Gepants (Nurtec, Qulipta) vs. CGRP monoclonal antibodies (Emgality, Ajovy, Vyepti, Aimovig) for migraine prevention? Which medication class works better?
The gepants (Nurtec, Qulipta) and calcitonin gene-related peptide (CGRP) monoclonal antibodies (Emgality, Ajovy, Vyepti, Aimovig) are both very effective medication classes in preventing migraines, but which medication class works best to prevent migraine attacks? Well, we now have a direct head to head clinical trial to help answer this question! We’ll talk about those results in a bit. Let’s review some general information about these medications first, and what CGRP actually is.
Qulipta vs. Emgality, Ajovy vs. Qulipta, Qulipta vs. Vyepti, Aimovig vs. Nurtec, Qulipta vs. Aimovig, Nurtec vs. Emgality, Ajovy vs. Nurtec, Vyepti vs. Nurtec, or Qulipta vs. Nurtec for migraine prevention? These are very common questions I get in clinical practice from patients.
The answer is that both classes of medicines have very good evidence in clinical trials for migraine prevention. However, there are differences that are unique to each treatment option. Using these unique differences can help you and your doctor narrow down which type of medication to try first.
Everyone’s migraine circuitry can have variation in what electrical pathways are most involved in their migraines. So if one type of medication or medication class does not work, it’s always worth trying another option, especially with a different target or mechanism of action. We’ll talk more about that soon.
What is CGRP, and how does CGRP relate to migraine?
CGRP is a very inflammatory protein released from the trigeminal nerves during a migraine attack. It is a main cause of neurogenic inflammation in the nervous system, and in the transmission of pain. It dilates blood vessels which triggers more CGRP release and thus, more pain. Basically, CGRP triggers migraines, intensifies migraine pain, and plays a role in triggering and sustaining a migraine. Many studies have now shown that blocking the CGRP receptors or the CGRP protein can help prevent migraine attacks (CGRP antagonists) by stopping the effect of CGRP. Blocking the CGRP receptor is also a very effective strategy in the acute treatment of migraine.
The CGRP monoclonal antibodies (mAbs) for migraine prevention
The CGRP pathway has been studied since the 1980s when it was initially discovered. Preventive migraine studies done since 2014 with a CGRP antibody to block the effects of CGRP eventually led to 3 FDA approved CGRP mAbs in 2018 (Aimovig, Emgality, Ajovy), and a 4th CGRP mAb FDA approved in 2020 (Vyepti).
The CGRP mAb receptor antagonists (CGRP mAbs) were the 1st migraine specific preventive medications that were FINALLY developed PURELY for migraine prevention, and became available in 2018. This was a major step forward for migraine management because prior to 2018, all of the migraine preventive treatments we used were “adopted” from other categories consisting of the anticonvulsant (anti-seizure), anti-depressant/anti-anxiety, and anti-hypertensive (blood pressure) medicine categories. None of these older classes were created specifically for migraine, but over time some were found to be helpful in migraine prevention, and subsequent studies also confirmed benefit. These older options can still be an effective treatment for pain relief in some, while many have side effects or have a lack of efficacy from lower response rate.
There are currently 4 CGRP monoclonal antibodies (mAbs) available. The first CGRP mAb available was (Aimovig (Erenumab)), and it came to market in Spring of 2018. Two additional CGRP mAbs followed shortly thereafter the same year and included Emgality (Eptinezumab) and Ajovy (Fremanezumab). Vyepti (Eptinezumab) was the 4th and most recent CGRP mAb that became available in 2020.
Aimovig is the only CGRP mAb which binds and blocks the CGRP receptor. Emgality, Ajovy, and Vyepti all bind to and block the CGRP protein (ligand) itself. Theoretically, the result should be the same either way in that the CGRP pathway is disabled and migraines are prevented. However, from my experience, some people may respond better to one target vs. the other. So if one type of CGRP mechanism is not working for you, it may be worth a discussion with your headache specialist about trying one with a different CGRP target.
Emgality, Ajovy, and Aimovig are a once monthly subcutaneous injection done as self-injections (Ajovy can be done quarterly with 3 injections at the same time) with an easy to use push button auto-injector device (similar to an EpiPen). Drug administration is typically injected in the stomach area or the upper outer thigh area. Emgality and Ajovy are also available in a preloaded syringe for those that do not like the auto-injector option (some feel the syringe is less painful). Vyepti is a once quarterly (every 3 months) 30 minute IV infusion. All 4 of the CGRP mAbs are compared to each other and discussed in much greater detail here.
The gepants enter the migraine scene as migraine abortives
In early 2020, the first of a new CGRP targeting migraine abortive (“as-needed basis”) class called the gepants came out with oral Ubrelvy (Ubrogepant), and oral Nurtec ODT (Rimegepant) followed by Zavspret (Zavegepant) nasal spray in July 2023. The gepants all bind to and block the CGRP receptor only (not the CGRP protein). The gepants were the first new class of acute migraine treatment developed since the triptans became available with Sumatriptan in 1992 (there are 7 different triptans available). The gepants, triptans, and ditans (another new abortive class that came out in 2020) are all compared to each other for migraine abortive treatment in much more detail here and are beyond the scope of today’s blog.
The gepants expand to migraine preventative treatment
Then, the gepants made a surprise pivot to include migraine preventive treatment to their repertoire in addition to abortive treatment. This began when Nurtec received dual FDA approval for episodic migraine prevention in May 2021, in addition to its pre-existing FDA approval for migraine abortive treatment. So, it became the first and remains the only dually approved migraine abortive and preventive medication. This makes Nurtec a handy option if someone needs a “mini-prophylaxis” during certain periods of time such as season changes, upcoming stressors, or other predictable triggers when they know their migraines will be more frequent. Then when they are outside of that triggering window of time, they can just use it abortively when needed.
Then in September 2021, the first gepant developed and studied purely for migraine prevention became available with Qulipta (Atogepant). Qulipta was initially FDA approved for prevention of episodic migraine and later also became FDA approved for chronic migraine in April 2023. This made Qulipta the only FDA approved oral pill for prevention of both episodic and chronic migraine! To date, Qulipta remains the only FDA approved pill for chronic migraine (in addition to episodic migraine). Nurtec and Qulipta are compared to each other for migraine prevention in much greater detail here, and are beyond today’s discussion.
Are the gepants or CGRP mAbs more effective for migraine prevention?
Ok, back to our original question. There has only been 1 head to head clinical trial comparing a gepant to a CGRP mAb in episodic migraine (4-14 headache days per month) prevention. That study was funded by Lilly, the maker of Emgality. It compared the migraine preventive benefit of Emgality (120 mg monthly injection) vs. Nurtec 75 mg every other day. Results showed that after 3 months of treatment, 62% of the people in the Emgality group and 61% of people in the Nurtec group had at least a 50% reduction in monthly migraine headache days (migraines cut by half or more). So both treatments were very effective, but Emgality was not statistically superior to Nurtec or vice versa.
Each of these medications has been a huge step forward in migraine preventive treatment, and there are no bad choices. As you can see in the table at the bottom of the page, we are seeing results such as 75% and 100% reduction (“super responders”) in monthly migraines with many of these medications with both the gepants and CGRP mAbs. The majority of patients receive a 50% or greater reduction in migraine days per month in general for both classes. These are significant treatment results that we’ve not been used to seeing with older preventive treatment options (although can certainly happen for some on the older options).
The table at the bottom compares the data on migraine prevention between the gepants (Nurtec and Qulipta), and the CGRP mAbs (Aimovig, Emgality, Ajovy, Vyepti). Keep in mind, most of these data are not from head-to-head studies between each of the medications, but rather from that reported within each individual medication compared to placebo in their respective trials.
How to pick between the gepants and CGRP mAbs for migraine prevention
So now that we suddenly have many new preventive migraine treatments working on different targets in the CGRP migraine pathway between the CGRP mAbs and the gepants, how do you know which you should try, or which might work best for you?
Here is what to ask yourself to help narrow down which to consider trying first for preventing migraine (not abortive/”as needed”). Do you prefer taking a pill, a once monthly self-injection (autoinjector by an easy push button vs. preloaded syringe), once quarterly (every 3 months) self injections, or a 30 minute quarterly (every 3 months) IV infusion?
If you prefer a pill, the options are the gepants and include either Nurtec ODT every other day or Qulipta once daily. If you have problems with constipation, Nurtec every other day would be the better choice to start with given some increased constipation risk that Qulipta has.
If you prefer a once monthly self-injection, the options are the CGRP mAbs and include Aimovig, Emgality, and Ajovy. All 3 come in an easy to use push button auto-injector device (like an EpiPen). Emgality and Ajovy also come in a preloaded syringe if you prefer that mechanism rather than an auto-injector. Of these 3 options, Ajovy lasts the longest (longest half life). So if your Emgality or Aimovig tends to wear off early each month, Ajovy may be a good consideration to switch to. If you have significant constipation issues, Ajovy and Emgality have the least constipation risk, so you may want to avoid Aimovig.
If you prefer once quarterly self-injections in auto-injector or preloaded syringe, Ajovy is the only option for this. Keep in mind, it is still 3 injections done all at once instead of doing only 1 injection each month for the same 3 month treatment window.
If you prefer a once quarterly 30-minute IV infusion and do not like the idea of self-injections, then the only CGRP monoclonal antibody option is Vyepti. If you have had injection site reactions with the self-injection options, Vyepti is also a good consideration to switch to. If your CGRP mAb self-injectable also tends to wear off early a week or two before you’re due for the next treatment, Vyepti is also a good consideration since it has such a high affinity for CGRP and binds the tightest. This is why it lasts the longest of all the CGRP mAbs at 3 months. Vyepti also does not cause constipation, as can be seen with some of the other CGRP mAbs (primarily Aimovig). So this might be another consideration to weigh if you have constipation problems.
If you are planning on becoming pregnant soon, then the gepants would be the better choice. The reason is that the current recommendations are to stop CGRP mAbs 6 months prior to pregnancy planning and conception given the extended period that that CGRP mAbs stay in the system. However, gepants can simply be stopped if you get pregnant without needing a long period of being off of them. Current recommendations are to avoid gepants and CGRP mAbs in both pregnancy and breast-feeding until further safety data are collected.
Conclusions
Everyone responds differently to medications in terms of benefits and side effects. This is because everyone’s migraine circuitry may have different pathways that are more prominently driving their migraines.
So first, decide if you have a preference on the route of administration as mentioned above (pill, injection, infusion). That’s the best place to start. You can always switch to another type if you’re not receiving benefit with one of them, or having side effects with one.
It is also important to know that failure of one medicine within a class (such as gepants) does not necessarily predict failure to other medicines within that class, or in another CGRP medicine class (such as CGRP mAbs). For example, I’ve seen Qulipta work wonders for people when they didn’t respond to Nurtec every other day, or vice versa. Similarly, failure of one CGRP mAb does not mean that you will not respond to the others. I have seen quite a few patients who failed 3 of them, and then did amazing with the 4th one they tried. In addition, as detailed above, if one type of CGRP mechanism is not working for you (such as CGRP receptor target), it may be worth a discussion with your headache specialist about trying one with a different CGRP target (such as CGRP protein target).
The bottom line is that the CGRP antagonists are all highly effective options for the majority of patients which healthcare providers now have to offer for prevention of migraine. They all can provide a significant drop in monthly migraine days and migraine symptoms. In fact, the American Headache Society now recommends that CGRP antagonists should be considered as a first-line treatment options incorporated into the treatment plans of patients for migraine prevention. The CGRP antagonists also generally have much fewer side effects than historical preventive medicines. It can sometimes be a trial and error process to determine which one you may respond to best, but hang in there!
| Nurtec ODT (Rimegepant) | Qulipta (Atogepant) | Aimovig (Erenumab) | Ajovy (Fremanezumab) | Emgality (Galcanezumab) | Vyepti (Eptinezumab) | |
|---|---|---|---|---|---|---|
| Medication Class | Gepant | Gepant | CGRP monoclonal antibody | CGRP monoclonal antibody | CGRP monoclonal antibody | CGRP monoclonal antibody |
| Mechanism of Action | CGRP receptor antagonist | CGRP receptor antagonist | CGRP receptor antagonist | CGRP ligand antagonist | CGRP ligand antagonist | CGRP ligand antagonist |
| Peak Serum Concentration | 90 minutes | 90 minutes | 6 days | 5-7 days | 5 days | 30 minutes (after infusion) |
| ½ life | 11 hours | 11 hours | 28 days | 31 days | 27 days | 27 days |
| Available dosing | 75 mg orally dissolvable tablet | 10 mg, 30 mg, 60 mg pill | 70 mg or 140 mg once monthly by subcutaneous autoinjector | 225 mg once monthly or 675 mg once quarterly by autoinjector or syringe | 240 mg subcutaneous autoinjector for 1stmonth followed by 120 mg monthly | 100 mg or 300 mg quarterly by 30-minute intravenous (IV) infusion |
| Dosing frequency | 1 pill every other day | 1 pill daily | One injection monthly | One injection monthly or 3 injections quarterly | One injection monthly | One infusion quarterly |
| Reduction of monthly migraine days across weeks 1-12 | Averaged weeks 9-12: 75 mg: -4.3 Placebo: -3.5 Averaged weeks 1-12: 75 mg: -3.6 Placebo: -2.7 | Averaged weeks 9-12: 10 mg: -4.24 30 mg: -4.25 60 mg: -4.44 Placebo: -2.5 Averaged weeks 1-12: 10 mg: -3.7 30 mg: -3.9 60 mg: -4.2 Placebo: -2.5 | N/A | 675 mg quarterly: -3.7 225 mg monthly: -3.4 Placebo: -2.2 *Months 1-3 in long term extension study (open label): 675 mg quarterly: -4.7 225 mg monthly: -4.8 | 120 mg monthly: -4.1 Placebo: -2.1 | 100 mg: -3.9 300 mg: -4.3 Placebo: -3.2 |
| % reduction of migraine days in week 1 | 75 mg: 30% Placebo: 9.4% | 10 mg: N/A 30 mg: N/A 60 mg: 53% Placebo: 15% | N/A | N/A | N/A | N/A |
| % reduction of migraine days in weeks 1-12 | N/A | 10 mg: N/A 30 mg: N/A 60 mg: 54% Placebo: 33% | N/A | N/A | N/A | N/A |
| % of patients with a 50% or more decrease in monthly migraine days across weeks 1-12 | 75 mg: 49% Placebo: 41% *Assessed during weeks 9-12 only, not weeks 1-12 | 10 mg: 56% 30 mg: 59% 60 mg: 61% -Weeks 1-4: 61% -Weeks 5-8: 66% -Weeks 9-12: 71% Placebo: 29% | 70 mg: 41.3% 140 mg: 48.1% Placebo: 26.3% | 675 mg quarterly: 44.4% 225 mg monthly: 47.7% Placebo: 27.9% *At month 3 alone (not averaged over months 1-3): 675 mg quarterly: 49% 225 mg monthly: 51% Placebo: 37% *At month 3 in long term extension study (open label): 675 mg quarterly: 59% 225 mg monthly: 61% | 120 mg: 55% Placebo: 32% *At month 2 alone: 120 mg: 54.1% Placebo: 34.5% *At month 3 alone: 120 mg: 57.7% Placebo: 37.9% | 100 mg: 49.8% 300 mg: 56.3% Placebo: 37.4% |
| % of patients with a 75% or more decrease in monthly migraine days across weeks 1-12 | N/A | 10 mg: 30% 30 mg: 30% 60 mg: 38% -Weeks 1-4: 39% -Weeks 5-8: 41% -Weeks 9-12: 50%
Placebo: 11% | N/A | 675 mg quarterly: 18.4% 225 mg monthly: 18.5% Placebo: 9.7% *At month 3 alone (not averaged over months 1-3): 675 mg quarterly: 30% 225 mg monthly: 29% Placebo: 10% | 120 mg: 30% Placebo: 14% *At month 2 alone: 120 mg: 31.2% Placebo: 11% *At month 3 alone: 120 mg: 34.2% Placebo: 12.8% | 100 mg: 22.2% 300 mg: 29.7% Placebo: 16.2% |
| % of patients with a 100% decrease in monthly migraine days across weeks 1-12 | N/A | 10 mg: 8% 30 mg: 5% 60 mg: 8% -Weeks 1-4: 19% -Weeks 5-8: 24% -Weeks 9-12: 28% Placebo: 1% | N/A | 675 mg quarterly: 0.7% 225 mg monthly: 2.4% Placebo: 0% | 120 mg: 11% Placebo: 4% *At month 2 alone: 120 mg: 11.8% Placebo: 3.7% *At month 3 alone: 120 mg: 12.2% Placebo: 7.3% | 100 mg: 11.4% 300 mg: 16.8% Placebo: 9.1% |
Side effects: Nasopharyngitis | N/A | N/A | 70 mg: 3-9.9% 140 mg: 2-11% Placebo 6-10% | 675 mg quarterly: 5-8% 225 mg monthly: <1-8% Placebo: 4-9% | 120 mg: 7.4% Placebo: 6.5% | 100 mg: 6% 300 mg: 8% Placebo: 6% |
Side effects: Hypersensitivity reactions | <1% | <1% | 70 mg: <1% 140 mg: <1% Placebo: <1% | 675 mg quarterly: <1% 225 mg monthly: <1% Placebo: <1% | 120 mg: 1% Placebo: 1% | 100 mg: 1% 300 mg: 2% Placebo: 0% |
Side effects: Constipation | N/A | Constipation 10 mg: 6% 30 mg: 6% 60 mg: 9% Placebo: 1% | 70 mg: 1% 140 mg: 3% Placebo 1% | 675 mg quarterly: <1% 225 mg monthly: <1% Placebo: <1% | 120 mg: 1% Placebo: <1% | 100 mg: <1% 300 mg: <1% Placebo: <1% |
Side effects: Nausea | 75 mg: 2.7% Placebo: 0.8% | Nausea 10 mg: 5% 30 mg: 6% 60 mg: 9% Placebo: 3% | N/A | N/A | N/A | N/A |
Side effects: Abdominal discomfort | 75 mg: 2.4% Placebo: 0.8% | N/A | N/A | N/A | N/A | N/A |
Side effects: Cramps, muscle spasms | N/A | N/A | 70 mg: <1% 140 mg: 2% Placebo <1% | 675 mg quarterly: <1% 225 mg monthly: <1% Placebo: <1% | 120 mg: <1% Placebo: <1% | 100 mg: <1% 300 mg: <1% Placebo: <1% |
Side effects: Injection site reactions | N/A | N/A | 70 mg: 6% 140 mg: 5% Placebo 3% | 675 mg quarterly: 18-19% 225 mg monthly: 23% Placebo: 4% | 120 mg: 18% Placebo: 13% | N/A |
Side effects: Somnolence/ fatigue | N/A | 10 mg: 4% 30 mg: 4% 60 mg: 6% Placebo: 3% | N/A | N/A | N/A | N/A |
Side effects: Decreased appetite
| N/A | 10 mg: 2% 30 mg: 1% 60 mg: 2% Placebo: <1% % of Patients with Weight Loss of 7% or More 10 mg: 3.8% 30 mg: 3.2% 60 mg: 4.9% Placebo: 2.8% | N/A | N/A | N/A | N/A |
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FAQ
Gepants are the newest class of migraine medications used to treat migraines as they happen. They should be taken when the migraine pain starts. Some are also used to prevent migraines. Gepants work by blocking the CGRP receptor and preventing the CGRP protein released during a migraine from triggering the migraine headache. Gepants are available in pills, nasal spray (pending), and disintegrating tablets. Some can be taken daily or every other day throughout the month to help decrease the number of migraines that a person has.
Some common types of gepants include: Ubrelvy, Nurtec, and Qulipta.
CGRP monoclonal antibodies are biological medications that are partly made from human proteins. They are used for migraine prevention. Monoclonal antibodies will bind and inactivate very specific inflammatory proteins that are already in your body which are normally involved in triggering a migraine attack. Some common types of monoclonal antibodies include: Aimovig, Ajovy, Emgality, and Vyepti.
CGRP is an abbreviation for calcitonin gene-related peptide. This is a very inflammatory protein that is released in the brain from the trigeminal nerves during a migraine. It’s a common source of inflammation that occurs during migraine attacks. Gepants block the binding of CGRP to the CGRP receptor quickly, which then stops the migraine. CGRP monoclonal antibodies work slower over time to keep CGRP from binding to the receptors in the brain, thus reducing the odds of CGRP triggering migraines.
CGRP monoclonal antibodies are used for the prevention of migraines. They are injected once monthly by self injection or once quarterly by IV infusion to avoid breaking down in the stomach. They tend to take longer to work, but do work faster than historical oral migraine preventive classes such as antiseizure, antidepressant, and antihypertensive medications. They have very few interactions with other drugs or harmful side effects, and are generally very well tolerated. They are discussed further here.
Gepants are faster acting and are taken orally. They are used to stop migraines once the pain starts (abortive or “as needed” medicines), but some are also FDA approved for preventing migraines. They are metabolized in the liver so there is the potential for some side effects and drug interactions, more so than with CGRP monoclonal antibodies.
Your doctor will look at a wide variety of different factors to determine whether or not gepants or CGRP monoclonal antibodies are a good fit. Keep in mind that there are many other options besides these newer medicine classes as well. If you are looking for pills, you will likely be prescribed Nurtec to take every other day or Qulipta once every day for migraine prevention, if your migraine frequency is high enough. Nurtec is unique in that it can be used as a migraine preventive or a migraine abortive (as needed) medication, or both. Some people opt for a one-time monthly CGRP monoclonal antibody self-injection, which will be either Aimovig, Emgality, or Ajovy. Another option on the market that will minimize the amount of time you have to go to the doctor is an IV option called Vyepti, which is administered quarterly in a 30 minute infusion.
Your options will likely vary based upon any medication that you are currently taking or any preexisting conditions that you may have, as well as the migraine pattern.
One of the newest options for migraines and headaches is Qulipta. This was approved by the FDA in September 2021. Qulipta’s primary goal is to serve as a preventative daily treatment for migraines in adults. A new nasal spray gepant called Zavegepant is anticipated to be coming out sometime in the near future and is expected to be used as a migraine abortive.
If you suffer from chronic migraines or high frequency episodic migraines you might be a good candidate for monoclonal antibody treatment. A chronic migraine is defined as having at least 15 headaches each month, with 8 of those days including headaches with migraine features, lasting for at least 3 months. Monoclonal antibodies are also a good option for those who take other types of medications and want to minimize drug interactions.
If you are experiencing migraines, you have a plethora of different options to try. If you have more concerns other than just taking medication via pill form or via injection. Here are some of the things to keep in mind:
- Depending on the patient, with either gepants or antibodies, a 75% to 100% reduction in monthly migraines could be possible in some patients.
- Each drug has small side effects that have been reported in studies. The most common side effect among some gepants and some monoclonal antibodies is constipation, but these occur in a small fraction of people. Some other rare side effects include nasopharyngitis, hypersensitivity, nausea, stomach discomfort, cramps, decreased appetite, and fatigue.
- Everyone responds to medications differently, so your doctor will help you make the best choice to help you treat your migraines.
