Protriptyline (Vivactil) is one of the tricyclic antidepressants (TCAs). It is rarely used, compared to amitriptyline and nortriptyline. This is probably because protriptyline has never been subjected to a controlled trial in migraines. However, even amitriptyline, which is the most popular and most studied TCA, is rated only as probably effective by the American Academy of Neurology and the American Headache Society guidelines. In the bad old days, very few drugs were tested in large double-blind trials and sometimes got approved without any testing.

The reason to use protriptyline is that it tends to have fewer side effects when compared to other TCAs. If someone has good relief of migraines on amitriptyline but drowsiness is a problem, protriptyline is worth trying.

Also, protriptyline is easier to titrate than other TCAs – the starting dose is 10 mg nightly and after a couple of weeks, it is increased to 20 mg and then, if needed and if tolerated, to 30 mg nightly.

The most common side effects of all TCAs besides sedation are constipation, dry mouth, dizziness, sexual dysfunction. Some patients refuse to consider TCAs because of their potential for weight gain, although it tends to happen at higher doses and in a minority of patients.

Pregabalin (Lyrica) is an epilepsy drug that is also approved by the FDA for the treatment of neuropathic (nerve) pain associated with diabetes, spinal cord injury, shingles (herpes zoster), and fibromyalgia. It is a controlled drug with a low risk of addiction and abuse, although it is often combined with other illicit drugs. Common side effects include dizziness, drowsiness, difficulty thinking clearly, weight gain, sexual dysfunction, and dry mouth. It also has many other less common side effects.

There are no large controlled trials of pregabalin for migraines only case series and anecdotal reports. However, because it does relieve pain and because two other epilepsy drugs, topiramate (Topamax, Trokendi, Qudexi) and divalproex sodium (Depakote) relieve migraines, at least theoretically it should be also effective for migraines. However, despite the few anecdotal reports, it does not appear to be very effective and often does cause side effects. I rarely prescribe it and have very few patients who benefit from it without side effects.

Propranolol (Inderal) belongs to the beta-blocker family of medications and it was approved by the FDA in 1967 for the treatment of high blood pressure. About a decade later it became the first drug to be approved by the FDA for the preventive treatment of migraine headaches. Propranolol is also used for essential tremor, performance anxiety, fast heart beating (tachycardia), angina, and other conditions. In 1988, a British scientist Sir James Black was awarded the Nobel Prize for the discovery of propranolol.

Propranolol is a very effective drug, but because it can lower blood pressure, side effects such as fatigue, lightheadedness, and fainting can occur. Because it slows down the heart rate it can also make it difficult to exercise, which is one of the best ways to prevent migraines. Propranolol can sometimes worsen pre-existing asthma but newer beta-blockers do not have this problem.

If someone along with migraines has a rapid heartbeat, anxiety, or difficulty making public presentations, this drug can provide dual benefits.

A typical starting dose of propranolol is 60 mg of the long-acting formulation. The dose is then increased to 80, 120, and 160 mg, if needed and if tolerated.

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.

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.

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.