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.

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.

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.

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.

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.

Ubrogepant (Ubrelvy) is the first oral anti-CGRP drug to be approved by the FDA for the acute treatment of migraine attacks. It was developed by Allergan, manufacturer of Botox, the safest and arguably the most effective preventive treatment for chronic migraines. Allergan took a risk and bought this drug from Merck after Merck ran into problems developing a similar drug, telcagepant. Fortunately, ubrogepant had none of telcagepant’s problems and it was shown to be safe and effective in two large double-blind placebo-controlled trials.

The FDA-approved package insert says that, UBRELVY is a calcitonin gene-related peptide receptor antagonist indicated for the acute treatment of migraine with or without aura in adults. The recommended dose is 50 mg or 100 mg taken as needed. If needed, a second dose may be administered at least 2 hours after the initial dose. The maximum dose in a 24-hour period is 200 mg. It can be taken with or without food. The most common side effects were nausea, seen in 2% of those receiving placebo, 2% of those on 50 mg of ubrogepant and 3% of patients taking 100 mg. The second most common side effect was somnolence, present in 1% of patients taking placebo, 2% of those taking 50 mg and 3% taking 100 mg.

Such a low incidence of side effects is extremely rare with oral drugs, but we also see this with injectable anti-CGRP drugs that are used for the prevention of migraines. The second oral anti-CGRP drug, rimegepant which is awaiting FDA approval, also seems to have very low rates of side effects, which is very reassuring.

The average cost of developing a new drug is $2.6 billion, which means that by necessity new drugs are expensive. This means that insurance companies will require that migraine patients first try and fail generic versions of triptans, such as sumatriptan (Imitrex) or have a contraindication to taking a triptan. Contraindications for the use of triptans include cardiovascular disease (coronary artery disease, strokes, heart attacks, etc.), uncontrolled hypertension, and a few other. Fortunately, ubrogepant can be safely used in such patients.

Oral triptans work well in about 60% of patients, which leaves millions of migraine sufferers without an effective abortive therapy and for these patients, the introduction of ubrogepant could be life-changing.