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Dual-Drug Approach Melts Migraine
MedPage Today
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco
April 03, 2007

Previous studies have also looked at the combination of analgesic and triptan but as separate medications. It is not known if combining an analgesic and triptan in the same tablet will have any advantages over taking them separately, though adherence may increase.

NASHVILLE, Tenn., April 3, 2007 -- Sumatriptan (Imitrex), the migraine drug, may be significantly more effective for two-hour to 24-hour sustained pain relief when augmented by naproxen (see below), the common analgesic, researchers here found.

Generic Name: naproxen (na PROX en)
Brand Names: Aleve, Aleve Caplet, Anaprox, Anaprox-DS, EC-Naprosyn, Naprelan '500', Naprosyn

According to two separate but identical four-arm studies, pain relief over 24 hours was significantly better with 85 mg of sumatriptan (Imitrex) and 500 mg of naproxen when combined as investigational agent, MT-400, than with either alone, or placebo (P<0.01 for all comparisons), reported Jan Lewis Brandes, M.D., of the Nashville Neuroscience Group, and colleagues.

While the two medications have been used together as separate pills to target multiple migraine pathways, a dual-drug tablet may allow improve efficacy, they wrote in the April 4 issue of the Journal of the American Medical Association. "It looks as if there's some synergistic boost," said Dr. Brandes, who led the studies.

In a previous pharmacokinetic study of the agent, combination tablets increased serum drug levels and prolonged half-life compared to separate tablets taken together, she said.

Furthermore, it may eliminate the "penalty" for patients who often wait to take a triptan medication until after over-the-counter analgesics have failed, which is a less effective approach to pain relief by multiple neural pathways, she added.

The double-blind clinical trials included 1,461 and 1,495 patients, respectively at 118 U.S. centers, who were diagnosed with migraine with or without aura. They were randomized to receive a single tablet containing 85 mg of sumatriptan and 500 mg of naproxen, or the same dose of either monotherapy or placebo.

Patient characteristics were similar between groups (71% to 77% migraine without aura, mean age about 40, 84% to 87% female). About 30% of patients typically took oral sumatriptan for their migraines before the study. Another 11% usually took another triptan formulation. Over-the-counter pain medication was used by 24% to 29% of patients, and about 37% usually used non-steroidal anti-inflammatory drugs (NSAIDs).

The drugs were to be used after onset migraine once pain was moderate to severe. No other medications or second doses were allowed. However, rescue medication -- except ergot-containing medications, serotonin agonists, or NSAID-containing products -- was permitted after two hours.

While previous studies have shown efficacy combining a triptan and NSAID, the many dose combinations possible made it difficult to extrapolate efficacy and safety findings, they said.

So, the researchers aimed high with their study design.

"These studies used more rigorous evaluation of efficacy than any approved acute migraine treatment to date," they wrote, "with the incorporation of six primary outcomes, all of which should be statistically significant, as opposed to the usual single primary outcome of headache relief two hours after dosing."

Among the findings, the researchers reported:

  • Combination tablets were more effective than placebo for headache relief at two hours (65% versus 28%, P<0.001, and 57% versus 29%, P<0.001).
  • Absence of light sensitivity at two hours was better with combination tablets than placebo (58% versus 26%, P<0.001, and 50% versus 32%, P<0.001).
  • Absence of sound sensitivity at two hours was better for the combination that placebo (61% versus 38%, P<0.001, and 56% versus 34%, P<0.001).
  • The absence of nausea at two hours was likewise higher with the combination than placebo though only in one study (71% versus 65%, P=0.007, and 65% versus 64%, P=0.71).
  • For two- to 24-hour sustained pain-free response, the combination was superior to sumatriptan alone (25% versus 16%, P<0.01, and 23% versus 14%, P<0.001).
  • For two- to 24-hour sustained pain-free response, the combination was superior to naproxen alone (25% versus 10%, P<0.001, and 23% versus 10%, P<0.001).
  • For two- to 24-hour sustained pain-free response, the combination was superior to placebo (25% versus 8%, P<0.001, and 23% versus 7%, P<0.001).
  • The better efficacy for combination therapy than for sumatriptan alone may be due to targeting multiple migraine pathogenesis pathways, the researchers suggested.

"None of the currently available monotherapeutic agents provides broad coverage of the multiple pathogenic processes in migraine," they wrote, "which is thought to involve multiple neural pathways that appear to be sequentially activated and sensitized as a migraine attack develops."

They added, "Together, a triptan and an NSAID hypothetically alter both peripheral activation of central pathways during the early stages of a migraine attack and the later developing central sensitization that is independent of peripheral input."

The adverse event incidence was similar between combination treatment and sumatriptan monotherapy and about twice as common for both as for placebo or naproxen sodium alone.

There was one serious adverse events considered probably attributed to the investigational combination medication. A 58-year-old woman with several cardiovascular risk factors experienced heart palpitations resulting in hospitalization, which resolved within a few days.

Dr. Brandes and colleagues acknowledged that their study was limited by not including sumatriptan and naproxen sodium taken together as separate tablets as an arm of the study, though the design used was at the FDA's recommendation.

Furthermore, since many patients had previously taken a triptan or NSAID, it is unknown how well the findings would extrapolate to NSAID- and triptan-naive patients or those with NSAID- or triptan-refractory migraine.

Ongoing studies are looking at the combination strategy for early intervention while pain is still mild, the researchers said.

The trials were funded by GlaxoSmithKline in partnership with Pozen Inc., sponsor of the investigational combination drug. Dr. Brandes reported having received clinical research or educational support from Merck, GlaxoSmithKline, UCB Pharma, Allergan, Johnson & Johnson, AstraZeneca, Pfizer, Bristol-Myers Squibb, Winston Laboratories, Sanofi-Aventis, Elan Pharmaceuticals, Novartis, Endo, POZEN, Vernalis, Ortho-McNeil, Advanced Bionics, Forest Laboratories, MedPointe Pharmaceuticals, and Aradigm Corp. Two researchers were employees of Pozen; two were employees of GlaxoSmithKline.

Primary source: Journal of the American Medical Association
Source reference: Brandes JL, et al "Sumatriptan-Naproxen for Acute Treatment of Migraine: A Randomized Trial" JAMA. 2007;297:1443-1454.
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