Granisetron (Kytril, Sancuso) is one of the anti-nausea medications in the family of setrons. Ondansetron (Zofran) and palonosetron (Aloxi) are the other two drugs in this family available in the US. These drugs are approved for the prevention and treatment of chemotherapy-induced and post-surgical nausea and vomiting, but are also used to treat nausea of migraine attacks.

Granisetron was found to relieve nausea as well as pain in one anecdotal observation of 7 patients and two controlled trials.

The first study was conducted in Canada and it involved 28 patients who presented to the emergency department with an acute migraine. This was a randomized, double-blind, placebo-controlled study of intravenous granisetron (40 micrograms/kg or 80 micrograms/kg). Significant improvement in headache pain was observed in the 80-micrograms/kg group. Except for more nausea at 30 min in the placebo group, no significant differences were noted between treatments. The authors concluded that “granisetron may be effective for acute migraine headache; however, further studies with increased patient numbers are required.”

The second Iranian study was also conducted in an emergency room and included 148 patients. The doctors compared intravenous granisetron, 2 mg with intravenous metoclopramide, 10 mg. They found that the drugs were equally effective in the treatment of nausea, but granisetron was somewhat better at relieving pain.

The general consensus is that setrons are not very effective for the treatment of migraine pain, while metoclopramide (Reglan) and phenothiazine drugs, such as prochlorperazine (Compazine), promethazine (Phenergan) and chlorpromazine (Thorazine) relieve both nausea and pain. However, setrons have the advantage of not having the potential to cause serious neurological side effects. These include severe restlessness and involuntary movements (tardive dyskinesia), which in rare cases can become permanent.

We do treat patients with an acute migraine in the office and after an infusion of magnesium usually start with ondansetron and a pain medicine such as ketorolac (Toradol), but in some people, metoclopramide is consistently more effective. If metoclopramide causes restlessness, intravenous diphenhydramine (Benadryl) almost always stops it.

Gabapentin (Neurontin) is a drug that was originally developed for the treatment of epilepsy but now it is used for a wide variety of conditions except for epilepsy. It is just not strong enough to control epileptic seizures. Gabapentin can be effective for various pain syndromes, including the treatment of sciatic pain and it has an official FDA approval for the treatment of a very painful condition, postherpetic neuralgia, or shingles pain.

Several positive studies of gabapentin have been also reported for the treatment of episodic as well as chronic migraines. However, a review of all rigorous clinical trials of gabapentin for the treatment of migraine found no evidence that it really works. The authors of the review concluded that, “Since adverse events were common among the gabapentin-treated patients, it is advocated that gabapentin should not be used in routine clinical practice”. The adverse events were mostly dizziness and somnolence.

My personal experience also suggests that gabapentin is not highly effective and I do not use it “in routine clinical practice”. However, because gabapentin is proven to relieve other painful conditions and because it has a relatively benign side effect profile, I do use it in some patients with migraine, especially those with associated neck pain. It can also help patients with insomnia, although this indication is also not proven in large trials.

Gabapentin is used in doses of up to 3,600 mg a day and higher, although there have been reports of gabapentin abuse and dependence at doses above 3,000 mg a day. We usually start with 300 mg a day and slowly escalate the dose as needed and as tolerated to about 1,800 mg a day. Some patients report good relief of insomnia with 300 mg taken at night. Transition to menopause can be accompanied by temporary worsening of migriane headaches and gabapentin can also help menopausal hot flashes (and sleep) at a dose of 900 mg a day.

Frovatriptan (Frova) is one of seven drugs in the family of triptans, drugs used to abort a migraine attack. The first drug to receive approval in 1992 was sumatriptan (Imitrex) in an injection form, followed by tablets and nasal spray. Other drugs in this category are rizatriptan (Maxalt), zolmitriptan (Zomig), naratriptan (Amerge), almotriptan (Axert), and eletriptan (Relpax).

Frovatriptan is probably the least effective triptan and this is in part because it is the longest-lasting triptan and takes the longest to start working. Its half-life is 26 hours, which means that the body clears out half of it in that period of time. The half-life of sumatriptan, rizatriptan and zolmitriptan is 2 to 3 hours, almotriptan – 3 to 4 hours, eletriptan – 4 hours, and naratriptan – 6 hours.

When speed of onset is not crucial, which is when migraine develops slowly over a few hours, frovatriptan has the advantage of longer effect. However, if it does not provide good relief to begin with, the amount of time it stays in the body is irrelevant. Short-acting triptans work quickly and stop the migraine attack.

Frovatriptan is sometimes used for “mini-prophylaxis” of menstrual migraines – it is taken the day before the expected menstrual migraine and throughout the period. However, other triptans, including sumatriptan and naratriptan can be also effective in preventing predictable migraines, such as those occurring with periods, physical exertion or sexual activity.

Another disadvantage of frovatriptan is that it is expensive even in a generic form – $20 a pill. The triptans that only recently lost patent protection, such as frovatriptan and eletriptan have fewer generic copies and their prices are still high.

Fremanezumab (Ajovy) is one of the three drugs in the family of CGRP monoclonal antibodies that have been approved for the prevention of migraine headaches.

Fremanezumab was approved by the FDA last September. After trying erenumab (Aimovig), which was approved first, I also injected myself with Ajovy monthly for two months. My migraine headaches do not cause any disability, so I did it to see if I can reduce my attacks from triggers such as red wine, which it did, and to reassure my patients about the relative safety of these drugs.

Over the years I’ve tried Botox a couple of times and a few other treatments, but not drugs such as topiramate (Topamax) or divalproex sodium (Depakote), which I rarely prescribe to my patients because of their potential to cause serious side effects. Fortunately, my occasional migraines have always been easily controlled with sumatriptan (Imitrex), so I do not need any preventive therapies.

Tosymra is a product that uses a novel way to deliver sumatriptan through the nasal passages. Unlike other nasal formulations of sumatriptan, Tosymra uses proprietary technology, Intravail, which enhances the absorption of sumatriptan through the nasal mucosa. This allows a dose of 10 mg to achieve similar blood level to that of a 4 mg injection of sumatriptan. Clinical trials have confirmed high efficacy of Tosymra in migraine patients.

Many migraine sufferers experience nausea, which makes oral medications ineffective they take too long to work. Sumatriptan injections can be very effective, but many patients are reluctant to use them and they tend to cause more side effects. Nasal delivery offers a good middle road – better and faster delivery than by mouth without the pain and side effects of an injection.

The regular liquid sumatriptan nasal spray (Imitrex NS) has been on the market for a couple of decades, but it has never become a popular product. This is partly due to the fact that it is not consistently or well absorbed. The spray contains 20 mg of sumatriptan delivered through a relatively large droplets of fluid. Some of it is drips out from the nose, while some is swallowed and gives an already nauseated migraine patient a bad taste in the mouth.

Another formulation of nasal sumatriptan was Onzetra, which delivered powdered sumatriptan through an ingenious device. It required the patient to blow the powder into the nose and it appeared to have good efficacy.  However, it was somewhat cumbersome to use, very expensive (up to $100 a dose) and because of that it never caught on. Onzetra is no longer being sold.

I think that Tosymra is going to be a very useful addition to our lineup of abortive migraine drugs, provided it is reasonably priced and is covered by insurance companies.

Fluvoxamine (Luvox) is one of the drugs in the selective serotonin reuptake inhibitor (SSRI) class. Unlike other SSRIs, which are approved for the treatment of anxiety and depression, it is approved for the treatment of obsessive-compulsive disorder (OCD), although OCD is often accompanied by anxiety and depression. Fluvoxamine does relieve anxiety and depression as well, but it has been mostly promoted and used for the treatment of OCD.

The SSRIs are not very effective for the prevention of migraines, but a single double-blind study involving 64 patients showed that fluvoxamine is as good as amitriptyline for the prevention of migraines with fewer side effects. It may be best suited for migraine patients who also suffer from OCD, but I would not prescribe it for migraines without OCD.

Fluvoxamine may have more side effects than other SSRIs, such as fluoxetine (Prozac). Potential side effects of fluvoxamine is similar to those of other SSRIs and include nausea, insomnia, somnolence, headache (most drugs have headache as a potential side effect), decreased libido, nervousness, and dizziness. All antidepressants can also increase the risk of suicide.

Flunarizine (Sibelium) is a calcium channel blocker approved for the preventive treatment of migraines in most countries, except for the US and Japan. In many countries, flunarizine is considered to be a first-line drug for the prevention of migraines.

It is as effective as propranolol (Inderal), a beta blocker which is approved world-wide for migraine prophylaxis (and hypertension). Flunarizine, 10 mg was found to be more effective than 50 mg of topiramate (Topamax), although the average dose of topiramate for migraines is 100 mg. It can take 6 to 8 weeks before flunarizine becomes effective.

Vestibular migraine is characterized by vertigo which can occur with or without headache and is often difficult to treat. One observational study suggested that flunarizine may improve the attacks of vertigo.

The two most common side effects of flunarizine are drowsiness and weight gain, but can also cause nausea, anxiety, depression, insomnia, and dry mouth. I’ve recommended purchasing flunarizine abroad to a few of my patients who exhausted other options. None have remained on it, either because of side effects or lack of efficacy. Clearly, giving it to the most severely affected patients is not a fair way to evaluate a drug, but I’ve stopped recommending it. This is also because of legal and logistical problems in getting flunarizine from outside the US.

In the US, we do have a different calcium channel blocker, verapamil (Calan). It is not FDA-approved for migraines (only for high blood pressure) and it is not as effective as flunarizine for migraines, but is the first-line drug for the prevention of cluster headaches.

Antidepressants are widely used for the preventive treatment of migraine headaches. However, some types of antidepressants are better for this purpose than other. Fluoxetine (Prozac, Sarafem) was the first drug in the family of selective serotonin reuptake inhibitors (SSRIs) to be introduced in 1986. This category of antidepressants became very popular not because these drugs were more effective than the older antidepressants, but because they had fewer side effects.

Because tricyclic antidepressants were known to relieve pain and prevent migraine headaches, when the SSRIs became available, they were also studied for various painful conditions.

Small studies suggested that fluoxetine and similar drugs may be effective for the prevention of migraines. Here is another such small study. However, larger and scientifically more rigorous trials showed no effect of fluoxetine on migraines.

Despite this lack of scientific evidence, SSRIs (escitalopram, or Lexapro, paroxetine, or Paxil, sertraline, or Zoloft) are often prescribed for migraines and some migraine sufferers report feeling better on these drugs. One possible explanation is the placebo effect, but it is more likely to be due to the relief of anxiety and depression with some secondary improvement of migraine headaches. In case of tricyclic and some other antidepressants, their pain relieving properties are independent of their effect on depression.

While SSRIs have fewer side effects than many other antidepressants, they also can cause nausea, dizziness, insomnia, loss of libido, inability to reach an orgasm, and other unpleasant symptoms.

Erenumab (Aimovig) was the first drug in the family of monoclonal antibodies (mAbs) against calcitonin gene-related peptide (CGRP) approved for the prevention of migraine headaches. CGRP is a substance released during a migraine attack. Erenumab was approved in May of this year, followed by approvals of fremanezumab (Ajovy) and galcanezumab (Emgality) in September. Erenumab is an antibody against the CGRP receptor located on a cell, while the other two drugs are antibodies against the molecule of CGRP. They have very similar efficacy and are surprisingly safe with very few side effects. Erenumab has no contraindications or drug interactions.

All these drugs are delivered by an injection and can cause a local injection site reaction or a rash, but erenumab can also cause constipation. It is possible that with the wider use of these drugs other side effects may become apparent. We have seen a handful of patients whose headaches worsened, a couple who developed fatigue and muscle aches, stomach pains and thinning of hair. The number of such patients is small and it is premature to attribute these effects to the drug. Just like our colleagues across the country, we at the New York Headache Center encourage our patients to report all potential side effects to the manufacturer or the FDA.

Erenumab dose is either a single 70 mg injection or two injections for a total of 140 mg. It comes in a prefilled pen-like device which is very easy to self-administer. It provides dramatic relief to about one in five patients and its overall efficacy is about 50% improvement in 50% of patients. About 30% obtain no relief. We do recommend at least two sets of monthly injections before giving up on erenumab.

Unlike Botox, which is approved for the prevention of only chronic migraines (15 or more headache days each month), erenumab is approved for migraines of any frequency. Usually, we consider preventive therapy in patients who have about 4 migraine attacks a month. Many insurance companies require a trial of two oral preventive drugs (which are extremely cheap) before they agree to pay for erenumab. The cost of erenumab is $575 a month, but the manufacturer offers a free trial and free treatment for up to a year if the insurer refuses to pay for it (you do need to get a denial of payment as well as a second denial upon appeal). The one-year free offer is not available to those on Medicaid or Medicare.

Erenumab and the other two CGRP mAbs are truly breakthrough medications which are changing lives of thousands of migraine sufferers. We are cautiously optimistic that their safety profile will remain as good as it appears to be now.