This activity is supported by an educational grant from Lilly. For further information concerning Lilly grant funding, visit www.lillygrantoffice.com.

The following industry-supported symposium is held in conjunction with the Diamond Headache Clinic Research & Educational Foundation Meeting.

Friday, July 13Disney’s Grand Floridian Resort & Spa

Lake Buena Vista, Florida

ADDITIONAL RESOURCES

DecodingComplexitiesStrategies in Diagnosis and Treatment of Migraine

2018

2

TABLE OF CONTENTS

Outcome Questions ...............................................................................................................................................3-4

Key References From the Presentation..............................................................................................................5-6

Key References From Infographics ..........................................................................................................................7

3

OUTCOME QUESTIONS

1. What percent of people with migraine, globally, have 4 or more migraine days per month? a. ~5-15%b. ~20-35%─correct answerc. ~50-65%d. ~70-85%

Additional information from presentation: The majority of the migraineurs (62.7%) had 1 to 4 headache days per month.

2. Which side effects are most likely to cause nonadherence to preventive treatment? a. Weight loss, jitteriness, anxietyb. Headache, nausea, yawningc. Sleepiness, tearing, hair loss d. Weight gain, memory loss, depression─correct answer

Additional information from presentation: 203 prophylactic-naive patients with migraine/chronic migraine were asked, “How much would you accept or reject the following side effects to get rid of your migraine headaches?” The side effects listed were dry mouth, epigastric burning, low energy, tingling, somnolence, depression, tremor, insomnia, memory loss, sluggishness, weight gain, and weight loss. The most rejected possible side effects were weight gain, memory loss, and depression. Weight loss was better accepted by patients with a higher body mass. In general, there was a higher acceptance of side effects for patients taking more than 10 symptomatic medications a month, especially for loss of energy and somnolence. Older patients lacked an acceptance of tremor.

3. Which of the following devices for delivering medication are FDA-approved and available in the US?a. Orally inhaled dihydroergotamine, iontophoretic patch sumatriptanb. Orally inhaled zolmitriptan, liquid nasal sumatriptanc. Adhesive Dermally Applied Microarray (ADAM) zolmitriptan, sumatriptan 3 mg autoinjectord. Breath-powered dry nasal powder sumatriptan, single-use prefilled 6 mg sumatriptan

autoinjectors─correct answer

Additional information from presentation: Breath-powered dry nasal powder sumatriptan and single-use prefilled 6 mg sumatriptan autoinjectors are currently FDA-approved and available in the United States. Other available FDA-approved devices are liquid nasal sumatriptan and the sumatriptan 3 mg autoinjector.

4

OUTCOME QUESTIONS (cont.)

4. Which is the only human monoclonal antibody against the calcitonin gene-related peptide (CGRP) receptor?a. Galcanezumabb. Fremanezumabc. Erenumab─correct answerd. Eptinezumabe. Ubrogepantf. Rimegepant

Additional information from presentation: Galcanezumab, fremanezumab, and eptinezumab are humanized MABs against the ligand CGRP. Ubrogepant and rimegepant are small-molecule CGRP receptor antagonists.

5. Which noninvasive neuromodulation devices are both FDA-approved?a. Remote nonpainful stimulation skin patch, combined occipital and supraorbital stimulationb. Sphenopalatine ganglion stimulation, single-pulse transcranial magnetic stimulationc. Noninvasive vagal nerve stimulation, transcutaneous supraorbital neurostimulation─

correct answerd. Caloric vestibular stimulation, occipital nerve stimulation

Additional information from presentation: The FDA approved noninvasive vagal nerve stimulation in April 2017 as a nonsignificant-risk device for acute treatment of episodic cluster headache attacks. It was approved in January 2018 for acute migraine treatment. Transcutaneous supraorbital neurostimulation was FDA-approved in 2017 for preventive and acute treatment of migraine as a nonsignificant-risk device.

5

MIGRAINE DIAGNOSIS AND TREATMENT (DIAMOND) SLIDES: REFERENCES IN ORDER OF APPEARANCE(All Hyperlinks Correct and Active)

1. Blumenfeld AM, Varon SF, Wilcox TK, et al. Disability, HRQoL and resource use among chronic and episodic migraineurs: results from the International Burden of Migraine Study (IBMS). Cephalalgia. 2011;31(3):301-315.

2. Hepp Z, Dodick DW, Varon SF, Gillard P, Hansen RN, Devine EB. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015;35(6):478-488.

3. GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388(10053):1545-1602.

4. Lipton RB, Bigal ME, Diamond M, et al; AMPP Advisory Group. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5):343-349.

5. Russo AF. Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev Pharmacol Toxicol. 2015;55:533-552.

6. Silberstein SD. Preventive migraine treatment. Continuum (Minneap Minn). 2015;21(4 Headache):973-989.7. Headache Classification Committee of the International Headache Society (IHS). The International Classification of

Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33(9):629-808.8. Bigal ME, Lipton RB. Concepts and mechanisms of migraine chronification. Headache. 2008;48(1):7-15.9. Manack A, Buse DC, Serrano D, Turkel CC, Lipton RB. Rates, predictors, and consequences of remission from chronic

migraine to episodic migraine. Neurology. 2011;76(8):711-718.10. Buse DC, Loder EW, Gorman JA, et al. Sex differences in the prevalence, symptoms, and associated features of

migraine, probable migraine and other severe headache: results of the American Migraine Prevalence and Prevention (AMPP) Study. Headache. 2013;53(8):1278-1299.

11. Diamond S, Bigal ME, Silberstein S, Loder E, Reed M, Lipton RB. Patterns of diagnosis and acute and preventive treatment for migraine in the United States: results from the American Migraine Prevalence and Prevention study. Headache. 2007;47(3):355-363.

12. Blumenfeld AM, Bloudek LM, Becker WJ, et al. Patterns of use and reasons for discontinuation of prophylactic medications for episodic migraine and chronic migraine: results from the second international burden of migraine study (IBMS-II). Headache. 2013;53(4):644-655.

13. Lipton RB, Buse DC, Serrano D, Holland S, Reed ML. Examination of unmet treatment needs among persons with episodic migraine: results of the American Migraine Prevalence and Prevention (AMPP) Study. Headache. 2013;53(8):1300-1311.

14. Bonafede M, Cappell K, Kim G, Sapra S, Shah N, P D. Healthcare utilization and annual direct costs in patients with migraine in a commercial claims database. J Manag Care Spec Pharm. 2015;21(suppl 10):S48-S49.

15. Shamliyan TA, Choi JY, Ramakrishnan R, et al. Preventive pharmacologic treatments for episodic migraine in adults. J Gen Intern Med. 2013;28(9):1225-1237.

16. Hargreaves RJ, Shepheard SL. Can J Neurol Sci. 1999;26(suppl3):S12-S1917. Benarroch EE. CGRP: sensory neuropeptide with multiple neurologic implications. Neurology. 2011;77(3):281-287.18. Tfelt-Hansen P. Excellent tolerability but relatively low initial clinical efficacy of telcagepant in migraine. Headache.

2011;51(1):118-123.

6

MIGRAINE DIAGNOSIS AND TREATMENT (DIAMOND) SLIDES: REFERENCES IN ORDER OF APPEARANCE (cont.)(All Hyperlinks Correct and Active)

19. Tepper SJ. History and review of anti-calcitonin gene-related peptide (CGRP) therapies: From translational research to treatment. Headache 2018;58:in press.

20. Lipton RB, Diamond ML, Tepper SJ. Expert perspectives--migraine prevention for highly impacted patients. US Neurology. 2018;14(suppl2):3-10.

21. Tepper SJ, Ashina M, Reuter U, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2017;16(6):425-434.

22. Andreou AP, Holland PR, Akerman S, et al. Transcranial magnetic stimulation and potential cortical and trigeminothalamic mechanisms in migraine. Brain. 2016;139:2002-2014.

23. Tepper D. Transcutaneous supraorbital neurostimulation (tSNS). Headache. 2014;54(8):1415-1416. 24. Mourdoukoutas AP, Truong DQ, Adair DK, Simon BJ, Bikson M. High-Resolution Multi-Scale Computational Model

for Non-Invasive Cervical Vagus Nerve Stimulation. Neuromodulation. 2018;21(3):261-268. 25. Wilkinson D, Ade KK, Rogers LL, et al. Preventing Episodic Migraine With Caloric Vestibular Stimulation: A

Randomized Controlled Trial. Headache. 2017;57(7):1065-1087.26. Yarnitsky D, Volokh L, Ironi A, et al. Nonpainful remote electrical stimulation alleviates episodic migraine pain.

Neurology. 2017;88(13):1250-1255. 27. Jurgens TP, Barloese M, May A, et al. Long-term effectiveness of sphenopalatine ganglion stimulation for cluster

headache. Cephalalgia. 2017;37(5):423-434.

7

KEY REFERENCES FROM INFOGRAPHICS 1. Rao P, Knaus EE. Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition

and beyond. J Pharm Pharm Sci. 2008;11(2):81s-110s.2. Peterson K, McDonagh M, Thakurta S, et al. Drug Class Reviews. Drug Class Review: Nonsteroidal Antiinflammatory

Drugs (NSAIDs): Final Update 4 Report. Portland (OR): Oregon Health & Science University; 2010. 3. Antonaci F, Ghiotto N, Wu S, Pucci E, Costa A. Recent advances in migraine therapy. Springerplus. 2016;5:637.4. Silberstein SD, McCrory DC. Ergotamine and dihydroergotamine: history, pharmacology, and efficacy. Headache.

2003;43(2):144-166.5. Obermann M, Holle D. Recent advances in the management of migraine. F1000Res. 2016;5:2726.6. Center for Drug Evaluation and Research. NDA 21-926 FDA approved labeling text dated April 15, 2008. website.

https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/021926s000_Lbl.pdf. Accessed February 6, 2018.7. Schwedt TJ, Vargas B. Neurostimulation for treatment of migraine and cluster headache. Pain Med.

2015;16(9):1827-1834.8. Puledda F, Messina R, Goadsby PJ. An update on migraine: current understanding and future directions. J Neurol.

2017;264(9):2031-2039.9. Luo G, Chen L, Conway CM, Kostich W, Macor JE, Dubowchik GM. Asymmetric synthesis of heterocyclic analogues

of a CGRP receptor antagonist for treating migraine. Org Lett. 2015;17(24):5982-5985.10. Munjal S, Brand-Schieber E, Allenby K, Spierings ELH, Cady RK, Rapoport AM. A multicenter, open-label, long-term

safety and tolerability study of DFN-02, an intranasal spray of sumatriptan 10 mg plus permeation enhancer DDM, for the acute treatment of episodic migraine. J Headache Pain. 2017;18(1):31.

11. Yuan H, Silberstein SD. Vagus nerve stimulation and headache. Headache. 2017;57 Suppl 1:29-33.12. Yarnitsky D, Volokh L, Ironi A, et al. Nonpainful remote electrical stimulation alleviates episodic migraine pain.

Neurology. 2017;88(13):1250-1255.13. Loder E. Prophylaxis: headaches that never happen. Headache. 2008;48(5):694-696.14. Feighner JP. Mechanism of action of antidepressant medications. J Clin Psychiatry. 1999;60 Suppl 4:4-11;

discussion 12-13.15. Gorre F, Vandekerckhove H. Beta-blockers: focus on mechanism of action. Which beta-blocker, when and why?

Acta Cardiol. 2010;65(5):565-570.16. Landmark CJ. Targets for antiepileptic drugs in the synapse. Med Sci Monit. 2007;13(1):Ra1-7.17. Escher CM, Paracka L, Dressler D, Kollewe K. Botulinum toxin in the management of chronic migraine: clinical evidence

and experience. Ther Adv Neurol Disord. 2017;10(2):127-135.

18. Cernuda-Morollon E, Ramon C, Martinez-Camblor P, Serrano-Pertierra E, Larrosa D, Pascual J. OnabotulinumtoxinA decreases interictal CGRP plasma levels in patients with chronic migraine. Pain. 2015;156(5):820-824.

19. Riederer F, Penning S, Schoenen J. Transcutaneous Supraorbital Nerve Stimulation (t-SNS) with the Cefaly(®) device for migraine prevention: a review of the available data. Pain Ther. 2015;4(2):135-147.

20. Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev. 2017;97(2):553-622.

21. Wilkinson D, Ade KK, Rogers LL, et al. Preventing episodic migraine with caloric vestibular stimulation: A randomized controlled trial. Headache. 2017;57(7):1065-1087.