Candesartan (Atacand) is a blood pressure medication in the class of ACE receptor blockers (ARBs), none of which are approved for the treatment of migraines. Because they are available in a cheap generic form no pharmaceutical company will spend hundreds of millions of dollars on large trials required for the official FDA approval. This does not mean that unapproved drugs are ineffective, it’s just the evidence is weaker because it is based on small trials. Unfortunately, only four oral drugs are FDA-approved for the prevention of migraines – two beta blockers and two epilepsy drugs (Botox and Aimovig or erenumab are injectable). So most of the preventive drugs we prescribe are “off label”, that is they lack FDA approval.

Candesartan was first shown to work for the prevention of migraine headaches in a 60-patients Norwegian trial published in JAMA in 2003. This was a double-blind crossover trial, which means that half of the patients were first placed on a placebo and then switched to candesartan and the second group started on candesartan and then were switched to placebo. This trial showed that when compared to placebo, 16 mg of candesartan resulted in a very significant reduction in mean number of days with headache, hours with headache, days with migraine, hours with migraine, headache severity index, level of disability, and days of sick leave. Candesartan was very well tolerated – there was no difference in side effects in patients taking the drug and those taking the placebo.

In another trial, the researchers compared candesartan to placebo as well as to propranolol, which is an FDA-approved blood pressure drug for the prevention of migraines. This trial in 72 migraine sufferers compared 16 mg of candesartan with placebo and with 160 mg of propranolol. Candesartan and propranolol were equally effective in reducing migraine days per month and both were significantly more effective than placebo.

One advantage of candesartan over propranolol and other beta blockers is that it does not lower heart rate, which can make exercise difficult. Both can cause fatigue and dizziness due to the lowering of blood pressure, but the weight gain and depression occasionally seen with propranolol does not happen with candesartan. On the other hand, propranolol can sometimes help reduce anxiety.

Baclofen (Lioresal) is one of several muscle relaxants that have been tested for the treatment of migraine headaches. The testing was not very rigorous – baclofen was subjected only to one open label trial. The trial done by an Israeli neurologist, Dr. Rachel Hering-Hanit involved 54 patients. After a 4-week baseline assessment period, patients were given baclofen for 12 weeks. The drug was given three times a day with the dose ranging from 15 to 40 mg.

What was impressive about this study is that not only 86% of patients improved by at least 50%, but also that 51 out of 54 patients completed the study. It is very likely that many would have dropped out if the treatment was ineffective or had a high rate of side effects. Only 3 patients dropped out because of side effects.

Dr. Hering-Hanit also tested baclofen in 9 cluster headache sufferers with six improving within a week on doses ranging from of 15 to 30 mg.

The main side effect of this drug is drowsiness. Some patients may not need to take it three times a day – one nightly dose may suffice. I start with 10 mg nightly and gradually increase the dose. However, another muscle relaxant, tizanidine has been shown to relieve chronic migraine in double-blind studies and I tend to use it much more frequently than baclofen. Tizanidine has the same main side effect – sedation.

Butalbital, a short-acting barbiturate, is one of the three ingredients in headache drugs such as Fioricet, Fiorinal, Esgic and their generic equivalents. Fiorinal and Fioricet derive their name from the Montefiore Headache Clinic, where they were developed over 60 years ago. In those days extensive clinical trials were not required by the FDA and they were approved without much testing. The approval was and still is only for the treatment of tension-type headaches. They have never been shown to be effective for migraines, although this is what they are mostly used for. Fioricet and Esgic contain butalbital, caffeine, and acetaminophen, while in Fiorinal acetaminophen is replaced with aspirin.

Neurologists have a strong dislike of this drug, although general practitioners tend to like it because they are very familiar with it. The dislike comes from the fact that butalbital is addictive and caffeine can make headaches worse. I’ve seen patients who openly admitted that they often take Fiorinal to relieve anxiety and many become physically dependent and addicted to it. My most memorable patient was one who took 20 to 30 tablets every day. I had to hospitalize her for detoxification. In patients who take more than 5-6 tablets a day sudden discontinuation can lead to an epileptic seizure. We usual switch patients to a long-acting barbiturate, phenobarbital, which is easier to stop. Withdrawal from caffeine worsens headaches, for which sumatriptan tablets or injections can help. Botox injections and other preventive migraine drugs can also make the withdrawal process less painful.

I should mention that I do have a very small number of patients for whom I prescribe these drugs for occasional use, but these exceptions confirm the rule – Fioricet and Fiorinal are ineffective for the vast majority of migraine sufferers and can lead to worsening of migraines and addiction.

Anxiety is one of the conditions comorbid with migraines – if you have migraines you are 2-3 times more likely to suffer from anxiety as well. The relationship is bidirectional, meaning that if you have anxiety, you are more likely to develop migraines. Antidepressants are proven to relieve anxiety even in the absence of depression and they are a better long-term solution than anxiety drugs such as diazepam (Valium) or alprazolam (Xanax) because they are not addictive and do not lose their efficacy over time. A unique drug that is used only for anxiety and not depression and does not cause addiction, is buspirone (Buspar).

Several studies suggest that buspirone is effective for the treatment of migraines. In a 74-patient randomized, prospective, parallel group, double-blind, placebo-controlled study (the most rigorous type of study) headache frequency showed a 43% reduction in the buspirone-treated group, but only a 10% reduction in the placebo group. This effect was independent of the presence or absence of anxiety. Similarly, antidepressants prevent migraines even if the patient is not depressed.

Buspirone has a favorable side effect profile and it does not cause withdrawal symptoms, which is often a problem with other anxiety drugs and to a lesser extent, antidepressants.

On June 1, I injected myself with erenumab (Aimovig). I still had to take sumatriptan for an incipient migraine on June 2 and June 5. On Thursday, June 7, I had a glass of red wine (pinot noir) with dinner and had no headache. Last night, June 9, I decided to stress-test my response to erenumab and had a beer before dinner and a big glass of sparkling wine with dinner. In the past, this combination had always resulted in a migraine a few hours later. This time, nothing happened!

And here is an excerpt from an email from a patient who was one of the first to receive Aimovig:

“Hello Doctor,
It has been a week now and I wanted to share with you the outcome.
It’s a very important improvement as I was able to stop taking Relpax compared to 40mg a day!
3-4 times I felt the migraine coming but it was like « stopped » and I was feeling ok.
It happened during the day and at night twice.
Overall it’s a fantastic improvement.”

Certainly, this all could be due to the placebo effect, but I doubt it, especially because my migraines did not stop right after the injection. I should stress that erenumab is not going to help everyone. Clinical trials suggest that about 60% of migraine sufferers will benefit, but this is a very high success rate, especially considering the lack of any significant side effects.

Cheers!

Propranolol (Inderal) and other blood pressure medications in the beta blocker family are effective for the prevention of migraines. In a previous post 4 years ago I mentioned a report of 7 patients whose migraines were aborted with beta blocker, timolol, eye drops that are used to treat glaucoma.

The same group of doctors at the University of Missouri, Kansas City conducted a double-blind crossover study of timolol eye drops for the treatment of acute migraines. The results of the trial were published this month in JAMA Neurology. The treatment consisted of 4 drops of 0.5% timolol (this compares with 10 to 30 mg dose taken orally. Ten patients treated almost 200 migraine attacks. Four participants found timolol highly effective compared with placebo and one patients rated placebo as highly effective compared with timolol. No side effects were observed.

Instilling timolol eye drops is not likely to become widely used for the treatment of acute migraines. However, this treatment maybe worth trying in patients who do not respond or do not tolerate triptans and NSAIDs.

Only about 20% of migraine sufferers experience an aura. The most common type of aura is visual and it typically consists of partial obscuration of vision with colorful zigzags and blind spots spreading over half of the visual field of both eyes. Sometimes, the aura consists of gradual narrowing of the visual fields which ends in tunnel vision or complete loss of vision. The typical duration is 20 to 60 minutes and usually the aura itself is not disabling, but the headache that follows can be more severe than during attacks without aura. Migraine aura can occur without a subsequent headache. In some people aura does interfere with normal functioning and can be more disabling than the headache. In rare instances, the visual disturbance persists for days, weeks, and months.

In such cases I do a battery of blood tests, including for RBC magnesium, vitamin B12, homocysteine, CoQ10 levels, and other. If RBC magnesium level is low or at the bottom of normal range, a gram of magnesium sulfate given intravenously can abort the aura. We sometimes give an infusion of magnesium without first doing a blood test.

Amiloride (Midamore) is a potassium-sparing diuretic (water pill), which means that unlike most diuretics, it does not deplete potassium. It is used to treat high blood pressure, heart failure and to remove excess fluid in the body. It has been reported to reduce aura and headache symptoms in 4 of 7 patients with otherwise intractable aura. Potential side effects of amiloride include dizziness, nausea, stomach pain, and diarrhea.

Other diuretics, such as acetazolamide, which is also used for barometric pressure-induced migraines and furosemide have also been reported to stop a prolonged visual aura. Other approaches to treat a persistent aura include the use of preventive migraine medications, such as a blood pressure medication, verapamil (Calan) or one of the epilepsy drugs, such as topiramate (Topamax), divalproex sodium (Depakote), or lamotrigine (Lamictal). An infusion of divalproex sodium derivative, valproic acid (Depakene) can be also tried.