Migraine Treatment of the Month: The best oral preventive medicine for migraine that you’ve probably never heard of: Zonisamide
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There are a myriad of therapies widely used for migraine prevention. A few are both FDA-approved and possessed of a solid scientific evidence base for such use. A few are so old, cheap and generic that no one will bother at this point to spend the money required to obtain an FDA indication, and yet they typically have some degree of an evidence base and can be quite effective for some patients (egs, amitriptyline, nortriptyline, candesartan, venlafaxine). Many are simply prescribed without any FDA indication or, more problematic, an acceptable scientific evidence base.
Zonisamide falls squarely in the second group. As we moved from the 20th century into the 21st, it became increasingly clear that migraine is more than a “vascular phenomenon” and that the biologic circuit responsible for generating migraine is complex and involves components of both the brain and the peripheral nervous system as well as cranial blood vessels. Coinciding with this, there commenced a flurry of investigations involving therapies known to prevent epilepsy by “desensitizing the brain” to see if those same therapies could be effective in desensitizing the “hypersensitive” brains of migraineurs.
Some drugs initially developsed for epilepsy (anti-epileptic drugs=AEDs) can prevent migraine episodes as well as seizures. Divalproex sodium (Depakote) clearly is effective as a preventive therapy for many patients with migraine, but its utility is limited by its potential for causing horrendous central nervous system effects on a developing fetus when the mother actively is taking Depakote for epilepsy, migraine prophylaxis, bipolar disorder, or other indications. There is even evidence now that active or recent Depakote use by a male predisposes to a risk of significant fetal abnormalities.
Following on the heels of Depakote as an anti-epileptic drug proven to be effective for migraine as well was topiramate (Topamax), which for a surprisingly extended period of time was America’s most commonly prescribed medication for migraine prevention. “Surprising” because topiramate, while effective both as a preventive therapy in episodic migraine and a suppression therapy for chronic migraine, can be extremely difficult to tolerate. Aside from the “numbness and tingling” side effects that the drug so commonly produces are less common but more bothersome and persistent side effects involving cognition: impaired concentration, impaired recent memory, distractibility, and – most vivid – impaired verbal fluency manifested by word finding difficulties.
During this halcyon decade when AEDs were being evaluated for their utility in migraine prevention the editor and his colleagues turned their attention to zonisamide, an AED which received FDA approval in 2000. At that time the drug was available as brand-only and marketed as Zonegran. Zonisamide is molecularly similar to topiramate but typically more tolerable (we dubbed it “Topamax lite“), and it appears to exert an inhibitory effect on the spread of electrochemical transmission from neuron to neuron.
To make it brief, we got as far as a multicenter national phase 2 study which evaluated several different doses of zonisamide versus placebo for the drug’s safety, tolerability and effectiveness in preventing headaches in the episodic migraine population. Each of the three doses evaluated was safe, well-tolerated and superior to placebo in effectiveness; no one dose stood out as being “the best“. Research conducted by other investigators similarly suggested that zonisamide is effective for episodic migraine and for treating chronic migraine as well. Several studies have suggested zonisamide may be especially effective for patients who responded to topiramate in terms of migraine burden reduction but could not tolerate the drug’s side effects.
And then Zonegran went generic, and like the proverbial carpet beneath one’s feet that is swept away, funding for further research involving zonisamide for migraine vanished. Poof. Despite the enormous burden on the public health imposed by migraine, the great majority of the funding for migraine therapeutics continues to come from the for-profit pharmaceutical industry rather than conventional sources such as the NIH. No for-profit company is likely to expend its money on generic zonisamide.
Those Who Know still commonly prescribe zonisamide and typically prefer it over topiramate consequent to its more favorable side effect profile. This is in spite of the fact that topiramate is FDA-approved for migraine prevention and clearly has a strong evidence base to support its use in episodic and chronic migraine (as confirmed by multiple well-designed and conducted clinical research trials involving many, many hundreds of migraine patients). Zonisamide has no FDA indication for treatment of migraine and a far thinner evidence base.
You will never see zonisamide advertised as a treatment for migraine prevention. Without FDA approval for that indication, it cannot be advertised and marketed as a migraine therapy. That’s a problem, but the same can be said for many migraine prevention medications that are widely used despite their lack of an FDA indication or much of a scientific evidence base: amitriptyline, nortriptyline, various of the beta blockers such as metoprolol, nadolol, and atenolol, candesartan and many more.
Do most physicians prefer to practice evidence-based medicine.? Definitely. Would most patients prefer to receive an evidence-based therapy? They should. Are there times when, unfortunately, the evidence-based therapies available simply do not “work” for a given patient? Absolutely – just hang out with the editor in his clinic for a day or two. At such times, would zonisamide represent a reasonable option? Yes.…and an option well worth discussing with your healthcare provider.
