Levetiracetam (Keppra) is an epilepsy drug that has been reported to help some patients with migraines. However, unlike divalproex sodium (Depakote) and topiramate (Topamax, Trokendi, Qudexy), the evidence for its efficacy in migraines is weak.

This evidence consists mostly of uncontrolled observational studies without a comparison to placebo. One small double-blind placebo-controlled study compared 500 mg of levetiracetam (27 patients) to 500 mg of divalproex sodium (32 patients) and to placebo (26 patients). Both epilepsy drugs were superior to placebo.

In one of the reports the mean dose of levetiracetam was 1,125 (and up to 2,000), while the maximum dose for epilepsy is 3,000). It is possible that the drug may work better at a higher dose. However, with an increase in the dose there is an increase in side effects. These include weakness, drowsiness, dizziness, anxiety, depression, irritability and aggressive behavior, and other.

Since this drug is not proven to be effective and can have serious side effects, I never prescribe this drug.

Ketorolac (Toradol) is one of many nonsteroidal anti-inflammatory (NSAID) pain medications used to treat migraine headaches. In a tablet form it is no more effective than ibuprofen, naproxen or any other NSAID, but has more side effects and its use is limited to 5 days. On the other hand, ketorolac in an injection is a unique and very useful drug. It provides pain relief comparable to that of opioid (narcotic) drugs without the side effects or addiction potential of those drugs.

Intravenous ketorolac has been proven to be an effective drug for the treatment of severe migraine attacks. A study done by Dr. B. Friedman and his colleagues at the emergency department of the Montefiore Medical Center in the Bronx compared intravenous infusion of 30 mg of ketorolac with an infusion of 10 mg of metoclopramide (Reglan) and 1,000 mg of valproate (Depacon). There were over 100 patients in each group, making this a highly reliable study. Ketorolac and metoclopramide were more effective than valproate, but metoclopramide caused severe restlessness in 6 (6%) of patients. This is a well known side effect of metoclopramide and a similar drug, prochlorperazine (Compazine). This side effect is extremely unpleasant, but can be relieved by diphenhydramine (Benadryl).

Intramuscular injection of 60 mg of ketorolac was compared to intravenous infusion of 25 mg of chlorpromazine (Thorazine) and they were found to be equally effective. Just like prochlorperazine, chlorpromazine carries a risk of restlessness, as well as involuntary movements and sedation. These two drugs belong to the phenothiazine family of drugs, which are also used for severe nausea and vomiting, and psychiatric disorders.

A review of eight published trials of ketorolac found it to be more effective than meperidine (Demerol) and sumatriptan and a little less effective than metoclopramide, chlorpromazine and prochlorperazine. However, ketorolac lacks the addiction potential and the risk of severe restlessness, sedation, and involuntary movements.

We given intravenous ketorolac to our patients whose migraine has not responded to an injection of sumatriptan or oral triptans, although we almost always give an infusion of magnesium before or along with ketorolac.

Here is a blog post with my advice on what to ask for if your migraine lands you in an emergency room.

Ketoprofen (Orudis, the branded version, is no longer available) is a prescription nonsteroidal antiinflammatory drug (NSAID) without any outstanding features. Just like all other NSAIDs, it is effective for the acute treatment of migraine headaches.

A double-blind placebo-controlled randomized trial compared ketoprofen, 75 mg, 150 mg and 2.5 mg of zolmitriptan (Zomig). All three active therapies were equally effective in relieving migraines and were much more effective than placebo. This does not mean that ketoprofen and zolmitriptan are equally effective in any particular migraine sufferer because some people will respond better to an NSAID and other to a triptan. Also, the usual dose of zolmitriptan is 5 mg, so it is possible that even on average, a 5 mg dose might be superior to ketoprofen. We often combine a triptan with an NSAID such as ibuprofen (Advil) or naproxen (Aleve, Naprosyn) and ketoprofen can also be combined with a triptan.

Another double-blind study compared 100 mg ketoprofen suppository (a compounding pharmacy can prepare such a suppository) with 2 mg ergotamine suppository and ketoprofen was found to be superior to ergotamine. Since the introduction of triptans ergotamine has not been widely used because it causes more side effects, particularly nausea.

Just like with other NSAIDs, the most common side effects are gastrointestinal – heartburn, stomach pain, bleeding ulcers, etc. NSAIDs can also cause tinnitus (ringing in the ears), rashes, and with long-term use, kidney and heart problems.

Indomethacin (Indocin) is one of the strongest non-steroidal anti-inflammatory drugs (NSAIDs), but unfortunately it is rarely used for the treatment of migraines. It has a higher chance of causing gastro-intestinal (GI) side effects than other NSAIDs, but some patients tolerate it very well, especially if it is used sporadically. The drug can be compounded into a rectal suppository, which reduces (but does not eliminate) GI side effects and provides faster onset of effect than an oral capsule. Even if nausea is not obviously present, migraine is often accompanied by gastric stasis, which means that absorption of oral drugs is slowed down. This is why pharmaceutical companies often try to formulate migraine drugs into nasal sprays, injections, patches and inhalers. Rectal route also bypasses the stomach, but suppositories are less popular in the US than they are in Europe. The dose of oral indomethacin is 25, 50 or 75 mg taken up to three times a day, while suppositories usually contain 50 mg.

Indomethacin has some unique properties that differentiate it from other NSAIDs and it is often the only NSAID that is highly effective for episodic and chronic paroxysmal hemicrania and hemicrania continua, rare conditions that are often mistaken for migraines. They are even described as indomethacin-sensitive headaches because no other drug provides such dramatic relief. Paroxysmal hemicrania also resembles cluster headache in that it is always one-sided and is often accompanied by nasal congestion and tearing on the side of the headache. Unlike cluster headaches, which last 30 minutes to 3 hours and occur once or a few times a day, the attacks of hemicrania last a few minutes but occur many times throughout the day. Hemicrania continua is also always one-sided and the pain is continuous without any pain-free periods. If indomethacin causes GI side effects, in some patients an anti-inflammatory herbal supplement, Boswellia can be as effective but without causing any side effects. Botox injections is another treatment that can provide relief of indomethacin-sensitive headaches.

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.