Butorphanol nasal spray (Stadol NS) is approved by the FDA for the treatment of acute migraine attacks. It belongs to the agonist-antagonist type of opioid (narcotic) drugs, while morphine, methadone, oxycodone, and most other opioids are pure agonist drugs. The agonist-antagonist drugs were originally thought to be less addictive, but unfortunately this is not the case.

Also, opioid analgesics despite being very strong pain killers, are not very effective for the treatment of migraines. This is in part due to the fact that migraine pain is accompanied by nausea (and other symptoms), while opioids tend to cause nausea or make it worse. Other side effects of butorphanol include constipation, upset stomach, dizziness, drowsiness, feeling strange or even having frank hallucinations.

The bottom line, despite the fact that it is FDA-approved for migraines, stay away from butorphanol – it is only modestly effective and has many potential side effects, including addiction.

Cyproheptadine (Periactin) is one of the most popular drugs for the prevention of migraine headaches in children. Unfortunately, there is only one scientific study suggesting that cyproheptadine (4 mg per day) is as effective as propranolol (80 mg per day) for the prevention of migraines in patients aged from 16 to 53. There are no double-blind placebo-controlled trials of this drug in children and it is not likely that any will be conducted. It may not be such a big loss since most headache specialists do not consider it to be very effective.

Cyproheptadine is an anti-histamine, which means that if allergies contribute to migraines, it could help. It is available in 2 mg and 4 mg tablets and the dose ranges from 2 to 12 mg taken at bedtime. Some kids can tolerate as much as 8 mg taken three times a day. The drug is popular with pediatricians because it is fairly safe, even if it is not very effective. Common side effects are sleepiness, dizziness, dry mouth, and weight gain. Parents of very skinny kids and of kids who are finicky eaters may like the weight gain.

Blood pressure medication propranolol was the first preventive drug approved for the treatment of migraine headaches over 50 years ago. It belongs to the family of beta blockers, but other types of blood pressure drugs can be effective for migraines as well.

Clonidine (Catapres) works not on beta but alpha receptors and has very limited scientific evidence for its efficacy in the prevention of migraines. It is used only if other blood pressure medications are ineffective, cause side effects, or are contraindicated. It is in category C of evidence (possibly effective) of the migraine treatment guidelines issued by the American Academy of Neurology.

Clonidine is also used to treat pain, but the evidence that it really helps is also slim. Anecdotally, it seems to help reduce withdrawal symptoms when stopping opioid (narcotic) drugs.

Besides beta blockers, ACE inhibitors (lisinopril), ACE receptor blockers (candesartan, olmesartan) and calcium channel blockers (flunarizine, verapamil) are probably more effective for the prevention of migraine headaches than clonidine, but most are also in the same category C – possibly effective.

Clonazepam (Klonopin) is a drug approved for the treatment of panic attacks and certain types of seizures. It is also used “off label” to treat anxiety, insomnia, and muscle spasm. Clonazepam belongs to the family of benzodiazepines, which includes diazepam (Valium), alprazolam (Xanax), and lorazepam (Ativan). Clonazepam tends to have a longer lasting effect and it is thought to be less likely to cause physical and psychological dependence and tolerance, i.e. the need to keep increasing the dose to achieve the same effect.

Clonazepam is not the first or even the tenth choice when treating migraine headaches. However, adding clonazepam to other medications can provide significant relief. This could be in part due to the fact that patients with migraines are 2-3 times more likely to have anxiety and panic attacks. They are also often anxious about getting their next migraine and this anxiety and tension becomes a self-fulfilling prophesy. Anecdotal reports, including one from a fellow headache expert and friend, Dr. Morris Meizels, suggest that in some patients who do not respond to a variety of other treatments, clonazepam can be very effective.

I use it in a very small number of patients whose anxiety, neck pain, and/or insomnia are major contributors to their migraine headaches and whose migraines do not respond to several standard preventive therapies. Before prescribing clonazepam, among the medications we try first are antidepressants, such as nortriptyline or duloxetine. These have no risk of addiction, but sometimes can be difficult to stop due to physical dependence and they can have other unpleasant side effects. I also always suggest aerobic exercise, meditation and cognitive behavioral therapy (CBT). ThisWayUp.org.au offers a very affordable and scientifically proven way to do CBT on your own.

Chlorpromazine (Thorazine) belongs to the phenothiazine family, which includes prochlorperazine (Compazine) and promethazine (Phenergan), drugs used to treat nausea and vomiting. These drugs can relieve not only the accompanying nausea, but the migraine headache as well. The Australian & New Zealand Association of Neurologists recommends chlorpromazine as one of the drugs for the treatment of moderate to severe migraine in an emergency setting.

Chlorpromazine is approved for the treatment of schizophrenia, severe mania and also for nausea, vomiting, severe hiccups, and other conditions. Chlorpromazine is considered to be a stronger antiemetic (anti-nausea) drug than prochlorperazine and promethazine, but it can have more side effects. Side effects include dizziness, drowsiness, but the most unpleasant side effect is severe restlessness and involuntary movements. Some patients describe it as wanting to crawl out of their skin. This side effect usually can be relieved by diphenhydramine (Benadryl). Prolonged use of phenothiazines can lead to persistent involuntary movements, which are extremely unpleasant and do not go away after the medicine is stopped. Higher incidence of side effects is why chlorpromazine should be used for nausea only if milder drugs such as ondansetron (Zofran), metoclopramide (Reglan) and prochlorperazine (Compazine) do not help.

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.