Migraine recurrence can cause significant pain and negatively affect a patient’s quality of life. What preventative measures should patients know about?
Patients with recurrent migraines often experience significant impairment as a result of their condition, which negatively affects their quality of life.¹ When discussing migraine prevention with your patients, they may ask about preventive measures and whether they require lifestyle changes or a more targeted treatment approach.
There are a number of options for patients seeking to prevent migraine recurrence that may be worth mentioning. Be sure to have a thorough discussion with them about their migraine history and overall health to determine whether lifestyle changes and medications are worth exploring for migraine prevention.
What should your patients know about how certain preventative measures affect migraine?
Food Management
Food management, in the context of migraine prevention, is about noticing the ways your diet affects your migraine; for example, keeping track of whether certain foods have seemingly triggered a migraine or if you’ve been eating meals at consistent times.² A consistent meal schedule may help keep migraine in check, whereas fasting can increase risk. In addition, keeping a food journal that also tracks migraine occurrences may help patients recognize potential triggers to avoid.
A 2020 study in Headache: The Journal of Head and Face Pain examined the role diet and nutrition play in migraine triggers and prevention. The researchers found that diets that eliminate certain foods may help reduce migraine risk.³ Specifically, alcohol and caffeine were often associated with an increased risk of migraine, therefore reducing consumption of both may help reduce migraine. The investigators also suggested that low-fat diets may be effective at reducing migraine, although they acknowledged more in-depth research is needed.
Other data the researchers analyzed suggested that diets rich in omega-3 polyunsaturated fatty acids show potential to reduce migraine frequency, and that ketogenic diets and diets that eliminate IgG-positive foods may also help depending on triggers. Discussing with your patients how different foods and nutrients affect migraine and overall quality of life may help to create a structured diet centered on preventing migraine.
Sleep Management
Migraines can potentially be triggered by a lack of quality sleep.² Therefore, prioritizing healthy sleep habits is key – and another instance in which keeping a journal may help identify what’s causing a lack of sleep and triggering migraines. Patients may find that distractions like their phone can affect their sleep. They might also find do exercise and dietary habits prior to bed play a role.
Patients experiencing migraine may also have comorbid sleep disorders, which can exacerbate one another. A 2021 study published in the International Journal of Molecular Sciences examined the association between migraine and sleep disorders, finding that insomnia, obstructive sleep apnea, and parasomnia were among the most common sleep disorders in patients with migraine.⁴ Per the researchers, patients with migraine and insomnia often have increased migraine attack frequency and pain intensity. The investigators also claim that, among parasomnias, sleepwalking has been associated with migraine and somnambulism has a higher rate in patients with migraine with aura.
Health care professionals may consider informing their patients of the ways sleep disorders may affect migraine and how to address the problem.
Stress
A common mnemonic device when discussing lifestyle changes for reducing migraine triggers is SEEDS: Sleep, Exercise, Eat, Diary, and Stress.⁵ Stress can be a trigger for migraine attacks, and if patients are finding an association between stress and migraine incidence, they may benefit from relaxation and mindfulness techniques. Patients may seek mental health care treatment if stress becomes overwhelming, or may opt to journal about their stress.
Beta Blockers
While lifestyle changes can be beneficial, many patients still require additional treatment to prevent migraine. Beta blockers, often used to treat blood pressure, may be an option. One beta blocker, propranolol, is a common first-line treatment for migraine and is seen as one of the most effective options.¹ As it is also used to regulate blood pressure, beta blockers may be considered for patients with migraine and cardiovascular disease.
Other options include atenolol, metoprolol, nadolol, and timolol.⁶ Though they may be effective, they also come with potential side effects patients should know about. These include fatigue, shortness of breath, nausea, insomnia, and low physical tolerance for exercise.
Various studies have come to similar conclusions about beta blockers – that they are potentially an effective option but may lead to side effects. A 2023 study in the Journal of Headache and Pain reviewed the comparative effectiveness of different migraine medications, including beta blockers.⁷ The researchers concluded that beta blockers were likely effective at creating a 50% or greater reduction in monthly migraine days for patients, but also had a higher likelihood of adverse events than other treatment options.
Antidepressants
Certain antidepressants have shown promise in their ability to prevent migraine, particularly amitriptyline.¹ Venlafaxine is another option that has been used for migraine. Side effects, depending on the antidepressant used, can include fluctuations in weight, dry mouth, and sedation.⁶
Calcitonin Gene-Related Peptide Therapies
Treatments that focus on inhibiting the calcitonin gene-related peptide (CGRP) to block the pain signal are designed specifically for the treatment of migraine.⁶ Some studies have suggested that antibodies inhibiting the CGRP or its receptor are among the most effective treatments at reducing monthly migraine days while posing a lesser risk of adverse events.⁷
Ultimately, patients will need to discuss with their health care professional the ways their migraine is affecting them and the specific triggers they’ve noticed to determine the best course of action for prevention
While the exact mechanisms behind migraines remain unclear, a number of different hypotheses have been raised. It appears to be a disorder of your central nervous system. Mitochondrial dysfunction also appears to be part of the puzzle
The influence of neurotransmitters may also play a role, as may nutritional deficiencies. Studies have identified several nutritional deficiencies that significantly raise your risk of migraines, including riboflavin (vitamin B2) deficiency
Riboflavin has been shown to ameliorate hallmarks of migraine, including oxidative stress, mitochondrial dysfunction, neuroinflammation, homocysteine neurotoxicity and glutamate excitotoxicity
Foods rich in riboflavin include spinach, beet greens, crimini and portabella mushrooms, pastured eggs, asparagus, almonds, organic turkey, grass fed beef liver and beef tenderloin
In one study, 400 milligrams of riboflavin per day reduced migraine frequency by 50%, from four days a month to two days a month, after three months of use.
Migraine affects an estimated 1 billion people worldwide, and is the third most common disease globally.1 In the U.S., self-reported migraine and severe headache affects 1 in 62 Women are up to three times more likely to suffer with migraines than men, likely due to hormone fluctuations.3
Despite its high prevalence, decades of research have failed to pin down the exact mechanisms behind the attacks — most of which tend to recur once or twice a month.4 The pain, which often occurs on one side of the head only, can be moderate to severe in intensity.
Along with throbbing, piercing or “burning” pain, other common symptoms include nausea, visual disturbances, dizziness, numbness in your extremities or face, and extreme sensitivity to light, sound, smell and touch.5 Attacks typically last from four hours to three days,6 often requiring bed rest in complete darkness and silence.
Reigning Migraine Hypotheses
While the exact mechanisms remain unclear, a number of different hypotheses have been raised. Over the last decade or two, researchers have started leaning toward migraine being a disorder of your central nervous system, most likely originating in your brain stem.7,8,9,10 While most brain regions do not register or transmit pain signals, the trigeminal nerve network does.
Pain is relayed through the trigeminal network to an area in your brain stem called the trigeminal nucleus. From there, it is conveyed to the sensory cortex in your brain that is involved in awareness of pain and other senses. As explained by Migrainedisorders.com:11
“[P]eople with migraine illness have a nervous system that is not working normally. It overreacts … when stimulated, there is an unusual wave of brain activity that leads to a headache.
Almost all migraine sufferers have a problem with a specific part of the nervous system, called the trigeminal nerve. The trigeminal nerve is a network of wiring that attaches to special sensors.
When stimulated, they send electrical signals to the brainstem with connections to nerves of the cortex and its covering, the dura. Normally this system allows us know what is going on in the world. When the system does not work properly, electrical signals set off a slowly moving wave of electrochemical activity across the surface of the brain.
People with migraine start to experience odd sensations, such as white sparks in an eye (a misfiring of the ocular nerve) followed by an intense pain in some part of the head and concluding with a long period of nausea (activation of the gastrointestinal system) and exhaustion (general inflammation and swelling of the cortex).”
The initial activation of your trigeminal nerve is thought to be triggered by a variety of internal and external stimuli, ranging from stress, hormone fluctuations and irregular sleep to a variety of foods, flashing lights, noise and weather changes.12
Still, migraines can sometimes occur even in the absence of an apparent trigger, suggesting we still don’t have a complete picture of the phenomenon. Mitochondrial dysfunction also appears to be part of the puzzle. As noted in one 2013 paper:13
“Abnormal [mitochondrial] function translates into high intracellular penetration of Ca(2+), excessive production of free radicals, and deficient oxidative phosphorylation, which ultimately causes energy failure in neurons and astrocytes, thus triggering migraine mechanisms.”
The influence of neurotransmitters such as calcitonin gene-related peptide (CGRP)14,15 may also play a role, as may nutritional deficiencies. At the very least, studies have identified nutritional deficiencies that significantly raise your risk of migraines. Among them is riboflavin (vitamin B2).
Riboflavin Deficiency Linked to Migraine
A paper,16 published in Frontiers in Neurology in 2017 looked at riboflavin’s influence on migraine and Parkinson’s disease, highlighting its neuroprotective potential.
According to this paper, “riboflavin ameliorates oxidative stress, mitochondrial dysfunction, neuroinflammation and glutamate excitotoxicity; all of which take part in the pathogenesis of PD, migraine headache and other neurological disorders.”
Here, the authors link migraine pain to neurovascular dysfunction, inflammation and “dysfunction in cranial vascular contractility,” and cite research showing people who have migraine with aura have lower levels of antioxidants and higher levels of oxidative stress than migraine-free controls.
They’ve also been shown to have higher levels of mitochondrial dysfunction, and at least two polymorphisms in mitochondrial DNA have been shown to heighten migraine susceptibility. The authors also note that:17
“[C]ommon triggers of migraine have the ability to generate oxidative stress; mechanisms include mitochondrial dysfunction, calcium excitotoxicity, activation of microglia, activation of NADPH oxidase, and as a byproduct of MAO (monoamine oxidase), cytochrome P450, or NO synthase. Collectively, it is indicated that oxidative stress is an important hallmark of migraine disease.”
Riboflavin may help by ameliorating many of the hallmarks of migraine, including oxidative stress, mitochondrial dysfunction, neuroinflammation, homocysteine neurotoxicity and glutamate excitotoxicity, as shown below.18
The paper goes into some detail, explaining the biochemical influence of riboflavin on all of these, so for a more comprehensive understanding, I’d suggest reading through the original paper.
In conclusion, the authors of this Frontiers in Neurology paper note that:19
“Riboflavin has demonstrated its ability to tackle significant pathogenesis-related mechanisms in neurological disorders, exemplified by the ones attributed to the pathogenesis of … migraine … In addition, riboflavin is required for pyridoxine activation.
Riboflavin and PLP, the active form of pyridoxine, play essential roles in homocysteine metabolism, and tryptophan-kynurenine pathway. Indeed, any accumulation of homocysteine or kynurenines due to vitamin insufficiency can lead to significant neurological consequences.
Taking into consideration the limited riboflavin absorption and utilization in 10–15% of global population, long term riboflavin insufficiency could participate in the development of multiple neurological disorders, emphasizing the importance of long-term riboflavin-sufficient diet especially in vulnerable populations.”
Since riboflavin is a water-soluble B vitamin, you need to get a consistent supply from your diet. Foods rich in riboflavin include:20
Identifying Riboflavin Deficiency, and Dosing Suggestions
While riboflavin deficiency is thought to be rare in the U.S., older adults, women on birth control pills, alcoholics, pregnant and lactating women, vegans and those with liver disorders are at increased risk for deficiency.21 Common signs and symptoms of deficiency include:22
Fatigue
Swollen throat
Blurred vision
Depression
Itchy or cracking skin
Dermatitis around the mouth
Liver degeneration
Hair loss
Reproductive problems
Urine analysis can identify a riboflavin deficiency. As a general rule, deficiency is said to be present if your urinary riboflavin is below 40 micrograms per day.23 The recommended daily intake is 1.3 milligrams for adult men, 1.1 mg for adult women, 1.3 mg for male adolescents (14 to 18 years of age) and 1.0 mg for female adolescents.24
If you struggle with migraines, however, you may need far higher doses. As noted in a study published in the European Journal of Neurology in 2004, researchers found 400 mg of riboflavin per day reduced migraine frequency by 50%, from four days a month to two days a month, after three months of use. The duration and intensity remained largely unaffected, however.25
Other Vitamin Deficiencies Implicated in Migraines
Aside from riboflavin, other nutrients deficiencies that have been implicated in migraines include:
• Vitamins B6, B12 and folic acid — One 2009 study26 evaluated the effect of 2 mg of folic acid, 25 mg vitamin B6 and 400 mcg of vitamin B12 in 52 patients diagnosed with migraine with aura. Compared to the placebo group, those receiving these supplements experienced a 50% reduction in the prevalence of migraine disability (from 60% to 30%) over a six-month period.
• Magnesium — Magnesium has also been shown to play an important role in the prevention and treatment of migraines, and migraine sufferers are more likely to suffer from magnesium deficiency than non-migraineurs.27
Since magnesium administration is both easy and safe, researchers have noted that empiric treatment with a magnesium supplement is justified for all migraine sufferers.28 As a prophylactic, be prepared to boost your magnesium intake for at least three months to experience results, ideally in combination with CoQ10.
In many cases, receiving a high dose of magnesium can also abort an attack in progress. The most effective way to administer magnesium for migraine would be to get an intravenous (IV) infusion. I used to regularly administer magnesium IVs for those with acute migraines and it seemed to work for most patients to abort the headache.
Barring that option, magnesium threonate may be your best option for an oral supplement. It has superior absorbability compared to other forms of magnesium, and since its ability to cross the blood-brain barrier makes it more likely to have a beneficial effect on your brain.
Foods rich in magnesium29 include: almonds and cashews, boiled spinach, peanut butter, avocado, potato, brown rice, banana, wild Alaskan salmon and yogurt made from organic grass fed milk with no added sugars, just to name a few.
• Coenzyme Q10 (CoQ10) — A migraine study30,31,32 presented at the annual American Headache Society meeting in 2016, which involved 7,420 children, teens and young adults, found 51% had low levels of CoQ10, 31% had low vitamin D status and 16% had low levels of riboflavin.
Those suffering from chronic migraines were overall more likely to have CoQ10 and riboflavin deficiency compared to those with episodic migraines. While the final study results do not appear to have been published yet, other research have found similar links.
For example, a 2015 study33 in The Journal of Headache and Pain found supplementation with a proprietary combination of magnesium, riboflavin and CoQ10 for three months lowered migraine frequency from 6.2 days at baseline to 4.4 days at three months. Pain intensity was also significantly reduced. Foods rich in CoQ1034 include: grass fed beef, herring, organic pastured chicken, sesame seeds, broccoli and cauliflower.
• Vitamin D — While many studies appear to refute a link between low vitamin D and migraine, there have been some showing vitamin D may play a role. For example, migraine research using vitamin D supplementation has demonstrated a reduction in C-reactive protein (a marker for inflammation) and a statistically significant reduction in migraine frequency.35
Another study36 by Finnish researchers, while not focused on migraines specifically, found men with the lowest vitamin D levels had 113% higher odds for frequent headaches than those with the highest levels. Overall, the lower the men’s blood level of vitamin D, the more frequent their headaches.
A 2013 study37 looking at the relationship between vitamin D levels and migraine found a weak but positive relationship in terms of frequency, but not in terms of severity. The best way to optimize your vitamin D level is through regular sun exposure. If taking an oral supplement, be sure to use vitamin D3 (not D2), along with magnesium, vitamin K2 and calcium.
Migraine Prevention 101
When it comes to migraines, your best bet is to take preventive action, as treating migraines acutely is very difficult. Migraine medications often do not work, and can have serious side effects.38
Your first step would be to identify and avoid potential triggers. While there are many (and what triggers a migraine for one might not trigger it in another), the list below includes some of the most common culprits. Keeping a journal where you record and track suspected triggers can help you determine any correlations.
Food and drink — Especially wheat and gluten, dairy, cane sugar, yeast, corn, citrus, eggs, artificial preservatives or chemical additives, cured or processed meats, alcohol (especially red wine and beer), aspartame, caffeine and MSG.39
Allergies — Including food allergies,40 food sensitivities and chemical sensitivities. Research41 published in the journal Lancet back in 1979 showed migraineurs with food antigen immunoreactivity experienced profound relief when put on an elimination diet. Another randomized, double-blind crossover study42 published in 2010 found that a six-week-long diet restriction produced a statistically significant reduction in migraines in those diagnosed with migraine without aura. If you suspect you might have a food allergy, I suggest doing a diet elimination challenge to see if your symptoms improve. Keep in mind that depending on your typical migraine frequency, you may need to avoid the suspected food for a few weeks in order to evaluate whether it had an effect or not. To confirm the results, reintroduce the food or drink on an empty stomach. If the suspected food is the culprit, you will generally be able to feel the symptoms return within an hour, although migraines can sometimes have a longer lag time than, say, bloating or drowsiness.
Hormones — Some women experience migraines before or during their periods, during pregnancy or during menopause. Others may get migraines from hormonal medications like birth control pills or hormone replacement therapy.
Light, noise and smells — Bright lights, fluorescent lights, loud noises and strong smells (even pleasant ones) can trigger and/or exacerbate a migraine. A study43,44 from Harvard Medical School found even blind migraine sufferers who still had melanopsin receptors were sensitive to light. Blue light in particular can be problematic. Many digital devices and LED light sources emit mostly blue light. Research has found that this light increases migraine pain and activates your trigeminal nerve, associated with the pain of migraines.45 Meanwhile, green light may help ease migraine pain and photosensitivity.46,47 At this time there are no lightbulbs or sunglasses that increase your exposure to pure wavelength green light that are cost effective. However, there are orange or red-tinted glasses that will block blue light, which may be helpful. You may also consider eliminating your exposure to your digital devices while you’re in the middle of a migraine.
Changes in sleep cycle — This includes both missing sleep and oversleeping.
Stress — Any kind of stress or emotional trauma can trigger a migraine, even after the stress has passed.
Dehydration and/or hunger — Skipping meals or fasting are also common triggers.
Physical overexertion — Extremely intense exercise, and even sex, has been known to bring on migraines.
The US Food and Drug Administration (FDA) has granted tentative approval to expand the label for an extended-release formulation of topiramate (Trokendi XR, Supernus Pharmaceuticals), approved for epilepsy, to include prophylaxis of migraine headache in adults, the company announced.
The approval of the company’s Supplemental New Drug Application (sNDA) is tentative because while the FDA has determined that the drug meets all the required quality, safety, and efficacy standards for approval, it is subject to pediatric exclusivity, which expires March 28, 2017, the company reports in a press release August 22.
Final approval may not be made effective until this exclusivity period has expired, the release notes.
“We will continue to work with the FDA to gain final approval upon the expiration of pediatric exclusivity,” said Jack Khattar, president and chief executive officer of Supernus Pharmaceuticals, in a press release. “We are prepared and ready to launch the migraine indication upon receiving full FDA approval.”
Supernus further announced that the FDA has granted final approval to expand the label for Trokendi XR for monotherapy treatment of partial-onset seizures to include patients 6 years and older, rather than 10 years and older, as well as adults.
In addition to now being indicated for initial monotherapy in patients 6 years and older with partial-onset or primary generalized tonic-clonic seizures, Trokendi XR is also indicated as adjunctive therapy in these patients and in those 6 years of age and older with seizures associated with Lennox-Gastaut syndrome.
The product is available in 25-mg, 50-mg, 100-mg, and 200-mg extended-release capsules.
Another extended-release topiramate (Qudexy, Upsher-Smith) received FDA approval as an initial monotherapy in patients as young as 2 years with partial-onset seizures or primary generalized tonic-clonic seizures in June 2015.
It was previously approved in March 2014 for use as initial monotherapy in patients 10 years of age and older with partial-onset seizures or primary generalized tonic-clonic seizures, and as adjunctive therapy in patients 2 years of age or older with partial-onset seizures, primary generalized tonic-clonic seizures, or seizures associated with Lennox-Gastaut syndrome.
New phase 2 data on the investigational calcitonin gene-related peptide (CGRP) monoclonal antibodies show significant efficacy in preventing migraine attacks with no major safety signals.
Phase 2 data for three different anti-CGRP drugs from Amgen (AMG 334), Teva Pharmaceuticals (TEV-48125), and Eli Lilly & Co (LY2951742) were presented here at the American Headache Society (AHS) 57th Annual Scientific Meeting by representatives from the three companies.
A fourth company, Alder Pharmaceuticals, is also developing an anti-CGRP agent but didn’t present data at this meeting. All four companies are planning to move their agents into phase 3 trials.
The drugs — administered as once-monthly injections — act by blocking CGRP, a vasodilator, without causing vasoconstriction. The Amgen product blocks the receptor for CGRP, while the other three are directed against the ligand itself. Lilly is developing its product for cluster headache as well as for migraine prophylaxis.
“They’re a new class to treat migraine preventatively,” AHS president Lawrence C. Newman, MD, professor of neurology at Icahn School of Medicine at Mount Sinai and director of The Headache Institute at Mount Sinai-Roosevelt Hospital, New York, told Medscape Medical News.. “We’re excited because there hasn’t been a new medicine designed specifically to prevent migraine in over 50 years.”
Session moderator Robert Shapiro, MD, PhD, professor in the Department of Neurological Sciences at the University of Vermont, Burlington, told Medscape Medical News, “to have a new category developed specifically for migraine and to have them all show in these early-phase studies significant efficacy and at the same time not have significant signals that there’s a serious adverse events is very encouraging…. This is not something we’ve experienced since 15 to 20 years ago when the triptans were rolling out.”
However, Dr Shapiro, who serves on the independent data monitoring committee for the Lilly drug, cautioned that these early studies are still too small and of short duration — none have data beyond 1 year — to fully establish efficacy and safety. “Any time there’s a new molecular entity, one has to be highly vigilant for safety concerns to emerge.”
Indeed, Thomas N. Ward, MD, professor of neurology at the Geisel School of Medicine, Dartmouth College, Lebanon, New Hampshire, and editor-in-chief of the AHS journal Headache: The Journal of Head and Face Pain, pointed out that CGRP is widely distributed throughout the body — in the kidney, lungs, eyes, liver, and gastrointestinal tract — as well as the brain.
“Could [the drugs] have a long-term effect on intraocular pressure, or renal function, or pulmonary function? CGRP is in your body for a reason and if you perturb it long enough, perhaps some people could accommodate well, but perhaps some people with underlying mild disease might not,” Dr Ward said. “It’s not really till you get to phase 3, with big, randomized, double-blind, placebo-controlled studies that you can really answer those questions.”
He pointed to previous experience with a related investigational drug that had generated similar excitement, Merck’s CGRP antagonist telcagepant. The company halted development in 2011 after liver toxicity was seen in a phase 3 study. “So far the [current agents] look safer…but things can appear that you weren’t expecting,” Dr Ward cautioned.
Results of a 1-year open-label extension of a 12-week randomized, double-blind, placebo-controlled, phase 2 study of AMG 334 for the prevention of episodic migraine were presented by Robert Lenz, MD, from the Department of Global Development at Amgen.
A total 483 patients with migraines on 4 to 14 days per month at baseline were randomly assigned to a once-monthly injection of placebo (n = 160 patients) or AMG 334 in doses of 7 mg (n = 108), 21 mg (n = 108), or 70 mg (n = 107). Most (80.5%) were female, with a mean age of 41 years.
The primary endpoint, a statistically significant change from baseline in monthly migraine days at week 12, was achieved with the 70-mg dose, with an average reduction of 3.4 days compared with 2.28 with placebo. Responses to lower doses were not statistically significant.
After the 12-week double-blind part of the trial, the 70-mg dose was given to all the study patients open-label. At 1 year, they had an average 4.9-day reduction in migraine days per month, down from 8.7 days at baseline, with no difference between those who had previously received the drug or placebo.
Also at 1 year, 62% of the patients achieved greater than a 50% reduction in monthly migraine days, 38% achieved greater than a 75% reduction, and 19% achieved a 100% reduction.
Adverse events occurred in about half of the drug and placebo groups and serious adverse events in less than 1% overall.
Events leading to discontinuation occurred in 2.8% with 70 mg vs 1.3% with placebo. Injection site pain or other problems occurred in less than 2% in all groups.
TEV-48125
Marcelo E. Bigal, MD, PhD, vice president of clinical development at Teva and formerly the chief medical officer at Labrys Biologics, where TEV-48125 was developed, presented the data for a randomized, double-blind, double-dummy, placebo-controlled, multidose, parallel-group study of once-monthly injections of the drug in patients with 8 to 14 days of migraine per month.
Patients could also take triptans and other acute migraine drugs for up to 14 days, but no more than 4 days per month of opioids or barbiturates were permitted.
A total 297 patients were randomly assigned to 225 mg or 675 mg of TEV-48125 or to placebo once monthly for 3 months.
For both doses, there was more than a 6-day decrease in the number of monthly migraine days, a highly significant difference from baseline (P < .0001) and also superior to placebo at months 1 and 2 (P< .001). Results were similar for the secondary endpoint of decrease in headache days (P < .001).
The proportions experiencing at least 50% improvement during the study were 59% with the 675-mg dose and 53% for the 225-mg dose, compared with 28% for placebo (P < .001). More than 75% improvement was seen in 31%, 34%, and 11%, respectively (P < .001).
Tolerability was similar to that seen with placebo, and no treatment-related serious adverse events occurred.
LY2951742
Phase 2b data on efficacy and safety for LY2951742 in a randomized, double-blind, placebo-controlled, dose-ranging study were presented by Aaron Schacht, global brand development leader for Lilly’s pain portfolio. Study participants had 4 to 14 migraine headache days and at least two attacks per month.
Subcutaneous injections of LY2951742 doses of 5 mg (n = 68), 50 mg (n = 68), 120 mg (n = 70), 300 mg (n = 67), or placebo (n = 137) were given once every 28 days for 12 weeks.
All four doses were numerically superior to placebo for the change from baseline in migraine headache days, although only the 120-mg dose achieved statistical significance in the last 28-day period of the 12-week treatment phase (P = .004).
Also statistically significant were the proportions achieving responses of at least 50% (P = .038), 75% (P= .003), and 100% (P = .038).
Treatment-emergent adverse events occurring in 5% or more of patients in any LY2951742 group and seen more often than in the placebo group included injection site pain, upper respiratory tract infection, nasopharyngitis, dysmenorrhea in women, and nausea. None of these occurred in more than 15% in any group.
Lilly is enrolling patients for phase 3 trials of LY2951742 for both chronic and episodic cluster headache and has received fast-track designation from the US Food and Drug Administration for cluster headache, Schacht said.
Awaiting Phase 3
Dr Shapiro noted that it’s also too early to be able to determine whether there are significant differences among the four anti-CGRP drugs, including whether the different target for the Amgen drug makes any difference in efficacy or safety.
“It’s way too soon on the basis of phase 2 trials to make significant comparisons between these agents,” he said. “It really requires larger numbers in phase 3 trials and sorting out inclusion/exclusion criteria…. All of them have positive data, and some have extraordinary signals for subsets of patients, but we can’t yet draw conclusions.”
However, Dr Ward noted, “If this class of medications pans out, it’s almost essentially the holy grail of prevention for migraine because we wouldn’t have a lot of side effects that we have with our current medications, such as weight gain, hair loss, or cognitive abnormalities. It might allow people to live a relatively normal life.”
The American Academy of Neurology and the American Headache Society have released updated guidelines on migraine prevention in Neurology.
Among the recommendations for prescription pharmacologic agents:
Most antiepileptic drugs (divalproex sodium, topiramate, sodium valproate), certain beta-blockers (metoprolol, propranolol, timolol), and one triptan (frovatriptan) are effective and should be offered to patients.
Certain antidepressants (amitriptyline, venlafaxine), other beta-blockers (atenolol, nadolol), and other triptans (naratriptan, zolmitriptan) are probably effective and should be considered.
Lamotrigine is not effective and should not be given.
Among the guidance on NSAIDs and complementary therapies:
Petasites (butterbur) is effective and should be offered.
Several NSAIDs (fenoprofen, ibuprofen, ketoprofen, naproxen), riboflavin, magnesium, feverfew, and histamine SC are probably effective and should be considered.
Montelukast is probably ineffective and should not be considered.
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