Hydroxyzine (Vistaril) is an underutilized old anti-histamine drug with some unique properties. Just like diphenhydramine (Benadryl) and other older anti-histamine drugs, hydroxyzine causes some sedation. However, it is the only anti-histamine that is officially approved for “anxiety and tension”. It is also approved for itching due to allergic conditions. Off-label (i.e. without FDA-approval) it is used to treat motion sickness, nausea, vomiting, and dizziness.

Hydroxyzine is often used as and adjuvant analgesic, that is as an add-on drug that makes pain medications work better.

A study comparing injections of hydroxyzine, 50 mg with a pain medication nalbuphine 10 mg, with a combination of hydroxyzine and nalbuphine, and with placebo found no benefit from adding hydroxyzine when treating migraines.

A study comparing an injection of hydroxyzine 50 mg plus meperidine (Demerol, a narcotic pain killer), 100 mg was similar to an injection of ketorolac (Toradol) 60 mg in its relief of an acute migraine. Nausea and drowsiness were similar in two groups.

Another study compared hydroxyzine 75 mg intravenously plus meperidine 75 mg intramuscularly to DHE 1 mg IV plus metoclopramide (Reglan) 10 mg IV. Pain reduction was greater with DHE/metoclopramide.

There have been no studies examining the efficacy of hydroxyzine alone, whether as an intravenous or intramuscular injection or as a tablet. It is likely that it will remain an adjuvant or add-on medication for the treatment of migraine headaches.

I sometimes prescribe it to be taken daily to patients whose allergies worsen their migraine headaches or even when there is only a suspicion of an allergic component. It is also useful when anxiety is a contributing factor, which is not unusual since those suffering from migraines are 2-3 times more likely to also have anxiety. For many patients it is too sedating to be taken during the day, unless they are treating an acute attack. Most people take 25 or 50 mg nightly, although some tolerate and benefit from 25 mg taken three times a day.

Hydrocodone (Vicodin, Lortab, Norco) is an opioid or narcotic pain killer, which should not have much of a role to play in the treatment of migraine headaches. Opioids are much less effective for the treatment of migraines than any other pain syndrome. They often make nausea worse, make patients sedated, and do not provide good pain relief.

Unfortunately, according to a study published in Headache, half of the patients presenting to an emergency room with a migraine headache are prescribed an opioid drug such as hydrocodone. Patients with migraines who are given an opioid injection stay in an ER longer than if they don’t get an opioid.
Opioids are not only ineffective, but if used more than once a week can also worsen headaches by causing medication overuse headache and cause addiction. Regular intake of opioids can also worsen other pain conditions, such as neck and back pain, by causing hyperalgesia, an increased sensitivity to pain.

Patients presenting to an ER with a migraine should be given and injection of sumatriptan (Imitrex) or a non-steroidal anti-inflammatory drug (NSAID), ketorolac (Toradol). Neither triptans nor NSAIDs are likely to cause rebound or medication overuse headache.

There are exceptions when occasional use of opioids is appropriate. Perhaps a fraction of one percent or one out of several hundred patients may respond only to an opioid analgesic and nothing else or some patients have to take an opioid if they have contraindications for the use of NSAIDs and triptans. Some patients do well on long-term opioid maintenance, but the number of such patients in our practice is also exceptionally low.

Haloperidol (Haldol) is a psychiatric drug prescribed  for the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, nausea and vomiting, delirium, agitation, and acute psychosis.

A cases series published in The Journal of Emergency Medicine in 1995 described six patients who presented with a severe migraine to an emergency room in Toronto and were given haloperidol intravenously. Within an hour all six were either pain-free or significantly improved and none returned to the emergency room within 48 hours.

A double blind placebo controlled study published by Finnish researchers in the journal Headache in 2006 examined the efficacy of 5 mg of haloperidol given intravenously in the treatment of severe migraines. Forty patients were enrolled in the study and 80% (16 patients out of 20) of those who received haloperidol had significant pain relief, compared with 15% (3 patients) in the placebo group. Because the majority of patients had taken regular NSAIDs analgesics and triptans without response, the authors concluded that haloperidol appears to be effective in treatment resistant migraine attacks. However, almost all patients who receive haloperidol complained of side effects, mostly sedation and unpleasant restlessness (akathisia). The side effects were mild to moderate in severity and reversible. The restlessness can be relieved by diphenhydramine (Benadryl).

Haloperidol is one of the neuroleptic drugs, a category that includes droperidol and phenothiazine drugs such as chlorpromazine mentioned in an earlier post. All these drugs have the potential to cause serious and in rare cases permanent neurological side effect of involuntary movements. This is why they are mostly used when other acute migraine therapies have failed. The neurological side effects are more common with continued daily use of haloperidol and other neuroleptics in psychiatric disorders.

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.