested: 2-6 mg ergotamine + 200-600 mg caffeine) (approved: 2 mg ergotamine + 200 mg caffeine)BFrequent Ergostine plus caffeine (tested: 2 mg + 200 mg)BFrequent

61. Acute Treatment Key Points Begin APPROPRIATE medication at APPROPRIATE dose at EARLIEST (<30 mins) sign of migraine painBegin APPROPRIATE medication at APPROPRIATE dose at EARLIEST (<30 mins) sign of migraine pain Cady R, et al. Headache. 2000. Cady R, et al. Clin Ther. 2000. Pascual J, et al. Headache. 2000. Dowson A, et al. Headache. 2004. Diener H, et al. Neurology. 2004. Hu X, et al. Headache. 2002. Mathew N, et al. Headache. 2004. Klapper J, et al. Cephalalgia. 2004. Cady R, et al. Curr Med Res Opin. 2004. Limited to no role for butalbital-containing analgesics or opiates/opioids as 1st line acute migraine therapyLimited to no role for butalbital-containing analgesics or opiates/opioids as 1st line acute migraine therapy Goals should be pain free in 2 hours and 24 hour pain reliefGoals should be pain free in 2 hours and 24 hour pain relief

62. RESCUERESCUE

63. RESCUE (Also contraindications to triptans, ergots, NSAIDs; or adjunctive therapy) AntiemeticsAntiemetics - Prochlorperazine 10 mg IV, Metoclopramide 10mg IV, Dolasetron 12.5 mg IV, Ondansetron 4 mg IV, Granisetron 1 mg IV, Promethazine 25 mg IV http://www.aan.com/professionals/practice/pdfs/gl0087.pdf AnticonvulsantsAnticonvulsants - Valproic acid 500-1000 mg IV, Levetiracetam 250-1000 mg IV Matchar DB, et al. http://www.aan.com/professionals/practice/pdfs/gl0087.pdf Edwards, et al. Cephalalgia. 1999. Edwards, et al. Headache. 2001. Mathew, et al. Cephalalgia. 1999. MagnesiumMagnesium - 1-2 g IV; may be more effective for migraine with aura Bigal, et al. Cephalalgia. 2002. Cete, et al. Cephalalgia. 2005.

64. RESCUERESCUE NSAIDSNSAIDS - Ketorolac 30 mg IV; 60 mg IM; 10 mg PO TID with food until HA free x 24 hours, or have used for 5 days. SteroidsSteroids - Dexamethasone 4-6 mg IV; 4 mg PO TID day 1, then 4 mg PO BID day 2, then 4 mg PO day 3; Methylprednisolone 250-500 mg IV Klapper JA, et al. Headache. 1991. Saper JR. Neurol Clin. 1989. Muscle RelaxersMuscle Relaxers - Methocarbamol 1-2 g IV; Chlorzoxazone 500-1000 mg qid x 5 days Neuroleptics (other than antiemetics) can also be usefulNeuroleptics (other than antiemetics) can also be useful - Olanzapine, Quetiapine, Haloperidol* *Fisher H. J Emerg Med. 1995.

65. “Dirty” Rescue: Butalbital combos and Opiates/Opioids No class I studies exist showing efficacy of barbiturates / butalbital-containing meds in acute migraine treatmentNo class I studies exist showing efficacy of barbiturates / butalbital-containing meds in acute migraine treatment Both butalbital combos and opiates/opioids pose a high risk of MOH (Rebound HA), dependency and are best avoidedBoth butalbital combos and opiates/opioids pose a high risk of MOH (Rebound HA), dependency and are best avoided

66. Rescue: Butalbital combos and Opiates/Opioids Limited role for opiate/opioid use in acute migraine treatment:Limited role for opiate/opioid use in acute migraine treatment: - Occasionally when abortives have failed - When abortives are contraindicated -Allergy-Pregnancy-Breastfeeding -Other medical contraindications

67. Summary: Acute Therapies for Migraine (2000) Group 1: Proven pronounced statistical and clinical benefit (at least 2 double- blind, placebo-controlled studies + clinical impression of effect) Group 2: Moderate statistical and clinical benefit (1 double- blind, placebo-controlled study + clinical impression of effect) Group 3: Statistically but not proven clinically OR clinically but not proven statistically effective (conflicting or inconsistent evidence) Group 4: Proven to be statistically or clinically ineffective (failed efficacy vs. placebo) Group 5: Clinical and statistical benefits unknown (insufficient evidence available) -Acetaminophen + ASA + Caffeine PO -ASA PO -DHE SC, IM, IV* -DHE IV + antiemetic -DHE IN -Ibuprofen PO -Naproxen sodium PO -Naratriptan PO -Prochlorperazine IV -Rizatriptan PO -Sumatriptan SC, IN, PO -Zolmitriptan PO -Butorphanol IN ************Almotriptan, Frovatriptan, Eletriptan, Sumatrip/Naproxen all released after these guidelines, but should be included. -Acetaminophen + Codeine PO -Butalbital + ASA + Caffeine + Codeine PO -Butorphanol IM -Chlorpromazine IM, IV -Diclofenac K, PO -Ergotamine + Caffeine + Pentobarbital + Belafolline® PO -Flurbiprofen, PO -Isometheptene compound, PO -Ketorolac IM -Lidocaine IN -Meperidine IM, IV -Methadone IM -Metoclopramide IV -Naproxen PO -Prochlorperazine IM, PR -Butalbital + ASA + Caffeine PO -Ergotamine PO -Ergotamine + Caffeine PO -Metoclopramide IM, PR -Acetaminophen PO -Chlorpromazine IM -Granisetron IV -Lidocaine IV -Dexamethasone IV -Hydrocortisone IV http://www.aan.com/prof essionals/practice/pdfs/gl 0087.pdf

68. **Final Word on Acute Treatments** Guard against medication-overuse headache (MOH; rebound HA). Causes of MOH: 1) NSAIDS or Triptans: > 10 days/month 2) Opioids: > 8 days/month 3) Butalbital compounds > 5 days/month Bigal ME, Lipton RB. Overuse of acute migraine medications and migraine chronification. Curr Pain Headache Rep. 2009 Aug;13(4):301-7.

69. Prevention in Episodic Migraine… Medication use: 1. Initiate meds with the highest level of evidence-based efficacy. 2. Initiate therapy with the lowest effective dose. Increase slowly until clinical benefits are achieved in the absence of, or until limited by, adverse events. 3. Give each drug an adequate trial (2 to 3 months). 4. Avoid interfering medications (e.g., overuse of acute medications). 5. Use of a long-acting formulation may improve compliance. http://www.neurology.org/content/55/6/754.full.pdf

70. Prevention in Episodic Migraine… Evaluation: 1. Monitor the patient’s headache through a headache diary +/- MIDAS: Migraine Disability Assessment Scale) 2. Re-evaluate therapy. If after 3 to 6 months headaches are well controlled, consider tapering or discontinuing treatment. http://www.neurology.org/content/55/6/754.full.pdf

71. Prevention in Episodic Migraine… Take coexisting conditions into account (stroke, CAD, Raynaud’s, epilepsy, mood disorders, weight, etc). 1. Select a drug that will treat the coexistent condition and migraine, if possible. 2. Establish that the treatments being used for migraine are not contraindicated for the coexistent disease. 3. Establish that the treatments being used for coexistent conditions do not exacerbate migraine. 4. Beware of all drug interactions. http://www.neurology.org/content/55/6/754.full.pdf

72. 2012 AHS/AAN Guidelines for Prevention of Episodic Migraine

73. Level A: established as effective for prevention Anticonvulsants: -Divalproex/sodium valproate: 400-1000 mg/day (FDA approved) -Topiramate 25-200 mg/day (FDA approved) Antihypertensives: -Metoprolol: 47.5-200 mg/day -Propranolol 120-240 mg/day (FDA approved) -Timolol 10-15 mg/day (FDA approved) Complementary: -Petasites (butterbur): 50-75 bid

74. Level B: probably effective as prevention Antidepressants: -Amitriptyline: 25-150 mg/day -Venlafaxine ER: 150 mg/day Antihypertensives: -Atenolol: 100 mg/day Complementary: -Magnesium: 600 mg trimagnesium dicitrate qd -Feverfew: 50-300 mg bid; 2.08-18.75 mg tid for MIG-99 preparation -Riboflavin: 400 mg/day -Histamine: 1-10 ng subcutaneously twice a week NSAIDs: -Fenoprofen: 200-600 mg tid -Ibuprofen: 200 mg bid -Ketoprofen: 50 mg tid -Naproxen: 500-1100 mg/day -Naproxen sodium: 550 mg bid

75. Level C: possibly effective for prevention Antihypertensives: -Candesartan: 16 mg/day -Lisinopril: 10-20 mg/day -Nebivolol: 5 mg/day -Pindolol: 10 mg/day -Clonidine: 0.75-0.15 mg/day; patch formulations also studied -Guanfacine: 0.5-1 mg/day Anticonvulsants: -Carbamazepine: 600 mg/day Complementary: -Coenzyme Q10: 100 mg tid Antihistamines: -Cyproheptadine: 4 mg/day NSAIDs: -Flurbiprofen: 200 mg/day -Mefenamic acid: 500 mg tid

76. Chronic Migraine Chronic migraine:Chronic migraine: -≥ 15 days/month with HA lasting ≥ 4 hours/day for ≥ 3 consecutive months in people with current or prior diagnosis of episodic migraine. Onabotulinum Toxin Type A (Botox)Onabotulinum Toxin Type A (Botox) -Only FDA-approved treatment of chronic migraine (approved for ≥ age 18). -Useful when other preventives fail or are contraindicated

77. ConclusionConclusion General Principles of Acute Migraine ManagementGeneral Principles of Acute Migraine Management 1. Educate pts about migraine, its treatment and encourage participation in management (triggers, HA diaries to determine need for prevention, etc.). 2. Use migraine specific meds (triptans, DHE) early with moderate-severe migraine and those poorly responsive to NSAIDS or combination analgesics.

78. ConclusionConclusion 3. Tailor triptan use based on patient and migraine characteristics (CORN). → 4. Consider a self-administered rescue med for severe migraine failing all other treatments. 5. Guard against medication-overuse headache (MOH; rebound HA). Causes of MOH: -NSAIDS or triptans: > 10 days/month -Opioids: > 8 days/month -Butalbital compounds > 5 days/month 6. Preventives should target other comorbidities, at same time of decreasing overall HA burden.