An Effective Migraine Combination

Summarized by Robert W. Griffith, MD
May 3, 2007

Summary

Sumatriptan plus naproxen - two effective drugs for treating migraine with different mechanisms of action - when given in a single fixed-dose tablet, show greater clinical effectiveness than single administration of either drug alone.

Introduction

There are several effective medications for treating migraine that come from different therapeutic classes - ergot derivatives, non-steroid anti-inflammatory painkillers, and serotonin-binding agents. Each type tackles one or other aspect of the complex mechanism that causes a migraine attack, and migraineurs often take two or more drugs in their attempts to get relief. Studies have shown that combining a triptan drug (i.e. a serotonin-binder) with an NSAID (a painkiller) is effective, but the possibility numerous dose combinations of different drugs has made it difficult to define clearly the effectiveness and safety findings.

A fixed combination drug is the formulation of two medications in the same dosage form (pill, tablet, or capsule). It has the advantage of providing two drugs in one dosage form, helping with adherence to taking what the doctor prescribed. It may also show the benefit of synergy - i.e. greater effectiveness than that expected from just adding the effectiveness of the two components. (Such synergy would likely be evident if the two component drugs were taken together as individual dosage forms, in a so-called 'free combination'. This aspect was not tested in the studies reported here).

GlaxoSmithKline and another drug manufacturer, Pozen Inc, have made a tablet containing 85 mg sumatriptan (Imitrex^®) and 500 mg naproxen sodium (Naprosyn^®) as a fixed combination. The results of two double-blind clinical studies were recently reported in the Journal of the American Medical Association, pointing up the advantages of this combination for the acute treatment of migraine. Below is a summary of the findings.

What was done

Two separate but identical studies were done at 118 different centers throughout the United States. There were almost 1,500 patients in each study; they had to have been diagnosed as having moderate or severe migraine, either with or without the typical aura.¹ The study design included a screening visit followed by outpatient treatment of a single migraine attack, and a follow-up visit 1 to 5 days after the treatment.

The volunteers were allocated to receive one of 4 treatments: a single combination tablet containing 85 mg of sumatriptan and 500 mg of naproxen, one with 85 mg of sumatriptan alone, one with 500 mg of naproxen alone, or a placebo tablet. They were instructed to take their study medication when the pain intensity was moderate or severe. Pain severity was rated immediately before dosing, and then 0.5, 1, and 1.5 hours after dosing; and hourly from 2 to 24 hours after dosing. A 4-point scale was used: 0 = none, 1 = mild, 2 = moderate and 3 = severe. The presence and absence of nausea, photophobia, and sound sensitivity were also recorded at these times.

What was found

The average age of the volunteers was about 40; three-quarters of them had no aura; and about 85% of them were women. Roughly 40% of them typically took a triptan medication for their migraines, while 40% took an analgesic like naproxen or ibuprophen.

	Combination	Sumatriptan	Naproxen	Placebo
Pain free at 2 h: study 1	65%*	55%	44%	28%
study 2	57%*	50%	43%	29%
Pain free 2-24 h: study 1	25%*	16%	10%	8%
study 2	23%*	14%	10%	7%
No photophobia: study 1	46%*	35%	31%	21%
(2-24 h) study 2	37%*	30%	27%	16%
An adverse event: study 1	27%	24%	13%	12%
study 2	26%	28%	14%	10%

* = significant difference to sumatriptan alone, naproxen alone, and placebo

It can be seen that pain relief and absence of photophobia over the full 24 hours was significantly better with the combination than with either of the components alone. Similar findings were obtained with the absence of sensitivity to sound; the absence of nausea was significantly superior with the combination in study 1, but there was no difference to that with sumatriptan alone in study 2.

The percentages of volunteers experiencing at least one adverse event - regardless of suspected cause - were significantly greater than placebo for the combination, but there were no differences between the combination and sumatriptan alone in this respect.

What the results mean

The results of these industry-sponsored studies (which form the major clinical part of a New Drug Application to the FDA) show what was expected - sumatriptan (85 mg) plus naproxen (500 mg) given in a single fixed-dose tablet show greater clinical effectiveness than single treatment with either drug alone. There was no real expectation that the combination tablet would be clinically superior to the two components taken together as separate tablets, and this possibility was not explored in the studies.

The chief investigator was quoted as saying "it looks as if there's some synergistic boost", but this was not demonstrated in these studies. In a previous pharmacokinetic study, the combination tablet yielded higher blood drug levels and longer half-life (persistence in the blood) than those obtained with separate component tablets taken together.² This might provide grounds for hope that the combination could be superior to the components taken separately, but the clinical evidence is not yet available, and would be very difficult to obtain.

The advantages of the fixed combination are convenience (one tablet instead of two) and therefore probable increased adherence by the patient. On the other hand, it will almost certainly be more expensive than its two components added together - especially when sumatriptan comes off patent in 2009.

Source

• Sumatriptan-naproxen for acute treatment of migraine. A randomized trial. JL. Brandes, D. Kudrow, SR. Stark,  et al. , JAMA, 2007, vol. 297, pp. 1443--1454

Footnotes
1. A migraine aura, which is a change in brain function, occurs as a warning of a migraine headache. It's usually a visual symptom, such as an arc of sparkling zigzag lines, or a blotting-out of vision. Other brain-related symptoms may occur, such as numbness of one side of the face and hand, weakness, unsteadiness, or altered consciousness.
2. Pharmacokinetics of a single-tablet formulation of sumatriptan RT Technology and naproxen sodium [abstract]. Kori S, Littlefield D, Taylor D, et al. Cephalgia 2005; Vol. 25: pp. 933

Related Links
Mayo Clinic: Migraine Headaches
More Help in Preventing Migraines
Acupuncture for Chronic Headache?

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