Managing Migraine: Primary Care for Primary Headaches

Jeffrey Unger, MD

Disclosures: Speakers Bureau: Novo Nordisk, Abbott Diabetes, Janssen Consultant: Novo Nordisk, Abbott Diabetes, Bayer Research Grants: Novo Nordisk, GSK, Abbott Diabetes, Merck, Sanofi, Lilly, Pfizer Stock Ownership: Novo Nordisk, Tandem Diabetes

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Managing Migraine: Primary Care for Primary Headaches

Jeff Unger, MD, FAAFP, FACE

Director, Unger Primary Care Concierge Medical Group

Rancho Cucamonga, CA.

Assistant Professor of Family Medicine, UC Riverside School of Medicine

Disclosures

2

Jeff Unger, MD, FAAFP, FACE serves as a speaker for Amgen Pharmaceuticals and a

consultant for Teva Pharmaceuticals

Learning Objectives 1. Utilize evidence-based strategies to diagnose patients presenting with headache;

2. Identify associated conditions (e.g. depression), and red flags for potentially life

threatening causes of headache;

3. Use evidence-based recommendations to prescribe treatment for patients presenting

with acute or emergent headache pain;

4. Develop collaborate management plans, emphasizing patient education on avoiding

triggers that cause headache, and adherence to prescribed treatment strategies;

5. Discuss newer pharmacologic targets for managing patients with Chronic Migraine.

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Prevalence of Headache in the General Population

Prevalence of any form of headache was 93% in men and 99% in women.

Among men, 8% had, at some point, experienced migraine compared with 25% of women.

Migraine is the 2nd most disabling disease state in the world (low back pain is most disabling).

Rasmussen BK. Epidemiology of headache in a general population- a prevalence study. JClinEpidemiol. 1991: 44 (11):1147-57

U

Primary vs Secondary Headaches

PRIMARY SECONDARY

NO structural or metabolic

abnormality

Structural or metabolic abnormality

Tension type

Migraine

Cluster

Other primary headaches

Extracranial (sinusitis, otitis media,

glaucoma, TMJ)

Intracranial (SAH, vasculitis, dissection,

central vein thrombosis, tumor, abscess,

meningitis

Metabolic (CO2 retention, CO poisoning)

5

Headache Time Course

Minutes Days Weeks/Months Months/Years

Vascular

Infectious

Inflammatory/Neoplastic

Primary

Headaches

Secondary Headaches

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Diagnostic Red Flags and Comfort Signs Red Flags:

◦ First or worst

◦ Abrupt onset

◦ Fundamental change in pattern

◦ New headache onset in patients < 5 or > 50 years of age

◦ Cancer, HIV, pregnancy

◦ Neurological dysfunction + headache

◦ HA onset with seizure or syncope

◦ HA onset with exertion, sex or Valsalva

◦ Abnormal vital signs

◦ In children, HA get progressively worse over time

Comfort signs:

◦ Stable pattern x 6 months

◦ Long history of same headaches

◦ In children-recurring, INTERMITTENT

◦ Normal neurologic exam

◦ Occur with menstruation

◦ +FH of same

◦ Known consistent triggers

Ravishankar K. Which headaches to investigate. When and How.

Headache. 2016 Nov;56(10):1685-1697 7

Definition of Migraine A stable pattern of recurrent disabling headaches without

evidence of underlying cause.

Migraineurs have a genetic sensitivity towards severe, disabling

headaches.

Migraineurs are born with a very sensitive nervous system

The goal of migraine management is to allow the migraineur to

learn to reduce their neurological sensitivity

Migraine events disrupt normal neurologic brain function which

increases the likelihood of having additional events

Unger J. Migraine prophylaxis. The Pain Practitioner. 17 (1). 32-36. 2007 8

Migraineurs are Born with a Genetically Predisposed Sensitive Neurological System

Triggers:

Stress

Hormonal changes

Skipping meals

Specific food (cheap red wine, caffeine)

Sleep disruptions

Medications and med overuse

Weather

Minor head trauma

Protective factors:

◦ Standardized sleep patterns

◦ Regular meals

◦ Exercise

◦ Stress management

◦ Pro-active treatment for menstrual

migraine and prodromes

◦ Post menopause treatment

◦ Avoidance of triggers

◦ Reduction caffeine usage

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Adapted from Cady RK. Headache. 2008;48(9):1415-1416.

Prodrome Aura 20 %

Mild Moderate to Severe

Postdrome

“Most Bothersome Symptoms”

Mig

rain

e In

ten

sity

Phases of a Migraine Attack (3-5 days Duration)

Migraine symptoms occurring hours/days

prior to headache

Migraine when headache is mild

Migraine when headache is moderate to severe

Migraine symptoms occurring

hours/days after headache resolution

Focal neurological symptoms preceding headache (<1 hour)

Symptoms : • Food cravings • Mood changes • Yawning • Fatigue

Symptoms: • Tiredness • Confusion •Dizzy • Lowered appetite • Stiff or sore muscles

Symptoms: • Same as mild but more intense •Can develop allodynia within 2-4 hours

Symptoms: • Flashing lights or wavy lines • Numbness • Tingling in face • Disturbed senses

Symptoms: • Sensitivity to light • Sensitivity to sound • Nausea • Pain in the back of the head and neck •Loss of cognition

Pre-HA Post-HA Headache

10

Nausea

Vertigo

Vomiting

Confusion

Light and sound sensitivity

Prodrome: Symptoms Irritability - 48 %

Nausea - 43 %

Muscle pain/tenderness - 38 %

Change in energy level - 30 %

Change in mood - 24 %

Change in appetite - 21 %

Yawning - 21 %

Luciani R, et al. Cephalgia 2000; 20:122-126 11

Migraine: Spreading Cortical Depression and Aura

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Patient Describing Aura

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Neck Pain During Migraine Prevalence

- 75% of subjects

Descriptions

- 69% - tightness

- 17% - stiffness

- 5% - throbbing

- 5% - other

Kaniecki R. Neurology. 2002;58(Suppl 6):S15-S20.

82% had previously been given a diagnosis of tension-type headache

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“Even My Hair Hurts” (allodynia)

Cutaneous allodynia ◦ “Hair hurts”

◦Painful when:

- Shaving

- Combing hair

- Touching scalp

- Resting head on pillow

- Pulling hair back (wearing a ponytail)

- Wearing eyeglasses or contact lenses

- Wearing hat or head band

Chen N, et al. Pain Med. 2015 Jun;16(6):1211-20 15

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Migraine Pathogenesis Genetic predisposition

Triggers evoke aberrant firing of neurons resulting in

cortical spreading depression (CSD)

CSD activates the release of neurokinins and CGRP

causing vascular dilation and increased platelet

adhesiveness.

Neuronal flow into the nucleus caudalis can eventually

cause nausea, vomiting, dizziness, and severe head pain

Hadjikhani N, Sanchez Del Rio M, Wu O, et al. Mechanisms of migraine aura revealed by

functional MRI in human visual cortex. Proc Natl Acad Sci USA. 2001;98(8):4687-4692

Video courtesy of American Headache Society. With Permission. 16

“PIN” The Migraine Diagnosis | History

2/3 YES = Migraine

Lipton RB, et al. Neurology. 2003;61:375-382.

During the last 3 months, did you have the following with your headaches?

(YES/NO)

P Photophobia

Light bothered you (a lot more than when you don’t have

headaches)

I Impairment

Your headaches limited your ability to work, study, or do

what you need to do

N Nausea

You felt nauseated or sick to your stomach

Episodic Migraine vs Chronic Migraine

Frequency

Severi

ty

Frequent Episodic Migraine

< 15 Headache Days/Month

Headache

Time to Recover

Lipton RB, et al. Managing migraine: A healthcare professional’s guide to collaborative migraine

care. Hamilton, Ontario: Baxter Publishing Inc; 2008:26. 18

Chronic Migraine: > 15 headache days per

month x 3 months with 8 days being

migraine-like headaches

Brain sensitivity is heightened. No time for

neurological recovery between attacks Brain can recover between attacks

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Free Iron Deposition in the PAG In a Patient With CDH

Control Chronic Daily Headache

Welch, et al. Periaqueductal Gray Matter Dysfunction in Migraine: Cause or the Burden of Illness? Headache. 41(7) P 629-637. 2001 With Permission

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Barriers and Pitfalls in Primary Headache Diagnosis

Headaches evaluated within Primary Care are rarely due to secondary causes

Remember, migraine is a neurologic event, not a pathologic process based

upon vasodilation and constriction

Be cautious of patient directed diagnoses: “Sinus, stress, or allergic

headaches”

Most patients will have tried OTC meds prior to seeking professional

consultation.

“Sinus headaches” and neck pain…think migraine

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Physical Exam Vital signs!

Look for any focal neurological findings

Listen to the head!

Feel the scalp and neck muscles

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Listen to the Head!

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Headache Lab Tests

CBC

ESR

T4, TSH, Thyroid Peroxidase Antibody

Unger Jeff, Cady Roger K, Farmer-Cady Kathleen. Migraine Headaches, Part 1:

Presentation and Diagnosis. The Female Patient. May 2003: Vol.28. 14-21 23

Heather History

Recurrent disabling headaches

Light Sensitivity

Nausea

Vomiting

+ Family History

Lasts 4 -72 hours

Unger J, Cady R, Farmer K. Migraine headaches, Part 1; The Female Patient. 2003. 8; 32-39.

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Imaging Patients With Migraine

Adapted from Frishberg BM, et al. www.aan.com.

Patients with migraine and normal neurologic exam Meta-analysis

99.82%

0.18% Significant

intracranial pathology

Primary

Secondary

DO NOT perform

neuroimaging studies in

patients with stable

headaches that meet

criteria for migraine (American Academy of Neurology)

One Nerve Pathway: Multiple Symptoms of Migraine

(V3)

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Does Peter Have Sinus Headaches?

Unger J, Cady R, Farmer K. Migraine headaches, Part 1; The Female Patient. 2003. 8; 32-39.

-

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Diagnosis of Sinusitis is Based on the Presence of at Least 2 Major or 1 Major + > 2 Minor Symptoms

Purulent nasal discharge

Nasal congestion or obstruction

Facial congestion or fullness

Facial pain or pressure

Loss of taste or smell

Fever (acute sinusitis only)

Headache

Ear pain, pressure or fullness

Halitosis

Dental pain

Cough

Fever (for subacute or chronic sinusitis)

Fatigue

Major Symptoms Minor Symptoms

Chow AW et al. IDSA clinical practice guidelines for acute bacterial rhinosinusitis in children and adults. Clinical Infectious Disease. 2012:

http://www.idsociety.org/uploadedFiles/IDSA/Guidelines-

Patient_Care/PDF_Library/IDSA%20Clinical%20Practice%20Guideline%20for%20Acute%20Bacterial%20Rhinosinusitis%20in%20Children%20and%20Adults.pdf 28

Nasal Endoscopy

No Headache

With a moderate to

severe “sinus” headache

1 hour after

treatment with

sumatriptan

6mg SC

Reference: Schreiber CP et al. Arch Intern Med. 2004;164:1769-1772.

Photos courtesy of Jeff Unger, MD

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Strategies for Migraine Treatment

Lifestyle interventions Acute treatment

• To stop pain and prevent progression

Preemptive treatment

• To preempt a predictable headache with a time-limited trigger

Preventive treatment

• To decrease frequency

Rescue therapy

• When all else fails

Lipton RB, et al. Headache. 1998;38:87–96; Silberstein SD, et al. Cephalalgia. 1997;17:67-72. 30

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Behavioral Approaches to Migraine Treatment

Relaxation exercises No meal skips

Exercise Sleep hygiene

Stop smoking Have a written plan!

Stop analgesics > 2× weekly 2 cups java per day

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Acute Migraine Treatment Goals

Acute medication

not needed >2

times/week

Relief of

associated

symptoms

Headache does not come back for 24 hours

Headache free in 2 hours

Back to full function

in 2 hours

Little to no side-

effects from

medication

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Triptans

Sumatriptan

Oral: 25, 50, 100 mg

Nasal: 5, 20 mg

Auto-injector: 4 or 6 mg

Needle-free injector: 6 mg

Zolmitriptan

Oral: 2.5, 5 mg

ODT: 2.5, 5 mg

Nasal: 5 mg

Naratriptan

Oral: 1, 2.5 mg

Rizatriptan

Oral: 5, 10 mg

ODT: 5, 10 mg

Almotriptan

Oral: 6.25, 12.5 mg

Frovatriptan

Oral: 2.5 mg

Eletriptan

Oral: 20, 40 mg

Sumatriptan/ Naproxen

Oral: 85 mg/500 mg ODT, orally

disintegrating

tablet

Physicians' Desk Reference, 2016. 70th ed. Montvale, NJ: PDR Network, LLC; 2016. 33

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Triptan Practical Strategies

Treat early after migraine onset

Use highest dose formulation

Expect to be pain free and associated symptom free within 2hrs

Migraine diary

Frequency, intensity, duration

Nausea

- Ondansetron 4-8 mg

- SQ injection or nasal spray

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Early Intervention: Triptan Efficacy vs. Pain Intensity

0%

20%

40%

60%

80%

Mild Moderate Severe

80%

58%

35%

Pain Intensity When HA Treated

2 Hour Pain Free Response

Adopted from Cady RK et al SPECTRUM Study. Headache 2000 38:173-83 35

When To Consider Preventive Therapy

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Migraine significantly interferes with patient’s daily routine, despite acute treatment

Attack frequency >1/wk

Acute medication ineffective, contraindicated, over-used, or not tolerated

Patient preference

Presence of uncommon migraine conditions

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Preventive Medications for Migraine

ß-blockers

Anticonvulsants

CGRP receptor mAb

CGRP ligand mAb

ACh release inhibitor (OnabotulinumtoxinA)

EPISODIC EPISODIC &

CHRONIC CHRONIC

Dodick DW. Lancet. 2018 Mar 31;391(10127):1315-1330. 37

Traditional vs New Preventive Treatments

TRADITIONAL NEW

Target Designed for other therapeutic areas Designed for primary migraine

prevention (EM, CM, MOH*)

Side Effects &

Tolerability Numerous side effects Minimal; similar to placebo

Time to Onset 2-4 months for effectiveness < 1 week – 1 month

Effectiveness ~ 50% reduction in HA frequency;

may lose effectiveness in MOH*

≥ 75% reduction in HA

frequency; lower all acute

medication use

*MOH: Medication overuse

(1) Stauffer VL, et al. JAMA Neurol. 2018 Sep 1;75(9):1080-1088. (2) Bigal ME, et al. Lancet Neurol. 2015 Nov;14(11):1081-90.

(3) Schwedt T, et al. J Headache Pain. 2018 Oct 1;19(1):92 (4) Dodick DW, et al. Lancet Neurol. 2014 Nov;13(11):1100-1107. 38

American Academy Neurology American Headache Society Preventive Recommendations

Divalproex Sodium

Sodium valproate

Topiramate

Metoprolol

Propranolol

Timolol

Frovatriptan(*)

Level A Level B

Amitriptyline

Venlafaxine

Atenolol

Nadolol

Naratriptan (*)

Zolmitriptan(*)

*= menstrual migraine

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Basic Rules For Traditional Preventive Medications

TREATMENT LENGTH 2–3 months to determine efficacy

6-months may be necessary for maximal response

TARGET GOALS in frequency, severity, and/or duration of acute attacks

Dodick DW. Lancet. 2018 Mar 31;391(10127):1315-1330.

FAMILY PLANNING Potential adverse fetal effects of antimigraine medications

Herbal Preventives Butterbur (Petadolex) 75 mg twice a day1

B2 (Riboflavin) 400 mg a day*

Magnesium 250-400 mg a day*

Feverfew 3 dried leaves daily*

Coenzyme Q-10 150-300 mg a day

Matchar DB, et al. AAN. US Headache Consortium. 2000:1-58. Level A evidence.

Levin M. Headache 2012;52;S2:76-80.

Markley H. Headache 2012;52:S2:81-87.

*= Effective for pediatric migraine

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CGRP (Calcitonin-gene related peptide) and Migraine CGRP is released from various locations in the body during times of physiologic or emotional stress

CGRP sensitizes trigeminal afferents recruiting other nerves which can potentiate migraine

As more nerves become sensitized, the thalamus becomes activated and patient develops central

sensitization

CGRP levels sampled from the external jugular vein are increased during migraine compared with controls

who do not have migraine

CGRP infusions can trigger migraine in migraineuers, but NOT healthy controls.

CGRP inhibitors block migraine progression and reduce frequency, intensity and duration of migraine

CRRP inhibition allows brain to recover more fully from a migraine event

A brain which has not fully recovered from a migraine event is more reactive. Another migraine will follow

Frequent migraine, result in more frequent events

Juhasz G, et al. NO-induced migraine attack: strong increase in plasma calcitonin gene- related peptide

(CGRP) concentration and negative correlation with platelet serotonin release. Pain. 2003;106:461–47 42

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CGRP and Migraine Trigeminal Nerve activation Migraine trigger

Pain!

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CGRP Inhibitor Prevents Migraine

Trigeminal Nerve activation Migraine trigger

CGRP Monoclonal Antibodies Prevent Receptor Activation

Trigeminal Nerve activation

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CGRP Inhibitors PHARMACOLOGIC TARGET INDICATION

Galcanezumab

(Emgality)

CGRP w/humanized

antibody

Episodic &

chronic migraine

Fremanezumab

(Ajovy)

CGRP w/humanized

antibody (CGRP ligand

binding)

Erenumab

(Aimovig)

CGRP receptor with

humanized antibody

Eptinezumab

(Not approved)

CGRP w/humanized

antibody

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Cluster Headaches

CGRP Inhibitors | Efficacy

(1) Stauffer VL, et al. JAMA Neurol. 2018 Sep 1;75(9):1080-1088 (2) Skljarevski V, et al. Cephalalgia. 2018 Jul;38(8):1442-1454. (3)

Detke HC, et al. Neurology. 2018 Dec 11;91(24):e2211-e2221. (4) Dodick DW, et al. JAMA. 2018 May 15;319(19):1999-2008. (5)

Silberstein SD, et al. N Engl J Med. 2017 Nov 30;377(22):2113-2122. (6) Dodick DW, Cephalalgia. 2018 May;38(6):1026-1037. (7)

Ashina M, et al. Neurology Apr 2018, 90 (15 Supplement) S32.006. (8) Saper J, et al. Neurology Apr 2018, 90 (15 Supplement) S20.001.

(9) Silberstein S, et al. American Academy of Neurology meeting, Los Angeles, CA, April 25, 2018 (abstract P4‐471).

EPISODIC

MIGRAINE

CHRONIC

MIGRAINE

Galcanezumab 56-62%1-2 27%3

Fremanezumab 48%4 38-41%5

Erenumab 39%6 38-42%7

Eptinezumab

(Not approved) 49-56%8 57-61%9

% of patients with ≥ 50% reduction in the

average number of headache days/month

47

-7.5

-6.5

-5.5

-4.5

-3.5

-2.5

-1.5

-0.5 Placebo (n=281)

Erenumab 70 mg (n=188)

Erenumab 140 mg (n=187)

Specific Migraine Treatment With Anti-CGRP mAb: Effects of

Erenumab in Chronic Migraine

LS=LEAST SQUARES. SE=STANDARD ERROR.

TEPPER S, ET AL. LANCET NEUROL. 2017;16:425-434. 48

-2.7

-3.6

-4.2 -5.0

-6.2 -5.1

-6.5 -6.6 -6.6

Ch

an

ge

in M

on

thly

Mig

rain

e D

ays

Erenumab (Aimovig®)

Week 4 Baseline Week 8 Week 12

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†

†

*

†

†

† -6

-5

-4

-3

-2

-1

0

Placebo (n=281)

Galcanezumab 120 mg

Galcanezumab 240 mg

LS

Mea

n C

han

ge

Fro

m B

ase

lin

e (S

E)

-2.7

-4.6 -4.8 *P<0.01

†P<0.001

Month 1 Baseline Month 2 Month 3

Galcanezumab (Emgality®) REGAIN

Specific Migraine Treatment With Anti-CGRP mAb:

Effects of Galcanezumab in Chronic Migraine

DETKE HC, ET AL. NEUROLOGY. 2018;91(24):E2211-E2221. 49

Specific Migraine Treatment With Anti-CGRP mAb:

Effects of Fremanezumab in Chronic Migraine

CM=CHRONIC MIGRAINE.

SILBERSTEIN SD, ET AL. N ENG J MED. 2017;377:2113-2122. 50

-10

-9

-8

-7

-6

-5

-4

-3

-2

-1

0

Placebo (n=371)

Fremanezumab quarterly (N=375)

Fremanezumab monthly (N=375)

LS

Mea

n C

han

ge

Fro

m B

ase

lin

e in

Ave

rag

e

Nu

mb

er o

f H

ead

ach

e D

ays

per

Mo

nth

Baseline

-2.5

-4.6 -4.3

12 4 8

Week After First Injection

Fremanezumab (Ajovy®) HALO

† † †

†

†

†

Fremanezumab was equally effective in preventing EM and CM whether administered subcutaneously monthly or quarterly (primary endpoints)

Difference between fremanezumab quarterly and placebo during 12-week period: -1.8±0.3 days/month (P<0.001)

Difference between fremanezumab monthly and placebo during 12-week period: -2.1±0.3 days/month (P<0.001)

CGRP Inhibitors | Safety

(1) https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/aimovig/aimovig_pi_hcp_english.ashx

(2) https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761089s000lbl.pdf

(3) https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761063s000lbl.pdf (4) Saper J, et al. Neurology Apr 2018, 90 (15 Supplement)

S20.001. (5) Silberstein S, et al. American Academy of Neurology meeting, Los Angeles, CA, April 25, 2018 (abstract P4‐471).

Erenumab1 Fremanezumab2 Galcanezumab3 Eptinezumab4-5

Systemic SEs No systemic effects (vs other biologics)

Injection site reactions

GI (constipation)

Respiratory (nasopharyngitis, URI)

Nausea, UTI,

arthralgia, dizziness,

anxiety, fatigue

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CGRP Inhibitors | Administration

52

MODE OF DELIVERY FREQUENCY

Galcanezumab

(Emgality)

Self-inject with autoinjector or

prefilled syringe Monthly

Fremanezumab

(Ajovy)

Self-inject with prefilled

syringe Monthly or every 3 months

Erenumab

(Aimovig) Self-inject with autoinjector Monthly

Eptinezumab

(Not approved) IV infusion Every 3 months

Menstrual Migraine Prevention Option

Frovatriptan 2.5 mg BID x 6 days beginning 2 days prior to onset of period

Frovatriptan 10 mg at onset of period

Frovatriptan 2.5 mg qd x 6 days beginning 2 days prior to onset of period

Tepper, SJ. Treatment of menstrual migraine: evidence-based review. Manag Care. 2007 Jul;16(7 Suppl 7):10-4; discussion 15-7.

Cady, RK, et al. Two center randomized pilot study of migraine prophylaxis comparing paradigms using pre-emptive frovatriptan or daily

topiramate: research and clinical implications. Headache. 2012; 52 (5) 749-764

53

Migraine Rescue Strategies Olanzepine 10 mg PO

Quetiapine 100 mg PO

Magnesium Sulfate 1 gram IV Push*

Occipital nerve block*

Sphenopaletine ganglion block*

- Use a “sphenocath”

- *= Office procedure by a family physician

Krusz JC. Aggressive Interventional Treatment of Intractable Headaches In The Clinic Setting.

In: Unger, J (ed). Clinics in Family Practice. Elsevier (Philadelphia). 545-567. Sept. 2005. 54

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IV Magnesium-Aborting Migraine Within 15 Seconds! NO KIDDING…

1 gram IV push over 1-2 minutes

Side effect: severe hot flash lasting < 1 minute

Eliminates migraine and migraine associated symptoms within 2-3 minutes

Works best for HA < 24 hour duration. For HA > 24 hour duration use depakon 500 mg IV push over 3-5 minutes

55

Summary Headaches evaluated within primary care are rarely due to secondary causes

Migraine diagnosed when there is presence of nausea, photophobia and/or disability

during headaches

- “Sinus headaches” and neck pain…think migraine

Avoid drugs that contain opioids and Butalbital as they cause MOH (American Academy

of Neurology)

Consider use of CGRP inhibitors for patients who have failed other preventative agents

56