Acute Treatment of Migraine. Robert Shapiro, MD, PhD

Transcription

1 Acute Treatment of Migraine Robert Shapiro, MD, PhD

2 Disclosures Since 2012: Lilly: Clinical Trial Data Monitoring Committee

3 Desired Properties of Acute Migraine Therapies Prompt freedom from headache associated symptoms disability No recurrence of symptoms No side effects No risk of medication overuse headache Convenient formulation Consistent efficacy Effective for all patients Not contraindicated for any patients

4 Principles of Acute Migraine Management Pharmacological therapies Treat aggressively stratify therapy to migraine burden Treat early during attacks Do not treat too often not more than 8 days per month Consider combining acute medication classes (e.g. triptan + NSAID) to improve pain-free response and reduce recurrence. Non-pharmacological therapies hot or cold compresses may help avoid excess sensation photophobia, phonophobia, etc. apply behavioral therapies cognitive, relaxation, biofeedback consider acupuncture

5 Acute PharmacologicTherapies for Migraine NSAIDs or aspirin (e.g. diclofenac, ibuprofen, naproxen sodium, indomethacin, cox-2 inhibitors, etc.) Dopamine antagonists (e.g. metoclopramide, prochlorperazine, chlorpromazine) 5-HT 1 agonists (specific: triptans / non-specific: ergotamines DHE nasal spray) Isometheptene / dichloralphenazone / APAP (Midrin) Caffeine combinations (e.g. APAP/ASA/caffeine, APAP/butalbital/caffeine, etc.) Opioid "rescue medications (e.g. butorphanol) FDA approved migraine therapies

6 Level A Established as Effective Triptans DHE Sumatriptan Oral 25mg, 50mg, 100mg (generic) Nasal spray 20mg Nasal applicator 22mg Needle injection 4mg, 6mg Needless injection 4mg, 6mg Iontophoretic patch Naratriptan Oral 1mg, 2.5mg (generic) Zolmitriptan Oral 2.5mg, 5mg / oral dissolving 5mg (generic) Nasal spray 2.5mg, 5mg Rizatriptan Oral 5mg, 10mg / oral dissolving 5mg, 10mg (generic) Almotriptan Oral 12.5mg (generic) Eletriptan Oral 20mg, 40mg, 80mg (generic 2016) Frovatriptan Oral 2.5mg (generic) Nasal spray 2mg

7 Level A Established as Effective NSAIDS / Acetaminophen Aspirin 500mg Diclofenac 50mg, 100mg Ibuprofen 200mg, 400mg Naproxyn 500mg, 550mg Refocoxib 25mg Acetaminophen 1gm Opioids Butorphanol nasal spray 1mg Combinations Sumatriptan 85mg / naproxyn 500mg Acetaminophen 500mg / aspirin 500mg / caffeine 130mg Codeine 25mg / acetaminophen 400mg

8 Level B Probably Effective Ergots - ergotamine 1-2mg, IV DHE 1mg NSAIDS - ketoprofen 100mg, IV ketorolac 30mg, Isometheptene 65mg, Opioids - tramadol 75mg Dopamine antagonists prochlorpramazine 10mg, droperidol, chlorpromazine, metoclopramide Magnesium IV 1-2gm Metimizole 1mg

9 Level C Possibly Effective Dexamethasone 4-16mg Valproic acid mg Butalbital 50mg / acetaminophen 650mg

10 The Limits of Acute Migraine Therapy: Treat Attacks Early, but Not Too Often Triptan efficacy is higher if delivered during the early phase of migraine before allodynia develops. Treat early. Frequent exposure to analgesics, including triptans, may transform episodic migraine to chronic daily headache in susceptible individuals. Treat no more than 8 days / month. Avoid opioids and barbiturates if possible.

11 mild pain / non-migrainous NSAIDS

12 Rational Development of Triptans: Role of Serotonin in Migraine In migraine attacks, blood levels of serotonin drop and urine levels of serotonin metabolites rise. Drugs which deplete platelet serotonin (e.g. reserpine) may trigger migraine-like attacks. Intravenous serotonin relieves migraine. Serotonin is implicated in mechanisms for many conditions co-morbid with migraine (e.g. depression, sleep, etc.). Sicuteri Headache 6:109 (1966) Anthony et al Arch Neurol 16:544 (1967) Kimball et al Neurol Minneap 10:107 (1960)

13 Serotonin Receptors and Migraine Therapies Serotonin (5HT) camp PI Na + K + camp camp camp camp Ca 2+ 5HT 1 5HT 2 5HT 3 5HT 4 5HT 5 5HT 6 5HT 7 5-HT 1A 5-HT 1B 5-HT 1D 5-HT 1E 5-HT 1F 5-HT 2A 5-HT 2B 5-HT 2C 5-HT 5A 5-HT 5B Agonists block acute migraine (e.g. triptans) Antagonists prevent migraine (e.g. methysergide) Antagonists prevent nausea (e.g. ondansetron) Adapted from: The Triptans. 2001

14 Trigeminovascular System CORTEX Neuropeptide Release PAIN THALAMUS 5-HT 1D Receptors Trigeminal Ganglion CGRP B B 5-HT 1B Receptors (on vascular smooth muscle) Vasoconstriction D VIP, NO Vasodilatation Nucleus Caudalis D 5-HT 1D Receptors Trigeminal Inhibition D Superior Salivatory Nucleus Recreated from Hargreaves et al. Can J Neurol Sci 1999;26:S12-S19.

15 Triptans Imitrex Amerge Relpax Frova Zomig Maxalt Axert Serotonin Agonists at selective serotonin receptors: 5-HT 1b, 5-HT 1d, 5-HT 1f Formulations: oral, iontophoretic, nasal, subcutaneous Response rates: ~70% pain 2hr ~30% 2 hr Contraindications: Concurrent CV risks Hemiplegic migraine? Serotonin syndrome risk

16 Triptan Considerations suma zolmi riza nara almo frova ele Renal Failure * * Hepatic Failure * * * Concomitant MAO Inhibitors * * * * Sulfonamide sensitivity * * * Menstrual Migraine * * (long half-life) Nausea & Vomiting Severe Pain and/or On Awakening * SC, IO, NS * SC * NS

17 New Sumatriptan Iontophoretic Patch Vikelis et al. Neuropsychiatr Dis Treat. 2012; 8:

18 New Sumatriptan Inhaler

19 Triptan Limitations Contraindications Ischemic or vasospastic heart disease Multiple risk factors for CAD Hemiplegic or basilar migraine Uncontrolled hypertension Use within 24 hours of ergot or another triptan Risks Pregnancy Risk: Category C Medication Overuse Headache Triptan side effect profile Serotonin Syndrome Alert AHS response: Headache 2010;50: Efficacy Therapeutic responses rarely immediate and may be inconsistent Recurrence common particularly with subcutaneous formulations ~30% of migraineurs do not respond at all Costly - in spite of availability of generic sumatriptan and naratriptan

20 Where are All the Triptan-Induced Cardiovascular Events?

21 Sumatriptan (85mg) Naproxen (500mg) Fixed Combination Khoury & Couch Drug Des Dev Ther 4:9 (2010)

22 Rizatriptan 10mg (RI) vs Dexamethasone 4mg (DE) vs Rizatriptan 10mg + Dexamethasone 4mg (RI+DE) Pain Free Bigal et al Headache 2008; 48:1286

23 Dexamethasone (10-24mg): 24 to 72 hour Headache Recurrence when added to Standard ER treatment Colman et al BMJ 2008; 336:1359

24 Butorphanol Nasal Spray Pain Free Pain Relief Hoffert et al Headache 35:65 (1995). High abuse potential Migraine transformation Unreliable formulation Prevalent side effects

25 Rebound Headache Substances which acutely relieve migraine may provoke migraine upon their withdrawal ("rebound ) opioids, barbiturates, caffeine, triptans, ergots, NSAIDs, etc. Frequent exposure may lead to INCREASED headache frequency in susceptible individuals ~4% of adults have chronic daily headache (CDH): 15 days/mon ~80% of patients with CDH have transformed migraine Transformed migraine typically begins with episodic migraine and gradually develops over months to years to chronic daily headaches.

26 Evolution of Medication Overuse Headache Tablets / day of caffeine-containing analgesics over 10 years Spierings, J Headache Pain 4:111 (2003)

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28 Single-pulse Transcranial Magnetic Stimulation Lipton et al Lancet Neurol 9:373 (2010)

29 Questions?