the diagnosis and preventive treatment of migraine headache in … · 2020-05-27 · migraine is...

The Diagnosis and Preventive Treatment of Migraine Headache

in Family Medicine

Prevalence of Migraine Headache

3rd

AMPP=American Migraine Prevalence and Prevention.1. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Lancet. 2016;388:1545-1602; 2. Buse DC et al. Headache. 2012;52:1456-1470; 3. Adams AM et al. Cephalalgia. 2015;35:563-578.

AMPP Study2

11.8

17.2

5.7

0

5

10

15

20

Overall Female Male

Pre

vale

nce

(%

)

• Overall, 8%–9% of people with migraine have chronic migraine (≥15 headache days/month for ≥3 months)2,3

Global Burden of Disease Study1

Most prevalent illness worldwide

Prevalence Among US Survey Respondents ≥12 Years of Age (N=162,756)

≈1 billion people

Migraine Is the Most Common Primary Headache Disorder Seen in Primary Care

Tepper SJ et al. Headache. 2004;44:856-864.

Multisite, prospective Landmark Study of adults consulting their physician (93% primary care) with episodic headache

• IHS diagnosis based on diary review (n=377)

94%

3%

3%

Migraine or Probable Migraine Tension-Type Unclassifiable

More Than a Headache — Migraine-Related Disability

• Worldwide, migraine is the second leading cause of years lived with disability2

*Defined as MIDAS (Migraine Disability Assessment questionnaire) Grade III/IV.CaMEO=Chronic Migraine Epidemiology and Outcomes.1. Lipton RB et al. Headache. 2016;56:1280-1289; 2. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Lancet. 2017;39:1211-1259.

Moderate to Severe Disability* in AMPP and CaMEOLongitudinal Cohort Studies1

23.031.8

66.978.9

26.7

37.9

71.082.6

0102030405060708090

100

Men Women Men Women

Episodic Migraine Chronic Migraine

Pro

po

rtio

n o

f R

esp

on

den

ts (

%)

AMPP CaMEO

“So Many Migraines, So Few Specialists…”

• Geographical analysis of United Council for Neurologic Subspecialties (UCNS) Certified Headache Specialists relative to expected episodic and chronic migraine populations (US Census data)

Mauser ED, Rosen NL. Headache. 2014;54:1347-1357.

0

20,000

40,000

60,000

80,000

100,000

120,000

Northeast Midwest South West

0

20,000

40,000

60,000

80,000

100,000

120,000

140,000

160,000

180,000Ratios by US Census Regions Ratios by US Census DivisionsExpected

Migraine Population per Headache Specialist

Expected Chronic Migraine Population per Headache Specialist

Rat

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Pop

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Migraine: A Sensitive Brain That Doesn’t Like Change

Charles A. Lancet Neurol. 2018;17:174-182; Akerman S et al. Pharmacol Ther. 2017;172:151-170.

Environment

• Barometric pressure

• Stress

Metabolism

• Diet

• Neuroendocrine function

Drugs

• Exacerbating medications

HyperexcitabilityHypersensitivity

Comorbid conditions

• Depression, anxiety, insomnia, chronic pain syndromes, structural heart defects (patent foramen ovale)

Hormones

• Menstrual cycle

• Pregnancy

Genes

• >38 migraine-associated gene polymorphisms

1. Charles A. N Engl J Med. 2017;377:553-561; 2. Charles A. Lancet Neurol. 2018;17:174-182; 3. No authors listed. Cephalalgia. 2018;38:1-211; 4. Giffin NJ et al. Neurology. 2016;87:1-5; 5. Houtveen JH, Sorbi MJ. PLoS One. 2013;8:e72827; 6. Vuralli D et al. J Headache Pain. 2018;19:109; 7. Ashkenazi A et al. Cephalalgia. 2009;29:1042-1048.

Migraine: Multiphasic Attacks With Diverse Clinical Symptomatology

Prodrome1-3 Aura1-3 Migraine (Ictal)1-3 Postdrome1,4 Interictal5-7

Fatigue

Food cravings

Nausea

Difficulty concentrating

Neck discomfort

Photophobia, phonophobia

Yawning

Pallor

≤48 hours

Visual changes

Numbness/tingling

Language dysfunction

Cognitive dysfunction

Dizziness, vertigo

5–60 min

Moderate-to-severe pain

Nausea/vomiting

Cutaneous allodynia

Cranial autonomic symptoms

Neck discomfort


4–72 hours

≤48 hours

Fatigue

Difficulty concentrating

Neck discomfort

Nausea


Fatigue

Cognitive symptoms


Pathophysiology of Migraine

K+= potassium; TG=trigeminal ganglion.Maniyar FH et al. Brain. 2014;137:232; Dodick DW. Headache. 2018;58(suppl 1):4-16.

Prodromal/Premonitory Phase

Aura

Headache

Hypothalamus

K+

K+

Cortical spreading depression (CSD)

Trigeminal ganglion

(TG)

Trigeminocervical complex (TCC)

Hypothalamus

Thalamus

CortexDura

Hyperemia and increased neuronal depolarization

Oligemia and decreased neuronal polarization

Trigeminovascular Pain Pathways in Migraine

Silberstein SD. Clin Pharmacol Ther. 2013;93:78-85; Goadsby PJ et al. Physiol Rev. 2017;97:553-562.

• Migraine involves altered modulation of normal sensory stimuli, activation of the trigeminovascular system, and dysfunction in multiple brain networks including pain modulation and affective regions

• Intracranial blood vessels and meninges

• Intracranial trigeminal peripheral terminals

• Brainstem trigeminal connections in the trigeminal nucleus caudalis (part of the TCC) and to the cranial parasympathetic pathways

• Local and descending pain modulation

Components

Hypothalamus

Thalamus

Cortex

TGTCC

Assessment, Diagnosis, and Classification of Migraine

Interactive Question #1

How would you rate your knowledge of criteria and strategies for diagnosing migraine headache?

A. Very low

B. Fair, but I need to learn more

C. Sufficient, but I could learn more

D. I think I know all I need to know

Patient Case Presentation: Jill

• 32-year-old woman with a 10-year history of recurrent headache, occurring approximately twice per month, and lasting about 12 hours

• Headache: • Pain is generalized, bilateral, and involves cervical and trapezius muscles • Quality: squeezing, band-like• Intensity: usually moderate without treatment or with delayed treatment • Associated features: yawning and tiredness (30 min before headache), nasal stuffiness,

blurred vision, fatigue, anxiety, nausea, and worsening with bending or walking • No photophobia or phonophobia

• Examination: • BMI 29; vitals, general physical and neurological examinations are normal


Which of the following is the most likely diagnosis? A. Migraine with aura

B. Migraine without aura

C. Tension-type headache

D. Chronic migraine

E. Idiopathic intracranial hypertension (pseudotumor cerebri)

F. Sinus headache

G. Cluster headache

First Things First — Primary or Secondary Headache Disorder?

Primary – determined by the nervous system someone is born with or acquires (eg, trauma) and the individual’s current environment

• Migraine• Tension-type• Trigeminal autonomic cephalalgias (eg, cluster headache)• Other

Secondary – caused by something else• Infection• Mass• Vascular• Trauma

No authors listed. Cephalalgia. 2018;38:1-211.

Diagnosis of Migraine — ICHD-3 Criteria

ICHD=International Classification of Headache Disorders.No authors listed. Cephalalgia. 2018;38:1-211.

Migraine Without AuraA: at least 5 attacks with the following:

B. Duration of headache

• 4–72 hours

AND

C. ≥2 characteristic headache features

• Unilateral location• Pulsating quality• Moderate or severe pain intensity• Aggravated by or causing avoidance of

routine physical activity

AND

D. ≥1 associated symptom during headache

• Nausea and/or vomiting• Photophobia and phonophobia

Symptoms must not be better accounted for by another ICHD-3 diagnosis

Migraine With AuraA: at least 2 attacks with the following:

B. ≥1 fully reversible aura symptom(s)

• Visual• Sensory• Speech and/or language• Motor • Brainstem • Retinal

AND

C. ≥3 characteristic features of aura symptoms

• ≥1 symptom spreads gradually over ≥5 min• ≥2 symptoms in succession• Each symptom lasts 5–60 min• ≥1 symptom is unilateral• ≥1 symptom is positive• Headache during or within 60 min

Cluster Headache

• Diagnostic delays are common

• 42% of patients in the US Cluster Headache Survey waited ≥5 years for correct diagnosis

No authors listed. Cephalalgia. 2018;38:1-211; Rozen TD, Fishman RS. Headache. 2012;52:99-113.

• Severe unilateral pain (orbital, supraorbital, and/or temporal)

• Lasts 15–180 minutes

• Attacks occur every other day to 8 times/day

• Typically ≥1 ipsilateral cranial autonomic symptoms (conjunctival injection, lacrimation, nasal congestion/discharge, sweating, miosis, or ptosis)

• Restlessness and agitation

• Required for diagnosis if autonomic symptoms are absent

Cluster Headache — Treatment

• Mainly off-label

• Acute/abortive treatment• Options include subcutaneous or intranasal triptans, high-flow oxygen,

dihydroergotamine, external vagus nerve stimulation

• Prophylactic treatment• Options include suboccipital steroid injections, verapamil, and most recently

galcanezumab (anti-calcitonin gene-related peptide [CGRP] monoclonal antibody therapy)

Doesborg P, Haan J. F1000Res. 2018;7:339; Goadsby PJ. Neurol Clin Pract. 2019;9:233-240; Robbins MS et al. Headache. 2016;56:1093-1106.

Ruling Out Secondary Headache — SNOOP4

Dodick DW. Semin Neurol. 2010;30:74-81; Lee VME et al. Singapore Med J. 2018;59:399-406.

S ystemic symptoms and signs

Neurologic symptoms or signs

Onset sudden

Older age at onset (>50 years)

Pattern change or progression

Precipitated by Valsalva maneuver

Positional aggravation

Papilledema

Indications for Imaging in Headache — ACR Guidelines

*Additional imaging may be recommended based on initial findings.ACR=American College of Radiology; CT=computed tomography; MRI=magnetic resonance imaging; SAH=subarachnoid hemorrhage; IIH=idiopathic intracranial hypertension. Douglas AC et al. J Am Coll Radiol. 2014;11:657-667.

Clinical Features/Red Flags Suspected Condition Recommended Imaging*

Associated with trauma Bleed CT head without contrast

New feature or neurologic deficitNeoplasm, vascular malformation, aneurysm

MRI brain

Thunderclap (sudden onset; severe) Bleed (esp SAH)CT head without contrast; MRI brain, MRA head and neck, MR venogram head (if CT negative)

Sudden unilateral, and/or pain radiating to the neck

Vascular (eg, arterial dissection)

CTA head and neck; MRA head and neck

Pain due to trigeminal autonomic cephalgia

Neoplasm MRI brain with/without gadolinium

Persistent or positional pain CSF leak/IIH MRI brain with/without gadolinium

Immunocompromised state Infection; malignancy MRI brain with/without gadolinium

Temporal pain in older individuals Giant cell arteritis MRI brain

Migraine Screening Tools and Diagnostic Aids

PPV=positive predictive value.Lipton RB et al. Neurology. 2003;61:375-382; Lipton RB et al. Headache. 2004;44:387-398; Detsky ME et al. JAMA. 2006;296:1274-1283; Ebell MH. Am Fam Physician. 2006;74:2087-2088.

Screening ID Migraine™ (PIN) Diagnosis P.O.U.N.D.

1. Does light bother you when you have a headache? (Photophobia)

2. Has a headache limited your activities for a day or more in the last three months? (Impairment)

3. Are you Nauseated or sick to your stomach when you have a headache?

Positive result: ≥2 “yes” responsesPPV: 93%

Pulsatile quality

Duration 4–72 hOurs

Unilateral location

Nausea or vomiting

Disabling intensity

Number of Features Probability of Migraine

1–2 17%3 64%

4–5 92%

Headache Diaries

• Days with headache

• Some measure of intensity• A scale based on functional level may be easiest

• Acute medication use and response

• Suspected potential triggers

Becker WJ. Headache. 2017;57:1471-1481.

1 Pain but activities possible

2 Activities are slowed

3 Activities are not possible

4 Patient is bedridden

Example

Chronic Migraine — ICHD-3 Criteria

No authors listed. Cephalalgia. 2018;38:1-211.

Headache on ≥15 days/month for >3 months with the following:

≥5 attacks fulfilling criteria B and C for migraine with aura and/or criteria B–D for migraine without aura

AND

On ≥8 days/month for >3 months fulfilling any of the following:

• Criteria B and C for migraine with aura• Criteria C and D for migraine without aura• Believed by the patient to be migraine at onset and relieved by

a triptan or ergot derivative

Symptoms must not be better accounted for by another ICHD-3 diagnosis

B. ≥1 fully reversible aura symptom(s)C. ≥3 characteristic features of aura symptoms

B. Duration of headache 4–72 hoursC. ≥2 characteristic headache featuresD. ≥1 associated symptom during headache

Migraine Frequency Continuum

23.7

41.4

14.7

8.9

4.11.6 1.9 1.4 0.6 0.7 1.0

0

10

20

30

40

50

0–1 2–3 4–6 7–9 10–11 12–14 15–18 19–21 22–24 25–27 28–31

Blumenfeld AM et al. Cephalalgia. 2011;31:301-315; Bigal ME et al. Headache. 2008;48:1157-1168; Lipton RB. Neurology. 2009;72(5 Suppl):S3-S7; Manack A et al. Neurology. 2011;76:711-718.

Pati

ents

(%

)

Headache Days per Month

2.5% progress per year

26% revert / 2 years

Modifiable• Attack frequency• Obesity• Snoring• Stressful life events• Acute medication overuse

(especially barbiturates and opiates)

• Caffeine overuse• Inadequate acute treatment

Not Readily Modifiable

• Age (younger)

• Female gender

• Low education or socioeconomic status

• Genetic factors

• Head injury

Risk Factors for Migraine Progression

Ashina S et al. Curr Treat Options Neurol. 2008;10:36-43; Bigal ME et al. Headache. 2008;48:1157-1168; Lipton RB et al. Neurology. 2015;84:688-695; Scher AI et al. Pain. 2003;106:81-89.

Management of Migraine

Individualized Migraine Treatment Plans

Becker WJ. Headache. 2017;57:1471-1481; Silberstein SD et al. Neurology. 2012;78:1337-1345.

Treatment of comorbidities(eg, anxiety and depression)

Management of triggers and exacerbating lifestyle factors

RescuePreventive/ Prophylactic

Acute

Behavioral and Lifestyle Factors for Successful Migraine Management

• Self-monitor to identify influencing factors

• Pace activities to avoid triggering or exacerbating headache

• Manage triggers effectively

• Practice stress management techniques (eg, build/increase/cultivate resilience)

• Maintain consistent and healthy diet

• Reduce or eliminate caffeine intake

• Exercise regularly at level that is tolerated

• Maintain adequate sleep and healthy sleep hygiene


Acute Pharmacologic Treatment

• Triptans; selective serotonin 5-HT1B/1D agonists (oral, SC, intranasal)

• NSAIDs (oral or IM)

• NSAID-triptan combinations

• Dihydroergotamine (SC, IM, intranasal)

• Analgesics• Acetaminophen is usually less effective• Opioids have a very limited role; use with caution

• Lasmiditan; selective serotonin 5-HT1F agonist

• CGRP-receptor antagonists (“gepants”)• Ubrogepant; rimegepant

Becker WJ. Headache. 2017;57:1471-1481; Pringsheim T et al. Headache. 2016;56:1194-1200; NeurologyLive. https://www.neurologylive.com/clinical-focus/lasmiditan-approved-for-migraine-treatment-in-adults. Accessed May 15, 2020; https://www.neurologylive.com/clinical-focus/ubrogepant-approved-for-acute-migraine-in-adults; Accessed May 15, 2020; https://www.neurologylive.com/clinical-focus/rimegepant-fdaapproved-for-acute-migraine-treatment. Accessed May 15, 2020; Dodick DW. Lancet. 2018;391:1315-1330.

Antiemetics as needed

• Medication selected based on attack severity and patient-specific clinical features

Stratified Care

Medication Overuse Headache — ICHD-3 Criteria

American Headache Society. Headache. 2019;59:1-18; No authors listed. Cephalalgia. 2018;38:1-211.

Headache on ≥15 days/month in a patient with a preexisting headache disorder

AND

Regular overuse for >3 months of 1 or more drugs that can be taken for acute and/or symptomatic treatment of headache

• ≥10 days/month for ergot derivatives, triptans, opioids, combination analgesics, or a combination of drugs from different classes that are not individually overused

• ≥15 days/month for nonopioid analgesics, acetaminophen, and NSAIDs

AND

Not better accounted for by another diagnosis

Commentary on Medication Overuse Headache (MOH)

• Evidence of cause and effect is weak• Especially weak for simple analgesics (eg, aspirin, ibuprofen)

• Medication withdrawal or limitation may benefit some patients• Withdrawal studies have been mostly uncontrolled with high dropout rates

• Ethics of withholding symptom-relieving medication?

Scher AI et al. Neurology. 2017;89:1296-1304.

“An entrenched idea in need of scrutiny”

“The concept of MOH should be viewed with more skepticism. Until the evidence is better, we should avoid dogmatism about the use of symptomatic medication. Frequent use of symptom-

relieving headache medications should be viewed more neutrally, as an indicator of poorly controlled headaches, and not invariably a cause.”

Safety of Triptans in Acute Migraine Treatment

Dodick D et al. Headache. 2004;44:414-425.

• Evaluation of data from placebo-controlled clinical trials, long-term, open-label studies, and postmarketing surveillance

Summary of evidence• Modestly elevated incidence of chest tightness, heaviness, pain, or pressure (ie, triptan sensations) relative to

placebo in well-controlled clinical trials that excluded patients with significant cardiac risk factors or known ischemic heart disease

• Symptoms are generally transient, mild, and nonserious

Conclusions• Determinants of cardiovascular AEs are poorly defined; several nonischemic mechanisms have been proposed• Among patients without known or suspected CAD, the safety profile of triptans is well defined and appears to

reflect a very low risk of serious cardiovascular AEs

Triptan Cardiovascular Safety Expert Panel Consensus Statement

In patients at low CAD risk, triptans can be prescribed confidently without prior cardiac status evaluation


How would you describe your level of experience/comfort using preventive migraine treatments?

A. Very low; I don’t prescribe them, nor do I have many patients in my practice who use preventive therapy

B. Low; I don’t prescribe them, but I have some patients in my practice who are prescribed preventive therapy by a specialist

C. Fair; I have prescribed them, but typically in consultation with a specialist

D. I am comfortable prescribing them and only refer to a specialist in certain cases

Jill: 1-Year Follow-Up• Diagnosed with migraine without aura

• Prescribed sumatriptan 100 mg plus naproxen 550 mg for treatment of acute migraine attack

• Initially experienced headache relief within 90 minutes, with minimal transient side effects of facial flushing and paresthesias of her hands

• However, over the past 8 months, the headache frequency has increased from 2 attacks per month, to 2 attacks per week

• Also, headache relief now takes up to 3 hours, the headache usually returns within 6 hours, and a second dose of medication is required

• No change in diet or sleep patterns

• Blood tests (CBC, serum chemistry, sTSH) are normal

• She has been under some stress at work because her productivity has declined, especially on days when she is experiencing headache

• Missed 2 days of work in the past 2 months

Migraine Preventive Therapy

Preventive treatment can be…• Preemptive

• Before a known trigger (eg, exercise)

• Short-term • Before a time-limited exposure (eg, ascent to high altitude or menstruation)

• Maintenance• When ongoing treatment is needed

Silberstein SD. Continuum (Minneap Minn). 2015;21:973-989.

Goals of Preventive Migraine Therapy

Reduce attack frequency by ≥50%

Reduce attack severity and duration

Improve responsiveness to and reduce reliance on acute therapy

Improve function and decrease disability

Prevent or reverse progression

Improve health-related quality of life, reduce headache-related distress and psychological symptoms

Silberstein SD et al. Neurology. 2000;55:754-762; Silberstein SD. Continuum (Minneap Minn). 2015;21:973-989; American Headache Society. Headache. 2019;59:1-18; Becker WJ. Headache. 2017;57:1471-1481.

• Although monotherapy is preferred, polytherapy may be necessary in some cases• Prevention should not be limited to pharmacologic interventions

Potential Indications for Migraine Prevention

• Significant interference with quality of life and daily routine despite trigger management, appropriate acute medication use, and lifestyle modification

• Frequent headaches (≥4 per month or ≥8 days per month)

• Contraindication to, failure of, overuse of, or troublesome side effects from acute medications

• Presence of certain migraine conditions (eg, hemiplegic migraine)

• Patient preference (desire to have as few attacks as possible)

Silberstein SD. Continuum (Minneap Minn). 2015;21:973-989; Becker WJ. Headache. 2017;57:1471-1481.

“By definition, essentially all patients with chronic migraine merit serious consideration for pharmacological prophylaxis.”

Should Offer

• ≥6 headache days/month

• ≥4 headache days with some impairment

• ≥3 headache days with severe impairment or bed rest

Should Consider

• 4 or 5 migraine days/month with normal functioning

• 3 migraine days with some impairment

• 2 migraine days with severe impairment

American Migraine Prevalence and Prevention (AMPP) Study Guidelines

Lipton RB et al. Neurology. 2007;68:343-349.

Not Indicated: • <4 headache days/month with no impairment

• ≤1 headache day/month regardless of impairment

Traditional Oral Preventive Therapies Available in US

Includes some therapies that may be used off label; prescribing information for each drug should be consulted for approved uses.Silberstein SD et al. Neurology. 2012;78:1337-1345; American Headache Society. Headache. 2019;59:1-18.

Established Efficacy

Antiepileptic drugs

Divalproex sodiumValproate sodiumTopiramate

Beta-blockers

MetoprololPropranololTimolol

Triptans

Frovatriptan (short-term for menstrual migraine)

Probably Effective

Antidepressants

AmitriptylineVenlafaxine

Beta-blockers

AtenololNadolol

Possibly Effective

Antiepileptic drugs

Carbamazepine

Beta-blockers

NebivololPindolol

Alpha-agonists

ClonidineGuanfacine

Antihistamines

Cyproheptadine

Angiotensin receptor blockers

Candesartan

Level A recommendation;Should be offered

Level B recommendation;Should be considered

Level C recommendation;May be considered

Level U recommendation;Not supported or refuted

Efficacy Uncertain

Antiepileptic drugsGabapentin

Beta-blockers

Bisoprolol

Antidepressants

Fluoxetine; fluvoxamineProtriptyline

Calcium-channel blockers

Nicardipine; nifedipine; nimodipine; verapamil

Antithrombotics (eg, coumadin)

AcetazolamideCyclandelate

OnabotulinumtoxinA (onaBoNT-A) for Migraine Prevention

• Mechanisms that may mediate its prophylactic effects• Block peripheral and central sensitization

• Relax head and neck muscles

Sprenger T et al. Neurotherapeutics. 2018;15:313-323; Simpson DM et al. Neurology. 2016;86:1818-1826.

Summary of AAN Practice Guideline

• Established as safe and effective for reducing the number of headache days in chronic migraine and probably effective for improving health-related QOL

• Should be offered as a treatment option to patients with chronic migraine to increase the number of headache-free days (Level A) and should be considered to reduce headache impact on health-related quality of life (Level B)

• Insufficient evidence to compare the effectiveness of onaBoNT-A with that of oral prophylactic topiramate • 1 study demonstrated similar efficacy

Patient Preferences for Migraine Preventive Therapy

2

2

3

3

6

12

72

0 10 20 30 40 50 60 70 80

Dosing Frequency

Type of Treatment

Out-of-Pocket Expense

Formulation

Absence of Side Effects

Speed of Onset

Efficacy

Most Important Aspect of Therapy

Patients (%)

Peres MF et al. Headache. 2007;47:540-545.

Adherence Rates to Oral Preventive Therapy in Patients With Chronic Migraine

29 29 28 2926 27

24 2619 21 20 20

16 18 17 17

0

10

20

30

40

50

60

70

80

90

100

MPR= Medication Possession Ratio; PDC= Proportion of Days Covered.Hepp Z et al. Cephalalgia. 2015;35:478-488.

Pro

po

rtio

n o

f Pa

tien

ts A

dh

eren

t (%

)

PDC

MPR

Antidepressants (n=3951)

Antihypertensives(n=1263)

Anticonvulsants(n=3474)

Total(n=8688)

6 Months 12 Months 6 Months 12 Months 6 Months 12 Months 6 Months 12 Months

Principles for Using Traditional Oral Preventive Therapies

• Use evidence-based treatments

• Start low and titrate

• Reach a therapeutic dose

• Give an adequate trial • ≥8 weeks; cumulative benefit may occur over 6–12 months

• Establish realistic expectations

• Maximize adherence

American Headache Society. Headache. 2019;59:1-18.

Optimizing Selection of Preventive Therapy


Concomitant medications

Factors to

consider

Comorbid & coexistent illnesses

Body habitus

Tolerability

Headache subtype

Patient preferences

Pregnancy potential

Clinician experience

Efficacy

Physiologic factors

Jill: 3 Months Later

• Started on preventive treatment with amitriptyline

• However, the dose could not be increased past 50 mg because of morning fatigue, dry mouth, and a 3-lb weight gain within a 6-week period

• Then tried topiramate, but experienced side effects of word-finding difficulty, paresthesias, and “mental clouding”

• There was a 30% reduction in attacks over the course of the month, but the dose could not be increased beyond 50 mg because of persistent side effects

Advances in Migraine Preventive Therapy

Calcitonin Gene-Related Peptide (CGRP)

• Neuropeptide expressed in trigeminal ganglion neurons and areas of the brain involved in pain modulation

• Physiological roles include sensory transmission and blood vessel dilation

• Blood levels are elevated during a migraine attack (and during cluster headache attack) • Concentration normalizes with triptan therapy

• Infusion of CGRP triggers delayed migraine in people with migraine

Sprenger T et al. Neurotherapeutics. 2018;15:313-323; Silberstein SD. Clin Pharmacol Ther. 2013;93:78-85; Charles A. Lancet Neurol. 2018;17:174-182.

CGRP and Other Vasoactive Neuropeptides as Therapeutic Targets

Silberstein SD. Clin Pharmacol Ther. 2013;93:78-85.

Trigeminal nerve ending

Dural blood vessel or 2nd order neuron

Substance PCGRP

GlutamateTriptans

Antibodies to CGRP

Antibodies to CGRP receptor and CGRP-receptor antagonists (gepants)

Antibody Therapies Targeting CGRP or Its Receptor for Migraine Prevention

Generic NameBrand Name

Type of mAb Target

Dose and Frequency Route; Device

FDA-Approved Indication(s)

Erenumab Aimovig® Human CGRP receptor

70 mg or 140 mg monthly

SC; autoinjector

Preventive treatment of migraine in adults

Fremanezumab Ajovy® Humanized CGRP 225 mg monthly or

675 mg quarterly

SC; prefilled syringe

Preventive treatment of migraine in adults

Galcanezumab Emgality® Humanized CGRP 240 mg first dose, then 120 mg

monthly

SC; prefilled syringe

Preventive treatment of migraine and

treatment of episodic cluster headache in

adults

Eptinezumab Vyepti™ Humanized CGRP 100 mg or 300 mg quarterly

IV Preventive treatment of migraine in adults

mAb=monoclonal antibody.Dodick DW. Cephalalgia. 2019;39:445-458; Tepper DE. Headache. 2019;59:477-480; FDA. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed May 15, 2020.

Anti-CGRP/CGRP-R mAbs in Episodic Migraine: ≥50% Responder RatesPa

tien

ts W

ith

≥5

0%

R

edu

ctio

n in

MM

D, %

4043

48

6259

50

30

5044

6157 56

27 28

3936 37

0

10

20

30

40

50

60

70

Erenumab(STRIVE)2

Fremanezumab(HALO-EM)3

Galcanezumab(EVOLVE-1)4

Eptinezumab(PROMISE-1)6

70 mg Monthly

PBO PBO PBO

MDD=monthly migraine days; PBO=placebo.1. Dodick DW et al. Cephalalgia. 2018;38:1026-1037; 2. Goadsby PJ et al. N Engl J Med. 2017;377:2123-2132; 3. Dodick DW et al. JAMA. 2018;319:1999-2008; 4. Stauffer VL et al. JAMA Neurol. 2018;75:1080-1088; 5. Skljarevski V et al. Cephalalgia. 2018;38:1442-1454; 6. Ashina M et al. Cephalalgia. 2020;40:241-254.

140 mg 225 mg Monthly

675 mg x1

120 mg 240 mg PBO100 mg x1

300 mg x1


PBO120 mg 240 mgMonthly

70 mg PBOMonthlyMonthly

Erenumab(ARISE)1

Anti-CGRP/CGRP-R mAbs in Chronic Migraine: ≥50% Responder Rates

40 41

28

55

4138

28

57

2318

15

41

0

10

20

30

40

50

60

Fremanezumab(HALO-CM)2

Galcanezumab(REGAIN)3

Eptinezumab(Phase 2b)4

PBO

1. Tepper S et al. Lancet Neurol. 2017;16:425-434; 2. Silberstein SD et al. N Engl J Med. 2017;377:2113-2122;3. Detke HC et al. Neurology. 2018;91:e2211-e2221; 4. Dodick DW et al. Cephalalgia. 2019;39:1075-1085.

140 mg 225 mg Monthly

675 mg x1

PBO100 mg x1

300 mg x1

PBO120 mg 240 mgMonthly

70 mg PBOMonthly

Erenumab(Phase 2)1

Pati

ents

Wit

h ≥

50

%

Red

uct

ion

in M

MD

, %

≥75% Responder Rates With Anti-CGRP mAbs in Episodic MigrainePa

tien

ts W

ith

≥7

5%

R

edu

ctio

n in

MM

D, %

39

34 34

22

39

3431 30

19 18

11

16

0

5

10

15

20

25

30

35

40

45

PBOPBO 225 mg Monthly

675 mg x1

120 mg 240 mg PBO100 mg x1

300 mg x1

PBO120 mg 240 mgMonthlyMonthly

Fremanezumab(Phase 2b)3


Eptinezumab(PROMISE-1)4

Galcanezmab(EVOLVE-2)2

1. Stauffer VL et al. JAMA Neurol. 2018;75:1080-1088; 2. Skljarevski V et al. Cephalalgia. 2018;38:1442-1454; 3. Bigal ME et al. Lancet Neurol. 2015;14:1081-1090; 4. Ashina M et al. Cephalalgia. 2020;40:241-254.

P=NS

P<0.001P=0.0008

P=0.0001P<0.001

P<0.001

P<0.001

P<0.001

Safety and Tolerability of Anti-CGRP/CGRP-R mAbs: Meta-Analysis of Randomized Controlled Trials

Glacanezumab (4 studies)

23/1260 14/11401.55

(0.80, 2. 99)

mAb Experimental Events/Total

Placebo Events/Total

Risk Ratio (95% CI)

Eptinezumab(1 study)

2/81 1/822.02

(0.19, 21.89)

Erenumab(3 studies)

19/1235 12/7610.94

(0.45, 1.94)

Fremanezumab(2 study)

10/773 7/3970.72

(0.29, 1.82)

Total 54/3349 32/23801.13

(0.74, 1.72)

Favors placebo Favors experimental0.01 0.1 1 10 100

Serious Adverse Events

32/1259 19/11411.62

(0.93, 2.82)

Experimental Events/Total

Placebo Events/Total

Risk Ratio (95% CI)

0/81 0/82Not

estimable

25/1229 11/7611.28

(0.65, 2.54)

15/772 7/3981.07

(0.45, 2.53)

72/3341 37/23821.39

(0.95, 2.04)

Favors placebo Favors experimental0.01 0.1 1 10 100

Withdrawal Due to Adverse Events

Xu D et al. Cephalalgia. 2019;39:1164-1179.

Drug Notable Side Effects/Cautions

ErenumabConstipation (October 2019 warning of serious complications); hypertension (April 2020 warning); latex allergy; injection site reactions; upper respiratory symptoms

Fremanezumab Injection site reactions; upper respiratory symptoms

Galcanezumab Injection site reactions; upper respiratory symptoms

Eptinezumab Nasopharyngitis; hypersensitivity

Side Effects and Cautions With Anti-CGRP/CGRP-R mAbs

• Data on long-term safety are limited • Over 3 years of exposure in a 5-year open-label extension study of erenumab, rates and types of

adverse events were consistent with those reported in shorter-term randomized controlled trials• No cases of discontinuation due to constipation

TEAE=treatment emergent adverse event.Tepper DE. Headache. 2019;59:477-480; Dodick DW et al. Cephalalgia. 2019;39:1075-1085; FDA. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed May 15, 2020; Ashina M et al. Cephalalgia. 2019;39:1455-1464; Ashina M et al. Presented at the 61st American Headache Society Annual Meeting; July 11-14, 2019; Philadelphia, PA; IOR10.

All USPIs include warnings and contraindications about

hypersensitivity reactions

Benefit-Risk Assessment of Prophylactic Therapies

Erenumab70 mg

Erenumab140 mg

Topiramate 100 mg

onaBoNT-AErenumab

70 mgErenumab

140 mgTopiramate

100 mgPropranolol

160 mgData set 1 Data set 2

NNT≥50% RR (95% CI)

7 (5, 13)

6(4, 12)

13(NE, NE)

4(3, 10)

9(6, 15)

6(5, 10)

6 (4, 9)

5(4, 6)

5 (4, 10)

NNH % D/C due to AEs (95% CI)

1000 (NE, NE)

250 (NE, NE)

21 (NE, NE)

13(NE, NE)

39 (23, 100)

1000(NE, NE)

1000(NE, NE)

8(6, 13)

11(6, 72)

LHH NNH/NNT (95% CI)

143 (14, 289)

42(5, 302)

2(0, 113)

3(1, 365)

4(2, 11)

167 (7, 269)

167(9, 299)

2 (1, 3)

2(1, 15)

NNT=number needed to treat; RR=responder rate; NNH=number needed to harm; AE=adverse event; D/C=discontinuation; LHH=likelihood of being helped or harmed (>1.0 more likely to help than harm); NE=not estimable.Vo P et al. Cephalalgia. 2019;39:608-616.

Chronic Migraine Episodic Migraine

All prophylactic treatments evaluated were more likely to help than harmMagnitude of likelihood varied

Advantages of Anti-CGRP/CGRP-R Antibodies for Migraine Prevention

Dodick DW. Cephalalgia. 2019;39:445-458.

Attribute Anti-CGRP/CGRP-R Antibodies Current Oral Therapies

Specificity for target High Low

Dose titration required No Yes

Frequency of intake Monthly/quarterly Daily

Onset of action Rapid; <1 week Slow; weeks to months

Side effects

Effect on weightEffect on moodDrowsiness/fatigue/sedationCognitive impairmentDizzinessTeratogenicity

–––––?

++++++

Adherence + –

Key Factors When Considering Use of Anti-CGRP/CGRP-R Antibodies

• No contraindications (except hypersensitivity to the actual mAb)

• Potential for rapid onset of effect and cumulative response over time

• Effective in patients with acute medication overuse and in those who failed multiple preventive medications

• May be useful in patients with • Polypharmacy (lack of drug-drug interactions)• Comorbid or coexistent disorders (eg, obesity and related disorders, renal/hepatic impairment)

• No effect on combined hormonal contraception pill (erenumab)

• Long-term (3+ years) safety in published open-label trial appears favorable

Dodick DW. Cephalalgia. 2019;39:445-458; Xu Y et al. CNS Drugs. 2019;33:513-522.

• Precaution: Hypersensitivity reactions, anaphylaxis

• Constipation with serious complications (erenumab)

• New or worsening of pre-existing hypertension (erenumab)

• No safety data in women who are pregnant or breastfeeding

Who Should Avoid Anti-CGRP/CGRP-R Antibody Therapy?

Avoid in patients with… Rationale

Infrequent headaches that respond to abortive treatment

These patients are not candidates for prophylaxis, and it is safer to treat headaches individually

Existing pregnancy or likelihood of becoming pregnant

Levels of CGRP are lower in women with preeclampsia than normal pregnancy

Loder EW, Burch RC. JAMA Neurol. 2018;75:1039-1040.

AHS Recommendations for Evidence of Treatment Benefits


Evidence of Treatment Benefits

A reduction in MMD of

≥50%compared withbaseline

A clinically meaningful improvement in a validated migraine-specific patient-reported outcome measurement that measures functional disability

Validated Patient-Reported Outcome Tools for Assessing Functional Disability

HIT-6=Headache Impact Test; MFIQ=Migraine Functional Impact Questionnaire; MIDAS=Migraine Disability Assessment Scale; PRO=patient-reported outcome.1. Kawata AK et al. Headache. 2019;59:1253-1269; 2. Hareendran A et al. Headache. 2018;58:1612-1628; 3. Stewart WF et al. Pain. 2000;88:41-52; 4. Yang M et al. Cephalalgia. 2011;31:357-367.

Social and emotional wellbeing

Physical functioning and everyday

activities

MFIQ1,2

Migraine-induced disability

Absenteeism/presenteeism

MIDAS3

Daily activities: work, home, and social situations

HIT-64

Examples of PRO tools that can be used to assess functional disability in migraine:

Optimizing Preventive Therapy


Suboptimal Response

Change dose?Switch to alternative

treatment?Add another

preventive treatment?

Discontinuation of Preventive Therapy

Preventive therapy should be stopped when:

• The patient develops intolerable side effects or a severe drug reaction

• The drug does not demonstrate even partial efficacy after 2 months of therapy and disorders such as acute medication overuse have been eliminated

• The patient has shown significant benefit (ie, headaches are well controlled for at least 6 months) • Withdrawal should begin with a slow taper

• Should be a shared decision between patient and clinician

• Premature discontinuation can lead to exacerbation and it may be difficult to regain control even after restarting a treatment that was once effective

Silberstein SD. Continuum (Minneap Minn). 2015;21:973-989; American Headache Society. Headache. 2019;59:1-18.

Referral to a Headache Specialist

• Prompt referral is indicated for patients with:• New daily persistent headaches

• Migraine that appears atypical or refractory to initial therapy• Timing of referral depends on the expertise and comfort of the clinician in headache management

and the patient’s response to initial therapy

• Most patients with chronic migraine would likely benefit from a comprehensive migraine treatment program


Clinical Headache Rescue

• Time to present = 104 hours (range 8–240 hours)

DHE= dihydroergotamine; VAS=visual analog scale.McAllister PJ et al. Headache. 2008;48(Suppl 1):S1-S72. Abstract F56.

AHS Poster: Associated Neurologists of Southern CT• Drop-in headache clinic • 500 patients seen between 9/05 and 8/07

8.5

1.5

0

2

4

6

8

10

Entry Discharge

VA

S Sc

ore

Headache PainTreatment

4

8

21

52

78

84

94

0 20 40 60 80 100

Magnesium IV

DHE

Metoclopromide

Prochlorperazine

Sumatriptan SC

Ketoralac

IVF

Patients (%)

423 visits

$33.6K (mean $80 per visit)

73 27

147.9K(mean $2027 per visit)

45.3K(mean $1690 per visit)

79% reported no functional disability at 24 hours

Clinical Headache Rescue: UAB Experience

UAB=University of Alabama.Morey V, Rothrock JF. Headache. 2008;48:939-943.

• 200 patients randomized to optimal self-administered therapy or optimal self-administered therapy + optional in-clinic headache rescue

Optimal Self-Administered Therapy

Clinic Rescue

ED visits

ED direct cost

Clinical Headache Rescue: UAB Experience (cont)

Morey V, Rothrock JF. Headache. 2008;48:939-943.

DrugNumber of Uses Drug Cost (US $)/Use

Droperidol 2.75 mg 218 3.00

Diphenhydramine 50 mg 201 1.25

DHE 1 mg 167 42

Prochlorperazine 5–10 mg 141 11.50

Promethazine 50 mg 68 4.00

Ketoralac 30 mg 38 9.00 + 11.00 (saline)

89% very satisfied

Summary and Conclusions

• Migraine is a common primary headache disorder that can be associated with substantial functional disability, especially in its chronic or high frequency episodic form

• Diagnosis is clinical, based on the presence of characteristic features and the exclusion of other conditions

• Migraine pain involves activation of the trigeminovascular system, which conveys nociceptive information from the meninges to central areas of the brain and cortex• Neuropeptides, such as CGRP, and other mediators of this pathway represent important therapeutic targets

• When indicated, preventive migraine treatment should be aimed at reducing headache frequency (by ≥50%) and severity, reducing reliance on acute therapy, and improving function and quality of life

• Effective management of migraine often requires a combination of nonpharmacologic and pharmacologic interventions

• Collaboration between primary care and specialist clinicians is essential for optimizing treatment

the diagnosis and preventive treatment of migraine headache in … · 2020-05-27 · migraine is...

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