Sumatriptan plus naproxen for acute migraine attacks in adults

  • Review
  • Intervention

Authors


Abstract

Background

Migraine is a common disabling condition and a burden for the individual, health services, and society. 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.

Objectives

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 for the acute treatment of migraine headaches in adults.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE, and EMBASE, together with two online databases (www.gsk-clinicalstudyregister.com and www.clinicaltrials.gov) for studies to 2 August 2013. We also searched the reference list of included studies and relevant reviews.

Selection criteria

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 to benefit (NNT) or harm (NNH) compared with placebo or a different active treatment.

Main results

We included 12 studies using sumatriptan 85 mg or 50 mg plus naproxen 500 mg to treat attacks of mild, moderate, or severe pain intensity: 3663 participants received combination treatment, 3682 placebo, 964 sumatriptan, and 982 naproxen. No studies were considered to be at high risk of bias for any of the criteria evaluated.

Overall, the combination was better than placebo for pain-free and headache relief responses. At two hours, the NNT for pain-free response was 3.1 (95% CI 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; risk ratio 3.65 (3.0 to 4.5); 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.

Where the data allowed direct comparison, combination treatment was superior to either monotherapy, but adverse events were less frequent with naproxen than sumatriptan.

Authors' conclusions

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 are 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.

Résumé scientifique

Association du sumatriptan et du naproxène contre les crises de migraine aiguës chez l’adulte

Contexte

La migraine est un trouble fréquent et incapacitant qui constitue un fardeau pour l’individu, les services de santé et la société. Les crises migraineuses peuvent être « coupées » efficacement, entre autres, en utilisant des médicaments appartenant à la classe des triptans et à celle des anti-inflammatoires non stéroïdiens (AINS). Ces médicaments ont des mécanismes d’action différents et leur combinaison peut apporter un meilleur soulagement. L’association du sumatriptan et du naproxène est aujourd’hui disponible sous forme combinée pour le traitement de la migraine aiguë.

Objectifs

Déterminer l’efficacité et la tolérabilité de l’association du sumatriptan avec le naproxène (comprimés administrés ensemble ou comprimé combiné à dose fixe) par rapport à un placebo et à d’autres interventions actives pour le traitement des migraines aiguës chez l’adulte.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre Cochrane des essais contrôlés (CENTRAL) dans la Bibliothèque Cochrane , MEDLINE et EMBASE, ainsi que dans deux bases de données d’études en ligne (www.gsk-clinicalstudyregister.com et www.clinicaltrials.gov), le 2 août 2013. Nous avons également consulté les références bibliographiques des études incluses et les revues pertinentes.

Critères de sélection

Nous avons inclus les essais randomisés en double aveugle contrôlés par placebo ou par un traitement actif, portant sur au moins 10 participants par bras de traitement et utilisant l’association du sumatriptan et du naproxène pour traiter un épisode migraineux.

Recueil et analyse des données

Deux auteurs de la revue ont évalué la qualité des essais et extrait les données de manière indépendante. Nous avons utilisé les nombres de participants atteignant chaque résultat pour calculer le risque relatif et le nombre de sujets à traiter pour observer un bénéfice (NST) ou pour nuire (NNN) par rapport à un placebo ou à un autre traitement actif.

Résultats principaux

Nous avons inclus 12 études utilisant le sumatriptan à 85 mg ou 50 mg associé au naproxène à 500 mg pour traiter les crises douloureuses d’intensité légère, modérée ou sévère : 3663 participants ont reçu un traitement combiné, 3682 un placebo, 964 le sumatriptan, et 982 le naproxène. Aucune étude n’a été jugée à risque élevé de biais pour les critères évalués.

Dans l’ensemble, la combinaison était plus efficace que le placebo pour la disparation de la douleur et le soulagement des céphalées. À deux heures, le NST pour l’absence de douleur était de 3,1 lorsque la douleur initiale était légère (réponse de 50 % avec le sumatriptan plus naproxène contre 18 % avec un placebo), et de 4,9 lors de la douleur initiale était modérée ou sévère (28 % avec le sumatriptan plus naproxène, contre 8 % avec un placebo) (RR de 3,65 (IC à 95 % de 3,0 à 4,5), preuves de bonne qualité). L’utilisation d’une dose de 50 mg de sumatriptan au lieu de 85 mg dans la combinaison n’a pas modifié significativement le résultat. Le traitement précoce, lorsque la douleur était encore légère, était significativement plus efficace que le traitement administré quand la douleur était modérée ou sévère en termes d’absence de douleur après deux heures et au cours des 24 heures suivant la prise. Les événements indésirables étaient généralement d’intensité légère ou modérée et ont rarement entraîné le retrait de l’étude ; ils étaient plus fréquents avec la combinaison qu’avec le placebo.

Lorsque les données ont permis une comparaison directe, le traitement combiné était supérieur à la monothérapie, mais les événements indésirables étaient moins fréquents avec le naproxène qu’avec le sumatriptan.

Conclusions des auteurs

Le traitement combiné est apparu efficace dans le traitement aigu des migraines. L’effet était plus marqué que pour la même dose de sumatriptan ou de naproxène seul, mais les bénéfices supplémentaires par rapport au sumatriptan seul ne sont pas considérables. Le nombre de participants bien soulagés a été plus élevé lorsque le médicament était pris au début de la crise, alors que la douleur était encore légère. Les événements indésirables ont été plus fréquents avec la combinaison et le sumatriptan seul qu’avec un placebo ou le naproxène seul.

Plain language summary

Sumatriptan plus naproxen for acute migraine attacks in adults

Migraine is a complex condition with a wide variety of symptoms. 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 non-steroidal 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 together. On 2 August 2013, we looked for clinical trials where sumatriptan plus naproxen was used to treat migraine headache. We found 12 good quality studies with about 9300 people.

The combination of sumatriptan plus naproxen was more effective than placebo for relieving acute migraine headache in adults. The combination was also better than the same dose of either drug given alone. When the starting headache intensity was mild, 5 in 10 (50%) of those 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%) of those 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. Results were 5 in 10 (52%) people with sumatriptan alone or about 4 in 10 (44%) with naproxen alone. Headaches were more successfully treated when medication was taken early in an attack when pain was mild. 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.

The combination of sumatriptan plus naproxen was useful for treating migraine in the studies we found. It was not a lot better than using sumatriptan alone, but it was much better than using naproxen alone.

Résumé simplifié

Association du sumatriptan et du naproxène contre les crises de migraine aiguës chez l’adulte

La migraine est une maladie complexe, qui produit un large éventail de symptômes. Pour de nombreuses personnes, elle se caractérise par de douloureux maux de tête. Les autres symptômes incluent des troubles de la vision, une sensibilité à la lumière, au bruit et aux odeurs, de nausées et des vomissements.

On utilise aussi bien des anti-inflammatoires non stéroïdiens (AINS) que la classe de médicaments appelés triptans pour traiter les migraines. Cette revue a examiné l’efficacité du naproxène (un AINS) et du sumatriptan (un triptan) lorsqu’ils sont combinés. Le 2 août 2013, nous avons recherché des essais cliniques associant sumatriptan et naproxène pour traiter la migraine. Nous avons trouvé 12 études de bonne qualité portant sur environ 9300 personnes.

La combinaison du sumatriptan et du naproxène est apparue plus efficace que le placebo pour soulager la migraine aiguë chez l’adulte. La combinaison était également plus efficace que la même dose de l’un ou l’autre médicament administré seul. Lorsque la céphalée était initialement peu intense, 5 personnes sur 10 (50 %) traitées avec la combinaison ne ressentaient plus de douleur après deux heures, contre environ 2 sur 10 (18 %) avec un placebo. Presque 6 personnes sur 10 (58 %) ressentant une douleur modérée ou sévère et traitées avec la combinaison faisaient état d’une douleur réduite à légère ou de l’absence de douleur après deux heures, contre 3 sur 10 (27 %) avec un placebo. Ces résultats étaient de 5 personnes sur 10 (52 %) avec le sumatriptan seul et environ 4 sur 10 (44 %) avec le naproxène seul. Les céphalées ont été traitées plus efficacement lorsque le médicament était pris tôt au cours d’une crise, alors que la douleur était légère. La combinaison a été plus efficace qu’un placebo ou l’un des deux médicaments seul pour soulager les autres symptômes de la migraine (nausées, sensibilité à la lumière ou au bruit) et rétablir une capacité fonctionnelle normale. Les événements indésirables (vertiges, picotements ou sensation de brûlure de la peau, somnolence, nausées, dyspepsie, sècheresse buccale, gêne thoracique) étaient plus fréquents avec le sumatriptan (seul ou en combinaison) qu’avec le placebo ou le naproxène. Ils étaient généralement légers à modérés et ont rarement entraîné le retrait de l’étude.

La combinaison du sumatriptan et du naproxène s’est avérée utile pour traiter la migraine dans les études que nous avons trouvées. Elle n’a pas été beaucoup plus efficace que le sumatriptan utilisé seul, mais beaucoup plus efficace que le naproxène seul.

Notes de traduction

Traduit par: French Cochrane Centre 1st January, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec-Sant� et Institut National d'Excellence en Sant� et en Services Sociaux; pour la France : Minist�re en charge de la Sant�

Summary of findings(Explanation)

Summary of findings for the main comparison. Sumatriptan 50 mg or 85 mg plus naproxen 500 mg compared with placebo for migraine headache
  1. 1 Quality of evidence downgraded from high because of threat from potential publication bias with modest effect size and modest number of events.

Sumatriptan 50 mg or 85 mg plus naproxen 500 mg compared with placebo for migraine headache

Patient or population: adults with migraine headache - moderate or severe and mild baseline pain

Settings: community

Intervention: sumatriptan 50 mg or 85 mg plus naproxen 500 mg

Comparison: placebo

Outcomes Probable outcome with
comparator
Probable outcome with
intervention
NNT or NNH
(95% CI)
No. of studies, attacks, eventsQuality of the evidence
(GRADE)
Comments
Pain-free response at 2 h for moderate to severe baseline pain77 in 1000280 in 1000NNT 4.9 (4.3 to 5.7)4 studies, 2596 attacks, 462 eventsHighLower NNTs are better than higher NNTs
Pain-free response at 2 h for mild baseline pain180 in 1000500 in 1000NNT 3.1 (2.9 to 3.5)8 studies, 3395 attacks, 1252 evevtsHighLower NNTs are better than higher NNTs
Headache relief at 2 h for moderate to severe baseline pain270 in 1000580 in 1000NNT 3.2 (2.9 to 3.6)4 studies, 2596 attacks, 1107 eventsHighLower NNTs are better than higher NNTs
Sustained pain-free during the 24 h post dose for moderate to severe baseline pain60 in 1000200 in 1000NNT 7.9 (5.9 to 8.5)4 studies, 2596 attacks, 339 eventsModerate1Lower NNTs are better than higher NNTs
Sustained pain-free during the 24 h post dose for mild baseline pain120 in 1000370 in 1000NNT 4.1 (3.7 to 4.6)8 studies, 3396 attacks, 907 eventsHighLower NNTs are better than higher NNTs
Sustained headache relief during the 24 h post dose for moderate or severe baseline pain160 in 1000430 in 1000NNT 3.8 (3.4 to 4.3)4 studies, 2596 attacks, 768 eventsHighLower NNTs are better than higher NNTs
At least 1 AE during treatment for moderate to severe baseline pain120 in 1000210 in 1000NNH 11 (8.3 to 15)4 studies, 2793 attacks, 465 eventsModerate1Higher NNHs are better than lower NNHs
At least 1 AE during treatment for mild baseline pain82 in 1000140 in 1000NNH 18 (13 to 30)6 studies, 2823 attacks, 329 eventsModerate1Higher NNHs are better than lower NNHs
Serious AE (all levels of baseline pain)No events1 event possibly related to intervention----

AE: adverse event; CI: confidence interval; NNT: number needed to treat; NNH: number needed to harm.

Note: NNT or NNH is reported when an outcome is statistically different from placebo or comparator. Where the result is not statistically different, a risk ratio or similar outcome is reported.

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Migraine is a common, disabling headache disorder, ranked seventh highest among specific causes of disability globally (Steiner 2013), and with considerable social and economic impact (Hazard 2009). Recent reviews found a one-year prevalence of 15% globally (Vos 2012) and for adults in European countries (Stovner 2010), 13% for all ages in the USA (Victor 2010), 21% in Russia (Ayzenberg 2012), and 9% for adults in China (Yu 2012). Migraine is more prevalent in women than in men (by a factor of two to three), and in the age range 30 to 50 years.

The International Headache Society (IHS) classifies two major subtypes (IHS 2013). Migraine without aura is the most common subtype. It is characterised by attacks lasting 4 to 72 hours that are typically of moderate to severe pain intensity (PI), unilateral, pulsating, aggravated by normal physical activity, and associated with nausea with or without photophobia and phonophobia. Migraine with aura is characterised by reversible focal neurological symptoms that develop over a period of at least 5 minutes and last for less than 60 minutes, followed by headache with the features of migraine without aura. In some cases, the headache may lack migrainous features or be absent altogether (IHS 2013).

A large prevalence study in the USA found that over half of migraineurs had severe impairment or required bed rest during attacks. Despite this high level of disability and a strong desire for successful treatment, only a proportion of migraine sufferers seek professional advice for the treatment of attacks. The majority were not taking any preventive medication, although one-third met guideline criteria for offering or considering it. Nearly all (98%) migraineurs used acute treatments for attacks, with 49% using over-the-counter (OTC) medication only, 20% using prescription medication, and 29% using both. OTC medications included aspirin, other non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol (acetaminophen), and paracetamol plus caffeine (Bigal 2008; Diamond 2007; Lipton 2007). Similar findings have been reported from other large studies in France and Germany (Lucas 2006; Radtke 2009).

The significant impact of migraine with regard to pain, functional health, and well-being is well documented (Buse 2011; Leonardi 2005); it is ranked in the top 10 disorders for global years lived with disability (Vos 2012). A cross-sectional survey of eight EU countries (representing 55% of the adult population) has estimated an annual direct and indirect cost of migraine per person of EUR 1222, and a total annual cost for the EU of EUR 111 billion for adults aged 18 to 65 years (Linde 2012). Costs vary between countries, probably due to differences in available therapies and the way they are delivered, and structural differences in healthcare systems (Bloudek 2012). In the USA, the mean annual direct cost per person has been estimated at USD 1757 for episodic migraine and USD 7750 for chronic migraine (Munakata 2009). Whatever the exact direct and indirect costs are for each country, it is clear that migraine presents a significant economic burden. Successful treatment of acute migraine attacks not only benefits patients by reducing their disability and improving health-related quality of life, but also has the potential to reduce the need for healthcare resources and increase economic productivity.

Description of the intervention

The symptomatic treatment of migraine advanced significantly with the development of the triptan class of drugs, of which sumatriptan was the first. Sumatriptan is available as 50 mg and 100 mg oral tablets (maximum dose 300 mg in 24 hours) and also as a subcutaneous injection (6 mg dose, maximum 12 mg in 24 hours), intranasal spray (20 mg, maximum 40 mg in 24 hours), and rectal suppositories (12.5 mg and 25 mg). In most parts of the world it is available only by prescription, but in some countries, it is available to the public without prescription. Naproxen is an NSAID first marketed in the mid-1970s, with confirmed efficacy in acute (Derry 2009) and chronic (Moore 2010a; Moore 2010b) pain, and limited efficacy in migraine (Law 2013). It is a propionic acid derivative (of the same family as ibuprofen), with analgesic, anti-inflammatory, and antipyretic properties. It has been widely used in treating arthritis, menstrual cramps, gout, sprains and strains, and a variety of acute pain conditions. Naproxen and its soluble sodium salt are commonly available as 250 mg and 500 mg tablets (275 mg and 550 mg of sodium salt). In many parts of the world it remains a prescription-only drug, but in others such as the USA, UK, and most parts of Canada, it is available OTC in restricted doses.

A fixed-dose combination tablet (trade name Trexima or Treximet; GlaxoSmithKline) containing sumatriptan 85 mg plus naproxen 500 mg is now available by prescription in the USA. It appears not to be available in Europe as of August 2013; we were unable to establish availability and licensing in other parts of the world.

In order to establish whether sumatriptan plus naproxen is an effective analgesic combination at a specified dose in acute migraine attacks, it is necessary to study its effects in circumstances that permit detection of pain relief (PR). Such studies are carried out in individuals with established pain of moderate to severe intensity, using single doses of the interventions. Participants who experience an inadequate response with either placebo or active treatment are permitted to use rescue medication, and the intervention is considered to have failed in those individuals. In clinical practice, however, individuals would not normally wait until pain is of at least moderate severity, and may take a second dose of medication if the first dose does not provide adequate relief. Once analgesic efficacy is established in studies using single doses in established pain, further studies may investigate different treatment strategies and patient preferences. These are likely to include treating the migraine attack early while pain is mild, and using a low dose initially, with a second dose if response is inadequate.

How the intervention might work

The challenge in optimising therapy for acute migraine headaches is in providing broad coverage of the multiple pathogenic processes involved, which are thought to include several neural pathways becoming sequentially activated and sensitised as an attack develops (Goadsby 2002).

Early in an attack, trigeminal nerve endings release vasoactive and inflammatory substances such as calcitonin gene-related peptide and kinins. Calcitonin gene-related peptide causes meningeal vasodilation, and kinins induce release of inflammatory prostaglandins. The resulting vascular and meningeal inflammation stimulates trigeminal nociceptors and activates central pathways via ascending pain pathways. Prolonged nociceptive input causes central foci to fire in a sustained continuous manner causing a symptomatic migraine attack. This is characteristic of the central sensitisation hypothesis (Burstein 2001).

Sumatriptan is a 5-HT1 agonist, selectively targeting the 5-HT (serotonin) 1B and 1D receptors. It is suggested that it inhibits synaptic transmission from the periphery before central sensitisation occurs. Three putative mechanisms of therapeutic action are involved (Ferrari 2002):

  • vasoconstriction of dilated meningeal blood vessels;

  • inhibition of the release of vasoactive neuropeptides from perivascular trigeminal sensory neurons;

  • reduction of pain signal transmission in the trigeminal dorsal horn.

Non-steroidal anti-inflammatory drugs (NSAIDs) block the effect of cyclo-oxygenase on arachidonic acid, which is responsible for the synthesis of prostaglandins. Prostaglandins mediate a variety of physiological functions including maintenance of the gastric mucosal barrier, regulation of renal blood flow, and regulation of endothelial tone, and they also play an important role in inflammatory and nociceptive processes. Naproxen is a reversible inhibitor of cyclo-oxygenase. Unlike the triptans, which exert their effect peripherally, naproxen is thought to inhibit central sensitisation by attenuating meningeal inflammation and preventing central sensitisation arising from glial cells in the brain stem. In one study, naproxen suppressed central trigeminal neurons in an animal model of intracranial pain (Jakubowski 2007). Because multiple mechanisms are involved in migraine, multi-mechanism targeted therapy with sumatriptan plus naproxen may confer advantages over conventional monotherapy.

Why it is important to do this review

Other Cochrane reviews of treatments for acute migraine in adults have shown that oral sumatriptan had good efficacy (Derry 2012), and naproxen alone had limited efficacy (Law 2013). It is important to assess and analyse the data now available for combination therapy involving these two agents, particularly in the light of recent research showing that fixed-dose combinations of analgesics generally provide enhanced analgesic efficacy in acute pain and migraine when compared with any single drug in the combination (Moore 2012).

Objectives

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.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised, double-blind, placebo- or active-controlled studies using sumatriptan plus naproxen to treat a migraine headache episode. Studies had to have a minimum of 10 participants per treatment arm and measure at least one of the outcomes specified below. We accepted studies reporting treatment of consecutive headache episodes if outcomes for the first, or each, episode were reported separately; first attack data were used preferentially. We accepted cross-over studies if there was adequate washout (≥ 48 hours) between treatments.

Types of participants

Studies enrolled adults (at least 18 years of age) with episodic migraine. We used the definition of migraine specified by the IHS (IHS 1988; IHS 2004; IHS 2013), and excluded trials evaluating treatments for chronic migraine. We applied no other restrictions on migraine frequency, duration, or type (with or without aura). We accepted studies that included participants taking stable prophylactic therapy to reduce the frequency of migraine attacks. We provided details on any prophylactic therapy prescribed or allowed in the Characteristics of included studies table.

Types of interventions

We included studies in which self administered sumatriptan plus naproxen (as separate tablets administered together, or as a fixed-dose combination tablet) was used to treat a migraine headache episode. We applied no restrictions on dose, dosing regimen (eg single dose versus optional second dose), or timing of the first dose in relation to headache intensity (eg taking the first dose when pain was of moderate to severe intensity versus when the pain was mild).

A placebo comparator is essential to demonstrate that sumatriptan plus naproxen is effective in this condition. We considered active-controlled trials without a placebo as secondary evidence. We excluded studies designed to demonstrate prophylactic efficacy in reducing the number or frequency of migraine headaches.

Types of outcome measures

Primary outcomes

In selecting the main outcome measures for this review, we considered scientific rigour, availability of data, and patient preferences (Lipton 1999). Patients with acute migraine headaches have rated complete PR, no headache recurrence, rapid onset of PR, and no side effects as the four most important outcomes (Lipton 1999).

In view of these patient preferences, and in line with the guidelines for controlled trials of drugs in migraine issued by the IHS (IHS 2000), the main outcomes that we considered were:

  • pain-free at two hours, without the use of rescue medication;

  • reduction in headache pain ('headache relief') at two hours (pain reduced from moderate or severe to none or mild without the use of rescue medication).

We also collected data for pain-free and headache relief outcomes at one hour if reported.

Secondary outcomes

We considered the following secondary outcomes:

  • sustained pain-free during the 24 hours post dose (pain-free within two hours, with no use of rescue medication or recurrence of moderate to severe pain within 24 hours);

  • sustained headache relief during the 24 hours post dose (headache relief at two hours, sustained for 24 hours, with no use of rescue medication or a second dose of study medication);

  • adverse events: participants with any adverse event during the 24 hours post dose; serious adverse events; adverse events leading to withdrawal.

Other outcomes

We also collected data for other outcomes, including:

  • use of rescue medication;

  • relief of headache-associated symptoms;

  • relief of functional disability.

PI or PR had to be measured by the participant (not the investigator or care provider). We accepted the following pain measures for the main efficacy outcomes:

  • PI: 4-point categorical scale, with wording equivalent to none, mild, moderate, and severe; or 100 mm visual analogue scale (VAS), where less than 30 mm was considered equivalent to mild or no pain and 30 mm or greater equivalent to moderate or severe pain (Collins 1997);

  • PR: 5-point categorical scale, with wording equivalent to none, a little, some, a lot, and complete; or 100 mm VAS, where less than 30 mm was considered equivalent to none or a little, and 30 mm or greater equivalent to some, a lot, or complete.

We considered only data obtained directly from the participant.

Definitions of important terms, including all measured outcomes, are provided in Appendix 1.

Search methods for identification of studies

Electronic searches

We searched the following databases:

  • the Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library, (Issue 6 of 12, 2013);

  • MEDLINE (via Ovid) (1947 to 2 August 2013);

  • EMBASE (via Ovid) (1974 to 2 August 2013).

See Appendix 2, Appendix 3, and Appendix 4 for the search strategies for CENTRAL, MEDLINE (via Ovid), and EMBASE (via Ovid), respectively.

We applied no language restrictions.

Searching other resources

We searched for additional studies in reference lists of retrieved studies and review articles, and in two clinical trials databases (www.clinicaltrials.gov and www.gsk-clinicalstudyregister.com). We contacted the manufacturer of the fixed-dose combination agent (GlaxoSmithKline) for information about both published and unpublished data, but no additional studies were identified in their response. We did not search grey literature and abstracts.

Data collection and analysis

Selection of studies

Two review authors independently carried out the searches and selected studies for inclusion. We viewed the titles and abstracts of all studies identified by electronic searches on screen and excluded any that clearly did not satisfy inclusion criteria. We read full copies of the remaining studies to identify those suitable for inclusion. Disagreements were settled by discussion with a third review author.

Data extraction and management

Two review authors independently extracted data from included studies using a standard data extraction form. We settled disagreements by discussion with a third review author. One review author entered data into Review Manager 5 (RevMan 2012).

Assessment of risk of bias in included studies

We used the Oxford Quality Score as the basis for inclusion (Jadad 1996), limiting inclusion to studies that were randomised and double-blind as a minimum. The scores for each study are reported in the Characteristics of included studies table.

Two review authors independently assessed risk of bias for each study, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and adapted from those used by the Cochrane Pregnancy and Childbirth Group, with any disagreements resolved by discussion. We assessed the following for each study.

  1. Random sequence generation (checking for possible selection bias). We assessed the method used to generate the allocation sequence as: low risk of bias (any truly random process, eg random number table; computer random number generator); unclear risk of bias (method used to generate sequence not clearly stated). We excluded studies using a non-random process (eg odd or even date of birth; hospital or clinic record number).

  2. Allocation concealment (checking for possible selection bias). The method used to conceal allocation to interventions prior to assignment determines whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment. We assessed the methods as: low risk of bias (eg telephone or central randomisation; consecutively numbered sealed opaque envelopes); unclear risk of bias (method not clearly stated). We excluded studies that did not conceal allocation (eg open list).

  3. Blinding of outcome assessment (checking for possible detection bias). We assessed the methods used to blind study participants and outcome assessors from knowledge of which intervention a participant received. We assessed the methods as: low risk of bias (study states that it was blinded and describes the method used to achieve blinding, eg identical tablets; matched in appearance and smell); unclear risk of bias (study states that it was blinded but does not provide an adequate description of how it was achieved). We excluded studies that were not double-blind.

  4. Incomplete outcome data (checking for possible attrition bias due to the amount, nature, and handling of incomplete outcome data). We assessed the methods used to deal with incomplete data as: low risk (< 10% of participants provided no data without acceptable reason - eg they were randomised but did not have a qualifying headache). We excluded studies with high data loss.

  5. Size of study (checking for possible biases confounded by small size). We assessed studies as being at low risk of bias (≥ 200 participants per treatment arm); unclear risk of bias (50 to 199 participants per treatment arm); high risk of bias (< 50 participants per treatment arm).

Measures of treatment effect

We used risk ratios (relative risk; RR) to establish statistical difference. Numbers needed to treat (NNT) and pooled percentages were used as absolute measures of benefit or harm.

We used the following terms to describe adverse outcomes in terms of harm or prevention of harm:

  • when significantly fewer adverse outcomes occurred with sumatriptan plus naproxen than with control (placebo or active), we use the term the number needed to treat to prevent one event (NNTp);

  • when significantly more adverse outcomes occur with sumatriptan plus naproxen compared with control (placebo or active), we use the term the number needed to harm or cause one event (NNH).

Unit of analysis issues

The unit of analysis was the individual participant.

Dealing with missing data

The most likely source of missing data was in cross-over studies; we planned to use only first-period data where possible, but where that was not provided, we treated the results as if they were parallel group results. Where there were substantial missing data in any study, we commented on this and performed sensitivity analyses to investigate their effects.

For all outcomes, we carried out analyses, as far as possible, on a modified intention-to-treat basis, that is, we included all participants who were randomised and received an intervention. Where sufficient information was reported, we re-included missing data in the analyses we undertook. We excluded data from outcomes where results from 10% or greater of participants were missing with no acceptable reason provided or apparent.

Assessment of heterogeneity

We assessed heterogeneity of response rates using L'Abbé plots, a visual method for assessing differences in results of individual studies (L'Abbé 1987). Where data could be pooled, we reported the I2 statistic.

Assessment of reporting biases

We assessed publication bias by examining the number of participants in trials with zero effect (RR 1.0) needed for the point estimate of the NNT to increase beyond a clinically useful level (Moore 2008). In this case, we specified a clinically useful level as an NNT of 8 or greater for pain-free at two hours, and NNT of 6 or greater for headache relief at two hours.

Data synthesis

We analysed studies using a single dose of sumatriptan plus naproxen in established pain of at least moderate intensity separately from studies in which medication was taken before pain became well established, or in which a second dose of medication was permitted.

We calculated effect sizes and combined data for analysis only for comparisons and outcomes where there were at least two studies and 200 participants (Moore 1998). Relative risk of benefit ('relative benefit') or harm ('relative risk') was calculated with 95% confidence intervals (CIs) using a fixed-effect model (Morris 1995). We calculated NNT, NNTp, and NNH with 95% CIs using the pooled number of events by the method of Cook and Sackett (Cook 1995). We assumed a statistically significant difference from control when the 95% CI of the RR of benefit or harm did not include the number one.

We used the z test to determine significant differences between NNT, NNTp, and NNH for different groups in subgroup and sensitivity analyses (Tramèr 1997).

We described data from comparisons and outcomes with only one study or fewer than 200 participants in the text or summary tables, or both where appropriate for information and comparison, but we did not analyse these data quantitatively.

Subgroup analysis and investigation of heterogeneity

Issues for potential subgroup analysis were dose, timing of doses, route of administration, and multiple dosing strategies.

Sensitivity analysis

We planned sensitivity analysis for study quality (Oxford Quality Score of 2 versus 3 or more), migraine type (with aura versus without aura), and menstrual migraine. A minimum of two studies and 200 participants had to be available for any sensitivity analysis.

Results

Description of studies

Results of the search

We identified 18 potentially relevant studies.

Included studies

Twelve studies (with data reported in seven primary publications) satisfied all inclusion criteria and are included in this review. Seven studies used a parallel group design (Brandes 2007 Study 1; Brandes 2007 Study 2; Mannix 2009 Study 1; Mannix 2009 Study 2; Silberstein 2008 Study 1; Silberstein 2008 Study 2; Smith 2005), and five studies were cross-over in design (Lipton 2009 Study 1; Lipton 2009 Study 2; Mathew 2009 Study 1; Mathew 2009 Study 2; TRX109011/13). TRX109011/13 was available only as a clinical trial summary with results at the time that initial data extraction was carried out, but has subsequently been published in a peer-reviewed journal (Derosier 2012). For the two cross-over studies treating more than one episode with the same medication, we used data from the first period (Lipton 2009 Study 1; Lipton 2009 Study 2). First period only data were not reported for the other three cross-over studies (Mathew 2009 Study 1; Mathew 2009 Study 2; TRX109011/13), so we used combined data for analyses, with a post-hoc sensitivity analysis in addition to those sensitivity analyses outlined in the protocol. In eight studies, medication was to be taken early in the attack, while PI was still mild (Lipton 2009 Study 1; Lipton 2009 Study 2; Mannix 2009 Study 1; Mannix 2009 Study 2; Mathew 2009 Study 1; Mathew 2009 Study 2; Silberstein 2008 Study 1; Silberstein 2008 Study 2), and in the remaining four studies when it was moderate or severe (Brandes 2007 Study 1; Brandes 2007 Study 2; Smith 2005; TRX109011/13). No studies employed multiple dosing strategies for a single attack.

Two further publications reported data on functional disability that were not reported in the primary publications; Landy 2007 for Brandes 2007 Study 1 and Brandes 2007 Study 2 and Taylor 2007 for Silberstein 2008 Study 1 and Silberstein 2008 Study 2. Another publication (Cady 2011) reported satisfaction, productivity, and functional disability outcomes for participants in Mannix 2009 Study 1 and Mannix 2009 Study 2, but data were not reported in a format that we could use in the meta-analysis.

All studies were multicentre and diagnosed migraine (with or without aura) according to IHS criteria. Individuals with frequent migraine headaches (> 6 or 8 attacks per month) were excluded. Most studies required that participants had previously tolerated treatment with a triptan or had no contraindications, or both, but Mathew 2009 Study 1 and Mathew 2009 Study 2 included participants who had specifically been previous poor responders to triptans with a short half life, including sumatriptan, and TRX109011/13 required that participants had previous experience using barbiturate-containing medicines. In all studies, participants self treated their headaches at home. Two studies included only participants with menstrual migraine (Mannix 2009 Study 1; Mannix 2009 Study 2). Overall, the mean age of participants ranged from 40 to 43 years, and between 85% and 100% were female. Generally, participants were eligible for inclusion if they were using stable prophylactic medication provided it was not a triptan, methysergide, or ergot derivative. Cross-over studies where we used combined data across treatment periods (Mathew 2009 Study 1; Mathew 2009 Study 2; TRX109011/13) had adequate washout periods between treatments of at least one week. The washout period was not specified in two other cross-over studies (Lipton 2009 Study 1; Lipton 2009 Study 2); for these, first period only data were available and were used for analyses.

Eleven studies gave sumatriptan 85 mg plus naproxen 500 mg formulated as a combination tablet, while Smith 2005 gave sumatriptan 50 mg plus naproxen 500 mg as separate tablets taken together. All studies compared sumatriptan plus naproxen versus placebo, and three studies included treatment arms using sumatriptan 85 mg (Brandes 2007 Study 1; Brandes 2007 Study 2) or 50 mg (Smith 2005) and naproxen 500 mg alone. One study compared the combination with placebo and a butalbital-containing active comparator (TRX109011/13); there were insufficient data for a head to head analysis of the active comparator from this single trial. There were no other active comparators. In total, 3663 participants who took sumatriptan plus naproxen were included in safety analyses for adverse events; 3682 took placebo, 964 took sumatriptan alone, 982 took naproxen alone, and 304 took a combination medication containing butalbital 50 mg, paracetamol (acetaminophen) 325 mg, and caffeine 40 mg. The number included in efficacy analyses was slightly lower because some participants were excluded from these analyses due to protocol violations.

The outcomes reported by individual studies are listed in the Characteristics of included studies table. All studies measured headache PI using a standard 4-point scale, and evaluated pain-free response at two hours and sustained pain-free during the 24 hours post dose as the primary outcome measures. Of the four studies treating headache of moderate or severe intensity, all measured headache relief at two hours and sustained headache relief during the 24 hours post dose (Brandes 2007 Study 1; Brandes 2007 Study 2; Smith 2005; TRX109011/13), with Smith 2005 also reporting headache relief at the earlier time of one hour. All studies reported on adverse events.

Details of individual studies are in the Characteristics of included studies table.

Excluded studies

We excluded six publications (Krymchantowski 2000; Landy 2009; Smith 2007; TRX107563; White 2011; Winner 2007). Details are in the Characteristics of excluded studies table.

Risk of bias in included studies

Methodological quality, assessed using the Oxford Quality Scale, was good in all studies. Three studies scored 5/5 (Silberstein 2008 Study 1; Silberstein 2008 Study 2; TRX109011/13), three scored 4/5 (Mannix 2009 Study 1; Mannix 2009 Study 2; Smith 2007), and six scored 3/5 (Brandes 2007 Study 1; Brandes 2007 Study 2; Lipton 2009 Study 1; Lipton 2009 Study 2; Mathew 2009 Study 1; Mathew 2009 Study 2). Points were lost due to failure to report the method of randomisation or blinding adequately. Full details are in the Characteristics of included studies table.

In addition, we created a Risk of bias table, which considered sequence generation, allocation concealment, blinding, incomplete outcome data, and study size (Figure 1). Only two studies adequately reported the method of allocation concealment (Mannix 2009 Study 1; Mannix 2009 Study 2). No study had substantial amounts of missing data, and no study was considered to be at high risk of bias.

Figure 1.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Effects of interventions

See: Summary of findings for the main comparison Sumatriptan 50 mg or 85 mg plus naproxen 500 mg compared with placebo for migraine headache

Studies treating headache early, when pain was still mild, were analysed separately from those treating only once pain was of moderate or severe intensity. For analysis, we chose to combine results from the study using sumatriptan 50 mg plus naproxen 500 mg, given as separate tablets, with studies that used sumatriptan 85 mg plus naproxen 500 mg, given as a combined formulation. We carried out sensitivity analyses to determine the effect of the combined formulation alone.

Details of the main efficacy outcomes in individual studies are in Appendix 5, and of adverse events and withdrawals are in Appendix 6. Results for pain-free and headache relief outcomes are summarised in Summary of results: Pain-free and headache relief.

Pain-free at two hours

Sumatriptan/naproxen versus placebo
Mild baseline pain

Eight studies (3395 attacks) provided data for early use of the combined formulation, compared with placebo, when pain was still mild (Lipton 2009 Study 1; Lipton 2009 Study 2; Mannix 2009 Study 1; Mannix 2009 Study 2; Mathew 2009 Study 1; Mathew 2009 Study 2; Silberstein 2008 Study 1; Silberstein 2008 Study 2).

  • The proportion of attacks pain-free at two hours with sumatriptan/naproxen 85/500 mg was 50% (1008/2025; range 40% to 52%).

  • The proportion of attacks pain-free at two hours with placebo was 18% (244/1370; range 14% to 23%).

  • The relative benefit of treatment compared with placebo was 2.8 (95% CI 2.4 to 3.1) (Figure 2); the NNT was 3.1 (95% CI 2.9 to 3.5).

    Figure 2.

    Forest plot of comparison: 1 Sumatriptan/naproxen versus placebo, outcome: 1.1 Pain-free at two hours.

Moderate/severe baseline pain

Four studies (2596 attacks) provided data for use of either the combined formulation (Brandes 2007 Study 1; Brandes 2007 Study 2; TRX109011/13), or separate tablets (Smith 2005), compared with placebo, when pain was moderate or severe.

  • The proportion of attacks pain-free at two hours with sumatriptan/naproxen 50 to 85/500 mg was 28% (362/1293; range 14% to 34%).

  • The proportion of attacks pain-free at two hours with placebo was 7.7% (100/1303; range 5% to 10%).

  • The relative benefit of treatment compared with placebo was 3.7 (95% CI 3.0 to 4.5) (Figure 2); the NNT was 4.9 (95% CI 4.3 to 5.7).

  • For sumatriptan/naproxen 85/500 mg only (excluding the 50/500 mg dose), the NNT was 5.4 (95% CI 4.6 to 6.5), which was not significantly different from the NNT for the combined analysis.

Treating headache early, when pain was still mild, was significantly better than treating once pain was of moderate or severe intensity (z = 5.548; P value < 0.00001). A L'Abbé plot shows no evidence of heterogeneity within each group (Figure 3).

Figure 3.

L'Abbé plot showing results for sumatriptan + naproxen versus placebo for pain-free at two hours. Each circle represents a different study; blue circles are studies with moderate or severe baseline pain and cream circles are mild baseline pain; size of circle is proportional to size of study; diagonal is line of equivalence.

Sumatriptan/naproxen versus sumatriptan or naproxen alone

Three studies provided data for use of either the combined formulation (Brandes 2007 Study 1; Brandes 2007 Study 2) or separate tablets (Smith 2005), compared with sumatriptan alone (1925 participants) or naproxen alone (1944 participants), when pain was moderate or severe.

  • The proportion of participants pain-free at two hours with sumatriptan/naproxen 50 to 85/500 mg was 32% (317/976; range 30% to 34%).

  • The proportion of participants pain-free at two hours with sumatriptan alone was 23% (217/949; range 20% to 25%).

  • The proportion of participants pain-free at two hours with naproxen alone was 16% (155/968; range 15% to 18%).

  • The relative benefit of the combination compared with sumatriptan alone was 1.4 (95% CI 1.2 to 1.7) (Analysis 2.1); the NNT was 10 (95% CI 7.4 to 18).

  • The relative benefit of the combination compared with naproxen alone was 2.0 (95% CI 1.7 to 2.4) (Analysis 3.1); the NNT was 6.1 (95% CI 5.0 to 7.9).

The combination was significantly better than either sumatriptan or naproxen alone.

Headache relief at two hours

Sumatriptan/naproxen versus placebo

Four studies (2596 attacks) provided data for use of either the combined formulation (Brandes 2007 Study 1; Brandes 2007 Study 2; TRX109011/13), or separate tablets (Smith 2005), compared with placebo, when pain was moderate or severe.

  • The proportion of attacks with headache relief at two hours with sumatriptan/naproxen 50 to 85/500 mg was 58% (755/1293; range 47% to 65%).

  • The proportion of attacks with headache relief at two hours with placebo was 27% (352/1303; range 24% to 29%).

  • The relative benefit of treatment compared with placebo was 2.2 (95% CI 2.0 to 2.4); the NNT was 3.2 (95% CI 2.9 to 3.6) (Figure 4).

    Figure 4.

    Forest plot of comparison: 1 Sumatriptan/naproxen versus placebo, outcome: 1.2 Headache relief at two hours.

  • For sumatriptan/naproxen 85/500 mg alone (excluding the 50/500 mg dose) the NNT was 3.4 (95% CI 3.0 to 3.9), which was not significantly different from the NNT for the combined analysis.

A L'Abbé plot showed no evidence of heterogeneity between the studies (Figure 5).

Figure 5.

L'Abbé plot showing results for sumatriptan + naproxen versus placebo for headache relief at two hours in studies with moderate or severe baseline pain. Each circle represents a different study; size of circle is proportional to size of study; diagonal is line of equivalence.

Sumatriptan/naproxen versus sumatriptan or naproxen alone

Three studies provided data for use of either the combined formulation (Brandes 2007 Study 1; Brandes 2007 Study 2), or separate tablets (Smith 2005), compared with sumatriptan alone (1925 participants) or naproxen alone (1944 participants), when pain was moderate or severe.

  • The proportion of participants experiencing headache relief at two hours with sumatriptan/naproxen 50 to 85/500 mg was 62% (607/976; range 57% to 65%).

  • The proportion of participants experiencing headache relief at two hours with sumatriptan alone was 52% (493/949; range 49% to 55%).

  • The proportion of participants experiencing headache relief at two hours with naproxen alone was 44% (426/968; range 43% to 45%).

  • The relative benefit of the combination compared with sumatriptan alone was 1.2 (95% CI 1.1 to 1.3); the NNT was 9.8 (95% CI 6.8 to 17) (Analysis 2.2).

  • The relative benefit of the combination compared with naproxen alone was 1.4 (95% CI 1.3 to 1.5); the NNT was 5.5 (95% CI 4.4 to 7.2) (Analysis 3.2).

The combination was significantly better than either sumatriptan or naproxen alone.

Headache relief at one hour

One study, treating moderate to severe baseline pain, provided data (Smith 2005); 73/250 participants experienced headache relief with combination therapy compared with 52/226 with sumatriptan alone, 67/248 with naproxen alone, and 29/241 with placebo. The data were insufficient for analysis.

Sustained pain-free during the 24 hours post dose

Sumatriptan/naproxen versus placebo
Mild baseline pain

Eight studies (3396 attacks) provided data (Lipton 2009 Study 1; Lipton 2009 Study 2; Mannix 2009 Study 1; Mannix 2009 Study 2; Mathew 2009 Study 1; Mathew 2009 Study 2; Silberstein 2008 Study 1; Silberstein 2008 Study 2) for early use of the combined formulation, compared with placebo, when pain was still mild.

  • The proportion of attacks with a 24-hour sustained pain-free response with sumatriptan/naproxen 85/500 mg was 37% (741/2026; range 26% to 45%).

  • The proportion of attacks with a 24-hour sustained pain-free response with placebo was 12% (166/1370; range 8% to 18%).

  • The relative benefit of treatment compared with placebo was 3.0 (95% CI 2.6 to 3.6) (Analysis 1.3); the NNT was 4.1 (95% CI 3.7 to 4.6).

Moderate/severe baseline pain

Four studies (2596 attacks) provided data for use of either the combined formulation (Brandes 2007 Study 1; Brandes 2007 Study 2; TRX109011/13), or separate tablets (Smith 2005), compared with placebo, when pain was moderate or severe.

  • The proportion of attacks with a 24-hour sustained pain-free response with sumatriptan/naproxen 50 to 85/500 mg was 20% (262/1293; range 8.2% to 25%).

  • The proportion of attacks with a 24-hour sustained pain-free response with placebo was 5.9% (77/1303; range 3.1% to 8.3%).

  • The relative benefit of treatment compared with placebo was 3.4 (95% CI 2.7 to 4.4) (Analysis 1.3); the NNT was 7.0 (95% CI 5.9 to 8.5).

  • For sumatriptan/naproxen 85/500 mg alone (excluding the 50/500 mg dose) the NNT was 7.7 (95% CI 6.4 to 9.8), which was not significantly different from the NNT for the combined analysis.

Treating headache early, when pain was still mild, was significantly better than treating once pain was of moderate or severe intensity (z = 5.326; P value = 0.0001). A L'Abbé plot showed no evidence of heterogeneity between the studies, and there was considerable overlap between the two groups (Figure 6).

Figure 6.

L'Abbé plot showing results for sumatriptan + naproxen versus placebo for 24-hour sustained pain-free. Each circle represents a different study; blue circles are studies with moderate or severe baseline pain and cream circles are mild baseline pain; size of circle is proportional to size of study; diagonal is line of equivalence.

Sumatriptan/naproxen versus sumatriptan or naproxen alone

Three studies provided data for use of either the combined formulation (Brandes 2007 Study 1; Brandes 2007 Study 2) or separate tablets (Smith 2005), compared with sumatriptan alone (1925 participants) or naproxen alone (1944 participants), when pain was moderate or severe.

  • The proportion of participants with a 24-hour sustained pain-free response with sumatriptan/naproxen 50 to 85/500 mg was 24% (236/976; range 23% to 25%).

  • The proportion of participants with a 24-hour sustained pain-free response with sumatriptan alone was 14% (135/949; range 11% to 16%).

  • The proportion of participants with a 24-hour sustained pain-free response with naproxen alone was 11% (104/968; range 10% to 12%).

  • The relative benefit of the combination compared with sumatriptan alone was 1.7 (95% CI 1.4 to 2.1); the NNT was 10 (95% CI 7.4 to 15) (Analysis 2.3).

  • The relative benefit of the combination compared with naproxen alone was 2.3 (95% CI 1.8 to 2.8); the NNT was 7.4 (95% CI 6.0 to 9.9) (Analysis 3.3).

The combination was significantly better than either sumatriptan or naproxen alone.

Sustained headache relief during the 24 hours post dose

Sumatriptan/naproxen versus placebo

Four studies (2596 attacks) provided data for use of either the combined formulation (Brandes 2007 Study 1; Brandes 2007 Study 2; TRX109011/13), or separate tablets (Smith 2005), compared with placebo, when pain was moderate or severe.

  • The proportion of attacks with 24-hour sustained headache relief with sumatriptan/naproxen 50 to 85/500 mg was 43% (554/1293; range 34% to 48%).

  • The proportion of attacks with 24-hour sustained headache relief with placebo was 16% (214/1303; range 14% to 18%).

  • The relative benefit of treatment compared with placebo was 2.6 (95% CI 2.3 to 3.0) (Analysis 1.4); the NNT was 3.8 (95% CI 3.4 to 4.3).

  • For sumatriptan/naproxen 85/500 mg alone (excluding the 50/500 mg dose) the NNT was 3.9 (95% CI 3.4 to 4.5), which was not significantly different from the NNT for the combined analysis.

Sumatriptan/naproxen versus sumatriptan or naproxen alone

Three studies provided data for use of either the combined formulation (Brandes 2007 Study 1; Brandes 2007 Study 2), or separate tablets (Smith 2005), compared with sumatriptan alone (1925 participants) or naproxen alone (1944 participants), when pain was moderate or severe.

  • The proportion of participants with 24-hour sustained headache relief with sumatriptan/naproxen 50 to 85/500 mg was 46% (447/976; range 44% to 48%).

  • The proportion of participants with 24-hour sustained headache relief with sumatriptan alone was 33% (314/949; range 29% to 35%).

  • The proportion of participants with 24-hour sustained headache relief with naproxen alone was 28% (271/968; range 25% to 30%).

  • The relative benefit of the combination compared with sumatriptan alone was 1.4 (95% CI 1.2 to 1.6); the NNT was 7.9 (95% CI 5.9 to 12) (Analysis 2.4).

  • The relative benefit of the combination compared with naproxen alone was 1.6 (95% CI 1.5 to 1.9); the NNT was 5.6 (95% CI 4.5 to 7.4) (Analysis 3.4).

The combination was significantly better than either sumatriptan or naproxen alone.

Summary of results: Pain-free and headache relief
 Baseline painStudies

Attacks

treated

Treatment

(%)

Placebo or comparator

(%)

Risk ratio (95% CI)

NNT

(95% CI)

Pain-free at 2 h       
Sumatriptan/naproxen 85/500 mg vs placebomild8339550182.8 (2.4 to 3.1)3.1 (2.9 to 3.5)
Sumatriptan/naproxen 50-85/500 mg vs placebo≥ mod42596287.73.7 (3.0 to 4.5)4.9 (4.3 to 5.7)
Sumatriptan/naproxen 85/500 mg vs placebo≥ mod32105278.13.3 (2.6 to 4.1)5.4 (4.6 to 6.5)
Sumatriptan/naproxen 50-85/500 mg vs sumatriptan 50-85 mg≥ mod3192532231.4 (1.2 to 1.7)10 (7.4 to 18)
Sumatriptan/naproxen 50-85/500 mg vs naproxen 500 mg≥ mod3194432162.0 (1.7 to 2.4)6.1 (5.0 to 7.9)
Headache relief at 2 h       
Sumatriptan/naproxen 50-85/500 mg vs placebo≥ mod4259658272.2 (2.0 to 2.4)3.2 (2.9 to 3.6)
Sumatriptan/naproxen 85/500 mg vs placebo≥ mod3210557272.1 (1.9 to 2.4)3.4 (3.0 to 3.9)
Sumatriptan/naproxen 50-85/500 mg vs sumatriptan 50-85 mg≥ mod3192562521.2 (1.1 to 1.3)9.8 (6.8 to 17)
Sumatriptan/naproxen 50-85/500 mg vs naproxen 500 mg≥ mod3194462441.4 (1.3 to 1.5)5.5 (4.4 to 7.2)
Sustained pain-free during the 24 h post dose       
Sumatriptan/naproxen 85/500 mg vs placebomild8339637123.0 (2.6 to 3.6)4.1 (3.7 to 4.6)
Sumatriptan/naproxen 50-85/500 mg vs placebo≥ mod425962063.4 (2.7 to 4.4)7.0 (5.9 to 8.5)
Sumatriptan/naproxen 85/500 mg vs placebo≥ mod320051963.1 (2.4 to 4.0)7.7 (6.4 to 9.8)
Sumatriptan/naproxen 50-85/500 mg vs sumatriptan 50-85 mg≥ mod3192524141.7 (1.4 to 2.1)10 (7.4 to 15)
Sumatriptan/naproxen 50-85/500 mg vs naproxen 500 mg≥ mod3194424112.3 (1.8 to 2.8)7.4 (6.0 to 9.9)
Sustained headache relief during the 24 h post dose       
Sumatriptan/naproxen 50-85/500 mg vs placebo≥ mod4259643162.6 (2.3 to 3.0)3.8 (3.4 to 4.3)
Sumatriptan/naproxen 85/500 mg vs placebo≥ mod3210742162.6 (2.2 to 3.0)3.9 (3.4 to 4.5)
Sumatriptan/naproxen 50-85/500 mg vs sumatriptan 50-85 mg≥ mod3192546331.4 (1.2 to 1.6)7.9 (5.9 to 12)
Sumatriptan/naproxen 50-85/500 mg vs naproxen 500 mg≥ mod3194446281.6 (1.5 to 1.9)5.6 (4.5 to 7.4)

Subgroup analysis of primary outcomes

Subgroup analysis according to the timing of initial medication (early while pain was mild, or once pain was moderate or severe) has been considered in the main analysis above, with early treatment giving better efficacy for pain-free responses at two hours and during the 24 hours post dose. Similarly, dose has been considered in the main analysis: all studies used sumatriptan 85 mg combined with naproxen 500 mg except Smith 2005, which used sumatriptan 50 mg combined with naproxen 500 mg. Inclusion of the lower dose did not significantly change the results.

All studies used the oral route of administration, and none used multiple dosing strategies.

Sensitivity analysis of primary outcomes

All studies scored at least 3/5 for methodological quality on the Oxford Quality Scale, and no studies provided separate data for participants with or without aura so no sensitivity analysis could be carried out for these criteria. There was no evidence that results from the studies reporting combined data from both phases of the cross-over differed from those reporting first phase only data (Mathew 2009 Study 1; Mathew 2009 Study 2; TRX109011/13). There was also no evidence that results for the study that enrolled only participants who had previously had a poor response to triptans with a short half-life (including sumatriptan) differed from those who enrolled participants who had previously tolerated treatment with a triptan or had no contraindications, or both (Mathew 2009 Study 1; Mathew 2009 Study 2).

Two studies included only participants with menstrual migraine (Mannix 2009 Study 1; Mannix 2009 Study 2). Results for these studies were similar to other studies treating mild pain for the outcomes of pain-free at two hours (Figure 2), and sustained pain-free during the 24 hours post dose (Analysis 1.3); removing the menstrual migraine studies from the analyses made no difference.

The three cross-over studies that did not report first period data separately, but only all period data (Mathew 2009 Study 1; Mathew 2009 Study 2; TRX109011/13), gave results that were indistinguishable from those from other studies (Figure 2; Figure 4; Analysis 1.3; Analysis 1.4).

Sumatriptan/naproxen versus active controls

One study compared the combination with a butalbital-containing active comparator (TRX109011/13); there were insufficient data for a head to head analysis of the two treatments from this single trial. Sumatriptan plus naproxen was reported to be statistically superior to the butalbital combination for pain-free response at all time points between 2 and 48 hours.

Adverse events

Any adverse event

All studies reported some information about participants who experienced one or more adverse events, but the reporting was inconsistent. Mannix 2009 Study 1 and Mannix 2009 Study 2 reported only that less than a certain percentage had experienced drug-related adverse events. Cross-over studies, Mathew 2009 Study 1 and Mathew 2009 Study 2, reported the percentage with adverse events for each treatment; the reported safety populations for the two studies were 144 and 139 participants, respectively; for the analysis, we have assumed that all took both study medications. The other studies reported participants with adverse events in each treatment arm, but Brandes 2007 Study 1; Brandes 2007 Study 2; and Smith 2005 reported events occurring within 24 hours of taking study medication, while Lipton 2009 Study 1; Lipton 2009 Study 2; and TRX109011/13 reported over 72 hours, and Silberstein 2008 Study 1 and Silberstein 2008 Study 2 up to one week. Since there was no obvious relationship between numbers of participants with adverse events and the time over which the data were collected, we have combined data from different time periods for analysis.

Sumatriptan/naproxen 85/500 mg versus placebo

Six studies (2823 attacks) treating when pain was still mild (Lipton 2009 Study 1; Lipton 2009 Study 2; Mathew 2009 Study 1; Mathew 2009 Study 2; Silberstein 2008 Study 1; Silberstein 2008 Study 2), and four (2793 attacks) treating when pain was moderate or severe (Brandes 2007 Study 1; Brandes 2007 Study 2; Smith 2005; TRX109011/13), provided data for analysis.

Mild baseline pain
  • The proportion of attacks with one or more adverse events with sumatriptan/naproxen 85/500 mg was 14% (241/1749; range 9.4% to 19%).

  • The proportion of attacks with one or more adverse events with placebo was 8.2% (88/1074; range 4.2% to 14%).

  • The RR of treatment compared with placebo was 1.5 (95% CI 1.2 to 1.9) (Analysis 1.5); the NNH was 18 (95% CI 13 to 30).

Moderate to severe baseline pain
  • The proportion of attacks with one or more adverse events with sumatriptan/naproxen 85/500 mg was 21% (291/1394; range 8.9% to 27%).

  • The proportion of attacks with one or more adverse events with placebo was 11% (148/1399; range 6.9% to 15%).

  • The RR of treatment compared with placebo was 2.0 (95% CI 1.6 to 2.4) (Analysis 1.5); the NNH was 9.7 (95% CI 7.7 to 13).

There was a significant difference in the number of attacks in which one or more adverse events was experienced between those treated early when pain was still mild, and those treated when pain was moderate or severe (z = 2.6167, P value = 0.0088).

Sumatriptan/naproxen 50 to 85/500 mg versus sumatriptan alone or naproxen alone

Three studies provided data comparing sumatriptan/naproxen versus both sumatriptan (1952 participants) and naproxen (1970 participants) alone (Brandes 2007 Study 1; Brandes 2007 Study 2; Smith 2005). Medication was taken when PI was moderate or severe.

  • The proportion of participants experiencing adverse events with sumatriptan/naproxen 85/500 mg was 26% (255/988; range 23% to 27%).

  • The proportion of participants experiencing adverse events with sumatriptan 85 mg alone was 26% (249/964; range 24% to 28%).

  • The proportion of participants experiencing adverse events with naproxen 500 mg alone was 15% (143/982; range 13% to 17%).

  • The RR of the combination compared with sumatriptan alone was 1.0 (95% CI 0.9 to 1.2) (Analysis 2.5); the NNH was not calculated.

  • The RR of the combination compared with naproxen alone was 1.8 (95% CI 1.5 to 2.1); the NNH was 8.9 (95% CI 6.8 to 13) (Analysis 3.7).

There was no difference in these studies between the combination and sumatriptan alone, but fewer participants experienced adverse events with naproxen alone.

Specific adverse events

Dizziness, paraesthesia, somnolence, nausea, dyspepsia, dry mouth, and chest discomfort were the most commonly reported adverse events, and were somewhat more common with combination therapy than monotherapy, and more common with active therapies than placebo. The incidence of any specific event in individual studies was low (less than 4%) and not consistently reported across studies, so numbers of reported events were small and no analysis was possible.

Serious adverse events

One participant, who had several cardiovascular risk factors, experienced heart palpitations and was admitted to hospital after receiving sumatriptan 85 mg; the event was judged probably related to study medication (Brandes 2007 Study 1). Seven participants in Lipton 2009 Study 1 and Lipton 2009 Study 2 experienced serious adverse events, none of which were judged related to study medication or occurred within 72 hours of receiving study medication. A further five serious adverse events occurred in TRX109011/13, which were also judged unrelated to the study medication.

Withdrawals

Six studies reported that there were no adverse event withdrawals (Brandes 2007 Study 1; Mannix 2009 Study 1; Mannix 2009 Study 2; Mathew 2009 Study 2; Silberstein 2008 Study 1; Silberstein 2008 Study 2), and another did not mention any adverse event withdrawals (Smith 2005). There was one withdrawal (palpitations following sumatriptan 85 mg) in Brandes 2007 Study 1; eight (all following combination treatment, three with mild or moderate chest discomfort) and six (three with mild or moderate chest discomfort - two following combination, one placebo) and three with nausea (two following combination, one placebo) withdrawals in Lipton 2009 Study 1 and Lipton 2009 Study 2, respectively; and one (muscle tightness, heaviness, anxiety, and nervousness following placebo) in Mathew 2009 Study 1. Four subjects were withdrawn in TRX109011/13; two due to pregnancy, one due to use of prohibited medication, and one due to a new diagnosis of breast cancer.

Participants who took rescue medication were classified as withdrawals due to lack of efficacy, and details are reported under 'Use of rescue medication' (Appendix 7).

Exclusion of participants from analyses after randomisation were mostly due to protocol violations or failing to take the medication (no qualifying headache, or cross-over not completed), and were generally well reported. Numbers of participants lost to follow-up, or withdrawing due for unspecified reasons were small and unlikely to influence results.

Other outcomes

Results for use of rescue medication, relief of headache-associated symptoms, and relief of functional disability are in Appendix 7.

Discussion

Summary of main results

This review included 12 randomised, double-blind, placebo-controlled studies. For the primary outcome of pain-free at two hours, data were available for 3318 headaches treated with sumatriptan plus naproxen and 2673 treated with placebo. Of these, 2025 headaches were treated when the pain was of mild severity and 1293 when the pain was moderate or severe. This allowed analysis of the effect of different dosing regimens on the primary outcomes. Most studies used a standard combination tablet of sumatriptan 85 mg and naproxen 500 mg, but one used two separate tablets of sumatriptan 50 mg and naproxen 500 mg. Two studies included active comparators, which allowed analysis of the combination formulation versus monotherapy, for example, sumatriptan or naproxen. One study included a different active comparator, but there were insufficient data for analysis (TRX109011/13).

For the IHS preferred outcome of pain-free at two hours, the combination formulation was better than placebo both when pain was mild at baseline and when it was moderate to severe. NNTs were 3.1 and 4.9, with 50% and 28% of people being pain-free with mild or moderate to severe pain, respectively. A greater response was seen when headaches were mild and this result was statistically significant (P value < 0.0001). For headache relief at two hours (analysis possible only for headaches with initial intensity of moderate or severe), the combination was better than placebo. The NNT was 3.2, with 58% of participants responding compared with 27% with placebo.

For the IHS preferred outcome of sustained pain-free during the 24 hours post dose, the combination formulation was better than placebo both when pain was mild at baseline and when it was moderate to severe. NNTs were 4.1 and 7.0, with 37% and 20% of people being pain free with the combination, compared with 12% and 6% with placebo, for mild and moderate to severe pain, respectively. A greater response was seen when headaches were mild and this result was statistically significant (P value < 0.0008). For sustained headache relief during the 24 hours post dose, combination was better than placebo, with an NNT of 3.8 and 43% of participants responding compared with 16% with placebo. Modest success rates for levels of PR considered useful by patients is the rule with different analgesics across many acute and chronic pain conditions (Moore 2013).

In all efficacy analyses, combination treatment was superior to monotherapy with either sumatriptan or naproxen alone. The use of separate tablets using sumatriptan in a lower dose (50 mg versus 85 mg) did not affect any results in a meaningful way.

No analysis was possible for times shorter than two hours. Overall, 58% of participants treated with combination experienced headache relief at two hours, and just under 43% sustained relief for 24 hours. Half of the participants were pain free at two hours when treated early (mild pain), but only 28% when treated when pain was moderate or severe. For sustained pain-free during the 24 hours post dose the percentages were lower, at 37% for mild pain and 20% for moderate or severe pain.

There was a significant difference in the number of participants experiencing one or more adverse events between those treating early when pain was still mild (NNH 18) and those treating when pain was moderate or severe (NNH 9.7). Most adverse events were described as mild or moderate, and transient. The incidence of any specific adverse event was low (< 4%) and serious adverse events and adverse event withdrawals were uncommon.

Additional analyses showed that combination was significantly better than placebo or either drug alone for relief of associated symptoms (nausea, photophobia, and phonophobia) and functional disability (Appendix 7).

Overall completeness and applicability of evidence

Included participants all had a diagnosis of migraine headaches according to IHS criteria and the information for active comparators was sufficiently large to allow for comparisons with placebo and both sumatriptan and naproxen monotherapy in order to generate conclusions about relative efficacy and harm. Most participants were recruited from neurology outpatient departments, so may be more refractory to treatment than the general public as a whole, and were carefully screened and excluded if there was any contraindication to a study medication. Additionally, two studies specifically recruited participants who had not previously experienced relief with short-acting triptans, including sumatriptan, and all studies excluded individuals who experience chronic migraine or very frequent migraines (> six or eight attacks per month), so results may not be applicable to those with frequent attacks. These factors could lead to an underestimate of treatment effect. All studies included participants with or without aura, but none reported results for the two types separately.

A study of sumatriptan plus naproxen in people with probable migraine (ie who satisfy all but one of the diagnostic criteria for migraine (IHS 2004)) found similar benefits, compared with placebo, to those found in people who satisfy the strict diagnostic criteria for migraine (Silberstein 2013). This is important because probable migraine is common amongst people seeking treatment for headache.

Individual studies are underpowered to determine differences between treatments for adverse events, and even pooling studies may not provide adequate numbers of events to demonstrate differences or allow confidence in the size of the effect. Single-dose studies are certainly unlikely to reveal rare, but potentially serious, adverse events. In these studies, the number of participants experiencing any adverse event with active treatment was greater than with placebo. It is likely that adverse event data continued to be recorded after taking rescue medication, which may confound the results due to adverse events associated with the rescue medication itself.

Quality of the evidence

Included studies were of good methodological quality and validity. Some did not adequately describe the method of randomisation or allocation concealment, but this may reflect the limitation of space in published articles rather than any flaw in methodology. Migraine was diagnosed using standard, validated criteria, and outcomes measured were generally those recommended by the IHS as being of clinical relevance, although not all studies reported the primary outcomes we sought.

We considered no studies to be at high risk of bias for any of the criteria evaluated.

Potential biases in the review process

One potential area of concern is the small numbers of events for some outcomes, particularly for specific adverse events.

For three of the cross-over studies (Mathew 2009 Study 1; Mathew 2009 Study 2; TRX109011/13), we have used data from all phases. While this may introduce unknown biases (Elbourne 2002), the data from these studies was entirely consistent with data from all others for efficacy outcomes.

We identified a large amount of data in comparisons with placebo. Approximately 2000 additional participants would have to have been involved in unpublished trials with zero treatment effect for the NNT for headache relief at two hours to increase above 6 (which we considered the limit of clinical utility in this situation) with the combination therapy (Moore 2008). This equates to five studies with over 400 participants in active and placebo treatment arms. Similarly, over 5000 additional participants would have to have been involved in unpublished trials with zero treatment effects for the NNT for pain-free at two hours to increase above 8 (considered to be the limit of clinical utility in this situation), when baseline pain was mild, or almost 2000 when baseline pain was moderate or severe. It is unlikely that such a large amount of unidentified data exists, so publication bias is not a concern.

Agreements and disagreements with other studies or reviews

Naproxen for acute migraine is the subject of two systematic reviews (Bandolier 2000; Law 2013). One Cochrane review provides information on oral sumatriptan alone (Derry 2012). NNT values for headache relief at two hours were:

Drug and dose (mg)NNT for headache relief at 2 h
Naproxen 500 mg vs placebo6.2
Sumatriptan 50 mg vs placebo4.0
Sumatriptan 100 mg vs placebo3.5
Sumatriptan 50-85 mg plus naproxen 500 mg vs placebo3.2

The results, for this outcome, of the sumatriptan plus naproxen combination show the additivity of pain-relieving drugs demonstrated in several acute pain conditions including migraine (Moore 2012). The combination produced lower (better) NNT values versus placebo for the outcome of headache relief at two hours than did sumatriptan or naproxen alone. Adverse event experiences were similar for sumatriptan alone and in combination.

Suthisisang 2011 is a meta-analysis of three of the 12 studies included in this review (Brandes 2007 Study 1; Brandes 2007 Study 2; Smith 2005). The meta-analysis quotes NNT values for sumatriptan plus naproxen versus sumatriptan monotherapy of 10 (95% CI 8 to 17) for pain-free at two hours, 10 (8 to 15) for sustained pain-free during the 24 hours post dose, 10 (7 to 17) for headache relief at two hours, and 8 (6 to 13) for sustained headache relief during the 24 hours post dose. These are the only studies that allow comparisons between the combination and sumatriptan monotherapy, and the results from the meta-analysis in Suthisisang 2011 are consistent with the results reported in this review for the same comparison with the same studies.

Khoury 2010 reviewed various aspects of the combination therapy including mode of action, pharmacokinetics, and efficacy, but no data synthesis was carried out. A combined analysis of two randomised studies reported on the composite endpoint of sustained pain-free with no adverse events (Landy 2009); this showed that with a composite endpoint sumatriptan plus naproxen was significantly better than placebo or either component alone.

A randomised, double blind, active controlled trial using the combination treatment and the individual monotherapies looked at the primary endpoint of changes in blood pressure from baseline over a six-month period (White 2011), but with no efficacy or adverse event data relating to single migraine episodes. This showed no clinically significant blood pressure changes, and also allowed some analysis of longer-term adverse events. In particular, the study showed that the type of adverse events were broadly similar over this longer time scale, and that the proportions of adverse events with each therapy (20%, 29%, and 18% for combination, sumatriptan alone, and naproxen alone, respectively) in White 2011 were equivalent to those seen here in single episode analyses (21%, 26%, and 15% for combination, sumatriptan alone, and naproxen alone, respectively, in participants with moderate to severe baseline pain).

Authors' conclusions

Implications for practice

The combination of sumatriptan plus naproxen is probably better than sumatriptan alone, and better than naproxen 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 rarely led to withdrawal in these studies.

Implications for research

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 would probably be more appropriate non-steroidal anti-inflammatory drugs to be used in combination with a triptan.

Acknowledgements

Institutional support for this review was from the Oxford Pain Research Trust. Lifting The Burden: the Global Campaign against Headache and the International Headache Society provided financial support for the editorial process.

Data and analyses

Download statistical data

Comparison 1. Sumatriptan/naproxen versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Pain-free at 2 h12 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Mild baseline pain83395Risk Ratio (M-H, Fixed, 95% CI)2.76 [2.43, 3.13]
1.2 Moderate/severe baseline pain42596Risk Ratio (M-H, Fixed, 95% CI)3.65 [2.97, 4.49]
2 Headache relief at 2 h4 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Moderate/severe baseline pain42596Risk Ratio (M-H, Fixed, 95% CI)2.16 [1.95, 2.39]
3 24-h sustained pain-free12 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 Mild baseline pain83396Risk Ratio (M-H, Fixed, 95% CI)3.04 [2.59, 3.56]
3.2 Moderate/severe baseline pain42596Risk Ratio (M-H, Fixed, 95% CI)3.43 [2.69, 4.36]
4 24-h sustained headache relief4 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Moderate/severe baseline pain42596Risk Ratio (M-H, Fixed, 95% CI)2.61 [2.27, 2.99]
5 Any adverse event105616Risk Ratio (M-H, Fixed, 95% CI)1.76 [1.53, 2.03]
5.1 Mild baseline pain62823Risk Ratio (M-H, Fixed, 95% CI)1.47 [1.16, 1.86]
5.2 Moderate/severe baseline pain42793Risk Ratio (M-H, Fixed, 95% CI)1.97 [1.64, 2.37]
6 Rescue medication125565Risk Ratio (M-H, Fixed, 95% CI)0.45 [0.41, 0.48]
6.1 Mild baseline pain83396Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.38, 0.47]
6.2 Moderate/severe baseline pain42169Risk Ratio (M-H, Fixed, 95% CI)0.47 [0.42, 0.53]
7 Relief of associated symptoms at 2 h8 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
7.1 Nausea81705Risk Ratio (M-H, Fixed, 95% CI)3.47 [2.79, 4.32]
7.2 Photophobia83127Risk Ratio (M-H, Fixed, 95% CI)2.77 [2.44, 3.13]
7.3 Phonophobia82856Risk Ratio (M-H, Fixed, 95% CI)2.63 [2.33, 2.97]
8 Relief of functional disability at 2 h5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
8.1 Mild baseline pain2981Risk Ratio (M-H, Fixed, 95% CI)2.91 [2.29, 3.72]
8.2 Moderate/severe baseline pain31984Risk Ratio (M-H, Fixed, 95% CI)3.36 [2.63, 4.29]
Analysis 1.1.

Comparison 1 Sumatriptan/naproxen versus placebo, Outcome 1 Pain-free at 2 h.

Analysis 1.2.

Comparison 1 Sumatriptan/naproxen versus placebo, Outcome 2 Headache relief at 2 h.

Analysis 1.3.

Comparison 1 Sumatriptan/naproxen versus placebo, Outcome 3 24-h sustained pain-free.

Analysis 1.4.

Comparison 1 Sumatriptan/naproxen versus placebo, Outcome 4 24-h sustained headache relief.

Analysis 1.5.

Comparison 1 Sumatriptan/naproxen versus placebo, Outcome 5 Any adverse event.

Analysis 1.6.

Comparison 1 Sumatriptan/naproxen versus placebo, Outcome 6 Rescue medication.

Analysis 1.7.

Comparison 1 Sumatriptan/naproxen versus placebo, Outcome 7 Relief of associated symptoms at 2 h.

Analysis 1.8.

Comparison 1 Sumatriptan/naproxen versus placebo, Outcome 8 Relief of functional disability at 2 h.

Comparison 2. Sumatriptan/naproxen versus sumatriptan alone
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Pain-free at 2 h31925Risk Ratio (M-H, Fixed, 95% CI)1.42 [1.23, 1.65]
2 Headache relief at 2 h31925Risk Ratio (M-H, Fixed, 95% CI)1.20 [1.11, 1.29]
3 24-h sustained pain-free31925Risk Ratio (M-H, Fixed, 95% CI)1.70 [1.41, 2.06]
4 24-h sustained headache relief31925Risk Ratio (M-H, Fixed, 95% CI)1.39 [1.24, 1.55]
5 Any adverse event31952Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.86, 1.16]
6 Rescue medication31925Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.58, 0.76]
7 Relief of associated symptoms at 2 h2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
7.1 Nausea2718Risk Ratio (M-H, Fixed, 95% CI)1.51 [1.21, 1.87]
7.2 Photophobia21186Risk Ratio (M-H, Fixed, 95% CI)1.20 [1.04, 1.39]
7.3 Phonophobia21146Risk Ratio (M-H, Fixed, 95% CI)1.26 [1.10, 1.45]
8 Relief of functional disability at 2 h21354Risk Ratio (M-H, Fixed, 95% CI)1.41 [1.18, 1.69]
Analysis 2.1.

Comparison 2 Sumatriptan/naproxen versus sumatriptan alone, Outcome 1 Pain-free at 2 h.

Analysis 2.2.

Comparison 2 Sumatriptan/naproxen versus sumatriptan alone, Outcome 2 Headache relief at 2 h.

Analysis 2.3.

Comparison 2 Sumatriptan/naproxen versus sumatriptan alone, Outcome 3 24-h sustained pain-free.

Analysis 2.4.

Comparison 2 Sumatriptan/naproxen versus sumatriptan alone, Outcome 4 24-h sustained headache relief.

Analysis 2.5.

Comparison 2 Sumatriptan/naproxen versus sumatriptan alone, Outcome 5 Any adverse event.

Analysis 2.6.

Comparison 2 Sumatriptan/naproxen versus sumatriptan alone, Outcome 6 Rescue medication.

Analysis 2.7.

Comparison 2 Sumatriptan/naproxen versus sumatriptan alone, Outcome 7 Relief of associated symptoms at 2 h.

Analysis 2.8.

Comparison 2 Sumatriptan/naproxen versus sumatriptan alone, Outcome 8 Relief of functional disability at 2 h.

Comparison 3. Sumatriptan/naproxen versus naproxen alone
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Pain-free at 2 h31944Risk Ratio (M-H, Fixed, 95% CI)2.03 [1.71, 2.40]
2 Headache relief at 2 h31944Risk Ratio (M-H, Fixed, 95% CI)1.41 [1.30, 1.54]
3 24-h sustained pain-free31944Risk Ratio (M-H, Fixed, 95% CI)2.25 [1.82, 2.78]
4 24-h sustained headache relief31944Risk Ratio (M-H, Fixed, 95% CI)1.64 [1.45, 1.85]
5 Any adverse event31970Risk Ratio (M-H, Fixed, 95% CI)1.77 [1.47, 2.13]
6 Rescue medication31944Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.54, 0.70]
7 Relief of associated symptoms at 2 h2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
7.1 Nausea2726Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.90, 1.32]
7.2 Photophobia21176Risk Ratio (M-H, Fixed, 95% CI)1.39 [1.19, 1.62]
7.3 Phonophobia21135Risk Ratio (M-H, Fixed, 95% CI)1.48 [1.28, 1.72]
8 Relief of functional disability at 2 h21352Risk Ratio (M-H, Fixed, 95% CI)1.63 [1.35, 1.97]
Analysis 3.1.

Comparison 3 Sumatriptan/naproxen versus naproxen alone, Outcome 1 Pain-free at 2 h.

Analysis 3.2.

Comparison 3 Sumatriptan/naproxen versus naproxen alone, Outcome 2 Headache relief at 2 h.

Analysis 3.3.

Comparison 3 Sumatriptan/naproxen versus naproxen alone, Outcome 3 24-h sustained pain-free.

Analysis 3.4.

Comparison 3 Sumatriptan/naproxen versus naproxen alone, Outcome 4 24-h sustained headache relief.

Analysis 3.5.

Comparison 3 Sumatriptan/naproxen versus naproxen alone, Outcome 5 Any adverse event.

Analysis 3.6.

Comparison 3 Sumatriptan/naproxen versus naproxen alone, Outcome 6 Rescue medication.

Analysis 3.7.

Comparison 3 Sumatriptan/naproxen versus naproxen alone, Outcome 7 Relief of associated symptoms at 2 h.

Analysis 3.8.

Comparison 3 Sumatriptan/naproxen versus naproxen alone, Outcome 8 Relief of functional disability at 2 h.

Appendices

Appendix 1. Definitions

All terms relating to primary efficacy outcomes are defined according to the effect of the treatment on headache pain, measured using a 4-point pain intensity (PI) scale (ranging from 0 to 3 or none, mild, moderate, and severe).

  • Baseline PI - level of pain participant must be experiencing in order to receive study medication, either 1 (mild pain) or 2/3 (moderate or severe pain).

  • Pain-free at two hours - number of participants with a PI of 0 (none) at two hours after administration of study medication, expressed as a fraction of the treated participants with the appropriate baseline pain.

  • Headache relief at two hours - number of participants with a reduction in PI from 2/3 (moderate/severe) to 0/1 (none/mild) at two hours after administration of study medication, expressed as a fraction of the treated participants with grade 2/3 baseline pain.

  • 24-hour sustained headache relief - number of participants with a reduction in PI from 2/3 (moderate/severe) to 0/1 (none/mild) at two hours after administration of study medication, which is then sustained between 2 and 24 hours without recurrence of headache or use of additional medication, expressed as a fraction of the treated participants with grade 2/3 baseline pain.

  • 24-hour sustained pain-free during - number of participants with a PI of 0 (none) at two hours after administration of study medication which is then sustained between 2 and 24 hours without recurrence of headache or use of additional medication, expressed as a fraction of the treated participants with the appropriate baseline pain.

  • Use of rescue medication - number of participants requiring the use of additional medication to treat an inadequate response to study medication, provided that the additional medication is not, or does not include, the study drug.

  • Relief of associated symptoms - number of participants with an absence of a headache-associated symptom (nausea, vomiting, photophobia, or phonophobia) at two hours after administration of study medication, expressed as a fraction of the treated participants for whom the symptom was present at baseline.

  • Relief of functional disability - reduction in the level of functional disability, measured using a 4-point scale, from moderate or severe disability (grade 2/3) at baseline to mild or none (grade 1/0) at two hours after administration of study medication, expressed as a fraction of the treated participants with moderate or severe functional disability at baseline.

Appendix 2. Search strategy for CENTRAL

  1. MeSH descriptor Sumatriptan AND MeSH descriptor Naproxen

  2. (sumatriptan AND naproxen) OR Treximet OR Trexima:ti,ab,kw.

  3. 1 OR 2

  4. MeSH descriptor Headache/ OR MeSH descriptor Headache Disorders explode all trees

  5. MeSH descriptor Migraine Disorders explode all trees

  6. (headach* OR migrain* OR cephalgi* OR cephalalgi*):ti,ab,kw.

  7. 4 OR 5 OR 6

  8. Randomized controlled trial:pt.

  9. MESH descriptor Double-blind Method

  10. random*:ti,ab,kw.

  11. OR/8-10

  12. 3 AND 7 AND 11

  13. Limit 12 to Clinical Trials (CENTRAL)

Appendix 3. Search strategy for MEDLINE via Ovid

  1. Sumatriptan/ AND Naproxen/

  2. (sumatriptan AND naproxen) OR Treximet OR Trexima.mp

  3. 1 OR 2

  4. Headache/ OR exp Headache Disorders/

  5. exp Migraine Disorders/

  6. (headach* OR migrain* OR cephalgi* OR cephalalgi*).mp.

  7. 4 OR 5 OR 6

  8. randomized controlled trial.pt.

  9. controlled clinical trial.pt.

  10. randomized.ab.

  11. placebo.ab.

  12. drug therapy.fs.

  13. randomly.ab.

  14. trial.ab.

  15. groups.ab.

  16. OR/8-15

  17. 3 AND 7 AND 16

Appendix 4. Search strategy for EMBASE via Ovid

  1. Naproxen plus Sumatriptan/

  2. (sumatriptan AND naproxen) OR Treximet OR Trexima.mp

  3. 1 OR 2

  4. Headache/ OR exp Headache and facial pain/

  5. exp Migraine/

  6. (headach* OR migrain* OR cephalgi* OR cephalalgi*).mp.

  7. 4 OR 5 OR 6

  8. clinical trials.sh.

  9. controlled clinical trials.sh.

  10. randomized controlled trial.sh.

  11. double-blind procedure.sh.

  12. (clin* adj25 trial*).ab.

  13. ((doubl* or trebl* or tripl*) adj25 (blind* or mask*)).ab.

  14. placebo*.ab.

  15. random*.ab.

  16. OR/8-15

  17. 3 AND 7 AND 16

Appendix 5. Summary of outcomes: efficacy and use of rescue medication

Study IDTreatmentHR 1 hHR 2 hPF 2 hSHR 24 hSPF 24 hUse of rescue medication
Brandes 2007 Study 1

(1) suma/naprox 85/500 mg, n = 370

(2) suma 85 mg, n = 365

(3) naprox 500 mg, n = 361

(4) placebo, n = 365

No data

(1) 237/364

(2) 200/361

(3) 157/356

(4) 102/360

(1)125/364

(2) 90/361

(3) 53/356

(4) 33/360

(1) 174/364

(2) 127/361

(3) 107/365

(4) 64/360

(1) 90/364

(2) 59/361

(3) 37/356

(4) 30/360

From 2 to 24 h

(1) 81/364

(2) 115/361

(3) 135/356

(4) 192/360

Brandes 2007 Study 2

(1) suma/naprox 85/500 mg, n = 367

(2) suma 85 mg, n = 370

(3) naprox 500 mg, n = 371

(4) placebo, n = 387

No data

(1) 207/362

(2) 182/362

(3) 158/364

(4) 109/382

(1)107/362

(2) 82/362

(3) 57/364

(4) 37/382

(1) 158/362

(2) 121/362

(3) 102/364

(4) 64/382

(1) 83/362

(2) 51/362

(3) 37/364

(4) 25/382

From 2 to 24 h

(1) 83/362

(2) 137/362

(3) 143/364

(4) 223/382

Lipton 2009 Study 1

(1) suma/naprox 85/500 mg, n = 447 (1693 attacks)

(2) placebo, n = 123 (424 attacks)

No dataNo data

1st attack:

(1) 230/443

(2) 25/123

All attacks:

(1) 856/1665

(2) 106/422

No data

1st attack:

(1) 168/443

(2) 15/123

All attacks:

(1) 608/1665

(2) 72/422

From 2 to 24 h

1st attack:

(1) 52/443

(2) 47/123

All attacks:

(1) 197/1668

(2) 141/422

Lipton 2009 Study 2

(1) suma/naprox 85/500 mg, n = 458 (1678 attacks)

(2) placebo, n = 107 (422 attacks)

No dataNo data

1st attack:

(1) 236/454

(2) 16/106

All attacks:

(1) 833/1655

(2) 83/416

No data

1st attack:

(1) 159/455

(2) 12/106

All attacks:

(1) 564/1655

(2) 52/416

1st attack:

(1) 52/455

(2) 43/106

All attacks:

(1) 183/1662

(2) 144/416

Mannix 2009 Study 1

(1) suma/naprox 85/500 mg, n = 152

(2) placebo, n = 160

No dataNo data

(1) 63/151

(2) 37/160

No data

(1) 44/151

(2) 29/160

From 2 to 48 h

(1) 56/151

(2) 85/160

Mannix 2009 Study 2

(1) suma/naprox 85/500 mg, n = 151

(2) placebo, n = 160

No dataNo data

(1) 79/151

(2) 35/159

No data

(1) 57/151

(2) 16/159

From 2 to 48 h

(1) 47/151

(2) 110/159

Mathew 2009 Study 1

(1) suma/naprox 85/500 mg, n = 136

(2) placebo, n = 134

No dataNo data

(1) 54/136

(2) 23/134

No data

(1) 35/136

(2) 11/134

From 2 to 24 h

(1) 39/136

(2) 84/134

Mathew 2009 Study 2

(1) suma/naprox 85/500 mg, n = 134

(2) placebo, n =133

No dataNo data

(1) 59/134

(2) 19/133

No data

(1) 42/134

(2) 11/133

From 2 to 24 h

(1) 29/134

(2) 73/133

Silberstein 2008 Study 1

(1) suma/naprox 85/500 mg, n = 280

(2) placebo, n = 296

No dataNo data

(1) 146/280

(2) 50/296

No data

(1) 126/280

(2) 36/296

From 2 to 24 h

(1) 56/280

(2) 139/296

Silberstein 2008 Study 2

(1) suma/naprox 85/500 mg, n = 276

(2) placebo, n = 259

No dataNo data

(1) 141/276

(2) 39/259

No data

(1) 110/276

(2) 36/259

From 2 to 24 h

(1) 44/276

(2) 117/259

Smith 2005

(1) suma/naprox 50/500 mg, n = 250

(2) suma 50 mg, n = 229

(3) naprox 500 mg, n = 250

(4) placebo, n = 241

(1) 73/250

(2) 52/226

(3) 67/248

(4) 29/241

(1) 163/250

(2) 111/226

(3) 114/248

(4) 65/241

(1) 85/250

(2) 45/226

(3) 45/248

(4) 14/241

(1) 115/250

(2) 66/226

(3) 62/248

(4) 41/241

(1) 63/250

(2) 25/226

(3) 30/248

(4) 12/241

From 2 to 24 h

(1) 88/250

(2) 115/226

(3) 129/248

(4) 154/241

TRX109011/132010

(1) suma/naprox 85/500 mg, n = 317

(2) BCM, n = 304

(3) placebo, n = 320

No data

(1) 148/317

(2) 114/304

(3) 76/320

(1) 45/317

(2) 26/304

(3) 16/320

(1) 107/317

(2) 67/304

(3) 45/320

(1) 26/317

(2) 18/304

(3) 10/320

First dose only

From 2 to 24 h (possibly 48 h)

(1) 52/107

(2) 67/108

(3) 74/103

BCM: butalbital-containing combination medication (butalbital 50 mg, paracetamol (acetaminophen) 325 mg, and caffeine 40 mg); HR: headache relief; naprox: naproxen; PF: pain-free; SHR: sustained headache relief; SPF: sustained pain-free; suma: sumatriptan.

Appendix 6. Summary of outcomes: adverse events and withdrawals

Study IDTreatmentAny AESAEAE withdrawalOther withdrawal
Brandes 2007 Study 1

(1) suma/naprox 85/500 mg, n = 370

(2) suma 85 mg, n = 365

(3) naprox 500 mg, n = 361

(4) placebo, n = 365

≤ 24 h:

(1) 100/370

(2) 89/365

(3) 48/361

(4) 45/365

No SAE with combination, naproxen alone, or placebo in either study. 1 person admitted to hospital with palpitations following sumatriptan 85 mg1 person in (2) with palpitations

Exclusions - took medication but no evaluable data:

(1) 6

(2) 4

(3) 5

(4) 5

Brandes 2007 Study 2

(1) suma/naprox 85/500 mg, n = 367

(2) suma 85 mg, n = 370

(3) naprox 500 mg, n = 371

(4) placebo, n = 387

≤ 24 h:

(1) 97/367

(2) 105/370

(3) 52/371

(4) 39/387

No SAENone

Exclusions - took medication but no evaluable data:

(1) 5

(2) 8

(3) 7

(4) 5

Lipton 2009 Study 1

(1) suma/naprox 85/500 mg, n = 447 (1693 attacks)

(2) placebo, n = 123 (424 attacks)

≤ 72 h:

Study 1, 1st attack:

(1) 57/447

(2) 15/123

All attacks:

(1) 153/1693

(2) 28/424

7 SAE across both studies, but judged not related to study medication, and occurred > 72 h after taking study medication. No details of groups

(1) 8 (3 chest discomfort)

(2) 0

All judged related to study medication; mild/mod severity

People lost to follow-up or withdrawn for any attack:

(1) < 6%

(2) < 8%

Lipton 2009 Study 2

(1) suma/naprox 85/500 mg, n = 458 (1678 attacks)

(2) placebo, n = 107 (422 attacks)

≤ 72 h:

1st attack:

(1) 85/458

(2) 15/107

All attacks:

(1) 219/1678

(2) 36/422

(1) 6 (3 chest discomfort, 3 nausea)

(2) 1 (nausea)

All judged related to study medication; mild/mod severity

People lost to follow-up or withdrawn for any attack:

(1) < 6%

(2) < 7%

Mannix 2009 Study 1

(1) suma/naprox 85/500 mg, n = 152

(2) placebo, n = 160

≤ 48 h (possibly 24 h)

AEs consistent with known profile of 2 drugs

Drug-related AE frequency < 1%

NoneNone

Excluded from efficacy analysis:

(1) 1

(2) 0

Mannix 2009 Study 2

(1) suma/naprox 85/500 mg, n = 151

(2) placebo, n = 160

≤ 48 h (possibly 24 h)

AEs consistent with known profile of 2 drugs

Drug-related AE frequency < 5%

NoneNone

Excluded from efficacy analysis:

(1) 0

(2) 1

Mathew 2009 Study 1

(1) suma/naprox 85/500 mg, n = 144

(2) placebo, n = 144

Assume AE reported for safety population within 24 h
(1) 16/144
(2) 6/144
None reported1 AE withdrawal following placebo5 people in (1) and (2) took medication, but not included in ITT. Unclear, but probably had no post-baseline efficacy data
Mathew 2009 Study 2

(1) suma/naprox 85/500 mg, n = 139

(2) placebo, n = 139

Assume AE reported for safety population within 24 h

(1) 13/139
(2) 7/139

None reportedNone2 people in (1) and (2) took medication, but not included in ITT. Unclear, but probably had no post-baseline efficacy data
Silberstein 2008 Study 1

(1) suma/naprox 85/500 mg, n = 283

(2) placebo, n = 297

AE reported for safety population during study period (up to 1 week)
(1) 31/283
(2) 21/297
NoneNone3 people in (1) and 1 in (2) took medication but had no post-baseline efficacy data
Silberstein 2008 Study 2

(1) suma/naprox 85/500 mg, n = 278

(2) placebo, n = 264

AE reported for safety population during study period (up to 1 week)

(1) 39/278

(2) 24/264

NoneNone2 people in (1) and 5 in (2) took medication but had no post-baseline efficacy data
Smith 2005

(1) suma/naprox 50/500 mg, n = 251

(2) suma 50 mg, n = 229

(3) naprox 500 mg, n = 250

(4) placebo, n = 241

AE reported for safety population up to 72 h

(1) 58/251

(2) 55/242

(3) 43/250

(4) 36/242

NoneNoneNone reported
TRX109011/13 2010

(1) suma/naprox 85/500 mg, n = 317

(2) BCM, n = 392

(3) placebo, n = 320

AE for safety population reported within 72 h:

(1) 36/406

(2) 21/392

(3) 28/405

(1) 2 (breast cancer diagnosis, chest pain, and hypertension)

(2) 0

(3) 1 (intestinal mass and viral meningitis)

None considered related to study medication

(1) 3, (2) 0, (3) 14 in total; pregnancy (2), breast cancer diagnosis (1), and use of prohibited medication (1)
AE: adverse event; BCM: barbiturate-containing medication; med: medication; naprox: naproxen; ITT: intention to treat; SAE: serious adverse event; suma: sumatriptan.

Appendix 7. Other outcomes

Use of rescue medication

All studies asked participants whose symptoms were not adequately controlled to wait for two hours before taking any additional medication in order to give the test medication enough time to have an effect. Use of rescue or 'escape' medication (usually a different analgesic), after that time was reported in all studies and is a measure of treatment failure (lack of efficacy). The time over which use of rescue medication was measured was 24 hours (or possibly 48 hours in Mannix 2009 Study 1; Mannix 2009 Study 2; TRX109011/13). A survival curve published in Deroiser 2011 (TRX109011/13) shows that the vast majority of participants who take rescue medication do so within six hours of initial treatment, so we have combined data for 24 and 48 hours.

Significantly fewer participants used rescue medication with the combination than with placebo or either component alone (Analysis 1.6; Analysis 2.6; Analysis 3.6).

Summary of results: use of rescue medication
 Baseline painStudiesAttacks treatedTreatment (%)Comparator (%)Risk ratio (95% CI)NNTp (95% CI)
Sumatriptan/naproxen 85/500 mg vs placebomild8339619510.42 (0.38 to 0.47)3.1 (2.8 to 3.4)
Sumatriptan/naproxen 85/500 mg vs placebo≥ mod4216928590.47 (0.42 to 0.53)3.2 (2.9 to 3.7)
Sumatriptan/naproxen 50-85/500 mg vs sumatriptan 50-85 mg≥ mod3192526390.66 (0.58 to 0.76)7.8 (5.9 to 11)
Sumatriptan/naproxen 50-85/500 mg vs naproxen 500 mg≥ mod3194426420.61 (0.54 to 0.70)6.2 (4.9 to 8.3)
CI: confidence interval; NNTp: number needed to treat to prevent one event.

Relief of headache-associated symptoms

Eight studies provided data on relief of nausea, photophobia, and phonophobia in comparisons of sumatriptan/naproxen versus placebo (Brandes 2007 Study 1; Brandes 2007 Study 2; Lipton 2009 Study 1; Lipton 2009 Study 2; Mathew 2009 Study 1; Mathew 2009 Study 2; Silberstein 2008 Study 1; Silberstein 2008 Study 2). Too few participants experienced vomiting to allow any analysis of this symptom. Two studies provided data comparing sumatriptan/naproxen versus both sumatriptan and naproxen alone (Brandes 2007 Study 1; Brandes 2007 Study 2). Medication was taken when pain intensity was moderate or severe. Too few participants experienced vomiting to allow any analysis of this symptom.

For all symptoms, the combination was better than either placebo or the individual components, except for nausea relief with naproxen 500 mg alone, which was not statistically different from the combination. Lower (better) NNTs were obtained for all three symptoms in comparisons with placebo than for comparisons with individual components, and for photophobia and phonophobia relief in comparisons with naproxen alone than for sumatriptan alone (Analysis 1.7; Analysis 2.7; Analysis 3.7).

Summary of results: relief of associated symptoms at two hours
InterventionStudiesAttacks with symptom presentTreatment (%)Control (%)Risk ratio (95% CI)NNT (95% CI)
Nausea      
Sumatriptan/naproxen 85/500 mg vs placebo8170536103.5 (2.8 to 4.3)3.9 (3.4 to 4.5)
Sumatriptan/naproxen 85/500 mg vs sumatriptan 85 mg271839261.5 (1.2 to 1.9)7.6 (5.0 to 16)
Sumatriptan/naproxen 85/500 mg vs naproxen 500 mg272639361.1 (0.90 to 1.3)not calculated
Photophobia      
Sumatriptan/naproxen 85/500 mg vs placebo8312753192.8 (2.4 to 3.1)2.9 (2.7 to 3.2)
Sumatriptan/naproxen 85/500 mg vs sumatriptan 85 mg2118643361.2 (1.04 to 1.4)14 (7.8 to 59)
Sumatriptan/naproxen 85/500 mg vs naproxen 500 mg2117643311.4 (1.2 to 1.6)8.3 (5.7 to 15)
Phonophobia      
Sumatriptan/naproxen 85/500 mg vs placebo8285654202.6 (2.3 to 3.0)2.9 (2.6 to 3.2)
Sumatriptan/naproxen 85/500 mg vs sumatriptan 85 mg2114648381.3 (1.1 to 1.5)10 (6.4 to 23)
Sumatriptan/naproxen 85/500 mg vs naproxen 500 mg2113548321.5 (1.3 to 1.7)6.4 (4.7 to 10)
CI: confidence interval; NNT: number needed to treat.

Relief of functional disability

Two studies treating when pain was still mild (Silberstein 2008 Study 1; Silberstein 2008 Study 2), and three treating when pain was moderate or severe (Brandes 2007 Study 1; Brandes 2007 Study 2; TRX109011/13), reported on participants with functional disability at baseline and at two hours. Two of these studies provided data comparing sumatriptan/naproxen with both sumatriptan and naproxen alone (Brandes 2007 Study 1; Brandes 2007 Study 2). Medication was taken when pain intensity was moderate or severe.

The combination was effective at relieving functional disability when compared with placebo or either component alone (Analysis 1.8; Analysis 2.8; Analysis 3.8). Treating early, when pain was still mild, was significantly better than treating once pain was moderate or severe (z = 3.132, P value = 0.0016).

Summary of results: complete relief of functional disability at two hours
 Baseline painStudiesAttacks treatedTreatment (%)Comparator (%)Risk ratio (95% CI)NNT (95% CI)
Sumatriptan/naproxen 85/500 mg vs placebomild298142142.9 (2.3 to 3.7)3.7 (3.1 to 4.6))
Sumatriptan/naproxen 85/500 mg vs placebo≥ mod31984257.33.4 (2.6 to 4.3)5.8 (4.9 to 7.0)
Sumatriptan/naproxen 85/500 mg vs sumatriptan 85 mg≥ mod2135432231.4 (1.2 to 1.7)11 (7.1 to 21)
Sumatriptan/naproxen 85/500 mg vs naproxen 500 mg≥ mod2135232201.6 (1.4 to 2.0)8.0 (5.9 to 13)
CI: confidence interval; mod: moderate; NNT: number needed to treat.

What's new

DateEventDescription
20 December 2013AmendedMinor changes made to definitions of 24-hour outcomes and Use of rescue medication in Appendix 1, and 95% confidence intervals added to NNTs in Abstract

Contributions of authors

SL and SD wrote the protocol, and carried out searches for studies, data extraction, and analyses. RAM acted as arbitrator. All review authors were involved with writing the final review.

Declarations of interest

RAM has consulted for various pharmaceutical companies and has received lecture fees from pharmaceutical companies related to analgesics and other healthcare interventions. RAM and SD have received research support from charities, government, and industry sources at various times. SL has no interests to declare.

Sources of support

Internal sources

  • Oxford Pain Relief Trust, UK.

    Institution support

External sources

  • Lifting The Burden: the Global Campaign against Headache, UK.

    Funding for administrative costs associated with editorial and peer review of the protocol

  • International Headache Society, UK.

    Funding for administrative costs associated with editorial and peer review of the full review

Differences between protocol and review

After discussion with headache specialists and editorial staff, and in line with Cochrane recommendations, we decided to limit our outcomes for acute migraine headache reviews in order to focus attention on the most important outcomes and to make them more readable for both clinicians and patients. For the majority of interventions we will now include two-hour pain-free and headache relief as primary outcomes, and 24-hour sustained pain-free, sustained headache relief, and adverse events as secondary outcomes. Pain-free headache relief outcomes at earlier time points will be included in special circumstances, if reported and relevant (eg if a 'fast acting' formulation is investigated). We have moved results for use of rescue medication and relief of headache-associated symptoms and functional disability to Appendix 7.

We have expanded the Risk of bias table; this review uses the new criteria for analysis. We have also included an assessment of publication bias, which was not included in the protocol. This assessment is now being added routinely to all our reviews as a measure of reliability/robustness of the results.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Brandes 2007 Study 1

Methods

Multicentre, R, DB, PC, parallel group. Single dose to treat single attack

Medication taken when PI ≥ moderate

Assessments at 0, 0.5, 1, 1.5, 2, then hourly to 24 h

Participants

Migraine ± aura (IHS 2004), aged 18-65 years. History: > 6 months with frequency of 2-6 per month and untreated severity ≥ moderate

Excluded: uncontrolled hypertension, cardio- or cerebrovascular disease, using MAOI, ergot, SJW, or NSAID

n = 1461

F = 86%

Mean age 40 years

72% without aura

Interventions

Sumatriptan 85 mg/naproxen 500 mg, n = 370 (364 analysed for efficacy)

Sumatriptan 85 mg, n = 365 (361 for efficacy)

Naproxen 500 mg, n = 361 (365 for efficacy)

Placebo, n = 365 (360 for efficacy)

Rescue medication allowed after 2 h if necessary (as prescribed by physician but not ergot-containing, serotonin agonist, or NSAID-containing medications)

Outcomes

Headache relief at 2 h

Pain-free at 2 h

24-h sustained headache relief

24-h sustained pain-free

Presence and relief of associated symptoms at 2 h

Presence and relief of functional disability at 2 h (from Landy 2007)

Use of rescue medication

AEs

Withdrawals

NotesOxford Quality Score: R1, DB1, W1. Total = 3
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs described
Study sizeLow risk> 200 participants per treatment arm

Brandes 2007 Study 2

Methods

Multicentre, R, DB, PC, parallel group. Single dose to treat single attack

Medication taken when PI ≥ moderate

Assessments at 0, 0.5, 1, 1.5, 2, then hourly to 24 h

Participants

Migraine ± aura (IHS 2004), aged 18-65 years. History: > 6 months with frequency of 2-6 per month and untreated severity ≥ moderate

Excluded: uncontrolled hypertension, cardio- or cerebrovascular disease, using MAOI, ergot, SJW, or NSAID

n = 1495

F = 88%

Mean age 40 years

76% without aura

Interventions

Sumatriptan 85 mg/naproxen 500 mg, n = 367 (362 for efficacy)

Sumatriptan 85 mg, n = 370 (362 for efficacy)

Naproxen 500 mg, n = 371 (364 for efficacy)

Placebo, n = 387 (382 for efficacy)

Rescue medication allowed after 2 h if necessary (as prescribed by physician but not ergot-containing, serotonin agonist, or NSAID-containing medications)

Outcomes

Headache relief at 2 h

Pain-free at 2 h

24-h sustained headache relief

24-h sustained pain-free

Presence and relief of associated symptoms at 2 h

Presence and relief of functional disability at 2 h (from Landy 2007)

Use of rescue medication

AEs

Withdrawals

NotesOxford Quality Score: R1, DB1, W1. Total = 3
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs described
Study sizeLow risk> 200 participants per treatment arm

Lipton 2009 Study 1

Methods

Multicentre, R, DB, PC, cross-over. Single dose/attack. 4 attacks treated: all with active or 3 active and 1 placebo (in random order). Washout between attacks not specified, but all headache medications prohibited within 24 h of a treated attack, and AE data collected for 72 h after treatment

Medication taken within 1 h of onset when PI was mild

Assessments at 0, 2, 4, 24 h

Participants

Migraine ± aura (IHS 2004), aged 18-65 years. History ≥ 6 months with frequency of 2-6 attacks per month and untreated severity ≥ moderate and identifiable mild phase

Excluded: uncontrolled hypertension, cardio- or cerebrovascular disease

n = 570 (568 for efficacy)

F = 89%

Mean age 42 years

Interventions

Sumatriptan/naproxen 85/500 mg (1693 attacks treated)

Placebo (424 attacks treated)

5 treatment groups with different medication sequences (N: naproxen; P: placebo; S: sumatriptan)

P, S/N, S/N, S/N; S/N, P, S/N, S/N; S/N, S/N, P, S/N; S/N, S/N, S/N, P; S/N, S/N, S/N, S/N

Rescue medication allowed after 2 h if necessary (recommended 2 x 220 mg naproxen sodium with additional 1 x 220 mg 6 h later if needed)

Outcomes

Pain-free at 2 h

24-h sustained pain-free

Presence and relief of associated symptoms at 2 h

Use of rescue medication

AEs

Withdrawals

NotesOxford Quality Score: R1, DB1, W1. Total = 3
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs described
Study sizeUnclear risk50-200 participants per treatment arm

Lipton 2009 Study 2

Methods

Multicentre, R, DB, PC, cross-over. Single dose/attack. 4 attacks treated: all with active or 3 active and 1 placebo (in random order). Washout between attacks not specified, but all headache medications prohibited within 24 h of a treated attack, and AE data collected for 72 h after treatment

Medication taken within 1 h of onset when PI was mild

Assessments at 0, 2, 4, 24 h

Participants

Migraine ± aura (IHS 2004), aged 18-65 years. History ≥ 6 months with frequency of 2-6 attacks per month and untreated severity ≥ moderate and identifiable mild phase

Excluded: uncontrolled hypertension, cardio- or cerebrovascular disease

n = 565 (563 for efficacy)

F = 90%

Mean age 41 years

Interventions

Sumatriptan/naproxen 85/500 mg (1678 attacks treated)

Placebo (422 attacks treated)

5 treatment groups with different medication sequences (N: naproxen; P: placebo; S: sumatriptan)

P, S/N, S/N, S/N; S/N, P, S/N, S/N; S/N, S/N, P, S/N; S/N, S/N, S/N, P; S/N, S/N, S/N, S/N

Rescue medication allowed after 2 h if necessary (recommended 2 x 220 mg naproxen sodium with additional 1 x 220 mg 6 h later if needed)

Outcomes

Pain-free at 2 h

24-h sustained pain-free

Presence and relief of associated symptoms at 2 h

Use of rescue medication

AEs

Withdrawals

NotesOxford Quality Score: R1, DB1, W1. Total = 3
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs described
Study sizeUnclear risk50-200 participants per treatment arm

Mannix 2009 Study 1

Methods

Multicentre, R, DB, PC, parallel group. Single dose to treat single attack

Medication taken when PI mild and within 1 h of onset

Assessments at 0, 0.5, 1, 1.5, 2, 4, 24, 48 h

Participants

Migraine ± aura (IHS 2004), aged ≥ 18 years. History: frequency of migraines 1-6 per month with menstrual migraine in 2/3 previous cycles and dysmenorrhoea in 2/3 cycles. Untreated severity ≥ moderate, with identifiable mild phase

n = 312 (311 for efficacy)

F = 100%

Mean age 37 years

Aura: 26%; primary dysmenorrhoea: 77%

Interventions

Sumatriptan 85 mg/naproxen 500 mg, n = 152

Placebo, n = 160

Rescue medication allowed after 2 h if necessary (including second dose, sumatriptan or naproxen sodium)

Outcomes

Pain-free at 2 h

24-h sustained pain-free

Use of rescue medication up to 48 h

AEs

Withdrawals

NotesOxford Quality Score: R2, DB1, W1. Total = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomly assigned by a computer generated code"
Allocation concealment (selection bias)Low riskRemote allocation (computerised registration and ordering system)
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs described
Study sizeUnclear risk50-200 participants per treatment arm

Mannix 2009 Study 2

Methods

Multicentre, R, DB, PC, parallel group. Single dose to treat single attack

Medication taken when PI mild and within 1 h of onset

Assessments at 0, 0.5, 1, 1.5, 2, 4, 24, 48 h

Participants

Migraine ± aura (IHS 2004), aged ≥ 18 years. History: frequency of migraines 1-6 per month with menstrual migraine in 2/3 previous cycles and dysmenorrhoea in 2/3 cycles. Untreated severity ≥ moderate, with identifiable mild phase

n = 311 (310 for efficacy)

F = 100%

Mean age 37 years

Aura: 40%; primary dysmenorrhoea: 92%

Interventions

Sumatriptan 85 mg/naproxen 500 mg, n = 151

Placebo, n = 160

Rescue medication allowed after 2 h if necessary (including second dose, sumatriptan or naproxen sodium)

Outcomes

Pain-free at 2 h

24-h sustained pain-free

Use of rescue medication up to 48 h

AEs

Withdrawals

NotesOxford Quality Score: R2, DB1, W1. Total = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomly assigned by a computer generated code"
Allocation concealment (selection bias)Low riskRemote allocation (computerised registration and ordering system)
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs described
Study sizeUnclear risk50-200 participants per treatment arm

Mathew 2009 Study 1

Methods

Multicentre, R, DB, PC, cross-over. Single dose to treat single attack. Washout between attacks ≥1 week

Medication taken when PI mild and within 1 h of onset

Assessments at 0, 0.5, 1, 1.5, 2, 4 24, 48 h

Participants

Migraine ± aura (IHS 2004), aged 18-65 years, poor response to triptans with short half-life. History: frequency of 1-8 per month, < 15 headache days monthly. Untreated severity ≥ mild

Excluded: uncontrolled hypertension, cardio- or cerebrovascular disease

n = 144 (139 for efficacy)

F = 85%

Mean age 41 years

Aura: 32%

Interventions

Sumatriptan 85 mg/naproxen 500 mg, n = 136

Placebo, n = 134

Rescue medication allowed after 2 h if necessary (not specified)

Outcomes

Pain-free at 2 h

24-h sustained pain-free

Presence and relief of associated symptoms at 2 h

Use of rescue medication

AEs

Withdrawals

NotesOxford Quality Score: R1, DB1, W1 Total = 3
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs described
Study sizeUnclear risk50-200 participants per treatment arm

Mathew 2009 Study 2

Methods

Multicentre, R, DB, PC, cross-over. Single dose to treat single attack. Washout between attacks ≥ 1 week

Medication taken when PI mild and within 1 h of onset

Assessments at 0, 0.5, 1, 1.5, 2, 4 24, 48 h

Participants

Migraine ± aura (IHS 2004), aged 18-65 years, poor response to triptans with short half-life. History: frequency of 1-8 per month, < 15 headache days monthly. Untreated severity ≥ mild

Excluded: uncontrolled hypertension, cardio- or cerebrovascular disease

n = 137 (131 for efficacy)

F = 93%

Mean age 40 years

27% without aura

Interventions

Sumatriptan 85 mg/naproxen 500 mg, n = 134

Placebo, n = 133

Rescue medication allowed after 2 h if necessary (not specified)

Outcomes

Pain-free at 2 h

24-h sustained pain-free

Presence and relief of associated symptoms at 2 h

Use of rescue medication

AEs

Withdrawals

NotesOxford Quality Score: R1, DB1, W1 Total = 3
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs described
Study sizeUnclear risk50-200 participants per treatment arm

Silberstein 2008 Study 1

Methods

Multicentre, R, DB, PC, parallel group. Single dose to treat single attack

Medication taken when PI mild and within 1 h of onset

Assessments at 0, 0.5, 1, 2, 4, 24 h

Participants

Migraine ± aura (IHS 2004), aged 18-65 years. History: ≥ 6 months with frequency of 2-6 attacks per month, and ≤ 15 per month. Untreated severity ≥ moderate, with identifiable mild pain phase

Excluded: uncontrolled hypertension, cardio- or cerebrovascular disease, gastrointestinal history

n = 580 (576 for efficacy)

F = 87.5%

Mean age 40 years

Aura: 20%

Interventions

Sumatriptan 85 mg/naproxen 500 mg, n = 283

Placebo, n = 297

Rescue medication allowed after 2 h if necessary (not triptans, NSAID-containing, ergot-containing or ergot-like medication)

Outcomes

Pain-free at 2 h

24-h sustained pain-free

Presence and relief of associated symptoms at 2 h

Presence and relief of functional disability at 2 h (from Taylor 2007)

Use of rescue medication

AEs

Withdrawals

NotesOxford Quality Score: R2, DB2, W1. Total = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Computer-generated randomization schedule"
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low risk"Matching placebo"
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs described
Study sizeLow risk> 200 participants per treatment arm

Silberstein 2008 Study 2

Methods

Multicentre, R, DB, PC, parallel group. Single dose to treat single attack

Medication taken when PI mild and within 1 h of onset

Assessments at 0, 0.5, 1, 2, 4, 24 h

Participants

Migraine ± aura (IHS 2004), aged 18-65 years. History: ≥ 6 months with frequency of 2-6 attacks per month, and ≤ 15 per month. Untreated severity ≥ moderate, with identifiable mild pain phase

Excluded: uncontrolled hypertension, cardio- or cerebrovascular disease, gastrointestinal history

n = 542 (535 for efficacy)

F = 90.5%

Mean age 41 years

66% without aura

Interventions

Sumatriptan 85 mg/naproxen 500 mg, n = 278

Placebo, n = 264

Rescue medication allowed after 2 h if necessary (not triptans, NSAID-containing, ergot-containing or ergot-like medication)

Outcomes

Pain-free at 2 h

24-h sustained pain-free

Presence and relief of associated symptoms at 2 h

Presence and relief of functional disability at 2 h (from Taylor 2007)

Use of rescue medication

AEs

Withdrawals

NotesOxford Quality Score: R2, DB2, W1. Total = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Computer-generated randomization schedule"
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low risk"Matching placebo"
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs described
Study sizeLow risk> 200 participants per treatment arm

Smith 2005

Methods

Multicentre, R, DB, DD, parallel group. Single dose to treat single attack

Medication taken when pain ≥ moderate

Assessments at 0, 15 min intervals to 2 h, 30 min to 4 h, hourly to 24 h

Participants

Migraine ± aura (IHS 2004), aged ≥18 years. History ≥ 1 year with 2-6 attacks per month, and able to tolerate oral triptan or ergot derivative

n = 972

F = 91%

Mean age 42 years

Without aura: > 70%

Interventions

Sumatriptan 50 mg/naproxen 500 mg, n = 251

Sumatriptan 50 mg, n = 229

Naproxen 500 mg, n = 250

Placebo, n = 242

Rescue medication allowed after 2 h if necessary (not specified)

Outcomes

Headache relief at 1 and 2 h

Pain-free at 2 h

24-h sustained headache relief

24-h sustained pain-free

Presence and relief of functional disability at 2 h

Presence and relief of associated symptoms at 2 h

Use of rescue medication

AEs

Withdrawals

NotesOxford Quality Score: R1, DB2, W1. Total = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low riskDD method, with sumatriptan encapsulated
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs described
Study sizeLow risk> 200 participants per treatment arm

TRX109011/13

  1. a

    AE: adverse effect; DB: double-blind; DD: double dummy; IHS: International Headache Society; ITT: intention to treat; MAOI: monoamine oxidase inhibitor; NSAID: non-steroidal anti-inflammatory drug; PC: placebo-controlled; R: randomised; SJW: St John's Wort; W: withdrawals.

Methods

Multicentre, R, DB, DD, 3 phase cross-over. Single dose of each medication to treat single attack. Washout between attacks ≥ 72 h

Medication taken when pain ≥ moderate

Assessments at 0, 2, 4, 6, 8, 24, 48 h

Participants

Migraine ± aura (IHS 2004), aged ≥18 years. History of 2-8 attacks per month in previous 3 months

n = 375 attacks (ITT; 442 attacks for safety)

F = 88%

Mean age 43 years

Interventions

Sumatriptan 50 mg/naproxen 500 mg, n = 406 (317 for efficacy)

Paracetamol (acetaminophen) 325 mg + caffeine 40 mg + butalbital 50 mg, n = 392 (304 for efficacy)

Placebo, n = 405 (320 for efficacy)

Outcomes

Headache relief at 2 h

Pain-free at 2 h

24-h sustained headache relief

24-h sustained pain-free

Presence and relief of functional disability at 2 h

Use of rescue medication

Mean time to first use of rescue medication

AEs

Withdrawals

NotesOxford Quality Score: R2, DB2, W1. Total = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low riskDD method
Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs described
Study sizeLow risk> 200 participants per treatment arm

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    IHS: International Headache Society.

Krymchantowski 2000Enriched enrolment study
Landy 2009Post hoc analysis of Landy 2007 (secondary publication under Brandes 2007 Study 1; Brandes 2007 Study 2)
Smith 2007Data pertains to quality of life and satisfaction outcomes only and not outcomes specified here
TRX107563No IHS definition of migraine for inclusion; participants had 'probable migraine without aura'
White 2011No single episode data for efficacy or adverse events
Winner 2007Open-label safety study