MIGRAINE IN PRIMARY CARE ADVISORS Implications of the new GP contract to headache management.
The Diagnosis and Preventive Treatment of Migraine Headache in … · 2020-05-27 · Migraine Is...
Transcript of 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
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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
io (
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Rat
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Pop
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t)
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
Photophobia, phonophobia
4–72 hours
≤48 hours
Fatigue
Difficulty concentrating
Neck discomfort
Nausea
Photophobia, phonophobia
Fatigue
Cognitive symptoms
Photophobia, phonophobia
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
Interactive Question #2
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
Becker WJ. Headache. 2017;57:1471-1481.
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
Interactive Question #3
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
American Headache Society. Headache. 2019;59:1-18.
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
Galcanezumab(EVOLVE-2)5
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
Galcanezumab(EVOLVE-1)1
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
American Headache Society. Headache. 2019;59:1-18.
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
American Headache Society. Headache. 2019;59:1-18.
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
Becker WJ. Headache. 2017;57:1471-1481.
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