Maximizing Relief: A Personalized Approach to the Acute Treatment of Migraine in an Era of New Therapeutic Delivery Mechanisms

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1 CME Maximizing Relief: A Personalized Approach to the Acute Treatment of Migraine in an Era of New Therapeutic Delivery Mechanisms Course Director Stewart J. Tepper, MD Geisel School of Medicine at Dartmouth Hanover, New Hampshire What s Inside Practical Considerations for Migraine Diagnosis An Overview of the Contemporary Therapeutic Landscape for the Acute Treatment of Migraine Attack-Based Care for the Acute Treatment of Migraine: The Role of New Drug Delivery Systems and Devices This CME activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. Participate in interactive questions, download activity slides, and obtain your instant CME credit online.

2 Activity Information Activity Description and Educational Objectives In this activity, an expert in neurology discusses the recognition and acute treatment of migraine. Upon completion of this activity, participants should be better able to: Employ current criteria to readily identify and accurately diagnose patients with migraine Apply current evidence on specific and nonspecific pharmacotherapies for the acute treatment of migraine Develop strategies to personalize the acute treatment of migraine according to an attack-based care approach Target Audience This activity has been designed to meet the educational needs of neurologists, general practitioners, family practitioners, and other clinicians involved in the management of patients with migraine. Requirements for Successful Completion In order to receive credit, participants must view the activity and complete the post-test and evaluation form. A score of 70% or higher is needed to obtain CME credit. There are no pre-requisites and there is no fee to participate in this activity or to receive CME credit. Statements of Credit are awarded upon successful completion of the post-test and evaluation form. Media: Enduring Material Release and Expiration Dates: August 30, August 29, 2017 Time to Complete: 30 minutes Faculty & Disclosure / Conflict of Interest Policy Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute, Inc. for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. The associates of Medical Learning Institute, Inc., the accredited provider for this activity, and PVI, PeerView Institute for Medical Education do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME activity for any amount during the past 12 months. Course Director Stewart J. Tepper, MD Professor of Neurology Geisel School of Medicine at Dartmouth Hanover, New Hampshire Stewart J. Tepper, MD, has a financial interest/relationship or affiliation in the form of: Consultant for Acorda Therapeutics; Alder BioPharmaceuticals Inc.; Allergan; Amgen Inc.; Autonomic Technologies Inc.; Avanir Pharmaceuticals, Inc.; Depomed, Inc.; electrocore LLC; eneura Inc.; Impax Laboratories, Inc.; Kimberly-Clark Corporation; Pfizer Inc.; Teva Pharmaceuticals USA; and Zosano Pharma Corporation. Grant/Research Support from Allergan; Amgen Inc.; Autonomic Technologies Inc.; Avanir Pharmaceuticals, Inc.; electrocore LLC; eneura Inc.; Teva Pharmaceuticals USA; and Zosano Pharma Corporation. Advisory Board for Allergan; Amgen Inc.; Autonomic Technologies Inc.; Avanir Pharmaceuticals, Inc.; Dr. Reddy s Laboratories Ltd.; Kimberly-Clark Corporation; Pfizer Inc.; Scion NeuroStim LLC; and Teva Pharmaceuticals USA. Other Financial or Material Support from Autonomic Technologies Inc. in the form of stock options. Dr. Tepper is also the Editor-in-Chief for the American Headache Society. CME Reviewer Randy M. Rosenberg, MD, FACP, FAAN Assistant Professor of Neurology Temple University School of Medicine Philadelphia, Pennsylvania Randy M. Rosenberg, MD, FACP, FAAN, has no financial interests/relationships or affiliations in relation to this activity. Medical Director Kirk A. Tacka, PhD PVI, PeerView Institute for Medical Education Kirk A. Tacka, PhD, has no financial interests/relationships or affiliations in relation to this activity. Disclaimer The information provided at this CME activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient's medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias towards or promotion for any agent discussed in this program should be inferred. Providership, Credit & Support This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. The Medical Learning Institute, Inc. is accredited by the ACCME to provide continuing medical education for physicians. The Medical Learning Institute, Inc. designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Providership This CME activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. Support This activity is supported by an educational grant from Avanir Pharmaceuticals, Inc. Disclosure of Unlabeled Use The faculty of this educational activity may include discussions of products or devices that are not currently labeled for use by the FDA. Faculty members have been advised to disclose to the audience any reference to an unlabeled or investigational use. No endorsement of unapproved products or uses is made or implied by coverage of these products or uses in our reports. No responsibility is taken for errors or omissions in reports. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The materials presented here are used with the permission of the authors and/or other sources. These materials do not necessarily reflect the views of PeerView Press or any of its partners, providers, and/or supporters. Stewart J. Tepper, MD, does intend to discuss either non FDA-approved or investigational use for the following products/devices: pharmacotherapies and neuromodulatory devices for the acute treatment of migraine. 2 Go online to complete the post-test and evaluation for CME credit

3 Maximizing Relief: A Personalized Approach to the Acute Treatment of Migraine in an Era of New Therapeutic Delivery Mechanisms Practical Considerations for Migraine Diagnosis Stewart J. Tepper, MD Geisel School of Medicine at Dartmouth Hanover, New Hampshire Dr. Tepper: Hello, this is Dr. Stewart Tepper from the Geisel School of Medicine at Dartmouth in Hanover, New Hampshire. Welcome to this educational activity on the recognition and treatment of migraine. After completing the activity, access the post-test and evaluation form by clicking the red "Get Certificate" button. I encourage you to download the slides, Practice Aids, and any other activity features that may interest you. The premonitory symptoms can include depression, cognitive dysfunction, and bouts of food cravings. Premonitory symptoms can then followed by an aura. About 20% of migraine patients get aura, which is defined as a reversible neurologic symptom generally lasting 5 to 60 minutes, and then followed by the actual migraine pain. Aura is generally followed by headache. [Some patients may have migraine headaches without aura.] But the headache is fairly stereotypical, unilateral, usually of gradual onset, throbbing, moderate to severe in intensity, aggravated by movement, and lasting 4 to 72 hours. Additional migraine features include nausea, photophobia, and phonophobia; often osmophobia occurs as well. Following the migraine pain there may be a postdrome, which can last for a day or two or even longer, in which the patient does not feel quite right. And finally, the entire migraine resolves in a resolution phase. Prevalence of Migraine 1 Migraine Symptomatology Phases of Migraine Premonitory Aura Headache Precede aura and headache Depression, cognitive dysfunction, bouts of food cravings Focal neurologic symptoms a Visual, sensory, and/or motor Unilateral, usually, of gradual onset, throbbing, moderate to severe in intensity, aggravated by movement, lasts 4-72 h; additional common features include nausea, vomiting, and sensory hypersensitivity 1-Year Prevalence, % Postdrome 0 Overall Females Males Resolution a Can precede, accompany, or follow an attack. 1. Silberstein SD. Clin Pharmacol Ther. 2013;93: Headache Classification Committee of the International Headache Society. Cephalalgia. 2013;33: Russell MB, Olesen J. Brain. 1996;119(pt 2): Stewart WF et al. Neurology. 1994;44(6 suppl 4):s24-s Silberstein SD. Headache. 1995;35: Lipton RB et al. Neurology. 2007;68: The prevalence of migraine has been established very clearly over the last three decades, and it comes out to between 17% and 18% women, 6% of men, and about 12% of the general population. Migraine is an idiopathic recurring headache disorder, which actually goes through four to five phases. The initial phases before pain can include premonitory symptoms or a prodrome. 3

4 Burden of Migraine: School/Work/Social Impact 1 Parameter (Previous 3 mo) Patients, % Missed 1 day of work/school % decreased work/school productivity 28.1 Unable to do any household work 47.7 To diagnose migraine, a patient needs to have had at least five attacks of headaches lasting from 4 to 72 hours with at least two of the following characteristics: one-sided location, throbbing quality, moderate or severe intensity and aggravation by or causing avoidance of routine physical activity. During the headache, the patient needs at least one of the following: nausea or dislike of light and dislike of noise [photophobia and phonophobia], and the headache cannot be better accounted for by another diagnosis. 50% decreased household productivity 34.3 ICHD-3 Diagnostic Criteria for Migraine With Aura 1 Missed family or social activity Lipton RB et al. Neurology. 2007;68: Migraine is a severely disabling disorder, and it has impact on work, home, school, and recreational activities. Prospective studies looking in the general population found that a quarter of migraine patients missed at least one day of work or school, and 28% had diminished productivity at work or school by at least 50% so-called presenteeism as opposed to absenteeism. Almost half had days in which they did no household work. A third had days in which household productivity was reduced by at least 50%, and almost one-third missed family and social activities. Migraine With Aura A. 2 attacks fulfilling B-C B. 1 of the following fully reversible aura symptoms: 1. Visual 2. Sensory 3. Speech and/or language 4. Motor 5. Brainstem 6. Retinal C. 2 of the following 4 characteristics: 1. 1 aura symptom spreads gradually over 5 min and/or 2 symptoms occur in succession 2. Each individual aura symptom lasts 5-60 min 3. 1 aura symptom is unilateral 4. Aura accompanied by, or followed within 60 min, by headache (ie, criteria B-D for migraine without aura) D. Not better accounted for by another ICHD-3 diagnosis and TIA has been excluded 1. Headache Classification Committee of the International Headache Society. Cephalalgia. 2013;33: ICHD-3 Diagnostic Criteria for Migraine Without Aura 1 Migraine Without Aura A. 5 headaches fulfilling B-D B. Headaches lasting 4-72 h (untreated or unsuccessfully treated) C. Headache has 2 of the following characteristics: 1. Unilateral location 2. Pulsating quality 3. Moderate or severe intensity 4. Aggravation by or causing avoidance of routine physical activity D. During headache, 1 of the following: 1. Nausea and/or vomiting 2. Photophobia and phonophobia E. Not better accounted for by another ICHD-3 diagnosis The ICHD-3 has subdivided migraine with aura into typical aura, which includes visual, sensory, speech and/or language dysfunction; and motor aura that is hemiplegic; brainstem aura, which used to be called basilar-type migraine; and retinal aura. In general, aura involves a reversible neurologic event, which spreads gradually over at least 5 minutes. Sometimes at least two symptoms will occur in succession, but each individual aura symptom lasts from 5 to 60 minutes. At least one aura symptom is unilateral. The aura is accompanied by or followed within 60 minutes by headache. Once again, in order to diagnose a migraine with aura, the patient needs to have had at least two attacks, and the diagnosis needs to not be better accounted for by a different diagnosis, especially TIA, which needs to be excluded. 1. Headache Classification Committee of the International Headache Society. Cephalalgia. 2013;33: The diagnostic criteria for migraine without aura have not changed since 1988, and these diagnostic criteria were promulgated by the International Headache Society in what is referred to as the International Classification of Headache Disorders, or ICHD. 4 Go online to complete the post-test and evaluation for CME credit

5 Differentiating Between Episodic and Chronic Migraine 1 Episodic migraine: <15 headache days per month ICHD-3 Diagnostic Criteria for Chronic Migraine A. Headache (tension-type like and/or migraine-like) on 15 d/mo for >3 mo, and fulfilling criteria B and C B. Headaches fulfill criteria B-D for migraine without aura ( 5 attacks) and/or criteria B and C for migraine with aura ( 2 attacks) C. On 8 d/mo for >3 mo, fulfilling any of the following a : 1. Criteria C and D for migraine without aura 2. Criteria B and C for migraine with aura 3. Believed by patient to be migraine at onset and relieved by triptan or ergot derivative D. Not better accounted for by another ICHD-3 diagnosis a Characterization of frequently recurring headache generally requires a headache diary to record information on pain and associated symptoms day by day for 1 month. 1. Headache Classification Committee of the International Headache Society. Cephalalgia. 2013;33: Migraine that occurs less than 15 days per month is episodic migraine. The ICHD-3 criteria for chronic migraine state that the headache needs to be present on at least 15 days a month for 3 months at least, and the patients have to have had headaches that fulfill criteria for migraine without aura or migraine with aura. On at least 8 days per month for greater than 3 months, either there has to be headache that meets criteria for migraine, or the patient has to believe that it's a migraine at onset, or the headache has to be relieved by a migraine-specific medication such as a triptan or ergot. Strictly speaking, the ICHD-3 diagnostic criteria for chronic migraine exclude medication overuse headache or rebound, and medication overuse headache becomes a secondary chronic daily headache. The ICHD-3 does allow a doctor or care provider to use both diagnoses until we sort out whether the patient has rebound or a primary chronic migraine. Facilitating the Diagnosis of Migraine in Practice 1 ID Migraine: A Three-Question Screening Tool Over the last 3 months 1. Have you limited your activities on at least 1 day because of your headaches? 2. Do lights bother you when you have a headache (a lot more than when you do not have a headache)? 3. Do you get sick to your stomach or nauseated with your headache? Narrator: Questionnaires such as the three-question ID Migraine Screener may also be useful in facilitating the recognition and diagnosis of migraine. Patients answering yes to at least two of these questions probably have migraine. Additional Considerations for Diagnosing Migraine 1 Stable pattern ( 6 mo) of episodic, disabling headache usually migraine Reserve workup for change in headache pattern, atypical presentations, and focal examination S N O O P P P P P 1. Dodick DW. Adv Stud Med. 2003;3: Systemic symptoms (fever, weight loss) or secondary risk factors (HIV, cancer) Neurologic symptoms or signs Onset: abrupt, peak <1 min Older: >50 (GCA, glaucoma, cardiac cephalgia) Previous headache history (new or change) or pattern change Postural, positional Precipitated by Valsalva, exertion Papilledema Progressive (intractable) Dr. Tepper: In general, a stable pattern of at least 6 months duration of episodic disabling headache is usually migraine, and that is a very reassuring pattern. One reserves the workup for change in headache pattern, atypical presentations, and a focal exam. David Dodick championed a mnemonic called SNOOP to tell us when to snoop that is when to do a workup for secondary headache. The S in SNOOP is systemic symptoms: fever or weight loss, or secondary risk factors: autoimmune disease, HIV, cancer. The N is neurologic symptoms or signs: alteration of consciousness or a focal neurologic exam. The first O is onset, so a thunderclap onset, which is abrupt, and a quick time to peak intensity of less than a minute warrants a workup. The second O is an older age in terms of first presentation of headache. The first P is the most important P, and that is a change in the pattern. If there is a change in frequency, severity, or duration of the attacks, that warrant serious consideration for a workup. The remaining Ps are also of concern. A positional or postural headache would make one worry about a CSF leak. A headache precipitated by Valsalva or exertion raises the question of an aneurysm. Papilledema raises the question of pseudotumor or a brain tumor. Finally, a progressive headache, which is intractable to conventional treatment, also raises the question of a mass lesion or underlying secondary condition. Patients answering yes to at least two of these questions probably have migraine 1. Lipton RB. Neurology. 2003;61:

6 An Overview of the Contemporary Therapeutic Landscape for the Acute Treatment of Migraine Stewart J. Tepper, MD Geisel School of Medicine at Dartmouth Hanover, New Hampshire AHS Evidence Assessment of Pharmacotherapies for Acute Treatment of Migraine in Adults 1 Nonspecific Medications Effective (Level A) Acetaminophen NSAIDs Aspirin Diclofenac, solubilized Ibuprofen Naproxen Opioids Butorphanol nasal spray: Do not use! Combinations Sumatriptan/naproxen Acetaminophen/aspirin/caffeine Specific Medications Effective (Level A) Triptans Almotriptan Eletriptan Frovatriptan Naratriptan Rizatriptan Sumatriptan Zolmitriptan Ergots DHE nasal spray Probably Effective (Level B) Ketoprofen IV and IM ketorolac Flurbiprofen IV magnesium a Probably Effective (Level B) Ergotamine Other forms of DHE a In migraine with aura. Acute Treatment of Migraine 1. Marmura MJ et al. Headache. 2015;55:3-20. Goal Terminate migraine attack and decrease risk of episodic migraine becoming chronic migraine Should be a one-and-done response: pain-free within 2 h, with minimal AEs, and low likelihood of recurrence The American Headache Society published their Evidence Assessment of Pharmacotherapies for Acute Treatment of Migraine in Adults in This amounted to an evidencebased guideline, and the medicines that were found to have level A evidence for acute treatment included some medications that were nonspecific and some that were specific. Potential Consequences of Suboptimal Treatment 1 Recent study showed inadequate treatment efficacy associated with increased risk of new onset chronic migraine over 1 y 1. Lipton RB et al. Neurology. 2015;84: Dr. Tepper: The goal of acute treatment of migraine is to terminate a migraine attack and decrease the risk of an episodic migraine patient becoming chronic. In order to do that, the acute treatment should result in a one-and-done response: pain freedom within 2 hours with minimal adverse events and a low likelihood of recurrence. It's actually worth talking to the patient and saying, This is what we're after. Interestingly, poor acute treatment is associated with an increased risk of transformation from episodic to chronic migraine. A very large study that was published in 2015, which was population-based, was able to show that in the patients that had optimal acute treatment one and done, pain freedom their likelihood of transforming into chronic migraine over the course of a year was much lower. In the nonspecific group, acetaminophen, certain nonsteroidal anti-inflammatories, in particular, solubilized diclofenac and naproxen sodium and combinations, all had level A evidence. Although butorphanol nasal spray has evidence in a randomized, controlled trial, the strong recommendation of the American Headache Society is that it not be used in the acute treatment of migraine. In the specific medications, triptans were all level A, and the DHE nasal spray also had level A evidence for effectiveness. Triptans for the Acute Treatment of Migraine 1-4 Class Rapid onset Slower onset Agent Sumatriptan 50 mg 100 mg 20 mg intranasal 6 mg subq Zolmitriptan 2.5 mg 5 mg 5 mg intranasal Rizatriptan 5 mg 10 mg Headache Response a 63% 59% 61% 69% 64% 66% 69% 62% 69% a All 2 h except for sumatriptan subq = 1 h. b 2-24 h. Therapeutic Gain a 31% 29% 31% 50% 34% 37% 38% 28% 35% Pain-Free Frequency a 28% 29% 27%-37% 48%-49% 25% 34% 36% 30% 40% Pain-Free Therapeutic Gain a 18% 20% 11%-28% 43%-46% 19% 28% 29% 22% 30% Recurrence Rate b 28% 30% 30% 34% 27% 39% 37% Almotriptan 12.5 mg 61% 25% 36% 21% 26% Eletriptan 40 mg 80 mg 60% 66% 35% 42% 27% 33% 22% 28% 21% 20% Frovatriptan 2.5 mg 42% 17% Naratriptan 2.5 mg 49% 22% 22% 14% 21% 1. Silberstein SD. Clin Pharmacol Ther. 2013;93: Ferrari MD et al. Lancet. 2001;358: Tfelt-Hansen P. Cephalalgia. 1998;18: Dahlof C, Lines C. Expert Opin Investig Drugs. 1999;8: Go online to complete the post-test and evaluation for CME credit

7 If one looks at multiple randomized, controlled trials for triptans, what one sees is that triptans can be divided into two broad groups: those which have rapid onset and similar headache relief at 2 hours, and those that have slower onset and not as good headache relief at 2 hours. The slower group of triptans, group B, does at 4 hours what the faster group of triptans, group A, does at 2 hours, as long as one is talking about oral formulations. The fast group of triptans includes sumatriptan, zolmitriptan, rizatriptan, almotriptan, and eletriptan. The slower group of triptans includes frovatriptan and naratriptan. Triptan Safety Considerations 1-6 Ergots for the Acute Treatment of Migraine 1-6 Dihydroergotamine (DHE) most widely available ergot alkaloid DHE nasal spray; one puff (0.5 mg) in each nostril, repeat in 15 minutes; 2-mg maximum daily dose Injected DHE 0.5 mg to 1 mg, repeat in 1 hour; 3-mg maximum daily dose; usually administered in ED or inpatient setting but can be self-administered at home Advantages: complete response and ability to treat late in an attack Contraindications: vascular disease, uncontrolled hypertension, renal or hepatic failure, and pregnancy Vasoconstrictive Properties Preclude use in patients with ischemic heart disease, stroke, uncontrolled hypertension, or hemiplegic migraine Cardiac evaluation reasonable before triptan initiation in patients with multiple vascular risk factors If patients develop suspected cardiac symptoms, triptans should be discontinued pending further evaluation Contraindications Triptans contraindicated in patients taking MAOIs The FDA issued a warning on triptans and SSRIs, SNRIs, and the risk of serotonin syndrome; the American Headache Society reviewed the cases and the risk and disagreed, classifying the evidence as inconclusive at best 1. Ferrari MD et al. Lancet. 2001;358: O Quinn S et al. Cephalalgia. 1999;19: Jamieson DG. Am J Med. 2002;112: Sclar DA et al. Headache. 2008;48: Morey SS. Am Fam Physician. 2000;62: Evans RW et al. Headache. 2010;50: There are important safety considerations when prescribing triptans. Triptans and ergots both have vasoconstrictive properties. Both classes of treatments are contraindicated in patients with vascular disease, ischemic heart disease, stroke, uncontrolled hypertension, and I would recommend not using them in peripheral vascular disease either. If a patient has multiple vascular risk factors, a functional cardiac evaluation would be reasonable before initiating triptans or ergots. If patients develop true suspected cardiac symptoms, triptans should be discontinued pending further evaluation. Some triptans are contraindicated in patients taking monoamine oxidase inhibitors. These are the triptans that go through the monoamine oxidase pathway in the liver and include sumatriptan, zolmitriptan, and rizatriptan. Eletriptan does not go through the monoamine oxidase system. 1. Silberstein S. Clin Pharmacol Therap. 2013;93: Monteith TS et al. Curr Treat Opt Neurol. 2011;13: Rizzoli PB. Continuum Lifelong Learning Neurol. 2012;18: Saper JR, Silberstein S. Headache. 2006;46(suppl 4):s171-s Rabbie R et al. Cochrane Database Syst Rev. 2010;10:CD Magis D, Schoenen J. Curr Opin Neurol. 2011;24: Dihydroergotamine, or DHE, is the most widely available and used ergot alkaloid. DHE nasal spray involves the patient spraying DHE, one puff, 0.5 mg, in each nostril without sniffing and then repeating in 15 minutes. Four puffs or pulses of the nasal spray equals one dose. Injected DHE, 0.5 mg to 1 mg, either IM or subcutaneous, can be repeated in an hour to a 3-mg maximum daily dose. IV DHE is usually administered in the emergency room, an infusion suite, or an inpatient setting, but IM and subcutaneous DHE can be self-administered at home. The advantage of DHE is that it tends to give a complete response with a low likelihood of recurrence, and it can be used to treat late in an attack, which is an advantage over triptans. DHE can reverse central sensitization and offers an opportunity in migraine that has escaped. Contraindications for ergots include the same vascular contraindications as triptans: untreated or uncontrolled hypertension, renal or hepatic failure, and pregnancy. The FDA issued a warning on triptans and SSRIs, SNRIs, and the risk of serotonin syndrome. The American Headache Society reviewed the cases and the risk and the evidence and disagreed, classifying the evidence as inconclusive at best. 7

8 Attack-Based Care for the Acute Treatment of Migraine: The Role of New Drug Delivery Systems and Devices Stewart J. Tepper, MD Geisel School of Medicine at Dartmouth Hanover, New Hampshire New Routes of Administration: Intranasal Delivery of Low-Dose Sumatriptan Powder 1,2 Sealing nosepiece Breath-actuated drug release into airflow Soft palate closes automatically Blow into delivery system Closed-palate, bi-directional, breath-powered intranasal delivery mechanism Delivers low-dose sumatriptan powder to upper posterior nasal regions beyond narrow nasal valve Allows targeted deposition deep into and throughout nasal cavity, while helping to avoid sumatriptan deposition in oropharynx or lungs Attack-Based Care: Personalizing the Acute Treatment of Migraine Migraine attacks vary from person to person, attack to attack Important to address attack, not simply the patient profile Which symptom has most impact? Where will patient be in 1 h? Which formulation is best for attack? Provide patients with tool box of treatment options Although triptans transformed acute treatment of migraine, for many patients, treatment is not 100% effective Research has focused on addressing these shortcomings with New delivery mechanisms/formulations Neuromodulatory devices Dr. Tepper: Attack-based care is a potential approach to personalizing acute treatment of migraine. Migraine attacks vary from person to person and from attack to attack. And every patient will tell you that. It may be important therapeutically to address the attack, not simply the patient profile. Which symptom is having the most impact for that patient? Where will the patient be in 1 hour? What is the time to peak? Which formulation would be right for particular attack? It may be most useful to provide patients with a toolbox of treatment options. Although oral triptans clearly transformed acute treatment of migraine, for many patients, oral treatment is not 100% effective. Research is focused on addressing the shortcomings with new delivery mechanisms and formulations and actually using devices to deliver neuromodulation rather than medications. 1. Cady R et al. Headache. 2015;55: Tepper SJ et al. Headache. 2015;55: We'll start with a formulation of sumatriptan that became available after FDA approval in early This is an intranasal delivery of low-dose sumatriptan powder. The way this device works is that the patient puts a spout in the mouth and a nozzle in the nose and blows the sumatriptan powder up the nose high up into the nasal cavity. This is referred to as a closedpalate, bidirectional, breath-powered, intranasal delivery mechanism. When the patient blows, the soft palate closes. That prevents the sumatriptan from going down the throat. The idea behind this device is that by closing the palate with the breath, one could deliver low-dose sumatriptan powder to the upper posterior nasal regions beyond the narrow nasal valve and deliver the sumatriptan to an area of richly vascular mucosa conducive to rapid drug absorption into the systemic circulation. TARGET: Intranasal Sumatriptan Powder for Acute Treatment of Migraine 1 N = y Diagnosed with episodic migraine 1 y prior to screening Randomized PBO (lactose powder) Sumatriptan powder 22 mg Endpoint PBO Sumatriptan P Headache relief at 2 h 45.2% 67.6%.002 Headache relief at 24 h 24.0% 44.4%.002 Pain free at 2 h 17.3% 34.3%.008 Pain free at 24 h 11.5% 27.8%.005 Total migraine freedom at 2 h 17.3% 29.6%.05 Rescue medication use 51.9% 37.0%.02 No serious AEs; no systemic AEs occurred in more than one patient; chest pain or pressure not reported, and only one patient taking sumatriptan powder reported mild paresthesia 1. Cady R et al. Headache. 2015;55: The randomized, controlled trial, phase 3, that was used by the FDA for the approval of this formulation was called the TARGET 8 Go online to complete the post-test and evaluation for CME credit

9 study and published in The patient treated a single attack with either 22 mg of sumatriptan powder or a placebo with lactose powder. The primary endpoint was headache relief at 2 hours. As you can see from this slide, sumatriptan easily beat placebo for headache relief and pain freedom. There were no serious adverse events and no systemic adverse events occurred in more than one patient. Chest pain or pressure was not even reported, and only one patient taking this device reported mild paresthesia. COMPASS: Safety 1 Nasal discomfort and abnormal taste more common with sumatriptan powder vs oral sumatriptan (16% vs 1% and 26% vs 4%, respectively) 90% of AEs were mild, leading to only one discontinuation Atypical sensation rates were significantly lower with sumatriptan powder than with conventional higher-dose oral sumatriptan 100 mg COMPASS: Results 1 Attacks Achieving Pain Relief, % Oral Sumatriptan P = Sumatriptan Powder P <.001 P =.03 P <.001 P < min 15 min 30 min 45 min 60 min 90 min Similarly, statistically significant differences in rates of pain freedom favored sumatriptan powder vs oral sumatriptan at every time point from 15 to 90 min post-dose Pain relief and pain freedom at 120 min, as well as sustained pain relief and pain freedom through 24 and 48 h, achieved in similar percentage of attacks for both treatments 1. Tepper SJ et al. Headache. 2015;55: This did not tell whether the device was going to be superior to conventional 100-mg oral sumatriptan tablets. The COMPASS trial was a randomized trial, double-dummy, in which patients treated five attacks with oral sumatriptan 100 mg and the inhaled placebo powder or the breath-powered powder versus the sumatriptan powder 22 mg and an oral placebo. And patients were then crossed over to treat a total of 10 attacks. The sumatriptan powder device was superior to the oral sumatriptan for headache relief and pain freedom beginning at 15 minutes, at 30 minutes, 45 minutes, 60 minutes, and 90 minutes. The tablet caught up to the breath-powered device at 2 hours. Sustained pain freedom and sustained pain relief across 24 and 48 hours were the same for the tablet and the breath-powered nasal sumatriptan. This suggests that a lower dose of sumatriptan, 22 mg, compared to 100 mg of oral sumatriptan, using this device, could outstrip the oral sumatriptan even though the actual dose was about a fifth for earlier endpoints all the way through to 2 hours. Narrator: This suggests that although the actual dose of the breath-powered nasal sumatriptan was about one-fifth of the 100-mg tablet, the device resulted in earlier comparative superior results all the way through to 2 hours. 1. Tepper SJ et al. Headache. 2015;55: Dr. Tepper: Nasal discomfort and abnormal taste were more common with the powder than the oral, but 90% of the patients who had abnormal taste described it as mild, and only one patient in the entire study discontinued due to taste. More importantly, atypical triptan sensation rates that is, the chest symptoms, jaw symptoms, and back of the neck symptoms were significantly lower with the breath-powered sumatriptan powder than with the conventional higher-dose, 100-mg oral sumatriptan. However, not all devices are successful. In June of 2016, a device which used an iontophoretic patch and a lithium battery to deliver sumatriptan transdermally was withdrawn from the market due to post-marketing reports of application-site burns and scars. At the time of this particular presentation, the FDA is evaluating these reports. Single-Pulse Transcranial Magnetic Stimulator for Acute Treatment of Migraine 1,2 1. Turn On 2. Power Up 3. Treat Disrupts rat CSD and likely inhibits thalamocortical pathways and central excitability Noninvasively delivers single brief pulse of magnetic energy to back of head Indicated for acute treatment of migraine with aura Treats migraine with two pulses within 1 h of aura onset Also being investigated for acute treatment of migraine without aura and migraine prevention 1. Andreou AP et al. Brain. 2016;139(pt 7): Lipton RB et al. Lancet Neurol. 2010;9:

10 Now I'd like to move on to nonmedication devices for the acute treatment of migraine and a little bit about the preventive treatment of migraine. The first device approved for the acute treatment of migraine that involved neuromodulation rather than medication was the single-pulse transcranial magnetic stimulator. The FDA approved this for acute treatment of migraine with aura in which a patient is instructed to treat a migraine with two magnetic pulses within 1 hour of aura onset. The device is also being investigated for acute treatment of migraine without aura, as well as for migraine prevention. Randomized, Double-Blind, Sham-Controlled Trial of stms for Acute Treatment of Migraine With Aura 1 stms: Open-Label Study 1 Acute Medication Days Reduction of Acute Medicine Days n = 15 MO Increase in Acute Medication n = 1 Migraine Without Aura (MO) n = 1 n = 10 n = 1 MA Increase in Acute Medication n = 1 MO MA Migraine With Aura (MA) Number of Migration Days MO 3.91 Reduction of Migraine Days Weeks 4.52 MA MO MA Median Standard D N = 201 Randomized treatment: sham stimulation or stms Patients Who Were Pain Free After 2 h, % Sham P = stms 1. Lipton RB et al. Lancet Neurol. 2010;9: No device-related SAEs recorded Incidence and severity of AEs similar between groups The study that led to the stms device being approved was a study in which patients with aura were given either a device which pulsed twice or a sham device which sounded like the real device but which, in fact, did not activate the magnet. The primary endpoint was pain freedom at 2 hours, and about 40% of those who pulsed with the stms were pain-free at 2 hours, and 22% of those who pulsed with sham were pain-free at 2 hours. [The device had minimal side effects and is categorized by the FDA as a minimal risk device.] 1. Bhola R et al. 57th Annual Scientific Meeting of the American Headache Society (AHS 2015). This is a study on 29 patients pulsing with the device twice daily four pulses in the morning and four pulses at night. They were also allowed to pulse acutely at a migraine attack onset. Over 3 months, the patients showed a reduction of medication use acutely and a reduction of their migraine days. Although this is an open-label study, it does suggest the possible advantage that stms may have in being able to be used preventively, as well as acutely, and there's a great deal of excitement about the device. It is available by prescription at headache centers in the US at the time of this recording. Three Letters to Remember on Regulatory Approval of Devices: CMC CMC: Chemistry, Manufacturing, and Control Companies must establish physicochemical properties of a new chemical entity Is the drug suitable to be made into specific current or new formulations? Devices must work according to specifications, and drugs or modulation must be delivered reliably in consistent aliquots The FDA has been updating CMC regulations as recently as April 22, 2016 Almost all of the devices have had holdups in CMC, and some are delayed (eg, inhalable DHE) Further new noninvasive neuromodulation devices are likely to be approved in 2016 to 2017, and new formulations of available medications are likely to be tested and become available over the next several years. Three letters to remember on the regulatory approval of devices are CMC. CMC stands for chemistry, manufacturing, and control. Companies must establish the physicochemical properties of a new chemical entity when they are developing this new medication for treatment. Is the drug suitable to be made into specific current 10 Go online to complete the post-test and evaluation for CME credit

11 or new formulations? Devices must work according to specs, and drugs or neuromodulation must be delivered reliably in consistent aliquots. The FDA has been updating CMC regulations as recently as April Almost all of the devices that I have gone over have had hold ups in CMC, and some have current delays, such as an orally inhalable DHE. Attack-Based Care: Practical Considerations for Mild to Moderate Migraine Attacks 1-5 Consider treatment with noninvasive devices: stms and others No Mild to Moderate Migraine Vomiting or Severe Nausea? Yes Attack-Based Care: Practical Considerations for Moderate to Severe Migraine Attacks 1-5 Consider treatment with noninvasive devices: stms and others Moderate to Severe Migraine No Vomiting or Severe Nausea? Yes Oral triptans Or NSAIDs Or Oral triptan + NSAID Sumatriptan/naproxen Nonoral medications such as: Intransal sumatriptan powder Nasal ketorolac Nasal zolmitriptan DHE nasal spray +/- Antiemetics Oral triptan Or NSAIDs Or Oral triptan + NSAID Sumatriptan/naproxen Nonoral medications with antiemetic: Nonoral triptans Nasal DHE Nonoral NSAIDs Rectal neuroleptics 1. Becker WJ. Headache. 2015;55: MacGregor EA. Ann Intern Med. 2013;159:ITC5. 3. Marmura MJ et al. Headache. 2015;55: Gilmore B, Michael M. Am Fam Physician. 2011;83: Becker WJ. Continuum (Minneap Minn). 2015;21: Becker WJ. Headache. 2015;55: MacGregor EA. Ann Intern Med. 2013;159:ITC5. 3. Marmura MJ et al. Headache. 2015;55: Gilmore B, Michael M. Am Fam Physician. 2011;83: Becker WJ. Continuum (Minneap Minn). 2015;21: Returning to attack-based care, I think it's important to ask patients whether they would like to use a neuromodulation device or whether they want to use medication. If they want to use a noninvasive neuromodulation device, the stms has FDA approval for acute treatment of migraine with aura. If the patient knows that the attack is going to be mild or moderate, there's not going to be vomiting or severe nausea. But if the patient has vomiting or severe nausea, then the attack really is no longer a mild to moderate migraine and one has to encourage the patient to use migraine-specific medicines, in another nonoral formulation. Practical consideration for moderate to severe attacks again require talking to the patient about whether they want to use a noninvasive neuromodulation device or whether they want to use medication. [It is possible to combine neuromodulation and medications at the same time.] If they know that it's a moderate to severe attack, but they don't have vomiting, they can use an oral triptan [or an oral NSAID], or [an oral triptan plus NSAID, such as] sumatriptan/naproxen. If they feel like they're going to have a fast time to peak intensity with severe nausea and vomiting, a nonoral medication becomes the reasonable choice. Intranasal sumatriptan breath-powered powder becomes a real possibility. Nasal zolmitriptan is not as foul-tasting as nasal sumatriptan and is very effective in this setting. DHE nasal spray can also be effective, although it is likely not as rapid onset as the intranasal sumatriptan powder or nasal zolmitriptan. [Certain NSAIDs are available in nonoral forms (eg, nasal ketorolac) and may also be useful in this setting.] Antiemetics should be considered in this setting as well. 11

12 Attack-Based Care: Practical Considerations for Variable Migraine Attacks 1-6 Many patients with migraine have attacks that vary in: Severity Time of onset Association with vomiting/ nausea Such patients often may require 2 options for acute treatment of migraine including: Oral medications for mild to moderate attacks Nonoral medications for more severe attacks or those associated with vomiting/severe nausea New noninvasive neuromodulation devices A number of specific and nonspecific medications are available for the acute treatment of migraine. Several nonoral formulations are available or have recently been approved. A number of novel formulations of existing medications are also in the later stages of clinical development but may be delayed due to CMC issues. The key to effective treatment is to provide the right medication with the right formulation for the right migraine attack, and that involves a serious discussion with patients about the variability of their attacks and the availability of alternative formulations and drugs. Employing an attack-based case approach may achieve this goal, and it is also worth discussing with patients whether they want medications, neuromodulation devices, or both. 1. Becker WJ. Headache. 2015;55: MacGregor EA. Ann Intern Med. 2013;159:ITC5. 3. Marmura MJ et al. Headache. 2015;55: Gilmore B, Michael M. Am Fam Physician. 2011;83: Taylor FR et al. Curr Treat Options Neurol. 2011;13: Becker WJ. Continuum (Minneap Minn). 2015;21: Now the trick is to sit patients down and discuss the probability that they're going to need different formulations for different attacks. Patients that have attacks that vary in severity, time of onset, time to peak, and association with vomiting and nausea may often require two or more options for acute treatment of migraine, including oral medications for mild to moderate attacks, nonoral formulations for more severe attacks or those associated with vomiting or severe nausea or rapid time to peak intensity, and use of the new noninvasive neuromodulation devices. Conclusions Migraine highly common and can be identified and diagnosed using the ICHD-3 criteria and or the ID-Migraine Screener A number of specific and nonspecific medications are available for the acute treatment of migraine; several nonoral formulations are available or have been recently approved A number of novel formulations of existing medications are also in the later stages of clinical development but may be delayed because of CMC issues Key to effective treatment is providing right medication with the right formulation for the right type of migraine attack Employing an attack-based care approach may help achieve this goal In conclusion, migraine is highly common and can be identified and diagnosed using the ICHD-3 criteria [or ID-Migraine as a shortcut]. Use SNOOP when you're thinking about whether the patient needs a workup. 12 Go online to complete the post-test and evaluation for CME credit

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14 CME Maximizing Relief: A Personalized Approach to the Acute Treatment of Migraine in an Era of New Therapeutic Delivery Mechanisms Expert commentary is based on data from recent medical literature. The materials presented here are used with the permission of the authors and/or other sources. These materials do not necessarily reflect the views of PeerView Press or any of its partners, providers, and/or supporters. This CME activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education. This activity is supported by an educational grant from Avanir Pharmaceuticals, Inc. PVI, PeerView Institute for Medical Education, and Medical Learning Institute, Inc. are responsible for the selection of this activity's topics, the preparation of editorial content, and the distribution of this activity. The preparation of PeerView activities is supported by educational grants subject to written agreements that clearly stipulate and enforce the editorial independence of PVI and Medical Learning Institute, Inc. Our activities may contain references to unapproved products or uses of these products in certain jurisdictions. For approved prescribing information, please consult the manufacturer's product labeling. No endorsement of unapproved products or uses is made or implied by coverage of these products or uses in our activities. No responsibility is taken for errors or omissions in activities. Copyright , PeerView Press Sign up for alerts on new clinical advances and educational activities in your specialty: New and improved source for free CME/CE