Second Line Migraine Prevention Drugs
Timothy C. Hain, M.D. Chicago
IL.• Page last modified:
September 26, 2020
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The Migraine approach flowchart outlines a general approach to migraine using 3 main groups of medications - -anticonvulsants and other drugs that work as nerve stabilizers, antidepressants that probably work mainly through neurotransmitters such as serotonin and dopamine, and medications that act on blood vessels such as verapamil and the beta-blocker family. As a general observation, drugs commonly used for bipolar affective disorder are often useful in migraine as well. This opens up a large universe of interesting drugs, often little studied.
The purpose of this page is to outline secondary agents, that can be used when the first set fails, or if the first set is not tolerated. We will again organize by mechanism, with the main addition being "mysterious" agents -- usually claimed to work on migraine. Of course, these agents are somewhat suspicious.
In general, in the USA, most of these drugs are FDA approved for other indications than migraine. Their use is generally "off label". Some popular migraine drugs are not approved by the FDA (e.g. flunarizine).
- Anticonvulsants and other nerve stabilizers
- Zonisamide (a similar drug to topiramate) Used when topiramate works but has too many side effects.
- Tizanidine (Zanaflex, reduces muscle spasms) -- thought to be effective by the Brazilian headache society (Kowacs, 2019).
- Antidepressants and other Neurotransmitter modulators. While these agents are generally highly effective, there may be substantial side effects.
- desvenlafaxine (if Venlafaxine fails or has drug interactions)
- aripiprazole (Abilify, atypical antipsychotic with agonist both at D2 and 5HT1A). Substantial side effects. One would think this drug would NOT work because it is a dopamine agonist.
- quetiapine (Seroquel, an atypical antipsychotic, used for bipolar). Serotonin agent and D2 dopamine blocker. This drug has substantial side effets.
- nefazodone (Serzone). Serotonin (5H2 antagonist). Can be very successful, many side effects.
- cyproheptadine or Pizotifen (not FDA approved) -- mainly used in children.
- Zyprexa (Olanzapine). A strong effect is reported. I have not used it at all.
- flunarizine (a calcium channel and dopamine blocker). A very large literature suggests that this drug works in Europe. We have not used it very much, and are just unsure. Also D2 blocker
- Agents that act on blood vessels
- Calcium channel blockers -- nearly every calcium channel blocker has some data suggesting it is helpful.
- Verapamil or Nimodipine (these are L-channel calcium channel blockers)
(considerable data supporting use, not FDA approved in the US). Also D2 blocker
- Avoid calcium channel vasodilators such as diltiazem as they are vasodilators (i.e. make migraine worse, just like nitroglycerine).
- Beta blockers -- other than propranolol or metoprolol.
- atenolol, timonol, nadolol (Corguard)
- Nebivolol (Bystolic, if generic versions of above are poorly tolerated) -- we are are not at all sure that this drug works for migraine.
- Agents that we are dubious about
- ACE inhibitors (e.g. lisinopril, candesartin)
- Clonidine, Tenex
- Methergine -- this drug works, but we don't think it is safe enough to use. See this story.
- Nonsteroidals (not to be taken every day)
- We don't think there is anything magical about using different types of nonsteroidal. Although there is a literature suggesting that some headaches only respond to indomethacin, we have never encountered any of these and we are doubtful.
- Occasionally hormonal supplements or blockers with HRT add back are used in women for migraine. Our guess is that they do work, but with substantial side effects. . See this page.
- Agents of uncertain mechanism
(no recommendation in general)
- Memantine (Namenda) -- this is a glutamate antagonist. We have no idea why it might help migraine. There is a small literature. (Charles et al, 2007 is one).
- Herbals -- there are an immense number of uncontrolled studies of these drugs, that are generally available in health food stores.
- Butterbur (Petadolux). -- This supplement has been banned in several countries due to liver toxicity.
- Ginkgolide B
- Tou Feng Yu pill (TFY) -- a traditional Chinese herbal medicine, Radix Angelicae dahuricae (Baizhi), Rhizome Ligustici (Chuanxiong) and Folium Camelliae sinensis (green tea)
- L. chuanxiong (traditional Chinese herbal)
- goshuyuto (Japanese herbal for migraine)
- Xiaoyao Nose Drops (XYND)
- Agents that we tend not to recommend due to lack of positive feedback about them.
- Riboflavin (B2) 400 mg/day. We have never encountered anyone who had a good response (amazingly enough).
- Co-Q 10. Often tried, rarely found useful.
- Combinations of well tolerated agents
- Nerve stabilizer and antidepressant
- Example, topiramate and venlafaxine; any beta-blocker and venlafaxine
- Botox and venlafaxine
- CGRP inhibitor and botox or venlafaxine.
- Nerve stabilizer and blood vessel agent
- Example, topiramate and verapamil
- Botox and verapamil
- Antidepressant and blood vessal agent
- example: venlafaxine and propranolol
- Charles, A., et al. (2007). "Memantine for prevention of migraine: a retrospective study of 60 cases." J Headache Pain 8(4): 248-250.
- Dusitanond, P. and W. B. Young (2009). "Neuroleptics and migraine." Cent Nerv Syst Agents Med Chem 9(1): 63-70.
- Evans, R. W. (2013). "A rational approach to the management of chronic migraine." Headache 53(1): 168-176.
- Kowacs, F., et al. (2019). "Consensus of the Brazilian Headache Society on the treatment of chronic migraine." Arq Neuropsiquiatr 77(7): 509-520.
- Louis, P. and E. L. Spierings (1982). "Comparison of flunarizine (Sibelium) and pizotifen (Sandomigran) in migraine treatment: a double-blind study." Cephalalgia 2(4): 197-203.