A Case-Based Discussion on Chronic and Episodic Migraine ... A Case-Based Discussion on Chronic and...

A Case-Based Discussion on Chronic and Episodic Migraine Prevention and Acute Migraine Management Presentation 1

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Dr. Silberstein: Hello, this is Dr. Stephen Silberstein from Thomas Jefferson University. Welcome to this educational activity on migraine prevention and management. This activity comprises two separate presentations. The slides, transcript, audio, Practice Aids, and other activity features are available for download for easy access anytime, anywhere. After completing the activity, access the post-test and evaluation form by clicking the red "Credit" button to the right.




Disclosures Course Director and Interviewee

Stephen D. Silberstein, MD, has a financial interest/relationship or affiliation in the form of: Consultant for Allergan, Inc.; Amgen Inc.; Capnia; Coherex; Eli Lilly and Company; GlaxoSmithKline; Iroko Pharmaceuticals Inc.; MAP Pharmaceuticals; Medtronic, Inc.; National Institute of Neurological Disorders and Stroke; Nautilus Neurosciences; Neuralieve Inc.; Novartis Corporation; NuPathe Inc.; OptiNose US Inc.; Pfizer Inc.; St. Jude Medical, Inc.; and Zogenix, Inc. Grant/Research Support from Allergan, Inc.; Bristol-Myers Squibb; Cumberland Pharmaceuticals Inc.; electroCore; Eli Lilly and Company; Merck & Co., Inc.; OptiNose US Inc.; St. Jude Medical, Inc.; and Troy HealthCare. Interviewee

Deborah Friedman, MD, has a financial interest/relationship or affiliation in the form of: Consultant for MAP Pharmaceuticals and Zogenix, Inc. Grant/Research Support from Gammacore (pending) and Merck & Co., Inc. Speakers Bureau participant with Allergan, Inc. CME Reviewer

Kalina Sanders, MD, has a financial interest/relationship or affiliation in the form of: Consultant for EMD Serono, Inc. Speakers Bureau participant with EMD Serono, Inc./Pfizer, Inc.; Biogen Idec; Teva Pharmaceuticals, Ltd.; and Novartis Pharmaceuticals Corporation. All financial relationships listed above have ended as of June 2012. Medical Director Kirk A. Tacka, PhD

PVI, PeerView Institute for Medical Education Kirk A. Tacka, PhD, currently has no financial interests/relationships or affiliations in relation to this activity.




Established and Emerging Strategies for Chronic Migraine Prevention and

Contemporary Approaches for Treating Severe Migraines

Narrator: In this presentation, Dr. Stephen Silberstein uses a case study to discuss strategies for chronic migraine prevention and contemporary approaches for treating severe migraine. Dr. Silberstein: I'm going to be starting with E.S., a 36-year-old woman who is a high school administrator who presents with a long history of headache. The pain typically occurs on one side in the temples, and occasionally in the back of her head. There is no history of visual disturbances with the headache. Typically, she has three to four attacks per month, lasting at least 72 hours. During the past 4 months, this has increased to five to six per month with similar duration. She worked through the pain in the past, dimmed the lights in her office, wore sunglasses, and minimized movement. However, the attacks have become increasingly disabling and she has missed multiple days of work over the past 4 months. Sodium valproate decreased headache frequency and severity, but was poorly tolerated. And typically she consumes six to eight aspirin/acetaminophen/caffeine tablets per day.




There's a family history of headache in her father; otherwise, unremarkable.




Dr. Silberstein: Her physical and neurologic examinations were normal. What was her diagnosis? Chronic migraine without aura. The question is: what preventative strategies have been shown to be safe and effective in individuals with chronic migraine such as E.S.?




Q4W: every 4 weeks; Q12W: every 12 weeks. 1. Dodick DW et al. Headache. 2010;50:921-936.

Dr. Silberstein: Let's talk about the PREEMPT trials. These were two large phase 3, multicenter, pivotal trials. Each included a 24-week randomized, double-blind phase followed by a 32-week open-label phase. Patients were randomized on onabotulinumtoxin type A, 155 to 195 units, or placebo, with injections being given every 12 weeks. The study visits occurred every 4 weeks. The primary variable in the study was a change from baseline and the frequency of headache days. As you can see from the graph, beginning at 4 weeks and continuing throughout the entire course of the study, onabotulinumtoxin was superior to placebo in headache days per 28 days in the change from baseline.




HIT-6: Headache Impact Test–6. 1. Dodick DW et al. Headache. 2010;50:921-936.

Dr. Silberstein: Let's look at the pooled analysis of the phase 3 PREEMPT trials, so-called secondary endpoints. There was a significant difference favoring onabotulinumtoxin type A over placebo on the following endpoints: the change from baseline in frequency of migraine days, the change from baseline in frequency of moderate/severe headache days, the change in total cumulative hours of headache on headache days, the change in frequency of headache episodes, and the change in the frequency of migraines or problem migraine episodes and the percentage of patients with severe HIT-6 score, which is the measure of disability.




1. Dodick DW et al. Headache. 2010;50:921-936.

Dr. Silberstein: What about adverse events? Most of them were related to neck pain. Some were muscle weakness, some were eyelid ptosis. Some patients have neck or injection-site pain, but that did not differentiate between the two groups: headache, as you would expect, and myalgia, as you'd expect, in this population. But in general, the drug is well tolerated.




1. Aurora SK et al. Headache. 2011;51:1358-1373.

Dr. Silberstein: Let's look at the PREEMPT clinical trials at 56 weeks. Patients originally treated with onabotulinumtoxin type A continued to do well, but the patients treated initially with placebo never caught up, suggesting a disease-modifying effect. Most patients completed the open-label phase. Few discontinued it. And there were no new safety or tolerability issues that emerged.




1. Silberstein SD et al. Headache. 2007;47:170-180. 2. Diener HC et al. Cephalalgia. 2007;27:814-823.

Dr. Silberstein: Let's look at the efficacy and safety of topiramate for chronic migraine prevention. The trials included 306 patients between 18 and 65 years of age, who had 15 or more headache days per month. And they were randomized to either placebo or to topiramate. The most commonly reported adverse events in the topiramate group were paresthesias, upper respiratory infections, which occurred in just about everybody, and fatigue. Continuations due to adverse events occurred in about 11% of the topiramate subjects and about 6% of the placebo subjects. There were no serious adverse events. And if you look at the data in terms of mean reduction in migraine or migrainous days, or headache days from baseline, topiramate was superior to placebo. And the results were quite similar in the TOP-CHROME study of Chris Diener.




CGRP: calcitonin gene-related peptide. 1. Lionetto L et al. Expert Opin Emerg Drugs. 2012;17:393-406.

Dr. Silberstein: What are some of the additional therapies under investigation for chronic migraine? Levetiracetam has been tried, magnesium valproate, lacosamide, BGG-492, serotonin agonists, CGRP receptor antagonists, ML-1 agonists, orexin receptor antagonists, plant-derived compounds, and other drugs.




Dr. Silberstein: Let's go back to E.S. Onabotulinumtoxin type A was used as a preventative strategy, 155 units, which is the PREEMPT protocol, every 12 weeks. At 4, 8, and 12 weeks follow-up, the patient reports a decrease in both the number and the duration of attacks per month. Approximately 4 weeks after the second dose of onabotulinumtoxinA, she called the office and reports experiencing a severe migraine, including nausea, vomiting, and disabling phono- and photophobia. How can you treat her?




SC: subcutaneous. 1. Silberstein SD. Clin Pharmacol Ther. 2013;93:78-85. 2. Ferrari MD et al. Lancet. 2001;358:1668-1675. 3. Tfelt-Hansen P. Cephalalgia. 1998;18:532-538. 4. Dahlof C, Lines C. Expert Opin Investig Drugs. 1999;8:671-685.

Dr. Silberstein: If you look at triptans for the acute treatment of migraine, there are a number of triptans that are currently licensed in the United States: almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, zolmitriptan, and sumatriptan. All are available in oral formulations, sumatriptan and zolmitriptan as a nasal spray, and sumatriptan as an injection. I think the crucial issue is these are all for the acute treatment of migraine and not tested in patients with very severe or frequent headache.




IN: intranasal. 1. Silberstein SD. Clin Pharmacol Ther. 2013;93:78-85. 2. Ferrari MD et al. Lancet. 2001;358:1668-1675. 3. Tfelt-Hansen P. Cephalalgia. 1998;18:532-538. 4. Dahlof C, Lines C. Expert Opin Investig Drugs. 1999;8:671-685.

Dr. Silberstein: The triptans have never been studied carefully in patients with very frequent migraine. In fact, triptans are very likely to produce [medication] overuse headache and increased headache frequency and convert episodic to chronic migraine. For that reason, many headache experts use a medication called DHE, or dihydroergotamine. In head-to-head trials, it's as effective as the triptans. It has the advantage of less recurrence and is much, much less likely to produce medication overuse headache. Narrator: The use of dihydroergotamine for the treatment of acute migraine is discussed in greater detail by Dr. Friedman in the next presentation




Dr. Silberstein: E.S. was treated with sumatriptan 50 mg. Her migraine symptoms subside approximately 2 hours later, and there were no symptoms of recurrent headache 24 hours later. The patient continues her current preventative regimen for chronic migraine, and she continues to be monitored closely for any increases in headache frequency, as well as the development of acute migraine exacerbations. In general, patients treated with a preventative medication, as the headaches come under control, respond better to their acute medication. And I believe this is what we saw here.




Dr. Silberstein: Onabotulinumtoxin type A is the first preventative therapy approved for chronic migraine. Additional therapies have either been shown to have efficacy for the prevention of chronic migraine or are being investigated in this patient cohort. Although available choices of medication for acute migraine treatment have changed, there's still a need for more specific and more potent agents.




Considerations for Episodic Migraine Prevention and the Potential Role of Novel Agents for Acute Migraine Management

Narrator: In this presentation, Dr. Deborah Friedman explores strategies for the prevention of episodic migraines. She also discusses the potential role of novel agents for acute migraine management. Dr. Friedman: Our patient is a 41-year-old man who presents with headaches. B.R. has had headaches since his early 20s, and he describes the pain as throbbing. It's moderate in intensity, located around his left eye. There's sensitivity to light and noise. But there's no history of any aura symptoms. Over the past few months his headaches have increased to two or three per week. And he says that he's missing several days of work every month because of increasing frequency and severity of his headaches. He's currently treating his headaches with eletriptan in combination with an antiemetic, but his symptoms really don't resolve for several hours after taking the medication. He has an unremarkable past medical history, and his family history is also unremarkable.




Dr. Friedman: When you see him in the office, he has a normal physical exam and a normal neurologic exam. So he meets criteria for episodic migraine without aura. And since he's having such frequent headaches, we're going to think about preventative therapy.




1. Silberstein SD et al. Neurology. 2012;78:1337-1345.

Dr. Friedman: So according to the American Academy of Neurology evidence-based guidelines that were published in 2012, there are four major categories of medications that are considered class A for migraine prevention. The first of these agents is divalproex sodium, or sodium valproate. That has been shown to be effective in migraine prevention based on [multiple] class I studies in both adults and in teenagers. Long-term use of valproate is associated with weight gain that may be substantial, as well as tremor, GI side effects, and hair loss. The most worrisome side effects with divalproex are rare, fortunately, but they include pancreatitis and liver failure. Importantly, in young women of childbearing potential, the risk of teratogenicity should also be considered with divalproex. Topiramate in doses between 50 and 200 mg daily have been studied in numerous double-blind randomized trials, and topiramate has been shown to be effective for migraine prevention. About 15% of subjects in the studies experienced adverse events, most typically paresthesias, sleepiness, and gastrointestinal symptoms.




There have been several head-to-head studies of topiramate with other agents that are used for migraine prevention, such as propranolol, valproate, and amitriptyline. And the efficacy seems to be quite similar, although topiramate has often been better tolerated than the other agents in those trials.




1. Silberstein SD et al. Neurology. 2012;78:1337-1345. 2. Stanley Stellar et al. JAMA. 1984;252:2576-2580.

Dr. Friedman: The next class of agents is the beta blockers. The most commonly used is probably propranolol, which has efficacy for migraine prevention, as shown in multiple class I studies. The most common adverse events of propranolol include fatigue and lethargy, orthostatic hypotension, exercise intolerance, depression, and weight gain. Timolol and metoprolol can also be used for migraine prevention, and seem to be better tolerated than propranolol. Lastly, frovatriptan has been shown to be effective for the short-term prevention of menstrually related migraine.




Dr. Friedman: So B.R. is started on topiramate at 25 mg at bedtime, and the dose is gradually increased to a final dose of 100 mg daily. [At] his 1-month follow-up visit, he reports that his headaches are decreasing in frequency and severity since commencing preventative therapy. However, he returns for follow-up, and he experiences more acute migraine symptoms that include severe sensitivity to light and noise and severe nausea and vomiting. So considering his history with triptan therapy that worked somewhat, but was not a complete success, what other strategies might be useful for treating his acute migraines?




DHE: dihydroergotamine. 1. Silberstein S. Clin Pharmacol Therap. 2013;93:78-85. 2. Monteith TS et al. Curr Treat Opt Neurol. 201;13:1-14. 3. Rizzoli PB. Continuum Lifelong Learning Neurol. 2012;18:764-782. 4. Saper JR, Silberstein S. Headache. 2006;46(Suppl 4):S171-S181. 5. Rabbie R et al. Cochrane Database Syst Rev. 2010;10:CD008039. 6. Magis D, Schoenen J. Curr Opin Neurol. 2011;24:203-210.

Dr. Friedman: Ergots have been used for many years for the treatment of acute migraine. Their mechanism is less specific than triptans' in serotonin receptor agonism, and they interact with other receptors as well, which likely explains both their efficacy and their side-effect profile. They are associated with vasoconstriction. They commonly produce nausea. And pretreatment with an antiemetic is generally necessary. Contraindications to the use of ergots include vascular disease, uncontrolled hypertension, renal or hepatic failure, and pregnancy. Dihydroergotamine is probably the most widely available ergot that is used in the treatment of migraine today. It is currently available as both a nasal spray and an injection. The nasal spray is administered by using one puff in each nostril, repeating in 15 minutes, for a maximum dose of 2 mg/day.




Dihydroergotamine can be injected, and some patients self-administer the medication at home. It can be given subcutaneously or intramuscularly at 0.5- to 1-mg doses. It can also be used intravenously. In addition, nonspecific therapies, including nonsteroidal anti-inflammatory drugs, acetaminophen, and aspirin, have often and long been used alone and in combination with other agents for the acute treatment of migraine. Many clinicians will prescribe either opioids or butalbital for symptomatic treatment, but these medications are really not recommended for the treatment of migraine. They tend to be ineffective and increase the risk of medication overuse headache, which renders the patient with more frequent migraines that are more difficult to treat.




1. Aurora SK et al. Headache. 2011;51:507-517.

Dr. Friedman: An emerging therapy for acute migraine treatment is orally inhaled dihydroergotamine. A phase 3 randomized, double-blind, placebo-controlled study of orally inhaled DHE was conducted in 903 adult patients with a history of episodic migraine and compared to placebo that was administered in the same manner. You can see, looking at the graph on the left, that when looking at post-treatment pain relief in various time intervals that the inhaled DHE in the gray bars was statistically significantly superior to placebo, the black bars, at all time points except at 10 minutes. The graph on the right shows pain freedom. And again, with similar results, orally inhaled DHE was statistically superior in achieving pain freedom at all time points except the first 10 minutes.




1. Aurora SK et al. Headache. 2011;51:507-517. 2. Kori S et al. Clin Ther. 2012;34:1920-1928.

Dr. Friedman: Additional data from the study shows that orally inhaled DHE was also significantly superior to placebo for patients achieving phonophobia relief at 2 hours and elimination of photophobia at 2 hours. The study also showed that the adverse event rate was quite low overall. The nausea rate was 4.5%, and these patients were not pretreated with an antiemetic, and the drug was very well tolerated. There was no association with EKG abnormalities, particularly prolonged QTC intervals, and they also studied asthmatics and found no effect on pulmonary function testing with the medication. A post hoc subanalysis showed that the product was similarly effective in patients whether or not allodynia was present at baseline [Tepper SJ et al. Headache. 2012;52:37-47].




1. Tepper SJ et al. Mayo Clin Proc. 2011;86:948-955.

Dr. Friedman: Additionally, a post hoc analysis looked at differences in the 2-hour pain relief between inhaled DHE and placebo with respect to the time that the drug was used in relationship to headache onset and found that with an interval up to 8 hours or more after headache onset, there was still a statistically significant benefit to inhaled DHE compared to placebo, with about 50% of patients having 2-hour headache relief, even though they waited 8 hours to use the medication.




1. Farkkila M et al. Lancet Neurol. 2012;11:405-413.

Dr. Friedman: Lasmiditan is another agent that is on the horizon for acute treatment of episodic migraine. These data come from a phase 2, randomized, dose-ranging study of lasmiditan that was performed in Europe. The efficacy of the drug increased in parallel with the dose of the drug. The most common side effects were dizziness, fatigue, vertigo, paresthesias, and somnolence. Lasmiditan appears to be safe and effective for treatment of acute migraine. The side effects of the drug also increased with increasing doses of the drug, and further studies are necessary to determine the potential of this agent for migraine therapy.




Dr. Friedman: So back to our patient. B.R. was treated with intranasal dihydroergotamine in combination with an antiemetic. His migraine symptoms subsided in just a couple of hours after taking this combination with little to no symptoms of recurrent headaches 24 to 48 hours later. He continues to use his current preventative medication, topiramate, for episodic migraines, and he is also monitored closely for any increases in headache frequency and severity, as well as the development of recurrent headaches following treatment of acute migraine attacks.




Dr. Friedman: So in conclusion, valproate, topiramate, metoprolol, propranolol, and timolol all have level A efficacy for episodic migraine prevention, with frovatriptan having level A efficacy for menstrual migraine prevention. In addition to the currently available triptans, DHE and nonspecific therapies, such as nonsteroidal anti-inflammatory drugs, are effective for the treatment of acute migraine. Orally inhaled dihydroergotamine and lasmiditan are among the agents currently under investigation for the treatment of acute migraine.




Narrator: This activity has been jointly sponsored by the University of Florida College of Medicine and PVI, PeerView Institute for Medical Education.

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