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Sumatriptan plus naproxen for acute migraine attacks in adults

  1. Simon Law1,
  2. Sheena Derry2,*,
  3. R Andrew Moore2

Editorial Group: Cochrane Pain, Palliative and Supportive Care Group

Published Online: 21 OCT 2013

Assessed as up-to-date: 3 OCT 2013

DOI: 10.1002/14651858.CD008541.pub2


How to Cite

Law S, Derry S, Moore RA. Sumatriptan plus naproxen for acute migraine attacks in adults. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD008541. DOI: 10.1002/14651858.CD008541.pub2.

Author Information

  1. 1

    Gloucester Hospitals NHS Foundation Trust, Department of Anaesthetics, Gloucestershire, UK

  2. 2

    University of Oxford, Pain Research and Nuffield Department of Clinical Neurosciences, Oxford, Oxfordshire, UK

*Sheena Derry, Pain Research and Nuffield Department of Clinical Neurosciences, University of Oxford, Pain Research Unit, Churchill Hospital, Oxford, Oxfordshire, OX3 7LE, UK. sheena.derry@ndcn.ox.ac.uk.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 21 OCT 2013

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

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

OutcomesProbable 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.

 1 Quality of evidence downgraded from high because of threat from potential publication bias with modest effect size and modest number of events.

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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.

 FigureFigure 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).
     FigureFigure 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).

 FigureFigure 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).
     FigureFigure 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).

 FigureFigure 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).

 FigureFigure 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 painStudiesAttacks

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
Download statistical data

 
Comparison 1. Sumatriptan/naproxen versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Pain-free at 2 h12Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Mild baseline pain
83395Risk Ratio (M-H, Fixed, 95% CI)2.76 [2.43, 3.13]

    1.2 Moderate/severe baseline pain
42596Risk Ratio (M-H, Fixed, 95% CI)3.65 [2.97, 4.49]

 2 Headache relief at 2 h4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Moderate/severe baseline pain
42596Risk Ratio (M-H, Fixed, 95% CI)2.16 [1.95, 2.39]

 3 24-h sustained pain-free12Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Mild baseline pain
83396Risk Ratio (M-H, Fixed, 95% CI)3.04 [2.59, 3.56]

    3.2 Moderate/severe baseline pain
42596Risk Ratio (M-H, Fixed, 95% CI)3.43 [2.69, 4.36]

 4 24-h sustained headache relief4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Moderate/severe baseline pain
42596Risk 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 pain
62823Risk Ratio (M-H, Fixed, 95% CI)1.47 [1.16, 1.86]

    5.2 Moderate/severe baseline pain
42793Risk 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 pain
83396Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.38, 0.47]

    6.2 Moderate/severe baseline pain
42169Risk Ratio (M-H, Fixed, 95% CI)0.47 [0.42, 0.53]

 7 Relief of associated symptoms at 2 h8Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 Nausea
81705Risk Ratio (M-H, Fixed, 95% CI)3.47 [2.79, 4.32]

    7.2 Photophobia
83127Risk Ratio (M-H, Fixed, 95% CI)2.77 [2.44, 3.13]

    7.3 Phonophobia
82856Risk Ratio (M-H, Fixed, 95% CI)2.63 [2.33, 2.97]

 8 Relief of functional disability at 2 h5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    8.1 Mild baseline pain
2981Risk Ratio (M-H, Fixed, 95% CI)2.91 [2.29, 3.72]

    8.2 Moderate/severe baseline pain
31984Risk Ratio (M-H, Fixed, 95% CI)3.36 [2.63, 4.29]

 
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 h2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 Nausea
2718Risk Ratio (M-H, Fixed, 95% CI)1.51 [1.21, 1.87]

    7.2 Photophobia
21186Risk Ratio (M-H, Fixed, 95% CI)1.20 [1.04, 1.39]

    7.3 Phonophobia
21146Risk 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]

 
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 h2Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 Nausea
2726Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.90, 1.32]

    7.2 Photophobia
21176Risk Ratio (M-H, Fixed, 95% CI)1.39 [1.19, 1.62]

    7.3 Phonophobia
21135Risk 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]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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 data1st attack:

(1) 230/443

(2) 25/123

All attacks:

(1) 856/1665

(2) 106/422
No data1st 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 data1st attack:

(1) 236/454

(2) 16/106

All attacks:

(1) 833/1655

(2) 83/416
No data1st 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 palpitationsExclusions - 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 SAENoneExclusions - 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%
NoneNoneExcluded 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%
NoneNoneExcluded 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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Last assessed as up-to-date: 3 October 2013.


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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
Brandes 2007 Study 1 {published data only}
  • Brandes JL, Kudrow D, Stark SR, O'Carroll CP, Adelman JU, O'Donnell FJ, et al. Sumatriptan-naproxen for acute treatment of migraine: a randomized trial. JAMA 2007;297(13):1443-54. [DOI: 10.1001/jama.297.13.1443]
  • Landy S, DeRossett SE, Rapoport A, Rothrock J, Ames MH, McDonald SA, et al. Two double-blind, multicentre, randomized, placebo-controlled, single-dose studies of sumatriptan/naproxen sodium in the acute treatment of migraine: function, productivity and satisfaction outcomes. Medscape General Medicine 2007;9(2):53.
Brandes 2007 Study 2 {published data only}
  • Brandes JL, Kudrow D, Stark SR, O'Carroll CP, Adelman JU, O'Donnell FJ, et al. Sumatriptan-naproxen for acute treatment of migraine: a randomized trial. JAMA 2007;297(13):1443-54. [DOI: 10.1001/jama.297.13.1443]
  • Landy S, DeRossett SE, Rapoport A, Rothrock J, Ames MH, McDonald SA, et al. Two double-blind, multicentre, randomized, placebo-controlled, single-dose studies of sumatriptan/naproxen sodium in the acute treatment of migraine: function, productivity and satisfaction outcomes. Medscape General Medicine 2007;9(2):53.
Lipton 2009 Study 1 {published data only}
Lipton 2009 Study 2 {published data only}
Mannix 2009 Study 1 {published data only}
Mannix 2009 Study 2 {published data only}
Mathew 2009 Study 1 {published data only}
Mathew 2009 Study 2 {published data only}
Silberstein 2008 Study 1 {published data only}
  • Silberstein SD, Mannix LK, Goldstein J, Couch JR, Byrd SC, Ames MH, et al. Multimechanistic (sumatriptan-naproxen) early intervention for the acute treatment of migraine. Neurology 2008;71(2):114-21. [DOI: 10.1212/01.wnl.0000316800.22949.20]
  • Taylor FR, Heiring JO, Messina E, Braverman-Panza J, Ames MH, Byrd SC, et al. Sumatriptan/naproxen sodium as early intervention for migraine: effects on functional ability, productivity, and satisfaction in 2 randomized controlled trials. Journal of Clinical Outcomes Management 2007;14(4):195-204.
Silberstein 2008 Study 2 {published data only}
  • Silberstein SD, Mannix LK, Goldstein J, Couch JR, Byrd SC, Ames MH, et al. Multimechanistic (sumatriptan-naproxen) early intervention for the acute treatment of migraine. Neurology 2008;71(2):114-21. [DOI: 10.1212/01.wnl.0000316800.22949.20]
  • Taylor FR, Heiring JO, Messina E, Braverman-Panza J, Ames MH, Byrd SC, et al. Sumatriptan/naproxen sodium as early intervention for migraine: effects on functional ability, productivity, and satisfaction in 2 randomized controlled trials. Journal of Clinical Outcomes Management 2007;14(4):195-204.
Smith 2005 {published data only}
TRX109011/13 {unpublished data only}
  • A randomized, double-blind, double-dummy, placebo-controlled, crossover study to evaluate the efficacy of TREXIMET (sumatriptan + naproxen sodium) versus Butalbital-Containing Combination Medications (BCM) for the acute treatment of migraine when administered during the moderate-severe pain phase of the migraine (pooled data), 2010. download.gsk-clinicalstudyregister.com/files/21144.pdf (accessed 23 September 2013).
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References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
Krymchantowski 2000 {published data only}
Landy 2009 {published data only}
  • Landy S, White J, Lener SE, McDonald SA. Fixed-dose sumatriptan/naproxen sodium compared with each monotherapy utilizing the novel composite endpoint of sustained pain-free/no adverse events. Therapeutic Advances in Neurological Disorders 2009;2:135. [DOI: 10.1177/1756285609102769]
Smith 2007 {published data only}
TRX107563 {unpublished data only}
  • Glazo Smith Kline study register. A randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and tolerability of TREXIMET (sumatriptan 85mg and naproxen sodium 500mg) for a single moderate or severe headache in adults diagnosed with probable migraine without aura. www.clinicaltrials.gov/ct2/show/NCT00387881 (accessed 23 September 2013).
White 2011 {published data only}
Winner 2007 {published data only}
  • Winner P, Cady RK, Ruoff GE, Frishberg BM, Alexander WJ, Zhang Y, et al. Twelve month tolerability and safety of sumatriptan-naproxen sodium for the treatment of acute migraine. Mayo Clinic Proceedings 2007;82(1):61-8.

Additional references

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  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
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