Timothy C. Hain, M.D. and Marcello Cherchi M.D. Ph.D., Chicago IL. Page last modified: May 30, 2017
Other links on this site:
For those who have more than 2 severe headaches/month and in patients with complicated migraine (migraine with stroke-like features), a daily medication may be worth while. These are generally highly effective (about 75% effective), but do require daily regular use. Only about 3-5% of migraine patients use prevention medications, according to Gray (1999).
These drugs fall into 5 major classes: anticonvulsants, antidepressants, antihypertensives, dopamine blockers, and Botox (? local anesthetic, placebo ?). Mechanistically, these drugs seem to work via several pathways: some are beta-blockers (e.g. Inderal, Corguard), some are calcium channel blockers (e.g. verapamil). Some work on electrical activity in the brain(e.g. topiramate). Some in mysterious ways, possibly through manipulations of serotonin(e.g. Nardil, amitriptyline, venlafaxine). More information about these is in the next section.
Trial/error is what you have to do in migraine.
Migraine is a "committee disease", with multiple genetic variants (probably thousands). It seems extremely likely that there is no single drug that will "work" in this collection of at least 12 genes, found to various extents in persons with migraine, that share some common features. In other words, prevention of migraine is a "trial and error" process.
If one accepts the idea that there are thousands of variants of Migraine (associated with various combination of genetic traits), it also follows that "adding on" one medication to another, may not be the best strategy. To use a military analogy, the additive strategy is based on the core assumption that one knows one's target, and one is just concentrating more firepower. If the targets are all over genetic map, one does not know for sure that one's weapons are even pointing in the same direction. This is why it is best to try things one by one.
Because migraine is basically a disorder where people check of symptoms and then they have "migraine", there is almost certainly very substantial mixture between many different disorders that have the same symptoms. To put this another way -- you can read the wikipedia description of migraine, go in to see your doctor, and Voila -- you have migraine. "Lumping" has been sooooo substantial in migraine. We are not treating a "disease" here -- we are really treating a collection of symptoms. It seems likely that to make more progress right now, we will have to take the "precision medicine" approach, and let the splitters deconstruct "migraine" -- we need to break migraine out into a collection of better defined enitities.
To use these drugs it is best to have a measure of effect. One way is to use a headache diary. Here we recommend a month/page style format, and a stoplight; color code - - red bad, yellow -- fair, green good. Another is to do it online -- see http://www.headachetest.com/.
Our approach to migraine prevention and use of these drugs can be found by clicking on the flowchart above. We call this "rational polypharmacology" -- we try to avoid drugs with similar mechanisms, and when we combine drugs, we try to use different mechanisms.
We also can point the reader to an extensive online review published in 1999 by a US government agency, and found on the NCBI bookshelf. Although it is extremely dated (i.e. somebody should put out a newer edition), it still summarizes an immense amount of data.
The author of this review usually starts patients with effexor (venlafaxine), and proceeds on to try topamax, verapamil, propranolol and then amitriptyline or nortriptyline. Botox injections is appropriate in certain patients with chronic migraine. Generally patients are also encouraged to take vitamin-D (2000 units/day), and magnesium supplements (500 mg/day).
It is very unusual that headache control is not attained. When one "group" doesn't work, the author may combine several groups simultaneously (anticonvulsant, blood-pressure agent, antidepressant, Botox ). Except in unusual cases, other than Botox, drugs are stopped in women intending to become pregnant.
We would urge great caution in believing the migraine literature. In general, those that commonly publish articles about migraine treatment are funded by the drug industry (e.g. see Botox). When one looks at the lists of drug companies who have funded the writers of these articles, they may take up several paragraphs ! Drugs that might be particularly likely to have "slanted" literature are those that are expensive (which includes many) and in which there is no generic drug yet available. There are many of these medications used for migraine treatment.
We have been asked several times whether or not migraine prophylactic medications will prevent evolution of the white matter lesions that are common in migraine. As of 2010, the literature is silent on this question. There are two general ideas about the origin of the white matter lesions -- 1. microemboli through a patent PFO or other type of shunt 2. Vasospasm due to some mysterious underlying neurochemical abnormality associated with migraine. If #1 is accurate, then one would think that persons with spots would be treatment resistant (as most medications we use have little to do with coagulation - -verapamil is the main exception). If #2 is accurate, one would think that persons with spots would be the same as anyone else regarding treatment, and in fact, should be treated more aggressively to prevent damage. The PFO theory has recently been deemphasized.
See this link for a list of drugs organized by mechanism.
There are so many studies of these drugs, a database would seem the most logical way to organize them. We do not know of any online (yet).
Ace inhibitors (candesartin, lisinopril) Slightly effective. (2012)
ACE inhibitors are presently mainly used for hypertension, but they also have some slight utility for migraine prevention. (Ashenazi et al, 2003; Tronvik et al, 2003). Studies of these drugs suggest that they are better than placebo. Nevertheless, it is the opinion of the writer of this review that they are much less effective than beta-blockers, venlafaxine, and amitriptyline.
Aripiprazole (Abilify). Need more data.
Recently there have been anecdotal reports concerning effectiveness of this atypical antipsychotic drug for migraine prevention. Aripiprazole is a partial agonist at both the dopamine D2 receptor and the serotonin 5-HT1A receptor. Dopamine agonism would be expected to worsen migraine and nausea, while 5-HT1A agonsm, treats migraine. Like the other atypical antipsychotics, aripiprazole displays an antagonist profile at the 5-HT2A receptor. Dose is 10 mg. Common side effects include akathisia (restlessness), headache, unusual tiredness or weakness, nausea, vomiting, an uncomfortable feeling in the stomach, constipation, light-headedness, insomnia, sleepiness, shaking, and blurred vision. This is an expensive drug with significant side effects, and it is unclear whether or not it works for migraine. We would say best to avoid right now.
amitriptyline (Elavil). Effective and inexpensive drug, with considerable side effects, used for prevention
Tricyclics, primarily amitriptyline, have been well studied (e.g. Couch et al, 2011). Usual dose is 50 mg at night but the starting dose is usually 10 mg. Some people do well with just 10 mg. Works very well, but takes 2-6 weeks to work. Amitriptyline doesn't lower the blood pressure. Dry mouth and sleepiness main side effects.
Weight gain of as much of 25 lbs is common. Elavil is inexpensive ! Similar tricyclic type drugs include nortriptyline, doxepin and protriptyline. While few studies are available comparing them, it is likely that they all work. Oddly enough though, although the literature is mixed, clomipramine probably does not work for Migraine (Langohr et al, 1985; Noone, 1977).
Amitriptyline is more likely to have serious side effects when used by people with heart block or urination problems or persons over the age of 60. Pregnancy is category D. We mainly use this drug when our favorites fail.
Amlodipine (Norvasc). Unknown efficacy.
While there have been some sporadic reports suggesting that the calcium channel blocker, amlodipine, works for migraine. There is simply not enough data. The data for other calcium channel blockers, such as nimodipine, nicardipine, and verapamil, is not that strong either. See the section on verapamil below.
Botox (Botulinum toxin injections). Slightly effective.
This agent has recently been FDA approved for prevention of migraine, based on a large trial funded by the drug manufacturer. The mechanism is thought to be action on sensory nerves in the head, not through paralysis of muscles in the head. It is weak and it is expensive. On the other hand, it has no systemic side effects.
carbamazepine (Tegretol) is not effective as a preventive (2012).
A related anticonvulsant, oxcarbazepine (Trileptal) has had some limited success in treating refractory migraine with about a 50% response rate (two abstracts suggest this -- Johnson et al, 2002; Nett and Krusz, 2002). Oxcarbazepine is not FDA approved for this indication. We are dubious that it has any effect on migraine.
Clonazepam -- not effective for migraine
CGRP antagonists. Hope for the best but so far all have been too toxic.
These drugs are presently (i.e. as of 2016) in trials. CGRP is a neuropeptide that is upregulated in migraine. Response rates to research agents are reasonable but significant liver toxicity has been encountered in all drugs tried so far. As of March, 2016, four monoclonal antibodies to CGRP are in phase III trials. These drugs are injected, and we would expect that their cost will be extremely high should they ever come to market. One can only wonder how the health care system will deal with a very expensive drug for persons who endorse a group of symptoms (i.e. migraine patients), but without a blood test or imaging methodology to distinguish between the poseurs and "real" migraine patients. Other conditions with extremely expensive drugs -- e.g. MS or hepatitis, have less ambiguous diagnostic methodologies that require something more than answering questions in the affirmative.
For the most part, the CGRP family of drugs have not been especially powerful agents. Nevertheless, a minority of patients treated, even with a single injection, have been headache free for weeks. Of course, given the heterogeneity of migraine, it would be unrealistic to expect even 50% effectiveness. Also, one would wonder how many patients treated with placebo are headache free.
M. Bigal et al (2016, Bigal is an employee of the Teva drug company) reported that a CGRP antagonist compound called TEV-48125 reduced hours of migraine by about 40 hours/week, in chronic migraine. In another study from Teva, TEV-48125 was reported to have no serious toxicity for injections every 28 days.
cyproheptadine (Periactin) is a preventive medication mainly used in children.
Weight gain is common. We do not favor it in general.
Clonidine. not effective. (2012). This is in spite of reports that a close relative, guanfacine may be helpful.
Cymbalta (duloxetine). This drug may be effective in high doses. It is not effective in starting doses. It resembles venlafaxine except larger doses are needed.
Depakote (sodium valproate). Effective but with many side effects. Pregnancy category D. (2012)
There are so many side effects that we don't see it as a first-line. Used for prevention. Usual dose is 250, three times/day. Side effects include a preeminent tremor, weight gain, and sometimes hair loss. Depakote also should not be used in women of childbearing age who are not using birth control as it is pregnancy category D. Among other things, it increases the risk of autism (Christensen et al, 2013). Some authors suggest that valproate is effective for persistent migraine aura (Rothrock, 1997). We have not been impressed that it is any better than any other drug. There are many possible reasons for it working and at this writing, it is not clear which one is correct (Cutrer et al, 1997).
Effexor (venlafaxine HCI), see here. We find this drug very effective.
Venlafaxine is one of several antidepressant drugs that are effective in migraine (e.g. amitriptyline, nortriptyline, venlafaxine, quetiapine ). All but venlafaxine tend to cause major weight gain.
Withdrawal is a big problem from larger doses of venlafaxine, and we prefer to use very small doses. We always start patients on 1/3 of a capsule of the 37.5 XL. Every week we increase the dose by 1/3, so that at the beginning of the third week, the person is on the full 37.5 capsule. Venlafaxine is generally thought to be safe in breast-feeding (see drugs.com site). Venlafaxine is not approved for use in children under the age of 16. We have no data concerning whether or not it is effective in children for migraine (generally nothing works). We have noted that patients in whom venlafaxine is effective for their dizziness often have a small amount of upbeating nystagmus with video-frenzel goggle testing.
It would seem logical that venlafaxine might work better in menopausal migraines than other agents, as it is also an effective medication for hot flashes.
As migraine is associated with major depression(Breslau et al, 1993), part of the good effect from venlafaxine may be related to this .
Escitalopram (Lexapro). An SSRI. Probably little effect.
We have had little experience with use of this drug for migraine, but it has been reported effective in a one study, e.g. Tarlaci, S. (2009). Lexapro is currently expensive compared to older, generic similar nearly identical drugs such as citalopram. We don't see a rationale why this drug would work. See the discussion of Prozac below.
Fluoxetine (Prozac). An SSRI. Mildly effective.
There have been several studies of modest size, generally reporting a mild-moderate effect. This medication, a member of the SSRI family (which also includes Paxil, Zoloft, Celexa, (escitalopram) Lexapro, and Luvox), is suggested to be effective (Silberstein, 2000; Silberstein et al, 2012). Nevertheless, of roughly 7 controlled trials of SSRI's for migraine, most have showed negligible effect. There is some evidence that another SSRI, paroxetine (Paxil) improves chronic daily headache (Langemark and Olesen, 1994; Foster and Bafaloukos, 1994).
Studies that directly compare fluoxetine to other antimigraine agents such as propranolol and amitriptyline, generally conclude that it is less effective. On the other hand, Fluoxetine has far less side effects than either.
Not everyone agrees that there is good evidence that the SSRI's help migraine(e.g. Goadsby, 2002). We rarely prescribe them for headache in our practice.
Flunarizine (Sibellium) is available in Europe. It is a mixed mechanism drug. We rarely prescribe it because of its dopamine blocking side effects (i.e. think major tranquilizer).
Flunarizine is at least as effective as propranolol (see later). Flunarizine is likely more effective than verapamil because it combines calcium channel and dopamine blocking activity in a single preparation (Afran et al, 1998). Flunarizine has an 18 day half-life, meaning that good effects as well as adverse effects might take a long time to start and end. Flunarizine has been reported as effective in cyclic vomiting (Kothare et al, 2005), and in childhood migraine (Visudtibhan et al, 2004; Peer Mohamed et al, 2012). The usual dose is 5 to 10 mg at night.
We have had a few patients where this drug worked, where nothing else worked. Usually these patients also responded to other dopamine blockers as well.
Gabapentin (Neurontin). Not very effective, but cheap and worth a try.
Neurontin is not very potent for migraine, but it has so few side effects, that it may be worth a try anyway. This anticonvulsant is a prophylactic drug for treatment of migraine (Silberstein, 2000). Gabapentin (strangely enough) does not affect Gaba-b receptors or other commonly studied receptors. It may nevertheless increase glutamate-dependent GABA synthesis and it also binds to the calcium channel. Adverse effects include sleepiness, dizziness, fatigue and weight gain associated with increased appetite. We think that gabapentin may be especially useful in hemiplegic migraine. A newer version of gabapentin is pregabalin ("Lyrica"). This is basically a far more expensive version of gabapentin with a few advantages. Imbalance is common as a side effect of Lyrica. Pregnancy category C.
Inderal LA (propranolol) and other beta-blockers such as timonol. Very effective. (2012).
Beta-blockers are generally accepted as being very effective in migraine, but they can have substantial side effects (Silberstein, 2015)
While propranolol is a very old beta-blocker, there are many others -- these include atenolol, bisprolol, metoprolol and nadolol, and nebivolol. There have been numerous trials of beta-blockers. No difference has been found between propranolol, metoprolol, timolol and nadolol. Beta-blockers are similarly effective to anticonvulsants (e.g. topiramate, valproate) and more effective than SSRI type antidepressants (e.g. flunarizine, citalopram).
Propranolol is a very effective drug, with moderate side effects, when used for prevention. The usual dose is 60 mg LA in the evening. Works as well as Verapamil, but generally has more side effects. Pulse may be slowed. Has a mildly calming effect. Nadolol (Corgard) has a similar effect. Both Inderal and Corgard are non-selective beta blockers. More selective beta blockers include metoprolol (Lopressor, Toprol, dose 25-75 at bedtime) and Atenolol (Tenorman), and Bystolic (nebivolol). Bystolic is particularly low in side effects.
Propranolol is OLD and it should be CHEAP. Oddly enough, propranolol has been getting more expensive. This may be due to the tendency of certain drug companies, such as Valient, to buy up old inexpensive generic drugs and hugely increase their price.
All beta-blockers have a tendency to have a withdrawal syndrome entailing hypertension, and for this reason, are best tapered off when there is a decision to stop. Beta-blockers also generally have a tendency to increase depression, cause weight gain, and to cause sexual dysfunction.
Selective beta blockers usually have less side effects than the unselective beta blockers. Studies of the more selective beta-blockers have shown similar efficacy to the unselective ones, and thus it would seem better to choose the ones that are more selective and have less side effects.
In general, beta-blockers shouldn't be used by persons with asthma, depression, heart failure, diabetes, or taking allergy shots. All beta blockers have some risk of hair loss. This is fortunately rare. This is not an absolute prohibition and in some cases beta-blockers are helpful depending on the overall situation. Combined use of verapamil and beta-blockers should also, generally speaking, be avoided.
Atenolol is pregnancy category D, while metoprolol, propranolol and nadolol are all pregnancy category C. The 'C' agents are preferable in women of childbearing age. Beta blockers, and particularly atenolol, have been reported to increase the chance of diabetes in older people.
A recent trial in which topiramate and Inderal were combined for chronic migraine, was stopped because of lack of evidence that there was any benefit (Silberstein et al, 2012). Of course, this does not mean that the combination is also ineffective in non-chronic migraine, which comprises about 97% of all migraine. Also, note that this combination competes with an alternative extremely expensive treatment for chronic migraine, Botox. Given the lack of certainty that migraine is homogeneous, and also the gigantic financial incentives involved in Migraine, we think it best give this combination a trial in spite of the single study to the contrary. In other words, in our opinion, it still is prudent to exhaust inexpensive combinations for chronic migraine, before turning to Botox.
Certain beta blockers, e.g. pindolol, are thought not to work in Migraine (Silberstein, 2015).
Lamotrigine (Lamictal). Mildly effective but substantial side effects.
This anticonvulsant can be used in a similar way as valproate (see above) to prevent migraine and migraine associated vertigo (Bisdorf, 2004). A recent review article said that there was evidence that Lamotrigine was not effective for migraine. (Silberstein et al. 2012; 2015). We are a little dubious about this. Lamotrigine overdose can cause dizziness and downbeating nystagmus, and there can be tricky interactions of lamotrigine with other drugs.
Lamotrigine can also have a very serious rash, in about 5% of persons. It is said to be more common in persons with Chinese ancestry. While we have not encountered this rash ourselves, this is the main reason that we are reluctant to prescribe lamotrigine for migraine.
Magnesium. Mildly effective, with very little side effect.
Dietary supplements of magnesium as well as intravenous injections of magnesium have been reported to be effective in migraine (Peikert et al, 1996; Mauskop, 1998). Brain magnesium has a complicated relationship to migraine (Boska et al, 2002). Magnesium is usually taken as a dietary supplement, in combination with calcium. About 500 mg/day is suggested. No prescription is necessary. Safety is unknown in pregnancy, but it is used very commonly during labor, and one would not expect that a mineral would cause birth defects.
Memantine (Namenda). Probably not effective.
There are some very preliminary, uncontrolled studies suggesting that this drug in the usual doses for Alzheimer's reduces headache frequency by about 50% (Charles et al, 2007; Peters et al, 2007). At this writing, we are trying this out in refractory patients. It is difficult to see why it would work. Memantine is a glutamate inhibitor. Glutamate is an excitatory neurotransmitter.
This drug is unavailable in the US as of 1/2003. It was very effective but potentially dangerous. Taken in a dose of 2mg TID. Every 6 months, you MUST stop this medication for one month. There is a danger of poor circulation. This drug is a last resort. Some authors recommend getting a CT scan of the kidney area one year after initiating treatment.
The relative of Sansert, methergine, is likely as dangerous as Sansert. It is only used off-label. We have encountered a patient on this drug for migraine who developed a severe cardiac arrhythmias. We advise against use of methergine for migraine.
Nimodipine, Nicardipine, Nifedipine -- weakly effective. These are calcium channel blockers. See the section on verapamil for more.
There have been many studies of nimodipine, all reporting weakly positive effects. We think that some calcium channel blockers increase migraine. Just because it says it is a calcium channel blocker doesn't mean it will work.
NSAIDS (non-steroidal anti-inflammatory drugs). Effective but substantial side effects.
Examples are aspirin, fenoprofen, flurbiprofen, ketoprofen, mefanamic acid, and naproxen. Indomethacin is not effective for prevention although perhaps effective as an abortive treatment. Naproxen is pregnancy category B, making it one of the safest and least expensive drugs in pregnancy. This entire group is under some suspicion of contributing to cardiovascular risk.
Oxcarbamazine (Trileptal) is not indicated for migraine, see comments above related to carbamazepine.
Pizotifen is a medication similar to cyproheptadine, with both antihistamine and anti-serotonin properties.
The usual dose is 0.5 mg daily. It is not FDA approved in the USA.
Propranolol - -see Inderal. Effective.
Quetiapine (Seroquel) is an atypical antipsychotic, mainly used for bipolar affective disorder.
There is a growing body of evidence that it is helpful to prevent migraine. (Krymchantowski, et al. 2010). Weight gain is a common side effect. The mechanism of action is attributed to D2 antagonism. This makes it similar to flunarizine (see above).
Simvasatin/Vitamin D -- not sure.
In 2015, Buettner and others published an article suggesting that the combination of simvistatin and vitamin D is "effective for prevention of headache in adults with episodic migraine". The dose was 20 mg of simvistatin, and 1000 mg of vitamin D3 taken twice/day. Only 57 patients were studied. 25% of the active participants experienced a greater than 50% reduction in migraine days. According to the authors, "The effect size of 30% fewer migraine days is a magnitude of reduction in migraine days that exceeds the effects of other agents considered to be clinically significant for migraine prevention". Two of the authors applied for a patent on the combination of statin and vit D for migraine.
At this writing, at the beginning of 2016, we think that this treatment is worth trying. We are dubious that there is a real effect on migraine, but we are supportive of the idea that vitamin D is good for most people, and we think that simvistatin is reasonable when lipids are elevated.
Tecagepant (CGRP antagonist). Don't get your hopes up too high.
This is an investigational drug that antagonizes CGRP. A recent trial was stopped because of liver toxicity (Ho et al, 2014). Calcitonin gene-related peptide agents (CGRP) are similar in efficacy to the triptan abortive drugs. Unfortunately, they have yet to emerge into clinical medicine. Another CGRP receptor antagonist (MK-3207) was also terminated due to liver test abnormalities. These drugs are monoclonal antibodies, and if they follow the pattern of other similar pharmaceuticals, they will likely be exorbitantly priced if/when they become available.
There are many drugs in phase 3 trials at this writing (2017). If one accepts the idea that migraine needs to be deconstructed into individual ailments, it is implausible that there will be any magic bullet that works 100% of the time. Still, we are eager to see this drug come into use.
Topiramate (Topamax). Moderately effective but expensive and category D in pregnancy. (2012)
Topamax is effective in roughly 50% of patients with migraine. This is on the low side for effectiveness. Topiramate also is on the high side for side effects.
Unlike most headache prevention medications, topiramate often promotes weight loss, even with low doses, due to loss of appetite. Typical doses are 25mg/day to 200 mg/d. In the author's clinical practice in Chicago, 50-100 mg is the usual target dose, as this amount seems to have the best combination of cost/benefit. Topiramate is expensive and in large doses has peculiar cognitive effects, such as trouble finding words (Mula et al, 2003), and drowsiness. Paresthesia (tingling) in the hands and taste perversion (citrus tastes metallic) is common.
Topiramate is not at all a good drug for people whose job involves manipulating words, i.e. writers, speakers, teachers, attorneys (Thompson et al, 2000). Additionally, about 50% of patients develop tingling in hands/fingers on startup. This effect usually fades out in about 2 weeks. Peak effect doesn't occur till 3 months, so trials must be made over long periods. Like other carbonic anhydrase drugs, topiramate can increase the frequency that kidney stones are developed.
The author has encountered a few patients who became severely depressed on topiramate -- they were also on venlafaxine, so this may be a drug-drug interaction (reducing venlafaxine). Venlafaxine is a tricky drug that depends on liver metabolism to be effective. On the positive side, small doses are usually side effect free. Also, topiramate does not affect blood pressure. Topiramate increases the blood levels of amitriptyline.
A recent trial in which topiramate and Inderal were combined for chronic migraine, was stopped because of lack of evidence that there was any benefit (Silberstein et al, 2012). Of course, this does not mean that the combination is also ineffective in non-chronic migraine, which comprises about 97% of all migraine. So we would not entirely rule this out. See comments above about other issues with making inferences from drug trials.
There have been many reports that topiramate can induce glaucoma, which is of the acute closed-angle type. According to Ho et al (2013), patients prescribed topiramate were found to have a 7.41 fold greater risk of being diagnosed with glaucoma during the first month after it was prescribed. However, this risk became nonsignificant after the first month. From this information, we suggest that new visual symptoms after starting topiramate, especially ocular pain, should be taken very seriously.
Pregnancy is category D at present (2011) -- D means dangerous. Recent data suggests a high risk of major congenital malformations such as oral cleft disorders (Hunt et al, 2008; Margulis, 2012), as is the case with most migraine medications. The odds ratio is roughly 10:1. Thus this drug is generally not suitable for migraine treatment in pregnancy. This can be an issue as the population most interested in this drug are generally women of child-bearing age.
The mechanism for this anticonvulsant drug's effect on migraine may include pharmacological effects including enhancement of GABA, inhibition of glutamate receptors, sodium channels, and calcium channels. It also has a weak inhibition of carbonic anhydrase. Due to the combination of migraine and carbonic anhydrase activity, it can be particularly helpful in the many people who have both migraine and Meniere's disease.
Venlafaxine (Effexor). Very effective for migraine prevention.
Please follow the link above for a detailed discussion of venlafaxine for migraine.
Verapamil (Calan ). Used for prevention. Effective, cheap, mild side effects, interacts with other drugs.
Relatively few trials have been made of calcium channel blockers, the majority of which were of nimodipine. The drug that we favor -- verapamil, has largely escaped study. According to Markley (1991), verapamil "may be as effective as traditional therapies". Greenberg (1986) also suggests that verapamil as well as nifedipine, nimodipine, and diltiazem are helpful. This suggestion is questionable as this is a very old paper, and also we have not had much success with calcium channel drugs than verapamil. Olesen (1986) suggested that studies he reviewed were unconvincing. Although there is good evidence for effectiveness of another drug with calcium channel blocking channel blocking activity, flunarizine, its main effects are likely exerted through dopamine blocking.
In our experience, verapamil is a very effective and inexpensive drug for migraine that takes about 2 weeks to work. We particularly favor this drug for persons who have high blood pressure, or who have nausea accompanying migraine. It is an excellent drug for "cyclic vomiting". Usual dose is 120 to 240mg per day, SR or ER. SR means sustained release. We start with dose in mg roughly = weight of patient (in pounds). In other words, someone who weighs 120 lbs, would start on the 120 mg dose. We usually increase the dose if not effective at one month intervals. We do not increase beyond 240 mg/day, and we also do not increase if there is constipation or hypotension.
Verapamil is a member of the L-channel calcium channel blocker family. Other calcium channel blockers are generally ineffective (i.e. nicardipine, nifedipine), and some even seem to increase migraines (the vasodilators). About 50% of users develop mild constipation. Sometimes it lowers blood pressure. Verapamil is a "phenylalkylamine", while nifedipine and nimodipine are dihydropyiridines (Greenberg, 1986).
About 1% of users develop palpitations (fluttering feeling in chest). It is usually best to stop taking this drug if you develop palpitations. Verapamil is generally safe in patients with asthma (as opposed to the beta-blocker family), and especially good in patients who also have high blood pressure.
Combined use of verapamil or other calcium channel blockers and beta-blockers should, in general, be avoided. Verapamil interacts with simvistatin (and probably other statins) and the dose of the latter should usually be reduced to 10 mg/day when both are prescribed. Verapamil is generally not for use in pregnancy (but it is category C).
Solomon (1983) in a tiny but blinded study of Verapamil in 12 patients reported a 49% effect. Verapamil is reportedly effective in hemiplegic migraine (Yu and Horowitz, 2003). Extremely large amounts of verapamil are sometimes used for Cluster headache. For this situation, heart EKG testing is recommended.
Recent "evidence based" review articles by Silberstein et al (2012, 2015), suggested that verapamil does not work for migraine. We are dubious about this assertion considering the many patients of ours who use it successfully, the lack of any studies concerning verapamil, and the inhomogeneity of migraine in general. Of course, lack of evidence for effect is not the same of evidence of lack of effect. In other words, although nobody has published a study about a drug working, this does not mean that the drug doesn't work. It just means that nobody has published a study. This of course is a general critique of "evidence based medicine", which translates into "no medicine", if nobody has done a study that provides evidence.
Wellbutrin (buproprion) has been reported useful in small studies for migraine, cluster and chronic daily headaches.
Wellbutrin has no clinically significant effect on serotonin neurotransmission. We have not had much success with this drug.
Zonegran, another anticonvulsant, may have some anti-migraine effects too.
Like Topiramate, it is a carbonic anhydrase inhibitor (among other things). Zonegran may also be associated with weight loss. Zonegran is a close relative of topiramate, and one would expect it would have the same (very long) side effect profile. Topiramate is especially a bad drug for cognitive workers -- we would expect zonegran to be similar. We have little experience with Zonegran and would not expect it to be any different than topiramate.
Medications that are reportedly (possibly or probably) not effective in preventing migraine include acebutolol (a beta blocker), clomipramine, clonazepam, clonidine, indomethacin, lamotrigine, namumetone, nicardipine, nifedipine, oxcarbamazine, and pindolol (Silberstein, 2000; 2015). There are also an immense number of medications with inadequate evidence -- this doesn't mean that they don't work, but just nobody has studied them sufficiently. These include some commonly used medications - -gabapentin and verapamil for example. (Silberstein, 2015). If one accepts the idea that "Migraine" is just a collection of many individual illnesses, it is unrealistic to think that any drug will work all the time. Certainly, most experienced clinicians have patients that do very well on of the medications listed above. It is naive to think that "evidence based medicine" can prove that one or another drug can work for a collection of symptoms, without a biomarker.
References: See this page.