1. 2019 MPhA Annual Networking Learning Event & MTM Symposium
Migraine Update
Natalie Roy, PharmD
Fairview Medication Therapy Management Pharmacist
MHealth Neurology Clinic

2. Disclosure
Natalie Roy reports no actual or potential conflicts of interest associated with this presentation

3. Learning Objectives
Upon successful completion of this activity, pharmacists should be able to:
Differentiate episodic and chronic migraine by listing criteria for diagnosis of each type, including concomitant symptoms and frequency of headaches.
Determine appropriateness of therapy for migraine prevention and develop a treatment plan for patient cases.
Explain the mechanism and place in therapy for the Calcitonin gene-related peptide (CGRP) inhibitors.
Define medication overuse in the context of migraine management.
List evidence-based abortive therapies based on the 2018 American Headache Society Guidelines.

4. Learning Objectives
Upon successful completion of this activity, pharmacy technicians should be able to:
Identify the three possible symptoms associated with migraines.
List at least five medications that can be used to prevent migraines.
Describe the consequences of medication overuse headaches.

5. Prevalence of Migraine
3rd most prevalent illness in the world
6th leading cause of disability
20.7% of females
9.7% of males
$26 billion/year
Highest prevalence age 18-44
Burch R et al. Headache. 2018

6. Diagnosis of Migraine At least 5 attacks
Each attack lasts 4-72 hours when untreated or unsuccessfully treated
Headache includes 2 of the following:
Unilateral location
Pulsating quality
Moderate or severe pain intensity
Aggravation by or causing avoidance of routine physical activity (ie: walking or climbing stairs)
During headache, 1 of the following occurs:
Nausea and/or vomiting
Photophobia and phonophobia
Position statement. Headache

7. Migraine Type Episodic Migraine*
Migraine-like or tension-type-like headache on <15 days/month (MHD)
Chronic Migraine*
Migraine-like or tension-type-like headache on ≥ 15 days/month for > 3 months (MHD)
Migraine with or without aura on ≥ 8 days/month (MMD)
*+/- Aura
MHD = monthly headache days
MMD = monthly migraine days
Position statement. Headache

8. Pathophysiology Migraine is a complex condition thought to involve:
Vasculature
Central and peripheral neuronal pathways involved in pain signaling
Inflammation
Activation of trigeminovascular system
Role of Calcitonin Gene-Related Peptide (CGRP)

9. Abortive Treatments Should be offered to ALL patients with migraine
Treat at first sign of pain to improve probability of achieving freedom from pain and reduce disability
Poorly controlled attacks are at risk of acute medication overuse, medication overuse headache, and progression to chronic migraine
Avoid overuse

10. Abortive Treatments Mild-moderate attacks Moderate-severe attacks
NSAIDs (including aspirin)
Acetaminophen
Caffeinated analgesic combinations (ie: Excedrin)
Moderate-severe attacks
Triptans
Dihydroergotamine (DHE)
Position statement. Headache

11. Management of Nausea/Vomiting
Use alternate formulations of abortive therapies
ODT: rizatriptan, zolmitriptan
Nasal spray: sumatriptan, zolmitriptan
SubQ: sumatriptan
Anti-emetics can also help abort refractory migraines

12. Abortive Treatment Pearls
Try higher dose first and decrease if side effects
ie: 100 mg of sumatriptan vs 50 mg
Attempt multiple trials of an abortive before determining lack of efficacy
Create a stratified migraine action plan
Plan for mild headache (ie: will take ibuprofen)
Plan for moderate-severe headache (ie: will take sumatriptan)
Plan for nausea/rescue treatment (ie: will take prochlorperazine)

13. Opioids? May improve pain, but not productivity
May increase risk of conversion to chronic migraine
Can interfere with triptan efficacy
Response decreases over time leading to escalating doses
Use of opioids may up-regulate CGRP receptors, resulting in increased migraines
Tepper SJ. Headache. 2012

14. Medication Overuse Headaches
American Headache Society (AHS):
≥ 10 days/month for ergot derivatives, triptans, opioids, combination analgesics, and drugs from other classes that are not individually overused
≥ 15 days/month for non-opioid analgesics, acetaminophen, and NSAIDs

15. Avoiding Medication Overuse
NSAIDs, acetaminophen, non-opioid combo (ie: Excedrin)
< 14 days/month total
Triptans
< 9 days/month total
Opioids
< 1 day/week total or AVOID altogether

16. Preventive Treatments
Lifestyle modification (nutrition, exercise, hydration, sleep)
Avoid triggers
Pharmacologic medication considered if:
Contraindication to acute treatments
Failure of acute treatments
Overuse of acute treatments

17. Preventive Treatments
Position statement. Headache

18. Oral Preventive Treatments
Position statement. Headache

19. Oral Preventive Treatment Use
Selection based on evidence of efficacy, tolerability, comorbidities, consideration of women of child-bearing age, provider/patient preference
Start low and titrate slowly until target response develops, maximum/target dose is reached, or tolerability issues
Adequate trial: at least 8 weeks at a target dose (cumulative benefits may occur over 6-12 months)
Combining preventive medications from different drug classes can be useful

20. “Successful” Migraine Prevention
50% reduction in frequency of MMD or MHD
Patient-reported decrease in attack duration and/or severity
Improved response to acute treatment
Reduction in migraine-related disability, reduction in psychological distress, and improvement in functioning

21. CGRP in Migraine
Calcitonin gene-related peptide (CGRP): 37-amino acid neuropeptide that functions as a messenger in nerve cells and as a vasodilator
Edvisson L et al. Nat Rev Neurol. 2018

22. CGRP Inhibitors Monoclonal antibodies to the CGRP receptor
Inhibit function of CGRP at receptor, leaving other calcitonin-family receptors functionally intact
Erenumab (Aimovig)
Monoclonal antibodies to the CGRP ligand
Inhibit function of CGRP at all calcitonin-family receptors
Galcanezumab (Emgality), Fremanezumab (Ajovy), Eptinezumab (??)
Monoclonal antibodies are eliminated via the reticuloendothelial system (no hepatotoxicity)
Approved for prevention of chronic and episodic migraine

23. CGRP Inhibitors Erenumab (Aimovig) Galcanezumab (Emgality)
Fremanezumab (Ajovy)
Eptinezumab (??)
Episodic Migraine,
decrease in monthly migraine days (MMD)
6 MONTH STUDY
Decrease in MMD by 3.2/3.7 (70 mg/140 mg) vs 1.8 placebo
Decrease in MMD by 4.7/4.3 (120 mg study 1/2) vs 2.8/2.3 placebo (study 1/2)
3 MONTH STUDY
Decrease in MMD by 3.7/3.4 (225 mg monthly/675 mg quarterly) vs 2.2 placebo
TBD
Episodic migraine, ≥ 50% response
43.3%/50% vs 26.6%
62%/59% vs 39%/36%
47.7%/44.4% vs 27.9%
Chronic Migraine, decrease in MMD or MHD of moderate severity (MHD-MS)
Decrease in MMD by 6.6/6.6 vs 4.2
Decrease in MMD by 4.8 vs 2.7
Decrease in MHD-MS 4.6/4.3 vs 2.5 and
MMD 5/4.9 vs 3.2
Chronic Migraine, ≥ 50% response
39.9%/41.2% vs 23.5%
28% vs 15%
40.8%/37.6% vs 18.1%
Data from prescribing information (package inserts)

24. CGRP Inhibitors Erenumab (Aimovig) Galcanezumab (Emgality)
Fremanezumab (Ajovy)
Eptinezumab (??)
Dosing
70 mg or 140 mg monthly SubQ injection
240 mg loading dose then 120 mg monthly SubQ injection
225 mg monthly or 675 mg quarterly SubQ injection
TBD dose IV
Adverse reactions
Injection site reactions; constipation
Injection site reactions
TBD
Cost (WAC)
$575/month

25. Longer-term Data
3-year safety data for erenumab in episodic migraine population: most common side effects included upper respiratory tract infections, sinusitis, back pain, but none were significantly different rates from placebo
4.5-year safety data for erenumab showing no new safety concerns
Open-label study for episodic migraine showing sustained efficacy through 4.5 years
No long-term RCT data

26. CGRP Inhibitors Summary
“Cautious Optimism” – Abby Metzler, U of MN Headache Neurologist
First class of preventive medications designed based on migraine pathophysiology
Monthly or quarterly dosing options
“Super-responders” but unable to identify who these patients are yet
Generally well tolerated
WAC $575/month – similar in cost to Botox treatments
May need to fail multiple other preventive agents first for insurance to approve

27. Preventive Treatment Pearls
Avoid most preventive medications in pregnant or lactating women, especially valproic acid and topiramate
Migraine may improve over time; re-evaluate therapeutic response at 3-6 months and if possible taper or discontinue therapy if patient no longer meets criteria for preventive treatment
Adherence to preventive treatments is often poor

28. Other Approved Therapies
OnabotulinumtoxinA (Botox)
FDA approved for chronic migraine
External Trigeminal Nerve Stimulation device (Cefaly)
FDA approved for prevention or acute treatment

29. Other Emerging Therapies
“Gepants” – CGRP receptor antagonists for acute treatment
May provide improved tolerability over triptans with similar efficacy
Lasmiditan – 5-HT1F receptor agonist for acute treatment
May reduce side effects related to vasoconstriction compared to triptans, which are 5-HT1B/D receptor agonists

30. Post-test Question 1
Which of the following CGRP inhibitors targets the CGRP receptor?
Erenumab
Galcanezumab
Fremanezumab
Eptinezumab

31. Post-test Question 2
Which is the MOST appropriate scenario for migraine preventive therapy?
2 headache days per month with moderate response to ibuprofen and minimal functional impairment
3 headache days per month with poor response to sumatriptan and severe functional impairment
4 headache days per month with good response to sumatriptan but minimal response to acetaminophen
5 headache days per month with good response to rizatriptan and minimal functional impairment

32. Post-test Question 3 Which is the LEAST appropriate treatment plan?
Topiramate for a 24 year old male with no co-morbid conditions who has not taken any preventive medications and currently takes ibuprofen 6-8 days/month
Amitriptyline for a 26 year old female with depression who is taking an oral contraceptive
Erenumab for a 34 year old female who has tried/failed topiramate, propranolol, and amitriptyline
Galcanezumb for a 30 year old male with hypertension who has not tried any preventive medications

33. Post-test Question 4
Which is NOT a preferred abortive medication for episodic migraine?
Imitrex SubQ
Aleve
Fiorinal
Excedrin
Maxalt-MLT

34. Post-test Question 5
Which is the best education point for a patient with chronic migraine on Ajovy and sumatriptan?
Limit oral sumatriptan use to < 15 days/month to avoid medication overuse
Take Ajovy as a monthly 225 mg SubQ injection to prevent migraines
If experiencing nausea during a migraine, you can take SubQ sumatriptan
Limit sleep during a migraine attack

35. MHealth Headache Care Team
Sarah Benish, MD – Neurologist
Abby Metzler, MD – Neurologist (UCNS certified headache specialist)
Farha Ikramuddin, MN MPH – Physiatrist
Parisa Salehi, MD – Physiatrist
Stephanie Standal, MD – Physiatrist
Ludmila Johnson, MSN, RN, CNP – Neurological Nurse Practitioner
William Robiner, PhD, ABPP, LP – Psychologist
Steve Palmer, MA, LMFT – Behavioral Health Clinician
Natalie Roy, PharmD – MTM Pharmacist

36. References
Burch R, Rizzoli P, Loder E. The Prevalence and Impact of Migraine and Severe Headache in the United States: Figures and Trends From Government Health Studies. Headache. 2018;58(4):
Migraine Facts. Migraine Research Foundation. Available at: Accessed September 2019.
The American Headache Society Position Statement On Integrating New Migraine Treatments Into Clinical Practice. Headache. 2019;59(1):1-18.
Tepper SJ. Opioids should not be used in migraine. Headache. 2012;52 Suppl 1:30-4.
Edvinsson L, Haanes KA, Warfvinge K, Krause DN. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol. 2018;14(6):
Amgen and Novartis. Aimovig (erenumba-aooe) [package insert]. US Food and Drug Administration website. Available at: Revised May Accessed September 2019.
Eli Lily. Emgality (galcanezumab-gnlm) [package insert]. US Food and Drug Administration website. Available at: Revised Septemeber Accessed September 2019.
Teva. Ajovy (fremanezumab-vfrm) [package insert]. US Food and Drug Administration website. Available at: Revised September Accessed September 2019.

37. Natalie Roy, PharmD nroy2@fairview.org
Questions?
Natalie Roy, PharmD