As scientists, we're natural skeptics. So it’s not surprising to see that the adoption of complementary or wellness-based approaches in migraine care has been slower than some might hope. 

Despite reservations, quality clinical evidence shows that these approaches, including exercise, cognitive behavioral therapy, and breathing/meditation, can all be effective in patients with migraine and help reduce not only migraine frequency and severity but also the overall burden that the condition places on patients.

As with any other disease, there are things said in the media and unfounded claims made about purported migraine treatments that aren’t evidence-based. It’s our job as clinicians to clearly inform our patients and help them make educated decisions about their care. 

With the newest class of migraine therapies, we are clearly witnessing an unprecedented time in treatment. We are able to reduce migraine frequency and severity in patients with both chronic and episodic disease and even in patients with debilitating disorders like cluster headache. But we have to look at the big picture: Reducing just the number of monthly migraine days doesn’t necessarily mean that our patients are suddenly well; producing clinically meaningful change is very important and encompasses not only the number of migraines that a person experiences but also symptom management and how the disease affects their day-to-day life. In the end, if patients’ quality of life is still significantly affected by their disorder, we haven’t completely done our job. And that’s where complementary medicine has a place in your practice. 

Complementary therapies are especially relevant for patients who experience adverse effects from pharmaceutical treatments, have contraindications to those treatments, or have an inadequate response, as well as for patients who are planning for pregnancy, are pregnant, or are breast-feeding. An emphasis on lifestyle and behavioral changes can also benefit patients with medication overuse and those with high levels of stress. In many cases, clinicians can use wellness-based approaches in conjunction with pharmaceutical therapies to improve overall treatment benefit.

Several complementary therapies, though not conclusively supported by clinical evidence, are widely used with a good degree of success. These include acupuncture, chiropractic care, hypnosis, and physical therapy. 

"IN MANY CASES, CLINICIANS CAN USE WELLNESS-BASED APPROACHES IN CONJUNCTION WITH PHARMACEUTICAL THERAPIES TO IMPROVE OVERALL TREATMENT BENEFIT." 

Significant evidence also supports the use of behavioral therapies for headache and migraine; these include relaxation training, biofeedback, and cognitive-behavioral therapy.

 These therapies help teach the patient how to modify physiological responses related to headache or migraine, including how to reduce muscle tension and nervous system arousal and stress related to triggers. 

Clinicians also cannot forget the impact of other good lifestyle habits, including exercise, good sleep hygiene, hydration, and vitamin support, notably with B2 and magnesium. Indeed, results of a 2011 study by Varkey et al

 showed that exercise 3 times per week, regular relaxation exercises, and topiramate use were all equally effective in reducing the frequency of migraines. Exercise can help reduce stress and improve sleep—2 central migraine triggers. 

Providing patients with support, resources, and access to wellness-based care can help them play a direct role in their disease management beyond taking their prescribed pharmaceutical therapy. In the end, taking better care of themselves both physically and mentally will help improve not only their migraine management but also their lives. 

Stephen D. Silberstein, MD, is a professor of neurology and the director of the Jefferson Headache Center at Thomas Jefferson University in Philadelphia, Pennsylvania. He is also Editor in Chief of NeurologyLive.

1. Puledda F, Shields K. Non-pharmacological approaches for migraine. Neurotherapeutics. 2018;15(2):336-345. doi: 10.1007/s13311-018-0623-6. 

2. Penzien DB, Taylor FR. Headache toolbox. Behavioral and other nonpharmacologic treatments for headache. Headache. 2014;54(5):955-956. doi: 10.1111/head.12369. 

3. Varkey E, Cider A, Carlsson J, Linde M. Exercise as migraine prophylaxis: a randomized study using relaxation and topiramate as controls. Cephalalgia. 2011;31(14):1428-1438. doi: 10.1177/0333102411419681. 

Articles

Clinical Viewpoint

Despite early reservations, available literature suggests that it may be time to invest in the utilization of wellness-based methods in the treatment of migraine.

Wellness for Migraine: Should You Buy In?

For years, no therapeutic area had been as ripe for new drug development as headache. Now, with a host of highly effective preventive therapies on the market, including anti—calcitonin gene-related peptide (CGRP) agents, clinicians are turning their attention to acute treatments, where cracks in the foundations of go-to OTC analgesics and triptans are hard to ignore. In an interview with 

™, Richard B. Lipton, MD, the Edwin S. Lowe Professor and vice chair of neurology, a professor of epidemiology and population health, and a professor of psychiatry and behavioral sciences at the Albert Einstein College of Medicine, and director of the Montefiore Headache Center, both in Bronx, New York, detailed the most urgent needs in migraine treatment and provided perspective on what will likely be another practice-changing period for the headache specialty.

Q:What makes headache and migraine in particular targets for safer, more effective therapies when several good treatment options are already available?

According to the Global Burden of Disease studies, migraine is the second-most-disabling disorder in the world, as measured by disability-adjusted life-years. The reason migraine plays such a prominent role in disability is because, first of all, it’s so common: Forty million Americans have migraine, and more than 1 billion people worldwide have migraine. Migraine produces so much disability because it’s a condition of long duration that affects people during their peak productive years. Migraine most often begins in adolescence or early adult life and may persist for many years. It produces a lot of interference with education and the workplace in the form of both absenteeism—missing work&mdash;and presenteeism&mdash;being at work while ill but unable to function with full effectiveness. In addition, migraine has an enormous burden on families because, again, it’s a disorder that’s very common in early and middle adult life.

There’s no question that since the early 1990s, we’ve made tremendous progress in migraine treatments, and there’s no question that triptans have been a major boon to people with migraine, but the triptans have limitations that we’ve become increasingly aware of the longer we’ve used them.

Although triptans have made a tremendous difference in migraine therapy, they certainly have limitations. One is that they produce a set of adverse effects that are called triptan sensations, which include flushing, sweating, and occasionally chest pressure. For some people, those adverse effects are difficult to tolerate and in turn limit use. A second limitation of triptans and, for that matter, all migraine therapies is that they don’t work for everyone. With so many millions of people with migraine, we believe there’s some diversity in terms of migraine mechanisms. The triptan mechanism works for a lot of people with migraine but not everyone. The final and perhaps most notable limitation of triptans is that they are vasoconstrictive agents, and [because] of that, the FDA label for triptans prohibits use in people who have had heart attacks, stroke, angina, claudication, ischemic colitis, and a variety of other disorders and recommends caution in people who are at high risk for those sorts of events.

Those contraindications have played out in 2 ways: In one way, people who have those triptan restrictions may well not be treated, but in addition, the real issues of cardiovascular safety have limited use among even people who might be able to safely take triptans. As a consequence, nearly 30 years into the triptan era, only something like a quarter of all migraine attacks treated with prescription drugs are treated with triptans. So triptans are underused and leave people with unmet needs for a number of reasons. Another issue with triptans is that they cause a phenomenon called rebound headache, or medication overuse headache. As triptans wear off, they may actually trigger headache, and if triptans are taken too often, that may make headaches worse. And that’s yet another important limitation for people with frequent migraine attacks. 

Ironically, I currently treat some people with disabling migraine with triptans despite concerns about cardiovascular safety, largely because I don’t have a good alternative. I think in a world where medications that don’t pose any cardiovascular risk [increasingly] become available, I think I will use triptans where they’re safe and effective. In cases where their safety is marginal or questionable, I think I’ll be more likely to use drugs that don’t constrict blood vessels, like the gepants or the ditans. 

Q: What is unique about these second-generation CGRP antagonists and ditans that might make them better suited for treatment of acute migraine? 

Over the past couple of years, there’s been an increasing emphasis on CGRP-targeted therapies, and we’ve known that CGRP plays an important role in migraine for a long time. We know that during migraine attack, CGRP is elevated in jugular blood. We know that successful treatment of migraine attacks results in reduction of CGRP levels in jugular blood. We know that CGRP, which is a peptide neural transmitter, is found in the pathways that play an important role in migraine, including the trigeminal nerve and the trigeminal nucleus caudalis. We know that if we give CGRP to people with migraine, that actually triggers a migraine attack, and we know that if we block CGRP with either monoclonal antibodies or small molecules, that relieves migraine attacks. So there’s abundant evidence that CGRP plays a crucial role in the pathophysiology of migraine. Of course, the wonderful thing about the emerging and already-arrived treatments that target CGRP is that they’re very much designer drugs for migraine; they are very much agents that were developed to target a specific neurotransmitter system or the receptors that that neurotransmitter binds to. There’s now abundant evidence that that’s a highly effective therapeutic strategy. So it’s a great example of translational research in which human science and animal science demonstrate a mechanism of disease, namely involvement of CGRP, and then new therapeutics emerge that target a relatively novel molecular mechanism. 

One of the advantages of CGRP-targeted therapies is that they are not vasoconstrictors, and similarly, ditans, which are 5HT1F [5-hydroxytryptamine receptor 1F] blockers, are also free of vasoconstrictive adverse effects. On that basis, we believe that gepants and ditans are likely to be free of the cardiovascular issues that have limited the use of triptans. 

Q: How has our clinical trial evaluation of migraine therapies evolved with these new drugs, and what do the results suggest? 

As acute treatments, the 2 gepants that are furthest along, ubrogepant and rimegepant, are being developed as oral, small molecule, CGRP receptor blockers. There is a phase 2 study and 2 large-scale phase 3 studies for ubrogepant; for rimegepant, there is a phase 2 study and 3 large-scale phase 3 studies. Both development programs have as their co-primary efficacy end points pain freedom at 2 hours and freedom from most bothersome symptom at 2 hours. Freedom from most bothersome symptom is a relatively new end point in the migraine world. In the past, because we understood that migraine was a symptom complex, the FDA wanted acute treatments for migraine to relieve pain and relieve the cardinal associated symptoms of migraine, including nausea, photophobia, and phonophobia. The challenge we faced in trials was that perhaps 60% of patients had nausea with a particular attack. Relieving nausea in people who don’t have nausea is a somewhat difficult job, and when acute treatment trials failed, they usually failed on nausea simply because nausea was the least common of the cardinal associated symptoms. So as an alternative regulatory pathway, the way most bothersome symptom works is that immediately before treatment, patients designate which symptom—nausea, photophobia, phonophobia&mdash; is most bothersome to them. Then we’re guaranteed that they have the symptom we’re trying to relieve, and we simply measure the proportion of people who are free of that patient-designated most bothersome symptom 2 hours after taking therapy. Both the ubrogepant and rimegepant trials use 2-hour pain freedom and 2-hour freedom from most bothersome symptom as their primary end points. 

AS A CONSEQUENCE [OF CONTRAINDICATIONS], NEARLY 30 YEARS INTO THE TRIPTAN ERA...TRIPTANS ARE UNDERUSED AND LEAVE PEOPLE WITH UNMENT NEEDS FOR A NUMBER OF REASONS. 

In all the studies, highly statistically significant results were achieved. For both drugs, the level of freedom from pain at 2 hours is relatively modest, in about the 20% range. Some people have said, “If only 20% of people become pain free, is the drug worth using?” And I would point out several things. First, from the triptan trials, for the most part, the primary end point wasn’t freedom from pain at 2 hours; it was relief of pain at 2 hours. In the trials, freedom from pain means that you go from moderate or severe pain to pain that is absent. Relief means that you go from moderate or severe pain to pain that is mild or absent. When we look at pain relief rates, they are much higher [with the gepants], and when we look at relief of disability and restoration of function, that tends to travel with relief of pain and is achieved well before pain freedom is achieved. My belief is that 2-hour pain freedom is very useful as a regulatory end point, but it doesn’t fully reflect the benefits of treatment, which I think are better reflected by headache relief measures and by measures of restoration of function. 

Of course, cross-study comparisons are always hazardous, but lasmiditan actually achieved higher pain-free rates than ubrogepant or rimegepant. But one of the strengths of ubrogepant and rimegepant is that those medications are really highly tolerable. There are relatively few adverse effects, and with lasmiditan, there was some sedation [and] some dizziness observed in the trials and also an issue with driving. There was a study showing that after you take lasmiditan, ability to drive is impaired for up to 8 hours. So on the one hand, I think lasmiditan is probably a bit more effective than the gepants, but on the other hand, I also think it causes more adverse effects. When you’re looking for a drug that works through a mechanism different [from that of] triptans for those who don’t respond to triptans, when you’re looking for drugs for people who can’t tolerate triptans, or when you’re looking for a drug that doesn’t have the cardiovascular contraindications of triptans, my best guess is that we will end up using gepants before we use lasmiditan simply because of its better tolerability profile. 

That said, I think lasmiditan will be the treatment of choice particularly for people who have migraine at night that interferes with sleep. If you have a migraine and it’s bedtime and you want a little relief of headache, you won’t really mind taking a drug that might cause a little bit of sedation because you’ll sleep 8 hours and wake up in the morning and be able to drive to work. So I think lasmiditan will certainly play an important role in people for whom gepants don’t work, and I think it will play an important role for people who have migraine at night or are in a position where they can take a migraine medication and then take a nap and don’t need to drive to or stay at work. But I think for most patients, gepants will likely be used first. 

Q: Data from some of the trials of the preventive anti-CGRP therapies suggest a cumulative benefit of the drugs over time. Has there been any indication in the acute treatment trials of a similar effect? 

I think it’s important to note that in the past, we really drew a bright line between acute and preventive treatments. But the reality is that the distinction between acute and preventive treatment is being blurred. We know that CGRP-targeted therapies work acutely when they’re given in the form of gepants. We know they work very well in the form of monoclonal antibodies, and we actually also know that gepants, if given frequently enough, have a preventive effect. A third gepant that we haven’t talked about yet is atogepant. Allergan, [the manufacturer of atogepant], has a phase 2 study [whose results] show that in comparison to a placebo-treated group, atogepant is effective as a preventive treatment for migraine. And with [its agent] rimegepant in the long-term safety studies, Biohaven has shown that frequent use of rimegepant as an acute treatment actually reduces the number of monthly migraine days that treated patients experience. The fascinating thing for me is that if you take triptans too often, they may make your headaches worse, but if you take gepants quite often, they may work acutely and may deliver preventive benefits as well. How that plays out in practice I think remains to be seen, but certainly not causing medication overuse and not making headaches worse are big advantages, and potentially making headaches better with frequent use is an even bigger advantage. 

Q: Are there any dosing or administration advantages between the gepants, and has there been any indication that the therapies for acute migraine might be effective when used in conjunction with preventives? 

Ubrogepant and rimegepant were both studied as tablets, but rimegepant was also studied in an ODT [orally dissolving tablet] formulation. The ODT pivotal efficacy study was recently published in Lancet, and broadly speaking, the expectation was that the ODT formulation might work quicker because one of the ways to predict treatment response is the Tmax [time to maximum plasma concentration]. The Tmax for the ODT formulation is 30 minutes faster than the Tmax for the rimegepant tablet formulation, and overall, though there are no head-to-head data, it seems that the ODT formulation shows statistically significant differences relative to placebo at earlier points than the tablets, so the ODT formulation may be an advantage for rimegepant in terms of both convenience and rapidity of onset. 

In terms of conjunctive use, there are preliminary indications that they work. I was a coauthor on a study in which we evaluated patients who took rimegepant on top of a couple of different monoclonal antibodies, and we found that they consistently delivered pain relief on top of the monoclonal antibody. That’s interesting because some people predicted it wouldn’t work, essentially saying, “Well, if you block CGRP and then you get a migraine, something else must be going on. Therefore, incremental CGRP blockade shouldn’t deliver incremental benefit.” But the anecdotal experience that we have thus far suggests that gepants will work on top of monoclonal antibodies, and based on open-label treatment trials, they seem to really work quite well. In a way, that’s not surprising because what it suggests is that the antibodies don’t produce complete 100% blockade of CGRP, and so maybe in the setting of partial blockade, it could be that gepants will work even better because there’s less CGRP around to mop up. 

Q: Do you foresee any particular barriers that would prevent you from prescribing gepants as first-line treatment versus trying out treatment with a triptan or other acute medication first? 

I think the biggest barrier to using the newer therapies will be access and reimbursement. Triptans are now generic drugs, although they’re not tremendously inexpensive, nor are they tremendously expensive. Undoubtedly, gepants and ditans will be at a higher price point than triptans. I imagine that managed care will in some way impose guidelines that limit the use of gepants and ditans to people who have failed triptans for tolerability or efficacy or people who can’t take triptans because of cardiovascular adverse effects. What’s concerning right now is that there is evidence, some of which was recently reported at the American Headache Society meeting in July, that when people get triptans and choose not to continue them, they are most frequently prescribed opioids next, and the difficulty with that is that opioids make pain worse on a long-term basis and are associated with risk for transitioning from episodic to chronic migraine. So I think in headache specialty practice right now, if somebody fails one triptan, generally what we do is understand the nature of that failure and switch to another triptan. But most triptans are prescribed in primary care, and the predominant pattern is that if the triptan fails, [patients] go to an opioid. Honestly, I find that practice pattern worrisome because we know opioids make migraine worse in the long run. 

My hope is that if there’s an alternative to triptans that is safe and effective and that doesn’t put people at risk of medication overuse the way both triptans and opioids do, access will be relatively easy, though managed care ultimately will write step therapy guidelines that will determine who has access and who doesn’t. My hope is that the American Headache Society has a position paper that basically recommends the use of gepants and ditans in people who have tried and failed a couple of triptans for tolerability or efficacy and in people who have cardiovascular risk factors that would make triptans less than safe. I would add that if someone has very frequent headaches, gepants in particular might be better a choice because of that characteristic of [cumulative] treatment resulting in a reduction of monthly headache days. So the more you take the drug, maybe the less you need the drug, and in that way, gepants may be partially self-limited, which may be attractive to managed care. 

All 3 of the drugs that are closest to approval are important tools that I think will make life better for people with migraine. The reality is, with 40 million Americans with migraine, there’s certainly no 1-size-fits-all solution on the one hand, but on the other hand, it’s great having new options emerge. This is definitely an exciting time for clinicians who treat migraine, for scientists who study it, and for people who are seeking relief. 

New classes of acute migraine therapies on the cusp of FDA approval look to fill in long-standing gaps in care. 

Blurring the Lines of Migraine Treatment

Migraine is a highly prevalent and disabling disorder, with an estimated 1 in 6 individuals in the United States affected by migraines, and is one of the leading reasons for emergency department visits.

 Despite its high prevalence and impact on disability rates, migraine remains underrecognized and undertreated.

 Migraine attacks are characterized by unilateral headache accompanied by a cluster of other sensory, autonomic, and cognitive symptoms that may include photophobia, phonophobia, allodynia, pain upon movement, and nausea/vomiting; different stages marking the clinical course of migraine include the premonitory, aura, headache, and postdromal phases.

 Migraine can occur with or without aura,

 and depending on the days per month a patient is affected, it is classified as episodic (<15 migraine or headache days) or chronic (at least 15 days, with 8 or more as migraine days).

 Developments over the past few decades have led to migraine’s classification as a complex neurological condition rather than a vascular disorder, with multiple cortical, subcortical, and brainstem regions involved in pain initiation and the broad spectrum of symptoms.

In the current neurovascular model for migraine pathogenesis, pain is thought to originate from the trigeminovascular system, with secondary changes in cerebral perfusion; upon activation, trigeminal nociceptive neurons on dural blood vessels trigger the release of plasma proteins and vasoactive substances, including calcitonin gene-related peptide (CGRP), substance P, and neurokinin A.

 The release of vasoactive factors triggers vasodilation and dural plasma extravasation, resulting in neurogenic inflammation and thereby producing pain. Subsequently, these pain impulses are transmitted along the trigeminovascular system to the trigeminal nucleus caudalis and eventually to the higher cortical pain centers.

 Among the vasoactive factors invoked in migraine pathogenesis, CGRP has been pinpointed as a key mediator in migraine pathophysiology by promising data from clinical studies.

Migraine Pathogenesis and Progression: Role of CGRP

Two isoforms of CGRP are present in humans: α-CGRP, abundant mostly in primary spinal afferents from sensory ganglia, and ß-CGRP, found mainly in the enteric nervous system.

 The α-CGRP isoform (hereafter referred to as CGRP), a product of alternative splicing of calcitonin mRNA, is the predominant calcitonin gene product outside the thyroid and coexists with substance P in sensory nerves and neurons.

 The CGRP peptide family, which includes calcitonin, adrenomedullin, and amylin, has been found in the trigeminal system and central nervous system.

 CGRP family receptors consist of a multicomponent receptor system: a calcitonin receptor-like receptor (CLR) that must be linked with 1 of 3 receptor activity—modifying proteins (RAMPs) to generate a functional CGRP receptor and a receptor component protein; the CGRP receptor is composed of CLR and RAMP1.

CGRP is a 37-amino acid peptide with an N-terminal disulfide bond and amidated C terminus, both of which are required for CGRP receptor activation.

 Structural studies of the CLR—RAMP1 ectodomain complex indicate that small-molecule antagonists of the CGRP pathway block the peptide-binding cleft at the CLR–RAMP1 interface.

 Given its role in migraine pathogenesis, it is perhaps not surprising that CGRP has been shown to regulate the cardiovascular system, mediate neurogenic inflammation, and modulate nociceptive input.

 CGRP is expressed in >50% of the trigeminal neurons and in small- to medium-sized nociceptive nerve fibers (C-fibers) in both central and peripheral branches.

 Although CGRP is widely expressed in neurons of the cerebral cortex, the hippocampus, the cerebellum, the thalamic nuclei, the hypothalamic nuclei, and the brainstem nuclei, the cognate receptor components colocalize predominantly in some of the trigeminal neurons, satellite glial cells, and vascular smooth muscle cells.

 However, the CGRP peptide and receptor are rarely co-expressed in the same cells; CGRP is expressed/stored in small-to-mid-sized trigeminal neurons, whereas the CGRP receptor is found in large neurons.

Upon trigeminal nerve activation, CGRP released into the plasma is rapidly degraded (half-life <10 min), suggesting that CGRP-mediated effects are focused on release site—proximal regions.

 CGRP release promotes non—endothelium-mediated vasodilation.

 CGRP released from terminals of C-fibers can sensitize nearby A-fibers, which express functional CLR—RAMP1 CGRP receptors.

The role of CGRP in migraine pathogenesis and progression is supported by several lines of evidence. First, CGRP levels are elevated in serum between attacks of episodic and chronic migraine

; this increase is reversed upon treatment with triptans, the selective 5-hydroxytryptamine receptor agonists that are often used as first-line treatment for migraine because of their ability to mitigate pain by reducing neurogenic inflammation.

 Second, moderate to severe headaches akin to migraine are induced by injection of the CGRP peptide. Notably, induction of delayed migraine-like headaches occurs in migraineurs, but only initial nonmigraine headache symptoms are reported by nonmigraineurs. The final line of evidence is the observation of relief from both the pain and associated symptoms of migraine in clinical studies of selective CGRP receptor antagonists.

 Taken together, these data establish a central role for the CGRP—CGRP receptor axis in migraine pathophysiology (

The broad distribution pattern of CGRP and CGRP receptors provides numerous targets where the CGRP pathway could impinge on neuromodulation of light aversion, central sensitization, and

cortical spreading depression, processes involved in migraine generation and progression.

 In the periphery, CGRP promotes dilation of vascular beds. CGRP also contributes to neurogenic inflammation and peripheral sensitization of nociceptive neurons.

 Transgenic studies in mice have established a role for CGRP in light aversion, a pathway that is a surrogate for migraine photophobia.

 CGRP can also enhance glutamatergic signaling-driven synaptic transmission, thereby promoting central sensitization.

The evidence implicating CGRP in migraine pathogenesis has led to increased interest in development of CGRP/CGRP receptor antagonists, with data from the first proof-of-concept phase 2 trial (NCT02198339) published in 2004.

 This trial, which evaluated olcegepant, established the clinical validity of CGRP as a therapeutic target in treating acute migraine attacks; olcegepant yielded a response rate of 66% compared with 27% with placebo (

 Olcegepant was the first of the gepants, small molecule CGRP receptor antagonists, to demonstrate clinical efficacy in migraine management. Many gepants, including rimegepant, telcagepant, and ubrogepant, have since been evaluated in acute migraine treatment. However, the development of some gepants was terminated because of an inability to administer the formulation orally (olcegepant) or increased hepatotoxicity risk (telcagepant, which forms a liver-toxic metabolite not formed by other gepants).26,27 Investigators are currently evaluating 3 gepants—rimegepant, ubrogepant, and atogepant&mdash;in late-phase clinical studies.

In addition to small-molecule CGRP receptor antagonists, CGRP- or CGRP receptor—directed monoclonal antibodies (mAbs) have also gained momentum in migraine therapy.

To date, investigators have evaluated 4 antibody-based agents in clinical studies: eptinezumab, galcanezumab, fremanezumab, and erenumab.

Investigators are conducting or have conducted phase 3 clinical trials to evaluate several gepants for the treatment of migraine: ubrogepant (NCT02828020, NCT02867709) in the acute setting, atogepant (NCT02848326, NCT03700320) in the preventive setting, and rimegepant (NCT03732638) in the preventive setting. Preliminary data

 from 2 pivotal phase 3 trials for rimegepant, an oral CGRP receptor antagonist, showed that with a single dose of rimegepant, 19.2% (

 <.03 vs placebo) of 543 patients and 19.6% (

 <.001 vs placebo) of 537 patients achieved freedom from pain at 2 hours compared with 14.2% of 541 patients and 12.0% of 535 patients who received placebo, respectively.

 Overall, the study authors concluded that a “single dose of rimegepant, without any rescue medications, was superior to placebo for pain freedom and pain relief at 2 hours post-dosing.” Notably, rimegepant-treated patients showed improvement on measures of functional disability, with a greater proportion of patients achieving normal function, and the safety profile of rimegepant was similar to that of placebo, including liver function assessments.

Preliminary data for ubrogepant, also orally administered, from phase 3 trials have been reported.31,32 In the ACHIEVE I (UBRMD-01) study, 1327 adult patients were randomly assigned 1:1:1 to placebo or ubrogepant (50 mg or 100 mg) and were treated for a single migraine attack of moderate to severe headache intensity. The topline data showed that compared with placebo (11.8%), pain freedom at 2 hours after the initial dose was achieved by more patients randomized to both the 50-mg (19.2%, 

 = .0023 vs placebo) and 100-mg ubrogepant arms (21.2%, 

 Freedom from the most bothersome symptom at 2 hours was also observed in more patients taking ubrogepant at both 50 mg (38.6%, 

 = .0023 vs placebo) compared with placebo (27.8%).

 In the ACHIEVE II study, 1686 patients were randomized 1:1:1 to placebo or a lower dose of ubrogepant (25 mg or 50 mg) than in ACHIEVE I. Again, the results showed an improvement in pain freedom at 2 hours (20.7% [

 = .0285 vs placebo] in the 25-mg group, 21.8% [

 = .0129 vs placebo] in the 50-mg group, and 14.3% in the placebo group). Although the percentage of patients with freedom from the most bothersome symptom at 2 hours was higher for both ubrogepant doses compared with placebo, this difference failed to achieve statistical significance for the 25-mg dose.

 No hepatotoxicity was observed in either trial.

Preliminary phase 2/3 data from a clinical trial of atogepant, another oral gepant, indicated a significant reduction in mean monthly migraine days across all doses (10 mg once daily to 60 mg twice daily) compared with placebo. In addition, no concerns regarding hepatic safety were noted.

 Forthcoming phase 3 results for atogepant, along with results from studies of other gepants in acute and prophylactic treatment, will help further clarify the role of gepants in the migraine treatment paradigm.

CGRP/CGRP Receptor—Targeted mAbs in Migraine Therapy

Therapeutic mAbs targeting CGRP are being developed for the treatment of migraine; of these, 3—galcanezumab (Emgality; Eli Lilly), fremanezumab (Ajovy; Teva), and erenumab (Aimovig; Amgen, Novartis)&mdash;have gained FDA approval for migraine treatment (

Erenumab, a fully human immunoglobulin (Ig) G2 mAb, was the first CGRP receptor—targeted mAb approved for migraine.

 Data from 2 phase 3 studies, ARISE and STRIVE, established its efficacy and safety in migraine prevention. In the ARISE study, which included 577 patients randomized to monthly injections of 70 mg erenumab or placebo, 39.7% (vs 29.5% in placebo, 

 = .010) achieved a ≥50% reduction in monthly migraine days.

 In STRIVE, 955 patients were randomized to monthly injections of erenumab 70 mg, erenumab 140 mg, or placebo; data showed a ≥50% reduction in monthly migraine days in 43.3% of patients in the 70-mg group (P <.001 vs placebo), 50.0% in the 140-mg group (

 <.001 vs placebo), and 26.6% in the placebo group.

 Adverse event profiles for erenumab and placebo were comparable in both studies.

Galcanezumab, which binds both CGRP isoforms, recently gained FDA approval for preventive migraine treatment.

 Results from 2 phase 3 clinical trials (EVOLVE-1, 862 patients randomized 1:1:2 to galcanezumab 120 mg, 240 mg, or placebo; and EVOLVE-2, 915 patients randomized 1:1:2 to galcanezumab 120 mg, 240 mg, or placebo) showed a ≥50% reduction in monthly headache days in 62.3% (

 <.001 vs placebo) of patients in the 120-mg group, 60.9% (

 <.001 vs placebo) in the 240-mg group, and 38.6% in the placebo group (EVOLVE-1).

 <.001 vs placebo) was observed in the 120-mg group, 57% (

 <.001 vs placebo) in the 240-mg group, and 36% in the placebo group.

 Although treatment-emergent antidrug antibodies were seen in a small percentage of patients, no effects on safety or tolerability were noted in either study.

Fremanezumab, a humanized IgG2 mAb that binds both isoforms of CGRP, was also recently FDA approved for preventive treatment of migraine.

 In a phase 3 trial (NCT02621931), 376 patients were randomly assigned to fremanezumab quarterly, 379 to monthly, and 375 to placebo. Results showed that 41% (

 <.001 vs placebo) of patients in the monthly and quarterly groups, respectively, achieved a ≥50% reduction in monthly headache days compared with 18% in the placebo group.49 In another phase 3 study, 875 patients with episodic migraine were randomized to monthly low-dose 225-mg injections, quarterly high-dose 675-mg injections, or placebo. Results showed that 47.7% (

 <.001 vs placebo) of patients in the monthly and quarterly groups, respectively, achieved a ≥50% reduction in monthly migraine days compared with 27.9% in the placebo group. A small percentage (1.4%) of patients developed antidrug antibodies in the low-dose monthly group.

Eptinezumab, a humanized IgG1 mAb that binds to both CGRP isoforms,28 was evaluated in 2 completed phase 3 trials, PROMISE 1 (NCT02559895; 888 patients randomized to receive eptinezumab 30 mg, 100 mg, 300 mg or placebo infusions once every 12 weeks)

 and PROMISE 2 (NCT02974153; 1072 patients randomized to eptinezumab 100 mg, 300 mg, or placebo),

 as well as a completed open-label safety study (PREVAIL/NCT02985398).

 Preliminary data from the PROMISE 1 study showed that for weeks 1 to 12, 49.8% (

 = .0001 vs placebo) of patients in the 100-mg and 300-mg groups, respectively, achieved a ≥50% reduction in monthly migraine days compared with 37.4% of patients in the placebo group.

 For months 6 to 12, 70.7% of patients had a ≥50% reduction in monthly migraine days compared with 58.7% in the placebo group.

 <.0001 vs placebo) of patients achieved a ≥50% reduction in monthly migraine days in weeks 1 to 12 compared with 39% in the placebo group.

The development and approval of mAbs targeting CGRP have shifted the migraine treatment paradigm, driven by high response rates and favorable safety profiles. Although clinical studies of CGRP pathway—targeted mAb-based agents in migraine have yielded ≥50% migraine reduction in a significant proportion of patients, subpopulations of patients achieved even higher migraine reduction (≥75% in some cases), indicating that these therapeutic agents have great potential yet to be explored and clarified in acute and prophylactic migraine treatment.

 Along with the data for gepants, this new class of drugs has provided much-needed options over the triptan-based mainstay modalities, ushering in a new era in migraine management.

Pathways

After a long period of time with minimally effective treatments for migraine, the growing understanding of the CGRP pathway has opened the door to a variety of new and highly efficacious therapies for patients with chronic and episodic forms of disease.

CGRP: Paving the Path to Migraine and Its Treatment

Migraine has a cumulative lifetime incidence of 43% in women and 18% in men,

 is ranked seventh in global disease burden,

 and is the top cause of disability in people aged 15 to 49 years.

 Migraine peaks during reproductive years, so understanding the link between the condition and hormones and how to treat migraine throughout pregnancy, lactation, perimenopause, and menopause is essential for medical providers. 

Migraine occurs more frequently in women than in men because of the effects of female sex hormones on migraine pathophysiology.

 In children, the prevalence of migraine is similar in boys and girls, with an increase occurring in women only after puberty and peaking in the fourth decade.

 Changes in estrogen levels have a direct effect on migraine, with menstrual migraine triggered by falling levels of estrogen in the late luteal phase of the menstrual cycle. This fall in estrogen can also cause migraine with use of oral contraceptives with a hormone-free (placebo) interval. During pregnancy, with a rise in estrogen levels, many women with migraine experience an improvement in migraine severity and frequency.

 They will feel this improvement, if it occurs, by the second trimester. During lactation, some notice continued protection from migraine because of the stability of female hormones. However, women may see an increase in migraines during perimenopause because of hormone irregularity,

 and in menopause, many will have a reduction of migraine severity and frequency because of lower levels of female sex hormones.

Unlike migraine without aura, migraine with aura may increase or occur for the first time in pregnancy, as aura can increase with a rise in estrogen.

 Migraine with aura does not generally change during menopause, and historically, aura symptoms become more predominant with age.

 Migraine with aura may also respond differently to exogenous hormones, occasionally being triggered by higher levels of estrogen seen in older formulations of oral contraceptive hormones. 

Addressing Migraine Throughout Pregnancy 

The treatment of migraine during vulnerable time periods, such as pregnancy and lactation, requires an important tool set. Treatment considerations are especially important because medications used for migraine may need to be stopped or changed when the patient becomes pregnant and may need to change again when the patient is lactating. A discussion about pregnancy and lactation and migraine treatment is best prior to a patient’s desire to become pregnant so the physician can put a treatment plan in place for this time. 

The safest treatment of migraine in pregnancy and lactation is with lifestyle modifications and behavioral therapy.

 Mild to moderate daily exercise and yoga have been shown to reduce the frequency of migraine attacks. Biofeedback, meditation, and mindfulness all have evidence supporting the prevention of migraine and are safe to learn and use during pregnancy. A discussion on adequate nutrition, hydration, and sleep hygiene during pregnancy is also encouraged prepregnancy. 

Lifestyle changes and biofeedback may not be enough to treat an acute migraine attack, so a discussion about acute options is necessary prepregnancy and during lactation. Clinicians need to balance consideration of the use of acetaminophen, metoclopramide, ibuprofen (during lactation), and sumatriptan (or eletriptan in lactation) with potential risks. Newer data indicate that magnesium and compounds containing butalbital may not be safe to use during pregnancy.

Clinicians may consider neuromodulation devices, particularly the transcutaneous supraorbital stimulator, for both acute treatment and prevention of migraine during pregnancy. While there are no studies of safety in pregnancy for these devices, the relative risk to the fetus is theoretically low. 

A small case series is evaluating the safety of peripheral nerve blocks with lidocaine only as treatment of migraine in pregnancy.

 In the 13 cases reported, no adverse outcomes of pregnancy were observed. Clinicians may consider greater occipital block with lidocaine only to treat migraine during pregnancy.

Preventive medications are generally stopped prior to pregnancy for patients with migraine because, as with most medications, the potential risk of continuing them may outweigh the benefit. In general, women should wait 5.5 half-lives after cessation of medication to become pregnant. If a patient is considering continuing her preventive medication during pregnancy or needs to be started on preventive medication during pregnancy, she should consider a maternal fetal medicine consult for a complete review of safety of medication use throughout pregnancy. 

Although migraine can improve in menopause for many women, it may worsen during perimenopause. With rapid fluctuations in hormones during this time, patients may see a rise in the frequency and severity of migraine attacks. Many patients are started on preventive treatments at this time to attempt to reduce migraine frequency. Because hormone irregularity is the cause of more frequent attacks, stabilizing hormones may help migraines. If menses are irregular, use of continuous combined hormonal contraceptives is an option, depending on the patient’s health and smoking status.

 If menses are regular, patients may consider perimenstrual estrogen supplementation. 

Hormone replacement therapy (HRT) in patients with migraine may potentially worsen migraine, though study results are inconsistent.

 The goal post menopause in women who have worsening migraine or who need to be on HRT for other reasons is to stabilize estrogen; this lessens the risk of migraine from HRT. For patients who decide to use HRT, nonoral routes of estradiol are less likely to have a negative impact on migraine.

Migraines throughout a woman’s life can vary and present different challenges in treatment. An ongoing dialogue with your patients throughout life’s stages can help ensure that their needs and concerns are met and addressed. 

Jessica Ailani, MD, FAHS, is the director of the MedStar Georgetown Headache Center, and an associate professor of neurology at MedStar Georgetown University Hospital. 

1. Stewart WF, Wood C, Reed ML, Roy J, Lipton RB; AMPP Advisory Group. Cumulative lifetime migraine incidence in women and men. Cephalalgia. 2008;28(11):1170-1178. doi: 10.1111/j.1468-2982.2008.01666.x. 

2. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1211-1259. doi: 10.1016/S0140-6736(17)32154-2. 

3. Steiner TW, Stovner LJ, Vos T, Jensen R, Katsarava Z. Migraine is first cause of disability in under 50s: will health politicians now take notice? J Headache Pain. 2018;19(1):17. doi: 10.1186/s10194-018-0846-2. 

4. MacGregor AE. Migraine, menopause and hormone replacement therapy. Post Reprod Health. 2018;24(1):11-18. doi: 10.1177/2053369117731172. 

5. Vetvik KG, MacGregor AE. Sex differences in the epidemiology, clinical features, and pathophysiology of migraine. Lancet Neurol. 2017:16(1):76-87. doi: 10.1016/S1474-4422(16)30293-9. 

6. Calhoun AH. Migraine treatment in pregnancy and lactation. Curr Pain Headache Rep. 2017;21(11):46. doi: 10.1007/s11916-017-0646-4. 

7. Martin VT, Pavlovic J, Fanning KM, Buse DC, Reed ML, Lipton RB. Perimenopause and menopause are associated with high frequency headache in women with migraine: results of the American Migraine Prevalence and Prevention Study. Headache. 2016;56(2):292-305. doi: 10.1111/head.12763. 

8. Matika K, Inagaki M, Kitamura S, Tatsuoka Y. Changes in migraine before and after menopause in Japanese climacteric women. Cephalalgia. 2017;37(11):1088-1092. doi: 10.1177/0333102416653234. 

9. Wells RE, Turner DP, Lee M, Bishop L, Strauss L. Managing migraine during pregnancy and lactation. Curr Neurol Neurosci Rep. 2016;16(4):40. doi: 10.1007/s11910-016-0634-9. 

10. Govindappagarti S, Grossman TB, Dayal AK, Grosberg BM, Vollbracht S, Robbins MS. Peripheral nerve blocks in the treatment of migraine in pregnancy. Obstet and Gynecol. 2014;124(6):1169-1174. doi: 10.1097/AOG.0000000000000555. 

Reproductive considerations and hormonal fluctuations throughout a woman’s life require careful consideration when treating migraine.

Managing Migraine in Women

More than 1 billion people live with migraine. The condition not only has an impact on probands but, like a stone thrown into a still lake, can also negatively affect others in widening concentric circles, including family members, friends, coworkers, employers, health care providers, and systems and society. Analysis of the 2016 Global Burden of Disease (GBD) data revealed that migraine was the second-most-disabling disease on the planet, following low back pain.

 The data estimated that migraine caused 45.1 million years lived with disability (YLDs) in 2016 alone. Disability was highest in women between the ages of 15 and 49, with 20.3 million YLDs in this group because of migraine. Disability is assessed as a function of the percentage of time lost because of a disease divided by the total amount of responsibilities, activities, and commitments. Therefore, the burden of migraine is amplified because migraine prevalence is highest in midlife, when work and family productivity, responsibilities, and demands are at their peak. During these decades, people may be juggling careers, advanced educations, and families and may be caring for both children and aging parents. This level of commitment and responsibility establishes potential for great associated disability in multiple important domains. 

The burden of migraine occurs both ictally (during) and interically (between attacks).

 The ictal burden is largely characterized by disability and limitations directly due to head pain and associated symptoms such as nausea, vomiting, and sensitivity to environmental stimuli, as well as potential cognitive impairment and other symptoms during the prodrome and postdrome phases. The interictal burden manifests in cognitive, psychological, and emotional symptoms roughly when the next attack may occur and a resulting reluctance to make plans or commitments along with potential symptoms of an activated trigeminovascular system.

 This interictal burden is associated with medication overuse, anxiety, depression, lowered quality of life, and both big and small impacts in all important areas of life, such as academic and occupational achievement, relationships and family planning, and financial status. For example, 9.6% of respondents with chronic migraine (CM) from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study reported that they chose to not have children, delayed having children, or had fewer children because of migraine.

Other recent US and international studies have revealed further far-reaching negative impacts that migraine can have on important areas of life. Like results of the CaMEO Study, the recent My Migraine Voice study, a global study of people with migraine for whom preventive treatments have failed, reported that approximately half of respondents noted missing important events and avoiding making commitments because of migraine. It also found that migraine had negative impacts on intimacy and respondents’ sex lives.

 Also in alignment with CaMEO, a study of populations from both the United States and the United Kingdom reported that individuals with migraine were more likely to argue with their children and partners and felt less involved in their children’s lives both at home and at school because of migraine.

Migraine can have a substantial negative impact on educational achievement, career success, and financial status as well.

 In data collected from headache centers in Austria, 34.0% of respondents reported that “headaches” had a negative impact on their careers and 21.5% reported negative impacts on financial earnings. Only 50.0% of respondents believed that colleagues accepted their headaches, highlighting the stigma experienced by individuals with migraine.

 The burden of migraine is significantly and consistently higher for people with CM who have greater headache-related disability, headache impact, and decrements in health-related quality of life (HRQOL); higher rates of comorbidities; increased health care resource utilization; higher direct and indirect costs; lower socioeconomic status; and a greater negative impact on educational attainment, career, personal and household finances, family stress, and stigma because of migraine compared with people with episodic migraine.

Furthermore, migraine affects not only the individual with the disease but also the relationships and interpersonal dynamics, psychological health and well-being, achievements, and financial stability of the entire family, most notably spouses/partners and children (

 Adolescent children of parents with migraine from the CaMEO Study reported negative impacts on school participation, participation in extracurricular activities such as sports and social activities, and relationships with family members and friends because of a parent’s migraine.

 Migraine can have negative effects on academic and occupational achievement, career success, and financial attainment of the spouses/partners of probands with migraine as well (

 In parallel to patterns seen with probands, the burden of migraine on the proband’s family members is highest among probands with CM.

In light of the abundance of evidence coupled with clinical reports directly from patients, importantly, health care professionals caring for individuals with migraine must assess the burden of disease on individuals and their families and intervene when appropriate. Successful treatment that results in reduction of headache days is associated with reduction in headache-related disability as well as reduction in depression and anxiety and improvements in HRQOL.24 In addition, direct intervention may be warranted via cognitive behavioral therapy or other educational intervention for probands and/or families.

Assessment and ongoing monitoring of disability is essential for optimized treatment planning.

 Simply opening with “Tell me about your headaches and how they affect your life” is effective in establishing a dialogue about headache-related disability and patient values that improves treatment planning, rapport, and patient and provider satisfaction while shortening visit length.

 Openly discussing and normalizing the challenges associated with living with a painful and unpredictable chronic disease can help destigmatize disability.

A range of validated generic and disease-specific instruments exist to aid in the assessment of disability, HRQoL and management of migraine.

 The Migraine Disability Assessment scale measures lost time due to headache in work and school, household work and chores, and family, social, and leisure activities and is free for use.

 The Headache Impact Test is a copywritten questionnaire that assesses activity limitations, pain severity, fatigue, frustration, and difficulty with concentration due to headache.

 The Migraine Physical Function Impact Diary and the Migraine Functional Impact Questionnaire are novel patient-reported outcome measures for assessing the impact of migraine that incorporate 2009 FDA guidance on development of patient-reported outcomes for inclusion in clinical trials,

 and the Impact of Migraine on Partners and Adolescent Children scale was developed from the CaMEO Study to assess and monitor the family burden of migraine.

Dawn Buse, PhD, is a clinical professor in the Department of Neurology at Albert Einstein College of Medicine and a Board Member at Large of the American Headache Society.

1. GBD 2016 Headache Collaborators. Global, regional, and national burden of migraine and tension-type headache, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. 

. 2018;17(11):954-976. doi: 10.1016/S1474-4422(18)30322-3.

2. Buse DC, Rupnow MFT, Lipton RB. Assessing and managing all aspects of migraine: migraine attacks, migraine-related functional impairment, common comorbidities, and quality of life. 

 2009;84(5):422-435. doi: 10.1016/S0025-6196(11)60561-

3. Lampl C, Thomas H, Stovner LJ, et al. Interictal burden attributable to episodic headache: findings from the Eurolight project. 

 2016;17:9. doi: 10.1186/s10194-016-0599-8.

4. Buse DC, Bigal MB, Rupnow M, Reed, M, Serrano D, Lipton RB. Development and validation of the Migraine Interictal Burden Scale (MIBS): a self-administered instrument for measuring the burden of migraine between attacks [abstract S05.003]. 

Reducing the frequency of migraine is only 1 step in the process of optimizing management and addressing the disease's impact on patients’ lives.

September 2019

Wellness for Migraine: Should You Buy In?

Blurring the Lines of Migraine Treatment

CGRP: Paving the Path to Migraine and Its Treatment

Managing Migraine in Women

A Big-Picture Look at the Burden of Migraine

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