Bisoprolol (Zebeta) is one of about a dozen drugs in the beta-blocker family, medications that were developed for the treatment of high blood pressure, or hypertension. The oldest beta blocker, propranolol (Inderal) was approved by the FDA for the treatment of hypertension about 60 years ago and a decade later it was also approved for the prevention of migraine headaches. Timolol (Blocadren) is the only other beta blocker that is officially approved for migraines, but most likely they all work. Even though they are very similar, beta blockers may have different efficacy and especially, different side effects from patient to patient. A drug that works well and without side effects in one person may cause side effects in the next. Also, not all beta blockers have been subjected to rigorous double-blind trials for the prevention of migraines, so we tend to prescribe the ones that do have some evidence supporting their efficacy in migraines.

Bisoprolol is one of the beta blockers that has scientific evidence suporting its use in migraines. A blinded study comparing bisoprolol, 5 mg with metoprolol (Lopressor, Toprol), 100 mg, another beta blocker showed them to be equally effective in the treatment of migraines.

The European Federation of Neurological Societies recommends bisoprolol as a second-line beta blocker for the prophylactic treatment of migraine headaches, after propranolol and metoprolol. THe US guidelines list bisoprolol further down the list.

Fremanezumab (Ajovy) was just approved by the FDA for the preventive treatment of migraine headaches. It is the second drug, following erenumab (Aimovig), with a similar mechanism of action. While erenumab blocks calcitonin gene-related peptide (CGRP) receptor, fremanezumab binds to the CGRP molecule and blocks its attachment to the CGRP receptor. Both are very effective in preventing migraine attacks and both, so far, appear to be very safe. Just like erenumab, it is approved for the prevention of migraines without regard to the frequency of attacks, unlike onabotulinumtoxinA (Botox), which is only approved for chronic migraines, which are defined as occurring on 15 or more days each month.

Here are some differences between the two drugs that we know of so far. Fremanezumab can be injected monthly or with a triple dose, every three months. Considering that one of my patients developed a rash from erenumab (no surprise there – any drug can cause an allergic reaction), I probably will start with a single shot once a month and then may give a triple dose every three months. The second difference is that constipation is not listed as a side effect of fremanezumab in the FDA-approved prescribing information, while it is listed as occurring in 3% of patients on erenumab. Since these drugs have a similar mode of action, I will not be surprised if fremanezumab also causes constipation in some patients. So far, only two of my patients (out of about 300) declined to continue erenumab because of constipation.

Erenumab is available only in an easy-to-use autoinjector pen, while fremanezumab comes only in a prefilled syringe. I suspect some patients will prefer to come into the office every three months to get their fremanezumab injections, rather than inject themselves, but the majority will self-inject it. One advantage of prefilled syringes is that a small test dose can be given before giving the entire amount. This is what I plan to do for my patient who developed a rash from erenumab.

Bupivacaine (Marcaine, Sensorcaine) is a numbing agent (local anesthetic) similar to lidocaine (Xylocaine), but with a longer duration of effect. Bupivacaine effect lasts 4 to 8 hours, while lidocaine, only 2 hours. However, lidocaine begins to work in 2 to 5 minutes, while bupivacaine takes 5 to 10 minutes.

We use bupivacaine to treat migraines in two ways. One is in combination with lidocaine to perform nerve blocks. Nerve blocks can be very effective in stopping a stubborn migraine that does not respond to medications such as triptans, NSAIDs, intravenous magnesium, ketorolac, and other. We also give nerve blocks to pregnant women who fail to respond to intravenous magnesium and before using systemic drugs, that is drugs taken by mouth or by injection and that are distributed throughout the body, including the fetus.

The nerve blocks are done with small needles, although during a migraine attack even a small needle can be painful. However, relief from the numbing effect of lidocaine comes within minutes, while bupivacaine in the mixture provides longer lasting relief. Some headache specialists give regular nerve blocks every 3 months in place of onabotulinumtoxinA (Botox) injections. Nerve blocks are not as effective as Botox, but we do give nerve blocks when the effect of Botox wears off sooner than 3 months. Ideally, we try to give Botox earlier, but many insurance companies will not allow Botox injections more often than every 3 months.

We also use bupivacaine by itself for sphenopalatine ganglion (SPG) blocks . These blocks are not painful since they are done without a needle. Bupivacaine is delivered to the ganglion which is located behind the nasal cavity and underneath the brain through a thin plastic catheter (we use Tx360 device). The SPG block can be also effective for the treatment of an acute cluster headache.

Dexamethasone (Decadron) is a strong corticosteroid (steroid) anti-inflammatory medication similar to prednisone and methylprednisolone (Medrol). Considering that inflammation occurs during a migraine attack and that non-steroidal anti-inflammatory drugs (NSAIDs) work well for migraines, you’d expect that a steroid medication would also be effective. And they do help, but mostly in combination with migraine drugs such as sumatriptan (Imitrex), rizatriptan (Maxalt) and other. In a blinded study, 4 mg of dexamethasone given along with 10 mg of rizatriptan was more effective than rizatriptan alone and it reduced the rate of migraine recurrence. Dexamethasone given intravenously in an emergency room setting also reduced the rate of migraine recurrence.

The usual oral and intravenous dose of dexamethasone is between 4 mg and 12 mg. Potential side effects include anxiety, or feeling “hyper”, depression, insomnia, dizziness, upset stomach, increased blood sugar, and other. The multitude of potential side effects is why we first try triptans (tablets and injections), NSAIDs, and nausea medications, before adding steroids. When these drugs not help and intravenous treatment is called for (and the patient is able to come to our office), before giving steroids we try magnesium sulfate, ketorolac (Toradol), ondansetron (Zofran) or metoclopramide (Reglan), and dihydroergotamine (DHE-45). We may also give nerve blocks or a sphenopalatine ganglion block to avoid giving a steroid medication.

Codeine is a mild opioid (narcotic) pain killer, which has less of an addiction potential of butorphanol, described in the previous post, or most other opioid drugs. However, it definitely can cause addiction and can be a “gateway drug” leading to the abuse of stronger prescription and illicit drugs. Some countries allow codeine to be sold without a doctor’s prescription, but it is always in a combination with other drugs. In Canada, codeine has to be mixed with two other drugs, usually with acetaminophen and caffeine and it is sold without a prescription, but from behind the counter rather than from open shelves.

A combination of codeine with caffeine, butalbital and either acetaminophen or aspirin (Fioricet with codeine and Fiorinal with codeine) is particularly problematic because caffeine can also cause medication overuse headache and butalbital is also addictive.

The main problem with codeine is that just like other opioid drugs it is not very effective and can cause or worsen nausea. If taken regularly (more than once a week) opioids can also cause medication overuse (or rebound) headache even in the absence of addiction. Codeine with acetaminophen is worth considering if triptans (sumatriptan or Imitrex and similar drugs) and NSAIDs (Advil or ibuprofen, Aleve or naproxen, and other) are ineffective or contraindicated.

I do have patients taking Fioricet or Fiorinal with codeine or codeine with acetaminophen with good relief and few side effects, but I can count those patients on the fingers of one hand.

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.