2020 Symposia Series 1 - Practicing Clinicians Exchange
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2020 Symposia Series 1
Embracing New Treatment Options in the Management of Migraine Headache
Learning Objectives
• Apply current diagnostic criteria for differential diagnosis of migraine to
increase early recognition and treatment
• Employ current migraine guideline recommendations and management
strategies to establish improved patient treatment plans
• Identify the appropriate use of established and emerging treatment options
for migraine and related monitoring and safety options
3
Migraine Is Common
30 US Prevalence (%)
Female
25 Female Male
Migraine Prevalence (%)
Male
20 Sex 17 6
15 Race
White 17 6
10
Black 14 4
5 Highest prevalence
Age 30 to 39 years 24 7
0
0 20 30 40 50 60 70 80 100
Age (years)
Lipton RB, et al. Headache. 2001;41:646-657; Lipton RB, et al. Neurology. 2007;68:343-349. 4
Migraine Is Debilitating
Attendance at work 8 18 47 • 2nd most disabling episodic
Family situation 4 23 38
condition after lower back pain
• Migraine is a chronic disease
Leisure time 8 14 37 with episodic manifestations
Pursuing studies 8 12 27
Sexual life 7 8 28
Social position 3 10 24
Very negative influence
Love 3 6 22 Quite negative influence
Finances 4 20 Some negative influence
6
Pursuing career 3 8 16
Finding friends 2 8
0 20 40 60 80
Percentage of Migraineurs (N = 423)
Feigin VL et al. Lancet Neurol. 2019, 18:459-480; Institute for Health Metrics and Evaluation (IHME). Findings from the Global Burden of Disease
Study 2017. Seattle, WA: IHME, 2018; Linde M, et al. Cephalalgia. 2004;24:455-465. 5
Pathophysiology of Migraine—Implications for Management
Pain perception Cortex
• Cortical spreading depolarization, altered connectivity
• Migraine aura and cognitive symptoms
Hypothalamus • Target for neuromodulation
• Activation in premonitory phase
• Premonitory symptoms Thalamus
• Target for hypothalamic • Sensitization of alteration of thalamocortical circuits
peptides and modulators • Sensory sensitivity and allodynia
• Target for neuromodulation
Upper Cervical Nerves Trigeminocervical Complex
• Pain transmission or • Pain transmission or sensitization
sensitization • Headache and neck pain
• Neck and head pain Throbbing
• Target for medications and neuromodulation
pain
• Target for local injections and
neuromodulation Release of CGRP
• Multiple potential sources or sites of action
• Headache and other symptoms
• Target for small-molecule antagonists and antibodies
Charles A. Lancet Neurol. 2018;17:174-182. 6
What Happens During a Migraine Attack?
Clinical Phases of Migraine
~4 to 72 hours
≤1 hour
Prodrome Aura (if present) Headache Postdrome
• Fatigue • Visual • Localization • Fatigue
• Food craving – Scintillating • Throbbing • GI upset
• Muscle pain scotoma • Nausea • Cognitive
• Cognitive change • Sensory • Vomiting change
• Mood change • Motor • Photophobia • Muscle pain
• Sensory disruption • Phonophobia • Mood change
Adapted from: American Migraine Foundation. americanmigrainefoundation.org/understanding-migraine/timeline-migraine-attack/.
Accessed Apr 13, 2020. 7
Case Study: Colleen, a 42-Year-Old Call Center Operator
Presenting Complaint History
• “Tension headaches” that have become • Minor headaches since she was in her teens
more frequent and debilitating in the past • No history of trauma or unusual stresses
10 years
• Bilateral tubal ligation
• Current headaches not relieved by
• Works from home most days
nonprescription NSAIDs
Physical Exam and Medications
• Recurrent insomnia, occasional
constipation • Height: 5 ft 6 in; weight: 186 lb; BMI: 30.0 kg/m2
• Hypertension controlled with amlodipine 5 mg/d
NSAID = nonsteroidal anti-inflammatory drug. 8
What to Ask About When Taking a Thorough Headache History
• Frequency and patterns
‒ Any significant changes
• Location
• Duration
• Quality and intensity
• Time to peak intensity
• Preceding symptoms (eg, how the headache begins; triggers)
• Warning symptoms and aura
• Associated symptoms and level of disability
• Aggravating or relieving factors
Weatherall MW. Ther Adv Chronic Dis. 2015;6:115-123. 9
Case Study (cont’d): Colleen’s History
• Unilateral pattern of pain, sometimes behind browbone
• Headaches often worse around menses
• Headaches 4 to 6 times a month for the last 2 years, lasting from a few
hours to up to a day
• Severity varies but is usually moderate or severe
• Interfere with work and household needs about 1 or 2 days a week
• Loud noises and bright lights make headaches worse; sometimes her
neck becomes sore
• Sometimes feels congested and has a runny nose
• Headaches often accompanied by nausea
• Neurologic exam within normal limits
10Typical Presentations of Common Forms of Headache
TENSION TYPE MIGRAINE CLUSTER “SINUS”
• Pain “like a band” • Unilateral pain • Pain in and around one • Pain behind browbone
squeezing the head • Often with nausea and eye and/or cheekbones
• Primary headache visual changes • Primary headache • Secondary headache per
per ICHD-3 • Primary headache per ICHD-3 ICHD-3
per ICHD-3 • Unless clear signs of active
infection, often is a migraine
headache
ICHD-3 = International Classification of Headache Disorders, 3rd edition.
Cady RK, Schreiber CP. Otolaryngol Clin North Am. 2004;37:267-288; Headache Classification Committee of the International Headache Society
(IHS). Cephalalgia. 2018;38:1-211; brgeneral.org www.brgeneral.org/healthy-lifestyle-blog/2018/november/4-major-types-of-headaches-and-where-
they-hurt/. Accessed Apr 22, 2020. 11Typical Presentations of Common Forms of Headache
TENSION TYPE MIGRAINE CLUSTER “SINUS”
• Pain “like a band” • Unilateral pain • Pain in and around one • Pain behind browbone
squeezing the head • Often with nausea and eye and/or cheekbones
• Primary headache visual changes • Primary headache • Secondary headache per
per ICHD-3 • Primary headache per ICHD-3 ICHD-3
per ICHD-3 • Unless clear signs of active
infection, often is a migraine
headache
ICHD-3 = International Classification of Headache Disorders, 3rd edition.
Cady RK, Schreiber CP. Otolaryngol Clin North Am. 2004;37:267-288; Headache Classification Committee of the International Headache Society
(IHS). Cephalalgia. 2018;38:1-211; brgeneral.org www.brgeneral.org/healthy-lifestyle-blog/2018/november/4-major-types-of-headaches-and-where-
they-hurt/. Accessed Apr 22, 2020. 12Migraine vs Tension-type Headache: A Common Misdiagnosis
Migraine Tension-type
≥2 of the following ≥2 of the following
• Unilateral (59% of migraines) • Bilateral
• Pulsating (85% of migraines) • Not pulsating
• Moderate to severe intensity lasting between 4 and • Mild to moderate intensity
72 hours • Not aggravated by routine physical activity
• Aggravation by routine physical activity
≥1 of the following • No nausea/vomiting
• Nausea/vomiting (73% of migraines) • One or neither: photophobia/phonophobia
• Photophobia/phonophobia (~80% of migraines)
Not attributable to another disorder Not attributable to another disorder
Headache Classification Committee of the International Headache Society (IHS). Cephalalgia. 2018;38:1-211; Lipton RB, et al. Headache.
2001;41:646-657. 13Landmark Study: How Likely Is it That an Episodic Headache
Is Migraine?
• Prospective, open-label study of patients with
episodic headache (N = 1203)
Probable
• >90% seen in primary care migraine
Episodic tension-type
• Self-report or physician diagnosis of migraine (n = 67) 18%
(n = 11) 3%
almost always correct Unclassifiable
(n = 11) 3%
• Self-report or physician diagnosis of
nonmigraine almost always later found Migraine
(n = 288) 76%
out to be migraine
Tepper SJ, et al. Headache. 2004;44:856-864. 14ID Migraine™: Simplified Diagnostic Criteria for Migraine
Symptoms in the last 3
months:
❑ Light sensitivity with
headache
❑ Nausea with headache
❑ Decreased ability to
function with headache
Any 2 of the 3 above symptoms = migraine
Lipton RB, et al. Neurology. 2003;12:375-382. 15Red Flags: SNOOP
S Systemic involvement (fever, myalgias, weight loss)
Systemic disease (cancer, AIDS)
N Neurologic symptoms or signs
O Onset sudden (thunderclap headache)
O Onset after age 50 years
Pattern of change: progressive headache/fewer headache-free periods; change in
P type of headache; headache associated with pregnancy; headache related to body
position
Be alert to signs/symptoms of secondary headache.
Dodick DW. Adv Stud Med. 2003;3:87-92; Dodick DW. N Engl J Med. 2006;354:158-165. 16Headache Impact Test (HIT)-6 and Migraine Disability Assessment (MIDAS) Test HIT-6 • Measures the impact headaches have on job, school, home and social situations • Total score ≥50 suggests significant impact MIDAS • Measures how migraines affect everyday functioning Kosinski M, et al. Qual Life Res. 2003;12:963-974. 17
Case Study (cont’d)
• Clinical findings are consistent with migraine without aura
• Colleen is surprised because she thought migraines were always
associated with an aura
• Says that she is “just happy to know what is going on”
• Headaches have a significant impact on her daily activity
18Importance of a Headache Diary
• Helps identify ‒ Records intensity of pain
– Triggers ‒ Monitors treatment progress
– Location ‒ Sometimes required for prior
– Warning signals authorization for certain
– Length medication coverage by insurers
– Stress, exercise, other related events
Time Intensity Preceding Medication Relief (complete/
Date Triggers
(start/finish) (rate 1-10: most severe being 10) Symptoms (and dosage) moderate/none)
19Common Migraine Triggers • Irregular meals, dehydration • Light, sunlight exposure • Irregular caffeine • Sensitivity to odors (osmophobia) • Chocolate, nuts, bananas, etc • Stress or “let-down” from stress • Irregular sleep (particularly • Air travel, change in barometric excessive sleep) pressure • Weather, changes in weather • Menstrual period Hoffmann J, et al. Curr Pain Headache Rep. 2013;17:370. 20
Lifestyle Modification: Consistency Is Key
Don’t skip Caffeine Six 8-oz glasses Sleep Exercise
mealsMedications That May Exacerbate Migraines • Oral contraceptives • Hormone replacement • SSRIs • Steroids (tapering) • Decongestants • Short-acting sedatives SSRI = selective serotonin reuptake inhibitor. Allais G, et al. Neurol Sci. 2009;30(suppl 1):S15-S17; MacGregor EA. Curr Pain Headache Rep. 2009;13:399-403; Nierenburg Hdel C, et al. Headache. 2015;55:1052-1071. 22
Acute Treatment Principles
• Establish what the patient’s goals are
Goal: quickly
• Treat at least two attacks with the same medication restore patient to normal
• If medication is ineffective: function in a safe and
effective manner that
⎻ Ensure that no other medications are interfering with response minimizes additional
⎻ Ensure patient is taking the drug at the correct time medication exposure and
⎻ Maximize dose resource use
⎻ Change formulation/route of administration
⎻ Change drug
⎻ Add drug
⎻ Try combination therapy (eg, sumatriptan + naproxen)
23Case Study (cont’d): Colleen’s Regimen for Acute Attacks • Colleen begins lifestyle modifications of drinking more water, reducing caffeine to
Treatment of Acute Migraine: Medications
Serotonin 5-HT1F
Triptans Ergots Nonspecific treatments Gepants Receptor Agonist
Almotriptan Dihydroergotamine Antiemetics Rimegepant Lasmiditan
Eletriptan Ergotamine + caffeine Aspirin +/‒ acetaminophen +/‒ caffeine Ubrogepant
Frovatriptan Diclofenac, ketorolac, other NSAIDs
Naratriptan Corticosteroids (IV; rescue therapy)
Rizatriptan
Sumatriptan
Sumatriptan + naproxen
Zolmitriptan
• A variety of routes of administration (oral, nasal spray, suppository, etc) and combinations are available
• Products containing butalbital are sometimes used despite evidence that butalbital is not effective for
migraine pain and can cause rebound headache
• Reserve opiates only for limited use in very severe migraine
Med Lett Drugs Ther. 2017;59:27-32. 25Lasmiditan, Rimegepant, and Ubrogepant:
New Options for Acute Migraine Treatment
Lasmiditan Rimegepant Ubrogepant
Mechanism Serotonin 5-HT1F receptor agonist CGRP receptor CGRP receptor antagonist
of Action antagonist
Indication Acute treatment of migraine with or without aura in adults
Dosing 50 mg, 100 mg, or 200 mg orally, 75 mg orally or 50 mg or 100 mg orally, as
as needed (not to exceed 1 dose sublingual, as needed needed; may take 2nd dose
in 24 hrs) (not to exceed 1 dose ≥2 hours later; not to exceed
in 24 hrs) 200 mg in 24 hrs
Adverse Dizziness, fatigue, paresthesia, Nausea Nausea and somnolence
Events sedation, driving or machinery
impairment for 8 hrs after
taking
Lasmiditan [prescribing information]. Eli Lilly and Company; 2019; Rimegepant [prescribing information]. Biohaven Pharmaceuticals, Inc; 2020;
Ubrogepant [prescribing information]. Allergan; 2019.. 26Case Study (cont’d)
• Colleen appears to be following lifestyle modifications
• You prescribe lasmiditan, 100 mg as needed
• Colleen reports success “sometimes,” but headaches worsening and still
missing work
• Review of headache diary:
‒ Headaches are more frequent than Colleen initially described, occurring
at least twice a week
‒ Headaches still cause impairment and often require bedrest
27When Should Preventive Treatment for Episodic
Migraine Be Considered/Offered?
• When patients have severe or frequent migraines: 3 or more days per month
• After failure or overuse of acute therapies
• When patients want to pursue another option
• Epidemiologic studies suggest that:
‒ ~38% of migraineurs would benefit from preventive therapy, but…
‒ Only 11% currently receive them
Lipton RB, et al. Headache. 2015;55(suppl 2):103-122; Lipton RB, et al. Neurology. 2007;68:343-349; Silberstein SD, et al. Neurology.
2012;78:1337-1345. 28Episodic vs Chronic Migraine: Definitions
Episodic migraine: Chronic migraine:
• Headache 3 months
• Features of migraine headache
present for ≥8 days/month
Lipton RB, et al. Headache. 2015;55(suppl 2):103-122. 29Principles of Preventive Pharmacotherapy
• Establish what the patient’s goals are
Goal: reduce
• Give each treatment an adequate trial
frequency, duration,
• Continue for at least several months and severity of
• Avoid interfering, overused, and contraindicated drugs individual events and
possibly reduce disease
• Re-evaluate therapy progression
• Women of childbearing potential should understand risks
• Involve patients in their care to maximize adherence
• Consider comorbidities and choose medications to treat coexisting disorders when
possible
• Choose drugs based on efficacy, patient preferences, headache profile, adverse effects
D’Amico D, et al. Neuropsychiatr Dis Treat. 2008;4:1155-1167. 30AAN/AHS Classification of Preventive Therapies for Episodic Migraine
Level A: Medications With Level B: Medications That Are Level C: Medications That Are
Established Efficacy Probably Effective Possibly Effective
(≥2 class I studies) (1 class I or 2 class II studies) (1 class II study) Considerations
Antiepileptic drugs Antidepressants/SSRI/SSNRI/TCA ACE inhibitors • Check for teratogenicity
Divalproex sodium Amitriptyline Lisinopril
Valproate sodium Venlafaxine
• Topiramate for patients
Angiotensin receptor blockers with obesity?
Topiramate
Candesartan
• β-blocker for hypertensive
-Blockers -Agonists
nonsmokers ≤60 years of
-Blockers Atenolol Clonidine
Metoprololl Nadolol Guanfacine age?
Propranolol Triptans (MRM) • Triptan for MRM?
Timolol Naratriptan* Antiepileptic drugs • Amitriptyline for patients
Triptans (MRM) Zolmitriptan* Carbamazepine with insomnia, mood
Frovatriptan*
-Blockers disorder, or depression?
Nebivolol, pindolol
• Anti-CGRP monoclonal
Antihistamines antibodies now also an
Cyproheptadine
option
Yellow = FDA approved for migraine prophylaxis.
*For short-term prophylaxis of MRM.
AAN/AHS = American Academy of Neurology/American Headache Society; ACE = angiotensin-converting enzyme; MRM = menstrual-related migraine;
SSNRI = selective serotonin norepinephrine reuptake inhibitor; TCA = tricyclic antidepressant.
Silberstein SD, et al. Neurology. 2012;78:1337-1345. 31FDA-Approved Preventive Therapies for Chronic Migraine • Anti-CGRP monoclonal antibodies* ‒ Eptinezumab ‒ Erenumab ‒ Fremanezumab ‒ Galcanezumab • OnabotulinumtoxinA *Also FDA approved for prevention of episodic migraine. Med Lett Drugs Ther. 2017;59:27-32. 32
Other Interventions for Prevention
Behavioral Interventions Neuromodulation Other
• Relaxation training • Single pulse transcranial • Acupuncture
• Biofeedback combined with magnetic stimulation • Physical therapy with
relaxation training (sTMS) massage and exercise
• Electromyography • Noninvasive vagal nerve • Nutritional supplements
biofeedback stimulation (nVNS) – Magnesium, riboflavin,
• Cognitive behavioral therapy • External trigeminal nerve CoQ10
stimulation (eTNS)
• Combination treatment
Silberstein SD et al. Neurology Sep 2000, 55 (6) 754-762; American Migraine Foundation. americanmigrainefoundation.org/understanding-
migraine/spotlight-neuromodulation-devices-headache/. Accessed Apr 13, 2020; Gaul et al. J Headache Pain. 2015;16:516. 33Collaborative Care of Migraine
• Migraine is a chronic disease and requires patients and clinicians to work
together toward common therapeutic goals
• Help patients understand and address all migraine-related health issues
and comorbidities
• Integrate assessment tools and relevant patient education into
management
• Recognize “stages” in the evolution of migraine so as to personalize care
on the basis of disease progression
34Case Study (cont’d)
• Colleen is prescribed topiramate 25 mg once a day, then over
1 month gradually increased to 50 mg twice a day
• She continues to follow lifestyle modifications
• Review of headache diary after 1 month:
‒ Headaches continue to occur at least twice a week
‒ Headaches still cause impairment and often require bedrest
• Switched from amlodipine to propranolol 40 mg twice a day, gradually
increased to 60 mg twice a day
• Cognitive behavioral therapy prescribed
35CGRP-Targeted Therapies Were Specifically Designed for the
Trigeminal Pain System and Headache
CGRP Release During Migraine • Landmark 1990 study showed that
Inhibited by Sumatriptan CGRP—a potent vasoactive
100
peptide—is released during
migraine headache
Concentration of CGRP (pmol/L)
80
• In 1993-1994, sumatriptan was
60 Control Attack shown to inhibit CGRP release at
the same time that it aborts a
40
headache attack
20
• Led to development of drugs
specifically designed to block the
0
actions of CGRP
With Aura Without Aura With Sumatriptan
Control refers to headache-free period, while attack refers to headache period.
Edvinsson L, et al. Nat Rev Neurol. 2018;14:338-350; Goadsby PJ, et al. Ann Neurol. 1990;28:183-187; Goadsby PJ, et al. Ann Neurol. 1993;33:48-56. 36Newer Therapies for Headache Disorders: Different Targets of Action Onabot-A = onabotulinumtoxinA. Edvinsson L, et al. Nat Rev Neurol. 2018;14:338-350. 37
Newer FDA-Approved Therapies for Headache Disorders:
Monoclonal Antibodies
Drug Indication(s) Dosing Examples of Common Adverse Events
Eptinezumab EM, CM IV, quarterly URI, nasopharyngitis, fatigue, diarrhea,
oropharyngeal pain
Erenumab EM, CM SC, monthly Injection site reactions, constipation
Fremanezumab* EM, CM SC, monthly Injection site reactions
or quarterly
Galcanezumab* EM, CM SC, monthly Injection site reactions
*Has also been studied for cluster headache.
CM = chronic migraine; EM = episodic migraine; SC = subcutaneous; URI = upper respiratory infection; UTI = urinary tract infection.
ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT03855137. Accessed Apr 13, 2020; ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT02605174.
Accessed Apr 13, 2020; ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT03732638. Accessed Apr 13, 2020; Edvinsson L, et al. Nat Rev Neurol.
2018;14:338-350. 38Newer Therapies for Headache Disorders:
Other Agents Approved and in Development
Drug Indication(s) Dosing Examples of Common Adverse Events Status
Serotonin 5-HT1F Receptor Agonist
Lasmiditan Migraine relief Oral, PRN Dizziness, paresthesia, somnolence FDA approved
CGRP Receptor Antagonists
Oral, once or
Atogepant EM, CM Nausea, fatigue, constipation, nasopharyngitis, UTI Phase 3
twice daily
FDA approved
Migraine for relief
Rimegepant Oral, PRN Nausea, dizziness, UTI
relief, EM, CM Phase 3 EM,
CM
Ubrogepant Migraine relief Oral, PRN Nausea, dizziness FDA approved
ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT03855137. Accessed Apr 13, 2020; ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT02605174.
Accessed Apr 13, 2020; ClinicalTrials.gov. clinicaltrials.gov/ct2/show/NCT03732638. Accessed Apr 13, 2020; Edvinsson L, et al. Nat Rev Neurol.
2018;14:338-350. 39CGRP/CGRP-R mAbs: Phase 3 Trials
Reduction in Monthly Migraine Headache Days
Eptinezumab: EM Eptinezumab: CM Erenumab: EM Erenumab: CM Fremanezumab: EM Fremanezumab: CM Galcanezumab: EM Galcanezumab: CM
0
-1
-1.8
-2 -2.2
-2.5 -2.7
-2.8
-3 -3.2
-3.7 -3.7
-4 -4.3 -4.2
-4.6 -4.7 -4.8
-5 -5.6
-6 -6.6
-7
-8 -8.2
-9
Most effective dose Placebo
All statistically significant
Holland C et al, Neurology. 2018;91:e2211-e2221; Stauffer VL. JAMA Neurol. 2018;75:1080-1088; Dodick DW et al, JAMA 2018;319:5-14;
VanderPluym J et al. Neurology. 2018;91:e1152-e1165; Goadsby PJ et al, N Engl J Med. 2017;377:2123-2132; Lipton et al. Neurology. 2019;92:
e2250-e2260; Ashina M et al. Cephalalgia. 2020;40: 241-254; Silberstein SD, et al. N Engl J Med. 2017;377:2113-2122; Stauffer VL et al, JAMA
Neurol. 2018;75:1080-1088; Sklijarveski V et al, Cephalagia 2018;38:1442-1454. 40Case Conclusion
• Colleen is prescribed fremanezumab, a CGRP-targeted monoclonal
antibody for prevention of her episodic migraine because she prefers
quarterly SC injection regimen
• At 6 months, she reports that her headaches occur no more than once or
twice a month; when they do occur, she uses lasmiditan
• She hasn’t missed a day of work in several months
• You recommend that she continue keeping her headache diary and taking
preventive therapy
41PCE Action Plan
✓ Consider migraine as the default diagnosis for recurring and disruptive headache
✓ Emphasize the importance of keeping a headache diary to identify triggers and the nature of
headache and to assess treatment progress
✓ Provide patient education and encourage use of nonpharmacologic interventions for
treatment/prevention
✓ Treat at least 2 acute migraines with same medication; consider alternatives if medication
remains ineffective
✓ When starting preventive pharmacotherapy, consider comorbidities and respect patient
preferences
✓ Participate in a collaborative care model of migraine treatment to improve communication and
involve patients in decision-making
PCE Promotes Practice Change
422020 Symposia Series 1
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