“CASE” CLOSED: MIGRAINE TREATMENT UPDATES

SATURDAY/2:00-3:00PM

ACPE UAN: 0107-9999-20-013-L01-P 0.1 CEU/1.0 hr

Activity Type: Application-Based

Learning Objectives for Pharmacists:

Upon completion of this CPE course participants should be able to:

1. Differentiate episodic and chronic migraine by listing criteria for diagnosis of each type, including

concomitant symptoms and frequency of headaches.

2. Determine appropriateness of medications for migraine prevention and develop a treatment plan for patient

cases.

3. Explain the mechanism and place in therapy for the Calcitonin Gene-related Peptide (CGRP) inhibitors.

4. Define medication overuse in the context of migraine management.

5. List evidence-based abortive therapies for migraine.

Speaker: Natalie Roy, PharmD

Natalie graduated from Drake University with her Doctor of Pharmacy degree and completed a two

year Pharmaceutical Care Leadership residency at the University of Minnesota. During residency,

she developed a new comprehensive medication management practice with the MHealth Fairview

Neurology clinic. Because of this unique experience, Natalie developed a passion and expertise in

neurology. Natalie provides medication management services to patients with various

neurodegenerative diseases including Parkinson's Disease, Multiple Sclerosis, Huntington's

Disease, and Amyotrophic Lateral Sclerosis to optimize their medications and improve their quality

of life. She has also recently joined the care team for the new Headache Care Program, which

launched at the MHealth Fairview Neurology clinic in 2019. Natalie is passionate about patient

empowerment and shared decision making, and she enjoys supporting patients and caregivers on their

journeys using health coaching strategies. Natalie has recently become a preceptor for Advanced Pharmacy

Practice Experience students from the University of Minnesota College of Pharmacy.

Speaker Disclosure: Natalie Roy reports no actual or potential conflicts of interest in relation to this CPE

activity. Off-label use of medications will be discussed during this presentation.

#RxExpo20

“Case” Closed: Migraine Treatment Updates

Natalie Roy, PharmDMedication Therapy Management Pharmacist

MHealth Fairview Neurology ClinicMinneapolis, MN

#RxExpo20

Disclosure

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

• Off-label use of medications will be discussed during the presentation.

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Learning Objectives

• Upon successful completion of this course, participants 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 medications 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 for migraine

#RxExpo20

Prevalence of Migraine

3rd most prevalent illness in the world

6th leading cause of disability

20.7% of females affected

9.7% of males affected

$26 billion/year

Highest prevalence age 18‐44

Burch et al. Headache 2018; 58(4): 496-505.Migraine Facts. www.migraineresearchfoundation.org

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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)

• Triggers can vary – including stress, hormonal changes, lack of food, lack of sleep, alcohol etc.

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Diagnosis of Migraine• At least 5 attacks• Each attack lasts 4-72 hours when untreated or unsuccessfully

treated• Headache includes two of the following:

• Unilateral location• Pulsating quality• Moderate or severe pain intensity• Aggravation by or causing avoidance of route physical activity (ie: walking or

climbing stairs)

• During headache, one of the following occurs:• Nausea and/or vomiting• Photophobia and phonophobia

Headache. 2019;59(1):1-18.

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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)

Headache. 2019;59(1):1-18.

MHD = monthly headache daysMMD = monthly migraine days*+/‐ Aura

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www.americanmigrainefoundation.org

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Migraine Aura

• Aura: sensory, motor or verbal disturbance preceding a migraine attack

• About one-third of patients experience aura

• Example: https://www.youtube.com/watch?v=qVFIcF9lyk8

Will not discuss aura for the remainder of the presentation as migraine treatment generally does not change, but keep in mind that patients with migraine with aura are at higher risk of stroke, so estrogen use should be avoided in these patients.

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Case #1

• KB is a 28 year old female with new onset of migraine attacks. She has experienced 4 moderate-severity attacks in the last month and each have lasted for 6-10 hours. She has experienced nausea with each of the 4 attacks and ibuprofen has been ineffective.

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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 of chronic migraine

• Educate patients to avoid overuse

Headache. 2019;59(1):1-18.

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Abortive Treatments Mild‐Moderate Attacks

NSAIDs (including aspirin)

Acetaminophen

Caffeinated analgesic combinations (ie: Excedrin)

Moderate‐Severe Attacks

Triptans

Dihydroergotamine (DHE)

Headache. 2019;59(1):1-18.

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Triptans

• First migraine-specific medication on the market

• 5-HT receptor agonists with high affinity for 5-HT1B and 5-HT1D receptors

• Typical side effects include nausea, dizziness, chest tightness/pressure, paresthesia, flushing

• May be combined with NSAIDs for possibly better efficacy (studies are conflicting)

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Triptan Pearls

• Sumatriptan and rizatriptan typically least expensive

• Sumatriptan SubQ and nasal spray typically fastest acting (10-15 minutes)

• Naratriptan typically best tolerated but slower onset (1-3 hours)

• Frovatriptan has longest half-life (26 hours)

• Eletriptan has relatively fast onset (30 minutes) plus longer half-life (4 hours) compared to oral sumatriptan with onset of 20-30 minutes and half-life of 2.5 hours

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Management of Nausea/Vomiting• Use alternate formulations of abortive therapies

• Oral disintegrating tablets (ODT): rizatriptan, zolmitriptan• Nasal spray: sumatriptan, zolmitriptan• Subcutaneous: sumatriptan

• Anti-emetics can also help abort refractory migraines• Prochlorperazine, promethazine, droperidol, chlorpromazine,

metoclopramide

Headache. 2019;59(1):1-18.

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Failure of First-line Treatments• “Rescue” medications can include:

• SubQ sumatriptan• DHE injection or intranasal spray• Corticosteroids (ie: dexamethasone)• IM NSAIDs (ie: ketorolac)• Anti-emetics • Anticonvulsants (ie: valproate sodium and topiramate) – typically only

for inpatients • IV magnesium sulfate

• Pregnant women – IV fluids

Headache. 2019;59(1):1-18.

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Opioids?• May improve pain, but not productivity

• May increase risk of conversion from episodic 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

• There is some evidence for butorphanol, but it is still not recommended by the American Headache Society

Tepper SJ. Headache. 2012;52 Suppl 1:30-4.

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Medication Overuse Headaches• American Headache Society (AHS) definition:

• ≥ 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

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Avoiding Medication Overuse

NSAIDs, acetaminophen, non‐opioid combination (ie: Excedrin)

• Limit to < 14 days/month total

Triptans

• Limit to < 9 days/month total

Opioids

• Limit < 1 day/week total

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Abortive Treatment Pearls• Be aware of contraindications:

• NSAIDs – GI/CV side effects• Triptans/ergotamine derivatives – should be avoided in patients with coronary

artery disease, peripheral vascular disease, uncontrolled hypertension, and other vascular risk factors and disorders

• In some patients, try higher dose first and decrease if side effects• ie: 100 mg of sumatriptan vs 50 mg

• Attempt at least 2 trials of an abortive medication before determining lack of efficacy

• Create a stratified migraine action plan• Plan for mild headache (ie: take ibuprofen)• Plan for moderate-severe headache (ie: take sumatriptan)• Plan for nausea/rescue treatment (ie: take prochlorperazine)

Headache. 2019;59(1):1-18.

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Case #1

• KB is a 28 year old female with new onset of migraine attacks. She has experienced 4 moderate-severity attacks in the last month and each have lasted for 6-10 hours. She has experienced nausea with each of the 4 attacks and ibuprofen has been ineffective.

#RxExpo20

Preventive Therapies• Lifestyle modification (nutrition, exercise, hydration, sleep)

• Avoid triggers

• Pharmacologic medication considered if:• Contraindication to acute treatments• Failure of acute treatments• Overuse of acute treatments

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Preventive Medication Indications

Headache. 2019;59(1):1-18.

Prevention should be… Headache days/month Degree of disability

Offered 6 or more None

Offered 4 or more Some 

Offered 3 or more Severe 

Considered 4 or 5 None 

Considered  3 Some 

Considered 2 Moderate 

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Oral Preventive Therapies

Headache. 2019;59(1):1-18.

Established Efficacy

• Divalproex sodium

• Valproate sodium

• Topiramate

• Metoprolol

• Propranolol 

• Timolol 

• Frovatriptan (short‐term for menstrual migraine)

Probably Effective

• Amitriptyline

• Venlafaxine 

• Atenolol

• Nadolol

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Preventive Medications• 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 achieved, maximum/target dose is reached, or tolerability issues arise

• 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

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“Successful” Migraine Prevention• 50% reduction in frequency of MMD or MHD

• Could be less for some patients

• 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

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CGRP in Migraine• Calcitonin gene-related

peptide (CGRP): • 37-amino acid neuropeptide

that functions as a messenger in nerve cells and as a vasodilator

• CGRP receptors are expressed in the trigeminal ganglion (outside the blood brain barrier)

• CGRP is increased during migraine attacks

Edvisson L et al. Nat Rev Neurol. 2018;14(6):338-350.

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CGRP Inhibitors for Migraine Prevention• Monoclonal antibody 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

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CGRP Inhibitors for Migraine Prevention

Data from prescribing information (package inserts)

Erenumab (Aimovig) Galcanezumab (Emgality) Fremanezumab (Ajovy)

Episodic Migraine

Decrease in MMD

≥  50% response

6 month study

Decrease in MMD by 3.2/3.7 (70 mg/140 mg) vs 1.8 placebo

43.3%/50% vs 26.6%

6 month study

Decrease in MMD by 4.7/4.3(120 mg study 1/2) vs 2.8/2.3 placebo (study 1/2)

62%/59% vs 39%/36%

3 month study

Decrease in MMD by 3.7/3.4 (225 mg monthly/675 mg quarterly) vs 2.2 placebo

47.7%/44.4% vs 27.9%

Chronic Migraine

Decrease in MMD or MHD‐MS

≥  50% response

3 month study

Decrease in MMD by 6.6/6.6 vs 4.2

39.9%/41.2% vs 23.5%

3 month study 

Decrease in MMD by 4.8 vs 2.7

28% vs 15%

3 month study

Decrease in MHD‐MS 4.6/4.3 vs 2.5 and MMD 5/4.9 vs 3.2

40.8%/37.6% vs 18.1%

MMD = monthly migraine daysMHD-MS = monthly headache days of moderate severity

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CGRP Inhibitors Erenumab (Aimovig) Galcanezumab

(Emgality)Fremanezumab (Ajovy)

Dosing 70 mg or 140 mg monthly SubQinjection 

240 mg loading dose then 120 mg monthly SubQ injection 

225 mg monthly or 675 mg quarterly SubQinjection

Device Auto‐injector Auto‐injector  Pre‐filled syringe

Adverse reactions

Injection site reactions; constipation

Injection site reactions Injection site reactions

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CGRP Inhibitors: Longer-term Data• 3-year open-label safety data for erenumab in episodic migraine

population: most common side effects include upper respiratory tract infections, sinusitis, and back pain, but none were significantly different rates from placebo

• No cardiovascular events were reported• 4.5-year safety data for erenumb so far is showing no new safety

concerns (5 year data to be published soon)

• Open-label study of erenumab for episodic migraine showing sustained efficacy through 4.5 years

• No long-term RCT data available

Ashina M et al. Cephalalgia. 2019;39(11):1455-1464.

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CGRP Inhibitors Pearls• “Cautious Optimism”

• First class of preventive medications designed based on migraine pathophysiology

• Consider for patients who have tried/failed multiple oral preventive therapies• Not studied in combination with Botox treatments

• Monthly or quarterly dosing options

• “ Super-responders” but unable to identify who these patients are yet

• Generally well tolerated without drug interactions

• WAC $575/month – similar in cost to Botox treatments• May need to fail multiple other preventive agents first for insurance to approve

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Preventive Treatment Pearls• Avoid preventive medications in pregnant or lactating women,

especially valproic acid and topiramate• CGRP inhibitors not studied in pregnant women but there is a registry

• Migraine may improve over time; reevaluate 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 oftentimes poor

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Case #2

• AR is a 35 year old female with chronic migraine and depression. She is taking venlafaxine (Effexor), fremanezumab(Ajovy) SubQ, and sumatriptan (Imitrex) orally.

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Other Therapies• OnabotulinumtoxinA (Botox)

• FDA approved for prevention of chronic migraine

• External Trigeminal Nerve Stimulation device (Cefaly)

• FDA approved for prevention or acute treatment of migraine

• Occipital nerve blocks may provide relief especially for concomitant neck pain

• CBD, chiropractor, PT, vitamins/supplements...

www.americanmigrainefoundation.org

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Recently FDA Approved Medications• Lasmiditan (Reyvow) – 5-HT1F receptor agonist for acute

treatment • Not showing side effects related to vasoconstriction like triptans (5-

HT1B/D receptor agonists) but potential to lower heart rate; was not studied in patients with ischemic heart disease

• Only one dose allowed in 24 hours due to risk of dizziness/sedation/fatigue – awaiting FDA determination for scheduling

• Warning to avoid driving 8 hours after taking a dose• Risk of serotonin syndrome and CNS depression, particularly with use

of concomitant medications• Safety of > 4 doses in 30 day-period has not been established

Data from prescribing information (package insert)

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Recently FDA Approved Medications• Lasmiditan (Reyvow) Efficacy

Data from prescribing information (package insert)

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Recently FDA Approved Medications• Urogepant (Ubrelvy) – CGRP receptor antagonist for acute

treatment• May provide improved tolerability over triptans• Treat at onset of migraine; may repeat 2 hours later• ADRs included nausea and somnolence; no liver toxicity noted• Contraindicated with concomitant use of strong CYP3A4 inhibitors • Efficacy results

• ”Pain free” at 2 hours: 19%/22% (50 mg study 1/2) vs 21% (100 mg study 1) vs 12%/14% (placebo study 1/2)

• Most bothersome symptom free at 2 hours: 39%/39% (50 mg study 1/2) vs 38% (100 mg study 1) vs 28%/27% (placebo study 1/2)

Data from prescribing information (package insert)

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Recently FDA Approved Medications• Urogepant and lasmiditan will likely be costly – reserve for

patients who have contraindications to the currently approved abortive therapies or who have tried/failed multiple medications

• As of December 2019, urogepant and lasmiditan not yet available for ordering

• More “gepants” to come

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Case #3

• EP is a 29 year old female who presents to the neurology clinic for medication review and to “taper off as many medications as possible” because she is thinking of becoming pregnant

• She is currently having daily headaches and was in the ED yesterday due to severe migraine (was given hydromorphone and metoclopramide, which helped somewhat)

• PMH: chronic migraine, anxiety, insomnia, acne, seasonal allergies

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Preventive Therapies

• Zonisamide 400 mg nightly

• Gabapentin 600 mg AM/1200 mg PM

• Duloxetine 90 mg daily

• Botox injections

• Acupuncture 

• Massage

Abortive Medications

• Ibuprofen 600 mg (daily)

• Hydrocodone‐APAP 5‐320 mg 

• Cyclobenzaprine 10 mg

• Ondansetron 8 mg ODT

Other Medications

• Drospirenone‐ethinyl estradiol

• Spironolactone 25 mg twice daily

• Bactrim DS twice daily 

• Clonidine 0.1 mg nightly

• Trazodone 200 mg nightly 

• Diazepam 2 mg nightly

• Alprazolam 0.5 mg as needed

Vitamins/

Supplements

• Prenatal vitamin

• Calcium/vit D

• Magnesium

• Vitamin B complex

• Iron

• CoQ10

• Omega3

• Digestive enzymes

• Memory Builder supplement

• Vision Health supplement

• Liver Health supplement

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Case #3

• Previous medication trials: topiramate, Depakote, amitriptyline, lamotrigine, propranolol, sumatriptan oral tablets, bupropion, citalopram

• Patient is currently on disability, but has goals of returning to work as an accountant and becoming pregnant in the next year

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Case #3: Plan

• Initial plan: • Start erenumab 70 mg daily (and stop Botox)• Start sumatriptan SubQ as needed• Taper zonisamide and gabapentin• Stop clonidine • Discontinue as many supplements as possible• Limit NSAIDs to < 14 days/month• Limit opioids to < 1 day/week• Limit triptan to < 9 days/month

• Ongoing plan:• Taper diazepam, trazodone• Discontinue spironolactone, Bactrim

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Preventive Therapies

• Emgality 120 mg SubQ monthly

• Duloxetine 60 mg daily

• Botox injections

• Acupuncture 

• Massage

Abortive Medications

• Sumatriptan SubQ

• Ondansetron 8 mg ODT

Other Medications

• Drospirenone‐ethinyl estradiol

Vitamins/

Supplements

• Prenatal vitamin

• Calcium/vit D

• Magnesium

• Vitamin B complex

• Iron

• CoQ10

Case #3: 9 months later

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Case #4

• DN is a 56 year old male presenting to the interprofessional headache clinic for comprehensive approach to migraine management

• PMH: chronic migraine, epilepsy, CAD s/p stent 2018, Type 2 diabetes, hypertension, COPD, psoriatic arthritis, anxiety (on 20-30 medications)

• Headaches were previously “well controlled” on daily ibuprofen but patient was instructed to stop ibuprofen after cardiac stenting

• Current preventive medications: Depakote and zonisamide (epilepsy doses), gabapentin 400 mg 4 times/day (for anxiety primarily), and metoprolol XL 25 mg daily; did not tolerate amitriptyline

• Migraine “cocktail” initial therapy: acetaminophen, diphenhydramine, metoclopramide

• 2nd line, uses ketamine nasal spray• 3rd line, will take ketorolac (no more than 5 days at a time)

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Take Home Points• Migraine attack frequency matters

• Episodic migraine: MHD on <15 days/month• Chronic migraine: MHD on ≥ 15 days/month of MMD on ≥ 8 days/month

• Avoid opioids as acute treatment of migraine attack• Limit abortive medications to avoid medication overuse headaches

• NSAIDs, APAP, Non-opioid combo: < 14 days/month• Triptans: < 9 days/month• Opioids: < 1 day/week

• Urogepant and lasmiditan may be possible migraine treatments for patients with concomitant CV disease

• Consider evidence-based preventive therapies for patients with frequent migraine attacks, disability, or poor efficacy from abortive treatments

• CGRP inhibitors are a new migraine preventive strategy for patients who have tried/failed multiple oral medications

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“Case” Closed: Migraine Treatment Updates

Natalie Roy, PharmDMedication Therapy Management Pharmacist

MHealth Fairview Neurology ClinicMinneapolis, MN

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