10/19/12. Headache: Tips and Tools for Management. Michael A. Rogawski, MD, PhD Disclosures

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1 10/19/12 Headache: Tips and Tools for Management Michael A. Rogawski, MD, PhD University of California, Davis Sacramento, CA Michael A. Rogawski, MD, PhD Disclosures Grants: Congressionally Directed Medical Research Programs; National Institute of Neurological Disorders and Stroke Research Support: Eisai Inc.; Gilead Sciences, Inc. Consultant: Eli Lilly and Company; ONO Pharma USA, Inc.; Sepracor, Inc.; SK Life Science, Inc.; Upsher-Smith Laboratories, Inc. 1

2 10/19/12 Learning Objective Implement evidencebased clinical strategies that promote early detection and treatment for common headache disorders Migraine A Primary Headache No other causative disorder Headache Red Flags S-N-O-O-P-S Systemic symptoms (fever, weight loss) Neurologic symptoms or abnormal signs (confusion, impaired alertness or consciousness) Onset: sudden, abrupt or split second Older: new onset or progressive headache, especially in patients > 50 years old (giant cell arteritis) Previous headache history: first headache or new or different headache (change in attack frequency, severity or clinical features) Secondary risk factors (HIV, systemic cancer) Dodick DW. Adv Stud Med. 2003;3(2): Dodick. AdvPhysicians Stud Med. 2003;3(2): Davies MB. J RDW Coll Edinb. 2006;36:

3 Migraine or Other Type of Headache? Many patients diagnosed with other types of headaches actually meet the International Headache Society (IHS) criteria for migraine 80% of sinus headache 85% of tension/stress headache Schreiber CP, et al. Arch Intern Med. 2004;164(16): PMID: Kaniecki R, et al. Curr Med Res Opin. 2006;22(8): PMID: Medications and Drugs That Can Cause Headache Hydralazine, isosorbide dinitrate, nitroglycerin Nifedipine Enalapril Ranitidine, famotidine, cimetidine Sildenafil Trimethoprim-sulfa Tetracyclines Estrogen, progesterone Tamoxifen Theophylline Pseudoephedrine Amphetamines Cocaine Bupropion Toth C. Clin Neuropharmacol. 2003;26(3): PMID: Treatment of Migraine Acute (Abortive) Preventive (Prophylactic) 3

4 Triptan Formulations Long half-life ; Gladstein J. Top Pain Manage. 2007;22: Contraindications and Precautions for Triptans Contraindications Ischemic cardiac disease Cerebrovascular disease Uncontrolled hypertension Use within 24 hours of other triptans or ergots Hemiplegic/basilar migraine Acephalgic migraine Precautions History of risk factors for coronary artery disease Selective serotonin reuptake inhibitor use? Risk of serious cardiac event ~1:1,000,000 Jamieson DG. Am J Med. 2002;112(2): PMID: Johnston MM, et al. Drugs. 2010;70(12): PMID: Common Triptan Side Effects a Sedation Nausea Muscle ache Chest tightness a Occur in 2%-5% of patients Johnston MM, et al. Drugs. 2010;70(12): PMID: Jamieson DG. Am J Med. 2002;112(2): PMID:

5 Triptan Combination Approaches Sumatriptan (85 mg) + naproxen sodium (500 mg) marketed Combinations with caffeine or acetaminophen under investigation Blumenfeld A, et al. Headache. 2012;52(4): PMID: Non-Oral Alternatives Safe effective alternatives to oral medications; nausea, vomiting and gastric stasis may limit the absorption of oral medications Nasal sprays Dihydroergotamine (DHE) Sumatriptan Zolmitriptan Injections Dihydroergotamine Sumatriptan Needle-Free subcutaneous delivery Sumatriptan Rapoport AM. Neurol Sci. 2008;29(Suppl 1):S PMID: When to Use Prophylactic Therapy Frequent headaches (3-4 episodes/month) with risk of medication overuse Frequent headaches interfere with quality of life Acute medications contraindicated, ineffective, or overused or intolerable adverse events (AEs) occur Hemiplegic migraine or complicated migraine with risk of permanent injury Patient preference Rapoport AM. Neurol Sci. 2008;29(Suppl 1):S PMID:

6 Food & Drug Administration (FDA) Approved for Migraine: Prophylactic Drugs Methysergide 1962 Propranolol 1979 Timolol 1990 Divalproex sodium 1996 Divalproex sodium ER 2000 Topiramate 2004 OnabotulinumtoxinA 2010 ER = extended release Rapoport AM. Neurol Sci 2008;29(Suppl 1):S PMID: Other Prophylactic Agents* Antidepressants (norepinephrine transporter inhibitors) Amitriptyline, nortriptyline, doxepin Antidepressants (monoamine oxidase inhibitors) Phenelzine β-blockers Atenolol, nadolol, metoprolol Angiotensin-converting enzyme inhibitors/angiotensin II receptor antagonists Captopril, lisinopril, candesartan Calcium channel blockers Verapamil Feverfew *Denotes an indication that is not approved by the FDA and is off-label for use in migraine Rapoport AM. Neurol Sci 2008;29(Suppl 1):S PMID: D'Andrea G, et al. Neurol Sci. 2011;32(Suppl 1):S PMID: Anecdotal Migraine Treatments* Used by Migraine Specialists Metoclopramide* (25 50 mg PO, 5 10 mg IV) Methylprednisolone* PO or IV Dexamethasone* PO Zonisamide* Ketorolac* (60 mg IV or nasal spray) Tizanidine* (4 mg start; 8-12 mg) Memantine* *Denotes an indication that is not approved by the FDA and is off-label for use in migraine mg = milligrams; PO = by mouth; IV = intravenously administered Ashkenazi A, et al. Cephalalgia. 2006;26(10): PMID Bigal M, et al. Headache. 2008;48(9): PMID: Coppola M, et al. Ann Emerg Med. 1995;26(5): PMID: D'Andrea G, et al. Neurol Sci. 2011;32(Suppl 1):S PMID: Krymchantowski AV, et al. Arq Neuropsiquiatr. 2001;59(3-B): PMID: Meredith JT, et al. Am J Emerg Med. 2003;21(3): PMID: Rozen TD, et al. Curr Treat Options Neurol. 2002;4(5): PMID: Saper JR, et al. Headache. 2002;42(6): PMID:

7 On the Horizon... Inhaled DHE Calcitonin gene-related peptide antagonist Inontophoretic sumatriptan patch Nasal powder delivery system of sumatriptan Rapoport AM Neuro Sci. 2012;33(Suppl 1)S119-S125. DOI s Rapoport AM. Neurol Sci. 2008;29(Suppl 1):S PMID: Treating Acephalgic Migraine Auras without Headache Visual aura, nausea, photophobia, hemiparesis Generally does not require treatment Inhaled isoproterenol* (β-agonist) may shorten aura Sublingual nitroglycerin* (if need to terminate symptoms rapidly) Rapid-acting non-steroidal anti-inflammatory drugs (NSAID): meclofenamate* or naproxen* can be used Lamotrigine* Do not use triptans *Denotes an indication that is not approved by the FDA and is off-label for use in migraine Kunkel RS. Cleve Clin J Med. 2005;72(6): PMID: Hormones and Migraine Falling estrogen or estrogen withdrawal can trigger migraine Migraine often improves during pregnancy (estradiol rising or high); worsen postpartum Migraine may worsen with aging (estradiol low) Simona S, et al. J Headache Pain. 2012;13(3): PMCID: MacGregor EA. Curr Pain Headache Rep. 2009;13(5): PMID:

8 Menstrual Migraine Of premenopausal women Short-term prophylactic treatment with migraine, 50% - 67% Naproxen sodium, 550 mg BID, consistently have attacks 6 d before to 7 d after menses during perimenstrual period Triptans 4-5 days during the Description perimenstrual period Migraine without aura Frovatriptan*, 2.5 QD or BID Naratriptan*, 1 mg BID More severe, disabling and refractory to abortive Zolmitriptan*, 2.5 mgs BID medications as compared and 2.5 mgs TID with migraine not related Magnesium: 360 mg/day, 3-4 to menstruation days before menses Diamox: 250 mg BID, 3-4 days before menses * Off label use as prophylactic tx BID = twice a day; QD = every day; TID = three times a day Simona S, et al. J Headache Pain. 2012; 13(3): PMCID: MacGregor EA. Curr Pain Headache Rep. 2009;13(5): PMID: Menstrual Migraine Hormones Estradiol patches and gels; 100 µg transdermal estradiol patches Long-duration oral contraceptives Avoid hormone-free interval 24/4 Extended cycle 84 days Continuous 365 d/y Bridge hormone-free interval with transdermal estradiol Calhoun AH. Headache. 2012;52(Suppl 1):8-11. PMID: Menopause Migraine may flare at menopause (may last 4 years) Thirty percent of peri-menopausal women experience migraine Postmenopausal hormone-replacement therapy (low-dose estrogen) May be used but risk of stroke must be considered Is relatively contraindicated in women with migraine with aura Simona S, et al. J Headache Pain. 2012; 13(3): PMCID: MacGregor EA. Curr Pain Headache Rep. 2009;13(5): PMID:

9 Indomethacin-Responsive Headache Syndromes Trigeminal-autonomic cephalgias Paroxysmal hemicranias Chronic paroxysmal hemicrania Episodic paroxysmal hemicrania Hemicrania continua Valsalva-induced headaches Primary cough headache Primary exertional headache Primary headache associated with sexual activity (pre-orgasmic and orgasmic) Primary stabbing headache (jabs and jolts syndrome) Hypnic headache Dodick DW. Curr Pain Headache Rep. 2004;8(1): Ergotamines Ergotamine tartrate not used because of side effects (overuse and rare ergotism) DHE Causes venoconstriction > vasoconstriction, so safer Modes of administration Intravenous for intractable headache Nasal spray Inhaled in late-stage development Rapoport AM. Headache. 2012;52(4): PMID: Dahlof C, et al. Headache. 2012;52(4): PMID: Intravenous DHE Very severe migraine, status migrainosis, medication overuse Should not be used within 24 h of triptans Metoclopramide* (5 or 10 mg IV push) or 25 or 50 mg PO for nausea Start with 0.5 mg; can repeat to maximum of 3 mg/24 h Use lower doses > age 50 Use caution in hypertension; do not use in patients with peripheral vascular disease or heart disease *Off label use Rapoport AM. Headache. 2012;52(4): PMID: Dahlof C, et al. Headache. 2012;52(4): PMID:

10 Treatment in Children and Adolescents Migraine is common in pediatric populations There is a lack of controlled trials Sleep may be an excellent treatment option Simple analgesics may be tried next Sumatriptan nasal spray (20 mg) efficacious and tolerable* Almotriptan (12.5 mg) is only triptan approved in the United States for adolescents (age 12 17) O'Brien HL, et al. Expert Opin Pharmacother. 2012;13(7): PMID: Medication-Overuse Headache (MOH) (IHS-2) Headache present on 15 days/month Regular overuse for 3 months of one or more drugs that can be taken for acute and/or symptomatic treatment of headache Headache has developed or markedly worsened during medication overuse Headache resolves or reverts to its previous pattern within 2 months after discontinuation of overused medication International Headache Society (IHS). IHS Classification ICHS-II All drugs used acutely can cause MOH Triptans (most common cause in U.S.) Opioids (particularly short acting) Butalbital-containing compounds Caffeine-containing compounds Ergotamine derivative Acetaminophen, aspirin, NSAID Isometheptene/acetaminophen/ dichloralphenazone (1:2 mixture of antipyrine with chloral hydrate) Obermann M, et al. Expert Rev Neurother. 2007;7(9): PMID:

11 Withdrawal Treatment for MOH Objectives Detoxify and stop the chronic headache Improve responsiveness to acute or prophylactic drugs Abrupt withdrawal leads to quickest resolution (usually 2 10 days) Taper opioids and barbiturates to reduce withdrawal symptoms (worsening headache, nausea, vomiting, hypotension, tachycardia, sleep disturbances, restlessness, anxiety) Start prophylactic drugs Obermann M, et al. Expert Rev Neurother. 2007;7(9): PMID: Treatment of Cluster Headache Acute treatment: oxygen and sumatriptan Long-term prophylaxis: verapamil (first-line), lithium, methysergide, melatonin, topiramate, gabapentin Short-term prevention (episodic cluster): prednisolone, methysergide, verapamil, greater occipital nerve injection, daily nocturnal ergotamine Avoid possible triggers (smoking, alcohol), especially during cluster period Tfelt-Hansen PC, et al. CNS Drugs. 2012;26(7): PMID: Sumatriptan for Treatment of Cluster Headache Significant response observed at 10 and 15 min vs. placebo Tfelt-Hansen PC, et al. CNS Drugs. 2012;26(7): PMID:

12 10/19/12 Co-sponsored by Save the Date! 6th Annual Chair Summit September 26-28, 2013 Westin Tampa Harbour Island Tampa, Florida 12