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Timothy C. Hain, M.D. and Marcello Cherchi M.D. Ph.D., Chicago
IL.
Page last modified:
June 9, 2010
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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.
These drugs fall into three major classes: anticonvulsants, antidepressants, and antihypertensives. Examples are: Amitriptyline (Elavil), Corgard, Depakote, Inderal, Nardil, Verapamil (Calan, Isoptin). 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 in mysterious ways (e.g. Depakote, Nardil, amitriptyline). More information about these is in the next section.
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.
General comments:
The author of this review usually starts patients with effexor, and proceeds on to try topamax, verapamil, propranolol and then ami or nortriptyline. It is very unusual that headache control is not attained. When one "group" doesn't work, he may combine two or 3 groups simultaneously (anticonvulsant, blood-pressure agent, antidepressant). Except in unusual cases, these 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. 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.
In a recent review (Silberstein, 2000), medications for prevention were grouped into 5 categories: Group 1 are medications with proven efficacy and mild-moderate adverse events. Group 2 are medications with lower efficacy. Group 3 are medications based on opinion. Group 4 are medications with proven efficacy but serious potential side effects. Group 5 are medications proven to have limited or no efficacy.
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.
Drugs (alphabetical).
See this link for a more recent list of drugs organized by mechanism.
Ace inhibitors (candesartin, lisinopril) Ineffective. 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). The writer of this review considers these medications ineffective. These drugs are also expensive compared to verapamil, propranolol and especially 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, treat 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.
amitriptyline (Elavil). Effective and inexpensive drug, with considerable side effects, used for prevention (Group 1).
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 is also common. Elavil is very inexpensive ! Similar tricyclic type drugs include nortriptyline, doxepin and protriptyline. 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.
carbamazepine (Tegretol) is not effective as a preventive (group 5). 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 do not prescribe it in our practice for this purpose either.
cyproheptadine (periactin) is a preventive medication mainly used in children. Weight gain is common.
Depakote (sodium valproate). Group 1.Effective but with many side effects
There are so many side effects that we generally avoid it. Used for prevention. Usual dose is 250, three times/day. Side effects include a prominant 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. Some authors suggest that this drug is effective for persistent migraine aura (Rothrock, 1997). 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 below. We find this drug very effective. Withdrawal is a big problem from larger doses, and we prefer to use very small doses. We always start patients on 1/3 of a capsule of the 37.5 XL (brand name) drug. 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.
escitalopram (Lexapro). We have had little experience with this drug, 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.
Fluoxetine (Prozac). Group 1.
Ineffective but perhaps worth a try anyway. This medication, a member of the SSRI family (which also includes Paxil, Zoloft, Celexa, (escitalopram) Lexapro, and Luvox), is listed as a "group 1" medication for therapy (Silberstein, 2000). There is some evidence that another SSRI, paroxetine (Paxil) improves chronic daily headache (Langemark and Olesen, 1994; Foster and Bafaloukos, 1994). Not everyone agrees that there is good evidence that the SSRI's help (e.g. Goadsby, 2002)
Flunarizine is a similar drug to verapamil, available in Europe. 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).
Gabapentin (Neurontin). Group 1. 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. . A newer version of Neurontin is "Lyrica". This is basically a far more expensive version of gabapentin with a few advantages. Pregnancy category C.
Inderal LA (propranolol, Group 1) and other beta-blockers such as timonol (group 1). Members in group 2 include atenolol, metaprolol and nadolol.
Very effective and cheap drug, with moderate side effects, 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). These may have less side effects than the unselective beta blockers.
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.
Lamotrigine (Lamictal). Effective but substantial side effects. This anticonulsant can be used in a similar way as Depakote (see above) to prevent migraine and migraine associated vertigo (Bisdorf, 2004).
Magnesium. 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). It is presently considered a group-2 drug. Brain magnesium has a complicated relationship to migraine (Boska et al, 2002). Magnesium is usually taken as a dietary supplement, in combination with calcium. No prescription is necessary. Safety is unknown in pregnancy.
Memantine (Namenda). 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.
Methysergide (Sansert):This drug is unavailable in the US as of 1/2003. 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.
NSAIDS (non-steroidal anti-inflammatory drugs) are generally group 2. Effective but substantial side effects. Examples are aspirin, fenoprofen, flurbiprofen, ketoprofen, mefanamic acid, and naproxen. . Indomethacin is not effective for prevention (group 5) 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.
Topiramate (Topamax). Moderately effective but expensive.
Topamax is effective in roughly 50% of patients with migraine.
Unlike most headache prevention medications, Topiramate often promotes weight loss, even with low doses, due to anorexia (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).
Topiramate is not a good drug for people whose job involves manipulating words (i.e. writers, speakers, attorneys). 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.
The author has encountered a few patients who became severely depressed on topiramate -- they were also on Effexor, so this may be a drug-drug interaction. 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.
Pregancy is category C at present (2006), but there recent data suggests about 9% of persons on this drug have major congenital malformations such as oral cleft disorders (Hunt et al, 2008).
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 but expensive.
Used for prevention. This antidepressant medication, of the SNRI group, is very effective and has relatively few side effects. (Diamond, Pepper et al. 1998; Nascimento 1998; Adelman, Adelman et al. 2000; Bulut, Berilgen et al. 2004; Ozyalcin, Talu et al. 2005; Tarlaci 2009). We particularly favor this drug for the visual dependence symptom commonly seen in migraine. The other SNRI, Cymbalta (duloxetine) is miminally effective (Taylor et al, 2007).
The usual dose of venlafaxine is small -- varying between 12.5 mg and 75 mg/day, taken in the morning. We usually start persons with 1/3 of the time release (37.5) and titrate upward every week.Venlafaxine increases the blood pressure, and is neutral in regards to weight. The most common side effect, in our experience, is "morning sickness". This can sometimes be avoided by taking it with food, or taking it in the evening rather than in the morning.
We have encountered withdrawal problems in persons who stop effexor in larger doses than 37.5 mg, but none with the low dose of 37.5 generally used for migraine. We have also occasionally encountered suicidal thinking in persons on venlafaxine in spite of good headache control and without previous depression-- we stop the drug or reduce the dose in this situation (see also Todder and Baune, 2007).
There have been occasional reports of the "serotonin syndrome" provoked by the combination of effexor and triptans (see abortives), as well as the "SSRI" family of antideprssants. It seems unlikely that this would occur when using the small doses typical for migraine prophylaxis (37.5 to 75 per day), but caution is advised.
A close relative of Venlafaxine is "Pristiq". The generic name is desvenlafaxine. This drug can be substituted for Venlafaxine, and is associated with less interactions with other drugs as well as a more predictable response. Desvenlafaxine is the active metabolite of Venlafaxine. The starting dose is somewhat higher than Venlafaxine (50 mg), and for this reason we generally switch to Pristiq only after Effexor fails at a lower dose. At this writing (6/2009), we are simply not sure if this drug works (for migraine). We have had a few patients complain of withdrawal. Pristiq is available only as a brand name drug.
Beta-blockers can be combined with venlafaxine with minimal side effects related to their interaction. However, recent data suggests that beta-receptors are critical for antidepressant efficacy in neuropathic pain (Yalcin et al, 2009), and for this reason, we reserve this option until side effects are noted.
Verapamil (Calan ). (Group 2) Used for prevention. Effective, cheap, mild side effects.
A very effective and inexpensive drug 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. 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), but diltiazem is a group 3 drug (possibly effective). About 50% of users develop mild constipation. Sometimes lowers blood pressure.
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. Verpamil is generally not for use in pregnancy (but it is category C). Verapamil is 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.
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. It is too early to say with this new drug whether it will have a role in migraine prevention.
Medications that are reportedly not effective in preventing migraine include acebutolol, clomipramine, clonazepam, clonidine, indomethacin, nicardipine, nifedipine, and pindolol (Silberstein, 2000).
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