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100 Migraine Drugs A to Z: propofol

By: Dr. Mauskop

04-06-2020

Chronic migraine, Headache medications, injections, Migraine

Propofol (Diprivan) was originally developed for general anesthesia during surgery. Smaller amounts were found to work well for “conscious sedation” to induce a semiconscious state for minor procedures such as colonoscopies.

In small doses, propofol appears to be effective for the treatment of migraines. A 2019 review of nine studies and case reports showed that “Propofol may be an effective rescue therapy for patients presenting to the ED for acute migraine, but its place in therapy based on the limited available evidence is unknown.”

Propofol was also tested for the emergency room treatment of 66 children with migraines. It was found to be as effective as the standard therapy but those give propofol had a lower rate of headache recurrence within 24 hours.

Propofol is a drug of abuse that was in part responsible for the death of Michael Jackson (it was one of several drugs found in his body). Because it is given only intravenously and is not easy to get, most of the cases of addiction reported occurred in healthcare professionals.

Propofol is administered only intravenously and at anesthetic doses it can have serious side effects such as a drop in blood pressure. However, it appears very safe for conscious sedation and is probably even safer at small doses used for migraines.

It should be considered when a patient does not respond to other intravenous therapies such as ketorolac, metoclopramide, and dihydroergotamine.

I’ve tried Ubrelvy (ubrogepant) and Nurtec ODT (rimegepant)

By: Dr. Mauskop

30-05-2020

Chronic migraine, Headache medications, Migraine, New treatments

My migraines respond very well to sumatriptan, but I do like to try new treatments that I recommend to my patients.

A few months ago two new abortive drugs to treat acute migraine attacks were approved by the FDA. Ubrelvy (ubrogepant) and Nurtec ODT (rimegepant) block CGRP, a substance released during a migraine attack. They work in a similar way to four injectable drugs used for the prevention of migraines – erenumab (Aimovig), fremanezumab (Ajovy), galcanezumab (Emgality), and eptinezumab (Vyepti). I’ve tried erenumab and fremanezumab with some relief, but stopped both because sumatriptan works well and I don’t really need any preventive medications.

Because the two injectable drugs did help, I expected the two new oral medications to work as well. Alas, neither one had any effect. This suggests that CGRP is not very operational in my case. The fact that sumatriptan, a drug that works on serotonin receptors works so well indicates that the serotonin system is dominant in producing my migraines.

Migraine is a very heterogeneous disorder with a variety of clinical presentations and with dozens of identified genetic abnormalities that predispose one to migraines. This means that we are not likely to have a drug that works for all migraine patients. What we do expect, is the advent of personalized medicine – having tests that predict which drug will work for which patient.

100 Migraine Drugs, A to Z: phenelzine

By: Dr. Mauskop

13-05-2020

Chronic migraine, Headache medications, Migraine

Phenelzine (Nardil) is an antidepressant which was approved by the FDA for the treatment of depression in 1961. It belongs to the family of monoamine oxidase (MAO) inhibitors and it is a very effective antidepressant. However, it is rarely used because of its potential to cause side effects and serious drug and food interactions.

There have been no good trials of phenelzine for the treatment of migraines. One small study compared phenelzine with and without a beta blocker, atenolol. Atenolol is known to help migraines and lowers blood pressure, so it could prevent an increase in blood pressure from phenelzine. Phenelzine worked well with and without atenolol. Another report described 11 patients with refractory (not responding to usual drugs) migraines. Ten of the 11 patients had a greater than 50% reduction in the number of headache attacks. Two patients developed low blood pressure and one, high pressure, which was easily controlled. There was also a case report of dramatic improvement in a patient with chronic and treatment-resistant migraines.

Phenelzine can interact with other antidepressants, appetite suppressants, drugs for attention deficit disorder, some epilepsy drugs, muscle relaxants, certain blood pressure medications, some opioid (narcotic) medications, and other. Foods that can interact with phenelzine include aged cheeses, aged/dried/fermented/salted/smoked/pickled/processed meats and fish, fava beans, Italian green beans, broad beans, overripe or spoiled fruits, packaged soups, sauerkraut, red wine, and some other types of alcohol.

An adverse interaction with these drugs and foods can cause a sudden increase in blood pressure or serotonin syndrome, which can be dangerous. However, it does not mean that every drug and food listed above will always cause a serious reaction. Most people will have mild or no reaction at all and if another drug needs to be added to phenelzine, it can be started at a very low dose, and then the dose can be slowly increased.

Besides drug and food interactions, phenelzine has some unpleasant side effects of its own. These include drowsiness, dizziness, constipation, dry mouth, weight gain, sexual dysfunction, and other.

We have many other antidepressants (tricyclics and SNRIs) and other categories of drugs (CGRP drugs, Botox, epilepsy and high blood pressure medications) that are very effective for the prevention of migraines, so phenelzine is almost never used. I prescribe it only after trying many other preventive drugs but it works exceptionally well for a handful of patients for whom no other drug helps.

100 Migraine Drugs, A to Z: ondansetron

By: Dr. Mauskop

06-05-2020

Headache medications, Migraine

Ondansetron (Zofran) is not a migraine drug per se, but it is used for the treatment of nausea that often accompanies a migraine attack. It belongs to a different class of nausea drugs than the older drugs such as prochlorperazine (Compazine), promethazine (Phenergan) or metoclopramide (Reglan). which are effective for both nausea and pain of migraine.

There are no good studies of ondansetron for the treatment of migraines, but the impression of most headache specialists is that it is helpful only for the treatment of nausea of migraine and not the pain. However, one large observational study does suggest that it may help more than just nausea, at least in children. Observational studies are much less reliable than double-blind placebo-controlled ones, however, the large size of this study provides some compensation for this deficiency. The researchers looked at the records of 32,124 children with migraine who presented to the emergency room. One fifth received ondansetron and it was as effective in preventing a return visit to the ER as metoclopramide, while prochlorperazine was a bit more effective.

The advantage of ondansetron is that it does not cause neurological symptoms of restlessness (akathisia) and drowsiness, which can occur with metoclopramide and prochlorperazine.

Ondansetron is available in a tablet, an orally disintegrating tablet, and as an injection, but not as a suppository. Rectal suppositories of prochlorperazine and promethazine work fast and are very useful for patients who are vomiting and cannot hold down a tablet.

100 Migraine Drugs, A to Z: metoclopramide

By: Dr. Mauskop

19-04-2020

Headache medications, injections, Migraine

Metoclopramide (Reglan) is an anti-nausea drug that has been in use since 1979. Controlled studies have shown that metoclopramide stops not only nausea and vomiting that often accompany migraine attacks, but also relieves the pain.

The American Headache Society (AHS) and the European Federation of Neurological Societies (EFNS) guidelines on the management of adults with acute migraine recommend intravenous metoclopramide as an effective and recommended treatment in the management of acute migraine. While intravenous (IV) administration is preferred, intramuscular (IM), subcutaneous (SC) and oral routes are also effective.

These guidelines were based on many high-quality blinded studies such as one comparing 10 mg of IV metoclopramide with 600 mg of ibuprofen in which metoclopramide was clearly superior. A meta-analysis of 13 studies of intravenous metoclopramide involving 655 patients showed that “Metoclopramide is an effective treatment for migraine headache..” and that “Given its non-narcotic and antiemetic properties, metoclopramide should be considered a primary agent in the treatment of acute migraines in emergency departments”. Another emergency room study that was done after this meta-analysis was published, compared IV metoclopramide with IV ketorolac (an NSAID pain drug) and IV valproate, (an epilepsy drug approved in a pill form for the prevention of migraines) in 330 patients. Metoclopramide was the most effective of the three.

We give IV metoclopramide in the office and prescribe it in a tablet form. However, this drug is not free of side effects. Drowsiness is one of the common side effects, but a much more unpleasant side effect is severe restlessness or akathisia. Some patients describe it as wanting to crawl out of their skin, being very restless and very uncomfortable. This side effect can be relieved by diphenhydramine (Benadryl) given IV or as a tablet. According to one study, the incidence of this side effect is 6% if the IV infusion is given over 15 minutes and 25% if given as a “push” in under a minute. We usually give it as a “push” and find that significantly fewer than 20% of patients develop this side effect.

A much more serious side effect of metoclopramide is tardive dyskinesia or involuntary movements of the mouth, face or another part of the body. The FDA warning states in part:
“The development of this condition is directly related to the length of time a patient is taking metoclopramide and the number of doses taken. Those at greatest risk include the elderly, especially older women, and people who have been on the drug for a long time. Tardive dyskinesia is rarely reversible and there is no known treatment. However, in some patients, symptoms may lessen or resolve after metoclopramide treatment is stopped”. A recent review estimates that tardive dyskinesia happens in less than 1% of patients.

This very rare but devastating side effect is not likely to occur in our patients who receive this drug very infrequently, only for emergencies. However, the thought of tardive dyskinesia is always lurking in the back of our minds so we tend to use IV ondansetron (Zofran) to treat nausea. Ondansetron does not help with pain and we have to combine it with IV ketorolac (Toradol) or another drug, but it is safer.

Galcanezumab can start to improve migraines within a day

By: Dr. Mauskop

08-03-2020

Headache medications, Migraine

Galcanezumab (Emgality) is one of the three injectable monoclonal antibodies approved for the prevention of migraines. Pharmacological studies show that it takes up to a week for these drugs to reach their highest concentration. However, it does not mean that it takes a week for them to start helping. Many of my patients report feeling better within a day. A new study of galcanezumab indicates that such a rapid onset of action is not just due to the placebo effect.

The authors analyzed the results of two large studies of patients with episodic migraines that were submitted to the FDA to gain its approval. The first study enrolled 858 patients and the second, 915. Patients were given monthly injections of galcanezumab 120 mg (with 240 mg loading dose) or 240 mg or placebo for up to 6 months. In both studies, the onset of effect was present the day after the injection.

I do tell my patients that they might start feeling better the day after they receive their first injection (the initial dose of two 120 mg injections), but it is more likely that they will begin to improve within a week or even later. Some patients notice only minimal relief even at the end of the first month and require 2 or 3 monthly shots before any significant improvement occurs. This is true for all three injectable CGRP monoclonal antibodies.

Vyepti, the fourth drug in this family, which was just approved and will be available in a month, is given intravenously. This may result in an even faster onset of action.

Rimegepant, another very safe and effective drug receives FDA approval for the acute treatment of migraine headaches

By: Dr. Mauskop

01-03-2020

Chronic migraine, Headache medications, Migraine, New treatments

Rimegepant (NURTEC ODT) is the second gepant approved for the acute treatment of migraine headaches. It blocks the same CGRP pathway as the injectable monoclonal antibodies that are used for the prevention of migraine attacks (erenumab/Aimovig, fremanezumab/Ajovy, galcanezumab/Emgality, and eptinezumab/Vyepti). It follows the recent introduction of a similar drug that also blocks the CGRP receptor, ubrogepant (Ubrelvy).

Since there have been no head-to-head trials comparing these two gepants, it is had to say if one is better than the other. On average, they appear to be very similar, but this does not mean that they will be equally effective or cause the same side effects in a particular patient. We see this with triptans (drugs like sumatriptan, eletriptan, and other) – the top 5 show similar efficacy in trials, but some patients strongly prefer one over another.

One difference is that rimegepant is an orally disintegrating tablet and does not require water, while ubrogepant is taken with water. This makes rimegepant easier to take on the go and could be easier to take for patients with severe nausea. Another minor difference is that the dose of rimegepant is 75 mg that is taken once a day, while ubrogepant comes in 50 and 100 mg tablets and either dose can be repeated for up to 2 tablets a day. This can be both an advantage and a disadvantage. The instructions are simple for rimegepant – take one tablet once on the day you have a migraine (and the earlier you take any abortive drug the better). With ubrogepant the doctor has to decide whether to give 50 or 100 mg dose and the patient needs to be instructed to take a second dose on the same day (as soon as 2 hours after the first one) if the headache returns or does not completely resolve with the first dose. In clinical trials, this second dose did produce additional improvement.

The safety of rimegepant is as remarkable as that of ubrogepant and the preventive injectable monoclonal antibodies. Rimegepant caused nausea in 2% of patients compared with 0.4% of those on placebo and less than 1% developed a rash or temporary difficulty breathing.

100 Migraine Drugs, A to Z: nortriptyline

By: Dr. Mauskop

26-02-2020

Chronic migraine, Headache medications, Migraine

Nortriptyline (Pamelor) is a tricyclic antidepressant approved by the FDA only for the treatment of depression. However, with the introduction of SSRI family of antidepressants such as fluoxetine (Prozac) which have fewer side effects, the use of tricyclic antidepressants for depression has declined.

Tricyclic antidepressants are still in wide use, but mostly for the treatment of headaches and pain. Nortriptyline is very similar to amitriptyline (Elavil) and is thought to cause fewer and milder side effects, although this has not been proven. This could be due to the fact that amitriptyline is broken down into nortriptyline, which is the active metabolite. Amitriptyline tends to be more sedating, which can be useful in patients with insomnia.

There are no good blinded studies of nortriptyline for the prevention of migraines and they are not likely to be done. We assume it is as good as amitriptyline, although studies of amitriptyline also lack in size and scientific rigor.

There are many trials of amitriptyline and nortriptyline for various pain conditions, but they are also not up to our modern standards. Amitriptyline was approved in the US in 1961.

Besides sedation, nortriptyline can cause dry mouth, constipation, urinary retention in older patients, and other side effects. The dose to treat migraines and pain is usually lower than the dose used to treat depression. Pain and headaches sometimes respond to as little as 10 or 25 mg while for depression, the dose goes up to 100 mg and higher.

In short-term studies of major depression, antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults. This is less likely to occur when treating pain, but many pain patients also experience depression.

Vyepti – Another breakthrough in the prevention of migraines

By: Dr. Mauskop

22-02-2020

Chronic migraine, Headache medications, Migraine

Eptienzumab (Vyepti) was just approved by the FDA for the preventive treatment of migraine headaches. Eptinezumab is another monoclonal antibody that blocks the effect of CGRP, a chemical released during a migraine attack. It joins erenumab (Aimovig), fremanezumab (Ajovy), and galcanezumab (Emgality), three other monoclonal antibodies approved for the preventive treatment of migraine headaches.

Eptinezumab is different from the other three drugs in that it is administered intravenously. It is given every three months by an infusion over 30 minutes. The other three drugs are self-administered subcutaneously every month, although fremaezumab can be also given every 3 months.

Eptinezumab may also have a faster onset of action because it is administered intravenously and quickly reaches its peak concentration in the blood. The other three drugs take up to a week to reach their maximum concentration. The reason for such a long delay (most drugs injected subcutaneously take less than an hour to peak) is that the monoclonal antibodies are large molecules and are distributed not by blood vessels, but the slow-moving lymphatic system. On the other hand, these are preventive therapies, so the speed of onset is less critical than for abortive drugs, such as NSAIDs, triptans, and gepants (ubrogepant, rimegepant).

Theoretically, it is possible that eptinezumab could work for patients who do not respond to the other three drugs because of a better distribution of the drug and because these drugs are not identical. About 10% of my patients report significantly better response when switched from erenumab, which was first to be approved, to either fremanezumab or galcanezumab.

We don’t know yet what the drug will cost and how well the insurance companies will pay for it. All three subcutaneous drugs cost about $650 a shot and all three manufacturers offer a one-year free trial if the insurance refuses to pay. This does not apply to patients who have Medicare or Medicaid, which do not allow free trials or discount coupons. Fortunately, more and more insurers, including the government plans, are covering these drugs, albeit with some paperwork that needs to be completed by the doctor. The cost of eptinezumab will consist of two parts – the cost of the drug and the cost of the infusion.

100 Migraine Drugs, A to Z: nebivolol

By: Dr. Mauskop

10-02-2020

Headache medications, Migraine

Nebivolol (Bystolic) is one of the newer, third generation beta-blockers, drugs used for the treatment of high blood pressure as well as migraine headaches. In Europe, it’s been in use for over 20 years.

In addition to beta-blockade, it may have additional beneficial effects on endothelium (blood vessel lining). It may also improve glucose metabolism by improving insulin sensitivity and other functions.

Nebivolol has the advantage of having fewer side effects than other beta blockers. including lower rates of fatigue and shortness of breath.

The majority of migraine sufferers are young women, many of who have low blood pressure, which predisposes them to side effects from beta blockers.

However, in the US, nebivolol is relatively expensive ($160 for one month supply) since it is not yet available in a generic form. Many insurers will not pay for it unless the patient cannot tolerate the widely used and inexpensive beta blockers such as propranolol, metoprolol, or atenolol.

100 Migraine Drugs, A to Z: naratriptan

By: Dr. Mauskop

26-01-2020

Headache medications, Migraine

Naratriptan (Amerge, Naramig) is a triptan with a longer duration of action of 6 hours, compared to sumatriptan, rizatirptan, zolmitriptan, eletriptan, and almotriptan, which work for 2-4 hours. The seventh triptan, frovatriptan has the longest half-life of 26 hours, but its overall efficacy is not as good as than that of other triptans. These numbers of 6, 2-4 and 26 hours actually refer to drug’s half-life – the time it takes for the blood level of the drug to drop by half.

The duration of the effect is not important for most migraine sufferers because a quick-acting and highly effective drug stops the migraine process and there is no need for it to remain in the body. However, in some patients sumatriptan or another short-acting triptan may relieve symptoms for 4-6 hours and then migraine returns. Taking a second dose often works well, but not always. Those patients can benefit from taking naratriptan. Naratriptan also tends to have fewer side effects.

The longer half-life makes naratriptan better suited for “mini-prophylaxis” – taking a drug daily for several days to prevent a predictable menstrual migraine. However, sumatriptan has been also shown to work in this manner.

Just like with other triptans, naratriptan can be combined with ibuprofen or naproxen for better efficacy. Many insurers limit the number of pills they will pay for to 6 or 9, but naratriptan, along with sumatriptan and rizatriptan is one of the cheaper triptans. This allows patients to buy additional quantities, although many doctors have the mistaken belief that triptans cause medication overuse headaches and refuse to write prescriptions for more than 9 pills a month.

100 Migraine Drugs, A to Z: naproxen

By: Dr. Mauskop

14-01-2020

Headache medications, Migraine

Naproxen (Aleve, Anaprox, Naprosyn) is a popular over-the-counter and prescription non-steroidal anti-inflammatory drug (NSAID), which is often used for the treatment of migraine headaches. A combination of naproxen with sumatriptan (Treximet) is approved by the FDA for the treatment of acute migraine attacks. Naproxen alone, while not specifically approved for the treatment of migraines, is widely considered to be an effective drug. A review of several double-blind studies confirmed this observation. It has the advantage of having longer duration of effect when compared to ibuprofen or aspirin.

Naproxen has been also studied and proven effective in a double-blind study for the prevention of migraine attacks. In another double-blind study naproxen, 550 mg taken twice a day was also effective for the prevention of menstrual migraines. It also helped relieve premenstrual pain. Naproxen is rarely used for the long-term prevention of migraines because of the risk of stomach ulcers and stomach bleeding.

NSAIDs carry a warning about the potential negative effects on the heart, but it should be of no concern to most migraine sufferers who tend to be young women with no risk factors for heart problems and who take naproxen only intermittently.

There is a myth that NSAIDs (and triptans) can cause rebound or medication overuse headaches (MOH). There is no scientific proof that this happens and in fact, when someone suffers from MOH due to caffeine-containing drugs (Excedrin, Fioricet) or opiates, naproxen is often prescribed to help withdrawal headaches.