UPDATE IN MIGRAINE MANAGEMENT Eric P. Baron, DO Cleveland Clinic Neurological Institute Center for Neurological Restoration Headache and Chronic Pain Medicine barone2@ccf.org @Neuralgroover
Disclosures Some medications discussed may be used off label No relevant personal disclosures
Goals and Objectives Review migraine pathophysiology Discuss selection and use of acute migraine treatments and other management Review preventive strategies and options Discuss updates in new migraine treatments
Migraine Epidemiology 18% of women, 6% of men 38 million migraineurs in the US 12% of US population 1 in 4 households have someone w/ migraine
Migraine Societal Impact 2 nd leading cause of all global disability 2 nd leading cause of all neurological disease burden 50% of all neurologic disability Costs $20 billion/year 113 million lost work days/year
Migraine Under-treatment Nearly 1/2 of all migraine sufferers never diagnosed Majority of migraineurs do not seek medical care for their pain Only 4% of migraine sufferers who seek medical care consult headache and pain specialists
Migraine Diagnostic Criteria: A) At least 5 attacks fulfilling criteria B D B) Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated) C) Headache has at least 2 of the following 4 characteristics: 1. unilateral location 2. pulsating quality 3. moderate or severe pain intensity 4. aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs) D) During headache at least 1 of the following: 1. nausea and/or vomiting 2. photophobia and phonophobia E) Not better accounted for by another ICHD-3 diagnosis
Migraine aura 25% have aura (classic migraine), 75% no aura (common migraine) 5-60 minutes in duration (up to 72 hrs for motor) Aura Types - Visual (most common) - Sensory (2 nd most common) - Speech and/or language (3 rd most common) - Motor (hemiplegic migraine) - Brainstem (previously basilar migraine) - Retinal
ID Migraine questionnaire screening tool Patient is given 3 questions - Have your headaches interfered with your ability to work, study, or do what you needed to do? - Have you felt nauseated or sick to your stomach when you have a headache? - Does light bother you when you have a headache (a lot more than when you don t have a headache)? Yes to 3 of these questions: 97% chance of migraine Yes to 2 of these questions: 93% chance of migraine Lipton RB, Dodick D, Sadovsky R et al (2003) A self-administered screener for migraine in primary care: the ID migraine validation study. Neurology 61:375 382.
Migraine is an ELECTRICAL NEUROLOGICAL event! The vascular theory of migraine is DEFUNCT!
Migraine Pathophysiology 1. Site of initiation debated: Cortical spreading depression vs. brainstem generator 2. Spreading wave of neuronal activation and hyperemia (aura) 3. Followed by spreading wave of neuronal depression and oligemia at 3 mm/minute (aura)
Migraine Pathophysiology 4. Trigeminovascular activation: release of inflammatory cytokines, neuroinflammatory peptides, and CGRP 5. Cerebral vasodilatation and neurogenic inflammation 6. Sensitized trigeminovascular pain signals travel to trigeminal ganglion (peripheral sensitization) 7. Pain signals travel from trigeminal ganglion to trigeminal nucleus caudalis thalamus cortex (central sensitization)
http://www.az-tmj.com/treatment-headaches.php
Standard of Care Goals of Acute Migraine Treatment 1. Treat attacks effectively, rapidly, consistently 2. Restore ability to function 3. Minimize need for back-up and rescue meds 4. Optimize self-care and reduce subsequent use of resources 5. Provide cost-effective management 6. Cause minimal or no adverse events
Treatment Strategy Stratified vs Step Care?
Stratified Care Treatment selection based on migraine severity and disability Supported by Class I evidence Stratified care more cost effective - May include initial use of more costly meds, but - ED/office visits + procedures Williams, et al. Pharmacoeconomics. 2001 Sculpher, et al. Pharmacoeconomics. 2002
Step Care Treatment escalated within or across attacks If simple analgesics ineffective, other combos given later in same attack or for future attacks Triptans or DHE considered after other steps have failed Step care causes a delay in necessary migraine-specific administration Long process of trial and error; many patients lapse from care untreated = unnecessary pain and impairment
Stratified Care vs Step Care across 6 attacks: Headache Resolution Attacks (%) 100 80 60 40 20 Stratified care Stepped care across attacks * 28 20 * 53 41 * 69 55 0 1 hour 2 hours 4 hours Time post-dose *p<0.001 vs stepped care across attacks Lipton RB, et al. JAMA. 2000;284(20):2599-2605. Courtesy of Dr. Stewart Tepper, MD
Delay in migraine specific meds wastes time as migraine pathways become stronger and more refractory
2015: The Acute Treatment of Migraine in Adults: The American Headache Society Evidence Assessment of Migraine Pharmacotherapies
Mild-moderate attacks: 1) NSAIDs 2) Combination analgesics Treatment Strategy: Individualize Treatment Moderate-severe attacks or poor response to NSAIDs or combo analgesics: 1) Triptans 2) Dihydroergotamine (DHE)
NSAIDs Inhibit arachidonic acid cascade and trigeminovascular inflammation Inhibit dural plasma extravasation Help prevent central sensitization Use max dose possible for most efficacy Evidence based support as a 1st line option for mild-moderate disability
Triptans Sumatriptan: PO, SC, Needle-less SC, NS, breath-powered intranasal delivery system Zolmitriptan: NS, PO, ODT Rizatriptan: PO, ODT Almotriptan: PO Eletriptan: PO Sumatriptan/Naproxen: PO Frovatriptan: PO Naratriptan: PO
Triptans Group 1: - Faster onset, higher potency, higher 24 hr recurrence -Sumatriptan -Sumatriptan/Naproxen -Zolmitriptan -Rizatriptan -Almotriptan -Eletriptan Group 2: - Slower onset, lower potency, lower 24 hr recurrence -Naratriptan -Frovatriptan Rapoport AM, Tepper SJ, et al. CNS Drugs. 2003.
Triptans 5-HT1B agonists: - Constrict pain-producing meningeal blood vessels - Also present in brainstem, significance uncertain - Intracranial arteries > periphery arteries (coronary arteries) Coronary vasoconstriction up to 10-20% may occur MaassenVanDenBrink A, et al. Circulation. 1998. MacIntyre PD, et al. Circulation. 1993
Triptans 5-HT1D agonists: - Presynaptically inhibit trigeminal peptide release - Inhibit trigeminal nucleus caudalis pain processing - Inhibit nausea/vomiting in nucleus tractus solitariuus Tepper SJ, Millson D. Expert Opin Drug Saf. 2003. Tepper SJ. Med Clin North Am. 2001.
Triptans End result: - Reversal of vasodilation - neurogenic inflammation - central pain signal transmission to thalamus, cortex - Cessation of ascending cortical pathways which lead to photo/phonophobia, N/V, central sensitization
Does it matter which triptan I pick??
Which Triptan Do I Pick? CORN
Contraindications Onset to peak pain Recurrence of migraine after treatment (within 24 hours?) Nausea and vomiting severity
Contraindications - Vascular disease (CAD, CVD, PAD) - Uncontrolled HTN - Pregnancy (Category C) - Breastfeeding (Sumatriptan ok) - Renal or hepatic failure - Sepsis - Prinz-Metal angina - Hemiplegic or basilar-type migraine
Contraindications Risk factors for arterial disease - Poorly controlled HTN, HLP, DM, smoking, premature CAD family hx (men < 55, women < 65), postmenopausal women 1 risk factor: ECG suggested in prescribing info >1 Framingham risk factor: further work-up suggested such as stress test
Onset to migraine peak pain Group 1 (quicker onset) vs. Group 2 (slower onset) - SC or NS triptan if: Patient wakes w/ migraines Peak pain within 30 minutes
Return of migraine after treatment If migraine recurrence occurs within 24 hours: - Combine triptan 1 st dose w/ NSAID (Naproxen) - Group 2 triptan (Naratriptan vs. Frovatriptan)
Nausea and vomiting severity If N/V occur early in attack or are severe: - SC or NS triptan should be used - *dissolvable tablets absorbed via GI tract, not sublingually
Triptan Pearls Sumatriptan: - Highest potency (SC) and quickest onset (SC+NS) of triptans - Greatest flexibility Rizatriptan: - Fastest onset of oral triptans - Greatest likelihood of 2h pain-free and sustained pain-free response - Propranolol increases its serum concentration so 5mg per dose if used together Rapoport AM, Tepper SJ, et al. CNS Drugs. 2003. Rapoport AM, Tepper SJ. Arch Neurol. 2001.
Zolmitriptan: - Most likely to treat persistent HA when 1st dose fails Almotriptan: - Group 1 triptan w/ least side effects Eletriptan: - Highest potential for drug interactions. Decrease dosage w/ CYP3A4 drugs macrolides, fungal, HIV, etc. Rapoport AM, Tepper SJ, et al. CNS Drugs. 2003. Rapoport AM, Tepper SJ. Arch Neurol. 2001.
Naratriptan: - The "gentle triptan", least side effects - Slower onset of action - Low 24 hr recurrence rate - Does not have monoamine oxidase metabolism, so can be given w/ MAOI (as can Eletriptan and Frovatriptan) Rapoport AM, Tepper SJ, et al. CNS Drugs. 2003. Rapoport AM, Tepper SJ. Arch Neurol. 2001.
Frovatriptan - Slower onset of action - Longest half life - Low 24 hr recurrence rate - Good choice to give night prior to expected migraine and known trigger (menstruation, travel, etc.) Rapoport AM, Tepper SJ, et al. CNS Drugs. 2003. Rapoport AM, Tepper SJ. Arch Neurol. 2001.
Triptan + NSAID Combination Increased efficacy and reduced recurrence for - Sumatriptan and Rizatriptan + NSAID - Rizatriptan + COX-2 inhibitors Krymchantowski A. Cephalalalgia 2001;21:425-426. Krymchantowski AV, Barbosa JS. Cephalalgia 2002; 22:309 312. Krymchantowski AV, Bigal ME. BMC Neurol 2004; 28; 4(1):10. Sumatriptan 85 mg/naproxen 500 mg combo pill: - Faster Sumatriptan Tmax w/ combo vs. Sumatriptan 100 mg alone (1h vs. 1.5 hrs) - Naproxen Cmax 36% lower w/ combo vs. Naproxen 550 mg alone - Naproxen Tmax 4 hrs later w/ combo vs. Naproxen 550 mg alone (5h vs. 1-2h) http://us.gsk.com/products/assets/us_treximet.pdf
The bad news on triptans 25% do not respond to triptans Only 1/3 pain-free at 2 hrs Only 25% remain pain-free
Ergots Dihydroergotamine (DHE), Ergotamine - Broader spectrum of receptors than triptans - Additional side effects possible, but additional efficacy in many triptan non-responders - Interact with adrenergic and dopaminergic receptors, 5-HT 1A, 1B, 1D, 1F, 2A, 2C, 3, 4 subtypes - Side effect profiles reflect agonist activity at: 5-HT1A receptors: nausea, dysphoria 5-HT2A and adrenergic receptors: peripheral vasoconstriction Dopamine D2 receptors: nausea, vomiting Bigal ME, Tepper SJ. Curr Pain Headache Rep. 2003 Baron EP, Tepper SJ. Headache. 2010
Dihydroergotamine (DHE) IV, SC, IM, IN formulations, (oral inhalation pending FDA approval) IV DHE is very useful to break status migrainosus No triptan use in pre or post 24 hours of DHE Contraindications same as triptans except pregnancy is Category X
IV DHE Raskins Protocol 1. IV Antiemetic +/- IV Diphenhydramine 30 mins prior to IV DHE (1 mg/1 ml) 2. 0.25 mg IV. Then, 0.25 mg q15 mins until 1 of the following: a) HA resolves b) Severe nausea or other intolerable side effects occur c) Cumulative dose of 1 mg reached 3. Repeat max tolerated dose (up to 1 mg) q8h with IV Antiemetic +/- IV Diphenhydramine 30 mins prior to IV DHE **AAN Practice Parameter Guidelines suggest IV DHE safe up to 3 mg/day and 20 mg/week (packaging says 6 mg/week)
IM / SC DHE 1 mg (1 ml) at onset of migraine Then, q1h x 2 for a max dose of 3 mg/attack Status migrainosus: Once every 8 hrs x 3-5 days or until HA free x 24 hrs IM and SC DHE are limited to 3 mg/day and 20 mg/week (packaging says 6 mg/week)
IN DHE Insert in nostril, aim away from face, don't sniff 1 spray in each nostril (0.5 mg each nostril = 1 mg total dose) In 15 minutes, repeat 1 spray in each nostril (0.5 mg each nostril = 1 mg total dose) Total treatment dose: 4 sprays = 2 mg; May repeat this cycle q8h x 72h or until HA is resolved (whichever comes first) Per packaging, max dose: 4 sprays (2mg)/attack, 6 sprays (3 mg)/day and 8 sprays (4 mg)/week. (As prior, we often use higher doses)
When to consider DHE? Long migraines including menstrually-related migraines Migraines w/ high 24 hr recurrence Waking migraines (therapeutic triptan window missed) Moderate to severe pain with central sensitization (allodynia) when triptans less effective Baron EP, Tepper SJ. Headache. 2010.
When to consider DHE? To break status migrainosis (migraine lasting > 72 hours) Repetitively for rescue Repetitively as a bridge to wean a patient out of medication overuse headache With nausea and vomiting, when a non-oral alternative is necessary Baron EP, Tepper SJ. Headache. 2010.
Butalbital Meds and Opiates/Opioids No class I studies support use of butalbital-containing meds in acute migraine treatment Butalbital meds and opiates/opioids pose a high risk of MOH (Rebound HA), dependency, best avoided - >5 days/month for butalbital - >8 days/month for opiates/opioids Limited role for opiate/opioid use in acute migraine treatment - Occasionally when abortives have failed, as rescue - When standard abortives are contraindicated
RESCUE
RESCUE AND/OR CONTRAINDICATIONS TO STANDARD MEDS Anti-emetics IV/PO - Prochlorperazine 10 mg, Metoclopramide 10 mg, Dolasetron 12.5 mg, Ondansetron 4-8 mg, Granisetron 1 mg, Promethazine 25 mg Anticonvulsants IV/PO - Valproic acid 500-1000 mg IV - Valproic acid 1000 mg PO QHS x 5 days, then 500 mg QHS x 5 days Magnesium IV - 2 g IV NSAIDS IV/PO - Ketorolac 30 mg IV; 60 mg IM - Ketorolac 10 mg PO TID until HA free x 24 hours, or have used 5 days
RESCUE AND/OR CONTRAINDICATIONS TO STANDARD MEDS Steroids IV/PO - Dexamethasone 4-10 mg IV - Dexamethasone 4 mg PO TID day 1, BID day 2, once day 3 - Prednisone 60 mg PO x 5 days, then decrease by 10 mg/day - Methylprednisolone 250-1000 mg IV Muscle Relaxers IV/PO - Methocarbamol 1-2 g IV - Chlorzoxazone 500-1000 mg PO qid x 5 days Neuroleptics/Antipsychotics PO - Olanzapine, Quetiapine, Haloperidol
MOH / Rebound Headache Causes of MOH - NSAIDS or Triptans: > 10 days/month - Opioids/Opiates: > 8 days/month - Butalbital meds > 5 days/month Weaning/detox - Headaches worsen before improving - Use bridge (prednisone, DHE, etc.) - Can take 4-8 weeks to improve AFTER wean Bigal ME, Lipton RB. Overuse of acute migraine medications and migraine chronification. Curr Pain Headache Rep. 2009 Aug;13(4):301-7.
Migraine Prevention Initiate meds w/ highest level of evidence Initiate meds w/ lowest effective dose. Increase slowly every couple weeks until: - Benefit, - Side effects, or - Ineffective trial Adequate trial mandatory - 4-6 weeks to start taking effect - 2-3 months for full effect (assuming therapeutic dose)
Migraine Prevention Avoid/eliminate interfering meds - MOH interferes with preventive med efficacy Long-acting formulations improve compliance If doing well at 6 months, consider tapering off Limit polypharmacy, take coexisting conditions into account (HTN, epilepsy, mood disorders, weight, etc.) - Treat migraine and coexistent conditions if possible
2012: American Headache Society/American Academy of Neurology Guidelines for Prevention of Episodic Migraine
Chronic Migraine Chronic migraine: - HA 15 days/month for 3 months, which, on at least 8 days/month, has migraine features Onabotulinum Toxin Type A - Only FDA-approved treatment of chronic migraine (approved for age 18)
OMT 70% of migraine attacks associated with neck pain - Trigeminocervical Nucleus OMT effective for both preventive + acute treatments directed at these regions
WHAT S NEW??
Calcitonin Gene-Related Peptide (CGRP) Antagonists Pathophysiology - CGRP released from trigeminal nerves during migraine - Blood vessel dilatation, inflammation - Cascade of pain, photo/phonophobia, nausea/vomiting 2 groups - Monoclonal antibodies - Gepants
Calcitonin Gene-Related Peptide (CGRP) Antagonists - Mabs Monoclonal Antibodies (Mabs) - Larger size, cannot cross blood-brain barrier - Cut migraine days by 50% in 50% of pts; small % eliminate migraine CGRP receptor antagonist (1) - Erenumab-aooe FDA approved 5/17/18 for migraine prevention in adults (episodic, chronic) Monthly injection, 70 mg or 140 mg
Calcitonin Gene-Related Peptide (CGRP) Antagonists - Mabs Target CGRP (3) - Fremanezumab-vfrm FDA approved 9/14/18 for migraine prevention in adults Monthly injection 225 mg, or 675 mg quarterly injections - Galcanezumab FDA approved 9/28/18 for migraine prevention in adults 240 mg loading dose x 1 in 2 consecutive 120 mg injections, followed by 120 mg monthly injection - Eptinezumab coming soon
Calcitonin Gene-Related Peptide (CGRP) Antagonists - Gepants Small Molecules (Gepants) - Smaller size, can cross blood-brain barrier - Gepants in trials (all PO) Acute/abortive: Rimegepant, Ubrogepant Preventive: Atogepant, BHV-3500 - Expected to be a safe option in vascular disease (where triptans are contraindicated)
Vagus Nerve Stimulator FDA approved 1/2018 for acute migraine tx 2 two-min stimulations 20 mins 2 two-min stimulations (if needed) 2 hours 2 two-min stimulations (if needed) Significant relief as soon as 30 mins 50% of pts had mild or no pain at 2 hrs for 50% of all HAs
To Image or Not to Image. That is the Question
Conclusions 1. Educate pts about migraine, its treatment and encourage participation in management (triggers, HA diaries to determine need for prevention, etc.). 2. Use migraine specific meds (triptans, DHE) early with moderate-severe migraine and those poorly responsive to NSAIDS or combination analgesics. 3. Tailor triptan use based on patient and migraine characteristics (CORN).
Conclusions 4. Consider a self-administered rescue med for severe migraine failing all other treatments. 5. Guard against medication-overuse headache (MOH; rebound HA). Causes of MOH: -NSAIDS or triptans: > 10 days/month -Opioids: > 8 days/month -Butalbital compounds > 5 days/month 6. Preventives should target other comorbidities, at same time of decreasing overall HA burden.