Lisinopril (Prinivil, Zestril) is a blood pressure medicine in the family of angiotensin-converting enzyme inhibitors (ACEI). At 20 mg a day it was effective in the prevention of migraine headaches, according to a double-blind cross-over study of 60 patients. Three patients stopped the drug due to cough.

An open-label study of 5 mg of lisinopril in 21 patients was also positive but 3 patients stopped it because of cough. ACEIs but not angiotensin receptor blockers (ARBs) which are similar to ACEIs can cause cough. The occurrence of cough is not dose-dependent.

A review of a large database of prescriptions showed that patients taking ACEIs or ARBs were getting 50% fewer prescriptions for abortive migraine drugs compared to those taking a diuretic, which is another type of drug to treat hypertension.

The advantage of ACE inhibitors and ARBs over beta-blockers such as propranolol is that they do not lower the heart rate, which can make exercise difficult. Both can cause fatigue and dizziness due to the lowering of blood pressure, but the weight gain and depression, occasionally seen with propranolol does not happen with ACEIs and ARBs. On the other hand, beta-blockers can sometimes help reduce anxiety and palpitations.

Promethazine (Phenergan) is a phenothiazine drug that can be very effective for the treatment of migraine-induced nausea and vomiting. Like other phenothiazine drugs, it can have some direct effect on pain of migraine although it has not been studied as extensively as prochlorperazine or metoclopramide.

A double-blind study in 216 patients comparing sumatriptan with promethazine with sumatriptan alone, showed that the combination was more effective in relieving pain, achieving pain-free state, and preventing recurrence of migraine.

Promethazine is available as a tablet and injection as well as a rectal suppository which is very useful for patients with severe nausea and vomiting.

Side effects of promethazine are similar to other phenothiazine drugs and include drowsiness, dizziness, and akathisia or restlessness. This restlessness can be very unpleasant but can be treated with oral or injected diphenhydramine (Benadryl).

Prochlorperazine (Compazine) belongs to the category of phenothiazine drugs. Chlorpromazine (Thorazine) was the first drug in this family and it was approved for the treatment of schizophrenia in 1950. Phenothiazine drugs have also been found to be effective for the treatment of nausea and vomiting, severe anxiety, and persistent hiccups.

Prochlorperazine is mostly used for the treatment of nausea and vomiting and it is available in tablets, rectal suppositories, and injections. Prochlorperazine appears to be an effective drug not only for the treatment of nausea and vomiting of migraine, but also for head pain and other symptoms.

Prochlorperazine was found to be more effective in treating all migraine symptoms than another antiemetic (nausea drug), metoclopramide (Reglan). In a study of children with migraine seen in an emergency department, intravenous prochlorperazine was more effective than an intravenous pain medication ketorolac (Toradol).

The main side effect of prochlorperazine is restlessness or akathisia, which occurs in a large minority of patients who receive it intravenously. In many patients this symptom is mild but in some, it is severe and extremely unpleasant. Many describe the sensation as if wanting to crawl out of their skin. With regular long-term intake of phenothiazine medications, involuntary movements can be a very serious side effect.

I do have patients for whom chlorpromazine works exceptionally well and with no side effects. Most of them need it not more than a few times a month and most use tablets and less often, suppositories. Suppositories work faster than tablets and are preferred by patients who experience vomiting with their migraines. I also use it occasionally as an intravenous injection in the office when a patient is known to respond to it well or when ondansetron (Zofran), a safer antiemetic, is ineffective.

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.