Susan Jeffrey

April 24, 2012

April 24, 2012 (New Orleans, Louisiana) — New guidelines for the prevention of episodic migraine, co-developed by the American Academy of Neurology (AAN) and the American Headache Society (AHA), upgrade the level of evidence supporting the use of some drugs but downgrade others.

Major changes include a new Level A endorsement for topiramate, but gabapentin and verapamil and other calcium-channel blockers are now considered Level U, or without sufficient evidence for or against their usefulness.

"The guidelines tell us about the evidence," Stephen D. Silberstein, MD, from the Jefferson Headache Center at Thomas Jefferson University in Philadelphia, Pennsylvania, lead author of the guidelines, told Medscape Medical News. "If there's a drug out there that's never been tested in migraine, that doesn't mean it doesn't work. The example is topiramate, which in the first guideline we didn't have good evidence for."

Dr. Stephen D. Silberstein

A second document looks separately at the role of nonsteroidal anti-inflammatory drugs (NSAIDs) and complementary treatments for migraine prevention. They did find sufficient evidence to allow recommendation of some of these treatments.

"Often patients will come to us who don't want to take medications but love natural products," Dr. Silberstein added. "Now we have, for the first time, a list of natural products that the patients can take, that the neurologists can recommend with proven efficacy.

"That to me is a major advantage," he added. "If they're going to take a natural product, at least take one that works."

The guidelines were released here at the American Academy of Neurology's 64th Annual Meeting and appear in the April 24 issue of Neurology.

Changing Criteria

The guidelines for migraine prevention were last updated in 2000. It's estimated that approximately 38% of migraineurs would benefit from migraine prevention strategies, but only 3% to 13% receive it, the authors note. The document looks only at patients with episodic migraine, in which attacks occur less than 15 days per month, and does not deal with acute migraine treatment or prevention of chronic migraine. Similarly, the guidelines do not examine use of botulinum toxin in migraine; a new guideline is in development, but a previous 2008 guideline noted botulinum toxin is probably ineffective for migraine prevention (Level B).

The new revision was undertaken to include a number of new studies that have been published in the interim, Dr. Silberstein noted. In addition, "the Academy changed the criteria for class I studies, taking into account dropouts."

It was on this basis that the level of evidence supporting gabapentin was changed in the current document, for example, because the quality of the trials was reclassified, he said. "The same thing happened for verapamil and the other calcium-channel blockers."

The guidelines make the following recommendations on currently available drugs for migraine prevention:

Level A agents are established as effective and "should be offered for migraine prevention," including:

  • Antiepileptic drugs: divalproex sodium, sodium valproate, topiramate;

  • Beta-blockers: metoprolol, propranolol, timolol; and

  • Triptans: frovatriptan for short-term prevention of menstrual migraine.

Level B agents are "probably effective and should be considered for migraine prevention," including:

  • Antidepressants: amitriptyline, venlafaxine;

  • Beta-blockers: atenolol, nadolol; and

  • Triptans: naratriptan, zolmitriptan for short-term prevention of menstrual migraine.

Level C medications are "possibly effective and may be considered for migraine prevention," including:

  • Angiotensin-converting enzyme inhibitors: lisinopril;

  • Angiotensin-receptor blockers: candesartan;

  • Alpha-agonists: clonidine, guanfacine;

  • Antiepileptic drugs: carbamazepine; and

  • Beta-blockers: nebivolol, pindolol

Level U agents have evidence that is conflicting or inadequate to support or refute their use, including:

  • Antiepileptic drugs: gabapentin;

  • Antidepressants;

  • Selective serotonin reuptake inhibitors (SSRIs)/selective serotonin-norepinephrine reuptake inhibitors (SNRIs): fluoxetine, fluvoxamine;

  • Tricyclics: protriptyline;

  • Antithrombotics: acenocoumarol, warfarin, picotamide;

  • Beta-blockers: bisoprolol;

  • Calcium-channel blockers: nicardipine, nifedipine, nimodipine, verapamil;

  • Acetazolamide; and

  • Cyclandelate.

Several other medications were found to be less than effective.

Level A negative: Lamotrigine was established as ineffective and shouldn't be offered for migraine prevention.

Level B negative: Clomipramine was considered probably ineffective and shouldn't be considered for migraine prevention.

Level C negative: The following medications were deemed "possibly ineffective" and may not be considered for migraine prevention:

  • Acebutolol;

  • Clonazepam;

  • Nabumetone;

  • Oxcarbazepine; and

  • Telmisartan.

Dr. Silberstein emphasized, though, that just because a drug has a lower rating in terms of the level of evidence, that doesn't mean it doesn't work, only that the evidence is limited.

"So whenever we see these drugs that have been downgraded or uncertain, there's always room for good clinical trials," he said. Amitriptyline, for example, is widely used for migraine prevention, "but the old trials were not adequate," he noted. "That doesn't mean it doesn't work. We often use it."

Another group of agents that should be looked at more closely is the SNRIs, Dr. Silberstein added. Migraine is comorbid with depression, and depression is a risk factor for migraine, he noted. "It would be great if we could do studies of drugs that are used for depression to find out which work and don't work for migraine."

SSRIs, used to treat depression, are not effective for migraine, but more recent evidence suggests that the SNRIs, such as venlafaxine, may be effective for both migraine and depression. "So that to me is a low-hanging fruit that needs to be looked at," he said.

However, the funding to study off-patent drugs for new indications is not always forthcoming, making these studies problematic.

"Here's a point I would make," Dr. Silberstein added. "Insurance carriers and agencies are always saying to us, 'use generic or over-the-counter drugs first,' and I would argue to them, 'why don't you support clinical trials of older generic drugs for modern indications, so we know whether or not they work, so we can use them?'"

NSAIDs and Complementary Approaches

In a separate document, the AAN/AHS guidelines committee reviewed evidence supporting the use of NSAIDs and other complementary therapies. Fifteen class I or class II studies involved these migraine prevention strategies.

Level A:

  • Petasites or butterbur is effective and should be offered to patients to reduce the frequency and severity of attacks.

Level B agents considered probably effective:

  • Fenoprofen;

  • Ibuprofen;

  • Ketoprofen;

  • Naproxen;

  • Naproxen sodium;

  • MIG-99 (feverfew);

  • Magnesium;

  • Riboflavin (vitamin B2); and

  • Subcutaneous histamine.

Level C medications considered possibly effective include:

  • Cyproheptadine;

  • Coenzyme Q10;

  • Estrogen;

  • Mefenamic acid; and

  • Flurbiprofen.

Level U agents have evidence that is conflicting or inadequate to support or refute their use, including:

  • Aspirin;

  • Indomethacin;

  • Omega-3; and

  • Hyperbaric oxygen.

Level B negative: Montelukast was considered probably ineffective for migraine prevention.

Art and Science

Richard B. Lipton, MD, F. Lowe Professor and vice chair of neurology, professor of epidemiology and population health, professor of psychiatry and behavioral science, and director, Division of Cognitive Aging and Dementia and the Montefiore Headache Center at Albert Einstein College of Medicine in New York City, noted that the guidelines are useful to neurologists, particularly those who are not headache specialists, because migraine and other headache disorders are among the most common reason for patient visits.

The advantage of the new guidelines is that they summarize the state of evidence not only for agents that are approved by the Food and Drug Administration — of which there are only 4 — but for a broader range of therapies that have a strong evidence base, he noted.

Migraine is biologically heterogenous, and clinical trials focus on the average patient response, so the reality is that when it comes to an individual patient, there is still an art to it. "Guidelines are always better at summarizing the science than in teaching the art," Dr. Lipton said.

He also applauded the examination of the complementary products. "To me, the crucial issue isn't, is the product a natural product or a prescription drug? To me, the crucial question is, is the treatment safe and effective for the patient in front of me?"

Very solid evidence supports the use of petasites (butterbur), a natural product, for example, or riboflavin, a vitamin, that otherwise might be perceived as fringe therapies, "but they actually have a solid scientific foundation for efficacy, more solid than many prescription drugs that we use." He cautioned, however, that butterbur is a complex natural extract, so buying a pure extract is important because the natural root has a toxic alkaloid in it. "If the extraction is not done correctly it can cause harm."

He recommends the product from Weber & Weber, the company that has done the studies supporting its use, because of this concern, but added that he has no financial interest. "I just don't want neurologists telling patients to take any butterbur they find."

Dr. Silberstein reports he is on the advisory panel of and receives honoraria from AGA, Allergan, Amgen, Capnia, Coherex, Colucid, Cydex, GlaxoSmithKline, Lilly, MAP, Medtronic, Merck, Minster, Neuralieve, National Institute of Neurologic Disorders and Stroke (NINDS), Nu-Pathe, Pfizer, St. Jude Medical, and Valeant. He is on the speakers' bureau of and receives honoraria from Endo Pharmaceuticals, GlaxoSmithKline, and Merck. He serves as a consultant for and receives honoraria from Amgen and Novartis. His employer receives research support from AGA, Allergan, Boston Scientific, Capnia, Coherex, Endo Pharmaceuticals, GlaxoSmithKline, Lilly, MAP, Medtronic, Merck, NINDS, NuPathe, St. Jude Medical, and Valeant Pharmaceuticals. Dr. Lipton has disclosed no relevant financial relationships.

American Academy of Neurology 64th Annual Meeting: Presented April 23, 2012.

Neurology. 2012;78:1337-1345, 1346-1353. Abstract Abstract

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