Preventive drugs for migraine headaches help less than half of the patients they are given to. There is no significant difference in effectiveness in these drugs. They reduce frequency of attacks by 50 percent, according to a review published in the recent issue of the Journal of General Internal Medicine.

Dr. Shamliyan from the University of Minnesota in Minneapolis and her colleagues conducted a literature review to identify high quality clinical trials of preventive drugs versus placebo.

Based on 215 published trials, the researchers found that all FDA-approved drugs, including topiramate (Topamax), divalproex (Depakote), timolol (Blocadren), propranolol (Inderal) and off-label medicines metoprolol (Toprol), atenolol (Tenormin), nadolol (Corgard), captopril (Capoten) and lisinopril (Zestril); and candesartan (Atacand) were effective in reducing monthly migraine frequency by 50 percent or more in 20% to 40% of patients. Topiramate, other off-label antiepileptics, and antidepressants had higher levels of side effects and were more likely to be stopped by patients because of side effects. While there were no significant differences in benefits between approved drugs, candesartan and other blood pressure drugs were the most effective and had fewest side effects for the prevention of episodic migraines.

The authors also noted that there was no evidence for long-term effects of drug treatments (that is trials lasting more than three months).

This review confirms my bias in favor of Botox injections over drugs. Botox helps not only 70% of chronic migraine patients, but in my anecdotal (but involving thousands of patients) experience it is equally effective for the prevention of frequent episodic migraines.

Photo credit: JulieMauskop.com

The release of a generic substitute of the branded drug Imitrex (sumatriptan) has dramatically reduced the cost and improved the access to this uniquely effective migraine drug. The generic sumatriptan was released four years ago and now the price of one tablet is down to about $3 from over $20. The cost of two other generic triptans, Amerge (naratriptan) and Maxalt (rizatriptan) has remained very high, but it is expected to drop as more companies begin making generic copies. However, generics are not always the exact copies of the original branded drug that we expect them to be. In my previous post in 2009 I mentioned a study that showed that the generic Topamax (topiramate) does not work as well as the brand for some patients. I have also seen this with sumatriptan – my patients tell me that some generics do not work very well or at all. Out of about 10 generics of sumatriptan, I would guess that two are of poor quality. Once you find a generic that works for you, try to stick with the same generic manufacturer. The name of the manufacturer is printed on the bottle the pharmacy gives you. If one pharmacy does not have your generic, try another one. Here is a part of an email I just received from a patient (she gave me permission to share it with you):
“Just wanted to share with you that my pharmacy filled my maxalt melt prescription with yet another generic brand yesterday, which I found very unpleasant.
Previously the generic refills I’d gotten were from a company called PAR. The PAR pills resembled the original MAXALT melts in style of packaging (foil packets in plastic case) in taste and most important in melt-ability (never timed it but it always seemed to dissolve within 5 to 10 seconds–basically immediate dissolve)
But yesterday’s refill was from Mylan. These melts came in a regular prescription bottle of pills. I called the pharmacy after they were delivered thinking they accidentally gave me non-melts. They checked and told me, no, these were melts, just from a different company. They explained that this company (Mylan) packages them like any other pill (in bottles).
When I took the pill last night it felt like what i imagine it would feel like if you took a chewable vitamin and then waited for it to disintegrate in your mouth. It took minutes to “melt”, instead of seconds, and a grainy feeling remained even after that. it also made my upper palate sore, and tasted bad.
Today I called my pharmacist to double check that this was a melt and they checked again and it is. Luckily they were good enough to switch the rest of the prescription to the PAR generic brand. They also told me they would no longer carry the ones from Mylan. (They did say the Mylan generic is cheaper, though, so not sure how this will work out in the future.)”

Cambia (diclofenac) is a prescription anti-inflammatory drug (NSAID) which is approved by the FDA for the treatment of migraine headaches. It is sold as a licorice-tasting powder that has to be dissolved in water before being ingested. This drug belongs to the same family as Advil or Motrin (ibuprofen), Aleve (naproxen), and prescription drugs, such as Relafen (nabumetone), Celebrex (celecoxib), and other. One of the drugs in this category, Viox (rofecoxib) was taken off the market because it increased the risk of heart attacks and strokes. A recent study published in an online medical journal, PLOS Medicine and translated into lay language in an NPR article indicates that diclofenac is as dangerous as Vioxx in causing heart attacks and strokes. The study also indicates that diclofenac unfortunately is one of the most popular NSAIDs in the world. It is probably safe to take Cambia a few times a month to treat migraine headaches, however, it should be avoided by people with other risk factors for heart disease and strokes. These risk factors include migraine with aura, high blood pressure, high cholesterol, diabetes, smoking, oral contraceptives, family history of heart disease, and other. Aspirin (in Migralex and other products), on the other hand, is the only NSAID that has been shown to prevent strokes, heart attacks, and several forms of cancer.

Photo credit: CambiaRx.com

Daily and prolonged intake of high doses of triptan medications (sumatriptan, or Imitrex, rizatriptan, or Maxalt, eletriptan, or Relpax and 4 others) has been shown to be safe in at least three clinical reports. I also have a few patients who have good control of their headaches and no side effects after many years of taking high doses of triptans daily. (I am not suggesting that it is healthy to take any medicine daily for years, but some people have no other choice because without this treatment they are disabled). A report just published in The Journal of Clinical Pharmacy and Therapeutics describes a patient who also was taking high doses of triptans daily (zolmitriptan or Zomig and frovatriptan or Frova tablets and sumatriptan injections), but who developed severe depression on two occasions when the triptans were stopped suddenly. The first bout of depression was very difficult to treat despite trials of several antidepressant drugs (amitriptyline, or Elavil, mirtazapine, or Remeron, and duloxetine, or Cymbalta, with addition of quetiapine, or Seroquel). All these antidepressants work through the serotonin system. His second bout of depression responded very well to bupropion (Wellbutrin), an antidepressant that works on norepinephrine and dopamine, rather than serotonin. This report suggests that while it may be safe to take triptans daily for a long time, they can affect the serotonin mechanisms in the brain and that they should never be stopped suddenly. Another important lesson is that if depression does develop after stopping daily triptans, the preferred drug may be bupropion.

Photo credit: JulieMauskop.com

Migraine headaches that occur at around the time of menstrual period tend to be more severe and more difficult to treat. Analysis of studies that involved 187 women with menstrual migraines who treated at least one of their attacks with frovatriptan (Frova) and one with another triptan showed that frovatriptan was more effective. While all triptans were equally effective in providing pain relief at 2 and 4 hours, rate of headache recurrence was significantly lower for frovatriptan. After 24 hours, 11% of women who took frovatriptan had a recurrence of their headache, but with other triptans 24% had their migraine come back. After 48 hours, the numbers were 15% for frovatriptan and 26% for other triptans. One caveat is that all of these studies were funded by the maker of frovatriptan.

I see many patients who tell me that “I’ve tried every migraine drug” and seek me out to explore non-drug approaches, such as herbs, supplements, Botox, acupuncture and other. I always try to avoid using medications (and have written books on non-drug approaches), but some patients do best with a combination of medications and non-drug approaches. So, when someone tells me that they’ve tried “every drug”, I tell them that I’ve never seen such a person because there are so many drugs that we use to treat headaches. For example, they might’ve tried a blood pressure medication, but we have many different anti-hypertensive drugs and they work in different ways. One type of blood pressure medication may work when another does not. Also, if one drug caused side effects, another in the same or different category may not.
Here is a brief description of blood pressure medications that are used for the prophylactic treatment of headaches. The first medication approved by the FDA for the prevention of migraine headaches was propranolol (inderal) (methysergide or Sansert was approved earlier, but it is no longer available in the US). Propranolol was originally developed for the treatment of hypertension and then accidentally was found to help migraine headaches as well. A second beta blocker, timolol (Blocadren) was also tested, was found to work well and it also received FDA approval. Other beta blockers, such as atenolol (Tenormin), labetalol (Normodyne), and nebivolol (Bystolic) were also shown to be effective. Nebivolol tends to have fewer side effect, but it is not yet available in a generic form, so it can be relatively expensive. Propranolol is available in a slow release form (Inderal LA) which can be taken once a day, while regular propranolol goes in and out of the body quickly and needs to be taken two or three times a day. Atenolol and nebivolol produce effect that lasts all day, so they can be taken once a day. Atenolol is very inexpensive and I always remind patients to ask the pharmacist about the price without insurance because the insurance co-pay can be higher than the out-of-pocket cost of the drug. Most pharmacists will not volunteer this information.
Because beta blockers worked for migraines other blood pressure medications were also tested. Calcium channel blockers, such as verapamil (Calan), amlodipine (Norvasc), diltiazem (Cardizem), and other do not seem to be as effective as beta blockers. High doses of verapamil are very effective for the prevention of cluster headaches.
Another category of blood pressure medications, ACE (angiotensin converting enzyme) inhibitors, such as lisinopril (Zestril, Prinivil), enalapril (Vasotec) and other do help probably as well as beta blockers. These medications sometimes cause cough or other side effects and can be substituted by similar drugs in the category of ACE receptor blockers (ARBs). ARBs do not cause cough and may have fewer other side effects. Drugs in this group that were studied for the prevention of migraine headaches include olmesartan (Benicar), losartan (Cozaar), and candesartan (Atacand).

Steroid injections are routinely used at our Center for the treatment of cluster headaches and occipital neuralgia. I just received a call from a concerned patient with cluster headaches who recently received an occipital nerve block with methylprednisolone acetate (Depo-Medrol), the same drug that caused fungal meningitis in almost 200 patients, of whom 14 died. His cluster headaches stopped after the injection and he had no symptoms of meningitis, but understandably he was still concerned. All of the patients who contracted meningitis were given epidural injections which are given for low back or neck pain with medicine deposited near the meninges or soft covering that envelopes the spinal cord. All of them received a tainted product manufactured by a compounding pharmacy, which was not licensed to mass produce such medications. Their product was significantly cheaper than the same medicine produced by the largest pharmaceutical company in the world, Pfizer. We have never used any other products except for the one made by Pfizer. I an addition to methylprednisolone (Depo-Medrol) some doctors use a different steroid, triamcinolone, which is manufactured by Brystol Myers Squibb under the name Kenalog. Whenever you receive a steroid injection for back pain, joint inflammation, cluster headaches, or any other indication, ask the doctor if the steroid you are going to receive was manufactured by a major pharmaceutical company. In case of epidural steroid injections, you should also question if these injections are really necessary because they have never been proven to be effective in the first place and even pure untainted products have been associated with spinal cord damage and other serious side effects.
Epidural steroid injection:

Steroid medications can be very effective for migraine headaches that fail to respond to other medications. Steroids, such as prednisone, dexamethasone, methylprednisolone have many potential serious side effects if taken for a long time. We know about these long-term side effects from patients with asthma, arthritis, lupus and other conditions who have take steroids daily for months and even years. However, these medications are relatively safe if taken for only a few days. If a severe headache does not respond to Migralex, sumatriptan, (Imitrex), or other medications, I prescribe a two-day course of dexamethasone. The usual dose is 8 mg daily for two days. Other doctors prescribe a six-day course of methylprednisolone (Medrol Dosepak). However, if a headache completely resolves after two days, it seems unnecessary to continue this medication for the full six days. In the office, we also give intravenous dexamethasone which provides faster relief than tablets. Another indication for steroids is for cluster headaches. A ten-day course of prednisone (starting with 100 mg and reducing by 10 mg every day) can sometimes stop the entire cluster period. Unfortunately, for some cluster headache sufferers headaches return as soon as the dose of prednisone is lowered. If no other preventive medication, such as verapamil, lithium, topiramate (Topamax) or divalproex (Depakote) work, some patients with severe attacks are willing to accept the risk of long-term side effects of steroids. Some of these side effects are weight gain, diabetes, stomach ulcers, glaucoma, high blood pressure, and osteoporosis.

Injections of sumatriptan (Imitrex) are very underutilized. Many doctors fail to offer this option to their migraine and cluster headache sufferers because they are not aware of this option or more often because they are not aware how debilitating migraines can be or because they consider it to be dangerous. Patients who wake up with a severe headache (migraines commonly occur in the morning) and have to go to work or take care of their children often become disabled for the day because oral medications are not effective. Another group of patients who benefit from injections are those with nausea and vomiting. But you do not have to have a severe attack or have vomiting to take an injection. I have occasional migraines, usually triggered by wine or lack of sleep and if I take an oral medication it will usually help, but it may take an hour or even two before it works. So, if I have a headache late in the evening, I take an injection which stops my migraine within 10 minutes and I can fall asleep right away instead of waiting for an hour before the tablet takes effect. Sumatriptan injection is the only drug approved for the treatment of cluster headaches and it is a true life saver for cluster sufferers.
It is very easy to give yourself an injection of sumatriptan. There are three different devices on the market. The oldest one is a little more cumbersome to use, which can be a factor when you are in the midst of a severe attack, but it costs the least and is more likely to be covered by the insurance. Another injector, Sumavel does not have a needle – the device shoots the medicine into the skin through a tiny hole. This device is easier to use but some people complain that it is more painful despite it being needleless. The third device, Alsuma is identical to the one used in the Epi-Pen and it is also very easy to use. Sumatriptan is also available in vials. Some people prefer to use vials for several reasons. First, they are cheaper, second, they may be less painful to inject since you can use a syringe with a smaller needle than the ones in autoinjectors and third, some people get excellent results and fewer side effects with a smaller dose and the vial allows them to use 2 or 3 mg. Being able to use 2 or 3 mg at a time is particularly useful for cluster headache patients who have one or two headaches a day for extended periods of time and don’t get enough injections from their insurer.
If you suffer from severe migraine or cluster headaches ask your doctor about injections of sumatriptan. The main contraindication is heart disease or multiple risk factors for heart disease, but otherwise it is a very safe medicine. In Europe tablets of sumatriptan are sold without doctor’s prescription.

Migraine patients can sometimes benefit from an Alzheimer’s drug, Namenda (memantine). All drugs for the preventive treatment of migraines, including Botox, had been first approved for a completely different indication. Beta blockers and other high blood pressure drugs, epilepsy drugs, and antidepressants are the most commonly used medications for migraine. It is surprising that such a wide variety of medications with very different mechanisms of action would all provide relief for migraines. We have only a basic understanding of how these drugs might work because they were discovered to help migraines by accident. Namenda is a very old medicine that has been available in Europe for over 30 years. It was used for a variety of neurological conditions, but in the US it was introduced and approved only for Alzheimer’s disease in 2003. It works by blocking an NMDA receptor, which is found in brain cells and which is responsible for letting calcium into the cells. Excessive inflow of calcium leads to many negative effects, including propagation of pain messages along the nervous system. Magnesium is a natural NMDA receptor blocker and we often add Namenda to magnesium for stronger effect. Namenda is not a very strong medication, meaning that it probably works for less than half of the patients, but it also causes fewer side effects than many other drugs. It is well tolerated even by the elderly Alzheimer patients, although like any other drug it can cause side effects, including nausea, drowsiness, and dizziness. Another problem with the drug is that some insurance companies do not pay for it because it is not approved for the prevention of migraines.

Chronic and episodic paroxysmal hemicrania and hemicrania continua are rare types of headaches that have one common feature – they respond very well to indomethacin (Indocin). The diagnosis is actually based not only on clinical features but also on the response to indomethacin. Indomethacin belongs to the category of NSAIDs (non-steroidal anti-inflammatory drugs) such as aspirin, ibuprofen, naproxen, and other. Indomethacin is somewhat unique in the way it works and it is often stronger, however it also causes more gastrointestinal side effects than other NSAIDs. Symptoms of paroxysmal hemicrania are similar to those of cluster headaches: the pain is very severe, very brief (lasting a few minutes) and occurs anywhere from a few times to a few hundred times a day. The pain is always one-sided, localized to the eye and it is often accompanied by tearing, nasal congestion, and redness of the eye. Hemicrania continua is very different in that it is present constantly and it is not very severe, but it also involves only one side of the head. Hemicrania continua is often mistaken for chronic migraine or chronic tension-type headache, which leads to ineffective treatments. The dose of indomethacin varies from 25 to 75 mg, taken three times a day. Some patients with these headache types do not tolerate indomethacin, which can cause heartburn, stomach ulcers, bleeding ulcers and other side effects. In those patients we try epilepsy drugs, other NSAIDs (which may or may not be better tolerated), as well as Botox injections and sometimes these treatment do help, if not as well as indomethacin, at least enough to improve patients’ quality of life.