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Naproxen with or without an antiemetic for acute migraine headaches in adults

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

Editorial Group: Cochrane Pain, Palliative and Supportive Care Group

Published Online: 20 OCT 2013

Assessed as up-to-date: 22 MAY 2013

DOI: 10.1002/14651858.CD009455.pub2


How to Cite

Law S, Derry S, Moore RA. Naproxen with or without an antiemetic for acute migraine headaches in adults. Cochrane Database of Systematic Reviews 2013, Issue 10. Art. No.: CD009455. DOI: 10.1002/14651858.CD009455.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: 20 OCT 2013

SEARCH

 
Characteristics of included studies [ordered by study ID]
Brandes 2007 Study 1

MethodsMulticentre, R, DB, PC, parallel-group. Single dose to treat a single attack
Medication taken when PI ≥ moderate
Assessments at 0, 0.5, 1, 1.5, 2, then hourly to 24 h


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

Excluded: uncontrolled hypertension, cardio- or cerebrovascular disease, using MAOI, ergot, SJW, or NSAID
N = 1461
F = 86%
Mean age 40 years
72% without aura


InterventionsSumatriptan 85 mg/naproxen 500 mg, n = 370 (364 analysed for efficacy)
Sumatriptan 85 mg, n = 365 (361 for efficacy)
Naproxen 500 mg, n = 361 (365 for efficacy)
Placebo, n = 365 (360 for efficacy)
Rescue medication allowed after 2 h if necessary (as prescribed by physician but not ergot-containing, serotonin agonist, or NSAID-containing medications)


OutcomesHeadache relief at 2 h
Pain-free at 2 h
24-h sustained headache relief
24-h sustained pain-free
Presence and relief of associated symptoms at 2 h
Presence and relief of functional disability at 2 h (from Landy 2007)
Use of rescue medication
Adverse events
Withdrawals


NotesOxford Quality Score: R1, DB1, W1. Total = 3


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described

Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs described

SizeLow risk> 200 participants in each treatment arm

Brandes 2007 Study 2

MethodsMulticentre, R, DB, PC, parallel-group. Single dose to treat a single attack
Medication taken when PI ≥ moderate
Assessments at 0, 0.5, 1, 1.5, 2, then hourly to 24 h


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

Excluded: uncontrolled hypertension, cardio- or cerebrovascular disease, using MAOI, ergot, SJW, or NSAID
N = 1495
F = 88%
Mean age 40 years
76% without aura


InterventionsSumatriptan 85 mg/naproxen 500 mg, n = 367 (362 for efficacy)
Sumatriptan 85 mg, n = 370 (362 for efficacy)
Naproxen 500 mg, n = 371 (364 for efficacy)
Placebo, n = 387 (382 for efficacy)
Rescue medication allowed after 2 h if necessary (as prescribed by physician but not ergot-containing, serotonin agonist, or NSAID-containing medications)


OutcomesHeadache relief at 2 h
Pain-free at 2 h
24-h sustained headache relief
24-h sustained pain-free
Presence and relief of associated symptoms at 2 h
Presence and relief of functional disability at 2 h (from Landy 2007)
Use of rescue medication
Adverse events
Withdrawals


NotesOxford Quality Score: R1, DB1, W1. Total = 3


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot described

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot described

Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs described

SizeLow risk> 200 participants in each treatment arm

S2WA4003

MethodsMulticentre, R, DB, PC, parallel-group. Single dose to treat single attack; several attacks treated over 12 weeks
Medication taken when PI ≥ moderate

Assessments at 0, 4 h, for efficacy and adverse events, MSQ at baseline and after 12 weeks of treatment


ParticipantsMigraine ± aura (IHS 1988), aged 18-65 years. History: > 12 months with frequency of 1-6 per month and untreated severity ≥ moderate

Excluded: previous use of triptan on > 3 occasions or had prescription for sumatriptan, ischaemic disease or symptoms, cardio- or cerebrovascular pathology, uncontrolled hypertension, epilepsy

N = 168
F = 85%
Mean age 39 years


InterventionsNaproxen sodium 275 mg, n = 81

Naratriptan 2.5 mg, n = 87


OutcomesAdverse events

Withdrawals


NotesOxford Quality Score: R1, DB2, W1. Total = 4


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Unclear riskNot reported

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Double dummy" method

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Double dummy" method

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for

SizeUnclear risk50-200 participants in each treatment arm

S2WA4004

MethodsMulticentre, R, DB, PC, parallel-group. Single dose to treat single attack; several attacks treated over 12 weeks
Medication taken when PI ≥ moderate

Assessments at 0, 4 h, for efficacy and adverse events, MSQ at baseline and after 12 weeks of treatment


ParticipantsMigraine ± aura (IHS 1988), aged 18-65 years. History: > 12 months with frequency of 1-6 per month and untreated severity ≥ moderate

Excluded: previous use of triptan on > 3 occasions or had prescription for sumatriptan, ischaemic disease or symptoms, cardio- or cerebrovascular pathology, uncontrolled hypertension, epilepsy

N = 171
F = 85%
Mean age 37 years


InterventionsNaproxen sodium 275 mg, n = 85

Naratriptan 2.5 mg, n = 86


OutcomesAdverse events

Withdrawals


NotesOxford Quality Score: R1, DB2, W1. Total = 4


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Low risk"Double dummy" method

Blinding of outcome assessment (detection bias)
All outcomes
Low risk"Double dummy" method

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants accounted for

SizeUnclear risk50-200 participants in each treatment arm

Smith 2005

MethodsMulticentre, R, DB, DD, parallel-group. Single dose to treat a single attack
Medication taken when pain ≥ moderate
Assessments at 0, 15 min intervals to 2 h, 30 min to 4 h, hourly to 24 h


ParticipantsMigraine ± aura (IHS 2004), aged ≥ 18 years. History ≥ 1 year with 2-6 attacks per month, and able to tolerate oral triptan or ergot derivative
N = 972
F = 91%
Mean age 42 years
Without aura: > 70%


InterventionsSumatriptan 50 mg + naproxen 500 mg, n = 251
Sumatriptan 50 mg, n = 229
Naproxen 500 mg, n = 250
Placebo, n = 242
Rescue medication allowed after 2 h if necessary (not specified)


OutcomesHeadache relief at 1 and 2 h
Pain-free at 2 h
24-h sustained headache relief
24-h sustained pain-free
Presence and relief of functional disability at 2 h
Presence and relief of associated symptoms at 2 h
Use of rescue medication
Adverse events
Withdrawals


NotesOxford Quality Score: R1, DB2, W1. Total = 4


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described

Allocation concealment (selection bias)Unclear riskNot described

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-dummy method

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-dummy method

Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs described

SizeLow risk> 200 participants in each treatment arm

Wentz 2008

MethodsMulticentre, multinational, R, DB, PC, parallel-group, double-dummy study. Single dose to treat a single attack

Medication taken when PI ≥ moderate

Assessments at 0, 0.5, 1, 1.5, 2, 3, 4 h


ParticipantsMigraine ± aura (IHS 2004), aged 18-65 years. History > 6 months
Frequency 6/month with untreated severity ≥ moderate
Excluded if > 15 headache days/month, associated disease, or if on acute or prophylactic medication

N = 284 (safety population, 283 for efficacy)

F = 81%

Mean age 41 years

Without aura: > 80%


InterventionsNaproxen 825 mg, n = 109

Placebo, n = 117

Rescue medication allowed after 2 h (patient's usual medication)

111 participants were also treated with an experimental COX-2 inhibitor (GW406381), which is not marketed


OutcomesHeadache relief at 1, 2, and 4 h

Pain-free response at 1 and 2 h

24-h sustained headache relief

24-h sustained pain-free

Adverse events

Withdrawals

Presence and relief of headache associated symptoms at 2 hours

Use of rescue medication


NotesOxford Quality Score: R2, DB2, W1. Total = 5


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskRandomised by computer-generated sequence

Allocation concealment (selection bias)Low riskNo concealment of allocations prior to assignments

Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-dummy blinding method used

Blinding of outcome assessment (detection bias)
All outcomes
Low riskDouble-dummy blinding method used

Incomplete outcome data (attrition bias)
All outcomes
Low riskDrop-outs accounted for

SizeUnclear risk50-200 participants in each treatment arm

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Adis 2006Not RCT - general review of naproxen sodium/metoclopramide formulation from Pozen Inc. Data from the Pozen studies are included in Appendix 8

Andersson 1989Did not use IHS diagnostic criteria (or equivalent) for migraine - diagnostic criteria judged not equivalent to IHS criteria

Johnson 1985Did not use IHS diagnostic criteria (or equivalent) for migraine - no diagnostic criteria reported

Krymchantowski 2005Not randomised. Quasi-randomised only

Misra 2010Fewer than 10 participants/treatment arm

NCT01726920Not double blind

Nestvold 1985Did not use IHS diagnostic criteria (or equivalent) for migraine - diagnostic criteria judged not equivalent to IHS criteria

Nestvold 1986Supplement article, not original study report (same study as Nestvold 1985), no additional data

Pradalier 1985Did not use IHS diagnostic criteria (or equivalent) for migraine - diagnostic criteria judged not equivalent to IHS criteria

Sargent 1988Did not use IHS diagnostic criteria (or equivalent) for migraine - diagnostic criteria judged not equivalent to IHS criteria

Smith 2007Same study as Smith 2005, but reporting only quality-of-life and satisfaction outcomes

Stronks 2003Low patient numbers (12 only). No data on individual attacks. A comparative study versus naratriptan without placebo

Treves 1992Did not use IHS diagnostic criteria (or equivalent) for migraine - diagnostic criteria judged not equivalent to IHS criteria

Welch 1986Supplement article, not original study report

 
Characteristics of studies awaiting assessment [ordered by study ID]
NCT01390324

MethodsMulticentre, randomised, double-blind, parallel-group

ParticipantsMigraine ± aura (IHS 2004 criteria), male or female, 3-month history of 2-6 moderate/severe attacks per month, aged 18-65 years

InterventionsNaratriptan 2.5 mg + naproxen 500 mg

Naratriptan 2.5 mg

Naproxen 500 mg

OutcomesHeadache relief at 2 and 4 h

Pain-free at 2 and 4 h

24-h sustained headache relief

24-h sustained pain-free

Associated symptoms

Use of rescue medication

Adverse events

NotesScheduled primary completion date October 2012

Contact person asked for update January 2013

 
Comparison 1. Naproxen versus placebo

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

 1 Pain-free response at 2 h42149Risk Ratio (M-H, Fixed, 95% CI)2.03 [1.61, 2.58]

 2 Headache relief at 2 h42149Risk Ratio (M-H, Fixed, 95% CI)1.58 [1.41, 1.77]

 3 24-h sustained pain-free42149Risk Ratio (M-H, Fixed, 95% CI)1.81 [1.37, 2.38]

 4 24-h sustained headache relief42149Risk Ratio (M-H, Fixed, 95% CI)1.69 [1.45, 1.98]

 5 Any adverse event42174Risk Ratio (M-H, Fixed, 95% CI)1.31 [1.05, 1.62]

 6 Use of rescue medication42149Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.65, 0.78]

 7 Relief of associated symptoms3Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    7.1 Nausea
3782Risk Ratio (M-H, Fixed, 95% CI)1.73 [1.38, 2.16]

    7.2 Photophobia
31342Risk Ratio (M-H, Fixed, 95% CI)1.73 [1.43, 2.10]

    7.3 Phonophobia
31313Risk Ratio (M-H, Fixed, 95% CI)1.68 [1.40, 2.01]

 8 Relief of functional disability21346Risk Ratio (M-H, Fixed, 95% CI)2.14 [1.62, 2.84]

 
Summary of findings for the main comparison. Naproxen 500 mg or 825 mg compared with placebo for migraine headache

Naproxen 500 mg or 825 mg compared with placebo for migraine headache

Patient or population: migraine headache - moderate or severe pain

Settings: community

Intervention: naproxen 500 mg or 825 mg

Comparison: placebo

OutcomesProbable outcome with
comparator
Probable outcome with
intervention
NNT or NNH and/or
relative effect
(95% CI)
No of studies, attacks, eventsQuality of the evidence
(GRADE)
Comments

Pain-free response at 2 h80 in 1000170 in 1000NNT 11 (8.7 to 17)4 studies, 2149 attacks, 275 eventsModerate1Lower NNTs are better than higher NNTs

Headache relief at 2 h290 in 1000450 in 1000NNT 6.0 (4.8 to 7.9)4 studies, 2149 attacks, 793 eventsModerate1Lower NNTs are better than higher NNTs

Sustained pain-free during the 24 h post dose70 in 1000120 in 1000NNT 19 (13 to 34)4 studies, 2149 attacks, 202 eventsModerate1Lower NNTs are better than higher NNTs

Sustained headache relief during the 24 h post dose180 in 1000300 in 1000NNT 8.3 (6.4 to 12)4 studies, 2149 attacks, 505 eventsModerate1Lower NNTs are better than higher NNTs

At least one AE120 in 1000150 in 1000NNH 28 (15 to 130)4 studies, 2174 attacks, 293 eventsLow2Higher NNHs are better than lower NNTs

Serious AEInsufficient data-



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 numbers of events.
2 - Quality of evidence downgraded from high because of threat from potential publication bias with modest effect size and numbers of events, combined with inconsistent reporting of the outcome.