Sumatriptan plus naproxen for the treatment of acute migraine attacks in adults
This is an updated version of the original Cochrane review published in October 2013 on 'Sumatriptan plus naproxen for acute migraine attacks in adults'.
Migraine is a common disabling condition and a burden for the individual, health services, and society. It affects two to three times more women than men, and is most common in the age range 30 to 50 years. Effective abortive treatments include the triptan and non‐steroidal anti‐inflammatory classes of drugs. These drugs have different mechanisms of action and combining them may provide better relief. Sumatriptan plus naproxen is now available in combination form for the acute treatment of migraine.
To determine the efficacy and tolerability of sumatriptan plus naproxen, administered together as separate tablets or taken as a fixed‐dose combination tablet, compared with placebo and other active interventions in the treatment of acute migraine attacks in adults.
For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) via The Cochrane Register of Studies Online (CRSO) to 28 October 2015, MEDLINE (via Ovid) from 1946 to 28 October 2015, and EMBASE (via Ovid) from 1974 to 28 October 2015, and two online databases (www.gsk‐clinicalstudyregister.com and www.clinicaltrials.gov). We also searched the reference lists of included studies and relevant reviews.
We included randomised, double‐blind, placebo‐ or active‐controlled studies, with at least 10 participants per treatment arm, using sumatriptan plus naproxen to treat a migraine headache episode.
Data collection and analysis
Two review authors independently assessed trial quality and extracted data. We used numbers of participants achieving each outcome to calculate risk ratio and numbers needed to treat for an additional beneficial outcome (NNT) or for an additional harmful outcome (NNH) compared with placebo or a different active treatment.
For this update we identified one new study (43 participants), but it did not contribute any data for analysis. The review included 13 studies using sumatriptan 85 mg or 50 mg plus naproxen 500 mg to treat attacks of mild, moderate, or severe pain intensity. Twelve studies contributed data for analyses: 3663 participants received combination treatment, 3682 placebo, 964 sumatriptan, and 982 naproxen. We judged only one small study to be at high risk of bias for any of the criteria evaluated; it did not contribute to any analyses.
Overall, the combination was better than placebo for the primary outcomes of pain‐free and headache relief at two hours. The NNT for pain‐free at two hours was 3.1 (95% confidence interval 2.9 to 3.5) when the baseline pain was mild (50% response with sumatriptan plus naproxen compared with 18% with placebo), and 4.9 (4.3 to 5.7) when baseline pain was moderate or severe (28% with sumatriptan plus naproxen compared with 8% with placebo) (high quality evidence). Using 50 mg of sumatriptan, rather than 85 mg, in the combination did not significantly change the result. Treating early, when pain was still mild, was significantly better than treating once pain was moderate or severe for pain‐free responses at two hours and during the 24 hours post dose. Adverse events were mostly mild or moderate in severity and rarely led to withdrawal; they were more common with the combination than with placebo (moderate quality evidence).
Where the data allowed direct comparison, combination treatment was superior to either monotherapy, but adverse events were less frequent with naproxen than with sumatriptan (moderate quality evidence).
The conclusions of this review were not changed. Combination treatment was effective in the acute treatment of migraine headaches. The effect was greater than for the same dose of either sumatriptan or naproxen alone, but additional benefits over sumatriptan alone were not large. More participants achieved good relief when medication was taken early in the attack, when pain was still mild. Adverse events were more common with the combination and sumatriptan alone than with placebo or naproxen alone.
Simon Law, Sheena Derry, R Andrew Moore
Plain language summary
Sumatriptan plus naproxen for acute migraine attacks in adults
The combination of sumatriptan plus naproxen was useful for treating migraine attacks in the studies we found. It was not a lot better than using sumatriptan alone, but it was much better than using naproxen alone. Attacks were more successfully treated when medication was taken early, when pain was mild.
Migraine is a complex condition with a wide variety of symptoms. It affects two to three times more women than men, and is most common in the age range 30 to 50 years. For many people, the main feature is a painful headache. Other symptoms include disturbed vision; sensitivity to light, sound, and smells; feeling sick; and vomiting.
Both nonsteroidal anti‐inflammatory drugs (NSAIDs) and the triptan class of drugs are used to treat migraine headaches. This review examined how well naproxen (an NSAID) and sumatriptan (a triptan) work when combined. The combination tablet is not available in most countries, but separate tablets are widely available and can be taken together.
On 28 October 2015, we looked for clinical trials using sumatriptan plus naproxen to treat migraine headache in adults. People were given either a combination of sumatriptan and naproxen, sumatriptan only, naproxen only, or a placebo (dummy) treatment. They did not know which treatment they were taking, and nor did the health professionals looking after them.
We found 13 studies, of which 12 (with about 9300 people) provided information on how well the combination treatment worked.
The combination of sumatriptan plus naproxen was better than placebo for relieving acute migraine attacks in adults. When the starting headache intensity was mild, 5 in 10 (50%) of people treated with the combination were pain‐free at two hours compared with about 2 in 10 (18%) with placebo. Almost 6 in 10 (58%) people with moderate or severe pain who were treated with the combination had pain reduced to mild or none at two hours, compared with 3 in 10 (27%) with placebo. The combination was also better than the same dose of either drug given alone in these people. Results were 5 in 10 (52%) people with sumatriptan alone or about 4 in 10 (44%) with naproxen alone.
The combination was better than placebo or either drug alone for relief of other migraine symptoms (nausea, sensitivity to light or sound) and loss of ability to function normally. Adverse events of dizziness, tingling or burning of the skin, sleepiness (somnolence), nausea, indigestion (dyspepsia), dry mouth, and chest discomfort were more common with sumatriptan (alone or in combination) than with placebo or naproxen. They were generally of mild to moderate severity and rarely led to withdrawal from the studies.
Quality of the evidence
The studies were carried out to high standards and were generally large enough to give reliable results, so that most of the results for efficacy were of high quality. Results for adverse events were downgraded to moderate quality because there were fewer events.
Simon Law, Sheena Derry, R Andrew Moore
Implications for practice
For people with migraine
The combination of sumatriptan plus naproxen is better than naproxen alone, and probably better than sumatriptan alone. It is not clear whether there is any clinical significance to the benefits observed with the combination over sumatriptan alone. More people get good relief when medication is taken early in the attack, when pain is still mild. Adverse events are more common with the combination and sumatriptan alone than with placebo or naproxen alone, but these events do not usually stop people from taking the medicine.
The combination tablet is not available in most countries, but the individual components are widely available and can be taken together.
The combination of sumatriptan plus naproxen provides good levels of relief to more people than either drug alone, but the clinical significance of the benefits observed with the combination over sumatriptan alone are unclear. More people get good relief when medication is taken early in the attack, when pain is still mild, so early treatment should be encouraged. Adverse events are more common with the combination and sumatriptan alone than with placebo or naproxen alone, but these events rarely led to withdrawal in these studies.
The combination tablet is not available in many countries outside the US, but the components as separate tablets can be taken simultaneously, although sumatriptan alone is available only in 50 and 100 mg doses. The included study using separate tablets used the 50 mg dose.
For policy makers
No single treatment provides a good response in all people with migraine. Combining two drugs with different actions is a rational option to increase the number who benefit, and the combination of sumatriptan with naproxen does provide good outcomes to more people than either drug alone, without compromising tolerability, although the benefits over sumatriptan alone are small. As with monotherapy, early treatment with this combination gives better results and should be promoted.
The combination tablet is not available in most countries outside the US, but the components as separate tablets can be taken simultaneously, although sumatriptan alone is available only in 50 and 100 mg doses. The included study using separate tablets used the 50 mg dose.
The combination of sumatriptan with naproxen provides good outcomes to more people than either drug alone, without compromising tolerability, although the benefits over sumatriptan alone are small. The combination tablet is not available in many countries outside the US, but the components as separate tablets can be taken simultaneously, although sumatriptan alone is available only in 50 and 100 mg doses. The included study using separate tablets used the 50 mg dose. Using separate tablets may be less convenient, but is considerably less costly.
Implications for research
Migraine is common and debilitating. Combining two drugs with different modes of action to treat migraine offers the opportunity to target different components of migraine pathophysiology. It may also be possible to achieve a good response with lower doses of one or both drugs.
These studies combining sumatriptan with naproxen demonstrate better results than either drug alone, but studies are needed to determine which triptan and which NSAID make the best combination, and for whom. To date there are few published trials of different combinations. Naproxen 500 mg is of limited efficacy when used as a monotherapy in migraine when pain is moderate or severe. Ibuprofen 400 mg and diclofenac 50 mg produce lower (better) NNTs, and may be more appropriate nonsteroidal anti‐inflammatory drugs to be used in combination with a triptan.
Including a broader spectrum of people with migraine‐like headaches, some of whom may not fulfil IHS criteria for migraine, could increase the generalisability of study results, and help to identify subpopulations who respond differently.
The design of the trials is good, and major changes appear unnecessary.
Clinically useful outcomes in migraine trials are well established, but part of the reason for investigating drug combinations is to achieve earlier responses and to reduce recurrence of the headache, which is not uncommon. This requires both routine measurement and reporting of outcomes at earlier (eg at half‐ and one‐hour) and later (eg at 24‐ and 48‐hour) time points.