Review of Migraine Treatment and Devices

My name is Richard Kim, a headache specialist with Premier’s Clinical Neuroscience Institute located in Miami Valley South in Centerville. I am also an assistant professor in Internal Medicine and Neurology with Wright State University School of Medicine.

Today, I will be reviewing the guidelines for migraine treatment and some just recently FDA-approved medications and devices. I have no disclosures. I will be discussing off label uses of medications, and I will be reviewing the guidelines for both acute and preventative treatment for migraine. I just want everyone to remember that our guidelines are based on the available evidence at the time they are written. Some of the older medications may not have enough funding to do a large clinical trial, which may affect recommendations.

Here are my objectives for today; I would like to review the diagnostic criteria for migraine and chronic migraine. I think it is important to have an accurate diagnosis before starting treatment. Also review the guidelines for acute and preventative migraine treatment and then discuss some recently approved FDA therapies and devices for migraine.

The diagnostic criterion for headache disorders comes from the International Classification of Headache Disorders and is currently in the 3rd Ed. Beta version. The diagnostic criterion for migraine is that the patient experiences at least five attacks fulfilling criteria B through D. So the headache attacks last anywhere from 4-72 hours, and it's important to realize that this is an untreated or unsuccessfully treated headache attack. Sometimes if the patient takes an over-the-counter medication for headache that may not progress, and they may not see all these symptoms or meet criteria.

The headache has at least two of the following four characteristics; unilateral, pulsating, moderate to severe in intensity, and aggravated by or causes avoidance of routine physical activity. During the headache at least one of the following are experienced by the patient; either nausea and/or vomiting or both light and sound sensitivity. So the patient does not have to experience all these symptoms, and classically when patients think about migraine they think they are nauseous and vomiting, but they don’t really need to experience those either.

The diagnostic criteria for chronic migraine include patients who experience headaches on at least fifteen days a month for the past three months. They have to have a prior history or diagnosis of migraine, and on eight or more days per month for the last three months, the headaches have to meet criteria for either migraine with aura or without aura. Or the headache attack must be believed by the patient to be migraine at the onset and relieved by migraine specific medications, such as triptan or ergot.

In 2015, the American Headache Society published an evidence assessment of the Abortive Treatments for Migraine. The Level A recommendation for medications proven to be effective include analgesics and combination medications; such as acetaminophen high dose at 1000 mg or the combination of acetaminophen, aspirin, and caffeine, brand name Excedrin. These seemed to be more effective for milder headaches. Also included in Level A recommendations are ergots, dihydroergotamine, both nasal spray and pulmonary inhaler, although the pulmonary inhaler is not FDA approved yet as they have been having some issues with manufacturing. There are several NSAIDs or nonsteroidal anti-inflammatory drugs that are proven to be effective. These include high dose aspirin, diclofenac, ibuprofen, and naproxen. All the triptans are Level A recommendations, as well as the opioid butorphanol nasal spray. However, it is generally not recommended to use opioids as first line, as they have an addictive potential and overuse can lead to medication abuse headache, which I will touch upon later.

Next, I will be discussing the triptans. I made this table to try and include clinically helpful relevant information. In the column labeled “dose and max dose,” the numbers prior to the slash are available strengths per dose. The max dose is the maximum dose in 24 hours. The triptans are seven different triptans, some of which have multiple routes of delivery.

Sumatriptan is the first triptan I will be discussing; available in three different routes. The subcut sumatriptan is available in doses ranging from 1-6mg with 12 mg the max for 24 hours. It has the fastest onset of action of all the triptans, starting at about 10 minutes. It's not able to be used with MAOIs and is pretty expensive, even for the generic STATdose pen.

Oral sumatriptan is available in three different doses; a little bit slower than the subcut sumatriptan, but still pretty quick. It is much cheaper than the injectable. Nasal sumatriptan also comes in three different doses. It is very quick as well, starting to work in about 15 minutes, but this has a very horrible taste and a lot of people cannot tolerate it very well. Even for a generic medication, it is still relatively expensive.

Naratriptan has a longer half-life of about six hours, but it also has a slower onset of action, as well.

Almotriptan is available orally, has an intermediate half-life, and in some people it seems to work pretty quickly in about 30 minutes. In other people, it takes a little bit longer up to two hours.

Frovatriptan has the longest half-life of all the triptans, the onset of action is the slowest at about two to three hours. Although it is a generic, it is still pretty expensive at about $55.00.

Rizatriptan is another oral triptan and it does work pretty quickly in some people (as quick as 30 minutes) and other people a little slower (up to two hours). It is another triptan that is not able to be used with an MAOI, but it is pretty cheap at $2.00.

Eletriptan is another triptan, with a slightly longer half-life but works pretty quickly in about 30 minutes but relatively expensive.

Zolmitriptan comes in two routes of administration. The oral form works in about 45 minutes. The nasal spray works in about 15 minutes. So of the triptans, the sumatriptan nasal spray and zolmitriptan nasal spray are the two quickest triptans available outside of using subcutaneous sumatriptan. Zolmitriptan cannot be used with MAOIs and it's still relatively expensive.

Next, we will go to Level B recommendations or medications found to be probably effective for acute treatment of migraine. This includes a class of medications called antiemetics. Of them, chlorpromazine, droperidol, metoclopramide, prochlorperazine have been found to be probably effective. Droperidol is not used very much anymore because it does have a black box warning of QTc prolongation and torsades.

DHE IV, IM, and subcutaneous is included in this category, as well as the combination of ergotamine plus caffeine. There are several other NSAIDs listed under Level B; flurbiprofen, ketoprofen, and Ketorolac. Magnesium sulfate is probably effective in patients with migraine with aura as opposed to migraine without aura. There are some combination medications; acetaminophen with codeine or Tramadol, but again it's not recommended to use opioids as a first line therapy for acute treatment of migraine.

Level C recommendations are medications found to be probably effective and include IV valproic acid, ergotamine, phenazone, which is an NSAID. Other opioids are in this category; IV dexamethasone, butalbital and butalbital containing medications, and intranasal lidocaine. I don’t prefer to use butalbital because there is a high risk of medication overuse headache with this medication. Also, it can be associated with a dangerous withdrawal syndrome, as well.

Next, we will talk about some pearls for acute treatment of migraine. Remember to choose a specific therapy based on effectiveness, contraindications, side effect profile, and patient preference. Some patients may really be needle phobic and want to avoid injecting sumatriptan. Use an adequate dose. I see this pretty frequently where a patient comes to me; they are on 25 mg of sumatriptan and say it doesn’t work for them. I will increase it to 100 mg and it does work for them. So using an adequate dose is important before giving up on the medication.

Treat the headache early in the attack; within 60 minutes from onset and when the pain is still mild. Studies show that if patients get cutaneous allodynia, which is tenderness in the scalp, the triptans are just not as effective. And that happens usually about 60 minutes from the onset of headache. Use a stratified care approach to treatment and match treatment with attack characteristics. I generally recommend an NSAID for mild to moderate headache and then a triptan for a severe headache. If they have nausea and vomiting, adding an antiemetic is also helpful.

Consider the route of administration. If they do have significant nausea and vomiting, using a non-oral route would probably be best so subcutaneous sumatriptan or nasal sumatriptan or zolmitriptan. Also if they have a quick onset headache, then using subcutaneous sumatriptan or nasal sumatriptan or zolmitriptan would be good options as well.

Although opioids are probably effective, it’s not recommended to use regularly. Again, they can get into medication overuse headache. Medication overuse headache can make headaches more frequent, more severe, or make other medications not as effective as they should be. This can happen with using simple analgesics like acetaminophen or ibuprofen or triptans just ten days a month. For opioids, it’s even less, eight days a month, and butalbital even less than that, four days a month. The other bad thing about opioids is that it can leave glutamate out on the synapses, and this is an excitatory nerve transmitter on the trigeminal nerve, which can make headaches worse.

If a patient is on propranolol and they’re prescribed rizatriptan, they should be given half the maximum dose, so 5 mg instead of 10 mg per dose.

Medications that can be used with an MAOI are naratriptan, almotriptan, frovatriptan, and eletriptan.

Some patients don’t tolerate sumatriptan very well. In that case, they may tolerate naratriptan or almotriptan better. Some patients may respond well to a triptan, but their headache may come back later that day or the next day. In these patients, trying frovatriptan might be a good option as it has the lowest recurrence rate for the headaches. Rizatriptan does have the best efficacy at two hours for the oral triptans, but it does have a higher recurrence rate. As I mentioned earlier, zolmitriptan nasal spray is a good, rapid acting alternative to injectable sumatriptan. If a patient is prescribed eletriptan and they’re on a cytochrome P450 3a4 inhibitor, the eletriptan dose should be decreased to half.

I included a couple of questions in this presentation just to highlight some important key points. So which of the following medications are FDA approved for the prevention of migraine? Valproic acid, topiramate, and propranolol; topiramate, propranolol, amitriptyline, lisinopril; valproic acid, topiramate, propranolol, timolol, and atenolol; or valproic acid, topiramate, propranolol, and timolol. So the answer is valproic acid, topiramate, propranolol, and timolol. And this often surprises audience members as far as the number of medications that are FDA approved for the prevention of migraine as well as which beta-blockers are FDA approved.

So treatment goals for the prevention of migraine, we want to decrease the attack frequency, intensity, and duration of the headaches. We want to improve the responsiveness to acute treatment so the medications have less of an uphill battle to start working. We’d like to improve function and quality of life. Reduce the need for abortive medications thereby reducing and/or eliminating medication overuse. And this is an important point, it’s not no headaches.

Although we’d like to get the headaches to go away completely, it’s often not realistic. There’s no cure for migraines at this point. And having a discussion with a patient regarding realistic expectations, I think is key to improving treatment success.

So in what situations might we consider starting a migraine preventive medication? The US Headache Consortium guidelines in 2012, lists a couple recommendations. They recommend starting a preventive in migrainers with six or more headache days a month or if they have four or more headache days with some degree of functional disability or if they have three or more headache days per month resulting in severe disability. There are some other instances you might consider starting a preventive; if the patient has failed or has contraindications to or troublesome side effects to abortive medications, if they’re overusing acute medications, or if their headaches are increasing in frequency.

So there are multiple societies that have published guidelines for the prevention of migraine, The American Headache Society, Canadian Headache Society, and the European Federation of Neurological Society. They all come to slightly different conclusions, but it’s all based on the same body of evidence. Why is that? Each society takes into consideration slightly different criteria. The American Headache Society/American Academy of neurology guidelines are based on efficacy alone. The Canadians also take into consideration benefits and harms of treatment, and the Europeans also take into consideration expert opinion. Although the guidelines vary, there are some areas of agreement in the four medications with the highest level of efficacy are divalproex, metoprolol, propranolol, and topiramate.

So I’ll be discussing the American Headache Society/American Academy of Neurology guidelines published in 2012, and their recommendations for Level A, or those medications shown to be effective, are divalproex sodium, valproate, and topiramate. In the third column, I did list a studied or target doses, and it’s important to try to get your patients up to this dose and have them stay at that dose for an adequate time. For divalproex sodium, it’s 1000 mg a day. For topiramate, it’s 50 mg twice a day. There are three beta-blockers, timolol, propranolol, and metoprolol with Level A recommendation.

Level B recommendations, or those medications found to be probably effective include some antidepressants, amitriptyline and venlafaxine, and some other beta-blockers, atenolol and nadolol.

Level C recommendations, medications found to be possibly effective, include lisinopril, although I see a lot of people in my clinic already on lisinopril before they come to me. And I don’t use this very much because I personally don’t think it works that well. Candesartan is Level C. There was a study that came out about two or three years ago that was positive for candesartan so I do use this occasionally. Clonidine and guanfacine are also Level C as well as carbamazepine, nebivolol, and pindolol. Cyproheptadine is a medication I sometimes use in pregnant patients because it is FDA a Category B for pregnancy.

Here’s another question. Which of the following are FDA approved for the prevention of chronic migraine? Topiramate, propranolol, onabotulinumtoxinA or Botox, valproic acid, topiramate and Botox, topiramate, propranolol, and Botox. So Botox is the only FDA approved medication for the prevention of chronic migraine.

Another question, which have the best evidence for efficacy for the prevention of chronic migraine? And the answer choices are the same as the slide before. Topiramate and Botox have the best evidence for efficacy for chronic migraine prevention.

The preempt one and two trial were the landmark trials that were used to obtain FDA approval for Botox for the prevention of chronic migraine. And I present data here in both the double blind phase as well as the open label phase. The double blind phase lasted 24 hours, and they compared placebo to Botox group. And you can see at about four weeks, the Botox group starts pulling away from placebo. Both groups did have improvement in their headaches, although some would argue that the placebo group started leveling out near the end of the 24 weeks.

The open label phase ran from 24-56 weeks, and the placebo group received Botox at that point. And you can see both groups continue to get improvement in their headaches. The original placebo group seemed to try to catch up to the original Botox group but not quite. The 50% responder rate at 24 weeks was about 47% in the Botox group compared to 35% in the placebo group. There does seem to be a cumulative effect though. And the longer the patients were on Botox, the more improvement they did receive. So at 56 weeks, the 50% responder rate was about 69% in the original Botox group and about 62% in the original placebo group. So the placebo group did try to catch up to the original Botox group but not quite.

The injection paradigm for Botox is 155 units in 31 injections, and these are in the corrugators, the procerus, the frontalis, temporalis, occipitalis, cervical paraspinal muscle groups, and the trapezi. And it’s five units per injection every 12 weeks.

So tips on migraine prevention, start low and go slow. We like to try to avoid side effects, and the longer patients can tolerate it, the more likely that we can get them up to an adequate target does. We want to titrate up the dose until they achieve a therapeutic response or the target dose is achieved or the patient experiences side effects. Again, adequate duration is important. We’d like the patients to be on an adequate dose or a target dose for at least two or three months. I have a lot of patients that come in, have tried an appropriate medication but quit after one or two weeks because they’ll say it didn’t work. They just were not on it long enough. So oftentimes, I’ll place these patients back on the original medication, keep them at the target dose for a couple of months, and they do seem to get better.

Try to get a twofer. If they have multiple comorbidities and you can treat all of them with one medication, that’s great. If they have depression, anxiety with migraines, trying a tricyclic antidepressant or venlafaxine might help. If they have anxiety or high blood pressure, trying a beta-blocker might be helpful. Topiramate, at doses over 200 mg a day can decrease the levels of oral contraceptive pills, and this is important in our migraine population as most of the patients are younger women in their childbearing age. So keep this in mind as a lot of medications including topiramate can cause birth defects.

We’ll switch gears to some newer treatments for migraine including treatments that have been reformulated and are delivered differently as well as some of the newer modulation devices. So current treatments delivered differently are old wine in new bottles. A lot of them are injectable sumatriptan as well as a different form of an intranasal sumatriptan. And then I’ll talk briefly about the sumatriptan iontophoretic patch.

There are several different sumatriptan auto-injectors. The picture in the top left is of the generic STATdose sumatriptan injectable. It’s a little cumbersome to use and a lot of steps. There’s a pen that is housed in the small circular pole in the container and then two syringe cartridges next to that. So when a patient is in the midst of a severe migraine, they’re vomiting, lying in the dark, they have to get this out, take the pen out, screw it on the syringe cartridge, inject themselves, put the syringe cartridge back into its housing, unscrew the pen off, and then house the pen again. It’s a lot of steps. There’s a needle-free sumatriptan injector, and this may be used in patients that are really needle phobic, but it uses air to drive the medication. And it’s actually more painful than the needle injections, and it leaves a pretty significant bruise. So many people don’t tolerate it. There is an EpiPen like sumatriptan auto-injector, but they have been out of stock for a long time. And I’m not sure if it’s coming back.

There are three newer prefilled auto-injectors, and two of them are available in the 6 mg doses and one available in a 3 mg dose. They’re all much easier to use, fewer steps. The steps are a little different for all three so I’d recommend that you and your patient go to the website and watch the videos on there.

We’ll talk about Zecuity very briefly as there may be some patients that have a couple patches left over floating around. So Zecuity is a sumatriptan iontophoretic patch that used a battery and an electric current to drive sumatriptan through the skin. However, in June of last year, the FDA announced that it is investigating reports of serious burns and scarring from the device. So about a week after that, the manufacturer pulled the device from the market. I haven't heard anything else from them yet so I’m not sure if it’s coming back or not.

This is a unique device, sumatriptan breath powered dry nasal powder, also called Onzetra Xsail. It’s unique in that it’s not your typical liquid nasal spray. It’s a dry form of sumatriptan. The patient places the nosepiece in their nose and blows through the mouthpiece. And what it does is it blows the powder in the nasal cavity, disperses it better than a liquid nasal spray, and at the same time as they’re blowing, it closes the soft pallet so they don’t swallow the medication avoiding much of the bad taste that’s often experienced by patients with a usual sumatriptan nasal spray. On the right is data from their study, and just briefly, in migraine studies, pain freedom is where a patient goes from moderate to severe pain to no pain whereas pain relief is moderate or severe pain to mild or no pain.

And so in the top chart, you can see that the Onzetra starts working in about ten minutes and then is better than oral sumatriptan at 100 mg up until about two hours when the oral sumatriptan catches up. And then sustained pain relief is about the same for both. Similar results for pain freedom, starts working in about ten minutes, better than oral sumatriptan up until about two hours, and then oral sumatriptan catches up. This is better tolerated than sumatriptan, and patients do have less side effects.

Switching gears, here’s another question. Which neuromodulation device is FDA approved for the prevention of migraine? Single pulse transcranial magnetic stimulation, transcutaneous supraorbital neuro stimulation, noninvasive vagal nerve stimulation, or noninvasive caloric vestibular stimulation. So the answer is transcutaneous supraorbital neuro stimulation. I’ll be talking about the two devices listed here. The last two devices are not FDA approved yet and so maybe that will come in the future.

The first device I’ll be talking about is a single pulse transcranial magnetic stimulator. This is for the acute treatment of migraine with aura, also called Spring TMS. Here they did a study, a randomized trial, for the acute treatment of migraine with aura where they compared two pulses of the device versus a sham given within one hour of the onset of aura. You can see here that the device was better than the sham at all points, at two hours, 24 hours, and 48 hours. And this was for the proportion of patients with pain freedom. In the UK they did an open label study on 29 patients where they did pulses twice a day as well as PRN pulses to treat acutely. And they went 12 weeks. And you can see that there was a reduction in number of acute treatment medications needed as well as a reduction in migraine days.

So to review the level of evidence for single pulse transcranial magnetic stimulation, it’s Level B for the acute treatment of migraine with aura. It is FDA approved. But this is based on one class one study. It is a minimal risk device, and the FDA does have a lower threshold of approving minimal risk devices. For the prevention of migraines, Level U. There’s been four randomized trials, but the data has been conflicting. There’s only been one positive trial and three negative trials. So further research does need to be done on this.

Next, we’ll talk about transcutaneous supraorbital neuro stimulation for the prevention of migraine, also called Cefaly. There was a randomized trial in 67 patients where they wore the device for 20 minutes a day. The endpoint of decrease in migraine days at the third month was actually nonsignificant, but the 50% responder rate was significant at about 38%. It is a little expensive, about $350.00 plus shipping, and then electrodes cost extra, each lasting about 20 sessions. It can be returned within 60 days for a refund, but it can take up to three months to work so they may be returning it before they got a full chance for it to work. It is also approved on this one study, since it is a minimal risk device back in 2014. It’s also approved in Canada and in Europe. In those countries it has three settings actually, for acute, prevention, and relaxation. In the US right now, it’s just for prevention but the company is considering doing studies on the acute treatment of migraine as well.

So to review the evidence and summary for the Spring TMS, it’s Level B for the acute treatment of episodic migraine with aura and Level U for prevention of migraine. And for Cefaly, it’s Level B for the prevention of episodic migraine.

And this is my last talking point. When might you refer a patient to a headache specialist? Consider referring the patient if they fail two or more typical migraine preventative medications at an adequate dose and duration, they fail two or more typical migraine abortive medications, they have contraindications to two or more preventative or abortive medications, if the patient experiences side effects to the medications, if a diagnosis is uncertain. Some patients have more than one or two headache types, and this could cloud the diagnosis, or if the migraine headaches are worsening.

The next several slides here are on the other levels of evidence just for completeness sake that you can refer to. I hope you found this presentation useful, and I appreciate your attention. Thank you.