Jessica Ailani, MD, is the director of the MedStar Georgetown Headache Center, and an associate professor of neurology at MedStar Georgetown University Hospital. She is involved in clinical trials of several potential new agents for migraine. An editor from The American Journal of Managed Care® recently conducted a question and answer session with Dr Ailani on the treatment and prevention of migraine.
The American Journal of Managed Care®
(AJMC®): What are some of the recent advances in the understanding of the biology of migraine?
Jessica Ailani, MD: We are starting to have a better understanding of the different pathways and the different parts of the brain that are involved in migraine. We have known that serotonin plays a role, but in the last several decades we have come to realize that dopamine may play a role in migraine prodrome, calcitonin gene-related peptide [CGRP] plays a role in migraine pathophysiology, nitrous oxide and glutamate changes are involved in migraine, and the thalamus and hypothalamus are involved in migraine pathophysiology.
Future targets currently being evaluated include pituitary adenylate cyclase-activating peptide, delta-opioid receptors, transient receptor potential vanilloid receptor 1, and glutamate.
: What are the phases of a migraine attack? What symptoms do patients experience during each phase, and how long does each phase last?
Ailani: There are 5 phases in migraine. Not all patients experience all phases and it is possible that some phases may happen in 1 migraine attack and others in another migraine attack. The total time from prodrome to postdrome can be up to 3 days, if a patient experiences all phases.
Prodrome (premonitory symptoms): This phase can occur up to 24 hour prior to headache. Symptoms can include mood changes (feeling irritable or depressed), food cravings (eg, for carbohydrates, chocolate), dizziness, mild cognitive changes, urinary retention, and nausea. Also, a sense of feeling unwell is often described. Up to 77% of patients experience a premonitory symptom.1
Aura: This phase involves neurological symptoms and often occurs prior to a migraine headache but can occur during a headache attack. Worldwide, 28% of patients with migraine experience aura.2 Patients commonly experience visual symptoms (90% of the time), including one-sided changes in vision. For example, they may report seeing bright flashing dots then dark spots; zig zag, colorful, or bright lines; blurring; or loss of vision often starting in the middle or peripheral vision and expanding over time.2,3 Patients who have aura may not have aura with every headache attack and may have aura with no headache pain. Some patients have other neurological symptoms such as one-sided numbness, weakness, or speech or balance changes.
Headache: This phase is characterized by headache, which is the symptom that gets the most attention and can cause significant disability if untreated. Migraine pain is moderate to severe, can affect 1 side of the head, may be worse with activity, and may be throbbing or pulsating in nature. The pain is accompanied by nausea and/or vomiting, or sensitivity to light or sound. Patients often describe difficulty with focus, concentration, and language skills. In addition to headache, patients may experience dizziness, appetite changes, mood changes, and a general sense of feeling unwell.
Postdrome: During this phase, patients experience mild headache, mild cognitive changes, changes in frequency of urination, dizziness, and fatigue. Patients often describe feeling hung over.
Interictal time period: The last phase of migraine is the period between attacks.
: Patients often manage their migraines by self-medicating with a combination of over-the-counter and prescription medications. How common is medication overuse, and what are the potential consequences?
Ailani: Medication overuse is very common, but it is important to understand that there is a difference between medication overuse and medication overuse headache (MOH). Medication overuse occurs frequently among patients with migraine as numerous medications are easy to obtain over the counter, and sometimes patients see several clinicians who prescribe different medications. Patients can end up using too many medications and the risks are tremendous. Newer studies show a high incidence of peptic ulcer disease in patients with migraine. We see this frequently in our young migraine patients who end up overusing NSAIDs [non-steroidal anti-inflammatory drugs]. We also see fluctuations in kidney and liver function, especially when medications are mixed. There is also a risk of overdose or over sedation if patients start combining sedating medications during a severe migraine.
MOH is a distinct type of headache. A diagnosis of MOH is made when a patient frequently takes acute medications to treat migraine (eg, triptans, mixed analgesics, butalbital-containing compounds, and opioids). In MOH, the medication itself increases the frequency of headache. To make the diagnosis, the offending medication is stopped. We would then expect migraine frequency to decrease. The problem with this approach is that we don’t ever recommend discontinuing acute medications without starting preventive medications to reduce migraine frequency. What is the chance that migraine frequency improves because the patient starts taking preventive medication versus because they stop excessive use of acute medication? What is the chance that the patient began to use more acute medications because the disease was not well controlled and if it were better controlled, the headache frequency would come down? I think it is hard to say.
It is debated whether NSAIDs cause medication overuse headache.4 The literature suggests if certain NSAIDs are used 8 to 9 days per month, they provide protection from migraine.5 The literature also suggests that if NSAIDs are used more than 15 days per month, they can cause MOH.3
My general suggestion when dealing with medication overuse is to discuss the danger of overuse with the patient, start a preventive, and gradually reduce the overused medication versus switch the acute treatments to something that is less likely to cause MOH. In general, opioids and butalbital should be avoided. Both opioids and butalbital may trigger MOH, [and when they do, the cycle of] MOH is much harder to break because of increased central sensitization caused by these agents.
: Could you describe the impact of migraine prevention on patients, caregivers, family members, and employers?
Ailani: The burden of migraine is large and affects quite possibly all of us. Migraine tends to occur more often in women in their 30s and 40s.6,7 With most women in the workplace, and those decades being peak productive years, every day lost to migraine affects employers, productivity, and the household. Patients will often avoid discussing their disease with friends or coworkers for fear of stigma. They may push through at work in order to be physically present, then get home and go to bed without spending time with friends and family. They may be physically present at work but are not as productive as they would be if they were not having a migraine.
: What preventive medication options are available? How do you select among the available options for an individual patient?
Ailani: There are numerous options for migraine prevention that are used by neurologists to reduce migraine frequency, including topiramate, valproic acid, propranolol, nadolol, metoprolol, onabotulinumtoxinA (prophylaxis for chronic migraine), erenumab, fremanezumab, and galcanezumab. Sometimes other medications can be used for migraine prevention that are not FDA approved specifically for migraine prophylaxis. Erenumab, fremanezumab, and galcanezumab are the only medications that were developed specifically for migraine prevention, taking into consideration the pathophysiology of the disease; the remainder were originally developed for other indications such as epilepsy and hypertension.
When working with a patient on a treatment plan, I present options to the patient and help them select the best option for them, taking into account side effect profiles, the patient’s goals for treatment, and their lifestyle and preferences. These drugs all have good data in the prevention of migraine, but they come in different formulations with different side effects and different costs and coverage concerns. All this needs to be reviewed with the patient in order to help them make a decision.
: From your standpoint, how do managed care policies impact patient access to acute migraine treatment or preventive medications?
Ailani: Managed care policies significantly restrict access [to treatment and preventive medications for migraine]. When making choices about options, we always have to consider managed care policies first, followed by patient preference. While cost savings is important, it is also important for managed care to take into consideration the impact of migraine on both patients and society in terms of reduced quality of life, decreased productivity, and negative effects on social relationships.
: From your perspective, what are some of the unmet needs in acute migraine treatment and in migraine prevention? What does the future hold for patients with migraine?
Ailani: There remains an unmet need for more options that are migraine-specific and that have fewer side effects. Also, we need additional options with different mechanisms of action. Hopefully, all patients will be able to access an effective option that is well tolerated in terms of side effects. Currently, up to half of our patients are left with options that cause significant side effects or that are not effective enough to allow them to live their life to full potential.
1. Laurell K, Artto V, Bendtsen L, et al. Premonitory symptoms in migraine: a cross-sectional study in 2714 persons. Cephalalgia. 2016;36(10):951-959. doi: 10.1177/0333102415620251.
2. DeLange JM, Cutrer FM. Our evolving understanding of migraine with aura. Curr Pain Headache Rep. 2014;18(10):453. doi: 10.1007/s11916-014-0453-0.
3. Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, 3rd ed. Cephalgia. 2018;38(1):1-211. doi: 10.1177/0333102417738202.
4. Holland S, Silberstein SD, Freitag F, Dodick DW, Argoff C, Ashman E; Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1346-1353. doi: 10.1212/WNL.0b013e3182535d0c.
5. Lipton RB, Serrano D, Nicholson RA, Buse DC, Runken MC, Reed ML. Impact of NSAID and triptan use on developing chronic migraine: results from the American Migraine Prevalence and Prevention (AMPP) study. Headache. 2013;53(10):1548-1563. doi: 10.1111/head.12201.
6. Ford JH, Jackson J, Milligan G, Cotton S, Ahl J, Aurora SK. A real-world analysis of migraine: a cross-sectional study of disease burden and treatment patterns. Headache. 2017;57(10):1532-1544. doi: 10.1111/head.13202.
7. American Headache Society. The American Headache Society position statement on integrating new migraine treatments into clinical practice. Headache. 2019;59(1):1-18. doi: 10.1111/head.13456.