Last updated on February 5th, 2021 at 01:01 am
Migraine is a very disruptive disorder to have to deal with. It interferes with patients’ family, work, and social lives. When the burden of migraine becomes excessive on one or more of these life aspects, preventive migraine therapy should be used. In general, if someone is averaging more than 4 migraines per month, preventive treatment should be offered and discussed, although this number is not an absolute. For example, if someone has 1 migraine per month, but it wipes them out for 1 week and they are missing work, there are certainly variations on when preventive medications should be considered, such as this scenario. If the decision to use a preventive migraine medication has been made, there are several important factors to keep in mind in order to optimize treatment success, as discussed below.
So this blog will focus on migraine preventive meds and treatments, which are a continuous treatment such as a daily pill or a monthly/quarterly treatment such as CGRP mAbs, all of which are detailed below. The goal of migraine preventive treatment is to lessen the frequency and/or severity of migraine attacks. This is in contrast to migraine abortive/acute (as needed) options such as triptans, gepants and ditans. The goal of migraine abortive treatments is to stop individual migraine attacks at onset so the migraine does not reach full severity, ends quickly, and your function is restored and maintained rather than having to go lay down and miss the whole day in bed. If you have migraine, you want to have both a good abortive and preventive treatment plan to lessen migraine’s nasty habit of interfering and disrupting life and function.
Any preventive medication needs an adequate “therapeutic trial”. In short, you need to be patient and give it enough time to work, as well as get to the correct dose. I see patients all the time that tell me their doctor put them on a medication (usually at too low of a dose), and they stopped it after 3 weeks because it “wasn’t doing anything”. Well, it’s not going to do anything that soon, and that is too early to expect any significant improvement. In general, any preventive medication needs 4-6 weeks to begin working, and 2-3 months until full effect is seen (assuming a good dose has been reached). A good rule of thumb is evaluation of response a minimum of 8 weeks after reaching a target therapeutic dose. If there is a partial response at that time, it’s possible that cumulative benefit can continue to occur over 6-12 months. So the decision on whether to continue really depends on how much benefit has been received, and how well the the patient is tolerating the medication. Unfortunately, there is no way to expedite this process. That doesn’t mean the treatment can’t work sooner. However, that is the standard duration of treatment for a medication to have had a fair trial. Finding a migraine preventive is often a trial and error process. If a treatment is not starting to help by at least 8 weeks at a good dose, changing to a different therapy is suggested. However, once an effective treatment is found, the wait is well worth the decline of migraine frequency and severity!
In addition to an adequate trial duration, an adequate trial dose is also necessary. For example, a common first line medication used for migraine prevention is Topiramate (which is also FDA approved for migraine prevention). I often see patients who come in on 25 mg or 50 mg and have been on that dose for a year or more without much benefit. I discuss with them that the goal dose is at least 100 mg total daily dose, so the dose is too low. For example, in the migraine preventive trials, once patients reached 100 mg and had been at that dose specifically for at least 4 weeks, that is when improvement of statistical significance began. So, I typically start 25 mg at bedtime for 1 week. Then each week increase by 25 mg at bedtime until 100 mg is reached, and then I give a 100 mg pill to begin. I tell them if there is no improvement starting after at least 4 weeks from reaching the 100 mg dose specifically, let me know. I usually dose it all at bedtime which can help limit side effect potential (since you’ll be sleeping). However, it is generally meant to be taken as a twice daily medicine (such as 50 mg twice daily), and most patients tolerate that fine too.
With that said, patients can certainly respond to low doses of medications. However, if improvement has been minimal after a month of a lower dose, it is always a good idea to begin titration up to a better dose. The American Headache Society and American Academy of Neurology published guidelines of migraine preventive medications which includes common goal dose targets for some of these preventive medications here.
There are many preventive treatments used, although most of them are considered “off-label” for migraine prevention. This means they are not actually FDA approved for migraine prevention, but there is enough evidence based on research trials or clinical experience to warrant them as a valid option to try. As far as true FDA approved oral (pills by mouth) preventive medications, there are 4 available that have this distinction; Topiramate, Divalproex, Propranolol, and Timolol. There are also a number of natural migraine treatments with supplements which have evidence for migraine prevention, and those are detailed and discussed here.
So, let’s discuss migraine prevention medicine. The categories of oral preventive migraine medications all sound bizarre. They consist of anti-seizure (anti-convulsant), anti-depressant/anti-anxiety, and anti-hypertension (blood pressure) medications. It is important for patients to know that the medicine is being used specifically for migraine. I often see patients who say they didn’t start the medicine their doctor prescribed because they got home, Googled it, and they tell me, “I’m not depressed”. I explain the reasoning for the medication and that it is not for depression, but for migraine prevention since there are overlapping electrical pathways between many of these types of disorders. Furthermore, there are select medications within each of these categories that have evidence from trials and clinical experience for migraine prevention, as listed here and here. For patients that have chronic migraine (15 or more headache days per month with 8 or more days having migrainous features), Botox is another highly effective option to consider.
It is also important to know that the medications in each of these medication classes are not a “one size fits all” for every medicine within that category. For example, there is no good evidence for migraine prevention in the SSRI (selective serotonin reuptake inhibitors) anti-depressant/anti-anxiety medication category (Fluoxetine, Sertraline, Escitalopram, Citalopram, etc.). However, there is evidence for benefit in some of the SNRIs (serotonin and norepinephrine reuptake inhibitors) such as Venlafaxine XR, Duloxetine, as well as some of the TCAs (tricyclic antidepressants), primarily Amitriptyline and Nortriptyline. Similarly, there are select medications within the anti-seizure/anti-convulsant category which have the best evidence (Topiramate, Divalproex), as well as the anti-hypertension category (Propranolol, Metoprolol, Atenolol, Nadolol, Verapamil).
There are now 4 monoclonal antibody CGRP receptor antagonists which have this FDA approval for migraine prevention also. Three of them are once monthly auto/self-injections (Aimovig, Ajovy, Emgality), and one is a once quarterly (every 3 months) 30 minute IV (intravenous) infusion (Vyepti). In general, these are an option for those with 4 or more migraines per month on average. The great thing about these treatment options as opposed to standard pill options is that they do not require a gradual dose escalation, they tend to have a much more rapid onset of improvement, and they have very low side effect risk. These medications are all discussed in much greater detail and comparison here.
Neuromodulatory devices that are FDA cleared for migraine prevention are also available and include sTMS (SAVI, SpringTMS, sTMS mini), eTNS (CEFALY), and nVNS (GAMMACORE), all of which are discussed in much greater detail here. There are also nutraceuticals and supplements which have good evidence for migraine prevention. Yoga, relaxation and wellness therapies are also helpful in migraine prevention.
An exciting development is that there are 2 migraine preventive medications in the new gepant classification which are currently in clinical trials, and showing good evidence of effectiveness. They are both oral pills and include Atogepant and Rimegepant (currently FDA approved for abortive migraine treatment under the name Nurtec ODT 75 mg). So these will open up another new class of preventive migraine medications engineered purely for migraine treatment! Notably, Biohaven submitted a request to the FDA in October 2020 to approve Rimegepant as a preventive migraine treatment, in addition to its current migraine abortive FDA approved indication. This decision is pending. This move followed clinical trials showing that patients taking 75 mg of Rimegepant every other day experienced a 4.3 day reduction from baseline in monthly migraine days.
When choosing a preventive treatment, I like to fine-tune the treatment to “hit as many birds with one stone”. In other words, pick something that will not only help with migraine prevention, but may also help with other medical conditions at the same time. Doing this can allow you to help minimize the number of medications used overall, by using something with benefit for several disorders in addition to the migraine. For example, if someone has depression or anxiety, targeting their migraine preventive medication with an anti-depressant/anti-anxiety category would make sense. If the patient has other chronic musculoskeletal pain issues, fibromyalgia, occipital neuralgia, etc., the SNRIs and the TCAs are good considerations. If the patient has insomnia, Amitriptyline or Nortriptyline are great options. If they have seizures, an anti-seizure medication such as Topiramate or Divalproex would make sense. If they are overweight, Topiramate also causes weight loss. Divalproex is another anti-seizure medicine which is also FDA approved for migraine prevention. However, this should be avoided when possible in young women of child-bearing age given the high risk of congenital birth defects while taking it (and most pregnancies are unplanned).
Here are some treatment considerations to take into account for migraine preventive therapy in addition to the following medical conditions the patient may also have:
-Obese/Overweight: Topiramate (Topamax), Topiramate ER/XR (extended release, Trokendi or Qudexy XR), Zonisamide (Zonegran): All can cause weight loss, which can be helpful in overweight patients. However, use with caution if patient is extremely thin to limit further weight loss. If they improve with Topamax, but have Topamax side effects (numbness and tingling, word-finding difficulty, speech disturbances, memory and cognitive disturbances, mood changes), changing to Topiramate ER/XR (extended release) or Zonisamide tend to have similar benefit with less side effects. Women who are on oral contraceptive pills are often warned prematurely by their pharmacist that Topiramate will effect their oral contraceptive. This is partly true. Topiramate at a daily dose of 200 mg or less does not interact with oral contraceptives according to this study, but it can at higher doses which could potentially decrease effectiveness. However, the goal dose for effective migraine prevention is typically 100 mg per day, well below that 200 mg dose that could impact effectiveness of the oral contraceptive. I would avoid Amitriptyline, Nortriptyline since there is a risk of weight gain for some.
-Underweight/Excessively thin: Side effects of Nortriptyline and Amitriptyline can occasionally be weight gain (but not necessarily), but this may be beneficial in some patients.
-Depression and/or anxiety: Venlafaxine ER, Duloxetine, Amitriptyline, Nortriptyline, Desvenlafaxine
-Mood disorder such as bipolar or psychosis: Divalproex, Topiramate, Carbamazepine
-Anxiety without depression: Venlafaxine ER, Amitriptyline, Duloxetine, Nortriptyline, Desvenlafaxine, Propranolol
-Insomnia: Amitriptyline, Nortriptyline
-Fatigue/Low energy: Venlafaxine ER, Duloxetine (these can be energizing for many, so are best taken in morning)
-Hypertension: Propranolol, Metoprolol, Nadolol, Atenolol, Lisinopril, Candesartan, Verapamil
-Palpitations: Propranolol, Metoprolol, Nadolol, Atenolol
-Chronic musculoskeletal pains, fibromyalgia, neuropathy/nerve pains: Amitriptyline, Duloxetine, Nortriptyline, Gabapentin
-Pregnancy: This one is tricky since the goal during pregnancy is to minimize the use of as many medications as possible. Mindfulness treatments such as yoga and meditation are always good recommendations. With that said, the first line option we typically begin with is magnesium supplementation of 400-800 mg daily. If a prescription medication is needed, cyproheptadine 4 mg at bedtime has been a long time medicine used in this scenario, and it can be titrated to 4 mg three times daily if needed. The good thing with pregnancy is that migraines improve in about 2/3rd of women (especially 2nd and 3rd trimester), and it is not uncommon to hear that migraines resolved during pregnancy. So many times a preventive treatment may not even be needed. For menstrually related migraine outside of pregnancy, further discussions and treatment considerations can be read here.
-Epilepsy: Topiramate, Topiramate ER/XR (extended release), Divalproex, Carbamazepine, and Zonisamide are the anticonvulsant medications we see most useful for migraine prevention. In fact, Topiramate and Divalproex are also FDA approved for migraine prevention. If patients improve with Topiramate but have side effects, changing to Topiramate ER/XR (extended release) or Zonisamide tend to have similar benefit with less side effects. Women who are on oral contraceptive pills are often warned prematurely by their pharmacist that Topiramate will effect their oral contraceptive. This is partly true. Topiramate at a daily dose of 200 mg or less does not interact with oral contraceptives according to this study, but it can at higher doses which could potentially decrease effectiveness. However, the goal dose for effective migraine prevention is typically 100 mg per day, well below that 200 mg dose that could impact effectiveness of the oral contraceptive.
-Non-oral route needed or preferred: Once monthly self/auto injections of monoclonal antibody CGRP receptor antagonists (Aimovig, Ajovy, Emgality) or once quarterly 30 minute IV infusion (Yvepti), which are all detailed here. Botox is another non-pill option for those averaging 15 or more headache days per month with at least 8 of those days having any migrainous features (throbbing, nausea, sensitivity to light (photophobia) or sound (phonophobia)) for 3 or more consecutive months (chronic migraine). Neuromodulatory devices that are FDA cleared for migraine prevention are also available and include sTMS (SAVI, SpringTMS, sTMS mini), eTNS (CEFALY), and nVNS (GAMMACORE), all of which are discussed in much greater detail here.
-Averaging 15 or more headache days per month with at least 8 of those days having any migrainous features (throbbing, nausea, sensitivity to light (photophobia) or sound (phonophobia)) for 3 or more consecutive months (chronic migraine): Botox (Onabotulinumtoxin-A) injections every 3 months according to the PREEMPT chronic migraine treatment protocol. This is the only truly FDA approved medication for prevention of chronic migraine as of 2010. Any of the above listed medications are also options to consider, and most insurances will require failure of at least 2 classes of preventative oral medications before Botox is approved anyway, but this varies by insurance.
Expectations in migraine management are important. If your expectation is that your migraines will stop completely when you use preventive medications, you will be sorely disappointed. Of course it can certainly happen, but that is rare and should never be the expectation or goal. The goal of preventive therapy is a decrease in migraine frequency and/or severity of attacks (optimally both) to some extent to make them more tolerable and less intrusive into life. A general goal is 50% improvement in frequency and/or severity. Some patients can get much more than that, while others get much less (which would signal trials of a different medication class). With that said, success with migraine preventive benefit can also be considered in significant decreases is migraine attack duration or severity, reduction in migraine associated disability, improving the patient’s functioning in various areas of life, improvements in quality of life, and improvement in acute treatment responses. In general, studies estimate that about 45% of patients on conventional preventive therapy (such as oral medications) receive 50% reduction in monthly migraine days. Thus, 55% will receive less improvement than this. The CGRP mAbs tend to have a higher rate of improvement then conventional treatments as detailed here.
WHEN TO STOP
There is no absolute answer of when to stop preventive therapy. It depends on how well one is doing, how long they have been doing well, and how much they want to get rid of treatments. Some people want off as soon as they can, others prefer to stay on for years since they are doing very well with few migraines, and don’t want to “rock the boat”. In general, the goal is to continue preventive therapy until the patient is doing significantly better for at least 3 months, but preferably closer to 6 months or so. I always make sure to tell patients that preventive medicines or treatments are not necessarily meant to be a life-long commitment. Rather, we use these treatments to “reboot” and “reset” the brain’s electrical system to have less frequent and/or severe migraines, and then try to sneak away off the medications once they are consistently doing better.
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