Posts Tagged "migraine medications"


Last updated on April 10th, 2021 at 05:00 am

WHEN TO SEE A HEADACHE SPECIALIST AND HOW TO PREPARE TO GET THE MOST FROM THE APPOINTMENT.

@Neuralgroover

 

Background

I see patients in our headache center from all over the United States and from many other countries. Many patients travel hundreds of miles by car or airplane for these visits, due to the shortage of available headache specialists (about 570 in the US). Many patients are lucky enough to be relatively close to a headache specialist. Whichever scenario you fall into, you want to get the most out of your appointment with a headache specialist in order to get on a better path to less headache or facial pain burden.

 

When to see a headache specialist

So first of all, when should you see a headache specialist? First off, any type of headache, head pain, or facial pain, is reason enough to see a headache specialist. Basically, headache specialists specialize in any type of pain or discomfort involving anywhere in the head or face. They also commonly see patients that may have other neurological symptoms which may not necessarily be associated with headaches, but their doctor wants to rule out a migraine “equivalent” disorder. Some patients can have neurologic symptoms without headache (visual, sensory, speech, vertigo, weakness, nausea/vomiting, abdominal pain), which may actually reflect a painless migraine disorder, such as migraine aura without headache. I have compiled a list below of a few of my thoughts of when your headache or facial pain treatment journey signals that it is time to see a headache specialist.

 

Reasons to see a headache specialist:

-You have a headache, head pain, or facial pain.

-Your doctor tells you, “your headache is all in your head”.

-Your doctor tells you, “there’s nothing else I can do for you”.

-Your doctor says, “I don’t treat much headache, but…”.

-You continue to have frequent headaches despite trying several preventive medications.

-You just don’t feel like you are making any progress despite a couple office visits with your doctor or their NP or PA (or you never even get to see the doctor).

-You don’t feel like your doctor is listening to you or taking your symptoms seriously.

-The doctor spends only a few minutes in the visit, so you feel rushed and unable to discuss all of your concerns.

-Your doctor is googling your symptoms in the office.

-Your doctor recommends that you take opiates/opioids for migraine treatment.

-Your doctor says it is ok to use NSAIDs, OTCs or triptans more than 10 days per month or butalbital/fioricet/fiorinal more than 5 days per month on average for migraine treatment.

-Your doctor says your headache is “because you are depressed”.

-Your doctor does not give you a more specific classification or name for your diagnosis.

 

What information should you gather before the visit?

Unfortunately, we all know how strapped for time most physicians are during office visits due to a variety of factors such as low insurance reimbursement and the need to increase patient volume to compensate for this and break even. So to get the most out of your office visit, making it efficient and helpful, it is important to compile certain information in preparation. Typing out this information and bringing it to your office visit is a great idea. It is also a great idea to keep this as a running file that you can continue adding to in your personal files. This helps to eliminate time wasted in the office that could easily be organized and thought through prior to the visit, allowing more time for the important parts of the office visit; optimizing the diagnosis and treatment plans. Some of this information you may not have available, and that is certainly ok. You may be able to retrieve some of it from records, memory, and your local pharmacist.

Never assume that your local doctor’s office has faxed all of your records ahead of the visit. If that happens, great. However, many times patients are told that the records will be sent, but when we see the patient, we have no records that were sent. So, it is always best to bring all of your records yourself. Furthermore, it is good to have copies of all of your medical records, testing, etc. for your personal files anyway.

 

The following list are items that I have found to be the most useful for patients to have gathered and thought of prior to the visit, allowing the most efficient and useful office visit:

A) Acute/abortive headache or pain treatments (used “as needed”). This information is also needed in order to pursue insurance approvals for various types of treatments such as the newer gepants (Ubrelvy, Nurtec) or ditans (Reyvow).

-All that have been tried (which triptans, NSAIDs, neuromodulation devices, etc.)

-Doses used

-Responses (effectiveness, side effects) of each treatment

 

B) Preventive headache or pain treatments (used daily to lessen headache frequency/severity). This information is also needed in order to pursue insurance approvals for various treatments such as Botox or the CGRP mAb antagonists (Aimovig, Ajovy, Emgality, Vyepti).

-All that have been tried

-Maximum doses used

-Duration that each treatment was used

-Responses (effectiveness, side effects) of each treatment

 

C) Testing

-All CD and radiology reports for all brain MRIs, CTs, and other relevant testing for your headache or pain. Most CDs do not include the radiology report, and you need to request that separately. It is a good idea to have copies of all of these things for your personal files regardless. Bring them all to the office visit for the doctor to review.

-All bloodwork done in the past 5 years. Labs particularly important for headache evaluations include TSH, CBC, CMP, Vitamin D, Vitamin B12, ESR, CRP, ANA, to name a few, but this may vary and include more or less, depending on the specific clinical scenario.

 

D) Think about the clinical features of your headache or facial pain as listed below. These will be important questions that your headache specialist will ask. So, it is good to answer these questions in your head prior to the visit, so you can provide more accurate and thought out answers. This helps to prevent being put on the spot by questions you never really thought about which may result in forgetting some important details. For a free headache and facial pain self-diagnosis tool which incorporates all of these important questions that a headache specialist asks, look here.

-Location of the headache or facial pain

-Frequency of the headache or facial pain attacks

-Duration of the headache or facial pain attacks

-Description and characterization of the headache or facial pain attacks

-Neurological symptoms associated with the headache or facial pain (visual disturbances, numbness, tingling, weakness, speech disturbances, vertigo, etc.)

-Other associated symptoms with the headache or facial pain (nausea, sensitivity to light or sound, one sided autonomic features (runny eye, red eye, runny or congested nose, droopy or puffiness around eye))

 

Conclusions:

If you are able to gather all or much of the above listed information prior to your headache specialist appointment, you’ll be well on your way to a much more efficient and beneficial office visit. As a result, you and your doctor will be able spend more time in the office discussing the most important things rather than spending it trying to look up records or digging through your memory for various details. As a result, your doctor will have more time to better formulate a list of the most likely diagnoses, and best treatment approaches for minimizing the disruption of your headache or facial pain on your life. Good luck!!

 

IF YOU HAVE HEADACHE, MIGRAINE, OR FACIAL PAIN AND ARE LOOKING FOR ANSWERS ON ANYTHING RELATED TO IT, A HEADACHE SPECIALIST IS HERE TO HELP, FOR FREE!

FIRST, LET’S DECIDE WHERE TO START:

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR THE LATEST INFORMATION, HOT TOPICS, AND TREATMENT TIPS, VISIT OUR FREE BLOG OF HOT TOPICS AND HEADACHE TIPS HERE. THIS IS WHERE I WRITE AND CONDENSE A BROAD VARIETY OF COMMON AND COMPLEX  MIGRAINE AND HEADACHE RELATED TOPICS INTO THE IMPORTANT FACTS AND HIGHLIGHTS YOU NEED TO KNOW, ALONG WITH PROVIDING FIRST HAND CLINICAL EXPERIENCE FROM THE PERSPECTIVE OF A HEADACHE SPECIALIST.

 

IF YOU DON’T HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR POSSIBLE TYPES OF HEADACHES OR FACIAL PAINS BASED ON YOUR SYMPTOMS, USE THE FREE HEADACHE AND FACIAL PAIN SYMPTOM CHECKER TOOL DEVELOPED BY A HEADACHE SPECIALIST NEUROLOGIST HERE!

 

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR FURTHER EDUCATION AND SELF-RESEARCH ON YOUR DIAGNOSIS, VISIT OUR FREE EDUCATION CENTER HERE.

 

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING TO ASK QUESTIONS TO A HEADACHE SPECIALIST OR OTHER HEADACHE, MIGRAINE, AND FACIAL PAIN WEBSITE MEMBERS, VISIT OUR FREE DISCUSSION FORUMS HERE.

 

Read More

Last updated on April 9th, 2021 at 12:50 am

AIMOVIG vs AJOVY vs EMGALITY vs VYEPTI. BATTLE OF THE CGRP MONOCLONAL ANTIBODY ANTAGONISTS; WHAT ARE THE DIFFERENCES AND WHICH IS BEST FOR YOU?
@Neuralgroover

Background

Aimovig vs. Ajovy, Aimovig vs. Emgality, Aimovig vs Vyepti, Ajovy vs. Emgality, Emgality vs. Vyepti, Ajovy vs. Vyepti. So many questions. so many answers. Let’s discuss them all. So it finally happened! The 1st migraine specific preventive medications FINALLY became available with the CGRP (calcitonin gene related peptide) monoclonal antibody (CGRP mAb) antagonists which first came to market in 2018. Prior to 2018, all of the migraine preventive medication options had been “adopted” from other specialties. For example, the 3 main categories of preventive medicines prior to 2018 were select evidence-based options within the anticonvulsant (antiseizure), antidepressant/antianxiety, and antihypertensive (blood pressure) medicine categories. These conventional migraine preventive treatments are certainly still used, can be very effective, and are discussed in much greater detail here. Migraine preventive therapies also include nutraceuticals and natural treatments, and neuromodulatory devices. This blog article will discuss and compare the 4 new options of CGRP mAb medications; Aimovig (Erenumab), Ajovy (Fremanezumab), Emgality (Galcanezumab), and Vyepti (Eptinezumab).

CGRP plays a strong role in neurogenic inflammation in the nervous system and is involved in the transmission of pain. It is also a potent vasodilator (dilates blood vessels), and increases overexcitability of neurons, both factors of which increase the intensity of migraine pain. CGRP has been studied since the early 1980s when it was discovered. It was found throughout the trigeminovascular system and trigeminal cranial nerves which transmit pain, so a role in migraine was suspected. The trigeminal nerves and their associated electrical circuitry throughout the brain, brainstem, and arteries in the brain is called the trigeminovascular system. This system is the basis and “on switch” for migraine. In the early 1990s it was shown that CGRP was released by the trigeminal nerves and levels increased during an acute migraine attack. In 2004, a CGRP antagonist (blocks the binding of CGRP to its receptor) was shown to abort an acute migraine attack, and decrease CGRP levels. Subsequent studies including 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, and a 4th CGRP mAb FDA approved in 2020.

 

How are the CGRP mAbs made and what is the science behind them?

The CGRP mAbs are considered biologic drugs because they are made by the cells of living organisms. This is in contrast to conventional medications made by chemical synthesis. The 4 CGRP mAbs are all classified as “humanized” monoclonal antibodies. Humanized CGRP mAbs are made in a laboratory by combining part of a human antibody with a small part of a non-human (such as hamster or yeast) monoclonal antibody by a process called recombinant DNA technology. The non-human part of the antibody binds to the target antigen (in this case, either the CGRP ligand (protein) or CGRP receptor), and the human part makes it less likely to be seen as a “foreign antigen” destroyed by our immune system. To explain further, these humanized CGRP mAbs are produced and cloned repeatedly in non-human immune system living cells (hamster ovarian cells or yeast cells), ensuring that they are all of identical genetic material (monoclonal), and their protein structure is modified to increase their similarity to antibody structures produced naturally in humans.

As a review, antibodies are proteins made by living organism cells which bind unique parts of other proteins that are recognized as a “foreign” to that biologic system. For example, when your body is exposed to a virus or bacteria by infection or immunization, your body makes specific antibodies against that microbe to destroy it. If your body encounters that microbe in the future, it remembers it (immune response), and your antibodies attach to it to neutralize and destroy it.

 

How do the CGRP mAbs work for migraine?

The CGRP mAbs target either the CGRP receptor and block it (antagonist) to prevent the CGRP ligand (protein) from binding, or they target the CGRP ligand itself and prevent it from binding (sticking) to the CGRP receptor. Clinically, some patients tend to respond better to the CGRP receptor blockade, whereas others tend to do better with binding the CGRP ligand itself. There is not really any data on this in terms of who may respond to which type of CGRP mAb target, but I’m sure it will be studied further eventually. In general, the CGRP mAbs tend to all be quite effective. However, the point is if one type of CGRP mAb doesn’t work, it doesn’t mean the others won’t work either. I have seen many patients who did not respond to one type of CGRP mAb, but responded dramatically well to another. So, if you do not respond to one type of CGRP mAb target (such as the CGRP receptor), it may be worth trying another type of CGRP mAb target (such as the CGRP ligand). The bottom-line is don’t lose hope if one type doesn’t work well for you!

The CGRP mAbs are administered by injection or infusion because oral absorption is poor and degradation in the gastrointestinal system would inactivate the antibodies before they would even be able to enter the circulatory system. They are systemically absorbed by transport through the lymphatic system and into the blood. Metabolism occurs in the reticuloendothelial system, not the liver or kidneys.

 

How effective are the CGRP mAbs?

All 4 of the CGRP mAbs have shown excellent tolerability, safety, and superior effectiveness in migraine prevention when compared to placebo. Compared to oral preventive therapies which have been the mainstay for decades (discussed here), the CGRP mAbs work much faster and do not require a slow dose titration, as is done with most oral preventives. They are sometimes seen to be effective in just a few days, often within a month, and the data suggests that the longer a patient is on a CGRP mAb, the more effective it is. I typically recommend a minimum of at least 3 months, and if receiving some benefit at that point, at least 6 months is suggested.

The majority of CGRP mAb studies had at least 50% (half) of patients who were 50% responders (migraine days cut in half), which is great! In general, the CGRP mAbs provide an overall average net reduction of around 2 migraine days per month for episodic migraine and 4-6 days for chronic migraine. With that said, this number can be much higher depending on the patient and migraine characteristics being studied, such as baseline migraine frequency.

There are a group of patients that we see called “super responders” because they improve dramatically to having greater than 75% decrease in migraine days, and sometimes even no migraines. In the CGRP mAb studies, about 1/3rd of patients were “super responders”, with many them obtaining 100% reduction in migraine days. Although this is wonderful to see when it happens, it should not be the expectation or goal (nor should this be the goal with any preventive migraine treatment).

 

What are the CGRP mAb side effects and are they safe in pregnancy and breastfeeding?

Side effects are minimal, and very similar to placebo in most of the studies, which is great compared to the frequent side effects seen with most of the oral preventive pills we often use. The most common side effects are listed in the table below, but mild injection site reactions tend to be the most common reported side effect among the 3 subcutaneous self-injection CGRP mAbs. Cumulative data show no immunological (they do not suppress or alter the immune system because they do not have a target within the immune system), cardiovascular, or neurological safety concerns of significance. CGRP is suspected to play a possible role in regulating uteroplacental blood flow, myometrial and uterine relaxation, and in maintaining normal gestational blood pressure. Since the mAbs have a long half-life and can last in the system for 5 months, it is recommended to stop it about 6 months prior to pregnancy planning. The CGRP mAbs are also not recommended to use during breast-feeding since we do not have enough safety data at this time.

 

Can I still use my CGRP monoclonal antibody treatment (Aimovig, Ajovy, Emgality, Vyepti) with the Covid-19 vaccine? 

The short answer is that we need to gather more data on this, so check back periodically for updates. However, this hasn’t been a reported issue thus far. There is no current evidence for an interaction between the Covid-19 vaccine and CGRP mAbs, the same as any other vaccine. This has also been stated by the American Migraine Foundation. Patients receiving CGRP monoclonal antibodies (Aimovig, Ajovy, Emgality, Vyepti) were not excluded from the Covid-19 vaccine trials. There is no evidence at this time that these treatments can not be used along with receiving Covid-19 vaccination, nor do they need to be delayed or timed any differently in relation to receiving Covid-19 vaccination. Most physicians feel that there should theoretically be no interaction or contraindication to receiving either of these treatments in relation to Covid-19 vaccination because they are entirely different proteins with different mechanisms of action. The Covid-19 vaccine stimulates the immune system to form antibodies against the virus, should you encounter it. The CGRP mAbs do not have any significant influence on the immune system (they do not cause immunosuppression, etc.). Rarely, the immune system of some patients can form neutralizing antibodies against the CGRP mAbs, and this can weaken the effectiveness of these treatments in their ability to decrease migraine frequency and severity. However, this rarity really has nothing to do with the mechanism and how the Covid-19 vaccine works. So, it is not felt that the Covid-19 vaccine will lessen the effectiveness of these treatments, nor will these treatments lessen the effectiveness of the Covid-19 vaccine.

Notably, there have been just a few isolated reports of dermal fillers used in dermatology causing some facial swelling in association with Covid-19 vaccination, but not with Botox or the CGRP mAbs. These reports were with the Moderna Covid vaccine and resolved with steroids and/or antihistamines. The topic of Covid-19 headache, Covid-19 vaccination, and the use of Botox is discussed further here.

 

Can I use a CGRP mAb with Botox injections or with the gepants (Nurtec, Ubrelvy)?

Insurance companies often present various hurdles to using preferred treatment options (the bane of my existence). One common issue for patients with chronic migraine who are receiving Botox injections is that most insurance companies will now make the patient choose between Botox or the CGRP mAb. There is of course no good scientific basis for this, other than the company doesn’t want to pay for both. In fact, there is evidence that using Botox with the CGRP mAbs works better together than with either individually. An abstract presented at the American Headache Society Annual Scientific meeting in June 2020 showed that in patients with chronic migraine and a baseline frequency of 25.7 days per month, the frequency dropped to 14.8 days with Botox, and 9.1 days with Botox plus a CGRP mAb.

A similar insurance battle often ensues when trying to use the large molecule preventive CGRP mAbs with the small molecule abortive gepant medications (Nurtec, Ubrelvy), which also work by a CGRP mechanism. Insurance companies will often not allow these to be used together, but again, no good scientific basis. Actually, there is some limited evidence showing that these medications can work synergistically together, which would make sense when taking their mechanisms of action into account. Specifically, there was a publication of data from only a 2-patient cohort showing that the use of these acute and preventive CGRP migraine therapies together can be successful and safe. These two patients had been using rimegepant (Nurtec) in a long-term safety study and had added erenumab (Aimovig). The combination of both successfully aborted 100% of their acute migraine attacks. Certainly we need need larger studies to confirm the suspicion that they likely work together synergistically.

The bottom line is that the CGRP mAbs as a class are all very effective for the majority of patients. Ultimately, the one prescribed will often depend on insurance formulary preferences, but there are no “bad options” among them!

 

Clinical comparisons of the CGRP mAbs

There are currently 4 CGRP mAbs available, and each is detailed and compared below in order of FDA approval and becoming available for use. There are some characteristics for each one which can be used to fine tune selection based on specific patient clinical perspectives.

 

Aimovig (Erenumab)

Aimovig was the first of the CGRP mAbs to come on the scene. It is made by Amgen and was FDA approved for migraine prevention 5/17/18. The antibody is produced by recombinant DNA technology in Chinese hamster ovary cells. It is the only one thus far which targets the CGRP receptor rather that the CGRP ligand (protein) itself. Therefore, it binds to the receptor, blocking the ability of the CGRP ligand to bind to the receptor and activate the migraine. It is dosed by either a 70 mg or 140 mg once monthly subcutaneous autoinjector. Since Aimovig came out first, we have longer term data available for it. At close to 5 years on the 140 mg dose, 77% of patients had a 50% reduction in monthly migraine days, 56% of patients had a 75% reduction in monthly migraine days, and 33% of patients had a 100% reduction in monthly migraine days. The dose can be administered to the abdomen, arm, buttocks, or thigh areas.

In post-marketing observations, there have been some reports of hypersensitivity reactions (rash, allergic reactions, itching) in which most were not serious and occurred within hours of administration, and up to 1 week after. Constipation was noted in the studies to occur in a very small percentage (1% for 70 mg, 3% for 140 mg). In post-marketing observations, there have been further reports of constipation with serious complications as well. Constipation occurs after the first dose in the majority of patients who will have this side effect (keep in mind the vast majority do not). Regardless, if you already have problems with constipation, I typically suggest trying one of the other CGRP mAbs (although it doesn’t mean it still can’t be tried). Post-marketing observations have also shown some worsening of pre-existing hypertension or development of hypertension. This observation was most frequently reported within 7 days of administration. Most of these patients already had pre-existing hypertension, or risk factors for developing it.

There is an Aimovig coupon available on the company’s website in which most commercial insurance plans can get the medication for $5 per month, with the first 3 doses free.

 

Ajovy (Fremanezumab)

Ajovy was the 2nd of the CGRP mAbs to come along. It is made by Teva and was FDA approved for migraine prevention 9/14/18. It is produced by recombinant DNA technology in Chinese hamster ovary cells. It targets the CGRP ligand, rather than the CGRP receptor. It binds to the CGRP ligand, interfering with its ability to bind to the CGRP receptor and activate the migraine. It is dosed by either a 225 mg once monthly or 675 mg once quarterly autoinjector or syringe. The dose can be administered to the abdomen, arm, buttocks, or thigh areas. There have been some reports of hypersensitivity reactions (rash, allergic reactions, itching) as well, typically mild to moderate and occurred hours to 1 month after administration. Ajovy has the least potential for constipation, so if that is an ongoing significant issue for a patient, then I typically suggest trying Ajovy first. Ajovy also has the longest half-life, so if the patient tends to wear off early towards the end of the month, it may help to extend relief closer to the next monthly injection.

Of note, in the Ajovy chronic migraine studies, all patients receiving medication were given a loading dose of 675 mg for dose 1 followed by the standard 225 mg each subsequent month. However, this is not how it is normally dosed clinically for patients doing monthly treatments of 225 mg (no loading dose). Therefore, this initial loading dose could have potentially influenced some of the subsequent data.

There is an Ajovy coupon available on the company’s website in which most commercial insurance plans can get the medication for $5 per month.

 

Emgality (Galcanezumab)

Emgality was the 3rd of the CGRP mAbs to come along. It is made by Eli Lilly and was FDA approved for migraine prevention 9/26/18. Notably, it is the only one which also has FDA approval for prevention of episodic cluster headache, which was received on 6/4/19. It is produced by recombinant DNA technology in Chinese hamster ovary cells. It targets the CGRP ligand, rather than the CGRP receptor. Thus, it binds to the CGRP ligand, interfering with its ability to bind to the CGRP receptor and activate the migraine. It is dosed by a 240 mg subcutaneous autoinjector for the 1st month only, followed by a 120 mg once monthly injection thereafter. The higher initial loading dose allows for obtaining a rapid steady state concentration level in the blood compared to Aimovig and Ajovy. The dose can be administered to the abdomen, arm, buttocks, or thigh areas. There have been some reports of hypersensitivity reactions (rash, allergic reactions, itching) as well.

There is an Emgality coupon available on the company’s website in which most commercial insurance plans can get the medication for $0 per month for up to 12 months.

 

Vyepti (Eptinezumab)

Vyepti was the 4th and most recent of the CGRP mAbs to become available. It is made by Lundbeck and was FDA approved for migraine prevention 2/21/20. The antibody is produced in Pichia pastoris yeast cells by recombinant DNA technology. It targets the CGRP ligand, rather than the CGRP receptor. It binds very strongly to the CGRP ligand, interfering with its ability to bind to the CGRP receptor and activate the migraine. It comes in 100 mg and 300 mg doses and is dosed once quarterly (every 3 months) by a quick 30-minute infusion. The 100 mg dose is the recommended starting dose which can be titrated as needed to the higher dose later.

This is the only intravenous (IV) option available. Since it is administered IV, it is 100% bioavailable compared to the bioavailability of the other subcutaneous injections of 50-82%. It also reaches Cmax (maximum concentration) in about 30 minutes compared to 5-7 days of the other subcutaneous injections. Therefore, not surprisingly Vyepti showed treatment benefit in the first 7 days, often as early as 1 day post treatment, and showed continued effect through week 4, which is great since many patients on the once monthly self-injection CGRP mAbs often report a wearing off effect as they are approaching their next due injection.

This is certainly a good first line consideration, but also a good option for patients who do not like the thought of giving themselves a once monthly shot, have injection site reactions, or have failed the other CGRP mAbs options. Studies have shown some impressive highlights compared to other mAbs. In both the chronic and episodic migraine studies, almost 31% of patients had 75% or more reduction in migraine days in the 1st month alone. In the chronic migraine studies, about 27% of patients had a 75% or more reduction in migraine days over the first 3 months with 100 mg. After the 2nd dose (months 4-6), this increased to over 39% of patients! In the episodic migraine studies, over 22% of patients had a 75% or more reduction in migraine days over the first 3 months with 100 mg. After the 2nd dose (months 4-6), this increased to over 33.5% of patients.

There is a Vyepti coupon available on the company’s website in which most commercial insurance plans can get the medication for $5 per infusion every 3 months.

 

Data comparisons of the CGRP mAbs

The comprehensive table which follows compares all available data between the 4 CGRP mAbs, as I lityhave compiled from a combination of published studies, scientific posters, and supplemental data provided from medical science liaisons from each company. I have highlighted some of the data throughout the table when it is a unique aspect or superior response in that category. All 4 CGRP mAbs have variable highlights that makes them stand out from the others in various categories, but overall they are all very effective options as a medication class. It is important to realize that the data compiled in the table should not be considered as a direct head to head comparison between the medications, and not all data points were looked at for each drug. For each CGRP mAb, there were variations and differences in many trial aspects such as the study designs, how responder rates were calculated, statistical analysis used, trial endpoints, some responses were based on open label portions of trials (in which patients typically report a higher response rate when they know they are receiving the drug and not placebo), varying definitions such as “headache of at least moderate severity”, what defined a “headache” or “migraine day”, preventive medications being used simultaneously, and baseline migraine frequencies included in the studies. The extent of reduction in migraine days can be influenced by the patient’s baseline migraine frequency in both the episodic and chronic migraine studies (high frequency vs lower frequency). For example, some studies included patients with a much higher baseline migraine frequency, and thus the extent of their migraine day reduction may not be as great as a group studied with a lower baseline frequency to start with.

 

  Aimovig (Erenumab) Ajovy (Fremanezumab) Emgality (Galcanezumab) Vyepti (Eptinezumab)
Dosing 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 1st month followed by 120 mg monthly 100 mg or 300 mg quarterly by 30-minute intravenous (IV) infusion
Target CGRP receptor CGRP ligand CGRP ligand CGRP ligand
Half-life 28 days 31 days 27 days 27 days
Median Peak Serum Concentration 6 days 5-7 days 5 days 30 minutes (after infusion)
Steady State 3 months 168 days (6 months) After the 240 mg loading dose After 1st dose
Bioavailability 82% 54-57% N/A 100%
Episodic migraine: Reduction in mean monthly migraine days in month 1 70 mg: -2.32 days

140 mg: -2.72 days Placebo: -0.9 days

675 mg quarterly: -3.3 days

225 mg monthly: -3.5 days

Placebo: -1.7 days

N/A N/A
Episodic migraine: Reduction in mean monthly migraine days in months 1-3 N/A 675 mg quarterly: -3.7 days

225 mg monthly: -3.4 days

Placebo: -2.2 days

 

*Months 1-3 in long term extension study (open label):

675 mg quarterly: -4.7 days

225 mg monthly: -4.8 days

120 mg monthly: -4.1 days

Placebo: -2.1 days

100 mg: -3.9 days

300 mg: -4.3 days

Placebo: -3.2 days

Episodic migraine: Reduction in mean monthly migraine days in months 4-6 70 mg: -3.2 +/- 0.2 days

140 mg: -3.7 +/- 0.2 days

Placebo: -1.8 +/- 0.2 days

N/A 120 mg monthly: -5 days

Placebo: -3 days

100 mg: -4.5 days

300 mg: -4.8 days

Placebo: -3.8 days

Episodic migraine: Reduction in mean monthly migraine days in months 1-6 N/A 675 mg quarterly: -5 days

225 mg monthly: -4.9 days

 

*months 1-3 placebo, months 4-6 open label

120 mg: -4.3-4.7 days

Placebo: -2.3-2.8 days

N/A
Episodic migraine: Reduction in mean monthly migraine days in months 1-12 70 mg: -4.22 +/- 0.22 days

140 mg: -4.64 +/- 0.19 days

Placebo: -1.8 days

675 mg quarterly: -5.2 days

225 mg monthly: -5.1 days

 

*months 1-3 placebo, months 4-12 open label

120 mg: -5.13 days

 

*12 month safety study with no placebo

100 mg: -4.6 days

300 mg: -5.2 days

Placebo: -4 days

 

*Reported as months 7-12

Episodic migraine:

50% or more reduction in migraine days in month 1

70 mg: 32.7%

140 mg: 35.5% Placebo: 15.5%

675 mg quarterly: 44%

225 mg monthly: 47% Placebo: 25%

 

120 mg: 50.8%

Placebo: 23.7%

100 mg: 59.3%

300 mg: 56.3%

Placebo: 40.5%

Episodic migraine:

50% or more reduction in migraine days in months 1-3

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%

Episodic migraine:

50% or more reduction in migraine days in months 4-6

70 mg: 43%

140 mg: 50%

Placebo: 26.6%

N/A 120 mg: 67%

Placebo: 43%

 

*At month 4 alone:

120 mg: 65.2%

Placebo: 41.9%

 

*At month 5 alone:

120 mg: 68.6%

Placebo: 43.7%

 

*At month 6 alone:

120 mg: 66%

Placebo: 44.8%

100 mg: 62%

300 mg: 65.3%

Placebo: 51.4%

Episodic migraine:

50% or more reduction in migraine days in months 1-6

N/A 675 mg quarterly: 65%

225 mg monthly: 60%

 

*months 1-3 placebo, months 4-6 open label, data is at month 6

120 mg: 59.3-62.3% days

Placebo: 36-38.6%

N/A
Episodic migraine:

50% or more reduction in migraine days in months 1-12

70 mg: 61%

140 mg: 64.9% Placebo: N/A

675 mg quarterly: 66%

225 mg monthly: 68%

 

*months 1-3 placebo, months 4-12 open label, data is at month 12

N/A 100 mg: 64.7%

300 mg: 69.4%

Placebo: 55.9%

 

*Reported as months 7-12

Episodic migraine:

75% or more reduction in migraine days in month 1

N/A 675 mg quarterly: 20%

225 mg monthly: 22% Placebo: 10%

 

120 mg: 25.7%

Placebo: 6.5%

 

100 mg: 30.8%

300 mg: 31.5%

Placebo: 20.3%

Episodic migraine:

75% or more reduction in migraine days in months 1-3

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%

Episodic migraine:

75% or more reduction in migraine days in months 4-6

70 mg: 20.8%

140 mg: 22%

Placebo: 7.9%

N/A 120 mg: 42%

Placebo: 24%

 

*At month 4 alone:

120 mg: 41.6%

Placebo: 15.2%

 

*At month 5 alone:

120 mg: 41.4%

Placebo: 15.5%

 

*At month 6 alone:

120 mg: 43.9%

Placebo: 15.8%

100 mg: 33.5%

300 mg: 40.1%

Placebo: 24.8%

Episodic migraine:

75% or more reduction in migraine days in months 1-6

N/A 675 mg quarterly: 39%

225 mg monthly: 37%

 

*months 1-3 placebo, months 4-6 open label, data is at month 6

120 mg: 33.5-38.8%

Placebo: 17.8%-19.3%

 

N/A
Episodic migraine:

75% or more reduction in migraine days in months 1-12

70 mg: 38.5%

140 mg: 40.8% Placebo: N/A

675 mg quarterly: 42%

225 mg monthly: 45%

 

*months 1-3 placebo, months 4-12 open label, data is at month 12

N/A 100 mg: 41.2%

300 mg: 47.7%

Placebo: 32%

 

*Reported as months 7-12

Episodic migraine:

100% reduction in migraine days in month 1

N/A 675 mg quarterly: 5%

225 mg monthly: 8% Placebo: 2%

 

120 mg: 8.8%

Placebo: 2.2%

 

100 mg: 8.6%

300 mg: 14.9%

Placebo: 5.9%

Episodic migraine:

100% reduction in migraine days in months 1-3

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%

Episodic migraine:

100% reduction in migraine days in months 4-6

70 mg: 3.2%

140 mg: 5%

Placebo: 2.8%

N/A 120 mg: 17%

Placebo: 9%

 

*At month 4 alone:

120 mg: 16.3%

Placebo: 8.5%

 

*At month 5 alone:

120 mg: 17.6%

Placebo: 8.7%

 

*At month 6 alone:

120 mg: 16.5%

Placebo: 9.5%

100 mg: 19.8%

300 mg: 24.5%

Placebo: 14.3%

Episodic migraine:

100% reduction in migraine days in months 1-6

N/A 675 mg quarterly: 18%

225 mg monthly: 20%

 

*months 1-3 placebo, months 4-6 open label, data is at month 6

120 mg: 11.5-15.6%

Placebo: 5.7-6.2%

 

N/A
Episodic migraine:

100% reduction in migraine days in months 1-12

70 mg: 19.8%

140 mg: 21.2% Placebo: N/A

675 mg quarterly: 17%

225 mg monthly: 21%

 

*months 1-3 placebo, months 4-12 open label, data is at month 12

N/A 100 mg: 26.8%

300 mg: 30.6%

Placebo: 20.5%

 

*Reported as months 7-12

Chronic migraine: Reduction in mean monthly migraine days in month 1 70 mg: -5 +/- 0.42 days

140 mg: -5.1 +/- 0.42 days

Placebo: -2.7 +/- 0.34 days

675 mg quarterly: -4.8 days

225 mg monthly: -4.7 days

Placebo: -2.7 days

120 mg: -4.06

Placebo: -1.78

 

N/A
Chronic migraine: Reduction in mean monthly migraine days in months 1-3 70 mg: -6.6 +/- 0.4 days

140 mg: -6.6 +/- 0.4 days

Placebo: -4.2 +/- 0.4 days

675 mg quarterly: -5 days

225 mg monthly: -4.9 days

Placebo: -3.2 days

 

*Months 1-3 in long term extension study (open label):

675 mg quarterly: -6 days

225 mg monthly: -6.7 days

120 mg: -4.8 days

Placebo -2.7 days

 

*At month 2 alone:

120 mg: -5.01

Placebo: -3.04

 

*At month 3 alone:

120 mg: -5.41

Placebo: -3.39

100 mg: -7.7 days

300 mg: -8.2 days

Placebo: -5.6 days

Chronic migraine: Reduction in mean monthly migraine days in months 4-6 N/A N/A N/A 100 mg: -8.2 days

300 mg: -8.8 days

Placebo: -6.2 days

Chronic migraine: Reduction in mean monthly migraine days in months 1-6 N/A 675 mg quarterly: -6.5 days

225 mg monthly: -7.6 days

 

*months 1-3 placebo, months 4-6 open label

N/A N/A
Chronic migraine: Reduction in mean monthly migraine days in months 1-12 70 mg: -8.5 days

140 mg: -10.5 days

Combined 70 mg and 140 mg: -9.3 days

Placebo: N/A

675 mg quarterly: -7.2 days

225 mg monthly: -8 days

 

*months 1-3 placebo, months 4-12 open label

120 mg: -7.21

 

*12 month safety study with no placebo

N/A
Chronic migraine:

50% or more reduction in migraine days in month 1

70 mg: 23.9%

140 mg: 28.3% Placebo: 11.4%

675 mg quarterly: 33%

225 mg monthly: 36%

Placebo: 19%

120 mg: 26.4%

Placebo 11%

 

100 mg: 54.5%

300 mg: 60.6%

Placebo: 36.1%

Chronic migraine:

50% or more reduction in migraine days in months 1-3

70 mg: 40%

140 mg: 41%

Placebo: 23%

675 mg quarterly: 30.7%

225 mg monthly: 33.3%

Placebo: 19.9%

 

*At month 3 alone (not averaged over months 1-3):

675 mg quarterly: 37%

225 mg monthly: 39% Placebo: 25%

 

*At month 3 in long term extension study (open label):

675 mg quarterly: 42%

225 mg monthly: 48%

120 mg: 27.6%

Placebo 15.4%

 

*At month 2 alone:

120 mg: 30.7%

Placebo: 17.7%

 

*At month 3 alone:

120 mg: 35.2%

Placebo: 24.7%

 

100 mg: 57.6%

300 mg: 61.4%

Placebo: 39.3%

Chronic migraine:

50% or more reduction in migraine days in months 4-6

N/A N/A N/A

 

 

100 mg: 61%

300 mg: 64%

Placebo: 44%

Chronic migraine:

50% or more reduction in migraine days in months 1-6

N/A 675 mg quarterly: 44%

225 mg monthly: 54%

 

*months 1-3 placebo, months 4-6 open label, data is at month 6

N/A, however:

 

*At month 6 in open label extension trial:

120 mg: 44.5%

N/A
Chronic migraine:

50% or more reduction in migraine days in months 1-12

70 mg: 53.3%

140 mg: 67.3%

Combined 70 mg and 140 mg: 59%

Placebo: N/A

675 mg quarterly: 53%

225 mg monthly: 57%

 

*months 1-3 placebo, months 4-12 open label, data is at month 12

N/A, however:

 

*At month 9 in open label extension trial:

120 mg: 53.9%

 

*At month 12 in open label extension trial:

120 mg: 56.9%

N/A
Chronic migraine:

75% or more reduction in migraine days in month 1

N/A Month 1 in long term extension study (open label):

675 mg quarterly: 21%

225 mg monthly: 21%

N/A 100 mg: 30.9%

300 mg: 36.9%

Placebo: 15.6%

Chronic migraine:

75% or more reduction in migraine days in months 1-3

70 mg: 17%

140 mg: 20.9% Placebo: 7.8%

675 mg quarterly: 9.6%

225 mg monthly: 12.3%

Placebo: 5.4%

 

*At month 3 in long term extension study (open label):

675 mg quarterly: 20%

225 mg monthly: 24%

120 mg: 7%

Placebo 4.5%

 

100 mg: 26.7%

300 mg: 33.1%

Placebo: 15%

Chronic migraine:

75% or more reduction in migraine days in months 4-6

N/A N/A N/A 100 mg: 39.3%

300 mg: 43.1%

Placebo: 23.8%

Chronic migraine:

75% or more reduction in migraine days in months 1-6

N/A 675 mg quarterly: 28%

225 mg monthly: 24%

 

*months 1-3 placebo, months 4-6 open label, data is at month 6

N/A, however:

 

*At month 6 in open label extension trial:

120 mg: 21.7%

N/A
Chronic migraine:

75% or more reduction in migraine days in months 1-12

70 mg: 27.1%

140 mg: 41.8%

Combined 70 mg and 140 mg: 33.2%

Placebo: N/A

675 mg quarterly: 28%

225 mg monthly: 31%

 

*months 1-3 placebo, months 4-12 open label, data is at month 12

N/A, however:

 

*At month 9 in open label extension trial:

120 mg: 27.9%

 

*At month 12 in open label extension trial:

120 mg: 31.1%

N/A
Chronic migraine:

100% reduction in migraine days in month 1

N/A Month 1 in long term extension study (open label):

675 mg quarterly: 6%

225 mg monthly: 5%

N/A 100 mg: 7.9%

300 mg: 13.4%

Placebo: 2.7%

Chronic migraine:

100% reduction in migraine days in months 1-3

70 mg: 4.3%

140 mg: 2.7%

Placebo: 0.4%

675 mg quarterly: 5.3%

225 mg monthly: 4.5%

Placebo: 4%

 

*At month 3 in long term extension study (open label):

675 mg quarterly: 5%

225 mg monthly: 6%

120 mg: 0.7%

Placebo 0.5%

 

100 mg: 10.8%

300 mg: 15.1%

Placebo: 5.1%

Chronic migraine:

100% reduction in migraine days in months 4-6

N/A N/A N/A 100 mg: 17.8%

300 mg: 20.8%

Placebo: 9.3%

Chronic migraine:

100% reduction in migraine days in months 1-6

N/A 675 mg quarterly: 8%

225 mg monthly: 8%

 

*months 1-3 placebo, months 4-6 open label, data is at month 6

N/A N/A
Chronic migraine:

100% reduction in migraine days in months 1-12

70 mg: 6.1%

140 mg: 12.7%

Combined 70 mg and 140 mg: 8.9%

Placebo: N/A

675 mg quarterly: 9%

225 mg monthly: 10%

 

*months 1-3 placebo, months 4-12 open label, data is at month 12

N/A N/A
Side effects:

Nasopharyngitis

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

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

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:

Cramps, muscle spasms

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

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

 

IF YOU HAVE HEADACHE, MIGRAINE, OR FACIAL PAIN AND ARE LOOKING FOR ANSWERS ON ANYTHING RELATED TO IT, A HEADACHE SPECIALIST IS HERE TO HELP, FOR FREE!

FIRST, LET’S DECIDE WHERE TO START:

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR THE LATEST INFORMATION, HOT TOPICS, AND TREATMENT TIPS, VISIT OUR FREE BLOG OF HOT TOPICS AND HEADACHE TIPS HERE. THIS IS WHERE I WRITE AND CONDENSE A BROAD VARIETY OF COMMON AND COMPLEX  MIGRAINE AND HEADACHE RELATED TOPICS INTO THE IMPORTANT FACTS AND HIGHLIGHTS YOU NEED TO KNOW, ALONG WITH PROVIDING FIRST HAND CLINICAL EXPERIENCE FROM THE PERSPECTIVE OF A HEADACHE SPECIALIST.

 

IF YOU DON’T HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR POSSIBLE TYPES OF HEADACHES OR FACIAL PAINS BASED ON YOUR SYMPTOMS, USE THE FREE HEADACHE AND FACIAL PAIN SYMPTOM CHECKER TOOL DEVELOPED BY A HEADACHE SPECIALIST NEUROLOGIST HERE!

 

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR FURTHER EDUCATION AND SELF-RESEARCH ON YOUR DIAGNOSIS, VISIT OUR FREE EDUCATION CENTER HERE.

 

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING TO ASK QUESTIONS TO A HEADACHE SPECIALIST OR OTHER HEADACHE, MIGRAINE, AND FACIAL PAIN WEBSITE MEMBERS, VISIT OUR FREE DISCUSSION FORUMS HERE.

Read More

Last updated on April 6th, 2021 at 07:23 am

NATURAL MIGRAINE TREATMENT FOR PREVENTION WITH VITAMINS AND SUPPLEMENTS. WHICH ARE BEST?

@Neuralgroover

Worldwide, migraine affects more than 10-12% of the population, with approximately 1 billion migraineurs estimated worldwide.1 It is estimated that there are 39 million migraineurs in the US, accounting for 12% of the US population. Migraine affects 18% of women and 6% of men2,3. Nearly 25% of U.S. households include someone with migraine.

 

In 2016, migraine was determined to be the 2nd leading cause of all global disability, and the 2nd leading cause of all neurological disease burden4. Migraine accounts for 50% of all neurologic disability. Furthermore, chronic pain in general is the largest contributor to years lived with disability globally5, and is associated with tremendous negative impacts on social, economic, and personal function.

 

In addition to the attack-related disability, many sufferers live in fear because their migraines disrupt their ability to work, go to school, partake in social activities, or care for their families, and this significantly limits their overall quality of life. More than 90% of migraine sufferers are unable to work or function normally during their attacks. American employers lose more than $20 billion each year as a result of 113 million lost workdays due to migraine.6

 

Migraine treatment is divided into acute (as needed) and preventive (prophylactic) therapy. Most existing preventive therapies are adopted from anti-epileptic, antidepressant, and antihypertensive medications. However, many of these medications are not well tolerated, resulting in poor compliance. Adherence to oral migraine preventative medication is around 26% at 6 months and declines to 17% at one year.7 This is often due to intolerable side effects. Many patients, due to lack of efficacy of preventative treatments, often resort to overuse of acute medications. This results in additional decline in quality of life and economic burden.8 Onabotulinumtoxin-A (Botox) is currently the only FDA-approved treatment available for chronic migraine. However, most patients must fail at least three preventative treatments prior to receiving Onabotulinumtoxin-A. As such, Onabotulinumtoxin-A is typically a fourth line option for the prevention of chronic migraine. In addition, it is not approved for patients who have episodic migraine. There are 4 calcitonin gene related peptide (CGRP) monoclonal antibody antagonists that have been approved for the prevention of migraine.  There also exists a limited number of neuromodulatory devices. Lack of insurance coverage of these devices precludes their routine use in clinical practice.  This confers a large unmet need for additional preventive migraine treatments and additional therapeutic targets.

 

Migraine prevention is a key aspect to maintaining a good quality of life.  Abnormal neuronal membrane ion channels, low ionized magnesium levels, increased excitatory glutamatergic activity, and mitochondrial dysfunction with abnormal energy metabolism are associated with migraine. The goal of nutraceuticals is to target these factors in order to improve energy metabolism and reduce neuronal hyperexcitability in the brain. Patients often seek natural migraine treatment with complementary and alternative medicine (CAM) after finding standard prescription treatments intolerable due to side effects, or just ineffective. Many patients feel that “natural” substances are less toxic than prescription medications. Thus, the nutraceutical and herbal supplement industry is a multibillion-dollar industry. CAMs include, but are not limited to, nutraceuticals (vitamins and supplements such as magnesium, coenzyme Q10 (CoQ10), vitamin B2 (riboflavin), alpha lipoic acid, vitamin D, 5-HTP, fish oil, melatonin), and herbal preparations (butterbur, feverfew, ginger, and cannabidiol). Other natural treatments such as yoga and meditation for migraine treatment can also be very helpful.

 

The use of CAMs has been significantly rising in the US and Europe9–12, and is becoming more evident especially in patients with migraine and other headache disorders. In a recent questionnaire-based survey in Germany and Austria, 81.7% of patients seen in tertiary outpatient headache clinics reported use of CAM13.  There are a multitude of different migraine related supplements on the market with variable combinations or sold separately as the individual components. Below, we discuss the most commonly used and studied supplements for migraine prevention.

 

VITAMINS and SUPPLEMENTS FOR MIGRAINE PREVENTION:

  1. Magnesium

Magnesium has a Level B (2nd highest) evidence recommendation for migraine prevention by the American Academy of Neurology and American Headache Society.14 It is also rated highly and recommended by the Canadian Headache Society.15 This is a higher evidence recommendation than many of the prescription medications we use for migraine prevention. More than 325 enzymes are magnesium dependent, many of which are brain enzymes. Magnesium is involved in all reactions that involve the formation and utilization of adenosine-5′-triphosphate (ATP) in energy metabolism16–19. Proper magnesium levels are known to help normalize blood pressure, have anticoagulant, anti-platelet aggregating effects, regulate cell proliferation, protein synthesis, cellular energy and cell membrane stability, as well as blood sugar levels19–21. Studies have shown low levels of brain magnesium22,23 may be a contributor to migraine pathophysiology. Magnesium influences multiple steps in the current understanding of migraine pathophysiology including cortical spreading depression, serotonin receptor activity, neurotransmitter release, interference with inflammatory mediators, nitric oxide production, platelet aggregation, vascular tone, NMDA receptor interaction, CGRP release, production and release of substance P which activates pain fibers24–31. Magnesium is a mineral that functions as a coenzyme for various neurologic functions and other physiologic mechanisms.    According to two double-blind studies, high-dose oral magnesium supplementation appears to be effective in migraine prophylaxis. Trials have shown that magnesium supplementation is very effective in migraine treatment, with migraine attack reductions of up to 42%.32–37 Other studies have also shown benefit in migraine prevention when combined with coenzyme Q10 and feverfew as well.38 Magnesium (250 mg twice a day or 500 mg at bed) has a relaxant effect on smooth muscles such as blood vessels. We often give intravenous magnesium to patients who come into the emergency department for migraine because it helps to break the migraine. Three trials found 40-90% average headache reduction when used as a preventative. Magnesium also demonstrated the benefit in menstrually related migraine. Magnesium is part of the messenger system in the serotonin cascade and it is a good muscle relaxant. Some forms can be useful for constipation which can be a side effect of other medications used to treat migraine. Good sources include nuts, whole grains, and tomatoes.

 

There are different forms of magnesium, and we’ll discuss the most common types. Magnesium types can be tailored to patient characteristics as follows.39 Magnesium glycinate is a good choice for those with a sensitive stomach who have gastrointestinal side effects such as diarrhea with other forms of magnesium. It is anecdotally also helpful with anxiety and sleep. Magnesium threonate also has low risk of gastrointestinal side effects and anecdotally helpful with cognitive function and brain fog symptoms. Magnesium malate has low gastrointestinal side effects and is reportedly more energizing and anecdotally often helpful in fibromyalgia and chronic fatigue syndrome. Magnesium citrate is one of the most studied, popular, and well-absorbed forms of magnesium. It can also be mixed easily with liquids if you can’t take pills. However, it comes with a higher risk of diarrhea and gastrointestinal side effects, although this could be helpful for those with constipation. Magnesium oxide is also well studied, cheap, and often used for heartburn and indigestion. However, it is not well absorbed and can have some laxative side effects as well, so can also be helpful for constipation.

 

Dosing should generally be somewhere between 400-800 mg daily. It should preferably contain 24 mmol (600 mg) of elemental magnesium daily as magnesium citrate​ based on trials that showed benefit with this specific one more than others, and this is the recommendation of the Canadian Headache Society.15 If this type is not tolerated, other forms of magnesium as discussed above are certainly acceptable.

 

  1. Vitamin D3 (Cholecalciferol)

Vitamin D deficiency is a worldwide problem. Vitamin D is not actually a vitamin, but a hormone that the body makes from a type of cholesterol in the skin when it is exposed to UVB radiation from the sun. Small amounts also come from diet. It has anti-inflammatory activities, analgesic effects, may reduce nitric oxide and assists in magnesium and calcium absorption. Deficiency is suspected to play a role in mechanisms responsible for migraine and other pain syndromes, and vitamin D levels have been shown to be low in chronic migraineurs40. The best form is vitamin D3 (cholecalciferol) anywhere from 1,000 to 4,000 IU daily.

 

  1. 5-HTP (5-Hydroxytryptophan)

This is an amino acid that is made by the body from tryptophan (amino acid you get from your diet), and is involved in mood, sleep, and pain regulation. 5-HTP is typically produced from the seeds of the Griffonia simplicifolia plant. 5-HTP is converted into serotonin (5-hydroxytryptamine), an important brain neurotransmitter involved in migraine pathways and other neurologic pathways. 5-HTP is also converted into melatonin which aids in sleep, as well as dopamine, another important neurotransmitter. The effects of 5-HTP are felt to be similar to the antidepressants that are thought to increase the amount of serotonin available to the brain, and thus a mood enhancing chemical. Some studies have suggested that 5-HTP was as effective as some prescription migraine medications such as propranolol and methysergide (75% improvement in methysergide vs. 71% improvement in 5-HTP) in reducing the frequency and severity of migraines41–45. Side effects can include nausea, diarrhea, and stomach pain, and it should be used cautiously with medications which increase serotonin levels (such as most antidepressants) due to potential risk of serotonin syndrome. Typical doses are around 100–200 mg, 2–3 times per day with meals.

 

  1. Fish oil (Eicosapentaenoic acid (EPA) + Docosahexaenoic acid (DHA))

Fish oils are found in the tissues of fish. They contain a certain type of fat called omega-3. Potential mechanisms for anti-inflammatory effects of fish oil include inhibition of inflammatory mediators (eicosanoids and cytokines), and synthesis of lipid suppressors of inflammation (resolvins)46. Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) give rise to these resolvins which are anti-inflammatory and inflammation resolving47. These compounds may relieve joint pain and stiffness in a similar way as non-steroidal anti-inflammatory drugs (NSAIDs)46,48. One study reported dramatic decreases in headache frequency (15 per month down to 2 per month) and decreases in headache severity (reduction from 5 to 3 on a 7-point scale)49. Fish oils have also been studied and found to be useful in other inflammatory conditions such as rheumatoid arthritis46,48,50–53. Large trials have showed a significant beneficial effect on pain, morning stiffness, number of painful and/or tender joints and NSAID consumption50. Recommended dosing consists of 30% EPA and DHA with a ratio of EPA to DHA of 1.5. Research suggests the minimum dose needed to reduce the joint inflammation associated with arthritis is 2.7 grams of omega-3 (EPA + DHA) daily, which could also be divided such as 900 mg EPA and 450 mg DHA twice daily.

 

  1. Melatonin:

Increasing evidence shows correlation between melatonin secretion and headache conditions. Melatonin supplementation has shown decreased headache intensity and duration. It is widely used as a sleep aid. Sleep is nature’s way of dealing with migraine. A dose of 3 mg is recommended to start for headaches including cluster headache. Higher doses up to 15 mg has been reviewed for use in cluster headache and have been used, if not making too groggy in the morning. The rationale behind using melatonin for cluster is that many theories regarding the cause of cluster headache center around the disruption of the normal circadian rhythm in the brain. This helps restore the normal circadian rhythm. It should be taken at least 2 hours before bedtime.

 

MITOCHONDRIAL SUPPLEMENTS FOR MIGRAINE PREVENTION:

Mitochondria are the powerhouses within all cells of the body. These crucial metabolic organelles use oxygen to produce ATP, which is the primary energy source for the cell, and thus, for your body. Mitochondrial dysfunction leads to impaired oxygen metabolism and is suspected to play a role in migraine pathophysiology. Some migraineurs have been shown to have reduced mitochondrial activity which may lead to altered neuronal processing, and therefore a lower threshold for migraine attacks54–58. Riboflavin (vitamin B2), CoQ10 (ubiquinone; CoQ10), and alpha lipoic acid (thioctic acid) all play key roles in mitochondrial activity, and therefore have been implicated in migraine treatment by optimizing mitochondrial functioning.

 

  1. Riboflavin (Vitamin B2)

Riboflavin assists nerve cells in the production of ATP, a principal energy storing molecule. Riboflavin is an essential precursor to coenzymes involved in electron transport in oxidation reduction reactions within the Krebs cycle. This metabolic cycle is critical in production of ATP and generation of energy in the mitochondria, oxidative metabolism, maintaining membrane stability, and for all energy-related cellular functions59,60. It is necessary for many chemical reactions in the body. Brain riboflavin metabolism is suspected to affect migraine pathophysiology via several mechanisms, providing migraine preventive benefit.36,37

 

Riboflavin has a Level B (2nd highest) evidence recommendation for migraine prevention by the American Academy of Neurology and American Headache Society.14 This is a higher evidence recommendation than many of the prescription medications we use for migraine prevention. The Canadian Headache Society Guidelines strongly recommend B2 for migraine prevention as well.15 There have been at least 3 clinical trials of riboflavin using 400 mg per day all of which suggested that migraine frequency can be decreased. All 3 trials showed significant improvement in over half of migraine sufferers. Trials of riboflavin have suggested significant improvements in migraine by up to 59%61. Riboflavin (Vitamin B2): 200 mg twice a day (or 400 mg daily). The supplement is found in bread, cereal, milk, meat, and poultry. Most Americans get more riboflavin than the recommended daily allowance, however riboflavin deficiency is not necessary for the supplements to help prevent headache. One side effect to be aware of is that it can turn your urine bright neon yellow, although this is not harmful. Recommended dosing is 200 mg twice daily (or 400 mg once daily).

 

  1. Coenzyme Q10 (Ubiquinone; Ubiquinol; CoQ10)

CoQ10 is present in every membrane of all cells in the body62. Similar to riboflavin, CoQ10 plays a crucial role in electron transport and energy metabolism given its heavy involvement in mitochondrial function. CoQ10 is incorporated into the mitochondria, where it facilitates the transformation of fats and sugars into energy, thus it is often marketed to be an “energy enhancer”. Studies have shown that a nutritional supplement of CoQ10 can reduce the frequency of migraine attacks by improving the energy production of cells as with riboflavin. It also functions as an antioxidant by protecting against toxic oxidative reactions in the body, and CoQ10 tissue levels are known to decrease with age19,63. In one study, CoQ10 was found to be low in about 1/3rd of patients studied, and when replaced, headache frequency improved64. Migraine frequency was shown to improve significantly in more than 61% of patients in one study65, and 50% of patients in another study,66 supporting use for migraine prevention.36 Other studies have also shown benefit in migraine prevention when combined with magnesium and feverfew as well.38 The Canadian Headache Society guidelines strongly recommend use of CoQ10.15 Suggested dosing is around 150 mg-200 mg twice a day.

 

  1. Alpha Lipoic Acid (Thioctic Acid)

Alpha lipoic acid enhances the metabolism of oxygen and energy production by mitochondria67, and has shown reduction of migraine frequency68 when studied. Doses are typically around 300 mg twice daily.

 

HERBAL SUPPLEMENTS FOR MIGRAINE PREVENTION:

  1. Feverfew (Tanacetum parthenium)

Feverfew is a common garden herb native to Europe and popular in Great Britain as a treatment for disorders typically controlled by aspirin. The mechanism of action is unknown but is believed to be related to a chemical called parthenolide which helps the body use serotonin more effectively. Serotonin helps prevent migraine and assists with resolution when it occurs. Parthenolide also inhibits the release of histamine which is linked to pain and inflammation. Consistency of active ingredients in different products can be a problem. Some formulations don’t have the active ingredient (parthenolide) that prevents migraine. A parthenolide content of 0.2% is generally recommended.

 

Feverfew has a Level B (2nd highest) evidence recommendation for migraine prevention by the American Academy of Neurology and American Headache Society.14 This is a higher evidence recommendation than many of the prescription medications we use for migraine prevention. The anti-migraine action36–38,69–75 of Feverfew is felt to be related to the parthenolides within the leaves. Studies have shown that the parthenolides provide anti-inflammatory and analgesic effects through several mechanisms involved in the migraine process that normally lead to pain. These include inhibition of phospholipase A, prostaglandin biosynthesis and platelet aggregation, and actions on serotonin including release of serotonin from platelets and white blood cells, as well as interaction at various serotonin receptor subtypes19,76–89. Study results have been variable based on wide variations in the strength of the parthenolides and differences in the stability of feverfew preparations used. However, a new, more stable feverfew extract (MIG-99) was created and showed a significant improvement in patients with high-frequency migraine90,91. The recommended dosing is generally around 50 mg twice daily (standardized to a high parthenolide content of 0.7% and stability measures of parthenolide), or, preferably MIG-99 6.25 mg three times daily if it can be found.

 

  1. Butterbur Extract (Petasites hybridus)

Butterbur is an extract derived from the petisides hybridus root, which has been used for medicinal purposes since ancient times. Butterbur is a well-researched and proven herbal supplements for migraine prevention36,69,70,92. For many years, it was the only supplement with a Level A (highest) evidence recommendation for migraine prevention by the American Academy of Neurology and American Headache Society,14 with a higher evidence recommendation than many of the prescription medications we use for migraine prevention. However, this recommendation was withdrawn a few years ago given a small handful of cases of liver failure reported in Germany. Although it is classified as an herbal supplement in the US, it is a licensed pharmaceutical medicine in Germany (Petadolex). Its two active compounds, petasin and isopetasin, help reduce cerebral blood vessel spasm and stop the inflammatory cascade which occurs in migraine93–95. Butterbur is thought to act through anti-inflammatory inhibition of leukotriene biosynthesis for its analgesic effects but also has calcium channel regulatory properties, both of which play a role in migraine19.

 

Studies have also shown anti-inflammatory effects mediated through inhibiting the additional inflammatory enzymes cyclooxygenase and prostaglandin production96. Notably, this is also what gives aspirin its anti-inflammatory effect. Trials have shown very positive results with significant decreases in migraine frequency of up to 58-77%, with 91% reporting overall improvement97–100. Side effects can include burping/belching. Raw butterbur root contains toxic chemicals that must be filtered out during the manufacturing process. To be sure you are choosing a safe product, look for a formulation that does not contain pyrrolizidine alkaloids since these are toxic to the liver. Recommended dosing is typically around 75 mg twice daily (free of Pyrrolizidine Alkaloids (PAs), standardized to contain a minimum of 7.5 mg of petasin and isopetasin).

 

  1. Ginger (Zingiber Officinale)

Ginger has anti-histamine and anti-inflammatory properties such as blocking pain-producing prostaglandins101,102, and helps with circulation and potentially headache. It is also widely used to treat nausea and vomiting, which accompany migraine103, and this is what it is primarily useful for. Recommended dosing ranges from 100-200 mg three times per day to 150 mg twice daily (standardized to contain 20% of gingerol and shogaol (dosage).

 

  1. CBD (Cannabidiol)

There have been a multitude of studies documenting the analgesic and anti-inflammatory benefits of medicinal cannabis (marijuana) across many chronic pain syndromes104–106, and it has been a historical treatment for headache and migraine for centuries.105–109 A detailed overview of medical cannabis for the treatment of migraine and chronic pain is discussed here. The vast majority of supporting evidence of cannabis and cannabinoids involves various chronic pain syndromes. These benefits are hypothesized to extend to headache disorders such as migraine given overlapping neurobiological pathways of pain. Some data suggests that cannabinoids appear to work uniquely within the inherent anatomical pathways of migraine (including serotonergic triptan pathways) and pain.104,105,107–139 Unfortunately, the majority of data supporting the use of cannabis and cannabinoids in migraine and headache disorders is based on case series, case reports, surveys and anecdotal evidence.105,107,145–154,108,155–161,134,135,140–144 There has been one retrospective study of cannabis use in the treatment of migraine which reported strong statistically significant findings of benefit.162 There have been only two limited prospective trials of cannabinoids containing a control group in headache disorders. One reported significant benefit in chronic daily headache associated with medication overuse headache,163 and the other reported significant benefit in both the acute and preventive treatment of chronic migraine.164

 

Given the growing evidence of cannabis and cannabinoids in the treatment of chronic pain and other medical conditions, in February 2019 The World Health Organization (WHO) recommended that cannabis be rescheduled and removed from the most restrictive scheduling category. In January 2017, the National Academies of Sciences, Engineering, and Medicine concluded that the use of cannabis for the treatment of pain is supported by well-controlled clinical trials and that there is substantial evidence that cannabis is an effective treatment for chronic pain in adults.165 In 2014, the Canadian Pain Society revised their consensus statement to recommend cannabinoids as a third-level therapy for chronic neuropathic pain based on the abundance of supporting evidence and a NNT (number needed to treat) estimated at approximately 3.166

 

Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the two predominant cannabinoids found in cannabis and are discussed in more detail here. CBD is several hundred more times anti-inflammatory than aspirin.104 There have been scientific, animal models, and limited human clinical trials documenting its anti-inflammatory and analgesic properties.167–176 In contrast to THC, CBD is non-intoxicating (no “high”).167 In November 2017, The World Health Organization (WHO) concluded that CBD exhibits no evidence for abuse or dependence potential, and that there is no evidence of public health related concerns associated with its use.177 In January 2018, the World Anti-Doping Agency (WADA) removed CBD from their prohibited list, no longer banning use by athletes.178

 

In December 2018, the Agriculture Improvement Act (Farm Bill) was signed into law in the United States. This legalized the agricultural growth and use of hemp (cannabis strains containing 0.3% THC or less) and hemp derivatives such as CBD, as well as removed hemp and its extracts (including CBD) from the Controlled Substances Act, making it no longer an illegal substance under federal law.

 

Thus, the use of CBD products has been exploding and is a new industry projected to exponentially increase into a multi-billion dollar industry179,180. Many patients are using these products for a variety of reasons181,182, most commonly in pain, including migraine prevention, given their easy access and availability. However, there are no studies evaluating CBD alone in treatment of migraine or any other headache disorders, so this is purely anecdotal. CBD products can readily be purchased online from a multitude of companies, in local health food and drug stores, and common retail pharmacies.183 CBD and suggested dosing (which are not currently clearly known) are discussed in much greater detail here. Medical marijuana (cannabis) for the treatment of migraine is also discussed in much greater

 

IF YOU HAVE HEADACHE, MIGRAINE, OR FACIAL PAIN AND ARE LOOKING FOR ANSWERS ON ANYTHING RELATED TO IT, A HEADACHE SPECIALIST IS HERE TO HELP, FOR FREE!

FIRST, LET’S DECIDE WHERE TO START:

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR THE LATEST INFORMATION, HOT TOPICS, AND TREATMENT TIPS, VISIT OUR FREE BLOG OF HOT TOPICS AND HEADACHE TIPS HERE. THIS IS WHERE I WRITE AND CONDENSE A BROAD VARIETY OF COMMON AND COMPLEX  MIGRAINE AND HEADACHE RELATED TOPICS INTO THE IMPORTANT FACTS AND HIGHLIGHTS YOU NEED TO KNOW, ALONG WITH PROVIDING FIRST HAND CLINICAL EXPERIENCE FROM THE PERSPECTIVE OF A HEADACHE SPECIALIST.

 

IF YOU DON’T HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR POSSIBLE TYPES OF HEADACHES OR FACIAL PAINS BASED ON YOUR SYMPTOMS, USE THE FREE HEADACHE AND FACIAL PAIN SYMPTOM CHECKER TOOL DEVELOPED BY A HEADACHE SPECIALIST NEUROLOGIST HERE!

 

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR FURTHER EDUCATION AND SELF-RESEARCH ON YOUR DIAGNOSIS, VISIT OUR FREE EDUCATION CENTER HERE.

 

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING TO ASK QUESTIONS TO A HEADACHE SPECIALIST OR OTHER HEADACHE, MIGRAINE, AND FACIAL PAIN WEBSITE MEMBERS, VISIT OUR FREE DISCUSSION FORUMS HERE.

 

REFERENCES

  1. Robbins MS, Lipton RB. The epidemiology of primary headache disorders. Semin Neurol. 2010;30(2):107-119. doi:10.1055/s-0030-1249220 [doi]
  2. Lipton RB, Bigal ME, Diamond M, Freitag F, Reed ML, Stewart WF. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5):343-349. doi:10.1212/01.wnl.0000252808.97649.21
  3. Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache. 2001;41(7):646-657.
  4. Steiner TJ, Birbeck GL, Jensen RH, Katsarava Z, Stovner LJ, Martelletti P. Headache disorders are third cause of disability worldwide. J Headache Pain. 2015;16:58. doi:10.1186/s10194-015-0544-2 [doi]
  5. Holland S, Silberstein SD, Freitag F, et al. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1346-1353. doi:10.1212/WNL.0b013e3182535d0c [doi]
  6. Evers S, Afra J, Frese A, et al. EFNS guideline on the drug treatment of migraine–revised report of an EFNS task force. Eur J Neurol. 2009;16(9):968-981. doi:10.1111/j.1468-1331.2009.02748.x [doi]
  7. Hepp Z, Dodick DW, Varon SF, Gillard P, Hansen RN, Devine EB. Adherence to oral migraine-preventive medications among patients with chronic migraine. Cephalalgia. 2015;35(6):478-488. doi:10.1177/0333102414547138
  8. Lanteri-Minet M, Duru G, Mudge M, Cottrell S. Quality of life impairment, disability and economic burden associated with chronic daily headache, focusing on chronic migraine with or without medication overuse: a systematic review. Cephalalgia. 2011;31(7):837-850. doi:10.1177/0333102411398400
  9. Tindle HA, Davis RB, Phillips RS, Eisenberg DM. Trends in use of complementary and alternative medicine by US adults: 1997-2002. Altern Ther Health Med. 2005;11(1):42-49.
  10. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990-1997: results of afollow-up national survey. JAMA. 1998;280(18):1569-1575.
  11. Kessler RC, Davis RB, Foster DF, et al. Long-term trends in the use of complementary and alternative medical therapies in the United States. Ann Intern Med. 2001;135(4):262-268.
  12. Haussermann D. Increased confidence in natural therapies. Deutsch Arztebl. 1997;94:1857-1858.
  13. Gaul C, Eismann R, Schmidt T, et al. Use of complementary and alternative medicine in patients suffering from primaryheadache disorders. Cephalalgia. 2009;29(10):1069-1078. doi:10.1111/j.1468-2982.2009.01841.x
  14. Loder E, Burch R, Rizzoli P. The 2012 AHS/AAN guidelines for prevention of episodic migraine: a summary and comparison with other recent clinical practice guidelines. Headache. 2012;52(6):930-945. doi:10.1111/j.1526-4610.2012.02185.x
  15. Pringsheim T, Davenport WJ, Mackie G, et al. Canadian Headache Society guideline for migraine prophylaxis. Can J Neurol Sci. 2012;39(2 Suppl 2):S1-59.
  16. Eby GA 3rd, Eby KL. Magnesium for treatment-resistant depression: a review and hypothesis. Med Hypotheses. 2010;74(4):649-660. doi:10.1016/j.mehy.2009.10.051
  17. Eby GA, Eby KL, Murk H. Magnesium and major depression. In: Vink R, Nechifor M, eds. Magnesium in the Central Nervous System [Internet]. Adelaide (AU); 2011.
  18. Connolly E, Worthley LI. Intravenous magnesium. Crit Care Resusc. 1999;1(2):162-172.
  19. Taylor FR. Nutraceuticals and headache: the biological basis. Headache. 2011;51(3):484-501. doi:10.1111/j.1526-4610.2011.01847.x
  20. Romani AMP. Magnesium homeostasis and alcohol consumption. Magnes Res. 2008;21(4):197-204.
  21. Wolf FI, Trapani V, Cittadini A. Magnesium and the control of cell proliferation: looking for a needle in a haystack. Magnes Res. 2008;21(2):83-91.
  22. Ramadan NM, Halvorson H, Vande-Linde A, Levine SR, Helpern JA, Welch KM. Low brain magnesium in migraine. Headache. 1989;29(9):590-593.
  23. Jain AC, Sethi NC, Babbar PK. A clinical electroencephalographic and trace element study with special reference to zinc, copper, and magnesium in serum and cerebrospinal fluid (CSF) in cases of migraine. J Neurol. 1985;(Suppl)(232):161.
  24. Mody I, Lambert JD, Heinemann U. Low extracellular magnesium induces epileptiform activity and spreading depression in rat hippocampal slices. J Neurophysiol. 1987;57(3):869-888. doi:10.1152/jn.1987.57.3.869
  25. Coan EJ, Collingridge GL. Magnesium ions block an N-methyl-D-aspartate receptor-mediated component of synaptic transmission in rat hippocampus. Neurosci Lett. 1985;53(1):21-26.
  26. Baudouin-Legros M, Dard B, Guicheney P. Hyperreactivity of platelets from spontaneously hypertensive rats. Role of external magnesium. Hypertens (Dallas, Tex 1979). 1986;8(8):694-699.
  27. Altura BM, Altura BT. Cardiovascular risk factors and magnesium: relationships to atherosclerosis, ischemic heart disease and hypertension. Magnes Trace Elem. 10(2-4):182-192.
  28. Altura BM, Altura BT. New perspectives on the role of magnesium in the pathophysiology of the cardiovascular system. I. Clinical aspects. Magnesium. 1985;4(5-6):226-244.
  29. Altura BT, Altura BM. The role of magnesium in etiology of strokes and cerebrovasospasm. Magnesium. 1982;1:277-291.
  30. Turlapaty PD, Altura BM. Magnesium deficiency produces spasms of coronary arteries: relationship to etiology of sudden death ischemic heart disease. Science. 1980;208(4440):198-200.
  31. Altura BM, Altura BT, Carella A, Gebrewold A, Murakawa T, Nishio A. Mg2+-Ca2+ interaction in contractility of vascular smooth muscle: Mg2+ versus organic calcium channel blockers on myogenic tone and agonist-induced responsiveness of blood vessels. Can J Physiol Pharmacol. 1987;65(4):729-745.
  32. Facchinetti F, Sances G, Borella P, Genazzani AR, Nappi G. Magnesium prophylaxis of menstrual migraine: effects on intracellular magnesium. Headache. 1991;31(5):298-301.
  33. Peikert A, Wilimzig C, Kohne-Volland R. Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia. 1996;16(4):257-263. doi:10.1046/j.1468-2982.1996.1604257.x
  34. Koseoglu E, Talaslioglu A, Gonul AS, Kula M. The effects of magnesium prophylaxis in migraine without aura. Magnes Res. 2008;21(2):101-108.
  35. Pfaffenrath V, Wessely P, Meyer C, et al. Magnesium in the prophylaxis of migraine–a double-blind placebo-controlled study. Cephalalgia. 1996;16(6):436-440. doi:10.1046/j.1468-2982.1996.1606436.x
  36. Rajapakse T, Pringsheim T. Nutraceuticals in Migraine: A Summary of Existing Guidelines for Use. Headache. 2016;56(4):808-816. doi:10.1111/head.12789
  37. Maizels M, Blumenfeld A, Burchette R. A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: arandomized trial. Headache. 2004;44(9):885-890. doi:10.1111/j.1526-4610.2004.04170.x
  38. Guilbot A, Bangratz M, Ait Abdellah S, Lucas C. A combination of coenzyme Q10, feverfew and magnesium for migraine prophylaxis: a prospective observational study. BMC Complement Altern Med. 2017;17(1):433. doi:10.1186/s12906-017-1933-7
  39. The Dizzy Cook. The Best Magnesium Supplements for Migraine. https://thedizzycook.com/magnesium-supplements-explained-which-one-is-best-for-vestibular-migraine/. Accessed December 6, 2020.
  40. Wheeler S. Vitamin D deficiency common in patients with chronic migraine. In: American Headache Society 50th Annual Scientific Meeting: Abstract S33.
  41. Titus F, Davalos A, Alom J, Codina A. 5-Hydroxytryptophan versus methysergide in the prophylaxis of migraine. Randomized clinical trial. Eur Neurol. 1986;25(5):327-329. doi:10.1159/000116030
  42. Bono G, Criscuoli M, Martignoni E, Salmon S, Nappi G. Serotonin precursors in migraine prophylaxis. Adv Neurol. 1982;33:357-363.
  43. Yoon M-S, Savidou I, Diener H-C, Limmroth V. Evidence-based medicine in migraine prevention. Expert Rev Neurother. 2005;5(3):333-341. doi:10.1586/14737175.5.3.333
  44. Maissen CP, Ludin HP. [Comparison of the effect of 5-hydroxytryptophan and propranolol in the intervaltreatment of migraine]. Schweiz Med Wochenschr. 1991;121(43):1585-1590.
  45. Ribeiro CA. L-5-Hydroxytryptophan in the prophylaxis of chronic tension-type headache: a double-blind, randomized, placebo-controlled study. For the Portuguese Head Society. Headache. 2000;40(6):451-456.
  46. James M, Proudman S, Cleland L. Fish oil and rheumatoid arthritis: past, present and future. Proc Nutr Soc. 2010;69(3):316-323. doi:10.1017/S0029665110001564
  47. Calder PC. Fatty acids and inflammation: the cutting edge between food and pharma. Eur J Pharmacol. 2011;668 Suppl:S50-8. doi:10.1016/j.ejphar.2011.05.085
  48. Proudman SM, James MJ, Spargo LD, et al. Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind controlled trial within algorithm-based drug use. Ann Rheum Dis. 2015;74(1):89-95. doi:10.1136/annrheumdis-2013-204145
  49. Harel Z, Gascon G, Riggs S, Vaz R, Brown W, Exil G. Supplementation with omega-3 polyunsaturated fatty acids in the management of recurrent migraines in adolescents. J Adolesc Health. 2002;31(2):154-161.
  50. Goldberg RJ, Katz J. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain. 2007;129(1-2):210-223. doi:10.1016/j.pain.2007.01.020
  51. Wall R, Ross RP, Fitzgerald GF, Stanton C. Fatty acids from fish: the anti-inflammatory potential of long-chain omega-3 fatty acids. Nutr Rev. 2010;68(5):280-289. doi:10.1111/j.1753-4887.2010.00287.x
  52. Rosenbaum CC, O’Mathuna DP, Chavez M, Shields K. Antioxidants and antiinflammatory dietary supplements for osteoarthritis and rheumatoid arthritis. Altern Ther Health Med. 2010;16(2):32-40.
  53. Hurst S, Zainal Z, Caterson B, Hughes CE, Harwood JL. Dietary fatty acids and arthritis. Prostaglandins Leukot Essent Fatty Acids. 2010;82(4-6):315-318. doi:10.1016/j.plefa.2010.02.008
  54. Koo B, Becker LE, Chuang S, et al. Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS): clinical, radiological, pathological, and genetic observations. Ann Neurol. 1993;34(1):25-32. doi:10.1002/ana.410340107
  55. Lanteri-Minet M, Desnuelle C. [Migraine and mitochondrial dysfunction]. Rev Neurol (Paris). 1996;152(4):234-238.
  56. Montagna P, Cortelli P, Monari L, et al. 31P-magnetic resonance spectroscopy in migraine without aura. Neurology. 1994;44(4):666-669. doi:10.1212/wnl.44.4.666
  57. Bresolin N, Martinelli P, Barbiroli B, et al. Muscle mitochondrial DNA deletion and 31P-NMR spectroscopy alterations in a migraine patient. J Neurol Sci. 1991;104(2):182-189.
  58. Sparaco M, Feleppa M, Lipton RB, Rapoport AM, Bigal ME. Mitochondrial dysfunction and migraine: evidence and hypotheses. Cephalalgia. 2006;26(4):361-372. doi:10.1111/j.1468-2982.2005.01059.x
  59. Evans RW, Taylor FR. “Natural” or alternative medications for migraine prevention. Headache. 2006;46(6):1012-1018. doi:10.1111/j.1526-4610.2006.00473.x
  60. O’Brien HL, Hershey AD. Vitamins and paediatric migraine: Riboflavin as a preventative medication. Cephalalgia. 2010;30(12):1417-1418. doi:10.1177/0333102410378358
  61. Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology. 1998;50(2):466-470. doi:10.1212/wnl.50.2.466
  62. Turunen M, Olsson J, Dallner G. Metabolism and function of coenzyme Q. Biochim Biophys Acta. 2004;1660(1-2):171-199.
  63. Beyer RE, Burnett BA, Cartwright KJ, et al. Tissue coenzyme Q (ubiquinone) and protein concentrations over the life span of the laboratory rat. Mech Ageing Dev. 1985;32(2-3):267-281.
  64. Hershey AD, Powers SW, Vockell A-LB, et al. Coenzyme Q10 deficiency and response to supplementation in pediatric and adolescent migraine. Headache. 2007;47(1):73-80. doi:10.1111/j.1526-4610.2007.00652.x
  65. Rozen TD, Oshinsky ML, Gebeline CA, et al. Open label trial of coenzyme Q10 as a migraine preventive. Cephalalgia. 2002;22(2):137-141. doi:10.1046/j.1468-2982.2002.00335.x
  66. Sandor PS, Di Clemente L, Coppola G, et al. Efficacy of coenzyme Q10 in migraine prophylaxis: a randomized controlled trial. Neurology. 2005;64(4):713-715. doi:10.1212/01.WNL.0000151975.03598.ED
  67. Matalon R, Stumpf DA, Michals K, Hart RD, Parks JK, Goodman SI. Lipoamide dehydrogenase deficiency with primary lactic acidosis: favorable response to treatment with oral lipoic acid. J Pediatr. 1984;104(1):65-69.
  68. Magis D, Ambrosini A, Sandor P, Jacquy J, Laloux P, Schoenen J. A randomized double-blind placebo-controlled trial of thioctic acid in migraine prophylaxis. Headache. 2007;47(1):52-57. doi:10.1111/j.1526-4610.2006.00626.x
  69. Silberstein SD. Preventive Migraine Treatment. Continuum (Minneap Minn). 2015;21(4 Headache):973-989. doi:10.1212/CON.0000000000000199
  70. D’Onofrio F, Raimo S, Spitaleri D, Casucci G, Bussone G. Usefulness of nutraceuticals in migraine prophylaxis. Neurol Sci Off J Ital Neurol Soc  Ital Soc Clin Neurophysiol. 2017;38(Suppl 1):117-120. doi:10.1007/s10072-017-2901-1
  71. Wider B, Pittler MH, Ernst E. Feverfew for preventing migraine. Cochrane database Syst Rev. 2015;4:CD002286. doi:10.1002/14651858.CD002286.pub3
  72. Saranitzky E, White CM, Baker EL, Baker WL, Coleman CI. Feverfew for migraine prophylaxis: a systematic review. J Diet Suppl. 2009;6(2):91-103. doi:10.1080/19390210902861809
  73. Pittler MH, Ernst E. Feverfew for preventing migraine. Cochrane database Syst Rev. 2004;(1):CD002286. doi:10.1002/14651858.CD002286.pub2
  74. Ernst E, Pittler MH. The efficacy and safety of feverfew (Tanacetum parthenium L.): an update of a systematic review. Public Health Nutr. 2000;3(4A):509-514. doi:10.1017/s1368980000000598
  75. Vogler BK, Pittler MH, Ernst E. Feverfew as a preventive treatment for migraine: a systematic review. Cephalalgia. 1998;18(10):704-708. doi:10.1046/j.1468-2982.1998.1810704.x
  76. Heptinstall S, White A, Williamson L, Mitchell JR. Extracts of feverfew inhibit granule secretion in blood platelets and polymorphonuclear leucocytes. Lancet (London, England). 1985;1(8437):1071-1074.
  77. Barsby RW, Salan U, Knight DW, Hoult JR. Feverfew and vascular smooth muscle: extracts from fresh and dried plants show opposing pharmacological profiles, dependent upon sesquiterpene lactone content. Planta Med. 1993;59(1):20-25. doi:10.1055/s-2006-959596
  78. Bejar E. Parthenolide inhibits the contractile responses of rat stomach fundus to fenfluramine and dextroamphetamine but not serotonin. J Ethnopharmacol. 1996;50(1):1-12.
  79. Weber JT, O’Connor MF, Hayataka K, et al. Activity of Parthenolide at 5HT2A receptors. J Nat Prod. 1997;60(6):651-653. doi:10.1021/np960644d
  80. Mittra S, Datta A, Singh SK, Singh A. 5-Hydroxytryptamine-inhibiting property of Feverfew: role of parthenolide content. Acta Pharmacol Sin. 2000;21(12):1106-1114.
  81. Shrivastava R, Pechadre JC, John GW. Tanacetum parthenium and Salix alba (Mig-RL) combination in migraine prophylaxis: a prospective, open-label study. Clin Drug Investig. 2006;26(5):287-296. doi:10.2165/00044011-200626050-00006
  82. Heptinstall S, Groenewegen WA, Spangenberg P, Losche W. Inhibition of platelet behaviour by feverfew: a mechanism of action involving sulphydryl groups. Folia Haematol Int Mag Klin Morphol Blutforsch. 1988;115(4):447-449.
  83. Heptinstall S, Groenewegen WA, Spangenberg P, Loesche W. Extracts of feverfew may inhibit platelet behaviour via neutralization of sulphydryl groups. J Pharm Pharmacol. 1987;39(6):459-465.
  84. Loesche W, Groenewegen WA, Krause S, Spangenberg P, Heptinstall S. Effects of an extract of feverfew (Tanacetum parthenium) on arachidonic acid metabolism in human blood platelets. Biomed Biochim Acta. 1988;47(10-11):S241-3.
  85. Pugh WJ, Sambo K. Prostaglandin synthetase inhibitors in feverfew. J Pharm Pharmacol. 1988;40(10):743-745.
  86. Makheja AN, Bailey JM. A platelet phospholipase inhibitor from the medicinal herb feverfew (Tanacetum parthenium). Prostaglandins Leukot Med. 1982;8(6):653-660.
  87. Collier HO, Butt NM, McDonald-Gibson WJ, Saeed SA. Extract of feverfew inhibits prostaglandin biosynthesis. Lancet (London, England). 1980;2(8200):922-923.
  88. Thakkar JK, Sperelakis N, Pang D, Franson RC. Characterization of phospholipase A2 activity in rat aorta smooth muscle cells. Biochim Biophys Acta. 1983;750(1):134-140.
  89. Marles RJ, Kaminski J, Arnason JT, et al. A bioassay for inhibition of serotonin release from bovine platelets. J Nat Prod. 1992;55(8):1044-1056.
  90. Diener HC, Pfaffenrath V, Schnitker J, Friede M, Henneicke-von Zepelin H-H. Efficacy and safety of 6.25 mg t.i.d. feverfew CO2-extract (MIG-99) in migraine prevention–a randomized, double-blind, multicentre, placebo-controlled study. Cephalalgia. 2005;25(11):1031-1041. doi:10.1111/j.1468-2982.2005.00950.x
  91. Pfaffenrath V, Diener HC, Fischer M, Friede M, Henneicke-von Zepelin HH. The efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis–a double-blind, multicentre, randomized placebo-controlled dose-response study. Cephalalgia. 2002;22(7):523-532. doi:10.1046/j.1468-2982.2002.00396.x
  92. Benemei S, De Logu F, Li Puma S, et al. The anti-migraine component of butterbur extracts, isopetasin, desensitizes peptidergic nociceptors by acting on TRPA1 cation channel. Br J Pharmacol. 2017;174(17):2897-2911. doi:10.1111/bph.13917
  93. Eaton J. Butterbur, herbal help for migraine. Nat Pharm. 1998;2:23-24.
  94. Pearlman EM, Fisher S. Preventive treatment for childhood and adolescent headache: Role of once-daily montelukast sodium. (Abstract). Cephalalgia. 2001;21:461.
  95. Sheftell F, Rapoport A, Weeks R, Walker B, Gammerman I, Baskin S. Montelukast in the prophylaxis of migraine: a potential role for leukotriene modifiers. Headache. 2000;40(2):158-163.
  96. Fiebich BL, Grozdeva M, Hess S, et al. Petasites hybridus extracts in vitro inhibit COX-2 and PGE2 release by direct interaction with the enzyme and by preventing p42/44 MAP kinase activation in rat primary microglial cells. Planta Med. 2005;71(1):12-19. doi:10.1055/s-2005-837744
  97. Pothmann R, Danesch U. Migraine prevention in children and adolescents: results of an open study with aspecial butterbur root extract. Headache. 2005;45(3):196-203. doi:10.1111/j.1526-4610.2005.05044.x
  98. Grossman M, Schmidrams H. An extract of Petasites hybridus is effective in the prophylaxis of migraine. Int J Clin Pharmacol Ther. 2000;38:430-435.
  99. Diener H, Rahlfs V, Danesch U. The first placebo-controlled trial of a special butterbur root extract for the prevention of migraine: Reanalysis of efficacy criteria. Eur Neurol. 2004;51(2):89-97. doi:10.1159/000076535
  100. Lipton RB, Gobel H, Einhaupl KM, Wilks K, Mauskop A. Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. Neurology. 2004;63(12):2240-2244. doi:10.1212/01.wnl.0000147290.68260.11
  101. Srivastava KC, Mustafa T. Ginger (Zingiber officinale) and rheumatic disorders. Med Hypotheses. 1989;29(1):25-28.
  102. Srivastava KC, Mustafa T. Ginger (Zingiber officinale) in rheumatism and musculoskeletal disorders. Med Hypotheses. 1992;39(4):342-348.
  103. Mustafa T, Srivastava KC. Ginger (Zingiber officinale) in migraine headache. J Ethnopharmacol. 1990;29(3):267-273.
  104. Baron EP. Medicinal Properties of Cannabinoids, Terpenes, and Flavonoids in Cannabis, and Benefits in Migraine, Headache, and Pain: An Update on Current Evidence and Cannabis Science. Headache J Head Face Pain. 2018;58(7):1139-1186. doi:10.1111/head.13345
  105. Baron EP. Comprehensive Review of Medicinal Marijuana, Cannabinoids, and Therapeutic Implications in Medicine and Headache: What a Long Strange Trip It’s Been …. Headache J Head Face Pain. 2015;55(6):885-916. doi:10.1111/head.12570
  106. Russo EB. Cannabinoids in the management of difficult to treat pain. Ther Clin Risk Manag. 2008;4(1):245-259.
  107. Russo E. Hemp for headache: an in-depth historical and scientific review of cannabis in migraine treatment. J Cannabis Ther. 2001;1:21-92.
  108. Russo E. Cannabis for migraine treatment: the once and future prescription? An historical and scientific review. Pain. 1998;76(1-2):3-8.
  109. Lochte BC, Beletsky A, Samuel NK, Grant I. The Use of Cannabis for Headache Disorders. Cannabis cannabinoid Res. 2017;2(1):61-71. doi:10.1089/can.2016.0033 [doi]
  110. Akerman S, Holland PR, Goadsby PJ. Diencephalic and brainstem mechanisms in migraine. Nat Rev. 2011;12(10):570-584. doi:10.1038/nrn3057 [doi]
  111. Greco R, Gasperi V, Sandrini G, et al. Alterations of the endocannabinoid system in an animal model of migraine: evaluation in cerebral areas of rat. Cephalalgia. 2010;30(3):296-302. doi:10.1111/j.1468-2982.2009.01924.x [doi]
  112. Haj-Dahmane S, Shen RY. Endocannabinoids suppress excitatory synaptic transmission to dorsal raphe serotonin neurons through the activation of presynaptic CB1 receptors. J Pharmacol Exp Ther. 2009;331(1):186-196. doi:10.1124/jpet.109.153858 [doi]
  113. Palazzo E, de Novellis V, Petrosino S, et al. Neuropathic pain and the endocannabinoid system in the dorsal raphe: pharmacological treatment and interactions with the serotonergic system. Eur J Neurosci. 2006;24(7):2011-2020. doi:EJN5086 [pii]
  114. Voth EA, Schwartz RH. Medicinal applications of delta-9-tetrahydrocannabinol and marijuana. Ann Intern Med. 1997;126(10):791-798.
  115. Akerman S, Kaube H, Goadsby PJ. Anandamide is able to inhibit trigeminal neurons using an in vivo model of trigeminovascular-mediated nociception. J Pharmacol Exp Ther. 2004;309(1):56-63. doi:10.1124/jpet.103.059808 [doi]
  116. Akerman S, Holland PR, Goadsby PJ. Cannabinoid (CB1) receptor activation inhibits trigeminovascular neurons. J Pharmacol Exp Ther. 2007;320(1):64-71. doi:jpet.106.106971 [pii]
  117. Kelly S, Chapman V. Selective cannabinoid CB1 receptor activation inhibits spinal nociceptive transmission in vivo. J Neurophysiol. 2001;86(6):3061-3064.
  118. Meng ID, Johansen JP. Antinociception and modulation of rostral ventromedial medulla neuronal activity by local microinfusion of a cannabinoid receptor agonist. Neuroscience. 2004;124(3):685-693. doi:10.1016/j.neuroscience.2003.10.001 [doi]
  119. Meng ID, Manning BH, Martin WJ, Fields HL. An analgesia circuit activated by cannabinoids. Nature. 1998;395(6700):381-383. doi:10.1038/26481 [doi]
  120. Palazzo E, Marabese I, de Novellis V, et al. Metabotropic and NMDA glutamate receptors participate in the cannabinoid-induced antinociception. Neuropharmacology. 2001;40(3):319-326. doi:S002839080000160X [pii]
  121. Finn DP, Jhaveri MD, Beckett SR, et al. Effects of direct periaqueductal grey administration of a cannabinoid receptor agonist on nociceptive and aversive responses in rats. Neuropharmacology. 2003;45(5):594-604. doi:S0028390803002351 [pii]
  122. Maione S, Bisogno T, de Novellis V, et al. Elevation of endocannabinoid levels in the ventrolateral periaqueductal grey through inhibition of fatty acid amide hydrolase affects descending nociceptive pathways via both cannabinoid receptor type 1 and transient receptor potential vanilloid type-1 re. J Pharmacol Exp Ther. 2006;316(3):969-982. doi:jpet.105.093286 [pii]
  123. de Novellis V, Mariani L, Palazzo E, et al. Periaqueductal grey CB1 cannabinoid and metabotropic glutamate subtype 5 receptors modulate changes in rostral ventromedial medulla neuronal activities induced by subcutaneous formalin in the rat. Neuroscience. 2005;134(1):269-281. doi:S0306-4522(05)00334-9 [pii]
  124. Akerman S, Holland PR, Lasalandra MP, Goadsby PJ. Endocannabinoids in the brainstem modulate dural trigeminovascular nociceptive traffic via CB1 and “triptan” receptors: implications in migraine. J Neurosci. 2013;33(37):14869-14877. doi:10.1523/JNEUROSCI.0943-13.2013 [doi]
  125. Knight YE, Goadsby PJ. The periaqueductal grey matter modulates trigeminovascular input: a role in migraine? Neuroscience. 2001;106(4):793-800. doi:S0306452201003037 [pii]
  126. Knight YE, Bartsch T, Kaube H, Goadsby PJ. P/Q-type calcium-channel blockade in the periaqueductal gray facilitates trigeminal nociception: a functional genetic link for migraine? J Neurosci. 2002;22(5):RC213-8P_$Fhttp://www.ncbi.nlm.nih. doi:20026167 [pii]
  127. Knight YE, Bartsch T, Goadsby PJ. Trigeminal antinociception induced by bicuculline in the periaqueductal gray (PAG) is not affected by PAG P/Q-type calcium channel blockade in rat. Neurosci Lett. 2003;336(2):113-116. doi:S0304394002012508 [pii]
  128. Juhasz G, Lazary J, Chase D, et al. Variations in the cannabinoid receptor 1 gene predispose to migraine. Neurosci Lett. 2009;461(2):116-120. doi:10.1016/j.neulet.2009.06.021 [doi]
  129. Nyholt DR, Morley KI, Ferreira MA, et al. Genomewide significant linkage to migrainous headache on chromosome 5q21. Am J Hum Genet. 2005;77(3):500-512. doi:S0002-9297(07)63030-4 [pii]
  130. Bartsch T, Knight YE, Goadsby PJ. Activation of 5-HT(1B/1D) receptor in the periaqueductal gray inhibits nociception. Ann Neurol. 2004;56(3):371-381. doi:10.1002/ana.20193 [doi]
  131. Vaughan CW, McGregor IS, Christie MJ. Cannabinoid receptor activation inhibits GABAergic neurotransmission in rostral ventromedial medulla neurons in vitro. Br J Pharmacol. 1999;127(4):935-940. doi:10.1038/sj.bjp.0702636 [doi]
  132. Vaughan CW, Connor M, Bagley EE, Christie MJ. Actions of cannabinoids on membrane properties and synaptic transmission in rat periaqueductal gray neurons in vitro. Mol Pharmacol. 2000;57(2):288-295.
  133. Greco R, Mangione AS, Sandrini G, Nappi G, Tassorelli C. Activation of CB2 receptors as a potential therapeutic target for migraine: evaluation in an animal model. J Headache Pain. 2014;15:14. doi:10.1186/1129-2377-15-14 [doi]
  134. Volfe Z, Dvilansky A, Nathan I. Cannabinoids block release of serotonin from platelets induced by plasma from migraine patients. Int J Clin Pharmacol Res. 1985;5(4):243-246.
  135. Greco R, Gasperi V, Maccarrone M, Tassorelli C. The endocannabinoid system and migraine. Exp Neurol. 2010;224(1):85-91. doi:10.1016/j.expneurol.2010.03.029 [doi]
  136. Mailleux P, Vanderhaeghen JJ. Localization of cannabinoid receptor in the human developing and adult basal ganglia. Higher levels in the striatonigral neurons. Neurosci Lett. 1992;148(1-2):173-176.
  137. Moldrich G, Wenger T. Localization of the CB1 cannabinoid receptor in the rat brain. An immunohistochemical study. Peptides. 2000;21(11):1735-1742. doi:S0196-9781(00)00324-7 [pii]
  138. Russo EB. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol Lett. 2008;29(2):192-200. doi:NEL290208R02 [pii]
  139. Russo EB. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol Lett. 2004;25(1-2):31-39. doi:NEL251204R02 [pii]
  140. Noyes Jr R, Baram DA. Cannabis analgesia. Compr Psychiatry. 1974;15(6):531-535.
  141. Schnelle M, Grotenhermen F, Reif M, Gorter RW. Results of a standardized survey on the medical use of cannabis products in the German-speaking area. Forsch Komplementarmed. 1999;6 Suppl 3:28-36. doi:57154 [pii]
  142. el-Mallakh RS. Marijuana and migraine. Headache. 1987;27(8):442-443.
  143. Grinspoon L, Bakalar JB. Marihuana: The Forbidden Medicine. New Haven, CT: Yale University; 1993.
  144. el-Mallakh RS. Migraine headaches and drug abuse. South Med J. 1989;82(6):805.
  145. Gorji A. Pharmacological treatment of headache using traditional Persian medicine. Trends Pharmacol Sci. 2003;24(7):331-334. doi:S0165-6147(03)00164-0 [pii]
  146. Robbins MS, Tarshish S, Solomon S, Grosberg BM. Cluster attacks responsive to recreational cannabis and dronabinol. Headache. 2009;49(6):914-916. doi:10.1111/j.1526-4610.2009.01344.x [doi]
  147. Donnet A, Lanteri-Minet M, Guegan-Massardier E, et al. Chronic cluster headache: a French clinical descriptive study. J Neurol Neurosurg Psychiatry. 2007;78(12):1354-1358. doi:jnnp.2006.112037 [pii]
  148. Leroux E, Taifas I, Valade D, Donnet A, Chagnon M, Ducros A. Use of cannabis among 139 cluster headache sufferers. Cephalalgia. 2013;33(3):208-213. doi:10.1177/0333102412468669 [doi]
  149. Evans RW, Ramadan NM. Are cannabis-based chemicals helpful in headache? Headache. 2004;44(7):726-727. doi:10.1111/j.1526-4610.2004.04133C.x [doi]
  150. Consroe P, Musty R, Rein J, Tillery W, Pertwee R. The perceived effects of smoked cannabis on patients with multiple sclerosis. Eur Neurol. 1997;38(1):44-48.
  151. Mackenzie S. Remarks on the value of Indian hemp in the treatment of a certain type of headache. Br Med J. 1887;1:97-98.
  152. Nunberg H, Kilmer B, Pacula RL, Burgdorf J. An Analysis of Applicants Presenting to a Medical Marijuana Specialty Practice in California. J Drug Policy Anal. 2011;4(1)://www.ncbi.nlm.nih. doi:1 [pii]
  153. Donovan M. On the physical and medicinal qualities of Indian hemp (Cannabis indica); with observations on the best mode of administration, and cases illustrative of its powers. Dublin J Med Sci. 1845;26:368-461.
  154. Reynolds JR. On some of the therapeutical uses of Indian hemp. Arch Med. 1868;2:154-160.
  155. Waring EJ. Practical Therapeutics. Philadelphia: Lindsay & Blakiston; 1874.
  156. Ringer S. A Handbook of Therapeutics. London: H.K. Lewis; 1886.
  157. Hare HA. Clinical and physiological notes on the action of Cannabis indica. There Gaz. 1887;11:225-228.
  158. Suckling CW. On the therapeutic value of Indian hemp. Br Med J. 1891;2:11-12.
  159. Mikuriya TH. Chronic Migraine Headache: Five Cases Successfully Treated with Marinol and/or Illicit Cannabis. Berkeley, CA: Schaffer Library of Drug Policy; 1991.
  160. Lucas P, Baron EP, Jikomes N. Medical cannabis patterns of use and substitution for opioids &amp; other pharmaceutical drugs, alcohol, tobacco, and illicit substances; results from a cross-sectional survey of authorized patients. Harm Reduct J. 2019;16(1):9. doi:10.1186/s12954-019-0278-6
  161. Baron EP, Lucas P, Eades J, Hogue O. Patterns of medicinal cannabis use, strain analysis, and substitution effect among patients with migraine, headache, arthritis, and chronic pain in a medicinal cannabis cohort. J Headache Pain. 2018;19(1):1-28. doi:10.1186/s10194-018-0862-2
  162. Rhyne DN, Anderson SL, Gedde M, Borgelt LM. Effects of Medical Marijuana on Migraine Headache Frequency in an Adult Population. Pharmacotherapy. 2016;36(5):505-510. doi:10.1002/phar.1673 [doi]
  163. Pini LA, Guerzoni S, Cainazzo MM, et al. Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial. J Headache Pain. 2012;13(8):677-684. doi:10.1007/s10194-012-0490-1 [doi]
  164. Nicolodi M, Sandoval V, Terrine A. Therapeutic use of cannabinoids – Dose Finding, Effects, and Pilot Data of Effects in Chronic Migraine and Cluster Headache. Abstract presentation at 3rd Congress of the European Academy of Neurology (EAN), Amsterdam, 6/24/17. In: 3rd Congress of the European Academy of Neurology (EAN), Amsterdam 6/24/17. Amsterdam.
  165. Committee of the Health Effects of Marijuana: An Evidence Review and Research. The Health Effects of Cannabis and Cannabinoids. The Current State of Evidence and Recommendations For Research.Washington, DC: The National Academies Press.; 2017.
  166. Moulin D, Boulanger A, Clark AJ, et al. Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society. Pain Res Manag. 2014;19(6):328-335.
  167. Russo EB. Cannabidiol Claims and Misconceptions. Trends Pharmacol Sci. 2017;38(3):198-201. doi:10.1016/j.tips.2016.12.004
  168. Pisanti S, Malfitano AM, Ciaglia E, et al. Cannabidiol: State of the art and new challenges for therapeutic applications. Pharmacol Ther. 2017;175:133-150. doi:S0163-7258(17)30065-7 [pii]
  169. White CM. A Review of Human Studies Assessing Cannabidiol’s (CBD) Therapeutic Actions and Potential. J Clin Pharmacol. 2019;59(7):923-934. doi:10.1002/jcph.1387
  170. Palmieri B, Laurino C, Vadala M. Short-Term Efficacy of CBD-Enriched Hemp Oil in Girls with Dysautonomic Syndrome after Human Papillomavirus Vaccination. Isr Med Assoc J. 2017;19(2):79-84.
  171. Cunetti L, Manzo L, Peyraube R, Arnaiz J, Curi L, Orihuela S. Chronic Pain Treatment With Cannabidiol in Kidney Transplant Patients in Uruguay. Transplant Proc. 2018;50(2):461-464. doi:10.1016/j.transproceed.2017.12.042
  172. Wade DT, Robson P, House H, Makela P, Aram J. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms. Clin Rehabil. 2003;17(1):21-29.
  173. Philpott HT, O’Brien M, McDougall JJ. Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Pain. 2017;158(12):2442-2451. doi:10.1097/j.pain.0000000000001052
  174. Hammell DC, Zhang LP, Ma F, et al. Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis. Eur J Pain. 2016;20(6):936-948. doi:10.1002/ejp.818
  175. Malfait AM, Gallily R, Sumariwalla PF, et al. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci U S A. 2000;97(17):9561-9566. doi:10.1073/pnas.160105897 [doi]
  176. Costa B, Colleoni M, Conti S, et al. Oral anti-inflammatory activity of cannabidiol, a non-psychoactive constituent of cannabis, in acute carrageenan-induced inflammation in the rat paw. Naunyn Schmiedebergs Arch Pharmacol. 2004;369(3):294-299. doi:10.1007/s00210-004-0871-3 [doi]
  177. World Health, Organization: Expert Committee on Drug Dependence. Cannabidiol (CBD) Pre-Review Report. http://www.who.int/medicines/access/controlled-substances/5.2_CBD.pdf.
  178. (WADA) WA-DA. “Prohibited List: January 2018”. The World Anti-Doping Code International Standard. https://www.wada-ama.org/sites/default/files/prohibited_list_2018_en.pdf.
  179. Garber-Paul E. Exclusive: New Report Predicts CBD Market Will Hit $22 Billion by 2022. Roll Stone. September 2018.
  180. Kovacevich N. With CBD, Cannabis Wellness Market Goes Big. Forbes. March 2019. https://www.forbes.com/sites/nickkovacevich/2019/03/06/with-cbd-cannabis-wellness-market-goes-big/#1591fba63fcb.
  181. Velasquez-Manoff M. Can CBD Really Do All That? How one molecule from the cannabis plant came to be seen as a therapeutic cure-all. New York Times. https://www.nytimes.com/interactive/2019/05/14/magazine/cbd-cannabis-cure.html. Published May 14, 2019.
  182. Williams A. Why is CBD Everywhere? New York Times. https://www.nytimes.com/2018/10/27/style/cbd-benefits.html. Published October 27, 2018.
  183. Schiller M. CVS and Walgreens Plan to Carry CBD Products: What’s Next for the Rapidly Growing Market? Cannabis Bus Times. April 2019. https://www.cannabisbusinesstimes.com/article/cvs-walgreens-carry-cbd-products-whats-next-for-market/.

 

Read More

Last updated on April 9th, 2021 at 12:43 am

UBRELVY (UBROGEPANT) vs. NURTEC ODT (RIMEGEPANT) vs. REYVOW (LASMIDITAN) vs. TRIPTANS. NEW MIGRAINE ABORTIVE OPTIONS ARE FINALLY HERE, BUT WHAT ARE THE DIFFERENCES AND IS ONE BEST FOR YOU?

@Neuralgroover

BACKGROUND

Ubrelvy vs. Nurtec, Ubrelvy vs. triptans, Nurtec vs. triptans, Ubrelvy vs. Reyvow, Nurtec vs. Reyvow, Reyvow vs. triptans, Rimegepant vs. Ubrogepant, Ubrogepepant vs. triptans, Rimegepant vs. triptans, Lasmiditan vs. Ubrelvy, Nurtec vs. Lasmiditan, Lasmiditan vs. triptans, Ubrogepant vs. Lasmiditan, Rimegepant vs. Lasmiditan. How do you know which one to pick??? Let’s discuss how to pick the best one for you.

 

First off, these medications are all migraine specific abortive/acute (as needed) options. 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. This is in contrast to migraine preventive treatments which are a continuous treatment. Preventive treatments include a daily pill, a monthly/quarterly treatment such as CGRP monoclonal antibodies (Aimovig, Ajovy, Emgality, Vyepti), or neuromodulation devices. The goal of migraine preventive treatment is to lessen the frequency and/or severity of migraine attacks, and these options are discussed in more detail here. 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.

 

Since the development and availability of sumatriptan in 1992, the primary migraine specific abortive/acute (as needed) option available has been the triptans. Triptans (Imitrex, Maxalt, etc.) work great for a lot of people. However, about 30% of patients do not respond to triptans. Others cannot tolerate side effects, or they cannot use them because of medical contraindications (such as coronary artery disease, peripheral artery disease, cerebrovascular disease, stroke, etc.). Triptans are also contraindicated in patients with visual snow, persistent migraine aura, and migrainous stroke (infarction). They have been historically contraindicated in hemiplegic migraine or basilar migraine (now called migraine with brainstem aura) due to theoretical concerns of vasoconstriction potentially causing stroke. When the triptan studies were done previously, they excluded patients with these forms of migraine due to the ongoing vascular theory of migraine at that time. The vascular theory of migraine assumed that vasoconstriction and lack of blood flow was the cause of aura and neurologic features with migraine. So the thinking was that if you cause further vasoconstriction with a triptan, you may cause stroke. However, we now know that these phenomenon are primarily of an electrical basis and not a vascular basis. Therefore many specialists have gotten more liberal with the use of triptans in patients with hemiplegic or basilar migraine, and there have been a number of case series and case reports of these patients using triptans without any problems.

 

The alternatives to triptans have historically been the ergots (ergotamine, DHE) which can be complicated to use, tend to have an excess of side effects for many, and have the same medical contraindications as triptans. NSAIDs and over the counter analgesics are also commonly used, although many do not respond to or cannot take them due to other medical conditions. Even worse are opiates/opioids and butalbital medications such as fioricet, both of which (as do excess triptans, NSAIDS, OTCs) have a high risk of leading to medication overuse headache (rebound headache), as discussed here.  For close to 3 decades, these have remained the only limited options of acute/abortive migraine treatment, despite migraine being such a widespread common disorder! More recently, neuromodulation devices have also become available as abortive options.

 

Thankfully, these limited options have now expanded to 3 new migraine abortive options in adults between 2 new classes which became available commercially in 2020; the gepants and the ditans. These medications can be used SAFELY in all of the medical contraindications mentioned above! These 3 new abortive medications are compared and contrasted with one another, as well as with the triptans in the table which I constructed below.

 

GEPANTS

The gepants were the first to emerge as new migraine abortive options, first with Ubrogepant (Ubrelvy) which became available from Allergan in January 2020 and then Rimegepant (Nurtec ODT (orally dissolvable tablet)) became available by Biohaven in February 2020.

 

During a migraine attack, the trigeminal nerves release a variety of inflammatory proteins. One of the main proteins is called CGRP (calcitonin gene related peptide). CGRP causes inflammation around the brain and cerebral arteries (“sterile inflammation”) in the dural membrane surrounding the brain, intensified pain signals, enhanced transmission of pain signals through the trigeminal nerves into the brainstem and into the brain, and dilation of the cerebral arteries through the dural membrane, which in turn leads to further increasing pain signals via the trigeminal nerve endings covering the cerebral arteries. The result is intense migraine pain (as you are unfortunately very familiar with). So, if we can block these steps of migraine pain, the attack should be aborted quickly, and not as severe. That’s the thinking here, and that’s where the CGRP medications (gepants and CGRP monoclonal antibodies) come into play.

 

Gepants work as CGRP receptor antagonists, which means they directly target and block (antagonist) the CGRP receptor. This results in the medication “blocking” the CGRP inflammatory protein from sticking to the CGRP receptor to activate it, and thus prevents it from “turning on” these pathways of pain. So, you get reversal of cerebral vasodilation, which decreases the firing off of the trigeminal nerves. Notably, the gepants do this in a way that does not cause vasconstriction, in contrast to the triptans. Thus, they are felt to be safe in those with cardiovascular or cerebrovascular disease (as opposed to the triptans). By blocking the CGRP receptor, you also get reversal of the neurogenic inflammation going on through the brain and around the arteries, and you block the electrical transmission of migraine pain from traveling from the trigeminal nerves into the brainstem, and ultimately into the brain.

 

The side effect profile of the gepants is minimal and similar to placebo compared to the triptans and their alternatives.  This is really great to have new options with much less side effect potential. In addition, there is no interaction with using them and triptans, NSAIDs, or other acute meds in case they happen to be taken close together. These medications are not associated with addiction potential, and do not cause medication overuse headache (rebound), which is great! Compared to the triptans and ergots, these medications are NOT contraindicated in patients with stable cardiovascular or peripheral vascular disease or risk factors because they do not cause vasoconstriction (narrowing) of the arteries, which is a HUGE benefit. There are many patients who have been stuck in limbo unable to use standard therapies such as triptans due to other medical problems such as heart disease, so we finally have a safe alternative for them, which is another highlight of these medications. Safety of these medications in pregnancy or breastfeeding is unknown because they haven’t been studied, and therefore are not recommended. The primary drug interactions to be aware of with these medications are when used with other medications that are metabolized by the liver enzyme system called CYP3A4. Many commonly used medications are metabolized by this system. Strong or moderate inhibitors of CYP3A4 (which slow down the metabolism activity) will cause an increase in gepant exposure. Strong or moderate inducers of CYP3A4 (which increase the metabolism activity) will cause a decrease in gepant exposure and possibly decreased effectiveness. These medications should be avoided in patients with severe liver disease or end stage kidney disease such as those on dialysis.

 

Many patients use once monthly CGRP antagonist monoclonal antibody (mAbs) self-injections (autoinjection devices) which are FDA approved for migraine prevention (Aimovig (Erenumab), Ajovy (Fremanezumab), Emgality (Galcanezumab), and Vyepti (Eptinezumab), which is a once quarterly 30 minute IV infusion). The CGRP mAbs are discussed in much greater detail and compared with one another here. These have little to no drug interactions and do not affect the liver or kidneys. However, patients often ask if these medications can be used with the gepants given similar mechanisms of action (although much different structure, molecule size, and metabolism). Further confirmatory research is needed, but it is theorized that these medicines can likely be used safely together, and they are metabolized by completely different mechanisms. The gepants are metabolized in the liver, while the CGRP mAbs are metabolized and cleared in the reticuloendothelial system. Furthermore, there is limited evidence suggesting that they may even provide a synergistic effect by working together, but more evidence is needed to confirm this. An insurance battle often ensues when trying to use the large molecule preventive CGRP mAbs with the small molecule abortive gepant medications (Nurtec, Ubrelvy), which also work by a CGRP mechanism. Insurance companies will often not allow these to be used together, despite no good scientific basis. Actually, there is some limited evidence showing that these medications can work synergistically together, which would make sense when taking their mechanisms of action into account. Specifically, there was a publication of data from only a 2-patient cohort showing that the use of these acute and preventive CGRP migraine therapies together can be successful and safe. These two patients had been using rimegepant (Nurtec) in a long-term safety study and had added erenumab (Aimovig). The combination of both successfully aborted 100% of their acute migraine attacks. Certainly we need need larger studies to confirm the suspicion that they likely work together synergistically.

 

Given that Ubrelvy and Nurtec ODT are of the same gepant class, they each have their own marketing pitch to differentiate them, although the bottom line is that they are both excellent options. Although they are both very effective for most patients, I commonly see patients who may respond to one better than the other. So if one of them does not help, it is worth trying the other one as well.

 

Ubrelvy (Ubrogepant)

Allergan markets Ubrelvy as quickly relieving migraine pain within 2 hours with just one dose, and that complete elimination of migraine pain with one dose is possible. Furthermore, they highlight that they provide the option of being able to repeat a 2nd dose if needed (similar to how triptans are dosed), with a higher proportion of patients achieving pain freedom 2 hours after taking the optional second dose. They also claim effective relief whether Ubrelvy was taken right away at migraine onset or within 4 hours. The half life is 5-7 hours, so duration of effect is extended compared to many options that we had up to this point. The clinical data highlights of Ubrelvy are that at 1 hour Ubrelvy 50 mg becomes statistically superior to placebo for pain relief, and at 2 hours the 100 mg dose also becomes statistically superior to placebo for pain relief. At 2 hours, both the 50 mg and 100 mg doses become statistically superior to placebo for pain freedom as well as freedom from most bothersome migraine symptom (nausea, photophobia or phonophobia). These benefits could extend into 24 and even 48 hours. In patients who received pain relief with the 1st dose and took an optional 2nd dose of 50 mg, 55% went on to become pain free 2 hours from that point.

Side effects were similar to placebo and the most common were nausea (placebo 2%, Ubrelvy 50 mg 2%, Ubrelvy 100 mg 4%), and somnolence (sleepiness) (placebo 1%, Ubrelvy 50 mg 2%, Ubrelvy 100 mg 3%).

They currently have a savings card program which should work with commercial insurances for $10 per month, which works out to $1 per pill (10 pills per month). You can get a digital copy of this savings card on your phone to show to the pharmacist if you text UBRELVY to 48764.

 

Nurtec ODT (Rimegepant)

Biohaven boasts that Nurtec ODT 75 mg dissolves under or on the tongue in seconds, and starts working in minutes (15 minutes in some patients). They highlight that it does not require water or other liquids to take with the dose, so it can be taken anytime and anywhere. It is taken as a simple single strength single dose. They also point out that pain relief and pain freedom lasts up to 48 hours for many patients, which makes sense because it has the longest half-life (11 hours). The clinical data highlights of Nurtec ODT are that at 15 minutes, you get separation from placebo of both pain relief and return to normal function (but not yet statistically superior). At 1 hour, pain relief and return to normal function become statistically superior to placebo. At 1.5 hours, you get additional statistical superiority over placebo of pain freedom and freedom from most bothersome migraine symptom (nausea, photophobia or phonophobia). For the vast majority of patients, the superiority of all of these trial endpoints over placebo remain sustained through 48 hours.

Side effects were similar to placebo and the most common was nausea (placebo 0.4%, Nurtec 2%).

They currently have a savings card program which should work with commercial insurances for $0 per month (8 pills per month). You can get a digital copy of this savings card on your phone to show to the pharmacist if you text NSAVE to 26789.

Notably, Biohaven submitted a request to the FDA in October 2020 to approve Rimegepant as a preventive migraine treatment as discussed further here, 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.

 

DITANS

Reyvow (Lasmiditan)

The ditans are another new class of migraine abortive, premiering with Lasmiditan (Reyvow) in January 2020 from Eli Lilly. Lasmiditan acts as a high affinity 5-HT1F (serotonin 1F) receptor agonist. The result of its action is a decrease in the release of inflammatory pain producing neurotransmitters and neuropeptides including CGRP from the trigeminal nerves during a migraine attack. These receptors are also involved in modulating other pain signals and blocking (inhibiting) other pain pathways. Notably, like the gepants, they also do not cause arterial vasoconstriction. Again, this is a tremendous benefit and another great option in patients who may not be able to use triptans due to medical contraindications such as coronary or peripheral vascular disease. Caution should be used with other serotonergic drugs given a potential for serotonin syndrome, which was reported in clinical trials.

Similar to the gepants, the Reyvow clinical data highlights showed superiority over placebo at trial endpoints of 2 hour pain freedom, freedom from most bothersome migraine symptom (nausea, photophobia or phonophobia), and pain relief.

In a driving study, 50 mg, 100 mg, or 200 mg doses of Lasmiditan significantly impaired subjects’ ability to drive, and more sleepiness was reported at 8 hours following a single dose compared to placebo. Therefore, patients should wait at least 8 hours between dosing and driving or operating machinery. This can certainly be a drawback in terms of being a treatment option for many patients as the goal of abortive therapy is partly to be able to maintain and restore function in order to not disrupt work, plans, etc. However, if you are in a position where this would not be an issue for you, it could certainly be a valid option to have in your migraine war chest. It should also be used with caution in combination with alcohol or other central nervous system depressants.

Notably, Lasmiditan is a Schedule V controlled substance compared to the other abortive options. Schedule V represents the lowest abuse potential category from the DEA. The reason is because in a human abuse potential study, doses of 100 mg, 200 mg, and a supratherapeutic dose of 400 mg were associated with statistically significantly higher “drug liking” scores than placebo, indicating possible abuse potential. However, it had statistically significantly lower “drug liking” scores compared to alprazolam 2 mg. Lasmiditan also produced adverse events of euphoria and hallucinations to a greater extent than placebo, although it was a low frequency (about 1% of patients). They currently have a savings card program which should work with commercial insurances for $0 per month (4 pills per month).

 

SUMMARY

The chart below compares and contrasts the treatment outcomes data between Rimegepant, Ubrogepant, Lasmiditan, and Sumatriptan (as representative of the triptan class since it was the first developed). The source of the data comes from the key trials of each medication, as well as some data obtained directly from the pharmaceutical companies. It’s important to note that the trials for each medication did not all include the same data point evaluations, so not all of the comparison data is available across the medications to compare. Also, this data is not reflective of head to head trials between these medications. The data is derived from separate independent trials, many times of which there were variations in study design and endpoints. So, they should not be thought of as head to head comparisons necessarily. In addition, the original triptan studies did not include many of the treatment outcome data points that have become more commonly used since they were developed such as 8 hour data, 2-48 hour data, most bothersome symptom, etc. Therefore, many of these data points within the columns of the different medications may be labeled by N/A (not available).

 

Overall, these are all very effective and useful medications to keep in mind for your migraine abortive war chest. They are all a welcome and much needed option for the abortive (acute) treatment of migraine. Notably, Ubrelvy, Nurtec ODT, and Reyvow were all proven to be statistically superior to placebo at 2 hours post-dose (some sooner) in terms of pain freedom, pain relief, and freedom from most bothersome migraine symptom (nausea, sensitivity to light (photophobia) or sensitivity to sound (phonophobia)). So there is no “bad” option. Many of the data points are fairly similar with some slight variations, and some data points weren’t compared. Regardless, I have highlighted some of the key differences to take note of in bold print. I hope this data can provide some guidance on some of the differences in these medications which may help to better select them based on the treatment goals, setting of use, and other patient characteristics.

 

Rimegepant Ubrogepant Lasmiditan Sumatriptan (100 mg)
Class Gepant Gepant Ditan Triptan
Mechanism of Action CGRP receptor antagonist CGRP receptor antagonist 5HT1F agonist 5HT1B and 5HT1Dagonist
Available dosing 75 mg orally dissolvable tablet 50 mg, 100 mg pill 50 mg, 100 mg, 200 mg (100 mg x 2) pill 25 mg, 50 mg, 100 mg pill; 3 mg, 4 mg, 6 mg injection; 5 mg, 10 mg, 20 mg nasal spray
Max dose per 24 hours 75 mg 200 mg 200 mg 200 mg
Pills per prescription (standard, may be more depending on insurance) 8 10 8 9
Dosing frequency 1 dose/24 hours Dose can repeated once in 2 hours; 2 doses/24 hours 1 dose/24 hours Dose can repeated once in 2 hours; 2 doses/24 hours
Suggested number of migraine attacks treated per 30 days 15 (however, currently also being studied as a daily preventive) 8 4 10
Time to reach statistically significant pain relief 60 minutes (however, there was a 15 minute measured clinical beneficial effect) 60 minutes with 50 mg or higher doses 30 minutes with 100 mg or higher doses;

60 minutes with 50 mg dose

30 minutes with 50 mg or higher doses
1 hour significant pain relief 37%

31% (placebo)

43% (50 mg)

N/A (100 mg)

36.7% (placebo)

37.3% (50 mg)

»41% (100 mg)

»46% (200 mg)

30.6% (placebo)

20-35% (100 mg)

12-21% (placebo)

Differences in pain relief at 15 minutes 8%

5% (placebo)

N/A N/A N/A
Differences in pain relief at 30 minutes 19%

17% (placebo)

19% (50 mg)

N/A (100 mg)

20% (placebo)

»15% (50 mg)

17.5% (100 mg)

19.1% (200 mg)

13.4% (placebo)

11% (100 mg)

12% (placebo)

2 hour pain relief 59%

43% (placebo)

61.7% (50 mg)

61.4% (100 mg)

48.7% (placebo)

59% (50 mg)

59.4-64.8% (100 mg)

59.5-65% (200 mg)

42.2-47.7% (placebo)

46-67% (100 mg)

18-44% (placebo)

2 hour pain freedom 21%

11% (placebo)

20.5% (50 mg)

21.2% (100 mg)

13% (placebo)

28% (50 mg)

28-31% (100 mg)

32-39% (200 mg)

15-21% (placebo)

22-33% (100 mg)

3-13% (placebo)

8 hour pain freedom with 1 dose 56%

33% (placebo)

82.3% (50 mg)

82.7% (100 mg)

69.8% (placebo)

N/A N/A
8 hour pain relief with 1 dose 74%

56% (placebo)

92% (50 mg)

N/A (100 mg)

82% (placebo)

N/A N/A
% of patients with 1st dose pain relief who achieved pain freedom after 2nddose N/A 54.7% (50 mg/50 mg)

33.3% (50 mg/placebo)

51.6% (100 mg/100 mg)

33.3% (100 mg/placebo)

N/A N/A
Sustained pain freedom 2-24 hours 15.7%

5.6% (placebo)

13.6% (50 mg)

15.4% (100 mg)

8.4% (placebo)

17.2% (50 mg)

14.8-17.9% (100 mg)

18.6-22.7% (200 mg)

7.6-13.4% (placebo)

N/A
Sustained pain relief 2-48 hours 47.8%

27.7% (placebo)

31.5% (50 mg)

34% (100 mg)

17.5% (placebo)

N/A N/A
2 hour absence of most bothersome migraine symptom 35%

27% (placebo)

38.7% (50 mg)

37.7% (100 mg)

27.6% (placebo)

41% (50 mg)

41-44% (100 mg)

41-49% (200 mg)

30-33% (placebo)

N/A
8 hour absence of most bothersome migraine symptom N/A 90.9% (50 mg)

92.4% (100 mg)

77.7% (placebo)

N/A N/A
Time to peak plasma concentration TMAX 1.5 hours 1.5 hours 1.8 hours 1.5-2.5 hours
½ life 11 hours 5-7 hours 5.7 hours 2-2.5 hours
Time to reach pharmacologically active concentration 15 minutes Within 11 minutes N/A N/A
Time the pharmacologically active concentration is maintained 48 hours 12 hours N/A N/A
Notable side effects Nausea

2%

0.4% (placebo)

Nausea

2% (50 mg)

4% (100 mg)

2% (placebo)

 

Somnolence/Sedation

2% (50 mg)

3% (100 mg)

1% (placebo)

Nausea

3% (50 mg)

4% (100 mg)

4% (200 mg)

2% (placebo)

 

Somnolence/Sedation

6% (50 mg)

6% (100 mg)

7% (200 mg)

2% (placebo)

 

Dizziness

9% (50 mg)

15% (100 mg)

17% (200 mg)

3% (placebo)

 

Paresthesias

3% (50 mg)

7% (100 mg)

9% (200 mg)

2% (placebo)

Widely variable, most common: Dizziness, fatigue, paresthesias, sedation, nausea, palpitations, anxiety, muscle tightness sensation in chest/neck/throat

 

IF YOU HAVE HEADACHE, MIGRAINE, OR FACIAL PAIN AND ARE LOOKING FOR ANSWERS ON ANYTHING RELATED TO IT, A HEADACHE SPECIALIST IS HERE TO HELP, FOR FREE!

FIRST, LET’S DECIDE WHERE TO START:

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR THE LATEST INFORMATION, HOT TOPICS, AND TREATMENT TIPS, VISIT OUR FREE BLOG OF HOT TOPICS AND HEADACHE TIPS HERE. THIS IS WHERE I WRITE AND CONDENSE A BROAD VARIETY OF COMMON AND COMPLEX  MIGRAINE AND HEADACHE RELATED TOPICS INTO THE IMPORTANT FACTS AND HIGHLIGHTS YOU NEED TO KNOW, ALONG WITH PROVIDING FIRST HAND CLINICAL EXPERIENCE FROM THE PERSPECTIVE OF A HEADACHE SPECIALIST.

 

IF YOU DON’T HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR POSSIBLE TYPES OF HEADACHES OR FACIAL PAINS BASED ON YOUR SYMPTOMS, USE THE FREE HEADACHE AND FACIAL PAIN SYMPTOM CHECKER TOOL DEVELOPED BY A HEADACHE SPECIALIST NEUROLOGIST HERE!

 

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR FURTHER EDUCATION AND SELF-RESEARCH ON YOUR DIAGNOSIS, VISIT OUR FREE EDUCATION CENTER HERE.

 

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING TO ASK QUESTIONS TO A HEADACHE SPECIALIST OR OTHER HEADACHE, MIGRAINE, AND FACIAL PAIN WEBSITE MEMBERS, VISIT OUR FREE DISCUSSION FORUMS HERE.

 

Read More

Last updated on April 12th, 2021 at 11:40 am

WHAT ARE THE TRIPTAN DIFFERENCES AND WHICH IS BEST? HOW TO FINE-TUNE WHICH TRIPTAN MAY BE MOST EFFECTIVE FOR YOU.

@Neuralgroover

BACKGROUND:

Imitrex vs. Maxalt, Zomig vs. Maxalt, Amerge vs. Relpax, Frova vs. Imitrex, Maxalt vs. Relpax, Zomig vs. Imitrex, Frova vs. Amerge, Imitrex vs. Treximet. Maxalt vs. Frova. Axert vs. Imitrex. These are the triptans for migraine. There are 8 triptan types within the triptans medication class and include Imitrex (Sumatriptan) vs. Maxalt (Rizatriptan) vs. Relpax (Eletriptan) vs. Zomig (Zolmitriptan) vs. Frova (Frovatriptan) vs. Amerge (Naratriptan) vs. Axert (Almotriptan) vs. Treximet (Sumatriptan/Naproxen).

 

So what are the best triptans to use? Well let’s back up a little first. The ergot based medications such as DHE (dihydroergotamine) and cafergot (ergotamine + caffeine) have been the oldest migraine abortive medications used, which are still used today. However, they often have many side effects for patients and eventually the migraine specific triptans were developed for aborting migraine. Since 1992 (when Sumatriptan first became available), the triptans have been the first and only migraine specific abortive medications available up until 2020 when two new classes of migraine specific abortive medications have FINALLY become available with the gepants (Ubrelvy, Nurtec) and ditans (Reyvow). These new migraine abortive medications can be read about in more detail here.

 

The first triptan developed was sumatriptan in 1991 and since that time there have been a total of 8 triptan options to choose from. So how do the triptans work? They work by activating (agonist) the serotonin sub-receptor 5-HT1B. The result of activating this receptor is that it helps to constrict (narrow) the dilated inflamed pain-producing meningeal blood vessels which occurs during a migraine attack. The 5-HT1B receptors are also present in the brainstem, and likely play a role in modulating the electrical event of a migraine. Triptans also work by activating (agonist) the serotonin sub-receptor 5-HT1D. The result of activating this receptor is that they stop the trigeminal nerves from releasing a variety of inflammatory proteins around the brain and blood vessels which normally leads to pain during a migraine attack. This also interferes with normal pain processing between the brainstem and the brain (helps to block this electrical transmission), and it helps to block the nausea and vomiting centers in the brainstem. Triptans help to normalize levels of and decrease the release of a very inflammatory protein released during a migraine called CGRP (calcitonin gene related protein). Triptans also inhibit mast cell degranulation in the dural membranes, which also lessens the sterile inflammation which occurs during a migraine.

 

SIDE EFFECTS OF TRIPTANS AND CONTRAINDICATIONS:

Most patients tolerate triptans very well, however, many patients have side effects and discontinue them. So let’s discuss triptans side effects. Just like any medicine, some patients may have more side effects than others. Furthermore, about 30% of patients with migraine may not respond to triptans (triptan non-responder). If side effects do occur, there is some variability between the different types of triptans. Potential side effects of the triptans include palpitations or racing heart beat, nausea, tingling, numbness or flushing in the face or extremities, drowsiness, fatigue, dizziness, and tightness or pressure in the chest, neck, or jaw. Although the chest pressure is not common, it is of a muscular and not a non-cardiac (heart) cause. However, it can be scary if you don’t know about this potential side effect.

 

With that said, triptans can cause a mild degree of artery constriction (narrowing) due to its activity at the 5-HT1B receptor as discussed above. This could theoretically occur in narrowed arteries from cholesterol build up, such as in the heart. Therefore, triptans should not be used in patients who have coronary artery disease, cerebrovascular disease (stroke), peripheral arterial disease, or uncontrolled risk factors for these diseases (high blood pressure, cholesterol, diabetes, smoking, family history of early heart disease) because chest pain for them could truly represent heart attack. If there is concern for the possibility of underlying cardiovascular disease, a cardiac stress test should be performed prior to triptan prescription.

 

Triptans are also considered to be contraindicated in patients with visual snow, persistent migraine aura, and migrainous stroke (infarction) due to theoretical concerns of vasoconstriction potentially causing stroke. This contraindication has historically also included hemiplegic migraine and basilar migraine (now called migraine with brainstem aura). When the triptan studies were done previously, they excluded patients with these forms of migraine due to the ongoing vascular theory of migraine at that time. The vascular theory of migraine assumed that vasoconstriction and lack of blood flow was the cause of aura and neurologic features with migraine. So the thinking was that if you cause further vasoconstriction with a triptan, you may cause stroke. However, we now know that these phenomenon are primarily of an electrical basis and not a vascular basis. Therefore many specialists have gotten more liberal with the use of triptans in patients with hemiplegic or basilar migraine, and there have been a number of case series and case reports of these patients using triptans without any problems. However, larger confirmatory studies would be preferable.

 

Patients that can not use triptans due to side effects, or if they have any of these medical contraindications noted above, should consider one of the newer types of migraine abortive medications available with either the gepants (Ubrelvy, Nurtec), ditans (Reyvow) or neuromodulatory devices. Ubrelvy, Nurtec, and Reyvow are not triptans. These newer options often have a much lower side effect profile, can be taken in the setting of these medical contraindications to triptans mentioned above, and work by an entirely different mechanism of action.

 

It is also important to know that triptans can cause medication overuse headache (rebound headache) if used consistently greater than 10 days per month on average. The result is that the headache continues to worsen in frequency and/or severity. This also happens with NSAIDs, over the counter pain meds, and other types of as-needed pain medications. The phenomenon of rebound headache is discussed in much greater detail here. Notably, the gepants (Ubrelvy, Nurtec) do not cause rebound headache. If triptans, or any migraine abortive medication, is having to be used at this high frequency, a preventive migraine treatment should be used until the migraine and headache frequency is significantly improved consistently for several months. This can be done with a variety of medications which may also include the CGRP monoclonal antibody (mAb) treatments (Aimovig, Ajovy, Emgality, Vyepti), Botox, natural supplements, herbals and vitamins, or neuromodulatory devices.

 

TRIPTAN SELECTION:

Triptans are all similar in mechanism of action. However, there are many differences between the triptans drugs which allow them to be tailored and fine-tuned towards different types of migraine characteristics, as discussed below. This is a very important clinical point that is almost always overlooked by most physicians prescribing these medications if they are not headache specialists. Tailoring triptans to specific migraine characteristics can make a dramatic difference in its effectiveness since triptans are not all one in the same medication. The information below can be discussed with your doctor to hopefully get a better response to your triptan therapy.

 

LIST OF TRIPTANS:

-Sumatriptan: oral, subcutaneous injection, needle-less subcutaneous injection, nasal spray, breath-powered intranasal delivery system
-Zolmitriptan: oral, orally dissolvable tablet, nasal spray
-Rizatriptan: oral, orally dissolvable tablet
-Almotriptan: oral
-Eletriptan: oral
-Sumatriptan/Naproxen: oral
-Frovatriptan: oral
-Naratriptan: oral

GROUP 1 TRIPTANS:

-Faster onset of action, higher potency (thus can have higher side effect potential), tend to have a higher 24-hour migraine recurrence
-Sumatriptan, Sumatriptan/Naproxen, Zolmitriptan, Rizatriptan, Almotriptan, Eletriptan

 

GROUP 2 TRIPTANS:

-Slower onset of action, lower potency (thus often have lower side effect potential), lower 24-hour migraine recurrence since the duration of action is longer:
-Frovatriptan, Naratriptan

 

FINE-TUNING YOUR TRIPTAN CHOICE: (Remember the mnemonic CORN, and this will help to narrow down the best triptan to consider):

Contraindications
Onset to peak pain
Recurrence of migraine after treatment
Nausea and vomiting severity

Contraindications: This is not an exhaustive list, but are the most common. Your doctor should be well aware of when triptans should not be used.
-Known vascular disease (coronary artery disease, peripheral vascular disease, history of stroke)
-Vascular risk factors (poorly controlled hypertension, hyperlipidemia, diabetes, smoking, premature family history of coronary artery disease (men less than age 55, women less than age 65), postmenopausal women, etc.
-Kidney or liver failure
-Prinz-Metal angina

 

Onset to migraine peak pain:
-Group 1 triptan (quicker onset) is generally much more useful than a Group 2 triptan (slower onset).
-A subcutaneous injection or nasal spray triptan will typically be most helpful if:
-Patient wakes with migraine already ongoing (waking migraine)
-Migraine hits its peak pain level within 30 minutes or so

 

Return of migraine after treatment:
-If migraine recurrence occurs within 24 hours (for example it goes away with the triptan, but keeps returning later in the day or the next day), or the migraine is usually multiple consecutive days long (such as menstrual migraine):
-Combine the 1st dose of the triptan with an NSAID (such as Naproxen)
-Use a group 2 triptan (Naratriptan vs. Frovatriptan)

 

Nausea and vomiting severity:
-If nausea and vomiting occur early in the attack, or are severe to where it is hard to keep a pill down without vomiting it back up:
-A subcutaneous injection or nasal spray triptan should be used.
-Of note, dissolvable triptan tablets are still absorbed by the gastrointestinal tract, not sublingually. So, vomiting will still make this route ineffective, similar to a regular pill.

 

TRIPTAN PEARLS IN FURTHER FINE-TUNING TRIPTAN CHOICES:

Sumatriptan:
-Highest potency (in subcutaneous form) and quickest onset (subcutaneous > nasal spray) of triptans
-Greatest flexibility is dosing route options

Rizatriptan:
-Fastest onset of oral triptans
-Greatest likelihood of 2h pain-free and sustained pain-free response
-Propranolol increases its serum concentration, so 5mg per dose should be if used together

Zolmitriptan:
-Most likely to treat persistent headache when 1st dose fails

Almotriptan:
-The group 1 triptan with the least side effects

Eletriptan:
-Highest potential for drug interactions. Decrease dosage with CYP3A4 drugs such as macrolides, fungal, HIV, etc.

Naratriptan:
-The “gentle triptan” with the least side effects given its slower onset of action
-Low 24 hour migraine recurrence rate
-Good choice to give shortly prior to an expected and known migraine trigger (menstruation, air travel, etc.)
-Does not have monoamine oxidase metabolism, so it can be given with MAOI (as can Eletriptan and Frovatriptan)

Frovatriptan:
-Low side effect potential given its slower onset of action
-Longest half life
-Low 24 hour migraine recurrence rate
-Good choice to give shortly prior to an expected and known migraine trigger (menstruation, air travel, etc.)

 

CONCLUSIONS:

The triptans were and have been a game changer for millions of migraine patients in aborting migraine attacks. Using the highest available triptan dose is also generally recommended to see the full effect. We see many patients who have “failed triptans”, but on further history they were put on very low doses (such as 25 mg sumatriptan, when 100 mg is the standard dose). Even so, about 30% of migraineurs do not respond to triptans, only 1/3rd are pain-free at 2 hours, and only 17-25% remain pain-free at 24 hours. Therefore, although the majority respond well to triptans, not everyone does. Luckily, there are other medication options including two brand new classes of migraine abortive medications (gepants, ditans), and these are detailed here.

 

IF YOU HAVE HEADACHE, MIGRAINE, OR FACIAL PAIN AND ARE LOOKING FOR ANSWERS ON ANYTHING RELATED TO IT, A HEADACHE SPECIALIST IS HERE TO HELP, FOR FREE!

FIRST, LET’S DECIDE WHERE TO START:

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR THE LATEST INFORMATION, HOT TOPICS, AND TREATMENT TIPS, VISIT OUR FREE BLOG OF HOT TOPICS AND HEADACHE TIPS HERE. THIS IS WHERE I WRITE AND CONDENSE A BROAD VARIETY OF COMMON AND COMPLEX  MIGRAINE AND HEADACHE RELATED TOPICS INTO THE IMPORTANT FACTS AND HIGHLIGHTS YOU NEED TO KNOW, ALONG WITH PROVIDING FIRST HAND CLINICAL EXPERIENCE FROM THE PERSPECTIVE OF A HEADACHE SPECIALIST.

 

IF YOU DON’T HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR POSSIBLE TYPES OF HEADACHES OR FACIAL PAINS BASED ON YOUR SYMPTOMS, USE THE FREE HEADACHE AND FACIAL PAIN SYMPTOM CHECKER TOOL DEVELOPED BY A HEADACHE SPECIALIST NEUROLOGIST HERE!

 

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING FOR FURTHER EDUCATION AND SELF-RESEARCH ON YOUR DIAGNOSIS, VISIT OUR FREE EDUCATION CENTER HERE.

 

IF YOU HAVE AN EXISTING HEADACHE, MIGRAINE, OR FACIAL PAIN DIAGNOSIS AND ARE LOOKING TO ASK QUESTIONS TO A HEADACHE SPECIALIST OR OTHER HEADACHE, MIGRAINE, AND FACIAL PAIN WEBSITE MEMBERS, VISIT OUR FREE DISCUSSION FORUMS HERE.

Read More